Preparative synthesis of β-amino alcohols from α-amino dicarboxylic acid derivatives

Article abstract of DOI:10.1134/S1070428009090024

A low-expensive preparative procedure has been developed for the synthesis of protected β-amino alcohols from α-amino dicarboxylic acid derivatives.

Full text of DOI:10.1134/S1070428009090024

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 9, pp. 1315–1317. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © Yu.G. Kirillova, A.V. Baranov, D.I. Prokhorov, O.V. Esipova, V.I. Shvets, 2009, published in Zhurnal Organicheskoi Khimii, 2009,
Vol. 45, No. 9, pp. 1330–1332.
Preparative Synthesis of β-Amino Alcohols from α-Amino
Dicarboxylic Acid Derivatives
Yu. G. Kirillova, A. V. Baranov, D. I. Prokhorov, O. V. Esipova, and V. I. Shvets
Lomonosov Moscow State Academy of Fine Chemical Technology, pr. Vernadskogo 86, Moscow, 119571 Russia
e-mail: pna-mitht@yandex.ru
Received November 13, 2008
Abstract—A low-expensive preparative procedure has been developed for the synthesis of protected β-amino
alcohols from α-amino dicarboxylic acid derivatives.
DOI: 10.1134/S1070428009090024
Reduction of N-protected α-amino acids to the
corresponding β-amino alcohols is the key step in the
synthesis of many analogs of biologically active pep-
tides, in particular caspase [1] and cathepsin inhibitors
[2], peptide analogs with ether bonds [3, 4], and neuro-
protectors [5]. β-Amino alcohols are also used as
starting compounds in the synthesis of such chemically
important intermediate products as α,α′-diamino di-
carboxylic acids [6], (3S)-amino-γ-butyrolactone [7],
(S)-γ-fluoroleucine [8], and various β-amino acids
through β-iodo amines [9].
method of synthesis of β-amino alcohols II from
amino dicarboxylic acid derivatives Ia–Ic.
Sodium (or lithium) tetrahydridoborate in water or
aqueous alcohol is frequently used as a cheap and
selective reducing agent capable of converting a car-
boxy group into hydroxymethyl. Hydrolysis of tetrahy-
dridoborate ion gives a complex of borane with water,
which is analogous to the complex formed by borane
with tetrahydrofuran molecule [12]. However, the
reduction of N-acyl amino acids with NaBH4 is often
accompanied by cleavage of the amide bond [13].
Therefore, the carboxy group should preliminarily be
activated via conversion into ester or mixed anhydride
moiety [5, 6, 14]. Thus one-step reduction with
borane–THF becomes a two-step process: in the first
step, activated derivative of N-protected amino acid is
obtained, and in the second step it is reduced in situ
with a solution of NaBH4 (Scheme 1).
Amino dicarboxylic acids could give rise to tri-
functional amino-, carboxy-, and hydroxy-containing
chiral synthons with selectively removable protective
groups, which can be used, e.g., for the preparation
of monomers of negatively charged peptidonucleic
acids [10, 11].
A standard procedure for selective reduction of
α-carboxy group to hydroxymethyl involves treatment
with a 1 M solution of BH3 in THF. Protected β-amino
alcohols are thus obtained in moderate yields (~50%),
the reaction should be carried out at –78°C, and the
reducing agent is toxic and expensive. Therefore, we
tried to develop a less expensive and reproducible
The transformation of protected amino acids into
the corresponding amino alcohols through mixed car-
boxylic acid anhydrides is performed according to the
procedures reported in [3, 15] with insignificant mod-
ifications [1, 4, 8, 16]. Using various combinations of
tertiary amines as bases (triethylamine and N-methyl-
Scheme 1.
Me2CHCH2OCOCl
N-methylmorpholine
DME, –20°C
O
O
O
NaBH4, H2O–MeOH
H
H
H
–10°C
N
N
Me
N
R1
OH
R1
O
O
R1
OH
R2
Ia–Ic
R2
Me
R2
IIIa–IIIc
IIa–IIc
R1 = Boc, R2 = (CH2)2CO2Bzl (a), CH2CO2Bzl (b); R1 = Cbz, R2 = (CH2)2CO2Bu-t (c).
1315

KIRILLOVA et al.
1316
morpholine), solvents (tetrahydrofuran and 1,1-dime-
thoxyethane), and isobutyl chloroformate as activating
agent, we obtained salt of the amino acid with tertiary
amine as a sticky material which hampered stirring of
the reaction mixture and reduced the conversion of
initial compound I even under relatively strong dilu-
tion. The best results were obtained with dimethoxy-
ethane as solvent and N-methylmorpholine as base;
therefore, all subsequent experiments were performed
using the same substances.
EXPERIMENTAL
All operations in the synthesis of mixed anhydrides
IIIa–IIIc were performed under dry argon with protec-
tion from moisture. Dimethoxyethane was dehydrated
by double distillation over KOH and distillation over
LiAlH4 just before use. Isobutyl chloroformate was
purified by vacuum distillation. N-Methylmorpholine
was dehydrated by distillation first over ninhydrin and
1
then over BaO. The H NMR spectra were recorded at
25°C on a Bruker MSL-200 spectrometer (Germany)
with Fourier transform at a frequency of 200 MHz
using tetramethylsilane as internal reference. The op-
tical rotations were measured on a Perkin–Elmer 241
polarimeter at 19–22°C. The progress of reactions was
monitored by TLC on Silica gel 60 F254 plates (Merck,
Germany); the solvents were removed under reduced
pressure (20 mm); the products were dried at a residual
pressure of 0.5 mm.
As shown in [17], in the synthesis of mixed anhy-
drides excess isobutyl chloroformate with respect to
amino acid should be maintained to avoid formation of
the corresponding amino acid anhydride. We proposed
to add equimolar solutions of amino acid and tertiary
amine simultaneously at similar rates from two drop-
ping funnels to a cold solution of isobutyl chloro-
formate in THF. In such a way we succeeded in attain-
ing complete conversion of initial amino acids Ia–Ic
into mixed anhydrides IIIa–IIIc.
Benzyl 4-(tert-butyloxycarbonylamino)-5-hy-
droxypentanoate (IIa). A solution of 0.68 g (0.62 ml,
4.2 mmol, 1.2 equiv) of isobutyl chloroformate in 7 ml
of dimethoxyethane was cooled to –30°C, and solu-
tions of 0.42 g (0.46 ml, 4.2 mmol, 1 equiv) of
N-methylmorpholine in 7 ml of dimethoxyethane and
of 1.4 g (4.2 mmol, 1 equiv) of 5-benzyloxy-2-(tert-
butoxycarbonylamino)-5-oxopentanoic acid (Ia) in
7 ml of dimethoxyethane were added dropwise at equal
rates simultaneously from two dropping funnels under
stirring in an argon atmosphere. When the addition was
complete, the mixture was stirred for 5 min at –30°C,
allowed to warm up to –15°C, and filtered, and the
precipitate was washed on a filter with 3 ml of dime-
thoxyethane. The filtrate was transferred into a 250-ml
flask and cooled to –15°C, and a freshly distilled
solution of 0.47 g (12.5 mmol, 3 equiv) of NaBH4 in
10 ml of aqueous methanol (1:1) was added in several
portions. The mixture was then stirred for 5 min, 12 ml
of water and 25 ml of ethyl acetate were added, the
organic phase was separated, the aqueous phase was
additionally extracted with ethyl acetate (2×25 ml; gas
evolution was observed), and the extracts were com-
bined with the organic phase, washed in succession
with a 1.5 M solution of citric acid (5 ml), a saturated
solution of NaHCO3 (2×15 ml), and a saturated solu-
tion of NaCl (20 ml), dried over Na2SO4, filtered, and
evaporated. The precipitate was treated with 20 ml of
hexane at 4°C. After 10 h, the colorless crystals were
filtered off and dried under reduced pressure (0.5 mm).
Yield 1.2 g (90%), Rf 0.35 (ethyl acetate–hexane,
While optimizing the conditions for the reduction
of intermediate IIIa (without isolation), we found that
the best results are obtained using 3 equiv of the
reducing agent. The order of mixing of the reactants is
also important. A solution of NaBH4 should be added
in portions to a cold solution of mixed anhydride III;
otherwise, the reaction may be accompanied by de-
protection of the amino group. Sodium tetrahydrido-
borate was dissolved in aqueous methanol (1:1) which
ensured better results as compared to aqueous solution
of NaBH4. The structure of compounds IIa–IIc was
1
confirmed by H NMR spectroscopy. Their purity was
evaluated by measuring their melting points which in
all cases coincided with published data. The enantio-
meric purity of amino alcohols IIa and IIb was deter-
mined from the optical rotation values which coincided
with the data reported for analogous compounds pre-
pared by reduction with borane in THF [7, 11].
We planned to use β-amino alcohols IIa and IIc in
the Mitsunobu condensation with o-nitrobenzylsul-
fonyl (Ns) derivatives of various amino acids to obtain
protected pseudopeptides BocGlu(γ-OBzl)-ψ(Ns)-
GlyOAll and CbzGlu(γ-OBu-t)-ψ(Ns)-His(Ns)OMe.
For this purpose, compounds IIa and IIc were dis-
solved in ethyl acetate, and the solutions were filtered
through a layer of aluminum oxide to remove im-
purities. Otherwise, compounds IIa and IIc failed to
react. The Mitsunobu reactions with purified amino
alcohols IIa and IIc gave the target condensation prod-
ucts in 65 and 30% yield, respectively.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

PREPARATIVE SYNTHESIS OF β-AMINO ALCOHOLS
1317
1:1), mp 76–77°C, [α]D20 = –6.2 (c = 1, MeOH); pub-
lished data: mp 76–77°C [4], [α]D20 = –6.0 [7]. 1H NMR
spectrum (CDCl3), δ, ppm: 1.40 s (9H, t-Bu), 1.79 m
(1H, β-CH), 1.90 m (1H, β-CH), 2.45 m (2H, γ-CH2),
3.55 m (1H, α-CH), 3.62 d (2H, CH2OH, J = 4.65 Hz),
4.71 s (1H, OH), 4.79 m (1H, NH), 5.11 s (2H,
CH2Ph), 7.35 s (5H, C6H5).
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droxybutanoate (IIb) was synthesized in a similar
way from 1 g of 4-benzyloxy-2-(tert-butoxycarbonyl-
amino)-4-oxobutanoic acid (Ib). Yield 0.68 g (71%),
Rf = 0.75 (ethyl acetate), mp 61–62°C, [α]D20 = –2.8
(c = 1, methanol); published data: mp 62–63.8°C [7],
no. 7, p. 1105.
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[α]D20 = –2.7 [11]. H NMR spectrum (CDCl3), δ, ppm:
1
Scheigetz, J., Synlett, 2005, no. 8, p. 1279.
1.45 s (9H, t-Bu), 2.71 d (2H, β-CH2, J = 6.0 Hz),
3.70 d (2H, CH2OH, J = 4.8 Hz), 4.02 m (1H, α-CH),
4.72 s (1H, OH), 5.15 s (2H, CH2Ph), 5.24 d (1H,
NH), 7.37 s (5H, C6H5).
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droxypentanoate (IIc) was synthesized from 1 g of
5-tert-butoxy-2-(benzyloxycarbonylamino)-5-oxo-
pentanoic acid (Ic). Yield 0.8 g (83%), oily substance,
1
Rf 0.3 (ethyl acetate–hexane, 1:1). H NMR spectrum
(CDCl3), δ, ppm: 1.43 s (9H, t-Bu), 1.59 s (1H, OH),
1.83 m (2H, β-CH2), 2.34 m (2H, γ-CH2), 3.58 m (1H,
α-CH), 3.68 m (2H, CH2OH), 5.09 s (2H, CH2Ph),
5.14 d (1H, NH), 7.35 s (5H, C6H5).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009