Diastereoselective formation of α-aminoamides from carbamoylsilanes and aldehyde imines

Article abstract of DOI:10.1016/j.tetasy.2005.01.025

Diastereoselectivities were determined for the reaction of a series of aldehyde imines with carbamoylsilanes, each containing chiral auxiliaries at nitrogen. A maximum de of 88% was achieved via a matched double differentiation.

Full text of DOI:10.1016/j.tetasy.2005.01.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 941–947
Diastereoselective formation of a-aminoamides from
carbamoylsilanes and aldehyde imines
ꢀ
*
Jianxin Chen, Rajesh K. Pandey and Robert F. Cunico
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, USA
Received 1 October 2004; revised 8 November 2004; accepted 18 January 2005
Abstract—Diastereoselectivities were determined for the reaction of a series of aldehyde imines with carbamoylsilanes, each contain-
ing chiral auxiliaries at nitrogen. A maximum de of 88% was achieved via a matched double differentiation.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tual N-deprotection of the resultant diastereomers to
4
provide enantioenriched a-aminoamides.
We recently reported a novel approach to the synthesis
of a-aminoamides in which aldehyde imines 1a–c were
shown to add a carbamoylsilane 4a promoted by equi-
2. Results and discussion
1
molar amounts of BF ÆEt O to form 5. This provides
3
2
a simple entry into compounds, which represent the
building blocks of peptides and proteins, and have
Initially obtained product mixtures exhibited complex
NMR spectra, as a total of four superimposed spectra
resulted from the two newly formed diastereomers,
each existing as a syn/anti mixture of amides (the syn
and anti isomers for a given diastereomer derived from
4a only differed by separate N-methyl resonances).
However, the H NMR region between d 2.3 and 6.5,
containing the N-methyl, the newly stereogenic C–H
and the tertiary ethyl C–H protons of both chiral
2
important pharmacological applications. However for
efficient application within these areas, enantioenriched
substrates are required. We thus explored the potential
3
of both single and double stereodifferentiation in these
1
addition reactions by incorporating chiral N-auxiliaries
into the imine and/or carbamoylsilane components,
thereby affording the possibility of separation and even-
O
O
1
. BF ·Et O
H
3
2
R3
Ar
N
R2
Ar
N
R3
+
TMS
N
Me
3
N
2
. H O
2
R1
a Ar = Ph, R = H, R = Et
R1
R2
Me
1
2
1
1
1
4a R = Me
4b R = 1-phenylethyl
5
1
2
3
b Ar = Ph, R = H, R = iPr
1
2
c Ar = Ph, R = H, R = Ph
1
2
2
2
2
a Ar = Ph, R = Me, R = Et
1
2
b Ar = Ph, R = Me, R = iPr
1
2
c Ar = Ph, R = Me, R = Ph
1
2
3
3
3
a Ar = 1-Nph, R = Me, R = Et
1
2
b Ar = 1-Nph, R = Me, R = iPr
1
2
c Ar = 1-Nph, R = Me, R = Ph
*
ꢀ
Corresponding author. Tel.: +1 815 753 1131; fax: +1 815 753 4802; e-mail: rfc@marilyn.chem.niu.edu
Current address: Datong Medical College, DaTong, Shanxi, China.
0
957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.025

942
J. Chen et al. / Tetrahedron: Asymmetry 16 (2005) 941–947
auxiliaries was amenable to quantification. Diastereo-
meric ratios were determined on crude reaction mix-
tures, and the assignments of other NMR data were
often possible after chromatographic separation or
concentration.
In an effort to improve the dr results, double stereodif-
ferentiation was explored, initially by employing combi-
nations of (S)-2 with (S)-4b (runs 13–17). This afforded
low de values, which were, in general, even smaller than
those obtained from the use of achiral 4a. The situation
was significantly improved, however, when (S)-2 and
(R)-4b combinations were investigated (runs 18–20).
Here, de values ranged from 43% to 87%, with the added
advantage that all imines now afforded improved yields
of adducts. These last two sets of runs (13–17 and 18–20)
therefore appear to reflect the use of, respectively, ꢁmis-
matchedꢂ and ꢁmatchedꢂ pairs of chiral reactants, which
exert their influence on both the stereoselectivity and
yield of the reaction. Although a detailed mechanism
of these transformations is undetermined, stereodifferen-
tiation is often enhanced by the presence of more steri-
cally-demanding groups, as conformational preferences
are thereby exaggerated. Our attention thus turned to
the use of the chiral N-[1-(1-naphthyl)ethyl]imines 3a–c
as reaction partners. Again, initial results with 4a were
disappointing (runs 21–23), with dr values similar to
those obtained with the corresponding N-(1-phenyl-
ethyl)imines (runs 5–12). When the (S)-ꢁnaphthylꢂ imines
were paired with (S)-4b, however (runs 24–26), a consid-
erable enhancement in the de was observed (de = 60–
Table 1 summarizes our results. Achiral imines 1a–c were
used first with carbamoylsilane (S)-4b. This combination
afforded negligible diastereoselectivity, either in THF or
benzene as solvent. In contrast, placing the (S)-1-phenyl-
ethyl group on the imine nitrogen instead of the amide
nitrogen led to an immediate improvement in stereoselec-
tivity when reactions of (S)-2a–c with achiral 4a were
examined (runs 5–12), affording de values between 33%
and 67%. At this point, several experimental parameters
were briefly examined to assess their influence on yield
and de. In runs 12, 15 and 16, BCl was used in place
3
of BF . Although run 12 afforded an increased yield of
3
adduct under these conditions relative to the use of
BF , the dr was unimpressive, and results in runs 15
3
and 16 (compared to BF run 14) were disappointing.
3
There were also indications at this point (runs 3–4, 5–9)
that of the solvents listed, benzene afforded the best
yields with little or no negative effect on the dr, and benz-
ene therefore became the solvent of choice for later runs.
7
8%), when compared with the ꢁphenylꢂ [(S)-2, (S)-4b]
pairings (de = 20–50%). The expected ꢁmatchedꢂ pairings
of (S)-3 and (R)-4b (runs 27–29) were then examined.
The de values obtained (71–88%) were uniformly higher
than with the ꢁphenylꢂ counterparts. As a check on these
values, the ꢁreversedꢂ pairings (R)-3a, (S)-4b and (R)-3c,
Table 1. Yields and diastereomeric ratios of 5 obtained from 1 to 3
and 4
a
Run Imine Carbamoylsilane Solvent Time Yield Dr
b
(
h)
(%)
c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
1a
1b
1c
1c
(S)-4b
(S)-4b
(S)-4b
(S)-4b
THF
THF
THF
PhH
THF
PhH
THF
13.5
20.5
12.5
17
—
(
S)-4b were investigated and found to give parallel dr
53
56
76
54
62
10
28
1:1
1:1
1:1
1:5
1:4
1:2
1:2
1:2.5
—
values (runs 30, 31).
As proof of the method, the major diastereomer from
Table 1, run 29, was isolated from a preparative run
(S)-2a 4a
(S)-2a 4a
11.5
17
(52% yield) and deprotected by hydrogenolysis of the
(S)-2b 4a
(S)-2b 4a
12
30
CH
2
Cl
2
naphthylethyl group. The resulting a-aminoamide was
then subjected to acidic hydrolysis. The hydrochloride
5
(S)-2b 4a
(S)-2c 4a
PhH
THF
PhH
PhH
THF
PhH
PhH
17
15
40
c
24
D
134:0, compared to an authentic sample of L-phenyl-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
of the phenylglycine thus obtained showed ½aꢀ ¼
24
c
(S)-2c 4a
(S)-2c 4a
18
18
—
ꢁ
d
38
1:2
1:3
1:2
1:1
1:1.5
1:2.5
1:14
1:5
1:2.5
1:3
1:2
1:3
1:8
1:4
1:7
1:16
1:6
1:9
1:15
1:9
glycine hydrochloride with ½aꢀ ¼ þ136:6. This result
D
indicates that the chiral auxiliaries employed in run 29
predominantly gave R stereochemistry in the adduct.
(S)-2a (S)-4b
(S)-2b (S)-4b
(S)-2b (S)-4b
(S)-2b (S)-4b
(S)-2c (S)-4b
(S)-2a (R)-4b
(S)-2b (R)-4b
(S)-2c (R)-4b
(S)-3a 4a
11
43
54
38
d
16
33
d
CH
2
Cl
2
13.5
35
25
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
56
72
51
60
37
20
41
48
22
58
59
30
52
49
50
3. Conclusions
18
58
44
11
Chiral auxiliaries have been shown to be effective in
inducing diastereoselectivity in the addition of carba-
moylsilanes to imines. The effect is negligible when only
the carbamoylsilane bears a chiral N-(1-phenylethyl)
group, but modest, and approximately equal, stereo-
selection is observed when either N-(1-phenylethyl) or
N-[1-(1-naphthyl)ethyl] substituents are present on the
imine alone. Double diastereoselection, employing chi-
ral substituents in both carbamoylsilane and imine co-
reactants, proved effective in enhancing dr values only
when ꢁmatchedꢂ sets of (S)-imines and (R)-carbamoylsil-
anes (or vice versa) were employed. N-[1-(1-Naph-
thyl)ethyl] substituted imines were found to be
superior to N-(1-phenylethyl) substituted imines in this
regard. Many of the diastereomeric mixtures of 5 were
(S)-3b 4a
(S)-3c 4a
18
23
(S)-3a (S)-4b
(S)-3b (S)-4b
(S)-3c (S)-4b
(S)-3a (R)-4b
(S)-3b (R)-4b
(S)-3c (R)-4b
(R)-3a (S)-4b
(R)-3c (S)-4b
10.5
63
45
16
64
40
16
51
a
b
c
To complete consumption of 4.
Isolated yield.
Little or no product was formed.
d
3 3
BCl instead of BF .

J. Chen et al. / Tetrahedron: Asymmetry 16 (2005) 941–947
943
ꢁ
842 cm . Anal. Calcd for C H NOSi: C, 66.33; H,
13 21
8.99; N, 5.95. Found: C, 66.02; H, 8.78; N, 6.26.
1
separable by column chromatography, thus suggesting a
possible route to enantiopure a-aminoamides.
4.4. Aminoamides 5
4. Experimental
Characterization data for these compounds follow, iden-
tified by imine and carbamoylsilane source. All IR spec-
tra of 5 were obtained on neat liquids and exhibited
4
.1. General
ꢁ
1
All NMR spectra were obtained at 11.75 T in CDCl un-
3
the expected N–H (3310–3330 cm
(1635–1642 cm ) stretching frequencies.
)
and C@O
ꢁ
1
less otherwise indicated. A JASCO P-1010 polarimeter
was used to determine optical rotations. The procedure
for additions of carbamoylsilanes to the imines and sub-
4.5. Compounds 1b and (S)-4b: N-methyl-N-[(S)-1-phen-
ylethyl]-2-(N-benzylamino)-3-methylbutanamide
sequent product isolation was identical to that reported
1
earlier. An imine–BF –carbamoylsilane molar ratio of
3
1
:1:1.2, respectively, was employed. (S)- and (R)-a-
Inseparable mixture of diastereomers; major syn/anti iso-
1
Methylbenzylamine and (S)- and (R)-a-(1-naphthyl)eth-
ylamine, each 99+% ee, were obtained from the Aldrich
Chemical Co.
mer. H NMR: d 7.15–7.45 (m, 10H); 6.26, 6.21 (2q, 1H,
J = 7 Hz); 3.93, 3.59 (2 apparent t [2 overlapped AB pat-
terns], 2H, J = 14 Hz); 3.23, 3.21 (2d, 1H, J = 7 Hz); 2.53
(coincident s, 3H); 2.34 (br s, 1H); 1.88 (m, 1H); 1.55,
1.51 (2d, 3H, J = 7 Hz); 1.08, 1.05 (2d, 3H, J = 7 Hz);
4
.2. Imines
1
3
1.00, 0.99 (2d, 3H, J = 6.5 Hz). C NMR: d 175.3,
1
These were prepared as reported ( H NMR). Com-
pound 1a: d 7.83 (t, 1H, J = 4 Hz); 7.2–7.4 (m, 5H);
175.0, 140.6, 140.5 (coincident?), 140.4, 128.7–126.9
(overlapped peaks), 62.4, 62.2, 52.4, 52.2, 50.7, 50.6,
31.9, 31.6, 29.1 (coincident?), 20.0, 19.8, 18.6, 18.1,
15.8, 15.6. Anal. Calcd for C H N O: C, 77.74; H,
6
4
.60 (s, 2H); 2.35 (m, 2H); 1.16 (t, 3H, J = 7 Hz). Com-
6
pound 1b: d 7.69 (d, 1H, J = 4.5 Hz); 7.2–7.4 (m, 5H);
2
1
28
2
7
2
8
2
1
.53 (m, 1H); 1.14 (d, 6H, J = 7 Hz). Compound 1c: d
8.70; N, 8.63. Found: C, 77.53; H, 8.73; N, 8.54.
.44 (s, 1H); 7.3–7.8 (m, 10H); 4.87 (s, 2H). Compound
8
a: d 7.78 (t, 1H, J = 4.5 Hz); 7.2–7.4 (m, 5H); 4.31 (q,
H, J = 6.5 Hz); 2.31 (m, 2H); 1.52 (d, 3H, J = 6.5); 1.13
4.6. Compounds 1c and (S)-4b: N-methyl-N-[(S)-1-phen-
ylethyl]-2-(N-benzylamino)-2-phenylethanamide
8
(
t, 3H, J = 7.5 Hz). Compound 2b: d 7.63 (d, 1H,
J = 5.5 Hz); 7.2–7.4 (m, 5H); 4.29 (q, J = 7 Hz); 2.50
m, 1H); 1.51 (d, J = 7 Hz); 1.14 (d, 3H, J = 7 Hz);
Inseparable mixture of diastereomers; syn/anti mixture.
H NMR: d 6.6–7.4 (m, 15H); 6.19, 6.17, 5.11, 5.02
1
(
8
1
7
1
.11 (d, 3H, J = 7 Hz). Compound 2c: d 8.43 (s, 1H);
.84 (m, 2H); 7.3–7.5 (m, 8H); 4.60 (q, 1H, J = 7 Hz);
,65 (d, 3H, J = 7 Hz). Compound 3a: d 8.17 (d, 1H,
(4q, 1H, J = 7 Hz); 4.70, 4.65, 4.50, 4.48 (4s, 1H); 3.80
(m, overlapping AB patterns, 2H); 2.87 (br s, 1H);
2.73, 2.60, 2.46, 2.42 (4s, 3H); 1.55, 1.52, 1.39, 1.05
(4d, 3H, J = 7 Hz). Anal. Calcd for C H N O: C,
9
J = 8.5 Hz); 7.7–7.9 (m, 4H); 7.4–7.6 (m, 3H); 5.14 (q,
1
2
4
26
2
H, J = 7 Hz); 2.34 (m, 2H); 1.66 (d, 3H, J = 7 Hz);
9
80.41; H, 7.31; N, 7.81. Found: C, 80.28; H, 7.08; N,
7.65.
1
.12 (t, 3H, J = 7 Hz). Compound 3b: d 8.17 (d, 1H,
J = 8 Hz); 7.89 (d, 1H, J = 8 Hz); 7.7–7.8 (m, 3H); 7.5–
.6 (m, 3H); 5.11 (q, 1H, J = 7 Hz); 2.53 (m, 1H); 1.65
d, 3H, J = 7 Hz); 1.13 (d, 3H, J = 7 Hz); 1.10 (d, 3H,
J = 7 Hz). Compound 3c: d 8.47 (s, 1H); 8.30 (d, 1H,
J = 8 Hz); 7.8–7.9 (m, 5H); 7.4–7.6 (m, 6H); 5.40 (q,
7
(
4.7. Compounds (S)-2a and 4a: N,N-dimethyl-2-{N-[(S)-
1-phenylethyl]amino}butanamide
1
0
1
Major diastereomer. H NMR: d 7.2–7.4 (m, 5H); 3.77
(q, 1H, J = 6 Hz); 3.41 (t, 1H, J = 6.5 Hz); 2.86 (s,
1
H, J = 7 Hz); 1.79 (d, 3H, J = 7 Hz).
3
H); 2.80 (s, 3H); 2.3 (br s, 1H); 1.60 (m, 2H); 1.36 (d,
1
3
4.3. Carbamoylsilane 4b: (S)- and (R)-N-methyl-N-(1-
phenylethyl)-1-(trimethylsilyl)methanamide
3H, J = 6.5 Hz); 0.93 (t, 3H, J = 7 Hz). C NMR: d
174.8, 145.4, 128.3, 128.2, 127.0, 56.5, 56.2, 36.7, 35.4,
2
1
6.4, 23.3, 10.2. Minor diastereomer. H NMR: d 7.2–
These were individually prepared by the general meth-
1
7.4 (m, 5H); 3.59 (q, 1H, J = 6.5 Hz); 3.19 (t, 1H,
J = 6.5 Hz); 3.02 (s, 3H); 2.71 (s, 3H); 2.15 (br s, 1H);
1.51 (m, 2H); 1.33 (d, 3H, J = 6.5 Hz); 0.92 (t, 3H,
1
od starting from P99.5:0.5 er 1-phenylethylamines
and existed as a 45:55 mixture of syn and anti forms at
1
3
2
5 °C as indicated by NMR spectroscopy. Compound
J = 7 Hz). C NMR: d 175.6, 145.6, 128.3, 127.0,
126.9, 56.6, 56.4, 36.5, 35.6, 27.0, 25.7, 10.5. Anal. Calcd
for C H N O: C, 71.76; H, 9.46; N, 11.95. Found: C,
24
(R)-4b: ½aꢀ ¼ þ113:2 (c 1.0, CH Cl ). Their spectral
data were identical with those of 4b prepared from race-
D
2
2
1
4
22
2
1
mic 1-phenylethylamine. Major syn/anti isomer.
H
71.62; H, 9.51; N, 11.70.
NMR (CD Cl ): d 7.35–7.45 (m, 5H); 5.22 (q, 1H,
2
2
J = 7 Hz); 2.61 (s, 3H); 1.71 (d, 3H, J = 7 Hz); 0.379 (s,
4.8. Compounds (S)-2b and 4a: N,N-dimethyl-2-{N-[(S)-
1-phenylethyl]amino}-3-methylbutanamide
1
3
9
1
H). C NMR (CD Cl ): d 186.7, 140.5, 128.3, 127.2,
2
2
1
26.7, 54.8, 25.7, 17.7, ꢁ1.0. Minor syn/anti isomer. H
1
NMR (CD Cl ): d 7.35–7.45 (m, 5H); 6.17 (q, 1H,
Major diastereomer. H NMR: d 7.2–7.4 (m, 5H); 3.66
2
2
J = 7 Hz); 2.79 (s, 3H); 1.52 (d, 3H, J = 7 Hz); 0.376 (s,
(q, 1H, J = 6.5 Hz); 3.21 (d, 1H, J = 6.5 Hz); 2.82 (s,
3H); 2.72 (s, 3H); 2.20 (br s, 1H); 1.78 (m, 1H); 1.33
(d, 3H, J = 6.5 Hz); 0.99 (d, 3H, J = 6.5 Hz); 0.94 (d,
1
3
9
1
H). C NMR (CD Cl ): d 186.2, 141.1, 128.3, 127.3,
26.9, 47.6, 29.7, 15.3, ꢁ1.3. IR: 1567, 1384, 1249,
2 2

944
J. Chen et al. / Tetrahedron: Asymmetry 16 (2005) 941–947
1
3
3
1
H, J = 6.5 Hz). C NMR: d 175.3, 146.2, 128.3, 127.0,
26.8, 60.6, 57.8, 36.8, 35.4, 32.3, 23.3, 19.5, 18.4. Minor
NMR (major syn/anti only): d 175.5, 175.2, 146.4,
145.8, 140.6, 140.4, 128.6–126.4 (overlapped peaks),
61.0, 60.9, 57.6, 56.7, 50.6, 50.4, 32.4, 31.7, 29.1, 28.9,
26.1, 23.3, 19.8, 19.7, 18.4, 18.2, 15.9, 15.6. Anal. Calcd
for C H N O: C, 78.06; H, 8.93; N, 8.28. Found: C,
1
diastereomer. H NMR: d 7.2–7.4 (m, 5H); 3.55 (q, 1H,
J = 6 Hz); 3.02 (s, 3H + overlapped d, 1H); 2.70 (s, 3H);
2
1
.2 (br s, 1H); 1.73 (m, 1H); 1.32 (d, 3H, J = 6.5 Hz);
C
2
2
30
2
1
3
.00 (d, 3H, J = 7 Hz); 0.85 (d, 3H, J = 7 Hz).
77.91; H, 8.99; N, 8.15.
NMR: d 175.7, 145.9, 128.5, 128.3, 127.1, 60.5, 56.7,
6.8, 35.5, 31.8, 25.9, 19.7, 18.5. Anal. Calcd for
C H N O: C, 72.54; H, 9.74; N, 11.28. Found: C,
3
4.12. Compounds (S)-2c and (S)-4b: N-methyl-N-[(S)-1-
phenylethyl]-2-phenyl-2-{N-[(S)-1-phenylethyl]amino}-
ethanamide
1
5
24
2
7
2.27; H, 10.01; N, 11.09.
1
4
{
.9. Compounds (S)-2c and 4a: N,N-dimethyl-2-phenyl-2-
N-[(S)-1-phenylethyl]amino}ethanamide
Major diastereomer, syn/anti mixture: H NMR: d 6.5–
7.4 (m, 15H); 6.09, 4.97 (2q, 1H, J = 7 Hz); 4.50, 4.37
(2s, 1H); 3.59; 3.56 (2q, 1H, J = 7 Hz); 2.85 (br s, 1H);
2.54, 2.31 (2s, 3H); 1.44, 1.37 (2d, 3H, J = 7 Hz); 1.38,
1
Major diastereomer. H NMR: d 7.2–7.4 (m, 10H); 4.37
1
3
(
1
s, 1H); 3.52 (q, 1H, J = 6.5 Hz); 2.89 (s, 3H); 2.7 (br s,
1.29 (2d, 3H, J = 7 Hz). C NMR: d 172.0, 171.8,
145.2, 145,1, 140.0, 139.9, 139.2, 138.5, 126.6–128.9
(overlapped peaks), 60.4, 59.8, 54.4, 54.3, 53.6, 50.9,
28.9, 28.1, 25.0, 24.9, 16.8, 15.1. Minor diastereomer,
1
H); 2.69 (s, 3H); 1.31 (d, 3H, J = 6.5 Hz). C NMR:
3
d 172.0, 145.1, 138.6, 128.7, 128.4, 128.0, 127.7, 127.1,
26.9, 59.6, 54.2, 36.6, 35.9, 24.9. Minor diastereomer.
H NMR: d 7.3–7.45 (m, 10H); 4.30 (s, 1H); 3.77 (q,
H, J = 6.5 Hz); 3.03 (s, 3H); 2.66 (s, 3H); 2.6 (br s,
H); 1.40 (d, 3H, J = 6.5 Hz). C NMR: d 172.7,
45.4, 139.0, 128.9, 128.5, 127.7, 127.5, 127.2, 127.1,
0.4, 57.1, 36.5, 35.8, 25.0. Anal. Calcd for
1
1
1
syn/anti mixture: H NMR: d 7.0–7.5 (m, 15H); 6.21,
1
4.80 (2q, 1H, J = 7 Hz); 4.57, 4.28 (2s, 1H); 3.91, 3.86
(2q, 1H, J = 7 Hz); 2.73, 2.27 (2s, 3H); 2.7 (br s, 1H);
1.57, 1.43 (2d, 3H, J = 7 Hz); 1.40, 0.96 (2d, 3H,
1
3
1
1
6
1
3
J = 7 Hz). C NMR: d 172.6, 172.1, 145.4, 145.3,
140.4, 139.8, 139.6, 138.7, 129.1–126.5 (overlapped
peaks), 61.4, 60.9, 57.5, 57.1, 53.4, 50.8, 28.7, 27.8,
C H N O: C, 76.56; H, 7.85; N, 9.92. Found: C,
1
5.94; H, 7.62; N, 10.28.
8
22
2
7
2
5.8, 25.0, 16.1, 16.0. HRMS (CI) calcd for
+
4.10. Compounds (S)-2a and (S)-4b: N-methyl-N-[(S)-1-
phenylethyl]-2-{N-[(S)-1-phenylethyl]amino}butanamide
C H N O [MH ] 373.2276; found 373.2274.
25 29 2
4.13. Compounds (S)-2a and (R)-4b: N-methyl-N-[(R)-1-
phenylethyl]-2-{N-[(S)-1-phenylethyl]amino}butanamide
1
Major diastereomer, syn/anti mixture: H NMR: d 7.1–
7
(
.4 (m, 10H); 6.09, 4.87 (2q, 1H, J = 7 Hz); 3.85, 3.81
2q, 1H, J = 7 Hz); 3.43 (t, 1H, J = 6.5 Hz); 2.66, 2.49
1
Major diastereomer, syn/anti mixture: H NMR: d 7.1–
(
3
2s, 3H); 2.30 (br s, 1H); 1.65 (m, 2H); 1.46, 1.40 (2d,
H, J = 7 Hz); 1.39, 1.37 (2d, 3H, J = 7 Hz); 1.02, 0.92
7.4 (m, 10H); 6.00, 4.98 (2q, 1H, J = 7 Hz); 3.80 (m, 1H);
3.56, 3.37 (2t, 1H, J = 7 Hz); 2.68, 2.41 (2s, 3H); 2.4 (br
s, 1H); 1.6–1.7 (m, 2H); 1.54, 1.40 (2d, 3H, J = 7 Hz);
1.37, 1.28 (2d, 3H, J = 7 Hz); 1.00, 0.98 (2t,
1
3
(
2t, 3H, J = 7 Hz). C NMR: d 175.0, 174.9, 145.9,
1
5
1
45.8, 128.6ꢁ126.4 (overlapped peaks), 56.8, 56.6,
1
3
6.4, 56.3, 54.1, 50.5, 29.0, 28.4, 26.8, 26.2, 23.9, 23.4,
7.9, 15.6, 10.4, 10.3. Minor diastereomer, syn/anti mix-
3H, J = 7 Hz). C NMR: d 175.1, 174.7, 145.8, 145.7,
140.7, 140.2, 128.6–126.4 (overlapped peaks), 57.0,
56.9, 56.4, 55.9, 53.6, 50.4, 28.9, 28.0, 26.8, 26.4, 23.5,
23.4, 17.7, 15.3, 10.4, 10.3. Minor diastereomer, syn/anti
1
ture: H NMR: d 7.1–7.4 (m, 10H); 6.18, 4.85 (2q, 1H,
J = 7 Hz); 3.68, 3.68 (2 coincident q, 1H, J = 7 Hz);
1
3
1
(
.17 (t, 1H, J = 6.5 Hz); 2.74, 2.30 (2s, 3H); 2.2 (br s,
H); 1.60 (m, 2H); 1.56, 1.54 (2d, 3H, J = 7 Hz); 1.37
2 overlapped d, 3H, J = 7 Hz); 1.05, 0.94 (2t, 3H,
mixture: H NMR: d 7.1–7.4 (m, 10H); 6.19, 4.75 (2q,
1H, J = 7 Hz); 3.69, 3.50 (2q, 1H, J = 7 Hz); 3.30, 3.16
(2t, 1H, J = 7 Hz); 2.70, 2.29 (2s, 3H); 2.0 (br s, 1H);
1.7–1.2 (m, 8H); 0.9–1.5 (m, 3H). Anal. Calcd for
C H N O: C, 77.74; H, 8.70; N, 8.63. Found: C,
1
3
J = 7 Hz). C NMR: d 175.5, 175.4, 145.7, 145.6,
1
5
2
40.5, 139.9, 128.5–125.5 (overlapped peaks), 57.4,
6.9, 56.6, 53.3, 50.5, 30.3, 28.7, 27.8, 27.6, 27.0, 26.2,
5.8, 17.4, 15.8, 10.8, 10.6. Anal. Calcd for
2
1
28
2
77.71; H, 8.99; N, 8.53.
C H N O: C, 77.74; H, 8.70; N, 8.63. Found: C,
1
4.14. Compounds (S)-2b and (R)-4b: N-methyl-N-[(R)-1-
phenylethyl]-3-methyl-2-{N-[(S)-1-phenylethyl]amino}-
butanamide
9
28
2
7
7.53; H, 8.46; N, 8.50.
4.11. Compounds (S)-2b and (S)-4b: N-methyl-N-[(S)-1-
phenylethyl]-3-methyl-2-{N-[(S)-1-phenylethyl]amino}-
butanamide
1
Major diastereomer, syn/anti mixture: H NMR: d 7.0–
7.4 (m, 10H); 6.00, 5.02 (2q, 1H, J = 7 Hz); 3.71, 3.66
(2q, 1H, J = 7 Hz); 3.51, 3.21 (d, J = 4 Hz, d, J = 6 Hz,
1H); 2.70, 2.37 (2s, 3H); 2.3 (br s, 1H); 1.82 (m, 1H);
Inseparable mixture of diastereomers; syn/anti isomers:
1
H NMR: d 7.0–7.4 (m, 10H); 6.22, 6.11, 4.92, 4.84
1.61, 1.38 (2d, 3H, J = 7 Hz); 1.33, 1.21 (2d, 3H,
J = 7 Hz); 1.11, 1.00, 0.99, 0.93 (4d, 6H, J = 7 Hz).
1
3
(
4q, 1H, J = 7 Hz); 3.72, 3.65, 3.60 (4q, last 2 over-
lapped, 1H, J = 7 Hz); 3.38 and 3.32, 3.26 and 3.01
2d, J = 4 Hz and 2d, J = 6.5 Hz, 1H); 2.76, 2.59, 2.47,
C
NMR: d 175.2, 174.8, 146.5, 146.4, 140.7, 140.4,
128.7–126.2 (overlapped peaks), 61.1, 60.3, 58.2, 57.3,
(
1
2
1
1
.46 (4s, 3H); 2.25 (br s, 1H); 1.87, 1.79 (2m, 1H);
.56, 1.55, 1.46, 1.35, 1.34 (4d, 6H, J = 7 Hz); 1.00–
53.7, 50.5. Minor diastereomer, syn/anti mixture:
H
NMR: d 7.0–7.4 (m, 10H); 6.23, 4.78 (2d, 1H,
J = 5.5 Hz); 3.68 (m, 1H); 2.98 (d, 1H, J = 7.5 Hz, sec-
1
3
.05 and 0.88 (3 overlapped d + d, 6H, J = 7 Hz).
C

J. Chen et al. / Tetrahedron: Asymmetry 16 (2005) 941–947
945
ond d obscured); 2.72, 2.28 (2s, 3H); 2.3 (br s, 1H); 1.8–
4.18. Compounds (S)-3c and 4a: N,N-dimethyl-2-{N-[(S)-
1-(1-naphthyl)ethyl]amino}-2-phenylethanamide
1
3
.9 (m, 1H); 1.47, 1.87 (2d, 3H, J = 7 Hz); 1.32, 1.29 (2d,
H, J = 7 Hz); 1.05, 1.01 (2d, 3H, J = 7 Hz); 0.98, 0.89
1
(
2d, 3H, J = 7 Hz). Anal. Calcd for C H N O: C,
2
Major diastereomer: H NMR: d 7.1–8.0 (m, 12H); 4.48
(s, 1H); 4.40 (q, 1H, J = 6.5 Hz); 2.95 (s, 3H); 2.7 (br s,
2
30
2
7
8
8.06; H, 8.93; N, 8.28. Found: C, 77.96; H, 9.26; N,
.32.
1
3
1H); 2.67 (s, 3H); 1.44 (d, 3H, J = 6.5 Hz). C NMR:
d 172.0, 140.6, 136.6, 134.0, 131.3, 128.8, 128.7, 128.1,
127.7, 127.2, 125.8, 125.6, 125.2, 123.6, 123.1, 59.6,
4.15. Compounds (S)-2c and (R)-4b: N-methyl-N-[(R)-1-
phenylethyl]-2-phenyl-2-{N-[(S)-1-phenylethyl]amino}-
ethanamide
1
49.3, 36.6, 35.9, 24.4. Minor diastereomer: H NMR: d
7.2–8.25 (m, 12H); 4.65 (q, 1H, J = 6.5 Hz); 4.33 (s,
1
H); 3.00 (s, 3H); 2.44 (s, 3H); 1.6 (br s, 1H); 1.54 (d,
1
13
Major diastereomer, syn/anti mixture: H NMR: d 7.0–
7
(
3H, J = 6.5 Hz). C NMR: d 172.8, 140.7, 139.1,
134.0, 131.6, 128.9 (coincident?), 127.7, 127.5, 127.4,
125.8, 125.6, 125.3, 124.2, 123.2, 60.6, 52.7, 36.4, 35.8,
24.2. Anal. Calcd for C H N O + C H N O (picrate,
mp 199.0–200.5 °C): C, 59.89; H, 4.85; N, 12.47. Found:
C, 59.73; H, 4.93; N, 12.42.
.4 (m, 15H); 6.08, 4.94 (2q, 1H, J = 7 Hz); 4.62, 4.39
2s, 1H); 3.61, 3.57 (2q, 1H, J = 7 Hz); 2.9 (br s, 1H);
.64, 2.32 (2s, 3H); 1.48, 1.33 (2d, 3H, J = 7 Hz); 1.36,
.98 (2d, 3H, J = 7 Hz). C NMR: d 172.1, 171.7,
45.1 (coincident?), 140.4, 139.9, 139.2, 138.3, 128.9–
26,4 (overlapped peaks), 60.4, 60.1, 54.4, 54.3, 53.6,
0.6, 28.9, 28.0, 25.0 (coincident?), 16.0, 15.5. Minor
diastereomer, syn/anti mixture: H NMR: d 6.5–7.5
m, 15H); 6.22, 4.84 (2q, 1H, J = 7 Hz); 4.46, 4.26 (2s,
2
0
1
1
5
2
2
24
2
6
3
3
7
1
3
4.19. Compounds (S)-3a + (S)-4b: N-methyl-N-[(S)-1-
phenylethyl]-2-{N-[(S)-1-(1-naphthyl)ethyl]amino}-
butanamide
1
(
1
1
1
H); 3.88 (m, 1H); 2.75 (br s, 1H); 2.60, 2.23 (2s, 3H);
.3–1.5 (m, 6H). C NMR: d 172.5, 172.1, 145.4,
45.2, 140.2, 139.6, 138.9, 138.8, 129.2–126.9 (over-
1
3
1
Major diastereomer, syn/anti mixture: H NMR: d 7.05–
8.35 (m, 12H); 6.19, 4.82 (2q, 1H, J = 7 Hz); 4.75, 4.73 (2
superimposed q, 1H, J = 6.5 Hz); 3.59, 3.54 (2t, J = 6.5,
6 Hz, 1H); 2.70, 2.52 (2s, 3H); 2.45 (br s, 1H); 1.73 (m,
2H); 1.57, 1.53 (2d, 3H, J = 6.5 Hz); 1.50, 1.27
lapped peaks), 61.0, 60.7, 57.4, 57.3, 53.6, 51.0, 28.7,
7.9, 25.3, 25.2, 16.6, 15.3. Anal. Calcd for
C H N O: C, 80.61; H, 7.58; N, 7.52. Found: C,
2
2
5
28
2
1
3
8
0.36; H, 7.92; N, 7.73.
(2d, 3H, J = 7 Hz); 1.03, 0.95 (2t, 3H, J = 7 Hz).
C
NMR: d 175.14, 175.08, 141.6, 141.5, 140.54, 140.45,
134.0, 133.9, 131.4, 131.3, 128.9–123.3 (overlapped
peaks), 56.6, 56.4, 54.2, 51.7 (br), 51.5 (br), 50.5, 29.1,
4.16. Compounds (S)-3a and 4a: N,N-dimethyl-2-{N-[(S)-
1-(1-naphthyl)ethyl]amino}butanamide
2
8.5, 27.0, 26.4, 23.6, 22.9, 18.0, 15.6, 10.4 (coincident?).
1
1
Major diastereomer: H NMR: d 7.45–8.31 (m, 7H);
4
Minor diastereomer, syn/anti mixture: H NMR: d 6.65–
8.35 (m, 12H); 6.18, 4.72 (2q, 1H, J = 7 Hz); 4.56 (2
overlapped q, 1H, J = 6.5 Hz); [3.63 (dd, J = 8.5,
3.5 Hz), 3.22 (t, J = 7 Hz), 1H]; 2.66, 2.03 (2s, 3H); 2.0
(br s, 1H); 1.59 (m, 2H); 1.40, 1.28 (2 overlapped d,
3H, J = 6 Hz); 1.87, 1.47 (2 overlapped d, 3H,
.69 (q, 1H, J = 6.5 Hz); 3.53 (t, 1H, J = 6.5 Hz); 2.90
s, 3H); 2.72 (s, 3H); 2.2 (br s, 1H); 1.62 (m, 2H); 1.55
(
(
1
d, 3H, J = 6.5 Hz); 0.94 (t, 3H, J = 7 Hz). C NMR:
3
d 175.0, 141.4, 133.9, 131.3, 128.8, 127.2, 125.8, 125.6,
25.3, 123.5, 123.2, 55.9, 51.2, 36.7, 35.5, 26.6, 23.0,
0.2. Minor diastereomer: H NMR: d 7.45–8.3 (m,
H); 4.47 (q, 1H, J = 6.5 Hz); 3.23 (t, 1H, J = 6.5 Hz);
.96 (s, 3H); 2.39 (s, 3H); 1.65 (br s, 1H); 1.54 (m,
H); 1.48 (d, 3H, J = 6.5 Hz); 0.94 (t, 3H, J = 6.5 Hz).
C NMR: d 175.7, 140.9, 133.9, 131.6, 128.8, 127.2,
25.7, 125.5, 125.2, 124.0, 123.2, 56.5, 52.1, 36.4, 35.5,
7.0, 24.7, 10.6. Anal. Calcd for C H N O: C, 76.07;
1
1
7
2
2
1
13
J = 7 Hz); 1.17, 0.97 (2t, 3H, J = 7 Hz). C NMR: d
175.7, 175.2, 140.8 (coincident?), 140.5, 139.2, 134.1,
133.9, 131.5 (coincident?), 128.9–123.2 (overlapped
peaks), 57.4, 57.0, 53.0, 52.4 (br), 50.5, 28.6, 27.6,
27.5, 27.0, 25.1, 24.8, 16.9, 15.7, 10.9, 10.7. Anal. Calcd
for C H N O: C, 80.17; H, 8.07; N, 7.48. Found: C,
1
3
1
2
2
5
30
2
79.97; H, 8.39; N, 7.40.
1
8
24
2
H, 8.51; N, 9.85. Found: C, 75.94; H, 8.74; N, 9.83.
4.20. Compounds (R)-3a and (R)-4b: N-methyl-N-[(R)-1-
phenylethyl]-2-{N-[(R)-1-(1-naphthyl)ethyl]amino}-
butanamide
4.17. Compounds (S)-3b and 4a: N,N-dimethyl-2-{N-[(S)-
1-(1-naphthyl)ethyl]amino}-3-methylbutanamide
1
1
Major diastereomer: H NMR: d 7.4–8.3 (m, 7H); 4.59
Major diastereomer, syn/anti mixture: H NMR: d 7.0–
(
3
(
(
1
q, 1H, J = 6.5 Hz); 3.30 (d, 1H; J = 6.5 Hz); 2.85 (s,
H); 2.63 (s, 3H); 2.20 (br s, 1H); 1.83 (m, 1H); 1.49
d, 3H, J = 6.5 Hz); 1.01 (d, 3H, J = 6.5 Hz); 0.94
8.35 (m, 12H); 6.17, 4.81 (2q, 1H, J = 7 Hz); 4.73, 4.70 (2
superimposed q, 1H, J = 6.5 Hz); 3.57, 3.51 (2t, 1H,
J = 6.5, 6 Hz); 2.68, 2.50 (2s, 3H); 2.35 (br s, 1H); 1.71
(m, 2H); 1.55, 1.48 (2d, 3H, J = 7 Hz); 1.51, 1.25 (2d,
1
3
d, 3H, J = 6.5 Hz). C NMR: d 175.2, 142.0, 133.8,
1
3
31.2, 128.8, 127.1, 125.7, 125.5, 125.2, 123.5, 123.3,
0.5, 52.6, 36.8, 35.4, 32.3, 22.8, 19.5, 18.5. Minor dia-
3H, J = 6.5 Hz); 1.01, 0.92 (2t, 3H, J = 6.5 Hz).
C
6
NMR: d 175.54, 175.47, 142.0, 141.9, 140.95. 140.89,
134.4, 134.3, 131.8, 131.7, 129.3–123.7 (overlapped
peaks), 57.0, 56.9, 54.6, 52.2, 51.9, 50.9, 29.5, 28.9,
27.4, 26.8, 24.0, 23.3, 18.4, 16.1, 10.8 (coincident?).
1
stereomer: H NMR: d 7.4–8.3 (m, 7H); 4.42 (q, 1H,
J = 7 Hz); 2.97 (s, 3H); 2.34 (s, 3H); 2.20 (br s, 1H);
1
J = 7 Hz); 0.85 (d, 3H, J = 7 Hz). Anal. Calcd for
C H N O: C, 76.47: H, 8.78; N, 9.39. Found: C,
1
7
.78 (m, 1H); 1.48 (d, 3H, J = 7 Hz); 1.06 (d, 3H,
1
Minor diastereomer, syn/anti mixture: H NMR: d
6.65–8.35 (m, 12H); 6.18, 4.73 (2q, 1H, J = 7 Hz); 4.57
(2 overlapped q, 1H, J = 7 Hz); [3.62 (dd, J = 8.5,
9
26
2
6.11; H, 8.78; N, 9.55.

946
J. Chen et al. / Tetrahedron: Asymmetry 16 (2005) 941–947
3
.5 Hz), 3.22 (t, J = 7 Hz), 1H]; 2.66, 2.03 (2s, 3H); 2.0
br s, 1H); 1.58 (m, 2H); 1.45–1.55 (m, 6H); 1.17, 0.97
C H N O: C, 80.17; H, 8.07; N, 7.48. Found: C,
25 30 2
79.94; H, 8.40; N, 7.38.
(
(
1
3
2t, 3H, J = 7 Hz). C NMR: d 175.7, 175.2, 140.9,
1
1
40.8, 140.5, 139.2, 134.1, 133.9, 131.5 (coincident?),
29.0–123.2 (overlapped peaks), 57.4, 57.0, 53.0, 52.4
4.24. Compounds (S)-3b and (R)-4b: N-methyl-N-[(R)-1-
phenylethyl]-3-methyl-2-{N-[(S)-1-(1-naphthyl)ethyl]-
amino}butanamide
(
1
br), 50.5, 28.6, 27.6, 27.5, 27.0, 25.1, 24.8, 16.9, 15.7,
0.9, 10.7. Anal. Calcd for C H N O: C, 80.17; H,
25 30 2
1
8
.07; N, 7.48. Found: C, 79.93; H, 8.26; N, 7.32.
Major diastereomer only; syn/anti isomers: H NMR: d
7
.0–8.3 (m, 12H); 6.06, 5.05 (2q, 1H, J = 7 Hz); 4.64,
4.21. Compounds (S)-3b and (S)-4b: N-methyl-N-[(S)-1-
phenylethyl]-3-methyl-2-{N-[(S)-1-(1-naphthyl)ethyl]-
amino}butanamide
4.52 (2q, 1H, J = 7 Hz); 3.58, 3.31 (2d, 1H, J = 4,
6 Hz); 2.77, 2.31 (2s, 3H); 1.87 (m, 1H); 1.62, 1.52 (2d,
3H, J = 7 Hz); 1.37, 1.33 (2d, 3H, J = 7 Hz); 1.13, 1.05
(
2d, 3H, J = 7 Hz); 1.00 (2 superimposed d, 3H,
1
3
Inseparable mixture of diastereomers; syn/anti isomers:
J = 7 Hz). C NMR: d 176.0, 175.2, 142.5, 142.3,
140.7, 140.6, 133.9 (coincident?), 131.3, 131.2, 128.8–
123.2 (overlapped peaks), 61.1, 60.3, 53.9, 52.9 (br),
50.5, 32.3, 31.9, 29.1, 28.2, 25.0, 23.0, 20.3, 19.8, 18.2,
18.1, 17.2, 15.3.
1
H NMR: d 7.0–8.3 (m, 12H); 6.22, 4.85, 4.73 (2 over-
lapped q, q, q, 1H, J = 7 Hz); 4.61, 4.51 (2 overlapped
q, 2 overlapped q, 1H, J = 6.5 Hz); 3.57, 3.44, 3.37,
3
1
1
.06 (2d, J = 4 Hz, 2d, J = 7 Hz, 1H); 2.68, 2.62, 2.51,
.99 (4s, 3H); 1.80–1.95 (m, 1H); 1.9 (br s, 1H); 1.95–
.55 (m, 6H); 0.85–1.20 (m, 6H). Anal. Calcd for
4.25. Compounds (S)-3c and (R)-4b: N-methyl-N-[(R)-1-
phenylethyl]-2-phenyl-2-{N-[(S)-1-(1-naphthyl)ethyl]-
amino}ethanamide
C H N O: C, 80.17; H, 8.07; N, 7.48. Found: C,
2
6
32
2
7
9.93; H, 8.26; N, 7.32.
1
4.22. Compounds (S)-3c and (S)-4b: N-methyl-N-[(S)-1-
phenylethyl]-2-phenyl-2-{N-[(S)-1-(1-naphthyl)ethyl]-
amino}ethanamide
Major diastereomer, syn/anti mixture: H NMR: d 6.95–
8.05 (m, 17H); 6.12, 4.86 (2q, 1H, J = 7 Hz); 4.69, 4.47
(2s, 1H); 4.42 (2 coincident q, 1H, J = 7 Hz); 3.0 (br s,
1
H); 2.66, 2.28 (2s, 3H); 1.50, 1.44 (2d, 3H, J = 7 Hz);
1
13
Major diastereomer, syn/anti mixture: H NMR: d 6.45–
1.43, 0.92 (2d, 3H, J = 7 Hz). C NMR: d 172.1,
171.8, 140.7, 140.5, 140.4, 139.8, 139.2, 138.4, 134.04,
134.01, 131.36, 131.33, 128.9–123.1 (overlapped peaks),
60.4, 60.1, 53.6, 50.6, 49.7 (br), 49.4 (br), 28.9, 28.0,
24.5, 24.4, 16.0, 15.6. Minor diastereomer, syn/anti mix-
8
1
2
1
1
1
6
1
.0 (17H); 6.15, 4.89 (2q, 1H, J = 7 Hz); 4.59, 4.47 (2s,
H); 4.44 (2 overlapped q, 1H); 2.95 (br s, 1H); 2.56,
.27 (2s, 3H); 1.47 (2 overlapped d, 3H, J = 7 Hz);
.38, 1.31 (2d, 3H, J = 7 Hz). C NMR: d 172.1,
71.8, 140.7, 140.5, 140.2, 139.2, 139.1, 138.5, 134.1,
34.0, 131.4, 131.3, 128.8–123.1 (overlapped peaks),
1
3
1
ture: H NMR: d 6.45–8.3 (m, 17H); 6.23, 4.66 (2q, 1H,
J = 7 Hz); 4.75 (2 coincident q, 1H, J = 6.5 Hz); 4.46,
4.34 (2s, 1H); 2.95 (br s, 1H); 2.56, 2.08 (2s, 3H); 1.58
(2 superimposed d, 3H, J = 7 Hz); 1.47, 0.87 (2d, 3H,
J = 7 Hz). C NMR: d 172.7, 172.3, 140.6 (coincident?),
140.1, 136.6, 139.0, 138.8, 134.05, 134.00, 131.7, 131.6,
129.1–123.0 (overlapped peaks), 61.03, 60.98, 53.5,
53.1 (br), 52.9 (br), 51.0, 28.7, 27.9, 24.4, 24.3, 15.9, 15.3.
0.3, 59.8, 53.6, 50.9, 49.6 (br), 28.9, 28.1, 24.4, 24.3,
6.7, 15.1. Minor diastereomer, syn/anti mixture:
1
H
1
3
NMR: d 6.6–8.3 (17H); 6.20, 4.72 (2q, 1H, J = 7 Hz);
4
.67, 4.30 (2s, 1H); 4.42 (m, 1H); 3.0 (br s, 1H); 2.66,
.07 (2s, 3H); 0.9–1.7 (m, 6H). Anal. Calcd for
2
C H N O: C, 82.43; H, 7.16; N, 6.63. Found: C,
2
9
30
2
8
2.23; H, 7.32; N, 6.63.
4.26. Deprotection of the major diastereomer of run 29
[(S)-3c + (R)-4b]
4.23. Compounds (S)-3a and (R)-4b: N-methyl-N-[(R)-1-
phenylethyl]-2-{N-[(S)-1-(1-naphthyl)ethyl]amino}-
butanamide
A mixture of 1.4 g (5.3 mmol) of imine, 0.77 g BF ÆEt O
3
2
and 1.6 g (6.4 mmol) of carbamoylsilane in 38 mL of
benzene afforded (48 h) 1.2 g (52%) of the major diaste-
reomer, obtained from flash chromatography (15%
1
Major diastereomer, syn/anti mixture: H NMR: d 7.1–
8
(
.35 (m, 12H); 6.06, 4.49 (2q, 1H, J = 7 Hz); 4.71, 4.18
2q, 1H, 7 Hz); 3.67, 3.49 (2t, 1H, J = 6.5 Hz); 2.73,
.35 (2s, 3H); 2.53 (br s, 1H); 1.65 (m, 2H); 1.55 (2d,
H, J = 7 Hz); 1.40 (2d, 3H, J = 7 Hz); 1.02, 0.99 (2t,
H, J = 7 Hz). C NMR: d 175.1, 174.9, 141.7, 141.6,
40.7, 140.3, 133.95, 133.94, 131.3, 131.2, 128.9–123.2
24
EtOAc/hexane), ½aꢀ ¼ þ42:6 (c 0.51, CHCl ). Hydro-
D
3
2
3
3
1
genolysis of 0.25 g of this material in 5 mL methanol
containing 50 mg of 10 wt % Pd/C under 1 atm at
25 °C for 10 h afforded 0.12 g (80%) of the aminoamide
1
3
1
from chromatography (EtOH–MeOH, 9:1), which H
(
2
overlapped peaks), 56.8, 56.3, 53.8, 51.7, 51.3, 50.5,
8.9, 28.1, 26.9, 26.6, 23.5, 23.1, 17.8, 15.4, 10.4, 10.3.
NMR indicated was totally amine deprotected. Further
characterization was carried out on the hydrochloride.
Thus, in another run, 0.80 g of the aminoamide was sim-
ilarly hydrogenated and the reaction mixture filtered
through Celite and concentrated. The residue was dis-
1
Minor diastereomer, syn/anti mixture: H NMR: d
.95–8.2 (m, 12H); 6.21, 4.46 (2q, 1H, J = 7 Hz); 4.52
2 overlapped q, 1H, J = 6.5 Hz); 3.35, 3.25 (2t, 1H,
J = 7 Hz); 2.63, 2.07 (2s, 3H); 2.35 (br s, 1H); 1.45–
6
(
solved in 15 mL Et O, and a solution of hydrogen chlo-
2
1
3
1
.65 (m, 8H); 0.99, 0.97 (2t, 3H, J = 7 Hz). C NMR:
ride in diethyl ether added dropwise with stirring to
pH 3. The resulting precipitate was filtered, washed with
ether and dried under vacuum to give 0.52 g (90%) of the
hydrochloride, mp 120–125 °C. This material showed
d (syn or anti only): 175.8, 140.8, 140.4, 133.9, 131.4,
1
2
28.8–123.9 (overlapped peaks), 57.0, 52.4 (br), 50.6,
8.7, 27.2, 24.9, 15.6, 10.7. Anal. Calcd for

J. Chen et al. / Tetrahedron: Asymmetry 16 (2005) 941–947
947
2
D
4
1
½
aꢀ ¼ þ3:0 (c 2.2, CHCl ). H NMR (mixture of syn
References
3
and anti): d (major stereoisomer) 8.96 (s, 3H), 7.0–7.8
m, 10H), 5.85 (q, J = 6 Hz, 1H), 5.72 (s, 1H), 2.50 (s,
H), 1.42 (d, J = 6 Hz, 3H); d (minor stereoisomer)
.05 (s, 3H), 7.0–7.8 (m, 10H), 6.02 (s, 1H), 5.08 (q,
J = 6 Hz, 1H), 2.48 (s, 3H), 0.88 (d, J = 6 Hz, 3H).
C NMR (mixture of syn and anti): d (major stereoiso-
mer) 167.8, 139.8, 127.0–131.5 (overlapped peaks), 55.9,
1.7, 29.3, 15.6; d (minor stereoisomer) 167.0, 138.7,
127.0–131.5 (overlapped peaks), 55.7, 54.4, 28.4, 15.3.
Anal. Calcd for C H ClN O: C, 66.76; H, 6.92; N,
(
3
9
1. Chen, J.; Cunico, R. F. Tetrahedron Lett. 2003, 44, 8025–
027.
. Katritzky, A. R.; Kirichenko, N.; Rogovoy, B. V.; He,
H.-Y. J. Org. Chem. 2003, 68, 9088–9092, and references
cited therein.
. Review: Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5953–
6
. Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New York,
1999; pp 638–639.
8
2
1
3
3
4
018.
5
1
7
21
2
9
.16. Found: C, 66.20; H, 7.07; N, 9.20.
5. A small amount of racemization is known to accompany
such hydrolysis. (a) Manning, J. M. J. Am. Chem. Soc.
1
J. Biol. Chem. 1968, 243, 5591–5597.
6. Tiollais, R. Bull. Soc. Chim. Fr. 1947, 708–724.
970, 92, 7449–7454; (b) Manning, J. M.; Moore, S.
Hydrolysis of the aminoamide obtained above was
accomplished by dissolving 120 mg in 2.0 mL of 6 M
HCl and heating at 110 °C in a sealed tube for 20 h.
The solution was concentrated and the solid washed
5
7
8
9
. Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1991, 56, 365–
72.
3
with EtOAc, kept at 60 °C (1 mmHg) for 15 h followed
. Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.; Villa, M.
Tetrahedron 1999, 55, 8103–8110.
. Harada, K.; Okawara, T. J. Org. Chem. 1973, 38, 707–
710.
by storage over P O (1 mmHg) for 24 h. We obtained
6
2
5
3 mg (75%) of phenylglycine hydrochloride, which had
24
aꢀ ¼ ꢁ134:0 (c 0.10, MeOH).
½
D
1
1
0. Lee, T.; Ahn, Y. Bull. Korean Chem. Soc. 2002, 23, 1490–
492.
1. Cunico, R. F.; Chen, J. Synth. Commun. 2003, 33, 1963–
968.
1
Acknowledgements
1
This work was supported by National Institutes of
Health grant R15 GM065864.