Stereocontrolled total synthesis of bengazole A: a marine bisoxazole natural product displaying potent

antifungal properties

Yunhui Zheng2012.10.12

Steve Ley has been the BP professor of chemistry at the University of Cambridge since 1992 and was president of the Royal Society of Chemistry from 2000-2002. He has published over 730 papers to date and has received numerous awards for his work including, the Royal Medal, the Tetrahedron Prize and the Perkin Prize for Organic Chemistry.His work on iron chemistry, microbial oxidation and microwave chemistry have been groundbreaking. He has devised many practical and useful protecting groups using acetal chemistry. He has done significant work in the area of organic catalysis and was one of the inventors of TPAP a catalytic oxidant that is now used worldwide.

The Ley group has published extensively on the synthesis of natural products and more than 130 target compounds have been synthesised. They also have a long history in developing new synthesis methodologies.

N

OO

N

O

O

OHOH

HO

OH

Bengazole A

Bengazole A was originally isolated in 1988 by Phillip Crews and co-workers from a sponge of the genus Jaspis, and to date the bengazole family consists of 22 members. The structure and absolute stereochemistry of this highly functionalized molecule was determined by a combination of NMR studies, analysis of degradation products, and circular dichroism.

Phillip Crews Jaspis

Retrosynthetic analysis of bengazole A

NN

N

O

N

NBF

FFF

TBTU

SO

O NC

TosMIC

R1 O

HN

R2

R3

O

- H2ON

O

R2

R3

R1

R1, R2, R3 = alkyl, aryl,heteroaryl

Robinson-Gabriel synthesis

R1 O

N

R2

R3

O

HN

OR1

R2

OH

R3

HN

O

R2

R3

R1

- H2O

OHO3SCSA

XR3

R2

(R1)3P

X = Cl, Br, I, OTs

Base(R1)3P

R3

R2(R1)3P

R3

R2

O

R5R4

(R1)3P O R5

R4 R2

R3X

Witting reaction

NSiSi

K

KHMDS

Nitrile Oxide cycloaddition

General reaction R

NO

XR'

N

X

O

R R'

R

NO

YR'

N

Y

O

R R'

X = CR2, O, S, NRY = CR, N

C N > C C C C C S C N C O> > > >

1. Solvent polarity has little effect.2. Conjugation of the dipolarophile enhances rates.3. Steric effects generally dominate.4. Electronic influences of the dipolarophile on reaction regiochemistry are minimal.

C. Grundmann, Synthesis 1970, 344

CONCLUTION

• They have completed a stereocontrolled total synthesis of bengazole A by using an oxazole synthesis under mild conditions and a diastereoselective 1,3-dipolar cycloaddition.

• The synthetic route is the first one to provide a single stereoisomer of the product and relies upon BDA(butane-2,3-diacetal) building blocks to establish the stereogenic centers.

•Thank you!

From Hydroximoyl Chlorides

N

R

OHoxidant N

R

OH

Cl

Et3NR N O

Oxidants include NCS, t-BuOCl, and NaOCl

K.-C. Liu et al., J. Org. Chem. 1980, 45, 3916G. Lee, Synthesis 1982, 508