A Short Synthesis of the Erythrina Skeleton and of (±)-α-Lycorane

Article abstract of DOI:10.1021/ol025534e

matrix presented A new nonchain 5-endo radical cyclization starting with xanthates was exploited in a short synthesis of (±)-α-lycorane and the erythrina ring system.

Full text of DOI:10.1021/ol025534e

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1135-1138
A Short Synthesis of the Erythrina
Skeleton and of (±)-r-Lycorane
Luis D. Miranda and Samir Z. Zard*
Laboratoire de Sythe`se Organique associe´ au CNRS, Ecole Polytechnique,
91128 Palaiseau, France
zard@poly.polytechnique.fr
Received January 9, 2002
ABSTRACT
A new nonchain 5-endo radical cyclization starting with xanthates was exploited in a short synthesis of (±)-r-lycorane and the erythrina ring
system.
We have shown, over the past few years, that xanthates and
related derivatives were clean and efficient precursors of a
variety of free radicals.1 The underlying mechanism of the
addition of an O-ethyl xanthate such as 1 to olefin 3 is
outlined in Scheme 1. The process offers many advantages,
is to be sustained, that the initial radical 2 be at least ass
and preferablysmore stable than adduct radical 4, to drive
the equilibrium in the last two propagating steps forward.
In other words, if radical 2 is more stable than radical 4,
intermediate radical 5 will evolve easily into the desired
product 6 and radical 2, which propagates the chain. This
limitation may, however, be lifted by designing a nonchain
sequence where the peroxide is used in stoichiometric
amounts, becoming a full-fledged reagent rather than a mere
initiator.
Scheme 1
Starting with a xanthate such as 7, we considered using
this latter feature to combine a 5-endo ring closure with a
cyclization onto an aromatic ring. This nonchain sequence
would lead in one step to the erythrina skeleton 10, as
pictured in Scheme 2. Radical 5-endo-trig cyclizations
involving enamides have been extensively explored.2 Most
are tin hydride-mediated reactions, whereby the stabilized
(2) (a) Ishibashi, H.; Nakamura, N.; Sato, T.; Takeuchi, M.; Ikeda, M.
Tetrahedron Lett. 1991, 32, 1725-28. (b) Sato, T.; Nakamura, N.; Ikeda,
K.; Okada, M.; Ishibashi, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1
1992, 2399-2407. (c) Ishibashi, H.; Fuke, Y.; Yamashita, T.; Ikeda, M.
Tetrahedron: Asymmetry 1996, 7, 2531-2538. (d) Ikeda, M.; Ohtami, S.;
Okada, M.; Minakuchi, E.; Sato, T.; Ishibashi, H. Heterocycles 1998, 47,
181-186. (e) Ishibashi, H.; Higuchi, M.; Ohba, M.; Ikeda, M. Tetrahedron
Lett. 1998, 39, 75-78. (f) Ikeda, M.; Ohtani, S.; Yamamoto, T.; Sato, T.;
Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1998, 1763-1768. (g) Goodall,
K.; Parson, A. F. J. Chem. Soc., Perkin Trans. 1 1994, 3257-3259. (h)
Goodall, K.; Parson, A. F. Tetrahedron 1996, 52, 6739-6758. (i) Goodall,
K.; Parson, A. F. Tetraedron Lett. 1997, 38, 491-494. (j) Sato, T.; Chono,
N.; Ishibashi, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1995, 1115-
most notably the absence of heavy metals and the possibility
of performing both intra- and, especially, intermolecular
additions to nonactivated olefins. It is important, if a chain
(1) (a) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur, Silicon 1999,
153-154, 137-154; J. Chin. Chem. Soc. 1999, 46, 139-145 (b) Zard, S.
Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672-685.
10.1021/ol025534e CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/07/2002

11 and phenethylamine 12 in refluxing toluene using a
Dean-Stark apparatus, followed by trapping the correspond-
ing imine with chloroacetyl chloride. Displacement of the
chloride with commercially available potassium O-ethyl
xanthate proceeded in excellent yield. However, when
xanthate 7 was exposed to the action of a stoichiometric
amount of lauroyl peroxide (added portionwise) in refluxing
1,2-dichloroethane, none of the desired tetracyclic derivative
10 was found. Instead, we isolated two isomeric lactams 14
and 15 in 62 and 20% yield, respectively (Scheme 3). When
Scheme 2
Scheme 3a
R-amino radical intermediate is ultimately reduced, affording
saturated γ-lactams. We have, in contrast, succeeded in
obtaining γ-lactams containing a diene system by starting
with trichloroacetenamides and generating the radical by
electron transfer from metallic nickel in combination with a
weak acid such as acetic acid.3
We have used this transformation as the key step in the
synthesis of γ-lycorane4 and 3-demethoxyerythratidinone.5
Oxidative termination of the radical sequence has recently
been accomplished using Mn(III)- and Cu(II)-based re-
agents.6
In the present study, it seemed to us that once the 5-endo-
trig closure takes place, the subsequent xanthate transfer from
the starting xanthate 7 to the stabilized, tertiary radical 9
would probably be unfavorable, and in any case quite
reversible. We hoped therefore that this would allow cy-
clization of radical 9 onto the aromatic system to give
ultimately compound 10 possessing the complete framework
of the erythrina alkaloids, many members of which exhibit
interesting biological activity (Scheme 2).7
a Conditions: (i) toluene, reflux, 3 h, then Et3N, chloroacetyl
chloride, CH2Cl2, rt; (ii) KSC(S)OEt, CH3CN, rt; (iii) lauroyl
peroxide, dichloroethane, reflux, 3 h.
the reaction mixture was heated for longer than 3 h, a more
polar compound became more and more visible. It was
identified as conjugated isomer 16, presumably the most
thermodynamically stable of the three isomers. By conduct-
ing the reaction in refluxing 2-propanol, lactam 16 was
rapidly produced and could be isolated in 78% yield. The
faster proton exchange in the more protic solvent allows the
isomerization process to occur within the addition time of
the peroxide.
The formation of unsaturated lactams 14-16 may occur
through direct oxidation by the peroxide of the intermediate,
ring-closed radical 9 into the cationic species 17, which then
loses a proton (Scheme 4). Compound 14 is kinetically the
most favored product, but it readily evolves into 15 and
ultimately 16 depending on the exact reaction conditions.
Alternatively, the formation of the olefinic bond may arise
from the disproportionation of the tertiary radical 9, upon
collision with another radical in the medium. Finally, if a
xanthate transfer did indeed take place, a xanthate such as
18 would be expected to be thermally labile with respect to
elimination of xanthic acid. Which of these processes is
actually operating or is the dominant pathway remains at
this point a matter of speculation.
The starting material for xanthate 7 was the corresponding
chloroacetenamide 13, prepared by heating cyclohexanone
1120. (k) Ikeda, M.; Hamada, M.; Yamashita, T.; Ikegami, F.; Sato, T.;
Ishibashi, H. Synlett 1998, 1246-1248. (l) Ikeda, M.; Hamada, M.;
Yamashita, T.; Matsui, K.; Sato, T.; Ishibashi, H. J. Chem. Soc., Perkin
Trans. 1 1999, 1949. (m) Ikeda, M.; Ohtani, S.; Sato, T.; Ishibashi, H.
Synthesis 1998, 1803-1806. (n) Ishibashi, H.; So, T. S.; Okochi, K.; Sato,
T.; Nakamura, N.; Nakatani, H.; Ikeda, M. J. Org. Chem. 1991, 56, 95-
102. (o) El Bialy, S. A. A.; Ohtani, S.; Sato, T.; Ikeda, M. Heterocycles
2001, 54, 1021.
(3) (a) Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron Lett. 1996,
37, 1397-1400. (b) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S.
Z. Tetrahedron 1998, 54, 1029-1040. (c) Cassayre, J.; Dauge, D.; Zard,
S. Z. Synlett 2000, 471-474.
(4) Cassayre, J.; Zard, S. Z. Synlett 1999, 501-503.
(5) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron
Lett. 1998, 39, 8995-8998.
(6) (a) Davies, D. T.; Kapur, N.; Parsons, A. F. Tetrahedron Lett. 1998,
39, 4397-4400; 1999, 40, 8615-8618; Tetrahedron 2000, 56, 3941-3949.
(c) Clark, A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh, J. P.
Tetrahedron Lett. 1999, 40, 8619-8622. (d) Clark, A. J.; Filik, R. P.;
Haddleton, D. M.; Radigue, A.; Sanders, C. J.; Thomas, G. H.; Smith, M.
E. J. Org. Chem. 1999, 64, 8954-8957. (e) Bryans, J. S.; Chessum, N. E.
A.; Parsons, A. F.; Ghelfi, F. Tetrahedron Lett. 2001, 42, 2901-2904. (f)
Ishibashi, H.; Toyao, A.; Takeda, Y. Synlett 1999, 1468-1470. (g) Toyao,
A.; Chikaoka, S.; Takeda, Y.; Tamura, O.; Muraoka, O.; Tanabe, G.;
Ishibashi, H. Tetrahedron Lett. 2001, 42, 1729-1732.
Although we could not accomplish the ring closure onto
the aromatic ring, the presence of the olefinic bond in the
product could be exploited in a more classical Friedel-Crafts
type approach to the erythrina framework.4,7 Moreover, by
(7) For a review of Erythrina alkaloids, see: Tsuda, Y.; Sano, T. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1996; Vol.
48, pp 249-337.
1136
Org. Lett., Vol. 4, No. 7, 2002

isomeric, intermediate unsaturated lactams 22 since they both
give the same iminium ion in the presence of acid. The
dioxolane ring does not survive these acidic conditions, and
it is ketone 23 (mp 162-165 °C) that is ultimately isolated
in good overall yield (82% from xanthate 21). As far as we
are aware, this three-step sequence represents the shortest
route to an erythrina derivative.
Scheme 4
A concise approach to (()-R-lycorane could also be
implemented by simply modifying the substituent on the
nitrogen atom and by combining the first 5-endo ring closure
with the 6-endo radical cyclization described a few years
ago by Rigby and Mateo.8 We have applied a similar ring
closure to a short synthesis of the epimeric (()-γ-lycorane.4
R-Lycorane 30 belongs to the large class of Amarylidacea
alkaloids, which have attracted much attention due to the
wide spectrum of biological activity exhibited by many of
its members.9 Our synthesis of (()-R-lycorane begins with
the condensation of cyclohexanone with bromobenzylamine
24 and direct chloroacetylation of the resulting Schiff base
to give chloroacetenamide 25 in 63% overall yield (Scheme
6). Displacement of the chloride with the xanthate salt
modifying the substituent on the nitrogen atom, a simple
entry into the galanthan skeleton of the lycoranes could be
implemented.
For the synthesis of the erythrina system, we started with
commercially available monoprotected 1,4-cyclohexanedione
19, which when condensed with homoveratrylamine and the
intermediate Schiff base directly converted into chloro-
acetenamide 20 by treatment with chloroacetyl chloride
(Scheme 5). The corresponding xanthate 21, obtained by
Scheme 6a
Scheme 5a
a Conditions: (i) toluene, reflux, 3 h, then chloroacetyl chloride,
Et3N; (ii) KSC(S)OEt, acetonitrile, rt; (iii) lauroyl peroxide, 1,2-
dichloroethane, reflux, 3 h, then p-toluensulfonic acid, catalytic,
reflux 30 min.
a Conditions: (i) toluene, reflux 3 h, then chloroacetyl chloride,
Et3N; (ii) KSC(S)OEt, acetonitrile, rt; (iii) lauroyl peroxide, 1,2-
dichloroethane, reflux 3 h; (iv) n-Bu3SnH, AIBN, benzene; (v)
LiAlH4, THF.
displacement of the chloride with potassium O-ethyl xanthate,
was heated in refluxing1,2-dichloroethane with a portionwise
addition of a stoichiometric amount of lauroyl peroxide. A
catalytic amount of p-toluenesulfonic acid was then added
to induce the Friedel-Crafts ring closure onto the aromatic
ring. There was thus no need to isolate the mixture of the
furnished the radical precursor 26, which was subjected to
the action of lauroyl peroxide in refluxing 1,2-dichloroethane,
to induce the key oxidative cyclization. As anticipated, this
(8) Rigby, J. H.; Mateo, M. E. Tetrahedron 1996, 52, 10569-10582.
Org. Lett., Vol. 4, No. 7, 2002
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operation produced a mixture of the isomeric tetrahydroin-
dolones 27 and 28 in 53 and 19% yield, respectively. In
accord with the literature,8 reaction of the major isomer with
tributyltin hydride and AIBN in boiling benzene gave the
desired tetracyclic structure 29 in 78% yield. Finally,
reduction with LiAlH4 completed the synthesis of (()-R-
lycorane 30 (mp 152-155 °C from CH2Cl2/hexane; lit.8 mp
155-156 °C). This expeditious synthesis is, as far as we
are aware, the shortest route to this substance.
In conclusion, the present routes to the erythrina ring
system and to (()-R-lycorane underscore the synthetic
potential of this new xanthate-mediated tin-free cyclization.
The essentially neutral, mild reaction conditions are in
principle compatible with a wide variety of functional groups.
Extension to more complex structures is currently under
investigation.
Supporting Information Available: Experimental details
and full spectral data for the main new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) For a review of Amaryllidaceae alkaloids, see: Martin, S. F. In The
Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987; Vol. 30, pp
251-376. (b) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 1998; Vol. 51, pp 323-424.
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