A rapid synthesis of the biotin core through a tandem michael reaction

Article abstract of DOI:10.1021/ol0710663

A biotin core has been assembled in a short and efficient sequence utilizing a tandem intramolecular Michael reaction/fragmentation/Michael reaction from vinyl sulfoxide and sulfone alcohols (12 and 13).

Full text of DOI:10.1021/ol0710663

ORGANIC
LETTERS
2007
Vol. 9, No. 16
2973-2975
A Rapid Synthesis of the Biotin Core
through a Tandem Michael Reaction
Kyungsoo Oh*
Department of Chemistry and Chemical Biology, Indiana UniVersity Purdue UniVeristy
Indianapolis, Indianapolis, Indiana 46202
oh@chem.iupui.edu
Received May 7, 2007
ABSTRACT
A biotin core has been assembled in a short and efficient sequence utilizing a tandem intramolecular Michael reaction/fragmentation/Michael
reaction from vinyl sulfoxide and sulfone alcohols (12 and 13).
(+)-Biotin (1), known as vitamin H, is an essential ingredient
in human metabolic cycles.1 An early discovery of this water-
soluble biocatalyst, participating in the reversible fixation
of carbon dioxide in the biosynthesis of organic molecules,
has attracted considerable interest in the synthetic com-
munity.2 In addition to its important biological roles in human
nutrition and animal health, biotinylation has allowed for
identification and purification of the protein complement of
cells in the genomic and postgenomic era.3 One of the
difficulties of using biotinylation in protein purification is
due to the fact that biotin has the strongest noncovalent
interaction known in nature with avidin (Kd ) 10-15 M).
Several approaches have been tested to facilitate the release
of biotinylated targets from (strept)avidin complexes.4 How-
ever, use of biotin derivatives that possess decreased affinity
for (strept)avidin has not been extensively exploited due to
the lack of a general synthetic approach to biotin analogues.
To facilitate the recovery of the biotinylated target from
(strept)avidin complexes, we have selected two variables in
the biotin analogue structures: (1) the oxidation state of
sulfur (3-6)5 and (2) the stereochemistry of the valeryl chain
(2, 4-6).6 Herein we report our preliminary results on a facile
approach to the biotin core utilizing a one-pot tandem
Figure 1. Structures of (+)-biotin and biotin analogues.
intramolecular Michael reaction from vinyl sulfoxide and
sulfone alcohols.
Our synthesis began with the Friedel-Crafts acylation of
1-heptyne 7 using R-chloroacetyl chloride in the presence
of aluminum chloride to give 1,4-dichlorobut-3-en-2-one
derivative 8.7 Simply mixing solid granules of sodium
hydrosulfide hydrate in neat 1,4-dichlorobut-3-en-2-one
derivatives 8 resulted in the exclusiVe formation of thiophen-
(1) Uskokovic, M. R. In Encyclopedia of Chemical Technology, 3rd ed.;
Kirk, R. E., Othemr, D. E., Eds.; Wiley: New York, 1984; Vol. 24, p 41.
10.1021/ol0710663 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/30/2007

3-one 9. The resulting product 9 was simply filtered through
a plug of Celite to remove the excess solid reagent. It is
worth noting that the preparation of the thiophen-3-one 9 is
highly efficient and easily scalable without much complica-
tion.8 The thiophen-3-one 9 is next converted to the corre-
sponding sulfoxide 10 and sulfone derivative 11 by using
m-chloroperbenzoic acid and Oxone, respectively. While
attempted reduction of the thiophen-3-one 9 was unsuccessful
under various conditions,9 the reduction of thiophen-3-one
oxide 10 and dioxide 11 with sodium borohydride gave clean
reduction products (12 and 13) in excellent yield and
selectivity.
isocyanate and potassium tert-butoxide.10 This tandem in-
tramolecular Michael reaction/fragmentation/Michael reac-
tion allows a facile entry to the requisite core of biotin.11
Moreover, intermediates 14, 16, and 17 in Scheme 2 can be
Scheme 2. Synthesis of Biotin Skeleton
Scheme 1. Synthesis of Thiophen-3-one Derivatives
isolated and the stepwise reactions proceed in excellent yields
(see the Supporting Information). Although the reaction gave
low diastereoselectivity at the C2 for sulfoxide 6 (sulfone
13 gave a 2R-H epimer 4 as the sole product),12 the high
chemical yield and the efficient chemical transformation are
noteworthy.
To access N,N′-dibenzyl-2-epi-biotin 2,13 the deoxygen-
ation of the 2,3-trans-sulfoxide 6 was performed with use
of phosphorus trichloride in dichloromethane at low tem-
perature.14 Likewise, the 2,3-cis-sulfoxide 6a yielded N,N′-
dibenzyldeoxybiotin 1811 after reduction of a mixture of
sulfide 18 and alkene 19. A similar strategy has been applied
to cis-sulfoxide 12 to give N,N′-dibenzyldeoxybiotin sul-
foxides (5 and 5a) (see the Supporting Information). The
debenzylation of the ureas (2 and 18) can be effected by the
Hoffmann-La Roche protocol.15
The alcohols (12 and 13) were then converted to bicyclic
urea (4 and 6) through a successive treatment of benzyl
(2) For the synthesis of biotin, see: (a) Chavan, S. P.; Chittiboyina, A.
G.; Ramakrishna, G.; Tejwani, R. B.; Ravindranathan, T.; Kamat, S. K.;
Rai, B.; Sivadasan, L.; Balkrishnan, K.; Ramalingam, S.; Deshpande, V.
H. Tetrahedron 2005, 61, 9273. (b) Chen, F.-E.; Chen, X.-X.; Dai, H.-F.;
Kuang, Y.-Y.; Xie, B.; Zhao, J.-F. AdV. Synth. Catal. 2005, 347, 549. (c)
Mori, Y.; Seki, M. Synlett 2005, 2233. (d) Chavan, S. P.; Chittiboyina, A.
G.; Ravindranathan, T.; Kamat, S. K.; Kalkota, U. R. J. Org. Chem. 2005,
70, 1901. (e) Chavan, S. P.; Ramakrishna, G.; Gonnade, R. G.; Bhadbhade,
M. M. Tetrahedron Lett. 2004, 45, 7307. (f) Seki, M.; Hatsuda, M.; Mori,
Y.; Yoshida, S.; Yamada, S.; Shimizu, T. Chem. Eur. J. 2004, 10, 6101.
(g) Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 1635. (h) Seki, M.;
Kimura, M. Yuki Gosei Kagaku Kyokaishi 2004, 62, 882. (i) Chen, F.-E.;
Dai, H.-F.; Kuang, Y.-Y.; Jia, H.-Q. Tetrahedron: Asymmetry, 2003, 14,
3667. (j) Seki, M.; Kimura, M.; Hatsuda, M.; Yoshida, S.; Shimizu.
Tetrahedron Lett. 2003, 44, 8905. (k) Chen, F.-E.; Yuan, J.-L.; Dai, H.-F.;
Kuang, Y.-Y.; Chu, Y. Synthesis 2003, 2155. (l) Shimizu, T.; Yakugaku
Zasshi 2003, 123, 43. (m) Seki, M.; Mori, Y.; Hatsuda, M.; Yamada, S. J.
Org. Chem. 2002, 67, 5527. (n) Shimizu, T.; Seki, M. Tetrahedron Lett.
2002, 43, 1039. (o) Mori, Y.; Seki, M. Heterocycles 2002, 58, 125. (p)
Seki, M.; Hatsuda, M.; Mori, Y.; Yamada, S. Tetrahedron Lett. 2002, 43,
3269. (q) Seki, M.; Shimizu, T.; Inubushi, K. Synthesis 2002, 361. (r)
Chavan, S. P.; Tejwani, R. B.; Ravindranathan, T. J. Org. Chem. 2001, 66,
6197. (s) Choi, C.; Tian, S.-K.; Deng, L. Synthesis 2001, 1737. (t) Shimizu,
T.; Seki, M. Tetrahedron Lett. 2000, 41, 5099. (u) Shimizu, M.; Nishigaki,
Y.; Wakabayashi, A. Tetrahedron Lett. 1999, 40, 8873. (v) Zhou, Z.; Yang,
H. Huaxue Jinzhan 1998, 10, 319. For a review on the synthesis of biotin,
see: (w) DeClercq, P. J. Chem. ReV. 1997, 97, 1755.
(4) Desarnaud, F.; Marie, J.; Larguier, R.; Lombard, C.; Jard, S.;
Bonnafous, J.-C. J. Chromatogr. 1992, 603, 95 and reference cited therein.
(5) For the relative avidin binding affinity of biotin and its metabolites,
see: (a) Sachon, E.; Tasseau, O.; Lavielle, S.; Sagan, S.; Bolbach, G. Anal.
Chem. 2003, 75, 6536. (b) Zempleni, J.; Mock, D. M. J. Nutr. 1999, 129,
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(6) Oh, K. Tetrahedron Lett. 2007, 48, 3685.
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(8) More detailed results will be published elsewhere.
(9) Low yield of the thiophene, presumably after dehydration, was
obtained.
(10) For intramolecular conjugate addition of carbamates, see: (a) Wee,
A. G. H.; McLeod, D. D.; Rankin, T. J. Heterocycles 1998, 48, 2263. (b)
Clayden, J.; Nelson, A.; Warren, S. Tetrahedron Lett. 1997, 38, 3471. (c)
Hirama, M.; Hioki, H.; Ito, S.; Kabuto, C. Tetrahedron Lett. 1988, 29, 3121.
(d) Hirama, M.; Hioki, H.; Ito, S. Tetrahedron Lett. 1988, 29, 3125.
(11) For the synthesis of N,N′-dibenzyl-cis-ureylenesulfone from 2,5-
dihydrothiophene S,S-dioxide, see: (a) Kotake, H.; Inomata, K.; Murata,
Y.; Kinoshita, H.; Katsuragana, M. Chem. Lett. 1976, 1073 (the reaction
of 3,4-dibromosulfolane with benzylamine). (b) Ellis, F.; Sammes, P. G. J.
Chem. Soc., Perkin Trans. 1 1972, 2866 (the intramolecular conjugate
addition of the carbamate from 3,4-bromohydrinsulfolane).
(12) For the stereochemical assignment of hexahydrothienoimidazolone
derivatives, see the Supporting Information.
(3) (a) van Werven, F. J.; Timmers, H. T. Nucleic Acids Res. 2006, 34,
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Org. Lett., Vol. 9, No. 16, 2007

Scheme 3. Synthesis of Deoxybiotin Derivatives
Scheme 4. Epimerization of N,N′-Dibenzyldeoxybiotin Sulfone
approach to biotin derivatives with varied oxidation states
of the sulfur atom. The investigation into the asymmetric
synthesis as well as the binding affinity assay of the prepared
biotin derivatives to strept(avidin) is currently underway in
our laboratory, and our results will be reported in due course.
While the trans-sulfoxide alcohol 12 produced a mixture
of diastereomers 6 and 6a, a single diastereomer 4 was
obtained from the sulfone alcohol 13.16 This serendipitous
selectivity allows facile access to N,N′-dibenzyl-2-epi-biotin
sulfone derivative 4. To seek out the origin of this selectivity
we isolated two allyl amine diastereomers 16 (2,3-cis/2,3-
trans). As expected, a rapid epimerization was observed
during the final Michael addition reaction to bicyclic biotin
sulfone 4.17 Subjection of the 2,3-cis-sulfone 17 to other mild
conditions such as sodium bicarbonate, sodium hydride in
THF, or a catalytic amount of DBU in THF, while following
reactions at regular intervals, failed to give the other isomeric
species. Attemped epimerization of N,N′-dibenzyl-2-epi-
deoxybiotin sulfone 4 under kinetic protonation also failed
to give the biotin sulfone 3.18
Acknowledgment. The School of Science (IUPUI) is
acknowledged for start-up funding. This investigation was
partially supported through the Research Support Funds
Grant (RSFG-IUPUI).
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0710663
(16) Sulfone 3 can be obtained through oxidation of biotin derivative
18, see ref 5.
(17) The sulfoxide 17 does not epimerize under identical conditions, the
stereoselectivity of 6 was derived from the sulfoxide 16 (2,3-trans:2,3-cis
) 3:2), see the Supporting Information.
(18) Treatment with LDA at -78 °C then tert-butanol quenching led to
decomposion as well as the recovery of the starting material.
In conclusion, we have developed a rapid synthetic
sequence to a biotin skeleton in six steps allowing a facile
(15) Lee, H. L.; Baggiolini, E. G.; Uskokovic, M. R. Tetrahedron 1987,
43, 4887.
Org. Lett., Vol. 9, No. 16, 2007
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