First total synthesis of (±)-strychnofoline via a highly selective ring-expansion reaction

Article abstract of DOI:10.1021/ja027906k

An efficient synthesis of the antitumor alkaloid (±)-strychnofoline is documented. Key to the development of the highly convergent strategy delineated is the coupling of a cyclic imine with spiro[cyclopropan-1,3'-oxindole], which takes place in a highly d

Full text of DOI:10.1021/ja027906k

Published on Web 11/22/2002
First Total Synthesis of (()-Strychnofoline via a Highly Selective
Ring-Expansion Reaction
Andreas Lerchner and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Zu¨rich, CH-8093 Zu¨rich, Switzerland
Received July 29, 2002
Scheme 1
Strychnofoline belongs to a class of natural products isolated
from the leaves of Strychnos usambarensis,1 which displays
antimitotic activity against cultures of mouse melanoma and Ehrlich
tumor cells with strychnofoline showing the highest activity.2 A
prominent structural feature of these and related spirotryprostatin
alkaloids3 is the presence of a spiro[pyrrolidin-3,3′-oxindole]
nucleus. Because of the biological activity of these molecules as
well as the synthetic challenges presented by their complex
architecture, we have embarked on a program that aims at
developing efficient strategies toward their preparation.4,5 In this
communication, we describe our efforts along these lines which
have led to the first total synthesis of (()-strychnofoline (Scheme
1). A key feature of the strategy delineated is the convergent
assembly of the core through the ring-expansion reaction of a spiro-
[cyclopropan-1,3′-oxindole] and a cyclic imine.
Scheme 2
In the context of complex molecule syntheses, preparation of
spiro[perhydroindolizine-oxindoles] has been effected following
three general strategies. The first was reported in the total synthesis
of the related antineoplastics, wherein condensation of a 2-ox-
ytryptamine with an aldehyde afforded an imine that subsequently
participated in an intramolecular Mannich reaction.6a-e In the
parallel, alternate approach, the oxidative rearrangement of yo-
himbinoids provided access to oxindole alkaloids.6f,g The third
approach reported to date is found in the elegant total synthesis of
pseudotabersonine, wherein the analogous spirofused quinolizidine-
oxindole ring system was formed by aza Diels-Alder reaction of
an imine and diene.7
Scheme 3
Scheme 4 a
In a preliminary study, we have reported a novel ring-expansion
reaction of a spiro[cyclopropan-1,3′-oxindole] with a range of
simple, unfunctionalized imines to furnish spiro[pyrrolidin-3,3′-
oxindoles]4 (Scheme 2). Although this reaction proved diastereo-
selective, the critical issue of stereocontrol as a function of
substitution on the imine was left unanswered. In this respect, the
question of whether stereoselectivity could be derived from the
imine fragment would be crucial to address if the method was to
be effective for asymmetric synthesis of more complex structures.
Investigations aimed at the total synthesis of strychnofoline thus
offered an opportunity to address this critical issue. The approach
devised for strychnofoline posed an additional synthetic chal-
lenge: access to and preparative use of cyclic imines such as 11
(Scheme 3). We found that routes involving generation of an amino
aldehyde which would subsequently undergo cyclocondensation to
give imine proved futile, as imines prepared under such conditions
underwent oligomerization. After considerable experimentation, we
found a new mild, convenient method that accesses the requisite
cyclic imine from Boc-protected enamine 9 upon treatment with
TMSOTf/NEt3 as described below.
a (a) (i) PhSeCl, LHMDS, THF, -78 °C; (ii) H2O2, EtOAc, room
temperature. (b) CuBr‚SMe2, allyl MgCl, TMSCl, THF, -78 °C. (c) (i)
DIBAL-H, THF, -78 °C; (ii) aqueous HCl, CH2Cl2, room temperature.
(d) TMSOTf, NEt3, CH2Cl2, -20 °C.
The synthesis of imine 16 commences with 12 (Scheme 4).8
Treatment of the enolate of 12 with PhSeCl, followed by H2O2,
furnished unsaturated lactam 13 (80%). Treatment of 13 with CuBr‚
SMe2/AllylMgCl gave 14 (75%) as a 5:1 mixture of inseparable
diastereoisomers.9 Reduction of 14 and the conversion of the
corresponding lactamol to enamine 15 (1 N aqueous HCl/CH2Cl2,
5 min, 75% yield) permitted facile isolation of a single diastere-
oisomer after chromatography on silica gel.10 Mild cleavage of the
Boc-group (NEt3, TMSOTf, -20 °C with aqueous workup)
converted enamine 15 into imine 16. This cyclic imine 16 was
directly employed without purification in the subsequent ring-
expansion reaction because of its instability. Thus, heating of 1711
with 16 in THF in the presence of MgI2 at 80 °C for 12 h afforded
key intermediate 18 as a single diastereomer in 55% yield over
two steps (Scheme 5). The relative stereochemistry between the
* To whom correspondence should be addressed. E-mail: carreira@
org.chem.ethz.ch.
9
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10.1021/ja027906k CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
(1.5:1) in a combined yield of 64%.16 Deprotection of 23 (Na in
NH3, THF, and t-BuOH warming from -78 to -45 °C) afforded
(()-strychnofoline (1) in 82% yield (Scheme 7). The synthetic
material isolated was in all respects identical to the material from
natural sources by TLC, mass spectrometry, 13C NMR, and 1H NMR
spectroscopy.
Scheme 5
In summary, we have reported an efficient synthesis of the
antitumor alkaloid (()-strychnofoline. Key to the development of
the highly convergent strategy delineated is the coupling of a cyclic
imine with spiro[cyclopropan-1,3′-oxindole], which takes place in
a highly diastereoselective manner. Additional studies on mecha-
nistic and preparative aspects of this reaction are underway and
will be reported as results are forthcoming.
Scheme 6 a
Acknowledgment. This work is dedicated to Professor Scott
E. Denmark. We are grateful to Prof. Luc Angenot for his assistance
in comparing the synthesized and natural products, Dr. B. Schweizer
for X-ray analysis, and Prof. B. Jaun for NMR studies. Support
has been provided by the ETH.
a (a) NMO, OsO4, H2O, dioxane, t-BuOH, room temperature. (b) NaIO4,
H2O, t-BuOH, dioxane, room temperature. (c) p-TsOH, MeOH, CH(OMe)3,
room temperature. (d) TBAF, THF, room temperature. (e) IBX, DMSO,
room temperature. (f) t-BuOK, Ph3PMeBr, THF, room temperature. (g) 10%
aqueous HCl, acetone, room temperature.
Supporting Information Available: Experimental procedures,
spectral data, and structure correlation for all relevant compounds (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
Scheme 7 a
References
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(8) The synthesis of 12 commences with 1,4,5,6-tetrahydro-6-oxo-1-(phenyl-
methyl)-3-pyridinecarboxylic acid methyl ester, whose synthesis in two
steps is reported: Cook, G. R.; Beholz, L. G.; Stille, R. G. J. Org. Chem.
1994, 59, 3575-3584. Reduction of the ester with LiBH4 to the alcohol,
deprotection of the benzyl moiety with Na in NH3, protection of the
hydroxyl-moiety with TBDPSCl, and protection of the amide with Boc2O
afforded 12.
a (a) N-Methyltryptamine, AcOH, toluene, 80 °C. (b) Na, NH3, THF,
t-BuOH, -78 to -45 °C.
two newly formed stereocenters at C-3 and C-7 was confirmed by
1H NMR NOE studies and ultimately through X-ray crystallographic
analysis of 20 (vide infra).12 Although the underlying stereodeter-
mining elements leading to the formation of 18 are difficult to
discern at present, the stereochemical outcome is congruent with
the known preferences in related alkaloids such as rhynchophylline
and isorhynchophylline.13 For these, the observed stereochemistry
has been suggested to result from thermodynamic considerations.
In this regard, analysis of diastereomers epimeric at C-3 reveals
that destabilizing axial interactions would be unavoidable, and
diastereomers epimeric at C-7 are suggested to be precluded because
of ensuing unfavorable interactions between the nitrogen and
carbonyl lone pairs.
Elaboration of the key intermediate to the natural product
commenced with conversion of alkene 18 to ketal 19 (Scheme 6).
Thus, oxidative cleavage of 18 (OsO4, NaIO4) furnished the
corresponding aldehyde, which was protected (CH(OMe)3 and
p-TsOH, MeOH) to afford dimethoxyacetal 19 (80%, over three
steps). Desilylation with TBAF, followed by an oxidation with IBX
in DMSO and Wittig olefination, provided 20 in 66% overall yield
(three steps).14 Deprotection of the acetal with aqueous HCl in
acetone provided aldehyde 21 (94%). Completion of the natural
product necessitated coupling the N-methyl carboline side chain.
In this respect, Pictet Spengler reaction15 of aldehyde 21 and
N-methyl-tryptamine using AcOH in toluene at 80 °C afforded a
diastereomeric mixture of products 22 and desired 23 nonselectively
(9) Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3, 1213-
1221.
(10) The facile conversion of the lactamol into the enamine was surprising,
considering that other less substituted lactamols were converted into the
corresponding enamine only upon heating to 160 °C in HMPA for several
hours: Dieter, R. K.; Sharma, R. R. J. Org. Chem. 1996, 61, 4180-
4184.
(11) The synthesis of 17 commences with 6-methoxyisatine which is com-
mercially available, see Supporting Information.
(12) Particularly useful was an observed NOE between the aromatic C-9 proton
and the appropriate Hâ at C-14.
(13) For an in-depth discussion, see: Brown, R. T. In Heterocyclic Compounds;
Saxon, J. E., Ed.; Wiley-Interscience: New York, 1983; Vol. 25, Part 4,
pp 85-97.
(14) Compound 20 yielded suitable crystals for X-ray structure determination,
thus confirming the stereochemical assignments made earlier on the basis
of 1H NMR, see Supporting Information.
(15) Burm, B. E. A.; Meijler, M. M.; Korver, J.; Wanner, J. M.; Koomen, G.
Tetrahedron 1998, 54, 6135-6146.
(16) Although we did not anticipate stereoselectivity in this condensation
reaction of the simple tryptamine derivative, it is important to note that
stereoselective Pictet Spengler reactions have been documented employing
tryptophan derivatives. Application of such methods at this stage would
likely provide the desired product stereoselectively. (a) Watson, W. H.;
Krawiec, M. J.; Cox, E. D.; Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski,
K. M.; Deng, L.; Bennet, D. W.; Cook, J. M. J. Org. Chem. 1997, 62,
44-61. (b) Waldmann, H.; Schmidt, G.; Jansen, M.; Geb, J. Tetrahedron
1994, 50, 11865-11884.
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