Synthesis of eight-membered iminocyclitols from d-glucose

Article abstract of DOI:10.1016/j.tet.2010.02.044

The Baylis-Hillman reaction of 3-O-benzyl-α-d-xylo-pentodialdo-1,4-furanose 2 afforded a diastereomeric mixture of l-ido- and d-gluco-configurated α-methylene-β-hydroxy esters 3a and 3b, respectively, in 1:1 ratio. Conjugate addition of benzyl amine on 3a gave adduct 4a as a major product while, addition of benzyl amine to 3b gave only one diastereomer 4b. Reduction of ester functionality in 4a/4b, opening of 1,2-acetonide functionality followed by reductive amino-cyclization under hydrogenation condition afforded azocanes 1c/1d in good yield.

Full text of DOI:10.1016/j.tet.2010.02.044

Tetrahedron 66 (2010) 2830–2834
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of eight-membered iminocyclitols from -glucose
D
,
Vrushali H. Jadhav a, Omprakash P. Bande a, Vedavati G. Puranik b, Dilip D. Dhavale a
*
a Garware Research Centre, Department of Chemistry, University of Pune, Pune 411 007, India
b Center for Materials Characterization, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 January 2010
Received in revised form 5 February 2010
Accepted 9 February 2010
Available online 13 February 2010
The Baylis–Hillman reaction of 3-O-benzyl-
a
-
D
-xylo-pentodialdo-1,4-furanose
2 afforded a di-
astereomeric mixture of
L-ido- and
D-gluco-configurated
a
-methylene- -hydroxy esters 3a and 3b, re-
b
spectively, in 1:1 ratio. Conjugate addition of benzyl amine on 3a gave adduct 4a as a major product
while, addition of benzyl amine to 3b gave only one diastereomer 4b. Reduction of ester functionality in
4a/4b, opening of 1,2-acetonide functionality followed by reductive amino-cyclization under hydroge-
nation condition afforded azocanes 1c/1d in good yield.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Baylis–Hillman reaction
Conjugate addition
Iminosugars
Diastereoselectivity
1. Introduction
H
N
Ts
N
HO
HO
HO
HO
Iminocyclitol is a class of modified sugars in which ring oxygen
atom is replaced with the nitrogen. These compounds, also known
as iminosugars, are promising glycosidase inhibitors and have
therefore become therapeutically useful in the treatment of dis-
eases such as cancer,1 diabetes2 and viral infections including
AIDS.3 Amongst, monocyclic iminosugars the five-, six- and seven-
membered iminosugars have witnessed spectacular development
in the past three decades. However, no report is available on the
natural occurrence of eight-membered iminosugarsdcommonly
known as polyhydroxylated azocanes, and till date only two re-
ports are available on their synthesis. In 2004, Martin and co-
workers first reported the synthesis and biological evaluation of
1a (Fig. 1)4 and later on Chang and co-workers (in 2007) described
the synthesis of another analogue of an eight-membered imino-
sugar 1b.5 While working in the area of mono- and bi-cyclic
iminosugars,6 we exploited the Baylis–Hillman reaction with
OH
OH
HO
OH
1a
1b
H
N
H
N
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
OH
1c
OH
1d
Figure 1. Eight-membered iminosugars/azocanes.
2. Result and discussion
As shown in Scheme 1, required 3-O-benzyl-
a-D-xylo-pento-
D-glucose derived 3-O-benzyl-a-D-xylo-pentodialdose, followed by
dialdo-1,4-furanose 2 was prepared from D-glucose in 60% overall
the conjugate addition of benzyl amine and reductive amino-
cyclization, in the synthesis of new analogues of eight-
membered iminocyclitols 1c/1d. Our results in this direction are
presented herein.
yield as reported earlier.7 The Baylis–Hillman reaction of 2 with
ethyl acrylate using DABCO as a base, in 1,4-dioxane/H2O (1:1),
afforded a diastereomeric mixture of a-methylene-b-hydroxy es-
ters 3a and 3b in the ratio 1:1 as evident from the 1H NMR spec-
trum of the crude product, in 85% yield. An appreciable difference
in the Rf value allowed us to separate a diastereomeric mixture 3 by
column chromatography. Assignment of absolute configuration at
the newly generated C-5 stereocentre in 3a and 3b was made on the
basis of coupling constant information between the H-4 and H-5
protons and comparing the 1H NMR data with analogous products
* Corresponding author. Tel.: þ91 2025691727; fax: þ91 2025691728.
E-mail address: ddd@chem.unipune.ernet.in (D.D. Dhavale).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.044

V.H. Jadhav et al. / Tetrahedron 66 (2010) 2830–2834
2831
obtained by us8 in the Baylis–Hillman reaction of 3-O-allyl-
a
-
D
-
Analogously, conjugate addition of benzyl amine to
D
-gluco-
xylo-pentodialdo-1,4-furanose.9 In case of 3a, the observed small
configurated -methylene-b-hydroxy ester 3b afforded a single
a
coupling constant value (3.3 Hz) between the H-4 and H-5 in-
diastereomer 4b as thick oil in 88% yield. The stereo chemical
assignment at the newly generated C-6 stereocentre in 4b was made
bycorrelation study. Thus, reaction of4bwith phosgenein tolueneat
0 ꢀC afforded a six-membered cyclic carbamate 4c (Scheme 2)
wherein, the coupling constant information between the H-5 and H-
6 protons is diagnostic in assigning the stereochemistry at C-6. We
assume that 4c attains chair conformation 4c0 in which the bulky
sugar group (R1) preferably adopts an equatorial position with axial
orientation of the H-5. As evident from the 1H NMR and decoupling
experiments of 4c, the H-5 appeared as a doublet of doublet
(J4,5¼8.7 Hz and J5,6¼4.2 Hz) and the H-6 appeared as an apparent
quartet with J5,6¼J6,7¼4.2 Hz. The lower coupling constant between
the H-5 and H-6 indicated their relative axial–equatorial relation-
ship (axial orientation of the –COOEt group), with 6S absolute con-
figuration. As carbamate 4c is obtained from 4b, the same 6S
absolute configuration was assigned in compound 4b.
dicated the
in case of 3b, the observed large coupling constant (7.5 Hz) is in
agreement with the -gluco-configuration with 5R absolute con-
L-ido-configuration with 5S absolute configuration and
D
figuration. This assignment was confirmed by the X-ray crystallo-
graphic data of the compound obtained in the next step.
O
O
(a)
H
OBn
D-Glucose
H
O
O
2
O
(b)
HO
O
H
4
O
O
HO
H
7
O
O
6
1
5
EtO
EtO
OBn
EtO
EtO
OBn
O
H
H
O
3
O
Bn
R
6
O
O
BnN
7
O
5
3a
3b
N
O
H
a
6
H
R1
4b
O
7
5
H
H
(c)
HO
(c)
H
H
O
COOEt
4c
O
OBn
4c'
O
HO
H
H
R1 = Sugar; R = COOEt
O
O
Scheme 2. Reagents and conditions: (a) COCl2, Et3N, toluene, 0 ꢀC, 10 min, 86%.
OBn
OBn
H
H
NHBn
O
O
NHBn
O
O
4a
4b
2.1. Explanation for the observed stereoselectivity
Scheme 1. Reagents and conditions: (a) Ref. 7; (b) DABCO, ethyl acrylate, 1,4-dioxane/
H2O (1:1), rt, 48 h; (c) BnNH2. rt, 6 h.
It is interesting to note that the conjugate addition of benzyl
amine to a-methylene-b-hydroxy esters 3a and 3b was found to be
In subsequent step, conjugate addition of benzyl amine to
L-ido-
highly stereoselective affording anti-isomers 4a and 4b, re-
spectively, as a major product. This fact could be rationalized as
follows (Scheme 3). We assume that addition of benzyl amine to 3a
and 3b in a conjugate fashion will lead to the corresponding ester
enolates that exist in chair conformations A and B, due to intra-
molecular hydrogen bonding, with preferred equatorial orientation
of bulky sugar group (R1). Reversion of ester enolates A/B will give
transition states A0/B0 wherein an empty lone pair of electrons will
adopt axial orientation due to the favourable overlap of the lone
pair of electrons with the carbonyl group.12 Subsequently, the axi-
ally oriented electron lone pair in A0/B0 will take up a proton (thus
orienting the benzyl amine group equatorially) to give 4a/4b. The
sigma electrons of the axial hydrogen bond are favourably located
configurated -methylene- -hydroxy ester 3a gave an inseparable
a
b
mixture of C-6 epimeric products in the ratio 4:1 (Scheme 1) as
evident from the 1H NMR of crude product. Our attempts to sepa-
rate a mixture by flash/column chromatography were unsuccessful,
however keeping the hexane solution of C6-epimeric mixture at
0 ꢀC for 24 h afforded major isomer 4a as a colourless crystalline
solid in 70% yield.10 Single crystal X-ray analysis11 of 4a (Fig. 2)
firmly established the absolute configurations as 5S and 6R and
confirmed our earlier assignment in the Baylis–Hillman products
3a and 3b with L-ido- and D-gluco-configuration, respectively.
for overlap with the
p-electrons of the carbonyl functionality as
shown in Scheme 3. The equatorial orientation of the bulky benzyl
amine group further stabilizes the structure 4.
Targeting the synthesis of azocanes, compound 4a was reacted
with LAH and the diol thus obtained was directly subjected to se-
lective –NCbz protection, using benzyl chloroformate, to give 5a
(Scheme 4). In the final steps, hydrolysis of 1,2-acetonide function-
ality in 5a using TFA/water (3:2) gavea mixtureof hemiacetal thaton
hydrogenation using 10% Pd/C in MeOH/HCl (9:1) afforded azocane
1c as a hydrochloride salt. Similarly, reduction of ester functionality
in compound 4b with LAH gave 5b in 67% yield that on 1,2-acetonide
cleavage (TFA/water) and hydrogenation (10% Pd/C in MeOH/HCl)
afforded azocane 1d as a hydrochloride salt. All the compounds were
characterized by spectral and analytical techniques and the datawas
found to be in agreement with the structures.
In the 1H NMR spectrum of 1c, the most deshielded doublet at
d
5.10 (J1,2¼4.2 Hz) and a broad singlet at
d
4.8 (WH¼1.5 Hz), in-
Figure 2. ORTEP diagram of 4a.
tegrating in the ratio 1:1.5 were assigned to the C-1 protons of two

2832
V.H. Jadhav et al. / Tetrahedron 66 (2010) 2830–2834
OEt
OEt
R1
H
OEt
H+
O
O
H
O
NHBn
H
O
O
BnNH2
BnNH2
NHBn
NHBn
NHBn
EtO
EtO
R1
3a
O
H
R1
R1
O
O
H
NHBn
A'
4a
A
OEt
OEt
H
OEt
O
O
H
O
H
H
O
O
R1
3b
NHBn
R1
O
O
R1
O
NHBn
R1
B
H
H+
NHBn
B'
4b
R1 = sugar
Scheme 3. Plausible mechanism for observed stereoselectivity.
3. Conclusions
H
N
.HCl
OH
OH
O
OBn
H
NBn
Cbz
(a)
(b)
(c)
(c)
HO
HO
In summary, we have adroitly exploited the Baylis–Hillman
reaction with 3-O-benzyl- -xylo-pentodialdose 2 that afforded
two -methylene -hydroxy esters 3a and 3b. The conjugate
OH
4a
HO
HO
O
a-D
O
HO
1c
OH
OH
a
b
5a
addition of benzyl amine to 3a and 3b was found to be highly
stereoselective to give anti-adducts 4a and 4b, respectively, which
were elaborated to the new eight-membered iminocyclitols 1c and
1d in overall yields of 19 and 20%, respectively, from easily avail-
.HCl
H
N
OH
OH
(a)
O
4b
OBn
OH
OH
H
NHBn
5b
O
HO
O
able a-D-xylo-pentodialdose 2.
OH
1d
Scheme 4. Reaction conditions: (a) LAH, THF, 0 ꢀC to rt, 2 h.; (b) CbzCl, NaHCO3,
MeOH/H2O (4:1), rt, 12 h.; (c) (i) TFA/H2O, 0 ꢀC to rt, 2 h.; (ii) H2, Pd/C, MeOH, one drop
concd HCl, 80 psi, 12 h.
4. Experimental
4.1. General methods
Melting points were recorded with Thomas Hoover Capillary
melting point apparatus and are uncorrected. IR spectra were recor-
ded with Shimadzu FTIR-8400 as a thin film or in Nujol mull or using
anomers. The small coupling constant between the H-1 and H-2 in
both the anomers indicated the equatorial orientation of the H-2, and
based on this analogy two chair–boat conformations I and II, with
most substituents adopting quasi-equatorial orientation, were as-
1
KBr pellets and are expressed in cmꢁ1. H (300 MHz) and 13C (75/
100 MHz) NMR spectra were recorded with Varian Mercury in-
strument using CDCl3 or D2O as the solvent. Chemical shifts were
sumed for 1c (Fig. 3). In conformation I (a-anomer), the drieding
model showed dihedral angle of w90ꢀ between the axially oriented
reported ind unit(ppm) withreferencetoTMS asaninternal standard
H-1 and the equatorial H-2 accounting for a broad singlet (very small
and J values are given in hertz. Elemental analyses were carried out
with Thermo-Electron Corporation CHNS analyzer Flash-EA 1112 at
Department of Chemistry, University of Pune, Pune. Optical rotations
were measured using Bellingham Stanley-ADP 220 digital polarim-
eter with sodium light (589.3 nm) at 25 ꢀC. Thin layer chromatogra-
phy was performed on pre-coated plates (0.25 mm, silica gel 60 F254).
Visualization was made by absorption of UV light or by thermal de-
velopment after spraying with 3.5% solution of 2,4-dinitrophenylhy-
drazine in ethanol/H2SO4 and with basic aqueous potassium
permanganate solution. Column chromatography was carried out
with silica gel (100–200 mesh). Reactions were carried out in oven-
dried glassware under dry N2 atmosphere. Distilled hexane and
EtOAc were used for column chromatography. After quenching of the
reaction mixture with water, reaction workup involved washing of
the combined organic layer with water, brine, drying over anhydrous
Na2SO4 and evaporation of solvent at reduced pressure.
coupling) while; in conformation II (b-anomer) the dihedral angle of
w30ꢀ between both the equatorially oriented H-1 and H-2 explains
the coupling constant of 4.2 Hz. Thus, azocane 1c exists in D2O solu-
tion asa mixture of
1:1.5. Similarly, the 1H NMR spectra of 1d showed two most
deshielded doubletsdone at 4.58
a- and b-anomers I and II, respectively, in the ratio
d
5.18 (J1,2¼3.9 Hz) and other at
d
(J1,2¼7.8 Hz), integrating in the ratio 1:2 for two different anomeric
protons. We assumed two chair–boat conformations III and IV (with
most quasi-equatorial substituents) for 1d. A doublet at d 5.18 (for H-
1) with small coupling constant (3.9 Hz) between the H-1 and H-2
protons accounts for their equatorial and axial relationship in con-
sistencewith conformation III for a-anomer. While a doublet at d 4.58
with the large coupling constant (7.8 Hz) indicated the axial–axial
orientation for both the H-1 and H-2 accounting conformation IV for
the b-anomer. Thus,1d exists in D2O solution as a mixture of a- and b-
anomers with conformations III and IV, respectively, in the ratio 1:2.
H
4.2. Ethyl-3-O-benzyl-6-deoxy-6-methylene-1,2-O-
isopropylidene-b-L-ido-1,4-hepto-furanoate (3a) and ethyl-3-
O-benzyl-6-deoxy-6-methylene-1,2-O-isopropylidene-
gluco-1,4-hepto-furanoate (3b)
H
H
1
H
N
H
HO
HO
H
H
N
7
OH
OH
OH
OH
a-D-
H
HO
HO
4
HO
OH
2
5
H
H
HO
H
OH
HO
HO
H
H
H
H
III
I
To a solution of sugar aldehyde 2 (1.40 g, 5.03 mmol) in 1,4-di-
oxane/H2O (1:1, 50 mL) were added DABCO (0.56 g, 5.03 mmol) and
ethyl acrylate (1.51 mL, 15.10 mmol) at 30 ꢀC. Reaction mixture was
stirred for 48 h and quenched by adding saturated NH4Cl solution.
The solution was extracted with ethyl acetate (3ꢂ20 mL) and ethyl
acetate was evaporated to give crude product. Purification by col-
umn chromatography and elution first with 10% EtOAc/n-hexane
gave 3b (0.80 g, 43%) as a thick liquid. Found: C, 63.60; H, 7.01.
H
H
OH
2
OH
OH
OH
1
H
N
H
H
7
H
N
OH
H
HO
H
H
5
HO
H
HO
H
OH
H
HO
H
II
Figure 3. Conformations of 1c and 1d.
IV

V.H. Jadhav et al. / Tetrahedron 66 (2010) 2830–2834
2833
C20H26O7 requires C, 63.48; H, 6.93; Rf (30% EtOAc/n-hexane) 0.6;
4.5. 3-O-Benzyl-6,7-dideoxy-7-N-benzylamino-6(S)-
carboethoxy-[7-N,5-O-carbonyl]-a-D-gluco-hepto-1,4-
furanose (4c)
25
[
a]
ꢁ10.5 (c 0.023, CHCl3); IR (neat) 3200–3600 (br), 1713,
D
1630 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.31 (3H, s, CH3), 1.31 (3H, t,
J¼7.2 Hz, OCH2CH3), 1.47 (3H, s, CH3), 2.90–3.60 (1H, br s, ex-
changeable with D2O), 4.10 (1H, d, J¼3.3 Hz, H-3), 4.23 (2H, q,
J¼7.2 Hz, –OCH2CH3), 4.39 (1H, dd, J¼7.5 and 3.3 Hz, H-4), 4.57 (1H,
d, J¼11.4 Hz, –OCH2Ph), 4.58 (1H, d, J¼3.6 Hz, H-2), 4.69 (1H, d,
J¼11.4 Hz, –OCH2Ph), 4.77 (1H, d, J¼7.5 Hz, H-5), 5.87 (1H, br s,
C]C), 5.93 (1H, d, J¼3.6 Hz, H-1), 6.33 (1H, br s, C]C), 7.20–7.40
To a solution of compound 4b (0.2 g, 0.4 mmol) in dry toluene were
added Et3N (0.07 g, 0.8 mmol) and phosgene (0.27 mL, 0.6 mmol) at
0 ꢀC and allowed to stir for 10 min. The reaction mixture was then
quenched by adding saturated NH4Cl (5 mL). Toluene was then evap-
orated and the reaction mixture was extracted with ethyl acetate
(1ꢂ10 mL) and ethyl acetate was evaporated to give the crude product,
which was purified by column chromatography (10% EtOAc/n-hexane)
(5H, m, Ar–H); 13C NMR (75 MHz, CDCl3)
d 14.2, 26.4, 26.8, 60.9,
69.7, 72.5, 80.1, 82.0, 82.4, 105.0, 111.7, 127.5, 127.7, 128.0, 128.4 (s),
137.0, 137.5, 139.1, 166.2. Further elution with 15% EtOAc/n-hexane
afforded 3a (0.79 g, 42%) as a thick liquid. Found: C, 63.55; H, 7.10.
to give 4c (0.18 g, 86%) as a thick liquid. Found: C, 65.70; H, 6.60.
25
C28H33NO8 requires C, 65.74; H, 6.50; Rf (20% EtOAc/n-hexane) 0.5; [a]
D
1
C20H26O7 requires C, 63.48; H, 6.93; Rf (30% EtOAc/n-hexane) 0.59;
ꢁ29.7 (c 1.10, CHCl3); IR (neat) 1749, 1715 cmꢁ1; H NMR (300 MHz,
25
[
a
]
ꢁ39.1 (c 0.006, CHCl3); IR (neat) 3200–3600 (br), 1713,
CDCl3)
d
1.22 (3H, t, J¼7.2 Hz, OCH2CH3), 1.30 (3H, s, CH3), 1.39 (3H, s,
D
1634 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.28 (3H, t, J¼7.2 Hz,
CH3), 3.11 (1H, q, J¼4.2 Hz, H-6), 3.40 (1H, dd, J¼12.3, 5.4 Hz, H-7a), 3.60
(1H, dd, J¼12.3, 3.3 Hz, H-7b), 4.00–4.25 (4H, m, H-3, H-4, OCH2CH3),
4.41 (1H, d, J¼14.4, OCH2Ph), 4.59 (1H, d, J¼3.6 Hz, H-2), 4.65–4.83 (3H,
m, OCH2Ph, NCH2Ph), 5.11 (1H, dd, J¼8.7, 4.2 Hz, H-5), 5.85 (1H, d,
J¼3.6 Hz, H-1), 7.25–7.42 (10H, m, Ar–H); 13C NMR (75 MHz, CDCl3)
OCH2CH3), 1.32 (3H, s, CH3), 1.46 (3H, s, CH3), 3.40–3.90 (1H, br s,
exchangeable with D2O), 4.09 (1H, d, J¼3.3 Hz, H-3), 4.18 (2H,
q, J¼7.2 Hz, OCH2CH3), 4.47 (1H, t, J¼3.3 Hz, H-4), 4.51 (1H, d,
J¼11.7 Hz, –OCH2Ph), 4.64 (1H, d, J¼3.9 Hz, H-2), 4.73 (1H,
d, J¼11.7 Hz, –OCH2Ph), 4.88 (1H, d, J¼3.0 Hz, H-5), 6.00 (1H, d,
J¼3.9 Hz, H-1), 6.05 (1H, br s, C]C), 6.38 (1H, br s, C]C), 7.25–7.44
d
14.0, 26.2, 27.0, 39.9, 43.8, 52.9, 61.7, 73.0, 73.5, 79.2, 81.1, 82.5, 105.2,
112.2, 127.8, 128.0, 128.2, 128.5, 128.7, 136.0, 137.3, 152.2, 169.8.
(5H, m, Ar–H); 13C NMR (75 MHz, CDCl3)
d 14.5, 26.8, 27.2, 61.1, 68.9,
72.5, 80.2, 82.5, 84.3, 105.2, 112.2, 127.8, 128.0 (s), 128.5, 128.9(s),
136.7, 138.7, 166.1.
4.6. 3-O-Benzyl-6-deoxy-6(S)-(N-benzyl-N-benzyloxy-
carbonylamino-methyl)-1,2-O-isopropylidene-a-L-ido-1,4-
hepto-furanose (5a)
4.3. Ethyl-3-O-benzyl-6-deoxy-6(R)-(N-benzylaminomethyl)-
1,2-O-isopropylidene-a-L-ido-1,4-hepto-furanoate (4a)
To a solution of lithium aluminium hydride (0.082 g, 2.16 mmol)
in THF (10 mL) at 0 ꢀC was added compound 4a (0.7 g, 1.44 mmol)
and the resulting reaction mixture was stirred at 0 ꢀC to room
temperature for 2 h. The reaction mixture was quenched by adding
saturated NH4Cl (5 mL). The reaction mixture was filtered through
Celite and washed with ethyl acetate. Now to this aminodiol in
methanol/water (9 mL, 8:1), benzyl chloroformate (0.37 mL,
2.16 mmol) was added along with sodium bicarbonate (0.36 g,
4.32 mmol) at 0 ꢀC and stirred for 12 h. Methanol was evaporated
under reduced pressure and the residue was extracted with ethyl
acetate (1ꢂ20 mL). Usual workup and purification by column
chromatography (25% EtOAc/n-hexane) gave 5a (0.57 g, 77%) as
To compound 3a (0.7 g, 1.85 mmol) was added benzyl amine
(0.3 mL, 2.77 mmol) and stirred for 6 h at rt. After completion of the
reaction, the reaction mixture was directly adsorbed on silica and
purified by column chromatography (20% EtOAc/n-hexane) to give
4a and 4a0 as a mixture of solid and liquid (0.77 g, 86.5%). After
keeping the mixture of 4a and 4a0 in hexane at 0 ꢀC for 24 h, solid
4a crystallized out. Found: C, 66.83; H, 7.00. C27H352N5 O7 requires C,
66.79; H, 7.27; Rf (40% EtOAc/n-hexane) 0.5; [
CHCl3); IR (neat) 3200–3600 (br), 1713 cmꢁ1 1H NMR (300 MHz,
CDCl3)
1.28 (3H, t, J¼7.2 Hz, OCH2CH3),1.37 (3H, s, CH3),1.50 (3H, s,
a]
ꢁ22.5 (c 0.6,
D
;
d
a thick liquid. Found: C, 68.40; H, 6.66. C33H39NO8 requires C, 68.61;
CH3), 2.61 (1H, m, H-6), 2.83 (1H, dd, J¼12.0, 6.0 Hz, H-7a), 3.07 (1H,
dd, J¼12.0, 4.2 Hz, H-7b), 3.77 (2H, ABq, J¼13.5 Hz, –NCH2Ph), 3.90–
4.27 (3H, m, OCH2COOEt, H-3), 4.29 (1H, dd, J¼6.6, 3.3 Hz, H-4), 4.36
(1H, dd, J¼6.6, 3.3 Hz, H-5), 4.48 (1H, d, J¼11.7 Hz, –OCH2Ph), 4.68
(1H, d, J¼3.9 Hz, H-2), 4.74 (1H, d, J¼11.7 Hz, –OCH2Ph), 6.03 (1H, d,
J¼3.9 Hz, H-1), 7.20–7.40 (10H, m, Ar–H); 13C NMR (75 MHz, CDCl3)
25
H, 6.80; Rf (50% EtOAc/n-hexane) 0.5; [
a
]
ꢁ29.2 (c 1.6, CHCl3); IR
D
(neat) 3442, 3350,1689 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.30 (3H,
s, CH3), 1.50 (3H, s, CH3), 3.20–4.20 (8H, m), 4.30–4.80 (5H, m), 5.14
(2H, br s, NCOOCH2), 6.01 (1H, d, J¼3.6 Hz, H-1), 7.20–7.40 (15H, m,
Ar–H); 13C NMR (75 MHz, CDCl3)
d 26.4, 28.2, 41.5, 50.8, 60.3, 67.6,
70.2, 71.9, 80.5, 81.9, 83.7, 104.9, 111.9, 127.3, 127.4, 127.5, 127.7,
127.9, 128.1, 128.2, 128.4, 128.5, 128.7, 136.3, 136.7, 137.4, 157.3.
d
14.2, 26.5, 26.9, 46.7, 49.3, 54.1, 60.7, 71.6, 71.7, 81.1, 82.1, 82.8,
105.1, 111.8, 127.1, 127.8, 128.1, 128.4, 128.6, 136.9, 139.7, 172.9.
4.7. 3-O-Benzyl-6-deoxy-6(R)-N-benzyl-methylene-1,2-O-
4.4. 3-O-Benzyl-6-deoxy-6(S)-(N-benzylaminomethyl)-1,2-O-
isopropylidene-a-D-gluco-hepto-1,4-furanose (5b)
isopropylidene-a-D-gluco-1,4-hepto-furanoate (4b)
To a solution of lithium aluminium hydride (0.082 g, 2.16 mmol) in
THF (10 mL) at 0 ꢀC was added compound 4b (0.7 g, 1.44 mmol) and
the resulting reaction mixture was stirred at 0 ꢀC to room temperature
for 2 h. The reaction mixture was quenched byadding saturated NH4Cl
(5 mL). The reaction mixture was filtered through Celite and washed
with ethyl acetate, which was purified by column chromatography
(80% EtOAc/n-hexane) to give 5b (0.42 g, 67%) as a thick liquid. Found:
Reaction of 3b (0.7 g, 1.85 mmol) with benzyl amine (0.3 mL,
2.77 mmol) as described for 4a gave after column purification (20%
EtOAc/n-hexane) 4b (0.79 g, 88.7%) as a thick liquid. Found: C, 66.90;
H, 7.01. C27H35NO7 requires C, 66.79; H, 7.27; Rf (40% EtOAc/n-hexane)
25
0.5; [
a
]
ꢁ61.39 (c 0.25,CHCl3); IR (neat) 3200–3600 (br),1713 cmꢁ1
;
D
1H NMR (300 MHz, CDCl3)
d
1.28 (3H, t, J¼7.2 Hz, OCH2CH3),1.30 (3H,
s, CH3), 1.38 (3H, s, CH3), 2.80–2.86 (1H, m, H-6), 2.92 (1H, dd, J¼12.6,
3.3 Hz, H-7a), 3.32 (1H, br d, J¼12.6, 1.8 Hz, H-7b), 3.76 (2H, ABq,
J¼13.2 Hz, –NCH2Ph), 4.02(1H, dd, J¼10.0, 2.7 Hz, H-4), 4.15–4.35(3H,
m, H-3, OCH2CH3), 4.56 (1H, d, J¼3.6 Hz, H-2), 4.60 (1H, dd, J¼10.0,
2.7 Hz, H-5), 4.72 (2H, ABq, J¼12.0 Hz, –OCH2Ph), 5.86 (1H, d,
J¼3.6 Hz, H-1), 7.17–7.42 (10H, m, Ar–H); 13C NMR (75 MHz, CDCl3)
C, 67.5; H, 7.30. C25H33NO6 requires C, 67.70; H, 7.50; Rf (100% EtOAc)
25
0.2; [
a
]
ꢁ51.84 (c 0.05,CHCl3); IR (neat) 3400–3600 cmꢁ1 (OH); 1H
D
NMR (300 MHz, CDCl3) d 1.27 (3H, s, CH3),1.38(3H, s, CH3), 1.94 (2H, s),
2.03 (2H, br s, exchangeable with D2O), 3.11 (2H, s), 3.80–3.95 (3H, m),
3.98 (1H, dd, J¼8.7, 2.7 Hz, H-4), 4.06 (1H, d, J¼2.7 Hz, H-3), 4.15 (1H,
dd, J¼8.7, 3.9 Hz, H-5), 4.52(1H, d, J¼3.6 Hz, H-2), 4.63 (2H, s, OCH2Ph),
5.20–5.60 (1H, br s, exchangeable with D2O), 5.82 (1H, d, J¼3.6 Hz, H-
d
14.2, 26.3, 27.1, 45.1, 46.3, 54.2, 60.9, 70.1, 72.9, 81.1, 81.5, 82.9,105.0,
111.6, 127.2, 127.6 (s), 128.0 (s), 128.2 (s), 128.4 (s), 137.7, 138.8, 173.8.
1), 7.31 (10H, s, Ar–H); 13C NMR(75 MHz, CDCl3)
d 26.2, 26.9, 40.4, 47.4,

2834
V.H. Jadhav et al. / Tetrahedron 66 (2010) 2830–2834
52.5, 64.1, 69.9, 72.5, 80.6, 81.5, 82.1,104.9,111.6,127.7, 127.8, 128.4 (s),
128.8 (s), 128.9 (s), 133.3, 137.3.
References and notes
1. (a) Truscheit, E.; Frommer, W.; Junge, B.; Muller, L.; Schmidt, D. D.; Wingender, W.
Angew. Chem., Int. Ed. Engl. 1981, 20, 744; (b) Furneaux, R. H.; Gainsford, G. J.;
Mason, J. M.; Tyler, P. C.; Hartley, O.; Winchester, B. G. Tetrahedron 1997, 53, 245.
2. Humphries, M. J.; Matsumoto, K.; White, S. L.; Olden, K. Cancer Res. 1986, 46,
5215.
3. (a) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.;
Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1988,
85, 9229; (b) Walker, B. D.; Kowalski, M.; Goh, W. C.; Kozarsky, K.; Krieger, M.;
Rosen, C.; Rohrschneider, L.; Haseltine, W. A.; Sodroski, J. Proc. Natl. Acad. Sci.
U.S.A. 1987, 84, 8120; (c) Sunkara, P. S.; Bowling, T. L.; Liu, P. S.; Sjoerdsma, A.
Biochem. Biophys. Res. Commun. 1987, 148, 206.
4.8. Azocane-7-(hydroxymethyl)-(3R,4S,5R,6S,7S)-2,3,4,5,6-
pentanol (1c)
A solution of 5a (0.2 g, 0.35 mmol) in TFA/H2O (3 mL, 2:1) was
stirred at 25 ꢀC for 2 h and trifluoroacetic acid was co-evaporated
with benzene to furnish a thick liquid. To a solution of above prod-
uct in methanolic hydrochloric acid (5 mL, 9:1) was added 10% Pd/C
(0.1 g). The solutionwas hydrogenated at 80 psi for 12 h. The catalyst
was filtered through Celite and washed with methanol. The filtrate
was concentrated and purified by column chromatography (70%
MeOH/CHCl3) to give 1c (0.08 g, 88%) as a semisolid. Found: C, 37.50;
4. Godin, G.; Garnier, E.; Compain, P.; Martin, O. R.; Ikeda, K.; Asano, N. Tetrahe-
dron Lett. 2004, 45, 579.
5. Chang, M. K.; Kung, Y. H.; Ma, C. C.; Chen, S. T. Tetrahedron 2007, 63, 1339.
6. (a) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org. Chem. 2001, 66, 1065; (b)
Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; Prakashareddy, J. J. Org. Chem.
2004, 69, 4760; (c) Karanjule, N. S.; Markad, S. D.; Shinde, V. S.; Dhavale, D. D. J.
Org. Chem. 2006, 71, 4667; (d) Karanjule, N. S.; Markad, S. D.; Dhavale, D. D. J.
Org. Chem. 2006, 71, 6273; (e) Bande, O. P.; Jadhav, V. H.; Puranik, V. G.; Dhavale,
D. D. Tetrahedron: Asymmetry 2007, 18, 1176; (f) Vyavahare, V. P.; Chattopadhyay,
S.; Puranik, V. G.; Dhavale, D. D. Synlett 2007, 559; (g) Bande, O. P.; Jadhav, V. H.;
Puranik, V. G.; Dhavale, D. D.; Lombardo, M. Tetrahedron Lett. 2009, 50, 6906;
(h) Bande, O. P.; Jadhav, V. H.; Puranik, V. G.; Dhavale, D. D. Synlett 2009, 1959
and references cited therein.
H, 7.30. C8H18ClNO6 requires C, 37.00; H, 6.99; Rf (50% CHCl3/MeOH)
25
0.25; [
a
]
D
þ46.8 (c 0.17, MeOH); IR (neat) 3200–3600 (br) cmꢁ1; 1H
NMR (300 MHz, D2O) for major isomer
d 1.50–1.80 (1H, m), 3.20–
3.37 (2H, m), 3.38–3.52 (2H, m), 3.61–3.88 (2H, m), 4.15–4.24 (1H,
m), 4.26–4.43 (1H, m), 4.85 (1H, br s); 13C NMR (100 MHz, D2O) for
major isomer d 39.3, 40.8, 55.5, 69.2, 74.8, 76.4, 79.6, 101.7.
7. Wolfrom, M. L.; Hanessian, S. J. Org. Chem. 1962, 27, 1800.
8. Jadhav, V. H.; Bande, O. P.; Pinjari, R. V.; Gejji, S. P.; Puranik, V. G.; Dhavale, D. D.
J. Org. Chem. 2009, 74, 6486.
9. In case of the Baylis–Hillman adducts, obtained from 3-O-methyl-
pentodialdo-1,4-furanose, the compound with large coupling constant
(J4,5¼8.9 Hz) was assigned the -ido-configuration and the product having
-gluco-configuration
see: (a) Radha Krishna, P.; Kannan, V.; Sharma, G. V. M.; Ramana Rao, M. H.
V. Synlett 2003, 888; (b) Radha Krishna, P.; Manjuvani, A.; Kannan, V. Tet-
rahedron: Asymmetry 2005, 16, 2691 An opposite trend was noticed in case
of 3a and 3b. However, we have unambiguously assigned the configurations
at C5 and C6 by single crystal X-ray data of subsequent Michael addition
a-D-xylo-
4.9. Azocane-7-(hydroxymethyl)-(3R,4S,5R,6R,7R)-2,3,4,5,6-
pentanol (1d)
L
small coupling constant (J4,5¼5.9 Hz) was assigned the
D
Reaction of 5b (0.2 g, 0.45 mmol) with TFA/H2O (3 mL, 2:1), 10%
Pd/C (0.1 g) and column purification (70% MeOH/CHCl3) gave 1d
(0.11 g, 84%) as a semisolid. Found: C, 37.25; H, 7.23. C8H18ClNO6 re-
25
quires C, 37.00; H, 6.99; Rf (MeOH/CHCl3) 0.25; [
a
]
þ23.9 (c 0.021,
D
product. In case of the Baylis–Hillman adduct 3a with
observed small coupling constant J4,5¼3.0 Hz, while large coupling constant
-gluco configurated product.
L-ido configuration, we
MeOH); IR (neat) 3200–3600 (br) cmꢁ1; 1H NMR (300 MHz, D2O) for
major isomer 2.30–2.42 (1H, m), 3.12–3.35 (2H, m), 3.39–3.42 (2H,
J4,5¼7.5 Hz was observed for the
D
d
10. The minor isomer was all the time contaminated with the major compound.
11. The crystallographic data have been deposited with the Cambridge Crys-
tallographic Data Centre as deposition no. CCDC-761145 (4a). Copies of the
data can be obtained, free of charge, on application to the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: þ44 1223 336033; e-mail: deposit@ccdc.
cam.ac.uk].
m), 3.43–3.62 (1H, m), 3.65 (1H, br d, J¼9.6 Hz), 3.77–3.88 (2H, m),
4.58 (1H, d, J¼7.8 Hz); 13C NMR (75 MHz, D2O) for the major isomers
d
37.8, 38.1, 61.6, 70.5, 74.2, 74.5, 75.9, 96.4.
12. We have extrapolated the 1H NMR analogy of six-membered chair confor-
mation system wherein; equatorial proton is deshielded as compared to the
axial proton and the axial–axial proton coupling is larger than the axial–
equatorial or equatorial–equatorial. Jackman, L. M.; Sternehell, S. Application
of nuclear magnetic resonance spectroscopy in organic chemistry; International
Series in Organic Chemistry, 2nd ed.; University of California: Pergamon,
1969; Vol. 10, pp 238–248 and 280–300.
Acknowledgements
We are thankful to the UGC, New Delhi, for Senior Research
Fellowship to V.H.J. and University of Pune, Pune for the financial
support under BCUD Seed Money project (2009).