Divergent cycloaddition and ring-closing metathesis approaches to indolizidine and pyrrolo[1,2-a]azepine skeletons from a chiral precursor: An expeditious route to (-)-8-epi-swainsonine triacetate

Article abstract of DOI:10.1021/ol052716a

A divergent strategy for the synthesis of diverse azabicyclic ring systems has been developed in which a chiral N-allylpyrrolidine derivative, obtained from a carbohydrate precursor was converted to (-)-8-ep/-swainsonine triacetate by RCM and to a pyrrolo

Full text of DOI:10.1021/ol052716a

ORGANIC
LETTERS
2006
Vol. 8, No. 2
317-320
Divergent Cycloaddition and
Ring-Closing Metathesis Approaches to
Indolizidine and Pyrrolo[1,2-a]azepine
Skeletons from a Chiral Precursor:
An Expeditious Route to
(−)-8-epi-Swainsonine Triacetate
Madhumita Nath, Ranjan Mukhopadhyay, and Anup Bhattacharjya*
Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road,
Kolkata 700032, India
anupbhattacharjya@iicb.res.in
Received November 9, 2005
ABSTRACT
A divergent strategy for the synthesis of diverse azabicyclic ring systems has been developed in which a chiral N-allylpyrrolidine derivative,
obtained from a carbohydrate precursor was converted to ( )-8-epi-swainsonine triacetate by RCM and to a pyrrolo[1,2-a]azepine derivative
and a 3-hydroxymethyl-substituted indolizidine by N-allylcarbohydrate nitrone and nitrile oxide cycloadditions.
−
The indolizidine and the pyrrolo[1,2-a]azepine skeleta are
present in a large number of naturally occurring azabicyclic
compounds.1,2 The well-known potent glycosidase inhibitors
castanospermine and swainsonine incorporate the indolizidine
nucleus A (Scheme 1), whereas the Stemona alkaloids, many
of which have diverse physiological properties, incorporate
the pyrrolo[1,2-a]azepine nucleus C (Scheme 1). The
biological activity of these compounds, coupled with their
complex structural features, have led to the development of
a large number of synthetic routes to these and similar
skeleta.3 Even so, the development of new expeditious
approaches that are capable of furnishing these molecules
in enantiomerically pure form from a common precursor
remains a worthwhile task because of the obvious advantages
of using the same starting material for multiple targets. N-
and O-alkenylcarbohydrate nitrone and nitrile oxide cycload-
ditions have provided efficient and operationally simple
(1) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625-649.
(2) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17,
117-127.
10.1021/ol052716a CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/23/2005

Scheme 1. Divergent Approaches to Indolizidine and
Scheme 2. Synthesis of the Pyrrolo[1,2-a]azepine 9 by
Pyrrolo[1,2-a]azepine Ring Systems from a Common Precursor
Nitrone Cycloaddition
routes to many enantiopure cyclic amines and ether deriva-
tives.4 In this regard, we recently reported the formation of
various six- and seven-membered nitrogen heterocycles by
the cycloaddition of nitrones generated from N-allyl carbo-
hydrate derivatives.5 We envisaged our application of the
aforementioned cycloadditions, as well as ring-closing me-
tathesis, to a common precursor might lead to some of the
azabicyclic skeleta depicted in Scheme 1.
An interesting feature of this scheme is that the B and C
skeleta retain all the carbon atoms of the precursor molecule
1, while skeleton A contains one carbon atom less than is
present in 1. We report herein the realization of the approach
shown in Scheme 1.
of the isoxazolidine was easily established from the 1H and
13C NMR spectra, which exhibited the bridge -CH2-
protons as two sets of doublets and the -CH2- carbon atom
as a high field signal. Additional support for the structure
of 7 was secured by mass spectral, COSY, HSQC, and
HMBC analysis. The stereochemistry of the bridge methylene
in 7 was established by NOESY analysis. The observed NOE
between 4-OH and one of the H-8 protons indicated the
assigned stereochemistry of 7. The formation of bridged
isoxazolidine 7 from the nitrone 6 is in agreement with the
previously reported cycloaddition of N-allylcarbohydrate
derivatives.5 Cleavage of the isoxazolidine ring in the diacetyl
derivative 8 with a view to exposing the pyrrolo[1,2-a]-
azepine skeleton incorporated within the structure proved
problematic, and the usual methods such as treatment with
Zn-AcOH or transfer hydrogenation in the presence of
cyclohexene and Pd-C were unsuccessful, with an intrac-
table mixture of products being obtained. Finally treatment
with Mo(CO)6 in aq MeCN, followed by acetylation, afforded
the azabicyclic derivative 9 in 35% yield after purification
Diol 2, which was obtained from the N-allylcarbohydrate
derivative 1 by a known procedure (Scheme 2),5b cyclized
in the presence of CCl4 and Ph3P to give the O-benzyl
derivative 4 via the pyrrolidine derivative 3 in 70% overall
yield. Removal of the 1,2-isopropylidene group with 4%
aqueous H2SO4-CH3CN at 25 °C afforded the furanoside-
fused pyrrolidine 5 as a 2:1 anomeric mixture in 97% yield.
The furanoside 5 proved to be a versatile precursor for the
synthesis of all three skeleta A, B and C via diverse
functionalization procedures. Furanosides or pyranosides
similar to 5 having free anomeric positions as well as off-
template alkenyl moieties have been directly converted to
nitrones in situ by reaction with secondary hydroxylamines.6
Accordingly 5 on treatment with N-methylhydroxylamine
hydrochloride in the presence of NaHCO3 in aqueous ethanol
at reflux for 20 h gave exclusively the bridged isoxazolidine
7 (71%) via the nitrone 6 (Scheme 2). The bridged nature
(3) (a) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. ReV. 1995,
95, 1677-1716. (b) Nemr, A. E. Tetrahedron 2000, 56, 8579-8629. (c)
Pyne, S. G. Curr. Org. Synth. 2005, 2, 39-57. (d) Pandit, U. K.; Overkleeft,
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H.; Polt, R. J. Org. Chem. 2000, 65, 5693-5706. (g) White, J. D.; Hrnciar,
P. J. Org. Chem. 2000, 65, 9129-9142. (h) Voigtmann, U.; Blechert, S.
Org. Lett. 2000, 2, 3971-3974. (i) Mmutlane, E. M.; Harris, J. M.; Padwa,
A. J. Org. Chem. 2005, 70, 8055-8063. (j) Roberts, E.; Sancon, J. P.;
Sweeney, J. B. Org. Lett. 2005; 7, 2075-2078. (k) Manzoni, L.; Arosio,
D.; Belvisi, L.; Bracci, A.; Colombo, M.; Invernizzi, D.; Scolastico, C. J.
Org. Chem. 2005, 70, 4124-4132.
(4) (a) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-
909. (b) Frederickson, M. Tetrahedron 1997, 53, 403-425. (c) Osborn, H.
M. I.; Gemmell, N.; Harwood: L. M. J. Chem. Soc., Perkin Trans. 1 2002,
2419-2438.
(5) (a) Majumdar, S.; Bhattacharjya, A.; Patra, A. Tetrahedron Lett. 1997,
38, 8581-8584. (b) Majumdar, S.; Bhattacharjya, A.; Patra, A. Tetrahedron
1999, 55, 12157-12174.
1
by HPLC.7 The H and 13C NMR spectra of 9 were rather
complex due to the restricted rotation of the tertiary amide
(6) (a) Bhattacharjya, A.; Chattopadhyay, P.; McPhail, A. T.; McPhail,
D. R. J. Chem. Soc., Chem. Commun. 1990, 1508-1509; corrigendum, J.
Chem. Soc., Chem. Commun. 1991, 136. (b) Shing, T. K. M.; Zhong, Y.-
L.; Mak, T. C. W.; Wang, R.-j; Xue, F. J. Org. Chem. 1998, 63, 414-415.
(c) Datta, S.; Chattopadhyay, P.; Mukhopadhyay, R.; Bhattacharjya, A.
Tetrahedron Lett. 1993, 34, 3585-3588. (d) Bhattacharjee, A.; Bhattachar-
jya, A.; Patra, A. Tetrahedron Lett. 1995, 36, 4677-4680. (e) Mukho-
padhyay, R.; Kundu, A. P.; Bhattacharjya, A. Tetrahedron Lett. 1995, 36,
7729-7730. (f) Pal, A.; Bhattacarjee, A.; Bhattacharjya, A.; Patra, A.
Tetrahedron 1999, 55, 4123-4132.
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Lett. 1990, 31, 3351-3354.
318
Org. Lett., Vol. 8, No. 2, 2006

group. This was indicated by the 1H NMR spectra obtained
at higher temperatures and the resulting shift of some of the
NMR signals.
Scheme 4. Synthesis of 3-Hydroxymethyl-Substituted
Indolizidine 22 by Nitrile Oxide Cycloaddition
In a separate route, Wittig reaction of the furanoside
intermediate 5 led to the diene intermediate 10 in 61% yield
(Scheme 3).8 The diacetate 11 prepared from 10 smoothly
Scheme 3. Synthesis of (-)-8-epi-Swainsonine Triacetate by
RCM
underwent ring-closing metathesis using the Grubbs’ first-
generation catalyst to provide the indolizidine derivative 12
1
in 82% yield. The H NMR spectrum of 12 in CDCl3
exhibited broad peaks for most of the protons indicating the
presence of two or more equilibrating conformers. The
1
appearance of the peaks in the H NMR spectrum obtained
in C2D2Cl4 changed with increasing temperature, and the
spectrum at 75 °C was found to be a better resolved one
and was fully consistent with the structure of 12. Hydrogena-
tion of 12 in EtOH, in the presence of 10% Pd-C, followed
by acetylation led to a 58% yield of (-)-8-epi-swainsonine
and after several attempts it was achieved by treatment with
HgCl2-HgO in acetone.10 The aldehyde 18 thus obtained
was immediately converted to the oxime 19 in 39% overall
yield by treatment with NH2OH. The nitrile oxide 20
generated from 19 by reaction with N-chlorosuccinimide
underwent in situ cycloaddition to give the isoxazoline 21
in 81% yield. The structure of 21 was secured by mass and
NMR spectral analysis (including HSQC, COSY and NOE-
SY). The observed NOE between H-4 and the benzyl protons
led to the assigned stereochemistry of the newly formed
chiral center. Reductive cleavage of the isoxazoline 21 by
hydrogenation in the presence of Raney nickel and boric acid
produced the indolizidine derivative 22 (28%). The mass
spectra and the 1H and 13C NMR spectra were fully consistent
with the assigned structure. An important structural feature
of 22 is that it represents a 3-hydroxymethyl substituted
indolizidine nucleus, which is expected to be a potentially
useful precursor of analogues of castanospermine and swain-
sonine. The common intermediate 5 has thus served as a
precursor of all three skeletal structures A, B, and C
represented in Scheme 1. Interestingly, the azabicyclic
derivatives 8 and 11, which were directly prepared from 5
could also be synthesized from the aldehyde intermediate
1
triacetate (13). The melting point, optical rotation, H and
13C NMR, IR, and mass spectra of 13 were in agreement
with those reported earlier.3f,9
The successful cycloaddition of the nitrone derived from
5 suggested the possibility of the cycloaddition of the
corresponding nitrile oxide. This was expected to lead to an
isoxazoline fused to a six-membered ring, in contrast to the
seven-membered ring observed for the nitrone 6. Attempted
preparation of the oxime 14 and its conversion to the nitrile
oxide followed by in situ cycloaddition to 15 proved
unsuccessful (Scheme 4). Treatment of the crude 14 with
N-chlorosuccinimide led to the formation of an intractable
mixture of products. Consequently, a more circuitous route
was developed in order to access the ring system of 15. The
furanoside 5 was treated with ethanethiol in the presence of
concd HCl to afford the diethyldithioacetal 16, acetylation
of which gave the diacetate 17 in 68% overall yield (Scheme
4). Cleavage of the dithioacetal moiety in 17 was difficult,
(8) Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis, D.
P.; Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4672-4685
(9) (a) Tadano, K.-I.; Iimura, Y.; Hotta, Y.; Fukabori, C.; Suami, T. Bull.
Chem. Soc. Jpn. 1986, 59, 3885-3892. (b) Blanco, M. J.; Sardina, F. J. J.
Org. Chem. 1996, 61, 4748-4755.
(10) Amoo, V. E.; De Bernardo, S.; Weigele, M. Tetrahedron Lett. 1988,
29, 2401-2404
Org. Lett., Vol. 8, No. 2, 2006
319

isolation of the bis-olefinic intermediate 11 (17%), the RCM
of which has already been described, proved particularly
troublesome.
Scheme 5. Alternative Syntheses of 8 and 11 Using the
Precursor 18
In conclusion, the above work described the conversion
of a carbohydrate derivative to the chiral N-allyl pyrrolidine
derivatives 5 and 18, which served as the common precursors
of two differently substituted indolizidine and a multisub-
stituted pyrrolo[1,2-a]azepine skeleta.11 The strategy is
expected to be important for the synthesis of skeletally
diverse complex azabicyclic systems, and work along this
line is in progress.
Acknowledgment. M.N. is grateful to CSIR, India, for
a Senior Research Fellowship. Thanks are due to Dr. A. K.
Chakraborty, Dr. P. K. Datta, Mr. A. Bannerjee, Mr. K.
Sarkar, Mr. E. Padmanabhan, Mr. S. Chowdhury, and Mr.
S. Samaddar for spectral analyses.
Supporting Information Available: Experimental pro-
cedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
18 according to Scheme 5. The nitrone 23 generated from
18 by treatment with MeNHOH‚HCl and pyridine smoothly
gave the isoxazolidine 8 in 27% yield. In contrast, the Wittig
reaction of 18 was found to be unexpectedly difficult, and
OL052716A
(11) Lindsay, K. B.; Pyne, S. G. Tetrahedron 2004, 60, 4173-4176.
320
Org. Lett., Vol. 8, No. 2, 2006