Efficient asymmetric synthesis of novel 4-substituted and configurationally stable analogues of thalidomide

Article abstract of DOI:10.1021/ol0623668

The preparation of new thalidomide derivatives 4-methyl-(3S,4R)-3a and 4-phenyl-(3S,4S)-3b starting from pyroglutamic acids (2R,3R)-7a and (2R,3S)-7b, possessing an inappropriate stereochemistry, was successfully realized due to stereochemically complete epimerization at the α-stereogenic center upon formation of the corresponding N-phthaloyl anhydrides 9a,b. The demonstrated conformational stability of these new thalidomide derivatives provides solid experimental evidence for practical feasibility of the approach described here to overcome the inherent problem of configurational instability of thalidomide by introducing an alkyl or aryl group in the C4 position.

Full text of DOI:10.1021/ol0623668

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5625-5628
Efficient Asymmetric Synthesis of Novel
4-Substituted and Configurationally
Stable Analogues of Thalidomide
Takeshi Yamada, Takuya Okada, Kazuhiko Sakaguchi, Yasufumi Ohfune,*
Hisanori Ueki, and Vadim A. Soloshonok*
Graduate School of Science, Osaka City UniVersity, Japan, and Department of
Chemistry and Biochemistry, The UniVersity of Oklahoma, Norman, Oklahoma 73019
Vadim@ou.edu; ohfune@sci.osaka-cu.ac.jp
Received September 26, 2006
ABSTRACT
The preparation of new thalidomide derivatives 4-methyl-(3S,4R)-3a and 4-phenyl-(3S,4S)-3b starting from pyroglutamic acids (2R,3R)-7a and
(2R,3S)-7b, possessing an inappropriate stereochemistry, was successfully realized due to stereochemically complete epimerization at the
r
-stereogenic center upon formation of the corresponding N-phthaloyl anhydrides 9a,b. The demonstrated conformational stability of these
new thalidomide derivatives provides solid experimental evidence for practical feasibility of the approach described here to overcome the
inherent problem of configurational instability of thalidomide by introducing an alkyl or aryl group in the C4 position.
Thalidomide (1) (Scheme 1) was marketed as a sedative in
1956. However, in 1961, it was withdrawn from the world
significant attention due to its selective inhibitory activity
of tumor necrosis factor-R (TNF-a),2 which is a clinically
important activity against serious diseases such as rheumatoid
arthritis, Crohn’s disease, leprosy, AIDS, and various
cancers.3 The comeback of thalidomide to the legitimate
status of a marketed drug came in 1998 when it received
FDA approval for the treatment of erythema nodosum
leprosum (ENL).4
Scheme 1
Thalidomide possesses a single chiral center and was used
clinically as a racemate. It has been widely thought that the
(1) (a) Eger, K.; Jalalian, B.; Verspohl, E. J.; Lupke, N.-P. Arzneim.
Forsch. 1990, 40, 1073. (b) Folkman, J. Ann. Intern. Med. 1975, 82, 96.
(2) (a) Sampio, E. P.; Sarno, E. N.; Galilly, R.; Cohn, Z. A.; Kaplan, G.
J. Exp. Med. 1991, 173, 699. (b) Moreira, A. L.; Sampio, E. P.; Zmuidzinas,
A.; Frindt, P.; Smith, K. A.; Kaplan, G. J. Exp. Med. 1993, 177, 1675.
(3) (a) Kumar, S.; Rajkumar, S. V. Expert ReV. Anticancer Ther. 2005,
5, 759. (b) Kumar, S.; Anderson, K. C. Nat. Clin. Pract. Oncol. 2005, 2,
262. (c) Eigler, A.; Sinha, B.; Hartmann, G.; Endres, S. Immun. Today 1997,
18, 487. (d) Teo, S. K.; Resztak, K. E.; Scheffler, M. A.; Kook, K. A.;
Zeldis, J. B.; Stirling, D. I.; Thomas, S. D. Microbes Infect. 2002, 4, 1193.
(e) Kruse, F. E.; Joussen, A. M.; Rohrschneider, K.; Becker, M. D.; Volcker,
H. E. Graefe’s Arch. Clin. Exp. Ophthalmol. 1998, 236, 461. (f) Bartlett, J.
B.; Dredge, K.; Dalgleish, A. G. Nat. ReV. Cancer 2004, 4, 314. (g) Singhal,
S.; Mehta, J. BioDrugs 2001, 15, 163.
market due to its serious side effects, i.e., teratogenic
activity.1 However, the recent decade has witnessed a true
renaissance in interest in its broad biological activity. In
particular, thalidomide (1) was reevaluated and attracted
(4) Sheskin, J. Clin. Pharmacol. Ther. 1965, 6, 303.
10.1021/ol0623668 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/26/2006

Scheme 2
(S)-enantiomer exhibits the teratogenic activity and that the
preliminary data convincingly suggest that introduction of a
substituent in the â-position of thalidomide is a feasible and
useful alternative approach to configurationally stable deriva-
tives of this potent and multibiologically active drug.
(R)-isomer is devoid of this side effect.5 However, it
remained uncertain which enantiomer exhibited the terato-
genic effect because optically active thalidomide undergoes
quite rapid racemization, via formation of the corresponding
enolate, under physiological conditions (T1/2 ) 8 h at pH
7.1, 37 °C in water).6 Therefore, it is generally recognized
that this inherent configurational instability of thalidomide
(1) plagues its potentially promising medicinal applications
in cases where the use of a single enantiomer is required.
As a response to this problem, the design and synthesis of
configurationally stable analogues of thalidomide have
recently been an important subject in organic and medicinal
chemistry. In particular, to prevent the undesired racemiza-
tion, an approach involving quaternization of the stereogenic
center in thalidomide (1) was successfully realized. Thus,
recently, several groups have reported the synthesis of
optically stable thalidomide analogues 2 (Scheme 1) having
a C3 substituent such as an alkyl group,7 a fluoroalkyl group,8
or a fluorine atom.7a,9 On the other hand, a conceptually
different appraoch that does not alter the geometry of the
stereogenic center in thalidomide (1) can be realized by
introducing a substituent in the â-position (C4). As one can
expect, in the compounds 3 (Scheme 1), the stereogenic
carbon at C3 might be configurationally stable as its
epimerization will lead to the corresponding conformationally
unfavorable and unstable cis derivative. However this
geometrically alternative approach to stabilize the C3 ste-
reogenic center in thalidomide (1) has never been explored.10
Here, we report an efficient asymmetric synthesis of
4-alkyl (Me)- (3a) and 4-aryl (Ph)- (3b) thalidomide deriva-
tives and demonstrate their configurational stability. Our
Recently, we have developed an operationally convenient
methodology for generalized asymmetric synthesis of various
types of â-substituted pyroglutamic acids 7 (Scheme 2).11
One of the methods involves highly diastereoselective,
organic base catalyzed Michael addition of achiral glycine
Schiff base derivatives 411 with chiral (R)- or (S)-N-(E-enoyl)-
4-phenyl-1,3-oxazolidine-2-one 5 to give addition products
6 as individual stereoisomers in quantitative chemical yields.
Products 6 can be easily hydrolyzed under mild conditions
and, upon a workup procedure, transformed to the pyro-
glutamic acids 7. We envisioned that â-substituted pyro-
glutamic acids 7 can be appropriate precursors for the
preparation of the corresponding derivatives of 4-substituted
thalidomide 3. However, considering the stereochemical
requirements for â-substituted pyroglutamic acids as starting
compounds for the preparation of 4-substituted thalidomides
3, it became clear that the trans-pyroglutamic acids 7
available by our method are not stereochemically suitable
(Figure 1). The corresponding cis-pyroglutamic acids 7,
possessing the correct stereochemistry, are unfortunately very
difficult to prepare in optically pure form.11f On the other
hand, considering our basic idea that cis-4-substituted
thalidomides 3 might be conformationally unstable and taking
into account that C-H acidity at C3 in 4-substituted 3 might
be as high as in the unsubstituted thalidomide (1), we
assumed that upon the corresponding glutarimide formation
the phthalimide group at C3 would undergo epimerization
giving rise to the target trans products 3. On the basis of
this stereochemical rationale, thalidomides 3a,b containing
4-methyl and 4-phenyl groups, representing general alkyl and
aryl groups, respectively, were chosen as the synthetic targets
to examine their 3,4-trans stability and to facilitate their
preliminary biological assay. To this end, diastereo- and
enantiomerically pure â-substituted pyroglutamates 7a,b and
(5) (a) Hoglund, P.; Eriksson, T.; Bjorkman, S. J. Pharmacokinet.
Biopharm. 1998, 26, 363. (b) Eriksson, T.; Bjorkman, S.; Roth, B.; Fyge,
A.; Hoglund, P. Chirality 1996, 7, 44. (c) Wintersk, W.; Frankus, E. Lancet
1992, 339, 365.
(6) (a) Eriksson, T.; Bjorkman, S.; Hoglund, P. Eur. J. Clin. Pharmacol.
2001, 57, 365. (b) Wnendt, S.; Finkam, M.; Winter, W.; Ossing, J.; Rabbe,
G.; Zwingenberger, K. Chirality 1996, 8, 390. (c) Knoche, B.; Blaschke,
G. J. Chromatographia 1994, 2, 183.
(7) (a) Chung, F.; Palmer, B. D.; Muller, G. W.; Man, H.-W.; Kestell,
P.; Baguley, B. C.; Ching, L.-M. Oncol. Res. 2003, 14, 75. (b) Miyachi,
H.; Kolso, Y.; Shirai, R.; Niwayama, S.; Liu, J. O.; Hashimoto, Y. Chem.
Pharm. Bull. 1998, 46, 1165. (c) Buech, H. P.; Omlor, G.; Knabe, J.
Arzneim. Forsch. 1990, 40, 32. (d) Knabe, J.; Omlor, G. Arch. Pharm. Chem.
Life Sci. 1989, 322, 499.
(8) Osipov, S. N.; Tsouker, P.; Hennig, L.; Burger, K. Tetrahedron 2004,
60, 271.
(9) Takeuchi, Y.; Shiragami, T.; Kimura, K.; Suzuki, E.; Shibata, N.
Org. Lett. 1999, 1, 1571.
(10) (a) Although the SciFinder search for 4-methyl-thalidomide gave a
reference to a patent, synthesis of this compound and its absolute
configuration was not found. Corot, C.; Port, M.; Gautheret, T.; Williard,
X. U.S. Pat. Appl. Publ. 2005, 17pp. (b) For some 4-hydroxy-substituted
derivatives, see: Luzzio, F. A.; Thomas, E. M.; Figg, W. D. Tetrahedron
Lett. 2000, 41, 7151.
(11) (a) Ellis, T. K.; Ueki, H.; Soloshonok, V. A. Tetrahedron Lett. 2005,
46, 941. (b) Ellis, T. K.; Ueki, H.; Yamada, T.; Ohfune, Y.; Soloshonok,
V. A. J. Org. Chem. 2006, 71, 8572-8578.
5626
Org. Lett., Vol. 8, No. 24, 2006

Figure 1. Synthetic approaches to trans-4-substituted thalidomides.
their enantiomers ent-7a,b (>98% ee) were prepared ac-
cording to the procedure as shown in Scheme 2.
with water in acetone, the intermediate 10b was smoothly
transformed to (3S,4S)-3b, which was isolated in 68% yield
(two steps). The target product (3S,4S)-3b was obtained as
a single diastereomer with >98% ee that was evident from
We chose the synthesis of â-phenyl thalidomide (3b) as
the first target. Hydrolysis of pyroglutamic acid (2R,3S)-7b
with 3 N HCl at reflux afforded (2R,3S)-3-phenylglutamic
acid 8b in high chemical yield.12b The next protocol,
transformation of acid 8b to N-phthaloyl anhydride 9b, was
a crucial step in our synthesis as we expected that at this
point the corresponding cis-9b would undergo epimerization
at the 3C stereogenic carbon giving rise to the desired trans-
9b. Using the literature protocol,13 we successfully trans-
formed starting acid 8b to N-phthaloyl anhydride 9b, which
was isolated as a single diastereomer in 67% (two steps)
yield. To our delight, determination of the relative stereo-
chemistry in the product 9b revealed a 3,4-trans relationship,
1
its H NMR spectrum and chiral HPLC analysis.
With this developed synthetic procedure, we next applied
it for the preparation of the alkyl derivative, (3S,4R)-4-methyl
thalidomide 3a. We found that under the same reaction
conditions described for the preparation of 9b from 7b
transformation of the starting pyroglutamic acid 7a to 9a
can be conducted in a bit lower 51% overall yield. However,
most importantly, the key epimerization at the C3 stereogenic
center allows preparation of (3S,4R)-3a starting from (2R,3R)-
7a and occurs cleanly and completely, as no cis-configured
product was observed in the reaction mixture. The final
transformation of 9a to the target thalidomide 3a was
conducted in noticeably higher (68%) chemical yield as
compared to that of the preparation of the 4-phenyl analogue
3b.
To provide for the systematic study of biological activity
of these new derivatives of thalidomide, the enantiomers of
(3S,4R)-3a and (3S,4S)-3b, compounds (3R,4S)-ent-3a and
(3R,4R)-ent-3b, were prepared according to Scheme 3 and
starting from (2S,3S)-7a (2S,3R)-7b, respectively.
The successful and stereochemically complete transforma-
tion of (2R,3R)-7a to (3S,4R)-3a and of (2R,3S)-7b to
(3S,4S)-3b has convincingly suggested that the thalidomide
derivatives (3S,4R)-3a and (3S,4S)-3a are conformationally
stable and that the corresponding cis analogues are strongly
conformationally disfavored and were not observed in the
reaction mixtures. Nevertheless, we decided to additionally
examine the configurational stability at the C3 stereogenic
1
as was evident from the diastereomer (3S,4S)-9b H NMR
data (J3-4 ) 12.6 Hz) and NOE experiments. Taking into
account that the transformation of 8b to 9b is a multistep
process, it is difficult to determine at which step the
epimerization took place. However, considering the substan-
tial increase in the C-H acidity of C3 in the step of the
intermediate N-phthaloyl formation, the presence of pyridine,
and the high reaction temperature, one can reasonably assume
that the desired epimerization at C3 (3R to 3S) can occur
before the cyclization step forming the anhydrate six-
membered ring. It is important to note that not a trace of
possible cis-9b was found in the reaction mixture.
For the final transformation of enantio- and diastereo-
merically pure 9b to the target 4-phenyl-substituted thali-
domide 3b, we decided to use a condensation reaction of
the intermediate dicarboxylate 10b with trifluoroacetoamide,
reported by Galons et al.14 After hydrolysis of anhydrate 9a
Scheme 3
Org. Lett., Vol. 8, No. 24, 2006
5627

carbon. To this end, thalidomide (3S,4R)-3a was subjected
to deuterium incorporation experiments. Under the neutral
or slightly acidic conditions (D2O, rt, 24 h or 40 °C, 8 h;
CD3OD, 24 h; CDCl3, D2O, rt, 48 h), no deuterium atom
was incorporated to the position C3. This result suggested
that the substituent at C4 disfavored the corresponding
enolization at C3, contrary to that of unsubstituted thalido-
mide (1). On the other hand, under the basic conditions (CD3-
OD, catalytic amounts of Et3N), C3-H was completely
deuterated after 24 h. Formation of some decomposition
products was observed under these basic conditions. How-
ever, not a trace of the corresponding 3,4-cis isomer was
R-stereogenic center upon formation of the corresponding
N-phthaloyl anhydrides 9a,b. The demonstrated conforma-
tional stability of these new thalidomide derivatives 3a,b
provides solid experimental evidence for practical feasibility
of the approach described here to overcome the inherent
problem of configurational instability of thalidomide. Con-
sidering the potent biological activity of thalidomide to
various diseases, 4-substituted derivatives 3a,b would be
useful as lead compounds for medicinal chemistry. Several
biological assays using 3a,b are currently under investigation.
Acknowledgment. This work was supported by JSPS
KAKENHI (No. 16201045 and 16073214) and a JSPS Grant
from the Research for the Future Program (99L01204) and
the Department of Chemistry and Biochemistry, the Uni-
versity of Oklahoma. V.A.S. gratefully acknowledges gener-
ous financial support from the Central Glass Company
(Tokyo, Japan) and the Ajinomoto Company (Tokyo, Japan).
1
observed by H NMR of the reaction mixture.
In summary, preparation of new thalidomide derivatives
4-methyl-(3S,4R)-3a and 4-phenyl-(3S,4S)-3b starting from
pyroglutamic acids (2R,3R)-7a and (2R,3S)-7b, possessing
an inappropriate stereochemistry, was successfully realized
due to stereochemically complete epimerization at the
(12) (a) Soloshonok, V. A.; Cai, C.; Hruby, V. J. J. Org. Chem. 2000,
65, 6688. (b) Cai, C.; Soloshonok, V. A.; Hruby, V. J. J. Org. Chem. 2001,
66, 1339. (c) Soloshonok, V. A.; Ueki, H.; Tiwari, R.; Cai, C.; Hruby, V.
J. J. Org. Chem. 2004, 69, 4984. (d) Soloshonok, V. A.; Cai, C.; Yamada,
T.; Ueki, H.; Ohfune, Y. J. Am. Chem. Soc. 2005, 127, 15296. (e)
Soloshonok, V. A.; Ueki, H.; Ellis, T. K.; Yamada, T.; Ohfune, Y.
Tetrahedron Lett. 2005, 46, 1107. (f) Soloshonok, V. A. Curr. Org. Chem.
2002, 6, 341-364.
Supporting Information Available: Experimental Sec-
tion including the general method and preparation and
physical properties for 8a, 9a, 3a, 8b, 9b, and 3b; 1H NMR
of 9a,b and 3a,b; NOESY spectrum of 3b; and HPLC spectra
of 3a,b. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) King, F. E.; Kidd, D. A. A. J. Org. Chem. 1949, 14, 3315.
(14) Flaih, N.; Pharm-Huy, C.; Galons, H. Tetrahedron Lett. 1999, 40,
3697.
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