X.-M. Zhang et al.
values increased along with the increase of the size of the
alkyl groups in the substrates (Table 2, entries 21–23). Be-
sides, cyclic substrates 1t, 1u, and 1y provided poor enantio-
selectivities but very high diastereoselectivities (Table 2, en-
tries 19, 20, and 24). It seems that the rigidity of the sub-
strate is very unfavorable to the coordination between cata-
lyst and substrate.
To test the practicality of the current method for the syn-
thesis of b-amino esters, the asymmetric hydrosilylation of
b-enamino esters 1c in a gram-scale was carried out using
10 mol% of 2c. The reaction proceeded smoothly to provide
3c in 82% yield and 95% ee (1.0 g, 3.5 mmol of 1c). Fur-
thermore, the N-PMP (PMP=p-methoxyphenyl) group of
product 3c was deprotected with CAN (CAN=ceric ammo-
nium nitrate) to give b-amino ester 5 in 65% yield without
racemization (Scheme 2). Fol-
Scheme 2. Gram-scale asymmetric hydrosilylation of 1c, deprotection of
the N-PMP group in product 3c and following protection of the amino
group with acetic group. ee for 3i given in parentheses is after a single re-
crystallization; determined by HPLC with a chiral AD-H column. [a]D20
=
À79.5 (c=0.6 in CHCl3, 99% ee); literature:[3n] [a]D20 =À79.9 (c=1.0 in
CHCl3, S, 99% ee).
lowing acetylation of the amino
group of
5
generated the
known compound N-acetyl b-
aminoester 3i.[3n] The absolute
configuration of 3c was deter-
mined as S by measurement of
the optical rotation value of
compound 3i.
Although detailed structural
and mechanistic studies remain
to be carried out, based on
these facts, we propose a mech-
anism shown in Scheme 3. First,
it is supposed that the reaction
proceeds through the imine tau-
tomer rather than the enamine
tautomer. The nitrogen atom of
the pyridine ring and the car-
Scheme 3. A plausible reaction mechanism for hydrosilylation of 1c catalyzed by 2c.
bonyl oxygen atom of catalyst
to a solution of the catalyst (0.02mmol) and the corresponding b-enami-
no ester (0.20 mmol) in dry CHCl3 (2mL) at À308C. The reaction mix-
ture was stirred at À308C for 48 h. Then the reaction was quenched with
saturated aqueous solution of NaHCO3. The mixture was extracted with
EtOAc, and the combined extracts was washed with brine and dried over
anhydrous MgSO4. Concentration in vacuo followed by flash chromatog-
raphy on silica gel with petroleum ether/ethyl acetate as the eluent af-
forded the b-amino esters. The ee values were determined using estab-
lished HPLC techniques with chiral stationary phases.
2c are coordinated to Cl3SiH. Meanwhile, the imine is acti-
vated by the hydroxy group of 2c through hydrogen bond-
ing. The less hindered transition state A is consistent with
the experimentally observed si-facial selectivity of the reac-
tion. It can also be hypothesized that A will be stabilized by
arene–arene interactions between the aromatic systems of
the catalyst and the substrate.
In summary, we have demonstrated the first general,
highly enantioselective Lewis base organocatalyzed hydrosi-
lylation of b-enamino esters that enables the straightforward
and mild synthesis of a broad range of b-amino acid deriva-
tives in high yields (up to 97%) and enantioselectivities (up
to 96% ee). The absolute configuration of product 3c has
been determined as S. Finally, a plausible mechanism has
been proposed. Detailed investigations of the mechanism
are in progress.
Acknowledgements
We are grateful for the financial support from National Sciences Founda-
tion of China (20572109 and 20772122) and Sichuan Youth Science and
Technology Foundation.
Keywords: amino acids
·
asymmetric synthesis
·
hydrosilylation · lactams · organocatalysis
Experimental Section
General procedure for asymmetric hydrosilylation of N-aryl b-enamino
esters: Trichlorosilane (41 mL, 0.40 mmol, 2.0 equiv) was added dropwise
[1] a) C. N. Drey in Chemistry and Biochemistry of the Amino Acids
(Ed.: G. C. Barrett), Chapman and Hall, New York, 1985, Chapter 3;
9866
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9864 – 9867