A convenient approach to (-)-8-epi-swainsonine

Article abstract of DOI:10.1055/s-2006-939710

A novel and efficient synthesis of (-)-8-epi-swainsonine (2) is reported. Face-selective diol formation from the bicyclic alkene 3 followed by a stereoselective vinylation of the aldehyde and ring-closing metathesis gave the indolizidine ring system, which was converted into (-)-8-epi-swainsonine (2). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939710

LETTER
1443
A Convenient Approach to (–)-8-epi-Swainsonine
A
Convenient
A
pp
d
roac
h
to (–)-
r
8-epi-Sw
i
ainson
a
ine n J. Murray, Philip J. Parsons*
Department of Chemistry, School of LifeSciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QJ, UK
Fax +44(1273)677196; E-mail: P.J.Parsons@sussex.ac.uk
Received 13 February 2006
Abstract: A novel and efficient synthesis of (–)-8-epi-swainsonine
(2) is reported. Face-selective diol formation from the bicyclic
alkene 3 followed by a stereoselective vinylation of the aldehyde
and ring-closing metathesis gave the indolizidine ring system,
which was converted into (–)-8-epi-swainsonine (2).
O
O
O
H
i
N
O
O
H
H
O
O
Key words: stereoselective, indolizidine synthesis, metathesis,
N
stereoelectronic
O
O
3
4
5
The synthesis of indolizidine alkaloids has been the sub-
ject of intense research due to their interesting chemical
structures and variable and potent biological properties.1
Swainsonine (1), which has been isolated from the fungus
Rhizoctonia leguminicola2 and was later isolated from
other fungal3 and plant sources,4 possesses a range of
interesting biological properties which include the inhibi-
tion of both lysosomal a-mannosidase5 and mannosidase
II.6 It is clear that the indolizidine alkaloids are an impor-
tant class of compounds in biological terms but that they
are often difficult to make on a scale which would permit
extensive biological evaluation.7 We have developed a
synthesis of (–)-8-epi-swainsonine (2) that will also allow
the simple construction of other members of this impor-
tant class of compounds (Figure 1).
Scheme 1 Reagents and conditions: i) hn, EtOAc (38%).
OH
O
HO
O
O
iii, iv
ii
i
N
N
O
N
O
O
O
O
3
6
7
O
O
O
O
O
O
v
vi
H
O
OH
OH
N
N
N
Boc
10
Boc
Boc
HO
OH
HO
OH
8
9
H
H
OH
OH
O
O
N
N
O
O
4
3
H
ix
x
vii, viii
5
2
H
OTBS
1
N
OTBS
9
1
2
10
N
6
11
H
7
8
Figure 1
11
12
We have recently discovered and reported that oxazol-
idinone 3 undergoes facile and unexpected addition reac-
tions (Scheme 1).8
Calculations from our laboratory9 have shown that the
HOMO reveals an unsymmetrical p-bond with a higher
electronic density on the endo-face of the bicyclic system
3. These data led us to devise new and efficient routes to
HO
OH
O
O
O
O
Ref. 19
xi
H
8
7
H
H
OH
9
OTBS
OTBS
N
6
3
1N
N
5
4
2
13
14
2
the indolizidine alkaloids including (–)-8-epi-swainso- Scheme 2 Reagents and conditions: i) OsO4, NMO, (CH3)2CO–
nine (2).7
H2O (1:1, 85%); ii) (CH3O)2C(CH3)2, PPTS, (CH3)2CO, D, (95%);
iii) LiOH, EtOH, D; iv) (Boc)2O, Et3N, MeCN (85% over two steps);
The synthetic route to (–)-8-epi-swainsonine (2) is shown
in Scheme 2.
v) TPAP, 4 Å MS, NMO, CH2Cl2, (88%); vi) CH2=CHMgBr, THF,
(85%); vii) TBSOTf, Et3N, CH2Cl2, (98%); viii) ZnBr2, CH2Cl2
(81%); ix) CH2CHCH2Br, K2CO3, THF, D (91%); x) Grubbs’ 2nd-
generation catalyst (20 mol%), CH2Cl2, D (70%); xi) 10% Pd/C, H2,
EtOAc (54%).
SYNLETT 2006, No. 9, pp 1443–1445
0
1.
0
6.
2
0
0
6
Advanced online publication: 26.04.2006
DOI: 10.1055/s-2006-939710; Art ID: D04406ST
© Georg Thieme Verlag Stuttgart · New York

1444
A. J. Murray, P. J. Parsons
LETTER
Treatment of the readily available alkene 38 with osmium genation of 13 using hydrogen and palladium on charcoal
tetroxide in the presence of N-methylmorpholine-N- gave the fully protected indolizidine ring system 14 which
oxide10 gave the diol 6 in high (85%) yield.9 The diol 6 is the direct precursor of (–)-8-epi-swainsonine (2).21
was smoothly converted into the acetal 7 with 2,2-
It has come to our attention that Battacharjya and co-
dimethoxypropane in the presence of PPTS.11 Lithium
workers have prepared epi-swainsonine triacetate using
hydroxide mediated hydrolysis of 7 followed by the addi-
ring-closing metathesis.22
tion of di-tert-butyl dicarbonate gave the alcohol 8 (85%).
The synthesis of (–)-8-epi-swainsonine 2 reported here is
Conversion of the alcohol 7 into the aldehyde 9 was
highly efficient and robust and can be tailored to the
preparation of a range of indolizidine alkaloids. Pyne and
his co-workers have also published work on the synthesis
of polyfunctionalised pyrrolidines, but seem to have over-
looked our original work in this area.23
achieved using TPAP (88%).12 Addition of vinylmag-
nesium bromide to a solution of the aldehyde 9 in tetra-
hydrofuran gave the allylic alcohol 10 as the exclusive
product. The addition of vinylmagnesium bromide to the
aldehyde 9 was conducted over a range of temperatures
(–78 °C to r.t.) and no change in stereoselectivity was ob-
served. We further investigated the addition of vinyl-
lithium in conjunction with DMPU in an attempt to
reverse the selectivity of addition as detailed by Donohoe
in a related system.13 We found, however, that no reversal
of stereochemistry occurred. We believe that this interest-
ing result could be due to prior chelation of the aldehyde
carbonyl group to magnesium and the Boc protecting
group (Scheme 3).
Acknowledgment
We thank Tocris Biosciences for their generous support of this
work.
References and Notes
(1) (a) Das, P. C.; Roberts, J. D.; White, S. L.; Olden, K. Oncol.
Res. 1995, 7, 425. (b) Goss, P. E.; Reid, C. L.; Bailey, D.;
Dennis, J. W. Clin. Cancer Res. 1997, 3, 1077. (c) Wang,
S.; Panter, K. E.; Holyoak, G. R.; Molyneux, R. J.; Lui, G.;
Evans, R. C.; Bunch, T. D. Anim. Reprod. Sci. 1999, 56, 19.
(2) (a) Guengerich, F. P.; DimMari, S. J.; Bromquist, H. P. J.
Am. Chem. Soc. 1973, 95, 2055. (b) Broquist, H. P. J.
Toxicol. Toxin Rev. 1986, 5, 241.
(3) Tamerler, C.; Kesharaz, T. Biotechnol. Lett. 1999, 21, 501.
(4) (a) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J.
Chem. 1979, 32, 2257. (b) Ermayanti, T. M.; McComb, J.
A.; O’Brien, P. A. Phytochemistry 1994, 36, 313.
(5) Liao, Y. F.; Lal, A.; Moreman, K. W. J. Biol. Chem. 1996,
271, 28348; and references cited therein.
O
O
O
O
O
O
i
H
OH
N
N
O
Boc
10
Mg
Scheme 3 Reagents and conditions: i) CH2=CHMgBr, THF, then
NH4Cl, H2O (85%).
(6) (a) Elbein, A. D.; Solf, R.; Dorling, P. R.; Vosbeck, K. Proc.
Natl. Acad. Sci. U. S. A. 1981, 78, 7393. (b) Kaushal, G. P.;
Szumilo, T.; Pastuszak, I.; Elbein, A. D. Biochemistry 1990,
29, 2168. (c) Pastuszak, I.; Kaushal, G. P.; Wall, K. A.; Pan,
Y. T.; Sturm, A.; Elbein, A. D. Glycobiology 1990, 1, 71.
(7) (a) El Nemr, A. Tetrahedron 2000, 56, 8579. (b) Pyne, S.
G. Curr. Org. Chem. 2005, 2, 39.
(8) Greenwood, E. S.; Parsons, P. J. Tetrahedron 2003, 59,
3307.
(9) Murray, A. J.; Parsons, P. J.; Greenwood, E. S.; Viseux, E.
M. E. Synlett 2004, 1589.
Removal of the N-Boc protecting group was achieved
using zinc bromide14 after prior protection of the alcohol
10 as its tert-butyldimethylsilyl ether. The aforemen-
tioned deprotection requires mild conditions and we
found that absorption of the allylic alcohol 10 onto silica
followed by microwave assisted irradiation at 140 °C
also removed the Boc protecting group (Scheme 4).15
N-Allylation of 11 was achieved using allyl bromide
in the presence of potassium carbonate16 to afford the
alkene 12.17
(10) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973.
(11) Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme:
Stuttgart, 2004, Chap. 3, 119; and references cited therein.
(12) Review: Ley, S.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
O
O
O
O
i
H
H
(13) Donohoe, T. J.; Sintim, H. O. Org. Lett. 2004, 6, 2003.
(14) Nigam, S. C.; Mann, A.; Taddei, M.; Wermuth, C.-G. Synth.
Commun. 1989, 19, 3139.
(15) Siro, J. G.; Martin, J.; Garcia-Navio, J. L.; Remuinan, M. J.;
Vaquero, J. J. Synlett 1998, 147.
OH
OH
N
N
H
Boc
10
15
Scheme 4 Reagents and conditions: i) SiO2, MW 200 °C, 4 min
(16) Molander, P. J.; Nichols, P. J. J. Org. Chem. 1996, 61, 6040.
(17) Data for Compound 12.
(41%).
Colourless oil; Rf = 0.66 (30% Et2O–PE); [a]D28 –50.5 (c 2.2,
CHCl3). IR (film): 3080, 2956, 2931, 2858, 2792, 1644,
1473, 1463, 1420, 1403, 1379, 1369, 1277, 1255, 1210,
1169, 1139, 1112, 1092, 1019, 1005, 926, 873, 838, 777, 676
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.03 and 0.08 [6 H,
2 × s, SiC(CH3)2], 0.90 [9 H, s, SiC(CH3)3], 1.28 and 1.53 [6
Ring-closing metathesis was attempted initially with first
generation Grubbs’ catalyst18 to no effect; however, the
second generation catalyst19 reacted with the alkene 12 to
afford the bicyclic amine 13 in respectable yield.20 Hydro-
Synlett 2006, No. 9, 1443–1445 © Thieme Stuttgart · New York

LETTER
H, 2 × s, C(CH3)2], 2.02 (1<H, dd, J = 3.7, 11.5 Hz, 5-H),
A Convenient Approach to (–)-8-epi-Swainsonine
1445
1011, 961, 938, 901, 860, 836, 775, 653 cm–1. 1H NMR (300
MHz, CDCl3): d = 0.11 and 0.13 [6 H, s, Si(CH3)2], 0.91 [9
H, s, SiC(CH3)3], 1.29 and 1.51 [6 H, s, C(CH3)2], 2.10–2.11
(1 H, m, 6-H), 2.14 (1 H, dd, J = 5.7, 11.4 Hz, 2-H), 2.59 (1
H, d, J = 17.1 Hz, 9-H), 3.33 (1 H, d, J = 11.4, 2-H), 3.60–
3.67 (1 H, m, 9-H), 4.50 (1 H, m, 5-H), 4.62 (1 H, dd, app. t,
J = 6.0 Hz, 7-H), 4.69 (1 H, dd, J = 3.8, 6.0 Hz, 8-H), 5.77–
5.79 (2 H, m, 3-H, 4-H). 13C NMR (75 MHz, CDCl3): d =
–5.3 and –4.4 [Si(CH3)2], 18.8 [SiC(CH3)3], 24.2 [C(CH3)2],
26.1 [SiC(CH3)3], 26.5 [C(CH3)2], 53.3 (C-9), 61.9 (C-2),
65.3 (C-5), 67.2 (C-6), 77.8 (C-7), 80.8 (C-8), 111.2
[C(CH3)2], 126.8 and 127.5 (C-3 and C-4). HRMS (ESI):
m/z calcd for C17H32NO3Si [M + H]+: 326.2146; found:
326.2138.
2.11 (1 H, dd, J = 3.4, 7.8 Hz, 2-H), 2.63 (1 H, dd, J = 7.7,
14.0 Hz, 6-H), 3.22 (1 H, d, J = 11.5 Hz, 5-H), 4.03 (1 H, m,
6-H), 4.49–4.56 (3 H, m, 3-H, 4-H, 9-H), 5.03–5.18 (3 H, m,
8-H, 11-H), 5.30 (1 H, d, J = 17.2 Hz, 11-H), 5.87 (1 H, m,
7-H), 6.15 (1 H, ddd, J = 5.9, 10.8, 17.2 Hz, 10-H). 13C NMR
(75 MHz, CDCl3): d = –4.7 and –4.0 [Si(CH3)2], 18.2
[SiC(CH3)3], 25.5 [C(CH3)2], 26.0 [SiC(CH3)3], 26.3
[C(CH3)2], 58.1 (C-6), 60.5 (C-5), 71.6 (C-2), 74.4, 77.3 and
81.5 (C-3, C-4, C-9), 110.8 [C(CH3)2], 115.1 (C-11), 116.2
(C-8), 135.9 (C-7), 139.6 (C-10). HRMS (ESI): m/z calcd for
C19H36NO3Si [M + H]+: 354.2459; found: 354.2448.
(18) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(21) Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693.
(22) Madhumita, N.; Mukhopadhyay, R.; Bhattacharjya, A. Org.
Lett. 2006, 8, 317.
(23) Davis, A. S.; Gates, N. J.; Lindsay, K. B.; Tang, M. Y.; Pyne,
S. G. Synlett 2004, 49.
(20) Data for Compound 13.
Colourless oil; Rf = 0.40 (75% Et2O–PE); [a]D28 19.6 (c 1.5
in CHCl3). IR (film): 3037, 2952, 2928, 2856 2781, 1719,
1660, 1461, 1379, 1253, 1207, 1167, 1150, 1119, 1045,
Synlett 2006, No. 9, 1443–1445 © Thieme Stuttgart · New York