methine C-H bond at the C6-ether,5 is avoided by
using the unconventional solvent tetrahydrofuran as a
component of the reaction medium (THF/MeOH; 10:1).
The resulting alcohol 11 was formed in high yield
(86%), and butyrolactone was isolated as a byproduct,
its amount increasing with increased reaction time. We
believe that THF effectively buffers the ozonolysis reac-
tion by acting as a sacrificial reductant, preventing
overoxidation of 10 and its derived products. The thio-
ethers 12-PT and 12-BT were then prepared from 11
using the Mitsunobu protocol (PTSH or BTSH, DIAD,
PPh3). Each was subsequently oxidized to the sulfone
13-PT or 13-BT (ammonium paramolybdate, H2O2).
We first attempted olefination using the potassium anion
of 13-PT and 13-BT. Preforming the anion (KHMDS,
THF, -78 °C) and addition of propionaldehyde provided
none of the expected olefination product, nor was the
starting sulfone recovered. When a solution of KHDMS
was added at -78 °C to a THF solution containing
both the sulfone 13-BT and propionaldehyde, the desired
propylidene coupling product was isolated in low yield
with the cis isomer predominating.
Scheme 1. Overview of the Coupling Strategies To Construct
Oxygenated Steroidal Side Chainsa
a St = generic steroid nucleus; BT = benzothiazolyl; PT = 1-phenyl-
1H-tetrazol-5-yl.
Scheme 3. Recovery/Stability of Sulfone Anionsa
donors were coupled with aldehyde acceptors 8 via
Wittig3n and classical Julia3o olefination reactions, respec-
tively (Scheme 1). In this study, we have established the
modified Julia coupling with donors 7c, primarily with the
benzothiazolyl (BT) sulfone [although we have also com-
pared the use of the 1-phenyl-1H-tetrazol-5-yl (PT) sulfone]
and a variety of acceptor aldehydes 8.
Scheme 2. Synthesis of the Key Sulfones 13-PT and 13-BT
a Stoichiometric ratio of sulfone/NaHMDS was 1:1.2.
We then turned our attention to the sodium anions derived
from 13-PT and 13-BT by studying the relative stability of the
sulfones upon metalation with NaHMDS in THF at -78 °C
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To test the feasibility, both the PT and BT sulfones
13-PT and 13-BT, respectively, were prepared as out-
lined in Scheme 2 from i-stigmasteryl methyl ether (10,
two steps, 74% yield from stigmasterol).4 Ozonolysis
(and reductive workup with NaBH4) of the disubsti-
tuted olefin smoothly provided the primary alcohol 11
[and (S)-2-ethyl-3-methylbutan-1-ol]. It is worth noting
that a major problem associated with the ozonolysis
of i-steroids, namely the undesired oxidation of the
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Org. Lett., Vol. 13, No. 4, 2011