ORGANIC
LETTERS
2002
Vol. 4, No. 22
3919-3922
Synthesis of (−)-Centrolobine by Prins
Cyclizations that Avoid Racemization
Shinji Marumoto, James J. Jaber, Justin P. Vitale, and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California-IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
Received August 19, 2002
ABSTRACT
The segment-coupling Prins cyclization avoids two of the problems common to other Prins cyclization protocols: side-chain exchange and
partial racemization by reversible 2-oxonia Cope rearrangement. Model studies demonstrate the stereochemical fidelity of Prins cyclizations
using r-acetoxy ethers compared with direct aldehyde−alcohol Prins reactions. Furthermore, we propose a mechanism for the racemization
observed in some intermolecular Prins cyclizations. Two straightforward syntheses of optically pure (−)-centrolobine highlight the utility of
Prins cyclizations.
The Prins cyclization is a potentially powerful method for
preparing tetrahydropyran rings.1 A number of groups have
been investigating Prins cyclization reactions and applying
these reactions to natural product syntheses.2 The segment-
coupling Prins cyclization developed in our lab3 is distinct
from other methods in that the key cyclization precursor is
an R-acetoxy ether, which is prepared by reductive acetyl-
ation of a homoallylic ester.4 Prins cyclizations can be
initiated from mixtures of aldehydes and homoallylic alco-
hols,2 and though this procedure may be more direct than
our segment-coupling route, a number of side reactions
associated with this approach have recently come to light.2e,g,6c
These side reactions include partial racemization and the
exchange of aldehyde and alcohol side chains leading to
mixtures of products. In this communication, we compare
the segment-coupling Prins cyclization with direct alcohol-
aldehyde cyclizations and show that these complications can
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10.1021/ol026751i CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/11/2002