Regio- and stereoselective double alkylation of β-enamino esters with organolithium reagents followed by one-pot reduction: convenient method for the synthesis of tertiary γ-amino alcohols

Article abstract of DOI:10.1016/j.tet.2006.07.044

An easy, high yielding and stereoselective procedure for the preparation of tertiary γ-amino alcohols starting from β-enamino esters is presented. In this procedure, the double alkylation of β-enamino esters with organolithium reagents is followed by one-

Full text of DOI:10.1016/j.tet.2006.07.044

Tetrahedron 62 (2006) 9423–9432
Regio- and stereoselective double alkylation of b-enamino esters
with organolithium reagents followed by one-pot reduction:
convenient method for the synthesis of tertiary g-amino alcohols
*
Cristina Cimarelli, Gianni Palmieri and Emanuela Volpini
Dipartimento di Scienze Chimiche, Universitaꢀ di Camerino, via s. Agostino 1, 62032 Camerino, Italy
Received 6 April 2006; revised 26 June 2006; accepted 13 July 2006
Available online 10 August 2006
Abstract—An easy, high yielding and stereoselective procedure for the preparation of tertiary g-amino alcohols starting from b-enamino
esters is presented. In this procedure, the double alkylation of b-enamino esters with organolithium reagents is followed by one-pot reduction
with sodium borohydride in methanol/acetic acid. A hypothesis of mechanism is given, explaining the observed diastereoselectivity through
molecular modeling. The configuration of the products was determined by 1H NMR spectroscopy coupled with conformational analysis.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
limited.29–35 We have proposed a general procedure for the
preparation of tertiary g-amino alcohols starting from b-
enamino ketones,36 and to the best of our knowledge other
procedures starting from b-enamino esters are not known.
In this paper, the scope and limitations of alkylation of
b-enamino esters with organolithium compounds are pre-
sented as a method for the efficient and diastereoselective
preparation of tertiary g-amino alcohols.
A field of great interest in modern organicchemistry is the de-
velopment of efficient enantioselective catalysts applicable
to a wide range of reactions.1–3 In previous studies4,5 we
have found that a substoichiometric amount of enantiopure
aminoalkyl phenols and aminoalkyl naphthols accelerates
the alkylation of aldehydes with alkylzincs, affording the
corresponding alcohols in good enantiomeric purity. These
chiral ligands are stable and highly accessible compounds,
obtained by stereoselective reduction6 or alkylation7,8 of
the corresponding 2-imidoyl phenols, or by aminoalkylation
of naphthols.9,10 Similarly to amino phenols, g-amino alco-
hols are efficient chelating agents applicable in asymmetric
synthesis promoted by chiral metallic catalyst. In addition
g-amino alcohols are useful building blocks in the synthesis
of many natural products, pharmaceuticals, and compounds
of biological interest.11–17 Known procedures for the synthe-
sis of g-amino alcohols include reduction of isoxazoles and
isoxazolines,18 b-amino carbonyl compounds19,20 or enami-
nones,21,22 reductive amination of b-hydroxy ketones via
Schiff bases,23 or by in situ reduction of the lithiated b-hy-
droxy imine obtained by directed aldol condensation devel-
oped by Wittig.24–28 All these reductive methods produce
only secondary or primary g-amino alcohols.
2. Results and discussion
A mild and general method for the regio- and stereoselective
synthesis of functionalized tertiary g-amino alcohols (2)
proceeds through the double alkylation of b-enamino esters
(1) with alkyllithium reagents, followed by one-pot reduc-
tion of the intermediate dilithium b-hydroxy imines. This
double alkylation works well with organolithium reagents
in toluene at 0 ꢀC or at room temperature, without the assis-
tance of a Lewis acid. Grignard reagents under these condi-
tions were unreactive. A number of examples were carried
out using various organolithium reagents with differently
functionalized b-enamino esters and the results are summa-
rized in Table 1. The addition of organolithium reagents to
enamino esters under these conditions is regioselective: the
double alkylation occurs exclusively to the carbonyl group
and not to the imine function.37,38
The preparation of tertiary g-amino alcohols is known
within the literature but the number of reports are
As shown in Table 1, the reduction occurs generally with
good yields and syn diastereoselectivity in the case of com-
pounds 2k–p. The overall yields are very good when the R3
substituent is a phenyl group (Table 1, entries 1–4) while
Keywords: b-Enamino esters; g-Amino alcohols; Alkylation; Reduction.
* Corresponding author. Fax: +39 0737 637345; e-mail: gianni.palmieri@
unicam.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.044

9424
C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
Table 1
H
N
R4
R3
H
R4
R3
H
1) R5Li, 4 eq, toluene
2) NaBH4/AcOH/MeOH
O
O
N
R5
R1O
R5
R2
R2
1a-i
2a-p
Entry
1
R1O
R2
R3
R4
2
R5
T (ꢀC)
Time (h)
Yield (%)a
d.r. (syn/anti)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1c
1d
1e
1f
1g
1g
1h
1i
1i
1i
EtO
EtO
EtO
EtO
BnO
BnO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
H
H
H
H
H
H
H
H
H
Me
Ph
Ph
Ph
Ph
Me
Me
Pr
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
R*c
Ph
Ph
Ph
Bn
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
Me
Bu
i-Pr
Ph
20
0
0
20
0
0
0
0
20
0
50
0
2
1
1
1
1
1
1
1
1
1
5
1
1
3
1
1
90
88
—
—
—
—
—
—
—
88 (42)b
91
49
Bu
i-Pr
Bu
Bu
Bu
Bu
Me
Bu
Bu
Me
Bu
i-Pr
59
57
65
47
55
62
—
9
73/27d
32/68
64/36
64/36 (76/24)b
87/13
69/31
65/35
51/49
10
11
12
13
14
15
16
(CH2)3
(CH2)3
(CH2)3
(CH2)4
(CH2)4
(CH2)4
72 (55)b
52
68
0
20
0
89
85
0
a
Combined yields of the two isolated diastereomers.
Reduction performed in absence of acetic acid.
R*-NH2¼(R)-1-phenylethylamine.
(2S,10R)/(R,R) d.r.
b
c
d
they decreases in the presence of aliphatic groups (entries 5–
7). b-Enamino esters derived from aniline (R4¼Ph) present
a more electrophile ester function toward the organolithium
reagents. Starting from b-enamino ester 1e, that contains the
chiral auxiliary (R)-(+)-phenylethylamino group, the reac-
tion affords the amino alcohol (2S,10R)-2i with reasonable
diastereoisomeric excess, and the pure diastereomer can be
obtained by flash chromatography. b-Enamino esters 1g–i
afford the amino alcohols syn-2k–p as major diastereomers
(see Table 1).
forming the intermediate D.17 The one-pot reduction of D
to the g-amino alcohol 2a–p occurs intramolecularly
through the intermediate E.
The presence of acetic acid in the reaction mixture in the re-
duction stage is important, because it allows a faster reduc-
tion and better yields in the final g-amino alcohol 2 than
the reduction conducted only in methanol. Anyway in this
second case a higher diastereomeric excess is observed (see
Table 1, entries 3 and 13 and Table 2, entry 3). After quench-
ing the intermediate lithium alkoxide (D) with acid (saturated
aqueous NH4Cl), the free hydroxy imine (4) can be isolated
(see Scheme 3), but its reduction with sodium borohydride
in methanol resulted in lower yields of the g-amino alcohol
(2) because the free b-hydroxy imine (4) is unstable and
dissociates spontaneously into the ketone 10 and imine
11 through a retroaldolic type process, as described in
Scheme 2.39
In the hypothesized mechanism, depicted in Scheme 1, the
first metalation of b-enamino esters 1a–i affords the interme-
diate A, in which the chelated lithium atom enhances the
electrophilicity of the ester function, making the addition
of a second alkyllithium molecule easier. The dilithiated in-
termediate B eliminates lithium alkoxide with formation of
the lithiated enamino ketone C. b-Enamino ketones 3 (see
Scheme 3) can be isolated in some cases, when only
2.5 equiv of alkyllithium are used.36 Generally, the lithiated
b-enamino ketone C is more reactive with respect to the in-
termediate A and adds an organolithium molecule again,
On the other hand, the one-pot reduction of the reaction mix-
ture with sodium borohydride, after methanol quenching
only, does not take place. On the basis of these observations,
R4
R3
R4
R3
R4
R3
Li
Li
R4
R3
Li
H
N
R5Li
O
O
N
O
N
O
N
Li
R1O
R5
R1O
R1O
R5
C
1a-i
A
B
R5Li
OAc
H
AcO
OAc
N
R4
H
N
AcO
O
B
B
R4
R3
H
R4
R3
Li
H
N
O
R4
R3
H3O+
NaBH4
O
O
N
Li
H
R5
R5
R5
R5
R5
R5
MeOH
AcOH
R3
R5
H
R5
H
2a-p
F
E
D
Scheme 1.

C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
9425
Table 2
H
N
H
N
1) R5Li, 2.5 eq, toluene
H
Ph
Ph
H
Ph
H
H
Ph
Ph
O
O
N
2) R6Li, 1.5 eq,
O
+
R5
R5
3) NaBH4/AcOH/MeOH
EtO
H
Ph
R6
R6
2q-s
2'q-s
1a
Entry
1
Step 1
T (ꢀC)
Step 2
T (ꢀC)
2
Yield (%)a
d.r. (2/20)
R5
Time (min)
R6
Time (min)
1
2
3
1a
1a
1a
Ph
Ph
t-Bu
0
0
0
30
30
60
Bu
i-Pr
Bu
0
0
20
60
60
60
2q
2r
2s
49
64
73/27
86/14
77 (41)b
84/16 (93/7)b
a
Combined yields of the two diastereomers isolated.
Reduction performed in absence of acetic acid.
b
R4
R3
R4
R3
different organolithium reagent on the intermediate enamino
ketone (see Table 2). From the reduction step g-amino alco-
hols 2q–s as major diastereomers were obtained, resulting
from the attack of the hydride from the same side of the
less bulky group, that is, the R6 substituent.
H
H3O+
N
O
N
O
R5
R5
+
D
R5
R5
4
10
11
Scheme 2.
H
R4
R3
Li
R4
R3
H
R4
R3
H3O+
R6Li
R5Li
N
O
N
O
O
N
the more convenient one-pot reduction with sodium boro-
hydride in methanol and acetic acid was chosen.
R1O
R5
R5
R2
R2
3
C
1a-i
The syn stereochemistry of the hydride transfer can be
explained by considering that the aminoborane complex
syn-F is more stable than the corresponding anti-F (see
the PM3 semiempirical level optimized geometries and the
relative formation enthalpies in Figure 1).40 The proposed
mechanism is consistent with literature reports41,42 and the
anti stereochemistry of the products obtained reflects the in-
tramolecular nature of the reaction. syn Products are gener-
ally obtained by intermolecular processes.43
R5Li
H
R4
H
N
H
R4
R3
Li
Li
H
R4
O
N
O
O
N
NaBH4
R5
R5
R3
R5
R6
R5
R5
R3
R2
MeOH
AcOH
H
2a-p
R2
H
2q-s
D
H3O+
CH2O
R4
NaBH4
R4
MeOH
O
N
OH
N
R5
R5
R5
R3
R3
R5
H
Generally, the addition of the organometallic reagents to the
intermediate lithium enamino ketones (C) is faster than
the first addition. The intermediate enamino ketones are
not isolable even with the use of a stoichiometric amount
(2.5 equiv) of the organolithium reagent. Only when phenyl-
lithium or tert-butyllithium is used, the preparation of the in-
termediate b-enamino ketones is possible with good yields44
(see Scheme 3). This chemoselectivity was utilized for the
stereoselective formation of a new stereogenic center at
the quaternary carbinolic atom by the addition of a second
5
4a: R5 = Me 4b: R5 = Bu
Scheme 3.
In the early phase of this research, the possibility of the syn-
thesis of the g-amino alcohol 2 by inverting the alkylation–
reduction sequence was evaluated. As shown in Scheme 4,
the b-amino esters 6a,b, obtained by the reduction of the
b-enamino esters 1a,d,45 were treated with n-butyllithium.
From this sequence, the g-amino alcohols 2b,h are obtained
F-TS
syn-F H = - 311.37 Kcal/mol
anti-F H = - 309.26 Kcal/mol
f
f
Figure 1. Transition structure for the intramolecular reduction of the b-hydroxy imine through the intermediate E with the formation of the thermodynamically
more stable aminoborane complex syn-F.

9426
C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
in very low yields (6–7%). The amines 7a,b, obtained as the
main product, are formed by alkylation of the imine 9a,b,
derived by the decomposition of the lithiated b-amino ester
60a,b through a retroaldol pathway, as depicted in Scheme 4.
In the g-amino alcohols 2, an intramolecular hydrogen bond
between the proton of the hydroxy group and the nitrogen
atom was observed, which makes the cyclic chair conforma-
tion rigid and stabilizes the molecule in a conformation sim-
ilar to that of the corresponding 1,3-tetrahydro oxazine (5),
,
as reported also in literature.22, 46
H
R
H
R
H
R
1) BuLi
2) H3O+
ref. 17
O
N
N
O
N
1a,d
+
+ 2b,h
The attribution of the relative syn/anti configuration for
products 2k–p was made on the basis of N-CH signals in
1H NMR for both diastereomers. In the major diastereomers
syn-2k–p this proton results in a broad singlet with
W1/2¼8.5–5.3 Hz. In the minor anti-2k–m, the same proton
EtO
Ph
Bu
Ph Bu
Ph
6a R = Ph
6b R = Bn
8a,b
6-8%
7a,b
6-7%
38-42%
3
Li
R
R
N
results upshifted by about 0.05–0.19 ppm with a Jax–ax of
O
N
7.2–8.0 Hz. Analogously in the minus diastereomers, anti-
2n–p, the N-CH proton is upshifted by about 0.47–
0.71 ppm with a 3Jax–ax of 10.3–10.7 Hz.
EtO
Ph
Ph
6'a,
b
9
Scheme 4.
In the case of the products (R*,R*)-2q and (R*,S*)-2q, the
relative configuration of the chiral centers was assigned on
the basis of NOE experiments on the corresponding 1,3-
tetrahydro oxazine derivative 5q. The (R*,S*) relative con-
figuration was attributed to the diastereomer that showed
a strong NOE effect exerted by H-4 (geminal to the phenyl
group) on the three nearer methylene protons H-2 and H-5
of the oxazine ring and H-10 in the lateral butyl chain.
Molecular modeling confirmed that in the more stable con-
formation all these protons are very close to each other, as
shown in Figure 2. The (R*,R*) relative configuration was
attributed to the other diastereomer that presented, instead
of the NOE effect, a strong upshift of 0.55 ppm for the
H-4 signal with respect to the corresponding proton of the
(R*,S*) diastereomer. In the more stable conformation
the phenyl ring in 6 assumes a position such as to exert a
shielding effect on H-4, as shown in Figure 2.
The molecular ion peak in the EI Mass Spectrometry of the
b-amino alcohols (2) is usually quite weak. The base peak
frequently results from C–C cleavage of a–b bond next to
the nitrogen atom (see Scheme 5 and Section 5). This pref-
erential fragmentation pathway is useful and routinely
used to distinguish the possible regioisomers.
R4
R4
H
R4
H
H
H
O
N
N
N
R5
R5
R3
R3
R3
2
Scheme 5.
3. Stereochemistry
The diastereoisomeric ratio was calculated by integration of
the 1H and 13C NMR data from the crude reaction mixture.
Separation of pure diastereoisomers was carried out by frac-
tional crystallization or by flash column chromatography.
In addition, the absolute configurations of both diastereomers
of g-amino alcohols 2i were attributed through 1,3-tetrahy-
dro oxazine derivatives 5i, whose more stable conformations
are depicted in Figure 3 and are in agreement with the
1H NMR spectra. In these spectra the H-4 presents
3J values of 11.0 and 11.5 Hz, typical of a trans-diaxial cou-
pling, and an axial–equatorial J values of 4.0 and 4.2 Hz,
respectively. The (R,R) absolute configuration was attributed
to the diastereomer that showed H-2 and H-4 upshifted
The configuration of the stereogenic centers of the g-amino
alcohols 2 was assigned by interpreting the chemical shifts’
general trend observed in H NMR spectra of the isolated
3
1
isomers on the basis of the more stable conformations calcu-
lated by molecular modeling.40
Figure 2. Models for the more stable conformation of 5q diastereomers.

C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
9427
Figure 3. Models for the more stable conformation of 3i diastereomers.
signals, of 0.25 and 0.27 ppm, respectively, due to the 10-
phenyl group arranged in the position depicted in Figure 3.
solution in cyclohexane/diethylether 70:30), i-PrLi (1.7 M
solution in pentane).
The relative trans configuration of (R*,R*)-5j is attributed on
the basis of N-CH proton at 3.34 ppm with a 3Jax–ax value of
10.2 Hz, that is upshifted by 0.35 ppm with respect to the
corresponding proton of cis-(R*,S*)-5j, at 3.69 ppm, with
a 3J value of 5.7 Hz.
5.3. Synthesis of b-enamino esters 1a–i
b-Enamino esters 1 were prepared by condensation of
b-ketoesters with amines according to standard literature
methods.47 b-Enamino esters 1b,c,g–i were prepared in sol-
ventless way by mixing the b-ketoester and the amine in
equimolecular amounts and stirring the mixture for 2–18 h
at room temperature until TLC or GC analysis of the mixture
revealed the complete consumption of the starting materials.
After this time the reaction mixture was dissolved in
n-hexane, dried with Na2SO4, and filtered. The solvent
was removed under reduced pressure and the resulting crude
b-enamino ester was purified by crystallization or filtration
on SiO2 with a 97:3 cyclohexane/ethyl acetate mixture as
eluent.
4. Conclusion
In summary, an easy, general and stereoselective method
for the direct preparation of tertiary g-amino alcohols from
b-enamino esters in good yields and satisfactory diastereo-
meric excess has been developed. The methodology consists
of the double alkylation of b-enamino esters 1 with organo-
lithium reagents followed by the one-pot reduction of the re-
action mixture with sodium borohydride in methanol/acetic
acid. The opportune choice of the reaction conditions and
reagents enables the generation of a quaternary chiral center
on the carbon atom bonded to the hydroxy function. Easily
available starting materials and practical experimental
conditions allow the facile preparation of these chiral
pre-catalysts.
5.4. General procedure for the alkylation and one-pot
reduction of b-enamino esters 1: synthesis of g-amino
alcohols 2a–p
The b-enamino esters 1a–i (1 mmol) were dissolved in tolu-
ene (3 mL), under nitrogen atmosphere, then was added the
organolithium reagent (4.0 mmol); according to the reaction
conditions and reagents reported in Table 1. Then the reac-
tion mixture was quenched with methanol (1 mL) and con-
centrated under reduced pressure. The crude mixture was
dissolved again in methanol (4 mL) at 0 ꢀC and acetic acid
(3 mL) and then NaBH4 (4 mmol) were added in portions.
After 1 h the mixture was treated with Na2CO3, until basic
pH was reached, and extracted with dichloromethane
(2ꢁ20 mL). The organic layer was dried with anhydrous
Na2SO4, then filtered and the solvent was removed under
reduced pressure. Chromatographic separation of the crude
oil on silica gel with AcOEt/cyclohexane (3:97–20:80 v/v)
afforded the pure g-amino alcohols. Spectral data of
products 2a–p are as follow.
5. Experimental
5.1. General
1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively, with CDCl3 as solvent at ambient
temperature and were calibrated using residual unadulter-
ated solvents as the internal reference. Coupling constants
are given in hertz. IR spectra were recorded using FTIR
apparatus.
5.2. Materials and solvents
All reagents were commercially available, were purchased
at the highest quality, and were purified by distillation
when necessary. Hexane and toluene were distilled and
stored on sodium wires before use. The following organo-
lithium reagents were used: MeLi (1.6 M solution in diethyl-
ether), BuLi (2.5 M solution in hexane), PhLi (1.8 M
5.4.1. 4-Anilino-2-methyl-4-phenylbutan-2-ol [2a]. Color-
less oil; IR (Neat) n 3368, 1602, 1500, 1314, 1269, 751,
1
699 cmꢂ1; H NMR (CDCl3) d 1.31 (s, 3H, Me), 1.42 (s,
3H, Me), 1.84 (dd, 1H, J¼14.8, 3.3 Hz, H0b), 2.01 (dd, 1H,
J¼14.8, 10.9 Hz, Hb), 2.85 (br s, 1H, NH), 4.30 (br s, 1H),
4.62 (dd, 1H, J¼10.9, 3.3 Hz, Hc), 6.50–6.70 (m, 3H),

9428
C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
7.05–7.40 (m, 7H, Ar-H); 13C NMR (CDCl3) d 28.2, 32.3,
50.9, 56.7, 71.6, 114.8, 118.3, 126.2, 127.2, 129.0, 129.3,
144.8, 147.4; MS (EI, 70 eV): m/z 255 (M+, 14), 182
(100), 104 (14), 93 (22), 77 (22). Anal. Calcd for
C17H21NO (255.4): C 79.96; H 8.29; N 5.49. Found: C
79.74; H 8.13; N 5.56.
5.4.6. 5-Anilino-3-isopropyl-2-methylhexan-3-ol [2f].
Colorless oil; IR (Neat) n 3350, 1601, 1498, 1381, 1255,
1137, 753, 692 cmꢂ1; 1H NMR (CDCl3) d 0.90 (d, 3H, J¼
6.6 Hz, Me), 0.95 (d, 3H, J¼7.0 Hz, Me), 1.01 (d, 3H,
J¼7.0 Hz, Me), 1.02 (d, 3H, J¼7.0 Hz, Me), 1.13 (d, 3H, J¼
6.2 Hz, Me), 1.51 (dd, 1H, J¼15.0, 10.6 Hz, Hb), 1.67 (dd,
1H, J¼15.0, 5.9 Hz, H0b), 1.85 (hept, 1 H, J¼6.8 Hz,
Me2CH), 1.94 (hept, 1H, J¼7.0 Hz, Me2CH), 3.10 (br s,
1H, NH), 3.75–3.95 (m, 1H, Hc), 4.40 (br s, 1H, OH),
6.70–6.90 (m, 3H, Ar-H), 7.15–7.25 (m, 2H, Ar-H); 13C
NMR (CDCl3) d 17.3, 17.4, 17.8, 18.1, 21.8, 34.8, 36.5,
38.2, 48.6, 76.7, 116.4, 119.9, 129.5, 146.8; MS (EI,
70 eV): m/z (%) 249 (M+, 4), 206 (2), 120 (100), 93 (5),
77 (5). Anal. Calcd for C16H27NO (249.4): C 77.06; H
10.91; N 5.62. Found: C 77.31; H 10.76; N 5.86.
5.4.2. 1-Anilino-3-butyl-1-phenylheptan-3-ol [2b]. Color-
less oil; IR (Neat) n 3370, 1602, 1500, 1317, 1268, 750,
699 cmꢂ1
;
1H NMR (CDCl3) d 0.91 (t, 3 H, J¼6.8 Hz,
Me), 0.96 (t, 3H, J¼6.6 Hz, Me), 1.20–1.53 (m, 10H),
1.58–1.75 (m, 2H), 1.81 (dd, 1H, J¼15.0, 3.7 Hz, H0b),
1.93 (dd, 1H, J¼15.0, 10.1 Hz, Hb), 2.60 (br s, 1H, NH),
4.55 (dd, 1H, J¼10.1, 3.7 Hz, Hc), 4.95 (br s, 1H, OH),
6.50–6.70 (m, 3H, Ar-H), 7.00–7.40 (m, 7H, Ar-H); 13C
NMR (CDCl3) d 14.3, 14.4, 23.5, 23.6, 25.6, 26.9, 38.0,
40.9, 47.5, 56.1, 75.4, 114.7, 118.1, 126.2, 127.1, 128.9,
129.2, 145.1, 147.5; MS (EI, 70 eV): m/z (%) 339 (M+, 9),
282 (2), 182 (100), 104 (8), 93 (12), 77 (10). Anal. Calcd
for C23H33NO (339.5): C 81.37; H 9.80; N 4.13. Found: C
81.21; H 9.89; N 4.01.
5.4.7. 7-Anilino-5-butyldecan-5-ol [2g]. Colorless oil; IR
(Neat) n 3364, 1602, 1498, 1319, 1253, 1146, 750,
692 cmꢂ1
;
1H NMR (CDCl3) d 0.87 (t, 3H, J¼7.3 Hz,
Me), 0.91 (t, 3H, J¼6.6 Hz, Me), 0.92 (t, 3H, J¼6.6 Hz, Me),
1.10–1.65 (m, 17H), 1.72 (dd, 1H, J¼15.0, 2.2 Hz, H0b), 3.55
(br s, 1H, NH), 3.55–3.75 (m, 1H, Hc), 3.95 (br s, 1H, OH),
6.65 (m, 3H, Ar-H), 7.10–7.25 (m, 2H, Ar-H); 13C NMR
(CDCl3) d 14.2, 14.3, 14.4, 19.2, 23.5, 23.6, 25.6, 26.7,
38.4, 38.8, 40.4, 42.3, 51.0, 74.4, 115.5, 119.1, 129.5,
147.0; MS (EI, 70 eV): m/z (%) 305 (M+, 4), 262 (1), 230
(5), 148 (100), 120 (53), 106 (22), 77 (9). Anal. Calcd for
C20H35NO (305.5): C 78.63; H 11.55; N 4.58. Found: C
78.79; H 11.41; N 4.75.
5.4.3. 1-Anilino-3-isopropyl-4-methyl-1-phenylpentan-3-
ol [2c]. Colorless oil; IR (Neat) n 3366, 1602, 1499, 1308,
1
1265, 752, 692 cmꢂ1; H NMR (CDCl3) d 0.93 (d, 3H,
J¼7.0 Hz, Me), 1.01 (d, 3H, J¼7.0 Hz, Me), 1.10 (d, 3H,
J¼7.0 Hz, Me), 1.15 (d, 3H, J¼7.0 Hz, Me), 1.80–2.16 (m,
4H), 3.41 (br s, 1H, NH), 4.66 (br s, 1H, OH), 4.71 (dd,
1H, J¼9.5, 4.4 Hz, Hc), 6.60–6.80 (m, 3H, Ar-H), 7.05–
7.40 (m, 7H, Ar-H); 13C NMR (CDCl3) d 17.5, 17.7,
18.0, 18.6, 35.2, 36.2, 40.8, 56.6, 77.7, 115.6, 119.0,
126.1, 127.3, 129.0, 129.3, 114.8, 147.0; MS (EI, 70 eV):
m/z (%) 311 (M+, 4), 268 (2), 182 (100), 114 (6), 104 (8),
93 (20), 77 (22), 43 (15). Anal. Calcd for C21H29NO
(311.5): C 80.98; H 9.38; N 4.50. Found: C 81.13; H 9.49;
N 4.31.
5.4.8. 5-(2-Benzylamino-2-phenylethyl)nonan-5-ol [2h].
Colorless oil; IR (Neat) n 3291, 1602, 1205, 1027, 744,
699 cmꢂ1
;
1H NMR (CDCl3) d 0.88 (t, 6H, J¼7.0 Hz,
2Me), 1.05–1.18 (m, 1H), 1.20–1.45 (m, 10H), 1.50–1.57
(m, 1H), 1.62 (dd, 1H, J¼14.6, 2.4 Hz, H0b), 1.78 (dd, 1H,
J¼14.6, 11.9 Hz, Hb), 3.48 (d, 1H, J¼12.8 Hz, Bn), 3.66
(d, 1H, J¼12.8 Hz, Bn), 3.20 (br s, 2H, NH, OH), 3.86
(dd, 1H, J¼11.9, 2.4 Hz, Hc), 7.20–7.50 (m, 10H, Ar-H);
13C NMR (CDCl3) d 14.3, 14.4, 23.5, 23.6, 25.6, 26.9,
38.5, 40.6, 45.5, 51.1, 58.9, 74.3, 126.6, 127.5, 127.6,
128.7, 128.9, 129.1, 139.2, 143.7; MS (EI, 70 eV): m/z (%)
296 (M+ꢂ57, 4), 278 (3), 196 (70), 106 (16), 91 (100).
Anal. Calcd for C24H35NO (353.4): C 81.53; H 9.98; N
3.96. Found: C 81.38; H 10.13; N 3.75.
5.4.4. 3-Anilino-1,1,3-triphenylpropan-1-ol [2d]. White
crystals; mp 128–130 ꢀC (n-hexane/CH2Cl2); IR (Nujol) n
1
3325, 1601, 1496, 1308, 1260, 753, 698 cmꢂ1; H NMR
(CDCl3) d 2.66 (dd, 1H, J¼14.8, 11.0 Hz, Hb), 2.86 (dd,
1H, J¼14.8, 2.0 Hz, H0b), 4.46 (dd, 1H, J¼11.0, 2.0 Hz,
Hc), 4.50 (br s, 1H, NH), 5.35 (br s, 1H, OH), 6.40–6.80
(m, 3H, Ar-H), 7.00–7.60 (m, 17H, Ar-H); 13C NMR
(CDCl3) d 49.1, 57.2, 78.9, 116.4, 119.9, 125.9, 126.1,
126.5, 127.1, 127.2, 127.5, 128.5, 128.6, 129.0, 129.3,
143.6, 146.3, 146.6, 147.8; MS (EI, 70 eV): m/z (%) 379
(M+, 3), 269 (6), 180 (100), 165 (35), 77 (44). Anal. Calcd
for C27H25NO (379.5): C 85.45; H 6.64; N 3.69. Found: C
85.43; H 6.73; N 3.64.
5.4.9. 5-{(2S)-2-[(10R)-10-Phenylethyl]amino-2-phenyl-
ethyl}nonan-5-ol [(2S,10R)-2i]. Colorless oil [a]2D0 ꢂ10.8
(c 1.9, CHCl3); IR (Neat) n 3293, 1601, 1375, 1141, 1028,
759, 699 cmꢂ1; 1H NMR (CDCl3) d 0.89 (t, 3H, J¼6.8 Hz,
Me), 1.01 (t, 3H, J¼7.0 Hz, Me), 1.18–1.55 (m, 10H), 1.40
(d, 3H, J¼6.2 Hz, Me-CH), 1.62–1.85 (m, 4H), 3.20 (br s,
1H, NH), 3.55 (q, 1H, J¼6.3 Hz, Me-CH), 4.17 (t, 1H,
J¼7.0 Hz, Hc), 4.40 (br s, 1H, OH), 7.10–7.40 (m, 10H,
Ar-H); 13C NMR (CDCl3) d 14.3, 14.4, 21.3, 23.6, 23.7,
25.5, 27.2, 38.6, 40.6, 45.9, 54.6, 57.0, 74.3, 126.3, 126.7,
127.5, 127.6, 128.8, 129.1, 143.5, 145.4; MS (EI, 70 eV):
m/z (%) 352 (M+ꢂ15, 3), 310 (7), 210 (78), 106 (96), 105
(100). Anal. Calcd for C25H37NO (367.6): C 81.70; H
10.15; N 3.81. Found: C 81.86; H 10.28; N 3.67.
5.4.5. 5-(2-Anilinopropyl)nonan-5-ol [2e]. Colorless oil;
IR (Neat) n 3368, 1602, 1498, 1320, 1252, 1151, 750,
692 cmꢂ1
;
1H NMR (CDCl3) d 0.93 (t, 3H, J¼6.6 Hz,
Me), 0.96 (t, 3H, J¼6.6 Hz, Me), 2.29 (d, 3H, J¼6.2 Hz,
Me), 1.15–1.50 (m, 10H), 1.55–1.75 (m, 4H), 3.67 (br s,
2H), 3.70–3.90 (m, 1H), 6.70–6.90 (m, 3H, Ar-H), 7.15–
7.25 (m, 2H, Ar-H); 13C NMR (CDCl3) d 14.3, 14.4, 22.3,
23.5, 23.6, 25.6, 26.8, 38.9, 40.3, 45.3, 47.2, 74.5, 115.7,
119.4, 129.5, 147.0; MS (EI, 70 eV): m/z (%) 277 (M+, 4),
220 (2), 202 (4), 120 (100), 93 (6), 77 (6). Anal. Calcd for
C18H31NO (277.4): C 77.92; H 11.26; N 5.05. Found: C
78.12; H 11.44; N 5.11.
5.4.10. 5-{(2R)-2-[(10R)-10-Phenylethyl]amino-2-phenyl-
ethyl}nonan-5-ol [(R,R)-2i]. Colorless oil; IR (Neat) n
1
3297, 1599, 1378, 1140, 1034, 759, 700 cmꢂ1; H NMR

C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
9429
(CDCl3) d 0.76 (t, 3H, J¼7.0 Hz, Me), 0.88 (t, 3H, J¼6.2 Hz,
Me), 0.90–1.40 (m, 12H), 1.28 (d, 3H, J¼6.6 Hz, Me-CH),
1.50 (dd, 1H, J¼14.6, 2.6 Hz, H0b), 1.75 (dd, 1H, J¼14.6,
11.7 Hz, Hb), 3.20 (br s, 1H, NH), 3.47 (q, 1H, J¼6.6 Hz,
Me-CH), 3.57 (dd, 1H, J¼11.7, 2.6 Hz, Hc), 4.00 (br s,
1H, OH), 7.10–7.45 (m, 10H, Ar-H); MS (EI, 70 eV): m/z
(%) 352 (M+ꢂ15, 1), 310 (5), 210 (85), 106 (87), 105
(100). Anal. Calcd for C25H37NO (367.6): C 81.7; H
10.15; N 3.81. Found: C 81.61; H 10.29; N 3.62.
32.3, 37.8, 38.4, 39.2, 49.7, 56.7, 76.0, 114.4, 117.6,
129.4, 147.9; MS (EI, 70 eV): m/z (%) 303 (M+, 11), 285
(3), 246 (14), 228 (16), 132 (74), 119 (100), 106 (13), 93
(32). Anal. Calcd for C20H33NO (303.5): C 79.15; H
10.96; N 4.62. Found: C 79.32; H 10.79; N 4.39.
5.4.16. 5-[(R*,R*)-2-Anilinocyclopentyl]nonan-5-ol
[trans-2l]. H NMR (CDCl3) d 0.85–1.00 (m, 6H, 2Me),
1
1.20–2.05 (m, 20H), 3.60 (br s, 1H, NH), 3.85 (td, 1H,
J¼7.3, 2.2 Hz, Hc), 6.60–7.30 (m, 5H, Ar-H).
5.4.11. 5-[(R*,R*)-2-Anilino-1-methylpropyl]nonan-5-ol
[trans-2j]. Oil; H NMR (CDCl3) d 0.85–1.00 (m, 6H),
1
5.4.17. 5-[(1R*,2S*)-2-(Benzylamino)cyclopentyl]nonan-
5-ol [cis-2m]. Colorless oil; IR (Neat) n 3271, 1605, 1260,
1.05–1.18 (m, 6H), 1.20–1.70 (m, 12H), 1.80 (dq, 1H,
J¼8.8, 7.0 Hz, Hb), 3.65 (br s, 2H, NH, OH), 3.70 (dq, 1H,
J¼8.8, 6.3 Hz, Hc), 6.70–7.30 (m, 5H, Ar-H); 13C NMR
(CDCl3) d 13.2, 14.4, 14.5, 19.8, 23.7, 23.9, 25.3, 25.7,
36.9, 37.6, 44.4, 52.3, 77.1, 116.0, 119.6, 129.6, 146.8;
MS (EI, 70 eV): m/z (%) 291 (M+, 2), 120 (100), 93 (9),
77 (6). Anal. Calcd for C19H33NO (291.5): C 78.29; H
11.41; N 4.81. Found: C 78.48; H 11.32; N 4.63.
1
1169, 745, 699 cmꢂ1; H NMR (CDCl3) d 0.88 (t, 3H,
J¼7.0 Hz, Me), 0.90 (t, 3H, J¼7.0 Hz, Me), 1.05–1.55 (m,
13H), 1.60–1.82 (m, 8H), 3.18–3.26 (m, 1H, Hc), 3.84 (d,
1H, J¼12.4 Hz, Bn), 3.66 (d, 1H, J¼12.4 Hz, Bn), 7.20–
7.35 (m, 5H, Ar-H); 13C NMR (CDCl3) d 14.3, 14.4, 20.8,
22.1, 23.6, 23.7, 25.7, 26.3, 31.0, 37.3, 39.4, 49.4, 52.4,
60.3, 74.9, 127.5, 128.6, 128.8, 139.6; MS (EI, 70 eV): m/z
(%) 298 (M+ꢂ19, 2), 277 (4), 260 (44), 146 (43), 106
(26), 91 (100). Anal. Calcd for C21H35NO (317.5): C
79.44; H 11.11; N 4.41. Found: C 79.27; H 11.18; N 4.24.
5.4.12. 5-[(1R*,2S*)-2-Anilino-1-methylpropyl]nonan-5-
ol [cis-2j]. Oil; H NMR (CDCl3) d 0.85–1.00 (m, 6H),
1
1.05–1.18 (m, 6H), 1.20–1.75 (m, 13H), 3.65 (br s, 2H,
NH, OH), 4.08 (qd, 1H, J¼6.3, 2.3 Hz, Hc), 6.70–7.30 (m,
5H, Ar-H); 13C NMR (CDCl3) d 6.6, 14.3, 14.4, 19.3,
23.6, 23.8, 25.9, 26.4, 36.0, 37.9, 41.9, 49.1, 77.7, 115.9,
119.6, 129.6, 146.8; MS (EI, 70 eV): m/z (%) 291 (M+, 2),
120 (100), 93 (8), 77 (8). Anal. Calcd for C19H33NO
(291.5): C 78.29; H 11.41; N 4.81. Found: C 78.52; H
11.57; N 4.59.
5.4.18. 5-[(R*,R*)-2-(Benzylamino)cyclopentyl]nonan-5-
1
ol [trans-2m]. H NMR (CDCl3) d 0.89 (t, 3H, J¼7.0 Hz,
Me), 0.91 (t, 3H, J¼6.6 Hz, Me), 1.10–1.90 (m, 20H),
2.05–2.25 (m, 1H), 3.00–3.15 (m, 1H, Hc), 3.72 (d, 1H,
J¼12.8 Hz, Bn), 3.91 (d, 1H, J¼12.8 Hz, Bn), 7.20–7.40
(m, 5H, Ar-H).
5.4.19. 2-[(1R*,2S*)-2-Anilinocyclohexyl]propan-2-ol
[cis-2n]. White crystals; mp 64–66 ꢀC (n-hexane/CH2Cl2);
IR (Nujol) n 3367, 1601, 1504, 1243, 1169, 749,
5.4.13. 2-[(1R*,2S*)-2-Anilinocyclopentyl]propan-2-ol
[cis-2k]. Colorless oil; IR (Neat) n 3371, 1601, 1505,
1
1
1322, 1190, 748, 693 cmꢂ1; H NMR (CDCl3) d 1.27 (s,
692 cmꢂ1; H NMR (CDCl3) d 1.20–1.70 (m, 6H, 2Me),
3H, Me), 1.34 (s, 3H, Me), 1.60–2.00 (m, 7H, NH), 3.00
(br s, 1H), 3.65 (br s, 1H), 3.90–3.98 (m, 1H, Hc), 6.60–
6.80 (m, 3H, Ar-H), 7.10–7.30 (m, 2H, Ar-H); 13C NMR
(CDCl3) d 21.5, 23.4, 29.9, 30.8, 32.5, 52.7, 57.3, 72.1,
114.4, 117.8, 129.4, 147.9; MS (EI, 70 eV): m/z (%) 219
(M+, 34), 204 (6), 186 (6), 132 (84), 119 (100), 106 (14),
93 (39). Anal. Calcd for C14H21NO (219.3): C 76.67; H
9.65; N 6.39. Found: C 76.49; H 9.84; N 6.24.
1.22 (s, 3H), 1.34 (s, 3H), 1.80–2.00 (m, 3H), 3.45 (br s,
1H, NH), 3.95 (br s, 1H, OH), 4.03–4.12 (m, 1H, Hc),
6.70–6.90 (m, 3H, Ar-H), 7.15–7.30 (m, 2H, Ar-H); 13C
NMR (CDCl3) d 20.1, 21.2, 26.1, 28.6, 29.3, 29.5,
48.6, 50.1, 72.8, 115.7, 119.2, 129.6, 147.0; MS (EI,
70 eV): m/z (%) 233 (M+, 31), 218 (9), 200 (6), 132 (100),
119 (26), 106 (20), 93 (42). Anal. Calcd for C15H23NO
(233.3): C 77.21; H 9.93; N 6.00. Found: C 77.36; H
10.19; N 5.81.
5.4.14. 2-[(R*,R*)-2-Anilinocyclopentyl]propan-2-ol
[trans-2k]. Colorless oil; IR (Neat) n 3400, 1602, 1503,
5.4.20. 2-[(R*,R*)-2-Anilinocyclohexyl]propan-2-ol
[trans-2n]. White crystals; mp 122–124 ꢀC (n-hexane/
CH2Cl2); IR (Nujol) n 3363, 1598, 1505, 1239, 1167, 745,
1
1320, 1180, 749, 692 cmꢂ1; H NMR (CDCl3) d 1.25 (s,
6H, 2Me), 1.30–1.54 (m, 2H), 1.60–1.88 (m, 4H), 2.02–
2.22 (m, 1H), 3.00 (br s, 1H, NH), 3.60 (br s, 1H, OH)
3.75 (q, 1H, J¼7.2 Hz, Hc), 6.60–6.90 (m, 3H, Ar-H),
7.10–7.30 (m, 2H, Ar-H); 13C NMR (CDCl3) d 22.9, 25.6,
27.3, 29.8, 33.5, 56.6, 57.4, 72.8, 114.6, 118.3, 129.4,
147.8; MS (EI, 70 eV): m/z (%) 219 (M+, 40), 204 (7), 186
(6), 132 (81), 119 (100), 106 (13), 93 (29). Anal. Calcd for
C14H21NO (219.3): C 76.67; H 9.65; N 6.29. Found: C
76.72; H 9.58; N 6.46.
1
687 cmꢂ1; H NMR (CDCl3) d 0.90–1.16 (m, 2H), 1.18–
1.40 (m, 2H), 1.21 (s, 3H, Me), 1.26 (s, 3H, Me), 1.52 (td,
1H, J¼11.2, 3.3 Hz), 1.64–1.84 (m, 2H), 1.85–2.00 (m,
1H), 2.06–2.20 (m, 1H), 3.36 (td, 1H, J¼10.7, 3.9 Hz, Hc),
4.15 (br s, 2H, NH, OH), 6.70–6.90 (m, 3H, Ar-H), 7.15–
7.30 (m, 2H, Ar-H); 13C NMR (CDCl3) d 24.8, 25.8, 26.3,
29.0, 29.5, 34.6, 52.8, 57.0, 74.2, 116.4, 120.2, 129.5,
146.5; MS (EI, 70 eV): m/z (%) 233 (M+, 29), 218 (6), 200
(6), 132 (100), 119 (28), 106 (22), 93 (54). Anal. Calcd for
C15H23NO (233.3): C 77.21; H 9.93; N 6.00. Found: C
77.37; H 9.82; N 6.18.
5.4.15. 5-[(1R*,2S*)-2-Anilinocyclopentyl]nonan-5-ol
[cis-2l]. Colorless oil; IR (Neat) n 3378, 1601, 1508, 1321,
1
1269, 747, 692 cmꢂ1; H NMR (CDCl3) d 0.86–0.98 (m,
6H, 2Me), 1.10–2.00 (m, 21H), 3.85–3.95 (m, 1H, Hc),
6.80–6.90 (m, 3H, Ar-H), 7.10–7.30 (m, 2H, Ar-H); 13C
NMR (CDCl3) d 14.3, 14.4, 21.1, 22.7, 23.5, 25.9, 26.3,
5.4.21. 5-[(1R*,2S*)-2-Anilinocyclohexyl]nonan-5-ol [cis-
2o]. Colorless oil; IR (Neat) n 3366, 1601, 1504, 1242, 1153,
749, 692 cmꢂ1; 1H NMR (CDCl3) d 0.92 (t, 6H, 2Me), 1.10–

9430
C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
1.75 (m, 17H), 1.80–2.00 (m, 4H), 3.80 (br s, 2H, NH, OH),
3.95–4.05 (m, 1H, Hc), 6.70–6.90 (m, 3H, Ar-H), 7.15–7.30
(m, 2H, Ar-H); 13C NMR (CDCl3) d 14.3, 14.4, 20.2, 20.6,
23.6, 23.7, 25.9, 26.2, 26.4, 29.3, 35.4, 37.3, 44.8, 49.8,
77.7, 115.8, 119.3, 129.6, 146.9; MS (EI, 70 eV): m/z (%)
317 (M+, 13), 299 (3), 260 (24), 242 (21), 132 (100), 119
(36), 106 (42), 93 (85). Anal. Calcd for C21H35NO
(317.5): C 79.44; H 11.11; N 4.41. Found: C 79.53; H
11.02; N 4.60.
5.5.1. (1R*,3S*)-1-Anilino-1,3-diphenylheptan-3-ol
[(1R*,3S*)-2q]. Colorless oil; IR (Neat) n 3419, 1601,
1504, 1314, 1266, 751, 700 cmꢂ1 1H NMR (CDCl3)
;
d 0.84 (t, 3H, J¼6.6 Hz, Me), 0.90–1.10 (m, 1H), 1.15–
1.45 (m, 3H), 1.98 (t, 2H, J¼7.7 Hz), 2.15–2.40 (m, 2H,
Hb, H0b), 2.95 (br s, 1H, NH), 4.30 (br s, 1H, OH), 4.68 (t,
1H, J¼7.0 Hz, Hc), 6.30–6.75 (m, 3H, Ar-H), 7.00–7.50
(m, 12H, Ar-H); 13C NMR (CDCl3) d 14.2, 23.2, 25.8,
42.1, 51.6, 55.9, 76.8, 114.6, 118.3, 125.2, 126.4,
126.8, 127.3, 128.2, 128.6, 129.0, 129.2, 144.5, 147.1; MS
(EI, 70 eV): m/z (%) 359 (M+, 3), 284 (1), 182 (100), 118
(56), 104 (18), 77 (49). Anal. Calcd for C25H29NO
(359.5): C 83.52; H 8.13; N 3.90. Found: C 83.47; H 7.92;
N 3.68.
5.4.22. 5-[(R*,R*)-2-Anilinocyclohexyl]nonan-5-ol
[trans-2o]. Colorless oil; IR (Neat) n 3359, 1603, 1500,
1245, 1151, 748, 694 cmꢂ1; 1H NMR (CDCl3) d 0.85–1.00
(m, 6H, 2Me), 1.15–1.85 (m, 20H), 2.05–2.20 (m, 1H),
3.46 (td, 1H, J¼10.3, 3.8 Hz, Hc), 4.00 (br s, 2H, NH,
OH), 6.70–6.90 (m, 3H, Ar-H), 7.15–7.25 (m, 2H, Ar-H);
13C NMR (CDCl3) d 14.4, 14.5, 23.8, 24.1, 25.0, 25.6,
26.0, 26.6, 28.6, 35.1, 36.9, 37.3, 49.2, 56.4, 77.0,
116.5, 120.2, 129.6, 146.7; MS (EI, 70 eV): m/z (%)
317 (M+, 20), 299 (4), 260 (49), 242 (18), 132 (100), 119
(32), 106 (36), 93 (78). Anal. Calcd for C21H35NO
(317.5): C 79.44; H 11.11; N 4.41. Found: C 79.40; H
11.16; N 4.54.
5.5.2. (1R*,3R*)-1-Anilino-1,3-diphenylheptan-3-ol
[(1R*,3R*)-2q]. Colorless oil; IR (Neat) n 3425, 1600,
1505, 1312, 1261, 750, 698 cmꢂ1 1H NMR (CDCl3)
;
d 0.85 (t, 3H, J¼7.1 Hz, Me), 1.00–1.50 (m, 4H), 1.75–
1.90 (m, 2H), 2.20–2.40 (m, 2H, Hb, H0b), 4.18 (t, 1H,
J¼6.8 Hz, Hc), 4.55 (br s, 2H, NH, OH), 6.40–6.70 (m,
3H, Ar-H), 7.00–7.60 (m, 12H, Ar-H); 13C NMR (CDCl3)
d 14.2, 23.2, 25.5, 44.5, 50.0, 56.8, 78.0, 116.2, 119.7,
125.1, 125.7, 125.9, 126.7, 127.2, 128.5, 128.9, 129.2,
143.7, 146.5; MS (EI, 70 eV): m/z (%) 359 (M+, 5), 284
(2), 182 (100), 118 (51), 105 (15), 77 (43). Anal. Calcd for
C25H29NO (359.5): C 83.52; H 8.13; N 3.90. Found: C
83.73; H 8.01; N 3.73.
5.4.23. 3-[(1R*,2S*)-2-Anilinocyclohexyl]-2,4-dimethyl-
pentan-3-ol [cis-2p]. Colorless oil; IR (Neat) n 3369,
1602, 1498, 1242, 1057, 751, 692 cmꢂ1; 1H NMR (CDCl3)
d 1.02 (d, 12H, J¼7.0 Hz, 4Me), 1.25–2.25 (m, 11H), 3.89
(br s, 2H, NH, OH), 4.04 (s, 1H, Hc), 6.70–6.90 (m, 3H,
Ar-H), 7.15–7.30 (m, 2H, Ar-H); 13C NMR (CDCl3)
d 18.4, 19.1, 19.3, 19.4, 20.2, 22.5, 26.3, 30.0, 32.2, 35.2,
42.4, 50.2, 78.8, 115.9, 119.4, 129.6, 146.6; MS (EI,
70 eV): m/z (%) 289 (M+, 30), 271 (8), 246 (100), 228
(14), 132 (99), 106 (48), 93 (97). Anal. Calcd for
C19H31NO (289.5): C 78.84; H 10.79; N 4.84. Found: C
78.97; H 10.55; N 4.97.
5.5.3. (1R*,3R*)-1-Anilino-4-methyl-1,3-diphenylpen-
tan-3-ol [(1R*,3R*)-2r]. Colorless oil; IR (Neat) n 3418,
1
1601, 1505, 1316, 1266, 1026, 752, 701 cmꢂ1; H NMR
(CDCl3) d 0.77 (d, 3H, J¼7.0 Hz, Me), 0.91 (d, 3H,
J¼6.6 Hz, Me), 2.11 (sept, 1H, J¼6.7 Hz, Me2CH), 2.31
(dd, 1H, J¼14.8, 8.8 Hz, Hb), 2.50 (dd, 1H, J¼14.8,
4.8 Hz, H0b), 2.77 (br s, 1H, NH), 4.02 (br s, 1H, OH),
4.55 (dd, 1H, J¼8.8, 4.8 Hz, Hc), 6.20–6.30 (m, 2H, Ar-
H), 6.54–6.66 (m, 1H, Ar-H), 6.94–7.08 (m, 2H, Ar-H),
7.20–7.40 (m, 10H, Ar-H); 13C NMR (CDCl3) d 16.9,
17.7, 38.4, 47.9, 55.5, 78.2, 114.1, 117.9, 125.9, 126.5,
126.7, 127.3, 128.2, 128.9, 129.0, 144.4, 145.5, 146.8; MS
(EI, 70 eV): m/z (%) 345 (M+, 7), 182 (100), 105 (20), 77
(29). Anal. Calcd for C24H27NO (345.8): C 83.44; H 7.88;
N 4.05. Found: C 83.28; H 8.08; N 4.22.
5.4.24. 3-[(R*,R*)-2-Anilinocyclohexyl]-2,4-dimethyl-
pentan-3-ol [trans-2p]. Colorless oil; IR (Neat) n 3279,
1
1602, 1498, 1242, 1060, 994, 754, 692 cmꢂ1; H NMR
(CDCl3) d 0.94 (d, 3H, J¼7.0 Hz, Me), 0.99 (d, 3H,
J¼7.0 Hz, Me), 1.05 (d, 3H, J¼7.0 Hz, Me), 1.12 (d, 3H,
J¼7.0 Hz, Me), 1.12–1.42 (m, 4H), 1.63–1.95 (m, 4H),
1.96–2.30 (m, 3H), 3.57 (td, 1 H, J¼10.3, 3.9 Hz, Hc),
4.50 (br s, 2H, NH, OH), 6.70–6.90 (m, 3H, Ar-H), 7.15–
7.30 (m, 2H, Ar-H); 13C NMR (CDCl3) d 18.0, 18.1, 19.4,
20.2, 25.8, 27.0, 29.2, 33.0, 33.8, 36.0, 48.2, 58.1, 79.4,
116.9, 120.4, 129.5, 146.4; MS (EI, 70 eV): m/z (%) 289
(M+, 19), 271 (17), 246 (97), 228 (17), 132 (93), 106 (43),
93 (100). Anal. Calcd for C19H31NO (289.5): C 78.84; H
10.79; N 4.84. Found: C 78.71; H 10.96; N 4.63.
5.5.4. (1R*,3S*)-1-Anilino-4-methyl-1,3-diphenylpentan-
3-ol [(1R*,3S*)-2r]. Colorless oil; IR (Neat) n 3379, 1601,
1500, 1314, 1265, 752, 699 cmꢂ1 1H NMR (CDCl3)
;
d 0.73 (d, 3H, J¼6.6 Hz, Me), 1.06 (d, 3H, J¼6.6 Hz, Me),
2.02 (sept, 1H, J¼6.8 Hz, Me2CH), 2.26 (dd, 1H, J¼14.7,
3.3 Hz, H0b), 2.37 (dd, 1H, J¼14.7, 10.1 Hz, Hb), 3.88 (br
s, 2H, NH, OH), 4.14 (dd, 1H, J¼10.1, 3.3 Hz, Hc), 6.15–
6.20 (m, 2H, Ar-H), 6.60–6.80 (m, 1H, Ar-H), 7.00–7.50
(m, 12H, Ar-H); 13C NMR (CDCl3) d 16.9, 17.5, 39.2,
47.4, 57.2, 80.0, 116.2, 119.7, 126.2, 126.7, 127.3, 127.7,
128.4, 128.9, 129.2, 143.9, 146.3, 146.5; MS (EI, 70 eV):
m/z (%) 345 (M+, 7), 182 (100), 105 (20), 77 (33). Anal.
Calcd for C24H27NO (345.8): C 83.44; H, 7.88; N 4.05.
Found: C 83.66; H, 7.63; N 4.31.
5.5. General procedure for the alkylation and one-pot
reduction for the synthesis of g-amino alcohols 2q–s
The b-enamino ester 1a (1 mmol) was dissolved in toluene
(3 mL), under nitrogen atmosphere at 0 ꢀC, then was added
the first organolithium reagent (2.5 mmol), according to the
reaction conditions and reagents reported in Table 2. After
the reaction time (see Table 2) the second organolithium re-
agent was added (1.5 mmol). After 1 h the reduction proce-
dure was performed (see above). Spectral data of products
2q–s are as follow.
5.5.5. (1S*,3R*)-1-Anilino-3-(tert-butyl)-1-phenylhep-
tan-3-ol [(1S*,3R*)-2s]. White crystals; mp 81–83 ꢀC
(n-hexane/CH2Cl2); IR (Nujol) n 3369, 1602, 1503, 1312,

C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
9431
1
1266, 751, 692 cmꢂ1; H NMR (CDCl3) d 0.99 (t, 3H,
(n-esano); IR (Nujol) nmax 1600, 1503, 1379, 1247, 1020,
749, 693 cmꢂ1; 1H NMR (CDCl3) d 0.74 (t, 3H, J¼7.0 Hz,
Me), 0.90 (d, 3H, J¼7.0 Hz, Me), 0.94 (t, 3H, J¼6.6 Hz,
Me), 1.00–1.70 (m, 12H), 1.28 (d, 3H, J¼6.2 Hz, Me),
2.08 (dq, 1H, J¼7.0, 10.2 Hz, Hb), 3.34 (dq, 1H, J¼6.2,
10.2 Hz, Hc), 4.83 (d, 1H, J¼11.0 Hz, O-CH2-N), 4.89 (d,
1H, J¼11.0 Hz, O-CH2-N), 6.80–7.30 (m, 5H, Ar-H); 13C
NMR (CDCl3) d 14.0, 14.2, 14.5, 19.3, 23.5, 23.6, 24.4,
25.4, 33.0, 37.2, 39.7, 56.7, 72.4, 78.4, 117.3, 120.1,
129.2, 149.2. Anal. Calcd for C20H33NO (303.5): C 79.15;
H 10.96; N 4.62. Found: C 79.23; H 10.79; N 4.81.
J¼6.8 Hz), 1.06 (s, 9H, t-Bu), 1.30–1.75 (m, 6H), 1.86
(dd, 1H, J¼15.4, 10.6 Hz, Hb), 2.08 (dd, 1H, J¼15.4,
2.6 Hz, H0b), 3.47 (br s, 1H, NH), 4.40 (br s, 1H, OH),
4.75 (dd, 1H, J¼10.6, 2.6 Hz, Hc), 6.60–6.80 (m, 3H, Ar-
H), 7.05–7.40 (m, 7H, Ar-H); 13C NMR (CDCl3) d 14.5,
23.8, 26.0, 26.7, 37.8, 39.0, 42.7, 57.0, 77.2, 115.6, 119.1,
126.2, 127.2, 129.0, 129.3, 144.6, 146.8; MS (EI, 70 eV):
m/z (%) 339 (M+, 5), 282 (2), 182 (100), 104 (14), 93 (16),
77 (14), 57 (11). Anal. Calcd for C23H33NO (339.5): C
81.37; H 9.80; N 4.13. Found: C 81.46; H 9.64; N 4.26.
5.5.6. (1R*,3R*)-1-Anilino-3-(tert-butyl)-1-phenylhep-
tan-3-ol [(1R*,3R*)-2s]. MS (EI, 70 eV): m/z (%) 339 (M+,
6), 278 (11), 182 (100), 104 (15), 93 (17), 77 (22), 57 (17).
5.7.2. (4S*,5R*)-6,6-Dibutyl-4,5-dimethyl-3-phenyl-1,3-
oxazinane [(4S*,5R*)-5j]. Colorless oil; IR (Neat) nmax
1
1598, 1379, 1252, 1188, 1018, 756, 696 cmꢂ1; H NMR
(CDCl3) d 0.84 (d, 3H, J¼7.3 Hz, Me), 0.88 (t, 3H, J¼
7.0 Hz, Me), 0.96 (t, 3H, J¼6.4 Hz), 1.08–1.42 (m, 9H),
1.40 (d, 3H, J¼7.3 Hz, Me), 1.47–1.63 (m, 2H), 1.92–2.10
(m, 1H), 2.19 (dq, 1H, J¼7.3, 5.7 Hz, Hb), 3.69 (dq, 1H, J¼
7.3, 5.7 Hz, Hc), 4.83 (s, 2H, O-CH2-N), 6.85–7.35 (m, 5H,
Ar-H); 13C NMR (CDCl3) d 13.0, 14.3, 14.4, 15.9, 23.6,
23.8, 25.2, 25.4, 32.7, 35.3, 36.8, 57.9, 70.3, 78.7, 119.4,
120.6, 129.1, 150.6. Anal. Calcd for C20H33NO (303.5): C
79.15; H 10.96; N 4.62. Found: C 79.34; H 10.84; N 4.48.
5.6. General procedure for the synthesis of b-hydroxy
imines 4
The b-enamino ester 1a (1 mmol) was dissolved in toluene
(3 mL), at 0 ꢀC and was added alkyllithium reagent (methyl-
lithium or butyllithium, 4 mmol) according to the reaction
conditions and reagents reported in Table 1, entries 1 and
2. The reaction mixture was then quenched with aqueous sat-
urated NH4Cl (5 mL) and extracted with dichloromethane
(2ꢁ10 mL). The organic layer was dried with anhydrous
Na2SO4, then filtered, and the solvent was removed under
reduced pressure. Spectral characterization of the b-hydroxy
imines 4 was done by analysis of the crude reaction mixture.
Spectral data of b-hydroxy imines 4a and 4b are as follows.
5.7.3. (4S)-6,6-Dibutyl-4-phenyl-3-[(10R)-10-phenyl-
ethyl]-1,3-oxazinane [(4S,10R)-5i]. Oil; [a]D20 +1.4 (c 1.6,
CHCl3); IR (liquid film) nmax 1595, 1498, 1374, 1013, 753,
687 cmꢂ1
;
1H NMR (CDCl3) d 0.87 (t, 3H, J¼6.9 Hz,
Me), 0.98 (t, 3H, J¼7.0 Hz, Me), 1.12–1.44 (m, 9H), 1.38
(d, 3H, J¼7.0 Hz, Me-CH), 1.47–1.60 (m, 2H), 1.75 (dd,
1H, J¼13.7, 3.9 Hz, H0b), 1.82–1.94 (m, 1H), 1.85 (dd,
1H, J¼13.7, 11.0 Hz, Hb), 3.94 (q, 1H, J¼7.0 Hz, Me-
CH), 4.04 (dd, 1H, J¼11.0, 3.9 Hz, Hc), 4.31 (d, 1H,
J¼10.0 Hz, O-CH2-N), 4.35 (d, 1H, J¼10.0 Hz, O-CH2-
N), 7.15–7.50 (m, 10H, Ar-H); 13C NMR (CDCl3) d 12.6,
14.2, 14.4, 23.4, 23.6, 25.3, 25.6, 33.1, 38.5, 42.5, 55.4,
58.0, 72.1, 75.8, 126.7, 127.2, 127.6, 127.7, 128.2, 128.7,
143.9, 144.4. Anal. Calcd for C26H37NO (379.6): C 82.27;
H 9.83; N 3.69. Found: C 82.45; H 9.61; N 3.52.
5.6.1. 2-Methyl-4-phenyl-4-(phenylimino)butan-2-ol
[4a]. Yield 58%; Oil; IR (liquid film) nmax 3392, 1630,
1
1594, 1212, 761, 696 cmꢂ1; H NMR (CDCl3) d 1.43 (s,
6H, 2Me), 2.92 (s, 2H, CH2), 5.93 (s, 1H, OH), 6.60–7.30
(m, 10H, Ar-H); 13C NMR (CDCl3): d 29.8, 50.5, 70.6,
121.4, 123.9, 127.7, 128.4, 128.8, 129.1, 138.2, 149.3,
172.6. Anal. Calcd for C17H19NO (253.3): C 80.60;
H 7.56; N 5.53%. Found: C 81.74; H 7.79; N 5.29%.
5.6.2. 3-Butyl-1-phenyl-1-(phenylimino)heptan-3-ol [4b].
Yield 63%; Oil; 1H NMR (CDCl3) d 0.91 (t, 6H J¼6.8 Hz,
2Me), 1.25–1.50 (m, 8H), 1.61–1.73 (m, 4H), 2.89 (s, 2H,
CH2), 5.79 (s, 1H, OH), 6.65–7.35 (m, 10H, Ar-H); 13C
NMR (CDCl3) d 14.4, 23.6, 26.4, 39.5, 47.2, 74.8, 121.4,
123.8, 127.7, 128.4, 128.8, 129.0, 138.4, 149.4, 172.8.
Anal. Calcd for C23H31NO (337.5): C 81.85; H 9.26; N
4.15%. Found: C 81.07; H 9.38; N 3.91%.
5.7.4. (R)-6,6-Dibutyl-4-phenyl-3-[(R)-10-phenylethyl]-
1,3-oxazinane [(R,R)-5i]. Oil; [a]2D0 +96.6 (c 1.1, CHCl3);
IR (liquid film) nmax 1596, 1501, 1374, 1245, 1016, 748,
690 cmꢂ1
;
1H NMR (CDCl3) d 0.84 (t, 3H, J¼6.8 Hz,
Me), 0.86 (t, 3H, J¼6.6 Hz, Me), 1.05–1.35 (m, 9H), 1.35
(d, 3H, J¼7.0 Hz, Me-CH), 1.40–1.65 (m, 3H), 1.61 (dd,
1H, J¼13.9, 4.0 Hz, H0b), 1.77 (dd, 1H, J¼13.9, 11.5 Hz,
Hb), 3.77 (dd, 1H, J¼11.5, 4.2 Hz, Hc), 3.95 (q, 1H,
J¼7.0 Hz, Me-CH), 4.06 (d, 1H, J¼9.9 Hz, O-CH2-N),
4.61 (d, 1H, J¼9.9 Hz, O-CH2-N), 7.10–7.50 (m, 10H, Ar-
H); 13C NMR (CDCl3) d 14.2, 14.3, 20.4, 23.4, 23.5, 25.2,
25.5, 32.4, 39.2, 43.6, 57.6, 58.6, 73.2, 75.8, 127.0, 127.1,
127.5, 128.2, 128.3, 128.8, 141.4, 145.4. Anal. Calcd for
C26H37NO (379.6): C 82.27; H 9.83; N 3.69. Found: C
82.43; H 9.60; N 3.88.
5.7. General procedure for the synthesis of 1,3-tetra-
hydro oxazines 5
The g-amino alcohols 2i,j,q (0.5 mmol) were dissolved in
THF (1 mL), and was added aqueous formaldehyde 35%
(0.085 mL, 1 mmol). After 6 h the solvent was removed
under reduced pressure and the crude tetrahydro oxazines
purified by short filtration on a thin pad of silica gel with
cyclohexane/AcOEt (97:3 v/v) or CH2Cl2/n-hexane (50:50
v/v) as eluent. Spectral data of tetrahydro oxazines 5 are as
follow.
5.7.5. (4S*,6R*)-6-Butyl-3,4,6-triphenyl-1,3-oxazinane
[(4S*,6R*)-5q]. Colorless oil; IR (Neat) nmax 1600, 1505,
1
1249, 1026, 753, 696 cmꢂ1; H NMR (CDCl3) d 0.79 (t,
3H, J¼7.0 Hz, Me), 0.86–1.04 (m, 1H), 1.10–1.42 (m,
3H), 1.78 (ddd, 1H, J¼11.6, 4.5, 1.6 Hz), 2.14 (ddd, 1H,
J¼11.8, 4.1, 1.5 Hz), 2.34 (dd, 1H, J¼14.5, 11.8 Hz, Hb),
5.7.1. (R*,R*)-6,6-Dibutyl-4,5-dimethyl-3-phenyl-1,3-
oxazinane [(R*,R*)-5j]. White crystals; mp 50–52 ꢀC

9432
C. Cimarelli et al. / Tetrahedron 62 (2006) 9423–9432
2.49 (dd, 1H, J¼14.5, 5.5 Hz, H0b), 4.77 (dd, 1H, J¼11.8,
5.5 Hz, Hc), 5.14 (d, 1H, J¼10.6 Hz, O-CH2-N), 5.33 (d,
1H, J¼10.6 Hz, O-CH2-N), 6.80–6.95 (m, 3H, Ar-H),
7.15–7.45 (m, 12H, Ar-H); 13C NMR (CDCl3) d 14.2,
23.2, 25.8, 40.3, 44.3, 58.2, 75.2, 78.3, 117.2, 120.1,
125.3, 126.4, 126.8, 127.2, 128.3, 128.9, 129.1, 144.1,
146.7, 149.7. Anal. Calcd for C26H29NO (371.5): C 84.06;
H 7.87; N 3.77. Found: C 83.87; H 7.73; N 3.59.
13. Tramontini, M. Synthesis 1982, 605–644.
14. Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem.
Soc. 1982, 104, 6465–6466.
15. Melnik, M.; Weinreb, S. J. Org. Chem. 1988, 53, 850–854.
16. Ohfune, H. Acc. Chem. Res. 1992, 25, 360–366; Knapp, S.
Chem. Rev. 1995, 95, 1859–1876.
17. Azzolina, O.; Collina, S.; Brusotti, G.; Loddo, G.; Linati, L.;
Lanza, E.; Ghislandi, V. Tetrahedron: Asymmetry 2004, 15,
1651–1658.
18. Lunn, G. J. Org. Chem. 1987, 52, 1043–1046.
19. Samaddar, A. K.; Konar, S. K.; Nasipuri, D. J. Chem. Soc.,
Perkin Trans. 1 1983, 1449–1451.
5.7.6. (4R*,6R*)-6-Butyl-3,4,6-triphenyl-1,3-oxazinane
[(4R*,6R*)-5q]. Colorless oil; IR (neat) nmax 1597, 1505,
1
1023, 755, 698 cmꢂ1; H NMR (CDCl3) d 0.82 (t, 3H,
20. Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin
Trans. 1 1990, 1213–1214 and references cited therein.
21. Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277–294.
22. Bartoli, G.; Cimarelli, C.; Palmieri, G. J. Chem. Soc., Perkin
Trans. 1 1994, 537–543.
J¼7.0 Hz, Me), 1.10–1.35 (m, 4H), 1.80 (t, 2H, J¼7.7 Hz),
2.38 (dd, 1H, J¼14.3, 11.7 Hz, Hb), 2.57 (dd, 1H, J¼14.3,
4.4 Hz, H0b), 4.22 (dd, 1H, J¼11.7, 4.4 Hz, Hc), 5.02
(d, 1H, J¼10.3 Hz, O-CH2-N), 5.12 (d, 1H, J¼10.3 Hz,
O-CH2-N), 6.70–6.85 (m, 3H, Ar-H), 7.00–7.50 (m, 12H,
Ar-H); 13C NMR (CDCl3) d 14.2, 23.2, 25.5, 42.8, 44.5,
58.5, 76.9, 79.3, 119.3, 120.9, 126.5, 126.6, 126.9, 127.2,
128.5, 128.8, 128.9, 143.7, 143.8, 148.2. Anal. Calcd for
C26H29NO (371.5): C 84.06; H 7.87; N 3.77. Found: C
84.27; H 7.99; N 3.58.
23. Haddad, M.; Dorbais, J.; Larcheveque, M. Tetrahedron Lett.
1997, 38, 5981–5984.
24. Wittig, G.; Reiff, H. Angew. Chem. 1968, 80, 7–14.
25. Wittig, G.; Hesse, A. Liebigs Ann. Chem. 1971, 746, 149–173.
26. Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178–2180.
27. Cuvigny, T.; Larcheveque, M.; Normant, H. Liebigs Ann.
Chem. 1975, 719–730.
Acknowledgements
ꢀ
28. Tirel, P.-J.; Vaultier, M.; Carrie, R. Tetrahedron Lett. 1989, 30,
1947–1950.
29. Fouquey, C.; Facques, J.; Angiolini, L.; Tramontini, M.
Tetrahedron 1974, 30, 2801–2809.
30. Barluenga, J.; Fananas, F. J.; Yus, M. J. Org. Chem. 1979, 44,
4798–4801.
The financial support of this research by grant from Univer-
sity of Camerino and from MIUR-PRIN (contract no.
2005037725_001) is gratefully acknowledged.
Supplementary data
31. Mizuno, K.; Ichimose, N.; Tamai, T.; Otsuji, Y. J. Org. Chem.
1992, 57, 4669–4675.
The computational results (Cartesian coordinates of the op-
timized geometries and semiempirical PM3 level enthalpies
of formation) for cis-2k–F, trans-2k–F, (R*,S*)-5q,
(R*,R*)-5q, (4S,10R)-3i, (R,R)-3i are given. Supplementary
data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2006.07.044.
32. Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1994, 59, 3210–
3215.
33. Yasuda, M.; Sone, T.; Tanabe, K.; Shima, K. Chem. Lett. 1994,
3, 453–456.
34. Yasuda, M.; Sone, T.; Tanabe, K.; Shima, K. J. Chem. Soc.,
Perkin Trans. 1 1995, 4, 459–464.
35. Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F.
Tetrahedron Lett. 2001, 42, 199–202.
References and notes
36. Cimarelli, C.; Giuli, S.; Palmieri, G. Eur. J. Org. Chem. 2006,
1017–1022.
37. Ciganek, E. J. Org. Chem. 1992, 57, 4527–4539.
38. Bartoli, G.; Marcantoni, E.; Petrini, M.; Sambri, L. Chem.—
Eur. J. 1996, 2, 913–918.
1. Carriera, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995,
117, 12360–12361.
2. Yuan, Y.; Long, J.; Sun, J.; Ding, K. Chem.—Eur. J. 2002, 8,
5033–5042.
39. Veenstra, S. J.; Kinderman, S. S. Synlett 2001, 7, 1109–1112.
40. Semiempirical PM3 calculations were performed with the
Spartan 5.0.3, Wavefunction: Irvine, CA. Stewart, J. J. P.
J. Comput. Aided Mol. Design 1990, 4, 1–105.
41. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155–158.
42. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
3. Kocovsky, P.; Vyscocil, S.; Smrcina, M. Chem. Rev. 2003, 103,
3213–3246.
4. Palmieri, G. Eur. J. Org. Chem. 1999, 805–811.
5. Palmieri, G. Tetrahedron: Asymmetry 2000, 11, 3361–3373.
6. Cimarelli, C.; Palmieri, G. Tetrahedron: Asymmetry 2000,
2555–2563.
7. Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron:
Asymmetry 2002, 13, 2011–2018.
43. Eames, J.; de las Heras, M. A.; Warren, S. Tetrahedron Lett.
1996, 37, 4077–4080.
8. Cimarelli, C.; Palmieri, G.; Volpini, E. J. Org. Chem. 2003, 68,
1200–1206.
44. Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron Lett. 2004,
35, 6629–6631.
9. Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org.
Chem. 2001, 66, 4759–4765.
45. Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini,
M. J. Org. Chem. 1994, 59, 5328–5335.
10. Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron:
Asymmetry 2002, 13, 2417–2426.
46. Barluenga, J.; Olano, B.; Fustero, S. J. Org. Chem. 1985, 50,
4052–4056.
11. Pohland, A.; Sullivan, H. R. J. Am. Chem. Soc. 1953, 75, 4458–
4461.
47. Furukawa, M.; Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem.
Pharm. Bull. 1979, 27, 2223–2226.
12. Jager, V.; Schwab, W.; Buss, V. Angew. Chem., Int. Ed. Engl.
1981, 20, 601–603.