6072
J. Am. Chem. Soc. 1999, 121, 6072-6073
Scheme 1. Retrosynthetic Analysis of (-)-Dendrobine
A Short Synthesis of (-)-Dendrobine
Je´roˆme Cassayre*,† and Samir Z. Zard*,†,‡
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-YVette, France
Laboratoire de Synthe`se Organique associe´ au CNRS
Ecole Polytechnique, 91128 Palaiseau, France
ReceiVed March 4, 1999
(-)-Dendrobine (1), the major alkaloid constituent of the
Chinese ornamental orchid Dendrobium nobile,1 exhibits interest-
ing antipyretic and hypotensive activities.2 Since the elucidation
of its structure in 1964,3 dendrobine (1) has attracted much
attention as a challenging synthetic target. The first total syntheses
of 1 were completed in the 1970’s,4 but efficient and stereo-
selective routes to this molecule were only reported in the 1990’s,5
all involving new synthetic methods, culminating in two formal5b,d
and one total5e enantioselective syntheses.
Scheme 2. Synthesis of the Intermediate Amino Alcohol 3
Our synthetic strategy to (-)-dendrobine (1) is based on the
early introduction of the three stereogenic centers at C(4), C(5),
and C(6), thus resolving all the stereochemical problems for the
final compound (Scheme 1). The amino alcohol 3 would therefore
constitute an attractive intermediate, since the amino group at
C(4) could serve as a template for the stereoselective construction
of the azatricyclo[6.2.1.04,11]undecane ring system by a Pauson-
Khand reaction (3 f 2),6,7 whereas the hydroxy group at C(5)
would control the stereochemistry of the bridged lactone, after
introduction of a carboxylate equivalent at C(7) (2 f 1). As part
as our general interest in new radical processes, we have recently
developped nitrogen-centered radical cyclizations,8 providing a
novel access to various heterocycles.9,10 As an application of this
new methodology, we presumed that key intermediate 3 would
be obtained from (+)-trans-verbenol (6), after a radical cascade
involving cyclization-fragmentation of a carbamyl radical 5, to
give oxazolidinone 4 with the desired stereochemistry.
addition of a tributylstannyl radical to the oxygen of the benzoate
would induce cleavage of the weak N-O bond, and formation
of the desired radical 5. Conversion of (+)-trans-verbenol (6),11
into 7 was accomplished by carbonyl imidazolide formation,
treatment with N-methyl hydroxylamine, and subsequent benzoyl-
ation to afford 7 in 49% overall yield without isolation of the in-
termediates (Scheme 2). As expected, slow addition of Bu3SnH
and AIBN to a refluxing solution of 7 in toluene produced the
desired oxazolidinone 4 in 71% yield. Hydrolysis of 4 afforded
the amino alcohol 3 in 68% yield.12 This represents an interesting
example of a successful cyclization of a carbamyl radical,9a-b and
opens the way to the synthesis of cyclic cis vicinal amino
alcohols.13
The O-benzoyl-N-hydroxyurethane 7 was chosen as a suitable
precursor for the crucial carbamyl radical cyclization, since the
Next, we investigated the construction of the tricyclic core of
dendrobine, involving the formation of the central C(1)-C(11)
bond. After unsuccessful attempts to form the hydroindole
skeleton via cyclization of a carbamoylmethyl radical onto the
C(11)-C(8) bond within 3,14 we turned to a different strategy,
involving Pauson-Khand reaction6 of the N-propargyl derivative
8, readily obtained from 3 by treatment with propargyl bromide,
and subsequent acetylation of the hydroxy group (88% yield).
Treatment of the alkyne-Co(CO)6 complex derived from 8 with
N-methylmorpholine oxide hydrate15 in the usual solvents (CH2-
Cl2 or THF/CH2Cl2) resulted in a slow conversion into the desired
† Institut de Chimie des Substances Naturelles.
‡ Laboratoire de Synthe`se Organique associe´ au CNRS.
(1) (a) Suzuki, H.; Keimatsu, I.; Ito, K. J. Pharm. Soc. Jpn. 1932, 52, 1049-
1060. (b) Suzuki, H.; Keimatsu, I.; Ito, K. J. Pharm. Soc. Jpn. 1934, 54, 802-
812.
(2) Porter, L. Chem. ReV. 1967, 67, 441-464.
(3) (a) Inubushi, Y.; Sazaki, Y.; Tsuda, Y.; Yasui, B.; Konika, T.;
Matsumoto, J. Katarao, E.; Nakano, J. Tetrahedron 1964, 20, 2007-2023.
(b) Inubushi, Y.; Sazaki, Y.; Tsuda, Y.; Nakano, J. Tetrahedron Lett. 1965,
20, 1519-1523.
(4) (a) Yamada, K.; Suzuki, M.; Hayakawa, Y.; Aoki, K.; Nakamura, H.;
Nagase, H.; Hirata, Y. J. Am. Chem. Soc. 1972, 94, 8278-8280. (b) Inubushi,
Y.; Kikushi, T.; Ibuka, T.; Tanaka, T.; Saji, I.; Tokane, K. Chem. Pharm.
Bull. 1974, 22, 349-369. (c) Kende, A. S.; Bentley, T. J.; Mader, R. A.;
Ridge, D. J. Am. Chem. Soc. 1974, 96, 4332-4334. (d) Roush, W. R. J. Am.
Chem. Soc. 1980, 102, 1390-1404.
(10) We have recently completed a short synthesis of (()-γ-lycorane
involving a cascade process starting with a nitrogen-centered radical: Hoang-
Cong, X.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1999, 39, 2125-
2126.
(5) (a) Martin, S. F.; Li, W. J. Org. Chem. 1991, 56, 642-650. (b) Trost,
B. M.; Tasker, A. S.; Ruther, G.; Brandes, A. J. Am. Chem. Soc. 1991, 113,
670-672. (c) Lee, C. H.; Westling, M.; Livinghouse, T.; Williams, A. C. J.
Am. Chem. Soc. 1992, 114, 4089-4095. (d) Mori, M.; Uesaka, N.; Shibasaki,
M.; Saitoh, F.; Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 5633-5642.
(e) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.; Liao,
F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130-4135.
(6) For a previous approach to the dendrobine skeleton using the Pauson-
Khand reaction, see: Takano, S.; Inomata, K.; Ogasawara, K. Chem. Lett.
1992, 443-446.
(7) For recent reviews of the Pauson-Khand reaction, see: (a) Schore, N.
E. Org. React. 1991, 40, 1-90. (b) Schore, N. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon: Oxford, 1991; Vol. 5,
pp 1037-1064. (c) Geis, O.; Schmalz, H.-G. Angew. Chem., Int. Ed. 1998,
37, 911-914.
(8) For reviews of cyclizations of nitrogen-centered radicals, see: (a) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543-17594. (b) Zard, S. Z.
Synlett 1996, 1148-1158.
(11) Whitham, G. H. J. Chem. Soc. 1961, 2232-2236.
(12) This two-step process was best carried out in one pot, without isolation
of 4, allowing a simple purification of 3 and separation of tin residues by an
acid-base extraction (68% yield from 7).
(13) The introduction of a cis vicinal amino alcohol functionality is
generally more challenging than for the trans isomer. See: (a) Knapp, S. Chem.
Soc. ReV. 1999, 28, 61-72. Interesting compounds in this class include the
aminocyclitols (e.g., (+)-valienamine), the aminocyclopentitols (e.g., (+)-
mannostatin), or the conduramines: (b) Balci, M.; Sutbeyaz, Y.; Secen, H.
Tetrahedron 1993, 49, 8039-8058. (c) Posternak, T. The Cyclitols Holden-
Day Inc.: San Francisco, 1965. (d) Trost, B. M.; Van Vranken, D. L. J. Am.
Chem. Soc. 1993, 115, 444-458.
(14) Our initial plan featured a 5-exo-trig radical cyclization of a dichlo-
roacetamide, induced by the Ni/AcOH combination, recently developed in
our laboratory: Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z.
Tetrahedron 1998, 54, 1029-1040 and references cited therein. In model
studies, the cyclization worked well in the absence of the methyl group on
C(11); however, when the methyl group was present, a rare 1,4-allylic
hydrogen abstraction on C(4) took place. These unwanted, but nevertheless
interesting, reactions will be detailed in the full paper.
(9) (a) Callier, A.-C.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1994,
35, 6109-6112. (b) Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-Sire, B.;
Schiano, A.-M.; Zard, S. Z. Tetrahedron 1995, 51, 6517-6528. (c) Callier-
Dublanchet, A.-C.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1995, 36,
8791-8794.
10.1021/ja990707p CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/15/1999