Enzymatic resolution of (R)- and (S)-2-(1-hydroxyalkyl)thiazoles, synthetic equivalents of (R)- and (S)-2-hydroxy aldehydes

Full text of DOI:10.1021/jo952082t

4144
J . Org. Chem. 1996, 61, 4144-4147
Notes
Sch em e 1
En zym a tic Resolu tion of (R)- a n d
(S)-2-(1-Hyd r oxya lk yl)th ia zoles, Syn th etic
Equ iva len ts of (R)- a n d (S)-2-Hyd r oxy
Ald eh yd es
Pietro Allevi, Pierangela Ciuffreda, Giorgio Tarocco, and
Mario Anastasia*
Department of Medical Chemistry and Biochemistry,
University of Milan, Via Saldini 50, 20133 - Milan, Italy
Received November 27, 1995
In tr od u ction
Attempts directed at obtaining enantioenriched 2-(1-
hydroxyalkyl)thiazoles, masked equivalents of chiral
2-hydroxy aldehyde, by a biological reduction of the
corresponding 2-acylthiazoles gave poor results,7b apart
from the case of 2-acetylthiazole which, with bakers’
yeast, undergoes reduction affording only the enantiomer
with the (S)-configuration.9
In connection with our studies on the synthesis1a-e and
biological evaluation2a,b of enantioenriched (E)-4-hydroxy-
and (E)-4,5-dihydroxy-2-alkenals formed during lipid
peroxidation, we confronted the problem of producing
various (R)- and (S)-2-hydroxy aldehydes, convenient
chiral building blocks1c,d for the synthesis of these physi-
ologically active3 hydroxylated 2-alkenals and of many
other important natural products.4a-d
A literature survey showed that 2-hydroxy aldehydes
of various structure can be obtained in high optical purity
by general methods involving either the chemical elabo-
ration of natural chiral precursors, like D-mannitol or
monosaccharides,1c,4b or the use of chiral acyl anion
equivalents.5 Also some methods based on biocatalytic
approaches have been reported, but these appear more
limited since they permit the satisfactory preparation of
only a restricted number of simple 2-hydroxy aldehydes
or, often, of only the single (S)-enantiomer. Such meth-
ods include the stereoselective hydrolysis of R-acetoxy or
R-butyroxy thioacetals by lipases6 or the bioreduction of
a small number of R-keto thioacetals by bakers’ yeast,7a-d
or of ketoacetals by other yeasts,8 followed by the
regeneration of the formyl group.
Considering that racemic 2-hydroxy aldehydes are
conveniently obtained10 via 2-(1-hydroxyalkyl)thiazoles,
which are easily and efficiently prepared using 2-(tri-
methylsilyl)thiazole,11 we decided to search for a simple
method for the enzymatic resolution of 2-(1-hydroxy-
alkyl)thiazoles. The approach we adopted involved enan-
tioselective esterification of the hydroxy group, using as
catalysts enzymes in organic solvents. Dondoni et al. had
already shown that thiazolyl to formyl deblocking occurs
without epimerization of a stereogenic center adjacent
to the formyl group;10,12 thus the resolution of 2-(1-
hydroxyalkyl)thiazoles via enzymes could provide a
simple access to enantioenriched 2-hydroxy aldehydes.
We report the resolution of several (R)- and (S)-2-(1-
hydroxyalkyl)thiazoles through the enantioselective acy-
lation of the racemic mixture. This route gives the
unreacted (S)-2-(1-hydroxyalkyl)thiazoles (S)-1c-m in
high enantiomeric purity due to a transesterification
reaction of the (R)-enantiomer with 2,2,2-trifluoroethyl
butanoate (TFEB) in diisopropyl ether under immobilized
Lipase PS catalysis.13 Using the same enzyme in an
aqueous medium, hydrolysis of the butanoates (2c-m ;
Scheme 1) afforded the (R)-enantiomers (R)-1c-m in
similar satisfactory optical purity.
(1) (a) Allevi, P.; Ciuffreda, P.; Tarocco, G.; Anastasia, M. Tetrahe-
dron Asymmetry 1995, 6, 2357. (b) Allevi, P.; Cajone, F.; Ciuffreda, P.;
Anastasia, M. Tetrahedron Lett. 1995, 36, 1347. (c) Allevi, P.; Anas-
tasia, M.; Ciuffreda, P.; Sanvito, A. M. Tetrahedron Asymmetry 1994,
5, 927. (d) Allevi, P.; Anastasia, M.; Cajone, F.; Ciuffreda, P.; Sanvito,
A. M. Tetrahedron Asymmetry 1994, 5, 13. (e) Allevi, P.; Anastasia,
M.; Cajone, F.; Ciuffreda, P.; Sanvito, A. M. J . Org. Chem. 1993, 58,
5000.
The utility of the method was then demonstrated in
the synthesis of (R)- and (S)-(E)-4-hydroxy-2-undecenals
(6; Scheme 2), cytotoxic aldehydes formed in the peroxi-
dation of (n-9)-polyunsaturated fatty acids bonded to
membrane phospholipids.3 However the method has a
(2) (a) Allevi, P.; Anastasia, M.; Cajone, F.; Ciuffreda, P.; Sanvito,
A. M. Free Radical Biol. Med. 1995, 18, 107. (b) Allevi, P.; Cajone, F.
Free Radical Res. Commun. 1992, 12.13.
(3) Esterbauer, H.; Zollner, H.; Schaur, R. J . Membrane Lipid
Oxidation; Vigo-Pelfrey, C., Boca Raton, FL: CRC Press, 1990; Vol. 1,
239.
(4) (a) Khanapure, S. P.; Manna, S.; Rokach, J .; Murphy, R. C.;
Wheelan, P.; Powell, W. S. J . Org. Chem. 1995, 60, 1806. (b) Merrer,
Y. L.; Gravier-Pelletier, C.; Micas-Languin, D.; Mestre, F.; Dureault,
A.; Depezay, J .-C. J . Org. Chem. 1989, 54, 2409. (c) Reetz, M. T.;
Kesseler, K. J . Org. Chem. 1985, 50, 5434. (d) Mead, K.; Mac Donald,
T. L. J . Org. Chem. 1985, 50, 422.
(5) Guanti, G.; Narisano, E.; Pero, F.; Banfi, L.; Scolastico, C. J .
Chem. Soc. Perkin Trans. 1 1984, 189, and references cited therein.
(6) Bianchi, D.; Cesti, P.; Golini, P. Tetrahedron 1989, 45, 869.
(7) (a) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron Lett. 1986,
27, 3547. (b) Guanti, G.; Banfi, L.; Guaragna, A.; Narisano, E. J . Chem.
Soc., Chem. Commun. 1986, 138. (c) Fujisawa. T.; Kojima, E.; Itoh,
T.; Sato, T. Chem. Lett. 1985, 1751. (d) Takaishi, Y.; Yang, Y.-L.;
DiTullio, D.; Sih, C. J . Tetrahedron Lett. 1982, 23, 5489.
(8) Ferraboschi, P.; Santaniello, E.; Tingoli, M.; Aragozzini, F.;
Molinari, F. Tetrahedron Asymmetry 1993, 4, 1931.
(9) Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.; Poli, S.;
Gardini, F.; Guerzoni, E. Tetrahedron Asymmetry 1991, 2, 243.
(10) Dondoni, A.; Merino, P. Org. Synth. 1993, 72, 21.
(11) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
J . Org. Chem. 1988, 53, 1748.
(12) Dondoni, A.; Perrone, D. J . Org. Chem. 1995, 60, 4749.
(13) Tested lipases were described as follows: lipase from Pseudomo-
nas sp. (SAM-II, Amano), lipase from Pseudomonas fluorescens (Sam-
2, Fluka), lipase from Candida cylindracea (CCL, type VII, Sigma),
lipase from Candida antarctica SP 435 L (LCA, immobilized on a
macroporous acrylic resin, Novo Nordisk, Denmark), lipase from
porcine pancreas (PPL, type II, crude, Sigma), lipase from Pseudomo-
nas cepacia (Lipase PS, Amano), Lipase PS was also immobilized on
Hyflo Super Cell according to reference 14.
S0022-3263(95)02082-2 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 12, 1996 4145
Sch em e 2
for all the substrates, except for 1a and 1b which have
the shortest alkyl chains. In agreement with the good
enantiomeric ratios, the lipase-catalyzed resolutions of
the racemic 2-(1-hydroxyalkyl)thiazoles 1c-m yielded
the unreacted (S)-alcohols in high optical purity, driving
the extent of the conversion to 53-57%, as suggested by
the equations for the quantitative treatment of enzymatic
kinetic resolution15a,b (Table 2).
In the case of the acylated (R)-compounds the enan-
tiomeric excesses was unsatisfactory. However, since
only a drastic reduction in the extent of the conversion
could bring about an acceptable improvement of their
optical purity,15b we tested the possibility of obtaining (R)-
2-(1-hydroxyalkyl)thiazoles (R)-1c-m by the hydrolysis
of the enantiomerically enriched (R)-butanoates under
catalysis of free Lipase PS. In fact, hydrolysis of the
butanoates (R)-2c-m , mediated by free Lipase PS in
phosphate buffer (pH 7), afforded the alcohols (R)-1c-m
with high optical purity (Table 2).16
more general relevance since 2-(1-hydroxyalkyl)thiazoles,
versatile intermediates in organic chemistry,12 are ob-
tained in a high enough optical purity for the synthesis
of natural compounds.
Resu lts a n d Discu ssion
The enantiomeric excess and the absolute configuration
of the (R)- and (S)-2-(1-hydroxyalkyl)thiazoles were de-
termined by 1H NMR analysis of their (R)- and (S)-
Mosher esters,17,18 while the enantiomeric excess of the
The 2-(1-hydroxyalkyl)thiazoles 1a -m were prepared
in good yields by reaction of an appropriate aldehyde with
2-(trimethylsilyl)thiazole.11 Preliminary experiments for
enzymatic resolution were then performed in order to
screen enzymes, solvents, and acylating agents and to
optimize the other reaction conditions.
For the enzyme screening, the transesterification
between vinyl acetate and 2-(1-hydroxyoctyl)thiazole 1g
was checked in tert-butyl methyl ether, a solvent we
found useful in some lipase-mediated acylations of race-
mic hydroxy acetals,1e in the presence of six commercial
lipases.13 One of these, Lipase PS, was tested both as a
free enzyme and after immobilization onto Hyflo Super
Cell.14
Of the screened enzymes, free and immobilized Lipase
PS showed the highest enantioselectivity (E > 16) and
activity, Candida cylindracea and immobilized Candida
antarctica lipases were practically inactive, porcine pan-
creas lipase displayed extremely low activity and very
poor selectivity (E = 1), lipases from Pseudomonas sp.
and from Pseudomonas fluorescens catalyzed the reac-
tion, showing low enantiospecificity (E < 10).
Immobilized Lipase PS was more active than the free
enzyme and was thus selected for further studies to
determine the possibility of improving the enzymatic
enantioselectivity by choosing the most appropriate
solvent and acyl donor. In these experiments the enan-
tioselective acylation of 1g, catalyzed by immobilized
Lipase PS, was carried out using, as the acylating agents,
vinyl acetate for the irreversibility of its reaction, and
TFEB, because the very weak nucleophilicity of 2,2,2-
trifluoroethanol makes the transesterification essentially
irreversible. Each acylating agent was tested in the
presence of eight solvents of different hydrophobicity (log
P) and dielectric constant (ꢀ), including tert-amyl alcohol
which has been shown to have excellent enantioselectiv-
ity with immobilized Lipase PS14 (Table 1).
1
butanoates (R)-2a -m was evaluated by H NMR using
tris[3-(heptafluoropropylhydroxymethylene)-d-camphora-
to]europium(III), [Eu(hfc)3].19
The utility of the present method was demonstrated
in the synthesis of (R)- and (S)-(E)-4-hydroxy-2-undecenal
(6, Scheme 2), an important hydroxy 2-alkenal derived
in LPO from (n-9) fatty acids. For this purpose (R)- and
(S)-2-(1-hydroxyoctyl)thiazoles (1g) were separately es-
terified with benzoyl chloride in pyridine and successively
converted, without racemization,10,12 into the correspond-
ing benzoyloxy aldehyde 4 [1H NMR at 500 MHz; using
Eu(hfc)3].
A two-carbon homologation of the obtained 2-benzoyl-
oxy aldehydes 4, by Wittig reaction with (formylmethyl-
ene)triphenylphosphorane, and regeneration of the 4-hy-
droxy group accomplished the synthesis.
In conclusion 2-(1-hydroxyalkyl)thiazoles, important
synthetic equivalents of 2-hydroxy aldehydes, have been
efficiently resolved by biochemical kinetic resolution.
This method fills the gap that can be seen in the poor
results (obtained until now) in the biocatalytic reduction
of 2-acyl thiazoles and affords enantioenriched synthons
which should find use in numerous organic syntheses.
Exp er im en ta l Section
The 1H NMR spectra (500.13 MHz) were recorded in CDCl3
at 303 K and were referenced to CHCl3 at 7.24 ppm. HPLC
analyses were carried out on a Merck superspher 100 RP-18
column, 4 mm × 25 cm, the flow rate was 1 mL/min, and the
detection was performed at 241 nm. Optical rotations were
measured for 1% CHCl3 solutions. TLC was carried out on silica
gel 60 F254 microplates. Column chromatography refers to flash
Since the best reaction results, in terms of enantiose-
lectivity, were with TFEB in diisopropyl ether, successive
experiments were performed under the same conditions
to determine the enantiomeric ratio (E) for all the
substrates 1a -m . These values are reported as the
average of three values, calculated for conversions rang-
ing from 10 to 50% (Table 2). It can be seen that the
enantioselectivity of the enzyme is always good (E g 20)
(15) (a) Chen, C.-S.; Sih, C. J . Angew. Chem., Int. Ed. Engl. 1989,
28, 695. (b) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, J . J . Am.
Chem. Soc. 1982, 104, 7294.
(16) Various attempts to perform the hydrolysis in diisopropyl ether
or cyclohexane saturated with water, according to Hirose, Y.; Kariya,
K.; Sasaki, I.; Kurono, Y.; Ebiike, H.; Achiwa, K. Tetrahedron Lett.
1992, 33, 7157, were unsuccessful.
(17) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(18) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092.
(14) Bovara, R.; Carrera, G.; Ferrara L.; Riva, S. Tetrahedron
Asymmetry 1991, 2, 931.
(19) McCreary, M. D.; Lewis, D. W.; Wernick, D. L.; Whitesides, G.
M. J . Am. Chem. Soc. 1974, 96, 1038.

4146 J . Org. Chem., Vol. 61, No. 12, 1996
Notes
Ta ble 1. Effects of th e Na tu r e of Or ga n ic Solven ts on th e En a n tioselectivity a n d Activity of Im m obilized Lip a se P S in
th e Acyla tion of 2-(1-Hyd r oxya lk yl)th ia zole (1g) w ith Vin yl Aceta te a n d 2,2,2-Tr iflu or oeth yl Bu ta n oa te
AcOCHdCH2
relative rate %b
Me(CH2)2CO2CH2CF3
relative rate %
solvents
log P
ꢀ
Ea
Ea
hexane
chloroform
3.50
2.00
1.90
1.90
1.45
0.85
0.49
-0.33
8.10
4.81
4.50
3.88
5.80
4.20
7.58
35.95
6
7
16
21
6
9
6
2
100
20
90
85
35
40
10
5
10
5
95
2
tert-butyl methyl ether
diisopropyl ether
2-methyl-2-butanol
diethyl ether
tetrahydrofuran
acetonitrile
31
50
-
-
2
90
100
<1
<1
5
-
<1
a
E (enantiomeric ratio) values were calculated from the degree of conversion and the ee of the product according to Chen, C.-S., et al.15
b
Each value was the average of three values calculated for conversions ranging from 10 to 50%. This parameter, average of three values,
is based on 10% conversions and compares the activity of the enzyme in different solvents.
Ta ble 2. Im m obilized Lip a se P S-Ca ta lyzed Resolu tion of
2-(1-Hyd r oxya lk yl)th ia zoles
d, J ) 3.5 Hz), 4.90 (1H, dd, J ) 7.7, 4.9 Hz), 1.86 (1H, dddd, J
) 13.3, 9.4, 5.6, 4.9 Hz), 1.78 (1H, dddd, J ) 13.3, 9.8, 7.7, 4.9
Hz), 1.46-1.16 (10H, m), 0.80 (3H, t, J ) 7.0 Hz); MS m/z 213
acylation
hydrolysis
(2), 170 (9), 114 (100), 86 (24), 59 (11). Anal. Calcd for C11H19
-
convna
(%)
(S)-1
(R)-2
(R)-1
NOS: C, 61.93; H, 8.98; N, 6.57; S, 15.03. Found: C, 62.01; H,
8.81; N, 6.60, S, 14.94.
ee (%)c
ee (%)e
ee (%)c
compd
R
E
(time, h)b (yield, %)d (yield, %)d (yield, %)f
2-(1-Hydroxynonyl)thiazole (1h , 85% yield): mp 44-46 °C
(from diethyl ether-hexane). Anal. Calcd for C12H21NOS: C,
63.39; H, 9.31; N, 6.16. Found: C, 63.42; H, 9.24; N, 6.27.
2-(1-Hydroxydecyl)thiazole (1i, 87% yield): mp 52-54 °C
(from diethyl ether-hexane). Anal. Calcd for C13H23NOS: C,
64.68; H, 9.60; N, 5.80. Found: C, 64.50; H, 9.43; N, 5.61.
2-(1-Hydroxyundecyl)thiazole (1l, 90% yield): mp 60-62 °C
(from diethyl ether-hexane). Anal. Calcd for C14H25NOS: C,
65.83; H, 9.87; N, 5.48. Found: C, 65.90; H, 9.77; N, 5.30.
2-(1-Hydroxy-1-phenylmethyl)thiazole11 (1m , 90% yield): mp
107-109 °C (from diethyl ether-hexane). Anal. Calcd for
1a
1b
1c
1d
1e
1f
1g
1h
1i
CH3
5
7
53 (96)
13 (260)
55 (43)
11 (83)
94 (41)
93 (42)
95 (42)
96 (42)
49 (49)
74 (10)
77 (49)
72 (49)
78 (51)
78 (52)
82 (50)
79 (50)
73 (53)
75 (53)
86 (49)
-
-
-
-
C2H5
C3H7
C4H9
27 55 (130)
20 56 (180)
98 (35)
96 (34)
98 (37)
98 (37)
>98 (39)
98 (35)
97 (35)
97 (37)
>98 (37)
C5H11 29 55 (160)
C6H13 32 55 (90)
C7H15 50 55 (110) >98 (41)
C8H17 34 55 (90)
C9H19 27 57 (110)
96 (41)
97 (40)
95 (42)
97 (44)
1l
1m
C10H21 25 56 (90)
C6H5
58 53 (80)
C
10H9NOS: C, 62.80; H, 4.74; N, 7.32. Found: C, 62.74; H, 4.91;
N, 7.20.
Lip a se-Med ia ted Acyla tion of Ra cem ic 2-(1-h yd r oxy-
a
b
Determined by HPLC. Referred to enzymatic esterification.
c Enantiomeric excesses were determined by 1H NMR analysis of
the Mosher esters. After flash chromatography. e Enantiomeric
d
a lk yl)t h ia zoles (1a -m ) in Or ga n ic Solven t s. Gen er a l
P r oced u r e. 2,2,2-Trifluoroethyl butanoate (2 mmol) and im-
mobilized Lipase PS (400 mg; 30% on Hyflo Super Cell) were
added to a solution of each of the racemic 2-(1-hydroxyalkyl)-
thiazoles (1a -m , 1 mmol) in diisopropyl ether (10 mL).
The resulting suspension was shaken at 25 °C and monitored
by HPLC (LiChroCART 250-4, Superspher 100 RP-18, 4 × 244
mm, Merck, 1 mL/min, λ 241 nm; the different thiazoles were
eluted with aqueous methanol ranging from 70 to 90%). When
the desired conversion was reached, the enzyme was recovered
by filtration and the solvent evaporated under reduced pressure.
Flash chromatography (hexane-AcOEt, 80:20 v/v) of the residue
afforded the unreacted alcohols (S)-1a -m and the butanoates
(R)-2a -m , with the yields and enantiomeric excess shown in
Table 2.
excesses were determined by 1H NMR using 0.1-0.2 equiv of
Eu(hfc)3. f After flash chromatography, referred to initial racemic
mixture.
chromatography.20 (S)- and (R)-R-Methoxy-R-(trifluoromethyl)-
phenylacetate [(S)- and (R)-MTPA] derivatives were prepared
from the appropriate (R)- and (S)-MTPA chlorides.17,18 All
organic solvents were dried before use.
Usual workup refers to washing the organic layer with water,
drying it over Na2SO4, and evaporating the solvent under
reduced pressure. The progress of all the reactions, the column
chromatography, and compound purity were monitored by TLC
and/or HPLC.
The 2-(1-hydroxyalkyl)thiazoles (1a -m ) were synthesized on
a 20 mmol scale using Dondoni’s methodology10 and showed the
following yields and properties.
2-(1-Hydroxyethyl)thiazole (1a , 85% yield): oil. Anal. Calcd
for C5H7NOS: C, 46.49; H, 5.46; N, 10.84. Found: C, 47.11; H,
5.30; N, 10.62.
2-(1-Hydroxypropyl)thiazole (1b, 87% yield): oil. Anal. Calcd
for C6H9NOS: C, 50.32; H, 6.33; N, 9.78. Found: C, 50.57; H,
6.01; N, 9.84.
2-(1-Hydroxybutyl)thiazole (1c, 86% yield): oil. Anal. Calcd
for C7H11NOS: C, 53.47; H, 7.05; N, 8.91. Found: C, 53.30; H,
7.19; N, 9.01.
In particular, the unreacted (S)-2-(1-hydroxyalkyl)thiazoles
(S)-1a -m (purity > 97% by HPLC) showed correct physico-
chemical properties, identical to those observed for their race-
mates, and the following optical rotations, [R]25D: -3.5 for (S)-
1a , -7.4 for (S)-1b, -32.4, for (S)-1c, -26.0 for (S)-1d , -18.5
for (S)-1e, -16.3 for (S)-1f, -18.1 for (S)-1g, -15.3 for (S)-1h ,
-13.9 for (S)-1i, -13.8 for (S)-1l, and -29.0 for (S)-1m .
The butanoates (R)-2a -m showed 1H NMR spectra with
appropriate proton signals and the following optical rotations,
[R]25D: +35.1 for (R)-2a , +29.4 for (R)-2b, +56.7 for (R)-2c, +58.1
for (R)-2d , +39.1 for (R)-2e, +42.1 for (R)-2f, +36.6 for (R)-2g,
+40.5 for (R)-2h , +40.0 for (R)-2i, +33.9 for (R)-2l, and +76.8
for (R)-2m . They were normally used directly in the next
hydrolysis.
Lip a se-Med ia ted Hyd r olysis of th e Bu ta n oa te (R)-2c-
m . Gen er a l P r oced u r e. Lipase PS (75 mg) was added to a
solution of the butanoates 2c-m (derived from the previous
acylation), in phosphate buffer (5 mL, 0.1 M, pH 7, kept constant
at the starting value by controlled addition of 0.1 M sodium
hydroxide) and acetone (0.5 mL). The hydrolysis was followed
by HPLC, and when the desired conversion was reached the
mixture was extracted with CH2Cl2. Usual workup afforded a
residue which was purified by flash chromatography (hexane-
AcOEt, 80:20 v/v) to give the (R)-2-(1-hydroxyalkyl)thiazoles (R)-
1c-m (purity > 97% by HPLC), which showed appropriate
2-(1-Hydroxypentyl)thiazole (1d , 90% yield): oil. Anal. Calcd
for C8H13NOS: C, 56.11; H, 7.65; N, 8.18. Found: C, 56.20; H,
7.49; N, 8.09.
2-(1-Hydroxyhexyl)thiazole (1e, 89% yield): oil. Anal. Calcd
for C9H15NOS: C, 58.34; H, 8.16; N, 7.56. Found: C, 58.50; H,
8.19; N, 7.47.
2-(1-Hydroxyheptyl)thiazole11 (1f, 88% yield): oil. Anal.
Calcd for C10H17NOS: C, 60.26; H, 8.60; N, 7.03. Found: C,
60.20; H, 8.74; N, 6.92.
2-(1-Hydroxyoctyl)thiazole (1g, 90% yield): oil; IR (film) 3230,
2920, 1500 cm-1; 1H NMR δ 7.56 (1H, d, J ) 3.5 Hz), 7.17 (1H,
(20) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Notes
J . Org. Chem., Vol. 61, No. 12, 1996 4147
physicochemical properties identical to those observed for (S)-
enantiomers, apart from optical rotations, [R]25D, which were:
+32.6 for (R)-1c, +26.9 for (R)-1d , +18.7 for (R)-1e, +16.6 for
(R)-1f, +18.3 for (R)-1g, +15.7 for (R)-1h , +14.2 for (R)-1i, +14.0
for (R)-1l, and +29.4 for (R)-1m .
Usual workup and column chromatography (hexane/AcOEt,
80:20 v/v) afforded the (R)-(E)-4-(benzoyloxy)-2-undecenal [(R)-
1
5, 188 mg, 86% yield] as an oil: [R]20 -53.6; H NMR (CDCl3)
D
δ 9.57 (1H, d, J ) 7.7 Hz), 8.05 (2H, d, J ) 7.7 Hz), 7.57 (1H,
dd, J ) 7.7, 7.7 Hz), 7.45 (2H, dd, J ) 7.7, 7.7 Hz), 6.83 (1H, dd,
J ) 15.4, 4.9 Hz), 6.27 (1H, ddd, J ) 15.4, 7.7, 1.4 Hz), 5.75
(1H, ddt, J ) 6.3, 4.9, 1.4 Hz), 1.90-1.79 (2H, m), 1.48-1.19
(10H, m), 0.85 (3H, t, J ) 7.7 Hz); MS m/z 167 (3), 122 (10), 105
(100), 77 (21). Anal. Calcd for C18H24O3: C, 74.97; H, 8.39.
Found: C, 75.09; H, 8.47.
Syn th esis of (R)-(E)-4-Hyd r oxy-2-u n d ecen a l (R)-6. (i)
Ben zoyla tion of (R)-2-(1-h yd r oxyoctyl)th ia zole (1g). To a
solution of thiazole (R)-1g (250 mg, 1.2 mmol) in pyridine (10
mL) was added benzoyl chloride (210 mg, 1.5 mmol) at 0 °C,
and the mixture was stirred at 25 °C for 1 h. After usual
workup, the resulting oil was purified by flash chromatography
(CH2Cl2) to give the ester (R)-4 (362 mg, 95% yield) as an oil:
(iv) Regen er a tion of th e Hyd r oxyl Gr ou p . The benzoyl-
oxy aldehyde (R)-5 (173 mg, 0.6 mmol), dissolved in CH2Cl2 (8
mL), was stirred with montmorillonite clay K-10 (200 mg) in
trimethyl orthoformiate (0.22 mL, 2 mmol) for 2 h. At this time
the reaction mixture was filtered, washed with saturated
aqueous NaHCO3, and worked up to give the crude benzoyloxy
acetal which was equilibrated with a methanolic solution of
sodium methoxide (5 mL, 0.1 M) at room temperature for 8 h.
Then the reaction mixture was diluted with water (15 mL) and
extracted with AcOEt (20 mL). Usual workup afforded a crude
hydroxy acetal which was dissolved in moist acetone (5 mL) and
treated with an acidic ion exchange resin (Dowex-50 W-hydro-
gen, 125 mg), for 1 h at room temperature. After filtration of
the resin, the solvent was evaporated and the crude residue
purified by flash chromatography (hexane-AcOEt, 70:30 v/v) to
give the (R)-(E)-4-hydroxy-2-undecenal [(R)-6, 82 mg, 74% yield)
[R]25 -18.4; 1H NMR δ 8.09 (2H, d, J ) 7.7 Hz), 7.75 (1H, d, J
D
) 3.5 Hz), 7.55 (1H, dd, J ) 7.7, 7.7 Hz), 7.43 (2H, dd, J ) 7.7,
7.7 Hz), 7.27 (1H, d, J ) 3.5 Hz), 6.35 (1H, t, J ) 6.3), 2.17 (2H,
dt, J ) 9.1, 6.3 Hz), 1.47-1.16 (10H, m), 0.83 (3H, t, J ) 7.0
Hz); MS m/z 317 (2), 212 (100), 114 (18), 105 (63), 77 (27). Anal.
Calcd for C18H23NO2S: C, 68.10; H, 7.30; N, 4.41. Found: C,
68.27; H, 7.24; N, 4.53.
(ii) Th ia zolyl-to-F or m yl Deblock in g. To a solution of ester
3 (320 mg, 1.5 mmol) in acetonitrile (10 mL) was added methyl
iodide (3.2 g, 22.5 mmol), and the resulting mixture was refluxed
for 15 h. The solvent was then removed under reduced pressure
and the residue dissolved in methanol (10 mL) and cooled to 0
°C. Sodium borohydride (85 mg, 2.25 mmol) was then added
under vigorous stirring. After 30 min acetone (0.5 mL) was
added and the solvent was removed under reduced pressure. The
residue was extracted with CH2Cl2, and the combined extracts
were worked up to afford an oil which was dissolved in
acetonitrile (1.5 mL) and slowly added to a vigorously stirred
solution of HgCl2 (488 mg, 1.8 mmol) in a mixture of acetoni-
trile-water (5 mL, 4:1 v/v). After 15 min, the reaction mixture
was filtered on a pad of Celite, and the inorganic residue was
washed with diethyl ether. The ethereal extracts were added
to the filtered solution, and the mixture was concentrated under
reduced pressure. The residue was diluted with brine (5.0 mL)
and extracted with CH2Cl2. Usual workup afforded a residue
which was purified by flash chromatography (hexane-AcOEt,
80:20 v/v) to give (R)-2-(benzoyloxy)nonanal (R)-4 (244 mg, 62%
as an oil: [R]20 -44.2. This compound showed appropriate
D
physicochemical properties identical to those reported.1e
Syn th esis of (S)-(E)-4-Hyd r oxy-2-u n d ecen a l [(S)-6]. This
aldehyde was obtained by a reaction sequence identical to that
described for the (R)-enantiomer. The final and intermediate
compounds showed appropriate physicochemical properties,
identical to those observed for (R)-enantiomers, but differing in
optical rotation. In fact compounds (S)-3, (S)-4, (S)-5, and (S)-6
showed, respectively: [R]21 +18.2; [R]23 -32.4; [R]21 +53.4;
D
D
D
[R]22 +44.0.
D
yield) as an oil: [R]23 +32.6; 1H NMR δ 9.62 (1H, d, J < 1),
D
Ack n ow led gm en t. This work was supported by
Regione Lombardia (Piano di Ricerche Finalizzate per
il Settore Sanitario, progetto no. 1560).
8.08 (2H, d, J ) 7.7 Hz), 7.59 (1H, dd, J ) 7.7, 7.7 Hz), 7.46
(2H, dd, J ) 7.7, 7.7 Hz), 5.20 (1H, dd, J ) 8.4, 4.9 Hz), 1.99-
1.83 (2H, m), 1.53-1.20 (10H, m), 0.86 (3H, t, J ) 7.7 Hz); MS
m/z 212 (14), 105 (100), 77 (23). Anal. Calcd for C16H22O3: C,
73.25; H, 8.45. Found: C, 73.42; H, 8.50.
Su p p or tin g In for m a tion Ava ila ble: IR, 1H NMR (500
MHz), and mass spectra of 2-(1-hydroxyalkyl)thiazoles (1a -
m ) (2 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(iii) Wittig Rea ction w ith (F or m ylm eth ylen e)tr ip h en -
ylp h osp h or a n e. To a solution of the benzoyloxy aldehyde (R)-4
(200 mg, 0.76 mmol) in toluene (20 mL) was added (formyl-
methylene)triphenylphosphorane (277 mg, 0.91 mmol), and the
resulting mixture was refluxed for 6 h. Then the mixture was
diluted with diethyl ether (30 mL), and the triphenylphosphine
oxide was filtered.
J O952082T