JOC YEAR IN REVIEW 1972 ALEXANDROS ZOGRAFOS THE BARAN GROUP MEETING 08/20/2003 The difficult decision Some statistics !Number of articles 1225! !Full articles 480 !More than 25 total synthesis !Isolation and characterization of 52 molecules !Several novel methods Total synthesis COOH O H OH HO H O HO OH HOOC HO O OH OH O Mirestrol (-)-Seychellene HOOC Prostagladins O Cubane derivatives OH O O O Guaiol OH O N HO O O O HO H Cinobufacin Dehydrojoubertiamine O (-)-Patchouli alcohol Jasmone O Total Synthesis of cis-Jasmone O ! Isolated from flower oils of Jasminum ! Indispensable in the reproduction of jasmine fragrance ! Several preparations have been reported First synthesis at 1952 by Harper ! Two total synthesis in 1972. Crombie, L.; Harper, S.; J. Chem Soc.; 1952, 869; Harper, S; Smith, J.; J. Chem. Soc.; 1955, 1512; Buchi, G.; Egger, B.; J. Org. Chem.; 1971, 36, 2021; Mc Murry, J.; Melton, J.; J. Am. Chem. Soc.; 1971, 93, 5309. Two Efficient Methods for the Construction of cis-Jasmone Berkowitz, W.; J. Org. Chem., 1972, 37, 341; Grieco, P.; J. Org. Chem., 1972, 37, 2363. Cl Cl C Cl O O O Et3N, 00C hexanes Cl + Corey, E.; Tetr. Lett., 1970, 307. O H2O2 Acetic acid Zn, Acetic acid Cl Cl O O DIBAL Toluene -780C O OH Cl Ph3P=CHCH2CH3 DMSO O O 1.MeLi 2.CrO3 NaOH/H2O 700C Jasmone 5150C glass wool -EtOH, CO Berkowitz, W.;J. Org. Chem. 1971, 36, 3787 Cl O O O NaH Benzene O O O cyclopropyloxopropanoate O Jones Reagent OH Highlights Baeyer-Villiger Ring Expansion O O O O H H2O2 acetic acid H O O O O O O A Thermal Two Carbon Ring-Expansion O O + CO O C O O O -EtOH O O Glass catalysed O H O O O O O H Si C O O H HO Si O + EtOH O Total Synthesis of Patchouli Alcohol HO !A tricyclic sesquiterpene isolated from patchouli oil !An important raw material for the composition of perfumes !First total synthesis by Buchi at 1956 Buchi, G.; Erickson, R.; J. Am. Chem. Soc., 1956, 78, 1262; Buchi, G.; Erickson, R.; J. Am. Chem. Soc., 1961, 927; Buchi, G.; McLeod, W.; J. Am. Chem. Soc., 1962, 84, 3205; Buchi, G.; McLeod, W.; Padilla, O.; J. Am. Chem. Soc., 1964, 86, 4438. A Synthetic Route to Racemic Patchouli Alcohol Mirrington, R.; Schmalzl, K.; J. Org. Chem., 1972, 37, 2871 O Diels Alder O + O BrZn O OH O O POCl pyridine TrCl Et3N OTr 1.B2H6, THF 2.CrO3 pyridine O OH H AcCl DMA Li,NH3 H EtOH + O + O O O O OTr OH Both E and Z regioisomers H Ratio 4:1 NaH, MeI EtONa O O 3 steps O O O OTr H O I Na sealed tube 1000C H HO (-)-Patchouli alcohol Mirrington, R.;Tetr.Lett., 1969, 5017. Danishefsky, D.; Chem.Commun., 1968, 1287. Highlights OH O O H+ maybe by carbocation O O O O AcCl O O O O H O Base elimination O O :B Li, NH3 EtOH Assisted cleavage O OH Both E and Z regioisomers OH H 4 Selective dehydration H 1 O H O O H Proton attacks from the less hindered side Stereochemistry of the reduction O Synthesis Of Cubane Derivatives HOOC ! Interesting molecular structure ! Original work by Eaton et al. at 1964 reporting several derivatives of cubane skeleton ! First synthesis of homocubane from 2cyclopentanone in less than 10% yield A Facile Synthesis of Homocubane Paquette, L.; Ward, J.; J. Org. Chem., 1972, 37, 3569 Jones Reagent SeO2 OH 1.Br2 2.Et3N Br H O O First synthesis of cubane derivatives hv O O COOH 1.KOH HOOC Br O 2.H3O Br 1.KOH hv 2.H3O Br Br O HOOC Br O 1.NBS, CCl4 2.Br2, pent-DCM O Spontaneous dimerization Br Et2NH, -200C Br O O Br Eaton, P.; Cole, T.; J. Am. Chem. Soc., 1964, 86, 962 Br Favorskii type rearrangement Highlights Spontaneous cyclization of bromo-cyclopentanones An intermolecular Diels-Alder Reaction O Br Br O Br Br O O Favorable intermediate O O Br Br Br Br O O Favorskii type rearrangement -Br OH Br Br O OH O HOOC Total Synthesis of Prostaglandins F1a and E1 O O O OH OH OH HO HO HO Prostaglandin F1a HO Prostaglandin E1 ! Prostaglandins are discovered by von Euler in 1932 ! Carbocyclic oxygenated C-20 molecules are hormones that elicit an unusually diverse array of physiological response ! Several preparations have been reported A New Method for the Preparation of Prostaglandins Schaaf, T.; Corey, E.; J. Org. Chem., 1972, 37, 2921 O O O HO O OH O 1.THP, TsOH 2.DIBAL -780C Ph3P OH DMSO, NaH THPO OCH2Ph OH OH THPO OCH2Ph OCH2Ph O P(OMe)2 O O 1.CH2N2, ether 2.Ac2O, pyridine 500C 3.H2, Pd/C 1atm 5%Acetic acid Ethanol Corey, E.; J. Am. Chem. Soc., 1969, 91, 5675 O O O O Collins Reagent, DCM 00C O O O THPO O O O O NaH, DME THPO THPO OH O O Corey, E.; J. Am. Chem. Soc., 1968, 90, 3247 NaBH4 DME, 250C O O O O THPO 1.Acetic acid/H2O, 400C 2.separation of epimers 3.KOH, MeOH, THF, 250C O OH OH HO HO HO O O OH HO Prostaglandin F1a HO Prostaglandin E1 Highlights Synthesis of Corey’s lactone PhH2CO PhH2CO NaH, THF Cl KOH, H2O DMSO CN Cu(BF4)2, 00C BnOCH2Cl -550C PhH2CO Cl O CN mCPBA NaHCO3 DCM O O 1.Ac2O, pyr. 2.n-Bu3SnH AIBN, PhH O O KI3, NaHCO3 H2O, 00C O I HO NaOH, H2O CO2 AcO OCH2Ph HO OCH2Ph HO OCH2Ph PhH2CO O O Novel Methods ! Thallium chemistry in organic synthesis ! Novel etherification of alcohols ! Palladium-Catalyzed Vinylic Hydrogen Substitution (Heck reaction) Novel Etherification of Alcohols Kashman Y.; J. Org. Chem., 1972, 37, 912 Dialkyl phosphites react with alcohols to give the corresponding ether in the presence of catalytic amount of acid R HOP(OCH3)2 O HO O P O R: C8H17 HOP(OCH3)2 H+ H OH RO: O P O H H protonated dimethyl phospite OH RO H -H+ ROCH3 O + O P O H Paladium-catalyzed Vinylic Hydrogen Substitution Background before the discovery of Heck Reaction H R H M' RMX + R + M'X HM'X M: Hg, Sn, etc HgOAc + example: Pd(OAc)2 + Hg(OAc)2 Transmetaletion PdOAc Easy to isolate H H + PdOAc H PdOAc H + PdOAc H HPdOAc + + H HPdOAc + β-elimination Disadvantages ! There is often a problem obtaining the organomercury, lead or tin compounds ! Thick slurries of salts difficult to manipulate if the reaction is carried out catalytically in palladium A New Method for the Arylation and Benzylation of Vinylic Hydrogen Heck R.; Nolley, J.; J. Org. Chem., 1972, 37, 2320 Mechanism of Heck Reaction RX + Pd RPdX H RPdX + H R PdX HPdX •Use of a base is essential in order to neutralize the hydrogen halide from the reaction R •Tolerate a number of functional groups •Iodides react rapidly. Benzyl halides are less reactive •Loss of stereochemistry. Both cis and trans products Thalium Chemistry in Organic Synthesis Background ! Thalium acetate was first described at 1903 by Meyer and Goldschmidt ! Among its applications are oxidative cleavage of cyclopropanes, the conversion of chalcones into isoflavones and the hydration of acetylenes Year 1972 ! Direct synthesis of allenic esters from βketoesters ! Oxidation of cyclohexanones to adipoins A New Synthesis of Allenic Esters Taylor, E.; Robey, R.; McKillop, A.; J. Org. Chem., 1972, 37, 2797 O R1 O R1 O R2 R H2N-NH2 R3 R2 N R3 N H R1 R3 C C C R2 O O TTN O MeOH R1, R2, R3=alkyl Mechanism R1 R1 R3 R2 N N H R3 R2 HN O TTN R2 HN O N H R1 H R3 Tl(NO3)2 O N H -H2 R1 R1 R3 C C C R2 O O R1 R3 Tl(NO3)2 R2 N N O MeOH TTN R3 Tl(NO3)2 R2 HN N H O Oxidation of Cyclohexane to Adipoins McKillop, A.; Hund, J.; J. Org. Chem., 1972, 37, 3381 McKillop, A. et al. J. Am. Chem. Soc., 1971, 93, 4919 O OH HO OH Tl Y HO O OH- HO OH OH Y H+ COOH H O -H2O O OH + OH