Chiral N-heterocyclic carbene catalyzed staudinger reaction of ketenes with imines: Highly enantioselective synthesis of N-boc β-lactams

Article abstract of DOI:10.1021/ol702759b

(Chemical Equation Presented) N-Heterocyclic carbenes (NHCs) were demonstrated to be efficient catalysts for the Staudinger reaction of ketenes with N-tosyl, N-benzyloxycarbonyl, or N-tert-butoxycarbonyl imines. Chiral NHC 8b, conveniently prepared from L

Full text of DOI:10.1021/ol702759b

ORGANIC
LETTERS
2008
Vol. 10, No. 2
277-280
Chiral N-Heterocyclic Carbene Catalyzed
Staudinger Reaction of Ketenes with
Imines: Highly Enantioselective
Synthesis of N-Boc
Yan-Rong Zhang, Lin He, Xu Wu, Pan-Lin Shao, and Song Ye*
â-Lactams
Beijing National Laboratory for Molecular Sciences, Laboratory of Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China
songye@iccas.ac.cn
Received November 15, 2007
ABSTRACT
N-Heterocyclic carbenes (NHCs) were demonstrated to be efficient catalysts for the Staudinger reaction of ketenes with N-tosyl,
N-benzyloxycarbonyl, or N-tert-butoxycarbonyl imines. Chiral NHC 8b, conveniently prepared from -pyroglutamic acid, catalyzed the reactions
of arylalkylketenes with a variety of N-tert-butoxycarbonyl arylimines to give the corresponding cis- -lactams in good yields with good
L
â
diastereoselectivities and excellent enantioselectivities (up to 99% ee). Two possible catalytic pathways, initiated by the addition of NHC to
ketenes or imines, were discussed.
The chemistry of N-heterocyclic carbenes (NHCs) has grown
dramatically since the discovery of stable carbenes.1 They
have been widely utilized as powerful reagents,2 applied as
ligands for organometallic catalysts,3 and have developed
into nucleophilic organocatalysts.4 Owing to their capability
to attack the carbon-oxygen double bond of aldehydes,
NHCs were demonstrated very successfully as catalysts for
the umpolung of aldehydes5 and the extended umpolung of
functionalized aldehydes, such as R,â-unsaturated aldehydes,6
7
R-haloaldehydes, R,â-epoxyaldehydes,8 cyclopropanecar-
boxaldehydes,9 and â-lactam aldehydes.10 NHCs were also
found to be excellent catalysts for transesterification, acyla-
tion, ring-opening polymerization, activation of silylated
nucleophiles, and other reactions.4,11
(5) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (b) Enders, D.;
Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed. 2006, 45, 1463. (c)
Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew. Chem., Int.
Ed. 2006, 45, 3492. (d) Li, G. Q.; Dai, L. X.; You, S. L. Chem. Commun.
2007, 852. (e) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 1029. (f) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552.
(6) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
(b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370. (c) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem.
Soc. 2006, 128, 8736. (d) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007,
129, 5334. (e) Chiang, P. C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem.
Soc. 2007, 129, 3520. (f) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt,
K. A. Angew. Chem., Int. Ed. 2007, 46, 3107. (g) Wadamoto, M.; Phillips,
E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098.
(7) (a) Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 9518. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 15088.
(1) (a) Igau, A.; Gru¨tzmaxher, H.; Baceiredo, A.; Bertrand, G. J. Am.
Chem. Soc. 1988, 110, 6463. (b) Arduengo, A. J., III; Harlow, R. L.; Kline,
M. J. Am. Chem. Soc. 1991, 113, 361. (c) Enders, D.; Breuer, K.; Raabe,
G.; Runsink, J.; Teles, J. H.; Melder, J.-P.; Ebel, K.; Brode, S. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1021.
(2) (a) Hahn, F. E. Angew. Chem., Int. Ed. 2006 45, 1348. (b) Cheng,
Y.; Meth-Cohn, O. Chem. ReV. 2004, 104, 2507. (c) Nair, V.; Bindu, S.;
Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130. (d) Bourissou, D.;
Guerret, O.; Gabba¨ı, F. P.; Bertrand, G. Chem. ReV. 2000, 100, 39.
(3) (a) N-Heterocyclic Carbenes in Transition Metal Catalysis; Glorius,
F., Ed.; Topics in Organometallic Chemistry, Vol. 28; Springer-Verlag:
Berlin/Heidelberg, 2007. (b) N-Heterocyclic Carbenes in Synthesis; Nolan,
S. P., Ed.; Wiley-VCH: Weinheim, Germany, 2006. (c) Ce´sar, V.; Bellemin-
Laponnaz, S.; Gade, L. H. Chem. Soc. ReV. 2004, 33, 619.
(4) For reviews, see: (a) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 2988. (b) Zeitler, K. Angew. Chem., Int.
Ed. 2005, 44. 7506. (c) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004,
37, 534.
(8) Chow, K. Y. K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126.
(9) Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021.
(10) Li, G.-Q.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett. 2007, 9, 3519.
10.1021/ol702759b CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/18/2007

Introduced by Staudinger a century ago, ketenes are
remarkable for the diverse range of useful products from their
reactions.12 In line with our research of NHC-catalyzed
reactions,13 we proposed that NHCs may be able to attack
ketene to give a reactive zwitterion A and thus be potential
catalysts for the Staudinger reactions of ketenes with imines
to give â-lactams (eq 1).14,15
We were pleased to find that 10 mol % of NHC 4 could
catalyze the reaction of phenylethylketene (1a) with N-
tosylphenylimine (2a) to give the corresponding â-lactam
3a in high yield, while only a trace amount of 3a was
detected in the absence of the catalyst (eq 2).
First reported by Staudinger, the cycloaddition reaction
of ketenes with imines is a versatile and efficient route to
construct â-lactams.16 However, there are only a few
examples for the catalytic enantioselective Staudinger reac-
tions. Lectka et al. reported their pioneering work that the
quinine derivatives, as the nucleophilic catalysts, could
catalyze the reaction of ketenes with N-tosyl R-iminoesters
with high enantioselectivities.17 This strategy was advanced
by Fu et al. to the reaction of ketenes with N-tosyl and
N-triflyl imines to give cis- and trans-â-lactams, respectively,
using planar-chiral derivatives of 4-(dimethylamino)pyridine
as catalysts.18 In this communication, NHCs proved to be
efficient catalysts for the Staudinger reaction of ketenes with
not only N-tosyl but also N-tert-butoxycarbonyl (Boc) imines.
Initially, N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene
(4),19 a stable NHC, was tested for the Staudinger reaction.
This result prompted us to explore chiral NHCs for the
enantioselective Staudinger reaction (Table 1). Several
Table 1. Investigation of Chiral NHCs for the Staudinger
Reaction
yield
(%)b
ee
entry
2: Ar, R
NHCa
cis/transc (%)d
(11) (a) Connor, E. F.; Nyce, G. W.; Myers, M.; Mo¨ck, A.; Hedrick, J.
L. J. Am. Chem. Soc. 2001, 124, 914. (b) Grasa, G. A.; Kissling, R. M.;
Nolan, S. P. Org. Lett. 2002, 4, 3583. (c) Nyce, G. W.; Lamboy, J. A.;
Connor, E. F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587.
(d) Suzuki, Y.; Yamauchi, K.; Muramatsu, K.; Sato, M. Chem. Commun.
2004, 2770. (e) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453.
(f) Song, J. J.; Tan, Z.; Refes, J. T.; Gallou, F.; Yee, N. K.; Senanayake, C.
H. Org. Lett. 2005, 7, 2193. (g) Wu, J.; Sun, X.; Ye, S.; Sun, W. Tetrahedron
Lett. 2006, 47, 4813. (h) Thomson, J. E.; Rix, K.; Smith, A. D. Org. Lett.
2006, 8, 3785.
1
2
3
4
5
6
7
8
2b: 2-furyl, Ts
2b: 2-furyl, Ts
2b: 2-furyl, Ts
2b: 2-furyl, Ts
2b: 2-furyl, Ts
2b: 2-furyl, Ts
2c: 4-ClC6H4, Ts
2d: 4-ClC6H4, Cbz 8b
2e: 4-ClC6H4, Boc
2e: 4-ClC6H4, Boc
5
6
6
7
8a
8b
8b
93
99
99
59
99
98
97
53
68
72
55:45
62:38
78:22
55:45
50:50
67:33
36:64
60:40
75:25
75:25
-38e
42
63
-9e
58
83
19
89
95
(12) (a) Tidwell, T. T. Ketenes, 2nd ed.; John Wiley & Sons: Hoboken,
NJ, 2006. (b) Tidwell, T. T. Angew. Chem., Int. Ed. 2005, 44, 5778. (c)
Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545.
9
10f
8b
8b
96
(13) He, L.; Jian, T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466.
(14) For the biological activity of â-lactams, see: (a) Chemistry and
Biology of â-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic
Press: New York, 1982; Vols. 1-3. (b) Burnett, D. A. Curr. Med. Chem.
2004, 11, 1873. (c) Buynak, J. D. Curr. Med. Chem. 2004, 11, 1951. (d)
Niccolai, D.; Tarsi, L.; Thomas, R. J. Chem. Commun. 1997, 2333.
(15) For the synthesis and application of â-lactams, see: (a) Alcaide,
B.; Almendros, P.; Aragoncillo, C. Chem. ReV. 2007, 107, 4437. (b) Dhawan,
R.; Dghaym, R. D.; Syr, D. J.; Arndtsen, B. A. Org. Lett. 2006, 8, 3927.
(c) Zhao, L.; Li, C.-J. Chem. Asian J. 2006, 1, 203. (d) Ye, M.-C.; Zhou,
J.; Tang, Y. J. Org. Chem. 2006, 71, 3576. (e) Shintani, R.; Fu, G. C. Angew.
Chem., Int. Ed. 2003, 42, 4082. (f) Lo, M. M.-C.; Fu, G. C. J. Am. Chem.
Soc. 2002, 124, 4572.
(16) (a) Staudinger, H. Justus Liebigs Ann. Chem. 1907, 356, 51. (b)
Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr. Med. Chem.
2004, 11, 1837. (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Eur. J. Org. Chem. 1999, 3223. (d) Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem.
Soc. 2006, 128, 6060.
(17) (a) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J.,
III; Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831. (b) Taggi, A. E.; Hafez,
A. M.; Wack, H.; Young, B.; Ferraris, D. F.; Lectka, T. J. Am. Chem. Soc.
2002, 124, 6626. (c) France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.;
Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206. (d) France, S.;
Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592.
(18) (a) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G. C. J.
Am. Chem. Soc. 2005, 127, 11586. (b) Hodous, B. L.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 1578. (c) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
a NHCs were generated in situ from the precursors 5-8 with 1 equiv
base of t-BuOK (entries 1 and 2) or Cs2CO3 (entries 3-10). b Isolated yield.
1
c Determined by H NMR of the reaction mixture. d Enantiomeric excess
of the cis-isomer. e Enantiomers with opposite absolute stereochemistry were
obtained. f 10 mol % of NHC was used.
reported chiral NHC precursors 5-720 were found to be
efficient catalysts for the reaction of ketene 1a and N-tosyl
2-furylimine (2b), but low to moderate enantioselectivities
were observed (entries 1-4). Triazolium salts 8a and 8b,
with bulky diphenyl(trialkylsilyloxy)methyl substituent, were
then designed and conveniently synthesized from L-pyro-
glutamic acid (Scheme 1). Both 8a and 8b catalyzed the
(19) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999,
55, 14523.
(20) (a) Kerr, M. S.; De Alaniz, J. R.; Rovis, T. J. Org. Chem. 2005,
70, 5725. (b) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int.
Ed. 2006, 45, 1463. (c) Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin
Trans. 1 1998, 1891.
278
Org. Lett., Vol. 10, No. 2, 2008

3). The meta- or para-substituted arylimines afforded â-lac-
tams with somewhat decreased diastereoselectivities as
compared to ortho-substituted ones, but excellent enantiose-
lectivities were still achieved (entries 2-5). Arylimines from
a strong electron-deficient one (4-NO2C6H4) to a less
electron-deficient one (2-furyl) worked well (entries 6-8).
Arylalkylketenes with either an electron-donating substituent
(4-MeO) or an electron-withdrawing substituent (4-Cl) are
suitable substrates (entries 9-13). It should be noted that
the reaction with alkylimines was sluggish and failed to give
the â-lactams under current standard reaction conditions.
An advantage of this work is that the resulting N-Boc-pro-
tected â-lactam 3 could be easily deprotected to afford the
free â-lactam in high yield (eq 3). Furthermore, the â-lactam
ring was reductively opened by LiAlH4 to afford γ-amino-
alcohol without erosion in stereochemical purity (eq 4).
Scheme 1. Synthesis of Chiral NHC Precursors 8a and 8b
Staudinger reaction efficiently, while 8b showed better
diastereo- and enantioselectivity (entries 5 and 6). It is
surprising to find that the enantioselectivity decreased sharply
when N-tosyl(4-chlorophenyl)imine 2c was employed instead
of furylimine 2b (entry 6 vs 7). We conjectured that the
electron-deficient 4-chlorophenyl group is the possible reason
for the decrease of selectivity. Thus, imines with a less
electron-withdrawing protective group were investigated. It
was found that the reaction with N-benzyloxycarbonyl (Cbz)
imine 2d, and N-tert-butoxycarbonyl (Boc) imine 2e afforded
the corresponding â-lactams with good cis-selectivity and
with 89 and 95% ee, respectively (entries 8 and 9). Further
experiments showed that decreasing the loading of catalyst
8b from 20 to 10 mol % made no notable change in yield
and selectivity (entry 10).
Substrate scope investigation revealed that a wide variety
of ketenes and imines reacted smoothly to afford corre-
sponding â-lactams in good yields with good to high
diastereoselectivities and excellent enantioselectivities (Table
2). The ortho-substituted arylimines (2-Cl, 2-BrC6H4) worked
well and benefited the diastereoselectivities (entries 2 and
Similarly to the mechanisms suggested by Fu et al. in their
catalytic Staudinger reactions,18a the NHC may add to ketene
(mechanism A) or imine (mechanism B) to initiate the
catalytic cycle (Figure 1).
Table 2. Asymmetric Staudinger Reaction Catalyzed by 8b
yield
(%)a
ee
entry
1: Ar1, R
Ph, Et
2: Ar2
cis/transb (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
4-ClC6H4
2-ClC6H4
2-BrC6H4
3-ClC6H4
4-BrC6H4
3e,d 72
3f,d 71
3g, 58
3h, 66
3i, 71
75:25
91:9
94:6
80:20
78:22
71:29
75:25
83:17
86:14
93:7
96
99
97
99
99
99
99
98
93
91
96
97
99
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Me
4-NO2C6H4 3j, 75
Ph
2-furyl
3k, 64
3l, 57
2,4-Cl2C6H3 3m, 53
3n, 78
4-MeOC6H4, Et 2,4-Cl2C6H3 3o, 62
4-MeOC6H4, Et 2-ClC6H4
89:11
99:1
83:17
4-ClC6H4, Et
4-ClC6H4, Et
2-ClC6H4
4-ClC6H4
3p, 61
3q, 53
Figure 1. Two possible catalytic mechanisms.
a Isolated yield. b Determined by 1H NMR of the reaction mixture.
c Enantiomeric excesses of the cis-isomer and the trans-isomer of 3e, 3h,
3j, 3k, 3n, and 3o are 27, 65, 81, 67, 10, and 30%, respectively. d The
absolute configuration of 3f and 3e was determined by X-ray and CD
spectra, respectively.
Experiments showed NHC 8b′ (generated from precursor
8b in situ) could react with ketene 1a rapidly, but we failed
to identify the ketene-NHC zwitterion A.
Org. Lett., Vol. 10, No. 2, 2008
279

It was reported that NHCs could react with N-tosyl
imines,21 and we successfully isolated the NHC-imine
adduct 13 (intermediate C in Figure 1) from the reaction of
NHC 4 with N-tosyl imine 2a.13,22 It was found that adduct
13 could react with phenylethylketene to give â-lactam 3a
in 88% yield with the same diastereoselectivity as that in
the catalytic version (eq 2 vs eq 5). However, it should be
noted that the formation of adduct 13 is reversible,13 and
the cyclization of intermediate D to â-lactam is disfavored
according to Baldwin’s rules.23 Thus, it cannot be ruled out
that adduct 13 may decompose in situ to imine and NHC
and then form â-lactam 3a by mechanism A.
with imines. The concept of activation of ketenes by NHC
may find further application in the catalytic transformation
of ketenes, especially those of the cycloaddition reaction.
Furthermore, to the best of our knowledge, this communica-
tion represents the first example of catalytic enantioselective
Staudinger reaction with N-Boc imines. Several advantages
of this methodology, including ready availability of catalyst
8b, excellent enantioselectivities, facile removal of the Boc
group, and easy scale-up of the reaction,25 make it potentially
useful in the synthesis of cis-â-lactams with R-quaternary
and â-tertiary stereocenters. Further investigation of substrate
scope and the detailed reaction mechanism is underway in
our laboratory.
Acknowledgment. We are grateful for the financial
support from Chinese Academy of Sciences and Natural
Sciences Foundation of China (No. 20602036).
Supporting Information Available: Experimental pro-
cedures and compound characterization including synthesis
of NHC precursors 8a and 8b, crystal structure data of lactam
3f, and CD spectra of lactams 3e and 3f. This material is
available free of charge via the Internet at http://pubs.acs.org.
As for the reaction of ketenes with less electron-deficient
imines, such as N-Cbz and N-Boc imines, mechanism A is
apparently favored over mechanism B because the NHC
reacts very sluggishly with those imines.
OL702759B
In conclusion, chiral NHCs were proven for the first time
to be efficient catalysts for the Staudinger reaction of ketenes
(23) Baldwin, J. E.; Kruse, L. I. J. Chem. Soc., Chem. Commun. 1977,
233.
(24) (a) Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron 2001,
57, 6353. (b) Ostendorf, M.; Dijkink, J.; Rutjes, F. P. J. T.; Hiemstra, H.
Eur. J. Org. Chem. 2000, 115.
(21) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
(22) It was found that NHC 8b′ could react with N-tosyl imines, but we
were unable to identify or isolate the corresponding NHC-imine adduct.
(25) Scaling up the reaction from 0.51 mmol (imine 2h) to 8.6 mmol
made no notable difference in yield and selectivity.
280
Org. Lett., Vol. 10, No. 2, 2008