Advanced Organic Reactions (Lecture notes) Carmelo J. Rizzo Associate Professor of Chemistry, Vanderbilt University Nashville, Tennessee, USA Source: http://www.vanderbilt.edu/AnS/Chemistry/Rizzo/chem223/chem223.htm SELECTIVITY SELECTIVITY Science 1983, 219, 245 Chemoselectivity preferential reactivity of one functional group (FG) over another - Chemoselective reduction of C=C over C=O: H2, Pd/C O O - Chemoselective reduction of C=O over C=C: O OH NaBH4 O O + NaBH4, CeCl3 OH only - Epoxidation: MCPBA + OH OH O O (2 : 1) VO(acac)2, tBuOOH OH OH O exclusively Regioselectivity - Hydration of C=C: 1) B2H6 2) H2O2, NaOH OH R R OH R 1) Hg(OAc)2, H2O 2) NaBH4 - Friedel-Crafts Reaction: O RCOCl, AlCl3 R + R O O SiMe3 RCOCl, AlCl3 R OH 1 SELECTIVITY - Diels-Alder Reaction: R R O O R + + O major O R minor O R + + R O minor major O O + O H OAc O O H OAc O O OAc O O OAc OAc Raney Ni, H2 + O H SPh O O H O O SPh H O Change in mechanism: SPh PhSH, H+ R R R SPh PhSH, (PhCO2)2 Stereochemistry: Relative stereochemistry: Stereochemical relationship between two or more stereogenic centers within a molecule H H HO cholesterol H enantiomers same relative stereochemistry H OH syn: on the same side ( cis) anti: on the opposite side (trans) - differences in relative stereochemistry lead to diastereomers. Diastereomers= stereoisomers which are not mirror images; usually have different physical properties 2 SELECTIVITY Absolute Stereochemistry: Absolute stereochemical assignment of each stereocenter (R vs S) Cahn-Ingold-Prelog Convention (sequence rules) - differences in absolute stereochemistry (of all stereocenters within the molecule) leads to enantiomers. - Reactions can "create" stereocenters O Ph MeMgBr HO H Ph MeMgBr CH3 H H 3C OH Ph H O enantiomers (racemic product) Ph H HO CH3 Ph H MeMgBr Diastereomeric transition states- not necessarily equal in energy Me Me Me N O Ph Zn O CH3 CH3 Zn Me N O O CH3 CH3 H Zn H 3C H Zn Ph H 3C HO Ph CH3 HO CH3 H H Ph Diastereoselectivity CH3MgBr Ph CH3 Ph CHO HO + CH3 Ph H H OH anti syn Diastereomers Cram Model (Cram's Rule): empirical O O M S R O S M H 3C Nu H CH3MgBr CH3MgBr L R L favored H Ph 3 SELECTIVITY 4 Felkin-Ahn Model S O O M L R L Nu Nu M R S disfavored favored Chelation Control Mode M OR O O R S M HO OR CH3MgBr CH3MgBr M S favored Nu M R S OR R HO TBSO O TBSO MgBr relative stereochemical control H O H O OBn OBn Stereospecific Stereochemictry of the product is related to the reactant in a mechanistically defined manner; no other stereochemical outcome is mechanistically possible. i.e.; SN2 reaction- inversion of configuration is required Br2 H H 3C Br Br2 H meso H CH3 Br CH3 Br + H CH3 Br CH3 H Br H CH3 Br enantiomers (racemic) Stereoselective When more than one stereochemical outcome is possible, but one is formed in excess (even if that excess is 100:0). CH3 H2, Pd/C H H α-pinene O only isomer O O H H O H + CH3 H not observed O O LDA, CH3I N O S N O + S N O S (96 : 4) Diasteromers Diastereoselective Enantiospecific OXIDATIONS Oxidations Carey & Sundberg: Chapter 12 problems: 1a,c,e,g,n,o,q; 2a,b,c,f,g,j,k; 5; 9 a,c,d,e,f,l,m,n; 13 Smith: Chapter 3 March: Chapter 19 I. Metal Based Reagents 1. Chromium Reagents 2. Manganese Rgts. 3. Silver 4. Ruthenium 5. other metals II Non-Metal Based Reagents 1. Activated DMSO 2. Peroxides and Peracids 3. Oxygen/ ozone 4. others III. Epoxidations Metal Based Reagents Chromium Reagents - Cr(VI) based - exact stucture depends on solvent and pH - Mechanism: formation of chromate ester intermediate Westheimer et al. Chem Rev. 1949, 45, 419 JACS 1951, 73, 65. HO R2CH-OH HCrO4 - R R H+ Cr C O O- R O- O R + HCrO3- + H+ H + H2O Jones Reagent (H 2CrO4, H2Cr2O7, K2Cr2O7) J. Chem. Soc. 1946 39 Org. Syn. Col. Vol. V, 1973, 310. - CrO3 + H2O → H2CrO4 (aqueous solution) K2Cr2O7 + K2SO4 - Cr(VI) → Cr(III) (black) (green) - 2°- alcohols are oxidized to ketones R2CH-OH Jones reagent R acetone R O - saturated 1° alcohols are oxidized to carboxylic acids. Jones reagent RCH2-OH acetone O R hydration H HO OH Jones reagent R acetone H O R OH - Acidic media!! Not a good method for H+ sensitive groups and compounds 5 OXIDATIONS 1) Jones, acetone SePh OH 6 SePh CO 2CH 3 2) CH2N2 Me 3Si Me 3Si JACS 1982, 104, 5558 H17C 8 H17C 8 O O O OH Jones acetone O O O JACS 1975, 97, 2870 O Collins Oxidation (CrO3•2pyridine) TL 1969, 3363 - CrO3 (anhydrous) + pyridine (anhydrous) → CrO 3•2pyridine↓ - 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH 2Cl2) without over-oxidation - Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent often leads to improved yields. - Useful for the oxidation of H+ sensitive cmpds. - not particularly basic or acidic - must use a large excess of the rgt. CrO3•(C 5H5N)2 OH ArO H CH 2Cl 2 O O ArO O JACS 1969, 91, 44318. O O CrO3 catalyzed (1-2 mol % oxidation with NaIO6 (2.5 equiv) as the reozidant in wet aceteonitrile. oxidized primary alcohols to carboxylic acids. Tetrahedron Lett. 1998, 39, 5323. Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation) TL 1975 2647 Synthesis 1982, 245 (review) CrO3 + 6M HCl + pyridine → pyH+CrO3 Cl- ↓ - Reagent can be used in close to stoichiometric amounts w/ substrate - PCC is slighly acidic but can be buffered w/ NaOAc PCC, CH 2Cl 2 OHC HO JACS 1977, 99, 3864. O O O PCC, CH 2Cl 2 OH O CHO TL, 1975, 2647 OXIDATIONS - Oxidative Rearrangements Me OH Me PCC, CH 2Cl 2 JOC 1977, 42, 682 O Me Me PCC, CH 2Cl 2 JOC 1976, 41, 380 OH O - Oxidation of Active Methylene Groups PCC, CH 2Cl 2 O O O JOC 1984, 49, 1647 PCC, CH 2Cl 2 O O O - PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole JOC 1984, 49, 550. NH NH N N - selective oxidation of allylic alcohols OH OH PCC, CH 2Cl 2 H 3,5-dimethyl pyrazole H HO H O H (87%) Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation) TL 1979, 399 - Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓ PDC PDC CHO CH 2Cl 2 OH DMF 1° alcohol -allylic alcohols are oxidized to α,β-unsaturated aldehydes CO 2H 7 OXIDATIONS - Supported Reagents Comprehensive Organic Synthesis 1991, 7, 839. PCC on alumina : Synthesis 1980, 223. - improved yields due to simplified work-up. PCC on polyvinylpyridine : JOC, 1978, 43, 2618. CH 2 CH cross-link N CH 2 CH R2CH-OH R2C=O CH 2 CH CrO3, HCl N N Cr(III) N Cr(VI)O3 •HCl 8 partially spent reagent to remove Cr(III) 1) HCl wash 2) KOH wash 3) H2O wash CrO3/Et2O/CH2Cl2/Celite Synthesis 1979, 815. - CrO3 in non-aqueous media does not oxidized alcohols - CrO3 in 1:3 Et2O/CH2Cl2/celite will oxidized alcohols to ketone and aldehydes C 8H17 C 8H17 CrO3 Et2O/CH 2Cl 2/celite (69%) HO Synthesis 1979, 815 O H2CrO7 on Silica - 10% CrO3 to SiO2 - 2-3g H2CrO3/SiO2 to mole of R-OH - ether is the solvent of choice Manganese Reagents Potassium Permanganate KMnO4/18-Crown-6 JACS 1972 94, 4024. (purple benzene) O O O K+ O MnO 4O O - 1° alcohols and aldehydes are oxidized to carboxylic acids - 1:1 dicyclohexyl-18-C-6 and KMnO4 in benzene at 25°C gives a clear purple solution as high as 0.06M in KMnO4. O JACS 1972, 94, 4024 CO 2H CHO Synthesis 1984, 43 CL 1979, 443 CHO OXIDATIONS 9 Sodium Permanganate TL 1981, 1655 - heterogeneous reaction in benzene - 1° alcohols are oxidized to acids - 2° alcohols are oxidized to ketones - multiple bonds are not oxidized Barium Permanganate (BaMnO4) TL 1978, 839. - Oxidation if 1° and 2° alcohols to aldehydes and ketones- No over oxidation - Multiple bonds are not oxidized - similar in reactivity to MnO2 Barium Manganate BCSJ 1983, 56, 914 Manganese Dioxide Review: Synthesis 1976, 65, 133 - Selective oxidation of α,β-unsatutrated (allylic, benzylic, acetylenic) alcohols. - Activity of MnO2 depends on method of preparation and choice of solvent - cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double bond. OH OH HO HO MnO 2, CHCl3 J. Chem. Soc. 1953, 2189 JACS 1955, 77, 4145. (62%) O HO - oxidation of 1° allylic alcohols to α,β-unsaturated esters OH MnO2, ROH, NaCN CO 2R OH CO 2Me JACS1968, 90, 5616. 5618 MnO 2, Hexanes MeOH, NaCN Manganese (III) Acetate α-hydroxylation of enones Synthesis 1990, 1119 TL 1984 25, 5839 O O Mn(OAc)3, AcOH AcO Ruthenium Reagents Ruthenium Tetroxide - effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones - oxidizes multiple bonds and 1,2-diols. OXIDATIONS Ph OH O H O JOC 1981, 46, 3936 RuO4, NaIO4 OH CH 3 CO 2H Ph CCl 4, H2O, CH3CN OH Ph RuO4, NaIO4 10 Ph CCl 4, H2O, CH3CN CO 2H H 96% ee CH 3 94%ee HO RuO2, NaIO4 O TL 1970, 4003 CCl 4, H2O O O O O Tetra-n-propylammonium Perruthenate (TPAP, nPr4N+ RuO4-) Aldrichimica Acta 1990, 23, 13. Synthesis 1994, 639 - mild oxidation of alcohols to ketones and aldehydes without over oxidation OH O TPAP MeO 2C MeO 2C OSiMe 2tBu OSiMe 2tBu O N+ -O Me TL 1989, 30, 433 (Ph3P)4RuO2Cl3 RuO2(bipy)Cl2 - oxidizes a wide range of 1°- and 2°-alcohols to aldehydes and ketones without oxidation of multiple bonds. OH CHO CHO OH JCS P1 1984, 681. H H Ba[Ru(OH)2O3] -oxidizes only the most reactive alcohols (benzylic and allylic) (Ph3P)3RuCl2 + Me3SiO-OSiMe3 - oxidation of benzylic and allylic alcohols TL 1983, 24, 2185. Silver Reagents Ag2CO3 ( Fetizon Oxidation) also Ag2CO3/celite - oxidation of only the most reactive hydroxyl O OH Synthesis 1979, 401 O Ag 2CO 3 O OH OH O O OH O OH Ag 2CO 3, C 6H6 O O O JACS 1981, 103, 1864. mechanism: TL 1972, 4445. OXIDATIONS - Oxidation of 2° alcohol over a 1° alcohol OH OH Ag2CO3, Celite OH JCS,CC 1969, 1102 (80%) O Silver Oxide (AgO2) - mild oxidation of aldehyde to carboxylic acids AgO 2, NaOH RCHO CHO RCO 2H CO 2H AgO 2 JACS 1982, 104, 5557 Ph Ph Prevost Reaction Ag(PhCO2)2, I2 Ag(PhCO 2)2, I2 AcO OAc AcOH AcO Ag(PhCO 2)2, I2 OH AcOH, H 2O Other Metal Based Oxidations Osmium Tetroxide OsO 4 review: Chem. Rev. 1980, 80, 187. -cis hydroxylation of olefins old mechanism: O OH Os O O OH O OsO 4, NMO osmate ester intermediate cis stereochemistry - use of R 3N-O as a reoxidant TL 1976, 1973. OsO 4, NMO O O O OH O OH OH OH TL 1983, 24, 2943, 3947 Stereoselectivity: OsO 4 R3 R2 RO H R4 OsO 4, NMO HO H R2 HO R3 RO H R4 11 OXIDATIONS - new mechanism: reaction is accelerated in the presences of an 3° amine R1 R1 O O O R2 Os O O [2+2] R3N R1 R2 O Os O 12 O Os O O O R2 O NR3 [O] [3+2] OsO2 R1 O O R2 O [O] hydrolysis R1 Os O R2 + O HO OH OsO4 - Oxidative cleavage of olefins to carboxylic acids. JOC 1956, 21, 478. - Oxidative cleavage of olefins to ketones & aldehydes. OH CHO CHO OH OsO 4, NMO O O NaIO4 OH O H2O O O O O O O OAc O OAc OAc JACS 1984, 105, 6755. Substrate directed hydroxylations: -by hydroxyl groups Chem. Rev. 1993, 93, 1307 HO OsO4, pyridine O HO HO O HO + O HO HO HO 3:1 HO OsO4, pyridine O HO O TMSO TMSO HO CH3 HO CH3 OH OsO4, Et2O HO OH CH3 CH3 + OH CH3 (86 : 14) - by amides AcO AcO OH MeS OsO4 MeS OH HN O OAc CH3 OH HN O OAc OXIDATIONS - by sulfoxides •• •• OMe O OsO4 S OMe OH O S OH 1) OsO4 2) Ac2O S HN OAc (2 : 1) •• •• O 13 O S O AcO O HN (20 : 1) - by sulfoximines O Ph S O Ph S OH MeN MeN OsO4, R3NO O OH ∆ OH OH OH OH CH3 Raney nickel H 3C OH OH OH CH3 - By nitro groups PhO2S PhO2S 1) OsO4 N NHR N + 2) acetone, H N NHR N O2N O2N N N N O N O N N HO HO NHR N NHR N N N N O N O - OsO4 bis-hydroxylation favors electon rich C=C. OsO4 X OH OH X + OH OH X= OH = OMe = OAc = NHSO2R - Ligand effect: 80 : 20 98 : 2 99 : 1 60 : 40 OsO4 OH K3Fe(CN)6, K2CO3 MeSO2NH2, tBuOH/H2O OH OH OsO4 (no ligand) Quinuclidine DHQD-PHAL X 4:1 9:1 > 49 : 1 + X (directing effect ?) (directing effect ?) OH OH OH OXIDATIONS Chem. Rev. 1994, 94, 2483. Sharpless Asymmetric Dihydroxylation (AD) - Ligand pair are really diastereomers!! 14 dihydroquinidine ester N "HO Ar OH" H H R3 OR' R2 R3 OH 0.2-0.4% OsO4 R2 R1 acetone, H 2O, MNO 80-95 % yield 20-80 % ee OH R1 H OR' "HO Ar OH" MeO Ar = N dihydroquinine ester N R'= p-chlorobenzoyl Mechanism of AD: L HO OH O O H 2O O O Os O O O O First Cycle (high enantioselectivity) O Os O O Second Cycle (low enantioselectivity) [O] [O] O O Os O O L Os O L O O O O Os O O O O R 3N HO OH H 2O, L - K3Fe(CN)6 as a reoxidant gives higher ee's- eliminates second cycle TL 1990, 31, 2999. - Sulfonamide effect: addition of MeSO2NH2 enhances hydrolysis of Os(VI) glycolate (accelerates reaction) - New phthalazine (PHAL) ligand's give higher ee's N Et Et O H Et N N N N N O H O H OMe MeO O H MeO N OMe N N N (DHQ)2-PHAL (DHQD)2-PHAL JOC 1992, 57, 2768. Et N N OXIDATIONS 15 - Other second generation ligands N Et Et O H MeO Et N Ph O N N H N OMe Ph N N O H O OMe N N PYR IND Proposed catalyst structure: O H O O Os N MeO N Os "Bystander quinoline (side wall) Asymmetric Binding Cleft O N H H N N O N N N O Phthalazine Floor OMe OMe OMe O Corey Model: JACS 1996, 118, 319 Enzyme like binding pocket; [3+2] addition of OsO4 to olefin. N O O Os O N O O N H N N O O N DHQL Rs RM RL H DHQ RL large and flat, i.e Aromatics work particularly well OXIDATIONS Olefin Preferred Ligand ee's PYR, PHAL 30 - 97 % PHAL 70 - 97 % IND 20 - 80 % PHAL 90 - 99.8 % PHAL 90 - 99 % PHAL, PYR + MeSO2NH2 20 - 97 % R1 R2 R1 R1 R2 R2 R1 R2 R3 R1 H R2 R3 R1 R4 "AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant AD-mix α (DHQ)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C) AD-mix β (DHQD)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 O HO O Campthothecin N N O OMe N OMe OMe AD (DHQD)2PYR O N N O 94 % ee O O OH OH OH - Kinetic resolution (not as good as Sharpless asymmetric epoxidation) H Ph tBu Ph H tBu H Ph H Ph AD mix α 30% conversion Ph H OH OH tBu tBu olefins with axial dissymmetry H Ph + OH OH + tBu (4 : 1) tBu enriched 16 OXIDATIONS 17 Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813, preparation of α-aminoalcohols from olefin. Syn addition as with the dihydroxylation regiochemistry can be a problem O Ph O N Na CO2Me Ph O OH Cl Ph O NH + CO2Me Ph K2OsO6H4 (cat) Ligand CO2Me Ph N OH O Ph O Ligand= PHAL AQN 4:1 1:4 Molybdenum Reagents MoOPH [MoO5•pyridine (HMPA)] JOC 1978, 43, 188. - α-hydroxylation of ketone, ester and lactone enolates. O OR' R O + Mo O L R O H R R Pd(OAc) 2, CH 3CN, 80° C HO H R O H R - CO 2 O O Pd - TL 1984, 25, 2791 Tetrahedron 1987, 43, 3903 O OH 2 HO CO H OH JACS 1989, 111, 8039. Pd2(DBA) 3•CHCl 3, CH 3CN, 80° C OH O R R Pd(0) O H H (Tsuji Oxidation) O O 2 CO OH R' OH L Palladium Reagents Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates Tetrahedron 1986, 42, 4361 R O THF, -78°C O H O O Oxidation of silylenol ethers and enol carbonates to enones O OTMS Pd(OAc) 2, CH 3CN O O O OTIPS Ph O Pd(OAc) 2, CH 3CN (NH 4)2Ce(NO 3)6 DMF, 0°C O O Ph TL 1995, 36, 3985 R Oppenauer Oxidation OXIDATIONS Organic reactions 1951, 6, 207 Synthesis 1994, 1007 OiPr +O Al R1R2CHOH (CH3)2C=O OiPr OiPr +O Al O OiPr H R1 R2 O R1 18 + Al(OiPr)3 R2 Nickel Peroxide Chem Rev. 1975, 75, 491 Thallium Nitrate (TNN, Tl(NO 3)3•3H2O Pure Appl. Chem. 1875, 43, 463. Lead Tetraacetrate Pb(OAc)4 Oxidations in Organic Chemistry (D), 1982, pp 1-145. Non-Metal Based Reagents Activated DMSO Review: Synthesis 1981, 165; 1990, 857. Me Me S+ S+ + E O- Me E O Organic Reactions 1990, 39, 297 Nu: Nu S Me Me + + E-O Me E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F 3CSO2H, PO5, H3PO4, Br2 Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, enols Swern Oxidation - trifluoroacetic anhydride can be used as the activating agent for DMSO O Me Me (COCl) 2 S + O- CH 2Cl 2, -78°C Me R2CH-OH Me Me Me -CO, -CO 2 Cl - Me S + Cl Me O R R S+ O Cl S+ O Et3N: Me R S + O Me R H B: O Cl O DMSO, (COCl) 2 OH Moffatt Oxidation (DMSO/DCC) O JACS 1965, 87, 5661, 5670. Me C 6H11 S + O- CF 3CO 2H, Pyridine Me + C 6H11 N C TL 1988, 29, 49. CH 2Cl 2, Et3N N C 6H11 OH CO 2Me O Me NH S + O C R2CH-OH Me R O H R B: C 6H11 CHO DCC/ DMSO CO 2Me CF 3CO 2H, Pyridine JACS 1978, 100, 5565 O S SO3/Pyridine S+ O N Me R R Me S JACS 1967, 89, 5505. CO 2Me HO H CONH 2 H HO OH OH CO 2Me H SO 3, pyridine, DMSO, CH 2Cl 2 CONH 2 H HO O JACS 1989, 111, 8039. OXIDATIONS Corey-Kim Oxidation (DMS/NCS) 19 JACS 1972, 94, 7586. O Me Me S: + S + Cl N Cl Me Me O N-Chlorosuccinimide (NCS) Acc. Chem. Res. 1980, 13, 419 •• •• •• O O singlet "ene" reaction H O Tetrahedron 1981, 37, 1825 hν •• •• •O O • •• •• triplet •• Oxygen & Ozone Singlet Oxygen Ph3P: H O O O OH Tetrahedron 1981, 1825 1) O2, hν, Ph2CO 2) reduction Ozone HO Comprehensive Organic Synthesis 1991, 7, 541 O O 3, CH 2Cl 2 O O -78°C O Ph3P: O O NaBH 4 + O O H Jones OH RCOOH Other Oxidations Mukaiyama Oxidation BCSJ 1977, 50, 2773 O R PrMgBr CH OH R N R N N N R O CH O MgBr O R THF R OH Cl MeO CH 3 O O NH O O SEt SEt MeO N Cl O N N N O MeO CH 3 OHC O NH OEt O tBuMgBr, THF (70%) SEt SEt MeO JACS 1979, 101, 7104 OEt OXIDATIONS 20 O OH tBuMgBr, THF O N N N N O O O Dess-Martin Periodinane JOC 1983, 48, 4155. - oxidation conducted in CHCl3, CH3CN or CH2Cl2 - excellent reagent for hindered alcohols - very mild JACS 1992, 113, 7277. OAc OAc AcO •• I O OAc R R2CH-OH I O + + 2 AcOH O R O O HO Dess-Martin O JOC 1991, 56, 6264 (99%) RO RO Chlorite Ion -oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids. Tetrahedron 1981, 37, 2091 NaClO 2, NaH2PO 4 OBn - HClO2 OBn OBn OH H tBuOH, H 2O CHO CO 2H -O-Cl-O Selenium Dioxide - Similar to singlet oxygen (allylic oxidation) 1) SeO2 2) NaBH 4 OAc OAc OH Phenyl Selenium Chloride O OLi PhSeCl O SePh H2O 2 Ph Se O- THF O - PhSeOH H - PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a selenoxide elinimation. Peroxides & Peracids - R3N: → R3N-O - sulfides → sulfoxides → sulfones -Baeyer-Villiger Oxidation- oxidation of ketones to esters and lactones via oxygen insertion Organic Reactions 1993, 43, 251 Comprehensive Organic Synthesis 1991, vol 7, 671. OXIDATIONS 21 m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide O O H O O 2N O O O H O R1 R2 O O HO O NO 2 Cl R1 H Ar O C R2 O R1 O + R2 ArCO2H Ar O O - Concerted R-migration and O-O bond breaking. No loss of stereochemistry - Migratory aptitude roughly follows the ability of the group to stabilize positive charge: 3° > 2° > benzyl = phenyl > 1° >> methyl JACS 1971, 93, 1491 O O mCPBA O HO O CO2H O CHO O HO O O CO2H HO OH PGE1 O O CH3 O mCPBA Tetrahedron Lett. 1977, 2173 Tetrahedron Lett. 1978, 1385 CH3 (80 %) CH3 CH3 Oxone (postassium peroxymonosulfate) Tetrahedron 1997, 54, 401 oxone RCHO RCOOH acetone (aq) Oxaziridines reviews: Tetrahedron 1989, 45, 5703; Chem. Rev. 1992, 92, 919 O N C R R3 R2 - hydroxylation of enolates O R O Base R R' O _ R R' O O PhSO2 O R Ph N R R' + PhSO2N=CHPh HO Ph O _ R' O R' _ NSO2Ph R + PhSO2N=CHPh Ph R' NHSO2Ph By-product supresed by using bulkier oxaziradine such as camphor oxaziradine OXIDATIONS 22 Asymmetric hydroxylations O O NaN(SiMe3)2, THF MeO 2C HO Tetrahedron 1991, 47, 173 MeO 2C OMe OMe N Ar MeO O SO 2 O MeO KN(SiMe3)2 CO2Me (67% ee) O O OH CO2Me OH O OH OH N SO2 O MeO MeO MeO O OH OH (>95% ee) - hydroxylation of organometallics R-Li or R-Mg → R-OH JACS 1979, 101, 1044 - Asymmetric oxidation of sulfides to chiral sulfoxides. JACS 1987, 109, 3370. Synlett, 1990, 643. Remote Oxidation (functionalization) Barton Reaction Comprehensive Organic Synthesis 1991, 7, 39. NOCl, CH2Cl2 pyridine OH hν O NO - NO • O • OH H • •NO JACS 1975, 97, 430 OH OH NO N N ketone oxidation state HO C5H11 perhydrohistricotoxin Epoxidations Peroxides & Peracids - olefins → epoxides Tetrahedron 1976, 32, 2855 - α,β-unsaturated ketones, aldehydes and ester → α,β-epoxy- ketones, aldehydes and esters (under basic conditions). O (CH 2)n tBuOOH triton B, C6H6 O O (CH 2)n JACS 1958, 80, 3845 OXIDATIONS O CO 2Me CO 2Me mCPBA, NaHPO3 TL 1988, 23, 2793 O O H H O O Henbest Epoxidation- epoxidation directed by a polar group OH OH OH mCPBA + O OAc O 10:1 diastereoselection OH OAc mCPBA + O O 1:4 diastereoselection O Ph O NH Ph NH "highly selective" mCPBA O Ar O H H O proposed transition state: -OH directs the epoxidation O O H - for acyclic systems, the Henbest epoxidation is often less selective Rubottom Oxidation: JOC 1978, 43, 1588 O OTMS LDA, TMSCl TMSO mCPBA O H2O O OH Sharpless Epoxidation tBuOOH w/ VO(acac)2, Mo(CO)6 or Ti(OR) 4 Reviews: Comprehensive Organic Synthesis 1991, vol 7, 389-438 Asymmetric Synthesis 1985, vol. 15, 247-308 Synthesis, 1986, 89. Org. React. 1996, 48, 1-299. Aldrichimica Acta 1979, 12, 63 review on transition mediated epoxidations: Chem. Rev. 1989, 89, 431. - Regioselective epoxidation of allylic and homo-allylic alcohols - will not epoxidize isolated double bonds - epoxidation occurs stereoselectively w/ respect to the alcohol. 23 OXIDATIONS - Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4 - Oxidant: tBuOOH; PhC(CH3)2OOH VO(acac)2 tBuOOH OH OH O OH OH (CH2)n O (CH2)n ring size 5 6 7 8 9 VO(acac)2 >99% >99 >99 97 91 MoO2(acac)2 -98 95 42 3 mCPBA 84 95 61 <1 <1 Acyclic Systems: L M 1,3-interaction O R3 A1,2-strain tBu O O R1 R3 L Rc Rt R1 Rt R2 Rc O O M R2 L A1,3-strain Major influences: A1,2-Strain between Rg and R1 A1,3 -strain between R2 and Rc 1,3-interactions between L and R1 O L (Rg and R2) (R1 and Rc) (L and R2) VO(acac)2, tBuOOH O OH + O OH OH (4 : 1) tBu CH3 H O L M H H L O O M L O O L tBu O H 3C H H H 24 OXIDATIONS VO(acac)2, tBuOOH O OH + O OH OH (19 : 1) tBu L H 3C H H H 3C O H M L H O O O H 3C H O M L L H O tBu CH3 SiMe3 SiMe3 VO(acac)2, tBuOOH O OH SiMe3 + OH O OH (> 99 : 1) - Careful conformational analysis of acyclic systems is needed. Homoallylic Systems L L O O OH V OtBu O OH dominent stereocontrol element Titanium Catalyst structure: RO2C OR Ti CO2R O O O RO O OR O Ti OR OR O OR CO2R O OR Ti CO2R O O O RO O OR O CO2R Ti O RO Ti O O CO2R O CO2R O O tBu OR Disfavored O O tBu OR Ti O Favored O CO2R 25 OXIDATIONS 26 Asymmetric Epoxidation tBuOOH, Ti(OiPr), (+) or (-) Diethyl Tartrate, 3Å molecular sieves Empirical Rule R1 (+)- DET epoxidation from the bottom (-)- DET epoxidation from the top R2 R3 OH Catalytic system: addition of molecular sieves to "soak" up any water with 3A sieves, 5-10 mol % catalyst is used. Preparation of Allylic Alcohols: R CO2R' [(CH3)2CHCH2]2AlH Na (MeOCH2CH2O)2AlH2 R (DIBAL) OH (REDAL) R CHO R C C CH2OH R CO2R' R [(CH3)2CHCH2]2AlH H2, Lindlar's Catalyst OH "In situ" derivatization of water soluble epoxy-alcohol (-)-DIPT O OH (R)-glycidol OH water soluble O (+)-DIPT O O OH OH (S)-glycidol O O S NO2 organic soluble O Alkoxide opening of epoxy-alcohol product reduced by use of Ti(OtBu)4 and catalytic conditions OO R OH O OH OH from Ti(OiPr)4 R Stoicheometric vs Catalytic epoxidation: (+)-DET Ti(OiPr)4 tBuOOH O OH stoicheometric: catalytic (6-7 mol %) in situ deriv. with PNB OH 85% ee 47% yield >95% ee 78% yield 92 % ee >98 %ee after 1 recrystallization (+)-DET Ti(OiPr)4 tBuOOH R R OH yields: 50 - 100 % ee: > 95% O OH OXIDATIONS Ring Opening of Epoxy-Alcohols OH REDAL R O AE R OH OH 1,3-Diol R OH DIBAL R OH OH 1,2-Diol Two dimensional amplification OH OH OH (+)-DIPT, Ti(OiPr)4, tBuOOH, 3A sieves + (90 % ee) O OH O OH 95 : 5 major major O O minor minor major minor 95 : 5 95 : 5 OH OH O O OH 90 % (>99.5 % ee) OH O O OH meso 9.75% (+)-DIPT, Ti(OiPr)4, tBuOOH, 3A sieves OH R + R OR Ti CO2R O O O RO O O tBu OR H Ti O O R CO2R O OH 0.25 % Kinetic Resolution of Allylic Alcohols OH OH O CO2R OH 27 OXIDATIONS R3 R4 R3 kinetic resolution -20 °C, 0.5 - 6 days OH R2 R4 R4 O + OH R2 R1 R3 R2 R1 OH R1 40 - 50 % yield > 99 % ee 40 - 50 % yield high ee Reiterative Approach to the Synthesis of Carbohydrate OR OR OR (+)-DET, Ti(OiPr)4, tBuOOH, 3A sieves DIBAL (MeO)2P(O)CH2CO2Me NaH CHO OH CO2Me OR OR HOO OH PhS OR OH OR OH acetone, H+ O mCPBA, Ac2O O - HO Pummerer O SPh SPh PhS- O O O O DIBAL OAc CHO OR OR OR O O O CHO HO H HO H HO H HO SPh O CHO H CH2OH L-glucose Jacobsen Aysmmetric Epoxidation JACS 1990, 112, 2801; JACS 1991, 113, 7063; JOC 1991, 56, 2296. - Reaction works best for cis C=C conjugated to an aromatic ring H H H N N H N NaOCl Mn Mn O O Cl O tBu O O tBu tBu O N 5 mol % Cat. ,NaOCl, H2O, CH2Cl2 tBu O (98% ee) O 86% ee O Methyltrioxoruthenium (MTO) Ru(VII) Sharpless et al. JACS 1997, 117, 7863, 11536. Ph 0.5 mol % MTO Ru (VII), pyridine, CH2Cl2 1.5 eq. 30% H2O2 (aq.) Ph O 28 OXIDATIONS Oxaziridines - Asymmetric epoxidation of olefins 29 Tetrahedron 1989 45 5703 CH3 Ph O2 O N S N * (Murray's Reagent) C6F5 * Ph Dioxiranes * Reviews: Chem. Rev. 1989, 89, 1187; ACR 1989, 27, 205 Org. Syn. 1996, 74, 91 O KHSO 5 O "oxone" O - epoxidation of olefins O OTBS TBSO TBSO - OTBS O O O TBSO TBSO CH 2Cl 2, acetone (100%) JOC 1990, 55, 2411 O Asymmetric epoxidation JACS 1996, 118, 491. oxidation of sulfides to sulfoxides and sulfones oxidation of amines to amine-N-oxides oxidation of aldehydes to carboxylic acids hydroxylation of enolates 1) LDA 2) Cp 2TiCl2 3) O OH H O JOC 1994, 59, 2358 O O - bis-trifluoromethyldioxirane, much more reactive JACS 1991, 113, 2205. F3C O F3C O - oxidation of alcohols to carbonyl compounds. 1° alcohols give a mixture of aldehydes and carboxylic acids. - Insertion into 3° C-H bonds to give R3C-OH DCC-H2O2 JOC 1998, 63, 2564 R R N C N R H2O2, MeOH H N R N C H O O O O R R + H N R C N R H REDUCTIONS Carey & Sundberg Chapter 5 problems: 1a,b,c,d,f,h,j; 2; 3a-g, n,o; 4b,j,k,l; 9; 11; Smith: Chapter 4 March: Chapter 19 30 Reductions 1. Hydrogenation 2. Boron Reagents 3. Aluminium Reagents 4. Tin Hydrides 5. Silanes 6. Dissolving Metal Reductions Hydrogenations Heterogeneous Catalytic Hydrogenation Transition metals absorbed onto a solid support metal: Pd, Pt, Ni, Rh support: Carbon, alumina, silica solvent: EtOH, EtOAc, Et2O, hexanes, etc. - Reduction of olefins & acetylenes to saturated hydrocarbons. Sensitive to steric effects and choice of solvent Polar functional groups, i.e. hydroxyls, can sometimes direct the delivery of H2. Cis addition of H2. R1 R1 R2 R2 H H2, Pd/C R1 H R2 R1 R2 - Catalyst can be "poisoned" - Directed heterogeneous hydrogenation O O H H2, Pd/C O O OH MeO O OH MeO H2, Pd/C H O O CO2Me MeO O CO2M2 (86 : 14) MeO Lindlar Catalyst ( Pd/ BaSO4/ quinoline)- partially poisoned to reduce activity; will only reduce the most reactive functional groups. acetylenes + H2, Pd/BaSO4/ quinoline → cis olefins Acid Chlorides + H2, Pd/BaSO4 → Aldehydes R SiMe 3 (Lindlar Reduction) (Rosemund Reduction) Org. Rxn. 1948, 4, 362 H2, Pd/BaSO4, Quinoline SiMe 3 TL 1976, 1539 R O O H2, Pd/BaSO4, pyridine CO 2Me CO 2Me JOC 1982, 47, 4254 REDUCTIONS HO OH H2, Lindlar Catalyst CH 2Cl 2: MeOH: Quinoline (90:9.5:0.5) 8π e- JACS 1982, 104, 5555 6π edisrotatory conrotatory HO OH HO H H HO OH H OH Ease of Reduction: (taken from H.O. House Modern Synthetic Reactions, 2nd edition) R COCl R CHO R NO 2 R NH 2 R R' R R CH 2-OH R CHO R CH CH R CH 2 CH 2 R' R' O R HO H R' Ar R' R O R R' Ar CH 3 + HO R R CH 2 NH 2 R C N O R CH 2-OH R + HO R' OR' O R' R R N CH 2 R' N R' R' requires high temperature & pressure R CO 2- Na+ no reaction Raney Nickel Desulfuriztion , Reviews: Org. Rxn. 1962, 12, 356; Chem. Rev. 1962, 62, 347. R R S R Raney Nickel R H R H (CH 2)n O R S 31 REDUCTIONS O O O O O HO 32 O HO Raney Nickel JOC 1987, 52, 3346 EtOH (74%) H S H S Homogeneous Catalytic Hydrogenation - catalyst is soluble in the reaction medium - catalyst not "poisoned" by sulfur - very sensitive to steric effects - terminal olefins faster than internal; cis olefins faster than trans R R > > R R R R > R R R > R R >> R R R - (Ph3P)3RhCl (Wilkinson's Catalyst); [R3P Ir(COD)py]+ PF6- (Crabtree's Catalyst) (Ph3P)3RhCl, H2 OH OH JOC 1992, 57, 2767 C 6H6 (92%) Directed Hydrogenation Review: Angew. Chem. Int. Ed. Engl. 1987, 26 , 190 - Diasterocontrolled hydrogenation of allylic alcohols directed by the -OH group - + O K O- K+ PPh3 O PPh3 Rh H H (Ph3P)3RhCl, H2 H MeO MeO Ph Ph P Rh+ P Ph Ph Brown's Catalyst BF4- Ir + P(C 6H11)3 N PF6 - (Crabtree's Ctalyst) JACS 1983, 105 , 1072 Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than isolated double bonds MeO2C OH MeO2C OH REDUCTIONS 33 mechanism: L + M H2 + M L L L + OH L S M L S O H lose H H H2 (oxidative addition) reductive elimination OH migratory insertion HO H L M L + H H M L S L O H Diastereoselective Hydrogenation: since -OH directs the H2, there is a possibility for control of stereochemistry - sensitive to: H2 pressure catalyst conc. substrate conc. solvent. Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than isolated double bonds HO "Ir" (20 mol %) HO O O H Brown's Catalyst OH JACS 1984, 106, 3866 H2 (640 psi), CH2Cl 2 H OMe OMe Me (24 : 1) OH OMe H Me OMe Brown's Catalyst H2 (1000 psi) O TL 1987, 28 , 3659 O OH OH Selectivity is often higher with lower catalyst concentration: OH OH OH 20 mol % Catalyst 2.5 mol % Catalyst 50 : 1 150 : 1 33 : 1 52 : 1 OH REDUCTIONS 34 Olefin Isomerization: CH3 (3 : 1) OH OH olefin isomerization O OH major product - Conducting the hydrogenation at high H 2 pressures supresses olefin isomerization and often gives higher diastereoselectivity. Other Lewis basic groups can direct the hydrogenation. (Ir seems to be superior to Rh for these cases) OMe CO2Me OMe Ir CO2Me + Ir+ 99 : 1 O O CO2H Ir+ 7 : 1 Rh+ 1 : 1 O O N O O N O 130 : 1 1:1 Acyclic Examples Rh+ (2 mol %) OH Me CH 3 JCSCC 1982, 348 H2 (15 psi) Me L L M OH (97:3) H O OH H H Ph H 3C H H L CH3 Ph M L Ph anti H H O H 32 : 1 CO2H > 99 : 1 O > 99 : 1 Rh+ OH 1,2-strain Ph syn REDUCTIONS L L R3 H OH R3 35 H O M R2 R1 OH favored R3 H syn R1 R2 R1 R2 R3 H L H R1 R2 M OH disfavored R3 1,2-strain R1 R2 O H L anti - Supression of olefin isomerization is critical for acyclic stereocontrol ! L L OH R2 H O M OH R2 H R1 CH3 R1 CH3 R2 H R1 anti R2 olefin isomerization OH R2 OH L L R1 H O M R2 H H R1 R2 CH2R2 R1 H - Rh+ catalyst is more selective than Ir + for acyclic stereoselection. Acyclic homoallylic systems: HO R1 R3 R2 relative stereochemistry is critical A E R2 A O H M R3 1,3-strain R3 L L E 1,2-strain R2 O H L M L syn REDUCTIONS Rh+ OH (20 mol %) 36 OH H2 (15 psi) OBz OBz TBSO 32 : 1 TBSO Tetrahedron Lett. 1985, 26, 6005 Rh+ (20 mol %) OH OH H2 (15 psi) OBz OBz TBSO 8:1 TBSO Asymmetric Homogeneous Hydrogenation - Chiral ligands for homogeneous hydrogenation of olefins and ketones H O P OMe MeO PPh2 PPh2 O P H DIOP PPh2 PPh2 PPh2 PPh2 PPh2 PPh2 R= -CH3 PROPHOS = -Ph PHENPHOS = -C6H11 CYCPHOS CHIRAPHOS DBPP DIPAMP Ph2P PPh2 PPh2 X PPh2 CO2tBu BPPM PPh2 CO 2H Ph HN PPPFA PPh2 P BINAP DIPHEMP Rh (I) L*, H2 CO 2H Ph HN Ph (95% ee) O CO 2Me Ph O CO 2H NHAc O NH 2 HO O OH L-DOPA DIOP DIPAMP PPPFA BINAP NORPHOS BPPM 85% ee 96% ee 93% ee 100% ee 95% ee 91% ee PPh2 PPh2 PPh2 PPh2 DUPHOS Fe N X= CH2 DPCP X= N-R PYRPHOS CAMPHOS P PPh2 PPh2 PPh2 PPh2 NORPHOS NMe2 ACR 1983, 16, 106. REDUCTIONS 37 General Mechanism: J. Halpern Science 1982, 217, 401 Asymmetric Synthesis 1985, vol 5, 41. CO2Me Ph S P Rh P Ph NHAc S P Rh NH O P (fast equilibrium) CO2Me CH3 rate limiting CO2Me Ph H2 (slow) NHAc Ph P H Rh P O S Ph H CO2Me NH S P (fast) P CO2Me H NH Rh O CH3 CH3 Detailed Mechanism: P * P MeO2C + S Ph CO2Me NHAc NH P * S Rh Ph Rh P P Ph CH3 O CO2Me HN H 3C P O major complex minor complex H2 (slow) MeO2C H H P * P H2 (slow) NH NH Ph Rh CH3 O H 3C Rh * S H CH3 NH Ph H N H 3C O P P * S CO2Me P H Rh O CH3 O CO2Me H Ph S P * Rh CO2Me Ph (R) Minor product HN MeO2C O S P Rh * H P Ph MeO2C Ph H N CH3 O (S) Major product REDUCTIONS + MeO2C H NH H Ph Rh P P Free Energy * NH 38 CH3 O + CO2Me H H Ph + CO2Me HN Rh O P P * P Ph H 3C H 3C Rh * P O minor complex MeO2C * Ph Rh P + NH P CH3 O major complex Reaction Coordinate Ph Ph O O P Ru O P O Ph Ph ACR 1990, 23, 345. BINAP O O (BINAP)RuAc2, H2 (100 atm) O O O R O O 50 °C, CH2Cl 2 (BINAP)RuAc2, H2 (100 atm) R O 50 °C, CH2Cl 2 (95 - 98 % ee) (94 % ee) CO 2H Ru(AcO)2(BINAP), H2 (135 atm), MeOH (97% ee) MeO CO 2H 97 % ee MeO (S)-naproxen MeO MeO MeO (BINAP)RuAc2, H2 (4 atm) NAc MeO MeO NAc NH MeO OMe OMe (95 - 100 % ee) OMe OMe OMe OMe Tetrahydropapaverine Directed Asymmetric Hydrogenation (BINAP)Ru (II), H2 OH CHO OH (96 - 99 % ee) OH OH HO J. Am. Chem. Soc. 1987, 109, 1596 O Vitamin E REDUCTIONS 39 Kinetic Resolution by Directed Hydrogenation CF 3SO 3- Rh+ MeO Ph P P Ph CO 2Me MeO 2C H2 (15 psi), L*Rh+ Et Ph OMe CO 2Me MeO 2C 0 °C (~60% conversion) R R= OMe R > 96 % ee 82 % 93 % Hydrogenation of Carbonyls 1,3-diketones: O R1 O O R1 OH H2 O H OH OH R2 R2 R1 O H O H syn anti Ru2Cl 4(BINAP) Et3N, H2 (100 atm) MeO 2C 99 : 1 16 : 1 (90 % ee) 32 : 1 49 : 1 R1 R2 R1 R2 Directed Reduction M O R1 anti : syn= OH R1 O R2 OH syn anti H O M OH R2 -CH3 -CH2CH3 -iPr -CH2CH3 R2 R2 + R1 R2= OH R1 OH R2 -CH3 -CH3 -CH2CH3 -CH2CH3 O R2 Ru (II) H2 (700 psi) O R1 O R1 R2 O R1= OH O OH JACS 1988, 110 , 6210 MeO 2C (98% ee) Decarbonylations O (Ph3P)3RhCl O (Ph3P)3RhCl R H R H - CO R Cl R Cl - CO REDUCTIONS 40 OHC (Ph3P)3RhCl Fe Fe Fe PhCH 3, ∆ JOC 1990, 55, 3688 Fe Diimide HN=NH Review: Organic Reactions 1991, 40J. Chem. Ed. 1965, 254 - Only reduces double bonds - Syn addition of H 2 - will selectivley reduce the more strained double bond - Unstable reagent which is generated in situ K+O2C-N=N-CO2K+ + AcOH → H-N=N-H H2N-NH2 + Cu2+ + H2O2 → H-N=N-H HN=NH ACIEE 1965, 271 (76%) O O +- CO 2MeK O 2C N N CO 2- K+ CO 2Me AcOH, MeOH (95%) NO 2 JACS 1986, 108 , 5908 NO 2 O HN HN hν (254 nm) S NH NH + COS + CO O O S O N N H H TL 1993, 34, 4137 hν, 16 hr (96%) Metal Hydrides Review on Metal Hydride Selectivity: Chem Soc Rev. 1976, 5 , 23 Comprehensive Organic Synthesis 1991, vol 8, 1. Boron Hydrides Review: Chem. Rev. 1986, 86 , 763. NaBH4 reduces ketones and aldehydes LiBH4 reduces ketones, aldehydes, esters and epoxides. THF soluble LiBH4/TMSCl stronger reducing agent. ACIEE 1989, 28, 218. Zn(BH4)2 reduces ketones and aldehydes R4N BH4 organic soluble (CH2Cl2) borohydrides. Synth Commun. 1990, 20, 907 LiEt3BH reduces ketones, aldehydes, esters, epoxides and R-X Li s-Bu3BH reduces ketones, aldehydes, esters and epoxides (hindered borohydride) Na(CN)NH3 reduces iminium ions, ketones and aldehydes Na(AcO)3BH reduces ketones and aldehydes (less reactive) NaBH2S3 reduces ketones and aldehydes REDUCTIONS 41 Sodium Borohydride NaBH4 - reduces aldehydes and ketones to alcohols - does not react with acids, esters, lactones, epoxides or nitriles. - Additives can increase reactivity. Sodium Cyanoborohydride Na (CN)BH3 Reviews: Synthesis 1975, 136; OPPI 1979, 11 , 201 - less reactive than NaBH4 - used in reductive aminations (Borch Reduction) Na(CN)BH3 reduces iminium ions much more quickly than ketones or aldehydes R"-2NH, MeOH, AcO - NH4+ , pH~ 8 R O R R' O CHO R N R' JACS 1971, 93 , 2897 R"-2NH, MeOH, AcO- NH4+ N H Na(CN)BH3 N R' R' R R R H Na(CN)BH3 N+ N - Related to Eschweiler-Clark Reaction H2CO, HCO 2H R NH 2 R or N H Me H2CO, H2/Pd - Reduction of tosylhydrazones gives saturated hydrocarbon O H H 1) TsNHNH 2, H+ 2) Na(CN)BH3 TL 1978, 1991 (90%) H HO H HO 1) TsNHNH 2, H+ 2) Na(CN)BH3 O (100%) JOC 1977, 42 , 3157 - migration of the olefin occurs w/ α,β-unsaturated ketones O JACS 1978, 100 , 7352 (75%) - Epoxide opening O OH NaBH3CN, BF3•OEt2, THF OH HO JOC 1994, 59, 4004 NaBH2S3 REDUCTIONS Synthesis 1972, 526 Can. J. Chem. 1970, 48 , 735. Lalancette Reduction 42 NaBH4/ NiCl 2 Chem. Pharm. Bull. 1981, 29 , 1159; Chem. Ber. 1984, 117 , 856. Ar-NO2 → Ar-NH2 Ar-NO → Ar- NH2 R2C=N-OH → R2CH-NH2 NaBH4 / TiCl 4 Synthesis 1980, 695. R-COOH → R-CH2-OH R-COOR' → R-CH2-OH R-CN → R-CH2-NH2 R-CONH2 → R-CH2-NH2 R2C=N-OH → R2CH-NH2 R-SO2-R' → R-S-R' NaBH4 / CeCl 3 Luche Reduction reduced α,β-unsaturated ketones in a 1,2-fashion OH NaBH 4/ CeCl3 R R NaBH 4 R R O OH O R + R R R R R R H R JCSCC 1978, 601 JACS 1978, 100 , 2226 O OH CO 2Me NaBH 4/ CeCl3 C 5H11 CO 2Me MeOH C 5H11 OH OH - selective reduction of ketones in the presence of aldehydes. OH O CO 2Me CO 2Me NaBH 4/ CeCl3 EtOH, H2O CHO CHO O CeCl 3 H2O 1) NaBH 4, CeCl3 2) work-up R JACS 1979, 101 , 5848 OH OH O OH CHO NaBH 4/ CeCl3 EtOH, H2O (78%) CHO REDUCTIONS Zinc Borohydride Zn(BH4)2 Synlett 1993, 885. ZnCl2 (ether) + NaBH 4 → Zn(BH4)2 - Ether solution of Zn(BH4)2 is neutral- good for base sensitive compounds - Chelation contol model Zn RO O R1 H O OR OH H B H H R2 OR R1 R2 H R1 R2 Zn(BH4)2, Et2O, 0°C OH OH OH O H H- Me TL 1983, 24 , 2653, 2657, 2661 O O Zn R Na + (AcO)3BH , Me4N + (AcO)3BH Review: OPPI 1985, 17 , 317 - used in Borch reductive amination TL 1990, 31 , 5595; Synlett 1990, 537 - selective reduction of aldehydes in the presence of ketones O Bu4N (AcO) 3BH C 6H6, ↑↓ O OH CHO (77%) TL 1983, 24 , 4287 AcO O Bu4N (AcO) 3BH C 6H6, ↑↓ CHO Ph H O OAc B OH O Ph Ph OH -hydroxyl-directed reduction of ketones TL 1983, 24 , 273; TL 1984, 25 , 5449 OH O Me O OH Ph N Me Me OH Me4N (AcO) 3BH, CH 3CN, AcOH, −40°C Me O Ph N Me O O Me O O TL 1986, 27 , 5939 JACS 1988, 110 , 3560 (98:2) OAc H O R B O OAc OAc H R R H OAc H O R minor major OH B O O Na+ BH(OAc)3 OH OH 50 : 1 43 REDUCTIONS OH O O OH Na+ BH(OAc)3 OH O CO2R CO2R OH Na+ BH(OAc)3 44 OH OH CO2R HO OBn BnO OBn BnO Me MeO OBn O OBn Me4N (AcO) 3BH, CH 3CN, AcOH, −40°C O Me MeO Me O MeO O O Me Me OH O N OH O Me O O HO OH OH Me FK-506 OH OH TL 1989, 30 , 1037 (Ph3P)2Cu BH4 reduction of acid chlorides to aldehydes reduction of alkyl and aryl azides to amines JOC 1989, 45, 3449 J. Chem. Res. (S) 1981, 17 R4N BH4 organic soluble borohydride (CH2Cl2) R4N= BnEt3N or Bu4N Heterocylces 1980, 14, 1437, 1441 reduction of amides to amines reduction of nitriles to amines BnEt3N BH4 / Me 3SiCl reduction of carbolxylic acids to alcohols LiBH4/ Me 3SiCl Synth. Commun. 1990, 20, 907 ACIEE 1989, 28, 218. Alkyl Borohydrides Selectrides M + HB 3 M + = Li (L-selectride) K (K-selectride) LS-selectride Li + HB 3 - hindered reducing agent increased selectivity based on steric considerations CO 2H O CO 2H OH L-selectride THF JACS 1971, 93, 1491 R R HO HO OH OH REDUCTIONS 45 - selective 1,4-reductions of α,β-unsaturated carbonyl cmpds. JOC 1975, 40 , 146; JOC 1976, 41 , 2194 O O K-selectride, THF (99%) - 1,4-reduction generates an enolate which can be subsequently alkylated. O O a) K-selectride, THF b) Br K+ HBPh3 Syn. Comm. 1988, 18 , 89. - even greater 1,4-selectivity Li + HBEt3 (Super Hydride) - very reactive hydride source - reduces ketones, aldehydes, esters, epoxides and C-X (alkyl halides and sulfonates) O HO Li Et3BH, THF HO HCA 1983, 66 , 760 HO H H HO HO CH 3 OH HO 1) TsCl, pyridine 2) Li Et3BH, THF HCA 1988, 71 , 872 HO H H Boranes Hydroboration H2O 2, NaOH B 2H6 B R R' R B 2H6 R' B R B 2H6 H HO H H H3O + H R B H2O 2, NaOH R R' H H R-CH 2CHO H - BH3 reduces carboxylic acids to 1° alcohols in the presence of esters, nitro and cyano groups. - BH3 reduces amides to amines HO 2C BH 3•SMe 2 O O THF HO O O - Boranes also reduce ketones and aldehydes to the corresponding alcohols. REDUCTIONS Hindered Boranes Disiamyl Borane (Sia2BH) B H Thexyl Borane B H H B 9-BNN = B H B H O Catecholborane BH O BH BH Pinylborane 2 2 B B H Alpine Borane BCl BCl IPC 2BCl (DIP-Cl) 2 2 B H Borolane Ph Oxazaborolidine N B H Ph O Asymmetric Reduction of Unsymmetrical Ketones Using Chiral Boron Reagents Review: Synthesis 1992, 605. Alpine Borane Midland Reduction JACS 1979, 111 , 2352; JACS 1980, 112 , 867 review: Chem. Rev. 1989, 89 , 1553. O alpine-borane THF, 0°C OH Tetrahedron 1984, 40 , 1371 (94% ee) 46 REDUCTIONS B H B = 9-BBN B B α-pinene 9-BBN B H Mechanism: OH O RL Rs RL Rs - works best for aryl- and acetylenic ketones - because of steric hindrance, alpine-borane is fairly unreactive Chloro Diisopinylcamphenylborane (DIP-Cl, Ipc2BCl) H.C. Brown Review: ACR 1992, 25 , 16. Aldrichimica Acta 1994, 27 (2), 43 BCl 2 - Cl increases the Lewis acidity of boron making it a more reactive reagent - saturated ketones are reduced to chiral alcohols with varying degrees of ee. O OH I CO2tBu Ipc2B-Cl, THF I CO2tBu JOC 1992, 57, 7044 PrO PrO OMe (90 % ee) OMe Borolane (Masamune's Reagent) JACS 1986, 108 , 7404; JACS 1985, 107, 4549 B H B O OH H MeSO 3H, pentane (80% ee) Asymmetric Hydroboration: a) B H b) H2O 2, NaOH OH (99.5% ee) (99.5% ee) 47 REDUCTIONS Oxazaborolidine (Corey) JACS 1987, 109 , 7925; TL 1990, 31, 611l ; TL 1992, 33 , 4141 Ph Ph O N B Ph N B H Ph O + BH3 CH 3 Catalytic O OH R R > 90 % ee OH O 92 % ee O OH I 86 % ee I O OH 93 % ee Ph Ph O O N B Me OH BH 3•THF, -0°C TL 1988, 29 , 6409 (90% ee) CF 3 O OH Cl O Cl • HCl N H CH 3 94 % ee Fluoxetine (Prozac) O O O O 90 : 10 BzO BzO O Aluminium Hydrides 1. LiAlH 4 2. AlH3 3. Li (tBuO)3AlH 4. (iBu)2AlH DIBAL-H 5. Na (MeOCH2CH2O)2AlH2 REDAL OH 48 REDUCTIONS 49 Chem. Rev. 1986, 86, 763 Org. Rxn. 1951, 6, 469. Lithium Aluminium Hydride LiAlH4 (LAH) - very powerful reducing agent - used as a suspension in ether or THF - Reduces carbonyl, carboxylic acids and esters to alcohols - Reduces nitrile, amides and aryl nitro groups to amines - opens epoxides - reduces C-X bonds to C-H - reduces acetylenic alcohols trans-allylic alcohols LAH OH R OH R H2N LAH, THF N H NH 2 H2N (62%) NH 2 N H NH 2 Lindlar/ H2 H2N O N H HO CO 2Me OH LAH, THF, ↑↓ TL 1988, 29 , 2793. (100%) O O H O H O BINAL-H (Noyori) - Chiral aluminium hydride for the asymmetric reduction of prochiral ketones OH OH 1) LiAlH4 2) ROH H O Li + Al O OR R= Me, Et, CF 3CH 2- BINOL BINAL-H O O O BINAL-H,THF Tetrahedron 1990, 46 , 4809 -100 to -78°C HO (94% ee) Intermediate for 3-Component Coupling Strategy to Prostaglandins I O Li+ O CO 2Me RO Li+ RCu RO OTBS O OTBS O CO 2H CO 2Me HO RO OTBS OH PGE 2 REDUCTIONS Alane 50 AlH3 LiAlH 4 + AlCl3 → AlH3 - superior to LAH for the 1,2-reduction of α,β-unsaturated carbonyls to allylic alcohols OMe Ph 1) AlH3, ether, 0°C 2) H3O + O O HO O Me O JACS 1989, 111 , 6649 Me O OH O Diisobutyl Aluminium Hydride DIBAL or DIBAL-H Al H - Reduces ketones and aldehydes to alcohols - reduces lactones to hemi-acetals O Al O OH CHO work up DIBAL O (CH 2)n O OH O (CH 2)n (CH 2)n (CH 2)n lactol (stable complex) - reduces esters to alcohols - under carefully controlled reactions conditions, will partially reduce an ester to an aldehyde Al O DIBAL R CO 2Me if complex is unstable R C OMe fast R CHO R CH 2 OH H if complex is stable R CHO O O O OBn O DIBAL, CH 2Cl 2 O HO OH HO HO H O HO OBn O OBn OH OBn OH JACS 1990, 112 , 9648 OBn OBn DIBAL, CH 2Cl 2 CO 2iPr iPrO2C OHC OBn O R OBn O TMS-Cl, Et3N OH CHO CH2Cl2 R O DiBAl-H OSiMe3 CH2Cl2, -78°C TL 1998, 39, 909 R H Reduction of O-Methyl hydroxamic acids O R O R'-M R' R O OMe N Me TL 1981, 22 , 3815 DIBAL or LAH R H REDUCTIONS 51 Sodium Bis(2-Methoxyethoxy)Aluminium Hydride REDAL Organic Reactions 1988, 36, 249 Organic Reactions 1985, 36, 1. MeO MeO Na+ H O Al O H - "Chelation" directed opening fo allylic epoxides OH O REDAL R OH DIBAL-H R R OH Ph 1,2-diol OH REDAL O OH Ph TL 1982, 23 , 2719 OH 1,3-diol Sharpless epoxidation OH OH DME LiAlH4 AlH3 OH OH + OH O JOC 1988, 53 , 4081 Ph 2 : 98 95 : 5 OH O OH BnO + OH BnO OH BnO OH REDAL DIBAL O OH Me HO OH O O Me OH OH 150 : 1 1 : 13 OH OH Me OH HO O OH Me Amphotericin B HO O NH 2 Me Me O Me O OH Me OH O O O sugar sugar Me Erythromycin A Li+ (tBuO)3AlH Lithium Tri(t-Butoxy)aluminium Hydride - hindered aluminium hydride, will only react with the most reactive FG's O R Li(tBuO)3AlH Cl R H Me Cl O N+ R-CO 2H O Me H R pyridine, -30°C O H Me N+ Me O Li(tBuO)3AlH CuI (cat), -78°C R TL 1983, 24 , 1543 H Meerwein-Ponndorf-Verley Reduction: opposite of Oppenauer oxidation Synthesis 1994, 1007 Organic Reactions 1944, 2, 178 O H O H Al(O-Pr)3, iPrOH O O O AcHN O O AcHN OH REDUCTIONS 52 Asymmetric M-P-V Reduction Bn Ph X O Ph N O Sm X O OH I JACS 1993, 115, 9800 iPrOH, THF X= H, Cl, OMe yield: 83-100 % 96% ee Dissolving Metal Reductions Birch Reductions reduction of aromatic rings Organic Reactions 1976, 23, 1. Tetrahedron 1986, 42, 6354. Comprehensice Organic Synthesis 1991, vol. 8, 107. - Li, Na or K metal in liquid ammonia H H H H M, NH3 _• • R R R R H H H - position of the double bond in the final product is dependent of the nature of the substituent R R R R= EWG R= ERG - ketones and nitro groups are also reduced but esters and nitrile are not. - α,β-unsaturated carbonyl cmpds are reduced in a 1,4-fashion to give an enolate which can be subsequently used to trap electrophiles Me HO Me Me O O K, NH3, MeOH, -78°C Me HO O JOC 1991, 56 , 6255 O (92%) O Me Me OH Me Me O O O O a) Li, NH3, tBuOH b) CH 2O JOC 1984, 59 , 3685 O O HO Other Metals - Mg Mg, MeOH X X X- CN, CO2R, CONR'2 H H Mg, MeOH EtO2C (98%) TL 1987, 28 , 5287 EtO2C - Zn reduction of α-halocarbonyls O O Br Zn, PhH, DMSO, MeI Me JACS 1967, 89, 5727 REDUCTIONS Cl R Zn O X Y Zn, AcOH R R' X= Cl, Br, I Y= X, OH R R-OH O CH 53 CH R' "Copper Hydrides" LAH or DIBAL-H + MeCu → "CuH" - selective 1,4-reduction of α,β-unsaturated ketones (even hindered enones) O O 1) MeCu, DIBAL, HMPA, THF, -50°C 2) MeLi 3) JOC 1987,52 , 439 Br O O MeCu, DIBAL, HMPA THF, -50°C H H JOC 1986,51 , 537 (85%) O H H O H [(Ph3P)CuH]6 Stryker Reagent JACS 1988, 110 , 291 ; TL 1988, 29 , 3749 - 1,4-reduction of α,β-unsaturated ketones and esters; saturated ketones are not reduced - halides and sulfonates are not reduced - 1,4-reduction gives an intermediate enolate which can be trapped with electrophiles. O Br O [(Ph3P)CuH] 6, THF TL 1990, 31 , 3237 Silyl Hydrides - Hydrosilylation Et3SiH + (Ph3P)3RhCl (cat) - selective 1,4-reduction of enones, 1,2-reduction of saturated ketones to alchohols. O Et3SiH, (Ph3P)3RhCl (cat) O SiEt3 H3O + O TL 1972, 5085 J. Organomet. Chem. 1975, 94 , 449 O O O iPr3SiH, Et2O Si O 2 Pt 2 OSi(iPr)3 O JOC 1994, 59, 2287 O (87%) - Buchwald Reduction JACS 1991, 113 , 5093 - catalytic reagent prepared from Cp2TiCl2 + nBuLi and stoichometric (Et)3SiH in THF will reduce ester, ketones and aldehydes to alcohols under very mild conditions. - α,b− unsaturated esters are reduced to allylic alcohols - free hydroxyl groups, aliphatic halides and epoxides are not reduced REDUCTIONS 54 Clemmensen Reduction Organic Reactions 1975, 22, 401 Comprehensive Organic Synthesis 1991, vol 8, 307. - reduction of ketones to saturated hydrocarbons Zn(Hg), HCl H O Wolff-Kishner Reduction H Organic Reactions 1948, 4, 378 Comprehensive Organic Synthesis 1991, vol. 8, 327. - reduction of ketones to saturated hydrocarbons H2N-NH2, KOH H O H Radical Deoxygenation Review: Tetrahedron 1983, 39 , 2609 Chem. Rev. 1989, 89, 1413. Comprehensive Organic Synthesis 1991, vol. 8, 811 Tetrahedron 1992, 48, 2529 W. B. Motherwell, D. Crich Free Radical Chain Reactions in Organic Synthesis (Academic Press: 1992) - free radical reduction of halide, thio ethers, xanthates, thionocarbanates by a radical chain mechanism. nBu3Sn-H, AIBN Ph-CH3 ↑↓ R3C-H R3C-X S X= -Cl, -Br, -I, -SPh, S S Ph , O O Barton-McCombie Reduction JCS P1 1975, 1574 R3C-X → R3C-H N N CN SMe , O CN AIBN N N X= -OC(=S)-SMe, -OC(=S)-Im, -OC(=S)Ph O O O O HO NaH, imidazole, THF, CS2, MeI O O O O O O O nBu3SnH, AIBN PhCH3, reflux O O O O (85%) O SMe S Xanthate R R Cl a) Ph nBu3SnH, AIBN PhCH3, reflux NMe2 , THF + S b) H2S, pyridine HO (73%) Ph (90%) R O Thionobenzoates S Ph O O O HO AcHN OBn N N N (CH2Cl)2 59% Ph N N N O O O O AcHN OBn S Thiocarbonyl Imidazolides nBu3SnH, AIBN PhCH3, reflux (57%) Ph O O AcHN O OBn REDUCTIONS - Cyclic Thionocarbonates: deoxygenation of 1,2- and 1,3-diols to alcohols 55 S OH N O HO MeO MeO S N O O MeO N N HO O JCS P1 1977, 1718 MeO (61%) MeO OMe nBu3SnH, AIBN PhCH3, reflux O MeO OMe OMe - Thionocarbonate Modification (Robbins) JACS 1981, 103 , 932; JACS 1983, 105 , 4059. iPr iPr O O Si PhOC(S)Cl, pyridine, DMAP B iPr iPr O nBu3SnH, AIBN PhCH3, reflux B O O > 90% Si O iPr iPr O Si OH iPr iPr O B O O (58-78%) Si O iPr iPr O Si Si O iPr iPr OPh S S OAr O O O CH3 nBu3SnH, AIBN, PhCH3 O O O Tetrahedron 1991, 47, 8969 O 88-91% O O O O Best method for deoxygenation of primary alcohols Ar= 2,4,6-trichlorophenyl, 4-fluorophenyl - N-Phenyl Thionocarbamates iPr iPr O O Si U PhNCS NaH, THF S O Si O iPr iPr Tetrahedron 1994, 34, 10193. iPr iPr O U Si O iPr iPr NHPh (TMS)3SiH, AIBN PhH, reflux S O (78%) O O Si O (93%) iPr iPr O O Si U O Si O iPr iPr NHPh Thiocarbamates - Methyl oxylates OAc O OAc O MeO2CCOCl THF OC nBu3SnH, AIBN PhCH3, reflux OC O HO CO2Me CO2Me MeO2C O OAc O OC CO2Me Methyl Oxylate Esters - Water Soluble Tin Hydride: [MeO(CH2)2O(CH2)3]3SnH / 4,4'-Azo(bis-4-cyanovaleric acid) TL 1990, 31 , 2957 - Silyl Hydride Radical Reducing Agents - replacement for nBu3SnH (Me3Si)3SiH Chem Rev. 1995, 95, 1229. JOC 1991, 56 , 678; JOC 1988, 53 , 3641; JACS 1987, 109 , 5267 Ph2SiH2 / Et3B / Air TL 1990, 31 , 4681; TL 1991, 32 , 2569 - hypophosphorous acid as radical chain carrier JOC 1993, 58, 6838 REDUCTIONS - Photosensitized electron transfer deoxygenation of m-trifluoromethylbenzoates JACS 1986, 108, 3115, JOC 1996, 61, 6092, JOC 1997, 62, 8257 iPr iPr O O Si U N-methylcarbazole, hν, iPrOH, H2O O Si O iPr iPr O iPr iPr (85%) O Si O CF3 O U O Si O iPr iPr Dissolving Metal : JACS 1972, 94, 5098 O OH O nBuLi, (Me2N)2P(O)Cl O P(NMe2)2 Li, EtNH2, THF, tBuOH O O H CH3 O O H O Radical Decarboxylation: Barton esters Aldrichimica Acta 1987, 20 (2), 35 S hn or ∆ N S R N nBu3SnH, ∆ O O R - CO2 Radical Deamination Comprehensive Organic Synthesis 1991, vol. 8, 811 Reduction of Nitroalkanes JOC 1998, 63, 5296 NO2 Bu3SnH, PhSiH3 O O initiator, PhCH3 (reflux) (75%) O O R H H 56 PROTECTING GROUPS Carey & Sundberg Chapter 13.1 problems # 1; 2; 3a, b, c ; Smith: Chapter 7 57 Protecting Groups T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd edition) J. Wiley & Sons, 1991. P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994 1. 2 3. 4. Hydroxyl groups Ketones and aldehydes Amines Carboxylic Acids - Protect functional groups which may be incompatible with a set of reaction conditions - 2 step process- must be efficient - Selectivity a. selective protection b. selective deprotection Hydroxyl Protecting Groups Ethers Methyl ethers R-OH → R-OMe Formation: Cleavage: - difficult to remove except for on phenols CH2N2, silica or HBF4 NaH, MeI, THF AlBr3, EtSH PhSe Ph2P Me3SiI OMe O OH O AlBr3, EtSH TL 1987, 28 , 3659 O O OBz Methoxymethyl ether MOM R-OH → R-OCH2OMe OBz stable to base and mild acid Formation: - MeOCH2Cl, NaH, THF - MeOCH2Cl, CH2Cl2, iPr2EtN Cleavage - Me2BBr2 TL 1983, 24 , 3969 PROTECTING GROUPS Methoxyethoxymethyl ethers (MEM) R-OH → R-OCH2OCH2CH2OMe stable to base and mild acid Formation: - MeOCH2CH2OCH2Cl, NaH, THF - MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN Cleavage - Lewis acids such as ZnBr2, TiCl4, Me2BBr2 TL 1976, 809 S B Cl MEM-O HO S C5H11 O-Si(Ph)2tBu O C5H11 TL 1983, 24 , 3965, 3969 O O-Si(Ph)2tBu - can also be cleaved in the presence of THP ethers Methyl Thiomethyl Ethers (MTM) R-OH → R-OCH2SMe Stable to base and mild acid Formation: - MeSCH2Cl, NaH, THF Cleavage: - HgCl2, CH3CN/H2O - AgNO3, THF, H2O, base Benzyloxymethyl Ethers (BOM) R-OH → R-OCH2OCH2Ph Stable to acid and base Formation: - PhOCH2CH2Cl, CH2Cl2, iPr2EtN Cleavage: - H2/ PtO2 - Na/ NH3, EtOH Tetrahydropyranyl Ether R-OH (THP) O H + , PhH Formation Cleavage: R O O Stable to base, acid labile - DHP (dihydropyran), pTSA, PhH - AcOH, THF, H2O - Amberlyst H-15, MeOH Ethoxyethyl ethers (EE) JACS 1979, 101 , 7104; JACS 1974, 96 , 4745. R-OH O H+ R Benzyl Ethers (R-OBn) R-OH → R-OCH2Ph Formation: Cleavage: O O (R-OEE) base stable, acid labile stable to acid and base - KH, THF, PhCH2Cl - PhCH2OC(=NH)CCl3, F3CSO3H - H2 / PtO2 - Li / NH3 JCS P1 1985, 2247 58 PROTECTING GROUPS 2-Napthylmethyl Ethers (NAP) JOC 1998, 63, 4172 formation: 2-chloromethylnapthalene, KH cleavage: hydrogenolysis OH O ONAP BnO OH H2, Pd/C - OH BnO (86%) p- Methoxybenzyl Ethers (PMB) Formation: - KH, THF, p-MeOPhCH2Cl - p-MeOPhCH2OC(=NH)CCl3, F3CSO3H Cleavage: O 59 TL 1988, 29 , 4139 H2 / PtO2 Li / NH3 DDQ Ce(NH4)2(NO3)6 (CAN) e- o-Nitrobenzyl ethers Review: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225 O 2N NaH, THF R-OH Cl R O NO 2 Cleavage: - photolysis at 320 nm NO 2 HO HO HO O HO hν, 320 nm, pyrex, H2O O HO HO OH O OH JOC 1972, 37 , 2281, 2282. OH p-Nitrobenzyl Ether TL 1990, 31 , 389 -selective removal with DDQ, hydrogenolysis or elctrochemically 9-Phenylxanthyl- (pixyl, px) TL 1998, 39, 1653 Formation: Ph Ph Cl OR pyridine ROH + O Removal: Ph O Ph OR OH hν (300 nm) ROH O CH3CN,H 2O + O Trityl Ethers -CPh3 = Tr R-OH → R-OCPh3 - selective for 1° alcohols - removed with mild acid; base stable formation: - Ph3C-Cl, pyridine, DMAP - Ph3C + BF4Cleavage: - mild acid PROTECTING GROUPS 60 Methoxytrityl Ethers JACS 1962, 84 , 430 - methoxy group(s) make it easier to remove R1 (p-Methoxyphenyl)diphenylmethyl ether 4'-methoxytrityl MMTr-OR R2 Di-(p-methoxyphenyl)phenylmethyl ether 4',4'-dimethoxytrityl DMTr-OR C O R Tri-(p-methoxyphenyl)methyl ether 4',4',4'-trimethoxytrityl TMTr-OR R3 Tr-OR < MMTr-OR < DMTr-OR << TMTr-OR O O HN R O HN O 80% AcOH (aq) N O HO O 20°C N O HO OH HO OH R = Tr 48 hr. R= MMTr 2 hr. R= DMTr 15 min. R= TMTr 1 min. (too labile to be useful) Oligonucleotide Synthesis (phosphoramidite method - Lessinger) Review: Tetrahedron 1992, 48 , 2223 S I L I C A S I L I C A OH OH OH S I L I C A O Si (CH 2)3 NH 2 O O DMTrO O O DMTrO O B O Cl 3CCOOH S O B' O P O CN O CN O DMTrO O O Base O B O P - O B O coupling S DMTrO O O HO B' O S B' O O O I2, H2O Si (CH 2)3 N C (CH 2)2 C OH H HO B' N (iPr)2 O B Si (CH 2)3 N C (CH 2)2 C O H O O O P O O B' O O O S I L I C A DMTrO O P OO- Cl 3CCOOH O B O P O B O O S O Repeat Cycle OO S O PROTECTING GROUPS Silyl Ethers Synthesis 1985, 817 Synthesis 1993, 11 Synthesis 1996, 1031 R-OH → R-O-SiR3 formation: - R3Si-Cl, pyridine, DMAP - R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP - R3Si-OTf, iPr2EtN, CH2Cl2 61 Trimethylsilyl ethers Me3Si-OR TMS-OR - very acid and water labile - useful for transiant protection Triethylsilyl ethers Et3Si-OR TES-OR - considerably more stable that TMS - can be selectively removed in the presence of more robust silyl ethers with with F - or mild acid O OH H2O/ACOH/THF (3:5:11), 15 hr TESO OTBS O (97%) Liebigs Ann. Chem. 1986, 1281 OTBS Triisopropylsilyl ethers iPr3Si-OR TIPS-OR - more stabile to hydrolysis than TMS Phenyldimethylsilyl ethers J. Org. Chem. 1987, 52 , 165 t-Butyldimethylsilyl Ether tBuMe 2Si-OR TBS-OR TBDMS-OR JACS 1972, 94 , 6190 - Stable to base and mild acid - under controlled condition is selective for 1° alcohols t-butyldimethylsilyl triflate tBuMe 2Si-OTf TL 1981, 22 , 3455 - very reactive silylating reagent, will silylate 2° alcohols cleavage: - acid - F- (HF, nBu4NF, CsF, KF) TBSO HO CO2Me HF, CH3CN CO2Me (70%) O OTBS O HO JCS Perkin Trans. 1 1981, 2055 t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR ∑-OR - stable to acid and base - selective for 1° alcohols - Me3Si- and iPr 3Si groups can be selectively removed in the presence of TBS or TBDPS groups. - TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19 PROTECTING GROUPS cleavage - F- Fluoride sources: - nBu 4NF (basic reagent) HF / H2O /CH3CN HF•pyridine SiF4. CH2Cl2 TL 1979, 3981. Synthesis 1986, 453 TL 1992, 33 , 2289 Me O Si OH tBu Me JOC 1981, 46 ,1506 TL 1989, 30 , 19. AcOH / THF/ H2O Ph O Si tBu O Si Me Ph tBu Ph Ph Me tBu Si 62 Me tBu O Si Me OTHP O OH PPTS / EtOH JACS 1984, 106 , 3748 Esters R-OH → R-O2CR' Formation: - "activated acid", base, solvent, (DMAP) Activated Acids Chem. Soc. Rev. 1983, 12, 129 Angew. Chem. Int. Ed. Engl. 1978, 17, 569. RCO2H → "activated acid" → carboxylic acid derivative (ester, amide, etc.) Acid Chlorides O O O O N N + N R R OH R R N Cl + N N acyl pyridinium ion (more reactive) 1. SOCl2 2. PCl5 3. (COCl)2 Anhydrides O O P2O 5 2 R OH R O O R Activating Agents: Carbonyl Diimidazole O O O R OH N + N R N N N N Acyl Imidazole NH + CO + N PROTECTING GROUPS 63 Dicyclohexylcarbodiimide C 6H11 O NH O R + OH R N C N O O Nu: O C N R +C 6H11 Nu N H N H C 6H11 C 6H11 Ketene formation is a common side reaction- scambling of chiral centers C 6H11 O NH R R O C N H C O "ketene" C 6H11 Hydroxybenzotriazole (HOBT) - reduces ketene formation C 6H11 O R O N NH + O C N N N O N R N N OH C 6H11 N-Hydroxysuccinimide (NHS) O C 6H11 O R O O NH HO + O C N R N O N O C 6H11 O 2,2'-Dipyridyl Disulfide (Aldrithiol, Corey Reagent) Aldrichimica Acta 1971, 4 , 33 O R OH O Ph3P: + N S S R N + S + N N Ph3P=O SH Mukaiyama's Reagent (2-Chloro-1-methyl pyridinium Iodide or 2-Fluoro-1methyl pyridinium p-toulenesulfonate) Aldrichimica Acta 1987, 20 , 54 Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575 O + R OH F + N Me O TsO R O + N I- Me Acetates R-OH → R-O2CCH3 - stable to acid and mild base - not compatable with strong base or strong nucleophiles such as organometallic reagents Formation: - acetic anhydride, pyridine - acetyl chloride, pyridine PROTECTING GROUPS Cleavage: - K2CO3, MeOH, reflux KCN, EtOH, reflux NH3, MeOH LiOH, THF, H2O enzymatic hydrolysis (Lipase) OAc 64 Org. Rxns. 1989, 37, 1. OAc Porcine Pancreatic Lipase TL 1988, 30 , 6189 OAc OH (96% ee) Chloroacetates - can be selectively cleaved with Zn dust or thiourea. O Me O OR O HO AcO Me OAc O Cl Me O OR Cl H2NNHCOSH O AcO Me O JCS CC 1987, 1026 O OAc O HO Cl O O OH O Trifluoroacetates Formation: - with trifluoroacetic anhydride or trifluoroacetyl chloride Cleavage: - K2CO3, MeOH Pivaloate (t-butyl ester) - Fairly selective for primary alcohols Formation: - tbutylacetyl chloride or t-butylacetic anhydride Cleavage: - removed with mild base Benzoate (Bz) - more stable to hydrolysis than acetates. Formation: - benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyl tetrazole (TL 1997, 38, 8811) Cleavage: - mild base - KCN, MeOH, reflux 1,2 and 1,3- Diols Synthesis 1981, 501 Chem. Rev. 1974, 74, 581 R2 O OH R1 R OH Isopropylidenes R3 H+ , -H2O R2 R3 O O R R1 (acetonides) H+ OH R R1 OH acetone or OMe MeO OMe or Me Me O O R R1 - in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored - cleaved with mild aqueous acid PROTECTING GROUPS 65 Cycloalkylidene Ketals - Cyclopentylidene are slightly easier to cleave than acetonides - Cyclohexylidenes are slightly harder to cleave than acetonides O (CH 2)n -or- OH OMe MeO (CH 2)n (CH 2)n R1 R O H+ , -H2O OH O R R1 Benzylidene Acetals PhCHO -orPhCH(OMe)2 OH R1 R Ph O O + H , -H2O OH R R1 - in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually favored - benzylidenes can be removed by acid hydrolysis or hydrogenolysis - benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins. p-Methoxybenzylidenes - hydrolyzed about 10X faster than regular benzylidenes - Can be oxidatively removed with Ce(NH 4)2(NO3)6 (CAN) OMe OBn BnO O MeO BnO OH (95%) O O OBn Ce(NH 4)2(NO3)6 CH 3CN, H2O MeO O OH Other Reactions of Benzylidenes - Reaction with NBS (Hanessian Reaction) H O Ph O O HO NBS, CCl 4 O Br Ph HO OMe O HO Org. Syn. 1987, 65, 243 O HO OMe - if benzylidene of a 1° alcohol, then 1° bromide - Reductive Cleavage Ph O Na(CN)BH3, TiCl4,CH 3CN O OH MeO 2C MeO 2C O MeO CO 2Me O O Ph O CO 2Me Synthesis 1988, 373. OBn O TMS-CN BF3•OEt2 OH Tetrahedron 1985, 41, 3867 MeO O O H Ph CN PROTECTING GROUPS Ph O O BnO OH DIBAL-H TL 1988, 29 , 4085 O O OMe OMe Carbonates O OH R1 R (Im)2CO O OH O R R1 - stable to acid; removed with base - more difficult to hydrolyze than esters Di-t-Butylsilylene (DTBS) TL 1981, 22 , 4999 - used for 1,3- and 1,4-diols; 1,2-diols are rapidly hydrolyzed - cleaved with fluoride (HF, CH 3CN -or- Bu4NF -or- HF•pyridine) - will not fuctionalize a 3°-alcohol OH (t-Bu)2SiCl 2, Et3N CH 3CN, HOBT O tBu Si O OH 1,3-(1,1,3,3)-tetraisopropyldisiloxanylidene (TIPDS) - specific for 1,3- and 1,4-diols - cleaved with fluoride or TMS-I tBu TL 1988, 29 , 1561 O O HN HN HO O N iPr2Si(Cl)-O-Si(Cl)iPr2 pyridine O O Si O N O O Si HO OH O OH Ketones and Aldehydes - ketones and aldehydes are protected as cyclic and acyclic ketals and acetals - Stable to base; removed with H3O+ R O MeOH, H+ R1 R R1 (CH 2OH)2, H+ PhH, -H2O -or(CH2OSiMe 3)2, TMS-OTf, CH2Cl 2 CH 2(CH 2OH)2, H+ , PhH, -H2O OMe OMe R O TL 1980, 21 , 1357 R1 O 1,3-dioxolanes R O R1 O 1,3-dioxanes 66 PROTECTING GROUPS 67 Cleavage rate of substituted 1,3-dioxanes: Chem. Rev. 1967, 67 , 427. R O R O R O > R1 O >> R1 O R1 O - Ketal formation of α,β-unsaturated carbonyls are usually slower than for the saturated case. O O O CH 2(CH 2OH)2, H+ , PhH, -H2O O O Fluoride cleavable ketal: O O LiBF4 O O (88%) O Me3Si TL 1997, 38, 1873 O O Base cleavable ketal: HO O SO2Ph SO2Ph DBU, CH2Cl 2 OH R1 R2 O pTSA, C6H6 R1 O TL 1998, 39, 2401 O R1 R2 R2 Carboxylic Acids Tetrahedron 1980, 36, 2409. Tetrahedron 1993, 49, 3691 Nucelophilic Ester Cleavage: Organic Reactions 1976, 24, 187. Esters Alkyl Esters formation: - Fisher esterification (RCOOH +R'OH + H+) - Acid Chloride + R-OH, pyridine - t-butyl esters: isobutylene and acid - methyl esters: diazomethane Cleavage: - LiOH, THF, H2O - enzymatic hydrolysis Org. Rxns. 1989, 37, 1. - t-butyl esters are cleaved with aqueous acid - Bu 2SnO, PhH, reflux (TL 1991, 32, 4239) OH MeO 2C CO 2Me O R Pig Liver Esterase pH 6.8 buffer Bu2SnO, PhH, ↑↓ OR' OH MeO 2C CO 2H O R OH TL 1991, 32, 4239 R= Me, Et, tBu 9-Fluorenylmethyl Esters (Fm) TL 1983, 24 , 281 - cleaved with mild base (Et2NH, piperidine) DCC RCO 2H + O OH R O PROTECTING GROUPS 2-Trimethylsilyl)ethoxymethyl Ester (SEM) HCA 1977, 60 , 2711. - Cleaved with Bu 4NF in DMF DCC RCO 2H HO + O R SiMe 3 O O SiMe 3 O - Cleaved with MgBr2•OEt2 TL 1991, 32, 3099. 2-(Trimethylsilyl)ethyl Esters JACS 1984, 106 , 3030 - cleaved with Fluoride ion DCC RCO 2H HO + R O SiMe 3 SiMe 3 O Haloesters - cleaved with Zn(0) dust or electrochemically DCC RCO 2H HO + CCl 3 R O CCl 3 O Benzyl Esters RCO2H + PhCH2OH → RCO2Bn Formation: Cleavage: - DCC Acid chloride and benzyl alcohol Hydrogenolysis Na, NH3 Diphenylmethyl Esters DCC RCO 2H HO + R O CHPh 2 CHPh 2 O Cleavage: - mild H3O+ - H2, Pd/C - BF3•OEt2 o-Nitrobenzyl Esters - selective removed by photolysis Orthoesters Synthesis 1974, 153 TL 1983, 24 , 5571 Chem. Soc. Rev. 1987, 75 O RCOCl O BF 3•OEt2 + R OH - Stable to base; cleaved with mild acid O R O O O O 68 PROTECTING GROUPS 69 Amines Carbamates 9-Fluorenylmethyl Carbamate (Fmoc) Acc. Chem. Res. 1987, 20 , 401 - Cleaved with mild base such as piperidine, morpholine or dicyclohexylamine NaHCO 3 H2O, dioxane + R2NH O O Cl O R2N O 2,2,2-Trichloroethyl Carbamate O O Cl 3C O R2NH, pyridine Cl 3C Cl O N R R - Cleaved with zinc dust or electrochemically. O N O CCl 3 S Te Te S TL 1986, 27 , 4687 NaBH 4 EtO2C NH EtO2C S S 2-Trimethylsilylethyl Carbamate (Teoc) - cleaved with fluoride ion. O O Me 3Si O O + O N Me 3Si R2NH O N R R O SiMe 3 OH Cl O MeO OTBS O N Cl Bu4NF, THF O CH 3 H N MeO O CH 3 (100%) H O SEt H O SEt OEt OEt SEt SEt JACS 1979, 101 7104 t-Butyl Carbamate (BOC) O O O R2NH Cleavage: tBuO O OtBu R2N OtBu - with strong protic acid (3M HCl, CF3COOH) - TMS-I O B Cl Allyl Carbamate (Alloc) O TL 1985, 26 , 1411 TL 1986, 27 , 3753 PROTECTING GROUPS O O R2NH O O O O R2N O - removed with Pd(0) and a reducing agent (Bu3SnH, Et 3SiH, HCO2H) O HN 1) Pd(OAc) 2, Et3N, Et3SiH 2) H3O + O CO 2Me Benzyl Carbanate NH 2 TL 1986, 27 , 3753 CO 2Me (Cbz) O BnO O Cl R2NH Cleavage: - R2N O Ph Hydrogenolysis PdCl 2, Et3SiH TMS-I BBr3 hν (254 nm) Na/ NH3 m-Nitrophenyl Carbamate JOC 1974, 39 , 192 NO 2 O R2N O - removed by photolysis Amides Formamides - removed with strong acid R2NH + O HCO 2Et R2N H Acetamides - removed with strong acid R2NH + O Ac2O R2N Trifluoroacetamides Cleavage: - base (K2CO3, MeOH, reflux) - NH3, MeOH R2NH Sulfonamides p-Toluenesulfonyl + O (CF3CO) 2O R2N (Ts) R2NH pTsCl, pyridine R2N CH 3 SO 2 CF 3 70 PROTECTING GROUPS Cleavage: Ts - Strong acid - sodium Naphthalide - Na(Hg) N N Na(Hg), MeOH Na2HPO 4 Ts H N N H JOC 1989, 54 , 2992 (65%) N N Ts H Trifluoromethanesulfonyl Tf Tf N N N NH Na, NH3 HN JOC 1992, 33, 5505 NH N HN Tf Tf Trimethylsilylethanesulfonamide (SES) TL 1986, 54 , 2990; JOC 1988, 53, 4143 - removed with CsF, DMF, 95°C SO 2Cl Me 3Si R2NH Et3N, DMF R2N O SiMe 3 S O tert-Butylsulfonyl (Bus) JOC 1997, 62, 8604 R-NH2 tBuSOCl, Et3N, CH2Cl2 mCPBA -orRuCl3, NaIO4 O R 2N S tBu R2N SO2tBu CF3SO3H, CH2Cl2, anisole R-NH2 71 C-C BOND FORMATION 72 Carbon- Carbon Bond Formation 1. Alkylation of enolates, enamines and hydrazones C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4) Smith: Chapt. 9 2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6) 3. Umpolung Smith: Chapt. 8.6 4. Organometallic Reagents C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2 Smith: Chapt. 8 5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op Smith Chapt. 11.12, 11.13 Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99. - α-deprotonation of a ketone, aldehyde or ester by treatment with a strong nonnucleophillic base. - carbonyl group stabilizes the resulting negative charge. O H H O- O B: H - R H H R H R H - Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater (lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3) O H 3C O H 3C CH3 pKa = 20 unfavorable enolate concentration MeO- pKa = 15 tBuO- pKa = 19 more favorable enolate concentration O CH2 OEt pKa = 10 - Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2, Na CH2S(O)CH3 Enolate Formation: - H+ Catalyzed (thermodynamic) O OH H+ - Base induced (thermodynamic or kinetic) O :B O- + B:H H Regioselective Enolate Formation Tetrahedron 1976, 32, 2979. - Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions. O - Li+ O LDA, THF, -78°C C-C BOND FORMATION typical conditions: strong hindered (non-nucleophilic) base such as LDA R2NH pKa= ~30 73 Li N Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide) O O OR' LDA, THF, -78°C N E+ R R O O- Li+ N Li OR' R OR' THF, -78°C R - Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form O - K+ O - K+ O tBuO- K+, tBuOH kinetic thermodynamic typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate formation. Enolate in small concentration (pKa of ROH= 15-18 range) - note: the kinetic and thermodynamic enolate in some cases may be the same - for α,β-unsaturated ketones O thermodynamic site kinetic site Trapping of Kinetic Enolates - enol acetates 1) NaH, DME 2) Ac2O Ph O Ph + Ph O O kinetic O isolatable separate & purify CH3Li, THF Regiochemically pure enolates O CH3Li, THF Ph Ph O- Li+ O- Li+ - silyl enolethers Synthesis 1977, 91. 1) LDA 2) Me3SiCl Ph O C-C BOND FORMATION Acc. Chem. Res. 1985, 18, 181. Ph + Ph OTMS OTMS kinetic isolatable separate & purify CH3Li, THF -orBu4NF -or- TiCl4 Ph Ph Geometrically pure enolates CH3Li, THF O- M+ O- M+ - tetraalkylammonium enolates- "naked" enolates - TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc. - Silyl enol ether formation with R 3SiCl+ Et3N gives thermodyanamic silyl enol ether - From Enones 1) MeLi 2) E+ 1) Li, NH3 2) TMS-Cl O O TMSO OSiMe3 H H E O OSiMe3 TMS-Cl, Et3N TMS-OTf Et3N O OSiMe3 Li, NH3, tBuOH TMS-Cl - From conjugate (1,4-) additions O O- Li+ O E+ (CH3)2CuLi E Trap or use directly - From reduction of α-halo carbonyls O Br Zn or Mg O- M+ Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 1° alkyl halides, allylic and benzylic halides work well 2° alkyl halides can be troublesome 3° alkyl halides don't work 74 C-C BOND FORMATION O 75 O a) LDA, THF, -78°C b) MeI Me - Rate of alkylation is increased in more polar solvents (or addition of additive) O (Me2N)3P R NMe2 R= H DMF R-CH3 DMA HMPA O O O S H 3C O CH3N CH3 CH3N NMe2 NCH3 Me2N DMSO TMEDA Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry X C 180 ° M+ -O Alkylation of 4-t-butylcyclohexanone: O O R E R equitorial anchor E H H A E tBu favored A Chair tBu R R B O O- M+ H O E tBu B Twist Boat R E on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This approach leads directly into a chair-like product. "Equitorial apprach leads to a higher energy twist-boat conformation. Alkylation of α,β-unsaturated carbonyls O- M+ R1 O R2 Kinetic R1 E O R1 H R2 E H R2 H H O- M+ R1 O R2 H E R1 R2 H Thermodynamic E C-C BOND FORMATION 76 Stork-Danheiser Enone Transposition: - overall γ-alkylation of an α,β-unsaturated ketone O O LDA PhCH2OCH2Cl HO CH3 CH3Li PhO OMe H3O PhO CH3 + PhO OMe OMe O J. Org. Chem. 1995, 60, 7837. Chiral enolates- Chiral auxilaries. D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23. Asymmetric Synthesis 1984, 3, 1. - N-Acyl oxazolidinones O O R H 2N OH Me Ph O N Me Ph norephedrine O O H 2N R OH O N valinol O O R R LDA, THF O N O O N O LiOH, H2O, THF O R OH Et-I Me Ph O O R N O Complimentary Methods for enantiospecific alkylations Me Ph major product (96:4) O O LDA, THF R N O LiOH, H2O, THF O R OH Et-I Diastereoselectivity: 92 - 98 % for most alkyl halides major product (96:4) Enolate Oxidation Chem. Rev. 1992, 92, 919. R O O O N O NaN(SiMe3)2, THF, -78°C R N N (88 - 98 % de) SO2Ph O LDA, THF R O tBuO O OH O Ph O Boc N N OtBu O O N N HN Boc O 1) HO2) CH2N2 3) TFA 4) Raney Ni (94 - 98 % de) O R OMe NH2 C-C BOND FORMATION O R Bu Bu O B N O Bu2BOTf, Et3N O O N N O N 1) LiOH 2) H2, Pd/C O O R N3 R D- amino acids O O N R KN(SiMe3)2, THF O OH NH2 Ph O O Ph Ph O O N3- Br Ph R O O NBS R R 77 O N O N3 SO2N3 Ph Ph Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969. diastereoselectivities on the order of 50 : 1 SO2Ph N O R Ar Ar N O R O SO2Ph O R N O SO2N(C6H11)2 O S O2 R H O H LDA, NBS Et2Cu•BF3 O O SO2N(C6H11)2 O H O Br O SO2N(C6H11)2 HO O SO2N(C6H11)2 Asymmetric Acetate Aldol O S O N O TIPSO H 1) Br Sn(OTf)2, CH2Cl 2, R3N, -40°C 2) TIPS-OTf, pyridine 3) NH3 O Br NH2 J. Am. Chem. Soc. 1998, 120, 591 J. Org. Chem. 1986, 51, 2391 85 %, 19:1 de Chiral lithium amide basess CH3 MeO CO2Et OMe Ph N Li THF, -78°C (CH3)2C=O CH3 OMe MeO O OMe O NH2 O (72% ee) C-C BOND FORMATION H N O Ph N H But O N Li Li N (97 % ee) THF, HMPA TMSCl tBu OTMS Ph N tBu N Me Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations OTMS O tBu-Cl, TiCl4, CH2Cl2, -40°C CH3 (79%) SPh OTMS R note: alkylation with a 3° alkyl halide C(CH3)3 O Cl SPh ACIEE1978, 17, 48 TL 1979, 1427 O Raney Ni R R (95 %) TiCl4, CH2Cl2, -40°C (78%) Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363. - Advantages: mono-alkylation, usually gives product from kinetic enolization O O N N "Thermodynamic" "Kinetic" O O N H can not become coplanar O O •• N + N R-I R H2O O E H+, (-H2O) enamine -Chiral enamines O N Imines E Isoelectronic with ketones Me O Ph N Li OMe N LDA, THF, -20°C Ph 1) E 2) H3O+ O E E = -CH3, -Et, Pr, PhCH2-, allylee 87 - 99 % 78 Hydrazones C-C BOND FORMATION isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503 O N N N Me2N-NH2 -N N LDA, THF 79 N - + H , (-H2O) N E+ N O hydrolysis E E - Hydrazone anions are more reactive than the corresponding ketone or aldehyde enolate. - Drawback: can be difficult to hydrolyze. - Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders "Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983) OMe MeO N N H 2N SAMP RAMP N LDA OMe N N NH2 O O3 OMe N H I OTBS (95 % de) TBSO TBSO N 1) LDA 2) Ts-CH3, THF -95 - -20 °C OMe 3) MeI, 2N HCl N O CH3 (100 % ee) Me O Li R1 E (C,C) MeO •• N N R2 H R1 N N R2 Z (C,N) H E E Aldol Condensation Comprehensive Organic Synthesis 1991, 2, 133, 181. O H R a) LDA, THF, -78°C b R'CHO O β-hydroxyl aldehyde (aldol) OH H R' R - The effects of the counterion on the reactivity of the enolates can be important Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers C-C BOND FORMATION - The aldol reaction is an equilibrium which can be "driven" to completion. M O- M+ O + R RCHO O H R' O work-up OH H R' 80 R' R R In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+ counterions will stabilize the intermediate β-alkoxycarbonyl and push the equillibrium towards products. (JACS 1973, 95, 3310) O O- M+ OH PhCHO, THF M= Li M= MgBr Ph 16% yield 93% yield - Dehydration of the intermediate β-alkoxy- or β-hydroxy ketone can also serve to drive the reaction to the right. O O O tBuO- Na +, tBuOH O JACS 1979, 101 , 1330 O H O H O Enolate Geometry - two possible enolate geometries O - Li+ O - Li+ O LDA, THF, -78°C H + H Z - enolate E - enolate - enolate geometry plays a major role in stereoselection. OM Z -enolate R R2 1 O R3CHO R R OM R H 1 3 erythro (syn) R2 H E -enolate OH 1 O R3CHO R OH 1 R R2 R 3 threo (anti) 2 - Zimmerman-Traxler Transition State : Ivanov condensation JACS 1957, 79 , 1920. + O - Ph H + MgBr - + PHCHCO2 MgBr Br H O Ph O Mg Ph H "pericyclic" T.S. OMgBr C-C BOND FORMATION 81 Analysis of Z-enolate stereoselectivity R2 O R3 O M R2 R2 O R3 M O R3 O M O O H H R1 H R1 H H R3 R1 H R1 OH R2 erythro (syn) favored R2 O H R2 O H R2 M O M R1 R3 O M O R3 R1 R3 R1 OH R1 H R3 H H O H O R2 threo (anti) disfavored Analysis of E-enolate stereoselectivity R3 H O R3 M R O 3 O R2 H R1 H O O M R2 H H R2 H R OH R1 R3 R2 threo (anti) favored H H O O R1 H R1 O M O M H H O M O H O 2 R1 R3 R2 R2 R3 R3 R1 O M O OH R1 R1 R3 R2 erthro (syn) disfavored Analysis of Boat Transition State for Z-Enolates R2 O R3 O O M R3 H R1 H R3 R1 H O HO O M R2 R2 R1 H Favored Chair Boat H O R2 O O O M H HO R1 H R3 R1 Disfavored Chair R3 R3 R2 staggered O R2 R1 H Boat: R1-R2 1,3-interaction is gone M C-C BOND FORMATION 82 Analysis of Boat Transition State for E-Enolates R3 H O M R3 O O O HO R1 R2 R1 H H R3 O M H R2 R1 R2 Favored Chair Boat H H O O O M O HO R3 H R1 R2 R3 O M H R2 R1 R3 staggered R1 R2 Disfavored Chair Boat: R1-R2 1,3-interaction is gone Summary of Aldol Transition State Analysis: 1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates usually give a higher degree of stereoselection than E-enolates. 2. Li+, Mg 2+, Al3+= enolates give comparable levels of diastereoselection for kinetic aldol reactions. 3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic diastereoselection. O- M+ O Path A R2 R1 R1 R3 Path B H R2 O- M+ O H R1 HO R1 Path A R2 HO R3 R2 When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent steric influence then path B proceeds. 4. The Zimmerman-Traxler like transition state model can involve either a chair or boat geometry. Noyori "Open" Transition State for non-Chelation Control Aldols Absence of a binding counterion. Typical counter ions: R4N+, K+/18-C-6, Cp2Zr2+ - Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. Z- Enolates: R1 O- R1 Favored H H R3 R2 R3 O- R1 H R3 O R2 H H R2 HO R1 Favored R1 O- O- R3 R2 Syn Aldol O H HO R3 H H R R2 3 O O O Disfavored H R3 H R2 O O R1 H O- R1 O- R1 H R2 O Disfavored R3 R2 Anti Aldol C-C BOND FORMATION 83 E- Enolate: - O - R1 - R1 O O favored H R3 R3 R2 H R3 H R1 - O H R3 O Syn Aldol R1 R1 O H R2 HO R3 H H R3 R2 R1 H O O R3 R2 R2 O favored disfavored H R1 H - O HO H H R2 O O - R1 O O disfavored R3 R2 R2 Anti Aldol NMR Stereochemical Assignment. Coupling constants (J) are a weighted average of various conformations. H O O R1 Syn Aldol JAB = 2 - 6 Hz HB R3 R2 HA 60 ° 60 ° HA H O O HB HB R3 R2 R2 O R3 OH R3 O R1 R2 R1 HA HA H R1 O HB non H-bonded O H OH B R1 Anti Aldol JAB = 1 - 10 Hz R3 R2 HA 60 ° HA H O O R3 R3 OH O R2 R2 O HB HA HB HB R1 R2 R1 60 ° HA H R1 O R3 non H-bonded Boron Enolates: Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1; Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3. - Alkali & alkaline earth metal enolates tend to be aggregates- complicates stereoselection models. - Boron enolates are monomeric and homogeneous - B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C bonds (more covalent character)- therefore tighter more organized transition state. Generation of Boron Enolates: O R2B-X iPrEtN OBR2 X= OTf, I R= Bu, 9-BBN C-C BOND FORMATION R3N: _ H R1 + BL2OTf O R2 H R3N: OBL2 Z-enolate OBEt2 _ H + BL2OTf O H R1 R2 R2 R1 R1 R2 E-enolate O OBR2 R 3B R OSiMe3 OBR2 R2B-X + Me3 Si-X O OBR'2 R' 3B N2 R Hooz Reaction R' R Diastereoselective Aldol Condensation with Boron Enolates O O OBEt2 Ph Ph Ph pure Z-enolate R2 R1 OH R3CHO R1 R3 R2 Z-enolate OBEt2 O R1 R3 R2 R2 generally > 95 : 5 syn : anti OH R3CHO R1 R 100% Syn Aldol O OBEt2 OBEt2 RCHO generally ~ 75 : 25 anti : syn E-enolate Asymmetric Aldol Condansations with Chiral AuxilariesD.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115. - Li+ enolates give poor selectivity (1:1) - Boron and tin enolates give much improved selectivity Bu Bu O Me B O N Bu2BOTf, EtNiPr2 , -78° O O - O + N O OH RCHO R O O N Me > 99:1 erythro O O 1) Bu2BOTf, EtNiPr2 , -78° Me N O 2) RCHO Ph OH R O X Me O 84 C-C BOND FORMATION L L B _ O H + O R L L B _ O O O N RCHO H R O B _ O + O R O N L L B _ O O + N L L L L O O B _ O O + + R N N O O O O preferred conformation R2 O O L H O B R3 L R3 N H L H R3 O B N L O O O O Favored O O R2 Disfavored O O OH N O R3 O OH N R2 R3 R2 Oppolzer Sultam L 2B O R2 N O R2 N S O2 S O2 O S O N O S O2 OH O R3CHO R2 R3 N S O2 R2 R3 N 1) LDA 2) Bu3SnCl R3 Sn OH O R3CHO R2 85 C-C BOND FORMATION Chiral Boron BOTf O OH StBu O Ph OH StBu iPrEt2N, PhCHO,-78°C when large, higher E-enolate selectivity O ArO2SN SPh Ph StBu 1 : 33 (> 99 % ee) Ph Ph R + O B Br NSO2Ar OH O Ph OH SPh + Ph SPh R iPrEt2N, PhCHO,-78°C O R > 95 : 5 (> 95 % ee) • In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors. Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes: proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates. OSiMe3 RCHO, TiCl4, CH2Cl2, -78°C OH OH CO2Et R OEt + CO2Et R CH3 CH3 R= iPr (anti : syn) = 100 : 0 C6H11 94 : 6 Ph 75 : 25 OSiMe3 RCHO, TiCl4, CH2Cl2, -78°C OH R OEt OH CO2Et + CO2Et R CH3 CH3 R= iPr (anti : syn) = 52 : 48 C6H11 63 : 37 Ph 67 : 33 Asymmetric Mukiayama Aldol: Ph H 3C O OSiMe3 NMe2 RCHO, TiCl4, CH2Cl2, -78°C OH R O OH Rc + R O Rc (90-94% de) syn : anti = 85 : 15 selectivity insenstivie to enolate geometry 86 C-C BOND FORMATION Ph N SO Ph 2 O O iPrCHO, TiCl4, CH2Cl2, -78°C HO 96 % de anti : syn = 93 : 7 Rc OSitBuMe2 CH3 O RCHO, TiCl4, CH2Cl2, -78°C O 87 HO + Syn product Rc CH3 OSitBuMe2 SO2N(C6H11)2 E-Enolate R= Ph % de= 90 nPr 85 iPr 85 anti : syn = 91 : 19 94 : 6 98 : 2 Z-Enolate R= iPr % de= 87 anti : syn = 97 : 7 Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals: OSiMe3 OH O TiCl4 or SnCl4 Mukaiyama-Johnson Aldol R RCHO or RCH(OR')2 CH2Cl2, -78°C via Ti or Sn enolate O O TiCl4, CHCl2, -78 °C O O O HO O O O OTMS + Cl4Ti O+ O Cl4Ti O O OSiMe3 OTMS Ph TiCl4, (CH3)2C(OEt)2 (78 %) O OEt Ph Fluoride promoted alkylation of silyl enol ethers Acc. Chem. Res. 1985, 18, 181 O OSiMe3 nBu4NF, THF, MeI C-C BOND FORMATION 88 Meyer's Oxazolines: O (ipc)2BOtf iPrEt2N, Et2O N 1) RCHO 2) 3N H2SO4 3) CH2N2 O H 3C CO2Me OH (ipc)2B Ester equiv. R + CO2Me (~ 30%) N H 3C R OH R= nPr %ee (anti) = 77 anti : syn = 91 : 9 C6H11 84 95 : 5 tBu 79 94 : 6 Anti-Aldols by Indirect Methods: SePh O PhSe C6H11 1) (C5H7)2BOTf R3N 1) TBS-Cl 2) DiBAl-H 3) NaIO4 4) CH2N2 O CO2Me HO CH3 O3 R R HO Anti Aldol Product CHO OTBS CO2Me OTBS O 1) LDA, THF, -78 °C 2) RCHO N OH 1) HIO6 2) CH2N2 O N MeO2C R CH3 R CH3 Anti Aldol O MOMO O O MeO O MOMO 1) LDA, THF, -78 °C N O R syn aldol CH3 3) TsCl 4) Ba(CN)BH3 C6H11 HO chiral auxillary CO2Me R R 2) RCHO OTBS 1) HF 2) [O] OTBS N N KBEt3H, Et2O, -78 °C O MeO CH3 CH3 CH3 syn : anti 1 : 99 OMOM CH3 OMOM 2) RCOCl HO O MOMO Zn(BH4)2 HO N CH3 syn : anti 97 : 3 CH3 OMOM Syn Aldols by Indirect Methods: O O O N O 1) LDA, THF, -78 °C O O O Zn(BH4)2 O 2) RCOCl O N R CH3 O OH N R CH3 syn : anti = 100 : 1 C-C BOND FORMATION Aldol Strategy to Erythromycin: O 9 10 8 11 OH 12 13 O 1 O 3 2 1 6 OH 4 Erythromycin seco acid CO2H 5 15 14 4 7 OH OH O OH OH 3 OH 2 [O] [O] syn aldol Erythromycin aglycone 3 CHO CO2H OH O syn aldol OH syn aldol 4 + CHO OH 1 CHO CHO O + CO2H OH syn aldol CHO 2 + CHO O 1 HO2C O O O O LDA, CH3CH 2COCl N O O OH OH O OH 3 5 9 11 13 O O O TiCl4, iPr 2EtN, CH2Cl2 O N 1 83%, (96:4) O N 90% (> 99:1) O O 1) 9-BBN, THF 2) Swern oxid. 3 5 73% (85:15) O O O 5 O O Ph O CHO N Ph Ph O 1) Zn(BH3)2 2) (H3C)2C(OMe)2 CSA OH CHO Ph O N O (100%) Ph O OH O O O Sn(OTf)2, Et3N, CH2Cl2 O N CH3CH 2CHO O O OH N 9 11 13 1) Na BH(OAc)3 2) TBS-OTf, 2,6-lutidine 3) AlMe3, (MeO)MeNH•HCl MeO 72% (>99:1) 84% (> 96:4) Ph O OH OTBS 11 13 EtMgBr 86% 8 Ph 1) PMBC(NH)CCl3 TfOH 2) (PhMe2Si)2NLi, TMS-Cl 48 % PMBO TMSO OTBS O N CH3 OH OTBS 89 C-C BOND FORMATION X L H3C H Sn H O L O X O O O X H O O O N O 3 H3C CH3 O CHO 7 O R H H anti-syn + O O 13 1) Zn(BH3)2 2) DDQ O O OH O N OTBS O O O OH PMBO O 3 5 7 9 13 70% O O O p-MeOC 6H4 O OTBS 1) LiOOH 2) TBAF O N O O O O OH Cl3C6H2COCl iPr2EtN, DMAP HO 63% Ph 11 OTBS 1) NaH, CS2, MeI 2) nBu3SnH, AIBN N Ph p-MeOC 6H4 O O Ph O 95% O O L 83% (95:5) p-MeOC 6H4 O L Ti O J. Am. Chem. Soc. 1990,112, 866 L H3C CH3 BF3•OEt2, CH 2Cl2, -78 °C OTBS 11 Ph O H CH3 CH3 X CH3 CH3 8 O Disfavored O H3C H OH X PMBO TMSO 5 O Disfavored O O L CH3 H anti-syn H L CH3 Sn H O O L O Ti CH3 CH3 H CH3 CH3 X L R H O L OH 13 p-MeOC 6H4 (86% O 9 O 9 10 1) Pd(OH)2, iPrOH 2) PCC 3) 1M HCl, THF 8 11 7 O 12 O 58 % 13 O 4 1 O OH 5 6 5 13 11 OH 1 3 O 3 2 O OH O Michael Addition - 1,4-addition of an enolate to an α,β-unsaturated carbonyl to give 1,5-dicarbonyl compounds - O + O O O M Ph R Ph R Organometallic Reagents Grignard reagents: O R-Br Mg(0) OH R-MgBr R THF O O OH R-MgBr THF R often a mixture of 1,2- and 1,4-addition + R 90 C-C BOND FORMATION 91 O OH R-MgBr O R-MgBr 1,2-addition R THF, CeCl3 O 1,4-addition CuI,THF, -78C R Organolithium reagents - usually gives 1,2-addition products - alkyllithium are prepared from lithium metal and the corresponding alkyl halide vinyl or aryl- lithium are prepared by metal-halogen exchange from the corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or tbutyllithium. Li(0) R-Br R-Li Et2 O X Li nBu-Li X= Br, I, Bu3Sn Et2 O Organocuprates Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1. - selective 1,4-addition to α,β-unsaturated carbonyls CuI, THF 2 R-Li R2CuLi O O R2CuLi R - curprate "wastes" one R group- use non transferable ligand _ MeO MeO Cu Li+ Cu R R-Li non-transferable ligand Other non transferable ligands _ _ + Bu3P Cu R Li Me2S Cu R Li+ _ _ NC Cu R Li + F3B Cu R Li+ 22Li Cu R S Mixed Higher Order Cuprate B. Lipshutz Tetrahedron 1984, 40 , 5005 Synthesis 1987, 325. + CN Addition to Acetals O R CH3 n-C6 H13 (n-C6H13)2CuLi H3C O Tetrahedron Asymmtetry 1990, 1, 477. O BF3•OEt 2 R 1) PCC 2 NaOEt OH LA O O H CH3 O O R CH3 Nu: H CH3 OH Chiral axulliary is destroyed 99 % ee LA R n-C6 H13 O H R O Nu TL 1984, 25, 3087 C-C BOND FORMATION 92 TMS O 1) TiCl4 O 2) [O] 3) TsOH JACS 1984, 106, 7588 OH 98 % ee Stereoselective Addition to Aldehydes - Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes may be stereoselective. - Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828. empirical rule O R 1 * OH - M S 1) "R2 - " 2) "H + " R1 R M S 2 L L O OH M S M R2 L R1 - R S 1 L R 2 - Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61. based on ab initio calculations of preferred geometry of aldehyde which considers the trajectory of the in coming nucleophile (Dunitz-Burgi trajectory). O L R2 R S vs. M R2 - L - S 1 O M better R 1 worse - Chelation Control Model- "Anti-Cram" selectivity - When L is a group capable of chelating a counterion such as alkoxide groups + M OH O R OR' R1 * S M 2 R 1 OR' "Anti-Cram" Selectivity M S M+ O OR' HO R2 M R 1 - M S OR' R2 R1 S Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239. i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic) O R Benzoin Condensation O- KCN PhCHO Ph H CN usually - R O + Comprehensive Organic Synthesis 1991, 1, 541. OH Ph - CN Cyanohydrin anion PhCHO HO Ph OCN Ph -O Ph CN O OH Ph Ph OH Ph Benzoin C-C BOND FORMATION 93 Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions H NH2 NH2 _ + N N N H 3C + S N N S OPO3PO3 H 3C H 3C N OPO3PO3 H 3C Thiamin pyrophosphate CHO H H 2C OH H + H OH H 2C OPO3 thiamin-PP O HO OH H 2C OH H 2C + OPO3 OPO3 glyceraldehyde-3-P (C3 aldose) D-ribulose-5-P (C5 ketose) D-ribose-5-P (C5 aldose) H OH H OH CHO O OH H H 2C OH H H OH H OH H OH H 2C OPO3 sedohepulose-7-P (C7 ketose) Trimethylsilycyanohydrins O R TMSO TMS-CN CN R H LDA, THF TMSO H CN acyl anion equivalent _ R O NC OMs OEE NaHMDS, THF, -60°C CSA, tBuOH CN O Tetrahedron Lett. 1997, 38, 7471 (72%) OEE O O O O O Dithianes B:, THF S S S R H R O Hg(II) R'-I S - S S R R' R R' Aldehyde Hydrazones B: H N R N tBu R H Heteroatom Stabilized Anions Sulfones R LDA, THF S O H O R E E (Dithiane anion is an example) O _ Ph tBu N E+ N Ph R S O O R' R' OH R' Al(Hg) R' R' OH R' Ph R O S O R O Sulfoxides O R' _ Ph R S O LDA, THF Ph R S O R' R' OH Raney Ni R' Ph R R' R' S O R OH C-C BOND FORMATION Epoxide Opening 94 Asymmetric Synthesis 1984, 5, 216. Basic (SN2) Condition Nu: R R Nu Steric Approach Control O HO Acid (SN1-like) Condition R R Nu: attachs site that best stabilizes a carbocation OH O+ Nu Nu H OH O OH BnO OH BnO + OH BnO TL 1983, 24, 1377 OH Me2CuLi AlMe3 O 6:1 1:5 OH Me3Al JACS 1981, 103, 7520 S S OH S _ O JOC 1974, 3645 S O S Ph + S _ S O OH Ph (69 %) 1) TBS-Cl 2) MeI, CaCO 3, H+ S OH Tetrahedron Lett. 1992, 33, 931 Ph Cyclic Sulfites and Sulfates (epoxide equivalents) Synthesis 1992, 1035. O OH R2 R1 SOCl2, Et3N O S O R1 OH O RuCl3, NaIO4 O S O O R1 Nu: R2 O R1 R2 R2 sulfate sulfite O O O S - O S O H H2O R2 Nu R1 HO H R2 Nu R1 H2O O O O S O R1 O R2 Nu: O S O R1 OH R2 Nu H Nu: Nu2 R1 H R Nu1 2 C-C BOND FORMATION CO2Me O SO2 O 2) TBS-Cl CH3 OBn MeO OMe O SO2 carpenter Bee pheromone O CO2Me O OMe OBn OMe H N H3C OMe NCH3 OMe 1) Ac2O 2) HCl ∆ O OH MeO OBn R2 1) H2, Rh 2) HF OTBS 1) (CH3)2CuLi CO2Me R1 NaH O O SO2 CO2Me CO2Me R2 R1 MeO2C MeO meso OBn OBn HO OBn OMe MeO OMe MeO NCH3 BnO NCH3 BnO OAc Irreversible Payne Rearrangement OH O OH O O SO2 OH Bu 4NF OTBS O O Payne Rearrangement of 2,3-epoxyalcohols Sigmatropic Rearrangements Nomenclature: σ bond that breaks Asymmetric Synthesis 1984, 3, 503. 1 2 3 R 1 3 R 2 ∆ 1 2 3 R 1 R R H σ bond that breaks σ bond that forms [3,3]-rearrangement 3 4 1 3 2 3 2 Aldrichimica Acta 1983, 16, 60 2 ∆ 5 4 1 R H 1 1 [1,5]-Hydogen migration 5 σ bond that forms 3,3-sigmatropic Rearrangements Cope Rearrangemets- requires high temperatures R ∆ R Organic Reaction 1975, 22, 1 95 C-C BOND FORMATION 96 Chair transition state: CH3 CH3 Z 220 °C H 3C H H 3C E H E,Z (99.7 %) Z,Z (0 %) E,E (0.3 %) CH3 H HH H 3C H 3C CH3 H CH3 Z E H 3C H 3C E E,Z (0 %) H 3C Z Z,Z (10 %) E,E (90 %) "Chirality Transfer" H Ph R S CH3 E Ph CH3 CH3 (87 %) Diastereomers Ph Ph H 3C H 3C Z CH3 R (13 %) H R E Ph R CH3 R H E Z CH3 Ph CH3 Diastereomers Ph Ph H 3C H 3C R Z Z H S CH3 - anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43, 93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971. C-C BOND FORMATION O OMe OH 97 KH, DME, 110°C OMe KH OH O O- Ring expansion to medium sized rings OH O KH, ∆ 9-membered ring Claisen Rearrangements - allyl vinyl ether to an γ,δ-unsaturated carbonyl Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis 1991, 5, 827. ∆ O O O OH CHO O 220 °C Hg(OAc)2 JACS 1979, 101 , 1330 O O O H H H O O O Chair Transition State for Claisen E-olefin R O O R H X X X=H X= OEt, NMe2, etc R O 1,3-diaxial interaction X R E/Z = 90 : 10 E/Z = > 99 : 1 Z-olefin R X X H O O new stereogenic centers R old stereogenic center O O H X R X C-C BOND FORMATION 98 - Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over non-enzymatic reaction CO2H O CO2H HO2C Chorismate mutase J. Knowles JACS 1987, 109, 5008, 5013 O CO2H OH OH Chorismate Prephenate - Claisen rearrangement usually proceed by a chair-like T.S. HO2C H HO2C O H CO2H H H O Chair T.S OH OH Opposite stereochemistry H H O CO2H CO2H CO2H H Boat T.S H OH O CO2H OH OH OH OH + O J. Org. Chem. 1976, 41, 3497, 3512 J. Org. Chem. 1978, 43, 3435 O + O R R O H H O s CH3 R O R H CH3 H s CH3 O H CH3 CH3 OH CH3 OH O CH3 H CH3 CO2R CH3 OH CH3 OH Tocopherol 94 - 99 % ee hydrophobically accelerated Claisen - JOC 1989, 54, 5849 C-C BOND FORMATION Johnson ortho-ester Claisen: EtO OEt OH OEt O H3C-C(OEt)3 ∆ OEt [3.3] O O - EtOH H+ Ireland ester-enolate Claisen. Aldrichimica Acta 1993, 26, 17. OTMS O LDA, THF TMS-Cl O OH [3.3] O O O LDA, THF TMS-Cl OBn O Me CO2H Me Me Me JOC 1983, 48, 5221 OBn Eschenmoser NMe2 R OH EtO OEt ∆ O O NMe2 NMe2 BF3 R R "Chirality Transfer" R R N O N R Ph N O aldehyde oxidation state O Ph Ph (86 - 96 % de) R= Et, Bn, iPr, tBu [2,3]-Sigmatropic Rearrangement H Z Comprehensive Organic Synthesis 1991, 6, 873. H H :X Y X Y: R R R H X Y: R R1 R H -Wittig Rearrangement :X Y Organic Reactions 1995, 46, 105 _ base O O SnR3 BuLi :X Y R R1 X Y: E HO _ O Synthesis 1991, 594. 99 C-C BOND FORMATION TBDPSO TBDPSO KH, 18-C-6, Me3SnCH2I TBDPSO nBuLi H MeO H O MeO H O MeO OH O O O SnMe3 TBDPSO + O H MeO H3C O OH (58%) (42%) CH3 Ph _ O CH3 H3C CH3 CH3 H (87 %) OH Ph H _ O CH3 Ph H3C Sulfoxide Rearrangement R J. Am. Chem. Soc. 1997, 119, 10935 Li TBDPSO H MeO 100 R S - O S (13 %) OH Ph (MeO) 3P HO O O O CO2Et CO2Et (MeO) 3P Ph S HO O- Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23, 876; ; Chem. Rev. 1992, 28, 1021. H H - Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl) R R H O H O H OH CHO JOC 1992, 57, 2766 Et2AlCl CH2Cl2 -78°C Ph O O O Ph O O H OH SnCl4 Ph O SnCl4 99.8 % de O OH + syn isomer H3C (94 : 6) C-C BOND FORMATION O TiCl2 O OH O H CO2Me CO2Me PhS + H OH OH O R Tetrahedron Lett. 1997, 38, 6513 (97% ee) + + PhS CO2Me CO2Me R syn (90 % ee) Angew. Chem. Int. Ed. Engl. 1989, 28, 38 CH3 CH3 C6H13 CH3 CO2Me R (9 : 1) anti (99 % ee) - Metallo-ene Reaction PhS C6H13 H2O C6H13 (10 %) H 3C ClMg Cl C6H13 MgCl H 3C C6H13 H2O H 3C ClMg H 3C (> 1%) intramolecular BrMg + (11 : 1) + MgBr BrMg 1) CH3 1) Mg(0), Et2 ) 2) 60 °C Li CHO 2) SOCl2 MgCl MgCl Cl CH3 O CH3 OH Cl SOCl2 CH3 CH3 MgCl O2 H 1) PCC 2) MeLi 3) O3 CH3 CHO 4) KOH 5) H2 6) Ph3 P=CH2 MgCl H3C H H O 1) Mg(0), Et2 ) 2) 60 °C Capnellene H OH 101 C-C BOND FORMATION Synthesis of Phyllanthocin O A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269. O O (Me3Si)2 NLi O N Ph O O 1) LAH 2) BnBr N Br Ph CH3 CH3 BnO 1) O3 2) H2, Lindlar's BnO MeAlCl CHO BnO 1) MEM-Cl 2) O3 H BnO BnO CH3 O H OH CHO OMEM O 1) 2) - O O 2) H O MEMO 3) Swern O 1) DBU 2) H2, Pd/C O 3) RuO4 O O O O (CH3 )2S(O)CH 2- CH O 3 O BnO O O O 1) LDA, TMSCl 2) BnMe3 NF, MeI O O HO2C O BnO O O BnO O + O H3O + O 1) ZnCl2 BnO CH3 O CH3 MeO2C O O O Ph Phyllanthocin 102 C=C BOND FORMATION C=C Bond Formation 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 11. 103 C&S Chapt. 2 # 5,6,8,9,12 Aldol Condensation Wittig Reaction (Smith, Ch. 8.8.A) Peterson Olefination Julia-Lythgoe Olefination Carbonyl Coupling Reactions (McMurry Reaction) (Smith Ch. 13.7.F) Tebbe Reagent Shapiro and Related Reaction β−Elimination and Dehydration From Diols and Epoxides From Acetylenes From Other Alkenes-Transition Metal Catalyzed Cross-Coupling and Olefin Metathesis Aldol Condensation -Aldol condensation initially give β-hydroxy ketones which under certain conditions readily eliminated to give α,β-unsaturated carbonyls. OMe OMe LDA, THF, -78°C O O OMe OR O O O Tetrahedron 1984, 40, 4741 CHO -78C → RT OMe OR O Robinson Annulation : Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-1one JOC 1984, 49 , 3685 Synthesis 1976, 777. O O O O O L-proline Weiland-Mischeler Ketone (chiral starting material) Mannich Reaction - α,β-unsaturated carbonyls (α-methylene carbonyls) O H2C=O, Me2NH•HCl Me H 2C N + Me O Cl- Mannich Reaction C=C BOND FORMATION 104 Wittig Reaction review: Chem. Rev. 1989, 89, 863. mechanism and stereochemistry: Topic in Stereochemistry 1994, 21, 1 - reaction of phosphonium ylide with aldehydes, ketones and lactols to give olefins R X Ph3P R X O R1 strong base + PPh3 R - + PPh3 R Ph3P O PPh3 phosphorane ylide + Ph3P O - R2 _ - Ph3P=O R2 R R R1 2 R R R1 2 R R1 oxaphosphetane betaine - Olefin Geometry O L S Z- olefin Ph3P L S O L S E- Olefin Ph3P S L - With "non-stabilized" ylides the Wittig Reaction gives predominantly Z-olefins. Seebach et al JACS - O O O L S L S S L L S O + PPh3 S - Ph3P=O L L S S S S S L L Z-olefins - "Stabilized ylides" give predominantly E-olefins O + Ph3P L O PPh3 Ph3P L S S PPh3 + + PPh3 L L _ L CO2Me S S L CO2Me C=C BOND FORMATION 105 - Betaine formation is reversible and the reaction becomes under thermodynamic control to give the most stable product. - There is NO evidence for a betaine intermediate. - Vedejs Model: R O H R Ph Ph P Pukered (cis) oxaphosphetane (kinetically favored) Cis H Ph H R Ph Ph P R H Planar (trans) oxaphosphetane (thermodynamically favored) Trans O Ph Phosphonate Modification (Horner-Wadsworth-Emmons) (EtO)3P R X Arbazov Reaction R _ R P(OEt)2 P(OEt)2 O O - R is usually restricted to EWG such as CO2H, CO2Me, CN, SO2Ph etc. and the olefin geometry is usually E. - Still Modification TL 1983, 24, 4405. (CF3CH2O)2P CO2Me O - CF3CH2O- groups make the betaine less stable, giving more Z-olefin. O CHO Me3Si (CF3CH2O)2P - CO2Me Me3Si + CO2Me (Me3Si)2N K , THF, 18-C-6 Peterson Olefination JACS 1988, 110, 2248 Z:E = 25:1 review: Synthesis 1984, 384 Organic Reactions 1990, 38 1. - O O Me3Si CO2Me LDA, THF Me3Si _ CO2Me R1 R2 R1 Me3Si MeO2C Silicon can stabilize an α- negative charge O R1 R2 Me3Si MeO2C - Me3Si-O R1 R2 H usually a mixture of E and Z olefins CO2Me R2 H C=C BOND FORMATION Julia-Lythgoe Olefination 106 TL 1973, 4833 Tetrahedron 1987, 43, 1027 OH SO2Ph LDA, THF, -78°C OTBS 1) MsCl, Et N OTBS 2) Na(Hg),3MeOH TL 1991, 32, 495 mixture of olefins CHO TBSO R PhO2S R R Tetrahedron Lett. 1993, 34, 7479 O O H O O 1) tBuLi, THF, HMPA, -78°C 2) Na(Hg) NaHPO4 THF, MeOH, -40°C OBz OSitBuPh2 HO O OSitBuPh2 HO O HO O O O OH OH OH Milbemycin α1 OR OTBDPS O SmI2, HMPA/THF O R= H, Ac O SO2Ph O O OBz + PhO2S O O OTBDPS Synlett 1994, 859 75 % yield E:Z = 3 : 1 Ramberg-Backlund Rearrangement Br OSiPh2tBu 1) Na2S•Al2O3 2) mCPBA OSiPh2tBu O OSiPh2tBu S SOCl2 OSiPh2tBu O Br Cl O OR S MeLi, THF OR O O OR S - SO2 OR OR O thiiarane dioxide OR JACS 1992, 114, 7360 Carbonyl Coupling Reactions (McMurry Reaction) Reviews: Chem. Rev. 1989, 89, 1513. - reductive coupling of carbonyls with low valent transition metals, Ti(0) or Ti(II), to give olefins O "low-valent Ti" R1 R2 R1 R1 R2 R2 + R1 R2 R2 R1 usually a mixture of E and Z olefins excellent method for the preparation of strained (highly substituted) olefins - Intramolecular coupling gives cyclic olefins C=C BOND FORMATION 107 CHO "low-valent Ti" JACS 1984, 106, 723 CHO OMe OMe TiCl4, Zn, pyridine (86 %) OMe OHC Tetrahedron Lett. 1993, 34, 7005 OMe OH OH O Tebbe Reagent Cp2Ti(CH2)ClAlMe2 - methylenation of ketones and lactones. The later gives cyclic enol ethers. H2 C Ti AlMe2 Cp Cl Cp O O O 200 °C O - Cp2TiMe2 will also do the methylenation chemistry JACS 1990, 112, 6393. Shapiro and Related Reactions Organic Reactions 1990, 39, 1 : 1976, 23, 405 - Reaction of a tosylhydrazone with a strong base to give an olefin. NNHTs Et N 2 eq. nBuLi _ N Et N N Ts Et Et - N2 _ THF Me _ Me Me E _ E+ Me Et Me Bamford-Stevens Reaction- initial conversion of a tosylhydrazone to a diazo intermediate H H R1 R2 R3 H R1 R2 base R1 R2 R3 NNHTs N N _ R3 +N _ N Ts a: aprotic- decomposition of the diazo intermediate under aprotic conditions gives and olefin through a carbene intermediate. H R1 R2 R3 H - N2 R1 R2 +N _ N R1 R3 •• R3 R2 Carbene b. protic- decomposition of the diazo intermediate under protic conditions an olefin through a carbonium ion intermediate. H R1 R2 H R3 +N _ N H+ R1 R2 R3 + N N H - N2 H R1 R2 R3 + H -H R1 + R2 R3 C=C BOND FORMATION 108 β- Eliminations Anti Eliminations - elimination of HX from vicinal saturated carbon centers to give a olefin, usually base promoted. - base promoted E2- type elimination proceeds through an anti-periplanar transition state. B: H R1 R3 R2 R4 R1 R2 R3 R4 X - typical bases: NaOMe, tBuOK, DBU, DBN, DABCO, etc. N N N N N N DBN DBU DABCO - X: -Br, -I, -Cl, -OR, epoxides O O O B: OH R R O R N AlEt2 R' OH R - or TMS-OTf, DBU "unactivated" BCSJ 1979, 52, 1705 JACS 1979, 101, 2738 R' Syn Elimination - often an intramolecular process H R1 R2 R1 R2 X R3 R4 R3 O X= R4 O Se S Ph Ph Cope Elimination- elimination of R2NOH from an amine oxide OLI O + Me2N=CH2 I - O NMe2 THF, -78°C ON Me2 mCPBA THF O O 1) Me2CuLi + 2) Me2N=CH2 CF3CO2- NMe2 JACS 1977, 99 , 944 Tetrahedron 1977, 35 , 613 O - Me2NOH C=C BOND FORMATION Selenoxide Elimination 109 Organic Reactions 1993, 44, 1. O N SePh R' R R Bu3P: O R' R - or NO2 OH mCPBA R' H SeAr - ArSeOH R' R JACS 1979, 101, 3704 Se O SeAr SeCN H 3C H3CHN O H 3C N H 3C PhSeO2H, PhH, 60 °C O N H3CHN (82%) Ph O H 3C O O JOC 1995, 60, 7224 JCS P1 1985, 1865 N N Ph O Dehydration of Alcohols - alcohols can be dehydrated with protic acid to give olefins via an E 1 mechanism. - other reactions dehydrate alcohols under milder conditions by first converting them into a better leaving group, i.e. POCl3/ pyridine, P2O5 Martin sulfurane; Ph2S[OCPh(CF3)2]2 JACS, 1972, 94, 4997 dehydration occurs under very mild, neutral conditions, usually gives the most stable olefin OH MSDA, CH2Cl2 BzO JACS 1989, 111 , 278 BzO H H Burgess Reagent (inner salt) JOC, 1973, 38, 26 occurs vis a syn elimination _ + MeO2CNSO2NEt3 H R1 R2 _ + MeO2CNSO2NEt3 R3 R4 MeO2C - N SO2 H O PhH, reflux OH Olefins from Vicinal Diols Corey-Winter Reaction R1 R2 R4 R3 R1 R4 R2 R3 JACS 1963, 85, 2677; TL 1982, 1979; TL 1978, 737 S OH R' Im2C=S O O R R3P: R OH R R' R' C=C BOND FORMATION 110 - vic-diols can be converted to olefins with K2WCl6 JCSCC 1972, 370; JACS 1972, 94, 6538 - This reaction worked best with more highly substituted diols and give predominantly syn elimination. - Low valent titanium; McMurry carbonyl coupling is believed to go through the vic-diol. vic-diols are smoothly converted to the corresponding olefins under these conditions. JOC 1976, 41 , 896 Olefins from Epoxides Ph2P - O R1 H HO H H R2 R2 HO H MeI H PPh2 R1 R2 H PPh2Me + R1 + PPh2Me HO R2 - NC-Se - O H H R1 R2 NCO H R1 H R1 R2 H H "inversion " of R groups H R1 R1 -Ph2MeP=O R2 - H SeCN OR 2 R1 R1 - NCOR 2 H H R1 R2 H H R2 H Se Se - NCSe O H Se R1 H H R2 H "retention" of R groups From Acetylenes - Hydrogenation with Lindlar's catalyst gives cis-olefins R R' Co2(CO)8 R H2, Rh R' R Co2(CO)6 R' Bu3SnH Tetrahedron Lett. 1998, 39, 2609 H SnBu3 R R' From Other Olefins Sigmatropic Rearrangements - transposition of double bonds Birch Reduction Tetrahedron 1989, 45, 1579 OMe OMe H3O+ O H C=C BOND FORMATION 111 Olefin Isomerization- a variety of transition metal (RhCl3•H2O) catalyst will isomerize doubles bonds to more thermodynamically favorable configurations (i.e. more substituted, trans, conjugated) RhCl3•3H2O JOC 1987, 52 , 2875 EtOH OH OH Cl Cl Ti JACS 1992 114 , 2276 + up to 80% ee Olefin Inversion Tetrahedron 1980, 557 - Conversion of cis to trans olefins - Conversion of trans to cis- olefins R R' R hν, PhSSPh R' OH OH I2, CH2Cl2 CO2Me HO C5H11 OH CO2Me C5H11 OH OH JACS, 1984, 107, xxxx Transition Metal Catralyzed Cross-Coupling Reactions Coupling of Vinyl Phosphonates and Triflates to Organometallic Reagents - vinyl phosphates review: Synthesis 1992, 333. O OP(OEt)2 Li, NH3, tBuOH R2CuLi R R O O O R2CuLi (EtO)2PCl - preparation of enol triflates Synthesis 1997, 735 O OTf LDA, THF, -78°C kinetic product Tf2NPh O R OP(OEt)2 O Tf2O, CH2Cl2 tBu N tBu OTf thermodynamic product C=C BOND FORMATION - reaction with cuprates. 112 Acc. Chem. Res. 1988, 25, 47 OTf Ph TL 1980, 21 , 4313 Ph2 CuLi tBu tBu - palladium (0) catlyzed cross-coupling of vinyl or aryl halides or triflates with organostannanes (Stille Reaction) Angew. Chem. Int. Ed. Engl. 1986, 25, 508.; Organic Reactions 1997, 50, 1-652 SnMe3 O O 1)LDA, Tf2NPh 2) Pd(PPh3)4 O JOC 1986, 51 , 3405 O O OH OTBS Bu3Sn I I Bu Sn 3 O O O OH J. Am. Chem. Soc. 1998, 120, 3935 OH HO TBSO Bu3Sn HO TBSO (-)-Macrolactin A I BOMe TESO CHO 1) 2 MgBr TESO O3, NaBH4 TESO 3) TBSCl, imidazole (76%) CHO 1) Dess-Martin Periodinane 2) Ph3P+CH2I, INaHMDS (38%) TBSO I TESO CO2H SnBu3 (42%) OH TBSO 3) DIBAL (50%) Bu3SnCHBr2, CrCl2 PdCl2(MeCN)2 (65%) TESO Bu3SnH, AIBN OH I OH TBSO TESO OTES I TBSO PdCl2(MeCN)2 TESO OH b) I2 (83% OPiv Bu3Sn 1) HF, MeCN 2) Me4NBH(OAc)3 OH a) nBu3SnH, (Ph3P)2PdCl2 OTES (77%) OPiv TBSO 3) Dess-Martin Periodinane (70%) 2) TESOTf, 2,6-lutidine (52%) TESO 1) O3, Me 2S 2) allyl bromide, Zn I Bu3Sn CO2H TESO CO2H C=C BOND FORMATION 113 I TESO OH + Bu3Sn Ph3P, DEAD TESO CO2H (50%) TESO TESO Bu3Sn OH I O 1) Pd2(dba)3 iPr2NEt 2) TBAF O O HO (35%) TESO O HO TESO (-)-Macrolactin A palladium (0) catalyzed carbonylations- coupling of a vinyl triflate with a organostanane to give α,b-unsaturated ketones. O OTf Ph Me3SnPh Pd(0), CO But JACS 1994, 106 , 7500 tBu Nickel (II) Catalyzed Cross-Coupling with Grignard Reagents (Kumada Reaction): Pure Appl. Chem. 1980, 52, 669 Bull Chem. Soc. Jpn. 1976, 49, 1958 R-MgBr (dppp)NiCl2 X R R= alkyl, vinyl or aryl Aryl or vinyl halide or triflate Br AcO OMe Br Ni 1) N H OAc HO Ni R1 N H OH (±)-Neocarazostatin B Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446. + olefin metathesis R2 catalyst catalyst (CH 2)n R1 R2 Ring-Opening Metathesis Polymerization (ROMP) (CH 2)n catalyst (CH 2)n Tetrahedron Lett. 1998, 39, 2537, 2947, (2 equiv), 65 °C 2) LiAlH4 , Et2 O (72%) Olefin Metathesis OMe Br (CH 2)n n Ring-Closing Metathesis (RCM) C=C BOND FORMATION Metathesis Catalysts: iPr H3C F3C F3C iPr (C6H11)3P Cl N Ru O Mo O F3C F3C Ph Ph Ph Cl (C6H11)3P (C6H11)3P Cl Ru Cl (C6H11)3P CH3 Schrock' s Catalyst Grubbs' Catalyst Mechanism: + R1 R2 [M] R1 [M] R1 [M] R1 R2 R2 + [M] Ph 114 C≡C BOND FORMATION 115 C≡C Bond Formation 1. 2. 3. 4. 5. 6. From other acetylenes From carbonyls From olefins From Strained Rings Eschenmosher Fragmentation Allenes From Other Acetylenes - The proton of terminal acetylenes is acidic (pKa= 25), thus they can be deprotonated to give acetylide anions which can undergo substitution reactions with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes. R R1-X R _ R H R1 O R2 OH R3 R R R2 3 M+ O Et2AlCl OH R - Since the acetylenic proton is acidic, it often needs to be protected as a trialkylsilyl derivative. It is conveniently deprotected with fluoride ion. R H F- B:, R3SiCl R SiR3 R H Acetylide anions and organoboranes R1 _ Li+ R3B _ R1 BR3 Li+ I2 R1 R JOC 1974, 39 , 731 JACS, 1973, 95 , 3080 Palladium Coupling Reactions: O O O Cl iPr3Si SnBu3 O JACS 1990, 112, 1607 Cl (Ph3P)4Pd iPr3Si SiiPr3 C≡C BOND FORMATION 116 OTBS OTBS CO2Me Br CO2Me C5H11 OTBS OTBS OTBS Pd(Ph3P)4, CuI iPr2NH, PhH TBSO JACS 1985, 107, 7515 C5H11 OH HO CO2H OH Copper Coupling- 1,3-diynes + R1 Cu(OAc)2 R2 R1 Adv. Org. Chem. 1963,4 , 63 R1 Nicholas Reaction - acetylenes as their Co2(CO)8 complex can stabilize an α-positive charge, which can subsequently be trapped with nucleophiles. OR4 R1 (CO)6Co2 Co2(CO)8 OR4 R1 R2 (CO)6Co2 R1 R2 (CO)6Co2 Nu: R1 oxidative decomplexation Nu Nu R1 R2 R3 R2 R3 N CO2Me R R3 2 R3 R3 N Tf2O, CH2Cl2, MeNO2, -10°C + CO2Me N I2 CO2Me JCSCC 1991, 544 O TBSO tBu HO N tBu O (OC)6Co2 Co2(CO)6 Co2(CO)6-acetylene deocomplexation: JOC 1997, 62, 9380 From Aldehydes and Ketones R'-X RCHO P3P, CBr4 Br R Br 2 eq. nBuLi R _ Li+ ClCO2Et R R' R CO2Et R H H2O C≡C BOND FORMATION Br2C OHC OSitBuPh2 OHC OSitBuPh2 OSitBuPh2 CBr4, Ph3P OSitBuPh2 Br2C a) nBuLi, THF, -78°C b) ClCO2Me MeO2C 117 OSitBuPh2 OSitBuPh2 MeO2C JACS 1992, 114 , 7360 - by conversion of ketones to gem-dihalides followed by elimination O PCl5 R' R Cl Cl R Cl tBuOK R' - HCl R' R tBuOK R - HCl R' - by conversion of ketones to enol phosphates followed by elimination LDA, (EtO)2P(O)Cl O O R' R P(O)(OEt)2 LiNH , NH 2 3 R JOC 1987, 52 , 4885 R' R' R - Insertion reaction of a vinyl carbene (terminal acetylenes) N2 R C N2CHP(O)(OMe)2 R' tBuOK R + -N2 R' •• O C R R R' JOC 1982, 47 , 1837 R' O Me3Si _ N2 Synlett 1994, 107 THF, -78°C → RT Via Elimination Reactions of Vinyl Halides - Treatment of vinyl halides with strong base gives acetylenes. X Base R' R R R' - HX H X= Cl, Br, I, OTf, O3SR, OP(O)R2 Base= LDA; tBuOK; NaNH2, DBU - Addition of Grignard reagents to 1,1-difluoroethylene yields an acetylide anion which can be subsequently trapped with electrophiles. H2C=CF2 R-MgX E+ _ R R E TL 1982, 23 , 4325 JOC 1976, 41 , 1487 Strained Rings Topics in Current Chemistry 1983, 109, 189. - Cyclopropenones and cyclobutendiones can be photolyzed or thermolyzed (FVP) to give acetylenes. O O O hν (209 nm) 8 °K C - CO O - CO JACS 1973, 95 , 6134 C O Benzyne C≡C BOND FORMATION 1) 370 °C 2) 12°K O 118 ACIEE 1988,27 , 398 JACS 1991, 113 , 6943 - CO R1 R2 FVP R1 (retro- D-A) + R2 CL 1982, 1241 Eschenmoser Fragmentation Ph N O Ph N R R O R' HCA 1972, 55 , 1276 O R' R' HN NH2 iPr iPr O O R Base -orheat O tBuOOH, triton B, C6H6 O JOC 1992, 57, 7052 iPr AcOH, CH2Cl2 Allenes Tetrahedron 1984, 40, 2805 - from dihalocyclopropanes Br R R' Br R' R _ •• R Br R' H R' R H - From SN2' Reactions Nu: X H Nu R R' R R' - from sigmatropic rearrangements from propargyl sulfoxides and phosphine oxides. Ph OH O R R' Ph :P Ph2PCl, Et3N R O Ph2P R R' R' H TL 1990, 31 , 2907 JACS 1990, 112 , 7825 FUNCTIONAL GROUP INTERCONVERSIONS 119 Functional Group Interconversions C&S Chapter 3 #1; 2; 4a,b, e; 5a, b, d; 6a,b,c,d; 8 1 2 3 4 5 6 7 sulfonates halides nitriles azides amines esters and lactones amides and lactams Sulfonate Esters - reaction of an alcohols (1° or 2°) with a sulfonyl chloride R OH O R'SO2Cl R'= R O S CH3 mesylate CF3 triflate R' O sulfonate ester CH3 - sulfonate esters are very good leaving groups. competing side reaction tosylate Elimination is often a Halides - halides are good leaving groups with the order of reactivity in SN2 reactions being I>Br>Cl. Halides are less reactive than sulfonate esters, however elimination as a competing side reaction is also reduced. - sulfonate esters can be converted to halides with the sodium halide in acetone at reflux. Chlorides are also converted to either bromides or iodides in the same fashion (Finkelstein Reaction). O R O S R' X- X= Cl, Br, I R X O R Cl NaI, acetone reflux - conversion of hydroxyl groups to halides: R OH - R-OH to R-Cl - SOCl2 - Ph3P, CCl4 - Ph3P, Cl2 - Ph3P, Cl3CCOCCl3 R I Organic Reactions 1983, 29, 1 R X FUNCTIONAL GROUP INTERCONVERSIONS - R-OH to R-Br - PBr3, pyridine - Ph3P, CBr4 - Ph3P, Br2 - R-OH to R-I - Ph3P, DEAD, MeI Nitriles - displacement of halides or sulfonates with cyanide anion KCN, 18-C-6 DMSO R X R C N - dehydration of amides O R - R C N NH2 POCl3, pyridine TsCl, pyridine P2O5 SOCl2 - Reaction of esters and lactones with dimethylaluminium amide TL 1979, 4907 Me H 3C Me2AlNH2 O O OH JOC 1987, 52, 1309 NC Ar Ar - Dehydration of oximes R CHO N H2NOH•HCl R OH P2O5 R C H N - Oxidation of hydrazones O O N NMe2 (97%) - Reduced to aldehydes with DIBAL. DIBAL RC≡N C N RCHO Tetrahedron Lett. 1998, 39, 2009 120 FUNCTIONAL GROUP INTERCONVERSIONS 121 Azides - displacement of halides and sulfonates with azide anion LDA, THF NBS O O O NaN3 O O O SO2N(C6H11)2 SO2N(C6H11)2 Br SO2N(C6H11)2 N3 O O O TL 1986, 27, 831 HO SO2N(C6H11)2 NH2 NH2 - activation of the alcohol R OH + + N + N F Me N Me + EtO2C N N CO2Et O Me TsO - R OH + R N3 OR Ph3P, NaN3 + PPh3 EtO2C N N _ CO2Et DEAD activated alcohol + R O PPh3 R-OH R N3 + Ph3P=O JOC 1993, 58, 5886 HO (PhO)2P(O)-N3 O N3 O O DBU, PhCH3 SN2 P(OPh)2 + + DBU-H - + N3 (91 %) O (97.5 % ee) Ar (99.6 % ee) - Photolyzed to aldehydes Amines - Gabriel Synthesis O N - K+ O R O - reduction of nitro groups R NO2 H2, Pd/C Al(Hg), H2O NaBH4 LiAlH 4 Zn, Sn or Fe and HCl H2NNH2 sodium dithionite X N R H2NNH2 O R NH2 R NH2 FUNCTIONAL GROUP INTERCONVERSIONS - reduction of nitriles R C N R CH2 NH2 H2, PtO 2/C B2H6 NaBH4 LiAlH 4 AlH3 Li, NH3 - reduction of azides R N3 H2, Pd/C B2H6 NaBH4 LiAlH 4 Zn, HCl (RO)3P Ph3P thiols R NH2 - reduction of oximes (from aldehydes and ketones) N R OH NH2 R' R R' R' R N H2, Pd/C Raney nickel NaBH4, TiCl4 LiAlH 4 Na(Hg), AcOH - reduction of amides O R N R' R'' R'' H2, Pd/C B2H6 NaBH4, TiCl4 LiBH4 LiAlH 4 AlH3 - Curtius rearrangement O O NaN3 R R N O isocyanate H2O O ∆ - N2 R •• N •• Cl •• R •• •• N N N + nitrene R NH2 122 FUNCTIONAL GROUP INTERCONVERSIONS - reductive aminations of aldehydes and ketones - Borsch Reaction - Eschweiler-Clark Reaction - alkylation of sulfonamides Tf Tf N HN N HN Tf Tf K2CO3, DMF 110°C Tf Br Br Tf N N N N Tf NH HN Na, NH3 TL 1992, 33 , 5505 NH HN Tf cyclam - transaminiation O Ph N PhCH2NH2 Ph N NH2 Can. J. Chem. 1970, 48, 570 H3O + tBuOK H+ Esters and Lactones - Reaction of alcohols with "activated acids" - Baeyer-Villigar Reaction Organic Reactions 1993, 43, 251 - Pd(0) catalyzed carboylation of enol triflates OTf CO2R CO, DMF Pd(0), ROH TL 1985, 26 , 1109 - Arndt-Eistert Reaction O R Angew. Chem. Int. Ed. Engl. 1975, 15, 32. O CH2 N2 Cl Et2 O O hν N2 R Wolff Rearrangement C O H O R'OH R OR' ketene O O TsN3, Et3N CO2Me R •• CH R ROH R diazo ketone N2 R - Diazoalkanes: carbene precursors R-CHO 1) NH2NH2 2) Pb(OAc)4, DMF R-N2 R3N H 2N R - Halo Lactonizations JOC 1995, 60, 4725 TsN3 N N2 R R review: Tetrahedron 1990, 46 , 3321 + I I I2-KI CO2H R H2O, NaHCO3 O O H O O 123 FUNCTIONAL GROUP INTERCONVERSIONS Pd(OAc)2 (5 mol %) CO2H JOC 1993, 58, 5298 O DMSO, air (86%) O - Selenolactonization PhSe O H 2O 2 O PhSeCl, CH2Cl2 O O JACS 1985, 107 , 1148 O OH - Mitsunobu Reaction Synthesis 1981 , 1; Organic Reactions, 1991, 42, 335 Mechanism: JACS 1988, 110 , 6487 O DEAD, Ph3P OH R O R''CO2H R' R R'' Inversion of alcohol stereochemistry R' Amides and Lactams - reaction of an "activated acid" with amines - Beckman Rearrangement Organic Reactions 1988, 35, 1 O R N R' R OH PCl5 O R' R NR' - Schmidt rearrangement O R O HN3 R' H+ R NR' - others O OTf NR2 CO, DMF Pd(0), R2NH TL 1985, 26 , 1109 OH O O O PhCH2NH2 N H AlMe3 OTHP Ph TL 1977, 4171 OTHP -Weinreb amide Tetrahedron Lett. 1981, 22, 3815 O DIBAL O R O H3CNH(OCH3) •HCl OR' AlMe3 R R N H OCH3 O CH3 R1-M R R1 124 THREE-MEMBERED RING FORMATION 3 Membered Rings 1. 2. 3. epoxides a. peracids, hydroperoxides and dioxiranes b. transition metal catalyzed epoxidations c. halohydrins d. Darzen's condensation e. sulfur ylides cyclopropanes a. Simmons-Smith reactions b. diazo compounds c. sulfur ylides d. S N2 displacements aziridines a. nitrenes b. SN2 displacements Epoxides - peracid, hydroperoxide and dioxirane oxidation of alkenes - transition metal catalyzed epoxidation of alkenes - Sharpless epoxidation - Metal oxo reagents (Jacobsen's reagent) - from halohydrins Br NBS, H2O base O OH bromohydrin - Darzen's Condensation O _ BrCHCO2Et B: BrCH2CO2Et R R R' OO CO2Et R' R' Br - sulfur ylides Chem. Rev. 1997,97, 2421. O O Me S + CH2Me Corey + Me2SCH2- Ph S CH2- + _ SPh2 NMe2 Johnson sulfoximine CO2Et R Trost 125 THREE-MEMBERED RING FORMATION 126 - dimethylsulfoxonium methylide and dimethylsulfonium methylide (Corey's reagent) review: Tetrahedron 1987, 43 , 2609. O O R - O DMSO, NaH R' O SMe2 R R R' R' - cyclopropyldiphenylsulfonium ylide (Trost's reagent) ACR 1974, 7, 85. + O R _ O SPh2 - O R' O SPh2 R BF3 R R' - sulfoximine ylides (Johnson's reagent) O Ph S CH2NMe2 O R ZnCu + R ACR 1973, 6 , 341 O R R' Cyclopropanes - Simmons-Smith Reaction R' R' R' Org. Reactions 1973, 20, 1. ICH2ZnI CH2I2 - polar groups (-OH, -NR2- CO2R) can direct the cyclopropanation OH OH JACS 1979, 101 , 2139 ZnCu, CH2I2 - sulfur ylides O O O Me2S CH2- Ph Ph O _ Ph S NMe2 Tetrahedron 1987, 43 , 2609 Ph Ph O O ACR 1973, 6 , 341 THREE-MEMBERED RING FORMATION 127 - diazo alkanes and diazo carbonyls Synthesis 1972, 351; 1985, 569 - cyclopropanation with diazoalkanes; olefin requires at least on electron withdrawing group. N N CO2Me MeO2C CH2N2 (MeO)2HC CO2Me CO2Me JACS 1975, 97 , 6075 MeO2C hν MeO2C (MeO)2HC (MeO)2HC - diazoketones; photochemical or metal catalyzed decomposition of diazoketones to carbenes followed by cyclopropanation of olefins. Org. Rxns. 1979, 26, 361; Tetrahedron 1981, 37, 2407 CuSO4 , ∆ N2 JACS 1970, 92 , 3429 JACS 1969, 91 , 4318 O O Rh2(OAc)2 O Ph O O O Ph Ph N2 O JACS 1993, 115, 9468 O O O Ph 91 % yield 89 % de Asymmetric cyclopropanation: Doyle, Chem Rev. 1998, 98, 911 Aldrichimica Acta 1997, 30, 107 O O CO2Et CO2Et TsN3 , Et3N N2 C5H11 C5H11 O O CO2Et - SPh JACS 1977, 99, 1940 CO2Et C5H11 C5H11 SPh - SN2 Reactions DBU O O O Br O O O CO2Et JACS 1978, 99 , 1940 CO2Et - Electrophillic Cyclopropanes review: ACR 1979, 12 , 66 in many ways, cyclopropanes react silmilarly to double bonds - homo-1,4-addition CO2R Nu: CO2R Nu CO2R CO2R ACR 1979,12 , 66 THREE-MEMBERED RING FORMATION Nu:= malonate anion, amines, thiolate anion, enamines, cuprates (usually requires double activation of cyclopropane) Me H MeO2C MeO2C Me2CuLi O TL 1976, 3875 O - hydrogenation CO2Me CH2I2, Zn-Cu O ArCO3H, Na2HPO4 CO2Me CO2Me H H H O CO2Me H2, PtO2, AcOH TL 1982, 23 , 1871 H - hydrolysis OH OH OH CH2I2, Zn-Cu H , MeOH MeO OMe JACS 1967 89 , 2507 + O Aziridines R2 R1 Ts Cu(acac)2 R3 PhN=ITs N R2 R1 J. Org. Chem. .1991, 56, 6744 R3 128 FOUR-MEMBERED RING FORMATION 4 Membered Rings 1. 2. cyclobutanes & cyclobutenes oxatanes Cyclobutanes - [2+2] cycloadditions - photochemical cycloadditions (2πs +2πs) Acc. Chem. Res. 1968, 1, 50; Synthesis 1970, 287; Acc. Chem. Res. 1971, 4, 41; Organic Photochemistry 1981, 5, 123; Angew. Chem. Int. Ed. Engl. 1982, 21, 820; Acc. Chem. Res. 1982, 15, 135; Organic Photochemistry 1989, 10, 1 Organic Reactions 1993, 44, 297 - for synthetic purposes, cyclic α,β-unsaturated carbonyl are the most useful. intersystem crossing 1 E* E 3 E* - symmetry requirements 2πs + 2πs * hν O O ~ 340 nm HOMO LUMO - enones with olefins O O + CH2 O O O hν + CH2 JCSCC 1966, 423 + (90%) O O O O hν H E.J. Corey JACS 1963, 85 , 362 + + H Caryophellene Base Hot Ground State? O O O H2C=CH2 hν 2πs + 2πa thermal cyclization CH3 N H H2C=CH2 hν, CH2Cl2 CH3 O N CH3 isomerization cis ring-fusion H CH3 O Ph H H CH3 O JACS 1986, 108 , 306 HO CH3 grandisol 129 FOUR-MEMBERED RING FORMATION O O O 130 H H + JACS 1984 106 , 4038 hν H H 2:1 - enones with acetylenes O O hν O O O JACS 1982 104, 5070 - DeMayo Reaction O O O hν, pyrex O O CO2Me H pTSA, MeOH reflux JACS 1986, 108 , 6425 O O H O R hν O R O R O O MeO2C H O O 70-80 % de favored O O O controls conformation O O hν H 3C O O CH3 O H CH3 O disfavored TL 1993, 34, 1425 H 3C H 3C H - Photochemistry of Ketones (Norrish Type I and II reactions) H H hν Norrish I cleavage O • • 254, 307 nm Norrish II cleavage HO Yang reaction OH • • H H H O O• • H H 3C O O H O CH3 CH3 controls addition O H O O H 3C H OH + FOUR-MEMBERED RING FORMATION - filtering photchemical reaction to prevent Norrish reactions quartz 180 nm Vycor 200 nm Pyrex 280 nm Uranium glass 320 nm - Yang Reaction MOMO MOMO O hν (254 nm) OH C6H6 SEMO CH3 JACS 1987, 109 , 3017 CH3 SEMO - thermal cycloadditons (2πa + 2πs) - symmetry requirements 2πa + 2πs O HOMO LUMO - ketenes O ∆ H O O H O Cl Et3N O H O Cl Zn O Cl O N2 R R hν O H - thermal cyclization of ketene with olefins Tetrahedron 1986, 42, 2587; 1981, 37, 2949; Organic Reactions 1994, 45, 159. LUMO of ketene 2πa pz py O HOMO of olefin 2πs 131 FOUR-MEMBERED RING FORMATION Cl O CH3 Ph O Cl Cl CH2N2 CH3 O O O Cl CCl3 CH3 Zn-Cu, Et2O Cl Ph H 3C H 3C N+ 2) H2O H 3C Ar JACS 1987, 109 , 4753 H O 1) CH3 R*O CH3 H 3C 132 N+ JACS 1982, 104, 2920 H OMe OMe -reaction of ketene with enamines H NR2 O O H NR2 O O NR2 R' R' - reaction of ketene with imines to give β-lactams (Staudinger Reaction) R H N O H NR O O O R N + H CH2Cl2 -78°C → 0°C N Ph O Bn N O N Ph N Ph H O O R O H O Bn R NBn O (90-96 % de) - reaction of difluorodihaloethylene with olefins Organic Reactions 1962, 12, 1 F F2C=CX2 R F X= F, Cl X X R - reaction of difluorodihaloethylene with acetylenes- biradical mechanism F F2C=CX2 R F X= F, Cl R X hydrolysis O X R O FOUR-MEMBERED RING FORMATION 133 - SN2 Reaction O O KH, DMSO JACS 1980, 102 , 1404 OTs O _ CN CN HO OR JACS 1974, 96, 5268, 5272 OH OR Grandisol - acyloin reaction Organic Reactions 1976, 23, 259 CO2Me OTMS Na, TMS-Cl (CH2)n O F- (CH2)n CO2Me (CH2)n OTMS OH R CO2Me R O R CO2Me R OH - benzocyclobutanes ACIEE 1984, 23, 539; Synthesis 1978, 793 O O O O O benzocyclobutane O o-quinodimethane - cyclotrimerization of 1,5-diyenes with an acetylenes SiMe3 Me3Si SiMe3 CpCo(CO)2 Me3Si - sulfur ylides + O R _ SPh2 R' O BF3 O R R' R' R Oxatanes Organic Photochemistry 1981, 5, 1 - [2+2] cycloaddition (Paterno-Buchi Reaction) O R R R' O R O hν R' hν (254 nm) R' O R R' FOUR-MEMBERED RING FORMATION O O hν O Me2C CMe2 O O 134 TL 1975 1001 O - SN2 reaction O NBS OH JCSCC 1979, 421 SiMe3 SiMe3 Br OH CO2Me Tf2O, CH2Cl2 CO2Me O C5H11 HO TL 1980,21 , 445 C5H11 OTBS OH OH Br Br CO2Me HO (MeO)3P, DEAD O CO2Me O C5H11 C5H11 O OH JACS 1984, 107 , 6372 OH - sulfur ylides O O - O O NTs H2C_ S Me S NTs O JACS 1979, 101 , 6135 CH3 β-Lactones R2 R1 LDA, THF SPh H BnO N H O R3 CO2H R1 R2 R1 O BnO JOC 1991, 56 , 1176 SPh R4 DEAD, Ph3P O O R4 O R3 OH O O- O R2CuLi O N H R2 R3 R4 CO2H R BnO NH JACS 1987, 109 , 4649 O O 1) MgBr2•OEt2 2) KF, H2O, CH3CN O OBn O OBn O O + H SiMe3 H 96 % de TL 1995, 36, 4159 BALDWIN'S RULES FOR RING CLOSURE Baldwin's Rules (Suggestions) for Ring Closure JOC 1977, 42 , 3846 JCSCC 1976, 734, 736, 738 135 Approach Vector Analysis - for an SN2 displacement at a tetrahedral center, the approach vector of the entering nucleophile is 180° from the departing leaving group Nu: Nu L Nu L :L - for the addition of a nucleophile to an Sp2 center, the nucleophile approaches perpendicular to the π-system. Nu Nu Nomenclature 1. indicate ring size being formed 3 membered ring = 3 4 membered ring = 4 etc. 2. indicate geometry of electrophilic atom if Y= Sp3 center; then Tet (tetrahedral) if Y= Sp2 center; then Trig (trigonal) if Y= Sp center; then Dig (digonal) Z Y X: 3. indicate where displaced electrons end up - if the displaced electron pair ends up out side the ring being formed; then Exo - if the displaced electron pair ends up within the ring being formed; then Endo Z Y X: Exo Z Y X: Endo BALDWIN'S RULES FOR RING CLOSURE 136 4. Ring forming reaction is designated as Favored or Disfavored disfavored does not imply the reaction can't or won't occur- it only means the reaction is more difficult than favored reactions. Rules (Suggestions) for Ring Closure - All Exo-Tet reactions are favored X: Y Z X: Y X: Z X: Y Z 3- 4- X: Y Y Z 5- Z 6- 7- - - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - - - 5-Endo-Tet and 6-Endo-Tet are disfavored Z Z Y Y X: X: 5- 6- - - - - -Disfavored- - - - - - All Exo-Trig reactions are favored X: Y Z X: Y Z X: X: Y Z 3- 4- 5- X: Y Y Z Z 6- 7- - - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - - - 3-Endo-Trig, 4-Endo-Trig and 5-Endo-Trig are disfavored; 6-Endo-Trig, 7Endo-Trig, etc. are favored Z Z X: Y 3- Z X: Y 4- Z Y X: 5- - - - - - - - - - - - - -Disfavored- - - - - - - - - - - - X: Y X: Z Y 76- - - - - -Favored- - - - - - BALDWIN'S RULES FOR RING CLOSURE 137 - 3-Exo-Dig and 4-Exo-Dig are disfavored; 5-Exo-Dig, 6-Exo-Dig, 7-Exo-Dig, etc. are favored X: X: Y X: Y Z Z 3- 4- Y X: Z Z 5- - - - - - -Disfavored- - - - - - X: Y Y Z 6- 7- - - - - - - - - - - - - -Favored- - - - - - - - - - - - - All Endo-Dig are favored Z Z X: Z Y Y X: X: 3- 4- Z Y 5- X: 6- Y X: Z Y 7- - - - - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - - - - - - EXCEPTION: There are many !!! (see March p 212-214) FIVE-MEMBERED RING FORMATION 5 Membered Rings HO O CO2H HO CO2H HO OH OH PGF2α PGE2 Me H Me Me Me Me Me Me Me Hirsutene 1. 2. 3. 4. 5. 6. 7. 8. 9. Isocumene Modhephane Intramolecular SN2 Reactions Intramolecular Aldol Condensation and Michael Addition Intramolecular Wittig Olefination Ring Expansion and Contraction Reactions a. 3 → 5 b. 4 → 5 c. 6 → 5 1,3-Dipolar additions Nazarov Cyclization Arene-Olefin Photocyclization Radical Cyclizations Others Synthesis 1973, 397; ACIEE 1982, 21 , 480; Intramolecular SN2 Reaction 5-exo-tet: favored O LDA O JCSCC 1973, 233 Br O O CO2Me O CO2Me Br CN CN OH JACS 1974, 96 , 5268 O 138 FIVE-MEMBERED RING FORMATION O Cl JACS 1979, 101 , 5081 O RO2C RO2C Cl CO2R CO2R O O NaH, DMSO JCSCC 1979, 817 TsO Intramolecular Aldol Condensation 5-exo-trig: favored intramolecular aldol condensation of 1,4-diketones O O R R O R' R' O O CH3 CH3 O TL 1982, 29, 2237 CH3 CH3 Br Br O NaOMe, MeOH O O CO2Me JACS 1980, 102 , 4262 CO2Me O O JOC 1983, 48 , 1217 NaOH O O O Intramolecular Michael Addition 5-exo-tet: favored Organic Reactions 1995, 47, 315-552 O O MeO2C O O JACS 1979, 101 , 7107 139 FIVE-MEMBERED RING FORMATION Tetrahedron 1980, 36, 1717 Intramolecular Wittig Olefination O O 1) (MeO) 2P(O)CH2 - O P(OMe)2 O 2) Collins O C5H11 THPO OTHP C5H11 THPO OTHP CO2H O JOC 1981, 46 , 1954 base C5H11 THPO OTHP C5H11 HO OH Ring Expansion Reactions - 3 → 5: Vinyl Cyclopropane Rearrangement _ O SPh2 O Organic Reactions 1985, 33, 247. O H OTMS O O O H O H O TMSO JACS 1979, 101 , 1328 O H O - 4 → 5: Reaction of cyclobutanones with Diazomethane Cl Me CH2N2 Me Me Cl O O O Me Cl Me Me CH2N2 TL 1980, 21 , 3059 O Cl Cl Cl Cl O O Cl Cl CH3 O CH3 CH2N2 Cl CH3 O CH3 JACS 1987,109 , 4752 Ph Ph 140 FIVE-MEMBERED RING FORMATION Ring Contraction Reactions - 6 → 5: Favorskii Reaction Organic Reactions 1960, 11 , 261 _ O O Cl OH - O OH CO2H _ 1,3-Dipolar Addition to Olefins 1,3-Dipolar Cycloaddition Chemistry , vol 1 & 2 (A. Padwa ed.) (Wiley, NY 1984); ACIEE 1977, 16 , 10. Chem Rev. 1998, 98, 863. 1,3-Dipole (4π) LUMO + _ b c a 4πs + 2πs - trimethylenemethane (TMM) Alkene (2π) HOMO ACIEE 1986, 25 , 1. Synlett 1992, 107. high temperature • • TMM CO2Me MeO2C ∆, MeCN N MeO2C H • • • -N2 N CO2Me CH3 H • JACS 1981, 103 , 2744 note: TMM usually reacts poorly w/ electron defficient olefins _ Pd(0) Me3Si OAc + PdLn O O Me3Si H OAc O O TL 1986, 27 , 4137 Pd(0), 80°C MeO2C CO2Me Ni(COD)2, 35 °C CO2Me ACIEE 1985, 24 , 316 TL 1983, 24 , 5847 CO2Me - α,α'-dihaloketones O OFeLn O Fe(CO)9 Ar ACR 1979, 12 , 61 + Br Br Ar 141 FIVE-MEMBERED RING FORMATION ACR 1979, 12 , 396; Organic Reactions, 1988, 36 , 1 - nitrones O+N O R1 N R2 R1 JACS 1964, 86 , 3756 O O N N Me O N MeNHOH, EtONa H O Me NH N S Me NH JOC 1984, 49 , 5021 H H MeO2C Bn OH Me2N 1) MeI 2) H2, Pd/C H H MeO2C R3 R2 R3 Nitrone - 142 Bn N O- JACS 1983, 104 , 6460 O S C 4H 9 C 4H 9 - nitrile oxides O O + O N N N O ArNCO CO2Et CO2Et O O N O O O N O O OTHP + _ N O THPO N O OH OTHP Bu3Sn (80%) OTHP H2, Raney Ni, H2 O, MeOH, B(OMe)3 (88%) 1) TBS-Cl, DMF, imidazole 2) nBuLi, THF OH O O OH O HF•pyridine, CH3 CN, pyridine 3) Swern (48%) TBSO O (88%) O 1) PPTS, EtOH, ↑↓ 2) (CH3 )2C(OMe)2 , PPTS O O (89%) OH Ph (99%) N 1) Swern 2) NH2OH•HCl AcONa, MeOH OTHP (60%) OTHP NaOCl, H2 O, CH2 Cl2 CO2Et 1) DHP, PPTS CH2 Cl2, ↑↓ 2) LAH CH3 H Ph JACS 1992, 104 , 4023 CO2Et OH Bu 2BOTf, iPr 2EtN, CH2 Cl2, -78°C OH O H2 Cassiol TL 1996, 37, 9292 (73%) O TBSO O HO OH OH FIVE-MEMBERED RING FORMATION OTBS OTBS OTBS LAH N + O _ TL 1993, 34, 3017 O N OH NH2 Arene -Olefin Photocyclization Organic Photochemistry 1989, 10 , 357 - the photochemistry of benzene is dominated by the singlet state 1 * hν * * hν OAc OAc * Me2CuLi O O JACS 1982, 104 , 5805 JCSCC, 1986 247 Me 1) FVP 2) H2, Pd/C * * hν + isocume + * Tetrahedron 1981,37 , 4445 * * * hν OMe OMe JACS 1981, 103 , 688 OMe cedrane AcO hν AcO * * HO H+ H TL 1982, 23 , 3983 TL 1983, 24 , 5325 143 FIVE-MEMBERED RING FORMATION 144 Intramolecular Photochemical [2+2] "Rule of Five" O O hν O O O O JOC 1975, 40 , 2702 JOC 1979, 44 , 1380 hν O O Nazarov Cyclization review: Synthesis 1983, 429 - cyclization of allyl vinyl or divinyl ketones Organic Reaction 1994, 45, 1 O O H3PO4/HCO2H O O H3PO4/HCO2H - 1,4-hydroxy-acetylenes HO H2SO4, MeOH OH H O OH JOC 1989, 54 , 3449 H OH - Silicon-Directed Nazarov O O Tetreahedron 1986, 42 , 2821 FeCl3 SiMe3 Me - Tin -directed Nazarov Me TL 1986, 27 , 5947 Radical Cyclization B. Giese Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds (Pergamon Press; NY) 1986; Bull. Soc. Chim. Fr. 1990, 127 , 675; Tetrahedron 1981, 37 , 3073; Tetrahedron 1987, 43, 3541; Advances in Free Radical Chemistry 1990, 1, 121. Organic Reactions 1996, 48, 301-856. Radical Addition to multiple bonds: 1. Free radical addition is a two stage process involving an addition step followed by an atom transfer step. 2. In general, the preferred regioselectivity of the addition is in a manor to give the most stable radical (thermodynamic control) FIVE-MEMBERED RING FORMATION Advantages of free radical reactions: 1. non-polar, little or no solvent effect 2. highly reactive- good for hindered or strained sysntems 3. insensitive to acidic protons in the substrates (i.e. hydroxyl groups do not necessarily need to be protected Mechanism of radical chain reactions 1. initiation 2. propagation 3. termination (bad) Formation of carbon centered radicals: tin hydride reduction of alkyl, vinyl and aryl halides, alcohol derivatives: xanthates, thionocarbonate, thiocarbonylimidazolides organosselenium & boron compounds carboxylic acid derivatives (Barton esters) reduction of organomercurials thermolysis of organolead compounds thermolysis or photolysis of azoalkanes. Radical Ring Closure For irreversible ring closure reaction, the kinetic product will predominate. Both the 5-exo-trig and 6-endo trip are favored reactions, with the 6 exo-trig mode producing the most stable radical. However, the 5-exo-trig is about 50 time faster • • k1,5 • k1,6 thermodynamically favored kinetically favored • • + • 100 : 0 • • + • • • 100 : 0 • 3-exo-trig vs 4-endo-trig 4-exo-trig vs 5-endo-trig 5-exo-trig vs 6-endo-trig + 98:2 • • • + 6-exo-trig vs 7-endo-trig 85:15 • • • + 100 : 0 7-exo-trig vs 8-endo-trig 145 FIVE-MEMBERED RING FORMATION • 146 • and radicals open up fast and are not synthetically useful; often used as probes for radical reaction Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization • • • + 48:1 • • • + >200:1 • • • + 2:3 • • • + < 1:100 Stereochemistry of 5-hexenyl radical cyclization 1-, or 3-substitued 5-hexenyl radicals give cis disubstituted cyclopentanes 2-, or 4-substituted 5-hexenyl radicals give trans disubstitued cyclopentanes 2 Br Bu3SnH H R • R H R + R 65 : 35 prefered transition state R • 3 R R Br R + H H 75 : 25 H 4 Br R H R 1 Bu3SnH Br + R • R R • 83 : 17 R + H R 73 : 27 R FIVE-MEMBERED RING FORMATION Br OH nBuSnH, AIBN 147 JACS 1983, 105 , 3720 OH CN CN Bu3SnH, AIBN CO2Me JACS 1990, 112, 5601 Br CO2Me Br OH Si O H Si O Bu3SnH THPO H H2O2 THPO OH THPO multiple cyclizations: D. Curran Advances in Free Radical Chemistry 1990, 1, 121. OTBS O OAc 1) NaBH4, CeCl3 2) Ac2O, Et3N 1) LDA, THF 2) TBSCl O 70 °C O OTBS PhSe H2O2 O PhSeCl, CH2Cl2 O O THPO O 1) PPTS, EtOH 2) LAH CO2H I CuSMe2 Li+ THPO I 1) Me3Si Li (1.0 equiv) I 3) (CF3SO2)2O pyridine 4) Bu4NI, PhH 2) CsF Me H • Bu3SnH, AIBN PhH, reflux JACS 1985, 107 , 1148 H H (±)-hirsutene O O CH3MgBr, CuBr•SMe2 HO O O 1) I2 2) DBU O O O MgBr CuBr•SMe2, THF O O HO O 1) LAH 2) CH3SO2Cl 3) NaI CO2Me 1) CH3MgBr (excess) Li 4) 5) CrO3, H2SO4, H2O Bu3SnH, AIBN PhH, reflux Br 2) Me3SiBr H H • H 3C H (±)-capnellene Tetrahedron Lett. 1985, 41, 3943 FIVE-MEMBERED RING FORMATION O O Me nBuSnH, AIBN O 148 O JACS 1986, 108, 1106 Me Me Me Br OH H CHO O JACS 1988, 110 , 5064 O SmI2, THF O O H radical trapping OEt I OEt OEt O O nBuSnH, AIBN RO O tBuNC JACS 1986, 108 , 6384 • RO CN RO can also be trapped with acrylate esters or acrylonitrile. OEt OEt I O O nBuSnH, AIBN O Me3Si OEt C5H11 OEt O SiMe3 C5H11 • RO RO RO 1) (S)-BINAL-H 2) HCl, H2O, THF O C5H11 RO 1) Wittig 2) deprotect CHO RO CO2H HO OH (+)-PGF2α O Paulson-Khand Reaction Tetrahedron 1985, 41 , 5855; Organic Reactions 1991, 40 , 1. O O R R'' R' R R R'' Organometallics 1982, 1 , 1560 + Co2(CO)6 R' R' R'' O JOC 1992, 57 , 5277 Co2(CO)8, NMO O O O O OTMS HO C5H11 C5H11 RO HO Brook rearrangement O OEt Pd(OAc)2, CH3 CN O 140° FIVE-MEMBERED RING FORMATION Ph Cp2TiCl2, EtMgBr, CO EtO2C CO2Et CO2Et Ph Ring-Closing Metathesis CO2Et Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446. O O N O OH Bu2BOTf, CH2Cl 2, -78°C P(C6H11)3 Ph Cl Ru Cl P(C6H11)3 O O N O (97%) CHO (82 %) Ph Ph OH JOC 1992, 57 , 5803 O O O N LiBH4, THF, MeOH OH J. Org. Chem. 1996, 61, 4192 O OH (78%) Ph Diazoketones Tetrahedron 1981, 37 , 2407; Organic Reactions 1979, 26 , 361 O R1 O N2 BF3 R1 TL 1975, 4225 R2 R2 FVP of Acetylenic Ketones O O R1 R2 FVP H R3 R1 R2 O R3 H •• R1 R2 R3 TL 1986, 27 , 19 149 6-MEMBERED RING FORMATION Six Membered Rings 1. 2. 3. 4. 5. Diels-Alder Reaction o-Quinodimethanes Intramolecular ene reaction Cation olefin cyclizations Robinson annulation Diels-Alder Reaction ACIEE 1984, 23 , 876; ACIEE 1977, 16 , 10; Organic Reactions 1984, 32 , 1 W. Carruthers Cycloadditions Reactions in Organic Synthesis (Pergamon Press, Oxford) 1990 - reaction of a 1,3-diene with an olefin to give a cyclohexene. - thermal symmetry allowed pericyclic reaction - diene must reaction is an s-cis conformation - highly stereocontrolled process- geometry of starting material is preserved in the product - possible control of 4 contiguous stereocenters in one step B B A A X B A Y X Y Y Y X + X Y X X + Y B A B A B A - Alder Endo Rule: In order to maximize secondary orbital interactions, the endo TS is favored in the D-A rxn. Tetrahedron 1983, 39, 2095 X X B Y Y B A A A X Y Y X B B A O O exo O O minor O H H O H endo O H O major O O O O Orientation Rules X X + Y X Y + Y major minor 150 6-MEMBERED RING FORMATION X Y + X + X 151 Y Y major minor - when both the diene and dienophile are "unactivated" the D-A rxn is sluggish - D-A rxns with electron rich dienes and electron defficient dienophiles work the best. Some electron deficient dienophiles are quinones, maleic ahydride, nitroalkenes, α,βunsaturated ketones, esters and nitriles. - D-A rxns with electron deficient dienes and electron rich dienophiles also work well. These are refered to as reverse demand D-A rxns. - D-A rxns are sensitive to steric effects of the dienephiles, particularly at the 1- and 2postions. Steric bulk at the 1-position may prevent approach of the dienophile while steric bulk at the 2-position may prevent the diene from adopting the s-cis conformation. - The D-A rxn is promoted by Lewis acids (TiCl4, BF3 AlCl3, AlEt2Cl, SnCl4,...) - The D-A rxn is promoted by high pressure (1 kbar ~ 14200 psi) Synthesis 1985, 1. O OMe OMe 5 Kbar Me Me O + JACS 1986, 108 , 3040 O O H NHBOC 20 kbars, 50°C H + Eu(fod)3 O OMe O NHBOC H + O OMe NHBOC Synthesis 1986, 928 OMe - The D-A rxn is usually insenstive to solvent effects, except for water. ACR 1991, 24 , 159 O isooctane + O + krel=1 O endo H exo 4:1 H2O JACS 1980, 102 , 7816 TL 1983, 24 , 1901 TL 1984 , 25 , 1239 20 : 1 krel= 700 CO2- Na+ CHO OHC CO2H CO2H H H + OHC H2O (70%) (15%) JOC 1984, 49 , 5257 JOC 1985, 50 , 1309 Tetrahedron 1986, 42 , 2847 6-MEMBERED RING FORMATION 152 - The mechanism of the D-A rxn is believed to be a one-step, concerted, non-synchronous process. - concerted- bond making and bond breaking processes take place in a single kinetic step (no dip in the transition state) - synchronous- bond making and bond breaking take place at the same time and to the same extent. M.J.S. Dewar JACS 1984, 104 , 203, 209. + - study of secondary D-isotope effects have indicated a highly symmetrical T.S. D H D H k1 D D H H + D JACS 1972, 94 , 1168 D D D k2 D D D D + Diels Alder Reactions: O O PhH, reflux O O H MeO2C H CHO MeO2C CO2H OAc OMe HO2C MeO Tetrahedron 1958, 2 , 1 N N H H O2CAr MeO2C reserpine H CHO H + NHCO2Bn OMe H O O trans trans H CHO BnO2CHN BnO2CHN NHCO2Bn JACS 1978, 100 , 5179 N H pumiliotoxin C CH3 H 6-MEMBERED RING FORMATION OMe MeO O R + O O R MeO2C CO2Me O MeO2C R O MeO2C PhS SPh PhS SPh MeO OMe O O JACS 1986, 108 , 5908 O Compactin OMe OMe R R R + Me3SiO ACR 1981, 14 , 400 O Me3Si-O Danishefsky's Diene OMe MeO2C OH O CO2Me H O + H Me3SiO O O H Vernolepin O Hetero Diels-Alder Reactions - Heterodienophiles OMe CO2Bn N + PhH, reflux O EtO2C Me3SiO N CO2Bn JACS 1982, 102 , 1428 CO2Et O CO2Me Me3SiO + HO N N H TsN Ts TL 1987, 28 , 813 HO PhH, 5°C OH CO2Me CH(OMe)2 CH(OMe)2 O + CH3 N O CO2Bn N CH3 OAc AcO CO2Bn AcO OH NAc CH3 TL 1985 27 , 4727 153 6-MEMBERED RING FORMATION Me Me Me Me O + S Me O S Me NTs Me Me Me S Ph S S Ph Ph H Ph 1) MgBr2 O 2) H3O+ OMe Me3SiO Tetrahedron, 1983, 39 , 1487 S O + TL 1983, 24 , 987 Me Me NTs NHTs Me O H OBn JACS 1985, 107 , 1256 O OBn OMe + Ar H Yb(fod)3 Me Me3SiO OMe OMe O Me HF, Pyridine O O Ar Me3SiO Me JACS 1985, 107 , 6647 Me Ar O Me Me O Me C3F7 M O O C3F7 M O 3 3 M(fod)3 M(hfc)3 - Heterodienes O H O O + AcO OAc Me O PhS OAc + OEt O O H O ACIEE 1983, 22 , 887 + MeO2C MeO2C H EtO endo:exo 10 : 1 O H endo: exo 1:2 Me MeO2C AcO HO H O OH SPh OAc Me OH ACR 1986, 19 , 250 154 6-MEMBERED RING FORMATION 155 OR' N O N O + RO O O RO RO RO N OR OR OR' OR' O O RO N OMe RO JACS 1987, 109 , 285 NHAc OR CO2R' H JOC 1985, 50 , 2719 ∆ AcO N N N O O O Intramolecular Diels-Alder Reactions - Type I IDA rxns (IDA) Fused bicyclc Bridged Bicyclic - Generally, for E-dienes, the fused product is observed unless the connecting chain is very long. For Z-dienes, either the fused or bicyclic products are possible. - Type II IDA rxns: gives bridgehead olefin 395°C JACS 1982, 104 , 5708, 5715 O O O O O O 185°C EtO2C EtO2C JACS 1987, 109 , 447 O EtO2C CO2Et AcO NHBz O 155°C Ph O OH ACIEE 1983, 24 , 419 O OH O O H OH BzO AcO Taxol O 6-MEMBERED RING FORMATION 156 - IDA reactions to give fused 6•5 (hydroindene) and 6•6 (hydronaphthalene) ring systems are usually favorable reactions. R' R' R (CH2)n R n= 1 or 2 (CH2)n - Intramolecular D-A rxns that give medium sized rings (7,8,9, 10) are much less favorable. - Intramolecular D-A rxn which form large rings are often favorable reactions with the diene and olefin portions act as if they were seperate molecules H H O O O + H H O O O endo + JACS 1980, 102 , 1390 H O O O O O H O O O O O exo 6.2 : 6.8 : 1 (77% combined yield) - Preference for endo or exo transition state depends on the substituition of the diene, dieneophile and connecting chain. - For intramolecular D-A rxns, geometric constraints can now reverse the normal regiochemistry of the addition as compared to the intermolecular rxn. + CO2R' CO2R' R R CO2R' CO2R' - for intramolecular D-A reactions, we will use endo and exo to described the disposition of the connecting chain R R' R' R H (CH2)n R' H (CH2)n R (CH2)n endo R R' R' R H (CH2)n (CH2)n exo H 6-MEMBERED RING FORMATION 157 - Lewis acids can greatly effect the endo/exo ratio of IDA reactions especially when the olefin portion is E. The effects for Z-olefins is much more subtle MeO2C MeO2C MeO2C H H + JACS 1982, 104 , 2269 H H 75 : 25 150°C (75% combined yield) 100 : 0 (RO)2AlCl2, rt CO2Me (72% combined yield) MeO2C MeO2C H H + H H 75 : 25 180°C 63 : 37 EtAlCl2, rt (74% combined yield) (60% combined yield) - the effect of substituents on the connectinng chain can influence the stereochemical course of the IDA reaction HN O HN EtAlCl2 O JOC 1981, 46 , 1509 H MeO2C rt MeO2C H R O R R R O H H Intramolecular Diels-Alder Reactions: CO2Me MeO2C 130°C TBSO H TBSO JOC 1981, 46 , 1506 H O O O 150°C O TL 1973, 4477 6-MEMBERED RING FORMATION OTBS OTBS CF3CO2H H JACS 1981, 103 , 4948 H H H O TBSO OTBS CO2Me H CO2Me JOC 1982, 47 , 180 EtAlCl2 H Asymmetric Diels-Alder Reactions - Chiral Auxillaries Chem. Rev. 1992, 92 , 953; Tetrahedron 1987, 43 , 1969 OAc O OAc O M O + HO OH BF3•OEt2, -40°C H CO2H HO H OH OAc OAc (-)- Shikimic Acid >98% d.e. O O O TiCl4, 0°C + JOC 1983, 48, 1137 JOC 1983, 43, 4441 ACIEE 1985, 24, 1 TL 1984, 25 , 2191 O R* O O (97:3) X O ∆ = 4.5 %ee TiCl4= 78% ee iBu2AlCl= 90% ee CO2R* O O CO2R* O O Ph O O O Ph + O + OR* O Ph Ph O JOC 1989, 54 , 2209 OR* 18 : 82 w/ BF3•OEt2 O Ar O O Et2AlCl + OTMS d.e > 95% 92 : 8 R* CH2Cl2, -80°C Chem Lett. 1989, 2149 O up to 70% d.e. O Ph H O Me O OR* + Eu(hfc)3 OTMS Ph O PhCHO O Me 8 : 92 OR* O Me JACS 1986, 108, 7060 158 6-MEMBERED RING FORMATION CH3 O Ph O O R* SnCl4, -78C N + O O N O O S S O R O R* PhMgBr R 97% d.e. 159 R* N H O S Ph O OH N R R JCSCC , 1985 , 1449 TL 1986, 27 , 1853 O O H (iPrO)2TiCl2, CH2Cl2, 0°C O H O SO2 N Tetrahedron 1987, 43 , 1969 H CO2R* O TL 1989, 30 , 6963 endo/exo= 86:4 98% de X EtAlCl2, -78°C Oppolzer Auxillary O O Evan's auxillaries N R O O O N R Me O Ph + O O CO2R* Me2AlCl N O CO2R* endo (major) endo CO2R* CO2R*+ exo endo/exo endo A/ endoB k(rel) O O + O O Me2AlCl N O 2 equiv. Me2AlCl 60:1 20:1 100 _ Me2AlCl2 _ Me2ClAl exo 1 equiv Me2AlCl 20:1 4:1 1 N O Me2AlCl + Al O O N O O H N Al O O 6-MEMBERED RING FORMATION O O N R O O OH R* EtAlCl2, -100°C Ph O O O R* N Ph R* H Me2AlCl H + TL 1984 , 25 , 4071 JACS 1988, 110 , 1238 Me H O O JACS 1984, 106, 4261 JACS 1988, 110 , 1238 (R)-(+)-α-terpineol O O 160 H 15 : 85 O N Me2AlCl Ph 95 : 5 - Chiral Dienes O OMe O Ph O CHO OHC OMe BF3•OEt2, -20°C BF3•OEt2, -78°C Ph 4:1 94:6 O O OH OMe O π-stacking arrangement MeO H Ph O + O Ph O OMe O H O OH O O H approach of dienophile O only product - Chiral Catalysts Chem. Rev. 1992, 92 , 1007; Synthesis 1991, 1; OPPI 1994, 26, 129158 OH CHO CHO + EtAlCl2, -78°C JCSCC 1979, 437 72% (ee) OtBu Me + Eu(hfc)3, -10°C O O TMSO Me TL 1983, 24 , 3451 PhCHO Ph Me 6-MEMBERED RING FORMATION 161 Ph Ph Ph O O O OH OH Me O Ph Ph N + O CL 1986, 1967 N O (iPrO)2TiCl2 O O O O Ph Ph O O N Ph O OH O Me O OH H O Ph Ph O 70% yield 95% ee O (iPrO)2TiCl2 O N O (30 mol % catalyst) H Ph O O OH OH + OH O JACS 1986, 108 , 3510 Ph BH3, -78°C OAc OH O OAc (98%) Ts N Et B Br O CHO O N H CHO + -78°C Br JACS 1992, 114 , 8290 (> 99% ee) H N O Br CHO O N B Bu Ts + CHO Br CH2Cl2, -78 °C, 16 hrs Br Br O (81%, 99% ee) OC O H N O B O N Ts OH HO approach of diene CO2H Gibberellic Acid Br Br H H N OTBS H 3C H CHO + O O O 1) NaBH4 2) DDQ OTBS O O N B H Ts CH2Cl2, PhCH3 -78 °C, 42 hrs 3) F O JACS 1994, 116, 3611 - 4) HCl CHO (83%, 97% ee) O O OH HO Cassiol OH 6-MEMBERED RING FORMATION 162 Ketene Equivalents in the D-A reaction - ketenes undergo thermal [2+2] cycloaddition with dienes to give vinyl cyclobutanones. - 2-chloroacrylonitrile as a ketene equiv. for D-A rxns. AcO + Cl Cl CN AcO ortho-Quinodimathanes CN KOH, tBuOH 70 °C R R R o-quinodimethane benzocyclobutane 1) Nature (London) 1994, 367, 630 ACIEE 1995, 34, 2079 Synthesis 1978, 793; Tetrahedron 1987, 43 , 2873 R O O HO O OTMS LiNH2, NH3, THF MgBr CuI, TMS-Cl Me3Si SiMe3 CpCo(CO)2 I O O O 170 °C Me3Si Me3Si H H H Me3Si Me3Si O 1) CF3CO2H, CCl4, -30°C 2) Pb(O2CCF3)4 H H ACIEE 1984, 23 , 539 JACS 1977, 99 , 5483 JACS 1979, 101 , 215 JACS 1980, 102 , 241 H HO Estrone O O HN HN JACS 1971, 93 , 3836 155 °C H O Me N O Me N 155 °C ACIEE 1971, 11 , 1031 O O Me O O N Me N 155 °C N O N ACIEE 1971, 11 , 1031 N OMe Me O OMe Me N ACIEE 1971, 11 , 1031 180 °C N H Me3Si Me3Si NH H 6-MEMBERED RING FORMATION Photoenolization Tetrahedron 1976, 22, 405 R O R • hν H R O• OH R MeO2C OH CO2Me CO2Me H CO2Me R R R O R O O -H2O R OH O R CO2Me O CO2Me O R Intramolecular Ene Reactions R ACIEE 1984, 23 , 876, Synthesis 1991, 1 H SnCl4 CHO JOC 1985, 50, 4144 OH H JACS 1991, 113 , 2071 Me2AlCl BnO H OH CHO OBn Binaphthol Tetrahedron Lett. 1985, 26, 5535 CHO OH Me2Zn 90% ee) Polyene Cyclization + Terpene Biosynthesis terpenes sesquiterpenes diterpenes steroids C 10 C 15 C 20 C 30 + geraniol farnesol geranylgeraniol squalene - isoprene- basic building block OPP isopentyl-PP isoprene unit OPP OPP OPP geraniol-PP (C10) Farnesyl-PP (C15) geranylgeraniol-PP (C20) squalene (C30) 163 6-MEMBERED RING FORMATION 164 O HO2C α-Cedrane Camphor Abietic Acid Biosynthesis of camphor: + OPP O + Biosynthesis of cedrane: OPP H + + H + + Stork-Eschenmoser Hypothesis- Olefin Geometry is preserved in the cyclization reaction, i.e. trans olefin leads to a trans fused ring jucntion A. Eschenmoser HCA 1955, 38, 1890; G. Stork JACS 1955, 77, 5068 Me Me + Me Me R H Me Me Me Me R H H H Biosynthesis of Abietic acid: OPP OPP + OPP H + H H H + H + H H H H H HO2C H 6-MEMBERED RING FORMATION 165 -Steroid Biosynthesis: H+ H squalene cyclase squalene epoxidase squalene H + H H HO +O H HO H H Protosterol squalene oxide H H + H H H H H H HO H HO H H HO H Lanosterol Cholesterol - Polyene cyclization in synthesis ACR 1968, 1, 1; Bioorg. Chem. 1976, 5, 51; Asymmetric Synthesis 1984, 3, 341-409; ACIEE 1976, 15, 9 SnCl4 CH3NO2, 0°C H E.E. van Tamelen JACS 1972, 94 , 8229 (8%) H HO O H δ- Amyrin OH CHO SnCl4 PhH, rt JACS 1974, 96 , 3333 H (38%) MeO MeO H SnCl4 pentane H (27%) O O HO CO2Me OPO(OEt)2 O W.S. Johnson JACS 1974, 96, 3979 H H CO2Me 1) Hg(O2CCF3)2 2) NaCl O ClHg H JACS 1980, 102 , 7612 6-MEMBERED RING FORMATION Robinson Annulation 166 Synthesis 1976, 777; Tetrahedron 1976, 32, 3. O acid or base (thermodynamic conditions) O O - unfavorable equillibium for the Michael addition under kinetic conditions O base (kinetic conditions) - O -O O - stabilizing the resulting enolate of the Michael Addition product can shift the equilibrium as in the case of the vinyl silane shown below O Me3Si Me3Si - O - O O O base (kinetic conditions) OR OR OR a) MeLi Me3SiO O H b) Me3Si O O JACS 1974, 96 , 6181 O H O O O c) MeONa - Methyl Vinyl Ketone equivalents I + mCPBA - O O Me3Si Me3Si Me3Si Aldol O O O H+ O O JACS 1974, 96 , 3862 I + O O O - O O O O 6-MEMBERED RING FORMATION Intramolecular Aldol Condensation of 1,5-Diketones 6-exo-trig; favored process O O R' R' base - H2O R R O - DeMayo reaction to 1,5-diketones O O O O O H DIBAL-H hν O O H 3C Intramolecular Alkylations (SN2 reaction) Radical Cyclizations Acyloin Reaction Birch Reduction Organic Reactions 1992, 42, 1. Aromatic Substitution (Carey & Sundberg, Chapter 11) Intramolecular Wittig Reaction Sigmatropic Rearrangements O 167 7-MEMBERED RING FORMATION 168 Medium Sized Rings 7-Membered Rings [4+2] cycloadditions - [4+2] cycloadditions between dienes and allylcations leads to cycloheptadienes review: ACIEE 1984, 23 , 1; ACIEE 1973, 12 , 819 + + + I + CF3CO2Ag ACIEE 1973, 12, 819 ACIEE 1984, 23, 1 -78°C Me ZnCl2, -30°C ACIEE 1982, 21, 442 + + H H F3CCO2 SiMe3 SiMe3 O O OTMS + JACS 1982, 104 , 1330 ZnCl2 Br O OMe O O + O O O + O O O O O JACS 1979, 101, 226 O mCPBA O HO - Noyori [4+2] cycloaddition of α,α'-dibromoketones and dienes review: ACR 1979, 12 , 61 O R R Br Br Fe2(CO)9 -orZn-Cu O OM R R R + R ACR 1979, 61 Organic Reactions 1983, 29, 163 7-MEMBERED RING FORMATION O O Br Fe2(CO)9 Br Br O Br Zn Br O O Br 169 O CO2Me O N Br Br Br MeO2C 1) N JACS 1978, 100 , 1786 Tetrahedron 1985, 41, 5879 Fe2(CO)9 2) Zn Br O O OMe O O O + O O + O O O O O O mCPBA JACS 1979, 101, 226 O HO O O Me Me Br Br 1) H2, Pd/C 2) CF3CO3H O 1) Fe2(CO)9 OH O O O H O JACS 1972, 94, 3940 JOC 1976, 41, 2075 H O O O 1) CF3CO3H 2) LDA, MeI O O Me O Me CO2H Me OH JCSCC 1985, 55 O Me OBn OBn OH OH OBn O - [4+2] cycloaddition between pentadienyl cations and olefins + + O HO OH ∆ O - O + O + O O Tetrahedron 1966, 22, 2387 JOC 1987, 52, 759 7-MEMBERED RING FORMATION O MeO OMe OMe SnCl4 OMe O O JACS 1977, 99, 8073 JACS 1979, 101, 6767 JACS 1981, 103, 2718 Seven-Membered Rings from Funnctionalization of Tropone Organic Reactions 1997, 49, 331-425 O- O O Cl R R JOC 1988, 53, 4596 JACS 1987, 109, 3147 O - [6+4] cycloadditions of tropones with dienes [6+4] O JACS 1986, 108, 4655 JOC 1986, 51, 2400 150°C O (88%) O HO HO HO OH Ingenol - [4+2] cycloaddition between tropone and olefins O O [4+2] 150°C (81%) Radical Ring Expansion Reactions - one carbon ring expansions O O CO2Me (CH2)n n = 1,2,3 NaH, CH2Br2 Br CO2Me nBu3SnH CO2Me (CH2)n (CH2)n • CO2Me (CH2)n (CH2)n O •O O nBu3SnH, AIBN • CO2Me O JACS 1987,109, 3493 JACS 1987,109 , 6548 (CH2)n CO2Me 170 7-MEMBERED RING FORMATION O O Bu3SnLi BrCH2SePh CH3 171 O • SePh SnBu3 SnBu3 Tetrahedron 1989, 45, 909 Tetrahedron 1991, 47, 6795 O •O + Bu3Sn• SnBu3 - more than one carbon expansion O R O X (CH2)n (CH2)n SnBu3 Tetrahedron 1989, 45, 909 Tetrahedron 1991, 47, 6795 R X= I, SePh n= 1,2 Br Bu3SnH, AIBN, C6H6, reflux Br + JOC 1992, 57, 7163 O O Eight-Membered Rings [4+4] Cycloaddition of Dienes O review:Tetrahedron 1992, 48 , 5757. Ni(COD)2, Ph3P MeO2C MeO2C JACS 1986, 108 , 4678 MeO2C MeO2C 60°C O O O O O O Ni(COD)2, Ph3P H 60°C H O Asteriscanolide Carbonyl Coupling Reactions - Acyloin Reaction CO2Me O Na CO2Me JACS 1971, 93 , 1673 OH - McMurry Reaction R R CO2Et Ti (0) O O JACS 1988, 110 , 5904 7-MEMBERED RING FORMATION 172 CHO OHC TiCl3, Zn-Cu H JACS 1986, 108 , 3513 H Aldol-like Condensations O O TiCl4 O OTMS OH JCSCC 1983, 703 O SiMe3 SiMe3 (CH2)n R Lewis Acid R O O (CH2)n OMe O JACS 1986, 108 , 3516 n= 1,2 Me3Si Cl SnCl4 OTs O tBuPh2SiO Cl Cl Me3Si OTs O O tBuPh2SiO OEt Laurenyne TiCl4 O SiMe3 JACS 1988, 110 , 2248 JOC 1988, 53 , 50 O Pinocol Rearrangement O Me3SiO SnCl4 Me3SiO + OMe JACS 1989, 111 , 1514 OMe OMe H OMe Tiffeneu-Demyanov Ring Expansion - one carbon ring expansion for virtually any size ring O HO 1) Me3SiCN 2) LAH N2 NH2 HONO O H O JOC 1980, 45 , 185 - also see Beckman and Schmidt rearrangements as a one atom ring expansion for the conversion of cyclic ketones to lactams. 7-MEMBERED RING FORMATION 173 DeMayo Reaction O O O O hν O O + OAc AcO O JCSCC 1984, 1695 O O O O O O hν, pyrex O O CO2Me H pTSA, MeOH reflux JACS 1986, 108 , 6425 O O H Ring Expansion/Contraction via Sigmatropic Rearrangements - Cope Rearrangement O O SMe TL 1991, 32 , 6969 55°C O O O O - Anion Accelerated Cope KH, 18-C-6 115°C O JACS 1989, 111, 8284 OH O OCOCH2OH Pleuromutilin - Claisen Rearrangement O O O Tebbe reagent O 185°C H TL 1990, 31 , 6799 7-MEMBERED RING FORMATION - Ester Enolate Claisen- 4 carbon ring contractions O 1) LDA, TBS-Cl 2) 110°C O CO2H JACS 1982, 104 , 4030 Tetrahedron 1986, 42 , 2831 MOMO MOMO H O O 1) LDA, TBS-Cl 2) 110°C JOC 1988, 53 , 4141 H H CO2TBS 174 Exam 1 page 1 of 5 1. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of the products and reactants is as shown. (20 pts) OH HO HO CO2CH3 OH OH O OH OH O OH O N CO2H O O O O O OH O O OH OH page 2 of 5 2. Give the product of the following reactions. The stereochemistry of the reactant is as shown. Give the proper sterochemistry of the major steroisomer of the product. (20 pts) OsO4, MNO O O O (CH3)2CuLi tBuMe2SiO O mCPBA O O 1) LDA, THF Ph N O 2) H 3C Ph O Ph SO2Ph N O Ph H O OCH3 CH3MgBr page 3 of 5 3. What are the following reagents used for. Please be specific. (8 pts each) + Ir P(C6H11)3 PF6 - N PPh2 PPh2 H H N N Bu2BOTf, iPr2NEt Mn O O tBu 4. O tBu Give the reagent(s) needed to selectively deprotect the substrate below to the desired product. (16 pts) BnO O OSitBuMe2 O BnO AcO O O OSitBuMe2 BnO O OSitBuMe2 OH AcO O OH OH BnO O OH O OH OSitBuMe2 O AcO O O O AcO O page 4 of 5 5. Provide the product and all intermediates for the following sequence of reactions. (20 pts) 1) LiAlH4 2) MnO2 3) tBuMe2SiCl, pyridine O O 4) pCH3C6H3SO2NHNH2 H+, C6H6 (- H2O) 5) NaCNBH3 page 5 of 5 6. Starting from cyclohexanone, provide a feasible synthesis target shown. Give all reagents and intermediates. (16 pts) O ~ 4 steps Exam 2 1. page 1 of 5. Give the product of the following reactions. The stereochemistry of the reactant is as shown. Give the proper sterochemistry of the major stereoisomer of the product. (24 pts) _ + MeO2CNSO 2NEt3 Me PhH, ∆ Ph OH O Cp2 Ti O CH2 Al(CH3 )2 Cl NNHTs a) BuLi (2 equiv) b) CH3I H O O 1) LDA, TMS-Cl 2) ∆ H OTf Pd(0), CO, MeOH O Cl 1) CH2 N2 2) hν, MeOH 2. page 2 of 5. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of the products and reactants is as shown. (24 pts) CHO CO2 Me O CO2 Me O O H O H H H H H H H O OH O O Ph O O H H page 3 of 5. 3. Give the expected product from a thermal and photochemical [2+2] cycloaddition of cycloheptenone with ethylene. Using MO's, clearly show why the photochemical and thermal pathways give different stereochemical outcomes. (12 pts) O + 4. page 4 of 5. Provide the product and all intermediates for the following sequence of reactions. (20 pts) 1) cyclopentene, hν O 2) DIBAL O 4a) (CH3)2CuLi 3) tBuO-K+ O b) Tf2NPh 5) Ph2CuLi 5. page 5 of 5. Complete the synthesis for the target shown. Give all reagents and intermediates. (20 pts). OH ~5 steps OH O O Exam 3 1. page 1 of 6. Give the product of the following reactions. The stereochemistry of the reactant is as shown. Give the proper sterochemistry of the major stereoisomer of the product. (20 pts) CpCo(CO)2 R R CHO NHBn I2 CO2 H H H2 , Pd/C O N H CH3 O O N Ph O a) Bu2BOTf, Et3N b) PhCHO 2. page 2 of 6. Give the reagent(s) necessary to carry out the following transformations. The stereochemistry of the products and reactants is as shown. (20 pts) Ph Ph CHO OH CH3 O OBn OBn OBn OBn OH O CO 2H O OMe OMe OMe O Me O O OH OH OEt O OEt I O CN page 3 of 6. 3. Short Answers. (5 points each, 20 points total) a. Define enantioselective and enantiospecific and give examples of each. b. What is the Stork-Eschenmoser hypothesis? page 4 of 6. c. What are Baldwin's Rules (be general, do not give each specific rule)? Be sure to explain what are the basis of the rules and give one example each of a reaction that is favored and disfavored according to Baldwin's rule. d. Define umpolung and give an example. page 5 of 6. 4. Provide the product and all intermediates for the following sequence of reactions. (20 pts) OH OH 1) (CH3)2 C(OCH3)2 , H+ 2) MnO2 3) (EtO)2P(O)CH2 CO 2Me, base 4) AcOH, THF, H2 O OH 5) tBuSiCl (1 equv), pyridine 6) TsCl, pyridine 7) Bu4NF 5. page 6 of 6. Complete the synthesis for the target shown. Give all reagents and intermediates. (20 pts). O ~ 6 steps O OBn O