Synthesis of GABOB and GABOB-based chiral units possessing distinct protecting groups

Article abstract of DOI:10.1002/ejoc.201301374

In addition to the varied biological activity of GABOB (4-amino-3- hydroxybutanoic acid), the structure of its protected derivatives makes them interesting chiral intermediates for the synthesis of more complex compounds. A stereoselective route to GABOB derivatives with three different protecting groups is presented, using anhydride desymmetrization as a chirality-inducing step. Selective removal of the protecting groups gave compounds with a free carboxylic acid or hydroxy group. Removal of all of the protecting groups allowed GABOB to be isolated in good yield and with excellent ee. A stereoselective route to GABOB (4-amino-3-hydroxybutanoic acid) derivatives with three different protecting groups is presented. Selective deprotection produced diprotected chiral building blocks with a free carboxylic acid or hydroxy group. Removal of all the protecting groups allowed GABOB to be isolated. Copyright

Full text of DOI:10.1002/ejoc.201301374

FULL PAPER
DOI: 10.1002/ejoc.201301374
Synthesis of GABOB and GABOB-Based Chiral Units Possessing Distinct
Protecting Groups
[a]
[a]
[a]
[a]
ˇ ´
ˇ
Trpimir Ivsic,* Irena Dokli, Ana Rimac, and Zdenko Hamersak
Keywords: Synthetic methods / Asymmetric synthesis / Anhydrides / Amino acids / Protecting groups / Alkylation
In addition to the varied biological activity of GABOB (4-
amino-3-hydroxybutanoic acid), the structure of its protected
derivatives makes them interesting chiral intermediates for
the synthesis of more complex compounds. A stereoselective
route to GABOB derivatives with three different protecting
groups is presented, using anhydride desymmetrization as a
chirality-inducing step. Selective removal of the protecting
groups gave compounds with a free carboxylic acid or
hydroxy group. Removal of all of the protecting groups
allowed GABOB to be isolated in good yield and with
excellent ee.
their use as building blocks for the synthesis of other biolo-
gically active compounds, different ways to synthesize GA-
BOB are known. Racemic GABOB is, for example, avail-
able from allyl cyanide in four steps: preparation of the ep-
oxide, opening with azide, hydrogenation, and hydrolysis.[6]
As regards the optically pure compound, syntheses of (R)-
GABOB have been described starting from chiral materials
such as ascorbic acid,[7] malic acid,[8] hydroxyproline es-
ters,[9] or 4-chloro-3-hydroxybutanoic acid.[10]
The asymmetric synthesis of enantiopure compounds
starting from achiral materials is a focus of current re-
search. Thus, several asymmetric routes to 1 and its ana-
logues have been reported,[1] including enzymatic meth-
ods,[11–13] the addition of organometallic reagents to lact-
ones,[14] or osmium-catalysed asymmetric aminohydroxyl-
ation.[15]
Introduction
As a metabolic derivative of the neurotransmitter γ-
aminobutanoic acid, GABOB (4-amino-3-hydroxybutanoic
acid; Figure 1)[1a] has various biological activities and may,
among other uses, be used in the treatment of personality
disorder conditions such as epilepsy and schizophrenia.[2,3]
In addition, due to its specific structure, it has recently been
recognized as an interesting chiral segment that could be
useful in the synthesis of other biologically active natural
products, such as carnitine (vitamin Bt), negamycin[4] (an
antibiotic), or microsclerodermin E[5] (an antitumor cyclic
peptide).
To address the need for metal-free catalytic methods suit-
able for the production of both enantiomers, we report in
this paper a stereoselective route to GABOB and its deriva-
tives with distinct protecting groups, using the organocata-
lytic opening of anhydrides for the introduction of chirality.
Results and Discussion
Figure 1. GABOB and structurally related natural products.
While planning the synthesis, the stable and easily remov-
able benzyl ether (Bn) seemed to be a reasonable choice for
a hydroxy protecting group (PG1). However, O-alkylation
of diethyl 3-hydroxyglutarate (2) proved to be quite chal-
lenging. While esters and silyl ethers[16] of 2 are readily
available, to the best of our knowledge, alkyl ethers of 2
have not been described in the literature.
With diethyl 3-hydroxyglutarate, our initial attempts met
with little success. Alkylation with silver oxide and benzyl
bromide, or via a trichloroacetimidate intermediate, pro-
ceeded in poor yields (Table 1, entries 2 and 3). Under
As research into γ-amino acids is an area of intense
study,[1b] due to both their pharmacological properties and
[a] Department of Organic Chemistry and Biochemistry, Rueer
Bosˇkovic´ Institute,
P. O. Box 180, 10002 Zagreb, Croatia
E-mail: tivsic@irb.hr
http://www.irb.hr/eng/People/Trpimir-Ivsic
http://www.irb.hr/eng/Research/Divisions-and-Centers/
Division-of-Organic-Chemistry-and-Biochemistry/Laboratory-
for-stereoselective-catalysis-and-biocatalysis
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301374.
Eur. J. Org. Chem. 2014, 631–638
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T. Ivsˇic´, I. Dokli, A. Rimac, Z. Hamersˇak
FULL PAPER
Williamson conditions (NaH, benzyl bromide), the desired
product was not observed at all.
Table 1. O-Protection of diethyl 3-hydroxyglutarate (2).
Entry PG1
Conditions
Yield [%]
1
2
3
4
Bn
Bn
Bn
Bn
NaH, BnBr
Ag2O, BnBr
–
Figure 2. Protection of the hydroxy group in diethyl 3-hydroxyglut-
arate. Conditions: [a] 1. Trimethylsilyl chloride, imidazole, CH2Cl2;
2. Benzaldehyde, triethylsilane, FeCl3, acetonitrile; [b] benzyloxy-
methyl chloride, diisopropylamine (DIPEA), tetra-n-butylammo-
nium iodide (TBAI), CH2Cl2; [c] tert-butyldimethylsilyl chloride,
imidazole, CH2Cl2.
30
35
76
BnOC(NH)CCl3, TfOH[a]
1. TMSCl, imidazole
2. FeCl3, Et3SiH, PhCHO
1. TMSCl, imidazole
2. FeCl3, Et3SiH, cinnamaldehyde
BOM-Cl, DIPEA, TBAI
5
Cinn
41
6
7
BOM
85
99
TBDMS TBDMS-Cl, imidazole
in the following step, as described in the literature.[16] De-
hydratation of the diacids in acetic anhydride yielded meso
glutaric anhydrides 9–11 in 64–81% overall yield (Figure 3).
[a] Trifluoromethanesulfonic acid.
Tamborini et al. have reported a similar problem in the
synthesis of the structurally related 3-hydroxyglutamate.[17]
While the Ag2O-catalysed alkylation with benzyl bromide
proceeded smoothly in their synthesis of the 4-hydroxy ana-
logue, no reaction took place with the 3-hydroxy analogue,
which forced them to move on to another route. Thus, it
became clear that the standard methods for ether synthesis
are not appropriate here. Consequently, we decided to in-
vestigate the known conversion of readily available silyl
ethers into alkyl ethers by reductive etherification.[18]
Figure 3. Preparation of O-protected 3-hydroxyglutaric anhydrides.
The enantioselective desymmetrization of the cyclic meso
The reaction of a silyl ether, an aldehyde, and triethyl-
silane is known to proceed in the presence of Lewis acids,
such as trityl perchlorate,[19] BiBr3,[20,21] or FeCl3.[22] In ad- anhydrides[25,26] has already been identified as a convenient
dition, Bourdreux et al. have reported several other iron method for stereochemical induction in the total syntheses
catalysts to be suitable for the alkylation of silyl protected of biologically active substances,[27–29] including Pregaba-
glucopyranosides.[23] In general, better results are obtained lin,[30] Biotin,[31] Baclofen,[32] Rolipram,[33] etc. The reaction
if polar aprotic solvents, such as nitromethane or aceto- works with a wide range of nuclephiles, so a variety of carb-
nitrile, are used.[22]
oxy-protecting groups may be introduced in the chiral-cen-
Under the conditions described above, benzyl ether pro- tre formation step (Figure 4).
tection was introduced onto the hydroxy group in 76% yield
starting from diethyl 3-hydroxyglutarate (2; Table 1, en-
try 4). The reaction was run overnight due to lower reacti-
vity of the parent protected secondary alcohol. When we
attempted to make the cinnamyl ether (Cinn) under the
same conditions (Table 1, entry 5), lower yields were ob-
tained, and the majority of the cinnamaldehyde remained
unreacted.
Alternatively, a benzyloxymethyl ether (BOM) was pro-
duced in a somewhat higher yield than the benzyl ether, and
Figure 4. Opening of cyclic anhydrides.
silyl derivatives such as the trimethylsilyl ether (TMS) or
The procedure using stoichiometric quantities of natural
the more stable tert-butyldimethylsilyl ether (TBDMS) were cinchona alkaloids at low temperatures was developed by
isolated almost quantitatively. Thus Bn, BOM, and Bolm and co-workers for the opening of succinic an-
TBDMS (Figure 2) were chosen to be PG1 in the continua- hydrides.[34] However, with the more challenging glutaric
tion of the synthesis.
anhydrides, worse results are typically obtained under these
Hydrolysis of diesters 4–6 gave the corresponding di- conditions. In addition, some authors have quite recently
acids. For benzyloxymethyl-protected compound 5, O-de- shown that the opposite enantiomer of the product may be
protection also occurred to some extent under the harsh produced at room temperature simply by using an organic
conditions. The 50% yield obtained using 1.5 m KOH im- acid additive.[35,36] Thus, using unmodified cinchona alk-
proved to 81% when 0.3 m LiOH was used instead. The aloids, the same chiral catalyst can be used to form both
silyl protected diacid was not isolated, due to its instability enantiomers in moderate to good ee, which can sub-
to strong acids[24] (which would normally be added prior to sequently be increased to the desired level by crystalli-
the extraction). Instead, the crude mixture was used directly zation.[33]
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Synthesis of GABOB and GABOB-Based Chiral Units
On the other hand, the use of modified alkaloids, includ- Table 2. Screening of conditions for anhydride desymmetrization.[a]
ing ethers,[37] ureas or thioureas,[38] and sulfonamides,[39] in
Catalyst
(equiv.)
t
Yield ee
Entry Product ROH
Solvent
[d] [%][b] [%]
catalytic amounts, has also been studied. Of these modified
compounds, sulfonamides (Figure 5) have a slightly better
overall performance.
1
2
12
12
BnOH
BnOH
toluene quinine (1.1)[c]
toluene quinidine (0.1)
X9A[d] (0.2)
8
3
58
67
63
62
3
4
ent-12
ent-13
BnOH
toluene quinine (0.1)
3
3
64
57
55[e]
50[e]
X9A[d] (0.2)
CinnOH toluene quinine (0.1)
X9A[d] (0.2)
5
6
7
8
9
10
11
12
12
13
13
13
12
12
BnOH
BnOH
toluene Q-TS (0.1)
toluene Q-TS (1)
2
1
2
2
1
2
1
61
58
56
70
77
63
63
77
87
70
83
86
90
92
CinnOH toluene Q-TS (0.1)
CinnOH MTBE Q-TS (0.1)
CinnOH MTBE Q-TS (1)
BnOH
BnOH
MTBE Q-TS (0.1)
MTBE Q-TS (1)
Figure 5. Quinine and sulfonamide catalyst Q-TS.
[a] All reactions were performed at room temperature with anhy-
dride 11 (0.1 g) in 0.1 m solution for the time indicated. [b] Isolated
yield. [c] Reaction was performed at –30 °C. [d] Xanthene-9-carb-
oxylic acid. [e] (S)-configured product.
The use of alcohols as nucleophiles in the enantioselec-
tive opening of O-protected anhydrides 9–11 introduces an
ester protecting group (PG2) to one of the carboxylic acids,
as well as introducing the chiral centre. The other carbox-
ylic acid remains free for further reaction to continue the
synthesis.
Table 3. Opening of anhydrides 9–11.[a]
Catalyst
(equiv.)
t
Yield
ee
Entry Product PG1
ROH
Initial screening of conditions for the desymmetrization
of the anhydrides was performed using anhydride 11 as the
substrate. In general, slightly better ee values were obtained
when the anhydride was opened with benzyl alcohol rather
than with cinnamyl alcohol. When natural alkaloids were
used as sources of chirality, both enantiomers could be pro-
duced in 55–63% ee (Table 2, entries 1–3), and the stereo-
chemistry of the product was controlled either by the in-
clusion of an acid additive or by the right choice of alka-
loid. Thus, following this route, the final product and all of
the intermediates are available in both enantiomeric forms
using the same reaction steps. On the other hand, when a
sulfonamide derivative (Q-TS) was used in toluene, the (R)-
configured enantiomer was produced under both stoichio-
metric and catalytic conditions, although some improve-
ment in the enantioselectivity was observed (Table 2, en-
tries 5–7). With methyl tert-butyl ether (MTBE) as the sol-
vent, the ee of the product was somewhat higher (up to
92%) than in toluene. The difference between catalytic and
stoichiometric conditions was minimal here, showing that
0.1 equiv. of the catalyst was sufficient. Under these condi-
tions, O-protected anhydride substrates 9–11 were all
opened on a gram scale with good to excellent ee’s
(Table 3). The highest selectivities were achieved for the
opening of anhydride 11 with benzyl alcohol (Table 3, en-
try 1). The absolute configuration of monoesters 12–16 was
initially assigned by analogy, since the direction of opening
is highly predictable under the reaction conditions used,
and it was later confirmed by comparing the sign of optical
rotation of the final product (i.e., 1) with literature values.
After the anhydride desymmetrization, a Curtius re-
arrangement can be used to transform the free carboxylic
acid into an amine protected by an N-protecting group
(PG3; Figure 6). Various N-protected unnatural amino
acids[28,30,40] are available starting from succinic or glutaric
acid monoesters by a one-pot sequence involving a Curtius
[d] [%][b] [%]
1
2
3
4
5
6
7
12
14
14
14
15
15
16
TBDMS BnOH
Q-TS (0.1)
2
2
1
1
1
1
1
79
40
79
84
73
79
79
90
66[c]
85
88
88
Bn
Bn
Bn
CinnOH quinine (1.1)
CinnOH Q-TS (0.1)
CinnOH Q-TS (0.2)
BOM
BOM
BOM
BnOH
BnOH
CinnOH Q-TS (0.2)
Q-TS (0.1)
Q-TS (0.3)
89
86
[a] All reactions were performed in MTBE on a gram scale (see
Exp. Sect.). [b] Isolated yield. [c] Reaction was performed at –20 °C.
rearrangement. The initially formed azide rearranges ther-
mally into an unstable isocyanate intermediate, which reacts
with a nucleophile to give N-protected amino esters.[41]
Figure 6. Curtius rearrangement of monoesters to give triprotected
derivatives of GABOB (1).
The choice of PG3 is made so that it is orthogonal to the
protecting groups already present in the molecule for easier
selective manipulation during the deprotection. Selected re-
sults are presented in Table 4.
Table 4. Curtius rearrangement of selected monoesters.
Entry Product PG1
PG2
PG3
Yield [%]
1
2
3
17
18
19
Bn
BOM
Cinn
Cinn
Bn-OC(O)–
Bn-OC(O)–
Cinn-OC(O)–
76
59
54
TBDMS Bn
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633

T. Ivsˇic´, I. Dokli, A. Rimac, Z. Hamersˇak
FULL PAPER
The deprotection of the GABOB derivatives with three
Selective deprotection of 20 was achieved by controlling
distinct protecting groups may be performed in several the hydrogen pressure (Figure 8). Thus, monoprotected
ways. Attempts were made to produce a diprotected com- amino acid 24 was isolated after hydrogenation of dipro-
pound with a free amino group. However, thermal depro- tected amino acid 20 at atmospheric pressure. The pro-
tection of similar compounds is known to result in lactam cedure was then repeated at a higher hydrogen pressure
formation by spontaneous cyclization of the amino ester (15 bar) to obtain pure 4-amino-3-hydroxyglutaric acid (1).
formed,[33] and transallylation would not proceed at room In addition, spontaneous enrichment of the product oc-
temperature. Thus, the preferred order of steps in this route curred, therefore GABOB was isolated in 66% yield with
would be to remove the protection of the carboxy group 97% ee (the ee of starting monoester 14 was 88%). A single
prior to that of the amine group. By this method, GABOB recrystallization from ethanol allowed the product to be iso-
itself and the protected intermediates may be isolated, as lated with 99% ee.
demonstrated below.
The cinnamyl ester protecting group of the carboxyl
moiety in compounds 17 and 18 was selectively removed by
transallylation of morpholine with a palladium catalyst. On
the other hand, glutaric acid monoesters tend to be un-
stable under alkaline conditions, slowly hydrolysing in di-
lute carbonate solution.[33,42] Thus, although the reaction
was slower, the carboxylic functionality could be depro-
tected with KOH (0.1 m in water/methanol), as demon-
strated for compound 19, where the cinnamyl group was
protecting the amine moiety (Figure 7). To avoid the de-
composition of the silyl protection during work-up, pH 5.4
buffer was used in place of strong acid during the extrac-
tion.
Figure 8. Stepwise deprotection of 20.
Conclusions
A stereoselective route to GABOB is presented, using an-
hydride desymmetrization as a step for the introduction of
chirality. Intermediate GABOB derivatives with three dif-
ferent protecting groups were selectively deprotected to pro-
duce diprotected derivatives with a free carboxylic acid or
hydroxy group. After all of the protecting groups were re-
moved, (S)-GABOB was isolated in good yield and with
excellent ee.
Experimental Section
General Methods: All reactions were carried out under an argon
atmosphere. Anhydride 11[16] and catalyst Q-TS[39] were prepared
according to literature procedures. Buffer pH 5.4 was prepared by
dissolving NaH2PO4 dihydrate (17.78 g) and citric acid mono-
hydrate (7.78 g) in 1 L of water. All other reagents and solvents
were purchased from commercial suppliers, and were used without
purification. 1H and 13C NMR spectra were recorded with a Bruker
AV 300 spectrometer. Chemical shifts (δH and δC) are quoted in
parts per million (ppm), and were referenced to tetramethylsilane.
High-resolution mass spectrometry (HRMS) was carried out with
a 4800 Plus MALDI TOF/TOF Analyzer. Optical rotations were
measured with an Optical Activity AA-10 automatic polarimeter.
Melting points were determined with an Electrothermal 9100 appa-
ratus in open capillaries. For the determination of purity and moni-
toring the progress of reactions, a Nucleosil 100–5 C18 column was
used.
Figure 7. Selective deprotection of triprotected GABOB derivatives
17–19.
As determined by HPLC, no racemization occurred un-
der these conditions, as the product (i.e., 22) was isolated
without any loss of enantiopurity. From the same precursor
(i.e., 19), diprotected hydroxy derivative 23 was obtained
after treatment with tetrabutylammonium fluoride (TBAF)
in THF to remove the TBDMS protecting group.
Diethyl 3-(Trimethylsilyloxy)glutarate (3): Diethyl 3-hydroxyglut-
arate (95% w/w; 5 g, 23.2 mmol) was dissolved in dry CH2Cl2
(40 mL), and then trimethylsilyl chloride (4.40 mL, 34.8 mmol,
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Synthesis of GABOB and GABOB-Based Chiral Units
1.5 equiv.) and imidazole (3.17 g, 46.4 mmol, 2 equiv.) were added.
The reaction mixture was stirred overnight at room temperature,
then it was diluted with diethyl ether (100 mL), and washed with
H2O (2ϫ 50 mL) and brine (50 mL). The organic phase was dried
with Na2SO4, filtered, and concentrated under reduced pressure to
give compound 3 (6.40 g, 99%) as a colourless viscous oil. 1H
NMR (300 MHz, CDCl3): δ = 0.13 (s, 9 H), 1.29 (t, J = 7.1 Hz, 6
3-(Benzyloxymethoxy)glutaric Acid (8): Diethyl 3-(benzyloxymeth-
oxy)glutarate (5; 4.9 g, 15.2 mmol) was dissolved in methanol
(70 mL). A solution of lithium hydroxide monohydrate (1.91 g,
45.6 mmol, 3 equiv.) in water (50 mL) was added. The reaction mix-
ture was stirred for 4 h at room temperature. The solvent was re-
moved under reduced pressure, and the residue was partitioned be-
tween water (50 mL) and CH2Cl2 (50 mL). The aqueous phase was
H), 2.54 (d, J = 6.3 Hz, 4 H), 4.08–4.24 (m, 4 H), 4.54–4.63 (m, 1 acidified with concd. HCl, and extracted with ethyl acetate (2ϫ
H) ppm. 13C NMR (75 MHz, CDCl3): δ = –0.01, 14.13, 42.68,
60.37, 66.30, 170.87 ppm.
50 mL). The combined organic extracts were washed with brine
(30 mL), dried with Na2SO4, filtered, and concentrated under re-
duced pressure to give compound 8 (3.3 g, 81%) as a viscous yellow
oil. 1H NMR (300 MHz, [D6]DMSO): δ = 2.49–2.62 (m, 4 H),
4.27–4.35 (m, 1 H), 4.54 (s, 2 H), 4.75 (s, 2 H), 7.28–7.35 (m, 5 H),
12.32 (br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 39.83,
69.36, 71.11, 93.62, 127.93, 128.27, 128.68, 138.44, 172.61 ppm.
Diethyl 3-(Benzyloxy)glutarate (4): Diethyl 3-(trimethylsilyloxy)-
glutarate (3; 6.4 g, 23.2 mmol) was dissolved in dry acetonitrile
(100 mL). Triethylsilane (4.45 mL, 27.8 mmol, 1.2 equiv.) was
added, followed by FeCl3 (0.75 g, 4.64 mmol, 0.2 equiv.). The mix-
ture was stirred for 15 min, and then benzaldehyde (2.83 mL,
27.8 mmol, 1.2 equiv.) was added. The mixture was stirred over-
night. The solvent was removed under reduced pressure, and the
residue was partitioned between water (100 mL) and CH2Cl2
(100 mL). The organic phase was washed with brine (50 mL), dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(hexane/diethyl ether, 9:1, to hexane/diethyl ether, 1:1) to give com-
pound 4 (5.22 g, 77%) as a colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 1.24 (t, J = 7.1 Hz, 6 H), 2.55–2.71 (m, 4 H), 4.13 (q,
J = 7.1 Hz, 4 H), 4.29–4.37 (m, 1 H), 4.59 (s, 2 H), 7.22–7.34 (m,
5 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.14, 39.79, 60.54,
72.11, 72.91, 127.62, 127.71, 128.28, 138.11, 170.88 ppm.
3-(Benzyloxy)glutaric Anhydride (9): 3-(Benzyloxy)glutaric acid (7;
3.26 g, 13.7 mmol) was dissolved in acetic anhydride (6.5 mL,
68 mmol, 5 equiv.). The mixture was stirred for 90 min at 100 °C.
The mixture was allowed to cool, and then the solvent was removed
under reduced pressure. The product was recrystallized from
chloroform/hexane to give anhydride 9 (2.54 g, 84%) as a white
solid, m.p. 84.3–84.9 °C. 1H NMR (300 MHz, CDCl3): δ = 2.76
(dd, J = 16.6, J = 2.9 Hz, 2 H), 3.13 (dd, J = 16.6, J = 3.8 Hz, 2
H), 4.08–4.12 (m, 1 H), 4.60 (s, 2 H), 7.29–7.42 (m, 5 H) ppm.
13C NMR (150 MHz, [D6]DMSO): δ = 35.80, 66.89, 70.90, 127.67,
128.27, 128.65, 136.53, 164.71 ppm.
3-(Benzyloxymethoxy)glutaric Anhydride (10): 3-(Benzyloxymeth-
oxy)glutaric acid (8; 3.3 g, 12.3 mmol) was dissolved in acetic an-
hydride (11.7 mL, 123 mmol, 10 equiv.). The mixture was stirred
for 90 min at 100 °C. The mixture was allowed to cool, and then
the solvent was removed under reduced pressure to give anhydride
Diethyl 3-(Benzyloxymethoxy)glutarate (5): Diethyl 3-hydroxyglut-
arate (95% w/w; 5 g, 23.2 mmol) was dissolved in dry CH2Cl2
(80 mL), and then benzyl chloromethyl ether (60% w/w; 7.53 mL,
1
10 (2.44, 79%). H NMR (300 MHz, CDCl3): δ = 2.69–2.76 (m, 2
32.5 mmol,
1.4 equiv.),
N-ethyldiisopropylamine
(7.9 mL,
H), 3.04–3.12 (m, 2 H), 4.26–4.31 (m, 1 H), 4.59 (s, 2 H), 4.82 (s,
2 H), 7.28–7.40 (m, 5 H) ppm. 13C NMR (150 MHz, CDCl3): δ =
35.93, 65.83, 70.07, 93.19, 127.52, 127.60, 128.09, 136.49,
165.32 ppm.
46.4 mmol, 2 equiv.), and tetrabutylammonium iodide (0.86 g,
2.32 mmol, 0.1 equiv.) were added. The reaction mixture was
stirred overnight at room temperature. Ammonium chloride (satu-
rated aq.; 30 mL) was added. The phases were separated. The or-
ganic phase was washed again with ammonium chloride (saturated
aq.; 30 mL) and with brine (30 mL), then it was dried with Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (hexane/diethyl
ether, 1:1) to give compound 5 (6.37 g, 85%) as a colourless oil. 1H
NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 7.15 Hz, 6 H), 2.62–2.77
(m, 4 H), 4.16 (q, J = 7.15 Hz, 4 H), 4.47–4.53 (m, 1 H), 4.63 (s, 2
H), 4.85 (s, 2 H), 7.30–7.39 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.14, 39.97, 60.53, 69.71, 71.63, 94.50, 127.66, 127.84,
128.37, 137.69, 170.72 ppm.
3-(tert-Butyldimethylsilyloxy)glutaric Anhydride (11): Compound
11 was prepared according to a literature procedure.[16] 1H NMR
(600 MHz, CDCl3): δ = –0.01 (s, 6 H), 0.75 (s, 9 H), 2.63–2.68
(m, 2 H), 2.78–2.83 (m, 2 H), 4.27–4.31 (m, 1 H) ppm. 13C NMR
(150 MHz, CDCl3):
165.03 ppm.
δ = –5.02, 17.79, 25.45, 39.14, 61.92,
General Procedure for the Desymmetrization of Anhydrides: The cat-
alyst and the alcohol were added to a 0.1 m solution of the an-
hydride, according to Table 3. The reaction mixture was stirred un-
til Ͼ90% conversion was reached (see Table 3), and then the reac-
tion was stopped by the addition of HCl (5%). The organic phase
was washed with HCl (5%), and the solvents were evaporated. The
oily residue was dissolved in K2CO3 (2% aq.), and then this solu-
tion was washed with EtOAc. The aqueous solution was acidified
with HCl to pH 2, and then it was extracted with EtOAc unless
noted otherwise. The organic extracts were dried with Na2SO4 and
evaporated in vacuo.
3-(Benzyloxy)glutaric Acid (7): Diethyl 3-(benzyloxy)glutarate (4;
3.67 g, 12.5 mmol) was dissolved in methanol (60 mL). A solution
of lithium hydroxide monohydrate (1.57 g, 37.5 mmol, 3 equiv.) in
water (60 mL) was added. The reaction mixture was stirred for 4 h
at room temperature. The solvent was removed under reduced pres-
sure, and the residue was partitioned between water (80 mL) and
CH2Cl2 (80 mL). The aqueous phase was separated, acidified with
concd. HCl, and extracted with diethyl ether (3ϫ 50 mL). The
combined ether phases were washed with brine (30 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure to give
compound 7 (2.83 g, 95%) as a white solid, m.p. 144.9–145.9 °C.
1H NMR (300 MHz, [D6]DMSO): δ = 2.52 (d, J = 6.1 Hz, 4 H),
4.13–4.21 (m, 1 H), 4.53 (s, 2 H), 7.23–7.34 (m, 5 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 39.61, 71.21, 73.39, 127.79,
127.89, 128.56, 139.01, 172.77 ppm. HRMS (MALDI): calcd. for
C11H14O5K [M + K]+ 277.0473; found 277.0475.
(R)-Monobenzyl 3-(tert-Butyldimethylsilyloxy)glutarate (12): Start-
ing from 3-(tert-butyldimethylsilyloxy)glutaric acid anhydride (11;
2 g, 8.20 mmol), benzyl alcohol (1.26 mL, 12.30 mmol, 1.5 equiv.),
and catalyst Q-TS (0.39 g, 0.82 mmol, 0.1 equiv.) in MTBE
(80 mL), following the general procedure, compound 12 (2.28 g,
79%) was obtained as a yellow oil. During the extraction work-up,
buffer pH 5.4 was used for the acidification instead of hydrochloric
acid. 1H NMR (600 MHz, CDCl3): δ = 0.09 (s, 3 H), 0.11 (s, 3 H),
0.88 (s, 9 H), 2.49–2.71 (m, 4 H), 4.54–4.64 (m, 1 H), 5.08–5.18 (m,
Eur. J. Org. Chem. 2014, 631–638
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
635

T. Ivsˇic´, I. Dokli, A. Rimac, Z. Hamersˇak
FULL PAPER
2 H) 7.31–7.42 (m, 5 H), 8–11 (br. s, 1 H) ppm. 13C NMR trated under reduced pressure. The residue was purified by column
(150 MHz, CDCl3): δ = –4.97, –4.91, 17.85, 25.62, 42.21, 42.33, chromatography on silica gel (CH2Cl2/EtOAc, 95:5) to give com-
66.08, 66.43, 127.00, 128.26, 128.54, 135.69, 170.69, 176.76 ppm. pound 17 (0.63 g, 76%) as a colourless oil. 1H NMR (300 MHz,
ee = 90% (Chiralcel OD; 210 nm; flow = 1 mL/min; n-hexane/
EtOH, 96:4). [α]2D5 = –2.24 (c = 0.894, CH2Cl2). HRMS (MALDI):
calcd. for C18H28O5SiNa [M + Na]+ 375.1598; found 375.1588.
CDCl3): δ = 2.61 (dd, J = 5.4, J = 15.5 Hz, 1 H), 2.71 (dd, J = 7.0,
J = 15.5 Hz, 1 H), 3.35–3.55 (m, 2 H), 4.00–4.14 (m, 1 H), 4.55–
4.66 (m, 2 H), 4.78 (d, J = 6.2 Hz, 2 H), 5.02–5.13 (m, 1 H), 5.13
(br. s, 2 H), 6.29 (dt, J = 6.5, J = 15.8 Hz, 1 H), 6.68 (d, J =
15.8 Hz, 1 H), 7.25–7.52 (m, 15 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 37.68, 43.81, 65.34, 66.83, 70.04, 74.76, 122.94, 126.66,
127.80, 127.85, 128.11, 128.12, 128.47, 128.52, 128.61, 134.50,
136.17, 136.50, 137.86, 156.50, 170.74 ppm. [α]2D5 = +5.46 (c = 1.83,
CHCl3). HRMS (MALDI): calcd. for C28H29NO5Na [M + Na]+
482.0938; found 482.0939.
(R)-Mono(3-phenylallyl) 3-(Benzyloxy)glutarate (14): Starting from
3-(benzyloxy)glutaric acid anhydride (9; 1.47 g, 6.70 mmol), cinn-
amyl alcohol (1.04 mL, 8.04 mmol, 1.2 equiv.), and catalyst 2
(0.64 g, 1.34 mmol, 0.2 equiv.) in MTBE (70 mL), following the ge-
neral procedure, compound 14 (2.0 g, 84%) was obtained as a yel-
low oil. 1H NMR (300 MHz, CDCl3): δ = 2.63–2.79 (m, 4 H), 4.30–
4.38 (m, 1 H), 4.60 (s, 2 H), 4.74 (d, J = 6.4 Hz, 2 H), 6.25 (dt, J
= 6.4, J = 15.9 Hz, 1 H), 6.64 (d, J = 15.9 Hz, 1 H), 7.22–7.37 (m,
10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 39.27, 39.54, 65.34,
72.26, 74.45, 122.87, 126.65, 127.80, 127.83, 128.11, 128.39, 128.60,
134.53, 136.14, 137.73, 170.60, 176.04 ppm. ee = 88% (Chiralcel
OD; 254 nm; flow = 1 mL/min; n-hexane/EtOH/TFA (trifluoro-
acetic acid), 95:5:0.1). [α]2D5 = +1.47 (c = 4.08, CH2Cl2). HRMS
(MALDI): calcd. for C21H22O5Na [M + Na]+ 377.1359; found
377.1356.
(S)-3-Phenylallyl 4-(Benzyloxycarbonylamino)-3-(benzyloxymeth-
oxy)butyrate (18): Diphenylphosphoryl azide (0.58 mL, 2.68 mmol,
1.2 equiv.) was added to a dry toluene solution (60 mL) of mono-
(3-phenylallyl)
3-(benzyloxymethoxy)glutarate
(15;
0.86 g,
2.24 mmol, 1 equiv.) and triethylamine (0.37 mL, 2.68 mmol,
1.2 equiv.) at 20 °C. The reaction mixture was stirred for 30 min,
and then it was slowly warmed to 90 °C. When the evolution of
nitrogen ceased (30–45 min), benzyl alcohol (0.28 mL, 2.68 mmol,
1.2 equiv.) was added, and the mixture was heated at reflux over-
night. The reaction mixture was washed with NaNO2 (1% aq.; 2ϫ
100 mL), then with NaHCO3 (1.5% aq.; 2ϫ 100 mL) and with
H2O (100 mL). The organic phase was dried with Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (CH2Cl2/EtOAc, 95:5) to
give compound 18 (0.65 g, 59%) as a colourless oil. 1H NMR
(300 MHz, CDCl3): δ = 2.53–2.70 (m, 2 H), 3.29–3.54 (m, 2 H),
4.13–4.23 (m, 1 H), 4.59 (m, 2 H), 4.72 (d, J = 6.5 Hz, 2 H), 4.81
(s, 2 H), 5.08 (s, 2 H), 5.23–5.28 (m, 1 H), 6.23 (dt, J = 6.5, J =
15.8 Hz, 1 H), 6.63 (d, J = 15.8 Hz, 1 H), 7.25–7.45 (m, 15 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 38.18, 44.54, 65.31, 66.81, 70.08,
74.73, 94.79, 122.90, 126.63, 127.83, 128.09, 128.46, 128.50, 128.60,
134.45, 136.16, 136.51, 137.38, 156.51, 170.52 ppm. [α]2D5 = +10.09
(c = 1.09, CH2Cl2). HRMS (MALDI): calcd. for C29H31NO6Na
[M + Na]+ 512.2043; found 512.2048.
(R)-Monobenzyl 3-(Benzyloxymethoxy)glutarate (15): Starting from
3-(benzyloxymethoxy)glutaric acid anhydride (10; 7.61 g,
30 mmol), benzyl alcohol (4.72 mL, 45 mmol, 1.5 equiv.), and cata-
lyst 2 (1.4 g, 3 mmol, 0.1 equiv.) in MTBE (300 mL), following the
general procedure, compound 15 (7.97 g, 73%) was obtained as a
1
yellow oil. H NMR (300 MHz, CDCl3): δ = 2.67–2.79 (m, 4 H),
4.46–4.50 (m, 1 H), 4.57 (d, J = 1.1 Hz, 1 H), 4.79 (s, 2 H), 5.11
(d, J = 2.1 Hz, 1 H), 7.25–7.36 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 39.58, 39.76, 66.51, 69.87, 71.31, 94.55, 127.72, 127.87,
128.28, 128.29, 128.40, 128.56, 135.66, 137.53, 169.98, 176.31 ppm.
[α]2D5 = +1.07 (c = 3.72, CHCl3). ee = 88% (Chiralcel OJ; 215 nm;
flow = 1 mL/min; n-hexane/EtOH/TFA, 50:50:0.2). [α]2D5 = +1.07 (c
= 3.72, CHCl3). HRMS (MALDI): calcd. for C20H22O6Na [M +
Na]+ 381.1305; found 381.1314.
(R)-Mono(3-phenylallyl) 3-(Benzyloxymethoxy)glutarate (16): Start-
ing from 3-(benzyloxymethoxy)glutaric acid anhydride (10; 1.76 g,
7.00 mmol), cinnamyl alcohol (1.13 g, 8.4 mmol, 1.2 equiv.), and
catalyst 2 (0.67 g, 0.2 equiv.) in MTBE (70 mL), following the gene-
ral procedure, compound 16 (2.13 g, 79%) was obtained as a yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 2.65–2.81 (m, 4 H), 4.46–
4.54 (m, 1 H), 4.59 (s, 2 H), 4.73 (dd, J = 6.4, J = 1.4 Hz, 2 H),
4.82 (s, 2 H), 6.24 (dt, J = 6.4, J = 15.9 Hz, 1 H), 6.63 (d, J =
15.9 Hz, 1 H), 7.22–7.42 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 39.58, 39.75, 65.31, 69.86, 71.25, 94.51, 122.80, 126.61,
127.73, 127.87, 128.09, 128.41, 128.58, 134.45, 136.08, 137.49,
170.48, 176.47 ppm. ee = 86% (Chiralpak AD; 254 nm; flow =
1 mL/min; n-hexane/EtOH/TFA, 90:10:0.1). [α]2D5 = +1.77 (c = 1.13,
CHCl3). HRMS (MALDI): calcd. for C22H24O6 [M + H]+
385.1645; found 385.1630.
(S)-Benzyl 3-(tert-Butyldimethylsilyloxy)-4-[(3-phenylallyloxy)carb-
onylamino]butyrate (19): Diphenylphosphoryl azide (1.14 mL,
5.28 mmol, 1 equiv.) was added to a dry toluene solution (40 mL)
of mono-benzyl 3-(tert-butyldimethylsilyloxy)glutarate (12; 1.86 g,
5.28 mmol, 1 equiv.) and triethylamine (0.81 mL, 5.80 mmol,
1.1 equiv.) at 20 °C. The reaction mixture was stirred for 30 min,
and then it was slowly warmed to 90 °C. When the evolution of
nitrogen ceased (30–45 min), cinnamyl alcohol (0.85 g, 6.33 mmol,
1.2 equiv.) in dry toluene (20 mL) was added, and the mixture was
heated at reflux overnight. The reaction mixture was washed with
NaNO2 (1% aq.; 2ϫ 100 mL), then with NaHCO3 (1.5% aq.; 2ϫ
100 mL), and with H2O (100 mL). The organic phase was dried
with Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(n-hexane/EtOAc, 5:1) to give compound 19 (1.37 g, 54%) as a
colourless oil. 1H NMR (300 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.12
(s, 3 H), 0.90 (s, 9 H), 2.55–2.60 (m, 2 H), 3.22–3.48 (m, 2 H), 4.25–
4.38 (m, 1 H), 4.70–4.80 (d, J = 6.38 Hz, 2 H), 4.95–5.07 (br. s, 1
H), 5.09–5.21 (m, 2 H), 6.25–6.38 (m, 1 H), 6.61–6.73 (d, J =
15.8 Hz, 1 H), 7.24–7.46 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = –4.96, –4.93, 17.93, 25.71, 40.21, 46.48, 65.53, 66.46,
68.20, 123.90, 126.61, 127.95, 128.12, 128.26, 128.29, 128.56,
133.71, 135.72, 136.36, 156.40, 170.85 ppm. ee = 90% (Chiralcel
(S)-3-Phenylallyl
3-(Benzyloxy)-4-(benzyloxycarbonylamino)but-
yrate (17): Diphenylphosphoryl azide (0.47 mL, 2.17 mmol,
1.2 equiv.) was added to a dry toluene solution (50 mL) of mono-
(3-phenylallyl) 3-(benzyloxy)glutarate (14; 0.64 g, 1.81 mmol,
1 equiv.) and triethylamine (0.31 mL, 2.17 mmol, 1.2 equiv.) at
20 °C. The reaction mixture was stirred for 30 min, and then it was
slowly warmed to 90 °C. When the evolution of nitrogen ceased
(30–45 min), benzyl alcohol (0.22 mL, 2.17 mmol, 1.2 equiv.) was
added, and the mixture was heated at reflux overnight. The reac-
tion mixture was washed with NaNO2 (1% aq.; 2ϫ 100 mL), then OJ; 254 nm; flow = 0.6 mL/min; EtOH). [α]2D5 = –9.20 (c = 0.87,
with NaHCO3 (1.5% aq.; 2ϫ 100 mL), and with H2O (100 mL).
The organic phase was dried with Na2SO4, filtered, and concen-
CH2Cl2). HRMS (MALDI): calcd. for C27H37NO5SiNa [M +
Na]+ 506.2333; found 506.2327.
636
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 631–638

Synthesis of GABOB and GABOB-Based Chiral Units
(S)-3-(Benzyloxy)-4-(benzyloxycarbonylamino)butyric Acid (20): (m, 5 H), 8.0–10.0 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
Morpholine (0.19 mL, 2.26 mmol, 2 equiv.) was added a solution
of 3-phenyl-allyl 4-(benzyloxycarbonylamino)-3-(benzyloxy)but-
yrate (17; 0.52 g, 1.13 mmol, 1 equiv.) in absolute EtOH (10 mL),
followed by triphenylphosphine (47 mg, 0.18 mmol) and Pd(OAc)2
(2 mg, 0.008 mmol). The reaction mixture was heated at reflux for
3 h, and then it was cooled to room temperature. The solvent was
evaporated. Na2CO3 (2% aq.; 100 mL) was added. The mixture
was stirred for 15 min, and then it was washed with EtOAc (2ϫ
50 mL). The aqueous phase was acidified with concd. HCl, then it
was extracted with diethyl ether (3ϫ 50 mL). The combined or-
ganic phases were washed with brine (30 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure to give com-
pound 20 (0.33 g, 85%) as a colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 2.55 (dd, J = 5.8, J = 15.8 Hz, 1 H), 2.65 (dd, J = 6.5,
J = 15.8 Hz, 1 H), 3.30–3.50 (m, 2 H), 3.94–4.04 (m, 1 H), 4.48–
4.65 (m, 2 H), 5.02–5.19 (m, 3 H), 7.20–7.40 (m, 10 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 37.13, 43.58, 66.95, 71.96, 74.39,
127.85, 127.92, 128.09, 128.18, 128.47, 128.51, 136.29, 137.59,
156.69, 175.66 ppm. [α]2D5 = +6.36 (c = 1.10, CHCl3). HRMS
(MALDI): calcd. for C19H21NO5K [M + K]+ 382.1051; found
382.1052.
δ = –4.95, –4.79, 17.93, 25.70, 39.92, 46.35, 65.68, 68.06, 123.78,
126.61, 127.97, 128.56, 133.83, 136.33, 156.60, 175.88 ppm. ee =
90% (Chiralcel OD; 254 nm; flow = 1 mL/min; hexane/EtOH,
93:7). [α]2D5 = –7.08 (c = 1.13, MeOH). HRMS (MALDI): calcd.
for C20H31NO5SiNa [M + Na]+ 416.1864; found 416.1853.
(S)-Benzyl 3-Hydroxy-4-[(3-phenylallyloxy)carbonylamino]butyrate
(23): Tetrabutylammonium fluoride (1 m in THF; 1.1 mL,
1.2 equiv.) was added to a solution of benzyl 3-(tert-butyldimethyl-
silyloxy)-4-[(3-phenylallyloxy)carbonylamino]butyrate (19; 388 mg,
0.80 mmol, 1 equiv.) in THF (3 mL). The reaction mixture was
stirred overnight, and then water (5 mL) was added. The mixture
was extracted with EtOAc (2ϫ 10 mL). The combined organic ex-
tracts were dried with Na2SO4 and evaporated in vacuo. The resi-
due was purified by column chromatography on silica gel (CH2Cl2/
MeOH, 20:1) to give compound 23 (221 mg, 75%) as a colourless
oil. 1H NMR (300 MHz, CDCl3): δ = 2.53–2.63 (m, 2 H), 3.12–
3.30 (m, 2 H), 3.10–3.29 (m, 1 H), 3.32–3.49 (m, 1 H), 3.43 (s, 1
H), 4.08–4.24 (m, 1 H), 4.66–4.79 (d, J = 6.34 Hz, 2 H), 5.12–5.18
(s, 2 H), 5.24 (br. s, 1 H), 6.20–6.36 (m, 1 H), 6.58–6.69 (d, J =
15.8 Hz, 1 H), 7.14–7.47 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 38.54, 45.78, 65.65, 66.70, 67.43, 123.68, 126.58,
127.96, 128.25, 128.43, 128.55, 128.62, 133.73, 135.36, 136.24,
156.85, 172.26 ppm. [α]2D5 = –2.98 (c = 1.006, CH2Cl2). HRMS
(MALDI): calcd. for C11H23NO5SiNa [M + Na]+ 392.1469; found
392.1464.
(S)-4-(Benzyloxycarbonylamino)-3-(benzyloxymethoxy)butyric Acid
(21): Morpholine (0.38 mL, 4.36 mmol, 2 equiv.) was added to a
solution of 3-phenyl-allyl 4-(benzyloxycarbonylamino)-3-(benzyl-
oxymethoxy)butyrate (18; 1.06 g, 2.18 mmol, 1 equiv.) in absolute
EtOH (30 mL), followed by triphenylphosphine (47 mg,
0.18 mmol) and Pd(OAc)2 (1 mg, 0.004 mmol). The reaction mix-
ture was heated at reflux for 3 h, and then it was cooled to room
temperature. The solvent was evaporated. Na2CO3 (2% aq.;
100 mL) was added. The mixture was stirred for 15 min, and then
it was washed with EtOAc (2ϫ 50 mL). The aqueous phase was
acidified with HCl (concd.) and extracted with diethyl ether (3ϫ
50 mL). The combined organic phases were washed with brine
(30 mL), dried with Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by column chromatog-
raphy on silica gel (CH2Cl2/EtOAc/CH3OH, 8:2:1) to give com-
pound 21 (0.51 g, 63%) as a colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 2.52–2.65 (m, 2 H), 3.31–3.47 (m, 2 H), 4.04–4.11 (m,
1 H), 4.56–4.61 (m, 2 H), 4.80 (s, 2 H), 5.08 (s, 2 H), 5.29 (br. s, 1
H), 7.24–7.35 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
37.72, 44.40, 66.93, 70.15, 74.45, 94.73, 127.04, 128.09, 128.13,
128.46, 128.51, 136.39, 137.32, 156.71, 175.32 ppm. [α]2D5 = +6.78
(c = 2.80, CH2Cl2). HRMS (MALDI): calcd. for C20H23NO6Na
[M + H]+ 396.1417; found 396.1427.
(S)-4-Amino-3-(benzyloxy)butyric Acid (24): 3-(Benzyloxy)-4-(benz-
yloxycarbonylamino)butyric acid (20; 300 mg, 0.87 mmol) was dis-
solved in methanol (30 mL). Pd/C (10%; 30 mg) was added, and
the mixture was hydrogenated under atmospheric pressure at room
temperature for 6 h. Water (1 mL) was added, and the mixture was
filtered. The filtrate was concentrated under reduced pressure, and
the residue was recrystallized from ethanol to give compound 24
1
(174 mg, 95%) as a white powder, m.p. 160.2–161.2 °C. H NMR
(300 MHz, D2O): δ = 2.37 (dd, J = 6.9, J = 14.9 Hz, 1 H), 2.62
(dd, J = 5.8, J = 14.9 Hz, 1 H), 3.02 (dd, J = 8.3, J = 13.4 Hz, 1
H), 3.20 (dd, J = 3.5, J = 13.4 Hz, 1 H), 4.05–4.14 (m, 1 H), 4.60
(d, J = 11.0 Hz, 1 H), 4.67 (d, J = 11.0 Hz, 1 H, partial overlap
with D2O), 7.31–7.52 (m, 5 H) ppm. 13C NMR (75 MHz, D2O): δ
= 40.29, 42.62, 71.41, 73.19, 128.49, 128.69, 128.84, 137.19,
178.23 ppm. [α]2D5 = +28.0 (c = 1, H2O). HRMS (MALDI): calcd.
for C11H15NO3Na [M + Na]+ 323.0944; found 323.0952.
(S)-4-Amino-3-hydroxybutyric Acid (1): (S)-4-Amino-3-(benzyl-
oxy)butyric acid (24; 140 mg, 0.67 mmol) was dissolved in meth-
anol (30 mL). Pd/C (10%; 80 mg) was added, and the mixture was
hydrogenated overnight at room temperature under hydrogen pres-
sure (15 bar). Water (1 mL) was added, and the mixture was fil-
tered. The filtrate was concentrated under reduced pressure, and
then the residue was crystallized from EtOH to give compound 1
(S)-3-(tert-Butyldimethylsilyloxy)-4-[(3-phenylallyloxy)carbonyl-
amino]butyric Acid (22): A solution of KOH (166 mg, 2.96 mmol,
4 equiv.) in water (5 mL) was added to a solution of benzyl 3-(tert-
butyldimethylsilyloxy)-4-[(3-phenylallyloxy)carbonylamino]but-
yrate (19; 357 mg, 0.74 mmol, 1 equiv.) in methanol (25 mL). The
reaction mixture was stirred until the starting material had disap-
peared (2 d, monitored by TLC). Water (5 mL) was added, and the
methanol was removed under reduced pressure. The mixture was
washed with EtOAc (2ϫ 10 mL), and then buffer pH 5.4 (30 mL)
and phosphoric acid (0.5 mL) were added. The mixture was ex-
tracted with EtOAc (2ϫ 10 mL). The combined organic extracts
were dried with Na2SO4 and evaporated in vacuo to give com-
pound 22 (201 mg, 73%) as a yellowish oil. Further purification
was performed by column chromatography on silica gel (CH2Cl2/
1
(58 mg, 73%) as a white powder. H NMR (300 MHz, D2O): δ =
2.41 (d, J = 6.5 Hz, 2 H), 2.94 (dd, J = 9.3, J = 13.1 Hz, 1 H), 3.15
(dd, J = 3.2, J = 13.1 Hz, 1 H), 4.13–4.23 (m, 1 H) ppm. 13C NMR
(75 MHz, D2O): δ = 42.44, 44.26, 65.65, 178.65 ppm. ee = 97%,
determined from optical rotation. [α]2D5 = +20.0 (c = 1.25, H2O)
{ref.[14] [α]2D5 = +20.7 (c = 1.9, H2O)}. Recrystallization from 78%
EtOH further increased the optical purity of the title compound to
ee = 99%. [α]2D5 = +20.56 (c = 1.41, H2O). HRMS (MALDI): calcd.
for C4H9NO3K [M + K]+ 158.0214; found 158.0208.
1
MeOH, 20:1). H NMR (300 MHz, [D4]methanol): δ = 0.06 (s, 3
H), 0.11 (s, 3 H), 0.86 (s, 9 H), 2.40–2.60 (m, 2 H), 3.20–3.42 (m,
2 H), 4.15–4.32 (m, 1 H), 4.65–4.80 (m, 2 H), 4.98–5.08 (br. s, 1
H), 6.21–6.34 (m, 1 H), 6.60–6.68 (d, J = 15.8 Hz, 1 H), 7.20–7.42
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra.
Eur. J. Org. Chem. 2014, 631–638
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Ivsˇic´, I. Dokli, A. Rimac, Z. Hamersˇak
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Published Online: November 25, 2013
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