Total Synthesis of (±)-Haouamine A

Noah Z. Burns and Phil S. Baran

Department of Chemistry, The Scripps Research Institute

J. Am. Chem. Soc. 2006, 128, 3908.

Juan Arredondo

April 1, 2006

Juan Arredondo @ Wipf Group 1 4/3/2006

! Isolated from a tunicate Aplidium haouarianum off Tarifa Island (Cádiz, Spain).

! Exists as an inseparable mixture of two interconverting isomers haouamine A and B.

! Haouamine A exhibits high and selective cytotoxic activity against human colon

carcinoma HT-29 cell line with IC50= 0.1 µg/mL. Haouamine B is less cytotixic, IC50=

5 µg/mL against the mice endothelial cells MS-1.

! Unprecedented class of alkaloids characterized by two constrained ring systems, the

indeno-tetrahydropyridine (left half) and the aza-paracyclophane (right half).

Garrido, L.; Zubía, E.; Ortega, M. J.; Salvá, J. J. Org. Chem. 2003, 68, 293. Smith, N. D.; Hayashida, J.;

Rawal, V. H. Org. Lett. 2005, 7, 4309.

Juan Arredondo @ Wipf Group 2 4/3/2006

Rawal’s Approach

Smith, N. D.; Hayashida, J.; Rawal, V. H. Org. Lett. 2005, 7, 4309.

N

OH

OH

OHOH

N

OR

OR

OROR

YX

HO

NH

HO

N

O

OMeO

N

O

OMeO

OMe

N

O

OMeO

OMe

Br

N

O

OMeO

OMe

Br

OMe

N

HO

OMeO

OMe

Br

OMeOMe

N

OMeO

OMe

Br

OMeOMe

1. dimethyl dicarbonate TEA, CH2Cl2

2. Swern oxdn.

1.pyrrolidine, PhH, reflux

2. 3-methoxybenzylchloride, CH3CN

96% 58%

1. NBS, ACN, 99%

2. IBX, DMSO

95%

HCl

1.

CuBr DMS2. PhSeCl3. H2O2

OMe

MgBr

OMe

MgBr

THF

CF3SO3H

CH2Cl2

71% 68%

57%

Juan Arredondo @ Wipf Group 3 4/3/2006

Trauner’s ApproachGrundi, M. A.; Trauner, D. Org. Lett. 2006, 8, 23.

N

OH

OH

OHOHFriedel-Crafts

Stork-Danheiseralkylation

N

OMeO

MeO

N

OMeMeO

N

O

OMeO

OiBuN

O

OMeO

R

X

OiBu

HO

MgBr

MeO OMe

N

O

OMeO

OMe

OiBu

MeO N

O

OMeO

OiBu

N

O

OMeO

OiBu

Ar

Ar+ +

20% 11% 10%

1.

MeOCOCl

2. 1N HCl

3. iBuOH,

Cat. TsOH

1. MeOCOCl

NaBH4

2. 1N HCl

3. iBuOH,

Cat. TsOH

45%

LiHMDS

BrMeO

R

X

X = I, R = H, 45%X = H, R = OMe, 51%

MgBr

OMe

1.

CeCl3

2. 1N HCl

RO

XMeO

X = I, R = H, 66%X = H, R = OMe, 66%

Juan Arredondo @ Wipf Group 4 4/3/2006

N

OMeO

MeO

MeOO

MeO

N

OMeO

MeO

O

IMeO

N

MeO

OMeOMe

N

OMe

OMeOMe

OMeO

OH

MeO

H

OMeO

MeO

N

OMeOMe

OMeO

+

Ar

-H+

66%

MgBr

OMe

CeCl3

77%

LiClO4, Et2O

cat. TfOH

N

OSO2CF3

OMe

OMeO

+

Ar

Tf2O2,6-BTP

N

OMe

OMe

H

OMeO

MeO

OTf-H+

63%

SnMe3

OMe

78%

Pd(PPh3)4CuI, CsF

Raical Cyclization Approach

N

OMe

OMe

H

OMeO

OAIBN, Bu3SnH

16%

Friedel-Crafts Cyclization Approach

Grundi, M. A.; Trauner, D. Org. Lett. 2006, 8, 23

Juan Arredondo @ Wipf Group 5 4/3/2006

Wipf’s Approach

Furegati, M.; Wipf, P. Org. Lett. (In press).

N

OH

OH

OHOH

Mitsunobu

NsNOH

OMe

NsNO

OMe

Allylicoxidation

Base catalyzedelimination

OMe

NsHN O

OMe

OMeHO

NsN

OMe

OMeHO

HNOMe

OMe

OMe

HO

O

OMe

B

NsN

O OBoc

OTf

OMe

TBDMSO

O

OO

+

Boc

NsNO

OMe

OMe

NsN

OMe

OMe

1. Pd(PPh3)4 Cs2CO3

2. TBAF

66%

1. 165 oC, neat

2. Mitsunobu

51%

1. mCPBA

2.CHCl3, HBF4

3. DMP, DCM

1. DIPEA, 2,2,2-tri- fluoroethanol2. Me2SO4, K2CO3, 90%

3. PhSH, K2CO3 DMF, 61%

6 stepseach

Commercially available

63%

Juan Arredondo @ Wipf Group 6 4/3/2006

Total Synthesis of (±)-Haouamine A

A

A

Baran, P. B.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908.

Juan Arredondo @ Wipf Group 7 4/3/2006

A

Baran, P. B.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908.

Cascade annulation

Juan Arredondo @ Wipf Group 8 4/3/2006

sm

Pyrone-alkyne Diels-Alder Reaction

Baran, P. B.; Burns, N. Z. J. Am. Chem. 2006, 288,,3908.

B

e. Pd(PPh3)4,

O O

SnMe3

OMe

(44 % overall)

B

f. TFA; K2CO3

OTs

Juan Arredondo @ Wipf Group 9 4/3/2006

Summary

! The first total synthesis of (±)-haouamione A has been achieved in 10 Steps

from commercial materials.

! Highlights of the synthesis include: an unprecedented halogen-induced cascade

cyclization of an unsaturated oxime to give the desire tetrahydropyridine ring

system, and an intramolecular pyrone-alkyne Diels-Alder macrocyclization.

! Asymmetric synthesis of an early intermediate makes an asymmetric synthesis

of haouamine A or B possible.

! “ it features some highly creative an unusual steps. It shows what can be

achieved in synthesis if one thinks outside the box.” Dirk Trauner C&E News

! “is definitely not the final word, because the percent conversion is relatively low.

There is room for further innovation here.” Steven M. Weinreb C&E News

Juan Arredondo @ Wipf Group 10 4/3/2006