Table 2 Effect on b-lactam diastereoselectivity by variation of the reaction parametersa
Entry
[Pd] (mol%)
CO/Bar
Temperature
Solvent
Time/h
Yield (%)b
d.r. (3a : 4a : 5a)c,d
1
2
3
4
5
6
7
8
9
10
10
5
1
1
1
1
1
r.t.
r.t.
r.t.
r.t.
Toluene
Toluene
1,2-DME
CH2Cl2
Toluene
1,2-DME
Toluene
Toluene
Toluene
CH2Cl2
2
2
16
5
120
72
2
2
2
20
77
30
67
44
56
62
60
75
69
44
3 : 3 : 94
13 : 23 : 64
1 : 20 : 79
0 : 8 : 92
34 : 56 : 10
14 : 67 : 19
0 : 0 : 100
14 : 28 : 58
29 : 52 : 19
10 : 79 : 11
10
10
10
10
10
10
4
ꢂ5 1C
1
ꢂ5 1C to r.t.
0.1
50
50
50
r.t.
r.t.
r.t.
r.t.
4
a
b
c
d
Aziridine concentration = 6 ꢁ 10ꢂ2 M. Isolated yield. Determined by 1H-NMR after chromatography. The cis-Z isomer was never
observed.
diastereomer is formed but also (in one case) whether a b- or
d-lactam is obtained.
VKA thanks the EPSRC for a Senior Research Fellowship.
FF thanks the ‘‘Universita degli Studi di Milano’’ for funding.
Scheme 3 Effect of pressure on the regioselectivity of carbonylation.
Notes and references
mechanism. At atmospheric pressure the p-allyl Pd complex 7
1 The b-Lactamases: A Major Cause of Resistance of b-Lactam
decomposes, probably through an elimination pathway.
However, at high pressure it is more rapidly captured by CO
leading preferentially to the trans-Z-b-lactam 3. In this case
Pd(0)-mediated isomerisation is evidently slower than when
R2 = Ph (compare Table 1 entry 14 with Table 2 entry 8) and
even though the concentration of 11 is expected to be lower
than 12 its faster rate of cyclisation leads to 3 being the
predominant isomer.
Antibiotics and b-Lactamase Inhibitors, ed. O. A. Mascaretti,
Bentham, Hilversum, Netherlands, 1999.
2 For selected examples see: (a) I. Ojima and F. Delaloge, Chem. Soc.
Rev., 1997, 26, 377; (b) A. K. Bose, M. S. Manhas, J. M. van der
Veen, S. S. Bari and D. R. Wagle, Tetrahedron, 1992, 48, 4831;
(c) H. Fujieda, M. Kanai, T. Kambara, A. Iida and
K. A. Tomioka, J. Am. Chem. Soc., 1997, 119, 2060;
(d) M. Miura, M. Enna, K. Okuro and M. Nomura, J. Org. Chem.,
1995, 60, 4999.
3 For reviews of the Staudinger reaction see: (a) C. Palomo,
J. M. Aizpurua, I. Ganboa and M. Oiarbide, Curr. Med. Chem.,
2004, 11, 1837; (b) S. France, A. Weatherwax, A. E. Taggi and
T. Lectka, Acc. Chem. Res., 2004, 37, 592.
4 For recent examples see: (a) E. C. Lee, B. L. Hodous, E. Bergin,
C. Shih and G. Fu, J. Am. Chem. Soc., 2005, 127, 11586;
(b) N. Duguet, C. D. Campbell, A. M. Z. Slawin and
A. D. Smith, Org. Biomol. Chem., 2008, 6, 1108;
(c) A. Weatherwax, C. J. Abraham and T. Lectka, Org. Lett.,
2005, 7, 3461; (d) D. Brown, G. A. Brown, M. Andrews,
J. M. Large, D. Urban, C. P. Butts, N. J. Hales and
T. Gallagher, J. Chem. Soc., Perkin Trans. 1, 2002, 2014.
5 G. W. Spears, K. Nakanishi and Y. Ohfune, Synlett, 1991, 91.
6 D. Tanner and P. Somfai, Bioorg. Med. Chem. Lett., 1993, 3, 2415.
7 V. K. Aggarwal, E. Alonso, G. Fang, M. Ferrera, G. Hynd and
M. Porcelloni, Angew. Chem., Int. Ed., 2001, 40, 1433. For a recent
review see: E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw,
S. L. Riches and V. K. Aggarwal, Chem. Rev., 2007, 107, 5841.
8 Knight et al.’s Pd(0)-catalysed carbonylation of vinyl oxazolidinones
to d-lactams occurs through related intermediates: (a) J. G. Knight,
S. W. Ainge, A. M. Harm, S. J. Harwood, H. I. Maughan,
D. R. Armour, D. M. Hollinshead and A. A. Jaxa-Chamiec,
J. Am. Chem. Soc., 2000, 122, 2944; (b) J. G. Knight,
I. M. Lawson and C. N. Johnson, Synthesis, 2006, 227.
The preference for the silyl-substituted aziridine 1i to give
the d-lactam over the b-lactam 3i is intriguing (Scheme 3). It
may result from an inherent preference for carbonylation to
occur adjacent to Si due to the shorter C–Pd bond length11 in
the unsymmetrical p-allyl Pd complex 15 to give the acyl Pd
species 16 (presumably other non-productive acyl Pd species
are also generated but revert back to the one that is ultimately
productive). This will subsequently undergo fast cyclisation to
give d-lactam 18 after protodesilylation. However, the acyl Pd
species 16 must be in very low concentration since it suffers
significant steric hindrance. We reasoned that since the equili-
brium ratios of the different acyl Pd species present in solution
could be influenced by the concentration of CO, a different
outcome could be expected at high CO concentration since the
system is less equilibrating. Indeed, operating at 50 bar now
gave the b-lactam predominantly as a mixture of diastereo-
mers (Scheme 3). This mixture is consistent with a reaction in
which there is fast carbonylation with minimal Pd(0)-mediated
isomerisation of the p-allyl Pd complex.
9 (a) T. Ibuka, N. Mimura, H. Aoyama, M. Akaji, H. Ohno,
Y. Miwa, T. Taga, K. Nakai, H. Tamamura, N. Fujii and
Y. Yamamoto, J. Org. Chem., 1997, 62, 999; (b) T. Ibuka,
N. Mimura, H. Ohno, K. Nakai, M. Akaji, H. Habashita,
H. Tamamura, Y. Miwa, T. Taga, N. Fujii and Y. Yamamoto,
J. Org. Chem., 1997, 62, 2982.
In conclusion, we have shown that b-substituted
a,b-unsaturated aziridines undergo Pd-catalysed carbonyl-
ation reactions to give b-lactams. The p-allyl Pd intermediates
undergo a high degree of isomerisation prior to formation
of the b-lactam. By carefully controlling the reaction para-
meters (temperature, [Pd], [CO]) we can influence the
degree of isomerisation and thereby control not only which
10 K. L. Gangberg and J.-E. Backvall, J. Am. Chem. Soc., 1992, 114,
6958.
¨
11 V. Branchadell, M. Moreno-Manas and R. Pleixats, Organo-
metallics, 2002, 21, 2407.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 267–269 | 269