Kinetic resolution of N-acyl-β-lactams via benzotetramisole-catalyzed enantioselective alcoholysis

Article abstract of DOI:10.1021/ja2058633

The first nonenzymatic kinetic resolution of β-lactams has been achieved. Alcoholysis of their N-aroyl derivatives in the presence of a simple chiral acyl transfer catalyst, benzotetramisole, produces β-amino acid derivatives with excellent enantioselecti

Full text of DOI:10.1021/ja2058633

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Kinetic Resolution of N-Acyl-β-Lactams via
Benzotetramisole-Catalyzed Enantioselective Alcoholysis
Valentina D. Bumbu and Vladimir B. Birman*
Department of Chemistry, Washington University, One Brookings Drive, St. Louis, Missouri 63130, United States
S Supporting Information
b
Scheme 1. BTM-Catalyzed DKR of Azlactones
ABSTRACT: The first nonenzymatic kinetic resolution of
β-lactams has been achieved. Alcoholysis of their N-aroyl
derivatives in the presence of a simple chiral acyl transfer
catalyst, benzotetramisole, produces β-amino acid deriva-
tives with excellent enantioselectivity.
mino acids and their derivatives have attracted a great
β-Adeal of attention, mainly due to the uniqueness of their
biological properties.1 One important approach to their synthesis
in enantiopure form is based on the ring-opening of β-lactams.2
Despite considerable progress achieved in the asymmetric synthe-
sis of the latter,3 kinetic resolution4 of the readily available
racemic β-lactams5 via enzymatic hydrolysis still remains preva-
lent.6 To the best of our knowledge, the catalytic, nonenzymatic
kinetic resolution of β-lactam derivatives has not been reported
until now.7,8 In this communication, we describe the first
examples of this process achieving excellent levels of enantio-
selectivity.
Figure 1. Amidine-based catalysts (ABCs) used in this study.
Table 1. KR of Oxazinone 6 and β-Lactam 7aa
In the course of our recent studies,9 we achieved dynamic
kinetic resolution (DKR)10 of azlactones (e.g., 1, Scheme 1) in
the presence of amidine-based catalyst benzotetramisole11a
(BTM, 3, Figure 1) and benzoic acid.12 Success of this enantio-
selective transformation prompted us to explore other classes of
substrates that might be similarly activated by a combination of a
chiral nucleophilic catalyst and a Brønsted acid. Initially, we
turned our attention to oxazinones, the ring-expanded homo-
logues of azlactones.13 Although substrate (()-6 did react with
di-(1-naphthyl)methanol in the presence of our catalytic system,
the level of enantioselectivity was disappointing (Table 1, entry 1).14
Interestingly, however, less bulky alcohols produced similar
selectivity factors (entries 2 and 3), which was in contrast to
the DKR of azlactones, wherein the enantioselectivity depended
critically on the alcohol used. This observation suggested to us that,
despite the structural similarity of oxazinones and azlactones, the
mechanism of enantioselection in these two cases might be com-
pletely different, and that the modest enantioselectivity observed
might originate in the first step of the catalytic cycle. With this in
mind, we decided to test N-benzoyl-4-phenyl-β-lactam (()-7a,
which is isomeric with oxazinone (()-6 and would produce the
same reactive intermediate upon ring-opening (Scheme 2).
entry
substrate
ROH
time (h)
% conv
s
1
2
3
4
5
6
6
(1-Np)2CHOH
PhCH2OH
MeOH
28
28
28
68
68
24
51
56
48
51
52
60
2.9
3.9
3.3
21
6
6
7a
7a
7a
(1-Np)2CHOH
PhCH2OH
MeOH
19
18
a Conditions: 0.1 mmol substrate, 0.05 mmol alcohol, 0.01 mmol
(S)-BTM 3, 0.01 mmol PhCO2H, 1 mL CDCl3, 23 °C.
reaction, although the enantioselectivity was diminished (entries 2
and 3). Variation of the acyl group on the β-lactam nitrogen was
explored next. Both N-Boc (7b) and N-isobutyryl (7c) derivatives
proved to be completely unreactive (entries 4 and 5). Introduction of
a 4-chlorobenzoyl group resulted in appreciable enhancement of
enantioselectivity (entry 6). 4-Nitrobenzoyl derivative 7e, as
expected, underwent the ring-opening at a faster rate, but,
unfortunately, produced a lower selectivity factor (entry 7),
which did not improve when the reaction temperature was
Gratifyingly, the kinetic resolution (KR) of 7a proved to be
considerably more enantioselective than that of oxazinone 6(Table1,
entries 4À6). Again, different alcohols produced essentially the same
selectivity factors in the case of this substrate. Encouraged by these
findings, we proceeded to optimize the new process (Table 2).
In addition to BTM 3 (entry 1), other amidine-based catalysts, 411b
and 511c (Figure 1) were found to be competent in promoting this
Received: June 23, 2011
Published: August 08, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja2058633 J. Am. Chem. Soc. 2011, 133, 13902–13905
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Scheme 2. Two Enantioselective Alcoholysis Mechanisms
Table 3. Substrate Scopec
Table 2. Optimization Studya
entry
cat
R
time
% conv
s
1
2b
3
4
5
3
3
3
3
3
3
Ph (7a)
Ph (7a)
Ph (7a)
24 h
7 d
60
18
2.5À1
12À1
NDe
ND
26
42
3
3 d
62
4
OBu-t (7b)
7 d
NRd
NR
53
5
Me2CH (7c)
7 d
6
p-ClC6H4 (7d)
p-NO2C6H4 (7e)
p-NO2C6H4 (7e)
3,5-(NO2)C6H3 (7f)
20 h
5 h
7
8c
53
20
36 h
1 h
50
20
9
72
2.6
a Conditions: 0.1 mmol substrate, 0.05 mmol MeOH, 0.01 mmol
catalyst 3À5, 0.01 mmol PhCO2H, 0.75 mL CDCl3, 23 °C, unless
specified otherwise. b Benzyl alcohol was used instead of methanol.
c Conducted at 0 °C. d NR = no reaction. e ND = not determined.
lowered (entry 8). 3,5-Dinitrobenzoyl derivative 7f reacted even
faster and with much lower enantioselectivity (entry 9).
Upon completion of the optimization studies, we undertook
exploration of the substrate scope (Table 3). Replacement of the
C4 phenyl group in 7d with a 1-naphthyl resulted in a slight
increase in enantioselectivity (entry 2 vs 1). 4-Isopropyl analogue
12 was resolved with an impressive selectivity factor of 78 (entry 3).
Even higher enantioselectivities were recorded in the case of ring-
fused β-lactams 13À18 (entries 4À9). On the other hand, the
trans-disubstituted monocyclic substrate 19 did not react at all
over the course of 1 week (entry 10). The practical utility of the
new process is illustrated by the 1-g scale resolution of substrate
17 easily available via [2 + 2]-cycloaddition of norbornene and
chlorosulfonyl isocyanate5 (Scheme 3).
All available evidence indicates that in the reaction described
above the enantioselectivity is determined during the irreversible
nucleophilic attack of the catalyst on the acyl donor. This is in
sharp contrast to all previously examined asymmetric transfor-
mations promoted by amidine-based catalysts, which rely upon
enantiodifferentiation of their N-acylated derivatives15À18 or the
corresponding enolate zwitterions.19 To rationalize our experi-
mentalobservations, weproposethemodelpresentedinFigure2.
a Absolute configuration of the fast-reacting enantiomer is shown. b Averaged
ee values of two or more experiments are shown. c Conditions: See Table 2.
We hypothesize that the catalyst approaches the β-lactam
carbonyl preferentially from the unsubstituted face with the C2
phenyl group pointing outward so as to minimize steric interac-
tions with the ring hydrogens. In this orientation, the phenyl
group will be repelled by the N-acyl group on the slow-reacting
substrate, but not on the fast-reacting one. The orientation of the
proton source (benzoic acid and/or the protonated form of
BTM) in the transition state is unclear at this point. It is logical to
assume that it activates the substrate via hydrogen bonding to the
carbonyl groups (no reaction occurs in the absence of added
Brønsted acid, analogously with the DKR of azlactones9,12). On
the basis of this model, one would predict that increasing the
steric bulk of the R3 and R2 groups on the same face of the
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dx.doi.org/10.1021/ja2058633 |J. Am. Chem. Soc. 2011, 133, 13902–13905

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Scheme 3. Preparative-Scale KR of Substrate 17
NY, 1997. (b) Juaristi, E., Soloshonok, V. A., Eds. In Enantioselective
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(7) Noncatalytic KR of β-lactams has been exploited in the semi-
synthesis of taxoids. Chiral alkoxides derived from baccatin III have been
shown to open racemic N-benzoyl- and N-Boc-β-lactams with significant
levels of diastereoselectivity. See, e.g.: (a) Holton, R. A., Biediger, R.J. U.
S. Patent 5,243,045, 1993. (b) Holton, R. A.; Biedinger, R. J.; Boatman,
P. D. Semisynthesis of Taxol and Taxotere. In Taxol Science and
Applications; Suffness, M., Ed.; CRC: Boca Raton, FL, 1995; 97.
(c) Ojima, I.; Slater, J. C. Chirality 1997, 9, 487. (d) Lin, S.; Geng, X.;
Qu, C.; Tynebor, R.; Gallagher, D. J.; Pollina, E.; Rutter, J.; Ojima, I.
Chirality 2000, 12, 431.
(8) An alternative nonenzymatic, catalytic method for the KR of
β-lactams has been recently developed in our laboratory: Yang, X.;
Bumbu, V. D.; Birman, V. B. Org. Lett. in press, DOI: 10.1021/
ol201911z.
(9) Yang, X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892.
(10) For recent reviews, see: (a) Turner, N. J. Curr. Opin. Chem. Biol.
2010, 14, 115. (b) Pellissier, H. Adv. Synth. Catal. 2011, 353, 659.
(11) For the development of amidine-based catalysts 3À5, see:
(a) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (b) Birman, V. B.;
Jiang, H. Org. Lett. 2005, 7, 3445. (c) Birman, V. B.; Li, X. Org. Lett. 2008,
10, 1115.
Figure 2. Proposed mode of enantiodiscrimination. The Brønsted acid
is omitted for the sake of simplicity.
substrate should lead to higher enantioselectivity by suppressing
the attack from that face, whereas substitution on both faces
should prevent the reaction altogether. The data in Table 3 are
fully consistent with this prediction.
In conclusion, we have developed the first nonenzymatic
method for the asymmetric opening of the β-lactam ring,
affording good to excellent enantioselectivities. In addition to
providing a new route to enantioenriched β-amino acid deriva-
tives, this study highlights a new facet in the chemistry of
amidine-based catalysts. Further elucidation of the origin of
enantioselectivity in this transformation and its application to
new classes of substrates will be the subject of our future studies.
(12) For an earlier report on the use of a Brønsted acid in combina-
tion with an enantioselective acyl transfer catalyst, see:Liang, J.; Ruble,
J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154.
(13) (()-Oxazinones have been resolved both enzymatically and
nonenzymatically: (a) Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew.
Chem., Int. Ed. 2005, 44, 7466. (b) Berkessel, A.; Jurkiewicz, I.; Mohan,
R. ChemCatChem 2011, 3, 319.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(14) Enantioselectivity in kinetic resolution is expressed in terms of
selectivity factors denoted as “s”, “E”, or “krel” and 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: s = ln[(1 À C)(1 À eeSM)]/ln[(1 À C)(1 + eeSM)]),
Corresponding Author
birman@wustl.edu
’ ACKNOWLEDGMENT
wherein C is conversion and can be calculated as: C = eeSM/(eeSM
+
We thank National Science Foundation for the financial
support of our study (CHE-1012979).
eePR). For more details, see ref 4.
(15) ABC-catalyzed KR of alcohols: see, e.g. ref 9 and: (a) Birman,
V. B.; Guo, L. Org. Lett. 2006, 8, 4859. (b) Li, X.; Liu, P.; Houk,
K. N.; Birman, V. B. J. Am. Chem. Soc. 2008, 130, 13836. (c) Xu, Q.;
Zhou, H.; Geng, X.; Chen, P. Tetrahedron 2009, 65, 2232. (d) Shiina, I.;
Nakata, K.; Ono, K.; Sugimoto, M.; Sekiguchi, A. Chem.—Eur. J. 2010,
’ REFERENCES
(1) For reviews on β-amino acids and β-peptides, see: (a) Juaristi, E.,
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