An unusual stereochemical outcome of radical cyclization: Synthesis of (+)-biotin

Article abstract of DOI:10.1016/j.tet.2005.07.070

An enantioselective synthesis of (+)-biotin 1 starting from naturally available cysteine is described. The key steps are the unusual stereochemical outcome of radical cyclization of compound 10 to prepare 5,5-fused system 11, and the introduction of C4-sidechain at C₆ in 13 via a Grignard reaction.

Full text of DOI:10.1016/j.tet.2005.07.070

Tetrahedron 61 (2005) 9273–9280
An unusual stereochemical outcome of radical cyclization:
synthesis of (C)-biotin
*
Subhash P. Chavan, Amar G. Chittiboyina, Guduru Ramakrishna, Rajkumar B. Tejwani,
*
T. Ravindranathan, Subhash K. Kamat, Beena Rai, Latha Sivadasan, Kamalam Balakrishnan,
S. Ramalingam and V. H. Deshpande
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 29 March 2005; revised 6 July 2005; accepted 21 July 2005
Available online 11 August 2005
Abstract—An enantioselective synthesis of (C)-biotin 1 starting from naturally available cysteine is described. The key steps are the
unusual stereochemical outcome of radical cyclization of compound 10 to prepare 5,5-fused system 11, and the introduction of C4-sidechain
at C6 in 13 via a Grignard reaction.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
where formation of 1,5-trans product is reported.3b,c,i,j
However, these are restricted to the formation of mono-
cyclic adducts. Although the formation of bicyclic
compounds employing radical cyclizations leading to 1,5-
trans adducts are known,3d they are restricted to the
formation of 6,5-fused systems. We are not aware of any
instance of acyliminium radical cyclization leading to the
formation of 5,5-fused system with 1,5-trans stereo-
chemistry. In our earlier route we have reported an efficient
conversion of 10 to a bicyclic 5,5-fused system, utilizing
acyliminium ion chemistry2d for the synthesis of biotin.
Based on literature precedents,3 it was our premise that
radical cyclization of 10 would lead to all cis bicyclic ether
11a, which is the intermediate having the requisite
stereochemistry for the synthesis of biotin. Our continued
interest in the synthesis of biotin2d–f led us to explore radical
cyclization of enol ether 10. Herein, we describe an
interesting approach to the synthesis of (C)-biotin using
intramolecular radical cyclization of a-amido radical to the
silyl enol ether in 10. This manuscript delineates our
findings towards this end. To the best of our knowledge
there is only one report of (C)-biotin synthesis using
intramolecular cyclization onto an alkyne.4
(C)-Biotin 1 is one of the water-soluble B-complex
vitamins. In bound from, it is widely distributed as a cell
constituent of animal and human tissues.
Biochemically, (C)-biotin functions as a cofactor in
carboxylation reactions and is also involved in important
processes such as gluconeogenesis and fatty acid synthesis.1
The importance of (C)-biotin in human nutrition and
animal health has stimulated the development of new
synthetic routes towards this vitamin. To date, a number of
new synthetic routes involving different strategies for
control of the three adjacent chiral centers have been
reported.2 The formation of five membered rings using
radical cyclization has been used extensively in the last few
years for the synthesis of complex molecules.3 From these
reports it is evident that the hex-5-enyl radicals predomi-
nantly undergo exo cyclization resulting in the formation of
1,5-cis derivatives. Only very few examples are reported
2. Results and discussion
Our synthetic route to 1 is outlined in the Schemes 1–3.
According to the planned synthesis, hydantoin 4 was
prepared from L-cysteine hydrochloride hydrate by a
literature procedure.5,6 Reduction of hydantoin 4 with
sodium borohydride gave hydroxy imidazothiazolone 5 in
Keywords: Biotin; Radical cyclization; Exocyclization.
*
Corresponding authors. Tel.: C91 20 5893300 2289; fax: C91 20
5893614; e-mail: sp.chavan@ncl.res.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.070

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S. P. Chavan et al. / Tetrahedron 61 (2005) 9273–9280
Scheme 1. (a) PhCHO, KOAc, MeOH:H2O (1:1), rt, 6 h, 98%; (b) BnNCO, DCM, 60 min, concd HCl, 60 min, reflux, 90 min, 90%; (c) NaBH4, MeOH, 0 8C to
rt, 1 h, 99%; (d) MeOH, p-TSA (cat.), 15 min, 98%; (e) PhSH, p-TSA (cat.), DCM 10 min, 93%; (f) DIBAL-H, toluene, K78 8C, 2 h, 78%; (g) TBSCl, DCM,
DBU, reflux, 30 min, 80%.
Scheme 2. (a) Bu3SnH, AIBN, benzene, reflux, 4 h, 53%.
98% yield, which on methoxylation in the presence of cat.
p-TSA furnished methoxy imidazothiazolone 6. Initial
attempts to effect reductive cleavage of carbon–sulfur
bond under conventional reaction conditions (Zn/AcOH)
resulted in exclusive formation of eliminated product by
loss of methanol.
without isolation was alkylated with ethyl chloroacetate
under anhydrous conditions in acetone using K2CO3,
furnished 7a. Potassium carbonate was proved necessary
for the success of the reaction. Additionally carbon–sulphur
bond cleavage was also achieved by using two other
methods. viz. (a) Li-naphthalide at K78 8C, (b) Zn/NH4Cl
according to conditions of Houlton.7 The resulting thiol in
both cases without isolation was alkylated under basic
conditions with alkyl halides (see Table 1) to furnish the
S-alkylated compounds (7a–7c). In order to establish the
generality of this protocol, the reductive cleavage of
carbon–sulphur bond was studied with a variety of allyl
halides. The results of the reductive cleavage followed by
It was therefore, necessary to cleave the carbon–sulphur
bond of 6 under nonacidic conditions, was achieved by three
different methods. Amongst them, compound 6 on reductive
cleavage of carbon–sulphur bond with Bu3SnH in the
presence of cat. amounts of AIBN in benzene at elevated
temperatures furnished the corresponding tin thiolate, which

S. P. Chavan et al. / Tetrahedron 61 (2005) 9273–9280
9275
Scheme 3. (a) BF3$Et2O, CHCl3, rt, 2 h, 75%; (b) (COCl)2, DMSO, DCM, Et3N, K78 8C to rt, 2.5 h, 61%; (c) Mg, BrCH2CH2CH2Br, THF, 12 h, then cooled
to K15 8C, CO2, 2 h, rt; (d) CH2N2, 15 min, 76% (two steps); (e) MsCl, Et3N, DCM, 0 8C to rt, 3 h; (f) DBU, 60 8C, 12 h, 80% (two steps); (g) 10% Pd–C, H2,
200 psi, 65 8C, 6 h, 99%; (h) HBr (47%), reflux, 5 h, 75%.
Table 1
7 (% Yield)
Alkylating agent
Method Aa
ClCH2COOMe
7a 80%
7a 74%
ClCH2C(O)(CH2)3COOMe
ClCH2CN
7c 78%
7c 76%
7c 70%
ClCH2CH]CH2
7d 85%
7d 80%
7b 70%
7b 64%
7b 58%
Method Bb
Method Cc
7a 63%
7d 73%
a Reduction of C–S bond with tri-n-butyltin hydride.
b Reduction of C–S bond with lithium-naphthalide.
c Reduction of C–S bond with zinc and saturated aqueous NH4Cl.
alkylation are tabulated in Table 1. These results clearly
establish the superiority of tri-n-butyltin hydride as an
efficient reagent for reductive cleavage of carbon–sulphur
bond as compared to Li-naphthalide or Zn/NH4Cl.
Additionally the presence of electronegative nitrogen may
also destabilize the transition state leading to the formation
of syn product.3h We believe that the bulky N-benzyl groups
of imidazolidinone tend to occupy quasi equatorial
positions. The formation of 1,5-trans product 11 can be
rationalized by a boat like transition state of 10a (Scheme 2)
in which the pseudo-axial radical attacks the C]C of the
enol ether in pseudo-equatorial side chain. By this way the
steric compression between N-benzyl adjacent to radical
carbon and the bulky OTBS group of enol ether could be
relieved as compared to the chair like transition state leading
to the formation of 1,5-cis product 11a. This unusual
behavior may also be ascribed to the presence of sulfur atom
in the chain, which mimics the six membered ring
formation.
Compound 7a was then taken up for the synthesis of biotin.
Thus, 7a was converted to its thiophenyl derivative 8 with
excess of thiophenol in dichloromethane and cat. amount of
p-TSA. The ester moiety in the compound 8 was then
reduced to aldehyde 9 with DIBAL-H in toluene at K78 8C,
the crude aldehyde 9 was then converted to its TBS enol
ether 10 (trans:cisZ3:1) by using TBDMSCl, and DBU in
dichloromethane at reflux for 30 min. The crucial step of
synthesis, the radical cyclisation of silyl enolether 10
according to literature precedents3 was expected to undergo
exo cyclisation leading to 1,5-cis substituted bicyclic
skeleton 11a, which would serve as an ideal precursor for
the synthesis of biotin. However, when the silyl enol ether
10 was refluxed with Bu3SnH and catalytic amount of AIBN
under argon atmosphere, a single cyclized product 11 was
obtained in 53% yield, which was eventually shown to be
the undesired 5,5-fused system 11 with incorrect stereo-
center at C-5 position.
This reaction shows that 1,5-trans cyclized products could
be synthesized by appropriately controlling the steric
requirements. More studies are required to arrive at a
proper conclusion.
Although the stereochemistry at the C-5 was not the desired
one, we decided to proceed further and rectify it at the later
stages of the synthesis. In the next step TBS group was
deprotected8 and oxidized to the corresponding aldehyde
under Swern oxidative conditions to furnish bicyclic
aldehyde 13 with undesired configuration at C-5 position
(with respect to (C)-biotin) as the sole product. Since the
isomer 13 is thermodynamically more stable, it cannot be
epimerized at the C-5 position. The side chain of biotin was
The exclusive formation of 1,5-trans product 11 (carbon
having radical assigned 1 in hex-5-enyl system 10a) is
unexpected since other structurally related radicals and their
carbocyclic analogues3d give a mixture with mostly 1,5-cis
products. This may be attributed to the manifestation of
steric and electronic effects of the acylimido radical.

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S. P. Chavan et al. / Tetrahedron 61 (2005) 9273–9280
introduced by the addition of excess of 1,3-propane
dimagnesium dibromide in THF at K15 8C followed by
4.1.2. 6-Benzyl-3-phenyl(3S,7aR)perhydroimidazo[1,5-
c][1,3]thiazol-5,7-dione (4). In a 500 mL two-necked
round bottom flask filled with nitrogen, (20.0 g,
95.6 mmol) thiazolidine carboxylic acid 3 was placed in
150 mL of anhydrous THF. To this suspension, a solution of
(15.2 g, 1.143 mol) benzyl isocyanate in 50 mL of THF was
added dropwise over a period of 20 min. The reaction
mixture was stirred for 1 h at 60 8C. The reaction mixture
was then cooled to 0 8C and concd HCl (20.0 mL) was
added and the reaction mixture was allowed to stir for
90 min at 60 8C. Then the reaction mixture was allowed to
cool to room temperature, water was added and extracted
with ethyl acetate (3!200 mL). The combined organic
layers were dried over anhydrous Na2SO4 filtered and
concentrated under reduced pressure. After triturating with
9
quenching with CO2 at K20 8C to furnish the carboxylic
acid. The carboxylic acid thus formed was characterized as
its methyl ester 14 by treating with diazomethane. The
hydroxy methyl ester 14 was then converted to (C)-biotin
by straight forward functional group manipulations. The
hydroxyl function of 14 was protected as its mesylate and
subsequent treatment of this with DBU afforded known
exocyclic olefin.10 Hydrogenation of this double bond
followed by debenzylation furnished (C)-biotin in 60%
yields over four steps.
3. Conclusion
methanol the hydantoin 4 was obtained as a white
crystalline solid 27.8 g, (90%). Mp 78 8C, [a] C1010
20
365
The synthesis of (C)-biotin starting from the commercially
available L-cysteine hydrochloride hydrate has been
achieved. The noteworthy feature of this synthesis is the
unusual stereochemistry observed during the radical
cyclization to furnish the cis fused bicyclic system, which
highlights the ability of radical cyclizations to form 1,5-
trans products of hexenyl radicals by appropriate control of
steric requirements.
(c 1, CHCl3); [a]DK250 (c 1.08, CHCl3) IR (CHCl3,
cmK1): 3040, 2960, 1720, 1700, 1510, 1420, 1230, 1050. 1H
NMR (CDCl3, 200 MHz): 3.17 (dd, 1H, JZ7.82, 11.2 Hz);
3.30 (dd, 1H, JZ6.81, 11.2 Hz); 4.52 (t, 1H, JZ7.32 Hz);
4.68 (s, 2H); 6.43 (s, 1H); 7.39 (m, 10H). 13C NMR (CDCl3,
125 MHz): 33.2 (t), 42.81 (t), 65.19 (d), 65.82 (d), 126.36
(d), 127.41 (d), 127.91 (d), 128.05 (d), 125.15 (d), 128.28
(d), 128.42 (d), 128.48 (d), 128.72 (d), 128.80 (d), 135.44
(s), 139.04 (s), 158.54 (s, C]O), 171.0 (s, C]O). Mass
(m/z): 325 (MC1, 30), 324 (MC, 100), 323 (MK1, 40), 291
(9), 278 (4), 233 (28), 162 (22), 145 (5), 132 (8), 122 (14),
117 (39), 104 (9), 91 (38), 77 (10), 65 (8), 55 (7). Anal.
Calcd for C18H16N2O2S: C, 66.64; H, 4.97; N, 8.64; S, 9.88.
Found: C, 66.38; H, 5.17; N, 8.43; S, 9.65.
4. Experimental
4.1. General methods
All solvents were freshly distilled before use and dry
solvents were distilled under argon from Na/benzophenone.
1
Melting points are uncorrected. Chemical shifts in H and
13C NMR are reported relative to residual solvents.
Abbreviations for 1H NMR: s, singlet; d, doublet; m,
multiplet. Progress of the reactions were monitored by TLC
using Merck silica gel. 60F254 precoated plates and
visualized by fluorescence quenching or by charring after
treatment with the mixture of p-anisaldehyde–H2SO4 in
ethanol. The products were purified by column chromato-
graphy (SiO2).
4.1.3. (3S,7aR)-6-Benzyl-7-hydroxy-3-phenyltetrahydro-
5H-imidazo[1,5-c][1,3]thiazol-5-one (5). The imidazo-
lidinone 4 (32.4 g, 0.1 mmol) was taken in aqueous THF
or methanol (300 mL) and cooled to 0 8C. Sodium
borohydride (5.6 g, 0.15 mol) was added gradually in
small portions over a period of time (30 min). After addition
of sodium borohydride was complete, the reaction mixture
was brought to room temperature and stirring continued for
additional half an hour. The reaction mixture was then
quenched with water and the contents were extracted with
ethyl acetate. The combined layers were washed with water
(100 mL), brine (100 mL) and dried over anhydrous
Na2SO4 and filtered. After concentration under reduced
pressure a white crystalline solid of hydroxy imidazo-
thiazolone 5, which was sufficiently pure. Yield: 32.5 g
(99%). Mp 113 8C, [a]DC52.58 (c 1, CHCl3) IR (CHCl3,
cmK1): 3400, 3010, 2960, 1700, 1510, 1438, 1310, 1239,
Analytical data of all known compounds were compared
with the literature, and new compounds were fully
characterized.
4.1.1. (2RS,4R)-2-Phenylthiazolidine-4-carboxylic acid
(3).5 To a solution of L-cysteine hydrochloride hydrate 2
(60 g, 0.34 mol), in water (525 mL) was added potassium
acetate (36 g, 0.37 mol) was added and allowed to stir till a
solution was obtained. To this solution 95% of methanol
(525 mL) was added followed by immediate addition of
benzaldehyde (44.2 g, 0.42 mol) in one portion. The
reaction mixture was kept at 25 8C for 3 h and an additional
3 h at 0 8C. The product was formed as a solid was filtered,
washed with methanol, and dried to afford 3 as a white solid.
Yield: 72.0 g (98%). Mp 155 8C (lit.5 159–160 8C), [a]DK
133 (c 1, DMSO) IR (KBr, cmK1): 3040, 2960, 2700–2400
(NHC3 ), 1600–1550 (CO2K) 1360. 1H NMR (DMSO-d6,
200 MHz): 3.50–3.30 (m, 2H, CH2); 4.40–4.0 (dd, 1H,
CHCOOH); 5.80 (s, 1H, CH); 6.80 (bm, 1H, NH); 7.40 (m,
5H). Mass (m/z): 209 (MC, 34), 170 (39), 164 (65), 137
(100), 77 (10), 65 (8), 55 (7).
1
1160, 959. H NMR (CDCl3, 200 MHz): 2.92 (dd, 1H, JZ
6.83, 11.72 Hz); 3.23 (d, 1H, JZ10.26 Hz, –OH, D2O
exchangeable); 3.33 (dd, 1H, JZ5.37, 11.72 Hz); 4.18
(d, 1H, JZ15.14 Hz); 4.19 (m, 1H, JZ5.37, 6.83 Hz,
–CH–CH–OH); 4.78 (d, 1H, JZ15.14 Hz); 5.04 (dd, 1H,
JZ6.84, 10.26 Hz, N–CH–OH); 6.38 (s, 1H); 7.30 (m, 8H);
7.40 (m, 2H). 13C NMR (CDCl3, 125 MHz): 31.60 (t), 43.83
(t), 64.37 (d), 66.03 (d), 77.74 (d), 126.08 (d), 127.93 (d),
128.03 (2C, d), 128.34 (2C, d), 128.41 (2C, d), 128.55
(2C, d), 136.40 (s), 140.98 (s), 159.55 (s, C]O). Mass
(m/z): 326 (MC, 25), 308 (19), 280 (13), 192 (9), 187 (19),
160 (6), 147 (5), 132 (27), 121 (36), 104 (23), 91 (100), 77
(14), 65 (6).

S. P. Chavan et al. / Tetrahedron 61 (2005) 9273–9280
9277
4.1.4. (3S,7aR)-6-Benzyl-7-methoxy-3-phenyltetra-
hydro-5H-imidazo[1,5-c][1,3]thiazol-5-one (6). To
hydroxy imidazothiazolone 5 (32.6 g, 0.1 mol) dissolved
in anhydrous methanol (300 mL) was added cat. amount of
p-TSA and the reaction mixture was stirred at room
temperature for 10 min. After completion of the reaction
(by TLC) the reaction mixture was quenched with solid
sodium carbonate and filtered. Removal of solvent and
extraction with EtOAc furnished the methoxy imidazo-
thiazolone 6. Yield: 33.8 g (99%). Mp 83 8C, [a]DK210 (c
1, CHCl3) IR (CHCl3, cmK1): 2930, 1705, 1510, 1420,
1360, 1236, 1160, 1005. 1H NMR (CDCl3, 200 MHz): 2.55
(t, 1H, JZ9.75 Hz); 3.13 (dd, 1H, JZ4.87, 12.19 Hz); 4.0
(dd, 1H, JZ4.87, 9.75 Hz); 3.30 (s, 3H); 4.21 (d, 1H, JZ
15.14 Hz); 4.65 (s, 1H); 4.90 (d, 1H, JZ15.14 Hz); 6.45 (s,
1H); 7.38 (m, 10H). 13C NMR (CDCl3, 125 MHz): 36.39 (t),
44.60 (t), 52.96 (q), 64.79 (d), 65.37 (d), 86.87 (d), 126.0
(d), 127.65 (d), 127.73 (d), 127.82 (d), 128.13 (d), 128.29
(2C, d), 128.42 (d), 128.55 (d), 128.70 (d), 136.12 (s),
141.36 (s), 160.01 (s, C]O). Mass (m/z): 340 (MC, 24),
309 (6), 294 (54), 240 (6), 203 (19), 187 (5), 174 (13), 144
(6), 132 (42), 121 (8), 106 (33), 91 (100), 77 (13), 65 (6).
Anal. Calcd for C19H20N2O2S: C, 67.03; H, 5.92; N, 8.23; S,
9.42. Found: C, 67.10; H, 5.87; N, 8.56; S, 8.90.
Progress of the reaction was monitored by TLC. After 12 h
the reaction mixture was diluted with water (20 mL) and
extracted with ethyl acetate (2!30 mL). The organic layer
was washed with two 20 mL portions of saturated aqueous
sodium bicarbonate solution, dried over anhydrous Na2SO4,
filtered and evaporated under reduced pressure. The crude
mass was subjected to S-alkylation with alkyl halides as
mentioned in method A.
4.2.1. Methyl ({[(4R)-1,3-dibenzyl-5-methoxy-2-oxo-
imidazolidin-4-yl]methyl}thio)acetate (7a). Yield:
0.386 g (80%). [a]DK18.4 (c 1.04, CHCl3) IR (neat, cmK1):
3006, 2930, 1725, 1701, 1450, 1358, 1234, 1077. 1H NMR
(CDCl3, 200 MHz): 2.50 (dd, 1H, JZ8.3, 12.50 Hz); 2.71
(dd, 1H, JZ4.16, 12.50 Hz); 2.87 (s, 2H); 3.01 (s, 3H); 3.58
(dd, 1H, JZ4.16, 8.3 Hz); 3.64 (s, 3H); 4.0 (d, 1H, JZ
15.46 Hz); 4.31 (d, 1H, JZ15.46 Hz); 4.52 (d, 1H, JZ
15.34 Hz); 4.57 (s, 1H); 5.11 (d, 1H, JZ15.46 Hz); 7.36 (m,
10H). Mass (m/z): 414 (MC, 1), 399 (1), 382 (3), 309 (5),
295 (15), 277 (10), 203 (2), 181 (5), 161 (4), 132 (5), 117
(2), 105 (6), 91 (100), 77 (4), 65 (14).
4.2.2. ({[(4R)-1,3-Dibenzyl-5-methoxy-2-oxoimidazoli-
din-4-yl]-methyl}thio)acetonitrile (7c). Yield: 0.297 g
(78%). [a]DC49.73 (c 1.0, CHCl3) IR (neat, cmK1):
2925, 2230, 1703, 1463, 1359, 1237, 1077. 1H NMR
(CDCl3, 200 MHz): 2.62 (dd, 1H, JZ7.54, 11.32 Hz); 2.80
(dd, 1H, JZ3.89, 11.32 Hz); 3.03 (s, 3H); 3.05 (s, 2H); 3.45
(m, 1H); 4.15 (dd, 2H, JZ15.10 Hz); 4.50 (d, 1H, JZ
1.3 Hz); 4.90 (dd, 2H, JZ15.10 Hz); 7.35 (m, 10H). 13C
NMR (CDCl3, 50 MHz): 17.12 (t), 33.3 (t), 44.6 (t), 45.5 (t),
52.3 (q), 56.3 (d), 88.1 (d), 116.0 (s), 127.5 (d), 127.8 (2C,
d), 128.2 (3C, d), 128.5 (2C, d), 128.8 (2C, d), 136.4 (s),
136.8 (s), 158.2 (s, C]O). Mass (m/z): 381 (MC1, 1), 361
(1), 349 (1), 295 (18), 277 (4), 269 (4), 257 (1), 233 (4), 204
(3), 187 (3), 177 (15), 162 (3), 149 (4), 134 (6), 121 (9), 106
(10), 91 (100), 77 (4), 65 (13). Anal. Calcd for
C21H23N3O2S: C, 66.12; H, 6.08; N, 11.01; S, 8.41.
Found: C, 66.30; H, 5.85; N, 10.82; S, 8.65.
4.2. General procedure for the reductive cleavage of C–S
bond of methoxy imidazothiazolone 6
(A) By using tri-n-butyltin hydride. A solution of methoxy
imidazothiazolone 6 (0.34 g, 1.0 mmol), tributyltin hydride
(0.349 g, 1.2 mmol) and AIBN (50 mg) in dry benzene
(4 mL) was refluxed for 30 min with addition of few crystals
(10 mg) of AIBN at the end of every 10 min. The progress
of the reaction was monitored by TLC. After completion of
reaction, the organic solvent was evaporated and the crude
reaction mixture was stirred with chloro compound
(1.0 mmol) and anhydrous potassium carbonate (0.414 g,
0.3 mmol) in anhydrous acetone (10 mL) for 10–12 h at
room temperature. Filtration and evaporation of organic
solvent furnished a residue, which was column chromato-
graphed on silica gel using 35% ethyl acetate:pet. ether as
eluent to furnish S-alkylated compounds.
4.2.3. (4R)-4-[(Allylthio)methyl]-1,3-dibenzyl-5-methoxy-
imidazolidin-2-one (7d). Yield: 0.325 g (85%). [a]DC41.3
(c 1, CHCl3) IR (neat, cmK1): 3062, 3026, 2922, 1709,
1620, 1494, 1424, 1356, 1224, 1094, 1029. 1H NMR
(CDCl3, 200 MHz): 2.21 (dd, 1H, JZ9.28, 13.68 Hz); 2.58
(dd, 1H, JZ3.90, 13.68 Hz); 2.93 (d, 2H, JZ7.33 Hz); 3.07
(s, 3H); 3.33 (m, 1H, JZ3.90, 9.28 Hz); 4.08 (d, 1H, JZ
15.62 Hz); 4.10 (d, 1H, JZ15.62 Hz); 4.47 (d, 1H, JZ
0.97 Hz); 4.91 (m, 4H); 5.58 (m, 1H); 7.29 (m, 10H). 13C
NMR (CDCl3, 50 MHz): 30.92 (d), 35.01 (d), 44.53 (q),
52.34 (2C, t), 56.77 (t), 88.24 (t), 117.53 (t), 127.36 (d),
127.48 (d), 127.61 (d), 127.94 (d), 128.21 (2C, d), 128.46
(2C, d), 128.67 (d), 133.78 (d), 137.02 (s), 137.16 (s),
159.73 (s, C]O). Mass (m/z): 382 (MC1, 1), 362 (1), 351
(1), 295 (18), 277 (4), 269 (4), 257 (1), 233 (4), 162 (3), 149
(4), 134 (6), 121 (9), 106 (10), 91 (100), 77 (4), 65 (13).
Anal. Calcd for C22H26N2O2S: C, 69.08; H, 6.85; N, 7.32; S,
8.38. Found: C, 69.30; H, 6.55; N, 7.65; S, 8.59.
(B) By using Li/Arene. To a cooled (K78 8C) suspension of
lithium (0.0347 g, 0.011 mmol) and naphthalene (0.0034 g;
0.026 mmol) in tetrahydrofuran (20 mL) was added
methoxy imidazothiazolone 6 (0.340 g, 1.0 mmol) in
tetrahydrofuran (10 mL) and stirred for 3 h. The reaction
mixture was quenched with water as an electrophile and
allowed to warm to room temperature over a period of 1 h.
The reaction mixture was filtered through a pad of Celitew
and washed with ethyl acetate. The organic layer was
separated from filtrate and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous sodium
sulfate, filtered and the solvent was removed under reduced
pressure to furnish the crude residue, which was subjected to
alkylation with halo compounds as mentioned in method A.
(C) By using Zn/saturated NH4Cl. To a solution of methoxy
imidazothiazolinone 6 (0.34 g, 1.0 mmol) in THF (7 mL)
was added activated zinc (2 g, 30.5 mmol) and saturated
aqueous ammonium chloride solution (7 mL). The mixture
was stirred vigorously at 25 8C under nitrogen atmosphere.
4.2.4. Methyl ({[(4S)-1,3-dibenzyl-2-oxo-5-(phenylthio)-
imidazolidin-4-yl]methyl}thio)acetate (8). Methoxy
imidazolidine 7 (4.14 g, 10 mmol) was dissolved in
thiophenol (20 mL) and the solution was cooled to 0 8C.

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S. P. Chavan et al. / Tetrahedron 61 (2005) 9273–9280
To this was then added cat. amount of p-TSA (20 mg,
0.1 mmol) and the mixture was stirred at 0 8C for 5 min.
Mixture of DCM (20 mL) and water (5 mL) was added to
reaction mixture, organic layer was separated, washed with
brine (5 mL), dried over anhydrous Na2SO4 and filtered.
Rotary evaporation of solvent under reduced pressure and
chromatographic purification (20% ethyl acetate:pet. ether)
afforded 4-thiophenoxy-imidazolidine 8. Yield: 4.70 g
(93%). [a]DK19.36 (c 0.98; CHCl3) IR (neat, cmK1):
3030, 2920, 2875, 1725, 1695, 1583, 1495, 1420, 1386,
1365, 1064. 1H NMR (CDCl3, 200 MHz): 2.53 (dd, 1H, JZ
14.0, 7.5 Hz); 2.70 (dd, 1H, JZ14.0, 3.7 Hz); 2.9 (s, 2H);
3.60 (ddd, 1H, JZ3.7, 3.7, 7.5 Hz); 4.0 (d, 1H, JZ15.5 Hz);
3.65 (s, 3H); 4.3 (d, 1H, JZ15.5 Hz); 4.53 (d, 1H, JZ
15.0 Hz); 4.57 (d, 1H, JZ3.7 Hz); 5.1 (d, 1H, JZ15.0 Hz);
7.09 (m, 3H); 7.28 (m, 12H). Mass (m/z): 383 (MCK109,
18), 277 (100), 264 (7), 187 (7), 110 (7), 91 (54). Anal.
Calcd for C27H28N2O3S2: C, 65.83; H, 5.73; N, 5.69; S,
13.02. Found: C, 65.63; H, 5.53; N, 5.39; S, 12.91.
11.6 Hz); 7.0 (m, 3H); 7.35 (m, 12H). Mass (m/z): 467
(MCK109, 5), 277 (40), 203 (7), 110 (29), 91 (100), 73
(28), 65 (13). Anal. Calcd for C32H40N2O2S2Si: C, 66.62; H,
6.99; N, 4.86; S, 11.12. Found: C, 66.40; H, 6.78; N, 4.70; S,
11.01.
4.2.7. (3aS,4S,6aR)-1,3-Dibenzyl-4-({[tert-butyl(di-
methyl)-silyl]oxy}methyl)tetrahydro-1H-thieno[3,4-d]
imidazol-2(3H)-one (11). A solution of phenylthio enol
ether 10 (0.30 g, 0.52 mmol), tributyltin hydride (0.18 g,
0.63 mmol) and AIBN (cat.) in dry benzene (20 mL) was
refluxed for 4 h with addition of few crystals of AIBN at the
end of 2 h. After removal of benzene under reduced
pressure, crude product thus obtained was purified by
column chromatography (SiO2) (10% ethyl acetate:pet.
ether) to furnish the bicyclic silyl ether 11 (0.13 g, 53%) as a
viscous liquid. [a]DC46.2 (c 1.09, CHCl3) IR (neat, cmK1):
2910, 2840, 1690, 1600, 1580, 1495, 1460, 1360, 1250,
1
1100. H NMR (CDCl3, 200 MHz): 0.01 (s, 6H); 0.78 (s,
9H); 2.90 (d, 2H, JZ2.0 Hz); 3.28 (dd, 1H, JZ4.8, 8.1 Hz);
3.40 (dd, 1H, JZ8.1, 10.1 Hz, CH2–OTBS); 3.50 (dd, 1H,
JZ4.8, 10.1 Hz, CH2–OTBS); 4.09 (m, 2H); 4.17 (d, 1H,
JZ15.0 Hz); 4.24 (d, 1H, JZ15.0 Hz); 4.75 (d, 1H, JZ
15.4 Hz); 4.80 (d, 1H, JZ15.4 Hz); 7.25 (m, 10H). Mass
(m/z): 468 (MC, 8), 453 (21), 435 (4), 411 (90), 91 (100).
Anal. Calcd for C26H36N2O2SSi: C, 66.62; H, 7.74; N, 5.98;
S, 6.87. Found: C, 66.40; H, 7.68; N, 5.68; S, 6.76.
4.2.5. ({[(4S)-1,3-Dibenzyl-2-oxo-5-(phenylthio)imidazo-
lidin-4-yl]methyl}thio)acetaldehyde (9). Thiophenoxy
methyl ester 8 (2.21 g, 4.37 mmol) was taken in a 100 mL
two-necked round bottom flask along with 30 mL of
anhydrous toluene under an atmosphere of argon. The
flask was cooled to K78 8C and DIBAL-H (0.68 g,
4.8 mmol) was added slowly at K78 8C and was stirred
for 2 h. After 2 h (TLC) it was quenched with 2.0 mL of
MeOH and 2.0 mL of water. The solution was then stirred
for half an hour and the white solid thus obtained was
filtered. The filtrate was evaporated under reduced pressure
and the residue taken in EtOAc and washed with water. The
organic layer was then dried over anhydrous Na2SO4,
filtered and the product obtained was chromatographed on
silica gel with 25% ethyl acetate:pet. ether to yield the
product aldehyde 9 (1.57 g) in 78% as a colorless viscous
liquid. [a]DK26.7 (c 0.9, CHCl3) IR (neat, cmK1): 3010,
2900, 1710, 1700, 1600, 1580, 1495, 1450, 1390, 1140,
4.2.8. (3aS,4S,6aR)-1,3-Dibenzyl-4-(hydroxymethyl)
tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one (12). To
TBDMS ether 11 (0.312 g, 0.66 mmol) dissolved in
anhydrous dichloromethane (10 mL) under nitrogen
atmosphere was added borontrifluoride etherate (0.473 g,
3.3 mmol). After stirring at room temperature (2 h), the
reaction mixture was neutralized with 1 M NaHCO3
solution and extracted with DCM (2!10 mL). Combined
organic layers were washed with water (2!10 mL), brine,
dried over anhydrous Na2SO4, filtered and chromato-
graphed (SiO2) to furnish the alcohol 12 (0.177 g, 75%) as
a viscous liquid. [a]DC60.38 (c 2, CHCl3) IR (neat, cmK1):
1
1070. H NMR (CDCl3, 200 MHz): 2.32 (m, 2H); 2.80 (d,
2H, JZ3.6 Hz); 3.45 (m, 1H); 3.94 (d, 1H, JZ15.2 Hz);
4.27 (d, 1H, JZ15.2 Hz); 4.40 (d, 1H, JZ15.2 Hz); 4.48 (d,
1H, JZ4 Hz); 5.10 (d, 1H, JZ15.2 Hz); 7.13 (m, 15H);
9.14 (t, 1H). Mass (m/z): 353 (MCK109, 5), 294 (6), 149
(5), 141 (7), 132 (14), 91 (100), 84 (11), 77 (17), 69 (13), 65
(18).
1
3400, 2910, 1690, 1600, 1505, 1480, 1380, 1260, 1100. H
NMR (CDCl3, 200 MHz): 2.20 (br s, 1H, D2O exchange-
able); 2.69 (dd, 1H, JZ4.6, 10.6 Hz); 2.71 (dd, 1H, JZ5.1,
10.6 Hz); 3.30 (s, 2H); 3.83 (d, 1H, JZ8.1 Hz); 4.01 (m,
2H); 4.07 (d, 1H, JZ15.0 Hz); 4.08 (d, 1H, JZ15.4 Hz);
4.71 (app. t, 2H, JZ15.4 Hz); 7.30 (m, 10H). Mass (m/z):
354 (MC, 22), 307 (7), 277 (23), 263 (20), 187 (9), 149 (7),
91 (100), 65 (13), 57 (10). Anal. Calcd for C20H22N2O2S: C,
67.77; H, 6.26; N, 7.90; S, 9.05. Found: C, 67.40; H, 6.28;
N, 7.70; S, 8.95.
4.2.6. (5R)-1,3-Dibenzyl-4-methoxy-5-[({(E/Z)-2-[(tri-
methyl-silyl)oxy]vinyl}thio)methyl]imidazolidin-2-one
(10). A solution of t-butyldimethylsilyl chloride (0.255 g,
1.69 mmol) in anhydrous DCM (5 mL) was added via
syringe to a solution of aldehyde 9 (0.650 g, 1.41 mmol) in
DCM (20 mL). After 5 min, DBU (0.28 g, 1.3 mmol) was
added dropwise and mixture was heated to reflux. After
30 min (TLC) the reaction mixture was concentrated and
purified by column chromatography eluting with 10% ethyl
acetate:pet. ether to furnish 0.65 g, (80%) of TBS enol ether
as a semi solid. IR (neat, cmK1): 2910, 2840, 1695, 1600,
1595, 1450, 1420, 1375, 1210, 1100, 940. 1H NMR (CDCl3,
200 MHz): 0.1 (s, 6H); 0.8 (s, 9H); 2.20 (dd, 1H, JZ7.0,
13.0 Hz); 2.40 (dd, 1H, JZ4.0, 13.0 Hz); 3.40 (m,1H); 3.90
(d, 1H, JZ15.0 Hz); 4.20 (d, 1H, JZ15.0 Hz); 4.30 (d, 1H,
JZ15.0 Hz); 4.55 (d, 1H, JZ3.5 Hz); 5.0 (d, 1H, JZ
15.0 Hz); 5.15 (d, 1H, JZ11.6 Hz); 6.56 (d, 1H, JZ
4.2.9. (3aS,4S,6aR)-1,3-Dibenzyl-2-oxohexahydro-1H-
thieno-[3,4-d]imidazole-4-carbaldehyde (13). To a flame
dried 50 mL round bottom flask equipped with a magnetic
stirrer under nitrogen atmosphere was added dichloro-
methane (5 mL, freshly distilled over P2O5). The flask was
cooled to K78 8C and oxalyl chloride (0.050 g,
0.395 mmol) was added, followed by DMSO (0.061 g,
0.790 mmol). After the mixture was stirred at K78 8C, a
solution of alcohol 12 (0.070 g, 0.197 mmol) in DCM
(2 mL) was added by syringe. The resulting cloudy solution
was stirred at K78 8C for 1 h. Et3N (0.12 g, 1.185 mmol)
was added and the milky white solution was stirred for

S. P. Chavan et al. / Tetrahedron 61 (2005) 9273–9280
9279
30 min at K78 8C. Reaction mixture was allowed to warm
gradually to ambient temperature. After 2 h, water (10 mL)
was added and the organic layer was separated, washed with
saturated aqueous NH4Cl (2 mL), aqueous NaHCO3 (2 mL),
and brine (5 mL). Organic layer was dried over anhydrous
Na2SO4, filtered, evaporated under reduced pressure and
chromatographic purification (SiO2) of the residue (25%
ethyl acetate:pet. ether) furnished aldehyde 13 as a solid
(0.043 g, 61%). Mp 140–141 8C, [a]DK62.4 (c 0.75,
CHCl3) IR (neat): 3120, 2940, 1720, 1695, 1605, 1595,
1500, 1450, 1250. 1H NMR (CDCl3, 200 MHz): 2.29 (dd, 1H,
JZ4.7, 13.2 Hz); 2.68 (dd, 1H, JZ4.7, 13.2 Hz); 3.59 (s, 1H);
4.11 (dd, 1H, JZ4.7, 7.8 Hz); 4.16 (d, 1H, JZ15.4 Hz); 4.34
(d, 1H, JZ7.9 Hz); 4.36 (d, 1H, JZ15.4 Hz); 4.47 (d, 1H, JZ
15.4 Hz); 4.68 (d, 1H, JZ15.4 Hz); 7.25 (m, 10H); 9.13 (s,
1H). Mass (m/z): 352 (MC, 5), 323 (5), 277 (93), 264 (6), 91
(100), 65(6). Anal. CalcdforC20H22N2O2S:C,68.16;H, 5.72;
N, 7.95; S, 9.1. Found: C, 67.73; H, 6.06; N, 7.81; S, 9.35.
was dissolved in anhydrous DCM (20 mL), cooled to 0 8C
and triethyl amine (0.067 g, 0.33 mmol), added. To this
reaction mixture MsCl (0.045 g, 0.393 mmol) was added
and mixture was stirred at room temperature for 3 h, then
diluted with water, and extracted with CH2Cl2 (3!10 mL).
The combined organic layers were washed with dil HCl,
aqueous NaHCO3, and dried over anhydrous Na2SO4.
Removal of the solvent in vacuum yielded 0.172 g (98%)
of mesylate as a dark yellow viscous liquid.
The crude mesylate (0.170 g, 0.32 mmol) was dissolved in
anhydrous DBU (0.486 g, 3.2 mmol) and heated to 60 8C for
12 h. After completion of reaction, the reaction mixture was
acidified with dil HCl (10 mL) and extracted with ethyl
acetate. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered and concen-
trated under reduced pressure. Column chromatography of
the residue over silica gel using ethyl acetate/pet. ether (35:
65) mixture as eluent furnished the olefin 15 as pale yellow
viscous liquid. Yield: (0.110 g, 80%); viscous liquid. [a]DC
194 (c 1, CHCl3) IR (CHCl3, cmK1): 3032, 2928, 1743,
4.2.10. Methyl 5-[(3aS,4S,6aR)-1,3-dibenzyl-2-oxohexa-
hydro-1H-thieno[3,4-d]imidazol-4-yl]-5-hydroxy-
pentanoate (14). Under nitrogen atmosphere, magnesium
(0.061 g, 2.54 mmol) turnings were initially introduced into
THF (10 mL) and the mixture was heated to boiling. A
solution of dibromopropane (0.516 g, 2.54 mmol) in THF
(10 mL) was added to this suspension during 30 min. The
reaction mixture was heated to reflux for 45 min and
subsequently stirred at room temperature for 12 h. It was
then cooled to K15 8C and a solution of cyclic aldehyde 13
(0.18 g, 0.51 mmol) in THF (10 mL) was added dropwise in
the course of 30 min at a temperature between K14 and
K16 8C. After stirring for 10 min the reaction vessel was
evacuated and charged with CO2 atmosphere. To this
reaction mixture solid carbon dioxide (w1 g) was added.
After 1 h, dil HCl (1 N, 5 mL) was added and the reaction
mixture was extracted with EtOAc. The combined organic
layers were washed with water (20 mL), brine (20 mL).
Organic layer was dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure and the crude
product was subjected to esterification with diazomethane.
Chromatographic purification of the residue (50% ethyl
acetate:pet. ether) furnished hydroxy methyl ester 14
(0.176 g, 76%); as a viscous liquid. IR (neat, cmK1):
3310, 3032, 2928, 1743, 1700, 1440, 1342, 1231, 1079, 789.
1H NMR (CDCl3, 200 MHz): 1.25 (m, 2H); 1.59 (m, 2H);
2.22 (t, 2H, JZ7.3 Hz); 2.70 (dd, 1H, JZ2.4, 12.2 Hz); 2.91
(dd, 1H, JZ1.5, 12.2 Hz); 3.20 (m, 1H, JZ1.5 Hz); 3.28 (br
s, 1H); 3.64 (s, 3H); 3.94 (dd, 1H, JZ7.8, 8.3 Hz); 4.06 (m,
2H); 4.12 (d, 1H, JZ15.6 Hz); 4.21 (d, 1H, JZ15.6 Hz);
4.73 (d, 1H, JZ15.1 Hz); 4.75 (d, 1H, JZ15.1 Hz); 7.28
(m, 10H). 13C NMR (CDCl3, 125 MHz): 20.97 (t), 33.48 (t),
35.07 (t), 36.23 (t), 46.27 (t), 46.82 (t), 51.52 (q), 59.49 (d),
62.39 (d), 65.65 (d), 71.63 (d), 127.51 (d), 127.60 (d),
127.97 (2C, d), 128.03 (2C, d), 128.61 (2C, d), 128.67 (2C,
d), 136.97 (2C, s), 159.31 (s, C]O), 173.66 (s, C]O).
Mass (m/z): 454 (MC, 5), 407 (4), 363 (11), 324 (33), 277
(55), 233 (11), 187 (21), 149 (14), 91 (100), 65 (11). Anal.
Calcd for C25H30N2O4S: C, 66.05; H, 6.65; N, 6.16; S, 7.05.
Found: C, 66.12; H, 6.36; N, 5.98; S, 6.87.
1
1701, 1634, 1440, 1415, 1342, 1219, 1143, 1079, 789. H
NMR (CDCl3, 200 MHz): 1.72 (m, 2H); 2.12 (m, 2H); 2.31
(t, JZ7.3 Hz, 2H); 3.05 (dd, JZ9.2, 10.2 Hz, 1H); 3.12 (dd,
JZ4.4, 10.2 Hz, 1H); 3.70 (s, 3H); 4.05 (d, JZ15.4 Hz,
1H); 4.10 (ddd, JZ4.4, 7.3, 9.5 Hz, 1H); 4.25 (d, JZ
15.1 Hz, 1H); 4.30 (d, JZ7.32 Hz, 1H); 4.85 (d, JZ
15.4 Hz, 1H); 5.01 (d, JZ16.0 Hz, 1H); 5.54 (t, JZ7.3 Hz,
1H); 7.35 (m, 10H). Mass (m/z): 436 (MC1, 1), 422 (1), 405
(1), 345 (1), 309 (45), 263 (37), 187 (6), 173 (4), 158 (4),
143 (5), 132 (17), 117 (8), 105 (25), 91 (100), 77 (10), 65
(6).
4.2.12. Dibenzylbiotin methyl ester. A mixture of olefin 15
(0.100 g, 0.23 mmol) and 10% palladium on charcoal
(10 mg) in methanol (20 mL) was hydrogenated (200 psi)
at 65 8C for 8 h. After cooling to room temperature, the
catalyst was removed by filtration and the filtrate was
evaporated under reduced pressure to give the crude N,N0-
dibenzyl biotin methyl ester, which was subjected to
debenzylation without further purification. Mp 78–80 8C,
[a]DK42.13 (c 1.05, CHCl3) IR (CHCl3, cmK1): 3028,
2932, 2840, 1741, 1698, 1448, 1440, 1425, 1347, 1198,
1
1134, 1081, 792. H NMR (CDCl3, 200 MHz): 1.67 (m,
6H); 2.33 (t, 2H); 3.10 (m, 1H); 3.69 (s, 3H); 3.90 (m, 3H);
4.15 (d, JZ15.4 Hz, 1H); 4.75 (d, JZ15.6 Hz, 1H); 5.10 (d,
JZ15.4 Hz, 1H); 7.32 (m, 10H). 13C NMR (CDCl3,
125 MHz): 24.42 (t), 28.14 (t), 28.29 (t), 33.65 (t), 34.53
(t), 46.40 (t), 47.76 (t), 51.25 (d), 54.05 (d), 60.99 (d), 62.46
(q), 127.42 (d, 2C), 128.04 (d, 4C), 128.45 (d, 4C), 136.79
(s, 2C); 160.83 (s, C]O), 173.66 (s, C]O). Mass (m/z):
438 (MC, 8), 347 (13), 277 (31), 265 (13), 240 (9), 187 (18),
149 (4), 91 (100), 77 (3), 65 (9).
4.2.13. D-(C)-Biotin. N,N0-Dibenzyl biotin methyl ester
(0.1 g, 0.23 mmol) was added to a solution of 47%
hydrobromic acid (5 mL). The reaction mixture was stirred
under reflux for 5 h. After cooling to room temperature, the
reaction mixture was extracted with toluene (2!10 mL).
The aqueous phase was concentrated under reduced
pressure to dryness. The residue was dissolved in anhydrous
methanol (5 mL) and refluxed for 2 h in the presence of
concd H2SO4 (one drop). The reaction mixture was
4.2.11. Methyl (5E/Z)-5-[(3aS,6aR)-1,3-dibenzyl-2-oxo-
hexahydro-4H-thieno[3,4-d]imidazol-4-ylidene] penta-
noate (15). The hydroxy ester 14 (0.15 g, 0.330 mmol)

9280
S. P. Chavan et al. / Tetrahedron 61 (2005) 9273–9280
J. Org. Chem. 2001, 66, 6197. (e) Chavan, S. P.; Ramakrishna,
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neutralized with solid NaHCO3, filtered and concentrated
under reduced pressure. Crude solid thus obtained was
dissolved in methanol (10 mL) and charcoal added, heated
and filtered. The filtrate was concentrated under reduced
pressure to furnish a residue, which was chromatographed to
furnish a white solid. The solid was heated on a water bath
with 1 N NaOH (10 mL) and the progress of the reaction
monitored by TLC. The solvent was reduced to 5 mL and
neutralized with concd HCl to pH 2. The white solid thus
obtained was filtered and dried at 80 8C under vacuum to
give pure 1 (0.041 g, 78%). Mp 230–231 8C (lit.11 229.5–
230 8C), [a]DC89.7 (c 1.01, 0.1 N NaOH) lit.11 [a]DC91.3
(c, 1.0, 0.1 N NaOH) IR (KBr, cmK1): 3308, 2929, 1701,
1
1672. H NMR (CDCl3): d 1.30–1.67 (m, 6H, 3!CH2);
2.14 (t, 2H, JZ7.3 Hz); 2.62 (dd, 1H, JZ1.7, 12.5 Hz); 2.78
(dd, 1H, JZ4.7, 12.5 Hz); 3.16 (m, 1H); 4.19 (m, 1H); 4.28
(m, 1H); 6.41 (s, 1H, NH); 6.52 (s, 1H).
Acknowledgements
CAG, GRK and RBT thank CSIR, New Delhi, India for
award of fellowships. Funding from CSIR, New Delhi, India
under YSA scheme is gratefully acknowledged.
4. Corey, E. J.; Mehrotra, M. M. Tetrahedron Lett. 1988, 29,
57–60.
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7. Houlton, R. A.; Crouse, D. J.; Williams, A. D.; Kennedy, R. M.
J. Org. Chem. 1987, 52, 2317.
References and notes
8. Kelly, D. R.; Roberts, S. M.; Newton, R. F. Synth. Commun.
1979, 9, 295.
1. Dakshinamurti, K.; Bhaganan, H. Eds.: Ann. N.Y. Acad. Sci.
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9. Eckstein, J.; Koppe, T.; Schwarz, M.; Casutt, M. Ger. Offen.
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10. Casutt, M.; Poetsch, E.; Speckamp, W. N. Ger. Offen. DE 3
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11. Volkmann, R. A.; Davis, J. T.; Meltz, C. N. J. Am. Chem. Soc.
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2. For a recent review on biotin see DeClercq, P. J. Chem. Rev.
1997, 97, 1755. (b) Zhao, J.; Li, Y.-Z.; Zhang, Q.-S.
Jingxi Huagong 2004, 21, 30. (c) Seki, M.; Kimura, M.;
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