An efficient synthesis of optically active 3-amino-3-alkyl-2-oxetanones

Article abstract of DOI:10.1016/j.tetlet.2005.07.058

An efficient two-step synthesis of p-toluenesulfonic acid salts of optically active 3-amino-3-alkyl-2-oxetanones is reported that involves cyclization of N-Boc-α-alkylserines under Mitsunobu reaction conditions followed by deprotection of the amino group with trifluoroacetic acid in the presence of anhydrous p-toluenesulfonic acid.

Full text of DOI:10.1016/j.tetlet.2005.07.058

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6239–6241
An efficient synthesis of optically active
3-amino-3-alkyl-2-oxetanones
Aleksandra Olma* and Adam Kudaj
_
Institute of Organic Chemistry, Technical University, 90-924 Ło´dz´, Zeromskiego 116, Poland
Received 12 May 2005; revised 4 July 2005; accepted 14 July 2005
Abstract—An efficient two-step synthesis of p-toluenesulfonic acid salts of optically active 3-amino-3-alkyl-2-oxetanones is reported
that involves cyclization of N-Boc-a-alkylserines under Mitsunobu reaction conditions followed by deprotection of the amino group
with trifluoroacetic acid in the presence of anhydrous p-toluenesulfonic acid.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
via N-protected b-lactones as intermediates.6 N-Benzyl-
oxycarbonyl-L-serine-b-lactone represents a newclass of
cysteine proteinase inhibitors7 and therefore our current
interest is focused on the synthesis of optically active a-
substituted-b-lactones. In this letter, we report an effi-
cient two-step synthesis of p-toluenesulfonic acid salts
of optically active 3-alkyl-2-oxetanones from optically
active N-Boc-a-alkylserines. The starting optically active
intermediates were easily available via a procedure
developed in our laboratory involving the synthesis of
racemic a-hydroxymethyl analogues of various amino
acids8 and their resolution by fractional crystallization
of appropriate diastereoisomeric salts. The absolute
configurations of some a-hydroxymethylamino acids
were determined by chemical correlation with relevant
a-methylamino acids or by X-ray analysis.9
The discovery of a significant number of natural b-lac-
tones (2-oxetanones) with very interesting biological
activities has attracted much attention towards the prep-
aration of the b-lactone moiety and its use as a synthetic
intermediate.1 N-Protected-a-amino-b-lactones are use-
ful and versatile intermediates for the synthesis of b-
substituted a-amino acids via ring opening by various
nucleophiles.2,3 The p-toluenesulfonic acid salt of (S)-
3-amino-2-oxetenone obtained from N-protected serine
b-lactone reacts with a variety of nucleophiles to afford
unprotected, optically pure a-amino acids.4 N-Boc-a-
methylserine-b-lactone has been used for the synthesis
of N- and S-protected a-methylcysteine.5
Recently, we described a transformation of various
Boc-a-hydroxymethylamino acids (a-alkylserines) into
Boc-a-mercaptomethyl-a-amino acids (a-alkylcysteines)
Scheme 1 outlines our approach for the preparation of
a-substituted-b-lactones, which involves transformation
R
R
R
O
O
O
+
BocHN
Ph P, DEAD
TFA
3
H3N
BocHN
o
OH THF, 0
C
TsOH
TsO
HOH2C
O
O
1
2
3
R = CH3 (a), CH(CH3)2 (b), CH2CH(CH3)2 (c), CH2C6H5 (d).
Scheme 1. Synthesis of p-toluenesulfonic acid salts of (S)- and (R)-3-amino-3-alkyl-2-oxetanones 3.
Keywords: 3-Amino-3-alkyl-2-oxetanones; b-Lactones; a-Alkylserines.
*
Corresponding author. Tel.: +48 426313155; fax: +48 426365530; e-mail: olmaola@p.lodz.pl
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.058

6240
A. Olma, A. Kudaj / Tetrahedron Letters 46 (2005) 6239–6241
Table 1. N-Boc- (2) and p-toluenesulfonic salts of 3-amino-3-alkyl-2-
oxetanones (3)
captomethyl-a-amino acids at the C-terminal position as
depicted in Scheme 2.
R
2 (yield %)
3 (yield %)
Incorporation of unnatural a,a-disubstituted amino
acids into peptides is of interest in the synthesis of pep-
tidomimetics. Conventional peptide synthetic methods
are often unsuccessful. In our hands, attempts to couple
the amino group of a-mercaptomethyl-a-amino acids
residues with most known reagents, failed. The ap-
proach depicted in Scheme 2 via the less hindered b-lac-
tone intermediates shows great promise in solving the
so-called ÔdifficultÕ coupling problem. Thus, the coupling
with 3-amino-3-alkyl-2-oxetanone proceeded smoothly
and the dipeptides (Boc-Asp(Bzl)-MmVal(Mob)-OH
and Boc-Asp(Bzl)-MmLeu(Mob)-OH) were obtained
in good yields (Scheme 2).12 Experiments are underway
to explore the further potential of this approach and to
evaluate the versatility of b-lactones as intermediates.
CH3
98
92
95
94
80
82
74
77
CH(CH3)2
CH2CH(CH3)2
CH2C6H5
of N-Boc-a-alkylserines into b-lactones under Mitsun-
obu reaction conditions and deprotection of the amino
function with trifluoroacetic acid in the presence of
anhydrous p-toluenesulfonic acid.
Attempts to use commercially available diisopropyl
azodicarboxylate (DIAD) were inefficient and only N-
Boc-a-methylserine-b-lactone could be obtained in rea-
sonable yield (60%) under these conditions. Instead,
the application of diethyl azodicarboxylate (DEAD)
for sterically hindered a-hydroxymethylamino acids
such as b-branched 1b (Val analog) or c-branched 1c
or 1d (Leu or Phe analogs) provided b-lactones in excel-
lent yields (Table 1).
2. General procedure for preparation of N-Boc-a-alkyl-
serine-b-lactones 2
To a solution of triphenylphosphine (525 mg, 2 mmol)
in dry THF, DEAD (313 ll, 2 mmol) was added at
0 °C. The mixture was stirred for 20 min at 0 °C and
then a solution of the Boc-a-hydroxymethylamino acid
(2 mmol) in dry THF (1 ml) was added. Stirring was
continued for 1 h at 0 °C and then for 16 h at room tem-
perature. The THF was removed in vacuo and the crude
product was purified by flash chromatography on silica
gel 60 (230–400 mesh) using ethyl acetate–n-hexane (1:1)
as eluent to give the N-Boc-a-alkylserine-b-lactones 2
in 92–98% yields. The products could be used without
further purification in the next step.
Under these conditions, Boc-a-hydroxymethylamino
acids undergo the cyclization reaction to N-Boc-a-alkyl-
serine-b-lactones in 92–98% yield. Although the effi-
ciency of the Mitsunobu reaction does not depend on
the alkyl groups of azodicarboxylate and diethyl or
diisopropyl azodicarboxylate can be used interchange-
ably,10 for the synthesis of N-Boc-a-alkylserine-b-lac-
tones, diethyl azodicarboxylate was the reagent of
choice. DEAD is easily accessible in a two-step sequence
as described by Rabjohn.11 In every case, pure N-pro-
tected b-lactones were obtained in good yields after flash
chromatography. Removal of the Boc group was carried
out using TFA in the presence of anhydrous p-toluene-
sulfonic acid. All products were characterized by 1H
NMR, IR and HR-MS (FAB).
3. General procedure for preparation of p-toluenesulfonic
acid salts of (S)-3-alkyl-2-oxetanones 3
To a cooled mixture of (1 mmol) of N-Boc-a-alkylser-
ine-b-lactone and (181 mg, 1.05 mmol) of anhydrous
p-toluenesulfonic acid under argon, anhydrous trifluoro-
a-Alkyl-serine-b-lactones showpromise as useful inter-
mediates in the synthesis of dipeptides containing a-mer-
R2
R1
R2
+
H3N
R1
H
O
O
O
N
TBTU/DIEA
+
BocNH
BocNH
O
OH
O
OTs
O
3
R2
SH
CH3O
R1
O
H
N
Cs CO
2
3
BocNH
OH
O
SMob
4
Mob = 4-methoxybenzyl
4a R1= CH(CH3)2, R2= CH2COOCH2C6H5 (61%)
4b R1= CH2CH(CH3)2, R2= CH2COOCH2C6H5 (70%)
Scheme 2. Synthesis of dipeptides via a-alkylserine-b-lactones.

A. Olma, A. Kudaj / Tetrahedron Letters 46 (2005) 6239–6241
6241
acetic acid (2.6 ml) was added. The mixture was stirred
for 2–4 h (TLC) and evaporated under vacuum. Anhy-
drous ether was added and the solid obtained was sepa-
rated, washed with ether and dried under reduced
pressure. Yield 74–82%.
(FAB) m/z 178.0872 (M+H), calcd for C10H12NO2
178.0686.
Acknowledgements
3.1. (S)-3-Amino-3-methyl-2-oxetanone p-toluenesulfonic
acid salt 3a
This work was supported by the Ministry of Scientific
Research and Information Technology (grant no.
T09A 167 22).
20
Yield 80%; colorless crystals, mp 186–188 °C (dec); ½aꢀD
ꢁ15.6 (c 1, MeOH); IR (film) 1832 cmꢁ1
;
1H NMR
(250 MHz, CDCl3/TFA) d: 1.93 (s, 3H); 2.42 (s, 3H);
4.45, 4.86 (AX system, 2H, J = 6.88 Hz); 7.28, 7.67
(AAÔXXÕ system, 4H, J = 8.11 Hz); HR-MS (FAB)
m/z 102.0559 (M+H), calcd for C4H8NO2 102.0555.
References and notes
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3.2. (S)-3-Amino-3-iso-propyl-2-oxetanone p-toluene-
sulfonic acid salt 3b
20
Yield 82%; colorless crystals, mp 187–189 °C (dec); ½aꢀD
ꢁ35.5 (c 1, MeOH), IR (film) 1832 cmꢁ1
;
1H NMR
(250 MHz, CDCl3/TFA) d: 1.11, 1.12 (2d, 6H,
J = 6.80 Hz); 2.22, 2.42 (heptet, 1H, J = 6.80 Hz); 2.35
(s, 3H); 4.36, 4.68 (AX system, 2H, J = 7.05 Hz); 7.25,
7.67 (AAÔXXÕ system, 4H, J = 8.10 Hz); HR-MS
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sulfonic acid salt 3c
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20
Yield 74%; colorless crystals, mp 209–211 °C (dec); ½aꢀD
ꢁ21.8 (c 1, MeOH); IR (film) 1832 cmꢁ1
;
1H NMR
´
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(250 MHz, CDCl3/TFA) d: 0.96, 1.02 (2d, 6H,
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2.41 (s, 3H); 4.49, 4.79 (AX system, 2H, J = 7.15 Hz);
7.28, 7.68 (AAÔXXÕ system, 4H, J = 8.32 Hz); HR-MS
(FAB) m/z 144.1019 (M+H), calcd for C7H14NO2
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´
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3.4. (S)-3-Amino-3-benzyl-2-oxetanone p-toluenesulfonic
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_
´
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20
Yield 77%; colorless crystals, mp 212–214 °C (dec); ½aꢀD
ꢁ44.2 (c 1, MeOH); IR (film) 1832 cmꢁ1
;
1H NMR
(250 MHz, CDCl3/TFA) d: 2.39 (s, 3H); 3.28, 3.42
(AB system, 2H, J = 14.2 Hz); 4.40, 4.89 (AX system,
2H, J = 11.5 Hz); 7.12, 7.21 (m, 2H); 7.25, 7.68 (AAÔXXÕ
system, 4H, J = 7.75 Hz); 7.30, 7.39 (m, 3H); HR-MS
´
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Pept. Sci. 1998, 4, 1–14.
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