A convenient method of preparing optically active (S)-N-tritylaziridine- 2-carboxylate esters from (S)-β-haloamino acids

Article abstract of DOI:10.1039/a909140h

A convenient method of preparing optically active (S)-N-tritylaziridine- 2-carboxylate esters via intramolecular cyclization of (S)-N-trityl-β- haloamino acid esters is described.

Full text of DOI:10.1039/a909140h

A convenient method of preparing optically active
(S)-N-tritylaziridine-2-carboxylate esters from (S)-b-haloamino acids
Yasuo Kato*ab and Kenji Fukumotob
a Biotechnology Research Center, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan.
E-mail: yasu@pu-toyama.ac.jp
b Life Science Research Center, Advanced Technology Research Laboratories, Nippon Steel Corporation,
Nakahara-ku, Kawasaki 211-0035, Japan
Received (in Cambridge, UK) 18th November 1999, Accepted 6th January 2000
A convenient method of preparing optically active (S)-N-
tritylaziridine-2-carboxylate esters via intramolecular cycli-
zation of (S)-N-trityl-b-haloamino acid esters is described.
could suppress both the 1,2-elimination and deprotection
reaction to give the aziridine 2 as the sole product, although the
reaction rate was decreased to one-third of that with KF (entry
5). Elongation of the reaction time could solve this problem and
afforded 2 in almost quantitative yield (entry 6). The choice of
the reaction solvent was quite important; alkyl nitriles i.e.
MeCN, EtCN, PrCN, PriCN, BuCN and BuiCN, were the only
suitable solvents to form aziridine 2. Other organic solvents
such as THF, DMSO, DMF, 1,4-dioxane, CH2Cl2 and Et2O
were not useful; only the recovery of the starting material 1 was
observed. The other weak acid salts of the potassium ion,
KHSO3, K2SO3, K2HPO4, K2WO4 and K2S2O5, and weak
organic amines, Et3N and Pri2NEt, were effective bases for the
cyclization reaction and gave the cyclized aziridine 2 as the sole
product. Interestingly, only a deprotected compound 4 was
obtained using sulfate and persulfate salts, KHSO4, K2SO4 and
K2S2O7. However, the use of stronger inorganic bases such as
RbF and CsF deserves comment and produced only 3 (e.g. entry
7).
The development of novel methods of synthesizing optically
pure unnatural amino acids is an area of current interest.1 (S)-N-
Tritylaziridine-2-carboxylate [N-Tr-(S)-AZC] esters represent
an interesting class of compounds since they can be considered
a versatile synthetic equivalent of the ‘b-alanyl cation’ synthon
suitable for elaboration into b-substituted (S)-amino acids,2
enzyme substrates,3 and irreversible inhibitors of proteases.4
Despite their importance for synthetic use, only a few studies on
the syntheses of N-Tr-(S)-AZC esters have been reported 5–9
and these methods involve multi-step procedures, require
expensive starting materials, and produce a low yield or partial
racemization of the intermediate in the synthetic scheme.
During the course of our studies on the application of
enzymes in organic syntheses, we have discovered an efficient
method for the production of halogen-containing a-amino acids
via chemo-enzymatic reaction.10 Using this process, optically
pure (S)-b-haloamino acids, especially, (S)-b-chloroalanine
(BCA) and threo-(2R,3S)-3-chloroaspartic acid, can be ob-
tained in large quantities. We report herein a convenient method
of synthesizing N-Tr-(S)-AZC esters via intramolecular cycliza-
tion of (S)-N-trityl-b-chloroalanine (N-Tr-BCA) esters,† which
were derived from the enzymatically prepared BCA (Scheme
1).
Under such suitable conditions,¶ the cyclization reactions of
various esters of N-Tr-BCA were examined. Methyl, ethyl, n-
propyl, n-butyl, n-pentyl, isopropyl and isobutyl esters of BCA
were converted to the corresponding aziridines in yields of 90,
95, 94, 98, 92, 97 and 96%, respectively. These results suggest
Table 1 Base-catalyzed transformation of (S)-N-Tri-b-chloroalanine benzyl
ester
In our first attempt at a base-catalyzed intramolecular
cyclization reaction of N-Tr-BCA benzyl ester 1 to benzyl N-Tr-
(S)-AZC 2 with 2 equiv. of strong base, such as NaH, ButOK,
DBU, DBN and ButLi, in THF at room temperature, however,
only the 1,2-elimination of hydrogen and chloride atoms
occurred and N-trityldehydroalanine benzyl ester 3‡ was
obtained as the sole product (Table 1, entry 1). Reaction in
another solvent, such as hexane, Et2O, CH2Cl2, MeCN, DMF
and DMSO, also gave 3. It turned out that the expected aziridine
2§ was formed when a weak inorganic base, KF, was used as the
base in refluxing MeCN (entry 2) with some formation of 3.
Encouraged by this result, we further investigated the inorganic
bases by changing their basicity and counter ions. Weaker bases
and neutral salts such as LiF, NaF, LiCl, NaCl, KCl, NaBr, KBr,
CsBr, RbBr, MgF2 and SrF2 were ineffective and afforded BCA
benzyl ester 4 which was formed by deprotection of the trityl
group of 1 (entry 4). However, the use of bisulfite salt, KHSO3,
Scheme 1 Chemoenzymatic synthesis of (S)-N-tritylaziridine-2-carboxylate esters.
Chem. Commun., 2000, 245–246
This journal is © The Royal Society of Chemistry 2000
245

Scheme 2 Reagents and conditions: i, KHSO3, MeCN, reflux, 63 h; ii, KHSO3, MeCN, reflux, 120 h; iii, CsF, DMF, 100 °C, 60 h; iv, CsF, MeCN, reflux,
4 h.
regeneration of NADH by formate dehydrogenase (Boehringer Mannheim
that changing the ester moiety does not affect the yield or
GmbH, Germany) as described previously (ref. 10). The BCA was
reaction rate of the formation of aziridine.
converted to N-Tr-BCA esters by an esterification with SOCl2 in an
appropriate alcohol followed by N-tritylation with Tr-Cl–Et3N in CH2Cl2.
‡ Selected data for 3: dH(400 MHz, CDCl3) 7.19–7.38 (m, 20H), 5.85 (br,
Based on these observations, we propose the following
reaction mechanisms for the cyclization or 1,2-elimination
reactions: (i) when the reagent is neutral or has Lewis acidity,
1H), 5.19 (s, 2H), 4.86 (dd, 1H, J 0.85, 1.7), 3.73 (d, 1H, J 0.85); dC(100
only deprotection of the trityl group is seen; (ii) if the reagent
MHz, CDCl3) 165.9, 144.5, 136.6, 135.6, 129.1, 128.5, 128.3, 128.0, 127.8,
exhibits basicity and dissociates into ions, the metal ions act as
a base and catalyzed the 1,2-elimination reaction; (iii) if the
reagent cannot dissociate into ions, it chelates both the chloride
atom and carbonyl oxygen, allowing the cyclization reaction.
This is supported by the fact that the KF-catalyzed cyclization
reaction proceeds only in MeCN; the 1,2-elimination reaction
preferentially occurred in polar solvents, such as DMF, DMSO,
THF and 1,4-dioxane, in which the reagents dissociate more
easily into the ion pairs (e.g. Table 1, entry 3).
We next examined the cyclization or 1,2-elimination reaction
for each diastereomer of methyl (S)-N-trityl-3-chloro-2-amino-
butyrate (N-Tr-BCAB), prepared from (S)-threonine or allo-(S)-
threonine. As shown in Scheme 2, only the threo isomer of N-
126.8, 95.4, 71.2, 67.3; nmax/cm21 (NaCl) 3400, 3060, 3030, 1705, 1615,
1485, 1440, 1295, 1195, 1170, 745, 695; mp 164–166 °C.
§ Selected data for 2: dH(400 MHz, CDCl3) 7.47–7.49 (m, 6H), 7.31–7.39
(m, 6H), 7.18–7.25 (m, 8H), 5.21 (ABq, 2H, J 3.8, 18.6), 2.28 (dd, 1H, J 1.5,
2.5), 1.92 (dd, 1H, J 2.5, 6.2), 1.41 (dd, 1H, J 1.5, 6.2 ); dC(100 MHz,
CDCl3) 171.4, 143.6, 135.8, 129.3, 128.6, 128.4, 128.3, 127.7, 126.9, 74.4,
66.7, 31.8, 28.8; nmax/cm21 (NaCl) 3060, 3030, 1740, 1590, 1485, 1445,
1235, 1170, 1015, 745, 705, 695, 625; mp 115–116 °C; [a]2D0 296.9 (c 1.0,
CHCl3); optical purity > 99.9% ee [determined by HPLC with Crownpak
CR(-) (Daicel, Tokyo, Japan) after derivatization of 3 to (S)-alanine by
hydrogenation with Pd/C].
¶ Typical reaction procedure: to a stirred suspension of KHSO3 (2.5 mmol)
in anhydrous MeCN (15 ml) was added N-Tr-BCA ester (0.5 mmol) and the
mixture was refluxed for several hours. After cooling to room temperature,
5 ml of 5% NaHCO3 was added to the mixture and the product was extracted
with CH2Cl2 (15 ml 3 2). The combined organic layer was dried over
anhydrous MgSO4 and concentrated in vacuo. The residue was purified by
preparative TLC (silica gel) and afforded aziridines as crystals or an oil.
∑ The structure of aziridine 6 and dehydroamino acid 7 were confirmed by
1H and 13C NMR and IR in comparison with reported values (ref. 11).
Tr-BCAB
(threo-5)
was
cyclized
to
form
(2S,3R)-3-methylaziridine-2-carboxylate 6,∑ but erythro-5 was
not. If we assume a chair-like transition state, we can conceive
a reaction mechanism. In the transition state, KHSO3, which
does not dissociate into K+ and HSO32, is chelated by both the
chloride atom and the carbonyl oxygen; it allows an attack by a
lone pair from nitrogen, giving cyclization and eliminating the
chloride ion via an SN2-like reaction (transition state A),
resulting in the formation of aziridine 6. In the case of erythro-5,
steric repulsion by the axial methyl group stopped the attack of
nitrogen (transition state B). In contrast, the 1,2-elimination
reaction occurred only for erythro-5 to give (E)-dehydroamino
acid 7∑ as the sole product. The results are explainable by
Newman projections. The dissociated caesium ion acts as a base
allowing the elimination of the chloride ion and antiperiplanar
proton, afforded 1,2-eliminated product 7 from erythro-5
(transition state D), while threo-5 cannot adopt a conformation
able to 1,2-eliminate due to steric repulsion between the methyl,
N-trityl and methoxycarbonyl groups, blocking reaction (transi-
tion state C).
In summary, we have shown here that (S)-N-tritylaziridine-
2-carboxylate esters are quantitatively synthesized via the weak
base-catalyzed cyclization of (S)-N-trityl-b-haloamino acid
esters under mild conditions. By changing slightly the reaction
conditions, 1,2-elimination takes place and affords N-trityl-
dehydroalanine esters in good yield. Syntheses of (S)-amino
acid derivatives by ring opening of the aziridine esters without
racemization are currently underway.
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This work was performed at the Life Science Research
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Notes and references
† BCA was enzymatically synthesized in high chemical ( > 90%) and
optical ( > 99.9% ee) yields from 3-chloropyruvate using alanine dehy-
drogenase from Bacillus stearothermophilus (Unitika, Kyoto, Japan) with
Communication a909140h
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Chem. Commun., 2000, 245–246