A parallel synthesis approach towards a family of C-nucleosides

Article abstract of DOI:10.1016/j.tet.2003.11.055

A synthetic route was devised for a sugar based α-chloroketone, which was subsequently used to generate a family of C-nucleosides via parallel synthetic methodology.

Full text of DOI:10.1016/j.tet.2003.11.055

Tetrahedron 60 (2004) 841–849
A parallel synthesis approach towards a family of C-nucleosides
b
b
b
Mauro F. A. Adamo,a Robert M. Adlington, Jack E. Baldwin and Anna L. Day
,
*
aCentre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry,
The Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Dublin, Ireland
bThe Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QY, UK
Received 12 September 2003; revised 28 October 2003; accepted 20 November 2003
Abstract—A synthetic route was devised for a sugar based a-chloroketone, which was subsequently used to generate a family of C-
nucleosides via parallel synthetic methodology.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
tricyclic analogue of Toyocamicin 2 constitutes a valid
example. Triciribine monophospate (TCN-P) is now in
phase II studies as a potential antineoplastic agent.10b
The discovery of new chemotherapeutic treatments for
controlling microbial infections is an important topic in
clinical medicine.
In general, nucleoside analogues can be divided into three
classes: (a) nucleosides bearing modification on the sugar
moiety, (b) nucleosides bearing modification on the base
moiety, (c) nucleosides bearing modification on both the
base and the sugar moieties. Typical modifications of class
(a) analogues include the alteration of sugar stereochemistry
or the removal of one or more stereogenic centre as in
Many nucleoside analogues of natural origin have been
found to be bioactive. Bredinine 11 (Mizoribine) is an
imidazole nucleoside antibiotic clinically used as an
immunosuppressant;2 Toyocamycin 2,3 Mycalisin A 3,4
and Thiosangivamycin 43 are three naturally occurring
nucleosides which exert potent antiviral and antineoplastic
activity (Fig. 1); Pseudouridine 5,5 Showdomycin 6,6
Pyrazofurin 77 and Tiazofurin 88 have been shown to
possess a wide range of medicinal properties, including
antibiotic, antiviral, and anti-tumor activity (Fig. 2).
In recent years a large number of compounds have been
prepared modelled on naturally occurring templates and
subsequently tested.9 Triciribine 910a (Fig. 3) a synthetic
Figure 2. Naturally occurring C-nucleosides.
Figure 1. Naturally occurring nucleosides analogues.
Keywords: C-Nucleosides; Parallel synthesis.
*
Corresponding author. Tel.: þ353-1-4022208; fax: þ353-1-4022168;
e-mail address: madamo@rcsi.ie
Figure 3. Synthetic nucleosides analogues.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.055

842
M. F. A. Adamo et al. / Tetrahedron 60 (2004) 841–849
20-deoxyadenosine 10 (Fig. 3); introduction of a different
moiety such as an azido group in Zidovudine 11, or
replacement of the sugar by acyclic structures. Compounds
having remarkable antiviral or antitumor activity have been
obtained through sugar modification, such as acyclovir 12.
Typical modifications of class (b) analogues include the
addition or removal of structural elements, as in 9.
Modifications for class (c) analogues include all previously
mentioned alterations for group (a) and (b). C-Nucleosides
constitute a category of analogues in which the modification
occurred at the linkage between the base and the sugar. In
C-nucleosides, the sugar and the base are linked through a
C–C linkage as opposed to N-nucleosides where a C–N
bond is present. This structural alteration is believed to
increase the nucleoside stability towards nucleoside hydrol-
ase enzymes, and to inhibit in general the cascade of events
leading to DNA or RNA formation.11 Many naturally
occurring C-nucleosides such as Pseudouridine 5, Showdo-
mycin 6 and Pyrazofurin 7 have been reported as strong
antibiotic agents,5–7 which has primed research on C-
nucleoside analogues. However, despite the large amount of
data collected, C-nucleosides and especially C-nucleosides
belonging to the 2-deoxy-D-ribose series have scarcely been
explored. Additionally, there is no data available on the
biological activity of 2-deoxy-C-nucleosides belonging
to the a-anomeric series. For these reasons, we believe
that C-nucleosides constitute an ideal template for use in
drug discovery.
Scheme 1. Synthetic plan.
parent carboxylic acids 16, through a modified Arndt–
Einstert reaction. The synthesis of 16 has been reported
from commercially available 2-deoxy-D-ribose 19 (Scheme
2).20 As a protecting group regime was needed, attention
was directed towards groups, which could be cleaved under
mild conditions. The benzoyl group was selected, due to its
ease of removal with aqueous base or methanolic ammonia.
Thus, commercially available 2-deoxy-D-ribose 19 was
firstly protected to give a tri-O-benzoyl deoxyribose
derivative 20, which in turn, was reacted to give nitrile
17. Hydrolysis of 17 in mild acidic conditions furnished acid
16. Conversion of 20 to 17 and of 17 to 16 were very
effective processes, leading to high reaction yields.
2. Results and discussion
Our research focuses on the development of parallel
synthetic methodologies which generate families of poten-
tially useful drug candidates.12–15 As part of this research
we set out to develop a synthetic route to a family of C-
nucleoside analogues of the 2-deoxy-D-series (Fig. 4). We
choose the following key features to define the new family:
(i) the C-linkage between the sugar and the heterocyclic
moiety; (ii) the presence of multiple heteroatoms, as
potential sites for H-bonding recognition; (iii) synthesis in
both the a and b anomeric series; (iv) sugar moiety derived
from the naturally occurring 2-deoxy-D-ribose 19.
Scheme 2. Reagents and conditions: (a) DCM, BzCl (4 equiv.), pyridine
(12 equiv.), rt, 1.5 h, 39%; (b) DCM, TMSCN (1.3 equiv.), BF3·Et2O
(3.3 equiv.), 0 8C, 1.5 h, 73%; (c) 1,4-dioxane, HCl (1 mL, 35% HCl in
water), 72%.
However, following this route, the overall yield was
restricted as compound 20 could be obtained in no more
than 39% yield from 19. This was due to the concomitant
formation of tribenzoylpyranose 21, which affected the
efficiency of the whole synthetic route. Furthermore, we
found that the purification of 20 from 21 was laborious and
time consuming.
Figure 4. A family of 2-D-deoxy-C-nucleosides.
A disconnection analysis towards target 13 placed a-
chloroketone 15 as the key intermediate in the synthetic plan
(Scheme 1).
Formation of 21 could be avoided by blocking the anomeric
position prior to benzoylation. Hence, selective methoxyla-
tion of the anomeric position furnished compound 2221 in
nearly quantitative yields, which was successively benzoyl-
ated to give 2322 in 73% yield (Scheme 3).
a-Haloketones have been shown to be versatile building
blocks for the synthesis of heterocycles,16–19 therefore we
targeted compound 15 as a key intermediate in our synthetic
approach. In turn, compound 15 can be accessed from the

M. F. A. Adamo et al. / Tetrahedron 60 (2004) 841–849
Table 1. Formation of benzoyl nucleosides
843
Entry
1
Nucleophile
Product
Yield (%)
35
R¼CH3 26a
Scheme 3. Reagents and conditions: (a) MeOH, AcCl (6.4 mol%), rt,
25 min, 99%; (b) DCM, BzCl (4 equiv.), pyridine (12 equiv.), rt, 1.5 h,
73%.
R¼CH3 26b
R¼Ph 27a
53
22
2
3
Compound 23 was then submitted to cyanation using
TMSCN in the presence of BF3·OEt2 (Scheme 4) to give
nitrile 17. Although conversion of 23 was complete under
the experimental conditions employed, the yields of 17
never exceeded 70–75%, due to the formation of acyclic
derivative 24 by product. This behaviour was not observed
when 20 was cyanated under similar conditions, and could
be rationalised by the fact that benzoate is a better leaving
group.
R¼Ph 27b
R¼NH2 28a
45
35
R¼NH2 28b
55
The stereochemistry at the anomeric position was assigned
by NOE experiments. Positive NOE was observed between
the anomeric H-10 and H-40 in the b anomer, and between
the H-10 and H-30 in the a anomer.
We have also employed 15 to make heterocycles other than
thiazoles. When chloroketone 15 was reacted with thio-
semicarbazide hydrochloride, rapid condensation occurred
and thiazidine 29a/b was isolated in 81% yield (Scheme 7).
Scheme 4. Reagents and conditions: DCM, TMSCN (1.3 equiv.), BF3·Et2O
(3.3 equiv.), 0 8C, 1.5 h, 71%.
The hydrolysis of nitrile 17 proceeded as reported and acid
16 was obtained in 72% yield (Scheme 5).20
Scheme 7. Reagents and conditions: 15, methanol, thiosemicarbazide
hydrochloride (1.0 equiv.), reflux, 1 h, 81%.
We have attempted to prepare sugar-based imidazoles by
reacting a-chloroketone 15 with amidines. In these
experiments no heterocycle was formed and repeatedly,
compound 32a/b was isolated in 60–70% yield (Scheme 8).
Scheme 5. Reagents and conditions: (a) dioxane/HCl, 70 8C, 6 h, 72%; (b)
DCM, a,a-dichloromethyl methyl ether (5 equiv.), reflux, 4 h, 99%; (c)
Et2O, CH2N2, (3 equiv.); (d) HCl gas, 30 min, 61%.
a-Chloroketone 15 was prepared from 16 through a
modified Arndt–Einstert procedure. This method involved
the activation of the acid to a mixed anhydride or an acyl
chloride such as 25, followed by displacement of chloride
by diazomethane and subsequent quenching with HCl
(Scheme 5). With the a-chloroketone 15 in hand we
explored its reactivity towards
polynucleophiles.
a
number of
We reacted 15 with various thioamide nucleophiles and
found that thiazoles 26–28 could be obtained in good yields
(Scheme 6 and Table 1).
Scheme 8. Reagents and conditions: 15, ethanol, benzamidine hydrochlo-
ride (1 equiv.), NaHCO3 (1 equiv.), reflux, 4 h, 65% yield.
Importantly, the a and b anomers could be separated at this
stage by simple flash chromatography.
It is possible that the basic character of amidines promotes
conversion of 15 to 32. A mechanism for this reaction is
proposed as follows (Scheme 8). It is noteworthy that
reaction of a-chloroketones with AcOK/AcOH to give
a0-propanones has been reported for substrates bearing
an a0-aryloxy, or a0-phenylthio substituent.23
Dibenzoyl C-nucleosides 26–28a/b, were finally depro-
tected using either LiOH in THF/H2O or NH3/MeOH. These
reactions proceeded in high yields and with no epimeriza-
tion at the anomeric position (Scheme 9 and Table 2).
Scheme 6. Reagents and conditions: 15, ethanol, thioamide (1.0 equiv.), or
thiourea, reflux, 16 h.

844
M. F. A. Adamo et al. / Tetrahedron 60 (2004) 841–849
High-resolution mass spectra were recorded on a Micromass
Autospec spectrometer and are accurate to ^5 ppm.
Melting points were obtained using a Bu¨chi 510 Cambridge
Instruments Gallene III hot stage melting point apparatus
and are uncorrected.
Scheme 9. Reagents and conditions: LiOH·H2O (1.1 equiv.) THF–H2O, rt,
24 h; or.MeOH,·NH3, rt, 24 h.
Specific optical rotations were recorded using a Perkin–
Elmer 241 automatic polarimeter with a cell of path length
1 dm. All concentrations are given in grams per 100 mL.
Table 2. Deprotection of dibenzoyl nucleosides
Entry
Protected nucleoside
Nucleoside
Yield (%)
Flash chromatography was carried out using silica gel 60
0.040–0.063 mm, 230–400 mesh as the stationary phase.
Thin layer chromatography was carried out on aluminium
backed plates pre-coated with Merck silica gel 60 F254
(1.05554), which were visualized by quenching of UV
fluorescence (lmax¼254 nm) or by staining with either 10%
(w/v) ammonium molybdate in 2 M sulphuric acid or basic
potassium permanganate solution (followed by heat) as
appropriate. Retention factors (Rf) are reported to ^0.5.
1a
2a
3a
4a
5b
6b
7b
26a
26b
27a
27b
28a
28b
29a/b
33a
33b
34a
34b
35a
35b
36a/b
71
78
82
86
65
68
75
a
Reagents and conditions: LiOH·H2O (1.1 equiv.) THF–H2O, rt, 24 h.
Reagents and conditions: MeOH·NH3, rt, 24 h.
b
In conclusion, parallel synthetic methodology towards a
family of C-nucleosides has been developed. This route
made use of an a-chloroketone as the key intermediate
derived from a naturally occurring sugar, which led to a
number of synthetic nucleosides.
All reactions were carried out under anhydrous conditions
and an argon atmosphere unless otherwise indicated.
3.1.1. 2R-Hydroxymethyl-5-methoxytetrahydrofuran-
3S-ol, 22.21 To a stirred solution of 2-deoxy-D-ribose
(5.00 g, 37.3 mmol) in methanol (60 mL) was added 1%
methanolic hydrogen chloride solution (prepared by adding
170 mL acetyl chloride to 10 mL MeOH). The reaction
mixture was stirred at room temperature under an Argon
atmosphere (25 min) then sodium bicarbonate (2 g) added
and the reaction stirring continued for further 10 min. The
solids were filtered and the solvent removed in vacuo to give
22 as an orange oil (5.46 g, 99% yield). This product was
found pure enough to be used without further purification;
dH (400 MHz, CDCl3) 5.11–5.08 (1H, m, CH3O–CH–O),
4.50–4.01 (2H, m, HOCH2CHCHO), 3.75–3.71 (2H, m,
HOCH2CHCHOH), 3.38 (3H, s, CH3OCHO), 2.17–1.83
(2H, m, MeOCHCH2CH).21
3. Experimental
3.1. General
Anhydrous DCM was obtained by stirring over calcium
hydride for 24 h followed by distillation under nitrogen. All
water used was distilled.
1H and 13C Spectra were recorded on, Bru¨ker DPX200
(200 MHz), Varian Gemini 200 (200 MHz), Bru¨ker DPX
250 (250 MHz), Bru¨ker DQX 400 (400 MHz), Bru¨ker
DPX400 (400 MHz) and Bru¨ker AMX 500 (500 MHz)
1
3.1.2. 3S-Benzoyloxy-2R-benzoyloxymethyl-5-methoxy-
tetrahydrofuran, 23.22 To a stirred solution of 22 (5.46 g,
36.9 mmol) in dichloromethane (90 mL) was added benzoyl
chloride (17.2 mL, 147 mmol, 4 equiv.) and the reaction
mixture cooled to 0 8C by ice bath cooling. A mixture of
dichloromethane (88 mL) and pyridine (44 mL) was added
dropwise and the reaction mixture was then stirred at room
temperature under Ar atmosphere (1.5 h). The reaction
mixture was washed with 10% sulphuric acid (4£300 mL),
then with saturated potassium bicarbonate solution
(2£200 mL) and finally with water (2£200 mL). The
organic layer was dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography on
silica gel eluting with dichloromethane to give the title
compound 23 as a colourless oil (9.63 g, 73% yield, a/
b¼40:60);24 Rf 0.2, dichloromethane.
spectrometers at ambient temperatures. H NMR spectral
assignments are supported by 1H–1H COSY where
necessary. For 1H NMR recorded in CDCl3 chemical shifts
(dH) are quoted in parts per million (ppm) and are referenced
to the residual solvent peak. The following abbreviations are
used: s, singlet, d, doublet, t, triplet, dd, doublet of doublets,
ddd, doublet of doublet of doublets, dt, doublet of triplets,
m, multiplet and br, broad. Coupling constants (J) were
recorded in Hertz (Hz) to the nearest 0.5 Hz. Carbon spectra
are supported by DEPT analysis where necessary.
Infrared (IR) spectra were recorded as thin films between
NaCl plates on a Perkin–Elmer Paragon Fourier Transform
spectrometer. Absorption maximum (nmax) was reported in
wave numbers (cm21) and only selected peaks are reported.
The following abbreviations are used: w, weak, m, medium,
s, strong and br, broad.
Compound 23a. dH (500 MHz, CDCl3) 8.16–8.08 (4H, m,
Ar); 7.62–7.59 (2H, m, Ar), 7.50–7.45 (4H, m, Ar), 5.52–
5.49 (1H, m, BzOCHCH2), 5.25 (1H, d, CH3OCHO
J¼4.5 Hz), 4.72–4.42 (3H, m, BzOCH2CHO, BzOCH2-
CHO), 3.48 (3H, s, CH3OCHO), 2.59 (1H, m, CHOHCH2)
2.27 (1H, m, CHOHCH2); dC (125.8 MHz, CDCl3) 105.51
Low-resolution mass spectra (m/z) were recorded using a
V.G.TRIO (GCMS) spectrometer, a Micromass Platform
(APCI) spectrometer, Micromass Autospec spectrometer
(CIþ) and a Micromass ZAB spectrometer (CIþ, EI). Only
molecular ion (Mþ) and other major peaks are reported.

M. F. A. Adamo et al. / Tetrahedron 60 (2004) 841–849
845
(CH3OCHO), 81.37 (BzOCH2CHO), 75.26 (BzOCHCHO),
64.93 (BzOCH2CHO), 55.58 (CH3OCHO), 39.54
(OCHCH2CHOBz).
65.6 (BzOCH2CHOH), 58.4 and 58.2 (BzOCHCH2CHCN),
34.9 and 34.5 (CH3OCHCN); nmax/cm21 (neat film) 3477m
br, 1202s, 1126s; m/z (electrospray) 401 (MNHþ4 , 100%);
HRMS found: MHþ 384.1463 (C21H22NO6 requires
384.1447).
Compound 23b. dH (500 MHz, CDCl3) 8.16–8.08 (4H, m,
Ar); 7.62–7.59 (2H, m, Ar), 7.50–7.45 (4H, m, Ar), 5.70–
5.67 (1H, m, BzOCHCH2), 5.29 (1H, dd, CH3OCHO, J¼2,
5.5 Hz), 4.72–4.42 (3H, m, BzOCH2CHO, BzOCH2CHO),
3.42 (3H, s, CH3OCHO), 2.63 (1H, m, CHOHCH2) 2.41
(1H, m, CHOHCH2); dC (125.8 MHz, CDCl3) 105.89
(CH3OCHO), 82.12 (BzOCH2CHO), 76.04 (BzOCHCHO),
65.74 (BzOCH2CHO), 55.67 (CH3OCHO), 39.85
(OCHCH2CHOBz).
3.1.4. 4S-Benzoyloxy-5R-benzoyloxymethyltetrahydro-
furan-2R/S-carboxylic acid 16.20 To a stirred solution of
17 (4.81 g, 13.7 mmol) in 1,4-dioxane (112 mL) was added
conc. HCl (11 mL). The reaction mixture was refluxed at
80 8C (6 h) and then the solvent was removed in vacuo. The
residue was purified by flash chromatography on silica gel
eluting with ethyl acetate/petrol/acetic acid (70:30:2) to
give 16 as a yellow oil (3.64 g, 72% yield); Rf 0.4, ethyl
acetate/petrol/acetic acid (70:30:2); dH (200 MHz, CDCl3)
8.90 (1H, br s, HOOCCH), 8.08–8.01 (3H, m, Ar), 7.96–
7.92 (1H, m, Ar), 7.62–7.37 (6H, m, Ar), 5.58–5.54 (1H, m,
BzOCHCH2) 4.48–4.71 (1H, m, HO2CCHO) 4.70–4.51
(3H, m, BzOCH2CHO), 2.82–2.43 (2H, m, BzOCHCH2);
dC (100.6 MHz, CDCl3) 177.03 (HOOCCH), 166.74
(PhCO), 165.90 (PhCO), 133.65 (Ar), 133.54 (Ar), 133.47
(Ar), 133.37 (Ar), 129.76 (Ar), 129.71 (Ar), 129.66 (Ar),
129.46 (Ar), 129.32 (Ar), 129.11 (Ar), 128.57 (Ar), 128.54
(Ar), 128.50 (Ar), 84.26 and 83.73 (BzOCHCH2), 75.86
and 75.34 (BzOCH2CHO), 67.04 (OCHCOOH), 64.43 and
Compound 23a/b. dC (125.8 MHz, CDCl3) 166.49, 166.64,
166.69, 166.86 (PhCO); 133.76, 133.69, 133.58, 133.50,
130.37, 130.27, 130.22, 130.20, 130.13, 130.10, 130.04,
129.06, 128.99, 128.89, 128.86, 128.82 (Ar); nmax/cm21
(neat film) 1723s, 1602m; m/z (GC–CI[NH3]) 374 (MNHþ4 ,
30%), 325 (100%); HRMS found: MNHþ4 374.1620
(C20H24NO6 requires 374.1604).
3.1.3. 4S-Benzoyloxy-5R-benzoyloxymethyltetrahydro-
furan-2R/S-carbonitrile, 17.20 To a stirred solution of 23
(9.62 g, 27.0 mmol) in dry dichloromethane (160 mL) was
added TMSCN (5.47 mL, 38.4 mmol, 1.4 equiv.) and
BF3·OEt2 (11.9 mL, 96.0 mmol, 3.6 equiv.). The reaction
mixture was stirred at 0 8C under an Argon atmosphere for
1.5 h. After this time, a saturated aqueous NaHCO3 solution
(300 mL) was slowly added and the reaction mixture stirred
until evolution of CO2 was finished. The product was
extracted with dichloromethane (2£300 mL), the organic
layer dried over Na2SO4 and the solvent removed in vacuo.
The residue was purified by flash chromatography on silica
gel eluting with chloroform/ethyl acetate (40:1) to give the
title compound 17 as a yellow oil (6.72 g, 71% yield); Rf
0.85; dH (250 MHz, CDCl3) 8.12–8.00 (4H, m, Ar), 7.51–
7.47 (6H, m, Ar), 5.65 (1H, m, BzOCHCH2) 5.08 (0.4H, dd,
J¼2, 7 Hz, OCHCN), 4.94 (0.6H, dd, J¼6.5, 9 Hz,
OCHCN), 4.71–4.52 (3H, m, BzOCH2CHO), 2.81–2.60
(2H, m, CHCH2CHCN); dC (62.5 MHz, CDCl3) 166.56
(PhCO), 166.45 (PhCO), 166.11 (PhCO), 134.19 (Ar),
134.14 (Ar), 133.84 (Ar), 130.37 (Ar), 130.17 (Ar), 130.13
(Ar), 130.05 (Ar), 129.79 (Ar), 129.34 (Ar), 129.06 (Ar),
129.02 (Ar), 128.98 (Ar), 118.84 (NCCHO), 118.29
(NCCHO), 84.64 (CNCHCH2CHOBz), 84.17 (CNCHCH2
CHOBz), 75.94 (BzOCH2CHO), 75.42 (BzOCH2CHO),
66.98 (NCCHO), 66.30 (NCCHO), 64.32 (BzOCH2CHO),
64.20 (BzOCH2CHO), 38.33 (NCCHCH2CH), 38.22
(NCCHCH2CHOBz); nmax/cm21 (neat film), 1722s, 1602s,;
m/z [CI(NH3)] 369 (MNHþ4 , 100%); HRMS found: MNH4þ
369.1438 (C20H21N2O5 requires 369.1450), and 4S,5R,6-
tribenzoyloxy-2R/S-methoxy-hexanenitrile 24: yellow oil
(2.25 g, 22% yield); Rf 0.25, chloroform/ethyl acetate
(40:1); dH (200 MHz, CDCl3), 8.09–8.01 (4H, m, Ar),
7.61–7.40 (6H, m, Ar), 5.51–5.42 (1H, m, NCCHOCH3),
4.61–4.17 (4H, m, BzOCH2CHO, BzOCHCH2), 3.45 and
3.48 (3H, 2£s, OCH3), 2.58–2.38 (2H, m, BzOCHCH2
CHCN); dC (50.3 MHz, CDCl3) 167.0 (PhCO), 166.0
(PhCO), 133.7 (Ar), 133.6 (Ar), 133.4 (Ar), 129.8 (Ar),
129.8 (Ar), 129.4 (Ar), 128.7 (Ar), 128.5 (Ar), 117.7
(NCCHOMe), 71.2 and 71.1 (NCCHOMe), 70.9 and 70.7
(BzOCHCHOH), 67.8 and 67.0 (BzOCH2CHOH), 65.7 and
64.17 (BzOCH2CHO), 36.37 (BzOCHCH2CHO); nmax
/
cm21 (neat film) 1721s, 1271s; m/z (electrospray) 393
(MNaþ, 100%); HRMS found: MNaþ 393.0943
(C20H18O7Na requires 393.0950).
3.1.5. 4S-Benzoyloxy-5R-benzoyloxymethyl-tetrahydro-
furan-2R/S-carbonyl chloride, 25. To a mixture of the 16
(100 mg, 0.27 mmol) in dry dichloromethane (5 mL) was
added a,a-dichloromethyl methyl ether (122 mL,
1.35 mmol, 5 equiv.). The mixture was then refluxed for
4 h, allowed to cool and concentrated in vacuo to yield the
desired acid chloride 25 as a light yellow oil (103 mg, 99%
yield); dH (400 MHz, CDCl3) 8.05–7.96 (4H, m, Ar), 7.62–
7.55 (2H, m, Ar), 7.48–7.45 (4H, m, Ar), 5.59 (1H, app s,
BzOCHCH2), 5.04 (1H, app t, ClCOCHO, J¼9 Hz), 4.61–
4.51 (3H, m, BzOCH2CHO), 2.79–2.64 (2H, m,
ClCOCHCH2); dC (50.3 MHz, CDCl3) 175.22 (ClCOCHO),
173.67 (ClCOCHO), 166.36 (PhCO), 166.01 (PhCO),
135.25 (Ar), 133.87 (Ar), 133.50 (Ar), 129.88 (Ar),
129.73 (Ar), 129.36 (Ar), 129.25 (Ar), 128.78 (Ar), 84.36
(BzOCHCH2), 83.89 (BzOCHCH2), 75.38 (ClCOCHO),
74.95 (ClCOCHO), 68.02 (BzOCH2CHO), 64.05 (BzOCH2-
CHO), 53.51 (BzOCH2CHO), 52.63 (BzOCH2CHO), 36.62
(BzOCHCH2CHO), 36.26 (BzOCHCH2CHO); nmax/cm21
3021 m, 2401 w, 1811 m, 1773s; this compound gave
unsatisfactory mass spectral data.
3.1.6. 2-Chloro-1-(4S-benzoyloxy-5R-benzoyloxymethyl-
tetrahydrofuran-2R/S-yl)-ethanone, 15. The crude acid
chloride 25, obtained from 16 (3.56 g, 9.62 mmol), was
taken up in dry diethyl ether (100 mL) and an ethereal
solution of freshly generated alcohol free diazomethane
added (6.18 g Diazald, 28.9 mmol, 3 equiv.). The reaction
mixture was stirred for 15 min and then bubbled through
with dry HCl gas for 30 min. The solution was diluted with
diethyl ether (125 mL) and the organic phase washed with
water (300 mL), then with saturated aqueous NaHCO3
solution (2£300 mL) and finally with water (300 mL). The

846
M. F. A. Adamo et al. / Tetrahedron 60 (2004) 841–849
reaction mixture was dried over CaCl2, filtered and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate/
petrol (30:70) to give 15 as a white solid (2.38 g, 61%
yield), m.p 122 8C; Rf 0.55, ethyl acetate/petrol (30:70); dH
(400 MHz, CDCl3) 8.17–7.90 (4H, m, Ar) 7.64–7.59 (2H,
m, Ar), 7.55–7.44 (4H, m, Ar), 5.58–5.55 (1H, m,
BzOCHCH2), 4.88–4.83 (1H, m, CHCOCH2Cl), 4.64
(2H, d, J¼5 Hz, BzOCH2CHO), 4.48 (2H, 2£s, COCH2Cl),
4.65–4.47 (1H, m, BzOCH2CHO), 2.77–2.37 (1H, m,
BzOCHCH2CH); dC (100.6 MHz, CDCl3) 203.31 and
201.02 (COCH2Cl), 166.08, 165.85 and 165.52 (PhCO);
133.65, 133.57, 133.43, 133.37, 129.66, 129.63, 129.59,
129.53, 129.44, 129.32, 129.20, 128.88, 128.62, 128.54 and
128.52 (Ar); 83.95 and 83.76 (BzOCHCH2), 83.20 and
82.54 (ClCH2COC), 75.80 and 75.65 (BzOCH2CH), 64.27
and 64.15 (BzOCH2CH), 47.56 and 46.51 (ClCH2CO),
35.82 and 35.72 (BzOCHCH2); nmax/cm21 (neat film)
1719s, 1269s, 1101s; m/z (electrospray) 403 (MHþ, 30%);
HRMS found: 403.0944 (C21H20O6Cl requires 403.0948).
(BzOCHCH2), 77.71 (OCHCvCH), 76.43 (BzOCH2CHO),
65.80 (BzOCH2CHO), 38.27 (BzOCHCH2), 19.22
(CH3CvN); nmax/cm21 (neat film) 1722s, 1275s; m/z
(electrospray) 446 (MNaþ, 100%); HRMS found: MNaþ
446.1047 (C23H21NO5SNa requires 446.1038); [a]2D0 þ10.0
[c 1.0, CHCl3].
3.2.3. 3S-Benzoyloxy-2R-benzoyloxymethyl-5R-(2-
phenylthiazol-4-yl)-tetrahydrofuran, 27b. Colourless
oil, 301 mg, 45% yield from 15, Rf 0.65 ethyl acetate/petrol
(10:90); dH (500 MHz, CDCl3) 8.17–8.13 (4H, m, Ph),
7.98–7.96 (2H, m, Ph), 7.60–7.45 (9H, m, Ph), 7.35 (1H, s,
OCHCvCHS), 5.76 (1H, d, J¼5.5 Hz, BzOCHCH2), 5.56
(1H, dd, J¼10, 5.5 Hz, OCHCv), 4.80–4.66 (2H, m,
BzOCH2CHO), 4.61 (1H, app d, J¼6.5 Hz, BzOCH2CHO),
2.78 (1H, dd, J¼14, 5.5 Hz, BzOCHCH2), 2.67 (1H, ddd,
J¼14, 10, 5.5 Hz, BzOCHCH2); dC (125.8 MHz, CDCl3)
168.65 (PhCvN); 166.21 (PhCO), 165.97 (PhCO), 156.90
(OCHCvCHS), 133.45, 133.26, 132.98, 129.94, 129.73,
129.61, 128.78, 128.74, 128.38, 128.33, 128.29, 126.42
(Ar), 114.83 (OCHCvCHS), 82.89 (BzOCHCH2), 77.90
(OCHCvCH), 77.64 (BzOCH2CHO), 64.69 (BzOCH2
CHO), 39.10 (BzOCHCH2); nmax/cm21 1722s, 1602m;
m/z (electrospray) 486 (MHþ, 100%); HRMS found: MHþ
486.1373 (C28H24NO5S requires 486.1375); [a]2D0 230.0 [c
1.0, CHCl3].
3.2. General procedure for the preparation of
compounds 26a/b, 27a/b, 28a/b
To a solution of 15 (556 mg, 1.38 mmol) in ethanol
(10.4 mL) was added the corresponding thioamide
(1.38 mmol, 1 equiv.) and the reaction mixture refluxed
for 20 h. Then the solvent was removed and the residue
purified by flash chromatography.
3.2.4. 3S-Benzoyloxy-2R-benzoyloxymethyl-5S-(2-phenyl-
thiazol-4-yl)-tetrahydrofuran, 27a. Colourless oil, 147 mg,
22% yield from 15, Rf 0.62 ethyl acetate/petrol (10:90); dH
(500 MHz, CDCl3) 8.10–8.09 (2H, m, Ar), 7.96–7.92 (2H,
m, Ar), 7.80–7.78 (2H, m, Ar), 7.60–7.58 (1H, m, Ar),
7.50–7.26 (9H, m, Ar), 5.61 (1H, dd, J¼6, 3 Hz,
BzOCHCH2), 5.58 (1H, dd, J¼4, 8 Hz, OCHCv), 4.74–
4.73 (1H, m, BzOCH2CH), 4.63 (2H, d, BzOCH2CH,
J¼4 Hz), 2.97 (1H, dt, J¼14, 7 Hz, BzOCHCH2),), 2.81
(1H, dt, J¼14, 4 Hz, BzOCHCH2); dC (100.6 MHz, CDCl3)
168.11 (PhCvN), 166.24 (PhCO), 165.88 (PhCO), 158.73
(OCHCvCHS), 133.50, 133.07, 166.06, 129.92, 129.62,
129.47, 128.79, 128.37, 128.17, 126.42 (Ar), 114.10
(OCHCvCHS), 82.37 (BzOCHCH2), 77.92 (OCHCvCH),
76.44 (BzOCH2CHO), 64.71 (BzOCH2CHO), 38.17
(BzOCH2CH); nmax/cm21 (neat film) 1722s; m/z (electro-
spray) 486 (MHþ, 100%); HRMS found: 486.1366
(C28H24NO5S requires 486.1375); [a]2D0 þ6.4 [c 1.0, CHCl3].
3.2.1. 3S-Benzoyloxy-2R-benzoyloxymethyl-5R-(2-
methylthiazol-4-yl)-tetrahydrofuran, 26b. Colourless oil,
310 mg, 53% yield from 15, Rf 0.4 ethyl acetate/petrol
(30:70); dH (400 MHz, CDCl3) 8.09–8.07 (4H, m, Ar),
7.61–7.55 (2H, m, Ar), 7.48–7.40 (4H, m, Ar), 7.12 (1H, s,
vCHS), 5.65 (1H, d, J¼6 Hz, BzOCHCH2), 5.41 (1H, dd,
J¼5.5, 10 Hz, OCHCv), 4.64 (2H, d, J¼2 Hz, BzOCH2-
CH), 4.56–4.55 (1H, m, BzOCH2CH), 2.68 (3H, s,
CH3Cv), 2.68–2.65 (1H, m, BzOCHCH2), 2.50 (1H,
ddd, J¼6, 10, 14 Hz, BzOCHCH2); dC (100.6 MHz,
CDCl3) 166.51 and 166.26 (PhCvO), 165.99 (CH3C),
155.49 (OCHCvCH), 133.29 133.01, 129.87, 129.72,
129.69, 129.43, 128.33, 128.27 (Ar), 114.34 (OCHCvCH),
82.88 (BzOCHCH2), 78.14 (OCHCvCH), 76.69 (BzOCH2
CHO), 64.74 (BzOCH2CHO), 39.71 (BzOCHCH2), 19.12
(CH3C); nmax/cm21 (neat film) 1722s, 1602 w, m/z
(electrospray) 446 (MNaþ, 100%); HRMS found: MNaþ
446.1042 (C23H21NO5SNa requires 446.1038); [a]2D0 268.0
[c 1.0, CHCl3].
3.2.5. 3S-Benzoyloxy-2R-benzoyloxymethyl-5R-(2-amino-
thiazol-4-yl)-tetrahydrofuran, 28b. Colourless oil,
322 mg, 55% yield from 15, Rf 0.55 ethyl acetate/petrol
(50:50); dH (400 MHz, CDCl3) 8.10–8.07 (4H, m, Ar),
7.67–7.56 (2H, m, Ar), 7.49–7.37 (4H, m, Ar), 6.51 (1H, s,
CvCH), 5.61 (1H, d, J¼5 Hz, BzOCHCH2), 5.19 (1H, dd,
J¼10, 6 Hz, CHCvCH), 5.01 (2H, br, NH2), 4.65–4.62
(2H, m, BzOCH2CHO), 4.53 (1H, app s, BzOCH2CHO),
2.56–2.45 (2H, m, BzOCHCH2); dC (100.6 MHz, CDCl3)
168.41 (vCNH2), 166.77 (PhCO), 166.48 (PhCO), 151.78
(CHCvCH), 133.77, 133.66, 130.37, 130.24, 130.14,
128.91, 128.87, and 128.81 (Ar), 105.25 (CHCvCH),
83.17 (BzOCHCH2), 77.93 (CHCvCH), 77.20 (BzOCH2-
CH), 65.23 (BzOCH2CH), 39.02(BzOCHCH2); nmax/cm21
(neat film) 3367 br m, 1721s; m/z (EI) 425 (MHþ, 100%);
HRMS found: MHþ 425.1178 (C22H21N2O5S requires
425.1171); [a]2D0 253 [c 1.0, CHCl3].
3.2.2. 3S-Benzoyloxy-2R-benzoyloxymethyl-5S-(2-
methylthiazol-4-yl)-tetrahydrofuran, 26a. Colourless oil,
205 mg, 35% yield from 15, Rf 0.2 ethyl acetate/petrol
(30:70); dH (400 MHz, CDCl3) 8.10–8.05 (2H, m, Ar),
7.84–7.81 (2H, m, 2H, Ar), 7.58–7.39 (6H, m, Ar), 7.14
(1H, s, vCHS), 5.62 (1H, ddd, J¼9, 7, 3 Hz, BzOCHCH2),
5.47 (1H, dd, J¼6, 5 Hz, OCHCv), 4.71 (1H, m,
BzOCH2CH), 4.61 (2H, d, J¼5 Hz, BzOCH2CH), 2.91
(1H, dd, J¼9, 7 Hz, BzOCHCH2), 2.69–2.60 (1H, m,
BzOCHCH2), 2.67 (3H, s, CH3); dC (100.6 MHz, CDCl3)
166.27 and 166.26 (PhCO), 165.99 (CH3CvN), 156.21
(OCHCvCH), 133.16, 133.11, 129.68, 129.65, 129.58,
129.21, 128.41, 128.27 (Ar), 113.72 (OCHCvCH), 82.13

M. F. A. Adamo et al. / Tetrahedron 60 (2004) 841–849
847
3.2.6. 3S-Benzoyloxy-2R-benzoyloxymethyl-5S-(2-ami-
nothiazol-4-yl)-tetrahydrofuran, 28a. Colourless oil,
205 mg, 35% yield from 15, Rf 0.45 ethyl acetate/petrol
(50:50) dH (400 MHz, CDCl3) 8.08–8.05 (2H, m, Ar),
7.93–7.90 (2H, m, Ar), 7.59–7.53 (2H, m, Ar), 7.45–7.39
(4H, m, Ar), 6.49 (1H, s, CvCH), 5.60 (1H, ddd, J¼10, 7,
4 Hz, BzOCHCH2), 5.24 (1H, dd, J¼8, 6 Hz, CHCvCH),
5.19 (2H, br, NH2), 4.67 (1H, dd, J¼8, 4 Hz, BzOCH2CH),
4.58 (2H, d, J¼8 Hz, BzOCH2CH), 2.83 (1H, dd, J¼13,
8 Hz, BzOCHCH2), 2.53 (1H, ddd, J¼13, 7, 6 Hz,
BzOCHCH2); dC (100.6 MHz, CDCl3) 168.15 (vCNH2),
166.32 (PhCO), 166.06 (PhCO), 152.64 (CHCvCH),
133.22, 133.14, 129.75, 129.68, 129.67, 129.62, 128.43
and 128.45 (Ar), 103.97 (CHCvCH), 81.87 (BzOCHCH2),
77.46 (CHCvCH), 76.28 (BzOCH2CH), 64.82 (BzOCH2-
CH), 37.82(BzOCHCH2); nmax/cm21 (neat film) 3367 br m,
1721s; m/z (EI) 425 (MHþ, 100%); HRMS found: MHþ
425.1172 (C22H21N2O5S requires 425.1171); [a]2D0 þ4.5 [c
1.0, CHCl3].
2.33 (0.9H, s, CH3CvO), 2.24 (2.1H, s, CH3CvO), 1.26
(2.1H, t, J¼7 Hz, CH3CH2OC), 1.17 (0.9H, t, J¼7 Hz,
CH3CH2OC); dC (100.6 MHz, CDCl3) 204.95 and 204.29
(CH3CvO), 166.15, 166.12, 166.10, 165.82 (PhCvO),
133.45, 133.38, 133.24, 133.18, 139.72, 129.68, 129.64,
129.56, 129.49, 129.22, 128.48, 128.44, 128.38, 128.26
(Ar), 109.43 and 109.15 (C–OCH2CH3), 83.30 and 83.06
(BzOCHCH2), 74.85 and 74.72 (BzOCH2CH), 64.34 and
64.06 (BzOCH2CH), 59.57 and 59.23 (COCH2CH3), 40.25
and 39.56 (BzOCHCH2), 25.43 and 25.37 (CH3CvO),
15.58 and 15.21 (COCH2CH3); nmax/cm21 (neat film)
1724s; m/z (electrospray) 430 (MNHþ4 , 100%); HRMS
found: MNHþ4 430.1870 (C23H28NO7 requires 430.1866).
3.3. General procedure for the preparation of
compounds 33a, 33b, 34a and 34b
To solution of the benzoylated nucleoside 26a, 26b, 27a
and 27b (0.4 mmol) in THF (20 mL) and water (20 mL) was
added LiOH·H2O (19 mg, 1.1 equiv.) and the solution
stirred at room temperature for 24 h. The reaction mixture
was concentrated in vacuo to leave a cloudy water phase,
which was extracted with ethyl acetate (3£10 mL). The
organic layer was dried Na2SO4 and concentrated in vacuo
to give pure 33a, 33b, 34a and 34b.
3.2.7. Preparation of 3S-benzoyloxy-2R-benzoyloxy-
methyl-5R/S-[6H-(1,3,4)-thiadiazin-2-amine-5-yl]-tetra-
hydro-furan 29a/b. To a solution of 15 (556 mg,
1.38 mmol) in methanol (20 mL) was added thiosemicarba-
zide hydrochloride (175 mg, 1.38 mmol, 1 equiv.) and the
reaction mixture refluxed for 1 h. Then the solvent was
removed and the residue purified by flash chromatography,
to yield 29a/b as a colourless oil, 490 mg, 81% yield from
15, Rf 0.65 ethyl acetate/methanol (50:50); dH (400 MHz,
CDCl3) 8.07–7.96 (4H, m, Ar), 7.62–7.55 (2H, m, Ar),
7.49–7.42 (4H, m, Ar), 5.59 (1H, m, BzOCHCH2), 5.15
(1H, m, CHCvN), 4.65–4.51 (3H, m, BzOCH2CH), 3.41
(0.4H, d, J¼14 Hz, NvCCH2), 3.30 (0.4H, d, J¼14 Hz,
NvCCH2), 3.29 (0.6H, d, J¼14 Hz, NvCCH2), 3.20
(0.6H, d, J¼14 Hz, NvCCH2), 2.92–2.84 (0.4H, m,
BzOCHCH2), 2.72–2.66 (0.4H, m, BzOCHCH2), 2.58–
2.31 (1.2H, m, BzOCHCH2); dC (100.6 MHz, CDCl3)
166.15(PhCO), 166.05(PhCO), 150.56 (vCNH2), 133.46,
133.32, 133.24, 129.70, 129.66, 129.54, 129.45 and 128.59
(Ar), 95.67 (CHCvN), 83.36 and 82.60 (BzOCHCH2),
80.53 and 80.08 (CHCvCH), 76.69 and 76.33 (BzOCH2-
CH), 64.73 and 64.54 (BzOCH2CH), 37.37 and 36.29
(BzOCHCH2), 20.58 and 20.36, (CH2S); nmax/cm21 (neat
film) 3320 br m, 1716s; m/z (APþ) 439 (Mþ, 100%); HRMS
found: MHþ 440.1281 (C22H22N3O5S requires 440.1280).
3.3.1. 2R-Hydroxymethyl-5R-(2-methylthiazol-4-yl)-tet-
rahydrofuran-3S-ol, 33b. Colourless oil, 67 mg, 78%
yield; dH (500 MHz, CDCl3) 7.06 (1H, s, CvCHS), 5.24
(1H, dd, J¼9, 1.5 Hz, HOCHCH2), 4.32–4.30 (2H, m,
HOCH2CHOCHCvN), 3.69 (1H, dd, J¼11.5, 4 Hz,
HOCH2CHO), 3.58 (1H, dd, J¼11.5, 6 Hz, HOCH2CHO),
2.70 (3H, s, CH3CvN), 2.58 (1H, ddd, J¼14, 9, 6.5 Hz,
HOCHCH2CHO), 2.17 (1H, m, HOCHCH2CHO); dC
(125.8 MHz,
CDCl3)
167.7
(CH3CvN),
156.4
(OCHCvCHS), 115.8 (OCHCvCHS), 89.2 (HOCHCH2),
76.4 (OCHCNvC), 73.7 (HOCH2CHO), 63.6 (HOCH2-
CH), 39.7 (HOCHCH2CHO), 19.0 (CH3CvN); nmax/cm21
(neat film) 3366 br, m/z (electrospray) 216 (MHþ,100%);
HRMS found: MHþ 216.0684 (C9H14NO3S requires
216.0694); [a]2D0 þ50.0 [c 1.0, CHCl3].
3.3.2. 2R-Hydroxymethyl-5S-(2-methylthiazol-4-yl)te-
trahydrofuran-3S-ol, 33a. Colourless oil, 61 mg (71%
yield); dH (500 MHz, CDCl3) 7.00 (1H, s, CvCHS), 5.30
(1H, dd, J¼9.5, 6.5 Hz, HOCHCH2), 4.66 (1H, d, J¼5 Hz,
OCHCvCH), 4.16 (1H, app s, HOCH2CHO), 3.93 (1H, dd,
J¼12.5, 2.5 Hz, HOCH2CHO), 3.72 (1H, d, J¼12.5 Hz,
HOCH2CHO), 2.69 (3H, s, CH3CvN), 2.56 (1H, ddd,
J¼13.5, 9.5, 5.5 Hz), 2.26 (1H, dd, J¼13.5, 6.5 Hz,
CH2CHO); dC (125.8 MHz, CDCl3) 167.7 (CH3CvN),
156.7 (OCHCvCH), 114.9 (OCHCvCH), 88.9
(OCHCH2), 76.2 (OCHCvCH), 75.4 (HOCH2CHO),
3.2.8. 1-(2R/S-Ethoxy-4S-benzoyloxy-5R-benzoyloxy-
methyl-tetrahydrofuran-2-yl)-ethanone 32. To a solution
of 15 (556 mg, 1.38 mmol) in ethanol (10.4 mL) was added
benzamidine hydrochloride (215 mg, 1.38 mmol, 1 equiv.)
and NaHCO3 (115 mg, 1.38 mmol, 1 equiv.). The reaction
mixture was refluxed for 4 h, then the solvent was removed
and the residue purified by flash chromatography to yield 32
as a colourless oil, 370 mg (65% yield), Rf 0.45 ethyl
acetate/petrol (20:80); dH (400 MHz, CDCl3) 8.10–7.99
(4H, m, Ar), 7.62–7.56 (2H, m, Ar), 7.48–7.42 (4H, m, Ar),
5.63 (0.3H, ddd, J¼3.5, 4.5, 7 Hz, BzOCHCH2), 5.54 (0.7H,
ddd, J¼8, 5.5, 2.5 Hz, BzOCHCH2), 4.71–4.53 (3H, m,
BzOCH2CH), 3.65 (1H, m, J¼7 Hz, CH3CH2OC), 3.49
(0.7H, m, CH3CH2OC), 3.40 (0.3H, m, CH3CH2OC), 2.77
(0.3H, dd, J¼14, 7 Hz, BzOCHCH2), 2.63 (0.7H, dd, J¼14,
7 Hz, BzOCHCH2), 2.49 (0.3H, dd, J¼15, 5 Hz,
BzOCHCH2), 2.42 (0.7H, dd, J¼15, 2 Hz, BzOCHCH2),
64.10
(HOCH2CH),
42.7
(HOCHCH2O),
19.1
(CH3CvN); nmax/cm21 (neat film) 3367 br; m/z (electro-
spray) 216 (MHþ, 100%); HRMS found: MHþ 216.0694
(C9H14NO3S requires 216.0694); [a]2D0 þ4.1 [c 1.0, CHCl3].
3.3.3. 2R-Hydroxymethyl-5R-(2-phenylthiazol-4-yl)-tet-
rahydrofuran-3S-ol, 34b. Colourless oil, 95 mg, 86%
yield; dH (400 MHz, CDCl3) 7.88–7.85 (2H, m, Ph),
7.49–7.39 (3H, m, Ph), 7.37 (1H, s, OCHCvCHS), 5.32
(1H, dd, J¼1.5, 9 Hz), 4.39–4.37 (2H, m HOCH2

848
M. F. A. Adamo et al. / Tetrahedron 60 (2004) 841–849
CHOCHCvCH), 3.73 (1H, dd, J¼11, 4 Hz, HOCH2CHO),
3.62 (1H, dd, J¼11, 5.5 Hz, HOCH2CHO), 2.63 (1H, ddd,
J¼14, 9, 6.5 Hz, HOCHCH2CHO), 2.34 (1H, m,
HOCHCH2CHO); dC (125.8 MHz, CDCl3) 169.88 (PhCvN),
157.68 (OCHCvCH), 132.64, 130.11, 128.21, 126.34 (Ar),
116.10 (OCHCvCH), 89.10 (OCHCH2), 76.22
(OCHCvCH), 74.10 (HOCH2CHO), 63.71 (HOCH2CH),
40.01(HOCHCH2O); nmax/cm21 (neat film) 3030 br; m/z
(electrospray) 278 (MHþ, 100%); HRMS found: MHþ
278.0848 (C14H16NO3S requires 278.0851). [a]2D0 þ45.0
[c 1.0, CHCl3].
38.06 (HOCHCH2); nmax/cm21 (neat film) 3030 br; m/z
(electrospray) 217 (MHþ, 100%); HRMS found: MHþ
217.0654 (C8H13N2O3S requires 217.0647); [a]2D0 þ5.6 [c
1.0, H2O].
3.4.3. 5-R/S (2-Amino-6H-[1,3,4]thiadiazin-5-yl)-2R-
hydroxymethyltetrahydrofuran-3S-ol, 36a/b. Colourless
oil, 69 mg, 75% yield; dH (200 MHz, D2O) 4.86 (1H, t,
HOCHCH2, J¼8 Hz), 4.32–4.28 (1H, m, OCHCvN),
3.96–3.93 (1H, m, HOCH2CHO), 3.64–3.51 (2H, m,
HOCH2CHO), 3.32–3.19 (2H, m, CH2S), 3.24 (2H, s,
NH2), 2.13–2.08 (2H, m, CH2CHO); dC (80 MHz, D2O),
171.65 (CNH2), 154.55 (OCHCvN), 87.86 (OCHCH2),
79.89 (OCHCvCH), 72.72 (HOCH2CHO), 62.26 (HOCH2
CH), 38.92 (HOCHCH2), 20.10 (CH2S); nmax/cm21 (neat
film) 3050 br; m/z (electrospray) 232 (MHþ, 35%); HRMS
found: MHþ 232.0764 (C8H14N3O3S requires 232.0756).
3.3.4. 2R-Hydroxymethyl-5S-(2-phenylthiazol-4-yl)tetra-
hydrofuran-3S-ol, 34a. Colourless oil, 91 mg (82% yield);
dH (400 MHz, CDCl3) 7.94–7.88 (2H, m, Ph), 7.49–7.39
(3H, m, Ph), 7.16 (1H, s, OCHCvCHS), 5.39 (1H, dd, J¼9,
7 Hz, HOCHCH2), 4.70 (1H, d, J¼5 Hz, OCHCvCH), 4.21
(1H, app s, HOCH2CHO), 3.97 (1H, dd, J¼2.5, 12 Hz,
HOCH2CHO), 3.76 (1H, dd, J¼9, 2 Hz, HOCH2CHO),
2.65 (1H, ddd, J¼14, 9, 5.5 Hz), 2.30 (1H, dd, J¼14,
6.5 Hz, CH2CHO); dC (80 MHz, CDCl3) 169.88 (PhCvN),
157.99 (OCHCvCH), 132.71, 130.34, 128.97 and 126.34
(Ar), 115.26 (OCHCvCH), 88.71 (OCHCH2), 76.31
(OCHCvCH), 75.19 (HOCH2CHO), 64.07 (HOCH2CH),
42.67(HOCHCH2O); nmax/cm21 (neat film) 3015 br; m/z
(electrospray) 278 (MHþ, 100%); HRMS found: MHþ
278.0854 (C14H16NO3S requires 278.0851). [a]2D0 þ10.8
[c 1.0, CHCl3].
Acknowledgements
We thank F. Hoffmann-La Roche (Basle), RCSI Research
Committee and Irish Government PTRLI cycle 3 for
financial support to MFAA. We also thank Mr Sean
Magee (DIT) for NMR support.
References and notes
3.4. General procedure for the preparation of
compounds 35a, 35b, and 36a/b
1. Mizuno, K.; Tsujino, M.; Takada, M.; Hayashi, K.; Atsumi,
K.; Asano, K.; Matsuda, T. J. Antibiot. 1974, 27, 775.
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methanol (20 mL) for 5 min. The reaction mixture was
stirred at room temperature for 24 h, then the solvent
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hydrofuran-3S-ol, 35b. Colourless oil, 59 mg, 68% yield;
dH (200 MHz, D2O) 6.33 (1H, s, OCHCvCHS), 4.72 (1H,
t, HOCHCH2, J¼8 Hz), 4.09 (1H, dd, J¼5, 2.5 Hz,
OCHCvCH), 3.67 (1H, dd, J¼8, 5 Hz, HOCH2CHO),
3.45–3.31 (2H, m, HOCH2CHO), 1.93–1.86 (2H, m,
CH2CHO); dC (80 MHz, CDCl3) 173.82 (CNH2), 152.88
(OCHCvCH), 108.67 (CvC–S), 89.82 (OCHCH2), 79.16
(OCHCvCH), 75.60 (HOCH2CHO), 65.10 (HOCH2CH),
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24. ratio calculated from the relative integration of OMe peaks; a
and banomers assigned by n.O.e experiments between H-10
and H-40.