Diastereoselective amidoallylation of glyoxylic acid with chiral tert-butanesulfinamide and allylboronic acid pinacol esters: Efficient synthesis of optically active γ,δ-unsaturated α-amino acids This work is dedicated to Dr. Masanori Sakamoto, Professor Emeritus of Meiji Pharmaceutical University, on the occasion of his 77th birthday (KIJU)

Article abstract of DOI:10.1016/j.tetasy.2013.07.026

A convenient synthesis of δ,γ-unsaturated amino acids has been developed. After a mixture of (R)-tert-butanesulfinamide and glyoxylic acid with molecular sieves in CH₂Cl₂ was stirred for 42 h at room temperature, allylboronic acid pinacol ester was added to the mixture to give (R)-2-((R)-tert-butanesulfinamido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of (Z)-crotylboronic acid pinacol ester produced no product; however, that of (E)-crotylboronic acid pinacol ester produced (2R,3S)-2-((R)-tert-butylsulfinamido)-3-methylpent-4- enoic acid with excellent diastereoselectivity.

Full text of DOI:10.1016/j.tetasy.2013.07.026

Tetrahedron: Asymmetry 24 (2013) 1069–1074
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective amidoallylation of glyoxylic acid with chiral
tert-butanesulfinamide and allylboronic acid pinacol esters: efficient
synthesis of optically active
c
,d-unsaturated a-amino acids
⇑
⇑
Shigeo Sugiyama , Saori Imai, Keitaro Ishii
Department of Life and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2013
Accepted 24 July 2013
A convenient synthesis of d,c-unsaturated amino acids has been developed. After a mixture of (R)-tert-
butanesulfinamide and glyoxylic acid with molecular sieves in CH2Cl2 was stirred for 42 h at room
temperature, allylboronic acid pinacol ester was added to the mixture to give (R)-2-((R)-tert-butanesulfi-
namido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of (Z)-crotylboronic
acid pinacol ester produced no product; however, that of (E)-crotylboronic acid pinacol ester produced
(2R,3S)-2-((R)-tert-butylsulfinamido)-3-methylpent-4-enoic acid with excellent diastereoselectivity.
Ó 2013 Elsevier Ltd. All rights reserved.
This work is dedicated to Dr. Masanori
Sakamoto, Professor Emeritus of Meiji
Pharmaceutical University, on the occasion
of his 77th birthday (KIJU)
1. Introduction
d,c
-unsaturated amino acid derivatives.18 The transfer of the Rh-
catalyzed allylic alkylation with chirality from the allyl substrate
to the attacking nucleophile was also investigated.19 The asymmet-
ric ester enolate Claisen rearrangement was developed using che-
late-bridged enolates in the presence of chiral bidentate ligands.20
The use of allylic boron compounds for allylation has emerged
as an important synthetic approach, providing a robust and
chemoselective method for efficient and stereocontrolled access
to various homoallylic amines.21 For example, a chiral imino ester,
d,c-Unsaturated amino acids are useful materials for medicinal
and organic chemistry. Allylglycine is known to block glutamic
acid decarboxylase1 and to be a synthetic intermediate of piperaz-
imycin A2 and 2-amino-8-oxodecanoic acids, which are present in
naturally occurring inhibitors of hystone deacetylase.3 2-Amino-
3-methylpent-4-enoic acid derivatives have been used for the
syntheses of isostatine (b-hydroxy-c
-amino acid),4 2-amino-3-
cyclopropylbutanoic acid (a plant growth regulator),5 (2S,3S)-N-
methyl-d-hydroxyisoleucine (a non-coded amino acid of halipeptin
A),6 and (2S,3S)-b-benzyloxyaspartic acid, (a potent non-transport-
able blocker activity to glutamate transporters).7 2-Amino-3-pro-
pylpent-4-enoic acid has been converted into bicyclic dipeptide
mimetics for the cholecystokinin and opioid receptors.8 2-Amino-
4-methylpent-4-enoic acid and its tert-butyl ester have been used
for the synthesis of eponemycin9 and manzacidin D,10,11 respec-
tively. Moreover, amino acids bearing the terminal double bonds
have been used as potential precursors of homologous dehydroa-
mino acids by means of olefin cross metathesis.12–14
which is obtained from a-methylbenzyl amine and butyl glyoxy-
late, reacts with allyl-9-BBN to afford an allylglycine derivative in
92% yield and 92% de.22,23 In this case, the catalytic hydrogenation
is needed to remove the
a-methylbenzyl group, and the double
bond in the side chain also converts into a single bond to give nor-
valine. Kobayashi et al. have developed the stereoselective synthe-
sis of homoallylic primary amines using allylboronic acid pinacol
esters.24 A concise stereoselective synthesis of alloisoleucine has
been achieved by using glyoxylic acid 1, ammonia, and (Z)-crot-
ylboronic acid pinacol ester 2b via allylation following catalytic
hydrogenation (Scheme 1, Eq. 1). Allylation of hydroxyglycine by
allylboronic acid pinacol esters has also been developed.25 Szabó
The asymmetric synthesis of d,
c-unsaturated amino acid
derivatives has been well studied.15 These derivatives have been
et al. have developed an efficient one-pot synthesis of
a-amino
obtained by fractional crystallization using (S)-
a
-methylbenzyl-
acids from allyl alcohols via the Petasis borono-Mannich reaction
of allyl boronates generated in situ.26 However, in these cases the
products are mixtures of enantiomers.
On the other hand, tert-butanesulfinamide 4 is one of the best
chiral auxiliaries in asymmetric synthesis by virtue of its excellent
diastereocontrol.27,28 The imines exhibit unique reactivity and ste-
reoselectivity in various reactions, especially in the diastereoselec-
tive addition of N-(tert-butylsulfinyl)imines, which can be
amine4 and kinetic resolution using acylases;9,16,17 they have also
been synthesized by asymmetric reactions. The [3,3]-sigmatropic
rearrangement of optically active (E)- and (Z)-1-(tert-butyldimeth-
ylsilyl)-2-butenyl N-tert-butyloxycarbonylglycinates produced
⇑
Corresponding authors. Tel.: +81 424 95 8791; fax: +81 424 95 8783 (S.S.).
E-mail address: sugiyama@my-pharm.ac.jp (S. Sugiyama).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.026

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S. Sugiyama et al. / Tetrahedron: Asymmetry 24 (2013) 1069–1074
2. Results and discussion
1)
O
B
2.1. Reaction conditions
O
O
2b
NH3, EtOH
NH2
Firstly, we investigated the reaction of (R)-tert-butanesulfina-
HO
mide (R)-4, glyoxylic acid 133,34 and allylboronic acid pinacol ester
2a. The results are summarized in Table 1. After a mixture of (R)-4
and 1 in CDCl3 was stirred for 6.5 h (conditions 1), allylboronic acid
pinacol ester 2a was added to the reaction mixture (conditions 2).
The desired allylglycine derivative 7a was obtained, but in low
yield (entry 1). We considered that the yield of 7a would increase
if the formation of the iminium intermediate 3 was enhanced, and
removal of H2O from the reaction system could provide this out-
come. The effect of drying agents in the reaction mixture was thus
studied, while molecular sieves (MS) 3 Å35 were found to improve
the yields at ambient temperature. The conversion of 2a to 7a in
the presence of MS reached 38% and 46% with 0.33 g/mmol and
0.66 g/mmol of MS 3 Å, respectively (entries 2 and 3). A somewhat
higher yield at a higher concentration (0.20 mol/L) was observed
(entry 5); however, we selected the lower concentration
(0.11 mol/L, entry 3) because of its good blending ability.
Next, we investigated the reaction times before and after adding
allyl boronate pinacol ester 2a (entries 6–8). A reaction time of
42 h before adding 2a was the best time among entries 6–8, and
the next allylation after adding 2a needed 23 h to give 7a in 88%
yield (entry 7). Reactions in EtOH at room temperature and in
1,2-dichloroethane at refluxing temperature decreased the yields
(entries 9 and 10).
HO
H
(1)
2) H2, Pd/C
O
O
1
dl-alloisoleucine
S
H2N
tBu
(R)-4
HO
B
O
O
S
S
HO
Ph
tBu
Ph
HN
tBu
N
5
HO
HO
(2)
O
O
3
6
O
B
O
S
O
tBu
HN
2a
HO
(3)
O
this study
7a
Scheme 1. Aminoallylation (Eq. 1) and Petasis borono–Mannich reaction (Eq. 2) in
the reported studies and an amidoallylation (Eq. 3) used in this study.
A characteristic 1H NMR signal in CDCl3 at 8.02 ppm was
observed from the mixture before adding allylboronic acid pinacol
ester 2a (Table 1). This signal was due to the imino proton of the N-
(tert-butylsulfinyl)iminoacetic acid 3. This allylation was also
examined using ethyl N-(tert-butylsulfinyl)iminoacetate 8,35
which is a substrate for the Rh- and Pd-mediate additions of phen-
ylboronic acid36,37 and Zn-mediated cinnamylation of cinnamyl-
zinc bromide.38 A mixture of imine 8 and allylboronic acid
pinacol ester 2a in CH2Cl2 was stirred for 15 h at room tempera-
ture; however, the reaction did not proceed and 8 was recovered
(Scheme 2).
prepared from aldehydes and ketones, while the tert-butylsulfinyl
group cleaves easily under mild conditions. The addition of
allylindium to N-(tert-butylsulfinyl)iminoacetic acid ester in satu-
rated aqueous NaBr produced N-(tert-butylsulfinyl)allylglycine
ethyl ester in excellent yield and with diastereoselectivity.29 Re-
cently, the diastereoselective Petasis borono-Mannich reaction30–32
of (R)-tert-butanesulfinamide (R)-4, glyoxylic acid 1 and 2-phenyl-
vinyl boronic acid 5 to give 2-phenylvinylglycine 6 was reported
(Scheme 1, Eq. 2)33 and the diastereoselectivity was then improved
upon by adding Lewis acids.34 Based on these reports, we consid-
ered that N-(tert-butylsulfinyl)iminoacetic acid 3 prepared from
glyoxylic acid 1 and 4 (Scheme 1, Eq. 2) would also be a good sub-
strate for allylation using allylboronic acid pinacol ester 2a to give
allylglycine 7a diastereoselectively (Scheme 1, Eq. 3). Herein we re-
port the amidoallylation of glyoxylic acid 1 with (R)-tert-butane-
sulfinamide (R)-4 and 2-alkenyl boronic acid pinacol esters 2 to
2.2. Scope of the reaction
The reaction conditions in entry 7 (Table 1) were then applied
to a variety of 2-alkenylboronic acid pinacol esters 2a–f in order
to determine the scope of the reactions (Table 2). Typically, after
a mixture of (R)-tert-butanesulfinamide (R)-4 and glyoxylic acid 1
was stirred for 42 h at room temperature, 2-alkenylboronic acid
give optically active c,d-unsaturated amino acids 7.
Table 1
Diastereoselective amidoallylation of glyoxylic acid 1
(R)-4
2a
7a
1
conditions 1
conditions 2
rt
Entry
Conditions 1
MS 3 Å (g/mmol)
Conditions 2
Time (h)
Yield of 7aa (%)
Solvent (mol/L)
Temp
rt
Time (h)
1
2
3
4
5
6
7
8
9
10
CDCl3 (0.11)
CDCl3 (0.11)
CDCl3 (0.11)
CDCl3 (0.20)
CDCl3 (0.20)
CH2Cl2 (0.11)
CH2Cl2 (0.11)
CH2Cl2 (0.11)
EtOH (0.11)
(ClCH2)2 (0.11)
—
6.5
6.5
6.5
6.5
6.5
17
42
68
47
4.5
15
15
15
15
15
22
23
44
20
19
12
38
46
19
49
47
88
68
70
38
rt
rt
rt
rt
rt
rt
rt
0.33
0.66
—
0.66
0.66
0.66
0.66
0.66
0.66
rt
Reflux
a
The yields of entries 1–5 were calibrated with the internal standard (Ph3CH) by 1H NMR integration, and yields of entries 6–10 were isolated yields.

S. Sugiyama et al. / Tetrahedron: Asymmetry 24 (2013) 1069–1074
1071
pinacol ester 2e39,40 gave no product (entry 7). The reaction of 2-
methyl-2-propenylboronic acid pinacol ester 2f40 gave isoprope-
nylalanine derivative 7f in 51% yield (entry 8).
syn-Products ent-7c, ent-7d, and ent-7f, which were the enanti-
omers of 7c, 7d, and 7f, respectively, were also synthesized from
(S)-4 instead of (R)-4 (entries 4, 6, and 9). The yields of 7 were
not optimized and not identical to those of the corresponding
enantiomers.
O
S
O
S
tBu
tBu
N
HN
2a
EtO
EtO
X
H
CH2Cl2, rt
15 h
O
O
8
9
Scheme 2.
pinacol esters 2a–f were added. The reactions were quenched after
23 h. The reaction of (Z)-crotylboronic acid pinacol ester 2b gave
no product (entry 2); however, that of (E)-crotylboronic acid pina-
col ester 2c gave syn-product 7c (entry 3). (E)-Hex-2-en-1-ylboron-
ic acid pinacol ester 2d39,40 also gave product 7d (entry 5);
however, the identical reaction of trans-cinnamylboronic acid
2.3. Removal of the N-tert-butylsulfinyl group
The optically active amino acids 7a, 7c–f, and ent-7c–f were
treated with HCl aq (6 mol/L) at 90 °C to remove the N-tert-butyl-
sulfinyl group27,28 and then ion-exchanged with DOWEX 50 W ꢀ 4.
Amino acids 10a, c, and d were formed in 69%, 82%, and 90% yields,
Table 2
Diastereoselective amidoallylation of glyoxylic acid 1a
R3
O
O
S
R1
B
O
tBu
HO
NH
R3
R2
2a-f
23h
(R)-4 or (S)-4
1
CH2Cl2, MS 3Å
42h
R1 R2
7a-f
O
Entry
(R)- or (S)-4
Boronic acid pinacol ester 2
Product 7
No.
R1
R2
R3
No.
Yieldb,c (%)
1d
2
3
4
5
6
7
8
9
(R)
(R)
(R)
(S)
(R)
(S)
(R)
(R)
(S)
2a
2b
2c
2c
2d
2d
2e
2f
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
7a
7b
7c
88
0
Me
Me
nPr
nPr
Ph
H
64
72
57
65
0
ent-7c
7d
ent-7d
7e
7f
ent-7f
51
65
2f
H
a
b
c
See Section 4 for the general procedure.
Isolated yields.
Yields were not optimized.
Identical data of entry 7 in Table 1.
d
Table 3
Removal of the N-tert-butylsulfinyl group from 7 and ent-7
O
S
NH2 R3
tBu
HO
NH
R3
NH2
conditions A or B
OH
HO
HO
then
DOWEX 50W-X4
R1
R1
O
O
O
7
10
11
Entry
Material 7
Conditionsa
Product 10
No.
R1
R3
No.
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
7a
7c
ent-7c
7d
ent-7d
7f
ent-7f
7f
H
H
H
H
H
H
Me
Me
Me
Me
A
A
A
A
A
A
A
B
B
10a
10c
ent-10c
10d
ent-10d
10f
ent-10f
10f
69
82b
94
>98
>98
>98
>98
Me
Me
nPr
nPr
H
H
H
H
84b
90
90
0 (11, 46)
0 (ent-11, 68)
(11, >98)
(ent-11, >98)
91
93
94
94
ent-7f
ent-10f
a
Condition A; HCl aq (6 mol/L), 90 °C, 4 h, condition B; HCl in dioxane (4 mol/L)/2-propanol (1:2), rt, 1 h.
Estimated by HPLC analysis.
b

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S. Sugiyama et al. / Tetrahedron: Asymmetry 24 (2013) 1069–1074
2a. The reaction may proceed via TS-1 instead of TS-3 because
O
O
O
O
O
O
O
O
N
S
the large tert-butyl group can control the approach of the pinacol
moiety of 2a, and the tert-butyl group would interact with the
pinacol group in TS-2. (E)-Crotylboronic acid pinacol ester 2c was
also reactive because the trans-methyl group was located outside
of TS-2; however, steric repulsion between the tert-butyl group
and cis-methyl group of (Z)-crotylboronic acid pinacol ester 2b,
which gave no product (Table 2, entry 2), may hinder the approach
of the tert-butylsulfinylimine and crotyl group of 2b (TS-4). A sim-
ilar transition state including a fused five- and six-membered ring
system has been proposed for a diastereoselective Pd/In mediated
B
B
R
O
N
N
O
O
B
O
O
O
S
S
tBu
tBu
tBu
O
TS-1, R = H (favored)
TS-2, R = Me (favored)
TS-3 (disfavored)
TS-4 (disfavored)
Figure 1. Mechanistic proposal for stereocontrol.
catalytic allylation of chiral N-sulfinyl-a
-imino esters.45
respectively (Table 3, entries 1, 2, and 4). In contrast, treatment of
compound 7f with HCl aq (6 mol/L) at 90 °C did not give amino
acid 10f but instead (R)-2-amino-4-hydroxy-4-methylpentanoic
acid 1141,42 in 92% yield. Thus, the N-tert-butylsulfinyl group was
removed smoothly; however, it was accompanied by conversion
of the 2-methylprop-2-enyl group to a 2-hydoxy-2-methylpropyl
group. In order to prevent the addition of water to the double bond
of 7f, we used a solution of HCl in dioxane (4 mol/L)/2-propanol
(1:2) instead of HCl aq (6 mol/L), and 10f and ent-10f were ob-
tained from 7f and ent-7f in 91% and 93% yields, respectively.
We determined their relative stereochemistry by comparison
with reported 1H and 13C NMR spectroscopic data. The enantio-
meric purities were determined with HPLC using a CROWNPAK
CR(ꢁ) column. The enantiomeric excess (ee) of 10a, 10f, and ent-
10f was 94% ee; and that of 10c–d, 11, and their corresponding
enantiomers, ent-10c–d and ent-11, was more than 98% ee. The
absolute stereochemistries of products 10a, c, and f were deter-
mined by comparison of the specific rotations reported in the Ref-
erences (see Section 4). The absolute stereochemistry of 10d was
determined by its elution order in HPLC using CROWNPAK CR(ꢁ).
3. Conclusion
In conclusion, we have developed a new diastereoselective
amidoallylation of glyoxylic acid 1 with (R)-tert-butanesulfinamide
(R)-4 and 2-alkenylboronic acid pinacol esters 2 to give N-(tert-
butylsulfinyl)-
nyl group was removed by HCl in water or 2-propanol to afford the
corresponding optically active ,d-unsaturated amino acids 10.
c,d-unsaturated amino acids 7. The N-tert-butylsulfi-
c
Considering the one-pot synthesis from glyoxylic acid 1 to allylgly-
cine derivatives 7 (Table 2), this procedure is the shortest route to
c,d-unsaturated amino acids 10 from commercially available start-
ing materials without fractional crystallization4,20 or enzymatic
kinetic resolution.9,16,17 These amino acids 10 have been used as
starting materials as described in the Introduction.2–14,17 In the
amidoallylation, the carboxylic group of imine 3 could coordinate
to the boron of the allylboronic acid esters (Fig. 1) likewise to the
carboxylic group in the Petasis borono–Mannich reaction.30–34
Since the aminoallylation (Scheme 1, Eq. 1) does not need a carbox-
ylic group,24 this is the first report of the reaction of imines and
allylboronic acid esters activated by a carboxylic group.
Using this column, the
L-amino acids were eluted prior to the
D
-amino acids.43 The stereochemistry of 11 must be identical to
that of 10f because both amino acids 11 and 10f were formed from
7f. We also checked the final reaction conditions by HPLC analysis.
A mixture of 10a (94% ee) in HCl aq (6 mol/L) was stirred for 4 h at
90 °C; however, no racemization occurred.
4. Experimental
4.1. General
2.4. Proposed transition states
Melting points were measured with a Yanaco MP-3 apparatus
and are uncorrected. Optical rotations were determined on a JASCO
DIP-140 polarimeter. NMR spectra were obtained with a JEOL JNM-
LA500 (1H NMR: 500 MHz and 13C NMR: 125 MHz) and a JEOL
JNM-GSX400 (1H NMR: 400 MHz and 13C NMR: 100 MHz) spec-
trometers using tetramethylsilane as an internal standard or 3-(tri-
methylsilyl)propionic-2,2,3,3-d4 acid sodium salt as an external
standard. IR spectra were recorded on a JEOL FT/IR-4100 spectro-
photometer. MS and high-resolution MS (HRMS) were taken on a
JEOL JMS-DX302 spectrometer. Column chromatography was per-
Some transition states for the allylation of imines have been
proposed. For example, in the allylation of some imines by allylbo-
ronic acid esters, six-membered transition states, including
coordination of the boron and the lone pair of N-phenyl- and
N-propylimines have been proposed.44 In the Zn-mediated asym-
metric cinnamylation to ethyl N-(tert-butylsulfinyl)iminoacetate
8, a six-membered chair-like transition state with the zinc coordi-
nated to the nitrogen of 8 and the oxygen of the tert-butylsulfinyl
group have been proposed.38 The nitrogen of the imines coordi-
nated with the boron and zinc in these transition states; however,
the nitrogen of the tert-butylsulfinyl group of 8 could not activate
the boronic acid ester 2a in our case. This would be a reason as to
why the allylation of ethyl N-(tert-butylsulfinyl)iminoacetate 8 did
not proceed (Scheme 2). On the other hand, reaction of boronates 2
and iminoacetic acid 3, which would be formed from (R)-tert-
butanesulfinamide (R)-4 and glyoxylic acid 1, proceeded smoothly
at room temperature without the addition of activators (Table 1).
Thus, boronates 2 need the carboxylic group for the activation of
2 in this reaction. This activation is similar to that of the Petasis
borono–Mannich reaction (Scheme 1, Eq. 2); the carboxylic group
of imine 3 activates the vinylboronic acids and then the vinyl group
attacks the imino group.32
formed with silica gel 60 (spherical, 40–50 lm, Kanto Chemical).
Analytical TLC was performed on plates pre-coated with 0.25 mm
layer of silica gel 60 F254 (Merck). HPLC conditions: CROWNPAK
CR(ꢁ) column eluted with pH 1.0 HClO4 aq at 0 °C. Flow rate:
0.4 mL/min. Detection: UV detector at 200 nm.
4.2. General procedure for the amidoallylation of glyoxylic acid
(Tables 1 and 2)
A mixture of (R)-tert-butanesulfinamide (R)-4 (121 mg,
1.00 mmol), glyoxylic acid monohydrate 1 (92.0 mg, 1.00 mmol)
and powdered molecular sieves 3 Å (648 mg) in CH2Cl2 (9.0 mL)
was stirred for 42 h at room temperature. Allylboronic acid pinacol
ester 2a (168 mg, 1.00 mol) was added to the mixture, and the
resulting mixture was stirred for 23 h at room temperature. The
reaction mixture was filtered through a pad of Celite and the fil-
trate was concentrated in vacuo. The residue was purified by silica
Based on the observed diastereofacial selectivity, the stereo-
chemistry of the products can be explained with the stereochemi-
cal models shown in Figure 1. In transition states TS-1 and TS-2,
the carboxylic groups activate the allylboronic acid pinacol ester

S. Sugiyama et al. / Tetrahedron: Asymmetry 24 (2013) 1069–1074
1073
gel column chromatography (CHCl3/MeOH, 9:1) to afford allylgly-
cine derivative 7a (194 mg, 88%). Other amino acid derivatives
7c, d, f and their enantiomers ent-7c, d, f were also synthesized
on a 1.00 mmol scale. For the syntheses of ent-7c, d, and f, (S)-
tert-butanesulfinamide (S)-4 was used instead of (R)-tert-butane-
sulfinamide (R)-4.
125 MHz) d: 174.0 (C@O), 140.3 (C@CH2), 114.6 (C@CH2), 57.5
(NCH), 57.0 (C), 42.5 (CH2), 23.0 (Me ꢀ 3), 22.0 (Me). IR (KBr) cmꢁ1
:
3248 (s), 1717 (s), 1266 (s), 1017 (s). HRMS (positive FAB) m/z:
234.1163 (M+1)+ (Calcd for C10H20NO3S: 234.1165).
4.2.7. (2S,SS)-2-(tert-Butylsulfinamido)-4-methylpent-4-enoic
acid ent-7f
½
a 3D0
ꢂ
¼ þ32:2 (c 1.0, CHCl3). 1H NMR spectra were identical to
4.2.1. (2R,RS)-2-(tert-Butylsulfinamido)pent-4-enoic acid 7a
those of 7f. HRMS (positive FAB) m/z: 234.1163 (M+1)+ (Calcd for
Pale yellow oil. ½a D23
ꢂ
¼ ꢁ32:6 (c 1.0, CHCl3). 1H NMR (500 MHz,
C10H20NO3S: 234.1165).
CDCl3) d: 5.70–5.78 (1H, m, H2C@CH), 5.13 (1H, d, J = 7.9 Hz,
HHC@CH), 5.10 (1H, s, HHC@CH), 4.45 (1H, d, J = 7.6 Hz, NH, D2O
exchangeable), 3.98 (1H, dd, J = 12.8, 7.3 Hz, NCH), 2.72–2.57 (1H,
m, CHH), 2.44–2.49 (1H, m, CHH), 1.24 (9H, s, tBu). 13C NMR (CDCl3,
125 MHz) d: 174.1 (C@O), 132.9 (CH@CH2), 119.1 (CH@CH2), 58.5
(NCH), 57.0 (C), 38.5 (CH2), 23.0 (Me ꢀ 3). IR (film) cmꢁ1: 3274
(s), 2976 (s), 1734 (s), 1475 (s), 1372 (s), 1150 (s), 1011 (s). HRMS
(positive FAB) m/z: 220.1002 (M+1)+ (Calcd for C9H18NO3S:
220.1008).
4.3. General procedure to remove the tert-butylsulfinyl group
(Table 3)
A mixture of 7a (41.5 mg, 0.189 mmol) in aq HCl (6 mol/L,
1.9 mL) was stirred for 4 h at 90 °C. After the reaction mixture
was concentrated in vacuo, the residue was purified over DOWEX
50 W ꢀ 4 (100–200 mesh, H+ activated, 0.80 g). Next, H2O followed
by 2.8% NH3 aq eluted 10a (15.0 mg, 69%). For the synthesis of 10d,
ent-10d, 11, and ent-11, the ion exchanged materials of them were
chromatographed on silica gel (neutral) (CHCl3/MeOH/28% NH3 aq,
70:30:2).
4.2.2. (2R,3S,RS)-2-(tert-Butylsulfinamido)-3-methylpent-4-
enoic acid 7c
Yellowish crystalline material, mp 127–129 °C. ½a D24
¼ ꢁ78:5 (c
ꢂ
1.0, CHCl3). 1H NMR (500 MHz, CDCl3) d: 5.73–5.80 (1H, m,
CH@CH2), 5.09 (1H, dd, J = 4.9, 0.9 Hz, CH@CHH), 5.06 (1H, d,
J = 0.9 Hz, CH@CHH), 4.40 (1H, d, J = 8.2 Hz, NH), 3.88 (1H, dd,
4.3.1. (R)-2-Aminopent-4-enoic acid 10a
Colorless powder, mp 149 °C (dec). ½a D25
¼ þ23:7 (c 0.11, H2O)
ꢂ
J = 8.2, 3.4 Hz, NCH), 2.61–2.68 (1H, m, MeCH), 1.29 (9H, s, Bu),
for 94% ee {Ref., ½a D22
ꢂ
¼ þ33:8 (c 1.05, H2O) for 95% ee29}. 1H
t
1.03 (3H, d, J = 7.0 Hz, Me). 13C NMR (CDCl3, 125 MHz) d: 172.9
(C@O), 139.3 (CH@CH2), 116.0 (CH@CH2), 62.9 (NCH), 57.1 (C),
41.5 (CH), 22.9 (Me ꢀ 3), 14.5 (Me). IR (KBr) cmꢁ1: 3268 (s), 2979
(s), 1721 (s), 1459 (m), 1384 (m), 1254 (m), 1024 (s). HRMS (posi-
tive FAB) m/z: 234.1160 (M+1)+ (Calcd for C10H20NO3S: 234.1165).
NMR (500 MHz, D2O) d: 5.75–5.83 (1H, m, CH@CH2), 5.29 (1H, d,
J = 17.1 Hz, CH@CHH), 5.27 (1H, d, J = 10.1 Hz, CH@CHH), 3.82
(1H, dd, J = 6.7, 5.2 Hz, NCH), 2.67 (1H, m, CHH), 2.63 (1H, m,
CHH). 13C NMR (D2O, 125 MHz) d: 177.0 (C@O), 134.2 (CH@CH2),
123.3 (CH@CH2), 56.8 (NCH), 37.7 (CH2). NMR data were good
agreement with those of the reported data.29 IR (KBr) cmꢁ1: 2928
(s), 1578 (s). HRMS (positive FAB) m/z: 116.0709 (M+1)+ (Calcd
for C5H10NO2: 116.0712). HPLC: tS = 5.5 min and tR = 7.0 min.
(RS)-Allylglycine (Aldrich) was used as a (RS)-sample. 10a:ent-
10a = 97:3 (94% ee).
4.2.3. (2S,3R,SS)-2-(tert-Butylsulfinamido)-3-methylpent-4-
enoic acid ent-7c
½
a 3D0
ꢂ
¼ þ74:1 (c 1.0, CHCl3). 1H NMR spectra were identical to
those of 7c. HRMS (positive FAB) m/z: 234.1166 (M+1)+ (Calcd for
C10H20NO3S: 234.1165).
4.3.2. (2R,3S)-2-Amino-3-methylpent-4-enoic acid 10c
Product 10c (31.9 mg, 82%) was obtained from 7c (70.0 mg,)
according to the procedure described in Section 4.3.1. Colorless
4.2.4. (2R,3S,RS)-2-(tert-Butylsulfinamido)-3-propylpent-4-
enoic acid 7d
Pale yellow oil. ½a D29
ꢂ
¼ ꢁ37:9 (c 1.0, CHCl3). 1H NMR (500 MHz,
powder, mp 205 °C (dec). ½a D26
¼ ꢁ15:8 (c 0.61, H2O) {Ref., for
ꢂ
CDCl3) d: 5.60 (1H, dt, J = 17.1, 9.8 Hz, CH@CH2), 5.11 (1H, d,
J = 10.7 Hz, CH@CHH), 5.08 (1H, d, J = 17.4 Hz, CH@CHH), 4.36
(1H, d, J = 8.5 Hz, NH), 3.86 (1H, dd, J = 8.5, 5.2 Hz, CH), 2.37–2.43
(1H, m, NCH), 1.44–1.50 (1H, m, CHH), 1.20–1.49 (3H, m, CHH
(2S,3R)-isomer, ½a D24
ꢂ
¼ þ16:0 (c 1.02, H2O)16}. 1H NMR (500 MHz,
D2O) d: 5.86 (1H, ddd, J = 17.7, 10.5, 6.3 Hz, CH@CH2), 5.27 (1H,
d, J = 11.0 Hz, CH@CHH), 5.26 (1H, d, J = 16.8 Hz, CH@CHH), 3.78
(1H, d, J = 4.0 Hz, MeCH), 2.86–2.93 (1H, m, NCH), 1.11 (3H, d,
J = 7.0 Hz, Me). 13C NMR (D2O, 125 MHz) d: 174.0 (C@O), 138.3
(CH@CH2), 118.2 (CH@CH2), 59.1 (NCH), 38.4 (CH), 13.8 (Me).
NMR data were good agreement with those of the reported data.25
IR (KBr) cmꢁ1: 2944 (m), 1583 (s), 1508 (s), 1412 (m). HRMS
(positive FAB) m/z: 130.0866 (M+1)+ (Calcd for C6H12NO2:
130.0869). HPLC: t2S = 8.6 min and t2R = 10.9 min. 10c:ent-
10c = >99:1 (>98% ee).
and CH2), 1.29 (9H, s, Bu). 13C NMR (CDCl3, 125 MHz) d: 172.8
t
(C@O), 137.6 (CH@CH2), 117.8 (CH@CH2), 62.7 (NCH), 57.0 (C),
48.1 (CH), 31.8 (CH2), 22.9 (Me ꢀ 3), 20.1, (CH2), 13.9 (Me). IR
(CHCl3) cmꢁ1: 2956 (s), 1729 (s), 1456 (m), 1368 (m), 1039 (m).
HRMS (positive FAB) m/z: 262.1482 (M+1)+ (Calcd for C12H24NO3S:
262.1478).
4.2.5. (2S,3R,SS)-2-(tert-Butylsulfinamido)-3-propylpent-4-enoic
acid ent-7d
Useful characteristic NMR signals to distinguish 10c from the
corresponding anti-amino acid are as follows;25 1H NMR (D2O),
syn 3.76 ppm (d, J = 4.1 Hz) and anti 3.61 ppm (d, J = 5.5 Hz). 13C
NMR (D2O), syn 13.6 ppm and anti 16.0 ppm.
½
a 2D9
ꢂ
¼ þ37:8 (c 1.3, CHCl3). 1H NMR spectra were identical to
those of 7d. HRMS (positive FAB) m/z: 262.1482 (M+1)+ (Calcd
for C12H24NO3S: 262.1478).
4.3.3. (2S,3R)-2-Amino-3-methylpent-4-enoic acid ent-10c
Product ent-10c (32.7 mg, 84%) was obtained from ent-7c
(70.0 mg) according to the procedure described in Section 4.3.1.
4.2.6. (2R,RS)-2-(tert-Butylsulfinamido)-4-methylpent-4-enoic
acid 7f
Pale yellow solid, mp 113–118 °C. ½a D28
ꢂ
¼ ꢁ33:9 (c 1.1, CHCl3).
Mp 208 °C (dec). ½a D26
ꢂ
¼ þ16:9 (c 0.61, H2O) {Ref.16
½
a 2D4
ꢂ
¼ þ16:0
1H NMR (500 MHz, CDCl3) d: 4.84 (1H, s, C@CHH), 4.77 (1H, s,
C@CHH), 4.41 (1H, d, J = 8.5 Hz, NH), 4.03 (1H, dt, J = 8.9, 5.2 Hz,
NCH), 2.53 (1H, dd, J = 14.0, 5.2 Hz, CHH), 2.33 (1H, dd, J = 14.0,
(c 1.02, H2O)}. 1H NMR spectra were identical to those of 10c.
HRMS (positive FAB) m/z: 130.0872 (M+1)+ (Calcd for C6H12NO2:
130.0869). HPLC: t2S = 8.6 min and t2R = 10.9 min. ent-10c:10c =
>99:1 (>98% ee).
9.2 Hz, CHH), 1.74 (3H, s, Me), 1.26 (9H, s, Bu). 13C NMR (CDCl3,
t

1074
S. Sugiyama et al. / Tetrahedron: Asymmetry 24 (2013) 1069–1074
4.3.4. (2R,3S)-2-Amino-3-propylpent-4-enoic acid 10d
{Ref., ½a 2D0
ꢂ
¼ ꢁ30:9 (c 1.04, H2O)9}. 1H NMR spectra were identical
Product 10d (26.8 mg, 90%) was obtained from 7d (50.0 mg)
according to the procedure described in Section 4.3.1. Colorless
to those of 10f. HRMS (positive FAB) m/z: 130.0869 (M+1)+ (Calcd
for C6H12NO2: 130.0869). HPLC: tS = 9.5 min. ent-10f:10f = 97:3
(94% ee).
powder, mp 142–145 °C (dec). ½a D23
ꢂ
¼ þ2:2 (c 0.54, MeOH). 1H
NMR (500 MHz, D2O) d: 5.62–5.74 (1H, m, CH@CH2), 5.23 (1H, d,
J = 11.7 Hz, CH@CHH), 5.22 (1H, d, J = 13.5 Hz, CH@CHH), 3.57
(1H, d, J = 3.6 Hz, NCH), 2.61 (1H, t, J = 4.2 Hz, CH), 1.28–1.53 (2H,
m, CH2), 1.41 (2H, q, J = 7.4 Hz, CH2), 0.92 (3H, t, J = 7.2 Hz, CH3).
13C NMR (D2O, 125 MHz) d: 176.0 (C@O), 138.9 (CH@CH2), 122.0
(CH@CH2), 61.1 (NCH), 47.1 (CH), 34.2 (CH2), 22.7 (CH2), 15.8
(CH3). IR (KBr) cmꢁ1: 2959 (s), 2936 (s), 1587 (s), 1405 (m). HRMS
(positive FAB) m/z: 158.1179 (M+1)+ (Calcd for C8H15NO2:
157.1104). HPLC: t2R = 63.2 min. 10d:ent-10d = >99:1 (>98% ee).
Acknowledgments
The authors wish to thank the staff of the Analysis Center of
Meiji Pharmaceutical University for performing the elemental
analysis (Ms. S. Yamada) and mass spectra (Ms. T. Koseki). We
are also grateful to Mr. S. Sunaga for his technical assistance.
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4.3.5. (2S,3R)-2-Amino-3-propylpent-4-enoic acid ent-10d
Product ent-10d (27.0 mg, 90%) was obtained from ent-7d
(50.0 mg) according to the procedure described in Section 4.3.1.
Colorless powder, mp 143–147 °C (dec.). ½a D25
¼ ꢁ3:2 (c 0.62,
ꢂ
MeOH). 1H NMR spectra were identical to those of 11d. HRMS (po-
sitive FAB) m/z: 158.1183 (M+1)+ (Calcd for C8H15NO2: 157.1104).
HPLC: t2R = 56.7 min. ent-10d:10d = >99:1 (>98% ee).
4.3.6. (R)-2-Amino-4-hydroxy-4-methylpentanoic acid 11
Product 11 (14.9 mg, 46%) was obtained from 7f (51.3 mg)
according to the procedure described in Section 4.3.1. Colorless so-
lid. Mp 154 °C (dec). ½a D31
ꢂ
¼ þ9:80 (c 0.33, MeOH). 1H NMR
(400 MHz, D2O) d: 3.94 (1H, dd, J = 9.6, 2.8 Hz, NCH), 2.11 (1H,
dd, J = 15.2, 2.8 Hz, CHH), 1.92 (1H, dd, J = 15.6, 10.4 Hz, CHH),
1.34 (6H, s, Me ꢀ 2). 13C NMR (D2O, 100 MHz) d: 175.6 (C@O),
71.6 (C), 53.2 (NCH), 42.6 (CH2), 30.5 (Me), 27.2 (Me). NMR data
were in good agreement with those of the reported data.42 HRMS
(positive FAB) m/z: 148.0969 (M+1)+ (Calcd for C6H14NO3:
148.0974). HPLC: tR = 8.8 min and tS = 5.9 min.
4.3.7. (S)-2-Amino-4-hydroxy-4-methylpentanoic acid ent-11
Product ent-11 (21.8 mg, 68%) was obtained from ent-7f
(50.6 mg) according to the procedure described in Section 4.3.1.
½
a 3D1
ꢂ
¼ ꢁ11:4 (c 0.51, MeOH). 1H NMR spectra were identical to
23. Yamamoto, Y.; Ito, W.; Maruyama, K. J. Chem. Soc., Chem. Commun. 1985, 1131–
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those of 11. HRMS (positive FAB) m/z: 148.0973 (M+1)+ (Calcd
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4.3.8. (R)-2-Amino-4-methylpent-4-enoic acid 10f
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A mixture of 7f (38.7 mg, 0.166 mmol) in HCl in dioxane (4 mol/
L)/2-propanol (1:2, 5.0 mL) was stirred for 1 h at room tempera-
ture. After the reaction mixture was concentrated in vacuo, the res-
idue was purified over DOWEX 50 W ꢀ 4 (100–200 mesh, H+
activated, 0.78 g). H2O followed by 2.8% NH3 aq eluted 10f
(19.5 mg, 91%). Colorless powder, mp 200 °C (dec.). ½a D18
¼ þ40:7
ꢂ
(c 0.39, H2O) {Ref., for (S)-isomer, ½a D20
ꢂ
¼ ꢁ30:9 (c 1.04, H2O)9}.
1H NMR (400 MHz, D2O) d: 5.00 (1H, d, J = 1.2 Hz, C@CHH), 4.89
(1H, s, C@CHH), 3.84 (1H, dd, J = 8.0, 6.8 Hz, NCH), 2.68 (1H, dd,
J = 14.7, 4.8 Hz, CHH), 2.50 (1H, dd, J = 14.4, 9.6 Hz, CHH), 1.77
(3H, s, CH3). 13C NMR (D2O, 100 MHz) d: 177.2 (C@O), 142.8 (C),
118 (C@CH2), 55.3 (NCH), 41.7 (CH2), 23.4 (CH3). NMR data were
in good agreement with those of the reported data.9 IR (KBr) cmꢁ1
:
2967 (s), 1555 (s), 1508 (m), 1405 (m). HRMS (positive FAB) m/z:
130.0872 (M+1)+ (Calcd for C6H12NO2: 130.0869). HPLC: tR = 15.2 -
min. 10f:ent-10f = 97:3 (94% ee).
4.3.9. (S)-2-Amino-4-methylpent-4-enoic acid ent-10f
Product ent-10f (20.3 mg, 93%) was obtained from ent-7f
(39.6 mg) according to the procedure described in Section 4.3.8.
Colorless powder, mp 202 °C (dec). ½a D20
¼ ꢁ36:3 (c 0.45, H2O)
ꢂ