Silicon-mediated asymmetric synthesis of fagomine and 3,4-di-epi-fagomine

Article abstract of DOI:10.1016/j.tetasy.2011.05.004

The synthesis of d-fagomine and its stereoisomer, d-3,4-di-epi-fagomine has been achieved from C₂-symmetric 3,4-bis-silyl substituted adipic acid di-oxazolidin-2-one derivatives via stereocontrolled azidation and silicon to hydroxyl conversion as the key steps. The Evans oxazolidin-2-one controlled the stereochemical outcome of the azidation which supersedes the directing effects of the silyl substituent.

Full text of DOI:10.1016/j.tetasy.2011.05.004

Tetrahedron: Asymmetry 22 (2011) 1090–1096
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Silicon-mediated asymmetric synthesis of fagomine and 3,4-di-epi-fagomine
⇑
Pintu K. Kundu, Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of D-fagomine and its stereoisomer, D-3,4-di-epi-fagomine has been achieved from C2-sym-
Received 27 April 2011
Accepted 12 May 2011
Available online 14 June 2011
metric 3,4-bis-silyl substituted adipic acid di-oxazolidin-2-one derivatives via stereocontrolled azidation
and silicon to hydroxyl conversion as the key steps. The Evans oxazolidin-2-one controlled the stereo-
chemical outcome of the azidation which supersedes the directing effects of the silyl substituent.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
number of syntheses of fagomine isomers such as 2 and 3 are rare.
The only synthesis of the stereoisomeric 3,4-di-epi-fagomine 3 has
Polyhydroxylated piperidines (azasugars) have gained increas-
ing synthetic interest due to their remarkable biological activity
as glycosidase inhibitors.1–3 Since glycosidases are involved in
numerous biological processes, azasugars are potential therapeutic
agents for the treatment of a wide range of diseases, including
diabetes, cancer, AIDS, viral infections and many more.4,5 These
important biological properties have led to many synthetic
approaches6,7 towards naturally occurring azasugars and their
analogues.
been reported as a mixture of diastereoisomers starting from a
-serine-derived Garner aldehyde.22 In a continuation of our efforts
for the silicon-mediated hydroxylated piperidine/pyrrolidine
syntheses,26–30 we herein report the synthesis of
-fagomine 1
and -3,4-di-epi-fagomine from C2-symmetric 3,4-bis-silyl
D
D
D
3
substituted adipic acid derivatives via stereocontrolled azidation
and silicon to hydroxyl conversion as the key steps.
2. Results and discussion
1,2-Dideoxy-azasugars, such as D-fagomine 1 and its stereoiso-
We have recently shown31 that reductive conditions using an
Mg/TMSCl/DMF system on silicon-tethered diacrylic acid N-oxaz-
olidin-2-one derivatives favored intramolecular reductive coupling
of the two acrylic units with the preferred formation of C2-sym-
metric 3,4-bis-silyl substituted adipic acid derivatives with very
high selectivity. Thus, disiloxane 4 led to the formation of a mix-
ture of diastereoisomeric cyclic products, cis-5 and two trans-prod-
ucts (trans-6:trans-7 = 60:40) with a strong preference for the
desired trans-isomers (trans:cis = 85:15) (Scheme 1). The isolated
yield of the mixture of cyclic products was also very high (85%)
but the individual isomers were not separable by column chroma-
tography. We adopted simple procedures in which the trans-iso-
mers were separated from cis-5 after which the individual trans-
isomers were separated by crystallisation. Initially, the mixture
of cis-5, trans-6 and trans-7 was dissolved in ethyl acetate and
the trans-isomers were precipitated out by adding hexane into
the solution. After separating the solid mixture of trans-6 and
trans-7 (55%), the gummy mixture containing all three isomers
(30%) was treated with lithium hexamethyldisilyl amide in THF
at ꢀ78 °C. Under these conditions, only cis-5 underwent Dieck-
mann-type cyclisation to cyclic b-keto esters 8a and 8b (Scheme 2)
while the trans-isomers (15%) remained unaffected leading to easy
separation by column chromatography. The combined yield of the
trans-isomers thus improved to 70%. The individual trans-isomers
were then separated by fractional crystallisation. For this, a
mers 2 and 3 (Fig. 1), have been isolated from the buckwheat seeds
of Japanese buckwheat Fagopyrum esculentum australe Moench8
and also from the seeds of Castanospermum australe (Legumino-
sae).9 More recently, the isomers of fagomine 2 and 3 have been
isolated from the leaves and roots of Xanthocericis zambesiaca.10
Fagomine itself has a strong inhibitory activity towards mamma-
lian
have a potent antihyperglycemic effect in streptozocin-induced
a
-glucosidase, b-galactosidase,10 and has also been found to
diabetic mice and
a potentiation of glucose-induced insulin
secretion.11,12
OH
OH
OH
OH
OH
OH
OH
OH
N
H
N
H
N
H
OH
3
2
1
Figure 1. Fagomine 1 and its stereoisomers 2 and 3.
Several syntheses of
D
-fagomine 113–25 have been reported from
carbohydrates, aminoacids and other precursors. However, the
⇑
Corresponding author. Tel.: +91 22 25595012; fax: +91 22 25505151.
E-mail address: ghsunil@barc.gov.in (S.K. Ghosh).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.004

P. K. Kundu, S. K. Ghosh / Tetrahedron: Asymmetry 22 (2011) 1090–1096
1091
O
tions required for the OH substituents at the 3- and 4-positions.
The introduction of an azido group at the -position of the carbox-
Me
Si
O
a
Me
N
amide in trans-7 was carried out following the electrophilic azida-
tion procedure as described by Evans et al.,32 using KHMDS and
trisyl azide. Azide 9 (Scheme 4) was formed as a single diastereo-
isomer. We were able to observe that the desired stereochemical
outcome could be controlled by the valine derived oxazolidin-2-
one auxiliary33 and not by the b-silyl group. The reduction of azide
9 and the in situ protection of the intermediate amine were
achieved by the addition of (Boc)2O in an H2/Pd–C system to give
urethane 10 in excellent yield. The oxazolidin-2-one groups from
10 were removed by treatment with K2CO3 in MeOH, resulting in
a mixture of dimethyl ester and dicarboxylic acid which upon
treatment with diazomethane yielded dimethyl ester derivative
11. The Boc-protecting group in 11 was removed by treatment
with trifluoroacetic acid and the resulting trifluoroacetate salt
was basified with NaHCO3 to give the intermediate amine which
spontaneously underwent cyclisation to lactam 12. An LiAlH4
reduction followed by a Fleming–Tamao oxidation34,35 of lactam
12 using potassium bifluoride and hydrogen peroxide yielded
O
O
O
O
O
Si
N
Me
Me
4
Mg, TMSCl
DMF, 0 o
85%
C
O
O
O
O
O
O
O
O
O
O
O
N
N
O
N
N
O
O
N
N
Me
Si
Me
Si
Me
Si
Me
Me
Me
+
+
O
O
O
Si
Si
Si
Me
Me
Me
D
-fagomine 1, as confirmed from the 1H and 13C chemical shift
Me
Me
Me
O
values, and also by comparing the specific rotation values {½a D22
¼
ꢁ
þ18:6 (c 0.43, H2O); lit.22
½
a 2D5
ꢁ
¼ þ18:0 (c 0.92, H2O)}.
O
cis-5
O
O
trans-7
The synthesis of 3,4-di-epi-fagomine 3 was achieved in an anal-
trans-6
ogous way as shown for D-fagomine 1. For this purpose, 3,4-bis-si-
Scheme 1. Intramolecular reductive coupling induced by magnesium.
lyl substituted adipic acid derivative trans-6 was chosen as the
starting material, because the configurations of the Si-bearing cen-
tres matched the configurations required for the OH substituents
at the 3- and 4-positions. The stereochemical outcome in the
electrophilic azidation in trans-6 was also controlled by the oxaz-
olidin-2-one auxiliary, thus giving azide 13 (Scheme 5) as a single
O
Me
Si
H
O
Me
O
Me
Si
N
LiHMDS, THF
-78 o
O
H
H
O
Me
C
O
+
Si
cis-5
diastereoisomer. Similar to the D-fagomine series, the reduction of
O
H
O
Me
O
Me
N
azide 13 and the in situ protection of the intermediate amine was
achieved by adding (Boc)2O in an H2/Pd–C system to give urethane
14. The oxazolidin-2-one groups from 13 were removed and con-
verted to dimethyl ester derivative 15. The Boc-protecting group
in 15 was removed by treatment with trifluoroacetic acid and
the resulting trifluoroacetate salt was basified with NaHCO3 to give
the amine 16. It is interesting to note that amine 16 is stable and
did not cyclise to lactam 17. The cyclisation of amine 16 to lactam
17 was finally achieved by refluxing a xylene solution of amine 16.
An LiAlH4 reduction followed by Fleming–Tamao34,35 oxidation of
lactam 17 using potassium bifluoride and hydrogen peroxide
yielded 3,4-di-epi-fagomine 3 as confirmed from the 1H and 13C
chemical shift values, and also by comparing the specific rotation
Si
Me
Me
8b
8a
Scheme 2. Dieckmann-type cyclisation of cis-5.
mixture of trans-6 and trans-7 was crystallised from benzene–hex-
ane to give the pure trans-6 product (38%) as needle shaped crys-
tals; the remaining mass was crystallised from hexane–ethyl
acetate to give trans-7 (27%) as sugar like crystals.
Our proposed general retrosynthetic strategy (Scheme 3) for the
synthesis of fagomine and its stereoisomers from 3,4-bis-silyl
substituted adipic acid derivatives I is based on; (i) stereoselective
values {½a 2D4
ꢁ
¼ þ12:1 (c 0.33, H2O); lit.22
½
a 2D5
ꢁ
¼ þ13:4 (c 0.32,
introduction of an amino functionality at the
a-position of one of
H2O)}.
the derivatised carboxylic acids to give amine II; (ii) intramolecular
cyclisation to give lactam III; and (iii) the reduction of the carbonyl
groups and the conversion of the silicon groups to hydroxyl groups
with retention of configuration to give 1,2-dideoxy azasugars IV.
For the synthesis of D-fagomine, 3,4-bis-silyl substituted adipic
acid derivative trans-7 was chosen as the starting material because
The lactamisation of the intermediate amine derived from 11
was smooth whereas the same sequence for amine 16 to lactam
17 was very difficult, as it required a high temperature and pro-
longed reaction time. The proposed transition states for both the
amines undergoing cyclisation is shown in Scheme 6. While the
cyclisation took place, amine 16 had to adopt a conformation
wherein the silyl groups have to be disposed axially and the
the configurations of the Si-bearing centres matched the configura-
Me
O
OR
O
OR
OR
Me
Si
OH
∗
O
Me
Si
Si
Me
Me
Me
O
∗
Me
O
Me
OH
OH
∗
∗
∗
Si
NH2
∗
∗
∗
∗
O
O
Si
Si
∗
∗
N
H
Me
Me
N
H
Me
Me
OR
O
OR
O
IV
III
II
I
Scheme 3. General retrosynthetic strategy for fagomine stereoisomers.

1092
P. K. Kundu, S. K. Ghosh / Tetrahedron: Asymmetry 22 (2011) 1090–1096
O
O
O
O
O
O
O
O
O
N
N
O
O
N
O
N
Me
Si
Me
Si
Me
Si
1. KHMDS, THF, -78 ºC
Me
Me
H2/Pd-C, (Boc)2O,
EtOAc
Me
Me
Me
Me
2. Trisyl azide, THF, -78 ºC
NHBoc
N3
O
O
O
3. AcOH, -78 ºC
Si
Si
Si
Me
Me
Me
N
O
O
N
O
O
O
trans-7
O
10
O
9
Me
O
O
OMe
OMe
NH2
Me
Si
OH
Me
O
Me
Si
Me
O
Me
Me
1. TFA/CH2Cl2
2. NaHCO3
OH
OH
Me Si
O
NHBoc
1. LiAlH4, Et2O
2. KHF2, H2O2
1. K2CO3, MeOH
Si
Me
O
Si
Si
O
2. H3O+
N
H
Me
N
3. CH2N2
H
Me
Me
OMe
OMe
O
OMe
11
12
1
Scheme 4. Synthesis of D-fagomine.
O
O
O
O
O
O
O
O
N
O
O
N
O
N
Me
Me
Si
Me
Si
H2/Pd-C, (Boc)2O,
EtOAc
1. KHMDS, THF, -78 ºC
Me
Me
Me
Me
Me
Si
2. Trisyl azide, THF, -78 ºC
N3
NHBoc
O
O
O
3. AcOH, -78 ºC
Si
Si
Si
Me
Me
Me
Me
N
N
O
O
N
O
O
O
O
O
trans-6
13
14
Me
Si
O
O
OMe
O
OMe
NH2
Me
Si
HO
Me
O
Me
Me
Me
Me
Xylene,
1. TFA/CH2Cl2
2. NaHCO3
OH
Me Si
O
NHBoc
1. K2CO3, MeOH
1. LiAlH4, Et2O
2. KHF2, H2O2
Si Me
Py (cat.)
O
2. H3O+
3. CH2N2
140 oC
O
Si
Si
O
N
H
Me
N
H
OH
Me
Me
OMe
OMe
O
OMe
3
15
16
17
Scheme 5. Synthesis of D-3,4-di-epi-fagomine.
methoxycarbonyl group can adopt equatorial positions making
the system favourable for lactamisation.
OMe
O
OMe
NH2
O
Me
Me
H
Me
Me
28 ºC
N
Si
Si
O
O
O
Si
Si
3. Conclusion
O
Me
OMe
Me
Me
Me
In conclusion, we have achieved the stereocontrolled synthesis
of D-fagomine and 3,4-di-epi-fagomine from C2-symmetric 3,4-bis-
silyl substituted adipic acid di-oxazolidin-2-ones. The Evans’
oxazolidin-2-one controlled the stereochemical outcome of the
azidation, which supersedes the directing effects of the silyl
substituent.
12
Me
O
Me
O
Me Si
Xylene,
Me Si
OMe
NH2
OMe
NH
Py (cat.)
O
O
O
140 ºC
O
Me Si
Me
16
OMe
Me Si
Me
17
4. Experimental
All reactions were performed in oven-dried (120 °C) or flame-
dried glass apparatus under a dry N2 or argon atmosphere. KHMDS
and LiHMDS were freshly prepared, whereas TFA was distilled
before use. THF and diethyl ether were distilled over Na/benzophe-
none. Lithium aluminium hydride, Pd/C (10%), (Boc)2O, trifluoro-
methanesulfonic acid, KHF2 and H2O2 (30%) were used as
received from commercial sources. 1H and 13C NMR spectra were
recorded on Bruker 200/500 MHz spectrometers. Spectra were
Scheme 6. Proposed transition states for amine cyclisation.
methoxycarbonyl group was in an equatorial position. This makes
the system energetically unfavourable, meaning that a very high
temperature was required for the lactamisation. On the other hand,
for the amine derived from urethane 11, the silyl groups and

P. K. Kundu, S. K. Ghosh / Tetrahedron: Asymmetry 22 (2011) 1090–1096
1093
referenced to residual chloroform (d 7.25 ppm, 1H; 77.00 ppm, 13C).
Chemical shifts are reported in ppm (d); multiplicities are indicated
by s (singlet), d (doublet), t (triplet), q (quartet), quint (pentet), m
(multiplet) and br (broad). Coupling constants, J, are reported in
Hertz. High resolution mass spectra were recorded at 60–70 eV
on a Waters Micromass Q-TOF spectrometer (ESI, Ar). Optical rota-
tions were measured in a JASCO DIP 360 polarimeter. Infrared
spectra (IR) were recorded on a JASCO FT IR spectrophotometer
in NaCl cells or in KBr discs. Peaks are reported in cmꢀ1. Melting
points (mp) were determined on a Fischer John’s melting point
apparatus and are uncorrected. Analytical thin-layer chromatogra-
phy was performed using home made silica gel plates (about
0.5 mm). Elemental analyses (C, H, N) were carried out at the Ana-
lytical Facility of Bio-Organic Division BARC, Mumbai, India.
1388, 1376, 1302, 1252, 1215, 1098, 919, 846, 759 cmꢀ1. m/z (EI):
483 (Mꢀ15, 5%), 327 (27), 328 (100), 260 (81), 228 (15), 213 (19),
199 (71), 174 (34), 149 (32), 133 (66), 117 (19), 73 (22), 69 (21). Anal.
Calcd for C22H38N2O7Si2: C, 52.98; H, 7.68; N, 5.62. Found: C, 52.95;
H, 7.85; N, 5.88.
4.1.2. Data for (4S,40S)-3,30-(2,20-((3R,4R)-2,2,5,5-tetramethyl-
1,2,5-oxadisilolane-3,4-diyl)bis(acetyl))bis(4-isopropyloxaz-
olidin-2-one) trans-7
Crystalline solid. Mp 141–142 °C (from hexane–EtOAc).
½
a 2D7
ꢁ
¼ þ152:9 (c 0.9, EtOH). Rf = 0.71 (hexane/EtOAc, 70:30). 1H
NMR (200 MHz, CDCl3): d 0.05 (s, 6H, 2 ꢂ SiMe), 0.30 (s, 6H,
2 ꢂ SiMe), 0.88 (d, J = 7.8 Hz, 6H, 2 ꢂ CHMeAMeB), 0.92 (d, J =
7.8 Hz, 6H, 2 ꢂ CHMeAMeB), 1.15–1.19 (m, 2H, 2 ꢂ Me2SiCHCH2),
2.28–2.44 (m, 2H, 2 ꢂ NCHCHMe2), 2.82 (dd, J = 10.4, 17.8 Hz, 2H,
2 ꢂ CHAHBCON), 3.41 (dd, J = 4.6, 17.8 Hz, 2H, 2 ꢂ CHAHBCON),
4.17–4.33 (m, 4H, 2 ꢂ NCO2CH2CH), 4.38–4.45 (m, 2H,
2 ꢂ NCHCHMe2). 13C NMR (50 MHz, CDCl3): d ꢀ2.3 (2C), 1.0 (2C),
14.5 (2C), 18.0 (2C), 25.9 (2C), 28.1 (2C), 38.1 (2C), 58.4 (2C),
63.2 (2C), 154.0 (2C), 173.7 (2C). IR (CHCl3 film): 3019, 2965,
2877, 1779, 1696, 1487, 1388, 1302, 1251, 1210, 1096, 920, 846,
751 cmꢀ1. m/z (EI): 483 (Mꢀ15, 5%), 327 (26), 328 (100), 260
(80), 228 (15), 213 (19), 199 (69), 174 (35), 149 (32), 133 (64),
117 (18), 73 (22), 69 (21). Anal. Calcd for C22H38N2O7Si2: C,
52.98; H, 7.68; N, 5.62. Found: C, 52.99; H, 7.74; N, 6.21.
4.1. Reductive cyclisation of 4 to give cis-5, trans-6 and trans-7
Freshly distilled trimethylsilyl chloride (21.4 mL, 168.8 mmol)
was added to a stirred suspension of magnesium turnings (4.1 g,
168 gatom) in dry DMF (400 mL) at room temperature under an ar-
gon atmosphere. After 30 min, the reaction mixture was cooled in
an ice-water bath and a solution of disiloxane 4 (7 g, 14.1 mmol) in
dry DMF (50 mL) was added slowly over 1.3 h. After the addition
was over, the reaction mixture was stirred for 5.5 h and the cold
bath was removed. The reaction mixture was allowed to return
to room temperature (about 30 min) and then poured into a cold
saturated sodium bicarbonate solution and extracted three times
with 10% ethyl acetate–hexane. The organic extract was washed
with brine, dried over anhydrous MgSO4 and evaporated. The res-
idue was purified by column chromatography on silica using hex-
ane–EtOAc as eluent to give a mixture of cis-5, trans-6 and trans-7
(6 g, 85%). The mixture was dissolved in ethyl acetate and the
trans-isomers were precipitated out by adding hexane into the
solution. The mixture was filtered to give a solid mixture of
trans-6 and trans-7 (3.9 g, 55%) and the filtrate was evaporated to
give a gummy mixture containing all three isomers (2.1 g, 30%).
A pure sample of cis-5 for characterisation purposes was obtained
by careful column chromatography of the gummy residue contain-
ing a mixture of all isomers.
4.1.3. Data for (4S,40S)-3,30-(2,20-((3R,4R)-2,2,5,5-tetramethyl-
1,2,5-oxadisilolane-3,4-diyl)bis(acetyl))bis(4-isopropyloxaz-
olidin-2-one) cis-5
Colourless thick gum. ½a D31
¼ þ58:2 (c 0.67, EtOH). Rf = 0.71
ꢁ
(hexane/EtOAc, 70:30). 1H NMR (500 MHz, CDCl3): d 0.16 (s, 3H,
SiMe), 0.17 (s, 3H, SiMe), 0.23 (s, 3H, SiMe), 0.25 (s, 3H, SiMe),
0.88 (d, J = 7.0 Hz, 6H, 2 ꢂ CHMeAMeB), 0.92 (d, J = 7.8 Hz, 6H,
2 ꢂ CHMeAMeB), 1.69–1.73 (m, 1H, Me2SiCHCH2), 1.82–1.86 (m,
1H, Me2SiCHCH2), 2.30–2.43 (m, 2H, 2 ꢂ NCHCHMe2), 2.95 (dd,
J = 9.0, 17.5 Hz, 2H, 2 ꢂ CHAHBCON), 3.15 (dd, J = 6.0, 17.5 Hz, 1H,
CHAHBCON), 3.22 (dd, J = 7.5, 18.0 Hz, 1H, CHAHBCON), 4.18–4.23
(m, 2H, NCO2CH2CH), 4.26–4.34 (m, 2H, NCO2CH2CH), 4.39–4.42
(m, 1H, NCHCHMe2), 4.44–4.47 (m, 1H, NCHCHMe2). 13C NMR
(125 MHz, CDCl3): d ꢀ1.3, ꢀ1.1, 0.1, 0.5, 14.5, 14.5, 18.0 (2C),
22.4, 22.9, 28.2, 28.3, 32.9, 33.5, 58.5 (2C), 63.2, 63.3, 154.1,
154.2, 173.4, 173.6. IR (CHCl3 film): 2963, 2977, 1780, 1698,
1387, 1302, 1252, 1208, 1097, 1012, 919 cmꢀ1. m/z (ESI): 521
(M+Na, 69%), 499 (M+H, 100), 481 (26), 370 (19), 279 (41), 132
(16). HRMS (ESI) calcd for C22H39N2O7Si2 [M+H]+: 499.2290; found:
499.2275.
The gummy mixture of isomers obtained after initial removal of
the trans-isomers (2.1 g, 4.2 mmol) was dissolved in THF (12 mL)
and then added dropwise to
a stirred solution of LiHMDS
(2.8 mL, 1 M in THF, 2.8 mmol) at ꢀ78 °C. After 3 h, the reaction
mixture was poured into an aqueous ammonium chloride solution
and extracted with ether. The extract was evaporated under re-
duced pressure and the residue was chromatographed to give a
mixture of trans-6 and trans-7 (1.05 g, 50%). The combined solid
trans-isomeric mixture was crystallised from benzene–hexane to
give pure major trans-6 product (2.7 g, 38% overall) followed by
crystallisation of the residual mass from hexane–ethyl acetate to
give the minor trans-7 product (1.9 g, 27% overall).
4.2. (S)-3-((R)-2-Azido-2-((3R,4R)-4-(2-((S)-4-isopropyl-2-
oxooxazolidin-3-yl)-2-oxoethyl)-2,2,5,5-tetramethyl-1,2,5-
oxadisilolan-3-yl)acetyl)-4-isopropyloxazolidin-2-one 9
A freshly prepared solution of potassium hexamethyldisilazide
(KHMDS) (1.3 mL, 1 M solution in THF, 1.3 mmol, 1.3 equiv) was
added to a stirred solution of trans-7 (0.5 g, 1 mmol) in dry THF
(2.5 mL) at ꢀ78 °C. After 30 min, a solution of trisyl azide (0.4 g,
1.3 mmol) in THF (3 mL) was canulated into the reaction mixture
and stirred for 8 min. The reaction mixture was quenched with
acetic acid (0.3 mL, 5 mmol) at ꢀ78 °C and then the temperature
was slowly raised to 30 °C. The reaction mixture was evaporated
under reduced pressure and the residue was diluted with brine.
The reaction mixture was extracted with chloroform and the com-
bined extract was washed with sodium bicarbonate solution, dried
over anhydrous MgSO4 and evaporated. The residue was purified
by column chromatography on silica using hexane–EtOAc (85:15)
4.1.1. Data for (4S,40S)-3,30-(2,20-((3S,4S)-2,2,5,5-tetramethyl-
1,2,5-oxadisilolane-3,4-diyl)bis(acetyl))bis(4-isopropyloxaz-
olidin-2-one) trans-6
Crystalline solid. Mp 162–163 °C (from hexane–EtOAc).
½
a 2D8
ꢁ
¼ ꢀ5:3 (c 0.87, EtOH). Rf = 0.71 (hexane/EtOAc, 70:30). 1H
NMR (200 MHz, CDCl3): d 0.04 (s, 6H, 2 ꢂ SiMe), 0.32 (s, 6H,
2 ꢂ SiMe), 0.87 (d, J = 7.8 Hz, 6H, 2 ꢂ CHMeAMeB), 0.92 (d, J =
7.8 Hz, 6H, 2 ꢂ CHMeAMeB), 1.10–1.51 (m, 2H, 2 ꢂ Me2SiCHCH2),
2.27–2.43 (m, 2H, 2 ꢂ NCHCHMe2), 2.81 (dd, J = 10.8, 18.6 Hz, 2H,
2 ꢂ CHAHBCON), 3.43 (dd, J = 4.4, 18.6 Hz, 2H, 2 ꢂ CHAHBCON),
4.17–4.33 (m, 4H, 2 ꢂ NCO2CH2CH), 4.37–4.44 (m, 2H, 2 ꢂ
NCHCHMe2). 13C NMR (50 MHz, CDCl3): d ꢀ2.4 (2C), 1.1 (2C), 14.6
(2C), 17.9 (2C), 25.8 (2C), 28.4 (2C), 38.2 (2C), 58.4 (2C), 63.5 (2C),
154.1 (2C), 173.7 (2C). IR (CHCl3 film): 3019, 2966, 1780, 1697,
as eluent to give azide
9 (0.41 g, 76%) as a thick gum.
½
a 2D5
ꢁ
¼ þ89:8 (c 1.06, CHCl3). Rf = 0.66 (hexane/EtOAc, 75:25). 1H

1094
P. K. Kundu, S. K. Ghosh / Tetrahedron: Asymmetry 22 (2011) 1090–1096
NMR (200 MHz, CDCl3): d 0.05 (s, 3H, SiMe), 0.16 (s, 3H, SiMe), 0.25
(s, 3H, SiMe), 0.34 (s, 3H, SiMe), 0.84–0.97 (m, 12H,
2 ꢂ NCO2CH2CHCHMe2), 1.41–1.59 (m, 2H, 2 ꢂ Me2SiCHCH2),
2.28–2.44 (m, 2H, 2 ꢂ NCHCHMe2), 2.82 (dd, J = 10.2, 18.4 Hz, 1H,
CHAHBCON), 3.39 (dd, J = 5.4, 18.4 Hz, 1H, CHAHBCON), 4.16–4.51
(m, 6H, 2 ꢂ NCO2CH2CH, 2 ꢂ NCHCHMe2), 5.36 (d, J = 6.3 Hz, 1H,
CHN3). 13C NMR (50 MHz, CDCl3): d ꢀ2.0, ꢀ0.7, 1.0, 1.3, 14.4,
14.6, 17.7 (2C), 21.7, 28.1, 28.3, 32.9, 38.9, 58.3, 58.8, 63.2, 63.5,
64.0, 153.5, 154.0, 169.7, 173.3. IR (CHCl3 film): 3013, 2965,
Calcd for C17H33NO7Si2: C, 48.66; H, 7.93; N, 3.34. Found: C,
49.08; H, 7.93; N, 2.91.
4.5. (3aR,4R,7aR)-Methyl octahydro-1,1,3,3-tetramethyl-6-oxo-
[1,2,5]oxadisilolo[3,4-c]pyridine-4-carboxylate 12
Freshly distilled TFA (0.3 mL) was added to a stirred solution of
11 (85 mg, 0.2 mmol) in CH2Cl2 (0.3 mL) at 30 °C. After 1 h, the
reaction mixture was evaporated and the residue was quenched
with an aqueous sodium bicarbonate solution. The reaction mix-
ture was extracted with CH2Cl2 and the organic extract was
washed with brine, dried over anhydrous MgSO4 and evaporated
to give the cyclised product 12 (57 mg, 99%) as a colourless liquid.
2878, 2106, 1780, 1698, 1388, 1252, 1207, 1101, 935, 846 cmꢀ1
.
Anal. Calcd for C22H37N5O7Si2: C, 48.96; H, 6.91; N, 12.98. Found:
C, 48.85; H, 6.93; N, 12.81.
4.3. (S)-3-((R)-2-((tert-Butyloxycarbonyl)amino)-2-((3R,4R)-4-
(2-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-2-oxoethyl)-2,2,5,5-
tetramethyl-1,2,5-oxadisilolan-3-yl)acetyl)-4-isopropyloxaz-
olidin-2-one 10
½
a 2D5
ꢁ
¼ ꢀ20:0 (c 1.0, CHCl3). Rf = 0.51 (CHCl3/MeOH, 95:5). 1H NMR
(200 MHz, CDCl3): d 0.10 (s, 3H, SiMe), 0.21 (s, 3H, SiMe), 0.25 (s,
3H, SiMe), 0.28 (s, 3H, SiMe), 1.02–1.34 (m, 2H, 2 ꢂ Me2SiCHCH2),
2.17 (dd, J = 12.0, 18.0 Hz, 1H, CHAHBCON), 2.54 (dd, J = 4.0,
18.0 Hz, 1H, CHAHBCON), 3.77 (s, 3H, CO2Me), 4.12 (d, J = 12 Hz,
1H, CHNH), 6.81 (s, br, 1H, NH). 13C NMR (50 MHz, CDCl3): d
ꢀ3.1, ꢀ2.5, ꢀ0.8, ꢀ0.1, 25.4, 30.2, 32.7, 52.3, 58.3, 171.9, 171.8.
IR (CHCl3 film): 3303, 3008, 2955, 2898, 1740, 1659, 1469, 1352,
1255, 1201, 1133, 1042, 927, 843 cmꢀ1. HRMS (ESI) calcd for
A catalytic amount of Pd–C (10%) was added to a solution of the
azide 9 (0.24 g, 0.44 mmol) and (Boc)2O (0.3 g, 1.4 mmol) in ethyl
acetate (8 mL) and the solution was stirred under hydrogen atmo-
sphere for 24 h at room temperature. The reaction mixture was fil-
tered through a Celite pad, and the filtrate was evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica using hexane–EtOAc (85:15) as eluent to give the
product 10 (0.25 g, 93%) as a colourless solid. Mp 147 °C (from
C
11H22NO4Si2 [M+H]+: 288.1087; found: 288.1080.
4.6. -Fagomine 1
D
hexane–EtOAc). ½a D23
ꢁ
¼ þ139:9 (c 1.07, CHCl3). Rf = 0.54 (hexane/
A solution of LAH (91 mg, 2.4 mmol) in dry ether (10 mL) was
cannulated into lactam 12 (50 mg, 0.17 mmol) at 0 °C under argon.
The reaction temperature was raised to 30 °C and then heated at
reflux for 4 h. After cooling to 0 °C, the reaction mixture was di-
luted with ether and quenched with 15% aqueous NaOH solution
and water. The reaction mixture was filtered and the residue was
washed well with ether. The combined filtrate was concentrated
and hydrogen peroxide (0.5 mL, 30%) was added to it followed by
the addition of KHF2 (90 mg, 1.2 mmol) and THF/MeOH (6 mL,
1:1) as the solvent. After 15 h at 60 °C, the solvent was evaporated
under reduced pressure and the white residue was purified by ion-
exchange resin to give pure fagomine 1 (17 mg, 68%) as a white so-
EtOAc, 75:25). 1H NMR (200 MHz, CDCl3): d 0.00 (s, 3H, SiMe),
0.15 (s, 3H, SiMe), 0.30 (s, 3H, SiMe), 0.33 (s, 3H, SiMe),
0.82–0.91 (m, 12H, 2 ꢂ NCO2CH2CHCHMe2), 1.19–1.52 (m, 2H,
2 ꢂ Me2SiCHCH2), 1.40 (s, 9H, NHBoc), 2.29–2.45 (m, 2H,
2 ꢂ NCHCHMe2), 2.63 (dd, J = 9.8, 19.0 Hz, 1H, CHAHBCON), 3.20
(dd, J = 4.4, 19.0 Hz, 1H, CHAHBCON), 4.15–4.47 (m, 6H, 2 ꢂ
NCO2CH2CH, 2 ꢂ NCHCHMe2), 5.36–5.50 (m, 2H, CHNHBoc). 13C
NMR (50 MHz, CDCl3): d ꢀ2.2, ꢀ0.9, 0.2, 1.0, 14.4, 14.6, 17.8 (2C),
19.1, 28.2 (5C), 33.1, 38.6, 52.0, 58.4, 59.1, 63.3, 64.0, 79.8, 153.4,
154.0, 155.3, 173.4, 174.7. IR (CHCl3 film): 3379, 3019, 2966,
2932, 2877, 1780, 1699, 1489, 1389, 1253, 1207, 929, 846 cmꢀ1
.
Anal. Calcd for C27H47N3O9Si2: C, 52.83; H, 7.72; N, 6.85. Found:
C, 52.92; H, 7.73; N, 6.76.
lid. ½a 2D2
ꢁ
¼ þ18:6 (c 0.43, H2O), {lit.22
½
a 2D5
ꢁ
¼ þ18:0 (c 0.92, H2O)}.
1H NMR (200 MHz, D2O): d 1.35 (dq, J = 4.4, 13 Hz, 1H), 1.80–1.95
(m, 1H), 2.46–2.64 (m, 2H), 2.91–3.04 (m, 1H), 3.09 (t, J = 9.4 Hz
1H), 3.35–3.57 (m, 2H), 3.71 (dd, J = 3.1, 12.0 Hz, 1H). 13C NMR
(125 MHz, D2O): d 32.0, 42.4, 60.7, 61.0, 72.6, 72.8.
4.4. (R)-Methyl 2-((tert-butyloxycarbonyl)amino)-2-((3R,4R)-4-
(2-methoxy-2-oxoethyl)-2,2,5,5-tetramethyl-1,2,5-oxadisilolan-
3-yl)acetate 11
4.7. (S)-3-((R)-2-Azido-2-((3S,4S)-4-(2-((S)-4-isopropyl-2-
oxooxazolidin-3-yl)-2-oxoethyl)-2,2,5,5-tetramethyl-1,2,5-
oxadisilolan-3-yl)acetyl)-4-isopropyloxazolidin-2-one 13
Potassium carbonate (138 mg, 1 mmol) was added to a solution
of 10 (0.21 g, 0.34 mmol) in methanol (8 mL) at 30 °C and stirred
for an hour. After removing the solvent under reduced pressure,
the residue was dissolved in water, acidified with dilute HCl and
extracted with ethyl acetate. The organic extract was evaporated
under reduced pressure and the residue was treated with ethereal
diazomethane. The reaction mixture was evaporated under re-
duced pressure and the residue was purified by column chroma-
tography on silica using hexane–EtOAc (85:10) as eluent to give
Following the procedure for the preparation of 9, trans-6 (2 g,
4 mmol), KHMDS (8 mL, 1 M solution in THF, 8 mmol, 2 equiv), tri-
syl azide (2.4 g, 8 mmol) and acetic acid (1.2 mL, 20 mmol) gave
azide 13 (1.6 g, 74%) as a colourless solid. Mp 125 °C (from hex-
ane–EtOAc). ½a 2D8
¼ þ35:8 (c 1.01, MeOH). Rf = 0.65 (hexane/EtOAc,
ꢁ
75:25). 1H NMR (200 MHz, CDCl3): d 0.06 (s, 3H, SiMe), 0.24 (s, 3H,
SiMe), 0.27 (s, 3H, SiMe), 0.34 (s, 3H, SiMe), 0.82–0.95 (m, 12H,
2 ꢂ NCO2CH2CHCHMe2), 1.18–1.40 (m, 1H, Me2SiCHCH2), 1.49–
1.59 (m, 1H, Me2SiCHCH2), 2.23–2.47 (m, 2H, 2 ꢂ NCHCHMe2),
2.58 (dd, J = 10.8, 18.0 Hz, 1H, CHAHBCON), 3.48 (dd, J = 5.4,
18.0 Hz, 1H, CHAHBCON), 4.05–4.59 (m, 6H, 2 ꢂ NCO2CH2CH,
2 ꢂ NCHCHMe2), 5.39 (d, J = 7.6 Hz, 1H, CHN3). 13C NMR (50 MHz,
CDCl3): d ꢀ2.3, ꢀ0.9, 0.8, 1.1, 14.4, 14.5, 17.7, 17.8, 23.2, 28.1
(2C), 33.3, 37.2, 58.2, 58.6, 61.9, 63.3, 63.9, 153.7, 154.0, 170.5,
173.2. IR (CHCl3 film): 3019, 2965, 2877, 2105, 1780, 1698, 1387,
1251, 1207, 1102, 934, 844 cmꢀ1. Anal. Calcd for C22H37N5O7Si2:
C, 48.96; H, 6.91; N, 12.98. Found: C, 49.10; H, 6.96; N, 12.96.
the product 11 (0.12 g, 84%) as a colourless liquid. ½a D25
¼ þ49:2
ꢁ
(c 1.2, CHCl3). Rf = 0.7 (hexane/EtOAc, 75:25). 1H NMR (200 MHz,
CDCl3): d 0.09 (s, 3H, SiMe), 0.11 (s, 3H, SiMe), 0.22 (s, 3H, SiMe),
0.26 (s, 3H, SiMe), 0.87–0.96 (m, 1H, Me2SiCHCH2), 1.21–1.40 (m,
1H, Me2SiCHCH2), 1.43 (s, 9H, NHBoc), 2.27 (dd, J = 9.7, 16.8 Hz,
1H, CHAHBCO2Me), 2.77 (dd, J = 5.0, 16.76 Hz, 1H, CHAHBCO2Me),
3.64 (s, 3H, CO2Me), 3.71 (s, 3H, CO2Me), 4.39–4.52 (m, 1H, NHCH),
5.29 (d, J = 8.6 Hz, 1H, NH). 13C NMR (50 MHz, CDCl3): d ꢀ2.4, ꢀ1.3,
0.6, 0.7, 22.5, 28.3 (3C), 34.3, 35.6, 51.5, 52.1, 53.2, 79.9, 155.2,
173.3, 174.3. IR (CHCl3 film): 3364, 3019, 2955, 2904, 1733,
1715, 1456, 1366, 1254, 1210, 1162, 1055, 933, 847 cmꢀ1. Anal.

P. K. Kundu, S. K. Ghosh / Tetrahedron: Asymmetry 22 (2011) 1090–1096
1095
4.8. (S)-3-((R)-2-((tert-Butyloxycarbonyl)amino)-2-((3S,4S)-4-
(2-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-2-oxoethyl)-2,2,5,5-
tetramethyl-1,2,5-oxadisilolan-3-yl)acetyl)-4-isopropyloxaz-
olidin-2-one 14
4.11. (3aS,4R,7aS)-Methyl octahydro-1,1,3,3-tetramethyl-6-oxo-
[1,2,5]oxadisilolo[3,4-c]pyridine-4-carboxylate 17
A solution of the amine 16 (0.35 g, 1.1 mmol) and pyridine
(0.3 mL) in freshly distilled p-xylene (45 mL) was gently refluxed
at 145 °C under an argon atmosphere. After 9 h, the reaction mix-
ture was evaporated under reduced pressure and the residue was
purified by column chromatography on silica using CHCl3/MeOH
(97:3) as eluent to give product 17 (0.22 g, 70%) as a colourless li-
Following the procedure for the preparation of 10, azide 13
(1.5 g, 2.8 mmol) and (Boc)2O (1.2 g, 5.5 mmol) gave protected
amine 14 (1.65 g, 96%) as a colourless solid. Mp 181 °C (from hex-
ane–EtOAc). ½a 2D8
¼ þ46:7 (c 1.01, CHCl3). Rf = 0.5 (hexane/EtOAc,
ꢁ
75:25). 1H NMR (200 MHz, CDCl3): d 0.02 (s, 3H, SiMe), 0.11 (s,
3H, SiMe), 0.27 (s, 3H, SiMe), 0.35 (s, 3H, SiMe), 0.82–0.91 (m,
12H, 2 ꢂ NCO2CH2CHCHMe2), 1.24–1.56 (m, 2H, 2 ꢂ Me2SiCHCH2),
1.40 (s, 9H, NHBoc), 2.24–2.45 (m, 2H, 2 ꢂ NCHCHMe2), 2.78 (dd,
J = 10.6, 19.2 Hz, 1H, CHAHBCON), 3.72 (dd, J = 4.6, 19.2 Hz, 1H,
CHAHBCON), 4.13–4.37 (m, 6H, 2 ꢂ NCO2CH2CH, 2 ꢂ NCHCHMe2),
4.98 (s, br, 1H, NH), 5.69–5.77 (m, 1H, CHNHBoc). 13C NMR
(50 MHz, CDCl3): d ꢀ2.5, ꢀ0.2, 0.6, 1.2, 14.4, 14.5, 17.6, 17.7,
21.8, 28.0 (3C), 28.3 (2C), 34.8, 36.9, 52.4, 58.2, 58.5, 63.2, 63.5,
79.6, 153.0, 153.7, 155.0, 173.7, 174.7. IR (CHCl3 film): 3453,
3345, 3019, 2967, 2878, 1782, 1697, 1488, 1389, 1251, 1205,
1101, 919, 844 cmꢀ1. Anal. Calcd for C27H47N3O9Si2: C, 52.83; H,
7.72; N, 6.85. Found: C, 53.03; H, 7.70; N, 6.86.
quid. ½a 2D7
ꢁ
¼ þ80:9 (c 0.88, CHCl3). Rf = 0.5 (CHCl3/MeOH, 95:5). 1H
NMR (200 MHz, CDCl3): d 0.00 (s, 3H, SiMe), 0.10 (s, 3H, SiMe), 0.20
(s, 3H, SiMe), 0.30 (s, 3H, SiMe), 1.33–1.43 (m, 1H, Me2SiCHCH2),
1.56–1.72 (m, 1H, Me2SiCHCH2), 2.16 (dd, J = 12.2, 17.7 Hz, 1H,
CHAHBCON), 2.51 (dd, J = 5.1, 17.7 Hz, 1H, CHAHBCON), 3.68 (s,
3H, CO2Me), 4.33 (dd, J = 3, 5.9 Hz, 1H, CHNH), 7.03 (s, br, 1H,
NH). 13C NMR (50 MHz, CDCl3): d ꢀ3.2, ꢀ1.7, ꢀ0.4 (2C), 19.8,
29.2, 32.7, 52.1, 55.5, 171.9, 172.9. IR (CHCl3 film): 3301, 3009,
2955, 2899, 1741, 1659, 1469, 1353, 1256, 1201, 1132, 1042,
.
925, 842 cmꢀ1 HRMS (ESI) calcd for C11H22NO4Si2 [M+H]+:
288.1087; found: 288.1094.
4.12. D-3,4-Di-epi-fagomine 3
Following the procedure for the preparation of fagomine 1, lac-
tam 17 (70 mg, 0.24 mmol), lithium aluminium hydride (100 mg,
2.6 mmol), hydrogen peroxide (0.6 mL, 30%) and KHF2 (0.11 g,
1.4 mmol) gave pure 3,4-di-epi-fagomine 3 (23 mg, 65%) as a col-
4.9. (R)-Methyl 2-((tert-butyloxycarbonyl)amino)-2-((3S,4S)-4-
(2-methoxy-2-oxoethyl)-2,2,5,5-tetramethyl-1,2,5-oxadisilolan-
3-yl)acetate 15
ourless liquid. ½a D25
ꢁ
¼ þ12:1 (c 0.33, H2O), {lit.22
½
a 2D5
ꢁ
¼ þ13:4 (c
Following the procedure for the preparation of 11, dioxazolidin-
2one 14 (1.4 g, 2.3 mmol), K2CO3 (1 g, 7.2 mmol), methanol
(30 mL) and diazomethane gave the pure product 15 (0.83 g,
0.32, H2O)}. 1H NMR (200 MHz, D2O): d 1.51–1.67 (m, 1H), 1.87–
2.06 (m, 1H), 2.90–3.02 (m, 2H), 3.16–3.27 (m, 1H), 3.58–3.66
(m, 2H), 3.66–3.74 (m, 1H), 3.79–3.88 (m, 1H). 13C NMR (50 MHz,
D2O): d 27.6, 41.0, 57.8, 62.2, 68.2, 69.3.
86%) as a colourless liquid. ½a D28
¼ ꢀ11:0 (c 1.02, CHCl3). Rf = 0.7
ꢁ
(hexane/EtOAc, 75:25). 1H NMR (200 MHz, CDCl3): d 0.10 (s, 3H,
SiMe), 0.12 (s, 3H, SiMe), 0.22 (s, 3H, SiMe), 0.30 (s, 3H, SiMe),
1.19–1.52 (m, 2H, 2 ꢂ Me2SiCHCH2), 1.43 (s, 9H, NHBoc), 2.18
(dd, J = 11.2, 16.2 Hz, 1H, CHAHBCO2Me), 2.90 (dd, J = 3.5, 16.2 Hz,
1H, CHAHBCO2Me), 3.64 (s, 3H, CO2Me), 3.73 (s, 3H, CO2Me),
4.44–4.59 (m, 1H, NHCH), 4.76 (s, br, 1H, NH). 13C NMR (50 MHz,
CDCl3): d ꢀ2.7, ꢀ0.3, 0.3, 0.6, 22.3, 28.0 (3C), 34.7, 35.1, 51.1,
51.8, 52.4, 79.8, 155.1, 173.8 (2C). IR (CHCl3 film): 3517, 3345,
3019, 2954, 2903, 1735, 1718, 1499, 1366, 1253, 1204, 1169,
936, 846 cmꢀ1. Anal. Calcd for C17H33NO7Si2: C, 48.66; H, 7.93; N,
3.34. Found: C, 48.76; H, 7.91; N, 3.41.
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ethyl)-2,2,5,5-tetramethyl-1,2,5-oxadisilolan-3-yl)acetate 16
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to give amine 16 (0.37 g, 96%) as a brown liquid. ½a D25
¼ ꢀ10:4 (c
ꢁ
1.04, CHCl3). Rf = 0.35 (hexane/EtOAc, 75:25). 1H NMR (200 MHz,
CDCl3): d ꢀ0.06 (s, 3H, SiMe), 0.04 (s, 3H, SiMe), 0.06 (s, 3H, SiMe),
0.12 (s, 3H, SiMe), 0.94–1.10 (m, 1H, Me2SiCHCH2), 1.25–1.39 (m,
1H, Me2SiCHCH2), 1.56 (s, br, 2H, NH2), 2.03 (dd, J = 11.4, 16.1 Hz,
1H, CHAHBCO2Me), 2.39 (dd, J = 5.0, 19.2 Hz, 1H, CHAHBCO2Me),
3.28 (d, J = 7.8 Hz, 1H, CHNH2), 3.49 (s, 3H, CO2Me), 3.57 (s, 3H,
CO2Me). 13C NMR (50 MHz, CDCl3): d ꢀ2.6, ꢀ0.8, 0.6, 1.2, 22.8,
34.9, 36.6, 51.2, 51.5, 54.8, 173.8, 177.4. IR (CHCl3 film): 3430,
3394, 3302, 3017, 2953, 2903, 2847, 1735, 1437, 1353, 1252,
1202, 1105, 1008, 930, 846 cmꢀ1
.

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