Literature Report 3 Rapid Syntheses of (+)-Limaspermidine and (+)-Kopsihainanine A Reporter : Xiao-Yong Zhai Checker : Shubo u Date : 2017-10-30 Pritchett, B. P.; Donckele, E. J.; Stoltz, B. M. Angew. Chem. Int. Ed. 2017, 56, 12624.
CV of Brian M. Stoltz Education: 1989 1993 B.S., Indiana University of Pennsylvania 1993 1996 M.S., Yale University (John L. Wood) 1996 1997 Ph.D., Yale University (John L. Wood) 1998 2000 I Postdoctoral Fellow, arvard University (Elias J. Corey) Brian M. Stoltz 2000 2006 Assistant professor, California Institute of Technology 2006 2017 Professor, California Institute of Technology Research: Developing new methodology for synthetic chemistry, such as oxidative kinetic resolution, enantioselective allylic alkylation and aerobic oxidative annulation etc; Designing new strategies for the preparation of complex molecules, such as Cyanthiwigin F and Aspewentins A, B, C etc. 2
Contents 1 2 3 4 5 Introduction Total Synthesis of (+)-Limaspermidine Total Synthesis of (+)-Kopsihainanine A Total Synthesis of (-)-Aspidospermidine Summary 3
Introduction (+)-Kopsihainanine A Kopsia hainanensis ( 海南蕊木 ) Isolated from the Kopsia hainanensis in 2011; Possessing 6/5/6/6/6 pentacyclic ring; Exhibiting inhibitory activity against acetylcholine esterase (AChE) (IC 50 38.5 μm). Gao, K. et al. rg. Biomol. Chem. 2011, 9, 5334. 4
Introduction Selected Aspidosperma and Kopsia alkaloids E D A B C C 2 Me (+)-Limaspermidine Cylindrocarine C 2 Me Minovincine E D E D C 2 Me Vincadifformine A B C (-)-Aspidospermidine A B C (+)-Kopsihainanine A Shao, Z-. et al. Angew. Chem. Int. Ed. 2013, 52, 4117. 5
Retrosynthetic analysis A B E C D (-)-Aspidospermidine A PG E D C PG A B C (+)-Kopsihainanine A B ydrolysis of the nitrile group Selective reduction ighly cis-selective cyclization C Enantioselective decarboxylative allylic alkylation C E PG D PG Shao, Z-. et al. Angew. Chem. Int. Ed. 2013, 52, 4117. 6
Total synthesis of (-)-Aspidospermidine Cl LDA, TF, -78 o C C t-buk TF/t-Bu (10:1) (83% ) (78% ) 1 2 [Pd2(dba)3] (2.5 mol %) L2 (6.25 mol %) C C toluene, 70 o C Asymmetric decarboxylative allylation 3 4 PPh 2 L2 t-bu 7
Asymmetric decarboxylative allylation C C C [Pd2(dba)3] (2.5 mol %) ligand (6.25 mol %) solvent, temperature 3 4 4' + Entry L Solvent T/ o C 4:4 Yield/% ee of 4 1 L1 toluene 70 0:100 0-2 L2 toluene 70 19:1 93 92 3 L3 toluene 70 6:1 75-74 PPh 2 Ph 2 P L1 4 L4 toluene 70 6:1 80-40 5 L5 toluene 70 3:1 66 22 PPh 2 PPh 2 6 L2 TF 70 1.6:1 51 89 L2 t-bu L3 Ph 7 L2 m-xylene 70 3.4:1 64 93 8 L2 benzene 70 4.6:1 74 76 9 L2 toluene 55 1.7:1 57 88 PPh 2 PPh 2 PPh 2 PPh 2 10 L2 toluene 80 2.7:1 67 91 L4 L5 8
Total synthesis of (-)-Aspidospermidine C C 2 LiAl 4, TF, -20 o C C 2, RT then Cl (2 M) (93% ) (94% ) Chemoselective reduction Diastereoselective cyclization ee = 92% ee = 91% 4 5 6 K 2 s 4 2 2, M TF/ 2 (1:1) then ai 4 (95% ) 1,2-ethanedithiol BF 3 Et 2, DCM (94% ) S S Raney nickel, 2 Et, 60 o C (91% ) 7 8 LiAl 4, Et 2, reflux a/ 3, TF, -78 o C (89% ) (95% ) 9 10 11 9
Diastereoselective cyclization C 2 LiAl 4, TF, -20 o C then Cl (2 M) C 2 2 2 She, X. et al. Chem. Eur. J. 2012, 18, 6729. 10
Total synthesis of (-)-Aspidospermidine C C 2 LiAl 4, TF, -20 o C C 2, RT then Cl (2 M) (93% ) (94% ) Chemoselective reduction Diastereoselective cyclization ee = 92% ee = 91% 4 5 6 K 2 s 4 2 2, M TF/ 2 (1:1) then ai 4 (95% ) 1,2-ethanedithiol BF 3 Et 2, DCM (94% ) S S Raney nickel, 2 Et, 60 o C (91% ) 7 8 LiAl 4, Et 2, reflux a/ 3, TF, -78 o C (89% ) (95% ) 9 10 11 11
Total synthesis of (-)-Aspidospermidine 2-chloroacetyl chloride Et 3, DCM, 2 h (69% ) Cl ai, acetone, reflux then EtAc (72% ) 11 12 13 LiAl 4, TF rt to reflux (62% ) (-)-Aspidospermidine (14) 12
Total synthesis of (+)-Kopsihainanine A B 3 TF, -20 o C then ab 3, RT MsCl, Et 3, DCM, 0 o C then a, DMF, 0 o C to RT (33% ) (50% ) 6 15 LDA, a 2 S 3 2, 0 o C to RT AlCl 3, toluene Cl Cl Cl Al (58% ) 16 17 saturated aqueous solution of Rochelle salt RT, overnight (71% ) (+)-Kopsihainanine A (18) 13
Retrosynthetic analysis of (+)-Kopsihainanine A Palladium Catalysis and Regiodivergent Cyclizations (2016) Et Pd-Catalyzed Allylic Alkylation 59-83% yield 87-96% ee Et Et Et Et Aspidospermidine Goniomitine Qubrachamine Stoltz, B. M. et al. Angew. Chem. Int. Ed. 2016, 55, 13529. 14
Retrosynthetic analysis of (+)-Kopsihainanine A R hydride addition is stereodefining C trans-fused (+)-Kopsihainanine A X B R C-C bond formation - 2 A R + - 2 X D R C-C bond formation is stereodefining (+)-Limaspermidine E cis-fused Stoltz, B. M. et al. Angew. Chem. Int. Ed. 2017, 56, 12624. R 15
Total synthesis of (+)-Limaspermidine (1) LMDS, allyl cyanoformate TF, -78 o C to 0 o C (2) C 2 C 2 I, K 2 C 3 (80% over 2 steps) L1 (12.5 mol %) Pd(pmdba)3 (5 mol %) TBME, 60 o C (82% yield, 94% ee) 1 2 Cp2Zr()Cl 2 S 3 TF Pictet-Spengler cyclization LiAl 4, Ac, 2 TF, 0 o C to 23 o C 2 3 4 5 K 2 C 3, BrC 2 C 2 (62% over 3 steps) PAr 2 6 Ar = 4-CF 3 -C 6 4 t-bu (S)-(CF3)3-t-BuPX (L1) 16
Pictet Spengler cyclization LiAl 4, Ac, 2 TF, 0 o C to 23 o C 2 LiAl 4 2-17
Total synthesis of (+)-Limaspermidine (1) LMDS, allyl cyanoformate TF, -78 o C to 0 o C (2) C 2 C 2 I, K 2 C 3 (80% over 2 steps) L1 (12.5 mol %) Pd(pmdba)3 (5 mol %) TBME, 60 o C (82% yield, 94% ee) 1 2 Cp2Zr()Cl 2 S 3 TF Pictet-Spengler cyclization LiAl 4, Ac, 2 TF, 0 o C to 23 o C 2 3 4 5 K 2 C 3, BrC 2 C 2 (62% over 3 steps) PAr 2 6 Ar = 4-CF 3 -C 6 4 t-bu (S)-(CF3)3-t-BuPX (L1) 18
Total synthesis of (+)-Limaspermidine MsCl, DIPEA, DCM, -20 o C ab 4 Kt-Bu, TF, 0 o C to 23 o C 6 7 Et, 0 o C (72% over 2 steps) BF 3 Et 2 EtS, 0 o C to 23 o C (84% yield) 8 (+)-Limaspermidine (9) 19
Total synthesis of (+)-Kopsihainanine A (1) LMDS, allyl cyanoformate TF, -78 o C to 0 o C (2) DBU, methyl acrylate (92% over 2 steps) 1 10 C 2 Me L1 (12.5 mol %) Pd(pmdba)3 (5 mol %) MTBE, 60 o C (90% yield, 92% ee) Rh-catalyzed hydroboration RhCl(PPh3)3 (5 mol %) catecholborane ab 3 4 2 (87% yield) 11 Me 2 C 12 Me 2 C (1) MsCl, Et 3, DCM, 0 o C (2) a 3, DMF, 60 o C (88% over 2 steps) 13 Me 2 C Staudinger reduction PPh 3 (polymer -bound) TF/ 2 (5:1), 65 o C 3 (81% yield) 14 C 2 Me PAr 2 Ar = 4-CF 3 -C 6 4 t-bu (S)-(CF3)3-t-BuPX (L1) 20
Rh-catalyzed hydroboration RhCl(PPh3)3 (5 mol %) catecholborane ab 3 4 2 Me 2 C Me 2 C R ab 3 4 2 B R [RhClL3] -L B [RhClL2] R B L Rh L Cl B L Rh L Cl -L R R B Rh L Cl oth,. et al. Angew. Chem. Int. Ed. 1985, 24, 878. 21
Total synthesis of (+)-Kopsihainanine A (1) LMDS, allyl cyanoformate TF, -78 o C to 0 o C (2) DBU, methyl acrylate MeC, 23 o C (92% over 2 steps) 1 10 C 2 Me L1 (12.5 mol %) Pd(pmdba)3 (5 mol %) MTBE, 60 o C (90% yield, 92% ee) Rh-catalyzed hydroboration RhCl(PPh3)3 (5 mol %) catecholbormate, TF, 23 o C ab 3 4 2 TF/ 2, 85 o C (87% yield) 11 Me 2 C 12 Me 2 C (1) MsCl, Et 3, DCM, 0 o C (2) a 3, DMF, 60 o C (88% over 2 steps) 13 Me 2 C Staudinger reduction PPh 3 (polymer -bound) TF/ 2 (5:1), 65 o C 3 (81% yield) 14 C 2 Me PAr 2 Ar = 4-CF 3 -C 6 4 t-bu (S)-(CF3)3-t-BuPX (L1) 22
Staudinger reduction PPh 3 (polymer -bound) TF/ 2 (5:1), 65 o C Me 2 C 3 (81% yield) C 2 Me R 1 R 1 R 1 + PPh 3 PPh 3 R 2 R 2 R 2 PPh 3 R 1 R 2 PPh 3 R 1 R 2 PPh 3 R 1 2 + PPh 3 R 2 23
Total synthesis of (+)-Kopsihainanine A 14 Bischler-apieralski Cyclization 2-Cl-pyr, Tf 2, DCM, -20 o C to 23 o C C 2 Me ab 4, Me, -20 o C (84% yield) 15 C 2 Me TBD toluene/tf (5:1), 80 o C (65% yield) 16 LDMA, MPA, (TMS)2 TF, -78 o C to 0 o C (91% yield) (+)-Kopsihainanine A (17) 24
Bischler-apieralski cyclization 2-Cl-pyr, Tf 2 DCM, -20 o C to 23 o C C 2 Me ab 4 C 2 Me Tf Tf -Tf Tf -Tf Tf Tf - ab 4 25
Total synthesis of (+)-Kopsihainanine A Bischler-apieralski cyclization 2-Cl-pyr, Tf 2, DCM, -20 o C to 23 o C TBD 14 C 2 Me ab 4 (84% yield) 15 C 2 Me toluene/tf (5:1), 80 o C (65% yield) 16 LDMA, MPA, (TMS)2 TF, -78 o C to 0 o C (91% yield) (+)-Kopsihainanine A (17) 26
Summary (-)-Aspidospermidine (-)-Aspidospermidine: 13 Steps, 11.1% overall yield; (+)-Kopsihainanine A: 9 Steps, 3.6% overall yield; The first catalytic enantioselective total synthesis of (+)-Kopsihainanine A; The first Pd-catalyzed enantioselective decarboxylative allylic alkylation of carbazolone enolates. Shao, Z-. et al. Angew. Chem. Int. Ed. 2013, 52, 4117. (+)-Limaspermidine (+)-Kopsihainanine A (+)-Limaspermidine: 8 Steps, 25.0% overall yield; (+)-Kopsihainanine A: 10 Steps, 16.0% overall yield; Enantioselective Pd-catalyzed allylic alkylations of DPI; ne-pot hydroamination/reduction/pictet Spengler sequence; Bischler apieralski cyclization. Stoltz, B. M. et al. Angew. Chem. Int. Ed. 2017, 56, 12624. 27
The first paragraph Monoterpene indole alkaloids from the structurally related Aspidosperma and Kopsia families have been studied for more than half a century owing to their intricate polycyclic structures and broad biological activities. ne significant structural difference between these families is the ring-fusion geometry of the octa- or decahydroquinoline moiety contained within the polycyclic core. Aspidosperma alkaloids typically possess a cis-fused azadecalin motif. Conversely, members of the Kopsia family often contain a trans-fused azadecalin substructure. 28
The last paragraph In conclusion, the combination of enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DPI) substrates with stereodivergent indole iminium cyclization strategies is a powerful tool for the synthesis of monoterpene indole alkaloids. The Aspidosperma family of alkaloids can be accessed through stereodefining C-C bond formation, as highlighted herein by our synthesis of (+)-limaspermidine in eight linear steps and in 25% overall yield from tricyclic DPI. Critically, a highly productive one-pot hydroamination/reduction/pictet Spengler sequence enabled the synthesis of the cis-fused decahydroquinoline moiety present in (+)-Limaspermidine. 29
The last paragraph Furthermore, the Kopsia family of alkaloids can be accessed using a Bischler apieralski cyclization, followed by stereodefining hydride addition to furnish the opposite diastereomeric series. This capability was demonstrated through a nine-step synthesis (28% overall yield) of strained lactam 29, thereby completing a formal synthesis of (+)- kopsihainanine A. Efforts to further exploit the synthetic utility conferred by the DPI substrate class, particularly in the synthesis of more highly caged Kopsia alkaloids, will be reported in due course. 30
Acknowledgement 31
The formation of DPI + Et 3, DMAP quant. C 2 (CCl)2, DMF, then AlCl 3, 50 o C 91% ab 4 TF, 0 o C to 23 o C TFA, Et 3 Si DCM, 0 o C to 23 o C 32
Formal anti-markovnikov hydroamination Cp2Zr()Cl 2 S 3, TF, 23 o C Cp2Zr()Cl 2 2 S 3 Cp2ZrCl Cp2ZrCl 33