DOMINO REACTIONS IN THE ENANTIOSELECTIVE SYNTHESIS OF BIOACTIVE NATURAL PRODUCTS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 274

H

TBSO

I 2
CH 2 Cl 2 /Et 2 O (2.5:1), r t

CO 2 Me

H

H

TBSO I

N

O H

TBSO

H

NH

H MeO

TBSO

27 28

I

H

H

O 13

H

H

TBSO H

TBSO O N O

N H O 42%

H

H

TBSO

TBSO

30 29

steps

H

H

O

N H O

H

O

O

H

(-)-Stemonine 31

SCHEME 9.6 Total synthesis of ( )-stemonine 31 by Williams and coworkers.

9.3. ANIONIC DOMINO REACTIONS

9.3.1. Domino Reactions with Michael Additions as the
Initiating Step
Natural products derived from marine sponges often present challenging synthetic
targets for synthetic chemists. This is apparent in the case of cylindramide

,
isolated from the sponge Halichondria cylindrata , containing a tetrameric acid lactam
ring system. The excellent cytotoxicity against B16 melanoma cells of this compound
is also an additional impetus for its synthesis. Laschat and coworkers have approached
the stereoselective bis-functionalization of the pentalene ring system, which,
however, is not a domino reaction in its strict definition [16]. In this case, the
enantiopure and advanced pentalenone

(35)

was first treated with TMS-protected
propynyl cuprate to provide the Michael-type adduct 33 , which was then quenched
with orthoformate/boron trifluoride diethyl etherate to give

32

(Scheme 9.7). The
following electrophilic trapping suitably functionalized the five-membered ring in an
anti manner to allow the correct stereochemical attachment of the larger macrolactam
ring system. This complex natural product synthesis, via this convergent approach,
spanned through 18 linear steps with an overall yield of 1%.
Another example of a cylindramide synthesis using a domino metathesis
approach is illustrated in Phillips' total synthesis [17]. The structure of tetronasin

34