Application of Unusual Grignard Reaction for the Stereoselective Synthesis of Antidepressant Drug (R)-(-)-Venlafaxine

Article abstract of DOI:10.1055/s-0036-1588911

An enantioselective synthesis of antidepressant drug (R)-(-)-venlafaxine is accomplished as an application of recently explored unusual Grignard reaction. An innovative method for the generation of chirality at extremely reactive benzylic center along with determination of absolute stereochemistry has been discussed. The key steps involved in the synthesis include Sharpless asymmetric dihydroxylation for the induction of chirality and an unusual Grignard reaction.

Full text of DOI:10.1055/s-0036-1588911

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
S. P. Chavan, H. S. Khatod
Paper
Synthesis
Application of Unusual Grignard Reaction for the Stereoselective
Synthesis of Antidepressant Drug (R)-(–)-Venlafaxine
Subhash P. Chavan*
N
Harshali S. Khatod
HO
OH
HO
Division of Organic Chemistry, CSIR-National
Chemical Laboratory, Dr. Homi Bhabha Road,
Pashan, Pune 411 008, India
HO
O
O
( )-venlafaxine
sp.chavan@ncl.res.in
( )
O
O
N
OH
OH
OH
(2R,3S)
O
OH
(2R,3S)
O
O
(R)-(–)-venlafaxine
Received: 18.10.2016
Accepted after revision: 20.10.2016
Published online: 28.11.2016
Hamilton depression rating scale and clinical global impres-
sion. Venlafaxine was among the best-sold antidepressants
in the world during the period ranging from 2008 to 2010.4
Venlafaxine possesses a chiral center at the benzylic po-
sition, a tertiary amine, and a tertiary hydroxy group, hence
is a representative of phenylethylamine class of antidepres-
sants, which have a distinctive structure. Since past few
years our lab is one of the most active group in the synthe-
sis of venlafaxine5 although over period of time many total
syntheses of this drug featuring racemic as well as chiral
synthesis were reported in the literature.6 The synthesis of
(S)-venlafaxine was reported by Davies et al. employing
Rh-catalyzed intermolecular C–H activation reaction. Later
Nanda et al. reported the synthesis of both the enantiomers
by employing lipase-catalyzed enzymatic kinetic resolu-
tion.7 Recently, two asymmetric syntheses using organocat-
alytic Michael addition reaction by using L-proline based
organocatalyst and Sharpless asymmetric epoxidation reac-
tion approach were reported by our group.8 We report here
the synthesis of (R)-(–)-venlafaxine as an application of
diastereoselective unusual Grignard reaction.9
In continuation of the ongoing research towards the en-
antioselective synthesis of venlafaxine, chirality induction
was planned by means of Sharpless asymmetric dihydrox-
ylation (Scheme 1, route 1). As per our reterosynthetic anal-
ysis, (R)-(–)-venlafaxine (1′) can be accessed from com-
pound 2 by displacing the tosyl group with dimethylamine.
The tosylate can be easily prepared from compound 3 by
hydrogenolysis at the benzylic center. The tricyclic com-
pound 3 can be synthesized from the acetonide protected
ester 4 by means of Grignard reaction with 1,5-(dibromo-
magnesio)pentane.5d The optically active ester 4 in turn can
be obtained by exomethylenation followed by Sharpless
asymmetric dihydroxylation of the methyl ester of p-meth-
oxyphenylacetic acid.
DOI: 10.1055/s-0036-1588911; Art ID: ss-2016-z0449-op
Abstract An enantioselective synthesis of antidepressant drug (R)-(–)-
venlafaxine is accomplished as an application of recently explored un-
usual Grignard reaction. An innovative method for the generation of
chirality at extremely reactive benzylic center along with determination
of absolute stereochemistry has been discussed. The key steps involved
in the synthesis include Sharpless asymmetric dihydroxylation for the
induction of chirality and an unusual Grignard reaction.
Key words antidepressant drug, unusual Grignard reaction, Sharpless
asymmetric dihydroxylation, reductive dehydroxylation
WHO reported that in the year 2002 among all diseases,
depression was the third leading cause of burden, which is
expected to show a rising trend during the next 20 years.1
Venlafaxine (1) is a modern age ‘in practice’ antidepressant
drug. It is licensed for the treatment of depression, panic
disorder, social phobia, anxiety, and vasomotor symptoms
as it works by altering unbalanced chemicals in brain. It is
marketed in the racemic form under trade names Effexor or
Effexor XR – XR for the extended release dosing property. It
shows minimum protein binding property as compared to
other antidepressants, hence is activity-specific and
demonstrates significantly minimum risk of side effects.2 It
inhibits reuptake of biogenic amines like serotonin and nor-
epinephrine, hence called as serotonin norepinephrine re-
uptake inhibitor (SNRI). (S)-Venlafaxine is a selective sero-
tonin reuptake inhibitor whereas (R)-venlafaxine is more
selective towards the norepinephrine transporter.3 Under
placebo-controlled clinical trials, the efficacy of venlafaxine
was shown to be significantly superior to placebo on the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
S. P. Chavan, H. S. Khatod
Paper
Synthesis
O
O
HO
O
route 1
OTs
N
O
O
3
OH
O
HO
O
O
O
O
( )-4
OH
(R)-4'
( )-2
(R)-2'
( )-venlafaxine (1)
(R)-(–)-venlafaxine (1')
route 2
OH
O
O
13
O
O
Scheme 1 Retrosynthetic analysis of venlafaxine
Before undertaking the asymmetric synthesis and to
optimize the proposed sequence of reactions, we first exe-
cuted the racemic synthesis of venlafaxine. When the ace-
tonide 4 was treated with the Grignard reagent prepared
from 1,5-dibromopentane, surprisingly it did not furnish
the desired addition product 3, instead formation of com-
pound 7 was observed in excellent yield and diastereoselec-
tivity (Scheme 2).9
With this secondary alcohol 7 in hand it was decided to
proceed towards synthesis of target molecule. IBX oxidation
of 7 gave the desired ketone 8 in 89% yield. Compound 8 on
treatment with vinylmagnesium bromide furnished alcohol
9 in 85% yield and not completely separable diastereomeric
mixture. As there is need to destroy the newly generated
chiral center in the next step of the synthesis, no attempt
was made to separate the diastereomers. The compound 9
was subjected to ring-closing metathesis in the presence of
the Grubbs’ first-generation catalyst to furnish cyclohexene
10, which was reduced under hydrogenation conditions to
afford the reduced product 3 in 95% yield (Scheme 3).
Compound 3 when refluxed in the presence of catalytic
p-TSA in THF as a solvent for one hour gave the acetonide
deprotected triol 11. Encouraged by our previous results
obtained in the case of enantioselective hydrogenolysis10 at
benzylic center in the total synthesis of optically active ar-
himachalene, this triol 11 was subjected to hydrogenation
reaction. Different hydrogenating reagents were tried for
conversion of compound 11 into compound 12 (Table 1). It
was found that by using Raney Ni, Pd/C, and Pearlman’s cat-
alyst, etc. the starting material (SM) was recovered un-
changed. Then, ionic hydrogenation employing triethylsi-
lane in the presence of catalytic BF3·OEt2 was performed to
furnish the product 12. Since ionic conditions lead to the
formation of carbocation, the expected product was pre-
dicted to be racemic.10 The primary hydroxy group in com-
pound 12 was selectively protected as its tosylate on treat-
ment with tosyl chloride in the presence of Et3N to furnish
Table 1 Conversion of Compound 11 into Compound 12
Entry Reagent
Hydrogenation conditions Time (h)
Yield (%)
1
2
3
4
5
7
Raney Ni
Pd/C
EtOH, reflux
H2, EtOH
3
10
12
SM
SM
Pd/C
H2, EtOH, reflux
H2, EtOH
SM
Pd(OH)2
Pd(OH)2
cat. BF3·OEt2
6–8
SM
H2, EtOH, reflux
Et3SiH, r.t./0 °C
4
SM
3/5
62/55
O
O
O
O
O
O
1,5-dibromopentane
O
HO
OH
Mg, THF, 0 °C, r.t.
O
O
O
O
7 (99%), dr >9:1
observed product
3
4
expected product
Scheme 2 Observation of unusual Grignard reaction9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
S. P. Chavan, H. S. Khatod
Paper
Synthesis
O
O
O
MgBr, THF
O
IBX, EtOAc
reflux, 3 h
O
0 °C to r.t., 3 h
(85%)
OH
O
O
(89%)
8
7
O
O
O
O
O
O
H2, Pd/C
Grubbs I
OH
HO
HO
O
EtOH, 2 h
(95%)
CH2Cl2, 2 h
(92%)
O
O
9
3
10
OH
OH
HO
TsCl, Et3N
HO
Table 1
THF–H2O, pTSA
DMAP (cat.), CH2Cl2
(88%)
HO
O
reflux, 1 h
(90%)
O
12
11
N
O
OH
O
S
O
aq Me2NH
r.t., 10 h
(70%)
O
HO
O
( )-venlafaxine (1)
2
Scheme 3 Synthesis of (±)-venlafaxine
the corresponding tosyl alcohol 2, which on displacement
with aqueous dimethylamine at room temperature for 10
hours afforded (±)-venlafaxine (1) (Scheme 3).
mation involved formation of benzylic carbocation, deoxy-
genated product 13 was obtained with excellent diastereo-
selectivity and enantioselectivity (96% ee).11 The primary
alcohol in 13 was selectively protected as its TBDMS ether
to furnish compound 14.
The disappointment in achieving asymmetric hydroge-
nolysis for the synthesis of venlafaxine along with the moti-
vating observation of diastereoselective unusual Grignard
reaction, prompted us to revise the retrosynthetic analysis
(Scheme 1, route 2). As the steric crowding around benzylic
hydroxy in compound 11 was the suspected reason for the
failure of enantioselective hydrogenolysis reaction, it was
planned to reduce benzylic hydroxy functionality at an ear-
lier stage of the synthesis of (R)-(–)-venlafaxine (1′). Ac-
cordingly, diol 13 could be obtained by unusual Grignard
reaction with the acetonide protected ester (R)-4′ followed
by reductive dehydroxylation at benzylic position. The chi-
ral ester (R)-6′ could be obtained by Sharpless asymmetric
dihydroxylation.
Accordingly, the exomethylene compound 5 was then
subjected to Sharpless asymmetric dihydroxylation by em-
ploying (DHQD)2PHAL as the chiral catalyst to furnish diol
(R)-6′ in 85% yield and in 99% ee (Scheme 4). The diol (R)-6′
was protected as its acetonide and then subjected to the
unusual Grignard reaction to furnish (R)-7′ with >98% ee,
which proves that the Grignard reaction was highly diaste-
reoselective as well as enantioselective. Deoxygenation of
tertiary alcohol in (R)-7′ using triethylsilane and catalytic
BF3·OEt2 was carried out at –40 °C. Although this transfor-
The syn relative configuration in compound 14 was de-
termined by inverting the free secondary hydroxyl chiral
center by treatment under Mitsunobu reaction conditions12
as well as by preparation of acetonide compounds 19 and
20, furthermore comparing reported literature for similar
compounds (Scheme 5,Table 2).13 The absolute stereochem-
istry at benzylic position was established based on the rela-
tive stereochemistry with respect to the secondary alcohol,
1
after careful H NMR analysis of both the enantiomers of
Mosher’s esters prepared from compound 14, which was
assigned to be ‘R’.14 This established that the transformation
of compound (R)-7 to compound (2R,3S)-13 took place as a
result of inversion of configuration at the benzylic carbon.
Having established the relative and absolute stereo-
chemistry, attention was focused towards completion of
(R)-(–)-venlafaxine (1′). Accordingly, oxidation of secondary
hydroxy group in compound (2R,3S)-14 with Dess–Martin
periodinane was carried out to obtain ketone (R)-15 with
>92% ee.11 This protected ketone (R)-15 was subjected to
the Grignard reaction with vinylmagnesium bromide to
furnish the alcohol 16 in 85% yield. The alcohol 16 was
treated under ring-closing metathesis conditions in the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
S. P. Chavan, H. S. Khatod
Paper
Synthesis
O
HO
Sharpless
asymmetric
O
HO
O
2,2-DMP, PTSA (cat.)
O
O
O
O
O
DMF, r.t.
(97%)
dihydroxylation
(DHQD)2PHAL
O
O
O
5
(R)-4'
(R)-6'
[α]25D = –42 (c 1, CHCl3)
[α]25D = +27 (c 1, CHCl3)
(85%), >99% ee
OH
O
1,5-dibromopentane
Mg, THF, 0 °C to r.t.
O
Et3SiH, BF3•OEt2
OH
(99%), >93% de
>98% ee
CH2Cl2, –40 °C, 3 h
OH
(2R,3S)-7'
[α]25D = +26 (c 1, CHCl3)
O
O
(59%), 96% ee
13
OTBDMS
OH
1.a) DEAD, PPh3, 4-O2NC6H4COOH,
0 °C to r.t., 6 h
b) 5% NaOH, 60 °C, 8 h
TBDMSCl
imidazole
OH
OH
DMAP, CH2Cl2
(88%)
O
O
2. 10% HCl, MeOH, r.t.,
2 h (51%)
14
13'
assignment of
relative stereochemistry
preparation of Mosher ester
derivatives to assign
absolute stereochemistry
Scheme 4 Synthesis of chiral diol
O
O
O
OH
DMP
PTSA (cat.)
LAH, THF
O
DMF, r.t.
OH
OH
(89%)
( )-23
( )-22
( )-21
O
OH
DMP, PTSA (cat.)
DMF, r.t.
O
OH
OH
19
O
O
O
(89%)
13
O
DMP, PTSA (cat.)
O
OH
DMF, r.t.
(89%)
O
20
13'
Scheme 5 Determination of relative configuration
presence of Grubbs’ first-generation catalyst to obtain cy-
clohexene 17 in 92% yield. Subjecting compound 17 to hy-
drogenation for eight hours led to the double bond reduc-
tion along with TBDMS deprotection to furnish diol (R)-
12′.15 Following the same sequence of reactions as in the ra-
cemic synthesis, compound (R)-12′ was converted into (R)-
(–)-venlafaxine (1′) with 97% ee after recrystallization
(Scheme 6).11,16 The venlafaxine thus obtained matched
well with the reported spectroscopic data in the literature.8
By employing (DHQ)2PHAL as the chiral catalyst in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
S. P. Chavan, H. S. Khatod
Paper
Synthesis
OTBDMS
O
OTBDMS
MgBr, THF
DMP, CH2Cl2
0 °C to r.t., 3 h
(85%)
r.t., 2 h
(72%), 92% ee
OH
O
O
(R)-15
(2R,3S)-14
OH
OH
OTBDMS
OH
OTBDMS
Grubbs I
H2, Pd/C
OH
CH2Cl2, 2 h
(92%)
EtOH, 8 h
(95%)
O
O
O
(R)-12'
17
16
N
OH
1. TsCl, Et3N,
DMAP (cat.), CH2Cl2 (88%)
2. aq Me2NH,
r.t., 10 h (70%)
O
(R)-(–)-venlafaxine (1')
Scheme 6 Completion of synthesis of (R)-(–)-venlafaxine
Table 2 Comparison of Data to Assign Relative Configuration
metal turnings were activated, washed, and dried before use. Com-
mercially available p-methoxyphenylacetic acid, 1,5-dibromopen-
tane, OsO4, N-methylmorpholine N-oxide (NMO), AD-mix-β, and
Grubbs’ first-generation catalyst were used as received.
Compound
Diola
13.2, 8.4, 4.5
Its acetonidea
Known compound
16.3, 10.4, 5.4
[(±)-23]
[(±)-22]
1-[4-(4-Methoxyphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl]hex-5-
en-1-one (8)
Before Mitsunobu reaction
After Mitsunobu reaction
11.1, 6.8, 4.5
[(2R,3S)-13]
11.2, 6.8, 4.6 (19)
Compound 7 (1.50 g, 1.00 mmol) was dissolved in EtOAc (8 mL), and
IBX (3.75 g, 2.50 mmol) was added in one portion. The resulting sus-
pension was refluxed at 80 °C and stirred vigorously. After 3 h, the re-
action mixture was cooled to r.t., filtered, and washed with EtOAc (3 ×
10 mL), and the combined filtrates were concentrated to furnish 8
(1.32 g, 89%) as a colorless oil.
13.1, 8.2, 4.8
[(2R,3R)-13′]
16.4, 10.8, 5.5 (20)
a J (coupling constant) values at benzylic CH (in Hz).
IR (CHCl3): 2948, 1710, 1660, 1558, 1492 cm–1
.
Sharpless asymmetric dihydroxylation reaction the ‘S’ en-
antiomer also could be prepared following the above reac-
tion sequence.
1H NMR (200 MHz, CDCl3): δ = 7.29 (d, J = 8.85 Hz, 2 H), 6.84 (d, J =
8.85 Hz, 2 H), 5.75–5.55 (m, 1 H), 4.90–4.81 (m, 2 H), 3.78 (s, 3 H),
2.76–2.60 (m, 1 H), 2.48–2.32 (m, 1 H), 1.96–1.84 (m, 2 H), 1.62–1.51
(m, 2 H), 1.48 (s, 3 H), 1.42 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 209.8, 159.4, 137.9, 130.7, 126.0, 115.1,
114.0, 111.0, 89.8, 71.9, 55.1, 35.7, 32.9, 26.7, 25.8, 22.5.
In conclusion, we have accomplished the synthesis of
(±)-venlafaxine (1) along with the enantioselective synthe-
sis of (R)-(–)-venlafaxine (1′) as an application of diastereo-
selective and enantioselective unusual Grignard reaction.
The synthetic sequence involved Sharpless asymmetric di-
hydroxylation reaction for chirality induction and unusual
diastereoselective Grignard reaction for the installation of
secondary alcohol followed by stereoselective dehydroxyl-
ation.
HRMS (ESI): m/z [M + Na]+ calcd for C18H24O4Na: 327.3231; found:
327.3228.
3-[4-(4-Methoxyphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl]octa-1,7-
dien-3-ol (9)
A solution of 8 (3.00 g, 20 mmol) in anhyd THF (15 mL) was added
dropwise to a solution of vinylmagnesium bromide (12.0 mL of a 1.7
M solution in THF, 22 mmol) at 0 °C. After 30 min, the reaction was
quenched with sat. aq NH4Cl (10 mL). The organic phase was then ex-
tracted with Et2O, the combined extracts were washed with H2O and
brine, dried (anhyd Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue obtained was purified by column chro-
matography using 200–400 mesh silica gel (8% EtOAc–PE) to furnish 9
(2.77 g, 85%) as a colorless oil.
The 1H NMR spectra were recorded on 200, 400, and 500 MHz NMR
spectrometer using TMS as the internal standard. The 13C NMR spec-
tra were recorded on 200 NMR spectrometer (50 MHz), 400 NMR
spectrometer (100 MHz), and 500 NMR spectrometer (125 MHz).
Mass spectra were recorded on a MS-TOF mass spectrometer. The IR
spectra were recorded on a PerkinElmer 1760 FT IR spectrometer. Mg
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
S. P. Chavan, H. S. Khatod
Paper
Synthesis
IR (CHCl3): 3435, 2968, 1610, 1525, 1393, 1272 cm–1
.
1-(1-Hydroxycyclohexyl)-1-(4-methoxyphenyl)ethane-1,2-diol
(11)
Data for pure diastereomer
To a stirred solution of 3 (1.0 g, 1.1 mmol) in THF–H2O (1:1, 12 mL)
was added a catalytic amount of p-TSA. The resulting reaction mix-
ture was heated at 65 °C for 1 h. After completion of the reaction, the
mixture was cooled to r.t., extracted with EtOAc (3 × 20 mL), followed
by subsequent washings with aq NaHCO3 (3 × 25 mL). The organic ex-
tracts were dried (anhyd Na2SO4), and filtered. The solvent was re-
moved under reduced pressure to afford 11 (0.869 g, 90%) as a white
semisolid.
1H NMR (200 MHz, CDCl3): δ = 7.28 (d, J = 8.85 Hz, 2 H), 6.81 (d, J =
8.85 Hz, 2 H), 5.76–5.62 (m, 2 H), 5.29–5.15 (m, 2 H), 4.94–4.83 (m, 2
H), 4.45 (d, J = 8.34 Hz, 1 H), 4.15 (d, J = 8.34 Hz, 1 H), 3.78 (s, 3 H),
1.96–1.85 (m, 2 H), 1.59–1.50 (m, 1 H), 1.47 (s, 3 H), 1.41–1.19 (m, 3
H), 1.15 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 158.8, 139.3, 138.6, 134.3, 128.5, 114.6,
114.5, 112.8, 110.0, 88.7, 77.9, 71.7, 55.0, 34.4, 34.0, 26.4, 26.0, 22.4.
IR (CHCl3): 3435, 3075, 2932, 1620, 1560, 1219 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C20H28O4Na: 355.4828; found:
355.4825.
1H NMR (200 MHz, CDCl3): δ = 7.37 (d, J = 8.84 Hz, 2 H), 6.85 (d, J =
8.84 Hz, 2 H), 4.16–3.96 (m, 2 H), 4.24 (d, J = 11.50 Hz, 1 H), 3.89 (d, J =
11.50 Hz, 1 H), 3.80 (s, 3 H), 1.89–1.65 (m, 4 H), 1.59–1.38 (m, 6 H).
1-[4-(4-Methoxyphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclo-
hex-2-en-1-ol (10)
13C NMR (50 MHz, CDCl3): δ = 158.7, 132.8, 128.0, 113.2, 79.7, 76.3,
66.3, 55.1, 31.6, 31.4, 25.5, 21.6, 21.0.
HRMS (ESI): m/z [M + 1]+ calcd for C15H23O4: 267.5621; found:
267.5618.
In a round-bottomed flask, Grubbs I catalyst (0.720 g, 1.2 mmol, 0.2
equiv) was dissolved in anhyd CH2Cl2 (8 mL). To this solution was add-
ed 9 (2.00 g, 6 mmol, 1 equiv) and stirred for 2 h. After complete con-
sumption of the starting material, the reaction mixture was filtered
and washed with CH2Cl2 (3 × 3 mL). The solvent extracts were com-
bined and evaporated under reduced pressure. The crude residue was
purified by silica gel column chromatograpy using PE–EtOAc (3:1) to
afford 10 (1.68 g, 92%) as a colorless oil.
1-[2-Hydroxy-1-(4-methoxyphenyl)ethyl]cyclohexanol (12)
To a stirred solution of 11 (0.8 g, 3 mmol, 1 equiv) in anhyd CH2Cl2 (6
mL) at 0 °C was added Et3SiH (0.693 mL, 6 mmol, 2 equiv) followed by
BF3·OEt2 (0.20 mL, 0.5 equiv). The reaction mixture was warmed to r.t.
over 30 min and stirred for 3 h. After completion of the reaction, mix-
ture was quenched by the addition of sat. aq NaHCO3 (5 mL) and ex-
tracted with CH2Cl2 (3 × 15 mL). The combined organic layers were
washed with brine (10 mL), dried (anhyd Na2SO4), and filtered. Evapo-
ration of solvent and purification of the residue by chromatography
on a 60–120 mesh silica gel column (eluent: 40% EtOAc–PE) furnished
12 (0.46 g, 62%) as a colorless oil.
IR (CHCl3): 3466, 2931, 1393 cm–1
.
1H NMR (200 MHz, CDCl3): δ (dr 6:4) = 7.30 (d, J = 8.34 Hz, 2 H), 6.80
(d, J = 8.34 Hz, 2 H), 6.01–5.63 (m, 2 H), 4.61 (d, J = 8.59 Hz, 0.63 H),
4.47 (d, J = 8.21 Hz, 0.37 H), 4.24–4.05 (m, 1 H), 3.78 (s, 3 H), 2.15–
1.80 (m, 3 H), 1.72–1.56 (m, 2 H), 1.53 and 1.48 (s, 3 H), 1.42–1.28 (m,
1 H), 1.23 and 1.16 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ (dr 6:4) = 158.6, 158.5, 134.7, 134.4,
133.7, 131.3, 128.9, 128.27, 128.21, 127.5, 112.6, 110.0, 88.9, 88.3,
72.3, 72.1, 71.6, 70.9, 54.9, 31.8, 31.1, 26.3, 26.0, 25.6, 25.0, 24.9, 18.2,
18.1.
IR (CHCl3): 3461, 3002, 2936, 2589, 1612 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.19 (d, J = 8.59 Hz, 2 H), 6.84 (d, J =
8.72 Hz, 2 H), 4.16–3.96 (m, 2 H), 3.79 (s, 3 H), 2.80 (t, J = 6.44 Hz, 1
H), 2.25 (br s, 2 H), 1.74–1.25 (m, 10 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H24O4Na: 327.6936; found:
327.6935.
13C NMR (50 MHz, CDCl3): δ = 158.6, 131.3, 130.5, 113.8, 74.0, 63.3,
56.2, 55.1, 36.7, 34.7, 25.6, 21.7, 21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22O3Na: 273.3329; found:
273.3332.
1-[4-(4-Methoxyphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclo-
hexan-1-ol (3)
To a stirred solution of 10 (1.5 g, 4.9 mmol) in anhyd EtOH (5 mL) was
added a catalytic amount of 10% Pd/C and the resulting reaction mix-
ture was vigorously stirred at r.t. for 2 h under H2 atmosphere (1–2
psi). After complete consumption of the starting material, as moni-
tored by TLC, the reaction mixture was filtered through a short pad of
Celite and washed carefully with EtOH. The EtOH extracts were com-
bined and evaporated under reduced pressure. The crude product
thus obtained was subjected to column chromatography using 60–
120 mesh silica gel with EtOAc–PE (15%) as an eluent to furnish 3
(1.43 g, 95%) as a colorless oil.
2-(1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl 4-Methylben-
zenesulfonate (2)
A round-bottomed flask was charged with 12 (0.250 g, 1 mmol, 1.00
equiv) and anhyd CH2Cl2 (10 mL). To the resulting solution were add-
ed DMAP (0.087 g, 0.6 mmol, 0.6 equiv), TsCl (0.339 g, 1.5 mmol, 1.5
equiv), and Et3N (0.16 mL, 1 mmol, 1.00 equiv) and the mixture was
stirred for 5 h at 0 °C. The suspension was diluted with Et2O (20 mL)
and stirred for an additional 30 min. The solution was then washed
sequentially with 10% aq NaHCO3 (2 × 10 mL) and brine (20 mL). The
combined organic layers were dried (anhyd Na2SO4), filtered, and con-
centrated under reduced pressure. The crude residue was purified by
chromatography on a 200–400 mesh silica gel column using 8%
EtOAc–PE as an eluent to furnish pure 2 (0.355 g, 88%) as a pale yellow
solid; mp 108 °C.
IR (CHCl3): 3475, 2930, 1608, 1293 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.30 (d, J = 8.85 Hz, 2 H), 6.83 (d, J =
8.85 Hz, 2 H), 4.53 (d, J = 8.47 Hz, 1 H), 4.20 (d, J = 8.47 Hz, 1 H), 3.81
(s, 3 H), 1.83 (br s, 1 H), 1.62–1.55 (m, 4 H), 1.50 (s, 3 H), 1.38–1.24 (m,
4 H), 1.30 (s, 3 H), 1.12–0.91 (m, 2 H).
IR (CHCl3): 3056, 2952, 1611, 1312, 1132, 725 cm–1
.
13C NMR (50 MHz, CDCl3): δ = 158.6, 134.6, 128.3, 112.7, 109.7, 89.7,
1H NMR (500 MHz, CDCl3): δ = 7.57 (d, J = 8.24 Hz, 2 H), 7.25 (d, J =
7.93 Hz, 2 H), 6.97 (d, J = 8.54 Hz, 2 H), 6.74 (d, J = 8.55 Hz, 2 H), 4.61
(dd, J = 9.76, 4.88 Hz, 1 H), 4.30 (t, J = 9.46 Hz, 1 H), 3.78 (s, 3 H), 2.91
(dd, J = 8.85, 5.19 Hz, 1 H), 2.44 (s, 3 H), 1.68–1.64 (m, 2 H), 1.67 (br s,
1 H), 1.54–1.50 (m, 3 H), 1.42–1.37 (m, 3 H), 1.22–1.16 (m, 2 H).
73.8, 70.8, 55.1, 32.1, 31.6, 26.4, 26.1, 25.5, 21.5, 21.3.
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O4Na: 329.4020; found:
329.4022.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
S. P. Chavan, H. S. Khatod
Paper
Synthesis
13C NMR (125 MHz, CDCl3): δ = 158.6, 144.2, 133.1, 130.2, 129.6,
127.9, 113.6, 72.6, 70.6, 55.0, 53.7, 36.2, 36.1, 25.4, 21.8, 21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C22H28O5SNa: 427.1690; found:
427.1692.
on a 200–400 mesh silica gel column using 10% EtOAc–PE ether to
furnish (2R,3S)-14 (1.53 g, 88%) as a pale yellow viscous oil; [α]D25 –28
(c 1, CHCl3).
IR (CHCl3): 3438, 2936, 2861, 1614, 1461, 1269 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.18 (d, J = 8.55 Hz, 2 H), 6.82 (d, J =
8.54 Hz, 2 H), 5.77 (ddt, J = 17.09, 10.38, 6.72 Hz, 1 H), 4.98–4.90 (m, 2
H), 4.03–3.98 (m, 2 H), 3.87 (dd, J = 9.76, 4.88 Hz, 1 H), 3.79 (s, 3 H),
2.76–2.73 (m, 1 H), 2.06–2.01 (m, 2 H), 1.62–1.55 (m, 2 H), 1.45–1.39
(m, 2 H), 0.89 (s, 9 H), 0.02 (s, 6 H).
13C NMR (50 MHz, CDCl3): δ = 158.3, 138.7, 131.3, 130.2, 114.4, 113.5,
72.7, 65.6, 55.1, 51.4, 34.0, 33.6, 25.8, 25.3, 18.1, –5.6.
1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-
ol [1, (±)-Venlafaxine]
To a stirred solution of 2 (0.220 g, 0.5 mmol, 1.0 equiv) was added 40%
aq Me2NH (3 mL). The resultant reaction mixture was stirred at r.t. for
10 h. After completion of the reaction, the mixture was concentrated
under reduced pressure at 60 °C to furnish a crude residue. The crude
residue was subjected to further purification by chromatography on a
60–120 mesh silica gel column to give 1 (0.105 g, 70%), and after re-
crystallization from EtOAc (64%) as a white solid; mp 286 °C.8
HRMS (ESI): m/z [M + Na]+ calcd for C21H36O3SiNa: 387.2326; found:
387.2324.
IR (CHCl3): 3164, 2982, 2938, 2860, 1610 cm–1
.
(R)-1-[(tert-Butyldimethylsilyl)oxy]-2-(4-methoxyphenyl)oct-7-
en-3-one [(R)-15]
1H NMR (200 MHz, CDCl3): δ = 7.03 (d, J = 8.84 Hz, 2 H), 6.79 (d, J =
8.84 Hz, 2 H), 3.78 (s, 3 H), 3.32 (t, J = 12.30 Hz, 1 H), 2.95 (dd, J =
12.30, 3.29 Hz, 1 H), 2.35 (s, 3 H), 2.31–2.28 (m, 1 H), 1.78–1.26 (m, 8
H), 1.03–0.88 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 158.3, 132.6, 130.3, 130.1, 113.4, 74.1,
61.2, 55.1, 51.7, 45.4, 38.0, 31.2, 26.0, 21.6, 21.3.
The alcohol (2R,3S)-14 (0.8 g, 2.2 mmol, 1.0 equiv) was dissolved in
anhyd CH2Cl2 (35 mL) and stirred at 0 °C in an ice bath. To this solu-
tion was added Dess–Martin periodinane (1.12 g, 3.3 mmol, 1.5
equiv) in one portion and the reaction mixture allowed to stir at r.t.
for 1 h. The reaction was quenched at 0 °C by stirring with sat. aq
Na2S2O3 and NaHCO3 (1:1, 20 mL) for 10 min to destroy any unreacted
Dess–Martin reagent. The mixture was poured into a separatory fun-
nel and extracted with CH2Cl2 (3 × 20 mL). The organic layers were
combined and washed with brine, dried (anhyd Na2SO4), filtered, and
concentrated under reduced pressure to furnish (R)-15 (0.572 g, 72%)
MS (ESI): m/z = 278 [M + 1]+.
(2R,3S)-2-(4-Methoxyphenyl)oct-7-ene-1,3-diol [(2R,3S)-13]
To a solution of (2R,3S)-7′ (1.5 g, 1 mmol, 1 equiv) in anhyd CH2Cl2 (3
mL) was added Et3SiH (1.38 mL, 2 mmol, 2 equiv) followed by BF3·OEt2
(0.39 mL, 0.5 mmol, 0.5 equiv) and the resulting suspension was
stirred at –40 °C over 3 h. After completion of the reaction, the mix-
ture was quenched by careful addition of sat. aq NH4Cl (0.5 mL),
warmed to r.t., and extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were washed with brine (10 mL) and dried (anhyd
Na2SO4). Evaporation of solvent and purification of the residue by
chromatography on a 200–400 mesh silica gel column (20% EtOAc–
PE) furnished (2R,3S)-13 (0.385 g, 59%) as a white solid; mp 64 °C;
[α]D25 +30 (c 1, CHCl3).
25
as almost pure product, which was isolated as a colorless oil; [α]D
–32 (c 1, CHCl3).
IR (CHCl3): 2967, 1713, 1611, 1510 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.15 (d, J = 8.71 Hz, 2 H), 6.85 (d, J =
8.71 Hz, 2 H), 5.80–5.60 (m, 1 H), 4.19 (dd, J = 9.35, 8.84 Hz, 1 H), 3.88
(dd, J = 8.84, 5.24 Hz, 1 H), 3.78 (s, 3 H), 3.65 (dd, J = 9.35, 5.24 Hz, 1
H), 2.47–2.29 (m, 2 H), 2.03–1.91 (m, 2 H), 1.69–1.58 (m, 2 H), 0.84 (s,
9 H), –0.01 (s, 3 H), –0.02 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 209.7, 158.9, 137.9, 129.4, 128.0, 115.0,
114.0, 65.0, 59.9, 55.2, 42.3, 32.9, 25.8, 22.5, 18.2, −5.58.
IR (CHCl3): 3482, 2925, 2860, 1616, 1435, 1069 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C21H34O3SiNa: 385.2168; found:
385.2165.
1H NMR (200 MHz, CDCl3): δ = 7.22 (d, J = 8.59 Hz, 2 H), 6.89 (d, J =
8.59 Hz, 2 H), 5.78 (ddt, J = 16.93, 11.11, 6.57 Hz, 1 H), 5.03–4.88 (m, 2
H), 4.08–3.84 (m, 3 H), 3.80 (s, 3 H), 2.84 (ddd, J = 11.11, 6.57, 4,55 Hz,
1 H), 2.08–1.99 (m, 2 H), 1.83 (br s, 2 H), 1.59–1.32 (m, 4 H).
3-{2-[(tert-Butyldimethylsilyl)oxy]-1-(4-methoxyphenyl)ethyl}oc-
13C NMR (50 MHz, CDCl3): δ = 158.7, 138.5, 130.22, 130.21, 114.5,
ta-1,7-dien-3-ol (16)
113.9, 72.3, 64.5, 55.1, 52.2, 34.3, 33.5, 25.1.
MS (ESI): m/z = 273 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22O3Na: 273.0659; found:
273.0655.
Compound 16 was prepared as per the previously mentioned experi-
mental procedure for compound 9; yield: 2.38 g from 2.50 g (88%);
colorless oil.
Data for pure diastereomer
IR (CHCl3): 3449, 2941, 1611, 1252, 1090 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.30 (d, J = 8.84 Hz, 2 H), 6.83 (d, J =
8.84 Hz, 2 H), 5.87–5.61 (m, 2 H), 5.41 (dd, J = 17.05, 2.03 Hz, 1 H),
5.21 (dd, J = 10.49, 2.03 Hz, 1 H), 4.97–4.32 (m, 2 H), 4.15 (dd, J = 9.86,
4.17 Hz, 1 H), 4.08 (br s, 1 H), 3.88 (dd, J = 9.86, 4.17 Hz, 1 H), 3.80 (s, 3
H), 2.63 (t, J = 4.17 Hz, 1 H), 1.96–1.85 (m, 2 H), 1.43–1.37 (m, 2 H),
1.34–1.28 (m, 2 H), 0.89 (s, 9 H), –0.03 (s, 6 H).
13C NMR (50 MHz, CDCl3): δ = 158.4, 143.6, 138.8, 132.1, 130.9, 114.3,
113.7, 113.3, 78.4, 66.3, 55.0, 53.4, 38.1, 34.1, 25.8, 22.6, 18.1, –5.7.
HRMS (ESI): m/z [M + Na]+ calcd for C23H38O3SiNa: 413.2482; found:
413.2480.
(2R,3S)-1-[(tert-Butyldimethylsilyl)oxy]-2-(4-methoxyphenyl)oct-
7-en-3-ol [(2R,3S)-14]
To a stirred solution of (2R,3S)-13 (1.20 g, 4.8 mmol, 1.0 equiv) in an-
hyd CH2Cl2 (10 mL) waas added TBDMSCl (0.705 g, 4.8 mmol, 1.0
equiv) followed by the addition of imidazole (0.480 g, 7.2 mmol, 1.5
equiv) and DMAP (0.058 g, 0.48 mmol, 0.1 equiv). The reaction mix-
ture was stirred at r.t. for 3 h and then diluted with CH2Cl2 (10 mL).
The CH2Cl2 layer was washed with aq NH4Cl (10 mL) and the aqueous
layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried (anhyd Na2SO4), filtered, and concentrated under
reduced pressure. The crude residue was purified by chromatography
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
S. P. Chavan, H. S. Khatod
Paper
Synthesis
1-{2-[(tert-Butyldimethylsilyl)oxy]-1-(4-methoxyphenyl)ethyl}cy-
clohex-2-enol (17)
References
(1) World Health Organization WHO, Collaborative Centre for Drug
Statistics Methodology: http://www.whocc.no/atcddd/ .
(2) (a) Golden, R. N.; Nicholas, L. Depress. Anxiety 2000, 12, 45.
(b) Preskorn, S. Eur. Psychiatry 1997, 12, 2855.
(3) Yardley, J. P.; Husbands, G. E. M.; Stack, G.; Butch, J.; Bicksler, J.;
Moyer, J. A.; Muth, E. A.; Andree, T.; Fletcher, H. III; James, M. N.
G.; Sielecki, A. R. J. Med. Chem. 1990, 33, 2899.
(4) Cipriani, A.; Signoretti, A.; Furukawa, T. A.; Churchill, A. R.;
Tomelleri, S.; Omori, I. M.; McGuire, H.; Barbui, C. Cochrane
Database Syst. Rev. 2007, 2, CD006530.
Compound 17 was prepared as per the previously mentioned experi-
mental procedure for compound 10; yield: 0.620 g from 0.690 g
(92%); colorless oil; [α]D25 +15 (c 1, CHCl3).
IR (CHCl3): 3460, 2931, 2868, 1611, 1350, 1096 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.80 Hz, 2 H), 6.82 (d, J =
8.80 Hz, 2 H), 5.85 (d, J = 10.27 Hz, 1 H), 5.74–5.69 (m, 1 H), 4.17–4.09
(m, 2 H), 3.78 (s, 3 H), 2.90 (t, J = 5.38 Hz, 1 H), 2.02–1.97 (m, 1 H),
1.88–1.80 (m, 1 H), 1.77–1.69 (m, 1 H), 1.66–1.57 (m, 1 H), 0.91 (s, 9
H), 0.05 (s, 6 H).
(5) (a) Chavan, S. P.; Kamat, S. K.; Sivadasan, L.; Balakrishnan, K.;
Khobragade, D. A.; Ravindranathan, T.; Gurjar, M. K.; Kalkote, U.
R. US Patent US 6350912B1, 2002; Chem. Abstr. 2002, 136,
200009. (b) Chavan, S. P.; Kamat, S. K.; Sivadasan, L.;
Balakrishnan, K.; Khobragade, D. A.; Ravindranathan, T.; Gurjar,
M. K.; Kalkote, U. R. US Patent US 6504044B2, 2003. (c) Chavan,
S. P.; Khobragade, D. A.; Kamat, S. K.; Sivadasan, L.;
Balakrishnan, K.; Ravindranathan, T.; Gurjar, M. K.; Kalkote, U.
R. Tetrahedron Lett. 2004, 45, 7291. (d) Chavan, S. P.;
Khobragade, D. A.; Thakkar, M.; Kalkote, U. R. Synth. Commun.
2007, 37, 2007.
(6) Few selected examples, see: (a) Jinpei, Z.; Huibin, Z.; Xuezhen,
H.; Wenlong, H. J. J. China Pharm. Univ. 1999, 30, 249.
(b) Husbands, G. E. M.; Yardley, J. P.; Mills, G.; Muth, E. A. US
Patent 4535186, 1985. (c) Rathod, D. M.; Rangaraju, S. G.;
Moreshwar, M.; Patel, N.; Deodhar, M.; Mandar, M. Patent EP
1249447, 2001. (d) Basappa Kavitha, C. V.; Rangappa, K. S.
Bioorg. Med. Chem. Lett. 2004, 14, 3279. (e) Saigal, J.; Gupta, R.;
Pandit, V. V.; Desai, A. J.; Mehta, N. V.; Rane, S. H. US Patent
7026513, 2006. (f) Dolitzky, B. Z.; Aronhime, J.; Wizel, S.;
Nisnevich, G. A. US Patent 6924393, 2005.
13C NMR (100 MHz, CDCl3): δ = 158.2, 132.5, 132.4, 130.4, 128.8,
113.2, 72.5, 65.4, 55.1, 53.8, 33.0, 25.7, 25.0, 18.7, 18.0, –5.7.
HRMS (ESI): m/z [M + Na]+ calcd for C21H34O3SiNa: 385.5432; found:
385.5437.
(R)-1-[2-Hydroxy-1-(4-methoxyphenyl)ethyl]cyclohexanol [(R)-
12′]
To a stirred solution of 17 (0.5 g, 1.38 mmol) in anhyd EtOH (5 mL)
was added 10% Pd/C (0.2 mg) in a single portion and the resulting re-
action mixture was vigorously stirred at r.t. for 8 h under H2 atmo-
sphere (1–2 psi). After complete consumption of the starting material,
the reaction mixture was filtered and washed carefully with EtOH.
The EtOH extracts were combined and evaporated under reduced
pressure. The crude product thus obtained was subjected to column
chromatography using 60–120 mesh silica gel with EtOAc–PE (15%) as
an eluent to furnish pure (R)-12′ (0.328 g, 95%) as a colorless oil;
[α]D25 +12.4 (c 1, CHCl3).
(R)-2-(1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl 4-Methyl-
benzenesulfonate [(R)-2′]
(7) (a) Davies, H. M. L.; Ni, A. Chem. Commun. 2006, 3110.
(b) Kochetkov, K. A.; Galkina, M. A.; Galkin, O. M. Mendeleev
Commun. 2010, 20, 314. (c) Bhuniya, R.; Nanda, S. Tetrahedron
Lett. 2012, 53, 1990.
Compound (R)-2′ was prepared as per the previously mentioned ex-
perimental procedure for compound 2; yield: 0.355 g from 0.250 g
(88%); pale yellow solid; mp 109 °C; [α]D25 –18.8 (c 1, CHCl3).
(8) (a) Chavan, S. P.; Garai, S.; Pawar, K. P. Tetrahedron Lett. 2013,
54, 2137. (b) Chavan, S. P.; Pawar, K. P.; Garai, S. RSC Adv. 2014,
4, 14468.
(9) Chavan, S. P.; Khatod, H. S.; Das, T.; Vanka, K. RSC Adv. 2016, 6,
50721.
(R)-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-
1-ol [(R)-1′, (R)-Venlafaxine]
Compound (R)-1′ was prepared as per the previously mentioned ex-
perimental procedure for compound 1; yield: 0.105 g from 0.220 g
25
(70%); white solid; mp 286 °C; [α]D25 –24.5 (c 1, EtOH) {Lit.3,16 [α]D
(10) Chavan, S. P.; Khatod, H. S. Tetrahedron: Asymmetry 2012, 23,
1410.
–27.1 (c 1.04, EtOH)}.
(11) The enantiomeric excess was confirmed with HPLC analysis and
the details are provided in the Supporting Information.
(12) (a) Veeraraghavan, P. R.; Chanda, P. B. Chem. Commun. 2013, 49,
3152. (b) (±)-22: IR (CHCl3): 3482, 2925, 2860, 1620, 1435, 1269
Acknowledgment
1
cm–1. H NMR (200 MHz, CDCl3): δ = 7.36–7.13 (m, 5 H), 4.11–
H.S.K. thanks CSIR, New Delhi, India, for the award of a research fel-
lowship. We also thank CSIR, New Delhi, India, for financial support as
part of XIIth five year plan program under title ACT (CSC–0301) and
ORIGIN (CSC–0108). The authors thank Dr. U. R. Kalkote and Dr. H. B.
Borate for helpful discussions.
3.98 (m, 2 H), 3.88 (dd, J = 10.74, 4.17, Hz, 1 H), 3.41 (br s, 1 H),
3.24 (br s, 1 H), 2.82 (ddd, J = 13.26, 8.46, 4.54, Hz, 1 H), 1.41–
1.17 (m, 8 H), 0.83 (t, J = 6.82 Hz, 3 H). 13C NMR (50 MHz,
CDCl3): δ = 140.0, 128.6, 128.1, 126.9, 76.3, 67.1, 53.5, 35.6, 31.5,
24.7, 22.5, 13.9. HRMS (ESI): m/z [M + Na]+ calcd for C15H22O3Na:
245.1659; found: 245.1655. (c) (±)-(23): IR (CHCl3): 1610, 1540,
1412, 1126 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.36–7.16 (m, 5
H), 4.07–3.99 (m, 1 H), 3.96–3.78 (m, 2 H), 2.75 (ddd, J = 16.30,
10,87, 5.43 Hz, 1 H), 1.58 (s, 3 H), 1.47 (s, 3 H), 1.33–1.15 (m, 8
H), 0.81 (t, J = 6.82 Hz, 3 H). 13C NMR (50 MHz, CDCl3): δ = 139.1,
128.6, 128.2, 127.0, 98.3, 73.2, 65.7, 47.5, 33.3, 31.6, 29.6, 24.7,
22.5, 19.4, 14.0. MS (ESI): m/z = 285 [M + Na]+. HRMS (ESI): m/z
[M + Na]+ calcd for C12H22O3Na: 285.1061; found: 285.1060.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588911.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
1
(d) (2R,3R)-13′: H NMR (200 MHz, CDCl3): δ = 7.08 (d, J = 8.54
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
S. P. Chavan, H. S. Khatod
Paper
Synthesis
Hz, 2 H), 6.85 (d, J = 8.54 Hz, 2 H), 5.72 (ddt, J = 17.09, 10.38,
6.72 Hz, 1 H), 4.95–4.88 (m, 2 H), 4.05–3.97 (m, 2 H), 3.90–3.86
(m, 1 H), 3.79 (s, 3 H), 2.78 (ddd, J = 13.12, 8.24, 4.88 Hz, 1 H),
2.02–1.90 [m, 3 H (contains two br s for 2-OH)], 1.56–1.51 (m, 1
H), 1.41–1.30 (m, 4 H). 13C NMR (50 MHz, CDCl3): δ = 158.5,
138.5, 132.0, 129.1, 114.6, 114.1, 76.2, 67.1, 55.2, 52.7, 35.1,
33.4, 24.4.
(14) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092. (b) Mosher’s ester of (S)-14: IR (CHCl3):
2952, 1752, 1672, 1643, 1172 cm−1. 1H NMR (200 MHz, CDCl3):
δ = 7.38–7.30 (m, 5 H), 7.10 (d, J = 8.80 Hz, 2 H), 6.78 (d, J = 8.80
Hz, 2 H), 5.75–5.65 (m, 2 H), 4.98–4.92 (m, 2 H), 3.78 (s, 3 H),
3.72–3.69 (m, 2 H), 3.32 (s, 3 H), 2.96–2.91 (m, 1 H), 2.05–1.96
(m, 2 H), 1.62–1.56 (m, 2 H), 1.40–1.28 (m, 2 H), 0.87 (s, 9 H),
0.04 (s, 6 H). 13C NMR (50 MHz, CDCl3): δ = 166.0, 158.5, 138.1,
132.3, 130.8, 130.1, 129.3, 128.2, 127.4, 114.8, 113.6, 77.2, 76.5,
64.2, 55.1, 55.0, 49.9, 33.3, 31.2, 25.7, 23.9, 18.1, –5.55, –5.62.
HRMS (ESI): m/z [M + 1]+ calcd for C31H43F3O5Si: 581.2374;
found: 581.2378. (c) Mosher’s ester of (R)-14: 1H NMR (200
MHz, CDCl3): δ = 7.48–7.44 (m, 2 H), 7.39–7.32 (m, 3 H), 7.03 (d,
J = 8.85 Hz, 2 H), 6.75 (d, J = 8.85 Hz, 2 H), 5.74 (ddt, J = 16.78,
10.07, 6.71 Hz, 1 H), 5.62–5.59 (m, 1 H), 5.00–4.92 (m, 2 H), 3.77
(s, 3 H), 3.60–3.54 (m, 2 H), 3.43 (s, 3 H), 2.91–2.87 (m, 1 H),
2.05–2.01 (m, 2 H), 1.66–1.58 (m, 2 H), 1.46–1.40 (m, 2 H), 0.86
(s, 9 H), –0.06 (s, 3 H), –0.07 (s, 3 H). 13C NMR (50 MHz, CDCl3):
δ = 165.9, 158.5, 138.0, 132.5, 130.2, 129.3, 128.2, 127.5, 127.2,
114.9, 113.5, 77.2, 76.4, 63.9, 55.3, 55.1, 50.1, 33.2, 31.4, 25.7,
24.5, 18.0, –5.55, –5.60.
(13) (a) 19: IR (CHCl3): 1610, 1556, 1412, 1226 cm–1 1H NMR (500
.
MHz, CDCl3): δ (dr: 9:1) = 7.40 (d, J = 8.53 Hz, 2 H), 7.08 (d, J =
7.63 Hz, 0.30 H), 6.82 (d, J = 8.53 Hz, 1.70 H), 5.71 (ddt, J = 17.06,
10.29, 6.77 Hz, 1 H), 4.95–4.86 (m, 2 H), 4.31 (dd, J = 11.55, 3.77
Hz, 1 H), 4.13 (ddd, J = 9.29, 6.53, 3.26 Hz, 1 H), 3.97–3.87 (m, 1
H), 3.80 (s, 3 H), 2.68 (ddd, J = 16.17, 10.68, 5.19 Hz, 0.10 H),
2.46–2.40 (m, 0.90 H), 1.97–1.92 (m, 2 H), 1.53 (s, 3 H), 1.52 (s, 3
H), 1.42–1.31 (m, 1 H), 1.34–1.30 (m, 1 H), 1.20–1.14 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 158.6, 158.3, 138.7, 138.6, 132.7,
131.1, 130.5, 129.0, 114.5, 114.4, 114.1, 113.4, 96.8, 96.2, 73.3,
71.2, 65.7, 55.1, 55.0, 46.5, 43.1, 33.6, 33.5, 33.0, 32.9, 29.4, 24.7,
24.4, 19.4, 19.1. HRMS (ESI): m/z [M
C
+
Na]+ calcd for
18H26O3Na: 313.2103; found: 313.2108. (b) 20: 1H NMR (500
MHz, CDCl3): δ = 7.10 (d, J = 8.55 Hz, 2 H), 6.86 (d, J = 8.55 Hz, 2
H), 5.72 (ddt, J = 16.79, 10.07, 6.41 Hz, 1 H), 4.94–4.86 (m, 2 H),
3.97 (ddd, J = 10.38, 6.43, 3.36 Hz, 1 H), 3.91 (t, J = 11.29 Hz, 1
H), 3.82–3.77 (m, 1 H), 3.79 (s, 3 H), 2.70 (ddd, J = 16.17, 10.38,
6.43 Hz, 1 H), 2.33–2.29 (m, 1 H), 2.06–1.98 (m, 1 H), 1.96–1.90
(m, 1 H), 1.57 (s, 3 H), 1.54–1.48 (m, 1 H), 1.45 (s, 3 H), 1.34–
1.30 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 158.5, 138.8,
131.0, 129.0, 114.2, 114.1, 98.3, 73.2, 65.8, 55.2, 46.5, 33.5, 32.8,
29.6, 24.3, 19.3.
(15) Ikawa, T.; Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60,
6901.
(16) HPLC conditions: column, Kromasil AmyCoat (250 mm × 4.6
mm); mobile phase, EtOH– PE–Et2NH (05:94.9:0.1); wave-
length, 254 nm; flow rate, 0.5 mL/min; injecting volume, 5 μL.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I