C O M M U N I C A T I O N S
in benzene for 2 h effected smooth E-ring closure, providing a 3:1
mixture of pentacyclic, allyl-radical reduction regioisomers,15 from
which the desired product 22 was isolated as a single diastereomer
in a respectable 58% yield. With the requisite aspidospermine core
now in place, all that remained to complete the total synthesis of
aspidophytine was installation of the lactone. Significant improve-
ment to reported yields for this type of transformation4b was realized
by employing a single-pot TBAF-mediated ester hydrolysis/
oxidative lactonization4a protocol, which furnished synthetic aspi-
dophytine in good yield (63%). All spectral data for the synthetic
material were identical to those published.4
In summary, we have accomplished a concise and efficient total
synthesis of aspidophytine, proceeding in 5% yield over the longest
linear sequence of 12 steps, which compares most favorably with
previous syntheses. Notably, the rapid assembly of the pentacyclic
aspidospermine framework through sequential annulation of the
D-ring to the indole nucleus imparts a high degree of convergency
to this approach, which should make it particularly amenable to a
total synthesis of haplophytine. Further studies toward this end will
be reported in due course.
Figure 2. ORTEP view of 13 (Thermal ellipsoids at 30% probability).11
Scheme 3. Fragment Coupling and Elaboration to Aspidophytinea
Acknowledgment. We thank Drs. D. H. Huang, G. Siuzak, and
R. Chadha for NMR spectroscopic, mass spectrometric, and X-ray
crystallographic assistance, respectively. Financial support for this
work was provided by A*STAR Singapore (fellowships to S.M.D.
and U.M.) and the Skaggs Institute for Chemical Biology.
Supporting Information Available: Experimental procedures,
abbreviations, and compound characterization (PDF, CIF). This material
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a Reagents and conditions: (a) t-BuLi, THF, 25 °C, 1 h; B(OMe)3, 30
min, 69%; (b) 5, PdCl2(dppf), Cs2CO3, DMF/H2O (10:1), 25 °C, 12 h, 86%;
(c) TBAF, THF, 25 °C, 2 h; TBSCl, imid, CH2Cl2, 25 °C, 1 h; NH4Cl
(59%); (d) Tf2O, DTBMP, CH2Cl2, 25 °C, 30 min; NaBH4, MeOH, 0 °C,
15 min, 88%, >95:5 d.r.; (e) HF·py, THF, 25 °C, 1 h; (f) NaH, CS2, THF,
-78 f 25 °C, 1 h; MeI, 83% (two steps); (g) n-Bu3SnH, AIBN (cat.),
PhH, 85 °C, 58%; (h) TBAF, THF, 25 °C, 12 h; K3Fe(CN)6, NaHCO3,
t-BuOH/H2O (1:2), 25 °C, 63%.
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corresponding carboxylic acid (19) to analogous conditions provided
the lactone 20 directly (Via 21) through a tandem cyclization
process, this compound proved too labile to be advanced to the
natural product, presumably due to the interaction of the electron-
rich indole with the rather sensitive N,O-acetal.
Chemoselective desilylation of 18 with HF ·py provided the
corresponding alcohol, which was converted to the alkyl radical
precursor, xanthate 4 (83%, two steps), in readiness for the crucial
radical cyclization. In the event, heating a mixture of 4, n-Bu3SnH
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(11) See the Supporting Information for the preparation of 13. CCDC 697197
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free of charge from The Cambridge Crystallographic Data Centre Via
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(13) 1H NMR analysis of the Mosher ester derivative of this alcohol indicated
stereochemical purity of 91% ee (see the Supporting Information).
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(15) See the Supporting Information for further details.
JA806176W
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J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008 14943