Direct catalytic synthesis of enantiopure 5-substituted oxazolidinones from racemic terminal epoxides

Article abstract of DOI:10.1021/ol050675c

(Chemical Equation Presented) A venerable scaffold for asymmetric synthesis and drug development, chiral 5-substituted oxazolidinones are obtained in almost enantiomerically pure form (up to 99.9% ee) starting from racemic terminal epoxides. The salient features of this process include the very simple and convenient experimental protocol and the employment of a readily accessible catalyst and inexpensive, easily handled starting materials. An enantioconvergent approach for the total conversion of racemic epoxide into a single stereoisomeric oxazolidinone is also described.

Full text of DOI:10.1021/ol050675c

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1983-1985
Direct Catalytic Synthesis of
Enantiopure 5-Substituted
Oxazolidinones from Racemic Terminal
Epoxides
Giuseppe Bartoli,* Marcella Bosco, Armando Carlone, Manuela Locatelli,
Paolo Melchiorre,* and Letizia Sambri
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna
V. le Risorgimento 4, 40136 Bologna, Italy
giuseppe.bartoli@unibo.it; pm@ms.fci.unibo.it
Received March 30, 2005
ABSTRACT
A venerable scaffold for asymmetric synthesis and drug development, chiral 5-substituted oxazolidinones are obtained in almost enantiomerically
pure form (up to 99.9% ee) starting from racemic terminal epoxides. The salient features of this process include the very simple and convenient
experimental protocol and the employment of
a readily accessible catalyst and inexpensive, easily handled starting materials. An
enantioconvergent approach for the total conversion of racemic epoxide into a single stereoisomeric oxazolidinone is also described.
The development of effective asymmetric routes for the
synthesis of valuable chiral building blocks in enantiomeri-
cally pure form is of pressing current importance, as single-
enantiomer small-molecule drugs have a commanding pres-
ence in the global pharmaceutical landscape.1 Chiral
5-substituted oxazolidinones represent a privileged structural
motif by virtue of the fact that they are widely used in organic
synthesis as chiral auxiliaries,2 and many of them have
relevance from a pharmaceutical point of view because of
their interesting biological activity.3 Such a scaffold is present
in a new class of synthetic antimicrobial agents that are
extremely effective against Gram-positive bacteria, many
strains of which are resistant to traditional antibiotics.3a
Importantly, the absolute configuration at C-5 of the key
5-substituted oxazolidinone pharmacophore is essential for
antibacterial activity. Therefore, simple catalytic methods that
allow the rapid generation of collections of enantiopure
oxazolidinones would have a significant enabling impact on
drug discovery and development.
Chiral 5-substituted oxazolidinones are generally acces-
sible by indirect routes involving preparation of enantioen-
riched 1-amino-2-ols and subsequent cyclization,4 but asym-
metric entries into these nonproteinogenic derived amino
alcohols are relatively uncommon.5 We report here a direct
catalytic synthesis of highly enantioenriched 5-substituted
oxazolidinones (up to 99.9% ee) starting from inexpensive
racemic terminal epoxides. The presented methodology
provides a very simple and practical tool for synthesizing a
plurality of structurally and electronically varied 5-substituted
oxazolidinones in almost enantiomerically pure form.
(1) Worldwide sales of single-enantiomer drugs reached more than $159
billion in 2002, and are expected to grow soon. See: Rouhi, A. M. Chem.
Eng. News 2003, 81, 45.
(2) (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23. (b) Ager, D. J.;
Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30, 3.
(3) (a) Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed. 2003, 42,
2010 and references therein. (b) Mukhtar, T. A.; Wright, G. D. Chem. ReV.
2005, 105, 529.
(4) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835.
(5) For some leading references, see: (a) Larrow, J. F.; Schaus, S. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420. (b) Ohkuma, T.; Ishii,
D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510. (c) Adderley,
N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´ D. I. Angew. Chem., Int. Ed.
2003, 42, 4241.
10.1021/ol050675c CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/19/2005

In our recent studies, we discovered that the asymmetric
carbamate-based aminolytic kinetic resolution (AKR) of
racemic terminal epoxides catalyzed by Jacobsen’s (salen)-
CoIII chiral complex affords N-Cbz or N-Boc protected
1-amino-2-ols in almost enantiomerically pure form.6 Con-
sidering the synthetic versatility of the carbamate moiety,
we envisioned the AKR strategy as a valuable platform for
the development of a direct synthesis of enantiopure 5-sub-
stituted oxazolidinones.7 A one-pot reaction sequence could
be envisaged wherein a highly selective ring opening of
racemic epoxides with carbamate would be followed by an
efficient base-mediated in situ cyclization of the aminol
intermediate (Scheme 1).
at room temperature with the commercially available com-
plex 1 (1.5 mol % relative to racemic epoxides) and
p-nitrobenzoic acid (3 mol %) in undistilled tert-butyl methyl
ether (TBME). Upon completion of the AKR reaction, the
sequential one-pot addition of NaH (2 equiv) and THF
afforded the enantiopure oxazolidinone 4a (ee >99%) in 94%
isolated yield based on 3.
We then sought to test the generality of the presented
methodology. A range of 5-substituted oxazolidinones bear-
ing aliphatic substituents was accessed in enantiopure form
starting from linear and relatively hindered racemic terminal
epoxides (Table 1, entries 1-4). The presence of coordinat-
Table 1. From Racemic Terminal Epoxides to Enantiopure
Oxazolidinonesa
Scheme 1. AKR-Based Strategy for a Direct Conversion of
Racemic Terminal Epoxides to Enantiopure 5-Substituted
Oxazolidinones
time yieldd
eee
(%)
entry xb
R
product (h)c
%)
1
2
3 f
4
1.5 CH3
1.5 (CH2)4CHdCH2
4b
4c
4d
4e
4f
4g
4h
4i
18
18
40
40
24
36
40
60
60
60
97
95
97
98
90
93
90
98
97
94
>99
>99
>99
>99
>99
99
>99
98.7
96.5
97.5
4
4
2
3
4
5
5
5
c-C6H11
CH2Ph
Proof-of-principle was provided through the direct forma-
tion of oxazolidinone 4a starting from racemic 1,2-epoxybu-
tane 2a (Scheme 2). The effective catalyst for the AKR step
5
CH2O(i-Pr)
CH2OTBS
Ph
4-ClC6H4
3-ClC6H4
3-NO2C6H4
6g
7 f
8 f,h
9 f
4j
4k
10 f
Scheme 2. Direct Catalytic Synthesis of Enantiopure
Oxazolidinone 4a from Racemic 2a
a Experimental conditions (1 mmol scale): open-air reactions run in
undistilled TBME (6 M), using a 2.1:1 ratio of 2 to 3. The cyclization was
performed by subsequent one-pot addition of THF (0.1 M) and 2 equiv of
NaH. b Catalyst loading relative to racemic epoxide. c Reaction time of
AKR. d Yield of isolated oxazolidinone 4 based on urethane 3. e The ee
values of 4 or of the corresponding N-benzoyl derivatives were determined
by HPLC or by GC analyses on commercially available chiral stationary
phases. See the Supporting Information for details. f Performed with 2.2
equiv of epoxide. g TBS ) tert-butyldimethylsilyl. h Cyclization step: upon
completion of the AKR, THF (0.1 M) and 2 equiv of t-BuOK were added
(rt, 16 h).
ing functional groups did not appear to affect the efficiency
of the system, as ether-containing epoxides 2f-g afforded
the corresponding enantiopure oxazolidinones in high yields
(entries 5 and 6). Noteworthy, enantiopure O-protected
oxazolidinone 4g was reported to be a key intermediate for
the synthesis of linezolid (Scheme 3),10 the first clinically
useful oxazolidinone antibacterial agent.3a
was a (salen)CoIII complex generated in situ by aerobic
oxidation of the catalytically inactive (salen)CoII complex 1
in the presence of p-nitrobenzoic acid as the oxidizing agent.8
A screening among a series of bases has envisaged sodium
hydride as the best candidate to promote the subsequent
cyclization step. We found that the oxazolidinone formation
was clean and fast when using an intermediate bearing an
ethyl carbamate moiety.9 The optimal procedure was achieved
by simply mixing (()-2a (2.1 equiv) and urethane 3 (1 equiv)
Aryl-substituted oxazolidinones were also synthesized in
high enantiomeric excess starting from various substituted
Scheme 3
(6) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Org. Lett. 2004, 6, 3973.
(7) For a direct preparation of 4,5-disubstituted oxazolidinones based
on asymmetric aminohydroxylation of olefins, see: Barta, N. S.; Sidler, D.
R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.; Reider, P. J. Org.
Lett. 2000, 2, 2821.
1984
Org. Lett., Vol. 7, No. 10, 2005

Scheme 4. Enantioconvergent Strategy for the Total Conversion of Racemic Epoxide into a Single Stereoisomeric Oxazolidinonea
a Boc ) tert-butoxycarbonyl, Ns ) 2-nitrobenzensulfonyl.
styrene oxide derivatives (entries 7-10). It is noteworthy
that, despite the fact that the ring opening of aromatic
epoxides might be plagued by conflicting steric and electronic
factors, the AKR step proceeded with complete regioselec-
tivity for the terminal position, thus providing only the
5-substituted isomers 4h-k.11
The impressive results obtained in the presented direct
synthesis of oxazolidinones stem from the extraordinary
scope and selectivity of the AKR strategy.12 However, kinetic
resolutions have the significant disadvantage of a 50%
maximum yield. To overcome this limitation, we sought to
use the unreacted epoxide through a separate pathway in an
enantioconvergent reaction sequence (Scheme 4).13 The
exceptionally high selectivity of the (R,R)-(salen)Co-
catalyzed AKR allowed the formation of both the aminol
product 5 and the “mismatched” epoxide (R)-2 in very high
optical purity at 50% conversion.14 Recently, it was reported
that the same catalyst was able to promote the nonselective
ring-opening of terminal epoxides with a different nitrogen-
based nucleophile such as N-Boc sulfonamide 6.15 These
considerations suggested the possibility for the (salen)CoIII
complex to catalyze an highly stereoselective AKR step with
urethane 3 and a sequential one-pot stereospecific ring-
opening of the enantioenriched “mismatched” epoxide with
6. The pseudo-enantiomeric aminol products 5 and 7 can be
easily isolated by chromatography and separately cyclized
via a retention (path a, Scheme 4) and an inversion (path
b)16 pathway, respectively, affording the same enantiomer
of the enantiopure oxazolidinone 4 (ee 99%) in high overall
yield starting from racemic epoxide. Proof-of-principle for
the enantioconvergent strategy was provided through the
synthesis of enantiopure oxazolidinones 4a and 4c.
(8) The identity of the counterion for the (salen)CoIII catalyst proved to
be crucial in terms of both reactivity and selectivity: among different
counterions tested (e.g. acetate, tosylate, triflate) 4-nitrobenzoate has been
found to provide the best catalyst. For a recent discussion on this topic,
see: Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E.
N. J. Am. Chem. Soc. 2004, 126, 1360.
(9) The presence of a different group on the carbamate moiety (e.g., tert-
butyl, benzyl) had a negative effect on the rate and the efficiency of the
cyclization step.
(10) (a) Mallesham, B.; Rajesh, B. M.; Reddy, P. R.; Srinivas, D.; Trehan,
S. Org. Lett. 2003, 5, 963. See also: (b) Madar, D. J.; Kopecka, H.; Pireh,
D.; Pease, J.; Pliushchev, M.; Sciotti, R. J.; Wiedeman, P. E.; Djuric, S.
W. Tetrahedron Lett. 2001, 42, 3681. For recent advances on N-arylation
of oxazolidinones, see: (c) Nandakumar, M. V. AdV. Synth. Catal. 2004,
346, 954. (d) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett.
2001, 3, 2539.
(11) Ring-opening of electron-rich styrene oxide derivatives (e.g.,
3-MeOC6H4) with urethane occurred with modest regioselectivity to afford
a mixture of isomeric amino alcohol adducts.
In summary, a general, direct, catalytic method for the
synthesis of a wide assortment of enantiopure 5-substituted
oxazolidinones has been devised. We are hopeful that the
ready access to these important building blocks in enan-
tiopure form through a convenient and easy experimental
protocol will be useful for the chemical community.
Acknowledgment. Work carried out in the framework
of the National Project “Stereoselezione in Sintesi Organica.
Metodologie e Applicazioni” supported by MIUR, Rome,
and FIRB National Project “Progettazione, preparazione e
valutazione farmacologica di nuove molecole organiche quali
potenziali farmaci innovativi”.
(12) For an evaluation of the exceptionally high selectivity of the AKR
(selectivity factors exceeding 3000 for selected substrates) see ref 6 and
the Supporting Information.
(13) For a review on this topic, see: Strauss, U. T.; Felfer, U.; Faber,
K. Tetrahedron: Asymmetry 1999, 10, 107.
(14) This scenario represents an ideal case and is very rare for a kinetic
resolution promoted by a chemo-catalyst. During the AKR, one enantiomer
is transformed quickly and the other is unreactive, thus the reaction comes
to a standstill at 50% conversion; therefore, over-resolution is not possible.
(15) Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2004, 43, 3952.
As reported, high regiocontrol for the terminal position was achieved only
in the ring-opening of aliphatic epoxides with sulfonamide 6.
(16) Conversion of 7 to oxazolidinone 4 was achieved by sequential
deprotection/stereoinversion steps in good overall yield (71-79%, nonop-
timized): (1) nosyl deprotection (PhSH/K2CO3/CH3CN); (2) cyclization with
stereoinversion (SOCl2/THF), see the Supporting Information for details.
Supporting Information Available: Experimental pro-
cedures, full characterization, and copies of both chiral HPLC
or GC analyses and proton spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL050675C
Org. Lett., Vol. 7, No. 10, 2005
1985