Regioselective monochloro substitution in carbohydrates and non-sugar alcohols via Mitsunobu reaction: Applications in the synthesis of reboxetine

Article abstract of DOI:10.1039/c3ob40853a

A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O- cyclohexylidene-d-glyceraldehyde in ～43% overall yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob40853a

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Regioselective monochloro substitution in
carbohydrates and non-sugar alcohols via Mitsunobu
reaction: applications in the synthesis of reboxetine†
Cite this: Org. Biomol. Chem., 2013, 11,
6195
Abdul Rouf Dar, Mushtaq A. Aga, Brijesh Kumar, Syed Khalid Yousuf and
Subhash Chandra Taneja*
A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is
reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlori-
nated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution
occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration,
as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology
was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant
drug reboxetine from (R)-2,3-O-cyclohexylidene-D-glyceraldehyde in ∼43% overall yields.
Received 25th April 2013,
Accepted 18th July 2013
DOI: 10.1039/c3ob40853a
www.rsc.org/obc
acid systems19 or by using ionic liquids20 and also from
diols.21 In carbohydrates, halogenation is usually achieved by
Introduction
The Mitsunobu reaction1 is a preferred reaction in synthetic2 Appel reaction22 or by using other halogenating reagents.23
and medicinal chemistry fields to introduce various functional Earlier work on the formation of chlorohydrins under Mitsu-
groups due to its efficacy, stereoselectivity, mild reaction con- nobu conditions, mainly for the purpose of mechanistic study
ditions and wide applicability.3 Compared to the extensive use using Ph3P and Me3SiX nucleophiles, was performed at −78 °C
of Mitsunobu reactions on the molecules containing mono for longer periods (1–18 h) with low selectivities by Evans
hydroxyl groups,4 there have been only a few reports on its et al.24 Therefore, an efficient method for halohydrin formation
applications in the molecules comprising multiple hydroxyls, in multihydroxy molecules in a ‘single step’ would be highly
especially vicinal hydroxyl groups.5
advantageous for a host of useful synthetic transformations.25
As a part of our ongoing interest in the carbohydrate chem-
The halo alcohols such as chiral 1,2- and 1,3-chlorohydrins
have attracted the interest of organic chemists both for their istry,26 and further development of our recent interesting
usefulness as versatile building blocks,6 key intermediates7 observations on regioselective azidation at the primary
and synthons8 for natural products9 and a diversity of impor- hydroxyl group in carbohydrates,27 we report herein the results
tant bioactive molecules10 as well as in asymmetric synthesis.11 of our investigations of monochloro substitution in sugars
The chlorodeoxy sugars are of interest as precursors6,12 for the (chlorohydrin formation), irrespective of the presence of other
synthesis of deoxy, amino-deoxy and unsaturated sugars. free hydroxyls in the carbohydrate ring as well as in non-sugars
Despite their importance, the synthesis of chlorohydrins is not under Mitsunobu conditions using Me3SiCl as a nucleophile.
straightforward. Although various synthetic methods have The indirect access to epoxides with the retention of configur-
been reported, most of them have limitations, such as harsh ation as against inversion in the normal Mitsunobu reaction is
reaction conditions, low regioselectivities and moderate an important application of the present methodology. Besides,
yields.13 The most common methods for the synthesis of 1,2- we also report the application of this reaction for an efficient
halohydrins are halohydroxylation of alkenes14 or ring synthesis of (2R,3S)-reboxetine 19 (an antidepressant drug) and
opening of 1,2-epoxides,15 which use silylhalides in the pres- (R)-hydroxymethylmorpholine 22, an intermediate of (2R,3S)-
ence of different promoters,16 elemental halogens with various reboxetine and other biologically active molecules.28
catalysts,17 borane halogenides18 and metal halides with Lewis
Results and discussion
CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
E-mail: sctaneja@iiim.ac.in, drsctaneja@gmail.com
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
The one-pot conversion to chlorohydrins was achieved by
adding DIAD to a suspension of the substrate and Ph3P in
NMR spectra are available. See DOI: 10.1039/c3ob40853a
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toluene at 0 °C. Trimethylsilyl chloride (Me3SiCl) was injected with diethoxytriphenylphosphorane (DTPP) and the structure
after 15 minutes and the reaction mixture was stirred for 2 h. was established by a 31P NMR spectrum, indicating the pres-
Initially, a series of solvents were screened to optimize the ence of 1,3,2λ5-dioxaphospholane (δ −37.5) and Ph3PO (δ
reaction conditions in 1,2-diols, wherein toluene emerged as 27.0 ppm). After the reaction of the dioxaphospholane inter-
the solvent of choice (ESI†).
mediate with trimethylsilyl reagents (Me3SiX) at −78 °C for
In the case of 1,2-diols (entries 1 and 2, Table 1) both 18 h, the regioisomeric (silyloxy)phosphonium ions were
the chloro regioisomers were obtained in the ratio of 3 : 1, observed at δ 62.0 and 63.5 ppm respectively (as monitored by
while in 1,3-diols (entries 4 and 5, Table 1), the 4 : 1 ratio 31P NMR spectroscopy). Though the mechanism proposed by
was observed. In sterically hindered non-sugars high Evans et al. was related to a different substrate, on the basis of
regioselectivity was observed, as chloro substitution occurred those studies we presume the formation of two conformational
exclusively at the primary hydroxyl position (entries 6–8, isomeric dioxaphospholanes 5a and 5b from 1,2- and 1,3-diols
Table 1). In the partially protected carbohydrates, it was with Ph3P and DIAD, which undergo a rapid interconversion
observed that only the primary hydroxyl was regioselectively through pseudorotation. The silylation at the more basic P–O
substituted by chlorine, furnishing chlorohydrins in high apical oxygen leads to the formation of (silyloxy)phosphonium
yields (Table 1).
ions 7a and 7b and subsequent SN2 displacement of Ph3PO by
Two possible mechanisms of regioselective chloro-substi- a chloride ion affords the formation of a thermodynamically
tution have been proposed to explain the product formation. less stable C-2 chlorinated regioisomer as the major product,
The first possible mechanism via Mitsunobu reaction is based followed by in situ silyl group deprotection, possibly due to low
on the work by Evans et al.,24 who claimed to have isolated the pH (acidic pH) of the reaction medium during the stipulated
dioxaphospholane intermediate. The intermediate was pre- reaction conditions, i.e. the addition of 1.3 equiv. of Me3SiCl
pared by bis(trans-oxyphosphoranylation) of 1,2-propanediol (Scheme 1).
Table 1 Mitsunobu reaction in non-sugars and sugar alcohols
Entry
1
Diol
Time (h)
2
Product
Product ratio (2/3)
Total isolated yield (%)
92
3 : 1
2
3
2
2
3 : 1
90
94
4
2
4 : 1
4 : 1
82
5
6
2
2
80
97
7
2
98
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Table 1 (Contd.)
Entry
8
Diol
Time (h)
2
Product
Product ratio (2/3)
Total isolated yield (%)
90
9
2
2
95
85
10
11
2
95
12
13
2
2
94
94
14
6
90b
a Diastereomeric ratio 46 : 54. b Isolated as an acetylated product.
The in situ deprotection of the silyl group was verified by silylation at secondary hydroxyl, followed by fast desilylation
isolating the silyl protected intermediate, when the same reac- under the stipulated experimental conditions to form the
tion was effected using less than a molar equivalent, i.e. 0.8 desired chlorohydrins (Scheme 2). According to another litera-
equiv. of Me3SiCl (ESI†). In conventional silyl protection pro- ture report in trans cyclic 1,2-diols, the reaction occurs through
cedures,29 the chloride ion is trapped by adding a base, while an epoxide intermediate.31
in the present methodology, the reaction is carried out with
The 1,2-diols have been reported to form epoxides under
1.3 equiv. of Me3SiCl in the absence of a base, indicating the Mitsunobu conditions with low to moderate yields with the
possible role of pH during the silyl deprotection. The use of inversion of configuration, when no additional nucleophiles
1.3 molar equivalents of Me3SiCl makes the reaction mixture are used.25 However, the present methodology has the advan-
acidic, thereby facilitating the in situ desilylation.
tage of providing indirect access to epoxides via chlorohydrin
In another proposed mechanism, the chloro-substitution in intermediates in high yields with the retention of configur-
sugars and sterically hindered non-sugars may also probably ation (Scheme 3). The epoxide formed can be easily trans-
proceed via the formation of an adduct at the primary carbon formed into a diversity of functionalities like amino alcohols,
through an imino-O-phosphorane intermediate30 followed by haloalcohols and other important moieties which can be
the silyl attack at the imino-nitrogen, causing the formation of highly useful in organic synthesis. The following scheme
oxo-phosphonium salt 8. This intermediate salt then under- depicts the formation of epoxides in high yields (92–98%)
goes a facile substitution by the chloride ion with concomitant using DBU as
a
base in dichloromethane, from the
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Scheme 1 Probable mechanism of Mitsunobu chloride substitution in 1,2-diols.
Scheme 2 Probable mechanism of Mitsunobu chloride substitution in sugars and sterically hindered non-sugars.
corresponding chlorohydrins with the retention of the con- 19 diastereomer could also possess interesting inhibitory
figuration (Table 2, entries 1–3).
properties.
There are several reported syntheses of the reboxetine in
To further explore its scope and versatility, we successfully
utilized this methodology in the synthesis of optically active both racemic and enantioenriched forms, which involve the
diastereoisomers, i.e. (2R,3S)- and (2S,3S)-reboxetine 19 separation of reboxetine enantiomers by optical resolution,36
and (R)-hydroxymethylmorpholine 22, an intermediate of capillary electrophoresis,37 or chiral HPLC38 and other syn-
(2R,3S)-reboxetine 19, using the synthon (R)-2,3-O-cyclohexyl- thetic approaches.39
idene-D-glyceraldehyde 14. The process is high yielding
The present approach utilizes the synthon (R)-2,3-O-cyclo-
and facile. Reboxetine is an antidepressant drug used in the hexylidene-D-glyceraldehyde 14, which can be easily obtained
treatment of clinical depression, panic disorders32 and from D-mannitol.40 Grignard reaction of aldehyde (R)-14 with
attention-deficit hyperactivity disorder (ADHD), as well as in bromobenzene afforded both syn- and anti-15 diastereomers in
neurodegenerative disorders including Alzheimer’s and a 1 : 1 ratio, which are easily separable by column chromato-
Parkinson’s disease.33 Among the reboxetine diastereomers, graphy. Thus, (2R,3R)-15 can be easily converted to (2R,3S)-15
the (S,S)-reboxetine exhibits the best affinity and selectivity and vice versa under the first Mitsunobu inversion via acetate
for the norepinephrine transporter (NET).34 Jobson et al.35 (16) formation. The (2R,3R)-15 undergoes a second Mitsunobu
in 2008 reported that iodinated (2R,3S)-reboxetine has transformation with 2-ethoxyphenol to form (2R,3S)-17. The
high affinity for the noradrenaline transporter (NAT), while (2R,3S)-diol 1g obtained by deprotection of the (2R,3S)-17
its enantiomer (2S,3S) was much less potent in the was directly converted to chlorohydrin intermediate (2S,3S)-3g
same binding assay. These observations suggest that (2R,3S)- by Mitsunobu chloride substitution with Me3SiCl as
a
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Scheme 3 Epoxide formation with retention of configuration in the present method.
Table 2 Epoxidation through chlorohydrin intermediate
chiral intermediate (S)-chlorohydrin 3h under Mitsunobu con-
ditions. Thus, the reductive amination of aldehyde (R)-14 by
2-aminoethanol in presence of NaBH4 afforded amino alcohol
20, followed by N-benzylation to give (S)-21, which on cyclo-
hexyl deprotection furnished (S)-1h in 90% yield. The (S)-1h
was transformed into chlorohydrin (S)-3h in high yield (∼73%
overall yield) by utilizing the present Mitsunobu chloride sub-
stitution methodology. The chlorohydrin may easily be con-
verted to (R)-morpholine 22 via an epoxide intermediate41,42
and then to (2R,3S)-reboxetine 19 by methods reported in the
literature (Scheme 5).39f
Entry Substrate
1
Time (h) Product
8
Yield (%)
97
2
3
8
8
92
98
Conclusions
In conclusion an efficient regioselective monochloride substi-
tution via Mitsunobu reaction is reported. In sugars and steri-
cally hindered non-sugars, only the primary hydroxyl group is
replaced by chlorine, while in non-sugar 1,2 and 1,3-diols, the
secondary hydroxyl group gets preferably chlorinated. The
methodology is successfully applied in the novel synthesis of
(2R,3S)- and (2S,3S)-reboxetine (antidepressant), as well as the
synthesis of a chiral hydroxymethyl morpholine derivative (also
an intermediate of (2R,3S)-reboxetine). The methodology of
chlorohydrin formation may also be used for the preparation of
epoxides in high yields with the retention of configuration.
nucleophile and subsequently converted to (2R,3S)-epoxide 4g
in 98% yield with the retention of configuration. The synthesis
of (2R,3S)-reboxetine 19 was finally accomplished via epoxide
ring opening with 2-aminoethyl hydrogen sulphate (2-AEHS),
followed by cyclization39b (∼43% overall yield, Scheme 4). The
(2R,3S)-15 isomer was also similarly converted to (2R,3S)-rebox-
etine via Mitsunobu reaction. By this process both the isomers
were successfully utilized for the synthesis of (2R,3S)-reboxe-
tine. Though not included here, theoretically the (2R,3S)-15
can also be easily used for the preparation of (2R,3R)-reboxe-
tine, by following
a similar synthetic pathway. For the
General experimental procedure
preparation of (2S,3S)-reboxetine 19, the diol (2R,3S)-1g was
converted to (2S,3S)-epoxide 4g under conventional Mitsunobu
conditions and finally to enantiomerically pure (2S,3S)-reboxe-
tine 19 by epoxide opening with 2-aminoethyl hydrogen sul-
phate (2-AEHS) and cyclization under basic conditions in good
yields (Scheme 4).
An alternate strategy was also devised for the synthesis of
(2R,3S)-19 by way of synthesizing (R)-N-benzyl-2-hydroxymethyl-
morpholine 22 intermediate, again using the aldehyde (R)-14
as a starting material. There have been only a few literature
reports related to the synthesis of racemic or a single enantio-
mer of 22.41 Herein, we report a novel and facile synthesis of
NMR experiments were performed using Bruker 200, 400 and
500 MHz spectrometers with TMS as the internal standard.
Chemical shifts are expressed in parts per million (δ ppm).
Reagents and solvents used were mostly of LR grade. Silica gel
coated aluminum plates from M/s Merck were used for TLC.
MS was performed using a High Resolution Mass Spectrometer
MS Q-TOF LC/MS, Agilent Technologies 6540. Optical rotations
were measured on a Perkin-Elmer 241 polarimeter at 25 °C
using sodium D light. Melting points were determined using
the Buchi B-542 apparatus by an open capillary method and
are uncorrected. Chemicals were purchased from M/s Aldrich
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Scheme 4 Synthesis of (2R,3S)- and (2S,3S)-reboxetine.
Scheme 5 Alternate synthesis of (2R,3S)-reboxetine.
Chemicals, Mumbai. All anhydrous reactions were carried out at this temperature, trimethylsilyl chloride (Me3SiCl)
under a nitrogen atmosphere using freshly dried solvents. The (2.6 mmol, 1.3 equiv.) under nitrogen was added. The reaction
organic extracts were dried over anhydrous Na2SO4.
mixture was stirred at room temperature for 2 h. After the com-
pletion of the reaction as indicated by TLC, the reaction was
quenched with ethyl acetate (3 × 25 mL). The combined
organic extract was washed with water (2 × 10 mL) and brine
General procedure of Mitsunobu chloride substitution for
1a–1m
Diisopropyl azodicarboxylate (DIAD) (3.0 mmol, 1.5 equiv.) was solution (1 × 5 mL), dried over anhydrous Na2SO4 and concen-
injected into a solution of an alcohol (2.0 mmol, 1.0 equiv.) trated in vacuo. The residue was subjected to column
and triphenylphosphine (Ph3P) (2.6 mmol, 1.3 equiv.) in chromatography (silica gel, 0–30% EtOAc–hexane) to obtain
15 mL anhydrous toluene at 0 °C. After stirring for 15 minutes the pure chlorohydrin product.
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(R)-3-(Benzyloxy)propane-1,2-diol (1a).43 Colorless liquid; to column chromatography (silica gel, 0–5% EtOAc–hexane) to
[α]2D5 = +5.5 (c 1.0, CHCl3); [lit.43 [α]D25 = +5.9 (c 1.0, CHCl3)]; obtain the pure silyl protected product 23 as a colorless liquid
1H NMR (400 MHz, CDCl3): δ 7.39–7.19 (m, 5H), 4.53 (s, 2H), in yield 23% (125 mg); [α]D25 = −4.1 (c 1.3, CHCl3); 1H NMR
3.94–3.84 (m, 1H, CH2OH), 3.67 (dd, J = 11.2, 3.6 Hz, 1H), 3.60 (400 MHz, CDCl3): δ 7.25–7.07 (m, 5H), 4.40 (s, 2H), 3.89–3.80
(dd, J = 11.5, 5.6 Hz, 1H), 3.55–3.47 (m, 2H), 3.02 (s, OH); (m, 1H), 3.54–3.46 (dd, J = 4.8, 4.0 Hz, 1H), 3.42–3.26 (m, 3H),
13C NMR (100 MHz, CDCl3): δ 137.67, 128.41, 127.80, 127.73, 0.10 (m, 9H); 13C NMR (100 MHz, CDCl3): δ 137.84, 128.22,
73.47, 71.62, 70.73 (CHOH), 63.96 (CH2OH); HRMS (ESI) Calc. 127.50, 74.18, 73.27, 71.47, 46.35 (CH2Cl), 0.00 (3C); HRMS
for C10H14NaO3 [M + Na]+ 205.0841, found 205.0834.
(ESI) Calc. for C13H21ClNaO2Si [M + Na]+ 295.0897, found
(S)-3-(Benzyloxy)-2-chloropropan-1-ol (2a). Prepared by the 295.0887.
general procedure of Mitsunobu chloride substitution; yield
Synthesis of (R)-3-((4-nitrobenzyl)oxy)propane-1,2-diol (1b).
69%; colorless liquid; [α]2D5 = −6.5 (c 1.0, CHCl3); 1H NMR Compound 1a (764 mg, 4.2 mmol) was slowly added dropwise
(400 MHz, CDCl3): δ 7.38–7.28 (m, 5H), 4.56 (s, 2H), 4.16–4.10 for 10 minutes to a solution of concentrated nitric acid (3 vol.,
(m, 1H, CH2OH), 3.91–3.81 (m, 2H), 3.74–3.69 (m, 2H), 1.38 (s, 6 mL) and sulfuric acid (1 vol., 2 mL) at 0 °C and stirred for
OH); 13C NMR (100 MHz, CDCl3): δ 137.49, 128.54, 127.97, 2 h. After the completion of the reaction, the extraction was
127.77, 73.56, 71.25, 64.69 (CH2OH), 60.09 (CHCl); HRMS (ESI) done with dichloromethane (3 × 15 mL), dried over anhydrous
Calc. for C10H13ClNaO2 [M + Na]+ 223.0502, found 223.0486.
Na2SO4and concentrated in vacuo. The residue was purified by
(S)-1-Chloro-3-benzyloxy-2-propanol (3a). Prepared by the column chromatography (silica gel, 0–9% EtOAc–hexane) to
general procedure of Mitsunobu chloride substitution; yield obtain the product 1b as a yellow solid in 83% yield (790 mg);
23%; colorless oil; [α]2D5 = −5.5 (c 1.0, CHCl3); 1H NMR mp. 101–103 °C; [α]2D5 = +3.3 (c 1.0, CHCl3); 1H NMR (400 MHz,
(400 MHz, CDCl3): δ 7.30–7.20 (m, 5H), 4.50 (s, 2H), 3.95–3.90 CDCl3): δ 8.17 (m, 2H), 7.62 (m, 2H), 4.55 (s, 2H), 3.95 (m, 1H),
(m, 1H, CHOH), 3.60–3.50 (m, 4H), 2.50 (s, OH); 13C NMR 3.80–3.50 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 148.66,
(100 MHz, CDCl3): δ 137.66, 128.35, 127.96, 127.76, 73.60, 143.88, 128.54, 124.45, 74.78, 72.34, 69.08 (CHOH), 64.32
70.82, 70.36 (CH2OH), 46.07 (CH2Cl); HRMS (ESI) Calc. for (CH2OH); HRMS (ESI) Calc. for C10H13NNaO5 [M + Na]+
C10H13ClNaO2 [M + Na]+ 223.0502, found 223.0484.
(R)-2-((Benzyloxy)methyl)oxirane (4a). 1,8-Diazabicyclo-
250.0691, found 250.0684.
(S)-2-Chloro-3-((4-nitrobenzyl)oxy)propan-1-ol (2b). Prepared
[5,4,0]-7-undecene (DBU) (212 mg, 1.4 mmol) was added to a by the general procedure of Mitsunobu chloride substitution;
mixture of chlorohydrins 2a and 3a [800 mg (400 mg each 2a yield 67%; yellow solid; mp. 45–48 °C; [α]2D5 = −1.6 (c 1.7,
and 3a), 4.0 mmol] dissolved in anhydrous dichloromethane CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.21 (m, 2H), 7.62 (m,
(15 mL) at 0 °C and stirred for 6 h until the consumption of 2H), 4.64 (s, 2H), 3.78–3.62 (m, 4H), 3.54 (m, 1H); 13C NMR
the starting material. The reaction mixture was extracted with (100 MHz, CDCl3): δ 148.98, 142.75, 129.09, 122.65, 74.91,
dichloromethane (3 × 20 mL). The organic layer was dried over 72.54, 65.09 (CH2OH), 60.64 (CHCl); HRMS (ESI) Calc. for
anhydrous Na2SO4 and the residue was purified by column C10H12ClNNaO4 [M + Na]+ 268.0353, found 268.0346.
chromatography (silica gel, 0–5% EtOAc–hexane) to yield the
(S)-1-Chloro-3-((4-nitrobenzyl)oxy)propan-2-ol (3b). Prepared
pure (R)-epoxide 4a in 97% yield (636 mg) as a colorless liquid; by the general procedure of Mitsunobu chloride substitution;
[α]2D5 = −6.8 (c 1.0, CHCl3); [lit.44 [α]D20 = −5.3 (c 4.5, toluene)]; yield 22%; yellow solid; mp. 40–42 °C; [α]D25 = −3.1 (c 1.3,
1H NMR (400 MHz, CDCl3): δ 7.32–7.24 (m, 5H), 4.62–4.53 (q, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.17 (m, 2H), 7.50 (m,
J = 23.6, 12.0 Hz, 2H), 3.77–3.74 (dd, J = 11.6, 2.8 Hz, 1H), 2H), 4.52 (s, 2H), 3.75 (m, 1H, CHOH), 3.49–3.30 (m, 4H);
3.45–3.41 (dd, J = 11.6, 6.0 Hz, 1H), 3.20–3.16 (m, 1H, 13C NMR (100 MHz, CDCl3):
δ 149.96, 144.78, 129.49,
CHOCH2), 2.85–2.80 (q, J = 9.2, 4.8 Hz, 1H, CH2OCH), 124.55, 74.01, 71.64, 70.29 (CHOH), 46.42 (CH2Cl); HRMS
2.61–2.60 (q, J = 4.8, 2.8 Hz, 1H, CH2OCH); 13C NMR (ESI) Calc. for C10H12ClNNaO4 [M + Na]+ 268.0353, found.
(100 MHz, CDCl3): δ 137.73, 128.22, 127.71, 127.55, 73.12, 268.0350.
70.62, 50.65 (CHOCH2), 44.07 (CH2OCH); HRMS (ESI) Calc. for
Synthesis of (R)-2-(((4-nitrobenzyl)oxy)methyl)oxirane (4b).
Compound 4b was prepared from 2b and 3b [980 mg (490 mg
C10H12NaO2 [M + Na]+ 187.0735, found 187.0730.
(S)-((1-(Benzyloxy)-3-chloropropan-2-yl)oxy)trimethylsilane each 2b and 3b)] by the same procedure described for 4a, as a
(23). Diisopropyl azodicarboxylate (DIAD) (606 mg, 3.0 mmol) yellowish semi-solid in 92% yield (769 mg); [α]2D5 = −2.3 (c 1.4,
was injected into a solution of (R)-3-(benzyloxy)propane-1,2- CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.13 (m, 2H), 7.59 (m,
diol 1a (364 mg, 2.0 mmol) and triphenylphosphine (Ph3P) 2H), 4.61 (s, 2H), 3.70 (q, J = 12.1, 2.6 Hz, 1H), 3.47–3.40 (m,
(681 mg, 2.6 mmol) in 15 mL anhydrous toluene at 0 °C. After 1H), 3.02 (m, 1H, CHOCH2), 2.66 (dd, J = 9.1, 4.8 Hz, 1H,
stirring for 15 minutes at this temperature, trimethylsilyl CH2OCH), 2.58 (dd, J = 4.9, 2.5 Hz, 1H, CH2OCH); 13C NMR
chloride (Me3SiCl) (172 mg, 1.6 mmol) under nitrogen was (100 MHz, CDCl3): δ 148.28, 143.65, 129.59, 121.65, 74.41,
added. The reaction mixture was stirred at room temperature 73.94, 51.49 (CHOCH2), 44.54 (CH2OCH); HRMS (ESI) Calc. for
for 2 h. After the completion of the reaction as indicated by C10H11NNaO4: [M + Na]+ 232.0586, found 232.0588.
TLC, the reaction was quenched with ethyl acetate (3 × 25 mL).
2,3-Dihydroxy-3-phenylpropanenitrile
(1c).45 Colorless
The combined organic extract was washed with water (2 × liquid: 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 4.77–4.75
10 mL) and brine solution (1 × 5 mL), dried over anhydrous (d, J = 6.4 Hz, 1H), 4.41–4.40 (d, J = 6.4 Hz, 1H); 13C NMR
Na2SO4 and concentrated in vacuo. The residue was subjected (125 MHz, CDCl3): δ 136.79, 129.14, 128.71, 126.82, 118.11,
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74.54 (CHOH), 66.00 (CHOHCN); HRMS (ESI) Calc. for
(2R)-3-Ethoxy-3-phenylpropane-1,2-diol (1f). Sodium hydride
(NaH) (552 mg, 24 mmol) was slowly added to diastereomer
C9H9NaNO2 [M + Na]+ 186.0531, found 186.0524.
3-Chloro-2-hydroxy-3-phenylpropanenitrile (2c). Prepared by (2R,3R/S)-15 (496 mg, 2.0 mmol) dissolved in anhydrous THF
the general procedure of Mitsunobu chloride substitution; (15 mL) at 0 °C. After 20 minutes ethyl iodide (403 mg,
yield 94%; transparent liquid; 1H NMR (400 MHz, CDCl3): δ 2.6 mmol) was added and the reaction mixture was stirred for
7.49–7.38 (m, 5H), 5.08–5.02 (dd, J = 18.0, 6.0 Hz, 1H, CHOH), about 8–9 h. After the consumption of the starting material
4.73 (s, 1H, CHCl), 3.46 (s, OH); 13C NMR (125 MHz, CDCl3): δ (TLC), the reaction was quenched with ethyl acetate (1 ×
134.48, 129.84, 129.07, 127.85, 116.91, 67.35 (CHOHCN), 63.02 10 mL). After extracting with ethyl acetate (3 × 25 mL), the
(CHCl); HRMS (ESI) Calc. for C9H8ClNaNO [M + Na]+ 204.0192, organic layer was dried over anhydrous Na2SO4, concentrated
found 204.0184.
in vacuo and purified by column chromatography (silica gel,
1-Phenylpropane-1,3-diol (1d).46 Transparent liquid; 1H 0–7% EtOAc–hexane) to get a mixture of (2R,3R/S)-diastereo-
NMR (200 MHz, CDCl3): δ 7.43–7.25 (m, 5H), 4.94–4.91 (q, J = mer as a colorless liquid in 85% yield (445 mg). This com-
8.8, 3.6 Hz, 1H), 3.83–3.81 (t, J = 6.4, 5.6 Hz, 2H), 2.02–1.88 (m, pound was transformed to diol (2R,3R/S)-1f according to the
2H); 13C NMR (125 MHz, CDCl3): δ 144.22, 128.35, 127.36, procedure described for 1g in 90% yield (299 mg) as a colorless
125.58, 73.56 (CHOH), 60.83 (CH2OH), 40.32; HRMS (ESI) Calc. liquid in a syn : anti ratio of 46 : 54; 1H NMR (400 MHz, CDCl3):
for C9H12NaO2 [M + Na]+ 175.0735, found 175.0730.
δ 7.47–7.21 (m, 10H), 4.33 (d, J = 6.1 Hz, 1H), 4.29 (d, J =
3-Chloro-3-phenylpropan-1-ol (2d). Prepared by the general 7.7 Hz, 1H), 3.81–3.59 (m, 4H), 3.53–3.26 (m, 6H), 1.18 (dt, J =
procedure of Mitsunobu chloride substitution; yield 65%; col- 7.0, 1.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 141.87, 141.53,
1
orless semi-solid; H NMR (400 MHz, CDCl3): δ 7.41–7.25 (m, 131.00, 130.69, 130.67, 85.42, 85.32, 78.66, 78.06, 67.92, 67.79,
5H), 5.14–5.11 (q, J = 9.2, 5.6 Hz, 1H, CHCl), 3.88–3.83 (m, 1H), 66.78 (CH2), 65.78 (CHOH), 65.22 (CH2OH), 17.79; HRMS (ESI)
3.74–3.70 (m, 1H), 2.34–2.23 (m, 2H), 1.85 (bs, OH); 13C NMR Calc. for C11H16NaO3 [M + Na]+ 219.0997, found 219.0988.
(125 MHz, CDCl3): δ 141.59, 128.75, 128.47, 127.06, 60.43
(CHCl), 59.78 (CHOH), 42.35 (CH2); HRMS (ESI) Calc. for the general procedure of Mitsunobu chloride substitution;
C9H11ClNaO [M + Na]+ 193.0396, found 193.0387. yield 97%; transparent liquid; syn : anti 46 : 54; 1H NMR
(2S)-1-Chloro-3-ethoxy-3-phenylpropan-2-ol (3f). Prepared by
3-Chloro-1-phenylpropan-1-ol (3d). Prepared by the general (400 MHz, CDCl3): δ 7.48–7.27 (m, 10H), 4.41 (d, J = 7.1 Hz,
procedure of Mitsunobu chloride substitution; yield 16%; col- 1H), 4.35 (d, J = 6.6 Hz, 1H), 3.93–3.88 (dd, J = 6.4, 4.1 Hz, 2H),
1
orless semi-solid; H NMR (400 MHz, CDCl3): δ 7.36–7.24 (m, 3.74–3.69 (m, 2H), 3.61–3.58 (dd, J = 4.0, 2.4 Hz, 1H), 3.47–3.34
5H), 4.94–4.90 (m, 1H, CHOH), 3.75–3.69 (m, 1H), 3.57–3.51 (m, 4H), 3.29–3.27 (dd, J = 4.6, 2.4 Hz, 1H), 1.19 (td, J = 7.0,
(m, 1H), 2.24–2.04 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 5.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 138.23, 128.52,
143.72, 128.68, 127.93, 125.79, 71.35 (CHOH), 41.71, 41.46 127.44, 82.06, 74.76, 74.57 (CHOH), 64.71 (CH2), 46.69
(CH2Cl); HRMS (ESI) Calc. for C9H11ClNaO [M + Na]+ 193.0396, (CH2OH), 45.26 (CH2Cl), 15.25; HRMS (ESI) Calc. for
found 193.0390.
C11H16ClO2 [M + H]+ 215.0839, found 215.0832.
(2S,3S)-1-Chloro-3-(2-ethoxyphenoxy)-3-phenylpropan-2-ol
4-Phenylbutane-1,3-diol (1e).47 Colorless semi-solid; 1H
NMR (200 MHz, CDCl3): δ 7.30–7.19 (m, 5H), 4.03–4.00 (d, J = (3g). Prepared by the general procedure of Mitsunobu chlor-
5.5 Hz, 1H, CH2OH), 3.84–3.73 (m, 2H), 3.06 (s, OH), 2.77–2.71 ide substitution; yield 98%; colorless oil; [α]2D5 = −44.2 (c 1.0,
(m, 2H), 1.69–1.66 (d, J = 4.7 Hz, 2H), 1.25 (s, OH); 13C NMR CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.49–4.47 (m, 2H),
(100 MHz, CDCl3): δ 138.40, 129.57, 128.63, 126.58, 72.59 7.40–7.37 (m, 3H), 6.96 (m, 1H), 6.88 (m, 1H), 6.69 (m, 1H),
(CHOH), 61.25 (CH2OH), 44.39, 37.89; HRMS (ESI) Calc. for 6.64 (m, 1H), 4.92 (d, J = 8.0 Hz, 1H), 4.42 (m, 1H), 4.15–4.11
C10H14NaO2 [M + Na]+ 189.0891, found 189.0886.
(m, 2H), 3.69–3.65 (dd, J = 11.6, 3.6 Hz, 1H), 3.28–3.24 (dd, J =
3-Chloro-4-phenylbutan-1-ol (2e). Prepared by the general 11.6, 4.0 Hz, 1H), 1.65 (s, OH) 1.51 (t, J = 7.1 Hz, 3H); 13C NMR
procedure of Mitsunobu chloride substitution; yield 64%; (100 MHz, CDCl3): δ 150.16, 147.86, 138.00, 128.71, 127.26,
semi-solid; 1H NMR (400 MHz, CDCl3): δ 7.32–7.21 (m, 5H), 123.84, 120.89, 120.10, 112.90, 86.64, 74.90 (CHOH), 64.28
4.33–4.30 (m, 1H, CHCl), 3.84–3.81 (m, 2H), 3.09–3.06 (q, J = (CH2), 45.15 (CH2Cl), 14.79; HRMS (ESI) Calc. for
7.2, 4.4 Hz, 2H), 2.08–2.02 (m, 1H), 1.89–1.81 (m, 1H), 1.66 (s, C17H19ClNaO3 [M + Na]+ 329.0920, found 329.0915.
OH); 13C NMR (125 MHz, CDCl3): δ 137.64, 129.64, 128.47,
126.88, 60.48 (CH2OH), 59.74 (CHCl), 45.21, 39.97; HRMS (ESI) Prepared by the general procedure of Mitsunobu chloride sub-
(S)-1-(Benzyl(2-hydroxyethyl)amino)-3-chloropropan-2-ol (3h).
Calc. for C10H13ClNaO [M + Na]+ 207.0553, found 207.0548.
stitution; yield 90%; light yellow oil; [α]2D5 = −15.5 (c 1.2,
4-Chloro-1-phenylbutan-2-ol (3e). Prepared by the general CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.35–7.26 (m, 5H),
procedure of Mitsunobu chloride substitution; yield 16%; 3.81–3.78 (m, 1H), 3.69–3.63 (m, 4H), 3.53–3.50 (q, J = 7.1, 5.5
semi-solid; 1H NMR (400 MHz, CDCl3): δ 7.33–7.29 (m, 2H), Hz, 2H), 2.72–2.67 (m, 4H), 1.25 (bs, OH); 13C NMR (125 MHz,
7.25–7.19 (m, 3H), 4.06–4.00 (m, 1H), 3.73–3.63 (m, 2H), CDCl3):
δ 138.78, 129.14, 129.00, 128.56, 127.54, 68.67
2.84–2.79 (dd, J = 13.6, 4.4 Hz, 1H), 2.70–2.64 (dd, J = 13.6, 8.8 (CHOH), 59.76, 57.52, 56.72, 47.35 (CH2Cl); HRMS (ESI) Calc.
Hz, 1H), 1.96–1.87 (m, 2H), 1.78 (s, OH); 13C NMR (100 MHz, for C12H19ClNO2 [M + H]+ 244.1104, found 244.1112.
CDCl3): δ 137.91, 129.47, 128.71, 126.74, 69.56 (CHOH), 44.08
6-Chloro-6-deoxy-3-O-benzyl-l,2-O-(l-methylethylidene)-
(CH2), 41.86 (CH2), 39.28 (CH2Cl); HRMS (ESI) Calc. for α-D-glucofuranose (3i). Prepared by the general procedure of
C10H13ClNaO [M + Na]+ 207.0553, found 207.0550.
Mitsunobu chloride substitution; yield 95%; semi-solid;
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[α]2D5 = −23 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ temperature, Me3SiCl (550 mg, 5.1 mmol) under nitrogen was
7.39–7.33 (m, 5H), 5.92–5.91 (d, J = 3.6 Hz, 1H), 4.73–4.70 (m, added using a syringe. The reaction mixture was stirred at
1H), 4.62–4.56 (m, 2H), 4.18–4.14 (m, 2H), 4.12–4.11 (d, J = room temperature for 3 h. After the completion of the reaction
2.4 Hz, 1H), 3.85–3.82 (m, 1H), 3.72–3.68 (dd, J = 11.2, 5.6 Hz, as indicated by TLC, pyridine (63 μL, 0.8 mmol) and acetic
1H), 2.42 (s, OH), 1.42 (s, 3H), 1.30 (s, 3H); 13C NMR anhydride (1.65 μL, 16.2 mmol) were added to the reaction
(100 MHz, CDCl3): δ 154.92, 137.25, 129.88, 128.49, 128.03, mixture. After the acetylation (6 h), the reaction was quenched
112.03, 105.22, 82.28, 81.61, 80.06, 72.34, 68.52, 48.36 (CH2Cl), with ethyl acetate (3 × 25 mL). The combined organic extracts
26.85, 26.34, 21.70; HRMS (ESI) Calc. for C16H22ClO5 [M + H]+ were washed with water (2 × 10 mL) and brine solution
329.1156, found 329.1113.
(1 × 5 mL), dried over anhydrous Na2SO4 and concentrated
6-Chloro-6-deoxy-l,2-O-(l-methylethylidene)-α-D-glucofuranose in vacuo. The residue was subjected to column chromatography
(3j). Prepared by the general procedure of Mitsunobu chloride (silica gel, 0–15% EtOAc–hexane) to obtain pure product 3n as
substitution; yield 85%; semi-solid; [α]2D5 = +3.8 (c 1.5, CHCl3); a viscous liquid in 90% yield (1.216 g); [α]2D5 = +30.6 (c 1.0,
1
1H NMR (400 MHz, CDCl3): δ 5.90–5.86 (dd, J = 14.4, 3.6 Hz, CHCl3); H NMR (400 MHz, CDCl3): δ 5.27–5.24 (m, 1H), 5.21
1H), 4.48–4.47 (q, J = 5.2, 4.0 Hz, 1H), 4.32–4.25 (m, 2H), (d, J = 9.4 Hz, 1H), 5.19–5.15 (m, 1H), 4.65 (d, J = 1.7 Hz, 1H),
4.13–4.05 (m, 1H), 3.98–3.90 (dd, J = 11.6, 4.7 Hz, 1H), 3.96–3.81 (m, 1H), 3.78–3.67 (dd, J = 5.2, 1.7 Hz, 1H), 3.63–3.52
3.92–3.85 (dd, J = 20.0, 4.6 Hz, 1H), 3.15 (s, OH), 1.63 (s, 3H), (dd, J = 5.3, 1.7 Hz, 1H), 3.35 (s, 3H), 2.12–1.96 (3 × s, 9H); 13C
1.50 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 111.59, 105.30, NMR (100 MHz, CDCl3): δ 170.43, 169.21, 98.39, 69.99, 69.70,
85.19, 81.44, 74.37, 68.60, 47.99 (CH2Cl), 26.93, 26.36; HRMS 68.82, 65.95, 55.09, 44.45 (CH2Cl), 22.15; HRMS (ESI) Calc. for
(ESI) Calc. for C9H16ClO5 [M + H]+ 239.0686, found 239.0680.
C13H20ClO8 [M + H]+ 339.0847, found 339.0842.
6-Chloro-6-deoxy-2,3-O-(l-methylethylidene)-1-O-acetyl-
(S)-2-((1,4-Dioxaspiro[4.5]decan-2-ylmethyl)amino)ethanol
α-D-mannofuranose (3k). Prepared by the general procedure of (20). In a solution comprising 2,3-O-cyclohexylideneglycer-
Mitsunobu chloride substitution; yield 95%; white solid; aldehyde 14 (850 mg, 5 mmol) and ethanol amine (366 mg,
1
mp. 83–85 °C; [α]2D5 = +13.5 (c 1.4, CHCl3); H NMR (400 MHz, 6 mmol) dissolved in methanol (30 mL) was slowly added
CDCl3): δ 6.42 (bs, OH), 6.19 (s, 1H), 4.99–4.92 (m, 1H), 4.72 NaBH4 (95 mg, 2.5 mmol), and the mixture was stirred over-
(dd, J = 5.8, 3.5 Hz, 1H), 4.17–4.08 (m, 2H), 3.87–3.84 (dd, J = night at room temperature. After the completion of the reac-
11.4, 3.1 Hz, 1H), 3.72–3.69 (dd, J = 11.4, 5.9 Hz, 1H), 2.06 (s, tion (TLC), the methanol was evaporated and the residue was
3H), 1.68 (s, OH), 1.47 (s, 3H), 1.34 (s, 3H); 13C NMR extracted with ethyl acetate (3 × 25 mL) and washed with brine
(125 MHz, CDCl3): δ 169.40, 113.45, 100.60, 84.88, 81.41, solution (1 × 5 mL) and the organic layer was dried over anhy-
79.53, 69.15, 47.78 (CH2Cl), 26.01, 24.75, 21.02; HRMS (ESI) drous Na2SO4 to obtain the crude product 20, which was puri-
Calc. for C11H18ClO6 [M + H]+ 281.0792, found 281.0789.
Methyl
6-chloro-6-deoxy-2,3-di-O-acetyl-α-D-mannopyrano- hexane) in 94% yield (1.01 g) as a colorless oil; [α]D25 = −9.1
side (3l). Prepared by the general procedure of Mitsunobu (c 1.0 CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.26–4.24 (t, J =
chloride substitution; yield 94%; colorless semi-solid; [α]D25
11.8, 5.9 Hz, 1H), 4.06–4.03 (q, J = 7.9, 6.7 Hz, 1H), 3.68–3.64
fied by column chromatography (silica gel, 0–20% EtOAc–
=
+89.6 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3): δ 5.31–5.28 (t, (m, 3H), 2.82–2.79 (q, J = 9.65, 4.71 Hz, 1H), 2.78–2.75 (q, J =
J = 19.20, 9.18 Hz, 1H), 4.94–4.93 (d, J = 3.62 Hz, 1H), 4.86–4.84 11.87, 5.52 Hz, 3H), 1.62–1.55 (m, 8H), 1.42–1.37 (m, 2H); 13C
(m, 1H), 3.91–3.87 (m, 1H), 3.81–3.77 (dd, J = 11.9, 5.7 Hz, 1H), NMR (125 MHz, CDCl3): δ 109.72, 74.70, 67.01, 60.67, 52.22,
3.68–3.62 (m, 2H), 3.43 (s, 3H), 2.10–2.06 (m, 6H); 13C NMR 51.21, 36.33, 34.80, 24.86, 23.87, 23.75; HRMS (ESI) Calc. for
(125 MHz, CDCl3): δ 171.43, 170.27, 96.55, 72.72, 70.53, 69.76, C11H21NNaO3 [M + Na]+ 238.1419, found 238.1411.
55.08, 44.00 (CH2Cl), 20.63, 20.50; HRMS (ESI) Calc. for
(S)-2-((1,4-Dioxaspiro[4.5]decan-2-ylmethyl)(benzyl)amino)-
ethanol (21). K2CO3 (137 mg, 3.6 mmol) was added to the
C11H18ClO7 [M + H]+ 297.0741, found 297.0738.
Thiophenyl 6-chloro-6-deoxy-2,3-di-O-acetyl-β-D-galactopyra- amino alcohol (S)-20 (262 mg, 1.2 mmol) dissolved in aceto-
noside (3m). Prepared by the general procedure of Mitsunobu nitrile (20 mL), followed by the addition of benzyl bromide
chloride substitution; yield 94%; colorless viscous liquid; [α]2D5 (209 mg, 1.2 mmol) after 20 minutes. The reaction mixture
1
= +4.5 (c 1.3, CHCl3); H NMR (500 MHz, CDCl3): δ 7.51–7.47 was stirred at room temperature for 8 h. After the consumption
(m, 3H), 7.28–7.26 (m, 2H), 5.26 (d, J = 4.0 Hz, 1H), 4.99–4.96 of the starting material, the reaction mixture was concentrated
(dd, J = 11.2, 5.7 Hz, 1H), 4.77–4.71 (d, J = 9.3 Hz, 1H), under reduced pressure and the residue was dissolved in water
4.35–4.28 (m, 1H), 3.96 (m, 1H), 3.92–3.81 (m, 1H), 3.71–3.68 (1 × 20 mL) and extracted with EtOAc (3 × 20 mL). The organic
(m, 1H), 2.09 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 170.32, layer was dried over anhydrous Na2SO4 and concentrated
170.28, 134.45, 132.09, 131.70, 128.54, 127.42, 126.23, 86.18, in vacuo. Purification of the residue by column chromato-
78.04, 76.23, 73.16, 68.86, 45.68 (CH2Cl), 20.30, 20.08; HRMS graphy (silica gel, 0–10% EtOAc–hexane) afforded (S)-21 in
(ESI) Calc. for C16H20ClO6S [M + H]+ 375.0669, found 375.0661. 95% yield (353 mg) as a colorless liquid; [α]D25 = +11.5 (c 1.0,
1
Methyl 6-chloro-6-deoxy-2,3,4-tri-O-acetyl-α-D-mannopyrano- CHCl3); H NMR (500 MHz, CDCl3): δ 7.36–7.26 (m, 5H), 4.22
side (3n). A mixture of methyl-α-D-mannopyranoside (776 mg, (m, 1H), 3.99 (m, 1H), 3.77–3.57 (m, 4H), 3.48–3.43 (m, 1H),
4.0 mmol) and Ph3P (1.36 g, 5.2 mmol) in toluene (20 mL) was 2.75–2.64 (m, 4H), 1.56 (m, 8H), 1.28 (s, 2H); 13C NMR
partially dissolved on warming and DIAD (1.19 g, 5.9 mmol) (125 MHz, CDCl3): δ 138.87, 128.45, 128.05, 127.33, 109.72,
was slowly added at 0 °C. After stirring for 15 minutes at this 76.67, 69.34, 65.45, 62.69, 56.98, 55.67, 36.67, 34.77, 24.56,
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23.67, 23.22; HRMS (ESI) Calc. for C18H28NO3 [M + H]+
306.2069, found 306.2057.
(2R,3R)-1,2-O-Cyclohexylidene-3-phenylpropane-3-ol
(15).
Yield 47%; colorless oil; [α]2D5 = +7.8 (c 1.0, CHCl3); {lit.49 for
(S)-3-(Benzyl(2-hydroxyethyl)amino)propane-1,2-diol (1h). A the (2R,3R/S) mixture, [α]2D2 = +11.0 (c 0.6, CHCl3)}; 1H NMR
mixture of (S)-21 (389 mg, 1.27 mmol) and PTSA (44 mg, (500 MHz, CDCl3): δ 7.49–7.43 (m, 5H), 5.05 (d, J = 4.4 Hz, 1H),
20 mol%) in MeOH (20 mL) was stirred at 50 °C until the start- 4.45–4.41 (m, 1H), 4.08–4.04 (m, 1H), 3.85–3.81 (m, 1H), 2.6 (s,
ing material disappeared (as monitored by TLC, 8 h). The OH), 1.80–1.65 (m, 10H); 13C NMR (125 MHz, CDCl3): δ 138.77,
mixture was concentrated in vacuo, treated with water (1 × 127.53, 127.19, 126.69, 125.99, 124.98, 109.06, 78.08, 71.61,
20 mL) and extracted with EtOAc (3 × 20 mL). A NaHCO3 solu- 63.12, 35.18, 33.66, 24.13, 23.03, 22.82; HRMS (ESI) Calc. for
tion (10%, 20 mL) was added to remove the excess PTSA. The C15H20NaO3 [M + Na]+ 271.1310, found 271.1306.
combined organic extracts were washed with brine solution
(2R,3S)-1,2-O-Cyclohexylidene-3-phenylpropane-3-ol
(15).
(1 × 10 mL), dried over anhydrous Na2SO4 and concentrated Yield 47%; colorless oil; [α]2D5 = −5.6 (c 1.5, CHCl3); 1H NMR
in vacuo. The residue was subjected to column chromato- (500 MHz, CDCl3): δ 7.41–7.31 (m, 5H), 4.90 (d, J = 8.4 Hz, 1H),
graphy (silica gel, 0–30% EtOAc–hexane) to obtain pure 3.89–3.85 (m, 2H), 3.64–3.61 (m, 1H), 2.06 (s, OH), 1.74–1.63
product (S)-1h in 92% yield (264 mg) as a colorless oil; [α]D25
=
(m, 8H), 1.54–1.40 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
−20.5 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.34–7.24 137.98, 128.52, 128.15, 126.47, 109.76, 83.19, 78.22, 60.33,
(m, 5H), 3.80–3.72 (m, 2H), 3.65–3.57 (m, 4H), 3.54–3.42 (dd, 36.67, 36.54, 25.01, 23.74; HRMS (ESI) Calc. for C15H20NaO3
J = 11.5, 5.4 Hz, 1H), 3.24 (bs, OH), 2.81–2.54 (m, 4H); [M + Na]+ 271.1310, found 271.1302.
13C NMR (125 MHz, CDCl3): δ 138.14, 129.13, 128.50, 127.44,
(2R,3R)-1,2-O-Cyclohexylidene-3-acetoxy-3-phenylpropane (16).
69.01, 64.74, 59.68, 56.57, 56.24; HRMS (ESI) Calc. for Diisopropyl azodicarboxylate (DIAD) (1.22 g, 6.0 mmol) at 0 °C
C12H20NO3 [M + H]+ 226.1443, found 226.1438.
was injected into a mixture of (2R,3S)-1,2-O-cyclohexylidene-3-
2,3-O-Cyclohexylidene-D-glyceraldehyde (14). To sodium phenylpropane-3-ol 15 (992 mg, 4.0 mmol), Ph3P (1.32 g,
metaperiodate (NaIO4) (7.3 g, 34 mmol) and tetrabutyl- 5.2 mmol) and acetic acid (368 μL, 6.0 mmol) in anhydrous
ammonium bromide (PTC) (200 mg, 0.62 mmol) in water THF (20 mL) for 10 minutes under a nitrogen atmosphere. The
(60 mL) was added a solution of 1,2,5,6-di-O-cyclohexylidene-D- reaction mixture was stirred at room temperature for 14 h.
mannitol (10.0 g, 29.3 mmol) in THF (100 mL), and the After the completion of the reaction as indicated by TLC, it
mixture was stirred for 3 h at room temperature. After the com- was extracted with ethyl acetate (3 × 20 mL). The combined
pletion of the reaction, the organic layer was separated and the organic extracts were washed with water (2 × 10 mL) and brine
aqueous layer was extracted with diethyl ether (3 × 35 mL). The solution (1 × 5 mL), dried with anhydrous Na2SO4 and concen-
combined diethyl ether solution was washed with water (1 × trated in vacuo. The residue was subjected to column
35 mL) and dried over anhydrous sodium sulfate. The solvent chromatography (silica gel, 0–7% EtOAc–hexane) to obtain
was dried in vacuo to yield the title compound (R)-14 in 90% pure acetate (2R,3R)-16 in 75% yield (870 mg), as a colorless
1
yield (8.94 g) as a colorless viscous liquid; bp. 90–94 °C oil; [α]2D5 = +11.5 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ
(2 mmHg) [lit.48 90–93 °C (2 mmHg)] [α]2D5 = +61.2 (c 3.4, 7.36–7.30 (m, 5H), 5.87 (d, J = 5.6 Hz, 1H), 4.35–4.31 (q, J =
benzene); 1H NMR (500 MHz, CDCl3): δ 9.7 (s, 1H), 4.40 (m, 12.0, 6.1 Hz, 1H), 3.99–3.92 (m, 2H), 2.11 (s, 3H), 1.65–1.52 (m,
1H), 4.22–3.90 (m, 2H), 1.80–1.43 (m, 10H); 13C NMR 10H); 13C NMR (100 MHz, CDCl3): δ 169.67, 136.92, 128.56,
(125 MHz, CDCl3): δ 202.15 (CHO), 110.65, 98.39, 65.70, 36.15, 127.52, 126.65, 110.48, 77.47, 74.95, 65.36, 36.07, 35.04, 25.09,
34.72, 25.00, 23.80; HRMS (ESI) Calc. for C9H15O3 [M + H]+ 23.77, 21.06; HRMS (ESI) Calc. for C17H22NaO4 [M + Na]+
171.1021, found 171.1019.
313.1416, found 313.1411.
(2R,3R/S)-1,2-O-Cyclohexylidene-3-phenylpropane-3-ol (15).
Synthesis of (2R,3R)-1,2-O-cyclohexylidene-3-phenylpropane-
Bromobenzene (452 mg, 2.92 mmol) was added dropwise over 3-ol (15) from (2R,3R)-16. The compound (2R,3R)-16 (580 mg,
45 minutes at room temperature under nitrogen in the pres- 2 mmol) was dissolved in THF–H2O (1 : 1 ratio), and lithium
ence of a crystal of I2 to magnesium turnings (75 mg, hydroxide (144 mg, 6 mmol) was added. The reaction mixture
2.92 mmol) placed in a reaction vessel comprising 60 mL was stirred for 3 h until the hydrolysis was complete. The reac-
anhydrous THF. After the generation of the Grignard reagent, tion was extracted with ethyl acetate (3 × 20 mL). The com-
the solution was cooled to −10 °C and cyclohexylideneglycer- bined organic extracts were washed with brine solution (1 ×
aldehyde (124 mg, 0.73 mmol) in THF (20 mL) was added
5 mL), dried with anhydrous Na2SO4 and concentrated
dropwise to the reaction mixture. The reaction mixture was in vacuo to get the pure (2R,3R)-15 in 97% yield (481 mg) as a
stirred at room temperature for 18 h and then cooled at 0 °C colorless liquid; HRMS (ESI) Calc. for C15H20NaO3 [M + Na]+
before the addition of saturated aqueous NH4Cl. The mixture 271.1310, found 271.1303.
was extracted three times with EtOAc (3 × 40 mL). The extracts
(2R,3S)-3-(2-Ethoxyphenoxy)-1,2-O-cyclohexylidene-3-phenyl-
were combined and dried over anhydrous Na2SO4 and the propane (17). Diisopropyl azodicarboxylate (DIAD) (490 mg,
solvent was evaporated under reduced pressure to get a 2.43 mmol) was added to a mixture of (2R,3R)-15 (300 mg,
mixture of syn- and anti-diastereomers in 95% total yield 1.21 mmol), triphenylphosphine (636 mg, 2.43 mmol) and
(687 mg). The crude products were purified by column chrom- 2-ethoxyphenol (335 mg, 2.43 mmol) in anhydrous THF
atography (silica gel, 0–15% EtOAc–hexane) to provide (2R,3R)- (15 mL) at 0 °C. The reaction mixture was allowed to reach
15 (46%) and (2R,3S)-15 (46%) as colourless oils.
room temperature and stirred for 24 h. After the completion of
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the reaction (TLC), the extraction was done with ethyl acetate 1.21 mmol) and triphenylphosphine (636 mg, 2.43 mmol) in
(3 × 30 mL). The organic layer was washed with water, dried anhydrous THF (15 mL) at 0 °C. The reaction mixture was
over anhydrous Na2SO4, and concentrated under reduced stirred for 24 h at room temperature. After the completion of
pressure and the crude product was purified by column the reaction (TLC), the extraction was done with ethyl acetate
chromatography (silica gel, 0–8% EtOAc–hexane) to provide (3 × 30 mL) and the solvent was dried over anhydrous Na2SO4.
(2R,3S)-17 in 85% yield (378 mg) as a colorless oil; [α]D25
=
The crude product was concentrated under reduced pressure
−12.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.34 (m, and purified by column chromatography (silica gel, 0–6%
2H), 7.32–7.27 (m, 3H), 6.85–6.81 (m, 2H), 6.78–6.65 (m, 2H), EtOAc–hexane) to provide (2S,3S)-4g in 65% yield (212 mg) as a
5.17 (d, J = 6.2 Hz, 1H), 4.57 (q, J = 6.6 Hz, 1H), 4.08–4.04 (m, colorless oil; the spectral data are the same as reported in ref.
2H), 3.84–3.78 (dd, J = 16.4, 8.5 Hz, 2H), 1.61–1.54 (m, 10H), 50. HRMS (ESI) Calc. for C17H18NaO3 [M + Na]+ 293.1156,
1.45–1.38 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 150.01, found 293.1151.
147.90, 137.67, 128.15, 127.53, 127.12, 122.27, 120.90, 118.40,
{[(2R,3S)-3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenyl-propyl]-
114.51, 110.52, 82.65, 78.23, 65.40, 64.73, 35.90, 35.27, 25.16, amino}ethyl hydrogen sulfate-((2R,3S)-18). Compound 18 was
23.86, 14.95; HRMS (ESI) Calc. for C23H28NaO4 [M + Na]+ prepared by following the procedure reported in ref. 39b in
391.1885, found 391.1891.
78% yield. The spectral data are the same as reported in ref.
(2R,3S)-3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenyl-1-propanol 39b. HRMS (ESI) Calc. for C19H25NNaO6S [M + H]+ 418.1300,
(1g). A mixture of (2R,3S)-17 (467 mg, 1.27 mmol) and PTSA found 418.1285.
(44 mg, 20 mol%) in MeOH (30 mL) was stirred at 50 °C until
{[(2S,3S)-3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenyl-propyl]-
the starting material disappeared (as monitored by TLC, 8 h). amino}ethyl hydrogen sulfate-((2S,3S)-18). Compound 18 was
The mixture was concentrated in vacuo and extracted with prepared by following the procedure reported in ref. 39b in
EtOAc (3 × 25 mL). A NaHCO3 solution (20%, 20 mL) was 78% yield. The spectral data are the same as reported in the lit-
added to remove the excess PTSA, and the solvent was dried erature. HRMS (ESI) Calc. for C19H25NNaO6S [M + H]+
over anhydrous Na2SO4 and concentrated in vacuo. The residue 418.1300, found 418.1291.
was subjected to column chromatography (silica gel, 0–30%
(2R,3S)-2-[α-(2-Ethoxyphenoxy)phenylmethyl]morpholine
EtOAc–hexane) to obtain pure 1g in 94% yield (343 mg) as a ((2R,3S)-19). NaOH (117 mg, 3 mmol) was added to a solution
white crystalline solid; mp. 73–75 °C; [α]2D5 = +6.4 (c 1.0, of (2R,3S)-18 (417 mg, 1 mmol) in THF (17 mL) and EtOH
ethanol); {lit.;50 mp. 78–79 °C; [α]2D5 = +7.8 (c 1.0, ethanol)}; (1.21 mL) at room temperature. The reaction mixture was
1H NMR (400 MHz, CDCl3): δ 7.46 (m, 1H); 7.41–7.33 (m, 4H), heated to reflux for 3 h and cooled to room temperature. The
6.96 (m, 1H), 6.89 (m, 1H), 6.74 (m, 1H), 6.63 (m, 1H), 4.87 reaction was quenched with water (1 × 20 mL) and extracted
(d, J = 8.0 Hz, 1H), 4.14 (m, 2H), 4.01 (m, 1H), 3.65 (m, 1H), with ethyl acetate (3 × 25 mL). The organic layer was dried over
3.42 (m, 1H), 1.51 (m, 3H); 13C NMR (125 MHz, CDCl3): anhydrous Na2SO4, concentrated in vacuo, and purified by
δ 149.61, 147.80, 138.27, 129.56, 128.20, 127.09, 123.10, column chromatography (silica gel, 0–20% EtOAc–hexane) to
120.81, 119.05, 112.66, 86.21, 75.51, 64.14, 62.03, 14.01; HRMS provide (2R,3S)-reboxetine 19 in 90% yield (281 mg) as a color-
(ESI) Calc. for C17H20NaO4 [M
311.1262.
+
Na]+ 311.1259, found less oil; [α]D25 = +11.6 (c 1.0, CHCl3); [lit.39a [α]D25 = +16.0 (c 0.68,
CH2Cl2)]; 1H NMR (400 MHz, CDCl3): δ 7.48 (m, 2H), 7.45–7.30
(2R,3S)-3-(2-Ethoxyphenoxy)-3-phenylpropene-1,2-epoxide (m, 3H), 6.87 (m, 1H), 6.81 (m, 2H), 6.60 (m, 1H), 5.23 (d, J =
((2R,3S)-4g). DBU (148 mg, 0.98 mmol) at 0 °C was added to 6.4 Hz, 1H), 4.15 (m, 2H), 3.65 (m, 1H), 3.34 (m, 1H), 2.90–2.83
the solution of chlorohydrin (2S,3S)-3g (100 mg, 3.3 mmol) in (m, 3H), 2.65 (m, 2H), 1.45 (t, J = 7.5 Hz, 3H); 13C NMR
DCM (15 mL) and the reaction was stirred at room temp- (125 MHz, CDCl3): δ 150.92, 148.71, 138.64, 129.32, 128.63,
erature. After the consumption of the starting material as 124.52, 121.92, 118.92, 114.51, 84.41, 79.82, 67.02, 65.73,
indicated by TLC (6–7 h), the reaction was extracted with DCM 47.81, 46.50, 15.36; HRMS (ESI) Calc. for C19H23NNaO3 [M +
(3 × 20 mL). The organic layer was dried over anhydrous Na]+ 336.1576, found 336.1572.
Na2SO4 and concentrated in vacuo to obtain the pure epoxide
(2S,3S)-2-[α-(2-Ethoxyphenoxy)phenylmethyl]morpholine
(2R,3S)-4g in 98% yield (86 mg) as a colorless oil; [α]2D5 = −10.8 ((2S,3S)-19). The compound (2S,3S)-19 was prepared by fol-
(c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.44 (m, 2H), lowing the procedure described for (2R,3S)-19 in 90% yield
7.37–7.30 (m, 3H), 6.89–6.86 (m, 3H), 6.78–6.75 (m, 1H), 4.91 (281 mg) as a colorless oil; the spectral data are the same as
(d, J = 6.0 Hz, 1H), 4.11–4.06 (q, J = 14.0, 7.2 Hz, 2H), 3.46 (m, reported in ref. 39f. HRMS (ESI) Calc. for C19H23NNaO3
1H), 2.82–2.80 (t, J = 8.8, 4.4 Hz, 1H), 2.72–2.71 (q, J = 4.8, [M + Na]+ 336.1576, found 336.1568.
2.8 Hz, 1H), 1.42 (t, J = 6.7 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 149.96, 147.80, 137.73, 130.03, 128.10, 126.83,
122.80, 120.98, 118.35, 114.24, 83.30, 64.77, 55.10, 44.65,
Acknowledgements
14.96; HRMS (ESI) Calc. for C17H18NaO3 [M + Na]+ 293.1156,
found 293.1148.
The authors (AR, MAA and BK) thank UGC and CSIR, New
(2S,3S)-3-(2-Ethoxyphenoxy)-3-phenylpropene-1,2-epoxide Delhi for the award of senior fellowships. The authors are
((2S,3S)-4g). Diisopropyl azodicarboxylate (DIAD) (490 mg, declaring the institutional Publication Number IIIM/1583/
2.43 mmol) was added to a mixture of (2R,3S)-1g (348 mg, 2013.
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