Communications
[a]
Table 1: Scope of the enantioselective amine conjugate addition to
enones.[a]
Table 2: Selectedscreening results for the aziridination of enones.
Entry
8
Solvent Additive
(2 equiv)
Conv.[b] 10:11[b] d.r.[b]
ee [%][c]
Entry
4
R1
R2
T [8C], t [h] 6:7[b] Yield[%] [c] ee [%][d]
1
2
3
4
a
b
c
a
a
a
a
a
a
pentyl
pentyl
pentyl
Me
Me
Me
Me
Me
Me
RT, 72
RT, 72
RT, 72
RT, 72
30, 72
30, 72
50, 96
30, 72
0, 40
8:1
(a) 85
99
99
99
95
94
93
95
95
95
1
2
3
4
5
6
a
b
c
c
c
c
c
c
c
c
toluene
toluene
toluene
H2O
THF
CHCl3
CHCl3
CHCl3 K2CO3 (s)
CHCl3 NaHCO3 (aq)
CHCl3 NaHCO3 (s)
–
–
–
–
–
–
–
21
67
78
57
58
65
56
<10
45
>95
1:99
1.1:1
4.3:1
4:1
2:1
7.3:1
9:1
>99:1
>99:1 >19:1
>99:1 19:1
–
–
77[d]
86
81
79
82
89
95
–
9.5:1 (b) 77
6:1
3:1
7.5:1 (e) 78
5.5:1 (f) 68
1:3
(c) 43
(d) 63
4:1
7:3
5.6:1
7.5:1
9:1
–
5[e]
6[e]
7[e]
8[e]
9
Ph
p-Cl-C6H4 Me
Ph
CO2Et
Ph
Me
(g) 51
7[e]
8[e]
9[e]
10[e]
9.5:1 (h) 65
0:100 (i) 85
(CH2)3
80
96
[a] Reactions carriedout on a 0.2 mmol scale with 1.2 equiv of 4 and
10 mol% of the catalyst salt 1a, unless otherwise noted. [b] Determined
by 1H NMR analysis. [c] Overall yieldof isolatedproducts (sum of 6 and
7). [d] Determined by chiral HPLC analysis. [e] 20 mol% of the catalyst
1a.
[a] Unless otherwise noted, the reactions were carried out on a 0.1 mmol
scale with 2 equiv of 9 and[ 8]0 =1m for 22 h in the presence of 20 mol%
of the catalyst salt combination 1b (30 mol% of 3 and20 mol% of 2).
[b] Determinedby 1H NMR analysis of the crude mixture. [c] Determined
by chiral HPLC analysis. [d] ee value of compound 11. [e] [9]0 =0.25m and
1.2 equiv of 8c were employed.
variation of the carbamate protecting group from benzyloxy-
carbonyl (Cbz) to Boc or CO2Et can be realized without loss
in enantiocontrol (Table 1,entries 1–3). Importantly,a wide
variety of different unsaturated ketones can be efficiently
activated by catalyst 1a: both linear compounds,including
chalcone (Table 1,entry 7),a particularly challenging class of
substrates for iminium catalysis,and a cyclic enone (Table 1,
entry 9) afforded the expected products in high optical purity.
The partitioning between the tandem or the conjugate
addition products 6 and 7,respectively,is strongly dependent
on the electronic as well as the steric contribution of the R2
substituent of enone 5.
Next,we moved toward the principal aim of our inves-
tigations,the development of a domino conjugate-cyclization
sequence,leading to chiral aziridines. From the outset,we
recognized the choice of the nitrogen-atom source as the
crucial parameter for developing an efficient aziridination
methodology. As planned in Scheme 1,a suitable compound
should first act as a nucleophile under iminium catalysis by 1,
affording a stereoselective heteroatom addition step,and then
should become electrophilic to facilitate the enamine-cata-
lyzed cyclization step.
To assess the feasibility of such an organocatalytic
aziridination strategy,we examined the reaction of enone 9
with different nitrogen-based reagents 8. Selected results of
the extensive screening of the reaction conditions by using the
catalyst salt combination 1b (1.5 equiv of 3 relative to 2) are
reported in Table 2.[14] The acylated hydroxycarbamate 8a,
which was employed in the aziridination of enals under
secondary amine catalysis,[7] provided only the conjugate
addition product 11 (Table 2,entry 1). Gratifyingly,installing
a better leaving group such as a tosyl moiety (8c; Table 2,
entry 3) allowed selective partitioning of the reaction mani-
fold toward the tandem sequence,leading to the desired
aziridine 10 as the major product. Further optimization of the
standard reaction parameters revealed that the choice of
solvent (compare Table 2,entries 3–6),the reagent concen-
tration,and the stoichiometric ratio of the reagents (Table 2,
entry 7) were important factors in the efficiency and general-
ity of the catalytic system. Finally,we envisaged that the p-
toluenesulfonic acid,generated during the enamine-induced
ring-closing step when using 8c,may affect the activity of the
catalyst. We reasoned that the presence of an inorganic base
could have a beneficial effect on both the reaction rate and
the selectivity of the aziridination. Carrying out the aziridi-
nation in CHCl3 with [9]0 = 0.25m,1.2 equivalents of 8c,and
2 equivalents of solid NaHCO3 induced higher chemo-,
diastereo-,and enantioselectivity (Table 2,entry 10). These
catalytic conditions were selected for further exploration
aimed at expanding the scope of this transformation.
As highlighted in Table 3,the method proved to be
successful for the synthesis of a wide range of N-Cbz as well as
N-Boc ketoaziridines 10 in good yield and with high levels of
stereoselectivity (single diastereoisomer and very high ee
values,up to 99%). By adjusting the reaction time,it was also
possible to decrease the catalyst loading to 5 mol% without
affecting the efficiency of the system (Table 3,entry 4).
Importantly,there appears to be significant tolerance
toward steric and electronic demands of the b-olefin sub-
stituent to enable access to a broad variety of both aliphatic
(Table 3,entries 1–6) and aromatic aziridines (Table 3,
entries 7 and 8). Moreover,the presented protocol is also
effective with cyclohexenone,affording the desired cyclic
aziridine 10h in very high optical purity (Table 3,entry 9).
This result has significant consequences from a synthetic
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 8703 –8706