A practical formal synthesis of D-(+)-biotin from 4-formylazetidin-2-one

Article abstract of DOI:10.1055/s-2007-965992

A practical synthesis of (3S,6R)-1,3-dibenzyltetrahydro-1H-furo[3,4-d] imidazole-2,4-dione, an important intermediate in the synthesis of biotin, from 4-formyl-3-mesyloxyazetidin-2-one has been achieved. Acid-catalyzed azetidin-2-one ring opening followed by a one-pot conversion of diamine hydrochloride to a cyclic urea and hydroxymethylene to chloromethylene by triphosgene to obtain (4S,5R)-methyl-1,3-dibenzyl-5-chloromethyl-2- oxoimidazolidine-4-carboxylate is the key step in this synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965992

PAPER
1159
A Practical Formal Synthesis of D-(+)-Biotin from 4-Formylazetidin-2-one
S
ynthesis of
D-(+)-
j
Biotinaykumar S. Kale,a Vedavati G. Puranik,b Abdul Rakeeb A. S. Deshmukh*a
a
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Center for Materials Characterization, National Chemical Laboratory, Pune 411 008, India
Fax +91(20)25902624; E-mail: Abdulrakeeb.Deshmukh@emcure.co.in
b
Received 19 July 2006; revised 16 February 2007
O
X
O
S
Abstract: A practical synthesis of (3S,6R)-1,3-dibenzyltetrahydro-
1H-furo[3,4-d]imidazole-2,4-dione, an important intermediate in
the synthesis of biotin, from 4-formyl-3-mesyloxyazetidin-2-one
has been achieved. Acid-catalyzed azetidin-2-one ring opening fol-
lowed by a one-pot conversion of diamine hydrochloride to a cyclic
urea and hydroxymethylene to chloromethylene by triphosgene to
obtain (4S,5R)-methyl-1,3-dibenzyl-5-chloromethyl-2-oxoimida-
zolidine-4-carboxylate is the key step in this synthesis.
BnN
H
NBn
H
HN
NH
H
H
O
HO2C
3
1a, X = O
1b, X = S
(+)-biotin (2)
Key words: b-lactams, cyclization, reduction, lactone, azetidin-2-
one
O
O
BnN
NBn
H
BnN
NBn
H
H
H
RO2C
CO2R
Azetidin-2-ones, present as moieties in a variety of b-lac-
tam antibiotics,1–3 are being recognized as an important
building block in the synthesis of variety of pharmaceuti-
cally useful products.4 The strain energy associated with
the four member azetidin-2-one ring makes it susceptible
for the nucleophilic ring cleavage. The selective bond
cleavage of the strained ring coupled with further interest-
ing transformations render this fascinating molecule a
powerful building block.5 Efforts have been made in ex-
ploring such new aspects of b-lactam chemistry using
enantiomerically pure b-lactams as a versatile synthon for
the synthesis of many heterocyclic non-b-lactam struc-
tures,6 aromatic b-amino acids and their derivatives,7 and
oligopeptides.4c One such synthetic intermediate, 4-
formylazetidin-2-one, has found wide applications as a
building block5,6 in organic synthesis. This is mainly due
to the fact that there are quite a few methods available for
the preparation of enantiopure 4-formylazetidin-2-ones.7
As a part of our ongoing research program on the synthe-
sis and application of azetidin-2-ones as synthon,8 we
have also used 4-formylazetidin-2-ones as a building
block for the synthesis of biologically useful organic mol-
ecules.9 We herein report an application of 4-formylazeti-
din-2-one as a building block in the synthesis of (3S,6R)-
1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-2,4-di-
one (1a), which is a crucial intermediate in the synthesis
D-(+)-biotin (2)10 (Figure 1).
O
O
X
3, R = H
4, R = alkyl
5, X = O
6, X = NBn
Figure 1 Compounds 1–6
sequent modifications is still one of the best syntheses.11a
The potential of this approach depends upon the efficient
method available for making optically active lactone 1a or
thiolactone 1b. This is considered to be one of the most
expedient approaches to the synthesis of biotin.10 Most of
the syntheses reported for the bicyclic lactone 1a revolve
around the desymmetrization of meso diacid 3, diester 4,
cyclic anhydride 5 and bicyclic imide 6, followed by fur-
ther transformations. The conversion of meso diacid 3 to
lactone 1a via enzymatic resolution involved multi-step
and also resulted in poor overall yield.10h Asymmetric hy-
drolysis of meso diester 4 using PLE (pig liver esterase)
gave low enantioselectivity for hemiesters.10i The desym-
metrization of cyclic anhydride10k,l 5 and cyclic imide10c,m
6 (Figure 1) by asymmetric reduction involved use of ex-
pensive chiral ligands in large quantities. A modified cin-
chona alkaloid was also reported as a catalyst for the
desymmetrization of cyclic anhydride 5 to a hemiester.10e
Apart from these methods a multi-step synthesis of lac-
tone 1a from L-aspartic acid in 11% overall yield was re-
ported.10f
In spite of the biological significance and the commercial
importance of biotin, there are very few practical methods
available for the synthesis of enantiopure lactone 1a, a key
intermediate in the synthesis of D-(+)-biotin (2). Our ex-
perience in the b-lactam synthesis inspired us to design a
retro-synthetic route (Scheme 1) for 1a, from 4-formyl-b-
lactam. We envisaged that the SN2 substitution of mesyl-
oxy group of 3-mesyloxy-4-hydroxymethyl-b-lactam (8)
with an azido group would provide the trans-3-azido-4-
The biological and commercial importance of biotin has
made it a fascinating target molecule for total synthesis
for more than fifty years.11 Although numerous synthetic
approaches have been reported to date, the first synthesis
of biotin described by Goldberg and Sternbach, and sub-
SYNTHESIS 2007, No. 8, pp 1159–1164
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.03.2007
DOI: 10.1055/s-2007-965992; Art ID: Z14706SS
© Georg Thieme Verlag Stuttgart · New York

1160
A. S. Kale et al.
PAPER
O
OH
OH
N3
BnHN
NHBn
H
H
H
N
H
H
N
NHBn
H
H
H
N
BnN
H
NBn
H
N3
MsO
CHO
Bn
MsO
H
H
O
O
O
O
O
O
O
Bn
O
O
Bn
1a
11
10
9
8
7
Scheme 1
OH
Bn
hydroxymethyl-b-lactam (9) with the desired stereochem-
istry, which on ring-expansion would provide the azido-
lactone 10. Further transformation of the azido group to
NHBn and tying both the nitrogens with a carbonyl group
would provide the target bicyclic lactone 1a.
Bn
H
H
H
H
N
N
MsO
CHO
Bn
MsO
H
H
b
a
N
O
O
O
O
7
8, 82%
12, 80%
In our recent communication9b we have shown that aziri-
dino-g-lactone 12 can be obtained in excellent yield from
3-mesyloxy-4-formylazetidin-2-one (7) in two steps
(Scheme 2). The same procedure was employed for the
preparation of optically pure starting N-benzyl-4-formyl-
3-mesyloxyazetidin-2-one and its reduction to N-benzyl-
4-hydroxymethyl-3-mesyloxyazetidin-2-one by sodium
borohydride. The displacement of the mesyloxy group
with an azide was achieved by heating 8 with sodium
azide in anhydrous DMF at 80 °C for 36 hours. The trans-
azido-b-lactam 9 was obtained in very good yield with a
complete inversion of the configuration at C3 of the aze-
tidin-2-one ring. The azetidin-2-one ring expansion reac-
tion of 9 with methanolic-HCl at room temperature
resulted in very poor yield (20%) of the azidolactone 10.
All our efforts to improve the yield of 10 were unsuccess-
ful. Moreover, the reduction of azido group by catalytic
hydrogenation or transfer hydrogenation gave a complex
mixture of products. The Staudinger reaction of azide 10
with n-tributylphosphine in the presence of benzyl bro-
mide also did not give the desired product 11 (R = Bn).
Scheme 2 Reagents and conditions: a) NaBH4, MeOH, r.t., 3 h; b)
HCl–MeOH (20%), reflux, 8 h.
cided to reduce azido-b-lactam 9 to the corresponding
amino-b-lactam 13 (R = H). The reduction of azido-b-lac-
tam 9 was successfully achieved by transfer hydrogena-
tion using Pd/C and ammonium formate in methanol to
afford amino-b-lactam 13 (R = H) in very good yield. The
amino-b-lactam 13 (R = H) was further converted to the
corresponding N-Cbz-derivative for the purpose of char-
acterization. The amino-b-lactam 13 (R = H) was then
transformed to N-benzyl derivative 14 in good yield by re-
acting with benzaldehyde followed by in situ reduction of
the corresponding Schiff base with sodium borohydride.
N-Benzylamino-b-lactam 14 was treated with methanolic
HCl (20%) at room temperature to obtain the highly polar
ring cleavage product, the dihydrochloride 15. Our efforts
to isolate the free base from the dihydrochloride 15 in pure
form were unsuccessful. Therefore, the dihydrochloride
15 was directly reacted with triphosgene in the presence
of triethylamine. Interestingly, a one-pot conversion of di-
amine to cyclic urea and hydroxymethylene to the corre-
Since all our efforts to improve the yield of azidolactone
10 and its further reduction to amino lactone failed, we de-
OH
OH
H
H
N
OH
H
H
H
H
N
BnHN
RHN
N3
a
d
e
b
8
N
O
Bn
O
Bn
O
Bn
13
14, 80%
9
R = H, 85%
c
R = Cbz, 90%
O
O
BnHN
NHBn
H
BnN
H
NBn
H
BnN
H
NBn
H
g
f
H
O
⋅2HCl
OH
O
Cl
O
OMe
O
OMe
1a, 85%
16, 65%
15
Scheme 3 Reagents and conditions: a) NaN3, DMF, 80 °C, 36 h; b) HCO2NH4, Pd/C (10%), MeOH, reflux, 45 min; c) CbzCl, NaHCO3, ace-
tone–H2O (2:1), 1.5 h; d) i. PhCHO, MgSO4, CH2Cl2, r.t., 12 h, ii. NaBH4, MeOH, 0 °C to r.t., 2.5 h; e) HCl–MeOH (20%), r.t., 14 h; f) Et3N,
triphosgene, –20 °C, 2 h; g) aq KOH (2.5%), THF, 0 °C to r.t., 5 h.
Synthesis 2007, No. 8, 1159–1164 © Thieme Stuttgart · New York

PAPER
Synthesis of D-(+)-Biotin
1161
(3R,4R)-1-Benzyl-4-formyl-3-mesyloxyazetidin-2-one (7)
sponding chloromethylene took place simultaneously to
afford chloroester 16 in 65% yield (Scheme 3). The struc-
ture of 16 was established by spectral data and further
confirmed by a single-crystal X-ray analyses (Figure 2).
The conversion of the chloroester 16 to the desired
(3S,6R)-1,3-dibenzyltetrahydro-1H-furo[3,4-d]imidazole-
2,4-dione (1a), was achieved by stirring with aqueous
KOH (2.5%) in THF at room temperature for 5 h in 85%
yield. The optical purity (ee >99%) was determined by
chiral HPLC. The spectral data and the specific rotation
were found to be identical with the reported values.10e,n
The synthesis of D-(+)-biotin 2 from the lactone 1a can be
achieved by using a reported synthetic protocol.11
This compound was prepared by our earlier reported procedure;9b
[a]D30 +18 (c = 1.0, CHCl3).
IR (CHCl3): 1772, 1733 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.14 (s, 3 H), 4.20 (dd, J = 1.3, 5.4
Hz, 1 H), 4.31 (d, J = 14.7, 1 H), 4.70 (d, J = 14.7 Hz, 1 H), 5.66 (d,
J = 5.3 Hz, 1 H), 7.12–7.31 (m, 5 H), 9.47 (d, J = 1.3 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 38.8, 46.1, 61.7, 78.4, 128.4,
128.8, 129.1, 133.4, 161.6, 195.6.
MS: m/z = 284 (M + 1).
Anal. Calcd for C12H13NO5S: C, 50.87; H, 4.63; N, 4.94; S, 11.30.
Found: C, 50.69; H, 4.56; N, 4.87; S, 11.19.
(3R,4S)-1-Benzyl-4-hydroxymethyl-3-mesyloxyazetidin-2-one
(8)
To a cooled solution of 79b (1.43 g, 5.0 mmol) in MeOH (30 mL) at
0 °C, was added NaBH4 (0.370 g, 10 mmol) portionwise under ar-
gon. The mixture was allowed to warm to r.t. and stirred for 3 h. Af-
ter completion of the reaction (TLC), H2O (10 mL) was added
carefully and the mixture was further stirred for 1 h. MeOH was re-
moved under reduced pressure and the residue was extracted with
EtOAc (2 × 40 mL). The combined organic layers were washed
with brine (10 mL) and dried (Na2SO4). Removal of the solvent un-
der reduced pressure gave the crude product, which was purified by
column chromatography using acetone–PE (20:80) to afford alco-
hol 8 (1.18 g, 82%) as a white solid; mp 79–80 °C; [a]D30 +7 (c =
1.0, CHCl3).
IR (CHCl3): 3458, 1751 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.90 (s, 1 H), 3.28 (s, 3 H), 3.81–
3.91 (m, 3 H), 4.35 (d, J = 14.9 Hz, 1 H), 4.64 (d, J = 14.9 Hz, 1 H),
5.58 (d, J = 4.4 Hz, 1 H), 7.27–7.40 (m, 5 H).
13C NMR (CDCl3, 50 MHz): d = 38.9, 45.4, 57.9, 59.6, 78.5, 128.2,
128.3, 129.0, 134.6, 162.9.
Figure 2 ORTEP diagram of 16
MS: m/z = 286 (M + 1).
Anal. Calcd for C12H15NO5S: C, 50.51; H, 5.30; N, 4.92; S, 11.22.
Found: C, 50.43; H, 5.17; N, 4.77; S, 11.04.
In conclusion we have demonstrated the utility of azeti-
din-2-one as a synthon for the synthesis of the bicyclic
lactone 1a, an important intermediate in biotin synthesis.
In this synthesis a crucial step is the azetidin-2-one ring
opening followed by a one-pot conversion of diamine hy-
drochloride to cyclic urea and hydroxymehylene to chlo-
romethylene by triphosgene to get the cyclic chloroester
16. The starting b-lactam is also easily available in opti-
cally pure form and all the other steps of the synthesis are
operationally simple and give very good yields.
(3S,4R)-3-Azido-1-benzyl-4-hydroxymethylazetidin-2-one (9)
To a solution of 8 (0.6 g, 2 mmol) in anhyd DMF (20 mL) was add-
ed NaN3 (0.650 g, 10 mmol) and stirred at 80 °C for 36 h. After
completion of the reaction (TLC), the solvent was removed under
reduced pressure. The residue was diluted with EtOAc (200 mL)
and washed with H2O (4 × 20 mL) and brine (10 mL) successively.
The organic layer was dried (Na2SO4) and the solvent was removed
under reduced pressure to afford the crude product, which was pu-
rified by column chromatography using acetone–PE (20:80) to af-
ford 3-azido b-lactam 9 (0.380 g, 78%) as a white solid; mp 72–
73 °C; [a]D25.5 –228 (c = 1.0, CHCl3).
1H NMR and 13C NMR Spectra were recorded in CDCl3 solution on
a Bruker AV 200 or Bruker AV 400 spectrometer and the chemical
shifts are reported in ppm downfield from TMS for 1H NMR spec-
tra. IR spectra were recorded on Shimadzu FTIR-8400 using NaCl
optics. Mass spectrometric measurements were carried out with
electron spray ionization (ESI) on API QSTAR Pulsar mass spec-
trometer. Melting points were recorded on a Büchi Melting Point B
540 and were uncorrected. Optical rotations were recorded on a
JASCO-181 digital polarimeter under standard conditions. The mi-
croanalyses were performed on a Carlo-Erba, CHNS-O EA 1108 el-
emental analyzer. Petroleum ether (PE) used had boiling range 60–
80 °C.
IR (CHCl3): 3392, 2102, 1731 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.79 (s, 1 H), 3.47–3.51 (m, 1 H),
3.67 (d, J = 3.3 Hz, 2 H), 4.33 (d, J = 15.2 Hz, 1 H), 4.52 (d,
J = 14.9 Hz, 1 H), 4.56 (s, 1 H), 7.26–7.39 (m, 5 H).
13C NMR (CDCl3, 50 MHz): d = 44.7, 58.6, 60.2, 64.8, 128.0,
128.9, 134.5, 164.7.
MS: m/z = 233 (M + 1).
Anal. Calcd for C11H12N4O2: C, 56.87; H, 5.21; N, 24.13. Found: C,
56.70; H, 5.17; N, 24.04.
Synthesis 2007, No. 8, 1159–1164 © Thieme Stuttgart · New York

1162
A. S. Kale et al.
PAPER
(3S,4R)-3-Azido-4-(benzylamino)dihydrofuran-2(3H)-one (10)
3-Azido-4-hydroxymethyl azetidin-2-one (9; 0.5 g, 2.15 mmol) was
dissolved in methanolic HCl (20%, 10 mL) and the mixture was
stirred for 34 h at r.t. After the reaction was over (TLC), MeOH was
removed under reduced pressure and sat. NaHCO3 solution was
added to the residue. It was then extracted with EtOAc (3 × 20 mL)
and the combined organic extracts were washed with brine (10 mL).
It was dried (Na2SO4) and the solvent was removed under reduced
pressure. The residual thick oil was quickly purified by flash col-
umn chromatography using acetone–PE (20:80) as an eluent to fur-
nish 10 (0.1 g, 20%) as a white solid; mp 143–144 °C (dec.);
[a]D30 –55.1 (c = 1.0, MeOH).
Anal. Calcd for C19H20N2O4: C, 67.03; H, 5.93; N, 8.23. Found: C,
67.1; H, 5.83; N, 8.18.
(3S,4R)-3-Aminobenzyl-1-benzyl-4-hydroxymethylazetidin-2-
one (14)
To a mixture of amine 13 (R = H) (0.38 g, 1.83 mmol) in anhyd
CH2Cl2 (15 mL) was added activated MgSO4 (0.4 g) and benzalde-
hyde (2.1 mL, 2.0 mmol) at 0 °C under argon. The mixture was then
allowed to warm up to r.t. and stirred for another 10 h. The resulting
mixture was filtered and the filtrate was concentrated under reduced
pressure. The residue was dissolved in MeOH (5 mL) and NaBH4
(0.08 g, 2.1 mmol) was added slowly at 0 °C with stirring. It was
further stirred at the same temperature for 2.5 h. The mixture was
poured into H2O (5 mL) and extracted with EtOAc (2 × 20 mL). The
organic extracts were washed with brine and dried (Na2SO4). The
solvent was removed under reduced pressure to get the crude prod-
uct, which was purified by silica gel column chromatography using
EtOAc–PE (40:60) to afford pure 14 (0.46 g, 85%) as a colorless oil;
[a]D25 –57.56 (c = 1.0, CHCl3).
IR (CHCl3): 3394, 2119, 1774 cm–1.
1H NMR (DMSO-d6, 200 MHz): d = 4.22–4.50 (m, 3 H), 4.53–4.80
(m, 1 H), 4.82 (d, J = 9.6 Hz, 1 H), 5.30 (d, J = 7.4 Hz, 1 H), 7.42–
7.58 (m, 5 H).
13C NMR (DMSO-d6, 125 MHz): d = 42.4, 49.5, 53.9, 69.8, 128.8,
128.9, 129.1, 130.4, 171.8.
IR (CHCl3): 3404, 1737 cm–1.
MS: m/z = 233 (M + 1).
1H NMR (CDCl3, 200 MHz): d = 1.95 (br s, 2 H), 3.37–3.43 (m, 1
H), 3.49–3.61 (m, 2 H), 3.84 (d, J = 13 Hz, 1 H), 3.94 (d, J = 13 Hz,
1 H), 4.02 (d, J = 1.9 Hz, 1 H), 4.36 (d, J = 15 Hz, 1 H), 4.48 (d,
J = 15 Hz, 1 H), 7.27–7.38 (m, 10 H).
13C NMR (CDCl3, 50 MHz): d = 44.8, 51.2, 60.4, 61.1, 66.6, 127.3,
127.9, 128.2, 128.3, 128.9, 129.1, 135.8, 139.0, 168.8.
Anal. Calcd for C11H12N4O2: C, 56.87; H, 5.21; N, 24.13. Found: C,
56.68; H, 5.14; N, 24.00.
(3S,4R)-3-Amino-1-benzyl-4-hydroxymethylazetidin-2-one (13,
R = H)
A mixture of 9 (0.5 g, 2.16 mmol), ammonium formate (0.41 g, 6.47
mmol), 10% Pd/C (0.05 g) in MeOH (10 mL) was heated at reflux
for 1 h. The mixture was filtered through a small pad of Celite and
washed with EtOAc (2 × 10 mL). The solvent was removed under
reduced pressure. The residue was diluted with EtOAc (50 mL) and
washed with H2O (2 × 5 mL) and brine (5 mL). The organic layer
was dried (Na2SO4) and the solvent was removed under reduced
pressure to afford 13 (R = H) (0.34 g, 85%) as a white solid. The
compound was unstable and the color changed to dark brown on
keeping; mp 115–116 °C; [a]D25 –60.28 (c = 1.0, CHCl3).
MS: m/z = 297 (M + 1).
Anal. Calcd for C18H20N2O2: C, 72.94; H, 6.81; N, 9.46. Found: C,
72.91; H, 6.78; N, 9.26.
(4S,5R)-1,3-Dibenzyl-5-chloromethyl-2-oxoimidazolidine-4-
carboxylic Acid Methyl Ester (16)
A solution of methanolic HCl (20%, 12 mL) was added slowly to 14
(0.4 g, 1.18 mmol) and the mixture was stirred at r.t. for 14 h. The
progress of the reaction was monitored by TLC. The solvent was
completely removed under reduced pressure and the residue was
taken up in anhyd THF (7 mL) and the suspension was cooled to
–20 °C. Et3N (0.86 mL, 6 mmol) was added to the mixture followed
by a solution of triphosgene (0.361 g, 1.21 mmol) in anyhd THF (5
mL) over a period of 1 h. The mixture was then stirred further for 2
h at –20 °C. The solvent was removed under reduced pressure and
the residue was dissolved in H2O (5 mL). It was extracted with
EtOAc (2 × 10 mL) and washed with brine (5 mL). The organic lay-
er was dried (Na2SO4) and the solvent was distilled off under re-
duced pressure to afford a crude product which was purified by
column chromatography using EtOAc–PE (15:85) to furnish pure
chloroester 16 (0.27 g, 65%) as a white crystalline solid; mp 85–
86 °C; [a]D25 +2.72 (c = 1.1, CHCl3).
IR (CHCl3): 3332, 3271, 1739 cm–1.
1H NMR (CDCl3, 200 MHz): d = 2.10–2.22 (m, 3 H), 3.29 (br s, 1
H), 3.60 (d, J = 3.6 Hz, 2 H), 3.99 (br s, 1 H), 4.26 (d, J = 14.9 Hz,
1 H), 4.41 (d, J = 14.9 Hz, 1 H), 7.20–7.29 (m, 5 H).
MS: m/z = 207 (M + 1).
(3S,4R)-3-Amino(benzyloxycarbonyl)-4-hydroxymethylazeti-
din-2-one (13, R = Cbz)
To a solution of 3-amino azetidin-2-one 13 (R = H) (0.2 g, 0.97
mmol) in acetone–H2O (8:2, 10 mL) was added NaHCO3 (0.37 g,
3.88 mmol) portionwise. After complete addition, the mixture was
stirred for 15 min and benzyl chloroformate (0.15 mL, 1.45 mmol)
was slowly added. After completion of the reaction (1.5 h by TLC),
acetone was removed under reduced pressure. The residue was dis-
solved in H2O (5 mL), extracted with EtOAc (2 × 20 mL). The
combined EtOAc extracts were washed with brine (5 mL). The or-
ganic layer was dried (Na2SO4) and the solvent was distilled off un-
der reduced pressure to afford a crude product, which was purified
by column chromatography using acetone–PE (20:80) to furnish
pure 13 (R = Cbz) (0.27 g, 65%) as a colorless oil; [a]D25.5 –14.47
(c = 1.0, CHCl3).
IR (CHCl3): 1743, 1708 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.45–3.56 (m, 2 H), 3.66 (s, 3 H),
3.70–3.80 (m, 1 H), 3.91 (d, J = 11.1 Hz, 1 H), 3.95 (d, J = 14.9 Hz,
1 H), 4.12 (d, J = 15.7 Hz, 1 H), 4.79 (d, J = 15.7 Hz, 1 H), 4.97 (d,
J = 14.9 Hz, 1 H), 7.13–7.30 (m, 10 H).
13C NMR (CDCl3, 50 MHz): d = 40.51, 46.3, 46.6, 52.5, 55.8, 57.5,
127.8, 128.5, 128.8, 129.1, 136.0, 136.5, 159.8, 168.9.
IR (CHCl3): 3415, 3332, 1747 cm–1.
MS: m/z = 373 (M + 1).
1H NMR (CDCl3, 200 MHz): d = 3.48–3.63 (m, 3 H), 4.25 (d,
J = 14.9 Hz, 1 H), 4.39–4.47 (m, 3 H), 5.63 (br s, 1 H), 4.99 (d,
J = 12.2 Hz, 1 H), 5.06 (d, J = 12.2 Hz, 1 H), 7.19–7.26 (m, 10 H).
Anal. Calcd for C20 H21ClN2O3: C, 64.49; H, 5.69; N, 7.55; Cl, 9.39.
Found: C, 64.38; H, 5.49; N, 7.43; Cl, 9.21.
X-ray Crystal Data for 16
13C NMR (CDCl3, 50 MHz): d = 45.0, 60.0, 60.5, 61.8, 67.3, 128.0,
Single crystals of the compound were grown by slow evaporation of
the solution mixture of CH2Cl2 and PE. Colorless needle of approx-
imate size 0.40 × 0.09 × 0.04 mm, was used for data collection on
128.1, 128.2, 128.5, 128.9, 135.2, 135.8, 156.2, 165.7.
MS: m/z = 341 (M + 1).
Synthesis 2007, No. 8, 1159–1164 © Thieme Stuttgart · New York

PAPER
Synthesis of D-(+)-Biotin
1163
Bruker SMART APEX CCD diffractometer using MoKa radiation
with fine focus tube with 50 kV and 30 mA. Crystal to detector dis-
tance 6.05 cm, 512 × 512 pixels/frame, multiscan data acquisition.
Total scans = 5, total frames = 2142, oscillation/frame –0.3°, expo-
sure/frame = 25.0 sec/frame, maximum detector swing angle =
–30.0°, beam center = (260.2, 252.5), in plane spot width = 1.24,
SAINT integration, q range = 2.21 to 22.49°, completeness to q of
22.49° is 99.8%. SADABS correction applied, C20H21ClN2O3,
M = 372.84. Crystals belong to orthorhombic, space group P212121,
a = 5.7271(4), b = 13.1934(9), c = 25.7863(17) Å, V = 1948.4(2)
Å3, Z = 4, Dc = 1.271 mg m–3, m (MoKa) = 0.217 mm–1, T = 293(2)
K, 13315 reflections measured, 2553 unique [I > 2s(I)], R value
0.0973, wR2 = 0.2043. All the data were corrected for Lorentzian,
polarization and absorption effects. SHELX-97 (ShelxTL)12 was
used for structure solution and full matrix least squares refinement
on F2. Hydrogen atoms were included in the refinement as per the
riding model.
Synthesis of Antibiotics and Related Microbial Products,
Vol. 2; Lukacs, G., Ed.; Springer-Verlag: Berlin, 1993, 621.
(d) Southgate, R. Contemp. Org. Synth. 1994, 1, 417.
(2) The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman &
Hall: London, 1992.
(3) For comprehensive general reviews, see: (a) Koppel, G. A.
In Small Ring Heterocycles, Vol. 42; Hasner, A., Ed.; Wiley:
New York, 1983, 219. (b) Backes, J. In Houben-Weyl,
Methoden der Organischen Chemie, Vol. E16B; Klamann,
D., Ed.; Thieme: Stuttgart, 1991, 31. (c) de Kimpe, N. In
Comprehensive Heterocyclic Chemistry II, Vol. 1B;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Padwa, A.,
Eds.; Pergamon: Oxford, 1996, 507.
(4) (a) Ojima, I. In The Chemistry of b-Lactams; Georg, G. I.,
Ed.; VCH: New York, 1993, 197; and references cited
therein. (b) Palomo, C.; Aizpurua, J.; Ganboa, I. In
Enantioselective Synthesis of Beta-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997, 279–357; and references
cited therein. (c) For a review on this subject, see: Ojima, I.;
Delaloge, F. Chem. Soc. Rev. 1997, 26, 377. (d) Alcaide,
B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226.
(e) Alcaide, B.; Almendros, P. Synlett 2002, 381.
(5) (a) Nagahara, T.; Kametani, T. Heterocycles 1987, 25, 729.
(b) Thomas, R. C. In Recent Progress in the Chemical
Synthesis of Antibiotics; Lukacs, G.; Ohno, M., Eds.;
Springer-Verlag: Berlin, 1990, 553. (c) Palomo, C. In
Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G.; Ohno, M., Eds.; Springer-Verlag: Berlin, 1990,
565. (d) Palomo, C.; Arrieta, A.; Cossio, F. P.; Aizpurua, J.
M.; Mielgo, A.; Aurrekoetxea, N. Tetrahedron Lett. 1990,
31, 6429. (e) Palomo, C.; Cabre, F.; Ontoria, J. M.
Tetrahedron Lett. 1992, 33, 4819. (f) Annunziata, R.;
Benaglia, M.; Cinquini, M.; Cozzi, F.; Ponzini, F. J. Org.
Chem. 1993, 58, 4746.
(6) Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226.
(7) (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M. J.
Org. Chem. 1994, 59, 932. (b) Jayaraman, M.; Nandi, M.;
Sathe, K. M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron: Asymmetry 1993, 4, 609. (c) Jayaraman, M.
J.; Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996,
52, 8989. (d) Banik, B. K.; Mathur, C.; Wagle, D. R.;
Manhas, M. S.; Bose, A. K. Tetrahedron 2000, 56, 5603.
(8) (a) Jayaraman, M.; Puranik, V. G.; Bhawal, B. M.
Tetrahedron 1996, 52, 9005. (b) Srirajan, V.; Deshmukh, A.
R. A. S.; Puranik, V. G.; Bhawal, B. M. Tetrahedron:
Asymmetry 1996, 7, 2733. (c) Deshmukh, A. R. A. S.;
Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.;
Shinkre, B. A.; Jayanthi, A. Curr. Med. Chem. 2004, 11,
1889. (d) Shirode, N. M.; Kulkarni, K. C.; Gumaste, V. K.;
Deshmukh, A. R. A. S. ARKIVOC 2005, (i), 53. (e) Tiwari,
D. K.; Gumaste, V. K.; Deshmukh, A. R. A. S. Synthesis
2006, 115.
X-ray crystal structure analysis revealed the stereochemistry of C4
and C5 carbon centers as 4S and 5R. The molecule has a disorder in
the alkyl halide group attached to C5 carbon atom (Figure 2).
(3aS,6aR)-1,3-Dibenzyltetrahydro-1H-furo[3,4-d]imidazole-
2,4-dione (1a)
To a cooled solution of 16 (0.140 g, 0.393 mmol) in THF (4 mL)
was added a solution of KOH (0.051 g, 0.78 mmol) in H2O (2 mL).
The mixture was stirred at r.t. for 5 h. The solvent was removed un-
der reduced pressure and the residue was neutralized by adding aq
HCl (20%) at 0 °C, stirred for 15 min and extracted with EtOAc
(2 × 20 mL). The combined organic extracts were washed with
brine (5 mL) and dried (Na2SO4). The solvent was removed under
reduced pressure and the crude product was purified by column
chromatography using EtOAc–PE (15:85) to give lactone 1a (0.107
g, 85%) as a white crystalline solid. The ee was determined to be
99.9% (HPLC conditions: Column: Daicel Chiralcel OD-H,
250 × 4.6 mm id; detector: UV set at l = 254 nm; mobile phase:
hexane: propan-2-ol, 7:3; flow rate: 0.5 mL/min; tR: = 31.0 min);
mp 118–119 °C (Lit.10n mp 120–121 °C); [a]D25 +58.1 (c = 1.2,
CHCl3) [Lit. [a]D25 +58.2 (c = 1, benzene);10n [a]D25 = +56.4 (c =
1.12, CHCl3)10e].
IR (CHCl3): 1782, 1703 cm–1.
1H NMR (CDCl3, 400 MHz): d = 3.84 (d, J = 8 Hz, 1 H), 4.02–4.07
(m, 3 H), 4.24 (d, J = 6.4 Hz, 1 H), 4.30 (d, J = 5.9 Hz, 1 H), 4.55
(d, J = 14.9 Hz, 1 H), 4.96 (d, J = 14.9 Hz, 1 H), 7.18–7.29 (m, 10
H).
13C NMR (CDCl3, 100 MHz): d = 45.2, 46.9, 52.4, 54.4, 70.1,
127.8, 128.1, 128.2, 128.7, 128.8, 129.0, 135.9, 136.0, 158.2, 172.7.
MS: m/z = 323 (M + 1).
Anal. Calcd for C19H18N2O3: C, 70.78; H, 5.63; N, 8.69. Found: C,
70.68; H, 5.60; N, 8.59.
(9) (a) Krishnaswamy, D.; Govande, V. V.; Deshmukh, A. R. A.
S. Synthesis 2003, 1903. (b) Kale, A. S.; Deshmukh, A. R.
A. S. Synlett 2005, 2370.
Acknowledgment
The authors thank Mrs. S. S. Kunte for carrying out HPLC analyses,
DST New Delhi for financial support and CSIR New Delhi for re-
search fellowship to A.S.K.
(10) (a) Seki, M.; Hatsuda, M.; Mori, Y.; Yoshida, S.-i.; Yamada,
S.-i.; Shimizu, T. Chem. Eur. J. 2004, 10, 6102.
(b) Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 1635.
(c) Chen, F. E.; Dai, H. F.; Kuang, Y. Y.; Jai, H. Q.
Tetrahedron: Asymmetry 2003, 14, 3667. (d) Seki, M.;
Kimura, M.; Hastuda, M.; Yoshida, S.-i.; Shimizu, T.
Tetrahedron Lett. 2003, 44, 8905. (e) Choi, C.; Tian, S.-K.;
Deng, L. Synthesis 2001, 1737. (f) Seki, M.; Shimizu, T.;
Inubushi, K. Synthesis 2002, 361. (g) Shimizu, T.; Seki, M.
Tetrahedron Lett. 2000, 41, 5099. (h) Wang, Y.-F.; Shi, C.
J. Tetrahedron Lett. 1984, 25, 4999. (i) Iriuchijima, S.;
Hasegawa, K.; Tsuchihashi, G. Agric. Biol. Chem. 1982, 46,
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Synthesis 2007, No. 8, 1159–1164 © Thieme Stuttgart · New York