Angewandte
Chemie
La(OAr1)3, indicating the coordination of the phosphine
oxide to the lanthanum metal center. In Figure 2, the extent of
a deuterium substitution[19] of the a protons in trichloro-
methyl ketone 3c upon reaction with Ar1OD catalyzed by
Scheme 1. Trialon the anti-selective catalytic enantioselective Mannich-
type reaction.
Figure 2. Deuterium exchange experiments with and without the Lewis
*
*
base; : with Lewis base 1b, : without Lewis base.
La(OAr3)3 was monitored by 1H NMR spectroscopy.
La(OAr3)3/Lewis base 1b gave 14% deuteration after
24 hours, whereas La(OAr3)3 alone resulted in only a trace,
if any, deuteration, providing direct evidence that the La–
enolate-formation step by deprotonation was accelerated by
Lewis base 1b. With only Lewis base 1b, deuteration was not
observed after 24 hours. These results led us to assume that a
catalytic amount of Lewis base 1b coordinated to the
lanthanum metal center and increased the Brønsted basicity
of the lanthanum aryloxide moiety. The present La(OAr)3/1a
or 1b system gives anti adducts,[20] whereas the previously
reported La(OAr)3/pybox afforded syn adducts. The observed
anti selectivity in the present system can be explained by the
difference in the nucleophilicity of the La–enolate. Strong
Lewis bases such as 1a and 1b would increase the nucleo-
philicity of the La–enolate, therefore leading to a favorable
sterically less-hindered acyclic anti-periplanar transition-state
(Figure 3A) to give the anti adduct, analogous to a Lewis base
promoted anti-Mannich reaction of silyl enolates.[21] With
pybox ligands, a crowded cyclic transition state (Figure 3B)
would be preferable because the imine is activated by the
Lewis acidic lanthanum metal center to compensate for the
lower nucleophilicity of the La–enolate. The La(OAr1)3/1a
(Ar1 = 4-MeO-C6H4) system gave 4ba in a anti/syn 42:1 ratio
(Table 2, entry 3), whereas the La(OAr2)3/1a (Ar2 = 4-Br-
C6H4) system resulted in poor diastereoselectivity (Table 2,
entry 5). Moreover, the strongly electron-donating Me2N
substituted iPr–pybox resulted in a significant loss of syn se-
lectivity compared to iPr–pybox (Table 1, entries 1 and 4).
These results support the idea that the nucleophilicity of the
La–enolate is one of the key factors in determining the
diastereoselectivity. Additional mechanistic studies are ongo-
ing to clarify the steric effects of the bidentate phosphine
oxides and the difference in the Lewis acidity of the
Scheme 2. Transformations of anti-Mannich adducts into b-amino
ester and azetidine esters. Reagents and conditions: a) NaOMe,
MeOH, 08C, 10 min, >99% yield; b) 1. Boc2O, DMAP, CH3CN, RT,
2 h, 94% yield; 2. Mg0, MeOH, RT, 2 h 93% yield; c) LiAlH4, THF,
À788C, 4 h, 7ba: 80% yield; 7da: 73% yield; 7ga: 76% yield;
d) 1. NaOH, DME/H2O (1.6:1), RT, 5 h; 2. TMSCHN2 in hexanes,
MeOH, RT, 8ba: 80% yield (2 steps from 7ba); 8da: 73% yield (2
steps from 7da); 8ga: 71% yield (2 steps from 7ga). Boc=tert-
butoxycarbonyl; DMAP =4-(dimethylamino)pyridine; DME=1,2-dime-
thoxyethane.
not only a b-amino acid, but also of an azetidine-2-carboxylic
acid, which is not readily accessible from Mannich adducts
lacking the trichloromethyl ketone moiety. b-Amino ester
5ba was obtained in greater than 99% yield from 4ba by
treatment with NaOMe in MeOH at 08C for 10 minutes.
Removal of the 2-pyridinesulfonyl group proceeded smoothly
with Mg0 in MeOH at room temperature,[8] to give 6ba in
good yield. Stereoselective reduction of 4 with LiAlH4, and
subsequent dichlorooxirane formation and stereoselective
intramolecular cyclization using NaOH in DME at room
temperature gave azetidine carboxylic acids.[18] Epimerization
was not observed during cyclization under basic conditions.
After methylation with TMSCHN2, azetidine esters 8 were
obtained in 80–71% yield (in 2 steps from 7).
In the present system, the addition of a suitable bidentate
phosphine oxide 1a or 1b was key to the increased reactivity
of La(OAr)3 and to the anti selectivity. 31P NMR analysis of
1a showed a downfield shift after complexation of 1a with
Angew. Chem. Int. Ed. 2008, 47, 9125 –9129
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9127