Chiral Silver Amides
Table 3. Asymmetric [3+2] cycloaddition of 1a with olefins 2.[a]
with high diastereo- and enantioselectivities (Table 2,
entry 14). It is noteworthy that the Schiff bases prepared
from other amino acid esters worked well and that the cy-
cloadducts with quaternary carbon centers were obtained
with high stereoselectivities (Table 2, entries 15–17). Next,
we tried to expand our methodology to reactions of Schiff
bases prepared from aliphatic aldehydes. Usually, [3+2] cy-
cloaddition reactions that use aliphatic Schiff bases are rec-
ognized to be difficult because the a-hydrogen is not acidic
enough for deprotonation by amine bases. Furthermore, ali-
phatic imines, especially primary alkyl imines, are easily con-
verted into enamines in the presence of bases, which lead to
undesired side reactions such as self-condensation, and so
on. In fact, successful examples of asymmetric [3+2] cyclo-
additions of aliphatic Schiff bases of glycine esters are quite
limited, and high enantioselectivities were obtained only in
the cases of secondary alkyl Schiff bases.[15] On the other
hand, we envisioned that the current silver amide system
could be applied to aliphatic Schiff bases, because the
system has a unique acid/base character. We tested the reac-
tion of cyclohexylcarboxyaldehyde Schiff base 1t and were
delighted to find that the reaction proceeded well in the
presence of the AgHMDS catalyst to afford the desired cy-
cloadduct in good yield with high enantioselectivity under
the same reaction conditions as for the Schiff base prepared
from benzaldehyde (Table 2, entry 18). The isopropylalde-
hyde Schiff base 1u also reacted with 2a in moderate yield
with high diastereo- and good enantioselectivities (Table 2,
entry 19). We then tried to use the most challenging primary
alkylaldehyde Schiff bases (Table 2, entries 20–24) and
found that the desired reactions also proceeded well to give
the adducts in moderate to good yields with good to high
enantioselectivities. In contrast, the [3+2] cycloaddition of
1y with 2a using typical silver catalyst systems (AgOT-
Entry R3
2
3
Yield [%] exo/endo ee [%]
(exo)
ACHTUNGTRENNUNG
1
2
3
4
5
6
CO[N
CONMe2
COMe
(CH2)2O
E
92
97
82
83
80
96
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
96
95
97
97
98
99
SO2Ph
P(O)
CN
ACHTUNGERTN(NUNG OEt)2
[a] The reaction of 1a with 2 was conducted in the presence of the Ag
catalyst (5 mol%) at 08C for 24 h in 0.6m.
Asymmetric [3+2] Cycloaddition of Imines of a-
Aminophosphonate with Olefins
Next, we focused on the asymmetric [3+2] cycloaddition of
a Schiff base that bore less acidic a-hydrogen atoms. The
phosphonic analogues of a-aminoesters, a-aminophospho-
nates, are interesting compounds as chiral building blocks
for constructing structures that mimic peptides. However,
application of the [3+2] cycloaddition methodology to a-
aminophosphonate Schiff bases is difficult because the acidi-
ty of their a-hydrogen is not high enough to be deprotonat-
ed.[16] To the best of our knowledge, all previous methods
use more than stoichiometric amounts of bases to conduct
stereoselective [3+2] cycloaddition of Schiff bases of a-ami-
nophosphonates.[17]
First, we applied the AgHMDS–(R)-DTBM-SEGPHOS
catalyst system to the reaction of Schiff bases of a-amino-
phosphonates 4 with acrylates. It was found that the reaction
of 4a with tert-butyl acrylate 2b gave excellent diastereo-
and enantioselectivities in the presence of 3 mol% of the
silver catalyst (Table 4, entry 1). In this reaction, only
1 mol% silver catalyst worked well to afford the desired
product in high yield with high diastereo- and enantioselec-
tivities (Table 4, entry 2). It is noted that the reaction of an
a-aminophosphonate Schiff base proceeded well in the pres-
ence of a catalytic amount of the silver complex. Schiff
bases 4 with electron-donating or electron-withdrawing
groups on their aromatic rings reacted with 2b smoothly to
afford the desired cycloadducts in high yields with high exo
selectivities and enantioselectivities (Table 4, entries 3–7).
Bulkiness of the aromatic group was found to affect the re-
action slightly, and the reaction of 1-naphthyl Schiff base 4g
required further optimal reaction conditions, whereas 2-
naphthyl Schiff base 4e showed similar reactivity to other
aromatic Schiff bases (Table 4, entries 8 and 9). The hetero-
aromatic moiety, 3-pyridyl, also did not affect the results
through some extra coordination to the silver atom (Table 4,
entry 10). The sterically less-hindered alkenyl group also
gave high reactivity and selectivity (Table 4, entry 11). When
the Schiff bases with alkyl substituents, isopropyl, cyclohex-
yl, and isobutyl groups were employed, the reactions also
f+Et3N or 1,8-diazabicycloACTHNUTRGNEUGN[5.4.0]undec-7-ene (DBU),
AgOAc) with (R)-DTBM-SEGPHOS did not proceed at all
under the same reaction conditions. It is worth noting that,
to the best of our knowledge, this is the first successful ex-
ample of asymmetric [3+2] cycloaddition of primary alkyl
Schiff bases.
The current catalyst system was also successfully applied
to asymmetric [3+2] cycloadditions with other olefins 2
(Table 3). Methyl acrylate 2a as well as acryl amides (2c
and 2d) reacted with 1a in high yields with high diastereo-
and enantioselectivities (Table 3, entries 1 and 2). The reac-
tion of methyl vinyl ketone (2e) also gave the desired prod-
uct with high selectivities (Table 3, entry 3). These results in-
dicated that the coordination ability of the carbonyl oxygen
of the olefins did not affect asymmetric environments in the
transition states. Other olefins with electron-withdrawing
groups were also examined, and the olefins that bear sulfo-
nyl, phosphonyl, and cyano groups reacted with 1a to afford
the corresponding pyrrolidine derivatives in high yields with
high selectivities. Thus, the wide scope of both substrates,
Schiff bases, and olefins in this chiral silver amide system is
remarkable. In addition, it is noteworthy that the reactions
proceeded smoothly without addition of any external bases.
Chem. Asian J. 2011, 6, 2550 – 2559
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2553