An asymmetric synthesis of both enantiomers of the indole alkaloid deplancheine

Article abstract of DOI:10.1021/jo040245k

(Chemical Equation Presented). We report a novel, facile and asymmetric approach to both enantiomers of the indole alkaloid deplancheine from a readily available, nonracemic chiral template. The natural product and its antipode are isolated with >95% ee.

Full text of DOI:10.1021/jo040245k

An Asymmetric Synthesis of Both
Enantiomers of the Indole Alkaloid
Deplancheine
Steven M. Allin,*,† Christopher I. Thomas,†
Kevin Doyle,‡ and Mark R. J. Elsegood†
Department of Chemistry, Loughborough University,
Loughborough, Leicestershire, LE11 3TU, England, and
OSI Pharmaceuticals, Watlington Road,
FIGURE 1. Some indole alkaloids containing the indolo[2,3-
a]quinolizine template.
Oxford, OX4 6LT, England
SCHEME 1. Preparation of Indolic Bicyclic
Lactams
s.m.allin@lboro.ac.uk
Received August 5, 2004
SCHEME 2. Stereoselective Cyclization of the
Indole Nucleus
We report a novel, facile and asymmetric approach to both
enantiomers of the indole alkaloid deplancheine from a
readily available, nonracemic chiral template. The natural
product and its antipode are isolated with >95% ee.
cyclization of pendent aromatic substituents onto N-
acyliminium intermediates as a key ring-forming step.8
On the basis of our novel approach to the indolizino[8,7-
b]indole ring system,8a we recognized that a suitably
substituted bicyclic lactam could act as a precursor in a
stereoselective approach to the indolo[2,3-a]quinolizine
ring system, and if successful this methodology might
allow us novel and stereoselective access to a wide range
of indole alkaloid targets and their synthetic derivatives.
Deplancheine, 1, an alkaloid isolated from the New
Caledonian plant Alstonia deplanchei,1 has been cited in
several racemic approaches demonstrating the construc-
tion of the indolo[2,3-a]quinolizine ring system.1b,c,d As a
consequence of the work of Meyers in 1986 that described
an asymmetric approach to deplancheine, the absolute
configuration of the natural product was determined to
be R.1a
The indolo[2,3-a]quinolizine ring system is of great
interest and significance because this heterocyclic tem-
plate is found within a plethora of indole alkaloids (see
Figure 1), including deplancheine 1,1 geissoschizine 2,2
and vellosimine 3.3 Recent approaches to the construction
of this heterocyclic target system by other groups have
included the diastereoselective vinylogous Mannich reac-
tion,4 the Bischler-Napieralski reaction,5 Fischer indole
synthesis,6 and the asymmetric Pictet-Spengler reac-
tion.7
We have recently developed a new and general ap-
proach for the stereoselective synthesis of a wide range
of nonracemic heterocycles. Our protocol involves the
† Loughborough University.
‡ OSI Pharmaceuticals.
(1) (a) Meyers, A. I.; Sohda, T.; Loewe, M. F. J. Org. Chem. 1986,
51, 3108-3112. (b) Itoh, T.; Matsuya, Y.; Enomoto, Y.; Ohsawa, A.
Heterocycles 2001, 55, 1165-1171. (c) Calabi, L.; Danieli, B.; Lesma,
G.; Palmisana, G. Tetrahedron Lett. 1982, 23, 2139-2142. (d) Overman,
L. E.; Malone, T. C. J. Org. Chem. 1982, 47, 5297-5300.
(2) Martin, S. F.; Chen, K. X.; Early, C. T. Org. Lett. 1999, 1, 79-
81.
In this paper we describe a new and asymmetric
synthesis of both enantiomers of deplancheine, which
delivers the natural product and its enantiomer with
>95% ee. Our route relies on a highly stereoselective
(3) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.;
Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565-7581.
(4) Deiters, A.; Chen, K.; Early, C. T.; Martin, S. F. J. Am. Chem.
Soc. 2003, 125, 4541-4550.
(8) (a) Allin, S. M.; Thomas, C. I.; Allard, J. E.; Duncton, M.;
Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2003, 44, 2335-2337.
(b) Allin, S. M.; Vaidya, D. G.; James, S. L.; Allard, J. E.; Smith, T. A.
D.; McKee, V.; Martin, W. P. Tetrahedron Lett. 2002, 43, 3661-3663.
(c) Allin, S. M.; James, S. L.; Martin, W. P.; Smith, T. A. D, Elsegood,
M. R. J. J. Chem. Soc., Perkin Trans. 1 2001, 3029-3036. (d) Allin, S.
M.; James, S. L.; Martin, W. P.; Smith, T. A. D. Tetrahedron Lett. 2001,
41, 3943-3946. (e) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin,
A. M. Z. Tetrahedron Lett. 1998, 39, 4905-4908.
(5) Deiters, A.; Martin, S. F. Org. Lett. 2002, 4, 3243-3245.
(6) Fornicola, R. S.; Subburaj, K.; Montgomery, J. Org. Lett. 2002,
4, 615-617.
(7) Liu, X.; Wang, T.; Xu, Q.; Ma, C.; Cook, J. M. Tetrahedron Lett.
2000, 41, 6299-6303.
10.1021/jo040245k CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/04/2004
J. Org. Chem. 2005, 70, 357-359
357

SCHEME 3. Template Manipulation to Access the Key Ring Systema
a Reagents and conditions: (i) IBX, DMSO, rt, 24 h (70%); (ii) Et3N, (Boc)2O, DMAP, THF, rt, 4 h (98%); (iii) NaClO2, NaH2PO4, 1-methyl-
1-cyclohexene, CH3CN, t-BuOH, H2O, 0 °C to rt, 18 h (83%); (iv) (PhSe)2, PBu3, CH2Cl2, 0 °C to rt, 18 h (83%); (v) n-Bu3SnH, AIBN,
toluene, 80 °C, 2 h (73%).
SCHEME 4. Asymmetric Synthesis of Deplancheinea
a Reagents and conditions: (i) LDA, CH3CHO, THF, -78 °C to rt, 24 h; (ii) Et3N, MsCl, DCM, -40 °C to rt, 3 h; (iii) DBN, THF, rt, 16
h (65% for 3 steps); (iv) TBAF, THF, ∆, 9 h (63%); (v) Me3OBF4, 2,6-di-t-Bu-Py, DCM, rt, 21 h; (vi) NaBH4, MeOH, 0 °C, 0.5 h (77% for
2 steps).
cyclization reaction to access the indolo[2,3-a]quinolizine
template from a readily available nonracemic chiral
template.
the cyclization reaction and led to the formation of the
desired indolo[2,3-a]quinolizine product as a single di-
astereoisomer (Scheme 2). The relative stereochemistry
of the single diastereoisomer 5 has been determined by
single-crystal X-ray analysis.10
The stereochemical outcome of this reaction was as
expected on the basis of our previous work with related
aromatic systems and follows the previously proposed
model used to rationalize product stereochemistry.8c-e
To highlight the potential synthetic utility of our new
methodology in the target synthesis of complex indole
alkaloids and their synthetic analogues, we then under-
took the synthesis of the indole alkaloid (R)-(+)-de-
plancheine, 1.
Our previously applied method to remove the hy-
droxymethyl “auxiliary” group from templates such
as 5 has involved a rhodium-induced decarbonylation
sequence.8a As a result of the rather long reaction times
generally needed for our substrates in this protocol we
have now applied a more facile approach that relies upon
a decarboxylation strategy. Compound 5 was oxidized to
the carboxylic acid derivative 8 through the correspond-
ing aldehyde; from 8 we then generated the correspond-
ing acyl selenide derivative 9 and subsequently per-
formed a tin-mediated deacylation to yield the desired
indolo[2,3-a]quinolizine template 10 (Scheme 3).
Construction of the ethylidene moiety was achieved
through a three-step procedure involving generation of
the lithium enolate from 10 and subsequent aldol reac-
tion with acetaldehyde, activation of the hydroxyl group
by mesylation, and finally DBN-induced elimination to
Our approach to the synthesis of the required bicyclic
lactam substrate 4 followed the general method previ-
ously used in our group.8 The â-amino alcohol derivative
of (S)-tryptophan was reacted under Dean-Stark condi-
tions in toluene with an appropriate functionalized
substrate9 for 48 h (Scheme 1). Under these reaction
conditions we were able to isolate the expected bicyclic
lactam in 69% yield as a 5:1 mixture of separable
diastereoisomers, 4a and 4b.
The relative stereochemistry of the major diastereoi-
somer 4a has been determined by single-crystal X-ray
analysis.10 This indole-containing bicyclic lactam is a
novel example of the fused 5,6-ring system favored by
Amat and Bosch,11 and the relative stereochemistry
observed for the major isomer 4a is consistent with
results obtained both by these researchers and our own
previous work in other areas.8b
Treatment of the mixture of bicyclic lactam diastere-
oisomers, 4a and 4b, with 2 M HCl in ethanol at room
temperature for 20 h gave an excellent yield of 95% for
(9) Methyl 5-oxopentanoate: Huckstep, M.; Taylor, R. J. K.; Caton,
H. P. L. Synthesis 1982, 881.
(10) Crystallographic data (excluding structure factors) for struc-
tures 4a (R ) 0.072) and 5 (R ) 0.031) in this paper have been
deposited with the Cambridge Crystallographic Data Centre (CCDC
227217-227218).
(11) Amat, M.; Bosch, J.; Hidalgo, J.; Canto, M.; Perez, M.; Llor,
N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem.
2000, 65, 3074-3084.
358 J. Org. Chem., Vol. 70, No. 1, 2005

give the initial target 11 (Scheme 4). We found that
whereas a THF/DCM solvent mixture in the elimination
step gave only a 4.7:1 ratio in favor of the desired
E-isomer 11, if the elimination procedure was carried out
in THF alone as solvent the E-regioisomer of the eth-
ylidene product 11 was obtained exclusively.12 TBAF-
induced deprotection of the indole nitrogen atom liber-
ated the lactam intermediate 12.
The synthesis of (R)-deplancheine was completed
through removal of the lactam carbonyl group as de-
scribed in Scheme 4 through application of a route
described by Martin and co-workers.2 The desired target,
(R)-(+)-deplancheine, 1, was obtained with an ee of >95%
and the same absolute configuration as the natural
product by comparison of optical rotation data.1a An X-ray
crystal structure of the product R-1 was obtained and is
presented in Supporting Information.13
synthesis of the enantiomer of the natural product. Our
route mirrors that described in Schemes 1-4 but uses
the R-enantiomer of tryptophan as the starting material.
The desired target, (S)-(-)-deplancheine (Scheme 4), was
isolated with an ee of >95% by comparison of optical
rotation data.1a
In summary, we report a facile and highly stereose-
lective approach to the important indolo[2,3-a]quinolizine
template from readily available nonracemic substrates
and have demonstrated the structural modification of the
template to deliver a simple indole alkaloid with high
enantiomeric purity and in both enantiomeric series.
Current work is focused on extending the methodology
described in this paper to other more complex indole
alkaloid targets. Our progress will be reported in due
course.
To demonstrate the potential synthetic utility of our
methodology we have also undertaken an asymmetric
Acknowledgment. We acknowledge Loughborough
University and OSI Pharmaceuticals for a joint stu-
dentship to C.I.T. We thank Professor Stephen F.
Martin for helpful discussions, and Professor Larry
Overman for the supply of a racemic sample of de-
plancheine and copies of corresponding NMR spectra.
(12) The E-regioisomer was found to display a chemical shift of δ
7.0-7.05 ppm for the olefinic proton, whereas the Z-regioisomer
displayed the olefinic proton in a more upfield position of δ 5.92-5.97
ppm. This pattern is in line with reports of NMR data of geometrical
isomers of similar indolo[2,3-a]quinolizidines.14 Compound 11 was
ultimately converted to target 1, for which structural confirmation was
obtained by X-ray crystallography, thus confirming the E stereochem-
istry of both the final product and its precursors.
(13) Crystal data for 1‚1/2H2O: C17H21N2O0.5, M ) 261.36, mono-
clinic, P21, a ) 12.7620(16), b ) 6.8946(9), c ) 17.222(2) Å, â ) 98.533-
(2)°, V ) 1498.5(3) Å3, Z ) 4, Dc ) 1.158 g cm-3, µ(Mo Ka) ) 0.070
mm-1, T ) 150(2) K, yellow blocks; 8486 reflections measured on a
Bruker SMART 1000 CCD diffractometer, of which 4933 were inde-
pendent, data corrected for absorption on the basis of symmetry
equivalent and repeated data (min and max transmission factors 0.960,
0.987) and Lp effects, Rint ) 0.032, structure solved by direct methods,
F2 refinement, R1) 0.043 for 3705 data with F2 > 2s(F2), wR2 ) 0.105
for all data, 367 parameters.
Supporting Information Available: Experimental pro-
cedures for the synthesis of compounds 1 and 4-12; 1H NMR
and 13C NMR spectra for compounds 1, 4, 5, 8, and 10-12;
crystallographic data for compound R-1 in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO040245K
(14) Banks, B. J.; Calverley, M. J.; Edwards, P. D.; Harley-Mason,
J. Tetrehedron Lett. 1981, 22, 1631-1634.
J. Org. Chem, Vol. 70, No. 1, 2005 359