Novel synthesis of the indolizidine alkaloid skeleton with appropriate functionality and stereochemistry for use as a 'chiral scaffold'

Article abstract of DOI:10.1039/a701193h

A stereocontrolled synthesis of the indolizidine alkaloid skeleton has been achieved via an intramolecular, photo-induced reaction of (5S)-5-triisopropylsilyloxymethyl-3-{2′-[(3″S)-3″- methoxypyrrolidinyl]ethyl}furan-2-(5H)-one, which can be obtained in a

Full text of DOI:10.1039/a701193h

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Novel synthesis of the indolizidine alkaloid skeleton with appropriate
functionality and stereochemistry for use as a ‘chiral scaffold’
Elizabeth Farrant and John Mann*
Department of Chemistry, Reading University, Whiteknights, Reading, RG6 6AD, UK
A stereocontrolled synthesis of the indolizidine alkaloid
skeleton has been achieved via an intramolecular, photo-
O
O
O
O
O
i
i
O
i
Pr3 SiO
Pr3 SiO
SPh
SPh
i
ii
Pr3 SiO
induced reaction of (5S)-5-triisopropylsilyloxymethyl-3-
{2Ј-[(3ЉS)-3Љ-methoxypyrrolidinyl]ethyl}furan-2-(5H )-one,
which can be obtained in a highly convergent fashion from
(5S)-5-triisopropylsilyloxymethyltetrahydrofuran-2-one
and (3S)-3-methoxypyrrolidine.
OHC
8
9
10
iii
O
O
O
O
The interesting pharmacology exhibited by the indolizidine
alkaloids ensures their popularity as targets for chemical syn-
thesis. The glycosidase inhibitors swainsonine 11 and castano-
i
i
Pr3 SiO
Pr3 SiO
iv
MeO
MeO
NH+AcO–
N
OHC
7
6
11
OH
OH
OH
OH
H
H
HO
HO
v
OH
N
N
O
O
O
O
H
i
i
Pr3 SiO
Pr3 SiO
H
H
H
H
H
1
2
MeO
N
N
spermine 22 are but two members of a family that comprises
several hundred known structures.3 In addition to their inherent
biological interest, structures of this type which possess much
functionality and defined stereochemistry have great potential
as ‘chiral scaffolds’ in combinatorial chemistry.4
Our previous work on the photoinduced addition of 1-
trimethylsilylpyrrolidine to the butenolide 3 to provide the
adducts 45 suggested that the intramolecular version of this
process (shown in Scheme 1) should provide access to the basic
MeO
12
13
Scheme 2 Reagents and conditions: i, LDA, THF, Ϫ78 ЊC, then allyl
bromide, then LDA, THF, PhSSPh, 52%; ii, O3, CH2Cl2, Ϫ78 ЊC, then
Me2S, room temp., 2 days, 67%; iii, Oxone, aq. MeOH, 88%; iv, NaC-
N BH 3, MeOH, (3S)-3-methoxypyrrolidinium acetate, 56%; v, hν,
MeCN, Ph2CO, Ϫ50 ЊC, 21%
2-one 8 was readily accessible from (S)-glutamic acid,7 and both
compounds could be prepared on a multigram scale.
Allylation of the tetrahydrofuranone 8 (LDA–THF at
Ϫ78 ЊC, then allyl bromide, 87%) followed by thiophenylation
(LDA–THF at Ϫ78 ЊC, then PhSSPh, 60%) provided the 3,3-
disubstituted derivative 9, and this was subjected to ozonolysis
(CH2Cl2 at Ϫ78 ЊC) and reductive processing (Me2S at room
temp. for 2 days) to yield the aldehyde 10 (60% overall). It was
noted that this procedure also gave rise to 38% of the exocyclic
alkene 11 and this became the major product (88% overall
from 9) if the product 10 was treated with Oxone in aqueous
methanol. We were delighted to discover that when compound
11 was reacted with the (3S)-3-methoxypyrrolidine under con-
ditions of reductive amination (NaCNBH3–MeOH)8 the
desired adduct 6 was obtained in a yield of 56%. All of these
reactions have been carried out routinely on at least a half-gram
scale.
O
ButMe2SiO
O
O
hν
ButMe2SiO
O
H
H
NSiMe3
NH
3
4
O
O
RO
O
RO
O
hν
H
H
H
(RO)n
N
(RO)n
N
5
Scheme 1
Finally, irradiation of this compound in acetonitrile in the
presence of 1 equiv. of benzophenone as photosensitiser (high
pressure lamp at Ϫ50 ЊC) resulted in a rapid (30 min) consump-
tion of starting materials and the formation of the two adducts
12 and 13 in a combined yield of 21% (and a ratio of ca. 1.6:1).
When 1,4-dicyanonaphthalene was used in place of benzo-
phenone, the yield rose to 40%. The structure of compound 12
has been confirmed by an X-ray structure determination† and
that of compound 13 through extensive NMR experiments.
skeleton 5 of the indolizidine alkaloids. This key intermediate is
also appropriately functionalised for further elaboration into a
wide variety of novel structures. The synthesis of compounds
of general structure 5 via a highly convergent and stere-
ocontrolled route is reported herein.
The substrate 6 for this intramolecular 6-endo-trig reaction
was prepared by the route shown in Scheme 2. The requisite
(3S)-3-methoxypyrrolidine 7 was synthesised from (2S)-malic
acid using the route of Naylor et al.6 but with minor modifi-
cations. The (5S)-5-triisopropylsilyloxymethyltetrahydrofuran-
† We thank Dr M. G. B. Drew for the X-ray studies, which will be
reported in detail elsewhere.
J. Chem. Soc., Perkin Trans. 1, 1997
1083

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Although the yields of this photochemical step remain to be
optimised, there is no reason why it should not also be viable
with other substituted pyrrolidines. This possibility, combined
with the presence within the adducts of latent functionality and
many stereogenic centres (five centres from the two centres
present in the starting materials), make them key intermediates
for the construction of a wide variety of indolizidine-type
compounds.
ϩ28.8 (c 1.2 in chloroform); νmax(film)/cmϪ1 2944s, 2865s, 2783
(C᎐H alkyl), 1769s (C᎐O lactone 5-ring); δ (CDCl , 400 MHz)
᎐
H
3
1.05 (3 H, m, Me2CHSi), 1.06 (18 H, s, Me2CHSi), 1.59 (1 H, m,
3-Ha), 1.73 (1 H, dd, J 17.6 and 7.0, 8-H), 1.89 (1 H, m, 11-Ha),
1.95 (1 H, dd, Jgem 11.4, J 1.8, 12-Ha), 2.06 (1 H, m, 3-Hb), 2.17
(1 H, d, Jgem 12.5, 11-Hb), 2.29 (1 H, q, J 9.2, 2-Ha), 2.59 (1 H,
dd, J 10.8 and 7.5, 4-H), 2.92 (1 H, m, 12-Hb), 3.01 (1 H, t, J 8.6,
2-Hb), 3.09 (1 H, t, J 6.8, 9-H), 3.29 (3 H, s, OMe), 3.65 (1 H, m,
10-H), 3.84 (1 H, dd, Jgem 10.8, J 3.1, SiOCHH), 3.92 (1 H,
dd, Jgem 10.8, J 4.9, SiOCHH), 4.60 (1 H, t, J 4.2, 7-H);
δC(CDCl3, 400 MHz) 12.1 (Me2CHSi), 18.2 (Me2CHSi), 22.9
(11-C), 28.4 (3-C), 37.4 (9-C), 42.0 (4-C), 50.5 (12-C), 53.1
(2-C), 57.4 (OMe), 64.5 (SiOCH2), 68.8 (8-C), 80.0 (7-C), 86.7
(10-C), 178.5 (5-C) [HRMS: found, 398.2734 (MHϩ).
C21H40NO4Si requires 398.2726]. Compound 13: Rf 0.07
(diethyl ether–methanol, 9.5:0.5); [α]2D5 Ϫ11.2 (c 0.54 in
chloroform); νmax(film)/cmϪ1 2929s, 2868s (C᎐H alkyl), 1781s
Experimental
Synthesis of (5S)-5-triisopropylsilyloxymethy-3-{2Ј-[(3ЉS)-3Љ-
methoxypyrrolidinyl]ethyl}furan-2-(5H)-one 6 by reductive
amination
A solution of the aldehyde 11 (1.50 g, 4.81 mmol) in dry
methanol (25 ml) was added to a solution of amine salt 7 (0.77
g, 4.81 mmol) in dry methanol (20 ml) under argon. NaCNBH3
(0.22 g, 3.37 mmol) was then added and the reaction was stirred
at room temperature for 1 h at which point no starting material
remained. The reaction was then diluted with CH2Cl2 (50 ml)
and washed with aqueous NaHCO3 (10 ml saturated, diluted
with 10 ml water). The aqueous phase was extracted with more
CH2Cl2 (3 × 10 ml) and the combined organic phases were
dried over anhydrous MgSO4, filtered and evaporated in vacuo
to give an oil. Purification by flash column chromatography,
eluting with diethyl ether–methanol (19:1 with 1% ammonia)
gave the required amine as an oil (1.06 g, 2.68 mmol, 56%); Rf
0.38 (diethyl ether–methanol, 19:1 with 1% ammonia);
[α]2D5 Ϫ11.9 (c 1.31 in CHCl3); νmax(film)/cmϪ1 2941, 2864,
(C᎐O lactone 5-ring); δ (CDCl , 400 MHz) 1.04 (3 H, m,
᎐
H
3
Me2CHSi), 1.05 (18 H, s, Me2CHSi), 1.49 (1 H, m, 10-Ha), 1.66
(1 H, dd, J 17.6 and 7.0, 8-H), 1.83 (1 H, m, 2-Ha), 2.13 (3 H,
m, 3-Hab, 12-Ha), 2.46 (1 H, dt, Jgem 14.5, J 7.3, 10-Hb), 2.53 (1 H,
m, 4-H), 2.97 (1 H, m, J 9.2, 2-Hb), 3.07 (1 H, t, J 7.3, 9-H), 3.16
(1 H, d, Jgem 10.6, 12-Hb), 3.28 (3 H, s, OCH3), 3.84 (2 H, m,
11-H and SiOCHH), 3.90 (1 H, dd, Jgem 9.7, J 4.8, SiOCHH ),
4.08 (1 H, t, J 4.2, 7-H); δC(CDCl3, 400 MHz) 11.8 (Me2CHSi),
17.9 (Me2CHSi), 22.3 (3-C), 37.1 (9-C), 38.0 (10-C), 43.0 (4-C),
49.7 (2-C), 56.5 (OCH3), 60.5 (12-C), 64.2 (SiOCH2), 64.3 (8-C),
77.8 (11-C), 80.8 (7-C), 178.0 (5-C) [HRMS: found, 398.2749
(MHϩ). C21H40NO4Si requires 398.2726].
2804s (C–H alkyl), 1758s (C᎐O lactone 5-ring); δ (250 MHz,
᎐
H
CDCl3) 1.05 (3 H, m, Me2CHSi), 1.06 (18 H, s, Me2CHSi), 1.81
(1 H, m, 4Љ-Ha), 2.47 (1 H, m, 4Љ-Hb), 2.51 (3 H, m, 1Ј-Ha, 2Ј-Ha,
5Љ-Ha), 2.79 (5 H, m, 2Љ-Hab, 5Љ-Hb, 2Ј-Hb, 1Ј-Hb), 3.29 (3 H, s,
OMe), 3.83 (1 H, dd, Jgem 10.6, J 5.5, 6-Ha), 3.92 (1 H, m, 3Љ-H),
3.99 (1 H, dd, Jgem 10.6, J 4.4, 6-Hb), 4.95 (1 H, m, 5-H), 7.18 (1
H, d, J 1.5, 4-H); δC(250 MHz, CDCl3), 11.8 (Me2CHSi), 17.9
(Me2CHSi), 24.5 (1Ј-C), 28.0 (4Љ-C), 52.5 and 53.8 (2Ј-C and
5Љ-C), 46.5 (OMe), 59.6 (2Љ-C), 63.6 (6-C), 80.1 (3Љ-C), 81.5
(5-C), 133.3 (3-C) 146.9 (4-C), 173.6 (2-C) [HRMS: found,
398.2724 (MHϩ). C21H40NO4Si requires 398.2727].
Acknowledgements
We thank the Wellcome Trust for a Wellcome Prize Studentship
awarded to E. F.
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Paper 7/01193H
Received 19th February 1997
Accepted 21st February 1997
1084
J. Chem. Soc., Perkin Trans. 1, 1997