One-pot synthesis of N-protected β-chiral amino alcohols

Article abstract of DOI:10.1081/SCC-120020188

N-tert-butyloxycarbonyl-S-benzyl-cysteine, N-fluorenylmethyloxycarbonyl-alanine-, S-trityl-cysteine-, O-tert-butyl-serine- and O-tertbutyl-tyrosine were converted to the corresponding alcohols via sodium borohydride reduction of their in situ formed methy

Full text of DOI:10.1081/SCC-120020188

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One-Pot Synthesis of N -Protected β-Chiral Amino
Alcohols
Csaba Somlai a , Antal Péter b , Péter Forgó c & Botond Penke a
a Department of Medical Chemistry, University of Szeged, Szeged, Hungary
b Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged, Hungary
c Department of Organic Chemistry, University of Szeged, Szeged, Hungary
Published online: 17 Aug 2006.
To cite this article: Csaba Somlai , Antal Pter , Pter Forg & Botond Penke (2003) One-Pot Synthesis of N -Protected β-
Chiral Amino Alcohols, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:11, 1815-1820, DOI: 10.1081/SCC-120020188
To link to this article: http://dx.doi.org/10.1081/SCC-120020188
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 11, pp. 1815–1820, 2003
One-Pot Synthesis of N-Protected
b-Chiral Amino Alcohols
2
3
Csaba Somlai,1, Antal Peter, Peter Forgo,
*
and Botond Penke1
2
1Department of Medical Chemistry, Department of
3
Inorganic and Analytical Chemistry, and Department
of Organic Chemistry, University of Szeged, Szeged,
Hungary
ABSTRACT
N-tert-butyloxycarbonyl-S-benzyl-cysteine, N-fluorenylmethyloxy-
carbonyl-alanine-, S-trityl-cysteine-, O-tert-butyl-serine- and O-tert-
butyl-tyrosine were converted to the corresponding alcohols via
sodium borohydride reduction of their in situ formed methyl
esters. Enantiopurity of the products was checked by chiral HPLC
method.
Key Words: Amino alcohols; Reduction; Enantiopurity.
*Correspondence: Csaba Somlai, Department of Medical Chemistry,
University of Szeged, Domte r 8, H-6720 Szeged, Hungary; E-mail: scsaba@
mdche.szote.u-szeged.hu.
1815
DOI: 10.1081/SCC-120020188
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1816
Somlai et al.
We report a convenient practical synthetic method for conversion
of N-protected amino acids to the corresponding N-protected amino
alcohols by sodiumborohydride reduction at roomtemperature via in situ
formation of their methyl esters. Fmoc-Ala-OMe, Fmoc-Cys(Trt)-OMe,
Boc-Cys(Bzl)-OMe, Fmoc-Ser(tBu)-OMe and Fmoc-Tyr(tBu)-OMe can
be obtained by direct esterification of the corresponding amino acids with
etheric solution of diazomethane (instead of trimethylsilyldiazomethane
in 20% methanol-benzene[1,2] or by methyl iodide and KHCO3 in DMF[3]).
Starting materials were dissolved in methyl alcohol at room temperature
and their methyl esters were formed immediately after dropping the
reagent solution prepared from N-methyl-N0-nitro-N-nitrosoguanidine
as usual.[4] Sodiumborohydride was added in small portions and we
found, that this reduction step can be completed in one hour, checked by
TLC. Cooling of the reaction mixtures was unnecessary. Simple extraction
with ethyl acetate was used to isolate Fmoc-Ala-ol (1), Fmoc-Cys(Trt)-ol
(2, new compound), Boc-Cys(Bzl)-ol (3), Fmoc-Ser(tBu)-ol (4, new com-
pound) and Fmoc-Tyr(tBu)-ol (5) fromthe reaction mixtures in 85–95%
yield and no silica gel column chromatography was needed for final
purification of the products. Physical data of the products are listed
in Tables 1 and 2.
Enantiopurity of the synthesized N-protected amino alcohols (hence
the degree of racemization of the hydride reductions) was measured
by chiral HPLC method. The stereoisomer N-protected amino alcohols
were separated on Chirobiotic T column. Table 3 depicts the chroma-
tographic data (capacity factors of the enantiomers, separation factors
and D-amino acid content) and also the degree of racemization in the
hydride reduction process which practically showed less than 1% in all
cases.
In conclusion, we offer here a straightforward hydride reduction
method for the synthesis of enantiopure N-protected amino alcohols
fromthe corresponding N-protected amino acids via their methyl esters.
X ¼ Boc. Fmoc
1 X ¼ Fmoc, AA ¼ Ala
AA ¼ amino acid
2 X ¼ Fmoc, AA ¼ Cys(Trt)
3 X ¼ Boc,
AA ¼ Cys(Bzl)
4 X ¼ Fmoc, AA ¼ Ser(tBu)
5 X ¼ Fmoc, AA ¼ Tyr(tBu)
Reaction Scheme

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N-Protected b-Chiral Amino Alcohols
Table 1. Compounds 1–5 prepared.
1817
Product Yield (%) M.p. (ꢀC) TLCa (Rf) HPLC tR (min) [a]546 (c ¼ 1)
1
2
3
4
5
93
89
95
85
91
157–158
152–153
56–58
0.23
0.37
0.44
0.29
0.32
8.16
12.87
9.19
À1.0
þ37.0
À20.0
þ20.5
À52.0
95–97
152–153
10.93
15.68
aEtOAc:n-hexane (1:1) solvent mixture.
Table 2. 1H NMR data of N-protected amino alcohols 1–5.
1H NMR (CDCl3/TMS), ꢀ(ppm), J(Hz)
Product
1
1.18 (s, 3H, CH3), 2.35 (b, 1H, OH), 3.55 (b, 2H, CH2OH),
3.80 (b, 1H, NH), 4.25 (b, 1H, CHa), 4.45 (d, 2H, J ¼ 1.90, CH2),
4.93 (b, 1H, CH), 7.31–7.78 (8H, CHaromatic
)
2
2.03 (b, 1H, OH), 2.44 (s, 2H, CH2S), 3.45 (b, 2H, CH2OH),
3.51(b, 1H, NH), 4.36 (d, 2H, J ¼ 6.69, CH2),
4.20 (b, 1H, CHa), 4.88 (d, 1H, J ¼ 1.55, CH),
7.18–7.35 (15H, CHaromatic), 7.31–7.72 (8H, CHaromatic
t
)
3
4
1.42 (s, 9H, Bu), 2.30 (b, 1H, OH), 2.58 (s, 2H, CH2S),
3.12 (b, 2H, CH2OH), 3.63 (b, 1H, NH), 3.75 (s, 2H, CH2),
4.11 (b, 1H, CHa), 7.10–7.33 (5H, CHaromatic
)
1.18 (s, 9H, Bu), 2.99 (b, 1H, OH), 3.58 (s, 2H, CH2OtBu),
3.81 (b, 2H, CH2OH), 3.85 (b, 1H, NH), 4.22 (b, 1H, CHa),
4.38 (d, 2H, J ¼ 1.13, CH2), 5.53 (b, 1H, CH),
t
7.30–7.74 (8H, CHaromatic
)
5
(CH2), 5.00 (b, 1H, CH), 6.59–7.05 (4H, CHaromatic),
7.30–7.74 (8H, CHaromatic
)
The attractive features of this method (which can be applied principally for
the conversion of each naturally occuring a-amino acid into b-functional-
ized amino alcohols) are mild reaction conditions, short reaction time, easy
work-up, excellent yields and negligible racemization. Methyl ester
formation of N-protected amino acids using diazomethane takes place in
a few moments in contrast to other methods and isolation of the esters
was unnecessary. N-protected amino alcohols might have important
application for synthesis of biologically active peptide analogues
containing C-terminal hydroxymethyl functional group.

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1818
Somlai et al.
Table 3. Chromatographic and racemization data of N-protected
amino alcohols 1–5.
k0
Racemization data
D (%) Racemization (%)
Product
L
D
a
1
2
3
4
5
0.96
1.01
0.84
0.92
0.91
2.33
2.33
2.19
2.33
2.32
2.42
2.31
2.61
2.53
2.55
0.43
0.14
0.02
0.15
0.04
0.86
0.28
0.04
0.30
0.08
k0 Retention factor.
a Separation factor.
This research was supported by the Hungarian Scientific Research
Foundation (OTKA, No. 030135). The authors gratefully acknowledge
the excellent technical assistance of E. Menyharth, E. D. Molnar, and
I. Nogradi.
EXPERIMENTAL
All reagents and solvents were of reagent grade and purchased from
commercial sources. Melting points were determined using a PAMK VEB
apparatus and are uncorrected. TLC was performed on 60 F254 silica gel
precoated glass plates. Spots on TLC plates were visualized with
TMD reagent (N,N,N0N0-tetramethyl-4,40-diaminodiphenylmethane) after
chlorination. The chemical purities of the products 6–10 (97–99.5%) were
checked by HPLC (column: LiChrosorb-100 10 RP 18, 250 Â 4 m m ,
eluents: A: 0.1% TFA/H2O, B: 80% MeCN in A, gradient: 80 ! 100%
B for 20 min, flow rate: 1.2 mL/min, detection: UV at 220 nm). The HPLC
systemapplied for chiral analyses consisted of an M-600 low-pressure
gradient pump, an M-996 photodiode-array detector (205 nm) and a
Millenium1 chromatography Manager data system (Water Chromatog-
raphy, Milford, MA, USA). The chromatographic system was equipped
with a Rheodyne Model 7125 injector (Cotati, CA, USA) with 20 mL loop.
The column (250 Â 4.6 mm, 5 mmparticle size) used for analytical
separation was Chirobiotic T, bonded with macrocyclic glycopeptide
antibiotic teicoplanin as chiral detector (Astec, Whippany, NJ, USA).
The chromatograph was operated isocratically with a flow rate of
1 mL/min and with MeOH/H2O, 10:90 (v/v) eluent systemat 20 ꢀC.

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N-Protected b-Chiral Amino Alcohols
1819
1H NMR were recorded at 500 MHz with a Bruker DRX instrument.
Optical rotations were measured in MeOH with a Polamat-A polarimeter
(Carl Zeiss, Jena) at 22ꢀC, ꢁ ¼ 546 nm. Microanalysis were made on a CHN
Analyser (Prague).
General Procedure for the Synthesis of N-Protected
Amino Alcohols 1–5
For generation of diazomethane, a mixture of diethyl ether (20 mL)
and 40% aqueous KOH solution (5 mL) was cooled to 0ꢀC and crystal-
line N-methyl-N0-nitro-N-nitrosoguanidine (1.5 g) was added in portions
with shaking. The yellow diazomethane solution was separated, dried
on solid KOH, then dropped to the N-protected starting materials
(10 mmol of each) dissolved in MeOH (40–50 mL) under stirring for
10–15 min. After checking by TLC, NaBH4 (10 equiv.) was added in
portions at room temperature in 1 h. The mixture was evaporated in
vacuo, the residue was acidified with 10% NaHSO4 solution and
extracted with EtOAc (50 mL). The organic layer was washed succes-
sively with water, 10% NaHCO3 solution and water, dried with
Na2SO4, filtered and evaporated. The crude products were recrystallized
fromEtOAc/ n-hexane solvent mixture to give the N-protected amino
alcohols 1, 2, 3, 4, and 5.
Fmoc-Ala-ol (1): C18H19NO3 (297.39), calcd. C (72.69%), H (6.44%),
N (4.71%), found C (72.43%), H (6.21%), N (4.60%).
Fmoc-Cys(Trt)-ol (2): C37H33NO3S (571.74), calcd. C (77.72%),
H (5.82%), N (2.45%), found C (77.58%), H (5.60%), N (2.31%).
Boc-Cys(Bzl)-ol (3): C15H23NO3S (297.42), calcd. C (60.57%),
H (7.80%), N (4.71%), found C (60.23%), H (7.58%), N (4.59%).
Fmoc-Ser(tBu)-ol (4): C22H27NO4 (369.47), calcd. C (71.51%),
H (7.37%), N (3.79%), found C (71.37%), H (7.25%), N (3.73%).
Fmoc-Tyr(tBu)-ol (5): C28H31NO4 (445.56), calcd. C (75.47%), H
(7.01%), N (3.14%), found C (75.21%), H (6.88%), N (3.03%).
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Received in the Netherlands February 2, 2002