Asymmetric synthesis of aliphatic α-amino and γ-hydroxy α-amino acids and introduction of a template for crystallization-induced asymmetric transformation

Article abstract of DOI:10.1055/s-2006-950319

The asymmetric synthesis of aliphatic α-amino and γ-hydroxy α-amino acids is described. The key step is an aza-Michael addition controlled by crystallization-induced asymmetric transformation (CIAT), affording excellent diastereomeric ratios (dr ≥96:4). C

Full text of DOI:10.1055/s-2006-950319

4032
PAPER
Asymmetric Synthesis of Aliphatic a-Amino and g-Hydroxy a-Amino Acids
and Introduction of a Template for Crystallization-Induced Asymmetric
Transformation
Asymmetric
S
a
ynthesis of
v
A
liphatic
a
-
o
A
mino and
g
l
-
Hydroxy
a
-A
J
minoA
c
a
ids kubec, Dušan Berkeš, Andrej Kolarovič,* František Považanec
Department of Organic Chemistry, Slovak Technical University, Radlinského 9, 81237 Bratislava, Slovak Republic
Fax +421(2)52968560; E-mail: andrej.kolarovic@stuba.sk
Received 21 June 2006; revised 9 August 2006
version towards this single stereoisomer. Thus one ends
Abstract: The asymmetric synthesis of aliphatic a-amino and g-hy-
droxy a-amino acids is described. The key step is an aza-Michael
addition controlled by crystallization-induced asymmetric transfor-
mation (CIAT), affording excellent diastereomeric ratios (dr
up with crystalline compound 3 and a solution containing
both stereoisomers, but with 3 the minor one. The ques-
tion was how to make this approach more general. Even a
≥96:4). Consecutive deoxygenation or stereoselective reduction (dr slight modification in structure of the reagents might
99:1) furnish various a-amino and g-hydroxy a-amino acids, re-
spectively.
cause the target not to crystallize, resulting in the low ste-
reoselectivity typical for this sort of reaction.
Key words: amino acids, asymmetric synthesis, Michael additions,
reductions, solvent effects
Our idea was to employ acylacrylic acids rather than es-
ters. Consequently, the reaction would lead to amino ac-
ids, whose solubilities differ significantly compared with
the starting reagents. Indeed, addition of (R)- or (S)-(1-
phenylethyl)amine to various aroylacrylic acids led to ex-
cellent stereoselectivities, with dr ≥97:3.6 However, a
couple of months after we had launched the project, re-
searchers from Kaneka published similar results.7 Hence
we focused on conditions allowing highly stereoselective
reductions of g-oxo a-amino acids8 and on applications of
amino alcohol auxiliaries in CIAT,9 enabling oxidative
cleavage. Afterwards we employed CIAT on dipeptidic
substrates,10 in simultaneous epimerization at two stereo-
genic centers,11 stereoconvergent lactonization,12 and syn-
thesis of b-furoylalanines.13 Our findings led us to believe
that the acylacrylic subunit, even when variously modi-
fied, represents a general template for performing CIAT.
Herein we would like to demonstrate the concept on short
and efficient syntheses of a wide scale of aliphatic a-ami-
no and g-hydroxy a-amino acids, as shown in Scheme 2.
We could find an impressive number of papers dealing
with asymmetric processes in which amino acids repre-
sent either a readily available starting material or an at-
tractive synthetic target.1 So far, rather little attention has
been paid to the synthesis of a-amino acids2 and their
derivatives3 by application of crystallization-induced
asymmetric transformation (CIAT).4 The main drawback
of the method is that it requires suitable and often specific
conditions to be effective. Therefore CIAT is frequently
reported as an accidental phenomenon observed by a care-
ful experimenter. On the other hand, as CIAT is, by defi-
nition, accompanied by crystallization of the target
compound, it is a very attractive method, particularly for
industrial chemists.4 Experimental accomplishment of
CIAT is usually straightforward and does not require low
temperatures, anhydrous conditions, or an inert atmo-
sphere.
The starting acylacrylic acids are readily available and
were prepared either by condensation of ketones
(Scheme 3) with glyoxylic acid or by ring opening of 2-
alkylfurans (Scheme 4).14 As demonstrated by the con-
densation reactions of 1,1,1-trichloroacetaldehyde,15 the
first method is suitable only for acetone (4a) or a- or b-
substituted ketones 4b–d (Scheme 3).
Our initial attention was attracted by a paper by Urbach
and Henning,5 describing CIAT based on reversible aza-
Michael addition (Scheme 1). The reaction itself gives
rise to a mixture of both stereoisomers. However, in the
course of the reaction, diastereomer 3 starts to precipitate,
and parallel equilibration in solution secures gradual con-
COOBn
O
O
HN
NH2
i
COOEt
+
COOEt
COOBn
3
2
1
Scheme 1 Reagents and conditions: (i) Et3N, EtOH, r.t., 77%.
SYNTHESIS 2006, No. 23, pp 4032–4040
x
x.
x
x
.
2
0
0
6
Advanced online publication: 12.10.2006
DOI: 10.1055/s-2006-950319; Art ID: T09106SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Aliphatic a-Amino and g-Hydroxy a-Amino Acids
4033
OH
NH2
COOH
Alk
O
O
HN
CIAT
Ph
Alk
COOH
Alk
COOH
NH2
COOH
Alk
Scheme 2
HO
HN
O
O
i
HO
R
O
R
COOH
O
Ph
4a–d
5a–d
+
COOH
H2N
Ph
COOH
5a
10
11
Scheme 3 Reagents and conditions: (i) 5a (R = Me): OHCCO2H,
H3PO4, 80 °C, 5 h, 46%; 5b (R = t-Bu): OHCCO2H, H2SO4, dioxane,
reflux, 2.5 h, 50%; 5c (R = i-Bu): OHCCO2H, H3PO4, 100 °C, 2 h,
41%; 5d (R = cyclopropyl): (a) OHCCO2H, 95 °C, 12 h; (b) toluene,
KHSO4, reflux, 3 h, 36% (2 steps).
Scheme 6
Table 1 Effect of the Solvent on the Reaction between Acid 5a and
(R)-2-Phenylglycinola
For the 2-alkylfuran oxidations we employed a modified
method of Kobayashi.14 The synthesis was performed in
two steps (Scheme 4). Aldehyde intermediates 7 are rath-
er unstable and were immediately used in the next step,
the oxidation to b-acylacrylic acids.
Solvent
Appearance
crystalline
crystalline
crystalline
crystalline
gel
drb
CH2Cl2
55:45
59:41
66:34
63:37
76:24
56:44
80:20
92:8
1,3-dioxolane
THF
O
O
O
1,4-dioxane–CH2Cl2, 1:1
1,4-dioxane–Et2O, 2:1
1,4-dioxane–H2O, 98:2
1,4-dioxane–H2O, 99.2:0.8
1,4-dioxane–H2O, 99.6:0.4
1,4-dioxane–H2O, 99.8:0.2
1,4-dioxane
R
i
ii
R
CHO
R
COOH
6e–h
7e–h
5e–h
crystalline
gel
Scheme 4 Reagents and conditions: (i) NBS, acetone–H2O (10:1),
–15 °C, 0.5 h; (ii) Jones reagent, acetone, 0–5 °C, 2 h; 5e (R = Et):
44%, 5f (R = Pr): 64%, 5g (R = Bu): 46%, 5h (R = Pent): 44%.
gel
gel
94:6
We chose acylacrylic acid 5a as a model substrate for
studies of aza-Michael additions (Scheme 5). Reaction
with racemic (1-phenylethyl)amine in dichloromethane
was accompanied by preferential crystallization of one
diastereomer in high purity (dr >95:5; 39%, configuration
undetermined). However, (S)-(1-phenylethyl)amine un-
der CIAT conditions only led to a mixture of (R,S)- and
(S,S)-9a (dr ca. 1:1; Scheme 5).
gel
96:4
a Reagents and conditions: 10 (1.10 equiv), 5a (1.00 equiv), r.t., 2 d.
b For gel mixtures, the best dr values we obtained are reported; the
configurations are unassigned.
Remarkable is the relation between the consistency of the
reaction mixture and diastereomeric enrichment. When
modifying the reaction conditions we observed an ‘illogi-
cal’ trend. Increasing gel character of the mixture was ac-
companied by improved dr values, and, contrarily,
crystallinity was reflected in poor diastereomeric ratios.
This observation might be considered to be the first exam-
ple of gelation-induced asymmetric transfomation. How-
Exchange of the auxiliary for (R)-2-phenylglycinol (10)
and experimenting with various solvents (Scheme 6,
Table 1) led to surprisingly high diastereomeric ratios of
11 when 1,4-dioxane was used.
O
O
HN
Ph
O
HN
Ph
CH2Cl2
+
+
COOH
H2N
Ph
COOH
COOH
8
5a
(R,S)-9a
(S,S)-9a
Scheme 5
Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York

4034
P. Jakubec et al.
PAPER
ever, isolation of a configurationally unstable amino acid no acids. Our method8 of reducing g-oxo a-amino acids
from the gel mixture is problematic. At the same time, re- gave 12b,c,f–h in excellent stereoselectivity (dr 98:2) and
stricted mixing of a gradually forming gel results in fluc- provided us with a range of aliphatic syn-g-hydroxy a-
tuations of dr values (drop of 5–10%).
amino acids (Scheme 8, Table 3). Reductive cleavage of
the auxiliary afforded 13b,c,f–h in quantitative yields
(over one step) after twelve hours (Scheme 8).
In spite of these complications, we hoped that this phe-
nomenon might have a more general application. Al-
though addition of (R)-2-phenylglycinol (8) to
homologous acids 5e and 5f resulted in formation of a gel,
the achieved diastereomeric ratios were disappointing.
Thus we returned to (S)-(1-phenylethyl)amine (8). Its ad-
dition to acid 5e resulted again in low dr values, but ho-
mologous substrate 5f (Scheme 7) provided us with a
completely different reaction profile. After 4 hours, the dr
was 55:45, after 18 hours it rose to 62:38, and in 30 hours
the dr was even 70:30. This tendency continued, and after
seven days crystalline amino acid (S,S)-9f was isolated in
a high yield and purity (dr 97:3). Analogous experiments
were performed with the remaining substrates 5b–d and
5g–h, providing excellent results (Table 2).
OH NH2
O
HN
Ph
ii
OH HN
Ph
i
R
COOH
13b,c,f–h
R
COOH
R
COOH
9b,c,f–h
12b,c,f–h
Scheme 8 Reagents and conditions: (i) NaBH4, MnCl2·4H2O,
MeOH, 0–5 °C, 30 min; (ii) H2/Pd/C, 12 h, r.t., ca. 100%.
Table 3 Stereoselective Reduction of g-Oxo a-Amino Acids
9b,c,f–h
Product
12b
R
dr (syn/anti)a dr (syn/anti)b Yield (%)
t-Bu
i-Bu
Pr
98:2
98:2
98:2
98:2
98:2
99:1
99:1
99:1
99:1
99:1
92
77
91
81
91
CH2Cl2,
Et2O
O
O
HN
Ph
12c
H2N
Ph
+
COOH
COOH
12f
5f
8
(S,S)-9f
dr = 97:3
12g
Bu
Scheme 7
12h
pentyl
a dr of reaction mixture.
b dr after isolation.
Apparently, for successful performance of CIAT, several
criteria need to be fulfilled, e.g. the right auxiliary needs
to be chosen. Structure of the substrate similarly plays an
essential role. Exchange of homologue 5e for 5f also re-
sulted in a substantial change in the final outcome of the
reaction.
To show the suitability of this method for the generation
of a-amino acids, it was necessary to find proper condi-
tions for deoxygenation of g-oxo a-amino acids. For
choosing the right method we kept in mind the configura-
tional lability of the starting substrate, particularly under
g-Oxo a-amino acids represent straightforward intermedi-
ates in the synthesis of a-amino and syn-g-hydroxy a-ami-
Table 2 Effect of Conditions on the Outcome of Addition of (S)-(1-Phenylethyl)amine (8) to Acids 5a–ha
Product
9a
R
Solvent
Time
7 d
c (mol·dm–3)
0.18
dr of crystalsb dr of liquidc
Yield (%)
Me
t-Bu
i-Bu
c-Pr
Et
CH2Cl2
1:1
–
70
70
76
80
9b
EtOH
3 d
0.32
98:2
98:2
96:4
2:3
64:36
63:37
–
9c
CH2Cl2–Et2O, 1:1
CH2Cl2–Et2O, 1:1
CH2Cl2–Et2O, 1:1d
CH2Cl2–Et2O, 1:1
CH2Cl2–Et2O, 1:1
CH2Cl2–Et2O, 1:1
7 d
0.12
9d
7–14 d
7 d
0.13
e
9e
0.16
–
–
9f
Pr
7–14 d
7 d
0.14
97:3
98:2
97:3
71:29
–
83
92
86
9g
Bu
0.10
9h
pentyl
7 d
0.10
52:48
a Reagents and conditions: 8 (1.10 equiv), 5 (1.00 equiv), r.t.
b dr of isolated crystals.
c dr of mother liquors.
d Similar results in CH2Cl2 and H2O.
e Not isolated from reaction mixture.
Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Aliphatic a-Amino and g-Hydroxy a-Amino Acids
4035
NH2
COOH
HN
Ph
O
HN
Ph
15c
15f
i
S
R
S
ii, iii
NH2
COOH
COOH
R
COOH
14c,f
9c,f
Scheme 9 Reagents and conditions: (i) HS(CH2)2SH, concd HCl, 24 h; 14c (R = i-Bu): 94%, 14f (R = Pr): 86%; (ii) H2/Raney Ni, MeOH, 48
h; (iii) H2/Pd/C, 24 h, r.t.; 15c (R = i-Bu): 55%; 15f (R = Pr): 65%.
basic conditions and at higher temperatures (i.e., possibil- ride (Scheme 8). Thus, in accordance with our previous
ity of retro-Michael and retro-Mannich reaction). We results,8 syn-12b is the major product of the stereoselec-
have decided to use a sequence based on reaction with sul- tive reductive step. Hydrolysis of cis-16b followed by de-
fur nucleophiles, followed by desulfuration. g-Oxo a-ami- benzylation provided us with anti-(2S,4S)-2-amino-4-
no acids 9c,f were smoothly transformed into 1,3- hydroxy-5,5-dimethylhexanoic acid (17b). By analogy,
dithiolane derivatives 14c,f (Scheme 9).
starting with the opposite enantiomer of 9b, we prepared
anti-(2R,4R)-2-amino-4-hydroxy-5,5-dimethylhexanoic
acid (17b). This has been synthesized and fully character-
ized by Hegedus.23 The optical rotation data correspond
By a subsequent simple desulfuration–debenzylation se-
quence, natural amino acids 15c and 15f were obtained
(Scheme 9). These amino acids are known to occur natu-
rally and have been isolated from Streptomyces diastati-
cus (subunit of longicatenamycin)16 and Claviceps
purpurea,17 respectively. Until now, reported preparations
of 15c and 15f have been based on resolution,18 chiral re-
agents derived from serine,19 aziridine ring opening,20
enantioselective reduction,21 and conjugate addition of or-
ganocuprates.22 Our methodology might afford a simple
and straightforward alternative.
25
25
very well {Lit.23: [a]D +39.3 (c 1.4, H2O); ours: [a]D
+40.2 (c 0.3, H2O)}, thus confirming that (S)- or (R)-(1-
phenylethyl)amine induce a stereogenic center at C-2
bearing an (S)- or (R)-configuration, respectively
(Scheme 7, Table 2). Again, this is in accordance with
previous observations.7,8,11 Another proof of this trend
was provided by optical rotation data published for amino
acid 15f,17 confirming the (S)-configuration at its C-2 po-
sition.
To assign the configuration of the newly built stereogenic
centers, model amino acid 9b was unselectively reduced
to a mixture of g-hydroxy a-amino acids syn-12b and
anti-12b (syn/anti 31:69). Successive lactonization and
chromatographic separation afforded pure lactones cis-
16b and trans-16b (Scheme 10).
In conclusion, we have demonstrated an efficient CIAT
methodology, enabling a short stereoselective synthesis of
aliphatic a-amino and syn-g-hydroxy a-amino acids.
More importantly, the acylacrylic subunit appears to have
a broad potential as a CIAT template. Further studies into
the applicability of CIAT are being carried out in our lab-
oratory.
O
O
O
HN
Ph
i–iii
1
Melting points are uncorrected. H and 13C NMR spectra were re-
O
O
+
corded on a Varian VXR-300 spectrometer (300 and 75.4 MHz, re-
spectively) with TMS as an internal standard. Elemental analyses
were performed on the analyzer NA 1500, Series 2, Carlo Erba In-
struments. Optical rotations were measured on a JASCO P-1020 or
POLAR L-mP (IBZ Mestechnik) polarimeter (concentration, c is
given as g/100 mL). HPLC analyses were performed on a PU-4015/
PU-4021 PYE UNICAM equipment (C18 5-mm reverse-phase col-
umn, MeCN–phosphate buffer, 1:9 or 1:4, pH 2.5–3.2). The detec-
tor PU-4021 was set in SUM ABS mode, l = 210–310 nm. (E)-4-
Oxopent-2-enoic acid (5a) was prepared by a published method.24
COOH
9b
HN
HN
Ph
Ph
cis-16b
trans-16b
O
O
H
N
OH NH2
Ph
H
1.2%
H
iv, v
COOH
1.3%
cis-16b
anti-17b
(E)-5,5-Dimethyl-4-oxohex-2-enoic Acid (5b)
Scheme 10 Reagents and conditions: (i) NaBH4, MeOH, r.t.; (ii) 6
M HCl, 0.5 h; (iii) K2CO3, chromatography; cis-16b: 53%, dr >99:1;
trans-16b: 17%, dr >99:1; (iv) NaOH, MeOH, 1 h; (v) H2/Pd/C, 12 h,
76% (2 steps).
H2SO4 (96%, 15 mL) was added to a mixture of 4b (10.00 g, 100
mmol) and OHCCO2H·H2O (13.81 g, 150 mmol) in dioxane (100
mL). The reaction mixture was refluxed for 4 h, allowed to cool to
r.t., mixed with H2O (150 mL) and extracted with EtOAc (3 × 50
mL). The organic layer was washed with H2O (50 mL) and extract-
ed with 10% aqueous K2CO3 (3 × 30 mL). The aq soln was adjusted
to pH 2 and extracted with EtOAc (3 × 30 mL), the organic solns
were dried (Na2SO4) and concentrated. The residue was crystallized
from heptane (150 mL); this afforded a pale yellow compound.
NOE experiments confirmed the cis configuration of lac-
tone cis-16b. Its ring opening allowed us to identify anti-
12b on HPLC, i.e. the minor diastereomer formed in ste-
reoselective reduction catalyzed by manganese(II) chlo-
Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York

4036
P. Jakubec et al.
PAPER
Yield: 7.80 g (50%); mp 85–92 °C (Lit.25 94–95 °C, Lit.26 93–
95 °C).
13C NMR (75.4 MHz, CDCl3): d = 13.8, 22.2, 25.7, 41.5, 129.6,
141.2, 170.8, 199.8.
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 9 H, t-Bu), 6.78 (d,
J = 15.2 Hz, 1 H, H-2), 7.63 (d, J = 15.2 Hz, 1 H, H-3).
13C NMR (75.4 MHz, CDCl3): d = 25.5, 43.6, 130.4, 137.3, 170.8,
203.5.
(E)-4-Oxohex-2-enoic Acid (5e)
Yield: 44%; off-white solid; mp 105–107 °C (Lit.29 107–108 °C).
1H NMR (300 MHz, CDCl3): d = 1.15 (t, J = 7.5 Hz, 3 H, H-6), 2.72
(q, J = 7.3 Hz, 2 H, H-5), 6.70 (d, J = 15.4 Hz, 1 H, H-2), 7.16 (d,
J = 15.4 Hz, 1 H, H-3), 11.30 (br s, 1 H, COOH).
13C NMR (75.4 MHz, CDCl3): d = 7.5, 35.0, 129.5, 140.9, 170.7,
200.0.
(E)-6-Methyl-4-oxohept-2-enoic Acid (5c)
H3PO4 (85%, 40 mL) was added to a mixture of 4c (52.23 g, 521.5
mmol) and OHCCO2H·H2O (20.00 g, 217.3 mmol). The reaction
mixture was stirred at 100 °C for 2 h, allowed to cool to r.t., mixed
with H2O (200 mL), and extracted with EtOAc (3 × 30 mL). The or-
ganic layer was washed with H2O (50 mL) and extracted with 10%
aq K2CO3 (2 × 50 mL). The aqueous soln was adjusted to pH 1 and
extracted with EtOAc (3 × 30 mL), the organic solns were dried
(Na2SO4) and concentrated. The residue was dissolved in boiling
heptane (400 mL), filtered, and crystallized; this afforded a pale yel-
low compound.
(E)-4-Oxohept-2-enoic Acid (5f)
Yield: 64%; off-white solid; mp 107–109 °C (Lit.28 99 °C).
1H NMR (300 MHz, CDCl3): d = 0.96 (t, J = 7.6 Hz, 3 H, H-7), 1.69
(sext, J = 7.6 Hz, 2 H, H-6), 2.66 (t, J = 7.6 Hz, 2 H, H-5), 6.69 (d,
J = 16.4 Hz, 1 H, H-2), 7.15 (d, J = 15.8 Hz, 1 H, H-3), 11.66 (br s,
1 H, COOH).
13C NMR (75.4 MHz, CDCl3): d = 13.6, 17.1, 43.6, 129.7, 141.2,
171.0, 199.8.
Yield: 13.86 g (41%); mp 76–80 °C (Lit.27 91.5–92.5 °C).
1H NMR (300 MHz, CDCl3): d = 0.94 (d, J = 6.4 Hz, 6 H, H-7),
2.09–2.28 (m, 1 H, H-6), 2.52 (d, J = 7.0 Hz, 2 H, H-5), 6.62 (d,
J = 16.4 Hz, 1 H, H-2), 7.15 (d, J = 16.4 Hz, 1 H, H-3).
13C NMR (75.4 MHz, CDCl3): d = 22.5, 24.7, 50.6, 129.7, 141.4,
199.6.
(E)-4-Oxonon-2-enoic Acid (5h)
Yield: 44%; off-white solid; mp 113–114 °C (Lit.28 110 °C, Lit.30
110–112 °C).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.0 Hz, 3 H, H-9),
1.26–1.40 (m, 4 H, H-8, H-7), 1.66 (quin, J = 7.0 Hz, 2 H, H-6),
2.67 (t, J = 7.0 Hz, 2 H, H-5), 6.69 (d, J = 15.8 Hz, 1 H, H-2), 7.13
(d, J = 15.8 Hz, 1 H, H-2), 11.66 (br s, 1 H, COOH).
13C NMR (75.4 MHz, CDCl3): d = 13.8, 22.4, 23.2, 31.2, 41.7,
129.6, 141.1, 171.0, 199.8.
(E)-4-Cyclopropyl-4-oxobut-2-enoic Acid (5d)
A mixture of 4d (2.00 g, 23.8 mmol) and OHCCO2H·H2O (3.28 g,
35.7 mmol) was stirred at 95 °C for 12 h and then quenched with
toluene (15 mL). KHSO4 (3.57 g, 26.2 mmol) was added and the
mixture was refluxed. After 3 h the mixture was filtered, and the res-
idue was extracted with boiling toluene (2 × 15 mL). The organic
solns were concentrated and the crude product was crystallized
from cyclohexane (150 mL); this afforded an off-white solid.
(2S)-4-Oxo-2-[(1S)-(1-phenylethyl)amino]heptanoic Acid (9f);
Typical Procedure
Acid 5f (0.60 g, 4.2 mmol) was dissolved in CH2Cl2–Et2O (1:1, 60
mL), and amine (S)-8 (0.59 mL, 4.6 mmol) was added. The mixture
was stirred at r.t. and monitored by HPLC. After 7 d, the crystalline
product was isolated by filtration, washed with Et2O, and dried; this
afforded an off-white solid.
Yield: 0.91 g (83%); dr 97:3; mp 142–143 °C (dec); [a]D25 –14.7 (c
0.8, MeOH–1 M HCl, 3:1).
1H NMR (300 MHz, acetone-d6–DCl): d = 0.81 (t, J = 7.3 Hz, 3 H,
H-7), 1.49 (sext, J = 7.3 Hz, 2 H, H-6), 1.81 (d, J = 6.7 Hz, 3 H, H-
2¢), 2.39–2.56 (m, 2 H, H-5), 3.28 (dd, J = 19.6, 4.9 Hz, 1 H, H-3A),
3.36 (dd, J = 19.6, 5.5 Hz, 1 H, H-3B), 3.91 (‘t’, J = 4.9 Hz, 1 H, H-
2), 4.78 (q, J = 6.7 Hz, 1 H, H-1¢), 7.42–7.71 (m, 5 H, H-Ar).
Yield: 1.19 g (36%); mp 94–96 °C.
1H NMR (300 MHz, CDCl3): d = 1.06–1.24 (m, 4 H, H-2¢, H-3¢),
2.20–2.28 (m, 1 H, H-1¢), 6.73 (d, J = 16.1 Hz, 1 H, H-2), 7.26 (d,
J = 15.4 Hz, 1 H, H-3), 8.98 (br s, 1 H, COOH).
13C NMR (75.4 MHz, CDCl3): d = 12.5, 12.5, 20.5, 129.4, 141.1,
170.3, 199.7.
(E)-4-Oxooct-2-enoic Acid (5g); Typical Procedure
A suspension of 6g (1.00 g, 8.1 mmol) and NaHCO3 (1.36 g, 16.2
mmol) in acetone–H2O (10:1, 20 mL) was cooled to –15 °C. A pre-
cooled soln of NBS (1.58 g, 8.9 mmol) in acetone–H2O (10:1, 10
mL) was added. The mixture was allowed to stand at –15 °C for 1
h, afterwards heated to r.t., quenched with EtOAc (30 mL), and the
pH was adjusted to 1 with 4 M HCl. The organic layer was washed
with H2O (10 mL) and concentrated, furnishing an emulsion. The
organic layer was separated, dissolved in acetone (10 mL), and
cooled to 0–5 °C. The Jones reagent (2.5 mL) was added portion-
wise (100 mL) over 5 min. The mixture was stirred at 0–5 °C for 2
h, afterwards concentrated, mixed with H2O (15 mL), and extracted
with EtOAc (3 × 15 mL). The organic layer was extracted with 10%
aq K2CO3 (2 × 20 mL). The pH of the aqueous soln was adjusted to
1 and the soln was extracted with EtOAc (3 × 15 mL). The organic
solns were washed with H2O (10 mL), dried (Na2SO4), and concen-
trated. The residue was dissolved in boiling heptane (50 mL), fil-
tered, and crystallized; this afforded an off-white solid.
13C NMR (75.4 MHz, acetone-d6–DCl): d = 14.6, 18.1, 21.6, 43.5,
45.3, 54.1, 60.3, 130.0, 130.9, 131.1, 137.3, 170.6, C-4 undetected.
Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C,
67.81; H, 8.12; N, 5.24.
(2S)-5,5-Dimethyl-4-oxo-2-[(1S)-(1-phenylethyl)amino]hexano-
ic Acid (9b)
Reaction in EtOH, 3 d.
25
Yield: 70%; dr 98:2; off-white solid; mp 213–214 °C (dec); [a]D
–14.7 (c 1.0, MeOH–1 M HCl, 3:1).
1H NMR (300 MHz, acetone-d6–DCl): d = 1.09 (s, 9 H, t-Bu), 1.85
(d, J = 6.8 Hz, 3 H, H-2¢), 3.48 (dd, J = 19.2, 5.1 Hz, 1 H, H-3A),
3.57 (dd, J = 19.2, 5.1 Hz, 1 H, H-3B), 3.89 (‘t’, J = 4.7 Hz, 1 H, H-
2), 4.83 (q, J = 6.8 Hz, 1 H, H-1¢), 7.40–7.48 (m, 3 H, H-Ar), 7.73–
7.75 (m, 2 H, H-Ar).
13C NMR (75.4 MHz, acetone-d6–DCl): d = 21.8, 27.4, 39.0, 45.1,
54.7, 60.7, 130.3, 131.0, 131.2, 137.6, 170.6, 213.4.
Yield: 0.58 g (46%); mp 103–104 °C (Lit.28 98–99.5 °C).
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.5 Hz, 3 H, H-8), 1.36
(sext, J = 7.5 Hz, 2 H, H-7), 1.64 (quin, J = 7.5 Hz, 2 H, H-6), 2.66
(t, J = 7.5 Hz, 2 H, H-5), 6.68 (d, J = 15.7 Hz, 1 H, H-2), 7.15 (d,
J = 15.7 Hz, 1 H, H-3), 10.5 (br s, 1 H, COOH).
Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Aliphatic a-Amino and g-Hydroxy a-Amino Acids
4037
Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C,
69.27; H, 8.50; N, 4.99.
(2S,4S)-4-Hydroxy-2-[(1S)-(1-Phenylethyl)amino]heptanoic
Acid (12f); Typical Procedure
Acid 9f (0.50 g, 1.9 mmol) was suspended in MeOH (25 mL), and
MnCl2·4H2O (0.075 g, 0.4 mmol) was added. The mixture was
cooled to 0–5 °C and NaBH4 (0.14 g, 3.8 mmol) was added portion-
wise over 20 min. The soln was stirred another 30 min, concentrat-
ed, and mixed with 10% aq K2CO3 (12.5 mL). The resulting
suspension was stirred at r.t. for 30 min and filtered. The cake was
washed with H2O. Filtrates were combined and the pH was adjusted
to 6–6.5. Precipitated solids were isolated by filtration, washed with
H2O and Et2O and dried.
(2S)-6-Methyl-4-oxo-2-[(1S)-(1-phenylethyl)amino]heptanoic
Acid (9c)
Yield: 76%; dr 98:2; off-white solid; mp 153–156 °C (dec); [a]D
–12.5 (c 0.3, MeOH–1 M HCl, 3:1).
1H NMR (300 MHz, acetone-d6–DCl): d = 0.82 (d, J = 6.7 Hz, 3 H,
H-7), 0.84 (d, J = 6.1 Hz, 3 H, H-7), 1.83 (d, J = 6.7 Hz, 3 H, H-2¢),
2.35 (dd, J = 16.5, 6.7 Hz, 1 H, H-5A), 2.43 (dd, J = 16.5, 6.7 Hz, 1
H, H-5B), 3.31 (dd, J = 18.3, 4.9 Hz, 1 H, H-3A), 3.38 (dd,
J = 18.3, 5.5 Hz, 1 H, H-3B), 3.92 (dd, J = 4.9, 5.5 Hz, 1 H, H-2),
4.80 (q, J = 6.7 Hz, 1 H, H-1¢), 7.40–7.49 (m, 3 H, H-Ar), 7.69–7.73
(m, 2 H, H-Ar).
25
25
Yield: 91%; dr 99:1; off-white solid; mp 215–216 °C (dec); [a]D
–35.2 (c 1.0, 0.1 M NaOH).
1H NMR (300 MHz, NaOD–D2O): d = 0.93 (t, J = 6.8 Hz, 3 H, H-
7), 1.31–1.44 (m, 4 H, H-5, H-6), 1.47 (d, J = 6.8 Hz, 3 H, H-2¢),
1.54–1.64 (m, 1 H, H-3A), 1.72–1.81 (m, 1 H, H-3B), 3.01 (dd,
J = 6.0, 9.4 Hz, 1 H, H-2), 3.67–3.75 (m, 1 H, H-4), 3.79 (q, J = 6.8
Hz, 1 H, H-1¢), 7.43–7.56 (m, 5 H, H-Ar).
13C NMR (75.4 MHz, NaOD–D2O): d = 16.1, 20.8, 26.3, 41.2, 42.4,
59.4, 63.4, 73.7, 130.1, 130.3, 131.6, 146.8, 184.8.
13C NMR (75.4 MHz, acetone-d6–DCl): d = 21.7, 23.6, 23.6, 25.6,
44.0, 52.3, 54.1, 60.5, 130.2, 131.0, 131.2, 137.5, 170.6, 207.5.
Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C,
68.91; H, 8.42; N, 5.27.
(2S)-4-Cyclopropyl-4-oxo-2-[(1S)-(1-phenylethyl)amino]bu-
tanoic Acid (9d)
Yield: 80%; dr 96:4; off-white solid; mp 145–147 °C.
1H NMR (300 MHz, acetone-d6–DCl): d = 0.88–1.01 (m, 4 H, H-2¢¢,
H-3¢¢), 1.85 (d, J = 6.8 Hz, 3 H, H-2¢), 3.50–3.61 (m, 2 H, H-3), 3.93
(‘t’, J = 4.3 Hz, 1 H, H-2), 4.83 (q, J = 6.8 Hz, 1 H, H-1¢), 7.40–7.51
(m, 3 H, H-Ar), 7.70–7.75 (m, 2 H, H-Ar), H-1¢ overlapped by ace-
tone-d6.
Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C,
67.20; H, 8.65; N, 5.51.
(2S,4R)-4-Hydroxy-5,5-dimethyl-2-[(1S)-(1-phenylethyl)ami-
no]hexanoic Acid (12b)
Yield: 92%; dr 99:1; off-white solid; mp 202–205 °C; [a]D25 –38.5
(c 1.0, 0.1 M NaOH).
13C NMR (75.4 MHz, acetone-d6–DCl): d = 12.3, 12.4, 21.8, 21.9,
1H NMR (300 MHz, NaOD–D2O): d = 0.79 (s, 9 H, t-Bu), 1.36–
1.49 (m, 4 H, H-2¢, H-3A), 1.71–1.78 (m, 1 H, H-3B), 2.94 (dd,
J = 7.6, 6.9 Hz, 1 H, H-2), 3.20–3.23 (m, 1 H, H-4), 3.72 (q, J = 6.9
Hz, 1 H, H-1¢), 7.34–7.47 (m, 5 H, H-Ar).
13C NMR (75.4 MHz, NaOD–D2O): d = 26.4, 27.8, 36.7, 37.0, 59.3,
64.0, 82.2, 130.2, 130.4, 131.6, 146.7, 184.9.
43.9, 54.4, 60.5, 130.3, 131.0, 131.2, 137.7, 170.5, C-4 undetected.
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.35; H, 7.25; N, 5.58.
(2S)-4-Oxo-2-[(1S)-(1-phenylethyl)amino]octanoic Acid (9g)
Yield: 92%; dr 98:2; off-white solid; mp 133 °C (dec); [a]D25 –10.7
(c 1.0, MeOH–1 M HCl, 3:1).
Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C,
69.29; H, 9.09; N, 5.37.
1H NMR (300 MHz, acetone-d6–DCl): d = 0.83 (t, J = 7.3 Hz, 3 H,
H-8), 1.25 (sext, J = 7.3 Hz, 2 H, H-7), 1.47 (quin, J = 7.3 Hz, 2 H,
H-6), 1.84 (d, J = 7.3 Hz, 2 H, H-2¢), 2.51 (t, J = 7.3 Hz, 2 H, H-5),
3.38 (br s, 2 H, H-3), 3.96 (dd, J = 5.1, 5.6 Hz, 1 H, H-2), 4.83 (q,
J = 7.3 Hz, 1 H, H-1¢), 7.43–7.52 (m, 3 H, H-Ar), 7.71–7.75 (m, 2
H, H-Ar).
13C NMR (75.4 MHz, acetone-d6–DCl): d = 15.0, 21.7, 23.6, 26.9,
43.3, 43.6, 54.4, 60.6, 130.3, 131.0, 131.2, 137.6, 170.6 (C-1), C-4
undetected.
(2S,4S)-4-Hydroxy-6-methyl-2-[(1S)-(1-phenylethyl)ami-
no]heptanoic Acid (12c)
Yield: 77%; dr 99:1; off-white solid; mp 197–200 °C; [a]D25 –48.4
(c 1.0, 0.1 M NaOH).
1H NMR (300 MHz, NaOD–D2O): d = 0.78 [d, J = 6.2 Hz, 3 H,
CH(CH3)2], 0.79 [d, J = 6.2 Hz, 3 H, CH(CH3)2], 1.06–1.16 (m, 1 H,
H-5A), 1.25–1.70 (m, 7 H, H-5B, H-3, H-2¢, H-6), 2.91 (dd,
J = 8.9, 4.8 Hz, 1 H, H-2), 3.64–3.73 (m, 2 H, H-4, H-1¢), 7.33–7.47
(m, 5 H, H-Ar).
13C NMR (75.4 MHz, NaOD–D2O): d = 24.0, 25.4, 26.3, 26.5, 42.9,
48.4, 59.4, 63.4, 72.2, 130.2, 130.4, 131.7, 146.7, 184.8.
Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C,
68.82; H, 8.39; N, 5.12.
(2S)-4-Oxo-2-[(1S)-(1-phenylethyl)amino]nonanoic Acid (9h)
Yield: 86%; dr 97:3; off-white solid; mp 146 °C (dec); [a]D –9.0
(c 1.0, MeOH–1 M HCl, 3:1).
Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C,
68.86; H, 9.08; N, 5.32.
25
1H NMR (300 MHz, acetone-d6–DCl): d = 0.81 (t, J = 6.7 Hz, 3 H,
H-9), 1.13–1.30 (m, 4 H, H-8, H-7), 1.47 (quin, J = 7.3 Hz, 2 H, H-
6), 1.81 (d, J = 7.3 Hz, 3 H, H-2¢), 2.42–2.57 (m, 2 H, H-5), 3.28
(dd, J = 19.6, 5.5 Hz, 1 H, H-3A), 3.36 (dd, J = 19.6, 4.9 Hz, 1 H,
H-3B), 3.91 (dd, J = 5.5, 4.9 Hz, 1 H, H-2), 4.78 (q, J = 6.7 Hz, 1 H,
H-1¢), 7.39–7.69 (m, 5 H, H-Ar).
13C NMR (75.4 MHz, acetone-d6–DCl): d = 15.0, 21.7, 23.8, 24.4,
32.6, 43.4, 43.5, 54.2, 60.4, 130.1, 131.1, 131.2, 137.4, 170.6, C-4
undetected.
(2S,4S)-4-Hydroxy-2-[(1S)-(1-phenylethyl)amino]octanoicAcid
(12g)
25
Yield: 81%; dr 99:1; off-white solid; mp 195–198 °C (dec); [a]D
–42.7 (c 1.0, 0.1 M NaOH).
1H NMR (300 MHz, NaOD–D2O): d = 0.84 (t, J = 7.0 Hz, 3 H, H-
8), 1.17–1.35 (m, 6 H, H-7, H-6, H-5), 1.37 (d, J = 7.0 Hz, 3 H, H-
2¢), 1.46–1.51 (m, 1 H, H-3A), 1.65–1.70 (m, 1 H, H-3B), 2.90 (dd,
J = 5.2, 9.4 Hz, 1 H, H-2), 3.56 –3.62 (m, 1 H, H-4), 3.69 (q, J = 7.0
Hz, 1 H, H-1¢), 7.35–7.45 (m, 5 H, H-Ar).
Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C,
70.00; H, 8.78; N, 4.64.
13C NMR (75.4 MHz, NaOD–D2O): d = 16.1, 24.8, 26.3, 29.7, 38.7,
42.5, 59.4, 63.5, 74.1, 130.2, 130.4, 131.6, 146.9, 184.9.
Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York

4038
P. Jakubec et al.
PAPER
Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C,
68.38; H, 9.11; N, 5.25.
1H NMR (300 MHz, NaOD–D2O): d = 0.89 (t, J = 5.9 Hz, 3 H, H-
8), 1.25–1.60 (m, 7 H, H-7, H-6, H-5, H-3A), 1.80–1.84 (m, 1 H, H-
3B), 3.34 (dd, J = 7.0, 6.4 Hz, 1 H, H-2), 3.74–3.81 (m, 1 H, H-4).
(2S,4S)-4-Hydroxy-2-[(1S)-(1-phenylethyl)amino]nonanoic
Acid (12h)
13C NMR (75.4 MHz, NaOD–D2O): d = 16.2, 24.8, 29.7, 38.8, 44.5,
57.4, 72.9, 186.1.
Yield: 91%; dr 99:1; off-white solid; mp 185–187 °C; [a]D25 –35.1
(c 0.5, 0.1 M NaOH).
Anal. Calcd for C8H17NO3: C, 54.84; H, 9.78; N, 7.99. Found: C,
54.80; H, 9.86; N, 8.08.
1H NMR (300 MHz, NaOD–D2O): d = 0.85 (t, J = 7.0 Hz, 3 H, H-
9), 1.17–1.34 (m, 8 H, H-8, H-7, H-6, H-5), 1.37 (d, J = 6.4 Hz, 3
H, H-2¢), 1.46–1.51 (m, 1 H, H-3A), 1.65–1.69 (m, 1 H, H-3B), 2.89
(dd, J = 5.3, 8.8 Hz, 1 H, H-2), 3.57–3.62 (m, 1 H, H-4), 3.69 (q,
J = 6.4 Hz, 1 H, H-1¢), 7.35–7.45 (m, 5 H, H-Ar).
13C NMR (75.4 MHz, NaOD–D2O): d = 16.2, 24.7, 26.3, 27.0, 33.8,
38.9, 42.4, 59.4, 63.4, 74.0, 130.1, 130.3, 131.6, 146.8, 184.8.
(2S,4S)-2-Amino-4-hydroxynonanoic Acid (13h)
Yield: 100%; dr 99:1; off-white solid; mp 210–215 °C; [a]D25 +7.8
(c 0.1, MeOH–0.7 M HCl, 3:1).
1H NMR (300 MHz, NaOD–D2O): d = 0.88 (t, J = 6.4 Hz, 3 H, H-
9), 1.24–1.60 (m, 9 H, H-8, H-7, H-6, H-5, H-3A), 1.79–1.86 (m, 1
H, H-3B), 3.34 (‘t’, J = 7.0 Hz, 1 H, H-2), 3.75–3.82 (m, 1 H, H-4).
Anal. Calcd for C17H27NO3: C, 69.59; H, 9.28; N, 4.77. Found: C,
68.98; H, 9.37; N, 4.81.
13C NMR (75.4 MHz, NaOD–D2O): d = 16.2, 24.8, 27.1, 33.9, 39.1,
44.5, 57.4, 73.0, 186.1.
Anal. Calcd for C9H19NO3: C, 57.12; H, 10.12; N, 7.40. Found: C,
56.69; H, 10.08; N, 7.22.
(2S,4S)-2-Amino-4-hydroxyheptanoic Acid (13f); Typical Pro-
cedure
Acid 12f (0.40 g, 1.5 mmol) was dissolved in MeOH (150 mL). 10%
Pd/C (80 mg) was added and the mixture was stirred under a H2 at-
mosphere (1.1 atm). The reaction was monitored by HPLC. After
complete conversion (typically 12 h), the catalyst was removed by
filtration, the cake was washed with MeOH (20 mL), and the com-
bined organic solns were concentrated.
Yield: 100%; dr 99:1; off-white solid; mp 225–230 °C; [a]D25 +5.5
(c 0.3, 0.1 M NaOH).
1H NMR (300 MHz, NaOD–D2O): d = 0.92 (t, J = 7.6 Hz, 3 H, H-
7), 1.29–1.54 (m, 4 H, H-5, H-6), 1.71–1.77 (m, 1 H, H-3A), 2.01–
2.14 (m, 1 H, H-3B), 3.75–3.81 (m, 1 H, H-2), 3.88–3.94 (m, 1 H,
H-4).
(2S)-3-(2-Isobutyl-1,3-dithiolan-2-yl)-2-[(1S)-(1-phenyleth-
yl)amino]propanoic Acid (14c); Typical Procedure
Acid 9c (4.00 g, 14.4 mmol) was dissolved in 37% aq HCl (40 mL)
at r.t. Ethane-1,2-dithiol (1.76 g, 1.57 mL, 18.7 mmol) was added
dropwise over 1 min. The mixture was stirred at r.t. for 24 h. Sub-
sequently it was placed in a cooling bath, the pH was adjusted to 6–
6.5, and the resulting suspension was stirred for 15 min. The precip-
itated solids were isolated by filtration, washed with H2O (3 × 100
mL) and Et2O and dried; this afforded an off-white solid.
Yield: 1.79 g (94%); dr >95:5 (by NMR); mp 204–205 °C (MeOH);
[a]D25 –34.2 (c 0.7, 0.1 M NaOH).
1H NMR (300 MHz, CD3OD–DCl): d = 0.94 (d, J = 6.4 Hz, 3 H, H-
7A), 0.95 (d, J = 6.4 Hz, 3 H, H-7B), 1.75–1.89 (m, 6 H, H-2¢, H-5,
H-6), 2.33 (dd, J = 15.8, 8.8 Hz, 1 H, H-3A), 2.54 (dd, J = 15.8, 2.9
Hz, 1 H, H-3B), 2.80–2.96 (m, 2 H, SCH2CH2S), 3.13–3.24 (m, 2
H, SCH2CH2), 3.66 (dd, J = 8.8, 2.9 Hz, 1 H, H-2), 4.46 (q, J = 6.4
Hz, 1 H, H-1¢), 7.47–7.56 (m, 5 H, H-Ar).
13C NMR (75.4 MHz, NaOD–D2O): d = 16.0, 20.8, 40.5, 41.9, 57.3,
73.2, C-1 undetected.
Anal. Calcd for C7H15NO3: C, 52.16; H, 9.38; N, 8.69. Found: C,
51.02; H, 9.48; N, 8.57.
(2S,4S)-2-Amino-4-hydroxy-5,5-dimethylhexanoic Acid (13b)
Yield: 100%; dr 99:1; off-white solid; mp 214–219 °C; [a]D25 +41.9
(c 1.0, 0.1 M NaOH).
1H NMR (300 MHz, NaOD–D2O): d = 0.87 (s, 9 H, t-Bu), 1.45–
1.55 (m, 1 H, H-3A), 1.87–1.95 (m, 1 H, H-3B), 3.31–3.40 (m, 2 H,
H-2, H-4).
13C NMR (75.4 MHz, CD3OD–DCl): d = 20.4, 24.8, 25.1, 27.4,
39.9, 41.2, 43.8, 54.0, 60.2, 60.8, 71.2, 129.5, 130.5, 130.9, 137.4,
C-1 undetected.
Anal. Calcd for C18H27NO2S2: C, 61.15; H, 7.70; N, 3.96. Found: C,
60.59; H, 7.74; N, 3.88.
13C NMR (75.4 MHz, NaOD–D2O): d = 37.8, 37.0, 38.8, 58.4, 81.2;
C-1 undetected.
(2S)-2-[(1S)-(1-Phenylethyl)amino]-3-(2-propyl-1,3-dithiolan-
2-yl)propanoic Acid (14f)
Yield: 86%; dr >95:5 (by NMR); off-white solid; mp 198–199 °C
Anal. Calcd for C8H17NO3: C, 54.84; H, 9.78; N, 7.99. Found: C,
53.93; H, 9.98; N, 7.84.
(MeOH); [a]D25 –29.8 (c 0.5, 0.1 M NaOH).
1H NMR (300 MHz, CD3OD–DCl): d = 0.90 (t, J = 7.0 Hz, 3 H, H-
7), 1.38–1.60 (m, 2 H, H-6), 1.76–1.81 (m, 5 H, H-2¢, H-5), 2.28
(dd, J = 15.8, 8.8 Hz, 1 H, H-3A), 2.52 (dd, J = 15.8, 1.8 Hz, 1 H,
H-3B), 2.76–2.95 (m, 2 H, SCH2), 3.09–3.20 (m, 2 H, SCH2), 3.69
(dd, J = 8.8, 1.8 Hz, 1 H, H-2), 4.49 (q, J = 7.0 Hz, 1 H, H-1¢), 7.49–
7.53 (m, 5 H, H-Ar).
13C NMR (75.4 MHz, CD3OD–DCl): d = 14.4, 20.3, 20.7, 40.4,
41.5, 43.4, 48.9, 60.1, 60.8, 71.4 (C-4), 129.6, 130.5, 131.0, 137.5,
C-1 undetected.
(2S,4S)-2-Amino-4-hydroxy-6-methylheptanoic Acid (13c)
Yield: 100%; dr 99:1; off-white solid; mp 216–220 °C; [a]D25 +7.4
(c 0.1, MeOH–0.7 M HCl, 3:1).
1H NMR (300 MHz, NaOD–D2O): d = 0.91 [d, J = 8.8 Hz, 6 H,
CH(CH3)2], 1.27–1.35 (m, 1 H, H-5A), 1.40–1.45 (m, 1 H, H-5B),
1.62–1.75 (m, 2 H, H-3A, H-6), 1.91–2.00 (m, 1 H, H-3B), 3.56 (dd,
J = 7.0, 6.4 Hz, 1 H, H-2), 3.88–3.96 (m, 1 H, H-4).
13C NMR (75.4 MHz, NaOD–D2O): d = 24.0, 25.4, 26.6, 43.0, 48.8,
57.3, 71.4, 182.3.
Anal. Calcd for C17H25NO2S2: C, 60.14; H, 7.42; N, 4.13. Found: C,
59.35; H, 7.38; N, 4.01.
Anal. Calcd for C8H17NO3: C, 54.84; H, 9.78; N, 7.99. Found: C,
54.32; H, 9.84; N, 8.05.
(2S)-2-Aminoheptanoic Acid (15f); Typical Procedure
Raney Ni (W-2, 3.00 g) was suspended in MeOH (10 mL) and the
mixture was stirred under H2 (1.1 atm) at 55 °C. After 0.5 h, a soln
of acid 14f (1.00 g, 2.9 mmol) in MeOH (40 mL) was added and the
heterogeneous mixture was stirred under H2 (1.1 atm) at 55 °C. In 1
(2S,4S)-2-Amino-4-hydroxyoctanoic Acid (13g)
Yield: 100%; dr 99:1; off-white solid; mp 227–232 °C; [a]D25 +5.2
(c 0.4, 0.1 M NaOH).
Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Aliphatic a-Amino and g-Hydroxy a-Amino Acids
4039
h, Raney-Ni (W-2, 5.00 g) in H2O (20 mL) was added, and the mix-
ture was stirred again under H2 (1.1 atm) at 55 °C. After 48 h the
mixture was filtered, the filter cake was washed with MeOH (2 × 20
mL, 50 °C) and H2O (10 mL). The filtrate was concentrated under
reduced pressure to a volume of ca. 10 mL and its pH was adjusted
to 6–6.5. The precipitated solid was isolated by filtration, washed
with H2O and Et2O, and dried; this afforded an off-white solid (470
mg, 65%). This was redissolved in MeOH (20 mL), and 10% Pd/C
(90 mg) was added. The mixture was stirred under H2 (1.1 atm) at
r.t. After the conversion was complete (HPLC; typically after 24 h),
the mixture was brought to a boil and filtered. The filter cake was
washed with hot MeOH (20 mL) and the combined filtrates were
concentrated; this afforded an off-white solid.
1H NMR (300 MHz, CDCl3): d = 0.84 (s, 9 H, t-Bu), 1.39 (d, J = 6.1
Hz, 3 H, H-2¢), 1.75–1.80 (m, 1 H, H-4A), 1.87–1.91 (m, 1 H, H-
4B), 3.36 (dd, J = 6.1, 8.4 Hz, 1 H, H-3), 4.14 (q, J = 6.1 Hz, 1 H,
H-1¢), 4.21 (dd, J = 7.7, 5.4 Hz, 1 H, H-5), 7.25–7.38 (m, 5 H, H-
Ar).
13C NMR (75.4 MHz, CDCl3): d = 24.2, 24.9, 31.4, 34.0, 55.2, 57.2,
86.1, 127.0, 127.3, 128.5, 144.5, 177.4.
Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C,
73.71; H, 8.93; N, 5.52.
(2S,4S)-2-Amino-4-hydroxy-5,5-dimethylhexanoic Acid (anti-
17b)
Compound cis-16b (0.46 g, 1.8 mmol) was dissolved in MeOH (12
mL). A 1 M aq soln of NaOH (3.5 mmol, 3.5 mL) was added and
the soln was stirred at r.t. After 1 h, the mixture was concentrated,
redissolved in H2O (10 mL), and the pH of the soln was adjusted to
6–6.5. The resulting suspension was stirred for 15 min and then fil-
tered. The isolated off-white solid was washed with Et2O, shortly
dried, and redissolved in MeOH (120 mL). 10% Pd/C (70 mg) was
added and the mixture was stirred under H2 (1.1 atm) at r.t. After the
conversion was complete (HPLC; typically after 12 h) the mixture
was filtered. The filter cake was washed with MeOH (30 mL) and
the combined filtrates were concentrated; this afforded an off-white
solid.
Yield: 272 mg (ca. 100%; 65% over 2 steps); mp 263–268 °C
(MeOH; Lit.20a 274–276 °C); [a]D25 +26.0 (c 0.1, 6 M HCl) [Lit.18a
+23.9 (c 0.1, 6 M HCl), Lit.20a +22.6 (c 0.45, 6 M HCl), Lit.31 +23.3
(c 2.0, 6 M HCl), Lit.21 +23.6 (c 0.1, 6 M HCl), Lit.20b +27.3 (c 0.34,
6 M HCl)].
1H NMR (300 MHz, CD3OD–DCl): d = 0.80–1.00 (m, 3 H, H-7),
1.21–1.57 (m, 6 H, H-4, H-5, H-6), 1.84–2.02 (m, 2 H, H-3), 3.99
(dd, J = 6.4, 5.9 Hz, 1 H, H-2).
13C NMR (75.4 MHz, CD3OD–DCl): d = 14.3, 23.3, 25.5, 31.5,
32.4, 53.9, 172.0.
25
(2S)-2-Amino-6-methylheptanoic Acid (15c)
Yield: 55%; off-white solid; mp 240–245 °C (MeOH; Lit.32 240–
245 °C); [a]D25 +29.6 (c 0.1, 6 M HCl).
1H NMR (300 MHz, CD3OD–DCl): d = 0.92 [d, J = 6.4 Hz, 6 H,
CH(CH3)2], 1.23–1.66 (m, 5 H, H-4, H-5, H-3A), 1.82–2.00 (m, 2
H, H-6, H-3B), 3.99 (dd, J = 5.9, 6.4 Hz, 1 H, H-2).
Yield: 233 mg (76%, 2 steps); dr 99:1; mp 246–249 °C; [a]D
–40.3 (c 0.3, H2O) [Lit.23 +39.3 (c 1.2, H2O) for (2R,4R)-isomer].
1H NMR (300 MHz, NaOD–D2O): d = 0.89 (s, 9 H, t-Bu), 1.78–
1.88 (m, 1 H, H-3A), 1.89–1.97 (m, 1 H, H-3B), 3.41–3.43 (m, 1 H,
H-4), 3.69–3.75 (m, 1 H, H-2).
13C NMR (75.4 MHz, NaOD–D2O): d = 36.1, 36.1, 37.7, 56.4, 79.5,
13C NMR (75.4 MHz, CD3OD–DCl): d = 22.9, 22.9, 23.7, 28.9,
31.7, 39.5, 54.0, 172.0.
C-1 undetected.
Acknowledgment
(3S,5S)- and (3S,5R)-5-tert-Butyl-3-[(1S)-(1-phenylethyl)ami-
no]dihydrofuran-2(3H)-one (cis- and trans-16b)
Financial support by the Slovak Grant Agency No. 1/2469/05 and
NMR measurements provided by the Slovak State Programme Pro-
ject No. 2003SP200280203 are gratefully acknowledged.
Acid 9b (2.00 g, 7.2 mmol) was suspended in MeOH (60 mL), and
NaBH4 (0.80 g, 21.6 mmol) was added over 5 min. The mixture was
concentrated under reduced pressure, redissolved in 6 M aq HCl (40
mL) and stirred at r.t. After 0.5 h, the precipitated solid was isolated
by filtration, dried, and suspended in EtOAc (50 mL). The suspen-
sion was washed with 10% aq K2CO3 (100 mL) and the aqueous
layer was extracted with EtOAc (2 × 30 mL). The combined organ-
ic solns were dried (Na2SO4) and concentrated; this afforded an off-
white solid [1.45 g (77%); syn/anti 69:31]. The mixture of diaste-
reomers was separated by column chromatography (silica gel,
EtOAc–heptane, 1:7).
References
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cis-16b
Yield 0.69 g (53%); dr 99:1; off-white solid; mp 65–67 °C (hep-
tane); [a]D25 –68.4 (c 0.2, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.87 (s, 9 H, t-Bu), 1.41 (d, J = 6.1
Hz, 3 H, H-2¢), 1.53–1.59 (m, 1 H, H-4A), 1.83–1.88 (m, 1 H, H-
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trans-16b
Yield 0.23 g (17%); dr 99:1); off-white solid; mp 107–109 °C
(EtOAc–heptane); [a]D25 –102.4 (c 0.5, CHCl3).
Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York

4040
P. Jakubec et al.
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Synthesis 2006, No. 23, 4032–4040 © Thieme Stuttgart · New York