Kinetic resolution of β-lactams via enantioselective N-acylation

Article abstract of DOI:10.1021/ol201911z

Enantioselective N-acylation of 4-aryl-β-lactams in the presence of acyl transfer catalyst Cl-PIQ provides an effective method for their non-enzymatic kinetic resolution.

Full text of DOI:10.1021/ol201911z

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4755–4757
Kinetic Resolution of β-Lactams via
Enantioselective N-Acylation
Xing Yang, Valentina D. Bumbu, and Vladimir B. Birman*
Department of Chemistry, Washington University, Campus Box 1134,
One Brookings Drive, St. Louis, Missouri 63130, United States
birman@wustl.edu
Received July 14, 2011
ABSTRACT
Enantioselective N-acylation of 4-aryl-β-lactams in the presence of acyl transfer catalyst Cl-PIQ provides an effective method for their non-
enzymatic kinetic resolution.
β-Lactams (azetidin-2-ones) are widely known both as
pharmaceuticals (e.g., antibiotics1 and cholesterol-lowering
drugs2) and as versatile intermediates in the preparation of
other classes of organic compounds.3 Enantioselective
approaches to their synthesis, despite the many advances
achieved in this field,4 remain limited in their scope. There-
fore, enzymatic kinetic resolution5 (KR) of their race-
mates, mostly via β-lactam ring opening6 or O-acylation
of N-hydroxymethyl derivatives,7 continues to be widely
used (Figure 1).8,9 Enantioselective N-acylation, which
would provide an alternative direct method for the KR
(1) (a) Testero, S. A.; Fisher, J. F.; Mobashery, S. β-Lactam Anti-
biotics. In Burger’s Medicinal Chemistry, Drug Discovery and Develop-
ment, 7th ed.; Abraham, D. J., Rotella, D. P., Eds.; Wiley: Hoboken, NJ,
2010; Vol. 7 (Antiinfectives), pp 259ꢀ404. (b) Troisi, L.; Granito, C.;
Pindinelli, E. Novel and Recent Synthesis and Applications of
β-Lactams. In Heterocyclic Scaffolds I; Banik, B. K., Ed.; Springer:
Berlin/Heidelberg, 2010; Vol. 22, pp 101ꢀ209.
(2) Discovery of Zetia (Ezetimibe): Rosenblum, S. B.; Huynh, T.;
Afonso, A.; Davis, H. R.; Yumibe, N.; Clader, J. W.; Burnett, D. A. J.
Med. Chem. 1998, 41, 973.
Figure 1. Enzymatic approaches to KR of β-lactams.
(3) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107,
4437.
of N-unsubstituted β-lactams, has not been previously
reported.
Several years ago, we disclosed the first examples of KR
of racemic oxazolidin-2-ones via catalytic, enantioselective
N-acylation.10 As part of a broader study aimed at
(4) For select examples, see: (a) Lo, M. M.-C.; Fu, G. C. J. Am. Chem.
Soc. 2002, 124, 4572. (b) France, S.; Weatherwax, A.; Taggi, A. E.;
Lectka, T. Acc. Chem. Res. 2004, 37, 592. (c) He, M.; Bode, J. W. J. Am.
Chem. Soc. 2008, 130, 418. For reviews, see: (d) Brandi, A.; Cicchi, S.;
Cordero, F. M. Chem. Rev. 2008, 108, 3988. (e) Aranda, M. T.; Perez-
Faginas, P.; Gonzalez-Muniz, R. Curr. Org. Chem. 2009, 6, 325.
(5) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(6) (a) Evans, C.; McCague, R.; Roberts, S. M.; Sutherland, A. G.;
Wisdom, R. J. Chem. Soc., Perkin Trans. 1 1991, 2276. (b) Brieva, R.;
ꢀ
(8) For a review of available enzymatic methods, see: Forro, E.;
€ €
Fulop, F. Mini-Rev. Org. Chem. 2004, 1, 93.
ꢀ
ꢀ
Crich, J. Z.; Sih, C. J. J. Org. Chem. 1993, 58, 1068. (c) Forro, E.; Paal,
(9) A non-enzymatic KR method based on enantioselective ring
opening of β-lactams has been developed recently: Bumbu, V. D.;
Birman, V. B. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja2058633.
(10) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am.
Chem. Soc. 2006, 128, 6536.
ꢀ
€ €
T.; Tasnadi, G.; Fulop, F. Adv. Synth. Catal. 2006, 348, 917.
(7) (a) Jouglet, B.; Rousseau, G. Tetrahedron Lett. 1993, 34, 2307. (b)
ꢀ
ꢀ
Csomos, P.; Kanerva, L. T.; Bernath, G.; Fulop, F. Tetrahedron:
€ €
Asymmetry 1996, 7, 1789.
r
10.1021/ol201911z
2011 American Chemical Society
Published on Web 08/22/2011

extending this methodology to other classes of secondary
amides,11ꢀ13 we decided to explore the KR of β-lactams.
Table 2. Substrate Scope
Table 1. Optimization Studies
entry catalyst
solvent
CDCl3
temp, °C time, h % convn
s
1
2
2
3
4
4
4
4
4
4
4
4
4
4
23
23
23
23
23
23
23
23
0
24
48
24
0a ND
∼10a ND
33 10
35a 1.0
35 1.8
21 5.5
22 6.6
45 16
CDCl3
3
CDCl3
4b
5c
CDCl3
4.0
CDCl3
10
24
24
10
24
48
24
10
6
CH2Cl2
7
THF
8d
9d
10e
11f
12d
EtMe2COH
EtMe2COH
EtMe2COH
EtMe2COH
HCtCMe2COH
47 20
0
33 19
0
35 21
23
41 16
General conditions: 0.1 M (()-1, 0.1 M (i-PrCO)2O, 0.1 M i-Pr2NEt,
0.01 M (10 mol %) catalyst, unless specified otherwise. The data
reported are for single runs. a Conversion was determined by 1H
NMR. b (MeCO)2O was used instead of (i-PrCO)2O. c (EtCO)2O was
used instead of (i-PrCO)2O. d 0.05 M (()-1 and 0.005 M (10 mol %) 4
were used. e 0.05 M (()-1 and 0.0025 M (5 mol %) 4 were used. f 0.05 M
(()-1, 0.05 M (i-PrCO)2O, 0.05 M i-Pr2NEt, and 0.005 M (10 mol %) 4
were used.
Figure 2. Amidine-based catalysts used in this study.
(11) The only other reported example of catalytic, enantioselective
N-acylation of secondary amides: Fowler, B. S.; Mikochik, P. J.; Miller,
S. J. J. Am. Chem. Soc. 2010, 132, 2870.
General conditions: 0.05 M racemic substrate, 0.1 M (i-PrCO)2O, 0.1
M i-Pr2NEt, 0.01 M (10 mol %) 4, tert-amyl alcohol, 0 °C, unless
specified otherwise. The data reported are averages of duplicate runs.
a Absolute configuration of the fast-reacting enantiomer is shown. b 0.2
M (4 equiv) of (i-PrCO)2O and i-Pr2NEt were used. c Reaction per-
formed in CDCl3 at rt. d Absolute stereochemistry notation is inverted in
this case according to CIP nomenclature rules.
(12) Enantioselective N-acylation of amines using non-enzymatic
catalysts has also been reported: (a) Arai, S.; Bellemin-Laponnaz, S.;
Fu, G. C. Angew. Chem., Int. Ed. 2001, 40, 234. (b) Arp, F. O.; Fu, G. C.
J. Am. Chem. Soc. 2006, 128, 14264. (c) Anstiss, M.; Nelson, A. Org.
Biomol. Chem. 2006, 4, 4135. (d) Arnold, K.; Davies, B.; Herault, D.;
Whiting, A. Angew. Chem., Int. Ed. 2008, 47, 2673. (e) De, C. K.;
Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060.
(f) Klauber, E. G.; De, C. K.; Shah, T. K.; Seidel, D. J. Am. Chem.
Soc. 2010, 132, 13624. (g) Klauber, E. G.; Mittal, N.; Shah, T. K.; Seidel,
D. Org. Lett. 2011, 13, 2464.
As the starting point, we subjected (()-4-phenyl-β-lac-
tam 1 to the set of conditions that proved to be most
successful in the KR of oxazolidinones. Disappointingly,
no reaction took place within 24 h in the presence of 10 mol
% of BTM14c 2 (Table 1, entry 1, and Figure 2). Further-
more, HBTM3,14e which typically displayshighercatalytic
activity than the previously developed catalysts 2, reached
(13) For recent reviews of non-enzymatic kinetic resolution and
€
enantioselective acylation catalysts, see: (a) Muller, C. E.; Schreiner,
P. R. Angew. Chem., Int. Ed. 2011, 50, 6012. (b) Pellissier, H. Adv. Synth.
Catal. 2011, 353, 1613. (c) Spivey, A. C.; Arseniyadis, S. Top. Curr.
Chem. 2010, 291, 233. (d) Denmark, S. E.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2008, 47, 1560. (e) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed.
2005, 44, 3974.
4756
Org. Lett., Vol. 13, No. 18, 2011

only low conversion after 2 days (entry 2). To our relief,
however, Cl-PIQ 414b produced a more promising result
(entry 3), which encouraged us to continue our investiga-
tion. The use of isobutyric anhydride proved critical for
the success of the KR, as its less hindered analogues,
acetic and propionic anhydrides, produced little to no
enantioselectivity15 (entries 4 and 5).
Survey of solvents revealed that tert-amyl alcohol sig-
nificantly increased both the enantioselectivity and the
reaction rate, although the substrate concentration had
to be lowered due to its limited solubility (entry 8). This
result was not particularly surprising, as the same solvent
proved to be optimal for the Cl-PIQ-catalyzed KR of
oxazolidinones.16 Lowering the temperature to 0 °C in-
creased the selectivity factor to a respectable level (entry 9).
Lowering the catalyst loading or the concentration of the
base and the acylating agent was deemed impractical due
to the increase in reaction times (entries 10 and 11).
Comparable results were also obtained at room tempera-
ture using the tertiary propargylic alcohol, 2-methyl-3-
butyn-2-ol (entry 12). However, due to its higher freezing
point compared to tert-amyl alcohol (þ3 vs ꢀ12 °C,
respectively), the latter was given preference in our ex-
ploration of the substrate scope (Table 2).
(entry 4). 4-(2-Naphthyl)-β-lactam 9 reacted with much
higher rate and enantioselectivity than its 1-naphthyl iso-
mer 8 (entries 5 and 6). Average results were obtained with
2-thienyl derivative 10 chosen asa representative of hetero-
aryl-substituted substrates (entry 7). Substitution at the C3
position of the β-lactam ring (11and 12) led to significantly
decreased reaction rates and enantioselectivities (cf. entries
8 vs 1 and 9 vs 6). Indene-derived substrate 13, which may
be regarded as a conformationally constrained analogue of
1, reacted at a similar rate and with a somewhat lower
selectivity factor (entry 10). This result was especially
surprising given the complete lack of enantioselectivity in
the acylation of 1-indanol under similar conditions.14a The
analogous bicyclic substrate 14 lacking the benzene ring,
however, proved to be completely unreactive (entry 11),
which suggests the importance of π-interactions for sub-
strate recogntion.14a,f,17 The absolute sense of enantiose-
lection observed with substrate 13 was confirmed to be the
same as with 1, as well as all oxazolidinones10 and several
classes of alcohols14 investigated in our earlier studies.
Although the latter two observations suggest at least
qualitativesimilaritybetween the transitionstateoperating
in the KR of β-lactams and those proposed in previous
cases,14 the validity of thisanalogyremains tobeprobed by
computational studies.
Somewhat unexpectedly, both p-chloro- and p-meth-
oxy-substituted analogues of substrate 1 (5 and 6) were
resolved with considerably higher selectivity factors
(Table 2, entries 2 and 3 vs 1). On the other hand,
o-chloro-substituted derivative 7 displayed rather disap-
pointing enantioselectivity and very low reaction rate
Inconclusion, wehaveachievedthe first enantioselective
N-acylation of β-lactams leading to their effective non-
enzymatic resolution. Extension of this methodology to
related classes of substrates will be reported in due course.
Acknowledgment. We thank National Science Founda-
tion for the financial support of our studies (CHE-
1012979).
(14) Development of amidine-based catalysts: (a) Birman, V. B.;
Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc.
2004, 126, 12226. (b) Birman, V. B.; Jiang, H. Org. Lett. 2005, 7, 3445. (c)
Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (d) Birman, V. B.; Guo, L.
Org. Lett. 2006, 8, 4859. (e) Birman, V. B.; Li, X. Org. Lett. 2008, 10,
1115. (f) Li, X.; Liu, P.; Houk, K. N.; Birman, V. B. J. Am. Chem. Soc.
2008, 130, 13836.
Supporting Information Available. Experimental pro-
cedures and NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) Enantioselectivity in KR is expressed in terms of a selectivity
factor (s) defined as the ratio of reaction rates of the fast- and the slow-
reacting enantiomers of the starting material: s = kfast/kslow. In the KR
of racemic mixtures, it is usually calculated from the ee values of the
product and the unreacted starting material according to Kagan’s
equations (ref 5): (1) conversion C = eeSM/(eeSM þ eePR); (2) selectivity
factor s = ln[(1 ꢀ C)(1 ꢀ eeSM)]/ln[(1 ꢀ C)(1 þ eeSM)].
(17) To demonstrate the scalability of the new KR protocol, (()-4-(p-
chlorophenyl)-azetidin-2-one 5 was resolved on a 3 mmol scale. The
starting material was recovered in 42% yield with 98% ee, in addition to
the acylated product (57% yield, 74% ee) and 65% of the recovered
catalyst. The calculated conversion (57%) and selectivity factor (s = 30)
were in perfect agreement with the small scale experiment (Table 2, entry 2).
See Supporting Information for further details.
(16) Superior performance of this solvent had been noted earlier in
the KR of alcohols with a planar chiral DMAP catalyst: Ruble, J. C.;
Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794.
Org. Lett., Vol. 13, No. 18, 2011
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