Annulations in bridged systems. An approach to the synthesis of Shikodonin

Article abstract of DOI:10.1016/0040-4039(93)88029-I

A broadly-useful strategy for the introduction of a bridgehead substituent and a substituent on an adjacent carbon is described. The addition of TMSX to a bridgehead enone generates an enol silyl ether regiospecifically. Reaction of the enol silyl ether w

Full text of DOI:10.1016/0040-4039(93)88029-I

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Vol. 33, No.
Britain
Press
Printed in
Annulations in Bridged Systems. An Approach to the
of Shikodonin
Synthesis
George A.
and Masayuki Kirihara
of Chemistry, Iowa State University, Ames, Iowa
1
A
s t r at egy for the introduc tion
bridgehead
generates an
in a vicinal
and a
on an adjacent
carbon is described. The addition
to a bridgehead
silyl ether
Reaction
the
ether
Adjacent stereogenic centers
often introduced by conjugate addition to an unsaturated ketone followed
trapping the resulting enolate with an electmphile. This versatile strategy commonly employs a
as the nucleophile and a halide, epoxide or aldehyde as the
A significant variant involves the use
of an enol silyl ether as the nucleophile followed by silylation to form a new enol silyl ether. We have examined
these protocols in the system shown below. Bicyclic compound 1 was chosen for a model study for our
approach to the synthesis of shikodonin (I).2
Because of the instability of the bridgehead
(in the absence of nucleophiles, it
the nucleophile needed to be as the was formed.3 A number of
(conjugate addition but no and
at
above -78
unsuccessful attempts at conjugate addition/trapping with
with enol silyl ethers (ether 2 was
forced us to rethink the problem We decided to examine
a two step approach using trimethylsilylcyanide
by the reaction of triethylamine with
as the nucleophilic reagent. Generation of the bridgehead
1 in the of 3 cleanly afforded 4 in 98%
yield. Only a single isomer was formed. The proton NMR spectrum, wherein the vinyl proton of the enol silyl
7
727

7
728
OTMS
4
ether was a singlet at 4.82, strongly supported the assigned structure. In analogy with other bridged systems,
the vinyl proton of enol silyl ether 5 would be split by the bridgehead proton into a doublet.
With enol silyl ether 4 in hand, the next task was to study electrophilic additions to 4. Of particular interest
was whether the inductive effect of the
would attenuate the reactivity of the enol silyl ether.
0
4
Lewis acid
CN
7
: X=H
8
:
:
6
9
the Lewis acid catalyst required for complexation with our electrophile might simply remove the
to generate an allylic
To these concerns, enol silyl ether 4 was reacted with
chloride and to afford the alkylated keto
6 in 70% yield. Keto
was a single isomer, as evidenced by proton NMR and TLC.
6
exo stereochemistry was established by a
NOE experiment. This reagent is known to
Additionally, the reaction of 4 with
with enol silyl ethers that had been inductively
afforded
7 and 8 in 18% and 35% yields, respectively.
These compounds appear to be single isomers by proton NMR and TLC. The exo stereochemistry is assigned in
analogy with 6. Hydroxy 9 was not produced in this reaction.
The Michael acceptor which would be employed in the synthesis of shikodonin would be more hindered
than our model system compounds. In order to determine whether sterically hindered electrophiles would react,
enol silyl ether 4 was treated with tert-butyl chloride in the presence of titanium tetrachloride. The keto
10
was formed in 42% yield. In like manner, 10 could also be formed
chloride 11 (prepared from the
reaction of
1
with
and triethylamine in 90% yield).
4
10
11
References
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4
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(Received in USA 24 July 1992; accepted 2 September 1992)