BINAPHANE-catalyzed asymmetric synthesis of trans-β-lactams from disubstituted ketenes and N-tosyl arylimines

Article abstract of DOI:10.1021/ol3003783

The development of a BINAPHANE-catalyzed formal [2 + 2]-cycloaddition of disubstituted ketenes and inexpensive N-tosyl arylimines that provides access to a variety of highly substituted β-lactams (16 examples) is described. The BINAPHANE catalytic system displays moderate to excellent enantioselectivity (up to 98% ee) and high diastereoselectivity in most cases, favoring formation of the trans-diastereomer (13 examples with dr ≥ 90:10).

Full text of DOI:10.1021/ol3003783

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1784–1787
BINAPHANE-Catalyzed Asymmetric
Synthesis of trans-β-Lactams from
Disubstituted Ketenes and N-Tosyl
Arylimines
Shi Chen,† Eric C. Salo,† Kraig A. Wheeler,‡ and Nessan J. Kerrigan*,†
Department of Chemistry, Oakland University, 2200 North Squirrel Road, Rochester,
Michigan 48309-4477, United States, and Department of Chemistry, Eastern Illinois
University, 600 Lincoln Avenue, Charleston, Illinois 61920-3099, United States
kerrigan@oakland.edu
Received February 15, 2012
ABSTRACT
The development of a BINAPHANE-catalyzed formal [2 þ 2]-cycloaddition of disubstituted ketenes and inexpensive N-tosyl arylimines that
provides access to a variety of highly substituted β-lactams (16 examples) is described. The BINAPHANE catalytic system displays moderate to
excellent enantioselectivity (up to 98% ee) and high diastereoselectivity in most cases, favoring formation of the trans-diastereomer (13 examples
with dr g 90:10).
β-Lactams are molecules that have attracted attention
for many years because of their prevalence as key structural
features of many antibiotics.1 They have also been used
as intermediates for the synthesis of complex molecules
(e.g., taxol).2 Recently, there has been a demand for access
to trans-β-lactams due to their potential for use as serine
protease inhibitors and β-lactamase inhibitors.3,4
An important route to enantioenriched β-lactams relies
on the nucleophile-catalyzed formal [2 þ 2] cycloaddition
of imines and ketenes (often referred to as a Staudinger
reaction-like process).5ꢀ8 A few catalytic asymmetric ap-
proaches have been reported.5ꢀ10 In 2000, Lectka’s
groundbreaking work demonstrated that certain alkaloids
† Oakland University.
‡ Eastern Illinois University.
(1) (a) Rolinson, G. N. J. Antimicrob. Chemother. 1998, 41, 589–603.
(b) Chemistry and Biology of Beta-Lactam Antibiotics; Morin, R. B.,
Gorman, M., Eds.; Academic: New York, 1982; Vols. 1ꢀ3. (c) The Organic
Chemistry of β-Lactams; Georg, G. I., Ed.; VCH Publications: New York,
1993.
(2) (a) Kingston, D. G. I. Chem. Commun. 2001, 867–880. (b) Holton,
R. A.; Biediger, R. J.; Boatman, P. D. In Taxol: Science and Applica-
tions; Suffness, M., Ed.; CRC Press: Boca Raton, FL, 1995; p 97.
(3) (a) Wilmouth, R. C.; Kassamally, S.; Westwood, N. J.; Sheppard,
R. J.; Claridge, T. D.; Alpin, R. T.; Wright, P. A.; Pritchard, G. J.;
Schofield, C. J. Biochemistry 1999, 38, 7989–7998. (b) Aoyama, Y.;
Uenaka, M.; Kii, M.; Tanaka, M.; Konoike, T.; Hayasaki-Kajiwara, Y.;
Naya, N.; Nakajima, M. Bioorg. Med. Chem. 2001, 9, 3065–3075.
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1437–1442. (b) Yoakim, C.; Ogilvie, W.; Cameron, D.; Chabot, C.;
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(5) (a) Paull, D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009,
65, 6771–6803. (b) Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545–
3565. (c) Chen, S.; Salo, E. C.; Kerrigan, N. J. Tertiary amine and
phosphine-catalyzed reactions of ketenes and R-halo ketones. In Science
of Synthesis Reference Library, Asymmetric Organocatalysis, Vol. 1,
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Chapter 1.1.10, pp 455ꢀ496.
r
10.1021/ol3003783
Published on Web 03/12/2012
2012 American Chemical Society

could catalyze the formal [2 þ 2]-cycloaddition of acyl
chlorides (precursors to monosubstituted ketenes) with
imino esters to give β-lactams with excellent enantioselec-
tivity and good diastereoselectivity favoring the cis-
isomer.6 Shortly afterward Fu’s group reported that an
azaferrocene possessing planar chirality could catalyze the
Staudinger reaction of N-tosyl imines with disubstituted
ketenes (ketoketenes) with high enantioselectivity and
good diastereoselectivity favoring the cis-isomer.7 Ye and
Smith also showed that chiral NHC catalysts could cata-
lyze the Staudinger reaction of N-Boc and N-tosyl aryli-
mines with ketoketenes, again favoring formation of the
cis-diastereomer.8
While most of these methods have shown a preference
for formation of the cis-diastereomer, Fu’s group showed
that, under chiral azaferrocene catalytic conditions, the use
of N-triflyl arylimines as coupling partners caused an
interesting change in diastereoselectivity to favor the
trans-diastereomer.9 Fu’s group proposed that the nucleo-
philic catalyst added first to the highly electrophilic imine
to give a zwitterionic species A (Scheme 1). Intermediate A
would then add to the ketoketene before 4-exo-tet cycliza-
tion would give the trans-β-lactam and regenerate the
catalyst.9 Lectka’s group also reported an anionic 2-aryl-
2-imidazoline nucleophilic catalytic system that catalyzed
formation of trans-β-lactams from imino esters with good
to excellent diastereoselectivity.11
which are prepared from the expensive trifluoromethane-
sulfonamide (ca. $500/10 g).12 Moreover, Fu’s system
works best with alkylarylketenes and diphenylketene as
ketene substrates. We considered that the use of N-tosyl
arylimines as starting materials might provide a more
practical approach to trans-β-lactams because of the in-
expensiveness of the p-toluenesulfonamide precursor (ca.
$1/10 g).12 We reasoned that the use of a chiral phosphine
catalyst would favor formation of adduct A (rather than B)
even when a less electrophilic imine such as an N-tosyl
imine was used (Scheme 2). This would be expected due to
the superior nucleophilicity of the phosphine catalyst
relative to amine catalysts.13 Our approach would thus
allow trans-β-lactams to be accessed from inexpensive
N-tosyl arylimines.
Scheme 2. Phosphine-Catalyzed Synthesis of trans-β-Lactams
Scheme 1. Fu’s Proposed Mechanisms for trans-β-Lactam and
cis-β-Lactam Formation
Our studies began with the optimization of the phos-
phine-catalyzed reaction of ethylphenylketene 1a with
various N-tosyl arylimines 2 (Table 1). As with our pre-
vious studies on β-lactone forming reactions, BINA-
PHANE was found to be the optimal catalyst with
respect to diastereoselectivity and enantioselectivity, albeit
modest (entry 3).14 A more satisfactory level of enantio-
selectivity (up to 60% ee) was observed after electronic
tuning of the aryl ring of the imine (entry 6). In this case an
electron-donating substituent (4-MeO) on the aryl imine
led to optimal enantioselectivity. It was found necessary to
add a solution of the ketene using a syringe pump to the
A disadvantage of Fu’s elegant asymmetric synthesis of
trans-β-lactams is that it relies on the use of N-triflyl imines
(6) (a) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J.,
III; Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831–7832. (b) Taggi, A. E.;
Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am.
Chem. Soc. 2002, 124, 6626–6635. (c) France, S.; Wack, H.; Hafez,
A. M.; Taggi, A. E.; Witsil, D. R.; Lectka, T. Org. Lett. 2002, 4, 1603–
1605. (d) France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.; Roth,
J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206–1215.
(7) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578–1579.
(8) (a) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett.
2008, 10, 277–280. (b) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.;
Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108–1113.
(12) From Aldrich catalog (www.sigmaaldrich.com): p-toluenesulfo-
namide (98%): $24 for 250 g; trifluoromethanesulfonamide (95%):
$264.50 for 5 g.
(9) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 11586–11587.
(13) (a) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89,
1827–1836. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
1035–1050. (c) Wei, Y.; Sastry, G. N.; Zipse, H. J. Am. Chem. Soc. 2008,
130, 3473–3477.
(14) (a) Mondal, M.; Ibrahim, A. A.; Wheeler, K. A.; Kerrigan, N. J.
Org. Lett. 2010, 12, 1664–1667. (b) Ibrahim, A. A.; Wei, P.-H.; Harzmann,
G. D.; Kerrigan, N. J. J. Org. Chem. 2010, 75, 7901–7904. (c) Ibrahim,
A. A.; Harzmann, G. D.; Kerrigan, N. J. J. Org. Chem. 2009, 74, 1777–
1780.
(10) Huang, Y.; Calter, M. A. Tetrahedron Lett. 2007, 48, 1657–1659.
(11) Nonenantioselective approaches to trans-β-lactams: (a) Weath-
erwax, A.; Abraham, C. J.; Lectka, T. Org. Lett. 2005, 7, 3461–3463.
(b) Townes, J. A.; Evans, M. A.; Queffelec, J.; Taylor, S. J.; Morken, J. P.
Org. Lett. 2002, 4, 2537–2540. (c) Tanaka, H.; Hai, A. K. M. A.;
Sadakane, M.; Okumoto, H.; Torii, S. J. Org. Chem. 1994, 59, 3040–
3046.
Org. Lett., Vol. 14, No. 7, 2012
1785

solution of phosphine and N-tosyl imine over 4 h in order
to maximize the yield of β-lactam obtained and minimize
competing ketene homodimerization. The success of our
approach, from a diastereoselectivity standpoint, seemed
to be confirmed by our finding that 3a (entry 3, Table 1) was
obtained with the trans-diastereomer as the major isomer
(by agreement with Ye’s characterization data for 3a).8a
Table 2. Substrate Scope of the BINAPHANE-Catalyzed
Asymmetric Synthesis of β-Lactams
Table 1. Optimization of the Phosphine-Catalyzed Asymmetric
Synthesis of β-Lactams
entry
R1
Ph
R2
R3
% yielda drb % eec product
1
Me
Et
4-MeOPh
4-MeOPh
71
69
57
69
91
68
>99
87
81
90
93
56
51
69
84
61
95:5
98:2
96:4
92:8
87:13
94:6
90:10
99:1
97:3
93:7
95:5
99:1
92:8
99:1
na
44
60
52
93
98
90
67
91
70
73
85
65
70
91
82
56
3e
3d
3f
2
Ph
3
Ph
n-Bu 4-MeOPh
n-Bu Ph
4
Ph
3g
3h
3i
5d
6
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me
Me
Me
Me
Me
Me
Me
2-ClPh
4-ClPh
4-NO2Ph
2-FPh
7d
8
3j
3k
3l
%
yielda
%
9
4-FPh
entry
catalyst
R1
drb
eec product
10
11
4-CF3Ph
4-BrPh
Ph
3m
3n
3o
3p
3q
3r
3s
1
2
3
4
5
6
PBu3
Josiphos
Ph
Ph
95
54
88
69
92
69
80:20
72:28
92:8
3a
12d c-Hex Me
6
3a
3a
3b
3c
3d
13
14
15
16
c-Hex Me
c-Hex Me
4-MeOPh
2-MePh
2-MeOPh
2-MeOPh
BINAPHANE Ph
27
BINAPHANE 4-ClPh
BINAPHANE 4-NO2Ph
BINAPHANE 4-MeOPh
85:15 18
Me
Et
Me
Me
88:12
98:2
6
73:27
60
a % yield is isolated yield for 3. b Diastereomeric ratio (dr) deter-
mined by HPLC or 1H NMR analysis of crude. c % ee for major
diastereomer; determined by chiral HPLC analysis. d 15 mol % BINA-
PHANE was used.
a % yield is isolated yield for 3. b Diastereomeric ratio (dr) deter-
1
mined by HPLC or H NMR analysis of crude. c % ee determined by
chiral HPLC analysis.
We then proceeded to examine the substrate scope of the
reaction with respect to variation of substitution on both
the ketene and N-tosyl arylimine components (Table 2).
Alkylarylketenes were found to be satisfactory substrates
with the best results obtained with n-butylphenylketene
(up to 93% ee, entry 4). However, dialkylketenes were
found to be excellent substrates for β-lactam formation,
with enantioselectivities up to 98% being observed. This is
a particularly significant finding given that Fu’s system
works best for alkylarylketenes and diphenylketene. As with
ethylphenylketene, the enantioselectivity in reactions invol-
ving dialkylketenes was found to be highly dependent upon
the electronic nature of the imine component (entry 6 vs 9).
Dialkylketenes typically gave a higher enantioselectivity
in reactions with N-tosyl arylimines possessing an ortho-
substituent on the aryl ring (entry 8 vs 9), so the steric effect
of the substituent appears to be a factor in determining
enantioselection as well. In cases that involved the use of
excess ketene (e.g., entries 5ꢀ11), a ketene dimer was
formed as a minor side product but was easily separated
from the desired β-lactam by flash column chromatography.
Diastereoselectivity favoring the trans-diastereomer was
excellent in most cases (g90:10 for 13 examples). The
relative configuration of the major diastereomer was con-
firmed to be trans by X-ray crystallographic analysis of
β-lactams 3e and 3t, while the absolute configuration of the
major diastereomer was determined to be (R,R) byX-raycry-
stallographic analysis of 3t (see Supporting Information for
more details).15,16 In general, good to high enantioselectivity
can be obtained for a variety of substitution patterns
within both the ketene and imine components, with
excellent enantioselectivity (g90% ee) being obtained
for 5 examples.
Some support for a mechanism involving initial addition
of the phosphine catalyst to the N-tosyl arylimine was
obtained through 31P NMR spectroscopic studies of the
reaction of PBu3 with N-tosyl imine 2a (Scheme 3). The
spectrum of the reaction showed that a significant propor-
tion (>90%) of the phosphorus species was in the form of
a tetravalent phosphonium ion, which we tentatively as-
signed as adduct A (Schemes 2 and 3).17 In contrast, when
Fu’s group carried out 1H NMR analysis of the reaction of
their azaferrocene catalyst with N-tosyl imine 2a, no
evidence of an interaction was observed.9 It is plausible
that the divergence in diastereoselectivity of the two meth-
ods originates from the two possible modes of addition.
(16) The absolute configuration of β-lactam 3t was determined to be
(R,R), through single crystal X-ray crystallographic analysis. The
absolute stereochemistry of most other β-lactams 3aꢀ3s was assigned
to be (R,R) by analogy.
(17) (a) Zhu, X.-F.; Henry, C. E.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 6722–6723. (b) Hudson, H. R.; Dillon, K. B.; Walker, B. J. 31P
NMR Data of Four Coordinate Phosphonium Salts and Betaines. In
Handbook of Phosphorus-31 Nuclear Magnetic Resonance Data; Tebby,
J. C., Ed.; CRC Press: Boca Raton, FL, 1991; pp 181ꢀ226.
(15) The relative stereochemistry of β-lactams 3e and 3t was deter-
mined to be trans through single crystal X-ray crystallographic analysis.
The relative stereochemistry of most other β-lactams 3aꢀ3s was as-
signed to be trans by analogy.
1786
Org. Lett., Vol. 14, No. 7, 2012

31P NMR monitoring of a PBu3-catalyzed reaction of N-
tosyl arylimine 2a and isopropylmethylketene at ꢀ78 °C
revealed the presence of a signal for adduct A (34.7 ppm),
along with a number of other signals in the same region
(34ꢀ35 ppm). We also analyzed the reaction of PBu3 with
isopropylmethylketene at ꢀ78 °C, but no new signal in the
10ꢀ40 ppm region was detected, which is where a phos-
phonium enolate (of type B, Scheme 2) would be expected
to appear.18 Therefore, at this point we cannot rule out
Mechanism B, involving adduct B, and more concrete
conclusions regarding the reaction mechanism will await
further studies.
N-tosyl arylimines and a range of disubstituted ketenes,
including dialkylketenes. The method affords access to
the highly prized trans-β-lactams in good to excellent
enantioselectivity (7 examples >80% ee, up to 98% ee),
and with excellent diastereoselectivity in most cases (dr
g90:10 for 13 examples). The methodology also tolerates
dialkylketenes, substrates which have not been incorpo-
rated into the synthesis of enantioenriched trans-β-lac-
tams before.9 Finally, our method nicely complements the
cis-selective method of Fu’s group, whereby use of a
different catalyst (azaferrocene or phosphine) in reactions
with N-tosyl arylimines will provide access to a particular
diastereomer of a given β-lactam in a predictable manner.
Scheme 3. Mechanistic Analysis through 31P NMR Studies
Acknowledgment. Support has been provided by the
National Science Foundation: Grant Nos. CHE-0911483
to N.J.K, CHE-0722547 to K.A.W., CHE-0821487 for
NMR facilities at Oakland University, and CHE-1048719
for LC-MS facilities at Oakland University. Support has
also been provided by Oakland University (N.J.K.).
Supporting Information Available. Experimental pro-
cedures, compound characterization data (PDF) and
X-ray crystallographic files (CIF). This information is
available free of charge via the Internet at http://pubs.acs.
org.
In summary, we have developed a chiral phosphine-cata-
lyzed asymmetric synthesis of β-lactams from inexpensive
(18) Wei, P.-H.; Ibrahim, A. A.; Mondal, M.; Nalla, D.; Harzmann,
G. D.; Tedeschi, F. A.; Wheeler, K. A.; Kerrigan, N. J. Tetrahedron Lett.
2010, 51, 6690–6694.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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