Collective Synthesis of Natural Products by Means of

Organocascade Catalysis

Spencer B. Jones, Bryon Simmons, Anthony Mastracchio, David W. C. MacMillan Nature 2011, 475, 183

Nate Ware, Wipf Group Current Literature 08/06/11

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Organocascade Catalysis•  Follows the “blueprints of biosynthesis”

–  cascade reaction sequences –  avoidance of protecting groups –  molecular complexity is built quickly and efficiently using simple key building

blocks

C. Grondal, M. Jeanty, D. Enders Nature Chem. 2010, 2, 167 D. Enders, C. Grondal, M. Huttl, ACIE, 2007, 46, 1570

Nate Ware @ Wipf Group Page 2 of 15 8/7/2011

Imine/Enamine Tandem Cascade

Y. Yoshitomi, H. Arai, K. Makino, Y. Hamada Tetrahedron 2008, 64, 11568

MeO2C CHO

NHTs

OBocHN

NH

Ph

OTES

Ph

MeCN, -20 ºC, 1 dayquant, 99% ee

NHBoc

N

Ph

OTES

Ph

MeO2C CHO

NHTs

NHBoc

N

Ph

OTES

Ph

MeO2C

NTs

O

IM EN

NTs

CHO

NHBoc

MeO2C

Formal Synthesisof

Martinelline

10 steps

NTs

NH2

MeO2C

HN3 HCl

Nate Ware @ Wipf Group Page 3 of 15 8/7/2011

Coupled Imine/Enamine Organocascade

B.-C. Hong, M.-F. Wu, H.-C. Tseng, G.-F. Huang, C.-F. Su, J.-H. Liao JOC, 2007, 72, 8459

O

N

O

O

H

N

AcO

AcO

O

O

AcO

N

O

O

H

NAcO

OO

AcO AcO

AcO

N

HO2C

N

O2C

AcO

AcO

CHO

70%, 95% ee

NH

CO2H

MeCN,-20 ºC, 8 h

IM IMEN EN

(+)-Palitantin

9 steps

OAc

O

HO

OH

Nate Ware @ Wipf Group Page 4 of 15 8/7/2011

Bronsted-Acid Catalysed Cascade

M. Rueping; A.P. Antonchick; T. Theissmann, ACIE, 2006, 45, 3683

N

O

OP

OH

O

Ar

Ar

Ar = 9-phenanthryl

Benzene, rt, 12 h88%, 90% ee

NH

EtO2C CO2Et NH

1. HCHO, AcOH

2. NaBH479%

N

N C5H11N C5H11

H

N

EtO2C CO2Et

P

O

ArO

OAr

OH

H

P

O

ArO

OAr

ON

EtO2C CO2Et

NH

C5H11

NH

EtO2C CO2Et

P

O

ArO

OAr

OH

NH

C5H11

N

EtO2C CO2Et

H

P

O

ArO

OAr

O

N

EtO2C CO2Et

NH

EtO2C CO2Et

NH

C5H11

P

O

ArOOAr

OP

O

ArOOAr

O

(-)-Angustureine

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Biosynthetic Intermediates to Title Paper Targets

S.B. Jones; B. Simmons; A. Mastracchio; D.W.C. MacMillan, Nature, 2011, 475, 183

NH

NH2

OMeO2C

OGluc

CHO

N

N

H

MeO2C

OH

Preakuammicine

Tryptamine Secologanin

NH

N

H

Norfluorocurarine

CHO

NH

CO2Me

N

Et

Didehydrosecodine

N

N

OO

H

H

H

Strychnine(Strychnos)

H NH

N

CO2Me

Vincadifformine(Aspidosperma or Kopsia)

Nate Ware @ Wipf Group Page 6 of 15 8/7/2011

Natural Products Derived from a Common Intermediate

S.B. Jones; B. Simmons; A. Mastracchio; D.W.C. MacMillan, Nature, 2011, 475, 183

N

N

OO

H

H

H

NH

N

H

NH

N

CO2Me

NH

N

CO2Me

NH

N

CO2MeNH

NO

NP

X

NHBoc

NP

NBoc

CHO

(-)-strychnine (+)-aspidospermidine

(-)-kopsinine

(-)-akuammicine

(+)-vincadifformine

(-)-kopsanone

H

Organocascade

Nate Ware @ Wipf Group Page 7 of 15 8/7/2011

Mechanism of Organocascade cycles

N

N

O Me

t-Bu

NPg

NBoc

CHO

N

NH

OMe

t-Bu

• HA

NPg

N XBoc

NPg

N XBoc

A

NPg

NH

XBoc

A

N

NH

OMe

t-Bu

• HA

NPg

NH

OBoc

ANPg

OR1N

R1 = Boc

NPg

NR2R1N

R1 = Boc

A

NPg

NH NR2

Boc

A

ANPg

NH NR2

Boc

A

SeMe

NPg

SeMe

NHBoc

A

1-Nap

1-Nap 1-Nap

endo[4+2]

NPg

SeMe

NHBoc

O

X =

Path B

X = OH

Path A

N

N

OMe

t-Bu

1-Nap

Cycle 1 Cycle 2

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Synthesis Towards Strychnine and Akuammicine

NH

NBoc

NPMB

CHO

1. PMB-Cl, NaH, DMF

2. SeO2, dioxane, H2O, 100 ºC

NHBoc

(EtO)2P

O

SeMe

18-c-6, KHMDS,THF, -78 ºC to rt

63% (3 steps)

NPMB

NHBoc

N

NH

OMe

1-Napt-Bu

• TBA

-40 ºC to rt, PhMe82%, 97% ee

O

H

N

NBoc

CHO

PMB

N

NH

PMB CO2MeH

N

NBoc

PMB CO2Me

1. Wilkinson's Catalyst, PhCN, PhMe, 120 ºC

2. COCl2, Et3N, PhMe, -45 ºC to rtthen MeOH, -30 ºC to rt

DIBAL-H,DCM, -78 ºC to rt

thenTFA, -78 ºC to rt61% (3 steps)

overall commonintermidiate

SeMe

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Completion of (-)-Strychnine

DBU, K2CO3, DMF

Br

I

OAc

2. DIBAL-H, DCMDCM, -78 ºC76% (2 steps)

1.

N

N

PMBH

OH

IOH

N

N

PMBH

OHO

H

H

NH

N

H

OHO

H

HN

N

OO

H

H

H

H

Pd(OAc)2 (25 mol%)

Bu4NCl, NaHCO3, EtOAc58%

PhSH,

TFA, 45 ºC66%

Wieland-Gumlichaldehyde

NaOAc, Ac2O, AcOH,

malonic acid, 120 ºC69%

(-)-strychnine

12 steps, 6.4% overall yield

N

NH

PMB CO2MeH

Nate Ware @ Wipf Group Page 10 of 15 8/7/2011

Completion of (-)-Akuammicine

N

NH

PMB CO2MeH

PhSH,

TFA, 60 ºC91%

NH

NH

CO2MeH N

H

N

CO2MeH

I

NH

N

H

Pd(OAc)2 (25 mol%), Bu4NCl,

NaHCO3, MeCN, 65 ºC47%

CO2Me

DBU, K2CO3, DMF76%

Br

I

(-)-akuammicine

10 steps, 10% overall yield

Nate Ware @ Wipf Group Page 11 of 15 8/7/2011

Synthesis of (+)-Aspidospermidine and (+)-Vincadifformine

NH

NBoc

NCHO

1. BnBr, NaH, DMF

2. SeO2, dioxane, H2O, 100 ºC

NHBoc

(EtO)2P

O

SeMe

18-c-6, KHMDS,THF, -78 ºC to rt

61% (3 steps)

N

NHBoc

N

NH

OMe

1-Napt-Bu

• TBA

-40 ºC to rt, PhMe83%, 97% ee

O

H

N

NBoc

CHO

Bn

N

N

Bn

1. Ph3PCH3I, n-BuLi, THF, 0 ºCthen AcOH, NaCNBH3, 0 ºC

2. TFA, DCM

K2CO3, DMF73% (3 steps)

ent- overall commonintermidiate

SeMe

BnBn

H3. IBr

I

N

N

BnH N

H

N

H

NH

N

CO2Me

Pd(PPh3)4, Et3N,

PhMe, 80 ºC65%

Pd(OH)2, H2 (200 psi)

MeOH, EtOAc98%

1. (COCl)2, DMSO,DCM 65%

2. NCCO2Me, n-BuLi, THF, -78 ºC to rt

57%

(+)-aspidospermidine

9 steps, 24% overall yield

(+)-vincadifformine

11 steps, 8.9% overall yield

Nate Ware @ Wipf Group Page 12 of 15 8/7/2011

Synthesis of (-)-Kopsinine and (-)-Kopsanone

R

N

NBocCHO

Bnoverall common

intermidiate

N

N

Bn N

N

Bn CO2Me

N

N

Bn CO2MeR = SO2Ph

NH

N

CO2Me

NH

NO

(-)-kopsanone

11 steps, 10% overall yield

NH

N

CO2H

HB:

H

NH

HN

HO O

200 ºC

neat

1 N HCl

130 ºC

74%

2 steps

Raney Ni,

EtOH, 78 ºC83%

(-)-kopsinine

9 steps, 14% overall yield

TMS-I, Et3N, DCM, 0 ºC

then MeOH, 40 ºC

then KOt-Bu, DCM, THF 0 ºC58%

PPh3Br

1. COCl2, Et3N, PhMethen MeOH

2. H2, Pd/C, EtOAc, EtOH69% (2 steps)

PhH, 100 ºC86%

SO2Ph

Nate Ware @ Wipf Group Page 13 of 15 8/7/2011

Title Paper Syntheses vs. Previous Syntheses

N

N

OO

H

H

H

NH

N

H

NH

N

CO2MeNH

N

CO2Me

NH

N

CO2Me

NH

NO

(-)-strychnine

(+)-aspidospermidine

(-)-kopsinine(-)-akuammicine

(+)-vincadifformine

(-)-kopsanone

H

9 (24) 13 (NA1) 11 (1.7)

12 (6.4) 25 (3) 16 (0.15)

9 (14) NA 19 (2.6)10 (10) NA NA

11 (8.9) NA 10 (8.5)

11 (10) NA NA

Title Paper# steps

(overall yield)

PSAC(overall yield)

PSCA(overall yield)

Title Paper# steps

(overall yield)

PSAC(overall yield)

PSCA (overall yield)

PSAC = Previous Shortest Asymetric Catalytic SynthesisPSCA = Previous Shortest Chiral Auxiliary or Chiral Pool Synthesis

1 - unreported yields for some steps of the sequence

Nate Ware @ Wipf Group Page 14 of 15 8/7/2011

Summary

•  An organo-catalyzed cascade was used to construct an advanced intermediate in the synthesis of a set of complex natural products.

•  Six natural products were efficiently constructed enantioselectively from that advanced intermediate.

•  All six syntheses represent some of the shortest routes to the respective targets.

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