Synthesis of 2-acetyl-5-(1,2,3,4,5,6-hexahydroxyhexyl)thiazoles

Article abstract of DOI:10.1007/s00706-011-0448-z

The syntheses of two diastereoisomers of 2-acetyl-5-(1,2,3,4,5,6- hexahydroxyhexyl)thiazole are reported. The synthesis of these diastereoisomers involved the coupling of 5-metallated 2-(1,1-dimethoxyethyl)thiazole with a Weinreb amide derived from d-gluconolactone, followed by asymmetric reduction of the ketone thus prepared. The stereochemistries and structures of some key compounds were determined by single-crystal X-ray structural analysis.

Full text of DOI:10.1007/s00706-011-0448-z

Monatsh Chem (2011) 142:297–303
DOI 10.1007/s00706-011-0448-z
ORIGINAL PAPER
Synthesis of 2-acetyl-5-(1,2,3,4,5,6-hexahydroxyhexyl)thiazoles
•
Alison T. Ung Stephen G. Pyne George R. Jeoffreys
•
•
•
Brian W. Skelton Allan H. White
Received: 10 October 2010 / Accepted: 13 January 2011 / Published online: 17 February 2011
Ó Springer-Verlag 2011
Abstract The syntheses of two diastereoisomers of
2-acetyl-5-(1,2,3,4,5,6-hexahydroxyhexyl)thiazole are re-
ported. The synthesis of these diastereoisomers involved the
coupling of 5-metallated 2-(1,1-dimethoxyethyl)thiazole
with a Weinreb amide derived from d-gluconolactone, fol-
lowed by asymmetric reduction of the ketone thus prepared.
The stereochemistries and structures of some key com-
pounds were determined by single-crystal X-ray structural
analysis.
(depression of blood lymphocyte counts), without any
apparent side-effects, in mice and rats that were given THI
in their drinking water [7, 8]. Thus THI and its analogues
have potential applications as an immunosuppressive agent
in organ transplant biology or for preventing the onset of
diabetes [9].
The synthesis of thiazole analogues of THI such as
compounds 2 (n = 1, 2) and 3 (n = 1, 2) was previously
reported by us [10]. We now report the details of the
synthesis of two of the more extended side-chain dia-
stereoisomers of the hexahydroxyhexyl analogues 4, as
shown in Fig. 1, and their X-ray structures to support
their stereochemical assignments. Our first strategy was
to introduce the hexahydroxyhexyl side chain with the
stereochemistries of (1R or 1S, 2R, 3S, 4R, 5R) onto the
thiazole ring at the 5-position. This involved the coupling
of 5-metallated 2-(1,1-dimethoxyethyl)thiazole (10) with
the novel Weinreb amide 8 to provide ketone 11, then
asymmetric reduction of the ketone to provide two
diastereomers 12 and 13 of the hexahydroxyhexyl
thiazoles.
Keywords THI analogues ꢀ Immunosuppressive agent ꢀ
Asymmetric reduction ꢀ Thiazole derivatives ꢀ
Hexahydroxy side chain
Introduction
As part of a medicinal chemistry project [1–6] we required
the synthesis of the 4- and 5-thiazole analogues, 2, 3, and 4
respectively, of the known immunosuppressive agent
(1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole
(THI, 1) [7–9]. THI is a minor component of the common
food additive Caramel Colour III. THI caused lymphopenia
Results and discussion
A. T. Ung (&)
Compound 8 was prepared from d-gluconolactone (5),
using a known procedure [11, 12] to provide triisopropy-
Department of Chemistry and Forensic Science,
University of Technology, Sydney,
P.O. Box 123, Broadway, Sydney, NSW 2007, Australia
e-mail: Alison.Ung@uts.edu.au
lidene-D-gluconate
6
(Scheme 1). The structure of
compound 6 was confirmed by single-crystal X-ray anal-
ysis (Fig. 2).
S. G. Pyne ꢀ G. R. Jeoffreys
Compound 6 was then heated in the presence of mor-
pholine in a sealed tube at 100 °C to afford the hydroxy
amide 7 in 95% yield. The hydroxy amide 7 was then
protected as the tert-butyldimethylsilyl ether which pro-
vided 8 in 97% yield. Single-crystal X-ray structural
School of Chemistry, University of Wollongong,
Wollongong, NSW 2522, Australia
B. W. Skelton ꢀ A. H. White
Department of Chemistry, University of Western Australia,
Nedlands, WA 6907, Australia
123

298
A. T. Ung et al.
OH OH
OH OH
OH
OH
n
HN
O
N
OH
S
N
OH
1
2 (n = 1, 2)
CH3
O
CH3
OH OH
OH OH OH
OH
OH
n
N
O
S
OH
N
O
S
OH OH
3 (n = 1, 2)
4
CH3
CH3
Fig. 1 THI (1) and its thiazole analogues (2–4)
O
O
O
O
O
O
O
Acetone
HO
HO
FeCl3, 63%
O
OH
O
Fig. 2 X-ray structure of compound 6
OH
5
6
100°C
sealed tube
24 h,95%
Morpholine
O
O
O
O
Imidazole,rt
O
O
TBDMSCl,DMF
97%
N
OH
N
O
OR
O
O
O
O
O
7
8
R = TBDMS
Scheme 1
analysis of 8 further confirmed the structure elucidation by
NMR analysis. The X-ray structure of compound 8 is
shown (Fig. 3) to have the same absolute configuration as
5. The SiMe2t-Bu ‘tail’ is disordered (occupancies:
0.852(2) and complement).
Fig. 3 X-ray structure of compound 8
Reduction of ketone 11 with diisobutylaluminium
hydride (DIBAL) in anhydrous diethyl ether at -78 °C
gave exclusively the syn-12 isomer in 90% yield
(Scheme 3). When the reaction was carried out at 0 °C
using sodium borohydride, a mixture of isomers 12 and 13
(1S/1R = 13:87) was produced in 86% yield. Both K- and
L-Selectride were also used at -78 °C to produce mixtures
of isomers (12/13 = 18:82, 83% yield) and (12/13 =
17:83, 88% yield), respectively. The results of the reduc-
tion of ketone 11 with various reducing agents and
suggested transition states are listed in Table 1. The dif-
ference in stereoselectivity is due to the various transition
states involved in the transformations which will be dis-
cussed later in this paper.
Commercially available 2-acetylthiazole (9) was con-
verted to its dimethoxyketal 10 in 80% yield, using
previously reported reaction conditions [10]. The 5-lithio-
thiazole derivative of 10 was generated at -78 °C and was
coupled with Weinreb amide 8 at the same temperature and
then at room temperature for 2 h to give 11 in 63% yield
with recovery of starting materials (Scheme 2).
1
The presence of the downfield singlet in the H NMR
spectrum of 11 at 8.7 ppm indicated the presence of the
coupled thiazole (H4). A suitable crystal of 11 was
obtained and analysed by single-crystal X-ray analysis to
give the structure, as shown in Fig. 4.
123

Synthesis of 2-acetyl-5-(1,2,3,4,5,6-hexahydroxyhexyl)thiazoles
299
CH(OCH3)3
TsOH,CH3OH
O
O
O
O
O
O
OH
OH
N
O
S
N
S
10
(R)
80%
(S)
H3CO
Hydride
11
N
S
OR
O
CH3
CH3
N
S
OR
O
H3CO
H3CO
9
H3CO
CH3
O
O
CH3
H3CO
13
H3CO
12
O
1. n-BuLi, THF
-78°C to rt, 2h
Reducing agent
DIBAL
dr (12:13)
100 : 0
13 : 87
18 : 82
17 : 83
N
OR
O
O
63%
O
8
NaBH4
R = TBDMS
K-Selectride
L-Selectride
O
O
O
Scheme 3
N
S
OR
O
O
H3CO
Table 1 Results of the reduction of ketone 11 with various reducing
agents and suggested transition states
CH3
H3CO
11
Scheme 2
Reagent
Yield (%) Ratio syn-12/anti-13 Transition state
DIBAL/-78 °C 90
100:0
13:87
17:83
b-Chelation
Felkin–Ahn
Felkin–Ahn
NaBH4/0 °C
L-Selectride/
86
88
When using DIBAL as the reducing agent at room
temperature, it was possible to obtain a 1:1 mixture of the
syn-12 and anti-13 isomers. This allowed an excellent
-78 °C
K-Selectride/
-78 °C
1
83
18:82
Felkin–Ahn
comparison of the H NMR data for the two isomers and
afforded both isomers for spectroscopic characterization
and future biological testing.
The stereochemistry of the major isomer 12 was
unequivocally determined by single-crystal X-ray crystal-
lography as shown in Fig. 5, confirming the structure of
compound 12 with the correct absolute configuration.
The stereochemistry of the major isomer 12 is that
predicted by the Felkin–Anh transition model A [13–18]
(Fig. 6), showing that the hydride attack between the small
and medium sized groups (where the OTBDMS group is
considered as the large group) at an angle of approximately
107° to the carbonyl oxygen would give rise to the syn-
isomer, as described by Dondoni et al. [16–18] in relation
to the reductions of related thiazolyl ketones. Similarly, the
typical b-chelation transition state B results in the forma-
tion of syn-isomer. Indeed, it was further found that with
sodium borohydride and both K- and L-Selectride, the
major product was the syn-isomer. The anti-isomer 13
would be expected from the a-chelation model C (Fig. 6).
Fig. 4 X-ray structure of
compound 11
123

300
A. T. Ung et al.
O
O
O
OH
O
O
O
OH
(R)
(S)
N
S
OR
O
N
S
OR
O
H3CO
H3CO
13
12
CH3
H3CO
CH3
H3CO
R = TBDMS
R = TBDMS
10% HCl
acetone
reflux, 2h
10% HCl
98%
96%
acetone
reflux, 2 h
OR
OR
OR
OR
OR
OR
OR
OR
N
O
S
OR
OR
N
O
S
OR
OR
CH3
CH3
14 (R = H)
15 (R = H)
Ac2O, HOAc
HClO4, rt, 1h
85%
Ac2O, HOAc
HClO4, rt, 1h
75%
16 (R = Ac)
17 (R = Ac)
Scheme 4
Fig. 5 X-ray structure of compound 12
a stereochemically defined manner. The stereochemistry of
1
the compounds was determined from a combination of H
This transition state is less favoured because of the steric
hindrance of the bulky TBDMS group [19].
NMR analysis and X-ray structural analysis. In the case of
d-gluconolactone (5), the conversion to amide functionality
in the form of the Weinreb amide 8 served this purpose
admirably, allowing access to analogues not available
under the generic methodology. The use of carbohydrates
such as 5 as starting materials allowed the incorporation of
the desired stereochemistry in the final products. Biological
activities of these compounds will be determined and
reported at a later stage.
The protected hexols 12 and 13 were individually hy-
drolysed in 10% HCl/acetone (1:1) by heating at reflux for
2 h to give the desired hexols 14 and 15, respectively, as
hydrochloride salts. These compounds were isolated as
clear yellow oils in 98 and 96% yields for the syn- (14) and
anti-isomers (15) respectively, as shown in Scheme 4.
1
The H NMR spectra of hexols 14 and 15 were very
similar but not identical. In order to confirm the identity of
these compounds, it was necessary to synthesise the
hexaacetate derivatives of both isomers. The hexaacetates
16 (syn-isomer) and 17 (anti-isomer) were obtained in
yields of 75 and 85% respectively after purification by
preparative TLC (Scheme 4).
Experimental
General procedures were as described previously [1, 3, 6].
Unless otherwise indicated, all NMR spectra were recorded
in CDCl3 solution, using tetramethylsilane (TMS) as an
In summary two novel hexahydroxyhexyl side chain
thiazole analogues (12 and 13) of THI were synthesized in
Fig. 6 Transition state models
i-Bu
B
A
C
O
i-Bu
used to rationalise the
diastereoselectivity of the
asymmetric reduction of ketone
11
-
i-Bu
Al i-Bu
H
Al
Si
O
O
O
O
O
O
O
O
-
H
O
Si
O
O
O
Si
H
O
-
H
H
H
O
O
S
O
S
S
N
N
N
O
O
O
O
O
O
O
α-Chelation, anti favoured
β-Chelation, syn favoured
Felkin-Ahn, syn favoured
123

Synthesis of 2-acetyl-5-(1,2,3,4,5,6-hexahydroxyhexyl)thiazoles
301
internal standard at 300 MHz (1H NMR) or 77.5 MHz (13C
NMR). 2-Acetylthiazole and d-gluconolactone were pur-
chased from Sigma-Aldrich. Compounds 6 [12] and 10
[10] were prepared following known procedures.
3.76–3.5 (br m, 5H, morpholine), 3.20 (br m, 1H,
morpholine), 1.39 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.34
(s, 3H, CH3), 1.33 (s, 3H, CH3), 0.92 (s, 9H, C(CH3)3),
0.10 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3) ppm; 13C NMR:
d = 169.7 (C), 109.8 (C), 109.7 (C), 81.9 (CH), 77.1 (CH),
76.9 (CH), 75.7 (CH), 67.9 (CH2), 67.1 (CH2), 66.8 (CH2),
46.3 (CH2), 43.0 (CH2), 27.1 (CH3), 26.6 (CH3), 26.3
(CH3), 25.6 (3CH3), 25.1 (CH3), 18.0 (C), -5.0 (CH3),
-5.6 (CH3) ppm; HRMS (ESI): calculated for
C22H42NO7Si (MH?) 460.2730, found 460.2730.
N-(3,4:5,6-Di-O-isopropylidene-2R,3S,4R,5R,6-
pentahydroxy-1-oxohexyl)morpholine (7, C16H27NO7)
1,2:3,4:5,6-Tri-O-isopropylidene-d-gluconolactone (6, 1.00
g, 3.16 mmol) and 1.03 g morpholine (1.01 cm3,
11.86 mmol, 3.75 eq) were combined in a sealed tube
and heated to 100 °C for 24 h, after which the reaction was
allowed to cool to room temperature. The solution was
diluted with 25 cm3 dichloromethane and washed with
0.1 M hydrochloric acid. The aqueous washings were
extracted with dichloromethane (3 9 15 cm3) and all
organic fractions were combined. After washing with
distilled water (3 9 50 cm3) and drying over magnesium
sulfate, the organic fraction was concentrated in vacuo to
2-(1,1-Dimethoxyethyl)-5-(2-O-tert-butyldimethylsilyl-
3,4:5,6-di-O-isopropylidene-2R,3S,4R,5R,6-penta-
hydroxy-1-oxohexyl)thiazole (11, C25H43NO8SSi)
2-(1,1-Dimethoxyethyl)thiazole (10, 1 g, 5.77 mmol,
1.17 eq) was dissolved in 15 cm3 dry tetrahydrofuran
(THF) and cooled to -78 °C under a nitrogen atmosphere.
n-BuLi (7.52 mmol, 4.7 cm3 of 1.6 M, 1.52 eq) was slowly
added and the mixture was stirred at -78 °C for 30 min
before the addition of a solution of 2.27 g 8 (4.94 mmol) in
15 cm3 dry THF. The reaction was stirred under N2
atmosphere while warming to room temperature over 2 h,
and then poured into 30 cm3 saturated ammonium chloride
solution. The aqueous fraction was extracted with dichlo-
romethane (3 9 30 cm3). The combined dichloromethane
extracts were washed with a saturated solution of sodium
chloride (3 9 30 cm3) and dried over magnesium sulfate
before concentrating in vacuo. Recrystallisation from
diethyl ether yielded 11 (1.055 g, 37%) as clear colourless
crystals. The starting material 8 (765 mg) was also
recovered by recrystallisation, in successive crystallisations
of this same solution. This gave an overall yield of 63% of
the title compound taking into account the recovered
starting material. M.p.: 102–105 °C; 1H NMR: d = 8.66 (s,
1H, H4), 4.63 (d, 1H, J = 2.2 Hz, H20), 4.25 (m, 1H,
J = 2.2 Hz, H30), 4.19 (m, 1H, J = 8.2 Hz, H60), 4.05 (m,
2H, H40 and H50), 3.84 (m, 1H, J = 8.2 Hz, H60), 3.28 (s,
3H, OCH3), 3.24 (s, 3H, OCH3), 1.73 (s, 3H, ThCCH3),
1.49 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.34 (s, 3H, CH3), 0.9
(s, 9H, t-butyl), 0.10 (s, 3H, SiCH3), -0.08 (s, 3H, SiCH3)
ppm; 13C NMR: d = 194.1 (C), 178.4 (C), 150.0 (C), 137.4
(CH), 110.7 (C), 109.8 (C), 100.9 (C), 82.3 (CH), 78.6
(CH), 77.4 (CH), 77.3 (CH), 68.3 (CH2), 49.5 (CH3), 49.5
(CH3), 27.3 (CH3), 26.7 (CH3), 26.4 (CH3), 25.8 (CH3),
25.1 (CH3), 23.9 (CH3), 18.2 (C), -4.7 (CH3), -5.1 (CH3)
ppm; HRMS (CI ?): calculated for C25H44NO8SSi (MH?)
546.2512, found 546.2557.
1
yield compound 7 (1.04 g, 95%) as a yellow syrup. H
NMR: d = 4.59 (dd, 1H, J = 1.1, 9.3 Hz, H20), 4.18 (m,
1H, H30), 4.08 (m, 1H, H6a0), 4.06 (m, 1H, H50), 4.00 (m,
1H, H6b0), 3.97 (m, 1H, H40), 3.79 (d, 1H, J = 9.3 Hz,
OH20), 3.75–3.45 (br m, 8H, 2(O–CH2) and 2(NCH2)),
1.44 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.39 (s, 3H, CH3),
1.34 (s, 3H, CH3) ppm; 13C NMR: d = 170.2 (C), 110.6
(C), 109.5 (C), 80.4 (CH), 77.5 (CH), 77.4 (CH), 68.0
(CH2), 66.6 (OCH2), 66.2 (OCH2), 66.2 (CH), 45.4
(N–CH2), 42.8 (N–CH2), 27.1 (CH3), 26.5 (CH3), 26.3
(CH3), 25.1 (CH3) ppm; HRMS (CI): calculated for
C16H27NO7 (MH?) 345.1788, found 345.1787.
N-(2-O-tert-Butyldimethylsilyl-3,4:5,6-di-O-isopropyli-
dene-2R,3S,4R,5R,6-pentahydroxy-1-oxohexyl)morpholine
(8, C22H41NO7Si)
The alcohol 7 (1.10 g, 3.19 mmol) was dissolved in
anhydrous 15 cm3 dimethyl formamide (DMF). While
stirring at room temperature, 1.30 g imidazole (19.1 mmol,
6.4 eq) was added and allowed to dissolve before the
addition of 0.80 g tert-butyldimethylsilyl chloride
(6.9 mmol, 2.35 eq). The reaction mixture was then stirred
at 40 °C for 72 h before being poured into 100 cm3 diethyl
ether and washed with 50 cm3 0.5 M hydrochloric acid.
The aqueous fraction was back extracted with diethyl ether
(3 9 50 cm3). The combined organic fractions were
washed with saturated sodium chloride (3 9 50 cm3),
dried over magnesium sulfate, and the solvent was
removed under reduced pressured to yield a white solid.
Recrystallisation from petroleum ether gave 8 (1.426 g,
97%) as large colourless crystals. M.p.: 64–66 °C; 1H
NMR: d = 4.53 (d, 1H, J = 2.5 Hz, H20), 4.30 (br m, 1H,
morpholine), 4.19 (dd, 1H, J = 2.5, 7.2 Hz, H30), 4.14 (dd,
1H, J = 6.1, 8.1 Hz, H6a0), 4.04 (ddd, 1H, J = 6.1, 7.0,
7.8 Hz, H50), 4.02 (m, 1H, morpholine), 3.96 (dd, 1H,
J = 7.2, 7.8 Hz, H40), 3.78 (dd, J = 7.0, 8.1 Hz, H6b0),
2-(1,1-Dimethoxyethyl)-5-(2-O-tert-butyldimethylsilyl-
3,4:5,6-di-O-isopropylidene-1S,2R,3S,4R,5R,6-
hexahydroxyhexyl)thiazole (12, C25H45NO8SSi)
To a stirred solution of 230 mg ketone 11 (0.42 mmol)
in 5 cm3 anhydrous diethyl ether at -78 °C was
added dropwise a solution of diisobutylaluminium hydride
123

302
A. T. Ung et al.
(0.69 mmol). Stirring was continued for 1 h after which the
reaction was quenched with 5 cm3 methanol. A saturated
solution of potassium tartrate (5 cm3) was added and the
reaction stirred for 1.5 h. The organic phase was collected
and the remaining aqueous phase extracted with diethyl
ether (3 9 10 cm3). The combined organic extracts were
washed with a saturated solution of sodium bicarbonate
and then distilled water, followed by drying over magne-
sium sulfate. Concentration in vacuo yielded solely the
(1S)-alcohol 12 (208 mg, 90.1%) as clear colourless
crystals. M.p.: 97–99 °C; 1H NMR: d = 7.67 (1H, s,
H4), 5.17 (ddd, 1H, J = 1.1, 2.8, 6.4 Hz, H10), 4.15 (dd,
1H, J = 6.0, 8.3 Hz, H30), 4.00 (m, 4H, H20, H50, H6a0,
H6b0), 3.88 (dd, 1H, J = 6.3, 8.3 Hz, H40), 3.49 (d, 1H,
J = 6.4 Hz, OH10), 3.25 (s, 3H, OCH3), 3.24 (s, 3H,
OCH3), 1.69 (s, 3H, ThCCH3), 1.42 (s, 3H, OCCH3), 1.41
(s, 3H, OCCH3), 1.34 (s, 3H, OCCH3), 1.32 (s, 3H,
OCCH3), 0.83 (s, 9H, t-butyl), 0.09 (s, 3H, SiCH3), -0.12
(s, 3H, SiCH3) ppm; 13C NMR: d = 171.2 (C), 141.8 (C),
139.3 (CH), 109.9 (C), 109.3 (C), 101.0 (C), 81.5 (CH),
78.0 (CH), 77.3 (CH), 77.1 (CH), 68.8 (CH), 67.8 (CH2),
49.4 (CH3), 49.4 (CH3), 27.0 (CH3), 26.9 (CH3), 26.3
(CH3), 25.9 (CH3), 25.2 (CH3), 24.2 (CH3), 18.4 (C), -4.0
(CH3), -4.8 (CH3) ppm; HRMS (CI): calculated for
C25H46NO8SSi (MH?) 548.2713, found 548.2713.
ThCCH3), 1.37 (s, 3H, OCCH3), 1.35 (s, 3H, OCCH3), 1.30
(s, 3H, OCCH3), 1.29 (s, 3H, OCCH3), 0.83 (9H, s,
t-butyl), 0.09 (3H, s, SiCH3), -0.12 (3H, s, SiCH3) ppm;
13C NMR: d = 172.3 (C), 141.1 (C), 140.1 (CH), 110.1
(2C), 101.3 (C), 79.1 (CH), 78.0 (CH), 77.5 (CH), 73.6
(CH), 71.3 (CH), 68.2 (CH2), 49.3 (CH3), 49.2 (CH3), 27.5
(CH3), 27.1 (CH3), 27.0 (CH3), 26.1 (CH3), 25.7 (CH3),
24.4 (CH3), 18. 5 (C), -4.4 (CH3), -4.7 (CH3) ppm;
HRMS (CI?): calculated for C25H46NO8SSi (MH?)
548.2713, found 548.2713.
Using L-Selectride: To a stirred solution of 36 mg
ketone 11 (0.066 mmol) in 5 cm3 dry THF at -78 °C was
added a solution of L-Selectride (0.2 mmol, 3 eq). After
stirring for 4 h the reaction was quenched with a solution
of 10% sodium hydroxide and 30% hydrogen peroxide
(2:1, 5 cm3). The reaction was stirred at room temperature
for 2 h, then diluted with 10 cm3 saturated sodium chloride
solution and extracted with ethyl acetate (3 9 20 cm3).
The combined organic extracts were washed with distilled
water and dried over magnesium sulfate. The solvent was
removed to provide a diastereoisomeric mixture of the
alcohols 12 and 13 (32 mg, 88%, 1S/1R = 17:83). The
1
products had identical H and 13C NMR spectra to those
seen above for the reduction reactions using sodium
borohydride and diisobutylaluminium hydride.
Using K-Selectride: To a stirred solution of 36 mg
ketone 11 (0.066 mmol) in 5 cm3 dry THF at -78 °C was
added a solution of K-Selectride (0.2 mmol, 3 eq). After
stirring for 4 h the reaction was quenched with a solution
of 10% sodium hydroxide and 30% hydrogen peroxide
(2:1, 5 cm3). The reaction was stirred at room temperature
for 2 h, then diluted with 10 cm3 saturated sodium chloride
solution and extracted with ethyl acetate (3 9 20 cm3).
The combined organic extracts were washed with distilled
water and dried over magnesium sulfate. The reaction
yielded a diastereoisomeric mixture of the alcohols 12 and
13 (30 mg, 83%, 1S/1R = 18:82).
2-(1,1-Dimethoxyethyl)-5-(2-O-tert-butyldimethylsilyl-
3,4:5,6-di-O-isopropylidene-1S,2R,3S,4R,5R,6-
hexahydroxyhexyl)thiazole (12, C25H45NO8SSi)
and 2-(1,1-dimethoxyethyl)-5-(2-O-tert-butyldimethylsilyl-
3,4:5,6-di-O-isopropylidene-1R,2R,3S,4R,5R,6-hexa-
hydroxyhexyl)thiazole (13, C25H45NO8SSi)
To a stirred solution of 200 mg ketone 11 (0.366 mmol) in
10 cm3 anhydrous methanol at 0 °C was added 70 mg
sodium borohydride (1.85 mmol, 5 eq) over 1 h. The
reaction was stirred until TLC analysis (15% ethyl acetate
in hexane on silica gel) indicated completion, after which
the reaction was quenched with 10 cm3 saturated solution
of ammonium chloride. The reaction was extracted with
dichloromethane (3 9 20 cm3) and the organic fractions
combined before washing with saturated sodium chloride
solution and drying over magnesium sulfate. Concentration
in vacuo yielded a mixture of the (1S)- and (1R)-
diastereomeric alcohols 12 and 13 (172 mg, 86%) as a
pale yellow solid (12/13 = 13:87). Recrystallisation of the
mixture from 1:5 ethyl acetate/petroleum ether separated
the alcohols 12 and 13 into white crystals and a white
powdery solid, respectively.
General synthesis procedure for 14 and 15
The alcohol 12 or 13 (31 mg, 0.056 mmol) was dissolved
in 5 cm3 of a 1:1 mixture of acetone and 10% hydrochloric
acid solution and the reaction mixture was heated at reflux
for 2 h. The acetone was removed in vacuo and the
aqueous phase washed with diethyl ether, before the
remaining water was removed in vacuo to yield the hexol
products 14 or 15, respectively.
2-Acetyl-5-(1S,2R,3S,4R,5R,6-hexahydroxyhexyl)thiazole
(14, C11H17NO7S)
1
1
Compound 13: H NMR: d = 7.67 (s, 1H, H4), 5.04 (d,
Yield 96%; dark yellow oil; H NMR (D2O): d = 7.80 (s,
1H, J = 5.1 Hz, H10), 4.07 (dd, 1H, J = 5.6, 8.6 Hz, H30),
3.96 and 3.88 (2 m, 4H, H40, H50, H6a0, H6b0), 3.79 (ddd,
1H, J = 1.1, 5.6 Hz, 8.1, H20), 3.24 (s, 3H, OCH3), 3.23 (s,
3H, OCH3), 2.74 (d, 1H, J = 8.1 Hz, OH), 1.72 (s, 3H,
1H, H4), 5.09 (d, 1H, H10), 3.75–3.35 (m, 6H, H20–H6a0
and H6b0), 2.48 (s, 3H, CH3) ppm; 13C NMR (D2O):
d = 192.69 (C), 165.07 (C), 149.20 (C), 139.95 (CH),
74.72 (CH), 72.64 (CH), 71.15 (CH), 71. 02 (CH), 68.18
123

Synthesis of 2-acetyl-5-(1,2,3,4,5,6-hexahydroxyhexyl)thiazoles
303
(CH), 64.41 (CH2), 25.27 (CH3) ppm; HRMS (ESI):
calculated for C11H18NO7S (MH?) 308.0799, found
308.0800.
4.39 (dd, 1H, J = 2.9, 11.1 Hz, H6a0), 4.15 (dd, 1H,
J = 6.3, 11.1 Hz, H6b0), 2.74 (s, 3H, CH3), 2.11 (s, 6H,
2CH3), 2.10 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.06 (s, 6H,
2CH3) ppm; HRMS (CI): calculated for C23H29NO13S
(MH?) 559.1351, found 559.1349.
2-Acetyl-5-(1R,2R,3S,4R,5R,6-hexahydroxyhexyl)thiazole
(15, C11H17NO7S)
1
Yield 98%; dark yellow oil; H NMR (D2O): d = 7.74 (s,
X-ray data for 6, 8, 11, and 12
1H, H4), 5.08 (d, 1H, J = 2.3 Hz, H10), 3.87 (dd, 1H,
J = 2.3, 7.8 Hz, H20), 3.80–3.67 (m, 2H, H30 and H40),
3.65 (dd, 1H, J = 2.8, 11.9 Hz, H5b0), 3.52 (dd, 1H,
J = 7.0, 11.9 Hz, H5a0), 2.54 (s, 3H, CH3) ppm; 13C NMR
(D2O): d = 193.36 (C), 165.28 (C), 145.76 (C), 141.95
(CH), 74.06 (CH), 72.64 (CH), 71.25 (CH), 70.98 (CH),
67.78 (CH), 64.31 (CH2), 25.28 (CH3) ppm; HRMS (ESI):
308.0797 calculated for C11H18NO7S (MH?) 308.0799,
found 308.0797.
The crystallographic data for the structures 6, 8, 11, and 12
reported in this paper have been deposited at the Cam-
bridge Structural Data Centre under CCDC numbers:
773751 (6), 773752 (8), 773753 (11), 773754 (12). The
data can be obtained free of charge via www.ccdc.cam.ac.
uk/data_request/cif or by e-mailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: ?44-1223-336033.
General synthesis procedure for 16 and 17
Acknowledgments We thank Johnson and Johnson Research Pty.
Limited, Sydney, and the University of Wollongong for supporting
this research, the Australian Research Council for an APA(I) schol-
arship to GRJ and Prof. Dennis Wade and Dr. David Atkins for
encouragement and support.
To a stirred solution of 3 cm3 acetic anhydride and 5 cm3
glacial acetic acid was added the hexol 14 or 15 (45 mg,
0.146 mmol). A perchloric acid/acetic anhydride catalyst
(1 g of 70% perchloric acid in 2.3 g acetic anhydride) was
added (4 drops) and the mixture stirred for 1 h before
pouring into 20 cm3 ice-water. The mixture was then
extracted with ethyl acetate (3 9 30 cm3). The combined
ethyl acetate extracts were dried over magnesium sulfate
and concentrated in vacuo. Purification using semi-
preparative TLC using silica gel plates with 15% ethyl
acetate in hexanes as the eluent yielded the hexaacetate
product.
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6.23 (d, 1H, J = 4.2 Hz, H10), 6.06 (1H, m, J = 3.4 Hz,
H40), 5.81 (dd, 1H, J = 3.4, 7.0 Hz, H30), 5.67 (dd, 1H,
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123