Total Synthesis of the Polycyclic Total Synthesis of the Polycyclic Total Synthesis of the Polycyclic Total Synthesis of the Polycyclic Fungal Metabolite (Fungal Metabolite (±±))--Communesin FCommunesin Fg (g ( ))

Li P S J H W i b S MLi P S J H W i b S M A Ch I EdA Ch I Ed 20102010 4949 20002000 20032003Liu, P.; Seo, J. H.; Weinreb, S. M. Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. EdAngew. Chem. Int. Ed. . 20102010, , 4949, 2000, 2000––2003.2003.

H

OMe

MeMe

NN

HH

NNH

Me

Current Literature PresentationCurrent Literature PresentationMarch 6March 6thth, 2010, 2010Mi h l YMi h l YMichael YangMichael Yang

Mike Yang @ Wipf Group Page 1 of 19 4/26/2010

Isolation of Communesin FIsolation of Communesin Fff

Isolated from Penicillium mold on marine algaeIsolated from Penicillium mold on marine algae

Enteromorpha interstinalisPenicillium expansum Enteromorpha interstinalisenicillium expansum

Kerzaon, I.; Pouchus, Y. F.; Monteau, F.; Le Bizec, B.; Nourrisson, M. R. Rapid Commun. Mass Spectrom. 2009, 23, 3928.

Mike Yang @ Wipf Group Page 2 of 19 4/26/2010

Communesin BackgroundCommunesin BackgroundCommunesin BackgroundCommunesin Background

Biological Activities:Biological Activities:

Communesins A−D are active against

various leukemia cell lines

Communesins D−F are insecticidal

Key Structural Features

Two contiguous quaternary centers

(C-7 and C-8)

Two aminalsTwo aminals

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, early view.

Mike Yang @ Wipf Group Page 3 of 19 4/26/2010

Biosynthetic Proposal 1:Biosynthetic Proposal 1:Oxidative Dimerization of TryptamineOxidative Dimerization of Tryptamine

Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561–569.

Mike Yang @ Wipf Group Page 4 of 19 4/26/2010

Biosynthetic Proposal 2:Biosynthetic Proposal 2:Dimerization of Tryptamine and AurantioclavineDimerization of Tryptamine and Aurantioclavine

O id ti di i ti b t t t i d ti l iOxidative dimerization between tryptamine and aurantioclavine

Aurantioclavine – Penicillium fungal metabolite

May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.

Mike Yang @ Wipf Group Page 5 of 19 4/26/2010

Biosynthetic Proposal 3:Biosynthetic Proposal 3:DielsDiels--Alder ReactionAlder Reaction

May, J. A.; Zeidan, R. K.; Stoltz, B. Tetrahedron Lett. 2003, 44, 1203–1205.May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.

Mike Yang @ Wipf Group Page 6 of 19 4/26/2010

Model Study:Model Study:yyCommunesin via DielsCommunesin via Diels--AlderAlder

NHHMeMe

NHHMeMeCl

TsHNCs2CO3 CH2Cl2

NBoc

NNTs

MeHN

NTs

MeH

+

Mg

89% (2:1 d.r.)

Cs2CO3, CH2Cl2-78 °C

NMe

Mg,NH4Cl,MeOH,80%

NHHMeMe

NHHMeMe

+

NNH

MeHN

NH

MeH

May, J. A.; Zeidan, R. K.; Stoltz, B. Tetrahedron Lett. 2003, 44, 1203–1205.May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271.

Mike Yang @ Wipf Group Page 7 of 19 4/26/2010

Retrosynthetic Analysis Retrosynthetic Analysis -- Qin Qin

N NHO

Me

HMeMe

NHHN

MeMeHO

R O

NNH

MeN

N

MeR

BrO

OBr O

Br

NN

MeR

NH

O

N2 N3

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

Mike Yang @ Wipf Group Page 8 of 19 4/26/2010

Diastereomers? Diastereomers? Br

NH

OH

OBr O

N2

1) SOCl22) Et3N, CH2Cl2, 95% (2 steps)3) TsNHNH2, TsOH, 85%4) DBU, CH2Cl2, 85%

+

N3

OHO

O

NH

N2 N3+

CuOTf,CH Cl

OBrO

HO O

H O OAr

CH2Cl2,88%

NMe

N3N

Me

ArN

Me

1 6 : 1

+Br Br

1.6:1 d.r.1.6 : 1

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

Mike Yang @ Wipf Group Page 9 of 19 4/26/2010

Cyclopropane RingCyclopropane Ring--openingopening

OBrO

NH

OBrO

N3 THF

PBu3

NMe

NNH

Me

N3

PBu3, aq THF

aq. THF83% single diastereomer

protontransfer

OBrO

OBrO

OBrO

aq. THF transfer

NMe

NH2NMe

NH2N

NH2

Me

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

Mike Yang @ Wipf Group Page 10 of 19 4/26/2010

Qin’s Mechanistic RationaleQin’s Mechanistic RationaleQ M RQ M R

Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187–2190.

Mike Yang @ Wipf Group Page 11 of 19 4/26/2010

Formation of the CFormation of the C--8 Quaternary Center:8 Quaternary Center:Formation of the CFormation of the C 8 Quaternary Center:8 Quaternary Center:Claisen RearrangementClaisen Rearrangement

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

Mike Yang @ Wipf Group Page 12 of 19 4/26/2010

Synthesis of Communesin F Synthesis of Communesin F -- QinQinMe1) DMP

Br

N

HNO

HO

N

OBrO CHO

NHHNO

Me MeBocHO

1) DMP2) NH2OH·HCl, Na2CO33) H2, Raney-Ni4) Boc2O, Na2CO350% - 4 steps

5) Pd(OA ) P( T l)

1) NH2OH·HCl, Na2CO32) H2, Raney-Ni, (87%, 2 steps, brsm)3) MeONa, MeOH, 70 °C, 98%

NN

MeCO2MeN

N

MeCO2Me

PPTS,

NN

MeCO2Me

5) Pd(OAc)2, P(o-Tol)3, 68%Me Me

HO

HO

Me

NH NHOEt1) silica gel, MeOH/CH2Cl2,

81% - 2 steps2) KOH M OH/H O 65% HOBoc

,CHCl366%

MeMeMeMe Me

MeN

NNH

NHH NH

NN

NH

M

2) KOH, MeOH/H2O, 65%3) NaBH4, AcOH/Ac2O, 73%

CO2Me

1) BF4OEt3, iPrNEt2, 95%2) 5% TFA, CH2Cl2 N

NN

HNO

CO Me

BocMe

MeMe N

MeCO2Me

Communesin F

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794–13795.

Mike Yang @ Wipf Group Page 13 of 19 4/26/2010

Retrosynthetic Analysis Retrosynthetic Analysis -- WeinrebWeinreb

N NHO

Me

HMeMe

NHHN

MeMeHO

R ONBOMO

OBoc

NNH

MeN

N

MeR N

NBoc

Me

BOMO N N NO2

CO2EtCO2EtBOMO

N

I

O

BOMO N

NMe

O

NO2

Me

BOMO

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

Mike Yang @ Wipf Group Page 14 of 19 4/26/2010

Intramolecular Heck Intramolecular Heck -- WeinrebWeinreb

BnN

Bn

EtO[Pd(PPh ) ] DME

NO2

B(OH)2

I

BOMO

1) LiOH, H2O, MeOH, 86%2) SOCl2; iPr2NEt, 87%

BOMO NBn

NBn

EtO

O OTf

O NO2

[Pd(PPh3)4], DME,H2O, Na2CO3

98%

NH2

NH

I

O

NO2

1) ClCO2Et, CH2Cl2, 96%2) NaH, THF, MeI, 92%

CO Et

N

I

O

BOMO N

NO

N NO2

CO2EtCO2Et

NO2Pd(OAc)2, PPh3, DMA, K2CO3, nBu4NBr, 150 °C, 90%

BOMO

N ONMe Me

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

Mike Yang @ Wipf Group Page 15 of 19 4/26/2010

1,3 Dipolar Cycloaddition 1,3 Dipolar Cycloaddition -- WeinrebWeinreb

a) 5% Pt/C, H2 (40 atm), PhMeb) Boc2O, K2CO3, THF, H2O, 87% (2 steps)

N NO2

CO2Et

BOMO N NHBocCO2Et

BOMO NEtO2C

BOMOAlH3·Me2NEt, THF74%

NMe

ONMe

ON

NBoc

Me

1M KOH, EtOH

HNBOMO

94 °C

NH NCN

HNO ON

NC

NNBoc

Me

HNBOMO

N

Me

NBoc

HN

NN

NCN3, MeCN93% (2 steps)

NNBoc

Me

HNBOMOOBOM

Me

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

Mike Yang @ Wipf Group Page 16 of 19 4/26/2010

Formation of CFormation of C--8 Quaternary Center8 Quaternary Center

HNBOMON

NC

1) 1M KOH, EtOH, 94 °C, 60%2) Boc O LiHMDS THF 95%

NBOMOOBoc

HN O

OBOM

KOtBu,allyl iodideTHF 78 °C

Boc

NNBoc

Me

2) Boc2O, LiHMDS, THF, 95%

NNBoc

Me3:1 mixture of epimers

N

Me

NBoc

THF, −78 C

87%

OBocOOMsO

OMs 1) 1M KOH, EtOH, 80 °C, 94%2) OsO4, NMO, THF, H2O;

NaIOa) Pearlman's catalyst

NNBoc

NBOMOOBoc

NNBoc

HNBOMOO

NNBoc

Me

HNO NaIO43) NaBH4, EtOH4) MsCl, NEt3, CH2Cl2, 0 °C, 83% (3 steps)

H2, THFb) DMP, CH2Cl2 75% (2 steps)

MeMeMe

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

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Qin’s IntermediateQin’s IntermediateOMs N3

1) Me2CO, 10% NaOH/H2O,60 °C 93% N3O Me

NNBoc

HNOO

OMs

NNBoc

HNOO

N3NaN3, DMF,90 °C, 61%

60 °C, 93%2) Boc2O, LiHMDS, THF, 81%

NNBoc

NO

N3BocO

NMe

NMe

NMe

PMe3, THF, H2O,70 °C, 88%,

NHHNOBoc

O Me

NHHNO

Me MeBocHO MeLi, THF,

-78 °C, 73%NH

HNO

Me MeBocHO

NNBoc

MeN

NBoc

MeN

N

MeCO2Me

Qin's IntermediateQin s Intermediate

Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem. Int. Ed. 2010, 49, 2000–2003.

Mike Yang @ Wipf Group Page 18 of 19 4/26/2010

SummarySummarySummarySummary

Qin Weinreb

C-7 Quaternary Center Cyclopropanation Heck

C 8 Q t C t Cl i t E l t lk l tiC-8 Quaternary Center Claisen rearrangement Enolate alkylation

Overall yield 3% 1%

Steps 23 30

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