An easy entry into berbane and alloyohimbane alkaloids via a 6-exo radical cyclization

Article abstract of DOI:10.1021/ol016424v

(formula presented) The pharmacologically important tetracyclic berbane and pentacyclic alloyohimbane structures were prepared efficiently in four steps including a stereoselective 6-exo radical cyclization using xanthates as the radical source.

Full text of DOI:10.1021/ol016424v

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3125-3127
An Easy Entry into Berbane and
Alloyohimbane Alkaloids via a 6-exo
Radical Cyclization
,†,‡
Talbi Kaoudi,† Luis D. Miranda,† and Samir Z. Zard*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France,
and Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
91128 Palaiseau, France
zard@poly.polytechnique.fr
Received July 11, 2001
ABSTRACT
The pharmacologically important tetracyclic berbane and pentacyclic alloyohimbane structures were prepared efficiently in four steps including
a stereoselective 6-exo radical cyclization using xanthates as the radical source.
The development of synthetic methods1 for constructing the
tetracyclic protoberberine-type and the pentacyclic yohim-
bine-type alkaloids has attracted much attention for several
decades because of their important pharmacological pro-
perties.1a,2 The stereoselective 6-exo-radical cyclization re-
ported by Stork and Mah3 a few years ago was of special
importance to our synthetic strategy, since this reaction would
afford the required cis-fused piperidone system (Scheme 1).
† Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-
Yvette, France.
‡ Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytech-
nique, 91128 Palaiseau, France.
Scheme 1a
(1) For reviews on yohimbine alkaloids, see: (a) Baxter, E. W.; Mariano,
P. S. In Alkaloids: Chemical and biological PerspertiVes; Pelletier, S. W.,
Ed.; Springer-Verlag: New York, 1992; Vol. 8, pp 197-319. (b) Aube, J.;
Ghosh, S. In AdVances in Heterocyclic Natural Products Synthesis; Pearson,
W. H., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 3, pp 99-150. For some
approaches to this alkaloid family, see: (c) Lee, A. W. M.; Chan, W. H.;
Mo, T. Tetrahedron Lett. 1997, 38, 3001. (d) Mehta, G.; Reddy, D. S. J.
Chem. Soc., Perkin Trans. 1 1998, 2125. (e) Hanessian, S.; Pan, J.; Carnell,
A.; Bouchard, H.; Lesage, L. J. Org. Chem. 1997, 62, 465. (f) Wender, P.
A.; Smith, T. E. J. Org. Chem. 1996, 61, 824-825. (g) Logers, M.;
Overman, L. E.; Welmanker, G. S. J. Am. Chem. Soc. 1995, 117, 9139. (h)
Martin, S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236.
(i) Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1999, 64, 3237. (j)
Yamaguchi, R.; Haasaki, T.; Sasaki, T.; Ohta, T.; Utimoto, K.; Kozima, S.
Takaya, H. J. Org. Chem. 1993, 58, 1136. (k) Heidelburgh, T. M.; Liu, B.;
Padwa, A. Tetrahedron Lett. 1998, 39, 4757. (l) Lounasmaa, M.; Jokela,
R. Tetrahedron 1990, 46, 615. (m) Wenkert, E.; Chang, C.; Chawla, H. P.
S.; Cochran, D. W.; Hagaman, E. W.; King, J. C.; Orita, K. J. Am. Chem.
Soc. 1976, 98, 3645. (n) Wenkert, E.; Dave, K. G. J. Am. Chem. Soc. 1965,
87, 5461. (o) Stork, G.; Hill, R. K. J. Am. Chem. Soc. 1954, 76, 949. (p)
Morrison, G. C.; Cetenko, W. A.; Shavel, J. J. Org. Chem. 1966, 31, 3237.
(q) Naito, T.; Miyata, O.; Tada, Y.; Nishiguchi, Y.; Kiguchi, T.; Ninomiya,
I. Chem. Pharm. Bull. 1986, 34, 4144. (r) Kuehne, M. E.; Muth, R. S. J.
Org. Chem. 1991, 56, 2701-2712.
a Conditions: n-Bu3SnH (or Ph3GeH), AIBN, benzene, reflux.
Under the reported tin-mediated reaction conditions, the cis-
fused piperidone was formed along with a considerable
amount of the prematurely reduced, uncyclized product. The
proportion of this side product could be decreased by using
the slower reducing triphenylgermanium hydride.
Over the past several years, we have shown that xanthates
behave as clean and efficient sources of free radicals.4 The
10.1021/ol016424v CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/31/2001

reactions can be conducted in the absence of heavy metals
under tin-free conditions, and the premature reduction of the
intermediate radicals is easily avoided: intermolecular ad-
ditions to unactivated olefins and difficult cyclizations can
often be readily accomplished.
products were formed: the desired product, 13, derived from
6-exo cyclization, in 48% yield, and azepinone 15, derived
from competitive ring closure onto the C-2 of the indole
system, in 22% yield (Scheme 4).7 The stereochemistry of
Building upon these observations, we envisioned a rapid
entry into alloyohimbane 4 and berbane 5 systems based on
a Stork-like cyclization as the key step and using xanthates
as the radical source. Thus, the alloyohimbane system could
be assembled in a short sequence by a 6-exo-radical
cyclization followed by Bischler-Napieralski cyclization,5
in only four steps, from easily available starting materials
(Scheme 2).
Scheme 4a
Scheme 2. Retrosynthetic Analysis
a Conditions: (i) 1,2-dichloroethane, lauroyl peroxide (20%),
reflux, 6 h; (ii) 2-propanol, lauroyl peroxide (120%), reflux, 4 h;
(iii) POCl3, benzene, reflux, 2 h; then, NaBH4, ethanol, rt, 0.5 h;
(iv) n-Bu3SnH, AIBN, benzene; (v) POCl3, then platinum oxide/
H2.
xanthate 13 was confirmed by COSY and NOESY NMR
experiments.
The formation of the seven-membered ring seems to occur
by a direct ring closure onto the free 2-position of the indole
nucleus, rather than through an initial attack at the 3-position
to give a spiro intermediate, which then rearranges to
azepinone 15.7b Such a rearrangement could in principle give
rise to two regioisomers, depending on which bond in the
spiro intermediate migrates to the 2-position. None of the
other possible isomer was observed. Moreover, in another
ancillary study, we have found that a bulky substituent on
the indole nitrogen, which hinders position 2 but not position
3 of the indole ring, causes a significant decrease in the
proportion of azepinone.
Exposure of compound 13 to the action of phosphoryl
oxychloride followed by reduction of the intermediate
iminium ion with sodium borohydride resulted in the
formation of pentacyclic derivative 16, possessing the
complete alloyohimbane skeleton in 87% yield. Indeed,
reductive removal of the xanthate group with tributyltin
hydride gave alloyohimbane 4 in 82% yield. Its spectroscopic
The required xanthate 12 was assembled by alkylation of
tryptamine 10 with the known mesylate 9,6 and the resulting
secondary amine was trapped with chloroacetyl chloride to
afford chloroacetamide 11 in 56% yield. Subsequent sub-
stitution of the chlorine atom by the xanthate group was
accomplished in nearly quantitative yield using the com-
mercially available xanthate salt (Scheme 3).
When xanthate 12 was heated in 1,2-dichloroethane in the
presence of a small amount of lauroyl peroxide, two major
Scheme 3a
(2) Simeon, S.; Rios, J. L.; Vilar, A. Plant Med. Phytothr. 1989, 23,
202.
(3) Stork, G.; Mah, R. Heterocycles 1989, 28, 723.
(4) (a) For an overview of this work, see: Quiclet-Sire, B.; Zard, S. Z.
J. Chin. Chem. Soc. 1999, 46, 139. (b) Zard, S. Z. Angew. Chem., Int. Ed.
Engl. 1997, 36, 672.
(5) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, p 74.
(6) Walton, J. C.J. Chem. Soc., Perkin Trans. 2 1986, 1641.
(7) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem.,
Int. Ed. 2000, 39, 731. (b) We thank a referee for raising this point.
a Conditions: (i) K2CO3, KI, acetonitrile, reflux, 72 h; (ii)
chloroacetyl chloride, Et3N, CH2Cl2, rt; (iii) EtOC(S)SK, MeOH,
rt, 2 h.
3126
Org. Lett., Vol. 3, No. 20, 2001

in this case (Scheme 4).8 Since compound 14 has already
been converted into alloyohimbane 4 by a reductive Bishler-
Napieralski sequence,1p this sequence is one step shorter than
through compound 16. The presence of the xanthate group
in intermediate 16 provides however a convenient handle
for accessing analogues of potential medicinal interest by
exploiting the vast chemistry of sulfur.
Scheme 5a
This approach was easily extended to the berbane-type
alkaloids. Thus, amine 17 was alkylated with mesylate 9 and
the resulting secondary amine was acylated with chloroacetyl
chloride to give the corresponding chloroacetamide, which
was finally converted into xanthate 18 in good overall yield
(Scheme 5).
Cyclization of xanthate 18 under the same radical condi-
tions into piperidone 19 proceeded efficiently: only a small
amount of azepinone 20 was observed. Finally, exposure of
piperidone 19 to the reductive Bischler-Napieralski cycliza-
tion furnished the berbane derivative 21 in high yield
(Scheme 5).
The present, expeditious approach to the alloyohimbane
and berbane skeleton underscores the synthetic potential of
the xanthate transfer technology. The use of more function-
alized homoallylamide precursors should allow access to the
more complex members of this family of alkaloids (e.g.,
reserpine). Work along these lines is underway.
a Conditions: (i) K2CO3, KI, acetonitrile, reflux, 72 h; (ii)
chloroacetyl chloride, Et3N, CH2Cl2, rt; (iii) MeOC(S)SK, MeOH,
rt, 2 h; (iv) 1,2-dichloroethane, lauroyl peroxide (20%), reflux, 6
h; (v) POCl3, benzene, reflux, 2 h; then NaBH4, ethanol, rt, 0.5 h.
Note Added after ASAP: There was an error in the title of
the version posted ASAP August 31, 2001; the corrected
version was posted September 17, 2001.
properties were identical to those published previously1b
(Scheme 4).
Supporting Information Available: Full analytical data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The direct formation of the known piperidone 141p in 54%
yield by simply performing the ring closure in 2-propanol
as the solvent, and using stoichiometric amounts of peroxide,
illustrates an interesting and important aspect of xanthate
technology. 2-Propanol is the source of the hydrogen atom
OL016424V
(8) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37,
5877.
Org. Lett., Vol. 3, No. 20, 2001
3127