C O M M U N I C A T I O N S
Scheme 3. Synthesis of Contra-Thermodynamic Spiroacetals by
Reductive Cyclization
possible the synthesis of this previously inaccessible or poorly
accessible class of compounds. The synthesis of spiroacetals is both
convergent and compatible with complex structures. In two cases
the initially formed spiroacetal was equilibrated to the thermo-
dynamically more stable isomer. Thus, the reductive cyclization
strategy presented can be used to prepare both contra-thermo-
dynamic and thermodynamic spiroacetals. We are investigating the
application of this strategy in natural product synthesis.
Acknowledgment. We thank the National Institutes of Health
(CA081635) and Schering-Plough Research Institute for financial
support.
Supporting Information Available: Experimental details for
preparation of the cyclization substrates and the cyclization reac-
tions. This material is available free of charge via the Internet at
References
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has the methylene rather than the oxygen axial to the pyran ring.
Thus the monoanomeric stabilized spiroacetal was produced as
expected.
The scope of the reaction was further explored using hemithio
ketene acetal 7 and four other diols that incorporate a variety of
leaving groups for the reductive cyclization. Each of the substrates
in Scheme 3 was prepared by spiro ortho ester synthesis14 followed
by TMSCN treatment and alcohol reprotection following the
protocol presented in Scheme 2.15 Reductive lithiation of cyano
acetal 12 followed by cyclization onto the methoxy alkene produced
spiro ortho ester 13 in excellent yield as a single diastereomer. The
alkene is cis to the pyran oxygen as expected,5 and the oxygen is
equatorial to the tetrahydropyran ring, confirming that this is a
monoanomeric stabilized spiroacetal. On treatment with CSA in
dichloromethane, spiroacetal 13 equilibrated quantitatively to the
epimeric spiroacetal, confirming that 13 is a contra-thermodynamic
spiroacetal. The cyclization of alkene 14 required higher temperature
and proceeded in lower yield than that of 12 but once again led to
a single diastereomer of spiroacetal 15 with the expected configura-
tions at the two new stereogenic centers. Both of these substrates
are sterically crowded and lead to more crowded products. Many
reactions become problematic with increased steric hindrance, but
reductive cyclizations, which are initiated by outer-sphere electron-
transfer reactions, are relatively insensitive to steric bulk.
The strategy is also successful in producing [5.5]-spiroacetals.
Cyclization of 16 produced 17 in excellent yield, and the structure
of the product was confirmed by NMR and NOE analysis.
Cyclization of methoxy alkene 18 gave the spiroacetal 19, with
only one anomeric stabilization present, in good yield as a single
diastereomer. The structure of spiroacetal 19 was confirmed by NOE
analysis. The examples in Scheme 3 demonstrate the impressive
scope of this strategy for the synthesis of spiroacetals with single
anomeric stabilization.
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105.8 ppm. This change in chemical shift of the acetal carbon going from
one anomeric stabilization to two is consistent with previous observations
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more stable epimer (106.7 ppm).
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(14) The spiro ortho esters precursors to 12, 14, 16, and 18 were prepared
from the appropriate diol and 7 in 67%, 81%, 93%, and 24% yields,
respectively. The spiroacetals were mixtures of diastereomers that ranged
from 1:1 to ca. 2:1.
(15) The cyano acetals 12, 14, 16, and 18 were prepared from the spiro ortho
esters in yields ranging from 81% to 95% and ranged from a 1:1 mixture
to a 10:1 mixture of diastereomers.
The first rational and general approach to contra-thermodynamic
spiroacetals has been described. The strategy presented makes
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