8166
J. Am. Chem. Soc. 1996, 118, 8166-8167
envisaged as arising from isoindigo (4), which is available in
Stereocontrolled Total Syntheses of
one simple high-yielding step from commercially available
oxindole and isatin.7 We conjectured that the pivotal conversion
of 4 to 7 could be accomplished by a reductive dialkylation,
whose stereochemical outcome would derive from chelate
assembly 6.8
meso-Chimonanthine and meso-Calycanthine via a
Novel Samarium Mediated Reductive Dialkylation
J. T. Link and Larry E. Overman*
Department of Chemistry, 516 Physical Sciences 1
UniVersity of California at IrVine
Isoindigo (4) was first converted to N-benzyl derivative 5.9
Treatment of 5 with 2 equiv of SmI2 apparently generates the
samarium diolate, since (N-benzyl)dihydroisoindigo was ob-
tained upon protolytic quenching.10,11 However, this dianion
did not react to an appreciable extent with cis-1,4-dichloro-2-
butene even in the presence of HMPA at room temperature.12
The presumed lithium diolate obtained upon treatment of (N-
benzyl)dihydroisoindigo with 2.1 equiv of n-BuLi did react at
room temperature with cis-1,4-dichloro-2-butene to deliver a
mixture of the desired meso product 7 and an isomeric
cyclobutane resulting from SN2′ closure. Related experiments
with the potassium diolate (formed from reaction of (N-benzyl)-
dihydroisoindigo with 2.2 equiv of KHMDS) gave a similar
product distribution. After some experimentation, a remarkable
procedure for converting 5 into 7 was discovered. Isoindigo 5
was reduced at room temperature with 2 equiv of SmI2 in the
presence of 10 equiv of LiCl and then alkylated at this
temperature with cis-1,4-dichloro-2-butene. After 8 h, cyclo-
hexene 7 was isolated in 82% yield. None of the corresponding
dl isomer was observed by 1H-NMR analysis of the crude
reaction mixture or of any chromatographic fraction, suggesting
that diastereoselectivity for this process was at least 20:1.
Although it is tempting to invoke transmetalation (Sm f Li)
to explain this reaction, subtle changes in the samarium
coordination sphere or degree of aggregation brought about by
the added halide salt could be responsible for the reaction
outcome.13 It should be noted that these reaction conditions
provide a room temperature alternative to lithium in liquid
ammonia, which in the present case would not have been
compatible with the benzyl protecting groups in 5.
IrVine, California 92697-2025
ReceiVed May 24, 1996
The dodecacyclic polyindoline alkaloid psycholeine (1) was
isolated from the New Caledonian plant Psychotria oleoides in
1992 by Se´venet and co-workers using a bioactivity-guided
fractionation approach.1 This novel natural product is reported
to be the first non-peptide antagonist of the somatostatin family
of receptors, and therefore is of potential therapeutic interest.2
Psycholeine (1), [R]20D -150, is structurally remarkable having
a central achiral hexacyclic core that is adorned with two
pyrroloindolines of the same absolute chirality. The achiral
hexacyclic unit also is found in meso-calycanthine (3), which
is obtained by acid-catalyzed rearrangement of the bis(pyrro-
loindoline) alkaloid meso-chimonanthine (2).3 In this com-
munication, we report the first stereocontrolled total syntheses
of meso-chimonanthine (2) and meso-calycanthine (3) as the
initial step in the development of a strategy for the total synthesis
of psycholeine (1).4
The conversion of cyclohexene 7 to meso-chimonanthine (2)
proved challenging due to the facile cleavage of the doubly
benzylic C3a,C3a′ bond.14 However, a satisfactory means of
attaining the desired oxidation state at C8a,C8a′ was found when
7 was treated with sodium bis(2-methoxyethoxy)aluminum
(7) (a) Stolle, R. J. Prakt. Chem. 1930, 128, 1. (b) Papageorgiou, C.;
Borer, X. HelV. Chim. Acta 1988, 71, 1079.
(8) Although not proposed by previous workers, a related chelate is
presumably responsible for the selectivity observed by Hino in his synthesis
of d,l-chimonanthine.6a
1
(9) New compounds were fully characterized by H and 13C NMR, IR,
and MS analysis, while elemental composition was confirmed by combustion
analysis or high-resolution mass spectrometry. Yields refer to isolated
products purified on silica gel unless noted otherwise. Standard abbreviations
employed are defined in: J. Org. Chem. 1996, 61, 22A.
(10) Addition of 2 equiv of SmI2 to 5 at room temperature yields a blue
solution that rapidly turns light yellow indicating complete consumption
of SmI2. Quenching with saturated aqueous NH4Cl provided both isomers
of (N-benzyl)dihydroisoindigo (in 1.5:1 ratio) in 97% yield.
(11) For a recent review of the chemistry mediated by samarium diiodide,
see: Molander, G. A. Org. React. 1994, 46, 2111.
(12) Enholm, E. J.; Schreier, J. A. J. Org. Chem. 1995, 60, 1110.
(13) A simple salt effect is not involved, since addition of KCl (instead
of LiCl) yielded (N-benzyl)dihydroisoindigo after protonolysis, rather than
cyclohexene 7.
(14) Cyclohexene 7 could be converted into 14 (R ) alkyl or R ) H
and CO2R′), which upon treatment with reducing agents typically lead to a
∼1:1 mixture of oxindole 15 and indole 16.
Past synthetic efforts directed toward bis(pyrroloindoline)
alkaloids have produced predominantly the racemic isomers
either by oxidative dimerization of oxindoles (or tryptamines)3,5
or from dialkylation of 3,3′-bis(oxindoles).6 We anticipated that
meso-chimonanthine (2) could be constructed from cyclohexene
7, an intermediate that contains the two key quaternary carbon
centers present in 2 and 3 (Scheme 1). Cyclohexene 7 was
(1) Gue´ritte-Voegelein, F.; Se´venet, T.; Pusset, J.; Adeline, M. T.; Gillet,
B.; Beloeil, J. C.; Gue´nard, D.; Potier, P.; Rasolonjanahary, R.; Kordon, C.
J. Nat. Prod. 1992, 55, 923.
(2) Rasolonjanahary, R.; Se´venet, T.; Voegelein, F. G.; Kordon, C. Eur.
J. Pharm. 1995, 285, 19.
(3) (a) Hendrickson, J. B.; Go¨schke, R.; Rees, R. Tetrahedron 1964, 20,
565. (b) Hall, E. S.; McCapra, F.; Scott, A. I. Tetrahedron 1967, 23, 4131.
(4) For reviews of previous synthetic efforts in this area, see: (a) Hino,
T.; Nakagawa, M. Alkaloids 1989, 34, 1. (b) Kutney, J. P. In Total Synthesis
of Natural Products; ApSimon, J., Ed.; Wiley: New York, 1977; Vol. 3,
pp 273-438. (c) Manske, R. H. F. Alkaloids 1965, 8, 581.
(5) (a) Hino, T.; Kodato, S.; Takahashi, K.; Yamaguchi, H.; Nakagawa,
M. Tetrahedron Lett. 1978, 19, 4913. (b) Fang, C. L.; Horne, S.; Taylor,
N.; Rodrigo, R. J. Am. Chem. Soc. 1994, 116, 9480.
(15) For previous reports of the preparation of similar ring systems,
see: (a) Hodson, H. F.; Smith, G. F.; Wro´bel, J. T. Chem. Ind. 1958, 1551.
(b) Hino, T. Chem. Pharm. Bull. 1961, 9, 988.
(6) (a) Hino, T. Chem. Pharm. Bull. 1961, 9, 979. (b) Hino, T.; Yamada,
S. Tetrahedron Lett. 1963, 4, 1757.
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