Diastereoselective amidoalkylation of (3S,7aR)-6-benzyl-7-hydroxy-3- phenyltetrahydro-5H-imidazo[1,5-c][1,3]thiazol-5-one: A short and highly efficient synthesis of (+)-biotin

Article abstract of DOI:10.1021/jo0488107

(Chemical Equation Presented) A short and highly efficient synthesis of (+)-biotin in 10 steps with 20% overall yield has been achieved from L-cysteine involving amidoalkylation of hydroxy imidazothiazolone 4 via an acyliminium ion intermediate to furnish C-7-substituted imidazothiazolones 5b as the key step.

Full text of DOI:10.1021/jo0488107

Diastereoselective Amidoalkylation of
(3S,7aR)-6-Benzyl-7-hydroxy-3-phenyltetra-
hydro-5H-imidazo[1,5-c][1,3]thiazol-5-one :
A Short and Highly Efficient Synthesis of
(+)-Biotin
FIGURE 1. Structure of the (+)-biotin.
Subhash P. Chavan,* Amar G. Chittiboyina,
T. Ravindranathan, Subhash K. Kamat, and
Uttam R. Kalkote
TABLE 1. Amidoalkylation of Hydroxy
Imidazothiazlone 4a
Division of Organic Chemistry: Technology, National
Chemical Laboratory, Pune, India 411 008
formation of
products (%)
nucleo-
phileb
time
yield
(%)
(equiv)
Lewis acid
T (°C)
(min)
5
6
spchavan@dalton.ncl.res.in
Received July 13, 2004
1
2
3
5
5
1.5
SnCl4 (3)
-78 to 25 300
100
90
98
TiCl4 (2)c
-30 to 0
0 to 25
300
10
10
100
BF3‚OEt2 (1.3)
>98
a All reactions were performed with 1.0 equiv of hydroxyimi-
dazothiazolone 4. b 1-Trimethylsilyloxycyclohexene was used as
nucleophile. c 1 M solution in dichloromethane.
powerful protocol in effecting C-C bond formation. Of
the various approaches described toward (+)-biotin syn-
thesis, cystine/cysteine1b,c,g,3 has attracted a great deal
of attention by virtue of it possessing requisite stereo-
chemistry and its ready availability. This has led to the
development of elegant syntheses of (+)-biotin via an
intramolecular cyclization by Speckamp3d and our group1c
to generate the cis-biotin skeleton with excellent stereo-
control. Our interest in acyliminium ion chemistry1c,d led
us to undertake the study of the diastereochemical
outcome of intermolecular carbon-carbon bond forma-
tion. Herein we disclose our efforts in the stereoselective
amido alkylations culminating in one of the highly
efficient syntheses of (+)-biotin.
The hydantoin 3 developed by Poetsch et al.3a,e ap-
peared to be an ideal scaffold to study the Lewis acid-
mediated amido alkylation due to its rigid framework
which would give rise to facial differentiation. Thus, the
bicyclic hydantoin 3 was prepared from cysteine accord-
ing to the procedure of Poetsch.3a,e The hydantoin was
then reduced with sodium borohydride to afford hydroxy
imidazothiazolone 4 in quantitative yield (Scheme 1).
Our initial attempts to effect carbon-carbon bond
formation at the C-7 position of hydroxy imidazothiaz-
olone 4 with 1-trimethylsilyloxy-1-cyclohexene in the
presence of SnCl4 at -78 °C resulted in exclusive forma-
tion of the eliminated product 6 (Scheme 2). Treatment
of hydroxy imidazothiazolone 4 with 1-trimethylsilyloxy-
1-cyclohexene in the presence of other Lewis acids, e.g.,
TiCl4 or SnCl4 in DCM at -78 °C, were also unsuccessful.
After careful screening of various Lewis acids at different
temperatures it was revealed that when the reaction was
performed at -20 to 0 °C with BF3‚OEt2, the desired
product was obtained in 50% yield. It follows then that
the choice of temperature was a critical parameter for
the successful formation of the desired product. Careful
experimentation also revealed that 1.5 equiv of nucleo-
phile was required to obtain optimum yields of the
amidoalkylated product. As anticipated, performing the
reaction between hydroxy imidazothiazolone 4 and 1-tri-
A short and highly efficient synthesis of (+)-biotin in 10 steps
with 20% overall yield has been achieved from L-cysteine
involving amidoalkylation of hydroxy imidazothiazolone 4
via an acyliminium ion intermediate to furnish C-7-
substituted imidazothiazolones 5b as the key step.
Vitamin H,1 more commonly known as (+)-biotin
(Figure 1), is involved in an essential part of the
metabolic cycle causing catalytic fixation of carbon
dioxide in the biosynthesis of organic molecules. In the
pharmaceutical context it is used as an additive and as
an avidin complex in the area of drug delivery, immuno
assay, isolation, and localization. To date, a number of
new synthetic routes involving different strategies for
control of three adjacent chiral centers are reported.1
However, to the best of our knowledge, none of the known
syntheses has a commercial advantage over the Stern-
bach synthesis developed by Hoffman-La Roche.2 Our
quest for and long-standing interest1c,d in this com-
mercially important molecule led us to explore a practical
synthesis of (+)-biotin.
Pioneering work by Speckamp et al.3d,e and others3f on
the utility of acyliminium ion chemistry has provided a
(1) (a) 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.; Hatsuda, M.; Yoshida, S.;
Shimizu, T. Tetrahedron Lett. 2003, 44, 8905. (d) Chavan, S. P.;
Tejwani, B.; Ravindranathan, T. J. Org. Chem. 2001, 66, 6197. (e)
Chavan, S. P.; Ramakrishna, G.; Gonnade, R. G.; Bhadbhade, M. M.
Tetrahedron Lett. 2004, 44, 7307. (f) Shimizu, T.; Seki, M. Tetrahedron
Lett. 2000, 41, 5099. (g) Seki, M.; Mori, Y.; Hatsuda, M.; Yamada, S.-
c. J. Org. Chem. 2002, 67, 5527.
(2) Sternbach, L. H. Comp. Biochem. 1963, 11, 66.
(3) (a) Poetsch, E.; Casutt, M. Chimia 1987, 41, 148. (b) Fusijawa,
T.; Nagai, M.; Kaike, Y.; Shimizu, M. J. Org. Chem. 1994, 59, 5865.
(c) Deroose, F. D.; De Clercq, P. J. J. Org. Chem. 1995, 60, 321. (d)
Moolenaar, M. J.; Speckamp, W. N.; Hiemstra, H.; Poetsch, E.; Casutt,
M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2391. (e) Casutt, M.; Poetsch,
E.; Speckamp, W. N. Ger. Offen. DE 3 926 690, 14 Feb 1991; Chem.
Abstr. 1991, 115, 8429k. (f) Liao, Z.-K.; Kohn, H. J. Org. Chem. 1984,
49, 4745.
10.1021/jo0488107 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/27/2005
J. Org. Chem. 2005, 70, 1901-1903
1901

TABLE 2. Amidoalkylation of Hydroxy Imidazothiazolone 4a with Various Nucleophiles
a All reactions were performed with 1.0 equiv of hydroxy imidazothiazolone 4. b 2 equiv of nucleophile was used. c 38% of eliminated
product 6 was isolated.
SCHEME 1
Having successfully established the appropriate condi-
tions for carbon-carbon bond formation, the amidoalky-
lation was performed with a variety of nucleophiles such
as enol ethers, aromatic compounds, allyltrimethylsilane,
tin acetylides, and ketene silyl acetal. The results ob-
tained are summarized in Table 2. From the table, it is
evident that the reaction proceeds with a very high
degree of diastereoselectivity to furnish the corresponding
7-substituted imidazothiazolone 5. The trans stereochem-
istry was confirmed by 1H NMR coupling constants (e.g.,
J ) 1.5 Hz for product in entry h, Table 2).
SCHEME 2. Nucleophilic Addition of 4a to
Hydroxy Imidazothiazolone 4
The compounds 5a and 5b were obtained as a mixture
of diastereomers in roughly equal amounts (1H NMR).
The establishment of exact stereochemistry at the third
center (5a and 5b) was of no consequence since it was to
be destroyed at a later stage in the biotin synthesis.
We reasoned the high degree of diastereoselectivity
was due to the facial differentiation of the bicyclic
hydroxy imidazothiazolone 4 in which the nucleophilic
attack takes place from the less hindered convex face of
the bicyclic imidazothiazolone (Scheme 2).
methylsilyloxy-1-cyclohexene, at 0 °C to ambient tem-
perature, furnished the desired product 5a exclusively
in almost quantitative yield. The results obtained are
recorded in Table 1.
Having established an efficient protocol for the syn-
thesis of 7-substituted imidazothiazolones, the prepara-
tive usefulness of new carbon-carbon bond formation
1902 J. Org. Chem., Vol. 70, No. 5, 2005

SCHEME 3a
dibenzylbiotin methyl ester in quantitative yield. Re-
moval of N-benzyl groups was achieved with aq HBr
(47%) at reflux temperature to afford (+)-biotin. The
biotin thus obtained was identical with an authentic
1
sample with respect to mp, IR, H NMR, mass spectra,
and specific rotation: mp 230-231 °C; [R]D ) +89.7 (c )
1.01, 0.1 N NaOH) (lit.5 mp 229.5-230 °C; [R]D ) +91.5
(c ) 1, 0.1 N NaOH).
In conclusion, a highly stereospecific protocol for ami-
doalkylation of imidazothiazolone has been developed
which has culminated in a highly efficient synthesis of
(+)-biotin. We believe that this protocol would potentially
provide easy access to trans vicinal diamines upon
hydrolysis.
a Conditions: (a) 1,2-bis(trimethylsilyloxy)cyclohexene (1.5 equiv),
BF3‚OEt2, DCM, 98%; (b) 70% TBHP, KOH-MeOH, 15 min; (c)
CH2N2, 10 min, 70%; (d) Zn/AcOH, 80 °C, 5 h; (e) AcOH/ piperidine,
100 °C, 90 min, 70%; (f) H2/Pd-C, MeOH, 200 psi, 100%; (g) 47%
HBr, 5 h, 78%.
Acknowledgment. C.A.G. thanks CSIR, New Delhi,
India, for the award of a fellowship. Funding from CSIR,
New Delhi, India, under the YSA (S.P.C.) Scheme is
gratefully acknowledged.
was demonstrated by efficiently converting 5b to biotin
(Scheme 3). The R-hydroxy ketone 5b was subjected to
Baeyer-Villiger oxidation with tert-butyl hydroperoxide
in alkaline methanol to furnish the keto acid in 70% yield.
This keto acid on esterification with diazomethane
furnished the keto ester 7 in quantitative yield. The
intermediate 7, being epimeric at C-7 with respect to (+)-
biotin, was epimerized by reductive cleavage of carbon-
sulfur bond with Zn/AcOH. Further cyclization of thiol
thus obtained with the carbonyl function was performed
in the presence of piperidine and acetic acid followed by
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 5a-i, 7, and 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0488107
(4) (a) For a review on acyliminium ion chemistry, see: Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (b) Schierle, K.;
Vaule. R.; Steckhan, E. Eur. J. Org. Chem. 1998, 509. (c) Schickli, C.
P.; Seebach, D. Liebigs. Ann. Chem. 1991, 655.
(5) Volkmann, R. A.; Davis, J -T.; Meltz, C. N. J. Am. Chem. Soc.
1983, 105, 5946.
3a
dehydration to afford the olefin 8.
Stereospecific hydrogenation was carried out in the
presence of 10% palladium on carbon to furnish N,N′-
J. Org. Chem, Vol. 70, No. 5, 2005 1903