Total syntheses of (+)-castanospermine and (+)-6-epicastanospermine

Article abstract of DOI:10.1039/a802741b

A divergent synthetic route to (+)-castanospermine 1 and (+)-6-epicastanospermine 2 has been developed via phenylselenoamidation of trichloroacetimidate derived from allylic alcohol 7, and dihydroxylations of trans-olefins 14 and 18 to dispose the three c

Full text of DOI:10.1039/a802741b

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Total syntheses of (+)-castanospermine and (+)-6-epicastanospermine
Sung Ho Kang*† and Joon Seop Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea
A divergent synthetic route to (+)-castanospermine 1 and
(+)-6-epicastanospermine 2 has been developed via phenyl-
selenoamidation of trichloroacetimidate derived from allylic
alcohol 7, and dihydroxylations of trans-olefins 14 and 18 to
dispose the three contiguous asymmetric centers, one amino
group and two hydroxy groups.
Cl3CCN in the presence of DBU in MeCN at 0 °C, and
subsequently cyclized using phenylselenyl chloride in the
presence of methyl 2,2,2-trichloroacetimidate and Et3N in
MeCN at 220 °C to produce an inseparable 15:1 mixture of
trans-oxazoline 8 and the isomeric cis-oxazoline in 63%
combined yield. In this cyclization, the addition of methyl
2,2,2-trichloroacetimidate was essential to suppress the forma-
tion of the corresponding trichloroacetate from trichloroaceti-
midate. Subjection of the mixture to PPTS in aqueous MeOH
induced partial hydrolysis of the oxazoline groups to give
hydroxy trichloroacetamides, of which the desired syn-stereoi-
somer, [a]2D2 26.8 (c 2.0, CHCl3), was readily separated in 87%
yield from the anti-stereoisomer. Oxidative elimination of the
syn-stereoisomer with H2O2 in THF afforded trans-olefin 9,
[a]2D4 +15.8 (c 3.7, CHCl3), in 84% yield contaminated with less
than 3% of cis-isomer.
The next event was a stereoselective dihydroxylation of the
introduced trans-olefinic double bond. In order to attain better
stereoselectivity, 9 was variously functionalized by changing
the protecting groups and the molecular structural shapes. It was
found that the most promising outcomes could be obtained with
benzyloxycarbonyl (Z)-protected pyrrolidine derivatives. Ac-
cordingly, 9 was desilylated in 92% yield and then the resultant
alcohol 10, [a]2D1 +34.9 (c 0.7, CHCl3), was cyclized under
Mitsunobu conditions13 using diisopropyl azodicarboxylate
(DIAD) and PPh3 in THF at 0 °C to provide pyrrolidine 11,
[a]2D4 +58.6 (c 1.0, CHCl3), in 88% yield. Treatment of 11 with
BnONa in THF resulted in the formation of Z-protected
pyrrolidine 12, [a]2D6 +54.9 (c 1.1, CHCl3), in 90% yield. After
removal of the acetonide group under acidic conditions, the
obtained triol 13, [a]D25 +17.0 (c 3.0, MeOH), was re-
gioselectively sulfonated with 2,4,6-triisopropylbenzenesulfo-
nyl chloride (TIPBSCl) in pyridine to furnish monosulfonate
14, [a]2D5 +18.9 (c 1.2, CHCl3), in 83% overall yield based on
15% of the recovered 13. Dihydroxylation of 14 with a catalytic
amount of OsO4 in the presence of NMO in aqueous acetone14
at 0 °C produced the requisite tetraol 15, [a]2D3 +9.2 (c 1.1,
CHCl3), in 88% yield along with less than 8% of 17, which was
undoubtedly formed by the spontaneous intramolecular ether-
ification of the isomeric tetraol 16. Subjection of 15 to
hydrogenolysis followed by in situ cyclization in the presence
of Et3N gave (+)-6-epicastanospermine 2, [a]2D3 +2.8 (c 0.6,
MeOH), in 66% yield.15
The naturally occurring hydroxylated indolizidine alkaloids
such as (2)-swainsonine, (+)-castanospermine 1 and (+)-6-epi-
castanospermine 2 continue to enjoy considerable attention
from synthetic and medicinal chemists due to their pronounced
biological activities. Their inhibition of enzymatic glycosidic
hydrolysis is closely related with the potential chemother-
apeutic utility for the treatment of diabetes,1 cancer,2 viral
diseases3 and AIDS.4 Their intriguing molecular structures and
promising medicinal value led us to explore their efficient
synthetic routes. Here we describe total syntheses5 of (+)-casta-
nospermine 1 and (+)-6-epicastanospermine 2, which have been
isolated from Castanospermum australe6 and Alexa leiope-
tala.7
Based on our retrosynthetic analysis toward 1 and 2, a crucial
synthetic step was a stereoselective dihydroxylation of trans-
olefin 3 (Scheme 1). While the effect of the allylic amino group
in 3 on the stereochemical outcome was in question,8 its allylic
alkoxy group was properly disposed for the desired
a-dihydroxylation according to Kishi’s empirical rule.9 An-
other key step was to produce a syn-amino alcohol as a
prospective precursor to 3 via intramolecular phenylselenoami-
dation of trichloroacetimidate derived from cis-olefinic allylic
alcohol 4.10
(S)-Butane-1,2,4-triol reacted with p-anisaldehyde in the
presence of PPTS in benzene using a Dean–Stark trap to give a
7.5–8:1 mixture of 6- and 5-membered benzylidenes (Scheme
2). After Swern oxidation11 of the inseparable mixture, the
resulting aldehydes were olefinated with phosphonium salt 5
prepared from (S)-butane-1,2,4-triol12 to afford a 19:1 mixture
of cis-olefin 6, [a]2D8 +110.8 (c 1.5, CHCl3), and the correspond-
ing trans-olefin in 69% combined overall yield, along with 7%
of the isomeric olefins generated from the 5-membered
benzylidenes. Hydrolysis of 6 with PPTS in MeOH at 0 °C
removed its p-methoxybenzylidene group chemoselectively to
provide diol 4, [a]2D7 +9.9 (c 1.3, CHCl3), in 86% yield. The
primary hydroxy group of 4 was regioselectively silylated with
TBDPSCl in the presence of imidazole at 260 °C to furnish
silyl ether 7, [a]2D2 22.6 (c 2.2, CHCl3), in 92% yield. For the
For the synthesis of (+)-castanospermine, 12 was converted
into silyl ether 18, [a]2D5 212.6 (c 1.7, CHCl3), in 88% overall
yield by protection of the secondary hydroxy group with
MeOCH2Cl (MOMCl), hydrolysis of the acetonide group and
monosilylation of the primary hydroxy group with TBDPSCl in
sequence (Scheme 3). Osmylation of 18 gave triol 19, [a]D24
24.9 (c 0.7, CHCl3), in 91% yield along with 6% of the
isomeric b-dihydroxylated triol. When 19 was exposed to
acetone in the presence of TsOH, the desired dioxolane 20,
[a]2D3 27.1 (c 1.5, CHCl3), was prepared in 92% yield by
ketalization of the two syn-hydroxy groups, accompanied by
2% of the regioisomeric dioxolane. In order to secure the correct
stereochemistry at 6-position of (+)-castanospermine, the
remaining hydroxy group of 20 was inverted by mesylation
followed by desilylation to afford epoxide 21, [a]2D1 219.7 (c
1.2, CHCl3), in 87% overall yield. Removal of the Z group in 21
unprecedent phenylselenoamidation,
7
was treated with
HO
OR2
OR3
OH
H
N
HO
R1O
N
X
R4
3
1 X = α-OH
2 X = β-OH
OH
OH
HO
HO
OH
O
O
4
Scheme 1
Chem. Commun., 1998
1353

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OH
p-MeOC6H4
OH
OMOM
i–iii
TBDPSO
HO
12
O
O
i, ii
N
Z
O
O
OH
18
OH
iv
6
5
iii
O
O
OH
OR
O
OMOM
OMOM
O
TBDPSO
RO
O
vi, vii
O
_
4 R = H
RO
19 R = H
N
Z
N
iv
7 R = TBDPS
PPh3 I
O
Z
v
21
v
20 R–R = CMe2
OH
OR
O
viii
SePh
O
O
vi, vii
O
HO
O
OH
OMOM
H
H
N
NHCOCCl3
O
HO
O
N
ix
OTBDPS
9 R = TBDPS
10 R = H
viii
N
HO
CCl3
HO
ix
8
1
22
O
O
Scheme 3 Reagents and conditions: i, MOMCl, Et3N, CH2Cl2, reflux; ii,
TsOH, MeOH, 20 °C; iii, TBDPSCl, imidazole, DMF, CH2Cl2, 260 °C; iv,
OsO4, NMO, H2O, acetone, 0 °C; v, TsOH, acetone, 20 °C; vi, MsCl,
DMAP, Et3N, CH2Cl2, 20 °C; vii, Bu4NF, THF, 20 °C, then 5 m NaOH; viii,
5% Pd/C, cyclohexene, EtOH, reflux; ix, conc. HCl, MeOH, reflux, then
Dowex 50WX8-100 ion-exchange resin
OH
OH
OH
xi
N
OR
N
R
Z
11 R = COCCl3
12 R = Z
13 R = H
14 R = TIPBS
xii
x
xiii
OH
OH
OH
OH
OH
OH
Notes and References
+
† E-mail: shkang@kaist.ac.kr
RO
HO
N
TIPBSO
HO
N
Z
16
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Z
15
xiv
O
HO
OH
OH
H
HO
HO
HO
HO
N
N
Z
2
17
Scheme 2 Reagents and conditions: i, p-anisaldehyde, PPTS, PhH, Dean–
Stark trap; ii, (COCl)2, DMSO, Et3N, then 5, BunLi, HMPA, THF, 278 to
0 °C; iii, PPTS, MeOH, 0 °C; iv, TBDPSCl, imidazole, DMF, CH2Cl2,
260 °C; v, Cl3CCN, DBU, MeCN, 0 °C, then PhSeCl, MeOC(NNH)CCl3,
Et3N, MeCN, 220 to 215 °C; vi, PPTS, H2O, MeOH, 20 °C; vii, 30%
H2O2, THF, 0 to 20 °C; viii, Bu4NF, THF, 25 to 0 °C, then aq. NaH2PO4;
ix, DIAD, Ph3P, THF, 0 °C; x, NaOBn, THF, 20 °C; xi, TsOH, MeOH,
20 °C; xii, TIPBSCl, pyridine, 20 °C; xiii, OsO4, NMO, acetone, 0 °C; xiv,
H2, 10% Pd/C, MeOH, 20 °C, then Et3N, reflux
was anticipated to induce 6-endo cyclization rather than 5-exo
cyclization due to the anti arrangement of the dioxolane ring.
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conditions16 provided only indolizidine 22, [a]2D2 +39.5 (c 0.8,
CHCl3), in 76% yield. Finally methanolysis of 22 with
methanolic HCl furnished (+)-castanospermine 1, mp
205–207 °C (decomp.), [a]2D2 +79.7 (c 1.0, MeOH), in 96%
yield.15
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(+)-castanospermine 1 and (+)-6-epicastanospermine 2, which
culminated in the stereoselective phenylselenoamidation of
trichloroacetimidate (from 7) and the asymmetric dihydroxyla-
tion of 14 and 18 to establish the four contiguous chiral
centers.
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This work was supported by the Korea Advanced Institute of
Science and Technology and the Organic Chemistry Research
Center sponsored by the Korea Science and Engineering
Foundation. Dedicated to Professor Yoshito Kishi on the
occasion of his 60th birthday.
Received in Cambridge, UK, 14th April 1998; 8/02741B
1354
Chem. Commun., 1998