6234
B. M. Trost et al. / Tetrahedron Letters 51 (2010) 6232–6235
TMS
TMS
TMS
TMS
TMS
TMS
TMSO
O
TMSO
HO
O
TMSO
HO
O
HO
O
O
O
O
KHMDS, HMPA,
THF, -78 oC;
Toluene, 4AMS
65 oC, 18 h
+
+
PhSSO2Ph,
-78oC to rt, 8 h
H
H
H
H
H
O
O
O
H
Ph
H
S
SPh
O
14
O
O
O
O
O
24
25 (77%)
26(12%)
17 (66%, dr = 10:1)
18 (15%)
Scheme 7. Formation of exocyclic
a
,b-unsaturated lactone.
mCPBA, NaHCO3,
DCM, 0 oC, 2 h
TMS
TMS
90 °C led to increased amounts of the undesired regioisomer 26
(25:26 69%:22%).
In summary, we have described an efficient approach to the
synthesis of the tricyclic core containing the AB-ring moiety of
rameswaralide (1), highlighted by a challenging formation of the
TMSO
O
TMSO
+
H
O
H
O
O
Ph
S
S
Ph
O
O
O
5,7-fused bicyclic skeleton and
a,b-unsaturated five-membered
20 (12%)
lactone. The ruthenium-catalyzed [5+2]-cycloaddition reaction
was employed to construct the 5,7-fused bicyclic system with
excellent diastereoselectivity. Use of reductive radical cyclization
followed by an oxidation/elimination approach was utilized to
19 (65%)
Scheme 4. Formation of phenyl sulfoxide 19.
form the exocyclic
good regioselectivity. Efforts to apply these strategies toward the
enantioselective total synthesis of rameswaralide (1) are ongoing.
a,b-unsaturated five-membered lactone with
TMS
TMS
TMS
TMSO
O
HO
O
HO
Toluene
+
90 oC, 6 h
82%
H
O
Acknowledgments
Ph
S
O
O
O
O
We thank the National Institutes of Health, General Medical
Sciences GM 033049, for their generous support of our research
programs. H.M.N. was supported by an NIH postdoctoral fellow-
ship. Mass spectra were provided by the Mass Spectrometry Regio-
nal Center of University of California—San Francisco, supported by
the NIH Division of Research Resources.
19
22
21
NOT OBSERVED
Scheme 5. Attempted elimination of sulfoxide 19.
TMS
TMS
TMS
H
Supplementary data
HO
O
HO
HO
O
O
1. KHMDS,
PhSSO2Ph (86%)
mCPBA, DCM
NaHCO3
Supplementary data associated with this article can be found, in
2. mCPBA (91%)
H
H
H
O
O
H
Ph
S
90%
O
O
O
O
13
References and notes
23
24
1. Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y.; Reddy, M. V. R.; Faulkner, J. D.
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Scheme 6. Epoxidation of endocyclic olefin.
2. Faulkner, J. D.; Venkateswarlue, Y. PCT Int. Appl. WO 00,27,839, 2000.
3. Srikrishna, A.; Dethe, D. H. Org. Lett. 2004, 6, 165–168; Mehta, G.; Lakshminath,
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resulted in the undesired conjugated diene 21 (Scheme 5) with the
concomitant deprotection of the TMS group of tertiary alcohol. The
desired c-lactone 22 was not observed in the elimination reaction.
Several factors can be attributed to favoring this regioselectiv-
ity. The first is the minimizing of the carbonyl group dipole and
sulfoxide group dipole interaction, which will favor formation of
the endocyclic regioisomer.11a Second is the allylic nature of the
bridgehead hydrogen, whose abstraction leads to lactone 21
(Scheme 5). Converting the double bond to the corresponding
epoxide 23 (Scheme 6) attenuates both factors to some extent. In
addition, it dramatically increases the steric hindrance for abstrac-
tion of the bridgehead hydrogen. We speculate that the combina-
tion of these effects might be enough to shift the regioselectivity.
As expected, the endocyclic olefin of lactone 13 (Scheme 6) was
smoothly converted to epoxide 23 in 90% yield as a single diaste-
reomer with mCPBA. Sulfenylation of 23 with PhSSO2Ph, followed
by mCPBA oxidation of the resulting intermediate sulfide, provided
sulfoxide 24 (Scheme 6).
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Gratifyingly, the treatment of sulfoxide 24 in toluene at 65 °C
for 18 h provided the desired exocyclic
25 in 77% yield (Scheme 7), along with 12% yield of the undesired
endocyclic -lactone 26. Increasing the reaction temperature to
a,b-unsaturated lactone
c