A switch of reactivity profile in ionic intramolecular annulation reactions: A short and efficient synthesis of D-(+)-biotin

Full text of DOI:10.1021/jo015730j

J . Org. Chem. 2001, 66, 6197-6201
6197
Sch em e 1
A Sw itch of Rea ctivity P r ofile in Ion ic
In tr a m olecu la r An n u la tion Rea ction s:
A Sh or t a n d Efficien t Syn th esis of
D-(+)-Biotin
Subhash P. Chavan,* Rajkumar B. Tejwani, and
T. Ravindranathan*
Division of Organic Chemistry: Technology,
National Chemical Laboratory, Pune 411 008, India
Sch em e 2
spchavan@dalton.ncl.res.in
Received May 4, 2001
Cyclization reactions to construct five- or six-membered
rings constitute the backbone of any synthetic strategy.
Although a variety of methods are available to effect
these annulations, there is still a need to develop mild
and efficient methods to effect these cyclizations. The
significance of this is evident by increase in number of
recent publications on newer methodologies to effect this
transformations.1
The subtle difference between reactivity and selectivity
becomes even more critical in effecting these transforma-
tions in the desired direction, and one needs to address
this issue. This aspect becomes even more important
while dealing with multifunctional groups where undes-
ired side reactions become more prominent.
A revealing case study will be the conversion of thio-
enol ether 2 to 5,5-fused system (Scheme 1) in connection
with an efficient D-(+)-biotin (1) synthesis described
herein. D-(+)-Biotin (vitamin H), a biocatalyst of revers-
ible metabolic reactions of carbondioxide transport in
organisms, is one of the B-complex group of vitamins and
has immense commercial importance in poultry feeds and
animal nutrition. It finds application in pharmaceutical
industries as an additive and as an avidin complex in
the area of drug delivery immunoassay, isolation, and
localization.
Although a variety of methods are known for its
synthesis,2 there exists a need to develop an efficient and
practical synthesis of this compound. After completion
of our work,4,5 Speckamp et al.2e published an elegant
synthesis of D-(+)-biotin based on a similar concept.
However, there are remarkable differences between our
approach and Speckamp’s in terms of different products
obtained and reaction conditions employed for the crucial
cyclization.
Ta ble 1. Rea ction of Com p ou n d 2 w ith Differ en t Lew is
Acid s
% of % of % of % of
entry
conditions
3
9
4
10
1
2
3
4
5
6
7
AlCl3, -78 °C, rt
55
62
43
20
30
61
TiCl4, -78 °C, rt
BF3‚Et2O, 0 °C, rt
AgOTf, 0 °C, rt
5
40
TBSOTf, 0 °C, rt
PhSH (1 equiv), rt,
PhSTBS (1 equiv), TBSOTf (cat.),
0 °C, rt
20
70
8
p-nitrobenzaldehyde/TBSOTf (cat.), 95
rt, 5 min
undesired 4 (20% yield) in the former and ureide 10 (40%
yield) (Scheme 3).
(2) For the synthesis of D-(+)-biotin, see: (a) Shimizu, T.; Seki, M.
Tetrahedron Lett. 2000, 41, 5099. (b) Chen, F.; Peng, Z.; Shao, L.;
Cheng, Y. Yaoxue Xuebao, 1999, 34, 822 (Chinese) and reference cited
therein. (c) Brieden, W.; Schroer, J . Eur. Pat. Appl. EP 827957 A1, 11
Mar 1998, 9 pp; Chem. Abstr. 1998, 128, 230190. (d) De Clercq, P. J .
Chem. Rev. 1997, 97, 1755 and references cited therein. (e) Moolenaer,
M. J .; Speckamp, W. N.; Hiemstra, H.; Poetsch, E.; Casutt, M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2391. Casutt, M.; Poetsch, E.;
Speckamp, W. N. Ger. Offen. DE 3.926,690, 14 Feb 1991; Chem. Abstr.
1991, 115, 8429k. (f) Deroose, F. D.; De Clercq, P. J . J . Org. Chem.
1995, 60, 321. (g) Deroose, F. D.; De Clercq, P. J . Tetrahedron Lett.
1994, 35, 265. (h) Fusijawa, T.; Nagai, M.; Kaike, Y.; Shimizu, M. J .
Org. Chem. 1994, 59, 5865. (i) Goldberg, M. W.; Sternbach, L. H. US
Patents 2,489,235 and 2,489,238. 1985; Chem. Abstr. 1951, 45, 186a,
186g. (j) Aoki, S.; Suzuki, H.; Akiyama, H.; Akano, S. US Patent 3,-
876,656, 1975; Chem. Abstr. 1974, 80, 95951z. (k) Declercq, P. J .;
Deroose, F. D. Tetrahedron Lett. 1993, 34, 4365. (l) Alcazar, V.; Tapia,
I.; Morau, J . R. Tetrahedron 1990, 46, 1057. (m) Bihovsky, R.;
Bodepudi, V. Tetrahedron 1990, 46, 7667. (n) Corey, E. J .; Mehrotra,
M. M. Tetrahedron Lett. 1988, 29, 57. (o) Poetsch, E.; Casutt, M.
Chimia 1987, 41, 148. (p) Lee, H. L.; Baggiolini, E. G.; Uskokivic, M.
R. Tetrahedron 1987, 43, 4887. (g) Bates, H. A.; Rosenblum, S. R. J .
Org. Chem. 1986, 51, 3447. (r) Bates, H. A.; Smilowtz, L.; Lin, J . J .
Org. Chem. 1985, 50, 899. (s) Bates, H. A.; Smilowitz, L.; Rosenblum,
S. B. J . Chem. Soc., Chem. Commun. 1985, 353. (t) Kinoshita, H.;
Futagami, M.; Inomata, K.; Kotahe, H. Chem. Lett. 1983, 1275.
(3) (a) Mori, I.; Bartlett, P. A.; Heathcock, C. H. J . Org. Chem. 1990,
55, 5966. (b) Mann, A.; Ricci, A. Tetrahedron Lett. 1988, 29, 6175.
(4) Ravindranathan, T.; Chavan, S. P.; Tejwani, R. B.; Varghese, J .
P. J . Chem. Soc., Chem. Commun. 1991, 1750.
Sulfides are well-known to complex with Lewis acids.3
It was surmised that selective complexation of the sulfide
to generate immonium ion followed by intramolecular
trapping of ionic intermediate 5 should chemoselectively
lead to formation of 3. Although 2 has all the function-
alities set for a 5,5-ring closure, all attempts to convert
2 to 3 met with failure under a variety of Lewis acid
mediated conditions (entries 1-4, Table 1).
The use of silver triflate in stoichiometric amounts
however led to the isolation of the desired 5,5-fused
cyclized product 3, albeit in poor yields (5% !) along with
(5) Ravindranathan, T.; Chavan, S. P.; Tejwani, R. B. Indian Patent
Appl. No. 65/DEL/92, US patent 5,274,107; Chem. Abstr. 1994, 120,
217097t.
(1) For a recent review on cyclization, see: Thebtaranonth, C.;
Thebtanonth, Y. Tetrahedron 1990, 46, 1385 and references therein.
10.1021/jo015730j CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/15/2001

6198 J . Org. Chem., Vol. 66, No. 18, 2001
Notes
Sch em e 3
Sch em e 4
Ta ble 2. Role of Nitr oben za ld eh yd es in Cycliza tion
Treatment of 2 with TBSOTf however, led to the
formation of thioacetal 9 in 20% yield! Formation of
thioacetal 9 along with 3 and 4 indicates that there is a
thin line of demarcation in the reaction pathways leading
to the formation of these products. Encouraged by the
formation of thioacetal 9, it was obvious that its forma-
tion can be rationalized by the liberation of thiophenol
from 2 and its further reaction with 2. It was surmised
that addition of external thiophenol should change the
course of the reaction in favor of thioacetal 9. However,
performing the reaction in the presence of thiophenol led
to the formation of 4 as the exclusive product in 61%
yield. The failure of an additional 1 equiv of thiophenol
to improve the yield of 9 led us to explore the silyl
thiophenol. Thus, PhSTBS was generated in situ and silyl
enol ether 2 was added to it followed by a catalytic
amount of TBSOTf, and as expected, thioacetal 9 was the
exclusive product obtained in 70% yield. Conventional
methods of deprotection (e.g., CAN, HgO) of this thioac-
etal led to poor yields (30%) of aldehyde 3. The thioacetal
9 was smoothly converted to aldehyde 3 by a novel
catalytic transthioacetalization protocol developed by us4
involving one-to-one exchange under anhydrous condi-
tions employing 4-nitrobenzaldehyde as the acceptor and
TMSOTf as the catalyst.
compd
% of 3
% of 4
2-nitrobenzaldehyde (11a )
3-nitrobenzaldehyde (11b)
4-nitrobenzaldehyde (11c)
50
75
95
40
20
Sch em e 5
To effect the cyclization to the desired 5,5-fused system
we chose nitrobenzaldehydes as the thiophenol scaven-
gers (see Table 2). Gratifyingly, the assumption turned
out to be the fact, when silyl enol ether 2 was treated
with catalytic amount of TMSOTf/(or TBSOTf), in the
presence of 4-nitrobenzaldehyde (11c), aldehyde 3 was
obtained as the sole product in 95% (98%) yield along
with formation of the thioacetal 12c in 98% yields. Of
the three nitroaldehydes screened (11a -c), 11c was
found to be the best thiophenol scavenger in terms of
driving the reaction to the formation of the desired
product 3 (Table 2) selectively and completely.
Having achieved the crucial cyclizaton (note: all of the
cyclization reactions were performed on the racemic
substrates), the next task was to convert 3 to D-(+)-biotin
(1). As depicted in Scheme 4, chiral hydantoin 13 was
obtained from L-cystine 12 in four steps.5
To achieve exclusive formation of aldehyde 3 from 2
directly without the intermediacy of thioacetal 9, a study
of product profile formed under a variety of conditions
was taken up. Formation of 4 in annulation reactions
along with formation of 10 and 3, isolation of thioacetal
9 in 20% yield using TMSOTf (which was increased to
70%) employing external source of thiophenol, and our
finding that thioacetals undergo facile conversion to
parent carbonyl compounds with 4-nitrobenzaldehyde
suggested that if thiophenol liberated in the reaction
mixture could be selectively and effectively scavenged,
formation of 4 and 9 could be suppressed or totally
avoided.
Reduction of the hydantoin 15 was effected employing
2.2 equiv of DIBAL-H6 in toluene at -78 °C to furnish
lactol 16 (72% yield). Treatment of lactol in thiophenol
(6) Winterfeldt, E. Synthesis 1975, 617.

Notes
J . Org. Chem., Vol. 66, No. 18, 2001 6199
Sch em e 6a
a
Conditions: (a) ref 12; (b) (i) BnNCO, DCM, rt, 1 h; (c) pTSA, rt, 6 h, 90% (two steps); (d) DIBAL-H, Tol, -78 °C, 2 h, 72%; (e) PhSH,
pTSA, 0 °C, 5 min, 70%; (f) DBU, TBSCl, DCM, reflux, 2 h, 92%; (g) p-nitrobenzaldehyde, DCM, TBSOTf, 5 min, 95%; (h)
Ph3PdCHCHdCHCOOCH3, DCM, rt, 12 h, 89%; (i) 1 M NaOH, MeOH, 0 °C, 12 h, 97%; (j) 10%Pd-C/H2 (3 atm), 8 h, 92%; (k) 48% HBr,
reflux, 2 h, 80%.
with pTSA as the catalyst furnished the desired thiophe-
nyl aldehyde 17 (70% yield). Aldehyde 17 was converted
to its silyl enol ether 2 (92% yield).7 Enol ether 2 was
transformed to the cyclized product 3 in 95% yield
employing the protocol developed by us as described
previously (treatment with catalytic amount of TMSOTf
in the presence of 4-nitrobenzladehyde). Alternatively,
17 could be smoothly converted to 3 in one pot without
isolation of 2. The bicycloaldehyde 3 obtained was
epimeric at C-2 with respect of biotin. Rectification of the
stereochemistry at C-2 and its conversion to D-(+)-biotin
was efficiently effected by the following sequence.
Thus, Wittig homologation of 3 furnished the unsatur-
ated ester 18 having biotin framework in 89% yield.
Usually R,â,γ,δ unsaturated esters require strong bases
(viz. LDA) for their conversion into â,γ,δ,ꢀ esters.8,9
However, we have observed that treatment with mild
bases such as NaOH (in MeOH) brings about deconju-
gation and concomitant hydrolysis in one step in almost
quantitative yields! We believe that this is the first report
of a sulfur-assisted deconjugation of R,â,γ,δ unsaturated
esters to â,γ,δ,ꢀ acids under mild conditions. A variety
of other bases were also shown to effect this transforma-
tion.
The acid 19 on hydrogenation provided the saturated
acid 20 in 96% yield (characterized as its methyl ester)
having cis stereochemistry as required for biotin. Deben-
zylation of 20 afforded D-(+)-biotin (1) (mp 230 °C (lit.
mp 232-233 °C)), which was also characterized as its
methyl ester (1a ), in 80% yield. 1HNMR, mass, and
optical rotation of synthetic as well as authentic samples
of D-(+)-biotin as well as biotin methyl ester (1a ) were
in perfect agreement with the ones reported in the
literature.
Thus, convenient synthesis of D-(+)-biotin has been
achieved from L-cystine involving facile intramolecular
cyclization to furnish 5,5-fused system and incorporation
extremely mild conditions of deconjugation as the key
steps.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions with moisture-sensitive
compounds were conducted in oven-dried glassware under an
atmosphere of dry nitrogen. Solvents were dried by distillation
from sodium benzophenone (THF) or from CaH2 (DCM). Starting
materials that were commercially available were used without
purification. Melting points are uncorrected and were deter-
mined using crystallized samples. NMR spectra were obtained
at Bruker WH90/22.63, Bruker AC200/50 and Bruker MSL300/
75.49 MHz in CDCl3 unless otherwise noted. N-aryl-S-car-
boxymethyl-L-cysteine was prepared from L-cystine 14 according
to literature procedure.12
(7) Weimer, D. F.; Becicka, b. T.; Koerwith, F. L.; Dritna, G. J .;
Baenzigei, N. C. J . Org. Chem. 1990, 50, 5613.
(8) Martin, S. F.; Tu, C.-Y.; Chou, T.-S. J . Am. Chem. Soc. 1980,
102, 5274
(9) Martin, S. F.; Desai, S. R.; Philip, G. W.; Miller, A. C. J . Am.
Chem. Soc. 1980, 102, 3294.
(10) Volkmannn, R. A.; Davis, J . T.; Meltz, C. N. J . Am. Chem. Soc.
1983, 105, 5946.

6200 J . Org. Chem., Vol. 66, No. 18, 2001
Notes
(R)-(+)-1,3-Diben zyl-5-(3-m eth oxyca r bon yl-2-th ia p r op y-
lh yd a n toin (15). A solution of benzyl isocyanate (10 mmol),
N-aryl-S-carboxymethyl-L-cysteine 14 (10 mmol) in dichlo-
romethante (10 mL) was stirred under argon atmosphere. After
1 h, pTSA (190 mg, 1 mmol) was added, and the reaction mixture
was stirred at room temperature for 4 h. Dichloromethane was
removed, and the residue was loaded on column and eluted with
(EtOAc/n-hexane 1:3) to furnish N,N-disubstituted hydantoin 15
in 90% yield.
1,3-Diben zyl-2-oxo-5-[(3E,3Z)-4-ter t-bu tyldim eth ylsilyloxy-
2-th ia bu t-3-en yl]-4-p h en ylth ioim id a zolid in e
(2).
1,8-
Diazabicyclo[5.4.0]undec-7-ene (0.33 mL, 2.2. mmol) was added
via syringe to a solution of aldehyde 17 (924 mg, 2 mmol) in
dichloromethane (20 mL). After 5 min, a solution of TBSCl (330
mg, 2.2 mol) in DCM (5 mL) was added dropwise and the
mixture was heated to reflux. After 2 h, the mixture was diluted
with DCM and washed with 1% HCl (5 mL) and saturated
NaHCO3 solution (5 mL). The combined organic layers were
dried over anhyd Na2SO4, filtered, and rotary evaporated.
Purification of the oily residue by column chromatography (1:9
EtOAc/n-hexane) furnished 1.06 g of silyl enol ether 2 as a
viscous liquid in 92% yield.
IR (CHCl3): 3040, 2910, 1765, 1740, 1705, 1600, 1590, 1495,
1260, 1000 cm-1
.
1H NMR (CDCl3, 90 MHz): δ 7.25 (10H, m), 5.05 (1H, d, J )
15 Hz), 4.7 (2H, s), 4.1 (1H, d, J ) 15 Hz), 4.0 (1H, t, J ) 4 Hz),
3.7 (3H, s), 3.1 (2H, d, J ) 4 Hz), 3.1 (1H, d, J ) 14 Hz), 2.9
(1H, d, J ) 14 Hz).
IR (neat): 2910, 2840, 1695, 1595, 1450, 1420, 1210, 1100,
940 cm-1
.
1H NMR (CDCl3, 90 MHz): δ 7.35 (12H, m), 7.0 (3H, m), 6.56
(1H, d, J ) 11.6 Hz), 5.15 (1H, d J ) 11.6 Hz), 5.0 (1H, d, J )
15 Hz), 4.55 (1H, d, J ) 3.5 Hz), 4.3 (d, 1H, J ) 15 Hz), 4.2 (1H,
d, J ) 15 Hz), 3.9 (1H, d, J ) 15 Hz), 3.4 (1H, m), 2.4 (1H, dd,
J ) 13, 4 Hz), 2.2 (1H, dd, J ) 13, 7 Hz), 0.8 (9H, s), 0.1(6H, s).
13C NMR (CDCl3, 50 MHz): δ 157.94 (s), 149.94 (d), 136.51
(s), 134.75 (d), 129.05 (d), 128.80 (d), 128.47 (d), 128.26 (d), 127.93
(d), 127.41 (d), 127.26 (d), 100.58 (d), 66.95 (d), 58.82 (d), 45.63
(t), 44.66 (t), 37.11 (t), 25.43 (q), 25.38 (q), 18.4 (s), -5.34 (q),
-5.42 (q).
13C NMR (CDCl3, 22.63 MHz): δ 170.92 (s), 169.95 (s), 156.43
(s), 135.89 (s), 135.57 (s), 129.10 (d), 128.49 (d), 128.34 (d), 127.91
(d), 58.49 (d), 51.86 (q), 44.78 (t), 42.37 (t), 33.53 (t), 31.00 (t).
MS: 398 (M+, 9), 366 (4), 333 (4), 292 (100), 279 (15), 215 (6),
201 (31), 173 (16), 149 (12), 132 (18), 119 (23), 91 (23).
Anal. Calcd for C21H22N2O4S: C, 63.30; H, 5,56; N, 7.03; S,
8.05. Found: C, 63.15; H, 5.50; N, 6.95; S, 8.00.
1,3-Dib e n zyl-5-h yd r oxy-1,4-oxxa t h iop a n o[5,4-f]d ih y-
d r oim id a zolid -2-on e (16). DIBAL-H (10.23 mL, 2.2M solution
in toluene) was added very slowly (during 1h) to a precooled (-78
°C) solution of hydantoin 15 (3.98 g, 10 mmol) in dry toluene
(30 mL) at -78 °C under argon atmosphere. The reaction
mixture was stirred for an additional 2 h and quenched by
addition of methanol (10 mL) at -78 °C. Water (2 mL) was then
added, and the resulting precipitate was filtered through Celite.
Rotary evaporation of the solvent afforded the residue that when
column chromatographed (1:1 EtOAc/n-hexane) furnished lactol
16 in 2.66 g (72%) as a white solid.
MS: 467 (M+ - 109, 5), 277 (40), 203 (7), 110 (29), 91 (100),
73 (28), 65 (13).
Anal. Calcd for C32H40N2O2S2Si: C, 66.62; H, 6.99. Found: C,
66.3; H, 6.89.
1,3-Diben zyl-4-for m yl-1H-tetr a h yd r oth ien o[3,4-d ]im id a -
zol-2(3H)-on e (3). To a solution of enol ether 2 (576 mg, 1 mmol)
and 4-nitrobenzaldehyde (90 mg, 0.6 mmol) in DCM (5 mL)
under argon atmosphere was added a catalytic amount of
TBSOTf (0.02 mL) at room temperature. After 5 min, saturated
NaHCO3 solution (1 mL) was added. The dichloromethane layer
was separated, washed with water (2 × 2 mL), dried over anhyd
Na2SO4, and filtered. Removal of dichloromethane in vacuo and
chromatography of the residue (2:3 EtOAc/n-hexane) furnished
the aldehyde 3 (334 mg, 95%) as viscous liquid and thioacetal
of 4-nitrobenzaldehyde (171 mg, 97%).
Mp: 141-143 °C.
IR (Nujol): 3243, 2926, 1652, 1585, 1495, 1076, 950, 825 cm-1
.
1H NMR (CDCl3, 90 MHz): δ 7.3 (10H, m), 4.95 (1H, d, J )
6.0 Hz), 4.83 (1H, d, J ) 14.5 Hz), 4.69 (1H, d, J ) 15.4 Hz), 4.6
(1H, m), 4.25 (1H, d, J ) 14.5 Hz), 4.14 (1H, d, J ) 15.4 Hz), 3.7
(bs, D2O exchangeable), 3.5 (1H, m), 2.55 (5H, m).
13C NMR (CDCl3, 77.49 MHz): δ 158.99 (s), 136.51 (s), 136.32
(s), 128.39 (d), 128.32 (d), 128.23 (d), 127.46 (d), 127.30 (d), 127.24
(d), 101.15 (d), 84.44 (d), 60.35 (d), 45.43 (t), 43.91 (t), 39.69 (t),
30.63 (t).
IR (neat): 3120, 2940, 1705, 1695, 1605, 1595, 1500, 1450,
1250 cm-1
.
1H NMR (CDCl3, 300 MHz): δ 9.13 (1H, s), 7.25 (10H, m),
4.68 (1H, d J ) 15.4 Hz), 4.47 (1H, d, J ) 15.4 Hz), 4.36 (1H, d,
J ) 15.4 Hz), 4.34 (1H, d, J ) 7.94 Hz), 4.16 (1H, d, J ) 15.4
Hz), 4.11 (1H, dd, J ) 7.78, 4.74 Hz), 3.59 (1H, s), 2.68 (1H, d,
J ) 13.15 Hz), 2.29 (1H, dd, J ) 13.15, 4.78 Hz).
MS: 370 (M+, 3), 352 (4), 324 (12), 277 (70), 264 (12), 233
(18), 203 (26), 187 (16), 175 (17), 132 (8), 119 (6), 106 (5), 91
(100).
Anal Calcd for C20H22N2O3S: C, 64.84; H, 5.99; N, 7.56; S,
8.65. Found: C, 65.00; H, 6.16; N, 7.51; S, 8.29.
1,3-Diben zyl-2-oxo-5-(3-for m yl-2-th iop r op yl)-4-p h en ylth -
ioim id a zolid in e (17). To a solution of lactol 16 (3.7 g, 10 mmol)
in thophenol (5 mL) at 0 °C was added pTSA (190 mg, 1 mmol).
The reaction mixture was stirred at 0 °C for 5 min. Water (10
mL) was then added, and the mixture was extracted with
dichloromethane (2 × 15 mL). The combined organic layers were
dried over anhyd Na2SO4 and filtered. Removal of solvent under
reduced pressure afforded a residue that when purified by
column chromatography (10-50% EtOAc/n-hexane) furnished
3.23 g (70%) of 17.
13C NMR (CDCl3, 77.49 MHz): δ 189.90 (d), 159.75 (s), 137.02
(s), 136.77 (s), 128.71 (d), 128.65 (d), 127.78 (d), 127.68 (d), 127.59
(d), 61.96 (d), 60.63 (d), 59.30 (d), 47.16 (t), 46.42 (t), 34.71 (t).
MS: 352 (M+, 5), 323 (5), 277 (93), 264 (6), 91 (100), 65 (6).
Anal. Calcd for C20H20N2O2S: C, 68.16; H, 5.72; N, 7.95; S,
9.1. Found: C, 67.95; H, 5.70; N, 7.84; S, 9.5.
1,3-Diben zyl-4-[1-(1E,3E)-4-m eth oxyca r bon yl-1,3-bu ta d i-
en yl]-1H-tetr a h yd r o-th ien o[3,4-d ]im id a zol-2(3H)-on e (18).
A mixture of aldehyde 3 (352 mg, 1 mmol) and 3-methoxycar-
bonyl-2-propenylidine triphenyl phosphonate (432 mg, 1.2 mmol)
in dichloromethane (5 mL) was stirred for 12 h and then
concentrated under reduced pressure at room temperature. The
residue was purified by column to give ester 18 (386 mg, 89%)
as a viscous liquid.
IR (neat): 3010, 2900, 1710, 1700, 1600, 1580, 1495, 1450,
1360 cm-1
.
1H NMR (CDCl3, 90 MHz): δ 9.2 (1H, t, J ) 4 Hz), 7.25 (12H,
m), 7.0 (3H, m), 5.1 (1H, d J ) 15 Hz), 4.52 (1H, d, J ) 4 Hz),
4.45 (1H, d, J ) 15 Hz), 4.3 (1H, d, J ) 15 Hz), 4.0 (1H, d, J )
15 Hz), 3.55 (1H, m), 2.85 (2H, d, J ) 4 Hz), 2.38 (2H, m).
13C NMR (CDCl3, 50 MHz): δ 192.60 (s), 157.65 (s), 136.07
(s), 135.91 (s), 129.82 (d), 128.53 (d), 128.42 (d), 128.10 (d), 127.90
(d), 127.50 (d), 126.6 (d), 66.32 (d), 57.98 (d), 45.97 (t), 44.54 (t),
40.50 (t), 32.52 (t).
IR (neat): 3020, 2920, 1700, 1650, 1600, 1510, 1450, 1370,
1260, 1150, 1020 cm-1
.
1H NMR (C6D6, 200 MHz): δ 7.25 (11H, m), 5.76 (1H, d, J )
15.2 Hz), 5.53 (1H, dd, J ) 15.2, 10.78 Hz), 5.27 (1H, dd, J )
15.2, 8.29 Hz), 4.7 (2H, d, J ) 15.2 Hz), 4.67 (2H, t, J ) 15.2
Hz), 3.42 (3H, s), 3.27 (1H, dd, J ) 8.89, 3.86 Hz), 2.35 (1H, dd,
J ) 12.25, 4.3 Hz), 2.22 (1H, dd, J ) 12.25, 5.8 Hz).
13C NMR (CDCl3, 75.49 MHz): δ 166.6 (s), 158.88 (s), 142.70
(d), 138.6 (d), 136.77 (s), 136.7 (d), 129.59 (d), 128.49 (d), 127.93
(d), 127.45 (d), 121.68 (d), 65.91 (d), 61.51 (d), 55.12 (q), 51.30
(d), 46.48 (t), 46.25 (t), 36.98 (t), 36.67 (t).
MS: 353 (M+ -109, 5), 294 (6), 149 (5), 141 (7), 132 (14), 109
(79), 91 (100), 84 (11), 77 (17), 69 (13), 65 (18).
Anal. Calculated for C26H26N2O2S2: C, 67.50; H, 5.66.
Found: C, 67.32; H, 5.40.
MS: 434 (M+, 43), 402 (7), 277 (100), 264 (13), 187 (15), 155
(9), 91 (76).
Anal. Calcd for C25H26N2O3S: C, 69.09; H, 6.03; N, 6.45; S,
7.38. Found: C, 69.40; H, 5.85; N, 6.1; S, 7.40.
(11) Schmidt, R. R.; Maier, M. Synthesis 1982, 747.
(12) Bevezovski, V. M.; Mikhno, S. D.; Kulachkina, N. S.; Zhuk, V.
B.; Preobrazhenskii, N. A. Zh. Obshch. Khim. 1963, 33, 2888.

Notes
P en ta n oic Acid , 5-[Hexa h yd r o-2-oxo-1,3-d iben zyl-4H-
J . Org. Chem., Vol. 66, No. 18, 2001 6201
ated ester 19a (434 mg, 1 mmol) and 10% palladium on charcoal
(150 mg) in methanol (10 mL) was hydrogenated (3 atm) for 8
h. Filtration of the catalyst and the removal of the solvent under
reduced pressure furnished a residue which was purified by
column chromatography (1:5 ethyl acetate/n-hexane) to furnish
ester 20 (403 mg, 92%) of biotin as a white solid.
th ien o(3,4-d )im id a zol-3,5-d ien yl] Meth yl Ester (19). To a
solution of ester 18 (434 mg, 1 mmol) in methanol (5 mL) was
added 1 M NaOH (5 mL), and the reaction mixture was stirred
for 3 h and left at 0 °C for 12 h. Methanol was removed by rotary
evaporation under reduced pressure, and the reside was diluted
with dichloromethane (20 mL) and water (5 mL). The pH of the
solution was adjusted to pH 2 with 1 N hydrochloric acid and
stirred for 5 min. The organic layer was washed with water and
brine, dried, and evaporated in vacuo to give acid 19 (310 mg,
97%) as viscous liquid, and it was characterized as its methyl
ester 19a .
Mp: 78 °C.
IR (Nujol + CHCl3): 2970, 2840, 1740, 1690, 1600, 1500, 1460,
1250 cm-1
.
1H NMR (CDCl3, 200 MHz): δ 7.25 (10H, m), 5.15 (1H, d, J
) 15.2 Hz), 4.75 (1H, d, J ) 15.2 Hz), 4.17 (1H, d, J ) 15.2 Hz),
4.0-3.84 (1H, m), 3.97 (1H, d, J ) 15.2 Hz), 3.70 (3H, s), 3.2-
(1H, m), 2.80 (1H, dd, J ) 12.6, 4.0 Hz), 2,68 (1H, dd, J ) 12.6,
5.8 Hz), 2.34 (2H, t, J ) 7 Hz), 1.75-1.25 (6H, m).
13C NMR (CDCl3, 50 MHz): δ 178.09 (s), 161.24 (s), 137.25
(s), 137.01 (s), 128,90 (d), 128.47 (d), 127.83 (d), 62.90 (d), 61.44
(d), 54.44 (d), 51.68 (q), 48.20 (t), 46.85 (t), 34.07 (t), 28.70 (t),
28.00 (t), 24.85 (t).
MS: 438 (M+, 6), 347 (15), 277 (29), 265 (14), 240 (9), 187
(17), 91 (100), 85 (6), 65 (9).
Anal. Calcd for C25H30N2O3S: C, 68.46; H, 6.89; N, 6.38; S,
7.31. Found: C, 68.52; H, 7.0; N, 6.52; S, 7.62.
IR (neat): 3040, 2940, 1740, 1700, 1610, 1600, 1510, 1460,
1380, 1260, 1190 cm-1
.
1H NMR (CDCl3, 200 MHz): δ 7.30 (10H, m), 6.2-5.5 (3H,
m), 5.1-4.6 (3H, m), 4.3-3.7 (3H, m), 3.65 (3H, s), 3.1 (1H, d, J
) 7.1 Hz), 3.0-2.6 (3H, m).
13C NMR (CDCl3, 50 MHz); δ 171.30 (s), 158.72 (s), 138.47
(s), 137.14 (s), 136.93 (s), 135.60 (s), 130.90 (d), 128.68 (d), 128.60
(d), 128.26 (d), 128.08 (d), 127.99 (d), 127.68 (d), 127.56 (d),
127.38 (d), 127.16 (d), 126.35 (d), 124.08 (d), 125.95 (d), 64.80
(d), 58.95 (d), 51.70 (q), 46.66 (t), 44.93 (t), 37.87 (t), 37.43 (t).
MS: 434 (M+, 6), 343 (3), 277 (7), 238 (3), 136 (5), 106 (29),
91 (100), 65 (10).
Anal. Calcd for C25H26N2O3S: C, 69.09; H, 6.03; N, 6.45; S,
7.40. Found: C, 69.26; H, 5.96; N, 6.51; S, 7.44.
1H-Th ien o(3,4-d )im id a zol-4-p en ta n oic Acid Hexa h yd r o-
2-oxo-1,3-d iben zyl Meth yl Ester (20). A mixture of unsatur-
Ack n ow led gm en t. R.B.T. thanks CSIR, New Delhi
for the award of a fellowship.
J O015730J