Synthesis of enantiopure (αS,βS)- or (αR,βS)-β- amino alcohols by complete regioselective opening of aminoepoxides by organolithium reagents LiAlH4 or LiAlD4

Article abstract of DOI:10.1021/jo0606756

The reaction of chiral (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl) epoxides, 1 or 2 with a variety of organolithium compounds to obtain the corresponding (αS,βS)- or (αR,βS)-β-amino alcohols in enantiopure form is reported. In both cases, the opening of the ox

Full text of DOI:10.1021/jo0606756

Synthesis of Enantiopure (rS,âS)- or (rR,âS)-â-Amino Alcohols by
Complete Regioselective Opening of Aminoepoxides by
Organolithium Reagents LiAlH4 or LiAlD4
Jose´ M. Concello´n,* Pablo L. Bernad, Virginia del Solar, and Jose´ Ramo´n Sua´rez
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, UniVersidad de OViedo, Julia´n
ClaVer´ıa, 8, 33071 OViedo, Spain
Santiago Garc´ıa-Granda and M. Rosario D´ıaz
Departamento de Qu´ımica F´ısica y Anal´ıtica, Facultad de Qu´ımica, UniVersidad de OViedo, Julia´n
ClaVer´ıa, 8, 33071 OViedo, Spain
jmcg@fq.unioVi.es
ReceiVed March 29, 2006
The reaction of chiral (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides, 1 or 2 with a variety of organolithium
compounds to obtain the corresponding (RS,âS)- or (RR,âS)- â-amino alcohols in enantiopure form is
reported. In both cases, the opening of the oxirane ring at C-3 proceeded with total regioselectivity.
Moreover, the ring opening of aminoepoxides 1 or 2 by hydride (utilizing LiAlH4) to obtain the
corresponding (2S,3S)- or (2R,3S)-3-aminoalkan-2-ols is also described. The reaction of 1 or 2 with LiAlD4
in place of LiAlH4 gave the corresponding (2S,3S)- or (2R,3S)-3-amino-1-deuterioalkan-2-ols.
Introduction
the synthesis of these compounds was the direct aminolysis of
epoxides.4 The opening of oxiranes by amines was limited by
the high temperature, long reaction time, and excess of amine
required. In addition, often the method failed when poorly
nucleophilic amines or sterically crowded amines or epoxides
were used. Finally, the total control of regioselectivity of the
ring opening was, generally, unresolved. For this reason, a
general synthesis of enantiopure â-amino alcohols with complete
selectivity, in which several enantiopure diastereoisomers could
be available, would be still desirable.
Enantiopure â-aminoalkanols are important building blocks
and have been used to prepare a large number of biologically
active natural and synthetic compounds,1 including unnatural
amino acids.2 The former compounds have also been used as
chiral auxiliaries for asymmetric synthesis.3 Consequently, a
large number of syntheses of enantiopure â-amino alcohols have
been published. The most common and practical method for
Previously, we reported the efficient synthesis of both
enantiopure (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides 1 or
2 by total stereoselective reduction of enantiopure R-amino-R′-
chloroketones with LiAlH4 or by highly stereoselective addition
reaction of iodomethyllithium to R-aminoaldehydes, respec-
tively.5 Building on these results, we described, more recently,
(1) (a) Corey, E. J.; Zhang, F. Angew. Chem., Int. Ed. Engl. 1999, 38,
1931-1934. (b) Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340-8347. (c) Chang, B.
L.; Ganesan, A. Bioorg. Med. Chem. Lett. 1997, 7, 1511-1514. (d) Rogers,
G. A.; Parsons, S. M.; Anderson, D. S.; Nilson, L. M.; Bahr, B. A.;
Kornreich, W. D.; Kaufman, R.; Jacobs, R. S.; Kirtman, B. J. Med. Chem.
1989, 32, 1217-1230.
(2) (a) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326-329. (b) Li,
G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
451-454.
(4) (a) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52,
14361-14384. (b) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.
(d) Hanson, R. M. Chem. ReV. 1991, 91, 437-476.
(3) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
875.
10.1021/jo0606756 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
6420
J. Org. Chem. 2006, 71, 6420-6426

Enantiopure (RS,âS)- or (RR,âS)-â-Amino Alcohols
SCHEME 1. Synthesis of (rS,âS)-â-Amino Alcohol 4
TABLE 1. Synthesis of (rS,âS)-â-Amino Alcohol 4
FIGURE 1.
the highly regioselective ring opening of these aminoepoxides
with ketones,6 nitriles,7 and carboxylic acids.8
entry
4
R1
R2
yield (%)a
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me
Me
Me
i-Bu
i-Bu
i-Bu
Bn
Me
Allyl
Ph
Me
Allyl
Ph
Me
Allyl
Ph
78
80
72
71
84
76
70
89
78
Very recently, we reported the transformation of aminoep-
oxides 1 and 2 into enantiopure allylamines 3 by reaction with
various organolithium compouds.9 To investigate the scope of
the synthetic applications of the reaction between the same
enantiopure aminoepoxides 1 and 2 and organolithium com-
pounds, we report herein the nucleophilic opening of the oxirane
ring of 1 or 2 with a variety of organolithium compounds, under
different reaction conditions to those previously reported in the
synthesis of allylamines.9 So, we describe the reaction conditions
to obtain enantiopure (RS,âS)- or (RR,âS)-â-amino alcohols 4
or 5 (instead of the allylamines previously reported) by reaction
of various organolithium compounds with compounds 1 or 2.
The ring opening at C-3 proceeded with total regioselectivity,
and â-amino alcohols 4 or 5 were readily available, in
enantiopure form. To the best of our knowledge, only one
example of the ring opening of aminoepoxides 1 or 2 with
organolithium compounds was previously described.10 More-
over, the ring opening of aminoepoxides 1 or 2 by LiAlH4 to
obtain the corresponding (2S,3S)- or (2R,3S)-3-aminoalkan-2-
ols 6 or 7 is also reported. When LiAlD4 was used instead of
LiAlH4, the corresponding deuterated amino alcohols 8 and 9
were obtained.
Bn
Bn
a Isolated yields after column chromatography based on the starting
aminoepoxide 1.
isolated as the only product by performing the transformation
with longer reaction times. On the basis of these results, and to
find the reaction conditions to obtain â-amino alcohols 4 as
only product, our initial attempts were carried out utilizing syn-
aminoepoxides 1 and methyllithium and with short reaction
times. Thus, treatment of a solution of aminoepoxides 1a-c
derived from alanine, leucine, and phenylalanine (R1 ) Me,
i-Bu, and Bn) in THF with methyllithium (3 equiv) at 0 °C
with short reaction time (30 min) provided a 3:1 mixture of the
corresponding allylamine 3 and the â-amino alcohol 4. No
â-amino alcohols were obtained, as only product, by using
shorter reaction times.
Taking into account the influence of the solvent in the
nucleophilicity and basicity of the organolithium compounds,11
we decided to perform the reaction using diethyl ether instead
of THF. Thus, treatment of a solution of aminoepoxides 1 in
diethyl ether with methyl, allyl, or phenyllithium at 0 °C
afforded, after hydrolysis, the corresponding (RS,âS)-â-amino
alcohol 4 in high yield (Scheme 1 and Table 1).
The reaction with allyllithium could also be performed in
THF instead of Et2O obtaining the corresponding amino alcohol
4, as the sole product, in similar yields. This result could be
obtained as consequence of the higher nucleophilicity of this
organolithiun compound.
Results and Discussion
Synthesis of (rS,âS)- or (rR,âS)-â-Amino Alcohols 4 or
5 Using Organolithium Compounds. In our recent paper,9 in
which we described the synthesis of allylamines 3 by reaction
of aminoepoxides 1 with organolithium compounds, the trans-
formation was promoted by the abstraction of a proton of the
oxirane ring by the organolithium compound because of its
strong basic character. These previous results prompted us to
find other different reaction conditions in order to use the
organolithium compounds such as nucleophiles instead of bases,
so that we could perform the selective ring opening of
compounds 1 to obtain the corresponding amino alcohols 4
instead of the allylamines 3 (Figure 1).
Previously, in some of the synthesis of allylamines we
detected the formation of â-amino alcohols 4, as a minor
reaction product, when less reactive organolithium compounds
were used, such as phenyllithium or methyllithium. This
inconvenience was then overcome, and the allylamines were
When aminoepoxides 1 were treated with other organolithium
reagents, such as i-propyl, n-butyl, sec-butyl, or tert-butyl in
diethyl ether, no â-amino alcohols were obtained, and the
corresponding allylamines were the only isolated product.
The reaction of aminoepoxides 1 derived from alanine, leucin,
and phenylalanine with these organolithium reagents was totally
1
regioselective. So, no regioisomers were observed by H and
13C NMR analysis (300 MHz) of crude reaction products 4,
within the limits of NMR assay. In addition, 1H and 13C NMR
spectra of compounds 4 showed the opening of the oxirane at
the C-3 position. The preservation of the absolute configuration
of the oxirane in the course of the ring opening and, conse-
quently, the structure of compounds 4 has been proposed on
the basis of previous reactions of aminoepoxides 1 with ketones,6
nitriles,7 and carboxylic acids8 and on the single-crystal X-ray
analysis of 5i (see below).
(5) (a) Barluenga, J.; Baragan˜a, B.; Alonso, A.; Concello´n, J. M. J. Chem.
Soc., Chem. Commun. 1994, 969-970. (b) Barluenga, J.; Baragan˜a, B.;
Concello´n, J. M. J. Org. Chem. 1995, 60, 6696-6699.
(6) Concello´n, J. M.; Sua´rez, J. R.; Garc´ıa-Granda, S.; D´ıaz, M. R. Org.
Lett. 2005, 7, 247-250.
(7) Concello´n, J. M.; Sua´rez, J. R.; del Solar, V. J. Org. Chem. 2005,
70, 7447-7450.
(8) Concello´n, J. M.; Sua´rez, J. R.; del Solar, V.; Llavona, R. J. Org.
Chem. 2005, 70, 10348-10353.
(9) Concello´n, J. M.; Sua´rez, J. R.; del Solar, V. Org. Lett. 2006, 8,
349-351.
To extend the scope of this reaction, we performed the
reaction of anti-aminoepoxides 2 with the same organolithium
(10) For the only example of the reaction of an organolithium compound
with aminoepoxide, see the following: Mena, M.; Bonjoch, J. Tetrahedron
2005, 61, 8264-8270.
(11) Najera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867-926.
J. Org. Chem, Vol. 71, No. 17, 2006 6421

Concello´n et al.
SCHEME 3. Synthesis of (S,S)-â-Amino Alcohols 6 or 8
SCHEME 2. Synthesis of (rR,âS)-â-Amino Alcohol 5
TABLE 2. Synthesis of (rR,âS)-â-Amino Alcohol 5
SCHEME 4. Synthesis of (R,S)-â-Amino Alcohols 7 or 9
entry
5
R1
R2
de (%)a
yield (%)b
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Me
Me
Me
i-Bu
i-Bu
i-Bu
Bn
Me
allyl
Ph
Me
allyl
Ph
Me
allyl
Ph
>98 (>98)
>98 (>98)
>98 (>98)
89 (91)
90 (91)
91 (91)
91 (92)
92 (92)
91 (92)
80
79
72
68
75
70
69
80
77
TABLE 3. Synthesis of (S,S)-â-Amino Alcohols 6 or 8
Bn
Bn
entry
compound
R1
yield (%)a
a Diastereoisomeric excess determined by 1H NMR analysis of the crude
products 5; de of the starting aminoepoxides 2 is given in parentheses
b Isolated yields after column chromatography based on the starting
aminoepoxide 2.
1
2
3
4
5
6a
6b
6c
8a
8c
Me
i-Bu
Bn
Me
Bn
80
81
90
82
84
a Isolated yields after column chromatography based on the starting amino
epoxide 1.
compounds and under the same reaction conditions (Scheme 2,
Table 2). In all cases, the corresponding (RR,âS)-â-amino
alcohols 5 were obtained in good yields, with high selectivity,
and no important differences in the yields were observed from
aminoepoxide 1 or 2.
TABLE 4. Synthesis of (R,S)-â-Amino Alcohols 7 or 9
entry
compound
R1
de (%)a
yield (%)b
1
The selectivity of the reaction was also determined by H
6
7
8
9
10
7a
7b
7c
9a
9c
Me
i-Bu
Bn
Me
Bn
>98 (>98)
90 (91)
91 (92)
>98 (>98)
90 (92)
82
85
91
81
83
NMR spectroscopy (300 MHz) of the crude mixture of products,
showing a mixture of diastereoisomers 5 in the same relationship
as the starting aminoepoxides 2. The synthesis of â-amino
alcohols 5 with the same diastereoisomeric excess (de) as the
starting aminoepoxides 25 was an indirect support of the total
selectivity of the ring opening reaction. After purification of
compounds 5 by column chromatography, the major diastere-
oisomer was isolated as a single stereoisomer. The structure of
compounds 5 and, consequently, the absolute configuration was
established by single-crystal X-ray analysis of 5i.12 The structure
of the other â-amino alcohols 5 as depicted in Scheme 4 was
assigned by analogy. The X-ray analysis of 5i, confirmed that
the ring opening of the oxirane took place at C-3, the absolute
configuration of the oxirane being preserved. In turn, the single-
crystal X-ray analysis of 5i confirmed the structure of amino
alcohols 4, as depicted in Scheme 1. Therefore, the epoxides 1
or 2 can be opened with total regioselectivity by the organo-
lithium reagents investigated to give the (S,S)- or (R,S)-â-amino
alcohols 4 or 5, exclusively.
Preparation of (2S,3S)- or (2R,3S)-3-Aminoalkan-2-ols 6
or 7 by Using LiAlH4. The reaction of a solution of aminoe-
poxides 1 or 2 in THF with LiAlH4 (1.5 equiv.) afforded, after
hydrolysis, the corresponding (2S,3S)- or (2R,3S)-3-aminoalkan-
2-ols 6 or 7 in high yield (>80%) (Schemes 3 and 4 and Tables
3 and 4). Similarly to the synthesis of 4 or 5, the reaction of 1
or 2 with LiAlH4 was not sensitive to the different stereochem-
istry and structure of the starting epoxides, and similar yields
of 6 or 7 were obtained in all cases.
a Diastereoisomeric excess determined by 1H NMR analysis of the crude
products 7 or 9; de of the starting aminoepoxides 2 is given in parentheses.
b Isolated yields after column chromatography based on the starting
aminoepoxide 2.
reaction products after column chromatography. Synthesis
of compounds 6 or 7 previously reported, afforded a mixture
of diastereoisomers 6/713 or took place in lower yields.14 The
structure of â-amino alcohols 6 or 7 (opening of the oxirane
1
at C-3) was established on the basis of their H and 13C NMR
1
data and by comparison with the H or 13C NMR spectro-
scopic data of the compounds 6a-c and 7b,c, previously
prepared by other methods.14 The regiochemistry of the reaction
was in accordance with the observed results in the ring
opening of compounds 1 or 2 when different nucleophiles were
used.6-8
In view of the utility of isotopically labeled compounds in
establishing the mechanisms of organic reactions and of the
biosynthesis of many natural compounds,15 we applied this
method to obtain deuterated â-amino alcohols 8 or 9 by using
LiAlD4 instead of LiAlH4.
No differences were observed during the course of the
reaction or on the outcome of the reaction, when aminoepoxides
1 or 2 were treated with LiAlD4 instead of LiAlH4 under the
same reaction conditions. In this case, the corresponding (2S,3S)-
or (2R,3S)-3-amino-1-deuterioalkan-2-ols 8 or 9, respectively,
The reaction of aminoepoxides 1 and 2 with LiAlH4 was also
totally regioselective, and no regioisomers or byproducts were
1
observed by H and 13C NMR analysis (300 MHz) of crude
(13) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141-1143.
(12) CCDC-602397 (5i) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc-
.cam.ac.uk/conts/retrieving.html (or the Cambridge Data Centre, 12, Union
Road, Cambridge CB21EZ, U.K. Fax: (+44)1223-336.033; or deposit@
ccdc.cam.ac.uk).
(14) Schwerdtfeger, J.; Kolczewski, S.; Weber, B.; Fro¨hlich, R.; Hoppe,
D. Synthesis 1999, 9, 1573-1592.
(15) Mann, J. Secondary Metabolism; Oxford University Press: Oxford,
U.K., 1986; p 23.
6422 J. Org. Chem., Vol. 71, No. 17, 2006

Enantiopure (RS,âS)- or (RR,âS)-â-Amino Alcohols
SCHEME 5. Mechanism Proposed
A similar mechanism could explain the reaction of aminoe-
poxides 2 with the organolithium compounds, hydride or
deuteride to afford, after hydrolysis, amino alcohols 5, 7, or 9.
Conclusions
We have reported the reaction conditions to transform the
chiral (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides 1 or 2 into
enantiopure (RS,âS)- or (RR,âS)-â-amino alcohols 4 or 5 by a
reaction with a variety of organolithium compounds in diethyl
ether. The opening of the oxirane ring at C-3 proceeded with
total regioselectivity. Moreover, the ring opening by hydride
(using LiAlH4) of aminoepoxides 1 or 2 to obtain the corre-
sponding (2S,3S)- or (2R,3S)-3-aminoalkan-2-ols 6 and 7 is also
reported. The reaction of 1 or 2 with LiAlD4 instead of LiAlH4
afforded the corresponding deuterated â-amino alcohols 8 or
9.
were obtained in high yield as the only product. Therefore,
isotopically labeled with deuterium â-amino alcohols 8 or 9
were readily available from aminoepoxides 1 or 2.
Scheme 5 shows both mechanisms proposed to explain the
transformation of aminoepoxides 1 into amino alcohols 4 or
into allylamines 3. Thus, the synthesis of allylamines 3 took
place by reaction of compounds 1 with 2 equiv of organolithium
compound in THF. The first equivalent of the organolithium
compound abstracted a proton at the less hindered side of the
oxirane ring. Then, the generated oxiranyl anion intermediate
10 suffered an R-elimination affording an R-alkoxycarbenoid
intermediate 11, which reacted with the second equivalent of
the organolithium compounds to give a dianion 12. Elimination
of lithium oxide from the dianion afforded allylamines 3. An
indirect support for this mechanism was provided by the
isolation of a 1:1 mixture of the starting aminoepoxide and the
corresponding allylamine when the reaction was carried out by
using only 1 equiv of organolithium compound.
Alternatively, when the reaction of 1 was carried out with
organolithium compounds in Et2O, a ring opening at the less
hindered side C-3 by nucleophilic attack of the organolithium
compound would occur affording the intermediate 13, which
could be hydrolyzed to give the corresponding (RS,âS)-â-amino
alcohols 3. The total regioselectivity can be explained on the
basis of steric grounds. The nucleophilic attack took place at
the less hindered side of the oxirane and, moreover, a bulky
substituent (dibenzylamino group) is attached at the R-carbon
of the substituent alkyl group of the oxirane ring. This observed
regiochemistry was in accordance to that observed in other ring
opening processes of compounds 1 by different nucleophiles,
such as ketones,6 nitriles,7 and carboxylic acids.8,16
Experimental Section
General Procedure of Synthesis of 4 and 5. To a stirred
solution of the corresponding aminoepoxide 1 or 2 (0.2 mmol) in
Et2O (1 mL), the corresponding organolithium (3 equiv) was added
at 0 °C. After the mixture was stirred at this temperature for 6 h,
an aqueous saturated solution of NH4Cl (5 mL) was added, and
the mixture was stirred at room temperature for 5 min. Then, the
aqueous phase was extracted with diethyl ether (3 × 5 mL), and
the combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. Flash column chromatography
on silica gel (hexane/EtOAc 20:1) provided pure compounds 4 or
5.
(2S,3S)-2-(Dibenzylamino)pentan-3-ol (4a): colorless oil. [R]25
D
) +42.5 (c 1.77, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.38-
7.25 (m, 10 H), 4.47 (br s, 1 H), 3.88 (d, J ) 13.3 Hz, 2 H), 3.46
(ddd, J ) 9.4, 8.3, 2.7 Hz, 1 H), 3.35 (d, J ) 13.3 Hz, 2 H), 2.61
(dq, J ) 9.4, 6.8 Hz, 1 H), 1.59 (ddq, J ) 14.0, 7.2, 2.7 Hz, 1 H),
1.24-1.10 (m, 1 H), 1.05 (d, J ) 6.8 Hz, 3 H), 0.98 (t, J ) 7.2
Hz, 3 H). 13C NMR (50 MHz, CDCl3): δ 138.8 (2 × C), 128.9 (4
× CH), 128.4 (4 × CH), 127.1 (2 × CH), 71.8 (CH), 57.9 (CH),
53.1 (2 × CH2), 26.3 (CH2), 9.9 (CH3), 7.9 (CH3). MS (70 eV, EI)
m/z (%): 265 (M+ - H2O, <1), 224 (70), 91 (100). HRMS (70
eV): calcd for C19H23N (M+ - H2O), 265.1830; found, 265.1836.
IR (neat): 3422, 2925, 2351, 1604, 1496, 1455, 1377 cm-1. Rf )
0.37 (hexane/EtOAc 10:1). Anal. Calcd for C19H25NO: C, 80.52;
H, 8.89; N, 4.94; O, 5.65. Found: C, 80.65; H, 8.97; N, 4.98; O,
5.60.
(2S,3S)-2-(Dibenzylamino)hept-6-en-3-ol (4b): colorless oil.
[R]25 ) +50.4 (c 1.44, CHCl3). H NMR (300 MHz, CDCl3): δ
1
D
7.37-7.27 (m, 10 H), 5.85 (ddt, J ) 17.0, 10.2, 6.6 Hz, 1 H), 5.07-
5.00 (m, 1 H), 4.98-4.94 (m, 1 H), 4.51 (br s, 1 H), 3.86 (d, J )
13.3 Hz, 2 H), 3.52 (dt, J ) 9.4, 2.5 Hz, 1 H), 3.34 (d, J ) 13.3
Hz, 2 H), 2.60 (dq, J ) 9.4, 6.7 Hz, 1 H), 2.36-2.24 (m, 1 H),
2.21-2.07 (m, 1 H), 1.64-1.53 (m, 1 H), 1.33-1.22 (m, 1 H),
1.05 (d, J ) 6.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 138.8
(2 × C), 138.7 (CH), 128.9 (4 × CH), 128.4 (4 × CH), 127.1 (2
× CH), 114.3 (CH2), 70.0 (CH), 58.2 (CH), 53.1 (2 × CH2), 33.0
(CH2), 29.9 (CH2), 7.9 (CH3). MS (70 eV, EI) m/z (%): 309 (M+,
<1), 225 (100), 91 (13). HRMS (70 eV): calcd for C21H27NO (M+),
309.2093; found, 309.2080. IR (neat): 3418, 2935, 2398, 1640,
1603, 1495, 1453, 1414, 1380 cm-1. Rf ) 0.39 (hexane/EtOAc 10:
1). Anal. Calcd for C21H27NO: C, 81.51; H, 8.79; N, 4.53; O, 5.17.
Found: C, 81.37; H, 8.88; N, 4.58; O, 5.11.
The different reactivity, of aminoepoxides 1 with organo-
lithium reagents depending on which solvent was used (Et2O
or THF) could be explained taking into account that in THF,
which is a more strongly coordinating solvent than Et2O, an
enhancement of the basicity of the organolithium reagent is
produced. So, the organolithium reagent in THF produced the
lithiation of the oxirane ring9 instead the ring opening which
took place in Et2O.
Similarly, when the reaction of 1 was carried out with LiAlH4
or LiAlD4 the nucleophilic attack of the hydride or deuteride at
C-3 of the oxirane afforded the corresponding alcoholate
(Scheme 5, 13, R2 ) H or D), which (after treatment with an
aqueous saturated solution of NH4Cl) afforded enantiopure
3-aminoalkan-2-ols 6 or 3-amino-1-deuterioalkan-2-ols 8.
(2S,3S)-3-(Dibenzylamino)-1-phenylbutan-2-ol (4c): colorless
1
oil. [R]25 ) +1.7 (c 1.64, CHCl3). H NMR (200 MHz, CDCl3):
D
δ 7.34-7.25 (m, 15 H), 4.62 (br s, 1 H), 3.88 (d, J ) 13.3 Hz, 2
H), 3.78 (ddd, J ) 9.0, 8.6, 2.7 Hz, 1 H), 3.36 (d, J ) 13.3 Hz, 2
H), 2.89 (dd, d, J ) 13.7, 2.7 Hz, 1 H), 2.68 (dq, J ) 9.0, 6.6 Hz,
1 H), 2.48 (dd, J ) 13.7, 9.0 Hz, 1 H), 1.14 (d, J ) 6.6 Hz, 3 H).
(16) These previous ring openings of the aminoepoxides 1 or 2 with
other nucleophiles (ketones, nitriles, and carboxylic acids) were carried out
in the presence of BF3‚Et2O.
J. Org. Chem, Vol. 71, No. 17, 2006 6423

Concello´n et al.
13C NMR (50 MHz, CDCl3): δ 138.6 (3 × C), 129.2 (2 × CH),
128.9 (4 × CH), 128.4 (4 × CH), 128.1 (2 × CH), 127.1 (2 ×
CH), 125.9 (CH), 71.8 (CH), 57.9 (CH), 53.1 (2 × CH2), 40.0
(CH2), 8.2 (CH3). MS (70 eV, EI) m/z (%): 345 (M+, <1), 224
(100), 181 (14), 91 (42), 69 (16). HRMS (70 eV): calcd for C24H27-
NO (M+), 345.2093; found, 345.2100. IR (neat): 3397, 3028, 2363,
1603, 1495, 1454, 1378 cm-1. Rf ) 0.34 (hexane/EtOAc 10:1).
Anal. Calcd for C24H27NO: C, 83.44; H, 7.88; N, 4.05; O, 4.63.
Found: C, 83.55; H, 7.79; N, 4.00; O, 4.69.
(3S,4S)-4-(Dibenzylamino)-6-methylheptan-3-ol (4d): colorless
oil. [R]25D ) +26.7 (c 1.35, CHCl3). 1H NMR (200 MHz, CDCl3):
δ 7.31-7.22 (m, 10 H), 3.89 (d, J ) 13.3 Hz, 2 H), 3.45 (d, J )
13.3 Hz, 2 H), 3.44-3.39 (m, 1 H), 2.53 (ddd, J ) 9.1, 6.4, 4.4
Hz, 1 H), 1.81-1.52 (m, 3 H), 1.30-1.14 (m, 2 H), 0.98 (d, J )
6.3 Hz, 6 H), 0.96 (t, J ) 7.3 Hz, 3 H). 13C NMR (50 MHz,
CDCl3): δ 139.1 (2 × C), 130.0 (4 × CH), 128.4 (4 × CH), 127.1
(2 × CH), 72.3 (CH), 60.4 (CH), 53.7 (2 × CH2), 35.6 (CH2),
26.6 (CH2 and CH), 23.3 (CH3), 22.9 (CH3), 10.2 (CH3). MS (70
eV, EI) m/z (%): 307 (M+ - H2O, 2), 251 (71), 69 (100), 57 (74).
HRMS (70 eV) calcd for C22H29N (M+ - H2O), 307.2300; found,
307.2327. IR (neat): 3422, 2957, 2350, 1603, 1495, 1454, 1368
cm-1. Rf ) 0.32 (hexane/EtOAc 10:1). Anal. Calcd for C22H31NO:
C, 81.18; H, 9.60; N, 4.30; O, 4.92. Found: C, 81.03; H, 9.71; N,
4.34; O, 4.86.
(16). HRMS (70 eV): calcd for C25H29NO (M+), 359.2249; found,
359.2228. IR (neat): 3421, 3027, 2350, 1602, 1495, 1454, 1374
cm-1. Rf ) 0.32 (hexane/EtOAc 10:1). Anal. Calcd for C25H29NO:
C, 83.52; H, 8.13; N, 3.90; O, 4.45. Found: C, 83.66; H, 8.21; N,
3.95; O, 4.40.
(2S,3S)-2-(Dibenzylamino)-1-phenylhept-6-en-3-ol (4h): color-
1
less oil. [R]25 ) +25.4 (c 1.39, CHCl3). H NMR (200 MHz,
D
CDCl3): δ 7.41-7.29 (m, 15 H), 5.78 (dt, J ) 16.9, 11.0, 6.8 Hz,
1 H), 5.02-4.92 (m, 2 H), 4.51 (br s, 1 H), 3.98 (d, J ) 13.3 Hz,
2 H), 3.68 (dt, J ) 8.8, 2.7 Hz, 1 H), 3.48 (d, J ) 13.3 Hz, 2 H),
3.17 (dd, J ) 13.9, 6.3 Hz, 1 H), 2.96 (ddd, J ) 8.8, 6.3, 6.1 Hz,
1 H), 2.74 (dd, J ) 13.9, 6.1 Hz, 1 H), 2.19-2.07 (m, 2 H), 1.65-
1.48 (m, 1 H), 1.35-1.14 (m, 1 H). 13C NMR (50 MHz, CDCl3):
δ 140.3 (C), 138.7 (2 × C), 138.6 (CH), 129.1 (2 × CH), 128.9 (4
× CH), 128.5 (2 × CH), 128.3 (4 × CH), 127.1 (2 × CH), 126.1
(CH), 114.3 (CH2), 69.7 (CH), 63.7 (CH), 53.7 (2 × CH2), 33.5
(CH2), 32.3 (CH2), 29.7 (CH2). MS (70 eV, EI) m/z (%): 385 (M+,
2), 301 (100), 295 (19), 250 (33), 181 (17). HRMS (70 eV): calcd
for C27H31NO (M+), 385.2406; found, 385.2395. IR (neat): 3417,
3027, 2924, 2349, 1602, 1495, 1454, 1375 cm-1. Rf ) 0.35 (hexane/
EtOAc 10:1). Anal. Calcd for C27H31NO: C, 84.11; H, 8.10; N,
3.63; O, 4.15. Found: C, 84.23; H, 8.03; N, 3.59; O, 4.21.
(2S,3S)-3-(Dibenzylamino)-1,4-diphenylbutan-2-ol (4i): color-
less oil. [R]25 ) +4.7 (c 1.43, CHCl3). 1H NMR (200 MHz,
D
CDCl3): δ 7.42-7.12 (m, 20 H), 3.99 (d, J ) 13.3 Hz, 2 H), 3.87
(dt, J ) 8.2, 2.7 Hz, 1 H), 3.43 (d, J ) 13.3 Hz, 2 H), 3.19 (dd, J
) 13.1, 5.9 Hz, 1 H), 2.99 (dt, J ) 8.2, 6.3 Hz, 1 H), 2.86 (dd, J
) 13.1, 6.5 Hz, 1 H), 2.74 (dd, J ) 14.1, 2.4 Hz, 1 H), 2.48 (dd,
J ) 14.1, 8.6 Hz, 1 H). 13C NMR (50 MHz, CDCl3): δ 140.3 (C),
139.1 (C), 138.8 (2 × C), 129.2 (2 × CH), 129.0 (5 × CH), 128.6
(2 × CH), 128.3 (5 × CH), 128.1 (2 × CH), 127.1 (2 × CH),
126.2 (CH), 126.0 (CH), 71.5 (CH), 63.4 (CH), 54.0 (2 × CH2),
40.8 (CH2), 32.3 (CH2). MS (70 eV, EI) m/z (%): 421 (M+, <1),
330 (100), 300 (78), 210 (24). HRMS (70 eV): calcd for C30H31-
NO (M+), 421.2406; found, 421.2412. IR (neat): 3421, 3026, 2343,
1602, 1495, 1454, 1367 cm-1. Rf ) 0.32 (hexane/EtOAc 10:1).
Anal. Calcd for C30H31NO: C, 85.47; H, 7.41; N, 3.32; O, 3.80.
Found: C, 85.58; H, 7.50; N, 3.26; O, 3.75.
(5S,6S)-6-(Dibenzylamino)-8-methylnon-1-en-5-ol (4e): color-
1
less oil. [R]25 ) +10.2 (c 2.14, CHCl3). H NMR (300 MHz,
D
CDCl3): δ 7.36-7.24 (m, 10 H), 5.86 (ddt, J ) 17.1, 10.2, 6.7
Hz, 1 H), 5.04 (dd, J ) 17.1, 2.0 Hz, 1 H), 4.76 (dd, J ) 10.2, 2.0
Hz, 1 H), 4.54 (br s, 1 H), 3.89 (d, J ) 13.4 Hz, 2 H), 3.51 (dt, J
) 9.0, 2.3 Hz, 1 H), 3.46 (d, J ) 13.4 Hz, 2 H), 2.54 (ddd, J )
9.0, 6.2, 4.7 Hz, 1 H), 2.35-2.23 (m, 1 H), 2.20-2.08 (m, 1 H),
1.81-1.72 (m, 1 H), 1.65-1.55 (m, 2 H), 1.37-1.22 (m, 2 H),
1.00 (d, J ) 6.5 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ 139.0
(2 × C), 138.7 (CH), 128.9 (4 × CH), 128.3 (4 × CH), 127.1 (2
× CH), 114.3 (CH2), 70.5 (CH), 60.7 (CH), 53.7 (2 × CH2), 35.5
(CH2), 33.3 (CH2), 30.2 (CH2), 26.6 (CH), 23.3 (CH3), 22.9 (CH3).
MS (70 eV, EI) m/z (%): 351 (M+, <1), 266 (100). HRMS (70
eV): calcd for C24H33NO (M+), 351.2562; found, 351.2558. IR
(neat): 3426, 2955, 2360, 1603, 1495, 1454, 1368 cm-1. Rf ) 0.42
(hexane/EtOAc 10:1). Anal. Calcd for C24H33NO: C, 82.00; H,
9.46; N, 3.98; O, 4.55. Found: C, 81.85; H, 9.38; N, 4.03; O, 4.61.
(2S,3S)-3-(Dibenzylamino)-5-methyl-1-phenylhexan-2-ol (4f):
colorless oil. [R]25D ) -25.1 (c 0.98, CHCl3). 1H NMR (200 MHz,
CDCl3): δ 7.33-7.20 (m, 15 H), 4.42 (br s, 1 H), 3.92 (d, J )
13.3 Hz, 2 H), 3.75 (dt, J ) 9.0, 2.3 Hz, 1 H), 3.49 (d, J ) 13.3
Hz, 2 H), 2.85 (dd, J ) 13.9, 2.3 Hz, 1 H), 2.69-2.59 (m, 1 H),
2.50 (dd, J ) 13.9, 9.0 Hz, 1 H), 1.90-1.61 (m, 2 H), 1.41-1.29
(2S,3R)-2-(Dibenzylamino)pentan-3-ol (5a): colorless oil. [R]25
D
) +33.0 (c 1.26, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.25-
7.12 (m, 10 H), 3.66 (d, J ) 13.8 Hz, 2 H), 3.45-3.40 (m, 1 H),
3.37 (d, J ) 13.8 Hz, 2 H), 2.61 (apparent qt, J ) 6.6 Hz, 1 H),
1.70-1.63 (m, 1 H), 1.25-1.18 (m, 1 H), 1.01 (d, J ) 6.8 Hz, 3
H), 0.76 (d, J ) 7.4 Hz, 3 H). 13C NMR (50 MHz, CDCl3): δ
140.1 (2 × C), 128.7 (4 × CH), 128.2 (4 × CH), 126.8 (2 × CH),
75.2 (CH), 57.0 (CH), 54.7 (2 × CH2), 27.1 (CH2), 10.3 (CH3),
8.6 (CH3). HRMS (70 eV): calcd for C18H22NO (M+ - CH3),
268.1701; found, 268.1689. IR (neat): 3396, 2963, 2359, 102, 1494,
1453, 1377 cm-1. Rf ) 0.40 (hexane/EtOAc 5:1). Anal. Calcd for
C19H25NO: C, 80.52; H, 8.89; N, 4.94; O, 5.65. Found: C, 80.39;
H, 8.80; N, 5.00; O, 5.71.
(m, 1 H), 0.99 (d, J ) 6.3 Hz, 3 H), 0.98 (d, J ) 6.3 Hz, 3 H). 13
C
NMR (75 MHz, CDCl3): δ 139.2 (C), 139.1 (2 × C), 129.2 (2 ×
CH), 129.0 (4 × CH), 128.4 (4 × CH), 128.2 (2 × CH), 127.1 (2
× CH), 126.0 (CH), 72.3 (CH), 60.4 (CH), 54.0 (2 × CH2), 40.6
(CH2), 35.9 (CH2), 26.6 (CH), 23.1 (2 × CH3). MS (70 eV, EI)
m/z (%): 443 (42), 387 (M+, 2), 181 (100), 175 (33), 169 (33).
HRMS (70 eV): calcd for C27H33NO (M+), 387.2562; found,
387.2581. IR (neat): 3422, 2955, 2357, 1602, 1495, 1454, 1367
cm-1. Rf ) 0.40 (hexane/EtOAc 20:1). Anal. Calcd for C27H33NO:
C, 83.68; H, 8.58; N, 3.61; O, 4.13. Found: C, 83.81; H, 8.69; N,
3.57; O, 4.19.
(2S,3R)-2-(Dibenzylamino)hept-6-en-3-ol (5b): colorless oil.
1
[R]25 ) +40.8 (c 1.05, CHCl3). H NMR (200 MHz, CDCl3): δ
D
7.42-7.25 (m, 10 H), 5.87 (ddt, J ) 17.1, 10.3, 6.7 Hz, 1 H), 5.11-
4.97 (m, 2 H), 3.82 (d, J ) 14.0 Hz, 2 H), 3.65 (apparent t, J )
6.7 Hz, 1 H), 3.50 (d, J ) 14.0 Hz, 2 H), 2.77 (apparent qt, J )
6.7 Hz, 1 H), 2.24-1.82 (m, 2 H), 1.52-1.31 (m, 2 H), 1.17 (d, J
) 6.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 139.9 (2 × C),
138.7 (CH), 128.8 (4 × CH), 128.3 (4 × CH), 126.8 (2 × CH),
114.6 (CH2), 73.0 (CH), 57.1 (CH), 54.6 (2 × CH2), 33.3 (CH2),
30.1 (CH2), 8.5 (CH3). MS (70 eV, EI) m/z (%): 309 (M+, 1), 224
(100). HRMS (70 eV): calcd for C21H27NO (M+), 309.2093; found,
309.2094. IR (neat): 3386, 2923, 2347, 1602, 1494, 1453, 1376
cm-1. Rf ) 0.20 (hexane/EtOAc 10:1). Anal. Calcd for C21H27NO:
C, 81.51; H, 8.79; N, 4.53; O, 5.17. Found: C, 81.62; H, 8.71; N,
4.57; O, 5.22.
(2S,3S)-2-(Dibenzylamino)-1-phenylpentan-3-ol (4g): colorless
oil. [R]25D ) +23.4 (c 1.49, CHCl3). 1H NMR (200 MHz, CDCl3):
δ 7.36-7.27 (m, 15 H), 4.51 (br s, 1 H), 3.96 (d, J ) 13.3 Hz, 2
H), 3.59 (dt, J ) 8.3, 2.4 Hz, 1 H), 3.42 (d, J ) 13.3 Hz, 2 H),
3.14 (dd, J ) 14.1, 6.3 Hz, 1 H), 2.99-2.89 (m, 1 H), 2.72 (dd, J
) 14.1, 5.9 Hz, 1 H), 1.58-1.43 (m, 1 H), 1.20-1.09 (m, 1 H),
0.86 (t, J ) 7.2 Hz, 3 H). 13C NMR (50 MHz, CDCl3): δ 140.5
(C), 138.7 (2 × C), 129.1 (2 × CH), 129.0 (4 × CH), 128.5 (2 ×
CH), 128.4 (4 × CH), 127.2 (2 × CH), 126.2 (CH), 71.4 (CH),
63.5 (CH), 53.8 (2 × CH2), 32.4 (CH2), 26.9 (CH2), 9.7 (CH3).
MS (70 eV, EI) m/z (%): 359 (M+, 1), 300 (100), 268 (15), 181
(2R,3S)-3-(Dibenzylamino)-1-phenylbutan-2-ol (5c): colorless
oil. [R]25D ) +11.1 (c 0.90, CHCl3). 1H NMR (200 MHz, CDCl3):
δ 7.51-7.20 (m, 15 H), 3.92 (d, J ) 13.7 Hz, 2 H), 3.85-3.73 (m,
6424 J. Org. Chem., Vol. 71, No. 17, 2006

Enantiopure (RS,âS)- or (RR,âS)-â-Amino Alcohols
1 H), 3.60 (d, J ) 13.7 Hz, 2 H), 3.42 (dd, J ) 13.7, 3.1 Hz, 1 H),
2.87 (apparent qt, J ) 6.8 Hz, 1 H), 2.43 (dd, J ) 13.7, 9.8 Hz, 1
H), 1.84, (br s, 1 H), 1.28 (d, J ) 6.7 Hz, 3 H). 13C NMR (50
MHz, CDCl3): δ 140.0 (2 × C), 139.3 (C), 129.2 (2 × CH), 128.7
(4 × CH), 128.4 (2 × CH), 128.2 (4 × CH), 126.8 (2 × CH),
126.2 (CH), 74.6 (CH), 51.2 (CH), 54.5 (2 × CH2), 41.4 (CH2),
8.5 (CH3). MS (70 eV, EI) m/z (%): 345 (M+, 1), 224 (100). HRMS
(70 eV): calcd for C24H27NO (M+), 345.2093; found, 345.2102.
IR (neat): 3419, 3027, 2352, 1602, 1494, 1453, 1377 cm-1. Rf )
0.26 (hexane/EtOAc 10:1). Anal. Calcd for C24H27NO: C, 83.44;
H, 7.88; N, 4.05; O, 4.63. Found: C, 83.58; H, 7.79; N, 4.10; O,
4.58.
(CH2), 10.8 (CH3). MS (70 eV, EI) m/z (%): 359 (M+, <1), 300
(28), 91 (24), 69 (100). HRMS (70 eV): calcd for C25H29NO (M+),
359.2249; found, 359.2244. IR (neat): 3427, 2929, 2360, 1602,
1494, 1454, 1365 cm-1. Rf ) 0.13 (hexane/EtOAc 10:1). Anal.
Calcd for C25H29NO: C, 83.52; H, 8.13; N, 3.90; O, 4.45. Found:
C, 83.67; H, 8.21; N, 3.95; O, 4.51.
(2S,3R)-2-(Dibenzylamino)-1-phenylhept-6-en-3-ol (5h): color-
1
less oil. [R]25 ) +17.4 (c 1.34, CHCl3). H NMR (300 MHz,
D
CDCl3): δ 7.26-7.10 (m, 15 H), 5.73 (ddt, J ) 17.1, 10.2, 6.7
Hz, 1 H), 4.98-4.88 (m, 2 H), 3.75-3.63 (m, 4 H), 3.57 (d, J )
13.7 Hz, 2 H), 3.07-2.94 (m, 2 H), 2.74 (dd, J ) 12.4, 5.7 Hz, 1
H), 2.19-2.09 (m, 1 H), 2.01-1.89 (m, 1 H), 1.74-1.64 (m, 1 H),
1.44-1.35 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ 140.4 (C),
139.6 (2 × C), 138.3 (CH), 129.2 (2 × CH), 128.7 (4 × CH),
128.2 (2 × CH), 128.1 (4 × CH), 126.9 (2 × CH), 125.9 (CH),
114.8 (CH2), 71.0 (CH), 63.2 (CH), 55.0 (2 × CH2), 33.7 (CH2),
31.9 (CH2), 30.5 (CH2). MS (70 eV, EI) m/z (%): 385 (M+, <1),
300 (100), 301 (27). HRMS (70 eV): calcd for C27H31NO (M+),
385.2406; found, 385.2381. IR (neat): 3432, 3026, 2360, 1602,
1494, 1453, 1364 cm-1. Rf ) 0.16 (hexane/EtOAc 10:1). Anal.
Calcd for C27H31NO: C, 84.11; H, 8.10; N, 3.63; O, 4.15. Found:
C, 84.28; H, 8.01; N, 3.58; O, 4.21.
(3R,4S)-4-(Dibenzylamino)-6-methylheptan-3-ol (5d): colorless
1
oil. [R]25 ) +1.5 (c 1.13, CHCl3). H NMR (200 MHz, CDCl3):
D
δ 7.37-7.26 (m, 10 H), 3.70 (AB syst., J ) 14.5 Hz, 4 H), 3.66-
3.61 (m, 1 H), 2.80-2.72 (m, 1 H), 1.87-1.04 (m, 5 H), 0.97 (t,
J ) 7.8 Hz, 3 H), 0.95 (d, J ) 6.7 Hz, 3 H), 0.76 (d, J ) 6.7 Hz,
3 H). 13C NMR (50 MHz, CDCl3): δ 140.2 (2 × C), 128.9 (4 ×
CH), 128.2 (4 × CH), 126.9 (2 × CH), 72.2 (CH), 58.1 (CH),
55.0 (2 × CH2), 34.4 (CH2), 27.5 (CH2), 24.7 (CH), 23.1 (CH3),
22.7 (CH3), 11.1 (CH3). MS (70 eV, EI) m/z (%): 310 (M+
-
CH3, <1), 266 (46), 91 (100). HRMS (70 eV): calcd for C21H28-
NO (M+ - CH3), 310.2171; found, 31.2169. IR (neat): 3448, 2956,
2350, 1494, 1455, 1364 cm-1. Rf ) 0.26 (hexane/EtOAc 10:1).
Anal. Calcd for C22H31NO: C, 81.18; H, 9.60; N, 4.30; O, 4.92.
Found: C, 81.36; H, 9.51; N, 4.34; O, 4.87.
(2S,3R)-3-(Dibenzylamino)-1,4-diphenylbutan-2-ol (5i): white
solid. [R]25 ) -5.7 (c 1.71, CHCl3). 1H NMR (300 MHz,
D
CDCl3): δ 7.29-7.02 (m, 20 H), 4.01-3.97 (m, 1 H), 3.65 (AB
syst., J ) 15.0 Hz, 4 H), 3.09-3.00 (m, 2 H), 2.96 (dd, J ) 13.6,
3.8 Hz, 1 H), 2.89 (dd, J ) 10.9, 3.1 Hz, 1 H), 2.44 (dd, J ) 13.6,
9.8 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ 140.7 (C), 139.7
(C), 138.9 (2 × C), 129.4 (2 × CH), 129.2 (2 × CH), 128.7 (4 ×
CH), 128.5 (2 × CH), 128.2 (2 × CH), 128.1 (4 × CH), 126.8 (2
× CH), 126.3 (CH), 125.8 (CH), 72.9 (CH), 62.8 (CH), 54.8 (2 ×
CH2), 41.9 (CH2), 32.0 (CH2). HRMS (70 eV): calcd for C30H31-
NO (M+) 421.2406; found, 421.2413. IR (neat): 3420, 3028, 2359,
1602, 1494, 1454, 1364 cm-1. Rf ) 0.17 (hexane/EtOAc 10:1).
Anal. Calcd for C30H31NO: C, 85.47; H, 7.41; N, 3.32; O, 3.80.
Found: C, 85.33; H, 7.50; N, 3.26; O, 3.86.
(5R,6S)-6-(Dibenzylamino)-8-methylnon-1-en-5-ol (5e): white
solid. [R]25 ) +0.2 (c 2.31, CHCl3). 1H NMR (300 MHz,
D
CDCl3): δ 7.25-7.15 (m, 10 H), 5.74 (ddt, J ) 17.2, 10.2, 6.6
Hz, 1 H), 5.00-4.93 (m, 1 H), 4.92-4.87 (m, 1 H), 3.70-3.63
(m, 1 H), 3.58 (s, 4 H), 2.66 (dt, J ) 7.0, 4.0 Hz, 1 H), 2.25-2.08
(m, 2 H), 2.05-1.92 (m, 1 H), 1.75-1.62 (m, 1 H), 1.57-1.33
(m, 3 H), 1.25-1.13 (m, 1 H), 0.84 (d, J ) 6.7 Hz, 3 H), 0.68 (d,
J ) 6.5, 3 H). 13C NMR (75 MHz, CDCl3): δ 140.0 (2 × C),
138.4 (CH), 128.9 (4 × CH), 128.2 (4 × CH), 127.0 (2 × CH),
114.8 (CH2), 70.0 (CH), 58.5 (CH), 55.1 (2 × CH2), 34.4 (CH2),
33.6 (CH2), 30.8 (CH2), 24.7 (CH), 22.9 (CH3), 22.8 (CH3). MS
(70 eV, EI) m/z (%): 351 (M+, <1), 266 (55), 91 (36), 69 (100).
HRMS (70 eV): calcd for C24H33NO (M+), 351.2562; found,
351.2553. IR (neat): 3387, 2952, 2361, 1603, 1494, 1453, 1367
cm-1. Rf ) 0.29 (hexane/EtOAc 10:1). Anal. Calcd for C24H33NO:
C, 82.00; H, 9.46; N, 3.98; O, 4.55. Found: C, 81.86; H, 9.58; N,
3.93; O, 4.61.
General Procedure of Synthesis of Compounds 6, 7, 8, and
9. To a stirred solution of the corresponding aminoepoxide 1 or 2
(0.2 mmol) in THF (1 mL), LiAlH4 or LiAlD4 (0.3 mmol, 0.3 mL,
1 M in THF) was added at 0 °C. After stirring at this temperature
for 2 h, an aqueous saturated solution of NH4Cl (5 mL) was added,
and the mixture was stirred at room temperature for 5 min. Then,
the aqueous phase was extracted with diethyl ether (3 × 5 mL),
and the combined organic layers were dried over anhydrous Na2-
SO4, filtered, and concentrated in vacuo. Flash column chroma-
tography on silica gel (hexane/EtOAc 10:1) provided pure com-
pounds 6, 7, 8, or 9.
(2R,3S)-3-(Dibenzylamino)-5-methyl-1-phenylhexan-2-ol (5f):
white solid. [R]25D ) -38.0 (c 1.25, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.41-7.20 (m, 15 H), 4.19-4.14 (m, 1 H), 3.82 (d, J
) 13.7 Hz, 2 H), 3.57 (d, J ) 13.7 Hz, 2 H), 2.87 (dd, J ) 13.5,
5.0 Hz, 1 H), 2.77-2.72 (m, 1 H), 2.66 (dd, J ) 13.5, 8.9 Hz, 1
H), 1.99-1.87 (m, 1 H), 1.73 (ddd, J ) 13.9, 8.5, 5.2 Hz, 1 H),
1.34-1.29 (m, 1 H), 0.98 (d, J ) 6.6 Hz, 3 H), 0.67 (d, J ) 6.6
Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 140.2 (2 × C), 138.9
(C), 129.3 (2 × CH), 129.0 (4 × CH), 128.6 (2 × CH), 128.1 (4
× CH), 126.7 (2 × CH), 126.3 (CH), 71.7 (CH), 57.7 (CH), 54.6
(2 × CH2), 42.1 (CH2), 34.6 (CH2), 24.6 (CH), 23.5 (CH3), 22.2
(CH3). MS (70 eV, EI) m/z (%): 387 (M+, 1), 278 (26), 266 (100).
HRMS (70 eV): calcd for C27H33NO (M+), 387.2562; found,
387.2571. IR (neat): 3389, 2948, 2357, 1601, 1493, 1454, 1362
cm-1. Rf ) 0.22 (hexane/EtOAc 10:1). Anal. Calcd for C27H33NO:
C, 83.68; H, 8.58; N, 3.61; O, 4.13. Found: C, 83.56; H, 8.65; N,
3.65; O, 4.09.
(2S,3S)-3-(Dibenzylamino)butan-2-ol (6a): colorless oil. [R]25
D
) +75.0 (c 2.30, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.38-
7.26 (m, 10 H), 4.41 (br s, 1 H), 3.87 (d, J ) 13.3 Hz, 2 H), 3.67
(dq, J ) 9.3, 6.1 Hz, 1 H), 3.36 (d, J ) 13.3 Hz, 2 H), 2.53 (dq,
J ) 9.3, 6.6 Hz, 1 H), 1.12 (d, J ) 6.1 Hz, 3 H), 1.05 (d, J ) 6.6
Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 138.8 (2 × C), 128.9 (4
× CH), 128.5 (4 × CH), 127.1 (2 × CH), 66.9 (CH), 60.2 (CH),
53.3 (2 × CH2), 19.3 (CH3), 7.8 (CH3). MS (70 eV, EI) m/z (%):
251 (M+ - H2O, <1), 224 (92), 91 (100). HRMS (70 eV): calcd
for C18H21N (M+-H2O), 251.1674; found, 251.1702. IR (neat): 3426,
2971, 2351, 1603, 1495, 1453, 1383 cm-1. Rf ) 0.17 (hexane/
EtOAc 10:1). Anal. Calcd for C18H23NO: C, 80.26; H, 8.61; N,
5.20; O, 5.94. Found: C, 80.40; H, 8.52; N, 5.15; O, 5.99.
(2S,3S)-3-(Dibenzylamino)-5-methylhexan-2-ol (6b): colorless
oil. [R]25D ) +60.9 (c 2.18, CHCl3). 1H NMR (300 MHz, CDCl3):
δ 7.38-7.26 (m, 10 H), 4.48 (br s, 1 H), 3.90 (d, J ) 13.4 Hz, 2
H), 3.67 (dq, J ) 9.0, 6.1 Hz, 1 H), 3.47 (d, J ) 13.4 Hz, 2 H),
2.48 (ddd, J ) 9.0, 6.6, 4.4 Hz, 1 H), 1.84-1.77 (m, 1 H), 1.63
(ddd, J ) 14.2, 8.2, 4.4 Hz, 1 H), 1.16 (d, J ) 6.1 Hz, 3 H), 1.08-
1.04 (m, 1 H), 1.02 (d, J ) 6.6 Hz, 6 H). 13C NMR (50 MHz,
CDCl3): δ 139.1 (2 × C), 128.8 (4 × CH), 128.3 (4 × CH), 127.0
(2 × CH), 67.2 (CH), 62.6 (CH), 53.7 (2 × CH2), 35.3 (CH2),
(2S,3R)-2-(Dibenzylamino)-1-phenylpentan-3-ol (5g): colorless
1
oil. [R]25 ) -9.6 (c 1.11, CHCl3). H NMR (300 MHz, CDCl3):
D
δ 7.28-7.05 (m, 15 H), 3.88-3.82 (m, 1 H), 3.67 (d, J ) 13.8 Hz,
2 H), 3.56 (d, J ) 13.8 Hz, 2 H), 3.43-3.32 (m, 1 H), 3.02-2.89
(m, 2 H), 2.70 (dd, J ) 12.6, 5.6 Hz, 1 H), 1.62-1.54 (m, 1 H),
1.35-1.23 (m, 1 H), 0.79 (t, J ) 7.4 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): δ 140.6 (C), 139.7 (2 × C), 129.3 (2 × CH), 128.7 (4 ×
CH), 128.3 (2 × CH), 128.2 (4 × CH), 126.9 (2 × CH), 125.9
(CH), 73.3 (CH), 63.0 (CH), 55.0 (2 × CH2), 31.8 (CH2), 27.6
J. Org. Chem, Vol. 71, No. 17, 2006 6425

Concello´n et al.
26.4 (CH), 23.3 (CH3), 22.8 (CH3), 19.7 (CH3). MS (70 eV, EI)
m/z (%): 311 (M+, <1), 266 (100), 181 (11). HRMS (70 eV): calcd
for C21H29NO (M+), 311.2249; found, 311.2266. IR (neat): 3441,
2956, 2360, 1603, 1495, 1454, 1377 cm-1. Rf ) 0.24 (hexane/
EtOAc 10:1). Anal. Calcd for C21H29NO: C, 80.98; H, 9.38; N,
4.50; O, 5.14. Found: C, 81.15; H, 9.30; N, 4.56; O, 5.08.
Hz, 2 H), 2.40 (dq, J ) 9.4, 6.6 Hz, 1 H), 0.98 (d, J ) 5.9 Hz, 2
H), 0.93 (d, J ) 6.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ
138.9 (2 × C), 128.9 (4 × CH), 128.3 (4 × CH), 127.1 (2 × CH),
66.8 (CH), 60.1 (CH), 53.2 (2 × CH2), 19.0 (t, J ) 76.4 Hz, CH2D),
7.7 (CH3). MS (70 eV, EI) m/z (%): 270 (M+, <1), 224 (84), 91
(100), 69 (27), 58 (43). HRMS (70 eV): calcd for C18H22DNO
(M+), 270.1842; found, 270.1858. IR (neat): 3431, 2969, 2361,
1603, 1495, 1453, 1377 cm-1. Rf ) 0.21 (hexane/EtOAc 10:1).
Anal. Calcd for C18H22DNO: C, 79.96; H, 8.95; N, 5.18; O, 5.92.
Found: C, 79.79; H, 9.03; N, 5.13; O, 5.98.
(2S,3S)-1-Deuterium-3-(dibenzylamino)-4-phenylbutan-2-ol (8c):
white solid. [R]25D ) +35.8 (c 1.97, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.28-7.11 (m, 15 H), 4.27 (br s, 1 H), 3.82 (d, J )
13.3 Hz, 2 H), 3.67 (dt, J ) 8.9, 6.0 Hz, 1 H), 3.30 (d, J ) 13.3
Hz, 2 H), 3.01 (dd, J ) 14.3, 6.3 Hz, 1 H), 2.73 (dt, J ) 8.9, 6.3
Hz, 1 H), 2.58 (dd, J ) 14.3, 6.3 Hz, 1 H), 0.90 (d, J ) 6.0 Hz, 2
H). 13C NMR (75 MHz, CDCl3): δ 140.4 (C), 138.8 (2 × C), 129.1
(2 × CH), 129.0 (4 × CH), 128.5 (2 × CH), 128.4 (4 × CH),
127.2 (2 × CH), 126.1 (CH), 66.5 (CH), 66.0 (CH), 53.8 (2 ×
CH2), 32.1 (CH2), 20.0 (t, J ) 76.4 Hz, CH2D). MS (70 eV, EI)
m/z (%): 346 (M+, <1), 300 (80), 210 (90), 91 (100). HRMS (70
eV): calcd for C24H26DNO (M+), 346.2155; found, 346.2158. IR
(neat): 3407, 3054, 2360, 1603, 1496, 1454, 1374 cm-1. Rf ) 0.22
(hexane/EtOAc 10:1). Anal. Calcd for C24H26DNO: C, 83.19; H,
8.14; N, 4.04; O, 4.62. Found: C, 83.06; H, 8.23; N, 4.08; O, 4.67.
(2S,3S)-3-(Dibenzylamino)-4-phenylbutan-2-ol (6c): white solid.
1
[R]25 ) +49.2 (c 1.60, CHCl3). H NMR (300 MHz, CDCl3): δ
D
7.39-7.26 (m, 15 H), 4.41 (br s, 1 H), 3.96 (d, J ) 13.3 Hz, 2 H),
3.81 (dq, J ) 8.7, 6.0 Hz, 1 H), 3.44 (d, J ) 13.3 Hz, 2 H), 3.14
(dd, J ) 14.2, 6.4 Hz, 1 H), 2.87 (ddd, J ) 8.7, 6.4, 6.3 Hz, 1 H),
2.72 (dd, J ) 14.2, 6.3 Hz, 1 H), 1.06 (d, J ) 6.0 Hz, 3 H). 13C
NMR (75 MHz, CDCl3): δ 140.4 (C), 138.8 (2 × C), 129.1 (2 ×
CH), 128.9 (4 × CH), 128.4 (2 × CH), 128.3 (4 × CH), 127.1 (2
× CH), 126.1 (CH), 66.5 (CH), 65.9 (CH), 53.7 (2 × CH2), 32.1
(CH2), 20.2 (CH3). MS (70 eV, EI) m/z (%): 345 (M+, <1), 300
(100). HRMS (70 eV): calcd for C24H27NO (M+), 345.2093; found,
345.2086. IR (neat): 3361, 3025, 2370, 1602, 1495, 1454, 1378
cm-1. Rf ) 0.20 (hexane/EtOAc 10:1). Anal. Calcd for C24H27NO:
C, 83.44; H, 7.88; N, 4.05; O, 4.63. Found: C, 83.30; H, 7.79; N,
4.10; O, 4.69.
(2R,3S)-3-(Dibenzylamino)butan-2-ol (7a): white solid. [R]25
D
) +78.8 (c 1.46, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.42-
7.27 (m, 10 H),), 3.82 (d, J ) 13.7 Hz, 2 H), 3.50 (d, J ) 13.7 Hz,
2 H), 3.43-3.35 (m, 1 H), 2.68 (apparent qt, J ) 6.7 Hz, 1 H),
2.14 (br s, 1 H), 1.26 (d, J ) 6.4 Hz, 3 H), 1.16 (d, J ) 6.7 Hz, 3
H). 13C NMR (75 MHz, CDCl3): δ 140.0 (2 × C), 128.6 (4 ×
CH), 128.1 (4 × CH), 126.8 (2 × CH), 70.0 (CH), 58.4 (CH),
54.6 (2 × CH2), 21.0 (CH3), 8.5 (CH3). MS (70 eV, EI) m/z (%):
254 (M+ - CH3), <1), 224 (100), 181 (20), 119 (28). HRMS (70
eV): calcd for C17H20NO (M+ - CH3), 254.1545; found, 254.1545.
(2R,3S)-1-Deuterium-3-(dibenzylamino)butan-2-ol (9a): white
solid. [R]25 ) +86.5 (c 0.99, CHCl3). 1H NMR (300 MHz,
D
CDCl3): δ 7.29-7.14 (m, 10 H), 3.69 (d, J ) 14.0 Hz, 2 H), 3.36
(d, J ) 14.0 Hz, 2 H), 3.29-3.22 (m, 1 H), 2.55 (apparent qt, J )
6.7 Hz, 1 H), 1.84 (br s, 1 H), 1.12 (d, J ) 6.2 Hz, 2 H), 1.03 (d,
J ) 6.8 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 140.0 (2 × C),
128.7 (4 × CH), 128.2 (4 × CH), 126.8 (2 × CH), 69.6 (CH),
58.4 (CH), 54.6 (2 × CH2), 20.7 (t, J ) 76.4 Hz, CDH2), 8.5 (CH3).
MS (70 eV, EI) m/z (%): 255 (M+ - CH3, <1), 224 (88), 91 (100).
HRMS (70 eV): calcd for C17H19DNO (M+ - CH3), 255.1608;
found, 255.1615. IR (neat): 3316, 2933, 2360, 1602, 1494, 1452,
1326 cm-1. Rf ) 0.31 (hexane/EtOAc 5:1). Anal. Calcd for C18H22-
DNO: C, 79.96; H, 8.95; N, 5.18; O, 5.92. Found: C, 79.81; H,
89.03; N, 5.14; O, 5.97.
IR (neat): 3262, 3022, 2970, 2356, 1602, 1494, 1453, 1364 cm-1
.
Rf ) 0.44 (hexane/EtOAc 3:1). Anal. Calcd for C18H23NO: C,
80.26; H, 8.61; N, 5.20; O, 5.94. Found: C, 80.42; H, 8.70; N,
5.24; O, 5.89.
(2R,3S)-3-(Dibenzylamino)-5-methylhexan-2-ol (7b): colorless
oil. [R]25D ) +34.2 (c 1.34, CHCl3). 1H NMR (300 MHz, CDCl3):
δ 7.29-7.13 (m, 10 H), 3.87 (dq, J ) 6.6, 4.2 Hz, 1 H), 3.60 (AB
syst., J ) 13.6 Hz, 4 H), 3.63 (ddd, J ) 6.9, 6.8, 4.2 Hz, 1 H),
2.33 (br s, 1 H), 1.76-1.63 (m, 1 H), 1.55-1.46 (m, 1 H), 1.25-
1.16 (m, 1 H), 1.11 (d, J ) 6.6 Hz, 3 H), 0.85 (d, J ) 6.5 Hz, 3
H), 0.71 (d, J ) 6.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ
140.0 (2 × C), 128.9 (4 × CH), 128.2 (4 × CH), 126.9 (2 × CH),
66.5 (CH), 59.1 (CH), 55.1 (2 × CH2), 34.5 (CH2), 24.8 (CH),
22.9 (CH3), 22.8 (CH3), 20.7 (CH3). MS (70 eV, EI) m/z (%): 311
(M+, <1), 266 (100), 91 (31). HRMS (70 eV): calcd for C21H29-
NO (M+), 311.2249; found, 311.2247. IR (neat): 3419, 2955, 2350,
1603, 1494, 1454, 1367 cm-1. Rf ) 0.21 (hexane/EtOAc 10:1).
Anal. Calcd for C21H29NO: C, 80.98; H, 9.38; N, 4.50; O, 5.14.
Found: C, 80.80; H, 9.46; N, 4.44; O, 5.19.
(2R,3S)-3-(Dibenzylamino)-4-phenylbutan-2-ol (7c): colorless
oil. [R]25D ) +13.7 (c 1.52, CHCl3). 1H NMR (300 MHz, CDCl3):
δ 7.25-7.10 (m, 15 H), 3.84-3.80 (m, 1 H), 3.74 (d, J ) 13.8 Hz,
2 H), 3.55 (d, J ) 13.8 Hz, 2 H), 3.02 (dd, J ) 13.3, 6.7 Hz, 1 H),
2.85 (dt, J ) 6.7, 4.8 Hz, 1 H), 2.74 (dd, J ) 13.3, 6.6 Hz, 1 H),
2.18 (br s, 1 H), 1.17 (d, J ) 6.5 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): δ 140.4 (C), 139.5 (2 × C), 129.2 (2 × CH), 128.7 (4 ×
CH), 128.3 (2 × CH), 128.2 (4 × CH), 126.9 (2 × CH), 125.9
(CH), 67.6 (CH), 64.0 (CH), 55.1 (2 × CH2), 32.0 (CH2), 20.9
(CH3). MS (70 eV, EI) m/z (%): 345 (M+, <1), 300 (97), 91 (100).
HRMS (70 eV): calcd for C24H27NO (M+), 345.2093; found,
345.2103. IR (neat): 3418, 3027, 2360, 1602, 1494, 1454, 1372
cm-1. Rf ) 0.37 (hexane/EtOAc 5:1). Anal. Calcd for C24H27NO:
C, 83.44; H, 7.88; N, 4.05; O, 4.63. Found: C, 83.58; H, 7.97; N,
4.00; O, 4.69.
(2R,3S)-1-Deuterium-3-(dibenzylamino)-4-phenylbutan-2-ol
(9c): colorless oil. [R]25D ) +22.5 (c 1.99, CHCl3). 1H NMR (300
MHz, CDCl3): δ 7.28-7.13 (m, 15 H), 3.83 (apparent q, J ) 5.9
Hz, 1 H), 3.75 (d, J ) 13.8 Hz, 2 H), 3.58 (d, J ) 13.8 Hz, 2 H),
3.04 (dd, J ) 13.3, 6.8 Hz, 1 H), 2.94 (dt, J ) 6.7, 4.9 Hz, 1 H),
2.75 (dd, J ) 13.3, 6.6 Hz, 1 H), 2.10 (br s, 1 H), 1.18 (d, J ) 6.5
Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ 140.5 (C), 139.6 (2 ×
C), 129.2 (2 × CH), 128.7 (4 × CH), 128.3 (2 × CH), 128.2 (4 ×
CH), 126.9 (2 × CH), 125.9 (CH), 67.5 (CH), 64.0 (CH), 55.1 (2
× CH2), 32.0 (CH2), 20.6 (t, J ) 76.4 Hz, CH2D). MS (70 eV, EI)
m/z (%): 346 (M+, <1), 300 (32), 208 (27), 91 (100), 69 (41).
HRMS (70 eV): calcd for C24H26DNO (M+), 346.2155; found,
346.2147. IR (neat): 3412, 3027, 2360, 1602, 1494, 1453, 1364
cm-1. Rf ) 0.36 (hexane/EtOAc 5:1). Anal. Calcd for C24H26-
DNO: C, 83.19; H, 8.14; N, 4.04; O, 4.62. Found: C, 83.25; H,
8.07; N, 4.09; O, 4.56.
Acknowledgment. We thank Ministerio de Ciencia y
Tecnolog´ıa (Grant CTQ2004-1191/BQU) for financial support
and Euan Goddard for his revision of the English. J.M.C. thanks
Carmen Ferna´ndez-Flo´rez for her time. V del S. thanks
Principado de Asturias for a contract investigation.
Supporting Information Available: 13C NMR spectra of 4, 5,
6, 7, 8, and 9. This material is available free of charge via the
Internet at http://pubs.acs.org.
(2S,3S)-1-Deuterium-3-(dibenzylamino)butan-2-ol (8a): color-
1
less oil. [R]25 ) +107.3 (c 1.45, CHCl3). H NMR (300 MHz,
D
CDCl3): δ 7.26-7.14 (m, 10 H), 4.27 (br s, 1 H), 3.75 (d, J )
13.3 Hz, 2 H), 3.54 (dt, J ) 9.4, 5.9 Hz, 1 H), 3.23 (d, J ) 13.3
JO0606756
6426 J. Org. Chem., Vol. 71, No. 17, 2006