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. Abbreviations: BOP=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; WSC= 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
O O H O N O N N HN H HN N H O O
MeO Horne’s Synthesis of Spirotryprostatin B ---Spirocylization Induced by Acyliminium
CO2CH3 CO2CH3 CO2CH3 NH2 NH2 N NCS Cl CH2Cl2 N Cl AcOH/HCO2H H N MgSO4 N H 23 °C, 20min + 95% H 70% CHO 1. N-Troc-Pro-Cl 2. TFA
O O C18 epimer of 10 O H N CO CH 2% H O HN 2 3 N Zn N N and + HN + HN H N MeOH N 18 O C18 epimer of 11 O H reflux O Troc O 7% 11 19% 10 37%
O O H O N Horne D. A. et al ACIEE 2004, 43, 5357 O N N HN H HN N H O O
MeO Horne’s Synthesis of Spirotryprostatin B
O O O O H N O H N O N O N O N HN H a N N HN N HN HN H O + + O O O
10 Spirotryprostatin B 15% 20% 20%
a) LiHMDS(3 equiv),THF, 0°C, 30 min; then PhSeCl (3 equiv), 3 h, 0°C; then PhSeCl (3 equiv), 23°C, 16 h.
O O H O N O N N HN H HN N H O O
MeO Horne’s Synthesis of Spirotryprostatin A
CO2CH3 CO2CH3 CO2CH3 NH2 NH 2 NBS Br N N Br AcOH/HCO H Br H N 2 N H 23 °C, 20 min + Br H 56% CHO 1. N-Troc-Pro-Cl 2. TFA
O O H O O N H N O HN CO2CH3 N Zn HN H N N + HN H O O MeOH N reflux O Troc Br Br 9 Br 8 30% 26%
O O H O N Horne D. A. et al OL 2004, 6, 4249 O N N HN H HN N H O O
MeO Horne’s Synthesis of Spirotryprostatin A
O O O H H N H O N O O N
N CuI HN N N HN H H HN H O O + O NaOMe DMF
Br 8 MeO MeO Spirotryprostatin A 11% 17%
O O H O N O N N HN H HN N H O O
MeO Overman’s Synthesis of Spirotryprostatin B
3 O O η – allylpalladium Asymmetric Heck O N N Capture Cylization N HN N H H H HN HN O O HN O O O HN O
Spirotryprostatin B IL2Pd 2
O O H O N Overman L. E. et al ACIEE 2000, 39, 4596 O N N H HN HN N H O O
MeO Overman’s Synthesis of Spirotryprostatin B
OH 1. LiOH 1. Ac O, pyridine O 2 MeO2C 2. TBDPS-Cl MeO2C 2. MgBr2·Et2O; 3. 2-iodoaniline, N H iPr2NEt, AcOH AcO 1-methyl-2-chloro- I (94%, >20:1 E:Z) pyridinium iodide OTBDPS (78%) O O 3. Dess–Martin oxid. tBuOK 1. SEM-Cl, NaH N Me2AlCl; N H iPr2NEt (93%) 2. TBAF O N N (61%) H H NH HN O SEMN O O O O PO(OMe)2 19 H [Pd2(dba)3]·CHCl3 O Spirotryprostatin B (otol)3P, KOAc + NH O O THF, 70 °C O N Me2AlCl; N (72%, 19:20 = 1:1) iPr2NEt (93%) 3 N 3 N H N O 18 H SEM SEMN O SEMN 18 O I O O 20 3,18-bis-epi-Spirotryprostatin B
O O H O N O N N HN H HN N H O O
MeO Fuji’s Synthesis of Spirotryprostatin B
O2N O2N
nBuLi, Et2O HCl, MeOH O O N Ph O TBDMS Ph N OMe TBDMS N H
N 86%, 97% ee 93% NO2
O O H O N O N Fuji K. et al Synlett 1995, 367 N HN H HN N H O O
MeO Fuji’s Synthesis of Spirotryprostatin B
O N O 2 O H CN HN CHO HN a b NHBn O 55% 91%(1:1) N H
c 48%(1:1)
MeO O O O H O CO2Me CN HN BocN HN HN e d HN NCbzBn NCbzBn H O 69% 87%
a) TiCl3 (20% aqueous, 5.0 equiv), NH4OAc (5.0 equiv),MeOH:H2O (4:1), rt, 3 h; b) i. BnNH2 (1.0 equiv), DCM, rt, 3 h;ii. TMSCN (1.05 equiv), rt, 3 h; c) CbzCl (1.2 equiv), Et3N (2.4 equiv), DCM, rt, 12 h; (d) i. K2CO3, MeOH, rt, 6 h; ii. aqueous 1M HCl, rt, 0.5 h; (e) i. Pd black (80 wt %), 5% HCO2H in MeOH,20 min; ii. N-Boc-L-prolide (1.1 equiv), WSC (1.2 equiv), DMC,12 h
O O H O N O N Fuji K. et al OL 2002, 4, 249 N HN H HN N H O O
MeO Fuji’s Synthesis of Spirotryprostatin B
MeO O O MeO O O O CO CH HN BocN HN HN 2 3 a BocN b BocN HN HN N 85% H H O O O H
OH 23%
O O O O + O N HO N H H O O O N O N HN CO2CH3 c BocN N N N HN H ++HN H HN N H + HN H N O O O O O H
24% spirotryprostatin B 9% 23% 10% 21%
a) i. m-CPBA (1.1 equiv), DCM, 0 °C, 6 h; ii. PhSeSePh (0.6 equiv), NaBH4 (1.2 equiv), MeOH, reflux, 10 h; iii. 30% H2O2 (20 equiv), THF, 0 °C, 6 h. b) p-TSA (10 mol %), CH3CN, reflux, 25 min; c) i. LiHMDS, THF, 0 °C, 30 min; ii. PhSeCl, THF, 0 °C, 2h; iii. DMDO, THF, 0 °C, 4 h; iv. 4 M HCl
in dioxan, 0 °C, 30 min; v. Et3N, DCM, 4 h.
O O H O N O N N HN H HN N H O O
MeO Carreira’s Synthesis of Spirotryprostatin B
Me I Me N2 a b O O OMgI N Me N H H N 71% H
N
Me Me TIPS
O I O N Me Me NH c or N HN HN N TIPS O TIPS OMgI N N H TIPS TIPS H 93% 68% dr = 6:1
a) Piperylene, [{Rh(OAc)2}2] (1 mol%), benzene, reflux, slow addition of 8 in CH2Cl2; b) MgI2
(1 equiv), THF, sealed tube, 75 °C;c) [Pd(PPh3)4] (6 mol%), NDMBA, CH2Cl2, 30 °C. TIPS=triisopropylsilyl,NDMBA=1,3-dimethylbarbituric acid.
O O H O N Carreira E. M. et al ACIEE 2003, 42, 694 O N N HN H Carreira E. M. et al JACS 2005, 127, 11505 HN N H O O
MeO Carreira’s Synthesis of Spirotryprostatin B
Me Me O H O a O O H b,c NBoc H NH N NBoc HN 45% HN 97% HN N O O
TIPS TIPS TIPS
d,e 89%
CO2Me CO2Me O O CO2Me H H O N NBoc g NBoc f H HN HN N NBoc HN N O O 99% O
TIPS
a) NEt3, Boc-l-ProCl, CH2Cl2, RT; b) NMO·H2O, OsO4 (4 mol%), THF/tBuOH/H2O 4:4:1, RT; c) Pb(OAc)4, EtOAc, rt; d) NaClO2, 2-methyl-2-butene, tBuOH, pH 3.6 buffer, rt; e) CH2N2, Et2O, RT; f) TBAF, THF, rt; g) H2, Pd/BaSO4 (33 wt%), quinoline, EtOH, RT;
O O H O N O N N HN H HN N H O O
MeO Carreira’s Synthesis of Spirotryprostatin B
CO2Me CO2Me CO2Me O O O H NBoc a,b H c H N N NBoc NBoc HN HN HN N O 77% N O O N O O O S N N Ph 78%
O CO2Me O O N H d N NBoc c HN HN N H O O 74% 74%
Spirotryprostatin B
a) NMO·H2O,OsO4 (1 equiv), THF/tBuOH/H2O 4:4:1, rt; b) Pb(OAc)4, EtOAc, rt; c) LHMDS, THF, 78 °C; d) 1. PhSeCl, LHMDS, THF,0 °C; 2. DMDO, THF, 0 °C;
e) i. TFA, CH2Cl2, RT; ii. NEt3, CH2Cl2, rt.
O O H O N O N N HN H HN N H O O
MeO