Stereoselective synthesis of enantiopure γ-aminoalcohols by reduction of chiral β-enaminoketones

Article abstract of DOI:10.1016/j.tetasy.2006.04.009

The results of the reduction of chiral β-enamino ketones with sodium borohydride in acetic acid are reported. The reaction is convenient, stereoselective and high yielding and allows the preparation of enantiopure γ-amino alcohols in syn diastereoselectiv

Full text of DOI:10.1016/j.tetasy.2006.04.009

Tetrahedron: Asymmetry 17 (2006) 1308–1317
Stereoselective synthesis of enantiopure c-aminoalcohols
by reduction of chiral b-enaminoketones
Cristina Cimarelli, Sandra Giuli and Gianni Palmieri*
Dip. di Scienze Chimiche, v. S. Agostino 1, 62032 Camerino, Italy
Received 2 April 2006; accepted 19 April 2006
Abstract—The results of the reduction of chiral b-enamino ketones with sodium borohydride in acetic acid are reported. The reaction is
convenient, stereoselective and high yielding and allows the preparation of enantiopure c-amino alcohols in syn diastereoselectivity. The
reaction is easy to perform and does not require expensive or hazardous chemicals. A mechanistic hypothesis is presented. The absolute
1
configuration of the products obtained is attributed by correlating H NMR spectral data with conformational analysis performed by
molecular modelling, and confirmed by X-ray analysis.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
nantly, while b-enamino esters afforded to the correspond-
ing primary c-aminoalcohols.19
The synthesis of c-amino alcohols is a matter of consider-
able interest because they frequently possess interesting
pharmacological properties.1–3 This functional unit is pres-
ent in several antibiotics and other biologically active nat-
ural products.4–7 Their synthesis has been achieved by a
variety of procedures: addition of amines or ammonia to
a,b-unsatured ketones or acrylic esters, followed by reduc-
tion;1,8–11 reduction of b-enamino ketones and b-enamino
esters12–14 or other 1,3-difunctionalized unsaturated com-
pounds.15–17
Reduction of b-enamino ketones to syn-c-amino alcohols
was performed also with the CeCl3/LiBH4 system in mod-
erate to good yields and de.20
Secondary b-enamino ketones were reduced in a mixture of
trifluoroacetic acid and isopropanol as solvent, with
NaBH4. After workup, a,b-unsaturated ketones were
obtained in 60–80% yield, with a trans-olefinic structure.21
The chemoselective reduction of b-enamino ketones has
been performed also with different reducing systems, such
as LiAlH4 also in the presence of Cu, PtO2, for the prepa-
ration of b-amino ketones (yields = 35–70%). Side reac-
tions were observed, such as deamination with enone
production, especially with LiAlH4, with or without Cu.22
Enaminones constitute very interesting starting materials
for the preparation of c-amino alcohols by reduction
and/or alkylation. The reduction of enaminones opens
some interesting challenges for the chemo- and diastereo-
selective reduction of b-enamino ketones and b-enamino
esters.18
Sodium triacetoxy borohydride proved to be a good
reagent for the reduction of substrates containing acid
protons, such as b-enaminoesters.18,19,23–25
In the past we have found that it is possible to prepare syn-
c-amino alcohols by reduction of b-enamino ketones. Dis-
solving metal reductions of enaminones were explored,
with sodium and isopropanol, and resulted in the complete
reduction of the unsatured system.6 b-Enamino ketones
afforded to secondary syn-c-amino alcohols predomi-
Also the reduction of b-enamino ketones is possible with
sodium triacetoxy borohydride in glacial acetic acid.26 c-
Amino alcohols are obtained in 70–98% yields in a syn
configuration predominantly (de 44–99%) as ascertained
by analysis of the corresponding tetrahydro oxazine deriv-
atives. The same authors have also patented this
procedure.27
*
Corresponding author. Tel.: +39 0737402241; fax: +39 0737402285;
e-mail: gianni.palmieri@unicam.it
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.009

C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
1309
Owing to our experience in the stereoselective reduction of
2. Results and discussion
enaminonic systems, we decided to apply this methodology
to the reduction of enantiopure b-enamino ketones. Herein
we report the results of the reduction of chiral b-enamino
ketones 1 with sodium borohydride in acetic acid.
The reduction of b-enamino ketones, performed at room
temperature, affords a syn/anti mixture of the c-amino alco-
hols, in which the syn isomer 3 is more abundant, with the
Table 1. Reduction of b-enamino ketones 1 to c-amino alcohols 3
AcO
OAc
H
H
B
H
R*
R3
H
R*
R3
H
R*
R3
O
N
O
N
O
N
NaBH4/AcOH
10 ºC, 2 h
R*
R3
O
N
H
R1
R1
R1
R1
R2
R2
R2
R2
1
2
3
R*-NH2 = (R)-1-phenylethylamine
Entry
1
1
R1
R2
H
R3
3a
Yielda (%)
62
drb
H
H
R*
O
N
1a
Me
Ph
Me
(S,R,R)-3a
(R,R,R)-3b
84/16
Me
Ph
Me
H
H
R*
O
N
2
1b
H
Me
66
81/19
Me
R*
H
H
O
N
3
4
1c
1d
(CH2)4
Me
Me
(S,R,R,R)-3c
(R,R,R,R)-3d
57
52
82/18
69/31
Me
H
H
R*
O
H
N
o-Ph-(CH2)2
Me
H
R*
O
N
5
6
1e
1f
Me
H
H
CF3
CF3
(S,R,R)-3e
(S,S,R)-3f
42
61
71/29c
76/24c
F3C
Me
H
H
R*
O
N
Ph
Ph
CF3
H
H
R*
O
N
7
1g
Me
Cl
Me
(S,S,R,R)-3g
62
83/17
Me
Me
Cl
H
H
R**
O
N
8
9
1hd
Ph
H
H
Me
Me
(R,R,R)-3hd
(S*,R*)-3i
64
79
83/17
Ph
Me
H
H
Bn
O
N
1ie
Me
89/11f
Me
Me
a Yield of the isolated pure major stereoisomer.
b Diastereomeric ratio of the syn stereoisomers.
c Diastereomeric ratio of the anti stereoisomers.
d R**–NH2 = (R)-1-naphthylethylamine.
e R* = Bn.
f syn/anti Diastereomeric ratio.

1310
C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
OAc
AcO
OAc
H
AcO
O
H
H
R*
H
R*
R*
B
H
R*
B
R*
O
N
NaBH4/AcOH
10 ˚C
O
O
N
N
O
N
N
AcOH
H
1'
AcO
1
B
A
AcO
H
OAc
R*
OAc
H
H
R*
H
H
H
B
H
B
R*
O
N
NaBH4/AcOH
10 ˚C
O
N
O
N
AcOH
C
D
2'
3
Scheme 1.
exception of starting materials 1e and f that afford mainly
the anti-c-amino alcohol. A possible explanation of this anti
diastereoselectivity is given later on. In the absence of acetic
acid, the reduction does not take place. Generally the ster-
eoisomers can be separated by liquid chromatography,
allowing the preparation in good yields of the enantiopure
c-amino alcohols 3 (see Table 1, Scheme 1).
the first step of the reduction by directing the hydride
transfer on the less hindered face of the C@N double bond,
affording to the b-amino ketone 2. In Figure 2 is depicted
the molecular modelling representation of the transition
states (TS) for the transfer of the hydride on the Re and
Si face of the C@N double bond, respectively, that show
that the Si-TS-2 is stabilized of 1.46 kcal/mol with respect
to the Re-TS-2.23,24
In the acid medium, the starting b-enamino ketone is in the
protonated form 10 (see Fig. 1), from which the formation
of a boron–enolate complex takes place by coordination of
the boron atom to the carbonyl oxygen and exchange of
one acetoxy group of the reducing agent with 10 itself. Then
the hydride is transferred on the iminium carbon atom and
the boron coordinates to the nitrogen atom. Solvolysis by
acetic acid affords the b-amino ketone 2. In the subsequent
step the nitrogen atom coordinates to a second reducing
unit, and the intermediate D is obtained, which gives the fi-
nal c-aminoalcohol 3.
Figure 2. Molecular modelling representation of the diastereoselective
transition state (TS) for the first reduction step.
The hypothesis of the boron–enol ester complex A as a key
intermediate in the first step is confirmed by the experimen-
tal evidence that the b-enamino ketone 1j prepared from
dimedone (5,5-dimethylcyclohexan-1,3-dione) and 1-phen-
ylethylamine, is inert in these reduction conditions. This
can be explained by considering that, in this molecule,
the enone system is constrained in the s-trans geometry,
with the borohydride group located too far from the elec-
trophilic carbon atom to transfer the hydride ion to the
iminium carbon atom (see Fig. 3), as compared with the
corresponding complex A derived from 1a–i23 as depicted
in Figure 2.
Figure 1. Simultaneous display of the LUMO and the colours code
electrostatic potential map on the electron density surface of the
protonated enamino ketones 10.
In the subsequent step the reduction of the carbonyl group
takes place, and also in this case the hydride is transferred
on the less hindered face of the C@O double bond. Also in
this case the molecular modelling representations of the
diastereoselective transition states (TS) are depicted in Fig-
ure 4 and the syn-TS is more stable by 1.09 kcal/mol with
respect to anti-TS, consistent with the stereoselectivity ob-
served in the final c-amino alcohols 3.
In Figure 1 the simultaneous display of the LUMO and the
colour coded electrostatic potential map of the electron
density surface of the protonated enamino ketones 10 are
reported, showing that the preferential site for nucleophilic
attack is the carbon atom of the C@N function.
An interpretation of the stereoselectivity of the reaction
can be suggested on the basis of the following consider-
ations. The chiral (R)-1-phenylethylamino group bonded
to the nitrogen atom induces a high stereoselectivity in
The apparently anomalous anti diastereoselectivity ob-
served for starting materials 1e and 1f (entries 5 and 6),

C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
1311
3. Stereochemistry
The absolute configuration of the various diastereomers
1
was attributed by interpreting H and 13C NMR spectra,
with the aid of computational methods,28 and confirmed
through X-ray diffraction. With the aim to attribute the
absolute configurations with a confidence, oxazinones 4
and oxazines 5 have been prepared, as reported in Scheme
2.
Spectroscopic data and X-ray diffraction show that c-
amino alcohols 3 form rings completed by intramolecular
hydrogen bonds, assuming a chair conformation, con-
firmed by molecular modelling conformational analysis.29
The discrimination from the syn- and anti-c-aminoalcohols
1
was ascertained by H NMR spectra of the isolated pure
major isomers or chromatographic fraction for the minor
diastereomers. While the syn-c-amino alcohols show Jaa
and Jae for both the CH–O and CH–N protons, the anti-
c-amino alcohols show Jaa and Jae for the CH–O and Jee
and Jae for CH–N proton.14,30,31 In addition, for the
COH–CH2–CNH methylene, the syn-c-amino alcohols
show two triplets (Jae and Jaa) and the anti-c-
amino alcohols show two double doublets (JaeJaa and
JeaJee).14,30,31
Figure 3. Interatomic distance between the hydrogen atom and the iminic
carbon atom in the reduction of 1j.
is in agreement with the mechanism depicted in Figure 4. In
the transition states syn-TS-3e and 3f, the CF3 group is lo-
cated near to a phenyl group and destabilizes the transition
state itself as compared to the anti-TS-3e and 3f.
The discrimination between the major and minor syn-c-
amino alcohols was performed on the basis of the chemical
shifts observed for the CH–O and CH–N protons. The
magnetic anisotropy of the phenyl group, on the minor
syn-3a exerts a shielding effect on the CH–O and as a more
relevant measure on the CH–N proton nearest to the Ph
group (Dd = 0.31 and 0.43 ppm, respectively). This is a
general trend observed for both the diastereomers of syn-
c-amino alcohols 3 (Fig. 6).
ΔΔHf = + 1.09 Kcal/mol
anti-TS-3a
syn-TS-3a
Figure 4. Molecular modelling representation of the diastereoselective
transition state (TS) for the second reduction step.
The crystalline c-amino alcohol 3f was submitted to X-ray
analysis.32 The structure determined with this technique is
O
O
O
H
H
R*
R*
R*
R*
O
N
O
N
HO
N
O
N
CDI/DMAP
CH2Cl2
Me
(2S,3R,1'R)-3
Me
Me
(4R,6S,1'R)-4
Me
Me
Me
Me
Me
(R,R)-6
(R,R,R)-4
Scheme 2.
Figure 5. Calculated chair conformations for the major diastereomers syn-c-amino alcohols 3a and the diagnostic 1H NMR chemical shifts for the CH–O
and CH–N protons.

1312
C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
This result validates the methodology used by us for the
attribution of the absolute configuration of the various iso-
lated c-amino alcohols 3 (compare Figs. 5 and 7).
3a
3b
3c
3e
3g
3h
5a
3.5
5.5
5.0
-O
4.5
4.0
3.0
2.5
ppm
C
H
CH
-N
CH
-O
CH-N
Syn-major diaster.
Syn-minus diaster.
Figure 7. X-ray structure of the c-amino alcohol (R,R,R,R)-3f major
diastereomer.
Figure 6. Chemical shifts for the major and minus syn-c-amino alcohols 3.
Note the major upshift of the CH–N respect to the CH–O proton.
Oxazinonic 4 and oxazinic 5 derivatives of c-amino alcohols
3 were obtained by treating the various c-amino alcohols
with carbonyl diimidazole or formaldehyde, respectively.
Their more rigid structure allows assignment of the stereo-
chemistry by 1H NMR spectra. While oxazines are formed
without racemization of the stereogenic centres, the cycliza-
tion with carbonyl diimidazole to give oxazinones takes
place with inversion of the configuration of the stereogenic
centre bonded to the hydroxy group (see Table 2).
1
in full agreement with the conclusions based on H NMR
spectral analysis and on conformational analysis per-
formed on all its possible diastereomers (see Fig. 7). The
lowest energy structure obtained with molecular modelling
for (R,R,R,R)-3f has the same conformation of the struc-
ture obtained by X-ray analysis, including the conforma-
tion of the chiral group R* bonded to the nitrogen atom.
Table 2. Cyclization of c-amino alcohols 3 to oxazinones 4 and oxazines 5
O
H
R*
H
R*
R*
O
N
O
N
O
N
i
ii
Me
Me
Me
Me
Me
Me
4
3
5
Entry
1
3
4
Yielda (%)
86
5
Yielda (%)
93
O
R*
Me
)-5a
R*
Me
O
N
R*
Me
(1S,3R,10R)-3a
O
N
Me
Me
(4
R
,6S
,1'
R
(
R
,R
,R
)-4a
O
O
N
R*
O
N
2
(R,R,R)-3b
89
91
Ph
Ph
Me
)-4b
(
R
,
R
,R
)-5b
(4
R
,6S
,1'
R
O
R*
O
N
3
4
(R,R,R,R)-3d
91
84
Me
(4
R
,4a
S
,10b
S
,1'
R
)-4d
O
Bn
Me
O
N
Bn
O
N
(S*,R*)-3i
89
Me
Me
Me
(
S
*,
R
*)-5i
(
S
*,
R
*)-4i
Reaction conditions: (i) carbonyl diimidazole, DMAP, CH2Cl2, rt, 1 h; (ii) HCHO 35%, THF, rt, 6 h.
R*–NH2 = (R)-1-phenylethylamine.
a Yield of the isolated pure stereoisomer.

C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
1313
In this case the less stable syn form is in equilibrium with
the more stable anti, through the open intermediate 6 as
depicted in Scheme 2. The calculation of the formation
enthalpies, shows that generally the anti-4 isomers are
more stable than the syn-4, justifying the observed epi-
merization.
(ddd, 1H, J = 14.3, 2.4, 2.0 Hz), 3.04 (dqd, 1H, J = 11.0,
6.4, 2.4 Hz), 3.92 (q, 1H, J = 6.6 Hz), 4.06 (dqd, 1H,
J = 10.2, 6.4, 2.0 Hz), 4.45 (br s, 2H), 7.15–7.42 (m, 5H);
13C NMR (CDCl3): d 21.7, 22.5, 24.1, 45.5, 52.3, 55.3,
69.2, 126.7, 127.6, 128.9, 145.8. EI-MS: m/z (%) 207 (M+,
2), 192 (51), 148 (43), 105 (100). Anal. Calcd for
C13H21NO (207.3): C, 75.32; H, 10.21; N, 6.76. Found:
C, 75.58; H, 10.39; N, 6.54.
4. Conclusion
5.3.2.
(2R,4S)-4-{[(1R)-1-Phenylethyl]amino}pentan-2-ol
1.07 (d, 3H,
(R,S,R)-3a. 1H NMR (CDCl3):
d
In summary a convenient, stereoselective and high yielding
method for the preparation of enantiopure c-amino alco-
hols 3 by the reduction of b-enamino ketones 1 is pre-
sented. The reaction is easy to perform and does not
require expensive or hazardous chemicals. The absolute
configuration of the products obtained was attributed by
correlating 1H NMR spectral data with conformational
analyses performed by molecular modelling. The conclu-
sions reached on the basis of spectral analysis and mole-
cular modelling are validated by X-ray analysis of product
3f, which confirms the attributed (R,R,R,R) absolute
configuration.
J = 6.2 Hz), 1.09 (d, 3H, J = 6.2 Hz), 1.27 (dt, 1H,
J = 14.3, 10.8 Hz), 1.35 (d, 3H, J = 6.6 Hz), 1.44 (ddd,
1H, J = 14.3, 2.8, 1.6 Hz), 2.61 (dqd, 1H, J = 11.4, 6.2,
2.9 Hz), 3.75 (dqd, 1H, J = 10.3, 6.2, 1.5 Hz), 4.01 (q,
1H, J = 6.6 Hz), 4.42 (br s, 2H), 7.16–7.42 (m, 5H); 13C
NMR (CDCl3): d 20.8, 23.8, 25.7, 45.7, 51.4, 55.0, 68.9,
127.2, 127.5, 128.9, 144.2.
5.3.3. (R,R)-1-Phenyl-3-{[(1R)-1-phenylethyl]amino}butan-
¼
20
1-ol (R,R,R)-3b. Mp 42–43 ꢁC (CH2Cl2–hexane); ½aꢀD
þ3:3 (c 4.7, CHCl3); IR (neat) 3084, 3062, 1452,
1152 cmꢁ1 1H NMR (CDCl3): d 1.14 (d, 3H, J =
;
6.2 Hz), 1.49 (d, 3H, J = 6.6 Hz), 1.57 (dt, 1H, J = 14.3,
10.6 Hz), 1.81 (dt, 1H, J = 14.3, 2.6 Hz), 3.26 (dqd, 1H,
J = 10.6, 6.6, 2.6 Hz), 4.02 (q, 1H, J = 6.6 Hz), 4.40 (br s,
2H), 5.04 (dd, 1H, J = 10.6, 2.2 Hz), 7.20–7.48 (m, 10H);
13C NMR (CDCl3): d 21.7, 22.5, 46.5, 52.6, 55.5, 75.6,
125.8, 127.1, 127.2, 127.7, 128.5, 129.0, 143.9, 145.6. EI-
MS: m/z (%) 269 (M+, 10), 254 (16), 148 (49), 132 (35),
105 (100). Anal. Calcd for C18H23NO (269.4): C, 80.26;
H, 8.61; N, 5.20. Found: C, 80.47; H, 8.39; N, 4.98.
5. Experimental
5.1. General methods
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 undeuter-
ated solvents as the internal reference. Coupling constants
are given in Hertz. IR spectra were recorded using FTIR
apparatus.
5.3.4.
(1S,3S)-1-Phenyl-3-{[(1R)-1-phenylethyl]amino}-
butan-1-ol (S,S,R)-3b. 1H NMR (CDCl3): d 1.15 (d, 3H,
J = 6.1 Hz), 1.43 (d, 3H, J = 6.6 Hz), 1.51–1.67 (m, 2H),
2.82 (dqd, 1H, J = 10.2, 5.9, 3.7 Hz), 4.08 (q, 1H,
J = 6.6 Hz), 4.40 (br s, 2H), 4.70 (dd, 1H, J = 9.9,
2.6 Hz), 7.10–7.80 (m, 10H); 13C NMR (CDCl3): d 20.8,
25.6, 46.7, 51.8, 55.3, 75.2, 125.7, 126.8, 127.4, 127.7,
128.4, 129.0, 145.2, 145.5.
5.2. Materials and solvents
All reagents were commercially available, were purchased
at the highest quality, and were purified by distillation
when necessary. b-Enamino ketones 1a–j were prepared
according to the literature methods.
5.3. General procedure for the reduction of b-enamino
ketones 1: synthesis of c-amino alcohols 3
5.3.5. (1S,2R)-2-((1R)-1-{[(1R)-1-Phenylethyl]amino}ethyl)-
20
cyclohexanol (S,R,R,R)-3c. Oil; ½aꢀD ¼ ꢁ36:4 (c 0.3,
The b-enamino ketones 1a–j (1 mmol) were dissolved in
acetic acid (3 mL) at 10 ꢁC, then sodium borohydride was
added in portions (4.0 mmol, 0.152 g) and allowed to stand
for 2 h. The reaction mixture was quenched with 30% so-
dium hydroxide solution, until basic pH was reached, and
extracted with dichloromethane (2 · 20 mL). The organic
layer was dried with anhydrous Na2SO4, filtered and the
solvent removed under reduced pressure. Chromatographic
separation of the crude oil on silica gel with AcOEt/cyclo-
hexane (3:97–20:80 v/v) afforded the pure c-amino alcohols
3. Spectral data of products 3 follow.
CHCl3); IR (neat) 3306, 3062, 3028, 2969, 2928, 2854,
1
1492, 1453; H NMR (CDCl3): d 1.10–1.84 (m, 9H), 1.15
(d, 3H, J = 5.9 Hz), 1.41 (d, 3H, J = 6.2 Hz), 3.11 (br s,
1H, W1/2 = 7.5 Hz), 3.82 (q, 1H, J = 6.6 Hz), 4.10 (q,
1H, J = 6.6 Hz), 4.55 (br s, 2H), 7.2–7.4 (m, 5H); 13C
NMR (CDCl3): d 18.5, 20.3, 20.5, 22.4, 25.5, 28.8, 45.5,
56.0, 56.5, 72.0, 126.7, 127.6, 128.9, 145.7. Anal. Calcd
for C16H25NO (247.4): C, 77.68; H, 10.19; N, 5.66. Found:
C, 77.82; H, 10.02; N, 5.41.
5.3.6. (1R,2R)-2-((1S)-1-{[(1R)-1-Phenylethyl]amino}ethyl)-
cyclohexanol (R,R,S,R)-3c. 1H NMR (CDCl3): d 0.95 (d,
3H, J = 6.6 Hz), 1.12–1.75 (m, 9H), 1.44 (d, 3H,
J = 6.6 Hz), 2.91 (dt, 1H, J = 5.8, 3.3 Hz), 3.82 (q, 1H,
J = 6.5 Hz), 3.94 (q, 1H, J = 6.6 Hz), 4.46 (br s, 2H),
7.25–7.40 (m, 5H).
5.3.1. (2S,4R)-4-{[(1R)-1-Phenylethyl]amino}pentan-2-ol (S,
20
R,R)-3a. Oil; ½aꢀD ¼ ꢁ61:3 (c 1.7, CHCl3); IR
1
(neat) 3084, 3055, 1450, 1140 cmꢁ1; H NMR (CDCl3): d
1.08 (d, 3H, J = 6.2 Hz), 1.16 (d, 3H, J = 6.2 Hz), 1.27
(dt, 1H, J = 14.3, 10.6 Hz), 1.38 (d, 3H, J = 6.6 Hz), 1.57

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C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
5.3.7. (1R,2R)-2-((1R)-1-{[(1R)-1-Phenylethyl]amino}ethyl)-
1,2,3,4-tetrahydronaphthalen-1-ol (R,R,R,R)-3d. Mp 87–
C, 59.76; H, 6.94; N, 5.36. Found: C, 59.81; H, 7.03; N,
5.24.
20
91 ꢁC; ½aꢀD ¼ ꢁ159:8 (c 0.8, CHCl3); IR (neat) 3061,
1
3025, 2922, 1454, 1383 cmꢁ1; H NMR (CDCl3): d 1.21
5.3.12. (2S,4S)-1,1,1-Trifluoro-4-{[(1R)-1-phenylethyl]amino}-
pentan-2-ol (S,S,R)-3e. Yield 10%. Oil; 1H NMR
(CDCl3): d 1.18 (d, 3H, J = 6.2 Hz), 1.38 (d, 3H, J =
6.6 Hz), 1.48 (dt, 1H, J = 14.1, 11.0 Hz), 1.66 (dt, 1H,
J = 14.1, 3.3 Hz), 2.70 (dqd, 1H, J = 11.3, 6.2, 2.9 Hz),
3.95 (dqd, 1H, J = 10.6, 6.2, 2.6 Hz), 4.02 (q, 1H,
J = 6.6 Hz), 4.22 (br s, 2H), 7.20–7.45 (m, 5H); 13C
NMR (CDCl3): d 20.8, 25.3, 35.4, 50.4, 55.1, 71.4 (q,
J = 31.1 Hz), 124.8 (q, J = 281.3 Hz), 127.2, 127.9, 129.1,
143.2. EI-MS: m/z (%) 261 (M+, 1), 246 (100), 184 (10),
148 (23), 105 (81).
(d, 3H, J = 6.2 Hz), 1.36–1.58 (m, 2H), 1.50 (d, 3H,
J = 6.6 Hz), 1.97 (m, 1H), 2.74–3.00 (m, 3H), 3.89 (q,
1H, J = 6.6 Hz), 4.26 (br s, 2H), 4.86 (d, 1H,
J = 8.43 Hz), 7.05–7.61 (m, 9H); 13C NMR (CDCl3): d
19.1, 22.7, 25.1, 29.4, 47.9, 56.1, 57.2, 75.1, 126.3, 126.6,
126.7, 126.8, 127.7, 128.0, 129.0, 135.7, 140.0, 145.5. EI-
MS: m/z (%) 295 (M+, 7), 148 (42), 105 (100). Anal. Calcd
for C20H25NO (295.4): C, 81.31; H, 8.53; N, 4.74. Found:
C, 81.54; H, 8.66; N, 4.51.
5.3.8. (1S,2S)-2-((1S)-1-{[(1R)-1-Phenylethyl]amino}ethyl)-
1,2,3,4-tetrahydronaphthalen-1-ol (S,S,S,R)-3d. 1H NMR
(CDCl3): d 1.13 (d, 3H, J = 6.6 Hz), 1.35–1.55 (m, 2H),
1.38 (d, 3H, J = 6.9 Hz), 2.11 (m, 1H), 2.70–2.94 (m,
3H), 4.06 (q, 1H, J = 6.9 Hz), 4.20 (br s, 2H), 4.96 (d,
1H, J = 10.26 Hz), 7.02–7.70 (m, 9H); 13C NMR (CDCl3):
d 15.8, 24.6, 25.1, 30.0, 41.1, 54.8, 55.1, 70.0, 126.3, 126.4,
126.6, 126.8, 127.5, 128.4, 129.0, 135.5, 140.5, 144.7.
5.3.13. (1S,3S)-4,4,4-Trifluoro-1-phenyl-3-{[(1R)-1-phen-
20
ylethyl]amino}butan-1-ol (S,S,R)-3f. Oil; ½aꢀD ¼ þ148:6
(c 0.8, CHCl3); 1H NMR (CDCl3): d 1.35 (d, 3H,
J = 6.6 Hz), 1.86 (ddd, 1H, J = 15.0, 5.5, 3.3 Hz), 2.04
(ddd, 1H, J = 15.0, 10.3, 4.4 Hz), 3.57 (q, 1H,
J = 6.6 Hz), 3.85 (dd, 1H, J = 10.3, 3.3 Hz), 4.02 (br s,
2H), 4.19 (qdd, 1H, J = 7.7, 5.5, 4.4 Hz), 7.10–7.50 (m,
10H); 13C NMR (CDCl3): d 24.7, 27.1, 55.3, 56.9, 69.3
(q, J = 30.6 Hz), 125.6 (q, J = 280.9 Hz), 126.7, 127.3,
127.8, 128.0, 128.8, 129.2, 141.7, 143.1. Anal. Calcd for
C18H20F3NO (323.4): C, 66.86; H, 6.23; N, 4.33. Found:
C, 66.98; H, 6.34; N, 4.12.
5.3.9. (2S,4R)-1,1,1-Trifluoro-4-{[(1R)-1-phenylethyl]-amino}-
20
pentan-2-ol (S,R,R)-3e. Yield 42%. Oil; ½aꢀD ¼ þ83:5 (c
0.6, CHCl3); IR (neat) 3276, 3065, 3030, 2969, 2929,
2873, 1453; 1H NMR (CDCl3): d 1.07 (d, 3H, J =
6.2 Hz), 1.39 (d, 3H, J = 6.6 Hz), 1.59 (ddd, 1H,
J = 14.8, 7.3, 4.4 Hz), 1.71 (ddd, 1H, J = 14.8, 6.6,
3.3 Hz), 3.04 (quint d, 1H, J = 6.6, 3.7 Hz), 3.84 (br s,
2H), 3.94 (q, 1H, J = 6.6 Hz), 4.22 (quint d, 1H, J = 7.3,
4.4 Hz), 7.20–7.40 (m, 5H); 13C NMR (CDCl3): d 19.6,
24.5, 33.8, 48.1, 55.2, 69.1 (q, J = 31.2 Hz), 125.5 (q,
J = 282.1 Hz), 127.0, 127.7, 128.9, 143.2. EI-MS: m/z (%)
261 (M+, 1), 246 (100), 184 (9), 148 (24), 105 (83). Anal.
Calcd for C13H18F3NO (261.3): C, 59.76; H, 6.94; N,
5.36. Found: C, 59.99; H, 6.71; N, 5.18.
5.3.14. (1R,3R)-4,4,4-Trifluoro-1-phenyl-3-{[(1R)-1-phen-
20
ylethyl]amino}butan-1-ol (R,R,R)-3f. Oil; ½aꢀD ¼ ꢁ20:4
(c 0.3, CHCl3); 1H NMR (CDCl3): d 1.43 (d, 3H,
J = 6.6 Hz), 1.92 (ddd, 1H, J = 15.0, 7.9, 4.8 Hz), 2.14
(ddd, 1H, J = 15.0, 5.9, 3.1 Hz), 3.79 (q, 1H,
J = 6.6 Hz), 3.98 (br s, 2H), 4.15 (qdd, 1H, J = 8.7, 5.9,
4.8 Hz), 4.27 (dd, 1H, J = 8.4, 2.9 Hz), 7.10–7.50 (m,
10H); 13C NMR (CDCl3): d 22.1, 33.5, 54.9, 57.3, 69.4
(q, J = 30.5 Hz), 125.8 (q, J = 300.8 Hz), 126.4, 126.6,
127.8, 128.1, 129.0, 129.2, 141.1, 141.4. Anal. Calcd for
C18H20F3NO (323.4): C, 66.86; H, 6.23; N, 4.33. Found:
C, 66.71; H, 6.28; N, 4.41.
5.3.10.
(2R,4S)-1,1,1-Trifluoro-4-{[(1R)-1-phenylethyl]-
1
amino}pentan-2-ol (R,S,R)-3e. Yield 17%. Oil; H NMR
(CDCl3): d 1.14 (d, 3H, J = 6.6 Hz), 1.38 (d, 3H,
J = 6.6 Hz), 1.50 (ddd, 1H, J = 14.6, 5.9, 3.3 Hz), 1.99
(ddd, 1H, J = 14.6, 8.8, 3.3 Hz), 3.14 (quint d, 1H,
J = 6.4, 3.3 Hz), 3.94 (q, 1H, J = 6.6 Hz), 4.12 (br s, 2H),
4.32 (dqd, 1H, J = 8.8, 7.3, 3.3 Hz), 7.20–7.40 (m, 5H);
13C NMR (CDCl3): d 20.2, 23.5, 30.8, 48.4, 55.3, 69.1 (q,
J = 30.7 Hz), 125.6 (q, J = 280.0 Hz), 126.3, 127.7, 129.1,
144.4. EI-MS: m/z (%) 261 (M+, 1), 246 (100), 184 (8),
148 (25), 105 (81).
5.3.15. (2S,3S,4R)-3-Chloro-4-{[(1R)-1-phenylethyl]amino}-
1
pentan-2-ol (S,S,R,R)-3g. Oil; H NMR (CDCl3): d 1.23
(d, 3H, J = 6.2 Hz), 1.29 (d, 3H, J = 6.2 Hz), 1.41 (d, 3H,
J = 6.6 Hz), 3.36 (qd, 1H, J = 6.2, 1.8 Hz), 3.83 (dd, 1H,
J = 1.8, 0.7 Hz), 3.92 (q, 1H, J = 6.6 Hz), 4.07 (br s, 2H),
4.29 (qd, 1H, J = 6.2, 0.7 Hz), 7.20–7.40 (m, 5H); 13C
NMR (CDCl3): d 13.8, 21.5, 23.6, 38.6, 49.2, 66.0, 69.6,
126.8, 127.1, 128.4, 144.9. EI-MS: m/z (%) 241 (M+, 1),
226 (4), 148 (36), 105 (100). Anal. Calcd for C13H20ClNO
(241.8): C, 64.59; H, 8.34; N, 5.79. Found: C, 64.72; H,
8.13; N, 5.96.
5.3.11.
amino}pentan-2-ol
(2R,4R)-1,1,1-Trifluoro-4-{[(1R)-1-phenylethyl]-
(R,R,R)-3e. Yield 23%. Oil;
20
1
½aꢀD ¼ ꢁ32:5 (c 0.1, CHCl3); H NMR (CDCl3): d 1.16
(d, 3H, J = 6.2 Hz), 1.40 (d, 3H, J = 6.6 Hz), 1.52 (dt,
1H, J = 14.3, 11.2 Hz), 1.79 (dt, 1H, J = 14.3, 2.6 Hz),
3.14 (d quint d, 1H, J = 11.0, 6.2, 2.6 Hz), 3.93 (q, 1H,
J = 6.6 Hz), 4.09 (br s, 2H), 4.30 (d quint d, 1H,
J = 11.0, 6.6, 2.6 Hz), 7.20–7.40 (m, 5H); 13C NMR
5.3.16. (2R,3R,4S)-3-Chloro-4-{[(1R)-1-phenylethyl]amino}-
pentan-2-ol (R,R,S,R)-3g. Oil; H NMR (CDCl3): d 1.18
1
(d, 3H, J = 6.2 Hz), 1.23 (d, 3H, J = 6.2 Hz), 1.38 (d, 3H,
J = 6.6 Hz), 2.88 (qd, 1H, J = 6.2, 2.2 Hz), 3.27 (br s,
2H), 3.67 (dd, 1H, J = 2.2, 1.1 Hz), 3.94 (qd, 1H, J = 6.2,
1.1 Hz), 3.98 (q, 1H, J = 6.6 Hz), 7.20–7.40 (m, 5H); 13C
NMR (CDCl3): d 17.6, 20.8, 25.2, 54.7, 55.1, 71.1, 72.0,
127.2, 127.9, 129.1, 143.3. EI-MS: m/z (%) 241 (M+, 1),
226 (5), 148 (38), 105 (100).
(CDCl3):
d 21.7, 22.1, 35.2, 51.3, 55.4, 71.8 (q,
J = 31.1 Hz), 125.0 (q, J = 283.1 Hz), 126.6, 127.9, 129.1,
145.0. EI-MS: m/z (%) 261 (M+, 2), 246 (100), 184 (11),
148 (26), 105 (85). Anal. Calcd for C13H18F3NO (261.3):

C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
1315
5.3.17. (1R,3R)-3-{[(1R)-1-(1-Naphthyl)ethyl]amino}-1-phen-
5.4.1. (4R,6R)-4,6-Dimethyl-3-[(1R)-1-phenylethyl]-1,3-oxaz-
20
20
ylbutan-1-ol (R,R,R)-3h. Oil; ½aꢀD ¼ ꢁ2:5 (c 0.6, CHCl3);
inan-2-one (R,R,R)-4a. Oil; ½aꢀD ¼ þ35:5 (c 3.4, CHCl3);
1
1
IR 3271, 3052, 2965, 1510, 1452 cmꢁ1; H NMR (CDCl3):
IR (neat) 3306, 2966, 2359, 1759, 1454 cmꢁ1; H NMR
d 1.22 (d, 3H, J = 6.2 Hz), 1.57 (dt, 1H, J = 14.3, 10.5 Hz),
1.63 (d, 3H, J = 6.6 Hz), 1.85 (dt, 1H, J = 14.3, 2.4 Hz),
3.37 (dqd, 1H, J = 10.3, 6.6, 2.6 Hz), 4.13 (br s, 2H), 4.88
(q, 1H, J = 6.6 Hz), 5.07 (dd, 1H, J = 10.6, 2.2 Hz), 7.20–
(CDCl3): d 1.10 (d, 3H, J = 6.2 Hz), 1.38 (d, 3H,
J = 6.6 Hz), 1.42 (d, 3H, J = 6.2 Hz), 1.48 (ddd, 1H,
J = 14.4, 8.4, 4.0 Hz), 2.07 (ddd, 1H, J = 14.4, 9.2,
4.7 Hz), 2.65 (dqd, 1H, J = 8.4, 6.2, 4.6 Hz), 3.90 (q, 1H,
J = 6.6 Hz), 5.18 (dqd, 1H, J = 9.2, 6.2, 3.9 Hz), 7.00–
7.90 (m, 5H); 13C NMR (CDCl3): d 20.8, 21.5, 24.5, 42.7,
46.9, 55.0, 74.5, 126.4, 128.7, 130.5, 137.1, 145.8. Anal.
Calcd for C14H19NO2 (233.3): C, 72.07; H, 8.21; N, 6.00.
Found: C, 71.83; H, 8.03; N, 6.24.
8.16 (m, 12H); 13C NMR (CDCl3):
d 21.6, 22.1,
46.5, 49.7, 52.6, 75.6, 122.5, 123.4, 125.7, 125.8, 126.0,
126.4, 127.1, 127.9, 128.4, 129.4, 130.6, 134.1, 141.4,
145.4. EI-MS: m/z (%) 319 (M+, 12), 304 (16), 198 (15),
182 (18), 155 (100). Anal. Calcd for C22H25NO (319.4):
C, 82.72; H, 7.89; N, 5.95. Found: C, 82.91; H, 7.66; N,
6.09.
5.4.2.
1,3-oxazinan-2-one (4R,6S,10R)-4b. Oil; ½aꢀD ¼ þ18:3
(c 1.6, CHCl3); IR (neat) mmax 3086, 3062, 3029, 2965,
(4R,6S)-4-Methyl-6-phenyl-3-[(1R)-1-phenylethyl]-
20
5.3.18. (1S,3S)-3-{[(1R)-1-(1-Naphthyl)ethyl]amino}-1-phen-
1
2927, 2851, 1744, 1493, 1454 cmꢁ1; H NMR (CDCl3): d
20
ylbutan-1-ol (S,S,R)-3h. Oil; ½aꢀD ¼ ꢁ3:42 (c 0.6, CHCl3);
1
IR 3260, 3050, 2955, 1521, 1413 cmꢁ1; H NMR (CDCl3):
1.10 (d, 3H, J = 6.2 Hz), 1.28 (d, 3H, J = 6.6 Hz), 1.85
(ddd, 1H, J = 13.9, 7.3, 5.5 Hz), 2.36 (ddd, 1H, J = 13.9,
8.8, 5.5 Hz), 2.67 (sext, 1H, J = 6.3 Hz), 3.90 (q, 1H,
J = 6.6 Hz), 6.07 (dd, 1H, J = 8.8, 5.5 Hz), 7.05–8.20 (m,
10H); 13C NMR (CDCl3): d 18.3, 21.7, 34.0, 56.3, 59.9,
65.0, 125.7, 126.7, 127.77, 127.81, 128.7, 128.9, 135.3,
145.3, 145.7. Anal. Calcd for C19H21NO2 (295.4): C,
77.26; H, 7.17; N, 4.74. Found: C, 77.08; H, 7.32; N, 4.54.
d 1.18 (d, 3H, J = 6.2 Hz), 1.57 (d, 3H, J = 6.6 Hz), 1.61–
1.73 (m, 2H), 2.90 (d quint, 1H, J = 8.1, 6.2 Hz), 4.27 (br
s, 2H), 4.77 (dd, 1H, J = 7.3, 5.1 Hz), 5.09 (q, 1H,
J = 6.2 Hz), 7.20–8.16 (m, 12H); 13C NMR (CDCl3): d
27.1, 30.3, 31.1, 46.6, 52.0, 75.1, 122.3, 124.1, 125.7,
126.2, 126.3, 126.4, 127.2, 127.9, 128.4, 129.4, 131.6,
134.1, 139.1, 145.0. EI-MS: m/z (%) 319 (M+, 11), 304
(14), 198 (15), 182 (18), 155 (100). Anal. Calcd for
C22H25NO (319.4): C, 82.72; H, 7.89; N, 5.95. Found: C,
82.88; H, 7.96; N, 5.88.
5.4.3. (4R,4aS,10bS)-4-Methyl-3-[(1R)-1-phenylethyl]-
3,4,4a,5,6,10b-hexahydro-2H-naphtho[2,1-e][1,3]oxazin-2-
20
one (4R,4aS,10bS,10R)-4d. Oil; ½aꢀD ¼ þ126:7 (c 0.8, CH-
Cl3); IR (neat) mmax 3400, 3024, 2928, 2851, 1603,
5.3.19. (2S*,3R*)-4-(Benzylamino)pentan-2-ol (S*,R*)-3i.
1454 cmꢁ1
;
1H NMR (CDCl3):
d
1.08 (d, 3H,
Oil; IR (neat) 3091, 3046, 1455, 1130 cmꢁ1 1H NMR
;
J = 6.2 Hz), 1.18 (d, 3H, J = 6.2 Hz), 1.38 (tdd, 1H,
J = 13.5, 5.5, 4.4 Hz), 1.84 (dq, 1H, J = 13.2, 2.2 Hz),
2.36 (m, 1H), 2.68 (br d, 1H, J = 14.6 Hz), 3.22 (td, 1H,
J = 14.3, 4.8 Hz), 3.45 (qd, 1H, J = 6.2, 4.4 Hz), 3.51 (q,
1H, J = 6.2 Hz), 4.55 (d, 1H, J = 7.7 Hz), 6.45 (d, 1H,
J = 7.3 Hz), 6.75–7.30 (m, 8H); 13C NMR (CDCl3): d
18.6, 25.1, 27.1, 27.8, 30.3, 36.9, 59.4, 61.4, 125.3, 126.7,
127.1, 127.8, 128.1, 128.5, 128.7, 130.3, 136.5, 140.8,
143.5. Anal. Calcd for C21H23NO2 (321.4): C, 78.47; H,
7.21; N, 4.36. Found: C, 78.69; H, 7.03; N, 4.09.
(CDCl3): d 1.13 (d, 3H, J = 6.2 Hz), 1.17 (d, 3H,
J = 6.2 Hz), 1.29 (dt, 1H, J = 14.0, 10.6 Hz), 1.52 (ddd,
1H, J = 14.1, 2.6, 2.2 Hz), 2.91 (dqd, 1H, J = 10.9, 6.2,
2.6 Hz), 3.70 (d, 1H, J = 12.6 Hz), 3.94 (d, 1H,
J = 12.6 Hz), 3.97 (dqd, 1H, J = 10.3, 6.2, 2.0 Hz), 4.41
(br s, 2H), 7.15–7.37 (m, 5H); 13C NMR (CDCl3): d 22.8,
24.0, 45.5, 49.7, 52.3, 67.2, 127.5, 128.1, 128.2, 140.6. EI-
MS: m/z (%) 193 (M+, 2), 178 (46), 134 (41), 91 (100). Anal.
Calcd for C12H19NO (193.3): C, 74.57; H, 9.91; N, 7.25.
Found: C, 74.81; H, 10.19; N, 6.98.
5.4.4. (4R*,6S*)-3-Benzyl-4,6-dimethyl-1,3-oxazinan-2-one
(4R*,6S*)-4i. Oil; IR (neat) 3015, 2966, 1765,
5.3.20. (2R*,3R*)-4-(Benzylamino)pentan-2-ol (S*,R*)-3i.
Oil; H NMR (CDCl3): d 1.16 (d, 3H, J = 7.2 Hz), 1.23
1
1472 cmꢁ1
;
1H NMR (CDCl3):
d
1.09 (d, 3H,
(d, 3H, J = 6.4 Hz), 1.40 (ddd, 1H, J = 14.2, 5.2, 2.6 Hz),
1.72 (ddd, 1H, J = 14.2, 8.8, 3.2 Hz), 3.10 (qdd, 1H,
J = 6.4, 3.2, 2.6 Hz), 3.70 (d, 1H, J = 12.6 Hz), 3.84 (d,
1H, J = 12.6 Hz), 4.17 (dqd, 1H, J = 8.9, 7.2, 4.9 Hz),
4.41 (br s, 2H), 7.18–7.35 (m, 5H).
J = 6.2 Hz), 1.26 (d, 3H, J = 6.2 Hz), 1.52 (dt, 1H,
J = 13.9, 11.3 Hz), 1.95 (ddd, 1H, J = 13.9, 5.5, 1.8 Hz),
3.36 (d quint, 1H, J = 11.3, 5.9 Hz), 4.19 (d, 1H,
J = 15.7 Hz), 4.21 (ddd, 1H, J = 11.3, 6.2, 2.0 Hz), 5.02
(d, 1H, J = 15.7 Hz), 7.10–7.28 (m, 5H); 13C NMR
(CDCl3): d 20.4, 20.6, 38.3, 48.0, 49.3, 71.5, 127.1, 127.3,
128.4, 137.2, 155.0. Anal. Calcd for C13H17NO2 (219.3):
C, 71.21; H, 7.81; N, 6.39. Found: C, 71.11; H, 8.02; N,
6.61.
5.4. Preparation of oxazinones 4
c-Amino alcohols 3a,b,d,i (2 mmol) in a 50 mL round bot-
tom flask equipped with magnetic stirring, in 10 mL
CH2Cl2 at rt, were treated with dimethylaminopyridine
(DMAP) (0.2 mmol) and cabonyl diimidazole (3 mmol).
The reaction mixture was allowed to stand at rt for 1 h,
then the mixture was filtered on a thin pad of silica gel
affording generally the pure 5. When necessary the final
oxazinones were further purified by recrystallization or
chromatographic separation. Spectral data follow.
5.5. General procedure for the synthesis of 1,3-tetrahydro
oxazines 5
The c-amino alcohols 3a,b,i (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

1316
C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
purified by short filtration on a thin pad of silica gel with
cyclohexane–AcOEt (97/3 v/v) or CH2Cl2/n-esano (50/50
v/v) as eluent. Spectral data of tetrahydro oxazines 5
follow.
support of this research by a grant from University of
Camerino and from MIUR-PRIN (contract no.
2005037725_001) is gratefully acknowledged.
5.5.1.
oxazinane (4R,6S,10R)-5a. Oil; ½aꢀD ¼ ꢁ48:1 (c 3.1,
(4R,6S)-4,6-Dimethyl-3-[(1R)-1-phenylethyl]-1,3-
20
References
CHCl3); IR (neat) 3402, 3028, 2970, 2932, 2905, 2839,
1. Gevorgyan, G. A.; Agababyan, A. G. Usp. Chim. 1984, 53,
971–1013.
1
1494, 1448, 1377 cmꢁ1; H NMR (CDCl3): d 1.18 (d, 3H,
J = 6.2 Hz), 1.23 (d, 3H, J = 6.2 Hz), 1.32 (d, 3H,
J = 7.0 Hz), 1.38 (dt, 1H, J = 12.8, 11.0 Hz), 1.58 (dt,
1H, J = 12.8, 2.9 Hz), 2.89 (dqd, 1H, J = 10.6, 6.2,
3.3 Hz), 3.54 (dqd, 1H, J = 11.0, 6.2, 2.6 Hz), 3.95 (d,
1H, J = 8.1 Hz), 4.28 (d, 1H, J = 8.1 Hz), 4.35 (q, 1H,
J = 7.0 Hz), 7.15–7.55 (m, 5H); 13C NMR (CDCl3): d
11.6, 20.4, 21.7, 42.1, 52.5, 53.3, 73.7, 79.6, 126.9, 128.1,
128.3, 143.4. Anal. Calcd for C13H21NO (207.3): C,
75.32; H, 10.21; N, 6.76. Found: C, 75.58; H, 10.39; N,
6.54.
2. Korner, J. K.; Otis, L.; Skinner, W. A. J. Med. Chem. 1967,
10, 387–391.
3. Robba, M.; Duval, D. Chim. Ter. 1973, 8, 22–31.
4. Wang, Y. F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am.
Chem. Soc. 1982, 104, 6465–6466.
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5.5.2.
(4S,6R)-4,6-Dimethyl-3-[(1R)-1-phenylethyl]-1,3-
oxazinane (4S,6R,10R)-5a. 1H NMR (CDCl3) d 1.15 (d,
3H, J = 6.2 Hz), 1.18 (d, 3H, J = 6.2 Hz), 1.15–1.50 (m,
2H), 1.54 (d, 3H, J = 7.0 Hz), 2.73 (sext, 1H, J = 6.8 Hz),
3.47 (sext, 1H, J = 6.4 Hz), 3.86 (d, 1H, J = 9.2 Hz), 4.28
(q, 1H, J = 7.0 Hz), 4.80 (d, 1H, J = 9.2 Hz), 7.20–7.50
(m, 5H); 13C NMR (200 MHz, CDCl3) d 20.3, 20.8, 21.9,
41.0, 53.4, 54.1, 73.5, 80.9, 126.9, 127.8, 128.2, 142.7.
14. Bartoli, G.; Cimarelli, C.; Palmieri, G. J. Chem. Soc., Perkin
Trans. 1 1994, 537–543.
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1513–1516.
16. Meschino, J. A.; Bond, C. H. J. Org. Chem. 1963, 28, 3129–
3134.
5.5.3. (R,R)-4-Methyl-6-phenyl-3-[(1R)-1-phenylethyl]-1,3-
20
oxazinane (R,R,R)-5b. Oil; ½aꢀD ¼ ꢁ32:8 (c 2.0, CHCl3);
IR (neat) 3418, 3019, 2975, 1510, 1471, 1327 cmꢁ1 1H
;
NMR (CDCl3): d 1.29 (d, 3H, J = 6.6 Hz), 1.42 (d, 3H,
J = 7.0 Hz), 1.71 (dt, 1H, J = 13.2, 10.8 Hz), 1.83 (dt,
1H, J = 13.2, 3.7 Hz), 3.12 (dqd, 1H, J = 10.3, 6.3,
4.0 Hz), 4.23 (d, 1H, J = 8.8 Hz), 4.42 (q, 1H,
J = 6.8 Hz), 4.50 (dd, 1H, J = 11.0, 3.3 Hz), 4.58 (d, 1H,
J = 8.8 Hz), 7.22–7.60 (m, 5H); 13C NMR (CDCl3): d
13.0, 18.3, 20.4, 41.8, 52.9, 53.7, 79.7, 126.0, 127.0, 127.5,
128.1, 128.3, 128.4, 142.6, 143.8. Anal. Calcd for
C19H23NO (281.4): C, 81.10; H, 8.24; N, 4.98. Found: C,
81.31; H, 7.97; N, 4.76.
17. Narasaka, K.; Ukaji, S.; Yamazaki, S. Bull. Chem. Soc. Jpn.
1986, 59, 525–533.
18. Palmieri, G.; Cimarelli, C.; Bartoli, G. Tetrahedron: Asym-
metry 1994, 5, 1455–1458.
19. Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.;
Petrini, M. J. Org. Chem. 1994, 59, 5328–5335.
20. Bartoli, G.; Cupone, G.; Dal Pozzo, R.; De Nino, A.;
Mariuolo, L.; Procopio, A.; Tagarelli, A. Tetrahedron Lett.
2000, 43, 7441–7444.
21. Nilsson, L. Acta Chem. Scand., Ser. B 1979, B33, 547–
550.
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Tetrahedron 1994, 50, 2255–2264.
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5563.
24. Palmieri, G. Eur. J. Chem. 1999, 805–811.
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31, 2943–2953.
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15, 971–975.
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Patent; CAN 128:243740.
28. Semiempirical PM3 calculations were performed with the
Spartan 5.0.3, Wavefunction, Inc. 18401 Von Karmen Ave.,
#370, Irvine, CA 92715.
5.5.4.
(4R*,6S*)-5i. Oil; IR (neat) 3009, 2982, 1615, 1452,
1365, 1055 cmꢁ1 1H NMR (CDCl3): d 1.23 (d, 3H,
(4R*,6S*)-3-Benzyl-4,6-dimethyl-1,3-oxazinane
;
J = 6.8 Hz), 1.24 (d, 3H, J = 6.2 Hz), 1.35–1.57 (m, 2H),
3.03 (d quint, 1H, J = 8.1, 6.6 Hz), 3.56 (d, 1H,
J = 13.8 Hz), 3.62 (d quint, 1H, J = 7.7, 6.2 Hz), 3.93 (d,
1H, J = 13.8 Hz), 4.09 (d, 1H, J = 9.7 Hz), 4.40 (d, 1H,
J = 9.7 Hz), 7.15–7.43 (m, 5H); 13C NMR (CDCl3): d
20.4, 20.6, 38.3, 48.0, 49.3, 71.5, 127.1, 127.3, 128.4,
137.2, 155.0. Anal. Calcd for C13H19NO (205.3): C,
76.06; H, 9.33; N, 6.82. Found: C, 76.29; H, 9.18; N, 7.07.
29. Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org.
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30. Gaudemer, A.. In Determination of Configurations by Spec-
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Stuttgart, 1977; Vol. 1, p 44.
Acknowledgements
We thanks Dr. Cristina Femoni (University of Bologna—
Department of Inorganic and Physic Chemistry) for pro-
viding X-ray diffraction data of product 3f. The financial
31. Barluenga, J.; Olano, B.; Fustero, S. J. Org. Chem. 1985, 50,
4052–4056.

C. Cimarelli et al. / Tetrahedron: Asymmetry 17 (2006) 1308–1317
1317
32. The crystallographic data for compound (R,R,R,R)-3d (For-
mula: C20H25NO Unit cell parameters: a 7.3524(13), b
28.645(5), c 8.4467(15), beta 100.635(2), space group P21)
have been deposited with the Cambridge Crystallographic
Data Center as supplementary material with the deposition
number CCDC 288236. This data can be obtained, free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.
html.