A novel and enantioselective synthesis of d-(+)-biotin via a Sharpless asymmetric dihydroxylation strategy

Article abstract of DOI:10.1016/j.tetasy.2013.10.002

A novel and enantioselective synthesis of d-(+)-biotin has been accomplished starting from commercially available cyclohexanone. The key steps in the sequence are the Sharpless asymmetric dihydroxylation of a (E)-ethyl 3-(2-chlorocyclohex-1-en-1-yl)acryla

Full text of DOI:10.1016/j.tetasy.2013.10.002

Tetrahedron: Asymmetry 24 (2013) 1473–1479
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel and enantioselective synthesis of D-(+)-biotin via a Sharpless
asymmetric dihydroxylation strategy
⇑
Subhash P. Chavan , Pradeep B. Lasonkar, Prakash N. Chavan
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2013
Accepted 4 October 2013
A novel and enantioselective synthesis of D-(+)-biotin has been accomplished starting from commercially
available cyclohexanone. The key steps in the sequence are the Sharpless asymmetric dihydroxylation of
a (E)-ethyl 3-(2-chlorocyclohex-1-en-1-yl)acrylate derivative to establish the stereocenters of -(+)-bio-
D
tin, the carboxyalkyl side chain is introduced by unmasking the cyclohexene by ozonolysis and enzymatic
hydrolysis of a thioacetate.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
different strategies for the control of three adjacent stereogenic
centers are reported in the literature. To the best of our knowledge,
D
-(+)-Biotin (vitamin H)1 is a water-soluble vitamin, involved in
an essential part of the metabolic cycle causing catalytic fixation of
carbon dioxide in the biosynthesis of fatty acids, sugars, and
very few syntheses of D-(+)-biotin that involve intermolecular
asymmetric induction are reported in the literature.1a Many syn-
thetic approaches, such as diastereoisomeric or enzymatic resolu-
tions,4 chiral pool methods involving carbohydrates,5 cysteine,6
a
-
amino acids. It is used as a feed additive particularly in the poultry
industry. In addition, it was recently found that biotin 1 enhances
insulin secretion in animals, suggesting it to be a promising thera-
peutic candidate as an anti-diabetic drug.2 Biotin has a remarkably
strong affinity toward avidin3 and streptavidin1b and their com-
plexes are extensively used in the area of drug delivery, immuno-
and
been actively involved in the stereoselective synthesis of
tin via chiral pool methods and has reported -(+)-biotin syntheses
starting from
-cysteine8 and glucosamine.9 Herein we report an
L
-aspartic acid7 have been described. Our research group has
D
-(+)-bio-
D
L
asymmetric total synthesis of 1 starting from a commercially avail-
able achiral starting material viz. cyclohexanone.
assay, isolation, and localization. D-(+)-Biotin (Fig. 1) finds use for
the clinical treatment of hair loss, brittle nails, and in tonic formu-
lations for children.3b The lack of efficient fermentation methods
for biotin has gained the attention of organic chemists toward its
synthesis.
The envisaged retrosynthetic strategy for biotin 1 is shown in
Scheme 1. A linear synthetic strategy was used wherein olefin 2
was conceived as the direct precursor to 1. Olefin 2 would then
in turn be accessed from thioacetate 3 upon hydrolysis and intra-
molecular cyclization. The carboxyalkyl side chain of biotin 1 could
be unmasked by ozonolysis of cyclohexene 5. The vicinal diamine
group can be introduced via sequences involving the opening of
a cyclic sulfite, which could be prepared from diol 6 and SN2 sub-
stitution of a leaving group by azide.
O
NH
HN
4
O
HO
S
2. Results and discussion
1
Following a literature procedure,10 cyclohexanone 7 was sub-
jected to Vilsmeier–Haack reaction to furnish aldehyde 8, which
was homologated using a Wittig reaction to afford unsaturated es-
ter 9 (Scheme 2).
This prochiral unsaturated ester 9 was deemed to be a suitable
substrate for installation of the stereogenic centers. Compound 9
was subjected to Sharpless asymmetric dihydroxylation (SAD)11
conditions with (DHQD)2PHAL as a chiral catalyst to yield chiral
diol 6 in 84% yield with P99% ee.12 To install the azido functional-
Figure 1. Structure of
D
-(+)-biotin.
Over the past few decades, many efforts have been made to-
ward the development of an efficient process for the total synthesis
of D-(+)-biotin 1. A number of new synthetic approaches involving
⇑
Corresponding author. Tel.: +91 020 25902289; fax: +91 020 25902629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.002

1474
S. P. Chavan et al. / Tetrahedron: Asymmetry 24 (2013) 1473–1479
O
O
O
BnN
NBn
BnN
NBn
NH
HN
O
SAc
O
O
S
O
HO
S
4
O
3
2
O
1
O
O
Cbz
Cl
Cl
OH
O
BnN
NBn
N
O
N
O
OTBS
O
O
OH
COOEt
O
O
4
6
5
Scheme 1. Key retrosynthetic disconnections.
Cl
O
Cl
O
CHO
ii) Ph3PCHCOOEt,
i) POCl3, DMF,
O
DCM, 0 °C,
95%
DCM, RT,
4h, 76%.
9
8
7
Scheme 2. Synthesis of unsaturated ester 9.
ity, diol 6 was converted into a cyclic sulfite/sulfate. Direct conver-
sion of the sulfite/sulfate into the corresponding diazide was
unsuccessful in our hands. Hence it was decided to convert the sul-
fite into a diamine in a stepwise fashion. This was carried out by
regioselective opening of the cyclic sulfite using NaN3 in DMF to
exclusively give b-azido ester 10 (Scheme 3).13
azidoamine 12. Again the azide was reduced by using Staudinger
reaction conditions to give the amine, which upon treatment with
ethyl chloroformate in the presence of triethylamine, gave a cyclic
protected urea 5 (Scheme 3).15
With compound 5 in hand, the ester was reduced using
NaBH4 in methanol at 0 °C, to furnish the hydroxyl compound
a) SOCl2, Et3N, DCM,
Cl
OH
O
(DHQD)2PHAL, OsO4
K3[Fe(CN)6], K2CO3
t BuOH:H2O (1:1)
0 °C, 30 min.
9
O
b) NaN3, DMF, RT
OH
12h, 75%
(over two steps)
2 days, 84%, ≥99% ee
6
Cbz
Cl
a) MsCl, Et3N
a) Ph3P, Et2O
RT, 2 h
NH
O
Cl
N3
O
DCM, 0 °C, 30 min.
O
O
b) CbzCl, K2CO3,
b) NaN3, DMF, 50 °C,
OH
OH
12 h, 82%
DCM, 0 °C, 80%
(over two steps)
11
(over two steps)
10
O
Cbz
Cl
Cbz
Cl
a) Ph3P, Et2O,
RT, 2 h
NH
O
N
O
N
O
O
b) ClCO2Et, Et3N,
DCM, 0 °C, 7 h, 86%
(over two steps)
N3
COOEt
12
5
Scheme 3. Synthesis of urea 5.
The azide was reduced under Staudinger reaction conditions14
followed by protection using CbzCl to furnish carbamate 11. The
second amine was installed by converting the hydroxyl group into
its mesylate using mesyl chloride and triethylamine, which was
displaced by an azide using sodium azide in DMF to give
13. The proximal carbamate was also selectively hydrolyzed
during the reduction. The protection of primary hydroxyl group
in 13 with tert-butylchlorodimethylsilane in the presence of
imidazole in dichloromethane at room temperature gave TBS
ether 14.

S. P. Chavan et al. / Tetrahedron: Asymmetry 24 (2013) 1473–1479
1475
O
O
Cbz
Cl
Cbz
Cl
N
N
NaBH4, MeOH,
NH
TBSCl, imdazole,
NH
5
DMAP, DCM,
24 h, 93%
0 °C, 4 h,
79%
OH
OTBS
13
14
O
O
Cl
BnN
BnN
NBn
O3, MeOH:DCM (1:5)
NaH, BnBr,
NBn
NaHCO3, -78 °C,
30 min, 92%
THF, 0 °C,
3 h, 95%
OTBS
O
OTBS
O
O
4
15
O
a) TsCl, Et3N
DMAP, DCM,
0 °C, 24 h,
85%
O
BnN
NBn
BnN
NBn
CSA, MeOH,
SAc
b) KSAc,
RT, 30 h, 90%
O
OH
DMF:THF
O
O
O
O
80 °C, 2 h, 83 %
O
16
3
Scheme 4. Synthesis of thioacetate 3.
Upon treatment with sodium hydride, benzyl bromide 14 was
converted into bisbenzyl imidazolidone 15. A noteworthy feature
of this transformation is the formation of a bis N-benzyl derivative,
which involved the deprotection of the carbamate followed by
alkylation in the same pot. We believe that the protection–depro-
tection proceeds via the reaction pathway illustrated in Scheme 5.
4 was carried out using camphorsulfonic acid to afford the corre-
sponding alcohol 16. We next set out to construct the tetrahydro-
thiophene ring. The introduction of sulfur was carried out by
converting the primary hydroxyl group into a good leaving group.
The hydroxyl group in compound 16 was converted into its tosyl-
ate after which it was displaced by potassium thioacetate in
Br
O
O
N
Br
O
O
O
N
O
Cl
O
O
Cl
O
Cl
N
N
NaH
NH
N
OTBS
OTBS
OTBS
14
Br
Br
O
N
O
NBn
O
N
O
O
N
Cl BnN
Cl
N
Cl
OTBS
OTBS
OTBS
15
Scheme 5. Possible mechanism for conversion of 14 into 15.
First, benzyl protection of the NH takes place under the basic reac-
tion conditions. The bromide generated is possibly responsible for
the nucleophilic deprotection of the carbamate. Finally, the anion
formed attacked on the benzyl bromide resulting in 15. The struc-
ture of 15 was determined by spectroscopic analysis. The IR spec-
DMF:THF to furnish thioacetate 3 (Scheme 4).16 With all of the
structural constituents for biotin being present and in place in
compound 3, the only thing left to do was the acetate deprotection
of 3. Efforts toward this seemingly simple deprotection of acetate 3
to thiol 17 failed under a variety of reaction conditions.17 Finally,
hydrolysis under enzymatic condition using lipase (Candida rug-
osa)18 gave thiol 17 in good yields. Subsequent cyclization of thiol
17 with a catalytic amount of DBU and elimination using pTSA gave
olefin 2 (Scheme 6).
The spectroscopic data for olefin 2 were in agreement with the
literature.8 Since the conversion of olefin 2 to (+)-biotin 1 has been
reported by us8,9 and others,1 this constitutes as a formal synthesis
of (+)-biotin.
trum of 15 showed the disappearance of a peak at 1775 cmꢀ1
,
which clearly indicated the loss of the Cbz group. The 1H NMR
spectrum of 15 revealed four upfield signals at 4.00, 4.08, 4.52,
and 4.93 thus indicating the installation of benzyl groups. The
HRMS peak at m/z 547.2523 further supported the formation of
bis N-benzyl derivative 15.
When performing the ozonolysis reaction, imidazolidone 15
was converted into ketoester 4. Deprotection of the TBS ether of

1476
S. P. Chavan et al. / Tetrahedron: Asymmetry 24 (2013) 1473–1479
O
S
O
i) DBU, toluene,
100 °C, 3 h.
BnN
NBn
lipase, phosphate
buffer (pH 6.8)
BnN
NBn
3
ii) pTSA, toluene,
RT, 4h, 82%
RT, 2 h, 80%
SH
O
O
O
over two steps
O
O
2
17
Scheme 6. Synthesis of
D-(+)-biotin.
rated and the aqueous layer was again extracted twice using DCM
(50 mL). The collected organics were dried over anhydrous Na2SO4,
filtered and concentrated in vacuo to furnish chloro aldehyde 8
(14.0 g, 95%) as a crude product.
The crude aldehyde (14.0 g, 97.22 mmol) was dissolved in DCM
(150 mL) and to it was added Ph3PCHCO2Et (50.7 g, 145.83 mmol).
The reaction mixture was stirred for 4 h. The crude residue was di-
rectly adsorbed on silica gel and purified using flash chromatogra-
3. Conclusion
We have accomplished an asymmetric synthesis of D-(+)-biotin
by employing Sharpless asymmetric dihydroxylation as the single
source of chirality. The enantioselectivity was introduced by inter-
molecular asymmetric induction, which is the first report of its
kind utilized in the synthesis of biotin. The carboxyalkyl side chain
of D-(+)-biotin was introduced by unmasking of a cyclohexene, and
phy (4% EtOAc/pet ether) to furnish the
(25.7 g, 76%) as a colorless liquid. Rf (10% EtOAc/pet ether) 0.6; IR
(CHCl3): 2938, 1713, 1622, 1292, 1175 cmꢀ1 1H NMR (200 MHz,
CDCl3+CCl4): d 1.30 (t, J = 7.1 Hz, 3H), 1.62–1.76 (m, 4H), 2.26 (br
s, 2 H), 2.51 (br s, 2H), 4.21 (q, J = 7.1 Hz, 2 H), 5.85 (d,
J = 15.9 Hz, 1 H), 7.91 (d, J = 15.9 Hz, 1 H); 13C NMR (100 MHz,
CDCl3+CCl4): d 14.2, 21.7, 23.3, 26.1, 35.1, 60.1, 118.1, 128.5,
139.0, 141.1, 166.7; HRMS ESI [M+H]+ calcd for C11H16O2Cl
215.0833, found 215.0832.
a,b-unsaturated ester 9
is a novel strategy in our synthesis.
;
4. Experimental
4.1. General
Melting points are recorded using a Buchi B-540 or M-560 melt-
ing point apparatus in capillary tubes and are uncorrected; the
temperatures are in °C. IR spectra were recorded on a Perkin–Elmer
Infrared Spectrophotometer Model 68B or on a Perkin–Elmer 1615
FT Infrared spectrophotometer. 1H (200, 400 and 500 MHz) and 13
C
4.3. (2S,3R)-Ethyl 3-(2-chlorocyclohex-1-en-1-yl)-2,3-dihydr
oxypropanoate 6
(50, 100 and 125 MHz) NMR spectra were recorded on a Bruker
spectrometer, using a 2:1 mixture of CDCl3 and CCl4 as solvent.
The chemical shifts (d ppm) and coupling constants (Hertz) are re-
ported in the standard fashion with reference to chloroform-d 7.26
To a mixture of K3Fe(CN)6 (13.8 g, 42.03 mmol), K2CO3 (5.8 g,
42.03 mmol), and (DHQD)2PHAL (0.109 g, 0.14 mmol) in tBuOH-
H2O (1:1, 120 mL) cooled at 0 °C was added osmium tetroxide
(1 mL, 0.1 M solution in toluene, 0.4 mol %) followed by methane
sulfonamide (1.32 g, 14.01 mmol). After stirring for 5 min at 0 °C,
olefin 9 (3.0 g, 14.01 mmol) was added in one portion. The reaction
mixture was stirred at 0 °C for 2 days and then quenched with solid
sodium sulfite (6 g). The stirring was continued for an additional
45 min and then the solution was extracted with EtOAc
(3 ꢁ 30 mL). The combined organic layers were dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
using silica gel (30% EtOAc/pet ether) to provide diol 6 (2.92 g,
84% yield) as a white solid. Melting point 65–67 °C. Rf (20%
(for 1H) or the central line (77.0 ppm) of CDCl3 (for 13C). In the 13
C
NMR spectra, the nature of the carbons (C, CH, CH2, or CH3) was
determined by recording the DEPT-135 spectra. The enantiomeric
excesses of the products were determined by HPLC employing a
chiralcel OJ-H column (250 ꢁ 4.6 mm) or comparing the specific
rotation of the known compounds. The reaction progress was mon-
itored by TLC analysis using thin layer plates precoated with silica
gel 60 F254 (Merck) and visualized by fluorescence quenching or io-
dine or by charring after treatment with p-anisaldehyde. Merck’s
flash silica gel (200–400 mesh) was used for column chromatogra-
phy. All small scale dry reactions were carried out using standard
syringe-septum techniques. Low temperature reactions were car-
ried out using a bath made of sodium chloride and ice. Dry DCM
was prepared by distillation over phosphorus pentoxide or calcium
hydride. Dry DMF was prepared by distillation over calcium hy-
dride. Dry toluene was prepared by distillation over calcium hy-
dride. All other reagents and solvents were used as received from
the manufacturer, unless otherwise specified. All air and water
sensitive reactions were performed in flame dried flasks under a
positive flow of argon and conducted under an argon atmosphere.
EtOAc/pet ether) 0.3; ½a D25
ꢂ
¼ þ5:2 (c 1.92, CHCl3); IR (CHCl3):
3446 (broad), 2937, 1736, 1105 cmꢀ1
;
1H NMR (500 MHz, CDCl3+-
CCl4): d 1.31 (t, J = 7.1 Hz, 3H), 1.59–1.79 (m, 4 H), 2.12–2.43 (m,
4H), 2.82 (br s, 1H), 3.29 (br s, 1H), 4.20–4.34 (m, 3H), 4.95 (d,
J = 4.2 Hz, 1H); 13C NMR (125 MHz, CDCl3+CCl4): d 14.2, 22.0,
23.7, 25.5, 34.1, 62.1, 72.1, 73.2, 128.5, 132.6, 172.8; HRMS ESI
[M+Na]+ calcd for C11H17O4ClNa 271.0708, found 271.0706.
4.4. (2S,3S)-Ethyl 3-azido-3-(2-chlorocyclohex-1-en-1-yl)-2-
hydroxypropanoate 10
4.2. (E)-Ethyl 3-(2-chlorocyclohex-1-en-1-yl)acrylate 9
To a cooled (0 °C) solution of diol 6 (2.5 g, 10.08 mmol) in DCM
(25 mL) was added Et3N (2.82 mL, 20.16 mmol) followed by thio-
nyl chloride (1.02 mL, 12.09 mmol) in a dropwise manner. The
resulting reaction mixture was then stirred for 2 h at room temper-
ature and concentrated under reduced pressure to obtain the sul-
fite as a thick oil. The crude sulfite was dissolved in DMF (30 mL)
and to this solution was added sodium azide (1.3 g, 20 mmol)
and stirred overnight. The reaction mixture was quenched using
water (150 mL) and extracted in EtOAc (2 ꢁ 20 mL). The combined
A mixture of anhydrous DCM (80 mL) and anhydrous DMF
(15.7 mL, 204.08 mmol) was cooled to 0 °C using ice and to this
was added POCl3 (15.1 mL, 163.26 mmol) dropwise and stirred
for 2 h at room temperature. Cyclohexanone
7
(10.0 g,
102.04 mmol) in DCM (20 mL) was then added dropwise at 0 °C
and stirred for 4 h at room temperature. The reaction mixture
was quenched first by using ice followed by the careful addition
of satd. NaHCO3 solution. The reaction mixture was allowed to sep-
arate in separating funnel, after which the organic layer was sepa-

S. P. Chavan et al. / Tetrahedron: Asymmetry 24 (2013) 1473–1479
1477
organics were washed with water, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo carefully. The crude product
was purified on flash chromatography using silica gel (20%
EtOAc/pet ether) to afford azidialcohol 10 (2.05 g, 75%) as a gummy
(br s, 1H), 4.99–5.15 (m, 2H), 5.21–5.38 (m, 2H), 7.27–7.44 (m,
5H); 13C NMR (100 MHz, CDCl3+CCl4): d 14.1, 22.1, 23.4, 27.0,
34.0, 53.4, 62.3, 64.8, 67.1, 128.1, 128.2 (2C), 128.5 (2C), 130.0,
130.6, 136.3, 155.2, 167.7; HRMS ESI [M+Na]+ calcd for C19H23O4-
N4ClNa 429.1300, found 429.1295.
liquid. Rf (20% EtOAc/pet ether) 0.5; ½a D25
ꢂ
¼ ꢀ40:9 (c 1.32, CHCl3);
IR (CHCl3): 3448 (broad), 2938, 2104, 1736, 1603, 1267 cmꢀ1
;
1H
NMR (200 MHz, CDCl3+CCl4): d 1.34 (t, J = 7.1 Hz, 3H), 1.54–1.88
(m, 4H), 2.19 (br s, 2H), 2.40 (br s, 2H), 2.92 (br s, 1H), 4.19–4.36
(m, 3H), 5.01 (d, J = 5.9 Hz, 1H); 13C NMR (100 MHz, CDCl3+CCl4):
d 14.1, 22.1, 23.6, 26.2, 34.2, 62.3, 65.1, 71.6, 128.6, 132.6, 172.4;
HRMS ESI [M+Na]+ calcd for C11H16O3N3ClNa 296.0772, found
296.0770.
4.7. (4R,5S)-1-Benzyl 3,4-diethyl 5-(2-chlorocyclohex-1-en-1-
yl)-2-oxoimidazolidine-1,3,4-tricar-boxylate 5
To a solution of azide 12 (2.1 g, 5.17 mmol) in diethyl ether
(20 mL) was added PPh3 (3.39 g, 12.92 mmol) and stirred until
the evolution of nitrogen gas ceased (2.5 h). After completion of
the reaction, the solvent was evaporated under reduced pressure
to obtain the amine as a thick oil. The crude amine was dissolved
in DCM (25 mL) and to this solution were added Et3N (5.74 mL,
40.96 mmol) and ethyl chloroformate (3.88 mL, 40.96 mmol) at
0 °C and stirred (12 h). The reaction mixture was then quenched
with water (30 mL) and extracted in DCM (2 ꢁ 20 mL). The com-
bined organics were washed with brine, dried over anhydrous Na2-
SO4, filtered, and concentrated in vacuo. The crude product was
purified on flash chromatography using silica gel (20% EtOAc/pet
ether) to afford urea 5 (2.1 g, 86%) as a gummy liquid. Rf (30%
4.5. (2S,3S)-Ethyl 3-(((benzyloxy)carbonyl)amino)-3-(2-chloro
cyclohex-1-en-1-yl)-2-hydroxypro panoate 11
To a solution of azidoalcohol 10 (2.0 g, 7.32 mmol) in diethyl
ether (20 mL) were added PPh3 (4.57 g, 18.31 mmol) and stirred
until the evolution of nitrogen gas ceased (2 h). After completion
of the reaction, the solvent was evaporated under reduced pressure
to obtain the amine as a thick oil. The crude amine was dissolved in
DCM (20 mL) and to this solution was added K2CO3 (2.51 g,
18.2 mmol), CbzCl (1.49 mL, 8.74 mmol) and stirred overnight
(12 h). The reaction mixture was filtered and the filtrate was trea-
ted with water (30 mL) and was extracted in DCM (2 ꢁ 20 mL). The
combined organics were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The crude product was
purified on flash chromatography using silica gel (20% EtOAc/pet
ether) to afford carbamate 11 (2.2 g, 80%) as a gummy liquid. Rf
EtOAc/pet ether) 0.4; ½a D25
ꢂ
¼ ꢀ8:1 (c 2.6, CHCl3); IR (CHCl3): 2929,
1818, 1750, 1726, 1694, 1437, 1250 cmꢀ1
;
1H NMR (200 MHz,
CDCl3+CCl4): d 1.25–1.38 (m, 6H), 1.53–1.71 (m, 4H), 1.89 (br s,
2H), 2.18–2.45 (m, 2H), 4.18–4.41 (m, 5H), 5.15 (d, J = 12.2 Hz,
1H), 5.29 (d, J = 2.9 Hz, 1H), 5.38 (d, J = 12.2 Hz, 1H), 7.27–7.44
(m, 5H); 13C NMR (100 MHz, CDCl3+CCl4): d 14.07, 14.14, 21.6,
23.2, 24.1, 33.9, 55.4, 58.0, 62.4, 63.7, 68.4, 128.3 (2C), 128.47,
128.53 (2C), 129.5, 131.7, 134.9, 147.4, 150.3, 151.0, 168.6; HRMS
ESI [M+Na]+ calcd for C23H27ClN2O7Na 501.1399, found 501.1400.
(30% EtOAc/pet ether) 0.4; ½a D25
ꢂ
¼ ꢀ17:9 (c 1.59, CHCl3); IR (CHCl3):
3393 (broad), 2932, 1732, 1690, 1511, 1218 cmꢀ1
;
1H NMR
(500 MHz, CDCl3+CCl4): d 1.30 (t, J = 7.2 Hz, 3H), 1.57–1.69 (m,
4H), 2.10 (br s, 2H), 2.22–2.45 (m, 2H), 2.96 (br s, 1H), 4.07–4.19
(m, 1H), 4.20–4.31 (m, 1H), 4.39 (d, J = 4.3 Hz, 1H), 5.05–5.14 (m,
2H), 5.25–5.29 (m, 1H), 5.55 (d, J = 8.2 Hz, 1H), 7.27–7.40 (m,
5H); 13C NMR (125 MHz, CDCl3+CCl4): d 14.0, 22.2, 23.6, 27.0,
34.3, 54.2, 62.3, 67.0, 72.4, 128.2, 128.3 (2C), 128.5 (2C), 129.4,
131.0, 136.4, 155.4, 172.5; HRMS ESI [M+H]+ calcd for C19H25O5NCl
382.1416, found 382.1408.
4.8. (4R,5S)-Benzyl 5-(2-chlorocyclohex-1-en-1-yl)-4-(hydroxy
methyl)-2-oxoimidazolidine-1-carboxylate 13
To a solution of urea 5 (1.8 g, 3.76 mmol) in methanol (15 mL)
was added NaBH4 (0.57 g, 15.04 mmol) at 0 °C portionwise. The
reaction mixture was allowed to stir for 4 h at room temperature.
After completion of the reaction, the reaction mixture was concen-
trated under reduced pressure. The aq solution of NH4Cl was added
to the semisolid mass and allowed to stir for 30 min after which
the reaction mixture was extracted with EtOAc (2 ꢁ 20 mL). The
combined organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The crude product was
purified on flash chromatography using silica gel (90% EtOAc/pet
ether) to afford alcohol 13 (0.9 g, 79%) as a white solid. Melting
4.6. (2R,3S)-Ethyl 2-azido-3-(((benzyloxy)carbonyl)amino)-3-
(2-chlorocyclohex-1-en-1-yl) propanoate 12
To a stirred solution of carbamate 11 (2 g, 5.27 mmol) in dry
DCM (20 mL) was added Et3N (2.21 mL, 15.81 mmol) at 0 °C, fol-
lowed by the dropwise addition of mesyl chloride (0.64 mL,
7.9 mmol) and the reaction mixture was stirred for 4 h under a
nitrogen atmosphere. The reaction mixture was diluted with
DCM (20 mL) and washed with a saturated solution of sodium
bicarbonate (20 mL) and water (20 mL). The organic layer was sep-
arated, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to afford the O-mesyl compound.
point 165–167 °C. Rf (EtOAc) 0.3 long tail; ½a D25
¼ ꢀ65:5 (c 2.0,
ꢂ
CHCl3); IR (CHCl3): 3370 (broad), 2931, 2860, 1773, 1389, 1337,
1288, 1117 cmꢀ1 1H NMR (400 MHz, CDCl3+CCl4): d 1.35–1.55
;
(m, 3H), 1.61–2.01 (m, 4H), 2.13–2.37 (m, 3H), 3.33 (br s, 1H),
3.54–3.65 (m, 1H), 3.73–3.76 (m, 1H), 4.99 (d, J = 12.1 Hz, 1H),
5.19 (d, J = 3.5 Hz, 1H), 5.33 (d, J = 12.1 Hz, 1H), 7.26–7.35 (m,
5H); 13C NMR (100 MHz, CDCl3+CCl4): d 21.8, 23.4, 24.4, 33.9,
56.7, 57.9, 64.1, 67.5, 128.3 (3C), 128.4 (2C), 128.8, 131.6, 135.4,
151.1, 156.5; HRMS ESI [M+Na]+ calcd for C18H21O4N2ClNa
387.1082, found 387.1080.
To a solution of the crude O-mesyl compound in anhydrous
DMF (25 mL) was added sodium azide (0.68 g, 10.44 mmol) and
the reaction mixture was stirred at 50 °C for 12 h under nitrogen
atmosphere. After completion of the reaction (monitored by TLC),
the reaction mixture was cooled to room temperature, diluted with
water (75 mL), and extracted with EtOAc (3 ꢁ 20 mL). The com-
bined organic extracts were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography using silica gel
(7% EtOAc/pet ether) to afford azide 12 (2.12 g, 82%) as a gummy
4.9. (4R,5S)-Benzyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-
(2-chlorocyclohex-1-en-1-yl)-2-oxoimidazolidine-1-carboxyl
ate 14
To a solution of alcohol 13 (800 mg, 2.65 mmol) in anhydrous
DCM (10 mL) was added imidazole (360 mg, 5.3 mmol) followed
by the addition of TBSCl (600 mg, 3.97 mmol) and DMAP (cat.) at
0 °C under a nitrogen atmosphere. The reaction was then allowed
to stir at room temperature for 24 h. After completion of the reac-
liquid. Rf (10% EtOAc/pet ether) 0.5; ½a D25
ꢂ
¼ þ11:6 (c 1.73, CHCl3);
IR (CHCl3): 2930, 2114, 1742, 1505, 1216 cmꢀ1
;
1H NMR
(400 MHz, CDCl3+CCl4): d 1.26 (t, J = 7.0 Hz, 3H), 1.60–1.73 (m,
4H), 1.98–2.19 (m, 2H), 2.39 (br s, 2H), 4.13–4.34 (m, 2H), 4.48

1478
S. P. Chavan et al. / Tetrahedron: Asymmetry 24 (2013) 1473–1479
tion (monitored by TLC), the reaction mixture was diluted with
water (15 mL) and extracted with DCM (3 ꢁ 15 mL). The combined
organic layer was dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was purified
on flash chromatography using silica gel (50% EtOAc/pet ether) to
afford TBS ether 14 (1.17 g, 93%) as a colorless liquid. Rf (50%
(100 MHz, CDCl3+CCl4) d ꢀ5.6, -5.5, 22.5, 24.2, 25.9 (3 C), 29.8,
33.7, 37.4, 46.3, 47.2, 51.5, 56.4, 62.7, 63.5, 127.69, 127.75, 128.1
(2 C), 128.7 (2 C), 128.7 (2 C), 128.8 (2 C), 136.5, 137.0, 159.6,
173.4, 207.4; HRMS ESI [M+Na]+ calcd for C31H44O5N2NaSi
575.2912, found 575.2915.
EtOAc/pet ether) 0.5; ½a D25
ꢂ
¼ ꢀ47:5 (c 4.0, CHCl3); IR (CHCl3):
4.12. Methyl 6-((4R,5R)-1,3-dibenzyl-5-(hydroxymethyl)-2-oxo
imidazolidin-4-yl)-6-oxohexanoate 16
2923, 2857, 1775, 1390, 1333, 1108 cmꢀ1
;
1H NMR (400 MHz,
CDCl3+CCl4): d 0.02 (s, 6H), 0.83 (s, 9H), 1.48–1.63 (m, 4H), 1.85–
2.03 (m, 2H), 2.18–2.26 (m, 2H), 3.28–3.31 (m, 1H), 3.63 (qd,
J = 10.4, 4.4 Hz, 2H), 5.06 (d, J = 12.3 Hz, 1H), 5.17 (d, J = 2.5 Hz,
1H), 5.32 (d, J = 12.3 Hz, 1H), 6.70 (s, 1H), 7.25–7.38 (m, 5H); 13C
NMR (100 MHz, CDCl3+CCl4): d ꢀ5.5, ꢀ5.4, 18.1, 21.7, 23.4, 24.4,
25.7 (3C), 33.8, 56.3, 57.8, 65.2, 67.4, 128.1, 128.27 (2C), 128.34
(2C), 128.8, 131.8, 135.6, 150.9, 155.9; HRMS ESI [M+Na]+ calcd
for C24H35O4N2ClNaSi 501.1947, found 501.1947.
To a solution of ester 4 (1 g, 1.81 mmol) in MeOH (10 mL) was
added camphorsulfonic acid (42 mg, 0.18 mmol) at 0 °C. The reac-
tion was then allowed to stir at room temperature for 30 h. After
completion of the reaction (as monitored by TLC), the reaction mix-
ture was concentrated under reduced pressure. An aq. solution of
NaHCO3 was then added to the semisolid mass and extracted with
EtOAc (2 ꢁ 20 mL). The combined organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified on flash chromatography
using silica gel (60% EtOAc/pet ether) to afford alcohol 16
(713 mg, 90%) as a white solid. Melting point 84–86 °C. Rf (60%
4.10. (4R,5S)-1,3-Dibenzyl-4-(((tert-butyldimethylsilyl)oxy)
methyl)-5-(2-chlorocyclohex-1-en-1-yl)imidazolidin-2-one 15
To a solution of 60% NaH (137 mg, 5.72 mmol, washed with dry
petroleum ether by 2–3 times) in dry THF (10 mL) was added TBS
ether 14 (1.1 g, 2.29 mmol) in anhydrous THF (5 mL) at 0 °C, stirred
for 10 min. Benzyl bromide (0.72 mL, 5.72 mmol) was then added
dropwise and the reaction was stirred for 3 h at room temperature.
Upon completion of the reaction, it was quenched by the addition
of satd. NH4Cl solution and extracted with EtOAc (2 ꢁ 15 mL),
washed with water then brine. The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The crude product was purified on flash chroma-
tography using silica gel (10% EtOAc/pet ether) to afford benzyl
protected cyclic urea 15 (1.14 g, 95%) as%) as a white solid. Melting
EtOAc/pet ether) 0.3; ½a D25
ꢂ
¼ ꢀ11:1 (c 2.0, CHCl3); IR (CHCl3):
3409 (broad), 2928, 1726, 1682, 1451, 1238 cmꢀ1
;
1H NMR
(500 MHz, CDCl3+CCl4) d 1.36 (br s, 4H), 2.10–2.25 (m, 4H), 2.76
(br s, 1H), 3.20 (br s, 1H), 3.49 (d, J = 11.6 Hz, 1H), 3.62 (br s, 1H),
3.67 (s, 3H), 3.86 (s, 1H), 4.12–4.15 (m, 2H), 4.75–4.89 (m, 2H),
7.19–7.40 (m, 10H); 13C NMR (125 MHz, CDCl3+CCl4) d 22.4, 24.1,
33.6, 37.7, 46.2, 47.4, 51.5, 56.7, 61.5, 63.5, 127.78, 127.8, 128.0
(2 C), 128.5 (2 C), 128.8 (2 C), 128.8 (2 C), 136.2, 136.8, 160.0,
173.5, 207.6; HRMS ESI [M+Na]+ calcd for C25H30O5N2Na
461.2047, found 461.2045.
point 87–89 °C. Rf (20% EtOAc/pet ether) 0.6; ½a D25
ꢂ
¼ ꢀ33:1 (c 2.9,
4.13. Methyl 6-((4R,5R)-5-((acetylthio)methyl)-1,3-dibenzyl-2-
oxoimidazolidin-4-yl)-6-oxohexanoate 3
CHCl3); IR (CHCl3): 2930, 2857, 1698, 1448, 1252, 1119 cmꢀ1
;
1H
NMR (200 MHz, CDCl3+CCl4) d ꢀ0.04 (s, 3H), -0.02 (s, 3H), 0.83
(s, 9H), 1.08–1.65 (m, 6H), 2.18–2.24 (m, 2H), 3.09 (dt, J = 6.1,
3.9 Hz, 1H), 3.40–3.67 (m, 2H), 4.00 (d, J = 12.3 Hz, 1H), 4.08 (d,
J = 12.3 Hz, 1H), 4.52 (d, J = 15.0 Hz, 1H), 4.56–4.59 (m, 1H), 4.93
(d, J = 15.0 Hz, 1H), 7.24–7.32 (m, 10H). 13C NMR (125 MHz,
CDCl3+CCl4) d ꢀ5.6, ꢀ5.5, 18.3, 21.7 (2C), 23.6, 25.9 (3C), 34.3,
46.2, 46.9, 56.6, 57.8, 62.6, 127.3, 127.4, 128.3 (2C), 128.4 (2C),
128.5 (2C), 128.8 (2C), 130.2, 131.1, 137.4, 137.4, 160.3; HRMS
ESI [M+Na]+ calcd for C30H41O2N2ClNaSi 547.2518, found 547.2523.
To a stirred solution of alcohol 16 (630 mg, 1.44 mmol) in dry
DCM (10 mL) was added Et3N (0.3 mL, 2.16 mmol) at 0 °C, followed
by the addition of tosyl chloride (328 mg, 1.73 mmol) and DMAP
(cat.). The reaction mixture was stirred for 24 h under a nitrogen
atmosphere; after completion of the reaction (monitored by TLC),
the reaction mixture was washed with a saturated solution of
NaHCO3 (10 mL), water (10 mL), and extracted with DCM
(2 ꢁ 20 mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to af-
ford an O-tosyl compound, which was used as such for the next
transformation.
4.11. Methyl 6-((4R,5R)-1,3-dibenzyl-5-(((tert-butyldimethyl
silyl)oxy)methyl)-2-oxoimidazolidin-4-yl)-6-oxohexanoa- te 4
To a solution of crude O-tosyl compound in anhydrous DMF
(8 mL) and anhydrous THF (12 mL) was added sodium thioacetate
(208 mg, 1.83 mmol) and the reaction mixture was stirred at 80 °C
for 2 h under a nitrogen atmosphere. After completion of the reac-
tion (as monitored by TLC), the reaction mixture was cooled to
room temperature, diluted with water (50 mL), and extracted with
EtOAc (3 ꢁ 20 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography using silica gel (20% EtOAc/pet ether) to afford
thioacetate 3 (502 mg, 83%) as a yellow liquid. Rf (20% EtOAc/pet
To
a solution of benzyl protected cyclic urea 15 (1.1 g,
2.10 mmol) and sodium hydrogen carbonate (352 mg, 4.20 mmol)
in dichloromethane (20 mL) and methanol (4 mL) at ꢀ78 °C, ozone
was bubbled. The ozone addition was stopped when the solution
turned blue (35 min) and dimethyl sulfide (1 mL, excess) was
added at the same temperature. The solution was then allowed
to warm to room temperature. All of the solvent was removed from
the reaction mixture under reduced pressure, washed with water,
and extracted with EtOAc (2 ꢁ 20 mL). The combined organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified on flash chroma-
tography using silica gel (20% EtOAc/pet ether) to afford methyl es-
ter 4 (1.07 g, 92%) as a white solid. Melting point 62–64 °C. Rf (30%
ether) 0.4; ½a 2D5
ꢂ
¼ þ40:0 (c 1.0, CHCl3); IR (CHCl3): 2923, 2851,
1728, 1710, 1695, 1451, 1215 cmꢀ1
;
1H NMR (500 MHz, CDCl3+-
CCl4): d 1.31–1.42 (m, 4H), 1.99–2.09 (m, 1H), 2.10–2.21 (m, 3H),
2.24 (s, 3H), 2.85 (dd, J = 14.2, 6.3 Hz, 1H), 3.15 (dd, J = 14.2,
2.7 Hz, 1H), 3.30–3.33 (m, 1H), 3.47 (d, J = 4.6 Hz, 1H), 3.65 (s,
3H), 3.95 (d, J = 15.1 Hz, 1H), 4.05 (d, J = 15.1 Hz, 1H), 4.87–4.90
(m, 2H), 7.21–7.41 (m, 10H); 13C NMR (125 MHz, CDCl3+CCl4): d
22.4, 24.1, 30.5, 31.4, 33.6, 37.8, 45.9, 47.0, 51.5, 54.2, 64.8,
127.82, 127.84, 128.3 (2 C), 128.72 (2 C), 128.76 (2 C), 128.8 (2
EtOAc/pet ether) 0.5; ½a D25
ꢂ
¼ ꢀ12:2 (c 2.0, CHCl3); IR (CHCl3): 2924,
1733, 1706, 1690, 1463, 1252 cmꢀ1
;
1H NMR (400 MHz, CDCl3+
CCl4) d ꢀ0.06 (s, 3H), -0.05 (s, 3H), 0.81 (s, 9H), 1.32–1.39 (m,
4H), 1.98–2.08 (m, 1H), 2.11–2.23 (m, 3H), 3.16 (q, J = 4.3 Hz,
1H), 3.39–3.55 (m, 2H), 3.66 (s, 3H), 3.70 (d, J = 4.3 Hz, 1H), 4.02–
4.06 (m, 2H), 4.79–4.94 (m, 2H), 7.19–7.33 (m, 10H); 13C NMR

S. P. Chavan et al. / Tetrahedron: Asymmetry 24 (2013) 1473–1479
1479
C), 136.2, 136.5, 159.0, 173.4, 194.2, 206.6; HRMS ESI [M+Na]+
calcd for C27H32O5N2NaS 519.1924, found 519.1918.
1H), 7.29–7.37 (m, 10H); HRMS ESI [M+Na]+ calcd for C25H28O3N2-
NaS 459.1713, found 459.1707.
4.14. Methyl 6-((4R,5R)-1,3-dibenzyl-5-(mercaptomethyl)-2-
Acknowledgments
oxoimidazolidin-4-yl)-6-oxohexanoate 17
P.L. thanks CSIR, New Delhi, India, for a fellowship. We thank Dr.
U. R. Kalkote for helpful discussion and Mrs Kunte for HPLC analy-
sis. S. P. C. is grateful to the Council of Scientific and Industrial Re-
search (CSIR)-New Delhi for research funding under the ACT
programme of the 12th five year plan.
A suspension of 3 (300 mg, 2.5 mM) in a phosphate buffer (pH
6.8, 50 mL) was purged with a stream of nitrogen for 5 min. Next,
the lipase (150 mg) from Candida rugosa (706 units/ mg) was added
and the contents were stirred vigorously. After 2 h, the reaction
mixture was extracted with DCM (3 ꢁ 20 mL). The organic extracts
were washed with brine, dried (Na2SO4), and then evaporated to
give thiol 17. The purification of thiol was effected by flash chroma-
tography using silica gel (20% EtOAc/pet ether) to afford thiol 17
(219 mg, 80%) as a yellow liquid. Rf (20% EtOAc/pet ether) 0.4;
References
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½
a 2D5
ꢂ
¼ þ17:5 (c 2.6, CHCl3); IR (CHCl3): 3016, 2923, 2851, 1725,
1695, 1451, 1215 cmꢀ1 1H NMR (200 MHz, CDCl3+CCl4): d 1.11
;
(dd, J = 9.2, 7.8 Hz, 1H), 1.27–1.44 (m, 4H), 2.01–2.28 (m, 4H),
2.47–2.71 (m, 2H), 3.21–3.38 (m, 1H), 3.65 (s, 3H), 3.77 (d,
J = 4.5 Hz, 1H), 4.02 (d, J = 15.2 Hz, 1H), 4.08 (d, J = 14.8 Hz, 1H),
4.85 (d, J = 14.8 Hz, 1H), 4.89 (d, J = 15.2 Hz, 1H), 7.19–7.36 (m,
10H); 13C NMR (50 MHz, CDCl3+CCl4): d 22.3, 24.0, 26.8, 33.5,
37.7, 45.7, 47.3, 51.4, 56.2, 64.5, 127.7 (2 C), 127.9 (2 C), 128.0,
128.4, 128.6 (2 C), 128.7 (2 C), 135.9, 136.3, 159.4, 173.4, 207.4;
HRMS ESI [M+H]+ calcd for C25H31O4N2S 455.1999, found 455.1993.
4.15. (Z)-Methyl 5-((3aS,6aR)-1,3-dibenzyl-2-oxotetrahydro-
1H-thieno[3,4-d]imidazol-4(2H)-ylidene)pentanoate 2
Thiol 17 (200 mg, 0.44 mmol) was dissolved in 5 mL of toluene,
after which DBU (0.03 mmol) was slowly added dropwise at room
temperature under a nitrogen atmosphere with continuous stir-
ring. After the complete addition, the reaction mixture was heated
at 100 °C for 3 h. After completion of the reaction (as monitored by
TLC), toluene was removed under reduced pressure, diluted with
EtOAc (10 mL), and washed with water (5 mL). The organic layer
was separated and washed with brine, dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure after which
it was subjected to elimination.
7. Seki, M.; Simizu, T.; Inubushi, K. Synthesis 2002, 361–364.
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The crude hydroxyl compound (200 mg, 0.44 mmol) was dis-
solved in toluene (5 mL) and pTSA (0.025 mmol) was added at
room temperature. The reaction mixture was then stirred continu-
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was monitored by TLC, which indicated that no unreacted starting
material remained after 4 h. Toluene was then removed under re-
duced pressure, after which was added EtOAc and neutralized with
sodium bicarbonate solution and washed with water (5 mL). The
organic layer was separated and washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification was effected by flash chromatography using silica
gel (20% EtOAc/pet ether) to afford olefin 2 (157 mg, 82%) as a yel-
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low liquid. Rf (30% EtOAc/pet ether) 0.4; ½a D25
¼ þ192 (c 1, CHCl3)
ꢂ
(lit. ½a 2D5
ꢂ
¼ þ194 (c 1, CHCl3)8b; IR (CHCl3): 3032, 2928, 1743,
1634, 1440 cmꢀ1 1H NMR (200 MHz, CDCl3+CCl4) d 1.65–1.75
;
(m, 2H), 2.03–2.11 (m, 2H), 2.27 (t, J = 7.5 Hz, 2H), 2.93–2.97 (m,
2H), 3.66 (s, 3H), 4.01 (d, J = 15.5 Hz, 1H), 4.10 (ddd, J = 9.0, 7.5,
4.0 Hz, 1H), 4.20 (d, J = 15.5 Hz, 1H), 4.73 (d, J = 10.1 Hz, 1H), 4.80
(d, J = 14.5 Hz, 1H), 4.95 (d, J = 15.6 Hz, 1H), 5.41 (t, J = 7.0 Hz,