chloromethane to give various N-carbamate-protected R-imi-
no esters such as N-Boc (N-tert-butoxycarbonyl)-, N-Cbz (N-
benzyloxycarbonyl)-, and N-Teoc (N-2-trimethylsilyleth-
oxycarbonyl)-protected8 R-imino esters, in excellent yields,
and with good purity (eq 1). In the case of R-imino esters
Table 1. Effect of Structure of Diamine Ligands
R-imino ester
R1
ligand
R2
entry
)
)
yield (%)a ee (%)b
1
2
3
4
5
6
7
8
9
Me (3a )
Et (3b)
iPr (3c)
tBu (3d )
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
1-naphthyl (5a )
1-naphthyl (5a )
1-naphthyl (5a )
1-naphthyl (5a )
Ph (5b)
97
96
85c
74c
92
92
89
87
92
96
84
87
81
53
85
86
85
86
91
22
having more electron-withdrawing N-carbamates such as
N-Troc (2,2,2-trichloroethoxycarbonyl)-protected9 R-imino
ester 3f, a substantial amount of decomposition of 3f occurred
during the imine formation using 2a. In this case, less
nucleophilic morpholinomethylpolystyrene 2b was more
effective than 2a for the reaction to proceed cleanly. As for
solvents, toluene or benzene could also be used instead of
dichloromethane with a slight decrease in the yield. It is
noteworthy that solutions of the R-imino esters can be
directly used for the following asymmetric Mannich-type
reactions by simply removing the polymer-supported amines.
We then conducted Mannich-type reaction of N-Boc-R-
imino ester 3a with silyl enol ether 4a as a model substrate
using a catalyst prepared from Cu(OTf)2 and diamine ligand
5a (Table 1, entry 1).1e,f The reaction was found to go to
m,m-Me2C6H3 (5c)
o-MeC6H4 (5d )
p-MeOC6H4 (5e)
o-MeOC6H4 (5f)
tBu (5g)
10
a Isolated yield from R-imino ester. b Determined by chiral HPLC
analysis. c Isolated yield from the corresponding 2-bromoglycine ester.
completion within 1 h at -20 °C to give the Mannich-type
adduct 6a in 97% yield with 84% ee. While the use of ethyl
R-imino ester 3b slightly improved the enantioselectivity
(entry 2), bulkier ester substituents resulted in lower enan-
tioselectivity (entries 3, 4). To improve the enantioselectivity,
several chiral diamine ligands were screened, and it was
revealed that most of the diamine ligands bearing substituted
benzyl groups on nitrogens such as 5b-e showed almost
the same enantioselectivity as 5a (entries 5-8). Interestingly,
N,N′-bis(o-methoxybenzyl)diamine ligand 5f was effective,
exhibiting higher enantioselectivity (91% ee, entry 9). Since
sterically similar ligand 5d (o-Me-substituted) or electroni-
cally similar ligand 5e (p-MeO-substituted) showed no
enhancement of the selectivity, we assume that coordination
of the o-methoxy oxygens of 5f to the copper may function
to control the enantioselective additions in the transition
states.10 On the other hand, N-tert-butyl-substituted diamine
5g showed only low selectivity (22% ee, entry 10).11
To extend the applicability of the reaction, R-imino esters
bearing other readily removable carbamates such as N-Cbz-
(3e), N-Troc- (3f), or N-Teoc-R-imino esters (3g) were then
investigated (Table 2). R-Imino esters 3e-g also reacted with
4a smoothly to give the Mannich-type adducts in high yields
with good enantioselectivity using the Cu(OTf)2-diamine 5f
complex. In all cases examined, the ligand 5f exhibited higher
enantioselectivity than 5a did.
(2) Only a few successful examples of catalytic enantioselective reactions
of imines bearing readily removable N-carbamates have been reported so
far. For Friedel-Crafts-type reactions of N-carbamate-protected R-imino
esters, see: (a) Sabby, S.; Bayon, P.; Aburel, P. S.; Jørgensen, K. A. J.
Org. Chem. 2002, 67, 4352. For Mannich-type reactions of N-Boc-imines
derived from aromatic aldehydes, see: (b) Wenzel, A. G.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 12964. For aziridinations of N-Boc- or
N-TcBoc-imines derived from aromatic aldehydes, see: (c) Aggarwal, V.
K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew.
Chem., Int. Ed. 2001, 40, 1433. See also: (d) Yao, S.; Saaby, S.; Hazell,
R. G.; Jørgensen, K. A. Chem. Eur. J. 2000, 6, 2435. In this paper, a
Mannich-type adduct was observed as a by-product in 37% ee in catalytic
asymmetric aza-Diels-Alder reaction of N-ethoxylcarbonyl R-imino ester
with Danishefsky’s diene.
(3) Lectka et al. have reported chiral Cu(I)-catalyzed Mannich-type
reactions using several N-sulfonyl-protected imines and deprotection of the
Mannich-type adducts; see: Ferraris, D.; Dudding, T.; Young, B.; Drurry,
W. J., III; Lectka, T. J. Org. Chem. 1999, 64, 2168.
(4) (a) Plieninger, H.; vor der Bruck, D. Tetrahedron Lett. 1968, 9, 4371.
(b) Jung, M. E.; Shishido, K.; Light, L.; Davis, L. Tetrahedron Lett. 1981,
22, 4607. See also ref 2a.
(5) (a) Kober, R.; Steglich, W. Liebigs Ann. Chem. 1983, 599. (b)
Bretschneider, T.; Miltz, W.; Munster, P.; Steglich, W. Tetrahedron 1988,
44, 5403 and references therein.
(6) Kobayashi, S.; Kitagawa, H.; Matsubara, R. J. Comb. Chem. 2001,
3, 401.
(7) For the synthesis of N-Cbz-R-bromoglycinates, see: Williams, R.
M.; Aldous, D. J.; Aldous, S. C. J. Org. Chem. 1990, 55, 4657.
(8) N-Teoc group can be easily deprotected by a fluoride ion or in mild
acidic conditions; see: ProtectiVe Groups in Organic Synthesis, 3rd ed.;
Greene, T. W., Wuts, P. G. M., Eds.; John Wiley & Sons: New York,
1999; p 512 and refs cited therein.
(9) N-Troc group can be easily deprotected by reduction with zinc; see:
ProtectiVe Groups in Organic Synthesis, 3rd ed.; Greene, T. W., Wuts, P.
G. M., Eds.; John Wiley & Sons: New York, 1999; p 510 and refs cited
therein.
As for nucleophiles, silyl enol ethers 4a-f derived from
aromatic ketones also reacted with 3b to afford the desired
(10) Buono et al. have reported the synthesis of a chiral phosphenium
compound bearing a N,N′-bis(o-methoxybenzyl)cyclohexane-1,2-diamine
moiety. They mentioned that coordination of the methoxy groups to the
cationic phosphorus atom played a key role on the stability of this species;
see: Brunel, J.-M.; Villard, R.; Buono, G. Tetrahedron Lett. 1999, 40, 4669.
(11) For the mechanism of this reaction, see ref 1f.
2482
Org. Lett., Vol. 5, No. 14, 2003