Synthesis of spirocyclic

Synthesis of Spirocyclic Compounds Yi He • Introduction • Synthetic methodologies • Syntheses of spirocyclics in natural products – Gelsemine – Spirotryprostatin – Histrionicotoxin – Ginkgolide B • Conclusion Introduction • “Spirocyclane” introduced by Baeyer in 1900 • Widely present in natural compounds • Synthetic challenging – Chiral quaternary carbon center – Synthesis of two fused rings Methodologies for Constructing Spirocenters • • • • • Alkylations Rearrangement reactions Cycloadditions Transition metal catalyzed reactions Cleavage of bridged systems Sannigrahi, M Tetrahedron 1999, 55, 9007-9071 Alkylation X n n m m Substitution X X n n m m 1,4 - Addition Alkylation using Bis-acetal MeO MeO OMe H H H TMSOTf H MeO MeO MeO CH2OTs OTs MeO MeO Solvent Yield% A% B% CH3CN 77 71 29 52 26 74 H H OTs A H MeO H O THF OTs MeO OTs O B Tanaka, T.; Okuda, O; Murakami, K; Yoshino, H.; Mikamiyama, H; Kanda, A; Iwata, C Tetrahedron Lett 1994, 35, 4125-4128 Alkylation using Ynamine R R O Me Ph N n O MgBr, CH3CN, 70 ºC H 60-70% O H n O C N Me Ph Ph Me N R R n O + n O Me N O Ph O A B n R A% B% CH3 85 15 CH3 80 20 i-Pr 100 (±)-Acoradiene Ficini, J.; Revial, G.; Genêt, J P Tetrahedron Lett 1981, 22, 629-632 Kaiser, R.; Naegeli, P Tetrahedron Lett 1972, 13, 2009-2012 Michael Addition Ph Ph N N O CO2Me EtO2C N Boc O O a) DIEPA, CH3CN b) H2, Pd/C, CH3OH 85% steps EtO2C O N Boc H CO2Me Ph N H O EtO2C N H H O Manzamine A Brands, K M.; DiMichele, L M Tetrahedron Lett 1998, 39, 1677-1680 Rearrangement Reactions for Spiroannulation • Vinylcyclopropanol/Vinylcyclobutanol rearrangement • Pinacol-type rearrangement • Sigmatropic rearrangement Vinylcyclobutanol/Vinylcyclopropanol Rearrangement OR OR Lewis acid n n OCH3 OCH3 m m OCH3 O n n = or m = or m OCH3 Trost, B M.; Lee, D C J Am Chem Soc 1988, 110, 6556-6558 Trost, B M.; Chen, D W D J Am Chem Soc 1996, 118, 12541-12554 Williams’ 1,3-Dipolar Cycloaddition Approach Ph Ph Ph Ph HN OHC O O Me OMe Me 4Å MS, PhCH3 O N Me MeO Ph O [1,3]-dipolar cycloaddition Me Ph MeO N Me O 82% HN CO2Et Me O EtO2C HN O N H O O HN N N O Spirotryprostatin B Sebahar, P R.; Williams R M J Am Chem Soc 2000, 122, 5666-5667 O H O CO2Et Overman’s Retrosynthesis of Spirotryprostatin B O O HN η3-allypalladium capture N O O HN N HN N O O asymmetric Heck cyclization L2Pd I I O N RN HN O O Overman, L E.; Rosen, M D Angew Chem Int Ed Engl 2000, 39, 4596-4599 Overman’s Intramolecular Heck Approach H 1) SEM-Cl, NaH 2) TBAF O I N N H OTBDPS NH O 3) Dess-Martin 4) A, t-BuOK O SEMN N O SEM O O N N HN N Me2AlCl N DIEPA (93%) O [Pd2(dba)3]•CHCl3 (otol)3P, KOAc THF, 70 °C (72%, B:C = 1:1) I O O O B O O SEMN N N O O O HN Me2AlCl DIEPA (93%) H N N N A= O O O NH PO(OMe)2 C Overman, L E.; Rosen, M D Angew Chem Int Ed Engl 2000, 39, 4596-4599 (-)-Histrionicotoxin • Isolated from the skin of frog Dendrobates histrionicus • Novel spiro-piperidine structure OH H N (-)-Histrionicotoxin Daly, J W.; Karle, I.; Myer, C W.; Tokuyama, T.; Walters, J A.; Witkop, B Proc Natl Acad Soc U S A 1971, 68, 1870 Retrosynthesis of (-)-Histrionicotoxin by Stork HO HN CONH2 HO Br N H R HO CO2Me O OTBS OTBS O + O R H H Br Stork, G.; Zhao, K J Am Chem Soc 1990, 112, 5875-5876 Stork’s Synthesis of (-)-Histrionicotoxin CO2Me OTBS + + - 2) (Ph3P CH2I)I , NaN(TMS)2 HMPA, THF, 52% OTBS O LDA O 1) O3, PPh3 O 3) 5% HCl, THF 43% H Br H O OH O 1) Ph3P, CBr4, ether, 2h, 53% 2) NH4Cl, AlMe3, PhH, 40 °C, 18h I AcO AcO Br 3) Ac2O, Pry, DMAP, 70% I I 1) (CF3CO2)2IPh CH3CN, H2O, d CONH2 I HN HO HN 2) Et3N, ClCH2CH2Cl 65-70 °C, 2h, 31% I Stork, G.; Zhao, K J Am Chem Soc 1990, 112, 5875-5876 I Retrosynthesis of (-)-Histrionicotoxin by Holmes N N H R' R O HO R N O R' R NH OH R' Williams, G, M.; Roughley, S D.; Davies, J E.; Holmes, A B J Am Chem Soc 1999, 121, 400-401 Holmes’ Synthesis of (-)-Histrionicotoxin O O NaN(TMS)2 1-chloro-1-nitrosocyclohexane X X THF, then HCl (aq), 70% (CH2)3OTBDPS NHOH (CH2)3OTBDPS X = (+)-10,2-camphorsultam CN 1) PHCH3, 80 °C, h 2) styrene, 75 °C 85%, steps (CH2)3OTBDPS X O BnO N O Ph N O Ph TMS PHCH3 BnO sealed tube BnO N O N CN CN N O O 1) Zn, AcOH, 30 min, 98% 2) K2CO3, MeOH, 94% N H HO Williams, G, M.; Roughley, S D.; Davies, J E.; Holmes, A B J Am Chem Soc 1999, 121, 400-401 TMS Ginkgolide B • Isolated from Ginkgo biloba • Complex structure – Six ring in a confined space – Eleven stereogenic carbons – Four contiguous quaternary centers – Ten oxygenated carbons O HO O HO O O O Me HO O O CMe3 Retrosynthesis of Ginkgolide B’s Synthetic Intermediate by Corey MeO O MeO O O t-Bu t-Bu t-Bu H H • O O CO2H OMe MeO O OMe t-Bu O O Corey, E J.; Kang, M.-C.; Desai, M J.; Ghosh, A K.; Houpis, I N J Am Chem Soc 1988, 110, 648-651 Corey’s Total Synthesis of Ginkgolide B OMe 1) t-Bu2Cu(CN)Li2, Et2O -78 to -45 °C 2) TMSCl, Et3N, -45 to -10 °C OMe O MeO O t-Bu O 3) 1,3,5-trioxane TiCl4, CH2Cl2 -78 °C, 65% steps; 1) LDA, DME, -78 to °C then PhNTf2, to RT, 80% 2) A, Pd(PPh3)4, CuI, n-PrNH2 PhH, 16 °C, 84%; MeO MeO O 1) (Cy-Hex)2BH, THF, °C 2) AcOH, H2O2, pH 10 t-Bu OO O O 1) (COCl2)2, PhH t-Bu 2) n-Bu3N, PhCH3 80% two steps 3) N HCl, pH 4) pH 11, h, pH 86% steps CO2H Me O MeO O O t-Bu t-Bu Me H O O HO O O H • O HO HO O CMe3 O O A = Me O O O Corey, E J.; Kang, M.-C.; Desai, M J.; Ghosh, A K.; Houpis, I N J Am Chem Soc 1988, 110, 648-651 Retrosynthesis of Ginkgolide B’s Synthetic Intermediate by Crimmins Me O HO O O O CO Et O O OMe O O CO2Et O OMe CMe3 Et3SiO CMe3 Et3SiO CMe3 O EtO2C Et3SiO CMe3 Crimmins, M T.; Pace, J M.; Nantermet, P G.; Kim-Meade, A S.; Thomas, J B Watterson, S H.; Wagman, A S J Am Chem Soc 1999, 121, 10249-10250 Crimmins’ Total Synthesis of Ginkgolide B O O EtO2C CO2Et (EtO2CCH2CH2)2ZnCu O hν, 366 nm hexane 100% Et3SiO CMe3 Et3SiO CMe3 O O O CO Et O O O H O O OH dimethyldioxirane O O OH OH H2O, p-TSA, 94% Et3SiO CMe3 CMe3 CMe3 O O 1) MeOH, p-TSA CH(OMe)3, 95% 2) CS2, MeI, DBU O O 3) Bu3SnH, AIBN 60 °C, 78% steps OMe O O O HO HO O OMe O Me CMe3 HO O CMe3 O Crimmins, M T.; Pace, J M.; Nantermet, P G.; Kim-Meade, A S.; Thomas, J B Watterson, S H.; Wagman, A S J Am Chem Soc 1999, 121 10249-10250 Conclusions • Structure diversity of spirocyclic compounds • Various approaches to spirocenters Thanks • Kiessling Group Members ... 1870 Retrosynthesis of (-)-Histrionicotoxin by Stork HO HN CONH2 HO Br N H R HO CO2Me O OTBS OTBS O + O R H H Br Stork, G.; Zhao, K J Am Chem Soc 1990, 112, 5875-5876 Stork’s Synthesis of (-)-Histrionicotoxin... Gelsemine • Major alkaloid component of Gelsemium sempervirens • Novel hexacyclic cage structure • Unique spiro-oxindole center O N Me H N O Retrosynthesis of Gelsemine by Johnson O H N O N N... center – Synthesis of two fused rings Methodologies for Constructing Spirocenters • • • • • Alkylations Rearrangement reactions Cycloadditions Transition metal catalyzed reactions Cleavage of bridged