Syntheses of ethyl 3-deoxy-3,3-difluoro-D-arabino-heptulosonate and analogues

Article abstract of DOI:10.1016/j.tet.2004.06.048

The difluorinated analogues of 3-deoxy-D-arabino-heptulosonic acid (DAH) 12, 24 and its enantiomer have been synthesised from D- and L-erythrose via a Reformatsky reaction which gave a mixture of diastereoiosmers in favour of the anti isomer.

Full text of DOI:10.1016/j.tet.2004.06.048

Tetrahedron 60 (2004) 6523–6531
Syntheses of ethyl 3-deoxy-3,3-difluoro-D-arabino-heptulosonate
and analogues
Yuan Li,a Michael G. B. Drew,b Elizabeth V. Welchman,a Rajeev K. Shirvastava,a Shende Jiang,a
Roy Valentinec and Gurdial Singha
,
*
aDepartment of Chemistry, University of Sunderland, Sunderland SR1 3SD, UK
bDepartment of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
cHigh Force Research Ltd, Bowburn, Durham DH6 5PF, UK
Received 16 March 2004; revised 14 May 2004; accepted 3 June 2004
Available online 24 June 2004
Abstract—The difluorinated analogues of 3-deoxy-D-arabino-heptulosonic acid (DAH) 12, 24 and its enantiomer have been synthesised
from D- and L-erythrose via a Reformatsky reaction which gave a mixture of diastereoiosmers in favour of the anti isomer.
q 2004 Elsevier Ltd. All rights reserved.
The enzymatic conversion of carbohydrates to essential
aromatics and aromatic amino acids utilised by micro-
organisms, fungi and higher plants forms the shikimate
pathway.1 The recent discovery that this pathway is also
operative in apicomplexan parasites including the most
virulent malarial parasites (Plasmodium falciparum) has led
to a resurgence of interest in the inhibitors of this
biosynthetic pathway.2 The shikimate pathway is absent in
mammals and they have to obtain the three aromatic amino
acids (L-phenylalanine, L-tyrosine, and L-tryptophan)
through dietary means. It is therefore expected that
inhibitors of the shikimate pathway will be devoid of
toxicity and have low environmental impact. The most
successful commercial enzyme inhibitor used in agriculture
is glyphosate (N-phosphonomethylglycine), the active
ingredient of the herbicide Roundup. It works by specifi-
cally inhibiting the 5-enolpyruvylshikimate-3-phosphate
(EPSP) synthase, the sixth enzyme of the shikimate
pathway.3 Numerous analogues of shikimate pathway
intermediates have been synthesised,4,5 among which the
fluorinated analogues have provided important insights into
the mechanisms of several of the enzymes including
dehydroquinate synthase,5h type I and II dehydro-
quinase,5j,k EPSP synthase5d and chorismate synthase.5b
To date extensive studies have yet to deliver a potent
inhibitor of the ‘upstream’ enzymes of the shikimate
pathway. Consideration of these results suggests the need
for an alternative avenue for the search of pathway
inhibitors, we therefore directed our attention to the study
of inhibitors of the early intermediates in the shikimate
pathway. Here we examined the synthesis of analogues of
3-deoxy-D-arabino-heptulosonic acid (DAH) as potential
inhibitors for the enzymes of type II dehydroquinase and
shikimate kinase,6 and report on our synthesis of difluori-
nated analogues of DAH which are expected to have
modified biological activities due to the replacement of
hydrogen by fluorine atoms.
We have synthesised both enantiomers of the difluorinated
DAH analogues. Treatment of D-ribose 1 in acetone with a
small amount of concentrated hydrochloric acid gave the
acetonide (90%) which was reduced with sodium boro-
hydride and then oxidised with sodium periodate in one-pot
to yield the L-erythrose derivative 2 in 80% yield (Scheme 1).
Deprotection of compound 2 with aqueous acetic acid gave
Keywords: Reformatsky reaction; Shikimate pathway; Carbohydrate;
Fluorinated ulosonates; Enzyme inhibitors.
*
Corresponding author. Tel.: þ44-191-5153094; fax: þ44-191-515-3148;
e-mail address: gurdial.singh@sunderland.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.048

6524
Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
Scheme 1. Reagents and conditions: (i) acetone, conc. HCl (cat.), rt, 4 h; (ii) NaBH4, MeOH–H2O, 0 8C, 1 h, then NaIO4, rt, 1 h; (iii) aq. HOAc, 4 h; (iv) conc.
HCl, EtSH, rt, 2 h; (v) BnBr, NaH, DMF, rt, 8 h; (vi) HgCl2, CaCO3, MeCN–H2O, rt, 3 h; (vii) Zn, BrCF2CO2Et, THF, reflux, 2 h; (viii) BnBr, NaH, DMF, rt,
8 h, 68% for 8 and 17% for 9.
the free L-erythrose 3 (70%). Its diethyl dithioacetal 4 was
prepared by treatment of L-erythrose with ethanethiol and
concentrated hydrochloric acid. Benzylation of the hydroxyl
groups in 4 with excess of benzyl bromide and sodium
hydride gave the tri-O-benzyl derivative 5 (93%). Dethioa-
cetalisation of compound 5 with mercury (II) chloride and
calcium carbonate in aqueous acetonitrile provided the
aldehyde 6 in 85% yield. With the aldehyde 6 available we
examined its reaction under Reformatsky conditions with
ethyl bromodifluoroacetate.7 The reaction afforded alcohol
7 as a mixture of diastereoisomers in a yield of 74%. Our
attempts to separate the diastereoisomers by flash chroma-
tography were unsuccessful. However, further protection of
alcohol 7 with benzyl bromide enabled the separation of the
subsequent two diastereoisomers 8 and 9 in a ratio of ca. 3:1.
At this juncture, we presumed that the major product 8 was
the syn isomer. This assumption was based on literature
precedence that gave support to a a-chelation transition
state during the addition of the nucleophile to the carbonyl
group, which often results in the syn isomer being formed
as the major product.7a,b,8 However, in our case this
assumption was proved to be erroneous, as shown by
our subsequent structural elaboration and data analysis
(Scheme 2).
The major isomer 8 was treated with 1-ethoxyvinyllithium
that was generated by treating ethyl vinyl ether with tert-
butyllithium in tetrahydropyran to yield the intermediate
ketone 10 in a yield of 91%.9 Ozonolysis of the double bond
in 10 gave the keto ester 11 (73%). Its debenzylation was
effected using Pearlman’s catalyst under transfer hydro-
genation conditions to furnish the ethyl ulosonate 12 (90%)
whose complex NMR spectrum made the stereochemical
assignment on C-4 very difficult. We therefore converted 12
to tetraacetate 13 by acetylation. The compound 13 was
crystalline and that enabled the single crystal X-ray
diffraction data to be obtained to establish the stereo-
chemistry at C-4.10 The result showed that the major isomer
8 was in fact the anti isomer and the Reformatsky reaction
probably proceeded by the Felkin-Anh transition state rather
than an a-chelation one.
Following the above results, we then undertook the same
chemistry using D-erythrose 16 as the starting material
(Scheme 3). D-Erythrose was obtained from D-isoascorbic
acid in four steps using published procedures,11 and was

Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
6525
Scheme 2. Reagents and conditions: (i) 1-ethoxyvinyllithium, THF, 278 8C, 1 h; (ii) O3, EtOH–CH2Cl2, 278 8C, 1 h, then Me2S; (iii) Pd(OH)2-C,
cyclohexene, EtOH, reflux, 4 h; (iv) Ac2O, DMAP, pyridine, rt, 2 h.
Scheme 3. Reagents and conditions: (i) Na2CO3, H2O, then H2O2, 45 8C, Norit PN5, then aq. HCl; (ii) acetone, Me2C(OMe)2, p-TsOH, MgSO4, rt, 3 h;
(iii) DIBAL-H, CH2Cl2, 278 8C, 1 h,; (iv) aq. HOAc, 4 h; (v) conc. HCl, EtSH, rt, 2 h; (vi) BnBr, NaH, DMF, rt, 8 h; (vii) HgCl2, CaCO3, MeCN–H2O, rt, 3 h;
(viii) Zn, BrCF2CO2Et, THF, reflux, 2 h; (ix) BnBr, NaH, DMF, rt, 8 h; (x) 1-ethoxyvinyllithium, THF, 278 8C, 1 h; (xi) O3, EtOH–CH2Cl2, 278 8C, 1 h, then
Me2S; (xii) Pd(OH)2-C, cyclohexene, EtOH, reflux, 4 h.

6526
Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
then converted to the alcohols 19 by a sequence of reactions
similar to those described above. The desired tetra-O-benzyl
isomer 20 was reacted with 1-ethoxyvinyllithium, followed
by ozonolysis and debenzylation to give the difluorinated
analogue of DAH 24. In much the same way that its
enantiomer was synthesised from compound 3.
1.1.2. 2,3,4-Tri-O-benzyl-L-erythro diethyl dithioacetal
5. A stirred, cooled (0 8C) solution, of 4 (2.15 g, 9.5 mmol)
in 35 ml of dry DMF was treated with 2.27 g of sodium
hydride (60% dispersion in mineral oil, 56.8 mmol). The
mixture was stirred for 10 min after which time a catalytic
amount of tetrabutyl ammonium iodide was added. After
further 20 min stirring, benzyl bromide (7.04 g, 41.2 mmol,
4.9 ml) was added dropwise to the mixture. The resultant
mixture was stirred at 0 8C for 15 min and then warmed to rt
and stirring continued for a further 10 h. The mixture was
cooled in an ice bath and ethanol was added, carefully, in
order to destroy the excess of sodium hydride. Following
this the mixture was evaporated under reduced pressure and
the residue partitioned between saturated aqueous sodium
chloride (100 ml) and ethyl acetate (100 ml). The aqueous
phase was extracted further with EtOAc (2£100 ml) and the
organic layers were combined, dried (Na2SO4) and
evaporated to afford a residue which was purified on silica
gel eluting with light petroleum ether–diethyl ether (10:1)
to afford to afford 5 (4.65 g, 99%) as a colourless oil.
[a]D¼226.7 (c 1.5 in CHCl3); nmax(film)/cm21 3087, 1604,
1585, 1051, 1027, 912. dH (270 MHz, CDCl3) 1.21–1.26
(3H, t, J¼7.4 Hz, CH2CH3), 1.26–1.31 (3H, t, J¼7.4 Hz,
CH2CH3), 2.63–2.77 (4H, m, 2£CH2CH3), 3.68–3.73 (1H,
dd, J¼4.0, 10.6 Hz, CHHOBn), 3.81–3.85 (1H, dd, J¼2.3,
10.6 Hz, CHHOBn), 3.99–4.04 (1H, ddd, J¼2.3, 4.0,
7.9 Hz, CHOBnCH2OBn), 4.06–4.10 (1H, dd, J¼2.5,
7.9 Hz, CHOBnCHOBnCH2OBn), 4.27–4.28 (1H, d, J¼
2.5 Hz, CHSEtSEt), 4.57–4.99 (6H, m, 3£CH2Ph) and
7.25–7.38 (15H, m, Ph); dC (67.8 MHz, CDCl3) 14.4,
14.5 (2C, 2£CH2CH3), 24.9, 26.0 (2C, 2£CH2CH3),
53.7 (CHSEtSEt), 68.5 (CH2OBn), 72.3, 73.3, 75.0
(3C, 3£CH2Ph), 78.9 (CH2OBnCHOBnCHOBn), 81.8
(CH2OBnCHOBn), 127.5, 127.5, 127.6, 127.7, 127.8,
127.9, 128.2, 128.3, 128.3 (15C, phenyl CH), 138.2, 138.3
and 138.4 (3C, phenyl C).
In summary, we have synthesised the difluorinated ana-
logues of 3-deoxy-D-arabino-heptulosonic acid (DAH)
from both L- and D-erythrose. These compounds are
currently undergoing biological testing, and the results
will be reported in due course.
1. Experimental
1.1. General
1H NMR spectra were measured at 270 MHz with JEOL
GSX 270 FT NMR spectrometer. Chemical shifts were
measured relative to internal tetramethyl silane (d 0). 13C
NMR spectra were recorded at 67.8 MHz on same
instrument with internal (CH3)4Si (d 0, CDCl3). IR spectra
were recorded on a UNICAM series FT- instrument. Mass
spectra were recorded on AEI MS 902 or VG ZAB-E
instruments. Melting points were determined on Gallen-
Kamp capillary melting point apparatus and are uncor-
rected. Optical rotations were measured in chloroform
solution using Bellingham and Stanley ADP 220 polari-
meter. Flash chromatography was performed using Fluka
silica gel 60 (230–400 mesh) and the solvent petroleum
ether (boiling range 40–60 8C) was distilled prior to use.
Thin layer chromatography was carried out using pre-coated
aluminium plates (Merck Kieselgel 60 F254) which were
visualised under UV light and then with either phospho-
molybdic acid or basic aqueous potassium permanganate as
appropriate. All anhydrous reactions were carried out under
argon or nitrogen. Anhydrous transfers were done with
standard syringe techniques, all glassware was pre-dried
overnight. Dichloromethane was distilled from calcium
1.1.3. 2,3,4-Tri-O-benzyl-L-erythrose 6. A solution of
2,3,4-tri-O-benzyl-L-erythrose diethyl dithioacetal
5
(3.7 g, 7.45 mmol) in 80 ml of CH3CN/H2O (4:1) was
treated with HgCl2 (5.06 g, 18.63 mmol) and CaCO3
(2.12 g, 21.16 mmol), and the mixture stirred for 2 h. The
mixture was filtered and the filtrate concentrated. The
residue was treated with 180 ml of CH2Cl2, washed with
150 ml KI (1% aqueous solution). The aqueous layer was
further extracted with CH2Cl2 (2£100 ml). The organic
layers were combined and washed again with 100 ml of KI
(1% aqueous solution) and water (2£100 ml). The organic
layer were dried, (Na2SO4), and evaporated to give a residue
which was purified by column chromatography, silica gel,
eluting with light petroleum ether–diethyl either (4:1) to
afford 6 (2.47 g, 85%) as a colourless oil. [a]D¼0; nmax
(film)/cm21 3087, 1731, 1604, 910. dH (270 MHz, CDCl3)
3.68–3.73 (1H, dd, J¼5.3, 9.9 Hz, CHHOBn), 3.80–3.86
(1H, dd, J¼6.6, 9.9 Hz, CHHOBn), 4.04–4.10 (1H, ddd,
J¼3.6, 6.6, 9.9 Hz, CHOBnCH2OBn), 4.15–4.17 (1H, dd,
J¼1.5, 3.6 Hz, CHOBnCHOBnCH2OBn), 4.49–4.85
(6H, m, 3£CH2Ph), 7.26–7.42 (15H, m, Ph) and 9.77–
9.78 (1H, d, J¼0.7 Hz, CHO); dC (67.8 MHz, CDCl3)
67.9 (CH2OBn), 72.29, 72.9, 73.2 (3C, 3£CH2Ph), 78.8
(CH2OBnCHOBn), 82.6 (CH2OBnCHOBnCHOBn), 127.5,
127.7, 127.9, 128.0, 128.1, 128.3, 128.4 (15C, phenyl CH),
137.2, 137.6, 137.7 (3C, phenyl C) and 201.7 (C-1).
˚
hydride and stored over 4 A molecular sieves.
1.1.1. L-Erythro diethyl dithioacetal 4.12a L-Erythrose
(4 g), was treated with conc. HCl (6 ml) and ethanethiol
(6 ml) the resultant mixture was stirred for 3 h at rt. To this
mixture water (60 ml) was added and the mixture
neutralised by the addition of aq. sodium carbonate. The
resultant mixture was extracted with CH2Cl2 (3£60 ml).
The organic extracts were combined, dried and evaporated
to yield L-erythrose diethyl dithioacetal as a syrup (4.6 g).
Chromatography on silica gel eluting with light petroleum
ether–diethyl ether (1:9) gave L-erythrose diethyl dithio-
acetal 4 (2.15 g, 31% for two steps) as colourless oil.
[a]D¼216.0 (c 1.3 in CHCl3); nmax(film)/cm21 3411. dH
(270 MHz, CDCl3) 1.19–1.25 (6H, t, J¼7.4 Hz,
2£CH2CH3), 2.54–2.76 (4H, m, 2£CH2CH3), 3.77–3.85
(5H, m), 4.09 (1H, s, OH), 4.10 (1H, s, OH), 4.14 (1H, s,
OH); dC (67.8 MHz, CDCl3) 14.3, 14.5 (2C, 2£CH3CH2),
25.2, 25.3 (2C, 2£CH2CH3), 54.4 (CHSEtSEt),
63.3 (CH2OH), 71.8 (CH2OHCHOHCHOH), 73.6
(CH2OHCHOH); m/z HRMS (CI, NH3) found: 244.1039
[MþNH4]þ C8H22NO3S2 requires 244.1041.

Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
6527
1.1.4. 4,5,6-Tri-O-benzyl-L-erythro 2-deoxy-2,2-difluoro
ethyl acetates 7. To a refluxing suspension of activated zinc
dust (0.505 g, 7.72 mmol) in dry THF (20 ml) was added
ethyl bromodifluoroacetate (1.18 g, 0.74 ml, 5.79 mmol).
After 1 min, a solution of 2,3,4-tri-O-benzyl-L-erythrose
(1.51 g, 3.86 mmol) dissolved in 10 ml of THF was added
dropwise, over 15 min. After complete addition the reaction
was refluxed for a further 2 h. The mixture was cooled to rt
and carefully poured into 20 ml 1 M HCl and 20 g of ice.
Stirring of the resultant mixture was continued until all of
the ice had melted. The mixture was extracted with EtOAc
(3£100 ml). The organic layers were combined and washed
with saturated NaHCO3 (2£100 ml) and sat. aq. NaCl
(2£100 ml), dried (Na2SO4) and concentrated in vacuo to
give a residue. Chromatography, silica gel, eluting with
light petroleum ether–diethyl either (4:1) gave 7 (two
diastereoisomers not separable) (1.48 g, 74%) as a colour-
less oil. [a]D¼þ10.1 (c 1.3 in CHCl3); nmax (film)/cm21
3450, 3089, 1770, 1606, 1587, 1093, 1027, 912.
tioned between saturated aqueous sodium chloride (150 ml)
and ethyl acetate (150 ml). The aqueous phase was extracted
further with EtOAc (2£150 ml) and the organic layers were
combined, dried (Na2SO4) and evaporated to afford a
residue which was purified on silica gel eluting with light
petroleum ether–diethyl ether (10:1) to afford two dia-
stereoisomers: 2-deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-
L-erythrose ethyl acetate (2.54 g, 85%) (ratio, major/minor,
3.2:1) as colourless oils.
Less polar 8 (anti product). [a]D¼23.1 (c 0.98 in CHCl3);
n
max(film)/cm21 3089, 1772, 1606, 1587, 1095, 1027, 910.
dH (270 MHz, CDCl3) 1.01–1.06 (3H, t, J¼7.1 Hz,
CH2CH3), 3.62–3.81 (3H, m), 3.84–4.00 (3H, m), 4.35–
4.83 (8H, m, 4£CH2Ph), 4.48–4.53 (1H, dd, J¼3.3, 9.1 Hz,
CHOBnCF2) and 7.18–7.34 (20H, m, Ph); dC (67.8 MHz,
CDCl3) 13.6 (CH2CH3), 62.3 (CH2CH3), 70.1 (CH2OBn),
72.6, 73.3, 73.4, 75.4–75.4 (1C, d, J(C,F)¼4.2 Hz) (4C,
4£CH2Ph), 77.2, 77.9, 78.3 (3C, 3£CHOBn), 111.8–119.3
(1C, dd, J(C,F)¼257.9, 259.6 Hz, CF2CO2), 127.6, 127.9,
128.2, 128.3, 128.7, 128.8, 128.9 and 129.6 (20C, phenyl
CH), 137.3, 137.5, 138.1, 138.4 (4C, phenyl C) and 162.5–
163.4 (1C, dd, J(C,F)¼32.5, 32.7 Hz, CF2CO2); dF
(67.8 MHz, CDCl3) 111.2–112.2 (1F, d, J¼257.2 Hz),
123.5–124.6 (1F, dd, J¼19.1, 263.5 Hz); m/z HRMS (CI,
NH3) found: 622.2973 [MþNH4]þ C36H42F2NO6 requires
622.2980.
Major diastereoisomer. dH (270 MHz, CDCl3) 1.11–1.16
(3H, t, J¼7.1 Hz, CH2CH3), 3.47–3.49 (1H, d, J¼5.1 Hz,
OH), 3.67–3.73 (1H, dd, J¼5.0, 10.1 Hz, CHHOBn), 3.82–
3.88 (1H, dd, J¼4.6, 10.1 Hz, CHHOBn), 3.92–4.08 (4H,
m), 4.44–4.75 (7H, m, 3£CH2Ph and CHOH) and 7.16–
7.40 (15H, m, Ph); dC (67.8 MHz, CDCl3) 13.6 (CH2CH3),
62.5 (CH2CH3), 68.9 (CH2OBn), 70.6–71.3 (1C, dd,
J(C,F)¼22.8, 23.6 Hz, CHOH), 72.6, 73.4, 73.5 (3C,
3£CH2Ph), 77.9, 78.6 (2C, 2£CHOBn), 110.7–118.2 (1C,
dd, J(C,F)¼251.0, 257.1 Hz, CF2CO2), 127.6, 127.7, 127.8,
128.0, 128.2, 128.4 and 128. 5 (15C, phenyl CH), 137.5
More polar 9 (syn product). [a]D¼0 (c 0.58 in CHCl3);
n
max(film)/cm21 3089, 1764, 1606, 1587, 1027, 910. dH
(270 MHz, CDCl3) 1.16–1.21 (3H, t, J¼7.1 Hz, CH2CH3),
3.63–3.71 (1H, m), 3.78–3.87 (2H, m), 4.07–4.16 (2H, q,
J¼7.1 Hz, CH2CH3), 4.26–4.46 (2H, m), 4.48–4.75 (8H,
m, 4£CH2Ph) and 7.10–7.33 (20H, m, Ph); dC (67.8 MHz,
CDCl3) 13.7 (CH2CH3), 62.8 (CH2CH3), 68.4 (CH2OBn),
71.8, 73.3, 74.2, 74.9 (4C, 4£CH2Ph), 76.5, 77.8, 78.1 (3C,
3£CHOBn), 111.2–118.7 (1C, dd, J(C,F)¼254.0, 260.0 Hz,
CF2CO2), 127.4, 127.6, 127.7, 127.8, 127.8, 128.0, 128.1,
128.2, 128.3, 128.5 and 128.8 (20C, phenyl CH), 137.6,
138.1, 138.2, 138.2 (4C, phenyl C) and 162.9–163.8 (1C, t,
J(C,F)¼31.0 Hz, CF2CO2); dF(67.8 MHz, CDCl3) 111.2–
112.2 (1F, d, J¼257.2 Hz), 123.5–124.6 (1F, dd, J¼19.1,
263.5 Hz); m/z HRMS (CI, NH3) found: 622.2990
[MþNH4]þ C36H42F2NO6 requires 622.2980.
(2C), 137.9 (3C, phenyl C) and 162.6–163.6 (1C, t, J(C,F)
¼
31.4 Hz, CF2CO2); dF (67.8 MHz, CDCl3) 111.2–112.2
(1F, d, J¼257.15 Hz), 123.5–124.61 (1F, dd, J¼19.1,
263.5 Hz); m/z HRMS (CI, NH3) found: 532.2514
[MþNH4]þ C29H36F2NO6 requires 532.2511.
Minor diastereoisomer. dH (270 MHz, CDCl3) 1.22–1.27
(3H, t, J¼7.1 Hz, CH2CH3), 3.31–3.35 (1H, d, J¼10.4 Hz,
OH), 3.70–3.81 (2H, m, CH2OBn), 3.92–4.09 (2H, m,
2£CHOBn), 4.23–4.29 (2H, q, J¼7.1 Hz, CH2CH3), 4.46–
4.76 (7H, m) and 7.26–7.35 (15H, m, Ph); dC (67.8 MHz,
CDCl3) 13.8 (CH2CH3), 63.0 (CH2CH3), 67.6 (CH2OBn),
69.5 (1C, t, J(C,F)¼23.6, CHOH), 72.5, 73.4, 73.9 (3C,
3£CH2Ph), 77.9, 78.6 (2C, 2£CHOBn), 110.8–118.3 (1C,
dd, J(C,F)¼261.4, 267.8, CF2CO2), 127.7–130.9 (15C,
phenyl CH), 137.3, 137.8, 137.9 (3C, phenyl C) and
163.1–163.9 (1C, t, J(C,F)¼30.4 Hz, CF2CO2).
1.1.6. 2-Deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-L-ery-
thro vinyl ether 10. To a stirred, cooled (278 8C) solution,
of ethyl vinyl ether (0.62 g, 8.64 mmol, 0.8 ml) in tetra-
hydropyran (THP, 3 ml), t-BuLi (6.64 mmol, 1.7 M, 3.9 ml)
was added dropwise. The mixture was stirred at 278 8C for
10 min, warmed to 23 to 25 8C, and stirred for a further
30 min. Following this the mixture was recooled to 278 8C,
diluted with THF (6.0 ml) and treated with 21 (0.80 g,
0.95 mmol) in THF (1 ml). After stirring for 1 h at 278 8C,
the reaction mixture was poured into water 20 ml) and
evaporated under reduced pressure. The resultant residue
was partitioned between water (150 ml) and EtOAc
(150 ml). The aqueous phase was extracted with EtOAc
(2£150 ml) and the combined organics dried (Na2SO4), and
evaporated to give a residue which was purified on silica gel
eluting with light petroleum ether–diethyl ether (10:1) to
afford 2-deoxy-2, 2-difluoro-3, 4, 5, 6-tetra-O-benzyl-L-
erythro vinyl ether 10 (1.58 g, 90%) as colourless oil.
1.1.5. 2-Deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-L-ery-
thro ethyl acetate 8,9. A stirred, cooled (0 8C) solution, of 7
(2.56 g, 5.0 mmol) in 60 ml of dry DMF was treated with
0.46 g of sodium hydride (60% dispersion in mineral oil,
10.15 mmol). The mixture was stirred for 10 min after
which time a catalytic amount of tetrabutyl ammonium
iodide was added. After further 20 min stirring, benzyl
bromide (1.30 g, 7.6 mmol, 0.9 ml) was added dropwise to
the mixture. The resultant mixture was stirred at 0 8C for
15 min and then warmed to rt and stirring continued for a
further 10 h. The mixture was cooled in an ice bath and
ethanol was added, carefully, in order to destroy the excess
of sodium hydride. Following this the mixture was
evaporated under reduced pressure and the residue parti-

6528
Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
[a]D¼þ26.9 (c 1.25 in CHCl3); nmax(film)/cm21 3031,
2927, 1729 (CvO), 1610 (CvC) and 1101. dH (270 MHz,
CDCl3) 1.20 (3H, t, J¼6.9 Hz, CH2CH3), 3.56–3.72 (4H,
m), 3.79 (1H, d, J¼9.7 Hz), 4.00 (1H, t, J¼5.7 Hz),
4.26 (1H, d, J¼10.9 Hz, CHHPh), 4.36–4.42 (3H, m,
3£CHHPh), 4.53 (1H, d, J¼11.1 Hz, CHHPh), 4.62–4.68
(3H, m, 2£CHHPh and CvCHH), 4.79 (1H, ddd, J¼3.1,
9.8, 21.4 Hz), 4.88 (1H, d, J¼10.7 Hz, CHHPh), 5.10 (1H,
d, J¼2.6 Hz, CvCHH) and 7.10–7.29 (20H, m, Ph); dC
(67.8 MHz, CDCl3) 14.0 (CH2CH3), 63.9 (CH2CH3), 70.5
(CH2OBn), 72.2 (CH2Ph), 72.8 (CH2Ph), 73.2 (CH2Ph),
75.2 (1C, d, J(C,F)¼4.4 Hz, CH2Ph); 77.8 (CHOBn), 78.1
(CHOBn), 78.7 (CHOBn), 94.5 (CvCH2), 118.1 (1C, dd,
J(C,F)¼251.6, 257.5 Hz, CF2CO2), 127.5–128.3 (20C,
phenyl CH), 137.2 (phenyl C), 137.4 (phenyl C), 138.2
(phenyl C), 138.6 (phenyl C), 155.0 (CvCH2) and 181.9
(1C, t, J(C,F)¼26.5 Hz, CF2CO2); dF (282.4MHz, CDCl3)
113.0 (1F, d, J¼257.2 Hz), 124.1 (1F, dd, J¼19.1,
263.5 Hz); m/z (CI, NH3) [MþNH4]þ found: 648.3140
C38H44F2NO6 requires 648.3137.
filtered through a pad of celite and concentrated in vacuo to
afford crude 3-deoxy-3,3-difluoro-L-arabino-hept-2-ethyl-
ulosonate which was utilised without further purification.
The crude product was treated with pyridine (4 ml) and
acetic anhydride (2 ml). The whole mixture was shaken
into clear solution and maintained at a temperature range of
0–4 8C for 12 h. Water (2 ml) was added into the mixture to
destroy the excess acetic anhydride. The mixture was
partitioned between H2SO4 (2.5 M) (50 ml) and CH2Cl2
(50 ml). The aqueous phase was extracted with CH2Cl2
(2£50 ml). The organic layers was combined, washed with
saturated NaHCO3 (50 ml) and sat. aq. NaCl (50 ml), dried
(Na2SO4) and concentrated in vacuo to give a residue which
was purified by column chromatography, silica gel, eluting
with diethyl ether to afford the title compound (0.21 g,
82%). [a]D¼269.1 (c 1.03, CHCl3); nmax (film)/cm21 2983,
1756 1083. dH (270 MHz, CDCl3) 1.30 (3H, t, J¼7.1 Hz,
CH2CH3), 2.02 (3H, s, OCOCH3), 2.08 (3H, s, OCOCH3),
2.22 (6H, s, 2£OCOCH3), 4.21–4.88 (5H, m), 5.19 (1H, d,
J¼8.7 Hz, CF2CHOAcCHOAc) and 5.72 (1H, ddd, J¼3.5,
5.8, 9.2 Hz, CF2CHOAc); dC (67.8 MHz, CDCl3) 13.6
(CH2CH3), 20.1 (OCOCH3), 20.2 (OCOCH3), 20.3
(OCOCH3), 20.4 (OCOCH3), 61.2 (CH2CH3), 64.1 (1C, d,
J¼3.9 Hz, CF2CHOAcCHOAc), 67.0 (AcOCH2CH), 67.3
(1C, dd, J¼24.9, 34.5 Hz, CF2CHOAc), 93.7 (1C, dd,
1.1.7. 2-Deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-L-ery-
thro-keto ethylacetate 11. The vinyl ether 10 (1.18 g,
1.87 mmol) was dissolved in 16 ml CH2Cl2–EtOH (1:1).
The solution was ozonolysised at 278 8C. The production
of the ozonide was determined by monitoring the presence
of an excess of ozone using starch-KI paper. After 1 h of
stirring, the reaction was quenched by the addition of 4 ml
Me2S at 278 8C. The reaction mixture was warmed to rt and
evaporated under vacuum. The residue was partitioned
between water (100 ml) and EtOAc (100 ml), and the
aqueous layer extracted further with EtOAc (2£100 ml).
The organic layers were combined, dried (Na2SO4) and
evaporated to afford a residue which was subjected to
chromatography, silica gel, eluting with light petroleum
ether–diethyl ether (2:1) to afford 2-deoxy-2,2-difluoro-
J¼27.5, 35.0 Hz, OCOAcCO2C2H5), 112.2 (1C, dd, J(C,F)
¼
251.6, 270.0 Hz, CF2), 161.7 (1C, d, J(C,F)¼1.6 Hz,
CO2C2H5), 167.0 (OCOCH3), 168.6 (OCOCH3), 168.8
(OCOCH3) and 170.6 (OCOCH3); dF (282.4 MHz, CDCl3)
116.5 (1F, dd, J¼2.0, 6.0 Hz), 116.8 (1F, d, J¼6.0 Hz); m/z
(CI, NH3) [MþNH4]þ found: 458.1477 C17H26F2NO11
requires 458.1474.
1.1.9. D-Erythro-diethyl dithioacetal 17.12a D-Erythrose
16 (3.78 g), was treated with conc. HCl (6 ml) and
ethanethiol (6 ml) were stirred for 3 h at rt. To this mixture
water (60 ml) was added and the mixture neutralised by the
addition of aq. sodium carbonate. The resultant mixture was
extracted with CH2Cl2 (3£60 ml). The organic extracts
were combined, dried and evaporated to yield D-erythro-
diethyl dithioacetal as a syrup (4.6 g). Chromatography,
silica, eluting with light petroleum ether–diethyl ether (1:9)
gave D-erythro-diethyl dithioacetal 17 (2.63 g, 40% for two
steps) as colourless oil. [a]D¼þ16.8 (c 0.97, CHCl3); nmax
(film)/cm21 3411, 2965, 1644. dH (270 MHz, CDCl3) 1.19–
1.25 (6H, t, J¼7.4 Hz, 2£CH2CH3), 2.54–2.76 (4H, m,
2£CH2CH3), 3.77–3.85 (5H, m), 4.09 (1H, s, OH), 4.10
(1H, s, OH), 4.14 (1H, s, OH); dC (67.8 MHz, CDCl3) 14.3,
14.5 (2C, 2£CH3CH2), 25.2, 25.3 (2C, 2£CH2CH3), 54.4
(CHSEtSEt), 63.3 (CH2OH), 71.8 (CH2OHCHOHCHOH),
73.6 (CH2OHCHOH).
3,4,5,6-tetra-O-benzyl-L-erythro-keto
ethylacetate
11
(0.86 g, 73%) as a colourless oil. [a]D¼þ6.0 (c 1.1 in
CHCl3); nmax (film)/cm21 3089, 1758, 1737, 1606, 1587,
975, 912. dH (270 MHz, CDCl3) 1.01–1.07 (3H, t,
J¼7.1 Hz, CH2CH3), 3.60–3.63 (1H, d, J¼5.8 Hz), 3.67–
3.75 (1H, m), 3.76–3.80 (1H, d, J¼10.1 Hz), 3.85–4.18
(3H, m), 4.42–4.98 (8H, m, 4£CH2Ph), 4.92–5.05 (1H,
ddd, J¼3.9, 10.6, 21.6 Hz, CHOBnCF2) and 7.09–7.31
(20H, m, Ph); dC (67.8 MHz, CDCl3) 13.4 (CH2CH3), 62.6
(CH2CH3), 69.8 (CH2OBn), 72.3, 72.8, 73.3, 75.4 (1C,
d, J(C,F)¼3.9 Hz) (4C, 4£CH2Ph), 77.8, 78.1, 78.1 (3C,
3£CHOBn), 113.3–120.7 (1C, dd, J(C,F)¼250.7, 258.4 Hz,
CF2CO2), 127.5, 127.6, 127.6, 127.7, 127.9, 127.9, 128.0,
128.1, 128.3, 128.3, 128.5, 128.5 and 128.8 (20C, phenyl
CH), 136.2, 137.2, 138.0, 138.2 (4C, phenyl C), 158.3
(CF2COCOOC2H5) and 174.8–175.6 (1C, t, J(C,F)
28.1 Hz, CF2CO2); dF (67.8 MHz, CDCl3) 111.2–112.2
(1F, d, J¼257.2 Hz), 123.5–124.6 (1F, dd, J¼19.1,
¼
1.1.10. 2,3,4-Tri-O-benzyl-D-erythrose 18.12b A stirred,
cooled, (0 8C), solution, of 17 (2.63 g, 11.6 mmol) in 40 ml
of dry DMF was treated with 2.77 g of sodium hydride (60%
dispersion in mineral oil, 69.3 mmol). The mixture was
stirred for 10 min after which time a catalytic amount of
tetrabutyl ammonium iodide was added. After further
20 min stirring, benzyl bromide (8.59 g, 50.2 mmol,
6.0 ml) was added dropwise to the mixture. The resultant
mixture was stirred at 0 8C for 15 min and then warmed to rt
and stirring continued for a further 10 h. The mixture was
cooled in an ice bath and ethanol was added, carefully, in
263.5 Hz););
655.2488.C37H38F2O7Na requires 655.2483.
m/z
(ESþ)
[MþNa]
found:
1.1.8. 3-Deoxy-3,3-difluoro-2,4,5,6-tetra-O-acetyl-L-ara-
bino-hept-2-ethylulosonate 13. The ester 11 (0.37 g,
0.58 mmol) was dissolved in ethanol (8 ml). To the resultant
solution Pd(OH)2-C (30 mg) and cyclohexene (2 ml) were
added. The mixture was heated at reflux for 48 h, cooled to
rt and stirred at this temperature for 24 h. The mixture was

Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
6529
order to destroy the excess of sodium hydride. Following
this, the mixture was evaporated under reduced pressure and
the residue partitioned between saturated aqueous sodium
chloride (100 ml) and ethyl acetate (100 ml). The aqueous
phase was extracted further with EtOAc (2£100 ml) and the
organic layers were combined, dried (Na2SO4) and
evaporated to afford a residue which was purified by
chromatography, silica, eluting with light petroleum ether–
diethyl ether (10:1) to afford the 2,3,4-tri-O-benzyl-D-
erythro-diethyl dithioacetal (5.60 g, 97%) as colourless oil.
[a]D¼þ27.1 (c 0.94, CHCl3); nmax(film)/cm21 3087, 3062,
1604. dH (270 MHz, CDCl3) 1.16–1.21 (3H, t, J¼7.4 Hz,
CH2CH3), 1.21–1.26 (3H, t, J¼7.4 Hz, CH2CH3), 2.58–
2.71 (4H, m, 2£CH2CH3), 3.63–3.69(1H, dd, J¼4.0,
10.6 Hz, CHHOBn), 3.76–3.81 (1H, dd, J¼2.3, 10.6 Hz,
CHHOBn), 3.94–4.05 (1H, ddd, J¼2.3, 3.9, 7.9 Hz,
CHOBnCH2OBn), 4.01–4.05 (1H, dd, J¼2.5, 7.9 Hz,
CHOBnCHOBnCH2OBn), 4.21–4.22 (1H, d, J¼2.6 Hz,
CHSEtSEt), 4.52–4.94 (6H, m, 3£CH2Ph) and 7.12–7.33
(15H, m, Ph); dC (67.8 MHz, CDCl3) 14.4, 14.5 (2C,
2£CH2CH3), 24.9, 26.1 (2C, 2£CH2CH3), 53.7 (CHSEt-
SEt), 68.6 (CH2OBn), 72.4, 73.3, 75.0 (3C, 3£CH2Ph), 78.9
(CH2OBnCHOBnCHOBn), 81.9 (CH2OBnCHOBn), 127.5,
127.5, 127.6, 127.7, 127.8, 127.9, 128.2, 128.3, 128.3,
128.4 (15C, phenyl CH) and 138.3, 138.3 and 138.4 (3C,
phenyl C).
(3H, t, J¼7.1 Hz, CH2CH3), 3.47–3.49 (1H, d, J¼5.1 Hz,
OH), 3.67–3.73 (1H, dd, J¼5.0, 10.1 Hz, CHHOBn), 3.82–
3.88 (1H, dd, J¼4.6, 10.1 Hz, CHHOBn), 3.92–4.08 (4H,
m), 4.44–4.75 (7H, m, 3£CH2Ph and CHOH) and 7.16–
7.40 (15H, m, Ph); dC (67.8 MHz, CDCl3) 13.6 (CH2CH3),
62.5 (CH2CH3), 68.9 (CH2OBn), 70.6–71.3 (1C, dd, J(C,F)
22.8, 23.6 Hz, CHOH), 72.6, 73.4, 73.5 (3C, 3£CH2Ph),
¼
77.9, 78.6 (2C, 2£CHOBn), 110.7–118.2 (1C, dd, J(C,F)
¼
251.0, 257.1 Hz, CF2CO2), 127.6, 127.7, 127.8, 128.08,
128.2, 128.4 and 128. 5 (15C, phenyl CH), 137.5 (2C),
137.9 (3C, phenyl C) and 162.6–163.6 (1C, t,
J(C,F)¼31.4 Hz, CF2CO2).
Minor diastereoisomer. dH (270 MHz, CDCl3) 1.22–1.27
(3H, t, J¼7.1 Hz, CH2CH3), 3.31–3.35 (1H, d, J¼10.4 Hz,
OH), 3.70–3.81 (2H, m, CH2OBn), 3.92–4.09 (2H, m,
2£CHOBn), 4.23–4.29 (2H, q, J¼7.1 Hz, CH2CH3), 4.46–
4.76 (7H, m) and 7.26–7.35 (15H, m, Ph); dC (67.8 MHz,
CDCl3) 13.8 (CH2CH3), 63.0 (CH2CH3), 67.6 (CH2OBn),
69.5 (1C, t, J(C,F)¼23.6 Hz, CHOH), 72.5, 73.4, 73.9
(3C, 3£CH2Ph), 77.9, 78.6 (2C, 2£CHOBn), 110.8–118.3
(1C, dd, J(C,F)¼261.4, 267.8 Hz, CF2CO2), 127.7–130.9
(15C, phenyl CH), 137.3, 137.8, 137.9 (3C, phenyl C) and
163.1–163.9 (1C, t, J(C,F)¼30.4 Hz, CF2CO2).
A stirred, cooled (0 8C) solution, of the above mixture of
daistereoisomers (3.0 g, 5.83 mmol), in 60 ml of dry DMF,
was treated with 0.46 g of sodium hydride (60% dispersion
in mineral oil, 10.15 mmol). The mixture was stirred for
10 min after which time a catalytic amount of tetrabutyl
ammonium iodide was added. After further 20 min stirring,
benzyl bromide (1.50 g, 8.75 mmol, 1.0 ml) was added
dropwise to the mixture. The resultant mixture was stirred at
0 8C for 15 min and then warmed to rt and stirring continued
for a further 10 h. The mixture was cooled in an ice bath and
ethanol was added, carefully, in order to destroy the excess
of sodium hydride. Following this the mixture was
evaporated under reduced pressure and the residue parti-
tioned between saturated aqueous sodium chloride (150 ml)
and ethyl acetate (150 ml). The aqueous phase was extracted
further with EtOAc (2£150 ml) and the organic layers
were combined, dried (Na2SO4) and evaporated to afford a
residue which was purified on silica gel eluting with light
petroleum ether–diethyl ether (10:1) to afford two dia-
stereoisomers: 2-deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-
D-erythrose ethyl acetate 20, 21 (2.69 g, 76%) (major/minor,
3.6:1) as colourless oils.
A solution of 2,3,4-tri-O-benzyl-D-erythrose diethyl
dithioacetal (5.5 g, 11.1 mmol) in 125 ml of CH3CN/H2O
(4:1) was treated with HgCl2 (7.51 g, 27.7 mmol) and
CaCO3 (3.15 g, 31.5 mmol), and the mixture stirred for 2 h.
The mixture was filtered and the filtrate concentrated. The
residue was treated with 180 ml of CH2Cl2, washed with
150 ml KI (1% aqueous solution). The aqueous layer was
further extracted with CH2Cl2 (2£100 ml). The organic
layers were combined and washed again with 100 ml of KI
(1% aqueous solution) and water (2£100 ml). The organic
layers were dried, (Na2SO4), and evaporated to give a
residue (4.3 g, 99.5%) which was directly used to next step.
1.1.11. 2-Deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-D-
erythro ethyl acetate 20, 21. To a refluxing suspension of
activated zinc dust (1.37 g, 21.0 mmol) in dry THF (35 ml)
was added ethyl bromodifluoroacetate (3.20 g, 2.02 ml,
15.75 mmol). After 1 min, a solution of 2,3,4-tri-O-benzyl-
D-erythrose (4.30 g, 11.0 mmol) dissolved in 15 ml of THF
was added dropwise, over 15 min. After complete addition
the reaction was refluxed for a further 2 h. The mixture was
cooled to rt and carefully poured into 50 ml 1 M HCl and
50 g ice. Stirring of the resultant mixture was continued
until all of the ice had melted. The mixture was extracted
with EtOAc (3£100 ml). The organic layers were combined
and washed with saturated NaHCO3 (2£100 ml) and sat. aq.
NaCl (2£100 ml), dried (Na2SO4) and concentrated in
vacuo to give a residue. Chromatography, silica gel, eluting
with light petroleum ether–diethyl either (4:1) gave two
diastereoisomers 19, (not separable) (4.49 g, 79% for two
steps) as colourless oils; nmax (film)/cm21 3450, 3089, 3064,
3031, 2981, 2908, 2871, 1955, 1876, 1770, 1606, 1587,
1496, 1454, 1371, 1311, 1209, 1093, 1027, 912, 852, 746
and 698.
Less polar (anti product). [a]D¼0; nmax(film)/cm21 3089,
3064, 1760, 1606, 1587, 910. dH (270 MHz, CDCl3) 3.34
(3H, s, CH3), 3.61–3.73 (2H, m, CH2OBn), 3.87–3.90 (1H,
d, J¼9.2 Hz, CH2OBnCHOBnCHOBn), 3.96–4.00 (1H, t,
J¼5.6 Hz, CH2OBnCHOBn), 4.48–4.52 (1H, dd, J¼3.2,
9.1 Hz, CHOBnCF2), 4.38–4.83 (8H, m, 4£CH2Ph) and
7.13–7.35 (20H, m, Ph); dC (67.8 MHz, CDCl3) 52.6
(CH3), 70.0 (CH2OBn), 72.7, 73.3, 73.5, 75.4–75.5 (1C, d,
J(C,F)¼4.4 Hz) (4C, 4£CH2Ph), 77.1–77.7 (1c, t, J(C,F)
¼
21.5 Hz), 78.0–78.1 (1C, d, J(C,F)¼2.9 Hz), 78.3 (3C,
3£CHOBn), 111.9–119.3 (1C, dd, J(C,F)¼258.3, 264.3 Hz,
CF2CO2), 127.6, 127.6, 127.7, 127. 9, 128.2, 128.2, 128.2,
128.3 and 128.4 (20C, phenyl CH), 137.3, 137.5, 138.2,
138.4 (4C, phenyl C) and 163.0–163.9 (1C, t, J(C,F)
31.9 Hz, CF2CO2); dF (67.8 MHz, CDCl3) 111.2–112.2
¼
Major diastereoisomer. dH (270 MHz, CDCl3) 1.11–1.16

6530
Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
(1F, d, J¼257.15 Hz), 123.5–124.6 (1F, dd, J¼19.1,
263.5 Hz)); m/z HRMS (CI, NH3) found: 622.2992
[MþNH4]þ C36H42F2NO6 requires 622.2980.
1.1.13. 2-Deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-D-
erythro-keto-ethylacetate 23. The vinyl ether 22 (1.45 g,
2.3 mmol) was dissolved in 18 ml CH2Cl2–EtOH (1:1). The
solution was ozonolysized at 278 8C. The production of the
ozonide was determined by monitoring the presence of an
excess of ozone using starch-KI paper. After 1 h of stirring,
the reaction was quenched by the addition of 4 ml Me2S at
278 8C. The reaction mixture was warmed to rt and
evaporated under vacuum. The residue was partitioned
between water (100 ml) and EtOAc (100 ml), and the
aqueous layer extracted further with EtOAc (2£100 ml).
The organic layers were combined, dried (Na2SO4) and
evaporated to afford a residue which was subjected to
chromatography, silica gel, eluting with light petroleum
ether–diethyl ether (3:1) to afford 2-deoxy-2,2-difluoro-3,4,
5,6-tetra-O-benzyl-D-erythrose-keto-ethylacetate 23 (1.06 g,
81%) as a colourless oil. [a]D¼28.9 (c 0.8 in CHCl3); nmax
(film)/cm21 3089, 3064, 3031, 2925, 2871, 1955, 1878,
1809, 1758, 1737, 1606, 1587, 1496, 1454, 1394, 1369,
1311, 1216, 1103, 1025, 975, 912, 740 and 698. dH
(270 MHz, CDCl3) 1.01–1.07 (3H, t, J¼7.1 Hz,
CH2CH3), 3.60–3.63 (1H, d, J¼5.8 Hz), 3.67–3.75 (1H,
m), 3.76–3.80 (1H, d, J¼10.1 Hz), 3.85–4.18 (3H, m),
4.42–4.98 (8H, m, 4£CH2Ph), 4.92–5.05 (1H, ddd, J¼3.9,
10.6, 21.6 Hz, CHOBnCF2) and 7.09–7.31 (20H, m, Ph); dC
(67.8 MHz, CDCl3) 13.4 (CH2CH3), 62.6 (CH2CH3), 69.8
More polar (syn product). [a]D¼þ3.4 (c 0.89 in CHCl3);
nmax (film)/cm21 3089, 3064, 1764, 1606, 1587, 910. dH
(270 MHz, CDCl3) 3.64 (3H, s, CH3), 3.67–3.71 (1H, m),
3.79–3.91 (2H, m), 4.05–4.09 (1H, t, J¼5.4 Hz), 4.24–
4.34 (1H, ddd, J¼4.3, 9.6, 13.7 Hz, CHOBnCF2), 4.42–
4.72 (8H, m, 4£CH2Ph) and 7.11–7.33 (20H, m, Ph); dC
(67.8 MHz, CDCl3) 53.2 (CH3), 68.5 (CH2OBn), 71.9, 73.3,
74.2, 75.0 (4C, 4£CH2Ph), 76.5, 77.6–78.3 (1C, t, J¼
25.5 Hz), 78.0 (3C, 3£CHOBn), 111.3–118.8 (1C, dd,
J(C,F)¼254.5, 260.0 Hz, CF2CO2), 127.5, 127.6, 127.7,
127.8, 127.9, 128.2, 128.3, 128.3 and 128.4 (20C, phenyl
CH), 137.5, 138.1, 138.2 (2C) (4C, phenyl C) and 163.8–
164.7 (1C, t, J(C,F)¼33.1 Hz, CF2CO2); dF (67.8 MHz,
CDCl3) 111.2–112.2 (1F, d, J¼257.2 Hz), 123.5–
124.6 (1F, dd, J¼19.1, 263.5 Hz)); m/z HRMS (CI, NH3)
found: 622.2985 [MþNH4]þ C36H42F2NO6 requires
622.2980.
1.1.12. 2-Deoxy-2,2-difluoro-3,4,5,6-tetra-O-benzyl-D-
erythro vinyl ether 22. To a stirred, cooled (278 8C)
solution, of ethyl vinyl ether (0.74 g, 10.3 mmol, 1.0 ml) in
THP (3.5 ml), t-BuLi (7.92 mmol, 1.7 M, 4.7 ml) was added
dropwise. The mixture was stirred at 278 8C for 10 min,
warmed to 23 to 25 8C, and stirred for a further 30 min.
Following this the mixture was recooled to 278 8C, diluted
with THF (8.0 ml) and treated with 19 (1.95 g, 3.3 mmol) in
THF (3.0 ml). After stirring for 1 h at 278 8C, the reaction
mixture was poured into water, (20 ml), and evaporated
under reduced pressure. The resultant residue was par-
titioned between water (150 ml) and EtOAc (150 ml). The
aqueous phase was extracted with EtOAc (2£150 ml) and
the combined organics dried (Na2SO4), and evaporated
to give a residue which was purified on silica gel eluting
with light petroleum ether–diethyl ether (10:1) to afford
2-deoxy-2, 2-difluoro-3,4,5,6-tetra-O-benzyl-D-erythrose
vinyl ether 22 (1.48 g, 85%) as colourless oil. [a]D¼
223.7 (c 0.9 in CHCl3); nmax (film)/cm21 3089, 3064, 3031,
2979, 2925, 2871, 1953, 1917, 1776, 1731, 1610, 1496,
1454, 1365, 1303, 1216, 1101, 1072, 1027, 973, 854, 738
and 698. dH (270 MHz, CDCl3) 1.18–1.23 (3H, t, J¼6.9 Hz,
CH2CH3), 3.55–3.73 (4H, m), 3.77–3.81 (1H, d, J¼
9.9 Hz), 3.98–4.02 (1H, t, J¼5.5 Hz), 4.24–4.28 (1H, d,
J¼10.9 Hz, CHHPh), 4.33–4.68 (7H, m), 4.72–4.85 (1H,
ddd, J¼3.3, 9.9, 21.3 Hz), 4.86–4.90 (1H, d, J¼10.7 Hz,
CHHPh), 5.11–5.12 (1H, d, J¼2.6 Hz, CvCHH) and
7.12–7.29 (20H, m, Ph); dC (67.8 MHz, CDCl3) 14.0
(CH2CH3), 63.9 (CH2CH3), 70.5 (CH2OBn), 72.3, 72.9,
73.2, 75.2–75.3 (1C, d, J(C,F)¼4.2 Hz) (4C, 4£CH2Ph);
77.8–78.5 (1C, t, J(C,F)¼20.9 Hz), 77.8–77.9 (1C, d,
J(C,F)¼3.9 Hz), 78.7 (3C, 3£CHOBn), 94.5–94.6 (1C, d,
(CH2OBn), 72.3, 72.8, 73.3, 75.4–75.4 (1C, d, J(C,F)
¼
3.9 Hz) (4C, 4£CH2Ph), 77.8, 78.1, 78.1 (3C, 3£CHOBn),
113.3–120.7 (1C, dd, J(C,F)¼250.7, 258.4 Hz, CF2CO2),
127. 5, 127.6, 127.6, 127.7, 127.9, 127.9, 128.0, 128.1,
128.3, 128.3, 128.5, 128.5, 128.8, 136.2, 137.2, 138.0, 138.2
(4C, phenyl C), 158.3 (CF2COCOOC2H5) and 174.8–175.6
(1C, t, J(C,F)¼28.1 Hz, CF2CO2); dF (67.8 MHz, CDCl3)
111.2–112.2 (1F, d, J¼257.2 Hz), 123.5–124.6 (1F,
dd, J¼19.1, 263.5 Hz); m/z (ESþ) [MþNa] found:
655.2485.C37H38F2O7Na requires 655.2483.
1.1.14. Ethyl-3-deoxy-3,3-difluoro-D-arabino ulosonate
24. The keto ester 23 (0.98 g, 1.55 mmol) was dissolved
in ethanol (15 ml). To the resultant solution Pd(OH)2-C
(100 mg) and cyclohexene (3 ml) were added. The mixture
was heated at reflux for 48 h, cooled to rt and stirred at this
temperature for 24 h. The mixture was filtered through a pad
of celite and concentrated in vacuo to afford crude ethyl-3-
deoxy-3,3-difluoro-D-arabino ulosonate. Chromatography,
silica gel, eluting with ethyl acetate, yielded the title
compound 20 (0.30 g, 72%). [a]D¼þ34.1 (c 1.0 in CHCl3);
n
max(film)/cm21 3451, 3359, 2987, 2942, 1745, 1643, 1448,
1396, 1374, 1301, 1284, 1224, 1178, 1095, 919 and 898. dH
(270 MHz, CD3OD) 1.29–1.34 (3H, t, J¼7.1 Hz, CH2CH3),
3.60–3.91 (3H, m), 4.05–4.12 (2H, m), 4.21–4.35 (2H, m)
and 4.88 (4H, s, 4£OH); dC (67.8 MHz, CDCl3) 14.2
(CH2CH3), 62.0 (CH2CH3), 63.7 (CH2OH), 66.1 (CHOCH2-
OH), 71.2 (CHOHCHOCH2OH), 72.0–72.8 (1C, t, J(C,F)
¼
J(C,F)¼2.3 Hz, CvCH2), 114.3–121.8 (1C, dd, J(C,F)
¼
26.1 Hz, CHOHCF2), 95.2–96.1 (1C, t, J(C,F)¼29.7 Hz,
COHCO2C2H5), 112.3–119.8 (1C, dd, J(C,F)¼254.0,
260.2 Hz, CF2CO2C2H5) and 168.3 (CO2C2H5); dF
(67.8 MHz, CDCl3) 111.2–112.2 (1F, d, J¼257.2 Hz),
123.5–124.6 (1F, dd, J¼19.1, 263.5 Hz); m/z (CI, NH3)
[MþNH4]þ found: 290.1054 C9H18F2NO7 requires 290.1051.
251.8, 257.6 Hz, CF2CO2), 127.5, 127.5, 127.5, 127.7,
127.9, 127.9, 128.2, 128.2, 128.3, 128.3, 128.3, 128.4,
137.2, 137.4, 138.2, 138.6 (4C, phenyl C), 155.1 (CvCH2)
and 181.5–182.3 (1C, t, J(C,F)¼27.0 Hz, CF2CO2); dF
(67.8 MHz, CDCl3) 111.2–112.2 (1F, d, J¼257.2 Hz),
123.5–124.6 (1F, dd, J¼19.1, 263.5 Hz)); m/z (CI, NH3)
[MþNH4]þ found: 648.3142 C38H44F2NO6 requires
648.3137.
1.1.15. Ethyl 3-deoxy-3,3-difluoro-D-arabino-ulosonate,
[C-4 diastereomer 24], (syn diastereoisomer). The C-4

Y. Li et al. / Tetrahedron 60 (2004) 6523–6531
6531
4. For reviews, see: (a) Campbell, M. M.; Sainsbury, M.; Searle,
P. A. Synthesis 1993, 179. (b) Jiang, S.; Singh, G. Tetrahedron
1998, 54, 4697.
syn diastereoisomer of 23 (0.11 g, 0.18 mmol) was dis-
solved in ethanol (8 ml). To the resultant solution Pd(OH)2-
C (100 mg) and cyclohexene (2 ml) were added. The
mixture was heated at reflux for 48 h, cooled to rt and
stirred at this temperature for 24 h. The mixture was filtered
through a pad of celite and concentrated in vacuo to afford
crude ethyl 3-deoxy-3,3-difluoro-D-arabino-ulosonate.
Chromatography, silica gel, eluting with ethyl acetate
gave the title compound [Diastereomeric 24] (37 mg,
75%). [a]D¼þ46.7 (c 0.9 in CH3OH). dH (270 MHz,
CD3OD) 1.32 (3H, t, J¼7.1 Hz, CH2CH3), 3.74–3.85 (3H,
m), 3.98 (1H, ddd, J¼5.4, 9.4, 21.6 Hz), 4.26–4.33 (3H, m)
and 4.94 (4H, s, 4£OH); dC (67.8 MHz, CD3OD) 14.3
(CH2CH3), 62.0 (CH2CH3), 63.7 (CH2OH), 69.6 (1C, d,
5. (a) Sutherland, J. K.; Watkins, W. J.; Bailey, J. P.; Chapman,
A. K.; Davies, G. M. J. Chem. Soc., Chem. Commun. 1989,
1386. (b) Ramjee, M. N.; Balasubramanian, S.; Abell, C.;
Coggins, J. R.; Davies, G. M.; Hawkes, T. R.; Lowe, D. J.;
Thornley, R. N. F. J. Am. Chem. Soc. 1992, 114, 3151. (c)
Sutherland, J. K.; Whitehead, R. C.; Davies, G. M. J. Chem.
Soc., Chem. Commun. 1993, 464. (d) Seto, C. T.; Bartlett, P. A.
J. Org. Chem. 1994, 59, 7130. (e) Blacker, A. J.; Booth, R. J.;
Davies, G. M.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 1
1995, 2861. (f) Adams, H.; Bailey, N. A.; Brettle, R.; Cross,
R.; Frederickson, M.; Haslam, E.; MacBeath, F. S.; Davies,
G. M. Tetrahedron 1996, 52, 8565. (g) Brettle, R.; Cross, R.;
Frederickson, M.; Haslam, E.; MacBeath, F. S.; Davies, G. M.
Tetrahedron 1996, 52, 10547. (h) Parker, E. J.; Coggins, J. R.;
Abell, C. J. Org. Chem. 1997, 62, 8582. (i) Jiang, S.; Singh, G.;
Boam, D. J.; Coggins, J. R. Tetrahedron: Asymmetry 1999, 10,
J(C,F)¼7.0 Hz, CHOHCHOCH2OH), 72.7 (1C, t, J(C,F)
¼
19.2 Hz, CHOHCF2), 75.3 (CHOCH2OH), 95.3 (1C, t,
J(C,F)¼35.1 Hz, COHCO2C2H5), 118.2 (1C, dd, J(C,F)
¼
247.4, 262.5 Hz, CF2CO2C2H5) and 168.3 (CO2C2H5); dF
(282.4 MHz, CD3OD) 122.7 (1F, d, J¼248.5 Hz), 130.3
(1F, d, J¼248.5 Hz); m/z (CI, NH3) [MþNH4]þ found:
290.1052 C9H18F2NO7 requires 290.1051.
´
4087. (j) Parker, E. J.; Gonzalez Bello, C. J. R.; Hawkins,
A. R.; Abell, C. Bioorg. Med. Chem. Lett. 2000, 10, 231. (k)
Frederickson, M.; Coggins, J. R.; Abell, C. J. Chem. Soc.,
Chem. Commun. 2002, 1886.
Acknowledgements
6. (a) Duggan, P. J.; Parker, E.; Coggins, J.; Abell, C. Bioorg.
Med. Chem. 1995, 5, 2347. (b) Sundaram, A. K.; Woodard,
R. W. J. Org. Chem. 2000, 65, 5891. and references therein.
7. (a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M.
J. Org. Chem. 1988, 53, 2406. (b) Chou, T. S.; Heath, P. C.;
Patterson, L. E.; Poteet, L. M.; Lakin, R. E.; Hunt, A. H.
Synthesis 1992, 565. (c) Doherty, A. M.; Sircar, I.; Kornberg,
B. E.; Quin, III., J.; Winters, R. T.; Kaltenbronn, J. S.; Taylor,
M. D.; Batley, B. L.; Rapundalo, S. R.; Ryan, M. J.;
Painchaud, C. A. J. Med. Chem. 1992, 35, 2. (d) Meffre, P.;
Dave, R. H.; Leroy, J.; Badet, B. Tetrahedron Lett. 2001, 42,
8625.
We thank the EPSRC for financial support and for access to
the mass spectrometry service at the University of Wales,
Swansea (Director, Prof. A. G. Brenton). We also thank the
University of Reading for funds for the Image Plate system.
References and notes
1. (a) Bentley, R. Crit. Rev. Biochem. Mol. Biol. 1990, 25, 307.
(b) Haslam, E. Shikimic Acid, Metabolism and Metabolites;
Wiley: Chichester, 1993. (c) Abell, C. Comprehensive Natural
Products Chemistry; Barton, D. H. R., Nakanishi, K.,
Meth-Cohn, O., Sankawa, U., Eds.; Elsevier: Amsterdam,
1999; Vol. 1, p 573.
8. Jiang, S.; Singh, G.; Wightman, R. H. Chem. Lett. 1996, 67,
and references therein.
9. (a) Shimano, M.; Meyers, A. I. Tetrahedron Lett. 1994, 35,
7727. (b) Jiang, S.; Singh, G.; Wang, X.-Z.; Wu, Y.-L.
Tetrahedron Lett. 1999, 40, 8911.
2. (a) Roberts, F.; Roberts, C. W.; Johnson, J. J.; Kyle, D. E.;
Krell, T.; Coggins, J. R.; Coombs, G. H.; Milhous, W. K.;
Tzipori, S.; Ferguson, D. J. P.; Chakrabarti, D.; McLeod, R.
Nature 1998, 393, 801. (b) Keeling, P. J.; Palmer, J. D.;
Donald, R. G. K.; Roos, D. S.; Waller, R. F.; McFadden, G. I.;
Roberts, C. W.; Finnerty, J.; Johnson, J. J.; Roberts, F.; Kyle,
D. E.; Krell, T.; Coggins, J. R.; Coombs, G. H.; Milhous,
W. K.; Tzipori, S.; Ferguson, D. J. P.; Chakrabarti, D.;
McLeod, R. Nature 1999, 397, 219.
10. Crystal data: C17H22F2O11, M¼440.35, monoclinic, space
˚
˚
˚
group C2, a¼23.77(3) A, b¼7.807(12) A, c¼14.215(17) A,
b¼125.49(1)8, U¼2148 A , dcalc¼1.362 g cm23, Z¼4. Cam-
3
˚
bridge crystallographic data reference no. CCDC194839.
11. (a) Cohen, N.; Banner, B. L.; Lopresti, R. J.; Wong, F.;
Rosenberger, M.; Liu, Y. Y.; Thom, E.; Liebman, A. A. J. Am.
Chem. Soc. 1983, 105, 3661. (b) Cohen, N.; Banner, B. L.;
Laurenzano, A. J.; Carozza, L. Organic Syntheses; Freeman,
J. P., Ed.; Wiley: New York, 1990; Coll. Vol. VII.
3. (a) Grossbard, E.; Atkinson, D. The Herbicide Glyphosate;
Butterworths: Boston, 1985. (b) Franz, J. E.; Mao, M. K.;
Sikorski, J. A. Glyphosate: A Unique Global Herbicide;
Americal Chemical Society: Washington, DC, 1997.
12. (a) Wiesler, W. T.; Nakanishi, K. J. Am. Chem. Soc. 1989, 111,
9205. (b) Stoez, T.; Bernet, B.; Vasella, A. Helv. Chim. Acta
1999, 82, 2380.