Catalytic enantioselective addition of propionate units to imines: An efficient synthesis of anti-α-methyl-β-amino acid derivatives

Article abstract of DOI:10.1002/1521-3765(20020916)8:18<4185::AID-CHEM4185>3.0.CO;2-6

Optically active anti-α-methyl-β-amino acid derivatives have been prepared based on catalytic enantioselective addition of propionate units to simple and inert imines using a chiral zirconium complex. High reactivity and selectivity with wide substrate sc

Full text of DOI:10.1002/1521-3765(20020916)8:18<4185::AID-CHEM4185>3.0.CO;2-6

FULL PAPER
Catalytic Enantioselective Addition of Propionate Units to Imines:
An Efficient Synthesis of anti-a-Methyl-b-Amino Acid Derivatives
Shu Kobayashi,* Jun Kobayashi, Haruro Ishiani, and Masaharu Ueno[a]
≈
Abstract: Optically active anti-a-methyl-b-amino acid derivatives have been pre-
pared based on catalytic enantioselective addition of propionate units to simple and
inert imines using a chiral zirconium complex. High reactivity and selectivity with
wide substrate scope were attained by using a new chiral ligand, (R)-6,6'-bis(penta-
fluoroethyl)-1,1'-bi-2-naphthol ((R)-6,6'-C2F5BINOL). The reactions using geometri-
cally isomeric ketene silyl acetals gave excellent anti-selectivity with high enantio-
meric excess in both cases. Synthetic utility of this reaction has been demonstrated by
the preparation of various anti-a-methyl-b-amino acid and trans-3,4-disubstituted b-
lactam derivatives.
Keywords: asymmetric catalysis
¥
b-amino acids ¥ BINOL derivatives
¥ Mannich reactions ¥ zirconium
synthesis of a-methyl-b-amino acid derivatives based on
catalytic enantioselective Mannich reactions of simple imines
with propionate units using a chiral zirconium complex.
Introduction
a-Methyl-b-hydroxy units are often observed in biologically
important compounds such as macrolides, polyethers, carbo-
hydrates, and several excellent methods for the preparation of
these units based on asymmetric catalysis have been devel-
oped.[1] On the other hand, the corresponding aza analogues,
a-methyl-b-amino units as shown in Scheme 1, are also
Results and Discussion
We first tested the reaction of aldimine 2a with ketene silyl
acetal 3(E) in the presence of 10 mol% chiral zirconium
catalyst 1a, which was prepared from Zr(OtBu)4, (R)-6,6'-
dibromo-1,1'-bi-2-naphthol ((R)-6,6'-BrBINOL), and N-
methylimidazole (NMI). The catalyst was known to be
effective in similar Mannich reactions of a-unsubstituted, a-
alkoxy, and a,a-dialkylsubstituted ketene silyl acetals with
imines.[13] The reaction proceeded smoothly in dichlorome-
thane at À458C to afford the corresponding a-methyl-b-
amino ester 4a in 94% yield with high anti-selectivity;
however, the enantiomeric excess of the anti-adduct was
proven to be less than 50% (Table 1, entry 1). When the
reaction was carried out at À788C, a slight increase in
enantioselectivity was observed (66% ee), albeit the yield and
diastereoselectivity were decreased.
To improve both reactivity and selectivity, we then searched
for more efficient ligands in this reaction. In previous
investigations, we have revealed that introduction of two
halogen atoms at the 6,6'-positions of BINOL derivatives was
very effective; namely, Lewis acidity of the zirconium was
increased by introducing electron-withdrawing groups at the
6,6'-positions of BINOLs.[13c] As one of the strongest electron-
withdrawing groups, we chose a pentafluoroethyl group, so
that (R)-6,6'-bis(pentafluoroethyl)-1,1'-bi-2-naphthol ((R)-
6,6'-C2F5BINOL) was designed as a new chiral ligand. The
OH
OH
OH
OH
CO2R2
CO2R2
CO2R2
CO2R2
CO2R2
CO2R2
CO2R2
CO2R2
R1
R1
R1
R1
NH2
NH2
NH2
NH2
R1
R1
R1
R1
Scheme 1. a-Methyl-b-hydroxy units and their aza analogues.
observed in nature such as biologically active peptides of
marine origin, for example nodularin,[2] onchidin,[3] majuscu-
lamide C.[4] In addition, these units are potentially valuable
for preparation of peptidomimetics,[5] and have also success-
fully been used as intermediates for synthesis of substituted b-
lactams,[6] which are candidates for pharmaceutically active
compounds. However, examples of catalytic enantioselective
methods for the preparation of these units have been
limited.[7 12] In this paper, we describe an efficient asymmetric
[a] Prof. Dr. S. Kobayashi, J. Kobayashi, Dr. H. Ishiani, Dr. M. Ueno
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (‡81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
Chem. Eur. J. 2002, 8, No. 18
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S. Kobayashi et al.
FULL PAPER
Table 2. Catalytic diastereo- and enantioselective Mannich reactions of
various aldimines 2a i with ketene silyl acetal 3(E).
reaction of 2a with 3(E) was performed using 10 mol% of
new catalyst 1b prepared from Zr(OtBu)4, (R)-6,6'-C2F5BI-
NOL, and NMI. It was found that catalyst 1b showed
significantly higher enantioselectivity (84% ee) at À458C
compared with catalyst 1a, and finally, the best result (96%
yield, syn/anti 4:96, anti 95% ee) was obtained when the
OH
NH
HO
OSiMe3
O
N
catalyst 1b (10 mol%)
R2
R1
OPh
R2
+
OPh
R1
H
CH2Cl2, 24-40 h
2a-e (R2 = H)
4a-e (R2 = H)
3(E)
X
X
2f-i (R2 = Me)
4f-i (R2 = Me)
NMI
Zr
O
O
O
O
R1
T [8C] Yield [%] dr (syn/anti) ee (anti) [%]
1Ph (
2a)
À 78
À 78
À 45
À 78
À 45
À 45
À 45
96
4/96
87
84
7/93
95
NMI
2[a] p-ClPh (2b)
815/95
816/94
78
9129/7185
88
87
93
54
X
X
3
o-MePh (2c)
4[a] 1-naphthyl (2d)
1a: X = Br
1b: X = C2F5
80
5
2-furyl (2e)
6[a,b] iC4H9 (2 f)
7[a,b] nC5H11 (2g)
11/89
8/92
2/98
96
93
93
90
reaction was carried out at À788C (entry 4).[14] It is noted that
the introduction of the pentafluoroethyl group increases not
only reactivity but also diastereo- and enantioselectivity of the
reaction.[15] In addition, it was interesting from a mechanistic
point of view that the reaction using geometrically isomeric
ketene silyl acetal 3(Z) also gave excellent anti-selectivity, and
that the enantiomeric excess of the anti-adduct was 83%
(entry 5).
8[a,b] TBSO(CH2)2 (2h) À 45
9[a,b] c-C6H11 (2i)
À 20
23/77
[a] 10 mol% of NMI was used. [b] The aldimine was prepared from the
corresponding aldehyde and 2-amino-m-cresol in situ in the presence of
MgSO4.
OR1
NH2
O
b)
NH
O
Ph
OMe
Table 1. Catalytic diastereo- and enantioselective Mannich reaction of
OR2
aldimine 2a with ketene silyl acetal 3(E).
Ph
6
OH
NH
HO
4a (R1 = H, R2 = Ph)
a)
(R1 = Me, R2 = Me)
OH
OSiMe3
5
O
N
catalyst 1 (10 mol%)
OPh
+
Ph
OPh
Ph
H
CH2Cl2, 24-40 h
Boc
3(E)[a]
NH
O
2a
4a
d)
NH
O
OMe
X
T [8C]
Yield [%]
94
dr (syn/anti)
ee (anti) [%]
OR
1Br
2
3
4
5[b]
À 45
À 78
À 45
À 78
À 78
9/9147
13/87
7/93
4/96
1/99
8
Br
52
92
96
quant.
66
84
95
83
4f (R = Ph)
7 (R = Me)
c)
C2F5
C2F5
C2F5
Scheme 2. Conversion of the Mannich adducts to a-methyl-b-amino acid
derivatives. a) 1) K2CO3, MeOH; 2) K2CO3, MeI/acetone, 78% (two
steps); b) AgNO3, (NH4)2S2O8, CH3CN/H2O, 70%; c) K2CO3, MeOH,
95%; d) 1) CAN, CH3CN/H2O; 2) Boc2O, CH2Cl2, 44% (two steps).
[a] E/Z 96:4. [b] 3(Z) (E/Z 22:78) was used.
We then examined reactions of other aldimines, and the
results are summarized in Table 2. In most cases, the reactions
proceeded smoothly to give the desired a-methyl-b-amino
esters in good yields with high anti-selectivity and excellent
enantioselectivity.[16] Catalyst 1b was effective in the reactions
of not only aromatic imines but also aliphatic imines. It is
noted that in some cases better yields and selectivity were
obtained in the presence of 10 mol% of NMI (entries 2, 4, 6
9). In the reactions of aliphatic substrates, aldimines were
prepared in situ from the corresponding aldehydes and
2-amino-m-cresol instead of 2-aminophenol.[13a] It is also
noteworthy that aliphatic substrates gave excellent yields and
selectivity in most cases.
comparison of the NMR data and the optical rotation with
those in the literature.[18] On the other hand, Mannich adduct
4 f was also converted to N-Boc-anti-a-methyl-b-amino ester
8 by transesterification and deprotection with cerium ammo-
nium nitrate (CAN)[19] followed by Boc protection of the
amino group. The absolute stereochemistry was established to
be (2R,3R) by comparison of the NMR data and the optical
rotation with those of the authentic sample prepared from
Boc-d-leucine.[5b]
Finally, to demonstrate the synthetic utility of this Mannich
reaction, we performed asymmetric synthesis of anti-a-
methyl-b-amino acid and b-lactam derivatives, which are
included in biologically important natural products. As shown
in Scheme 3, the reaction of the aldimine prepared from
5-hexynal (9) and 2-amino-m-cresol with ketene silyl acetal
3(E) gave the desired Mannich adduct 10 in 93% yield and
high stereoselectivity (syn/anti 7:93, anti 97% ee). Trans-
esterification of 10 followed by isolation of a single diaste-
reoisomer and deprotection of the amino group with CAN[19]
Relative and absolute configurations of the Mannich
adducts were determined after converting to useful a-
methyl-b-amino acid derivatives (Scheme 2). Transesterifica-
tion of the Mannich adduct 4a followed by methylation of the
phenolic OH and deprotection using catalytic AgNO3 in the
[17]
presence of excess (NH4)2S2O8 gave b-amino ester 6. The
absolute configuration of 6 was determined to be (2R,3S) by
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Chem. Eur. J. 2002, 8, No. 1 8

Catalytic Enantioselective Addition
4185 4190
afforded (2R,3R)-methyl 3-amino-2-methyl-7-octynoate
(AMO methyl ester) (12).[20] A new b-amino acid, AMO, is
one of the units of onchidin,[3] a cytotoxic cyclic depsipeptide
from marine mollusc.
Conclusion
In summary, we have developed an efficient method for the
preparation of anti-a-methyl-b-amino acid derivatives based
on highly diastereo- and enantioselective Mannich reactions
using a novel chiral zirconium catalyst. This is indeed the first
example of catalytic enantioselective Mannich reactions of
simple and inert aldimines with propionate units, while many
examples of catalytic enantioselective aldol reactions of
aldehydes with propionate units have been developed. It is
noted that several interesting features have been revealed in
this novel aldimine propionate condensation compared with
aldehyde propionate condensations. Synthetic utility of this
reaction has been demonstrated for the preparation of various
anti-a-methyl-b-amino acid and trans-3,4-disubstituted b-
lactam derivatives, which are included in biologically impor-
tant compounds. This procedure will also be applied to
synthesis of nitrogen-containing analogues of a-methyl-b-
hydroxy units, which are important components of macrolide
antibiotics derived from propionyl-CoA.
OH
OSiMe3
O
+
+
OPh
3(E)
NH2
H
9
OH
NH
a)
O
OPh
10: 93% yield, syn/anti 7:93
97% ee (anti)
b)
OH
NH2
O
c)
NH
O
OMe
OMe
12
11
Scheme 3. Synthesis of (2R,3R)-AMO methyl ester. a) catalyst 1b
(10 mol%), MgSO4, CH2Cl2, À458C, 24 h; b) K2CO3, MeOH, 91%;
c) CAN, CH3CN/H2O, 54%.
Experimental Section
General: Melting points were uncorrected. Optical rotations were recorded
on a JASCO P-1010 digital polarimeter. IR spectra were recorded on a
Furthermore, the Mannich reaction of 3-benzyloxypropa-
nal (13), 2-amino-m-cresol, and ketene silyl acetal 14(E)
derived from phenyl butanoate also proceeded smoothly in
high yield and high diastereo- and enantioselectivity
(Scheme 4). Deprotection of the Mannich adduct 15 and
isolation of an anti-isomer gave b-amino ester 16, which was
cyclized smoothly using lithium diisopropylamide (LDA)[21]
followed by cleavage of O-benzyl bond with Pd(OH)2/C
under hydrogen atmosphere to afford (3R,4R)-b-lactam 18.[22]
Since 18 has previously been converted to carbapenem
antibiotic (‡)-PS-5,[23, 24] this method provides a highly
efficient asymmetric synthetic route to (‡)-PS-5.
1
JASCO FT/IR-610 infrared spectrometer. H and 13C NMR spectra were
recorded on a JEOL JNM-LA300, JNM-LA400, or JNM-LA500 spec-
trometer in CDCl3. Tetramethylsilane (TMS) served as internal standard
1
(d ˆ 0) for H NMR, and CDCl3 was used internal standard (d ˆ 77.0) for
13C NMR. High performance liquid chromatography (HPLC) was carried
out using following apparatuses: liquid chromatograph SHIMADZU LC-
10AT, UV-VIS detector SHIMADZU SPD-10A, and chromatopac SHI-
MADZU C-R6A or C-R8A. Column chromatography was performed on
Silica gel 60 (Merck) and preparative thin-layer chromatography was
carried out using Wakogel B-5F. Dichloromethane was distilled from P2O5,
then from CaH2, and dried over MS 4 ä. Aldimines of aromatic aldehydes
and heteroaromatic aldehydes were prepared from the corresponding
aldehyde and 2-aminophenol by usual methods. The crude aldimines were
recrystallized from ethanol to give the pure materials. Ketene silyl acetals
3(E),[25] 3(Z),[26] and 14(E)[25] were prepared according to the literature. All
other solvents and chemical compounds were purified based on standard
procedures.
OH
OSiMe3
O
OPh
+
+
NH2
BnO
H
Diastereo- and enantioselective Mannich reactions of aromatic imines with
ketene silyl acetals using a chiral zirconium catalyst: A typical experimen-
tal procedure is described for the reaction of aldimine 2a with ketene silyl
acetal 3(E). Zr(OtBu)4 (0.04 mmol) in dichloromethane (0.25 mL) and N-
methylimidazole (0.08 mmol) in dichloromethane (0.25 mL) were added at
room temperature to a solution of (R)-6,6'-bis(pentafluoroethyl)-1,1'-bi-2-
naphthol (0.088 mmol) in dichloromethane (0.5 mL). The mixture was
stirred for 1h at the same temperature and then cooled to À788C.
Dichloromethane solutions (1.5 mL) of 2a (0.4 mmol) and 3(E)
(0.48 mmol) were successively added. The mixture was stirred for 24 h,
and saturated aqueous NaHCO3 was then added to quench the reaction.
The aqueous layer was extracted with dichloromethane, and the crude
adduct was treated with THF/1n HCl (10:1) at 08C for 30 min. After a
usual work-up, the crude product was chromatographed on silica gel to give
the desired adduct 4a. The diastereomer ratio was determined by 1H NMR
analysis, and the optical purity was determined by HPLC analysis using a
chiral column (see below).
13
14(E)
OH
NH
a)
O
BnO
OPh
15: 89% yield, syn/anti 4:96
97% ee (anti)
NH2
O
O
HN
c)
b)
BnO
OPh
BnO
H
H
16
17
H
H
N
O
HN
d)
S
NHAc
HO
O
Diastereo- and enantioselective Mannich reactions of aliphatic imines with
ketene silyl acetals using a chiral zirconium catalyst: A typical experimen-
tal procedure is described for the reaction of aldimine 2f with ketene silyl
acetal 3(E). Isovaleraldehyde (0.48 mmol) in dichloromethane (0.4 mL)
H
H
CO2H
(+)-PS-5
18
Scheme 4. Formal synthesis of the antibiotic (‡)-PS-5. a) catalyst 1b
(10 mol%), MgSO4, CH2Cl2, À458C, 24 h; b) CAN, CH3CN/H2O, 78%;
c) LDA, THF, 55%; d) Pd(OH)2/C, H2, EtOH, 82%.
was added at room temperature to
a mixture of 2-amino-m-cresol
(0.40 mmol) and MgSO4 (200 mg) in dichloromethane (0.2 mL). The
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S. Kobayashi et al.
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mixture was stirred for 20 min at the same temperature and then cooled to
À458C. A dichloromethane solution (1.0 mL) of catalyst 1b (0.04 mmol)
prepared by the same procedure described above and dichloromethane
solution (0.4 mL) of 3(E) (0.48 mmol) were successively added. The
mixture was stirred for 24 h, and saturated aqueous NaHCO3 was then
added to quench the reaction. The aqueous layer was extracted with
dichloromethane, and the crude product was chromatographed on silica gel
to give the desired adduct 4 f. The diastereomer ratio was determined by
1H NMR analysis, and the optical purity was determined by HPLC analysis
using a chiral column (see below).
anti: tR ˆ 15.5 min (minor ˆ 2S,3R), tR ˆ 29.8 min (majorˆ 2R,3S); syn:
tR ˆ 17.8 min (minorˆ 2R,3R), tR ˆ 42.9 min (majorˆ 2S,3S); elemental
analysis calcd (%) for C23H23NO3: C 76.43, H 6.41, N 3.88; found: C
76.19, H 6.71, N 3.78.
Phenyl
3-(2-hydroxyphenyl)amino-2-methyl-3-(1-naphthyl)propanoate
(4d) (syn/anti 3:97): IR (neat): nÄ ˆ 3420, 3056, 1737, 1610, 1589, 1514,
738, 691cm À1
;
1H NMR (CDCl3): anti: d ˆ 1.38 (d, J ˆ 6.8 Hz, 3H), 3.39
(dq, J ˆ 6.8, 7.1Hz, 1H), 5.47 (d, J ˆ 7.1Hz, 1H), 6.30 6.63 (m, 4H), 6.87
7.87 (m, 11H), 8.22 (d, J ˆ 8.3 Hz, 1H); syn: d ˆ 1.21 (d, J ˆ 7.1Hz, 3H),
3.52 (dq, J ˆ 4.1, 7.1 Hz, 1 H), 5.84 (d, J ˆ 4.1Hz, 1H), 6.30 6.63 (m, 4H),
6.87 7.87 (m, 11H), 8.35 (d, J ˆ 8.5 Hz, 1H); 13C NMR (CDCl3): anti: d ˆ
15.7, 46.6, 56.4, 113.2, 114.3, 117.9, 121.0, 121.5, 122.2, 123.7, 125.5, 125.7,
125.9, 126.4, 128.1, 129.3, 129.3, 131.5, 133.9, 135.4, 136.7, 144.1, 150.3, 174.5;
syn: d ˆ 10.2, 44.3, 55.5, 113.0, 114.3, 117.7, 121.1, 121.6, 122.3, 124.4, 125.5,
125.6, 125.9, 126.6, 128.1, 129.3, 129.4, 130.6, 134.1, 135.6, 136.7, 143.5, 150.7,
173.4; HPLC (Daicel Chiralpak AD, hexane/iPrOH 19:1, flow rate ˆ
1.0 mLminÀ1): anti: tR ˆ 43.7 min (minorˆ 2S,3R), tR ˆ 53.4 min (majorˆ
2R,3S); syn: tR ˆ 28.3 min (minorˆ 2R,3R), tR ˆ 32.2 min (majorˆ 2S,3S);
elemental analysis calcd (%) for C26H23NO3: C 78.57, H 5.83, N 3.52; found:
C 78.28, H 6.12, N 3.42.
(R)-6,6'-Bis(pentafluoroethyl)-1,1'-bi-2-naphthol ((R)-6,6'-C2F5BINOL):
We previously reported that (R)-2,2'-bis(methoxymethyloxy)-6,6'-bis(pen-
tafluoroethyl)-1,1'-binaphthyl (MOM-(R)-6,6'-C2F5BINOL) was prepared
from (R)-2,2'-bis(methoxymethyloxy)-6,6'-diiodo-1,1'-binaphthyl (MOM-
(R)-6,6'-IBINOL).[15b] A saturated HCl methanolic solution (8.0 mL) was
added at 08C to
a solution of MOM-(R)-6,6'-C2F5BINOL (3.50 g,
5.7 mmol) in CH2Cl2 (5.0 mL). After 30 min the resulting solution was
diluted with water and extracted with CH2Cl2. The combined organic layer
was washed with water and sat. aq. NaHCO3, and dried over Na2SO4. After
evaporation of the solvents the residue was purified by chromatography on
silica gel (hexane/CH2Cl2 1:2) to afford (R)-6,6'-C2F5BINOL (2.87 g, 96%).
[a]1D9 ˆ À23.2 (c ˆ 1.05, CHCl3); M.p. 87 898C; IR (KBr): nÄ ˆ 3460, 1613,
Phenyl 3-(2-furyl)-3-(2-hydroxyphenyl)amino-2-methylpropanoate (4e)
(syn/anti 29:71): IR (neat): nÄ ˆ 3412, 1737, 1603, 1515, 1445, 741,
1478, 1208, 1132 cmÀ1
;
1H NMR (CDCl3): d ˆ 5.28 (s, 2H), 7.21(d, J ˆ
694 cmÀ1
;
1H NMR (CDCl3): anti: d ˆ 1.26 (d, J ˆ 7.1Hz, 3H), 3.31(dq,
8.8 Hz, 2H), 7.43 (d, J ˆ 9.1Hz, 2H), 7.45 (d, J ˆ 8.8 Hz, 2H), 8.06 (d, J ˆ
9.1Hz, 2H), 8.19 (s, 2H); 13C NMR (CDCl3): d ˆ 110.6, 113.6 (tq, J ˆ 38.3,
253.5 Hz), 119.2 (tq, J ˆ 39.6, 285.9 Hz), 119.3, 124.2 (t, J ˆ 5.7 Hz), 124.5 (t,
J ˆ 24.3 Hz), 124.9, 127.8 (t, J ˆ 6.7 Hz), 128.4, 132.6, 135.0, 154.6; 19F NMR
(283 MHz, CF3COOH: d ˆ À76.5, CDCl3): d ˆ À114.5 (4F), À84.85 (6F);
elemental analysis calcd (%) for C24H12F10O2: C 55.19, H 2.32; found: C
55.09, H 2.55.
J ˆ 7.1, 9.0 Hz, 1 H), 4.56 (d, J ˆ 9.0 Hz, 1H), 6.15 6.76 (m, 6H), 7.06 7.09
(m, 2H), 7.30 7.40 (m, 4H); syn: d ˆ 1.39 (d, J ˆ 7.1Hz, 3H), 3.36 (dq, J ˆ
5.9, 7.1Hz, 1H), 4.96 (d, J ˆ 5.9 Hz, 1H), 6.15 6.76 (m, 6H), 6.93 6.96 (m,
2H), 7.30 7.40 (m, 4H); 13C NMR (CDCl3): anti: d ˆ 14.2, 44.4, 56.1, 108.2,
110.1, 114.6, 114.8, 116.9, 120.5, 121.4, 125.9, 129.4, 134.1, 142.1, 146.4, 150.5,
152.7, 174.3; syn: d ˆ 12.6, 44.2, 54.8, 107.4, 110.2, 114.2, 115.2, 119.0, 121.0,
121.4, 125.8, 129.3, 135.2, 141.9, 144.6, 150.5, 153.7, 173.0; HPLC (Daicel
Chiralpak AD (double), hexane/iPrOH 9:1, flow rateˆ 0.80 mLminÀ1):
anti: tR ˆ 33.4 min (majorˆ 2R,3S), tR ˆ 39.2 min (minorˆ 2S,3R); syn:
tR ˆ 31.4 min (majorˆ 2S,3S), tR ˆ 44.8 min (minorˆ 2R,3R); elemental
analysis calcd (%) for C20H19NO4: C 71.20, H 5.68, N 4.15; found: C 70.91,
H 5.98, N 4.09.
Phenyl 3-(2-hydroxyphenyl)amino-2-methyl-3-phenylpropanoate (4a)
(syn/anti 4:96): IR (neat): nÄ ˆ 3420, 3053, 1739, 1604, 1517, 742, 701 cmÀ1
;
1H NMR (CDCl3): anti: d ˆ 1.24 (d, J ˆ 7.0 Hz, 3H), 3.12 (dq, J ˆ 7.0,
8.7 Hz, 1H), 4.55 (d, J ˆ 8.7 Hz, 1H), 6.44 6.69 (m, 4H), 6.98 7.00 (m,
2H), 7.13 7.44 (m, 8H); syn: d ˆ 1.36 (d, J ˆ 7.1Hz, 3H), 3.24 (dq, J ˆ 6.0,
7.1Hz, 1H), 4.89 (d, J ˆ 6.0 Hz, 1H), 6.44 6.69 (m, 4H), 6.81 6.83 (m,
2H), 7.13 7.44 (m, 8H); 13C NMR (CDCl3): anti: d ˆ 15.2, 47.0, 61.7, 114.5,
114.9, 118.8, 120.9, 121.5, 126.0, 127.1, 127.7, 128.6, 129.4, 135.0, 140.6, 144.9,
150.5, 174.6; syn: d ˆ 12.4, 46.7, 60.7, 113.2, 114.3, 117.8, 121.2, 121.4, 125.9,
127.1, 127.5, 128.6, 129.3, 135.7, 140.6, 143.7, 150.4, 173.2; HPLC (Daicel
Phenyl 2,5-dimethyl-3-(2-hydroxy-6-methylphenyl)aminohexanoate (4 f)
(syn/anti 9:91): IR (neat): nÄ ˆ 3369, 2953, 2868, 1740, 1590, 1492, 740,
689 cmÀ1; 1H NMR (CDCl3): anti: d ˆ 0.85 (d, J ˆ 6.6 Hz, 3H), 0.87 (d, J ˆ
6.3 Hz, 3H), 1.38 (d, J ˆ 7.1 Hz, 3H), 1.40 1.49 (m, 1 H), 1.62 1.76 (m,
1H), 2.29 (s, 3H), 2.85 (dq, J ˆ 5.7, 7.1Hz, 1H), 3.77 (dt, J ˆ 5.7, 7.3 Hz, 1H),
6.66 7.39 (m, 8H); syn: d ˆ 0.88 (d, J ˆ 6.3 Hz, 3H), 0.92 (d, J ˆ 6.6 Hz,
3H), 1.34 (d, J ˆ 7.3 Hz, 3H), 1.40 1.49 (m, 1 H), 1.62 1.76 (m, 1 H), 2.28
(s, 3H), 2.93 (dq, J ˆ 2.8, 7.3 Hz, 1H), 3.69 (dt, J ˆ 2.8, 6.8 Hz, 1H), 6.66
7.39 (m, 8H); 13C NMR (CDCl3): anti: d ˆ 13.2, 18.4, 22.4, 23.2, 25.1, 43.3,
44.2, 56.0, 113.4, 121.4, 122.5, 123.1, 125.9, 129.4, 130.7, 132.5, 149.8, 150.5,
175.0; syn: d ˆ 10.9, 18.2, 22.5, 22.9, 25.1, 41.1, 41.8, 56.1, 113.6, 121.4, 122.2,
124.1, 126.0, 129.4, 131.4, 132.4, 150.5, 151.4, 174.7; HPLC (Daicel
Chiralpak AD (double), hexane/iPrOH 9:1, flow rateˆ 0.80 mLminÀ1):
anti: tR ˆ 17.9 min (minorˆ 2S,3S), tR ˆ 19.2 min (majorˆ 2R,3R); syn:
tR ˆ 20.5 min (majorˆ 2S,3R), tR ˆ 31.8 min (minorˆ 2R,3S); elemental
analysis calcd (%) for C21H27NO3: C 73.87, H 7.97, N 4.10; found: C 74.10, H
7.78, N 4.26.
Chiralcel OD-H, hexane/iPrOH 19:1, flow rate ˆ 0.75 mLminÀ1): anti: tR
ˆ
18.0 min (minorˆ 2S,3R), tR ˆ 35.4 min (majorˆ 2R,3S); syn: tR ˆ 23.3 min
(minorˆ 2R,3R), tR ˆ 44.9 min (majorˆ 2S,3S); elemental analysis calcd
(%) for C22H21NO3: C 76.06, H 6.09, N 4.03; found: C 76.14, H 6.27, N 3.98.
Phenyl
3-(4-chlorophenyl)-3-(2-hydroxyphenyl)amino-2-methylpropa-
noate (4b) (syn/anti 5:95): IR (neat): nÄ ˆ 3419, 3055, 1739, 1611, 1589,
1515, 740, 689 cmÀ1
;
1H NMR (CDCl3): anti: d ˆ 1.26 (d, J ˆ 7.1Hz, 3H),
3.08 (dq, J ˆ 7.1, 8.4 Hz, 1 H), 4.53 (d, J ˆ 8.4 Hz, 1H), 6.39 6.67 (m, 4H),
6.98 7.01(m, 2H), 7.14 7.35 (m, 7H); syn: d ˆ 1.32 (d, J ˆ 6.9 Hz, 3H),
3.19 (dq, J ˆ 6.0, 6.9 Hz, 1H), 4.88 (d, J ˆ 6.0 Hz, 1H), 6.39 6.67 (m, 4H),
6.83 6.86 (m, 2H), 7.14 7.35 (m, 7H); 13C NMR (CDCl3): anti: d ˆ 15.1,
46.8, 61.0, 114.6, 114.7, 119.0, 121.0, 121.4, 126.0, 128.3, 128.8, 129.4, 133.3,
134.7, 139.2, 144.7, 150.4, 174.2; syn: d ˆ 12.2, 46.4, 59.5, 114.3, 114.7, 118.0,
121.0, 121.3, 126.0, 128.3, 128.7, 129.4, 133.2, 135.3, 139.1, 143.5, 150.3, 172.9;
HPLC (Daicel Chiralcel OD, hexane/iPrOH 19:1, flow rate ˆ
1.0 mLminÀ1): anti: tR ˆ 19.2 min (minorˆ 2S,3R), tR ˆ 35.4 min (majorˆ
2R,3S); syn: tR ˆ 22.8 min (minorˆ 2R,3R), tR ˆ 44.0 min (majorˆ 2S,3S);
elemental analysis calcd (%) for C22H20ClNO3: C 69.20, H 5.28, N 3.67;
found: C 69.35, H 5.51, N 3.57.
Phenyl 3-(2-hydroxy-6-methylphenyl)amino-2-methyloctanoate (4g) (syn/
anti 9:91): IR (neat): nÄ ˆ 3368, 2930, 2857, 1742, 1590, 1492, 741, 689 cmÀ1
;
1H NMR (CDCl3): anti: d ˆ 0.86 (t, J ˆ 6.8 Hz, 3H), 1.17 1.58 (m, 8H),
1.40 (d, J ˆ 7.1Hz, 3H), 2.27 (s, 3H), 2.88 (dq, J ˆ 6.8, 7.1Hz, 1H), 3.55
3.61(m, 1H), 6.66 7.39 (m, 8H); syn: d ˆ 0.86 (t, J ˆ 6.8 Hz, 3H), 1.17
1.58 (m, 8H), 1.36 (d, J ˆ 7.3 Hz, 3H), 2.28 (s, 3H), 2.97 (dq, J ˆ 2.9, 7.3 Hz,
1H), 3.55 3.61 (m, 1H), 6.66 7.39 (m, 8H); 13C NMR (CDCl3): anti: d ˆ
13.9, 14.2, 18.2, 22.5, 24.7, 32.0, 32.0, 43.6, 58.2, 113.6, 115.3, 121.4, 122.2,
123.5, 125.9, 129.4, 131.0, 132.3, 150.5, 175.6; syn: d ˆ 10.7, 13.9, 18.1, 22.5,
26.4, 31.7, 31.8, 41.6, 58.3, 113.4, 117.5, 121.4, 122.1, 124.3, 126.0, 129.4, 131.3,
132.6, 151.7, 174.7; HPLC (Daicel Chiralcel OD-H (double), hexane/iPrOH
19:1, flow rate ˆ 0.40 mLminÀ1): anti: tR ˆ 41.7 min (majorˆ 2R,3R), tR ˆ
45.0 min (minorˆ 2S,3S); syn: tR ˆ 38.8 min (majorˆ 2S,3R), tR ˆ 48.1min
(minorˆ 2R,3S); elemental analysis calcd (%) for C22H29NO3: C 74.33, H
8.22, N 3.94; found: C 74.13, H 8.49, N 4.16.
Phenyl
3-(2-hydroxyphenyl)amino-2-methyl-3-(2-methylphenyl)propa-
noate (4c) (syn/anti 6:94): IR (neat): nÄ ˆ 3417, 1735, 1604, 1517, 1425,
741, 688 cmÀ1; 1H NMR (CDCl3): anti: d ˆ 1.28 (d, J ˆ 7.1Hz, 3H), 2.34 (s,
3H), 3.15 (dq, J ˆ 7.1, 8.8 Hz, 1 H), 4.81 (d, J ˆ 8.8 Hz, 1H), 6.31 6.66 (m,
4H), 6.98 7.00 (m, 2H), 7.11 7.35 (m, 7H); syn: d ˆ 1.33 (d, J ˆ 7.0 Hz,
3H), 2.49 (s, 3H), 3.20 (dq, J ˆ 5.3, 7.0 Hz, 1H), 5.20 (d, J ˆ 5.3 Hz, 1H),
6.31 6.66 (m, 4H), 6.80 6.82 (m, 2H), 7.11 7.35 (m, 7H); 13C NMR
(CDCl3): anti: d ˆ 15.1, 19.5, 46.6, 57.5, 114.6, 115.6, 119.5, 120.7, 121.5,
125.4, 126.0, 126.7, 127.2, 129.4, 130.5, 134.7, 136.0, 139.1, 145.6, 150.4, 174.9;
syn: d ˆ 11.6, 19.2, 44.8, 56.2, 114.4, 115.4, 119.5, 121.2, 121.4, 125.8, 126.2,
126.5, 127.2, 129.3, 130.8, 135.2, 135.7, 138.7, 145.6, 150.5, 173.5; HPLC
(Daicel Chiralcel OD-H, hexane/iPrOH 19:1, flow rate ˆ 0.75 mLminÀ1):
Phenyl 5-tert-butyldimethylsiloxy-3-(2-hydroxy-6-methylphenyl)amino-2-
methylpentanoate (4h) (syn/anti 2:98): IR (neat): nÄ ˆ 3369, 2936, 2863,
1746, 1590, 1469 cmÀ1
;
1H NMR (CDCl3): anti: d ˆ 0.08 (s, 3H), 0.09 (s,
4188
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0818-4188 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 1 8

Catalytic Enantioselective Addition
4185 4190
3H), 0.91(s, 9H), 1.37 (d, J ˆ 7.1 Hz, 3H), 1.63 1.71 (m, 1 H), 1.84 1.92
(m, 1H), 2.30 (s, 3H), 2.92 (dq, J ˆ 5.7, 7.1Hz, 1H), 3.78 3.83 (m, 1H),
3.86 3.96 (m, 2H), 6.65 7.38 (m, 8H); syn: d ˆ 0.10 (s, 3H), 0.11 (s, 3H),
0.91(s, 9H), 1.30 (d, J ˆ 7.3 Hz, 3H), 1.69 1.76 (m, 1 H), 1.84 1.92 (m,
1H), 2.30 (s, 3H), 2.99 (dq, J ˆ 2.7, 7.3 Hz, 1H), 3.78 3.83 (m, 1H), 3.93
4.03 (m, 2H), 6.65 7.38 (m, 8H); 13C NMR (CDCl3): anti: d ˆ À5.5, À5.4,
13.4, 18.3, 18.4, 25.9, 34.1, 43.7, 55.4, 60.4, 114.0, 121.4, 122.1, 123.3, 125.8,
129.3, 130.9, 132.4, 150.4, 150.5, 174.7; syn: d ˆ À5.4, À5.4, 12.8, 18.3, 18.3,
25.9, 33.2, 42.4, 56.6, 60.7, 113.9, 121.4, 121.9, 123.9, 126.0, 129.4, 131.7, 132.1,
150.4, 150.4, 174.0; HPLC (Daicel Chiralcel OD-H, hexane/iPrOH 100:1,
flow rate ˆ 1.0 mLminÀ1): anti: tR ˆ 24.2 min (minorˆ 2S,3S), tR ˆ 30.3 min
(majorˆ 2R,3R); syn: tR ˆ 17.9 min (majorˆ 2S,3R), tR ˆ 33.2 min (minor
ˆ 2R,3S); elemental analysis calcd (%) for C25H37NO4Si: C 67.68, H 8.41, N
3.16; found: C 67.64, H 8.49, N 3.19.
3H); 13C NMR (CDCl3): d ˆ 13.8, 18.3, 22.2, 23.2, 25.0, 43.8, 44.6, 51.8, 55.8,
113.6, 122.3, 122.8, 130.3, 132.7, 149.8, 177.2.
(2R,3R)-Methyl
3-(tert-butoxycarbonyl)amino-2,5-dimethylhexanoate
(8):[5b] Cerium ammonium nitrate (CAN)[19] (459 mg, 0.84 mmol) was
added at 08C to a solution of 7 (78 mg, 0.28 mmol) in a CH3CN/H2O (4:1 )
solution (3.5 mL). After being stirred for 20 min, the reaction mixture was
diluted with water and EtOAc, treated with K2CO3 to a pH of over 7.
Insoluble inorganic materials were filtered through a pad of celite and the
aqueous layer was extracted with EtOAc. The combined organic layer was
washed with 10% aq. Na2CO3, 10% aq. Na2SO3 and brine, and dried over
Na2SO4. Filtration and evaporation of solvents afforded (2R,3R)-methyl
3-amino-2,5-dimethylhexanoate as a crude mixture, which was dissolved in
CH2Cl2 (3.0 mL), followed by addition of Boc2O (183 mg, 0.84 mmol) in
CH2Cl2 (0.8 mL) at room temperature. After 4 h, solvents were removed
under reduced pressure and the crude product was chromatographed on
silica gel to afford N-Boc-b-amino ester 8 (34 mg, 44%). [a]2D3 ˆ ‡23.4 (c ˆ
1.42, CHCl3) (authentic sample of 8[5b] prepared according to the literature:
[a]2D1 ˆ ‡25.7 (c ˆ 1.43, CHCl3)); IR (neat): nÄ ˆ 3374, 2959, 2883, 1718,
1508, 1366, 1166 cmÀ1; 1H NMR (CDCl3): d ˆ 0.90 (d, J ˆ 6.6 Hz, 3H), 0.92
(d, J ˆ 6.3 Hz, 3H), 1.14 1.21 (m, 1 H), 1.20 (d,J ˆ 7.1Hz, 3H), 1.31 1.38
(m, 1 H), 1.44 (s, 8H, rotamer), 1.47 (s, 1 H, rotamer), 1.60 1.70 (m, 1 H),
2.59 2.69 (m, 1H), 3.68 (s, 3H), 3.80 3.87 (m, 1H), 4.72 (d, J ˆ 10.7 Hz,
0.1H, rotamer), 5.04 (d, J ˆ 10.0 Hz, 0.9H, rotamer); 13C NMR (CDCl3):
d ˆ 14.3, 22.0, 23.1, 24.9, 28.3, 43.0, 43.2, 50.6, 51.5, 78.9, 155.9, 175.8.
Phenyl 3-cyclohexyl-3-(2-hydroxy-6-methylphenyl)amino-2-methylpropa-
noate (4i) (syn/anti 27:73): IR (neat): nÄ ˆ 3378, 2923, 2851, 1738, 1590,
1492, 745, 689 cmÀ1; 1H NMR (CDCl3): anti: d ˆ 1.07 1.90 (m, 11 H), 1.37
(d, J ˆ 7.1Hz, 3H), 2.29 (s, 3H), 2.92 (dq, J ˆ 7.1, 8.3 Hz, 1 H), 3.74 (dd, J ˆ
3.3, 8.3 Hz, 1H), 6.65 6.82 (m, 3H), 7.00 7.03 (m, 2H), 7.19 7.36 (m, 3H);
syn: d ˆ 1.07 1.90 (m, 11 H), 1.36 (d,J ˆ 7.2 Hz, 3H), 2.28 (s, 3H), 3.00 (dq,
J ˆ 3.1, 7.2 Hz, 1 H), 3.70 (dd, J ˆ 3.1, 5.1 Hz, 1 H) 6.65 6.82 (m, 3H), 6.90
6.93 (m, 2H), 7.19 7.36 (m, 3H); 13C NMR (CDCl3): anti: d ˆ 15.5, 18.6,
26.5, 26.6, 26.7, 28.3, 29.6, 41.1, 43.2, 61.7, 114.8, 121.4, 122.1, 122.6, 126.0,
128.9, 129.4, 133.7, 149.1, 150.5, 176.6; syn: d 11.9, 18.6, 26.3, 26.5, 26.6, 30.2,
30.7, 41.2, 42.4, 61.6, 114.4, 121.4, 122.5, 122.8, 125.9, 129.4, 130.2, 133.3,
149.5, 150.8, 175.3; HPLC (Daicel Chiralcel OD-H (double), hexane/
iPrOH 24:1, flow rateˆ 0.60 mLminÀ1): anti: tR ˆ 35.4 min (majorˆ
2R,3R), tR ˆ 44.3 min (minor ˆ 2S,3S); syn: tR ˆ 33.2 min (majorˆ 2S,3R),
tR ˆ 40.5 min (minor ˆ 2R,3S); elemental analysis calcd (%) for
C23H29NO3: C 75.17, H 7.95, N 3.81; found: C 75.20, H 8.15, N 3.84.
Phenyl 3-(2-hydroxy-6-methylphenyl)amino-2-methyl-7-octynoate (10)
(syn/anti 7:93): IR (neat): nÄ ˆ 3366, 3299, 2942, 2863, 1739, 1489, 1458,
1
1190, 1161, 744, 688 cmÀ1; H NMR (CDCl3): anti: d ˆ 1.41 (d, J ˆ 7.2 Hz,
3H), 1.60 1.75 (m, 4H), 1.94 (t, J ˆ 2.6 Hz, 1H), 2.14 2.19 (m, 2H), 2.28
(s, 3H), 2.88 (dq, J ˆ 7.0, 7.2 Hz, 1H), 3.61 3.67 (m, 1H), 6.66 6.93 (m,
3H), 7.06 7.40 (m, 5H); syn: d ˆ 1.38 (d, J ˆ 7.3 Hz, 3H), 1.60 1.75 (m,
4H), 1.95 (t, J ˆ 2.7 Hz, 1H), 2.14 2.19 (m, 2H), 2.26 (s, 3H), 2.97 (dq, J ˆ
3.0, 7.3 Hz, 1H), 3.61 3.67 (m, 1H), 6.66 6.93 (m, 3H), 7.06 7.40 (m,
5H); 13C NMR (CDCl3): anti: d ˆ 14.0, 18.4, 18.5, 24.3, 31.5, 43.8, 57.7, 68.9,
83.7, 113.7, 121.4, 122.4, 123.3, 125.9, 129.4, 130.8, 132.2, 150.0, 150.4, 175.3;
syn: d ˆ 10.9, 18.2, 18.4, 25.6, 30.8, 41.9, 58.0, 68.9, 83.6, 113.6, 121.4, 122.3,
124.3, 126.0, 129.4, 131.2, 132.4, 150.4, 151.3, 174.5; HPLC (Daicel Chiralcel
OD-H (double), hexane/iPrOH 19:1, flow rateˆ 0.50 mLminÀ1) anti: tR ˆ
54.0 min (majorˆ 2R,3R), tR ˆ 63.6 min (minorˆ 2S,3S); syn: tR ˆ 49.6 min
(majorˆ 2S,3R), tR ˆ 67.6 min (minorˆ 2R,3S); elemental analysis calcd (%)
for C22H25NO3: C 75.19, H 7.17, N 3.99; found: C 74.92, H 7.35, N 3.97.
(2R,3S)-Methyl 3-(2-methoxyphenyl)amino-2-methyl-3-phenylpropanoate
(5): K2CO3 (166 mg, 1.20 mmol) was added at room temperature to a
solution of 4a (syn/anti 2:98, anti ˆ 92% ee) (210 mg, 0.60 mmol) in MeOH
(8.0 mL). After being stirred for 20 min, the reaction mixture was quenched
with sat. aq. NH4Cl, extracted with CH2Cl2 and dried over Na2SO4.
Filtration and removal of the solvents afforded methyl 3-(2-hydroxyphe-
nyl)amino-2-methyl-3-phenylpropanoate, a crude sample of which was
dissolved in a MeI/acetone (1:5) solution (8.0 mL), followed by addition of
K2CO3 (332 mg, 2.40 mmol) at room temperature. After the mixture was
stirred for 8 h, sat. aq. NH4Cl was added to quench the reaction. After a
usual work-up, the crude product was chromatographed on silica gel to give
5 (131 mg, 78%) as a pure anti-isomer. [a]1D8 ˆ À16.0 (c ˆ 1.34, CHCl3); IR
(2R,3R)-Methyl
3-(2-hydroxy-6-methylphenyl)amino-2-methyl-7-octy-
noate (11): According to the same procedure for 7 from 4 f, Mannich
adduct 10 (syn/anti 7:93, anti 97% ee) (285 mg, 0.81mmol) was converted
to the corresponding methyl ester and isolated as a pure anti-isomer 11
(neat): nÄ ˆ 3414, 2944, 1733, 1603, 1513, 1456, 736, 703 cmÀ1
;
1H NMR
(CDCl3): d ˆ 1.14 (d, J ˆ 7.0 Hz, 3H), 2.88 (dq, J ˆ 7.0, 7.7 Hz, 1H), 3.63 (s,
3H), 3.85 (s, 3H), 4.51(d, J ˆ 7.7 Hz, 1H), 6.39 6.73 (m, 4H), 7.17 7.29
(m, 5H); 13C NMR (CDCl3): d ˆ 15.0, 46.7, 51.7, 55.5, 60.4, 109.4, 110.9,
116.4, 121.0, 126.9, 127.3, 128.4, 136.7, 141.2, 146.8, 175.3.
1
(214 mg, 91%). H NMR (CDCl3): d ˆ 1.27 (d, J ˆ 7.2 Hz, 3H), 1.47 1.65
(m, 4H), 1.93 (t, J ˆ 2.7 Hz, 1H), 2.11 2.17 (m, 2H), 2.25 (s, 3H), 2.63 (dq,
J ˆ 7.2, 7.9 Hz, 1H), 3.47 3.53 (m, 1H), 3.73 (s, 3H), 6.63 6.85 (m, 3H);
13C NMR (CDCl3): d ˆ 14.7, 18.3, 18.5, 24.1, 31.7, 44.1, 52.0, 57.6, 68.8, 83.6,
113.9, 122.1, 123.4, 130.6, 132.3, 150.4, 177.5.
(2R,3S)-Methyl 3-amino-2-methyl-3-phenylpropanoate (6):[18] A catalytic
amount of AgNO3 (14 mg, 0.08 mmol) was added at 608C to a solution of 5
(50 mg, 0.17 mmol) in a CH3CN/H2O (2:1) solution (2.8 mL), followed by
(2R,3R)-Methyl 3-amino-2-methyl-7-octynoate (AMO methyl ester)
(12):[20] According to the same conversion of 7 to 8, the amino group of
11 (40 mg, 0.14 mmol) was deprotected to afford the desired b-amino ester
12 (14 mg, 54%). [a]D22 ˆ À9.6 (c ˆ 0.14, CHCl3) (lit.:[20] [a]D ˆ À6.0 (c ˆ
0.40, CHCl3)); 1H NMR (CDCl3): d ˆ 1.19 (d, J ˆ 7.0 Hz, 3H), 1.37 1.80
(m, 6H), 1.96 (t, J ˆ 2.7 Hz, 1H), 2.20 2.25 (m, 2H), 2.49 (dq, J ˆ 6.8,
7.0 Hz, 1H), 2.91 (m, 1H), 3.70 (s, 3H); 13C NMR (CDCl3): d ˆ 14.2, 18.3,
25.0, 33.7, 46.0, 51.6, 53.6, 68.6, 84.1, 175.8.
[17]
portionwise addition of excess (NH4)2S2O8
(306 mg, 1.34 mmol) for
20 min. After being stirred for 4 h, the reaction mixture was cooled at room
temperature, diluted with water, treated with K2CO3 to a pH of over 7, and
extracted with EtOAc. After a usual work-up, the crude product was
chromatographed on silica gel to afford the desired b-amino ester 6 (23 mg,
70%). [a]2D2 ˆ À30.8 (c ˆ 1.12, CHCl3) (lit.:[18] [a]2D5 ˆ À29.2 (c ˆ 1.00,
CHCl3)); IR (neat): nÄ ˆ 3379, 2944, 1736, 1454, 766, 704 cmÀ1
;
1H NMR
(CDCl3): d ˆ 0.95 (d, J ˆ 7.1Hz, 3H), 1.86 (brs, 2H), 2.71 (dq, J ˆ 7.1,
9.5 Hz, 1H), 3.73 (s, 3H), 4.02 (d, J ˆ 9.5 Hz, 1H), 7.25 7.36 (m, 5H);
13C NMR (CDCl3): d ˆ 15.3, 47.9, 51.7, 59.1, 127.0, 127.5, 128.6, 143.4, 176.4.
Phenyl
5-benzyloxy-2-ethyl-3-(2-hydroxy-6-methylphenyl)aminopenta-
noate (15) (syn/anti 4:96): IR (neat): nÄ ˆ3365, 2932, 2870, 1746, 1590,
1
1490, 1452, 1195, 1159, 745, 695 cmÀ1; H NMR (CDCl3): anti: d ˆ 1.01 (t,
(2R,3R)-Methyl 2,5-dimethyl-3-(2-hydroxy-6-methylphenyl)aminohexa-
noate (7): K2CO3 (102 mg, 0.74 mmol) was added at room temperature to
a solution of 4 f (syn/anti 9:91, anti 92% ee) (127 mg, 0.37 mmol) in MeOH
(5.0 mL). After being stirred for 20 min, the reaction mixture was quenched
with sat. aq. NH4Cl. After a usual work-up, the crude product was
chromatographed on silica gel to afford 7 (98 mg, 95%) as a pure anti-
isomer. [a]1D7 ˆ ‡5.2 (c ˆ 1.10, CHCl3); IR (neat): nÄ ˆ 3367, 2954, 2863, 1711,
J ˆ 7.6 Hz, 3H), 1.50 2.08 (m, 4H), 2.25 (s, 3H), 2.67 2.74 (m, 1 H), 3.56
3.72 (m, 2H), 3.84 3.89 (m, 1H), 4.48 (d, J ˆ 11.8 Hz, 1H), 4.52 (d, J ˆ
11.8 Hz, 1H), 6.64 6.89 (m, 3H), 7.01 7.40 (m, 10H); syn: d ˆ 0.97 (t, J ˆ
7.3 Hz, 3H), 1.50 2.08 (m, 4H), 2.30 (s, 3H), 2.67 2.74 (m, 1 H), 3.56 3.72
(m, 2H), 3.84 3.89 (m, 1H), 4.53 (d, J ˆ 12.0 Hz, 1H), 4.59 (d, J ˆ 12.0 Hz,
1H), 6.64 6.89 (m, 3H), 7.01 7.40 (m, 10H); 13C NMR (CDCl3): anti: d ˆ
12.2, 18.3, 22.4, 32.0, 51.9, 54.7, 66.7, 73.2, 114.4, 121.5, 122.3, 123.1, 125.9,
127.8, 128.0, 128.4, 129.4, 130.1, 132.6, 137.5, 150.1, 150.4, 174.6; syn: d 12.4,
18.1, 21.9, 30.8, 50.8, 56.3, 67.4, 73.1, 114.0, 121.4, 122.1, 124.1, 126.0, 127.8,
128.0, 128.4, 129.5, 132.2, 132.6, 137.4, 150.3, 151.4, 173.2; HPLC (Daicel
1588, 1461 cmÀ1
;
1H NMR (CDCl3): d ˆ 0.79 (d, J ˆ 6.3 Hz, 6H), 1.24 (d,
J ˆ 7.1 Hz, 3H), 1.31 1.36 (m, 2H), 1.54 1.64 (m, 1 H), 2.25 (s, 3H), 2.59
(dq, J ˆ 7.0, 7.1Hz, 1H), 3.57 3.62 (m, 1H), 3.69 (s, 3H), 6.63 6.80 (m,
Chem. Eur. J. 2002, 8, No. 18
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S. Kobayashi et al.
FULL PAPER
Chiralpak AD (double), hexane/iPrOH 19:1, flow rate ˆ 1.0 mLminÀ1):
anti: tR ˆ 38.1min (major ˆ 2R,3R), tR ˆ 44.1min (minor ˆ 2S,3S); syn:
tR ˆ 41.4 min (majorˆ 2S,3R), tR ˆ 53.3 min (minorˆ 2R,3S); elemental
analysis calcd (%) for C27H31NO4: C 74.80, H 7.21, N 3.23; found: C 74.66, H
7.32, N 3.24.
Chem. Soc. 1986, 108, 6054; b) C. Gennari, I. Venturini, G. Gislon, G.
Schimperna, Tetrahedron Lett. 1987, 28, 227; c) T. Yamada, H. Suzuki,
T. Mukaiyama, Chem. Lett. 1987, 293; d) D. A. Evans, F. UrpÌ, T. C.
Sommers, J. S. Clark, M. T. Bilodeau, J. Am. Chem. Soc. 1990, 112,
8215; e) E. J. Corey, C. P. Decicco, R. C. Newbold, Tetrahedron Lett.
1991, 32, 5287; f) K. Hattori, M. Miyata, H. Yamamoto, J. Am. Chem.
Soc. 1993, 115, 1151; g) D. Enders, D. Ward, J. Adam, G. Raabe,
Angew. Chem. 1996, 108, 1059; Angew. Chem. Int. Ed. Engl. 1996, 35,
981; h) H. Fujieda, M. Kanai, T. Kambara, A. Iida, K. Tomioka, J. Am.
Chem. Soc. 1997, 119, 2060.
(2R,3R)-Phenyl 3-amino-5-benzyloxy-2-ethylpentanoate (16): The amino
group of 15 (113 mg, 0.26 mmol) was also deprotected with CAN under the
similar condition described above and diastereoisomers of the product
were separated to give the desired pure anti-isomer 16 (66 mg, 78%).
1H NMR (CDCl3): d ˆ 1.05 (t, J ˆ 7.3 Hz, 3H), 1.60 2.28 (m, 6H), 2.51
2.62 (m, 1H), 3.22 3.46 (m, 2H), 3.64 3.69 (m, 1H), 4.52 (s, 2H), 7.06
7.39 (m, 10H); 13C NMR (CDCl3): d ˆ 12.0, 22.7, 35.2, 51.0, 53.4, 67.7, 73.1,
121.6, 125.8, 126.9, 127.6, 128.4, 129.4, 138.2, 150.5, 173.5.
[9] Catalytic diastereo- and enantioselective synthesis of a-alkyl-b-amino
units derived from a-imino esters: D. Ferraris, B. Young, C. Cox, T.
Dudding, W. J. Drury III, L. Ryzhkov, A. E. Taggi, T. Lectka, J. Am.
Chem. Soc. 2002, 124, 67.
(3R,4R)-4-(2-Benzyloxyethyl)-3-ethylazetidin-2-one (17): nBuLi (1.58m
hexane solution, 0.30 mL, 0.47 mmol) was added at 08C to a THF solution
(0.5 mL) of diisopropylamine (47 mg, 0.47 mmol). After stirred for 10 min,
the mixture was cooled to À788C. b-Amino ester 16 (51mg, 0.16 mmol) in
THF (1.7 mL) was added and the mixture was stirred for 24 h at the same
temperature.[21] Water was added to quench the reaction and after a usual
work-up, the crude product was chromatographed on silica gel to afford b-
lactam 17 (20 mg, 55%). 1H NMR (CDCl3): d ˆ 1.01 (t, J ˆ 7.4 Hz, 3H),
1.59 1.84 (m, 2H), 1.92 (dt, J ˆ 4.5, 6.6 Hz, 2H), 2.76 (dddd, J ˆ 1.3, 2.2,
6.2, 8.3 Hz, 1H), 3.44 (dt, J ˆ 2.2, 6.6 Hz, 1H), 3.54 3.60 (m, 2H), 4.49 (s,
2H), 5.88 (brs, 1H), 7.28 7.39 (m, 5H); 13C NMR (CDCl3): d ˆ 11.4, 21.4,
34.9, 53.0, 58.5, 68.1, 73.2, 127.6, 127.8, 128.5, 138.0, 170.7.
(3R,4R)-3-Ethyl-4-(2-hydroxyethyl)azetidin-2-one (18):[22] The mixture of
17 (20 mg, 0.085 mmol) and 20% Pd(OH)2/C (13 mg) in EtOH (1.0 mL)
was stirred under hydrogen at room temperature for 14 h. After filtration
and evaporation, the crude product was purified by chromatography on
silica gel to afford 18 (10 mg, 82%). [a]2D2 ˆ ‡20.9 (c ˆ 0.40, CHCl3) (lit.:[22d]
[a]2D1 ˆ ‡21.6 (c ˆ 0.35, CHCl3)); 1H NMR (CDCl3): d ˆ 1.03 (t, J ˆ 7.4 Hz,
3H), 1.63 1.95 (m, 4H), 2.78 (ddd, J ˆ 2.1, 6.3, 8.3 Hz, 1 H), 3.47 (ddd, J ˆ
2.1, 5.1, 7.8 Hz, 1H), 3.72 3.83 (m, 2H), 6.25 (brs, 1H); 13C NMR (CDCl3):
d ˆ 11.4, 21.4, 37.3, 52.8, 58.5, 60.6, 171.1.
[10] Catalytic asymmetric direct Mannich reactions were recently report-
ed: a) S. Yamasaki, T. Iida, M. Shibasaki, Tetrahedron 1999, 55, 8857;
b) K. Juhl, N. Gathergood, K. A. J˘rgensen, Angew. Chem. 2001, 113,
3083; Angew. Chem. Int. Ed. Engl. 2001, 40, 2995; c) B. List, P.
Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124, 827.
[11] Some methods using diastereoselective hydrogenation and kinetic
resolution of a-(a-aminoalkyl)acrylates were also reported: a) J. M.
Brown, A. P. James, L. M. Prior, Tetrahedron Lett. 1987, 28, 2179;
b) M. Takagi, K. Yamamoto, Tetrahedron 1991, 47, 8869.
[12] For asymmetric synthesis of a-methyl-b-amino units using catalytic
enantioselective Mannich reactions of simple imines with enolate
components, only one example was reported to the best of our
knowledge, but regioselectivity was moderate (see ref. [10c]).
[13] a) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119,
7153; b) S. Kobayashi, H. Ishitani, M. Ueno, J. Am. Chem. Soc. 1998,
120, 431; c) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc.
2000, 122, 8180; d) S. Kobayashi, H. Ishitani, Y. Yamashita, M. Ueno,
H. Shimizu, Tetrahedron 2001, 57, 861.
[14] Ketene silyl acetals derived from alkyl esters gave lower selectivity.
[15] Similar effects of the pentafluoroethyl group has been observed in a
different catalyst system: a) Y. Yamashita, S. Saito, H. Ishitani, S.
Kobayashi, Org. Lett. 2002, 4, 1221; b) Y. Yamashita, H. Ishitani, H.
Shimizu, S. Kobayashi, J. Am. Chem. Soc. 2002, 124, 3292.
[16] anti-Selectivity was remarkable because syn- and anti-selectivity was
observed in the reactions of a-tert-butyldimethylsilyloxy and a-
benzyloxy ketene silyl acetals, respectively. It was reported in aldol
reactions that syn-selectivity was obtained in the reactions of
propionate components and a-tert-butyldimethylsilyloxy ketene silyl
acetals, while only a-benzyloxy ketene silyl acetals gave anti-adducts:
T. Mukaiyama, I. Shiina, H. Uchiro, S. Kobayashi, Bull. Chem. Soc.
Jpn. 1994, 67, 1708.
Acknowledgement
This work was partially supported by CREST and SORST, Japan Science
and Technology Corporation (JST), and a Grant-in-Aid for Scientific
Research from the Japan Society of the Promotion of Science.
[1] The catalytic asymmetric aldol reaction is one of the most powerful
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1999, p. 998.
[2] K. L. Rinehart, K. Harada, M. Namikoshi, C. Chen, C. A. Harvis,
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2765.
¬
¬
¬
[20] M. Fernandez-Suarez, L. Munƒoz, R. Fernandez, R. Riguera, Tetrahe-
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[21] K. Ikeda, Y. Terao, M. Sekiya, Chem. Pharm. Bull. 1981, 29, 1747.
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¬
¬
ƒ
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¡
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52, 13867; b) O. Miyata, Y. Fujiwara, I. Ninomiya, T. Naito, J. Chem.
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references therein.
[7] Reviews on asymmetric synthesis of b-amino acids and a-substituted
b-amino acids: a) Enantioselective Synthesis of b-Amino Acids (Ed.:
E. Juaristi), VCH, Weinheim, 1997; b) E. Juaristi, D. Quintana, J.
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[8] Examples of asymmetric synthesis of a-alkyl-b-amino carbonyl
compounds based on diastereoselective enolate-imine condensations:
a) D. J. Hart, C.-S. Lee, W. H. Pirkle, M. H. Hyon, A. Tsipouras, J. Am.
Received: May 21, 2002 [F4108]
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