Enantiopure α-imino glyoxylate: A versatile substrate for the spontaneous asymmetric synthesis of unnatural hydroxyaryl glycinates

Article abstract of DOI:10.1016/j.tetasy.2011.03.008

A novel synthesis of useful enantiomerically pure arylglycinates via spontaneous reaction between phenol or naphthol derivatives and enantiopure α-imino glyoxylate in the absence of an acid catalyst is reported. A library of enantiopure substituted phenol

Full text of DOI:10.1016/j.tetasy.2011.03.008

Tetrahedron: Asymmetry 22 (2011) 591–596
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiopure
a-imino glyoxylate: a versatile substrate for the spontaneous
asymmetric synthesis of unnatural hydroxyaryl glycinates
Cristina Cimarelli a, Davide Fratoni a, Andrea Mazzanti b, Gianni Palmieri a,
⇑
a School of Science & Technology, University of Camerino, v. S.Agostino 1, 62032 Camerino, Italy
b Dept. of Organic Chemistry’’A. Mangini’’, University of Bologna, viale Risorgimento 4, 40136 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 February 2011
Accepted 24 March 2011
A novel synthesis of useful enantiomerically pure arylglycinates via spontaneous reaction between phe-
nol or naphthol derivatives and enantiopure -imino glyoxylate in the absence of an acid catalyst is
a
reported. A library of enantiopure substituted phenol or naphthol glycinates was obtained in good yields
and high diastereoselectivities. Diastereoisomerically pure aryl glycinates were obtained by direct flash
chromatography separation of the crude reaction mixture. The free OH moiety of the phenols or naph-
thols contributed to the activation of the imino group to form an intermolecular hydrogen bond and pro-
moted the reaction in the absence of an acid catalyst, as shown in the transition state reported. The
diastereoselectivity is due to thermodynamic control in the addition step.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
hydantoin derivative intermediate under alkaline conditions, has
already been published.3
There has been considerable interest within the synthetic com-
munity in the development of practical methods to prepare non-
natural
2. Results and discussion
a
-amino acid derivatives,1 due to their potential pharma-
cological properties and their use as precursors for novel peptide
structures. Arylglycines constitute an important class of non-pro-
teinogenic a-amino acids. Glycopeptidic antibiotics, such as vanco-
mycin, are one of the best studied and most important natural
sources of arylglycines. In addition to the naturally occurring aryl-
glycines, there are also a number of synthetic arylglycine deriva-
tives that could serve as a side-chain moiety of semisynthetic
penicillins and cephalosporins. Furthermore, it has recently been
found that molecules of this type are potent and selective agonists
or antagonists of metabotropic glutamate receptors.
Herein, we report the spontaneous reaction between either
naphthol or phenol derivatives 1 and ethyl glyoxylate imines 2,
in toluene at ꢀ15 °C, without the use of an acid catalyst, which af-
fords arylglicinate 3 with moderate to high yields obtained after a
few hours (Scheme and Table 1). Chiral a-imino ester 2 was readily
prepared by condensing ethyl glyoxylate and the (R)-(+)-1-phenyl-
ethylamine and can either be synthesized prior to use or one pot
in situ, according to described methods.4 The yields and diastere-
oselectivities varied in different solvents. The best result was ob-
tained in toluene (0.5 mol solution) at ꢀ15 °C for 3–10 h. To
evaluate the scope and limitations of the reaction, a variety of
substituted phenols and naphthols were employed as substrates
giving the results summarized in Table 1.
Moreover, the reaction does not require an anhydrous or inert
atmosphere, and takes place in the absence of strong acids, strong
bases, heavy metal catalysts or other undesirable chemicals. As
shown in Table 1, the reaction of enantiopure ethyl (E,R)-2-(1-phe-
nylethylimino)glyoxylate with electron rich aromatic compounds
1a–g proceeded smoothly.
The direct asymmetric addition of organic nucleophiles (elec-
tron rich aromatic compounds) to preformed or in situ generated
a-imino esters has emerged as one of the most promising and in-
tensely investigated routes to enantiomerically enriched
a-amino
acid derivatives.
In particular, imines derived from ethyl glyoxylate are excellent
electrophiles for the stereoselective construction of optically active
arylglycine derivatives, which have not received much attention.2
A cumbersome non direct synthesis of racemic 2-amino-2-(20-
hydroxinaphthalen-10-yl)acetic acid hydrochloride, as a Maillard
reaction inhibitor, obtained by hydrolysis of the corresponding
The pure stereoisomers can be isolated without a work-up of
the reaction mixture, via the direct flash chromatographic separa-
tion of the crude reaction mixture.
We found that the reaction does not occur when the
2-methoxynaphthalene is reacted with glyoxylate imine 2. The free
naphthol OH moiety probably promoted a cyclic transition state,
⇑
Corresponding author. Tel.: +39 0737 402241; fax: +39 0737 637345.
E-mail address: gianni.palmieri@unicam.it (G. Palmieri).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.008

592
C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 591–596
Table 1
H
H
H
Toluene,
N
Ph
O
O
O
-15 ºC, 3-10 h
N
Ph
+
O
yield 58-79 %
Et
Et
R
R
d.e. = 62-87 %
O
O
½ ꢁ
a 2D0
Entry
1
Product 3
3 Yielda (%)
drb
H
H
O
N
(R) Ph
O
(S)
1
1a
(R,S)-3a 74
82:18
+144.4 (c 2.3)
O
H
H
S
N (R) Ph
(S)
O
O
2
1b
(R,S)-3b 73
84:16
+213.2 (c 2.1)
H
H
N
N
(R) Ph
O
O
(S)
3
4
1c
(R,S)-3c 58
81:19
86:14
+87.9 (c 1.3)
O
O
H
H
Ph
(R)
(S)
O
1d
(R,S)-3d 67
+83.1 (c 2.7)
O
OMe
H
N
H
Ph
(R)
O
(S)
5
6
7
1e
(R,S)-3e 69
(R,S)-3f 79
(R,S)-3g 61
88:12
+70.6 (c 2.1)
+133.3 (c 2.7)
+132.7 (c 3.0)
O
O
MeO
OMe
H
H
N (R) Ph
O
O
(S)
1f
93:7
O
O
H
H
(R)
N
Ph
O
(S)
1g
86:14
O
O
H2N

C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 591–596
593
Table 1 (continued)
Entry
1
Product 3
3 Yielda (%)
(R,S)-3h 70
drb
½ ꢁ
a 2D0
OH
Ph
H
H
N
(R)
O
(S)
O
8
1a
77:23
ꢀ96.7 (c 2.1)
O
a
Isolated yield.
b
Determined by 1H NMR.
Figure 1. The thermodynamically favoured transition state for the addition step of
the direct asymmetric reaction (optimized using DFT at the B3LYP/6-31G(d) level5).
activating the imino group in situ via intermolecular hydrogen
bonding, and promoting the reaction in the absence of an acid cat-
alyst (Fig. 1).
Based on these results, the diastereoselectivity of this reaction
between the electron rich aromatic compounds 1a–g and chiral
imines was next studied.
Figure 2. X-ray structure of the glycinate derivate (1R,
indicates an intra-molecular hydrogen bond.
a
S)-3aꢂHCl.6 Dotted line
The stereochemical outcome of the direct asymmetric reactions
can be explained by a Si-facial attack on the imine that has an E-
configuration, by the Re-face of the naphthol 1a (Fig. 1).
The single imaginary frequency for the calculated transition
state corresponds to the transfer of the hydrogen from the oxygen
to the nitrogen atom. An IRC calculation started from this transi-
tion structure showed the absence of other transition states. This
is in agreement with the experimental data, which shows that
the free naphthol OH moiety is necessary for the success of the
reaction, in the absence of acid catalysis.
A switch in the facial selectivity is disfavoured by the steric
repulsion between the (R)-1-phenylethylimino group and the
naphthol.2 The transition state leading to diastereoisomer (R,R)-
3a, with an attack on the Si-face of naphthol, has an energy of
1.5 kcal/mol greater than that which leads to the obtained product
(1R,aS)-3a. The diastereoselectivity is due to thermodynamic con-
trol in the addition step.
2.1. Assignment of the absolute configuration
The configurational assignments of aminoesters 3 are based
upon X-ray crystallographic analysis of (ꢀ)-3aꢂHCl (Fig. 2) and pro-
vide a basis for understanding the stereochemistry of the reaction
and the induction when 1-(R)-phenylethylamine was used as chi-
ral source.
Figure 3. 1H NMR chemical shifts of benzylic proton H1 and H
isomeric -aminoesters (R,R)-3 and (1R, S)-3.
a of the diastereo-
a
a

594
C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 591–596
Figure 4. Most stable conformations of glycine derivatives (R,R)- and (1R,
a
S)-3a (optimized using DFT at the B3LYP/6-31G level7).
The following considerations contribute to the configurational
were calibrated using residual undeuterated solvents as the inter-
nal reference. Coupling constants (J) are given in Hertz. When nec-
essary, assignments of the structures of prepared compounds were
aided by a self consistency check using the 1H NOESY correlation
spectrum and decoupling experiments. IR spectra were recorded
using FTIR apparatus. Optical rotations were measured in a 1 dm
cell at 20 °C. All melting points are uncorrected. Where only the
major diastereomer was obtained pure, the 1H NMR signals for
the minor diastereomer were deduced from the spectra of the
crude reaction mixture or of the enriched chromatographic frac-
tions. All reagents were commercially available, purchased at the
highest quality, and purified by distillation when necessary.
assignments of all the arylglycine 3a–h. In all the pairs of the dia-
stereoisomeric arylglycines (R,S)-3 and (R,R)-3, the 1H NMR chem-
ical shifts of benzylic protons H1 and H
a bonded to the two
stereogenic carbon atoms show a common trend. In the diastereo-
isomer (R,S)-3 these protons are shifted upfield with respect to the
corresponding protons of the diastereoisomer (R,R)-3; the differ-
ence in chemical shifts reach up to 0.41 ppm as in the case of 3b
(Fig. 3).
Further confirmation was found when calculating the structure
of the more stable conformer for both diastereoisomeric products
(R,R)-3a and (1R,
a
S)-3a (Fig. 4). It was evident that in (1R,
aS)-3a,
the benzylic proton H
a
takes up a position in the shielding cones
of the phenyl group attached to the opposite carbon atom. On
4.2. Synthesis of enantiopure arylglicinates 3a–h
the basis of the conformational analysis results obtained from
molecular modelling (Fig. 4), the major arylglycine (1R,
a
S)-3a, that
In a typical procedure, sodium sulfate (2.0 g), ethyl glyoxylate
(3.0 mmol, 0.6 mL, 50% solution in toluene) and (R)-(+)-1-phenyl-
ethylamine (3.0 mmol, 0.364 g, 0.382 mL) were mixed in toluene
(5 mL) and stirred at rt for 2 h. Into the resulting filtered iminoester
solution naphthol or phenol derivatives (3.0 mmol) were added
and stirred at ꢀ15 °C for 3–10 h. Flash chromatography of the
crude reaction mixture on silica gel (hexane/EtOAc, 4:1) afforded
the pure diastereomers in the yields reported in the Table 1. The
isolated arylglicinates are spectroscopically characterized as
follows.
derives from the favoured transition state, is the more stable dia-
stereomer (thermodynamic control) and shows a molecular geom-
etry consistent with the X-ray crystallographic structure of (ꢀ)-3a
(Fig. 2).
3. Conclusion
In conclusion, a novel synthesis of useful enantiomerically pure
arylglycinates 3 via the spontaneous reaction between either phe-
nol or naphthol derivatives 1 and enantiopure glyoxylate imine 2
in the absence of an acid catalyst was observed. A variety of substi-
tuted phenol or naphthol glycinates were obtained in good yields
and high diastereoselectivities. Diastereoisomerically pure aryl
glycinates were obtained via flash chromatography separation of
the crude reaction mixture. O-Substituted naphthols were ineffec-
tive in this reaction. The free OH moiety of the phenols or naph-
thols probably contributed to the activation of the imino group
by intermolecular hydrogen bonding and promoted the reaction
in the absence of an acid catalyst, as shown in the transition state
reported. The diastereoselectivity is due to thermodynamic control
in the addition step.
4.2.1. Synthesis of (S)-ethyl 2-((R)-1-phenylethylamino)-2-(2-
hydroxynaphthalen-1-yl)acetate (R,S)-3a
Crystals; mp 86–88 °C (CH2Cl2/hexane); ½a D20
¼ þ144:4 (c 2.3,
ꢁ
CHCl3); IR (Nujol): mmax 3317, 1732, 1263, 1197, 1106, 735 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 0.97 (t, 3H, J = 7.3 Hz), 1.48 (d, 3H,
J = 6.8 Hz), 3.22 (br s, 1H), 3.68 (q, 1H, J = 6.8 Hz), 3.97 (dq, 1H,
J = 10.7, 7.3 Hz), 4.07 (dq, 1H, J = 10.7, 7.3 Hz), 5.06 (s, 1H), 7.06–
7.77 (m, 11H), 12.35 (br s, 1H); 13C NMR (100 MHz, CDCl3): d
13.9, 23.2, 54.8, 56.6, 61.9, 110.5, 119.8, 121.9, 122.7, 126.5,
126.8, 128.0, 128.8, 128.9, 129.0, 130.5, 133.4, 142.6, 157.0,
171.5. Anal. Calcd for C22H23NO3 (349.42): C, 75.62; H, 6.63; N,
4.01. Found: C, 75.78; H, 6.41; N, 4.22.
4. Experimental
4.1. General
4.2.1.1. (R)-Ethyl
2-((R)-1-phenylethylamino)-2-(2-hydrox-
ynaphthalen-1-yl)acetate (R,R)-3a.
Oil, ½a 2D0
¼ ꢀ69:2 (c 1.5,
ꢁ
CHCl3); IR (Nujol): mmax 3312, 1725, 1463, 1203, 1126, 731 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.08 (t, 3H, J = 7.3 Hz), 1.53 (d, 3H,
J = 6.4 Hz), 3.20 (br s, 1H), 3.97 (q, 1H, J = 6.4 Hz), 4.04 (dq, 1H,
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, with CDCl3 as solvent at ambient temperature and

C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 591–596
595
J = 10.7, 7.3 Hz), 4.19 (dq, 1H, J = 10.7, 7.3 Hz), 5.44 (s, 1H), 7.07–
7.88 (m, 11H), 12.40 (br s, 1H); 13C NMR (100 MHz, CDCl3): d
14.1, 21.4, 55.2, 57.0, 61.9, 111.4, 119.9, 121.6, 122.7,126.4,
126.7, 127.7, 128.7, 128.8, 128.9, 130.5, 132.9, 142.6, 156.6,
171.2. Anal. Calcd for C22H23NO3 (349.42): C, 75.62; H, 6.63; N,
4.01. Found: C, 75.71; H, 6.49; N, 4.25.
11.17 (br s, 1H); 13C NMR (100 MHz, CDCl3): d 14.1, 23.3, 54.6,
54.8, 55.3, 55.8, 61.8, 90.9, 94.3, 126.7, 127.7, 127.8, 128.8, 142.9,
159.6, 160.0, 161.3, 172.2. Anal. Calcd for C20H25NO5 (359.42): C,
66.83; H, 7.01; N, 3.90. Found: C, 66.69; H, 6.81; N, 4.12.
4.2.5.1. (R)-Ethyl 2-((R)-1-phenylethylamino)-2-(2-hydroxy-4,6-
dimethoxyphenyl)acetate (R,R)-3e.
1H NMR (400 MHz,
4.2.2. (S)-Ethyl 2-((R)-1-phenylethylamino)-2-(2-
mercaptonaphthalen-1-yl)acetate (R,S)-3b
CDCl3): d 1.18 (t, 3H, J = 7.0 Hz), 1.48 (d, 3H, J = 6.6 Hz), 3.12 (br
s, 1H), 3.74 (s, 6H), 3.85 (q, 1H, J = 6.6 Hz), 4.10 (dq, 1H, J = 10.7,
6.8 Hz), 4.18 (dq, 1H, J = 10.7, 7.3 Hz), 5.03 (s, 1H), 5.95 (d, 1H,
J = 2.6 Hz), 6.01 (d, 1H, J = 2.6 Hz), 7.18–7.36 (m, 5H), 11.40 (br s,
1H); 13C NMR (100 MHz, CDCl3): d 14.2, 21.1, 55.0, 55.1, 55.4,
56.0, 61.8, 90.9, 94.6, 102.2, 126.8, 127.6, 128.6, 143.2, 159.0,
159.7, 161.3, 172.4.
½
a 2D0
ꢁ
¼ þ213:2 (c 2.1, CHCl3); IR (Nujol):
mmax 3345, 1732, 1495,
1181, 812, 737 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.21 (t, 3H,
;
J = 6.8 Hz), 1.41 (d, 3H, J = 6.8 Hz), 2.40 (br s, 1H), 4.14 (dq, 1H,
J = 10.7, 6.8 Hz), 4.21 (dq, 1H, J = 10.7, 6.8 Hz), 4.51 (q, 1H,
J = 6.8 Hz), 4.52 (s, 1H), 7.25–7.95 (m, 12H); 13C NMR (100 MHz,
CDCl3): d 14.2, 24.7, 53.8, 61.5, 67.9, 127.5, 127.7, 128.3, 128.4,
128.5, 128.6, 128.7, 129.5, 129.7, 129.8, 133.2, 134.6, 136.2,
143.6, 169.3. Anal. Calcd for C22H23NO2S (365.49): C, 72.30; H,
6.34; N, 3.83. Found: C, 72.46; H, 6.49; N, 3.98.
4.2.6. (S)-Ethyl 2-((R)-1-phenylethylamino)-2-(1,3-dihydro-5-
hydroxyisobenzofuran-6-yl)acetate (R,S)-3f
Oil; ½a 2D0
ꢁ
¼ þ133:3 (c 2.7, CHCl3); IR (Nujol): mmax 3319, 1728,
1213, 1119, 743, 698 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.14 (t,
4.2.2.1.
(R)-Ethyl
2-((R)-1-phenylethylamino)-2-(2-merca-
1H NMR (400 MHz,
3H, J = 7.3 Hz), 1.47 (d, 3H, J = 6.8 Hz), 2.90 (br s, 1H), 3.74 (q, 1H,
J = 6.8 Hz), 4.00 (s, 1H), 4.07 (dq, 1H, J = 10.7, 7.3 Hz), 4.13 (dq,
1H, J = 10.7, 7.3 Hz), 5.87–5.92 (m, 4H), 6.36 (s 1H), 6.44 (s, 1H),
7.15–7.21 (m, 5H), 12.35 (br s, 1H); 13C NMR (100 MHz, CDCl3): d
14.1, 23.6, 27.1, 54.8, 62.1, 99.4, 101.1, 109.7, 110.9, 126.6, 127.9
128.0, 129.2, 140.5, 142.3 148.5, 155.3, 171.4. Anal. Calcd for
ptonaphthalen-1-yl)acetate (R,R)-3b.
CDCl3): d 1.24 (t, 3H, J = 7.3 Hz), 1.39 (d, 3H, J = 6.6 Hz), 2.40 (br
s, 1H), 4.16–4.22 (m, 2H), 4.38 (q, 1H, J = 6.6 Hz), 4.93 (s, 1H),
7.25–7.95 (m, 12H);
4.2.3. (S)-Ethyl 2-((R)-1-phenylethylamino)-2-(1-
hydroxynaphthalen-2-yl)acetate (R,S)-3c
C20H23NO4 (341.40): C, 70.36; H, 6.79; N, 4.10. Found: C, 70.18;
H, 6.95; N, 3.92.
Crystals; mp 110–112 °C (CH2Cl2/hexane); ½a D20
¼ þ87:9 (c 1.3,
ꢁ
CHCl3); IR (Nujol): mmax 3315, 1729, 1623, 1198, 1106, 735,
4.2.6.1. (R)-Ethyl 2-((R)-1-phenylethylamino)-2-(1,3-dihydro-5-
700 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.10 (t, 3H, J = 7.3 Hz),
hydroxyisobenzofuran-6-yl)acetate (R,R)-3f.
(c 1.9, CHCl3); IR (Nujol): mmax 3322, 1726, 1210, 1123, 741,
694 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.27 (t, 3H, J = 7.2 Hz),
½
a 2D0
ꢁ
¼ þ14:4
1.52 (d, 3H, J = 6.8 Hz), 3.12 (br s, 1H), 3.78 (q, 1H, J = 6.8 Hz),
4.04 (dq, 1H, J = 10.7, 7.3 Hz), 4.13 (dq, 1H, J = 10.7, 7.3 Hz), 4.31
(s, 1H), 7.01–8.35 (m, 11H), 12.20 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 14.1, 23.6, 55.0, 62.1, 62.4, 112.2, 118.6, 122.6, 125.1,
125.6, 126.6, 126.7, 127.4, 128.0, 128.2, 129.2, 134.4, 142.6,
154.1, 171.6. Anal. Calcd for C22H23NO3 (349.42): C, 75.62; H,
6.63; N, 4.01. Found: C, 75.40; H, 6.45; N, 4.26.
;
1.48 (d, 3H, J = 6.6 Hz), 2.90 (br s, 1H), 3.83 (q, 1H, J = 6.6 Hz),
4.22 (dq, 1H, J = 10.7, 7.2 Hz), 4.29 (dq, 1H, J = 10.7, 7.2 Hz), 4.32
(s, 1H), 5.82–5.86 (m, 4H), 6.37 (s 2H), 7.10–7.40 (m, 5H), 10.35
(br s, 1H); 13C NMR (100 MHz, CDCl3): d 14.4, 22.6, 56.2, 62.0,
62.1, 99.6, 101.2, 107.8, 112.1, 127.1, 128.1, 128.9, 129.0, 140.6,
142.5, 148.4, 153.1, 171.7. Anal. Calcd for C20H23NO4 (341.40): C,
70.36; H, 6.79; N, 4.10. Found: C, 70.49; H, 7.02; N, 4.01.
4.2.3.1.
(R)-Ethyl
2-((R)-1-phenylethylamino)-2-(1-hydrox-
1H NMR (400 MHz,
ynaphthalen-2-yl)acetate (R,R)-3c.
CDCl3): d 1.26 (t, 3H, J = 7.3 Hz), 1.54 (d, 3H, J = 6.8 Hz), 3.15 (br
s, 1H), 3.93 (q, 1H, J = 6.8 Hz), 4.22 (dq, 1H, J = 10.7, 7.3 Hz), 4. 31
(dq, 1H, J = 10.7, 7.3 Hz), 4.62 (s, 1H), 6.95–8.29 (m, 11H), 12.10
(br s, 1H).
4.2.7. (S)-Ethyl 2-((R)-1-phenylethylamino)-2-(4-amino-2-
hydroxyphenyl)acetate (R,S)-3g
Oil: ½a 2D0
ꢁ
¼ þ132:7 (c 3.0, CHCl3); IR (Nujol): mmax 3273, 1733,
1243, 1121, 743, 697 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.12 (t,
3H, J = 6.4 Hz), 1.45 (d, 3H, J = 6.8 Hz), 3.02 (br s, 2H), 3.74 (q, 1H,
J = 6.8 Hz), 3.97–4.15 (m, 3H), 4.06 (s, 1H), 6.14 (dd, 1H, J = 8.1,
2.1 Hz), 6.20 (d, 1H, J = 2.1 Hz), 6.67 (d, 1H, J = 8.1 Hz), 7.14–7.40
(m, 6H); 13C NMR (100 MHz, CDCl3): d 14.2, 23.6, 54.7, 61.9, 62.0,
103.6, 106.8, 110.1, 126.7, 127.9, 129.1, 131.5, 142.9, 148.1,
159.0, 172.1. Anal. Calcd for C18H22N2O3 (314.38): C, 68.77; H,
7.05; N, 8.91. Found: C, 68.92; H, 7.22; N, 9.18.
4.2.4. (S)-Ethyl 2-((R)-1-phenylethylamino)-2-(1-hydroxy-4-
methoxynaphthalen-2-yl)acetate (R,S)-3d
Oil, ½a 2D0
ꢁ
¼ þ83:1 (c 2.7, CHCl3); IR (Nujol): mmax 3302, 1732,
1459, 1213, 731, 658 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 1.12 (t,
3H, J = 7.0 Hz), 1.52 (d, 3H, J = 6.8 Hz), 2.60 (br s, 1H), 3.80 (q, 1H,
J = 6.8 Hz), 3.92 (s, 3H), 4.07 (dq, 1H, J = 10.7, 7.0 Hz), 4.14 (dq,
1H, J = 10.7, 7.0 Hz), 4.26 (s, 1H), 6.37 (s, 1H), 7.18–8.33 (m, 9H),
11.60 (br s, 1H); 13C NMR (100 MHz, CDCl3): d 14.1, 23.7, 55.1,
56.1, 62.0, 62.8, 106.4, 111.1, 121.6, 122.4, 125.8, 126.1, 126.2,
126.3, 126.7, 127.9, 129.1, 142.8, 147.7, 148.3, 171.5. Anal. Calcd
for C23H25NO4 (379.45): C, 72.80; H, 6.64; N, 3.69. Found: C,
72.68; H, 6.41; N, 3.87.
4.2.8. (S)-Eethyl 2-((R)-2-hydroxy-1-phenylethylamino)-2-(2-
hydroxynaphthalen-1-yl)acetate (R,S)-3h
Oil: ½a 2D0
ꢁ
¼ ꢀ96:7 (c 2.1, CHCl3); IR (Nujol): mmax 3303, 1722,
1623, 1211, 743, 700 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 0.99 (td,
3H, J = 7.3, 1.7 Hz), 3.70 (t, 1H, J = 5.1 Hz), 3.80–3.89 (m, 2H), 4.00
(dqd, 1H, J = 10.7, 7.3, 1.7 Hz), 4.09 (dqd, 1H, J = 10.7, 7.3, 1.7 Hz),
4.55 (br s, 2H) 5.15 (s, 1H), 7.07–7.79 (m, 11H), 12.05 (br s, 1H);
13C NMR (100 MHz, CDCl3): d 14.0, 56.2, 61.4, 62.3, 65.8, 109.7,
118.4, 119.6, 121.7, 128.1, 128.4, 128.6, 128.8, 129.0, 129.1, 129.3,
131.2, 133.8, 156.4, 171.0. Anal. Calcd for C22H23NO4 (365.42): C,
72.31; H, 6.34; N, 3.83. Found: C, 72.51; H, 6.46; N, 4.02.
4.2.5. (S)-Ethyl 2-((R)-1-phenylethylamino)-2-(2-hydroxy-4,6-
dimethoxyphenyl)acetate (R,S)-3e
Oil; ½a 2D0
ꢁ
¼ þ70:6 (c 2.1, CHCl3); IR (Nujol): mmax 3318, 1721,
1413, 1193, 1106, 731, 650 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d
1.10 (t, 3H, J = 6.8 Hz), 1.42 (d, 3H, J = 6.8 Hz), 3.02 (br s, 1H),
3.66 (s, 3H), 3.68 (q, 1H, J = 6.8 Hz), 3.78 (s, 3H), 4.05 (dq, 1H,
J = 10.7, 6.8 Hz), 4.09 (dq, 1H, J = 10.7, 6.8 Hz), 4.68 (s, 1H), 6.02
(d, 1H, J = 2.6 Hz), 6.09 (d, 1H, J = 2.6 Hz), 7.14–7.38 (m, 5H),
4.2.8.1. (R)-Ethyl 2-((R)-2-hydroxy-1-phenylethylamino)-2-
(2-hydroxynaphthalen-1-yl)acetate
(R,R)-3h.
1H
NMR

596
C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 591–596
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5. GAUSSIAN 09, Revision A.1, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A.
F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J.
J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.;
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2009.
(400 MHz, CDCl3): d 1.06 (td, 3H, J = 7.3, 1.7 Hz), 3.87–4.22 (m, 5H),
4.55 (br s, 2H) 5.45 (s, 1H), 6.95–7.82 (m, 11H), 12.05 (br s, 1H).
Acknowledgements
The financial support of this research by a grant from University
of Camerino and from MIUR-PRIN is gratefully acknowledged.
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