A short formal route to (±)-lepadin B using a xanthate-mediated free radical cyclisation/vinylation sequence

Article abstract of DOI:10.1039/b203604e

A short route towards (±)-lepadin B has been developed starting from cyclohexenylamine, featuring a diastereose-lective xanthate-mediated free radical cyclisation/vinylation sequence.

Full text of DOI:10.1039/b203604e

A short formal route to (±)-lepadin B using a xanthate-mediated free
radical cyclisation/vinylation sequence†
Chakib Kalaï, Edward Tate and Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France.
E-mail: Zard@poly.polytechnique.fr; Fax: (+33) 1-69-33-30-10
Received (in Cambridge, UK) 15th April 2002, Accepted 21st May 2002
First published as an Advance Article on the web 5th June 2002
A short route towards ( )-lepadin B has been developed
starting from cyclohexenylamine, featuring a diastereose-
lective xanthate-mediated free radical cyclisation/vinylation
sequence.
dichloroethane (DCE), under which conditions the bicyclic
xanthate 5 was formed in 89% yield over 2 hours, with 4 being
recovered in 8% yield (Scheme 2).‡ The bicycle of 5 was
formed exclusively cis,6 and as an approximately 3+2 mixture
of epimers at the carbon bearing the xanthate group; the lack of
selectivity at this latter centre is of no consequence since it is
subsequently regenerated as a secondary radical. The fortuitous
concurrent epimerisation of the a-methyl group to the thermo-
dynamically favoured cis isomer may be catalysed by the trace
of lauric acid, known to form during the thermal homolytic
fission of DLP.
(2)-Lepadin B 1 is a decahydroquinoline alkaloid first isolated
in 1995 from Clavelina lepadiformis;1 it possesses significant in
vitro cytotoxicity against human cancer cell lines,1 and has been
the subject of two recent total syntheses.2,3 Our continuing
interest in developing reactions using xanthates as free radical
precursors has led to several recent applications in synthesis,4
and here we present a new approach to (±)-1 (Fig. 1) based on
a xanthate-mediated radical cyclisation/vinylation sequence.
We planned to introduce a carbon substituent at the xanthate-
bearing carbon using radical vinylation methodology developed
in our laboratories.7 However, attempts to react xanthate 5 with
ethyl styryl sulfone8 under established conditions (chlor-
obenzene 1.5 M in 5, 4.5 M in ethyl styryl sulfone, 30 mol%
tert-butyl peroxide, reflux, 12 h) met with very low conversion
to the desired styryl bicycle, accompanied by substantial
reduction by hydrogen transfer. Such a reduction may be
facilitated by the activated nature of the hydrogen lying between
the carbamate and the ketone in 5, which would generate a
tertiary capto-dative radical upon abstraction. Following this
hypothesis, we supposed that temporary protection of the
ketone moiety with ethylene glycol (2 eq. ethylene glycol, 3
mol% p-toluene sulfonic acid (PTSA), toluene, Dean-Stark, 5 h,
98% yield) might alleviate this problem; in fact we found that
ketone protection did indeed largely suppress reduction, and
that complete conversion of 5 could be achieved if mesylstyrene
79 was used as the vinylating reagent.10 Thus treatment of a 1.5
M solution of the acetal 6 and a three-fold excess of 7 in
refluxing chlorobenzene with 30 mol% tert-butyl peroxide for
12 h gave 8 in 75–80% yield as a 8+1 exo/endo mixture at the
newly formed centre, along with a variable quantity (10–15%)
of the corresponding reduced product 9. The high concentration
of 6 and 7 is key to obtaining high conversion. Both
diastereoisomers of 8 and reduced product 9 proved inseparable
by chromatography at this stage, though 9 was evident in the
proton NMR and mass spectra by comparison to an authentic
sample prepared via tributyltin hydride/AIBN reduction of 6
Fig. 1 (2)-Lepadin B 1
The xanthate radical cyclisation precursor 4 was prepared in
four steps from readily available cyclohex-2-enylamine.5 Thus
condensation with acetoin and protection of the nitrogen with
methylchloroformate gave methoxycarbamate 2 in quantitative
yield (Scheme 1). One-pot bromination of crude 2 via formation
of the trimethylsilyl (TMS) enol ether in dichloromethane
followed by treatment with N-bromosuccinimide (NBS) led to
a-bromo ketone 3 in 86% yield, and displacement of the
bromine with potassium O-ethyldithiocarbonate afforded the
desired xanthate 4 in 99% yield.
Initiation of the radical cyclisation was best performed using
12 mol% dilauroyl peroxide (DLP) in degassed refluxing
Scheme 1
† Electronic supplementary information (ESI) available: experimental and
characterisation data for the transformation of 13 and 14. See http://
www.rsc.org/suppdata/cc/b2/b203604e/
Scheme 2
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CHEM. COMMUN., 2002, 1430–1431
This journal is © The Royal Society of Chemistry 2002

(1.2 eq. tributyltin hydride, 10 mol% AIBN, benzene, reflux 2h,
79% yield).
mesylation and displacement with sodium phenylthiolate,
followed by oxidation with meta-chloroperbenzoic acid
(mCPBA), in 91% yield over the 3 steps. This concludes our
formal route towards lepadin B, as Toyooka et al. have shown
that sulfone 14 may be converted to lepadin B in a five step
sequence utilising a Julia coupling with commercially available
2-heptenal.2
The short route towards (±)-lepadin B described here should
prove amenable to the synthesis of related natural products
lepadins A and C.11 Furthermore, the ready availability of S-
cyclohex-2-enylamine12 suggests that an enantioselective total
synthesis of (2)-lepadin B could be straightforwardly re-
alised.
Treatment of acetal 8 with 50% aqueous trifluoroacetic acid
gave crude ketone 10 which was reduced without further
purification with NaBH4 in methanol to give alcohol 11
(Scheme 3). It appears that a high degree of control is exerted by
the convex bicycle of 10, and no evidence of the epimeric
alcohol was observed in the proton NMR of the crude alcohol.
Furthermore, careful column chromatography of the crude
product allowed removal of both the alcohol derived from the
reduced compound 9 and the undesired endo isomer of 11,
affording alcohol 11 as a single isomer in 73% overall yield
from acetal 8. Protection of the alcohol with chloromethoxy-
methane gave MOM ether 12 in 99% yield. Introduction of the
diene side chain in lepadin B was initiated by reductive
ozonolysis of the styryl moiety to give alcohol 13 (96% yield).
Conversion to the known sulfone 143 was performed via
We are grateful to the Royal Commission for the Exhibition
of 1851 for a fellowship (EWT).
Notes and references
‡ Interestingly, when cyclisation was performed on a tosyl protected
analogue of 4, the cyclisation proceeded with only 30% conversion,
presumably for reasons of steric hindrance.
1 J. Kubanek, D. E. Williams, E. D. de Silva, T. Allen and R. J. Anderson,
Tetrahedron Lett., 1995, 36, 6189.
2 N. Toyooka, M. Okumura and H. Takahata, J. Org. Chem., 1999, 64,
2182; N. Toyooka, M. Okumura, H. Takahata and H. Nemoto,
Tetrahedron, 1999, 55, 10673.
3 T. Ozawa, S. Aoyagi and C. Kibayashi, Org. Lett., 2000, 2955.
4 S. Z. Zard in ‘Radicals in Organic Synthesis’, ed. P. Renaud and M. Sibi,
Wiley YCH, Weinheim, 2001, p. 90–108S. Z. Zard, Angew. Chem., Int.
Ed. Engl., 1997, 36, 672; B. Quiclet-Sire and S. Z. Zard, Phosphorus,
Sulfur Silicon, 1999, 153-154, 137.
5 For a synthesis see: W. Brouillette, A. Saeed, A. Abuelyaman, T.
Hutchison, P. Wolkowicz and J. McMillin, J. Org. Chem., 1994, 59,
4297.
6 Cis formation of six-six bicyles via radical cyclisations of this nature has
some precedent, see: G. Stork and R. Mah, Heterocycles, 1989, 28,
723–727.
7 F. Bertrand, B. Quiclet-Sire and S. Zard, Angew. Chem., Int. Ed., 1999,
38, 1943.
8 Previous vinylation studies carried out in these laboratories have used
ethylstyryl sulfone to effect styrylation of secondary iodides and
xanthates. F. Bertrand, F. Leguyader, L. Liguori, G. Ouvry, G. B.
Quiclet-Sire, S. Seguin and S. Z. Zard, Comp. Rend., 2001, II4, 547.
9 W. Truce and C. Goralski, J. Org. Chem., 1971, 36, 2536.
10 Similar observations have been made by Kim et al. in their work on
radical imination reactions, see: S. Kim, H.-J. Song, T.-L. Choi and J.-Y.
Yoon, Angew. Chem., Int. Ed., 2001, 40, 2524.
11 B. Steffan, Tetrahedron, 1991, 47, 8729.
Scheme 3
12 B. Trost, R. Bunt and S. Pulley, J. Org. Chem., 1994, 59, 4202–4205.
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