Synthesis of analogues of the marine anti-tumour agent curacin

Article abstract of DOI:10.1039/a904378k

A concise, multigram synthesis of (4R)-2-[(1′R2′S)-1′, 2′-methano-3′-(/er/-butyldiphenylsiloxy)propyl]-4-hydroxymethyl-4, 5-dihydrothiazole has been achieved, and this compound has been used for the production of a range of analogues of the anti-mitotic a

Full text of DOI:10.1039/a904378k

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Synthesis of analogues of the marine anti-tumour agent curacin A
Barbara K. D. Martin, John Mann* and Olivia A. Sageot
Department of Chemistry, Reading University, Whiteknights, Reading, UK RG6 6AD
Received (in Cambridge) 2nd June 1999, Accepted 12th July 1999
A concise, multigram synthesis of (4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-methano-3Ј-(tert-butyldiphenylsiloxy)propyl]-4-
hydroxymethyl-4,5-dihydrothiazole has been achieved, and this compound has been used for the production
of a range of analogues of the anti-mitotic agent curacin A.
Curacin A, 1, from the marine cyanobacterium Lyngbya majus-
cula,1 has excited the interest of chemists and biologists not
least because its cytotoxic potency (at the nanogram level) is
combined with a relatively simple structure. It binds to tubulin
at the colchicine-binding site, which provides further fascin-
ation, since there is no obvious structural similarity between
these two secondary metabolites. The possibility of devising a
completely novel class of anti-cancer drugs is thus most
appealing.
anes), followed by protection of the hydroxy group provided
the unsaturated ether 5 (overall yield 90% for the two steps)
(Scheme 1). A highly stereoselective Simmons–Smith methyl-
A number of total syntheses of curacin A have already been
completed,2 but since the compound is very sensitive to oxid-
ation, acids and bases, and must be stored under an inert
atmosphere at Ϫ80 ЊC, its viability as a drug is clearly com-
promised. Some information concerning structure–activity data
for analogues has also been published,3 with the survey by
Gerwick, White and coworkers being the most extensive. They
reported the activity of 23 analogues, and the main conclusions
from this and the other studies were that the unsaturated side-
chain and cyclopropylthiazoline† were required for optimal
activity, though the relative stereochemistry of the cyclopropyl
substitutents could be varied without loss of too much activity.
To date no analogues with a modification to the cyclopropyl
methyl group have been reported. With this in mind, we
embarked upon a programme of research that would provide
efficient access to the compounds 2 and 3, which are ideally
functionalised for elaboration into a wide array of analogues of
this type. The successful syntheses of these key intermediates,
and the production of a number of novel analogues of curacin
A, are the subjects of this paper.
Scheme 1 Reagents and conditions: i, DIBAL-H; ii, TBDPS-Cl; iii,
Et2Zn–CH2I2, Ϫ23 ЊC; iv, H5IO6, ether, RT; v, KMnO4.
enation was accomplished using diethylzinc and diiodomethane
at Ϫ20 ЊC (97% isolated yield), according to the method of
Taguchi et al.,5 and like these authors, we only obtained stereo-
isomer 6. The isopropylidene group was removed (PTSA–
aqueous MeOH, 80%) and the resultant diol cleaved to provide
the aldehyde 7 (NaIO4–aqueous THF, 81%). Unfortunately, the
acid-catalysed step was only effective when carried out under
conditions of high-dilution. More concentrated reaction mix-
tures inevitably led to concomitant removal of the TBDPS
group. To circumvent this problem, we employed periodic acid
in anhydrous ether6 to effect removal of the isopropylidene
group and oxidative cleavage of the resultant diol to provide the
aldehyde 7 in essentially quantitative yield. This aldehyde was
then oxidised with KMnO4 to produce the desired acid 8 (97%
for the three steps).
Our synthesis of compound 2 is shown in Schemes 1 and 2,
and commenced with the Wittig product
4 from (R)-
glyceraldehyde acetonide and methoxycarbonylmethylidene-
(triphenyl)phosphorane.4 Reduction with DIBAL-H (in hex-
In many of the reported syntheses of curacin A, a major
problem has been the construction of the thiazoline ring, and
† IUPAC name: cyclopropyl-4,5-dihydrothiazole.
J. Chem. Soc., Perkin Trans. 1, 1999, 2455–2460
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the synthetic sequences have either been lengthy or low-
yielding. Typically, the expensive Burgess reagent7 has been
used to effect the dehydration needed for the construction of
the thiazoline ring. Our solution was to prepare the mixed
anhydride 9 from the acid 8 (BuiOCOCl–N-methylmorpholine,
quant.) and thence the cysteinyl amide 10 (-cysteine methyl
esterؒHCl–N-methylmorpholine, 65%) (Scheme 2). Finally,
adjacent double bond, we chose to replace the natural side-
chain with a farnesyl ether to try to overcome these problems. It
was our fervent hope that the farnesyl chain would have enough
structural similarity to the natural chain, so that the biological
effect of this substitution would be effectively ‘neutral’. This
would then allow us to probe the effects of introducing func-
tionality at the cyclopropyl methyl group.
Reaction of 2 with farnesyl bromide (NaH, 18-crown-6, NaI,
benzene) yielded the anticipated farnesyl ether 12 (55%), and
removal of the TBDPS group (Bu4NF, THF) produced the
alcohol 13 (86%). The acetate 14 (Ac2O, pyridine, 61%) and the
hexanoate 15 (hexanoic acid, Ph3P, DEAD, 80%) were then
produced using conventional chemistry. In addition, although
the methyl ether 16 could not be prepared using base and
methyl iodide, it could be prepared (in low yield, 25%) through
the use of diazomethane on silica.9 We also tried to reduce the
hydroxy group of compound 13 via formation of the xanthate
17, which could be prepared in the usual way (NaH–THF–CS2–
MeI) and in good yield (75%). However, reaction with Bu3SnH
in the presence of AIBN in toluene led to the not unexpected
formation of the 2-but-3-enylthiazoline 18 via ring opening of
the cyclopropylmethylene radical. Other attempts to convert
the alcohol 13 into the bromide and tosylate led to decom-
position.
Biological evaluation of compounds 13 to 16 was carried
out using the Cancer Research Campaign’s panel of human
ovarian carcinoma cell lines: A2780, A2780 (cisplatin resistant),
CH1, CH1 (cisplatin resistant), and SKOV-3; but unfortunately
none of these compounds showed any cytotoxic activity at
concentrations up to 25 µM. In contrast, curacin A has been
reported3 to have an IC50 of 0.038 µM against the human breast
cancer cell line MCF-7. While it is a common finding that com-
pounds have very different activities against different tumour
cell lines, and our compounds will be tested in other systems,
these results are none the less disappointing. This lack of
activity may reveal that the natural unsaturated side-chain is
an absolute requirement for good levels of potency, and we
are presently using the key intermediates 2 and 3 to prepare
analogues of compounds 13 to 16 with unsaturated side-chains
that more closely resemble the one present in curacin A. It has
to be admitted, however, that an increase in potency may be
negated by a decrease in stability, and that analogues of curacin
A that are viable clinical candidates may be impossible to
prepare.
Scheme
2
Reagents and conditions: i, isobutyl chloroformate,
N-methylmorpholine; ii, -cysteine methyl ester HCl; iii, TiCl4; iv,
LiAlH4.
treatment of this amide with TiCl4 in DCM8 effected ring clos-
ure to provide the thiazoline ester 11 in excellent (91%) yield.
Although this methodology had been used to prepare oxazoline
and thiazoline rings, it had not been used to prepare thiazoline
rings in delicate systems like 11. Finally, reduction of the ester
using LiAlH4 provided the desired intermediate 2, which was
also converted into the alternative alcohol 3 through acetyl-
ation (Ac2O, pyridine, quant.) and reaction with fluoride
(TBAF–THF, 73%).
With multigram quantities of intermediate 2 in hand, we
embarked upon the synthesis of a number of simple analogues
of curacin A for biological evaluation. Since the natural prod-
uct is relatively unstable due to the lability of the 4-hydrogen
of the thiazoline ring, and cis to trans isomerisation of the
Experimental
IR spectra were recorded using a Perkin-Elmer 881 series
2456
J. Chem. Soc., Perkin Trans. 1, 1999, 2455–2460

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double beam spectrophotometer, and samples were run as thin
films or in solution using NaCl plates. Low resolution and
accurate mass data were recorded on a VG Autospec spec-
trometer. Elemental analyses were carried out by Medac Ltd.,
Brunel University on those compounds that were stable. All
compounds for which exact mass data are provided were
homogeneous by TLC in three different solvent systems, and
exhibited no spurious signals in their 1H NMR spectra at
400 MHz. NMR spectra were recorded using JEOL EX4000,
Bruker DPX 250, or Bruker WM 250 spectrometers. In 13C
NMR assignments 3C refers to tertiary carbon. [α]D Values are
given in units of 10Ϫ1 deg cm2 gϪ1. Solvents were dried by dis-
tillation from calcium hydride (DCM, dichloromethane) or
from sodium–benzophenone (ether, THF).
6H, 6 × diphenyl-H), 7.66 (m, 4H, 4 × diphenyl-H); 13C NMR
δC (100 MHz; CDCl3; Me4Si): 19.11 (3C, tert-butyl-C), 25.85
and 26.75 (2 × CH3, isopropylidene), 60.27 (CH2, C-5), 69.38
(CH2, C-1), 71.95 (CH, C-4), 109.17 [3C, C(CH3)2], 127.72 (CH,
diphenyl), 128.16 (CH, C-3), 129.73 (CH, diphenyl), 133.33
(CH, C-2), 133.39, 133.50, 135.56 (2 × 3C, CH, remaining
diphenyl-C); CI-MS m/z: 66 (17%), 130 (18), 199 (38), 251 (16),
281 (100), 339 (40), 397 (22); C24H32O3Si requires 397.2205,
found 397.2191; [α]D20 Ϫ3.1 (c = 1.0, CHCl3), lit.5 [α]D Ϫ3.9
(c = 1.12, CHCl3).
(1R,2S,4ЈS)-2-[(tert-Butyldiphenylsilyloxy)methyl]-1-(2Ј,2Ј-
dimethyl-1Ј,3Ј-dioxolan-4Ј-yl)cyclopropane (6)
Diethylzinc (61.0 ml, 0.060 mol, 1 M solution in hexane, 5 eq)
and diiodomethane (9.83 ml, 0.12 mol, 10 eq) were added to the
alkene (5) (4.84 g, 0.012 mol) in dichloromethane (60 ml, dry),
under an argon atmosphere at Ϫ23 ЊC. The reaction was stirred
vigorously overnight at Ϫ23 to 0 ЊC, followed by treatment with
aqueous ammonium chloride and the products were extracted
into ether. The organic phase was washed with saturated
sodium bicarbonate solution followed by brine, and the com-
bined organic layers were dried (MgSO4) and evaporated under
reduced pressure. The resulting residue was purified by column
chromatography on silica gel [eluent: 8:2, petroleum ether (bp
40–60 ЊC)–ether] affording the required cyclopropane (6) (4.88
g, 97%).
Methyl (4S)-(Z)-4,5-isopropylidenedioxypent-2-enoate (4)
Methoxycarbonylmethylene(triphenyl)phosphorane (61.6 g,
0.18 mol) was added in portions to a solution of (R)-glycer-
aldehyde acetonide (24 g, 0.184 mol) in methanol (AnalaR; 170
ml) at 0 ЊC, and the mixture was shaken for 1 h. The solvent was
removed under reduced pressure and the residue extracted with
warm light petroleum (bp 40–60 ЊC). After cooling, the extract
was filtered and evaporated to dryness. The resultant colourless
oil (30 g, 87%) comprised a mixture of cis and trans alkenes.
The major (cis) product was isolated by flash chromatography
on silica gel [eluent: 7:3, petroleum ether (bp 40–60 ЊC)–ether].
Isolated yields were cis-4 (27.4 g, 80%) and trans-4 (2.3 g, 7%),
giving a cis:trans ratio 12:1. The spectroscopic data were in
accord with the literature.4
IR (thin film in CHCl3) νmax/cmϪ1: 3050 (C–H, cyclo-
propane), 2933 (C–H), 1589, 1470, 1428, 1110 (Si–O), 1064 (Si–
1
O), 705 (Si–O), 613; H NMR δH (400 MHz; CDCl3; Me4Si):
Spectral data for cis-product (4): IR (thin film in CHCl3) νmax
/
0.36 (dd, 1H, Jgem 10.9, J3,1 5.4 Hz, H-3), 0.84 (m, 1H, H-3a),
1.03 (m, 1H, J1,3 5.4 Hz, H-1), 1.05 (s, 9H, tert-butyl), 1.20 (m,
1H, H-2), 1.35 (s, 3H, acetonide-CH3), 1.46 (s, 3H, acetonide-
CH3), 3.40 (dd, 1H, Jgem 11.3, J5Ј,4Ј 9.5 Hz, H-5Ј), 3.78 (m, 2H,
CH2OTBDPS), 3.91 (dd, 1H, Jgem 11.3, J5aЈ,4Ј 5.5 Hz, H-5Јa),
4.21 (m, 1H, H-4Ј), 7.40 (m, 6H, 6 × diphenyl-H), 7.66 (m, 4H,
4 × diphenyl-H); 13C NMR δC (100 MHz; CDCl3; Me4Si): 8.17
(CH2, C-3), 17.53 (3C, tert-butyl), 18.361 (CH, C-1), 19.16 (CH,
C-2), 25.79 (CH3, acetonide), 26.90 (4 × CH3, tert-butyl and
acetonide), 64.17 (CH2, C-5Ј), 70.17 (CH2, CH2OTBDPS),
108.55 (CH, C-4Ј), 127.66 [3C, C(CH3)2], 127.70, 127.90, 129.68,
133.61, 135.49, 135.58 (12 × diphenyl-C); CI-MS m/z: 97 (30%),
155 (30), 199 (55), 295 (100), 353 (83), 411 (11); C25H34O3Si
requires 410.2277, M ϩ Hϩ requires 411.2355, found 411.2301;
[α]D20 Ϫ1.2 (c = 1.0, CHCl3), lit.5 [α]D Ϫ1.4 (c = 1.06, CHCl3).
1
cmϪ1: 1725, 1650, 1210, 1065; H NMR δH (400 MHz; CDCl3;
Me4Si): 1.39 and 1.45 (2 × s, 6H, 2 × Me), 3.62 (dd, 1H, Jgem
8.2, J5,4 6.9 Hz, H-5), 3.73 (s, 3H, OMe), 4.39 (dd, 1H, Jgem 8.2,
J5a,4 7.0 Hz, H-5a), 5.49 (m, 1H, H-4), 5.86 (dd, 1H, J2,3 11.4, J2,4
1.8 Hz, H-2), 6.31 (dd, 1H, J3,2 11.4, J3,4 6.6 Hz, H-3); [α]D20 ϩ90.8
(c = 1, CHCl3).
(4S)-(Z)-1-(tert-Butyldiphenylsilyloxy)-4,5-isopropylidene-
dioxypent-2-ene (5)
The cis-alkene (4) (2.00 g, 0.011 mol) in DCM (40 ml), was
treated at Ϫ78 ЊC with DIBAL-H (26.9 ml, 0.027 mol of a 1 M
solution, 2.5 eq). After stirring the resulting solution at this
temperature for 30 min the reaction was quenched by the
addition of methanol (5 ml), and the mixture was warmed to
room temperature, then filtered through Celite. The Celite was
washed thoroughly with EtOAc, and the combined filtrates
were dried and concentrated, prior to purification by silica
chromatography [eluent: 3:1, petroleum ether (bp 40–60 ЊC)–
EtOAc] to provide the required alcohol (1.65 g, 97%) as a col-
ourless oil. To a solution of this alcohol (1.6 g, 0.010 mol) in
DCM (20 ml), under an argon atmosphere at 0 ЊC, was added
triethylamine (2 ml). After stirring for 10 min tert-butyl-
diphenylsilyl chloride (2.63 ml, 0.010 mol, 1 eq) was added and
a small amount of DMAP (≈10 mg). The reaction was then
quenched by addition of water followed by extraction into
ether. The organic phase was washed with water, sodium
bicarbonate solution and brine and then dried (MgSO4) and
concentrated under reduced pressure, to yield a crude oil (4.2 g)
which was purified by column chromatography [eluent: 9:1,
petroleum ether (bp 40–60 ЊC)–ethyl acetate] affording 3.7 g,
93% of the title compound (5).
(2R,3S)-4-(tert-Butyldiphenylsilyloxy)-2,3-methanobutanal (7)
Periodic acid (1.36 g, 6 mmol, 2.5 eq) was added to the acetal
(6) (1.0 g, 2.4 mmol) dissolved in anhydrous ether (100 ml) held
at RT under an atmosphere of argon. The reaction was com-
plete after around 10 h, and the mixture was then filtered prior
to evaporation of the ether. The crude product was dissolved
in chloroform, insoluble salts were removed by filtration,
and the filtrate was evaporated to yield an off-white solid (0.81
g, quant.). This was used without further purification but an
analytical sample was obtained by chromatography [eluent:
8:2, petroleum ether (bp 40–60 ЊC)–ether].
Mp 87–88 ЊC; IR (thin film in CHCl3) νmax/cmϪ1: 3049 (C–H,
cyclopropane), 2930 (C–H), 2723 (H–C᎐O, w), 1707 (H–C᎐O),
᎐
᎐
1
1113 and 704 (Si–O); H NMR δH (400 MHz; CDCl3; Me4Si):
1.03 (s, 9H, tert-butyl), 1.19 (m, 1H, CH2), 1.28 (m, 1H, CH2),
1.77 (m, 1H, H-3), 1.96 (m, 1H, H-2), 3.66 (dd, 1H, Jgem 11.3,
J4,3 8.0 Hz, H-4), 3.99 (dd, 1H, Jgem 11.3, J4a,3 5.5 Hz, H-4a),
7.36–7.40 (m, 6H, 6 × diphenyl-H), 7.62–7.67 (m, 4H, 4 ×
diphenyl-H), 9.36 (d, 1H, J1,2 5.5 Hz, H-1); 13C NMR δC (100
MHz; CDCl3; Me4Si): 12.19 (CH2), 19.16 (3C, tert-butyl), 25.87
(CH, C-3), 26.77 (CH3, 3 × CH3, tert-butyl), 27.43 (CH, C-2),
62.05 (CH2, C-4), 127.73–135.55 (2 × 3C and 10 × CH, 2 ×
diphenyl), 200.76 (3C, C-1); CI-MS m/z: 78 (20), 198 (16), 281
IR (thin film in CHCl3) νmax/cmϪ1: 2932 (CH), 1590 (w, aro-
matic), 1474 (aromatic), 1113 (Si–O), 1062 (Si–O), 703 (Si–O);
1H NMR δH (400 MHz; CDCl3; Me4Si): 1.04 (s, 9H, tert-butyl),
1.31 (s, 3H, CH3), 1.38 (s, 3H, CH3), 3.43 (t, 1H, Jgem 8.0, J5,4 7.6
Hz, H-5), 3.89 (dd, 1H, Jgem 8.0, J5a,4 6.2 Hz, H-5a), 4.28 (m,
1H, Jgem 6.2, J1,2 1.8 Hz, H-1), 4.32 (m, 1H, Jgem 6.2, J1a,2 1.4 Hz,
H-1a), 4.62 (m, 1H, J4,5a 6.2, J4,3 1.8 Hz, H-4), 5.45 (m, 1H, J3,2
5.5, J3,4 1.8, J3,1 1.4 Hz, H-3), 5.81 (m, 1H, H-2), 7.32 (m,
J. Chem. Soc., Perkin Trans. 1, 1999, 2455–2460
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(60), 339 (100); C21H26O2Si requires 338.1702, M ϩ Hϩ requires
339.1780, found 339.1772; requires C, 74.51, H, 7.74%, found
C, 74.52, H, 7.69%; [α]D20 Ϫ11.9 (c = 1.0, CHCl3).
(4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-Methano-3Ј-(tert-butyldiphenylsilyloxy)-
propyl]-4-methoxycarbonyl-4,5-dihydrothiazole (11)
Titanium tetrachloride (0.53 ml of a 1 M solution in DCM, 1
eq) was added to the amide (10) (0.25 g, 0.525 mmol) in DCM
(20 ml) at 0 ЊC. The mixture was stirred for 2 h until starting
material had been consumed. The reaction was quenched by the
addition of sodium bicarbonate solution followed by extraction
with DCM. The organic phase was washed with water and
brine then dried (MgSO4), followed by evaporation of solvents
to afford the title compound (11), (0.22 g, 91%). Purification
was not necessary.
(2R,3S)-4-(tert-Butyldiphenylsilyloxy)-2,3-methanobutanoic
acid (8)
Potassium hydrogen orthophosphate buffer (40 ml, 1.25 M) was
added to aldehyde (7) (1.561 g, 4.61 mmol) in tert-butyl alcohol
(50 ml) to adjust the pH to 4.4. Aqueous KMnO4 (48 ml, 1 M
solution) was then added and the mixture was stirred vigor-
ously for 5 min until all the aldehyde had been consumed. The
reaction was quenched by addition of saturated sodium sulfite
solution and acidified with cold dilute HCl (2 M) to pH 3,
where the solution lost its colour. The mixture was extracted
with DCM and washed with brine, the organic phase was dried
(MgSO4) and concentrated under reduced pressure to yield
the title compound (8) (1.59 g, 97%), which was used without
further purification.
IR (thin film in CHCl3) νmax/cmϪ1: 3011 (CH, cyclopropane),
2931 (CH), 1745 (C᎐O), 1614 (C᎐N), 1111, 1068 and 824 (Si–
᎐
᎐
1
O), 611 and 704 (diphenyl); H NMR δH (400 MHz; CDCl3;
Me4Si): 1.04 (s, 9H, tert-butyl), 1.05 (m, 1H, H-4Јa), 1.14 (m,
1H, Jgem 11.9, J4Ј,1Ј 5.9 Hz, H-4Ј), 1.63 (m, 1H, H-2Ј), 1.99 (m,
1H, J1Ј,4Ј 5.9 Hz, H-1Ј), 3.40 (dd, 1H, Jgem 11.0, J3Ј,2Ј 9.4 Hz,
H-3Ј), 3.47 (dd, 1H, Jgem 11.0, J3aЈ,2Ј 9.9 Hz, H-3Јa), 3.69 (dd, 1H,
Jgem 11.0, J5,4 8.8 Hz, H-5), 3.77 (s, 3H, OMe), 3.83 (dd, 1H, Jgem
11.0, J5a,4 5.9 Hz, H-5a), 4.74 (m, 1H, H-4), 7.35–7.41 (m, 6H,
6 × diphenyl-H), 7.64–6.67 (m, 4H, 4 × diphenyl-H); 13C NMR
δC (100 MHz; CDCl3; Me4Si): 11.51 (CH2, C-4Ј), 19.19 (CH,
C-2Ј), 19.26 (3C, tert-butyl), 23.96 (CH, C-1Ј), 26.76 (CH3,
3 × CH3, tert-butyl), 35.74 (CH2, C-3Ј), 52.62 (CH3, OMe),
62.20 (CH2, C-5), 77.00 (CH, C-4), 127.54–135.57 (diphenyl-C),
171.56 (3C, CO2Me), 172.79 (3C, C-2); CI-MS m/z: 112 (29%),
198 (22), 278 (11), 396 (100), 454 (18); C25H31O3NSSi requires
453.1794, M ϩ Hϩ calculated 454.1872, found 454.1879;
requires C, 66.19, H, 6.89, N, 3.09%, found C, 66.24, H, 6.93, N,
3.06%; [α]D20 Ϫ13.5 (c = 1.0, CHCl3).
IR (thin film in CHCl3) νmax/cmϪ1: 2600–3200 (br, OH), 3050
(CH, cyclopropane), 2931 (CH), 1695 (C᎐O), 1113, 824 (Si–O);
᎐
1H NMR δH (400 MHz; CDCl3; Me4Si): 1.01 (s, 9H, tert-butyl),
1.02–1.06 (m, 2H, CH2), 1.64 (m, 1H, H-3), 1.76 (m, 1H, H-2),
3.78 (dd, 1H, Jgem 11.0, J4,3 8.4 Hz, H-4), 3.94 (dd, 1H, Jgem 11.0,
J4a,3 6.2 Hz, H-4a), 7.32–7.43 (m, 6H, 6 × diphenyl-H), 7.62–
7.69 (m, 4H, 4 × diphenyl-H); 13C NMR δC (100 MHz; CDCl3;
Me4Si): 12.94 (CH2), 17.35 (3C, tert-butyl), 19.184 (CH, C-3),
24.506 (CH, C-2), 26.719 (3 × CH3, tert-butyl), 61.996 (CH2,
C-4), 127.59–135.55 (diphenyl carbons), 178.83 (3C, C-1);
CI-MS m/z: 94 (22%), 138 (23), 175 (19), 199 (100), 236
(21), 277 (30), 297 (49), 355 (69); C21H26O3Si requires
Mϩ 354.1651, found 354.166; requires C, 70.95, H, 7.37%,
found C, 70.90, H, 7.35%; [α]D20 ϩ27.8 (c = 1, CHCl3).
(4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-Methano-3Ј-(tert-butyldiphenylsilyl-
oxy)propyl]-4-hydroxymethyl-4,5-dihydrothiazole (2)
Diethylamine (0.05 ml, 0.464 mmol, 1 eq) and lithium alu-
minium hydride (0.018 g, 0.464 mmol) were added to a solution
of methyl ester (11) (210 mg, 0.464 mmol) in THF (10 ml). The
reaction was stirred vigorously for 5 min then quenched by the
addition of water (0.5 ml). The mixture was filtered followed by
extraction of the filtrate with DCM, washed with brine, dried
(MgSO4) and then evaporated under reduced pressure. The
crude residue was purified by column chromatography on silica
gel [eluent: 4:6, petroleum ether (bp 40–60 ЊC)–ether] to yield
the alcohol (2) in 82% yield.
N-[(2ЈR,3ЈS)-4Ј-(tert-Butyldiphenylsilyloxy)-2Ј,3Ј-methano-
butanoyl]-(S)-cysteine methyl ester (10)
A mixture of isobutyl chloroformate (0.60 ml, 4.65 mmol, 1 eq)
and N-methylmorpholine (0.51 ml, 4.65 mmol, 1 eq) were
added to the carboxylic acid (8) (1.65 g, 4.65 mmol) in DCM
(100 ml) at Ϫ10 ЊC, and the mixture was stirred for 15 min to
produce the mixed anhydride (9). To this mixture was added a
stirred suspension of -cysteine methyl ester hydrochloride
(0.798 g, 4.65 mmol) in DCM (20 ml) and N-methylmorpholine
(0.51 ml, 4.65 mmol, 1 eq). The mixture was stirred for 2 h at
room temperature followed by addition of water, extraction
with DCM, and the organic phase was washed with water and
brine. The organic phase was dried (MgSO4), filtered and the
filtrate was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel [eluent: 1:1,
petroleum ether (bp 40–60 ЊC)–ether] to give the required amide
(10) (1.43 g, 65%), as a colourless viscous oil.
IR (thin film in CHCl3) νmax/cmϪ1: 3426 (br, OH), 3011 (CH,
cyclopropane), 2931 (CH), 1614 (C᎐N), 1101, 1064 and 821 (Si–
᎐
1
O), 619 and 706 (diphenyl); H NMR δH (400 MHz; CDCl3;
Me4Si): 0.97 (m, 2H, H-4Ј, 4Јa), 1.05 (s, 9H, tert-butyl), 1.57 (m,
1H, H-2Ј), 1.96 (m, 1H, H-1Ј), 3.13 (dd, 1H, Jgem 10.8, J3Ј,2Ј 9.5
Hz, H-3Ј), 3.24 (dd, 1H, Jgem 10.8, J3aЈ,2Ј 8.8 Hz, H-3Јa), 3.60 (dd,
1H, Jgem 11.4, J6,4 5.8 Hz, H-6), 3.69 (dd, 1H, Jgem 11.4, J6a,4 8.8
Hz, H-6a), 3.83 (dd, 1H, Jgem 11.1, J5,4 5.8 Hz, H-5), 3.87 (dd,
1H, Jgem 11.1, J5a,4 4.4 Hz, H-5a), 4.37 (m, 1H, J4,6a 8.8, J4,5 5.8
Hz, H-4), 7.36–7.43 (m, 6H, 6 × diphenyl-H), 7.64–6.69 (m, 4H,
4 × diphenyl-H); 13C NMR δC (100 MHz; CDCl3; Me4Si): 11.27
(CH2, C-4Ј), 19.12 (3C, tert-butyl), 19.19 (CH, C-1Ј), 23.40 (CH,
C-2Ј), 26.80 (CH3, 3 × CH3, tert-butyl), 34.70 (CH2, C-5), 62.48
(CH2, C-3Ј), 64.67 (CH2, C-6), 78.44 (CH, C-4), 127.5–135.7
(phenyl-C), 171.3 (3C, C-2); CI-MS m/z: 130 (21%), 199 (88),
278 (100), 336 (18), 368 (55), 426 (16); C24H31O2NSSi requires
425.1837, M ϩ Hϩ requires 426.1915, found 426.1950; [α]D20
ϩ14.1 (c = 2.0, CHCl3).
IR (thin film in CHCl3) νmax/cmϪ1: 3318 (N–H, 2Њ amide
stretch), 3011 (CH, cyclopropane), 2931 (CH stretches), 1744
(C᎐O, ester), 1655 (C᎐O, amide), 1526 (br, C–N stretch), 1111
᎐
᎐
(Si–O), 823 (Si–O), 792, 741, 690 (diphenyl); 1H NMR δH (400
MHz; CDCl3; Me4Si): 0.88–1.01 (m, 1H, J5Ј,2Ј 8.0 Hz, H-5Ј),
1.04 (s, 9H, tert-butyl), 1.37 (m, 1H, H-5Јa), 1.47 (m, 1H, H-3Ј),
1.66 (m, 1H, J2Ј,5Ј 8.0 Hz, H-2Ј), 2.87–3.01 (m, 2H, CH2S),
3.78 (s, 3H, OMe), 3.82–3.94 (m, 2H, Jgem 10.9, J4Ј,3Ј 5.5 Hz,
H-4Ј, 4Јa), 4.89–4.93 (m, 1H, CHN), 6.61 (d, 1H, J 7.3 Hz,
N-H), 7.26–7.42 (m, 6H, 6 × diphenyl-H), 7.65–7.69 (m, 4H,
4 × diphenyl-H); 13C NMR δC (100 MHz; CDCl3; Me4Si): 10.17
(CH2, C-5Ј), 19.21 (3C, tert-butyl), 19.48 (CH, C-3Ј), 19.23 (CH,
C-2Ј), 26.87 (3 × CH3, tert-butyl), 27.05 (CH2, C-4Ј), 52.75
(CH3, OMe), 53.59 (CHN), 62.13 (CH2S), 127.54–135.52
(diphenyl carbons), 170.76 (3C, C-1Ј), 170.83 (3C, CO2Me);
CI-MS m/z: 94 (10%), 122 (21), 198 (52), 278 (20), 319 (15), 348
(27), 380 (100), 414 (59), 438 (17); C25H33O4NSSi Mϩ requires
471.1961, found 471.1957; [α]D20 Ϫ18.4 (c = 2, CHCl3).
(4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-Methano-3Ј-(tert-butyldiphenylsilyl-
oxy)propyl]-4R-farnesyloxymethyl-4,5-dihydrothiazole (12)
To a solution of the alcohol (2) (300 mg, 0.71 mmol) in dry
benzene (distilled over CaH2 under an argon atmosphere) was
added sodium hydride (60% in mineral oil, 4–5 eq) under argon.
The reaction mixture was stirred for one hour, then a catalytic
2458
J. Chem. Soc., Perkin Trans. 1, 1999, 2455–2460

View Article Online
amount of 18-crown-6 (10%) was added. After stirring for
another hour, a catalytic amount of sodium iodide was added
and after a further hour, trans,trans-farnesyl bromide (201
mg, 0.71 mmol) was added dropwise. The reaction mixture
was stirred overnight before adding petroleum ether (40–
60 ЊC) then filtered to remove salts then evaporated and puri-
fied by flash column chromatography on silica gel in petrol-
eum ether (40–60 ЊC)–ether (gradient: 1:0, 8:1, 5:1, 3:1,
1:1). The desired ether (12) was isolated as a colourless oil
(246 mg, yield 55%).
(4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-Methano-3Ј-acetoxypropyl]-4-farnesyl-
oxymethyl-4,5-dihydrothiazole (14)
To a solution of alcohol (13) (48 mg, 0.12 mmol) in dichloro-
methane (1 ml) was added at room temperature a catalytic
amount of DMAP (0.1 eq). Acetic anhydride (11.6 µl, 1 eq)
then pyridine (20 µl, 2 eq) were added slowly and the mixture
was stirred at room temperature overnight. The solvent was
evaporated and the crude product was directly purified by flash
column chromatography on silica gel in petroleum ether (40–
60 ЊC)–ether 1:1. The desired product was isolated as a colour-
less oil (32 mg, 61%).
IR (in paraffin oil) νmax/cmϪ1: 3071 (C–H, cyclopropane),
2925 and 2854 (C–H), 2359, 1668 (C᎐C, trisubstituted),
᎐
IR (in paraffin oil) νmax/cmϪ1: 3070 (C–H, cyclopropane),
1622 (C᎐N), 1462 (CH ), 1428, 1377 (CH , t-Bu), 1263 (Si–C,
᎐
2
3
2924 and 2854 (C–H), 2356, 2246, 1744 (C᎐O), 1668 (C᎐C,
᎐
᎐
stretch), 1112 (Si–O), 1086 (Si–O, C–O–R), 824 (Si–O–C), 738,
trisubstituted), 1620 (C᎐N), 1456, 1368, 1236 and 1112 (C–O–
1
᎐
701, 614 (aromatic); H NMR δH (400 MHz, CDCl3, Me4Si):
1
C, stretch), 1060, 1027, 988, 908, 735, 648; H NMR δH (250
0.90–1.10 (m, 2H, H-4Ј), 1.05 (s, 9H, 3 × CH3, t-Bu), 1.60 (s,
6H, 2 × Me), 1.63 (m, 1H, H-2Ј), 1.66 (s, 3H, Me), 1.67 (s, 3H,
Me), 1.84–2.06 (m, 9H, H-1Ј and 4 × CH2: H-d, H-e, H-h, H-i),
3.13–3.34 (m, 2H, H-5), 3.38 (t, 1H, J 8.4 Hz, H-6), 3.66–3.87
(m, 3H, H-6 and H-3Ј), 4.02 (d, 2H, J 6.8 Hz, H-a), 4.39–4.51
(m, 1H, H-4), 5.09 (m, 2H, H-f and H-j), 5.34 (t, 1H, J 6.8 Hz,
H-b), 7.33–7.44 (m, 6H, Ar-H), 7.63–7.73 (m, 4H, Ar-H);
13C NMR δC (100 MHz, CDCl3, Me4Si): 11.35 (CH2, C-4Ј),
15.96 (Me-n), 16.47 (Me-m), 17.64 (Me-n), 19.17 (t-Bu-C and
CH, C-1Ј), 23.36 (CH, C-2Ј), 25.65 (Me-l), 26.25 (CH2,
farnesyl), 26.65 (CH2, farnesyl), 26.76 (t-Bu-Me), 36.25 (CH2,
C-5), 39.64 (2CH2, farnesyl), 62.50 (CH2, C-3Ј), 67.60 (CH2,
C-a), 70.98 (CH2, C-6), 75.99 (CH, C-4), 120.55 (CH, C-b),
123.78 (CH, C-i), 124.27 (CH, C-f), 127.51 (4CH, aromatic),
MHz, CDCl3, Me4Si): 1.11–1.23 (m, 2H, H-4Ј), 1.60 (s, 6H,
Me), 1.67 (s, 3H, Me), 1.68 (s, 3H, Me), 2.04 (s, 3H, Me), 1.95–
2.20 (m, 10H, H-1Ј and H-2Ј and 4CH2: H-d, H-e, H-h and
H-i), 3.19–3.42 (m, 2H, H-5), 3.46 (m, 1H, H-6), 4.73 (dd, 1H,
J 4.4 and 9.5 Hz, H-6), 4.05 (m, 2H, J 5.1, H-d), 4.15 (m, 2H,
H-3Ј), 4.55 (m, 1H, H-4), 5.10 (m, 2H, H-f and H-j), 5.34 (t, 1H,
J 6.6 Hz, H-b); 13C NMR δC (100 MHz, CDCl3, Me4Si): 11.59
(CH2, C-4Ј), 16.02 (CH3, Me-n), 16.54 (CH3, farnesyl), 17.70
(CH3, Me-n), 19.14 (CH, C-1Ј), 20.94 (C-2Ј and OAc), 25.70
(CH3, farnesyl), 26.32 (CH2, farnesyl), 26.74 (CH2, farnesyl),
36.54 (CH2, C-5), 39.62 (CH2, farnesyl), 39.71 (CH2, farnesyl),
63.32 (CH2, C-3Ј), 67.74 (CH2, C-a), 70.96 (CH2, C-6), 76.52
(CH, C-4), 120.66 (CH, C-b), 123.84 (CH, C-i), 124.34 (CH,
C-f), 131.31 (3C, farnesyl), 135.32 (3C, farnesyl), 140.55 (3C,
3
129.43 (2CH, aromatic), 131.21 (3C, farnesyl), 134.02 (2 C,
farnesyl), 170.97 (2C, C᎐O and N᎐C–S, C-2); m/z: 434 (100%),
᎐
᎐
aromatic), 135.21 (3C, farnesyl), 135.50 (4CH, aromatic),
374 (11), 296 (21), 213 (51), 170 (11), 138 (28), 93 (6), 69 (33);
C25H39NO3S requires 433.2651, found M ϩ H 434.2731; [α]D20
Ϫ2.8 (c = 0.60, CHCl3).
140.31 (3C, farnesyl), 170.89 (N᎐C–S, C-2); m/z: 630 (100%),
᎐
572 (26), 492 (7), 409 (6), 368 (29), 336 (7), 278 (19), 199 (20),
137 (16), 69 (53); C39H55NO2SSi requires: 630.3787, found Mϩ
630.3782; [α]D20 ϩ3.9 (c = 0.65, CHCl3).
(4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-Methano-3Ј-methoxypropyl]-4-farnesyl-
oxymethyl-4,5-dihydrothiazole (16)
(4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-Methano-3Ј-hydroxypropyl]-4-farnesyl-
The alcohol (13) (100 mg, 0.25 mmol) was added to 770 mg
of silica gel (Kieselgel 60, 0.063–0.200 nm) in 2.5 ml of dry
ether under argon. After cooling to 0 ЊC, a solution of diazo-
methane in ether (20 eq, freshly prepared from 2 g of Diazald
in 12 ml of ether) was added dropwise over 45 min. After
stirring for 5 h at 0 ЊC, the mixture was warmed to room
temperature. The reaction mixture was then filtered, concen-
trated and the crude product purified by column chromatog-
raphy on silica gel in petroleum ether (40–60 ЊC)–ether 1:1
then ether to furnish the methyl ether as a colourless oil
(27 mg, 26%).
oxymethyl-4,5-dihydrothiazole (13)
To the ether (12) (230 mg, 0.36 mmol) in dry THF (freshly
distilled under argon using Na–benzophenone, 1–2 ml) under
an argon atmosphere, was added TBAF (1.0 M in THF, 2 eq,
0.730 ml) at 0 ЊC. After addition, the mixture was maintained at
room temperature overnight. The solvent was evaporated and
the crude product was purified by flash column chromatog-
raphy on silica gel in petroleum ether (40–60 ЊC)–ether 1:1 then
ether. The desired product was isolated as a colourless oil (123
mg, 86%).
IR (in paraffin oil) νmax/cmϪ1: 3396 (br, OH), 3070 (C–H, cyclo-
IR (in paraffin oil) νmax/cmϪ1: 3070 (C–H, cyclopropane),
propane), 2924 and 2854 (C–H), 2360, 1668 (C᎐C, trisubsti-
2968 and 2861 (C–H), 2361, 2338, 1653 (C᎐C, trisubstituted),
᎐
᎐
tuted), 1616 (C᎐N), 1456 (CH ), 1428, 1377, 1239, 1112, 1057
(C–O–R), 836; H NMR δH (250 MHz, CDCl3, Me4Si): 0.96–
1617 (C᎐N), 1456, 1385, 1261, 1197, 1093, 1055 (C–O–R), 985,
᎐
᎐
2
823; 1H NMR δH (250 MHz, CDCl3, MeSi): 1.10 (m, 2H, H-4Ј),
1.55 (m, 1H, H-2Ј), 1.60 (s, 6H, 2 × Me), 1.67 (s, 6H, 2 × Me),
1.90–2.13 (m, 9H, 4CH2: H-d, H-e, H-h, H-i and H-1Ј), 3.19
(dd, 1H, J4,5 7.5, J5,5Ј 12.5 Hz, H-5), 3.31 (s, 3H, OMe), 3.35 (dd,
1H, J4,5 7.5, J5,5Ј 12.5 Hz, H-5), 3.41–3.48 (dd, 1H, J6,6Ј 17.5, J6,4
5.0 Hz, H-6), 3.45 (d, 2H, J 7.5 Hz, H-3Ј), 3.74 (dd, 1H, J6Ј,4
10.0 Hz, H-6), 4.05 (d, 2H, Ja,b 7.5 Hz, H-a), 4.55 (m, 1H, H-4),
5.09 (m, 2H, H-f and H-j), 5.35 (t, 1H, J 7.5 Hz, H-b); 13C
NMR δC (100 MHz, CDCl3, TMS): 11.55 (CH2, C-4Ј), 16.03
(CH3, Me-n), 16.55 (CH3, farnesyl), 17.70 (CH3, Me-n), 19.00
(CH, C-2Ј), 20.36 (CH, C-1Ј), 25.70 (CH3, farnesyl), 26.35
(CH2, farnesyl), 26.76 (CH2, farnesyl), 36.58 (CH2, C-5), 39.65
(CH2, farnesyl), 39.73 (CH2, farnesyl), 58.43 (OCH3), 70.93
(CH2, C-3Ј), 67.78 (CH2, C-a), 71.13 (CH2, C-6), 76.66 (CH,
C-4), 120.73 (CH, C-b), 123.86 (CH, C-j), 124.37 (CH, C-f),
131.31 (3C, farnesyl), 135.35 (3C, farnesyl), 140.52 (3C,
1
1.18 (m, 2H, H-4Ј), 1.59 (s, 6H, 2 × Me), 1.61 (m, 1H, H-2Ј),
1.67 (s, 3H, Me), 1.68 (s, 3H, Me), 1.83 (m, 1H, H-1Ј), 1.93–2.27
(m, 8H, 4CH2: H-d, H-e, H-h, H-i), 3.29 (m, 1H, H-5), 3.40 (m,
2H, H-5 and H-6), 3.49 (m, 1H, H-3Ј), 3.61 (dd, 1H, J 4.3 and
9.4 Hz, H-6), 3.96 (m, 1H, H-3Ј), 4.02 (d, 2H, J 6.1, H-a), 4.69
(m, 1H, H-4), 5.10 (m, 2H, H-f and H-j), 5.33 (t, 1H, J 7.1 Hz,
H-b); 13C NMR δC (100 MHz, CDCl3, Me4Si): 11.75 (CH2,
C-4Ј), 16.02 (CH3, Me-n), 16.53 (CH3, farnesyl), 17.70 (CH3,
Me-n), 18.61 (CH, C-1Ј), 23.42 (CH, C-2Ј), 25.70 (CH3,
farnesyl), 26.32 (CH2, farnesyl), 26.74 (CH2, farnesyl), 35.84
(CH2, C-5), 39.61 (CH2, farnesyl), 39.71 (CH2, farnesyl), 61.35
(CH2, C-3Ј), 67.77 (CH2, C-a), 70.38 (CH2, C-6), 75.99 (CH,
C-4), 120.49 (CH, C-b), 123.82 (CH, C-j), 124.34 (CH, C-f),
131.32 (3C, farnesyl), 135.34 (3C, farnesyl), 140.72 (3C,
farnesyl), 173.15 (N᎐C–S, C-2); m/z: 392 (100%), 322 (11), 254
᎐
(22), 171 (63), 112 (21), 69 (42); C23H37NO2S Mϩ requires
391.2545, found M ϩ Hϩ 392.2632; [α]2D0 Ϫ5.64 (c = 0.55,
CHCl3).
farnesyl), 170.11 (N᎐C–S, C-2); m/z: 406 (100%), 336 (13), 268
᎐
(33), 185 (72), 112 (62), 81 (37); C24H39NO2S requires 405.2712,
found M ϩ H 406.2780; [α]D20 ϩ17.1 (c = 0.55, CHCl3).
J. Chem. Soc., Perkin Trans. 1, 1999, 2455–2460
2459

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(4R)-2-[(1ЈR,2ЈS)-1Ј,2Ј-Methano-3Ј-hydroxypropyl]-4-acetoxy-
methyl-4,5-dihydrothiazole (3)
Acknowledgements
We thank the Association for International Cancer Research
for generous financial support; Dr Lloyd Kelland of the CRC
Centre for Cancer Therapeutics for the biological evaluations;
and the EPSRC Mass Spectrometry Service at Swansea for
numerous high resolution spectra.
To a solution of alcohol (2) (500 mg, 1.175 mmol) in dry
methylene chloride (10 ml) at room temperature was added
4-dimethylaminopyridine (15 mg, 0.1 eq). Acetic anhydride
(111 µl, 1 eq) then pyridine (190 µl, 2 eq) were added slowly and
the mixture was stirred at room temperature until starting
material had disappeared. Water was added, the organic phase
was separated, washed with water and brine then dried
(MgSO4) and evaporated. The acetate was isolated as a colour-
less oil (550 mg, 100%) and was used without further
purification.
References
1 W. H. Gerwick, P. J. Proteau, D. G. Nagle, E. Hamel, A. Blokhin and
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3 A. Nishikawa, R. Shirai, Y. Koiso, Y. Hashimoto and S. Iwasaki,
Bioorg. Med. Chem. Lett., 1997, 7, 2657; P. Verdier-Pinard, J.-Y. Lai,
H.-D. Yoo, J. Yu, B. Marquez, D. G. Nagle, M. Nambu, J. D. White,
J. R. Falck, W. H. Gerwick, B. W. Day and E. Hamel, Mol.
Pharmacol., 1998, 53, 62.
To a sample of this acetate (732 mg, 1.56 mmol) in dry THF
(distilled under argon using Na–benzophenone, 20 ml) under
an argon atmosphere was added TBAF (1.0 M in THF, 2 eq,
3.13 ml) at 0 ЊC. After the addition, stirring was maintained at
room temperature for 2 h. The solvent was evaporated and the
crude product was purified by flash column chromatography on
silica gel in petroleum ether (40–60 ЊC)–ether 1:1 then ether.
The desired product (3) was isolated as a colourless oil (260 mg,
73%).
IR (in paraffin oil) νmax/cmϪ1: 3382 (br, OH), 3073 (C–H,
cyclopropane), 3006, 2948 and 2879 (C–H), 1737, 1615 (C᎐N),
᎐
1441, 1382, 1365, 1229, 1118, 1044 (C–O–R), 979, 913, 836; 1H
NMR δH (250 MHz, CDCl3, Me4Si): 1.00 (m, 1H, H-4Ј), 1.15
(m, 1H, H-4Ј), 1.63 (m, 1H, H-2Ј), 1.84 (m, 1H, H-1Ј), 2.08 (s,
3H, OAc), 3.15 (dd, 1H, J4,5 6.9, J5,5Ј 11.2 Hz, H-5), 3.42 (dd,
1H, J4,5Ј 8.9 Hz, H-5Ј), 3.49 (m, 1H, H-3Ј), 3.97 (dd, 1H, J2Ј,3Ј 4.0
Hz, H-3Ј), 4.12 (dd, 1H, J4,6 6.2, Jgem 11.1 Hz, H-6), 4.23 (m,
1H, H-6), 4.42 (m, 1H, H-4); 13C NMR δC (100 MHz, CDCl3,
Me4Si): 11.98 (CH2, C-4Ј), 18.59 (CH, C-1Ј), 20.80 (CH3), 23.55
(CH, C-2Ј), 35.27 (CH2, C-5), 61.31 (CH2, C-3Ј), 64.74 (CH2,
4 N. K. Partlett, J. Mann and A. Thomas, J. Chem. Res. (S), 1987, 369.
5 T. Morikawa, H. Sasaki, R. Hanai, A. Shibuya and T. Taguchi,
J. Org. Chem., 1994, 59, 97.
6 W.-L. Wu and Y.-L. Wu, J. Org. Chem., 1993, 58, 3586.
7 G. M. Atkins and E. M. Burgess, J. Am. Chem. Soc., 1968, 90, 4744.
8 M. A. Walker and C. H. Heathcock, J. Org. Chem., 1992, 57, 5566.
9 R. W. Hoffmann and A. Schlapbach, Tetrahedron, 1992, 48, 1959; K.
Ohno, H. Nishiyama and H. Nagase, Tetrahedron Lett., 1979, 4405.
C-6), 74.61 (CH, C-4), 170.85 (C᎐O), 173.82 (N᎐C–S, C-2);
᎐
᎐
m/z: C10H15NO3S requires 229.0773, found M ϩ H 230.0851;
[α]D20 ϩ23.3 (c = 1, CHCl3).
Paper 9/04378K
2460
J. Chem. Soc., Perkin Trans. 1, 1999, 2455–2460