The combined use of stereoelectronic control and ring closing metathesis for the synthesis of (-)-8-epi-swainsonine

Article abstract of DOI:10.1016/j.tet.2007.03.103

A novel and efficient synthesis of (-)-8-epi-swainsonine 2 is reported. Stereocontrolled 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.

Full text of DOI:10.1016/j.tet.2007.03.103

Tetrahedron 63 (2007) 6485–6492
The combined use of stereoelectronic control and ring closing
metathesis for the synthesis of (L)-8-epi-swainsonine
*
Adrian J. Murray, Philip J. Parsons and Peter Hitchcock
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QJ, UK
Received 22 January 2007; revised 1 March 2007; accepted 16 March 2007
Available online 21 March 2007
Abstract—A novel and efficient synthesis of (ꢀ)-8-epi-swainsonine 2 is reported. Stereocontrolled 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.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of the indolizidine family we developed a new route to
(ꢀ)-8-epi-swainsonine 2, which features a remarkable
stereoselective hydroxylation reaction of the oxazolidinone
3, followed later by a key ring closing metathesis reaction.
There are many examples in the literature, which have shown
the huge potential of the RCM reaction for the formation
of heterocyclic rings,13–15 and our approach to (ꢀ)-8-epi-
swainsonine 2 further illustrates the power of this reaction.
The indolizidine alkaloids occur widely in nature and these
together with many other structural analogues possess wide
ranging and interesting biological activity.1 Fleet et al. in
a series of seminal papers have pointed the way to a therapy
for tuberculosis based on the glycosidase inhibitor swainso-
nine and other indolizidine structures.2 Other glycosidase in-
hibitors including castanospermine and deoxynojirimycin
are useful agents in viral and cancer research.3 Swainsonine
1, which has been isolated from the fungus Rhizoctonia
leguminicola,4 and also isolated from other fungal5 and plant
sources,6 has been found to possess properties, which in-
clude the inhibition of both lysosomal a-manosidase7 and
monosidase II.8 Due to the fact that the glycosidases are in-
volved in the degradation of carbohydrates associated with
cell walls,9 the synthesis of glycosidase inhibitors becomes
important in the research areas and drug discovery. It is clear
that the indolizidine alkaloids are an important class of com-
pounds in the armoury of the drug discovery scientists, but
they are often difficult to make on a scale, which would
permit extensive biological evaluation.10 Although over 30
syntheses of (ꢀ)-swainsonine 1 have been reported,3,10,11
many of these utilise the asymmetry present in carbohydrate
starting materials to engineer the synthesis of 1. Non-carbo-
hydrate based starting materials have also been used to con-
struct (ꢀ)-swainsonine 1 and have often inspired useful
solutions to tackle the problem of indolizidine ring forma-
tion. Fewer syntheses of (ꢀ)-8-epi-swainsonine 2 have
been reported12 hitherto and given the biological importance
We have now developed a procedure for the synthesis of
(ꢀ)-8-epi-swainsonine 2 that is flexible and will allow
the construction of a wide range of other members of the
indolizidine alkaloid family.
HO
OH
HO
OH
H
H
OH
OH
N
N
1
2
2. Results and discussion
During our work on the synthesis of the excitatory amino
acids including the kainates, we discovered that the light me-
diated addition of the oxazolidinone 3 to the acetal 4 resulted
in the formation of the cyclobutane 5.16 The stereochemical
outcome of the cycloaddition was a great surprise because
the addition occurred on the most hindered face of the
oxazolidinone 3 (Scheme 1).
Calculations from our laboratory have shown that the
HOMO of alkene 3 reveals an unsymmetrical p-bond with
a higher electronic density on its endo face (Fig. 1).17 These
data led us to devise new and effective routes to the indo-
lizidine alkaloids including (ꢀ)-8-epi-swainsonine 2.
Keywords: Stereoselective; Indolizidine synthesis; Stereoelectronic;
Metathesis.
* Corresponding author. Fax: +44 01273 677196; e-mail: p.j.parsons@
sussex.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.103

6486
A. J. Murray et al. / Tetrahedron 63 (2007) 6485–6492
O
O
O
O
O
O
O
H
Me
H
H
O
2
i
H
OTBS
N
+
O
O
H
OTBS
N
N
O
O
N
O
19
14
O
5
3
4
O
O
Scheme 1. Reagents: (i) hn, EtOAc (38%).
N
O
O
N
O
H
Boc
10
3
Scheme 3.
O
O
O
O
ii
i
6
N
O
N
H
OH
O
7
8
O
O
O
O
iii
iv
O
N
Boc
9
N
Boc
10
OH
H
Figure 1. 6-31G representation of the HOMO of oxazolidinone 3.17
Scheme 4. Reagents: (i) (CH3O)2C(CH3)2, PPTS, acetone, D (95%); (ii)
LiOH, EtOH, D; (iii) (Boc)2O, Et3N, CH3CN (85% over two steps); (iv)
˚
TPAP, 4 A MS, NMO, CH2Cl2 (88%).
Following our discovery that the photochemical additions to
the oxazolidinone 3 occur from its most hindered face, we
found that electrophilic reagents in general also add from
the most hindered face of the alkene present in 3. Pyne
et al. have also reported similar results but overlooked our
previous work in this area.18 Treatment of the oxazolidinone
3 with osmium tetroxide19 in tertiary butanol gave an excel-
lent yield of the diol 6,17 which served as the starting point in
our indolizidine alkaloid synthesis (Scheme 2).
Conversion of the acetonide 7 into alcohol 8 was achieved
using lithium hydroxide in hot ethanol. The resulting amino
alcohol 8 was treated with di-tert-butyl dicarbonate to afford
the N-Boc protected amine 9 in high yield. Under these
reaction conditions only a small amount of carbonate forma-
tion was observed.21 Treatment of the alcohol 9 with TPAP22
in dry dichloromethane gave the aldehyde 10, which proved
to be configurationally stable. At this stage, we hoped to be
able to control the stereochemistry of addition of a vinyl
anion to the aldehyde 10. Felkin–Ahn addition would lead
to the stereochemistry required for the formation of swainso-
nine 1, whereas chelation control would result in the stereo-
chemistry required for the synthesis of epi-swainsonine 2
(Scheme 5).
OH
HO
i
N
N
O
O
O
O
3
6
Scheme 2. Reagents: (i) OsO4, tBuOH, H2O, acetone, NMO (85%).
Donohoe et al. studied the addition of a series of metallo-
alkenes to a related aldehyde and found that the stereochem-
istry of the resulting allylic alcohols depended on the metal
counter ion selected.23,24
Retrosynthetic analysis of the indolizidine ring system re-
vealed that alkene metathesis could be key to the construc-
tion of the six-membered ring present in the swainsonine 1
and epi-swainsonine 2 (Scheme 3).
Encouraged by these results, we investigated the reaction of
the aldehyde 10 with vinylmagnesium bromide, which under
all conditions carried out, gave the allylic alcohol 11 as the
exclusive product (Scheme 6; Table 1). The stereochemical
outcome of alcohol 11 was later confirmed by X-ray analysis
(Fig. 2).
After further functional group interconversions, stereoselec-
tive diol formation from 3 would provide the aldehyde 10. It
was envisaged that the aldehyde 10 could be converted into
the allylamine 14 and that ring closing metathesis performed
on 14 would furnish the epi-swainsonine precursor 19.
In order to carry out the synthesis of epi-swainsonine 2 the
diol 6 was converted into the acetonide 7.20 Smooth conver-
sion of the diol 6 into the acetonide 7 was achieved using a
refluxing mixture of acetone/2,2-dimethoxypropane (3:1) in
the presence of pyridinium p-toluenesulfonate (Scheme 4).
The results were interesting but in contrast to Donohoe’s
observations on a related system.23,24
With the alcohol 11 in hand we were able to continue our
synthesis of (ꢀ)-8-epi-swainsonine 2.

A. J. Murray et al. / Tetrahedron 63 (2007) 6485–6492
6487
O
N
O
O
O
O
O
H
O
Chelation
Felkin-Ahn
O
N
H
O
O
H
H
N
M
H
Boc
Boc
O
10
O
O
O
O
H
H
OH
OH
N
Boc
11
N
Boc
11a
Scheme 5.
O
O
O
O
i
H
Figure 2. X-ray analysis of alcohol 11.
O
H
OH
N
Boc
10
N
Boc
11
O
O
O
O
O
Scheme 6. (i) See Table 1.
ii
i
H
H
OH
OTBS
N
N
Table 1
Boc
Boc
11
12
Entry Reaction conditions
Temp Yielda
Product
(ꢁC)
(Conversion, %)
O
N
O
O
1
2
3
4
5
6
CH2]CHMgBr
(1.5 equiv), THF
CH2]CHMgBr
(2.5 equiv), THF
CH2]CHMgBr
(1.5 equiv), THF
CH2]CHLi
ꢀ78
69 (93)
11
11
11
11
11
11
iii
H
H
OTBS
OTBS
ꢀ78
rt
87 (89)
85 (100)
46 (77)
40 (65)
55 (40)
N
H
13
14
ꢀ78
Scheme 7. Reagents: (i) TBSOTf, Et3N, CH2Cl2 (98%); (ii) ZnBr2, CH2Cl2
(81%); (iii) CH2CHCH2Br, K2CO3, THF, D (91%).
(2.0 equiv), Et2O
CH2]CHLi (2.0 equiv), ꢀ78
DMPU, Et2O
CH2]CHLi (4.0 equiv), ꢀ90
DMPU, Et2O
During this time period we were investigating the micro-
wave assisted removal of Boc protecting group from amine
systems. Previous work by Siro et al. showed that this could
be accomplished when using a silica gel solution.29 We
intended to further expand this methodology by exploiting
the benefits associated with a solvent free system. It was
hoped that substrate adsorption onto silica, followed by
microwave irradiation would furnish the desired free amine.
a
Yield based on recovered starting material.
Boc deprotection of 11 was foreseen to be problematic, due
to the presence of an acid labile acetonide moiety. As a result
more contemporary approaches towards the deprotection of
a Boc group were considered.25
Studies in our laboratory showed that microwave irradiation
of the readily available Boc protected lactam 1530 afforded
the deprotected product 16 in good yield (Scheme 8). Hop-
ing to demonstrate the synthetic usefulness of this methodol-
ogy, microwave irradiation was used in the Boc deprotection
of compound 11.
Williams et al. successfully demonstrated the use of zinc
bromide as a reagent to Boc deprotect a similarly acid sensi-
tive system.26 As alcohol functionality has been shown to
reduce the reactivity of zinc bromide mediated reactions,27
the alcohol 11 was protected as its TBS ether.
Treatment of the allylic alcohol 11 with tert-butyldimethyl-
silyl triflate gave the TBS protected acetonide 12 in high
yield. The acetonide 12 was then treated with zinc dibromide
in dichloromethane to afford the amine 13.28 Allylation of 13
was straightforward and the alkene metathesis precursor 14
was isolated in 91% yield (Scheme 7).
OTBS
OTBS
i
O
N
Boc
O
N
H
16
15
Scheme 8. Reagents: (i) SiO2, MW, 160 ꢁC, 3 min (87%).

6488
A. J. Murray et al. / Tetrahedron 63 (2007) 6485–6492
After using microwave heating to deprotect the epi-swainso-
nine intermediate 11, the desired crude amine 17 was iso-
lated in only 41% yield. It was found that extraction and
purification of the desired product 17 from the dry loaded sil-
ica were both difficult and problematic. Although the pres-
camphorsulfonate salt did not undergo metathesis, the
para-toluene sulfonate did yield indolizidine 19 under iden-
tical reaction conditions. Interestingly, complete conversion
to 19 in 62% yield was only accomplished when benzene was
used as the reaction medium, with only 5 mol % catalyst
loading.
ence of the crude amine 17 could be seen by 1H NMR, 13
C
NMR and mass spectroscopy, further evidence was provided
by converting some of the alcohol 17 into the known TBS
ether 13 (Scheme 9).
Hydrogenation of the acetonide 19 gave the (ꢀ)-8-epi-
swainsonine precursor 20 (Scheme 11).
O
O
O
O
O
O
O
O
i
Ref. 32
i
H
H
H
H
OH
OH
OTBS
OTBS
N
N
H
N
N
Boc
11
17
19
20
Scheme 9. Reagents: (i) SiO2, MW, 200 ꢁC, 4 min (41%).
OH
HO
H
OH
Due to the problems associated with microwave irradiation,
the zinc bromide mediated removal of the Boc protecting
group remained the preferred method.
N
2
Scheme 11. Reagents: (i) 10% Pd/C, H2, EtOAc, (54%).
To continue the synthesis of epi-swainsonine 2, diene 14 was
treated with Grubbs’ second generation catalyst 18 (Scheme
10).31 As shown in Table 2, 20 mol % of catalyst 18, added in
two separate portions over 24 h, was needed to complete the
ring closing metathesis of diene 14.
The acetonide 20 has previously been converted into (ꢀ)-8-
epi-swainsonine (2) using trifluoroacetic acid as the global
deprotecting agent.12a This approach to (ꢀ)-epi-8-swainso-
nine 2 is efficient and can be tailored to the preparation of
a range of indolizidine alkaloids.
O
O
O
O
N
N
H
i
Mes
Cl
Mes
H
OTBS
3. Conclusions
OTBS
N
Ru
N
Ph
Cl
PCy3
We have developed an efficient route to (ꢀ)-8-epi-swainso-
nine 2. The route is very flexible and allows the preparation
of a wide range of indolizidines. Bhatacharjya et al. have
now disclosed their synthesis of epi-swainsonine triacetate,
which utilises ring closing metathesis but involves an en-
tirely different route to the pyrrolidine core.12a
18
14
19
Scheme 10. Reagents: (i) 18 (see Tables 2 and 3).
In order to increase the catalytic efficiency, efforts were made
to first form the ammonium salt of 14, before attempting the
ring closing metathesis. Table 3 shows that although the
4. Experimental
Table 2
4.1. General procedure
Entry
18a (mol %)
Solvent
Temp
Yieldb
(Conversion, %)
Unless otherwise stated, commercially available reagents
were used without purification and solvents were dried ac-
cording to standard procedures. Microwave reactions were
carried out on a Biotage Initiator 2.0. Product purification
was carried out using flash chromatography on silica gel
1
2
3
4
5
C6H6
rt
rt
D
D
29 (66)
49 (72)
55 (91)
70 (100)
2ꢂ5
CH2Cl2
CH2Cl2
CH2Cl2
15
2ꢂ10
a
With respect to the substrate.
Yield based on recovered starting material.
1
b
(Merck silica gel 60 (230–400 mesh)). H and 13C NMR
spectra were recorded on a Bruker DPX-300 spectrometer
(300 MHz for 1H and 75 MHz for 13C) using CDCl3 as the
solvent and TMS as internal reference. Spectra were re-
corded in parts per million downfield from TMS (d¼0) for
1H NMR and relative to the CDCl3 resonance (d¼77.0) for
13C spectra. Mass spectra were recorded on a Fisons VG Au-
tospec Mass Spectrometer. Optical rotations were measured
on a Perkin–Elmer 241 polarimeter.
Table 3
Entry Acid
18a (mol %) Solvent Temp Yieldb
(Conversion, %)
1
2
3
4
5
CSA
CSA
pTsOH
5
5
5
CH2Cl2 rt
CH2Cl2
CH2Cl2 rt
CH2Cl2 rt
SM
SM
81 (40)
53 (66)
62 (100)
D
pTsOH 10
pTsOH
5
C6H6
rt
4.1.1. (6R,7S,7aR)-6,7-Dihydroxy-tetrahydro-pyr-
rolo[1,2-c]oxazol-3-one (6). To a stirred solution of
(S)-5,7a-dihydro-1H-pyrrolo[1,2-c]oxazol-3-one 3 (6.60 g,
a
With respect to the substrate.
Yield based on recovered starting material.
b

A. J. Murray et al. / Tetrahedron 63 (2007) 6485–6492
6489
52.8 mmol) and 4-methylmorpholine N-oxide (6.80 g,
58.1 mmol) in acetone (60 mL) and water (60 mL) at 0 ꢁC
was added 0.1 M osmium tetroxide solution in tert-butanol
(26.4 mL, 2.64 mmol). The reaction mixture was allowed
to warm to room temperature and stirred for 6 h, before
concentrating under reduced pressure. The mixture was
taken up in 10% methanol/dichloromethane (200 mL) and
filtered through Celite. The Celite was further washed with
10% methanol/dichloromethane (3ꢂ100 mL) and the com-
bined filtrates were concentrated under reduced pressure.
The resulting residue was subjected to flash column chroma-
tography on silica, eluted with 5% methanol/dichloro-
methane to give 6 as a white solid (7.54 g, 90%). TLC (10%
MeOH/CHCl2) Rf¼0.40. Mp 142–144 ꢁC. [a]D23 ꢀ8.6 (c
1.91, CHCl3). m/z (EI): 159 (M+, 6%), 142 ([MꢀOH]+,
96%), 69 (88), 57 (100), 55 (85), 41 (87). HRMS (ESI):
calcd for C9H13NO3Na [M+Na]+ 206.0788, found
206.0785. nmax (film/cmꢀ1): 3052, 3024, 2993, 2955 and
2885 (s, CH), 1744 (br, N–C]O), 1548, 1480, 1451,
1422, 1378, 1363, 1317, 1292, 1256, 1225, 1206, 1149,
1114, 1079, 1007, 981, 931, 892. dH (500 MHz, CDCl3):
4.51 (1H, dd, J 8.8 and 4.2 Hz, 4-Hd), 4.36 (1H, dd, app. t,
J 8.8 Hz, 4-Hu), 4.40 (1H, ddd, app. dt, J 7.7 and 3.3 Hz,
7-H), 4.02 (1H, ddd, J 9.3, 4.2 and 3.3 Hz, 5-H), 3.86 (1H,
t, J 3.3 Hz, 6-H), 3.40 (1H, dd, J 10.7 and 7.8 Hz, 8-Hd),
3.20–3.24 (1H, m, 8-Hu). dC (75 MHz, CDCl3): 165.4 (C-
2), 75.6 (C-7), 72.5 (C-6), 65.2 (C-4), 63.3 (C-5), 51.3 (C-8).
dichloromethane (100 mL) and filtered through Celite. The
Celite was further washed with dichloromethane (3ꢂ
100 mL) and the combined filtrates were concentrated under
reduced pressure to give 8 as a crude white solid (4.71 g). A
small sample (0.500 g) was subjected to flash column chro-
matography on silica, eluted with 10% methanol/dichloro-
methane to give 8 as a white solid (0.438 g, 93%). TLC
(10% MeOH/CH2Cl2) Rf¼0.22. Mp 109–111 ꢁC. [a]D29
ꢀ54.0 (c 3.50, CHCl3). m/z (EI): 158 (9%), 142 (100), 84
(42), 68 (37), 57 (34), 55 (35). HRMS (ESI): calcd for
C8H15NO3Na [M+Na]+ 196.0944, found 196.0942. nmax
(film/cmꢀ1): 3232 (s, OH), 2977, 2925 and 2874 (s, CH),
1605, 1474, 1440, 1385, 1367, 1307, 1272, 1251, 1242,
1207, 1193, 1166, 1126, 1112, 1098, 1062, 1043, 1032,
1015, 992, 956, 914, 883, 856, 826, 813, 766, 699. dH
(300 MHz, CDCl3): 4.60–4.53 (1H, m, 4-H), 4.53–4.42
(1H, m, 3-H), 3.70–3.51 (2H, m, CH2OH), 2.87 (1H, dd, J
12.9 and 2.6 Hz, 5-H), 2.64 (1H, ddd, app. dt, J 6.4 and
3.9 Hz, 2-H), 2.53–2.42 (1H, m, 5-H), 3.13 and 2.83 (6H,
2ꢂs, C(CH3)2). dC (75 MHz, CDCl3): 111.9 (C(CH3)2),
82.7 (C-4), 82.0 (C-3), 65.8 (C-2), 60.9 (CH2OH), 53.2
(C-5), 24.0 and 25.9 (C(CH3)2).
4.1.4. (3aS,4R,6aR)-4-Hydroxymethyl-2,2-dimethyl-tet-
rahydro-1,3-dioxolo[4,5-c]pyrrole-5-carboxylic acid
tert-butyl ester (9). To a stirred solution of crude ((3aS,
4R,6aR)-2,2-dimethyl-tetrahydro-1,3-dioxolo[4,5-c]pyrrol-
4-yl)-methanol 8 (31.6 mmol) and triethylamine (8.82 mL,
63.3 mmol) in acetonitrile (200 mL) at 0 ꢁC was added
di-tert-butyl dicarbonate (6.84 g, 31.6 mmol) in acetonitrile
(100 mL) dropwise over 10 min. The reaction mixture was
allowed to warm to room temperature and stirred for 15 h,
before concentrating under reduced pressure. The resulting
residuewas subjected to flash column chromatography onsil-
ica, eluted with 50% diethyl ether/petrol 40:60 to give 9 as
a colourless oil (7.40 g, 86%, over two steps). TLC (50%
Et2O/petrol) Rf ¼0.43. [a]2D5 ꢀ33.8 (c 2.10, CHCl3). m/z
(EI): 273 (M+, 6%), 258 (13), 242 (11), 186 (28), 142 (61),
57 (100). HRMS (ESI): calcd for C13H23NO5Na [M+Na]+
296.1468, found 296.1449. nmax (film/cmꢀ1): 3415 (br, OH),
2980 and 2936 (s, CH), 1743 (w, s), 1694 (br, N–C]O),
1478, 1456, 1404, 1369, 1279, 1249, 1212, 1165, 1135,
1086, 1048, 994, 925, 861, 821, 777, 749. dH (300 MHz,
CDCl3): 4.83–4.71 (1H, m, 3-H), 4.71–4.57 (1H, m, 4-H),
4.08–3.91 (1H, m, CH2OH), 3.91–3.66 (3H, m, CH2OH, 5-
H and OH), 3.61–3.40 (2H, m, 2-H and 5-H), 1.45 (3H, s,
C(CH3)2), 1.41 and 1.42 (9H, 2ꢂs, C(CH3)3), 1.29 (3H, s,
C(CH3)2). dC (75 MHz, CDCl3): 112.6 (C(CH3)2), 81.1
(C(CH3)3), 80.8 (C-3), 77.9 (C-4), 62.8 (CH2OH), 52.3
(C-5), 28.7 (C(CH3)3), 25.2 and 26.7 (C(CH3)2).
4.1.2. (3aS,3bR,8aR)-2,2-Dimethyl-tetrahydro-1,3-diox-
olo[3,4]pyrrolo[1,2-c]oxazol-6-one (7). To a stirred suspen-
sion of (6R,7S,7aR)-6,7-dihydroxy-tetrahydro-pyrrolo[1,2-
c]oxazol-3-one 6 (5.30 g, 33.3 mmol) in dimethoxypropane
(50 mL) and acetone (150 mL) at room temperature was
added pyridinium p-toluenesulfonate (0.837 g, 3.33 mmol).
The reaction mixture was heated to reflux and stirred for
20 h, before concentrating under reduced pressure. The re-
sulting residue was subjected to flash column chromato-
graphy on silica, eluted with ethyl acetate to give 7 as
a white solid (6.30 g, 95%). TLC (EtOAc) Rf¼0.54. Mp
112–114 ꢁC. [a]D27 ꢀ4.92 (c 2.40, CHCl3). m/z (EI): 199
(M+, 9%), 184 (77), 140 (100), 86 (83), 69 (96), 41 (59).
HRMS (ESI): calcd for C9H13NO4Na [M+Na]+ 222.0737,
found 222.0724. nmax (film/cmꢀ1): 2973, 2991 and 2948
(s, CH), 1737 (s, N–C]O), 1699, 1552, 1480, 1438, 1396,
1377, 1366, 1339, 1321, 1277, 1257, 1208, 1167, 1147,
1101, 1073, 1045, 1024, 1011, 992, 925, 892, 878, 843,
810, 778, 770, 736, 667, 650, 634. dH (300 MHz, CDCl3):
4.76 (1H, dd, app. t, J 4.5 Hz, 7-H), 4.57 (1H, dd, app. t, J
4.5 Hz, 6-H), 4.47–4.33 (2H, m 4-H), 3.92 (1H, ddd, J 7.5,
4.5 and 3.0 Hz, 5-H), 3.72 (1H, d, J 13.3 Hz, 8-H), 3.09
(1H, dd, J 13.3 and 4.5 Hz, 8-H), 1.24 and 1.31 (6H, 2ꢂs,
C(CH3)2). dC (75 MHz, CD3OD): 164.2 (C-2), 113.3
(C(CH3)2), 83.1 (C-7), 81.1 (C-6), 64.2 (C-4), 63.6 (C-5),
52.5 (C-8), 24.1 and 26.5 (C(CH3)2).
4.1.5. (3aS,4S,6aR)-4-Formyl-2,2-dimethyl-tetrahydro-
1,3-dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl
ester (10). To a stirred solution of (3aS,4R,6aR)-4-hydroxy-
methyl-2,2-dimethyl-tetrahydro-1,3-dioxolo[4,5-c]pyrrole-
5-carboxylic acid tert-butyl ester 9 (2.12 g, 7.75 mmol) and
4-methylmorpholine N-oxide (1.32 g, 11.6 mmol) in di-
chloromethane (15 mL) over powdered molecular sieves
4.1.3. ((3aS,4R,6aR)-2,2-Dimethyl-tetrahydro-1,3-di-
oxolo[4,5-c]pyrrol-4-yl)-methanol (8). To a stirred solution
of (3aS,3bR,8aR)-2,2-dimethyl-tetrahydro-1,3-dioxolo[3,4]-
pyrrolo[1,2-c]oxazol-6-one 7 (5.00 g, 25.1 mmol) in ethanol
(100 mL) was added lithium hydroxide (3.01 g, 126 mmol)
at room temperature. The reaction mixture was heated
to reflux and stirred for 5 days, before concentrating
under reduced pressure. The mixture was taken up in
ꢁ
˚
4 A (4.00 g) at 0 C was added tetrapropylammonium per-
ruthenate (0.137 g, 0.387 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 3 h,
before subjecting to flash column chromatography on silica,
eluted with 30% diethyl ether/petrol 40:60 to give 10 as a

6490
A. J. Murray et al. / Tetrahedron 63 (2007) 6485–6492
colourless oil, which formed a white solid when cooled
below 0 ꢁC (1.40 g, 88%). TLC (80% Et2O/petrol) Rf ¼
0.63. Mp 64 ꢁC. [a]D27 ꢀ51.6 (c 3.06, CHCl3). m/z (EI):
242 (6%), 186 (28), 142 (69), 57 (100), 41 (70), 28 (49).
HRMS (ESI): calcd for C13H21NO5Na [M+Na]+ 294.1312,
found 294.1312. nmax (film/cmꢀ1): 2981, 2938 (s, CH), 1740
(s, C]O), 1699 (br, N–C]O), 1478, 1458, 1395, 1292,
1259, 1212, 1163, 1131, 1088, 1053, 997, 969, 950, 924,
909, 856, 773, 750, 666. dH (300 MHz, CDCl3): 9.51–9.40
(1H, m, CH]O), 5.15–4.92 (1H, m, 3-H), 4.86–4.76 (1H,
m, 4-H), 4.17–3.94 (1H, m, 2-H), 3.87–3.43 (2H, m, 5-H),
1.47 (3H, s, C(CH3)2), 1.41 and 1.45 (9H, s, C(CH3)3), 1.30
(3H, s, C(CH3)2). dC (75 MHz, CDCl3): 197.9 and 198.3
(C]O), 154.1 (N–C]O), 112.9 (C(CH3)2), 81.0 (C(CH3)3),
80.3 and 80.4 (C-3), 78.02 and 78.96 (C-4), 67.2 (C-2), 51.8
(C-5), 28.1 (C(CH3)3), 24.4 and 26.1 (C(CH3)2).
sulfate and concentrated under reduced pressure. The result-
ing residue was subjected to flash column chromatography
on silica, eluted with 10% diethyl ether/petrol 40:60 to
give 12 as a colourless oil (5.19 g, 81%). TLC (50% Et2O/
petrol) Rf ¼0.75. [a]D26 ꢀ39.1 (c 3.80, CHCl3). m/z (EI):
414 (M+, 2%), 300 (23), 186 (49), 142 (92), 73 (39), 57
(100). HRMS (ESI): calcd for C21H39NO5SiNa [M+Na]+
436.2458, found 436.2440. nmax (film/cmꢀ1): 2980, 2955,
2931, 2890 and 2858 (s, CH), 1701 (s, C]C), 1474, 1462,
1401, 1367, 1252, 1214, 1167, 1087, 1041, 996, 970, 923,
837, 813, 776, 673. dH (300 MHz, CDCl3): 6.14 (1H, ddd,
J 17.4, 10.4 and 7.0 Hz, 7-H), 5.16 (1H, d, J 17.4 Hz, 8-
Hb), 5.06 (1H, d, J 10.4 Hz, 8-Ha), 4.75 (1H, dd, app. t, J
6.3 Hz, 3-H), 4.70–4.52 (2H, m, 4-H and 6-H), 4.01 (1H,
dd, app. t, J 6.3 Hz, 2-H), 4.09–3.85 (1H, m, 5-H), 3.07
(1H, dd, J 11.7 and 6.6 Hz, 5-H), 1.51 (3H, s, C(CH3)2),
1.44 (9H, s, C(CH3)3), 1.30 (3H, s, C(CH3)2), 0.88 (9H, s,
SiC(CH3)3), 0.03 and 0.05 (6H, 2ꢂs, Si(CH3)2). dC
(75 MHz, CDCl3): 154.1 (C]O), 139.9 (C-7), 115.6 (C-
8), 113.0 (C(CH3)2), 80.3 (C-3), 79.7 (C(CH3)3), 77.4 (C-
4), 72.4 (C-6), 62.7 (C-2), 51.1 (C-5), 28.4 (C(CH3)3),
27.2 (C(CH3)2), 25.8 (SiC(CH3)3), 25.2 (C(CH3)2), 18.1
(SiC(CH3)3), ꢀ4.7 and ꢀ4.4 (Si(CH3)2).
4.1.6. (3aS,4R,6aR)-4-((S)-1-Hydroxy-allyl)-2,2-di-
methyl-tetrahydro-1,3-dioxolo[4,5-c]pyrrole-5-carb-
oxylic acid tert-butyl ester (11). To a stirred solution of
(3aS,4S,6aR)-4-formyl-2,2-dimethyl-tetrahydro-1,3-di-
oxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester 10
(5.85 g, 21.6 mmol) in tetrahydrofuran (100 mL) at 0 ꢁC
was added 1.6 M vinylmagnesium bromide solution in tetra-
hydrofuran (20.2 mL, 32.3 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 3 h, be-
fore adding saturated ammonium chloride solution (100 mL)
and diethyl ether (100 mL). The phases were separated and
the aqueous was further extracted with diethyl ether (3ꢂ
100 mL). The combined organic extracts were dried over
magnesium sulfate and concentrated under reduced pres-
sure. The resulting residue was subjected to flash column
chromatography on silica, eluted with 30% diethyl ether/
petrol 40:60 to give 11 as a colourless oil, which formed
a white solid when cooled below 0 ꢁC (5.47 g, 85%). TLC
(80% Et2O/petrol) Rf ¼0.67. Mp 56–58 C. [a]2D8 ꢀ52.1 (c
2.90, CHCl3). m/z (EI): 288 (2%), 256 (10), 142 (100), 75
(17), 73 (15), 57 (10). HRMS (ESI): calcd for C15H25NO5Na
[M+Na]+ 322.1625, found 322.1614. dH (300 MHz, CDCl3):
6.16–6.03 (1H, m, 7-H), 5.45 (1H, d, J 17.0 Hz, 8-Hb), 5.18
(1H, d, J 10.6 Hz, 8-Ha), 4.80–4.58 (2H, m, 3-H and 4-H),
4.54 (1H, dd app. t, J 6.2 Hz, 6-H), 3.96–3.60 (2H, m, 2-H
and 5-H), 3.41 (1H, d, J 10.0, 5-H), 1.49 (3H, s, C(CH3)2),
1.43 (9H, s, C(CH3)3), 1.30 (3H, s, C(CH3)2). dC (75 MHz,
CDCl3): 156.0 (N–C]O), 137.9 (C-7), 115.9 (C-8), 112.6
(C(CH3)2), 80.9 (C(CH3)3), 80.2 (C-4), 77.1 (C-3), 71.5
(C-6), 65.5 (C-2), 52.1 (C-5), 28.3 (C(CH3)3), 25.0 and
26.8 (C(CH3)2).
4.1.8. (3aS,4S,6aR)-4-[(S)-1-(tert-Butyl-dimethyl-silanyl-
oxy)-allyl]-2,2-dimethyl-tetrahydro-1,3-dioxolo[4,5-
c]pyrrole (13). To a stirred suspension of (3aS,4S,6aR)-4-
[(S)-1-(tert-butyl-dimethyl-silanyloxy)-allyl]-2,2-dimethyl-
tetrahydro-1,3-dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-
butyl ester 12 (0.839 g, 2.03 mmol) in dichloromethane
(25 mL) at room temperature was added zinc(II) bromide
(2.29 g, 10.2 mmol). The reaction mixture was stirred for
24 h, before adding diethyl ether (150 mL) and saturated so-
dium bicarbonate solution (150 mL). The phases were sepa-
rated and the aqueous further extracted with diethyl ether
(3ꢂ100 mL). The combined organic extracts were dried
over magnesium sulfate and concentrated under reduced
pressure. The resulting residue was subjected to flash col-
umn chromatography on silica, eluted with 30% diethyl
ether/petrol 40:60 to give 13 as a colourless oil (5.13 g,
81%). TLC (50% Et2O/petrol) Rf¼0.75. [a]2D9 ꢀ40.0 (c 1.20,
CHCl3). m/z (EI): 242 (8%), 186 (45), 142 (64), 59 (29), 57
(100), 41 (27). HRMS (ESI): calcd for C16H32NO3Si
[M+H]+314.2146, found 314.2115. nmax (film/cmꢀ1):
2955, 2930, 2857 and 2821 (CH, s), 1644 (s, C]C), 1473,
1463, 1422, 1403, 1380, 1371, 1254, 1208, 1165, 1125,
1089, 1015, 982, 926, 905, 838, 777, 671, 646. dH
(300 MHz, CDCl3): 6.04 (1H, ddd, J 17.0, 10.5 and
5.8 Hz, 7-H), 5.32 (1H, d, J 17.0 Hz, 8-Hb), 5.13 (1H, d, J
10.5 Hz, 8-Ha), 4.68–4.56 (1H, m, 4-H), 4.45 (1H, dd, J
5.4 and 4.2 Hz, 3-H), 4.41–4.31 (1H, m, 6-H), 3.12 (1H, d,
J 12.2 Hz, 5-H), 2.66 (1H, dd, J 12.2 and 4.1 Hz, 5-H),
2.59 (1H, dd, J 8.1 and 4.2 Hz, 2-H), 2.13 (1H, br s, NH),
1.28 and 1.47 (6H, 2ꢂs, C(CH3)2), 0.90 (9H, s, SiC(CH3)3),
0.05 and 0.09 (6H, 2ꢂs, Si(CH3)2). dC (75 MHz, CDCl3):
139.0 (C-7), 115.3 (C-8), 110.7 (C(CH3)2), 81.0 (C-4),
80.2 (C-3), 73.5 (C-6), 69.0 (C-2), 52.4 (C-5), 26.0
(SiC(CH3)3), 24.4 and 25.9 (C(CH3)2), 18.3 (SiC(CH3),
ꢀ4.7 and ꢀ4.3 (Si(CH3)2).
4.1.7. (3aS,4S,6aR)-4-[(S)-1-(tert-Butyl-dimethyl-silanyl-
oxy)-allyl]-2,2-dimethyl-tetrahydro-1,3-dioxolo[4,5-
c]pyrrole-5-carboxylic acid tert-butyl ester (12). To a
stirred solution of (3aS,4R,6aR)-4-((S)-1-hydroxy-allyl)-
2,2-dimethyl-tetrahydro-1,3-dioxolo[4,5-c]pyrrole-5-carboxy-
lic acid tert-butyl ester 11 (4.64 g, 15.5 mmol) and triethyl-
amine (2.16 mL, 15.5 mmol) in dichloromethane (100 mL)
at 0 ꢁC was added tert-butyldimethylsilyl trifluoromethane-
sulfonate (3.57 mL, 15.5 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 1 h,
before adding saturated ammonium chloride solution
(100 mL). The phases were separated and the aqueous was
further extracted with dichloromethane (3ꢂ50 mL). The
combined organic extracts were dried over magnesium
4.1.9. (3aS,4S,6aR)-5-Allyl-4-[(S)-1-(tert-butyl-dimethyl-
silanyloxy)-allyl]-2,2-dimethyl-tetrahydro-1,3-di-
oxolo[4,5-c]pyrrole (14). To a stirred suspension of

A. J. Murray et al. / Tetrahedron 63 (2007) 6485–6492
6491
(3aS,4S,6aR)-4-[(S)-1-(tert-butyl-dimethyl-silanyloxy)-allyl]-
2,2-dimethyl-tetrahydro-1,3-dioxolo[4,5-c]pyrrole 13 (1.5 g,
4.79 mmol) and potassium carbonate (0.993 g, 7.19 mmol)
in tetrahydrofuran (50 mL) at room temperature was added
allyl bromide (0.456 mL, 5.27 mmol). The reaction mixture
was refluxed for 24 h, before concentrating under reduced
pressure. The residue was taken up in dichloromethane
(150 mL) and filtered through Celite. The Celite was further
washed with dichloromethane (3ꢂ50 mL) and the combined
filtrates were concentrated under reduced pressure. The
resulting residue was subjected to flash column chromato-
graphy on silica, eluted with 10% diethyl ether/petrol 40:60
to give 14 as a colourless oil (1.63 g, 96%). TLC (30%
Et2O/petrol) Rf ¼0.66. [a]2D8 ꢀ50.5 (c 2.20, CHCl3). m/z (EI):
338 (5%), 284 (12), 212 (12), 182 (100), 73 (42), 41 (35).
HRMS (ESI): calcd for C19H36NO3Si [M+H]+ 354.2459,
found 354.2448. nmax (film/cmꢀ1): 3080, 2956, 2931, 2858
and 2792 (s, CH), 1644 (ws, C]C), 1473, 1463, 1420, 1403,
1379, 1369, 1277, 1255, 1210, 1169, 1139, 1112, 1092, 1019,
1005, 926, 873, 838, 777, 676. dH (300 MHz, CDCl3): 6.15
(1H, ddd, J 17.2, 10.8 and 5.9 Hz, 10-H), 5.96–5.72 (1H,
m, 7-H), 5.30 (1H, d, J 17.2 Hz, 11-H), 5.22–4.91 (3H, m,
8-H and 11-H), 4.57–4.41 (3H, m, 3-H, 4-H, and 9-H),
4.09–3.98 (1H, m, 6-H), 3.22 (1H, d, J 11.5 Hz, 5-H), 2.63
(1H, dd, J 14.0 and 7.7 Hz, 6-H), 2.11 (1H, dd, J 7.8 and
3.4 Hz, 2-H), 2.02 (1H, dd, J 11.5 and 3.7 Hz, 5-H), 1.28
and 1.53 (6H, 2ꢂs, C(CH3)2), 0.90 (9H, s, SiC(CH3)3),
0.03 and 0.08 (6H, 2ꢂs, SiC(CH3)2). dC (75 MHz, CDCl3):
ꢀ4.7 and ꢀ4.0 (Si(CH3)2), 18.2 (SiC(CH3)3), 25.5
(C(CH3)2), 26.0 (Si(C(CH3)3), 26.3 (C(CH3)2), 58.1 (C-6),
60.5 (C-5), 71.6 (C-2), 81.5 (C-3, C-4 or C-9), 77.3 (C-3,
C-4 or C-9), 74.4 (C-3, C-4 or C-9), 110.8 (C(CH3)2),
115.1 (C-11), 116.2 (C-8), 135.9 (C-7), 139.6 (C-10).
70%). TLC (75% Et2O/petrol) Rf ¼0.40. [a]3D8 19.6 (c 1.50,
CHCl3). m/z (EI): 326 (M+, 36%), 184 (87), 127 (100), 75
(61), 73 (65). HRMS (ESI): calcd for C17H32NO3Si
[M+H]+ 326.2146, found 326.2138. nmax (film/cmꢀ1):
3037, 2952, 2928, 2856 and 2781 (s, CH), 1719 (br), 1660
(br), 1461, 1379, 1253, 1207, 1167, 1150, 1119, 1045,
1011, 961, 938, 901, 860, 836, 775, 653. dH (300 MHz,
CDCl3): 5.86–5.72 (2H, m, 3-H and 4-H), 4.69 (1H, dd, J
6.0 and 3.8 Hz, 8-H), 4.62 (1H, dd, app. t, J 6.0 Hz, 7-H),
4.53–4.47 (1H, m, 5-H), 3.68–3.58 (1H, m, 9-H), 3.33
(1H, d, J 11.4, 2-H), 2.59 (1H, d, J 17.1 Hz, 9-H), 2.14
(1H, dd, J 11.4 and 5.7 Hz, 2-H), 2.13–2.08 (1H, m, 6-H),
1.29 and 1.51 (6H, s, C(CH3)2), 0.91 (9H, s, SiC(CH3)3),
0.11 and 0.13 (6H, s, Si(CH3)2). dC (75 MHz, CDCl3):
127.5 (C-3 or C-4), 126.8 (C-3 or C-4), 111.2 (C(CH3)2),
80.8 (C-8), 77.8 (C-7), 67.2 (C-6), 65.3 (C-5), 61.9 (C-2),
53.3 (C-9), 26.5 (C(CH3)2), 26.1 (SiC(CH3)3), 24.2
(C(CH3)2), 18.8 (SiC(CH3)3), ꢀ5.3 and ꢀ4.4 (Si(CH3)2).
4.1.12. (3aR,9S,9aS,9bS)-9-(tert-Butyl-dimethyl-silanyl-
oxy)-2,2-dimethyl-octahydro-1,3-dioxolo[4,5-a]indolizi-
dine (20). To a stirred suspension of 10% palladium on
carbon (0.025 g, 0.024 mmol) in ethyl acetate (1 mL) at
room temperature was added (3aR,9S,9aS,9bS)-9-(tert-
butyl-dimethyl-silanyloxy)-2,2-dimethyl-3a,4,6,9,9a,9b-hexa-
hydro-1,3-dioxolo[4,5-a]indolizidine 19 (0.067 g, 0.26 mmol).
A hydrogen atmosphere was introduced and the reaction
mixture stirred for 16 h, before filtering through Celite.
The Celite was further washed with dichloromethane
(3ꢂ10 mL) and the combined filtrates were concentrated un-
der reduced pressure. The resulting residue was subjected to
flash column chromatography on silica, eluted with ethyl
acetate to give 20 as a colourless oil (0.036 g, 45%). TLC
(EtOAc) Rf ¼0.40. [a]D34 ꢀ44.1 (c 2.70, CHCl3). m/z (EI):
327 (M+, 6%), 270 (45), 212 (94), 156 (100), 120 (56), 75
(35). HRMS (ESI): calcd for C17H34NO3Si [M+H]+
328.2303, found 328.2304. nmax (film/cmꢀ1): 2929, 2856
and 2785 (s, CH), 1472, 1463, 1379, 1370, 1329, 1321,
1255, 1206, 1168, 1156, 1141, 1125, 1115, 1077, 1036,
1006, 972, 956, 930, 907, 877, 853, 835, 813, 775, 735,
676. dH (300 MHz, CDCl3): 4.66–4.51 (2H, m, 7-H and 8-
H), 4.22 (1H, ddd, app. td, J 6.2 and 3.3 Hz, 5-H), 3.22
(1H, dd, J 6.4 and 3.4 Hz, 2-H), 3.16 (1H, d, J 11.8 Hz, 9-
H), 2.22 (1H, dd, J 11.8 and 4.3 Hz, 9-H), 2.45–1.76 (4H,
m, 2-H, 3-H, 4-H and 6-H), 1.50 (3H, s, C(CH3)2), 1.54–
1.34 (2H, m, 3-H and 4-H), 1.26 (3H, s, C(CH3)2), 0.89
(9H, s, SiC(CH3)3), 0.07 (6H, s, Si(CH3)2). dC (75 MHz,
CDCl3): 111.1 (C(CH3)2), 81.6 (C-7), 78.9 (C-8), 69.2 (C-
6), 67.2 (C-5), 60.7 (C-9), 52.6 (C-2), 32.4 (C-4), 26.4
(C(CH3)2), 26.0 (SiC(CH3)3), 23.8 (C(CH3)2), 21.3 (C-3),
18.4 (SiC(CH3)3), ꢀ5.0 and ꢀ4.6 (Si(CH3)2).
4.1.10. (S)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-1,5-
dihydro-pyrrol-2-one (16) and general procedure for mi-
crowave assisted removal of a Boc group. Silica (1.2 g)
loaded with (S)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-
5-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester
15 (0.500 g, 1.28 mmol) was heated using microwave irradi-
ation to 160 ꢁC for 5 min before adding dichloromethane
(100 mL). The suspension was filtered and concentrated un-
der reduced pressure. The resulting residue was purified by
column chromatography on silica, eluted with 90% ethyl ace-
tate/petrol 40:60 to give 16 as a colourless oil (0.255 g, 87%).
Analysis in agreement with literature values.26
4.1.11. (3aR,9S,9aS,9bS)-9-(tert-Butyl-dimethyl-silanyl-
oxy)-2,2-dimethyl-3a,4,6,9,9a,9b-hexahydro-1,3-dioxolo-
[4,5-a]indolizidine (19). To a stirred solution of (3aS,4S,
6aR)-5-allyl-4-[(S)-1-(tert-butyl-dimethyl-silanyloxy)-allyl]-
2,2-dimethyl-tetrahydro-1,3-dioxolo[4,5-c]pyrrole 19 (0.193 g,
0.546 mmol) in dichloromethane (5 mL) at room tempera-
ture under an argon atmosphere was added Grubbs’ second
generation catalyst 18 (0.0464 g, 0.0546 mmol). The reac-
tion mixture was heated to reflux and stirred for 24 h, before
adding a further portion of Grubbs’ second generation cata-
lyst 18 (0.0464 g, 0.0546 mmol). The reaction mixture was
heated to reflux for a further 24 h, before concentrating un-
der reduced pressure. The resulting residue was purified by
column chromatography on silica, eluted with 50% diethyl
ether/petrol 40:60 to give 19 as a colourless oil (0.125 g,
Acknowledgements
We thank Tocris Biosciences for their generous support of
this work.
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