An organocatalytic approach to the construction of chiral oxazolidinone rings and application in the synthesis of antibiotic linezolid and its analogues

Article abstract of DOI:10.1021/ol802333n

(Chemical Equation Presented) An efficient, catalytic asymmetric approach to antibacterial agent linezolid has been developed. The route features organocatalytic, highly enantioselective aldol and Beckman rearrangement reactions. The strategy has also bee

Full text of DOI:10.1021/ol802333n

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5489-5492
An Organocatalytic Approach to the
Construction of Chiral Oxazolidinone
Rings and Application in the Synthesis
of Antibiotic Linezolid and Its
Analogues
Lirong Song,† Xiaobei Chen,† Shilei Zhang,*,† Haoyi Zhang,† Ping Li,†
Guangshun Luo,† Wenjing Liu,† Wenhu Duan,*,†,‡ and Wei Wang*,†,§
Department of Pharmaceutical Sciences, School of Pharmacy, East China UniVersity
of Science & Technology, Shanghai 200237, People’s Republic of China, Shanghai
Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese
Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai
201203, People’s Republic of China, and Department of Chemistry & Chemical
Biology, UniVersity of New Mexico, Albuquerque, New Mexico 87131-0001
zsl103@yahoo.com.cn; whduan@mail.shcnc.ac.cn; wwang@unm.edu
Received October 8, 2008
ABSTRACT
An efficient, catalytic asymmetric approach to antibacterial agent linezolid has been developed. The route features organocatalytic, highly
enantioselective aldol and Beckman rearrangement reactions. The strategy has also been successfully applied for the preparation of new
r-substituted analogues with high enantio- and diastereoselectivity.
Oxazolidinones are an important class of molecular archi-
tectures found in a broad range of synthetically and biologi-
cally interesting compounds. The widely used Evans chiral
oxazolidinone-based auxiliaries are one of the most reliable
methods in asymmetric synthesis.1 The five-membered
heterocycles display a broad spectrum of biological activities,
serving as inhibitors of monoamine oxidase,2 HIV-1 inhibi-
tory activity,3 NPC1L1 ligands,4 and RNA-binding agents.5
Moreover, the interest in this structure has recently surged
significantly as a result of new antibiotic agent linezolid 1
(Zyvox) (Figure 1).6
(3) Reddy, G. S. K. K.; Ali, A.; Nalam, M. N. L.; Anjum, S. G.; Cao,
H.; Nathans, R. S.; Schiffer, C. A.; Rana, T. M. J. Med. Chem. 2007, 50,
4316.
(4) Pfefferkorn, J. A.; Larsen, S. D.; Huis, C. V.; Sorenson, R.; Barton,
T.; Winters, T.; Auerbach, B.; Wu, C.; Wolfram, T. J.; Cai, H.; Welch, K.;
Esmaiel, N.; Davis, J.; Bousley, R.; Olsen, K.; Mueller, S. B.; Mertz, T.
Bioorg. Med. Chem. Lett. 2008, 18, 546.
† East China University of Science & Technology.
‡ Graduate School of the Chinese Academy of Sciences.
§ University of New Mexico.
(1) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96,
835. (c) Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 2005, 61,
8173.
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Bergmeier, S. C. Bioorg. Med. Chem. Lett. 2006, 16, 3600.
(6) For reviews of linezolid, see: (a) Barbachyn, M. R; Ford, C. W.
Angew. Chem., Int. Ed. 2003, 42, 2010. (b) Renslo, A. R.; Luehr, G. W.;
Gordeev, M. F. Bioorg. Med. Chem. 2006, 14, 4227. (c) Vardakas, K. Z.;
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10.1021/ol802333n CCC: $40.75
Published on Web 11/12/2008
2008 American Chemical Society

Linezolid, a new class of synthetic antibacterial with potent
activity against Gram-positive nosocomial infections, was
approved for use in humans in April 2000. Since then, a
great deal of research effort has been devoted to the synthesis
of oxazolidinone analogues aimed at seeking new antibac-
terials.7 The general approach to the chiral oxazolidinone
scaffold mainly relies on the use of the chiral precursors.8
To our knowledge, a catalytic asymmetric method has not
yet been described. In conjunction with our ongoing studies
on the synthesis of new oxazolidinone analogues for
antibacterial applications with fewer side effects, we have
decided to develop an alternative, versatile catalytic enan-
tioselective approach to the construction of the chiral
architecture. It is noteworthy that both morpholine-ring and
amide moieties play key roles in bioactivity.7 As a result of
the lack of an efficient catalytic method for the building of
the chiral oxazolidinone framework and introducing diversity
at the R-position of the amide, it is not surprising that only
simple amides have been synthesized. It is realized that
introducing the substituents at the R-position is a challenging
task because such modification will create a new stereogenic
center (Figure 1).
simplicity, and environmental friendliness.9 Despite the fact
that a number of highly enantioselective organocatalytic
processes have been developed, their synthetic value in the
application of preparation of biologically significant natural
products and synthetic molecules remains to be demon-
strated.10 Toward this end, recently our group has become
interested in exploring these asymmetric approaches to
synthetically valuable targets. Herein, we disclose the results
of an investigation that has resulted in an unprecedented
organocatalytic enantioselective aldol and Beckman reactions
as key steps for efficient preparation of linezolid 1. Moreover,
the strategy serves as a facile approach to its R-substituted
analogues 2 (Figure 1).
A concise total synthesis of linezolid 1 and its R-substi-
tuted oxazolidinone analogues is shown in Scheme 1. We
envisioned that the up to two stereogenic centers and amide
moiety could be facilely constructed by organocatalytic
enantioselective aldol reaction and Beckman rearrangement,
respectively.
On the basis of this synthetic plan, indeed, the prerequisite
aldehyde 5 could be prepared straightforwardly in four steps
in an overall 70% yield (Scheme 2). Reductive amination
of readily available aniline 6 with glyceraldehyde acetonide
7 in the presence of NaBH(OAc)3 produced amine 8 in 82%
yield. Protection of the resulting amino group 8 with ethyl
chlorformate, followed by removal of the isopropylidene
group of compound 9 and oxidation of corresponding diol
10 with sodium metaperiodate, afforded desired aldehyde 5
in very high yields.
Scheme 1
.
Retrosynthetic Analysis of Linezolid 1 and Its
Analogues 2
Figure 1
2.
.
Structures of linezolid 1 and its R-substituted analogues
In the past decade, organocatalysis has received consider-
able attention due to the novelty of the concept, operational
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see: (a) Brickner, S. J.; Barbachyn, M. R.; Hutchinson, D. K.; Manninen,
P. R. J. Med. Chem. 2008, 51, 1981. (b) Ebner, D. C.; Culhane, J. C.;
Winkelman, T. N.; Haustein, M. D.; Jayna, L.; Ditty, J. L.; Ippoliti, J. T.
Bioorg. Med. Chem. 2008, 16, 2651. (c) Rudra, S.; Yadav, A.; Rao,
A. V. S. R.; Srinivas, A. S. S. V.; Pandya, M.; Bhateja, P.; Mathur, T.;
Malhotra, S.; Rattan, A.; Salman, M.; Mehta, A.; Cliffe, I. A.; Das, B.
Bioorg. Med. Chem. Lett. 2007, 17, 6714. (d) Prasad, J. V. N. V.; Boyer,
F. E.; Chupak, L.; Dermyer, M.; Ding, Q.; Gavardinas, K.; Hagen, S. E.;
Huband, M. D.; Jiao, W.; Kaneko, T.; Maiti, S. N.; Melnick, M.; Romero,
K.; Pattersonb, M.; Wu, X. Bioorg. Med. Chem. Lett. 2006, 16, 5392. (e)
Renslo, A. R.; Jaishankar, P.; Venkatachalam, R.; Hackbarth, C.; Lopez,
S.; Patel, D. V.; Gordeev, M. F. J. Med. Chem. 2005, 48, 5009.
With the compound 5 in hand, we set the stage for the
critical catalytic enantioselective aldol reaction. Despite the
fact that the organocatalytic asymmetric aldol process has
(8) (a) Mora´n-Ramallal, R.; Liz, R.; Gotor, V. Org. Lett. 2008, 10, 1935.
(b) Madhusudhan, G.; Om Reddy, G.; Rajesh, T.; Ramanatham, J.; Dubey,
P. K. Tetrahedron Lett. 2008, 49, 3060. (c) Narina, S. V.; Sudalai, A.
Tetrahedron Lett. 2006, 47, 6799. (d) Xu, G.-Y.; Zhou, Y.; Xu, M.- C.
Chin. Chem. Lett. 2006, 17, 302. (e) Kim, S.-W.; Lee, J.-G.; Lee, E.-J.;
Choo, H.-Y. P.; Yoo, C.-Y.; Lee, D. Y.; Roh, K. R.; Kim, E. K. J. Comb.
Chem. 2004, 6, 851. (f) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.;
Jeganathan, A.; Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.;
Gadwood, R. C.; Chan, L.; Lyster, M. A.; Maloney, M. T.; Moeslein, J. A.;
Greene, M. L.; Barbachyn, M. R. Org. Process Res. DeV. 2003, 7, 533. (g)
Lohray, B. B.; Baskaran, S.; Rao, B. S.; Reddy, B. Y.; Rao, I. N.
Tetrahedron Lett. 1999, 40, 4855.
(9) For reviews of organocatalysis, see: (a) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138. (c) Houk, K. N.; List, B. Acc. Chem. Res.
2004,37,487.(d)Berkessel,A.;Groger,H.AsymmetricOrganocatalysis-From
Biomimetic Concepts to Applications in Asymmetric Synthesis: Wiley-VCH
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synthesis, see: de Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem.
2007, 2575.
5490
Org. Lett., Vol. 10, No. 23, 2008

Scheme 2
.
Synthesis of Aldehyde 5
Scheme 3. Synthesis of Linezolid 1
gave the best results. In this case, a good yield (67%) and
high ee (88%) at -35 °C were achieved (Table 1, entry 5).
been intensively explored,11-13 the utilization of the specific
R-amino aldehyde 5 for the reaction has not been reported.
Our experience indicated that the enantioselectivity and
reaction yield of the aldol reaction is highly substrate-
dependent. Accordingly, the exploration of the aldol process
aimed at seeking the optimal reaction conditions was
performed intensively with aldehyde 5 and acetone. The
results are shown in Table 1. Commonly used organocatalysts
such as (R)-proline 12a and (R)-pyrrolidinyl tetrazole 12b
gave disappointing results in terms of reaction yields and
enantioselectivity (Table 1, entries 1-4). The long reaction
times and low yields made it impossible to further improve
the enantioselectivities by lowering the reaction temperature.
After extensive survey of a variety of chiral pyrrolidine-
derived catalysts, to our delight we found that amide 12c11l
Table 1. Aldol Reaction of Aldehyde 5 and Acetone 11aa
entry
solvent
catalyst
t (h)
% yieldb
% eec
(11) For a review of organocatalytic aldol reactions, see: (a) Guillena,
G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249. For
selected examples, see: (b) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am.
Chem. Soc. 2000, 122, 2395. (c) Saito, S.; Nakadai, M.; Yamamoto, H.
Synlett 2001, 1245. (d) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2004, 43, 2420. (e) Cobb, A. J. A.; Shaw, D. M.; Ley,
S. V. Synlett 2004, 558. (f) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (g) Tang, Z.; Yang,
Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am.
Chem. Soc. 2005, 127, 9285. (h) Samanta, S.; Liu, J.; Dodda, R.; Zhao,
C.-G. Org. Lett. 2005, 7, 5321. (i) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng,
L.; Wan, J.; Xiao, W.-J. Org. Lett. 2005, 7, 4543. (j) Zou, W.; Ibrahem, I.;
Dziedzic, P.; Sunde´n, H.; Co´rdova, A. Chem. Commun. 2005, 4946. (k)
Enders, D.; Voith, M.; Lenzen, A. Angew. Chem., Int. Ed. 2005, 44, 1304.
(l) Raj, M.; Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8,
4097. (m) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka,
1
2
3
DMF
acetone
DMF
acetone
acetone
12a
12a
12b
12b
12c
70
70
72
48
17
17
30
20
40
67
58
67
56
72
88
4
5d
a Unless otherwise indicated, all reactions were carried out on a 0.10
mmol scale with 0.1 mL of acetone and 0.4 mL of solvent in the presence
of 20 mol % of the catalyst at room temperature. b Isolated yield.
c Determined by chiral HPLC analysis. d Reaction performed at -35 °C.
Finally, we turned our attention to the synthesis of target
molecule linezolid 1 from compound 4a. The synthesis is
straightforward. Treatment of ꢀ-hydroxyketone 4a with
hydroxylamine hydrochloride gave oxime 13a in a nearly
quantitative yield (97%). Subsequent cyclization in the
presence of K2CO3/MeOH to provide oxazolidinone 3a was
followed by a two-step Beckman rearrangement to afford
linezolid 1 in 50% yield (Scheme 3). The spectral data of
the synthetic substance 1 were in full agreement with those
described in the literature.14
F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734
.
(12) For examples of organocatalytic aldol reactions of R-hydroxy,
R-alkoxy, and R-halo-ketoens/aldehdyes, see: (a) Thayumanavan, R.;
Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 3541. (b) Enders, Dieter;
Grondal, C Angew. Chem., Int. Ed. 2005, 44, 1210. (c) Chen, X.-H.; Luo,
S.-W.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Chem.
Eur. J. 2007, 132, 689
.
(13) For examples of organocatalytic aldol reaction in drug and total
synthesis, see: (a) Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130,
6737. (b) Carpenter, J.; Northrup, A. B.; Chung, D.; Wiener, J. J. M.; Kim,
S.-G.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2008, 47, 3568. (c)
Zhang, S.; Chen, X.; Zhang, J.; Wang, W.; Duan, W. Synthesis 2008, 383.
(d) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int.
Ed. 2007, 46, 5734. (e) Zhang, S.; Duan, W.; Wang, W. AdV. Synth. Catal.
2006, 348, 1228. (f) Pihko, P. M.; Wekkila¨, A. Tetrahedron Lett. 2003, 44,
The generality of the synthetic strategy was further
explored in the synthesis of the analogues 2 of linezolid 1.
7607
.
Org. Lett., Vol. 10, No. 23, 2008
5491

Table 2. Aldol Condensation of Aldehyde 5 and Cycloketones
11a-ca
Scheme 4. Synthesis of Analogues 2 of Linezolid
entry
X
solvent catalyst t (h) % yieldb % eec
1
2
CH2, 11b
O, 11c
NBoc, 11d DMF
NBoc, 11d DMSO
NBoc, 11d DMSO
11b
11c
12a
12a
12a
12a
12b
20
48
21
28
48
96
95
61
77
55
95
97
90
93
93
3d
4d
5d
a Unless otherwise indicated, all reactions were carried out on a 0.10
mmol scale with 0.1 mL of acetone and 0.4 mL of solvent in the presence
of 10 mol % of the catalyst at room temperature. b Isolated yield.
c Determined by chiral HPLC analysis. d 2.5 mmol 11d used.
As demonstrated, the strategy serves as a powerful tool for
the efficient preparation of the new R-substituted analogues
of linezolid 1 in high yields and with enantio- and diaste-
reoselectivities. It is anticipated that the reaction efficiency
of the organocatalyzed aldol reaction of aldehyde 5 with
cyclic ketones 11b-d highly depends on organocatalysts and
reaction conditions. After the optimization of reaction
conditions, it was found that the best outcomes were obtained
with (R)-proline 12a as catalyst for cyclohexanone 11b and
tetrahydropyran-4-one 11c. In both cases, high yields and
excellent levels of enantioselectivity were achieved (Table
2, entries 1 and 2). When solid ketone 11d was employed
as aldol donor, a solvent was necessary for the process
(entries 3-5). Although (R)-pyrrolidinyl tetrazole 12b gave
a similar level of enantioselectivity (93% ee, entry 5) in
DMSO, a higher yield was obtained with (R)-proline 12a
(77% yield, Table 2, entry 4).
The highly enantio-enriched aldol adducts 4b-d were
smoothly transformed into the R-substituted analogs of
linezolid 2 according to the established synthetic protocols
described above (Scheme 4). It is known that the chiral center
at the R-position of the carbonyl group is prone to racem-
ization under a basic condition. This is particularly prob-
lematic for ꢀ-hydroxy ketones. To minimize the problem,
we first converted the ketones in 4b-d to oximes 13b-d.
Then compound 13 was exposed to K2CO3/MeOH to give
cyclic oxazolidinone 3. Finally two-step Beckman rearrange-
ment furnished the amides 2a-c in good yields. During these
transformations, no racemization was observed.15
In conclusion, we have developed a concise and flexible
asymmetric approach to the antibacterial agent linezolid and
its analogues in an efficient way. The route features orga-
nocatalytic, highly enantioselective aldol and Beckman
rearrangement reactions. The strategy, reported for the first
time, serves as a powerful tool for synthesis of analogues of
linezolid with branches at the R-position. Further elaboration
of the method for preparation of more analogues and their
biological activity studies are currently in progress in our
laboratory.
Acknowledgment. We are grateful for financial support
from National Science Foundation of China (0801031005),
Chinese National Programs for High Technology Research
and Development (0604071005 and 0704051005), and the
New Drug Basic Research Program of the Shanghai Institute
of Materia Medica (07G603B005).
Supporting Information Available: Experimental pro-
cedures and spectra data for compounds 1-10 and 13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) See Supporting Information and Brickner, S. J.; Hutchinson, D. K.;
Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.;
Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E.
J. Med. Chem. 1996, 39, 673.
OL802333N
(15) Chiral HPLC analysis of final products showed no racemization
occurred during these transformations (see Supporting Information for
product 2a).
5492
Org. Lett., Vol. 10, No. 23, 2008