Manipulating L-aspartic and L-glutamic acids - Diastereoselective synthesis of enantiopure β-amino-γ-hydroxy acids and γ-amino-δ-hydroxy acids

Article abstract of DOI:10.1002/ejoc.200300199

Enantiopure (3S,4R)- and (3S,4S)-3-amino-4-hydroxyhexanoic acids and (4S,5R)- and (4S,5S)-4-amino-5-hydroxyheptanoic acid derivatives have been prepared by stereodivergent synthesis from L-aspartic and L-glutamic acids, respectively. The stereochemistry at the carbon atom attached to the amino group was determined from the starting material but the configuration at C-4 or C-5 is controlled by diastereoselective alkylation with diethylzinc or ethylmagnesium bromide. The protection of the carboxylic group as OBO orthoester improved the yields in the final products. Wiley-VCH Verlag GmbH & Co, KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300199

FULL PAPER
Manipulating
L
-Aspartic and
L
-Glutamic Acids ؊ Diastereoselective Synthesis
of Enantiopure β-Amino-γ-hydroxy Acids and γ-Amino-δ-hydroxy Acids
[a]
[a]
[a]
[a]
´
´
´
˜
Jose M. Andres, Eva M. Munoz, Rafael Pedrosa,* and Alfonso Perez-Encabo
Keywords: Alkylation / Amino acids / Amino aldehydes / Asymmetric synthesis / Chiral pool
Enantiopure (3S,4R)- and (3S,4S)-3-amino-4-hydroxyhex- the configuration at C-4 or C-5 is controlled by diastereo-
anoic acids and (4S,5R)- and (4S,5S)-4-amino-5-hydroxyhep- selective alkylation with diethylzinc or ethylmagnesium
tanoic acid derivatives have been prepared by stereodiverg- bromide. The protection of the carboxylic group as OBO or-
ent synthesis from L-aspartic and L-glutamic acids, respect- thoester improved the yields in the final products.
ively. The stereochemistry at the carbon atom attached to the
amino group was determined from the starting material, but
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
α-Unsubstituted β-amino-γ-hydroxy acids are interesting excellent dr’s by reaction with diethylzinc or ethylmag-
compounds because they are components of peptides of nesium bromide (Scheme 1 and Table 1).
pharmacological interest,[1] and biological activity.[2Ϫ5] Ad-
ditionally, they can be used as enzymatic inhibitors,[6] and
can be transformed into 4-hydroxy-β-lactams,[7] or β-am-
ino-γ-butyrolactones[8] which are intermediates to β-amino
alcohols,[9] antibiotic β-lactams,[10,11] and macrolides.[12]
β-Amino-γ-hydroxy acids have been prepared from α-
hydroxy-β-lactams with hydroxylated substituents at C-4,[13]
by degradation of β-lactams[14] or, more recently, by sodium
cyanoborohydride reduction of chiral γ-hydroxy tert-butyl
alkenoates with moderate diastereoselectivity.[15] Dihydrox-
ylation of γ,δ-unsaturated β-amino esters[16] or pal-
ladium()-catalyzed intramolecular aminocarbonylation of
endo carbamates[17] also give β-amino-γ-hydroxy acid de-
rivatives in good yields. In spite of their interest, surpris-
Scheme 1. Reagents and conditions: (i) Et2Zn, toluene/hexane, 0
°C. 76% for syn-2a, 67% for syn-2b. (ii) EtMgBr, Et2O, 0 °C. 70%
for anti-2a, 73% for anti-2b.
ingly there are not antecedents on the diastereoselective
synthesis of γ-amino-δ-hydroxy acids, to the best of our
knowledge.
Recently, we have prepared both threo- and erythro-β-
hydroxynorvalines by diastereo-divergent synthesis from
(S)-serine-derived N,N-dibenzyl-α-amino aldehydes,[18] and
now we report on the preparation of enantiopure syn- and
anti-aminohydroxy acids from amino aldehyde derivatives
1a, b. These compounds were obtained from -aspartic and
-glutamic acids in 40% and 32%, respectively, by benzyl-
ation, lithium aluminum hydride (LAH) reduction, monop-
rotection as tert-butyldimethylsilyl ether (TBDMS) and
Swern oxidation.[19,20] α-Amino aldehydes 1a, b were trans-
formed into syn- and anti-3-amino-1,4-diols 2a and syn-
and anti-4-amino-1,5-diol derivatives 2b in good yields and
As expected, the reaction of 1a with diethylzinc in tolu-
ene/hexane at 0 °C gives syn-2a as a single diastereomer,
and 1b yields, under the same experimental conditions, a
mixture of syn-2b and anti-2b in good dr (87:13), indicating
that the addition occurs in agreement with a chelated inter-
mediate.[18] On the contrary, 1a and 1b react with ethylmag-
nesium bromide leading to anti-2a, as a single isomer, and
anti-2b and syn-2b in a dr 92:8[21] in agreement with a non-
chelated model.[22,23]
The stereochemistry of diastereoisomers syn- and anti-2a,
b was determined as described previously,[24,25] and con-
firmed by the 1H NMR spectroscopic data of the oxazolidi-
nones prepared by debenzylation followed by treatment
with triphosgene (Scheme 2). The vicinal coupling con-
stants between the protons at C-4 and C-5 in oxazolidi-
nones 3a, b derived from syn-2a, b (1,3J ϭ 6.3 Hz and 1,3J ϭ
[a]
´
´
Departamento de Quımica Organica, Facultad de Ciencias,
Universidad de Valladolid
Doctor Mergelina s/n, 47011 Valladolid, Spain
Fax: (internat.) ϩ 34-983/423013
E-mail: pedrosa@qo.uva.es
Eur. J. Org. Chem. 2003, 3387Ϫ3397
DOI: 10.1002/ejoc.200300199
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3387

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J. M. Andres, E. M. Mun˜oz, R. Pedrosa, A. Perez-Encabo
FULL PAPER
Table 1. Addition of Et2Zn and EtMgBr to amino aldehydes 1a and 1b
Entry[a]
Amino aldehyde
RM
Amino alcohol
Yield (%)[b]
syn/anti[c]
1
2
3
4
1a
1a
1b
1b
Et2Zn
EtMgBr
Et2Zn
syn-2a
anti-2a
syn-2b
anti-2b
76
70
67
73
Ͼ 95:5[d]
Ͻ 5:95[d]
87:13
EtMgBr
8:92
[a]
[b]
[c]
Reactions were run at 0 °C.
Numbers correspond to combined yield of pure and isolated diastereoisomers. The diastereomeric
ratio was determined by integration of the 1H NMR spectra of the reaction mixture.
NMR spectroscopy.
Only one diastereomer was detected by 1H
[d]
5.7 Hz, respectively) are smaller than those derived from
anti-2a, b (1,3J ϭ 7.6 Hz and 1,3J ϭ 7.5 Hz) indicating a
trans relationship for the former and a cis stereochemistry
for the later.[26,27]
Scheme 2. Reagents and conditions: (i) 1. H2/Pd(OH)2/C, MeOH.
2. (CCl3O)2CO, DIPEA, CH2Cl2, room temp. 72% for trans-3a,
46% for trans-3b, 70% for cis-3a, 50% for cis-3b
The transformation of 2a, b into the aminohydroxy acids
7a, b was achieved as summarized in Scheme 3 by protec-
tion of the secondary alcohol by reaction with (2-methoxye-
thoxy)methyl chloride (MEMCl) in dichloromethane at
room temp., deprotection of the primary hydroxy group by
treatment with tetra-n-butylammonium fluoride (TBAF) in
THF at 0 °C, and subsequent oxidation. First, we attempt
the preparation of the acids by two-steps oxidation of 5a, b
as described previously for 2-dibenzylamino-1,3-diols,[18]
but this protocol fails for these compounds. Swern oxi-
dation of syn-5a lead to a complex reaction mixture where
it was possible to detect (1H NMR) dibenzylamine and α,β-
unsaturated aldehydes. This fact points to that the β-amino-
γ-hydroxy aldehyde is not stable and decomposes by retro-
condensation to the amine and the unsaturated aldehyde.
Scheme 3. Reagents and conditions: (i) MEMCl, DIPEA, CH2Cl2,
room temp. (ii) TBAF, THF, 0 °C. (iii) H2, Pd(OH)2/C, Boc2O,
MeOH. (iv) PDC, DMF, room temp. (v) 1. HCl 2 , room temp.
2. Propylene oxide, EtOH, reflux. (vi) Ac2O, pyridine, room temp.
Alternatively we tested the direct oxidation of amino al- protection with 2  solution of HCl at rt[28] followed by
cohols 5a, b with pyridinium dichromate (PDC), but this treatment with propylene oxide in absolute ethanol. The
oxidation previously required a change of the benzyl protec- stereochemistry for syn-8a was confirmed by lactonization
tion of the amino group into urethane. This process oc- to the known[14] cis-9 by reaction with Ac2O in pyridine at
curred in one step by hydrogenolysis of 5a, b on Pd(OH)2/ room temp. (Scheme 3).
C in the presence of di-tert-butyl dicarbonate leading to 6a,
A shorter approach to syn- and anti-8a from -aspartic
b which were oxidized into 7a, b by treatment with PDC (5 acid was attempted. The idea was to reduce selectively the
equiv.) in DMF at room temp. This protocol allowed the carboxylic group at C-1 maintaining the carboxylic group
synthesis of protected aminohydroxy acids 7a, b from 2a, b at C-4, avoiding the protection of the secondary hydroxylic
in four steps with total yields of 22Ϫ31%. Compounds syn- group and the final oxidation of the primary one. The first
and anti-7a were transformed into the 3-amino-4-hydroxy attempt was done by selective monoesterification[29] of as-
acids syn-8a and anti-8a in low yields (18 and 20%) by de- partic acid to 10a which was transformed into 11a by re-
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Eur. J. Org. Chem. 2003, 3387Ϫ3397

Enantiopure β-Amino-γ-hydroxy Acids and γ-Amino-δ-hydroxy Acids
FULL PAPER
ductive dibenzylation with benzaldehyde and sodium cy-
Finally, we tested a different protective group of the ter-
anoborohydride in water at pH ϭ 7 followed by reduction minal carboxylic group to avoid the easy lactonization pro-
with diborane of the carboxylic acid,[30] but the final com- cess. To this end, the known compound 17a[32] was con-
pound was obtained in only 13%. In an alternative trans- verted, in excellent yield, into the 2,6,7-trioxabicy-
formation, 10a was protected as benzyloxycarbonyl deriva- clo[2.2.2]octane (OBO) orthoester 19a by treatment with ce-
tive 12a and then converted into 13a by reaction with ethyl sium carbonate and reaction with 3-bromomethyl-3-
chloroformate followed by in situ reduction with sodium methyloxetane in DMF to 18a followed by treatment with
borohydride in THF/MeOH.[31] The change of Z protective boron trifluorideϪdiethyl ether at 0 °C in dichloromethane.
group by two benzyl substituents was tried by hydro- LAH reduction of 19a lead to 20a that was deprotected
genolysis with Pd/C in a solution of hydrochloric acid in
methanol followed by dibenzylation with benzyl bromide
and potassium carbonate in refluxing acetonitrile. Unfortu-
nately, the only isolated product was lactone 14a. Trying to
circumvent this problem, 13a was protected as TBDMS
ether 15a that was subjected to the change of protective
group at nitrogen as described for 13a. In this case com-
pound 16a was isolated in high yield, but it was trans-
formed by deprotection with 1% hydrochloric acid in THF
or acetic acid in water-THF into a mixture of lactone 14a
and 3-N,N-dibenzyl-4-hydroxybutyrate 11a. This acid lac-
tonized quantitatively into 14a after a few days in the re-
frigerator (Scheme 4).
Scheme 5. Reagents and conditions: (i) 1. Cs2CO3, H2O, 20 °C. 2.
Scheme 4. Reagents and conditions: (i) 1. CH3COCl, MeOH, 0 °C.
3-(Bromomethyl)-2-methyloxetane, DMF, 20 °C. (81%). (ii)
2. Propylene oxide, EtOH, reflux. (ii) ZCl, K2CO3, H2O/Et2O, 20 BF3·Et2O, CH2Cl2, Ϫ30 °C. (90%). (iii) LAH, THF, 0 °C. (78%).
°C. (95%). (iii) 1. ClCO2Et, 4-methylmorpholine, THF, Ϫ10 °C. 2. (iv) 1. H2, Pd(OH)2/C, MeOH, room temp. 2. BnBr, K2CO3,
NaBH4, MeOH, 0 °C. (48%). (iv) 1. H2, Pd-C, HCl in MeOH. 2. CH3CN, room temp. (73%). (v) (COCl)2, DMSO, Et3N, CH2Cl2,
BnBr, K2CO3, CH3CN, reflux. (66%). (v) TBDMSCl, imidazole,
DMF, 20 °C. (85%). (vi) 1. H2, Pd-C, MeOH, room temp. 2. BnBr,
Ϫ78 °C. (95%). (vi) Et2Zn, hexane/toluene, 0 °C. (70%). (vii)
EtMgBr, THF/Et2O, 0 °C. (62%). (viii) 2  HCl THF/H2O, reflux.
K2CO3, CH3CN, reflux. (75%). (vii) 1% HCl in THF, 0 °C. 11a 64% for trans-26a, and 52% for syn-24a. (ix) H2, Pd(OH)2-C,
(34%), plus 14a (26%)
MeOH/H2O (1:1). (60%)
Eur. J. Org. Chem. 2003, 3387Ϫ3397
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FULL PAPER
by hydrogenolysis with palladium hydroxide on carbon and best results were obtained by protection of that functional
dibenzylated with benzyl bromide and potassium carbonate group as OBO orthoester derivatives.
to give 21a. Swern oxidation of the protected amino alcohol
lead to the OBO-N,N-dibenzylamino aldehyde 22a in very
good yield (Scheme 5).
Experimental Section
α-Amino aldehyde derivative 22a reacts with diethylzinc
(2 equiv.) in hexane/toluene at 0 °C leading to syn-23a as
a single diastereomer in 70%. The stereochemistry of this
compound was determined by X-ray diffraction studies[33]
(Figure 1), and the configuration at the stereocenter was, as
expected, the predicted by the Cram-chelated model. This
compound was transformed into syn-3-dibenzylamino-4-
hydroxyhexanoic acid (syn-24a) by hydrolysis of the OBO
group with 2  HCl in THF/water, and syn-24a lead to en-
antiopure β-amino-γ-hydroxy acid syn-8a by hydrogenolysis
on Pd(OH)2/C in methanol/water. The reaction of the am-
General: The reactions were carried out in oven-dried glassware,
under argon, and using anhydrous solvents. Starting N,N-dibenzyl-
α-amino aldehydes 1aϪb were prepared by a modified described
method.[19,20] Diethylzinc (1  solution in hexanes) is commercially
available. The 1H NMR (300 MHz) and 13C NMR (75 MHz) spec-
tra were registered with a Bruker AC 300 or Bruker AMX 300,
TMS was used as internal standard. IR spectra were recorded with
a Philips PU 9706 Spectrometer, as film or KBr dispersion. Optical
rotations were measured with a PerkinϪElmer 241 Polarimeter in
a 1-dm cell. Microanalyses were performed with a PerkinϪElmer
2400-CHN elemental analyser.
ino aldehyde 22a with ethylmagnesium bromide (2 equiv.) Amino Alcohol syn-2a: A solution of amino aldehyde 1a (2.0 g,
5 mmol) in anhydrous toluene (60 mL) at 0 °C (ice bath) under
argon was added dropwise to 10 mL of 1  solution of diethylzinc
in hexane (10 mmol, 2 equiv.). The mixture was stirred at 0 °C until
the reaction was finished (TLC), and then quenched with aqueous
saturated solution of ammonium chloride (70 mL). The organic
layer was separated and the aqueous phase was extracted with di-
ethyl ether (3 ϫ 50 mL). The combined organic layers were washed
with brine, and dried with anhydrous Na2SO4. The solvents were
eliminated under vacuum and the residue was purified by flash
chromatography (silica gel, hexane/EtOAc, 25:1): 1.63 g (3.8 mmol,
76%). Colorless oil. [α]2D0 ϭ ϩ28.3 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ
in diethyl ether at 0 °C gave the spiranic adduct anti-25a as
a single diastereomer in 62%. This orthoester was trans-
formed into the lactone trans-26a, derived from anti-8a, as
described for compound syn-23a.
3400, 740, 695 cmϪ1 1H NMR (CDCl3): δ ϭ 0.11 [s, 6 H,
.
Si(CH3)2], 0.93 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 0.94 [s, 9 H,
C(CH3)3], 1.18 (m, 1 H, CHHCH3), 1.58 (m, 2 H, CHHCH3 and
CHHCHN), 2.01 (m, 1 H, CHHCHN), 2.56 (m, 1 H, CHN), 3.43
(m, 1 H, CHOH), 3.45 (d, J ϭ 13.3 Hz, 2 H, CHHPh), 3.73 (t, J ϭ
7.0 Hz, 2 H, TBDMSOCH2), 3.86 (d, J ϭ 13.3 Hz, 2 H, CHHPh),
4.39 (br. s, 1 H, OH), 7.20Ϫ7.40 (m, 10 H, Harom.) ppm. 13C NMR
(CDCl3): δ ϭ Ϫ5.3 (SiCH3), 10.1 (CH3CH2), 18.4 [C(CH3)3], 26.0
[C(CH3)3], 26.6 (CH2CH3), 29.4 (TBDMSOCH2CH2), 54.0
(CH2Ph), 59.4 (CHN), 62.0 (TBDMSOCH2), 71.7 (CHOH), 127.1,
128.4, 129.1 (CHarom.), 139.1 (Carom.) ppm. C26H41NO2Si (427.7):
calcd. C 73.01, H 9.66, N 3.27; found C 73.11, H 9.82, N 3.12.
Amino Alcohol syn-2b: Compound syn-2b was obtained from am-
ino aldehyde 1b (2.06 g, 5 mmol) by reaction with Et2Zn as de-
scribed for compound syn-2a. The product was purified by flash
chromatography (silica gel, hexane/EtOAc, 30:1): 1.48 g
(3.35 mmol, 67%). Colorless oil. [α]2D0 ؍ ϩ36.8 (c ϭ 1.0, CHCl3).
Figure 1. ORTEP representation of X-ray for compound syn-23a
1
IR (film): ν˜ ϭ 3420, 740, 695 cmϪ1. H NMR (CDCl3): δ ϭ 0.10
The formation of the spiranic orthoester anti-25a can be
explained as a consequence of the intramolecular displace-
ment of one of the alkoxy group of the OBO derivative by
the intermediate alkoxide A formed by reaction of 22a with
the Grignard derivative (Scheme 5).
In summary, the disclosed methodology constitutes a
stereodivergent synthesis of enantiopure 3-amino-4-
hydroxyhexanoic acids or 4-amino-5-hydroxyheptanoic acid
derivatives from easily available -aspartic and -glutamic
acids, respectively. The key step of the transformation is the
diastereoselective alkylation of the chiral α-amino alde-
hydes, obtained from the corresponding amino acids, by
zinc or magnesium derivatives. The election of the protec-
tive group of the additional carboxylic group has been
(s, 3 H, CH3Si), 0.11 (s, 3 H, CH3Si), 0.91 (t, J ϭ 6.2 Hz, 3 H,
CH3CH2), 0.95 [s, 9 H, C(CH3)3], 1.16 (m, 1 H, CHHCH3), 1.34
(m, 1 H, CHHCHN), 1.60 (m, 1 H, CHHCH3), 1.66 (m, 2 H,
CH2CH2CHN), 1.80 (m, 1 H, CHHCHN), 2.43 (m, 1 H, CHN),
3.43 (m, 1 H, CHOH), 3.45 (d, J ϭ 13.2 Hz, 2 H, CHHPh), 3.64
(t, J ϭ 6.2 Hz, 2 H, TBDMSOCH2), 3.88 (d, J ϭ 13.2 Hz, 2 H,
CHHPh), 4.47 (br. s, 1 H, OH), 7.20Ϫ7.35 (m, 10 H, Harom.) ppm.
13C NMR (CDCl3): δ ϭ Ϫ5.3 [(CH3)2Si], 10.2 (CH3CH2), 18.3
[C(CH3)3], 22.0 (CH2CHN), 25.9 [C(CH3)3], 26.7 (CH2CH3), 32.4
(CH2CH2CHN), 53.9 (CH2Ph), 62.4 (CHN), 62.9 (TBDMSOCH2),
71.7 (CHOH), 127.1, 128.4, 129.1 (CHarom.), 138.9 (Carom.) ppm.
C27H43NO2Si (441.7): calcd. C 73.41, H 9.81, N 3.17; found C
73.54, H 10.01, N 2.98.
Amino Alcohol anti-2a: A solution of EtMgBr (8.4 mmol, 1.25
shown to be crucial for the total yield of the process. The equiv.) in diethyl ether (12 mL) at 0 °C was added dropwise to a
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Eur. J. Org. Chem. 2003, 3387Ϫ3397

Enantiopure β-Amino-γ-hydroxy Acids and γ-Amino-δ-hydroxy Acids
solution of amino aldehyde 1a (2.7 g, 6.7 mmol) in diethyl ether
FULL PAPER
0.90 [s, 9 H, (CH3)3C], 1.06 (t, J ϭ 7.4 Hz, 3 H, CH2CH3), 1.65
(12 mL). After stirring at this temperature for 1 h, saturated NH4Cl (m, 4 H, CHHCH3 and CH2CHN), 3.78 (m, 2 H, TBDMSOCH2),
(40 mL) was added and the mixture was extracted with diethyl
ether (2 ϫ 20 mL). The combined organic layers were washed with
brine, dried with anhydrous Na2SO4 and the solvent evaporated
under vacuum. After flash chromatography (silica gel: hexane/
EtOAc, 15:1), the compound anti-2a was obtained as a colorless
oil: 2.01 g (4.7 mmol, 70%). [α]2D0 ϭ ϩ10.7 (c ϭ 1.0, CHCl3). IR
(film): ν˜ ϭ 3420, 740, 690 cmϪ1. 1H NMR (CDCl3): δ ϭ 0.03 (s, 3
H, SiCH3), 0.05 (s, 3 H, SiCH3), 0.87 (t, J ϭ 7.4 Hz, 3 H,
CH3CH2), 0.87 [s, 9 H, C(CH3)3], 1.37 (m, 1 H, CHHCH3), 1.73
(m, 2 H, CHHCH3 and CHHCHN), 2.01 (m, 1 H, CHHCHN),
2.69 (m, 1 H, CHN), 3.00 (d, J ϭ 5.8 Hz, 1 H, OH), 3.53 (d, J ϭ
13.8 Hz, 2 H, CHHPh), 3.58 (m, 2 H, TBDMSOCHH and
CHOH), 3.71 (d, J ϭ 13.8 Hz, 2 H, CHHPh), 3.84 (m, 1 H,
TBDMSOCHH), 7.20Ϫ7.40 (m, 10 H, Harom.) ppm. 13C NMR
(CDCl3): δ ϭ Ϫ0.5 [Si(CH3)2], 10.2 (CH3CH2), 18.2 [C(CH3)3],
25.9 [C(CH3)3], 27.8 (CH2CH3), 28.5 (TBDMSOCH2CH2), 54.7
(CH2Ph), 59.4 (CHN): 62.4 (TBDMSOCH2), 72.9 (CHOH), 126.8,
128.1, 128.8 (CHarom.), 139.9 (Carom.) ppm. C26H41NO2Si (427.7):
calcd. C 73.01, H 9.66, N 3.27; found C 73.23, H 9.86, N 3.09.
3.92 (ddd, J1 ϭ 8.8, J2 ϭ 7.6, J3 ϭ 4.4 Hz, 1 H, CHN), 4.51 (ddd,
J1 ϭ 9.7, J2 ϭ 7.6, J3 ϭ 4.2 Hz, 1 H, CHO), 5.75 (br. s, 1 H, NH)
ppm. C13H27NO3Si (273.4): calcd. C 57.10, H 9.95, N 5.12; found
C 56.92, H 9.78, N 5.24.
Oxazolidinone trans-3b: Oxazolidinone trans-3b was prepared from
syn-2b (88 mg, 0.2 mmol) using the same procedure as for trans-3a,
and purified by flash chromatography (silica gel, hexane/EtOAc,
3:1): 26 mg (0.09 mmol, 46%). Colorless oil. [α]2D0 ؍ ؊43.5 (c ϭ
1.1, CHCl3). IR (film): ν˜ ϭ 3260, 1740, 1460, 1385 cmϪ1. 1H NMR
(CDCl3): δ ϭ 0.06 (s, 6 H, CH3Si), 0.89 (s, 9 H, CCH3), 1.02 (t,
J ϭ 7.4 Hz, 3 H, CH3CH2), 1.55Ϫ1.80 (m, 6 H, CH2CHN,
CH2CH2CHN, CH2CH3), 3.48 (m, 1 H, CHN), 3.65 (t, J ϭ 5.5 Hz,
2 H, TBDMSOCH2), 4.10 (dt, J1 ϭ 5.7, J2 ϭ 6.7 Hz, 1 H, CHO),
6.17 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.4
[(CH3)2Si], 9.0 (CH3CH2), 18.3 [C(CH3)3], 25.9 [C(CH3)3], 27.7
(CH2CH3), 28.7 (CH2CHN), 32.6 (TBDMSOCH2CH2), 57.5
(CHN), 62.5 (TBDMSOCH2), 83.8 (CHO), 159.2 (NHCO2) ppm.
C14H29NO3Si (287.5): calcd. C 58.49, H 10.17, N 4.87; found C
58.32 H 10.38, N 4.75.
Amino Alcohol anti-2b: Compound anti-2b was obtained from am-
ino aldehyde 1b (2.06 g, 5 mmol) by reaction with EtMgBr as de-
scribed for compound anti-2a. The product was purified by flash
chromatography (silica gel, hexane/EtOAc, 20:1): 1.61 g
(3.65 mmol, 73%). Colorless oil. [α]2D0 ؍ ϩ24.4 (c ϭ 1.0, CHCl3).
Oxazolidinone cis-3b: Oxazolidinone cis-3b was prepared from anti-
2b (88 mg, 0.2 mmol) using the same procedure as for trans-3a, and
purified by flash chromatography (silica gel, hexane/EtOAc, 3:1):
29 mg (0.1 mmol, 50%). Colorless solid. M.p. 100Ϫ102 °C (from
hexane). [α]2D0 ϭ Ϫ9.6 (c ϭ 1.9, CHCl3). IR (KBr): ν˜ ϭ 3250, 1730,
1
IR (film): ν˜ ϭ 3420, 740, 690 cmϪ1. H NMR (CDCl3): δ ϭ 0.04
1
1450, 1380 cmϪ1. H NMR (CDCl3): δ ϭ 0.06 [s, 6 H, (CH3)2Si],
(s, 3 H, CH3Si), 0.05 (s, 3 H, CH3Si), 0.90 [s, 9 H, C(CH3)3], 0.92
(t, J ϭ 7.3 Hz, 3 H, CH3CH2), 1.35 (m, 1 H, CHHCH3), 1.54 (m,
3 H, CHHCH3, CHHCH2CHN), 1.75 (m, 2 H, CHHCHN), 2.16
(br. s, 1 H, OH), 2.64 (m, 1 H, CHN), 3.58 (m, 3 H, CHOH,
0.89 [s, 9 H, C(CH3)3], 1.06 (t, J ϭ 7.3 Hz, 3 H, CH3CH2),
1.45Ϫ1.85 (m, 6 H, CH2CH3, CH2CH2CHN, CH2CHN), 3.66 (m,
2 H, TBDMSOCH2), 3.78 (m, 1 H, CHN), 4.50 (ddd, J1 ϭ 9.6,
J2 ϭ 7.5, J3 ϭ 4.4 Hz, 1 H, CHO), 6.17 (br. s, 1 H, NH) ppm. 13C
NMR (CDCl3): δ ϭ Ϫ5.4 [(CH3)2Si], 10.4 (CH3CH2), 18.2
[C(CH3)3], 22.4 (CH2CH3), 25.9 [C(CH3)3], 26.9 (CH2CHN), 29.2
(TBDMSOCH2CH2), 55.5 (CHN), 62.6 (TBDMSOCH2), 81.7
(CHO), 159.6 (NHCO2) ppm. C14H29NO3Si (287.5): calcd. C
58.49, H 10.17, N 4.87; found C 58.26, H 10.36, N 4.69.
TBDMSOCH2), 3.67 (s, 4 H, CH2Ph), 7.20Ϫ7.35 (m, 10 H, Harom.
)
ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.3 [(CH3)2Si], 11.0 (CH3CH2),
18.3 [C(CH3)3], 21.3 (CH2CHN), 25.9 [C(CH3)3], 27.6 (CH2CH3),
30.6 (CH2CH2CHN), 54.9 (CH2Ph), 60.5 (CHN), 63.0
(TBDMSOCH2), 72.5 (CHOH), 126.9, 128.2, 128.9 (CHarom.),
140.0 (Carom.) ppm. C27H43NO2Si (441.7): calcd. C 73.41, H 9.81,
N 3.17; found C 73.68, H 9.97, N 2.95.
Protected Aminodiol syn-4a: A solution of syn-2a (1.32 g, 3 mmol)
and diisopropylethylamine (1.62 mL, 9.3 mmol) in CH2Cl2 (25 mL)
at 0 °C was added dropwise to MEM chloride (1.02 mL, 9 mmol).
After 16 h at room temperature, the reaction was quenched with
saturated aqueous NH4Cl (35 mL). The aqueous phase was ex-
tracted with CH2Cl2 (3 ϫ 25 mL), and the combined organic layers
were washed with brine, dried (MgSO4), concentrated and chroma-
tographed (silica gel, hexane/EtOAc, 20:1) to give syn-4a as a color-
less oil: 1.21 g (2.34 mmol, 78%). Colorless oil. [α]2D0 ϭ ϩ25.6 (c ϭ
1.0, CHCl3). IR (film): ν˜ ϭ 740, 700 cmϪ1. 1H NMR (CDCl3): δ ϭ
0.04 (s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3), 0.41 (t, J ϭ 7.4 Hz, 3
H, CH3CH2), 0.88 [s, 9 H, C(CH3)3], 1.58 (m, 1 H, CHHCH3), 1.81
(m, 2 H, CHHCH3 and CHHCHN), 1.96 (m, 1 H, CHHCHN),
2.81 (m, 1 H, CHN), 3.37 (s, 3 H, OCH3), 3.42 (d, J ϭ 13.4 Hz, 2
H, CHHPh), 3.44 (m, 1 H, CHOMEM), 3.51 (m, 2 H, CH2O),
3.68 (m, 4 H, CH2O and CH2OTBDMS), 3.95 (d, J ϭ 13.4 Hz, 2
H, CHHPh), 4.64 (d, J ϭ 7.0 Hz, 1 H, OCHHO), 4.71 (d, J ϭ
7.0 Hz, 1 H, OCHHO), 7.15Ϫ7.40 (m, 10 H, CHarom.) ppm. 13C
NMR (CDCl3): δ ϭ Ϫ5.3 [Si (CH3)2], 9.7 (CH3CH2), 18.3
Oxazolidinone trans-3a: A solution of compound syn-2a (86 mg,
0.2 mmol) in MeOH (5 mL) and Pd(OH)2/C (25 mg) was stirred for
1 h under hydrogen. The catalyst was removed by filtration through
celite, washed with methanol, and the solvent was evaporated under
reduced pressure. A stirred solution of the residue and diisopropy-
lethylamine (87 µL, 0.5 mmol, 2.5 equiv.) in anhydrous CH2Cl2
(6 mL) at 0 °C was added to triphosgene (30 mg, 0.1 mmol, 0.5
equiv.). The reaction solution was warmed to room temperature
with stirring for 2 h. H2O (2.5 mL) and EtOAc (20 mL) were added
to the mixture, and the organic phase was separated, dried with
anhydrous MgSO4, concentrated under reduced pressure and chro-
matographed (silica gel, hexane/EtOAc, 3:1) to afford trans-3a as
colorless oil: 39 mg (0.14 mmol, 72%). [α]2D0 ؍ ؊39.1 (c ϭ 0.4,
1
CHCl3). H NMR (CDCl3): δ ϭ 0.07 [s, 6 H, (CH3)2Si], 0.90 [s, 9
H, (CH3)3C], 1.03 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 1.75 (m, 4 H,
CH2CH3 and CH2CHN), 3.58 (ddd, J1 ϭ 8.6, J2 ϭ 6.3, J3
ϭ
4.0 Hz, 1 H, CHNH), 3.76 (m, 2 H, TBDMSOCH2), 4.16 (ddd,
J1 ϭ 6.7, J2 ϭ 6.3, J3 ϭ 5.7 Hz, CHO), 5.30 (br. s, 1 H, NH) ppm.
C13H27NO3Si (273.4): calcd. C 57.10, H 9.95, N 5.12; found C
57.18, H 9.69, N 5.32.
[C(CH3)3],
23.9
(CH2CH3),
26.0
[C(CH3)3],
27.4
(TBDMSOCH2CH2), 54.0 (CHN), 55.4 (CH2Ph), 59.0 (OCH3),
61.0 (TBDMSOCH2), 67.2 (OCH2CH2O), 71.7 (OCH2CH2O),
81.80 (CHOH), 95.2 (OCH2O), 126.6, 127.9, 129.2 (CHarom.), 140.9
(Carom.) ppm. C30H49NO4Si (515.8): calcd. C 69.86, H 9.58, N 2.72;
found C 69.74, H 9.78, N 2.80.
Oxazolidinone cis-3a: This compound was prepared from anti-2a
(86 mg, 0.20 mmol) by the same procedure as for trans-3a. It was
obtained as colorless oil: 38 mg (0.14 mmol, 70%). [α]2D0 ؍ ؊12.9
1
(c ϭ 0.4, CHCl3). H NMR (CDCl3): δ ϭ 0.10 [s, 6 H, (CH3)2Si],
Eur. J. Org. Chem. 2003, 3387Ϫ3397
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3391

´
´
J. M. Andres, E. M. Mun˜oz, R. Pedrosa, A. Perez-Encabo
FULL PAPER
Protected Aminodiol anti-4a: This compound was obtained from
amino alcohol anti-2a (1.92 g, 4.5 mmol) by the method described
for syn-4a, and purified by flash chromatography (hexane/EtOAc,
20:1): 1.74 g (3.37 mmol, 75%). Colorless oil. [α]2D0 ϭ Ϫ9.0 (c ϭ 1.0,
Amino Alcohol syn-5a: A solution of syn-4a (1.14 g, 2.2 mmol) in
THF (20 mL) at 0 °C was slowly added to a solution of tetrabu-
tylammonium fluoride (1.05 g, 3.3 mmol) in THF (5 mL). The mix-
ture was stirred at 0 °C during 8 h, and the reaction was quenched
CHCl3). IR (film): ν˜ ϭ 740, 695 cmϪ1 1H NMR (CDCl3): δ ϭ by addition of water (20 mL). The aqueous phase was extracted
.
0.04 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3), 0.62 (t, J ϭ 7.4 Hz, 3 with diethyl ether (2 ϫ 25 mL), and the combined organic extracts
H, CH3CH2), 0.89 [s, 9 H, C(CH3)3], 1.53 (m, 1 H, CHHCH3), 1.70 were washed with brine, dried (Na2SO4), concentrated and chroma-
(m, 2 H, CHHCH3 and CHHCHN), 1.96 (m, 1 H, CHHCHN), tographed (silica gel, hexane/EtOAc, 3:2) to yield syn-5a as color-
2.72 (m, 1 H, CHN), 3.40 (s, 3 H, OCH3), 3.55 (m, 2 H, OCH2-
less oil: 0.75 g (1.87 mmol, 85%). Colorless oil. [α]2D0 ϭ Ϫ35.8 (c ϭ
CH2O), 3.57 (d, J ϭ 13.6 Hz, 2 H, CHHPh), 3.73 (m, 5 H, 1.0, CHCl3). IR (film): ν˜ ϭ 3440, 750, 700 cmϪ1 1H NMR
(CDCl3): δ ϭ 0.68 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 1.57 (m, 1 H,
CHHCH3), 1.74 (m, 2 H, CHHCH2OH y CHHCH3), 1.92 (m, 1
.
TBDMSOCH2, CHOMEM, OCH2CH2O), 3.74 (d, J ϭ 13.6 Hz, 2
H, CHHPh), 4.75 (d, J ϭ 7.0 Hz, 1 H, OCHHO), 4.81 (d, J ϭ
7.0 Hz, 1 H, OCHHO), 7.20Ϫ7.40 (m, 10 H, CHarom.) ppm. 13C H, CHHCH2OH), 2.83 (m, 1 H, CHN), 3.15 (br. s, 1 H, OH), 3.40
NMR (CDCl3):
δ
ϭ
Ϫ0.5 [Si(CH3)2], 9.3 (CH3CH2), 18.9 (s, 3 H, OCH3), 3.50Ϫ3.70 (m, 6 H, OCH2CH2O, CHOMEM and
[C(CH3)3], 24.6
(CH2CH3), 26.0 [C(CH3)3], 29.7 CH2CHHOH), 3.63 (d, J ϭ 13.2 Hz, 2 H, CHHPh), 3.84 (m, 1 H,
(TBDMSOCH2CH2), 54.4 (CH2Ph), 55.2 (CHN), 59.0 (OCH3), CH2CHHOH), 3.85 (d, J ϭ 13.2 Hz, 2 H, CHHPh), 4.71 (d, J ϭ
62.1 (TBDMSOCH2), 67.4 (OCH2CH2O), 71.8 (OCH2CH2O), 79.3 10.1 Hz, 1 H, OCHHO), 4.72 (d, J ϭ 10.1 Hz, 1 H, OCHHO),
(CHOMEM), 95.0 (OCH2O), 126.7, 128.0, 128.9 (CHarom.), 140.3 7.20Ϫ7.40 (m, 10 H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ 9.5
(Carom.) ppm. C30H49NO4Si (515.8): calcd. C 69.86, H 9.58, N 2.72;
found C 69.68, H 9.84, N 2.92.
(CH3CH2), 24.3 (CH2CH3), 27.6 (CH2CHN), 54.8 (CH2Ph), 56.6
(CHN), 58.9 (OCH3), 61.7 (CH2OH), 67.6 (OCH2CH2O), 71.8
(OCH2CH2O), 81.4 (CHOMEM), 95.2 (OCH2O), 126.8, 128.1,
129.2 (CHarom.), 140.0 (Carom.) ppm. C24H35NO4 (401.5): calcd. C
71.79, H 8.79, N 3.49; found C 71.51, H 8.67, N 3.71.
Protected Aminodiol syn-4b: The compound syn-4b was obtained
from amino alcohol syn-2b (1.37 g, 3.1 mmol) by the method de-
scribed for syn-4a, and purified by flash chromatography (CH2Cl2/
hexane, 2:1): 1.22 g (2.3 mmol, 74%). Colorless oil. [α]2D0 ؍ ϩ25.1
(c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ 1600, 1490, 1450, 1360, 1250, 750,
Amino Alcohol anti-5a: The amino alcohol anti-5a was obtained
from anti-4a (1.47 g, 2.85 mmol) by the method described for syn-
5a and purified by flash chromatography (silica gel, hexane/EtOAc,
3:2): 0.92 g (2.28 mmol, 80%). Colorless oil. [α]2D0 ϭ Ϫ55.0 (c ϭ 1.1,
1
700 cmϪ1. H NMR (CDCl3): δ ϭ 0.07 [s, 6 H, (CH3)2Si], 0.48 (t,
CHCl3). IR (film): ν˜ ϭ 3420, 740, 695 cmϪ1 1H NMR (CDCl3):
.
J ϭ 7.4 Hz, 3 H, CH3CH2), 0.92 [s, 9 H, C(CH3)3], 1.57 (m, 4 H,
CHHCH3, CHHCHN, CH2CH2CHN), 1.78 (m, 2 H, CHHCH3,
CHHCHN), 2.53 (m, 1 H, CHN), 3.37 (s, 3 H, OCH3), 3.45 (d,
J ϭ 13.4 Hz, 2 H, CHHPh), 3.52 (m, 3 H, CHOMEM, OCH2-
CH2O), 3.59 (m, 2 H, TBDMSOCH2), 3.68 (m, 2 H, OCH2CH2O),
3.95 (d, J ϭ 13.4 Hz, 2 H, CHHPh), 4.64 (d, J ϭ 7.0 Hz, 1 H,
OCHHO), 4.71 (d, J ϭ 7.0 Hz, 1 H, OCHHO), 7.15Ϫ7.40 (m, 10
H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.3 [(CH3)2Si], 9.9
(CH3CH2), 18.3 [C(CH3)3], 20.3 (CH2CH3), 24.1 (CH2CHN)), 26.0
[C(CH3)3], 30.7 (CH2CH2CHN), 55.3 (CH2Ph), 57.6 (CHN), 59.0
(OCH3), 63.2 (TBDMSOCH2), 67.3 (OCH2CH2O), 71.7 (OCH2-
CH2O), 81.5 (CHOMEM), 95.3 (OCH2O), 126.6, 128.0, 129.2
(CHarom.), 140.9 (Carom.) ppm. C31H51NO4Si (529.8): calcd. C
70.27, H 9.70, N 2.64; found C 70.47, H 9.88, N 2.38.
δ ϭ 0.71 (t, J ϭ 7.5 Hz, 3 H, CH3CH2), 1.50 (m, 1 H, CHHCH3),
1.60 (m, 1 H, CHHCHN), 1.75 (m, 1 H, CHHCH3), 2.12 (m, 1 H,
CHHCHN), 2.80 (m, 1 H, CHN), 3.39 (s, 3 H, OCH3), 3.46 (d,
J ϭ 13.5 Hz, 2 H, CHHPh), 3.55 (m, 2 H, OCH2CH2O), 3.62 (m,
1 H, CHHOH), 3.74 (m, 3 H, OCH2CH2O and CHHOH), 3.88
(m, 1 H, CHOMEM), 3.90 (d, J ϭ 13.5 Hz, 2 H, CHHPh), 4.79
(d, J ϭ 7.1 Hz, 1 H, OCHHO), 4.86 (d, J ϭ 7.1 Hz, 1 H, OCHHO),
7.20Ϫ7.35 (m, 10 H, CHarom.) ppm. 13C NMR (CDCl3): δ ϭ 9.4
(CH3CH2), 24.8 (CH2CH3), 27.3 (CH2CHN), 54.1 (CH2Ph), 58.2
(CHN), 58.9 (OCH3), 62.6 (CH2OH), 67.7 (OCH2CH2O), 71.6
(OCH2CH2O), 77.4 (CHOMEM), 94.9 (OCH2O), 127.0, 128.2,
129.0 (CHarom.), 139.2 (Carom.) ppm. C24H35NO4 (401.5): calcd. C
71.79, H 8.79, N 3.49; found C 71.70, H 8.62, N 3.63.
Amino Alcohol syn-5b: The amino alcohol syn-5b was obtained
from syn-4b (1.06 g, 2 mmol) by the method described for syn-5a
and purified by flash chromatography (silica gel, hexane/EtOAc,
2:1): 657 mg (1.58 mmol, 79%). Colorless oil. [α]2D0 ؍ ϩ54.4 (c ϭ
Protected Amino-diol anti-4b: The compound anti-4b was obtained
from amino alcohol anti-2b (1.55 g, 3.5 mmol) by the method de-
scribed for syn-4a, and purified by flash chromatography (CH2Cl2):
1.30 g (2.45 mmol, 70%). Colorless oil. [α]2D0 ؍ Ϫ3.4 (c ϭ 1.0,
1.0, CHCl3). IR (film): ν˜ ϭ 3380, 755, 705 cmϪ1 1H NMR
.
1
CHCl3). IR (film): ν˜ ϭ 1595, 1490, 1450, 1360, 745, 700 cmϪ1. H
(CDCl3): δ ϭ 0.47 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 1.45Ϫ1.85 (m, 6
H, CHHCH3, CH2CHHCHN), 2.15 (br. s, 1 H, OH), 2.55 (m, 1
H, CHN), 3.39 (s, 3 H, OCH3), 3.45 (d, J ϭ 13.4 Hz, 2 H,
CHHPh), 3.55 (m, 5 H, CHOMEM, OCH2CH2O and CH2OH),
3.65 (m, 1 H, OCHHCH2O), 3.84 (m, 1 H, OCHHCH2O), 3.98 (d,
J ϭ 13.4 Hz, 2 H, CHHPh), 4.64 (d, J ϭ 7.2 Hz, 1 H, OCHHO),
NMR (CDCl3): δ ϭ 0.02 (s, 3 H, CH3Si), 0.03 (s, 3 H, CH3Si),
0.62 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 0.88 [s, 9 H, C(CH3)3], 1.49
(m, 3 H, CHHCH3, CHHCHN and CHHCH2OTBDMS), 1.70 (m,
3 H, CHHCH3, CHHCHN and CHHCH2OTBDMS), 2.56 (m, 1
H, CHN), 3.37 (s, 3 H, OCH3), 3.52 (m, 4 H, OCH2CH2O and
CH2OTBDMS), 3.53 (d, J ϭ 13.8 Hz, 2 H, CHHPh), 3.71 (m, 3
H, CHOMEM and OCH2CH2O), 3.76 (d, J ϭ 13.8 Hz, 2 H,
CHHPh), 4.72 (d, J ϭ 7.0 Hz, 1 H, OCHHO), 4.77 (d, J ϭ 7.0 Hz,
1 H, OCHHO), 7.15Ϫ7.35 (m, 10 H, Harom.) ppm. 13C NMR
(CDCl3): δ ϭ Ϫ5.3 [(CH3)2Si], 9.4 (CH3CH2), 18.3 [C(CH3)3], 21.9
(CH2CH3), 24.9 (CH2CHN), 26.0 [C(CH3)3], 31.3 (CH2CH2CHN),
54.3 (CH2Ph), 58.1 (CHN), 59.0 (OCH3), 63.2 (TBDMSOCH2),
67.4 (OCH2CH2O), 71.8 (OCH2CH2O), 79.1 (CHOMEM), 95.1
(OCH2O), 126.7, 128.0, 128.9 (CHarom.), 140.4 (Carom.) ppm.
4.72 (d, J ϭ 7.2 Hz, 1 H, OCHHO), 7.20Ϫ7.40 (m, 10 H, Harom.
)
ppm. 13C NMR (CDCl3): δ ϭ 9.9 (CH3CH2), 20.3 (CH2CHN),
24.0 (CH2CH3), 30.6 (CH2CH2CHN), 55.3 (CH2Ph), 57.7 (CHN),
59.1 (OCH3), 63.0 (CH2OH), 67.6 (OCH2CH2O), 71.9 (OCH2-
CH2O), 81.5 (CHOMEM), 95.3 (OCH2O), 126.7, 128.0, 129.2
(CHarom.), 140.8 (Carom.) ppm. C25H37NO4 (415.6): calcd. C 72.26,
H 8.97, N 3.37; found C 72.52, H 9.15, N 3.12.
Amino Alcohol anti-5b: The amino alcohol anti-5b was obtained
C31H51NO4Si (529.8): calcd. C 70.27, H 9.70, N 2.64; found C from anti-4b (1.27 g, 2.4 mmol) by the method described for syn-
70.38, H 9.90, N 2.44. 5a and purified by flash chromatography (silica gel, hexane/EtOAc,
3392
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3387Ϫ3397

Enantiopure β-Amino-γ-hydroxy Acids and γ-Amino-δ-hydroxy Acids
2:1): 870 mg (2.09 mmol, 87%). Colorless oil. [α]2D0 ϭ Ϫ23.2 (c ϭ
FULL PAPER
4.79 (d, J ϭ 7.1 Hz, 1 H, OCHHO), 4.82 (d, J ϭ 10.5 Hz, 1 H,
1.0, CHCl3). IR (film): ν˜ ϭ 3440, 750, 695 cmϪ1 1H NMR NH) ppm. 13C NMR (CDCl3): δ ϭ 9.8 (CH3CH2), 24.0 (CH2CH3),
.
(CDCl3): δ ϭ 0.66 (t, J ϭ 7.5 Hz, 3 H, CH3CH2), 1.61 (m, 6 H,
28.2 [C(CH3)3], 28.9 (CH2CHN), 29.4 (CH2CH2CHN), 51.4
CHHCH2CHN, CHHCH3, CHHCHN), 2.61 (m, 1 H, CHN), 3.38 (CHN), 58.8 (OCH3), 62.1 (CH2OH), 67.2 (OCH2CH2O), 71.6
(s, 3 H, OCH3), 3.54 (d, J ϭ 13.8 Hz, 2 H, CHHPh), 3.56 (m, 4 H, (OCH2CH2O), 78.8 [C(CH3)3], 80.3 (CHOMEM), 94.7 (OCH2O),
OCH2CH2O), 3.71 (m, 2 H, CH2OH), 3.78 (m, 1 H, CHOMEM),
156.1 (NHCO2) ppm. C16H33NO6 (335.4): calcd. C 57.29, H 9.92,
3.79 (d, J ϭ 13.8 Hz, 2 H, CHHPh), 4.75 (d, J ϭ 7.0 Hz, 1 H, N 4.18; found C 57.08, H 10.06, N 4.02.
OCHHO), 4.80 (d, J ϭ 7.0 Hz, 1 H, OCHHO), 7.20Ϫ7.40 (m, 10
Amino Alcohol anti-6b: The amino alcohol anti-6b was obtained
H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ 9.4 (CH3CH2), 22.1
(CH2CHN), 24.9 (CH2CH3), 31.1 (CH2CH2CHN), 54.2 (CH2Ph),
58.1 (CHN), 59.0 (OCH3), 62.9 (CH2OH), 67.5 (OCH2CH2O), 71.7
(OCH2CH2O), 78.9 (CHOMEM), 95.1 (OCH2O), 126.7, 128.0,
128.9 (CHarom.), 140.1 (Carom.) ppm. C25H37NO4 (415.6): calcd. C
72.26, H 8.97, N 3.37; found C 72.16, H 8.90, N 3.31.
from anti-5b (831 mg, 2 mmol) by the method described for syn-6a
and purified by flash chromatography (silica gel, hexane/EtOAc,
1:1): 403 mg (1.2 mmol, 60%). Colorless oil. [α]2D0 ϭ Ϫ48.0 (c ϭ
1.0, CHCl3). IR (film): ν˜ ϭ 3340, 1685, 1450, 1365 cmϪ1. 1H NMR
(CDCl3): δ ϭ 0.94 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 1.44 [s, 9 H,
C(CH3)3], 1.60 (m, 6 H, CHHCHN, CH2CH2CHN, CHHCH3),
3.40 (s, 3 H, OCH3), 3.47 (m, 1 H, CHOMEM), 3.58 (m, 2 H,
Amino Alcohol syn-6a: A solution of dibenzylamino alcohol syn-5a
(574 mg, 1.43 mmol) in EtOAc (15 mL) was added to di-tert-butyl OCH2CH2O), 3.66 (m, 4 H, CH2OH, OCH2CH2O), 3.81 (m, 1 H,
dicarbonate (468 mg, 2.15 mmol, 1.5 equiv.) and Pd(OH)2/C
(145 mg) in one portion. The mixture was stirred under 1 hydrogen
and the reaction monitored by TLC. When the reaction was com-
pleted, the catalyst was removed by filtration through celite and
washed with EtOAc (25 mL). The solvent was concentrated under
reduced pressure and the residue purified by flash chromatography
(silica gel, hexane/EtOAc, 1:1): 303 mg (0.94 mmol, 66%). Colorless
oil. [α]2D0 ϭ ϩ13.9 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ 3450, 1690
cmϪ1. 1H NMR (CDCl3): δ ϭ 0.91 (t, J ϭ 7.4 Hz, 3 H, CH3CH2),
1.45 [s, 9 H, (CH3)3C], 1.65 (m, 4 H, CH2CH3, HOCH2CH2), 3.39
(s, 3 H, CH3O), 3.49 (m, 1 H, CHOMEM) 3.55 (m, 2 H, OCH2-
CH2O), 3.66 (m, 2 H, CH2OH), 3.75 (m, 2 H, OCH2CH2O), 3.89
(m, 1 H, CHN), 4.70 (d, J ϭ 7.1 Hz, 1 H, OCHHO), 4.80 (d, J ϭ
7.1 Hz, 1 H, OCHHO), 4.95 (d, J ϭ 9.4 Hz, 1 H, NH) ppm. 13C
CHN), 4.71 (d, J ϭ 7.2 Hz, 1 H, OCHHO), 4.80 (d, J ϭ 7.2 Hz, 1
H, OCHHO), 5.45 (d, J ϭ 9.6 Hz, 1 H, NH) ppm. 13C NMR
(CDCl3): δ ϭ 10.2 (CH3CH2), 25.2 (CH2CH3), 25.5 (CH2CHN),
28.4 [C(CH3)3], 29.0 (CH2CH2OH), 52.2 (CHN), 59.0 (OCH3), 62.6
(CH2OH), 67.4 (OCH2CH2O), 71.7 (OCH2CH2O), 78.9 [C(CH3)3],
85.0 (CHOMEM), 96.3 (OCH2O), 156.2 (NHCO2) ppm.
C16H33NO6 (335.4): calcd. C 57.29, H 9.92, N 4.18; found C 57.11,
H 10.12, N 4.00.
Amino Acid syn-7a: A solution of syn-6a (289 mg, 0.9 mmol) in
freshly distilled DMF (4 mL) was slowly added to PDC (1.69 g,
4.5 mmol, 5 equiv.). The orange suspension was stirred at room
temperature overnight, and quenched by addition of H2O (30 mL).
The solution was extracted with diethyl ether (10 ϫ 25 mL), the
combined ethereal layers were washed with H2O and saturated
NaCl solution, dried (MgSO4) and the volatiles were evaporated.
The residue was purified by flash chromatography (silica gel, hex-
ane/EtOAc, 1:4) to yield syn-7a as colorless oil: 214 mg (0.64 mmol,
71%). Colorless oil. [α]2D0 ϭ ϩ14.8 (c ϭ 0.7, CHCl3). IR (film): ν˜ ϭ
3280, 1700 cmϪ1.1H NMR (CDCl3): δ ϭ 0.93 (t, J ϭ 7.4 Hz, 3 H,
CH2CH3), 1.44 [s, 9 H, (CH3)3C], 1.56 (m, 2 H, CH2CH3), 2.61
(m, 2 H, CH2CO2H), 3.40 (s, 3 H, CH3O), 3.57 (m, 1 H, CHO-
MEM), 3.57 (m, 2 H, OCH2CH2O), 3.68 (m, 1 H, OCHHCH2O),
NMR (CDCl3):
δ ϭ 9.7 (CH2CH3), 24.3 (CH2CH3), 28.2
[(CH3)3C], 36.4 (CH2CHN), 48.3 (CHN), 58.6 (CH2OH), 58.9
(OCH3), 67.2 (OCH2CH2O), 71.6 (OCH2CH2O), 79.6 [C(CH3)3],
80.6 (CHOMEM), 94.7 (OCH2O), 157.3 (CO2tBu) ppm.
C15H31NO6 (321.41): calcd. C 56.05, H 9.72, N 4.36; found C
55.80, H 9.75, N 4.30.
Amino Alcohol anti-6a: The compound anti-6a was obtained from
anti-5a (602 mg, 1.5 mmol) by the method described for syn-6a.
Yield: 328 mg (1.02 mmol, 68%). Colorless oil. [α]2D0 ϭ Ϫ62.2 3.78 (m, 1 H, OCHHCH2O), 4.16 (m, 1 H, CHN), 4.72 (d, J ϭ
(CHCl3, c ϭ 1.0). IR (film): ν˜ ϭ 3340, 1680 cmϪ1
(CDCl3): δ ϭ 0.94 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 1.45 (m, 2 H, (d, J ϭ 9.4 Hz, 1 H, NH) ppm. 13C NMR (CDCl3): δ ϭ 9.7
CHHCH3 and CHHCH2OH; 1.46 [s, 9 H, C(CH3)3], 1.62 (m, 1 H, (CH2CH3), 24.1 (CH2CH3), 28.3 [C(CH3)3], 37.4 (CH2CHN), 48.8
.
1H NMR
7.1 Hz, 1 H; OCHHO), 4.77 (d, J ϭ 7.1 Hz, 1 H, OCHHO), 5.05
CHHCH3), 1.81 (m, 1 H, CHHCH2OH), 3.40 (s, 3 H, OCH3), 3.60 (CHN), 58.9 (CH3O), 67.4 (OCH2CH2O), 71.6 (OCH2CH2O), 79.5
(m, 7 H, OCH2CH2O, CHOMEM, CHHOH, OH), 3.82 (m, 2 H, [C(CH3)3], 80.0 (CHOMEM), 95.0 (OCH2O), 155.7 (CO2tBu),
CHHOH, CHN), 4.73 (d, J ϭ 7.1 Hz, 1 H, OCHHO), 4.81 (d, J ϭ
7.1 Hz, 1 H, OCHHO), 5.86 (d, J ϭ 9.1 Hz, 1 H, NH) ppm. 13C
NMR (CDCl3): δ ϭ 10.1 (CH3CH2), 25.4 (CH2CH3), 28.2
[C(CH3)3], 31.4 (CH2CHN), 48.9 (CHN), 58.3 (CH2OH), 58.9
(OCH3), 67.5 (OCH2CH2O), 71.4 (OCH2CH2O), 79.4 [C(CH3)3],
85.7 (CHOMEM), 96.6 (OCH2O), 157.2 (CO2tBu) ppm.
C15H31NO6 (321.4): calcd. C 56.05, H 9.72, N 4.36; found C 55.75,
H 9.69, N 4.21.
175.5 (CO2H) ppm. C15H29NO7 (335.4): calcd. C 53.72, H 8.72, N
4.18; found C 53.76, H 8.77, N 4.14.
Amino Acid anti-7a: The protected amino acid anti-7a was obtained
by oxidation of anti-6a (257 mg, 0.8 mmol) by the procedure de-
scribed for syn-7a. Yield: 204 mg (0.61 mmol, 76%). Colorless oil.
[α]2D0ϭ Ϫ43.7 (c ϭ 1.0, CHCl3). IR (film): ν˜ ϭ 3340, 1700 cmϪ1
.
1H NMR (CDCl3): δ ϭ 0.95 (t, J ϭ 7.4 Hz, 3 H, CH2CH3), 1.44
[s, 9 H, (CH3)3C]], 1.54 (m, 2 H, CH2CH3), 2.56 (m, 2 H,
CH2CO2H), 3.40 (s, 3 H, CH3O), 3.58 (m, 3 H, CHOMEM), OCH-
2CH2O), 3.68 (m, 1 H, OCHHCH2O), 3.78 (m,1 H, OCHHCH2O),
4.03 (m, 1 H, CHN), 4.71 (d, J ϭ 7.1 Hz, 1 H, OCHHO), 4.77 (d,
Amino Alcohol syn-6b: The amino alcohol syn-6b was obtained
from syn-5b (582 mg, 1.4 mmol) by the method described for syn-
6a and purified by flash chromatography (silica gel, hexane/EtOAc,
2:1): 292 mg (0.87 mmol, 62%). Colorless oil. [α]2D0 ؍ ϩ12.1 (c ϭ J ϭ 7.1 Hz, 1 H, OCHHO), 5.82 (d, J ϭ 9.2 Hz, 1 H, NH) ppm.
0.8, CHCl3). IR (film): ν˜ ϭ 3400, 1670, 1480, 1440, 1350, 750 cmϪ1
1H NMR (CDCl3): δ ϭ 0.91 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 1.43 [(CH3)3C], 34.4 (CH2CO2H), 49.8 (CHN), 58.8 (CH3O), 67.4
[s, H, C(CH3)3], 1.56 (m, H, CHHCH3, CHHCHN, (CH2O), 71.5 (CH2O), 79.2 [(CH3)3C], 83.1 (CHOMEM), 96.1
CH2CH2CHN), 3.40 (s, 3 H, OCH3), 3.48 (m, 1 H, CHOMEM), (OCH2O), 155.5 (NHCO2tBu), 176.3 (CO2H) ppm. C15H29NO7
3.57 (m, 2 H, OCH2CH2O), 3.65 (m, 4 H, OCH2CH2O and (335.4): calcd. C 53.72, H 8.72, N 4.18; found C 53.81, H 8.75,
CH2OH), 3.82 (m, 1 H, CHN), 4.70 (d, J ϭ 7.1 Hz, 1 H, OCHHO), N 4.11.
.
13C NMR (CDCl3): δ ϭ 9.7 (CH3CH2), 24.9 (CH2CH3), 28.2
9
6
Eur. J. Org. Chem. 2003, 3387Ϫ3397
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3393

´
´
J. M. Andres, E. M. Mun˜oz, R. Pedrosa, A. Perez-Encabo
FULL PAPER
Amino Acid syn-7b: The compound syn-7b was obtained by oxi-
dation of syn-6b (201 mg, 0.6 mmol) by the procedure described for
syn-7a and purified by flash chromatography (silica gel, hexane/
EtOAc, 2:1): 130 mg (0.37 mmol, 62%). Colorless oil. [α]2D0 ϭ Ϫ25.3
74.5 (CHOH), 180.6 (CO2H) ppm. C6H13NO3 (147.2): calcd. C
48.97, H 8.90, N 9.52; found C 48.04, H 8.80, N 9.58.
Methyl (S)-3-Dibenzylamino-4-hydroxybutanoate (11a): This com-
pound was obtained by desilylation of 16a with 1% HCl solution
in THF. The reaction yielded a mixture of lactone 14a (26%) and
11a[30] (34%) as unstable colorless oil. 1H NMR (CDCl3): δ ϭ 2.24
(dd, J1 ϭ 14.5, J2 ϭ 8.3 Hz, 1 H, CHHCO2), 2.70 (dd, J1 ϭ 14.5,
J2 ϭ 5.1 Hz, 1 H, CHHCO2), 3.43 (d, J ϭ 13.3 Hz, 2 H, CHHPh),
3.53 (m, 3 H, CHN, CHHOH), 3.67 (s, 3 H, OCH3), 3.78 (d, J ϭ
13.3 Hz, 2 H, CHHPh), 7.20Ϫ7.35 (m, 10 H, Harom.) ppm. 13C
NMR (CDCl3): δ ϭ 31.2 (CH2CO2), 51.8 (OCH3), 53.3 (CH2Ph),
56.5 (CHN), 61.3 (CH2OH), 127.3, 128.4, 128.9 (CHarom.), 138.7
(Carom.), 172.5 (CO2CH3) ppm. This compound lactonized com-
pletely after 12 h in the refrigerator.
1
(c ϭ 1.2, CHCl3). H NMR (CDCl3): δ ϭ 0.98 (t, J ϭ 7.4 Hz, 3
H, CH3CH2), 1.44 (m, 2 H, CHHCH3), 1.53 [s, 9 H, C(CH3)3], 2.05
(m, 2 H, CHHCHN), 2.49 (m, 2 H, CHHCO2H), 3.39 (s, 3 H,
OCH3), 3.55 (t, J ϭ 4.6 Hz, 2 H, OCH2CH2O), 3.72 (m, 2 H, OCH2-
CH2O), 3.80 (m, 1 H, CHOMEM), 4.43 (m, 1 H, CHN), 4.75 (d,
J ϭ 7.1 Hz, 1 H, OCHHO), 4.78 (d, J ϭ 7.1 Hz, 1 H, OCHHO)
ppm. 13C NMR (CDCl3): δ ϭ 10.2 (CH3CH2), 18.6 (CH2CH3),
22.0 (CH2CHN), 27.9 [C(CH3)3], 32.0 (CH2CO2H), 58.8 (CHN),
59.0 (OCH3), 67.3 (OCH2CH2O), 71.6 (OCH2CH2O), 79.6 (CHO-
MEM), 82.8 [C(CH3)3], 95.4 (OCH2O), 149.7 (NHCO2), 174.9
(CO2H) ppm. C16H31NO7 (349.4): calcd. C 55.00, H 8.94, N 4.01;
found C 54.83, H 9.15, N 3.90.
(S)-2-[(Benzyloxycarbonyl)amino]-3-(methoxycarbonyl)propionic
Acid (12a): To the -aspartic acid β-methyl ester (10a)[29] (2.94 g,
20 mmol) dissolved in water (70 mL), was added diethyl ether
(25 mL), potassium carbonate (3.87 g, 28 mmol, 1.4 equiv.) and
benzyl chloroformate (4 mL, 28 mmol, 1.4 equiv.). The solution
was stirred at room temp. for 4 h, the layers were separated, the
aqueous layer was washed with diethyl ether (2 ϫ 30 mL) and acidi-
fied to pH 1 with 1  HCl. The resulting solution was extracted
with diethyl ether (3 ϫ 20 mL). The combined organic phases were
dried (MgSO4) and the solvents evaporated in vacuo to give Z de-
rivative 12a: 5.34 g (19 mmol, 95%). Colorless oil. [α]2D0 ϭ ϩ31.5
(c ϭ 1.2, CHCl3). 1H NMR (CDCl3): δ ϭ 2.88 (dd, J1 ϭ 17.4, J2 ϭ
4.6 Hz, 1 H, CHHCHN), 3.07 (dd, J1 ϭ 17.4, J2 ϭ 4.5 Hz, 1 H,
CHHCHN), 3.68 (s, 3 H, CO2CH3), 4.68 (m, 1 H, CHN), 5.12 (s,
2 H, CH2Ph), 5.87 (d, J ϭ 8.6 Hz, 1 H, NH), 7.20Ϫ7.30 (m, 5 H,
Harom.), 8.10 (br. s, 1 H, CO2H) ppm. 13C NMR (CDCl3): δ ϭ 36.2
(CH2CO2CH3), 50.1 (CHN), 52.2 (OCH3), 67.3 (CH2Ph), 128.1,
128.2, 128.5 (CHarom.), 135.9 (Carom.), 156.1 (NCO2Bn), 171.5
(CO2CH3), 175.1 (CO2H) ppm. C13H15NO6 (281.3): calcd. C 55.51,
H 5.38, N 4.98; found C 55.83, H 5.42, N 4.96.
Amino Acid anti-7b: The compound anti-7b was obtained by oxi-
dation of anti-6b (385 mg, 1.15 mmol) by the procedure described
for syn-7a and purified by flash chromatography (silica gel, hexane/
EtOAc, 2:1): 273 mg (0.78 mmol, 68%). Colorless oil. [α]2D0
ϭ
Ϫ104.8 (c ϭ 1.0, CHCl3). 1H NMR (CDCl3): δ ϭ 0.96 (t, J ϭ
7.5 Hz, 3 H, CH3CH2), 1.47 (m, 1 H, CHHCH3), 1.54 [s, 9 H,
C(CH3)3], 1.70 (m, 1 H, CHHCH3), 2.00 (m, 2 H, CHHCHN),
2.36 (ddd, J1 ϭ 17.6, J2 ϭ 10.0, J3 ϭ 2.2 Hz, 1 H, CHHCO2H),
2.72 (dt, J1 ϭ 17.6, J2 ϭ 10.0 Hz, 1 H, CHHCO2H), 3.37 (s, 3 H,
OCH3), 3.52 (m, 2 H, OCH2CH2O), 3.61 (m, 2 H, OCH2CH2O),
3.95 (m, 1 H, CHOMEM), 4.19 (d, J ϭ 9.2 Hz, 1 H, CHN), 4.62
(d, J ϭ 7.1 Hz, 1 H, OCHHO), 4.74 (d, J ϭ 7.1 Hz, 1 H, OCHHO)
ppm. 13C NMR (CDCl3): δ ϭ 10.1 (CH3CH2), 17.3 (CH2CH3),
24.2 (CH2CHN), 27.9 [C(CH3)3], 32.5 (CH2CO2H), 58.8 (OCH3),
59.3 (CHN), 67.3 (OCH2CH2O), 71.6 (OCH2CH2O), 79.1 (CHO-
MEM), 82.6 [C(CH3)3], 94.6 (OCH2O), 149.5 (NHCO2), 175.4
(CO2H) ppm. C16H31NO7 (349.4): calcd. C 55.00, H 8.94, N 4.01;
found C 54.88, H 8.97, N 3.96.
(3S,4S)-3-Amino-4-hydroxyhexanoic Acid (syn-8a): 2  HCl solu-
tion in THF/H2O (1:1) (10 mL) was added to syn-7a (202 mg,
0.64 mmol) and the solution was stirred at room temp. overnight.
The THF was eliminated in a Rotary evaporator, the mixture was
extracted with diethyl ether (2 ϫ 10 mL) and the aqueous layer was
evaporated in vacuo. Anhydrous ethanol (8 mL) and a large excess
of propylene oxide (4 mL) was added to the solid residue and the
mixture was refluxed for 1 h. After removal of the volatiles on Ro-
tavapor, the white residue was purified by flash chromatography
(silica gel, CH2Cl2/MeOH/NH4OH, 6:4:1) to give syn-8a as a color-
less solid: 18 mg (0.12 mmol, 18%). [α]2D0ϭ Ϫ23.1 (c ϭ 0.6, H2O).
1H NMR (D2O): δ ϭ 0.92 (t, J ϭ 7.4 Hz, 3 H, CH3), 1.40 (m, 1
H, CHHCH3), 1.60 (m, 1 H, CHHCH3), 2.42 (dd, J1 ϭ 17.0, J2 ϭ
8.2 Hz, 1 H, CHHCO2H), 2.55 (dd, J1 ϭ 17.0, J2 ϭ 4.7 Hz, 1 H,
CHHCO2H), 3.36 (ddd, J1 ϭ 8.2, J2 ϭ 7.0, J3 ϭ 4.7 Hz, 1 H,
CHN), 3.56 (m, 1 H, CHOH) ppm. 13C NMR (D2O): δ ϭ 11.4
(CH3), 28.1 (CH2CH3), 38.2 (CH2CO2H), 55.9 (CHN), 74.2
(CHOH), 180.0 (CO2H) ppm. C6H13NO3 (147.2): calcd. C 48.97,
H 8.90, N 9.52; found C 49.07, H 8.87, N 9.73.
Methyl
(S)-3-[(Benzyloxycarbonyl)amino]-4-hydroxybutanoate
(13a): To a stirred solution of N-protected amino acid 12a (5.17 g,
18.4 mmol, 1equiv.) in anhydrous THF (90 mL) at Ϫ10 °C, 4-meth-
ylmorpholine (2.0 mL, 18.4 mmol, 1 equiv.) was added, followed
by ethyl choroformate (2.22 mL, 18.4 mmol, 1 equiv.). After
5Ϫ10 min, NaBH4 (2.1 g, 55.2 mmol, 3 equiv.) was added in one
portion. MeOH (190 mL) was then added dropwise to the mixture.
The solution was stirred for additional 10 min, and then neu-
tralized with 1  HCl to pH 1. The organic solvents were evapo-
rated under reduced pressure and the product was extracted with
EtOAc (3 ϫ 20 mL). The organic phase was washed consecutively
with 1  HCl (10 mL), H2O (10 mL), 5% aq NaHCO3 (10 mL),
H2O (10 mL), dried (Na2SO4), and the solvent was evaporated un-
der reduced pressure. The residue was purified by flash chromatog-
raphy (silica gel, hexane/EtOAc, 1:1): 2.33 g (8.8 mmol, 48%). Col-
orless solid, m.p. 53Ϫ55 °C (from hexane/EtOAc). [α]2D0 ϭ ϩ2.1
(c ϭ 1.0, MeOH). IR (film): ν˜ ϭ 3350, 1710, 1690, 740, 690 cmϪ1
.
1H NMR (CDCl3): δ ϭ 2.63 (d, J ϭ 6.0 Hz, 2 H, CH2CO2CH3),
2.90 (br. s, 1 H, OH), 3.66 (s, 3 H, OCH3), 3.67 (m, 2 H, CH2OH),
4.05 (m, 1 H, CHN), 5.08 (s, 2 H, CH2Ph), 5.61 (d, J ϭ 8.0 Hz, 1
H, NH), 7.34 (m, 5 H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ 35.4
(CH2CO2CH3), 49.6 (CHN), 51.6 (OCH3), 63.6 (CH2Ph), 66.6
(CH2OH), 127.9, 128.1, 128.3 (CHarom.), 136.1 (Carom.), 156.1
(CO2Bn), 172.0 (CO2CH3) ppm. C13H17NO5 (267.3): calcd. C
58.42, H 6.41, N 5.24; found C 58.45, H 6.42, N 5.20.
(3S,4R)-3-Amino-4-hydroxyhexanoic Acid (anti-8a): The compound
anti-7a (141 mg, 0.42 mmol) was deprotected by the same pro-
cedure to afford anti-8a as a colorless solid. M.p. 152Ϫ154 (dec)
(from MeOH/Et2O). 12 mg (0.084 mmol, 20%). [α]2D0 ϭ Ϫ40.5 (c ϭ
1
0.7, H2O). H NMR (D2O): δ ϭ 0.92 (t, J ϭ 7.4 Hz, 3 H, CH3),
1.45 (m, 2 H, CHHCH3), 2.35 (dd, J1 ϭ 17.0, J2 ϭ 10.1 Hz, 1 H,
CHHCO2H), 2.52 (dd, J1 ϭ 17.0, J2 ϭ 4.1 Hz, 1 H, CHHCO2H),
3.51 (m, 1 H, CHN), 3.69 (m, 1 H, CHOH) ppm. 13C NMR (D2O): (S)-3-Dibenzylaminobutyrolactone (14a): This compound was ob-
δ ϭ 12.0 (CH3), 27.4 (CH2CH3), 35.4 (CH2CO2H), 55.4 (CHN),
tained by hydrogenolysis of 13a with palladium on carbon in a
3394
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3387Ϫ3397

Enantiopure β-Amino-γ-hydroxy Acids and γ-Amino-δ-hydroxy Acids
FULL PAPER
solution of HCl in methanol, followed by treatment with excess of
benzyl bromide and potassium carbonate in refluxing acetonitrile.
The residue was chromatographed (silica gel, hexane/EtOAc, 6:1)
(c ϭ 1.0, MeOH). IR (KBr): ν˜ ϭ 3600Ϫ2500, 1735, 1700, 1680,
1
750, 690 cmϪ1. H NMR (CDCl3): δ ϭ 2.90 (dd, J1 ϭ 17.6, J2 ϭ
4.4 Hz, 1 H, CHHCO2H), 3.10 (dd, J1 ϭ 17.6, J2 ϭ 4.4 Hz, 1 H,
yielding 14a (66%) as colorless oil. [α]2D0 ϭ ϩ18.9 (c ϭ 0.7, CHCl3). CHHCO2H), 4.68 (m, 1 H, CHN), 5.11 (s, 2 H, CH2Ph), 5.17 (s, 2
1
IR (film): ν˜ ϭ 1770, 1160, 745, 695 cmϪ1. H NMR (CDCl3): δ ϭ
H, CH2Ph), 5.81 (d, J ϭ 8.6 Hz, 1 H, NH), 7.30Ϫ7.35 (m, 10 H,
2.54 (dd, J1 ϭ 17.8, J2 ϭ 8.1 Hz, 1 H, CHHCO), 2.61 (dd, J1
ϭ
Harom.) ppm. 13C NMR (CDCl3): δ ϭ 36.4 (CH2CO2H), 50.2
17.8, J2 ϭ 8.1 Hz, 1 H, CHHCO), 3.51 (d, J ϭ 13.8 Hz, 2 H, (CHN), 67.3, 67.7 (CH2Ph), 128.1, 128.2, 128.5, 128.6 (CHarom.),
CHHPh), 3.66 (d, J ϭ 13.8 Hz, 2 H, CHHPh), 3.76 (m, 1 H, CHN), 135.0, 135.9 (Carom.), 156.0 (NHCO2), 170.3 (CO2Bn), 171.6
4.28 (dd, J1 ϭ 9.9, J2 ϭ 5.2 Hz, 1 H, CHHO), 4.33 (dd, J1 ϭ 9.9,
(CO2H) ppm. C19H19NO6 (357.4): calcd. C 63.86, H 5.36, N 3.92;
J2 ϭ 7.1 Hz, 1 H, CHHO), 7.20Ϫ7.40 (m, 10 H, Harom.) ppm. 13C found C 63.77, H 5.24, N 4.09.
NMR (CDCl3): δ ϭ 30.7 (CH2COO), 54.5 (CH2Ph), 56.0 (CHN),
Oxetane 18a: Compound 17a (8.94 g, 25 mmol) was suspended in
71.0 (CH2O2C), 127.4, 128.4, 128.5 (CHarom.), 138.2 (Carom.), 176.2
(CO2) ppm. C18H19NO2 (281.3): calcd. C 76.84, H 6.81, N 4.98;
found C 76.93, H 6.83, N 4.93.
distilled H2O (60 mL). CsCO3 (4.07 g, 12.5 mmol, 0.5 equiv.) was
added in three portions, and the reaction was stirred vigorously.
After 2 h the solution was concentrated under vacuum. The re-
sulting white solid was dissolved in dry DMF (80 mL), and oxetane
Methyl (S)-3-[(Benzyloxycarbonyl)amino]-4-(tert-butyldimethylsily-
loxy)butanoate (15a): This compound was prepared from 13a bromide (5.16 g, 31.25 mmol, 1.25 equiv.) was then added. The re-
(1.34 g, 5.04 mmol) by reaction with TBDMSCl (1.5 equiv.) at
room temp. as described previously[19] and purified by flash chro-
matography (silica gel, hexane/EtOAc, 6:1): 1.64 g (4.3 mmol,
85%). Colorless oil. [α]2D0 ϭ Ϫ15.0 (c ϭ 0.5, CHCl3). IR (film): ν˜ ϭ
action mixture was stirred under nitrogen at room temperature for
24 h. DMF was removed using a rotary evaporator at 45 °C con-
nected to a pump. The white crude product was dissolved in EtOAc
(200 mL), washed with 5% NaHCO3, 3% NH4Cl (twice), saturated
3330, 1720, 730, 695 cmϪ1 1H NMR (CDCl3): δ ϭ 0.03 [s, 6 H, NaCl, dried (MgSO4), and the solvents evaporated to dryness. The
.
Si(CH3)2], 0.87 [s, 9 H, C(CH3)3], 2.60 (m, 2 H, CH2CO2CH3), 3.66 crude product was purified by flash chromatography (hexane/
(s, 3 H, OCH3), 3.68 (m, 2 H, CH2OTBDMS), 4.11 (m, 1 H, CHN), EtOAc, 1:1) yielding 8.94 g of 18a (20.2 mmol, 81%) as colorless
5.09 (s, 2 H, CH2Ph), 5.35 (d, J ϭ 8.9 Hz, 1 H, NH), 7.35 (m, 5 oil. [α]2D0 ϭ ϩ3.0 (c ϭ 1.6, CHCl3). IR (film): ν˜ ϭ 3310, 1710, 740,
H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.7 [Si(CH3)2], 18.1 690 cmϪ1 1H NMR (CDCl3): δ ϭ 1.24 (s, 3 H, CH3), 2.92 (dd,
.
[C(CH3)3], 25.7 [C(CH3)3], 35.2 (CH2CO2CH3), 49.2 (CHN), 51.5 J1 ϭ 17.2, J2 ϭ 4.5 Hz, 1 H, CHHCHN), 3.10 (dd, J1 ϭ 17.2, J2 ϭ
(OCH3), 63.8 (TBDMSOCH2), 66.5 (CH2Ph), 128.0, 128.4 4.5 Hz, 1 H, CHHCHN), 3.98 (d, J ϭ 11.1 Hz, 1 H, CHHO2C),
(CHarom.), 136.3 (Carom.), 155.6 (NCO2Bn), 171.8 (CO2CH3) ppm. 4.14 (d, J ϭ 11.1 Hz, 1 H, CHHO2C), 4.37 (m, 4 H, OCH2), 4.71
C19H31NO5Si (381.5): calcd. C 59.81, H 8.19, N 3.67; found C
59.92, H 8.28, N 3.47.
(m, 1 H, CHN), 5.11 (s, 2 H, CH2Ph), 5.16 (d, J ϭ 17.8 Hz, 1 H,
CHHPh), 5.20 (d, J ϭ 17.8 Hz, 1 H, CHHPh), 6.05 (br. s, 1 H,
NH), 7.25Ϫ7.40 (m, 10 H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ
20.8 (CH3), 36.7 (CH2CHN), 38.9 (CCH3), 50.4 (CHN), 67.0, 67.5
(CH2Ph), 68.9 (CH2O2C), 79.2, 79.3 (OCH2), 128.0, 128.1, 128.3,
128.5, 128.6 (CHarom.), 135.1, 136.1 (Carom.), 156.0 (NHCO2), 170.4
(CO2), 170.6 (CO2) ppm. C24H27NO7 (441.5): calcd. C 65.29, H
6.16, N 3.17; found C 65.55, H 6.34, N 2.97.
Methyl (S)-3-Dibenzylamino-4-(tert-butyldimethylsilyloxy)butano-
ate (16a): Compound 15a (1.58 g, 4.14 mmol) was quantitatively
debenzylated over Pd/C in MeOH. A mixture of the residue, benzyl
bromide (2.5 mL, 20.7 mmol, 5 equiv.), K2CO3 (3.43 g, 24.8 mmol,
6 equiv.) in acetonitrile (25 mL) was stirred at reflux. When the
reaction was finished (TLC), the solid was separated by filtration,
the filtrate was concentrated under reduced pressure and the resi-
Amino Ester 19a: Compound 18a (3.5 g, 7.9 mmol) was dissolved
due was purified by flash chromatography (silica gel, hexane/ in freshly distilled CH2Cl2 (15 mL) and cooled to Ϫ30 °C under
EtOAc, 15:1): 1.24 g (3.1 mmol, 75%). Colorless oil. [α]2D0 ϭ Ϫ25.3 N2. A solution of BF3·OEt2 (300 µL) in CH2Cl2 was added, and
1
(c ϭ 1.2, CHCl3). IR (film): ν˜ ϭ 1725, 740, 695 cmϪ1. H NMR the solution was stirred and warmed to room temperature. After
(CDCl3): δ ϭ 0.02 (2s, 6 H, Si(CH3)2], 0.87 [s, 9 H, C(CH3)3], 2.47 8 h, Et3N (250 µL) in Et2O (100 mL) was added, the solid was
(dd, J1 ϭ 14.5, J2 ϭ 6.3 Hz, 1 H, CHHCO2CH3), 2.59 (dd, J1 ϭ
removed by filtration and the solution evaporated to dryness. The
14.5, J2 ϭ 8.0 Hz, 1 H, CHHCO2CH3), 3.28 (m, 1 H, CHN), 3.57 residue was purified by recrystallization from CH2Cl2/hexane to
(s, 3 H, OCH3), 3.62 (d, J ϭ 13.8 Hz, 2 H, CHHPh), 3.72 (d, J ϭ yield 3.14 g (7.1 mmol, 90%) of colorless crystals, mp. 102Ϫ103 °C
13.8 Hz, 2 H, CHHPh), 3.73 (d, J ϭ 5.5 Hz, 2 H, TBDMSOCH2),
7.15Ϫ7.35 (m, 10 H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ Ϫ5.7 ν˜ ϭ 3400, 1730, 1700, 740, 695 cmϪ1. 1H NMR (CDCl3): δ ϭ 0.73
(SiCH3), Ϫ5.6 (SiCH3), 18.1 [C(CH3)3], 25.8 [C(CH3)3], 33.9 (s, 3 H, CH3), 2.14 (dd, J1 ϭ 14.7, J2 ϭ 4.4 Hz, 1 H, CHHCHN),
(CH2CO2Me), 51.4 (OCH3), 54.3 (CH2Ph), 56.5 (CHN), 62.7 2.39 (dd, J1 ϭ 14.7, J2 ϭ 5.8 Hz, 1 H, CHHCHN), 3.77 (s, 6 H,
(TBDMSOCH2), 126.7, 128.0, 128.7 (CHarom.), 140.0 (Carom.), OCH2), 4.52 (m, 1 H, CHN), 5.11 (s, 2 H, CH2Ph), 5.14 (s, 2 H,
172.9 (CO2CH3) ppm. C25H37NO3Si (427.6): calcd. C 70.21, H CH2Ph), 6.07 (d, J ϭ 8.3 Hz, 1 H, NH), 7.30Ϫ7.35 (m, 10 H,
(from hexane/EtOAc). [α]2D0 ϭ Ϫ4.8 (c ϭ 0.5, CHCl3). IR (KBr):
8.72, N 3.28; found C 70.07, H 8.75, N 3.32.
Harom.) ppm. 13C NMR (CDCl3): δ ϭ 14.2 (CH3), 30.1 (CCH3),
37.1 (CH2CHN), 50.3 (CHN), 66.7 (CH2Ph), 72.2 (OCH2), 108.0
(CO3), 128.0, 128.1, 128.2, 128.3, 128.4 (CHarom.), 135.7, 136.4
(Carom.), 156.0 (NHCO2), 171.2 (CO2Bn) ppm. C24H27NO7 (441.5):
calcd. C 65.29, H 6.16, N 3.17; found C 65.48, H 6.26, N 3.02.
N-Benzyloxycarbonyl- -aspartic Acid α-Benzyl Ester (17a): A solu-
L
tion of N-Benzyloxycarbonyl--aspartic anhydride[32] (7.24 g,
29.0 mmol) in benzyl alcohol was heated at 90 °C for 3.5 h. The
excess of BnOH was eliminated under reduced pressure and the
residue was dissolved in Et2O (150 mL) and extracted with
NaHCO3 saturated solution (twice). The aqueous layer was washed
with Et2O and acidified with 10% HCl solution. The resulting oil
was extracted with CHCl3, washed with H2O, dried with anhydrous
Na2SO4 and the solvent evaporated under vacuum. The residue was
crystallized from hexane yielding 7.46 g of 17a (20.9 mmol, 72%).
Amino Alcohol 20a: A solution of 19a (2.4 g, 5.4 mmol) in anhy-
drous THF (25 mL) was added dropwise at 0 °C to a suspension
of LAH (307 mg. 8.1 mmol, 1.5 equiv.) in the same solvent
(25 mL). The suspension was stirred at that temperature for 0.5 h,
and then treated with H2O (0.3 mL), 15% NaOH solution (0.3 mL)
and H2O (0.9 mL), and stirred for 2 h. The white solids were re-
Colorless solid, m.p. 100Ϫ102 °C (from hexane). [α]2D0 ϭ Ϫ10.5 moved by filtration, the solvent of the filtrate was evaporated and
Eur. J. Org. Chem. 2003, 3387Ϫ3397
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3395

´
´
J. M. Andres, E. M. Mun˜oz, R. Pedrosa, A. Perez-Encabo
FULL PAPER
the residue was purified by flash chromatography (silica gel treated
with Et3N, hexane/EtOAc, 1:1): 1.43 g (4.2 mmol, 78%). Colorless
oil. [α]2D0 ϭ Ϫ5.5 (c ϭ 1.2, CHCl3). IR (film): ν˜ ϭ 3420, 1715, 1045,
139.6 (Carom.) ppm. C25H33NO4 (411.5): calcd. C 72.96, H 8.08, N
3.40; found C 72.79, H 8.30, N 3.22.
(3S,4S)-3-Dibenzylamino-4-hydroxyhexanoic Acid (syn-24a): A mix-
ture of syn-23a (140 mg, 0.34 mmol) and 2  HCl in THF/H2O
(5 mL) was stirred at reflux for 5 h. The pH of the reaction was
adjusted to 6 with saturated NaHCO3 solution and the mixture
extracted with diethyl ether (3 ϫ 10 mL). The combined organic
layers were washed with brine, dried with MgSO4, concentrated
and chromatographed (hexane/EtOAc, 1:2) to yield syn-24a as a
colorless oil: 58 mg (0.18 mmol, 52%). [α]2D0 ϭ Ϫ6.1 (c ϭ 0.2,
990, 740, 700 cmϪ1 1H NMR (CDCl3): δ ϭ 0.79 (s, 3 H, CH3),
.
1.94 (dd, J1 ϭ 15.0, J2 ϭ 5.5 Hz, 1 H, CHHCHN), 2.06 (dd, J1 ϭ
15.0, J2 ϭ 6.4 Hz, 1 H, CHHCHN), 3.66 (m, 2 H, CHN and
CHHOH), 3.86 (s, 6 H, CH2O), 3.96 (dd, J1 ϭ 12.0, J2 ϭ 6.3 Hz,
1 H, CHHOH), 5.08 (s, 2 H, CH2Ph), 5.60 (d, J ϭ 7.4 Hz, 1 H,
NH), 7.25Ϫ7.40 (m, 5 H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ
14.3 (CH3), 30.2 (CCH3), 36.9 (CH2CHN), 49.3 (CHN), 64.5
(CH2OH), 66.6 (CH2Ph), 72.4 (CH2O), 108.3 (CO3), 128.1, 128.4
(CHarom.), 136.5 (Carom.), 156.4 (NHCO2) ppm. C17H23NO6
(337.4): calcd. C 60.52, H 6.87, N 4.15; found C 60.32, H 6.89,
N 4.12.
CHCl3). IR (film): ν˜ ϭ 3280, 1720, 735, 700 cmϪ1
(CDCl3): δ ϭ 0.92 (t, J ϭ 7.3 Hz, 3 H, CH3), 1.28 (m, 1 H,
CHHCH3), 1.56 (m, 1 H, CHHCH3), 2.37 (dd, J1 ϭ 16.4, J2
.
1H NMR
ϭ
5.7 Hz, 1 H, CHHCO2H), 2.48 (dd, J1 ϭ 16.4, J2 ϭ 8.9 Hz, 1 H,
CHHCO2H), 3.32 (m, 1 H, CHN), 3.78 (m, 1 H, CHOH), 3.90 (d,
J ϭ 12.9 Hz, 2 H, CHHPh), 4.19 (d, J ϭ 12.9 Hz, 2 H, CHHPh),
7.20Ϫ7.40 (m, 10 H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ 9.1
(CH3), 26.7 (CH2CH3), 31.3 (CH2CO2H), 53.8 (CH2Ph), 59.6
(CHN), 71.5 (CHOH), 128.3, 128.7, 130.1 (CHarom.), 134.8 (Carom.),
175.3 (CO2) ppm. C20H25NO3 (327.4): calcd. C 73.37, H 7.70, N
4.28; found C 73.25, H 7.84, N 4.16.
Amino Alcohol 21a: Compound 20a (1.15 g, 3.4 mmol) was trans-
formed in the derivative 21a by debenzylation with Pd(OH)2/C in
MeOH followed by treatment with BnBr (0.85 mL, 7.1 mmol, 2.1
equiv.) and K2CO3 (0.94 g, 6.8 mmol, 2 equiv.) in acetonitrile
(20 mL) at room temp. as described for compound 16a. After flash
chromatography (silica gel treated with Et3N, hexane/EtOAc, 3:1),
the compound 21a was obtained as colorless oil: 952 mg (2.5 mmol,
73%). [α]2D0 ϭ ϩ34.2 (c ϭ 0.5, CHCl3). IR (film): ν˜ ϭ 3460, 1040,
Spirane anti-25a: This compound was obtained as a single product
in the reaction of 22a (191 mg, 0.5 mmol) with EtMgBr (2 equiv.)
in THF/Et2O as described for anti-2a, b, and purified by flash chro-
matography (silica gel treated with Et3N, hexane/EtOAc, 5:1):
127 mg (0.31 mmol, 62%). Colorless oil. [α]2D0 ϭ ϩ73.0 (c ϭ 1.1,
990, 750, 700 cmϪ1 1H NMR (CDCl3): δ ϭ 0.80 (s, 3 H, CH3),
.
1.57 (dd, J1 ϭ 14.3, J2 ϭ 9.1 Hz, 1 H, CHHCHN), 2.18 (dd, J1 ϭ
14.3, J2 ϭ 2.3 Hz, 1 H, CHHCHN), 3.20 (m, 1 H, CHN), 3.37 (d,
J ϭ 13.2 Hz, 2 H, CHHPh), 3.44 (m, 1 H, CHHOH), 3.69 (m, 1
H, CHHOH), 3.75 (d, J ϭ 13.2 Hz, 2 H, CHHPh), 3.89 (s, 6 H,
CH2O), 7.20Ϫ7.40 (m, 10 H, Harom.) ppm. 13C NMR (CDCl3):
δ ϭ 14.4 (CH3), 30.2 (CCH3), 32.2 (CH2CHN), 53.0 (CH2Ph), 54.6
(CHN), 61.7 (CH2OH), 72.5 (CH2O), 108.4 (CO3), 127.0, 128.2,
129.2 (CHarom.), 139.3 (Carom.) ppm. C23H29NO4 (383.5): calcd. C
72.04, H 7.62, N 3.65; found C 72.09, H 7.48, N 3.90.
CHCl3). IR (film): ν˜ ϭ 3450, 1050, 750, 700 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 0.88 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 1.16 (s, 3 H,
CH3C), 1.45 (m, 1 H, CHHCH3), 1.65 (m, 1 H, CHHCH3), 1.72
(br. s, 1 H, OH), 2.10 (dd, J1 ϭ 13.5, J2 ϭ 9.3 Hz, 1 H, CHHCHN),
2.18 (dd, J1 ϭ 13.5, J2 ϭ 7.4 Hz, 1 H, CHHCHN), 3.24 (m, 1 H,
CHN), 3.33 (m, 4 H, CHHO and CH2O), 3.38 (d, J ϭ 14.0 Hz, 2
H, CHHPh), 3.80 (d, J ϭ 14.0 Hz, 2 H, CHHPh), 3.89 (m, 1 H,
CHOH), 4.03 (dd, J1 ϭ 11.0, J2 ϭ 4.4 Hz, 2 H, CHHO), 7.15Ϫ7.40
(m, 10 H, Harom.) ppm. 13C NMR (CDCl3): δ ϭ 10.3 (CH3C), 18.1
(CH3CH2), 27.1 (CH2CH3), 29.6 (CCH3), 34.4 (CH2CHN), 55.0
(CH2Ph), 61.8 (CHN), 66.8, 67.1, 67.4 (CH2O and CH2OH), 81.2
Amino Aldehyde 22a: This compound was obtained from amino
alcohol 21a (575 mg, 1.5 mmol) by Swern oxidation as de-
scribed[19,20] for compounds 1a, b: 544 mg (1.42 mmol, 95%). Col-
orless oil. [α]2D0 ϭ Ϫ28.2 (c ϭ 1.1, CHCl3). IR (film): ν˜ ϭ 1725,
1
1495, 1555, 1055, 750, 700 cmϪ1. H NMR (CDCl3): δ ϭ 0.77 (s,
(CHOH), 117.9 (CO3), 126.9, 128.2, 128.5 (CHarom.), 139.6 (Carom.
ppm. C25H33NO4 (411.5): calcd. C 72.96, H 8.08, N 3.40; found C
72.76, H 8.24, N 3.26.
)
3 H, CH3), 2.02 (dd, J1 ϭ 14.4, J2 ϭ 3.3 Hz, 1 H, CHHCHN),
2.37 (dd, J1 ϭ 14.4, J2 ϭ 7.4 Hz, 1 H, CHHCHN), 3.59 (d, J ϭ
13.4 Hz, 2 H, CHHPh), 3.65 (d, J ϭ 13.4 Hz, 2 H, CHHPh), 3.83
(m, 6 H, CH2O), 7.20Ϫ7.45 (m, 10 H, Harom.). 9.59 (s, 1 H, CHO)
ppm. 13C NMR (CDCl3): δ ϭ 14.3 (CH3), 29.9 (CH2CHN), 30.1
(CCH3), 54.6 (CH2Ph), 62.1 (CHN), 72.4 (CH2O), 108.3 (CO3),
127.0, 128.0, 128.9 (CHarom.), 139.2 (Carom.), 200.9 (CHO) ppm.
C23H27NO4 (381.5): calcd. C 72.42, H 7.13, N 3.67; found C 72.18,
H 7.28, N 3.51.
(3S,4R)-3-Dibenzylamino-4-ethylbutyrolactone (trans-26a): Pre-
pared from anti-25a (123 mg, 0.3 mmol) by treatment with HCl 2
 at reflux for 1 h as described for syn-24a and purified by flash
chromatography (silica gel, hexane/EtOAc, 8:1): 59 mg (0.19 mmol,
64%). Colorless oil. [α]2D0 ϭ ϩ84.0 (c ϭ 0.4, CHCl3). IR (film): ν˜ ϭ
1775, 1170, 975, 750, 700 cmϪ1 1H NMR (CDCl3): δ ϭ 0.90 (t,
.
J ϭ 7.4 Hz, 3 H, CH3), 1.59 (m, 2 H, CH2CH3), 2.55 (dd, J1 ϭ 18.2,
J2 ϭ 8.6 Hz, 1 H, CHHCO2), 2.65 (dd, J1 ϭ 18.2, J2 ϭ 5.7 Hz, 1
H, CHHCO2), 3.39 (ddd, J ϭ 8.6, J ϭ 5.7, J ϭ 4.6 Hz, 1 H, CHN),
3.46 (d, J ϭ 13.7 Hz, 2 H, CHHPh), 3.72 (d, J ϭ 13.7 Hz, 2 H,
CHHPh), 4.43 (m, 1 H, CHOH), 7.20Ϫ7.40 (m, 10 H, Harom.) ppm.
Amino Alcohol syn-23a: This amino alcohol was obtained from 22a
(191 mg, 0.5 mmol) by reaction with Et2Zn (2 equiv.) by the
method described for compounds 2a, b. The product syn-23a was
purified by flash chromatography (silica gel treated with Et3N, hex-
ane/EtOAc, 8:1): 144 mg (0.35 mmol, 70%). Colorless solid, mp.
108Ϫ109 °C (from hexane). [α]2D0 ϭ ϩ31.9 (c ϭ 0.8, CHCl3). IR
(film): ν˜ ϭ 3290, 1045, 990, 740, 700 cmϪ1. 1H NMR (CDCl3): δ ϭ
0.83 (s, 3 H, CH3), 0.86 (t, J ϭ 7.4 Hz, 3 H, CH3CH2), 1.22 (m, 1
H, CHHCH3), 1.61 (m, 1 H, CHHCH3), 1.66 (dd, J1 ϭ 15.4, J2 ϭ
4.3 Hz, 1 H, CHHCHN), 2.18 (dd, J1 ϭ 15.4, J2 ϭ 5.8 Hz, 1 H,
CHHCHN), 2.87 (m, 1 H, CHN), 3.32 (m, 1 H, CHOH), 3.56 (d,
J ϭ 13.1 Hz, 2 H, CHHPh), 3.73 (d, J ϭ 13.1 Hz, 2 H, CHHPh),
3.92 (s, 6 H, CH2O), 7.20Ϫ7.40 (m, 10 H, Harom.) ppm. 13C NMR
(CDCl3): δ ϭ 10.3 (CH3C), 14.5 (CH3CH2), 26.1 (CH2CH3), 30.3
13C NMR (CDCl3):
δ ϭ 9.4 (CH3), 27.4 (CH2CH3), 28.8
(CH2CO2), 54.1 (CH2Ph), 59.2 (CHN), 83.9 (CHOH), 127.3, 128.4,
128.5 (CHarom.), 138.3 (Carom.), 175.9 (CO2) ppm. C20H23NO2
(309.4): calcd. C 77.64, H 7.49, N 4.53; found C 77.50, H 7.45,
N 4.58.
Acknowledgments
The financial support provided by the Spanish DGIC (Project
´
(CCH3), 32.7 (CH2CHN), 53.5 (CH2Ph), 57.3 (CHN), 71.8 BQU2002Ϫ1046) and Junta de Castilla y Leon (Project VA042/03)
(CHOH), 72.5 (CH2O), 108.5 (CO3), 126.9, 128.2, 129.2 (CHarom.), is gratefully acknowledged.
3396
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3387Ϫ3397

Enantiopure β-Amino-γ-hydroxy Acids and γ-Amino-δ-hydroxy Acids
FULL PAPER
[18]
[19]
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2.64 ppm (m).
[5]
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CCDC-206911 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
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Received March 27, 2003
Eur. J. Org. Chem. 2003, 3387Ϫ3397
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3397