Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Background Stereochemical outcome "We define as cheletropic reactions those processes in 150 °C 150 °C H3C CH3 H3C H which two σ bonds which terminate at a single atom H3C CH3 H3C H are made, or broken, in concert." H S H -SO H H H S CH3 -SO H CH O 2 O 2 3 Woodward, R.B.; Hoffman, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781–853. 2 2 disrotatory elimination disrotatory elimination Cheletropic reactions are a separate class of pericyclic reactions J. Am. Chem. Soc. 1966, 88, 2857. that are subject to orbital symmetry analysis. They must obey the J. Am. Chem. Soc. 1966, 88, 2858. Woodward-Hoffman rules the same way that cycloadditions and sigmatropic rearrangements do. Most frequently encountered examples Reactivity general guidline

Cycloreversion Linear approach vs. Non-linear approach O Cycloreversion & Cheletropic reaction analysis is typically done in the addition direction. S SO2 Only Cycloaddition Consider fragment "x" to be a single atom that contributes two O C O S electrons to the pericyclic transition state. The approach of "x" O O can be either linear or non-linear. The rotation of the system π N N + N N will be either disrotatory or conrotatory based on the approach N N of fragment "x" 1 C 2 Linear Non-linear O R R N N O singlet carbenes The HOMO of x + C O The HOMO of x approaches the points directly at x π system at x the π system. a skew angle. Singlet carbene addition to olefins Disrotatory Conrotatory Singlet carbenes have an unoccupied p orbital and two non-bonding electrons in the σ orbital. Only singlet carbenes can participate in cheletropic reactions. LUMO LUMO HOMO HOMO "The most importatnt cheletropic reaction is the addition of singlet carbenes to make cyclopropanes." Anslyn and Dougherty

Selection rules for cheletropic reactions Linear approach Non-linear approach Allowed Ground State Reactions π electrons Linear Nonlinear 4n disrotatory conrotatory 4n+2 conrotatory disrotatory 4-electron 2-electron 4-electron 2-electron Allowed Excited State Reaction Hückel forbidden Möbius forbidden Möbius allowed Hückel allowed 4n conrotatory disrotatory 4n+2 disrotatory conrotatory Only select carbene examples will be discussed here. See K. Chen's GM on carbenes Angew. Chem. Int. Ed. Engl. 1969, 8, 781. Sankararaman, S. Pericyclic Reactions; Wiley-VCH: Weinheim, 2005. Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Sequential cycloaddition-cycloreversion and a strange caged structure Intramolecular [4+1] Cycloaddition Howard, J. A. K. Tetrahedron, 1993, 49, 4699. O Spino, C. J. Am. Chem. Soc. 2004, 126, 9926. Evidence: Org. Lett. 2007, 9, 5361. Cl MeO2C Cl Ph Ph Ph CO Me Cl Ph Cl N N OMe 2 Ph Cl PhMe, reflux Cl Ph Ph Ph Cl O O OMe Cl Cl bromobenzene, 160 °C, 48h Cl 80% O 40% Cl Cl [4+1] Cl [π2 +π2 + σ2 ] N2 O Cl CO Cl s a a Cl Ph Cl Ph OMe CO Me Cl Cl OMe CO2Me 2 via: O Cl Ph O O 3 O 3 MeO CO Me Cl Cl Ph Cl 2 Cl Cl Ph Ph Ph Ph Ph Cl Ph Cl O Ph Ph An unprecedented tandem 1,3-dipolar cycloaddition-cheletropic elimination: Cl Cl a facile approach to novel push-pull olefins Cheng, Y. Org. Biomol. Chem. 2007, 5, 1282. Cheletropic elimination of CO and formation of annulenes Helv. Chim. Acta. 1989, 72, 1311. Ph O Et Et N Et S O 1 4 SH N CO2Me R R 1 N N S R4 R DMAD 3 2 R -CO R N NPh CH Cl , 30 °C N N CO2Me R2 R3 2 2 CO2Me Bn Bn Bn 78% 1 4 3 CO2Me R , R = CO2Me R2 R Ph N C R2, R3 = Ph R1 R4 Germanium Analogues of Carbenes 90% Chrostowska. A. J. Organomet. Chem. 2009, 694, 43. Synthesis of new chiral σ2λ2 -phosphenium cations Buono, G. Tetrahedron Lett. 1999, 40, 4669. Et Et R R N N X X Δ Δ Ge Ge + Ge Ge + N N CH2Cl2, rt N Y P + P N X=O,S Y N 40% N OTf Et Et Y=S, NH R=o-anisyl R OTf R The Chemistry of Organic Germanium, Tin and Lead Compounds, John Wiley and Sons, Chichester, 2002 (Chapter 1) 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. Tellurium Extrusion: Synthesis of Benzocyclobutene MacNicol, D.D. Tetrahedron Lett. 1975, 24, 1893.

1.) EtMgBr Br Na2Te 500 °C Br Te 2 Br 2.) t-BuOK, PhH, rt C6H5 SO O "moderate yield" 74% 2 THF, -78 °C 95% C6H5 Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Tandem Cope-cheletropic reaction: a new molecular rearrangment Nitric oxide cheletropic traps (NOCTs) Mai, D. Chem. Comm. 1996, 1181. 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 hυ NO O N O 89% -CO H O O O 12h, rt O

hυ O -CO O O CO "magic dust"

Ph Ph Ph retro-Cheletropic ene Reactions with 2-carbena-1,3-dioxolane as the chelefuge Vidal, A.; Sanchez-Andrada, P. Tetrahedron 2011, 67, 5590. h NO O υ N O -CO Ph O PhMe, reflux, 1 h Ph Ph Ph Ph O H Ph 44% N N C C fluorescent reduction Ph CO2Et non-radical products EtO2C Phenanthryne and bis-benzyne Murata, S. J. Org. Chem. 1995, 60, 2344. Yabe, A. J. Am. Chem. Soc. 2002, 124, 4512. Me

O N OMe O NH hυ hυ O C PhMe, 160 °C, 24 h -CO2 -CO H O O + CO N N Ar matrix S 55% hυ -197 °C S CO Et O +CO CO2Et 2 Ar matrix 6π electrocyclic ring closure CF J. Am. Chem. Soc. 1966, 88, 582. O 3 O O CF3 O CF3 CF3 Chem. Commun. 1994, 2155. Ar hυ hυ O retro-cheletropic O O O O O N O H ene reaction -CO2 O O CO2 + H2C CH2 Ar matrix Ar matrix O O O O N CF3 CF3 CF3 CF3 S characterized by IR CO2Et Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Applications in Total Synthesis Synthesis of estra-1,3,5,(10)-trien-17-one Nicolaou, K.C. J. Org. Chem. 1980, 45, 1463. -The examples presented here will consist of the three main cheletropic reactions seen in total synthesis. Cheletropic reactions involving Fischer carbenes will not be O discussed here beyond examples of the Simmons-Smith cyclopropanation. For an O O in depth presentation and discussion of Fischer carbenes see K. Chen's group TsO 1.) KH meeting on Fischer carbenes. DME, 25 °C, 15 h SO SO2 + 2 2.) AcOH-THF-H2O Early studies on the formation of cyclobutarene 45 °C, 24 h Cava, M.P. J. Am. Chem. Soc. 1959, 81, 4266. 2 equiv. 1 equiv. 77%,1:1 mixture DBP, 210 °C, 8 h separated by chromatography Δ SO O 2 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. H H 85% Staudinger, H. German Patent 506,839; [Chem. Abstr. 1913, 25, 522] Staudinger, H. Chem. Ber. 1935, 68B, 455. Stereoselective Synthesis of the Taxane Ring System. Winkler. J.; Houk, K. J. Org. Chem. 1997, 62, 2957. Cheletropic extrusion of SO2: The search for a diene equivalent

Inspiration from W. Oppolzer Winkler's retrosynthetic analysis:

H H +

H H H Oppolzer, W. Synthesis 1978, 11, 793. O O O

K.C.N.'s idea: intramolecular trapping of o-quinodimethanes I S O O PhMe, reflux 2 steps from LHMDS, THF O2S -78 C, 57% brsm 50 min, 80% SO known diene alcohol 2 O H BF3-Et2O (6 equiv) ZnCl2 (2 equiv) 5 mM in PhMe DCM, rt Potential problem 82% H n O 63% n The methylstyrene side product 1,5-hydride shift was observed in only a small H "It is interesting to note that neither Lewis acid is H CH (unspecified) amount. 3 capable of catalyzing both Diels-Alder reactions." n= 2,3 n= 2,3 H H O Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Total Synthesis of Colombiasin A O Total Synthesis of (+)-Rishirilide B Nicolaou, K.C. Angew. Chem. Int. Ed. 2001, 40, 2482. 2 OH Pettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625. Full paper: Chem. Eur. J. 2001, 7, 5359. 12 1 O OMe OMe H 1.) SO2, hυ ZnO 11 First generation: 7 O 2.) MeOH, p-TsOH 155 °C 9 8 SO2 OMe O H 10 colombiasin A O OMe OMe OBn OBn Me OBn AgO, 6M HNO3 + "numerous unidentified steps TBSO HO by-products" H OMe 1,4-dioxane, rt, 3 h H O O Diel-Alder and 7 7 12 27% 12 O β-elimination 9 9 O

O O Second generation: H steps O OMe O Me DDQ OMe OMe HO OH O HO O AgO, 6M HNO3 many by-products O HO O O TBSO HO + lacking the 1,4-dioxane, rt, 3 h H (+)-rishirilide B H OMe O diene system O O 7 7 12 <1% desired product 12

9 9

An "almost" cheletropic elimination of SO3 from 11-gorgiacerol Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834. The solution: OMe OMe OMe CO Me 2 CO2Me OMe AgO SO TBSO 2 H 6M HNO3 O O TBSO OMe Burgess' reagent H rt, 20 min 7 1,4-dioxane NHR OMe O 7 9 H rt, 3h PhH, reflux 12 91% O SO2 85 % 40% 9 O OH R = CO Me 12 O 2 O CO2Me O OMe

BBr3 2 OH O cyclooctene 12 PhMe HO H colombiasin A 1 H O H O O DCM HO H 180 °C, 20 min 7 O O -78 C, 30 min 11 O ° 7 O 89% 9 H MeO2H2CN S 9 43% brsm 8 exclusive endo product SO O H 10 2 O SO2 O 12 NHCO2Me Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Ramberg–Bäcklund Reaction Total Synthesis of (+)-Estradiol The reaction was first discovered in 1940 but no further Rigby, J. H. J. Am. Chem. Soc. 1999, 121, 8237. work was published until 1950. O O 2 O2 2 1.) PhMe, reflux S S LG 1 2 R1 R2 S R R (MeCN)3Cr(CO)3 Base SO2 30% + TMSC CH Co2(CO)6 R1 S R2 THF LG H S (Z) 2.) Br2, Et3N O O O O (CO)3Cr 70% TMS 85% TMS R1 S R2 + + O O 1 2 LG R R R2 R1 OTBS 1 2 S R S R O O (E) O O 2 OTBS H 1.) t-BuOk, -105 °C O S H 1.) hυ 2.) NCS (1 equiv.) + H Early studies toward the synthesis of the enediyne moeity of calicheamicin 2.) CO SO2 3.) t-BuOK, 105 °C Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 7360. (CO)3Cr H 70% 65% TMS TMS H TBDPSO 1.) Na SAl O Cl TBDPSO Br 2 2 3 1.) MeLi OH 2.) mCPBA 2.)TBAF OTBS OTBS O2S 3.) SO2Cl2 Br OH 4.) mCPBA TBDPSO TBDPSO 1.) HF/MeCN KNH(CH2)3NH2 H 2.) Et3SiH/TFA H THF, rt H A Novel application of the Ramberg-Bäcklund Rearrangement 38% TMS TMS inseparable mixture 71% to a Highly StereoselectiveSynthesis of (+)-Eremantholide A Boeckman, R. K. J. Am. Chem. Soc. 1991, 113, 9682. OH 6N HCl-THF OH 25 °C, 10 h O O H oxone H Pb(OTFA)4 steps TMS2S O O MeOH-H2O TFA O O H H H H NaOMe 25 °C, 6h 80% TMS HO H H Amberlyst-15 I THF, 0 °C estradiol O 50% S O DCM, 25 °C, 4h 99% O Br O Total Synthesis of Ampelopsin D O Snyder, S. A. J. Am. Chem. Soc. 2009, 131, 1753. MeO 1.) (Et) COK O 3 O MeO OMe OMe OH HMPA 1.) p-TsOH O O HS OMe O DME, 70 °C O O 1.) LiHMDS O steps OMe OMe 5 min THF, - 78 °C H O H H OMe O 2.) 6N HCl-THF O S O 2.) Cl3CCCl3 S O OH 2 2.) m-CPBA MeO 25 °C, 4h 20 °C, 1 h O O O S O 70 % Cl O 57% MeO eremantholide A over two steps O OMe OMe Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Total Synthesis of Ampelopsin D continued Directed Heterodimerization: Stereocontrolled Assembly via Solvent-Caged Unsymmetrical Diazene Fragmentation Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 13002. MeO HO OMe 1.) t-BuOH, OH ONa O aq. KOH O S O Cl S O OMe OH CCl4 HN CO2Me HN CO2Me 80 °C oxalyl chloride OMe OH N N 2.) BBr CO Me DMF CO Me MeO 3 H 2 H 2 O HO N N S 40% over two steps CO2Me CO2Me O OH MeO2C OMe ampelopsin D H N MeO2C N DMAP, Et3N CH2Cl2 NH2 BnO2C Total Synthesis of Hirsutellone B Nicolaou, K. C. Angew. Chem. Int. Ed. 2009, 48, 6870. MeO C MeO2C O 2 H N H N I S O MeO C AcS MeO2C 2 N N O O O O N NCS, BEMP BnO C HN O steps H H 1.) NaOMe BnO2C 2 H H S O N CO2Me HN CO2Me 2.)H2O2 Na2WO4 N N H H CO2Me CO Me Me Me H H N H N H 2

CO2Me CO2Me

CF2Br2, hυ "...the first example of directed and stereoselective C–C KOH/Al2O3 t-BuOH bond construction fusing two different cyclotryptamine DCM, t-BuOH, fragments at vicinal quaternary stereocenters." 0 °C to rt

MeO2C MeO2C OH H N H N MeO2C MeO2C steps O N N O O NH O H H H H BnO C BnO C O 2 2 CO2Me CO2Me N H H Me H H N CO2Me Me CO Me N H hirsutellone B N H 2 CO2Me CO2Me Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Simmons-Smith cyclopropanation First discovered in 1944. Many asymmetric modifications have been throughout the years. The most notable being Hydroxyl directed Simmons-Smith the Charette asymmetric modification. O O Et O R2 R3 Zn I H Li, NH CH2 13 3 R1 R4 1.) Zn-Ag, CH2I2 O O R2 3 R2 R3 H ZnEt2 + CH2I2 EtZnCH I R -78 °C, 15 min 2 4 1 4 OH 2.) PDC R1 R R R H H H EtI For an excellent review on stereoselective EtZnI cyclopropanation reactions see: Chem. Rev. 2003, 103, 977.

Total synthesis of (±)longifolene Oppolzer, W. J. Am. Chem. Soc. 1978, 100, 2583. Enantioselective total synthesis of oleanolic acid, erythrodiol, β-amyrin, and other pentacyclic triterpenes from a common intermediate O O Corey, E.J. J. Am. Chem. Soc. 1993, 115, 8873. BzO BzO 1.) H (3 atm) 3 steps O O 2 hυ, pyrex filter Pd/C (10%) cyclohexane 2.) selective 15-30 °C Wittig 12 18 13 11 Et2Zn, CH2I2 O 83% O olefination O 17 PhMe, rt, 8h 56% H H BzO BzO H H 3 steps Zn-Ag, CH2I2 PtO2

HOAc, rt, 18h Et2O, 35 °C, 60 h 96% 78% O O 1.) PhCO2O-t-Bu, CuBr longifolene PhCl, 115 °C, 4h CH2OH 51% 2.) aq. NaOH, H Simple synthetic route to the limonoid system H MeOH-THF Corey, E.J. J. Am. Chem. Soc. 1987, 109, 918. BzO 95% TBSO H H "The most obvious approach" gave poor results

β-amyrin O O O various H 13 organocopper Li, NH3-THF erythrodiol reagents R CH2OH O O + OH -78 °C, 2 h 93% H H H H H BzO oleanolic acid H H unreacted S.M. 1,2-addition Baran Group Meeting Ruben Martinez Cheletropic Reactions 06/01/13

Total Synthesis of (±)-Taxusin Total Synthesis of (±)-Maoecrystal V Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186. Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860. OBn OBn OMOM OMOE OBn OBn steps steps OH 1.) Lombardo reagent OH 1.) Et2Zn, CH2I2 TESO Et O, rt, 6h TESO 2 2.) CH2I2, Zn/Ag O O O 2.) PDC H H 75% 85% O O HO O O O O O OAc OH O O OAc OH H2, PtO2 PCC 1.) Li, NH 4 steps 3 t-BuOH AcOH AcO HO O O 2.) MeOH 40% 76% O O O O H H H H 91% OAc O O Me taxusin O

Me O Total Synthesis of (+)-Ambruticin Me O O Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772. maoecrystal V Regioselective, asymmetric cyclopropanation

Highly Enantioselective Simmons-Smith Fluorocyclopropanation of Allylic Alcohols Charette A. B. J. Am. Chem. Soc. 2013, 135, 7819. Zn(CH3CHI)2•DME HO O HO O CONMe2 State of the art in cyclopropanation Me ICHF2 F ZnI O CONMe2 IZnEt 86% -EtI B O F Bu halogen ∗ scrambling O F ZnF F OH R3 B O trans 2 1 OH i.) Et2Zn Bu I R R R2 OH O ZnEt 1 CONMe2 3 R 1 R OH O R O CONMe2 3 CO2H R Me B O R2 (+)-ambruticin Bu