A concise asymmetric total synthesis of aspidophytine

Article abstract of DOI:10.1021/ja806176w

An expedient asymmetric total synthesis of aspidophytine is reported. A highly convergent strategy involving the sequential annulation of vinyl iodide 5 with indole 6 exploits varying modes of indole reactivity to provide aspidophytine in 23% over six steps from 5. Copyright

Full text of DOI:10.1021/ja806176w

Published on Web 10/15/2008
A Concise Asymmetric Total Synthesis of Aspidophytine
K. C. Nicolaou,* Stephen M. Dalby, and Utpal Majumder
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry,
UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093
Received August 11, 2008; E-mail: kcn@scripps.edu
The structure of the dimeric indole alkaloid haplophytine (1,
Figure 1) was first disclosed in 1973 by the groups of Cava and
Yates,1 having been isolated from the dried leaves of Haplophyton
cimicidum over 20 years previously.2 Acid-mediated degradation
of haplophytine led to the isolation of its right-hand constituent,
aspidophytine (2), an aspidospermine-type alkaloid distinguished
by a C,D-ring-fused lactone.3 Owing both to its appealing structure
and importance as a probable biosynthetic (and thus potential
Figure 1. Structures of haplophytine (1) and aspidophytine (2).
synthetic) precursor to haplophytine, a number of total syntheses
of aspidophytine have been reported,4 beginning with Corey’s
Scheme 1. Retrosynthetic Analysis of Aspidophytine
memorable conquest in 1999.4a As part of ongoing studies in our
laboratory toward a total synthesis of haplophytine, for which we
have recently reported the construction of a left-hand domain
fragment,5 we now wish to disclose a concise stereocontrolled
approach to the accompanying aspidophytine domain.
Our approach is outlined retrosynthetically in Scheme 1. We
envisaged that the congested aspidophytine skeleton could arise
through sequential annulation of the D-ring to a suitably substituted
indole, exploiting varying modes of reactivity. Thus, oxidative
lactonization4a (3,a, Scheme 1) would be carried out at a late stage,
subsequent to closure of the E-ring through a 5-exo-trig radical
process (3,b, Scheme 1), designed to exploit the C-ring olefin and
indoline nitrogen as an effective radical trap.6 Formation of the
C-ring itself would exploit the nucleophilicity of the electron-rich
indole through a reductive Vilsmeier-Haack-type process (4,c,
Scheme 1),7 while the final bond adjoining the key building blocks
5 and 6 was to be forged by Suzuki coupling (4,d, Scheme 1).8
Notably, substrate-based stereocontrol would be relied upon
throughout, templated for by the chiral vinyl iodide 5.
Scheme 2. Preparation of Vinyl Iodide 5a
A straightforward chiral auxiliary approach was developed for
the preparation of 5, which commenced with N-alkylation of
δ-valerolactam (7) with iodide 89 (Scheme 2). Acylation with the
methyl-(R)-lactate derivative 910 then afforded the chiral ꢀ-ketoa-
mide 10 in high yield (89%). Installation of the crucial quaternary
stereocenter was then effected by alkylation of 10 with bromide
11, which furnished a 4:1 mixture of adducts, from which the
desired product 12 could be isolated in good yield (66%) after
chromatographic purification. The stereochemical outcome of this
reaction was confirmed by X-ray crystallographic analysis of the
lactone derivative 13 (see ORTEP drawing, Figure 2)11 and is in
accord with that observed for the aldol reactions of related lactate-
derived ketones.12 Following hydrogenolysis of the benzyl ether,13
the lactate auxiliary could be efficiently cleaved through a reduction/
oxidative glycol cleavage process to deliver aldehyde 14 (65%, two
steps). Finally, Stork-Wittig homologation14 of 14 afforded the
targeted vinyl iodide 5 as a single geometric isomer in excellent
yield (88%, 23% over six steps from 7). This short sequence proved
most robust and made multigram quantities of this pivotal building
block readily accessible.
a Reagents and conditions: (a) NaH, DMF, 25 °C; 8, 4 h, 68%; (b) LDA,
THF; 9, -78 °C, 2 h, 89%; (c) KHMDS, 11, DME, -78 f -30 °C, 12 h,
66%; (d) H2, Pd(OH)2 (cat.), EtOAc, 25 °C, 4 h, 82%; (e) NaBH4, MeOH,
0 °C, 15 min; NaIO4, MeOH/pH 7 buffer (3:1), 25 °C, 2 h, 79%; (f)
NaHMDS, Ph3PCH2I2, THF, -78 °C, 30 min, 88%.
The coupling partner for vinyl iodide 5, boronic acid 6, was itself
prepared from the known indole 154a (69%, Scheme 3). Smooth
union of the key fragments 5 and 6 was brought about through
Suzuki coupling, which furnished the targeted amide 16 in excellent
yield (86%). Treatment of 16 with Tf2O initiated a rapid 6-exo-
trig cyclization to generate the C-ring and, following rearomatiza-
tion, the isolable iminium species 17, which was reduced with
NaBH4 to provide the tetracyclic piperidine 18 as essentially a single
diastereomer in excellent yield (88%). While exposure of the
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10.1021/ja806176w CCC: $40.75
2008 American Chemical Society

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
is available free of charge via the Internet at http://pubs.acs.org.
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