Epoxy amino acids produced from allylglycines intramolecularly cyclised to yield four stereoisomers of 4-hydroxyproline derivatives

Article abstract of DOI:10.1039/c3ra45184d

Derivatives of 2-amino-4-pentenoic acid (allylglycine) were efficiently resolved using Subtilisin or acylase. The side-chain unsaturated bond of the enantiomerically pure amino acid with tert-butoxycarbonyl (Boc) protection was smoothly epoxidized with m-chloroperbenzoic acid. When the Boc protection of the amino group was removed, the amino group intramolecularly attacked the side-chain epoxide, generating compounds with five-membered rings: the 4-hydroxyproline derivatives. Two diastereomeric products were formed through the cyclisation reaction, for example, (2S,4S)-4-hydroxyproline benzyl ester (cis-8) and (2S,4R)-4-hydroxyproline benzyl ester (trans-8) were formed from (2S)-amino acid with a side-chain epoxide. Compound (2S,4S)-4-hydroxyproline benzyl ester (cis-8) was transformed to a lactone (cis-hydroxyproline lactone, 10) with the removal of benzyl alcohol. The cis-conformation was essential for the intramolecular ester exchange reaction; in fact, no lactone formation was observed for the trans isomer (trans-8). The separation of cis-hydroxyproline lactone and the trans-isomeric hydroxyproline benzyl ester was facile and clear, in contrast to the difficult separation of cis- and trans-hydroxyproline derivatives. Thus, two diastereomers of hydroxyproline derivatives for l-hydroxyproline and also for d-hydroxyproline were obtained, i.e., four diastereomers of hydroxyproline derivatives.

Full text of DOI:10.1039/c3ra45184d

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Epoxy amino acids produced from allylglycines
intramolecularly cyclised to yield four
Cite this: RSC Adv., 2014, 4, 2482
stereoisomers of 4-hydroxyproline derivatives†
a
a
Suvratha Krishnamurthy, Toru Arai, Kanae Nakanishib and Norikazu Nishinob
*
Derivatives of 2-amino-4-pentenoic acid (allylglycine) were efficiently resolved using Subtilisin or acylase.
The side-chain unsaturated bond of the enantiomerically pure amino acid with tert-butoxycarbonyl (Boc)
protection was smoothly epoxidized with m-chloroperbenzoic acid. When the Boc protection of the
amino group was removed, the amino group intramolecularly attacked the side-chain epoxide,
generating compounds with five-membered rings: the 4-hydroxyproline derivatives. Two diastereomeric
products were formed through the cyclisation reaction, for example, (2S,4S)-4-hydroxyproline benzyl
ester (cis-8) and (2S,4R)-4-hydroxyproline benzyl ester (trans-8) were formed from (2S)-amino acid with
a side-chain epoxide. Compound (2S,4S)-4-hydroxyproline benzyl ester (cis-8) was transformed to a
lactone (cis-hydroxyproline lactone, 10) with the removal of benzyl alcohol. The cis-conformation was
essential for the intramolecular ester exchange reaction; in fact, no lactone formation was observed for
the trans isomer (trans-8). The separation of cis-hydroxyproline lactone and the trans-isomeric
hydroxyproline benzyl ester was facile and clear, in contrast to the difficult separation of cis- and trans-
hydroxyproline derivatives. Thus, two diastereomers of hydroxyproline derivatives for L-hydroxyproline
and also for D-hydroxyproline were obtained, i.e., four diastereomers of hydroxyproline derivatives.
Received 17th September 2013
Accepted 12th November 2013
DOI: 10.1039/c3ra45184d
www.rsc.org/advances
prolyl 4-hydroxylase selectively forms trans-hydroxylated prolines,
(2S,4S)-4-hydroxyproline (cis-L-hydroxyproline, L-cisHyp) exists in
an immunosuppressive natural product, microcolin A.6 Recently
L-cisHyp derivatives have been tested as potential anticancer drugs
because L-cisHyp inhibits collagen biosynthesis by preventing
procollagen folding.7,8 The conformation of 4-hydroxyproline’s
ve-membered ring has been thoroughly elucidated recently.9
Furthermore, non-natural hydroxyprolines have been incorpo-
rated into a synthetic antagonist of a histamine H3 receptor10 and
into a diverse articial polypeptide library.11
Various methods have been proposed for the synthesis of
hydroxyprolines. Inversion of the 4-hydroxyl group of natural
L-Hyp under Mitsunobu conditions6,12–15 and other reac-
tions10,16,17 gave L-cisHyp. Hydroxyproline derivatives have been
elaborated by using chiral compounds as starting materials.18,19
Biological methods have also been applied to obtain the dia-
stereomers of hydroxyprolines.8,20,21 Here, the proposed
methods provides four isomers of hydroxyprolines combining
the enzymatic and organic reactions with moderate reaction
yields and facile separation procedures.22
Introduction
Compound (2S,4R)-4-hydroxyproline (trans-L-hydroxyproline,
L-Hyp) is the most abundant non-coded amino acid in nature
(Fig. 1). L-Hyp residues are generated by post-translational modi-
cation and are essential to stabilize the triple-helical supercoil of
collagen.1–4 Reactions of proline hydroxylase using ascorbic acid
and molecular oxygen are highly relevant for molecular biology but
still not well understood. Recent structure-determination of
proline hydroxyalse will afford several mechanistic and kinetic
studies. L-Hyp is also found in biochemicals such as echino-
candins, which are important antifungal peptides.5 Although
Fig. 1 Stereoisomers of 4-hydroxyprolines.
Results and discussion
Enzymatic resolutions of 2-amino-4-pentenoic acid
aDepartment of Applied Chemistry, Kyushu Institute of Technology, Kitakyushu
804-8550, Japan. E-mail: arai@che.kyutech.ac.jp
bGraduate School of Life Science and Systems Engineering, Kyushu Institute of
(allylglycine) derivatives as starting materials
Technology, Kitakyushu 808-0196, Japan
The racemic 2-amino-4-pentenoic acid (DL-allylglycine) deriva-
tives were synthesized from malonate derivatives and resolved
† Electronic supplementary information (ESI) available: NMR spectra for all novel
compounds and the selected compounds. See DOI: 10.1039/c3ra45184d
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Scheme 1 Enzymatic synthesis of 2-amino-4-pentenoic acid derivatives.
enzymatically. Subtilisin resolution of amino acid esters and isolated amounts of (R)-3 and (S)-4 were not high (28% and 22%,
acylase resolution of acetyl amino acids were tested (Scheme 1). respectively, based on diethyl acetamidomalonate). However,
Racemic ethyl 2-Boc-amino-4-pentenoate (1, Boc ¼ tert- these procedures (i.e., kinetic enzymatic resolution using acy-
butoxycarbonyl) was synthesized from diethyl (2-Boc-amino) lase) also produced the chemically and enantiomerically pure
malonate. Reaction of this malonate with excess allyl bromide (S)-4 and (R)-4 (obtained from (R)-3),30 which were analyzed by
in reuxing EtOH using NaOEt produced the allyl-substituted 1H NMR and chiral HPLC.
malonate, which was half saponied and then reuxed in
toluene for the decarboxylation to generate racemic 1 (91% yield
in three steps based on diethyl (2-Boc-amino)malonate).
Epoxidation of amino acid derivatives with unsaturated side
chains
In H2O–DMF (3 : 1, v/v), 1 was enzymatically hydrolyzed
using Subtilisin while the pH was maintained at 8.0 (aqueous
NH3) at 40 ꢀC. Aer 3 h of enzymatic treatment, unreacted (R)-1
was initially recovered via diethyl ether extraction from the
aqueous reaction mixture. The aqueous reaction mixture was
subsequently acidied to pH 3 and then (S)-2-Boc-amino-4-
pentenoic acid ((S)-2) was extracted with EtOAc. Both yields of
recovered (R)-1 and selectively hydrolyzed (S)-2 were approxi-
mately 48% based on racemic 1. The chemical and enantio-
meric purities of (S)-2 and (R)-1 (aer deprotection) were
Kinetically resolved Boc-amino acid (S)-2 was esteried with
benzyl bromide using Et3N to afford benzyl (S)-2-Boc-amino-4-
pentenoate ((S)-5) in 64% yield. This Boc-amino acid ester with
an unsaturated side chain was epoxidized with excess m-chlor-
operbenzoic acid (m-CPBA) in CH2Cl2.31–33 The reaction was
nearly completed aer 24 h at room temperature (TLC), then the
excess m-CPBA was subsequently reduced with Na2SO3. Aer
being washed and chromatographed over silica gel (hexane–
15% EtOAc), Boc-amino acid benzyl esters with side-chain
epoxy group, benzyl (2S)-2-Boc-amino-3-(2-oxiranyl)propionate
isomers ((2S)-6) were obtained in 69% yield (Scheme 2).34,35
Compound (2S)-6 was obtained as a diastereomeric mixture
owing to the newly generated chiral center at C4, though these
isomers were not separated under our TLC conditions. 1H NMR
spectra of (2S)-6 in CDCl3 (Fig. 2 and S2†) showed two sets of
1
ascertained by H NMR, chiral HPLC (eluting with dilute Cu2+
solution) and the specic rotation measurements, in which no
impurities were found in 1H NMR and in chiral HPLC.23–26 Thus,
(S)-2 and (R)-1 were successfully obtained from racemic 1 by
kinetic enzymatic (Subtilisin) resolution.
Next, diethyl acetamidomalonate, which is less expensive
than diethyl (2-Boc-amino)malonate, was selected as a starting
material. Similar to diethyl (2-Boc-amino)malonate, diethyl
acetamidomalonate was reacted with allyl bromide, half
saponied, decarboxylated in reuxing toluene and then sub-
jected to second saponication affording racemic 2-acetamido-
4-pentenoic acid (3, Fig. S1 in ESI,† 37% yield in four steps
based on diethyl acetamidomalonate).
This racemic acetyl amino acid 3 was treated with acylase
under pH 7.0 (aqueous LiOH) conditions with Co2+ at 37 ꢀC.27–29
Aer 24 h, the solution was acidied and extracted with EtOAc
to afford unreacted (R)-3, which was puried by silica gel
column chromatography to yield
a
brown semi-solid
compound. The remaining acidic solution was subjected to the
ion-exchange resin (–SO3H type) and then product (S)-2-amino-
4-pentenoic acid ((S)-4) eluted when the resin was washed with
aqueous NH3, which became a white solid aer evaporation. In
these procedures, the isolations of products 3 and 4 were not
Scheme 2 Epoxidation of side chain C]C bond of benzyl (S)-2-Boc-
easy because these compounds were highly water soluble. The amino-4-pentenoate.
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Fig. 2 1H NMR (1D and 2D-COSY) spectra of (2S)-6 in CDCl3 (high-
field region). See Scheme 2 for C3H, C4H and C5H.
C3H protons, d 2.19 and 1.81 ppm, 0.43H, respectively, for
(2S,4R)-6 and d 2.00 and 1.95 ppm, 0.57H, respectively, for
(2S,4S)-6 (see subsequent discussion for assignments). The
geminal couplings between the C3H protons of (2S,4R)-6 and
also between the C3H protons of (2S,4S)-6 were clearly observed
1
in the 2D H–1H COSY spectrum (Fig. 2 and S3†). C4H signals
Scheme 3 Formation of N-Boc-L-cis-hydroxyproline lactone (10) and
benzyl N-Boc-L-trans-hydroxyproline (trans-9) (–R ¼ –CH2Ph).
(ꢁd 2.99 and 2.96) and also some 13C NMR signals (Fig. S4†)
appeared as two sets. These diastereomers were assigned with
reference to the pure methyl (2S,4S)-2-Boc-amino-3-(2-oxiranyl)
propionate reported earlier.35
This epoxidation of allylglycine derivative 5 (with a –CH2–
CH]CH2 side chain) slightly favored (2S,4S)-6 diastereomer
than (2S,4R)-6 diastereomer at a ratio of 57 : 43 (within 1% error
in three independent experiments). In this context, (R)-vinyl-
glycine (with a –CH]CH2 side chain) was epoxidized in an
80 : 20 ratio for (2R,3R)- and (2R,3S)-diastereomers.31 However
no stereoselectivity has been noted for the epoxidation of
butenylglycine (with a –CH2–CH2–CH]CH2 side chain).32,33
The free amino group of (2S)-7 slowly attacks the epoxy ring
intramolecularly. Aer 24 h, TLC analysis (butanol/pyridine/
acetic acid/H2O, 4/1/1/2 by volume) of the reaction mixture
showed that (2S)-7 still remained (Rf ¼ 0.34, purple color with
ninhydrin) and also showed two ninhydrin-active yellow spots
at Rf ¼ 0.52 and 0.79 (yellow spotting with ninhydrin is a
characteristic of proline-like molecule). Aer 72 h, TLC results
1
showed the disappearance of the reactant. H NMR analysis of
the evaporated reaction mixture showed the absence of char-
acteristic epoxide signals at d 2.72 and 2.44 (C5H signals). These
facts strongly suggest that the nucleophilic ring opening of the
epoxide occurred intramolecularly, possibly to produce ve-
membered cyclic imino acids (secondary amino acids), cis-L-
Intramolecular cyclisation to generate cis-hydroxyproline
lactone and trans-hydroxyproline ester
Next, intramolecular attack of the epoxy ring by the amino hydroxyproline benzyl ester (cis-8) and trans-L-hydroxyproline
group of the amino acid was performed (Scheme 3). First, the benzyl ester (trans-8).
Boc protection of (2S)-6 was removed by treating with 4 mol Lꢂ1
However, these products (a mixture of L-hydroxyproline
HCl in dioxane for 2.5 h.36 TLC analysis showed the complete benzyl esters cis-8 and trans-8) were not isolated, because their
deprotection; the spot of (2S)-6 disappeared and a ninhydrin- isolation required polar conditions for the silica gel column
positive spot appeared. The HCl salt of benzyl (2S)-2-amino-3-(2- chromatography. Instead, this reaction mixture was re-dis-
oxiranyl)propionate ((2S)-7$HCl, not isolated) was quantitatively solved in dioxane and reacted with a small excess of Boc2O
produced as a white solid upon evaporation.
using Et3N to re-protect the secondary amino groups to give N-
Aer (2S)-7$HCl was dissolved in DMF (4.6 mmol in 30 mL Boc-cis-L-hydroxyproline benzyl ester (cis-9) and N-Boc-trans-L-
DMF), two equivalents of Et3N were added to neutralize HCl. hydroxyproline benzyl ester (trans-9). Aer 24 h, evaporation
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Fig. 3 1H NMR spectra of (a) 10 and (b) trans-9 in CDCl3 (high-field region). X denotes solvents and known impurities. See Fig. 4 for CaH, CbH,
CgH and CdH.
and washing with brine afforded the Boc-protected products as (0.21H, minor); CaH 4.47 (minor), 4.41 (major); CbH 2.89
yellow oil. Two spots were observed on TLC, which were (0.21H, minor), 2.68 (0.79H, major), 2.45 (0.79H, major), 2.06
1
ninhydrin negative and H3(PMo12O40) positive. H NMR anal- (0.21H, minor). The geminal couplings between the bCH
ysis was difficult at this stage because the spectrum exhibited protons of major isomers and also between those of minor
many overlapping peaks; however, two products were success- isomers were clearly observed in the 2D 1H–1H COSY spectrum
fully isolated by silica gel column chromatography using (Fig. S6†). The spin–spin coupling between CbH and CgH was
hexane–50% EtOAc (v/v) as the eluent.
observed only for one set of CbH protons, probably because of
The rst eluted product was a white solid and was identi- their dihedral angles. The 2D NOESY spectrum (Fig. S7†) indi-
ed as (1S,4S)-tert-butyl-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane- cated a NOE signal between CbH (d 2.68 and 2.06) and CgH
5-carboxylate (L-cis-hydroxyproline lactone, 10),12,13,37,38 not (Fig. 4b). This NOE signal is the direct evidence for the bicyclic
the expected N-Boc-cis-L-hydroxyproline benzyl ester, cis-9. structure of 10 because monocyclic trans-9 showed no NOE
Compound 10 was obtained as a white solid in 29–42% yield signals under the same conditions (see below). The most
based on (2S)-6. The 1H NMR spectrum of 10 showed no signals intense peak appeared at m/z ¼ 272 (and 274) of [M + H +
of a benzyl group and –OH group (Fig. 3a and S5†). This spec- Na35Cl]+ (and [M + H + Na37Cl]+) in the ESI-mass spectrum
trum is slightly complex because Boc-proline (hydroxyproline) (Fig. S8†), where M (213) indicated the intramolecular lactone
derivative usually exists as a two-rotamers mixture based on the formation, with no signals derived from cis-9.
secondary amino N-carbamate C bond (Fig. 4a).11,39 In fact, two
The second eluted product from the column was yellowish
sets of signals for a major isomer and a minor isomer were oil and was identied as N-Boc-L-trans-hydroxyproline benzyl
observed in the spectrum of 10: CgH d 4.92 (0.79H, major), 4.65 ester (trans-9). Compound trans-9 was obtained as yellowish oil
in 18–38% yield based on (2S)-6. The 1H NMR of trans-9 (Fig. 3b)
also indicated a mixture of rotamers but clearly showed the
signals of a benzyl group at d 7.35 (5H) and ꢁ5.2 (2H). No NOE
signals were observed under the same measurement conditions
used for 10; however, an –OH signal was detected at ꢁ3.2 as an
exchanging proton by phase-sensitive NOESY. The 1H NMR and
MS spectra of this sample agreed with those of the authentic
sample of trans-9 sample, which was separately synthesized
from commercial N-Boc-L-trans-hydroxyproline and benzyl
bromide.40 The mass spectrum of trans-9 showed peaks at m/z ¼
322 for [M + H]+ and fragment peaks derived from [M + H]+,
where M (321) supported the structure of trans-9.
The 1H NMR spectra of trans-9 and 10 shows signicant
differences in the positions of CgH signals (d 4.92, 4.65 for 10
and d ꢁ4.4 for trans-9) and CbH signals (d 2.89, 2.68, 2.45, 2.06
for 10 and d 2.31, 2.07 for trans-9). The two CbH protons of 10 (d
2.89 and 2.68) were high-eld shied compared to 9 and the
other two CbH protons of 10 (d 2.45 and 2.06) were similar to 9.
Interestingly, the high-eld-shied CbH protons of 10 (d 2.89
and 2.68) showed NOE signals with CdH signals.
Fig. 4 (a) Two conformers of Boc-hydroxyproline. (b) NOE signals
observed for 10.
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The –OH and ester (–COOCH2Ph) groups are closely located oxyproline), 14 was less soluble in CDCl3, therefore, the 1H NMR
in cis-9; therefore, lactone molecule 10 may be intramolecularly spectra of 14 and O-benzyl N-Boc-trans-L-hydroxyproline were
formed in the work-up or purication process. Fortunately, acquired in CD3OD (Fig. S10 and S11†). The CbH protons
lactone 10 is less polar than cis-9 and trans-9; therefore, sepa- showed difference; CbH protons appeared at ꢁ2.34 (m, 2H) in
ration between 10 and trans-9 was easy. Thus, practical the cis-isomer (14) and appeared at 2.44 (m, 1H) and 2.07 (m,
syntheses of both 10 (L-cis-hydroxyproline derivative) and trans-9 1H) in the trans-isomer. Utilization of 14 for the synthesis of
(L-trans-hydroxyproline derivative) were successfully performed. biologically active peptides by the introduction of cis-L-hydroxy-
proline residues is underway.
Hydroxyproline derivatives with (2R)-stereoconguration and
Conclusions
O-benzyl derivatives for peptide synthesis
To prepare the D-hydroxyproline derivatives with (2R)-stereo-
congurations, (R)-1 obtained by the Subtilisin resolution was
proline derivatives were synthesized. The conguration of the
epoxidized by m-CPBA and saponied to obtain (2R)-2-Boc-
amino-3-(2-oxiranyl)propionic acid ((2R)-11) (Scheme 4 and
Fig. S9†). This Boc-amino acid with a side-chain epoxide group
was deprotected with HCl/dioxane, neutralized with Et3N and
then (aer completion of the nucleophilic opening of the
epoxide, 72 h) re-protected by Boc2O similar to the procedure
acids with side-chain epoxide groups were subjected to the
used to prepare the (2S)-isomeric series (Scheme 3). Silica gel
chromatography afforded (1R,4R)-tert-butyl-3-oxo-2-oxa-5-aza-
bicyclo[2.2.1]heptane-5-carboxylate (12)10 and N-Boc-D-trans-
hydroxyproline benzyl ester (trans-13) in 43% and 32% yields,
respectively. Products 12 and trans-13 are the mirror images of
stereoselectivity; however, 4-hydroxyproline derivatives with cis
10 and commercial N-Boc-L-trans-hydroxyproline, respectively.
The protection of the amino acid –COOH group was not
necessary in intramolecular cyclisation.
For practical use of cis-L-hydroxyproline derivatives in
peptide synthesis, O-benzyl N-Boc-cis-L-hydroxyproline ((2S,4S)-
N-Boc-4-benzyloxyproline, 14) was synthesized. Compound cis-L-
fore, the silica gel column chromatographic separation of (2S,
hydroxyproline 10 was cleaved with aqueous NaOH (slight
excess). The N-Boc-cis-L-hydroxyproline Na salt was obtained
aer evaporation, to which NaH and benzyl bromide were
In summary, (2S,4R)-, (2S,4S)-, (2R,4S)- and (2R,4R)-hydroxy-
chiral center at C2 position was determined by the enzymatic
resolution of the racemic amino acid ester (Subtilisin) or an
acetyl amino acid (acylase). The L- and D-amino acids derivatives
were obtained in enantiomerically pure forms. Aer the epoxi-
dation of the side chain by treatment with m-CPBA, the amino
nucleophilic attack of the amino acid H2N- group to the epoxide
ring. Intramolecular cyclisation generated 4-hydroxyproline
with ve-membered rings.
The chiral center at the C4 position was generated with low
orientations, i.e., (2S,4S)- and (2R,4R)-hydroxyproline derivatives,
formed bicyclic lactone molecules during the work-up process.
Intramolecular ester exchange reactions occurred, i.e., the benzyl
ester moieties was attacked by the 4-OH group. The lactone
molecules were more hydrophobic than hydroxyprolines; there-
4R)-isomer (L-hydroxyproline) and (2S,4S)-isomer (L-cis-hydroxy-
proline lactone) was straightforward. Thus, stereoisomers of
hydroxyproline derivatives were prepared successfully.
added to produce 14. Contrary to commercially available
O-benzyl N-Boc-trans-L-hydroxyproline ((2S,4R)-N-Boc-4-benzyl-
Experimental section
General
Reagents and solvents including Subtilisin (Carslberg, from
Bacillus lichenirmis) and L-aminoacylase (from Aspergillus
genus, 3 ꢃ 104 unit per g) were from commercial sources. DCM
and DMF were used aer routine drying. DOWEX 50WX8
(50–100) was used as an ion exchange resin, aer thoroughly
washing with aqueous HCl. TLC was visualized by UV (F254), I2,
H3(PMo12O40) and/or ninhydrin. Daicel CHIRALPAK WH
column (250 ꢃ 4.6 mm) was used for chiral HPLC of the amino
acids eluting with 0.25 mmol Lꢂ1 CuSO4 (1.0 mL minꢂ1), 50 ꢀC
1
and 220 nm detection. H (1D, 2D-COSY, 2D-NOESY) and 13C
NMR spectra were measured in CDCl3 or CD3OD at 500 or 600
MHz. Normal- and high resolution-FAB mass and ESI TOF mass
spectra were measured routinely. Optical rotations were
ꢀ
measured in a 100 mm cell at 26 C.
Kinetic resolutions of 2-amino-4-pentenoic acid derivative by
Subtilisin, racemic ethyl 2-Boc-amino-4-pentenoate (1)23
Diethyl (2-Boc-amino)malonate (25.4 mL, 100 mmol) and NaOEt
(100 mmol) in 100 mL EtOH was reuxed for 30 min. Allyl
Scheme 4 Formation of N-Boc-D-cis-hydroxyproline lactone (12) and
benzyl N-Boc-trans-D-hydroxyproline (trans-13).
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bromide (11.2 mL, 130 mmol) was added to the above cooled (9.30 g, 39.6 mmol) was reuxed in 90 mL toluene for 24 h,
mixture and further reuxed for 5 h. AcOH (5.7 mL) was added which afforded crude ethyl 2-(acetamido)-4-pentenoate (5.92 g)
aer cooling, then the mixture was evaporated, dissolved in aer evaporation. This crude ethyl ester was hydrolyzed with
EtOAc, washed (brine) and again evaporated to obtain diethyl 2- excess NaOH (with two batches) in EtOH–H2O (1.3 : 1, v/v) at
allyl-(2-Boc-amino)malonate (28.7 g). To the EtOH (60 mL) 0 ꢀC for 3 h. Aer evaporation of EtOH, the remaining aqueous
solution of diethyl 2-allyl-(2-Boc-amino)malonate (16.3 g, solution was washed (diethyl ether), acidied (aqueous HCl)
51.7 mmol), 60 mL of aqueous NaOH (1.0 mol Lꢂ1) was added at and extracted with EtOAc. Evaporation of the organic phase
ꢀ
0 C. Aer 3 h, the mixture was concentrated, acidied (pH 3, afforded racemic 3 as a creamy oil (total 2.29 g, 14.6 mmol, 37%
1
citric acid) and extracted with EtOAc. Aer evaporation, crude from diethyl acetamidomalonate). H NMR (CDCl3, 500 MHz,
ethyl 2-Boc-amino-2-ethoxycarbonyl-4-pentenoate was obtained Fig. S1†): d 6.00 (d, J ¼ 7 Hz, 1H, NH), 5.74 (m, 1H, C4H), 5.19 (m,
(15.2 g). This ester was not puried but dissolved in 100 mL 2H, C5H), 4.65 (m, 1H, C2H), 2.64 and 2.59 (m, 2H, C3H), 2.06 (s,
toluene and reuxed for 6 h. Racemic 1 was obtained aer 3H, Ac).
evaporation as a viscous liquid (12.5 g, 51.4 mmol, 91% based
on diethyl (2-Boc-amino)malonate). 1H NMR (CDCl3, 500 MHz):
(S)-2-Amino-4-pentenoic acid ((S)-4)
d 5.70 (m, 1H, C4H), 5.13 (m, 2H, C5H), 5.06 (d, J ¼ 7 Hz, 1H,
NH), 4.36 (q, J ¼ 7 Hz, 1H, C1H), 4.20 (m, 2H, OCH2), 2.55 and Racemic 3 (1.60 g, 10.2 mmol) and CoCl2$6H2O (11 mg, 50 mmol)
2.50 (m, total 2H, C2H), 1.44 (s, 9H, Boc), 1.28 (t, J ¼ 7 Hz, 3H, was dissolved in 16 mL H2O at 37 ꢀC, while maintaining its pH at
OCH2CH3), which was similar to the literature data.26
7.0 with aqueous LiOH (ca. 14 mL). L-Aminoacylase (0.46 g,
13 800 units) in 4.0 mL H2O was added. Aer 24 h, while
adjusting the pH at 7.0 with small amount of aqueous NH3, the
reaction mixture was concentrated, acidied to pH 1.5 (aqueous
HCl) and the unreacted (R)-3 was extracted with EtOAc.
The acidic aqueous phase was applied to a column of ion
exchange resin (DOWEX 50WX8, 150 ꢃ 20 mm). Aer sample
charging and washing with 1.0 mol Lꢂ1 aqueous HCl, (S)-4
eluted with 1.0 mol Lꢂ1 aqueous NH3. Evaporation of the eluent
afforded (S)-4 as white solids (330 mg, 2.87 mmol, 28% based on
racemic 3). Only (S)-isomer of 2-amino-4-pentenoic acid was
detected at retention time 23.60 min. 1H NMR (CD3OD, 500
MHz): d 5.81 (m, 1H, C4H), 5.22 (m, 2H, C5H), 3.58 (m, 1H, C2H),
2.66 and 2.57 (m, 2H, C3H), which was identical to the
commercial sample.
(S)-2-Boc-amino-4-pentenoic acid ((S)-2)
The solution of racemic 1 (17.4 g, 71.5 mmol) in 72 mL DMF was
diluted with 200 mL H2O, then 70 mg (ꢁ840 units) of Subtilisin
was added. The mixture was stirred at 40 ꢀC for 3 h, while
maintaining its pH at 8.0 (aqueous NH3). The mixture was
extracted by diethyl ether, then the remaining aqueous solution
was acidied (pH 3, citric acid). (S)-2 was extracted with EtOAc,
washed (brine) and evaporated to yield 7.53 g (35.0 mmol, 49%
based on racemic 1) as an oil. HPLC (aer removal of Boc with 4
mol Lꢂ1 HCl in dioxane): Only (S)-isomer 2-amino-4-pentenoic
acid was detected at retention time 23.18 min. [a]2D6 ¼ +9.65ꢀ
1
(c ¼ 1.3, MeOH). H NMR was similar to the literature data.25
Ethyl (R)-2-Boc-amino-4-pentenoate ((R)-1)
The diethyl ether extract of the Subtilisin reaction mixture was (R)-2-Acetamido-4-pentenoic acid ((R)-3)
evaporated to afford (R)-1 (8.54 g, 35.1 mmol, 49% based on
The EtOAc extract of the acidied acylase reaction mixture was
racemic 1). HPLC (aer removal of -OEt with 1 mol Lꢂ1 aqueous
NaOH, 2 h, then Boc removal): Only (R)-isomer 2-amino-4-pen-
tenoic acid was detected at retention time 19.38 min.
evaporated to give (R)-3 as a brown oil (2.53 g). A part (1.75 g) of
this sample was chromatographed over silica gel (CHCl3–
MeOH–AcOH ¼ 90/10/2, by volume) to afford pure (R)-3 as a
semi-solid (249 mg, 1.58 mmol, 22% based on racemic 3). HPLC
(aer removal of Ac by 1 mol Lꢂ1 aqueous HCl, reux):30 Only
(R)-isomer of 2-amino-4-pentenoic acid was detected at reten-
Kinetic resolutions of 2-amino-4-pentenoic acid derivative by
acylase, racemic 2-acetamido-4-pentenoic acid (3)
Diethyl acetamidomalonate (10.0 g, 46.0 mmol) and NaOEt tion time 19.53 min.
(50.7 mmol) was reuxed in 40 mL EtOH for 5 h, then allyl
bromide (5.0 mL, 59 mmol) was added to the cooled reaction
mixture and further reuxed for 15 h. Aer cooling, neutralized
(2 mL AcOH) mixture was evaporated, taken up in EtOAc,
Epoxidation in the side chain of (S)-2, benzyl (S)-2-Boc-amino-
4-pentenoate ((S)-5)
washed (brine) and again evaporated to obtain an oily diethyl 2- To the solution of (S)-2 (6.93 g, 32.2 mmol) in 100 mL DMF,
acetylamido-2-allylmalonate quantitatively (11.9 g). This crude benzyl bromide (5.13 g, 45.0 mmol) and Et3N (2.43 g, 36 mmol)
malonate (11.9 g, supposed to be 46.0 mmol) dissolved in 45 mL was added at 0 ꢀC. Aer 5 h, the mixture was evaporated, taken
EtOH was mixed with 56 mL aqueous NaOH (1.0 mol Lꢂ1) at up in EtOAc, washed (aqueous citric acid/aqueous NaHCO3) and
0 ꢀC. The reaction was complete aer 3 h (TLC), then EtOH was again evaporated. The residue was chromatographed over silica
evaporated, the remaining aqueous solution was washed gel (CHCl3–1% MeOH, v/v) to obtain pure (S)-5 (6.32 g, 20.7
(diethyl ether), acidied (pH 2, aqueous HCl) and extracted with mmol, 64%) as an oil. 1H NMR (CDCl3, 500 MHz): d 7.36 (m, 5H,
EtOAc. Evaporation of the organic phase afforded white solid of Ph), 5.65 (m, 1H, C4H), 5.17 (m, 2H, CH2Ph), 5.1 (m, 3H, overlap
ethyl 2-acetamido-2-(ethoxycarbonyl)-4-pentenoate (10.8 g). A of NH and C5H), 4.43 (q, J ¼ 7 Hz, 1H, C2H), 2.52 (m, 2H, C3H),
part of this ethyl 2-acetamido-2-(ethoxycarbonyl)-4-pentenote 1.43 (s, 9H, Boc), which was similar to the literature data.41
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Benzyl (2S)-2-Boc-amino-3-(2-oxiranyl)propionate ((2S)-6)
tert-Butyl (1S,4S)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-
carboxylate (10)
To the ice-cooled solution of (S)-5 (8.00 g, 26.2 mmol) in
100 mL DCM, m-CPBA (9.59 g, 40.0 mmol) in 50 mL DCM 1H NMR (CDCl3, 500 MHz, Fig. 3, S5, S6 and S7†): d 4.92 (br s,
was added in 5 portions and warmed to room temperature. 0.79H, CgH of major isomer), 4.65 (sextet, J ¼ 5 Hz, 0.21H, CgH
Aer 24 h, the solution was concentrated to ca. 1/4 volume of minor isomer), 4.47 and 4.41 (both m, total 1H, CaH of minor
and was mixed with Na2SO3 solution (3.0 g in 25 mL H2O). and major isomers, respectively), 3.66–3.79 (m, 2H, CdH), 2.89
The biphasic mixture was stirred vigorously for 2 h, then the (m, 0.21H, CbH of minor isomer), 2.68 (t, J ¼ 20 Hz, 0.79H, CbH
organic phase was washed (aqueous NaHCO3) and evaporated of major isomer), 2.45 (dt, J ¼ 10 and 13 Hz, 0.79H, CbH of
to obtain the crude (2S)-6 (9.26 g) as a white syrup, which was major isomer), 2.06 (q, J ¼ 11 Hz, 0.21H, CbH of minor isomer),
puried by silica gel column chromatography (hexane–15% 1.46 (s, 9H, Boc), which were similar to the literature data.37 ESI-
EtOAc, v/v) to obtain pure (2S)-6 (5.79 g, 18.0 mmol, 69%) as MS (Fig. S8†): m/z 272 ([M + H + Na35Cl]+), 274 ([M + H +
1
a colorless oil. H NMR (CDCl3, 500 MHz, Fig. 2, S2 and S3†): Na37Cl]+), 216 ([272–C4H8]+).
d 7.36 (m, 5H, Ph), 5.31 (d, 1H, J ¼ 8 Hz, NH), 5.19 (m, 2H,
CH2Ph), 4.52 (m, 1H, C2H), 2.99 (m) and 2.96 (m) (C4H of
N-Boc-(2S,4R)-4-hydroxyproline benzyl ester (trans-9)
(2S,4R)-6 and C4H of (2S,4S)-6, respectively, total 1H), 2.72 (t,
1H NMR (CDCl3, 500 MHz, Fig. 3): d 7.35 (m. 5H, Ph), 5.07–5.27
1H, J ¼ 5 Hz, C5H), 2.44 (m, 1H, C5H), 2.19 (m, 0.43H, C3H of
(m, 2H, CH2Ph), 4.44–4.48 (m, 2H, CaH, CgH), 3.65 (minor
(2S,4R)-6), 2.00 (m, 0.57H, C3H of (2S,4S)-6), 1.95 (m, 0.57H,
isomer) and 3.63 (major isomer) (both d, J ¼ 4 Hz, total 1H,
CdH), 3.56 (major isomer) and 3.45 (minor isomer) (both d, J ¼
12 Hz, total 1H, Cd’H), 3.27–3.16 (m, 1H, OH), 2.31 (m, 1H, CbH),
2.07 (m, 1H, CbH), 1.46 (s, 3.2H, minor isomer, Boc), 1.35 (s,
5.8H, major isomer, Boc). FAB-MS: m/z 322 ([M + H]+, 26), 266
([M + H–C4H8]+, 76), 222 ([M + H–C4H8–CO2]+, 100).
C3H of (2S,4S)-6), 1.81 (m, 0.43H, C3H of (2S,4R)-6), 1.45 (s,
9H, Boc). 13C NMR (CDCl3, 125 MHz, Fig. S4†): d 171.9 and
171.8, 155.3, 135.3, 128.6, 128.5, 128.4, 80.1, 67.4, 52.1 and
52.0, 49.1 and 49.0, 46.7 and 46.5, 35.6 and 35.5, 28.3. FAB-
MS: m/z 344 ([M + Na]+, 7), 322 ([M + H]+, 14), 266 ([M + H–
C4H8]+, 100), 222 ([M + H–C4H8–CO2]+, 38); HR-FAB-MS
[C17H24NO5]+ ([M + H]+): calculated ¼ 322.1655, found ¼
322.1639.
cis-Hydroxyproline lactone and trans-hydroxyproline of (2R)-
isomers, (2R)-2-Boc-amino-3-(2-oxiranyl)propionic acid ((2R)-11)
The reaction of (R)-1 (7.30 g, 30.0 mmol) with m-CPBA (1.5
equivalent) in DCM, in a similar manner to the synthesis of (2S)-6,
yielded ethyl (2R)-2-Boc-amino-3-(2-oxiranyl)propionate (5.98 g,
23.1 mol, 77%). Without purication, 3.63 g of this ethyl ester
(14.9 mmol) in50 mL EtOH wasmixed with 17 mLaqueous NaOH
(1.0molLꢂ1)at0ꢀC.Aer2h,AcOH(1.2mL)wasaddedandEtOH
was evaporated. The remaining aqueous solution was washed
(diethyl ether/aqueous NaHCO3), acidied and extracted with
EtOAc. Evaporation of the organic phase afforded (2R)-11 as white
solid (2.31 g, 10.0 mmol, 55% from (R)-1 in two steps). 1H NMR
(CD3OD, 500MHz):d4.63(d,1H,C2H), 4.49(m, 1H,C4H),3.77 (m,
1H, C5H), 3.61 (m, 1H, C5H), 2.46, 2.34, 2.02 (m, total 2H, C3H),
1.44 (s, 9H, Boc). 13C NMR (CD3OD, 125 MHz, Fig. S9†): d 178.3
and 177.3, 157.7, 80.9 and 79.7, 79.5, 64.7 and 64.1, 52.0 and 51.1,
31.4 and 31.2, 28.7. FAB-MS: m/z ¼ 254 ([M + Na]+, 29), 232 ([M +
H]+, 29), 176([M+ H–C4H8]+, 100); HR-FAB-MS [C10H18NO5]+ ([M +
H]+): calculated ¼ 232.1185, found ¼ 232.1193.
Intramolecular epoxide opening to generate cis-
hydroxyproline lactone and trans-hydroxyproline ester, tert-
butyl (1S,4S)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-
carboxylate (10) and N-Boc-(2S,4R)-4-hydroxyproline benzyl
ester (trans-9)
(2S)-6 (1.49 g, 4.64 mmol) in 3.0 mL of dioxane was added to
the ice-cooled solution of HCl in dioxane (4 mol Lꢂ1, 40.0
mL) within 5 min and warmed to room temperature. Aer
2.5 h, the solution with white precipitate was evaporated and
kept in vacuo overnight. HCl salt of benzyl 2-amino-3-(2-
oxiranyl)propionate ((2S)-7$HCl) was obtained quantitatively
(1.20 g) as a white oily solid, which was not characterized.
(2S)-7$HCl thus obtained was dissolved in 30 mL of DMF,
then Et3N (1.3 mL, 9.3 mmol) was added and the resultant
yellowish mixture was stirred for 72 h. Aer evaporation, a
white solid was yielded (1.51 g). A mixture of (2S,4S)-4-
hydroxyproline benzyl ester ((2S,4S)-8) and (2S,4R)-4-hydrox-
yproline benzyl ester ((2S,4R)-8) were obtained quantitatively,
which were analyzed by TLC and 1H NMR, but these benzyl
esters were not isolated. Instead, some of this crude benzyl
esters (1.40 g, 4.30 mmol) was mixed with 30 mL of dioxane,
tert-Butyl (1R,4R)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-
carboxylate (12) and N-Boc-(2R,4S)-4-hydroxyproline ethyl
ester (trans-13)
then Et3N (0.59 mL, 4.23 mmol) and Boc2O (1.13 g, (2R)-11 (2.71 g, 11.7 mmol) was added to the HCl solution in
5.18 mmol) in 3.0 mL dioxane was added. Aer 18 h, the dioxane (4 mol Lꢂ1, 25 mL, 0 ꢀC) and warmed to room
mixture was concentrated, dissolved in EtOAc, washed (brine) temperature. Aer 1 h, the mixture was evaporated to obtain
and evaporated to afford yellow oil (1.12 g). 0.49 g (calculated (2R)-2-amino-3-(2-oxiranyl)propionic acid quantitatively. This
to be 1.88 mmol) of this crude product was puried by silica (2R)-2-amino-3-(2-oxiranyl)propionic acid was dissolved in
gel column chromatography (hexane–50% EtOAc, v/v) to 40 mL DMF, then Et3N (2.00 mL, 14.4 mmol) was added and the
obtain pure 10 (yellowish solid aer crystallization from resultant mixture was stirred for 72 h. Boc2O (2.55 g, 11.7 mmol)
EtOAc, 115 mg, 539 mmol, 29%) and trans-9 (brownish oil, and Et3N (1.63 mL, 11.7 mmol) were further added. Aer 8 h,
106 mg, 330 mmol, 18%).
the mixture was concentrated, dissolved in EtOAc, washed
2488 | RSC Adv., 2014, 4, 2482–2490
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(aqueous citric acid) and evaporated to obtain yellow oil (1.45 g). 11 A. K. Pandey, D. Naduthambi, K. M. Thomas and
This crude product was puried by silica gel column chroma- N. J. Zondlo, J. Am. Chem. Soc., 2013, 135, 4333–4363.
tography (hexane–50% EtOAc, v/v) to obtain 12 (ref. 10) (1.07 g, 12 D. Papaioannou, G. Stavropoulos, K. Karagiannis,
5.03 mmol, 43%) and trans-13 (866 mg, 3.74 mmol, 32%). The
1H NMR spectra of these compounds were similar to the data of
their enantiomers, 10 and Boc-Hyp, respectively.
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4-Benzyl derivatives of (2S)-hydroxyprolines, (2S,4S)-N-Boc-4-
benzyloxyproline (14)
The EtOH (3.0 mL) solution of 10 (213 mg, 1.00 mmol) was mixed
with 1.2 mL aqueous NaOH (1.0 mol Lꢂ1) for 1 h, then the mixture
was evaporated in vacuo. The residue was dissolved in 3.0 mL
THF, 55% NaH (52.4 mg, 1.2 mmol) and benzyl bromide (205 mg,
1.2 mmol) was added and stirred for 4 h. Aer evaporation, the
residue taken up in EtOAc was washed and again evaporated to
yield 14 as a white solid (267 mg, 83.1 mmol, 83%). 1H NMR
(CD3OD, 500 MHz, Fig. S10†): d 7.31 (m, 5H, Ph), 4.49 (m, 2H,
CH2Ph), 4.34 and 4.28 (m, total 1H, CaH), 4.16 (m. 1H, CgH), 3.61
(m, 1H, CgH), 3.48 (m, 1H, CgH), 2.34 (m, 2H, CbH), 1.46 and 1.43
(s, total 9H, Boc). 13C NMR (CD3OD, 125 MHz, Fig. S11†): d 175.9
and 175.6, 156.3 and 156.1, 139.5, 129.3, 129.0, 128.7, 81.5, 78.4
and 77.4, 73.2 and 72.0, 59.2 and 58.8, 53.4 and 52.7, 36.8 and
36.0, 28.6. ESI-MS: m/z 344 ([M + Na]+), 288 ([M + Na–C4H8]+), 244
([M + Na–C4H8–CO2]+); HR-ESI-MS [C17H23N1Na1O5]+ ([M + Na]+):
calculated ¼ 344.1474, found ¼ 344.1460.
¨
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