Nine-Step Enantioselective Total Synthesis of (+)-Minﬁensineccc.chem.pitt.edu/wipf/Current...

Nine-Step Enantioselective Total Synthesisof (+)-Minfiensine

Jones, S. B.; Simmons, B.; MacMillan, D. W. C.* J. Am. Chem. Soc.2009, ASAP. DOI: 10.1021/ja906472m

Kara GeorgeWipf Group - Current Literature

September 12, 2009

NNH

Me

OH

NH

OH

N

Kara George @ Wipf Group of 14 10/3/2009

Strychnos Alkaloids

Biological Relevance: folk medicine, antimalarial, cytotoxic, antitumor

Synthetic Relevance: Excellent substrates for showcasing methodologiesaimed at rapidly assembling polycyclic structures

NH

OH

N

minfiensine

NN

MeO

Me

CO2Me

vincorine

NH N

CO2Me

Me OH

HO

echitamine

NH H

CHO

N

18-desoxy-Wieland-Gulmich aldehyde

NH

N

OH

normacusine B

NH

O O

N

H

H

strychnine

Ramirez, A.; Garcia-Rubio, S. Curr. Med. Chem. 2003, 10, 1891.Bonjoch, J.; Solé, D. Chem. Rev. 2000, 100, 3455.


History of Minfiensine

Massiot, G.; Thépenier, P.; Jaquier, M.-J.; Le Men-Olivier, L.; Delaude, C. Heterocycles 1989, 29, 1435.Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186.Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.Bobeck, D. R.; France, S.; Leverett, C. A.; Sánchez-Cantalejo, F.; Padwa, A. Tet. Lett. 2009, 50, 3145.

1989: Isolated from the African plant Strychnos minfiensis by Massiot and coworkers

2005: First total synthesis of (+)-minfiensine reported by Overman and coworkers

2008: Overman and coworkers publish a full paper including problems encountered in the 1st generation synthesis and a 2nd generation end play for the total synthesis of (+)-minfiensine

Qin and coworkers report a total synthesis of (±)-minfiensine

Padwa and coworkers report cycloaddition studies directed toward the tetracyclic core of minfiensine

2009: MacMillan and coworkers publish a nine-step total synthesis of (+)- minfiensine


Overman’s Approach to (+)-Minfiensine

NH

OH

N

Heck Cyclization-Carbonylation Sequence

Catalytic Assymetric Heck

Iminium Ion Cyclization

1st Generation:

2nd Generation:

NH

OH

N

Pd-catalyzed intramolecular enolate/vinyl iodide coupling

Catalytic Assymetric Heck

Iminium Ion Cyclization

Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am.Chem. Soc. 2005, 127, 10186.

Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.


Overmann’s Route to the Carbazole Core

Features: - Catalytic asymmetric Heck-iminium ion cyclization sequence provides access to the carbazole framework in an enantioselective fashion1 2

NHBoc

Ph2P N

O

t-Bu

NH2

OTIPS

N

OO 1. p-TsOH, PhH 50 °C

2. NCCO2Me, LHMDS, THF, -78 °C

85%

1. Comins' reagent, NaHMDS THF, -78 °C

2. i. 9-BBN, 1, 0 °C to rt ii. NaOH, rt iii. PdCl2(dppf), THF, rt

58%

Comins' reagent CsF, Cs2CO3

DMF, rt

85-95%

N

TIPSO

O

CO2Me

N

TIPSO CO2Me

BocHN

NNBocMeO2C

75%, 2 steps

20% Pd(OAc)2, 2, PMP toluene, 100 °C, 70 h; or

10% Pd(OAc)2, 2, PMP toluene, microwave 170 °C, 30-45 min

N

OTf CO2Me

BocHN

TFA, CH2Cl2

75-87%, 99% ee

N

CO2Me

NHBoc


Overman’s 1st Generation End Play

NH

OH

N

(+)-minfiensine

1. LiAlH4

2. NaOH

85%

Features: - Heck cyclization-carbonylation sequence to generate the fifth ring of (+)-minfiensine - 13.4% yield and 16 steps from cat. asymmetric Heck - 4.1% overall yield and 22 total steps

1. m-CPBA, CH2Cl2, 0 °C to rt2. CF3CO2H, 0 °C to rt

3. CH2=CHCH2OCOCl, K2CO3, rt

78%

NNAllocMeO2C

O

NNAllocMeO2C

OTES

NN

MeO2C I

OTES

NN

MeO2C

OTES

NN

MeO2C

OH

CO2Me

NN

MeO2C

CO2Me

NNBocMeO2C

1. (PhSe)2, NaBH4 THF/MEOH, 70 °C; H2O2, 0 to 70 °C

2. TESCl, imidazole CH2Cl2, rt

75%

Pd(PPh3)4, pyrrolidine, THF, rt;

(Z)-2-iodo-2-butenyl tosylateK2CO3, MeCN, 70 °C

96%80%

Pd(OAc)2, K2CO3, Bu4NClNaO2CH, DMF, 80 °C

1. TBAF, THF, rt2. DMP, CH2Cl2, rt

3. CNCO2Me, LiHMDS THF, -78 °C

70%

1. NaBH4, MeOH/THF, 0 °C2. BzOTf, pyridine, CH2Cl2, 60 °C

3. KHMDS, THF, -78 °C

50%


Overman’s 2nd Generation End Play

Features: - Intramolecular Pd-catalyzed ketone enolate vinyl iodide coupling to construct the final ring of (+)-minfiensine - 19.7% yield and 9 steps from cat. asymmetric Heck - 6.5% overall yield and 15 total steps

1. 9-BBN, THF, 100 °C; H2O2, NaOH

2. TPAP, NMO, CH2Cl2 NNBocMeO2C

O

NN

MeO2C

O

I

N

O

NMeO2C

63%

1. TFA, CH2Cl2, rt

2.

K2CO3, MeCN

65%

Br

I

10 mol % PdCl2(dppf)K2CO3 (4 equiv)

MeOH, 70 °C

NH

OH

N

(+)-minfiensine

N

CO2Me

NMeO2C

1. NaHMDS, Comins' reagent THF, -78 °C

2. Pd(OAc)2, Ph3P, Et3N CO, MeOH, DMF

77%

1. LiAlH4

2. NaOH

NNBocMeO2C

85%

74%


Macmillanʼs Approach to (+)-Minfiensine

NH

OH

N

Organocatalytic Diels-AlderCyclization

Amine CyclizationRadical Cyclization

Jones, S. B.; Simmons, B.; MacMillan, D. W. C.* J. Am. Chem. Soc. 2009, ASAP. DOI: 10.1021/ja906472m


Precedence for Cyclization Cascade Sequence

Diels-Alder/amine cyclization sequence to access the echitamine ring system

Lévy, J.; Sapi, J.; Laronze, J. Y.; Royer, D.; Toupet, L. Synlett 1992, 601.

Enatioselective organocatalytic construction of pyrroloindolines

Austin, J. F.; Kim, S.-G.; Sinz, C. S.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482.

NH

NOMe

Ph

t-Bu

imidazolidinone catalyst

NH N

CO2Me

Me OH

HO

echitamine

NN

E

N

N

Bn

E

H

E

E

E

E

Bn

tol., sealed tube160-170 °C, 36 h

NN

E

E

E

Bn

45% 5%E= CO2Me

NR

NHR

X O NR

NRH

CHOX

imidazolidinone catalyst


Enatioselective Organocatalytic Construction ofPyrroloindolines: Catalytic Cycle

Austin, J. F.; Kim, S.-G.; Sinz, C. S.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.2004, 101, 5482.


Enantioselective Catalytic Cascade Sequence toAccess the Tetracyclic Carbazole Framework of

(+)-Minfiensine

O

N

SMe

Boc

N

PMB


Organocatalytic Diels-Alder CyclizationCascade Studies

NH

NHO

Me

Me

Me

catalyst 14

NH

NHO

Me

Me

Me

catalyst 7

N

NHBoc

SMe

PMB

O

3 equiv

X mol% cat.

-40 °C, Et2O; NaBH4, CeCl3

MeOH

N

OH

NSMe

BocPMB


Nine-Step Total Synthesis of (+)-Minfiensine

NH

NHO

Me

Me

Me

catalyst 14

NH

NHBoc

1. NaH, PMBCl, DMF, 0 °C

2. i. n-BuLi, THF, -78 °C; ii. DMF, -78 °C to rt

N

NHBoc

O

(EtO)2P(O)CH2SMe NaH, THF, 0 °C to rt

N

NHBoc

SMe

PMB PMB73%

87%, 6:1 E:Z

O

cat. 14 TBA87%, 96% ee

N

OH

NSMe

BocPMB

N

OTES

NSMe

PMB

N

OH

N •

1. TESOTf, MeCN, 0 °C

2. 4-(tert-Butylthio)but-2-ynal NaBH(OAc)3, CH2Cl2, rt

59%, 2 steps

1. Pd/C, H2, THF, -15 °C

2. PhSH, TFA, rt

90%, >20:1 E:Z

3 equiv. t-Bu3SnH

NH

OH

N

(+)-minfiensine

PMB

StBu


Conclusions and Future Directions

• MacMillan and coworkers were able to synthesize (+)-minfiensine in only 9steps and 21% overall yield from commercial materials - 53% yield and 5 steps from the tetracyclic intermediate

• Access to the tetracyclic carbazole framework was achieved rapidly andenantioselectively by a new organocatalytic Diels-Alder/amine cyclizationsequence

• The final ring system of (+)-minfiensine was accomplished via a 6-exo-digradical cyclization

• Application of this methodology could be utilized to access the tetracycliccarbazole moiety of related alkaloids

NH

NHBoc

O NH

OH

N

(+)-minfiensine

9 Steps


Nine-Step Enantioselective Total Synthesis of (+)-Minﬁensineccc.chem.pitt.edu/wipf/Current...

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