A practical o-hydroxybenzylamines promoted enantioselective addition of dialkylzincs to aldehydes with asymmetric amplification

Article abstract of DOI:10.1016/S0957-4166(00)00290-1

The addition of dialkylzincs to aldehydes is accelerated considerably by the presence of a catalytic amount of o-hydroxybenzylamine (R,R)-2e to give, after hydrolysis, the corresponding alcohol (S)-9 in good enantiomeric purity. The origins of the enantioselection have been elucidated. A strong positive nonlinear relationship was observed for the reaction enantioselctivity with the use of o-hydroxybenzylamine 2e, which is very accessible through a short stereoselective synthetic route. The enantiomeric purity of the product 9 is much higher than the d.e. of the chiral source 2e, and the rate of the enantioselective catalysis increases considerably with the increase of the d.e. of (R,R)-2e. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00290-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3361–3373
A practical o-hydroxybenzylamines promoted
enantioselective addition of dialkylzincs to aldehydes with
asymmetric amplification
Gianni Palmieri
Dipartimento di Scienze Chimiche, v. S. Agostino 1, I-62032 Camerino, Italy
Received 5 July 2000; accepted 21 July 2000
Abstract
The addition of dialkylzincs to aldehydes is accelerated considerably by the presence of a catalytic
amount of o-hydroxybenzylamine (R,R)-2e to give, after hydrolysis, the corresponding alcohol (S)-9 in
good enantiomeric purity. The origins of the enantioselection have been elucidated. A strong positive
nonlinear relationship was observed for the reaction enantioselctivity with the use of o-hydroxybenzy-
lamine 2e, which is very accessible through a short stereoselective synthetic route. The enantiomeric purity
of the product 9 is much higher than the d.e. of the chiral source 2e, and the rate of the enantioselective
catalysis increases considerably with the increase of the d.e. of (R,R)-2e. © 2000 Elsevier Science Ltd. All
rights reserved.
1. Introduction
In recent years, there has been a great deal of interest in the development of metal catalyzed
asymmetric reactions and also in the synthesis of ligands that result in high enantioselectivity in
the catalytic asymmetric carbonꢀcarbon bond formation.1–17 A practical consequence is the
discovery of ligand-accelerated catalysis (LAC).1 Thus, an existing catalyzed process is improved
by the addition of a specific ligand, which leads to a faster, ‘ligand-accelerated’ reaction. In this
field, asymmetric addition of diethylzinc to aldehydes using a catalytic amount of chiral catalyst
has attracted much attention. It is interesting therefore to develop a much simpler and readily
available ligand possessing high catalytic effect that features a deep chiral pocket after
complexation with the zinc organometallic reagent in order to realise an efficient catalytic and
enantioselective process. Numerous efforts have been made to search for new effective chiral
ligands2–15 and to investigate the reaction mechanism.16,17 Numerous chiral chelating ligands
have been applied in enantioselective additions of organozincs to aldehydes, but ligands
obtainable by short synthetic routes are still desirable.
E-mail: palmieri@camserv.unicam.it
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00290-1

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G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
In this paper, following on from previous works,18,19 I have developed the potentially useful
o-hydroxybenzylamine ligands 2 to use in the catalytic enantioselective alkylation of aldehydes.
2. Results and discussion
Initial studies were focused on the diethylzinc addition to benzaldehyde, a model reaction,
investigating the effect of the different ligands 1–4, 6 and 7 used as precatalysts (see Scheme 1
and Table 1).
Scheme 1. Synthesis of o-hydroxybenzylamines and 2-hydroxy-1-naphthalenemethylamine
The o-hydroxybenzylamines 2a–e are the best precatalysts and generally the diastereomer
(R,R)-2 gives the better performances that the ligand (1S,1%R)-2, enhancing the reactivity of the
dialkylzinc and the enantioselectivity towards the aldehydic carbonyl group. In particular the
ligand (R,R)-2e gives the best results and only a catalytic amount of this (6%) is enough to
perform good enantioselectivity and reactivity (see Fig. 1 and Table 2). The o-hydroxybenzyl-
amines (1S,1%R)-2c–e are by-products of the reduction of the corresponding imines (R)-1.
Comparing the e.e. values obtained with the use of ligands (1%R)-2f (16%) and (1R)-6e (42%)
it is possible to conclude that the presence of the stereogenic C-1 is more important than the
stereogoenic C-1% in transferring steric information to the enantioselective alkylation of
aldehydes.
It is reported in the literature that generally tertiary amines give better results than secondary
ones.2–15,20–24 The tertiary amine (R,R)-4e, which can be prepared by a problematic selective
alkylation of (R,R)-2e,20–24 or more conveniently through my reported procedure (see Scheme 1),
gives no particularly advantageous results (see Table 1, entry 13). With the use of tertiary amines
the alkylation reaction is slower and with a lower enantioselectivity (see (R,R)-4e in Fig. 2).12

G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
3363
Table 1
Enantioselective addition of diethylzinc to benzaldehyde promoted by enantiopure o-hydroxybenzylamines 2a–f
and derivatives
Entry
Catalyst
R
Time (h)
Yield (%)a
e.e.b
Config.c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
(R)-1b
Et
Me
Et
9
4
4
4
15
4
15
4
12
5
44
48
5
92
96
93
92
89
94
88
93
84
92
78
73
88
90
89
18
55
57
35
10
62
8
89
60
16
12
5
S
S
S
S
R
S
S
S
R
S
S
S
S
S
S
(R,R)-2a
(R,R)-2b
(R,R)-2c
(1S,1%R)-2c
(R,R)-2d
(1S,1%R)-2d
(R,R)-2e
(1S,1%R)-2e
(R)-2f
(R,R)-3e
(4S,1%R)-3e
(R,R)-4e
(R)-6e
iPr
iPr
tBu
tBu
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
71
42
87
4
4
(R,R)-7e
a GC yield on the mixture of the two enantiomers.
b Determined by capillary chiral GC analysis using the chiral column MEGADEX DMP b.39
c Configuration determined by the sign of optical rotation.
Figure 1. The e.e. of product (S)-9b and the initial rate of the reaction (Vo) as a function of the amount of ligand
(R,R)-2e used in the addition of diethylzinc to benzaldehyde. Conditions: [DEZ]=1.00 M; [BzH]=0.83 M; toluene;
20°C

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G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
Table 2
Optimisation of the enantioselective addition of dialkylzincs to benzaldehyde promoted by o-hydroxybenzylamine
(R,R)-2ea
(R,R)-2e (cat.)
8b+1.2 R2Znꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢁ (S)-9
Yield (%)b
e.e.prod.
c
Entry
R2Zn
Catalyst (%)
e.d.cat.
Time (h)/temp. (°C)
1
2
3
4
5
6
7
8
9
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
1.1 M/toluene
1.1 M/toluene
1.1 M/toluene
1.1 M/toluene
1.1 M/toluene
1.1 M/toluene
0
3
6
10
20
10
10
10
6
–
45/20
15/20
4/20
3/20
3/20
4/20
60/20
3/20
2/20
7/0
72
86
93
92
94
90
87
91
90
88
84
0
80
89
90
91
88
87
91
87
88
88
100
100
100
100
68
100
100
100
100
100
Me2Zn 2.0 M/toluene
Bu2Zn 1.0 M/heptane
Et2Zn
Et2Zn
Et2Zn
1.0 M/hexane
1.0 M/hexane
1.0 M/hexane
10
110
6
6
60/−15
a Conditions: [R2Zn]=1.00 M; [BzH]=0.83 M.
b GC yield on the mixture of the two enantiomers.
c Determined by capillary chiral GC analysis using the chiral column MEGADEX DMP b.39
More interesting performances are obtained with the amine (R,R)-7e, which gives results
comparable to the amine (R,R)-2e (see Table 1 and Fig. 2). The potentiality of this ligand will
be exploited in due course. The ligand (R,R)-7e, structurally similar to the well known Betti
Figure 2. Correlation from the enantioselectivity and the Vo observed for the different ligand precatalyst in the
addition of diethylzinc to benzaldehyde. Conditions: [ligand]=0.050 M; [DEZ]=1.00 M; [BzH] 0.83 M; toluene; 20°C
(* lack of the ligand)

G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
3365
base,25–27 was prepared through a stereoselective solvent free, very simple and straightforward
synthesis optimised as shown in Scheme 1. The forming aminonaphthol (R,R)-7e crystallises
spontaneously from the reaction mixture (yield 93%, d.e. 99%).
When the initial reaction rates (Vo), observed with the different ligands, are plotted against
the enantioselectivity obtained in the reaction of diethylzinc with benzaldehyde, the direct
proportionality reported in Fig. 2 is observed. This shows that in the (R,R)-2 series, the
performance of the catalyst increases approximately with the bulkiness of the R substituent
(R=tBu, Ph, Et, Me). Presumably, a phenyl group enhances diastereomeric recognition in the
transition state due to a larger contact area and multiple interaction sites. The best performances
are achieved with (R,R)-2e (R=Ph), the best precatalyst, which is much better than (1S,1%R)-2e.
Likewise (R,R)-2d (R=tBu) is much better than (1S,1%R)-2d, which shows negligible catalytic
ability. Luckily, the more efficient precatalysts (R,R)-2a–f are very accessible materials obtained
through a short stereoselective synthetic route in high yields as the major diastereomers under
the reduction conditions optimised previously.18 This makes the methodology convenient and of
practical use, although e.e. values observed in the alkylation reactions are not very high. Lack
of the ligand makes the reaction extremely slow (see Table 2 and Fig. 2). In hexane the reactions
are faster than in toluene but the same enantioselectivities are observed. There is no enhance-
ment of the enantioselectivity on lowering of reaction temperature, while the reaction time
becomes extremely long even at 0°C. It is noteworthy that when the ligand (R,R)-2e with 68%
d.e. (such as results from the reduction of imidoylphenol (R)-1e18) is used, a product of 88% e.e.
(Table 2, entry 6; Fig. 4(a), black point) is obtained. This situation is typical for ligands that
show asymmetric amplification.28,29 The alkylation reaction can be performed with dimethyl-,
diethyl-, and dibutylzinc with comparable results. With dimethylzinc the methylation reaction
proceeds rather slowly (Table 2, compare entry 7 vs. entries 6 and 8).
The results for the addition of diethylzinc to several aromatic and aliphatic aldehydes in the
presence of (R,R)-2e are summarised in Table 3. All the reactions proceeded smoothly to give
the corresponding alcohols (S)-9a–u in good yields. Various substituted aromatic aldehydes gave
high enantioselectivity. Generally electron donating substituents in the aldehyde give better e.e.
values as in 9a–e. This is consistent with a strong coordination of the aldehyde to the zinc atom
of the catalyst. The presence of halogen substituents lowered the enantioselectivity as in 9m,n.
Branched aliphatic aldehydes (8o–r) gave high enantioselectivities, better than linear ones,
suggesting that the stereoselection is steric in origin. All reactions produced 2–8% of the
corresponding benzyl alcohol as a by-product, deriving from the reduction of the aldehydes by
dialkylzincs.
The currently accepted mechanism for the b-amino alcohol catalysed addition of dialkylzinc
to aldehydes2,3,16,17 has been reviewed and applied to o-hydroxybenzylamines (see Scheme 2). It
can be assumed that the active catalytic species is the zincoxazine 10e, which acts as a
bifunctional catalyst that assembles the aldehyde and dialkylzinc, leading to the product forming
transition states 15-Ts. The second equivalent of dialkylzinc facilitates the dissociation of the
dimer 11 by the formation of coordinatively unsaturated monomeric 13. Coordination of the
aldehyde to 13 gives the product forming intermediate complex 14. The latter can be performed
by an inverse order of coordination of aldehyde and dialkylzinc to 10. A subsequent transfer of
an alkyl anion from zinc to the coordinated aldehyde gives 16 through the transition state 15-Ts.
This is the turnover limiting and the stereodetermining step. A theoretical scrutiny of the

3366
G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
numerous geometries and relative energies of the possible transition states would greatly help in
the understanding of the observed enantioselectivities. In order to estimate the relative energies,
at the PM3 semiempirical level,38 of the possible transition states, dimethylzinc has been
considered for simplicity.17,31–33 The structures anti-Re-15-Ts and anti-Si-15-Ts are the two
products forming transition states of lowest energy (see Fig. 3). The major transition state
anti-Si-15-Ts, more stable that anti-Re-15-Ts of 1.32 kcal/mol, leads to alkyl addition of the
aldehyde to the Si face to afford the alcohol (S)-9, in agreement with the experimental results.
The nonlinear effect observed3,16,28,29 is clear in Fig. 4(a), which shows the e.e. of the product
(S)-9b as a function of the d.e. of the chiral auxiliary (R,R)-2e. The enormous convexity of the
Table 3
Enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes promoted by enantiopure o-hydrox-
ybenzylamine (R,R)-2ea
Entry
Aldehyde
8
Time (h)
9
Yield (%)b
% e.e.c
[h]2D0 (c, solvent)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
m,p-(MeO)2C6H3CHO
PhCHO
8a
8b
8c
8d
8e
8f
8g
8h
8i
4
4
5
4
5
5
3
4
2
23
4
5
7
6
8
8
4
5
21
6
4
9a
9b
9c
9d
9e
9f
9g
9h
9i
92
93
88
92
92
85
92
87
89
81
89
83
94d
89
86d
86
94
83
83
81
80
78d
73
70
86
51
94
97
93
83
76
75
72
−31.4 (1.1, C6H6)
−41.8 (2.3, CHCl3)8
−18.5 (1.7, C6H6)
−35.4 (1.9, CHCl3)5
−34.8 (2.1, C6H6)5
−35.2 (1.3, C6H6)
−42.3 (2.7, C6H6)10
−28.3 (1.6, C6H6)6
−17.8 (1.1, C6H6)11
−7.46 (1.6, CHCl3)
−13.9 (2.6, CHCl3)6
−14.5 (2.1, CHCl3)13
−17.9 (1.8, C6H6)8
+1.6 (2.1, C5H12)9
−0.40 (1.9, CHCl3)7
−15.2 (1.3, EtOH)30
−9.19 (1.4, Et2O)7
+29.2 (1.1, CHCl3)10
−5.7 (2.5, CHCl3)8
+6.3 (1.6, CHCl3)8
+18.7 (1.9, EtOH)7
m,m%,p-(MeO)3C6H2CHO
p-MeC6H4CHO
p-MeOC6H4CHO
p-BrC6H4CHO
1-Naphthaldehyde
2-Naphthaldehyde
o-MeOC6H4CHO
9-Anthraldehyde
2-Furaldehyde
2-Thiofuraldehyde
p-ClC6H4CHO
C6F5CHO
Et2CHCHO
Me2CHCHO
8j
8k
8l
9j
9k
9l
8m
8n
8o
8p
8q
8r
8s
8t
9m 93
9n
9o
9p
9q
9r
9s
9t
94
83
86
82
82
83
95
92
c-C6H11CHO
(E)-C6H5CHꢂCMeCHO
(E)-C6H5CHꢂCHCHO
nC6H13CHO
PhCH2CH2CHO
8u
9u
a Conditions: [(R,R)-2e]=0.050 M; [DEZ]=1.00 M; [BzH]=0.83 M; toluene; 20°C.
b GC yield on the mixture of the two enantiomers.
c
Determined by capillary chiral GC analysis using the chiral column MEGADEX DMP b.39
d Determined by HPLC analysis using the chiral column LiChroCART® 254-4 (S,S)-Whelk-01.40

G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
3367
Scheme 2. Proposed mechanism for the catalytic cycle in the addition of dimethylzinc to benzaldehyde [R*=(R)-(+)-l-
phenylethylamine]
curve with respect to a linear correlation is due to diastereomer recognition in the binuclear
catalyst precursors 11, as shown in Scheme 3. The initial reaction rate (Vo) appeared to be
sensitive to diastereomeric purity of the auxiliary ligand (see Fig. 4(b)).
The auxiliary (R,R)-2e gives the ethylation of benzaldehyde four times faster than the reaction
with (1S,1%R)-2e, and with a better e.e. The nonlinearity is a result of noticeable difference in
chemical properties of the catalyst. On the basis of the experimental evidences observed, the
heterochiral binuclear complex (R,R)·(S,R)-11e must be thermodynamically more stable than
the homochiral (R,R)·(R,R)-11e and (S,R)·(S,R)-11e;17 the major (R,R)-10e sequestrate the
minus (1S,1%R)-10e (see Scheme 3). The complex (R,R)·(R,R)-11e, less stable, possesses the
major tendency to dissociate into the active monomer (R,R)-10e.
3. Conclusions
These results demonstrate that the o-hydroxybenzylamines 2, very accessible materials
obtained through a short stereoselective synthetic route, are ligands that may be of general use
in asymmetric Lewis acid catalysis. In summary, I have developed a practical and convenient
synthesis and application of o-hydroxybenzylamines 2 as ligands for chiral catalysts in the
enantioselective addition of dialkylzincs to aldehydes with high asymmetric amplification.

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G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
Figure 3. The lowest energy selected transition structures proposed for the methyl migration to the Re and Si face of
benzaldehyde, optimised at the PM3 level38
4. Experimental
4.1. General remarks
1H and 13C NMR spectra were recorded with a Varian VXR 300 instrument. Chemical shifts
are given in ppm downfield from Me4Si in CDCl3 solution. Coupling constants are given in
hertz. IR spectra were recorded with a Perkin–Elmer 257 spectrometer. GC–MS analyses were
performed with an HP 59970 workstation formed by an HP-5890 gas chromatograph equipped
with a methyl silicone capillary column and by an HP-5970 mass detector. All melting points are
uncorrected. THF was dried by refluxing over sodium wires until the blue colour of benzophen-
one ketyl persisted and then distilled into a dry receiver under a nitrogen atmosphere. All
reagents and solvents were distilled prior to use or were of commercial quality from freshly
opened containers. Commercial methyllithium and butyllithium solutions (Aldrich) were
employed under a dry atmosphere.

G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
3369
Figure 4. Curves obtained for the product (S)-9b e.e. (a) The initial rate of the reaction Vo; (b) as a function of the
composition of auxiliary chelant (R,R)-2e d.e.% (black point 68% d.e., such as resulting from the reduction of
(R)-1e18). Conditions: [2e]=0.050 M; [DEZ]=1.00 M; [BzH]=0.83 M; toluene; 20°C
Scheme 3. The homo- [(R,R)·(R,R)-11e, (S,R)·(S,R)-11e] and heterochiral [(R,R)·(S,R)-11e] dimeric species of the
catalyst

3370
G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
The 2-imidoyl phenols 1 and 5 were prepared by direct condensation of the appropriate
o-acylphenol34 and (R)-(+)-1-phenylethylamine (99%) according to described procedure.35–37 The
2-imidoyl phenol 1c was prepared by methylation of the 2-imidoyl phenol 1b.19 The o-hydroxy-
benzylamines 2a–f and 6 were prepared by reduction of the corresponding 2-imidoyl phenols 1
and 5.18
4.2. Synthesis of o-hydroxybenzylamines (R,R)-4e by reduction of the intermediate
3,4-dihydro-2H-1,3-benzoxazine (R,R)-3e
The benzoxazine (R,R)-3e (0.63 g, 2.0 mmol), prepared following a described procedure,18 was
dissolved in ethanol (8 mL) and treated with sodium borohydride (0.114 g, 3.0 mmol). After 90
min at room temperature the reduction was complete. The reaction mixture, diluted with
CH2Cl2 (100 mL), was treated with a saturated aqueous solution (20 mL) of ammonium
chloride. The organic layer was dried and evaporated. The residue, purified by flash chromatog-
raphy (cyclohexane/ethyl acetate: 95/5 as eluent), gave (R,R)-4e (0.58 g, yield 92%).
4.2.1. (4R)-4-Phenyl-3-[(1%R)-1%-phenylethyl]-3,4-dihydro-2H-1,3-benzoxazine (R,R)-3e
Yield 91% colourless crystals, mp 98–100°C (hexane). [h]2D0=−36.1 (c=1.6, CHCl3). IR
1
(Nujol): 1608, 1491, 1227, 940 cm−1. H NMR (300 MHz, CDCl3): l=1.53 (d, 3H, J=6.6 Hz),
3.98 (q, 1H, J=6.6 Hz), 4.72 (br s, 1H), 4.83 (d, 1H, J=10.9 Hz), 5.07 (dd, 1H, J=10.9, 2.0
Hz), 6.80–7.50 (m). 13C NMR (75 MHz, CDCl3): l=21.5, 58.8, 59.3, 74.4, 116.5, 120.1, 120.3,
127.1, 127.5, 127.7, 128.0, 128.2, 128.6, 128.9, 130.2, 143.8, 145.2, 155.0. C22H21NO (315.4):
calcd C, 83.78, H, 6.71; N, 4.44; found: C, 83.92, H, 6.81; N, 4.27.
4.2.2. 2-[(R)-{Methyl[(1%R)-1%-phenylethyl]amino}(phenyl)methyl]phenol (R,R)-4e
1
Colourless oil. [h]2D0=−147.6 (c=1.9, CHCl3). IR (film): 2977, 1587, 1255, 755 cm−1. H NMR
(300 MHz, CDCl3): l=1.45 (d, 3H, J=7.0 Hz), 2.09 (s, 3H), 4.08 (q, 1H, J=7.0 Hz), 4.71 (s,
1H), 6.60–7.60 (m, 14H), 12.52 (br s, 1H). 13C NMR (75 MHz, CDCl3): l=14.1, 33.9, 57.6,
73.7, 117.5, 119.8, 128.0, 128.4, 128.6, 128.8, 128.9, 129.0, 129.1, 129.4, 129.6, 130.2, 141.1,
157.4. C22H23NO: calcd C, 83.24; H, 7.30; N, 4.41; found: C, 83.37; H, 7.41; N, 4.49.
4.3. Synthesis of o-hydroxybenzylamines (R)-6e by reduction of the imidoyl phenol 5 and
resolution of the racemic ( )-6 with (R,R)-(+)-tartaric acid
A mixture of the racemic o-hydroxybenzylamine ( )-6 (1.44 g, 5.0 mmol), prepared following
a described procedure,18 and (R,R)-(+)-tartaric acid (0.75 g, 5.0 mmol) were dissolved in ethanol
(5 mL) by delicate heating. A white precipitate, collected after 15 h (1.02 g, yield 46%), was
treated with 2 M K2CO3 (1.4 g in 5 mL of H2O) with stirring for 30 min. The resulting mixture
was extracted with CH2Cl2 and the organic phase was dried and evaporated under reduced
pressure. The crystalline white residue was purified by crystallisation from hexane (0.61 g, 2.1
mmol, yield 42%).
4.3.1. 2-[(R)-(Benzylamino)(phenyl)methyl]phenol (R)-6e
Colourless crystals, mp 68–70°C (CH2Cl2/hexane). [h]2D0 −34.9 (c=2.3, CHCl3). IR (film):
1
3271, 1621, 1238, 1077, 743 cm−1. H NMR (300 MHz, CDCl3): l=1.45 (s, 1H), 3.80 and 3.95
(two d, 2H, JAB=12.9 Hz), 5.00 (s, 1H), 6.70–7.45 (m, 14H), 12.30 (br s, 1H). 13C NMR (75

G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
3371
MHz, CDCl3): l=52.5, 67.4, 117.6, 119.8, 124.8, 127.9, 128.2, 128.4, 129.0, 129.3, 129.4, 129.5,
129.8, 138.6, 142.0, 158.2. C20H19NO: calcd C, 83.01; H, 6.62; N, 4.84; found: C, 82.92; H, 6.74;
N, 5.02.
4.4. Synthesis of 1-((R)-phenyl{[(1%R)-1%-phenylethyl]amino}methyl)-2-naphthol (R,R)-7e
A mixture of 2-naphthol (0.72 g, 5.0 mmol), benzaldehyde (0.64 g, 6.00 mmol) and (R)-(+)-1-
phenylethylamine (0.64 g, 5.25 mmol) was stirred at 60°C for 8 h under a nitrogen atmosphere.
1
Following the progress of the reaction by TLC and H NMR, it can be seen that the formation
of the product occurs in the first two hours, but the initial d.e. of (R,R)-7e (44% at 2 h) increases
in time (98% at 8 h) with the formation of a solid and crystalline reaction mixture. The reaction
mixture was triturated at room temperature with EtOH (5 mL). The white crystals separated
were collected and washed with EtOH (3×3 mL). The crystalline white residue, purified by
crystallisation from EtOAc/hexane, gave the pure (R,R)-7e (1.64 g, 4.65 mmol, yield 93%).
4.4.1. 1-((R)-Phenyl{[(1%R)-1%-phenylethyl]amino}methyl)-2-naphthol (R,R)-7e
Colourless crystals, mp 155–156°C (EtOAc/hexane). [h]2D0=−220.7 (c=2.1, CHCl3). IR (film):
3271, 1621, 1238, 1077, 743, 696 cm−1. 1H NMR (300 MHz, CDCl3): l=1.52 (d, 3H, J=6.9 Hz),
2.35 (br s, 1H), 3.92 (q, 1H, J=6.9 Hz), 5.47 (s, 1H), 7.15–7.83 (m, 16H), 13.70 (br s, 1H). 13C
NMR (75 MHz, CDCl3): l=23.0, 56.7, 60.3, 113.1, 120.1, 121.1, 122.4, 126.4, 126.7, 127.7,
127.9, 128.0, 128.7, 128.8, 129.0, 129.1, 129.7, 132.6, 141.5, 143.1, 157.3. M/z 232 (M+−121, 38),
231 (100), 202 (23), 116 (21). C25H23NO: calcd C, 84.95; H, 6.56; N, 3.96; found: C, 85.21; H,
6.37; N, 3.77.
4.4.2. 1-((S)-Phenyl{[(1%R)-1%-phenylethyl]amino}methyl)-2-naphthol (1S,1%R)-7e
1H NMR (300 MHz, CDCl3) (minus diastereomer, deduced from the spectra of the crude
reaction mixtures): l=1.60 (d, 3H, J=6.7 Hz), 2.35 (br s, 1H), 3.99 (q, 1H, J=6.7 Hz), 5.90 (s,
1H), 7.15–7.83 (m, 16H), 13.70 (br s, 1H).
4.5. Enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes 8a–u promoted
by enantiopure o-hydroxybenzylamine (R,R)-2e
Under a nitrogen atmosphere, a toluene solution of Et2Zn (6.0 mmol, 1.1 M) was added to
a mixture of aldehyde 8 (5.0 mmol) and o-hydroxybenzylamine (R,R)-2e (0.30 mmol) at 0°C and
the whole solution was stirred at room temperature for 2–23 h. The progress of the reaction was
monitored by GC analysis of aliquots of the reaction mixture, after quenching. Aqueous
hydrochloric acid (2N) was added to quench the reaction under cooling with ice-water. The
resulting mixture was extracted with CH2Cl2, and the extract was dried and evaporated under
reduced pressure. The residue was purified by column chromatography on silica gel (hexane/
EtOAc) and then bulb-to-bulb distillation. The product was identified by spectroscopic methods
and the optical rotation was measured. Enantiomeric excesses (% e.e.) were determined by GC
analyses of the resulting alcohols on a chiral capillary column MEGADEX DMP b (30%
dimethylpentil-b-cyclodedextrine on OV1701, 25 m, 0.25 mm ID, 0.25 mm film)39 or by HPLC
analysis using the chiral column LiChroCART® 254-4 (S,S)-Whelk-01 and mixtures n-hexane/2-
propanol as eluent.40 Yields are reported in Table 3. The data for the characterisation of a
number of unknown alcohols follows.

3372
G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
4.5.1. 1-(3,4-Dimethoxyphenyl)propan-1-ol (S)-9a
Colourless crystals, mp 36–38°C (hexane). [h]2D0=−31.4 (c=1.6, CHCl3). IR (Nujol): 3401,
1
1593, 1027, 764 cm−1. H NMR (300 MHz, CDCl3): l=0.89 (t, 3H, J=7.4 Hz); 1.60–1.90
(m, 2H), 1.93 (br s, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.52 (t, 1H, J=6.7 Hz); 6.75–6.93 (m,
3H). 13C NMR: l=10.2, 31.8, 55.8, 55.9, 75.9, 109.0, 110.8, 118.2, 137.3, 148.3, 149.0.
C11H16O3: calcd C, 67.32; H, 8.22; found: C, 67.44; H, 8.07.
4.5.2. 1-(3,4,5-Trimethoxyphenyl)propan-1-ol (S)-9c
Colourless oil, [h]2D0=−18.55 (c=2.1, CHCl3). IR (film): 3428, 1593, 1234, 1128 cm−1. H
1
NMR (300 MHz, CDCl3): l=0.94 (t, 3H, J=7.4 Hz); 1.60–1.90 (m, 2H), 2.10 (br s, 1H),
3.83 (s, 3H), 3.87 (s, 6H), 4.53 (t, 1H, J=6.5 Hz); 6.75 (s, 2H). 13C NMR (75 MHz, CDCl3):
l=10.7, 32.4, 56.6, 61.3, 76.7, 103.3, 137.6, 141.0, 153.7. C12H18O4: calcd C, 63.70; H, 8.02;
found: C, 3.51; H, 8.17.
4.5.3. 1-(4-Bromophenyl)propan-1-ol (S)-9f
Colourless oil, [h]2D0=−35.2 (c=1.9, CHCl3). IR (film): 3350, 1487, 1071, 820 cm−1. H NMR
1
(300 MHz, CDCl3): l=0.84 (t, 3H, J=7.4 Hz); 1.58–1.89 (m, 2H), 2.19 (br s, 1H), 4.53 (t, 1H,
J=6.6 Hz); 7.19 and 7.45 (two d, 4H, J=8.4 Hz). 13C NMR (75 MHz, CDCl3): l=10.4, 32.4,
75.7, 121.6, 128.2, 131.9, 144.0. C9H11BrO: calcd C, 50.26; H, 5.15; found: C, 50.04; H, 5.32.
4.5.4. 1-(9-Anthryl)propan-1-ol (S)-9j
Colourless crystals, mp 98–100°C (EtOAc/hexane), [h]2D0=−7.46 (c=1.2, CHCl3). IR (Nujol):
1
3308, 1459, 1014, 729 cm−1. H NMR (300 MHz, CDCl3): l=1.03 (t, 3H, J=7.4 Hz); 2.10–2.55
(m, 3H), 6.16 (t, 1H, J=7.3 Hz); 7.40–8.75 (m, 9H). 13C NMR (75 MHz, CDCl3): l=11.9, 31.2,
73.1, 125.2, 125.5, 125.9, 127.7, 128.5, 129.8, 134.6, 135.4. C17H16O: calcd C, 86.40; H, 6.82;
found: C, 86.64; H, 6.94.
Acknowledgements
Financial support from the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica,
Rome, and the University of Camerino (National Project ‘Stereoselezione in Sintesi Organica.
Metodologie ed applicazioni’) is gratefully acknowledged.
References
1. Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059–1070.
2. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856.
3. Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028–4036.
4. Juaristi, E.; Escalante, J.; Leo`n-Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry 1998, 9, 715–740.
5. Rijnberg, E.; Hovestad, N. J.; Kleij, A. W.; Jastrzebski, J. T. B. H.; Boersma, J.; Janssen, M. D.; Spek, A. L.;
van Koten, G. Organometallics 1997, 16, 2847–2857.
6. Nakano, H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.; Hongo, V. Tetrahedron: Asymmetry 1997, 8, 1391–1401.
7. Watanabe, V.; Araki, V.; Butsugan, V. J. Org. Chem. 1991, 56, 2218–2224.
8. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071–6072.
9. Hayase, T.; Sugiyama, T.; Suzuki, M.; Shibata, T.; Soai, K., J. Fluorine Chem. 1997, 1–5.

G. Palmieri / Tetrahedron: Asymmetry 11 (2000) 3361–3373
3373
10. Sola`, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.
F. J. Org. Chem. 1998, 63, 7078–7082.
11. Gibson, C. L. Tetrahedron: Asymmetry 1999, 10, 1551–1561.
12. Iuliano, A.; Pini, D.; Salvadori, P. Tetrahedron: Asymmetry 1995, 6, 739–744.
13. Hayashi, M.; Kaneko, T.; Ognuni, N. J. Chem. Soc., Perkin Trans. 1 1991, 25–28.
14. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; John Wiley: New York, 1994.
15. Knochel, P. In Comprehensive Organic Synthesis; Trost, B. M., Ed. Pergamon: Oxford, 1991; pp. 211–229.
16. Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800–9809.
17. Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327–6335.
18. Palmieri, G. Eur. J. Org. Chem. 1999, 805–811.
19. Cimarelli, C.; Palmieri, G. Tetrahedron 1998, 54, 15711–15720.
20. Beliczey, J.; Giffels, G.; Kragl, U.; Wandrey, C. Tetrahedron: Asymmetry 1997, 8, 1529–1530.
21. Wilken, J.; Groger, H.; Kossenjans, M.; Martens, J. Tetrahedron: Asymmetry 1997, 8, 2761–2771.
22. Yang, X.; Shen, J.; Da, C.; Wang, R.; Choi, M.; Yang, L.; Wong, K. Tetrahedron: Asymmetry 1999, 10, 133–138.
23. Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1998, 9, 1489–1492.
24. Behnen, W.; Mehler, T.; Martens, J. Tetrahedron: Asymmetry 1993, 4, 1413–1416.
25. Betti, M. Org. Synth. Collect. 1941, 1, 381–383.
26. Cardellicchio, C.; Ciccarella, G.; Naso, F.; Schingaro, E.; Scordari, F. Tetrahedron: Asymmetry 1998, 9,
3667–3675.
27. Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna, F.; Tortorella, P. Tetrahedron 1999, 55, 14685–14692.
28. Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1998, 37, 2922–2959.
29. Avalos, M.; Babiano, R.; Cintas, P.; Jime`nez, J. L.; Palacios, J. C. Tetrahedron: Asymmetry 1997, 8, 2997–3017.
30. Mori, K.; Nomi, H.; Chuman, T.; Kohno, M.; Kato, K.; Noguchi, M. Tetrahedron 1982, 38, 3705–3711.
31. Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1997, 38, 8773–8776.
32. Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63, 8998–9006.
33. Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk, K. N. J. Org. Chem. 2000, 65, 77–82.
34. The not commercially available o-pivaloyl phenol was prepared as described in: Miller, J. A. J. Org. Chem. 1987,
52, 322–323.
35. Boatman, S.; Hauser, C. R. J. Org. Chem. 1966, 31, 1785–1789.
36. Singh, R. V.; Tandon, J. P. J. Prakt. Chem. 1979, 321, 151.
37. Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902–903.
38. Semiempirical PM3 calculations were performed with the Spartan 5.0.3, Wavefunction, Inc. 18401 Von Karmen
Ave., c370, Irvine, CA 92715.
39. Optical purities (% e.e.) were determined by GC analyses of the resulting alcohols on a chiral capillary column
MEGADEX DMP b (30% dimethylpentil-b-cyclodedextrine on OV1701, 25 m, 0.25 mm ID, 0.25 mm film).
40. Optical purities (% e.e.) were determined by HPLC analyses of the resulting alcohols on a LiChroCART® 250-4,
(S,S)-Whelk-01 chiral column. Chiral selector: (3S,4S)-4-(3,5-dinitrobenzamido)-1,2,3,4-tetrahydrophenantrene.
E. Merck 64271 Darmstadt, Germany.
.