Cheletropic Reactions Ruben Martinez Stereochemical outcome Background "We define as cheletropic reactions those processes in which two σ bonds which terminate at a single atom are made, or broken, in concert." Woodward, R.B.; Hoffman, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781–853. Cheletropic reactions are a separate class of pericyclic reactions that are subject to orbital symmetry analysis. They must obey the Woodward-Hoffman rules the same way that cycloadditions and sigmatropic rearrangements do. The HOMO of x points directly at the π system. x Disrotatory LUMO HOMO HOMO Selection rules for cheletropic reactions π electrons 4n 4n+2 4n 4n+2 S O2 CH3 150 °C H3C H -SO2 CH3 H H disrotatory elimination O S Allowed Ground State Reactions Linear Nonlinear disrotatory conrotatory conrotatory disrotatory Allowed Excited State Reaction conrotatory disrotatory disrotatory conrotatory Angew. Chem. Int. Ed. Engl. 1969, 8, 781. Sankararaman, S. Pericyclic Reactions; Wiley-VCH: Weinheim, 2005. H3C H S O2 H 150 °C H3C CH3 -SO2 Reactivity general guidline Cycloreversion & Cycloaddition C O + N N N N O S O N N O C R1 R2 singlet carbenes N N O + H H CH3 disrotatory elimination J. Am. Chem. Soc. 1966, 88, 2857. J. Am. Chem. Soc. 1966, 88, 2858. Cycloreversion Only SO2 O The HOMO of x approaches the π system at a skew angle. Conrotatory LUMO H3C H Most frequently encountered examples Linear approach vs. Non-linear approach Cheletropic reaction analysis is typically done in the addition direction. Consider fragment "x" to be a single atom that contributes two electrons to the pericyclic transition state. The approach of "x" can be either linear or non-linear. The rotation of the π system will be either disrotatory or conrotatory based on the approach of fragment "x" Linear Non-linear x Baran Group Meeting 06/01/13 C O Singlet carbene addition to olefins Singlet carbenes have an unoccupied p orbital and two non-bonding electrons in the σ orbital. Only singlet carbenes can participate in cheletropic reactions. "The most importatnt cheletropic reaction is the addition of singlet carbenes to make cyclopropanes." Anslyn and Dougherty Linear approach 4-electron Hückel forbidden 2-electron Möbius forbidden Non-linear approach 4-electron Möbius allowed 2-electron Hückel allowed Only select carbene examples will be discussed here. See K. Chen's GM on carbenes Cheletropic Reactions Ruben Martinez Sequential cycloaddition-cycloreversion and a strange caged structure Howard, J. A. K. Tetrahedron, 1993, 49, 4699. O Cl Ph Ph Cl Ph Ph Cl Cl Cl Ph Cl Ph Ph Cl Ph Cl Cl Cl bromobenzene, 160 °C, 48h 40% Cl Cl Cl [π2s+π2a+ σ2a] Cl CO Cl Ph Cl Cl Ph Cl Cl Ph Cl Cl Cl Cl Ph Cl Cl Ph Ph Ph Ph Cl Ph Cl Ph Ph Ph O Cl Cl Cheletropic elimination of CO and formation of annulenes Helv. Chim. Acta. 1989, 72, 1311. O O 1 R4 R R4 R3 -CO R3 R2 R1, R4 = CO2Me R2, R3 = Ph R2 R1 R4 90% Synthesis of new chiral σ λ -phosphenium cations Buono, G. Tetrahedron Lett. 1999, 40, 4669. R P + N 80% OMe O O 3 N 40% N P N Bn SH Et N N DMAD NPh CH2Cl2, 30 °C O via: CO2Me MeO 3 Ph Et S N S N Bn N CO2Me Bn CO Me 2 CO2Me CO2Me 78% Ph N C Δ N Et OTf Et N X Ge Ge + Y N Et Δ X=O,S Y=S, NH X Ge + Y The Chemistry of Organic Germanium, Tin and Lead Compounds, John Wiley and Sons, Chichester, 2002 (Chapter 1) Tellurium Extrusion: Synthesis of Benzocyclobutene MacNicol, D.D. Tetrahedron Lett. 1975, 24, 1893. 1.) EtMgBr Br2 PhH, rt 95% CO2Me An unprecedented tandem 1,3-dipolar cycloaddition-cheletropic elimination: a facile approach to novel push-pull olefins Cheng, Y. Org. Biomol. Chem. 2007, 5, 1282. Et N Ge R CH2Cl2, rt OMe Germanium Analogues of Carbenes Chrostowska. A. J. Organomet. Chem. 2009, 694, 43. R OTf R The intramolecular Ramberg-Bäcklund reaction: a convenient method for the synthesis of strained bridgehead olefins O Becker, K. B. Helv. Chim. Acta, 1983, 66, 1090. 2.) t-BuOK, THF, -78 °C OMe CO2Me O [4+1] O N2 O MeO2C PhMe, reflux O O R=o-anisyl SO2 CO2Me N N OMe R3 R2 2 2 N Intramolecular [4+1] Cycloaddition Spino, C. J. Am. Chem. Soc. 2004, 126, 9926. Evidence: Org. Lett. 2007, 9, 5361. Et N R1 Baran Group Meeting 06/01/13 O C6H5 C6H5 Br Na2Te Br "moderate yield" Te 500 °C 74% Cheletropic Reactions Ruben Martinez Tandem Cope-cheletropic reaction: a new molecular rearrangment Mai, D. Chem. Comm. 1996, 1181. Nitric oxide cheletropic traps (NOCTs) Ingold, K.U. J. Am. Chem. Soc. 1994, 116, 2767. Korth, H.G. Angew. Chem. Int. Ed. Engl. 1997, 36, 1501. O O heat H 89% O O O Baran Group Meeting 06/01/13 O H hυ NO N O -CO 12h, rt O hυ O O O CO "magic dust" Ph retro-Cheletropic ene Reactions with 2-carbena-1,3-dioxolane as the chelefuge Vidal, A.; Sanchez-Andrada, P. Tetrahedron 2011, 67, 5590. PhMe, reflux, 1 h H O 44% Ph Ph EtO2C H N OMe C O N S O NH PhMe, 160 °C, 24 h 55% CO2Et O N S O Ar J. Am. Chem. Soc. 1966, 88, 582. Chem. Commun. 1994, 2155. retro-cheletropic ene reaction N S CO2Et O CF3 O O O CO2 + H2C CH2 O O O CF3 hυ -CO2 -CO2 O Ar matrix + CO hυ +CO Ar matrix O hυ hυ -CO O Ar matrix -197 °C O CO2Et 6π electrocyclic ring closure O H N reduction Phenanthryne and bis-benzyne Murata, S. J. Org. Chem. 1995, 60, 2344. Yabe, A. J. Am. Chem. Soc. 2002, 124, 4512. Me O Ph Ph fluorescent non-radical products CO2Et N O -CO N N C C NO hυ Ph Ph Ph Ph O Ph O -CO CF3 O O O O CF3 hυ Ar matrix CF3 CF3 O O CF3 CF3 characterized by IR Cheletropic Reactions Ruben Martinez Applications in Total Synthesis -The examples presented here will consist of the three main cheletropic reactions seen in total synthesis. Cheletropic reactions involving Fischer carbenes will not be discussed here beyond examples of the Simmons-Smith cyclopropanation. For an in depth presentation and discussion of Fischer carbenes see K. Chen's group meeting on Fischer carbenes. Synthesis of estra-1,3,5,(10)-trien-17-one Nicolaou, K.C. J. Org. Chem. 1980, 45, 1463. O SO2 O TsO SO2 Early studies on the formation of cyclobutarene Cava, M.P. J. Am. Chem. Soc. 1959, 81, 4266. Baran Group Meeting 06/01/13 + 2 equiv. O 1.) KH DME, 25 °C, 15 h SO2 2.) AcOH-THF-H2O 45 °C, 24 h 1 equiv. 77%,1:1 mixture separated by chromatography DBP, 210 °C, 8 h Δ O O H -The first report of this type of reactivity dates back to 1913. This topic remained unexplored until it was returned to in 1935. Staudinger, H. German Patent 506,839; [Chem. Abstr. 1913, 25, 522] Staudinger, H. Chem. Ber. 1935, 68B, 455. H 85% H Cheletropic extrusion of SO2: The search for a diene equivalent Stereoselective Synthesis of the Taxane Ring System. Winkler. J.; Houk, K. J. Org. Chem. 1997, 62, 2957. Inspiration from W. Oppolzer Winkler's retrosynthetic analysis: H H + Oppolzer, W. Synthesis 1978, 11, 793. H O H O K.C.N.'s idea: intramolecular trapping of o-quinodimethanes H I O S O O2S LHMDS, THF -78 C, 57% brsm 2 steps from known diene alcohol SO2 O O H BF3-Et2O (6 equiv) 5 mM in PhMe 82% Potential problem n H n= 2,3 n 1,5-hydride shift CH3 n= 2,3 The methylstyrene side product was observed in only a small (unspecified) amount. ZnCl2 (2 equiv) O H DCM, rt 63% H "It is interesting to note that neither Lewis acid is capable of catalyzing both Diels-Alder reactions." H O H PhMe, reflux 50 min, 80% Cheletropic Reactions Ruben Martinez O Total Synthesis of Colombiasin A Nicolaou, K.C. Angew. Chem. Int. Ed. 2001, 40, 2482. Full paper: Chem. Eur. J. 2001, 7, 5359. OH 2 Total Synthesis of (+)-Rishirilide B Pettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625. 12 1 O H First generation: 7 AgO, 6M HNO 3 H 7 HO 1,4-dioxane, rt, 3 h 27% OMe 12 H O OBn O O 12 HO OMe 1,4-dioxane, rt, 3 h <1% desired product HO + H O 7 many by-products lacking the diene system H steps DDQ Me OH O O HO O HO (+)-rishirilide B O O O O 12 9 9 The solution: An "almost" cheletropic elimination of SO3 from 11-gorgiacerol Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834. OMe OMe SO2 OMe 12 CO 2Me OMe OMe 7 O O OMe H β -elimination O AgO, 6M HNO 3 7 Diel-Alder and O O OMe H OBn Me steps 12 Second generation: OMe TBSO OBn SO2 OMe ZnO 155 °C 9 9 TBSO OMe 1.) SO2, h υ 2.) MeOH, p-TsOH + "numerous unidentified by-products" O 7 11 H 10 colombiasin A OMe OMe TBSO 9 8 O OMe O Baran Group Meeting 06/01/13 TBSO H rt, 20 min OMe 7 9 91% 9 H SO2 AgO 6M HNO 3 1,4-dioxane rt, 3h 85 % O CO 2Me O NHR Burgess' reagent O PhH, reflux OH O O 40% 12 colombiasin A BBr 3 cyclooctene DCM HO H -78 °C, 30 min 7 43% brsm OH 2 8 PhMe 12 1 9 H O 10 CO 2Me OMe O 11 HO O H 180 °C, 20 min 89% exclusive endo product O 7 9 H SO2 12 R = CO 2Me O O H O O O O SO2 NHCO 2Me MeO 2H 2CN H O O S O O Cheletropic Reactions Ruben Martinez Total Synthesis of (+)-Estradiol Rigby, J. H. J. Am. Chem. Soc. 1999, 121, 8237. Ramberg–Bäcklund Reaction The reaction was first discovered in 1940 but no further work was published until 1950. LG Base LG R1 O S R1 H O O R1 S O R2 O R2 R1 O S R2 S O R2 O R1 SO2 + TMSC CH Co2(CO)6 + + R2 S O2 S R2 (Z) O R1 LG O Br Br TBDPSO 1.) Na2SAl2O3 Cl 2.) mCPBA O2S 3.) SO2Cl2 4.) mCPBA TBDPSO O2 S 1.) MeLi 2.)TBAF steps O H O I Br O OH O O H O O O eremantholide A TMS2S NaOMe O THF, 0 °C 50% S O H O O O 1.) (Et)3COK O HMPA DME, 70 °C O 5 min 2.) 6N HCl-THF O2S H O 25 °C, 4h 70 % Cl over two steps HH 1.) hυ 2.) CO 70% TMS H TMS 1.) HF/MeCN TMS SO2 1.) t-BuOk, -105 °C 2.) NCS (1 equiv.) H 3.) t-BuOK, 105 °C 65% H 2.) Cl3CCCl3 20 °C, 1 h 57% S O inseparable mixture THF, rt 71% H OH H H Pb(OTFA)4 TFA 80% H TMS H H steps MeO OMe OMe 1.) p-TsOH HS OMe OMe OMe OH O H HO estradiol O H O H TMS Total Synthesis of Ampelopsin D Snyder, S. A. J. Am. Chem. Soc. 2009, 131, 1753. O O H OH 6N HCl-THF 25 °C, 10 h oxone MeOH-H2O 25 °C, 6h Amberlyst-15 DCM, 25 °C, 4h 99% 1.) LiHMDS THF, - 78 °C OTBS KNH(CH2)3NH2 2.) Et3SiH/TFA TMS 38% MeO O (CO)3Cr 85% OTBS O O TMS OH OH O OTBS + (CO)3Cr TBDPSO O (MeCN)3Cr(CO)3 THF 2.) Br2, Et3N 70% O2 S OTBS (E) A Novel application of the Ramberg-Bäcklund Rearrangement to a Highly StereoselectiveSynthesis of (+)-Eremantholide A Boeckman, R. K. J. Am. Chem. Soc. 1991, 113, 9682. O2 S 1.) PhMe, reflux 30% R2 R1 Early studies toward the synthesis of the enediyne moeity of calicheamicin Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 7360. TBDPSO Baran Group Meeting 06/01/13 2.) m-CPBA MeO OMe OMe MeO O S O OMe Cheletropic Reactions Ruben Martinez Total Synthesis of Ampelopsin D continued MeO OMe OMe MeO 2.) BBr3 O S O Directed Heterodimerization: Stereocontrolled Assembly via Solvent-Caged Unsymmetrical Diazene Fragmentation Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 13002. HO 1.) t-BuOH, aq. KOH CCl4 80 °C OMe ONa O S O HN OH OH 40% over two steps OH ampelopsin D O S O I AcS steps O H O H 1.) NaOMe H O O H MeO2C H N MeO2C N H H Me O NH steps H O Me H H hirsutellone B Me O O H H H H BnO2C CO2Me hυ t-BuOH HN HN N CO2Me N H CO2Me OH O NCS, BEMP N H H Me CF2Br2, KOH/Al2O3 DCM, t-BuOH, 0 °C to rt H MeO2C H N MeO2C N N 2.)H2O2 Na2WO4 DMAP, Et3N CH2Cl2 NH2 MeO2C H N MeO2C N BnO2C CO2Me N CO2Me N H CO2Me DMF BnO2C Total Synthesis of Hirsutellone B Nicolaou, K. C. Angew. Chem. Int. Ed. 2009, 48, 6870. O Cl S O HN CO2Me oxalyl chloride N CO2Me N H CO2Me OH HO OMe Baran Group Meeting 06/01/13 O S O CO2Me N CO2Me N H CO2Me "...the first example of directed and stereoselective C–C bond construction fusing two different cyclotryptamine fragments at vicinal quaternary stereocenters." MeO2C H N MeO2C N MeO2C H N MeO2C N BnO2C CO2Me N BnO2C CO2Me N CO2Me N H CO2Me CO2Me N H CO2Me Cheletropic Reactions Ruben Martinez Simmons-Smith cyclopropanation First discovered in 1944. Many asymmetric modifications have been throughout the years. The most notable being the Charette asymmetric modification. Et R2 R3 Zn ZnEt2 + CH2I2 EtZnCH2I EtI R1 R4 R2 R1 Hydroxyl directed Simmons-Smith I CH2 R2 R1 R3 R4 R3 R4 BzO cyclohexane 15-30 °C 83% O O hυ, pyrex filter 1.) H2 (3 atm) Pd/C (10%) 2.) selective Wittig olefination O 11 O 12 13 18 17 H BzO 3 steps O PtO2 HOAc, rt, 18h 96% longifolene O H Zn-Ag, CH2I2 PhMe, rt, 8h 56% BzO H H Simple synthetic route to the limonoid system Corey, E.J. J. Am. Chem. Soc. 1987, 109, 918. BzO "The most obvious approach" gave poor results 13 O H H H O various organocopper reagents O H H R OH H H unreacted S.M. 1,2-addition H H H β-amyrin O + H 1.) PhCO2O-t-Bu, CuBr PhCl, 115 °C, 4h 51% 2.) aq. NaOH, MeOH-THF TBSO 95% CH2OH O O -78 °C, 15 min Et2Zn, CH2I2 Et2O, 35 °C, 60 h 78% O H Li, NH3 Enantioselective total synthesis of oleanolic acid, erythrodiol, β-amyrin, and other pentacyclic triterpenes from a common intermediate Corey, E.J. J. Am. Chem. Soc. 1993, 115, 8873. O O H 1.) Zn-Ag, CH2I2 2.) PDC OH H For an excellent review on stereoselective EtZnI cyclopropanation reactions see: Chem. Rev. 2003, 103, 977. O 3 steps 13 O O O Total synthesis of (±)longifolene Oppolzer, W. J. Am. Chem. Soc. 1978, 100, 2583. BzO Baran Group Meeting 06/01/13 H Li, NH3-THF CH2OH -78 °C, 2 h 93% erythrodiol H BzO H oleanolic acid Cheletropic Reactions Ruben Martinez Total Synthesis of (±)-Taxusin Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186. OBn OBn 1.) Et2Zn, CH2I2 Et2O, rt, 6h TESO HO 4 steps AcO H H O O 1.) Li, NH3 t-BuOH H O H O 40% O O O Me O Me O Highly Enantioselective Simmons-Smith Fluorocyclopropanation of Allylic Alcohols Charette A. B. J. Am. Chem. Soc. 2013, 135, 7819. Zn(CH3CHI)2•DME HO CONMe2 O B O Bu O 76% O Me O O maoecrystal V Total Synthesis of (+)-Ambruticin Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772. Regioselective, asymmetric cyclopropanation HO O Me CONMe2 State of the art in cyclopropanation IZnEt 86% ICHF2 F -EtI ZnI F halogen scrambling ∗ OH O B O Bu O ZnEt R3 OH CO2H R2 O Me (+)-ambruticin O O PCC O taxusin O O H2, PtO2 AcOH O O O O 2.) MeOH 91% OH 2.) CH2I2, Zn/Ag 75% O O OH OMOE 1.) Lombardo reagent OH O HO OAc OMOM steps H OH OAc OBn TESO 2.) PDC 85% H OAc Total Synthesis of (±)-Maoecrystal V Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860. OBn steps Baran Group Meeting 06/01/13 OH R1 i.) Et2Zn CONMe2 O B O Bu CONMe2 R1 R3 R2 F ZnF I F R2 R3 trans R1 OH