Highly diastereoselective Morita-Baylis-Hillman chemistry: A remote activation effect in the diastereoface selective synthesis of densely functionalized branched cyclic enones from d-glucose

Article abstract of DOI:10.1016/j.tetasy.2012.03.009

A highly diastereoselective C-2 alkylation of sugar derived cyclic enone 1 in the presence of diethylaluminium iodide by utilizing Morita-Baylis-Hillman chemistry is reported. While diethylaluminium iodide was found to be a suitable Lewis acid for this tr

Full text of DOI:10.1016/j.tetasy.2012.03.009

Tetrahedron: Asymmetry 23 (2012) 449–456
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Tetrahedron: Asymmetry
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Highly diastereoselective Morita–Baylis–Hillman chemistry: a remote
activation effect in the diastereoface selective synthesis of densely
functionalized branched cyclic enones from D-glucose
⇑
Vikas Kumar, Partha Ghosal, Pintu Das, Arun K. Shaw
Division of Medicinal and Process Chemistry, CSIR—Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly diastereoselective C-2 alkylation of sugar derived cyclic enone 1 in the presence of diethylalu-
minium iodide by utilizing Morita–Baylis–Hillman chemistry is reported. While diethylaluminium iodide
was found to be a suitable Lewis acid for this transformation, the widely employed TiCl4 was ineffective.
A plausible mechanism, which considered the involvement of a Zimmerman–Traxler type of closed tran-
sition state and an orthoester intermediate, has been discussed.
Received 16 February 2012
Accepted 20 March 2012
Available online 24 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
OH OH
Cl
O
HO
HO
HO
HO
HO
HO
Highly functionalized cyclohexanoid substructure form the ba-
sic skeleton of several complex natural products and biologically
important molecules. In addition, polyoxygenated cyclohexanoids
are also present in several small natural products such as conduri-
tols, streptol, gabosine and pericosine (Fig 1).1 These natural prod-
ucts exhibit glycosidase inhibitory, antitumour (including
anticancer), antiviral, antifungal, antibacterial and antimalarial
activities.2 Many analogues and structural variants of these natu-
rally occurring molecules have been synthesized and evaluated
for their bioactivity.1e,1f,3 However, there is a demand for novel
stereochemically pure analogues of these polyoxygenated cyclo-
hexenoid natural products. Recently, we have described the syn-
thesis of gabosines, molecules with C-2 branching of the
polyoxygenated cyclohexanoid system as shown in Figure 1.4 Due
to the biological properties associated with natural products con-
taining C-2 alkylated cyclohexanoids as a substructure, we decided
to design and synthesize new, stereochemically pure, highly func-
tionalized cyclohexanoid molecules with C-2 branching. The struc-
ture of the prototype molecule I shown in Figure 1 can be prepared
by C–C bond forming reactions.
OMe
OH
streptol
OH
conduritol
pericosine A
O
OH
OMe
O
O
OH
*
1
HO
HO
HO
HO
6
2
RO
RO
OMe
R
3
5
4
OH
gabosine
OH
OR
pericosine B,C
I
Figure 1. Representative examples of C-2 alkylated cyclohexanoid based natural
products and prototype structure I.
However, in carbohydrate chemistry, the application of the asym-
metric MBH reaction is very limited.9 We have previously used
MBH chemistry to synthesize anti-mycobacterial higher acyclic
sugar derivatives and acyclic amino alcohols.10,11
The Morita–Baylis–Hillman (MBH) reaction is one of the most
frequently used carbon–carbon bond forming reactions5,6 between
an activated alkene or alkyne and an aldehyde or a ketone in the
A few years ago, we reported that the TiCl4/TBAI mediated sub-
strate controlled MBH reaction of sugar derived enulosides with
several aromatic aldehydes and few aliphatic aldehydes proceeded
with very high diastereoselectivity.12,13 We observed that the dia-
stereoselectivity of the reaction was controlled by the nature of the
protecting group at the C-6 position. While C-6 acyl protected
enulosides furnished the MBH adducts in very good yields and
with high diastereoselectivity (>99%), the C-6 alkyl protected
presence of a suitable catalyst to yield
a-methylene-b-hydroxy
derivatives, generally called MBH adducts. Highly diastereoselec-
tive MBH reactions have been studied extensively over the last
few years.7 The synthesis of important, biologically active mole-
cules involving asymmetric MBH reactions has also been reported.8
⇑
Corresponding author.
E-mail address: akshaw55@yahoo.com (A.K. Shaw).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.009

450
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 449–456
enulosides generated MBH adducts with low yields and moderate
selectivities. On the basis of these results, we thought that a high
diastereoselectivity could be achieved in the MBH reaction
between C-6 acyl protected enuloside and aromatic or aliphatic
aldehydes via the formation of a supramolecular closed transition
state TSII (Scheme 1).
In a continuation of our interests to synthesize biologically rel-
evant compounds from the commercially available carbohydrate
derivatives involving MBH chemistry, we herein report an efficient
strategy for the synthesis of C-2 branched analogues of natural
gabosines involving the Lewis acid mediated MBH reaction with
same equivalent of Et2AlI to the reaction mixture at ꢀ78 °C over
the same period of time. The stirring was continued at ꢀ30 °C
when the formation of several spots on TLC was noticed. However,
when the stirring was carried out at ꢀ50 °C instead of ꢀ30 °C after
the addition of Et2AlI at ꢀ78 °C, the reaction was very clean but
complete disappearance of starting material did not occur after
8 h and therefore, the stirring was continued for 24 h. Unfortu-
nately there was no change on the TLC profile of the reaction mix-
ture even after 24 h and at this stage it was worked up. The column
chromatography purification of the product mixture led to the iso-
lation of a pure compound in 85% yield (calculated on the basis of
the starting material recovered) which was identified as compound
2a from its detailed spectroscopic analysis (Table 1).
high diastereoselectivity. Herein represents
a substrate con-
trolled/directed, highly diastereoselective MBH reaction between
various aromatic aldehydes as electrophiles and sugar derived acti-
vated alkenes as a chiral source in the presence of Et2AlI.
Table 1
Optimization of the equivalents of Et2AlI
2. Results and discussion
CHO
O
O
OH
AcO
BnO
AcO
BnO
Et2AlI
Initially, we decided to investigate the title reaction of a sugar
derived cyclic enone with an active aldehyde by utilizing TiCl4, a
widely employed Lewis acid catalyst in MBH reactions.11 The
+
DCM
-78 °C to -50 °C
24h
NO2
required enone 1 was synthesized from methyl
a
,
D
-glucopyrano-
OBn
NO2
OBn
side according to the literature.14 In our previous study on the
MBH reactions of acyl protected enulosides with various aromatic
and aliphatic aldehydes, we hypothesized that the C-6 acyl group
in an enuloside could assist the formation of an orthoester
intermediate in the presence of TiCl4 and an activator, TBAI.12
This intermediate and TiCl4 coordinated aldehyde could then form
1
2a
a
Entry
No. of equivalents of Et2AlI (n)
Yield (%)
1
2
3
4
5
0.5
1.0
1.5
2.0
3.0
30
56
85
82
82
a
Zimmerman–Traxler15 type of closed transition state TSII
a
(Scheme 1) leaving only one of the diastereotopic faces of the alde-
hyde available to furnish the adduct with very high diastereofacial
selectivity. Herein the reaction of enone 1 with 4-nitrobenzalde-
hyde in the presence of TiCl4 and TBAI did not give the expected
adduct. Instead, monodebenzylation of 1 took place as observed
from the 1H NMR spectrum of the reaction product. The deprotec-
tion of benzyl group with TiCl4 and its incompatibility with the
MBH reaction of substituted cyclohexenones are well documented
in the literature.16,17 Therefore, we assumed that TiCl4 could not be
used as a Lewis acid for the MBH reaction of enone 1 with 4-nitro-
benzaldehyde. Based on the literature reports of Et2AlI mediated
MBH reactions, we decided to explore Et2AlI as the Lewis acid for
the title reaction.18
Yields were calculated on the basis of recovered starting material.
In order to improve the yield of adduct 2a, several sets of MBH
reactions of enone 1 with 4-nitrobenzaldehyde were carried out
with increasing equivalents of Et2AlI (from 0.5 to 3.0 equiv in equal
intervals). We observed that a loading of 1.5 equiv of Et2AlI was suf-
ficient to furnish 2a in 85% isolated yield (Table 1, entry 3). In order
to further optimize the reaction conditions, the time of the addition
of Et2AlI to the reaction mixture was increased from 1 to 3 h but no
improvement in yield of the adduct 2a was observed. Our efforts to
improve the yield of the adduct when a catalytic amount of TBAI
(20 mol %) was used as an activator were unsuccessful.12a
At this stage, with the optimized reaction conditions in hand
(Table 1, entry 3), we tried to explore the applicability of this enone
1 as an activated alkene in Et2AlI mediated MBH reactions with
various representative aromatic aldehydes. Thus, the coupling
reaction of enone 1 with various aromatic aldehydes was also car-
ried out under similar reaction conditions and in each case, the
Initially, we performed the reaction of enone 1 (1 equiv) with
4-nitrobenzaldehyde (2 equiv) in dry DCM at 0 °C by the dropwise
addition of 1.5 equiv of Et2AlI over a period of 1 h, which caused
the decomposition of the starting material. We then slightly mod-
ified the experimental protocol by the dropwise addition of the
R1CHO
OR
OR
R1CHO
TiCl4/TBAI
OR
O
O
O
O
O
O
TiCl4/TBAI
R = acyl
R = alkyl
HO
OiPr
HO
OiPr
enuloside
OiPr
H
H
R1
R1
R = acyl
R = alkyl
moderate diastereoselectivity
very high diastereoselectivity
(>99:1)
O
TiCl3
′R
O
H
Cl
Cl
Cl
O
I
Ti
Cl
O
O
OiPr
R1
TS II
H
Attack at Siface of carbonyl
Scheme 1. Highly diastereoselective MBH reaction of sugar derived enulosides using TiCl4 as a Lewis acid catalyst.

V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 449–456
451
Table 2
results were not good since the starting material was recovered
with only trace amounts of the desired MBH adduct. It is worth
mentioning that although the MBH reaction of enone 10, having p-
nitrobenzoyl protection at the C-6 position, with 2,3-dichlorobenz-
aldehyde under the optimized reaction conditions was also
highly diasteroselective (Table 2, entry 10), the yield of adduct 2j
was low (49%) compared to adduct 2g derived from enone 1.
In order to determine the stereochemistry of the newly created
stereocentre in adduct 2b, it was subjected to a Luche reduction fol-
lowed by acetonide protection of the resulting diol to afford 3
(Scheme 2). In its 1H NMR spectrum, signals appearing at 4.63,
5.39 and 4.54 ppm due to H-8a, H-4 and H-5 respectively were
confirmed by 1D and 2D NMR spectroscopic analyses. The stereo-
chemistry of the new stereogenic centre in adduct 2b was deter-
mined on the basis of the NOE spectrum of its reduced derivative
3. The H-4 showed an NOE correlation with H-8a, thus confirming
the cis relationship of H-4 with H-8a, which also showed an NOE
correlation with H-7. Thus, all of these correlations supported the
syn relationship between H-8a, H-4 and H-7 and therefore, the ste-
reochemistry of the newly created stereocentre in 2b was assigned
as (S) (Fig. 2).
MBH reactions of enones with various aromatic aldehydes
O
O
OH
RO
RO
Et2AlI
Ar
+
ArCHO
DCM,
-78 oC to -50 o
8h
BnO
BnO
C
OBn
1 R = CH3CO-
OBn
2
1' R = p-NO2C6H4CO-
Entry
Enone
ArCHO
Time (h)
8
Product
Yielda (%)
85
CHO
CHO
1
1
2a
2b
2c
O2N
NC
2
3
1
1
8
8
71
80
CHO
NO2
CHO
2
4
5
6
1
1
1
8
8
8
2d
2e
2f
67
62
70
1O
O
F
H
H
AcO
CHO
8a
4
8
H
BnO
5
7
CN
6
F
F
CHO
OBn
3
Cl
Figure 2. NOE correlations for compound 3.
CHO
When the MBH reaction of benzyl protected enone 44 with 4-
nitrobenzaldehyde in the presence of Et2AlI under identical condi-
tions was carried out, a mixture of products was formed from which
one of the isomeric MBH adducts 5 was isolated in 18% yield along
with an inseparable mixture of products containing another diaste-
reoisomer of 5, which was evident from the 1H NMR spectrum of the
product mixture. The same problem was encountered in the MBH
reaction between enone 4 and 4-cyanobenzaldehyde with only
one of the isomeric adducts 6 being isolated in 15% yield (Scheme 3).
Based on our previous observations on TiCl4/TBAI mediated
highly MBH reaction of enulosides with aromatic and aliphatic
aldehydes12 and the results obtained from Et2AlI induced MBH
reactions of enone 1 and 4 with aromatic aldehydes, the difference
in the behaviour of enones 1 and 4 with regards to their reactions
with aromatic aldehydes could be explained on the basis of a plau-
sible nucleophilic attack of the iodide (from Et2AlI) to the alumin-
ium coordinated enone (1a or 4a) from the opposite side to the
benzyloxy group at the C-4 position with concomitant shifting of
the 2, 3 double bond to the 1,2-position generating an aluminium
coordinated oxyanion (1b or 4b). In the case of enone 1, the oxyan-
ion 1b is converted into the orthoester20 intermediate A or B,
which causes remote activation at the site of reaction (C-2) of
the enolate. Amongst the two possible orthoesters A and B, the
7
1
8
2g
91
Cl
Cl
CHO
Cl
8
9
1
1
8
8
2h
2i
76
82
Cl
CHO
O2N
NO2
CHO
Cl
10
10
8
2j
49
Cl
Yields were calculated on the basis of the starting material recovered.
a
desired adduct was obtained as a single diastereoisomer with
up to 91% yield (calculated on the basis of starting material
recovered).
These results (Table 2) clearly demonstrated that the reaction
was highly diastereoselective.19 With aliphatic aldehydes, the
O
OH
O
O
i. NaBH4
CeCl3·7H2O
EtOH, 0 °C, 2h
AcO
BnO
AcO
BnO
ii.
MeO
OMe
CN
CN
OBn
OBn
2b
CSA, 12h,
3
70% for 2 steps
Scheme 2. Synthesis of compound 3.

452
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 449–456
O
CHO
O
OH
BnO
BnO
BnO
BnO
Et2AlI, DCM
+
+
-78 oC to -50 o
8h, 18%
C
NO2
NO2
OBn
4
OBn
O
5
O
CHO
OH
BnO
BnO
BnO
BnO
Et2AlI, DCM
-78 oC to -50 o
8h, 15%
C
CN
CN
OBn
OBn
6
4
Scheme 3. MBH reactions of enone 4.
latter one is disfavoured due to the 1,3-diaxial interactions be-
tween the methyl of the acetate group and H-6. The Et2AlI coordi-
nated aryl aldehyde can approach the favoured form A to generate
two possible Zimmerman–Traxler type of closed transition states C
and D. Transition state D (path b) is disfavoured due to a 1,3-diax-
ial type interaction between the R group of the aldehyde and the
ethyl group of the diethyl aluminium. Thus, the favoured transition
state C (path a) is responsible for the exclusive formation of the
MBH adduct 2 with very high diastereoselectivity. In the case of
enone 4, the conjugate addition of the iodide in the presence of a
Lewis acid could generate an unfavourable intermediate 4c, where
a 1,3-diaxial type interaction between H-6 and the ethyl group of
aluminium makes it unstable (Scheme 4). Thus, this mechanistic
argument justifies the formation of the mixture of isomeric ad-
ducts from the Et2AlI mediated MBH reaction of 4 with either 4-
nitrobenzaldehyde or 4-cyanobenzaldehyde (Scheme 3).
stated using CDCl3 as the solvent. Chemical shifts are given on
the d scale and are referenced to the TMS at 0.00 ppm for proton
and 0.00 ppm for carbon. For 13C NMR, reference CDCl3 appeared
at 77.4 ppm. Mass spectra were recorded using EI and DART mode
at 70 eV, and IR spectra were recorded with FT-IR as a thin film and
expressed in cmꢀ1. Optical rotations were determined using a 1 dm
cell at 28 °C in chloroform as the solvent; concentrations men-
tioned are in g/100 mL. Visualization of spots on analytical TLC
was accomplished with CeSO4 (1% in 2 N H2SO4) followed by char-
ring over a hot plate. Silica gel (100–200 mesh) was used for col-
umn chromatography.
4.1.1. Synthesis of (1S,5S,6R)-5,6-bis(benzyloxy)-2-oxocyclohex-
3-enyl 4-nitrobenzoate 10
To a stirred solution of methyl 6-deoxy-6-iodo-2,3-di-O-benzyl-
a,D-glucopyranoside (1.5 g, 3.1 mmol) in THF (30 mL) was added
tBuOK (1.04 g, 9.3 mmol) in portions at 0 °C over 2 h. The reaction
was then stirred for 24 h at room temperature. The reaction mix-
ture was then diluted with ethyl acetate (30 mL) and washed with
H2O (2 ꢁ 15 mL) and brine (2 ꢁ 15 mL). The organic layer was sep-
arated, dried (Na2SO4), and concentrated under reduced pressure
to give a residue (1.2 g).
3. Conclusions
In conclusion, we have reported on a highly diastereoselective
Et2AlI induced C-2 hydroxyalkylation of sugar derived cyclic enone
1 involving MBH chemistry. While the diastereoselectivity depends
on the acyl protection regardless of whether it is an acetyl, benzoyl
or other acyl group, as it was evident from our mechanistic argu-
ments on the proposed hypothesis, a mixture of adducts was ob-
tained from enone 4. Thus, it could be argued on the basis of the
above experimental observations that the acyl protected enone of
type 1 could be a better active alkene for Et2AlI induced diastereo-
selective MBH reactions with active aldehydes. Mechanistically at
this stage it is presumed that the formation of an orthoester20
intermediate 1c could be responsible for the remote activation of
the diastereofacial selectivity in the C–C bond formation in the title
reaction by involving a supramolecular closed transition state C of
a Zimmerman–Traxler-type. All adducts 2a–j are novel analogues
of naturally occurring bioactive gabosines and this flexible syn-
thetic strategy paves the way for the rapid library generation of
numerous analogues of gabosines and several other bioactive mol-
ecules. It is worth mentioning that the whole study was substrate
(enone) controlled and the diastereoselectivity of the reaction does
not require any chiral reagents.
To a solution of the above residue (0.6 g) in pyridine (4 mL)
was added p-nitrobenzoyl chloride (0.3 mL, 3.3 mmol) at 0 °C,
and this reaction mixture was allowed to warm to room temper-
ature. After 4 h, the reaction mixture was concentrated under
reduced pressure to give a residue, which upon column chroma-
tography purification yielded (3S,4S,5R,6S)-4,5-bis(benzyloxy)-6-
methoxy-2-methylenetetrahydro-2H-pyran-3-yl 4-nitrobenzoate
(394 mg, 82% for two steps). White semisolid, eluent for column
chromatography: EtOAc/hexane (1:11, v/v); ½a D28
¼ ꢀ33:3 (c 0.21,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3) d 8.20–8.15 (m, 2H), 8.07–
8.04 (m, 2H), 7.30–7.02 (m, 10H), 5.58–5.55 (m, 1H), 4.82–4.75
(m, 2H), 4.66–4.56 (m, 4H), 4.40–4.37 (m, 1H), 4.07–4.00 (m,
1H), 3.72–3.68 (m, 1H), 3.39 (s, 3H); 13C NMR (CDCl3, 50 MHz) d
163.7 (C@O), 151.1 (@qC), 138.4 (ArqC), 138.1 (ArqC), 135.2
(ArqC), 134.1 (ArqC), 131.3 (ArC), 129.0 (ArC), 128.9 (ArC), 128.6
(ArC), 128.55 (ArC), 128.3 (ArC), 128.0 (ArC), 123.9 (CH), 99.5
(CH), 97.0 (@CH2), 79.8 (CH), 78.9 (CH), 75.6 (CH2), 74.1 (CH2),
72.6 (CH), 56.2 (CH3); IR (Neat, cmꢀ1) 3027, 1642, 1217, 767;
+
+
HRMS (ESI+) Calcd for C28H28NO8 (M+H)
506.1815, found
506.1805.
4. Experimental
4.1. General
To a suspension of (3S,4S,5R,6S)-4,5-bis(benzyloxy)-6-methoxy-
2-methylenetetrahydro-2H-pyran-3-yl 4-nitrobenzoate (398 mg,
1 mmol) in 10 mL acetone/water (2:1, v/v) was added mercury(II)
trifluoroacetate (43 mg, 0.1 mmol). The reaction mixture was then
stirred for 12 h. The reaction mixture was then concentrated under
The 1H and 13C spectra of all of the compounds synthesized
were recorded at 300 and 75 MHz respectively unless otherwise

V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 449–456
453
Et
Et
Et
Et
1,3-diaxial interaction
Al
Al
O
O
Et
Al
Et
Al
H
RO
BnO
RO
BnO
I
for 4b
I
Et
Et
X
O
O
BnO
I
BnO
O
Bn
OBn
OBn
4c
1a R=Ac
4a R=Bn
1b R=Ac
4b R=Bn
H
R
for 1b
AlEt2
1,3-diaxial interaction
O
Et
O
Al
Et
Al
H
CH3
O
O
Et
H
BnO
BnO
BnO
I
BnO
I
X
CH3
O
O
O
O
O
Et
BnO
I
OBn
H
B (Disfavoured)
A (Favoured)
1c
Et
Al
Et
O
OH
H
O
O
BnO
BnO
AcO
BnO
I
R
O
O
H
Al
R
OBn
H
Et
Al
C
2
(favoured)
Et
Diastereofacial
choice
O
Et
H
BnO
BnO
CH3
O
O
I
Al
O
OH
O
H
A (Favoured)
Et
X
BnO
BnO
I
AcO
BnO
R
O
O
H
O
H
Al
OBn
2′
R
D
(disfavoured)
Scheme 4. Model proposed to explain the origin of the diastereoselectivity.
reduced pressure to give a residue, which was dissolved in ethyl
acetate (15 mL) and washed with water (5 mL) and brine (5 mL).
The organic layer was dried over Na2SO4 and evaporated under re-
duced pressure to give a clear oil (390 mg), which was used with-
out further purification.
To this oil (390 mg), dissolved in DCM (15 mL), were added tri-
ethylamine (1.2 mL) and methanesulfonyl chloride (0.31 mL,
2.2 mmol) at 0 °C. The reaction mixture was then brought to room
temperature and stirring was continued for additional 2 h. A satu-
rated aqueous solution of NH4Cl (15 mL) was then added and the
resulting solution was extracted with dichloromethane
(4 ꢁ 20 mL). The combined organic phase was dried over Na2SO4
and the solvent was removed under reduced pressure to give a res-
idue, which upon purification by column chromatography fur-
nished 10 (264 mg, 75% over two steps). White semisolid, eluent
for column chromatography: EtOAc/hexane (1:7, v/v);
½
a 2D8
ꢂ
¼ ꢀ18:7 (c 0.29, CHCl3);1H NMR (300 MHz, CDCl3) d 8.21 (d,
J = 8.9 Hz, 2H), 8.08 (d, J = 8.9 Hz, 2H), 7.31 (br m, 5H), 7.11 (br
m, 5H), 6.90–6.86 (m, 1H), 6.09–6.05 (m, 1H), 5.58 (d, J = 11.3 Hz,
1H), 4.84–4.68 (m, 4H), 4.50–4.47 (m, 1H), 4.16–4.09 (m, 1H);
13C NMR (CDCl3, 50 MHz) d 191.6 (C@O), 164.1 (C@O), 151.1
(ArqC), 149.2 (@CH), 137.8, 137.5, 135.1, 131.4, 129.1, 128.8,
128.7, 128.4,128.3, 127.9, 127.5, 123.9 (14 ArC and @CH2), 82.6
(CH), 79.7 (CH), 78.2 (CH), 75.7 (CH2), 74.1 (CH2); IR (Neat, cmꢀ1
)
3154, 1638, 1216, 765; HRMS (ESI+) Calcd for C27H24NO7 (M+H)
+
+
474.1553, found 474.1546.

454
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 449–456
4.1.2. General procedure for the MBH reaction of the sugar
derived enone and aromatic aldehydes
4.1.6. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((R)-(2-fluorophenyl)
(hydroxy)methyl)-2-oxocyclohex-3-enyl acetate 2d
To a solution of the enone (0.5 mmol) and the aromatic alde-
hyde (1.0 mmol) in dry DCM under an argon atmosphere was
added Et2AlI (0.75 mmol 0.8 M solution in toluene) at ꢀ78 °C
over 1 h. After 1 h, the reaction was warmed to -50 °C and al-
lowed to stir for 7 h at the same temperature. An aqueous satu-
rated solution of NaHCO3 was then added to the reaction
mixture and the resulting mixture was extracted with DCM
(3 ꢁ 10 mL). The combined organic layer was dried over Na2SO4
and concentrated under reduced pressure to give a yellowish res-
idue, which was purified by column chromatography to give the
MBH adduct.
Yield 67%, yellowish oil, eluent for column chromatography:
EtOAc/hexane (9:41, v/v); ½a D28
¼ þ60:1 (c 2.03, CHCl3), Rf 0.21
ꢂ
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3) d 7.40 (dt, J = 1.5,
7.4 Hz, 1H), 7.31–7.26 (m, 11H), 7.15 (t, J = 7.5 Hz, 1H), 7.02 (t,
J = 9.4 Hz, 1H), 6.75 (s, 1H), 5.83 (d, J = 3.9 Hz, 1H), 5.41 (d,
J = 11.3 Hz, 1H), 4.86–4.70 (m, 4H), 4.46 (d, J = 8.3 Hz, 1H), 4.03
(dd, J = 8.4, 11.2 Hz, 1H), 3.12 (d, J = 5.3 Hz, 1H), 2.10 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 192.5 (C@O), 170.2 (C@O), 161.8 (ArqC),
158.5 (ArqC), 145.3 (@CH), 138.9 (qC), 138.2 (ArqC), 137.6 (ArqC),
130.1, 130.0, 129.0, 128.8, 128.5, 128.4, 128.3, 128.1, 128.0, 124.8,
124.7, 116.0, 115.7 (ArC), 82.8 (CH), 78.9 (CH), 77.3 (CH), 75.6
(CH2), 73.9 (CH2), 65.8 (CH), 20.9 (CH3); IR (neat, cmꢀ1) 3435,
3023, 2921, 1751, 1686 1634, 1451, 1373, 1218, 1095; Mass (ESI-
MS) m/z 490, found 513 [M+Na]+; DART-HRMS: calcd for
C29H28FO6 [M+H]+ 491.1870, measured 491.1876.
4.1.3. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((S)-hydroxy(4-nitrophen-
yl)methyl)-2-oxocyclohex-3-enyl acetate 2a
Yield 85%, yellowish oil, eluent for column chromatography:
EtOAc/hexane (9:41, v/v); ½a D28
ꢂ
¼ þ207:9 (c 3.0, CHCl3), Rf 0.2
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3)
d
8.14 (d,
4.1.7. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((R)-(2,4-difluorophenyl)
(hydroxy)methyl)-2-oxocyclohex-3-enyl acetate 2e
J = 8.6 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.27–7.25 (m, 10 H),
6.69 (s, 1H), 5.58 (s, 1H), 5.32 (d, J = 11.3 Hz, 1H), 4.81–4.68
(m, 4H), 4.41 (d, J = 8.1 Hz, 1H), 3.90 (dd, J = 8.5, 11.2 Hz, 1H),
2.06 (s, 3H); 13C NMR (75 MHz, CDCl3) d 192.2 (C@O), 170.4
(C@O), 148.7(ArqC), 147.8 (ArqC), 145.6 (@CH), 139.7 (qC),
138.0 (ArqC), 137.5 (ArqC), 129.0 (ArC), 128.8 (ArC), 128.6
(ArC), 128.3 (ArC), 128.2 (ArC), 127.8 (ArC), 124.0 (ArC), 82.6
(CH), 78.9 (CH), 77.3 (CH), 75.7 (CH2), 74.2 (CH2), 69.8 (CH),
20.9 (CH3); IR (neat, cmꢀ1) 3428, 3020, 1749, 1689, 1631, 1524,
1425, 1349, 1216, 1044; Mass (ESI-MS) m/z 517, found 516
[MꢀH]+; DART-HRMS: calcd for C29H28NO8 [M+H]+ 518.1815,
measured 518.1787.
Yield 62%, yellowish oil, eluent for column chromatography:
EtOAc/hexane (9:41, v/v); ½a D28
¼ þ53:9 (c 1.21, CHCl3), Rf 0.2
ꢂ
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3) d 7.32–7.26 (m,
11H), 6.88 (t, J = 8.5 Hz, 1H), 6.81–6.74 (m, 1H), 6.70 (s, 1H), 5.77
(s, 1H), 5.40 (d, J = 11.3 Hz, 1H), 4.87–4.71 (m, 4H), 4.46 (d,
J = 8.2 Hz, 1H), 4.02 (dd, J = 8.4, 11.2 Hz, 1H), 3.08 (d, J = 4.5 Hz,
1H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCl3) d 192.6 (C@O), 170.2
(C@O), 145.4 (@CH), 138.7 (qC), 138.2 (ArqC), 137.6 (ArqC),
129.6, 129.5, 129.4, 129.0, 128.8, 128.6, 128.4, 128.3, 128.2 (ArC),
124.2 (ArqC), 112.11, 112.06, 111.83, 111.78, 104.7, 104.3, 104.0
(ArC), 82.8 (CH), 79.0 (CH), 77.3 (CH), 75.7 (CH2), 74.1 (CH2),
65.46, 65.42 (CH), 20.9 (CH3); IR (neat, cmꢀ1) 3423, 3022, 2923,
1746, 1694, 1616, 1508, 1217, 1094; Mass (ESI-MS) m/z 508, found
526 [M+NH4]+; DART-HRMS: calcd for C29H27F2O6 [M+H]+
509.1776, measured 509.1789.
4.1.4. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((S)-(4-cyanophenyl) (hyd-
roxy)methyl)-2-oxocyclohex-3-enyl acetate 2b
Yield 71%, yellowish oil, eluent for column chromatography:
EtOAc/hexane (9:41, v/v); ½a D28
ꢂ
¼ þ57:8 (c 0.48, CHCl3), Rf 0.2
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3)
d
7.60 (d,
4.1.8. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((S)-(4-chlorophenyl) (hyd-
roxy)methyl)-2-oxocyclohex-3-enyl acetate 2f
J = 7.9 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.29–7.26 (m,10H), 6.67 (s,
1H), 5.54 (s, 1H), 5.32 (d, J = 11.3 Hz, 1H), 4.82–4.68 (m, 4H), 4.40
(d, J = 7.0 Hz, 1H), 3.95–3.88 (m, 1H), 2.93 (br s, 1H), 2.07 (s, 3H);
13C NMR (50 MHz, CDCl3 + CCl4) d 191.9 (C@O), 169.8 (C@O),
146.7 (ArqC), 145.2 (@CH), 139.9 (qC), 138.1(ArqC), 137.6(ArqC),
132.6, 129.0, 128.8, 128.6, 128.4, 128.2, 127.7 (ArC), 118.6 (CN),
112.4 (ArqC), 82.7 (CH), 78.9 (CH), 77.3 (CH), 75.7 (CH2), 74.2
(CH2), 70.0 (CH), 20.8 (CH3); IR (neat, cmꢀ1) 3452, 3021, 2359,
1750, 1692, 1608, 1522, 1423, 1378, 1217, 1049; Mass (ESI-MS)
m/z 497, found 496 [MꢀH]+; DART-HRMS: calcd for C30H28NO6
[M+H]+ 498.1917, measured 498.1910.
Yield 70%, yellowish oil, eluent for column chromatography:
EtOAc/hexane (1:4, v/v); ½a D28
¼ þ189:8 (c 0.28, CHCl3), Rf 0.22
ꢂ
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3) d 7.32–7.25 (m,
14H), 6.78 (s, 1H), 5.51 (s, 1H), 5.40 (d, J = 11.3 Hz, 1H), 4.85–
4.72 (m, 4H), 4.48–4.44 (m, 1H), 3.97 (dd, J = 8.3, 11.3 Hz, 1H),
2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) d 192.4 (C@O), 170.3
(C@O), 144.9 (@CH), 140.0 (ArqC), 139.6 (qC), 138.1 (ArqC), 137.5
(ArqC), 134.2 (ArqC), 129.1, 129.0, 128.8, 128.6, 128.43, 128.40
128.3, 128.2 (ArC), 82.8 (CH), 79.0 (CH), 77.3 (CH), 75.7 (CH2),
74.2 (CH2), 70.5 (CH), 20.9 (CH3); IR (neat, cmꢀ1) 3522, 3031,
2922, 1750, 1691, 1222, 1101, 1054; DART-HRMS: calcd for
4.1.5. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((S)-hydroxy(2-nitrophen-
yl)methyl)-2-oxocyclohex-3-enyl acetate 2c
C
29H26ClO5 [MꢀOH]+ 489.1469 measured 489.1465.
Yield 80%, yellowish oil, eluent for column chromatography:
4.1.9. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((R)-(2,3-dichlorophenyl)
(hydroxy)methyl)-2-oxocyclohex-3-enyl acetate 2g
EtOAc/hexane (1:4, v/v); ½a D28
ꢂ
¼ þ365:0 (c 0.60, CHCl3), Rf 0.18
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3)
d
7.96 (d,
Yield 91%, yellowish oil, eluent for column chromatography:
J = 7.8 Hz, 1H), 7.65–7.63 (m, 2H), 7.49–7.45 (m, 1H), 7.30–7.26
(m, 10 H), 6.71 (s, 1H), 6.13 (s, 1H), 5.41 (d, J = 11.3 Hz, 1H),
4.87–4.69 (m, 4H), 4.48–4.45 (m, 1H), 4.04 (dd, J = 8.3, 11.2 Hz,
1H), 3.35 (br s, 1H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) d
191.9 (C@O), 170.2 (C@O), 148.4 (ArqC), 145.4 (@CH), 138.8 (qC),
138.2 (ArqC), 137.6 (ArqC), 136.0 (ArqC), 134.0, 129.2, 128.9,
128.8, 128.5, 128.33, 128.27, 128.1, 125.2 (ArC), 82.7 (CH), 78.9
(CH), 77.2 (CH), 75.7 (CH2), 73.9 (CH2), 66.3 (CH), 20.9 (CH3); IR
(neat, cmꢀ1) 3460, 3022, 2927, 1751, 1698, 1525, 1216, 1022;
DART-HRMS: calcd for C29H28NO8 [M+H]+ 518.1815, measured
518.1822.
EtOAc/hexane (9:41, v/v); ½a D28
¼ þ66:6 (c 2.66, CHCl3), Rf 0.22
ꢂ
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3) d 7.47–7.44 (m,
2H), 7.36–7.23 (m, 11H), 6.49 (s, 1H), 5.98 (br s, 1H), 5.44 (dd,
J = 2.3, 11.3 Hz, 1H), 4.90–4.65 (m, 4H), 4.46 (d, J = 8.3 Hz, 1H),
4.09–4.03 (m, 1H), 3.24 (d, J = 3.3 Hz, 1H), 2.14 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 192.5 (C@O), 170.3 (C@O), 146.1 (@CH), 140.6
(qC), 138.4 (ArqC), 138.2 (ArqC), 137.5 (ArqC), 133.6 (ArqC),
131.0 (ArqC), 130.2, 128.9, 128.8, 128.5, 128.34, 128.26, 128.1,
127.9, 126.6 (ArC), 82.7 (CH), 79.1 (CH), 77.4 (CH), 75.7 (CH2),
74.0 (CH2), 68.1 (CH), 20.9 (CH3); IR (neat, cmꢀ1) 3422, 3023,
1748, 1687, 1634, 1434, 1375, 1217, 1102; Mass (ESI-MS) m/z

V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 449–456
455
540, found 558 [M+NH4]+; DART-HRMS: calcd for C29H27Cl2O6
[M+H]+ 541.1185, measured 541.1169.
further purification. To this oil (53 mg) dissolved in acetone (2 mL)
were added 2,2-dimethoxypropane (16 mg, 0.15 mmol) and cam-
phorsulfonic acid (12 mg, 0.05 mmol). After 12 h stirring, the reac-
tion mixture was concentrated under reduced pressure to give a
colourless oil, which upon column chromatography purification
gave the pure compound 3 (38 mg, 70% from 2b) as a white semi-
solid. Yield 70%, eluent for column chromatography: EtOAc/hexane
4.1.10. ((1S,5S,6R)-5,6-Bis(benzyloxy)-3-((R)-(2,4-dichloro-
phenyl)(hydroxy)methyl)-2-oxocyclohex-3-enyl acetate 2h
Yield 76%, yellowish oil, eluent for column chromatography:
EtOAc/hexane (1:4, v/v); ½a D28
¼ þ155:4 (c 0.71, CHCl3), Rf 0.2
ꢂ
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3) d 7.34–7.25 (m,
13H), 6.42 (d, J = 0.6 Hz, 1H), 5.88 (d, J = 4.7 Hz, 1H), 5.41 (d,
J = 11.3 Hz, 1H), 4.88–4.64 (m, 4H), 4.43 (dt, J = 1.5, 8.3 Hz, 1H),
4.03 (dd, J = 8.3, 11.3 Hz, 1H), 3.16 (d, J = 5.0 Hz, 1H), 2.12 (s, 3H);
13C NMR (75 MHz, CDCl3) d 192.5 (C@O), 170.2 (C@O), 146.0
(@CH), 138.4 (qC), 138.2 (ArqC), 137.5 (ArqC), 136.8 (ArqC), 134.6
(ArqC), 133.5 (ArqC), 129.7, 129.5, 128.9, 128.8, 128.5, 128.4, 128.3,
128.1, 127.8 (ArC), 82.7 (CH), 79.1 (CH), 77.4 (CH), 75.7 (CH2), 74.1
(CH2), 67.4 (CH), 20.9 (CH3); IR (neat, cmꢀ1) 3429, 3022, 2927,
1749, 1695, 1521, 1216, 1096, 1027; DART-HRMS: calcd for
(3:47, v/v); ½a 2D8
¼ þ109:3 (c 0.38, CHCl3), Rf 0.6 (1:4 EtOAc/hex-
ꢂ
ane); 1H NMR (400 MHz, CDCl3) d 7.64 (d, J = 8.3 Hz, 2H), 7.41 (d,
J = 8.2 Hz, 2H), 7.32–7.14 (m, 10H), 5.39 (s, 1H), 5.25 (dd, J = 8.0,
10.9 Hz, 1H), 4.82 (d, J = 11.6 Hz, 1H), 4.70 (d, J = 11.6 Hz, 1H),
4.63 (d, J = 8.0 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 1.6 Hz,
1H), 4.42 (d, J = 11.6 Hz, 1H), 4.16–4.13 (m, 1H), 3.65 (dd, J = 7.9,
10.9 Hz, 1H), 2.02 (s, 3H), 1.59 (s, 3H, CH3), 1.45 (s, 3H, CH3); 13C
NMR (100 MHz, CDCl3) d 170.4 (C@O), 143.5 (qC), 138.6 (ArqC),
138.1 (ArqC), 134.5 (ArqC), 132.5, 129.1 (ArC), 128.8, 128.7,
128.3, 128.2, 128.0 (ArC), 124.0 (@CH), 119.0 (C„N), 112.5 (ArqC),
99.9 (qC), 80.6 (CH), 80.2 (CH), 75.3 (CH2), 73.8 (CH), 73.6 (CH2),
73.4 (CH), 71.2 (CH), 29.8 (CH3), 21.4 (CH3), 19.8 (CH3); IR (KBr,
cmꢀ1) 2924, 2361, 1747, 1650, 1235, 1067, 1022; (ESI-MS) m/z
539, found 557 [M+NH4]+; DART-HRMS: calcd for C33H35NO6
[M+2H]+ 541.2462, measured 541.2478.
C
29H27Cl2O6 [M+H]+ 541.1185, measured 541.1174.
4.1.11. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((S)-(2,4-dinitrophenyl)
(hyd-roxy)methyl)-2-oxocyclohex-3-enyl acetate 2i
Yield 82%, yellowish semisolid, eluent for column chromatogra-
phy: EtOAc/hexane (1:4, v/v); ½a D28
¼ þ291:5 (c 0.76, CHCl3), Rf 0.19
ꢂ
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3) d 8.77 (d, J = 2.3 Hz,
1H), 8.43 (dd, J = 2.3, 8.6 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.33–7.26
(m, 10H), 6.62 (s, 1H), 6.22 (br s, 1H), 5.38 (d, J = 11.3 Hz, 1H), 4.87–
4.67 (m, 4H), 4.46 (d, J = 8.3 Hz, 1H), 4.03 (dd, J = 8.3, 11.2 Hz, 1H),
3.36 (d, J = 4.7 Hz, 1H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) d
191.8 (C@O), 170.4 (C@O), 148.0 (ArqC), 147.6 (ArqC), 145.8
(@CH), 142.9 (qC), 138.3 (ArqC), 138.0 (ArqC), 137.6 (ArqC),
131.1, 128.9, 128.8, 128.5, 128.32, 128.28, 128.15, 127.8, 120.6
(ArC), 82.6 (CH), 79.1 (CH), 77.2 (CH), 75.8 (CH2), 74.2 (CH2), 65.8
(CH), 20.9 (CH3); IR (neat, cmꢀ1) 3428, 3089, 2925, 2858, 1751,
1696, 1607, 1536, 1231, 1094; Mass (ESI-MS) m/z 562, found 580
[M+NH4]+, 545 [M-OH]+; DART-HRMS: calcd for C29H27N2O10
[M+H]+ 563.1666 measured 563.1687.
4.1.14. (4S,5R,6S)-4,5,6-Tris(benzyloxy)-2-(hydroxy(4-nitrophen-
yl)methyl)cyclohex-2-enone 5
Yield 18%, yellowish oil, eluent for column chromatography:
EtOAc/hexane (9:41, v/v); ½a D28
ꢂ
¼ þ13:9 (c 0.067, CHCl3), Rf 0.37
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3)
d
8.18 (d,
J = 8.7 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.39–7.29 (m, 15H), 6.62
(s, 1H), 5.65 (br s, 1H), 5.06–4.91 (m, 2H), 4.82–4.67 (m, 4H),
4.36 (d, J = 8.1 Hz, 1H), 4.03 (d, J = 10.7 Hz, 1H), 3.91 (dd, J = 8.1,
10.5 Hz, 1H), 3.03 (br s, 0.8H); 13C NMR (75 MHz, CDCl3) d 197.8
(C@O), 148.5 (ArqC), 147.9 (ArqC), 145.6 (@CH), 139.5 (qC), 138.3
(ArqC), 137.8 (ArqC), 137.7 (ArqC), 128.9, 128.8, 128.58, 128.54,
128.48, 128.35, 128.25, 127.8, 124.1 (ArC), 84.7 (CH), 84.3 (CH),
78.8 (CH), 76.1 (CH2), 75.3 (CH2), 74.4 (CH2), 70.9 (CH); IR (neat,
cmꢀ1) 3425, 3023, 2926, 2858, 1689, 1520, 1347, 1218, 1082; Mass
(ESI-MS) m/z 565, found 583 [M+NH4]+; DART-HRMS: calcd for
4.1.12. (1S,5S,6R)-5,6-Bis(benzyloxy)-3-((R)-(2,3-dichlorophenyl)-
(hydroxy)methyl)-2-oxocyclohex-3-enyl 4-nitrobenzoate 2j
Yield 49%, yellowish semisolid, eluent for column chromatogra-
C
34H31NNaO7 [M+Na]+ 588.1998, measured 588.1992.
phy: EtOAc/hexane (1:4, v/v); ½a D28
ꢂ
¼ ꢀ10:6 (c 0.3, CHCl3); 1H NMR
4.1.15. 4-(Hydroxy((3S,4R,5S)-3,4,5-tris(benzyloxy)-6-oxocyclo-
hex-1-enyl)methyl)benzonitrile 6
(300 MHz, CDCl3) d 8.27 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.8 Hz, 2H),
7.46- 7.19 (m, 13H), 6.51 (s, 1H), 5.98 (br s, 1H), 5.67 (d,
J = 11.3 Hz, 1H), 4.91–4.68 (m, 4H), 4.53 (d, J = 8.1 Hz, 1H), 4.23–
4.13 (m, 1H), 3.19 (br s, 1H, OH); 13C NMR (50 MHz, CDCl3) d
191.4 (C@O), 163.7 (C@O), 150.8 (ArqC), 146.0 (@CH), 139.9 (ArqC),
137.9 (ArqC), 137.4 (ArqC), 137.0 (ArqC), 134.5 (ArqC), 133.3
(ArqC), 131.0 (2 ArC), 130.7 (ArqC), 130.0, 128.6, 128.4, 128.3,
128.0, 127.9, 127.6, 126.2, 123.5 (ArC), 81.9 (CH), 79.0 (CH), 77.9
(CH), 75.3 (CH2), 73.7 (CH2), 68.0 (CH); IR (Neat, cmꢀ1) 3019,
Yield 15%, colourless oil, eluent for column chromatography:
EtOAc/hexane (9:41, v/v); ½a D28
ꢂ
¼ þ100:5 (c 0.32, CHCl3), Rf 0.35
(1:4 EtOAc/hexane); 1H NMR (300 MHz, CDCl3)
d
7.61 (d,
J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.40–7.27 (m, 15H), 6.64
(s, 1H), 5.59 (s, 1H), 5.01 (d, J = 11.2 Hz, 1H), 4.92 (d, J = 11.0 Hz,
1H), 4.82–4.67 (m, 4H), 4.35 (d, J = 8.1 Hz, 1H), 4.03 (d,
J = 10.7 Hz, 1H), 3.90 (dd, J = 8.1, 10.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 197.8 (C@O), 146.6 (ArqC), 145.5 (@CH), 139.6 (qC),
138.3 (ArqC), 137.8 (ArqC), 137.7 (ArqC), 132.7, 129.0, 128.82,
128.80, 128.58, 128.55, 128.47, 128.35, 128.25, 127.6 (ArC), 119.0
(CN), 112.1 (ArqC), 84.7 (CH), 84.3 (CH), 78.7 (CH), 76.1 (CH2),
75.3 (CH2), 74.3 (CH2), 70.9 (CH); IR (neat, cmꢀ1) 3452, 3028,
2924, 2858, 2229, 1689, 1608, 1354, 1211, 1152, 1090; Mass
(ESI-MS) m/z 545, found 546 [M+H]+; DART-HRMS: calcd for
1639, 1217, 767; HRMS (ESI+) Calcd for C34H28Cl2NO8 (M+H)
+
+
648.1192, found 648.1185.
4.1.13. (4S,6S,7R,8R,8aS)-6,7-Bis(benzyloxy)-4-(4-cyanophenyl)-
2,2-dimethyl-6,7,8,8a-tetrahydro-4H-benzo[d][1,3]dioxin-8-yl
acetate 3
To a solution of compound 2b (50 mg, 0.10 mmol) in ethanol
(2 mL) at 0 °C was added CeCl3ꢃ7H2O (38 mg, 0.10 mmol). After
30 minutes, NaBH4 (2 mg, 0.05 mmol) was added at the same tem-
perature and the reaction was stirred at 0 °C. After 2 h, acetone
(2 mL) was added and the resulting mixture was concentrated un-
der reduced pressure to give a residue, which was dissolved in
ethyl acetate and washed with water (2 ꢁ 4 mL) and brine
(4 mL). The organic layer was dried and concentrated under re-
duced pressure to give a clear oil (53 mg), which was used without
C
35H32NO5 [M+H]+ 546.2281, measured 546.2294.
Acknowledgments
The authors would like to thank the Sophisticated Analytical
Instrument Facility, CDRI for providing spectroscopic data and
Mr. A. K. Pandey for technical assistance. V.K., P.D. and P.G. thank
the CSIR New Delhi for financial support. CDRI communication
number is 8228.

456
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 449–456
Koert, U. Org. Lett. 2007, 9, 4777–4779; (f) Lee, S. I. I.; Hwang, G.-S.; Shin, S. C.;
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in our above referred to article. In this proposed transition state 1,3-diaxial
type interaction between R1 and the iodide atom at the C-2 position makes it
disfavoured. Therefore, TSII should be the favoured transition state since it is
devoid of such a type of interaction between R1 and iodide at C-2 to give the
desired MBH adduct with an (R)-configuration at the newly generated
stereocenter.
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O
TiCl3
O TiCl3
′R
′
I
R
O
O
H
Cl
Cl
Cl
Cl
Cl
Cl
O
O
R1
H
Ti
Cl
Ti
Cl
O
O
I
O
O
OiPr
OiPr
R1
H
H
4. Kumar, V.; Das, P.; Ghosal, P.; Shaw, A. K. Tetrahedron 2011, 67, 4539–4546.
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1972, 77, 34174q.
TS I
TS II
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19. In order to check the diasteroselectivity of the reaction, we recorded the 1H
NMR spectrum of the crude reaction mixture. The spectrum was highly
ambiguous for interpretation. However, the crude reaction mixture upon
column chromatography furnished the desired product as
a single
diastereoisomer only along with an inseparable mixture. The 1H NMR of the
inseparable mixture showed the presence of the starting materials and some
unidentified side products.
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20. The formation of orthoester intermediates for compounds containing an acyl
group and hydroxyl/amino groups on adjacent carbons is well known in
carbohydrate chemistry. For example see: Kunz, H.; Müller, B.; Weissmüller, J.
Carbohydr. Res. 1987, 171, 25–34.