Exploratory Studies Aimed at a Synthesis of Vinigrol. 4
SCHEME 1a
was obtained in a straightforward manner (86% yield)
from diol 82 (Scheme 3). When 9 was treated with sodium
sulfide under a variety of judiciously chosen conditions
consisting mainly of solvent modifications and temper-
ature variations, its proclivity for eliminating HI or
underlying only monosubstitution8 soon became appar-
ent.
We next addressed the acidic hydrolysis of 11 so as to
generate dibromo ketone 12 with proportionate reduction
in the level of nonbonded steric interactions. Although
this transformation was readily accomplished, the recal-
citrance of 12 for conversion to 14 paralleled closely that
previously observed with 13. Our recourse to dibromides
rather than diiodides was guided by a recent publication9
that reported a dramatic difference in the behavior of the
dihalide alternatives in a similar transformation. It was
at this stage that we investigated an analogous reaction
with 16.8 The question at issue was whether useful levels
of cyclization would occur in a precursor having a bulky,
equatorially disposed, and therefore conformationally
controlling substituent in â-orientation at C(7). Stated
differently, would such structural modification facilitate
the conformational change conducive to the cyclization
reaction? Once again, the outcome was not at all favor-
able; no spectroscopic indication could be secured that
any 17 had been formed (Scheme 4).
Following scrutiny of the above failed transformations,
we were of the opinion that success might be realized if
enhanced conformational freedom were available. Might
the thiacyclononane ring be more readily formed if the
cyclohexene ring were first cleaved? Diol 18 was available
from an earlier phase of this investigation,2 and this
disassembled structure evolved to serve as our point of
departure (Scheme 5). Following conversion to dimesylate
19 in quantitative yield, heating with excess lithium
dibromide in refluxing acetone gave dibromide 20 (98%).
This intermediate was, inter alia, heated in anhydrous
ethanol with a stoichiometric amount of sodium sulfide
nonhydrate (1.5 × 10-4 M) under N2 for 1 day.9 Only
starting material was returned (97% recovery). Alterna-
tive recourse to freshly distilled dry HMPA and Na2S (1.5
equiv)10,11 for 20 h at 60 °C did not change the outcome.
On the other hand, multiple products (but no 21) were
generated when the temperature was increased to 100
°C and reaction time was prolonged to 2 days. Matters
took a favorable turn when recourse was made to DMF
as the reaction medium. Heating dilute solutions in the
80-95 °C range for a total of 11 h gave rise rather
unexpectedly to sulfone 22 in yields ranging from 39 to
72%. We know of no precedent for concurrent oxidation
a Reagents and conditions: (a) Ph3P, imidazole, I2, CH2Cl2
(98%); (b) DDQ, CH2Cl2, H2O (99%); (c) Swern oxidation (98%).
SCHEME 2
aware of the possible shortcomings of this protocol from
two directions: (a) the unfavorable conformational fea-
tures of the cis octalin ring system which holds the
aldehyde-bearing side chains in a rather distal relation-
ship1,2 and (b) the fact that a vast majority of pinacol-
type reactions are conducted at low temperatures, since
they do not require added thermal activation.5,6 An
inability to employ heat as a means of populating
alternative, more well-suited conformers of 6 would
surely be disadvantageous. These reasons undoubtedly
6d
6e
underlie the fact that neither SmI2
nor Zn/TiCl4
induced conversion to 7.
Strategy Based on Adaptation of the Ramberg-
Ba1cklund Rearrangement. The formation of a larger
cycle followed by ring contraction constitutes an orthogo-
nal route to the vinigrol skeleton. The Ramberg-Ba¨ck-
lund reaction7 is exemplary of such applications. In the
present context, its adaptation would require initial
formation of a thiacyclononane typified by B. The pro-
totypical A f B step can be expected to benefit from the
need to generate a larger ring than heretofore, and also
from the heightened nucleophilicity of divalent sulfur
during the formation of this tricyclic intermediate. To
gauge steric accessibility, the first experimental evalu-
ation was performed on derivatives containing the acetal
protecting group. At the experimental level, diiodide 9
(5) Robertson, G. M. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; pp 563-610.
(6) (a) Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 1041.
(b) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S. J. Org. Chem.
1976, 41, 260. (c) Imamoto, T.; Kusumoto, T.; Hatanaka, Y.; Yokayama,
M. Tetrahedron Lett. 1982, 23, 1353. (d) Namy, J. L.; Souppe, J.; Kagan,
H. B. Tetrahedron Lett. 1983, 24, 765. (e) McMurry, J. E.; Rico, J. G.
Tetrahedron Lett. 1989, 30, 1169.
(8) Efremov, I. V. Ph.D. Dissertation, The Ohio State University,
2001.
(9) MaGee, D. I.; Beck, E. J. Can. J. Chem. 2000, 78, 1060.
(10) Paquette, L. A.; Wingard, R. E., Jr.; Philips, J. C.; Thompson,
G. L.; Read, L. K.; Clardy, J. J. Am. Chem. Soc. 1971, 93, 4508.
(11) Alvarez, E.; Diaz, M. T.; Liu, H.; Martin, J. D. J. Am. Chem.
Soc. 1995, 117, 1437.
(7) (a) Paquette, L. A. Org. React. (N.Y.) 1977, 25, 1. (b) Taylor, R.
J. K.; Casy, G. Org. React. (N.Y.) 2003, 62, 357.
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