REARRANGEMENTS IN NATURAL PRODUCT SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 258

R 2 R 2

R 2 R 2

Base and workup Base and workup

[2,3]-Wittig rearrangement

HO HO

O R 3 O R 3

R 3 R 3

[1,2]-Wittig rearrangement

R 1 R 1

R 1 R 1

SCHEME 8.27 Wittig rearrangements.

Wittig and Lohmann [148], and the [2,3]-rearrangement of an allyl alkyl ether to the
corresponding homoallylic alcohol, which was first reported by Wittig et al. [149a]
and then by Stevens and coworkers [149b] (Scheme 8.27).
The [1,2]-Wittig rearrangement takes place when R 1 (Scheme 8.27) is able to
stabilize a carbanion species. Unfortunately, the yields are usually moderate due to
the harsh conditions that are required to prevent the competing [1,4]-Wittig rear-
rangement. The [2,3]-Wittig rearrangement, on the other hand, proceeds under mild
reaction conditions and leads to higher chemical yields. It is worth pointing out that
the competing [1,2]-Wittig rearrangement can be avoided by carefully optimizing the
temperature. Typical conditions imply the use of LDA or n -BuLi as the base and
temperatures ranging from

85 C. The [2,3]-Wittig rearrangement is
highly stereoselective regarding the stereochemistry of the double bond and the two
newly formed stereogenic centers. The Still variant of the [2,3]-Wittig rearrange-
ment [150], which involves a tin-lithium exchange, was shown to be very useful, as
illustrated in the synthesis of (

60 Cto

þ

)-astrophylline [151].
An application of the [1,2]-Wittig rearrangement of hydroximates has recently
been reported by Naito and coworkers in their synthesis of ( þ )-cytoxazone [152]

(Scheme 8.28).
The preparation of the 6,7-dihydroisobenzofuran ring moiety present in the
natural product ( )-xestoquinone was carried out using a very regiospecific [1,2]-

Wittig rearrangement of a carefully chosen precursor, itself prepared from
2-( t -butyldimethylsilyl)-3-(hydroxymethyl)furan (Scheme 8.29) [153].
One of the key strategic steps in the synthesis of (

þ

)-candelalide A, a natural
product isolated from Sesquicillium candelabrum that behaves as a novel blocker of

Ph Ph Ph

OH OH OH

O O O

LDA (4 equiv)
THF, -78°C
63%

N N N

R

S

+

O

OH OH

MeO MeO MeO

NaBH 3 CN, 0°C 78%

Ph

OH

O O

1. LiAlH 4 , rt
2. (Boc) 2 O, DMAP

1. O 3 , -78°C
2. NaBH 4 , -78 to 0°C

HN O

HN HN

O O

50% 3. TFA

OH

36%

OH

MeO MeO MeO

(+)-Cytoxazone

SCHEME 8.28 [1,2]-Wittig rearrangement as a key step in the synthesis of ( þ )-cytoxazone.