Synthesis of trihydroxy quinolizidine alkaloids: 1,3-Addition reaction of allylmagnesium bromide to a sugar nitrone

Article abstract of DOI:10.1016/j.tet.2004.01.085

The synthesis of (1R,2R,3S,9aR) and (1R,2R,3S,9aS) trihydroxy quinolizidine alkaloids 3a and 3b from D-glucose derived nitrone 4 is described. The key transformation involves the 1,3-addition of allylmagnesium bromide to nitrone 4 that afforded high diast

Full text of DOI:10.1016/j.tet.2004.01.085

Tetrahedron 60 (2004) 3009–3016
Synthesis of trihydroxy quinolizidine alkaloids: 1,3-addition
reaction of allylmagnesium bromide to a sugar nitrone
a
a
b
Dilip D. Dhavale,a Santosh M. Jachak, Navnath P. Karche and Claudio Trombini
,
*
aDepartment of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
bDipartimento di Chimica “G. Ciamician”, via Selmi-2, 40126 Bologna, Italy
Received 1 December 2003; revised 2 January 2004; accepted 29 January 2004
Abstract—The synthesis of (1R,2R,3S,9aR) and (1R,2R,3S,9aS) trihydroxy quinolizidine alkaloids 3a and 3b from D-glucose derived nitrone
4 is described. The key transformation involves the 1,3-addition of allylmagnesium bromide to nitrone 4 that afforded high
diastereoselectivity in the presence of TMSOTf. The N–O bond reductive cleavage, N-Cbz protection, ozonolysis, Wittig olefination,
lactum formation and reductive amination cascade afforded the target compounds 3a and 3b in good overall yield.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Nitrones are becoming increasingly important in providing
intermediates for the synthesis of complex molecules,
including natural products and bioactive compounds.1 In
general, nitrones are employed in the 1,3-dipolar cyclo-
addition pathway with different olefinic compounds both in
the inter- and intramolecular version. Alternatively, the
reactions of nitrones as electrophiles with organometallic
reagents (1,3-addition) are gaining a lot of interest in recent
years.2 Easy availability of organometallic compounds as
nucleophiles (different metals combined with aryl or alkyl
Figure 1.
substituents), high electrophilicity of nitrones and feasibility
to manipulate the stereoselectivity at the prochiral nitrone-
activity—the process that plays a crucial role in many
carbon, under different chelation and non-chelation con-
biological processes, including breakdown of edible carbo-
ditions by the use of suitable Lewis acids, made this
hydrates, eukaryotic glycoprotein processing and poly-
approach versatile in organic synthesis. This approach is
saccharide and glycoconjugate anabolism and catabolism.5
now finding applications in carbohydrate chemistry,
especially in the synthesis of polyhydroxylated indolizidine,
The quinolizidine alkaloids are frequently encountered in
pyrrolidine and piperidine alkaloids.3 In this context, we
nature especially in ant species and in the skin of frogs and
have recently reported on the diastereoselective 1,3-addition
toads.6 Although a variety of structurally complex quino-
of methylmagnesium chloride and silyl ketene acetals to
lizidine alkaloids are known, the synthesis of polyhydroxyl-
D-glucose derived nitrones in the synthesis of 6-deoxy-
ated quinolizidine alkaloids and evaluation of their
nojirimycin 1a (Fig. 1) and 1-deoxy-D-gluco/L-ido-homo-
glycosidase inhibitory activity is a topic of current interest.7
nojirimycin, 1b/1c, respectively.4 This class of compounds,
As part of our continuing efforts in the synthesis of
in particular polyhydroxylated piperidine (e.g. nojirimycin
azasugars,4,8 we are now describing a synthesis of
1d), indolizidine (e.g. castanospermine 2) and quino-
trihydroxy quinolizidine alkaloids 3a and 3b using the
lizidine-alkaloids 3a and 3b have attracted considerable
1,3-addition reaction of allylmagnesium bromide to a
attention because of their promising glycosidase inhibitory
D-glucose derived nitrone 4 as a key step. Although, a few
reports are available for the synthesis of polyhydroxylated
Keywords: Nitrone; Azasugar; Carbohydrate; Quinolizidine; Glycosidase;
quinolizidine alkaloids only a single report describes the
Inhibitor.
synthesis of 3b,9 while the synthesis of 3a is not reported so
far.
*
Corresponding author. Tel.: þ91-2025601225; fax: þ91-2025691728;
e-mail address: ddd@chem.unipune.ernet.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.085

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D. D. Dhavale et al. / Tetrahedron 60 (2004) 3009–3016
2. Results and discussion
stereoselectivity while no product was obtained when
dichloromethane was used (entries 2 and 3). Change in the
stoichiometry of the reactants (i.e. decreasing the Grignard
to nitrone ratio) lowered the combined yield with no
significant change in the stereoselectivity (entries 4 and 5).
In case of nitrones it is known that the presence of an oxygen
atom, formally carrying a net negative charge, allows a
strong complexation with Lewis acid to occur. The resulting
N-oxy-immonium species thus displayed enhanced
reactivity and, in some cases, different stereochemical
outcomes in reaction with nucleophiles.10 In this context,
we have demonstrated the utility of trimethylsilyltriflate
(TMSOTf) as a promoter that leads to good stereoselectivity
with high yield under kinetic and non-chelation controlled
conditions.10d–h Inspired by this observation, the reaction of
nitrone 4 with allylmagnesium bromide (2.5 equiv.) in the
presence of TMSOTf (1 equiv.) was performed. The
product on desilylation afforded 5a and 5b in the ratio
2.1. Stereoselective 1,3-addition of allylmagnesium
bromide to sugar derived nitrone 4
The desired sugar nitrone 4 was prepared by the reaction of
1,2-O-isopropylidene-3-O-benzyl-a-D-xylo-pento-dialdose
with N-benzylhydroxylamine hydrochloride, in the presence
of sodium acetate in ethanol-water, as reported earlier by
us.4a The 1,3-addition of allylmagnesium bromide to 4 at
278 8C in dry THF for 2 h afforded a diastereomeric
mixture of N-benzylhydroxylamines 5a and 5b in 92% yield
in the ratio D-gluco:L-ido¼7:3, as evident from the 1H NMR
spectrum of the crude product (Scheme 1). To improve the
stereoselectivity at the prochiral C5 center, various reaction
conditions (e.g. change of solvent, temperature and
stoichiometry of reactants) were tried (Table 1). Performing
the reaction using ether as solvent had no effect on the
Scheme 1. Reagents and conditions: (i) Ref. 4a 78%; (ii) Allylmagnesium bromide (2.5 equiv.), THF, 278 8C, 2 h, 93%; (iii) Zn (2 equiv.), Cu(OAc)2, AcOH,
70 8C, 1 h, 78%; (iv) Cbz-Cl (1.5 equiv.), NaHCO3, aq. EtOH, 2 h, 75%; (v) O3, DCM, DMS, 240 8C, 1 h, 90%; (vi) a) Ph3PvCHCOOEt (1.5 equiv.), MeOH,
rt, 2 h; (b) H2, 10% Pd–C, MeOH, 25 8C, 12 h; (c) CH3COONa (4 equiv.), MeOH, reflux, 6 h, 69%; (vii) a) LAH (5 equiv.), THF, 0 8C, 1 h; (b) Cbz-Cl
(1.5 equiv.), NaHCO3, aq. EtOH, 2 h, 74%; (Viii) (a) TFA/H2O (3:2), 0 8C to rt, 2.5 h; (b) H2, 10% Pd–C, MeOH, 25 8C, 12 h, 87%.
Table 1. 1,3-Addition reaction of allylmagnesium bromide to sugar derived nitrone 4
Entry
RMgBr R¼allyl (equiv.)
Solvent
Lewis acid
Temperature (8C)
Time (h)
Product ratioa 5a and 5b
Yieldb (%)
1
2
3
4
5
6
2.5
2.5
2.5
2.0
1.5
2.5
THF
—
—
—
—
—
TMSOTf
278
230
230
278
278
278
2
4
48
2
5
2
70/30
65/35
92
94
—
78d
48d
93
Et2O
CH2Cl2
THF
THF
THF
No reactionc
69/31
65/35
86/14
a
Ratio was calculated by 1H NMR data of the crude product.
Yields refer to the isolated yields after chromatography.
Starting was recovered ,100%.
b
c
d
Starting was recovered.

D. D. Dhavale et al. / Tetrahedron 60 (2004) 3009–3016
3011
86:14, respectively, resulting in a significant improvement
of the diastereoselective in favor of D-gluco isomer with
high yield.
protected with benzyloxycarbonyl chloride in the presence
of sodium bicarbonate in aq. ethanol to afford N-Cbz
protected compound 7a in 95% yield.15 Ozonolysis of 7a at
240 8C in dry CH2Cl2 for 2 h afforded aldehyde 8a in
80% yield. Wittig reaction of aldehyde 8a with Ph3-
PvCHCOOEt in methanol gave a geometric mixture of
a,b-unsaturated-d-amino esters in 92% yield which was
directly subjected to hydrogenation followed by treatment
with sodium acetate in methanol to afford six membered
d-lactam 9a in 70% yield. In the subsequent steps, reduction
of the lactam functionality in 9a with LAH in THF and
N-protection with benzyl chloroformate gave 10a in 78%
yield. Finally, compound 10a was reacted with TFA–H2O
and the hemiacetal thus obtained was subjected to
hydrogenation to give (1R,2R,3S,9aR)-octahydro-2H-
quinolizine-1,2,3-triol 3a. The same reaction sequence
was repeated for the N-hydroxylamine 5b (Scheme 1).
The corresponding C5-epimeric compounds 6b, 7b, 8b and
9b were isolated and characterized by spectral and
analytical data. Comparison of the IR and 1H NMR spectra
of C5-epimeric compounds 9a and 9b led to an interesting
observation. In the IR spectrum, compound 9a (D-gluco)
showed the amide carbonyl stretching frequency at
1658 cm21 while; in compound 9b (L-ido) amide stretching
frequency was appeared at 1624 cm21. The decrease in IR
carbonyl frequency in 9b could be attributed to the
intramolecular hydrogen bonding between C3–OH and
amide carbonyl oxygen as shown in Figure 3. This
observation is substantiated by the fact that, in the 1H
NMR spectra, the observed J4,5 is found to be larger in
D-gluco isomer 9a (9.3 Hz) than the corresponding C5
epimeric L-ido isomer 9b (4.8 Hz). This finding is opposite
to that reported (J4,5 in L-ido.D-gluco)11 and could be
attributed to the possible six membered intramolecular
hydrogen bonding in 9a and 9b between NH and C3 oxygen
by rotation about the C4–C5 bond (Fig. 3). In this situation,
the molecule is held in such a way that, for the hydrogen
bonded D-gluco isomer 9a, the dihedral angle between H4
and H5 is ,1808 and that for L-ido isomer 9b is ,458 thus
resulting in the observed coupling constants.
2.2. Assignment of the relative stereochemistry at C5 of
the 5a and 5b
The relative stereochemistry at C5 in 5a and 5b was
assigned on the basis of 1H NMR data. It is known that for a
given C5-epimeric pair, derived from the D-gluco-furanose,
the J4,5 in the L-ido isomer (threo-relationship) is con-
sistently larger than that of the corresponding D-gluco
isomer (erythro-relationship).11 The higher value of J4,5
observed in the diastereomer 5b (9.5 Hz), as compared to 5a
(8.3 Hz) indicated the L-ido configuration for 5b and the
D-gluco configuration for 5a. This assignment was further
supported by comparison of the chemical shifts of H3 in
both the isomers. The chemical shift of H3 is reported to be
diagnostic such that in the L-ido isomer, which is
significantly upfield (d,3.6) as compared to that in the
D-gluco (d,4.0).11 In 5b H3 appeared upfield at d 3.84 as
compared to 5a at d 4.01, further supporting the D-gluco and
L-ido configuration at C5 to 5a and 5b, respectively. Thus,
the absolute configurations at C-5 in 5a and 5b were
assigned as (5R) and (5S), respectively.
2.3. Explanation for the observed stereochemistry
The observed facial selectivity in the 1,3-addition of
allylmagnesium bromide to nitrone 4 could be rationalized
by Felkin-Anh like transition states (TS) A and B (Fig. 2).
According to Felkin-Anh model12 the large substituent is
kept perpendicular to the CvN bond. We believe that the
C–O bond will adopt this position; in fact it is known that
nucleophilic attack seeks the LUMO of the nitrone which
may be stabilized through mixing of the pp CvN orbital
with the lowest energy sp orbital of a substituent, generally
associated with the most electronegative substituent.13
Amongst the two transition states, the TS A offers the
more favorable Burgi–Dunitz trajectory for the incoming
nucleophile14 thus favoring the formation of D-gluco isomer
in a major amount and this effect is magnified in the
presence of TMSOTf.
Figure 3.
In the next step, reduction of the lactam functionality in 9b
with LAH in THF followed by the N-Cbz protection
afforded 10b.16 Compound 10b was reacted with TFA–H2O
and the hemiacetal thus obtained was subjected for
hydrogenation to give (1R,2R,3S,9aS)-octahydro-2H-quino-
lizine-1,2,3-triol 3b.
Figure 2.
2.4. Synthesis of 3a and 3b
The utility of 5a and 5b were demonstrated in the formation
of the corresponding quinolizidine alkaloids 3a and 3b. As
shown in Scheme 1, the N–O bond reductive cleavage of
N-benzylhydroxylamine 5a with zinc in acetic acid–water
(85:15) at 70 8C for 1 h afforded the N-benzylamino sugar
6a in good yield. The amino functionality in 6a was
2.5. Conformational assignment of 3a and 3b
Azasugars can exist in different conformations. For
4
example, nojirimycin exists in C1 conformation and the
castanospermine and 1-deoxy-castanospermine are present

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D. D. Dhavale et al. / Tetrahedron 60 (2004) 3009–3016
in 8C5 conformation while; we have reported that the
1-deoxy-8a-epi-castanospermine is present in C8 confor-
or in nujol mull and are expressed in cm21 1H NMR
.
(300 MHz) and 13C NMR (75 MHz) spectra were recorded
in CDCl3 as a solvent unless otherwise noted. NMR
Chemical shifts are reported in d (ppm) downfield from
TMS. Elemental analyses were carried out with an
elemental analyzer. Optical rotations were measured with
a polarimeter using sodium light (D line 589.3 nm) at 25 8C.
TLC was performed on pre-coated plates (0.25 mm, silica
gel 60 F254). Column chromatography was carried out with
100–200 mesh silica gel. The reactions were carried out in
oven-dried glassware under dry N2. Allylmagnesium
bromide was prepared from Mg and allyl bromide in dry
ether prior to use. N-Benzylhydroxylamine hydrochloride,
LAH, Cbz-Cl was purchased from Aldrich and/or Fluka.
Methanol, diethyl ether, dichloromethane, THF were
purified and dried before use. Petroleum ether (PE) is a
distillation fraction between 40–60 8C. After work up,
organic layer was washed with water, brine and dried over
anhydrous sodium sulfate and evaporated at reduced
pressure. Sugar nitrone 4 was prepared from 1,2-O-
benzyl-a-D-xylo-pento-dialdose in 78% yield as reported
earlier.4a 1H NMR (300 MHz) and 13C NMR (75 MHz) of
compounds 7a, 7b and 8a, 8b showed doubling of signals
and therefore not stated in the experimental.15
5
mation.8h The quinolizidine alkaloids 3a and 3b have the
framework of aza-decalin system wherein one can expect
trans or cis ring fusion. In order to know the conformations,
we studied the 1H NMR spectra of 3a and 3b and the
coupling constant information was obtained by decoupling
1
experiments. In the H NMR spectra of 3a the doublet of
triplet (J3,4e¼4.4 Hz and J3,4a¼J3,2¼9.5 Hz), corresponding
to H3 proton, indicated the axial orientation of this proton.
The triplet (J2,3¼J2,1¼9.5 Hz), corresponding to H2,
requires trans-diaxial relationship with H3 and H1. As the
trans aza-decalin is conformationally rigid chair-chair
system, the conformation A was assigned to 3a. Since the
1H NMR spectrum of 3b is very different from 3a it was
thought that 3b could exist in different conformation. Thus,
for 3b we considered two conformations—one with cis ring
fusion and equatorially oriented OH substituents (confor-
mation B) and the other trans ring fusion with axially
oriented OH substituents (conformation C). The initial
geometry in the precursor 10b ensures that in the product 3b
the substituents at C1, C2 and C2, C3 should be trans. The
1H NMR of 3b showed the low coupling constant values
(J1,2¼J2,3,3 Hz) between the H1-H2 and H2-H3. This
indicated the equatorial orientation of these protons at C1/
C2/C3. This fact is supported by the noticeable downfield
shift of H1/H2/H3 as compared to the respective protons in
3a. Based on this observation, we assigned the preferred
trans ring fused conformation C, with axial orientation of
the OH substituents, for compound 3b.17
3.1.1. 3-O-Benzyl-1,2-O-isopropylidene-5,6,7,8-tetra-
deoxy-5-(N-benzyl-N-hydroxyamino)-a-D-gluco-7-eno-
octo-1,4-furanose (5a) and 3-O-benzyl-1,2-O-isopropyl-
idene-5,6,7,8-tetra-deoxy-5-(N-benzyl-N-hydroxy-
amino)-b-L-ido-7-eno-octo-1,4-furanose (5b). To a stirred
solution of nitrone 4 (1 g, 2.61 mmol) in THF under
nitrogen atmosphere, at 210 8C, was added dropwise
TMSOTf (0.47 mL, 2.61 mmol). After stirring for 10 min.
the mixture was cooled to 278 8C and allylmagnesium
bromide (1 M in diethylether, 1.4 mL, 6.52 mmol) was
added dropwise with stirring at 278 8C for 2 h. Quenching
was performed with 2 M HCl (2 mL), with stirring at room
temperature for 30 min. The reaction mixture was neutral-
ized with saturated solution of NaHCO3 and was extracted
with diethyl ether (3£15 mL). The ethereal layer on work up
afforded a thick oil. Column chromatograph using (2%
EtOAc/Pet. Ether) gave 5a (0.890 g, 80%) as thick liquid;
[Found: C, 70.51; H, 7.30. C25H31NO5 requires C, 70.57; H,
7.34%]; Rf (30% EtOAc/Hexane) 0.52; [a]D 230.0 (c 2.40,
CHCl3); nmax(neat) 3510–3160 (br), 1639 cm21; dH
(300 MHz, CDCl3) 1.26 (3H, s, Me), 1.44 (3H, s, Me),
2.49–2.69 (2H, m, H6), 3.41 (1H, ddd, J¼8.3, 7.8, 4.8 Hz,
H5), 3.76 (1H, d, J¼13.6 Hz, CH2Ph), 3.94 (1H, d,
J¼13.6 Hz, CH2Ph), 4.01 (1H, d, J¼3.0 Hz, H3), 4.37
(1H, dd, J¼8.3, 3.0 Hz, H4), 4.40–4.45 (1H, bs, exchanges
with D2O, OH), 4.50 (1H, d, J¼11.7 Hz, CH2Ph), 4.54 (1H,
d, J¼3.9 Hz, H2), 4.63 (1H, d, J¼11.7 Hz, CH2Ph), 4.98
(1H, dd, J¼11.1, 1.6 Hz, vCH2), 5.10 (1H, dd, J¼17.0,
1.6 Hz, vCH2), 5.87 (1H, d, J¼3.9 Hz, H1), 5.92–6.10
(1H, m, vCH), 7.12–7.28 (10H, m, ArH); dC (75 MHz,
CDCl3) 26.2, 26.7, 31.4, 60.8, 63.4, 72.0, 79.6, 81.9, 82.5,
104.5, 111.3, 115.6, 127.1, 127.5, 127.6, 128.2, 128.4,
129.1, 137.6, 137.7, 138.3. Further elution with (5% EtOAc/
Pet. Ether) afforded 5b (0.145, 13%) as a thick liquid;
[Found: C, 70.29; H, 7.59. C25H31NO5 requires C, 70.57; H,
7.34%]; Rf (30% EtOAc/Hexane) 0.44; [a]D 248.0 (c 0.25,
CHCl3); nmax(neat) 3530–3150 (br), 1639 cm21; dH
(300 MHz, CDCl3) 1.27 (3H, s, Me), 1.46 (3H, s, Me),
In conclusion, we have demonstrated that the 1,3-addition
reaction of allylmagnesium bromide to sugar derived
nitrone 4 can be stereocontrolled in favor of D-gluco isomer
by the use of TMSOTf. The two diastereomeric g-alkeny-
lamines thus obtained were successfully utilized in the
synthesis of trihydroxy quinolizidine alkaloids 3a and 3b.
3. Experimental
3.1. General
Melting points were recorded with a Thomas-Hoover
melting point apparatus and are uncorrected. IR spectra
were recorded with FTIR spectrophotometer as a thin film

D. D. Dhavale et al. / Tetrahedron 60 (2004) 3009–3016
3013
1.91–2.09 (1H, m, H6a), 2.21–2.35 (1H, m, H6b), 3.38 (1H,
ddd, J¼9.5, 8.1, 4.3 Hz, H5), 3.84 (1H, d, J¼3.0 Hz, H3),
3.92 (1H, d, J¼13.9 Hz, CH2Ph), 4.09 (1H, d, J¼13.9 Hz,
CH2Ph), 4.39 (1H, d, J¼11.6 Hz, CH2Ph), 4.44 (1H, dd,
J¼9.5, 3.0 Hz, H4), 4.57 (1H, d, J¼3.8 Hz, H2), 4.61 (1H,
d, J¼11.6 Hz, CH2Ph), 4.84–4.92 (2H, m, vCH2), 4.93–
4.96 (1H, bs, exchanges with D2O, OH), 5.83–6.05 (1H, m,
vCH), 5.93 (1H, d, J¼3.8 Hz, H1), 7.10–7.38 (10H, m,
ArH); dC (75 MHz, CDCl3) 26.5, 26.8, 34.3, 49.4, 57.3,
72.0, 81.3, 81.9, 83.5, 104.9, 111.3, 115.0, 126.2, 127.4,
127.5, 127.7, 128.2, 128.4, 137.9, 138.2, 141.5.
3.1.4. 3-O-Benzyl-5,6-dideoxy-1,2-O-isopropylidene-5-
(N-benzyl-N-benzoxycarbonylamino)-a-D-gluco-7-eno-
octo-1,4-furanose (7a). To a stirred solution of N-benzyl-
amine 6a (0.622 g, 1.52 mmol) in methanol (5 mL) was
added benzyloxycarbonyl chloride (0.322 g, 2.28 mmol)
and sodium bicarbonate (0.253 g, 3.00 mmol) and the
reaction mixture was stirred at room temperature for 2 h.
The methanol was evaporated under reduced pressure and
water (10 mL) was added and extracted with chloroform
(20 mL£3). Usual work up gave an oil which on purification
by column chromatography (5% EtOAc/Pet. Ether) gave 7a
(0.610 g, 73%) as a thick liquid; [Found: C, 73.11; H, 7.09.
C33H37NO6 requires C, 72.91; H, 6.86%]; Rf (30% EtOAc/
Hexane) 0.72; [a]D 243.8 (c 3.75, CHCl3); nmax(neat) 1695,
3.1.2. 3-O-Benzyl-1,2-O-isopropylidene-5,6,7,8-tetra-
deoxy-5-N-(benzylamino)-a-D-gluco-7-eno-octo1,4-fura-
nose (6a). Zinc dust (0.275 g, 4.23 mmol) was added to a
solution of copper(II) acetate (0.015 g) in glacial acetic acid
(1 mL) under nitrogen and the mixture was stirred at 25 8C
for 15 min until the color disappeared. N-Benzylhydroxyl-
amine 5a (0.30 g, 0.70 mmol) in glacial acetic acid (0.7 ml)
and water (0.3 mL) was successively added; the reaction
mixture was heated at 70 8C for 1 h and cooled to room
temperature. The sodium salt of EDTA (0.1 g) was added to
the mixture and stirred for 10 min and then made alkaline to
pH 10 by addition of 3 M NaOH. The resulting solution was
extracted with chloroform (3£15 mL) and the combined
organic layer was evaporated to give an oil. Purification by
column chromatography (15% EtOAc/Pet. Ether) gave 6a
(0.22 g, 76%) as a thick liquid; [Found: C, 73.26; H, 7.58.
C25H31NO4 requires C, 73.32; H, 7.63]; Rf 0.19 (50%
EtOAc/Hexane); [a]D 231.0 (c 1.55, CHCl3); nmax(neat)
3640–3310 (br), 1588 cm21; dH (300 MHz, CDCl3) 1.31
(3H, s, Me), 1.47 (3H, s, Me), 1.59–1.62 (1H, bs, exchanges
with D2O, OH), 2.31–2.42 (1H, m, H6a), 2.51–2.61 (1H, m,
H6b), 3.20 (1H, ddd, J¼9.3, 6.0, 4.0 Hz, H5), 3.68 (1H, d,
J¼12.7 Hz, CH2Ph), 3.85 (1H, d, J¼12.7 Hz, CH2Ph), 3.99
(1H, dd, J¼9.3, 3.1 Hz, H4), 4.09 (1H, d, J¼3.1 Hz, H3),
4.53 (1H, d, J¼11.5 Hz, CH2Ph), 4.60 (1H, d, J¼3.8 Hz,
H2), 4.68 (1H, d, J¼11.5 Hz, CH2Ph), 5.10–5.20 (2H, m,
vCH2), 5.71–6.00 (1H, m, vCH), 5.92 (1H, d, J¼3.8 Hz,
H1), 7.18–7.38 (10H, m, ArH); dC (75 MHz, CDCl3) 26.3,
26.8, 34.8, 51.5, 54.0, 71.9, 81.7, 81.8, 81.9, 104.7, 111.4, 118.1,
126.8, 127.7, 127.8, 128.1, 128.3, 128.4, 134.5, 137.5, 140.7.
1601 cm21
.
3.1.5. 3-O-Benzyl-5,6-dideoxy-1,2-O-isopropylidene-5-
(N-benzyl-N-benzoxycarbonylamino)-b-L-ido-7-eno-
octo-1,4-furanose (7b). The reaction of 6b (1.5 g,
3.66 mmol) with benzyloxycarbonyl chloride (0.775 g,
5.50 mmol) and sodium bicarbonate (0.610 g, 7.26 mmol)
was performed under the same conditions as reported for 7a.
Column chromatography (5% EtOAc/Pet. Ether) afforded
7b (1.5 g, 79%) as a thick liquid; [Found: C, 72.98; H, 7.13.
C33H37NO6 requires C, 72.91; H, 6.86%]; Rf (30% EtOAc/
Hexane) 0.59; [a]D 28.1 (c 1.85, CHCl3); nmax(neat) 1697,
1598 cm21
.
3.1.6. 3-O-Benzyl-5,6-dideoxy-1,2-O-isopropylidene-5-
(N-benzyl-N-benzoxycarbonylamino)-a-D-gluco-hepto-
dialdo-1,4-furanose (8a). Ozone was bubbled through a
solution of 7a (0.3 g, 0.55 mmol) in dichloromethane
(10 mL) at 240 8C until a blue color persisted. The reaction
mixture was purged with O2 until the blue color disappeared
Dimethyl sulfide (1 mL, 5.5 mmol) was added and the
reaction mixture was allow to attain room temperature and
stirred for 2 h. The solvent was evaporated under reduced
pressure to give a crude product that was purified by column
chromatography (10% EtOAc/Pet. Ether) to give aldehyde
8a (0.275 g, 91%) as a thick liquid; [Found: C, 70.31; H,
6.38. C32H35NO7 requires C, 70.44; H, 6.47%]; Rf
(30% EtOAc/Hexane) 0.65; [a]D 228.7 (c 3.35, CHCl3);
n
max(neat) 2731, 1722.3, 1697.2 cm21
.
3.1.3. 3-O-Benzyl-1,2-O-isopropylidene-5,6,7,8-tetra-
deoxy-5-N-(benzylamino)-b-L-ido-7-eno-octo-1,4-fura-
nose (6b). The reaction of N-benzylhydroxylamine 5b
(0.30 g, 0.70 mmol) with Zn/Cu couple under the same
reaction conditions reported for 6a, gave N-benzylamine 6b
(0.23 g, 80%) as a thick liquid; [Found: C, 73.22; H, 7.51.
C25H31NO4 requires C, 73.32; H, 7.63%]; Rf (50% EtOAc/
Hexane) 0.11; [a]D 260.0 (c 1.0, CHCl3); nmax(neat) 3620–
3260 (br), 1638.6 cm21; dH (300 MHz, CDCl3) 1.33 (3H, s,
Me), 1.49 (3H, s, Me), 1.80–1.97 (1H, bs, exchanges with
D2O, OH), 2.01–2.14 (1H, m, H6a), 2.20–2.32 (1H, m,
H6b), 3.19 (1H, ddd, J¼10.0, 9.3, 5.1 Hz, H5), 3.83 (2H,
ABq, J¼12.3 Hz, CH2Ph), 3.89 (1H, d, J¼3.0 Hz, H3), 4.08
(1H, dd, J¼9.3, 3.0 Hz, H4), 4.44 (1H, d, J¼11.7 Hz,
CH2Ph), 4.64 (1H, d, J¼3.9 Hz, H2), 4.86 (1H, d,
J¼11.7 Hz, CH2Ph), 4.93–5.08 (2H, m, vCH2), 5.81–
5.98 (1H, m, vCH), 5.93 (1H, d, J¼3.9 Hz, H1), 7.19–
7.39 (10H, m, ArH); dC (75 MHz, CDCl3) 26.4, 26.7, 34.8,
51.7, 55.3, 71.4, 81.3, 81.7, 82.6, 104.5, 111.4, 116.7, 126.6,
127.8, 127.9, 128.1, 128.2, 128.3, 135.1, 136.9, 140.5.
3.1.7. 3-O-Benzyl-5,6-dideoxy-1,2-O-isopropylidene-5-
(N-benzyl-N-benzoxycarbonylamino)-b-L-ido-hepto-
dialdo-1,4-furanose (8b). The reaction of 7b (1.0 g,
1.84 mmol)) with ozone in dichloromethane at 240 8C
was performed under the same conditions as reported for 8a.
Column chromatography (10% EtOAc/Pet. Ether) afforded
8b (0.900 g, 89%) as a thick liquid; [Found: C, 70.29; H,
6.32. C32H35NO7 requires C, 70.44; H, 6.47%]; Rf
(30% EtOAc/Hexane) 0.61; [a]D 223.0 (c 2.0, CHCl3);
n
max(neat) 2722, 1726, 1697 cm21
.
3.1.8. 1,2-O-Isopropylidene-5,6,7,8-tetra-deoxy-5,9-
imino-a-D-gluco-nona-1,4-furan-9-ulose (9a). To
a
solution of aldehyde 8a (1 g, 1.83 mmol) in methanol
(5 mL), Wittig reagent, triphenylethoxycarbonylmethylene
phosphorane (0.957 g, 2.75 mmol) was added and reaction
mixture was stirred for 2.5 h at room temperature. The
methanol was evaporated the thick liquid obtained which on
usual work up gave an oil. The crude product was directly

3014
D. D. Dhavale et al. / Tetrahedron 60 (2004) 3009–3016
subjected to hydrogenation with 10% Pd/C (0.200 g) in
methanol (10 mL) at 80 psi for 12 h. The solution was
filtered through Celite and washed with methanol. To the
filtrate anhydrous sodium acetate (0.265 g, 3.18 mmol) was
added and refluxed for 6 h. The pH of the solution
was adjusted to eight by addition of 1 M NaOH. Methanol
was removed and the solution was extracted with chloro-
form (3£15 mL). The combined chloroform layer was dried
and evaporated to give gummy solid, which was purified by
column chromatography (2% MeOH/CHCl3) to give 9a
(0.321 g, 68%) as a white solid; melting point 166–168 8C;
[Found: C, 55.94; H, 7.29. C12H19NO5 requires C, 56.02; H,
7.44%]; Rf (10% MeOH/CHCl3) 0.61; [a]D 224.0 (c 2.0,
CHCl3); nmax(neat) 3330–2880, 1658 cm21; dH (300 MHz,
CDCl3) 1.32 (3H, s, Me), 1.50 (3H, s, Me), 1.62–2.08 (4H,
m, H6, H7), 2.19–2.36 (2H, m, H8), 3.64–3.76 (1H, m,
H5), 3.95 (1H, dd, J¼9.3, 2.4 Hz, H4), 4.27 (1H, d,
J¼2.4 Hz, H3), 4.55 (1H, d, J¼3.6 Hz, H2), 4.78–5.11 (1H,
bs, exchanges with D2O, OH), 5.91 (1H, d, J¼3.6 Hz, H1),
8.05–8.22 (1H, bs, exchanges with D2O, NH); dC (75 MHz,
CDCl3) 17.8, 24.5, 26.1, 26.9, 31.2, 50.3, 73.4, 82.1, 85.5,
104.8, 111.3, 174.4.
Ether) to give 10a (0.365 g, 80%) as a thick liquid; [Found:
C, 63.51; H, 7.09. C20H27NO6 requires C, 64.63; H, 7.21%];
Rf (60% EtOAc/Hexane) 0.76; [a]D 243.0 (c 2.0, CHCl3);
n
max(neat) 3475, 1674 cm21; dH (300 MHz, CDCl3þD2O)
1.31 (3H, s, Me), 1.48 (3H, s, Me), 1.88–2.02 (4H, m, H6,
H7), 2.20–2.35 (2H, m, H8), 3.38–3.48 (2H, m, H9), 3.79
(1H, dd, J¼9.9, 1.8 Hz, H4), 4.02 (1H, d, J¼1.8 Hz, H3),
4.08–4.19 (1H, m, H5), 4.58 (1H, d, J¼3.6 Hz, H2), 5.12
(2H, ABq, J¼12.0 Hz, CH2Ph), 5.88 (1H, d, J¼3.6 Hz, H1),
7.22–7.41 (5H, m, ArH); dC (75 MHz, CDCl3) 18.9, 25.1,
25.3, 26.2, 27.0, 41.1, 48.5, 67.8, 73.6, 76.6, 84.5, 104.8,
111.3, 127.8, 128.4, 128.5, 135.9, 156.9.
3.1.11. 1,2-O-Isopropylidine-5,6,7,8,9-penta-deoxy-5,9-
(N-benzoxycarbonyl-imino)-b-L-ido-nona-1,4-furanose
(10b). The reaction of 9b (0.342 g, 1.33 mmol) with LAH
(0.250 g, 6.65 mmol) followd by reaction with sodium
bicarbonate (0.223 g, 2.66 mmol) and benzyloxycarbonyl
chloride (0.340 g, 1.99 mmol) under the same conditions as
reported for 10a and column chromatography (15% EtOAc/
Pet. Ether) afforded 10b (0.350 g, 69%) as a thick liquid;
[Found: C, 63.86; H, 7.45. C20H27NO6 requires C, 64.63; H,
7.21%]; Rf (60% EtOAc/ Hexane) 0.68; [a]D 272.3 (c 1.55,
CHCl3); nmax(neat) 3110–3620, 1674 cm21; dH (300 MHz,
CDCl3þD2O) 1.32 (3H, s, Me), 1.51 (3H, s, Me), 1.60–1.80
(2H, m, H6), 1.81–1.98 (2H, m, H7), 2.01–2.22 (2H, m,
H8), 3.41–3.60 (2H, m, H9), 3.98 (1H, dd, J¼3.0, 1.8 Hz,
H4), 4.13 (1H, d, J¼1.8 Hz, H3), 4.28–4.35 (1H, m, H5),
4.47 (1H, d, J¼3.6 Hz, H2), 5.13 (2H, ABq, J¼12.3 Hz,
CH2Ph), 5.87 (1H, d, J¼3.6 Hz, H1), 7.21–7.41 (5H, m,
ArH); dC (75 MHz, CDCl3) 19.6, 25.2, 26.1, 26.2, 26.8,
40.0, 48.9, 66.9, 74.6, 77.6, 85.4, 104.1, 111.1, 127.3, 127.5,
128.2, 136.8, 156.2.
3.1.9. 1,2-O-Isopropylidene-5,6,7,8-tetra-deoxy-5,9-
imino-b-L-ido-nona-1,4-furan-9-ulose (9b). The reaction
of 8b (0.91 g, 1.67 mmol) with Wittig reagent triphenyl-
ethoxycarbonylmethylene
phosphorane
(0.871 g,
2.50 mmol) and followed by hydrogenation with 10% Pd/
C (0.180 g) and sodium acetate (0.242 g, 2.96 mmol) was
performed under the same conditions as reported for 9a.
Column chromatography (4% MeOH/CHCl3) afforded 9b
(0.330 g, 70%) as a white solid; melting point 156–157 8C;
[Found: C, 55.91; H, 7.25. C12H19NO5 requires C, 56.02; H,
7.44%]; Rf (10% CHCl3/MeOH) 0.58; [a]D 211.5 (c 2.25,
CHCl3); nmax(neat) 3330– 2880, 1624,cm21; dH (300 MHz,
CDCl3) 1.30 (3H, s, Me), 1.49 (3H, s, Me), 1.59–1.81 (2H,
m, H6), 1.82 (2H, m, H7), 2.21–2.49 (2H, m, H8), 3.65–
3.80 (1H, m, H5), 3.95 (1H, dd, J¼4.8, 2.7 Hz, H4), 4.22
(1H, d, J¼2.7 Hz, H3), 4.51 (1H, d, J¼3.6 Hz, H2), 5.01–
5.21 (1H, bs, exchanges with D2O, OH), 5.95 (1H, d,
J¼3.6 Hz, H1), 7.10–7.22 (1H, bs, exchanges with D2O,
NH); dC (75 MHz, CDCl3) 19.8, 25.9, 26.2, 26.8, 30.9, 52.6,
75.7, 81.3, 85.2, 104.6, 111.5, 173.16.
3.1.12. (1R,2R,3S,9aR)-Octahydro-2H-quinolizine-1,2,3-
triol (3a). A solution of 10a (0.100 g, 0.26 mmol) in TFA–
H2O (2 mL, 3/2) was stirred at 25 8C for 2 h. Trifluroacetic
acid was co-evaporated with benzene to furnish a thick
liquid, which was directly used in the next reaction. To a
solution of above product in methanol (5 mL) was added
10% Pd/C (0.01 g) and solution was hydrogenated at 80 psi
for 16 h. The solution was filtered through Celite and
washed with methanol and the filtrate concentrated to get a
sticky solid which was purified by column chromatography
(5% MeOH/CHCl3) to give 3a (0.042 g, 85%) as a thick
liquid; [Found: C, 51.51; H, 10.99. C9H17NO33H2O
requires C, 51.65; H, 11.08%]; Rf (30% chloroform/
methanol) 0.29; [a]D 236.0 (c 0.2, MeOH); nmax(neat)
3676–3250 cm21; dH (300 MHz, D2O) 1.24–1.53 (2H, m,
H7), 1.55–1.72 (1H, m, H9), 1.79–1.98 (3H, m, H8, H9),
2.26 (1H, brd, J¼13.2 Hz, H6a), 2.60–2.86 (3H, m, H4,
H6b), 3.22–3.36 (2H, m, H1, H9a), 3.41 (1H, t, J¼9.5 Hz,
H2), 3.69 (1H, dt, J¼9.5, 4.5 Hz, H3); dC (75 MHz, D2O)
21.6, 23.4, 26.9, 55.3, 56.8, 65.0, 67.0, 72.7, 76.5.
3.1.10. 1,2-O-Isopropylidine-5,6,7,8,9-penta-deoxy-5,9-
(N-benzoxycarbonyl-imino)-a-D-gluco-nona-1,4-fura-
nose (10a). To an ice cooled suspension of LAH (0.223 g,
6.03 mmol) in dry THF (10 mL) was added a solution of 9a
(0.310 g, 1.20 mmol) in dry THF (15 mL) over a period of
10 min. The mixture was allowed to attain the room
temperature and stirred for 2 h. Ethyl acetate (10 mL) was
added at 0 8C and stirred for 10 min. The reaction was
quenched by slow addition of saturated aq. solution of
NH4Cl (2 mL), filtered and residue rinsed with ethyl acetate
(5 mL). The usual work up afforded a thick oil that was
dissolved in ethanol/water (2 mL, 1/1). The solution was
cooled to 0 8C and sodium bicarbonate (0.299 g,
2.41 mmol), benzyloxycarbonyl chloride (0.304 g,
1.80 mmol) was added successively. The mixture was
stirred at 25 8C for 2 h. Ethanol was evaporated at reduced
pressure and the residue was extracted with chloroform
(3£15 mL). The usual work up afforded a thick liquid, that
was purified by column chromatography (15% EtOAc/Pet.
3.1.13. (1R,2R,3S,9aS)-Octahydro-2H-quinolizine-1,2,3-
triol (3b). The reaction of 10b (0.13 g, 0.34 mmol) with
TFA–H2O (3 mL, 3/2) followed by hydrogenation with
10% Pd/C (0.02 g) as reported for 3a. Column chromato-
graphy (10% MeOH/CHCl3) afforded 3b (0.058 g, 91%) as
a thick liquid; [Found: C, 51.95; H, 10.30. C9H17NO3.2H2O
requires C, 52.15; H, 10.21%]; Rf (30% chloroform/
methanol) 0.25; [a]D 280.0 (c 0.1, MeOH); nmax(neat)

D. D. Dhavale et al. / Tetrahedron 60 (2004) 3009–3016
3015
3640–3180 cm21; dH (300 MHz, D2O) 1.42–1.80 (6H, m,
H7, H8, H9), 2.79–2.91 (1H, m, H6a), 3.15–3.38 (4H, m,
H4, H6b, H9a), 3.65 (1H, bs, WH 6 Hz, H3), 3.87 (2H, bs,
WH 6 Hz, H2, H1); dC (75 MHz, D2O) 21.7, 22.9, 25.7, 55.7,
61.6, 66.4, 67.2, 70.2 (strong).
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Acknowledgements
We are thankful to CSIR, New Delhi for financial support
and UGC, New Delhi for the funds to procure 300 MHz
NMR Instrument.
6. Jones, T.; Gorman, J.; Snelling, R.; Delabie, J.; Blum, M.;
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1
15. The H and 13C NMR spectra of compounds 7a, 8a, and 7b,
8b, in which a N-Cbz group is present, showed doubling of

3016
D. D. Dhavale et al. / Tetrahedron 60 (2004) 3009–3016
signals. This was due to isomerisation by restricted rotation
conformation while; in the conformation C the butane–guache
interactions are minimum and in addition the intramolecular
hydrogen bonding in the six membered transition state
stabilize the conformation C for 3b. The counting of
butane–guache interactions in the decalin systems reveal
three such interactions in the cis isomer and none in the trans.
Therefore, the calculated difference in heats of formation
between the decalins is 2.7 kcal/mol, the trans isomer being
the more stable. See: In Stereochemistry of organic
compounds; Eliel, E. L., Wilen, S. H., Eds.; Wiley: New
York, 1994; p 777.
around CvN, see: In Applications of NMR spectroscopy in
organic chemistry; Jackman, L. M., Sternhell, S., Eds.;
Pergamon: Elmsford, NY, 1978; p 361. An analogous
observation was also noticed by us and others see Ref. 8h.
16. Here also we have observed an analogues observation as in
case of 9a and 9b. The 1H NMR data of 10a and 10b showed
coupling constant between H4 and H5 as 9.9 and 3.0 Hz,
respectively, (for 9a and 9b J4,5 is 9.3 and 4.8 Hz). Similar
findings we have reported earlier see Ref. 8h.
17. Although, the OH substituents are equatorial in the confor-
mation B, the butane–gauche interactions destabilize this