A preparation of protected 2-deoxy-2-hydroxymethyl-D-mannose and -D- glucose derivatives not involving organometallic reagents

Article abstract of DOI:10.1016/S0008-6215(98)00080-9

The branched chain protected sugar, 2-C-hydroxymethyl-2,3;5,6-di-O- isopropylidene-D-mannofuranose was specifically benzylated at the primary hydroxyl group position by the stannylene procedure (93%). Oxidation with pyridinium chlorochromate gave in 71% yield 2-C-benzyloxymethyl-2,3;5,6-di- O-isopropylidene-D-mannonolactone which was reduced with 3 equiv of samarium diiodide in oxolane to a 56:44 mixture of the 2-deoxy derivatives, 2-C- benzyloxymethyl-2-deoxy-5,6-O-isopropylidene-D-mannono- (5) and -D-glucono- lactones in 83% combined yield. Reduction of lactone 5 with DIBAH in dichloromethane gave the protected branched chain sugar, 2-C-benzyloxy-2- deoxy-5,6-O-isopropylidene-D-mannose in 63% yield. In the reduction of 2-C- hydroxymethyl-2,3;5,6-di-O-isopropylidene-D-mannonolactone and 2-C- hydroxymethyl-D-mannonolactone in water solution, only lactones with the D- manno configuration, 2-deoxy-2-C-hydroxymethyl-5,6-O-isopropylidene-D- mannonolactone and 2-deoxy-2-C-hydroxymethyl-D-mannono-(1,5)-lactone, could be isolated or characterized among the products of the reaction.

Full text of DOI:10.1016/S0008-6215(98)00080-9

Carbohydrate Research 308 (1998) 93±98
A preparation of protected 2-deoxy-2-
hydroxymethyl-d-mannose and
-d-glucose derivatives not involving
organometallic reagents1
Annie Malleron, Serge David*
 Â
Institut de Chimie Moleculaire d'Orsay, Universite de Paris-Sud, Bt 420, F-91405 Orsay, France
Received 15 December 1997; accepted 21 March 1998
Abstract
The branched chain protected sugar, 2-C-hydroxymethyl-2,3;5,6-di-O-isopropylidene-d-manno-
furanose was speci®cally benzylated at the primary hydroxyl group position by the stannylene
procedure (93%). Oxidation with pyridinium chlorochromate gave in 71% yield 2-C-benzyloxy-
methyl-2,3;5,6-di-O-isopropylidene-d-mannonolactone which was reduced with 3 equiv of samarium
diiodide in oxolane to a 56:44 mixture of the 2-deoxy derivatives, 2-C-benzyloxymethyl-2-
deoxy-5,6-O-isopropylidene-d-mannono- (5) and -d-glucono-lactones in 83% combined yield.
Reduction of lactone 5 with DIBAH in dichloromethane gave the protected branched chain
sugar, 2-C-benzyloxy-2-deoxy-5,6-O-isopropylidene-d-mannose in 63% yield. In the reduction of
2-C-hydroxymethyl-2,3;5,6-di-O-isopropylidene-d-mannonolactone and 2-C-hydroxymethyl-d-
mannonolactone in water solution, only lactones with the d-manno con®guration, 2-deoxy-2-C-
hydroxymethyl-5,6-O-isopropylidene-d-mannonolactone and 2-deoxy-2-C-hydroxymethyl-d-man-
nono-(1,5)-lactone, could be isolated or characterized among the products of the reaction. # 1998
Elsevier Science Ltd. All rights reserved
Keywords: Branched-chain sugars; Stannylenes; Samarium diiodide
1. Introduction
pyruvate yielded a precursor of sequence 12±20 of
Amphothericin B. The key step for the branching
was the copper-catalysed conjugate addition of
vinylmagnesium bromide to an unsaturated ester, a
product of a Wittig±Horner condensation. We now
report a method for the preparation of derivatives
of the same branched-chain hexose which does not
involve organometallic reagents.
We have recently reported a synthesis of the
branched-chain hexose, 2-deoxy-2-hydroxymethyl-
d-mannose [1]. Interest in this sugar stemmed from
the fact that enzymatic aldol condensation with
* Corresponding author.
1
Most textbooks report the Fischer±Kiliani con-
densation of cyanide with ketoses as a route to
Dedicated to Professor Roger Jeanloz on the occasion
of his 80th birthday.
0008-6215/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00080-9

94
A. Malleron, S. David/Carbohydrate Research 308 (1998) 93±98
branched-chain sugars. We are aware of only two
applications of this method which are closely rela-
ted. Wood and Neish [2] prepared the cyanohydrin
of d-fructose following the method of Zervas and
Sessler [3] with pure liquid hydrogen cyanide in
great excess. After acidic hydrolysis, and some
puri®cation steps, they isolated a crystalline lac-
tone from which 2-C-hydroxymethyl-d-glucose
was prepared on the mole scale by sodium amal-
gam reduction. Gorin and Perlin [4] achieved cya-
nohydration of 3-O-benzyl-d-fructose with sodium
cyanide at pH 9.3. Partial crystallisation of the
lactone occurred after several months to give 3-O-
benzyl-2-C-hydroxymethyl-d-mannono-ꢀ-lactone in
24% yield from the mixture.
was 2-C-hydroxymethyl-2,3;5,6-di-O-isopropylidene-
d-mannose (2) (Scheme 1). Compound 2 is readily
available in 86% yield by aldol condensation of
2,3;5,6-di-O-isopropylidene-d-mannose 1 with for-
maldehyde [5]. Benzylation of 2 by the stannylene
procedure gave the benzyl ether 3 (93% yield),
rather than the benzyl mannoside. This is in agree-
ment with the general observation that the primary
position is preferred in similar reactions. Although
1
the interpretation of the H NMR spectrum was
not straightforward, TLC (1:1 hexane±ethyl acetate)
gave no evidence for the presence of a presumably
more polar primary alcohol. Furthermore, lactone
4 was obtained in 71% yield by oxidation of 3 with
pyridinium chlorochromate [6].
The next step was the replacement by hydrogen
of the tertiary oxygen atom. It has been reported
that the free radical deoxygenation of tertiary
alcohols via dithiocarbonates involves large
amounts of initiators [7]. Paracyanobenzoates of
tertiary alcohols are reduced by tributylstannane
2. Discussion
In view of all these practical diculties, we con-
sidered that the most convenient starting material
Scheme 1.

A. Malleron, S. David/Carbohydrate Research 308 (1998) 93±98
95
when geminal to a carbonyl [8] but the utilization
of this method in the present case would have
involved several additionnal steps. At this stage,
our attention was turned to a paper describing the
ꢁ-deoxygenation of aldonolactones [9] by samar-
ium diiodide [10]. It was then of interest to test this
approach for the deoxygenation of a tertiary alco-
hol. A solution of lactone 4 in oxolane±ethylene
glycol was treated at room temperature by SmI2 in
the same solvent (3 equiv) to give a 56:44 mixture
of the d-manno (5) and d-gluco (6) isomers. The
reduction was instantaneous and the combined
yield of reduced lactones (83%) was comparable to
that reported in the reduction of secondary hydro-
xyl groups at the same position. The d-manno
con®guration was ascribed to the lactone with the
larger J2,3 coupling (5 Hz). The corresponding
value for its isomer was 1.5 Hz. The chemical shifts
of H-2 protons in deuterium oxide were 2.95 and
2.77 ppm, respectively, for lactones 5 and 6.
E€orts were made towards minimal protection.
Reduction, under the same conditions of lactone 8
(Scheme 2), readily prepared according to ref. [8],
gave also a mixture of products with the d-manno
and d-gluco con®gurations in very good combined
yield (91%), but in this case the proportion of the
d-manno derivative in the mixture was increased to
75%. Partial hydrolysis of the acetal function
occurred during the work-up, thus for identi®ca-
tion purpose the preparations were converted to
the free lactones 9 and 10 by treatment with an
acidic resin. The relevant NMR data for H-2 were
ꢂ 3.15 ppm (J2,3 5 Hz) for 9 and ꢂ 2.83 ppm (J2,3
2 Hz) for 10.
A more recent paper [11] reported on the reduc-
tion of sugar lactones in oxolane±water mixtures.
We examined the behaviour in this solvent system
of the same lactone 8 and also that of the free lac-
tone 12 (Scheme 2). Lactone 12 was prepared by
acidic hydrolysis of 8. The product appeared
1
homogeneous by H NMR. The constitution of a
ꢀ-lactone and its con®guration were indicated by
the small value of the coupling constant, 3.5 Hz,
between protons H-3 and H-4. These would exhibit
a trans diaxial relationship in a ꢂ-lactone. The car-
1
bonyl infrared frequency, 1772.7 cm is of poor
diagnostic value.
Reduction of lactone 8 occurred very rapidly in
water±oxolane mixture as evidenced by the dis-
appearance of the blue colour of SmI2. However,
the ethereal extract contained only the d-manno
product 11, isolated in 51% yield. In the experi-
ments with lactone 12, ether extraction of the
reduced products is obviously not suitable. After
the removal of cations over an ion-exchange col-
umn and partial chromatographic puri®cation, a
1
crude fraction was obtained in 81% yield. Its H
NMR spectrum characterized it as a mixture of the
d-mannonolactone 9 (55%) and another, uni-
denti®ed compound. It is remarkable that, in these
two reductions in the presence of water, we have
not observed, in the products, the NMR signal that
Scheme 2.

96
A. Malleron, S. David/Carbohydrate Research 308 (1998) 93±98
could possibly correspond to H-2 of the d-gluco
isomer 10.
®ltration and washed with ether. Chromatography
of the residue (85:5 and then 4:1 hexane±EtOAc)
gave lactone 4 (1.69 g; 71%), mp 87±88 C (ether±
ꢀ
For the conversion of the lactones to the hemi-
acetals, we ®rst tried the classical method, sodium
amalgam in water. In this way, 2-C-hydroxy-d-
gluconolactone has previously been reduced to 2-
C-hydroxymethyl-d-glucose on the mole scale in
65% yield [2]. The conditions of the reduction of
d-gluconolactone to d-glucose have been carefully
worked out [12], and these experiments were repe-
ated without any problem. However, the same
technique failed when applied to lactone 9 as
checked by the triphenyltetrazolium test [13]. We
also failed to obtain any reducing sugar with
sodium borohydride in acidi®ed water [14]. Finally,
the protected lactone 5 was reduced in dichlor-
omethane solution by diisobutylaluminium hydride
[15] in hexane, to give the protected sugar, 2-C-
benzyloxymethyl-2-deoxy-5,6-O-isopropylidene-d-
mannose (7) (Scheme 1) in 63% yield.
hexane); [ꢁ]D +39.4ꢀ (c 1.27, CH2Cl2); H NMR
(CDCl3): ꢂ 7.43±7.2 (m, 5 H, Ph), 4.76 (d, 1 H, J3,4
3 Hz, H-3), 4.61 (d, 1 H, J 12 Hz, PhCHH), 4.52 (d,
1 H, PhCHH), 4.47±4.34 (m, 2 H, H-4, H-5), 4.15
20
1
0
(dd, 1 H, J5,6 5, J6,6 10 Hz, H-6), 4.07 (dd, 1 H,
0
0
J5,6 4 Hz, H-6 ), 3.94 (d, 1 H, Jab 9 Hz, Hb), 3.72 (d,
1 H, Ha), 1.47 (s, 6 H, 2 Me), 1.38 (s, 6 H, 2 Me).
Anal. Calcd for C20H2607: C, 63.46; H, 6.93; O,
29.61. Found: C, 63.37; H, 6.99; O, 29.82.
2-C - Benzyloxymethyl - 2 - deoxy - 5,6 - O-isopropyli-
dene-d-mannono- (5) and -d-glucono- (6) lactones.ÐTo
a soln of lactone 4 (151 mg; 0.4 mol.) and ethylene
glycol (297 mg; 12 equiv) in oxolane (4 mL), under
an argon atmosphere, was added dropwise a soln
of SmI2 in oxolane (0.1 M; 18 mL). Filtration of
the mixture over a layer of silica gel, removal of
volatiles from the ®ltered soln and chromato-
graphy of the residue (1:1 light petroleum±EtOAc)
separated ®rst the mannonolactone 5 (58 mg;
56%), mp 98±99 ꢀC (hexane±EtOAc); [ꢁ]D
20
3. Experimental
+31.2ꢀ (c 1.025, CH2Cl2); H NMR (CDCl3): ꢂ
1
General methods.ÐChromatographic separa-
tions have been performed on silica gel columns. In
the descriptions of the NMR spectra, Ha and Hb
refer to the proton of the branched group.
7.4±7.2 (m, 5 H, Ph), 4.71 (ddd, 1 H, J2,3 5, J3,4 3,
J3,OH 3 Hz, H-3), 4.57 (s, 2 H, PhCH2), 4.45 (ddd, 1
0
H, J4,5 8, J5,6 6, J5,6 4 Hz, H-5), 4.20 (dd, 1 H, H-
0
4), 4.16 (dd, 1 H, J6,6 9 Hz, H-6), 4.04 (dd, 1 H, H-
2-C-Benzyloxymethyl-2,3;5,6-di-O-isopropylidene-
d-mannose (3).ÐA soln of the protected sugar 2
(3.1 g; 10.7 mmol) and Bu2SnO (2.93 g; 1.1 equiv)
in toluene (100 mL) was re¯uxed for 16 h (Dean-
Stark), and then concentrated to about 50 mL and
cooled to room temperature. Tetrabutylammonium
bromide (1.7 g; 0.5 equiv) and benzyl bromide
(1.53 mL; 1.2 ꢀequiv) were added and the soln was
heated at 80 C for 1 h. Evaporation of volatiles
gave a residue, from which the benzyl ether 3 was
separated by chromatography (3:1 hexane±
60), 3.95 (d, 1 H, J2,b 7 Hz, Hb), 3.94 (d,1 H, J2a
5 Hz, Ha), 3.22 (d, 1 H, OH), 2.95 (ddd, 1 H, H-2),
1.45 (s, 3 H, Me), 1.37 (s, 3 H, Me). Anal. Calcd
for C17H22O6: C, 63.33; H, 6.88; O, 29.79. Found:
C, 63.09; H, 6.92; O, 29.62.
Further elution gave the gluconolactone 6
ꢀ
(45 mg; 44%), mp ꢀ75±76 C (2-isopropoxyprop-
20
1
ane); [ꢁ]D +43.7 (c 0.48, CH2Cl2); H NMR
(CDCl3): ꢂ 7.45±7.15 (m, 5 H, Ph), 4.60 (m, 1 H, H-
3), 4.56 (d, 1 H, J 12 Hz, PhCHH), 4.47 (d, 1 H,
PhCHH), 4.37 (m, 2 H, H-4, H-5), 4.19 (m, 1 H, H-
EtOAc), as a syrup (3.54 g; 93%), [ꢁ]D +5.5ꢀ (c
60), 4.04 (dd, 1 H, J6,6 9, J5,6 4 Hz, H-6), 3.84 (dd, 1
20
0
1.1, CH2Cl2). Anal. Calcd for C20H28O7: C, 63.13;
H, 7.42, O, 29.45. Found: C, 62.83; H, 7.31; O,
29.37.
H, J2,a 3, Ja,b 9 Hz, Ha), 3.77 (dd, 1 H, J2,b 4 Hz,
Hb), 2.77 (ddd, 1 H, J2,3 1.5 Hz, H-2), 2.75 (s,1 H,
OH), 1.46 (s, 3 H, Me), 1.37 (s, 3 H, Me). Anal.
Calcd for C17H2206: C, 63.33; H, 6.88; O, 29.79.
Found: C, 62.99; H, 6.91; O, 29.96.
2-C-Benzyloxymethyl-2,3;5,6-di-O-isopropylidene-
d-mannonolactone (4).ÐPyridinium chlorochrom-
ate (2.04 g; 1.5 equiv) was added to a suspension of
3 (2.4 g; 6.3 mmol) and powdered 4 A molecular
sieves in CH2Cl2 (40 mL) under a N2 atmosphere.
The suspension was stirred for 2 h at room
temperature, dry ether was added (200 mL) and
stirring was continued until the black precipitate
became granular. The precipitate was removed by
2-C-Benzyloxymethyl-2-deoxy-5,6-O-isopropyli-
dene-d-mannose (7).ÐA soln of DIBAH in hexane
(1 M, 0.28 mL) was added to a soln of 5 (82 mg;
ꢀ
0.25 mmol) in CH2Cl2 (2.5 mL), kept at 78 C.
The reaction was stopped after 30 min by the
addition of a saturated soln of NH4Cl, the mixture
was diluted with CH2Cl2 and the organic layer

A. Malleron, S. David/Carbohydrate Research 308 (1998) 93±98
97
washed with water, dried and evaporated. Chro-
matography of the residue (3:1 light petroleum±
H-60), 3.92 (dd, 1 H, J2,a 5.5, Ja,b 12 Hz, Ha), 3.84
(dd, 1 H, J2,b 7.5 Hz, Hb), 3.14 (ddd, 1 H, H-2),
1.45 (s, 3 H, Me), 1.37 (s, 3 H, Me). Anal. Calcd
for C10H16O6: C, 51.70, H, 6.95, O, 41.35. Found:
C, 51.55; H, 6.95; O, 41.62.
2-C-Hydroxymethyl-d-mannonolactone (12).ÐA
soln of lactone 8 (1.49 g; 5.13 mmol) in water
(20 mL) was heated at 70 ꢀC for 5 h in the presence
of Dowex-50 (H+) resin, (wet, 2 g). After ®ltration,
the soln was evaporated to dryness. Chromato-
graphy of the residue (9:1 1-propanol±water) allowed
separation of lactone 12 as a syrup (912 mg; 92%);
20
EtOAc) gave 7 as a syrup (51 mg; 63%); [ꢁ]D
11.3ꢀ (c 0.92 CH2Cl2). Anal. Calcd for C17H24O6:
C, 62.93. H, 7.46; O, 29.61. Found: C, 62.89, H,
7.65; O, 29.71.
2-Deoxy-2-hydroxymethyl-d-glucono- (10) and
-d-mannono (9) -(1,4)-lactones.ÐA soln of SmI2
in oxolane (0.1 M; 39 mL) was added dropwise to a
soln of lactone 8 (460 mg; 1.6 mmol) and ethylene
glycol (1.07 mL; 12.2 mmol) in oxolane (10 mL)
under an argon atmosphere. The mixture was ®l-
tered through a layer of silica gel and the solvent
was removed by evaporation from the ®ltered soln.
Chromatography of the residue (1:1 and 1:2 light
petroleum±EtOAc) gave in succession the pro-
tected d-gluco derivative (46 mg), a mixed fraction
(74 mg) and the protected d-manno derivative
(217 mg). Deprotection of each of these fractions
was achieved by brief treatment in water soln with
Dowex-50 (H+) resin.
1
1
IR (KBr): ꢃmax 1772.7 cm
(CO), 3422.8 cm
1
(OH); H NMR (D2O): ꢂ 4.56 (dd,1 H, J3,4 3.5 Hz,
J4,5 9 Hz, H-4), 4.40 (d, 1 H, H-3), 4.02 (ddd, 1 H, J5,6
0
0
3.5, J5,6 5 Hz, H-5), 3.82 (dd, 1 H, J6,6 12Hz, H-6),
3.77 (s, 2 H, HaHb), 3.68 (dd, 1 H, H-60).
Reduction of lactone 12 by SmI2 in water.ÐA
soln of SmI2 in oxolane (0.1 M; 52 mL) was added
dropwise to a soln of lactone 12 (360 mg;
ꢀ
1.73 mmol) in degassed water (17 mL) kept at 0 C
Lactone 10 was obtained as a syrup, [ꢁ]D20 +67ꢀ
under argon. After removal of oxolane by eva-
poration, the soln was passed through a 1.5Â15 cm
column of Dowex-50 (H+) resin. Acidic fractions
were collected and evaporated to dryness, then
kept for 16 h at room temperature to allow lacto-
nisation. Chromatography (95:5 then 9:1 CH2Cl2±
MeOH) allowed the separation of the reduced
1
(c 0.6, H2O); H NMR (D2O): ꢂ 4.63 (dd, 1 H, J2,3
2, J3,4 4 Hz, H-3), 4.52 (dd, 1 H, J4,5 7 Hz, H-4),
0
4.03 (ddd, 1 H, J5,6 2.5, J5,6 4.5 Hz, H-5), 3.90 (dd,
0
2 H, J 4 Hz, Ha, Hb), 3.80 (dd, 1H, J6,6 10 Hz, H-
6), 3.68 (dd, 1H, H-60), 2.83 (ddd, 1H, H-2). Anal.
Calcd for C7H12O6, 0.5 H2O: C, 41.79; H, 6.46.
Found: C, 41.51; H, 6.28.
1
products (271 mg). The H NMR spectrum (D2O)
was consistent with the presence of 55% of lactone
9 in this mixture.
Lactone 9 was obtained as a syrup, [ꢁ]D +70ꢀ
20
(c 1 in H2O); 1H NMR (D2O): ꢂ 4.72 (dd, 1 H, J2,3
5, J3,4 3 Hz, H-3), 4.38 (dd, 1 H, J4,5 9 Hz, H-4)
0
3.96 (ddd, 1 H, J5,6 3, J 5,6 5.5 Hz, H-5), 3.895 (d, 1
H, J2,a 5.5 Hz, Ha), 3.890 (d, 1 H, J2,b 7.5 Hz, Hb),
0
Acknowledgement
3.80 (dd, 1 H, J6,6 12 Hz, H-6), 3.66 (dd, 1 H, H-
60), 3.15 (ddd, 1 H, H-2). Anal. Calcd for C7H12O6:
C, 43.75; H, 6.25; O, 50.00. Found: C, 43.64; H,
6.11; O, 49.66.
The authors are indebted to Professor A. Lubi-
neau for his support in the completion of this
work.
2-Deoxy-2-C-hydroxymethyl-5,6-O-isopropylidene-
d-mannonolactone (11).ÐA soln of SmI2 in oxo-
lane (0.1 M; 45 mL) was added dropwise to a soln
of 8 (432 mg; 1.5 mmol) in degassed water (10 mL)
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ꢀ
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20
1
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