Enantioselective total synthesis of the indole alkaloid 16-episilicine

Article abstract of DOI:10.1039/b904521j

The first total synthesis of (-)-16-episilicine has been completed from a phenylglycinol-derived bicyclic lactam, the key steps being stereoselective conjugate addition and alkylation reactions, and a ring-closing metathesis.

Full text of DOI:10.1039/b904521j

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Enantioselective total synthesis of the indole alkaloid 16-episilicinew
˜ ´
Mercedes Amat,*a Begona Checa,a Nuria Llor,a Elies Molinsb and Joan Bosch*a
Received (in Cambridge, UK) 5th March 2009, Accepted 18th March 2009
First published as an Advance Article on the web 3rd April 2009
DOI: 10.1039/b904521j
The first total synthesis of (À)-16-episilicine has been completed
from a phenylglycinol-derived bicyclic lactam, the key steps being
stereoselective conjugate addition and alkylation reactions, and a
ring-closing metathesis.
The silicine alkaloids1 constitute a relatively numerous group
of 2-acylindole alkaloids of the corynanthean type2 with an
unusual skeleton in which the carbon atoms of the tryptamine
fragment (C5–C6) are in a rearranged position, forming
C5–C16 and C6–C16 bonds.3 They differ in the relative stereo-
chemistry of C-16 and C-20 and in the oxidation level of C-6,
with the configuration of the C-15 stereocentre presumed to be
S (15b-H) in all the members of the series as a consequence of
their biogenetic origin from secologanin2 (Fig. 1).
Fig. 2 Synthetic strategy.
Fig. 2: the stereoselective conjugate addition of a vinyl
fragment to an appropriate unsaturated bicyclic lactam A,
the stereoselective introduction of the 3-indolylmethyl moiety
B at the a-position of the lactam carbonyl group, and the
closure of the central seven-membered ring by a ring-closing
metathesis.
Lactam 2, bearing a C-8 ethyl substituent with the absolute
configuration required for the synthesis of 16-episilicine, was
envisaged as the starting material for the synthesis. The easily
removable electron-withdrawing tert-butoxycarbonyl group
would provide activation towards the two subsequent steps
of conjugate addition8 and alkylation. Lactam 2 was readily
prepared in excellent yield from the known lactam 19 and, due
to its instability, directly used in the next reaction without
further purification (Scheme 1).
Fig. 1 Indole alkaloids of the silicine group.
Although these alkaloids have received certain attention
from the synthetic standpoint in the racemic series,4 their
enantioselective synthesis has not been explored so far. The
control of the relative and absolute stereochemistry of the
three contiguous stereocentres on the piperidine ring
represents a major challenge that turns these natural products
into attractive targets to evaluate the potential of synthetic
methodology.
We report herein the first total synthesis of 16-episilicine,5
which also constitutes the first enantioselective total synthesis of
an alkaloid of the silicine group.6 The synthesis takes advantage
of the versatility of phenylglycinol-derived oxazolopiperidone
lactams as chiral building blocks for the enantioselective
construction of diversely substituted piperidine-containing
derivatives.7
The introduction of the vinyl substituent was satisfactorily
accomplished in excellent yield (84% overall yield from 1) with
vinylmagnesium bromide in the presence of CuI, LiCl, and
trimethylsilyl chloride. The reaction took place with complete
stereoselectivity, cis with respect to the ethyl substituent,
as a consequence of the stereoelectronic control10 (Fig. 3).
Alkylation of the resulting mixture of C-6 epimeric lactams 3
with the N-protected indole derivative 411 afforded 5 in 75%
yield as a single stereoisomer, thus confirming the facial
stereoselectivity of the conjugate addition.
The stereocontrolled assembling of the tetracyclic skeleton
of 16-episilicine was planned in three key steps, as outlined in
a Laboratory of Organic Chemistry, Faculty of Pharmacy, and
Institute of Biomedicine (IBUB), University of Barcelona,
08028-Barcelona, Spain. E-mail: amat@ub.edu, joanbosch@ub.edu;
Fax: +34 93 402 45 39; Tel: +34 93 402 45 38
`
Institut de Ciencia de Materials (CSIC), Campus UAB,
08193-Cerdanyola, Spain
b
Fig. 3 Stereoelectronic control in the conjugate addition.
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all new compounds. CCDC
708534. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b904521j
Wittig methylenation of 5 followed by removal of the
activating tert-butoxycarbonyl group with TFA gave diene 6
in 57% overall yield. Minor amounts (10%) of the C-6 epimer
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Chem. Commun., 2009, 2935–2937 | 2935

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the presence of (Boc)2O, led to the N-Boc protected piperidine
13
derivative 9. A chemoselective oxidation with I2O5 installed
the 2-acylindole carbonyl group. Finally, the exchange of the
Boc protecting group for methyl furnished (À)-16-episilicine,
thus completing the first synthesis of this natural product. The
1H and 13C NMR data of our synthetic 16-episilicine were in
complete agreement with those previously reported5b for the
alkaloid. However, the specific rotation of our synthetic
22
material, [a]D À20 (c 1.0 in CHCl3), although coincident in
its absolute value with that reported for 16-episilicine,
[a]D22 +20 (c 1.0 in CHCl3),5 had the opposite sign.14 Taking
into account that the C-15 configuration (S, 15b-H) of our
synthetic 16-episilicine stems from the X-ray crystallographic
analysis of the advanced intermediate 7, the discrepancy in the
sign of the [a]D values is striking in that it might point to an
uncommon 15a-H absolute configuration (opposite to that
depicted in Fig. 1) for the alkaloid 16-episilicine.
Financial support from the Ministry of Science and Techno-
logy (Spain)-FEDER (project CTQ2006-02390/BQU) and the
DURSI, Generalitat de Catalunya (Grant 2005-SGR-0603), is
gratefully acknowledged. Thanks are also due to the Ministry of
Science and Technology (Spain) for a fellowship to B.C.
Notes and references
1 (a) J. A. Joule, Indoles, The Monoterpenoid Indole Alkaloids, in The
Chemistry of Heterocyclic Compounds, ed. J. E. Saxton,
A. Weissberger, E. C. Taylor, Wiley, New York, vol. 25, part 4,
1983, pp. 232–239; (b) B. Danieli and G. Palmisano, in The
Alkaloids, ed. A. Brossi, Academic Press, Orlando, vol. 27, 1986,
pp. 1–130. For more recent isolations, see: (c) H. Zhang and
J.-M. Yue, Helv. Chim. Acta, 2005, 88, 2537.
Scheme
1
Enantioselective total synthesis of (À)-16-episilicine.
2 M. V. Kisakurek, A. J M. Leeuwenberg and M. Hesse, in Alkaloids:
¨
Reagents and conditions: (a) 1, LiHMDS, (Boc)2O, C6H5SeCl, THF,
6 h, À78 1C, then O3, CH2Cl2, 1 h, À78 1C; (b) CH2QCHMgBr, CuI,
LiCl, TMSCl, THF, 16 h, À78 1C, 84% from 1; (c) 4, NaH, DMF, 20 h,
rt, 75%; (d) (C6H5)3PCH3Br, KHMDS, THF, 6 h, reflux, 74%;
(e) TFA, CH2Cl2, 1 h, rt, then toluene, reflux, 15 h, 77%; (f) 2nd
generation Grubbs catalyst, toluene, 1 week, reflux, 87%; (g) H2, PtO2,
EtAcO, 24 h, rt, 72%; (h) AlCl3, LiAlH4, THF, À78 1C to 0 1C, 3 h,
88%; (i) Mg, MeOH, 6 h, rt, 81%; (j) H2, Pd(OH)2, (Boc)2O, EtOAc,
24 h, rt, 60%; (k) I2O5, THF–H2O, 83%; (l) TFA, THF, then
MeI, 55%.
Chemical and Biological Perspectives, ed. S. W. Pelletier, Wiley,
New York, 1983, ch. 5.
3 The biogenetic numbering is used throughout this paper for all
tetracyclic compounds: J. Le Men and W. I. Taylor, Experientia,
1965, 21, 508.
4 Total syntheses: (a) F. Reis, K. Bannai and H.-P. Husson, Tetra-
hedron Lett., 1976, 1085; (b) H.-P. Husson, K. Bannai, R. Freire,
B. Mompon and F. A. M. Reis, Tetrahedron, 1978, 34, 1363;
(c) M.-L. Bennasar, B. Vidal and J. Bosch, Chem. Commun., 1996,
2755; (d) M.-L. Bennasar, B. Vidal, R. Kumar, A. La
J. Bosch, Eur. J. Org. Chem., 2000, 3919.
´
zaro and
5 (a) Isolation from Pandaca caducifolia: M. Zeches, M. M. Debray,
G. Ledouble, L. Le Men-Olivier and J. Le Men, Phytochemistry, 1975,
14, 1122; (b) Structural elucidation: P. Clivio, B. Richard,
J.-M. Nuzillard and M. Zeches-Hanrot, Phytochemistry, 1995, 40, 987.
6 For the synthesis of 6-oxosilicine by oxidation of natural silicine,
see: A.-M. Bui, M.-M. Debray, P. Boiteau and P. Potier,
Phytochemistry, 1977, 16, 703.
7 For reviews, see: (a) D. Romo and A. I. Meyers, Tetrahedron, 1991,
47, 9503; (b) A. I. Meyers and G. P. Brengel, Chem. Commun.,
1997, 1; (c) M. D. Groaning and A. I. Meyers, Tetrahedron, 2000,
56, 9843; (d) C. Escolano, M. Amat and J. Bosch, Chem.–Eur. J.,
were also isolated. Ring-closing metathesis of 6 was efficiently
performed using the second generation Grubbs catalyst12
under refluxing toluene for five days to give the trans-fused
pentacycle 7 in 87% yield. The absolute configuration of 7,
coinciding at C-15 with the natural configuration (15b-H),2
was unambiguously established by X-ray crystallographic
analysis.
2006, 12, 8198. For more recent work, see: (e) M. Amat, M. Perez,
´
Once the tetracyclic ring system of the target alkaloid, with
the required trans-C15–C16, cis-C15–C20 configuration,3 was
assembled, to complete the synthesis we only needed to
remove the chiral auxiliary and indole protecting group and
to adjust the oxidation level.
A. T. Minaglia, B. Peretto and J. Bosch, Tetrahedron, 2007, 63,
5839; (f) M. Amat, O. Lozano, C. Escolano, E. Molins and
J. Bosch, J. Org. Chem., 2007, 72, 4431; (g) M. Amat, M. Perez,
´
A. T. Minaglia and J. Bosch, J. Org. Chem., 2008, 73, 6920;
(h) I. Soteras, O. Lozano, C. Escolano, M. Orozco, M. Amat,
J. Bosch and J. J. Luque, J. Org. Chem., 2008, 73, 7756;
(i) M. Amat, R. Griera, R. Fabregat, E. Molins and J. Bosch,
Angew. Chem., Int. Ed., 2008, 47, 3348; (j) M. Amat, R. Fabregat,
R. Griera and J. Bosch, J. Org. Chem., 2009, 74, 1794.
The alkene functionality of 7 was hydrogenated and the
resulting pentacyclic lactam was treated with alane, which
brought about both the reduction of the lactam carbonyl
group and the reductive opening of the oxazolidine ring to
give tetracycle 8. Deprotection of the indole nitrogen under
smooth conditions, followed by a catalytic debenzylation in
8 (a) L. E. Overman and A. J. Robichaud, J. Am. Chem. Soc., 1989,
111, 300; (b) M. Amat, N. Llor, J. Bosch and X. Solans,
´
Tetrahedron, 1997, 53, 719; (c) J. Cossy, O. Mirguet, D. Gomez
Pardo and J.-R. Desmurs, New J. Chem., 2003, 27, 475;
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(d) A. Deiters, M. Pettersson and S. F. Martin, J. Org. Chem.,
2006, 71, 6547, and references therein.
D. W. M. Benzies, P. Martinez-Fresneda and R. A. Jones, Synth.
Commun., 1986, 16, 1799.
9 M. Amat, C. Escolano, A. Go
´
mez-Esque
´
, O. Lozano, N. Llor,
12 (a) Handbook of Metathesis, ed. R. H. Grubbs, Wiley-VCH,
Weinheim, vol. 1–3, 2003; (b) F.-X. Felpin and J. Lebreton, Eur.
J. Org. Chem., 2003, 3693; (c) A. Deiters and S. F. Martin, Chem.
Rev., 2004, 104, 2199.
13 K. Yoshida, J. Goto and Y. Ban, Chem. Pharm. Bull., 1987, 35,
4700.
14 We acknowledge Dr. J.-M. Nuzillard (University of Reims) for
providing us with a recently measured [a]D value (+19.6, c 1.0,
CHCl3) of the isolated 16-episilicine.
R. Griera, E. Molins and J. Bosch, Tetrahedron: Asymmetry, 2006,
17, 1581.
10 (a) P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon Press, Oxford, 1983, p. 221; (b) P. Perlmutter, Conjugate
Addition Reactions in Organic Synthesis, Pergamon Press, Oxford,
1992, p. 25.
11 Indole 4 was obtained by NBS bromination of 1-benzenesulfonyl-
3-methylindole-2-carbaldehyde, which was prepared according to:
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