A short and common stereoselective approach to 5/6, 6/6, 6/7 bicyclic aza sugars

Article abstract of DOI:10.1016/j.tetasy.2009.03.038

An efficient and highly stereoselective approach to bicyclic aza sugars is described using Grignard reaction on an N-benzyl imine derived from 3-O-benzyl-1,2-O-isopropylidine-α-d-xylo-pentodialdofuranose, ring closing metathesis, and reductive cyclization

Full text of DOI:10.1016/j.tetasy.2009.03.038

Tetrahedron: Asymmetry 20 (2009) 1217–1223
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A short and common stereoselective approach to 5/6, 6/6, 6/7 bicyclic aza sugars
b
b
B. Chandrasekhar a, B. Venkateswara Rao a, , K. Veera Mohana Rao , B. Jagadeesh
*
a Organic Division III, Indian institute of Chemical Technology, Hyderabad 500607, India
b Nuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and highly stereoselective approach to bicyclic aza sugars is described using Grignard reac-
Received 10 February 2009
Accepted 10 March 2009
Available online 8 June 2009
tion on an N-benzyl imine derived from 3-O-benzyl-1,2-O-isopropylidine-a-D-xylo-pentodialdofuranose,
ring closing metathesis, and reductive cyclization as key steps.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
logues of these compounds created much interest, since the biolog-
ical activity of these compounds varies substantially with the
number, position, and stereochemistry of the hydroxy groups in
the parent skeletons.11
These reports and our interest in the area of azasugars
prompted us to explore the development of a general synthetic
method which includes considerable flexibility for the construction
of several bicyclic azasugars starting from carbohydrates.
In the past few years, our laboratory demonstrated the merit
and potency of ring-closing metathesis (RCM) in the construction
of carbocycles, azasugars, and oxygenated heterocycles from com-
mercially available starting materials.12 Earlier we utilized a stere-
oselective Grignard addition reaction on chiral imines for the
synthesis of important bioactive compounds and the combination
of a Grignard reaction on chiral imines and RCM was utilized for
the construction of polyhydroxylated pyrrolidines.12c,d,13 In order
to expand the utility of this reaction in the construction of bicyclic
iminosugars herein we report the stereoselective synthesis of acet-
yl derivatives of bicyclic azasugars (5,6), (6,6), and (6,7) such as 1-
deoxy-castanospermine 4, trihydroxy quinolizidine 5, and novel
trihydroxy pyrido-azepene 6 by using a Grignard addition on N-
benzyl amine-derived imine, ring closing metathesis, and reductive
cyclization reactions as key steps. Several approaches to 1-deoxy-
castanospermine 414 and trihydroxy quinolizidine 515 are re-
ported; to the best of our knowledge trihydroxy (6,7) bicyclic
azasugar 6 is not reported in the literature (Fig. 1).
Polyhydroxylated derivatives of nitrogen heterocycles have at-
tracted considerable interest due to their anticancer, antiviral,
and antidiabetes activities.1 Members of this class include nojiri-
mycin, 1-deoxynojirimycin (DNJ), Castanospermine, and their
derivatives. These imino sugars can inhibit various glycosidases
because of their structural resemblance to the sugar moiety of nat-
ural substrates. Possibly this specificity is connected with the sub-
stitution pattern of the a–d region and it may serve as a recognition
pattern in the substrate–enzyme interaction.2 DNJ 1 was first re-
ported to have antiviral activity against both moloney murine leuc-
amia virus and HIV-I. N-Alkyl substitution of DNJ was reported to
enhance glycosidase I inhibitor activity and the N-methyl and N-
butyl derivatives were shown to be more potent than the parent
molecule at inhibiting HIV-induced syncytia.3 N-Butyl-1-deoxy
nojirimycin 2a is an inhibitor of ceramide-specific glycosyl trans-
ferase and has been approved for the oral treatment of substrate
reduction therapy in type-I gaucher disease.4 N-Hydroxy ethenyl-
1-deoxynojirimycin 2b, which corresponds to the D-glucose config-
uration, has been approved as a second-generation glycosidase
inhibitor to treat type-II diabetes.5
The bicyclic iminosugars having a six-membered ring system
are analogues of Nojirimycin and 1-deoxy nojirimycin and are also
known to show a variety of biological activities. Castanospermine 3
isolated from castanospermum australe6 shows high anticancer,
antiviral, and anti retroviral activities.7 6-O-Butanoyl castanosper-
mine an acylated derivative of the parent compound 3 was found
to have enhanced potency against HIV and moloney murine leuc-
amia virus.8 Because of their important biological activity and
increasing popularity as new therapeutic agents, several ap-
proaches have been developed for their synthesis.9,10 In particular
the preparation of unnatural epimers and other structural ana-
2. Results and discussion
The key aspect of our strategy is the synthesis of chiral amines
9a–d and their elaboration to all of the target compounds based on
our strategy. These amines are envisaged to derive from the sugar
imine 8 by appropriate nucleophilic addition; chiral imine 8 in turn
can be obtained from aldehyde 7.16 Generally the nucleophilic
addition of organometallic reagents to carbon–nitrogen double
bonds constitutes an extremely useful method for preparing a vari-
ety of amines.17 Earlier compounds 9a and 9c are prepared by
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. Venkateswara
Rao).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.038

1218
B. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1217–1223
OR
OR
OH
OH
R
OH
OH
OH
OH
HN
N
H
N
H
N
HO
HO
HO
X
OR
OH
OH
R= n-C4H9, 2a
OH
1
3
R=H, 4
R=Ac, 4a
R= -CH2-CH2-OH, 2b
OR
OR
OR
N
Y
N
H
O
R= H, X=Y= O, 7
R= H, X=Y= NHBn, 8
O
R
OR
H
R= allyl, X= H, Y= NHBn, 9a
R= homoallyl, X= H, Y=NHBn, 9b
R= vinyl, X= NHBn, Y= H, 9c
R= homoallyl, X=NHBn, Y= H, 9d
OR
OR
O
BnO
R= H, 5
R= Ac, 5a
R= H, 6
R= Ac, 6a
Figure 1.
nucleophilic addition to nitro imine derived from aldehyde 8 with
poor diastereoselectivity;15b,18b efforts to improve the selectivity in
the presence of Lewis acids were not that successful.18 By utilizing
the above reaction Dhavale et al. developed a nice approach for the
synthesis of castanospermine, deoxy castanospermine, and other
molecules, but the above procedure requires more manipulations
to synthesize the required target as well as the separation of
isomers.15,19 Van Boom et al. and Martin et al. independently
developed nucleophilic addition onto sugar imines derived from
galactopyranose and sarbofuranose.20 After their successful ap-
proach, to the best of our knowledge, little exploitation of this reac-
tion was reported on different sugar imines. As an extension of our
earlier strategy,12c,d that is, utilization of stereoselective Grignard
addition and RCM for the synthesis of nitrogen heterocycles, it
was felt that the nucleophilic addition onto imines such as 8 would
give direct access to amines 9a–d in a single step and also that
imine 8 can be prepared conveniently from inexpensive glucose
diacetonide. In order to study the stereochemical outcome in the
Grignard reaction on imine 8 we initially under took the synthesis
of triacetoxy quinolizidine 5a.
configuration of the newly created stereogenic center in compound
9a was found to be syn whose spectral data were identical with the
reported values.15b The excellent stereoselectivity observed in this
reaction can be rationalized in terms of chelation-controlled mode
with the formation of cyclic intermediate I (Fig. 2).17 Blocking of
the re-face of the imine functionality by the O-benzyl group and
the presence of ring oxygen chelation might have helped the nucle-
ophile addition to proceed with high selectivity. Allylation of ami-
no olefin 9a under standard reaction conditions gave diene 10. This
diene 10, on reaction with Grubbs’ first generation catalyst in DCM,
afforded the desired heterocyclic ring on the sugar moiety.21 Final-
ly 1,2-O-isopropylidine deprotection of compound 11 by treatment
with aq TFA gave the corresponding lactol. In order to achieve N,O-
debenzylation, olefin reduction followed by reductive cyclization
in a single pot, the lactol was treated with reducing agents such
as Pd/C and Pd(OH)2, even in the presence of a variety of hydrogen
donors such as formic acid and ammonium formate which all
failed to give the desired bicyclic skeleton. Then we tried the re-
moval of benzyl groups and reduction of the double bond with
Pd/C on compound 11 followed by acetonide deprotection and
reductive amination with NaBH3CN, but this also gave mixtures
of compounds. Finally reacting the crude TFA treated product with
a 1:1 mixture of Pd/C, and Pd(OH)2 in dry ethanol condition22 cir-
cumvented the problem and gave bicyclic tri hydroxy quinolizidine
5 in 70% yield from compound 11 (Scheme 2). This compound was
The benzylimine 8 was prepared by condensation of aldehyde 7
with benzyl amine in the presence of 4 Å molecular sieves in DCM.
This was used as such without any purification. Treatment of imine
8 with allylmagnesium bromide at 0 °C gave the amino olefin 9a as
an exclusive diastereoisomer in 95% yield (Scheme 1). The absolute
BnHN
O
O
b
O
O
BnO
BnHN
O
O
a
n=1, 9a
n=2, 9b
O
where
O
c
O
O
BnO
BnO
BnHN
8
7
O
O
O
BnO
where n= 0, 9c
n= 2, 9d
Scheme 1. Reagents and conditions: (a) BnNH2, 4 Å molecular sieves, DCM; (b) allylmagnesium bromide, ether, 0 °C (or) homoallylmagnesium bromide, THF, 0 °C; (c)
BF3ꢀOEt2, vinylmagnesium bromide, THF, ꢁ78 °C (or) BF3ꢀOEt2, homoallylmagnesium bromide, THF, ꢁ78 °C.

B. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1217–1223
1219
NBn
NBn
BnHN
b
a
O
O
O
O
O
O
O
O
O
BnO
BnO
BnO
9a
10
11
H
f
OAc
OAc
c
H
H
j
d
N
H
n
H
h
H
N
OAc
b
g
H
e
H
H
k
H
OAc
c
H
l
H
H
5a
i
a
H
b
H
OAc
m
c
OAc
a
Scheme 2. Reagents and conditions: (a) NaH, allyl bromide, DMF, rt; (b) Grubbs’ first generation catalyst, DCM, rt; (c) (i) TFA/H2O (3:2), then H2, Pd/Pd (OH)2 (1:1), EtOH, rt;
(ii) Ac2O, Et3N, DCM, rt.
NBn
NBn
BnHN
b
a
O
O
O
O
O
O
O
O
O
BnO
BnO
BnO
9b
12
13
H
f
H
h
H
g
OAc
OAc
c
N
H
H
H
c
i
H
H
H
d
a
N
H
j
OAc
OAc
H
k
c
OAc
p
H
6a
b
OAc
a
H
H
e
l
b
H
H
o
H
n
m
Scheme 3. Reagents and conditions: (a) NaH, allyl bromide, DMF, rt; (b) Grubbs first generation catalyst, DCM, rt; (c) (i) TFA/H2O (3:2), then H2, Pd/Pd (OH)2 (1:1), EtOH, rt;
(ii) Ac2O, Et3N, DCM, rt.
characterized by converting into acetylated derivative 5a in a con-
ventional manner. In structure 5a JHn–Ha = 3.4 Hz with a strong NOE
confirms that they are spatially closer to each other with cis confor-
mation and JHn–Hm = 11.6 Hz further confirms the axial orientation
of these protons. The strong NOE cross-peaks between Hi–Hm, Hl–
Ha, Hn–Hj, Hn–Hf, Hn–Hd, and Hf–Hd support the syn relationship of
these two protons and also confirm the structure depicted in 5a.
A hybrid bicyclic (6,7) molecule 6a which is a homologue of tri-
hydroxy quinolizidine analogue 5a was also prepared from imine
8. Treatment of 8 with homoallylmagnesium bromide at 0 °C gave
syn adduct 9b as the exclusive isomer in 70% yield (Scheme 1), the
stereochemistry of this compound was not conformed at this stage.
The olefin compound was converted to novel bicyclic (6,7) azasug-
ars 6a using a similar reaction pathway, as used for compound 5a
and the stereochemistry of the newly created center in compound
6a was conformed from 2D-NMR techniques (Scheme 3). In struc-
ture 6a JHa–Hp = 5.4 Hz with strong NOE confirms that they are spa-
tially closer with a cis-conformation. The strong NOE cross-peaks
between Hb–Ho, Hb–He, He–Ho, Ha–Hc, Hp–Hg, and Hp–Hj confirm
the structure of molecule 6a.
sium bromide at various temperatures (0, ꢁ40, ꢁ78 °C) failed to
give good selectivity. The poor diasteroselectivity in this reaction
may be because of size of the reactive vinyl magnesium bromide.
In order to improve the diastereoselectivity the nucleophilic addi-
tion was conducted in the presence of Lewis acid.20 To the benzyli-
mine derivative 8 in THF was added BF3ꢀEt2O at ꢁ78 °C followed by
vinylmagnesium bromide at ꢁ78 °C to give the single diasteromer
9c in 70% yield (Scheme 1). The newly introduced stereocenter in
compound 9c was established to have the anti configuration by
comparing it with the reported values.18b The excellent stereose-
lectivity observed in this reaction can be rationalized according
to open transition state II (Fig. 2) with a rigid antiperiplanar confor-
mation due to electrostatic repulsion.20 Allylation, ring closing
metathesis, and 1,2-O-isopropylidine cleavage followed by reduc-
tive cyclization of compound 9c as described for 5a gave the de-
sired 1-deoxy castanospermine 4. This was converted to its
acetylated derivative 4a by using Ac2O, Et3N whose physical prop-
erties are in good agreement with the reported values (Scheme
4).14b Structure 4a JHk–Hl = 9.3 Hz with weak range NOE confirms
that they are spatially far and are in trans position. The observed
NOE cross-peaks between Hj–Hh, Hl–Hh, Hl–Hj, Hl–Hd, Ha–He, Ha–
Hk, and Hk–Hi support the structure of the molecule 4a with an
anti-arrangement of Hk–Hl protons.
Successfully preparing the bicyclic systems (6,6) and (6,7) the
next task was to synthesize deoxy castanospermine 4 a trihydroxy
indolizidine alkaloid. Chiral imine 8, on reaction with vinylmagne-

1220
B. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1217–1223
R
BF3
R
M
BnO
-F3B
BnO
Bn
H
BF3
Bn
BnN
N
M
O
N+
O
NBn
O
O
OBn
O
OBn
H
H
Nu
H
H
O
O
O
O
O
O
H
O
Nu
Nu
II
I
Nu
H
H
BF3
syn
anti
Figure 2.
BnHN
NBn
NBn
O
O
O
b
a
O
O
O
O
O
O
BnO
BnO
BnO
9c
14
15
H
i
k
H
e
OAc
OAc
H
c
H
N
a
g
H
H
N
OAc
a
f
c
OAc
b
H
H
OAc
H
OAc
h
c
H
b
4a
H
H
l
H
j
d
Scheme 4. Reagents and conditions: (a) NaH, allyl bromide, DMF, rt; (b) Grubbs first generation catalyst, DCM, rt; (c) (i) TFA/H2O (3:2), then H2, Pd/Pd (OH)2 (1:1), EtOH, rt;
(ii) Ac2O, Et3N, DCM, rt.
In order to observe the reversal of stereo selectivity as observed
by Martin et al.,20 the chiral imine 8 was treated with homoallyl-
magnesium bromide in the presence of BF3ꢀOEt2 at ꢁ78 °C, and
gave exclusively anti-isomer 9d (Scheme 1). Elaboration of this will
give the 10a-epimer of 6a.
rotations were measured with Horiba-SEPA-300 digital polarimeter.
Accurate mass measurement was performed on Q STAR mass spec-
trometer (Applied Biosystems, USA). The bicyclic compounds are
analyzed by using proton1D, homonuclear 1H decoupling, and 2D
NMR techniques such as DQF-COSY, TOCSY, and NOESY. Here the
conformations are fixed by considering the observed Js and NOEs.
3. Conclusion
4.1.1. N-Benzyl-(3aR,5S,6S,6aR)-6-(benzyloxy)-2,2-dimethyltet-
rahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde 8
We have developed a short and efficient route for the synthesis
of bicyclic azasugars with high stereoselectivity. This approach is
general and useful for the preparation of various analogues of bicy-
clic azasugars, that is, indolizidines, quinolizidines, azepines, and
pyrrolizidines. Its application in the synthesis of polyhydroxylated
pyrrolizidines is in progress.
To a solution of aldehyde 7 (0.9 g, 3.23 mmol) in dry CH2Cl2
(10 mL) and molecular sieves 4 Å (200 mg) was added benzyl-
amine (0.35 mL, 3.23 mmol) at room temperature and kept at
0 °C for 4 h. The reaction mixture was filtered and concentrated
to give crude imine 8, which was used as such for the next step.
4.1.2. (S)-N-Benzyl-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dim-
ethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)but-3-en-1-amine 9a
To the solution of allyl magnesium bromide prepared from Mg
(0.78 g, 32.4 mmol) and allyl bromide (1.37 mL, 16.2 mmol) in
ether (20 mL) was added the solution of chiral imine 8 (1.19 g,
3.24 mmol) in ether over 10 min at 0 °C under nitrogen. After stir-
ring overnight at room temperature, the mixture was poured into
saturated NH4Cl (50 mL) and extracted into ethylacetate
(3 ꢂ 50 mL). The collected organic layers were combined, washed
with water, brine, then dried over Na2SO4, concentrated under re-
duced pressure, and purified through column chromatography
(hexane/ethyl acetate, 8:2) affording the corresponding amino ole-
4. Experimental
4.1. General
TLC was performed on Merck Kiesel gel 60, F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on sil-
icagel(60–120mesh) usingethylacetateand hexanemixtureaselu-
ent. Melting points were determined on a Fisher John’s melting point
apparatus and are uncorrected. IR spectra were recorded on a Per-
kin–Elmer RX-1 FT-IR system. 1H NMR and 13C NMR spectra were
recorded using Bruker Avance-300 MHz, Varian-400, and 500 MHz
spectrometers. 1H NMR data are expressed as chemical shifts in
ppm followed by multiplicity (s-singlet; d-doublet; t-triplet;
q-quartet; m-multiplet), number of proton(s), and coupling con-
stant(s)J (Hz). 13C NMR chemicalshiftsare expressed in ppm. Optical
fin 9a as a yellow oil (1.25 g, 95% for two steps). ½a D30
ꢃ
¼ ꢁ55:6 (c
0.52, CHC3); IR mmax, 2925, 1636,1455, 1076, 1025 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz) d 7.4–7.14 (m, 10H), 5.88 (d, 1H, J = 4.2 Hz),
5.95–5.8 (m, 1H), 5.0 (m, 2H), 4.66 (d, 1H, J = 12 Hz), 4.57 (d, 1H,

B. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1217–1223
1221
J = 4.2 Hz), 4.43 (d, 1H, J = 12 Hz), 4.0 (dd, 1H, J = 9.1 and 3.0 Hz),
3.83 (m, 3H), 3.14 (m, 1H), 2.2 (m, 1H), 2.0 (m, 1H), 1.45, 1.3 (2s,
6H); 13C NMR (CDCl3, 75 MHz) d 140.8, 137.2, 135.3, 128.5, 128.3,
128.26, 128.0, 127.9, 126.7, 116.8, 111.5, 104.6, 82.7, 81.8, 81.6,
71.5, 55.4, 51.7, 34.8, 26.7, 26.3. ESIMS m/z: 410 [M+H]+. Hrms
(esi) Calcd for C25H32NO4 [M+H]+ 410.2331, found 410.2335.
(5 mL) at 0 °C for 12 h. The reaction mixture was diluted with
DCM (25 mL) and washed with saturated NH4Cl (25 mL), dried over
Na2SO4, and concentrated in vacuo to give crude product, which on
purification by column chromatography (hexane/ethyl acetate 7:3)
gave triacetate derivative 5a (50 mg, 70% from 11). ½a D30
ꢃ
¼ þ8:4 (c
1.3, CHCl3); IR mmax 2925, 2855, 1744, 1232, 1046 cmꢁ1
;
1H NMR
(CDCl3, 500 MHz) d 4.93 (t, 1H, JHb–Ha, Hb–Hc = 3.4 Hz, Hb), 4.87 (q,
4.1.3. (S)-N-Allyl-N-benzyl-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)but-3-en-1-
amine 10
1H, JHc–Hb, Hc–Hd = 3.4 Hz, Hc), 4.81 (t, 1H, JHa–Hn,
=
Ha–Hb
Hc–He,
3.4 Hz, Ha), 2.94 (dd, 1H, JHe–Hc = 3.4 Hz, JHe–Hd = 13.2 Hz, He), 2.88
(m, 1H, Hg), 2.50 (dd, 1H, JHd–Hc = 3.4 Hz, JHd–He = 13.2 Hz, Hd),
2.38 (dt, 1H, JHn–Hl, Hn–Ha = 3.4 Hz, JHn–Hm = 11.6 Hz, Hn), 2.13 (s,
3H, OAca), 2.12 (s, 3H, OAcb), 2.10 (m, 4H, Hf, OAcc), 1.81 (m, 1H,
Hk), 1.72 (m, 1H, Hi), 1.54 (m, 2H, Hh, Hm), 1.42 (m, 1H, Hl), 1.32
(m, 1H, Hj). 13C NMR (CDCl3, 100 MHz) d 170.4, 170.2, 168.7,
70.1, 67.9, 67.1, 59.2, 56.3, 54.0, 26.0, 24.2, 24.1, 21.3, 20.9, 20.8.
ESIMS m/z: 314 [M+H]+. Hrms (esi) Calcd for C15H24NO6 [M+H]+
314.1603, found 314.1590.
To an ice-cold solution of olefin compound 9a (0.5 g,
1.22 mmol) in DMF was added NaH (0.097 g, 2.4 mmol) after
30 min, allylbromide (0.25 mL, 2.9 mmol) was added and stirred
for 12 h at room temperature. The reaction was quenched with sat-
urated NH4Cl (25 mL) and extracted with ether (3 ꢂ 50 mL). The
combined organic layers were collected, dried (Na2SO4), filtered,
and concentrated in vacuo to give a crude oil. Purification of the
residual product by chromatography (hexane/ethyl acetate, 9:1)
afforded diene 10 in 90% yield (0.49 g). ½a D30
ꢃ
¼ ꢁ38:6 (c 0.95,
4.1.6. (S)-N-Benzyl-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)pent-4-en-1-
amine 9b
CHCl3); IR mmax 3448, 2923, 1644, 1076 cmꢁ1
;
1H NMR (CDCl3,
300 MHz) d 7.4–7.1 (m, 10H), 5.93 (d, 1H, J = 4.2 Hz), 5.87–5.72
(m, 2H), 5.12 (dd, 1H, J = 17 and 2 Hz), 4.98 (dd, 1H, J = 10 and
2 Hz), 4.92 (dd, 1H, J = 10 and 2 Hz), 4.87 (dd, 1H, J = 17 and
2 Hz), 4.64 (d, 1H, J = 12 Hz), 4.54 (d, 1H, J = 3.8 Hz), 4.40 (d, 1H,
J = 12 Hz), 4.2 (dd, 1H, J = 9.8 and 3.0 Hz), 3.87 (d, 1H, J = 13.6 Hz),
3.76 (d, 1H, J = 13.6 Hz), 3.72 (d, 1H, J = 3.0 Hz), 3.38–3.2 (m, 3H),
2.15–2.0 (m, 1H), 1.84–1.73 (m, 1H), 1.48 (s, 3H), 1.32 (s, 3H).
13C NMR (CDCl3, 75 MHz) d 141.3, 138.3, 137.4, 137.2, 129, 128.4,
127.9, 127.8, 127.5, 126.4, 115.9, 115.2, 111.3, 104.9, 82.6, 81.9,
81.2, 71.3, 56.9, 55.0, 53.3, 34.5, 26.8, 26.3. ESIMS m/z: 450
[M+H]+. Hrms (esi) Calcd for C28H36NO4 [M+H]+ 450.2644, found
450.2631.
Compound 8 was treated with homoallyl magnesium bromine
according to the procedure described for the preparation of 9a.
Purification of crude product of the reaction mixture by silica gel
column chromatography (hexane/ethyl acetate, 8:2) provided title
compound 9b as a yellow oil. (70% for two steps). ½a D30
¼ ꢁ30:5 (c
ꢃ
0.85, CHCl3); IR m
max 2923, 2854, 1644, 1076 cmꢁ1; 1H NMR (CDCl3,
300 MHz) d 7.37–7.13 (m, 10H), 5.88 (d, 1H, J = 3.8 Hz), 5.77–5.6
(m, 1H), 4.97–4.84 (m, 2H), 4.68 (d, 1H, J = 12.1 Hz) 4.57 (d, 1H,
J = 3.8 Hz), 4.42 (d, 1H, J = 11.7 Hz), 4.1 (dd, 1H, J = 9.0 and
3.0 Hz), 3.82 (d, 1H, J = 3.4 Hz), 3.77 (s, 2H), 3.13–3.04 (m, 1H),
2.2–2.1 (m, 2H), 1.46 (s, 3H), 1.3(s, 3H), 1.44–1.21 (m, 2H). 13C
NMR (CDCl3, 75 MHz) d 140.8, 138.7, 137, 128.5, 128.3, 128.2,
128, 127.9, 126.7, 114.4, 111.4, 104.6, 82.5, 81.8, 81.7, 71.6, 55.1,
51, 29.4, 29.3, 26.7, 26.2. ESIMS m/z: 424 [M+H]+. Hrms (esi) Calcd
for C26H34NO4 [M+H]+ 424.2487, found 424.2471.
4.1.4. (S)-1-Benzyl-2-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dim-
ethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-1,2,3,6-tetrahydro-
pyridine 11
Diene 10 (0.25 g, 0.55 mmol) was dissolved in dry CH2Cl2
(200 mL). Grubbs’ first generation catalyst (0.046 g, 0.055 mmol)
was added and the resulting purple solution turned brown after
10 min. The reaction mixture was stirred at room temperature for
12 h, concentrated in vacuo, and the residue was purified by column
chromatography (hexane/ethyl acetate, 8:2) to give title compound
4.1.7. (S)-N-Allyl-N-benzyl-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)pent-4-en-1-
amine 12
The olefin compound 9b was treated with NaH and allyl bromide
according to the procedure described for 10 to give compound 12 in
11 as a light brown oil (0.21 g, 90%). ½a D30
ꢃ
¼ ꢁ25:2 (c 0.25, CHCl3); IR
80% yield. ½a 3D0
¼ ꢁ57:6 (c 4.3, CHCl3); IR mmax 3068, 2927, 1639,
ꢃ
m
max 2925, 1638, 1454, 1377, 1076 cmꢁ1; 1H NMR(CDCl3, 300 MHz)d
1076 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 7.37–7.11 (m, 10H), 5.94
;
7.45–7.14 (m, 10H), 5.94 (d, 1H, J = 3.8 Hz), 5.6 (m, 2H), 4.67 (d, 1H,
J = 11.7 Hz), 4.53 (d, 1H, J = 3.8 Hz), 4.46 (dd, 1H, J = 9.8 and 3.0 Hz),
4.40 (d, 1H, J = 11.7 Hz), 3.97 (d, 1H, J = 14 Hz), 3.84 (d, 1H,
J = 14 Hz) 3.72 (d, 1H, J = 3.0 Hz), 3.52–3.42 (m, 1H), 3.22–3.07 (m,
2H), 2.46–2.33 (m, 1H), 1.73–1.6 (m, 1H), 1.45, 1.31 (2s, 6H). 13C
NMR (CDCl3, 75 MHz) d 140.4, 137.3, 128.34, 127.9, 127.8, 127.6,
126.4, 125.7, 123.5, 111.3, 105.1, 82.7, 81.1, 78.4, 71.5, 58.4, 54.3,
47.0, 29.6, 26.8, 26.3. ESIMS m/z: 422 [M+H]+. Hrms (esi) Calcd for
C26H32NO4 [M+H]+ 422.2331, found 422.2338.
(d, 1H, J = 3.7 Hz), 5.88–5.73 (m, 1H), 5.66–5.5 (m, 1H), 5.12 (d, 1H,
J = 17 Hz) 5.0 (d, 1H, J = 10 Hz), 4.84 (dd, 1H, J = 17 and 1.5 Hz),
4.78 (d, 1H, J = 10 Hz) 4.65 (d, 1H, J = 11.7 Hz), 4.53 (d, 1H,
J = 3.8 Hz), 4.37 (d, 1H, J=11.7 Hz), 4.2 (dd, 1H, J = 10.2 and 2.6 Hz),
3.87 (d, 1H, J = 13.6 Hz), 3.75 (d, 1H, J = 13.6 Hz), 3.71 (d, 1H,
J = 3.0 Hz), 3.27 (d, 2H, J = 6.4 Hz), 3.17 (dt, 1H, J = 2.6 and 11.3 Hz),
2.38–2.23 (m, 1H), 1.98–1.83 (m, 1H), 1.48 (s, 3H), 1.32 (s, 3H), 1–
0.84 (m, 2H). 13C NMR (CDCl3, 75 MHz) d 141.3, 139, 138.3, 137.1,
129, 128.3, 127.8, 127.7, 127.6, 126.2, 115.9, 113.9, 111.1, 82.4,
82.2, 81, 71.3, 56.1, 55, 53.1, 30.1, 29, 26.7, 26.2. ESIMS m/z: 464
[M+H]+. Hrms (esi) Calcd for C29H38NO4 [M+H]+ 464.2800, found
464.2798.
4.1.5. (1R,2R,3S,9aS)-Octahydro-1H-quinolizine-1,2,3-triyltriac-
etate 5a
The heterocyclic olefin compound 11 (0.1 g, 0.237 mmol) was
treated with 2 mL of TFA:H2O (3:2) at 0 °C then the reaction mix-
ture was warmed to room temperature and stirred for 3 h. Solvents
were removed by three co-evaporations with toluene (10 mL), and
the residual product was taken into dry ethanol and to it 1:1 Pd/C
and Pd(OH)2 (100 mg) was added then the flask was purged with
H2 and hydrogenated at room temperature for 48 h. The reaction
mixture was filtered and the filtrate was concentrated under
reduced pressure to give syrup, which was acetylated with Ac2O
(0.12 mL, 1.18 mmol) and Et3N (0.34 mL, 2.37 mmol) in DCM
4.1.8. (S)-1-Benzyl-2-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2,3,4,7-
tetrahydro-1H-azepine 13
The title compound 13 was obtained from 12 in 80% yield follow-
ing the procedure used for the preparation of 11. ½a D30
¼ ꢁ155:6
ꢃ
(c 0.25, CHCl3); IR mmax 2925, 1670, 1452, 1374, 1075, 1020 cmꢁ1
;
1H NMR (CDCl3, 300 MHz) d 7.4–7.1 (m, 10H), 5.94 (d, 1H,
J = 3.7 Hz), 5.81–5.7 (m, 1H), 5.47–5.37 (m, 1H), 4.68 (d, 1H,
J = 11.7 Hz) 4.58 (d, 1H, J = 3.7 Hz), 4.41 (d, 1H, J = 12 Hz), 4.2 (dd,

1222
B. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1217–1223
1H, J = 9.4 and 3.0 Hz), 3.91 (d, 1H, J = 13.6 Hz), 3.78 (d, 1H,
J = 13.6 Hz), 3.75 (d, J = 3.7 Hz), 3.47–3.28 (m, 2H), 3.03 (dd, 1H,
J = 4.9 and 17.3 Hz), 2.38–2.2 (m, 1H), 2.2–2.06 (m, 1H), 1.61–1.5
(m, 2H), 1.45 (s, 3H), 1.35 (s, 3H). 13C NMR (CDCl3, 75 MHz) d
140.7, 137.3, 131.6, 129.3, 128.9, 128.4, 128, 127.9, 127.7, 126.5,
111.2, 104.8, 82.1, 81.5, 80.5, 71.4, 63.1, 56.1, 47.1, 29.6, 27.5, 26.7,
26.3. ESIMS m/z: 436 [M+H]+.
81.6, 80.3, 71.9, 59.9, 54.7, 54.3, 26.7, 26.1. ESIMS m/z: 436
[M+H]+. Hrms (esi) Calcd for C27H34NO4 [M+H]+ 436.2487, found
436.2484.
4.1.12. (R)-1-Benzyl-2-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2,5-dihydro-
1H-pyrrole 15
Treatment of compound 14 with Grubbs’ first generation cata-
lyst following the same procedure described for 11 gave compound
4.1.9. (1R,2R,3S,10aS)-Decahydropyrido[1,2-a]azepine-1,2,3-
triyl triacetate 6a
15 as a yellow liquid in 90% yield. ½a D30
ꢃ
¼ ꢁ9:2 (c 1.2, CHCl3); IR
Compound 6a was prepared from 13 in 70% yield, following the
mmax 3063, 2985, 2928, 1452, 1376, 1076, 1021 cmꢁ1 1H NMR
;
procedure described for 5a. ½a D30
ꢃ
¼ þ3:3 (c 0.9, CHCl3); IR mmax
(CDCl3, 300 MHz) d 7.34–7.1 (m, 10H), 5.99–5.89 (m, 1H), 5.86 (d,
1H, J = 4.2 Hz), 5.8–5.7 (m, 1H), 4.62 (d, 1H, J = 11.3 Hz), 4.56 (d,
1H, J = 3.8 Hz), 4.36 (d, 1H, J = 11.7 Hz), 4.15–4.0 (m, 3H), 3.9 (dd,
1H, J = 8.7 and 3.0 Hz), 3.8–3.67 (m, 1H), 3.55 (d, 1H, J = 14.0 Hz),
3.25–3.13 (m, 1H), 1.49 (s, 3H), 1.30 (s, 3H). 13C NMR (CDCl3
100 MHz) d 140.4, 137.2, 129.8, 128.4, 128.2, 128.1, 127.8, 127.6,
127.5, 126.6, 111.5, 104.8, 84.5, 81.9, 81.4, 71.3, 68.8, 61.1, 60.2,
26.7, 26.3. ESIMS m/z: 408 [M+H]+. Hrms (esi) Calcd for
C25H30NO4 [M+H]+ 408.2174, found 408.2165.
2927, 1746, 1228, 1034 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 5.19 (t,
;
1H, JHb–Ha, Hb–Hc = 9.2 Hz, Hb), 4.95 (dd, 1H, JHa–Hp = 5.4 Hz, JHa–Hb
=
9.2 Hz, Ha), 4.87 (dt, 1H, JHc–Hd = 5.6 Hz, JHc–Hb, Hc–He = 9.2 Hz, Hc),
3.23 (m, 1H, Hp), 2.99 (dt, 1H, JHf–Hh, Hf–Hi = 4.2 Hz, JHf–Hg = 14.6 Hz,
Hf), 2.93 (dd, 1H, JHd–Hc = 5.6 Hz, JHd–He = 11.7 Hz, Hd), 2.86 (m, 1H,
Hg), 2.77 (dd, 1H, JHe–Hc = 9.2 Hz, JHe–Hd = 11.7 Hz, He), 2.04 (s, 3H,
OAc), 2.03 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.80 (m, 1H, Ho), 1.75–
1.60 (m, 4H, Hn, Hl, Hk, Hh), 1.59–1.48 (m, 3H, Hn, Ho, Hp). 13C NMR
(CDCl3, 100 MHz) d 170.2, 170.15, 170.0, 72.7, 71.1, 70.5, 59.8, 55.6,
48.0, 29.6, 26.8, 25.7, 24.3, 20.9, 20.8. ESIMS m/z: 328 [M+H]+. Hrms
(esi) Calcd for C16H26NO6 [M+H]+ 328.1760, found 328.1765.
4.1.13. 6,7,8-Triacetyl, 1-deoxy, castanospermine 4a
Triacetoxy indolizidine 4a was obtained from 15 in 70% yield
using a similar reaction sequence used for the preparation of 5a.
4.1.10. (R)-N-Benzyl-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)prop-2-en-1-
amine 9c
½
a 3D0
ꢃ
¼ þ38:3 (c 0.36, CHCl3); IR mmax 2980, 2831, 1745, 1225,
1034 cmꢁ1 1H NMR (C6D6, 500 MHz) d 5.34 (t, 1H, JHj–Hi,
;
=
Hj–Hk
9.3 Hz, Hj), 5.31 (dt, 1H, JHi–Hg = 5.0 Hz, JHi–Hj, Hi–Hh = 9.3 Hz, Hi),
5.13 (t, 1H, JHk–Hl, Hk–Hj = 9.3 Hz, Hk), 3.11 (dd, 1H, JHg–Hi = 5.0 Hz,
To the solution of vinyl magnesium bromide prepared from Mg
(0.78 g, 32.4 mmol) and vinyl bromide (1.2 mL, 16.2 mmol) in THF
(20 mL) was added the premixed solution of chiral imine 8 (1.19 g,
3.24 mmol) and BF3ꢀOEt3 (2 mL, 16.2 mmol) in THF (20 mL) over
10 min at ꢁ78 °C under nitrogen. After stirring overnight at room
temperature, the reaction was quenched with saturated NH4Cl
(50 mL) and diluted with ethyl acetate (100 mL) and washed sev-
eral times with aq NaHCO3. The collected organic layers were com-
bined, washed with water and brine, then dried over Na2SO4,
concentrated under reduced pressure, and purified through col-
umn chromatography (hexane/ethyl acetate, 8:2) to give olefin
JHg–Hh = 10.2 Hz, Hg), 2.63 (dt, 1H, JHe–Hc = 2.8 Hz, JHe–Hf,
He–
Hd = 8.5 Hz, He), 1.91 (dt, 1H, JHl–Hb = 6.5 Hz, JHl–Hk, Hl–Ha = 9.3 Hz,
Hl), 1.85 (dd, 1H, JHh–Hi = 9.3 Hz, JHh–Hg = 10.2 Hz, Hh), 1.79 (m, 1H,
Hf), 1.76 (s, 3H, OAc), 1.73 (s, 3H, OAc), 1.68 (s, 3H, OAc), 1.60 (m,
1H, Hb), 1.56–1.53 (m, 2H, Ha, Hd), 1.30 (m, 1H, Hc). 13C NMR (C6D6
100 MHz) d 169.9, 169.4 (st), 75.4, 74.6, 71.1, 65.5, 52.9, 52.7, 28.2,
22.2, 20.4, 20.38. ESIMS m/z: 300 [M+H]+. Hrms (esi) Calcd for
C14H22NO6 [M+H]+ 300.1447, found 300.1458.
4.1.14. (R)-N-Benzyl-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)pent-4-en-1-
amine 9d
9c in 70% (overall yield for two steps) as
¼ ꢁ15:1 (c 0.62, CHCl3); IR mmax 3449, 2930, 1455,
1075 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 7.32–7.12 (m, 10H), 5.85
a colorless oil.
½ ꢃ
a 3D0
;
The title compound 9d was obtained from 8 in 70% yield follow-
ing the similar procedure used for the preparation of 9c.
(d, 1H, J = 3.8 Hz), 5.82–5.67 (m, 1H), 5.3–5.2 (m, 2H), 4.68 (d,
1H, J = 11.7 Hz), 4.55–4.48 (m, 2H), 4.02 (d, 1H, J = 3.0 Hz), 3.95
(dd, 1H, J = 3.0 and 8.8 Hz), 3.82 (d, 1H, J = 13.0 Hz), 3.59–3.46
(m, 2H), 1.45 and 1.28 (2s, 6H). 13C NMR (CDCl3, 75 MHz) d
140.1, 137.57, 137.3, 128.4, 128.2, 128.0, 127.8, 127.7, 126.7,
117.8, 111.3, 104.8, 82.4, 81.7, 81.4, 71.8, 59.0, 50.9, 26.6, 26.2.
ESIMS m/z: 396 [M+H]+. Hrms (esi) Calcd for C24H30NO4 [M+H]+
396.2174, found 396.2159.
½
a 3D0
ꢃ
¼ ꢁ34:5 (c 0.575, CHCl3); IR mmax 3368, 2931, 1639, 1454,
1076 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 7.28–7.13 (m, 10H),
;
5.89–5.74 (m, 1H), 5.86 (d, 1H, J = 3.7 Hz), 5.03–4.88 (m, 2H),
4.67 (d, 1H, J = 11.7 Hz), 4.54 (d, 1H, J = 4 Hz), 4.48 (d, 1H,
J = 11.7 Hz), 4.0–3.94 (m, 2H), 3.74 (q, 2H, J = 12.8 Hz), 3.14–3.06
(m, 1H), 2.26–2.06 (m, 2H), 1.87–1.76 (m, 1H), 1.66–1.55 (m,
1H), 1.46 (s, 3H), 1.3 (s, 3H). 13C NMR (CDCl3, 75 MHz) d 140.88,
138.88, 137.31, 128.43, 128.25, 127.99, 127.86, 127.75, 126.76,
114.4, 111.3, 104.7, 82.34, 81.8, 81.67, 71.7, 54.38, 51.3, 30.29,
29.32, 26.7, 26.22. ESIMS m/z: 424 [M+H]+.
4.1.11. (R)-N-Allyl-N-benzyl-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)prop-2-en-
1-amine 14
The title compound 14 was prepared in 90% yield according to
Acknowledgments
the procedure used for the synthesis of 10. ½a D30
ꢃ
¼ ꢁ16:8 (c 0.475,
CHCl3); IR mmax 3068, 2928, 1638, 1452, 1076 cmꢁ1
;
1H NMR
B.C. and K.V. thank the CSIR, New Delhi, for research fellowship.
We also thank Dr. J.S. Yadav and Dr. A.C. Kunwar for their support
and encouragement. We also thank DST (SR/S1/OC-14/2007), New
Delhi, for financial support.
(CDCl3, 300 MHz) d 7.34–7.1 (m, 10H), 5.97–5.8 (m, 1H), 5.82 (d,
1H, J = 3.8 Hz), 5.77–5.62 (m, 1H), 5.36 (dd, 1H, J = 10.3 and
2.0 Hz), 5.20 (dd, 1H, J = 17 and 1.8 Hz), 5.06 (d, 1H, J = 16.8 Hz),
4.93 (d, 1H, J = 10.1 Hz), 4.63 (d, 1H, J = 11.9 Hz), 4.53 (d, 1H,
J = 11.9 Hz), 4.45 (d, 1H, J = 3.8 Hz), 4.24 (dd, 1H, J = 3.0 and
8.8 Hz), 3.98 (d, 1H, J = 3.0 Hz), 3.82 (d, 1H, J = 13.9 Hz), 3.7
(t, 1H, J = 8.8 Hz), 3.4 (d, 1H, J = 13.9 Hz), 3.17 (dd, 1H, J = 14.0
and 5.0 Hz), 2.96 (dd, 1H, J = 14.0 and 7.7 Hz), 1.42, 1.25 (2s, 6H);
13C NMR (CDCl3, 75 MHz) d 140.1, 137.7, 136.9, 132.9, 128.5,
128.3, 128.2, 127.6, 127.5, 126.8, 119.8, 116.9, 111.3, 104.8, 81.8,
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