(either 6 or 10) which was stirred in DCE at the temperature
ICI 182,780-17-ketone 19
stated.
Oxalyl dichloride (0.05 mL, 0.073 g, 0.58 mmol) was stirred in
dry DCM (3 mL) at Ϫ70 ЊC under nitrogen. A solution of
dimethyl sulfoxide (0.1 mL, 0.1101 g, 1.41 mmol) in dry DCM
was added dropwise over a period of 10–15 min, keeping the
internal temperature below Ϫ60 ЊC. The mixture was stirred for
5 min, then a solution of ICI 182,780 1 (0.305 g, 0.5 mmol) in
dry DCM (3 mL) was added dropwise over a period of 15 min,
maintaining the same temperature. After stirring of the mixture
at Ϫ70 ЊC for 2 h, diisopropylamine (0.5 mL) was added over
a period of 5 min and the mixture was stirred at Ϫ70 ЊC for a
further 30 min, then allowed to warm to room temperature.
Water (5 mL) and DCM (5 mL) were successively added and
the mixture was stirred for 25 min before the addition of further
water (10 mL) and DCM (10 mL). The phases were separated
and the organic phase was washed with water (30 mL), then
dried over anhydrous MgSO4 for 16 h and evaporated to give an
oil which solidified on storage. Chromatography, eluting
with EtOAc–toluene (7 : 3 v/v), afforded on evaporation of
appropriate fractions the product 19 as a clear oil (0.195 g, 65%)
(Found: Mϩ, 604.2990. C32H45F5O3S requires M, 604.3010.
Micromass GCT instrument, EI); δ (400 MHz; CDCl3) inter
alia 0.9 (3 H, s, 18-H3), 2.2 (2 H, m, 16-H2), 6.58 (1 H, narrow d,
4-H), 6.65 (1 H, dd, 2-H) and 7.13 (1 H, d, 1-H); δC inter alia
220.5 (C-17); m/z (EI) 604 (Mϩ).
B. ‘Inverse’ addition. A solution of imidate 6 or 10 in DCE
was added dropwise over a period of 10 min at Ϫ10 to Ϫ15 ЊC
to a stirred mixture of aglycone and BF3ؒEt2O in DCE. Work-
up of both methods A and B was performed as described for
the conversion of 2 to 7.
Methyl 1-O-cyclohexyl-2,3,4-tri-O-acetyl-ꢀ-D-glucopyranuron-
ate 14
This compound, prepared from cyclohexanol 13 and imidate 6
by method A or B, had mp 137–140 ЊC (from ethanol) (lit.,20
137.5–139 ЊC); δ (Perkin-Elmer R12B, 220 MHz; CDCl3) 1.15–
1.95 (10 H, m, 5 × CCH2), 2.03, 2.05 (9 H, 3 s, 3 × CH3CO),
3.65–3.75 (1 H, m, cyclohexyl methine H), 3.78 (3 H, s, OCH3),
4.05 (1 H, d, 5-H), 4.68 (1 H, d, 1-H), 5.00 (1 H, m, 2-H) and
5.18–5.33 (2 H, m, 3-H ϩ 4-H).
Methyl 1-O-cyclohexyl-2,3,4-tri-O-isobutyryl-ꢀ-D-glucopyran-
uronate 15
This compound was prepared from cyclohexanol 13 and imidate
10 using either method A or B with the results shown in Table 1
after purification by chromatography on silica, and eluting
with 20% EtOAc–isohexane, then 30% EtOAc–isohexane.
Compound 15 had mp 138–141 ЊC (from EtOAc–isohexane)
(Found: C, 60.2; H, 8.1. C25H40O10 requires C, 60.0; H, 8.0%);
δ (Perkin-Elmer R12B, 220 MHz; CDCl3) inter alia 1.05–1.22
[18 H, m, 3 × (CH3)2CH], 2.40–2.60 [3 H, m, 3 × (CH3)2CH],
3.60–3.72 (1 H, m, cyclohexyl methine H), 3.75 (3 H, s, CH3O),
4.06 (1 H, d, 5Ј-H), 4.68 (1 H, d, 1Ј-H), 5.05 (1 H, m, 2Ј-H) and
5.20–5.40 (2 H, m, 3Ј-H ϩ 4Ј-H); m/z (CI) 518 (MNH4ϩ, 100%).
When 13 and 10 were allowed to react using ZnCl2 (0.5 eq.)
as catalyst and the reaction was quenched before completion
(saturated aq. NaHCO3 added, followed by extraction with
EtOAc), a product less polar than 15 could be isolated as an
oil which had spectral data corresponding to methyl 1,2-O-
[1-(cyclohexyloxy)-2-methylpropylidene]-3,4-di-O-isobutyryl-
α--glucopyranuronate 18 (Found: m/z, 501.2707. C25H41O10
requires MHϩ, 501.2700); δ (Bruker 250 MHz) inter alia 3.60
(1 H, m, cyclohexyl CHO), 3.77 (3 H, s, CH3O), 4.28 (1 H, m,
2-H), 4.51 (1 H, d, J 7.25 Hz, 5-H), 5.15 (1 H, dd, 4-H), 5.27
(1 H, m, 3-H) and 5.89 (1 H, d, J 5 Hz, 1-H); m/z (CI) 501
(MHϩ, 10%) and 518 (MNH4ϩ, 5). The assignments were con-
firmed by irradiation of the signal at δ 4.28, which caused the
signal at δ 5.27 to become a doublet while that at δ 5.89 became
a singlet, and irradiation of the signal at δ 4.51 which caused the
signal at δ 5.15 to become a doublet. The shift values are typical
for an orthoester in the glucuronic acid series.21 When the
ZnCl2-catalysed reaction was allowed to proceed to completion,
compound 15 was isolated in 39% yield.
Acknowledgements
We are grateful to Dr G. Robinson (Process Development
Department, AstraZeneca UK Ltd.) for valuable technical
discussions on the chemistry of 1, to Mr I. Cumpstey (St. John’s
College, Oxford) for skilled experimental assistance and to
Mrs V. Boote (University of Manchester) for high-resolution
mass spectrometry in the fast-atom bombardment mode.
References
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Methyl 1-O-(3,20-dioxopregn-4-en-11ꢁ-yl)-2,3,4-tri-O-
isobutyryl-ꢀ-D-glucopyranuronate 17
11α-Hydroxyprogesterone 16 was treated with imidate 10 using
method A or B (Table 1). The crude product was dissolved
in DCM and chromatographed, eluting with 5%, then 10%,
EtOAc–isohexane; appropriate fractions were pooled and
evaporated to give pure 17, yields as in Table 1, mp 205–208 ЊC
(from ethanol) (Found: C, 64.0; H, 8.2. C40H58O12ؒ2C2H5OH
requires C, 64.2; H, 8.5%); νmax(film)/cmϪ1 2973, 2940, 2880,
1751, 1704, 1670 and 1470; δ (CDCl3) inter alia 0.74 (3 H, s,
19-H3), 1.08–1.22 [18 H, m, 3 × (CH3)2CH], 1.35 (3 H, s, 18-H3),
2.18 (3 H, s, 21-H3), 3.75 (3 H, s, CH3O), 4.10 (1 H, d, J 10 Hz,
5Ј-H), 4.75 (1 H, d, J 8 Hz, 1Ј-H), 5.03 (1 H, dd, 2Ј-H), 5.27
(1 H, dd, 4Ј-H), 5.39 (1 H, t, 3Ј-H) and 5.75 (1 H, s, 4-H); m/z
(FAB) 731 (MHϩ).
J. Chem. Soc., Perkin Trans. 1, 2001, 3037–3041
3041