Application of furyl-stabilized sulfur ylides to a concise synthesis of 8a-epi-swainsonine

Article abstract of DOI:10.1039/b713447a

The total synthesis of 8a-epi-swainsonine has been achieved in 20% overall yield from R-glyceraldehyde dimethylacetonide 3 through epoxidation with the achiral furyl-substituted sulfonium ylide 2d as one of the key steps. The Royal Society of Chemistry.

Full text of DOI:10.1039/b713447a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Application of furyl-stabilized sulfur ylides to a concise synthesis of 8a-
epi-swainsonine{
Jie Bi and Varinder K. Aggarwal*
Received (in Cambridge, UK) 3rd September 2007, Accepted 8th October 2007
First published as an Advance Article on the web 17th October 2007
DOI: 10.1039/b713447a
The total synthesis of 8a-epi-swainsonine has been achieved in
20% overall yield from R-glyceraldehyde dimethylacetonide 3
through epoxidation with the achiral furyl-substituted sulfo-
nium ylide 2d as one of the key steps.
Swainsonine 1 (Fig. 1), a naturally occurring polyhydroxyindoli-
zidine, was first isolated from the fungus Rhizoctonia leguminicola
in 19731 and has since attracted much attention, primarily because
Scheme 1 Reaction of chiral sulfur ylide with chiral aldehyde.
of its significant biological activity. For example, it was found to
be an effective inhibitor of a-D-mannosidases,2 including the
reacted with PhCHO (as shown previously),13 the related reaction
with glyceraldehyde dimethylacetonide 3 under the same condi-
tions failed (Scheme 3). This is presumably due to the instability of
the aldehyde at 40 uC over a prolonged period.
glycoprotein-processing enzyme mannosidase II.3 It also exhibits
important antimetastatic,4 antitumor-proliferative,5 anticancer,6
and immunoregulating activities.7 Swainsonine was also the first
inhibitor to be selected for testing as an anticancer drug, reaching
phase II clinical trials in the US.8 Furthermore, considerable
structural variants (alternative epimers, other structural analogues)
have also been prepared in order to try to improve the biological
activity and/or the selectivity of the natural compound.9
Application of the stoichiometric sulfur ylide reaction was
therefore explored.14 However, all attempts to form simple furfuryl
sulfonium salt 2c led to polymers or very low yields of products
(Scheme 4).15 We therefore attempted to stabilize the sulfonium
salt by blocking the 5-position on the furyl ring with a suitable
electron-withdrawing group. Of the substrates explored, only the
chloro and sulfonyl groups led to stable intermediates and of these
only the sulfonyl substituted salt 2d reacted with glyceraldehyde
dimethylacetonide 3. This furnished a mixture of epoxides (6 : 83 :
11) in which 11b predominated. The stereochemical outcome at C2
(11a + 11b : 11c) is in keeping with a polar Felkin–Anh controlled
addition of the ylide to the chiral aldehyde. Interestingly, use of
either of the two chiral sulfonium salts (+)-2e and (2)-2e gave
similar results, indicating that the ylide reaction was now under
substrate control rather than reagent control. This implies that
betaine formation (which would be expected to be controlled by
the reagent) must be reversible, and the epoxide selectivity is
determined by the equilibrium ratios of the betaine intermediates
and their rates of ring closure. Thus, the introduction of the
Its considerable biological activity and interesting structure has
made swainsonine a popular target amongst synthetic chemists.9,10
Our own analysis of a potential route to this compound evolved
from our work on sulfur ylides.11 In early studies, we had shown
that the phenyl-stabilized ylide 2a reacted with glyceraldehyde
dimethylacetonide 3 to give the cis epoxide 4a (Scheme 1).12 In this
kinetically controlled reaction, the C1 stereochemistry is controlled
by the chiral sulfur ylide (reagent control) and the C2
stereochemistry is controlled by the substrate. We reasoned that
if we could effect the same type of reaction with the related furyl-
stabilized ylide 2b to give epoxide 5a, then following ring opening
by NH3 and application of the Achmatowicz reaction we should
arrive at piperidine 7a (Scheme 2). Piperidine 7a is just a few
functional group interconversions away from swainsonine.
Realization of this strategy, however, quickly revealed a
significant obstacle. Although the furyl-stabilized ylide 9 could
be generated from the corresponding tosylhydrazone salt 10 and
Fig. 1 Structure of swainsonine.
Cantock’s Close, School of Chemistry, University of Bristol, UK
BS8 1TS. E-mail: V.Aggarwal@Bristol.ac.uk; Fax: +44 117 929 8611;
Tel: +44 117 954 6315
{ Electronic supplementary information (ESI) available: Full experimental
details and X-ray structure of 20. See DOI: 10.1039/b713447a
Scheme 2 Proposed route to swainsonine.
120 | Chem. Commun., 2008, 120–122
This journal is ß The Royal Society of Chemistry 2008

View Article Online
from which the sulfone group was subsequently removed with
sodium amalgam to give the amino alcohol 6b (Scheme 5).
Attempts to effect ring opening of the epoxide with a retention of
configuration were not successful. Use of TMSN318 only returned
starting material, presumably because the sulfonyl group destabi-
lized carbocation formation adjacent to the furyl group.
Furthermore, removal of the sulfonyl group using Na/Hg
amalgam could not be effected without destroying the epoxide.
A double inversion strategy,19 using MgBr2 followed by NaN3,
ultimately gave the same major isomer as that obtained from direct
aminolysis, indicating that the initial ring opening had occurred
with retention in this case! Presumably, the bromohydrin was
formed under thermodynamic control through multiple attacks by
the bromide ion.
Scheme 3 Attempts to use the catalytic sulfur ylide reaction. PTC =
phase transfer catalyst.
sulfonyl group on the furyl ring, necessary to stabilize the
sulfonium salt, has changed the nature of the ylide from a semi-
stabilized ylide that would otherwise react non-reversibly, to a
stabilized ylide that reacts reversibly. In fact, the level of selectivity
observed is similar to that reported for amide-stabilized sulfur
ylides (0 : 84 : 16; a : b : c) which are also believed to react
reversibly.16
Access to multigram quantities of 6b nevertheless allowed us to
potentially obtain 8a-epi-swainsonine and so we next considered
the oxidative ring rearrangement—the aza-Achmatowicz reac-
tion.20 A key issue in this regard was the choice of the protecting
groups for the amino alcohol subunit to advance our synthesis.
Despite the common use of a sulfonamide N-protecting group in
the aza-Achmatowicz reaction due to its compatibility with the
acidic reaction conditions,21 we decided to carry forward a Cbz-
protecting group due to the potential for a one-pot reduction–
deprotection at the end of our total synthesis.22 We were pleased to
find that when Cbz-protected a-hydroxy amine 12 was subjected
to the oxidative reaction conditions (using anhydrous mCPBA),22
the ring expanded dihydropyridinone 7b was obtained in 72%
yield. Key to the success of this reaction was the use of anhydrous
mCPBA and avoidance of an aqueous work-up. Evidently the
dihydropyridinone 7b was quite water soluble.
With a scalable synthesis of trans epoxide 11b in hand we
continued our synthesis, the next step of which involved ring
opening of the epoxide with an appropriate nitrogen nucleophile.
If this occurred with retention of configuration this would lead to
swainsonine, whilst inversion would lead to 8a-epi-swainsonine.
Direct aminolysis with aqueous ammonia smoothly ring-opened
the oxirane with inversion to give the anti amino alcohol subunit,17
We proposed to protect the hemi-aminal 7b with the internal
hydroxyl group, leading to bicycle 13, prior to the regio- and
diastereoselective reduction of the carbonyl group. This anhydro-
bridged structure would not only simultaneously protect both
functionalities (the alcohol and the hemi-aminal) but would also
effectively block the Re face of the enone, and thus should result in
high diastereoselectivity in attack of sodium borohydride from the
less hindered Si (lower) face.
Thus, treatment of 7b with TsOH?H2O, in toluene in the
presence of 4 A molecular sieves23,24 gave the anhydro-bicycle 13 in
˚
Scheme 4 Synthesis and reactions of furyl-substituted ylides. THT =
tetrahydrothiophene.
Scheme 5 Completion of the synthesis of 8a-epi-swainsonine.
Chem. Commun., 2008, 120–122 | 121
This journal is ß The Royal Society of Chemistry 2008

View Article Online
82% yield. As expected, Luche reduction25 gave essentially one
diastereomer, 15, and in high (95%) yield.26 Subsequent hydro-
genation with Pd/C simultaneously effected reduction of the
alkene, N,O-acetal and Cbz cleavage to furnish the free amine 19.
The synthesis was completed by first deprotection of the acetonide
to the free tetrahydroxy amine 8b under standard catalytic acidic
conditions, followed by an intramolecular N-alkylation under
Appel conditions,27 which finally gave 8a-epi-swainsonine in the
form of its hydrochloride salt 20. An X-ray structure of 20
confirmed its relative (and absolute) stereochemistry (see ESI).{,{
In conclusion we have achieved a concise synthesis of 8a-epi-
swainsonine in an overall yield of 20% from R-glyceraldehyde by
applying our epoxidation reaction with furyl-substituted sulfur
ylides. The synthesis is also noteworthy for its brevity, minimal use
of protecting groups, and for demonstrating the latent function-
ality inherent in furyl epoxides.
14 V. K. Aggarwal, I. Bae, H. Y. Lee, J. Richardson and D. T. Williams,
Angew. Chem., Int. Ed., 2003, 42, 3274.
15 Furfuryl sulfonium salts have been obtained in low yield from the
corresponding alcohol and HPF6: S. Zhang, D. Marshall and
L. S. Liebeskind, J. Org. Chem., 1999, 64, 2796.
16 (a) M. Valpuesta, P. Durante and F. J. Lopez-Herrera, Tetrahedron,
1993, 49, 9547; (b) M. Valpuesta, P. Durante and F. J. Lopez-Herrera,
Tetrahedron, 1990, 46, 7911.
17 (a) M. Valpuesta, P. Durante and F. J. Lopez-Herrera, Tetrahedron
Lett., 1995, 36, 4681; (b) B. Olofsson and P. Somfai, J. Org. Chem.,
2002, 67, 8574.
18 B. Alcaide, C. Biurrun, A. Martinez and J. Plumet, Tetrahedron Lett.,
1995, 36, 5417.
19 P. Lupattelli, C. Bonini, L. Caruso and A. Gambacorta, J. Org. Chem.,
2003, 68, 3360.
20 (a) Z. M. Wang and W. S. Zhou, Tetrahedron, 1987, 43, 2935; (b)
M. D. Burke, E. M. Berger and S. T. Schreiber, J. Am. Chem. Soc.,
2004, 126, 14095.
21 C. F. Yang, Y. M. Xu, L. X. Liao and W. S. Zhou, Tetrahedron Lett.,
1998, 39, 9227.
22 M. H. Haukaas and G. A. O’Doherty, Org. Lett., 2001, 3,
401.
˚
23 In the absence of 4 A sieves the polycyclic ether 14 was obtained via
hydrolysis of the acetonide followed by addition.
We thank the ORS and University of Bristol for a Scholarship
(JB) in support of this work and Dr J. P. H. Charmant and Mr
Saowanit Saithong for X-ray analysis. VKA thanks the Royal
Society for a Wolfson Research Merit Award and EPSRC for a
Senior Research Fellowship.
Notes and references
{ CCDC 659348. For crystallographic data in CIF format see DOI:
10.1039/b713447a
1 F. P. Guengerich, S. J. DiMari and H. P. Broquist, J. Am. Chem. Soc.,
1973, 95, 2055.
2 P. R. Dorling, C. R. Huxtable and S. M. Colegate, Biochem. J., 1980,
191, 649.
24 J. Ostrowski, H. J. Altenbach, R. Wischnat and D. J. Brauer, Eur. J.
Org. Chem., 2003, 1104.
25 J. L. Luche, J. Am. Chem. Soc., 1978, 110, 2226.
26 In the absence of protection of the alcohol, Luche reduction on enone 16
did not give the expected allylic alcohol 17, but instead formed bicycle
18. It is believed that the free hydroxyl group adds to the enone (perhaps
catalyzed by CeCl3) prior to reduction of the carbonyl group. Protection
of the hydroxyl group was therefore required.
3 A. D. Elbein, P. R. Dorling, K. Vosbeck and M. Horisberger, J. Biol.
Chem., 1982, 257, 1573.
4 D. A. Winkler and G. Holan, J. Med. Chem., 1989, 32, 2084.
5 J. W. Dennis, Cancer Res., 1986, 46, 5131.
6 M. J. Humphries, K. Matsumoto, S. L. White and K. Olden, Cancer
Res., 1986, 46, 5215.
7 H. Motohiro, N. Kunio, T. Hiroshi, H. Junji, K. Masanobu, A. Hatsuo
and I. Hiroshi, Chem. Abs., 1984, 101, 28283x.
8 P. C. Das, J. D. Roberts, S. L. White and K. Olden, Oncol. Res., 1995,
7, 425.
9 For reviews see: (a) S. G. Pyne, Curr. Org. Synth., 2005, 2, 39; (b)
A. E. Nemr, Tetrahedron, 2000, 56, 8579.
10 For recent examples see: A. J. Murray, P. J. Parsons and P. Hitchcock,
Tetrahedron, 2007, 63, 6485(a) J. Ceccon, A. E. Greene and J. F. Poisson,
Org. Lett., 2006, 8, 4739; (b) N. S. Kumar and B. M. Pinto, J. Org.
Chem., 2006, 71, 1262; (c) C. W. G. Au and S. G. Pyne, J. Org. Chem.,
2006, 71, 7097; (d) H. Guo and G. A. O’Doherty, Org. Lett., 2006, 8,
1609.
11 V. K. Aggarwal and C. L. Winn, Acc. Chem. Res., 2004, 611.
12 V. K. Aggarwal and J. Bi, Beilstein J. Org. Chem., 2005, 1, DOI:
10.1186/1860-5397-1-4.
13 V. K. Aggarwal, E. Alonso, I. Bae, G. Hynd, K. M. Lydon,
M. J. Palmer, M. Patel, M. Porcelloni, J. Richardson, R. A. Stenson,
J. R. Studley, J.-L. Vasse and C. L. Winn, J. Am. Chem. Soc., 2003, 125,
10926.
27 Y. W. Chen and P. Vogel, J. Org. Chem., 1994, 59,
2487.
122 | Chem. Commun., 2008, 120–122
This journal is ß The Royal Society of Chemistry 2008