Intramolecular Michael addition of benzylamine to sugar derived α,β-unsaturated ester: A new diastereoselective synthesis of a higher homologue of 1-deoxy-L-ido-nojirimycin

Article abstract of DOI:10.1039/a905440e

The diastereoselective intramolecular Michael addition of the benzylamine generated in situ from hemiacetal 3 leads to the lactone 4a with the required homoazasugar ring skeleton; reduction of the lactone functionality and removal of the protecting groups

Full text of DOI:10.1039/a905440e

Intramolecular Michael addition of benzylamine to sugar derived
a,b-unsaturated ester: a new diastereoselective synthesis of a higher homologue
of 1-deoxy-l-ido-nojirimycin
Vijaya N. Desai, Nabendu N. Saha and Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, University of Pune, Pune - 411 007, India.
E-mail: ddd@chem.unipune.ernet.in
Received (in Cambridge, UK) 6th July 1999, Accepted 23rd July 1999
The diastereoselective intramolecular Michael addition of
the benzylamine generated in situ from hemiacetal 3 leads to
the lactone 4a with the required homoazasugar ring skel-
eton; reduction of the lactone functionality and removal of
the protecting groups afford 1-deoxy-L-ido-homonojirimy-
cin.
at the anomeric carbon and concomitant intramolecular con-
jugate addition should lead to the homoazasugar ring skeleton.
Reduction of the ester group and removal of the protecting
groups should lead the target molecule. Although the intra-
molecular Michael addition of amines to a,b-unsaturated
carbonyl compounds is widely utilized in the synthesis of
polyhydroxylated pyrrolidenes and piperidine derivatives,5 its
application to the homoazasugars is highly restricted.6
Naturally occurring polyhydroxylated piperidine alkaloids such
as nojirimycin and mannonojirimycin are glycosidase inhibitors
of great potential therapeutic value.1 In order to examine the
structure–activity relationship, a number of synthetic analogues
of nojirimycin have been synthesised and evaluated for
glycosidase inhibition in the treatment of various diseases such
as diabetes, cancer, AIDS and viral infections. This includes
synthesis of 6-deoxynojirimycin,2a 1-deoxynojirimycin,2b N-
alkyl nojirimycin2c and N-linked disaccharide units.2d In recent
years, preparation and evaluation of homoazasugars with a CH2
homologation either at C-1 or in the C-5 side chain and
nojirimycin with d and l sugar derivatives have received much
attention.3 As a part of our continuing efforts in the synthesis of
nojirimycin analogues4 we report herewith the synthesis of a
one carbon higher (in the C-5 side chain) homologue of
1-deoxy-l-ido-nojirimycin 6. We envisioned that the removal
of the 1,2-O-isopropylidene in the d-glucose derived a,b
unsaturated ester 2 (Scheme 1) followed by reductive amination
Our synthetic route involves 2 as the starting compound,
which was prepared in high yield from d-glucose. Thus, the
Wittig reaction7 of a-d-xylo-pentodialdose8
1
with
PPh3CHCO2Et gave an isomeric mixture of 2 (E:Z = 73+27)
which was separated by chromatography to afford 2a (E, 64%)
and 2b (Z, 24%). The cleavage of acetonide group in 2a
afforded hemiacetal 3 (anomeric mixture, a:b = 7+3) with an
exclusively E geometry at the double bond.† The one pot
reaction of 3 with BnNH2 (1.0 equiv.) in the presence of
catalytic amounts of AcOH in MeOH followed by treatment
with NaCNBH3 afforded a lactone 4a as the only isolable
product (Scheme 1). Thus, the overall three step transformation
presumably involves amine as the primary reaction product
which undergoes concomitant intramolecular Michael addition
and domino9 lactonisation to yield diastereoselective formation
of 4a in 79% yield. The lactone 4a was acetylated with Ac2O in
pyridine to give 4b (78%).‡ The spectroscopic and analytical
data obtained for 4a and 4b were in full accord with the assigned
structures.§ The configuration at C-5 and conformation of 4a
and 4b were determined from their high field 1H NMR spectra
based on the coupling constant values. The initial geometry
ensures that, in the product, the substituents at C-2, C-3 and C-3,
C-4 should be trans. The low values of J3,2 ( ~ 6.4 Hz) and J3,4
( ~ 4.3 Hz) indicate that the protons at these carbons are
equatorial and the substituents are axial. This suggests that the
bicyclic lactones have the 1C4 conformation. The small value of
J5,4 ( ~ 5.3 Hz) along with the axial orientation of the C-4
hydroxy group suggests that the C-5 substituent is equatorial
with the (5S) configuration. This confirms that the six
membered piperidine ring is cis fused with the lactone ring.
The diastereoselective formation of 4a can be explained by
considering the transition states A and B (Fig. 1). In general, the
stereoelectronic and steric factors often play an integral role in
affecting the stereochemical outcome of the intramolecular
Michael addition reactions.10 However we believe that, under
the reaction conditions of borohydride reductive amination and
in situ Michael addition, the complexation of boron with
nitrogen and the C-2 and C-4 hydroxy groups determines the
Scheme 1 Reagents and conditions i, ref 8; ii, PPh3CHCO2Et (1.3 equiv.),
MeCN, reflux, 2 h; iii, TFA–H2O (3+2), rt, 2 h; iv, BnNH2 (1.0 equiv.),
NaCNBH3 (2.0 equiv.), AcOH (0.2 equiv.), MeOH, 278 °C, 2 h, rt, 24 h;
v, Ac2O, pyridine, DMAP, rt, 24 h; vi, LAH (3.0 equiv.), dry THF, 0 °C to
rt, 2 h; vii, 10% Pd/C, HCO2NH4, MeOH, reflux, 1 h.
Fig. 1
Chem. Commun., 1999, 1719–1720
1719

amine addition.5 Thus, the complexation of the boron with the
C-2,4 hydroxy and amine groups holds the nitrogen atom in
such a way that the preferred Si face attack at the diastereotopic
b-carbon atom, as shown in transition state A (Fig. 1), leads to
the formation of 4a.¶ However, transition state B (Fig. 1), in
which Re face attack leads to the formation of the other isomer,
is destabilised due to the non-bonded interactions of the a-
olefinic hydrogen with the C-1 axial hydrogen and C-3 O-
benzyl group.
In the subsequent steps, lactone 4a was reduced with LAH in
Et2O, and the primary alcohol 5a (colorless solid, 84%) thus
obtained was peracetylated to afford 5b (80%).∑ In the 1H NMR
spectra of 5a and 5b, H-3 showed a double doublet with large
coupling constants (J2,3 and J3,4 ~ 8.8 Hz).§ This indicated the
axial–axial relationship of H-3 with H-2 and H-4, confirming
the change in conformation of piperidine ring from 1C4 to 4C1.
Finally, removal of the benzyl groups in 5a was achieved in one
step using HCO2NH4 and 10% Pd/C in MeOH to give 1-deoxy-
l-ido-homonojirimycin 6 (90%). The 1H and 13C NMR spectra
and analytical data are in agreement with the proposed structure
with the 4C1 conformation.§
In conclusion, the one pot reaction sequence of introduction
of amine functionality and concomitant intramolecular con-
jugate addition to d-glucose derived a,b-unsaturated ester
provides a unique strategy for the synthesis of homoazasugars.
Easy availability of starting materials, mild reaction conditions,
high diastereoselectivity and good yields make the route
attractive and indicate that it could operate on a gram scale.
Work is in progress to study the intermolecular Michael
addition of amines to 2 and its applications to the synthesis of
homoazasugars and indolizidine alkaloids.
(1H, q, J 6.6, 5-H), 3.74 (1H, dd, J 6.2, 6.9, 3-H), 3.78 (1H, d, J 14.0,
NCH2Ph), 4.52 (1H, dd, J 6.6, 6.9, 4-H), 4.68 (1H, d, J 11.7, OCH2Ph), 4.76
(1H, d, J 11.7, OCH2Ph), 4.93 (1H, m, 2-H), 7.24–7.37 (10H, m, Ar-H);
dC(CDCl3, 125 MHz) 21.0, 31.0, 48.4, 57.4, 58.6, 69.4, 73.2, 75.7, 80.1,
127.7, 127.8, 128.0, 128.41, 128.5, 128.6, 137.0, 137.6, 170.3, 174.6 (Calc.
for C23H25NO5: C, 69.85; H, 6.37. Found: C, 69.72; H, 6.15%). For 5a:
white solid, mp 105–107 °C, [a]D 23.66 (c 0.5, CHCl3); nmax(Nujol)/cm21
3500–3050, 3453, 3200 (OH); dH(CDCl3, 300 MHz) 1.87–1.92 (2H, m,
6-H), 2.20–2.55 (3H, br, exchanges with D2O, OH), 2.68–2.77 (2H, m,
1-H), 3.10 (1H, ddd, J 6.11, 4.8, 5.9, 5-H), 3.49 (1H, t, J 8.8, 3-H), 3.65–3.70
(2H, m, 7-H, NCH2Ph), 3.73–3.77 (1H, m, 7-H), 3.83 (1H, d, J 13.2,
NCH2Ph), 3.84–3.90 (1H, m, 2-H), 3.92 (1H, dd, J 4.8, 8.8, 4-H), 4.78 (1H,
d, J 11.7, OCH2Ph), 4.85 (1H, d, J 11.7, OCH2Ph), 7.25–7.40 (10H, m, Ar-
H); dC (CDCl3, 125 MHz) 26.6, 50.7, 58.2, 61.2, 62.0, 69.1, 69.9, 74.4, 82.8,
127.4, 127.7, 127.9, 128.5, 128.6, 138.3, 138.5 (Calc. for C21H27NO4: C,
70.56; H, 7.61. Found: C, 70.36; H, 7.89%). For 5b: thick liquid; [a]D
215.60 (c 0.35, CHCl3); nmax(neat)/cm21 1736 (CNO); dH(CDCl3, 300
MHz) 1.80–1.88 (2H, m, 6-H), 1.92 (3H, s, CH3), 1.95 (3H, s, CH3), 2.01
(3H, s, CH3), 2.61 (1H, dd, J 10.6, 13.5, 1a-H), 2.93 (1H, dd, J 5.5, 13.5, 1e-
H), 3.20–3.24 (1H, m, 5-H), 3.71 (1H, t, J 9.9, 3-H), 3.82 (1H, d, J 13.2,
NCH2Ph), 3.89 (1H, d, J 13.2, NCH2Ph), 3.95–4.10 (2H, m, 7-H), 4.67 (2H,
s, OCH2Ph), 5.06–5.14 (1H, m, 2-H), 5.23 (1H, dd, J 5.5, 9.9, 4-H),
7.21–7.36 (10H, m, Ar-H); dC (CDCl3, 125 MHz) 21.0(s), 23.7, 46.9, 55.0,
58.4, 62.2, 71.0, 71.8, 74.6, 78.6, 127.5, 128.4, 128.7, 138.5, 169.9(s), 171.0
(Calc. for C27H33NO7: C, 67.06; H, 6.88. Found: C, 66.83; H, 6.84%. For
6: foamy solid, mp 132–135 °C; [a]D 213.85 (c 0.8, H2O); nmax(KBr)/
cm21 3336, 3062, 1216, 1094; dH(D2O, 300 MHz) 1.62–1.78 (2H, m, 6-H),
2.62 (1H, dd J 8.2, 13.6, 1a-H), 2.88 (1H, dd J 4.2, 13.6, 1e-H), 3.04–3.18
(1H, m, 5-H), 3.40–3.76 (5H, m, 2-H, 3-H, 4-H, 7-H); dC(D2O, 125 MHz)
30.9, 46.7, 55.1, 62.1, 73.2, 74.5, 75.3 (Calc. for C7H15NO4: C, 47.44; H,
8.53. Found: C, 47.25; H, 8.74%).
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We are thankful to AICTE, New Delhi, for the financial
support, TIFR Bombay for high resolution NMR spectra and to
UGC, New Delhi, for the JRF to V. N. D. We are grateful to
Professor M. S. Wadia for helpful discussions.
Notes and references
1
† As indicated from the H NMR spectrum, the cleavage of the acetonide
group either in the isomeric mixture 2 or in 2b (Z-isomer) with TFA–H2O
afforded hemiacetal 3 (a+b = 7+3) with exclusively E geometry. Acid
catalysed Z ? E isomerisation has been reported (ref. 11).
‡ Our attempts to isolate either the diastereomer or other products in pure
form were unsuccessful. The 1H NMR spectrum of the crude mixture
indicated the presence of signals ( < 10%) corresponding to an ethyl group.
This could be the uncyclised open ester with (5S) configuration. Lactone 4a
was easily removed from the mixture by column chromatography followed
by recrystallisation. The other diastereomer could not be detected even
though the subsequent transformations were conducted without separation
of 4a. For example the direct acetylation of crude mixture of 4a with Ac2O
and DMAP in pyridine gave 4b as the only isolable product in 88%
yield.
¶ This argument would be valid even if lactonisation precedes Michael
addition.
∑ The direct reduction of crude mixture 4a with LAH followed by
peracetylation afforded 5b in 68% yield.
§ Selected data for 4a: white solid, mp 95 °C, [a]D = +38.45 (c 0.5,
CHCl3); nmax(Nujol)/cm21 3500–3300 (OH), 1770 (CNO); dH(CDCl3, 300
MHz) 2.33 (1H, dd, J 6.9, 11.9, 1a-H), 2.42 (1H, dd, J 6.4, 16.7, 6a-H), 2.53
(1H, brd, exchanges with D2O, OH), 2.81 (1H, dd, J 6.0, 16.7, 6e-H), 2.98
(1H, dd, J 2.9, 11.9, 1e-H), 3.44 (1H, d, J 13.4, NCH2Ph), 3.46 (1H, ddd,
J 5.3, 6.0, 6.4, 5-H), 3.63 (1H, dd, J 4.3, 6.8, 3-H), 3.73 (1H, d, J 13.4,
NCH2Ph), 3.90 (1H, m, 2-H), 4.54 (1H, d, J 11.7, OCH2Ph), 4.72 (1H, dd,
J 4.3, 5.3, 4-H), 4.77 (1H, d, J 11.7, OCH2Ph), 7.26–7.37 (10H, m, Ar-H);
dC(CDCl3, 125 MHz) 31.6, 49.9, 58.2, 58.7, 66.5, 72.9, 76.1, 76.9, 127.6,
127.8, 127.9, 128.4, 128.5, 128.6, 136.7, 137.3, 175.2 (Calc). for
C21H23NO4: C, 71.37; H, 6.56. Found: C, 71.62; H, 6.77%). For 4b: white
solid, mp 89–90 °C; [a]D +38.68 (c 0.4, CHCl3); nmax(Nujol)/cm21 1783
(CNO), 1742 (CNO); dH(CDCl3, 300 MHz) 2.01 (3H, s, CH3), 2.48 (1H, dd,
J 6.6, 16.8, 6a-H), 2.62 (1H, dd, J 5.9, 12.5, 1a-H), 2.65 (1H, dd, J 6.6, 16.8,
6e-H), 2.80 (1H, dd, J 3.7, 12.5, 1e-H), 3.43 (1H, d, J 14.0, NCH2Ph), 3.58
11 Stereochemistry of alkenes, in Stereochemistry of Organic Compounds,
ed. E. L. Eliel, S. H. Wilen and L. N. Mander, Wiley, New York, 1994,
p. 579.
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