Stereoselective synthesis of thymine polyoxin C using an allylic trifluoroacetimidate-trifluoroacetamide rearrangement

Article abstract of DOI:10.1039/a905771d

A stereoselective synthesis of thymine polyoxin C 3 is described in which the key step is the [3,3] sigmatropic rearrangement of the trifluoroacetimidate 12 to the trifluoroacetamide 13. Exchange of the protecting groups followed by ozonolysis and further oxidation then gave the methyl ester 20 which was converted into thymine polyoxin C 3 by introduction of the pyrimidine followed by final deprotection. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a905771d

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Stereoselective synthesis of thymine polyoxin C using an allylic
trifluoroacetimidate–trifluoroacetamide rearrangement
Anqi Chen, Eric J. Thomas* and Peter D. Wilson
The Department of Chemistry, The University of Manchester, Manchester, UK M13 9PL
Received (in Cambridge, UK) 19th July 1999, Accepted 10th September 1999
A stereoselective synthesis of thymine polyoxin C 3 is described in which the key step is the [3,3] sigmatropic
rearrangement of the trifluoroacetimidate 12 to the trifluoroacetamide 13. Exchange of the protecting groups
followed by ozonolysis and further oxidation then gave the methyl ester 20 which was converted into thymine
polyoxin C 3 by introduction of the pyrimidine followed by final deprotection.
The polyoxins are an important group of nucleoside antibiotics
which have found use as agricultural fungicides.1 Because of
their biological activities, the synthesis of the polyoxins and the
structurally related nikkomycins2 has been of considerable
interest and several total syntheses have been described.3,4 In
the preceeding paper,5 the [3,3] sigmatropic rearrangement of
allylic trifluoroacetimidates 1 to trifluoroacetamides 2 was
on the scale of the reaction, being ≥98:2 on a small scale (1–
2 g), but ca. 90:10 for larger scale reactions. When sodium
borohydride was used for the reduction, an almost 50:50
mixture of the epimeric alcohols was obtained. The major anti-
alcohol 10 was converted into its trifluoroacetimidate using
a sub-stoicheiometric amount of butyllithium and trifluoro-
acetonitrile at Ϫ78 ЊC.5 The rearrangement of the trifluoro-
acetimidate was then carried out in xylene heated under reflux
and was complete after 10 h giving the trifluoroacetamide 13
with excellent stereoselectivity (≥96:4) and in good yield
(90%). The configuration of the rearrangement product 13
was not confirmed at this stage but was provisionally assigned
by analogy with earlier trifluoroacetimidate rearrangements.5
It was subsequently confirmed by conversion of the trifluoro-
acetamide 13 into thymine polyoxin C 3. The completion of a
synthesis of thymine polyoxin C now required functional group
manipulation, oxidative cleavage of the alkene and introduction
of the pyrimidine base.
The trifluoroacetamide 13 was converted into the amine 14
by treatment with barium hydroxide in methanol and the amine
was converted into its benzyloxycarbonyl derivative 15 using
standard conditions.14 Ozonolysis of the alkene 15 followed by
oxidation using bromine in methanol15 gave the methyl esters
22 and 23 in yields of 75% and 65%, respectively. The methyl
ester 22 was not taken further in the synthesis, but the isolation
of both esters 22 and 23 demonstrates that at least, in principle,
the (R)-lactate used to prepare the chiral phosphonate 8 can be
recovered at this stage, albeit as its methyl ester.
For the synthesis of the thymine polyoxin C, the p-methoxy-
benzyl group was removed using dichlorodicyanoquinone and
acetylation of the free hydroxy gave the acetate 17. Hydrolysis
of the dioxolane ring was accompanied by loss of the benzyl-
oxymethyl group and gave the triol 18 which was converted
into the tetraacetate 19. Ozonolysis of the double-bond
followed by further oxidation using bromine in methanol15 then
gave the methyl ester 20 together with the lactate 23, and the
ester 20 was converted into the protected thymine polyoxin C 21
using Vorbruggen’s conditions.16 Hydrogenolysis of the benz-
yloxycarbonyl group followed by saponification of the methyl
ester finally gave thymine polyoxin C 3 purified by ion exchange
chromatography. The synthetic thymine polyoxin C was found
to be identical to an authentic sample by TLC and spectroscopic
analysis.4
reported.6 This was found to be an efficient rearrangement
analogous to the well established rearrangement of allylic
trichloroacetimidates developed by Overman.7 The trifluoro-
acetimidate rearrangement proceeds with excellent 1,3-transfer
of asymmetry, and was applied to complete total syntheses of
polyoxamic acid and derivatives of other α-amino acids. In
the present paper we report a total synthesis of thymine
polyoxin C 3 in which the key step is a [3,3] sigmatropic
rearrangement of an allylic trifluoroacetimidate.8
Results and discussion
The alcohol 4 is readily available from diacetone -glucose by
oxidation using pyridinium dichromate followed by reduction
using sodium borohydride.9 Protection using p-methoxybenzyl
chloride10 followed by mild acid hydrolysis11 gave the diol 6
which was cleaved using lead tetraacetate to give the aldehyde
7, see Scheme 1. This was condensed with the ketophosphonate
8,5 which is available from isobutyl (R)-lactate in two steps, to
give the enone 9.12 Reduction of the enone using zinc boro-
hydride gave a mixture of the epimeric alcohols 10 and 11 in
which the product of chelation control,13 isomer 10, was the
major component. The ratio 10:11 appeared to be dependent
This synthesis of thymine polyoxin C 3 demonstrates the use
of the [3,3] sigmatropic rearrangement of allylic trifluoro-
acetimidates in natural product synthesis. The rearrangement is
efficient, proceeds with excellent stereoselectivity and requires
less vigorous conditions than rearrangement of the analogous
trichloroacetimidates. Although the latter compounds are more
J. Chem. Soc., Perkin Trans. 1, 1999, 3305–3310
This journal is © The Royal Society of Chemistry 1999
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Scheme 1 Reagents and conditions: i, sodium hydride, 18-crown-6, 4-methoxybenzyl chloride (92%); ii, 70% aq. acetic acid, 18 h (93%); iii,
lead tetraacetate, sodium carbonate, dichloromethane (96%); iv, 8, lithium chloride, 1,8-diazabicyclo[5.4.0]undec-7-ene, 16 h, room tem-
perature (94%); v, zinc borohydride, ether 6 h (98%; 10:11 ≥ 98:2); vi, sodium borohydride, ethanol (95%; 10:11 = 47:53); vii, butyllithium,
trifluoroacetonitrile, Ϫ78 ЊC (98%); viii, xylene, heat under reflux, 12 h (90%); ix, barium hydroxide, methanol; x, benzyl chloroformate, potassium
bicarbonate (96% from 13); xi, dichlorodicyanoquinone, dichloromethane, tert-butyl alcohol (73%); xii, 4-dimethylaminopyridine, triethyl-
amine, acetic anhydride (98%); xiii, aq. acetic acid, 70 ЊC, 40 h; xiv, 4-dimethylaminopyridine, triethylamine, acetic anhydride (88%); xv, ozone,
Ϫ78 ЊC, then dimethyl sulfide followed by bromine, methanol, room temperature, 6 h (74% from 19); xvi, bis-silylated thymine, trimethylsilyl
triflate, 1,2-dichloroethane, heat under reflux, 45 min (82%); xvii, lithium hydroxide, aq. tetrahydrofuran; xviii, 10% Pd/C, methanol, hydrogen
(47% from 21).
3306
J. Chem. Soc., Perkin Trans. 1, 1999, 3305–3310

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accessible, the trifluoroacetimidate rearrangement may be pre-
ferred in some cases where rearrangement of the trichloroaceti-
midate is slow because of the presence of electron withdrawing
groups.
3.85 (1 H, m, 3-H), 4.47 (1 H, dd, J 9.5, 1.5, 4-H), 4.56 (1 H, m,
2-H), 4.58 and 4.69 (each 1 H, d, J 12, ArCHH), 5.82 (1 H, d,
J 3.5, 1-H), 6.88 and 7.27 (each 2 H, m, ArH) and 9.61 (1 H, d,
J 1.5, CHO); δC 26.8, 27.1, 55.4, 72.2, 77.7, 78.1, 82.4, 104.9,
114.1, 114.2, 128.9, 129.9, 159.7 and 198.6; m/z (CI) 308 (Mϩ,
18%), 250 (14) and 121 (100).
Experimental
For general experimental details see the preceding paper.5
3-O-(4-Methoxybenzyl)-4-[(R,E)-4-benzyloxymethoxy-3-
oxopent-1-enyl]-1,2-O-isopropylidene-ꢀ-D-erythrofuranose 9
3-O-(4-Methoxybenzyl)-1,2:5,6-di-O-isopropylidene-ꢀ-D-
allofuranose 5
A solution of the ketophosphonate 85 (2.6 g, 8.2 mmol) in
acetonitrile (50 cm3) was added to a suspension of lithium
chloride (0.36 g, 8.5 mmol) in acetonitrile (30 cm3) at 0 ЊC.
The suspension was stirred for 15 min then 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (0.97 cm3, 7.08 mmol) was added.
After 30 min, a solution of the aldehyde 7 (2.18 g, 7.08 mmol) in
acetonitrile (5 cm3) was added and the solution was stirred for
16 h at ambient temperature. Saturated aqueous ammonium
chloride (30 cm3) was added and the mixture extracted with
dichloromethane (3 × 50 cm3). The organic extracts were
washed with water (20 cm3), brine (20 cm3), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate–light petroleum (1:4) as eluent
afforded the title compound 9 (3.32 g, 94%) as a colourless oil;
[α]D21 ϩ75 (c 0.3 in CHCl3) (Found: Mϩ ϩ NH4, 516.2597.
C28H38NO8 requires M, 516.2597); νmax/cmϪ1 1701, 1613, 1515,
1455 and 1028; δH 1.31 (3 H, d, J 6, 5Ј-H3), 1.33 and 1.58 (each
3 H, s, CH3), 3.46 (1 H, dd, J 9, 4, 3-H), 3.77 (3 H, s, OCH3), 4.32
(1 H, q, J 7, 4Ј-H), 4.55 (6 H, m, 2-H, 4-H, 2 × ArCH2), 4.72
and 4.8 (each 1 H, d, J 8, OCHHO), 5.73 (1 H, d, J 4, 1-H), 6.70
(1 H, dd, J 16, 1.5, 2Ј-H), 6.83 (2 H, m, ArH), 6.94 (1 H, dd,
J 16.5, 5.5, 1Ј-H) and 7.22–7.33 (7 H, m, ArH); δC 17.8, 26.6,
27.0, 55.4, 70.2, 72.3, 77.6, 77.7, 81.7, 94.1, 104.2, 113.4, 114.1,
124.9, 127.9, 128.0, 128.6, 129.2, 129.9, 137.7, 143.2, 159.8 and
199.5; m/z (CI) 516 (Mϩ ϩ 18, 71%), 499 (Mϩ ϩ 1, 3), 498 (Mϩ,
1) and 122 (100).
18-Crown-6 (10 mg) was added to a suspension of sodium
hydride (60% dispersion in oil; 800 mg, 20 mmol) in tetrahydro-
furan (50 cm3) and the suspension stirred for 10 min before
dropwise addition of the alcohol 49 (2.8 g, 10.7 mmol) in tetra-
hydrofuran (8 cm3) at 0 ЊC. The mixture was stirred at ambient
temperature for 1 h and then cooled to 0 ЊC. 4-Methoxybenzyl
chloride (1.8 cm3, 12.8 mmol) was added and the reaction
mixture stirred for a further 32 h at ambient temperature before
being poured slowly into water (30 cm3) and extracted with
ethyl acetate (2 × 60 cm3). The organic extracts were washed
with brine and dried (MgSO4). Concentration under reduced
pressure and chromatography of the residue using light
petroleum–ethyl acetate (1:2) as eluent afforded the title com-
pound 5 (3.76 g, 92%) as a white crystalline solid; mp 77.5–
79 ЊC; [α]D23 ϩ106.6 (c 1.1 in CHCl3) (Found: Mϩ Ϫ CH3,
365.1614. C19H25O7 requires M, 365.1600); νmax/cmϪ1 1614,
1586, 1515, 1461, 1372, 1254 and 1031; δH 1.34, 1.36, 1.39 and
1.6 (each 3 H, s, CH3), 3.80 (3 H, s, OCH3), 3.86 (1 H, dd,
J 11, 4.5, 3-H), 3.97 (2 H, m, 6-H2), 4.12 (1 H, dd, J 8.5, 3, 4-H),
4.36 (1 H, dt, J 8.5, 3, 5-H), 4.53 (2 H, m, 2-H and ArCHH),
4.69 (1 H, d, J 11.5, ArCHH), 5.74 (1 H, d, J 4, 1-H) and 6.88
and 7.20 (each 2 H, d, J 8.5, ArH); δC 25.3, 26.4, 26.8, 27.0,
55.5, 65.2, 72.0, 74.9, 78.0, 78.2, 104.1, 109.8, 113.1, 114.0,
130.0 and 159.7; m/z (EI) 365 (Mϩ Ϫ 15, 7%).
3-O-(4-Methoxybenzyl)-4-[(3S,4R,1E)-4-benzyloxymethoxy-3-
hydroxypent-1-enyl]-1,2-O-isopropylidene-ꢀ-D-erythrofuranose
10
3-O-(4-Methoxybenzyl)-1,2-O-isopropylidene-ꢀ-D-allofuranose
6
A solution of the acetonide 5 (3.5 g, 9.2 mmol) in 70% aqueous
acetic acid (60 cm3) was stirred for 18 h at ambient temperature.
Concentration under reduced pressure and chromatography
of the residue using light petroleum–ethyl acetate (1:9) as
eluent gave the title compound 6 (2.91 g, 93%) as a colourless
gum; [α]D20 ϩ104 (c 1.2 in CHCl3) (Found: Mϩ ϩ NH4, 358.1873.
C17H28NO7 requires M, 358.1866); νmax/cmϪ1 3451, 1613, 1589,
1515, 1249 and 1027; δH 1.37 and 1.59 (each 3 H, s, CH3), 2.38
(2 H, br s, 2 × OH), 3.67 (2 H, m, 6-H2), 3.82 (3 H, s, OCH3),
3.91 (1 H, dd, J 9, 4.5, 3-H), 3.99 (1 H, m, 5-H), 4.09 (1 H, dd,
J 9, 3.5, 4-H), 4.49 (1 H, d, J 11, ArCHH), 4.60 (1 H, m, 2-H),
4.73 (1 H, d, J 11, ArCHH), 5.76 (1 H, d, J 3.5, 1-H) and 6.39
and 7.32 (each 2 H, d, J 8, ArH); δC 26.7, 26.9, 55.4, 63.2, 70.9,
72.0, 76.6, 77.4, 79.3, 104.4, 113.4, 114.2, 128.9, 130.2 and
159.9; m/z (CI) 358 (Mϩ ϩ 18, 2%) and 121 (100).
A solution of zinc borohydride in ether (0.17 M; 30 cm3, 5.04
mmol) was added dropwise to a solution of the enone 9 (2.4 g,
4.82 mmol) in ether (40 cm3) at Ϫ40 ЊC and the solution stirred
for 6 h. Water (25 cm3) and then a solution of acetic acid (6 cm3)
in water (25 cm3) were added. The mixture was allowed to warm
to ambient temperature and extracted with ether (2 × 75 cm3).
The organic extracts were washed with saturated aqueous
sodium hydrogen carbonate (2 × 50 cm3), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate–light petroleum (3:2) as eluent
afforded the title compound 10 (2.36 g, 98%) as a colourless oil;
[α]D21 ϩ13.8 (c 0.8 in CHCl3) (Found: Mϩ ϩ NH4, 518.2755.
C28H40NO8 requires M, 518.2754); νmax/cmϪ1 3477, 1613, 1587
and 1383; δH 1.12 (3 H, d, J 7, 5Ј-H3), 1.33 and 1.59 (each 3 H, s,
CH3), 2.2 (1 H, br s, OH), 3.46 (1 H, dd, J 9, 5, 3-H), 3.77 (3 H,
s, OCH3), 3.82 (1 H, dq, J 3, 7, 4Ј-H), 4.15 (1 H, m, 3Ј-H), 4.55
(6 H, m, 2-H, 4-H, 2 × ArCH2), 4.78 and 4.82 (each 1 H, d, J 8,
OCHHO), 5.70 (2 H, m, 1-H and 1Ј-H), 5.88 (1 H, ddd, J 16, 6,
1, 2Ј-H), 6.85 (2 H, m, ArH) and 7.23–7.35 (7 H, m, ArH); δC
15.4, 26.6, 26.9, 55.5, 70.1, 72.0, 74.3, 77.6, 77.8, 78.5, 81.7,
94.1, 103.7, 113.1, 114.0, 128.0, 128.1, 128.7, 129.2, 129.7,
129.8, 132.6, 137.7 and 159.7; m/z (CI) 518 (Mϩ ϩ 18, 72%),
501 (Mϩ ϩ 1, 3) and 108 (100). Less than 1% of the (3ЈR)-
epimer 11 was present as indicated by 1H NMR.
3-O-(4-Methoxybenzyl)-1,2-O-isopropylidene-4-formylerythro-
furanose 7
Lead tetraacetate (3.9 g, 8.82 mmol) was added to a suspension
of the diol 6 (2.5 g, 7.35 mmol) and sodium carbonate (3 g, 28
mmol) in dichloromethane (60 cm3) at 0 ЊC. The mixture was
stirred for 2 h then diluted with dichloromethane (40 cm3) and
filtered through a pad of Celite and silica. The solid residue
was washed with dichloromethane and the filtrate concentrated
under reduced pressure. Chromatography of the residue using
light petroleum–ethyl acetate (1:5) as eluent gave the title
compound 7 (2.18 g, 96%) as a colourless gum; [α]D21 ϩ107 (c 0.5
in CHCl3) (Found: Mϩ, 308.1272. C16H20O6 requires M,
308.1260); νmax/cmϪ1 3445, 1736, 1613, 1587, 1515, 1249 and
1032; δH 1.37 and 1.62 (each 3 H, s, CH3), 3.79 (3 H, s, OCH3),
3-O-(4-Methoxybenzyl)-4-[(3S,4R,1E)-4-benzyloxymethoxy-
3-(2,2,2-trifluoroacetimidoyloxy)pent-1-enyl]-1,2-O-isopropyl-
idene-ꢀ-D-erythrofuranose 12
An intimate mixture of powdered trifluoroacetamide (12 g, 106
J. Chem. Soc., Perkin Trans. 1, 1999, 3305–3310
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mmol) and phosphorus pentoxide (24 g, 148 mmol) was
prepared in a 500 cm3 round bottomed flask equipped with a
nitrogen inlet and a water cooled condenser. From the top of
the condenser a PTFE tube led first to a trap cooled in an ice–
salt mixture, then to a trap cooled to ~Ϫ100 ЊC (ether–liq.
N2) and, finally, via a tube packed with calcium chloride, to a
scrubber containing aqueous sodium hydroxide. The reaction
mixture was heated gradually to 150 ЊC under a gentle stream
of dry nitrogen and held at this temperature for 3 h. Trifluoro-
acetonitrile distilled out and was collected as a colourless liquid
(~6 cm3) in the low temperature trap before being dissolved in
pre-cooled tetrahydrofuran (10 cm3).
(5 cm3), ethyl acetate (15 cm3), potassium bicarbonate (1.2 g, 12
mmol) and benzyl chloroformate (0.32 cm3, 2.82 mmol) were
added and the mixture stirred for 14 h at ambient temperature.
The reaction mixture was then diluted with ethyl acetate (100
cm3), washed with saturated aqueous ammonium hydroxide
(2 × 40 cm3), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate–
light petroleum (1:4) as eluent afforded the title compound 15
(1.43 g, 96%) as a colourless gum; [α]D24 ϩ103 (c 1.1 in CHCl3)
(Found: Mϩ ϩ H, 634.2990. C36H44NO9 requires M, 634.3016);
νmax/cmϪ1 3348, 1721, 1612, 1587, 1514, 1455, 1249 and 1027; δH
1.24 (3 H, d, J 6.5, 5Ј-H3), 1.35, 1.60 (each 3 H, s, CH3), 3.57
(1 H, m, 3-H), 3.70 (3 H, s, OCH3), 4.13 (1 H, dd, J 9, 4.5, 4-H),
4.24 (1 H, m, 4Ј-H), 4.41 (1 H, m, 1Ј-H), 4.51 (1 H, t, J 4, 2-H),
4.43–4.76 (6 H, m, PhCH2, OCH2O and ArCH2), 5.13 (2 H, s,
CO2CH2), 5.23 (1 H, br d, J 9, NH), 5.56 (2 H, m, 2Ј-H and
3Ј-H), 5.69 (1 H, d, J 3.5, 1-H), 6.88 (2 H, m, ArH) and 7.27–
7.45 (12 H, m, ArH); m/z (FAB) 634 (Mϩ ϩ 1, 5%) and 496 (35).
Butyllithium (1.8 M in hexane; 0.72 cm3, 1.3 mmol) was
added to the alcohol 10 (1.64 g, 3.28 mmol) in tetrahydrofuran
(20 cm3) at Ϫ78 ЊC and the mixture stirred for 40 min. The
solution of trifluoroacetonitrile prepared above was then added
via a cannula and the mixture stirred for 1 h then allowed to
warm to ambient temperature to allow evaporation of the
excess of trifluoroacetonitrile. Ammonium chloride (0.5 g) and
light petroleum (60 cm3) were added, the mixture was filtered
and the solid residue washed with diethyl ether. The filtrates
were combined and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate–light petrol-
eum (1:6) as eluent afforded the title compound 12 (1.82 g, 98%)
as an oil; [α]D25 ϩ79.5 (c 1 in benzene) (Found: Mϩ ϩ NH4,
613.2745. C30H40F3N2O8 requires M, 613.2737); νmax/cmϪ1 3300,
1688, 1613, 1514, 1250, 1200, 1167 and 1027; δH (C6D6) 1.12
(3 H, d, J 6.5, 5Ј-H3), 1.27 and 1.59 (each 3 H, s, CH3), 3.32
(1 H, dd, J 9, 4, 3-H), 3.37 (3 H, s, OCH3), 3.98 (1 H, dq, J 3.5,
6.5, 4Ј-H), 4.18 (1 H, m, 2-H), 4.37–4.76 (6 H, m, OCH2O,
PhCH2 and ArCH2), 4.79 (1 H, dd, J 10, 3.5, 4-H), 5.63 (1 H, d,
J 3.5, 1-H), 5.69 (1 H, m, 3Ј-H), 6.07 (2 H, m, 1Ј-H and 2Ј-H),
6.88 (2 H, d, J 10, ArH), 7.1–7.4 (7 H, m, ArH) and 8.02 (1 H,
br s, NH); δC 15.9, 26.8, 26.9, 54.8, 69.4, 71.7, 73.5, 77.6,
78.3, 79.8, 82.5, 93.3, 104.6, 112.7, 114.1, 116.3, 127.7, 129.5,
130.3, 133.2, 138.6, 157.0 and 160.0; δF Ϫ75.98; m/z (CI) 613
(Mϩ ϩ 18, 7%).
4-[(1R,4R,2E)-1-Benzyloxycarbonylamino-4-benzyloxymeth-
oxypent-2-enyl)-1,2-O-isopropylidene-ꢀ-D-erythrofuranose 16
Dichlorodicyanoquinone (0.4 g, 1.76 mmol) was added to a
solution of the p-methoxybenzyl ether 15 (0.66 g, 1.04 mmol) in
a mixture of dichloromethane (25 cm3), pH 7 buffer (4 cm3) and
tert-butyl alcohol (1 cm3). The resulting mixture was stirred
for 6 h, a further portion of dichlorodicyanoquinone (0.2 g,
0.88 mmol) was added and the mixture stirred overnight. The
resulting suspension was diluted with dichloromethane (60 cm3)
and washed with saturated aqueous sodium hydrogen carb-
onate (2 × 20 cm3), water (20 cm3) and brine then dried
(MgSO4). Concentration under reduced pressure and chrom-
atography of the residue using ethyl acetate–light petroleum
(2:3) as eluent afforded the title compound 16 (0.4 g, 73%) as a
colourless gum; [α]D25 ϩ79 (c 1.6 in CHCl3) (Found: Mϩ ϩ Na,
536.2287. C28H35NO8Na requires M, 536.2261); νmax/cmϪ1 3343,
3033, 1718, 1612, 1587, 1520 and 1025; δH 1.29 (3 H, d, J 6.5, 5Ј-
H3), 1.35 and 1.57 (each 3 H, s, CH3), 2.56 (1 H, br s, OH), 3.83
(1 H, m, 3-H), 3.88 (1 H, dd, J 9, 3.4, 4-H), 4.29 (1 H, m, 4Ј-H),
4.5 (2 H, m, 1Ј-H and 2-H), 4.61 and 4.68 (each 1 H, d, J 10,
ArHCH), 4.77 (2 H, s, CH2), 5.14 (2 H, s, OCH2O), 5.32 (1 H,
br d, J 8, NH), 5.64 (1 H, dd, J 8, 3, 2Ј-H), 5.75 (2 H, m, 1-H
and 3Ј-H) and 7.37 (10 H, m, ArH); δC 21.4, 26.5, 26.5, 53.3,
66.9, 69.5, 72.4, 72.7, 78.6, 81.8, 92.1, 103.9, 112.9, 126.5, 127.8,
127.9, 128.0, 128.1, 128.2, 128.3, 128.5, 128.5, 128.6, 136.0,
136.4, 137.9 and 155.7; m/z (FAB) 536 (Mϩ ϩ 23, 3%), 456 (17),
426 (10), 376 (100) and 318 (43).
3-O-(4-Methoxybenzyl)-4-[(1R,4R,2E)-4-benzyloxymethoxy-1-
(2,2,2-trifluoroacetylamino)pent-2-enyl]-1,2-O-isopropylidene-
ꢀ-D-erythrofuranose 13
A degassed solution of the trifluoroacetimidate 12 (1.4 g, 2.35
mmol) in xylene (30 cm3) was heated under reflux for 12 h then
allowed to cool to ambient temperature and concentrated under
reduced pressure. Chromatography of the residue using ethyl
acetate–light petroleum (1:4) as eluent afforded the title com-
pound 13 (1.38 g, 98%) as a colourless gum; [α]D23 ϩ108 (c 3 in
CHCl3) (Found: Mϩ ϩ NH4, 613.2740. C30H40F3N2O8 requires
M, 613.2737); νmax/cmϪ1 3312, 1721, 1613, 1514 and 1250; δH
1.21 (3 H, d, J 6.5, 5Ј-H3), 1.36 and 1.59 (each 3 H, s, CH3), 3.56
(1 H, dd, J 9, 4.5, 3-H), 3.78 (3 H, s, OCH3), 4.10 (1 H, dd, J 9,
4, 4-H), 4.21 (1 H, m, 4Ј-H), 4.40–4.70 (8 H, m, 1Ј-H, 2-H,
OCH2O, PhCH2 and ArCH2), 5.54 (2 H, m, 2Ј-H and 3Ј-H),
5.68 (1 H, d, J 4, 1-H), 6.68 (1 H, br d, J 8, NH), 6.88 (2 H, m,
ArH) and 7.25–7.40 (7 H, m, ArH); δC 21.2, 26.5, 26.8, 52.6,
55.3, 69.5, 71.7, 71.8, 77.2, 78.2, 79.2, 92.0, 104.4, 113.4, 114.0,
115.6, 124.5, 127.8, 127.9, 128.5, 129.0, 129.8, 137.5, 137.9,
156.3 and 159.73; δF Ϫ77.36; m/z (CI) 613 (Mϩ ϩ 18, 30%) and
458 (35).
3-O-Acetyl-4-[(1R,4R,2E)-1-benzyloxycarbonylamino-4-benzyl-
oxymethoxypent-2-enyl)-1,2-O-isopropylidene-ꢀ-D-erythro-
furanose 17
4-Dimethylaminopyridine (10 mg), triethylamine (0.28 cm3, 2
mmol) and acetic anhydride (0.12 cm3, 1.3 mmol) were added to
a solution of the alcohol 16 (0.51 g, 1 mmol) in dichlorometh-
ane (30 cm3) at 0 ЊC. The mixture stirred at ambient temper-
ature for 1 h then diluted with ethyl acetate (50 cm3), washed
with saturated aqueous sodium hydrogen carbonate (20 cm3)
and dried (MgSO4). Concentration under reduced pressure and
chromatography of the residue using ethyl acetate–light petrol-
eum (2:3) as eluent afforded the title compound 17 (0.54 g, 98%)
as a colourless gum; [α]D20 ϩ118 (c 0.9 in CHCl3) (Found:
3-O-(4-Methoxybenzyl)-4-[(1R,4R,2E)-1-benzyloxycarbonyl-
amino-4-benzyloxymethoxypent-2-enyl]-1,2-O-isopropylidene-
ꢀ-D-erythrofuranose 15
Mϩ ϩ NH4, 573.2824. C30H41N2O9 requires M, 573.2812); νmax
/
cmϪ1 3343, 1742, 1710, 1525, 1375, 1240, 1169 and 1027; δH 1.29
(3 H, d, J 6.3, 5Ј-H3), 1.35 and 1.57 (each 3 H, s, CH3), 2.12
(3 H, s, COCH3), 4.23 (1 H, dd, J 9, 3.5, 4-H), 4.29 (1 H, quintet,
J 6, 4Ј-H), 4.45 (1 H, m, 3-H), 4.65–4.76 (6 H, m, 2-H, 1Ј-H,
ArCH2, and CH2Ph), 5.13 (2 H, s, OCH2O), 5.20 (1 H, br d, J 8,
NH), 5.67 (2 H, m, 2Ј-H and 3Ј-H), 5.76 (1 H, d, J 4, 1-H) and
7.38 (10 H, m, ArH); δC 20.6, 21.3, 26.6, 53.0, 67.1, 69.5, 72.0,
72.9, 79.1, 92.0, 104.1, 113.3, 126.0, 127.7, 127.9, 128.2, 128.2,
Barium hydroxide (3.2 g, 10.2 mmol) was added to a solution of
the trifluoroacetamide 13 (1.4 g, 2.35 mmol) in methanol (30
cm3) at 0 ЊC. The resulting suspension was stirred for 16 h then
filtered through a pad of Celite and silica and the solid residue
washed with ethyl acetate (2 × 50 cm3). Concentration under
reduced pressure afforded the amine 14 (1.17 g, 100%). Water
3308
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128.5, 136.2, 136.3, 138.0, 155.5 and 170.1; m/z (CI) 573
(Mϩ ϩ 18, 5%), 466 (24) and 419 (100).
7.03 (1 H, br s, 6-H), 7.29 (5 H, m, ArH) and 8.85 (1 H, s,
3-NH); δC 12.5, 20.5, 29.7, 53.0, 55.1, 60.4, 67.5, 69.7, 72.3,
77.3, 81.9, 87.6, 112.1, 128.1, 128.4, 128.6, 135.5, 135.8, 150.3,
156.4, 163.2, 169.3, 169.6 and 169.7; m/z (CI) 551 (Mϩ ϩ 18,
4%), 534 (Mϩ ϩ 1, 10) and 426 (10).
1,2,3-Tri-O-acetyl-4-[(1R,4R,2E)-4-acetoxy-1-benzyloxycarb-
onylaminopent-2-enyl)-D-erythrofuranose 19
Lithium hydroxide monohydrate (28 mg, 0.67 mmol) was
added as a solid to a solution of the diacetate 21 (82 mg, 0.15
mmol) in tetrahydrofuran (6 cm3) and water (1.5 cm3) at 0 ЊC
and the resulting yellow solution stirred at 0 ЊC for 6 h. The
mixture was diluted with water (15 cm3) and extracted with
dichloromethane (2 × 20 cm3). The aqueous phase was cooled
to 0 ЊC, acidified to pH ~2 with aqueous hydrogen chloride
(1 M) and extracted with ethyl acetate (5 × 20 cm3). The organic
extracts were washed with brine, dried (MgSO4) and concen-
trated under reduced pressure to give a yellow solid (46 mg). A
portion of the solid (23 mg, 0.056 mmol) was dissolved in
methanol (5 cm3) and stirred with 10% Pd/C (14 mg) under an
atmosphere of hydrogen for 6 h. The suspension was then
diluted with methanol (10 cm3), filtered through a pad of
Celite and the solid residue washed with methanol (2 × 10
cm3) and water (2 × 10 cm3). The filtrate was concentrated
under reduced pressure to give a yellow solid (15 mg). Ion
exchange chromatography (Dowex 50 X8-400, 3 cm3) eluting
with a mixture of pyridine and acetic acid (3:17, pH ~3.1)
followed by azeotropic concentration under reduced pressure
gave thymine polyoxin C 33,4 (10 mg, 47%) as a pale yellow
solid; Rf 0.22, authentic sample Rf 0.22, in CHCl3–MeOH–H2O
(5:4:1); mp 184–187 ЊC, authentic sample mp 190–193 ЊC
(lit.,4 182–185 ЊC); [α]D20 ϩ8 (c 0.3 in H2O), authentic sample [α]D20
ϩ8.5 (c 0.3 in H2O) [lit.,4 ϩ8 (c 0.37 in H2O)]; νmax/cmϪ1 (KBr)
3573, 3422 and 3334, 1712, 1688, 1670, 1611, 1323 and 1042; δH
(D2O) 1.86 (3 H, s, 5-CH3), 4.07 (1 H, d, J 2.2, 5Ј-H), 4.29 (2 H,
m, 2Ј-H and 4Ј-H), 4.57 (1 H, t, J 5.5, 3Ј-H), 5.80 (1 H, d, J 5,
1Ј-H) and 7.45 (1 H, s, 2-H); δC 12.5, 56.3, 70.4, 73.6, 83.2, 90.6,
112.7, 138.9, 152.8, 167.4 and 171.3; m/z (FAB) 301 (Mϩ,
100%), 234 (39), 199 (34), 160 (38) and 146 (33).
A solution of the acetonide 17 (0.76 g, 1.37 mmol) in 70%
aqueous acetic acid was heated to 70 ЊC for 40 h. Concentration
under reduced pressure gave the triol 18 which was dissolved
in dichloromethane (15 cm3) and 4-dimethylaminopyridine
(5 mg), triethylamine (2 cm3, 14.2 mmol) and acetic anhydride
(0.5 cm3, 5.3 mmol) were added at 0 ЊC. The mixture was stirred
at ambient temperature for 45 min then diluted with ethyl
acetate (50 cm3), washed with saturated aqueous sodium hydro-
gen carbonate (20 cm3) and dried (MgSO4). Concentration
under reduced pressure and chromatography of the residue
using ethyl acetate–light petroleum (2:3) as eluent afforded
an anomeric mixture of the title compound 19 (0.63 g, 88%) as
a colourless gum (Found: Mϩ Ϫ OH, 504.1875. C25H30NO10
requires M, 504.1870); νmax/cmϪ1 3340, 1747, 1526, 1372, 1328,
1235, 1078 and 969; δH 1.24 (2 H, d, J 6, 5Ј-H3), 1.26 (1 H, d, J 6,
5Ј-H3), 1.96–2.09 (12 H, s, 4 × COCH3), 4.26 (0.3 H, m, 4Ј-H),
4.36 (0.7 H, m, 4Ј-H), 4.97–5.77 (9 H, m, 2-H, 3-H, 4-H, 1Ј-H,
2Ј-H, 3Ј-H, NH and CH2Ph), 6.07 (0.3 H, 1β-H), 6.85 (0.7 H,
1α-H) and 7.31 (5 H, m, ArH); m/z (CI) 539 (Mϩ ϩ 18, 25%),
521 (Mϩ, 100), 504 (41), 444 (23) and 431 (47).
1,2,3-Tri-O-acetyl-4-[(S)-Benzyloxycarbonylamino(methoxy-
oxycarbonyl)methyl]-D-erythrofuranose 20
A solution of the tetraacetate 19 (0.42 g, 0.8 mmol) in methanol
(20 cm3) was cooled to Ϫ78 ЊC whilst oxygen was bubbled
through the solution. After 10 min, ozone was bubbled into the
reaction for 25 min and the mixture purged with oxygen for
a further 10 min. Dimethyl sulfide (0.8 cm3, 10.9 mmol) was
added and the reaction mixture allowed to warm to ambient
temperature over 1 h then concentrated under reduced pressure.
The residual oil was dissolved in methanol (15 cm3) and water
(2 cm3) and cooled to 0 ЊC. Sodium hydrogen carbonate (2 g,
23.8 mmol) and bromine (1.56 g, 10 mmol) were added and the
resulting suspension stirred at ambient temperature for 6 h. The
mixture was then diluted with ether (100 cm3) and washed with
aqueous sodium thiosulfate solution (1.0 M; 2 × 20 cm3), brine
and dried (MgSO4). Concentration under reduced pressure and
chromatography of the residue using ethyl acetate–light petrol-
eum (1:1) as eluent afforded an anomeric mixture of the ester
204 (0.28 g, 74%) as a colourless gum (Found: Mϩ Ϫ CH3-
CO2H, 407.1214. C19H21NO9 requires M, 407.1216); νmax/cmϪ1
3354, 1752, 1710, 1526, 1372 and 1224; δH 3.8 (3 H, s, OCH3);
m/z (EI) 407 (Mϩ Ϫ 60, 1%), 347 (2) and 270 (9).
3-O-(4-Methoxybenzyl)-4-[(S)-(benzyloxycarbonylamino)(meth-
oxycarbonyl)methyl]-1,2-O-isopropylidene-ꢀ-D-erythrofuranose
22
Following the procedure outlined for the preparation of the
methyl ester 20, the alkene 15 (0.83 g, 1.32 mmol), after chrom-
atography using light petroleum–ether as eluent (gradient elu-
tion), afforded the methyl ester 23 (0.19 g, 65%) as a colourless
oil, [α]D23 ϩ67 (c 1.3, CHCl3), followed by the title compound 22
(0.50 g, 75%) as a white foam, [α]D24 ϩ51 (c 0.2, CHCl3); νmax
/
cmϪ1 3354, 1726, 1605, 1501, 1282, 1259, 1055 and 1024; δH
1.34 and 1.58 (each 3 H, s, CH3), 3.69 (3 H, s, OCH3), 3.85 (1 H,
dd, J 9, 5, 3-H), 3.88 (3 H, s, OCH3), 4.27 (1 H, dd, J 9, 4, 4-H),
4.47 (2 H, m, OCHH and 2-H), 4.65 (2 H, m, OCHH and CH-
NH), 5.10 (2 H, s, CO2CH2), 5.49 (1 H, br d, J 7, NH), 5.68 (1 H,
d, J 3.5, 1-H), 6.85 (2 H, m, ArH) and 7.25–7.60 (7 H, m, ArH).
Thymine polyoxin C 3
Bis-silylated thymine (0.27 g, 1.16 mmol) and trimethylsilyl tri-
flate (0.25 cm3, 1.27 mmol) were added to a solution of the
triacetate 20 (0.18 g, 0.39 mmol) in 1,2-dichloroethane (6 cm3)
and the yellow solution heated under reflux for 45 min. The
reaction mixture was allowed to cool to ambient temperature,
dichloromethane (50 cm3) was added, and the mixture was
washed with saturated aqueous hydrogen carbonate (2 × 20
cm3), brine and dried (MgSO4). Concentration under reduced
pressure and chromatography of the residue using ethyl
acetate–light petroleum (2:3) with 5% methanol as eluent
afforded the protected thymine polyoxin C 214 (0.17 g, 82%) as
a foam; [α]D22 ϩ16 (c 1 in CHCl3) [lit.,4 ϩ19.8 (c 0.56 in CHCl3)]
(Found: Mϩ ϩ H, 534.1718. C24H28N3O11 requires M,
534.1724); νmax/cmϪ1 3295, 1750, 1696, 1528 and 1238; δH 1.87
(3 H, br s, 5-CH3), 2.07 (6 H, s, 2 × COCH3), 3.79 (3 H, s,
CO2CH3), 4.39 (1 H, dd, J 5, 4, 4Ј-H), 4.81 (1 H, dd, J 8.5, 3.5,
5Ј-H), 5.12 (2 H, s, CH2Ph), 5.26 (1 H, t, J 6, 2Ј-H), 5.51 (1 H, t,
J 6, 3Ј-H), 5.85 (1 H, d, J 8.5, NH), 5.92 (1 H, d, J 5.5, 1Ј-H),
Acknowledgements
We thank Dr I. Savage for preliminary studies, Dr G. H.
Whitham for helpful discussions and the EPSRC for a student-
ship (to P. D. W.) and support (to A. C.). We should also like
to thank Professor P. Garner of the Case Western University
for spectra of the protected nucleoside 21 and Professor K.
Isono of Tokai University for a sample of authentic thymine
polyoxin C.
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