Fructose-6-phosphate aldolases as versatile biocatalysts for nitrocyclitol syntheses

Article abstract of DOI:10.1016/j.tetasy.2013.07.016

Efficient and stereoselective polyhydroxylated nitrocyclitol syntheses were performed via biocatalysed aldol reactions. The key step was based on a one-pot/one-enzyme cascade reaction process where two reactions occur: aldolase-catalysed aldolisation and spontaneous intramolecular nitroaldolisation. The synthetic methodology was investigated using fructose-6-phosphate aldolase A129S for the synthesis of known nitrocyclitols. Improvements were obtained which involved less steps and increased yields. Several new nitrocyclitols were also prepared using hydroxyacetone (HA) as the donor and FSA wt. From nitrocyclitol stereochemical analyses, the intramolecular nitro-Henry reaction stereoselectivity was dependent on the donor substrate used, HA or dihydroxyacetone (DHA). Whereas DHA provided two stereoisomers, four were obtained using HA.

Full text of DOI:10.1016/j.tetasy.2013.07.016

Tetrahedron: Asymmetry 24 (2013) 1075–1081
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Fructose-6-phosphate aldolases as versatile biocatalysts
for nitrocyclitol syntheses
⇑
Flora Camps Bres, Christine Guérard-Hélaine, Carlos Fernandes, José A. Castillo, Marielle Lemaire
Clermont Université, Université Blaise Pascal, ICCF, BP 10448, F-63000 Clermont-Ferrand, France
CNRS, UMR 6296, BP 80026, F-63171 Aubière, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient and stereoselective polyhydroxylated nitrocyclitol syntheses were performed via biocatalysed
aldol reactions. The key step was based on a one-pot/one-enzyme cascade reaction process where two
reactions occur: aldolase-catalysed aldolisation and spontaneous intramolecular nitroaldolisation. The
synthetic methodology was investigated using fructose-6-phosphate aldolase A129S for the synthesis
of known nitrocyclitols. Improvements were obtained which involved less steps and increased yields.
Several new nitrocyclitols were also prepared using hydroxyacetone (HA) as the donor and FSA wt. From
nitrocyclitol stereochemical analyses, the intramolecular nitro-Henry reaction stereoselectivity was
dependent on the donor substrate used, HA or dihydroxyacetone (DHA). Whereas DHA provided two ster-
eoisomers, four were obtained using HA.
Received 29 May 2013
Accepted 16 July 2013
Available online 29 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
enlarging the carbon skeleton of molecules by stereoselectively
catalysing the addition of a ketone donor onto an aldehyde accep-
Cyclitols or carbocyclic polyols are entities that include inosi-
tols, conduritols and carbasugars among other variants.1 These
families are involved in the function and regulation of a number
of biological processes, such as cellular recognition, signal trans-
duction and selective inhibition of glycosidases.2 Among them,
aminocyclitols, defined as cyclitols bearing one or more amino
groups, have emerged as an important, rapidly expanding and
diversified family of bioactive compounds with interesting biolog-
ical properties.3,4 For instance, certain aminocyclitol derivatives
have been shown to act as antibiotics, potent glycosidase inhibitors
and have been involved as key components of antiviral agents and
artificial receptors.3a Thus, there have been continuous efforts over
the last decade to prepare natural cyclitols and aminocyclitols as
well as their synthetic analogues with enhanced or more selective
biological profiles in order to study in depth the influence of this
moiety.1a,5 Nitrocyclitols are essentially found as synthetic precur-
sors of aminocyclitols,3b,5b,6 to the best of our knowledge, no such
naturally occurring cores are described in the literature. However,
it should be noted that nitrosugar moieties naturally derived from
aminosugars via an oxidation can decorate over 50 bioactive natu-
ral products.7
tor. The usefulness of aldolases in organic synthesis has recently
been reviewed.8 Among these biocatalysts, fructose 6-phosphate
aldolase (FSA) has been well established as an efficient tool for
the synthesis of compounds such as rare ketose sugars and imino-
sugars.8,9 This enzyme displays excellent activity towards several
donor substrates such as dihydroxyacetone (DHA), hydroxyacetone
(HA), hydroxybutanone and even more remarkably, glycolalde-
hyde.10 In addition, this aldolase accepts a large variety of alde-
hydes to form optically active ketoses with the highly conserved
(3S,4R) stereochemistry.
Herein we explore the acceptor substrate promiscuous poten-
tial of FSA for the synthesis of nitrocyclitols. Based on an original
strategy recently developed,6d–f various nitrocyclitols are accessi-
ble. The key step is a cascade C–C bond formation, which begins
with an aldolase-catalysed aldol reaction followed by a spontane-
ous intramolecular Henry reaction leading to the cyclitol ring
(Scheme 1), a process by which four new stereocenters are
generated.
R'
OH
OH
FSA
Henry
OH
OH
O
HO
HO
NO2
OH
R'
Aldol reactions which form C–C bonds have tremendous syn-
thetic utility. In this field, aldolases are one of the most important
groups of asymmetric C–C-bond forming enzymes capable of
O2N
reaction
+
HO
O
O2N
R'
O
R
R
OH
R=H, OH
R
R'=CH2OH, CH3
R'=CH2OH: FSA A129S
R'=CH3: FSA wt
⇑
Corresponding author. Tel.: +33 4 73 40 75 84; fax: +33 4 73 40 77 17.
E-mail address: marielle.lemaire@univ-bpclermont.fr (M. Lemaire).
Scheme 1. One-pot cascade aldolisation and intramolecular Henry reaction leading
to nitrocyclitols.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.016

1076
F. Camps Bres et al. / Tetrahedron: Asymmetry 24 (2013) 1075–1081
OH
Improved syntheses of the nitrobutyraldehyde acceptors are
OEt
OEt
presented. The variant FSA A129S with increased activity for DHA
is used with DHA as the donor and FSA wt with its best donor
HA, the latter affording a new family of C7 deoxy nitrocyclitols.6c
A discussion on the Henry reaction stereoselectivity is proposed
as four stereocenters are created during the cascade reaction
process.
OEt
OEt
1) H2O2, KHCO3, CH3CN,
CH3OH, 82%
CAL-B
OEt
OEt
(S)-5
vinylacetate
49%, 96% ee
2) Me3SI, nBuLi,
OH
+
Pentane/THF, 81%
OAc
5
OEt
OEt
45%, >98% ee
(R)-6
2. Results and discussion
OH
OAc
OEt
OEt
O
OEt
(S)-5
(S)
O2N
(S)-2
2.1. Aldehyde acceptor syntheses
OH
OEt
(S)-8
(S)-7
CH3NO2,
H+, H2O
O3,
DPPE, 74%
Inspired by our previous work, we first revisited the synthesis of
NaOH 1M, 80%
the nitroaldehydes ( )-1, (R)-2 and (S)-26d,f (Fig. 1).
OH
OAc
OEt
OEt
(R)-6
O
(R)
(R)-2
OEt
O2N
(R)-8
OH
OEt
(R)-7
OH
OH
O
O
O
Scheme 3. Synthesis of nitroaldehydes (R)-2 and (S)-2.
O2N
O2N
O2N
OH
( )-1
OH
(S)-2
OH
(R)-2
CN
HO
OMe
OMe
Figure 1. Structure of FSA acceptor substrates.
OMe
OMe
11
RuCl3, NaIO4,
CH3CN, 85%
OMe
OMe
MeO
O
NC
NaCN
base
OMe
10
OH
9
The first nitroaldehyde targeted was the 3-hydroxy-4-nitrobut-
anal 1 (Scheme 2). Starting from 4,4-diethoxybut-1-ene 3, which
was dihydroxylated with KMnO4 and then oxidised with NaIO4
supported on silica gel, aldehyde 4 was prepared in better overall
yield (96%) than the previously reported method using ozonolysis6f
(78%). Replacement of KMnO4 by catalytic RuO4 as an oxidising
agent was less valuable leading to only 72% yield. Following a pre-
viously described protocol,6f 4 was reacted with nitromethane to
afford an intermediate nitro alcohol. Acetal was then hydrolysed
to give the desired nitroaldehyde 1, which was used directly in
the next step.
CN
HO
vinyl acetate
CAL-B
73 %
Ac2O, NEt3
OMe
NC
OMe
Ni Raney
OHC
OMe
OMe
H2O, Pyr
NaH2PO2
OAc
OAc
13
12
ee=27%
67%
Scheme 4. Dynamic kinetic resolution strategy via reversible formation of
cyanohydrin. Synthesis of racemic aldehyde 13.
a
OEt
transesterification catalysed by a lipase was investigated on the
hydroxyl group. In connection with this, several dynamic kinetic
resolutions starting from aromatic and aliphatic aldehydes have
been reported in the literature, some of which employ CAL-B as
the catalyst.12
OEt
OEt
OH
ref 6f
1) KMnO4, H2O
O2N
OEt
O
O
2) NaIO4/SiO2
CH2Cl2
1
4
3
96%
Scheme 2. Improvement of 3-hydroxy-4-nitrobutanal synthesis.
The methodology depicted in Scheme 4 was first confirmed on
the racemic series. Aldehyde 10 was isolated from alkene 9 by clas-
sical ruthenium/periodate oxidation. The nitrile ester 12 was then
formed chemically using acetone cyanohydrin and acetic anhy-
dride. The desired aldehyde 13 was then directly prepared in 67%
yield from 12 by reduction of the nitrile group in the presence of
Raney Ni and sodium hypophosphite.13 Secondly, the dynamic ki-
netic resolution was studied. Different reaction conditions were
varied, for instance the nature of the base (NaCN, KCN, CuCN,
etc) and the acylating agent (vinyl acetate, vinyl butyrate, isopre-
nyl acetate, etc). However, the chemical transesterification was
generally much faster than the biocatalysed one and the best con-
ditions (NaCN as a base and vinylacetate) led to 27% ee in 78%
yield. Unfortunately, this low ee did not allow further exploitation
of this strategy.
Nitroaldehydes (R)-2 and (S)-2 were synthesised via a new
pathway starting from acrolein diethylacetal (Scheme 3). Epoxida-
tion of the alkene with H2O2 in the presence of acetonitrile (82%
yield) followed by treatment with an excess of dimethylsulfonium
methylide afforded the corresponding one-carbon homologated al-
lyl alcohol 5 in 81% yield.11 Applying a previously described kinetic
resolution methodology,6d the Candida antartica lipase B catalysed
transesterification gave enantiomers (S)-5 and (R)-6 (ee >96%) from
racemic alcohol 5. For the next steps, the strategy consisted of the
esterification of alcohol (S)-5 while both esters 6 were ozonolysed,
followed by a Henry reaction with nitromethane and finally acetal
deprotection. During the nitroaldol reaction step, no chiral induc-
tion was detected. As for the dimethoxy series,6d the compounds
were obtained as a 50/50 diastereomeric mixture and were not
separable by silica gel chromatography. Nitroaldehydes (R)-2 and
(S)-2 were used directly in the next step. The overall yields to reach
the protected forms of aldehydes 2 were increased from 10% and
13%6d to 15% and 18%, respectively.
2.2. Nitrocyclitol syntheses
With the three aldehydes ( )-1, (R)-2 and (S)-2 in hand, the
enzymatic reactions were conducted (see Scheme 1) in water at
room temperature. The results from the aldolisation catalysed by
FSA A129S6c in the presence of DHA at pH 7.5 are presented in
Table 1. The yields and diastereomeric ratios are compared with
the ones previously published using the dihydroxyacetone
We also explored another strategy based on a dynamic kinetic
resolution in order to prepare theoretically 100% of one enantiomer
of aldehyde 13, analogous to aldehyde 7 (Scheme 4). Via the
reversible formation of
a cyanohydrin, an enantioselective

F. Camps Bres et al. / Tetrahedron: Asymmetry 24 (2013) 1075–1081
1077
Table 1
Overall, comparable stereoisomer ratios were obtained when
using FSA A129S instead of FBA/phytase. The slight differences
can probably be explained by the reaction and work-up conditions.
As discussed in previous publications,6d,f under smooth heating
during the water removal or at a slightly alkaline pH, whatever
the C3 configuration of the acceptor aldehyde, compounds 15, 17
and 19 can be partially isomerised into the corresponding com-
pounds 14, 16 and 18, respectively. This has suggested a twofold
retroaldolisation process as illustrated in Scheme 5.15 In all of the
series, the (1S,6R)-stereoisomer was the thermodynamic one.
We next studied FSA wt, which is known to have a better activ-
ity towards HA than DHA.6c We focused some of our work on the
synthesis of a new class of nitrocyclitols based on the aldolisation
between HA and the nitroaldehydes ( )-1 and (R)-2 and (S)-2 (Ta-
ble 2). The same procedure discussed above was applied for the
synthesis of nitrocyclitols from DHA.
FSA A129S biocatalysed preparation of nitrocyclitols
Aldehyde
Nitrocyclitol
Ratio
Yield%
OH
OH
55/45
(50/50)
71 FSA
OH
OH
(64) FBAa
OH
OH
HO
HO
NO2
OH
HO
HO
NO2
OH
1
2
( )-1
15
14
OH
OH
59/41
(65/35)
71 FSA
(49) FBAb
HO
HO
NO2
OH
HO
HO
NO2
OH
(R)-2
(S)-2
OH
OH
16
17
OH
OH
73/27
(61/39)
69 FSA
OH
OH
(41) FBAb
HO
HO
NO2
OH
HO
HO
NO2
OH
OH
19
OH
18
The reactions with HA and the three different aldehydes ( )-1,
(R)-2 and (S)-2 catalysed by FSA wt afforded the nitrocyclitols in
higher overall yields than with DHA and FSA A129S. All the isomers
were separated by flash chromatography after two rounds of puri-
fication. Based on the (3S)-stereoselectivity afforded by the aldol-
ase and on NMR studies (e.g., coupling constants and NOESY
experiments) the nitrocyclitol conformations and stereochemist-
ries (Fig. 2) were determined.
a
Ref. 6f.
Ref. 6d.
b
phosphate (DHAP) dependent fructose-1,6-bisphosphate aldolase
(FBA) combined with a phytase for phosphate hydrolysis.6d,f
In general, the aldolisations afforded the same nitrocyclitols but
in higher yields when FSA was employed rather than FBA/phytase.
Contrary to what has been reported on biocatalysed nitro-Henry
reactions and more precisely on rabbit muscle FBA aldolase,14
the intramolecular nitro-Henry cyclisation was not catalysed by
an aldolase as this reaction occurs spontaneously due to classical
reactivity of nitro derivatives in slightly basic medium.15 As ex-
pected, the FSA A129S variant and FBA have shown a similar accep-
tor substrate tolerance. These results confirm once more FSA as an
efficient tool for aldolisation avoiding laborious DHAP production
and the use of a phosphatase. As previously observed, the Henry
reaction stereoselectivity was determined by the C-3 hydroxyl con-
figuration of the nitroaldehyde, affording two series of diastereoi-
somers: (1S,6R) when C-3 is (R) [14 (1S,2S,3R,5S,6R), 16
(1S,2S,3R,4R,5R,6R) and 18 (1S,2S,3R,4S,5R,6R)) and (1R,6S) when
C-3 was (S) [15 (1R,2S,3R,5R,6S), 17 (1R,2S,3R,4R,5S,6S) and 19
(1R,2S,3R,4S,5S,6S)].
OH
OH
OH
HO
CH3
R
H2
R
H2
H6
H5
H2
H5
H2
HO
H5
H6
HO
H5
OH
OH
OH
H3
R
H3
R
CH3
OH
NO2
R
R
NO2
R
R
HO
OH
CH3
HO
CH3
H3
OH
OH
HO
NO2
NO2
H3
H6
H6
20(5S)
21(5R)
22(5R)
23(5S)
24(4R,5R)
28(4S,5R)
25(4R,5S)
29(4S,5S)
26(4R,5S)
30(4S,5S)
27(4R,5R)
31(4S,5R)
(1R,2S,3R,6R)
(1S,2S,3R,6S)
(1R,2S,3R,6S)
R = H or OH
(1S,2S,3R,6R)
Figure 2. Conformation of deoxy C7 nitrocyclitols, prepared using aldehydes 1 or 2
and HA.
The stereoselectivity of the nitroaldol reaction was lower in the
presence of the methyl group than in the presence of the hydroxy-
methyl group at the C1 position. In fact the two major isomers
bearing a methyl at the equatorial position were formed together
with two minor isomers bearing the methyl group at the axial po-
sition. The nitro group was always found at the equatorial position.
A difference of 1.5 kJ molꢀ1 for the free energy calculated at the ab
initio level in the gas phase6d was found as expected, to disfavour
21 and by 11 kJ molꢀ1 disfavour 23, compared to 20. The lower ste-
reoselectivity could be explained by a decrease of the electronic ef-
fects or a lack of hydrogen bonds stabilising the transition state
while a C1–C6 bond forms due to the missing hydroxyl. It could
R'
R'
OH
R'
O
OH
NO2
O
HO
HO
HO
HO
HO
HO
NO2
OH
NO2
OH
R
R
R
Scheme 5. Retro-Henry reaction possible in two directions.
Table 2
FSA wt biocatalysed preparation of deoxy C7 nitrocyclitols
Aldehyde
Nitrocyclitol ratio
Yielda
%
OH
OH
OH
OH
OH
OH
OH
HO
HO
NO2
OH
HO
HO
NO2
OH
HO
HO
NO2
OH
HO
HO
NO2
OH
1
2
8
25
5
62
( )-1
84
85
23
21
22
20
OH
HO
HO
NO2
HO
HO
NO2
OH
HO
HO
NO2
HO
HO
NO2
32
OH 9
OH 45
OH 14
(R)-2
(S)-2
OH
25
OH
OH
OH
26
24
27
OH
OH
OH
OH
HO
HO
NO2
HO
HO
NO2
HO
HO
NO2
HO
HO
NO2
OH 67
OH 20
OH 3
OH 9
86
OH
OH
OH
OH
28
29
30
31
a
Overall yields (see Section 4 for individual yields).

1078
F. Camps Bres et al. / Tetrahedron: Asymmetry 24 (2013) 1075–1081
also be explained by steric effects, with methyl and hydroxyl
groups being closer in size than hydroxymethyl and hydroxyl
groups.
without further purification. Rf = 0.4 (Cyclohexane/EtOAc 8:2). 1H
NMR (400 MHz, CDCl3): d = 4.32 (d, J = 4.4 Hz, 1H, 3-H), 3.72–3.58
(m, 4H, 4-H, 40-H), 3.08 (m, 1H, 2-H), 2.76 (m, 2H, 1-H), 1.23 (pt,
J = 7.0 Hz, 3H, 5-H), 1.20 (t, J = 7.0 Hz, 3H, 50-H). 13C NMR
(100 MHz, CDCl3): d = 101.4 (3-C), 62.8 (4-C), 62.3 (40-C), 51.8 (2-
C), 43.8 (1-C), 15.2 (5-C, 50-C).
3. Conclusion
To a suspension of trimethylsulfonium iodide (21 g, 100 mmol)
in a mixture of anhydrous THF/pentane 50:50 (350 mL) was added
dropwise an n-BuLi solution (2.5 M in hexane, 40 mL, 100 mmol) at
ꢀ10 °C under argon. The reaction mixture was stirred for 90 min at
ꢀ10 °C. The epoxide (5 g, 34 mmol) diluted in anhydrous THF
(100 mL) was then added. The resulting mixture was stirred for
30 min at ꢀ10 °C and then 1 h at room temperature. The reaction
was neutralised with saturated aqueous NH4Cl (50 mL). Volatile
compounds were removed (20 °C, 300 mmHg) before extraction
of the alkene with DCM. The combined organic phases were
washed with brine, dried over MgSO4, filtered and concentrated
under vacuum. The crude product was purified by flash chroma-
tography (DCM/acetone 98:2 then 96:4) to afford 5 as a yellow
oil (4.4 g, 81%). Rf = 0.3 (Cyclohexane/EtOAc 8:2). 1H NMR
(400 MHz, CDCl3): d = 5.92 (ddd, J = 5.3, 10.8, 17.4 Hz, 1H, 3-H),
5.39 (dd, J = 1.6, 17.4 Hz, 1H, 4-H), 5.22 (dd, J = 1.6, 10.6 Hz, 1H,
40-H), 4.28 (d, J = 6.0 Hz, 1H, 1-H), 4.07 (dd, J = 5.3, 6.0 Hz, 1H, 2-
H), 3.75–3.57 (m, 4H, H5, H50 ), 2.28 (s, 1H, O-H), 1.23 (pt,
J = 7.0 Hz, 3H, 6-H), 1.20 (pt, J = 7.0 Hz, 3H, 60-H) ppm. 13C NMR
(100 MHz, CDCl3): d = 135.6 (3-C), 116.6 (4-C), 104.6 (1-C), 72.7
(2-C), 63.5 (5-C, 50-C), 15.2 (6-C, 60-C) ppm.
Herein, we have demonstrated the high efficiency of FSA A129S
in the nitrocyclitol syntheses, which is applicable on a larger scale
and can be carried out in fewer steps than when the FBA/phytase
couple was used. These improvements, concerning the preparation
of the acceptor aldehydes, also led to better overall yields. Remark-
ably, twelve new nitrocyclitols were prepared from the aldolisation
between HA and the nitroaldehydes catalysed by FSA wt. The
Henry reaction in the presence of the methyl group (i.e., using
HA as donor substrate) was less stereoselective as four isomers
were isolated whereas only two isomers were formed with the
hydroxymethyl group (i.e., using DHA as a donor substrate).
4. Experimental
4.1. General
FSA wt and FSA A129S biocatalysts were produced and their
activities were measured as described in the literature.6c,16 All of
the reactions were monitored by TLC with Merck 60F-254 pre-
coated silica (0.2 mm) on aluminium. Flash chromatography was
performed using Merck Kieselgel 60 (40–63 lm); the solvent sys-
tems are given in v/v. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker Avance 400 in CDCl3,
CD3OD or D2O (see indication). Chemical shifts (d) are reported in
ppm and coupling constants are given in Hz. IR spectra were re-
corded on a Perkin–Elmer FT-IR Paragon 500. Optical rotations were
measured on a JASCO DIP-370 polarimeter with a sodium (589 nm)
lamp at 25 °C. High resolution mass spectra (HRMS) were recorded
by the Centre Régional de Mesures Physiques, Aubière, France.
4.2.3. Kinetic resolution of alcohol 5
To a solution of alcohol 5 (4.4 g, 28 mmol) in vinyl acetate
(80 mL) was added Novozym435Ò lipase (C. antartica, 2.2 g) and
the mixture was stirred at room temperature. The reaction course
was monitored by GC and when the conversion reached 50% (28 h),
the reaction was quenched by filtration. The solvent was evapo-
rated and the mixture was purified by flash chromatography
(DCM/acetone 99:01 then 96:04). Ester (R)-6 was isolated (2.5 g,
45%, ee >98%, ½a 2D5
¼ þ27 (c 1.0, CHCl3)) and alcohol (S)-5 was iso-
ꢂ
lated (2.0 g, 49%, ee = 96%, ½a D25
¼ ꢀ29 (c 1.0, CHCl3)).
ꢂ
4.2. Aldehyde syntheses
4.2.1. 3,3-Diethoxypropanal 4
4.2.4. (R)-1-(1,1-Diethoxy)prop-2-enyl acetate (R)-6
½
a 2D5
ꢂ
¼ þ27 (c 1.0, CHCl3). Rf = 0.8 (Cyclohexane/EtOAc 6:4). 1H
To a suspension of alkene 3 (1 g, 7.1 mmol) in water (10 mL)
was added 1.1 equiv of KMnO4 (1.2 g) diluted in water (30 mL) at
0 °C. The mixture was then stirred overnight at rt. Sodium bisulph-
ite (1.6 g, 1.2 equiv) was then added and the reaction medium was
stirred continuously until discoloration. The reaction medium was
then filtered and continuously extracted with ethyl acetate to af-
ford the crude diol. It was then dissolved in dichloromethane
(DCM) (32 mL) and NaIO4 supported on silica gel17 (13 g, 2.4 equiv,
17 mmol) was added. The suspension was stirred for 30 min, then
filtered and the solid was rinsed with DCM (3 ꢁ 20 mL). The organ-
ic phase was dried over MgSO4 filtered and concentrated under
vacuum. Aldehyde 4 was isolated in 96% yield (0.99 g). It was used
as crude in the next step.
NMR (400 MHz, CDCl3): d = 5.90 (ddd, J = 5.9 Hz, 10.6 Hz, 17.2 Hz,
3
1H, 3-H), 5.31 (m, 2H, 4-H, 40-H), 5.25 (ddd, J4–2 = 1.5, 5.9,
5.7 Hz, 1H, 2-H), 4.44 (d, J = 5.7 Hz, 1H, 1-H), 3.70–3.56 (m, 4H,
5-H, 50-H), 2.10 (s, 3H, CO CH3), 1.20 (t, J = 7.1 Hz, 3H, 6-H), 1.19
(t, J = 7.1 Hz, 3H, 60-H) ppm. 13C NMR (100 MHz, CDCl3): d = 169.9
(C@O), 132.3 (3-C), 118.1 (4-C), 102.3 (1-C), 73.7 (2-C), 63.5 (5-
C), 62.8 (50-C), 21.0 (COCH3), 15.2 (6-C), 15.1 (60-C) ppm. IR:
m
= 3092, 2976–2888, 1744, 1645, 1236, 1067, 1445–1373,
737 cmꢀ1. HRMS (ES+): m/z calcd for C10H18O4+Na+: 225.1103
[M+Na+], found: 225.1105. Elemental analysis calcd (%) for
C10H18O4: C, 59.39; H, 8.97; O, 31.64. Found: C, 59.62; H, 9.19; O,
31.19.
The protocol applied for aldehyde 1 preparation is described in
the literature.6f
4.2.5. (S)-1-(1,1-Diethoxy)prop-2-enyl acetate (S)-6
Following the procedure for the protection of the hydroxyl
group previously described,6d compound (S)-6 was purified by
flash chromatography (DCM/acetone 99:01) and isolated as
4.2.2. 1,1-Diethoxybut-3-en-2-ol 5
2-(Diethoxymethyl)oxirane: To a suspension of KHCO3 (3.1 g,
30 mmol) in methanol (80 mL) was added acrolein diethyl acetal
(23.4 mL, 150 mmol) followed by acetonitrile (9,7 mL, 180 mmol)
and 30% hydrogen peroxide (18.9 mL, 180 mmol). The reaction
mixture was heated at 40 °C for several hours. After 10, 20 and
30 h of reaction, 1 equiv of hydrogen peroxide (16 mL) and aceto-
nitrile (8 mL) were added. After stirring for 40 h, the reaction was
quenched with water (20 mL) and extracted with DCM. The residue
was a clear oil (18.3 g, 82% crude), which was used in the next step
slightly yellow oil {1.7 g, 83%, ½a D25
¼ ꢀ27 (c 1.0, CHCl3)}.
ꢂ
4.2.6. 2-Acetoxy-3,3-diethoxypropanal 7
Compound 7 was isolated after flash chromatography (DCM/
acetone 98:02) (1.5 g, 74%) following the general procedure for
ozonolysis previously described using 1,2-bis(diphenylphos-
phino)ethane (DPPE) instead of PPh3 to simplify the purification.6d
(S)-7: ½a 2D5
ꢂ
¼ ꢀ28 (c 1.0, CHCl3). (R)-7: ½a D25
¼ þ29 (c 1, CHCl3).
ꢂ

F. Camps Bres et al. / Tetrahedron: Asymmetry 24 (2013) 1075–1081
1079
Rf = 0.6 (Cyclohexane/EtOAc 6:4). 1H NMR (400 MHz, CDCl3):
d = 9.62 (s, 1H, 3-H), 5.17 (d, J = 4.8 Hz, 1H, 2-H), 4.72 (d,
J = 4.9 Hz, 1H, 1-H), 3.75–3.59 (m, 4H, 4-H, 40-H), 2.18 (s, 3H,
COCH3), 1.23 (m, 3H, 5-H), 1.21 (m, 3H, 50-H) ppm. 13C NMR
(100 MHz, CDCl3): d = 195.9 (3-C), 169.9 (6-C), 101.0 (1-C), 77.7
(2-C), 64.3 (4-C), 63.5 (40-C), 20.4 (COCH3), 15.1 (5-C), 15.0 (50-C)
DCM. The combined organic phases were washed with 5% aqueous
NaHCO3, dried over MgSO4, filtered and concentrated under vac-
uum to give aldehyde 13 as a clear liquid (65 mg, 67% crude).
Rf = 0.6 (Cyclohexane/EtOAc 6:4). 1H NMR (400 MHz, CDCl3):
d = 9.6 (d, J = 2.2 Hz, 1H, 1-H), 5.2 (dd, J = 4.9, 2.2 Hz, 1H, 2-H), 4.6
(d, J = 4.9 Hz, 1H, 3-H), 3.47–3,46 (s, 6H, 4-H, 40-H), 2.2 (s, 3H,
COCH3) ppm. 13C NMR (100 MHz, CDCl3): d = 195.6 (HC@O),
169.8 (OC@O), 102.7 (3-C), 77 (2-C), 56–54.9 (4-C, 40-C), 20.5
(COCH3) ppm.
ppm. IR:
m = 2980–2899, 2733, 1740, 1233, 1067, 1445–
1375 cmꢀ1. HRMS (ES+): m/z calcd for C9H16O5 + CH3OH Na+:
259.1158 [M+CH3OH+Na+], found: 259.1158.
4.2.7. 4,4-Diethoxy-1-nitrobutan-2,3-diol 8 (protected form of
aldehyde 2)
4.3. Nitrocyclitol syntheses
Compound 8 was isolated in the form of 2 diastereoisomers
after flash chromatography (Cyclohexane/EtOAc 2:8) (1.79 g, 80%)
following the general procedure for the Henry reaction previously
General procedure for the preparation of nitrocyclitols with FSA
A129S: To a solution of acetal 1a, (R)-8, (S)-8 (4.3 mmol) in H2O
(5 mL) was added a cation exchange resin (Dowex 50x8, H+ form,
1 g). The suspension was stirred at 45 °C overnight to afford alde-
hyde 1, (R)-2 and (S)-2, respectively (quantitative by TLC). The re-
sin was filtered off and rinsed with H2O (3.5 mL). Next, pH was
adjusted to 7.5 with 1 M NaOH affording a 0.5 M solution of aque-
ous aldehyde. To this solution were added DHA (350 mg,
3.9 mmol) followed by FSA A129S (100 mg lyophilised powder,
300 U).15 The reaction mixture was placed on a reciprocal shaker
for 17 h at 25 °C (175 rpm). MeOH (50 mL) was added and the mix-
ture was centrifuged (20,000 rpm, 40 min, 5 °C). The supernatant
was concentrated under reduced pressure. The residue was puri-
fied by flash chromatography (DCM/MeOH gradient 9:1 to 8:2),
to afford the desired nitrocyclitols 14 (39%), 15 (32%), 16 (42%),
17 (29%), 18 (50%) and 19 (19%). The NMR data were identical to
those previously reported.6d,f
described.6d (S)-8: ½a 2D5
ꢂ
¼ ꢀ21 (c 1.6, CHCl3). (R)-8: ½a D25
¼ 20 (c 1,
ꢂ
CHCl3). Rf = 0.4–0.35 (Cyclohexane/EtOAc 2:8). 1H NMR (400 MHz,
CDCl3): d = 4.71–4.51 (m, 2H, 1-H), 4.61–4.51 (m, 1H, 2-H), 4.61–
3
4.60 (2 d, J4–3 = 5.4–7.0 Hz, 1H, 4-H), 3.82–3.63 (m, 4H, 5-H, 50-
H), 3.63–3.51 (2 dd, J = 5.4–7.0 Hz, 1.1–1.5 Hz, 1H, 3-H), 3.35–
2.99 (s, 2H,
2 OH), 1.25 (pt, J = 7.0 Hz, 3H, 6-H),1.24 (pt,
J = 7.0 Hz, 3H, 60-H) ppm. 13C NMR (100 MHz, CDCl3): d = 102.6
(4-C), 78.1–77.8 (1-C), 71.2–70.8 (2-C), 69.0–67.5 (3-C), 64.8–
64.1 (5-C), 64.0–63.8 (50-C), 15.0 (6-C), 14.9–14.8 (60-C) ppm. IR:
m
= 3430, 2978–2901, 1557, 1381, 1117, 1061, 1423–1348 cmꢀ1
.
HRMS (ES+): m/z calcd for C8H17NO6+Na+: 246.0962 [M+Na+],
found: 246.0954. Elemental analysis calcd (%) for C8H17NO6: C,
43.04; H, 7.68; N, 6.27; O, 43.01. Found: C, 42.88; H, 7.65; N,
6.08; O, 43.39.
General procedure for the preparation of nitrocyclitols with FSA
wt: To a solution of 0.5 M aqueous aldehyde 1, (R)-2 and (S)-2
(6.5 mL, 3.25 mmol) adjusted at pH 7.5 with NaOH 0.1 M were
added HA (200 mg, 2.7 mmol) followed by FSA wt (680 mg lyoph-
ilised powder, 210 U).15 The reaction mixture was placed on a re-
ciprocal shaker for 18 h at 25 °C (175 rpm). MeOH (40 mL) was
added and the mixture was centrifuged (20000 rpm, 40 min,
5 °C). The supernatant was concentrated under reduced pressure.
The residue was purified by flash chromatography (DCM/MeOH
gradient 9:1 to 8:2, two rounds of purification), affording the de-
sired nitrocyclitols 20 (52%), 21 (21%), 22 (4%), 23 (7%), 24 (38%),
25 (27%), 26 (8%), 27 (12%), 28 (58%), 29 (17%), 30 (3%), 31 (8%).
4.2.8. Dimethoxyacetaldehyde 10
To a suspension of NaIO4 (3 g, 14 mmol) supported on silica
(10 g) in DCM (30 mL) was added alkene 9 (355 mg, 2 mmol) pre-
viously diluted in DCM (20 mL). The mixture was stirred for 30 min
at room temperature before being filtered. The solid residue was
washed twice with DCM (20 mL). The organic phase was dried over
MgSO4, filtered and concentrated under vacuum very carefully
(20 °C, 300 mmHg) due to the high volatility of aldehyde 10. The
residue was a clear liquid (350 mg, 85% crude) used in the next
step without further purification. 1H NMR (400 MHz, CDCl3):
d = 9.47 (d, J = 1.5 Hz, 1H, 1-H), 4.50 (d, J = 1.5 Hz, 1H, 2-H), 3.46
(s, 6H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): d = 199.2 (1-C),
122.3 (2-C), 54.6 (3-C) ppm.
For all isomers 20–23: IR:
m = 3368, 1551, 1372, 1067–
1034 cmꢀ1. HRMS (ES+): m/z calcd for C7H13NO6+Na+: 230.0640
[M+Na+], found 230.0636.
4.2.9. 1-Cyano-2,2-dimethoxyethyl acetate 12
To a solution of aldehyde 10 freshly prepared, (2.85 mmol,
300 mg) diluted in anhydrous DCM (5 mL) were added acetone
4.3.1. (1R,2S,3R,5S,6R)-1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrol
20
cyanohydrin (2.85 mmol, 260
l
L), triethylamine (5.7 mmol,
L). The mixture
Rf = 0.26 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ þ13 (c 1, CH3OH). 1H NMR
800 L) and acetic anhydride (4.28 mmol, 400
l
l
(400 MHz, MeOD): d = 4.43 (ddd, J = 10.2, 10.6, 4.9 Hz, 1H, 5ax-
H), 4.35 (d, J = 10.2 Hz, 1H, 6ax-H), 3.76 (ddd, J = 12.2, 9.1, 4.9 Hz,
1H, 3ax-H), 3.07 (d, J = 9.1 Hz, 1H, 2ax-H), 2.25 (m, 1H, 4eq-H),
1.42 (ddd, J = 12.2, 10.6, 11.9 Hz, 1H, 4ax-H), 1.32 (s, 3H, CH3)
ppm. 13C NMR (100 MHz, MeOD): d = 98.2 (6-C), 79.6 (2-C), 74.3
(1-C), 69.2 (3-C), 66.7 (5-C), 39.3 (4-C), 23.1 (7-C) ppm.
was stirred at room temperature overnight. The reaction was neu-
tralised with saturated aqueous NH4Cl (5 mL) and extracted with
DCM. The combined organic phases were washed with brine, dried
over MgSO4, filtered and concentrated under vacuum. The residue
was purified by flash chromatography (Cyclohexane/EtOAc 7:3) to
afford 12 (360 mg, 73%). Rf = 0.3 (Cyclohexane/EtOAc 7:3). 1H NMR
(400 MHz, CDCl3): d = 5.40 (d, J = 5.9 Hz 1H, 2-H), 4.60 (d, J = 5.9 Hz,
1H, 3-H), 3.53 (s, 3H, 4-H), 3.43 (s, 3H, 40-H), 2.17 (s, 3H, COCH3)
ppm. 13C NMR (100 MHz, CDCl3): d = 170.2 (C@O), 120.6 (1-C),
102.9 (3-C), 70.3 (2-C), 54.7–54.5 (4-C, 40-C), 20.3 (COCH3) ppm.
4.3.2. (1S,2S,3R,5R,6S)-1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrol
21
Rf = 0.49 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ ꢀ15 (c 1, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.62 (ddd, J = 11.3, 11.3, 4.8 Hz, 1H, 5ax-
H), 4.52 (d, J = 10.4 Hz, 1H, 6ax-H), 3.97 (m, 1H, 3eq-H), 3.57 (d,
J = 2.0 Hz, 1H, 2eq-H), 2.12 (ddd, J = 4.8, 2.1, 13.5 Hz, 1H, 4eq-H),
1.93 (ddd, J = 11.3, 11.3, 2.4 Hz, 1H, 4ax-H), 1.28 (s, 3H, CH3)
ppm.13C NMR (100 MHz, MeOD): d = 96.3 (6-C), 77.1 (1-C), 74.8
(2-C), 72.6 (3-C), 65.0 (5-C), 36.4 (4-C), 24.2 (7-C) ppm. IR:
4.2.10. Racemic 2-acetoxy-3,3-dimethoxypropanal 13
To a solution of 12 (0.55 mmol, 95 mg) diluted in a mixture of
1:1:2 water–acetic acid–pyridine (6 mL) was added at 0 °C Raney
nickel (6.6 mmol, 0.4 g) followed by sodium hypophosphite
(3.3 mmol, 0.4 g). The reaction mixture was stirred at 0 °C for
30 min before being filtered. The filtrate was extracted with
m
= 3374 (OH), 1549 (NO), 1377 (CN), 1047 (CO) cmꢀ1. HRMS

1080
F. Camps Bres et al. / Tetrahedron: Asymmetry 24 (2013) 1075–1081
(ES+): m/z calcd for C7H13NO6+Na+: 230.0640 [M+Na+], found
230.0634.
For all isomers 28–31: IR: m .
= 3368, 1552, 1376, 1042 cmꢀ1
HRMS (ES+): m/z calcd for C7H13NO7+Na+: 246.0590 [M+Na+],
found 246.0582.
4.3.3. (1R,2S,3R,5R,6S)-1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrol
22
4.3.9. (1R,2S,3R,4S,5R,6R)-1-Methyl-6-nitrocyclohexane-1,2,3,4,
Rf = 0.41 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ þ32 (c 1.0, CH3OH). 1H NMR
5-pentol 28
(400 MHz, MeOD): d = 4.63 (d, J = 10.6 Hz, 1H, 6ax-H), 4.35 (m, 1H,
5ax-H), 3.97 (m, 1H, 3eq-H), 3.54 (d, J = 2.4 Hz, 1H, 2eq-H), 1.98 (m,
1H, 4eq-H), 1.91 (ddd, J = 11.3, 11.3, 3.3 Hz, 1H, 4ax-H), 1.34 (s, 3H,
CH3) ppm. 13C NMR (100 MHz, MeOD): d = 97.9 (6-C), 78.1 (2-C),
74.8 (1-C), 70.4 (3-C), 66.6 (5-C), 36.5 (4-C), 21.7 (7-C) ppm. IR:
Rf = 0.2 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ þ27 (c 1, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.60 (d, J = 10.6 Hz, 1H, 6ax-H), 4.41 (dd,
J = 10.6, 11.0 Hz, 1H, 5ax-H), 4.01 (pt, J = 11.1, 11.1 Hz, 1H, 4ax-
H), 3.71 (dd, J = 11.1, 9.7 Hz, 1H, 3ax-H), 3.43 (d, J = 9.7 Hz, 1H,
2ax-H), 1.33 (s, 3H, CH3) ppm. 13C NMR (100 MHz, MeOD):
d = 94.1 (6-C), 77.1 (1-C), 74.8 (2-C), 73.5 (4-C), 71.9 (3-C), 69.5
(5-C), 24.1 (7-C) ppm.
m
= 3362 (OH), 1549 (NO), 1377 (CN), 1046 (CO) cmꢀ1. HRMS
(ES+): m/z calcd for C7H13NO6+Na+: 230.0640 [M+Na+], found
230.0632.
4.3.10. (1S,2S,3R,4S,5S,6S)-1-Methyl-6-nitrocyclohexane-1,2,3,4,
4.3.4. (1S,2S,3R,5S,6R)-1-Methyl-6-nitrocyclohexane-1,2,3,5-tetrol
5-pentol 29
23
Rf = 0.43 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ ꢀ15 (c 1.0, CH3OH). 1H NMR
Rf = 0.30 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ ꢀ35 (c 1, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.60 (d, J = 10.6 Hz, 1H, 6ax-H), 4.39 (dd,
J = 11.0, 3.3 Hz, 1H, 5ax-H), 3.99 (dd, J = 3.5, 3.1 Hz, 1H, 3eq-H),
3.75 (pt, J = 3.1, 3.1 Hz, 1H, 4eq-H), 3.61 (d, J = 3.5 Hz, 1H, 2eq-H),
1.28 (s, 3H, CH3) ppm. 13C NMR (100 MHz, MeOD): d = 94.9 (6-C),
76.6 (4-C), 75.0 (2-C), 71.7 (3-C), 71.2 (1-C), 69.5 (5-C), 20.0 (7-C)
ppm.
(400 MHz, MeOD): d = 4.41 (d, J = 10.8 Hz, 1H, 6ax-H), 4.16 (ddd,
J = 10, 11.2, 4.9 Hz, 1H, 5ax-H), 3.46 (ddd, J = 11.2, 9.5, 4.9 Hz, 1H,
3ax-H), 3.26 (d, J = 9.5 Hz, 1H, 2ax-H), 2.25 (m, 1H, 4eq-H), 1.46
(q, J = 11.7 Hz, 1H, 4ax-H), 1.17 (s, 3H, CH3) ppm. 13C NMR
(100 MHz, MeOD): d = 99.6 (6-C), 81.3 (2-C), 74.7 (1-C), 68.8 (3-
C), 66.9 (5-C), 39.7 (4-C), 16.4 (7-C) ppm.
For all isomers 24–27: IR:
m
= 3357, 1554, 1375, 1053 cmꢀ1
.
4.3.11. (1R,2S,3R,4S,5S,6S)-1-Methyl-6-nitrocyclohexane-1,2,3,4,
HRMS (ES+): m/z calcd for C7H13NO7+Na+: 246.0590 [M+Na+],
5-pentol 30
found 246.0578.
Rf = 0.37 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ þ25 (c 1.0, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.79 (d, J = 11.2 Hz, 1H, 6ax-H), 4.12 (dd,
J = 11.0, 3.2 Hz, 1H, 5ax-H), 4.00 (dd, J = 3.1, 2.5 Hz, 1H, 3eq-H),
3.69 (pt, J = 3.1, 3.1 Hz, 1H, 4eq-H), 3.45 (d, J = 2.5 Hz, 1H, 2eq-H),
1.18 (s, 3H, CH3) ppm.13C NMR (100 MHz, MeOD): d = 95.1 (6-C),
76.7 (4-C), 73.1 (2-C), 72.6 (1-C), 71.7 (3-C), 68.7 (5-C), 21.1 (7-C)
ppm.
4.3.5. (1R,2S,3R,4R,5R,6R)-1-Methyl-6-nitrocyclohexane-1,2,3,4,
5-pentol 24
Rf = 0.22 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ þ28 (c 1.0, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.64 (d, J = 10.8 Hz, 1H, 6ax-H), 4.39 (dd,
J = 10.8, 3.1 Hz, 1H, 5ax-H), 4.03 (t, J = 3.1 Hz, 1H, 4eq-H), 3.70
(dd, J = 3.1, 9.7 Hz, 1H, 3ax-H), 3.46 (d, J = 9.7 Hz, 1H, 2ax-H), 1.33
(s, 3H, CH3) ppm. 13C NMR (100 MHz, MeOD): d = 94.0 (6-C), 77.0
(1-C), 74.7 (2-C), 73.3 (4-C), 71.8 (3-C), 69.3 (5-C), 23.2 (7-C) ppm.
4.3.12. (1S,2S,3R,4S,5R,6R)-1-Methyl-6-nitrocyclohexane-1,2,3,4,
5-pentol 31
Rf = 0.27 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ ꢀ25 (c 1.0, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.69 (d, J = 11.0 Hz,1H, 6ax-H), 4.09 (dd,
J = 10.6, 9.9 Hz, 1H, H-5ax), 3.99 (pt, J = 9.9, 9.9 Hz, 1H, 4ax-H),
3.72 (dd, J = 10.0, 10.0 Hz, 1H, 3ax-H), 3.40 (d, J = 10.0 Hz, 1H,
2ax-H), 1.19 (s, 3H, CH3) ppm. 13C NMR (100 MHz, MeOD):
d = 95.0 (6-C), 75.6 (2-C), 73.8 (1-C), 73.3 (4-C), 70.5 (3-C), 69.7
(C-5), 22.0 (7-C) ppm.
4.3.6. (1S,2S,3R,4R,5S,6S)-1-Methyl-6-nitrocyclohexane-1,2,3,5-
pentol 25
Rf = 0.42 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ ꢀ16 (c 1.0, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.56 (d, J = 10.6 Hz, 1H, 6ax-H), 4.43 (pt, 9.9,
9.9 Hz, 1H, 5ax-H), 3.99 (m, 1H, 3eq-H), 3.75 (dd, J = 9.7, 3.5 Hz, 1H,
4ax-H), 3.69 (d, J = 3.5 Hz, 1H, 2eq-H), 1.28 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, MeOD): d = 94.9 (6-C), 75.8 (3-C), 75.4 (2-C),
73.7 (1-C), 72.6 (4-C), 69.6 (5-C), 24.0 (7-C) ppm.
Acknowledgments
This work was supported in part, by the French Association
‘Vaincre les maladies lysosomales’ Grant (to J.A.C.). This work
was also supported in part, by the CNRS GDR RDR2 «Aller vers
une chimie éco-compatible» Grant (to F.C.B.).
4.3.7. (1R,2S,3R,4R,5S,6S)-1-Methyl-6-nitrocyclohexane-1,2,3,4,
5-pentol 26
Rf = 0.37 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ þ33 (c 1.0, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.67 (d, J = 11.0 Hz, 1H, 6ax-H), 4.16 (dd, J
=11.0, 9.9 Hz, 1H, 5ax-H), 3.99 (m, 1H, 3eq-H), 3.75 (m, 1H, 4ax-
H), 3.65 (d, J = 3.5 Hz, 1H, 2eq-H), 1.36 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, MeOD): d = 96.1 (6-C), 78.4 (2-C), 76.9 (1-C),
76.0 (4-C), 73.4 (3-C), 70.4 (5-C), 21.9 (7-C) ppm.
References
1. (a) Duchek, J.; Adams, D. R.; Hudlicky, T. Chem. Rev. 2011, 111, 4223–4258; (b)
Kilbas, B.; Balci, M. Tetrahedron 2011, 67, 2355–2389; (c) Hudlicky, T.; Cebulak,
M. In Cyclitols and their Derivatives: A Handbook of Physical Spectral and Synthetic
Data; Wiley-VCH: New York, USA, 1993.
2. (a) Cosgrove, D. J; Irving, G. C.
J In Inositol Phosphates: their Chemistry,
4.3.8. (1S,2S,3R,4R,5R,6R)-1-Methyl-6-nitrocyclohexane-1,2,3,4,
Biochemistry, and Physiology; Elsevier Scientific Pub., 1980; (b) Greimel, P.;
Spreitz, J.; Sprenger, F. K.; Stütz, A. E.; Wrodnigg, T. M. In The Organic Chemistry
of Sugars; Levy, D. E., Fügedi, P., Eds.; CRC Press, 2006; (c) Kobayashi, Y. In
Glycoscience; Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin,
Germany, 2008; pp 1913–1997.
5-pentol 27
Rf = 0.28 (DCM/MeOH 8:2). ½a D25
ꢂ
¼ ꢀ35 (c 1.0, CH3OH). 1H NMR
(400 MHz, MeOD): d = 4.79 (d, J = 11.2 Hz,1H, 6ax-H), 4.10 (dd,
J = 11.0, 3.3 Hz, 1H, 5ax-H), 4.00 (pt, J = 3.3, 3.3 Hz, 1H, 4eq-H),
3.72 (d, J = 9.9 Hz, 1H, 2ax-H), 3.40 (dd, J = 3.1, 10.2 Hz, 1H, 3ax-
H), 1.19 (s, 3H, CH3) ppm. 13C NMR (100 MHz, MeOD): d = 95.3
(6-C), 76.4 (1-C), 75.3 (4-C), 73.2 (2-C), 72.6 (3-C), 69.8 (5-C),
23.9 (7-C) ppm.
3. (a) Diaz, L.; Delgado, A. Curr. Med. Chem. 2010, 17, 2393–2418; (b) Chen, X.; Fan,
Y.; Zheng, Y.; Shen, Y. Chem. Rev. 2003, 103, 1955–1977; (c) Ogawa, S. In
Carbohydrate Mimics: Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH:
Weinheim, Germany, 1998; pp 87–106.
4. Mahmud, T. Nat. Prod. Rep. 2003, 20, 137–166; (b) Mahmud, T. Curr. Opin. Chem.
Biol. 2009, 13, 161–170.

F. Camps Bres et al. / Tetrahedron: Asymmetry 24 (2013) 1075–1081
1081
5. For a review see: (a) Delgado, A. Eur. J. Org. Chem. 2008, 3893–3906; (b)
Soengas, R. G.; Otero, J. M.; Estevez, A. M.; Rauter, A. P.; Cachatra, V.; Estevez, J.
C.; Estevez, R. J. Carbohydr. Chem. 2012, 38, 263–302; Other selected recent
references: (c) Ghosal, P.; Shaw, A. K. J. Org. Chem. 2012, 77, 7627–7632; (d) Lo,
H.-J.; Chang, Y.-K.; Yan, T.-H. Org. Lett. 2012, 14, 5896–5899; (e) Worawalai, W.;
Wacharasindhu, S.; Phuwapraisirisan, P. Med. Chem. Commun. 2012, 3, 1466–
1470; (f) Trapero, A.; Gonzalez-Bulnes, P.; Butters, T. D.; Llebaria, A. J. Med.
Chem. 2012, 55, 4479–4488; (g) Harrack, Y.; Barrra, C. M.; Delgado, A.; Castano,
A. R.; Lleberia, A. J. Am. Chem. Soc. 2011, 133, 12079–12084; (h) Gupta, P.; Pal, A.
P. J.; Reddy, Y. S.; Vankar, Y. D. Eur. J. Org. Chem. 2011, 1166–1175.
9. (a) Simon, G.; Eljezi, T.; Légeret, B.; Charmantray, F.; Castillo, J. A.; Guérard-
Hélaine, C.; Lemaire, M.; Bouzon, M.; Marlière, P.; Hélaine, V.; Hecquet, L.
ChemCatChem 2013, 5, 784–795; (b) Concia, A. L.; Gomez, L.; Bujons, J.; Parella,
T.; Vilaplana, C.; Cardona, P. J.; Joglar, J.; Clapés, P. Org. Biomol. Chem. 2013, 11,
2005–2021; (c) Mifsud, M.; Szekrenyi, A.; Joglar, J.; Clapés, P. J. Mol. Catal. B:
Enzym. 2012, 84, 102–107; (d) Sanchez-Moreno, I.; Helaine, V.; Poupard, N.;
Charmantray, F.; Legeret, B.; Hecquet, L.; Garcia-Junceda, E.; Wohlgemuth, R.;
Guerard-Helaine, C.; Lemaire, M. Adv. Synth. Catal. 2012, 354, 1725–1730; (e)
Gutierrez, M.; Parella, T.; Joglar, J.; Bujons, J.; Clapés, P. Chem. Commun. 2011,
47, 5762–5764.
6. (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178; (b) Cagide-
Fagin, F.; Nieto-Garcia, O.; Lago-Santome, H.; Alonso, R. J. Org. Chem. 2012, 77,
11377–11382; (c) Castillo, J. A.; Guérard-Hélaine, C.; Gutierrez, M.; Garrabou,
X.; Sancelme, M.; Schuermann, M.; Inoue, T.; Hélaine, V.; Charmantray, F.;
Gefflaut, T.; Hecquet, L.; Joglar, J.; Clapés, P.; Sprenger, G. A.; Lemaire, M. Adv.
Synth. Catal. 2010, 352, 1039–1046; (d) El Blidi, L.; Assaf, Z.; Camps Bres, F.;
Veschambre, H.; Thery, V.; Bolte, J.; Lemaire, M. ChemCatChem 2009, 1, 463–
471; (e) El Blidi, L.; Crestia, D.; Gallienne, E.; Demuynck, C.; Bolte, J.; Lemaire,
M. Tetrahedron: Asymmetry 2004, 15, 2951–2954; (f) El Blidi, L.; Ahbala, M.;
Bolte, J.; Lemaire, M. Tetrahedron: Asymmetry 2006, 17, 2684–2688; (g) Ortiz, J.
C.; Ozores, L.; Cagide-Fagin, F.; Alonso, R. Chem. Commun. 2006, 4239–4241.
7. (a) Timmons, S. C.; Thorson, J. S. Curr. Opin. Chem. Biol. 2008, 12, 297–305; (b)
Fu, Y.; Al-Mestarihi, A.; Grimes, C. L.; Kahne, D.; Bachmann, B. O. J. Am. Chem.
Soc. 2008, 130, 15756–15757; (c) Zhang, H.; White-Phillip, J. A.; Melançon, C. E.,
III; Kwon, H.-J.; Yu, W.-I.; Liu, H.-W. J. Am. Chem. Soc. 2007, 129, 14670–14683.
8. (a) Clapés, P.; Fessner, W.-D.; Sprenger, G. A.; Samland, A. K. Curr. Opin. Chem.
Biol. 2010, 14, 154–167; (b) Brovetto, M.; Gamenara, D.; Saenz Mendez, P.;
Seoane, G. A. Chem. Rev. 2011, 111, 4346–4403; (c) Clapés, P.; Garrabou, X. Adv.
Synth. Catal. 2011, 353, 2263–2283; (d) Muller, M. Adv. Synth. Catal. 2012, 354,
3161–3174.
10. Garrabou, X.; Castillo, J. A.; Guérard-Hélaine, C.; Parella, T.; Joglar, J.; Lemaire,
M.; Clapes, P. Angew. Chem. 2009, 121, 5629–5633. Angew. Chem., Int. Ed. 2009,
48, 5521–5525.
11. Alcarez, L.; Hamett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449–5452; See also: Baylon, C.; Heck,
M.-P.; Mioskowski, C. J. Org. Chem. 1999, 64, 3354–3360.
12. (a) Holt, J.; Hanefeld, U. Curr. Org. Synth. 2009, 6, 15–37; (b) Veum, L.; Hanefeld,
U. Synlett 2005, 2382–2384.
13. Staskun, B.; van Es, T. S. Afr. J. Chem. 2008, 61, 144–156.
14. Milner, S. E.; Moody, T. S.; Maguire, A. R. Eur. J. Org. Chem. 2012, 3059–3067.
15. For a recent review see (a) Ballini, R.; Barboni, L.; Fringuelli, F.; Palmieri, A.;
Pizzo, F.; Vaccaro, L. Green Chem. 2007, 9, 823–838; (b) Ballini, R. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, M., Ed.; Elsevier: Amsterdam,
1997; Vol. 19, pp 117–184.
16. One unit of FSA cleaves 1 mol of D-fructose-6-phosphate per min to afford
glyceraldehydes-3-phosphate and dihydroxyacetone at pH 7.5 (TEA 50 mM
buffer) and 25 °C.
17. Shing, T. K. M.; Zhong, Y. J. Org. Chem. 1997, 62, 2622–2624.