Efficient synthesis of N-benzyloxycarbonyl- and N-tert-butoxycarbonyl-(S)-isoserine and their derivatives

Article abstract of DOI:10.1055/s-2002-35597

A mild and efficient synthesis of N-protected (S)-isoserine from (S)-malic acid monoester via an oxazolidin-2-one is described.

Full text of DOI:10.1055/s-2002-35597

LETTER
2101
Efficient Synthesis of N-Benzyloxycarbonyl- and N-tert-Butoxycarbonyl-(S)-
Isoserine and their Derivatives
Synthesis of
N
-
Be
y
nzyloxycarb
s
onyl- and
z
N
-
tert
-
But
a
oxycarbony
r
l-(
S
)-Iso
d
serine Andruszkiewicz,* Monika Wyszogrodzka
Department of Pharmaceutical Technology and Biochemistry, Gda sk University of Technology, 80-952 Gda sk, Poland
Fax +48(58)3471144; E-mail: ryszarda@chem.pg.gda.pl
Received 23 September 2002
its constrained analogue to be built into peptide conju-
Abstract: A mild and efficient synthesis of N-protected (S)-iso-
gates or to serve as a chiral synthon for further synthesis.
Therefore, we report here a simple synthetic approach to
N-protected isoserine and its cyclic derivative, which
serine from (S)-malic acid monoester via an oxazolidin-2-one is de-
scribed.
Key words: amino acids, asymmetric synthesis, oxazolidin-2-ones,
starts from cheap starting materials, proceeds in good
ring opening, protecting groups
yields, and allows easy scale-up to multigram scale.
The preparation of the title compounds was carried out
from enantiomerically pure 1-monoesters of (S)-malic ac-
id, which are easily accessible from (S)-malic acid 1 by
adopting a literature reported procedure,11 in which treat-
ment of malic acid with trifluoroacetic acid anhydride fur-
nished the corresponding trifluoroacetate of (S)-malic
anhydride (Scheme 1). Regioselective opening of the an-
hydride with one equivalent of anhydrous benzyl or meth-
yl alcohol provided optically active 1-monoesters. The 1-
monoesters 2a and 2b were then converted to the corre-
sponding oxazolidin-2-ones 4a and 4b. Oxazolidin-2-
ones were effectively formed by refluxing 2a and 2b with
diphenylphosphoryl azide (DPPA) and triethylamine
(Et3N) in t-BuOH. The isocyanates 3a and 3b transiently
formed underwent internal cyclization to 4a and 4b with
good yields.12 However, due to the good solubility of 4b
in aqueous phase, the extraction process was ineffective,
therefore, pure 4b was obtained by using column chroma-
tography. For further synthetic use, there is no need to use
column chromatography and compound 4b may also be
used without isolation for the next reaction. Owing to the
(S)-Isoserine, i.e. (S)-3-amino-2-hydroxypropanoic acid
is an amino acid component of biologically active pep-
4
tides produced by the Bacillus brevis Vm strain: edeine
antibiotics and tatumine.1 It has also been found in a group
of keramamides F-K2, cytotoxic peptides isolated from
Theonella sp sponges. These marine organisms are also
known to produce a variety of cyclic glycopeptides in-
cluding theopalauamide,3 theonellamides A-F,4 and the-
onegramide,5 all containing (S)-isoserine. This non-
protein amino acid has also been applied in a semisynthet-
ic aminoglycoside antibiotic derivatives (e.g. gentamycin
and butyrosin).6 Recently, polyamides containing (S)-
isoserine have been used in DNA recognition studies.7
Several practical methods for the synthesis of optically ac-
tive isoserines using malic acid, substituted imidazolin-2-
ones, or chiral cyanohydrins as starting materials have
been reported.8
In connection with our program centered on edeine anti-
biotic analogues9 and glucosamine-6-phosphate synthase
inhibitors10 we needed an N-protected (S)-isoserine and
O
O
O
1. TFAA
2. R1OH
OH
DPPA, Et3N
OH
R1O
N=C=O
HO
R1O
t-BuOH, reflux 4h
OH
OH
O
OH
O
2a R1 = PhCH2 (70%)
3a R1 = PhCH2
3b R1 = Me
1
2b R1 = Me
(77%)
R2
O
N
HN
H
H
O
[Me3N CH2C6H5]+ OH-
R2
Et3N, DMAP, THF
(Boc)2O or CbzCl
OR1
OR1
N
OH
O
O
O
THF, –40 °C
O
H
OH
O
6a R2 = Boc (75%)
6b R2 = Cbz (75%)
5a R1 = PhCH2 R2 = Boc (85%)
5b R1 = PhCH2 R2= Cbz (80%)
4a R1 = PhCH2 (70%)
4b R1 = Me
(80%)
5c R1 = Me
R2 = Boc (70%)
Scheme 1
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2101,2103,ftx,en;G27902st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2102
R. Andruszkiewicz, M. Wyszogrodzka
LETTER
(3) (a) Schmidt, E. W.; Bewley, C. A.; Faulkner, D. J. J. Org.
Chem. 1998, 63, 1254. (b) Moore, B. S. Nat. Prod. Rep.
1999, 16, 653.
low reactivity of the nitrogen atom in a heterocyclic ring,
the nitrogen in 4a was proteced using di-tert-butyl dicar-
bonate (Boc)2O, Et3N and a catalytic amount of DMAP in
THF at –20 °C,13 thus obtaining the desired N-Boc deriv-
ative 5a in good yield. Under the same reaction condi-
tions, compound 5c was obtained from 4b. On the other
hand, the reaction of 4a with an excess of benzyloxycar-
bonyl chloride (Cbz-Cl) in a THF/Et3N solution at –20 °C
and DMAP furnished the N-Cbz derivative 5b.14 The crit-
ical ring opening in the protected oxazolidin-2-ones 5a,
5b and 5c was performed using benzyltrimethylammoni-
um hydroxide in THF at –40 °C.15 In all cases, hydrolysis
of the esters was also observed. The low temperature con-
ditions for base induced opening of the oxazolidin-2-ones
were essential to avoid the formation of undesired by-
products. We also found that the treatment of protected
oxazolidin-2-ones with NaOH or LiOH in THF solutions,
even at low temperature gave rise to N-deprotected and
other non identified products. Hydrolysis of 5a and 5c
yielded the same products 6a with the same melting point
and optical rotation.
(4) (a) Matsunaga, S.; Fusetani, N. J. Org. Chem. 1995, 60,
1177. (b) Taylor, C. M. Tetrahedron 1998, 54, 11317.
(5) Bewley, C.; Faulkner, D. J. J. Org. Chem. 1994, 59, 4849.
(6) (a) Wright, J. J.; Cooper, A.; Daniels, P. J. L.; Nagabhushan,
T. L.; Rane, D.; Turner, W. N.; Weinstein, J. J. Antibiot.
1976, 29, 714. (b) Haskell, T. H.; Rodebaugh, R.; Plessas,
N.; Watson, D.; Westland, R. D. Carbohydr. Res. 1973, 28,
263.
(7) Floreancig, P. E.; Swalley, S. E.; Trauger, J. W.; Dervan, P.
B. J. Am. Chem. Soc. 2000, 122, 6342.
(8) For a review see: Andruszkiewicz, R. Pol. J. Chem. 1998,
72, 1.
(9) (a) Andruszkiewicz, R.; Walkowiak, A. Org. Prep. Proc.
Int. 2001, 33, 379. (b) Czajgucki, Z.; Sowinski, P.;
Andruszkiewicz, R. Amino Acids 2002, in press.
(10) (a) Andruszkiewicz, R.; Milewski, S.; Borowski, E. J.
Enzyme Inhib. 1995, 9, 123. (b) Andruszkiewicz, R.;
Jedrzejczak, R.; Zieniawa, T.; Wojciechowski, M.;
Borowski, E. J. Enzyme Inhib. 2000, 15, 429.
(11) Cammas, S.; Renard, I.; Boutault, K.; Guerin, P.
Tetrahedron: Asymmetry 1993, 4, 1925.
(12) Typical Procedure for the Preparation of 4a and 4b: The
appropriate substrate 2a,b (5 mmol), and DPPA (1.18 mL,
5.5 mmol) were dissolved in t-BuOH (20 mL). The reaction
flask was flushed with argon, and Et3N (0.75 mL, 5.5 mmol)
was added. The reaction mixture was refluxed for 4 h and
cooled to r.t. The solvent was removed under reduced
pressure, the residue dissolved in EtOAc (50 mL). In the
case of 4a, the solution was washed with sat. NaHCO3
solution, water and finally dried over anhyd MgSO4. After
evaporation of the solvent, the solid residue was crystallized
from EtOAc and hexane to yield 4a (0.77 g, 70%). Mp: 128–
129 °C; [ ]D +10.0 (c 1, EtOAc). 1H NMR (200 MHz,
CDCl3): = 3.66–3,74 (dd, J4a,4b = 9.5 Hz, J4a,5a = 5.6 Hz, 1
H CHCH2, 4Ha), 3.85–3.95 (dd, J4b,4a = 9.5 Hz, 1 H, CHCH2,
4 Hb), 5.05–5.10 (dd, J5a,4b = 9.5 Hz, J5a,4a = 5.6 Hz, 1 H,
CHCH2, 5 Ha), 5.28 (s, 2 H, CH2C6H5), 5.9 (br s, 1 H, NH),
7.40(s, 5 H, C6H5). Anal. Calcd for C11H11NO4: C, 59.73; H,
5.01; N, 6.33. Found: C, 59.58; H, 5.12; N, 6.38. In the case
of 4b, after evaporation of the solvent, the product was
purified by column chromatography (silica gel, hexane–
ethyl acetate 2:3) furnishing 4b (0.58g, 80%) which was
crystallized from ethyl acetate and hexane. Mp: 95–97 °C;
Finally, catalytic hydrogenation (Scheme 2) of 5a in me-
thyl alcohol afforded the Boc protected acid 7a in good
yield.16 Hydrogenolysis did not damage the heterocyclic
ring.
O
O
H2, Pd/C
THF, MeOH
O
N
O
N
H
O
H
O
O
OH
94%
O
O
O
O
7a
5a
Scheme 2
In conclusion, we have developed a new, mild and effi-
cient route to N-protected isoserines and isoserine cyclic
derivative from 1-monoesters of (S)-malic acid via ox-
azolidin-2-ones.
[ ]D +20.1 (c 1, EtOAc). 1H NMR (200 MHz, CDCl3):
=
3.65–3.75(dd, J4a,4b = 9.6 Hz, J4a,5a = 5.5 Hz, 1 H, CHCH2, 4
Ha), 3.85 (s, 3 H, CH3), 3.86–3.96 (dd, J4a,4b = 9.6,
Acknowledgment
J4b,5a = 5.5 Hz, 1 H, CHCH2, 4 Hb), 5.01–5.09 (dd,
The authors are indebted to the Faculty of Chemistry, Gda sk Uni-
versity of Technology for financial support.
J5a,4b = 9.6 Hz, J5a,4b = 5.5 Hz, 1 H, CHCH2, 5 Ha), 6.24
(br s, 1 H, NH). Anal. Calcd for C5H7NO4: C, 41.38; H, 4.86;
N, 9.65. Found: C, 41.22; H, 4.74; N, 9.60.
(13) Typical Procedure, 4a,b to 5a–5c: Compound 4a or 4b (9
mmol), DMAP (25 mg) and Et3N (1.5 mL, 11 mmol) were
dissolved in dry THF (25 mL) and cooled in an ice bath. A
solution of (Boc)2O (2.05 g, 9.4 mmol) in THF (8 mL) was
added to a stirred reaction mixture over 20 min. The
References
(1) (a) Hettinger, T. P.; Craig, L. C. Biochemistry 1970, 9,
1224. (b) Heaney-Kieras, J.; Kurylo-Borowska, Z. J.
Antibiot. 1980, 33, 359.
temperature of the reaction was kept between 5 °C and 10 °C
overnight. Then, equimolar amounts of NaHSO4 (1.32 g, 11
mmol) in water (10 mL) were added. After evaporation of
the solvent under reduced pressure, the white suspension
was dissolved in EtOAc (50 mL), and the solution was
washed with dilute NaHSO4 solution, water and finally dried
(MgSO4) and evaporated. The solid was crystallized from
diethyl ethyl ether and hexane to give 5a (2.5 g, 85%). Mp:
130–131 °C; [ ]D +24.0 (c 1, EtOAc). 1H NMR (200 MHz,
(2) (a) Sowinski, J. F.; Toogood, P. L. Tetrahedron Lett. 1995,
68, 67. (b) Kobayashi, J.; Itagaki, F.; Shigemori, I.; Takao,
T.; Shimonishi, Y. Tetrahedron 1995, 51, 2525.
(c) Sowinski, J. F.; Toogood, P. L. Chem. Commun. 1999,
981. (d) Uemoto, H.; Yahiro, Y.; Shigemori, H.; Tsuda, M.;
Takao, T.; Shimonishi, Y.; Kobayashi, J. Tetrahedron 1998,
54, 6719. (e) Dohren, H.; von Kleinkauf, H. Biotechnology
1999-2001, 7, 313.
Synlett 2002, No. 12, 2101–2103 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Benzyloxycarbonyl- and N-tert-Butoxycarbonyl-(S)-Isoserine
2103
CDCl3): = 1.56 [s, 9 H (CH3)C],. 4.00–4.07 (dd,
4a,4b = 10.7, J4a,5a = 5.5 Hz, 1 H, CHCH2, 4 Ha), 4.14–4.24
10 H, 2 C6H5). Anal. Calcd for C19H17NO6: C, 64.22; H,
4.82; N, 3.94. Found: C, 64.34; H, 4.68; N, 3.88.
J
(dd, J5a,4b = 9.5 Hz, J4a,4b = 10.7 Hz, 1 H, CHCH2, 4 Hb),
4.91–4.99 (dd, J5a,4b = 9.5 Hz, J5a,4a = 5.5 Hz, 1 H, CHCH2),
5.29 (s, 2 H, CH2C6H5), 7.40 (s, 5 H, C6H5). Anal. Calcd for
C16H19NO6: C, 59.18; H, 5.96; N, 4.36. Found: C, 59.34; H,
5.92; N, 4.22. In the same manner compound 5c was
obtained (1.54 g, 70%). Mp: 76–78 °C; [ ]D +36.8 (c 2.5,
MeOH). 1H NMR (200 MHz, CDCl3): = 1.55 [s, 9 H
(CH3)C], 3.87 (s, 3 H, CH3), 4.00–4.08 (dd, J4a,4b = 10.7,
J4a,5a = 5.5 Hz, 1 H, CHCH2, 4Ha), 4.14–4.25 (dd, J5a,4b = 9.5
Hz, J4a,4b = 10.7 Hz, 1 H, CHCH2, 4 Hb), 4.89–4.97 (dd,
J5a,4b = 9.5 Hz, J5a,4a = 5.5 Hz, 1 H, CHCH2). Anal. Calcd for
C10H15NO6: C, 48.98; H, 6.17; N, 5.71. Found: C, 49.17; H,
6.22; N, 5.58.
(15) (a) Representative Experimental Procedure: Compound
5a–5c (5 mmol) was quickly dissolved in dry THF (50 mL)
and cooled under argon to –40 °C. Benzyltrimethyl-
ammonium hydroxide (5.5 mL of 40% solution in methanol,
10.5 mmol) was added over 20 min to the solution of 5a–5c
and stirred for an additional 1 h. HOAc (1.1 mL) and water
(2.5 mL) were then added and the reaction mixture was
warmed to r.t. and the solvent was evaporated under reduced
pressure. The residue was extracted with EtOAc (2 50
mL). The extracts were washed, dried over MgSO4 and
evaporated. The solid residue was crystallized from a
mixture of EtOAc and hexane to yield 6a (0.77 g, 75%). Mp:
93–94 °C; [ ]D +6.4 (c 2.5, MeOH). Similarily, 6b was also
obtained (0.89 g, 75%). Mp: 117–119 °C; [ ]D +3.2 (c 2.5,
MeOH). Physical and spectral data for 6a and 6b are in
agreement with literature values, see ref.15b (b) Burger, K.;
Windeisen, E.; Pires, R. J. Org. Chem. 1995, 60, 7641.
(16) Preparation of 7a: Compound 5a (0.64 g, 2 mmol) was
dissolved in a mixture of THF (10 mL) and MeOH (15 mL)
and palladium on activated carbon (5%, 50 mg) was added.
The reaction flask was flushed with hydrogen and the
hydrogenation was performed at atmospheric pressure for 1
h at r.t. The catalyst was filtered off and the solvents were
evaporated. The residue was crystallized from a mixture of
EtOAc and hexane to give 7a (0.43g, 94%). Mp: 99–100 °C;
(14) Synthesis of 5b: (5S)-5-Benzyloxycarbonyl-2-oxazol-
idinone 4a (1.99 g, 9 mmol) was dissolved in THF (30 mL)
and Et3N (10 mL). The reaction mixture was cooled to
–20 °C. A solution of benzyl chloroformate (2.6 mL, 18
mmol) in THF (3.3 mL) was slowly added over 20 min. The
stirred reaction mixture was then kept at –10 °C overnight.
The reaction mixture was quickly neutralized with a
stoichiometric amount of cold 10% aq solution of NaHSO4
and extracted with EtOAc (2 50 mL). The extracts were
washed with water, dried (MgSO4) and evaporated. The
solid residue was dissolved in a small volume of hot EtOAc
and diluted with a large volume of diethyl ether. Crystals
were collected to give 5b (2.4g, 80%). Mp: 112–114 °C;
[ ]D +24.0 (c 2.5, EtOAc). 1H NMR (200 MHz, CDCl3):
= 4.04–4.12 (dd, J4a,4b = 10.6, J4a,5a = 5.5 Hz, 1 H, CHCH2,
4Ha), 4.18–4.28 (dd, J5a,4b = 9.5 Hz, J4a,4b = 10.6 Hz, 1 H,
CHCH2, 4 Hb), 4.93–5.01 (dd, J5a,4b = 9.5 Hz, J5a,4a = 5.5 Hz,
1 H, CHCH2), 5.27 (s, 2 H, CH2C6H5-benzyl ester), 5.31 (s,
2 H, CH2C6H5-benzyloxycarbonyl group), 7.35–7.45 (br s,
[ ]D +28.2 (c 1, MeOH). 1H NMR (500 MHz, CDCl3):
1.56 [s, 9 H (CH3)C],. 4.08–4.11 (dd, J4a,4b = 10.7,
=
J4a,5a = 5.4 Hz, 1 H, CHCH2, 4 Ha), 4.21–4.25 (dd, J5a,4b = 9.8
Hz, J4a,4b = 10.7 Hz, 1 H, CHCH2, 4 Hb), 4.95–4.98 (dd,
J5a,4b = 9.8 Hz, J5a,4a = 5.4 Hz, 1 H, CHCH2). Anal. Calcd for
C9H13NO6: C, 46.75; H, 5.67; N, 6.06. Found: C, 46.78; H,
5.52; N, 5.98.
Synlett 2002, No. 12, 2101–2103 ISSN 0936-5214 © Thieme Stuttgart · New York