Stereoselective cyanation of chiral α-amino aldehydes by reaction with Nagata's reagent: A route to enantiopure β-amino-α-hydroxy acids

Article abstract of DOI:10.1016/S0957-4166(01)00044-1

Chiral α-dibenzylamino aldehydes react with diethylaluminum cyanide leading to anti-β-dibenzylamino-α-hydroxycyanides as the major diastereoisomers in good yields and diastereomeric excesses. Hydrolysis of the nitrile derivatives allows the synthesis of enantiopure β-amino-α-hydroxy acids.

Full text of DOI:10.1016/S0957-4166(01)00044-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 347–353
Stereoselective cyanation of chiral a-amino aldehydes by reaction
with Nagata’s reagent: a route to enantiopure
b-amino-a-hydroxy acids
Jose´ M. Andre´s, Mar´ıa A. Mart´ınez, Rafael Pedrosa* and Alfonso Pe´rez-Encabo
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Valladolid, Doctor Mergelina s/n,
47011 Valladolid, Spain
Received 15 January 2001; accepted 24 January 2001
Abstract—Chiral a-dibenzylamino aldehydes react with diethylaluminum cyanide leading to anti-b-dibenzylamino-a-hydroxy-
cyanides as the major diastereoisomers in good yields and diastereomeric excesses. Hydrolysis of the nitrile derivatives allows the
synthesis of enantiopure b-amino-a-hydroxy acids. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
as major diastereoisomers when using ZnBr2, BF3 or
SnCl4 as the Lewis acid. Very good anti-stereoselectivi-
ties (90–93%) were observed in the cyanation of a-
amino aldehyde derivatives with acetone cyanohydrin
in the presence of trimethylaluminum or ethylaluminum
dichloride as Lewis acids.11
b-Amino-a-hydroxy acids are of great interest because
they are starting materials in the synthesis of b-lactam
antibiotics1 and constituents of biologically active pep-
tides. For example, (2S,3R)-3-amino-2-hydroxy-4-
phenylbutanoic acid (AHPBA) is a component of
bestatin,2 a dipeptide inhibitor of aminopeptidase B
and leucine aminopeptidase.3 (2S,3R)-3-Amino-2-
hydroxy-5-methylhexanoic acid (AHMHA) is a con-
stituent in amastatine,4 whereas (2R,3S)-3-phenyliso-
serine is the amino acid present at the lateral chain of
taxol.5 Because of this occurrence in drugs and natural
products many different methods have been directed
into the stereoselective synthesis of these compounds.6,7
Previously, we have reported12,13 that diethylzinc reacts
with a-dibenzylamino aldehydes with excellent stereose-
lectivities leading to syn-adducts as the major stereoiso-
mers, as an alternative to the use of other
organometallic reagents.14 Herein, we report on the
diastereoselective cyanation of chiral a-amino alde-
hydes with diethylaluminum cyanide, because Nagata’s
reagent behaves not only as a good cyanating agent but
also as a Lewis acid with the possibility of reacting after
coordination to the heteroatoms in the starting a-amino
aldehyde.
Cyanohydrins prepared from protected a-amino alde-
hydes have been used as key intermediates in the syn-
thesis of b-amino-a-hydroxy acids. Thus, 2-N-benzyl-
oxycarbonylamino
aldehydes
were
transformed
The reaction of a-dibenzylamino aldehydes 1a–f12 with
diethylaluminum cyanide (1.1 equiv.) in toluene at
−78°C led, after hydrolysis, to a mixture of epimeric
cyanohydrins anti- and syn-2a–f in good yields and
diastereomeric excesses (Scheme 1 and Table 1). The
best diastereoselection (82:18) was obtained for the
stereoselectively into cyanohydrins by reaction with
trimethylsilyl cyanide8 (TMSCN) or tributyltin cyanide9
in good yields and with moderate threo-selectivity. The
diastereoselective addition of TMSCN to N,N-dibenzyl-
amino aldehydes has also been tested in the presence of
Lewis acids,10 and it is interesting that the nature of the
acid directs the stereochemistry of the reaction. The
syn-adducts were formed when MgBr2 or TiCl4 were
used, whereas the anti-addition products were obtained
cyanation of the
L
-valine derivative 1b whereas the
addition to the (R)-2-phenylglycine derivative ent-1e
yielded a mixture of diastereomers ent-2e in very low
d.e. (entry 6). It is also noteworthy that the presence of
an additional heteroatom b- to the aldehyde carbonyl
in the
L
-serine derivative 1f did not affect the facial
* Corresponding author.
discrimination. The anti-addition products were always
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00044-1

348
J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 347–353
Scheme 1.
Table 1. Stereoselective addition of Et2AlCN to N,N-dibenzylamino aldehydes 1a–f
Entry
Aldehyde
Time (h)
Yield (%)a
2
anti:synb
1
2
3
4
5
6
7
1a
1a
1b
1c
1d
ent-1e
1f
2
2
2
2
2
2
2
79
78
72
80
84
85
72
2a
2a
2b
2c
2d
ent-2e
2f
79:21
80:20c
82:18
70:30
75:25
58:42
80:20
a Combined yield of diastereomers after purification by flash chromatography.
b Determined by 1H NMR analysis of the crude of the reactions.
c Reaction performed with 2 equiv. of Nagata’s reagent.
obtained as major diastereoisomers, showing that the
reaction occurred with a non-chelated intermediate in
agreement with the Felkin–Ahn model previously
reported.14 This was also observed when 2 equiv. of
diethylaluminum cyanide were used or when Lewis
acids such as MgBr2 or ZnBr2 were added prior to the
reaction with Nagata’s reagent; only in the case of
addition of TiCl4 was a decrease in the stereoselection
observed, although the anti-diastereoisomers were
obtained as the predominant products.
in good yields. Treatment of the cyanohydrins with
concentrated hydrochloric acid in dioxane at reflux7a
gave the corresponding b-dibenzylamino-a-hydroxy
acid derivatives syn- and anti-3a,c–e, which were
debenzylated by hydrogenolysis (under hydrogen at
atmospheric pressure with palladium hydroxide in
methanol at rt) to afford enantiopure syn- and anti-
4a,c–e (Scheme 2).
In summary, this work demonstrates that diethylalu-
minum cyanide (Nagata’s reagent) is a good cyanating
agent and is capable of reacting with chiral a-dibenzyl-
amino aldehydes to afford the corresponding b-diben-
zylamino-a-hydroxynitriles in good yields and
diastereomeric excesses. The stereochemistry of the pre-
dominant anti-product can be explained in agreement
with the Felkin–Ahn non-chelation model.
Diastereomeric cyanohydrins syn- and anti-2a–f were
easily separated by flash chromatography on silica gel
using hexane–dichloromethane eluent mixtures. The
stereochemistry for syn- and anti-2a was assigned by
1
comparison of its H NMR data with that described in
the literature.10 In this way, the vicinal coupling con-
stant (J1,3) between C-(2)H and C-(3)H is higher for
syn-2a than for anti-2a, and this fact is general for syn-
and anti-2b–e and related compounds.15,16
2. Experimental
2.1. General
The stereochemistry for all diastereoisomers was ini-
tially assigned on the basis of this data, and finally
confirmed by chemical correlation. To this end, after
isolation, syn- and anti-2a,c–e were transformed into
the known b-amino-a-hydroxy acids over two steps and
The reactions were carried out in oven-dried glassware,
under an argon atmosphere, using anhydrous solvents.
Starting aminoaldehydes 1 were prepared as previously
Scheme 2.

J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 347–353
349
described.12 Diethylaluminum cyanide, as a 1 M solu-
tion in toluene, was purchased from Aldrich. The H
Hz, CH3
(CH3)2CH
3.63 (d, 2H, J=13.2 Hz, CHH
Hz, CHHN), 4.29 (br s, 1H, OH
Hz, CHOH), 7.20–7.40 (m, 10H, Harom.
(CDCl3): 19.7 (CH3), 22.4 (CH3), 27.2 ((CH3)2C
(CH2N), 58.8 (CHN), 65.4 (CHOH); 120.0 (CN), 127.5,
128.5, 129.1 (CHarom.), 138.0 (Carom.). MS (CI), m/z (%):
6
), 1.21 (d, 3H, J=6.9 Hz, CH3
6
), 2.31 (m, 1H,
1
6
), 2.81 (dd, 1H, J=5.8 Hz, J=8.4 Hz, CH
N), 3.82 (d, 2H, J=13.2
), 4.36 (d, 1H, J=8.4
). 13C NMR
H), 54.0
6 N),
NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded on Bruker AC 300 or AMX 300 spec-
trometers, using TMS as internal standard. IR spectra
were recorded on a Philips PU 9706 spectrometer, as a
film or in a Nujol dispersion. Mass spectra were per-
formed by chemical ionisation (CI). Optical rotations
were measured on a Perkin–Elmer 241 polarimeter in a
1 dm cell. Microanalyses were performed with a
Perkin–Elmer 2400-CHN elemental analyser.
6
6
6
6
6
6
6
6
6
6
6
6
6
6
309 (M++1, 53), 282 (100), 252 (97). Anal. calcd for
C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C:
77.72; H, 7.70; N, 9.03%.
2.2. Reaction of amino aldehydes 1 with Et2AlCN:
general method
2.6. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
methylpentanenitrile anti-2b
To a solution of amino aldehyde 1 (1 mmol) in anhy-
drous toluene (8 mL) at −78°C under argon was added
dropwise a 1 M solution of diethylaluminum cyanide in
toluene (1.1 mL, 1.1 mmol, 1.1 equiv.). The mixture
was stirred at that temperature until the reaction was
finished (TLC), and then quenched with a solution of
aqueous saturated ammonium chloride (10 mL). The
organic layer was separated and the aqueous phase was
extracted with diethyl ether (2×10 mL). The combined
organic layers were washed with brine, and dried over
anhydrous Na2SO4. The solvent was removed under
vacuum and the residue was purified by flash chro-
matography (silica gel, hexane–dichloromethane).
Colorless oil. Mp 83–84°C (from hexane–ethyl acetate).
[h]2D3=−49.5 (c=1.0, CHCl3). IR (Nujol): 3260, 2200
1
cm−1. H NMR (CDCl3): 0.97 (d, 3H, J=6.5 Hz, CH3
6
),
),
1.34 (d, 3H, J=6.5 Hz, CH3
2.66 (dd, 1H, J=5.6 Hz, J=10.8 Hz, CH
2H, J=13.0 Hz, CHHN), 4.19 (d, 2H, J=13.0 Hz,
CHHN), 4.25 (dd, 1H, J=5.6 Hz, J=9.2 Hz, CHOH),
4.64 (d, 1H, J=9.2 Hz, OH), 7.15–7.40 (m, 10H,
arom.). 13C NMR (CDCl3): 20.1 (C
H3), 22.4 (CH3),
28.9 ((CH3)2CH), 55.0 (NCH2), 59.3 (CHN), 64.7
(CHOH), 119.5 (CN), 127.7, 128.7, 129.5 (C arom.),
138.2 (Carom.
). MS (CI), m/z (%): 310 (M++2, 9), 382
6 ), 2.46 (m, 1H, (CH3)2CH6
6
N), 3.73 (d,
6
6
6
6
H
6
6
6
6
6
6
6
6
6 H
6
(100), 252 (51). Anal. calcd for C20H24N2O: C, 77.89;
H, 7.84; N, 9.08. Found: C 77.69; H, 7.73; N, 9.14%.
2.3. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxybutane-
nitrile syn-2a10
2.7. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-5-
methylhexanenitrile syn-2c
Colorless oil. [h]2D3=+90.3 (c=1.1, CHCl3). IR (film):
3400, 2240 cm−1. 1H NMR (CDCl3): 1.23 (d, 3H, J=6.8
Colorless oil. [h]2D3=+45.5 (c=1.1, CHCl3). IR (film):
3400, 2240 cm−1. 1H NMR (CDCl3): 0.92 (d, 3H, J=6.5
Hz, CH
3.38 (d, 2H, J=13.2 Hz, CHH
J=13.2 Hz), 4.12 (d, 1H, CHOH, J=10.1 Hz), 4.25 (br
s, 1H, OH), 7.20–7.40 (m, 10H, Harom.
). 13C NMR
(CDCl3): 8.6 (CH3), 53.1 (NCH2), 57.0 (CHN), 61.9
(CHOH), 118.9 (CN), 127.7, 128.7, 128.9 (CHarom.),
137.5 (Carom.
). MS (CI), m/z (%): 281 (M++1, 20), 254
6
6 N),
Hz, CH3
(CHHCH), 1.70 (m, 1H, CHH
(CH3)2CH), 3.03 (m, 1H, CHN), 3.53 (d, 2H, J=13.3
Hz, CHHN), 3.76 (d, 2H, J=13.3 Hz, CHHN), 4.15 (d,
1H, J=8.9 Hz, CHOH), 4.30 (br s, 1H, OH), 7.20–7.40
arom.). 13C NMR (CDCl3): 22.7 (C
(m, 10H, H H3), 22.8
(CH3), 25.3 ((CH3)2CH), 35.8 (CH2CH), 53.8 (CH2N),
58.6 (CHN), 61.6 (CHOH), 119.5 (CN), 127.6, 128.6,
129.0 (CHarom.), 138.0 (Carom.). MS (CI), m/z (%): 324
6
), 0.96 (d, 3H, J=6.5 Hz, CH3
6 ), 1.37 (m, 1H,
6
6
CH), 1.93 (m, 1H,
6
6
6
6
6
6
6
6
(100), 224 (44).
6
6
6
6
6
6
2.4. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxybutane-
nitrile anti-2a10
6
6
6
6
6
(M++2, 11), 296 (100), 266 (43). Anal. calcd for
C21H26N2O: C, 78.22; H, 8.13; N, 8.69. Found: C,
78.44; H, 8.32; N, 8.64%.
Colorless solid. Mp 89–90°C (from hexane–ethyl ace-
tate). [h]2D3=+24.7 (c=0.9, CHCl3). IR (film): 3400,
1
2260 cm−1. H NMR (CDCl3): 1.28 (d, 3H, J=6.9 Hz,
CH3
CHHN), 4.04 (d, 2H, J=13.2 Hz, CHH
J=6.3 Hz, CHOH), 4.42 (br s, 1H, OH
10H, H H3), 53.5
(NCH2), 54.5 (C6 HN), 62.2 (C6 HOH), 119.4 (C6 N), 127.6,
6 ), 3.14 (m, 1H, CH6 N), 3.40 (d, 2H, J=13.2 Hz,
6
6
N), 4.17 (d, 1H,
6 ), 7.20–7.40 (m,
2.8. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-5-
methylhexanenitrile anti-2c
6
6
arom.). 13C NMR (CDCl3): 8.9 (C
6
Colorless oil. [h]2D3=+23.3 (c=1.0, CHCl3). IR (film):
3400, 2260 cm−1. 1H NMR (CDCl3): 0.89 (d, 3H, J=6.3
6
128.6, 129.0 (C6 Harom.), 138.0 (C6 arom.); MS (CI), m/z (%):
282 (M++2, 29), 254 (100), 224 (29), 210 (31), 107 (44).
Hz, CH3
(CH3)2CH
3.41 (d, 2H, J=13.2 Hz, CHH
Hz, CHHN), 4.26 (d, 1H, J=5.8 Hz, CH
s, 1H, OH), 7.20–7.40 (m, 10H, Harom.
(CDCl3): 21.7 (CH3), 23.8 (C
(CH2CH), 54.2 (CH2N), 56.5 (C
6
), 1.00 (d, 3H, J=6.3 Hz, CH3
), 1.70 (m, 2H, CH2CH), 3.04 (m, 1H, CH
N), 4.05 (d, 2H, J=13.2
6
), 1.58 (m, 1H,
6
6
6
N),
2.5. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
methylpentanenitrile syn-2b
6
6
6
OH), 4.71 (br
6
6
). 13C NMR
Colorless oil. [h]2D3=+15.8 (c=1.2, CHCl3). IR (film):
3420, 2250 cm−1. 1H NMR (CDCl3): 1.11 (d, 3H, J=6.9
6
6
H3), 24.8 ((CH3)2C
6
H), 33.7
HOH),
6
6
6
HN), 60.0 (C
6

350
J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 347–353
119.3 (C
6
N), 127.7, 128.7, 129.2 (C
6
Harom.), 138.0
(C
6
HOH), 119.8 (C
6 N), 127.2, 128.3, 128.4, 128.8, 129.1
(Carom.
6
). MS (CI), m/z (%): 324 (M++2, 10), 296 (100),
(C
6
Harom.), 132.0 (Carom.), 138.2 (C6 arom.). MS (CI), m/z
6
266 (38). Anal. calcd for C21H26N2O: C, 78.22; H, 8.13;
N, 8.69. Found: C, 78.40; H, 8.26; N, 8.61%.
(%): 344 (M++2, 15), 316 (100), 286 (19). Anal. calcd for
C23H22N2O: C, 80.67; H, 6.47; N, 8.18. Found: C:
80.47; H, 6.34; N, 8.15%.
2.9. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
phenylbutanenitrile syn-2d
2.13. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
[(2-methoxyethoxy)methoxy]butanenitrile syn-2f
Colorless solid. Mp 110–111°C (from hexane–ethyl ace-
tate). [h]2D3=+46.8 (c=1.0, CHCl3) [Lit.11 [h]2D3=+47.9
(c=1.05, CHCl3)]. IR (Nujol): 3400, 2250 cm−1. 1H
NMR (CDCl3): 2.96 (dd, 1H, J=13.9 Hz, J=6.3 Hz,
Colorless oil. [h]2D3=+9.8 (c=1.2, CHCl3). IR (film):
3400, 2240 cm−1. 1H NMR (CDCl3): 3.19 (m, 1H,
CH
3.61 (d, 2H, J=13.5 Hz, CH
OCH2CH2O), 3.98 (m, 2H, CH2
13.5 Hz, CHH
NMR (CDCl3): 54.7 (NC
59.9 (CH), 63.1 (CH2), 67.4 (C
(OCH2O), 119.6 (CN), 127.6, 128.6, 128.9 (C
138.2 (Carom.
). MS (CI), m/z (%): 386 (M++2, 13), 358
6 N), 3.42 (s, 3H, CH6 3O), 3.59 (m, 2H, OCH6 2CH2O),
PhCH
PhCHH
Hz, CH
(br s, 1H, OH
7.10–7.40 (m, 15H, H
(PhCH2CH), 54.1 (NCH2), 61.7 (C
119.1 (CN), 126.9, 127.6, 128.6, 128.8, 128.9, 129.3
6
HCH), 3.08 (dd, 1H, J=13.9 Hz, J=7.8 Hz,
CH), 3.28 (m, 1H, CHN), 3.44 (d, 2H, J=13.3
HN), 3.85 (d, 2H, J=13.3 Hz, CHHN), 3.93
), 4.23 (d, 1H, J=8.5 Hz, CHOH),
arom.). 13C NMR (CDCl3): 32.1
HN), 62.3 (CHOH),
6
HPh), 3.75 (m, 2H,
6
6
6
6
O), 4.00 (d, 2H, J=
6
6
6
Ph), 7.15–7.40 (m, 10H, H
H2), 59.1 (CH3), 59.7 (C
H2), 71.7 (CH2), 95.6
Harom.),
6
arom.). 13C
6
6
6
6
6 H),
6
6
6
6
6
6
6
6
6
6
6
6
6
6
(Carom.), 137.9 (Carom.), 138.0 (Carom.). MS (CI), m/z
(100), 328 (23), 282 (69), 252 (44). Anal. calcd for
C22H28N2O4: C, 68.73; H, 7.34; N, 7.29. Found: C,
68.59; H, 7.22; N, 7.25%.
(%): 358 (M++2, 13), 330 (100), 300 (33), 238 (24).
2.10. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
phenylbutanenitrile anti-2d
2.14. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
[(2-methoxyethoxy)methoxy]butanenitrile anti-2f
Colorless solid. Mp 98–99°C (from hexane–ethyl ace-
tate) [Lit.11 mp 98°C (CH2Cl2–hexane)]. [h]2D3 +48.0
(c=1.0, CHCl3) [Lit.11 [h]D23=+49.4 (c=1.01, CHCl3)].
Colorless oil. [h]2D3=+24.2 (c=0.6, CHCl3). IR (film):
3380, 2260 cm−1. 1H NMR (CDCl3): 3.23 (m, 1H,
1
IR (Nujol): 3400, 2220 cm−1. H NMR (CDCl3): 2.93
CH
3.59 (d, 2H, J=13.5 Hz, CH
OCH2CH2O), 3.97 (m, 2H, CH2
13.5 Hz, CHH
4.73 (s, 2H, OCH
NMR (CDCl3): 55.0 (NC
59.8 (CH), 63.5 (CH2), 67.3 (C
(CH2), 119.6 (CN), 127.6, 128.6, 129.1 (C
(C
arom.). MS (CI), m/z (%): 386 (M++2, 12), 358 (100),
6 N), 3.39 (s, 3H, CH6 3O), 3.57 (m, 2H, OCH6 2CH2O),
(dd, 1H, J=9.8 Hz, J=12.5 Hz, PhCHHCH), 3.25 (m,
2H, PhCHHCH, CHN), 3.56 (d, 2H, J=13.2 Hz,
6
HPh), 3.72 (m, 2H,
O), 4.03 (d, 2H, J=
6
6
CHHN), 4.02 (d, 1H, J=5.2 Hz, CH
J=13.2 Hz, CHHN), 4.51 (br s, 1H, OH
(m, 15H, H
arom.). 13C NMR (CDCl3): 31.2 (PhC
54.4 (CH2N), 59.5 (CHN), 61.0 (CHOH), 119.4 (C
127.0, 127.8, 128.8, 128.9, 129.0, 129.2 (Carom.), 136.7
(Carom.), 137.7 (Carom.
). MS (CI), m/z (%): 358 (M++2,
13), 330 (100), 300 (27), 238 (25).
6
OH), 4.24 (d, 2H,
), 7.20–7.40
H2CH),
N),
6
Ph), 4.58 (d, 1H, CH
2O), 7.25–7.40 (m, 10H, Harom.
H2), 58.9 (CH3), 59.0 (C
H2), 71.7 (CH2), 95.7
Harom.), 138.3
6
OH, J=7.5 Hz),
). 13C
H),
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
328 (21), 282 (69), 252 (58). Anal. calcd for
C22H28N2O4: C, 68.73; H, 7.34; N, 7.29. Found: C,
68.61; H, 7.25; N, 7.21%.
2.11. (2S,3R)-3-(N,N-Dibenzylamino)-2-hydroxy-3-
phenylpropanenitrile ent-syn-2e
2.15. Hydrolysis of the cyanohydrins 2: general method
Colorless oil. [h]2D3=−139.7 (c=1.0, CHCl3). IR (film):
3380, 2250 cm−1. 1H NMR (CDCl3): 3.13 (d, 2H,
A solution of cyanohydrin 2 (1 mmol) in dioxane–con-
centrated HCl (1:1, 10 mL) was heated under reflux for
12 h. The hydrolysate was washed with Et2O and dried
in vacuo. The residue was dissolved in water (10 mL),
the solution adjusted to pH 5.5–6 with 2N NaOH and
the mixture extracted with EtOAc (3×10 mL). The
combined organic layers were washed with brine, dried
over Na2SO4, concentrated and chromatographed (sil-
ica gel, hexane–ethyl acetate or CHCl3–EtOH).
J=13.2 Hz, NCH
CHHN), 4.04 (d, 1H, J=10.7 Hz, CH
1H, OH), 4.89 (d, 1H, J=10.7 Hz, CH
(m, 15H, Harom.
(CHN), 65.3 (C
129.3, 129.5 (C
6 HN), 3.85 (d, 2H, J=13.2 Hz,
6
6
N), 4.32 (br s,
6
6 OH), 7.20–7.55
6
). 13C NMR (CDCl3): 53.5 (NC
6
H2), 59.8
N), 127.9, 129.0, 129.1,
), 137.8 (Carom.). MS
6
6
HOH), 118.5 (C
6
6
arom.), 131.2 (Carom.
6
6
(CI), m/z (%): 344 (M++2, 14), 316 (100), 286 (19).
Anal. calcd for C23H22N2O: C, 80.67; H, 6.47; N, 8.18.
Found: C: 80.46; H, 6.30; N, 8.20%.
2.16. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxybu-
tanoic acid syn-3a
2.12. (2R,3R)-3-(N,N-Dibenzylamino)-2-hydroxy-3-
phenylpropanenitrile ent-anti-2e
84% yield. Colorless oil. [h]2D3=+66.0 (c=1.1, CHCl3).
1
Colorless oil. [h]2D3=−81.6 (c=1.1, CHCl3). IR (film):
IR (film): 3600–2000 cm−1. H NMR (CDCl3): 1.31 (d,
3400, 2240 cm−1. 1H NMR (CDCl3): 3.18 (d, 2H,
3H, J=6.6 Hz, CH3
J=13.4 Hz, CHHPh), 4.05 (d, 1H; J=4.8 Hz, CH
4.25 (d, 2H, J=13.4 Hz, CHHPh), 7.20–7.40 (m, 10H,
Harom.), 8.09 (br s, 2H, OH, COOH
). 13C NMR
(CDCl3): 8.9 (CH3), 54.0 (NCH2), 56.8 (CHN), 71.5
6
), 3.28 (m, 1H, CH
6
N), 3.62 (d, 2H,
J=13.5 Hz, NCH
CHHN), 4.09 (d, 1H, J=8.6 Hz, CH
J=8.6 Hz, CHOH), 7.20–7.60 (m, 15H, Harom.
NMR (CDCl3): 54.6 (CH2N), 62.0 (CHN), 64.4
6
HN), 3.96 (d, 2H, J=13.5 Hz,
N), 4.82 (d, 1H,
). 13C
6
6
OH),
6
6
6
6
6
6
6
6
6
6
6
6
6

J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 347–353
351
(C
176.5 (C
6
HOH), 128.1, 128.6, 129.3 (C
6
Harom.), 134.2 (Carom.
6
),
J=12.7 Hz, J=10.4 Hz, PhCHH
3.65 (d, 2H, J=13.5 Hz, CH
Hz, CHOH), 4.43 (d, 2H, J=13.5 Hz, CHH
7.40 (m, 15H, Harom.), 7.96 (br s, 2H, OH, COOH
NMR (CDCl3): 29.1 (CH2CH), 54.8 (CH2N), 61.6
(CHN), 69.1 (CHOH), 126.2, 128.0, 128.2, 128.4, 129.1,
129.3 (C
6
), 3.33 (m, 1H, CH
6
N),
6
O2H). MS (CI), m/z (%): 328 (M++29, 14), 300
6
HN), 3.88 (d, 1H, J=3.8
N), 7.05–
). 13C
(M++1, 100), 224 (15). Anal. calcd for C18H21NO3: C,
77.22; H, 7.07; N, 4.68. Found: C, 77.44; H, 7.21; N,
4.61%.
6
6
6
6
6
6
6
6
6
6
Harom.), 134.5, 137.1 (C6 arom.), 176.9 (C6 O2H).
2.17. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxybu-
tanoic acid anti-3a
MS (CI), m/z (%): 404 (M++29, 18), 376 (M++1, 100),
300 (53), 284 (18). Anal. calcd for C24H25NO3: C, 76.77;
H, 6.71; N, 3.73. Found: C, 76.79; H, 6.75; N, 3.68%.
78% yield. Colorless oil. [h]2D3=+40.2 (c=1.0, CHCl3).
IR (film): 3700–2000 cm−1. H NMR (CDCl3): 1.38 (d,
1
3H, J=6.7 Hz, CH3
Hz, CHN), 3.66 (d, 2H, J=13.2 Hz, CH
1H, J=9.8 Hz, CHOH), 4.14 (d, 2H, J=13.2 Hz,
CHHPh), 7.30–7.50 (m, 10H, Harom.
). 13C NMR
(CDCl3): 9.2 (CH3), 53.3 (CH2), 57.5 (CHN), 67.6
(CHOH), 129.0, 129.7 (CHarom.), 131.4 (Carom.), 175.7
(C
6
), 3.18 (dq, 1H, J=9.8 Hz, J=6.7
2.21. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
phenylbutanoic acid anti-3d
6
6
HPh), 3.99 (d,
6
6
6
80% yield. Colorless solid. Mp 59–60°C (from hexane–
ethyl acetate). [h]2D3=+49.9 (c=1.1, CHCl3). IR (Nujol):
6
6
6
1
3600–2500, 740, 700 cm−1. H NMR (CDCl3): 3.08 (dd,
6
6
6
6
O2H). MS (CI), m/z (%): 328 (M++29, 14), 300
1H, J=15.0 Hz, J=9.6 Hz, PhCH
J=15.0 Hz, J=3.3 Hz, PhCHH), 3.50 (m, 1H, CH
3.71 (d, 2H, J=13.5 Hz, CHHN), 3.95 (d, 2H, J=13.5
Hz, CHHN), 4.25 (d, 1H, J=7.7 Hz, CHOH), 7.05–
7.40 (m, 15H, Harom.), 9.20 (br s, 2H, OH, CO2H
). 13C
NMR (CDCl3): 31.9 (CH2CHN), 54.3 (CH2N), 62.9
(CHN), 67.4 (CHOH), 126.7, 128.2, 128.6, 129.4
(CHarom.), 133.7, 138.3 (C6 arom.), 176.2 (C6 O2H). MS (CI),
6
H), 3.28 (dd, 1H,
(M++1, 100), 224 (21). Anal. calcd for C18H21NO3: C,
77.22; H, 7.07; N, 4.68. Found: C, 77.39; H, 6.96; N,
4.80%.
6
6
N),
6
6
6
6
6
6
6
6
2.18. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-5-
methylhexanoic acid syn-3c
6
6
6
m/z (%): 404 (M++29, 15), 376 (M++1, 100), 300 (65),
284 (23). Anal. calcd for C24H25NO3: C, 76.77; H, 6.71;
N, 3.73. Found: C, 76.86; H, 6.69; N, 3.78%.
79% yield. Colorless oil. [h]2D3=+60.3 (c=1.1, CHCl3).
1H NMR (CDCl3): 0.78 (d, 3H, J=6.3 Hz, CH3
6
), 0.95
HCHN), 1.72
CHN), 3.24 (m,
N), 3.61 (d, 2H, J=13.3 Hz, CHHN), 4.18 (d,
1H, J=4.3 Hz, CHOH), 4.38 (d, 2H, J=13.3 Hz,
CHHN), 7.20–7.40 (m, 10H, Harom.), 8.55 (br s, 2H,
OH, CO2H
). 13C NMR (CDCl3): 21.6 (C
(CH3), 24.5 (CH), 31.8 (CH2), 54.7 (NC
(CHN), 69.7 (C
134.2 (Carom.), 177.1 (C
(d, 3H, J=6.3 Hz, CH3
(m, 1H, (CH3)2CH), 2.01 (m, 1H, CHH
1H, CH
6 ), 1.43 (m, 1H, CH6
6
6
6
6
2.22. (2S,3R)-3-(N,N-Dibenzylamino)-2-hydroxy-3-
phenylpropanoic acid ent-syn-3e
6
6
6
6
6
6
H3), 23.9
6 H2), 58.3
71% yield. Colorless solid. Mp 254–255°C (from hex-
ane–ethyl acetate). [h]2D3=−83.0 (c=1.0, CHCl3). IR
6
6
6
(Nujol): 2700–2400 cm−1. H NMR (CDCl3): 3.33 (d,
6
6
HOH), 128.5, 128.8, 129.6 (C
6
Harom.),
1
6
6
O2H). Anal. calcd for
C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
74.08; H, 7.78; N, 4.16%.
2H, J=13.5 Hz, CH
CHN), 4.17 (d, 2H, J=13.5 Hz, CHH
J=7.1 Hz, CHOH), 7.20–7.50 (m, 15H, H
(br s, 2H, OH, CO2H
). 13C NMR (CDCl3): 54.3
(NCH2), 65.4 (CH), 68.4 (CH), 128.2, 128.6, 128.9,
129.3, 130.2 (CHarom.), 135.4 (Carom.), 174.1 (CO2H).
6
HN), 4.13 (d, 1H, J=7.1 Hz,
N), 4.57 (d, 1H,
arom.), 8.45
6
6
6
6
6
6
6
6
6
2.19. (2S,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-5-
methylhexanoic acid anti-3c
6
6
6
MS (CI), m/z (%): 390 (M++29, 15), 362 (M++1, 100),
286 (27), 198 (41), 121 (77). Anal. calcd for C23H23NO3:
C, 76.43; H, 6.41; N, 3.87. Found: C, 76.28; H, 6.29; N,
3.83%.
74% yield. Colorless oil. [h]2D3=+33.8 (c=0.9, CHCl3).
1H NMR (CDCl3): 0.91 (d, 3H, J=6.6 Hz, CH3
6
), 0.92
CHN), 2.15
N), 3.76 (d, 2H,
HPh), 4.10 (d, 2H, J=13.4 Hz,
Ph), 4.15 (d, 1H, J=8.9 Hz, CHOH), 7.25–7.40
(m, 10H, Harom. H3), 23.3
). 13C NMR (CDCl3): 22.3 (C
(CH3), 25.3 (CH), 36.2 (CH2), 53.8 (CH2N), 59.0
(CHN), 68.7 (CHOH), 128.8, 129.0, 129.8 (CHarom.),
132.8 (Carom.), 176.2 (CO2H). Anal. calcd for
(d, 3H, J=6.6 Hz, CH
(m, 1H, CH(CH3)2), 3.17 (m, 1H, CH
J=13.4 Hz, CH
CHH
6 3), 1.70 (m, 2H, CH6 2
6
6
6
2.23. (2R,3R)-3-(N,N-Dibenzylamino)-2-hydroxy-3-
phenylpropanoic acid ent-anti-3e
6
6
6
6
6
6
6
6
68% yield. Colorless solid. Mp 183–184°C (from hex-
6
6
6
ane–ethyl acetate). [h]2D3=−77.0 (c=1.1, CHCl3). IR
6
6
1
(film): 2700–2400 cm−1. H NMR (CDCl3): 3.31 (d, 2H,
C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
73.60; H, 7.85; N, 3.95%.
J=13.2 Hz, CH
4.20 (d, 2H, J=13.2 Hz, CHH
Hz, CHOH), 7.25–7.60 (m, 15H, Harom.
(CDCl3): 54.1 (CH2N), 64.3 (CH), 65.4 (C
128.8, 129.1, 129.4, 129.6, 130.4 (CHarom.), 132.0
6
HN), 4.19 (d, 1H, J=10.8 Hz, CH
N), 4.72 (d, 1H, J=10.8
). 13C NMR
H), 128.1,
6 N),
6
6
6
2.20. (2R,3S)-3-(N,N-Dibenzylamino)-2-hydroxy-4-
phenylbutanoic acid syn-3d
6
6
6
6
76% yield. Colorless solid. Mp 86–87°C (from hexane–
(C6 arom.), 175.4 (C6
O2H). MS (CI), m/z (%): 390 (M++29,
ethyl acetate). [h]2D3=+33.4 (c=1.0, CHCl3). IR (Nujol):
13), 362 (M++1, 100), 286 (25), 198 (52), 121 (95). Anal.
calcd for C23H23NO3: C, 76.43; H, 6.41; N, 3.87.
Found: C, 76.09; H, 6.45; N, 3.88%.
1
3600–3150, 750, 690 cm−1. H NMR (CDCl3): 3.02 (dd,
1H, J=12.7 Hz, J=4.2 Hz, PhCH6 H), 3.20 (dd, 1H,

352
J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 347–353
1
2.24. General method for the hydrogenolysis of N,N-
[h]2D3=−31.0 (1N HCl)]. H NMR (D2O): 2.76 (dd, 1H,
J=8.4 Hz, J=14.1 Hz, PhCHH), 2.95 (dd, 1H, J=6.8
Hz, J=14.1 Hz, PhCHH), 3.64 (ddd, 1H, J=3.4 Hz,
J=6.8 Hz, J=8.4 Hz, CH
CHOH), 7.14–7.26 (m, 5H, Harom.
37.7 (CH2), 57.5 (CHN), 72.3 (C
dibenzylamino acids 3
6
6
To a solution of the appropriate N,N-dibenzylamino
acid 3 (1 mmol) in a 1:1 mixture MeOH–H2O (10 mL)
was added 20% Pd(OH)2-C (50 mg) in one portion. The
mixture was stirred under a hydrogen atmosphere and
the reaction was monitored by TLC. After completion
of the reaction, the catalyst was removed by filtration
through Celite and washed with water. The solvent was
concentrated under reduced pressure to afford the pure
product, which was crystallized from ethanol–water
where necessary.
6 N), 3.93 (d, 1H, J=3.4 Hz,
6
6
). 13C NMR (D2O):
6 HOH), 130.0, 131.6,
6
6
131.8 (C6 Harom.), 137.7 (C6 arom.), 178.6 (C6 O2H). MS (CI),
m/z (%): 196 (M++1, 100), 120 (30), 104 (19).
2.30. (2S,3S)-3-Amino-2-hydroxy-4-phenylbutanoic acid
anti-4d
89% yield. Colorless solid. Mp 134–135°C (from
EtOH–H2O). [h]D23=−5.1 (c=0.9, 1N HCl) [Lit.20
1
[h]2D3=−5.4 (c=0.5, 1N HCl)]. H NMR (D2O): 2.72
2.25. (2R,3S)-3-Amino-2-hydroxybutanoic acid syn-4a
(dd, 1H, J=9.5 Hz, J=14.4 Hz, PhCH
1H, J=6.5 Hz, J=14.4 Hz, PhCHH), 3.79 (ddd, 1H,
J=3.0 Hz, J=6.5 Hz, J=9.5 Hz, CHN), 4.31 (d, 1H,
J=3.0 Hz, CHOH), 7.10–7.30 (m, 5H, Harom.
). 13C
NMR (D2O): 34.0 (CH2), 55.9 (CHN), 70.7 (CHOH),
128.8, 130.1, 130.6 (CHarom.), 135.9 (Carom.), 175.1
(C
O2H). MS (CI), m/z (%): 196 (M++1, 45), 120 (100),
107 (34).
6 H), 2.81 (dd,
6
92% yield. Colorless solid. Mp 223–225°C (dec.) (from
EtOH–H2O). [h]D23=+21.6 (c=1.1, H2O) [Lit.17 [h]D23=
+22.2 (c=0.5, H2O)]. 1H NMR (D2O): 1.10 (d, 3H,
6
6
6
6
6
6
J=6.8 Hz, CH3
CHN), 3.88 (d, 1H, J=4.9 Hz, CH
(D2O): 15.5 (CH3), 50.8 (CHN), 73.1 (C
(C
O2H). MS (CI), m/z (%): 120 (M++1, 100), 102 (4).
6
), 3.36 (dq, 1H, J=4.9 Hz, J=6.8 Hz,
OH). 13C NMR
HOH), 177.2
6
6
6
6
6
6
6
6
6
2.31. (2S,3R)-3-Amino-2-hydroxy-3-phenylpropanoic
acid ent-syn-4e
2.26. (2S,3S)-3-Amino-2-hydroxybutanoic acid anti-4a
95% yield. Colorless solid. Mp 240–241°C (from
EtOH–H2O). [h]D23=−25.7 (c=1.1, H2O) [Lit.17 [h]D23=
−26.1 (c=1.1, H2O)]. 1H NMR (D2O): 0.99 (d, 3H,
90% yield. Colorless solid. Mp 255–256°C (dec.) (from
EtOH–H2O). [h]D23=+14.4 (c=0.5, 6N HCl) [Lit.21
1
[h]2D3=+14.9 (c=0.7, 6N HCl)]. H NMR (D2O): 4.08
J=6.8 Hz, CH3
CHN), 4.14 (d, 1H, J=3.4 Hz, CH
(D2O): 14.2 (CH3), 51.7 (CHN), 73.1 (C
(C
O2H). MS (CI), m/z (%): 120 (M++1, 100), 102 (6).
6
), 3.55 (dq, 1H, J=3.4 Hz, J=6.8 Hz,
OH). 13C NMR
HOH), 177.8
(d, 1H, J=6.2 Hz, CH
CHOH), 7.15–7.30 (m, 5H, Harom.
59.9 (CHN), 75.8 (CHOH), 129.7, 131.5, 131.8
(CHarom.), 135.9 (C6 arom.), 178.8 (C6 O2H). MS (CI), m/z
6
N), 4.30 (d, 1H, J=6.2 Hz,
6
6
6
6
). 13C NMR (D2O):
6
6
6
6
6
6
6
(%): 182 (M++1, 100), 165 (29), 119 (60), 106 (85).
2.27. (2R,3S)-3-Amino-2-hydroxy-5-methylhexanoic
acid syn-4c
2.32. (2R,3R)-3-Amino-2-hydroxy-3-phenylpropanoic
acid ent-anti-4e
92% yield. Colorless solid. Mp 222–224°C (from
EtOH–H2O). [h]D23=+28.7 (c=0.3, AcOH) [Lit.18
96% yield. Colorless solid. Mp 109–110°C (from
1
[h]2D3=+28.4 (c=0.45, AcOH)]. H NMR (CDCl3): 0.74
1
EtOH–H2O). [h]2D3=+3.6 (c=0.5, 6N HCl). H NMR
(d, 3H, J=6.3 Hz, CH3
1.36 (m, 2H, CH2); 1.50 (m, 1H, CH
1H, CHN), 3.96 (d, 1H, J=3.7 Hz, CH
(CDCl3): 23.3 (CH3), 23.8 (CH3), 25.8 (C
(CH2), 54.1 (CHN), 72.8 (CHOH), 178.8 (C
6
), 0.75 (d, 3H, J=6.3 Hz, CH3
(CH3)2), 3.37 (m,
OH). 13C NMR
H(CH3)2), 40.0
O2H).
6 ),
(D2O): 4.72 (d, 1H, J=4.2 Hz, CH
J=4.1 Hz, CHOH), 7.35–7.45 (m, 5H, Harom.
NMR (D2O): 57.9 (CHN), 73.0 (CHOH), 129.0, 130.0,
130.6 (C ), 176.7 (CO2H). MS (CI),
6
N), 4.77 (d, 1H,
6
6
). 13C
6
6
6
6
6
6
6
6
6
6
Harom.), 133.4 (Carom.
6
6
m/z (%): 182 (M++1, 100), 165 (22), 119 (25), 106 (68).
Anal. calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73.
Found: C, 59.87; H, 6.00; N, 7.55%.
6
6
6
6
2.28. (2S,3S)-3-Amino-2-hydroxy-5-methylhexanoic acid
anti-4c
96% yield. Colorless solid. Mp 240–242°C (from
Acknowledgements
EtOH–H2O) [Lit.19 mp 225–230°C]. [h]2D3=−16.0 (c=
1
0.4, AcOH). H NMR (D2O): 0.68 (d, 3H, J=6.4 Hz,
CH3
CHHCH), 1.40 (m, 2H, CHH
(m, 1H, CHN), 4.02 (d, 1H, J=3.2 Hz, CH
NMR (D2O): 23.0 (CH3), 24.8 (CH3), 25.9 (CH(CH3)2),
38.3 (CH2), 54.4 (CHN), 74.3 (CHOH), 179.0 (CO2H).
6
), 0.73 (d, 3H, J=6.4 Hz, CH3
6
), 1.12 (m, 1H,
(CH3)2), 3.44
OH). 13C
The authors gratefully acknowledge the financial sup-
port provided by the Spanish DGESYC (Project PB98-
0361) and Junta de Castilla y Leo´n (Project VA67/99).
6
6
CH and CH
6
6
6
6
6
6
6
6
6
6
References
2.29. (2R,3S)-3-Amino-2-hydroxy-4-phenylbutanoic acid
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J. M. Andre´s et al. / Tetrahedron: Asymmetry 12 (2001) 347–353
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