A Review of Total Synthesis of Spirotryprostatin A and B Jinglong Chen Supergroup meeting Princeton University June 28 2006 Novel Mammalian Cell Cycle Inhibitors, Spirotryprostatins A and B O O H N O O N N HN H N O HN H O MeO Spirotryprostatin A Spirotryprostatin B Isolated from the fermentation broth of Aspergillus fumigatus BM939 in 1996 by Osada et al. Both compounds inhibit the mammalian cell cycle in the G2/M phase Spirotryprostatin B shows cytotoxic activity on the growth of human leukemia cell line Osada H. J. Antibiot. 1996,49,832 Osada H. Tetrahedron 1996, 52, 12651 Structure features O O H H O N O N HN N H HN N H O O MeO MeO L Spirotryprostatin A OH - O P r O o HN li N NH2 n O e HO N H HN O e NH d O O y L h -T e r d ip MeO l to ia p c h ne a e Spirotryprostatin B n S A unique spiro-fusion to a pyrrolidine (dihydro-pyrrole) at the 3-position of the oxindole The annulated diketopiperazine ring A prenyl appenage and it’s relative stereochemistry with spiro linkage Key Players Oxidative spirorearrangement of an indole ----Samuel J. Danishefsky, Spirotryprostatin A ----A. Ganesan, Spirotryprostatin B Mannich reaction on an oxindole ---- Samuel J. Danishefsky, Spirotryprostatin B Stereoselective [1,3]-dipolar cycloaddition ----Robert M. Williams, Spirotryprostatin A and B Asymmetric heck cyclization ----Larry E. Overman, Spirotryprostatin B Asymmetric nitroolefination ----Kaoru Fuji, Spirotryprostatin B Stereoselective intramolecular N-acyliminium ion spirocyclization ----David A. Horne, Spirotryprostatin A and B MgI2-catalyzed ring-expansion reaction ----Erick M. Carreira, Spirotryprostatin B O O H O N O N N H HN HN N H O O MeO Danishefsky’s Synthesis of Spirotryprostatin A 6-methoxytryptophan O O X L Oxidation N N Y MeO N OH H H R MeO N H R Tetrahydro-ß-carboline O H O N O Install double bond X HN N H O MeO R N Y N H H O Spirotryprostatin A Spiropyrrolidine-3,3’-oxindole O O H O N Danishefsky S. J. et al ACIEE 1998, 37, 1138 O N N H HN Danishefsky S. J. et al JACS 1999, 121, 2147 HN N H O O MeO Pictet-Spengler Reaction and Oxidative Rearrangement Build Spiropyrrolidine-3,3’-oxindole O PhS H CO2Me CO2Me + a NH b O 18 NBoc OMe N MeO H MeO N H H H NH2 PhS PhS cis:trans = 2:1 MeO N H c O O CO Me HN HN 2 CO Me CO Me 2 2 Br d NBoc NH NBoc MeO N OH H MeO MeO PhS PhS PhS a) CH2Cl2 , CF3CO2H,molecular sieves (4 Å), 0 °C-20 °C, 88%; b) Boc2O, CH3CN, Et3N, ∆ ,84%;c) NBS, THF, H2O, HOAc, 46%;d) CF3CO2H, CH2Cl2 , 93%. O O H O N O N N H HN HN N H O O MeO Formation of Diketopiperazine Ring and Complete the Synthesis O O O H H HN O N O N CO2Me TrocN a b N N NH + Cl HN H HN H O O O MeO SPh PhS PhS O MeO MeO O O H H O N O N c N N HN H + HN H O O d MeO MeO Spirotryprostatin A a) CH2Cl2 , Et3N; Zn,NH4Cl, H2O, THF, MeOH, 68%; b) NaIO4 , H2O, MeOH; c) PhCH3 , ∆, 80% over two steps; d) RhCl33H2O, EtOH, ∆, 41%. Troc:2,2,2-trichloroethoxycarbonyl. O O H O N O N N H HN HN N H O O MeO Danishefsky’s Synthesis of Spirotryprostatin B O H O O 8 N H O N 9 N Base HN H N O HN D O MeO MeO O OMe CO Me Ox+ 2 NH2 Pictet-Spengler ? Cyclization NH 18 X N + H X N H Ox+ H OHC O O H O N Danishefsky S. J. et al ACIEE 2000, 39, 2175 O N N H HN HN N H O O MeO Formation of Spiropyrrolidine-3,3’-oxindole by Mannich Reaction CO2CH3 O CO2CH3 CO CH HN 2 3 NH2HCl a b 3 S NH2HCl 18 NH O S N H N H CHO + O O CO CH CO CH HN 2 3 HN 2 3 CO2CH3 c CO2CH3 S R NH N R HN HN NH + NH + R N R CO2H R O Boc O O BocN 3-epi 3-epi-18-epi 18-epi a). 1.05 equiv DMSO, 6 equiv 12 N HCl, AcOH, [5 mol% PhOH],25 °C, 4 h (95%); b). NEt3 , MS 3 Å, pyridine, 0°C to RT, 9 h; c). 1.2 equiv BOP-Cl, CH2Cl2, 2.5 equiv NEt3, 0°C to 25°C, 2 d, (90%) O O H O N O N N HN H HN N H O O MeO Danishefsky’s Synthesis of Spirotryprostatin B O O O (1) TFA/CH2Cl2 (1/5) O N HN CO2CH3 HN CO2CH3 25°C, 30 min (2) N(C H ) , CH Cl s 2 5 3 2 2 HN N H N N 25°C, 4 h s N N O O Boc O Boc 86% 78% (1) 2.2 equiv LiHMDS + spirotryprostatin B THF, 0°C, 30 min 5 steps (7%) (2) 2.2 equiv PhSeCl O THF, 0°C, 2 h CO2CH3 O R SePh HN N R N HN HN CO2CH3 R N N O Boc s s O O N O N 48% 3-epi-spirotryprostatin B O Boc (3) 4 equiv DMDO 3-epi THF, 0°C, 4 h + 5 steps (7%) 81% + O CO2CH3 R HN N R N R N HN N O Boc R s O O O 6% 18-epi 18-epi-spirotryprostatin B 5 steps (1%) O O H O N O N N H HN HN N H O O MeO Ganesan’s Synthesis of Spirotryprostatin B ---Amazing effect of Proline CO2CH3 CO CH 2 3 CO2CH3 Fmoc-L-Pro-Cl O NH2 N HC(OMe)3 Pyridine, CH2Cl2 NFmoc 46% 2 steps N N N H CHO H H 68% NBS, THF-AcOH-H2O O CO2CH3 H Spirotryprostatin B 1. LDA, -78 °C 20% piperidine O 2% N HN N N and in CH Cl NFmoc 18 2 2 HN 2. PhSeBr, -75 °C O H Byproducts O 100% O O O H O N N Ganesan A. et al JOC 2000, 65, 4685 O N H HN HN N H O O MeO Williams’ Synthesis of Spirotryprostatin B X H 4 R O C 3 N 2 R O CO2H [1,3] dipolar H NR2 CO R4 O + HN 2 N 1 H COR 5 CO2R N H X O O N N N N O O O H O CO R4 HN HN 2 Spirotryprostatin B O O H O N Williams R. M. et al JACS 2000, 122, 5666 O N N HN H Williams R. M. et al Tetrahedron 2002, 58, 6311 HN N H O O MeO Asymmetric [1,3] Dipolar Cycloaddition Build the Spiropyrrolidine-3,3’-oxindole Core Ph Ph Ph Ph Ph MeO Ph O O N O HN O N O O MeO H O Diphenylmorpholinone CO Et 2 HN CO2Et Me 82% OHC OMe Toluene, MS O Me N H Isovaleraldehyde EtO2C O N H Oxindolylideneacetate O O H O N O N N HN H HN N H O O MeO Williams’ Synthesis of Spirotryprostatin B Ph MeO H MeO Ph MeO O H OH 1. D-pro-OBn, O N N BOP, Et3N, N H2, PdCl2 O N O H O MeCN (74%) O H O H O THF, EtOH HN CO2Et 2. H , Pd-C,EtOH HN CO2Et 60 psi, 36h 2 HN CO2Et 99% 3. BOP,Et3N,MeCN 94% (2 steps) TsOH 1. DCC, DMAP Toluene 89% HO N H H O O H S O N BrCCl , Heat N N 3 N LiI, py., reflux N O 34-43% O N O H O O 2. NaOMe,MeOH 70-74% H O HN HN CO2H HN CO2Et Spirotryprostatin B O O H O N O N N HN H HN N H O O MeO Williams’ Synthesis of Spirotryprostatin A Ph Ph Ph Ph O TMS O HN N OH TFA O O O O H O Toluene N Me HN MeO N 0 °C MeO OHC OMe H H Me Toluene, MS 3A 20% OMe Ph MeO MeO MeO Ph O H OH H OH N N nPrCHO, N H2, Pd(OH)2, O O O O O H O H AcOH, 65 °C THF-MeOH (quant.) HN HN HN 44% OMe OMe OMe O O H O N Williams R. M. et al OL 2003, 5, 3135 O N N Williams R. M. et al Tetrahedron 2004, 60, 9503 HN H HN N H O O MeO Williams’ Synthesis of Spirotryprostatin A MeO H H H MeO O MeO O HO O H OH N N N N N O N N O O a-c O O d O O H O H HN H + HN HN HN 31% OMe 10% 9% OMe OMe OMe + d H H H O O O N N N N N N O O O O H O H O H + HN HN HN 44% 2% 43% OMe OMe OMe 9-epi-Spirotryprostatin A Spirotryprostatin A Spirotryprostatin A (a) L-Pro-OBn HCl, BOP, Et3N, MeCN;(b) H2, Pd/C, EtOH-MeOH; (c) WSC, Et3N, MeCN; (d) p-TsOH,H2O, 3 Å sieves, toluene, 110 °C.