The synthesis of polyoxygenated, enantiomerically pure cyclopentane derivatives on route to neplanocin A stereoisomers via alkylidenecarbene species prepared from sugar templates

Article abstract of DOI:10.1016/j.carres.2009.04.006

Our new method for the generation of alkylidenecarbenes, based on the reaction of trimethylsilylazide/Bu₂SnO with α-cyanomesylates, has been applied to the synthesis of enantiomerically pure polyhydroxylated cyclopentane derivatives from conven

Full text of DOI:10.1016/j.carres.2009.04.006

Carbohydrate Research 344 (2009) 1605–1611
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
The synthesis of polyoxygenated, enantiomerically pure cyclopentane
derivatives on route to neplanocin A stereoisomers via alkylidenecarbene
species prepared from sugar templates
b
b
a,
Albert Nguyen Van Nhien a, , Elena Soriano , José Marco-Contelles , Denis Postel
*
*
a Laboratoire des Glucides UMR6219, Université de Picardie Jules Verne, Faculté des Sciences, 33, rue Saint Leu, 80039 Amiens, France
b Laboratorio de Radicales Libres y Química Computacional (IQOG, CSIC), C/Juan de la Cierva, 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Our new method for the generation of alkylidenecarbenes, based on the reaction of trimethylsilylazide/
Bu2SnO with -cyanomesylates, has been applied to the synthesis of enantiomerically pure polyhydroxy-
lated cyclopentane derivatives from conveniently functionalized sugar intermediates prepared from
Received 21 January 2009
Received in revised form 31 March 2009
Accepted 9 April 2009
a
D
-mannose. The stereoselectivity of the 1,5 C–H insertion reaction leading to the major trans-isomers
Available online 14 April 2009
(8a,b) has been assigned by 1H RMN spectroscopic data, and correctly rationalized by a computational
analysis at DFT level. Compounds 8a and 8b have been designed as suitable intermediates for the synthe-
sis of neplanocin A enantiomer.
Keywords:
Alkylidenecarbenes
Ó 2009 Elsevier Ltd. All rights reserved.
a-Cyanomesylates
1,5 C–H bond insertion reactions
Polyhydroxylated cyclopentanes
Neplanocin A stereoisomers
DFT analysis
1. Introduction
methodology was hampered by the well-known explosive combi-
nation of sodium azide and halogenated solvents.4,5
In the last years, the synthesis and subsequent transformation
of reactive species such as alkylidenecarbenes have been the object
of a continuous interest.1 Accordingly, a number of methods have
been documented for the generation of these highly reactive spe-
Some years ago,6 and starting from
a-cyanomesylates, we have
reported that the synthesis of 5-substituted tetrazoles, according
to Wittenberger’s method7 (trimethylsilyl azide, dibutyltin oxide,
toluene), provided a-mesyltetrazolyl intermediates that smoothly
cies, such as fluoride-induced
anes or silylvinyl triflates,2a,b thermal decomposition of tosylazo-
alkenes,2c or diazoalkenes,2d weak base-induced
-elimination of
alkenyliodonium salts,2e samarium diiodide reaction with 1,1-
dihalogenoalkenes,2f or from ,b-epoxy-N-aziridinyl imines.2g
Czernecki was the first to use -cyanomesylates for this pur-
pose; upon treatment with sodium azide/DMF a presumed alkyl-
idenecarbene species were formed that after 1,2-H shift gave
acetylenic derivatives.3 The reaction of sodium azide in methylene
chloride, at room temperature, in the presence of tetrabutylammo-
a
-elimination of
a
-chlorovinylsil-
and in mild reaction conditions led to the desired alkylidenecarb-
enes species, giving some useful intramolecular transformations
(see for instance the transformation of compound 1 to 2, via inter-
mediate A, Scheme 1) via rare 1,6 C–H bond insertion reactions.8
As a proof of concept, and in order to extend these results to
other substrates, we have now directed our attention to the syn-
thesis and reactivity of conveniently functionalized precursors for
the synthesis of polyhydroxylated cyclopentane derivatives after
1,5 C–H insertion reactions, a simple methodology that has proved
its efficiency in the synthesis of several natural products including
cyclopentene scaffold such as neplanocin A.9,10 In these approaches
major trans-isomers were isolated and characterized by 1H NMR
analysis, due to a presumed steric hindrance that shifts the equilib-
rium of the alkylidenecarbene species (X1/X2) to X2, and taking
into account the vicinal coupling constants at the newly formed
stereocenters (Scheme 2). In this communication we describe the
results that we have obtained on related chemistry but using
a
a
a
nium hydrogenosulfate, with a-cyanomesylates derived from con-
veniently functionalized uloses, produced alkylidenecarbenes as
very reactive intermediates that were trapped in situ in intermolec-
ular processes with an azide anion, the solvent, or alkenes to give
branched sugars and nucleosides.4 The obvious interest of this
D-mannose as precursor for the synthesis of suitable intermediates
* Corresponding authors. Fax: +33 3 22827568 (D.P.).
E-mail addresses: albert.nguyen-van-nhien@u-picardie.fr (A. Nguyen Van
Nhien), denis.postel@u-picardie.fr (D. Postel).
leading to advanced compounds targeted for the preparation of
neplanocin A stereoisomers (Fig. 1).9,10
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.04.006

1606
A. Nguyen Van Nhien et al. / Carbohydrate Research 344 (2009) 1605–1611
NH2
N
O
O
TMSN3
O
N
O
BnO
BnO
OSnBu2
TBAF
O
HO
O
N
- FSiMe3
F- Bu4N+
N
N
OMs
NC OMs
N
N
(45-50%)
SiMe3
N
O
1
HO
OH
Figure 1. Neplanocin A.
O
O
N
O
N
- N2
BnO
BnO
- OMs
O
O
N
OMs
OMs
N
OH
O
O
O
OH
N
OH
N
b or c
O
N
N
O
a
O
O
O
O
O
O
O
4
3
H
O
O
O
O
6a
(46/54)
OR
O
O
BnO
OH
O
O
NC
OR
OMs
O
O
d
O
e
O
H
Ph
2β/α (1:4)
O
Ph
O
O
A
O
6b
(14/86)
Scheme 1.
5a R= TBDMS
5b R= Bz
6a R= TBDMS
6b
R= Bz
2. Results and discussion
Starting from commercial 2,3:5,6-di-O-isopropylidene-
H
OR
4
H
O
O
O
4
D-man-
OR
3a
nose (3), reduction with LAH as described,11 provided diol 4
(Scheme 3) that after routine transformations involving selective
O-protection as the monosilyl (5a)12 and monobenzoate (5b)13
derivatives, followed by oxidation of the remaining secondary
alcohol, addition of cyanide, and subsequent mesylation gave com-
pounds 6a and 6b, respectively, as a mixture of diastereoisomers at
C4, which we did not try to separate, but were submitted together
to further reaction. Formation of the alkylidenecarbene species as
usual6 gave the cyclopentane derivatives 7a (7%) and 8a (18%), iso-
lated in a 25% total yield (Scheme 3). Similarly, but using benzoate
5b, the 1,5 C–H insertion reaction gave the expected carbocyclic
derivatives 7b and 8b in 5% and 36% chemical yield, respectively
O
O
6a
3a
+
6a
O
O
O
8a
R= TBDMS (18%)
J3a,6a= 5.7 Hz
8b R= Bz (36%)
3a,6a= 5.8 Hz
7a R= TBDMS (7%)
J4,3a, J3a,6a= 5.5 Hz
J4,3a= 0 Hz
7b
R= Bz (5%)
J4,3a, J3a,6a= 5.5 Hz
J
J4,3a= 0.7 Hz
Scheme 3. Reagents and conditions: (a) AlLiH4, THF, 0 °C to rt (96%); (b) TBDMSCl,
imidazole, DMF (87%); (c) BzCl, pyridine, CH2Cl2 (70%); (d) (i) PDC, Ac2O, molecular
sieves, CH2Cl2, reflux; (ii) KCN, NaHCO2, CH2Cl2, H2O, rt; (iii) MsCl, Et2N, CH2Cl2, rt
(5a to 6a (75%), 5b to 6b (72%); (e) TMSN3, Bu2SnO, toluene, 100 °C.
H
H
R1
R1
OR2
H
OR2
H
O
O
(Scheme 3). The assignment of the absolute configuration at the
newly formed stereocenter (C4) in compounds 7 and 8 as shown
has been established by comparison of the observed vicinal cou-
plings constant for H3a, with the values reported for similar com-
pounds described in the literature.9 Consequently, and as
expected,9 the formation of major isomers 8a,b takes place from
the opposite face where the bulky O-isopropylidene group is
located (see Scheme 2), leading to major trans-isomers.
These results compared favorably with those reported in the lit-
erature for the synthesis of related cyclopentane intermediates,
using lithiotrimethylsilyldiazomethane in THF at 0 °C,14 as in the
case of compound of type B (Scheme 2), bearing a O-trityl substitu-
ent at C-5 and a O-tert-butyldimethylsilyl group at C-1, the global
yield for the cyclization reaction was 55–65%, and the ratio of iso-
mer was 2:7,9 while for compounds of type C (Scheme 2), bearing
O
O
X2
( ) R = CH2OTr, R = OTBDMS (ref. 9)
X1
1
2
B
1
2
C
( ) R = CH2OTr, R = purin-9-yl (ref. 10)
OR2
OR2
R1
H
R1
H
J= 0 Hz
J= 5.5 Hz
+
H
H
O
O
O
O
trans-
cis-
<<<<<<<<<<
Scheme 2. 1,5 C–H insertion reactions leading to cyclopentane derivatives.

A. Nguyen Van Nhien et al. / Carbohydrate Research 344 (2009) 1605–1611
1607
an O-trityl substituent at C-5 and a purin-9-yl group at C-1, the glo-
bal yield for the cyclization reaction was 30%, and the ratio of iso-
mer was 1:2.10 However, and in spite of these clear evidences, we
decided to undertake a computational analysis in order to clearly
evaluate the preferred way for the formation of the major isomers
observed in these cyclizations.
is originally attached and the doubly bound carbon atoms of the
carbene (deviation of 0.7° and 10.3°, respectively, Table 1).
In this arrangement, the alkane C–H bond molecular orbital is
periplanar with and therefore can overlap with the empty orbital
of the alkylidenecarbene.16 It could be thought that steric interac-
tions between the H and the carbons would be reduced if the
breaking C–H bond were out of the plane defined by C1–C2–
C5.17 However, the geometric parameters of the structures in the
transition state (long C5–H and C1–C5 distances and a nearly
formed C1–H bond, Table 1) ensure minor van der Waals repul-
sions. Furthermore, these distances reveal that the new carbon–
hydrogen bond forms much faster than does the new carbon–car-
bon bond. To note that it is due to an acute asynchronicity in the
formation of the C–C and C–H bonds in a single step, as IRC calcu-
lations have confirmed. H lies between C1 and C5 in the molecular
plane. As the C5–H distance increases, C1 approaches C5. In the
further course of the reaction the C1–C5 and C1–H bonds are built,
and cyclopentenes 10 and 11 are obtained. Therefore, the cycliza-
tion is a concerted process, although strongly asynchronous.
As we have observed previously in related calculations,6b the C–H
insertion can be viewed as having an electrophilic phase (involving
the empty p empty orbital) followed by a nucleophilic phase (involv-
ing the nonbonding orbital). The initial electrophilic stage consists of
3. Computational study
We have also carried out a DFT computational analysis to ex-
plain the stereoselectivity observed for the 1,5-C–H insertion. This
transformation takes place through the key transient intermedi-
ates alkylidenecarbenes. Accordingly, in the present study, carbene
9 has been selected as theoretical model 9 (Chart 1, see labeling).
Previous observations6b on related alkylidenecarbenes have
shown us that they exist in singlet state, S0, as ground state.
According to the traditional assumption, in S0 there is an empty
p
orbital on the carbene carbon, and the nonbonding unshared
p
spin-paired electrons occupy an sp-like orbital in the plane of the
molecule. The computed HOMO of the alkylidencarbene 9 is delo-
calized over several atoms, but a great contribution to the HOMO
comes from C1 (Fig. 2; for numbering, see Chart 1). On the other
hand, the LUMO orbital is a p orbital mainly located at the carbene
p
the formation of a complex by interaction of the
relectrons of the C–
carbon C1.
Hbondwiththeemptyporbitalofthecarbenecarbon(NPAchargeof
0.155 for C1 in 9, Table 2). This flow of charge is maximum at the
transition state and is followed by a nucleophilic phase where the
nonbonding electrons of the carbene interact with the hydrogen
atom. This interaction is favored by the C–H elongation promoted
in the first phase of the C–H insertion step. Namely, the insertion oc-
curs initially through an electrophilic phase followed by a nucleo-
philic phase resulting in a net charge flow from the alkane to the
inserting carbene during the first part of the reaction (Table 2).
The transition structures TS10 and TS11 show similar key dis-
tances between the involved atoms, although they suggest a
slightly earlier transition state for TS11. Selected structural param-
eters of transition states and intermediates are given in Table 1.
From an energetic point of view, our results clearly reveal a
In addition, the NBO analysis on 9 shows that the carbene car-
bon is approximately sp1.5 hybridized (sp1.46) and contains a lone
pair in the NBO of predominant s character with 36.5% p mixing.
These facts indicate the reactive site in 9.15
Two stereoisomers can be formed by 1,5 C–H insertion of the
alkylidencarbenes, 10 and 11. The half chair-like transition struc-
tures TS10 and TS11 found (Fig. 3), respectively, show the hydrogen
atom of interest in a plane defined by the carbon atom to which it
H
1
OBz
H
kinetic preference for the formation of 11 (2.9 vs 5.4 kcal molꢀ1
,
O
2
5
3
4
Fig. 2), where the bulky protecting group is located in the opposite
face of the O-benzoylic moiety at the new stereocenter. This result
is supported by the experimental results which describe the forma-
tion of major trans-isomers 8a,b.
O
O
O
The kinetic preference is due to an electrostatic repulsion be-
tween the oxygen atoms of the dioxolane and benzoate moieties.
Thus, while in TS11 we have not observed critical destabilizing
9
Chart 1.
Figure 2. LUMO and HOMO of 9.

1608
A. Nguyen Van Nhien et al. / Carbohydrate Research 344 (2009) 1605–1611
Figure 3. Enthalpy profile (in kcal molꢀ1) for the 1,5 C–H insertion process of the alkylidenecarbene into the alkane carbon C5, to yield two possible stereoisomers, 10 and 11
(free energy differences are shown in parentheses).
Table 1
Table 2
Structural key parameters (distances in Å, bond angles and dihedral angles in °)
NPA charges in the 1,5 C–H insertion process
during the 1,5 C–H insertion process
9
TS10
10
TS11
11
9
TS10
10
TS11
11
C1
C2
C3
C4
C5
H
0.155
ꢀ0.172
ꢀ0.229
0.0553
0.029
0.049
0.258
ꢀ0.215
ꢀ0.072
0.038
0.050
0.027
ꢀ0.167
ꢀ0.227
0.056
0.027
0.039
ꢀ0.219
ꢀ0.071
0.039
0.057
0.027
C1–C2
C2–C3
C3–C4
C4–C5
C5–H
H–C1
C1–C5
C1–C2–C3
C2–C3–C4
C3–C4–C5
C4–C5–H
C5–H–C1
C5–C1–C2
C2–C1–H–C5
1.305
1.541
1.537
1.517
1.096
2.180
2.857
127.8
116.7
116.8
110.4
117.5
85.5
1.324
1.530
1.539
1.508
1.461
1.159
2.271
124.1
109.1
112.1
119.5
119.7
93.6
1.337
1.515
1.561
1.566
1.324
1.530
1.540
1.503
1.440
1.168
2.245
124.1
108.4
112.8
118.9
118.5
94.0
1.337
1.517
1.557
1.543
ꢀ0.392
0.070
0.041
ꢀ0.143
0.252
0.259
0.267
0.267
1.084
1.500
112.0
104.8
105.5
1.083
1.505
112.0
104.0
106.1
4. Conclusions
The generation of alkylidenecarbene species, based on the
reaction of trimethylsilylazide/Bu2SnO with -cyanomesylates,
has been applied to the synthesis of enantiomerically pure poly-
112.9
0.5
112.3
0.5
a
33.8
ꢀ0.7
10.3
hydroxylated cyclopentane derivatives from conveniently func-
interactions, in TS10
a
short OꢁꢁꢁO distance can be detected
tionalized sugar intermediates prepared from D-mannose. The
(2.666 Å), shorter than the sum of the van der Waals radii. This
repulsive interaction destabilizes the transition structure TS10 that
leads to the S-isomer. From a thermodynamic perspective, the 1,5-
insertion reaction with C–H by the carbene is strongly exothermic
(ꢂꢀ80 kcal molꢀ1, Fig. 2), whatever the configuration at the new
stereocenter, and hence irreversible.
stereoselectivity of the 1,5 C–H insertion reaction leading to
the major trans-isomers (8a,b) has been assigned by 1H RMN
spectroscopic data, and correctly rationalized by a computational
analysis at DFT level. Compounds 8 have been designed as
suitable intermediates for the synthesis of neplanocin
stereoisomers.
A

A. Nguyen Van Nhien et al. / Carbohydrate Research 344 (2009) 1605–1611
1609
5.4.2. 1-O-tert-Butyldimethylsilyl-2,3:5,6-di-O-isopropylidene-
-mannitol (5a)
To a solution of compound 4 (2.0 g, 7.63 mmol) in DMF (10 mL)
5. Experimental
D
5.1. Materials and methods
were added imidazole (1.04 g, 15.26 mmol) and TBDMSCl (1.26 g,
8.39 mmol). After stirring overnight at room temperature, DMF
was eliminated under reduced pressure. The residue was extracted
with diethyl ether and a saturated solution of NaCl. The organic
layer was dried over Na2SO4, filtered, and evaporated under vacuo.
The residue was purified by flash chromatography (EtOAc/cyclo-
hexane, 20/80) to give product 5a (2.50 g, 87%) as a colorless syrup
Melting points were determined on a digital melting-point appa-
ratus (Electrothermal) and are uncorrected. Optical rotations were
recorded in CH2Cl2, CHCl3, and MeOH, with a digital polarimeter
using a 1 dm cell. 1H NMR and 13C NMR spectra were recorded in
CDCl3, acetone-d6, Me2SO-d6, or MeOD-d3 (internal SiMe4), respec-
tively, at 300.13 MHz and at 75.47 MHz. TLC was performed on Silica
F254 and detection by UV light at 254 nm or by charring with phos-
phomolybdic acid–H2SO4 reagent. Column chromatography was ef-
fected on Silica Gel 60 (230 mesh). Acetone, hexane, cyclohexane,
ethyl acetate, and diethyl ether were distilled before use. Bases
and solvents were used as supplied. 13C NMR resonances have been
assigned by using standard NMR (DEPT, COSY, HSQC) experiments.
{½a D20
ꢄ
ꢀ16.0 (c 0.59, CHCl3); IR (ATR):
m 2985, 2931, 2858, 1724,
1462, 1371, 1251, 1213, 1066 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d
4.39 (d, J2,3 = 7.0 Hz, 1H, H-3), 4.24 (dt, J2,3 = J1a,2 = 7.0 Hz,
J1,2 = 3.8 Hz, 1H, H-2), 4.11 (m, 2H, H-5, H-6A), 4.02 (m, 2H, H-1A,
H-6B), 3.83 (dd, J1a,1b = 10.9 Hz, 1H, H-1B), 3.67 (m, 1H, H-4),
3.17 (m, 1H, OH), 1.50, 1.41, 1.39, 1.36 (s, 12H, 4 ꢃ CH3), 0.91 [s,
9H, SiC(CH3)], 0.11 (s, 6H, 2 ꢃ SiCH3); 13C NMR (CDCl3, 75 MHz) d
109.6 [OC(CH3)2], 108.6 [OC(CH3)2], 76.9, 76.2, 76.1 (C-2, C-3, C-
5), 70.7 (C-4), 67.9 (C-6), 61.9 (C-1), 27.2, 27.0, 25.7, 25.2
(4 ꢃ CH3), 26.2 [C(CH3)], 18.6 [C(CH3)], ꢀ5.0, ꢀ5.1 (2 ꢃ SiCH3).
HRMS: C18H36O6NaSi calcd 399.2203, found 399.2191}, in good
agreement with those reported in the literature.12
FTIR spectra were obtained neat using ATR and are reported in cmꢀ1
.
5.2. General method for oxidation with PDC (A)
To a solution of starting material in CH2Cl2 and powder molec-
ular sieves 3 Å (2.5 equiv w/w), Ac2O (3.5 equiv) was added and the
mixture was refluxed. PDC (0.7 equiv) was added portion wise and
the reaction mixture was stirred for 4–22 h. After evaporation of
the solvent, the reaction mixture was dissolved with EtOAc, and fil-
tered through a silica pad. The filtrate was concentrated under vac-
uum and the crude ulose was used in the next step without further
purification.
5.4.3. 1-O-tert-Butyldimethylsilyl-4-C-cyano-4-O-mesyl-2,3:5,6-
di-O-isopropylidene-D-mann(tall)itol (6a)
Following the general method A, compound 5a (1.0 g, 2.66
mmol), Ac2O (0.87 mL, 9.30 mmol), and PDC (0.70 g, 1.86 mmol)
for 4 h gave a crude ulose, which following the general method
B, was dissolved in CH2Cl2 (20 mL), and treated with added NaH-
CO3 (446 mg, 5.32 mmol), in water (6.18 mL) and with KCN
(370 mg, 5.69 mmol). After stirring for 17 h, the crude cyanohy-
drins were dissolved in CH2Cl2 (20 mL) followed by addition of
Et3N (2.99 mL, 21.28 mmol) and MsCl (1.13 mL, 14.63 mmol). After
2 h and extraction, the residue was purified by flash chromatogra-
phy (EtOAc/cyclohexane, 15/85) to give compound 6a (960 mg,
75%) as an inseparable mixture of diastereoisomers in a 46/54 ra-
5.3. General method for cyanomesylation (B)
Toa solutionofcrudeuloseinCH2Cl2 wasaddeda solutionofNaH-
CO3 (2 equiv) in water and KCN (2.1 equiv). The resulting mixture
was stirred vigorously at rt then extracted with CH2Cl2 (ꢃ2). The or-
ganic phase was separated, dried (Na2SO4), filtered, and evaporated
to dryness. The crude cyanohydrins were dissolved in CH2Cl2 fol-
lowed by addition of Et3N (8 equiv) and MsCl (5.5 equiv) at 0 °C. After
stirring at rt, the mixture wasextractedby slow additionof water and
CH2Cl2. The residue was purified by flash chromatography.
tio: IR (ATR):
m
2949, 2932, 2857, 1472, 1464, 1373, 1361, 1253,
1220, 1183, 1068, 957 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 4.77–
4.09 (m, 7H, 2H-1, H-2, H-3, H-5, 2H-6), 3.27 (s, 3H, OSO2CH3),
1.56, 1.51, 1.40, 1.34 (s, 12H, 4 ꢃ CH3), 0.90 [s, 9H, SiC(CH3)3],
0.10, 0.08 (s, 6H, 2 ꢃ SiCH3); 13C NMR (CDCl3, 75 MHz) d 114.2
(CN), 110.8, 110.7 {2 ꢃ [OC(CH3)2]}, 83.5 (C-4), 79.7 (C-5), 77.6
(C-3), 77.0, (C-2), 67.5 (C-6), 61.3 (C-1), 41.0 (OSO2CH3), 27.1–
25.1 (4 ꢃ CH3, tBu), 18.8 [Si(CH3)3], ꢀ4.7, ꢀ4.8 (SiCH3). HRMS:
C20H37NO8SSi calcd 502.1907, found 502.1902.
5.4. General method for alkylidenecarbene generation (C)
To a solution of cyanomesylate in dry toluene under argon,
dibutyltin oxide (1 equiv) and TMSN3 (2 equiv) were added. The
reaction was heated to 100 °C and stirred for 22-23 h and then
the solvent was removed under vacuo. The crude product was sub-
mitted to flash chromatography (EtOAc/cyclohexane).
5'
5
4'
O
6
4
O
OTBDMS
5.4.1. 2,3:5,6-Di-O-isopropylidene-
D-mannitol (4)
OTBDMS
O
O
6a
A solution of commercial 2,3:5,6-di-O-isopropylidene-
D
-man-
3a
nose (3) (6.0 g, 23.07 mmol) in dry THF (50 mL), cooled at 0 °C,
was treated with AlLiH4 (3.07 g, 80.76 mmol). After stirring for
4 h at room temperature, EtOAc and HCl 2 M were carefully added.
The aqueous layer was extracted with EtOAc (ꢃ3). The organic lay-
ers were dried over Na2SO4, filtered, and concentrated to dryness
to give alditol 4 (5.83 g, 96%) as a white solid [mp 156–157 °C;
O
O
3
O
O
1
2
8a
7a
5.4.4. tert-Butyl {(3aS,4R,6aS)-6-[(S)-2,2-dimethyl-1,3-dioxolan-
4-yl]-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-
4-yloxy}dimethylsilane (7a), and tert-butyl {(3aS,4S,6aS)-6-[(S)-
2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-4,6a-dihydro-
3aH-cyclopenta[d][1,3]dioxol-4-yloxy}dimethylsilane (8a)
Following the general method C, compound 6a (456 mg,
0.95 mmol), Bu2SnO (237 mg, 0.95 mmol) and TMSN3 (0.25 mL,
1.9 mmol) in toluene (9.5 mL) for 23 h at 100 °C gave after flash
chromatography (EtOAc/cyclohexane, 10/90), compounds 7a
(25 mg, 7%) and 8a (63 mg, 18%) as slight yellow solids. Compound
½
a D20
ꢄ
+15.0 (c 0.08, H2O)], showing spectroscopic data {IR (ATR)
3190, 2931, 1450, 1325, 1261, 1078, 1022 cmꢀ1 1H NMR (CDCl3,
75 MHz) 4.92 (t, J1a,OH = J1B,OH = 5.3 Hz, 1H, OH), 4.67 (d,
m
;
d
J4,OH = 6.8 Hz, 1H, OH), 4.16 (m, 2H, H-2, H-3), 3.95 (m, 2H, H-5,
H-6A), 3.82 (dd, J5,6A = 8.1 Hz, J6A,6B = 11.1 Hz, 1H, H-6B), 3.66 (m,
2H, H-1), 3.38 (m, 1H, H-4), 1.38, 1.30, 1.26, 1.25 (s, 12H,
4 ꢃ CH3); 13C NMR (CDCl3, 300 MHz)
d
109.1, 108.1
(2 ꢃ [OC(CH3)2]), 78.2, 76.6, 76.5 (C-2, C-3, C-4), 70.2 (C-5), 67.3
(C-6), 60.5 (C-1), 27.5, 27.4, 26.2, 26.0 (4 ꢃ CH3)} in good agree-
ment with those reported in the literature.11
7a: ½a D20
ꢄ
+47.0 (c 0.10, CHCl3); IR (ATR): m 2985, 2929, 2856, 1471,

1610
A. Nguyen Van Nhien et al. / Carbohydrate Research 344 (2009) 1605–1611
1369, 1244, 1209, 1157, 1107, 1060 cmꢀ1
;
1H NMR (CDCl3,
26.4, 26.1, 25.4 (4 ꢃ CH3). HRMS: C21H27O9NSNa calcd 492.1304,
300 MHz) d 5.77 (s, 1H, H-5), 4.85 (t, J3a,4 = 5.5 Hz, J3a,6a = 5.5 Hz,
found 492.1296.
1H, H-3a), 4.66 (m, 3H, H-4, H-6a, H-40), 4.22 (dd, J4 ,5 A = 6.1 Hz,
0
0
J5 A,5 B = 8.1 Hz, 1H, H-50A), 3.81 (t, J4 ,5 B = 8.1 Hz, 1H, H-50B), 1.45,
1.42, 1.40, 1.37 (s, 12H, 4 ꢃ CH3), 0.93 [SiC(CH3)], 0.14 (SiCH3),
0.13 (SiCH3); 13C NMR (CDCl3, 75 MHz) d 142.9 (C-6), 130.4 (C-5),
112.6 [OC(CH3)2], 109.3 [OC(CH3)2], 83.5 (C-3a), 79.0, 74.8, 73.8
(C-4, C-6a, C-40), 69.6 (C-50), 27.8, 27.0, 26.8, 26.3 (4 ꢃ CH3), 26.3
[SiC(CH3)3], 18.9 [SiC(CH3)3], ꢀ3.9 (SiCH3), ꢀ4.3 (SiCH3). HRMS:
0
0
0
0
5
O
4
6
O
OBz
OBz
O
6a
O
3a
3
O
O
1
2
O
O
C19H34O5Si calcd 393.2073, found 393.2089. Compound 8a: ½a 2D0
ꢄ
7b
8b
+73.0 (c 0.32, CHCl3); IR (ATR)
m 2985, 2929, 2856, 1471, 1464,
1369, 1249, 1209, 1155, 1058 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d
5.75 (s, 1H, H-5), 5.16 (d, J3a,6a = 5.7 Hz, 1H, H-3a), 4.72 (s, 1H, H-
4), 4.63 (m, 1H, H-40), 4.50 (d, 1H, H-6a), 4.21 (dd, J4 ,5 A = 6.3 Hz,
0
0
J5 A,5 B = 8.3 Hz, 1H, H-50A), 3.74 (t, J4 ,5 B = 8.3 Hz, 1H, H-50B), 1.44,
1.42, 1.38, 1.33 (s, 12H, 4 ꢃ CH3), 0.91 [SiC(CH3)], 0.13 (SiCH3),
0.11 (SiCH3); 13C NMR (CDCl3, 75 MHz) d 145.9 (C-6), 128.8 (C-5),
112.2 [OC(CH3)2], 109.3 [OC(CH3)2], 87.5 (C-6a), 84.2 (C-3a), 81.2
(C-4), 74.2 (C-40), 69.5 (C-50), 27.3, 26.7, 26.3, 26.2 (4 ꢃ CH3), 26.1
[SiC(CH3)3], 18.5 [SiC(CH3)3], ꢀ4.2 (SiCH3), ꢀ4.3 (SiCH3). HRMS:
C19H34O5Si calcd 393.2073, found 393.2075.
5.4.7. (3aR,4R,6aS)-6-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl
benzoate (7b), and (3aR,4S,6aS)-6-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2,2-dimethyl-4,6a-dihydro-3aH-
0
0
0
0
cyclopenta[d][1,3]dioxol-4-yl benzoate (8b)
Following the general method C, compound 6b (924 mg,
1.97 mmol), Bu2SnO (490 mg, 1.97 mmol), and TMSN3 (0.52 mL,
3.94 mmol) in toluene (19.7 mL) for 22 h at 100 °C gave after flash
chromatography (EtOAc/cyclohexane, 15/85), compounds 7b
(39 mg, 5%) and 8b (258 mg, 36%). Compound 7b: ½a 2D0
ꢄ
+28.0 (c
5.4.5. 1-O-Benzoyl-2,3:5,6-di-O-isopropylidene-D-mannitol (5b)
To a solution of compound 4 (1.96 g, 7.48 mmol) in pyridine
(10 mL) and CH2Cl2 (50 mL) was added benzoyl chloride
(0.95 mL, 8.23 mmol) at 0 °C. After stirring for 19 h at room tem-
perature, water and diethyl ether were added. The organic layer
was washed with HCl 1 M, dried over Na2SO4, filtered, and evapo-
rated under vacuo. The residue was purified by flash chromatogra-
phy (EtOAc/cyclohexane, 25/75) to give product 5b (1.94 g, 70%) as
0.29, CHCl3); IR (ATR):
m 2985, 2935, 1718, 1452, 1371, 1269,
1209, 1155, 1109, 1062, 1026 cmꢀ1 1H NMR (CDCl3, 300 MHz)
;
d 8.11–7.42 (m, 5H, C6H5), 5.97 (t, J4,5 = J5,6a = 1.7 Hz, 1H, H-5),
5.61 (ddd, J4,6a = 1.7 Hz, J4,3a = 5.5 Hz, 1H, H-4), 5.09 (t,
J6a,3a = 5.5 Hz, 1H, H-3a), 5.00 (d, 1H, H-6a), 4.71 (m, 1H, H-40),
4.28 (dd, J4 ,5 A = 6.3 Hz, J5 A,5 B = 8.3 Hz, 1H, H-50A), 3.88 (t,
0
0
0
0
J4 ,5 B = 8.3 Hz, 1H, H-50B), 1.49, 1.43, 1.38, 1.35 (s, 12H,
4 ꢃ CH3); 13C NMR (CDCl3, 75 MHz) d 166.3 (CO), 147.2 (C-6),
133.4-128.7 (C6H5), 126.0 (C-5), 113.5 [OC(CH3)2], 109.6
[OC(CH3)2], 83.7 (C-6a), 77.6 (C-3a), 75.8 (C-4), 73.9 (C-40), 69.5
(C-50), 27.8, 27.1, 26.8, 26.2 (4 ꢃ CH3). HRMS: C20H24O6Na calcd
0
0
a white solid [mp 98–99 °C; ½a 2D0
ꢄ
+19.0 (c 0.3, H2O)], showing spec-
troscopic data {IR (ATR)
m
3466, 2989, 2939, 2885, 1691, 1456,
1365, 1286, 1215, 1128, 1068, 1051 cmꢀ1
;
1H NMR (CDCl3,
300 MHz) d 8.07, 7.56–7.28 (m, 5H, C6H5), 4.68–4.48 (m, 5H, OH,
2H-1, H-2, H-3), 4.13–4.02 (m, 3H, H-5, H-6A, H-6B), 3.67 (dd,
J4,OH = 7.5 Hz, J4,5 = 1.5 Hz, 1H, H-4), 1.54 (s, 3H, CH3), 1.42 (s, 6H,
2 ꢃ CH3), 1.36 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz) d 166.6
(CO), 133.5–128.7 (C6H5), 109.9, 109.2 [2 ꢃ OC(CH3)2], 76.6, 75.8,
75.4 (C-2, C-3, C-4), 70.6 (C-5), 67.6 (C-6), 64.6 (C-1), 27.2 (CH3),
27.1 (CH3), 25.6 (CH3), 25.0 (CH3). HRMS: C19H26O7Na calcd
389.1576, found 389.1578}, in good agreement with those re-
ported in the literature.13
383.1471, found 383.1483. Compound 8b: ½a 2D0
ꢄ
+133.0 (c 0.63,
m 2985, 2935, 1716, 1452, 1371, 1247, 1207,
CHCl3); IR (ATR):
; d
1153, 1109, 1062, 1026 cmꢀ1 1H NMR (CDCl3, 300 MHz)
8.01–7.46 (m, 5H, C6H5), 5.98 (s, 1H, H-5), 5.79 (d, J4,3a = 0.7 Hz,
1H, H-4), 5.21 (dd, J6a,3a = 5.8 Hz, 1H, H-3a), 4.80 (d, 1H, H-6a),
4.67 (m, 1H, H-40), 4.25 (dd, J4 ,5 A = 6.3 Hz, J5 A,5 B = 8.3 Hz, 1H,
0
0
0
0
H-50A), 3.78 (dd, J4 ,5 B = 8.3 Hz, 1H, H-50B), 1.45, 1.43, 1.42, 1.31
(s, 12H, 4 ꢃ CH3); 13C NMR (CDCl3, 75 MHz) d 166.3 (CO), 149.8
(C-6), 133.5–128.7 (C6H5), 124.9 (C-5), 113.0 [OC(CH3)2], 109.5
[OC(CH3)2], 84.3 (C-6a), 84.0 (C-3a), 83.1 (C-4), 74.1 (C-40), 69.5
(C-50), 27.6, 26.7, 26.2, 26.1 (4 ꢃ CH3). HRMS: C20H24O6Na calcd
383.1471, found 383.1483.
0
0
5.4.6. 1-O-Benzoyl-4-C-cyano-4-O-mesyl-2,3:5,6-di-O-
isopropylidene-D-mann(tall)itol (6b)
Following general method A, compound 5b (1.94 g, 5.30 mmol),
Ac2O (1.74 mL, 18.55 mmol), and PDC (1.39 g, 3.71 mmol) for 22 h
gave crude ulose. Following the general method B, to a solution of
this crude ulose in CH2Cl2 (50 mL) were added NaHCO3 (890 mg,
10.6 mmol) in water (12.33 mL) and KCN (737 mg, 11.34 mmol).
After stirring for 19 h, the crude cyanohydrins were dissolved in
CH2Cl2 (50 mL) followed by addition of Et3N (5.95 mL, 42.4 mmol)
and MsCl (2.25 mL, 29.15 mmol). After 22 h and extraction, the res-
idue was purified by flash chromatography (EtOAc/cyclohexane,
30/70) to give product 6b (1.8 g, 72%) as an inseparable mixture
of diastereoisomers in 86/14 ratio, as a slight yellow syrup: IR
5.5. Computational methods
All calculations were carried out with the GAUSSIAN 03 program.18
The optimizations were carried out using hybrid density functional
B3LYP19 with the 6-31G(d,p) basis set. This polarized basis set adds
p functions to hydrogen atoms in addition to the d functions on
heavy atoms. Single-point energy calculations with the triple split
valence basis set 6-311+G(d,p) were later performed on the opti-
mized geometries. Basis sets with diffuse functions are recom-
mended for molecules with lone pairs, for anions, and for
systems with significant negative charge. Vibrational frequency
analyses were carried out in order to assess the nature of the sta-
tionary points and to obtain the zeropoint vibrational energies
(ZPVEs) and thermodynamic parameters. From the transition
structures, the intrinsic reaction coordinate (IRC) was obtained
using the IRC routine in Gaussian. Natural bond orbital (NBO) anal-
yses20 have been performed by the module NBO v.3.1 implemented
in GAUSSIAN 03 at the optimization level.
(ATR)
m
2993, 2983, 1724, 1454, 1384, 1363, 1271, 1249, 1215,
1182, 1118, 1070 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 8.07, 7.55–
7.40 (m, 5H, C6H5), 5.09 (m, 1H, H-1A), 4.83–4.75 (m, 3H, H-1B,
H-2, H-5), 4.63 (d, J2,3 = 4.8 Hz, 1H, H-3), 4.26 (dd, J5,6A = 6.9 Hz,
J6A,6B = 10.1 Hz, 1H, H-6A), 4.20 (dd, J5,6B = 7.4 Hz, 1H, H-6B), 3.32
(s, 3H, OSO2CH3), 1.62, 1.54, 1.42, 1.38 (s, 12H, 4 ꢃ CH3); 13C
NMR (CDCl3, 75 MHz) d 166.5 (CO), 133.5–128.7 (C6H5), 114.1
(CN), 111.5, 111.1 (2 ꢃ [OC(CH3)2]), 82.8 (C-4), 77.7 (C-5), 77.0
(C-3), 76.4, (C-2), 67.3 (C-6), 62.6 (C-1), 41.0 (OSO2CH3), 27.0,

A. Nguyen Van Nhien et al. / Carbohydrate Research 344 (2009) 1605–1611
1611
K. Tetrahedron Lett. 1990, 31, 4727; (c) Brown, R. F. C.; Eastwood, F. W.;
Harrington, K. J.; McMullen, G. L. Aust. J. Chem. 1974, 27, 2393.
Acknowledgments
9. Ohira, S.; Sawamoto, T.; Yamato, M. Tetrahedron Lett. 1995, 36, 1537.
10. Niizuma, S.; Shuto, S.; Matsuda, A. Tetrahedron 1997, 53, 13621.
11. Fick, W.; Kuelle, T.; Schmidt, R. R. Helv. Chim. Acta 1991, 435.
12. Li, L.-S.; Wu, Y.-L. Tetrahedron 2002, 58, 9049.
A.N.V.N. and D.P. thank the Conseil Régional de Picardie and the
Ministère de la Recherche for financial support.
13. Setoi, H.; Takeno, H.; Hashimoto, M. Tetrahedron Lett. 1985, 26, 4617.
14. Ohira, S.; Okai, K.; Moritanui, T. J. Chem. Soc., Chem. Commun. 1992, 721.
15. Similar results have been reported for a related alkylidencarbene: Markovic, S.;
Stankovic, S.; Radenkovic, S.; Gutman, I. J. Chem. Inf. Model. 2008, 48, 1984.
16. Taber, D. F.; Meagley, R. P.; Doren, D. J. J. Org. Chem. 1996, 61, 5723.
17. Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem. 1985, 50, 2557.
18. Frisch, M. J.; Trucks G. W.; Schlegel H. B.; Scuseria G. E.; Robb M. A.; Cheeseman
J. R.; Montgomery, Jr. J. A.; Vreven T.; Kudin K. N.; Burant J. C.; Millam J. M.;
Iyengar S. S.; Tomasi J.; Barone V.; Mennucci B.; Cossi M.; Scalmani G.; Rega N.;
Petersson G. A.; Nakatsuji H.; Hada M.; Ehara M.; Toyota K.; Fukuda R.;
Hasegawa J.; Ishida M.; Nakajima T.; Honda Y.; Kitao O.; Nakai H.; Klene M.; Li
X.; Knox J. E.; Hratchian H. P.; Cross J. B.; Bakken V.; Adamo C.; Jaramillo J.;
Gomperts R.; Stratmann R. E.; Yazyev O.; Austin A. J.; Cammi R.; Pomelli C.;
Ochterski J. W.; Ayala P. Y.; Morokuma K.; Voth G. A.; Salvador P.; Dannenberg
J. J.; Zakrzewski V. G.; Dapprich S.; Daniels A. D.; Strain M. C.; Farkas O.; Malick
D. K.; Rabuck A. D.; Raghavachari K.; Foresman J. B.; Ortiz J. V.; Cui Q.; Baboul A.
G.; Clifford S.; Cioslowski J.; Stefanov B. B.; Liu G. Liashenko A.; Piskorz P.;
Komaromi I.; Martin R. L.; Fox D. J.; Keith T.; Al-Laham M. A.; Peng C. Y.;
Nanayakkara A.; Challacombe M.; Gill P. M. W.; Johnson B.; Chen W.; Wong M.
W.; Gonzalez C.; Pople J. A. GAUSSIAN 03, Revision B.03, Gaussian, Wallingford CT,
2003.
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