Benzotetramisole-catalyzed dynamic kinetic resolution of azlactones

Article abstract of DOI:10.1021/ol902969j

(Figure Presented) Enantioselective acyl transfer catalyst benzotetramisole (BTM) has been found to promote dynamic kinetic resolution of azlactones providing di(1-naphthyl)methyl esters of α-amino acids with up to 96% ee.

Full text of DOI:10.1021/ol902969j

ORGANIC
LETTERS
2010
Vol. 12, No. 4
892-895
Benzotetramisole-Catalyzed Dynamic
Kinetic Resolution of Azlactones
Xing Yang, Guojian Lu, and Vladimir B. Birman*
Department of Chemistry, Washington UniVersity, Campus Box 1134, One Brookings
DriVe, St. Louis, Missouri 63130
birman@wustl.edu
Received December 28, 2009
ABSTRACT
Enantioselective acyl transfer catalyst benzotetramisole (BTM) has been found to promote dynamic kinetic resolution of azlactones providing
di(1-naphthyl)methyl esters of r-amino acids with up to 96% ee.
Dynamic kinetic resolution (DKR)1 of azlactones2 by way
of their enantioselective alcoholysis (Figure 1) provides an
attractive approach to the asymmetric synthesis of R-amino
acid derivatives. Enzymatic variant of this transformation,3
while often successful, suffers from one inherent drawback:
since enzymes are available in only one enantiomeric form,
the reversal of enantioselectivity in a given reaction requires
identification of a different enzyme, which is not always a
trivial matter. Therefore, the development of nonenzymatic
alternatives is of significant practical interest. Several
mechanistically different approaches to activating azlactones
toward alcoholysis have been employed. In 1997, Seebach
Figure 1. Dynamic kinetic resolution of azlactones.
et al. reported a Lewis acid-catalyzed version of this reaction
using Ti(IV) TADDOLate 3 producing moderate ee’s (up
to 68%).4 Promising levels of enantioselectivity (up to 78%
ee) were achieved by Fu et al. in 1998 using enantioselective
acyl transfer catalyst 4 (Figure 2). However, the reaction was
extremely slow (50% conversion/1 week).5 Low enantiose-
lectivities (<39% ee) were reported by Hua et al. in 1999
using a combination of a chiral diketopiperazine, cyclo-[(S)-
His-(S)-Phe] 5, with diisopropyl L-tartrate, presumed to
activate azlactones via hydrogen bonding.6 More recently
(2005-2008), encouraging results have been obtained by
Berkessel et al.7 and Connon et al.8 using bifunctional
catalysts 6 (72-95% ee) and 7 (78-88% ee), respectively.
(1) For a recent review of dynamic kinetic resolution, see: Pellissier,
H. Tetrahedron 2008, 64, 1563.
(2) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. ReV. 2007, 36,
1432.
(3) See, e.g., (a) Crich, J. Z.; Brieva, R.; Marquart, P.; Gu, R. L.;
Flemming, S.; Sih, C. J. J. Org. Chem. 1993, 58, 3252. (b) Brown, S. A.;
Parker, M.-C.; Turner, N. J. Tetrahedron: Asymmetry 2000, 11, 1687, and
references cited therein.
(4) (a) Seebach, D.; Jaeschke, G.; Gottwald, K.; Mastsuda, K.; Form-
isano, R.; Chaplin, D. A.; Breuning, M.; Bringmann, G. Tetrahedron 1997,
53, 7539. (b) Gottwald, K.; Seebach, D. Tetrahedron 1999, 55, 723.
(5) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154.
(6) Xie, L.; Hua, W.; Chan, A. S. C.; Leung, Y.-C. Tetrahedron:
Asymmetry 1999, 10, 4715.
10.1021/ol902969j  2010 American Chemical Society
Published on Web 01/25/2010

were pleased to discover that BTM is much more effective
in this reaction. Encouraging results were obtained even using
methanol (entry 5); however, the bulky di(1-naphthyl)metha-
nol10,11 was required to bring the enantiomeric excess to a
respectable 85% (entry 11). A single recrystallization from
ethyl acetate produced completely enantiopure material
(>99.5% ee). The earlier imidazoline-based catalysts, 8 and
9, proved to be competent but less active and less enanti-
oselective than BTM (entries 12-14).
Figure 2. Catalysts previously employed for the DKR of azlactones.
Table 1. Catalyst and Alcohol Screening
Surprisingly, apart from Fu’s seminal study, there have
been no other reported attempts to achieve DKR of azlac-
tones using enantioselective acyl transfer catalysis. Over the
past several years, our group has developed amidine-based
catalysts 8-11 (Figure 3), which display high enantioselec-
tivity in the acylation of several classes of alcohols and
oxazolidinones.9 Recently, Shiina et al.10 have demonstrated
the utility of BTM 10 in the kinetic resolution (KR) of
R-arylpropionic acids via enantioselective alcoholysis of their
mixed anhydrides. We have found that HBTM 11 is also
effective in the KR of R-aryloxy- and arylthioalkanoic acids
via their symmetrical anhydrides.11 These results have
encouraged us to re-examine the possibility of DKR of
azlactones via the acyl transfer mechanism.
entry catalyst (mol %) time, d
R2
% convna % ee
1
11 (5)
11 (5)
11 (5)
11 (10)
10 (5)
10 (5)
10 (5)
10 (5)
10 (5)
10 (5)
10 (5)
10 (10)
8 (10)
9 (10)
1
Me
54
47
5
<5
<3
-25
ND
ND
2
1
PhCH2
Ph2CH
1-Np2CH
Me
PhCH2
1-NpCH2
2-NpCH2
Me2CH
Ph2CH
1-Np2CH
1-Np2CH
1-Np2CH
1-Np2CH
3
1
4
1
5
2
91b
94b
97b
96b
<5
34b
6
2
48b
51b
47b
7
2
8
2
9
2
ND
10
11
12
13
14
2
2
0.4
2
2
91b
96b
92b
47
75b
85b
80b
59
47
-52
a Conversion was determined by 1H NMR, unless indicated otherwise.
b Reported % isolated yields and % ee’s are averages of two runs.
Changing the amount of benzoic acid relative to the
catalyst did not have a significant effect on the reaction rate
or the enantioselectivity, although in the absence of the acid
promoter the reaction did not proceed at all, consistent with
Fu’s original report5 (entries 1-4, Table 2). Lower catalyst
loadings, down to 2 mol %, were still effective, although
required prolonged reaction times (entries 5 and 6). De-
creased temperatures proved to be detrimental to the enan-
tioselectivity, while higher temperatures resulted in a higher
rates, but the same ee (entries 7-9). Solvents other than
chloroform were less effective, in line with our earlier
experience with the KR of alcohols9c (entries 10-13).
DKR of other azlactones bearing primary alkyl substituents
1b-e produced uniformly good yields and ee’s in the
80-90% range (Table 3, entries 1-5). Isopropyl-substituted
substrate 1f proved resistant to alcoholysis under the same
conditions (entry 6). On the other hand, excellent enanti-
oselectivity (94% ee) was obtained in the case of 2,4-
diphenylazlactone 1g (entry 7). This result was all the more
remarkable given the fact that the highest ee previously
reported for either enzymatic3a or nonenzymatic7a DKR of
this substrate (or any other 4-aryl-substituted azlactones) has
been 75%. Variation of electronic properties of the C4-aryl
Figure 3. Amidine-based catalysts used in this study.
An equimolar combination of HBTM and benzoic acid
was found to promote the methanolysis of substrate (()-1a
without any appreciable enantioselectivity (Table 1, entry
1). Switching to benzyl alcohol resulted in a modest ee (entry
2). The reaction with diarylcarbinols was extremely slow
(entries 3 and 4). After these disappointing first results, we
(7) (a) Berkessel, A.; Cleeman, F.; Mukherjee, S.; Mu¨ller, T. N.; Lex,
J. Angew. Chem. 2005, 44, 807. (b) Berkessel, A.; Mukherjee, S.; Cleemann,
F.; Mu¨ller, T. N.; Lex, J. Chem. Commun. 2005, 1898. (c) Berkessel, A.;
Mukherjee, S.; Mu¨ller, T. N.; Cleeman, F.; Roland, K.; Brandenburg, M.;
Neudo¨rfl, J.-M.; Lex, J. Org. Biomol. Chem. 2006, 4, 4319.
(8) Peschiulli, A.; Quigley, C.; Tallon, S.; Gun’ko, Yu.K.; Connon, S. J.
J. Org. Chem. 2008, 73, 6409.
(9) (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.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem.
Soc. 2006, 128, 6536. (e) Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859.
(f) Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115. Zhang, Y.; Birman,
V. B. AdV. Synth. Catal. 2009, 351, 2525.
(10) Shiina, I.; Nakata, K.; Onda, Y. Eur. J. Org. Chem. 2008, 5887.
(11) Yang, X.; Birman, V. B. AdV. Synth. Catal. 2009, 351, 2301.
Org. Lett., Vol. 12, No. 4, 2010
893

Initially, azlactones 1a-m used in this study were
synthesized in a separate step and purified by recrystallization
before subjecting them to the DKR conditions. Later,
however, we found that in situ cyclization of N-benzoyl-R-
amino acids with DCC followed by addition of di-(1-
naphthyl)methanol and the catalyst works just as well as the
earlier, more time-consuming protocol (cf. entries 14-16 vs
8 and 9, Table 3). Coupled with the one-step synthesis of
starting materials via the Ben-Ishai amidoalkylation12 of
simple arenes, this procedure provides an attractive route to
enantioenriched arylglycine derivatives13 illustrated in Scheme
1. Hydrogenolysis of dinaphthylmethyl ester 2i proceeded
without appreciable erosion of enantiomeric purity.
Table 2. Variation of Reaction Conditionsa
mol % 10/
entry mol % BzOH time d temp °C solvent % convn % ee
1
2
3
4
5
6
7
8
10/0
10/5
10/10
10/20
5/5
2/2
5/5
10/5
5/5
5/5
1
23
23
23
23
23
23
0
-20
45
23
23
23
23
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
C6D6
<5
90
92
93
96
94
95
94
91
98
95
85
<5
ND
83
80
82
85
84
72
55
84
80
74
66
ND
0.4
0.4
0.4
2
4
2
2
1
2
2
Scheme 1. Asymmetric Synthesis of Arylglycines
9
10
11
12
13
a
5/5
5/5
5/5
CH2Cl2
CH3CN
THF
2
2
1
Conversion in all cases was determined by H NMR.
substituent had only a slight effect on the enantioselectivity
or reaction rate (entries 8-11). DKR of the 1-naphthyl-
substituted substrate 1l, however, proceeded rather slowly
and with lower enantioselectivity (entry 12). Substrate 1m
was completely unreactive, presumably due to the presence
of an ortho-substitutuent (entry 13).
It is of interest to analyze the mechanism of enantiodif-
ferentiation in the DKR of azlactones. Berkessel et al.7a
proposed that the thiourea-catalyzed version of this process
occurs via irreversible, hydrogen bonding-assisted attack of
the alcohol on the less hindered face of the substrate, which
results in the highest enantioselectivity being observed in
the case of the bulkiest C4-substituents (cf. general structure
1, R1 ) isobutyl (1b), isopropyl (1f), or tert-butyl). The
situation is clearly different in our case. The strong depen-
dence of the enantioselectivity on the alcohol nucleophile
indicates that enantiodifferentiation occurs in the second step
of the catalytic cycle (Figure 4). The absolute sense of
asymmetric induction and structure-selectivity trends can be
explained by transition state model 15, which invokes
hydrogen bonding between the benzamide group and the
reacting carbonyl. The involvement of π-π interactions with
the C2-phenyl group on the catalyst and/or lower steric
repulsion may explain the higher enantioselectivity generally
Table 3. Structural Variation of Azlactone Substratesa
entry substrate time d
R1
% yieldb % eeb
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1h
1i
0.4
7
3
4
4
4
2
2
2
2
2
7
2
2
2
2
Me
90
97
92
94
88
<5
89
87
88
90
88
46
0
83
80
90
83
83
ND
94
91
96
95
91
76
ND
92
97
95
Me2CHCH2
MeSCH2CH2
PhCH2
CH2dCHCH2
Me2CH
Ph
p-MeOC6H4
p-ClC6H4
9
10
11
12
13
14c
15c
16c
p-BrC6H4
2-naphthyl
1-naphthyl
2,4-(MeO)2C6H3
p-MeOC6H4
p-ClC6H4
86
86
90
1n
p-FC6H4
a Na2SO4 was added to prevent loss of catalytic activity of BTM during
prolonged reactions (see ref 9c). b Reported % isolated yields and % ee’s
are averages of two runs. c Azlactone was generated in situ. The yield is
based on the N-benzoyl-R-arylglycine starting material (see Scheme 1).
Figure 4
anion omitted for clarity).
. Proposed catalytic cycle and transition state (benzoate
894
Org. Lett., Vol. 12, No. 4, 2010

observed in the DKR of the aryl-substituted azlactones 1g-k
compared to the alkyl-substituted ones 1a-e. The low
reactivity of substrate bearing bulky C4 substituents (cf. 1f,
1l, and 1m) is also consistent with this proposal.
In conclusion, we have developed a new, highly enanti-
oselective method for the DKR of azlactones. It is especially
suited for the C4-aryl-substituted substrates, thus comple-
menting the previously available enzymatic and nonenzy-
matic protocols. Further exploration of its substrate scope is
under active investigation in our laboratory.
Acknowledgment. We thank Washington University for
the financial support of this study. Mass spectrometry was
provided by the Wash. U. Mass Spectrometry Resource, an
NIH Research Resource (Grant No. P41RR0954).
Supporting Information Available: Experimental pro-
cedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Ben-Ishai, D.; Satati, I.; Bernstein, Z. Tetrahedron 1976, 32, 1571.
(13) (a) For a review of asymmetric routes to R-arylglycines, see:
Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889. For more recent
examples, see: (b) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem.
Soc. 2006, 128, 6304, and references cited therein.
OL902969J
Org. Lett., Vol. 12, No. 4, 2010
895