l-Threonine-catalysed asymmetric α-hydroxymethylation of cyclohexanone: application to the synthesis of pharmaceutical compounds and natural products

Article abstract of DOI:10.1016/j.tet.2009.11.100

l-Threonine has been found to be an efficient catalyst for the asymmetric α-hydroxymethylation of cyclohexanone with formalin. Reducing the amount of water in the reaction by the addition of magnesium sulfate as a dehydrating additive significantly improves the yield. Applications of (S)-2-hydroxymethyl cyclohexanone and the chiral building blocks derived therefrom for the synthesis of pharmaceutical compounds and natural products have been explored.

Full text of DOI:10.1016/j.tet.2009.11.100

Tetrahedron 66 (2010) 1489–1495
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
L
-Threonine-catalysed asymmetric
a-hydroxymethylation of cyclohexanone:
application to the synthesis of pharmaceutical compounds and natural products
*
*
Anqi Chen , Jin Xu, Winnie Chiang, Christina L.L. Chai
Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 1 Pesek Road, Jurong Island 627833, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
L-Threonine has been found to be an efficient catalyst for the asymmetric a-hydroxymethylation of
Received 10 September 2009
Received in revised form 11 November 2009
Accepted 20 November 2009
Available online 2 December 2009
cyclohexanone with formalin. Reducing the amount of water in the reaction by the addition of
magnesium sulfate as a dehydrating additive significantly improves the yield. Applications of (S)-
2-hydroxymethyl cyclohexanone and the chiral building blocks derived therefrom for the synthesis of
pharmaceutical compounds and natural products have been explored.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Hydroxymethylation
Formaldehyde
Threonine
Aldol reaction
Rociverine
1. Introduction
As such, several methods have been developed for the synthesis
of (S)-1 and its derivatives. Lipase-mediated resolution of (ꢀ)-1
Optically active
a
-hydroxymethyl cyclohexanone and chiral
using vinyl acetate provided (S)-1 in 42% yield and 87% ee.3 Lewis
acid-catalysed aldol reaction of cyclohexyl silyl enol ether with
formalin in the presence of (R)-BINAP afforded (S)-1 in 31% yield
and 57% ee.4 More recently, organocatalytic direct aldol reactions
have been developed for the synthesis of (S)-1. For example, the
building blocks derived therefrom are high value and versatile
chiral intermediates for synthetic applications. For example,
(S)-2-hydroxymethyl cyclohexanone (S)-1 (Fig. 1) is a key building
block for a potent spasmolitic agent (R,R)-rociverine 2.1 Chiral 6-
hydroxyl heptanoates 3a–b obtainable from (S)-1 are present in
many pharmaceutical compounds and natural products.2
reaction of cyclohexanone with formalin in the presence of
line (4a)5a or its derivatives 4b–c5b–c provided (S)-1 in 37–47% yield
and 96–99% ee. -Threonine 5, which contains a primary amine
L-pro-
L
group, has also been reported to catalyse this aldol reaction, pro-
O
viding (S)-1 in 63% yield and 93% ee.6
Me
CO2CH3
Cy
O
HO
R
HO
NEt2
Our interest in optically active a-hydroxymethyl cyclohexanone
O
OH
arose from the recognition that these are high value intermediates
for the pharmaceutical industry and in natural product syntheses
due to the scope of downstream transformations. We report herein
3a
(S)- (R = OH)
(S)-1
2 (Cy=cyclohexyl)
3b
(R)- (R = H)
R
our independent work on the identification of
L-threonine as an
OH
efficient organocatalyst for the asymmetric -hydroxymethylation
a
N
N
N
CO2H
N
H
CO2H
N
H
of cyclohexanones with formalin as well as the use of (S)-1 and the
chiral building blocks obtained therefrom for the synthesis of
pharmaceutical compounds and natural products.
N
H
NH2
5
4a: R = H
4b
4c
: R = OTBDPS
Figure 1. Structure of compound 1–5.
2. Results and discussion
2.1. L-Threonine-catalysed asymmetric a-hydroxymethylation
of cyclohexanone
* Corresponding authors. Fax: þ65 63166184.
E-mail addresses: chen_anqi@ices.a-star.edu.sg (A. Chen), christina_chai@ices.a-
star.edu.sg (C.L.L. Chai).
Our studies on the organocatalytic
a-hydroxymethylation of
cyclohexanone commenced with a reported procedure5a wherein
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.100

1490
A. Chen et al. / Tetrahedron 66 (2010) 1489–1495
cyclohexanone was treated with formalin using proline 4a as the
catalyst and the desired product (S)-1 was obtained in 47% yield
and 99% ee. In our hands, the desired product could only be
obtained in low yields (<20%) in ca. 94% ee in spite of numerous
attempts to reproduce as well as to optimise the conditions. These
disappointing results prompted us to search for a more effective
catalyst for the reaction.
First, the relationship between catalyst loading and the product
yields was examined (Table 3). It was found that 10 mol % loading
(entry 2) was optimal as further increase in the amount of catalyst
resulted in slightly decreased yields due to catalyst precipitation.
Considering the fact that formaldehyde is strongly hydrated,7
which results in a low concentration of the reactive form, we
envisioned that removal of water by the addition of a dehydrating
agent as an additive would shift the equilibrium to the free form-
aldehyde and thus facilitate the reaction.
The catalyst for this purpose should ideally be readily available
and inexpensive while providing the hydroxymethyl compounds in
both good yield and optical purity. Thus a number of L-amino acids
Table 3
were screened for the reaction of cyclohexanone with formalin
(Table 1). Most of these showed either no catalytic activity (entries
6–8) or afforded products in very poor yields (entries 1–4) after
24 h at room temperature. Amino acids with either an acidic or
basic residue (entries 7–8) were found to be ineffective.
Surprisingly, L-threonine, which has not often been reported as
a catalyst for the aldol reaction, gave the best yield of the desired
product in 33% yield and 90% ee (entry 5).
Optimisation of conditionsa
Entry
Catalyst (mol %)
Additive (equiv)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
5
10
15
20
10
10
10
10
10
10
10
10
d
24
24
24
24
24
24
24
24
48
72
96
120
15
37
36
33
43
54
46
39
62
74
82
85
d
d
d
MgSO4 (0.5)
MgSO4 (1)
MgSO4 (1.5)
MgSO4 (2)
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
MgSO4 (1)
Table 1
Screening of catalystsa
9
10
11
12
O
O
catalyst (10 mol%)
rt, 24 h
HO
+ CH2O (37% aq.)
a
The reactions were performed with CH2O (37% aq solution, 1.0 mmol) and
cyclohexanone (2.0 mmol) in THF (1 mL) with L-threonine (5–20 mol %) and MgSO4
(S)-1
(0.5–2.0 equiv) at rt for 24–120 h.
b
Determined by 1H NMR spectroscopic analysis of the crude product.
Entry
Catalyst
Yieldb (%)
eed (%)
1
2
3
4
5
6
7
8
L
L
L
L
L
L
L
L
-Tryptophan
-trans-4-Hydroxy-proline
-Serine
-Proline
-Threonine
-Leucine
<8
n.d.e
n.d.e
n.d.e
94
90
d
Screening several dehydrating additives, including Na2SO4,
MgSO4, 4 Å molecular sieves and CaCl2, it was found that the ad-
dition of 1 equiv of MgSO4 (Table 3, entry 6) afforded the best yield
of 54% in 24 h. However, further increase in the amount of MgSO4
(entries 7–8) resulted in a decreased yield. This adverse effect could
be attributed to the over removal of water as some water is needed
in order to release the catalyst bound to the aldol adduct.8,9
Therefore, a fine balance of the amount of water seems paramount
to the success of the reaction. The dual roles of water in the ac-
celeration and deceleration of an organocatalytic aldol reaction
<7
12
18
33
dc
d
-Lysine
-Glutamic acid
d
d
d
a
The reactions were performed with CH2O (37% aq solution, 1.0 mmol) and
cyclohexanone (2.0 mmol) in DMSO (1 mL) with the catalyst (10 mol %) at rt for 24 h.
b
Determined by 1H NMR spectroscopic analysis of the crude product.
c
Not detectable by 1H NMR spectroscopic analysis.
Determined by chiral GC analysis after trifluoroacetylation.
Not determined.
have been studied for L
-proline catalysed aldol reaction.8 In addi-
d
e
tion, the presence of water has also been found to be essential for
primary amino acid-catalysed aldol reactions.9a With MgSO4 being
identified as a beneficial additive, the reaction time was extended
to maximise the conversion. It was found that the yield increased to
82% in 96 h but the increase in yields is less significant thereafter.
The optimised conditions were applied to a few substituted
cyclohexanones (Table 4), providing the hydroxymethyl products in
55–74% yield and in 60–98% ee (entries 1–4). For (R)-3-methyl
cyclohexanone (entry 3), the regioisomeric products 6b and 6b0 are
each formed as a pair of diastereomers with the major isomers
shown, and the isomeric excess is expressed as diastereomeric
excess (de).
With this encouraging result, the reaction was further optimised.
From screening for the best solvents for the reaction (Table 2),
DMSO and THF were found to give comparable yields (entries 1–2)
and ee whereas reactions carried out in other solvents or in the
absence of a solvent (neat) afforded lower yields and/or lower
enantioselectivity of the desired hydroxymethylated product. For
convenience and ease of work-up, THF was chosen as the solvent of
choice in subsequent optimisation studies.
Table 2
Screening of solventsa
The S-configuration of the hydroxymethyl products, predicted
on the basis of a generally accepted model of stereochemical in-
duction for primary amino acid-catalysed aldol reactions,6,9 was
verified by optical rotation measurement (for (S)-1).10 This was
further confirmed by single crystal X-ray analysis of compound 6b,
obtained from (R)-3-methyl cyclohexanone (entry 3), after deriva-
tisation to its (1S)-(ꢁ)-camphanate 7 using (1S)-(ꢁ)-camphanic
chloride. The crystal structure (Fig. 2) clearly revealed the trans
relationship of the 2-hydroxymethyl to the 5-methyl group and its
(2S,5R)-configuration.11 In addition, we have observed that the
stereochemical induction is predominantly governed by the con-
figuration of the amino acid motif and less influenced by the
Entry
Solvent
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
DMSO
THF
33
37
22
11
14
25
29
33
90
91
db
n.d.e
n.d.e
n.d.e
16
DMF
Toluene
DCM
CH3CN
Ethyl acetate
69
9
a
The reactions were performed with CH2O (37% aq solution, 1.0 mmol) and
cyclohexanone (2.0 mmol) in the solvents (1 mL) with
for 24 h.
L-threonine (10 mol %) at rt
b
Neat reaction.
hydroxyl group as L-allo-threonine (8) catalysed reaction of cyclo-
hexanone provided the product (S)-1 with the same configuration
despite in a lower ee of 75%.
c
Determined by 1H NMR spectroscopic analysis of the crude product.
Determined by chiral GC analysis after trifluoroacetylation.
Not determined.
d
e

A. Chen et al. / Tetrahedron 66 (2010) 1489–1495
1491
Table 4
-Threonine-catalysed asymmetric a
-hydroxymethylation of cyclohexanonesa
L
O
O
l-threonine (10 mol%)
rt, 120 h
+ CH2O (37% aq.)
HO
R
R
Entry
1
Ketone
Product
Yieldb (%)
ee/de (%)
O
O
74
90c
HO
(S)-1
O
O
O
HO
HO
+
72
6a (96)d
6a0 (42)d
2
3
(6a: 6a0)¼5:4
6a'
6a
O
O
O
O
6b (98)d, e
6b0 (67)d, e
HO
HO
55
(6b: 6b0¼7.5:1)
+
6b
6b'
O
HO
4
56
70d
O
O
O
O
6c
a
The reactions were carried out with a cyclohexanone (8.0 mmol), CH2O (37% aq solution, 4.0 mmol) and MgSO4 (4.0 mmol) in THF (4 ml) with
L-threonine (10 mol %) at rt
for five days.
b
Isolated yields after silica gel column chromatography.
Determined by chiral GC analysis after trifluoroacetylation.
Determined by direct chiral GC analysis.
c
d
e
Diastereomeric excess (de, see text).
Rociverine (2), the most potent muscarinic antagonist among the
four stereoisomers12 whose activity resides in the chirality of the
cyclohexane ring, has previously only been obtained by chemical
resolution.1 No enantioselective synthesis of 2 has been achieved to
date. We envisioned that a formal synthesis of 2 can be achieved
concisely via intermediate 9 from (S)-1. This would involve two key
steps, which include a stereo-controlled anti-addition of a cyclo-
hexyl Grignard reagent to the carbonyl group of (S)-1 and selective
oxidation of the primary alcohol within 10 to provide the carboxylic
acid 9 (Scheme 1).
It has been shown13 that it was necessary to protect the
hydroxyl group as methoxyisopropyl (MIP) ketal to facilitate
a chelation-controlled, anti-selectivity Grignard addition and to
Cy
HO
Me
Cy
O
HO
CO2H
NEt2
O
Figure 2. Structure of 7–8 and X-ray structure of 7 with displacement ellipsoids drawn
at the 30% probability level.
9
2
2.2. Synthetic application of (S)-(2-hydroxymethyl)
cyclohexanone
O
Cy
HO
OH
The optimised conditions were applied to the multigram syn-
thesis of (S)-1. At w10 ꢂC, the enantiomeric excess of the product
was further improved to 98% although the yield was lower (w42%)
by vacuum distillation (see Experimental Section). With quantities
of (S)-1 in hand, its synthetic application was explored. (R,R)-
OH
(S)-1
10
Scheme 1. Retrosynthesis of 2 from (S)-1.

1492
A. Chen et al. / Tetrahedron 66 (2010) 1489–1495
avoid enolisation of the b-hydroxyl ketone. In our hands, the MIP
O
O
Br
O
O
O
ketal 11 was found to be unstable to chromatographic purification
on silica gel. Consequently, a one-pot, three-step procedure was
developed for the synthesis of 10. Thus, protection of the hydroxyl
group with 2-methoxypropene in the presence of PPTS led to the
ketal intermediate 11, which was reacted with cyclo-
hexylmagnesium chloride at ꢁ10 ꢂC to introduce the cyclohexyl
group diastereoselectively. Acidic workup resulted in the depro-
tection of the MIP protecting group, providing the desired diol 10 in
76% yield. The selective oxidation of the primary alcohol within 10
to the carboxylic acid 9 was not as straightforward as it appeared.
As the tertiary alcohol is prone to elimination, conventional
strongly acidic oxidation conditions, such as H2Cr2O7/Hþ, KMnO4/
Hþ, were avoided. After screening a few milder oxidation methods
including CuCl/tBuOOH,14 O2ꢁPt/C,15 it was found that a one-pot,
two-step sequence, involving TEMPO/NaOCl to the intermediate
aldehyde followed by further oxidation using NaClO2/NaH2PO4 in
a biphasic solvent system (DCM:H2Ow7:1) in the presence of 2-
methyl-2-butene,16 provided the required acid 9 in 87% yield
(Scheme 2).
HO
a
b
d
HO
14
(S)-
(S)-1
(S)-13
c
d
O
O
CO2CH3
R
OH
(R)-15
(S)-3a (R = OH)
(R)-3b (R = H)
Scheme 3. Downstream transformation of (S)-1 to chiral building blocks. a. m-CPBA,
NaHCO3, DCM, rt, 3 h, 98%; b. CBr4, PPh3, DCM, 0 ꢂC to rt, 5 h, 58%; c. nBu3SnH, AIBN
(30 mol %), toluene, 100 ꢂC, 3 h, 77%; d. NaOMe, MeOH, rt, 2 h, 85% for (S)-3a, 84% for
(R)-3b.
3. Conclusion
In conclusion, we have independently identified L-threonine as
Cy
HO
O
an efficient catalyst for the stereoselective hydroxymethylation of
cyclohexanones. The addition of MgSO4 as a dehydrating additive
has been found to promote the hydroxymethylation reaction. The
hydroxymethyl compounds were obtained in 55–74% yield and
60–98% ee. The synthetic application of (S)-1 has been demon-
strated in a formal synthesis of pharmaceutical compound (R, R)-
rociverine and chiral building blocks with general synthetic
applications.
Cy
HO
CO2H
a
OH
b
OH
1
9
(S)-
c
10
Cy
Lit.1
O
O
O
HO
O
OMe
Ph
2
4. Experimental
4.1. General
11
12
Scheme 2. Formal synthesis of 2 from (S)-1. a. (i) 2-methoxypropene, PPTS (3 mol %),
Et2O, ꢁ10 ꢂC, 30 min; (ii) c-C6H11MgCl, Et2O, ꢁ10–0 ꢂC, 1 h; (iii) 0.2 M HCl, rt, 4 h, 76%;
n
b. (i) NaOCl, TEMPO (30 mol %), Bu4NBr, DCM/H2O (7:1), 0 ꢂC to rt, 3 h; (ii). NaClO2,
Melting points were measured on a Bu¨ chi B-540 capillary
melting point apparatus. 1H/13C NMR spectra were recorded at
400/100 MHz on a Bruker Advance 400 spectrometer in CDCl3
unless otherwise stated, using either TMS or the undeuterated
solvent residual signal as the reference. IR spectra were recorded
on a Bio-Rad FTS 3000MX FTIR spectrometer as liquid film or
evaporated film (EF). Optical rotations were measured using
a JASCO P-1030 polarometer. Mass spectra were run by the
electro spray ionization time-of-flight (ESI-TOF) mode on an
Agilent 6210 mass spectrometer. Chiral GC and HPLC analyses
were performed on an Agilent Technologies 6890N Network GC
system or Agilent 1100 HPLC system. Solvents for moisture sen-
sitive reactions were taken from a Glasscontour solvent purifi-
cation system under nitrogen. Commercially available reagents
were used as received unless otherwise indicated. Reactions
Flash column chromatography purification was carried out either
manually or by using a Biotage SP1Ô purification system by
gradient elution.
NaH2PO4, 2-methyl-2-butene, tBuOH, rt, 3 h, 87%; c. NaHCO3, nBu4NBr, PhCH2Br, DCM,
rt, 4 h, 88%.
The optical purity of the product was determined by con-
verting the acid 9 to its benzyl ester 12, which was analysed by
chiral HPLC and shown to be 98% ee. The retention of optical
purity from (S)-1 highlighted the Grignard reaction proceeded
in a highly diastereoselective manner and racemisation did not
occur under the mild oxidation conditions. As (ꢀ)-9 has pre-
viously been converted to (ꢀ)-2 by reacting with 2-chloro-1-
diethylaminopropane,12 this concise route constitutes a highly
efficient and stereoselective formal synthesis of (R,R)-Rociver-
ine (2).
Having achieved a formal synthesis of 2, the synthetic appli-
cation of (S)-1 was further demonstrated by its downstream
transformation to chiral building blocks with general synthetic
application (Scheme 3). Bayer–Villiger oxidation of (S)-1 afforded
6-hydroxymethyl-3-caprolactone (S)-13 in 89% yield. It is worth
noting that aqueous workup should be avoided to prevent loss of
the product due to its water solubility. The hydroxymethyl lac-
tone (S)-13 was converted to the bromide (S)-14, which was
further debrominated under free radical conditions (nBu3SnH/
4.2. General procedure for the optimisation of reaction
conditions
4.2.1. Procedure for the screening of catalysts for the
a-hydroxy-
AIBN) to provide (R)-6-methyl-
3
-caprolactone (R)-15,17 which has
methylation of cyclohexanone. To a vial containing a catalyst
been used for the synthesis of a chiral polymer.18 Finally, both
optically active caprolactones, (S)-13 and (R)-15, were ring-
opened with sodium methoxide in methanol, providing two
novel optically active 6-hydroxyl heptanoate (S)-3a and (R)-3b,
which are valuable chiral building blocks for the synthesis of
natural products, such as pyranicin,2a cladospolides2d and
daumone.2e
(0.1 mmol, 10 mol % to CH2O) was added formalin (37% aqueous
solution, 75
mL, 1.0 mmol). The mixture was stirred at rt for 10 min
before DMSO (1 mL) and cyclohexanone (210
mL, 2.0 mmol) were
added. The vial was sealed and the mixture was stirred at rt for
24 h. The reaction was quenched by the addition of saturated NH4Cl
aqueous solution (1.0 mL) and stirred for 5 min. The mixture was
extracted with ethyl acetate (3ꢃ10 mL). The combined extracts

A. Chen et al. / Tetrahedron 66 (2010) 1489–1495
1493
were washed with brine and dried (MgSO4). The solvent was
evaporated under reduced pressure and the yield of the reaction
was obtained by 1H NMR spectroscopic analysis of a weighed
sample dissolved in CDCl3 (0.50 mL containing 0.01 mmol DMF as
the internal reference). The enantiomeric excess of the product was
determined by chiral GC analysis on a Chiraldex G-TA column after
conversion to the trifluoroacetate. The results are given in Table 1.
180 ꢂC; detector temperature: 250 ꢂC; flow rate: 1.0 mL/min (ex-
cept for 1 at 0.8 mL/min).
4.3.1. (S)-2-(Hydroxymethyl)cyclohexanone ((S)-1). The compound
(S)-1 was obtained as a colourless liquid (380 mg, 74%) in 90% ee;
22
26
[a
]
þ11.4 (c 1.0, CHCl3) {lit.19
[
a
]
D
ꢁ8.5 (c 0.41, CHCl3) for (R)ꢁ1,
D
78% ee}; GC: after trifluoroacetylation, tmajor¼27.4 min, tminor
¼
27.8 min; IR (film) 3406 (OH), 2937, 2865, 1703 (C]O), 1025 cmꢁ1
1H NMR (400 MHz, CDCl3)
;
4.2.2. Procedure for the screening of solvents. To a vial containing
d
3.71 (dd, J¼11.3, 7.3 Hz, 1H), 3.57 (dd,
L
-threonine (12 mg, 0.1 mmol, 10 mol % to CH2O) was added for-
malin (37% aqueous solution, 75 L, 1.0 mmol). The mixture was
stirred at rt for 10 min before the solvent (1 mL) and cyclohexanone
(210 L, 2.0 mmol) were added. The vial was sealed and the mixture
J¼11.3, 3.7 Hz, 1H), 2.72 (br s, 1H), 2.53–2.45 (m,1H), 2.41–2.25 (m,
m
2H), 2.12–1.97 (m, 2H), 1.92–1.86 (m, 1H), 1.73–1.56 (m, 2H), 1.50–
1.39 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 214.9, 62.8, 52.3, 42.2,
m
30.1, 27.5, 24.8; HRMS (ESI-TOF) m/z calcd for C7H12O2Na [MþNa]þ
was stirred at rt for 24 h. The solvent was evaporated under
reduced pressure and the yield was obtained by 1H NMR spectro-
scopic analysis of a weighed sample dissolved in CDCl3 (0.50 mL
containing 0.01 mmol DMF as the internal reference). The enan-
tiomeric excess of the product was determined by chiral GC analysis
on a Chiraldex G-TA column after conversion to the trifluoroacetate.
The results are given in Table 2.
151.0730, found 151.0726.
4.3.2. (2S,4R)-2-(Hydroxymethyl)-4-methylcyclohexanone (6a) and
(2S,4S)-2-(hydroxymethyl)-4-methylcyclohexan-one (6a0). The two
isomeric products were obtained as a mixture in a ratio of 5:4 (by
1H NMR spectroscopic analysis) as a colourless liquid (410 mg, 72%).
Separation of the mixture by silica gel column chromatography
provided the trans-isomer 6a, which was analysed by chiral GC
22
4.2.3. Procedure for the optimisation of catalyst loading. To a vial
to be 96% ee; [
a]
ꢁ28.1 (c 1.0, CHCl3); GC: tmajor¼46.4 min, tminor¼
D
containing
added formalin (37% aqueous solution, 75
ture was stirred at rt for 10 min before THF (1 mL) and cyclohexa-
none (210 L, 2.0 mmol) were added. The vial was sealed and the
L-threonine (0.05–0.2 mmol, 5–20 mol % to CH2O) was
47.2 min; IR (film) 3410 (OH), 2955, 2928, 2872, 1701 (C]O),
m
L, 1.0 mmol). The mix-
1048 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
3.75 (ddd, J¼12.2, 7.7,
5.2 Hz, 1H), 3.60 (ddd, J¼12.2, 8.2, 4.2 Hz, 1H), 2.71–2.63 (m, 1H),
2.54 (dd, J¼8.2, 5.2 Hz, 1H), 2.51–2.44 (m, 1H), 2.32–2.24 (m, 1H),
2.16–2.11 (m, 1H), 1.95–1.87 (m, 1H), 1.80–1.71 (m, 3H), 1.18 (d,
m
mixture was stirred at rt for 24 h. The solvent was evaporated under
reduced pressure and the yield was obtained by 1H NMR spectro-
scopic analysis of a weighed sample dissolved in CDCl3 (0.50 mL
containing 0.01 mmol DMF as the internal reference). The results
are given in Table 3.
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 215.3, 63.1, 48.1, 37.8,
35.5, 32.9, 26.7, 18.4; HRMS (ESI-TOF) m/z calcd for C8H14O2Na
[MþNa]þ 165.0886, found 165.0882.
The cis-isomer 6a0 was partially separated from 6a and analysed
to be 42% ee; GC: tmajor¼39.8 min, tminor¼40.6 min; IR (film) 3410
4.2.4. Procedure for the study of the effect of MgSO4. To a vial con-
(OH), 2955, 2928, 2872, 1701 (C]O), 1048 cmꢁ1 1H NMR
;
taining
formalin (37% aqueous solution, 75
stirred at rt for 10 min before THF (1 mL), cyclohexanone (210
L
-threonine (12 mg, 0.1 mmol, 10 mol % to CH2O) was added
L, 1.0 mmol). The mixture was
L,
(400 MHz, CDCl3)
d
3.69 (ddd, J¼12.2, 7.3, 5.3 Hz, 1H), 3.57 (ddd,
m
J¼12.2, 8.5, 3.8 Hz, 1H), 2.65 (dd, J¼8.5, 5.3 Hz, 1H), 2.59–2.52 (m,
1H), 2.39–2.36 (m, 2H), 2.06–1.91 (m, 3H), 1.42–1.31 (m, 1H), 1.26–
1.17 (m, 1H), 1.00 (d, J¼8.3 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)
m
2.0 mmol) and MgSO4 (0–2.0 mmol) were added. The vial was
sealed and the mixture stirred at rt for 24 h. The mixture was fil-
tered through a cotton wool plug and the solid residue washed with
ethyl acetate (5 mL). The solvents were evaporated under reduced
pressure and the yield was obtained by 1H NMR spectroscopic
analysis of a weighed sample dissolved in CDCl3 (0.50 mL con-
taining 0.01 mmol DMF as the internal reference). The results are
given in Table 3.
d
215.1, 62.7, 51.2, 41.5, 38.1, 35.4, 31.5, 21.3; HRMS (ESI-TOF) m/z
calcd for C8H14O2Na [MþNa]þ 165.0886, found 165.0887.
4.3.3. (2S,5R)-2-(Hydroxymethyl)-5-methylcyclohexanone (6b) and
(2S,3R)-2-(hydroxymethyl)-3-methylcyclohexan-one (6b0). The two
isomeric products were obtained as a mixture in a ratio of 7.5:1 (by
1H NMR spectroscopic analysis) as a colourless liquid (313 mg, 55%).
Separation of the mixture by silica gel column chromatography
provided the major isomer 6b, which was analysed to be 98% ee
22
4.3. General procedure for the
cyclohexanones
a-hydroxymethylation of
by chiral GC; [
a
]
þ33.0 (c 1.0, CHCl3); GC: tmajor¼36.0 min, tminor¼
D
39.0 min; IR (film) 3410 (OH), 2954, 2928, 2872, 1703 (C]O) cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
3.71 (m, 1H), 3.59 (m, 1H), 2.68 (t,
To a vial containing
CH2O) was added formalin (37% aqueous solution, 300
L
-threonine (48 mg, 0.4 mmol, 10 mol % to
J¼6.5 Hz, 1H), 2.48–2.41 (m, 1H), 2.40–2.34 (m, 1H), 2.05–1.95 (m,
mL,
2H), 1.90–1.79 (m, 2H), 1.51–1.34 (m, 2H), 1.03 (d, J¼6.3 Hz, 3H); 13C
4.0 mmol). The mixture was stirred at rt for 10 min before THF
(4 mL), the cyclohexanone (8.0 mmol) and MgSO4 (480 mg,
4.0 mmol) were added. The vial was sealed and the mixture was
stirred at rt for five days. The mixture was filtered and the solid
residue washed with ethyl acetate (10 mL). Saturated aqueous
NH4Cl solution (5 mL) was added to the filtrates and the solution
was stirred for 10 min. The organic phase was separated and the
aqueous phase was extracted with ethyl acetate (2ꢃ15 mL). The
combined organic phases were washed with brine (10 mL) and
dried (MgSO4). The solvents were evaporated under reduced
pressure and the crude product was purified by silica gel column
chromatography by gradient elution with ethyl acetate in petro-
leum ether to provide the hydroxymethyl cyclohexanones (Table 4).
The enantiomeric excess of the products was determined by chiral
GC analysis on a Chiraldex G-TA column: injection temperature:
NMR (100 MHz, CDCl3) d 214.4, 62.6, 51.3, 50.4, 35.3, 33.4, 28.9, 22.3.
HRMS (ESI-TOF) m/z calcd for C8H14O2Na [MþNa]þ 165.0886, found
165.0890.
The isomer 6b0 was partially separated from 6b and analysed to
be 67% ee; GC: tmajor¼45.5 min, tminor¼42.7 min; IR (film) 3421
(OH), 2955, 2934, 2875,1701,1037 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
4.00 (t, J¼10.2 Hz,1H), 3.41 (br s,1H), 2.73–2.68 (m,1H), 2.44–2.20
(m, 4H), 1.97–1.82 (m, 2H), 1.78–1.63 (m, 1H), 0.81 (d, J¼7.3 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3)
d 214.6, 61.2, 56.5, 41.8, 34.2, 32.0,
22.3, 14.6; HRMS (ESI-TOF) m/z calcd for C8H14O2Na [MþNa]þ
165.0886, found 165.0882.
4.3.4. (S)-7-(Hydroxymethyl)-1,4-dioxaspiro[4.5]decan-8-one
(6c). The compound 6c was obtained as a colourless liquid (417 mg,
22
56%) in 70% ee; [
a]
ꢁ3.0 (c 1.0, CHCl3); GC: tmajor¼69.8 min,
D

1494
A. Chen et al. / Tetrahedron 66 (2010) 1489–1495
tminor¼68.5 min; IR (film) 3425 (OH), 2959, 2889, 1710 (C]O), 1143,
1061 cmꢁ1 1H NMR (400 MHz, CDCl3)
4.07–3.99 (m, 4H), 3.66
unspecified}; IR (EF) 3305 (OH), 2926, 2853, 1448, 1017; 1H NMR
(400 MHz, CDCl3)
4.09 (dt, J¼11.0, 2.9 Hz, 1H), 3.54 (ddd, J¼11.0,
6.2, 2.9 Hz, 1H), 2.63 (dd, J¼6.2, 2.9 Hz, 1H), 2.33 (s, 1H), 1.98–1.47
(m, 13H), 1.30–0.93 (m, 7H); 13C NMR (100 MHz, CDCl3)
76.8, 64.7,
45.5, 41.3, 31.3, 27.9, 26.9 (2C), 26.7, 26.2, 25.73, 25.67, 21.5; HRMS
(ESI-TOF) m/z calcd for C13H24O2Na [MþNa]þ 235.1669, found
235.1671.
;
d
d
(t, J¼5.9 Hz, 2H), 2.88–2.80 (m, 1H), 2.68 (td, J¼13.5, 5.8 Hz), 2.58
(br d, 1H), 2.38 (dt, J¼13.5, 4.0 Hz), 2.08–1.97 (m, 3H) 1.94–1.84
d
(m, 1H); 13C NMR (100 MHz, CDCl3)
d
213.2, 107.2, 64.9, 64.7, 62.2,
48.3, 38.5, 36.9, 34.4; HRMS (ESI-TOF) m/z calcd for C9H14O4Na
[MþNa]þ 209.0784, found 209.0791.
4.3.5. Larger scale synthesis of (S)-1. To a flask containing
L
-thre-
4.4.2. Synthesis of (1R,2R)-1-hydroxy-1,10-bicyclohexyl-2- carboxylic
acid (9). To a solution of the diol (10) (191 mg, 0.9 mmol) in CH2Cl2
(20 mL) and H2O (3 mL) was added sequentially aqueous solutions
of NaBr (1 M, 0.5 mL) and nBu4NBr (1 M, 1 mL), saturated aqueous
NaHCO3 (2.5 mL), TEMPO (44 mg, 0.3 mmol) and aqueous NaOCl
(13%, 2 mL) with stirring at 0 ꢂC. The reaction mixture was stirred at
rt for 3 h. After, which time, the mixture was acidified to pH 7 with
2 N HCl aqueous solution, followed by sequential addition of tBuOH
(14 mL), 2-methyl-2-butene (2 M in THF, 28 mL, 56 mmol) and an
aqueous solution of NaClO2 (1.2 g, 13 mmol) and NaH2PO4 mono-
hydrate (800 mg, 5.8 mmol) in H2O (4 mL). The mixture was stirred
vigorously at rt for 3 h. The solvents were removed under reduced
pressure and the residue was diluted with EtOAc (20 mL) and H2O
(10 mL). The phases were separated and the aqueous phase was
extracted with EtOAc (2ꢃ30 mL). The combined organic phases
were washed with brine, dried (MgSO4) and concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography by gradient elution with 0–50% EtOAc in
petroleum ether with 0.05% formic acid to provide the acid 9
onine (1.49 g, 0.0125 mol) was added formalin (37% aqueous
solution, 9.5 mL, 0.125 mol). The mixture was stirred at rt for
30 min until the catalyst fully dissolved. THF (250 mL) was added
and the solution was cooled to 10 ꢂC using a chiller circulator
before cyclohexanone (20.0 mL, 0.19 mol) and powdered
anhydrous MgSO4 (15.0 g, 0.125 mol) were added. The reaction
was stirred at 10–12 ꢂC for five days. After, which time, it was
filtered and the solid residue washed with ethyl acetate
(2ꢃ50 mL). Saturated aqueous NH4Cl solution (40 mL) was added
to the filtrates and the solution was stirred for 20 min. The
organic phase was separated, dried (MgSO4) and the solvent was
evaporated. Vacuum distillation of the crude product provided
(S)-1 (6.67 g, 41.7%, 107–109 ꢂC/0.15 mbar) as a colourless oil. The
optical purity of the product (98% ee) was determined by chiral
GC analysis as described in 4.3.1.
4.3.6. Synthesis of camphanate (7). To a solution of the alcohol 6b
(50 mg, 0.352 mmol) in dry DCM was added DMAP (215 mg,
1.76 mmol) and then (ꢁ)-(S)-camphanic chloride (99 mg,
0.458 mmol) at rt. The mixture was stirred at rt for 4 h and then
concentrated under reduced pressure. The crude product was pu-
rified by column chromatography using 0–25% EtOAc in petroleum
ether to afford pure product (45 mg, 40% yield) as a white solid,
which was then re-crystallized from EtOAc/pentane to afford col-
ourless single crystals suitable for X-ray analysis. Mp: 111–112 ꢂC;
(177 mg, 87%) as a white solid. Mp: 128–129 ꢂC (lit.1130–132 ꢂC);
25
[a
]
þ12.4 (c 1.0, 0.5 N NaOH) {lit.1 [
D þ10.3, (c 1.0, 0.5 N NaOH),
a
]
D
temperature unspecified}; IR (EF) 3345 (OH), 2928, 1695 (C]O),
1446, 1189 cmꢁ1
4.4 Hz, 1H), 2.01 (s, 1H), 1.95–1.052 (m, 12H), 1.48–1.39 (m, 1H),
1.30–0.94 (m, 7H); 13C NMR (100 MHz, CDCl3)
180.5, 73.9, 48.1,
;
1H NMR (400 MHz, CDCl3)
d
2.64 (dd, J¼12.1,
d
47.8, 29.9, 28.2, 26.9, 26.7, 26.5, 26.33, 26.26, 25.0, 20.6; HRMS (ESI-
IR (EF) 2974, 2877, 1784, 1710, 1640, 1279, 1175 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
TOF) m/z calcd for C13H21O3 [M-H]- 225.1496, found 225.1489.
d
4.50 (dd, J¼11.3, 5.6 Hz, 1H), 4.20 (dd, J¼11.3,
6.4 Hz, 1H), 2.66 (m, 1H), 2.43–2.37 (m, 2H), 2.22–2.16 (m, 2H),
2.07–1.98 (m, 2H), 1.93–1.82 (m, 3H), 1.70–1.64 (m, 1H), 1.52–1.36
(m, 2H), 1.11 (s, 3H), 1.05 (d, J¼5.4 Hz, 3H), 1.04 (s, 3H), 0.95 (s, 3H);
4.4.3. Synthesis of benzyl (1R,2R)-1-hydroxy-1,10-bicyclo-hexyl-2-
carboxylate (12). To a solution of carboxylic acid 9 (40 mg,
0.177 mmol) in DCM (2 mL) was added nBu4NI (78 mg,
0.212 mmol), saturated aqueous NaHCO3 (1 mL) and benzyl
13C NMR (100 MHz, CDCl3)
d 209.3, 178.3, 167.4, 91.2, 64.3, 54.8,
54.2, 50.2, 48.3, 35.3, 33.3, 30.6, 29.8, 28.9, 22.3, 16.7, 16.7, 9.7;
HRMS (ESI-TOF) m/z calcd for C18H26O5Na [MþNa]þ 345.1673,
found 345.1684.
bromide (32 mL, 0.266 mmol). The mixture was stirred at rt for
4 h, followed by addition of saturated aqueous NH4Cl solution
(1 mL) and DCM (3 mL). The phases were separated and the
aqueous phase was extracted with DCM (2ꢃ5 mL). The combined
extracts were washed with brine, dried (MgSO4) and concen-
trated under reduced pressure. The crude product was purified
by silica gel column chromatography by gradient elution with 0–
10% EtOAc in petroleum ether to afford the benzyl ester 12
4.4. Synthesis of (1R, 2R)-1-hydroxy-1,10-bicyclohexyl-2-
carboxylic acid (9)
4.4.1. Synthesis of (1R,2S)-1-hydroxy-1,10-bicyclohexyl-2-methanol
(10). To a solution of (S)-1 (98% ee, 128 mg, 1.0 mmol) and PPTS
(8 mg, 3 mol %) in anhydrous Et2O (2 mL) was added 2-methoxy-
(49 mg, 88%) as a colourless oil. 1H NMR (400 MHz, CDCl3)
d 7.40–
7.31 (m, 5H), 5.23 (d, J¼12.1 Hz, 1H), 5.06 (d, J¼12.1 Hz, 1H), 3.25
(d, J¼2.6 Hz, 1H), 2.63 (dd, J¼12.4, 3.6 Hz, 1H), 1.98–1.87 (m, 2H),
1.78–1.57 (m, 8H), 1.53–1.46 (m, 1H), 1.22–0.85 (m, 8H); 13C NMR
propene (377
m
L, 4 mmol) dropwise at ꢁ10 ꢂC. After stirring for
30 min at ꢁ10 ꢂC, Et2O (3 mL) was added, followed by the addition
of cyclohexylmagnesium chloride (2 M in Et2O, 1.4 mL, 2.8 mmol)
over 20 min at ꢁ10 ꢂC. The reaction mixture was allowed to warm
to 0 ꢂC and continued stirring at this temperature for 1 h before
being quenched by the addition of aqueous NH4Cl solution (2 mL)
and water (1 mL). The organic phase was separated and the aque-
ous phase was extracted with Et2O (2ꢃ10 mL). The combined ex-
tracts were evaporated under reduced pressure to give a viscous
residue to which was added saturated NH4Cl (5 mL) and 0.2 M HCl
until pH 4. The mixture was stirred at rt for 4 h and then extracted
with Et2O (3ꢃ20 mL). The combined extracts were washed with
brine and dried (MgSO4). The crude white solid was washed with
(100 MHz, CDCl3)
d 176.7, 135.7, 128.7 (2C), 128.4, 128.3 (2C), 73.5,
66.2, 48.1, 48.0, 29.9, 28.3, 26.79, 26.77, 26.6, 26.3, 26.2, 25.1,
20.7; HPLC: 98% ee, tmajor¼11.0 min (1R, 2R), tminor¼13.7 min (1S,
2R); 0.5% IPA in hexane; Chiralpak AS-H column (4.6ꢃ250 mm);
flow rate: 1 mL/min.
4.5. Synthesis of compounds 3, 13–15
4.5.1. Synthesis of (S)-7-(hydroxymethyl)oxepan-2-one ((S)-13). To
a solution of (S)-1 (98% ee, 1.02 g, 7.97 mmol) in dry DCM (40 mL)
was added NaHCO3 (1.0 g, 12 mmol) followed by m-CPBA (77%,
2.14 g, 9.6 mmol) at 0 ꢂC. The resulting mixture was allowed to
warm to rt and stirred for 3 h. The reaction was diluted with DCM
(20 mL) and quenched by the addition of solid sodium thiosulphate
w5% Et2O in petroleum ether and dried under vacuum to afford the
24
diol (9) as a white solid (162 mg, 76%). Mp: 168–169 ꢂC; [
a
]
þ27.9
D
24
(c 1.2, EtOH) {lit.13
[
a
]
D
ꢁ10.66 (c 1.22, EtOH) for (1S, 2R)-10, ee

A. Chen et al. / Tetrahedron 66 (2010) 1489–1495
1495
(0.63 g, 4 mmol). The mixture was stirred for 10 min, filtered and
the solid residues were washed with DCM (30 mL). The filtrates
were evaporated under reduced pressure and the crude product
was purified by silica gel column chromatography by gradient
HRMS (ESI-TOF) m/z calcd for C8H16O4Na [MþNa]þ 199.0941, found
199.0938.
4.5.5. Synthesis of (R)-methyl 6-hydroxyheptanoate ((R)-3b). Com-
elution with 50–100% EtOAc in petroleum ether to afford the lac-
pound (R)-3b (53 mg, 84% yield) was similarly prepared from
24
25
tone (S)-13 as a colourless oil (1,03 g, 89%); [
a
]
þ41.2 (c 1.3,
lactone (R)-15 (50 mg, 0.391 mmol) as a colourless oil; [
a
]
ꢁ12.7
D
D
CHCl3); IR (film) 3420 (OH), 2939, 2866, 1717 (C]O), 1182 cmꢁ1; 1H
NMR (400 MHz, CDCl3)
(c 1.0, CHCl3); IR (film) 3410 (OH), 2936, 2865, 1739 (C]O),
d
4.33–4.28 (m, 1H), 3.65 (dd, J¼12.0, 7.3 Hz,
1437 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.84–3.75 (m, 1H), 3.65 (s,
1H), 3.55 (dd, J¼12.0, 4.0 Hz, 1H), 3.31 (br s, 1H), 2.67–2.54 (m, 2H),
3H), 2.32 (t, J¼7.4 Hz, 2H), 1.75 (br s, 1H), 1.68–1.59 (m, 2H),
1.97–1.82 (m, 3H), 1.62–1.45 (m, 3H); 13C NMR (100 MHz, CDCl3)
1.51–1.26 (m, 4H), 1.17 (d, J¼6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
175.7, 81.0, 65.0, 34.7, 30.4, 27.7, 22.8; HRMS (ESI-TOF) m/z calcd
d 174.2, 67.8, 51.5, 38.8, 34.0, 25.3, 24.8, 23.5; HRMS (ESI-TOF) m/z
for C7H12O3Na [MþNa]þ167.0679, found 167.0687; GC: 96% ee
(Chiraldex G-TA), tmajor¼10.7 min, tminor¼13.7 min; flow rate:
2.0 mL/min.
calcd for C8H16O3Na [MþNa]þ 183.0992, found 183.0983.
Acknowledgements
4.5.2. Synthesis of (S)-7-(bromomethyl)oxepan-2-one ((S)-14). To
the solution of the hydroxymethyl lactone (S)-13 (144 mg,
1.0 mmol) in dry DCM (5 mL) was added PPh3 (525 mg, 2.0 mmol)
and CBr4 (663 mg, 2.0 mmol) at 0 ꢂC under argon. The mixture was
stirred at rt for 5 h, followed by concentration under reduced
pressure. The residues was purified by silica gel column chroma-
tography by gradient elution with 0–20% EtOAc in petroleum ether
to afford the bromide (S)-14 (120 mg, 58%) as a colourless oil. 1H
We are most grateful to our scientific advisors Professor Brian
Cox (AstraZeneca) and Professor Richard Taylor (University of York)
for their valuable discussions. We also thank Drs Murugapillai
Venugopal and Shanti Thavaneswaran for their contributions at the
early stage of this study, Ms Sze Chen Chia and Dr. Cun Wang for
their assistance on the X-ray structure analysis, and the Agency for
Science, Technology and Research (A*STAR), Singapore for sup-
porting this work.
NMR (400 MHz, CDCl3)
d
4.47–4.42 (m,1H), 3.54 (dd, J¼10.6, 5.8 Hz,
1H), 3.41 (dd, J¼10.8, 6.2 Hz, 1H), 2.76–2.70 (m, 1H), 2.63–2.55 (m,
1H), 2.24–2.17 (m, 1H), 2.05–1.94 (m, 2H), 1.73–1.59 (m, 3H); 13C
References and notes
NMR (100 MHz, CDCl3)
d 174.1, 79.3, 34.8, 34.2, 33.0, 27.9, 22.8;
HRMS (ESI-TOF) m/z calcd for C7H11BrO2Na [MþNa]þ 228.9840
1. Di Bugno, C.; Colombani, S. M.; Dapporto, P.; Garzelli, G.; Giorgi, R.; Paoli, P.;
Subissi, A.; Turbanti, L. Chirality 1997, 9, 713.
(
79Br), found 228.9831.
2. See for examples: (a) Crimmins, M. T.; Jacobs, D. L. Org. Lett. 2009, 11, 2695;
(b) Mohapatra, D. K.; Bhattasali, D.; Gurjar, M. K.; Khan, M. I.; Shashishara, K. S.
Eur. J. Org. Chem. 2008, 36, 6213; (c) Lampe, T.; Kast, R.; Stoll, F.; Schuhmacher, J.
WO 2009065472, 2009; (d) Xing, Y.; O’Doherty, G. A. Org. Lett. 2009, 11, 1107; (e)
Guo, H.; O’Doherty, G. A. Org. Lett. 2005, 7, 3921; (f) Mlynarski, J.; Ruiz-Caro, J.;
Fu¨rstner, A. Chem.dEur. J. 2004, 10, 2214.
4.5.3. Synthesis of (R)-7-methyloxepan-2-one ((R)-15). To a solu-
tion of bromide (S)-14 (100 mg, 0.69 mmol) in dry toluene (5 mL)
was added AIBN (35 mg, 0.2 mmol) and nBu3SnH (368
mL,
1.38 mmol) under argon. The mixture was heated at 100 ꢂC for
3 h. After cooled to rt, the solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography by gradient elution with 0–30% EtOAc in pe-
troleum ether to afford the lactone (R)-15 (69 mg, 77%) as a col-
3. Barili, P. L.; Catelani, G.; Giorgi, R.; Mastrorilli, E.; Rosini, C. Enantiomer 1998, 3,
357.
4. Ozasa, N.; Wadamoto, M.; Ishihara, K.; Yamamoto, H. Synlett 2003, 2219.
5. (a) Casas, J.; Sunde´n, H.; Co´ rdova, A. Tetrahedron Lett. 2004, 45, 6117; (b) Torii,
H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004,
43, 1983; (c) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem., Int. Ed. 2006, 45, 958.
6. Mase, N.; Inoue, A.; Nishio, M.; Takabe, K. Bioorg. Med. Chem. Lett. 2009, 19, 3955.
7. Winkelman, J. G. M.; Voorwinde, O. K.; Ottens, M.; Beenackers, A. A. C. M.;
Janssen, L. P. B. M. Chem. Eng. Sci. 2002, 57, 4067.
8. Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2000,
129, 15100.
9. (a) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 2047 and references cited therein;
(b) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem. 2008, 285, 1; (c) Chen, Y.-C. Synlett
24
23
ourless oil; [
a
]
þ27.4 (c 1.0, CHCl3) {lit.17
[
a
]
þ25.0 (c 1.8,
D
D
CHCl3)}; IR (film) 2936, 2864, 1727 (C]O), 1179, 1017 cmꢁ1 1H
;
NMR (400 MHz, CDCl3)
d 4.47–4.40 (m, 1H, CHO), 2.70–2.56 (m,
2H, CH2CO), 1.95–1.86 (m, 3H), 1.69–1.55 (m, 3H), 1.35 (d,
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 175.6, 76.8, 36.2, 35.0,
28.3, 22.9, 22.6; HRMS (ESI-TOF) m/z calcd for C7H12O2Na
[MþNa]þ 151.0730, found151.0734.
2008, 1919.
23
10. (S)-1 {[
a
]
D
þ11.4 (c 1.0, CHCl3)} has the same sign of rotation as the (S)-en-
antiomer obtained from enzymatic resolution.3
4.5.4. Synthesis of (S)-methyl 6,7-dihydroxyheptanoate (S)-3a. To
a solution of lactone (S)-15 (144 mg, 1.0 mmol) in dry MeOH (5 mL)
was added sodium methoxide (216 mg, 4.0 mmol) and the mixture
was stirred at rt for 3 h. The reaction was quenched by the addition
of saturated aqueous NH4Cl, followed by removal of MeOH under
reduced pressure. The residue was diluted with EtOAc (10 mL) and
water (2 mL). The phases were separated and the aqueous phase
was extracted with EtOAc (2ꢃ8 mL). The combined extracts were
washed with brine, dried (MgSO4) and evaporated under reduced
pressure. The crude product was purified by silica gel column
11. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no CCDC 742698. Copies of the data can be ob-
tained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
12. Barbier, P.; Renzetti, A. R.; Turbanti, L.; Di Bugno, C.; Fornai, F.; Vaglini, F.;
Maggio, R.; Corsini, G. U. Eur. J. Pharmacol. 1995, 290, 125.
13. Di Bussolo, V.; Catelani, G.; Mastrorilli, E. Tetrahedron: Asymmetry 1996, 7, 3585.
14. Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49, 2457.
15. (a) Monk, K. A.; Duncan, N. C.; Bauch, E. A.; Garner, C. M. Tetrahedron 2008, 64,
8605; (b) Ainge, D.; Ennis, D.; Gidlund, M.; Stefinovic, M.; Vaz, L. M. Org. Process
Res. Dev. 2003, 7, 198.
16. Huang, L.; Teumelsan, N.; Huang, X. Chem.dEur. J. 2006, 12, 5246.
17. (a) Pirkle, W. H; Adams, P. E. J. Org. Chem 1979, 44, 2169; (b) van As, B. A. C.;
Chan, D.-K.; Kivit, P. J. J.; Palmans, A. R. A.; Meijer, E. W. Tetrahedron: Asymmetry
2007, 18, 787.
18. (a) van As, B. A. C.; van Buijtenen, J.; Broxterman, Q. B.; Verzijl, G. K. M.; Heise,
A.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2005, 127, 9964; (b) van
Buijtenen, J.; van As, B. A. C.; Meuldijk, J.; Palmans, A. R. A.; Vekemans, J. A. J. M.;
Hulshof, L. A.; Meijer, E. W. Chem. Commun. 2006, 3169.
chromatography by gradient elution with 5–10% MeOH in DCM to
26
afford the methyl ester (S)-3a (150 mg, 85%) as a colourless oil. [a]
D
ꢁ20.1 (c 1.07, EtOH); IR (film) 3393 (OH), 2943, 2867, 1734 (C]O),
1437 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.74–3.68 (m, 1H), 3.66 (s,
3H), 3.64(dd, J¼11.0, 2.9 Hz,1H), 3.43 (dd, J¼11.0, 7.3 Hz,1H), 2.33 (t,
J¼7.3 Hz, 1H), 1.70–1.60 (m, 2H), 1.53–1.34 (m, 4H); 13C NMR
19. Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
12236.
(100 MHz, CDCl3):
d 174.3, 71.9, 66.8, 51.6, 33.9, 32.7, 25.0, 24.7;