Application of a Raney-cobalt-mediated tandem reductive cyclization protocol to total syntheses of the aspidosperma alkaloids (±)- limaspermidine and (±)-1-acetylaspidoalbidine

Article abstract of DOI:10.1021/ol3026846

The racemic modification of the Aspidosperma alkaloid limaspermidine (1) has been prepared in ten steps including one involving a Raney-cobalt-mediated tandem reductive cyclization of nitrile 8 to give the tetracyclic system 9b. Compound (±)-1 has been converted over two steps into (±)-1-acetylaspidoalbidine [(±)-13].

Full text of DOI:10.1021/ol3026846

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5621–5623
Application of a Raney-Cobalt-Mediated
Tandem Reductive Cyclization Protocol
to Total Syntheses of the Aspidosperma
Alkaloids (()-Limaspermidine and
(()-1-Acetylaspidoalbidine
Shen H. Tan, Martin G. Banwell,* Anthony C. Willis, and Tristan A. Reekie
Research School of Chemistry, Institute of Advanced Studies, The Australian National
University, Canberra ACT 0200, Australia
mgb@rsc.anu.edu.au
Received September 27, 2012
ABSTRACT
The racemic modification of the Aspidosperma alkaloid limaspermidine (1) has been prepared in ten steps including one involving a Raney-
cobalt-mediated tandem reductive cyclization of nitrile 8 to give the tetracyclic system 9b. Compound (()-1 has been converted over two steps
into (()-1-acetylaspidoalbidine [(()-13].
The natural product limaspermidine (1, Figure 1) was
isolated from the trunk bark of the small tree A. rhombeo-
signatum MARKGRAF found growing in the Venezuelan
Amazonas1 and shown to be the C21-hydroxylated deriv-
ative of the more well-known alkaloid aspidospermidine.2
The racemic modification of compound 1 was first de-
scribed by Ban et al. in the mid-1970s3 and served as an
advanced intermediate in that group’s landmark synthesis
of (()-fendleridine (2).3,4 It also served as an advanced
Figure 1. Structures of limaspermidine and fendleridine.
intermediate in Overman’s 1991 synthesis of compound 2.5
Our own interest in compound 1 and certain related
kopsine, and vincadifformine series.6 Accordingly, we now
systems stems from their potential to serve as precursors to
a rangeof alkaloidsincluding thoseoftheaspidofractinine,
report a novel synthesis of itwherein the B- and D-rings are
formed in a tandem reductive cyclization process that is
mediated, in a remarkably chemo- and stereoselective
fashion, by hydrogen in the presence of Raney-cobalt.7
(1) Medina, J. D.; Di Genova, L. Planta Med. 1979, 37, 165.
(2) For details of the most recent synthesis of this alkaloid as well as
useful background material, see: Jones, S. B.; Simmons, B.; Mastracchio,
A.; MacMillan, D. W. C. Nature 2011, 475, 183.
(3) Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.
(4) For the second and enantioselective synthesis of this alkaloid, see:
Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L. J. Am. Chem. Soc.
2010, 132, 3009.
(5) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am.
Chem. Soc. 1991, 113, 2598.
(6) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
San Diego, 1998; Vol. 50, p 343.
(7) For previous applications of Raney-cobalt to the selective reduc-
tion of nitriles, see: (a) White, L. V.; Schwartz, B. D.; Banwell, M. G.;
Willis, A. C. J. Org. Chem. 2011, 76, 6250 and references therein. (b)
Kukula, P.; Studer, M.; Blaser, H.-U. Adv. Synth. Catal. 2004, 346, 1487.
r
10.1021/ol3026846
2012 American Chemical Society
Published on Web 10/30/2012

This work emphasizes the particularly effective manner in
which this activated alloy can selectively bring about the
reduction of nitrogen-containing functionalities, especially
nitro and nitrile units, in the presence of other potentially
reactive groups, especially ketones, alkenes, and enamines.
The reaction sequence leading to (()-limaspermidine
[(()-1] is shown in Scheme 1 and starts with the alkenyl
oxirane 3, a compound that is easily prepared from
2-cyclohexenone via nucleophilic epoxidation and methyl-
enation of the 7-oxabicyclo[4.1.0]heptan-2-one so-formed.8
Treatment of substrate 3 with the readily available xanthate
NCCH2SC(S)OEt in the presence of triethylborane and
oxygen led, via a free-radical addition process,9 to the
2-cyclohexen-1-ol 4 (74%) that engaged in an Eschenmoserꢀ
Claisen rearrangement10 on treatment with the dimethyl-
acetal of N,N-dimethylacetamide in refluxing toluene. The
product cyclohexene-amide 5 (80%), now incorporating
a quaternary carbon center, was subjected to allylic oxida-
tion with manganese triacetate/tert-butylhydroperoxide
under conditions reported by Shing et al.11 The product
2-cyclohexen-1-one 6 (74%) was subjected to Johnson-
typeiodination,12 and the resulting iodide7(73%) engaged
in a Pd[0]-catalyzed Ullmann cross-coupling reaction13
with o-nitroiodobenzene, thus providing the R-arylated
cyclohexenone 8 (85%), the substrate required for the
Raney-cobalt-mediated tandem reductive cyclization
reaction.
Scheme 1. Total Synthesis of Limaspermidine [(()-1]
In the pivotal step, compound 8 was exposed to a large
excess of freshly prepared Raney-cobalt in MeOH with
5 mol equiv of p-TsOH at 40 °C. A chromatographically
separable mixture of indole 9b (85%) and its N-hydroxy
counterpart 9a (variable yields) was thereby obtained, and
the structures of both of these products were established by
single-crystal X-ray analyses.14 The ORTEP derived from
the latter analysis is shown in Figure 2. Resubjection of the
compound 9a to the reductive cyclization conditions re-
sulted in the generation of additional quantities of con-
gener 9b, while running the original process at higher
temperatures and/or for extended reaction times resulted
in the exclusive formation of the former product (9b) in
85% yield.
There are several rather interesting features to the con-
version 8 f 9b. Inparticular, the exclusiveformation of the
cis-ring fused product 9b over its (presumably) more stable
trans-configured counterpart suggests that the cycliza-
tion event leading to D-ring formation is a kinetically
controlled process. Furthermore, it appears that the
(8) Welker, M.; Woodward, S.; Alexakis, A. Org. Lett. 2010, 12, 576.
(9) Charrier, N.; Gravestock, D.; Zard, S. Z. Angew. Chem., Int. Ed.
2006, 45, 6520.
(10) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130,
16162 and references therein.
(11) Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149.
(12) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake,
ꢀ
C. B. W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett.
1992, 33, 917.
(13) Banwell, M. G.; Jones, M. T.; Reekie, T. A. Chemistry in New
cyclization process leading to B-ring formation proceeds,
atleast tosomedegree, throughthe hydroxylaminederived
from reduction of the nitro group in substrate 8.
Zealand 2011, 75, 122.
(14) CCDC 894937ꢀ894939 contain the crystallographic data for 1,
9b, and 9a, respectively. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
With amide 9b in hand the completion of the synthesis of
(()-limaspermidine (1) proved relatively straightforward.
Thus, the former compound served as the substrate for an
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Org. Lett., Vol. 14, No. 22, 2012

Scheme 2. Conversion of (()-Limaspermidine [(()-1] into
(()-1-Acetylaspidoalbidine [(()-13]
unspecified yield. Although we have been unable to repro-
duce this converison, when the readily derived 1-acetyl-
limaspermidine was treated under essentially the same con-
ditions then the racemic modification, (()-13, of the natural
product 1-acetylaspidoalbidine (the N-acetyl derivative of
fendleridine) was obtained in 30% yield (over two steps)
(Scheme 2). The 1H and 13C NMR spectral data obtained on
this material matched those reported by Boger et al.4
The protocols reported here should be amenable to the
enantioselective synthesis of either the (þ)- or (ꢀ)-forms
of the title alkaloids given the now ready availability of
both (S,S)- and (R,R)-7-oxabicyclo[4.1.0]heptan-2-one17
and the capacity of the EschenmoserꢀClaisen reaction to
faithfully convert, in a predictable manner, chiral non-
racemic allylic alcohols into the corresponding γ,δ-unsatur-
ated amides.10
Efforts are also underway to identify reaction conditions
whereby compound 8 can be engaged in a reductive
cyclization process that affords the trans-ring-fused isomer
of compound 9b since such a system could serve as a
precursor to kopsihainanines A and B, two unusual alka-
loids recently isolated from Kopsiahainanensis.18 Details of
the outcomes of such studies will be reported in due course.
Figure 2. ORTEP derived from the single-crystal X-ray analysis
of compound 9a with labeling of selected atoms. Anisotropic
displacement ellipsoids display 30% probability levels. Hydro-
gen atoms are drawn as circles with small radii.
E-ring annulation protocol introduced by Toczko and
Heathcock.15 Specifically, amide 9b was treated with
R-chloroacetyl chloride in the presence of triethylamine,
and the resulting acylated compound 10 (60%) was sub-
jected to a Finkelstein reaction using sodium iodide in
acetone, thus affording congener 11 that upon treatment
with silver triflate in DCM produced the pentacyclic
lactam 12 (61% from 10). Finally, treatment of compound
12 with LiBH3(NH2)16 in THF resulted in removal of
the lactam carbonyl, reduction of the imine residue, and
conversion of the amide into the corresponding primary
alcohol to form (()-limapermidine (1) in 60% yield. The
1H and 13C NMR spectral data obtained on this material
matched those reported5 by Overman et al., and its struc-
ture was secured by single-crystal X-ray analysis.14
Acknowledgment. We thank the Australian Research
Council and the Institute of Advanced Studies for gener-
ous financial support, Dr. Laurent Petit (ANU) for helpful
suggestions regarding the synthesis of compound 4, and
Professor Dale Boger (Scripps, La Jolla) for providing
spectral data on compound (þ)-13.
Ban and co-workers have reported3 that treatment of
compound (()-1 with mercuric acetate in 5% acetic
acid at 75 °C for 40ꢀ45 h provides (()-fendleridine in an
Supporting Information Available. Full experimental
procedures; data derived from the single-crystal X-ray
analyses of compounds 1, 9a, and 9b; anisotropic dis-
placement ellipsoid plots for compounds 1 and 9b; and
1H and 13C NMR spectra of compounds (()-1 and
4ꢀ(()-13. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642.
(16) Pasumansky, L; Goralski, C. T.; Singaram, B. Org. Process Res.
Dev. 2006, 10, 959.
(17) See, for example: (a) Wang, X.; Reisinger, C. M.; List, B. J. Am.
Chem. Soc. 2008, 130, 6070. (b) Jiang, H.; Holub, N.; Jørgensen, K. A.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20630. (c) Lu, Y.; Zheng, C.;
Yang, Y.; Zhao, G.; Zou, G. Adv. Synth. Catal. 2011, 353, 3129.
(18) Chen, J.; Chen, J.-J.; Yao, X.; Gao, K. Org. Biomol. Chem. 2011,
9, 5334.
The authors declare no competing financial interest.
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