A chemoenzymatic total synthesis of (+)-amabiline

Article abstract of DOI:10.1021/ol901230w

The readily available and enzymatically derived cis-1,2-dihydrocatechol 3 has been converted, over 15 steps, into (+)-amabiline, the nonnatural enantiomeric form of a crinine-type alkaloid.

Full text of DOI:10.1021/ol901230w

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3160-3162
A Chemoenzymatic Total Synthesis of
(+)-Amabiline
Alison D. Findlay and Martin G. Banwell*
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received June 1, 2009
ABSTRACT
The readily available and enzymatically derived cis-1,2-dihydrocatechol 3 has been converted, over 15 steps, into (+)-amabiline, the non-
natural enantiomeric form of a crinine-type alkaloid.
Crinine [(-)-1, Figure 1] is the parent member of a
significant class of Amaryllidaceae alkaloids characterized
by the presence of a 5,10b-ethanophenanthridine ring
system. Vittatine [(+)-1] is another member of the class
and one that embodies the alternate enantiomeric form of
the constituent framework. A broad range of biological
activities have been attributed to these natural products,
including antitumor, antiviral and immunostimulant prop-
erties.1 (-)-Amabiline [(-)-2], which was isolated during
a search for new, plant-derived antimalarial agents,2 is a
further example of a crinine alkaloid and one that
possesses a novel oxygenation pattern in the six-membered
D-ring. Thus far, it has been the subject of a single
synthetic study that served to confirm the proposed
structure.3 Herein we outline a chemoenzymatic approach
to (+)-amabiline [(+)-2)], the non-natural enantiomeric
form of the alkaloid, that makes use of an Eschenmoser-
Figure 1. Structures of the alkaloids (-)-crinine, (+)-vittatine,
(-)-amabiline and (+)-amabiline.
Claisen rearrangement,4 an intramolecular SN′ displace-
ment process and a Pictet-Spengler cyclization reaction
to assemble the requisite framework. The route described,
which allows for the introduction of functionality at all
relevant positions on the D-ring of the crinine alkaloid
(1) For reviews on the crinine alkaloids see: (a) Martin, S. F. In The
Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, 1987; Vol. 30, p
251. (b) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
San Diego, 1998; Vol. 51, p 323. (c) Lewis, J. R. Nat. Prod. Rep. 1998,
15, 107.
(2) Likhitwitayawuid, K.; Angerhofer, C. K.; Chai, H.; Pezzuto, J. M.;
Cordell, G. A.; Ruangrungsi, N. J. Nat. Prod. 1993, 56, 1331.
(3) (a) Pearson, W. H.; Lovering, F. E. J. Am. Chem. Soc. 1995, 117,
12336. (b) Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607.
(4) (a) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chim.
Acta 1964, 47, 2425. Muxfeldt and co-workers employed this reaction in
developing the first total synthesis of (()-crinine: (b) Muxfeldt, H.;
Schneider, R. S.; Mooberry, J. B. J. Am. Chem. Soc. 1966, 88, 3670.
10.1021/ol901230w CCC: $40.75
Published on Web 06/17/2009
 2009 American Chemical Society

framework, should be useful in preparing many other
members of the family.
The early stages of our approach to (+)-amabiline
involved functionalization of the non-halogenated double
bond within the cis-1,2-dihydrocatechol 3 (Scheme 1), a
prevent cleavage of the TBS ether. The stage was now
set for a Suzuki-Miyaura cross coupling8 of compound
6 with the commercially available boronic acid 7 which
proceeded smoothly [using (Pd(PPh3)4, Na2CO3 and
benzene] to give the desired product 8 in 90% yield.
Removal of the TBS ether within the last compound was
readily achieved using TBAF and so generating allylic
alcohol 9 in 94% yield.
Scheme 1. Synthesis of Substrate 9 for the
Eschenmoser-Claisen Rearrangement Reaction
With compound 9 in hand, the construction of the
quaternary carbon center associated with (+)-amabiline
could now be addressed (Scheme 2). We envisaged that
the Eschenmoser variant of the Claisen rearrangement
reaction4 would provide an effective means for doing so.
Pleasingly, exposure of substrate 9 to N,N-dimethylac-
etamide dimethyl acetal in toluene at 120 °C for 16 h
resulted in the generation of the expected product 10 in
95% yield. Reduction of the newly introduced tertiary
amide moiety was effected by treating compound 10 with
lithium triethylborohydride, and in this manner the cor-
responding primary alcohol, 11, could be obtained in 94%
yield. A short sequence of steps was now required to
obtain a substrate capable of engaging in an intramolecular
SN′ reaction to establish the 5-membered C-ring of the
target framework. Toward such ends (Scheme 2), alcohol
11 was converted (using I2 and PPh3) into the correspond-
ing iodide 12 which was, in turn, treated with sodium azide
to give compound 13 (85% yield, 2 steps). DDQ-mediated
cleavage of the PMB ether moiety within azide 13 then
gave allylic alcohol 14 in 92% yield. Conversion of
compound 14 into the corresponding mesylate 15 (MsCl,
Et3N) proved straightforward and set the stage for a
Staudinger reduction.9 It was anticipated this would
generate a primary amine capable of engaging in a
spontaneous intramolecular SN′-reaction, thereby forming
the C-ring of target (+)-2. In accord with such expecta-
tions, treatment of azide 15 with PPh3 in THF/H2O resulted
in the formation of the 3a-arylhexahydroindole 16 in good
yield (70%, over 2 steps). Subjection of compound 16 to
treatment with paraformaldehyde and formic acid at 80
°C for 16 h effected a Pictet-Spengler cyclization
reaction, accompanied by cleavage of the acetonide residue
and formylation of the resulting diol, to give 17 (70%).
Completion of the synthesis of (+)-amabiline required
reduction of the ∆3-double bond and hydrolysis of the
formate ester moieties within 17. Conveniently, this could
be achieved in a one-pot process, whereby K2CO3 was
added to the reaction mixture used for effecting hydro-
genation (H2, 5% Pd/C, MeOH). In this manner (+)-
amabiline was obtained directly and in 93% yield from
precursor 17. The spectral data (NMR, MS, IR) derived
from this material were in full accord with the assigned
structure and in excellent agreement with the literature
commodity chemical that can be obtained in large quantity
and enantiomerically pure form via the whole-cell medi-
ated biotransformation of bromobenzene.5 Thus, the
conversion of compound 3 into diol 46 was readily
achieved by initial formation of the corresponding ac-
etonide followed by dihydroxylation of this intermediate
(94% yield, 2 steps). Selective protection (TBSCl, imi-
dazole) of the allylic hydroxyl group within product 4 was
readily achieved under conventional conditions and so
afforded monoether 5. Conversion of the latter compound
into the corresponding PMB ether 6 (93%, 2 steps)
required the use of p-methoxybenzyl trichloroacetimidate
-7
(PMBTCA) in combination with Ph3C+BF4 so as to
(5) Compound 3 can be obtained from the Aldrich Chemical Co.
(Catalogue Number 489492) or from Questor, Queen’s University of Belfast,
Northern Ireland (http://questor.qub.ac.uk/newsite/contact.htm). For reviews
on methods for generating cis-1,2-dihydrocatechols by microbial dihy-
droxylation of the corresponding aromatics, as well as the synthetic
applications of these metabolites, see: (a) Hudlicky, T.; Gonzalez, D.;
Gibson, D. T. Aldrichim. Acta 1999, 32, 35. (b) Banwell, M. G.; Edwards,
A. J.; Harfoot, G. J.; Jolliffe, K. A.; McLeod, M. D.; McRae, K. J.; Stewart,
S. G.; Vo¨gtle, M. Pure Appl. Chem. 2003, 75, 223. (c) Johnson, R. A. Org.
React. 2004, 63, 117. (d) Hudlicky, T.; Reed, J. W. Synlett 2009, 685.
(6) (a) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem.
Soc. 1990, 112, 9439. (b) Hudlicky, T.; Rulin, F.; Tsunoda, T.; Luna, H.;
Andersen, C.; Price, J. D. Isr. J. Chem. 1991, 31, 229.
(7) (a) Ireland, R. E.; Liu, L.; Roper, T. D. Tetrahedron 1997, 53, 13221.
(b) Paterson, I.; Coster, M. J.; Chen, D. Y.-K.; Acen˜a, J. L.; Bach, J.; Keown,
L. E.; Trieselmann, T. Org. Biomol. Chem. 2005, 3, 2420.
(8) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(9) For a useful point-of-entry into the literature on the Staudinger
reaction see: Ku¨rti, L.; Czako´, B. Strategic Applications of Named Reactions
in Organic Synthesis; Elsevier Academic: Burlington, MA, 2005; pp
428-429.
Org. Lett., Vol. 11, No. 14, 2009
3161

Scheme 2. Completion of the Synthesis of (+)-Amabiline
data available for the natural product.2,3 Furthermore, the
specific rotation of (+)-amabiline {[R]D +31.8 (c 0.25,
EtOH)} was of similar magnitude but opposite sign to that
reported2 for the naturally occurring enantiomer {[R]D -32
(c 0.3, EtOH)}.
It is anticipated that minor modifications to the reaction
sequence presented here should provide access to related
members of the crinine alkaloid family. Work toward such
ends is now underway and results will be reported in due
course.
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for generous
financial support.
Supporting Information Available: Full experimental
procedures; 1H and/or 13C NMR spectra of compounds (+)-
2, 5, 6, 8-10, 12-14, 16 and 17. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 11, No. 14, 2009