Asymmetric Mannich-type reactions with a chiral acetate: Effect of Lewis acid on activation of aldimine

Article abstract of DOI:10.1016/S0040-4020(00)01042-5

We introduce here a strategy that enables effective addition of lithium enolates of acetates to aldimines. The new method depends strongly on the use of ortho-alkoxy (or ortho-fluoro) aniline-derived aldimines which found to have a potential effect on the enolate addition. This scope was expanded to the asymmetric process using the chiral acetate, which has optically pure 2,6-bis(2-isopropylphenyl)-3,5-dimethylphenol as a chiral auxiliary with axial chirality. A Lewis acid additive is likely to have a complementary role in the pronounced activation of imine functionalities in the Mannich-type addition of the bulky chiral acetate.

Full text of DOI:10.1016/S0040-4020(00)01042-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 875±887
Asymmetric Mannich-type reactions with a chiral acetate:
effect of Lewis acid on activation of aldimine
Susumu Saito, Keiko Hatanaka and Hisashi Yamamotop
Graduate School of Engineering, Nagoya University, CREST, Japan Science and Technology Corporation (JST),
Furo-cho, Chikusa, Nagoya 464-8603, Japan
Received 26 May 2000; accepted 25 August 2000
AbstractÐWe introduce here a strategy that enables effective addition of lithium enolates of acetates to aldimines. The new method depends
strongly on the use of ortho-alkoxy (or ortho-¯uoro) aniline-derived aldimines which found to have a potential effect on the enolate addition.
This scope was expanded to the asymmetric process using the chiral acetate, which has optically pure 2,6-bis(2-isopropylphenyl)-3,5-
dimethylphenol as a chiral auxiliary with axial chirality. A Lewis acid additive is likely to have a complementary role in the pronounced
activation of imine functionalities in the Mannich-type addition of the bulky chiral acetate. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
reaction using this approach. We address these limitations
using 2,6-bis(2-isopropylphenyl)-3,5-dimethylphenol (1)5
as an effective chiral auxiliary in the diastereoselective
Mannich-type reaction of acetate 26 with specialized aldi-
mines (Scheme 1).
Chiral auxiliaries are powerful molecular elements for
creating optically active compounds. When covalently
attached to the auxiliaries, carboxylic acid derivatives
expanded the scope of the asymmetric aldol reaction with
aldehydes and have constituted a molecular library of
b-hydroxycarbonyl compounds.1 In contrast, due to the
inherent instability of imines (e.g. imine±enamine equili-
bration) and the poor electrophilicity of stable N-substituted
imines2 especially toward acetate enolates, there are few
reports in the literature3,4 on the asymmetric Mannich-type
2. Results and Discussion
Although studies have investigated many aspects of high
reactivity of the enolates of propionates and isobutylates,3a
the lithium enolates of acetates are almost inert to the
Scheme 1.
Keywords: asymmetric reaction; chelation; enolates; imines; Mannich reaction.
* Corresponding author. Tel.: 181-52-789-3331; fax: 181-52-789-3222; e-mail: yamamoto@cc.nagoya-u.ac.jp
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01042-5

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S. Saito et al. / Tetrahedron 57 (2001) 875±887
Table 1. Reaction of the lithium enolate of methyl acetate with various aldimines (unless otherwise speci®ed, reaction was performed using the acetate
(1.0 equiv.), a THF solution of LDA (1.0 equiv.) and aldimine (1.0 equiv.) at 2788C for 3 h)
Entry
Aldimine, R1
Ph (9)
Me3Si (10)
2-MeO±C6H4 (11)
3-MeO±C6H4(12)
4-MeO±C6H4 (13)
2-MOMO±C6H4 (14)
2-F±C6H4 (15)
Yield%a
Entry
Aldimine, R1
Yield %a
1
2
3
4
5
6
7
8
24b,c
14b,d
71
NR
NR
69
9
2,5-(MeO)2±C6H3 (17)
2,6-(MeO)2±C6H3 (18)
2-MeO±6-Me±C6H4 (19)
2,6-F2±C6H4 (20)
Bn (21)
73
10
11
12
13
14
15
NR
NR
NR
NR
NR
4
MeO (22)
Ms (23)
83
56
2,4-(MeO)2±C6H3 (16)
a Of isolated b-aminoesters. NRˆno reaction.
b The isolated yield of the corresponding b-lactam.
c See Ref. 7a.
d See Ref. 7b.
N-phenyl-7a and N-trimethylsilylaldimines7b of benz-
aldehyde.7 Thus, our ®rst attempt was to ®nd a potential
aldimine partner that reacts smoothly with the acetate
enolates. The results are summarized in Table 1, which
shows that the aldimines of o-anisidine and ortho-¯uoroani-
line (11 and 15) facilitate the reaction most ef®ciently
(entries 3 and 7).8² The alkoxy and the ¯uoro groups are
essential and must be attached to the ortho-position of the
aniline nitrogen. For example, m- and p-anisidine deriva-
tives 12 and 13 did not lead to the desired adducts (entries 4
and 5). These results imply that the rather low Lewis acidic
Li1 requires chelation to enable the effective activation of
aldimines. Indeed, aldimine 14 with which the chelation
control further operates had a similar effect on the addition
ef®cacy (entry 6); dimethoxy derivatives 16 and 17 showed
similar productivity (entries 8 and 9). However, o,o-
disubstituted derivatives 18±20 were absolutely inert
under the present conditions even at higher temperature
(08C) (entries 10±12).
more signi®cant role in enhancing diastereoselectivity. In
other words, Li1 is proximal, while the additional Lewis
acid is distal, to a requisite transition structure created.
Another critical parameter for high asymmetric induction
seems the direct attachment of an aromatic ring to the
imine nitrogen (entries 14±18); however, imines 9 and 27
proved to be totally ineffective for productivity even in the
presence of Et2Zn. On the contrary, the attachment of N-
sulfonyl and N-phosphoryl groups gave adducts in higher
yields (entries 20 and 21), but unfortunately, a signi®cant
decline in de was observed. An attempt to form six-
membered chelation with Li1 to activate imine 30 effec-
tively was disappointing (entry 22).
Other o-anisidine-derived aldimines were reacted with
(R,R)-2 in the presence of a Zn-reagent, and the results are
listed in Table 3. With the exception of inertness with the
2-hexenal-derived aldimine (entry 5), the table shows that
this method proved to be effective in substrate scope, to give
high diastereoselectivities up to 98% de. Using 1.0 equiv. of
Et2Zn was generally ineffective in terms of chemical yield
due to side reactions, which in some cases generated a
considerable amount of ethylated products (entry 10).9³
o,o-Disubstituted aniline-derived aldimines 18 and 19
underwent no addition to give complete recovery of the
acetate.
Unfortunately, the lithium enolate of 2, generated by treat-
ment with n-BuLi in THF at 2788C for 0.5 h, was almost
inert to aldimines 11 and 15 under the above optimized
conditions (for aldimine 11, 15% yield, 86% de). We thus
focused on the use of a Lewis acid additive, anticipating the
pronounced activation of imine functionalities (Scheme 1
and Table 2). The addition of 2 to aldimine 11 occurred
effectively in the presence of 0.5 equiv. of R2Zn (RˆMe,
Et) at 2788C to give b-aminoester 3 in 70 and 69% yields
with diastereomeric excesses (de) of ca. 91% de. Compar-
able yield and de were obtained whether a Lewis acid was
added after or before treatment of aldimine with the enolate.
While varying Lewis acids for 11 (entries 1±9) had appreci-
able effect, absolute S con®guration at the emerging chiral
center was induced throughout. These results also suggest
that Li1, rather than an externally added Lewis acid, plays a
The equilibrium between (E)- and (Z)-aldimines is known to
be involved in the presence of Lewis acid and to affect the
stereochemistry of the asymmetric Mannich-type reaction.§
Thus, there is a possibility that the isomerization to (Z)-
³
To explain the difference in the reaction pro®les using 0.5 and 1.0 equiv.
of Et2Zn, distinctive zincate species (enolate)R2ZnLi (Li-enolate:
R2Znˆ1:1) and (enolate)2R2ZnLi2 (Li-enolate:R2Znˆ2:1) might be
invoked. At present, we have no evidence of the formation of these
species and further research is needed. Regarding the search on the reac-
tivity difference between R3ZnLi and R4ZnLi2, see Ref. 9.
²
§
In the meantime, restraining effects of the ortho-methoxyphenyl sub-
For example, the reaction of the aldimine derived from 3-trimethylsilyl-2-
stituent of aldimines on the formation of b-amino esters, not the b-
lactams, was reported in the Refomatsky reaction using a-bromoacetate
and Zn (Ref. 8). Moreover, Kobayashi, et al. reported marked in¯uence of
aldimines 11 and 28 on the enantioselectivity and/or reactivity in the
Mannich-type reaction using chiral zirconium reagents (Refs. 3i and
3j). Although both aldimines are employable, the reaction mechanism
remains totally unclear.
propynal with a ketene silyl acetal exhibits reversal in the absolute con®g-
uration, compared with the aldimine derived from benzaldehyde using a
chiral boron reagent. This implies that the (Z)-structure is the reactive
form of the former aldimine, whereas it is (E)-isomer of the latter, see
Ref. 3k. In good contrast, the present reaction using the o-anisidine-
derived aldimines derived from these two types of aldehydes showed
an identical S con®guration.

S. Saito et al. / Tetrahedron 57 (2001) 875±887
877
Table 2. Asymmetric Mannich-type reaction of aldimines derived from PhCHO with (R,R)-2 (unless otherwise speci®ed, reaction was performed by mixing
enolate (1.0 eq), aldimine (1.0 equiv.) and Lewis acid (0.5 equiv.) in this order at 2788C for 8,48 h)
a
Of isolated puri®ed product.
b Determined by HPLC analysis.
Absolute con®guration of the chiral centers, which was determined in comparison with authentic samples.
c
d 1.0 equiv. of a Lewis acid was used.
0.1 equiv. of a Lewis acid was used.
e
f
Aldimine and Lewis acid were mixed prior to treatment with enolate.
g (S,S)-2 was used.

878
S. Saito et al. / Tetrahedron 57 (2001) 875±887
Table 3. Asymmetric Mannich-type reaction of aldimines derived from o-anisidine with (R,R)-2 (unless otherwise speci®ed, reaction was performed by mixing
enolate (1.0 equiv.), aldimine (1.0 equiv.) and R2Zn (0.5 equiv.) at 2788C for 18 h,48 h)
Entry
Aldimine (RCHˆNR1)
Additive
Product
Yield %a (de)b
Absolu con®g.c
1
2
Et2Zn
Et2Zn
4
4
73 (91% de)
50 (84% de)
3
4
Me2Zn
Et2Zn
5
5
62 (84% de)
75 (84% de)
5
Et2Zn
6
28 (99% de)
6
7
Me2Zn
Et2Zn
7
7
70 (93% de)
72 (91% de)
S
S
8
9
10
t-Bu2Zne
Et2Zn
8
8
8
55 (91% de)
63 (85% de)
51 (86% de)f
S
S
S
Et2Znd
a Of isolated puri®ed product.
b Determined by HPLC analysis.
c Absolute con®guration of the chiral centers, which was determined in comparison with authentic samples.
d Et2Zn (1.0 equiv.) was used.
e Salt free reagent. See Ref. 10.
f Ethylated product was obtained (10%).
Scheme 2.
aldimines could have potential effect on the rate accelera-
tion of the Mannich addition. In fact, when the SnCl4-(Z)-11
complex11 was exposed to the lithium enolate of (R,R)-2,
adduct 3 was obtained in 70% de (3S:3Rˆ85:15) (Scheme
2), the absolute con®guration being consistent with the other
examples we tested (entries 1±9, Table 2; entries 6±10,
Table 3). As expected, the reaction of SnCl4-(Z)-19 with
the lithium enolate of (R,R)-2 or methyl acetate did not
lead to the desired adducts (Scheme 3). In contrast, the
corresponding ketene silyl acetal afforded the Mannich-
type addition to give 45, where an extended transition
state was likely to be invoked (Scheme 3). This implies
that the lithium enolates ®rst attack the Sn-center to give a
tin±enolate intermediate such as A, which prefers a cyclic
transition state rather than an extended one. However, steric
constraints may not allow intramolecular enolate addition to
the imine carbon via a cyclic transition structure which is
usually sterically more unfavorable. Indeed, Fig. 1 shows
that both the si and re face of SnCl4-(Z)-19 are sterically
more shielded synergistically by the methyl, phenyl and the
chloro groups compared with SnCl4-(Z)-11. In addition,
SnCl4-(Z)-19 has a higher rotational barrier around the
C±N single bond axis, and thus exposure of the imine
faces to a favorable enolate addition would be highly
restricted. Although we cannot rule out other possible
mechanisms at this point, it is thus conceivable that
SnCl4-(Z)-11 might also be attacked by lithium enolates
via a cyclic transition structure, resulting in 3S- con®gu-
ration. The structure of SnCl4-(Z)-19 was rigorously estab-
lished by the X-ray single crystal analysis.12
The reactions showed general preference for the si face
attack of aldimines, which is opposite to that for the addition
of aldehydes.6 Steric considerations of the single crystal
structure of 26 and high probability in the U-form (Fig.
2)13¶ of the corresponding enolate give us a putative transition
structure for the asymmetric induction (Fig. 3). The twist boat
model, which is accommodated by the U-form and by the
chelation complex of a putative (Z)-aldimine with a Lewis
acid, validates the si face attack by the chiral enolate. Signi®-
cant steric repulsion has been con®rmed by modeling of the
(E)-aldimines in possible transition structures.
¶
It was proposed that the boron enolates of a-unsubstituted ketones favor
the more stable U-form by 1±2 kcal/mol than the W-form (Ref. 13).
Similarly, it is conceivable that the bulky phenoxy group of the enolate
of 2 renders the U-form most likely, and gives a twist-boat transition
structure.

S. Saito et al. / Tetrahedron 57 (2001) 875±887
879
Scheme 3.
Figure 1. The X-ray crystal structures of (a) SnCl4-(Z)-11 and (b) SnCl4-(Z)-19. The structure of SnCl4-(Z)-11 was cited from the CD-ROM data deposited at
CCDC.
The chiral auxiliary can readily be recovered (.99%) from
the Mannich adduct 3 (91% de) by treatment with Bu4NOH
in THF,14 followed by subsequent methylation of the
resulting acid with TMSCHN2. Oxidative cleavage of the
methoxyphenyl group was effected by catalytic AgNO3
(0.29 equiv.) in the presence of excess (NH4)2S2O8
(7.0 equiv.)15 to afford aminoester 49 in 53% yield (90%
ee) (Scheme 4). When we used CAN as an alternative
oxidant, aminoester 46 underwent considerable dimeri-
zation, resulting in negligible formation of 49.16k An attempt
to remove the o-¯uorophenyl group from 47 under similar
conditions using CAN gave 49 in only 14% yield. This can
be circumvented by use of 16 as an aldimine to give
k
Although it has been reported that aminoester 46 was readily oxidized by
CAN to give 49 (Ref. 8), we were unable to detect the formation of 49
using CAN by varying numerous reaction conditions. No attempt was
made here to characterize the exact structure of the dimer. Competitive
dimerization is a signi®cant problem in certain cases using CAN.
Figure 2. Equilibrium between U- and W-form.

880
S. Saito et al. / Tetrahedron 57 (2001) 875±887
Figure 3. One plausible transition structure.
Scheme 4. (a) Bu4NOH, THF, 08C, 99%; (b) TMSCHN2, MeOH, rt, 99% for 3 and 33: (c) AgNO3, (NH4)2S2O8, THF±H2O±MeCN, 608C, 53% for 46;
(d) CAN, H2O±MeCN, 08C, 91% for 48; 14% for rac-47.
Mannich adduct 33 in 63% yield (92% de, using Me2Zn).
Sequential hydrolysis and methylation was followed by
oxidation of 48 with CAN (4 equiv.) to give 49 in 91%
yield (92% ee), where no dimerization was observed.
temperature. Chemical shifts were recorded in ppm from the
solvent resonance employed as the internal standard
(deuterochloroform at 77.07 ppm). Chiral high-performance
liquid chromatography (chiral HPLC) analyses were
conducted using Shimazu LC-10AD coupled with diode
array-detector SPD-MA10A-VP and the chiral column of
CHIRALCEL OD±H or AD (Daicel Chemical Industries,
Ltd). All experiments were carried out under an atmosphere
of dry argon. For thin-layer chromatography (TLC) analysis
throughout this work, Merck precoated TLC plates (silica
gel 60 GF254 0.25 mm) were used. The products were puri-
®ed by preparative column chromatography on normal
silica gel (Merck Art. 9385: Cl ,0.02%; Fe, ,0.02%) or
for some instances, on silanized silica gel (Merck Art. 7719)
or on extra pure one (Merck Art. 7754: Cl ,0.008%; Fe,
,0.002%). Microanalyses were accomplished at the
Faculty of Agriculture, Nagoya University.
3. Conclusion
This work features a strategy that enabled effective addition
of acetate enolates to aldimines and expanded this scope to
the asymmetric process using a chiral auxiliary. We propose
that the successful asymmetric reaction originated in part
from: (1) the control of the two possible aldimine con®gu-
rations (E and Z) by chelation effect of Lewis acids using
readily isomerizable aldimine;11 and (2) the control of the
two possible enolate conformations W-form and U-form13
using the bulky auxiliary, which have been proposed to
contribute to the chair and twist boat transition structures,
respectively. However, an understanding of further mecha-
nistic aspects of the reaction is required to give marked
improvement in synthetic ef®ciency. Efforts toward this
end are currently being made in our laboratory.
In experiments which required dry solvent toluene and
CH2Cl2 were freshly distilled from calcium hydride, and
tetrahydrofuran (THF) was freshly distilled from sodium
metal using benzophenone ketyl as indicator. Organic
substrate 21 was commercially available, and was used
without any puri®cation. n-BuLi (hexane solution) was
obtained from Mitsuwa. Compounds 1,5 26 and aldimines
9,7a 10,7b 11,17 12,18 13,19 15,20 16,21 19,22 22,23 23,24 24;25
27,26 28,27 29,28 30,29 31,30 40,31 41,32 43,33 468 and 4934 are
all known compounds, and were prepared as described in
the literature. However, in many cases spectroscopic
properties of aldimines have not been recorded and are
included here to provide full or partial documentation of
structural evidence.
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a Shimazu FTIR-
8100 spectrometer. H NMR spectra were measured on a
1
Varian Gemini-300 spectrometer (300 MHz) at ambient
temperature. Data were recorded as follows: chemical
shift in ppm from internal tetramethylsilane on the d
scale, multiplicity (bˆbroad, sˆsinglet, dˆdoublet, tˆ
triplet, and mˆmultiplet), coupling constant (Hz), inte-
gration, and assignment. 13C NMR spectra were recorded
on Varian Gemini-300 (75 MHz) spectrometer at ambient
4.2. Preparation of (R,R)-2
To a solution of (R,R)-1 (1.57 g, 4.4 mmol) in anhydrous
THF (9 mL) was added a 1.62 M hexane solution of n-BuLi

S. Saito et al. / Tetrahedron 57 (2001) 875±887
881
(3.27 mL, 5.3 mmol) dropwise at 08C under an argon atmos-
phere. After 15 min of stirring, to the mixture was added
acetyl chloride (469 mL, 6.6 mmol) dropwise at this
temperature, and stirring was maintained for additional
1.5 h. The reaction mixture was quenched with H2O,
extracted with diethyl ether, dried, and concentrated. The
residue was puri®ed by column chromatography on sila-
nized silica gel (hexane only as the eluent. The top of the
silica gel-column should be cooled with dry-ice or some-
thing in order to avoid decomposition of the desired chiral
acetate prior to charging the crude mixture) to give (R,R)-2
(1.78 g, yield .99%) as a colorless solid.
24.2, 20.1. HRFABMS (PEG) m/z Calcd for C41H42FNO2
(M1): 599.3200; Found: 599.3198. The de% was deter-
mined by conversion into the corresponding methyl ester
by: (1) removal of (R,R)-1; and (2) methylation. See the
Experimental below for this derivation. The chiral HPLC
analytical data (column OD±H) of the methyl ester derived
from 3b: retention times: tRˆ8.3 min (minor): tRˆ15.8 min
(major) using i-PrOH/hexane (1/9) as eluent at a ¯ow rate of
1.0 mL/min.
4.3.3.
phenyl 3-[(2-methoxyethoxy)phenyl] amino-3-phenyl-
propionate (3c). IR (neat) 3372, 1750, 1521 cm21 1H
(R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
;
NMR (300 MHz, CDCl3) d 7.28 (d, 2H, Jˆ8.1 Hz), 7.19±
6.94 (m, 12H), 6.75 (dd, 1H, Jˆ1.5, 7.8 Hz), 6.68 (ddd, 1H,
Jˆ1.5, 7.5, 7.8 Hz), 6.57 (ddd, 1H, Jˆ1.5, 7.5, 7.8 Hz), 6.33
(dd, 1H, Jˆ1.5, 7.8 Hz), 4.71 (bs, 1H), 4.08 (t, 2H,
Jˆ4.8 Hz), 3.95 (bs, 1H), 3.71 (t, 2H, Jˆ4.8 Hz), 3.63 (s,
3H), 2.70 (bs, 2H), 2.17 (dd, 1H, Jˆ7.2, 15.6 Hz), 2.04 (s,
6H), 2.03 (dd, 1H, Jˆ6.0, 15.6 Hz), 1.14 (bd, 6H, Jˆ
6.9 Hz), 1.08 (bs, 6H); 13C NMR (75 MHz, CDCl3) d
168.4, 146.5, 146.0, 142.4, 137.3, 136.7, 134.3, 132.1,
130.2, 128.8, 128.5, 127.9, 127.0, 126.1, 125.2, 125.17,
121.7, 116.4, 112.1, 111.7, 71.1, 68.5, 59.1, 53.7, 41.3,
30.0, 24.2, 20.1. Anal. Calcd for C44H49NO4: C, 80.58, H,
7.53, N, 2.14; Found: C, 80.45, H, 7.74, N, 2.15. The chiral
HPLC analytical data (column AD) of 3c: retention times:
tRˆ12.8 min (major); tRˆ16.6 min (minor) using i-PrOH/
hexane (1/200) as eluent at a ¯ow rate of 0.5 mL/min.
4.3. General procedure for asymmetric Mannich-type
addition using chiral acetate 2 and aldimine 11
To a solution of (R,R)-2 (80.0 mg, 0.2 mmol) in THF
(0.80 mL) was added a 1.61 M hexane solution of n-BuLi
(0.12 mL, 0.20 mL) at 2788C under argon atmosphere, and
the mixture was stirred at this temperature for 0.5 h. Sequen-
tial treatment with a 1.0 M hexane solution of Et2Zn
(0.10 mL, 0.1 mmol) for 0.5 h and aldimine 9 (42 mg,
0.2 mmol) in THF (0.40 mL) was followed by being stirred
at 2788C for 27 h. The reaction mixture was quenched with
H2O, and extracted with diethyl ether, and dried over
Na2SO4. Evaporation of solvents and puri®cation by column
chromatography on silica gel (diethyl ether/hexaneˆ1/20 to
1/5 as the eluent) gave b-aminoester 3 (84 mg, yield, 69%)
in 91% de as colorless solids.
4.3.4.
phenyl 3-[(2-methoxymethoxy)phenyl] amino-3-phenyl-
propionate (3d). IR (neat) 3391, 1748, 1514 cm21 1H
(R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
4.3.1.
(R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2-methoxyphenyl) amino-3-phenylpropionate
(3). IR (KBr) 3425, 1759, 1514 cm21; 1H NMR (300 MHz,
CDCl3) d 7.28 (d, 1H, Jˆ7.8 Hz), 7.25 (s, 1H), 7.20±7.13
(m, 5H), 7.12 (s, 1H), 6.98±6.96 (m, 6H), 6.71 (dd, 1H,
Jˆ2.4, 7.2 Hz), 6.66±6.60 (m, 2H), 6.03 (dd, 1H, Jˆ2.7,
7.2 Hz), 4.54 (bs, 1H), 3.98 (bdd, 1H, Jˆ6.3, 6.6 Hz), 2.70
(bs, 2H), 2.18 (dd, 1H, Jˆ8.1, 15.3 Hz), 2.04 (s, 6H), 2.00
(dd, 1H, Jˆ5.4, 15.3 Hz), 1.14 (d, 6H, Jˆ6.9 Hz), 1.07 (bd,
6H, Jˆ5.7 Hz); 13C NMR (75 MHz, CDCl3) d 168.6, 147.3,
146.9, 146.5, 142.4, 136.7, 136.6, 134.4, 132.1, 130.3,
128.8, 128.6, 127.8, 127.0, 126.1, 125.3, 125.2, 120.8,
116.6, 111.4, 109.0, 55.3, 53.8, 41.9, 30.1, 24.2, 20.1.
Anal. Calcd for C42H45NO3: C, 82.45, H, 7.41, N, 2.29;
Found: C, 82.24, H, 7.62, N, 2.24. The chiral HPLC ana-
lytical data (column OD±H) of 3: retention times:
tRˆ5.9 min for (3S)-3 and tRˆ10.3 min for (3R)-3 using
i-PrOH/hexane (1/200) as eluent at a ¯ow rate of 1.0 mL/
min.
;
NMR (300 MHz, CDCl3) d 7.30±6.95 (m, 15H), 6.70 (dd,
1H, Jˆ7.5, 7.8 Hz), 6.58 (dd, 1H, Jˆ6.9, 7.8 Hz), 6.05 (d,
1H, Jˆ7.5 Hz), 5.15 (s, 2H), 4.63 (bs, 1H), 3.91 (bs, 1H),
3.48 (s, 3H), 2.80±2.60 (m, 2H), 2.17 (dd, 1H, Jˆ8.1,
15.3 Hz), 2.04 (s, 6H), 2.03 (dd, 1H, Jˆ5.4, 15.3 Hz),
1.15 (d, 6H, Jˆ6.9 Hz), 1.09 (bs, 6H); 13C NMR
(75 MHz, CDCl3) d 168.5, 147.2, 146.4, 144.5, 142.3,
137.3, 136.7, 134.3, 132.0, 130.2, 128.8, 128.5, 127.9,
127.0, 126.0, 125.2, 125.16, 122.2, 116.7, 113.7, 112.1,
95.0, 56.1, 53.8, 41.3, 30.0, 24.3, 24.2, 20.1. Anal. Calcd
for C43H47NO4: C, 80.47, H, 7.38, N, 2.18; Found: C, 80.47,
H, 7.65, N, 2.18. The chiral HPLC analytical data (column
AD) of 3d: retention times: tRˆ9.7 min (major);
tRˆ11.1 min (minor) using i-PrOH/hexane (1/200) as eluent
at a ¯ow rate of 0.5 mL/min.
4.3.5. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2-methoxyphenyl) amino-3-(2-naphthyl)pro-
4.3.2. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2-¯uorophenyl) amino-3-phenylpropionate (3b).
1
pionate (4). IR (KBr) 3430, 1759, 1510 cm21; H NMR
1
IR (KBr) 3422, 1759, 1515 cm21; H NMR (300 MHz,
(300 MHz, CDCl3) d 7.85±6.90 (m, 16H), 6.74 (d, 1H,
Jˆ7.8 Hz), 6.58 (dd, 1H, Jˆ7.5, 7.8 Hz), 6.54 (dd, 1H,
Jˆ7.8, 7.8 Hz), 5.86 (d, 1H, Jˆ7.5 Hz), 4.72 (bs, 2H),
3.84 (s, 3H), 2.71 (bs, 2H), 2.29 (dd, 1H, Jˆ3.6, 15.9 Hz),
2.15 (dd, 1H, Jˆ9.6, 15.9 Hz), 2.05 (s, 6H), 1.16 (d, 6H, Jˆ
6.9 Hz), 1.06 (d, 6H, Jˆ6.6 Hz); 13C NMR (75 MHz,
CDCl3) d 168.8, 147.0, 146.5, 136.8, 136.5, 134.3, 134.0,
132.1, 130.2, 130.1, 128.9, 128.8, 127.9, 127.6, 126.1,
125.7, 125.3, 125.2, 122.9, 122.6, 122.4, 120.7, 116.6,
111.6, 108.9, 50.1, 40.1, 30.1, 24.2, 20.1. Anal. Calcd for
C46H47NO3: C, 83.47, H, 7.16, N, 2.12; Found: C, 83.42, H,
CDCl3) d 7.36±6.88 (m, 15H), 6.74 (dd, 1H, Jˆ7.5,
7.5 Hz), 6.59±6.50 (m, 1H), 6.10 (dd, 1H, Jˆ7.8, 7.8 Hz),
4.21 (bs, 1H), 4.00 (bs, 1H), 2.80±2.60 (m, 2H), 2.13 (dd,
1H, Jˆ8.7, 15.1 Hz), 2.05 (s, 6H), 2.01 (dd, 1H, Jˆ4.2,
15.1 Hz), 1.14 (d, 6H, Jˆ6.6 Hz), 1.07 (bs, 6H); 13C NMR
(75 MHz, CDCl3) d 168.3, 151.6 (d, 1JCFˆ237.9 Hz), 147.3,
146.4, 135.2 (d, 2JCFˆ11.4 Hz), 134.3, 132.0, 130.5, 130.2,
128.9, 128.7, 127.9, 127.7, 127.2, 125.8, 125.3, 125.1, 124.0
4
3
(d, JCFˆ2.9 Hz), 116.8 (d, JCFˆ7.1 Hz), 114.0 (d,
2JCFˆ18.5 Hz), 113.7 (d, JCFˆ3.2 Hz), 53.8, 41.7, 30.0,
3

882
S. Saito et al. / Tetrahedron 57 (2001) 875±887
7.23, N, 2.22. The de% was determined by conversion into
the corresponding methyl ester by: (1) removal of (R,R)-1;
and (2) methylation. See the experimental procedure below
for this derivation. The chiral HPLC analytical data (column
AD) of the methyl ester derived from 4: retention times:
tRˆ15.7 min (minor); tRˆ18.9 min (major) using i-PrOH/
hexane (1/20) as eluent at a ¯ow rate of 0.5 mL/min.
for C44H47NO3: C, 82.85, H, 7.43, N, 2.20; Found: C, 82.71,
H, 7.65, N, 2.26. The chiral HPLC analytical data (column
OD±H) of 7: retention times: tRˆ8.9 min for (3R)-7 (minor)
and tRˆ23.0 min for (3S)-7 (major) using i-PrOH/hexane
(1/200) as eluent at a ¯ow rate of 1.0 mL/min. The absolute
con®guration was determined by derivation to the authentic
aminocarboxylic acid:35 (1) Pd/C, H2 (1 atm), EtOAc, rt,
12 h; (2) Bu4NOH, THF, rt (see below for details); (3)
oxidation with Ag(I) (see below for details).
4.3.6. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2-methoxyphenyl) amino-3-(2-furfuryl)pro-
1
pionate (5). IR (KBr) 3419, 1759, 1513 cm21; H NMR
4.3.8.
phenyl 3-(2-methoxyphenyl) amino-5-phenyl-4-pentyno-
ate (8). IR (KBr) 3394, 1761, 1510 cm21 1H NMR
(R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
(300 MHz, CDCl3) d 7.31±7.00 (m, 10H), 6.75 (ddd, 1H,
Jˆ1.8, 7.8, 7.8 Hz), 6.65 (ddd, 1H, Jˆ1.5, 7.2, 7.2 Hz), 6.71
(dd, 1H, Jˆ2.1, 7.8 Hz), 6.27 (dd, 1H, Jˆ1.8, 7.8 Hz), 6.08
(dd, 1H, Jˆ1.8, 3.8 Hz), 5.59 (dd, 1H, Jˆ0.9, 3.3 Hz), 4.38
(bs, 2H), 3.76 (s, 3H), 2.71 (bs, 2H), 2.25 (dd, 1H, Jˆ4.8,
16.2 Hz), 2.17 (dd, 1H, Jˆ7.2, 16.2 Hz), 2.06 (s, 6H), 1.15
(d, 6H, Jˆ6.9 Hz), 1.08 (bs, 6H); 13C NMR (75 MHz,
CDCl3) d 168.2, 153.6, 147.3, 146.9, 146.5, 141.5, 136.7,
135.8, 134.4, 132.0, 130.9, 130.3, 128.8, 127.8, 125.3,
125.2, 120.9, 117.0, 110.6, 110.4, 109.3, 106.3, 55.2, 47.3,
37.3, 30.0, 24.2, 20.1. HREIMS m/z Calcd for C40H43NO4
(M1): 601.3192; Found: 601.3206. The chiral HPLC
analytical data (column: an array of two ADs) of 5:
retention times: tRˆ10.8 min (minor); tRˆ11.5 min
(major) using i-PrOH/hexane (1/200) as eluent at a ¯ow
rate of 1.0 mL/min.
;
(300 MHz, CDCl3) d 7.27±7.04 (m, 14H), 6.81 (ddd, 1H,
Jˆ2.1, 7.2, 7.2 Hz), 6.74 (dd, 1H, Jˆ2.1, 8.1 Hz), 6.70 (dd,
1H, Jˆ8.4, 8.4 Hz), 6.48 (d, 1H, Jˆ7.2 Hz), 4.31 (bs, 1H),
4.09 (bs, 1H), 3.79 (s, 3H), 2.80±2.60 (bs, 2H), 2.15 (dd, 1H,
Jˆ 4.8, 15.6 Hz), 2.06 (s, 6H), 1.89 (dd, 1H, Jˆ8.2,
15.5 Hz), 1.15 (d, 6H, Jˆ6.6 Hz), 1.05 (bs, 6H); 13C NMR
(75 MHz, CDCl3) d 167.6, 147.2, 146.5, 136.7, 135.5,
134.3, 132.1, 131.8, 130.2, 128.8, 128.0, 127.89, 127.85,
125.4, 125.2, 122.8, 120.9, 117.5, 111.4, 109.4, 88.3, 82.7,
55.2, 41.8, 39.4, 30.0, 24.3, 24.2, 20.1. Anal. Calcd for
C44H45NO3: C, 83.11, H, 7.13, N, 2.20; Found: C, 83.10,
H, 7.25, N, 2.14. The chiral HPLC analytical data (column
OD±H) of 8: retention times: tRˆ12.9 min for (3R)-8
(minor) and tRˆ16.6 min for (3S)-8 (major) using i-PrOH/
hexane (1/200) as eluent at a ¯ow rate of 0.5 mL/min. The
absolute con®guration was determined by derivation to the
authentic aminocarboxylic acid:35 (1) Pd/C, H2 (1 atm),
EtOAc, rt, 2 h; (2) Bu4NOH, THF, rt (see below for details);
(3) oxidation with Ag(I) (see below for details).
4.3.6.
phenyl 3-(2-methoxyphenyl) amino-4-octenoate (6). IR
(neat) 3425, 1756, 1514 cm21 1H NMR (300 MHz,
(R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
;
CDCl3) d 7.34±7.03 (m, 9H), 6.75 (dd, 1H, Jˆ7.2,
7.8 Hz), 6.70 (d, 1H, Jˆ7.8 Hz), 6.36 (dd, 1H, Jˆ7.2,
7.8 Hz), 6.25 (d, 1H, Jˆ7.8 Hz), 5.24 (dt, 1H, Jˆ6.9,
15.6 Hz), 4.77 (dd, 1H, Jˆ5.4, 15.6 Hz), 4.05 (bs, 1H),
3.80 (s, 3H), 3.62 (bs, 1H), 2.70 (bs, 2H), 2.06 (s, 6H),
2.02 (dd, 1H, Jˆ4.2, 15.0 Hz), 1.80 (dt, 2H, Jˆ7.2,
7.2 Hz), 1.75 (dd, 1H, Jˆ15.0, 8.4 Hz), 1.25 (tq, 2H, 7.2,
7.5 Hz), 1.17 (d, 6H, Jˆ6.9 Hz), 1.13 (d, 6H, Jˆ6.3 Hz),
0.81 (t, 3H, Jˆ7.5 Hz); 13C NMR (75 MHz, CDCl3) d
168.7, 147.3, 146.7, 146.6, 136.7, 136.3, 134.5, 132.1,
131.0, 130.4, 129.4, 128.8, 127.9, 125.3, 125.2, 121.0,
116.3, 110.7, 109.2, 55.2, 50.1, 39.4, 34.1, 30.1, 24.1, 22.3,
20.1, 13.7. Anal. Calcd for C41H49NO3: C, 81.55, H, 8.18, N,
2.32; Found: C, 81.67, H, 8.36, N, 2.39. The chiral HPLC
analytical data (column OD±H) of 6: retention times:
tRˆ9.0 min (minor); tRˆ9.7 min (major) using i-PrOH/
hexane (1/100) as eluent at a ¯ow rate of 0.5 mL/min.
4.3.9. 3-Methoxy-N-(phenylmethylene)benzenamine (12).18
1H NMR (300 MHz, CDCl3) d 8.46 (s, 1H), 7.94±7.88 (m,
2H), 7.50±7.48 (m, 3H), 7.26 (s, 1H), 6.81±6.78 (m, 3H), 3.85
(s, 3H); 13C NMR (75 MHz, CDCl3) d 160.5, 160.2, 153.4,
136.0, 131.6, 129.8, 128.7, 112.8, 111.7, 106.6, 55.2.
4.3.10. 2-(Methoxymethoxy)-N-(phenylmethylene)benz-
1
enamine (14). IR (neat) 1630, 1242, 1078 cm21; H NMR
(300 MHz, CDCl3) d 8.45 (s, 1H), 7.92 (dd, 2H, Jˆ2.1,
7.5 Hz), 7.47 (d, 2H, Jˆ2.1 Hz), 7.46 (s, 1H), 7.19 (d, 1H,
Jˆ8.1 Hz), 7.15 (dd, 1H, Jˆ8.1, 8.1 Hz), 7.04 (d, 1H,
Jˆ7.8 Hz), 7.02 (dd, 1H, Jˆ7.8, 7.8 Hz), 5.23 (s, 2H),
3.49 (s, 3H); 13C NMR (75 MHz, CDCl3) d 161.4, 149.7,
143.1, 136.3, 131.4, 128.9, 128.7, 126.5, 122.9, 120.5,
117.2, 95.7, 56.3. HRFABMS (NBA) m/z Calcd for
C15H15NO2 (M1): 241.1103; Found: 241.1114.
4.3.7.
phenyl 3-(2-methoxyphenyl) amino-5-phenyl-4-penteno-
ate (7). IR (KBr) 3420, 1755, 1509 cm21 1H NMR
(R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
4.3.11. Methyl 3-[(2-methoxymethoxy)phenyl]amino-3-
phenylpropionate. (Table 1, entry 6). IR (KBr) 3400,
;
1
(300 MHz, CDCl3) d 7.32±7.02 (m, 14H), 6.76 (ddd, 1H,
Jˆ2.0, 7.5, 7.5 Hz), 6.73 (dd, 1H, Jˆ1.7, 8.3 Hz), 6.64 (ddd,
1H, Jˆ1.5, 8.0, 8.0 Hz), 6.31 (d, 1H, Jˆ1.5, 7.8 Hz), 6.29
(d, 1H, Jˆ 15.9), 5.68 (dd, 1H, Jˆ5.7, 15.9 Hz), 4.20 (bs,
1H), 3.82 (bs, 1H), 3.80 (s, 3H), 2.80±2.60 (bs, 2H), 2.15
(dd, 1H, Jˆ 4.8, 15.6 Hz), 2.06 (s, 6H), 1.89 (dd, 1H, Jˆ8.4,
15.5 Hz), 1.16 (bs, 6H), 1.00 (bs, 6H); 13C NMR (75 MHz,
CDCl3) d 168.5, 147.3, 146.8, 146.5, 136.73, 136.67, 136.1,
134.4, 132.1, 130.3, 129.5, 128.8, 128.2, 127.9, 127.3,
126.6, 125.4, 125.2, 125.15, 121.0, 116.6, 110.8, 109.2,
55.2, 50.5, 39.0, 31.6, 30.0, 24.4, 24.1, 22.6. Anal. Calcd
1740, 1516 cm21; H NMR (300 MHz, CDCl3) d 7.36 (d,
2H, Jˆ7.8 Hz), 7.30 (dd, 2H, Jˆ7.2, 7.8 Hz), 7.21 (d, 1H,
Jˆ 7.2 Hz), 6.98 (d, 1H, Jˆ7.8 Hz), 6.75 (dd, 1H, Jˆ7.5,
7.8 Hz), 6.58 (dd, 1H, Jˆ7.5, 7.8 Hz), 6.44 (d, 1H, Jˆ
7.8 Hz), 5.21 (s, 2H), 5.08 (bs, 1H), 4.85 (t, 1H, Jˆ
6.6 Hz), 3.62 (s, 3H), 3.50 (s, 3H), 2.83 (d, 2H, Jˆ
6.6 Hz); 13C NMR (75 MHz, CDCl3) d 171.3, 144.4,
142.2, 137.2, 128.7, 127.3, 126.1, 122.4, 116.9, 113.8,
111.7, 95.0, 56.0, 54.7, 51.7, 42.9. Anal. Calcd for
C18H21NO4: C, 68.55, H, 6.71, N, 4.44; Found: C, 68.40,
H, 6.89, N, 4.44.

S. Saito et al. / Tetrahedron 57 (2001) 875±887
883
2
3
4.3.12. 2-Fluoro-N-(phenylmethylene)benzenamine (15).20
1H NMR (300 MHz, CDCl3) d 8.51 (s, 1H), 7.94±7.91 (m,
2H), 7.49±7.47 (m, 3H), 7.16±7.14 (m, 4H); 13C NMR
111.8 (d, JCFˆ 23.9 Hz), 111.8 (d, JCFˆ8.9 Hz). Anal.
HRFABMS (NBA) m/z Calcd for C13H9F2N (M1):
217.0703; Found: 217.0717.
1
(75 MHz, CDCl3) d 162.7, 155.1 (d, JCFˆ247 Hz), 139.9
2
(d, JCFˆ10.3 Hz), 135.8, 131.6, 128.9, 128.6, 126.6 (d,
4.3.19. 2-Chloro-N-(phenylmethylene)benzenamine (24).25
1H NMR (300 MHz, CDCl3) d 8.39 (s, 1H), 7.97±7.51 (m,
2H), 7.43±7.15 (m, 3H), 7.28 (dd, 1H, Jˆ7.2, 7.5 Hz), 7.14
(dd, 1H, Jˆ7.2, 7.5 Hz), 7.02 (dd, 1H, Jˆ7.5, 7.5 Hz).
3
4
3JCFˆ7.7 Hz), 124.4 (d, JCFˆ3.7 Hz), 121.8 (d, JCFˆ
1.7 Hz), 116.1 (d, 2JCFˆ19.9 Hz).
4.3.13. 2,4-Dimethoxy-N-(phenylmethylene)benzenamine
(16).21 1H NMR (300 MHz, CDCl3) d 8.51 (s, 1H), 7.92±
7.89 (m, 2H), 7.46±7.44 (m, 3H), 7.02 (d, 1H, Jˆ8.4 Hz),
6.55±6.48 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 159.4, 159.0, 153.6, 136.5, 134.9,
130.9, 128.6, 120.3, 104.2, 99.4, 55.8, 55.4.
4.3.20. 2-(Methoxyethoxy)-N-(phenylmethylene)benz-
enamine (25). IR (neat) 1630, 1248, 1116 cm21; H NMR
1
(300 MHz, CDCl3) d 8.49 (s, 1H), 7.91 (dd, 2H, Jˆ3.6,
3.6 Hz), 7.47 (d, 3H, Jˆ3.6 Hz), 7.15 (dd, 1H, Jˆ8.1,
8.4 Hz), 7.05±6.97 (m, 3H), 4.18 (t, 2H, Jˆ5.1 Hz), 3.73
(t, 2H, Jˆ5.1 Hz), 3.40 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 161.5, 151.1, 142.3, 136.4, 131.1, 128.7, 128.5, 126.3,
121.7, 121.0, 114.4, 71.0, 68.8, 59.2. Anal. Calcd for
C16H17NO2: C, 75.27, H, 6.71, N, 5.49; Found: C, 74.57,
H, 6.74, N, 5.67.
4.3.14. 2,5-Dimethoxy-N-(phenylmethylene)benzenamine
(17). IR (KBr) 1628, 1264, 1075 cm21; 1H NMR
(300 MHz, CDCl3) d 8.47 (s, 1H), 7.94±7.91 (m, 2H),
7.48±7.45 (m, 3H), 6.88 (d, 1H, Jˆ9.0 Hz), 6.71 (dd, 1H,
Jˆ3.0, 9.0 Hz), 6.63 (d, 1H, Jˆ3.0 Hz), 3.82 (s, 3H), 3.80 (s,
3H); 13C NMR (75 MHz, CDCl3) d 161.7, 153.9, 146.4,
142.5, 136.1, 131.4, 128.9, 128.6, 112.7, 110.6, 106.8, 56.5,
55.7. HRFABMS (NBA) m/z Calcd for C15H15NO2 (M1H1):
242.1181; Found: 242.1140.
4.3.21.
2,3-Dimethoxy-N-(phenylmethylene)benzen-
amine (26). IR (KBr) 1634 cm21; H NMR (300 MHz,
CDCl3) d 8.45 (s, 1H), 7.94±7.91 (m, 2H), 7.49±7.45 (m,
3H), 7.04 (dd, 1H, Jˆ8.1, 8.1 Hz), 6.79 (d, 1H, Jˆ8.1 Hz),
6.66 (d, 1H, Jˆ 8.1 Hz), 3.89 (s, 3H), 3.86 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 161.7, 153.2, 146.4, 141.4, 136.2,
131.4, 128.8, 128.7, 123.8, 113.1, 109.5, 60.7, 56.0. Anal.
HREIMS (PFK) m/z Calcd for C15H15NO2 (M1): 241.1103;
Found: 241.1121.
1
4.3.15. Methyl 3-(2,5-dimethoxyphenyl)amino-3-phenyl-
propionate. (Table 1, entry 9). IR (KBr) 3407, 1736,
1
1518 cm21; H NMR (300 MHz, CDCl3) d 7.38±7.22 (m,
5H), 6.65 (d, 1H, Jˆ8.4 Hz), 6.11 (dd, 1H, Jˆ3.0, 8.4 Hz),
6.04 (d, 1H, Jˆ3.0 Hz), 5.06 (bs, 1H), 4.81 (t, 1H,
Jˆ6.6 Hz), 3.82 (s, 3H), 3.64 (s, 3H), 3.62 (s, 3H), 2.86
(dd, 1H, Jˆ7.8, 15.0 Hz), 2.81 (dd, 1H, Jˆ6.3, 15.0 Hz);
13C NMR (75 MHz, CDCl3) d 171.3, 154.4, 142.0, 141.5,
137.6, 128.7, 127.4, 126.1, 109.9, 99.3, 99.2, 56.0, 55.3,
54.6, 51.8, 42.8. Anal. Calcd for C18H21NO4: C, 68.55, H,
6.71, N, 4.44; Found: C, 68.52, H, 6.90, N, 4.49.
4.3.22. 2-(Phenylmethylene)aminophenol (28).27 IR (KBr)
3130, 1630 cm21; H NMR (300 MHz, CDCl3) d 8.68 (s,
1
1H), 7.92±7.89 (m, 2H), 7.51±7.46 (m, 3H), 7.30 (dd, 1H,
Jˆ1.5, 7.8 Hz), 7.20 (ddd, 1H, Jˆ1.5, 7.2, 8.1 Hz), 7.02 (dd,
1H, Jˆ1.5, 8.1 Hz), 6.90 (ddd, 1H, Jˆ1.5, 7.2, 7.8 Hz).
4.3.23. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2,3-dimethoxyphenyl)amino-3-phenylpropio-
4.3.16. 2,6-Dimethoxy-N-(phenylmethylene)benzenamine
(18). IR (neat) 1640, 1252, 1036 cm21; 1H NMR
(300 MHz, CDCl3) d 8.50 (s, 1H), 7.95±7.92 (m, 2H),
7.47±7.45 (m, 3H), 7.06 (t, 1H, Jˆ8.4 Hz), 6.64 (d, 2H,
Jˆ8.4 Hz), 3.80 (s, 6H); 13C NMR (75 MHz, CDCl3) d
165.5, 151.5, 136.4, 131.2, 128.7, 128.5 (two peaks are over-
lapped), 124.8, 104.8, 56.1. HRFABMS (NBA) m/z Calcd for
C15H15NO2 (M1): 241.1103; Found: 241.1088.
1
nate (32). IR (CHCl3) 3432, 1752, 1510 cm21; H NMR
(300 MHz, CDCl3) d 7.31±6.23 (m, 14H), 6.70 (dd, 1H,
Jˆ8.1, 8.4 Hz), 6.26 (dd, 1H, Jˆ1.2, 8.4 Hz), 5.76 (dd,
1H, Jˆ1.2, 8.1 Hz), 4.66 (bs, 1H), 3.97±3.90 (m, 1H),
3.82 (s, 3H), 3.73 (s, 3H), 2.70 (bs, 2H), 2.15 (dd, 1H,
Jˆ7.8, 15.6 Hz), 2.04 (s, 6H), 2.00 (dd, 1H, Jˆ5.4,
15.6 Hz), 1.15 (d, 6H, Jˆ6.6 Hz), 1.06 (bs, 6H); 13C NMR
(75 MHz, CDCl3) d 168.4, 152.2, 147.2, 146.5, 142.4,
140.9, 136.7, 135.5, 134.3, 132.0, 130.3, 128.8, 128.5,
127.9, 127.0, 125.9, 125.3, 125.2, 123.8, 105.9, 101.3,
59.8, 55.6, 53.7, 41.3, 30.0, 24.2, 20.1. Anal. Calcd for
C43H47NO4: C, 80.47, H, 7.38, N, 2.18; Found: C, 80.45,
H, 7.28, N, 2.15.
4.3.17. (E)-2-Methoxy-6-methyl-N-(phenylmethylene)-
1
benzenamine (19).22 IR (KBr) 1624, 1283 cm21; H NMR
(300 MHz, CDCl3) d 8.34 (s, 1H), 7.95±7.91 (m, 2H),
7.49±7.47 (m, 3H), 7.00 (dd, 1H, Jˆ7.8, 8.1 Hz), 6.86 (d,
1H, Jˆ7.8 Hz), 6.82 (d, 1H, Jˆ8.1 Hz), 3.75 (s, 3H), 2.23
(s, 3H); 13C NMR (75 MHz, CDCl3) d 163.9, 149.4, 140.4,
136.4, 131.1, 131.0, 128.54, 128.46, 124.3, 122.5, 109.4,
55.7, 18.0. The E structure was determined by NOE
measurement.
4.3.24. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2,4-dimethoxyphenyl)amino-3-phenylpropio-
nate (33). IR (KBr) 3400, 1754, 1518 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.28 (d, 1H, Jˆ7.5 Hz), 7.26 (s,
1H), 7.20±7.12 (m, 6H), 7.10 (s, 1H), 6.98 (bd, 5H,
Jˆ6.3 Hz), 6.39 (d, 1H, Jˆ3.0 Hz), 6.17 (dd, 1H, Jˆ3.0,
8.4 Hz), 5.92 (d, 1H, Jˆ8.4 Hz), 4.23 (s, 1H), 3.88 (dd, 1H,
Jˆ4.8, 8.4 Hz), 2.70 (bs, 2H), 2.15 (dd, 1H, Jˆ8.4,
15.3 Hz), 2.04 (s, 6H), 1.99 (dd, 1H, Jˆ4.8, 15.3 Hz),
1.14 (d, 6H, Jˆ6.6 Hz), 1.09 (bs, 6H); 13C NMR
(75 MHz, CDCl3) d 168.5, 151.4, 147.9, 147.0, 146.4,
4.3.18. 2,6-Di¯uoro-N-(phenylmethylene)benzenamine
1
(20). IR (KBr) 1634 cm21; H NMR (300 MHz, CDCl3) d
8.56 (s, 1H), 7.93 (d, 2H, Jˆ8.1 Hz), 7.50 (d, 1H,
Jˆ7.8 Hz), 7.47 (dd, 2H, Jˆ7.8, 8.1 Hz), 7.10±7.00 (m,
1H), 6.95 (dd, 2H, Jˆ6.9, 7.8 Hz); 13C NMR (75 MHz,
1
3
CDCl3) d 166.8, 155.1 (dd, JCFˆ247.6 Hz; JCFˆ5.4 Hz),
3
135.7, 132.1, 129.0, 128.7, 125.0 (dd, JCFˆ8.9, 10.8 Hz),

884
S. Saito et al. / Tetrahedron 57 (2001) 875±887
142.6, 136.5, 134.2, 131.9, 130.8, 130.1, 128.7, 128.3,
127.7, 126.8, 125.8, 125.1, 111.6, 103.0, 98.5, 55.3, 55.1,
54.3, 41.9, 29.9, 24.1, 20.0. Anal. Calcd for C43H47NO4: C,
80.47, H, 7.38, N, 2.18; Found: C, 80.48, H, 7.68, N, 2.22.
The chiral HPLC analytical data (column OD±H) of 19:
retention times: tRˆ9.4 min for (3S)-19 and tRˆ14.7 min
for (3R)-19 using i-PrOH/hexane (1/200) as eluent at a
¯ow rate of 1.0 mL/min.
(37). IR (CHCl3) 3410, 1749, 1515 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.82±6.94 (m, 14H), 6.71 (dd, 1H,
Jˆ1.8, 7.5 Hz), 6.69 (ddd, 1H, Jˆ1.8, 7.2, 7.8 Hz), 6.61
(ddd, 1H, Jˆ1.8, 7.2, 7.5 Hz), 6.18 (dd, 1H, Jˆ1.8,
7.8 Hz), 5.44 (bs, 1H), 3.96 (dd, 1H, Jˆ4.2, 9.6 Hz),
3.80±3.70 (bs, 1H), 2.71 (bs, 2H), 2.19 (dd, 1H, Jˆ9.6,
15.6 Hz), 2.05 (s, 6H), 1.96 (dd, 1H, Jˆ4.2, 15.6 Hz),
1.15 (d, 6H, Jˆ6.9 Hz), 1.07 (bs, 6H); 13C NMR
(75 MHz, CDCl3) d 169.4, 146.4, 141.9, 136.9, 134.5,
134.3, 131.9, 130.3, 128.9, 128.5, 127.9, 127.2, 126.2,
126.1, 125.3, 125.2, 120.5, 120.0, 117.0, 114.4, 55.2, 41.4,
30.1, 24.2, 20.1. Anal. HREIMS m/z Calcd for C41H43ON
(M1): 597.3243; Found: 597.3228. The chiral HPLC analy-
tical data (column OD±H) of 36: retention times: tRˆ
6.2 min [(3S)-37] and tRˆ12.0 min [(3R)-37] using
i-PrOH/hexane (1/200) as eluent at a ¯ow rate of 1.0 mL/
min. The absolute con®guration was determined by deriva-
tion to 3 by methyl ether formation (MeI, K2CO3 acetone, rt,
2.5 h).3j
4.3.25. (S,S)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2,5-dimethoxyphenyl)amino-3-phenylpropio-
nate. (anti-34), which was derived from (S,S)-2. IR
(CHCl3) 3447, 1750, 1522 cm21 1H NMR (300 MHz,
;
CDCl3) d 7.29±6.97 (m, 14H), 6.60 (d, 1H, Jˆ8.4 Hz),
6.09 (dd, 1H, Jˆ2.7, 8.4 Hz), 5.66 (d, 1H, Jˆ2.7 Hz),
4.40 (d, 1H, Jˆ4.2 Hz), 3.92±3.86 (m, 1H), 3.78 (s, 3H),
3.58 (s, 3H), 2.76±2.60 (m, 2H), 2.15 (dd, 1H, Jˆ8.7,
15.6 Hz), 2.04 (s, 6H), 1.98 (dd, 1H, Jˆ4.8, 15.6 Hz),
1.14 (d, 6H, Jˆ6.9 Hz), 1.08 (bs, 6H); 13C NMR
(75 MHz, CDCl3) d 168.4, 154.2, 147.3, 146.5, 142.3,
141.6, 137.6, 136.7, 134.3, 132.0, 130.2, 128.8, 128.6,
127.8, 127.0, 125.9, 125.3, 125.2, 109.4, 99.8, 99.1, 55.9,
55.3, 53.8, 41.6, 30.0, 24.2, 20.1. Anal. Calcd for
C43H47NO4: C, 80.47, H, 2.18, N, 2.18; Found: C, 80.31,
H, 2.14, N, 2.14. The chiral HPLC analytical data (column
AD) of epi-34: retention times: tRˆ12.2 min (minor isomer)
and tRˆ16.8 min (major isomer) using i-PrOH/hexane
(1/100) as eluent at a ¯ow rate of 0.5 mL/min.
4.3.29. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-methansulfonylamino-3-phenylpropionate (38).
1
IR (CHCl3) 3375, 1755, 1148 cm21; H NMR (300 MHz,
CDCl3) major diastereomer: d 7.38±6.88 (m, 14H), 5.04 (s,
1H, Jˆ7.8 Hz), 4.37 (ddd, 1H, Jˆ4.5, 7.2, 7.5 Hz), 2.67 (bs,
2H), 2.57 (s, 3H), 2.15 (dd, 1H, Jˆ4.5, 17.4 Hz), 2.07 (s,
6H), 2.00 (dd, 1H, Jˆ7.5, 17.4 Hz), 1.20±1.00 (m, 12H);
minor diastereomer: d 7.38±6.88 (m, 14H), 4.52 (d, 1H,
Jˆ6.9 Hz), 4.28 (ddd, 1H, Jˆ5.4, 5.7, 7.2 Hz), 2.67 (bs,
2H), 2.50 (s, 3H), 2.29 (dd, 1H, Jˆ5.7, 17.4 Hz), 2.05 (s,
6H), 1.98 (dd, 1H, Jˆ6.0, 17.4 Hz), 1.20±1.00 (m, 12H);
13C NMR (75 MHz, CDCl3) major diastereomer: d 168.0,
147.6, 146.3, 139.5, 136.9, 134.3, 131.7, 130.4, 129.1,
128.7, 128.1, 127.8, 126.3, 125.7, 125.3, 53.1, 41.3, 39.7,
30.0, 24.2, 20.10; minor diastereomer: d 168.4, 147.5,
146.3, 139.2, 136.9, 134.2, 131.7, 130.4, 129.0, 128.6,
128.1, 127.6, 126.2, 125.7, 125.3, 53.0, 41.7, 39.1, 30.0,
24.1, 20.08. Anal. Calcd for C36H41NO4S: C, 74.04, H,
7.08, N, 2.40; Found: C, 74.05, H, 6.99, N, 2.50.
4.3.26.
(S,S)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-phenylamino-3-phenylpropionate. (anti-35),
which was derived from (S,S)-2. 1H NMR (300 MHz,
CDCl3) d 7.49±7.00 (m, 16H), 6.63 (t, 1H, Jˆ7.2 Hz),
6.22 (d, 2H, Jˆ7.5 Hz), 3.99±3.95 (m, 1H), 3.90±3.50
(bs, 1H), 2.73±2.65 (m, 2H), 2.13±1.95 (m, 2H), 2.05 (s,
6H), 1.16 (d, 6H, Jˆ6.9 Hz), 1.12 (d, 6H, Jˆ6.9 Hz). Anal.
HREIMS m/z Calcd for C41H43ON (M1): 581.3294; Found:
581.3318. The chiral HPLC analytical data (column OD±H)
of epi-35: retention times: tRˆ8.6 min (major isomer) and
tRˆ9.8 min (minor isomer) using i-PrOH/hexane (1/100) as
eluent at a ¯ow rate of 0.5 mL/min.
4.3.30. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-diphenylphosphinylamino-3-phenylpropionate
1
4.3.27. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2-pyridyl)amino-3-phenylpropionate (36). IR
(39). IR (KBr) 3388, 1759, 1439, 1206, 1142 cm21; H
NMR (300 MHz, CDCl3) major diastereomer: d 7.80±
6.78 (m, 24H), 4.19±4.10 (m, 1H), 3.66 (dd, 1H, Jˆ8.7,
10.2 Hz), 2.71±2.54 (m, 2H), 2.31 (dd, 1H, Jˆ6.0,
17.1 Hz), 2.16 (dd, 1H, Jˆ4.5, 17.1 Hz), 2.02 (s, 6H),
1.11 (d, 6H, Jˆ6.9 Hz), 1.0±0.50 (m, 6H); minor diastereo-
mer: d 4.05 (d, 1H, Jˆ10.5 Hz), other peaks are identical;
13C NMR (75 MHz, CDCl3) major diastereomer: d 168.6,
147.3, 146.4, 141.0 (JCPˆ15.9 Hz), 136.7, 134.2, 133.2
(JCPˆ41.1 Hz), 133.1 (JCPˆ40.8 Hz), 132.24 (JCPˆ
19.5 Hz), 132.18 (JCPˆ 19.2 Hz), 131.9, 131.8 (JCPˆ
9.3 Hz), 131.68, 130.3, 128.8, 128.4, 128.27, 128.23,
127.9, 126.8, 126.2, 125.15, 50.5, 40.3 (JCPˆ18.3 Hz),
29.9, 24.1, 20.1; minor diastereomer: d 168.9, 147.3,
146.2, 140.8 (JCPˆ16.5 Hz), 136.7, 134.2, 133.2 (JCPˆ
41.1 Hz), 133.1 (JCPˆ40.8 Hz), 132.24 (JCPˆ19.5 Hz),
132.18 (JCPˆ19.2 Hz), 132.1 (JCPˆ9.0 Hz), 132.0, 131.8
(JCPˆ9.3 Hz), 131.71, 130.2, 128.8, 128.4, 128.34, 128.1,
127.9, 126.6, 126.1, 125.05, 49.8, 39.0 (JCPˆ19.5 Hz), 29.9,
24.1, 20.1. Anal. Calcd for C47H48NO3P: C, 79.97, H, 6.85,
N, 1.98; Found: C, 79.57, H, 7.15, N, 1.99. The chiral HPLC
(KBr) 3416, 3245, 1759, 1599, 1572 cm21 1H NMR
;
(300 MHz, CDCl3) d 8.00 (dd, 1H, Jˆ1.5, 4.8 Hz), 7.29±
6.93 (m, 15H); 6.53 (ddd, 1H, Jˆ1.5, 4.8, 7.2 Hz), 6.03 (d,
1H, Jˆ 8.4 Hz), 4.76 (d, 1H, Jˆ6.9 Hz), 4.52 (ddd, 1H,
Jˆ5.1, 6.9, 7.8 Hz), 2.74±2.60 (m, 2H), 2.22 (dd, 1H,
Jˆ7.8, 15.9 Hz), 2.04 (s, 6H), 2.01 (dd, 1H, Jˆ5.1,
15.9 Hz), 1.13 (d, 6H, Jˆ6.9 Hz), 1.12±0.80 (bs, 6H); 13C
NMR (75 MHz, CDCl3) d 168.5, 157.4, 147.9, 146.5, 141.7,
136.8, 136.7, 134.3, 132.0, 130.3, 128.8, 128.5, 127.8,
126.9, 125.9, 125.4, 125.1, 113.1, 107.7, 51.4, 40.1, 30.0,
24.2, 20.1. Anal. Calcd for C40H42N2O2: C, 82.44, H, 7.26,
N, 4.81; Found: C, 82.42, H, 7.32, N, 4.71. The chiral HPLC
analytical data (column OD±H) of 36: retention times:
tRˆ25.8 min (major isomer) and tRˆ30.4 min (minor
isomer) using i-PrOH/hexane (1/400) as eluent at a ¯ow
rate of 1.0 mL/min.
4.3.28. (R,R)-2,6-Bis(2-isopropylphenyl)-3,5-dimethyl-
phenyl 3-(2-hydroxyphenyl)amino-3-phenylpropionate

S. Saito et al. / Tetrahedron 57 (2001) 875±887
885
analytical data (column OD±H) of 39: retention times:
tRˆ6.5 min (minor) and tRˆ 8.5 min (major) using i-
PrOH/hexane (1/20) as eluent at a ¯ow rate of 1.0 mL/min.
6.9 Hz); 13C NMR (75 MHz, CDCl3) d 171.2, 151.6 (d,
2
1JCFˆ237 Hz), 141.7, 135.1 (d, JCFˆ11.3 Hz), 128.8,
3
3
127.6, 126.1, 124.4, (d, JCFˆ3.2 Hz), 117.1 (d, JCFˆ
2
7.1 Hz), 114.3 (d, JCFˆ18.4 Hz), 54.6, 51.9, 42.7. Anal.
4.3.31. Methyl 3-(methanesulfonyl)amino-3-phenylpro-
pionate (Table 1, entry 15). H NMR (300 MHz, CDCl3)
Calcd for C16H16FNO2: C, 70.31, H, 5.90, N, 5.13; Found:
C, 70.18, H, 6.07, N, 5.13.
1
d 7.34±7.27 (m, 5H), 5.70 (bs, 1H), 4.93 (dt, 1H, Jˆ6.3,
4.3.38. Methyl 3-(2,4-dimethoxyphenyl)amino-3-phenyl-
8.4 Hz), 3.66 (s, 3H), 2.89 (d, 2H, Jˆ6.3 Hz), 2.69 (s, 3H)).
propionate (48). IR (neat) 3407, 1736, 1518 cm21 1H
;
NMR (300 MHz, CDCl3) d 7.36±7.18 (m, 5H), 6.42 (d,
1H, Jˆ2.4 Hz), 6.34 (d, 1H, 8.7 Hz), 4.78 (dd, 1H, Jˆ6.3,
7.5 Hz), 4.97 (bs, 1H), 3.82 (s, 3H), 3.66 (s, 3H), 3.62 (s,
3H), 2.85 (dd, 1H, Jˆ7.5 15.0 Hz), 2.78 (dd, 1H, Jˆ6.3,
15.0 Hz); 13C NMR (75 MHz, CDCl3) d 171.5, 151.9,
147.9, 142.5, 130.8, 128.6, 127.2, 126.1, 111.6, 103.4,
99.0, 55.5, 55.4, 55.3, 51.7, 42.9. Anal. Calcd for
C18H21NO4: C, 68.55, H, 6.71, N, 4.44; Found: C, 68.55,
H, 6.70, N, 4.50.
4.3.32. 2-Methoxy-N-(2-naphthylenylmethylene)benz-
enamine (40).31 1H NMR (300 MHz, CDCl3) d 9.16 (s,
1H), 8.95 (d, 1H, Jˆ8.4 Hz), 8.17 (d, 1H, Jˆ7.2 Hz), 7.97
(d, 1H, Jˆ8.1 Hz), 7.91 (d, 1H, Jˆ8.1 Hz), 7.65±7.52 (m,
3H), 7.26±7.19 (m, 1H), 7.11±6.98 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 160.3, 152.1, 142.2, 133.6, 131.5,
131.4, 131.3, 129.2, 128.4, 127.1, 126.4, 125.9, 125.0,
123.9, 120.8, 120.1, 111.4, 55.6.
4.3.33. N-(Furfurylidene)-2-methoxybenzenamine (41).32
1H NMR (300 MHz, CDCl3) d 8.33 (s, 1H), 7.60 (d, 1H, Jˆ
0.9 Hz), 7.19 (ddd, 1H, Jˆ1.8, 7.8, 8.1 Hz), 7.04 (dd, 1H,
Jˆ1.8, 8.1 Hz), 6.96±6.30 (m, 3H), 6.53 (ss, 1H, Jˆ1.8,
3.6 Hz), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3) d
152.3, 152.0, 148.3, 145.2, 140.6, 126.7, 120.6, 120.0,
115.7, 111.8, 111.1, 55.4.
4.4. Removal and recovery of chiral auxiliary 1
To a solution of 3 (184 mg, 0.3 mmol) in dry THF
(1.20 mL) was added dropwise a concentrated n-Bu4NOH
in THF (1.50 mL), which was prepared from commercially
available n-Bu4NOH (565 mL: 40 wt% in H2O) by azeo-
tropic removal of H2O by evaporation after treatment with
DME (1.50 mL) and toluene (1.50 mL) which was repeated
twice. After being stirred at 08C for 1.5 h, the reaction
mixture was quenched with 3N HCl, extracted with
EtOAc ®ve times and dried over Na2SO4. Filtration and
concentration of solvents afforded a crude mixture, which
was dissolved in MeOH (1.0 mL), followed by addition of a
1.0 M hexane solution of Me3SiCHN2 at rt. The mixture was
stirred until no gas evolution was observed, and subse-
quently quenched with HCO2H until no more N2 evolution
was observed, and washed with H2O. The organic layer was
dried oved Na2SO4. Evaporation of solvents and puri®cation
by column chromatography on extra pure silica gel (EtOAc/
hexaneˆ1/20 to 1/0 as the eluent) gave b-aminoester 46
(81 mg, .99%) in 91% ee as colorless solids.
4.3.34. 2-Methoxy-N-(2-hexenylidene)benzenamine (42).
This compound was prepared by treatment of (E)-2-hexenal
with o-anisidine over MS 4A in toluene at rt and used with-
out any puri®cation. The aldimine mixture was transferred
by a cannula to a mixture of the lithium enolate of 2 and
Et2Zn.
4.3.35. 2-Methoxy-N-(3-phenyl-2-propylenylidene)ben-
zenamine (44). IR (KBr) 2203, 1601 cm21 1H NMR
;
(300 MHz, CDCl3) d 8.00 (s, 1H), 7.60±7.40 (m, 2H),
7.41±7.30 (m, 3H), 7.22 (d, 1H, Jˆ6.6 Hz), 7.02 (d, 1H,
Jˆ8.1 Hz), 6.97 (d, 1H, Jˆ6.6 Hz), 6.95 (d, 1H, Jˆ8.1 Hz);
13C NMR (75 MHz, CDCl3) d 152.5, 144.3, 140.4, 132.4,
129.7, 128.4, 128.0, 121.5, 120.9, 120.1, 111.5, 94.6, 88.0,
55.7. HRFABMS (NBA) m/z Calcd for C16H13NO (M1):
235.0997; Found: 235.1010.
4.5. Oxidative removal of methoxyphenyl moiety using
AgNO3 and (NH4)2S2O8,15 and determination of the
absolute con®guration
4.3.36. Methyl 3-(2-methoxyphenyl)amino-3-phenylpro-
pionate (46).8 IR (neat) 3376, 1730 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.35 (d, 2H, Jˆ7.8 Hz), 7.29 (dd,
2H, Jˆ7.2, 7.8 Hz), 7.22 (d, 1H, Jˆ7.2 Hz), 6.74 (d, 1H,
Jˆ7.8 Hz), 6.71 (dd, 1H, Jˆ7.5, 7.8 Hz), 6.61 (dd, 1H,
Jˆ7.5, 7.8 Hz), 6.42 (d, 1H, Jˆ7.8 Hz), 5.03 (bd, 1H,
Jˆ6.3 Hz), 4.87 (dt, 1H, Jˆ6.3, 6.9 Hz), 3.84 (s, 3H),
3.62 (s, 3H), 2.86 (dd, 1H, Jˆ7.8, 15.0 Hz), 2.80 (dd, 1H,
Jˆ6.3, 15.0 Hz); 13C NMR (75 MHz, CDCl3) d 171.4,
146.8, 142.2, 136.5, 128.6, 127.3, 126.1, 121.0, 116.8,
111.1, 109.3, 55.4, 54.6, 51.7, 42.9. Anal. Calcd for
C17H19NO3: C, 71.56, H, 6.71, N, 4.91; Found: C, 71.73,
H, 6.80, N, 5.02.
To a solution of 46 (145 mg, 0.50 mmol) in a mixture of
H2O (2.5 mL)-MeCN (5.0 mL)-THF (0.5 mL) was added
catalytic AgNO3 (24 mg, 0.15 mmol), followed by portion-
wise addition of excess (NH4)2S2O8 (807 mg, 3.54 mmol)
over 7.5 min, during which time the temperature was kept at
608C. After 4 h, the mixture was cooled at rt, neutralized
with NaHCO3 and extracted with EtOAc. The organic layer
was dried over Na2SO4. Evaporation of solvents and puri®-
cation by column chromatography on extra pure silica gel
(EtOAc/hexaneˆ1/1 to 1/0 as the eluent) gave b-aminoester
49 (49 mg, 53%) in 91% ee as colorless solids. The absolute
con®guration of 49, derived from (R,R)-2, was determined
to be 3S in comparison with the authentic sample.34
4.3.37. Methyl 3-(2-¯uorophenyl)amino-3-phenylpropio-
nate. (Rac-47), IR (KBr) 3382, 1717, 1534 cm21; 1H NMR
(300 MHz, CDCl3) d 7.39±7.22 (m,5H), 6.95 (dd, 1H, Jˆ
8.1, 11.7 Hz), 6.84 (dd, 1H, Jˆ7.8 Hz), 6.59 (ddd, 1H, Jˆ
5.1, 7.8, 8.1 Hz), 6.51 (d, 1H, Jˆ8.1 Hz), 4.86 (dt, 1H, Jˆ
6.6, 6.9 Hz), 4.75 (bs, 1H), 3.67 (s, 3H), 2.85 (d, 2H, Jˆ
4.5. Oxidative removal of dimethoxyphenyl moiety using
cerium ammonium nitrate (CAN)16
Following the above procedure for the reaction of aldimine

886
S. Saito et al. / Tetrahedron 57 (2001) 875±887
11 with the lithium enolate of 2 except that aldimine 16 was
used, b-aminoester 33 was obtained in 63% yield (92% de)
using 0.5 equiv. of Me2Zn. Subsequently following the
above procedures for the sequential removal of auxiliary 1
from 3 and methylation with Me3SiCHN2, b-aminoester 48
was obtained quantitatively. To a solution of CAN (537 mg,
0.98 mmol) in H2O (3.30 mL) was added 48 (78.0 mg,
0.24 mmol) in MeCN (2.50 mL) at 08C over 10 min. After
being stirred for 40 min, H2O (5.0 mL) was added to the
reaction mixture, which was extracted with diethyl ether.
After separation of the two layers, the aqueous layer was
treated with Na2CO3 until pH of the solution became 7, and
®ltered through a pad of celite. The obtained aqueous ®ltrate
was extracted with EtOAc, and the organic layer was dried
over Na2SO4. Filtration and evaporation of solvents,
followed by puri®cation by column chromatography on
extra pure silica gel (EtOAc/hexaneˆ1/0 as the eluent)
gave b-aminoester 49 (90±99% yield) in 91% ee as color-
less solids.
obtained with graphite-monochromated MoKa radiation
on a MAC Science DIP2030 diffractometer at 298 K.
Standard re¯ections for each data set showed no signi®cant
decrease in intensity throughout acquisition. The structure
was solved by direct method and re®ned by full-matrix
least-squares on F2. All non-hydrogen atoms were re®ned
anisotropically, and hydrogens were found by Fourier
synthesis, using isotropic temperature factors. Crystallo-
graphic computations were performed on a Silicon Graphics
INDY computer using the maXus program for data reduc-
tion, determining the structure, re®ning the structure, and
molecular graphics. MAC DENZO software was used for
cell re®nement. Crystal data: aˆ12.2120 (9), bˆ9.9470 (3),
Ê
cˆ9.9060 (6) A, aˆ74.263 (4)8, bˆ94.465 (3)8, gˆ99.377
(4)8, triclinic, P1, Zˆ2, m(Mo)ˆ15.86 cm21, Rˆ0.044,
Rwˆ0.059, GOFˆ1.163, 4242 unique re¯ections with
I.3.0s(I).
Acknowledgements
4.6. Mannich-type addition of chiral acetate 2 to the
SnCl4-(Z)-11 complex
We are grateful to Mr S. Komai and H. Choshi (Nagoya
University) for performing high resolution mass spectro-
metric analysis.
To a solution of (R,R)-2 (80 mg, 0.2 mmol) in THF
(0.80 mL) was added a 1.59 M hexane solution of n-BuLi
(0.13 mL, 0.20 mL) at 2788C under argon atmosphere, and
the mixture was stirred at this temperature for 0.5 h. The
SnCl4-(Z)-11 complex,12a which was prepared by treatment
of (E)-11 (42 mg, 0.2 mmol) with SnCl4 (200 mL,
0.2 mmol) in CH2Cl2 (1.4 mL) at 08C followed by being
stirred at for 5 min, was transferred by a steel cannula to
the solution of the lithium enolate of acetate 2 at 2788C.
After 20 h, the reaction mixture was quenched by addition
of aqueous NaHCO3, ®ltered through a short path of celite
pad, extracted with diethyl ether, and dried over Na2SO4.
Filtration and evaporation of solvents, followed by puri®-
cation by column chromatography on silica gel (EtOAc/
hexaneˆ1/20 to 1/5 as the eluent) gave b-aminoester 3
(34 mg, 26% yield) in 70% de as colorless solids.
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To a solution of (E)-19 (45 mg, 0.2 mmol) in CH2Cl2
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È
4.8. X-ray crystallographic determinations of SnCl4-(Z)-
19
A single crystal of the SnCl4-(Z)-19 complex suitable for
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capillary tube as quickly as possible under air atmosphere,
and the glass capillary was mounted with a sticky compound
on a goniometer for measurement. Diffraction data were
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