Synthesis of (S)-N-Boc-3-amino-2-arylpropanol from optically active β-amino esters

Article abstract of DOI:10.1055/s-2001-15237

The reduction of various (αS,3′R)-pantolactonyl-2-aryl-3-phthalimidopropanoates 3 followed by an acidic treatment and direct N-Boc protection afforded the corresponding (S)-N-Boc-3-amino-2-arylpropanols 4 in good yield and without loss of the optical purity.

Full text of DOI:10.1055/s-2001-15237

1302
SHORT PAPER
Synthesis of (S)-N-Boc-3-Amino-2-Arylpropanol from Optically Active
-Amino Esters
Synthesis of
(
S
)-
N
-
Boc
o
-3-Amino-2-
n
A
rylpropano
i
l
que Calmès,* Françoise Escale, Jean Martinez
Laboratoire des Aminoacides, Peptides et Protéines, UMR-CNRS 5810, Universités Montpellier I et II, Place E. Bataillon, 34095 Montpel-
lier cedex 5, France
Fax +33(4)67144866; E-mail: monique@univ-montp2.fr
Received 23 February 2001; revised 23 March 2001
The ketenes 2 were obtained in situ by dehydrochlorina-
Abstract: The reduction of various ( S,3'R)-pantolactonyl-2-aryl-
tion of the corresponding acyl chloride resulting from rac-
1 after treatment at room temperature with oxalyl chlo-
3-phthalimidopropanoates 3 followed by an acidic treatment and di-
rect N-Boc protection afforded the corresponding (S)-N-Boc-3-ami-
ride. The corresponding ( S,3’R)-N-phthalyl pantolacto-
nyl esters 38 were obtained both in high chemical yield
and with high diastereoisomeric excess (de = 86–94%).
Although the reaction was not totally diastereoselective,
the optically pure ( S,3'R)-esters 3 could be easily isolat-
ed by recrystallization.7
It was shown9 that the phthalimido protecting group of
amino acids could be removed under mild conditions us-
ing successively sodium borohydride and glacial acetic
acid. Furthermore, lithium aluminium hydride has been
used for the reductive removal of pantolactonyl esters to
give the corresponding alcohols.10
no-2-arylpropanols 4 in good yield and without loss of the optical
purity.
Keys words: 1,3-amino alcohols, reduction -amino esters
Synthesis of optically active amino alcohols is of great
importance in synthetic organic chemistry since they are a
well established source of ligands in asymmetric synthesis
including the enantioselective borane reduction of
prochiral ketones,1 enantioselective addition of dialkylz-
inc,2 or asymmetric hydrogen transfer from alcohols to
ketones.3 1,2-Amino alcohols have received much atten-
tion because they are generally readily accessible in enan-
tiomerically pure form from natural precursors.4 On the
other hand, the synthesis and use of chiral 1,3-amino
alcohols5 are rather rare although these compounds fre-
quently possess interesting pharmacological properties.6
This prompted us to synthesize new 1,3-aminoalcohols
from the recently obtained optically pure -amino esters.
Therefore, we envisaged the possible simultaneous reduc-
tion of the phthalimido group and the pantolactonyl ester
of the optically pure compounds 3a–e to produce directly
the corresponding chiral 1,3-amino alcohols 4a–e
(Scheme 2).
We have recently reported7 the asymmetric synthesis of
2
(S)- -homoarylglycines through the stereoselective addi-
tion of the (R)-pantolactone chiral alcohol to N-phthalyl-
2-aminomethyl-2-aryl ketenes 2 (Scheme 1).
Scheme 2 Reagents and conditions: a) NaBH4, 2-PrOH–H2O (6:1),
12 h; HOAc (pH 5), 80°C, 6 h; b) BOC2O, CH2Cl2, 12 h
The best results were obtained when an excess of sodium
borohydride (5 equivalents) was used, at room tempera-
ture for 12 hours, followed by an acidic treatment (pH 5)
at 80°C for 6 hours. The amino group of the correspond-
ing chiral 1,3-amino alcohol was then directly converted
into its N-Boc derivative using the conventional method.
The (S)-N-Boc-3-amino-2-arylpropanol 4a–e were ob-
tained in good yield and without loss of the stereochemi-
cal integrity (Table).
Scheme 1 Reagents and conditions: a) (COCl)2, 30°C, 12 h; b) NR3,
THF, r.t.; c) (R)-pantolactone, r.t. or 0°C, THF
The enantiomeric purity of 4a–e was controlled by HPLC
after removal of the Boc group of an aliquot and derivati-
zation with Marfey's reagent11 (FDAA = 1-fluoro 2,4-
dinitrophenyl 5-(S)-alanine amide).
Synthesis 2001, No. 9, 29 06 2001. Article Identifier:
1437-210X,E;2001,0,09,1302,1304,ftx,en;E02201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Mps were determined with a Büchi apparatus and are uncorrected.
Optical rotations were measured with a Perkin–Elmer, model 241

SHORT PAPER
Synthesis of (S)-N-Boc-3-amino-2-arylpropanol
1303
(S)-N-Boc-3-amino-2-(4-methoxyphenyl)propanol [(S)-4b]
Table (S)-N-Boc-3-amino-2-arylpropanol 4a–e Obtained
Prepared from ( S,3'R)-3b (655 mg, 1.5 mmol). Obtained as a co-
lourless solid after chromatography (EtOAc–Hexane, 1:1),
Rf = 0.40.
(S)-4
Ar
Yield
62
ee (%)
98
a
b
c
phenyl
Yield: 310 mg (1.1 mmol, 72%); mp 86.5°C.
[ ]D20 +20 (c = 1.0, CH2Cl2)
p-methoxyphenyl
p-fluorophenyl
o,p-dimethoxyphenyl
-naphthyl
72
99
HPLC (column I): tR = 20.3 min.
67
99
1H NMR (CDCl3): = 1.48 [s, 9H, (CH3)3C], 2.91 (m, 1H, CH-
C6H4OCH3), 3.48 (t, 2H, J1 = J2 = 6.3 Hz, CH2-N), 3.80 (d, 2H,
J = 6.3 Hz, CH2-O), 3.83 (s, 3H, OCH3), 4.73 (br, 1H, NHBoc), 6.91
(d, 2H, J = 8.6 Hz, Ar-H), 7.19 (d, 2H, J = 8.6 Hz, Ar-H).
d
e
65
96
58
95
13C NMR (CDCl3): = 28.77 [(CH3)3C], 42.74 (CH2-N), 47.92
(CH-C6H4OCH3), 55.69 (OCH3), 64.00 (CH2-O), 80.30 [(CH3)3C],
114.58 (Ar-CH), 129.39 (Ar-CH), 132.91 (Ar-CH), 157.50 (N-CO-
O) 159.05 (Ar-C-OCH3).
polarimeter. NMR spectra were recorded with a Bruker DRX 400
spectrometer. Data are reported as follows: chemical shifts ( ) are
in ppm with respect to TMS, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad), coupling constants
(J) in Hz. HPLC analyses were performed with a water 510 instru-
ment with variable detector; column I: chiracel OD, 25 cm 4 mm,
flow: 1 mL/min, eluent: hexane–2-PrOH, 95:5; column II: nucleosil
C18, 5 , 25 cm 4.6 mm, flow: 1 mL/min, H2O–CH3CN–0.1%
TFA: gradient A: 10% to 60% CH3CN/30 min followed by 60%
CH3CN/10 min; gradient B: 10% to 50%/40 min followed by 50%
CH3CN/10 min; gradient C: 10% to 40%/60 min followed by 40%
CH3CN/10 min.
ESI-MS: m/z (%) = 226.0 (70), 282.2 (100) [M + H+], 563.2 (18).
Anal. Calcd for C15H23NO4 (281.35): C, 64.03; H, 8.24; N, 4.98.
Found: C, 64.10; H, 8.28; N, 5.04.
(S)-N-Boc-3-amino-2-(4-fluorophenyl)propanol [(S)-4c]
Prepared from ( S,3'R)-3c (637 mg, 1.5 mmol). Obtained as a co-
lourless solid after chromatography (EtOAc–Hexane, 1:1),
Rf = 0.46.
Yield: 269 mg (1.0 mmol, 67%); mp 78°C.
[ ]D20 +18 (c 1.0, CH2Cl2)
The ESI mass spectra were recorded with a platform II quadrupole
mass spectrometer (Micromass, Manchester, UK) fitted with an
electrospray source and the voltages were set at 3.5 kV for the cap-
illary and 30 V for the cone.
HPLC (column I) : tR = 13.5 min.
1H NMR (CDCl3): = 1.48 [s, 9H, (CH3)3C], 2.92 (m, 1H, CH-
C6H4F), 3.47 (m, 2H, CH2-N), 3.82 (m, 2H, CH2-O), 4.77 (br, 1H,
NHBoc), 7.04 (t, 2H, J1 = J2 = 8.7 Hz, Ar-H), 7.19 (q, 2H, J1 = 8.7
Hz, J2 = 3 Hz, Ar-H).
13C NMR (CDCl3): = 28.75 [(CH3)3C], 42.63 (CH2-N), 48.03
(CH-C6H4F), 63.73 (CH2-O), 80.48 [(CH3)3C], 115.81 (Ar-CH),
116.02 (Ar-CH), 129.90 (Ar-CH), 136.79 (Ar-C), 157.56 (N-CO-
O), 162.30 (d, J = 220 Hz, Ar-CF).
(S)-N-Boc-3-amino-2-arylpropanol (4a–e): General Procedure
To a stirred solution of ( S,3’R)-N-phthalyl pantolactonyl ester 3
(1.5 mmol) in 2-PrOH–H2O (6:1, 19 mL) was added slowly NaBH4
(5 equiv, 7.5 mmol). After stirring for 12 h at r.t., TLC indicated
complete consumption of the starting material. Glacial HOAc was
added dropwise to adjust the pH to 5 and the mixture was heated to
80°C for 6 h. The reaction mixture was dried by repeated co-evap-
oration with MeOH and toluene and finally dried in vacuo over
phosphorus pentoxide. To the solution of this deprotected aminoal-
cohol in CH2Cl2 (15 mL) was added di-tert-butyldicarbonate (1.2
equiv). After stirring for 12 h at r.t., salts were removed by filtration
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel chromatography to yield 4.
ESI-MS: m/z (%) = 213.9 (90), 270.2 (100) [M + H+].
Anal. Calcd for C14H20FNO3 (269.31): C, 62.44; H, 7.49; N, 5.20.
Found: C, 62.79; H, 7.54; N, 5.31.
(S)-N-Boc-3-amino-2-(3,4-dimethoxyphenyl)propanol [(S)-4d]
Prepared from ( S,3'R)-3d (700 mg, 1.5 mmol). Obtained as a co-
lourless solid after chromatography (EtOAc–Hexane, 1:1),
Rf = 0.32.
(S)-N-Boc-3-amino-2-phenylpropanol [(S)-4a]
Prepared from ( S,3'R)-3a (610 mg, 1.5 mmol). Obtained as a co-
lourless solid after flash chromatography (CH2Cl2–EtOAc, 9:1),
Rf = 0.3.
Yield: 305 mg (0.97 mmol, 65%); mp 87.5°C.
[ ]D20 +16 (c 1.0, CH2Cl2)
Yield: 233 mg (0.93 mmol, 62%); mp 70°C.
[ ]D20 +17 (c 1.0, CH2Cl2)
HPLC (column I): tR = 18.6 min.
1H NMR (CDCl3): = 1.48 [s, 9H, (CH3)3C], 2.89 [m, 1H, CH-
C6H3(OCH3)2], 3.48 (m, 2H, CH2-N), 3.81 (d, 2H, J = 5.6 Hz, CH2-
O), 3.89 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.75 (br, 1H, NHBoc),
6.79 (d, 1H, J = 8.0 Hz, Ar-H), 6.80 (s, 1H, Ar-H), 6.86 (d, 1H,
J = 8.0 Hz, Ar-H).
13C NMR (CDCl3): = 28.78 [(CH3)3C], 42.73 (CH2-N), 48.35
[CH-C6H3(OCH3)2], 56.30 (OCH3), 64.09 (CH2-O), 80.29
[(CH3)3C], 111.80 (Ar-CH), 120.27 (Ar-CH), 133.44 (Ar-C),
148.50 (Ar-COCH3), 149.50 (Ar-COCH3), 157.44 (N-CO-O).
HPLC (column I): tR = 18.1 min.
1H NMR (CDCl3): = 1.37 [s, 9H, (CH3)3C], 2.84 (m, 1H, CH-
C6H5), 3.42 (t, 2H, J1 = J2 = 6.3 Hz, CH2-N), 3.73 (d, 2H, J = 6.3 Hz,
CH2-O), 4.66 (br, 1H, NHBoc), 7.17 (m, 3H, Ar-H), 7.25 (m, 2H,
Ar-H).
13C NMR (CDCl3): = 28.77 [(CH3)3C], 42.62 (CH2-N), 48.77
(CH), 63.85 (CH2-O), 80.34 [(CH3)3C], 127.48 (Ar-CH), 128.44
(Ar-CH), 129.32 (Ar-CH), 140.99 (Ar-C), 157.53 (N-CO-O).
ESI-MS: m/z (%) = 256.0 (80), 312.1 (100) [M + H+], 623.4 (38).
ESI-MS: m/z (%) = 195.9 (100), 252.0 (50) [M + H+], 503.1 (12).
Anal. Calcd for C16H25NO5 (311.37): C, 61.72; H, 8.09; N, 4.50.
Found: C, 61.33; H, 8.02; N, 4.48.
Anal. Calcd for C14H21NO3 (251.32): C, 66.91; H, 8.42; N, 5.57.
Found: C, 66.72; H, 8.52; N, 5.41.
Synthesis 2001, No. 9, 1302–1304 ISSN 0039-7881 © Thieme Stuttgart · New York

1304
M. Calmès et al.
SHORT PAPER
(S)-N-Boc-3-amino-2-( -naphthyl)propanol [(S)-4e]
References
Prepared from ( S,3’R)-3e (685 mg, 1.5 mmol). Obtained as a co-
lourless solid after flash chromatography (EtOAc–Hexane, 1:1),
Rf = 0.25
(1) (a) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito,
K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Perkin Trans. 1
1985, 2039. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J.
Am. Chem. Soc. 1987, 109, 5551. (c) Deloux, L.; Screbnik,
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Schaad, D. R. Chem. Rev. 1996, 96, 835. (e) Martens, J.;
Reiners, I. Tetrahedron: Asymmetry 1997, 8, 27.
(f) Calmès, M.; Escale, F.; Paolini, F. Tetrahedron:
Asymmetry 1997, 8, 3691. (g) Corey, E. J.; Hlal, C. J.
Angew. Chem., Int. Ed. Engl. 1998, 37, 1986; and references
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(2) (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am.
Chem. Soc. 1986, 108, 6071. (b) Kossenjans, M.; Martens,
J. Tetrahedron: Asymmetry 1998, 9, 1409.
(3) (a) Takehara, J.; Hashiguch, S.; Fuji, A.; Inoue, S. I.; Ikariya,
T.; Noyori, R. Chem. Commun. 1996, 223. (b) Soai, K.;
Hayasaka, T.; Ugajin, S. J. Chem. Soc., Chem. Commun.
1989, 516.
Yield: 262 mg (0.87 mmol, 58%); mp 90°C.
[ ]D20 +26 (c 1.0, CH2Cl2)
HPLC (column I): tR = 26.2 min.
1H NMR (CDCl3): = 1.37 [s, 9H, (CH3)3C], 3.50 (m, 2H, CH2-N),
3.77 (m, 1H, CH-naphthyl), 3.89 (m, 2H, CH2-O), 4.67 (br, 1H, NH-
Boc), 7.31 (d, 1H, J = 7.6 Hz, Ar-H), 7.41 (m, 3H, Ar-H), 7.68 (d,
1H, J = 8.6 Hz, Ar-H), 7.79 (d, 1H, J = 8.1 Hz, Ar-H), 7.98 (d, 1H,
J = 8.6 Hz, Ar-H).
13C NMR (CDCl3): = 28.78 [(CH3)3C], 42.19 (CH2-N), 42.56
(CH-naphthyl), 63.54 (CH2-O), 80.40 [(CH3)3C], 123.18 (Ar-CH),
124.41 (Ar-CH), 125.83 (Ar-CH), 126.08 (Ar-CH), 126.75 (Ar-
CH), 127.90 (Ar-CH), 129.53 (Ar-CH), 132.15 (Ar-C), 134.50 (Ar-
C), 136.75 (Ar-C), 157.70 (N-CO-O).
ESI-MS: m/z (%) = 246.4 (100), 302.2 (70) [M + H+], 603.8 (10).
(4) (a) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew.
Chem., Int. Ed. Engl. 1987, 26, 1141. (b) Delair, P.;
Einhorn, C.; Einhorn, J.; Luch, J. L. J. Org. Chem. 1994, 59,
4680. (c) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835.
Anal. Calcd for C18H23NO3 (301.38): C, 71.73; H, 7.69; N, 4.65.
Found: C, 71.58; H, 7.82; N, 4.76.
FDAA Derivatives; General Procedure
(5) (a) Didier, E.; Loubinoux, B.; Ramos Tombo, G. M.; Rihs,
G. Tetrahedron 1991, 47, 4941. (b) Barluenga, J.; Viado, A.
L.; Aguilar, E.; Fustero, S.; Olano, B. J. Org. Chem. 1993,
58, 5972. (c) Bartoli, G.; Cimarelli, C.; Marcantoni, E.;
Palmieri, G.; Petrini, M. J. Org. Chem. 1994, 59, 5328.
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Tetrahedron: Asymmetry 1999, 10, 759. (e) Kossenjans,
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Martinez, J. Eur. J. Org. Chem. 2000, 2459.
(8) The ( S,3'R) configuration of the main esters form 3 has
been ascertained from the X-ray diffraction patterns:
Calmès, M.; Escale, F.; Rolland, M.; Martinez, J. Acta
Crystallogr., Sect. C 2000, 56, 445.
(S)-N-Boc-3-amino-2-arylpropanol 4 (10 mol) was deprotected
with TFA in CH2Cl2 (30:70) after standing for 30 min at r.t. The so-
lution was then concentrated under reduce pressure and the residue
was dissolved in 400 L of 1% acetone solution of 1-fluoro-2,4-
dinitrophenyl-5-(S)-alanine amide (FDAA) (4 mg, 15 mol) and
NaHCO3 (1 M, 80 L). The reaction mixture was heated at 40°C for
1 h with frequent stirring. After cooling to r.t., HCl (1 N, 80 L) was
added and the combined solvents were evaporated under reduced
pressure. The resulting residue was dried in vacuo over phosphorus
pentoxide and analysed by HPLC. The optical purity was deduced
by comparison with the data of the racemic mixture.
To obtain racemic samples of 4 and then prepared racemic FDAA
derivatives, racemic N-phthalyl pantolactonyl esters 3 were reduced
as previously described.
HPLC (column II): (S)-4a: tR = 30.5 min, (R)-4a: tR = 30.8 min (gra-
dient A), (S)-4b: tR = 41.8 min, (R)-4b: tR = 42.3 min (gradient B),
(S)-4c: tR = 31.1 min, (R)-4c: tR = 31.4 min (gradient A), (S)-4d:
tR = 58.7 min, (R)-4d: tR = 58.9 min (gradient C), (S)-4e: tR = 34.1
min, (R)-4e: tR = 34.3 min (gradient A).
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1984, 25, 2093.
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Synthesis 2001, No. 9, 1302–1304 ISSN 0039-7881 © Thieme Stuttgart · New York