Stereoselective synthesis of a novel carbamoyl oxybiotin

Article abstract of DOI:10.1016/j.tetlet.2005.07.104

Utilizing an L-serine derived enantiopure aminobutenolide as a chiral template, an efficient synthesis of a doubly modified novel biotin analog has been achieved. In view of the renewed interest in understanding the various biological roles of biotin, the

Full text of DOI:10.1016/j.tetlet.2005.07.104

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6469–6471
Stereoselective synthesis of a novel carbamoyl oxybiotin
Christina S. Stauffer and Apurba Datta*
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
Received 6 July 2005; revised 20 July 2005; accepted 21 July 2005
Abstract—Utilizing an L-serine derived enantiopure aminobutenolide as a chiral template, an efficient synthesis of a doubly modified
novel biotin analog has been achieved. In view of the renewed interest in understanding the various biological roles of biotin, the title
analog could provide some as yet unreported structure–activity relationship information on this important vitamin.
Ó 2005 Elsevier Ltd. All rights reserved.
(+)-Biotin (1), a water-soluble vitamin,1 is an essential
O
enzyme cofactor that plays a critical role in gluconeo-
genesis, fatty acid biosynthesis, and amino acid catabo-
lism. Acting as a mobile carrier of an activated carboxyl
group, biotin facilitates the carboxylation of appropriate
substrates by the biotin dependent enzymes pyruvate
carboxylase, acetyl CoA carboxylases 1 and 2, propionyl
CoA carboxylase, and b-methyl crotonyl CoA carboxyl-
ase.2 In recent studies, there has also been evidence sug-
gesting the involvement of biotin in the regulation of
gene expression.3 Additionally, a recent report has sug-
gested that biotin deficiency might enhance the resis-
tance of cancer cells to various antineoplastic agents.4
Furthermore, in rodent models, deficiency of biotin dur-
ing pregnancy has proven to be teratogenic and also the
cause of several neurologic diseases.5
1'
HN
3'
NH
2'
4
3
(CH2)4CO2H
2
X
1: X = S; (+)-Biotin
2: X = O; Oxybiotin
Figure 1. Structures of biotin and oxybiotin.
directly involved in the carboxyl transfer reactions.6 The
interesting structural features and its critical biological
role in the human system has rendered biotin an attrac-
tive target for continued chemical and biological
research.7 For example, in structural modification
studies, oxybiotin (2), an oxygenated analog (synthetic)
of biotin,8 was found to retain the growth-stimulatory
activity of natural biotin,9 indicating that replacement
of the sulfur atom with a smaller and more electronega-
tive oxygen atom does not adversely effect the biological
activity of biotin. Similarly, various structural modifica-
tions of the valeryl side chain, the thiophane core and
the cyclic urea moiety have also provided important
structure–activity relationship (SAR) information on
the various functionalities as present in biotin.10
From a structural viewpoint (Fig. 1), the heterobicyclic
core of biotin is comprised of a cyclic urea fused to a tetra-
hydrothiophene ring, with a valeric acid substituent
attached to the 2-position of the thiophane. The three
contiguous chiral centers of natural (+)-biotin are
arranged in an all cis-(2S,3S,4R) configuration. Bio-
chemically, an important function of the valeric acid
side chain is to act as a linker that attaches biotin cova-
lently to its client enzymes, through amide bond forma-
tion between the carboxylic acid of the biotin side chain
and the e-amino group of an appropriately located
lysine residue present in the enzyme.2 On the other hand,
the 10-nitrogen (N-10) on the ureido portion of biotin is
In a study aimed at a hitherto unreported biotin struc-
tural modification, the present research reports the syn-
thesis of a novel, doubly modified Ôcarbamoyl oxybiotinÕ
3, wherein, simultaneous bioisosteric replacement of the
sulfur (S) atom in the thiophane ring and the 30-nitrogen
(30-NH) on the ureido ring with oxygen atoms have been
achieved. The retrosynthetic strategy and approach for
the desired biotin analog is shown below (Fig. 2).
Keywords: Biotin; Bioisosteric replacement; Structure–activity rela-
tionship; Stereoselective.
*
Corresponding author. Tel.: +1 785 864 4117; fax: +1 785 864
5326; e-mail: adutta@ku.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.104

6470
C. S. Stauffer, A. Datta / Tetrahedron Letters 46 (2005) 6469–6471
3-carbon alkyl donor Wittig reagent resulted in the
O
O
formation of the E- and Z-mixture of olefins 7. As
expected,12 during this reaction process, the C3-second-
ary oxyanion, generated by the opening of the lactol,
also underwent spontaneous intramolecular addition
to the carbonyl carbon of the favorably placed N-Cbz
group, resulting in concomitant formation of the desired
bicyclic carbamoyl oxybiotin structural core. Toward
completion of the synthesis, in a one-pot reaction,
catalytic hydrogenation of 7 resulted in saturation of
the olefinic moiety and simultaneous cleavage of the
benzylic ether linkage to generate the free primary alco-
hol 8. Finally, oxidation of the primary hydroxy group
under standard reaction conditions culminated in the
target oxybiotin derivative 3.13
CbzHN
HN
O
O
O
CO2H
( )4
O
4
Carbamoyl Oxybiotin (3)
NH2
CO2H
NCbz
O
O
O
OH
L-Serine
5
Figure 2. Retrosynthetic strategy and approach.
Although the key role of biotin in several key enzymatic
reactions is a relatively well understood process, the
recent findings suggesting potential involvement of
biotin in the regulation of gene expression3 has created
renewed interest in this important vitamin. By modify-
ing two hydrogen bond donor–acceptor functionalities
of the biotin core, the present synthesis of a novel biotin
analog has created an opportunity toward further inves-
tigating the role of the above functionalities in the bio-
activity of biotin and possible utilization of the
described analog as a potential tool in future biochemi-
cal studies. The synthetic route can also be easily
extended toward further modifications at the C-2
position of the molecule, leading to various uniquely
modified biotin analogs for future structure–activity
relationship investigations.
In recent studies from our group, we have reported an
efficient route to enantiopure amino butenolides 5 and
ent-5, starting from easily available L- or D-serine,
respectively.11,12 It has also been shown that, under
appropriate conditions, hydrolysis of the acetonide link-
age of 5 leads to the stereoselective formation of the
cis-fused bicyclic lactone 4 in good yield.12 Taking
advantage of the above observation, the present study
has been designed to utilize the butenolide 5 as a key
chiral template toward construction of the required
bicyclic core of the target oxybiotin analog 3.
Accordingly, following a slight modification of our
earlier reported procedure,12 deprotection of the N,O-
acetonide of 5 and basic workup of the reaction mixture
resulted in the bicyclic lactone 4 (Scheme 1) in high
yield. Partial reduction of the lactone to the correspond-
ing lactol 6 and subsequent reaction with an appropriate
Acknowledgment
C.S.S. thanks the Medicinal Chemistry Division of the
American Chemical Society for the award of a pre-
doctoral fellowship (sponsored by Aventis).
Dowex,
aq. MeOH,
NH2
CO2H
NCbz
50 ˚C,
then,
O
O
O
Ref. 11
NaHCO3,
EtOAc-H2O
OH
L-Serine
References and notes
5
89%
1. Uskokovic, M. R. Biotin, In Kirk-Othmer Encyclopedia of
Chemical Technology, 3rd ed.; Grayson, M., Eckroth, D.,
Eds.; Wiley: New York, 1983; Vol. 24, pp 41–49.
2. Nelson, D. L.; Cox, M. M. Lehninger Principles of
Biochemistry, 4th ed.; Freeman: New York, 2005.
3. For a review, see: Rodriguez-Melendez, R.; Zempleni, J.
J. Nutr. Biochem. 2003, 14, 680–690.
CbzNH
CbzNH
DIBAL,
O
O
-78 ˚C
OH
O
91%
O
O
4
6
O
-
O
4. Griffin, J. B.; Zempleni, J. J. Nutr. Biochem. 2005, 16, 96–
103.
HN
Br
H2, Pd-C,
EtOH, rt.
+
BnO
OBn
( )2
Ph3P
5. Alvarez-Pacheco, D.; Vargas-Solorzano, R. S.; Rio, A. L.
D. Arch. Med. Res. 2002, 33, 439, and references cited
therein.
6. Guchait, R. B.; Polakis, S. F.; Hollis, D.; Fenselau, C.;
Lane, M. D. J. Biol. Chem. 1974, 249, 6646–6656.
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1997, 97, 1755; (b) McMahon, R. J. Annu. Rev. Nutr. 2002,
22, 221–239; (c) Jarrett, J. E. Chem. Biol. 2005, 12, 409–
415, and references cited therein.
8. For synthesis of (+)-oxybiotin, see: Popsavin, V.; Bene-
dekovic, G.; Popsavin, M.; Divjakovic, V.; Armbruster, T.
Tetrahedron 2004, 60, 5225–5235, and references cited
therein.
t-BuOK, THF,
-78 ˚C to rt.
92%
O
77%
7
O
O
RuCl3,
NaIO4,
MeCN,
CCl4, H2O
HN
O
HN
O
OH
CO2H
( )4
70%
( )4
O
O
8
3
Scheme 1.

C. S. Stauffer, A. Datta / Tetrahedron Letters 46 (2005) 6469–6471
6471
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25
13. White solid; mp 146–148 °C; ½aꢀD 68.1 (c 1.55, MeOH); IR
(Teflon) 3249, 1749, 1714, 1699 cmꢁ1
;
1H NMR
(400 MHz, CD3OD) d 1.49–1.55 (m, 2H), 1.65–1.77 (m,
4H), 2.34 (t, J = 7.4 Hz, 2H), 3.53–3.61 (m, 2H), 3.86 (d,
J = 10.3 Hz, 1H), 4.40 (dd, J = 4.0 and 7.5 Hz, 1H), 5.03
(dd, J = 3.6 and 7.5 Hz, 1H); 13C NMR (100.6 MHz,
CD3OD) d 25.0, 25.6, 28.0, 33.8, 57.7, 73.3, 81.5, 83.0,
160.7, 176.5; HRMS (ES+) calcd for C10H15NO5Na m/z
(M+Na)+, 252.0848; found, 252.0823; Anal. Calcd for
C10H15NO5: C, 52.40; H, 6.60; N, 6.11. Found: C, 52.63;
H, 6.78; N, 6.0.