A preparatively simple access to homochiral heterocyclic α-hydroxy acids and their derivatives

Article abstract of DOI:10.1007/s007060270005

The synthesis of homochiral heterocyclic α-hydroxy acids starting from (S)- and (R)-malic acid using hexafluoroacetone as protecting and activating agent is described. The new compounds are useful building blocks for peptide and depsipeptide modification.

Full text of DOI:10.1007/s007060270005

Monatshefte fuÈr Chemie 133, 41±58 (2002)
A Preparatively Simple Access
to Homochiral Heterocyclic a-Hydroxy Acids
and their Derivatives
Klaus Burger1;Ã, Elisabeth Windeisen1, Elisabeth Heistracher1,
Torsten Lange1, and Abdel-Aleem H. Abdel-Aleem2
1
Department of OrganicChemistry, University of Leipzig, D-04103 Leipzig, Germany
2 Department of Organic Chemistry, Faculty of Science, Menou®a University, Shebin El-Kom, Egypt
Summary. The synthesis of homochiral heterocyclic ꢀ-hydroxy acids starting from (S)- and
(R)-malic acid using hexa¯uoroacetone as protecting and activating agent is described. The new
compounds are useful building blocks for peptide and depsipeptide modi®cation.
Keywords. Hexa¯uoroacetone; Malic acid; Thiazoles; ꢀ-Hydroxy acids; Dipeptide and tripeptide
surrogates.
Introduction
ꢀ-Hydroxy acids, besides ꢀ-amino acids and carbohydrates, belong to the most
important representatives of low molecular compounds of the naturally occurring
chiral pool [1]. Although the chemistry of ꢀ-hydroxy acids never has gained the
popularity of that of ꢀ-amino acids, they are of eminent importance because of
their diversity of biological functions [2, 3].
They play a major part in the metabolism of human beings, animals (citric acid
cycle [4]), plants, and microorganisms (glyoxylate cycle [5]), in the gluconeogen-
esis [6], as metabolites in the CO2-®xing process of C4 plants (Hatch-Slack cycle
[7]), and as intermediates in the biogenesis of certain amino acids [3]. Pantoinic
acid is a constituent of the vitamin pantothenic acid and of coenzym A, respec-
tively [8]. Furthermore, ꢀ-hydroxy acids have been identi®ed as substructures of
molecular transport systems for metals [9]. Blespharismon acts as conjugation
hormon of ciliates (Blespharisma japonica); the ꢀ-hydroxy group is essential for
the hormon activity [10]. ꢀ-Hydroxy acids can be found not only as constituents of
natural products, like depsipeptides [11], but are also present as substructures in
man-made biologically active compounds like spasmolytica [12], pesticides [13],
and insecticides [14].
Heterocyclic compounds, especially thiazol derivatives, exhibit a broad range
of biological activities. The thiazol substructure is present in numerous natural
Ã
Corresponding author. E-mail: burger@organic.chemie.uni-leipzig.de

42
K. Burger et al.
products, drugs, and pesticides [15]. Some of the natural occurring thiazol deriva-
tives exhibiting antibiotic activity are amino acids. As the ®rst representative of this
class of compounds, 3-amino-3-(thiazol-2-yl)propanoic acid was isolated from the
antibioticbottromycin ( Streptomyces bottropensis).
Naturally occurring thiazol-substituted hydroxy acids, like 4-amino-4-(4-
carboxythiazol-2-yl)-2-hydroxybutanoic acid, isolated from the macrocycle noshi-
heptid, are rare [17]. 3-(Thiazol-4-yl)-lactic acid derivatives are unknown to the
best of our knowledge. Subsequently, we report on a new, preparatively simple,
stereoconservative access to this class of compounds starting from (S)- and (R)-
malicacid.
Results and Discussion
We found that a recently described protection/activation concept for the regio-
selective functionalization of multifunctional ꢀ-amino acids [18] can also be ap-
plied to ꢀ-hydroxy acids. Upon reaction with hexa¯uoroacetone, ꢀ-hydroxy acids
give 2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-ones in good to excellent yields [19].
In only one step, protection of both the ꢀ-hydroxy and the adjacent carboxy group
can be achieved. Concomitantly, the ꢀ-carboxy group is activated towards
nucleophiles. The new methodology tolerates a variety of functional groups in the
side chain, e.g. the !-carboxy groups of malic and citramalic acid remain
Scheme 1

Homochiral Heterocyclic ꢀ-Hydroxy Acids
43
unchanged and can be selectively derivatized [20]. On exclusion of moisture the
dioxolan-4-ones are stable at room temperature for weeks; in a refrigerator, they
can be stored for months.
Compounds of type 2 can be applied for a regioselective functionalization of
the ꢀ-carboxy function. Since protection and activation or funtionalization and
deblocking of the hydroxy group can be achieved in each case in one step, the
new strategy offers a save of steps compared to conventional strategies. Therefore,
compounds of type 2 represent new versatile syntheticintermediates.
Upon heating with thionyl chloride, compound 2 is transformed into the
acid chloride 3 [20]. By this operation the position of highest electrophilicity is
transferred from the ꢀ- to the !-carboxy group. Compound 3 represents a doubly
activated malic acid derivative with two centers of different reactivity towards
nucleophiles. Consequently, a new preparatively simple method for ef®cient regio-
selective derivatization of ꢀ,!-dicarboxylic acids is now available [21].
Compounds of type 3 exhibit the typical reactivity pattern of an acid chloride.
Reaction with diazomethane affords the corresponding diazoketone (3 ! 4). Treat-
ment of 4 with conc. HBr leads to bromoketone 5 which offers a general access to
heterocyclic ꢀ-hydroxy acids and their derivatives via a Hantzsch reaction [22].
Acetone proved to be the best solvent for the reaction of 5 with thioamides
and thioureas. When the compounds are heated in acetone, the hydrobromides 6
crystallize after a short induction period. Upon stirring in a two-phase system
(aqueous NaHCO3/ether) the thiazolium salts were transformed into the thiazoles
(6 ! 7). By this work-up procedure the 2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-
ones 7 are obtained in high purity. The structure of the new compounds was proved
by IR and NMR spectroscopy. An IR absorption in the region of 1865±1840 cmÀ1
unequivocally reveals the presence of a lactone moiety, whereas the 13C NMR
spectra show resonance signals for an unchanged dioxolan-4-one and the newly
formed thiazole ring system. Exemplary, the 13C NMR chemical shifts of 7d
(Scheme 2) are presented because of its structural similarity with the antiin-
¯ammatory drug Myalex1 ((2-(4-chlorophenyl)-thiazol-4-yl)-acetic acid, [23]).
Because of the presence of a centre of chirality at C-5, the geminal tri-
¯uoromethyl groups are diastereotopic. They resonate as two quartets with a
4
coupling constant of J ˆ 9 Hz in the region of À2 to À4 ppm. Compounds 7 are
synthetically valuable multifunctional building blocks, because they are hydroxy
group protected, carboxy activated, homochiral heterocyclic ꢀ-hydroxy acid
derivatives.
Scheme 2. 13C chemical shifts (ꢁ/ppm) of 7d

44
K. Burger et al.
Scheme 3
In Scheme 3, some synthetically useful reactions of 7 are shown. Deprotection
to ꢀ-hydroxy acids 8 can be achieved by heating in THF/water at 40ꢀC. Esters
9 were obtained in nearly quantitative yield on heating with an excess of the
corresponding alcohol. Reaction of 7 with ammonia, amines, and hydroxyl amine
at room temperature provides ready access to amides 10 and hydroxamicacids 11.
Because of their broad spectrum of biological activities, the development of new
synthetic routes to hydroxamic acid derivatives is of current interest [24±27];
peptide hydroxamicacid derivatives have been applied as enzyme inhibitors and
metal chelating agents [28].
Aminolytic ring opening reaction of the lactones occurs ef®ciently when the
resulting products are poorly soluble in the solvent used and therefore crystallize
spontaneously. The compounds obtained are analytically pure in most cases; the
progress of the reaction can be readily monitored by 19F NMR spectroscopy.

Homochiral Heterocyclic ꢀ-Hydroxy Acids
45
All reaction steps starting from compound 1 studied so far were found to occur
stereoconservatively. Consequently, the corresponding compounds of the (R)-series
are obtainable by the same syntheticrepertoire starting from ( R)-malicaicd.
(S)- and (R)-con®gurated heterocyclic ꢀ-hydroxy acids and their derivatives, now
readily available, are an interesting class of compounds per se because some of
them are biologically active. On the other hand they are promising building blocks
for the construction of peptidomimetics.
From the reaction of 7 with (S)-Phe-OMe, besides the expected compound 12
also the symmetrical diketopiperazine was obtained. To get satisfactory yields of
12, an excess of (S)-Phe-OMe has to be added. Diketopiperazine formation can be
avoided when the tertiary butylesters, benzylesters, or amides of the corresponding
amino acids are used. When 7 was reacted with (S)-benzyl prolinate, after peptide
bond formation a subsequent intramolecular transesterifacation could be observed.
The structural assignment of the newly formed compounds 13 is based on their IR
as well as 1H and 13C NMR data. The IR spectra show two absorptions at 1730 and
Scheme 4

46
K. Burger et al.
1685 cmÀ1, which we assign to a lactone and a lactame function. An absorption for
an OH moiety could not be detected. The resonance signal for the methine proton
(ꢁ ˆ 5.5 ppm) was found in the same region as in the starting material, whereas in
the 13C spectrum the resonance absorption of the methine carbon was shifted
down®eld to ꢁ ˆ 77±78 ppm. Furthermore, from the 13C NMR spectra a pyrrolidine
and a thiazol substructure can be extracted. The reason for the readily formed
six-membered ring system is the low barrier of the cis/trans isomerization of the
amide bond in the case of proline [29]. The development of new routes to chiral
pyrrolidine derivatives is of current interest, because they are present as substruc-
tures in natural products as well as in a series of drugs [30, 31].
With methoxy carbonyl hydrazine, compounds 7 react to give azaglycine
derivatives 14 [31]. On treatment of a solution of 7 in ether with a slight excess of
hydrazine hydrate, the hydrazides 15 crystallize spontaneously. Compounds 15
react readily with isocyanates derived from amino acids, e.g. benzyl 2-isocyanato-
propionate, to give tripeptidomimetics 16 which contain three different types of
monomers: ꢀ-hydroxy acids, azaamino acids, and ꢀ-amino acids.
The design of compounds in which noncovalent forces stabilize secondary
structures is an area of peptidomimetic chemistry of current interest [33, 34]. Two
strategies have been developed so far. A series of oligomers has been synthesized,
like ꢂ-peptides [35, 36], sulfonyl peptides [37], and peptoids [38] consisting of
only one type of monomer. On the other hand, a growing number of reports deals
with the synthesis of structured peptidomimetic compounds built from two or
more types of monomers [39]. Gellman et al. have recently prepared ꢂ-peptide/
depsipeptide hybrides that adopt antiparallel ꢂ-sheet structures [40]. Sewaldet al.
studied the in¯uence of the replacement of one ꢀ-amino acid by its ꢂ-homo
analogue on the secondary structure of cyclopeptides and found that they can act as
ꢃ-turn-mimetics [41].
The described synthetic sequence is well suited for the construction of libraries
of small peptide surrogates [42] consisting of two or three types of monomers,
respectively. Studies of secondary structure phenomena of peptidomimetics
containing the new motifs and their ability to act as metal chelating agents will
be reported elsewhere.
Experimental
General
Solvents were puri®ed and dried prior to use. Reagents were used as purchased. Melting points
21
(uncorrected) were determined on a Boetius heating table. Optical rotation indices ꢁ‰ꢀŠ † were
D
measured with a Polartronic polarimeter (Schmidt & Haensch) in a 5 cm cell. For C,H,N analyses a
CHNO-Rapid-Elemental-Analyser (Hereaus) was used; for all compounds, satisfactory elemental
analyses were obtained. Mass spectra were recorded on a VG 12-250 (Masslab) electron ionization
spectrometer (EI ˆ 70 eV) or by GC/MS on a HP5890 MSD. IR spectra were obtained using a
Specord spectrometer (Carl-Zeiss, Jena). 1H (200.041 or 300.075 MHz), 13C (50.305 or 75.462
MHz), and 19F NMR (188.205 or 282.33 MHz) spectra were recorded on a Varian Gemini 200 or a
1
Varian Gemini 300 spectrometer. TMS was used as reference standard for H and 13C NMR spectra
(internal), TFA for 19F NMR spectra (external). Flash chromatography was performed using silica gel
(32±63 ꢄm).

Homochiral Heterocyclic ꢀ-Hydroxy Acids
47
((5S)-2,2-Bis-(tri¯uoromethyl)-4-oxo-1,3-dioxolan-5-yl)-acetic acid (2; C7H4F6O5)
For data, see Ref. [20].
((5S)-2,2-Bis-(tri¯uoromethyl)-4-oxo-1,3-dioxolan-5-yl)-acetyl chloride (3; C7H3ClF6O4)
For data, see Ref. [20].
(5S)-5-(3-Diazo-2-oxopropyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one (4; C8H4F6N2O4)
To a stirred solution of diazomethane (15.0 mmol) in diethyl ether (10 cm3), 3 (1.50 g, 5.0 mmol) in
diethyl ether (10 cm3) was slowly added with cooling (0ꢀC). Then the solvent was evaporated in
vacuo to give yellow crystals.
21
D
1
Yield: 92% (1.41 g); m.p.: 45ꢀC; ‰ꢀŠ ˆ À50:0 (c ˆ 1.0, CHCl3); H NMR (CDCl3): ꢁ ˆ 2.85
(dd, J ˆ 7.5 Hz, J ˆ 16 Hz, 1H, CH2), 2.98 (dd, J ˆ 3 Hz, J ˆ 16 Hz, 1H, CH2), 5.17 (dd, J ˆ 3 Hz,
J ˆ 7.5 Hz, 1H, CHO), 5.41 (s, 1H, CHˆN2) ppm; 13C NMR (CDCl3): ꢁ ˆ 41.2 (CH2), 56.2
(CHˆN2), 71.6 (CHO), 97.9 (sept, J ˆ 36 Hz, C(CF3)2), 119.0 (q, J ˆ 287 Hz, CF3), 119.8 (q,
J ˆ 289 Hz, CF3), 167.8 (CˆOlactone), 187.0 (CˆOketone) ppm; 19F NMR (CDCl3): ꢁ ˆ À2.22 (q,
J ˆ 6 Hz, 3F, CF3), À2.06 (q, J ˆ 6 Hz, 3F, CF3) ppm; IR (KBr): ꢅ ˆ 2120, 1845, 1630 cmÀ1; MS
‡
‡
‡
‡
‡
(EI): m/z ˆ 306 [M] , 278 [M±N2] , 265 [M±CHN2] , 237 [M±CF3] , 69 [CF3] , 55
‡
‡
[C3H3O] , 28 [CO]
.
(5S)-5-(3-Bromo-2-oxopropyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one (5; C8H5BrF6O4)
To a stirred solution of diazoketone 4 (3.59 g, 10.0 mmol) in THF (25 cm3) at À30ꢀC, conc. HBr
(7 cm3) was added dropwise. After gas formation ceased, the mixture was warmed up to 0ꢀC and the
solvents and the HBr were evaporated in vacuo. The residue was dissolved in CH2Cl2 (100 cm3),
washed with cold NaHCO3 solution, and dried over MgSO4. The solvent was evaporated in vacuo
and the residue was subjected to column chromatography (eluent: CHCl3 : hexane ˆ 8:1) and
recrystallized from CHCl3/pentane.
21
D
1
Yield: 81% (2.91 g); m.p.: 56ꢀC; ‰ꢀŠ ˆ À23:6 (c ˆ 1.1, CHCl3); H NMR (CDCl3): ꢁ ˆ 3.26
(dd, J ˆ 7 Hz, J ˆ 18 Hz, 1H, CH2), 3.43 (dd, J ˆ 4 Hz, J ˆ 18 Hz, 1H, CH2), 3.95 (s, 2H, CH2Br),
5.12 (dd, J ˆ 4 Hz, J ˆ 7 Hz, 1H, CHO) ppm; 13C NMR (CDCl3): ꢁ ˆ 33.0 (CH2Br), 40.8 (CH2), 70.9
(CHO), 97.9 (sept, J ˆ 36 Hz, C(CF3)2), 119.0 (q, J ˆ 287 Hz, CF3), 119.6 (q, J ˆ 289 Hz, CF3),
167.4 (CˆOlactone), 195.7 (CˆOketone) ppm; 19F NMR (CDCl3): ꢁ ˆ À2.31 (q, J ˆ 7 Hz, 3F, CF3),
À1.98 (q, J ˆ 7 Hz, 3F, CF3) ppm; IR (KBr): ꢅ ˆ 1845, 1740 cmÀ1; MS (EI): m/z ˆ 360 [M ‡ H] ,
‡
‡
‡
‡
265 [M±CH2Br] , 122 [CH2BrCO] , 99 [M±HFA, ±CH2Br] .
(5S)-5-(Thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-ones (7); general procedure
To a stirred solution of 5 (1.79 g, 5.0 mmol) in acetone (5 cm3) at 50ꢀC a solution of the cor-
responding thioamide or N,N-disubstituted thiourea (5.0 mmol) in acetone (5 cm3) was added
dropwise. After 3 h the solvent was evaporated in vacuo, and the residue was suspended in diethyl
ether (50 cm3) and washed with ice-cold NaHCO3 solution. The aqueous phase was extracted with
diethyl ether (3x). The combined organic layers were washed with ice cold H2O (3x) and dried over
MgSO4. The solvent was evaporated in vacuo, and the residue was recrystallized from CHCl3/hexane.
(5S)-5-(Thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one (7a; C9H5F6NO3S)
5 (1.80 g, 5.0 mmol) was reacted with thioformamide (0.31 g, 5.0 mmol) in acetone (10 cm3). Yield:
21
D
39% (0.63 g); oil; ‰ꢀŠ ˆ À76:1 (c ˆ 0.4, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 3.34 (dd, J ˆ 7.5 Hz,
J ˆ 15.5 Hz, 1H, CH2), 3.53 (dd, J ˆ 4.5 Hz, J ˆ 15.5 Hz, 1H, CH2), 5.15 (dd, J ˆ 4.5 Hz, J ˆ 7.5 Hz,

48
K. Burger et al.
1H, CHO), 7.21 (d, J ˆ 2 Hz, 1H, (C-5)Hthiazol), 8.82 (d, J ˆ 2 Hz, 1H, (C-2)Hthiazol) ppm; 13C NMR
(CDCl3): ꢁ ˆ 33.1 (CH2), 74.3 (CH), 97.7 (sept, J ˆ 36 Hz, C(CF3)2), 117.3 (C-5thiazol), 118.8 (q,
J ˆ 287 Hz, CF3), 119.7 (q, J ˆ 289 Hz, CF3), 149.2 (C-4thiazol), 153.9 (C-2thiazol), 167.2 (C ˆ
Olactone) ppm; 19F NMR (CDCl3): ꢁ ˆ À3.32 (s, (CF3)2) ppm; IR (®lm): ꢅ ˆ 1845 cmÀ1; MS (EI):
‡
‡
‡
.
m/z ˆ 321 [M] , 98 [C4H4NS] , 69 [CF3]
(5S)-5-(2-(4-Methylphenyl)-1,3-thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one
(7b; C16H11F6NO3S)
5 (1.80 g, 5.0 mmol) was reacted with 4-methylthiobenzamide (0.75 g, 5.0 mmol) in acetone
21
1
(10 cm3). Yield: 90% (1.85 g); m.p.: 55ꢀC; ‰ꢀŠ ˆ À44:4 (c ˆ 1.1, CHCl3); H NMR (CDCl3): ꢁ ˆ
D
2.38 (s, 3H, CH3), 3.29 (dd, J ˆ 7 Hz, J ˆ 15 Hz, 1H, CH2), 3.49 (dd, J ˆ 5 Hz, J ˆ 15 Hz, 1H, CH2),
5.19 (dd, J ˆ 5 Hz, J ˆ 7 Hz, 1H, CHO), 7.04 (s, 1Hthiazol), 7.23 (m, 2H, arom), 7.84 (m, 2H, arom)
ppm; 13C NMR (CDCl3): ꢁ ˆ 21.4 (CH3), 33.7 (CH2), 74.4 (CHO), 97.6 (sept, J ˆ 36 Hz, C(CF3)2),
116.2 (C-5thiazol), 118.8 (q, J ˆ 288 Hz, CF3), 119.7 (q, J ˆ 289 Hz, CF3), 126.5 (C-2tolyl), 129.7
(C-3tolyl), 138.7 (C-4tolyl), 144.7 (C-1tolyl), 149.2 (C-4thiazol), 167.3, 169.0 (C ˆ Olactone, C-2thiazol
)
ppm; 19F NMR (CDCl3): ꢁ ˆ À2.23 (s, (CF3)2) ppm; IR (CHCl3): ꢅ ˆ 1840 cmÀ1; MS (EI): m/z ˆ
‡
‡
‡
‡
‡
411 [M] , 363 [M±F, ±CO] , 342 [M±CF3] , 188 [M±HFA, ±COCHO] , 118 [CH3C6H4CNH] .
(5S)-5-(2-(4-Fluorophenyl)-1,3-thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one
(7c; C15H8F7NO3S)
5 (1.80 g, 5.0 mmol) was reacted with p-¯uorothiobenzamide (0.77 g, 5.0 mmol) in acetone (10 cm3).
21
D
1
Yield: 95% (1.97 g); m.p.: 58ꢀC; ‰ꢀŠ ˆ À11:0 (c ˆ 1.0, CHCl3); H NMR (CDCl3): ꢁ ˆ 3.47 (dd,
J ˆ 6 Hz, J ˆ 16 Hz, 1H, CH2), 3.61 (dd, J ˆ 5 Hz, J ˆ 16 Hz, 1H, CH2), 5.56 (dd, J ˆ 5 Hz, J ˆ 6 Hz,
1H, CHO), 7.24 (dd, J ˆ 9 Hz, J ˆ 9 Hz, 2H, arom), 7.97 (s, 1Hthiazol), 8.00 (dd, J ˆ 5 Hz, J ˆ 9 Hz,
2H, arom) ppm; 13C NMR (CDCl3): ꢁ ˆ 33.4 (CH2), 75.3 (CHO), 98.0 (sept, J ˆ 36 Hz, C(CF3)2),
116.8 (d, J ˆ 22 Hz, C-3¯uorophenyl), 118.1 (C-5thiazol), 119.8 (q, J ˆ 286 Hz, CF3), 120.8
(q, J ˆ 289 Hz, CF3), 129.2 (d, J ˆ 9 Hz, C-2¯uorophenyl), 130.8 (d, J ˆ 3 Hz, C-1¯uorophenyl), 150.7
(C-4thiazol), 164.7 (d, J ˆ 249 Hz, C-4¯uorophenyl), 167.5, 168.0 (CˆOlactone, C-2thiazol) ppm; 19F NMR
(CDCl3): ꢁ ˆ À33.79 (tt, J ˆ 5 Hz, J ˆ 10 Hz, 1F¯uorophenyl), À3.66 (q, J ˆ 9 Hz, 3F, CF3), À3.47 (q,
J ˆ 9 Hz, 3F, CF3) ppm; IR (KBr): ꢅ ˆ 1855 cmÀ1; MS (EI): m/z ˆ 415 [M] , 346 [M±CF3] , 192
‡
‡
‡
‡
‡
[M±HFA, ±COCHO] , 122 [FC6H4CNH] , 71 [CH2COCHO] .
(5S)-5-(2-(4-Chlorophenyl)-1,3-thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one
(7d; C15H8ClF6NO3S)
5 (1.80 g, 5.0 mmol) was reacted with p-chlorothiobenzamide (0.85 g, 5.0 mmol) in acetone (10 cm3).
21
D
1
Yield: 90% (1.94 g); m.p.: 61ꢀC; ‰ꢀŠ ˆ À32:9 (c ˆ 1.0, CHCl3); H NMR (acetone-d6): ꢁ ˆ 3.48
(ddd, J ˆ 0.5 Hz, J ˆ 6 Hz, J ˆ 15.5 Hz, 1H, CH2), 3.62 (ddd, J ˆ 0.5 Hz, J ˆ 5.5 Hz, J ˆ 15.5 Hz, 1H,
CH2), 5.59 (dd, J ˆ 5.5 Hz, J ˆ 6 Hz, 1H, CHO), 7.50 (m, 2H, arom), 7.94 (m, 2H, arom), 7.97 (s,
1Hthiazol) ppm; 13C NMR (acetone-d6): ꢁ ˆ 33.4 (CH2), 75.3 (CHO), 98.0 (sept, J ˆ 36 Hz, C(CF3)2),
118.6 (C-5thiazol), 119.8 (q, J ˆ 286 Hz, CF3), 120.8 (q, J ˆ 290 Hz, CF3), 128.5, 130.0, 133.0, 136.4
(C, arom), 150.9 (C-4thiazol), 167.3, 168.0 (C-2thiazol, CˆOlactone) ppm; 19F NMR (acetone-d6):
ꢁ ˆ À3.49 (m, 6F, (CF3)2) ppm; IR (KBr): ꢅ ˆ 1860 cmÀ1; MS (EI): m/z ˆ 432 [M] , 363 [M±
‡
‡
‡
‡
‡
CF3] , 71 [CH2COCHO] , 69 [CF3] , 28 [CO] .
(5S)-5-(2-(2-Furyl)-1,3-thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one
(7e; C13H7F6NO4S)
5 (1.80 g, 5.0 mmol) was reacted with furan-2-thiocarboxamide (0.64 g, 5.0 mmol) in acetone
21
(10 cm3). Yield: 65% (1.26 g); oil; ‰ꢀŠ ˆ À46:9 (c ˆ 1.0, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 3.28 (dd,
D

Homochiral Heterocyclic ꢀ-Hydroxy Acids
49
J ˆ 8 Hz, J ˆ 15 Hz, 1H, CH2), 3.48 (dd, J ˆ 4.5 Hz, J ˆ 15 Hz, 1H, CH2), 5.18 (dd, J ˆ 4.5 Hz,
J ˆ 8 Hz, 1H, CHO), 6.53 (m, 1Hfuran), 6.99 (m, 1Hfuran), 7.06 (s, 1Hthiazol), 7.50 (m, 1Hfuran) ppm;
13C NMR (CDCl3): ꢁ ˆ 33.5 (CH2), 74.1 (CHO), 97.5 (sept, J ˆ 36 Hz, C(CF3)2), 109.4, 112.2
(Cfuran), 116.0 (C-5thiazol), 118.7 (q, J ˆ 287 Hz, CF3), 119.5 (q, J ˆ 289 Hz, CF3), 143.8, 148.8
(Cfuran), 149.2 (C-4thiazol), 158.6 (C-2thiazol), 167.1 (CˆOlactone) ppm; 19F NMR (CDCl3): ꢁ ˆ À3.25
‡
‡
(m, 6F, (CF3)2) ppm; IR (CHCl3): ꢅ ˆ 1845 cmÀ1; MS (EI): m/z ˆ 387 [M] , 368 [M±F] , 318 [M±
‡
‡
.
CF3] , 71 [CH2COCHO]
(5S)-5-(2-(2-Thienyl)-1,3-thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-one
(7f; C13H7F6NO3S2)
5 (1.80 g, 5.0 mmol) was reacted with thiophene-2-thiocarboxamide (0.72 g, 5.0 mmol) in acetone
21
1
(10 cm3). Yield: 88% (1.77 g); oil; ‰ꢀŠ ˆ À39:9 (c ˆ 1.0, CHCl3); H NMR (CDCl3): ꢁ ˆ 3.25
D
(dd, J ˆ 7.5 Hz, J ˆ 15 Hz, 1H, CH2), 3.44 (ddd, J ˆ 0.5 Hz, J ˆ 4.5 Hz, J ˆ 15 Hz, 1H, CH2), 5.16
(dd, J ˆ 4.5 Hz , J ˆ 7.5 Hz, 1H, CHO), 6.98 (s, br, 1Hthiazol), 7.04 (m, 1Hthiophene), 7.36 (m,
1Hthiophene), 7.48 (m, 1Hthiophene) ppm; 13C NMR (CDCl3): ꢁ ˆ 33.4 (CH2), 74.1 (CHO), 97.5
(sept, J ˆ 36 Hz, C(CF3)2), 115.9 (C-5thiazol), 118.7 (q, J ˆ 287 Hz, CF3), 119.6 (q, J ˆ 289 Hz, CF3),
126.8, 127.8, 127.9, 136.9 (Cthiophene), 148.9 (C-4thiazol), 162.2 (C-2thiazol), 167.1 (CˆOlactone) ppm;
19F NMR (CDCl3): ꢁ ˆ À3.25 (q, J ˆ 7 Hz, 3F, CF3), À3.19 (q, J ˆ 7 Hz, 3F, CF3) ppm; IR
‡
‡
(CHCl3): ꢅ ˆ 1845 cmÀ1; MS (GC/EI): m/z ˆ 403 [M] , 180 [M±HFA, ±CO, ±CHO] , 71
‡
[CH2COCHO]
.
(5S)-5-(2-(4-Methylphenyl)-4-tri¯uoromethyl-2-50-bisthiazolyl-4-ylmethyl)-2,2-bis-
(tri¯uoromethyl)-1,3-dioxolan-4-one (7g; C20H11F9N2O3S2)
5 (1.80 g, 5.0 mmol) was reacted with 4-methylphenyl-4-tri¯uoromethyl-thiazol-5-thiocarbox-
21
amide (1.51 g, 5.0 mmol) in acetone (10 cm3). Yield: 96% (2.70 g); m.p.: 71ꢀC; ‰ꢀŠ ˆ À30:0
D
(c ˆ 0.9, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 2.40 (s, 3H, CH3), 3.33 (dd, J ˆ 7 Hz, J ˆ 15 Hz, 1H, CH2),
3.50 (dd, J ˆ 5 Hz, J ˆ 15 Hz, 1H, CH2), 5.16 (dd, J ˆ 5 Hz, J ˆ 7 Hz, 1H, CHO), 7.26 (m, 2H,
arom), 7.29 (s, 1Hthiazol), 7.86 (m, 2H, arom) ppm; 13C NMR (CDCl3): ꢁ ˆ 21.5 (CH3), 33.1
(CH2), 74.1 (CHO), 97.6 (sept, J ˆ 36 Hz, C(CF3)2), 118.7 (q, J ˆ 287 Hz, CF3), 119.6 (q,
J ˆ 289 Hz, CF3), 120.0 (C-5thiazol), 120.6 (CF3 thiazol), 126.7, 129.4, 129.8 (Ctolyl), 132.8 (q,
J ˆ 2 Hz, C-5thiazol), 140.1 (q, J ˆ 37 , C-4thiazol), 142.0 (Ctolyl), 149.3 (C-4thiazol), 155.4 (C-2thiazol),
167.0, 168.9 (CˆOlactone, C-2thiazol) ppm; 19F NMR (CDCl3): ꢁ ˆ À2.17 (s, br, 6F, (CF3)2), 18.65
‡
(3F, CF3 thiazol) ppm; IR (KBr): ꢅ ˆ 1855 cmÀ1; MS (EI): m/z ˆ 562 [M] , 339 [M±HFA, ±CO,
‡
±CHO] .
(5S)-5-(2-(N-Methyl-N-phenylamino)-1,3-thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-
1,3-dioxolan-4-one (7h; C16H12F6N2O3S)
5 (1.80 g, 5.0 mmol) was reacted with N-methyl-N-phenyl-thiourea (0.89 g, 5.0 mmol) in acetone
21
(10 cm3). Yield: 60% (1.28 g); oil; ‰ꢀŠ ˆ À27:0 (c ˆ 1.1, CHCl3); 1H NMR (CDCl3): ꢁ ˆ 3.08 (dd,
D
J ˆ 7 Hz, J ˆ 15 Hz, 1H, CH2), 3.23 (dd, J ˆ 4.5 Hz, J ˆ 15 Hz, 1H, CH2), 3.49 (s, 3H, NCH3), 5.09
(dd, J ˆ 4.5 Hz, J ˆ 7 Hz, 1H, CHO), 6.22 (s, 1Hthiazol), 7.25 (m, 1H, arom), 7.33±7.48 (m, 4H, arom)
ppm; 13C NMR (CDCl3): ꢁ ˆ 33.9 (CH2), 74.3 (NCH3), 97.6 (sept, J ˆ 36 Hz, C(CF3)2), 105.0
(C-5thiazol), 118.9 (q, J ˆ 287 Hz, CF3), 119.8 (q, J ˆ 290 Hz, CF3), 125.0, 126.6, 129.8, 144.8 (C,
arom), 146.2 (C-4thiazol), 167.6 (CˆOlactone), 170.4 (C-2thiazol) ppm; 19F NMR (CDCl3): ꢁ ˆ À3.19
(q, J ˆ 8 Hz, 3F, CF3), À2.97 (q, J ˆ 8 Hz, 3F, CF3) ppm; IR (Film): ꢅ ˆ 2940, 1845 cmÀ1; MS (EI):
‡
‡
‡
‡
m/z ˆ 426 [M] , 349 [M±C6H5] , 334 [349-CH3] , 91 [C7H7] .

50
K. Burger et al.
Hydrolysis of 5-(Thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-ones (8);
general procedure
7 (2.0 mmol) was heated under re¯ux for 3 h in a mixture of THF/H2O or diethylether/H2O
(25 cm3, 1:1). After removal of the solvent the residue was dissolved in CH2Cl2, washed with H2O
and dried over MgSO4. The solvent was evaporated in vacuo and the residue recrystallized from
acetone.
3-(2-(4-Fluorophenyl)-1,3-thiazol-4-yl)-(S)-lactic acid (8a; C12H10FNO3S)
7c (0.83 g, 2.0 mmol) was heated in a THF/H2O mixture. Yield: 60% (0.32 g); m.p.: 112ꢀC;
21
D
‰ꢀŠ ˆ À7:0 (c ˆ 1.0, CHCl3); 1H NMR (acetone-d6): ꢁ ˆ 3.16 (dd, J ˆ 7.5 Hz, J ˆ 15 Hz, 1H, CH2),
3.33 (ddd, J ˆ 1 Hz, J ˆ 4 Hz, J ˆ 15 Hz, 1H, CH2), 4.63 (dd, J ˆ 4 Hz, J ˆ 7.5 Hz, 1H, CHO), 7.26
(m, 2H, arom), 7.33 (s, br, 1Hthiazol), 8.02 (m, 2H, arom) ppm; 13C NMR (acetone-d6): ꢁ ˆ 36.7
(CH2), 70.4 (CHO), 116.7 (d, J ˆ 22 Hz, C, arom), 116.7 (C-5thiazol), 129.2 (d, J ˆ 9 Hz, C, arom),
131.1 (C, arom), 154.8 (C-4thiazol), 164.5 (d, J ˆ 249 Hz, C, arom), 166.6 (C-2thiazol), 175.1
(CˆOacid) ppm; 19F NMR (CDCl3): ꢁ ˆ À3.19 (m) ppm; IR (KBr): ꢅ ˆ 3700±2300, 3530, 3510,
‡
‡
‡
1720, 1600, 1520 cmÀ1; MS (EI): m/z ˆ 267 [M] , 222 [M±CO2H] , 192 [222±CHOH] , 71
‡
‡
[CH2COCHO] , 45 [CO2H] .
3-(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)-(S)-lactic acid (8b; C12H10ClNO3S)
7d (0.86 g, 0.2 mmol) was heated in a THF/H2O mixture. Yield: 88% (0.50 g); m.p.: 116ꢀC;
21
D
‰ꢀŠ ˆ À43:9 (c ˆ 1.0, acetone); 1H NMR (acetone-d6): ꢁ ˆ 3.16 (ddd, J ˆ 0.5 Hz, J ˆ 7.5 Hz,
J ˆ 14.5 Hz, 1H, CH2), 3.34 (ddd, J ˆ 0.5 Hz, J ˆ 4.5 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.63 (dd,
J ˆ 4.5 Hz, J ˆ 7.5 Hz, 1H, CHO), 7.37 (s, br, 1Hthiazol), 7.51 (m, 2H, arom), 7.97 (m, 2H, arom)
ppm; 13C NMR (acetone-d6): ꢁ ˆ 36.8 (CH2), 70.5 (CHO), 117.1 (C-5thiazol), 128.6, 130.0, 133.3,
136.1 (C, arom), 155.0 (C-4thiazol), 166.4 (C-2thiazol), 175.2 (CˆOacid) ppm; IR (KBr): ꢅ ˆ 3400±
‡
‡
2700, 1730, 1600, 1530, 1500 cmÀ1; MS (EI): m/z ˆ 284 [M] , 239 [M±CO2H] , 209 [239-
‡
‡
‡
CHOH] , 71 [CH2COCHO] , 45 [CO2H] .
3-(2-(2-Furyl)-1,3-thiazol-4-yl)-(S)-lactic acid (8c; C10H9NO4S)
7e (0.77 g, 2.0 mmol) was heated in a diethyl ether/H2O mixture. Yield: 79% (0.38 g); m.p.: 167ꢀC;
21
D
1
‰ꢀŠ ˆ À27:7 (c ˆ 1.3, DMSO); H NMR (DMSO-d6): ꢁ ˆ 2.94 (dd, J ˆ 8.5 Hz, J ˆ 14.5 Hz, 1H,
CH2), 3.12 (dd, J ˆ 4.5 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.35 (dd, J ˆ 4.5 Hz, J ˆ 8.5 Hz, 1H, CHO), 5.41
(s, br, 1H, OH), 6.68 (m, 1Hfuran), 7.04 (m, 1Hfuran), 7.35 (s, 1Hthiazol), 7.85 (m, 1Hfuran) ppm; 13C
NMR (DMSO-d6): ꢁ ˆ 35.8 (CH2), 69.3 (CHO), 108.7, 112.4 (Cfuran), 115.2 (C-5thiazol), 144.5
(Cfuran), 153.9 (C-4thiazol), 156.1 (C-2thiazol), 160.1 (Cfuran), 174.9 (C ˆ Oacid) ppm; IR (KBr):
ꢅ ˆ 3600±3200, 3124, 1720, 1513 cmÀ1; MS (EI): m/z ˆ 240 [M ‡ H] , 208 [M±H2O,±OH] , 194
‡
‡
‡
‡
[M±CO2H] , 154 [M±C4H3O, ±H2O] .
3-(2-(2-Thienyl)-1,3-thiazol-4-yl)-(S)-lactic acid (8d; C10H9NO3S2)
7f (0.81 g, 2.0 mmol) was heated in a diethyl ether/H2O mixture. Yield: 63% (0.32 g); m.p.: 162ꢀC;
21
D
1
‰ꢀŠ ˆ À34:9 (c ˆ 0.4, acetone); H NMR (DMSO-d6): ꢁ ˆ 2.94 (dd, J ˆ 8.5 Hz, J ˆ 14.5 Hz, 1H,
CH2), 3.12 (ddd, J ˆ 1 Hz, J ˆ 4.5 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.36 (dd, J ˆ 4.5 Hz, J ˆ 8.5 Hz, 1H,
CHO), 7.14 (m, 1Hthiophene), 7.30 (s, br, 1Hthiazol), 7.60 (m, 1Hthiophene), 7.67 (m, 1Hthiophene) ppm;
13C NMR (DMSO-d6): ꢁ ˆ 35.9 (CH2), 69.4 (CHO), 115.4 (C-5thiazol), 126.8, 128.3, 128.4, 136.8
(Cthiophene), 153.5 (C-4thiazol), 160.0 (C-2thiazol), 175.0 (C=Oacid) ppm; IR (KBr): ꢅ ˆ 3600±3200,

Homochiral Heterocyclic ꢀ-Hydroxy Acids
51
‡
‡
‡
3130, 1710, 1510 cmÀ1; MS (EI): m/z ˆ 255 [M] , 210 [M±CO2H] , 180 [210-CHOH] , 71
‡
‡
[CH2COCHO] , 45 [CO2H] .
Alcoholysis of 5-(Thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-ones (7);
general procedure
A solution of 7 (2.0 mmol) in MeOH (25 cm3) was stirred under re¯ux for 3 h. After removal of the
solvent, the residue was distilled in vacuo.
Methyl 3-(2-(2-furyl)-1,3-thiazol-4-yl)-(S)-lactate (9a; C11H11NO4S)
21
7e (0.77 g, 2.0 mmol) was heated in MeOH. Yield: 99% (0.50 g); m.p.: 64ꢀC; ‰ꢀŠ ˆ À35:8 (c ˆ 1.1,
D
CHCl3); 1H NMR (CDCl3): ꢁ ˆ 3.18 (dd, J ˆ 7 Hz, J ˆ 15 Hz, 1H, CH2), 3.31 (dd, J ˆ 4 Hz, J ˆ 15 Hz,
1H, CH2), 3.76 (s, 3H, OCH3), 4.62 (dd, J ˆ 4 Hz , J ˆ 7 Hz, 1H, CHO), 6.50 (m, 1Hfuran), 6.95 (m,
1Hfuran), 7.01 (s, 1Hthiazol), 7.48 (m, 1Hfuran) ppm; 13C NMR (CDCl3): ꢁ ˆ 35.6 (CH2), 52.4 (OCH3),
70.1 (CHO), 109.0, 112.2 (Cfuran), 114.7 (C-5thiazol), 143.6, 148.8 (Cfuran), 152.7 (C-4thiazol), 157.9 (C-
2thiazol), 174.1 (CˆOester) ppm; IR (KBr): ꢅ ˆ 3100, 1725, 1590, 1530, 1500 cmÀ1; MS (EI): m/z ˆ 253
‡
‡
‡
‡
‡
‡
[M] , 235 [M±H2O] , 194 [M±CO2CH3] , 164 [194-CHOH] , 71 [CH2COCHO] , 45 [CO2H] .
Methyl 3-(2-(2-thienyl)-1,3-thiazol-4-yl)-(S)-lactate (9b; C11H11NO3S2)
21
7f (0.81 g, 2.0 mmol) was heated in MeOH. Yield: 91% (0.49 g); oil; ‰ꢀŠ ˆ À23:0 (c ˆ 2.0, CHCl3);
D
1H NMR (CDCl3): ꢁ ˆ 3.26 (dd, J ˆ 6.6 Hz, J ˆ 15 Hz, 1H, CH2), 3.31 (dd, J ˆ 4.5 Hz, J ˆ 15 Hz,
1H, CH2), 3.84 (s, 3H, OCH3), 4.65 (dd, J ˆ 4.5 Hz , J ˆ 6.6 Hz, 1H, CHO), 7.01 (s, 1Hthiazol), 7.10
(m, 1Hthiophene), 7.41 (m, 1Hthiophene), 7.54 (m, 1Hthiophene) ppm; 13C NMR (CDCl3): ꢁ ˆ 35.3 (CH2),
52.7 (OCH3), 70.2 (CHO), 114.8 (C-5thiazol), 127.0, 128.0, 128.1 (Cthiophene), 152.1 (C-4thiazol), 161.0
(C-2thiazol), 174.2 (CˆOester) ppm; IR (KBr): ꢅ ˆ 3500±3210, 3108, 2954, 1741, 1219 cmÀ1
;
‡
‡
‡
‡
MS (EI): m/z ˆ 269 [M] , 251 [M±H2O] , 210 [M±C2H2S, ±H] , 180 [M±CHOHCO2CH3] , 115
‡
[CH2CHOHCO2CH3]
.
Aminolysis of (5S)-5-(Thiazol-4-ylmethyl)-2,2-bis-(tri¯uoromethyl)-1,3-dioxolan-4-ones (7);
general procedure
MethodA : A solution of 7 (2 mmol) in diethyl ether (10 cm3) was reacted at room temperature with
an excess of the corresponding amine, hydroxylamine, hydrazine hydrate, or benzyl (S)-prolinate
under stirring. After a few minutes the product began to crystallize. After completion of the reaction
(19F NMR analysis) the precipitate was ®ltered off, washed with diethyl ether, and dried in vacuo.
MethodB : A solution of 7 (2.0 mmol) in diethyl ether (10 cm3) was reacted with an excess of the
corresponding amino acid ester (5.0 mmol) at room temperature under stirring. After the reaction
was complete (19F NMR analysis) the solvent was evaporated. The residue was dissolved in CH2Cl2,
washed with H2O (3x), and dried over MgSO4. After ®ltration the solvent was evaporated, and the
residue was recrystallized from hexane/CHCl3 or from diethyl ether (12c).
N-(3-(2-(4-Fluorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl)-benzylamine (10a; C19H17FN2O2S)
7c (0.83 g, 2.0 mmol) and benzylamine (0.21 g, 2.0 mmol) were reacted in diethyl ether (40 cm3).
21
D
1
Yield: 81% (0.58 g); m.p.: 135ꢀC; ‰ꢀŠ ˆ À69:3 (c ˆ 1.0, DMSO); H NMR (DMSO-d6): ꢁ ˆ 2.98
(dd, J ˆ 8.5 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH), 3.24 (dd, J ˆ 3.5 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH),
4.32 (d, J ˆ 6 Hz, 2H, CH2NH), 4.40 (dd, J ˆ 3.5 Hz, J ˆ 8.5 Hz, 1H, CHO), 5.80 (s, br, 1H, OH),
7.26 (m, 1Hthiazol, 7H, arom), 7.96 (m, 2H, arom), 8.41 (t, J ˆ 6 Hz, 1H, NH) ppm; 13C NMR

52
K. Burger et al.
(DMSO-d6): ꢁ ˆ 36.1 (CH2CHOH), 41.5 (CH2NH), 70.6 (CHO), 115.8 (C-5thiazol), 115.9 (d,
J ˆ 22 Hz, C, arom), 126.3, 126.9, 127.9 (C, arom), 128.0 (d, J ˆ 9 Hz, C, arom), 129.6 (d, J ˆ 3 Hz,
C, arom), 139.3 (C, arom), 154.2 (C-4thiazol), 162.8 (d, J ˆ 248 Hz, C, arom), 164.6 (C-2thiazol), 172.9
‡
(CˆOamide) ppm; IR (KBr): ꢅ ˆ 3330, 1645, 1510 cmÀ1, MS (EI): m/z ˆ 356 [M] , 265 [M±
‡
‡
‡
‡
C7H7] , 222 [M±C7H7,±CONH] , 193 [222-CHO] , 91 [C7H7] .
N-(3-(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl)-benzylamine (10b; C19H17ClN2O2S)
7d (0.86 g, 2.0 mmol) and benzylamine (0.21 g, 2.0 mmol) were reacted in diethyl ether (25 cm3).
21
D
1
Yield: 73% (0.54 g); m.p.: 141ꢀC; ‰ꢀŠ ˆ À63:4 (c ˆ 1.0, DMSO); H NMR (DMSO-d6): ꢁ ˆ 2.98
(dd, J ˆ 8 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH), 3.24 (dd, J ˆ 3.5 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH), 4.32
(d, J ˆ 6 Hz, 2H, CH2NH), 4.40 (dd, J ˆ 3.5 Hz, J ˆ 8 Hz, 1H, CHO), 5.77 (s, br, 1H, OH), 7.24 (m,
5H, arom), 7.38 (s, 1Hthiazol), 7.53 (m, 2H, arom), 7.92 (m, 2H, arom), 8.40 (t, J ˆ 6 Hz, 1H, NH)
ppm; 13C NMR (DMSO-d6): ꢁ ˆ 36.3 (CH2CHOH), 41.7 (CH2NH), 70.6 (CHO), 116.4 (C(5)thiazol),
126.5, 127.0, 127.5, 128.0, 129.1, 131.9, 134.4, 139.4 (C, arom), 154.5 (C-4thiazol), 164.5 (C-2thiazol),
173.0 (CˆOamide) ppm; IR (KBr): ꢅ ˆ 3290, 1650, 1550 cmÀ1; MS (EI): m/z ˆ 373 [M] , 239 [M±
‡
‡
‡
‡
‡
C7H7, ±CONH] , 210 [239-CHO] , 106 [C7H8N] , 91 [C7H7] .
3-(2-(2-Furyl)-1,3-thiazol-4-yl)-(S)-lactamide (10c; C10H10N2O3S)
7e (0.78 g, 2.0 mmol) was reacted with conc. NH3 (2 cm3) in diethyl ether (20 cm3). Yield: 83%
21
D
(0.40 g); m.p.: 130ꢀC; ‰ꢀŠ ˆ ‡ 200 (c ˆ 0.1, DMSO); 1H NMR (DMSO-d6): ꢁ ˆ 2.87 (dd, J ˆ 9 Hz,
J ˆ 14.5 Hz, 1H, CH2), 3.16 (dd, J ˆ 3.5 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.23 (dd, J ˆ 3.5 Hz, J ˆ 9 Hz,
1H, CHO), 5.58 (s, br, 1H, OH), 6.66 (m, 1Hfuran), 7.04 (m, 1Hfuran), 7.21 (s, 1Hthiazol), 7.32 (s, 2H,
NH2), 7.82 (m, 1Hfuran) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 36.2 (CH2), 70.5 (CHO), 108.7, 112.5
(Cfuran), 115.0 (C-5thiazol), 144.4, 148.4 (Cfuran), 154.6 (C-4thiazol), 156.0 (C-2thiazol), 175.7
‡
(CˆOamide) ppm; IR (KBr): ꢅ ˆ 3600±3000, 1635, 1520, 1500 cmÀ1; MS (EI): m/z ˆ 238 [M] ,
‡
194 [M±CONH2]
.
3-(2-(2-Thienyl)-1,3-thiazol-4-yl)-(S)-lactamide (10d; C10H10N2O2S2)
7f (0.81 g, 2.0 mmol) was reacted with conc. NH3 (2 cm3) in diethyl ether (20 cm3). Yield: 79%
21
D
(0.40 g); m.p.: 160ꢀC; ‰ꢀŠ ˆ À40:0 (c ˆ 1.0, DMSO); 1H NMR (DMSO-d6): ꢁ ˆ 2.85 (dd, J ˆ 9 Hz,
J ˆ 14.5 Hz, 1H, CH2), 3.12 (dd, J ˆ 3.6 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.22 (dd, J ˆ 3.6 Hz, J ˆ 9 Hz,
1H, CHO), 5.56 (m, 1H, OH), 7.18 (m, 1Hthiophene), 7.22 (s, 1Hthiazol), 7.31 (s, 2H, NH2), 7.67 (m,
2Hthiophene) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 36.8 (CH2), 71.2 (CHO), 115.9 (C-5thiazol), 127.4,
128.9, 129.0, 137.4 (Cthiophene), 154.8 (C-4thiazol), 160.5 (C-2thiazol), 176.3 (CˆOhydroxyamide) ppm; IR
‡
‡
(KBr): ꢅ ˆ 3600-3000, 1660 cmÀ1; MS (FAB): m/z ˆ 255 [M ‡ H] , 210 [M±CONH2] .
N-(3-(2-(4-Fluorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl)-hydroxylamine (11a; C12H11FN2O3S)
7c (0.83 g, 2.0 mmol) and hydroxylamine (0.33 g, 10.0 mmol) were reacted in diethyl ether (20 cm3).
21
D
1
Yield: 89% (0.50 g); m.p.: 151ꢀC; ‰ꢀŠ ˆ À23:3 (c ˆ 0.3, DMSO); H NMR (DMSO-d6): ꢁ ˆ 2.93
(dd, J ˆ 8.5 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.15 (dd, J ˆ 4 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.29 (dd, J ˆ 4 Hz,
J ˆ 8.5 Hz, 1H, CHO), 7.30 (m, 2H, arom), 7.34 (s, 1Hthiazol), 7.95 (m, 2H, arom) ppm; 13C NMR
(DMSO-d6): ꢁ ˆ 36.5 (CH2), 69.7 (CHO), 116.2 (C-5thiazol), 116.2 (d, J ˆ 22 Hz, C, arom), 128.4 (d,
J ˆ 9 Hz, C, arom), 130.0 (d, J ˆ 3 Hz, C, arom), 154.4 (C-4thiazol), 163.1 (d, J ˆ 248 Hz, C, arom),
164.9 (C-2thiazol), 169.6 (CˆOhydroxyamide) ppm; IR (KBr): ꢅ ˆ 3600±3000, 1650, 1510 cmÀ1; MS
‡
‡
‡
‡
‡
,
(EI): m/z ˆ 282 [M] , 250 [M±NHOH] , 222 [250-CO] , 193 [222-CHO] , 71 [CH2COCHO]
‡
‡
43 [CONH] , 28 [CO] .

Homochiral Heterocyclic ꢀ-Hydroxy Acids
53
N-(3-(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl)-hydroxylamine (11b; C12H11ClN2O3S)
7d (0.86 g, 2.0 mmol) was reacted with hydroxylamine (0.33 g, 10.0 mmol) in diethyl ether (20 cm3).
21
D
1
Yield: 84% (0.50 g); m.p.: 149ꢀC (decomp.); ‰ꢀŠ ˆ ‡ 64:0 (c ˆ 1.0, DMSO); H NMR DMSO-d6:
ꢁ ˆ 2.94 (dd, J ˆ 8.5 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.16 (dd, J ˆ 4 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.30 (dd,
J ˆ 4 Hz, J ˆ 8.5 Hz, 1H, CHO), 7.37 (s, 1Hthiazol), 7.51 (m, 2H, arom), 7.90 (m, 2H, arom) ppm; 13
C
NMR (DMSO-d6): ꢁ ˆ 36.5 (CH2), 69.7 (CHO), 116.6 (C-5thiazol), 127.8, 129.3, 132.1, 134.6 (C,
arom), 154.6 (C-4thiazol), 164.7 (C-2thiazol), 169.5 (CˆOhydroxyamide) ppm; IR (KBr): ꢅ ˆ 3600±2400,
‡
‡
‡
1655, 1530, 1500 cmÀ1; MS (EI): m/z ˆ 299 [M] , 238 [M±H2O,±CONH] , 210 [238-CO] , 71
‡
‡
[CH2COCHO] , 44 [CO2] .
N-(3-(2-(2-Thienyl)-1,3-thiazol-4-yl)-(S)-lactoyl)-hydroxylamine (11c; C10H10N2O3S2 (270.34))
7f (0.81 g, 2.0 mmol) and hydroxylamine (0.20 g, 6.0 mmol) were reacted in diethyl ether (10 cm3).
21
D
1
Yield: 89% (0.48 g); m.p.: 147ꢀC; ‰ꢀŠ ˆ À43:9 (c ˆ 1.0, DMSO); H NMR (DMSO-d6): ꢁ ˆ 2.98
(dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.20 (ddd, J ˆ 0.5 Hz, J ˆ 4 Hz, J ˆ 15 Hz, 1H, CH2), 4.38 (dd,
J ˆ 4 Hz, J ˆ 9 Hz, 1H, CHO), 7.16 (m, 1Hthiophene), 7.30 (s, br, 1Hthiazol), 7.61 (m, 1Hthiophene), 7.66
(m, 1Hthiophene) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 36.8 (CH2), 70.3 (CHO), 115.6 (C-5thiazol), 127.1,
128.6, 128.6, 137.6 (Cthiophene), 154.5 (C-4thiazol), 160.6 (C-2thiazol), 170.3 (CˆOhydroxyamide) ppm; IR
(KBr): ꢅ ˆ 3500±3000, 2900, 1635, 1530, 1520 cmÀ1; MS (EI): m/z ˆ 270 [M] , 238 [M±NHOH] ,
‡
‡
‡
‡
‡
210 [238-CO] , 181 [210-CHO] , 71 [CH2COCHO] .
3-(1,3-Thiazol-4-yl)-(S)-lactoyl-(S)-alanine tert.-butyl ester (12a; C13H20N2O4S)
7a (0.64 g, 2.0 mmol) was reacted with (S)-alanine tert.-butyl ester (0.58 g, 4.0 mmol) in diethyl ether
21
(10 cm3). Yield: 60% (0.36 g); m.p.: 70ꢀC; ‰ꢀŠ ˆ À30:4 (c ˆ 1.0, CHCl3); 1H NMR (CDCl3):
D
ꢁ ˆ 1.19 (d, J ˆ 7 Hz, 3H, CH3 ala), 1.38 (s, 9H, C(CH3)3), 3.09 (dd, br, J ˆ 7.5 Hz, J ˆ 15 Hz, 1H,
CH2), 3.30 (dd, br, J ˆ 3.5 Hz, J ˆ 15 Hz, 1H, CH2), 4.29±4.37 (m, 2H, CHala, CHO), 5.36 (d,
J ˆ 4 Hz, 1H, OH), 7.07 (dd, J ˆ 0.5 Hz, J ˆ 1.5 Hz, 1H, (C-5)Hthiazol), 7.37 (d, J ˆ 7.5 Hz, 1H, NH),
8.70 (d, J ˆ 1.5 Hz, 1H, (C-2)Hthiazol) ppm; 13C NMR (CDCl3): ꢁ ˆ 18.5 (CH3 ala), 27.9 (C(CH3)3),
34.7 (CH2), 48.2 (CHala), 71.6 (CHO), 81.8 (C(CH3)3), 115.2 (C-5thiazol), 153.0, 153.5, (C-4thiazol
,
C-2thiazol), 171.8, 172.4 (CˆOamide, ester) ppm; IR (KBr): ꢅ ˆ 3600±3040, 3370, 2980, 1745, 1665,
‡
‡
‡
1515 cmÀ1; MS (GC/EI): m/z ˆ 227 [M±OC(CH3)] , 199 [227-CO] , 156 [199-NHCHCH3] , 128
‡
‡
.
[156-CO] , 57 [C(CH3)3]
3-(2-(4-Methylphenyl)-1,3-thiazol-4-yl)-(S)-lactoyl-(S)-valine amide (12b; C18H23N3O3S)
7b (0.82 g, 2 mmol) and (S)-valine amide (0.26 g, 2.2 mmol) were reacted in THF (25 cm3). Yield: 69%
21
D
1
(0.50 g); m.p.: 170ꢀC (decomp.); ‰ꢀŠ ˆ À42:12 (cˆ 1.0, DMSO); H NMR (DMSO-d6): ꢁ ˆ 0.75 (d,
Jˆ 7Hz, 3H, CH3val), 0.79 (d, Jˆ 7Hz, 3H, CH3val), 1.93 (m, 1H, CH(CH3)2), 2.33 (s, 3H, CH3 tolyl),
2.93 (dd, J ˆ 8.5 Hz, Jˆ 14.5 Hz, 1H, CH2), 3.18 (dd, Jˆ 3Hz, Jˆ 14.5 Hz, 1H, CH2), 4.18 (m, 1H,
CHO), 4.33 (m, 1H, CHO), 5.92 (d, J ˆ 5.5 Hz, 1H, OH), 7.14 (s, br, 1H, NH), 7.28 (m, 2H, arom), 7.33
(s, 1Hthiazol), 7.51 (s, br, 1H, NH), 7.54 (s, br, 1H, NH), 7.79 (m, 2H, arom) ppm; 13C NMR (DMSO-d6):
ꢁ ˆ 17.4, 19.0 (CH3val), 20.7 (CH3tolyl), 31.0 (CH(CH3)2), 36.3 (CH2), 56.3 (CHCH(CH3)2), 70.6 (CHO),
115.4 (C-5thiazol), 125.8, 129.5, 130.5, 139.5 (C, arom), 154.0 (C-4thiazol), 166.0 (C-2thiazol), 172.4, 172.5
(CˆOamide) ppm; IR (KBr): ꢅ ˆ 3600±3000, 2970, 1660, 1640, 1520 cmÀ1; MS (EI): m/zˆ 361 [M] ,
‡
‡
‡
‡
317 [M±CONH2] , 246 [317-NHCH, ±CH(CH3)2] , 218 [246-CO] .
3-(2-(4-Fluorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl-(S)-phenylalanine methyl ester
(12c; C22H21FN2O4S)
7c (0.83 g, 2.0 mmol) was reacted with (S)-phenylalanine methyl ester (1.07 g, 6.0 mmol) in diethyl
21
ether (20 cm3). Yield: 79% (0.68 g); m.p.: 107ꢀC; ‰ꢀŠ ˆ À29:2 (c ˆ 1.0, CHCl3); 1H NMR
D

54
K. Burger et al.
(acetone-d6): ꢁ ˆ 2.96 (dd, J ˆ 8.5 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH), 3.08 (dd, J ˆ 7 Hz, J ˆ 14 Hz,
1H, CH2 phe), 3.13 (dd, J ˆ 6 Hz, J ˆ 14 Hz, 1H, CH2 phe), 3.26 (dd, br, J ˆ 3.5 Hz, J ˆ 14.5 Hz, 1H,
CH2CHOH), 3.68 (s, 3H, OCH3), 4.46 (ddd, J ˆ 3.5 Hz, J ˆ 5 Hz, J ˆ 8.5 Hz, 1H, CHO), 4.79 (ddd,
J ˆ 6 Hz, J ˆ 7 Hz, J ˆ 8 Hz, 1H, CHphe), 5.18 (d, J ˆ 5 Hz, 1H, OH), 7.16 (m, 2H, arom), 7.19±7.29
(m, 5H, arom, 1Hthiazol), 7.55 (d, J ˆ 8 Hz, 1H, NH), 8.02 (m, 2H, arom) ppm; 13C NMR (DMSO-d6):
ꢁ ˆ 36.8 (CH2CHOH), 38.3 (CH2phe), 52.4, 53.6 (CHphe, OCH3), 72.1 (CHO), 116.6 (C-5thiazol),
116.8 (d, J ˆ 22 Hz, C, arom), 127.6, 129.2, 129.3 (d, J ˆ 9 Hz, C, arom), 130.1, 131.0 (d, J ˆ 3 Hz,
C, arom), 137.6 (C, arom), 155.2 (C-4thiazol), 164.6 (d, J ˆ 248 Hz, C, arom), 166.8 (C-2thiazol),
172.4, 173.2 (CˆOamide, ester) ppm; 19F NMR (acetone-d6): ꢁ ˆ À33.53 (m, 1F) ppm; IR (KBr):
‡
‡
ꢅ ˆ 3290, 1750, 1640, 1510 cmÀ1; MS (FAB): m/z ˆ 429 [M ‡ H] , 370 [429-CO2CH3] , 222 [370-
‡
C7H7±CH±NH±CO]
.
3-(2-(4-Fluorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl-(S)-alanine tert.-butyl ester
(12d; C19H23FN2O4S)
7c (0.83 g, 2.0 mmol) and (S)-alanine tert.-butyl ester (0.58 g, 4.0 mmol) were reacted in diethyl ether
21
1
(20 cm3). Yield: 66% (0.52 g); m.p.: 78ꢀC; ‰ꢀŠ ˆ À80:8 (c ˆ 1.0, CHCl3); H NMR (CDCl3):
D
ꢁ ˆ 1.28 (d, J ˆ 7 Hz, 3H, CH3 ala), 1.45 (s, 9H, C(CH3)3), 3.13 (dd, J ˆ 7.5 Hz, J ˆ 15 Hz, 1H, CH2),
3.36 (dd, J ˆ 3.5 Hz, J ˆ 15 Hz, 1H, CH2), 4.43 (dq, J ˆ 7 Hz, J ˆ 7.5 Hz, 1H, CHala), 4.47 (dd,
J ˆ 3.5 Hz, J ˆ 7.5 Hz, 1H, CHOH), 5.47 (s, br, 1H, OH), 7.05 (s, 1Hthiazol), 7.11 (m, 2H, arom), 7.52
(d, J ˆ 7.5 Hz, 1H, NH), 7.87 (m, 2H, arom) ppm; 13C NMR (CDCl3): ꢁ ˆ 18.5 (CH3 ala), 27.9
(C(CH3)3), 35.0 (CH2), 48.3 (CHala), 71.7 (CHOH), 81.9 (C(CH3)3), 115.3 (C-5thiazol), 116.1 (d,
J ˆ 22 Hz, C, arom), 128.4 (d, J ˆ 9 Hz, C, arom), 129.4 (d, J ˆ 3 Hz, C, arom), 153.7, (C-4thiazol),
163.9 (d, J ˆ 251 Hz, C, arom), 167.2 (C-2thiazol), 171.8, 172.4 (CˆOamide, ester) ppm; IR (®lm):
‡
‡
ꢅ ˆ 3600±3140, 2985, 1720, 1650, 1505 cmÀ1; MS (EI): m/z ˆ 394 [M] , 321 [M±OC(CH3)3] ,
‡
‡
‡
293 [321-CO] , 250 [293-NHCHCH3] , 222 [250-CO] .
3-(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl-(S)-phenylalanine tert.-butyl ester
(12e; C25H27ClN2O4S)
7d (0.86 g, 2.0 mmol) and (S)-phenylalanine tert.-butyl ester (0.66 g, 3.0 mmol) were reacted in
21
1
diethyl ether (20 cm3). Yield: 43% (0.42 g); m.p.: 85ꢀC; ‰ꢀŠ ˆ À44:9 (c ˆ 1.0, CHCl3); H NMR
D
(CDCl3): ꢁ ˆ 1.38 (s, 9H, C(CH3)3), 2.99 (dd, J ˆ 6 Hz, J ˆ 14 Hz, CH2 phe), 3.01 (dd, J ˆ 6 Hz,
J ˆ 14 Hz, 1H, CH2 phe), 3.12 (dd, J ˆ 7 Hz, J ˆ 15 Hz, 1H, CH2CHOH), 3.31 (dd, J ˆ 3.5 Hz, J ˆ
15 Hz, 1H, CH2CHOH), 4.43 (dd, J ˆ 3.5 Hz, J ˆ 7 Hz, 1H, CHO), 4.75 (ddd, J ˆ 6 Hz, J ˆ 6 Hz,
J ˆ 8 Hz, 1H, CHphe), 5.43 (s, br, 1H, OH), 7.00 (m, 2H, arom), 7.05 (s, 1Hthiazol), 7.11 (m, 3H,
arom), 7.40 (m, 2H, arom), 7.45 (d, J ˆ 8 Hz, 1H, NH), 7.82 (m, 2H, arom) ppm; 13C NMR (CDCl3):
ꢁ ˆ 27.8 (C(CH3)3), 34.4 (CH2CHOH), 38.2 (CH2 phe), 53.0 (CHphe), 71.1 (CHO), 82.2 (C(CH3)3),
115.5 (C-5thiazol), 126.7, 127.5, 128.1, 129.2, 129.2, 131.3, 136.0, 136.3 (C, arom), 153.6 (C-4thiazol),
167.2 (C-2thiazol), 170.0, 172.1 (CˆOamide, ester) ppm; IR (KBr): ꢅ ˆ 3500±3100, 3405, 1730, 1640,
‡
‡
‡
1525 cmÀ1; MS (EI): m/z ˆ 487 [M] , 431 [M±C(CH3)3] , 238 [M±C14H18NO3] .
(3S,6S)-3-(2-(4-Methylphenyl)-thiazol-4-ylmethyl)-2,5-dioxo-1-aza-4-oxabicyclo[4.3.0]nonane
(13a; C18H18N2O3S)
7b (0.82 g, 2.0 mmol) and (S)-proline benzyl ester (0.99 g, 4.8 mmol) were reacted in diethyl ether
21
(10 cm3). Yield: 58% (0.40 g); m.p.: 191ꢀC; ‰ꢀŠ ˆ À246:8 (c ˆ 1.1, DMSO); 1H NMR (DMSO-d6):
D
ꢁ ˆ 1.88 (m, 2H, CH2), 2.04 (m, 1H, CH2), 2.25 (m, 1H, CH2), 2.36 (m, 3H, CH3 tolyl), 3.15 (dd,
J ˆ 9 Hz, J ˆ 16 Hz, 1H, CH2CHOH), 3.45 (m, 2H, CH2), 3.54 (dd, J ˆ 3.5 Hz, J ˆ 16 Hz, 1H,
CH2CHOH), 4.63 (dd, J ˆ 7 Hz, J ˆ 8 Hz, 1H, CH), 5.56 (dd, J ˆ 3.5 Hz, J ˆ 9 Hz, 1H, CHO), 7.31
(m, 2H, arom), 7.45 (s, 1Hthiazol), 7.82 (m, 2H, arom) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 20.9

Homochiral Heterocyclic ꢀ-Hydroxy Acids
55
(CH3 tolyl), 22.7 (CH2), 27.7 (CH2), 31.3 (CH2CHOH), 44.8 (CH2), 57.2 (CH), 77.2 (CHO), 115.9 (C-
5
thiazol), 126.0, 129.7, 130.5, 139.9 (C, arom), 152.6 (C-4thiazol), 164.0 (C-2thiazol), 166.6, 169.6
‡
(C=Odioxomorpholine) ppm; IR (KBr): ꢅ ˆ 1735, 1680 cmÀ1; MS (FAB in NBA): m/z ˆ 365 [M ‡ Na] ,
‡
‡
.
343 [M ‡ H] , 218 [343-C6H7NO2]
(3S,6S)-3-(2-(4-Fluorophenyl)-thiazol-4-ylmethyl)-2,5-dioxo-1-aza-4-oxabicyclo[4.3.0]nonane
(13b; C17H15FN2O3S)
7c (0.83 g, 2.0 mmol) and (S)-proline benzyl ester (1.23 g, 6.0 mmol) were reacted in diethyl ether
21
(10 cm3).Yield: 38% (0.26 g); m.p.: 155ꢀC; ‰ꢀŠ ˆ À214:6 (c ˆ 0.2, DMSO); 1H NMR (acetone-d6):
D
ꢁ ˆ 1.96 (m, 2H, CH2), 2.18 (m, 1H, CH2), 2.33 (m, 1H, CH2), 3.18 (ddd, J ˆ 0.5, J ˆ 9 Hz,
J ˆ 15.5 Hz, 1H, CH2CHOH), 3.53 (m, 2H, CH2), 3.64 (dd, J ˆ 3.5 Hz, J ˆ 15.5 Hz, 1H,
CH2CHOH), 4.61 (dd, J ˆ 8 Hz, J ˆ 8 Hz, 1H, CH), 5.51 (dd, J ˆ 3.5 Hz, J ˆ 9 Hz, 1H, CHO),
7.25 (m, 2H, arom), 7.37 (s, br, 1Hthiazol), 8.01 (m, 2H, arom) ppm; 13C NMR (acetone-d6): ꢁ ˆ 23.7
(CH2), 28.9 (CH2), 32.4 (CH2CHOH), 45.7 (CH2), 58.3 (CH), 78.4 (CHO), 116.8 (C-5thiazol), 116.8
(d, J ˆ 22 Hz, C, arom), 129.2 (d, J ˆ 9 Hz, C, arom), 131.2 (d, J ˆ 3 Hz, C, arom), 154.2 (C-4thiazol),
164.6 (d, J ˆ 248 Hz, C, arom), 165.0 (C-2thiazol), 166.6, 170.0 (CˆOdioxomorpholine) ppm; 19F NMR
‡
(acetone-d6): ꢁ ˆ À33.73 (m) ppm; IR (KBr): ꢅ ˆ 1730, 1685 cmÀ1; MS (FAB): m/z ˆ 347 [M ‡ H] ,
‡
222 [347-C6H7NO2]
.
(3S,6S)-3-(2-(4-Chlorophenyl)-thiazol-4-ylmethyl)-2,5-dioxo-1-aza-4-oxabicyclo[4.3.0]nonane
(13c; C17H15ClN2O3S)
7d (0.86 g, 2.0 mmol) and (S)-proline benzyl ester (0.82 g, 4.0 mmol) were reacted in diethyl ether
21
(10 cm3). Yield: 82% (0.59 g); m.p.: 197ꢀC; ‰ꢀŠ ˆ À204:2 (c ˆ 0.5, DMSO); 1H NMR (DMSO-d6):
D
ꢁ ˆ 1.86 (m, 2H, CH2), 2.03 (m, 1H, CH2), 2.22 (m, 1H, CH2), 3.15 (dd, J ˆ 9 Hz, J ˆ 16 Hz, 1H,
CH2CHOH), 3.44 (m, 2H, CH2), 3.53 (ddd, J ˆ 0.5 Hz, J ˆ 3.5 Hz, J ˆ 16 Hz, 1H, CH2CHOH), 4.60
(dd, J ˆ 8 Hz, J ˆ 8 Hz, 1H, CH), 5.54 (dd, J ˆ 3.5 Hz, J ˆ 9 Hz, 1H, CHOH), 7.51 (s, br, 1Hthiazol),
7.54 (m, 2H, arom), 7.92 (m, 2H, arom) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 22.8 (CH2), 27.9 (CH2),
31.4 (CH2CHOH), 45.0 (CH2), 57.4 (CH), 77.3 (CHO), 117.1 (C-5thiazol), 127.9, 129.4, 132.1, 134.9
(C, arom), 153.2 (C-4thiazol), 164.1 (C-2thiazol), 165.3, 169.6 (CˆOdioxomorpholine) ppm; IR (KBr):
‡
‡
‡
‡
.
ꢅ ˆ 1730, 1685 cmÀ1; MS (EI): m/z ˆ 364 [M ‡ H] , 363 [M] , 319 [M±CO2] , 70 [C4H8N]
3-(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl-azaglycine methyl ester
(14a; C14H14ClN3O4S)
7d (0.86 g, 2.0 mmol) was reacted with methoxy carbonyl hydrazine (0.18 g, 2.0 mmol) in diethyl
21
ether (10 cm3). Yield: 51% (0.36 g); m.p.: 178ꢀC; ‰ꢀŠ ˆ À46:8 (c ˆ 1.0, DMSO); 1H NMR (DMSO-
D
d6): ꢁ ˆ 2.96 (dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.19 (dd, J ˆ 3.5 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.61
(s, 3H, OCH3), 4.38±4.43 (m, 1H, CH), 5.74 (d, J ˆ 6.5 Hz, 1H, OH), 7.45 (s, 1Hthiazol), 7.49 (m, 2H,
arom), 7.95 (m, 2H, arom), 9.04 (s, br, 1H, NH), 9.77 (s, br, 1H, NH) ppm; 13C NMR (DMSO-d6):
ꢁ ˆ 36.3 (CH2), 51.8 (OCH3), 69.9 (CH), 116.6 (C-5thiazol), 127.6, 129.1, 132.0, 134.4 (C, arom),
154.2 (C-4thiazol), 156.4 (CˆOester), 164.6 (C-2thiazol), 172.7 (CˆOhydrazide) ppm; IR (KBr): ꢅ ˆ 3300,
‡
‡
‡
1725, 1680, 1500 cmÀ1; MS (EI): m/z ˆ 356 [M] , 267 [M±NHNHCO2CH3] , 239 [267-CO] ,
‡
210 [239-CHO], 71 [CH2COCHO]
.
3-(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl-azaglycine-4-methoxy benzyl ester
(14b; C21H20ClN3O5S)
7d (0.86 g, 2.0 mmol) and 4-methoxybenzylcarbonyl hydrazine (0.36 g, 2.0 mmol) were reacted in
21
diethyl ether (20 cm3). Yield: 52% (0.48 g); m.p.: 150ꢀC; ‰ꢀŠ ˆ À34:6 (c ˆ 0.3, DMSO); 1H NMR
D

56
K. Burger et al.
(DMSO-d6): ꢁ ˆ 2.96 (dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH), 3.19 (m, 1H, CH2CHOH), 3.76 (s,
3H, OCH3), 4.40 (m, 1H, CHOH), 5.02 (s, 2H, OCH2), 5.73 (s, br, 1H, OH), 6.94 (m, 2H, arom),
7.33 (m, 2H, arom), 7.45 (s, 1Hthiazol), 7.56 (m, 2H, arom), 7.95 (m, 2H, arom), 9.13 (s, 1H, NH),
9.78 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 36.2 (CH2CHOH), 54.9 (OCH3), 65.5 (OCH2),
69.8 (CHO), 113.5 (C, arom), 116.4 (C-5thiazol), 127.5, 128.3, 129.0, 129.7, 131.8, 134.3 (C, arom),
154.1 (C-4thiazol), 155.8 (CˆOester), 158.9 (C, arom), 164.4 (C-2thiazol), 172.6 (CˆOhydrazide) ppm;
IR (KBr): ꢅ ˆ 3600±3100, 1725, 1670, 1640 1520 cmÀ1; MS (EI): m/z ˆ 297 [M±
‡
‡
‡
‡
‡
CO2CH2C6H4OCH3] , 266 [297-NHNH2] , 238 [266-CO] , 138 [HOCH2C6H4OCH3] , 121
‡
‡
[CH2C6H4OCH3] , 77 [C6H5] , 44 [CO2] .
3-(2-(4-Methylphenyl)-1,3-thiazol-4-yl)-(S)-lactoyl hydrazine (15a; C13H15N3O2S)
7b (0.82 g, 2.0 mmol) and hydrazine hydrate (0.13 g, 2.5 mmol) were reacted in diethyl ether
21
1
(30 cm3). Yield: 91% (0.50 g); m.p.: 139ꢀC; ‰ꢀŠ ˆ À58:7 (c ˆ 1.1, DMSO); H NMR (DMSO-d6):
D
ꢁ ˆ 2.33 (s, 3H, CH3), 2.90 (dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.17 (dd, J ˆ 4 Hz, J ˆ 14.5 Hz, 1H,
CH2), 4.33 (dd, J ˆ 4 Hz, J ˆ 9 Hz, 1H, CHO), 4.74 (s, 2H, NH2), 7.28 (m, 2H, arom), 7.30 (s,
1Hthiazol), 7.79 (m, 2H, arom), 9.06 (s, br, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 21.0 (CH3), 36.6
(CH2), 70.2 (CHO), 115.5 (C-5thiazol), 126.1, 129.8, 130.8, 139.9 (C, arom), 154.4 (C-4thiazol), 166.3
(C-2thiazol), 172.1 (CˆOhydrazide) ppm; IR (KBr): ꢅ ˆ 3275, 1665, 1635, 1540 cmÀ1; MS (FAB):
‡
‡
.
m/z ˆ 278 [M ‡ H] , 218 [M±CONHNH2]
3-(2-(4-Fluorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl hydrazine (15b; C12H12FN3O2S)
7d (0.86 g, 2.0 mmol) was reacted with hydrazine hydrate (0.13 g, 2.5 mmol) in diethyl ether
21
1
(30 cm3). Yield: 90% (0.51 g); m.p.: 158ꢀC; ‰ꢀŠ ˆ À54:7 (c ˆ 1.0, DMSO); H NMR (DMSO-d6):
D
ꢁ ˆ 2.89 (dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.15 (dd, J ˆ 4 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.25 (s, br,
2H, NH2), 4.30 (m, 1H, CHOH), 5.50 (d, J ˆ 6 Hz, 1H, OH), 7.31 (m, 2H, arom, 1Hthiazol), 7.96 (m,
2H, arom), 8.98 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 36.3 (CH2), 70.0 (CHO), 115.9 (C-
5thiazol), 116.0 (d, J ˆ 22 Hz, C, arom), 128.2 (d, J ˆ 9 Hz, C, arom), 129.8 (d, J ˆ 3 Hz, C, arom),
154.3 (C-4thiazol), 162.9 (d, J ˆ 248 Hz, C, arom), 164.7 (C-2thiazol), 171.8 (CˆOhydrazide) ppm;
‡
IR (KBr): ꢅ ˆ 3270, 3160, 1665, 1635, 1540, 1520 cmÀ1; MS (FAB): m/z ˆ 282 [M ‡ H] , 222
‡
[M±CONHNH2]
.
3-(2-(2-Furyl)-1,3-thiazol-4-yl)-(S)-lactoyl hydrazine (15c; C10H11N3O3S)
7e (0.78 g, 2.0 mmol) was reacted with hydrazine hydrate (0.13 g, 2.5 mmol) in diethyl ether
21
(30 cm3). Yield: 91% (0.46 g); foam; ‰ꢀŠ ˆ À22:7 (c ˆ 1.5, DMSO); 1H NMR (DMSO-d6): ꢁ ˆ 2.86
D
(dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H, CH2), 3.12 (ddd, J ˆ 0.5 Hz, J ˆ 4 Hz, J ˆ 14.5 Hz, 1H, CH2), 4.28
(m, 1H, CHO), 4.30 (s, br, 2H, NH2), 5.53 (s, br, 1H, OH), 6.67 (m, 1Hfuran), 7.04 (m, 1Hfuran), 7.31
(s, br, 1Hthiazol), 7.84 (m, 1Hfuran), 9.01 (s, br, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢁ ˆ 36.3 (CH2),
69.9 (CH), 108.7, 112.4 (Cfuran), 115.0 (C-5thiazol), 144.4, 148.3 (Cfuran), 154.3 (C-4thiazol), 156.2 (C-
2thiazol), 171.8 (CˆOhydrazide) ppm; IR (KBr): ꢅ ˆ 3600±3000, 1660, 1510 cmÀ1; MS (EI): m/z ˆ 253
‡
‡
‡
[M] , 222 [M±NHNH2] , 194 [222-CO] .
Reaction of (S)-3-(1,3-thiazol-4-yl)-lactoyl hydrazine 15 with (2S)-benzyl
2-isocyanatopropionates; general procedure
(S)-3-(1,3-Thiazol-4-yl)-lactoyl hydrazine 15 (1.0 mmol) was reacted with the corresponding (S)-
isocyanate in CHCl3. After completion of the reaction (IR analysis) the solvent was evaporated in
vacuo, and the residue was puri®ed by chromatography (eluent: ethyl acetate).

Homochiral Heterocyclic ꢀ-Hydroxy Acids
57
3-(2-(4-Fluorophenyl)-1,3-thiazol-4-yl)-(S)-lactoyl-azaglycyl-(S)-alanine benzyl ester
(16a; C23H23FN4O5S)
15b (0.28g, 1.0 mmol) and (2S)-benzyl 2-isocyanatopropionate (0.21 g, 1.0 mmol) were reacted in
21
1
40 cm3 of CHCl3 (40 ml). Yield: 62% (0.30 g); m.p.: 153ꢀC; ‰ꢀŠ ˆ À32:2 (c ˆ 1.4, DMSO); H
D
NMR (DMSO-d6): ꢁ ˆ 1.30 (d, J ˆ 7.5 Hz, 3H, CH3 ala), 2.97 (dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H,
CH2CHOH), 3.19 (dd, J ˆ 4 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH), 4.28 (dq, J ˆ 7.5 Hz, J ˆ 7.5 Hz,
CHala), 4.41 (dd, J ˆ 4 Hz, J ˆ 9 Hz, 1H, CHO), 5.14 (s, 2H, OCH2), 6.68 (d, J ˆ 7.5, 1H, NH), 7.33±
7.41 (m, 7H, arom, 1Hthiazol), 7.96±8.00 (m, 2H, arom, 1H, NH), 9.61 (s, br, 1H, NH) ppm; 13C NMR
(DMSO-d6): ꢁ ˆ 18.0 (CH3 ala), 36.4 (CH2CHOH), 48.5 (CHala), 66.0 (OCH2), 70.2 (CHO), 116.3
(C-5thiazol), 116.3 (d, J ˆ 22 Hz, C, arom), 127.9, 128.1 (C, arom), 128.5 (d, J ˆ 9 Hz, C, arom), 128.6
(C, arom), 130.1 (d, J ˆ 3 Hz, C, arom), 136.2 (C, arom), 154.4 (C-4thiazol), 157.4 (CˆOagly), 163.2
(d, J ˆ 248 Hz, C, arom), 165.0 (C-2thiazol), 172.8, 173.3 (CˆOester, hydrazide) ppm; IR (KBr):
‡
ꢅ ˆ 3360, 3310, 1725, 1670, 1645, 1550, 1515 cmÀ1; MS (FAB): m/z ˆ 487 [M ‡ H] , 308 [M±
‡
‡
.
C10H12NO2] , 222 [308-CONHNHCO]
3-(2-(2-Furyl)-1,3-thiazol-4-yl)-(S)-lactoyl-azaglycyl-(S)-alanine benzyl ester
(16b; C21H22FN4O6S)
15c (0.25 g, 1.0 mmol) was reacted with (2S)-benzyl 2-isocyanatopropionate (0.21 g, 1.0 mmol) in
21
CHCl3 (10 cm3). Yield: 61% (0.28 g); m.p.: 173ꢀC; ‰ꢀŠ ˆ À35:8 (c ˆ 1.0, DMSO); 1H NMR
D
(DMSO-d6): ꢁ ˆ 1.29 (d, J ˆ 7 Hz, 3H, CH3 ala), 2.93 (dd, J ˆ 9 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH),
3.14 (dd, J ˆ 4 Hz, J ˆ 14.5 Hz, 1H, CH2CHOH), 4.26 (dq, J ˆ 7.5 Hz, J ˆ 7 Hz, CHala), 4.35 (m, 1H,
CHO), 5.12 (s, 2H, OCH2), 5.59 (s, br, 1H, OH), 6.64±6.68 (m, 2Hfuran), 7.05 (m, 1Hfuran), 7.29±7.37
(m, 5H, arom, 1H, C(5)-Hthiazol), 7.84 (s, 1H, NH), 7.95 (s, 1H, NH), 9.57 (s, 1H, NH) ppm; 13C
NMR (DMSO-d6): ꢁ ˆ 17.6 (CH3 ala), 35.9 (CH2CHOH), 48.1 (CHala), 65.6 (OCH2), 69.7 (CHO),
108.5, 112.3 (Cfuran), 115.0 (C-5thiazol), 127.5, 127.7, 128.2, 135.8 (C, arom), 144.2, 148.2 (Cfuran),
153.9 (C-4thiazol), 155.9 (CˆOagly), 157.0 (C-2thiazol), 172.4, 172.9 (CˆOester, hydrazide) ppm; IR
‡
(KBr): ꢅ ˆ 3600±2900, 3375, 3320, 1735, 1615, 1580, 1550 cmÀ1; MS (FAB): m/z ˆ 459 [M ‡ H] ,
‡
‡
‡
280 [M±C10H12NO2] , 222 [280-CONHNHCO] , 194 [222-CO] .
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (A.-A. H. Abdel-Aleem), the
Fonds der Chemischen Industrie, and the European Community (TMR-Projekt: Fluorine as a unique
tool for engineering molecular properties).
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ReceivedMay 21, 2001. Accepted(revised) July 6, 2001