Asymmetric synthesis of (1R,2S,3R)-2-acetyl-4-(1,2,3,4- tetrahydroxybutyl)thiazole

Article abstract of DOI:10.1016/S0957-4166(98)00104-9

Two different methods for preparing the thiazole analogue 3 of the biologically active compound (1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4- tetrahydroxybutyl)imidazole 1 are reported.

Full text of DOI:10.1016/S0957-4166(98)00104-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1395–1407
Asymmetric synthesis of (1R,2S,3R)-2-acetyl-4-
(1,2,3,4-tetrahydroxybutyl)thiazole
Alison T. Ung and Stephen G. Pyne ∗
Department of Chemistry, University of Wollongong, Wollongong, NSW, 2522, Australia
Received 11 February 1998; accepted 11 March 1998
Abstract
Two different methods for preparing the thiazole analogue 3 of the biologically active compound (1R,2S,3R)-2-
acetyl-4(5)-(1,2,3,4- tetrahydroxybutyl)imidazole 1 are reported. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
(1R,2S,3R)-2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI) 1, a constituent of Caramel
Colour III, has been found to depress blood lymphocyte counts in both mice and rats.1 THI produces
lymphopenia, apparently without toxic effects, in rats and mice and is able to affect the immune compe-
tence in the rat in quite small quantities (e.g. 1–50 ppm in drinking water).2 THI has also been reported to
prevent spontaneous and cyclophosphamide-induced diabetes in non-obese diabetic mice.3 To investigate
the structure–activity relationships of this structurally simple but biologically intriguing molecule we
have developed a general and flexible synthesis of THI and its analogues,4–6 including the 5-thiazole
analogue 2.7 We now report the asymmetric synthesis of the 4-thiazole analogue 3 of THI, using two
different synthetic strategies. The first strategy involved a double Sharpless asymmetric dihydroxylation
(AD) of a 1,3-butadiene to introduce the tetrahydroxybutyl side chain of 3. In an alternative synthesis of
3 the tetrahydroxybutyl side chain was introduced via the condensation of a 4-lithiothiazole derivative
and 2,3-O-isopropylidene-D-erythrono-1,4-lactone.
∗
Corresponding author. E-mail: Stephen_Pyne@uow.edu.au
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00104-9

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2. Results and discussion
2.1. Synthesis of 3 via double Sharpless asymmetric dihydroxylation (AD)
Ethyl 2-bromothiazole-4-carboxylate 48a,b was reduced with DIBAL to its carboxaldehyde derivative
5 in 72% yield using standard conditions (Scheme 1). The Wittig reaction between 5 and allyl tri-
phenylphosphonium bromide, under phase transfer catalysis,9 gave exclusively the (Z)-diene 6, however
the yield of 6 was poor (25%). Catalytic asymmetric dihydroxylation (AD) of 6 at 0°C for 18 h
using commercially available AD mix-α,4,5,10,11 additional chiral ligand [(DHQ)2-PHAL (4 mol%)] and
methanesulfonamide (2 equiv.) in tert-BuOH/H2O gave the diol 7 in 89% crude yield.
Scheme 1.
The enantiomeric excess of 7 was determined to be 32% from 1H NMR analysis of its Mosher diester
8 which was obtained as a 66:34 mixture of diastereoisomers. The (S) stereochemistry assigned to 7 was
based upon Sharpless’s mnemonic (compare with Scheme 3).11–13 Diol 7 was converted to its acetonide
derivative 9, using 2,2-dimethoxypropane in the presence of BF3·Et2O , in 44% overall yield from 6 after
purification by column chromatography. Lithium–bromine exchange between 9 and n-butyllithium gave
the corresponding 2-lithiothiazole derivative that was acetylated with N-methoxy-N-methylacetamide4,6

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to give the 2-acetylthiazole 10 in 87% yield. Irradiation of a solution of 10 in chloroform with UV light
(140 W mercury lamp) under nitrogen for 2.5 h gave an equilibrium mixture (1:1) of the (E) and (Z)
alkenes 11 and 10 that could be separated by PTLC (Scheme 1). Recovered 10 could be further recycled
by photolysis to produce more 11.
Catalytic asymmetric dihydroxylation (AD) of 11 at 0°C for 5 days using commercially available AD
mix-β,4,5,9,10 additional chiral ligand [(DHQD)2-PHAL (4 mol%)] and methanesulfonamide (2 equiv.) in
tert-BuOH/H2O gave a mixture of the syn diols 12 and 14 in a ratio of 65:35, respectively (Scheme 2).
These diastereoisomeric diols were readily separated by column chromatography on silica gel. The
enantiomeric excess of the individual diols, 12 and 14, was determined to be 93% and 84%, respectively,
from 1H NMR analysis of their respective Mosher diesters 13 and 15.
Scheme 2.
The AD reaction of both (S)-11 and (R)-11 therefore proceeds with very high π-facial diastereo-

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selectivity and thus allows for the preparation of 12 and 14, respectively, in high enantiomeric purities.
We have found that the AD reaction of chiral trans-disubstituted alkenes related to 11 were also
highly diastereoselective, in both the matched (d.r.=99:1) and mismatched cases (d.r.=95:5).6 The
stereochemistry assigned to 12 and 14 was based on our previous work4–6 and Sharpless’s mnemonic
(Scheme 3).10,11 The AD reaction of (S)-11 (Scheme 3) would be expected to be the matched case while
that of (R)-11 would be the mismatched case. These predictions are consistent with the magnitude of
the enantiomeric purities of their respective AD products 12 and 14. Finally, deprotection of 12 and 14
was achieved by acid hydrolysis with aqueous hydrochloric acid/acetone at rt for 2 h to give the desired
1
compound 3 and its diastereoisomer 16, respectively. The H NMR spectrum of 3 [δ (D2O) 5.00 (d,
1
J=2.4 Hz, H10)] was similar to that of THI 1 [δ (D2O) 4.91 (s, H10)], while the H NMR of 16 was
very different [δ (D2O) 4.89 (d, J=5.7 Hz, H10)]. The latter spectrum more closely matched that of the
(10R,20S,30S) analogue of THI 1 [δ (D2O) 5.04 (d, J=4.8 Hz, H10)].6
Scheme 3.
2.2. Synthesis of 3 from 2,3-O-isopropylidene-D-erythrono-1,4-lactone
Treatment of 2,4-dibromothiazole14 with n-BuLi in THF at −78°C followed by acetylation of the re-
sulting 2-lithiothiazole compound with N-acetylmorpholine15 gave 2-acetyl-4-bromothiazole 17 in 61%
yield (Scheme 4). The keto group of 17 was protected as its dimethoxyketal 18 and its 4-lithiothiazole
derivative was treated with 2,3-O-isopropylidene-D-erythrono-1,4-lactone 19 at −78°C to give the lactol
20 in 58% yield along with a small amount (<10%) of the C-2 epimerized ketone 21. Treatment of 20
with sodium borohydride/methanol at −10°C gave a 67:33 mixture of the diastereoisomeric diols 22 and
23, respectively, which could readily separated by PTLC. The stereochemistry assigned to 22 and 23
1
was determined by H NMR analysis whereby comparisons were made with their 5-thiazole analogues
of known stereochemistry16 while that of 23 was unequivocally determined from a single-crystal X-ray
structural analysis.17 The stereochemistry of the major diol 22 is that expected from the Felkin–Anh
transition state model A18 or the γ-chelated transition state structure B19 in which hydride attack would
be expected to occur from the convex face of the bicyclo[5.3.0]decane ring system in B. In contrast, the
reduction of the lactol 20 with L-selectride in THF at −78°C proceeded with reverse diastereoselectivity
and gave a 16:84 mixture of the diastereoisomeric diols 22 and 23, respectively. Acid hydrolysis of the
individual diastereoisomers 22 and 23 gave 3 and 24, respectively. Compound 3 had identical spectral
properties to those obtained for 3 prepared according to Scheme 2 above.

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Scheme 4.
In summary, we have developed two independent methods for the synthesis of the 4-thiazole analogue
3 of the biologically active molecule THI 1 either using a double AD reaction of a 1,3-butadiene13 or
from 2,3-O-isopropylidene-D-erythrono-1,4-lactone.

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3. Experimental
General procedures were as described previously.4 All NMR were determined in CDCl3 solution,
unless otherwise indicated, at 300 MHz (1H NMR) or 77.5 MHz (13C NMR).
3.1. Ethyl 2-bromothiazole-4-carboxylate 4
The title compound was prepared in two steps using the following modifications to the literature
procedures. A mixture of solid thiourea (7.95 g, 0.104 mol) and ethyl bromopyruvate (20.40 g, 0.104
mol) was cautiously heated with stirring at 100°C for 1 h. After cooling, the dark solid that formed was
washed with acetone and filtered to give a dark yellow solid which was further purified by crystallisation
from ethanol to give ethyl 2-aminothiazole-4-carboxylate hydrobromide salt as a colourless solid (22.92
1
g, 87%), m.p: 184–185°C (lit.8a m.p: 179–180°C). H NMR (D2O) δ 7.56 (s, 1H, H5), 4.23 (q, 2H,
J=6.9 Hz, CH2), 1.20 (t, 3H, J=6.9 Hz, CH3). 13C NMR (D2O) δ 178.93 (CO), 167.34 (C2), 139.94
(C4), 126.40 (C5), 72.28 (CH2), 22.14 (CH3). MS (ES +ve) m/z 173.00 (M+1, 100%), 127.00 (100%). A
solution of dry CuBr2 (10.72 g, 48 mmol) and tert-butyl nitrite (6.20 g, 60 mmol) in dry acetonitrile (160
mL) was cooled to 0°C.8b Then solid ethyl 2-aminothiazole-4-carboxylate (10.12 g, 40 mmol) was added
portion-wise to the solution with stirring over 20 min. The reaction mixture was allowed to warm to rt
over 2 h, then was poured into a 20% solution of HCl (450 mL) and the aqueous solution was extracted
with ether (800 mL). The combined ether extracts were washed with a 10% solution of HCl and dried
over MgSO4. The solvent was removed to give a dark orange oil which solidified upon standing at rt. The
crude product was purified by column chromatography (15% ethyl acetate/hexane) to give 4 as a white
crystalline solid (6.59 g, 88%), m.p: 65–65.5°C (lit.8a m.p: 68.5–69.2°C) and ethyl 2,5-dibromothiazole-
4-carboxylate as a pale yellow oil (1.83 g). 4: 1H NMR δ 8.11 (s, 1H, H5), 4.41 (q, 2H, J=6.9 Hz, CH2),
1.38 (t, 3H, J=6.9 Hz, CH3). 13C NMR δ 159.98 (CO), 147.21 (C2), 136.63 (C4), 130.69 (C5), 61.53
(CH2), 14.17 (CH3). MS (ES +ve) m/z 236.9 (M+1, 90%), 235.9 (M, 100%).
1
Ethyl 2,5-dibromothiazole-4-carboxylate: H NMR δ 4.40 (q, 2H, J=7.2 Hz, CH2), 1.39 (t, 3H, J=7.2
Hz, CH3). 13C NMR δ 159.55 (CO), 143.73 (C2), 135.62 (C4), 118.76 (C5), 61.97 (CH2), 14.13 (CH3).
3.2. 2-Bromothiazole-4-carboxaldehyde 5
To a solution of 4 (3.00 g, 12.7 mmol) in dry THF/CH2Cl2 (1:1, 200 mL) at −78°C was added dropwise
a solution of DIBAL (3 equiv., 38 mmol, 25.4 mL of 1 M solution) to maintain the temperature at −70°C.
The reaction was left to stir at −78°C for 5 h then was quenched with dry methanol (20 mL) at the same
temperature. The reaction mixture was poured into an ice-cold solution of 1 M HCl (100 mL) and the
aqueous layer was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with

A. T. Ung, S. G. Pyne / Tetrahedron: Asymmetry 9 (1998) 1395–1407
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a sat. solution of NaCl and dried over MgSO4. The solvent was removed to give a white solid material
which was purified by column chromatography (25% ethyl acetate/hexane) to give 5 as a white solid
1
(1.751 g, 72%), m.p: 122–123°C, plus a trace of its over-reduced alcohol derivative. H NMR δ 9.94 (s,
1H, CHO), 8.12 (s, 1H, H5). 13C NMR δ 183.19 (CHO), 154.33 (C2), 137.68 (C4), 130.29 (C5). MS
(ES +ve) m/z: 193.4 (M+1, 90%), 191.50 (M−1, 100%).
3.3. (Z)-2-Bromo-4-(1,3-butadienyl)thiazole 6
A mixture of the aldehyde 5 (1.134 g, 5.91 mmol), allyltriphenylphosphonium bromide (2.3 g, 6.07
mmol), triethylbenzylammonium chloride (0.023 g) in dry benzene (50 mL) was set to stir at 0°C.
Potassium tert-butoxide (0.93 g, 8.3 mmol) was added in small portions to the reaction mixture. After
stirring for 30 min at rt, the mixture was diluted with petroleum spirit (50 mL) and filtered through a small
column of silica gel and the column was washed with 10% ethyl acetate/hexane (100 mL). The solvent
was removed to give a yellow oil which was purified by column chromatography to give a colourless
1
oil (0.33 g, 25%). The product was relatively unstable and was directly used for the next reaction. H
NMR δ 7.6 (m, 1H, thia–CH_CH), 7.07 (s, 1H, H5), 6.53–6.4 (m, 1H, thia–CH_CH), 6.26–6.20 (m,
1H, CH_CHaHb), 5.40 (dd, 1H, J=2.1, 16.8 Hz, CHaHb), 5.32 (dd, 1H, J=1.8, 10.3 Hz, CHaHb).
3.4. (1Z,3S)-2-Bromo-4-(3,4-dihydroxy-1-butenyl)thiazole 7
A mixture of AD mix-α10 (2.12 g), (DHQ)2-PHAL (0.005 g), MeSO2NH2 (0.28 g) was added to a
cold solution of the diene 8 (0.33 g, 1.53 mmol) in tert-butanol/H2O (1:1, 15 mL). The reaction mixture
was left to stir at 0°C for 20 h. Solid Na2SO3 (1.28 g) was then added to the mixture at 0°C and allowed
to warm up to rt over 1 h. The mixture was diluted with H2O (25 mL) and extracted with CH2Cl2 (3×20
mL). The combined organic extracts were washed with a sat. solution of NaCl and dried over MgSO4.
1
The solvent was removed to give a dark yellow oil (0.34 g, 89%). H NMR δ 7.09 (s, 1H, H5), 6.39
(ddd, 1H, J=0.6, 1.5, 11.1 Hz, thia–CH_CH), 5.82 (dd, 1H, J=6.3, 11.7 Hz, thia–CH_CH), 4.84 (m, 1H,
HCOH), 3.76 (dd, 1H, J=3.6, 11.1 Hz, CHaHb), 3.66 (dd, 1H, J=7.5, 11.1 Hz, CHaHb). 13C NMR δ
152.40 (C2), 151.07 (C4), 132.84 (C5), 123.39 (thia–CH_CH), 119.73 (thia–CH_CH), 68.54 (HCOH),
66.02 (CH2). MS (ES +ve) m/z: 251.5 (M+1, 55%). HRMS calcd for C7H9Br NO2S 249.95377; found
249.95374.
3.5. Mosher diester 8
A mixture of the diol 7 (0.048 g, 0.192 mmol), (R)-(−) MTPA-Cl (0.150 g, 0.563 mmol), and a crystal
of N,N-dimethylaminopyridine was dissolved in CH2Cl2 (4 mL). Pyridine (7 drops) was added to the
solution and it was left to stir at rt overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and
was washed with a cold solution of 5% HCl then a cold solution of NaHCO3, and dried over MgSO4.
1
The diastereoisomeric ratio (66:34) was determined by H NMR on the crude reaction mixture. The
solvent was removed to give a dark yellow oil which was purified by thin layer chromatography (30%
1
ethyl acetate/hexane) to give a yellow oil (55 mg, 44%, d.r.=66:34). Major diastereoisomer: H NMR δ
7.54–7.31 (m, 10H, 2×C6H5), 7.20 (s, 1H, H5), 6.93–6.86 (m, 1H, thia–CH_CH), 6.42 (dd, 1H, J=1.5,
12.0 Hz, thia–CH_CH), 5.41 (dd, 1H, J=7.5, 11.7 Hz, HCO), 4.86 (dd, 1H, J=2.7, 12.0 Hz, CHaHb), 4.43
(dd, 1H, J=6.9, 12.0 Hz, CHaHb), 3.43 (bs, 3H, OCH3), 3.40 (d, 3H, J=0.9 Hz, OCH3). MS (ES +ve) m/z
682 (M(Br81)+1, 80%), 682.1 (M(Br80)+1, 50%). Minor diastereoisomer: 1H NMR δ 7.54–7.31 (m, 10H,
C6H5), 7.19 (s, 1H, H5), 7.02–6.96 (m, 1H, thia–CH_CH), 6.43 (dd, 1H, J=1.2, 12.0 Hz, thia–CH_CH),

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5.61 (dd, 1H, J=7.8, 11.7 Hz, HCO), 4.81 (dd, 1H, J=2.7, 12.0 Hz, CHaHb), 4.45 (dd, 1H, J=6.0, 12.0
Hz, CHaHb), 3.52 (d, 3H, J=0.9 Hz, OCH3), 3.49 (d, 3H, J: 0.9 Hz, OCH3).
3.6. (1Z,3S)-2-Bromo-4-[30,4-0O-(2-propylidene)-30 ,40-dihydroxy-but-1-enyl]thiazole 9
2,2-Dimethoxypropane (1.11 mL) was added to a solution of diol 7 (0.611 g, 22.45 mmol) in dry
acetone (10 mL) then BF3·Et2O (18 µL) was added dropwise and the mixture was left to stir at rt under
N2 atmosphere for 4 h. The acetone was removed under reduced pressure and the residue was dissolved in
CH2Cl2 (60 mL). The resulting solution was washed with a half sat. solution of NaHCO3, a sat. solution
of NaCl and dried over MgSO4. The solvent was removed to give a dark oil which was purified by column
chromatography (20% ethyl acetate/hexane) to give 9 as a pale yellow oil (0.576 g, 81%). 1H NMR δ 7.11
(s, 1H, H5), 6.39 (dd, 1H, J=1.5, 12.0 Hz, thia–CH_CH), 5.84 (dd, 1H, J=7.5, 11.7 Hz, thia–CH_CH),
5.55 (dddd, 1H, J=1.5, 7.8, 7.8, 7.8 Hz, HCO), 4.47 (dd, 1H, J=6.3, 8.1 Hz, CHaHb), 3.65 (dd, 1H, J=6.9,
8.1 Hz, CHaHb), 1.47 (s, 3H, CH3), 1.43 (s, 3H, CH3). 13C NMR δ 152.27 (C2), 135.39 (C4), 133.00
(C5), 122.42 (thia–CH_CH), 121.02 (thia–CH_CH), 109.15 (C(CH3)2), 73.19 (HCO), 69.62 (CH2),
26.62 (CH3), 25.65 (CH3). MS (ES +ve) m/z: 292.38 (M(Br81)+1, 60%), 291.50 (M(Br80)+1, 50%).
3.7. (1Z,3S)-2-Acetyl-4-[30,40-O-(2-propylidene)-3,4-dihydroxy-1-but-1-enyl]thiazole 10
n-Butyl lithium (2.25 mmol) was added to a solution of protected diol 9 (0.438 g, 1.5 mmol) in dry
ether (20 mL) at −78°C and the resulting solution was left to stir at this temperature for 90 min. A
solution of freshly distilled N-methoxy-N-methylacetamide (0.5 g, 4.85 mmol) in dry ether (5 mL) was
then added dropwise and the reaction mixture was left to stir at −78°C for 2 h then warmed to rt over
2 h. The reaction mixture was diluted with ether (20 mL) and the resulting solution was washed with a
sat. solution of NaHCO3 and dried over MgSO4. The solvent was removed to give a yellow oil which
was purified by column chromatography (20% ethyl acetate/hexane) to give the title compound as a pale
1
yellow oil (0.33 g, 87%). H NMR δ 7.49 (s, 1H, H5), 6.51 (dd, 1H, J=1.5, 11.7 Hz, thia–CH_CH),
5.92 (dd, 1H, J=7.5, 11.7 Hz, thia–CH_CH), 5.67 (dddd, 1H, J=1.5, 6.6, 7.2, 7.8 Hz, HCO), 4.40 (dd,
1H, J=6.3, 8.1 Hz, CHaHb), 3.70 (dd, 1H, J=7.2, 7.8 Hz, CHaHb), 2.72 (s, 3H, COCH3), 1.48 (s, 3H,
CH3), 1.43 (s, 3H, CH3). 13C NMR δ 191.34 (CO), 166.45 (C2), 154.28 (C4), 133.54 (C5), 124.87
(thia–CH_CH), 122.88 (thia–CH_CH), 109.42 (C(CH3)2), 73.53 (HCO), 69.71 (CH2), 26.69 (COCH3),
25.95 (CH3), 25.71 (CH3). MS (ES +ve) m/z: 254.03 (M+1, 100%).
3.8. (1E,3S)-2-Acetyl-4-[3,4-O-(20 -propylidene)-3,4-dihydroxybut-1-enyl]thiazole 11
The cis-alkene 10 (0.33 g, 1.303 mmol) was dissolved in CHCl3 (100 mL) and the resulting solution
was first purged with N2 for 10 min and then irradiated with a 140 W mercury lamp under N2 for 3 h. The
solvent was removed to give a dark yellow oil which was a 1:1 mixture of 10 and 11. These geometric
isomers could be separated by thin layer chromatography (20% ethyl acetate/hexane) to give the E and
Z isomers 10 and 11. 1H NMR δ 7.41 (s, 1H, H5), 6.74 (d, 1H, J=15.6 Hz, thia–CH_CH), 6.63 (dd, 1H,
J=6.3, 15.6 Hz, thia–CH_CH), 4.71 (ddd, 1H, J=6.6, 7.05, 7.5 Hz, HCO), 4.20 (dd, 1H. J=6.3, 8.1 Hz,
CHaHb), 3.73 (dd, 1H, J=7.8, 7.8 Hz, CHaHb), 2.72 (s, 3H, COCH3), 1.49 (s, 3H, CH3), 1.43 (s, 3H,
CH3). 13C NMR δ 191.77 (CO), 166.93 (C2), 155.01 (C4), 139.22 (C5), 124.80 (thia–CH_CH), 122.26
(thia–CH_CH), 76.34 (HCO), 69.46 (CH2), 26.64 (COCH3), 25.95 (CH3), 25.85 (CH3).

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3.9. (1R,2S,3R)- and (1R,2S,3S)-2-Acetyl-4-[3,4-O-(20 -propylidene)-3,4-dihydroxybutyl]thiazole 12
and 14
A mixture of AD mix-β (0.78 g), (DHQD)2-PHAL (0.017 g) MeSO2NH2 (0.103 g) and 5 mol% of
K2OsO4·2H2O was added to a cold solution of trans-protected diol 11 (0.136 g, 0.53 mmol) in tert-
butanol/H2O (1:1, 8 mL) at 0°C. The resulting mixture was left to stir at 0°C for 5 days then Na2SO3
(0.93 g) was added at 0°C and the mixture was allowed to warm up to rt over 1 h. The reaction mixture
was diluted with water (20 mL) and extracted with CH2Cl2 (4×30 mL). The combined organic extracts
were washed with a sat. solution of NaCl and dried over MgSO4. The solvent was removed to give
a yellow oil (0.123 g, 87%, d.r.=65:35) which was purified by thin layer chromatography (75% ethyl
acetate/hexane) to afford 12 (32% yield) and 14 (32% yield). 12: 1H NMR δ 7.70 (d, 1H, J=0.9 Hz, H5),
5.05 (ddd, 1H, J=0.6, 2.4, 7.5 Hz, H10), 4.18–4.11 (m, 2H, 2×OH), 4.05 (ddd, 1H, J=2.4, 2.7, 3.0 Hz,
H20), 3.99 (ddd, 1H, J=2.4, 6.6, 6.45 Hz, H30), 3.35 (d, 1H, J=7.8 Hz, CHaHb), 3.26 (d, 1H, J=6.0 Hz,
CHaHb), 2.68 (s, 3H, COCH3), 1.45 (s, 3H, CH3), 1.35 (s, 3H, CH3). 13C NMR δ 191.20 (CO), 1167.10
(C2), 159.18 (C4), 123.12 (C5), 109.58 (C(CH3)2), 75.34 (C10), 73.98 (C20), 69.14 (C30), 66.80 (CH2),
20
26.73 (COCH3), 25.92 (CH3), 25.17 (CH3). [α]D −14.0 (c 0.5, CH2Cl2). Anal. calcd for C12H17NO5S:
1
C, 50.16; H, 5.96; N, 4.87; S, 11.16; found C, 50.23; H, 5.99; N, 4.79; S, 11.17. 14: H NMR δ 7.70
(d, 1H, J=0.9 Hz, H5), 5.00 (ddd, 1H, J=0.9, 3.3, 3.0 Hz, H10), 4.36 (ddd, 1H, J=3.6, 6.9, 6.6 Hz, H20),
4.12–3.98 (m, 3H, H30 and 2×OH), 3.46 (d, 1H, J=3.9 Hz, CHaHb), 2.77 (d, 1H, J=7.8 Hz, CHaHb),
2.68 (s, 3H, COCH3), 1.48 (s, 3H, CH3), 1,40 (s, 3H, CH3). 13C NMR δ 191.40 (CO), 166.84 (C2),
158.32 (C4), 123.04 (C5), 109.89 (C(CH3)2), 77.06 (C10), 72.31 (C20), 72.21 (C30), 65.95 (CH2), 26.28
21
(COCH3), 25.92 (CH3), 25.29 (CH3). [α]D −22.7 (c 0.75, CH2Cl2). MS (ES +ve) m/z: 288.4 (M+1,
45%), 287.6 (M, 60%). HRMS calcd for C12H18NO2S 288.09054; found 288.09057.
3.10. Mosher diesters 13 and 16
These diesters were prepared from the diols 12 and 14, respectively, as described above for the
synthesis of 8. Compound 13 was a 96.5:3.5 mixture of diastereoisomers, while 14 was a 92:8 mixture
of diastereoisomers. 13: 1H NMR (major diastereoisomer) δ 7.56–7.26 (m, 10H, 2×C6H5), 7.16 (d, 1H,
J=0.9 Hz, H5), 6.56 (dd, 1H, J=0.6, 1.8 Hz, H10), 5.63 (dd, 1H, J=1.8, 8.4 Hz, H20), 4.08 (ddd, 1H, J=5.0,
5.7, 8.4 Hz, H30), 3.86 (dd, 1H, J=5.7, 8.7 Hz, CHaHb), 3.75 (dd, 1H, J=5.7, 8.7 Hz, CHaHb), 3.53 (d,
3H, J=0.9 Hz, OCH3), 3.33 (d, 3H, J=0.9 Hz, OCH3), 2.50 (s, 3H, COCH3), 1.50 (s, 3H, CH3), 1.33 (s,
3H, CH3). MS (ES +ve) m/z: 720.2 (M+1, 35%). 16: 1H NMR (major diastereoisomer) δ 7.51–7.29 (m,
10H, 2×C6H5), 7.03 (s, 1H, H5), 6.27 (d, 1H, J=2.4 Hz, H10), 5.67 (dd, 1H, J: 2.7, 7.5 Hz, H20), 4.13
(ddd, 1H, J=6.3, 7.2, 13.5 Hz, H30), 4.05 (dd, 1H, J=7.7, 7.7 Hz, CHaHb), 3.92 (dd, 1H, J=5.7, 9.0 Hz,
CHaHb), 3.49 (s, 3H, OCH3), 3.37 (s, 3H, OCH3), 2.64 (s, 3H, COCH3), 1.38 (s, 3H, CH3), 1.29 (s,
3H, CH3). Minor diastereoisomer: δ 6.97 (s, 1H, H5), 6.33 (d, J=7.2 Hz, H10). MS (ES +ve) m/z: 720.0
(M+1, 100%).
3.11. (1R,2S,3R)-2-Acetyl-4-(1,2,3,4-tetrahydroxybutyl)thiazole 3
Compound 12 (57 mg, 0.198 mmol) was dissolved in acetone/H2O (1:1, 4 mL) and conc. HCl (1.71
mL) was added to the solution. The reaction mixture was left to stir at rt for 3 h. The acetone was removed
under reduced pressure at 25°C and water was removed on a freeze-dryer to give a yellow solid (33 mg,
67%) that was judged to be >95% pure by 1H NMR. 1H NMR (D2O/DCl) δ 7.80 (s, 1H, H5), 5.00 (d,
1H, J=2.4 Hz, H10), 3.74 (dd, 1H, J=2.4, 7.8 Hz, H20), 3.66–3.52 (m, 2H, H30 and CHaHb), 3.45 (dd, 1H,

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A. T. Ung, S. G. Pyne / Tetrahedron: Asymmetry 9 (1998) 1395–1407
J=5.4, 11.1 Hz, CHaHb), 2.49 (s, 3H, CH3). 13C NMR (D2O/DCl) δ 193.03 (CO), 165.20 (C2), 157.88
(C4), 123.94 (C5), 72.50 (C10), 70.40 (C20), 69.95 (C30), 62.11 (CH2), 25.28 (CH3). MS (ES +ve) m/z:
248.3 (M+1, 100%), 247.5 (M, 80%). HRMS calcd for C9H14NO5S 248.05925; found 248.05927.
3.12. (1R,2S,3S)-2-Acetyl-4-(1,2,3,4-tetrahydroxybutyl)thiazole 16
Compound 14 (10 mg, 0.035 mmol) was dissolved in acetone/H2O (1:1, 1 mL) and conc. HCl (0.3
mL). The resulting solution was left to stir at rt for 2 h. The acetone was removed under pressure and
water was removed on a freeze-dryer to yield a yellow oil (9 mg, 91%) that was judged to be >95% pure
by 1H NMR. 1H NMR (D2O) δ 7.76 (s, 1H, H5), 4.89 (d, 1H, J=5.7 Hz, H10), 3.83 (dd, 1H, J=3.6, 5.7
Hz, H20), 3.45 (m, 3H, H30 and CH2), 2.53 (s, 3H, CH3). 13C NMR (D2O) δ 193.75 (CO), 166.00 (C2),
157.88 (C4), 123.94 (C5), 72.50 (C10), 70.40 (C20), 68.43 (C30), 62.15 (CH2), 25.29 (CH3). MS (ES
23
+ve) m/z: 248.0 (M+1, 10%), 247.4 (M, 15%). MS (ES −ve) m/z: 282.2 (M+ Cl−, 15%). [α]D −16.0
(c 0.5, H2O).
3.13. 2-Acetyl-4-bromothiazole 17
Solid 2,4-dibromothiazole (4.93 g, 20.32 mmol) was dissolved in anhydrous ether (50 mL) and the
resulting solution was allowed to stir under N2 atmosphere at −78°C. To the solution was added n-BuLi
(1.1 equiv., 22.35 mmol, 14 mL of 1.6 M solution) and the stirring continued for 30 min. To the reaction
was then added dropwise 4-acetylmorpholine (1.3 equiv., 26.42 mmol, 3 mL). After stirring for 90 min,
the reaction mixture was diluted with ether and the resulting organic layer was washed with a saturated
solution of NaHCO3, dried over MgSO4. The solvent was removed to give a dark yellow solid which
was purified by column chromatography to give a white crystalline solid (2.78 g, 66%). 1H NMR δ 7.57
(s, 1H, H5), 2.70 (s, 3H, CH3); 13C NMR δ 190.36 (CO), 166.91 (C2), 126.92 (C4), 124.96 (C5), 25.80
(CH3); MS (ES +ve) m/z 207.8 (MBr81+1, 20%), 205.8 (MBr80+1, 15%), 205.1 (MBr79+1, 100%); mp
90–91°C. Anal. calcd for C5H4BrNOS: C, 29.14; H, 1.96; N, 6.79; S, 15.56. Found: C, 29.25; H, 1.89;
N, 6.94; S, 15.29.
3.14. 2-(2,2-Dimethoxyethyl)-4-bromothiazole 18
To the solution of 2-acetyl-4-bromothiazole 17 (0.85 g, 4.12 mmol) in dry MeOH (15 ml) was added
trimethyl orthoformate (41 mmol, 4.84 ml) and p-toluene sulfonic acid (0.7 g). After heating under reflux
for 24 h and cooling to rt, the reaction mixture was diluted with a saturated solution of NaHCO3 (30
ml). The aqueous layer was extracted with ether and the combined organic extracts were washed with a
solution of 1 M NaOH, a saturated solution of NaCl and dried over MgSO4. The solvent was removed
under reduced pressure to give a brown solid which was purified by column chromatography (10% ethyl
1
acetate/hexane) to give a pale yellow solid (0.94 g, 90%). H NMR δ 7.22 (s, 1H, H5), 3.24 (s, 6H,
2×OCH3), 1.71 (s, 3H, CH3); 13C NMR δ 172.60 (C2), 124.68 (C4), 118.13 (C5), 100.28 (C(OCH3)2),
49.21 (2×OCH3), 23.75 (CH3); MS (ES +ve) m/z 253.9 (MBr81+1, 50%), 251.9 (MBr79+1, 40%), 221.8
(MBr81−OCH3, 100%), 219.9 (MBr79−OCH3, 100%); mp 49–50°C. Anal. calcd for C7H10BrNO2S: C,
33.35; H, 4.00; N, 5.56; S, 12.72. Found: C, 33.27; H, 3.93; N, 5.13; S, 12.62.

A. T. Ung, S. G. Pyne / Tetrahedron: Asymmetry 9 (1998) 1395–1407
1405
3.15. 2,3-O-Isopropylidene-1-[2-(2,2-dimethoxyethyl)-4-thiazolyl]-α-D-furanose 20
To a solution of 2-(2,2-dimethoxyethyl)-4-bromothiazole (2.73 g, 10.82 mmol) in anhydrous ether (40
ml) at −78°C was added dropwise n-BuLi (11.90 mmol, 7.5 mL of 1.6 M solution). The resulting mixture
was left to stir at −78°C for 30 min then a solution of 2,3-O-isopropylidene-D-erythrono-1,4-lactone 19
(1.8 g, 11.36 mmol) in anhydrous ether (50 mL) was added. After stirring for 1.5 h, the reaction mixture
was diluted with ether and the aqueous layer was extracted with ethyl acetate. The combined organic
extracts were dried over MgSO4 and the solvent was removed to give a dark yellow oil which was
purified by column chromatography (75% ethyl acetate/n-hexane) to give a mixture of diastereomeric
compounds in the ratio of 80:20 (2.06 g, 58%) and plus a small trace of the open-chain ketone.
Major isomer: 1H NMR δ 7.55 (s, 1H, H5), 5.02 (dd, 1H, J=4.2, 6.0 Hz, H20), 4.69 (d, 1H, J=5.4 Hz,
H30), 4.53 (s, 1H, OH), 4.19 (dd, 1H, J=3.9, 10.2 Hz, CHaHb), 4.05 (d, 1H, J=10.2 Hz, CHaHb), 3.24
(s, 3H, OCH3), 3.24 (s, 3H, OCH3), 1,73 (s, 3H, CH3), 1.50 (s, 3H CH3CCH3), 1.32 (CH3CCH3); 13
C
NMR δ 170.49 (C2), 153.17 (C4), 118.76 (C5), 112.50 (C10), 103.41 (CH3CCH3), 100.76 (C(OCH3)2),
85.58 (C20), 80.63 (C30), 71.12 (C40), 49.32 (OCH3), 49.29 (OCH3), 26.24 (CH3), 24.87 (CH3CCH3),
24.01 (CH3CCH3); MS (ES +ve) m/z 332.0 (M+1, 100%), 300.0 (M−OCH3, 100%). HRMS calcd for
1
C14H22NO6S 332.116752; found 332.116785. Minor isomer: H NMR δ 7.54 (s, 1H, H5), 4.97 (dd,
1H, J=3.9, 6.3 Hz, H20), 4.92 (d, 1H, J=6.0 Hz, H30), 4.50 (s, 1H, OH), 4.12 (dd, 1H, J=7.5, 14.4 Hz,
CHaHb), 3.96 (dd, J=3.9, 10.8 Hz, CHaHb), 3.22 (s, 6H, 2×OCH3), 1.71 (s, 3H, CH3), 1.62 (s, 3H,
CH3CCH3), 1.42 (s, 3H, CH3CCH3); 13C NMR δ 171.99 (C2), 115.80 (C4), 117.09 (C5), 113.33 (C10),
101.80 (CH3CCH3), 100.71 (C(OCH3)2), 82.01 (C20). 80.58 (C30), 69.77 (C40), 49.31 (OCH3), 49.27
(OCH3), 26.16 (CH3), 24.87 (CH3CCH3), 23.96 (CH3CCH3).
3.16. (1R,2S,3R) and (1S,2S,3R)-2-(2,2-Dimethoxyethyl)-4-[2,3-O-(20 -propylidene)-1,4-dihydroxy-
butyl]thiazole 22 and 23
To a stirred solution of 4-lactol 20 (0.557 g, 1.68 mmol) in dry MeOH (20 mL) at −10°C was added
portionwise solid NaBH4 (10 equiv., 16.80 mmol, 0.67 g). After stirring for 2 h, methanol was removed
under reduced pressure, the residue was taken up in H2O (20 mL) and the aqueous layer was extracted
with ethyl acetate (3×30 mL). The combined organic extracts were dried over MgSO4 and the solvent was
removed under reduced pressure to give a colourless oil which was purified by column chromatography
(80% ethyl acetate/hexane) to give a mixture of the syn- and anti-diols in the ratio of 2:1. The two
alcohols was isolated by preparative TLC (75% ethyl acetate/n-hexane) to give syn-diol (0.251 g, 45%)
and anti-diol (0.126 g, 22%) as an oil and a colourless crystalline solid respectively.
3.17. Reduction of 20 with L-selectride
To the stirred solution of the lactol 20 (0.168 g, 0.41 mmol) in dry THF (5 mL) at −78°C was added a
solution of L-selectride (5 equiv., 2.03 mmol, 2.03 mL of 1 M solution in THF). After stirring at −78°C
for 2.5 days, the reaction mixture was quenched with a solution of 10% NaOH (4 mL) and 30% H2O2 (2
mL). The reaction was stirred at rt for another 2 h and was then diluted with a saturated solution of NaCl
(2 mL) and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and the
solvent was removed to give a thick oil which was purified on a preparative TLC plate to give the anti-
and syn-diols, in the ratio of 84:16 (95 mg, 57%), plus unreacted lactol 20 (35 mg).
1
syn-Diol 22: H NMR δ 7.39 (d, 1H, J=0.9 Hz, H5), 5.05 (d, 1H, J=5.4 Hz, H10), 4.48 (t, 1H, J=5.7
Hz, H20), 4.34–4.28 (m, 1H, H30), 3.91 (dd, 1H, J=5.7, 11.7 Hz, CHaHb), 3.79 (dd, 1H, J=3.9, 11.7 Hz,

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A. T. Ung, S. G. Pyne / Tetrahedron: Asymmetry 9 (1998) 1395–1407
CHaHb), 3.24 (s, 3H, OCH3), 3.22 (s, 3H, OCH3), 1.70 (s, 3H, CH3), 1.52 (s, 3H, CH3CCH3), 1.38
(s, 3H, CH3CCH3); 13C NMR δ 172.41 (C2), 156.24 (C4), 116.51 (C5), 108.33 (CH3CCH3), 100.76
(C(OCH3)2), 79.23 (C10), 77.54 (C20), 68.48 (C30), 60.60 (C40), 49.40 (OCH3), 49.36 (OCH3), 27.30
(CH3), 25.07 (CH3CCH3), 24.30 (CH3CCH3); MS (ES +ve) m/z 334.0 (M+1, 70%), 301.9 (M−OCH3,
26
100%); [α]D −45.0 (c 0.8, CH2Cl2). HRMS calcd for C14H24NO6S 334.13240; found 334.132425.
anti-Diol 23: 1H NMR δ 7.29 (d, J=0.6 Hz, H5), 4.98 (dd, 1H, J=5.1, 8.1 Hz, H10), 4.47 (dd, 1H, J=5.7,
8.1 Hz, H20), 4.37 (ddd, 1H, J=5.4, 6.9, 6.0 Hz, H30), 4.25 (d, 1H, J=5.1 Hz, OH), 3.91 (ddd, 1H, J=5.4,
6.9, 12.0 Hz, CHaHb), 3.77 (ddd, 1H, J=4.8, 7.5, 12.0 Hz, CHaHb), 3.52 (dd, 1H, J=6.0, 12.0 Hz, OH),
3.23 (s, 6H, 2×OCH3), 1.70 (s, 3H, CH3), 1.46 (s, 3H, CH3CCH3), 1.35 (s, 3H, CH3CCH3); 13C NMR
δ 171.87 (C2), 155.94 (C4), 116.61 (C5), 108.35 (CH3CCH3), 100.77 (C(OCH3)2), 78.83 (C10), 77.43
(C20), 68.30 (C30), 60.62 (C40), 49.32 (2×OCH3), 27.70 (CH3), 25.20 (CH3CCH3), 24.14 (CH3CCH3);
26
MS (ES +ve) m/z 33.9 (M+1, 100%), 301.8 (M−OCH3, 100%); mp 78–79°C; [α]D −28.89 (c 0.9,
CH2Cl2). Anal. calcd for C14H23NO6S: C, 50.44; H, 6.95; N, 4.20; S, 9.62. Found: C, 50.59; H, 7.06; N,
3.93; S, 9.60%.
3.18. (1R,2S,3R)-2-Acetyl-4-(1,2,3,4-tetrahydroxybutyl)thiazole 3
To the stirred solution of syn-diol 22 (0.67 mg, 0.2 mmol) in ethanol (2 mL) was added a solution of
10% HCl (1 mL). The reaction was left to stir at rt for 2 h. Ethanol was removed under reduced pressure
and the aqueous layer was washed with ether. Water was removed under high vacuum to give a pale
23
yellow hydroscopic solid (40 mg, 70%) that was judged to be >95% pure from 1H NMR analysis, [α]D
−29.83 (c 1.75, H2O). The spectral data for this compound were identical to those obtained above for the
synthesis of 3 from 12.
3.19. (1S,2S,3R)-2-Acetyl-4-(1,2,3,4-tetrahydroxybutyl)thiazole 24
To the stirred solution of anti-diol 23 (69 mg, 0.21 mmol) in ethanol (2 mL) was added a solution of
10% HCl (1 mL). The reaction was left to stir at rt for 2 h. Ethanol was removed under reduced pressure
and the aqueous layer was washed with ether. Water was removed under high vacuum to give a dark
yellow solid (53 mg, 90%) that was judged to be >95% pure from 1H NMR analysis. 1H NMR δ (D2O)
7.66 (s, 1H, H5), 4.89 (d, 1H, J=5.1 Hz, H10), 3.76 (t, 1H, J=6.0 Hz, H20), 3.52 (dd, 1H, J=6.0, 13.5 Hz,
H30), 3.39 (m, 2H, CH2), 2.44 (s, 3H, CH3); 13C NMR (D2O) δ 193.78 (CO), 165.56 (C2), 156.88 (C4),
124.73 (C5), 73.17 (C10), 71.36 (C20), 69.48 (C30), 61.89 (C40), 25.29 (CH3); MS (ES +ve) m/z 247.8
23
(M+1, 35%); [α]D +23.64 (c 1.65, H2O).
Acknowledgements
We thank Johnson and Johnson Research Pty. Limited for financial support and Drs. David Atkins and
Matthew Cliff for valuable discussions and encouragement.
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