Total selective synthesis of enantiopure O1-acyl-3-aminoalkane- 1,2-diols by ring opening of aminoepoxides with carboxylic acids

Article abstract of DOI:10.1021/jo0514873

Synthesis of (2R,3S)- or (2S,3S)-O¹-acyl-3-aminoalkane-1,2-diols by ring opening of enantiopure (2R,1′S)- or (2S,1′S)-2-(1- aminoalkyl)epoxides 1 or 2, with carboxylic acids in the presence of BF ₃·Et₂O and chlorotrimethyl

Full text of DOI:10.1021/jo0514873

Total Selective Synthesis of Enantiopure
O1-Acyl-3-aminoalkane-1,2-diols by Ring Opening of
Aminoepoxides with Carboxylic Acids
Jose´ M. Concello´n,* Jose´ Ramo´n Sua´rez, Virginia del Solar, and Ricardo Llavona
Departamento de Quı´mica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo,
Julia´n Claverı´a, 8, 33071 Oviedo, Spain
jmcg@fq.uniovi.es
Received July 18, 2005
Synthesis of (2R,3S)- or (2S,3S)-O1-acyl-3-aminoalkane-1,2-diols by ring opening of enantiopure
(2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides 1 or 2, with carboxylic acids in the presence of
BF3‚Et2O and chlorotrimethylsilane, is described. The conversion takes place with total selectivity
and in good yield. In addition, (2R,3S)-O,O-diacyl-3-aminoalkane-1,2-diols 3 were also prepared
from reaction of (2R,1′S)-2-(1-aminoalkyl)epoxides 1 with carboxylic acids under the same reaction
conditions and without chlorotrimethylsilane. Mechanisms to explain both transformations are
proposed.
Introduction
protected syn and anti (2R,3S)- or (2S,3S)-3-amino-
alkane-1,2-diols in an enantiopure manner are scarce.
Previously, we reported an efficient synthesis of enan-
tiopure (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides by
total stereoselective reduction with LiAlH4 of the easily
available, from natural R-amino acids, R-amino-R′-chlo-
roketones5 or by highly stereoselective addition of in situ
generated iodomethyllithium (from diiodomethane and
methyllithium) to R-amino aldehydes.6
3-Amino-1,2-alkanediols have proved to be valuable
building blocks for the synthesis of various biologically
active molecules such as protease inhibitors,1 glycosph-
ingolipides,2 or polyhydroxylated nitrogen heterocycles.3
A common structural feature of most of these com-
pounds is the absolute S configuration of the carbon
bonded to the amine function, as in natural R-amino
acids, with the absolute configuration of the secondary
carbon bearing the hydroxy group R or S. Accordingly, a
general and efficient method to prepare the diastereo-
isomers (2R,3S)- or (2S,3S)-3-aminoalkane-1,2-diols would
be desirable.
According to these results, we now report a new and
easy methodology to prepare both syn and anti diaste-
reoisomers (2R,3S)- and (2S,3S)-O1-acyl-3-aminoalkane-
(4) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619.
(b) Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J.
Chem. Soc., Perkin Trans. 1 1994, 2373. (c) Pasto´, M.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron: Asymmetry 1995, 6, 2329-2342.
(d) Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron:
Asymmetry 1996, 7, 243-262 and references cited therein. (e) Meunier,
N.; Veith, U.; Ja¨ger, V. J. Chem. Soc., Chem. Commun. 1996, 331-
332. (f) Rayner, C. Synlett 1997, 11-21. (g) Bloch, R. Chem. Rev. 1998,
98, 1407-1438 and references cited therein. (h) Hutin, P.; Larcheveque,
M. Tetrahedron Lett. 2000, 41, 2369-2372. (i) Righi, G.; Chionne, A.;
Bonini, C. Eur. J. Org. Chem. 2000, 3127-3131. (j) Righi, G.; Ronconi,
S.; Bonini, C. Eur. J. Org. Chem. 2002, 1573-1577. (k) Bickley, J. F.;
Roberts, S. M.; Runhui, Y.; Skidmore, J.; Smith, C. B. Tetrahedron
2003, 59, 5731-5736.
Despite the efforts devoted to the synthesis of enan-
tiopure 3-amino-1,2-alkanediols,4 there are no broad
scope methodologies for preparing such compounds.
Especially, the methods to obtain efficiently both mono-
(1) Kempf, D.; Sham, H. Curr. Pharm. Des. 1996, 2, 225-246.
(2) Peterson, M. A.; Polt, R. J. Org. Chem. 1993, 58, 4309-4314 and
references cited therein.
(3) For some syntheses, see: (a) Overhand, M.; Hecht, S. M. J. Org.
Chem. 1994, 59, 4721-4722. (b) Veith, U.; Schwardt, O.; Ja¨ger, V.
Synlett 1996, 1181-1183. (c) Zanardi, F.; Battistini, L.; Nespi, M.;
Rassu, G.; Spanu, P.; Cornia, M.; Casiraghi, G. Tetrahedron: Asym-
metry 1996, 7, 1169-1180. (d) Hu¨mmer, W.; Dubois, E.; Gracza, T.;
Ja¨ger, V. Synthesis 1997, 634-642. (e) Du Bois, J.; Tomooka, C. S.;
Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179-3180.
(5) Barluenga, J.; Baragan˜a, B.; Alonso, A.; Concello´n, J. M. J. Chem.
Soc., Chem. Commun. 1994, 969-970.
(6) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1995,
60, 6696-6699.
10.1021/jo0514873 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/08/2005
10348
J. Org. Chem. 2005, 70, 10348-10353

Synthesis of O1-Acyl-3-aminoalkane-1,2-diols
SCHEME 1. Ring Opening of
SCHEME 2. Synthesis of Aminodiesters 5
(2R,1′S)-2-(1-Dibenzylaminoethyl)epoxide 1 with
H2O
TABLE 2. Synthesis of Aminodiesters 5
TABLE 1. Ring Opening of
R1
R2
yield (%)a
(2R,1′S)-2-(1-Dibenzylaminoethyl)epoxide 1 with H2O
entry
5
T
time
yield
1
2
3
5a
5b
5c
i-Bu
Bn
Me
Me
78
74
70
entry epoxide R1
acid
solvent (°C) (min) 3/4a (%)b
Bn
PhCHdCH
1
2
3
4
5
1a
1a
1a
1c
2c
Me BF3‚Et2O toluene 80 30 3:1 76
Me BF3‚Et2O toluene 25 120 1:3.6 74
Me p-TsOH CH3CN 80
Bn p-TsOH CH3CN 80
Bn p-TsOH CH3CN 80
a Isolated yield after column chromatography based on the
starting aminoepoxide 1.
30 3:2
30 1:1
30 1:1
79
82
84
SCHEME 3. Reduction of 5a
a Relation determined by 1H NMR analysis of the crude
products. b Isolated yield after column chromatography based on
the starting aminoepoxide 1.
1,2-diols in enantiopure form by a selective opening of
the oxirane ring of (2R,1′S)- and (2S,1′S)-2-(1-amino-
alkyl)epoxides with different carboxylic acids in the
presence of BF3‚OEt2 and chlorotrimethylsilane. In ad-
dition, (2R,3S)-O,O-diacyl-3-aminoalkane-1,2-diols were
also obtained by ring opening of (2R,1′S)-2-(1-amino-
alkyl)epoxides with carboxylic acids in the absence of
chlorotrimethylsilane under the same reaction conditions.
Reaction mechanisms have been proposed to justify the
formation of these products.
sential7 to carry out the epoxide ring opening; in the
absence of BF3‚Et2O, unreacted epoxide 1b was fully
recovered after treatment of a solution of 1b in acetoni-
trile with acetic acid during 6 h at reflux temperature.
When the aminoepoxide 1c was treated with a lower
amount of acetic acid (1 equiv instead of 3), a 1:1 mixture
of the diester 5 and the 4-phenyl-3-aminobutane-1,2-diol,
produced by the ring opening of 1c with H2O during the
final hydrolysis of the reaction, was isolated.8 This result
indicates that the esterification reaction of the alkoxide
group generated after the ring opening of the epoxide is
faster than the oxirane ring opening.
The ring-opening reaction of aminoepoxides 1 with
carboxylic acids was totally selective, as shown by the
1H NMR (300 MHz) and 13C NMR spectra of the crude
reaction mixtures, in which no isomers were observed.
Other products such as those derived from the epoxide
ring opening by nitrile were not observed, indicating that
the reaction of nitrile is slower than that with carboxylic
acids.
The structure of compounds 5, as depicted in Scheme
2, was further conformed after reduction of compound
5a with LiAlH4 (Scheme 3). The 1H and 13C NMR spectral
data of the obtained aminodiols 3b were identical to the
same materials prepared by a different method.9
To explain the regio- and stereochemistry of the
reaction of 1 with carboxylic acids, we propose the
mechanism outlined in Scheme 4. After coordination of
the oxirane oxygen with the Lewis acid, a ring opening
Results and Discussion
A conceptually simple approach to (2R,3S)- or (2S,3S)-
3-aminoalkane-1,2-diols would involve the ring opening
of (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides with
H2O. Consequently, initial attempts to obtain (2R,3S)-
3-aminoalkane-1,2-diols 3 were performed by treating a
solution of (2R,1′S)-2-(1-dibenzylaminoethyl)epoxide 1a
in toluene with H2O in the presence of BF3‚Et2O at 80
°C or at room temperature. In both cases, a mixture of
the diastereoisomers (2R,3S)- and (2S,3S)-3-aminobu-
tane-1,2-diol (3:1 and 1:3.6, respectively) was obtained
(Scheme 1, Table 1, entries 1 and 2). Different reaction
conditions were tested to improve this low stereoselec-
tivity. So, a solution of aminoepoxides 1a and 1c in
acetonitrile was allowed to react with H2O in the presence
of p-toluenesulfonic acid (p-TsOH) at reflux temperature;
however, a 3:2 and 1:1 mixture of the same diastereo-
isomersof (2R,3S)- and (2S,3S)-3-aminoalkane-1,2-diols
was again obtained. The same reaction conditions applied
to the anti aminoepoxide 2c also produced a 1:1 mixture
of diastereoisomers (Scheme 1, Table 1).
Synthesis of Enantiopure Aminodiesters 5. As a
consequence of the previous results, another alternative
method to obtain (2R,3S)- or (2S,3S)-3-aminoalkane-1,2-
diols was examined. This is the reaction of the corre-
sponding aminoepoxides 1 or 2 with carboxylic acids and
further deprotection. So, treatment of 1 with a solution
of 3 equiv of acetic or cynnamic acid in acetonitrile in
the presence of BF3‚Et2O at reflux temperature for 6 h
gave the corresponding aminodiester 5 in high yield
(Scheme 2, Table 2). The presence of BF3‚Et2O is es-
(7) To see a recent paper describing the ring opening of amino-
epoxides with nitriles to obtain (2R,3S)- and (2S,3S)-1,3-diaminoal-
kane-2-ols, see: Concello´n, J. M.; Suarez, J. R.; del Solar, V. J. Org.
Chem. 2005, 70, 7447-7450.
(8) The 4-phenyl-3-aminobutane-1,2-diol was obtained as a 1:1
mixture of diastereoisomers according to the described results of the
ring opening of aminoepoxide 1c with H2O.
(9) 3-Aminoalkane-1,2-diols can be obtained by successive reaction
of (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides with ketones in the
presence of BF3‚Et2O and further treatment with HCl: Concello´n, J.
M.; Sua´rez, J. R.; Garc´ıa-Granda, S.; D´ıaz, M. R. Org. Lett. 2005, 7,
247-250.
J. Org. Chem, Vol. 70, No. 25, 2005 10349

Concello´n et al.
SCHEME 6. Synthesis of Chlorohydrine 10b
SCHEME 4. Proposed Mechanism
SCHEME 7. Synthesis of
(2S,3S)-O1-Acyl-3-aminoalkane-1,2-diols 9
TABLE 4. Synthesis of
(2S,3S)-O1-Acyl-3-aminoalkane-1,2-diols 9
yield
(%)b
SCHEME 5. Synthesis of
entry
9
R1
R2
de (%)a
(2R,3S)-O1-Acyl-3-aminoalkane-1,2-diols 8
1
2
3
4
5
6
9a
9b
9c
9d
9e
4f
Me
Me
CH3CH2CHdCH
CH3(CH2)4
Me
CH3(CH2)4
Me
CH3CH2CHdCH
>98 (>98)
>98 (>98)
92 (91)
72
71
66
63
61
60
i-Bu
i-Bu
Bn
89 (91)
90 (92)
Bn
91 (92)
1
a Diastereoisomeric excess determined by H NMR analysis of
the crude products 9; de of the starting aminoepoxides 2 is given
in parentheses. b Isolated yield after column chromatography
based on the starting aminoepoxide 2.
TABLE 3. Synthesis of
(2R,3S)-O1-Acyl-3-aminoalkane-1,2-diols 8
entry
8
R1
R2
yield (%)a
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
Me
CH3(CH2)4
PhCHdCH
Me
CH3(CH2)4
Me
CH3CH2CHdCH
70
73
63
69
71
64
Me
SCHEME 8. Reduction of 8c and 9c
i-Bu
i-Bu
Bn
Bn
a Isolated yield after column chromatography based on the
starting aminoepoxide 1.
at C-3 by nucleophilic attack of the carboxylic acid would
occur. The alcoholate function in intermediate 7 would
react with a second equivalent of carboxylic acid to afford
the diester 5. Therefore, no change in the absolute
configuration of both stereogenic centers takes place
during the reaction.
Synthesis of Enantiopure Aminoesters 8 and 9.
Interestingly, when the ring opening of aminoepoxides
1 was carried out with 1.5 equiv of carboxylic acid and
in the presence of 1.5 equiv of chlorotrimethylsilane (with
BF3‚Et2O at reflux of acetonitrile), (2R,3S)-O1-acyl-3-
aminoalkane-1,2-diols 8 were obtained in good yield and
with total selectivity (Scheme 5, Table 3).
In the absence of BF3‚Et2O, no ring opening of 1 by
the carboxylic acids took place and the oxirane ring
eventually was opened by a chloride anion generated
from chlorotrimethylsilane; so, treatment of 1b with
acetic acid in the presence of chlorotrimethylsilane
(without BF3‚Et2O) afforded (2R,3S)-3-amino-1-chloro-6-
methylhexan-2-ol 10b as a single diastereoisomer. This
transformation could be explained by taking into account
that, after coordination of ClSiMe3 with the oxiranic
oxygen of compounds 1, chloride anions would be gener-
ated and could open the oxirane ring by attacking at C-3,
affording the corresponding chlorohydrine (Scheme 6).
To investigate the scope of the ring opening by car-
boxylic acids in the presence of ClSiMe3, we have submit-
ted the other diastereoisomers, (2S,3S)-2-(1-aminoalkyl)-
epoxides 2, to the same reaction conditions, obtaining the
corresponding (2S,3S)-O1-acyl-3-aminoalkane-1,2-diols 9
in good yield and with total or very high selectivity
(Scheme 7, Table 4).
The selectivity of the reactions was determined by 1H
NMR spectroscopy (300 MHz) of the crude mixture of
products, showing the presence of a single diastereoiso-
mer 8 (from aminoepoxide 1) and a mixture of diastere-
oisomers 9 (from 2) in the same relationship as that of
the starting aminoepoxides 2. The synthesis of amino-
diesters 9 with the same diastereoisomeric excess (de)
as that of the starting aminoepoxides 25 was an indirect
support of the total selectivity of the ring-opening reac-
tion. After purification of compounds 9 by column chro-
matography, the major diastereoisomer was isolated as
a single stereoisomer.
The absolute configuration of aminoesters 8 and 9
was established after reduction of 8c and 9c with LiAlH4
and comparison of the spectroscopic data of the obtained
3b and 4b with that recorded from the same diols
(Scheme 8).8
The regiochemistry of the ester group in compounds 8
1
and 9 was determined by comparison of the H and 13C
10350 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of O1-Acyl-3-aminoalkane-1,2-diols
SCHEME 9. Proposed Mechanism
the presence of BF3‚OEt2 and chlorotrimethylsilane.
When the reaction was carried out in the absence of
chlorotrimethylsilane, (2R,3S)- or (2S,3S)-O,O-diacyl-3-
aminoalkane-1,2-diols were obtained, without epimer-
ization, in high yield. Mechanisms to explain both
transformations are proposed.
Experimental Section
General Procedure for the Synthesis of 5. To a stirred
solution of the corresponding aminoepoxide 1 (0.2 mmol) in
acetonitrile (2 mL) were added BF3‚OEt2 (0.025 mL, 0.2 mmol)
and the corresponding carboxylic acid (3 equiv) at room
temperature. After stirring at 80 °C for 12 h, an aqueous
saturated solution of sodium bicarbonate (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 5. Yields are given in Table 1.
NMR data of diester 5a with the corresponding mono-
ester 8c. The signals of the methine CH-OAc group in
1
the 13C and H NMR spectra of 5a were shifted upfield
(2R,3S)-O,O-Diacetyl-3-dibenzylamino-5-methylhexane-
1
1,2-diol (5a): colorless oil; [R]25 ) -14.3 (c 1.05, CHCl3); H
in the monoacylated derivative 8c (from 72.7 and 5.25
to 62.0 and 3.10 ppm, respectively), which indicates that
the unprotected hydroxyl function in 8c is attached to
this carbon. Opposite to that, the signals of the meth-
ylene CH2-OAc group in compound 5a display shifts
similar to those of 8c. This regiochemistry has also
been confirmed by the HMBC 2D-NMR experiment
performed on 8b, which showed correlation between the
methylene hydrogens of the CH2OCOCHdCHPh and the
carbonyl carbon (CH2OCOCHdCHPh) and no interaction
between the hydrogens of CHOH and the carbonyl
carbon. Consequently, the acylated hydroxy group of 8b
would be the primary alcohol function, and hence, all
these data can support the assigned structures for
compounds 8 and 9.
D
NMR (300 MHz, CDCl3) δ 7.36-7.26 (m, 10 H), 5.27-5.22 (m,
1 H), 4.29 (dd, J ) 11.7, 7.3 Hz, 1 H), 4.12 (dd, J ) 6.8, 4.1
Hz, 1 H), 3.91 (d, J ) 13.3 Hz, 2 H), 3.44 (d, J ) 13.3 Hz, 2 H),
2.92-2.85 (m, 1 H), 2.12 (s, 3 H), 1.93 (s, 3 H), 1.74-1.63 (m,
1 H), 1.53-1.45 (m, 1 H), 1.40-1.29 (m, 1 H), 0.87 (d, J ) 6.6
Hz, 3 H), 0.84 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
δ 170.6 (C), 170.2 (C), 139.9 (2 × C), 129.0 (4 × CH), 128.2 (4
× CH), 126.9 (2 × CH), 72.7 (CH), 64.8 (CH2), 55.0 (2 × CH2),
54.5 (CH), 33.3 (CH2), 24.5 (CH), 23.4 (CH3), 22.1 (CH3), 21.0
(CH3), 20.7 (CH3); MS (70 eV, EI) m/z (%) 411 (M+, <1), 282
(10), 266 (100), 181 (19), 91 (98), 65 (8); HRMS (70 eV) calcd
for C25H33NO4 (M+) 411.2404, found 411.2411; IR (neat) 3027,
2959, 1741, 1493, 1454 cm-1; Rf ) 0.60 (hexane/EtOAc 10:1).
Anal. Calcd for C25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found:
C, 73.08; H, 8.15; N, 3.32.
(2R,3S)-O,O-Diacetyl-3-dibenzylamino-4-phenylbutane-
1
1,2-diol (5b): colorless oil; [R]25 ) -8.7 (c 1.60, CHCl3); H
The reaction seems to be general, and as is shown in
Tables 3 and 4, the opening of the oxirane ring can be
performed by using aliphatic saturated or unsaturated
carboxylic acids with aminoepoxides derived from ala-
nine, phenylalanine, or leucine.
D
NMR (300 MHz, CDCl3) δ 7.38-7.13 (m, 15 H), 5.11-5.06 (m,
1 H), 4.31 (dd, J ) 11.6, 7.3 Hz, 1 H), 4.12 (d, J ) 13.3 Hz, 2
H), 4.04 (dd, J ) 11.6, 4.4 Hz, 1 H), 3.53 (d, J ) 13.3 Hz, 2 H),
3.22-3.10 (m, 2 H), 2.74 (dd, J ) 12.7, 8.9 Hz, 1 H), 2.18 (s, 3
H), 1.85 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.5 (C), 169.1
(C), 139.5 (2 × C), 138.8 (C), 129.1 (2 × CH), 128.9 (4 × CH),
128.5 (2 × CH), 128.2 (4 × CH), 127.0 (2 × CH), 126.2 (CH),
72.3 (CH), 64.4 (CH2), 59.3 (CH), 55.3 (2 × CH2), 30.6 (CH2),
21.1 (CH3), 20.6 (CH3); MS (70 eV, EI) m/z (%) 445 (M+, 5),
354 (100), 300 (88), 294 (47), 181 (28); HRMS (70 eV) calcd for
C28H31NO4 (M+) 445.2253, found 445.2210; IR (neat) 3062,
3028, 2962, 1742, 1494, 1454 cm-1; Rf ) 0.53 (hexane/EtOAc
10:1). Anal. Calcd for C28H31NO4: C, 75.48; H, 7.01; N, 3.14.
Found: C, 75.60; H, 6.95; N, 3.21.
It is noteworthy that the selective monoprotection of
diols is difficult to achieve.10
The formation of compounds 8 or 9 can be explained
by assuming that, after reaction with BF3, the oxi-
rane ring is opened at C-3 by the carboxylic acid with
total selectivity. The alcoholate intermediate 7 would
be silylated by chlorotrimethylsilane affording an ami-
nodiol, 11, with both oxygen atoms protected. The sily-
lated oxygen moiety would be deprotected by the BF3
during the final hydrolysis to afford the final product 8
(Scheme 9).
(2R,3S)-O,O-Dicinamoyl-3-dibenzylamino-4-phenylbu-
tane-1,2-diol (5c): colorless oil; [R]25D ) -10.9 (c 2.10, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.75 (d, J ) 15.9 Hz, 1 H), 7.56-
7.23 (m, 26 H), 6.55 (d, J ) 15.9 Hz, 1 H), 6.22 (d, J ) 15.9
Hz, 1 H), 5.42-5.35 (m, 1 H), 4.59 (dd, J ) 11.5, 7.4 Hz, 1 H),
4.30-4.16 (m, 3 H), 3.62 (d, J ) 13.3 Hz, 2 H), 3.32-3.23 (m,
2 H), 2.85 (dd, J ) 14.1, 10.5 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 166.2 (C), 165.8 (C), 145.6 (CH), 144.6 (CH), 139.6
(2 × C), 139.0 (C), 134.3 (C), 134.0 (C), 130.4 (CH), 130.1 (CH),
129.3, 128.9, 128.7, 128.6, 128.5, 128.3, 128.1, 127.9 (20 × CH),
127.1 (2 × CH), 126.2 (CH), 117.7 (CH), 117.5 (CH), 72.2 (CH),
64.5 (CH2), 59.6 (CH), 55.6 (2 × CH2), 30.8 (CH2); MS (70 eV,
EI) m/z (%) 530 (M+ - C7H7, 5), 300 (31), 181 (54), 170 (50),
Conclusions
We have described an easy synthesis of (2R,3S)- or
(2S,3S)-O1-acyl-3-aminoalkane-1,2-diols in high yield and
with total or very high stereoselectivity by a selective
opening of the oxirane ring of (2R,1′S)- and (2S,1′S)-2-
(1-aminoalkyl)epoxides with different carboxylic acids in
131 (100), 119 (40); HRMS (70 eV) calcd for C35H32NO4 (M+
-
(10) Previous transformations of the N-Boc aminoepoxide derived
from leucine into (2S,3S)-O1-acetyl-3-amino-4-methylpentane-1,2-diol
have been described: Ohmoto, K.; Okuma, M.; Yamamoto, T.; Kijima,
H.; Sekioka, T.; Kitagawa, K.; Yamamoto, S.; Tanaka, K.; Kawabata,
K.; Sakata, A.; Imawaka, H.; Nakai, H.; Toda, M. Bioorg. Med. Chem.
2001, 9, 1307-1323.
C7H7) 530.2331, found 530.2355; IR (neat) 3062, 3028, 2956,
1714, 1634, 1495, 1451 cm-1; Rf ) 0.65 (hexane/EtOAc 10:1).
Anal. Calcd for C42H39NO4: C, 81.13; H, 6.32; N, 2.25. Found:
C, 81.26; H, 6.41; N, 2.16.
J. Org. Chem, Vol. 70, No. 25, 2005 10351

Concello´n et al.
General Procedure for the Synthesis of Compounds
8 and 9. To a stirred solution of the corresponding amino-
epoxide 1 or 2 (0.2 mmol) in acetonitrile (2 mL) were added
BF3‚OEt2 (0.025 mL, 0.2 mmol), ClSiMe3 (0.03 mL, 0.22 mmol),
and the corresponding carboxylic acid (1.5 equiv) at room
temperature. After stirring at 80 °C for 12 h, an aqueous
saturated solution of sodium bicarbonate (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 8 and 9. Yields are given in Tables
3 and 4.
407.2813; IR (neat) 3364, 2959, 1740, 1494, 1455 cm-1; Rf )
0.41 (hexane/EtOAc 10:1). Anal. Calcd for C27H39NO3: C, 76.20;
H, 9.24; N, 3.29. Found: C, 76.38; H, 9.14; N, 3.36.
(2R,3S)-O1-Acetyl-3-dibenzylamino-4-phenylbutane-
1
1,2-diol (8e): colorless oil; [R]25 ) +21.1 (c 1.90, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.41-7.22 (m, 15 H), 4.51 (dd, J )
11.6, 7.9 Hz, 1 H), 4.27 (d, J ) 13.5 Hz, 2 H), 3.94-3.87 (m, 1
H), 3.50 (d, J ) 13.5 Hz, 2 H), 3.24-3.14 (m, 4 H), 1.86 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 170.3 (C), 139.3 (2 × C), 138.8
(C), 129.1 (2 × CH), 128.7 (4 × CH), 128.4 (2 × CH), 128.3 (4
× CH), 127.2 (2 × CH), 126.4 (CH), 67.1 (CH2), 61.1 (CH), 60.4
(CH), 55.8 (2 × CH2), 30.9 (CH2), 20.6 (CH3); MS (70 eV, EI)
m/z (%) 385 (M+ - H2O, 3), 330 (100), 300 (46), 270 (14),
181 (8); HRMS (70 eV) calcd for C26H27NO2 (M+ - H2O)
385.2042, found 385.2071; IR (neat): 3434, 3027, 2932, 1743,
1495, 1454 cm-1; Rf ) 0.46 (hexane/EtOAc 10:1). Anal. Calcd
for C26H29NO3: C, 77.39; H, 7.24; N, 3.47. Found: C, 77.53;
H, 7.46; N, 3.32.
(2R,3S)-O1-Hexanoyl-3-dibenzylaminobutane-1,2-di-
1
ol (8a): colorless oil; [R]25 ) -22.2 (c 1.11, CHCl3); H NMR
D
(200 MHz, CDCl3) δ 7.40-7.27 (m, 10 H), 5.23-5.15 (m, 1 H),
3.93 (d, J ) 13.6 Hz, 2 H), 3.78 (dd, J ) 11.8, 7.2 Hz, 1 H),
3.57 (dd, J ) 8.2, 3.6 Hz, 1 H), 3.38 (d, J ) 13.6 Hz, 2 H), 3.11
(dd, J ) 5.4, 1.3 Hz, 1 H), 2.39 (apparent q, J ) 6.9 Hz, 2 H),
1.73-1.63 (m, 2 H), 1.39-1.29 (m, 4 H), 1.12 (d, J ) 6.9 Hz, 3
H), 0.98-0.92 (m 3 H); 13C NMR (50 MHz, CDCl3) δ 173.1 (C),
139.6 (2 × C), 128.8 (4 × CH), 128.2 (4 × CH), 127.0 (2 × CH),
75.8 (CH), 54.6 (2 × CH2), 53.6 (CH), 45.3 (CH2), 34.4 (CH2),
31.2 (CH2), 24.6 (CH2), 22.3 (CH2), 13.9 (CH3), 9.1 (CH3); IR
(neat) 3454, 2956, 2902, 1737, 1494, 1454 cm-1; Rf ) 0.42
(hexane/EtOAc 10:1). Anal. Calcd for C24H33NO3: C, 75.16; H,
8.67; N, 3.65. Found: C, 75.29; H, 8.76; N, 6.57.
(2R,3S)-O1-Penta-2-enoyl-3-dibenzylamino-4-phenyl-
butane-1,2-diol (8f): colorless oil; [R]25 ) +14.5 (c 1.30,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.43-7.24 (m, 15 H),
5.56-5.37 (m, 2 H), 4.55 (dd, J ) 11.6, 7.9 Hz, 1 H), 4.27 (d,
J ) 13.5 Hz, 2 H), 3.95-3.85 (m, 1 H), 3.50 (d, J ) 13.5 Hz, 2
H), 3.22-3.08 (m, 4 H), 2.82 (apparent d, J ) 5.8 Hz, 1 H),
2.22-2.12 (m, 1 H), 1.67 (dd, J ) 6.0, 1.2 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 170.5 (C), 138.4 (2 × C), 137.9 (C), 128.4
(2 × CH), 128.1 (4 × CH), 127.7 (2 × CH), 127.4 (4 × CH),
127.1 (CH), 126.2 (2 × CH), 125.4 (CH), 121.4 (CH), 66.2 (CH2),
60.2 (CH), 59.5 (CH), 54.9 (2 × CH2), 36.6 (CH2), 30.0 (CH2),
16.9 (CH3); MS (70 eV, EI) m/z (%) 333 (M+ - C7H7, 2), 225
(60), 224 (100), 181 (22), 91 (97); HRMS (70 eV) calcd for
C19H43N2S (M+ - C7H7) 321.2359, found 321.2351; IR (neat)
3449, 3027, 2936, 1740, 1602, 1495, 1454 cm-1; Rf ) 0.47
(hexane/EtOAc 10:1).
(2R,3S)-O1-(3-Phenylpropenoyl)-3-dibenzylaminobu-
tane-1,2-diol (8b): colorless oil; [R]25D ) -12.3 (c 1.01, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.64 (d, J ) 16.0 Hz, 1 H), 7.55-
7.28 (m, 15 H), 6.39 (d, J ) 16.0 Hz, 1 H), 4.42 (dd, J ) 11.8,
2.3 Hz, 1 H), 4.11 (dd, J ) 11.8, 5.4 Hz, 1 H), 3.90 (d, J ) 13.1
Hz, 2 H), 3.86-3.81 (m, 1 H), 3.40 (d, J ) 13.1 Hz, 2 H), 2.92-
2.83 (m, 1 H), 1.17 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 166.7 (C), 144.8 (CH), 138.4 (2 × C), 134.3 (C), 130.1
(CH), 128.9 (4 × CH), 128.7 (2 × CH), 128.5 (4 × CH), 128.0
(2 × CH), 127.2 (2 × CH), 117.7 (CH), 69.5 (CH), 65.6 (CH2),
54.2 (CH), 53.1 (2 × CH2), 8.2 (CH3); IR (neat) 3403, 3028,
2968, 1712, 1638, 1496, 1451 cm-1; Rf ) 0.44 (hexane/EtOAc
10:1). Anal. Calcd for C27H29NO3: C, 78.04; H, 7.03; N, 3.37.
Found: C, 78.18; H, 7.15; N, 3.29.
(2S,3S)-O1-Penta-2-enoyl-3-dibenzylaminobutane-1,2-
diol (9a): colorless oil; [R]25D ) +33.3 (c 2.76, CHCl3); 1H NMR
(200 MHz, CDCl3) δ 7.41-7.24 (m, 11 H), 5.55-5.51 (m, 1 H),
4.66-4.58 (m, 1 H), 4.17-4.12 (m, 2 H), 3.77 (d, J ) 13.6 Hz,
2 H), 3.44 (d, J ) 13.6 Hz, 2 H), 3.11-2.97 (m, 1 H), 2.90-
2.86 (m, 2 H), 1.71 (d, J ) 5.0 Hz, 3 H), 1.28 (d, J ) 6.7 Hz, 3
H); 13C NMR (50 MHz, CDCl3) δ 171.8 (C), 139.1 (2 × C), 129.4
(CH), 128.8 (4 × CH), 128.3 (4 × CH), 127.1 (2 × CH), 122.4
(CH), 66.0 (CH2), 61.5 (CH), 54.7 (CH), 54.1 (2 × CH2), 37.5
(CH2), 17.9 (CH3), 9.7 (CH3); MS (70 eV, EI) m/z (%) 350 (M+
- OH, 2), 322 (11), 255 (13), 224 (100), 181 (11); HRMS (70
eV) calcd for C23H28NO2 (M+ - OH) 350.2120, found 350.2126;
IR (neat) 3456, 3029, 2969, 1740, 1494, 1453 cm-1; Rf ) 0.39
(hexane/EtOAc 10:1). Anal. Calcd for C23H29NO3: C, 75.17; H,
7.95; N, 3.81. Found: C, 75.32; H, 8.09; N, 3.78.
(2R,3S)-O1-Acetyl-3-dibenzylamino-5-methylhexane-
1
1,2-diol (8c): colorless oil; [R]25 ) -17.1 (c 1.47, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.42-7.27 (m, 10 H), 4.55 (dd, J )
11.6, 6.2 Hz, 1 H), 4.41 (dd, J ) 11.6, 6.2 Hz, 1 H), 4.12 (d, J
) 13.5 Hz, 2 H), 3.62 (d, J ) 13.5 Hz, 2 H), 3.10 (apparent t,
J ) 6.2 Hz, 1 H), 2.13 (s, 3 H), 1.91-1.82 (m, 1 H), 1.73-1.62
(m, 2 H), 1.24-1.25 (m, 1 H), 0.88 (d, J ) 6.6 Hz, 3 H), 0.79
(d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.7 (C),
139.5 (2 × C), 129.1 (4 × CH), 128.1 (4 × CH), 127.0 (2 × CH),
62.0 (CH), 61.7 (CH2), 59.7 (CH), 55.5 (2 × CH2), 44.3 (CH2),
24.8 (CH), 23.1 (CH3), 21.0 (2 × CH3); MS (70 eV, EI) m/z (%)
351 (M+ - H2O, <1), 300 (10), 282 (100), 266 (54), 148 (8);
HRMS (70 eV) calcd for C23H29NO2 (M+ - H2O) 351.2198,
(2S,3S)-O1-Hexanoyl-3-dibenzylaminobutane-1,2-diol
(9b): colorless oil; [R]25 ) +35.3 (c 2.04, CHCl3); 1H NMR
D
(200 MHz, CDCl3) δ 7.35-7.27 (m, 10 H), 4.63-4.50 (m, 1 H),
4.18-4.13 (m, 2 H), 3.64 (d, J ) 13.6 Hz, 2 H), 3.44 (d, J )
13.6 Hz, 2 H), 3.08-2.96 (m, 1 H), 2.16 (apparent t, J ) 6.9
Hz, 1 H), 1.63-1.53 (m, 2 H), 1.49-1.27 (m, 8 H), 0.91 (t, J )
4.9 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ 173.4 (C), 139.2 (2
× C), 128.8 (4 × CH), 128.7 (4 × CH), 127.0 (2 × CH), 66.6
(CH2), 61.6 (CH), 54.7 (CH), 54.1 (2 × CH2), 33.9 (CH2), 31.1
(CH2), 24.3 (CH2), 22.2 (CH2), 13.9 (CH3), 9.7 (CH3); MS (70
eV, EI) m/z (%) 366 (M+ - OH, <1), 339 (13), 338 (45), 225
(12), 224 (100); HRMS (70 eV) calcd for C24H32NO2 (M+ - OH)
366.2433, found 366.2433; IR (neat) 3453, 2957, 2902, 1739,
1495, 1454 cm-1; Rf ) 0.44 (hexane/EtOAc 10:1). Anal. Calcd
for C24H33NO3: C, 75.16; H, 8.67; N, 3.65. Found: C, 75.33;
H, 8.74; N, 6.59.
found 351.2166; IR (neat) 3365, 2957, 1745, 1455, 1369 cm-1
;
Rf ) 0.40 (hexane/EtOAc 10:1). Anal. Calcd for C23H31NO3: C,
74.76; H, 8.46; N, 3.79. Found: C, 74.89; H, 8.31; N, 3.68.
(2R,3S)-O1-Hexanoyl-3-dibenzylamino-5-methylhexane-
1
1,2-diol (8d): colorless oil; [R]25 ) -3.6 (c 1.57, CHCl3); H
D
NMR (200 MHz, CDCl3) δ 7.45-7.23 (m, 10 H), 4.57 (dd, J )
11.5, 5.9 Hz, 1 H), 4.42 (dd, J ) 11.3, 5.9 Hz, 1 H), 4.15 (d, J
) 13.6 Hz, 2 H), 3.62 (d, J ) 13.6 Hz, 2 H), 3.09 (dd, J ) 5.9,
5.1 Hz, 1 H), 2.39 (apparent t, J ) 7.2 Hz, 2 H), 1.86-1.59 (m,
4 H), 1.40-1.19 (m, 6 H), 0.90 (apparent t, J ) 6.5 Hz, 6 H),
0.80 (d, J ) 6.4 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ 173.5
(C), 139.5 (2 × C), 129.1 (4 × CH), 128.1 (4 × CH), 127.0 (2 ×
CH), 62.0 (CH), 61.5 (CH2), 59.8 (CH), 55.5 (2 × CH2), 44.3
(CH2), 34.3 (CH2), 31.2 (CH2), 24.8 (CH), 24.6 (CH2), 23.1 (CH3),
22.2 (CH2), 20.9 (CH3), 13.8 (CH3); MS (70 eV, EI) m/z (%) 407
(M+ - H2O, <1), 338 (67), 267 (44), 181 (100), 148 (8); HRMS
(70 eV) calcd for C27H37NO2 (M+ - H2O) 407.2824, found
(2S,3S)-O1-Acetyl-3-dibenzylamino-5-methylhexane-
1,2-diol (9c): colorless oil; [R]25D ) +11.1 (c 0.85, CHCl3); 1H
NMR (200 MHz, CDCl3) δ 7.41-7.28 (m, 10 H), 4.52-4.49 (m,
2 H), 4.28-4.23 (m, 1 H), 3.78 (AB system, J ) 13.9, 6.0 Hz,
4 H), 3.06 (apparent q, J ) 5.9 Hz, 1 H), 2.14 (s, 3 H), 1.82-
1.62 (m, 2 H), 1.53-1.43 (m, 1 H), 0.91 (d, J ) 2.3 Hz, 3 H),
0.88 (d, J ) 2.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.7
10352 J. Org. Chem., Vol. 70, No. 25, 2005

Synthesis of O1-Acyl-3-aminoalkane-1,2-diols
(C), 139.3 (2 × C), 128.8 (4 × CH), 128.2 (4 × CH), 127.1 (2 ×
CH), 61.6 (CH2), 60.4 (CH), 60.2 (CH), 54.8 (2 × CH), 45.5
(CH2), 25.0 (CH), 23.2 (CH3), 21.1 (CH3), 21.0 (CH3); MS (70
eV, EI) m/z (%) 352 (M+ - OH, <1), 282 (92), 269 (70), 266
(100); HRMS (70 eV) calcd for C23H30NO2 (M+ - OH) 352.2277,
(CH2), 59.5 (CH), 54.7 (2 × CH2), 42.8 (CH2), 21.0 (CH3); MS
(70 eV, EI) m/z (%) 403 (M+, <1), 386 (15), 330 (29), 282 (100);
HRMS (70 eV) calcd for C26H29NO3 (M+) 403.2147, found
403.2161; IR (neat) 3430, 3062, 3028, 1741, 1495, 1454 cm-1
;
Rf ) 0.48 (hexane/EtOAc 10:1). Anal. Calcd for C26H29NO3: C,
found 352.2270; IR (neat) 3364, 2958, 1743, 1454, 1368 cm-1
;
77.39; H, 7.24; N, 3.47. Found: C, 77.50; H, 7.39; N, 3.35.
(2S,3S)-O1-Penta-2-enoyl-3-dibenzylamino-4-phenyl-
Rf ) 0.42 (hexane/EtOAc 10:1). Anal. Calcd for C23H31NO3: C,
butane-1,2-diol (9f): colorless oil. [R]25 ) -5.8 (c 1.80,
74.76; H, 8.46; N, 3.79. Found: C, 74.92; H, 8.35; N, 3.65.
D
(2S,3S)-O1-Hexanoyl-3-dibenzylamino-5-methylhexane-
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.39-7.21 (m, 16 H),
5.68-5.60 (m, 1 H), 4.72-4.51 (m, 2 H), 4.30-4.11 (m, 2 H),
3.62 (AB system, J ) 13.7 Hz, 4 H), 3.59-3.52 (m, 1 H), 3.20-
3.02 (m, 2 H), 2.67 (dd, J ) 14.1, 9.3 Hz, 1 H), 1.72 (d, J ) 4.8
Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 172.9 (C), 139.0 (2 ×
C), 138.1 (C), 129.2 (2 × CH), 128.8 (4 × CH), 128.4 (2 × CH),
128.3 (5 × CH), 127.1 (2 × CH), 126.7 (CH), 122.4 (CH), 61.9
(CH2), 61.3 (CH), 59.5 (CH), 54.7 (2 × CH2), 42.7 (CH2), 38.2
(CH2), 17.9 (CH3); MS (70 eV, EI) m/z (%) 425 (M+ - H2O, 1),
370 (21), 339 (26), 338 (81), 323 (27), 322 (100); HRMS (70
eV) calcd for C29H31NO2 (M+ - H2O) 425.2355, found 425.2354;
IR (neat)3414, 3063, 2960, 1737, 1495, 1454 cm-1; Rf ) 0.50
(hexane/EtOAc 10:1). Anal. Calcd for C29H33NO3: C, 78.52; H,
7.50; N, 3.16. Found: C, 78-72; H, 7.36; N, 3.02.
1
1,2-diol (9d): colorless oil; [R]25 ) +1.3 (c 1.50, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.37-7.07 (m, 10 H), 4.50 (apparent
d, J ) 5.4 Hz, 1 H), 4.17-4.09 (m, 2 H), 3.84 (d, J ) 13.7 Hz,
2 H), 3.70 (d, J ) 13.7 Hz, 2 H), 3.56 (dd, J ) 17.5, 13.3 Hz,
1 H), 3.05 (apparent q, J ) 5.6 Hz, 1 H), 2.40-2.33 (m, 3 H),
1.80-1.47 (m, 3 H), 1.41-1.31 (m, 4 H), 0.94 (t, J ) 6.9 Hz, 3
H), 0.89 (d, J ) 4.1 Hz, 3 H), 0.87 (d, J ) 4.1 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ 174.1 (C), 139.3 (2 × C), 128.8 (4 ×
CH), 128.2 (4 × CH), 127.1 (2 × CH), 61.3 (CH2), 60.5 (CH),
60.2 (CH), 54.8 (2 × CH2), 45.4 (CH2), 34.4 (CH2), 31.3 (CH2),
24.9 (CH), 24.6 (CH2), 23.2 (CH3), 22.3 (CH2), 20.9 (CH3), 13.9
(CH3); MS (70 eV, EI) m/z (%) 354 (M+- C5H11, <1), 339 (24),
266 (73), 147 (34), 144 (23), 105 (100); HRMS (70 eV) calcd for
C22H28NO3 (M+ - C5H11) 354.2069, found 354.2077; IR (neat)
3363, 2957, 1738, 1494, 1454 cm-1; Rf ) 0.43 (hexane/EtOAc
10:1). Anal. Calcd for C27H39NO3: C, 76.20; H, 9.24; N, 3.29.
Found: C, 76.43; H, 9.16; N, 3.34.
Acknowledgment. We thank the Ministerio de
Educacio´n y Cultura (CTQ2004-01191) for financial
support. J. M. C. thanks Carmen Ferna´ndez-Flo´rez for
her time. Our thanks to Vicente de Amo for his revision
of the english.
(2S,3S)-O1-Acetyl-3-dibenzylamino-4-phenylbutane-
1
1,2-diol (9e): colorless oil; [R]25 ) -11.2 (c 0.87, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.31-7.12 (m, 15 H), 4.61 (dd, J )
12.1, 3.5 Hz, 1 H), 4.48 (dd, J ) 11.4, 6.9 Hz, 1 H), 4.36-4.29
(m, 1 H), 3.75 (AB system, J ) 13.6 Hz, 4 H), 3.60-3.51 (m, 1
H), 3.19-3.13 (m, 1 H), 2.70 (dd, J ) 14.3, 9.1 Hz, 1 H), 2.10
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.7 (C), 139.1 (2 × C),
138.1 (C), 129.3 (2 × CH), 128.8 (4 × CH), 128.4 (2 × CH),
128.3 (4 × CH), 127.1 (2 × CH), 126.7 (CH), 62.0 (CH), 61.2
Supporting Information Available: 13C NMR spectra of
compounds 5, 8, and 9. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0514873
J. Org. Chem, Vol. 70, No. 25, 2005 10353