Oxonia-cope prins cyclizations: A facile method for the synthesis of tetrahydropyranones bearing quaternary centers

Article abstract of DOI:10.1021/ja044736y

A new cationic cascade reaction has been developed that produces 4-tetrahydropyranones in good yield. The reaction is based on the facile 2-oxonia Cope rearrangement of allyl-substituted oxocarbenium ions. In the presence of a more nucleophilic silyl enol

Full text of DOI:10.1021/ja044736y

Published on Web 11/12/2004
Oxonia-Cope Prins Cyclizations: A Facile Method for the Synthesis of
Tetrahydropyranones Bearing Quaternary Centers
Jackline E. Dalgard and Scott D. Rychnovsky*
Department of Chemistry, UniVersity of California, IrVine, IrVine, California 92697-2025
Received August 31, 2004; E-mail: srychnov@uci.edu
Table 1. Preparation of Oxonia-Cope Prins Substrates
Investigations from this lab and others have demonstrated the
prevalence of 2-oxonia Cope rearrangements in Prins cyclization
reactions.1,2 In most cases, the 2-oxonia Cope rearrangement3 takes
place in the background and is not directly observable by product
analysis.4 In a few cases, the rearrangement leads to unwanted side
reactions.1a-c Herein, we report a new oxocarbenium ion cascade
reaction5,6 and cyclization where the 2-oxonia Cope rearrangement
is an integral step in the cascade. This oxonia-Cope Prins (OCP)
process is efficient and allows for the preparation of tetrahydro-
pyrans with quaternary carbon centers, synthetic targets that are
normally not accessible by Prins cyclization strategies.7
The strategy for the oxonia-Cope Prins cyclization is outlined
in Figure 1. The R-acetoxy ether 1 is a typical substrate for a
segment-coupling Prins cyclization except that it contains a silyl
enol ether. Treatment with a Lewis acid would generate the
oxocarbenium ion 2, the normal intermediate for a Prins cyclization.
As we have shown previously,1c the 2-oxonia Cope rearrangement
is fast, and oxocarbenium ions 2 and 3 should be in rapid
equilibrium. Now the enol ether comes into play. As the best
nucleophile in the system it would cyclize on the oxocarbenium
ion via conformer 4 to produce the tetrahydropyranone 5.8 If a chair
conformation dominates in the cyclization transition state, then the
configuration of the product should be predictable from the
geometry of the enol ether. Note that there is an apparent inversion
at the secondary ether center in 1 en route to the C2 position in 5
that arises from the rearrangement and cyclization cascade. The
successful realization of this strategy is described below.
Figure 1. 2-Oxonia-Cope rearrangement of the oxocarbenium ion 2 sets
up the intramolecular cyclization reaction of 4.
a Method A: Acid chloride and Et3N were combined with silyl ketene
acetal in THF from 0 to 23 °C. Method B: the R-bromo acetyl bromide
was treated with zinc dust in THF at 0 °C for 30 min, and the ketene solution
was decanted before use. b (E)-Crotonyl chloride was used to generate the
ketene. c Enol ether produced as a 1.5:1 mixture of Z/E isomers.
The proposed cascade reaction is only practical if the substrates
are synthetically accessible. Preparation of the silyl enol ether
substrates is presented in Table 1. Rathke’s strategy was employed
to assemble the targets from ketenes 7 and the silyl enol ether 8.9
In Rathke’s procedure, the ketenes were prepared by elimination
of acid chlorides (method A). Method A worked well with
unsubstituted and monosubstituted ketenes (entries 1-3) but led
to moderate yields with some disubstituted ketenes (entries 5 and
8). Zinc reduction of the R-bromo acid bromides was used to
produce disubstituted ketenes (method B).10 One or the other method
worked well and with all of the substrates investigated. The
asymmetric ketenes in entries 2, 3, and 7 led to the (Z)-silyl enol
ethers selectively, as would be expected by addition to the less
hindered face of the ketene. The asymmetric ketene in entry 8 only
produces a 1.5:1 mixture of silyl enol ethers. Presumably, the facial
bias of the ketene was insufficient to ensure good selectivity. The
second step was a reductive acetylation with DIBAL-H followed
by acetic anhydride treatment that proceeded in uniformly good
yields.11 The OCP cyclization substrates were prepared in two steps
from the silyl ketene acetal 8.
Cyclization of the substrates is illustrated in Table 2. The cascade
cyclization works remarkably well. We found that TMSOTf was a
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J. AM. CHEM. SOC. 2004, 126, 15662-15663
10.1021/ja044736y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Oxonia-Cope Prins Cyclization of Silyl Enol Ether
Substrates
Scheme 1. Oxonia-Cope Prins Cascade Leads to an Inversion of
Configuration at the C2 Center in the Cyclization
The cyclizations described so far used racemic starting material.
The use of optically pure starting material 24 in Scheme 1 produced
optically pure tetrahydropyranone 25. Compound 25 was reduced
to alcohol 26,13 and its configuration was determined by Mosher’s
analysis.15 As predicted by the proposed mechanism in Figure 1,
the stereogenic center in (S)-24 was transformed to the inverted
C2 center in compound (-)-26. The oxonia-Cope Prins sequence
is stereospecific.
We describe a new method for the synthesis of tetrahydropyra-
none rings based on an oxonia-Cope rearrangement and Prins
cyclization. The reactions proceed in high yield and are stereose-
lective with some substrates. This new method will be useful in
the synthesis of the many natural products that incorporate
tetrahydropyran rings.
Acknowledgment. We thank the National Institutes of Health
(CA081635) for financial support.
Supporting Information Available: Experimental details for the
reactions described (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
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