Fig. 1 O-acylated conjugate addition products of (S)-N-(a-methyl-
benzylamine)hydroxylamine.
conjugate addition of 6 to ethyl methacrylate and ethyl trans-
crotonate (entries 8 and 9, diastereoselectivity 63 : 37 and 82 : 18
respectively) proceeded in quantitative yields. Disappointingly our
attempts at incorporating an amide functional group via the
conjugate addition of 6 with N-acryloylmorpholine failed.
Employing our standard reaction protocol for the in situ
synthesis of 6 (from 5, Scheme 2) and either methyl, ethyl or tert-
butyl cinnamate, yielded none of the desired conjugate addition
products. Perhaps not surprisingly, given the lack of reactivity
between 6 and the cinnamates mentioned, ethyl tiglate failed to
react with 6, even after prolonged periods of heating. Likewise the
trans,trans-a,b,c,d-diene of ethyl 2,4-hexadienoate (entry 11) also
failed to react with 6, even after refluxing in THF for 72 hours. In
contrast, phenyl cinnamate (entry 10), similar to phenyl acrylate
(entry 4), underwent a conjugate addition reaction with 6 but, as
observed for phenyl acrylate, the subsequent addition product
underwent cyclisation.7 Interestingly the CLC bonds of the
phenyl esters of cinnamic and acrylic acid underwent conjugate
addition reactions. This contrasts sharply with the lack of
reactivity with the alkyl esters, i.e. methyl, ethyl or tert-butyl
esters of cinnamic acid.
Fig. 2 Optically active aziridines synthesised from 9, 10 and 11 and
X-ray crystal structure of (S,S)-14.
The (S,S) and (S,R) diastereomers for 14 were readily separated
using flash chromatography. In agreement with published data,9
the absolute stereochemistry for the major diastereomer (13) was
assigned (S,S). X-ray analysis of a crystal of the minor
diastereomer of 14 conclusively proved that our assignment as
the (S,S) configuration was correct (Fig. 2).{ Attempts at purifying
and or separating the diastereomers of 15 resulted in their
decomposition.
Utilising 6 and methyl acrylate the conjugate addition product
was synthesised in quantitative yield and O-acylated. Deprotona-
tion afforded a diastereomeric mixture of separable aziridines
(S,S)-16 (52% yield) and (S,R)-17 (76 : 24 respectively, Scheme 4).
Physicochemical data for (S,S)-16 and (S,R)-17 were essentially the
same as reported by Farooq et al.10 and Seebach et al.11
Employing 8, the conditions outlined in Scheme 3 and various
temperatures we investigated the yield and diastereoselectivity of
the reaction. At 2100 uC or 278 uC the ratio of 3 : 12 was
approximately the same (77 : 23). Conducting the cyclisation at
260 uC the yield of 3 : 12 fell to 45% but, interestingly, the dia-
stereoselectivity increased. Remarkably, at 240 uC the diastereo-
selectivity increased still further to 91 : 9 and at 220 uC the
diastereoselectivities and yields were both excellent (90 : 10, 93%).
Further studies, employing 8, investigated the effect on the
reaction when alternative bases7 and solvents7 were employed at
240 uC. Substituting LHMDS for either NaH, BEMP, n-BuLi or
t-BuOK afforded 8 or poor yields of 3 and 12. However LDA,
LHMDS, NaHMDS, KHMDS or lithium diphenylamide
returned excellent yields of 3 and 12 with poor (45 : 55 for
LDA) to excellent (93 : 7 for LHMDS) diastereomeric ratios of
3 : 12 resulting.
Acylation of the conjugate addition adducts with either pivaloyl
chloride or cyanide of selected hydroxyamines (entries 1, 2, 5, and
6, Table 1) was attempted. The optically active (S)-N-(a-methyl-
benzylamine)-O-pivaloyl hydroxylamine adducts 8–11 (Fig. 1)
were afforded in good to excellent yields (75–93%).
With O-pivaloyl hydroxylamines 8–11 in hand, our attention
was directed to their transformation into chiral non-racemic
aziridines via a diastereoselective 3-exo-tet cyclisation. A solution
of 8 was cooled (278 uC) and LHMDS added, presumably
forming the corresponding enolate. The enolate attacks the
nitrogen of 8 affording the desired optically active aziridines
(Scheme 3). Gratifyingly a 66% yield of both 3 and 12 was
returned as a partially separable mixture of diastereomers (67 : 33
respectively). Assignment of 3 and 12 as the (S,S) and (S,R)
1
diastereomers respectively was based on reported H-NMR and
[a]D values.9
Repeating the reaction protocol in Scheme 3 with O-pivaloyl
hydroxylamines 9, 10 and 11 the synthesis of the corresponding
aziridines was attempted. We were delighted to find after aqueous
work-up diastereomeric mixtures of aziridines 13–15 (13, 75 : 25;
14, 78 : 22; 15, 69 : 31) were afforded in 42–67% yields.
Scheme 3 Asymmetric synthesis of (S,S)-3 and (S,R)-12.
3514 | Chem. Commun., 2006, 3513–3515
Scheme 4
This journal is ß The Royal Society of Chemistry 2006