C O M M U N I C A T I O N S
Scheme 5. Synthesis of (()-11-O-Debenzoyltashironin 1
Scheme 3. Synthesis of Oxidative Dearomatization Precursor 18
a
a
Key: (a) Pd2(dba)3, tBu3P, DMF, 80 °C, (77%); (b) DMP, DCM,
Key: (a) NaBH4, DCM/MeOH (3:1), -78 °C (83%); (b) TMS-
0 °C, (98%); (c) 2-propargyloxyTBS 4eq, Et2Zn, Ti(OiPr)4, rt, (91%); (d)
MsCl, TEA, rt, then; (e) Me2Cu(CN)Li2, -78 °C, (88% over two steps);
(f) TBAF, AcOH, rt, (95%).
imidazole, neat, rt (>99%); (c) mCPBA 1.9eq, DCM, 0 °C (39%; 71%
BORSM); (d) (PPh3)3RhCl, H2, benzene, 100 psi (74%); (e) LiEt3BH 52eq,
THF, 100 °C (32%); (f) DMP, DCM, rt (96%); (g) HF-pyr. TBAF, THF,
rt (87%); (h) H2, Pd/C 10%, EtOAc (91%).
polymerization and other side reactions severely compromised the
efficiency of the reaction, presumably due to the sensitivity of the
â,γ-unsaturated aldehyde. Examination of a variety of known alkyne
addition conditions revealed the Et2Zn/Ti(iPrO)4 (without BINOL)
system, developed by Pu et al., to be highly effective, providing
the desired product (16) in consistently high yield.7 Mesylation of
propargyl alcohol 16 under standard conditions, followed by SN2′
nucleophilic methylation using the higher-order Lipshutz dimeth-
ylcyano cuprate,4c provided 17 in 60% yield over five steps.
Although removal of the silyl protecting groups was initially
problematic due to the sensitivity of the allene-containing skipped
diene, high yields of 18 were ultimately obtained through the use
of excess tetrabutylammonium fluoride (TBAF), buffered in acetic
acid.
With substrate 18 in hand, we were able to examine the key
biomimetic oxidative dearomatization/transannular Diels-Alder
sequence. In the event, upon exposure of 18 to PIDA, a mixture of
oxidized quinone monoketal intermediate (19) and Diels-Alder
adduct (20) was observed (Scheme 4). Subsequent heating of this
mixture for 4 min under microwave irradiation produced Diels-
Alder adduct 20 as the only isolable compound in 65% yield. In
short, this remarkable transformation had produced all four rings
of 11-O-debenzoyltashironin in a single transannular Diels-Alder
reaction of a tetrasubstituted diene with a trisubstituted allenic
dienophile.
dride) in a sealed tube at 100 °C.12 The harsh conditions required
to open the epoxide also resulted in the reductive cleavage of the
tosyl enol ether to provide 23. Interestingly, the hindered TMS ether
survived the reaction conditions, at least to the extent of being
present on the isolated product (Vide 23). Dess-Martin mediated
oxidation of the secondary alcohol, followed by TMS deprotection
afforded 24 in high yield. Exposure of 24 to 10% Pd/C under a
hydrogen atmosphere afforded 11-O-debenzoyltashironin (1), whose
spectral data were identical to those derived from natural sources.1
In summary, we have developed a concise synthesis of 11-O-
debenzoyltashironin (1). The key transformation in our sequence
involved a remarkable oxidative dearomatization/ transannular
Diels-Alder cascade, which allowed for the rapid assembly of the
tetracyclic carbon skeleton of the natural product. We are currently
investigating an asymmetric version of this synthesis and applying
our sequence to the synthesis of analog structures with the aim of
identifying optimal therapeutic agents. Results of these studies will
be forthcoming.13
Acknowledgment. Support for this work was provided by the
National Institutes of Health (HL25848).
Supporting Information Available: Experimental procedures and
characterization for new compounds. This material is available free of
Scheme 4. Oxidative Dearomatization/Transannular Diels-Alder
References
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2001, 64, 428.
(2) Cook, S. P.; Gaul, C.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 843.
(3) Barber, J.; Staunton, J. J. Chem. Soc., Perkin Trans. 1 1981, 1685.
(4) (a) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc.
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Reuter, D. C. Tetrahedron Lett. 1989, 30, 2065. (c) Lipshutz, B. H.;
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Having assembled the entire carbon skeleton of 1, we could now
focus on completing the synthesis through a series of deprotections
and substrate-controlled diastereoselective oxidation state adjust-
ments. Thus, adduct 20 was found to undergo NaBH4-mediated
reduction of the ketone at C10 in good yield and diastereoselectivity
(>9:1) (Scheme 5). Although protection of the newly formed
secondary alcohol proved difficult (presumably due to the highly
hindered nature of the alcohol), silylation could be achieved by
stirring the substrate in neat trimethylsilyl-imidazole to afford 21.8
Differentiation of the olefins in triene 21 proved to be a formidable
challenge. The Prilezhaev reaction9 led to selective epoxidation at
the less hindered R-face of the trisubstituted (C3-C4) olefin after
brief exposure of 21 to mCPBA in cold CH2Cl2. The short reaction
time resulted in low conversions but prevented significant over-
oxidation. The exomethylene group (C1-C15) was then reduced with
Wilkinson’s catalyst under a hydrogen atmosphere at 100 psi to
provide compound 22.10,11 The reductive opening of the epoxide
of 22 was accomplished in modest yield with LiEt3BH (Superhy-
(11) In some runs, there was observed appreciable quantities of a minor product,
which has not yet been identified.
(12) Krishnamurthy, S.; Schubert, R. M.; Brown, H. C. J. Am. Chem. Soc.
1973, 95, 8486.
(13) The results described herein are part of a much larger study of the
tashironin problem, described in the PhD thesis of Silas Cook (Columbia
University, 2006). This thesis contains confirmatory crystallographic
studies of related compounds, which will be disclosed as part of a full
paper.
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J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006 16441