Difluorinated analogues of shikimic acid

Article abstract of DOI:10.1016/S0040-4020(03)00697-5

Investigations into the quinate to shikimate transformation have been carried out, the results of which have been exploited in the synthesis of a novel difluoromethylene homologue of shikimic acid from (-)-quinic acid. Martin's sulfurane {Ph₂S[OC(CF₃)₂Ph]₂} was the reagent of choice for the key dehydration step of this synthesis. The results of investigations into the synthesis of the important natural product analogue, 6,6-difluoroshikimic acid are also reported.

Full text of DOI:10.1016/S0040-4020(03)00697-5

Tetrahedron 59 (2003) 4827–4841
Difluorinated analogues of shikimic acid
Lovely Begum,a Julian M. Box,a Michael G. B. Drew,a Laurence M. Harwood,a
Jane L. Humphreys,b David J. Lowes,b Gareth A. Morris,b Perrine M. Redon,b
Francine M. Walkerb and Roger C. Whiteheadb
,
*
aDepartment of Chemistry, The University of Reading, Whiteknights, Reading RG6 6AD, UK
bDepartment of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 31 January 2003; revised 31 March 2003; accepted 28 April 2003
Abstract—Investigations into the quinate to shikimate transformation have been carried out, the results of which have been exploited in the
synthesis of a novel difluoromethylene homologue of shikimic acid from (2)-quinic acid. Martin’s sulfurane {Ph2S[OC(CF3)2Ph]2} was the
reagent of choice for the key dehydration step of this synthesis. The results of investigations into the synthesis of the important natural
product analogue, 6,6-difluoroshikimic acid are also reported. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Over the last decade, there has been much interest from
chemists and biochemists alike, in fluorinated analogues of
shikimic acid (1).1a–g Many of these compounds, by virtue
of their structural similarity to (1), have been targeted as
likely inhibitors of enzymes on the shikimic acid pathway
and are of biological interest as potential antifungal and
antibacterial agents. The recent discovery of the shikimic
acid pathway in the apicomplexan parasites Toxoplasma
gondii, Plasmodium falciparum and Cryptosporidium
parvum has provided a new impetus for the design and
synthesis of inhibitors of the pathway as potential
antiparasitic agents.2a–c
During the course of an ongoing research programme
concerned with the biochemical fate of gem-difluorinated
analogues of polyoxygenated enzyme substrates, we
became interested in two analogues of shikimic acid (2
and 3) (Fig. 1). The difluoromethylene homologue of
shikimic acid (2) and 6,6-difluoroshikimic acid (3) were
both of interest as possible prodrugs for the intracellular
generation of the corresponding difluorinated analogues (4)
and (5) of 5-enolpyruvylshikimicacid-3-phosphate. In turn,
compounds (4) and (5) were targeted as likely competitive
inhibitors of chorismate synthase, the enzyme which
catalyses the seventh step of the shikimic acid pathway.3
In this paper, we provide details of the completed synthesis
of compound (2) as well as the results of investigations into
the preparation of compound (3).
Figure 1.
2. Results and discussion
2.1. Synthesis of the difluoromethylene homologue of
shikimic acid4
The ‘chiral pool’ material (2)-quinic acid (6) was selected
as the starting material for our synthesis of the difluoro-
methylene homologue of shikimic acid (Scheme 1). The
cyclohexane diacetal (CDA) and butane diacetal (BDA)
derivatives (7 and 8) of methyl quinate were prepared from
(6) in 73 and 85% yields, respectively.5,6 Selective silylation
of the remaining secondary hydroxyl of both compounds
was accomplished most efficiently using the reactive
Keywords: shikimic acid; Martin’s sulfurane; fluorinated analogues.
*
Corresponding author. Tel.: þ44-161-275-7856; fax: þ44-161-275-4939;
e-mail: roger.whitehead@man.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00697-5

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L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
majority of the work reported herein will therefore focus on
the BDA series of compounds.
Reduction of the ester function of (10) was initially
accomplished in 70% yield using an excess of DIBAL-H
in toluene, however, a much more efficient procedure was
subsequently adopted which involved the use of an excess of
sodium borohydride in methanol. This protocol furnished
the corresponding diol (11) in 96% yield. Oxidative
cleavage of the diol with NaIO4 proceeded smoothly over
a period of several days to give the crystalline ketone (12) in
86% yield. This highly efficient four-step sequence has
allowed the preparation of multi-gram quantities of ketone
(12). The reactivity of this compound towards a number of
nucleophilic reagents has therefore been investigated.
It was our expectation that the constrained trans-decalin like
structure of (12), coupled with the steric influence of the
axially located tert-butyldimethylsilyloxy substituent at C3,
would ensure preferential ‘equatorial’ approach of nucleo-
philes to give products possessing quinate-stereochemistry
at C1. This, indeed, proved to be the case (Scheme 2). Thus,
reduction of (12) with NaBH4 in methanol gave a 5:2
mixture of axial alcohol (13) and equatorial alcohol (14)
whereas, the use of K-Selectridew proved more discriminat-
ing and furnished (13) exclusively in 70% yield after
purification by chromatography. Treatment of (12) with the
zinc reagent derived from ethyl bromodifluoroacetate8 in
THF under reflux, gave a single adduct (15), the structure of
which was confirmed by extensive NMR analysis of a
sample in C6D6, which included the use of heteronuclear
nOe measurements (19F–1H). Similarly, addition of the zinc
reagent derived from ethyl bromofluoroacetate in THF
under reflux, gave an inseparable mixture (,1:1) of two
diastereoisomeric adducts (16a,b), both of which were
shown to possess ‘quinate’ stereochemistry at C1. A full
discussion of the NMR techniques used for the structural
determination of several fluorinated intermediates prepared
during this programme is given in a later section.
Scheme 1. Reagents. (i) CH3OH, Amberlitew IR 120 (H), K, (ii) 1,1,2,2-
tetramethoxycyclohexane, (CH3O)3CH, camphorsulfonic acid, CH3OH, K,
73% yield of 7 over 2 steps, (iii) butan-2,3-dione, (CH3O)3CH,
camphorsulfonic acid, CH3OH, K, 85% yield of 8 over one step, (iv) tert-
butyldimethylsilyl trifluoromethanesulfonate, Et3N, CH2Cl2, 08C, 79% for
9, 97% for 10, (v) NaBH4, CH3OH, 08C to rt, 96%, (vi) NaIO4, H2O,
CH3OH, pH 6.9, 86%.
silylating reagent, tert-butyldimethylsilyltrifluoromethane-
sulfonate. Accordingly, the crystalline tert-butyldimethyl-
silyl ethers (9 and 10) were prepared in 79 and 97% yields,
respectively.7 Although much of our chemistry has been
carried out on both series of bis-acetal protected com-
pounds, the higher overall yield of preparation of (10) has
made the BDA our protecting group of preference. The
At the outset of our investigations into the synthesis of the
difluoromethylene homologue of shikimic acid, we
envisaged that the key transformation of the sequence
would be dehydration of compound (15) to give a product
Scheme 2. Reagents. (i) K-Selectridew, THF, 2788C, 8 h, (ii) CF2BrCO2Et, Zn, THF, K, (iii) CFBrHCO2Et, Zn, THF, K.

L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
4829
possessing a shikimate regiochemistry. Previous literature
reports indicated that dehydration of quinic acid derivatives
proceeded with varying levels of regioselectivity, although
the majority of such reactions were found to proceed via
preferential loss of a hydrogen at C2 to give the shikimate
isomer as major product.9 In anticipation of possible
problems with the dehydration of (15), we carried out
further investigations into the quinate to shikimate trans-
formation using alcohols (10) and (13) as substrates
(Scheme 3 and Table 1).
A variety of dehydration conditions was investigated and
the ratios of isomeric alkenes arising from these reactions
were assessed by examination of the 1H NMR spectra of the
crude reaction products and comparison of the integrals for
the vinyl hydrogens of the isomeric products. For
dehydration of protected methyl quinate (10), Martin’s
sulfurane {Ph2S[OC(CF3)2Ph]2}10a,b proved to be the
reagent of choice, giving a crude product mixture compris-
ing almost exclusively of (17). Accordingly, on preparative
scale, treatment of (10) with an excess of Martin’s sulfurane
in dichloromethane followed by purification by flash
chromatography and recrystallisation gave (17) in 84%
yield. In agreement with results of dehydration studies
reported recently on a substrate similar to (10), the use of
POCl3 in pyridine at slightly elevated temperature also gave
(17) as the major product isomer.11 In our hands, however, it
proved impossible to purify (17) completely free of the
regioisomer (18) when using these conditions.
Scheme 4. Reagents. (i) Ph2S[OC(CF3)2Ph]2, DCM, rt, (ii) TBAF, THF,
08C to rt.
confirmed as follows: dehydration of CDA protected methyl
quinate (9) with Martin’s sulfurane in dichloromethane gave
a single product (21) in 97% yield. Selective deprotection of
this material with tetrabutylammonium fluoride in THF
gave the crystalline allylic alcohol (22), the structure of
which was confirmed by X-ray crystallographic analysis
(Scheme 4).
The regiochemical outcome of these dehydrations was
Dehydration of the secondary alcohol (13) with POCl3 in
pyridine proceeded with good regioselectively to give (19)
as the major component of an inseparable mixture of
isomers. We were surprised, however, to find that Martin’s
sulfurane was a much inferior reagent with this substrate,
giving a 3:1 mixture of isomers (19) and (20). Treatment of
both (10) and (13) with the Burgess reagent [H3CO2CN2-
SO2Nþ(C2H5)3]13 in acetonitrile at elevated temperature
also gave the shikimate isomers (17) and (19) as the major
products. An unambiguous explanation for the regio-
selectivities of these dehydrations is not apparent, however,
if product stability is reflected in the transition states for the
reactions, then preferential formation of the trans-decalin
ring-system in (17) and (19) would be expected.
The structural similarities between (15) and (10/13) led us to
believe that the Reformatsky adduct (15) would exhibit
similar dehydration behaviour under the conditions
described above. We were thus disappointed to find that
treatment of (15) with either POCl3 in pyridine or Burgess
reagent in CH3CN at elevated temperature, induced no
detectable reaction. However, treatment of (15) with an
excess of diethylaminosulfurtrifluoride (DAST) in dichloro-
methane followed by careful chromatographic purification
gave (23) contaminated with ,7% of the undesired
regioisomer (24). Pleasingly, treatment of (15) with an
excess of Martin’s sulfurane in dichloromethane cleanly
gave (23) which was assigned a ‘shikimate’ regiochemistry
Scheme 3.
Table 1.
Conditions
Isomer ratio
17–18
19–20
Martin’s sulfurane, CH2Cl2, rt10a,b
POCl3, py, K
,30:1
15:1
8:1
3:1
10:1
10:1
–
Burgess reagent, CH3CN, K13
DAST, CH2Cl2, 08C to rt12a,b
4:1

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L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
Scheme 6.
not been studied previously and the outcome of these
investigations was therefore of general interest.
The vinyl iodide (29) proved to be an excellent substrate in
both Stille15 and Suzuki16 cross-coupling reactions and
accordingly, the 2-furyl and phenyl substituted compounds
(30) and (31) were prepared in excellent yields (Scheme 7).
Oxidation of furan (30) using the Sharpless17 modification
of the Djerassi/Engle18 conditions gave the conjugated acid
(32) in just 7% yield. Direct preparation of (32) by
palladium-catalyzed carbonylation of (29) also proceeded
in a disappointing 11% yield. It was very pleasing, however,
to find that palladium catalyzed carbonylation of (29) in the
presence of methanol gave the conjugated ester (33) in a
yield of 55% (89% based on recovered starting material).
The success of this transformation provided encouragement
that we could proceed with the approach outlined in
Scheme 6 with a reasonable level of confidence that the
Scheme 5. Reagents. (i) DAST, DCM, 08C for 1 h, then rt for 24 h,
(ii) Martin’s sulfurane, CH2Cl2, rt, (iii) LiOH, H2O, CH3OH, (iv) TFA–
H2O (7:1), 08C.
by comparison of its 1H NMR data with those of compound
(17). It proved impossible to separate (23) from minor
amounts of aromatic contaminants arising from decompo-
sition of the sulfurane, however, subsequent ester hydrolysis
under basic conditions followed by chromatographic
purification gave the carboxylic acid (25) in 50% yield
over two steps from (15). This compound, not surprisingly,
underwent rapid desilylation on storage in a concentrated
state and it was therefore exposed immediately to the acidic
conditions necessary for concomitant removal of the silyl
and bis-acetal protecting groups. Purification of the product
of this sequence by reverse phase HPLC gave the target
compound (2) in pure form (Scheme 5).
2.2. Approaches towards 6,6-difluoroshikimic acid (3)
A suitably protected a-halo enone (26) (X¼Br or I) was
selected as a key intermediate in our synthetic approach to
(3) (Scheme 6). It was envisaged that fluorodeoxygenation
of (26) would provide a gem-difluoride (27) and subsequent
palladium catalyzed carbonylation (or alternative trans-
metallation protocol) would lead to ester (28) which,
following complete deprotection, would provide the target
compound. It should be noted that previous work by our
group in this area had indicated that compounds of type
(26), wherein X is an alkoxycarbonyl moiety, were quite
unstable and prone to facile aromatisation thus precluding
their consideration as fluorination substrates.
Prior to embarking on a synthetic approach to compounds of
type 26 we investigated procedures suitable for the
conversion of (27) to (28) using the vinyl iodide (29)14 as
a test substrate (Scheme 7). To our knowledge, palladium
catalyzed coupling reactions of substrates of this type had
Scheme 7. Reagents. (i) 2-tributylstannyl furan, NMP, (C6H5CN)2PdCl2,
tri-2-furylphosphine, CuI, (ii) C6H5B(OH)2, Pd(Ph3P)4, LiCl, Na2CO3
(aq.), DME, (iii) CO, KOAc, Pd(OAc)2, DMF, Ph3P, (iv) CO, Pd(OAc)2,
DMF, CH3OH, tri-2-fuylphosphine, N,N-diisopropylethylamine.

L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
4831
Scheme 8. Reagents. (i) PDC, DMF, 08C, (ii) Ac2O, pyridine, DMAP, CH2Cl2, 08C, (iii) Bu3SnH, AIBN, C6H6, K, (iv) I2, PDC, CH2Cl2.
conversion of (27) to (28) could be accomplished
successfully.
Selective benzylation of the allylic hydroxyl of (35) was
accomplished in reasonable yield via an intermediate
stannylene acetal.22a,b Subsequent exposure of (41) to the
standard conditions for introduction of the BDA protecting
group resulted in the generation of an inseparable mixture of
compounds, the major component of which was the desired
bis-acetal (42). Acetylation of this mixture under standard
conditions followed by purification and methanolysis of the
resulting acetate (44) provided pure allylic alcohol (42) in
48% yield from (41). Oxidation of the free allylic hydroxyl
of (42) using Swern conditions23 lead cleanly to enone (43)
in 78% yield. This synthesis furnished the gem-difluorina-
tion precursor (43) in five steps from (35) and was not
plagued with any of the instability problems associated with
the previous approach.
Our first approach towards an a-haloenone of type 26,
utilized the diol (35), which was prepared in a straight-
forward manner from the commercially available compound
(34) in two steps (Scheme 8).19 Selective oxidation of the
allylic hydroxyl of (35) to give enone (36) proved to be a
capricious transformation, however, it could be accom-
plished in a maximum 65% yield using 1.5 equiv. of PDC in
DMF at 08C.20 Acetylation of the remaining free hydroxyl
group of (36) proceeded smoothly to give a-acetoxyketone
(37) in excellent yield, however, it was found subsequently
that this compound underwent partial epimerisation at the
center adjacent to the carbonyl during the course of
chromatography on silica gel as well as when stored in a
concentrated state.
Recent investigations by our group into the fluorodeoxy-
genation of a number of simple enones have shown that
Radical debromination of (37) proved to be a problematic
transformation and furnished enone (38) in ,40% yield as
an inseparable mixture (7:1) with an unidentified side-
product. This unstable enone was treated rapidly with iodine
and PDC in dichloromethane21 to give the a-iodoenone (39)
in ,52% yield. Altering the order of the hydroxyl protection
and dehalogenation steps in this sequence had no beneficial
effect on the efficiency of the synthesis since radical
debromination of (36) proceeded in just 33% yield. The
problems of inconsistent yields and product instability,
which were associated with the synthesis of a-iodoenone
(39) precluded preparation of sufficient pure material to
allow an investigation into the key difluorination step on this
compound.
The problems encountered during the synthetic sequence
described above, prompted us to consider an alternative
approach which did not involve a cumbersome dehalogena-
tion–rehalogenation sequence and which proceeded via
robust intermediates which were less susceptible to the
problems of epimerisation and elimination (Scheme 9). A
key feature of our new approach was the selection of a BDA
to block the trans disposed oxygens at C4/C5 of (35): the
stability and conformational rigidity of the trans-decalin
ring system present in the BDA protected compounds was
expected to disfavor epimerisation and elimination during
the synthesis.5
Scheme 9. Reagents. (i) Bu2SnO, C6H6, K then CsF, BnBr, DMF, rt,
(ii) butan-2,3-dione, (CH3O)3CH, CSA, CH3OH, K, (iii) Ac2O, pyridine,
DMAP, CH2Cl2, (iv) K2CO3, CH3OH, (v) DMSO, (COCl)2, Et3N, CH2Cl2,
2788C to rt.

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L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
unusual rearrangement has not been investigated in detail,
however, we believe that the reaction almost certainly
proceeds via reversible formation of an intermediate allylic
carbocation (48) (Fig. 2). Unfortunately, all attempts to
induce an analogous isomerisation of compound (46) were
unsuccessful. This finding was particularly disappointing,
given the perceived greater thermodynamic stability of the
trans-decalin ring-system in (45) compared with that in
(46), and is believed to be due to the influence of the highly
oxygenated cyclohexene ring in (46) which disfavors
formation of the necessary cationic intermediate.
With the key difluoride (45) in hand, palladium catalyzed
carbonylation of this material was investigated using a
variety of reaction conditions, however, all of these attempts
met with failure. We believe that the contrasting behaviour
of compounds (29) and (45) under similar carbonylation
conditions reflects the documented finding that vinyl iodides
are superior substrates in palladium catalyzed coupling
reactions than the corresponding vinyl bromides. Several
attempts have also been made to carry out trans-metallation
of (45) with tBuLi and to quench the resulting vinyl lithium
species with CO2, however, these also proved to be
unsuccessful.
Scheme 10. Reagents. [CH3O(CH2)2]2NSF3, rt.
reasonable levels of substrate conversion can be achieved
either in solution, by the application of ultra high pressure,14
or under solvent free conditions by using the fluorinating
agent,
(bis-(2-methoxyethyl)amino]sulfurtrifluoride
(Deoxo-Fluorw).24 In the first instance, we decided to
investigate the latter of these procedures and a solution of
enone (43) in the fluorinating agent was stirred for 72 h at rt.
Analysis of the crude product mixture indicated complete
consumption of starting material and clean formation of two
fluorinated compounds (45) and (46) in an approximately
3:2 ratio. The crystalline gem-difluoro compound (45) was
isolated in 54% yield after careful column chromatography
(Scheme 10).
Although the synthetic approach to 6,6-difluoroshikimic
acid described above was thwarted at a late stage, the results
arising from our endeavours have stimulated renewed
investigations into an alternative route to this important
natural product analogue, the results of which will be
reported in due course.
1
2.3. Structure determination using H–19F nuclear
Overhauser effect measurements
Heteronuclear nOe measurements (19F–1H) confirmed the
pseudo-axial location of the fluorine atom at the 6-position
of (46) (see Section 2.3). Mechanistically, this compound
may be derived via SN20 attack by fluoride anion on an
activated a-fluorohydrin derived from (43) or, alternatively,
SN10 attack on an allylic carbocation derived from the same
intermediate.
19F often makes a significant contribution to the spin-lattice
relaxation of neighbouring protons, allowing nuclear Over-
hauser effect measurements to provide information on local
geometry. Figure 3 shows a 2D heteronuclear Overhauser
effect spectroscopy (HOESY) spectrum of compound (15)
measured using a simple 908F–1/2t1–1808H–1/2t1–908F–
tm–908H—acquire pulse sequence.25–27 For particularly
concentrated samples it can be advantageous to add a further
908F pulse to the end of this sequence to suppress 19F dipolar
demagnetizing field effects,28,29 but this was not necessary
with the dilute samples used here. Numerous nOe cross-
peaks between 19F and 1H are visible in Figure 3, with those
to protons 2b, 6b, 2a and 6a (in descending order of size)
particularly prominent. The partial second-order character
of the 19F AB quartet leads to slight perturbations of the
relative intensity ratios in the F1 (19F) multiplet structure;
such effects are analogous to those seen in nOe difference
spectra of strongly coupled spin systems.30 In addition to the
strong responses seen for protons 2 and 6, a number of
smaller nOe’s to other protons were seen. A series of five
experiments with mixing times tm of 100, 200, 300, 400 and
500 ms were carried out and cross-peak volumes plotted
against tm to confirm that all the responses were dominated
by direct Overhauser effects and not complicated by spin
diffusion. The relative buildup rates for the nOe cross-peak
volumes are listed in Table 2. All the cross-peak intensities
showed linear initial growth, confirming that the magnetiza-
tion exchange is direct and not mediated by spin diffusion.
Previous investigations by our group had demonstrated that
a structurally simplified analogue (47) of the vinyl fluoride
(46) underwent facile isomerisation to the corresponding
gem-difluorinated isomer (29) when stored as a solution in
CH2Cl2 over 4 A molecular sieves.14 The mechanism of this
˚
Figure 2.

L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
4833
Figure 3.
Table 2. Relative 19F–1H nOe cross-peak buildup rates
Figure 4 shows a cross-section, at the chemical shift of
C(6)F, through a 2D phase sensitive gradient-enhanced
heteronuclear Overhauser effect (gHOESY) spectrum31 of
compound (46), with the full proton spectrum for compari-
son purposes. Clear nOe contacts are seen between C(6)F
and C(4)H, C(5)H and C(6)H, with a very small nOe to one
of the methoxy groups.
Proton
Buildup rate (arbitrary units)
2b
6b
2a
6a
OH
tBu
100
89
76
56
13
3
3. Conclusions
The buildup rates reflect the time average of the inverse
sixth power of the proton–fluorine separation; the sub-
stantial enhancement of the 2/6b buildup rates over those
for 2/6a indicates that the b protons in each case are closer
to the fluorine than the a, providing clear support for the
stereochemistry shown in Figure 3.
In conclusion, extensive investigations into the quinate to
shikimate transformation have been carried out using two
different substrates and a number of different dehydration
conditions. In all cases, a preference for the formation of a
shikimate regiochemistry was observed although the extent
Figure 4.

4834
L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
of the selectivity was dependent on the nature of both the
reagent and the substrate. The results of these investigations
have been exploited in the synthesis of a novel difluoro-
methylene homologue of shikimic acid from (2)-quinic
acid. Problems with the key dehydration step of this
synthesis were solved by the use of Martin’s sulfurane
{Ph2S[OC(CF3)2Ph]2}.
configuration also allows time-shared decoupling of protons
from 19F.
Mass spectra were recorded on Fisons VG Autospec (EI/CI,
low and high resolution), Fisons VG Trio 2000 quadrupole
(EI/CI, low resolution), Kratos Concept 1S (EI/CI, high
resolution) and Micromass Platform (electrospray)
spectrometers.
An approach to the synthesis of the important natural
product analogue, 6,6-difluoroshikimic acid has also been
investigated using the enantiopure diol derived from
microbial dihydroxylation of bromobenzene as starting
material. The fluorodeoxygenation step of this synthesis was
successfully accomplished, however, in spite of the success
of model studies using a simpler substrate, the approach was
abandoned due to the failure of a key palladium catalyzed
carbonylation step.
4.1.1. (20S,30S)-Methyl-4-O,5-O-(20,30-dimethoxybutane-
20,30-diyl)-quinate (8). To a solution of (2)-quinic acid
(11.01 g, 57.3 mmol) and CSA (1.50 g, 6.5 mmol) in
CH3OH (250 mL) was added trimethylorthoformate
(49 mL, 448 mmol) and butan-2,3-dione (11.8 mL,
134 mmol). The yellow solution was heated under reflux
for 6 h, stirred at rt overnight and then heated under reflux
for a further 6 h. After cooling to rt, Et3N (15 mL,
108 mmol) was added and the solution was concentrated
in vacuo to give the crude product as a brown solid.
Decolorization of a solution of the crude product in EtOAc
with activated charcoal followed by concentration in vacuo
and recrystallisation from hot EtOAc and petrol ether
(40:60) provided the title compound as colorless crystals
(15.67 g, 85%). Mp 134–1358C (lit.6 Mp 139.8–140.28C);
[a]D22¼þ137.7 (c 0.83, CH2Cl2) (lit.6 [a]2D0¼þ116.3 (c 1.06,
CH2Cl2)); (Found: C, 52.8; H, 7.7. C14H24O8 requires C,
52.5; H, 7.6%); other spectroscopic data in agreement with
those reported in the literature.6
4. Experimental
4.1. General
Solvents were dried and distilled before use. Chromato-
graphy was performed over Merck silica gel 60
(40–63 mm).
Zinc metal was obtained from Fisher Scientific and was
freshly activated by successive washes with 20% aq. HCl,
water, acetone and anhydrous diethyl ether before being
dried in vacuo.
4.1.2. (20S,30S)-Methyl-3-O-tbutyldimethylsilyl-4-O,5-O-
(20,30-dimethoxybutane-20,30-diyl)-quinate
(10).
A
solution of (8) (3.57 g, 11.1 mmol) in CH2Cl2 (30 mL)
was stirred at 08C under an atmosphere of nitrogen.
Triethylamine (5.1 mL, 36.6 mmol) was added dropwise
by syringe followed by a solution of TBDMSOTf (2.6 mL,
11.3 mmol) in CH2Cl2 (16 mL) and the resulting pale
yellow solution was stirred at 08C for 2 h. The reaction
mixture was then poured into H2O (60 mL), the organic
phase was collected and combined with two subsequent
CH2Cl2 extracts (2£60 mL). The combined organic extracts
were washed with water (60 mL), dried (MgSO4) and
concentrated in vacuo to give the crude product as a pale
yellow solid. Purification by recrystallisation from hot
CH3OH and H2O gave the target compound as a colorless
solid (4.70 g, 97%). Mp 114–1158C; [a]2D4¼þ100.5 (c 1.10,
CH2Cl2); (Found: C, 55.15; H, 8.8. C20H38O8Si requires C,
55.3; H 8.8%); nmax (Nujol)/cm21 3456 (OH), 1736
(CvO); dH (300 MHz; CDCl3), 0.11 and 0.17 (2£3H,
2£s, (CH3)2Si), 0.90 (9H, s, (CH3)3C), 1.26 and 1.28 (2£3H,
2£s, 2£butyl CH3), 1.86 (1H, ,t, J¼12.5 Hz, C(6)Hb),
2.05–2.09 (2H, m, C(2)H2), 2.18 (1H, ,dd, J¼12.8, 4.6 Hz,
C(6)Ha), 3.21 and 3.23 (2£3H, 2£s, 2£acetal OCH3), 3.48
(1H, dd, J¼10.1, 2.5 Hz, C(4)H), 3.76 (3H, s, CO2CH3),
4.20–4.31 (2H, m, C(3)H and C(5)H); dC (75.4 MHz;
CDCl3), 25.41 and 24.92 ((CH3)2Si), 17.47 and 17.69
(2£butyl CH3), 17.97 ((CH3)3CSi), 25.56 (CH3)3C), 38.33
and 39.30 (C(2)H2 and C(6)H2), 47.47 and 47.66 (2£acetal
OCH3), 52.45 (CO2CH3), 62.33, 70.85 and 72.67 (C(3)H,
C(4)H and C(5)H), 76.54 (C(1)), 99.29 and 99.80 (2£acetal
C), 173.53 (CO2CH3); m/z (CI–NH3) 452 (MNHþ4 , 10%),
435 (MHþ, 12), 420 (80), 403 (100), 388 (20), 371 (20), 85
(50); (Found: 435.2415. C20H39O8Si (MHþ) requires
435.2414).
Martin’s sulfurane and the Burgess reagent were both
obtained from Aldrich and were used without further
purification.
IR spectra were recorded on a Perkin–Elmer 881 spec-
trometer or an AT1-Mattson Genesis Series FTIR
spectrometer.
1H, 13C NMR spectra were recorded on a JEOL EX400
FT-NMR, a Varian Inova 400 MHz spectrometer, a Varian
Inova 300 MHz spectrometer or a Bruker DMX250 pulse
FT-NMR spectrometer. Chemical shifts are referenced to
the residual solvent peak. A , sign is used to describe the
apparent splitting pattern of a particular resonance when a
different pattern is expected but cannot be resolved.
1
Heteronuclear H–19F NMR experiments were carried out
using a Varian INOVA 400 spectrometer equipped with a
5 mm pulsed field gradient indirect detection probe. The
only instrument modification used was the exchange of the
synthesizer inputs to the two radiofrequency transmitters,
with concomitant exchange of the relevant parameters in the
software, to allow the transmitter normally used for proton
decoupling to provide 19F pulses. No special filters were
used, and the probe was tuned solely to the proton Larmor
frequency. In this configuration the instrument can produce
both proton and 19F pulses, with both being fed to the
observe coil of the probe. This gives full sensitivity and a
normal 908 pulse width of 5 ms for protons; because the
probe is far from electrical resonance at the 19F Larmor
frequency the 19F 908 pulse lengthens to 100 ms, but this is
perfectly adequate for most purposes. This instrument

L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
4835
4.1.3. (1R,20S,30S,3R,4S,5R)-1-Hydroxymethyl-3-
O-tbutyldimethylsilyl-4-O,5-O-(20,30-dimethoxybutane-
20,30-diyl)-cyclohexane-1,3,4,5-tetraol (11). Sodium boro-
hydride (4.26 g, 113 mmol) was carefully added portion-
wise to a stirred solution of (10) (7.0 g, 16.1 mmol) in
CH3OH (70 mL) at 08C. Once effervescence had ceased, the
reaction mixture was stirred for 24 h at rt when it was
quenched by the addition of a saturated aqueous solution of
ammonium chloride (100 mL). Organic material was
extracted into EtOAc (3£100 mL) and the combined
organic extracts were dried (MgSO4) and concentrated in
vacuo to give the crude product as a pale, yellow oil.
Purification by flash column chromatography (SiO2;
EtOAc–cyclohexane, 1:1) furnished the diol (11) as a
colorless, viscous oil (6.31 g, 96%); [a]2D4¼þ93.0 (c 2.62,
CH2Cl2); (Found: C, 56.1; H, 9.7. C19H38O7Si requires C,
56.1; H, 9.4%); nmax (film)/cm21 3498 (bs, O–H), 2951 and
2857 (s, C–H); dH (400 MHz; CDCl3), 0.13 and 0.18
(2£3H, 2£s, (CH3)2Si), 0.91 (9H, s, (CH3)3CSi), 1.27 and
1.29 (2£3H, 2£s, 2£butyl CH3), 1.40 (1H, ,t, J¼12.5 Hz,
C(6)Hb), 1.49 (1H, dd, J¼14.5, 2.3 Hz, one of C(2)H2), 1.93
(1H, ddd, J¼12.7, 4.6, 2.8 Hz, C(6)Ha), 2.07 (1H, ,dt,
J¼14.5, 3.3 Hz, one of C(2)H2), 2.22 (1H, dd, J¼8.6,
4.0 Hz, CH2OH), 3.22 and 3.23 (2£3H, 2£s, 2£acetal
OCH3), 3.31 (1H, dd, J¼11.0, 8.6 Hz, one of CH2OH), 3.41
(1H, dd, J¼10.1, 2.5 Hz, C(4)H), 3.43 (1H, dd, J¼11.0,
4.0 Hz, one of CH2OH), 4.21–4.25 (1H, m, C(3)H), 4.26
(1H, ddd, J¼12.1, 10.1 Hz, 4.6. C(5)H), 4.79 (1H, s, OH); dc
(100 MHz; CDCl3), 25.52 and 24.83 ((CH3)2Si), 17.51
and 17.76 (2£butyl CH3), 18.04 ((CH3)3CSi), 25.58
((CH3)3CSi), 37.48 (C(2)H2), 38.09 (C(6)H2), 47.54 and
47.65 (2£acetal OCH3), 62.75 (C(5)H), 70.42 (CH2OH),
70.98 (C(3)H), 73.35 (C(4)H), 74.12 (C(1)), 99.16 and
99.73 (2£acetal C); m/z (CI–NH3) 407 (MHþ, 4%), 375
(100), 85 (52); (Found: 407.2456. C19H39O7Si (MHþ)
requires 407.2465).
47.50 and 47.66 (2£acetal OCH3), 48.65 (C(2)H2), 63.95
(C(5)H), 69.37 (C(3)H), 72.89 (C(4)H), 99.15 and 100.05
(2£acetal C), 203.53 (CvO); m/z (CI–NH3) 392 (MNHþ4 ,
10%), 360 (45), 343 (60), 311 (20), 85 (100); (Found:
392.2471. C18H38O6NSi (MNHþ4 ), requires 392.2468).
4.1.5. Treatment of (12) with K-Selectridew. To a stirred
solution of the ketone (12) (0.085 g, 0.23 mmol) in freshly
distilled THF (3 mL) at 2788C under an atmosphere of
nitrogen was added a 1 M solution of K-Selectridew in THF
(0.27 mL, 0.27 mmol) and the reaction mixture was stirred
at 2788C for 8 h before being quenched by the addition of a
saturated aqueous solution of NH4Cl (3 mL). The mixture
was allowed to warm to rt when the organic material was
extracted into EtOAc (3£10 mL). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo to
give an oily white solid. Purification by flash column
chromatography (SiO2; EtOAc–petroleum ether (40:60),
7:20) gave the axial alcohol (13) as white crystals (0.060 g,
70%). Mp 79–808C; [a]2D2¼þ109.3 (c 0.91, CH2Cl2);
(Found: C, 57.5; H, 9.7. C18H36O6Si requires C, 57.4; H,
9.6%); nmax (Nujol)/cm21 3528 (m, OH); dH (300 MHz;
CDCl3) 0.12 and 0.17 (2£3H, 2£s, (CH3)2Si), 0.91 (9H, s,
(CH3)3CSi), 1.28 (6H, s, 2£butyl CH3), 1.54 (1H, ,td,
J¼12.6, 2.6 Hz, one of C(2)Hb or C(6)Hb), 1.62 (1H, ,dt,
J¼14.6, 2.7 Hz, one of C(2)Hb or C(6)Hb), 1.70 (1H, bs,
OH), 2.07–2.19 (2H, m, C(2)Ha and C(6)Ha), 3.23 (6H, s,
2£acetal OCH3), 3.41 (1H, dd, J¼10.0, 2.4 Hz, C(4)H),
4.12–4.18 (1H, m, C(1)H), 4.20 (1H, bdd, J¼4.9, 2.4 Hz,
C(3)H), 4.29 (1H, ddd, J¼12.3, 10.0, 4.6 Hz, C(5)H); dC
(75 MHz; CDCl3), 25.54 and 24.83 ((CH3)2Si), 17.55 and
17.81 (2£butyl CH3), 18.07 ((CH3)3CSi), 25.61
((CH3)3CSi), 36.77 and 37.26 (C(2)H2 and C(6)H2), 47.54
and 47.64 (2£acetal OCH3), 62.21 (C(5)H), 68.11 (C(3)H),
71.72 (C(1)H), 73.31 (C(4)H), 99.20 and 99.74 (2£acetal
C); m/z (CI–NH3) 394 (MNHþ4 , 3%), 377 (MHþ, 7), 362
(90), 345 (100), 330 (20), 313 (20), 85 (100); (Found:
377.2359. C18H37O6Si (MHþ) requires 377.2359).
4.1.4. (20S,30S,3R,4S,5R)-1-Oxa-3-O-tbutyldimethylsilyl-
4-O,5-O-(20,30-dimethoxybutane-20,30-diyl)-cyclohexane-
3,4,5-triol (12). Sodium periodate (4.97 g, 23.0 mmol) was
added portionwise to a mixture of the diol (11) (6.30 g,
15.5 mmol), CH3OH (40 mL) and aqueous phosphate buffer
(pH 6.9, 40 mL) and the reaction mixture was then stirred at
rt for 3 days. The reaction mixture was diluted with H2O
(200 mL) and the organic material was extracted into
EtOAc (3£180 mL). The combined organic extracts were
dried (MgSO4) and concentrated in vacuo to give a colorless
solid. Purification by flash column chromatography (SiO2;
EtOAc–petroleum ether (40:60), 3:7) furnished the title
compound as a colorless crystalline solid (5.00 g, 86%). Mp
100–1018C; [a]2D3¼þ93.5 (c 0.86, CH2Cl2); (Found: C,
57.8; H, 9.2. C18H34O6Si requires C, 57.7; H, 9.15%); nmax
(Nujol)/cm21 1713 (s, CvO); dH (400 MHz; C6D6), 0.07
and 0.19 (2£3H, 2£s, (CH3)2Si), 0.96 (9H, s, (CH3)3CSi),
1.27 and 1.28 (2£3H, 2£s, 2£butyl CH3), 1.82 (1H, dd,
J¼15.2, 2.8 Hz, C(2)Hb), 2.25 (1H, dd, J¼14.0, 12.4 Hz,
C(6)Hb), 2.31 (1H, ,dt, J¼15.2, 2.8 Hz, C(2)Ha), 2.71 (1H,
ddd, J¼14.0, 5.4, 2.8 Hz, C(6)Ha), 2.94 and 3.07 (2£3H,
2£s, 2£acetal OCH3), 3.57 (1H, dd, J¼10.0, 2.4 Hz,
C(4)H), 3.84 (1H, ,q, J¼2.8 Hz, C(3)H), 4.30 (1H, ddd,
J¼12.4, 10.0, 5.4 Hz, C(5)H); dC (100 MHz; C6D6), 24.96
and 24.38 ((CH3)2Si), 17.97 and 18.04 (2£butyl CH3),
18.59 ((CH3)3CSi), 26.01 ((CH3)3CSi), 45.17 ((C(6)H2),
When the reduction was carried out using NaBH4 in
methanol, the isomeric compound (14) was also isolated as a
colorless crystalline solid. Mp 76–788C; [a]2D7¼þ110.6 (c
1.74, CH2Cl2); nmax (Nujol)/cm21 3319–3260 (b, OH); dH
(300 MHz; CDCl3), 0.06 and 0.10 (2£3H, 2£s, (CH3)2Si),
0.89 (9H, s, (CH3)3CSi), 1.26 and 1.27 (2£3H, 2£s, 2£butyl
CH3), 1.37–1.47 (2H, m, two of C(2)H2 and C(6)H2), 1.68
(1H, bs, OH, confirmed by D2O shake), 2.03–2.17 (2H, m,
two of C(2)H2 and C(6)H2), 3.21 and 3.23 (2£3H, 2£s,
2£acetal OCH3), 3.36 (1H, dd, J¼10.0, 2.5 Hz, C(4)H),
3.97 (1H, ddd, J¼12.1, 10.0, 4.3 Hz, C(5)H), 4.02–4.05
(1H, m, C(3)H), 4.12–4.16 (1H, m, C(1)H); dC (75 MHz;
CDCl3), 25.37 and 24.87 ((CH3)2Si), 17.52 and 17.74
(2£butyl CH3), 18.09 ((CH3)3CSi), 25.62 ((CH3)3CSi),
38.83 and 41.63 (C(2)H2 and C(6)H2), 47.37 and 47.57
(2£acetal OCH3), 63.34 (C(5)H), 65.39 (C(3)H), 68.60
(C(1)H), 73.17 (C(4)H), 98.82 and 99.50 (acetal C); m/z
(CI–NH3) 362 (MNHþ4 2MeOH 40%), 345 (100), 330 (5),
313 (5), 287 (20), 227 (20), 187 (15), 171 (20), 85 (100).
4.1.6. Treatment of (12) with the zinc reagent derived
from ethyl bromodifluoroacetate. A solution of the ketone
(12) (0.98 g, 2.62 mmol) in freshly distilled THF (11 mL)
was added, under an atmosphere of nitrogen, to a stirred

4836
L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
dispersion of freshly activated zinc (0.30 g, 4.6 mmol) in
THF (5 mL). Ethyl bromodifluoroacetate (0.47 mL,
3.67 mmol) was added to the stirred mixture, which was
then heated directly to reflux and maintained at that
temperature for 1.5 h. The reaction mixture was allowed
to cool to rt when it was poured into an aqueous solution
containing NaHCO3 and NaHSO4. The organic material was
extracted into EtOAc (3£50 mL) and the combined extracts
were dried (MgSO4) and concentrated in vacuo to give the
crude product as a solid. Purification by flash column
chromatography (SiO2; EtOAc–petroleum ether (40:60),
1:9) furnished the adduct (15) as a colorless, crystalline
solid (1.03 g, 79%). Mp 94–958C; (Found: C, 53.3; H, 8.5;
F, 7.4. C22H40F2O8Si requires C, 53.0; H, 8.1; F, 7.6%);
[a]2D5¼þ110.2 (c 0.25, CH2Cl2); nmax (Nujol)/cm21 3451
(OH), 1754 (CvO); dH (400 MHz; C6D6), 0.04 and 0.19
(2£3H, 2£s, (CH3)2Si), 0.84 (3H, t, J¼7.2 Hz, CH3CH2),
0.90 (9H, s, (CH3)3CSi), 1.26 and 1.31 (2£3H, 2£s, 2£butyl
CH3), 1.65 (1H, dd, J¼14.7, 2.5 Hz, C(2)Hb), 2.00 (1H,
ddd, J¼12.8, 12.1, 1.9 Hz, C(6)Hb), 2.30 (1H, dddd,
J¼14.7, 3.9, 3.1, 0.9 Hz, C(2)Ha), 2.78 (1H, dddd,
J¼12.8, 4.7, 3.1, 0.9 Hz, C(6)Ha), 2.99 and 3.02 (2£3H,
2£s, 2£acetal OCH3), 3.41 (1H, dd, J¼10.0, 2.5 Hz,
C(4)H), 3.91 (2H, q, J¼7.2 Hz, CH3CH2), 3.91 (1H, ,dt,
J¼3.9, 2.5 Hz, C(3)H), 4.44 (1H, ddd, J¼12.1, 10.0, 4.7 Hz,
C(5)H); dC (100 MHz; C6D6), 25.21 and 24.41 ((CH3)2Si),
13.87 (CH3CH2), 18.15 and 18.41 (2£butyl CH3), 18.44
((CH3)3CSi), 25.93 ((CH3)3CSi), 35.10 (C(2)H2), 35.90
((C(6)H2), 47.48 and 47.59 (2£acetal OCH3), 62.61
(CH3CH2), 62.79 (C(5)H), 71.33 (C(3)H), 73.23 (C(4)H),
76.90 (t, JCF¼25 Hz, C(1)), 99.69 and 100.19 (2£acetal C),
115.71 (t, JCF¼256.4 Hz, CF2), 163.41 (t, JCF¼31.8 Hz,
CvO); dF (376 MHz; C6D6), 2113.42 (1F, d, JFF¼251 Hz),
2114.85 (1F, d, JFF¼251 Hz); m/z (CI–NH3) 516 (MNHþ4 ,
10%), 499 (MHþ, 10), 484 (50), 467 (100), 452 (20), 435
(20), 85 (95); (Found: 499.2538. C22H41F2O8Si (MHþ)
requires 499.2538).
C(2)Hb for 16b), 1.71 (1H, ddd, J¼13.0, 12.4, 1.6 Hz,
C(6)Hb for 16a), 1.81 (1H, ddd, J¼13.0, 12.0, 1.2 Hz,
C(6)Hb for 16b), 2.04 (1H, ,dt, J¼14.8, 3.2 Hz, C(2)Ha for
16b), 2.15 (1H, ,dtd, J¼14.4, 2.8, 1.1 Hz, C(2)Ha for 16a),
2.53 (1H, ,dt, J¼13.0, 4.4 Hz, C(6)Ha for 16a), 2.54 (1H,
,dt, J¼13.0, 4.4 Hz, C(6)Ha for 16b), 3.01, 3.01, 3.02 and
3.03 (4£3H, 4£s, 4£acetal OCH3 for 16a and 16b), 3.37
(1H, dd, J¼10.0, 2.4 Hz, C(4)H for 16a or 16b), 3.39 (1H,
dd, J¼10.4, 2.4 Hz, C(4)H for 16a or 16b), 3.85–4.06 (6H,
m, CH3CH2 and C(3)H for 16a and 16b), 4.39–4.48 (2H, m,
C(5)H for 16a and 16b) 4.47 (1H, dd, J¼48.4, 0.8 Hz,
CHFCO2Et for 16a), 4.60 (1H, d, J¼48.4 Hz, CHFCO2Et
for 16b), 4.80 (1H, br, OH for 16a), 4.90 (1H, d, J¼1.2 Hz,
OH for 16b); dF (376 MHz; C6D6), 2192.6 (1F, d,
J¼48.4 Hz), 2193.70 (1F, d, J¼48.4 Hz); m/z (CI–NH3)
498 (MNHþ4 , 2%), 481 (MHþ, 2), 466 (20), 449 (100);
(Found: 481.2647. C22H42FO8Si (MHþ) requires 481.2633).
4.2. Representative dehydration procedures
4.2.1. (20S,30S)-Methyl-3-O-tbutyldimethylsilyl-4-O,5-O-
(20,30-dimethoxybutane-20,30-diyl)-shikimate (17). Using
Martin’s sulfurane. A solution of Martin’s sulfurane
(0.949 g, 1.41 mmol) in CH2Cl2 (5 mL) was slowly added
under an atmosphere of nitrogen to a stirred solution of (10)
(0.41 g, 0.94 mmol) in CH2Cl2 (10 mL) at rt. The resulting
pale yellow solution was stirred for 24 h when the residual
solvent was removed in vacuo to yield the crude product as a
pale yellow oil. Purification by flash column chromato-
graphy (SiO2; EtOAc–petroleum ether (40:60), 1:9)
followed by recrystallisation (CH3OH–H2O) furnished the
title compound (17) as a colorless solid (0.33 g, 84%). Mp
74–758C; (Found: C, 57.7; H, 8.7. C20H36O7Si requires C,
57.7; H 8.7%); [a]D22¼216.4 (c 1.0, CH2Cl2); nmax (film)/
cm21 1724 (s, CvO), 1649 (w, CvC); dH (400 MHz;
CDCl3), 0.10 and 0.12 (2£3H, 2£s, (CH3)2Si), 0.89 (9H, s,
(CH3)3C), 1.28 and 1.29 (2£3H, 2£s, 2£butyl CH3), 2.21
(1H, ddd, J¼17.6, 10.4, 2.6 Hz, C(6)Hb), 2.80 (1H, dd,
J¼17.6, 6.0 Hz, C(6)Ha), 3.23 and 3.24 (2£3H, 2£s,
2£acetal OCH3), 3.48 (1H, dd, J¼10.9, 3.9 Hz, C(4)H),
3.75 (3H, s, CO2CH3), 4.11 (1H, ddd, J¼10.9, 10.4, 6.0 Hz,
C(5)H), 4.31 (1H, dd, J¼5.5, 3.9 Hz, C(3)H), 6.77 (1H, dd,
J¼5.5, 2.6 Hz, C(2)H); dC (75.4 MHz; CDCl3), 24.89 and
24.76 ((CH3)2Si), 17.60 and 17.76 (2£butyl CH3), 18.27
((CH3)3CSi), 25.68 (CH3)3CSi), 30.34 (C(6)H2), 47.53 and
47.68 (2£acetal OCH3), 51.87 (CO2CH3), 62.29 (C(5)H),
65.89 (C(3)H), 70.75 (C(4)H), 98.64 and 99.41 (2£acetal
C), 129.67 (C(1)), 136.64 (C(2)H), 166.97 (CO2CH3); m/z
(CI–NH3) 434 (MNHþ4 , 25%), 402 (95), 385 (80), 285 (45),
270 (85), 85 (100); (Found: 434.2584. C20H40NO7Si
(MNHþ4 ) requires 434.2574).
4.1.7. Treatment of (12) with the zinc reagent derived
from ethyl bromofluoroacetate. A solution of the ketone
(12) (2.29 g, 6.11 mmol) in freshly distilled THF (24 mL)
was added, under an atmosphere of nitrogen, to a stirred
dispersion of freshly activated zinc (0.68 g, 10.4 mmol) in
THF (12 mL). Ethyl bromofluoroacetate (0.9 mL,
7.6 mmol) was added to the stirred mixture, which was
then heated directly to reflux and maintained at that
temperature for 1 h. The reaction mixture was allowed to
cool to rt when it was poured into an aqueous solution
containing NaHCO3 and KHSO4. The organic material was
extracted into EtOAc (3£100 mL) and the combined
extracts were dried (MgSO4) and concentrated in vacuo to
give the crude product as a solid. Purification by flash
column chromatography (SiO2; EtOAc–petroleum ether
(40:60), 1:4) furnished an inseparable mixture of the
adducts (16a,b) as a colorless, crystalline solid (1.65 g,
56%); nmax (KBr)/cm21 3469 (OH), 1752 (CvO); dH
(400 MHz; C6D6) 0.05, 0.07, 0.21 and 0.22 (4£3H, 4£s,
(CH3)2Si for 16a and 16b), 0.87 (3H, t, J¼6.8 Hz, CH3CH2
for 16a or 16b), 0.92 (9H, s, (CH3)3CSi for 16a or 16b), 0.92
(3H, t, J¼6.8 Hz, CH3CH2 for 16a or 16b), 0.93 (9H, s,
(CH3)3CSi for 16a or 16b), 1.27, 1.27, 1.31 and 1.32 (4£3H,
4£s, 4£butyl CH3 for 16a and 16b), 1.47 (1H, dd, J¼14.4,
2.4 Hz, C(2)Hb for 16a), 1.57 (1H, br, dd, J¼14.4, 2.4 Hz,
Using POCl3. POCl3 (1.4 mL, 15 mmol) was added, under
an atmosphere of nitrogen, to a solution of (10) (3.50 g,
8.05 mmol) in freshly distilled pyridine (12 mL), at 08C.
The reaction mixture was warmed at 408C for 3 days when it
was cooled to 08C and quenched by the careful addition of a
saturated aqueous solution of ammonium chloride (40 mL).
The organic material was extracted into EtOAc (3£50 mL).
The combined extracts were dried (MgSO4), concentrated in
vacuo and the remaining pyridine was removed by
azeotropic distillation with toluene to provide yellow
crystals of the crude product. Recrystallisation from

L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
4837
CH3OH–H2O afforded the title compound (17) (contami-
nated with ,6% of regioisomer (18)) as colorless crystals
(2.72 g, 81%).
C(5)H), 4.29–4.34 (1H, m, C(3)H), 4.34 (2H, q, J¼7.2 Hz,
CH3CH2O), 6.19 (1H, br, s, C(2)H); dC (75 MHz; CDCl3),
25.00 and 24.78 (Si(CH3)2), 13.83 (CH3CH2O), 17.58 and
17.73 (2£butyl CH3), 18.23 (SiC(CH3)3), 25.62
(SiC(CH3)3), 28.68 (C(6)H2), 47.72 (br, 2£acetal OCH3,
overlapping), 62.01, 65.46 and 70.56 (C(3)H, C(4)H and
C(5)H), 63.01 (CH3CH2O), 98.73 and 99.46 (2£acetal C),
112.80 (t, J¼251.5 Hz, CF2CO2C2H5), 129.15 (t, J¼8.3 Hz,
C(2)H), 130.51 (t, J¼23.8 Hz, C(1)), 163.35 (t, J¼33.9 Hz,
CvO); m/z (CI–NH3) 498 (MNHþ4 , 5%), 466 (45), 449
(100), 417 (35), 331 (30), 85 (50); (Found: 449.2179.
C21H35F2O6Si [(M2OCH3)þ] requires 449.2171).
4.2.2. (20S,30S,3R,4R,5S)-3-O-tButyldimethylsilyl-4-O,5-
O-(20,30-dimethoxybutane-20,30-diyl)-cyclohex-1-ene-
3,4,5-triol (19). Using the Burgess reagent. A solution of
the Burgess reagent (0.380 g, 1.60 mmol) in dry acetonitrile
(5 mL) was added, under an atmosphere of nitrogen, to a
solution of (13) (0.500 g, 1.33 mmol) in acetonitrile (5 mL).
The reaction mixture was heated at reflux for 12 h, then
cooled to rt and washed successively with water (30 mL)
and brine (40 mL). The aqueous washes were extracted with
EtOAc (3£40 mL), and the combined organic extracts were
dried (MgSO4) and concentrated in vacuo to provide the
crude product as an oil. Purification by flash column
chromatography (SiO2; EtOAc–petroleum ether (40:60),
1:4) gave the title compound (19) (contaminated with ,5%
of regioisomer (20)) as a viscous oil (0.272 g, 57%). nmax
(film)/cm21 3058, 2990, 2950, 2929, 2855, 2831 (CH), 1647
(w, CvC); dH (300 MHz; CDCl3), 0.09 and 0.11 (2£3H,
2£s, (CH3)2Si), 0.89 (9H, s, (CH3)3C), 1.27 and 1.29 (2£3H,
2£s, 2£butyl CH3), 2.10 (1H, br, dd, J¼17.6, 10.1 Hz,
C(6)Hb), 2.39 (1H, ddd, J¼17.6, 6.1, 4.0 Hz, C(6)Ha), 3.23
and 3.25 (2£3H, 2£s, 2£acetal OCH3), 3.51 (1H, dd,
J¼10.8, 3.7 Hz, C(4)H), 4.14 (1H, ddd, J¼10.8, 10.1,
4.0 Hz, C(5)H), 4.19 (1H, ,t, J¼3.7 Hz, C(3)H), 5.67–5.69
(2H, m, C(1)H and C(2)H); dC (75 MHz; CDCl3), 24.85
and 24.68 ((CH3)2Si), 17.66 and 17.84 (2£butyl CH3),
18.32 ((CH3)3CSi), 25.78 (CH3)3CSi), 31.28 (C(6)H2),
47.52 and 47.63 (2£acetal OCH3), 62.76 (C(5)H), 66.74
(C(3)H), 71.29 (C(4)H), 98.57 and 99.33 (2£acetal C),
126.88 and 128.00 (C(1)H and C(2)H); m/z (CI–NH3) 376
(MNHþ4 , 8%), 344 (10), 327 (100), 312 (10), 295 (5), 269
(30), 209 (40), 169 (45), 74 (50); (Found: 376.2509.
C18H38NO5Si (MNH4þ) requires 376.2518).
4.2.4. (200S,300S,30R,40S,50R)-2,2-Difluoro-2-[30-O-tbutyl-
dimethylsilyl-40-O,50-O-(200,300-dimethoxybutane-200,300-
diyl)-30,40,50-trihydroxycyclohex-10-ene-10-yl]-acetic acid
(25). A solution of Martin’s sulfurane (1.08 g, 1.61 mmol)
in CH2Cl2 (5 mL) was slowly added under an atmosphere of
nitrogen to a stirred solution of (15) (0.401 g, 0.80 mmol) in
CH2Cl2 (10 mL) at rt. The resulting pale yellow solution
was stirred for 4 h when a second portion of the sulfurane
(1.08 g, 1.61 mmol) was added. The reaction mixture was
stirred for a further 16 h when the residual solvent was
removed in vacuo to yield the crude product as an orange
oil. Purification by flash column chromatography (SiO2;
EtOAc–cyclohexane,1:19) gave the desired compound
(23), contaminated with small amounts of impurities arising
from decomposition of the sulfurane, as a colorless oil. This
material was stirred as a dispersion in a mixture of CH3OH
(4 mL) and H2O (2 mL) and LiOH.H2O (0.037 g,
0.89 mmol) was added in one portion. The reaction mixture
was stirred at rt for 3 h when it was acidified to pH¼2 by the
addition of 10% HCl. The organic material was extracted
into EtOAc (3£10 mL) and the combined extracts were
dried (MgSO4) and concentrated in vacuo to give the crude
product. Purification by flash column chromatography
(SiO2; EtOAc–acetic acid, 99:1) gave the title compound
(25) as a viscous oil (0.182 g, 50%). (This compound
underwent rapid desilylation when stored in a concentrated
state). dH (400 MHz; CDCl3), 0.10 and 0.12 (2£3H, 2£s,
(CH3)2Si), 0.89 (9H, s, SiC(CH3)3), 1.29 and 1.32 (2£3H,
2£s, 2£butyl CH3), 2.10–2.20 (1H, m, C(6)Hb), 2.56 (1H,
dd, J¼17.0, 6.0 Hz, C(6)Ha), 3.25 and 3.26 (2£3H, 2£s,
2£acetal OCH3), 3.54 (1H, dd, J¼10.8, 4.0 Hz, C(4)H),
4.19 (1H, ,td, J¼10.8, 6.0 Hz, C(5)H), 4.31 (1H, ,t,
J¼4.2 Hz, C(3)H), 6.19 (1H, br, s, C(2)H); dC (100 MHz;
CDCl3), 24.70 and 24.56 (Si(CH3)2), 17.80 (2£butyl CH3,
overlapping), 18.47 (SiC(CH3)3), 25.84 (SiC(CH3)3), 28.71
(C(6)H2), 47.91 and 47.95 (2£acetal OCH3), 62.47, 65.58
and 70.61 (C(3)H, C(4)H and C(5)H), 99.00 and 99.81
(2£acetal C), 128.79 (br, C(2)H), 130.39 (t, J¼22.8 Hz,
C(1)), 165.76 (br, CvO) [CF2 not observed]; dF (376 MHz;
CDCl3), 2103.04 (1F, d, JFF¼254 Hz), 2106.35 (1F, d,
JFF¼254 Hz); m/z (negative ion electrospray) 451 (100%,
[M2H]2).
4.2.3. (200S,300S,30R,40S,50R)-Ethyl-2,020 -difluoro-2-[30-
O-tbutyldimethylsilyl0-40-O,50-O-(2 ,300-dimethoxy-
butane-200,300-diyl)-30,40,50-trihydroxycyclohex-10-ene-10-
yl]-acetate (23). Using DAST. A pre-dried sample of the
Reformatsky adduct (15) (0.570 g, 1.14 mmol) was dis-
solved, under an atmosphere of nitrogen, in freshly distilled
CH2Cl2 (15 mL) and the solution was cooled to 08C. DAST
(0.42 mL, 3.18 mmol) was added carefully by syringe. After
stirring at 08C for 1 h, the reaction mixture was allowed to
warm to rt and it was then stirred for a further 24 h. The
reaction mixture was cooled in ice and quenched by the
careful addition of a saturated aqueous solution of NaHCO3.
The organic material was extracted into EtOAc (3£25 mL)
and the combined extracts were dried (MgSO4) and
concentrated in vacuo to give the crude product as a
brown oil Purification by flash column chromatography
(SiO2; EtOAc–petroleum ether (40:60), 1:49) gave the title
compound (23), contaminated with ,7% of the double bond
regioisomer (24), as a colorless oil (0.357 g, 65%). nmax
(film)/cm21 2952, 2857 (CH), 1768 (CvO); dH (300 MHz;
CDCl3), 0.11 and 0.14 (2£3H, 2£s, (CH3)2Si), 0.91 (9H, s,
SiC(CH3)3), 1.31 and 1.32 (2£3H, 2£s, 2£butyl CH3), 1.36
(3H, t, J¼7.2 Hz, CH3CH2O), 2.20 (1H, br dd, J¼17.2 Hz,
10.6, C(6)Hb), 2.57 (1H, dd, J¼17.2, 6.1 Hz, C(6)Ha), 3.26
and 3.27 (2£3H, 2£s, 2£acetal OCH3), 3.52 (1H, dd,
J¼10.6, 3.8 Hz, C(4)H), 4.17 (1H, ,td, J¼10.6, 6.1 Hz,
4.2.5. (30R,40S,50R)-2,2-Difluoro-2-[30,40,50-trihydroxy-
cyclohex-10-ene-10-yl]-acetic acid (2). A solution of the
carboxylic acid (25) (0.182 g, 0.40 mmol) in a mixture of
TFA (2.75 mL) and H2O (0.25 mL) was stirred at rt for 2 h
when the residual solvents were removed directly in vacuo
to give a yellow oil. Trituration with Et2O (2£5 mL)
followed by storage of the insoluble material under high

4838
L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
vacuum gave the title compound in essentially pure form as
a colorless oil (0.068 g, 75%). Analytical material could be
obtained by purification by reverse phase HPLC [Rainin
Dynamax C18 (21.4£250 mm); eluent: H2O; refractive
index detection]; dH (300 MHz; D2O), 1.96 (1H, dd,
J¼17.7, 7.0 Hz, one of C(6)H2), 2.46 (1H, dd, J¼17.7,
5.4 Hz, one of C(6)H2), 3.56 (1H, dd, J¼8.9, 4.5 Hz,
C(4)H), 3.85 (1H, ddd, J¼8.9, 7.0, 5.4 Hz, C(5)H), 4.19–
4.25 (1H, m, C(3)H), 6.01 (1H, br, s, C(2)H); dC (75.4 MHz;
D2O), 28.99 (C(6)H2), 65.26, 65.97 and 71.16 (C(3)H,
C(4)H and C(5)H), 113.90 (t, J¼251 Hz, CF2CO2H), 127.38
(t, J¼8 Hz, C(2)H), 131.25 (t, J¼24.1 Hz, C(1)), 167.73 (br,
CvO); dF (282.4 MHz; D2O), 2105.26 (1F, d, J¼245 Hz),
2105.59 (1F, d, J¼245 Hz); m/z (negative ion electro-
spray), 223 ((M2H)2); (Found: 223.0416, C8H10F2O5
[(M2H)2] requires 223.0418).
(0.3 mL). The aqueous layer was extracted with CH2Cl2
(3£20 mL) and the combined organic extracts were washed
with water (3£50 mL), dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography (SiO2;
CHCl3:petroleum ether (30:40), 1:49) gave the title
compound (31) as a colorless oil (0.093 g, 96%); dH
(400 MHz; CDCl3), 1.88–1.94 (2H, m), 2.13–2.32 (4H,
m), 6.26 (1H, tt, J¼4.0, 2.0 Hz, C(2)H), 7.26–7.35 (3H, m,
aromatic CH), 7.41–7.47 (2H, m, aromatic CH); dF
(235 MHz; CDCl3), 290.12 to 290.30 (m); m/z (CI) 194
(Mþ, 54%) 175 (100), 130 (30), 115 (9); (Found: 194.0912.
C12H12F2 requires 194.0907).
4.2.8. 6,6-Difluoro-1-methoxycarbonyl-cyclohex-1-ene
(33). 6,6-Difluoro-1-iodocyclohex-1-ene (29) (0.122 g,
0.50 mmol) was dissolved in dry dimethylformamide
(2 mL). N,N-diisopropylethylamine (0.09 mL, 0.52 mmol),
palladium acetate (0.003 g, 0.013 mmol), tri-2-furylphos-
phine (0.007 g, 0.03 mmol) and methanol (0.9 mL,
23 mmol) were added to the solution. The mixture was
degassed, flushed three times with carbon monoxide and
then stirred under an atmosphere of carbon monoxide at rt
for 24 h. Diethyl ether (20 mL) and water (10 mL) were
added and the phases were separated. The organic phase was
washed with water (3£10 mL), dried (MgSO4) and the
solvent removed in vacuo. The product was purified by flash
column chromatography (SiO2; Et2O–pentane, 1:9) to yield
the title compound (33) as a colorless oil (0.048 g, 55%).
Starting material was also recovered (0.046 g, 38%). nmax
(thin film)/cm21 2965, 1725 (CvO), 1645 (CvC); dH
(400 MHz; CDCl3), 1.81–1.88 (2H, m), 2.08–2.18 (2H, m),
2.27–2.35 (2H, m), 3.82 (3H, s, CO2CH3), 7.34 (1H, tt,
J¼4.0, 1.8 Hz, C(2)H); dC (100 MHz; CDCl3) 18.93 (t,
J¼4.8 Hz), 25.73 (t, J¼1.8 Hz), 33.74 (t, J¼24.6 Hz,
C(5)H2), 52.03 (CO2CH3), 118.05 (t, J¼238.1 Hz,
C(6)F2), 127.74 (t, J¼25.9 Hz, C(1)), 148.92 (t, J¼7.0 Hz,
C(2)H), 164.08 (t, J¼1.7 Hz, CO2CH3); m/z (EI) 176 (Mþ,
6%) 156 (15), 145 (100), 117 (22), 97 (53); (Found:
176.0656, C8H10F2O2 (Mþ) requires 176.0649).
4.2.6. 6,6-Difluoro-1-(2-furyl)-cyclohex-1-ene (30). 6,6-
Difluoro-1-iodocyclohex-1-ene (29)(0.300 g, 1.23 mmol)
was dissolved in N-methyl-pyrrolidinone (4 mL) under an
inert atmosphere. To the stirred solution was added bis-
(benzonitrile)dichloropalladium(II) (0.024 g, 0.063 mmol),
copper(I) iodide (0.027 g, 0.14 mmol), and tri-2-furyl-
phosphine (0.029 g, 0.12 mmol). 2-(tributylstannyl)furan
(0.483 g, 1.35 mmol) was added dropwise and the reaction
mixture was stirred at rt. On completion of the reaction (as
judged by tlc analysis) the solution was diluted with EtOAc
(15 mL). The organic phase was washed with a 10%
aqueous solution of potassium fluoride (8 mL) followed by
1 M aqueous ammonium hydroxide solution (4£8 mL). The
combined aqueous washes were extracted with EtOAc
(3£8 mL) and the combined organic extracts were washed
with brine (10 mL) and dried (MgSO4). The solvent was
removed in vacuo and the product was purified by flash
column chromatography (SiO2; CHCl3–petroleum ether
(30:40), 3:97) to yield the title compound (30) as a colorless
solid (0.195 g, 86%). Mp 45–478C; nmax (KBr)/cm21 2965,
1645 (CvC); dH (400 MHz; CDCl3), 1.82–1.89 (2H, m),
2.14–2.24 (2H, m), 2.27–2.34 (2H, m), 6.41 (1H, dd,
J¼3.3, 1.8 Hz), 6.50 (1H, d, J¼2.5 Hz), 6.62–6.64 (1H, m),
7.38 (1H, d, J¼1.5 Hz); dC (100 MHz; CDCl3), 19.34 (t,
J¼4.5 Hz), 24.99 (t, J¼2.0 Hz), 33.76 (t, J¼24.5 Hz,
C(5)H2), 107.92 and 111.36 (furan C(3)H and C(4)H),
119.56 (t, J¼237 Hz, C(6)F2), 125.96 (t, J¼24.5 Hz, C(1)),
130.87 (t, J¼7 Hz, C(2)H), 141.63 and 148.64 (furan C(2),
and C(5)H); dF (235 MHz; CDCl3), 299.65 to 2100.87
(m); m/z (EI) 184 (Mþ, 100%) 169 (20), 120 (42), 91 (76),
77 (36); (Found: 184.0699. C10H10F2O (Mþ) requires
184.0700).
4.2.9. (3R,4R,5S,6S)-1-Bromo-3-benzyloxy-4-hydroxy-
5,6-isopropylidenedioxy-cyclohex-1-ene (41). The diol
(35) (0.481 g, 1.81 mmol) and dibutyltinoxide (0.472 g,
1.9 mmol) were placed in a round bottom flask which was
evacuated and then purged with nitrogen several times. Dry
toluene (10 mL) was added, and the reaction mixture was
heated at reflux for 5.5 h in apparatus fitted with a Dean–
Stark trap before being allowed to cool to rt. Residual
solvents were removed in vacuo to give a crude sample of
the stannylene acetal. CsF (pre-dried by storage in vacuo,
0.289 g, 1.90 mmol) was added to the crude stannylene
acetal and the flask was kept under vacuum for 1 h. At the
end of this time, the mixture was suspended in dry DMF,
and benzyl bromide (0.23 mL, 1.93 mmol) was added to the
stirred mixture. After stirring for 18 h at rt, the reaction
mixture was diluted with water (150 mL) and extracted with
Et2O (3£150 mL). The combined organic extracts were
dried (MgSO4) and concentrated in vacuo. The resulting
crude oil was purified by flash column chromatography
(SiO2; EtOAc–petroleum ether (40:60), 3:17) with a pad of
KF placed at the top of the column to remove tin residues.
The title compound (41) was isolated as a colorless oil
(0.403 g, 63%); [a]D20¼237.7 (c0.80, CH2Cl2); nmax (film)/
4.2.7. 6,6-Difluoro-1-phenylcyclohex-1-ene (31). 6,6-
Difluoro-1-iodocyclohex-1-ene (29)(0.122 g, 0.50 mmol)
was dissolved in dry dimethoxyethane (7.5 mL) and the
solution was degassed by bubbling nitrogen through for
15 min. Phenylboronic acid (0.085 g, 0.70 mmol), lithium
chloride (0.045 g, 1.06 mmol), an aqueous solution of
sodium carbonate (2 M, 2.5 mL) and tetrakis(triphenyl-
phosphine)palladium(0) (0.022 g, 0.019 mmol) were added.
The reaction vessel was evacuated and flushed with nitrogen
six times and the reaction mixture was then heated at reflux
for 15 h. After cooling to rt, CH2Cl2 (20 mL) was added and
the organic phase was washed with a 2 M sodium carbonate
solution (10 mL) containing concentrated aqueous ammonia

L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
4839
cm21 3580–3399 (bw, O–H), 2986, 2944 and 2891 (w,
C–H), 1646 (w, CvC); dH (300 MHz; CDCl3), 1.41 and
1.42 (2£3H, 2£s, 2£acetonide CH3), 2.48 (1H, bs, OH),
4.12–4.17 (1H, m, C(3)H), 4.34 (1H, ,t, J¼3.8 Hz,
C(4)H), 4.49 (1H, ,t, J¼5.1 Hz, C(5)H), 4.65–4.70 (3H,
m, C(6)H and benzyl CH2), 7.34–7.42 (5H, m, aromatic
CH); dC (75 MHz; CDCl3), 26.07 and 27.52 (2£acetonide
CH3), 71.60 (benzyl CH2), 67.46, 74.22, 75.97 and 76.07
(C(3)H, C(4)H, C(5)H and C(6)H), 110.01 (acetal C),
124.18 (C(1)), 127.72, 128.13, 128.46 and 128.57 (aromatic
CH and C(2)H), 137.18 (aromatic ipso-C); m/z (CI–NH3)
374 (MNHþ4 , 81Br, 100%), 372 (MNHþ4 , 79Br, 100), 281
0.86 mmol) was stirred with K2CO3 (0.071 g, 0.52 mmol)
in CH3OH (15 mL) for 5.5 h at rt. The reaction mixture was
then diluted with a saturated aqueous solution of ammonium
chloride (80 mL) and extracted with CH2Cl2 (4£40 mL).
The combined organic extracts were dried (MgSO4) and
concentrated in vacuo to afford the title compound (42) in
essentially pure form (0.357 g, 97%). Mp 69–718C;
[a]2D2¼26.2 (c 0.94, CH2Cl2); nmax (film)/cm21 3506–
3451 (bm, O–H), 3061, 3021 (w, C–H), 2992, 2945, 2927,
2832 (m, C–H), 1640 (m, CvC); dH (300 MHz; CDCl3),
1.28 (6H, s, 2£butyl CH3, overlapping), 2.85 (1H, bs, OH),
3.19 and 3.24 (2£3H, 2£s, 2£acetal OCH3), 3.96–4.04 (2H,
m, C(3)H and one of C(5)H or C(6)H), 4.23–4.28 (2H, m,
C(4)H and one of C(5)H or C(6)H), 4.51–4.95 (2H, ABq,
JAB¼11.2 Hz, benzyl CH2), 6.16 (1H, d, J¼5.6 Hz, C(2)H),
7.19–7.29 (3H, m, aromatic CH), 7.36–7.39 (2H, m,
aromatic CH); dC (75 MHz; CDCl3), 17.66 and 17.75
(2£butyl CH3), 47.92 and 48.08 (2£acetal OCH3), 65.52,
65.55, 72.37 and 72.94 (C(3)H, C(4)H, C(5)H and C(6)H),
73.72 (benzyl CH2), 99.33 and 99.63 (2£acetal C), 126.01
(C(1)), 127.64, 128.15 and 128.26 (aromatic CH), 130.48
(C(2)H), 138.51 (aromatic ipso-C); m/z (CI–NH3) 448
(MNH4þ, 81Br, 20%), 446 (MNHþ4 , 79Br, 20), 416 (45), 414
(15), 279 (25), 108 (30), 101 (55), 91 (30); (Found:
372.0807, C16H BrNO4 (MNHþ4 ) requires 372.0810).
79
23
4.2.10. (20S,30S,3R,4R,5S,6S)-1-Bromo-3-O-benzyl-4-O,5-
O-(20,30-dimethoxybutane-20,30-diyl)-6-O-acetyl-cyclo-
hex-1-ene-3,4,5,6-tetraol (44). CSA (0.05 g, 0.22 mmol),
trimethylorthoformate (1.9 mL, 17.4 mmol) and 2,3-butan-
dione (0.38 mL, 4.33 mmol) were added to a solution of the
alcohol (41) (0.615 g, 1.73 mmol) in CH3OH (15 mL) under
an atmosphere of nitrogen. The reaction mixture was heated
at reflux for 24 h during which time the yellow color
disappeared and then became dark red. After cooling to rt,
Et3N (0.7 mL, 5.0 mmol) was added and the reaction
mixture was concentrated in vacuo. Purification by flash
column chromatography (SiO2; EtOAc–petroleum ether
(40:60), 1:9) yielded a colorless foam which consisted
predominantly of compound (42) together with starting
material and an unidentified isomer of (42). The foam
(,1.16 g) was dissolved in CH2Cl2 (15 mL) and to the
resulting solution was added Ac2O (1 mL), pyridine (1 mL)
and DMAP (a few crystals). The reaction mixture was
stirred at rt for 6 h, then washed with a saturated aqueous
solution of ammonium chloride (40 mL) and extracted with
CH2Cl2 (3£40 mL). The combined organic extracts were
dried (MgSO4) and concentrated in vacuo to give a crude
oil. Purification by flash column chromatography (SiO2;
EtOAc–petroleum ether (40:60), 1:9) provided compound
(44) as colorless crystals (0.404 g, 49.5%). Mp 133–1358C;
[a]2D0¼246.4 (c 0.61, CH2Cl2); nmax (film)/cm21 2992,
2950, 2915, 2832 (m, C–H), 1751 (s, CvO), 1638 (w,
CvC); dH (300 MHz; CDCl3), 1.16 and 1.26 (2£3H, 2£s,
2£butyl CH3), 2.06 (3H, s, OC(O)CH3), 3.19 and 3.21
(2£3H, 2£s, 2£acetal OCH3), 3.95–4.02 (2H, m, C(3)H and
C(4)H), 4.31 (1H, dd, J¼10.6, 4.6 Hz, C(5)H), 4.51–4.96
(2H, ABq, JAB¼11.1 Hz, benzyl CH2), 5.68 (1H, d,
J¼4.6 Hz, C(6)H), 6.23 (1H, d, J¼5.6 Hz, C(2)H), 7.19–
7.30 (3H, m, aromatic CH), 7.37–7.39 (2H, m, aromatic
CH); dC (75 MHz; CDCl3), 17.50 and 17.69 (2£butyl CH3),
20.64 (OC(O)CH3), 47.88 and 48.04 (2£acetal OCH3),
64.31, 66.10, 72.09 and 72.63 (C(3)H, C(4)H, C(5)H and
C(6)H), 73.86 (benzyl CH2), 99.12 and 99.21 (2£acetal C),
122.93 (C(1)), 127.69, 128.19 and 128.27 (aromatic CH),
132.57 (C(2)H), 138.43 (aromatic ipso-C), 170.11 (CvO);
m/z (CI–NH3) 490 (MNHþ4 , 81Br, 100%), 488 (MNH4þ,
(45), 399 (15), 397 (15), 384 (8), 382 (8), 367 (10), 365 (10),
79
29
108 (50), 85 (100); (Found: 446.1175, C19H BrNO6
(MNHþ4 ) requires 446.1179).
4.2.12. (20S,30S,4R,5R,6S)-2-Bromo-4-O-benzyl-5-O,6-O-
(20,30-dimethoxybutane-20,30-diyl)-cyclohex-2-ene-1-one-
3,4,5,-triol (43). To a solution of oxalyl chloride (0.09 mL,
1.03 mmol) in freshly distilled CH2Cl2 (3 mL) at 2788C,
was added a pre-cooled solution of DMSO (0.08 mL,
1.13 mmol) in CH2Cl2 (3 mL), dropwise so as to maintain
the temperature below 2608C. The resulting solution was
stirred for 30 min at 2788C and then a pre-cooled solution
of the allylic alcohol (42) (0.359 g, 0.84 mmol) in CH2Cl2
was added dropwise. The reaction mixture was stirred at
2788C for a further 65 min, then Et3N (0.53 mL,
3.80 mmol) was added dropwise and the reaction mixture
was allowed to warm to rt. The yellow colored solution was
stirred at rt for 4 h, then washed with a saturated aqueous
solution of ammonium chloride (200 mL) and extracted
with CH2Cl2 (3£100 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo. The crude
orange product which still contained triethylammonium
salts was washed with water (2£100 mL) and extracted with
DCM (2£100 mL). The combined organic extracts were
dried (MgSO4) and concentrated in vacuo to furnish the title
compound (43), in essentially pure form, as a pale orange oil
(0.279 g, 78%). nmax (film)/cm21 3027 (w, C–H), 2994,
2948, 2883, 2834 (m, C–H), 1718 (s, CvO), 1600 (w,
CvC); dH (300 MHz; CDCl3) 1.42 and 1.46 (2£3H, 2£s,
2£butyl CH3), 3.31 and 3.38 (2£3H, 2£s, 2£acetal OCH3),
4.12 (1H, dd, J¼10.9, 3.4 Hz, C(5)H), 4.33 (1H, dd, J¼6.6,
3.4 Hz, C(4)H), 4.71–5.14 (2H, ABq, JAB¼11.2 Hz, benzyl
CH2), 5.02 (1H, d, J¼10.9 Hz, C(6)H), 7.26 (1H, d,
J¼6.6 Hz, C(3)H), 7.36–7.44 (3H, m, aromatic CH),
7.48–7.51 (2H, m, aromatic CH); dC (75 MHz; CDCl3),
17.50 and 17.55 (2£butyl CH3), 48.07 and 48.39 (2£acetal
OCH3), 69.23, 69.88 and 72.10 (C(4)H, C(5)H and C(6)H),
74.02 (benzyl CH2), 99.36 and 99.97 (2£acetal C), 126.60
(C(2)), 128.02, 128.26 and 128.43 (aromatic CH), 137.90
(aromatic ipso-C), 143.02 (C(3)H), 186.85 (CvO); m/z
79Br, 100), 458 (80), 456 (70), 441 (20), 439 (15), 108 (65),
79
31
85 (90); (Found: 488.1274, C21H BrNO7 (MNHþ4 ) requires
488.1284).
4.2.11. (20S,30S,3R,4R,5S)-1-Bromo-3-O-benzyl-4-O,5-O-
(20,30-dimethoxybutane-20,30-diyl)-cyclohex-1-ene-
3,4,5,6-tetraol (42). The allylic acetate (44) (0.404 g,

4840
L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
(CI–NH3) 446 (MNH4þ, 81Br, 35%), 444 (MNHþ4 , 79Br, 35),
414 (45), 412 (45), 397 (8), 395 (8), 382 (8), 380 (8), 365
(8), 363 (8), 260 (30), 228 (30), 108 (100), 85 (100); (Found:
Plate System using Mo Ka radiation. The crystals were
positioned at 70 mm from the Image Plate. 100 frames were
measured at 28 intervals with a counting time of 2 min. The
structure was solved with the Shelx86 program.32 All non-
hydrogen atoms were refined anisotropically. Two solvent
water molecules were located in the asymmetric unit.
Hydrogen atoms bonded to carbon were positioned in
geometric positions, those bonded to oxygen were located in
a difference Fourier map. All were refined isotropically with
thermal parameters equivalent to 1.2 times that of the atom
to which they were bonded. The structure was refined on F 2
using Shelxl33 to R1 0.0668, wR2 0.1590 for 1198
reflections with I.2s(I). Crystallographic details have
been deposited with the Cambridge Crystallographic Data
Centre: reference CCDC 168251. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: þ44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
79
444.1019. C19H BrNO6 (MNHþ4 ) requires 444.1022).
27
4.2.13. Reaction of (43) with Deoxo-Fluorw in the
absence of solvent. The enone (43) (0.221 g, 0.52 mmol)
was cooled to 08C and bis-(2-methoxyethyl)aminosulphur
trifluoride (1.5 mL) was added dropwise. The reaction
mixture was stirred at rt, under a nitrogen atmosphere, for
72 h, then diluted with CHCl3 (10 mL) and quenched by the
careful addition of a saturated aqueous solution of sodium
bicarbonate (250 mL). The organic components were
extracted into CHCl3 (3£100 mL), dried (MgSO4) and
concentrated in vacuo to give a brown oil. Purification by
flash column chromatography (SiO2; EtOAc–petroleum
ether (40:60), 1:19) furnished the vinyl fluoride (46) as a
colorless viscous oil, Rf 0.59 (EtOAc–petroleum ether
(40:60), 1:4), (0.070 g, 30%) and the gem-difluoride (45) as
colorless crystals, Rf 0.47 (EtOAc–petroleum ether (40:60),
1:4), (0.126 g, 54%). Data for (45); [a]2D3¼þ30.1 (c 0.63,
CH2Cl2); nmax (film)/cm21 3062, 3028, 2994, 2949, 2835
(m, C–H), 1638 (w, CvC); dH (300 MHz; CDCl3), 1.29
and 1.34 (2£3H, 2£s, 2£butyl CH3), 3.22 and 3.28 (2£3H,
2£s, 2£acetal OCH3), 3.89 (1H, dd, J¼11.0, 3.6 Hz,
C(4)H), 4.02–4.06 (1H, dd, J¼6.2, 3.6 Hz, C(3)H), 4.50
(1H, ddd, J¼14.6, 11.0, 9.2 Hz, C(5)H), 4.52–4.96 (2H,
ABq, JAB¼11.2 Hz, benzyl CH2), 6.36 (1H, dd, J¼6.2,
3.1 Hz, C(2)H), 7.18–7.37 (5H, m, aromatic CH); dC
(75 MHz; CDCl3), 17.50 and 17.59 (2£butyl CH3), 48.14
(2£acetal OCH3, overlapping), 66.38 (dd, J¼22.3, 17.4 Hz,
C(5)H), 66.90 (d, J¼8.5 Hz, C(4)H), 71.71 (C(3)H), 74.01
(benzyl CH2), 99.25 and 99.49 (2£acetal C), 114.27 (t,
J¼245.3 Hz, C(6)F2), 121.07 (,d, J¼31.1 Hz, C(1)),
127.88, 128.17 and 128.35 (aromatic CH), 133.92 (dd,
J¼6.7, 5.5 Hz, C(2)H), 138.05 (aromatic ipso-C); dF
(376 MHz; CDCl3), 2107.84 (1F, dd, J¼267.7, 14.6 Hz,
one of C(6)F2), 299.95 (1F, ddd, J¼267.7, 9.2, 3.1 Hz, one
of C(6)F2); m/z (CI–NH3) 466 (MNHþ4 , 79Br, 7%), 436
Acknowledgements
We acknowledge with thanks the University of Reading for
providing a studentship (J. M. B), the EPSRC for funding
(J. L. H and D. J. L) and AstraZeneca for kindly supplying
Martin’s Sulfurane dehydrating agent. We also thank the
EPSRC and the University of Reading for funds for the
Image Plate System. We are very grateful to Rehana Sung
for assistance with the purification of compound 2.
References
1. (a) Rich, R. H.; Bartlett, P. A. J. Org. Chem. 1996, 61,
3916–3919. (b) Brettle, R.; Cross, R.; Frederickson, M.;
Haslam, E.; MacBeath, F. S.; Davies, G. M. Bioorg. Med.
Chem. Lett. 1996, 6, 1275–1278. (c) Brettle, R.; Cross, R.;
Frederickson, M.; Haslam, E.; MacBeath, F. S. Tetrahedron
1996, 52, 10547–10556. (d) Jiang, S.; Singh, G.; Boam, D. J.;
Coggins, J. R. Tetrahedron: Asymmetry 1999, 10, 4087–4090.
(e) Weigert, F. J.; Shenvi, A. J. Fluorine Chem. 1994, 66,
19–21. (f) Sutherland, J. K.; Watkins, W. J.; Bailey, J. P.;
Chapman, A. K.; Davies, G. M. J. Chem. Soc., Chem.
Commun. 1989, 1386–1387. (g) Bowles, S.; Campbell, M. M.;
Sainsbury, M.; Davies, G. M. Tetrahedron Lett. 1989, 30,
3711–3714.
(15), 434 (15), 419 (7), 417 (7), 404 (10), 402 (10), 387 (15),
79
385 (15), 108 (30), 85 (100); (Found: 466.1059. C19H -
27
BrF2NO5 requires 466.1041). Data for (46): [a]2D3¼þ108.9
(c 1.33, CH2Cl2); nmax (film)/cm21 3029, 2994, 2950, 2911,
2835 (m, C–H), 1680 (m, CvC); dH (400 MHz; CDCl3)
1.38 and 1.39 (2£3H, 2£s, 2£butyl CH3), 3.28 and 3.33
(2£3H, 2£s, 2£acetal OCH3), 4.03 (1H, ddd, J¼8.5, 2.7 Hz,
2.0 C(5)H), 4.12 (1H, ,dt, J¼8.9, 2.0 Hz, C(4)H), 4.67–
4.98 (2H, ABq, JAB¼11.6 Hz, benzyl CH2), 4.83 (1H, ddd,
J¼11.9, 8.9, 3.2 Hz, C(3)H), 4.97 (1H, ddd, J¼47.2, 7.6,
2.7 Hz, C(6)HF), 7.31–7.40 (5H, aromatic CH); dF
(376 MHz; CDCl3) 2167.01 2167.23 (1F, m, C(6)HF),
2100.88 (1F, ddd, J¼7.6, 5.2, 3.2 Hz, C(2)F); m/z (CI–
NH3) 468 (MNH4þ, 81Br, 10%), 466 (MNHþ4 , 79Br, 10), 436
(30), 434 (30), 419 (20), 417 (10), 404 (15), 402 (15), 387
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.; Chakrabarti, D.; McLeod, R.
Nature 1998, 393, 801–805. (b) McConkey, G. A. Antimicrob.
Agents Chemother. 1999, 43, 175–177. (c) Roberts, C. W.;
Roberts, F.; Lyons, R. E.; Kirisits, M. J.; Mui, E. J.; Finnerty,
J.; Johnson, J. J.; Ferguson, D. J. P.; Coggins, J. R.; Krell, T.;
Coombs, G. H.; Milhous, W. K.; Kyle, D. E.; Tzipori, S.;
Barnwell, J.; Dame, J. B.; Carlton, J.; McLeod, R. J. Infect.
Dis. 2002, 185, S25–S36.
(23), 385 (26), 108 (60), 85 (100); (Found: 466.1051.
C19H BrF2NO5 (MNH4þ) requires 466.1041).
79
27
4.3. X-Ray crystallographic analysis of (22)
3. Haslam, E. Shikimic Acid, Metabolites and Metabolism;
Wiley: New York, 1993.
Crystal data. C16H28O9, monoclinic, P21, Z¼2,
˚
˚
˚
a¼6.800(10) A, b¼12.093(16) A, c¼11.789(17) A, b¼
4. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.;
Redon, P. M.; Whitehead, R. C. Synlett 2002, 358–360.
5. For a review see; Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.;
3
105.63(1)8, U¼934 A , dcalc¼1.296 g cm23, 1701 indepen-
˚
dent reflections were measured on a MARresearch Image

L. Begum et al. / Tetrahedron 59 (2003) 4827–4841
4841
Foster, A. C.; Owen, D. R.; Ince, S. J.; Priepke, H. W. M.;
Reynolds, D. J. Chem. Rev. 2001, 101, 53–80.
6. Montchamp, J. L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org.
Chem. 1996, 61, 3897–3899.
18. Djerassi, C. D.; Engle, R. R. J. Am. Chem. Soc. 1953, 75,
3838–3840.
19. Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem.
Soc. 1990, 112, 9439–9440.
7. Shinada, T.; Yoshida, Y.; Ohfune, Y. Tetrahedron Lett. 1998,
39, 6027–6028.
20. Zamir, L. O.; Luthe, C. Can. J. Chem. 1984, 62, 1169–1175.
21. Bovonsombat, P.; Angara, G. J.; McNelis, E. Tetrahedron
Lett. 1994, 35, 6787–6790.
8. Hallinan, E. A.; Fried, J. Tetrahedron Lett. 1984, 25,
2301–2302.
22. (a) Nagashima, N.; Ohno, M. Chem. Lett. 1987, 141.
(b) Nagashima, N.; Ohno, M. Chem. Pharm. Bull. 1991, 39,
1972.
9. see: Jiang, S.; Singh, G. Tetrahedron 1998, 54, 4697–4753,
and references cited therein.
10. (a) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94,
5003–5010. (b) Martin, J. C.; Arhart, R. J.; Franz, J. A.;
Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1988, 163–166.
11. Shih, T.-L.; Wu, S.-H. Tetrahedron Lett. 2000, 41,
2957–2959.
23. Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
24. Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng,
H. J. Org. Chem. 1999, 64, 7048–7054.
25. Rinaldi, P. J. Am. Chem. Soc. 1983, 105, 5167.
26. Yu, C.; Levy, G. C. J. Am. Chem. Soc. 1983, 105, 6994.
27. Yu, C.; Levy, G. C. J. Am. Chem. Soc. 1984, 106, 6533.
¨
28. Lix, B.; Sonnichsen, F. D.; Sykes, B. D. J. Magn. Reson., Ser.
A 1996, 121, 83–87.
12. (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574–578.
(b) Hudlicky, M. Org. React. (NY) 1988, 35, 513–637.
13. Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26–31.
29. Levitt, M. H. Concepts Magn. Reson. 1996, 8, 77–103.
30. Keeler, J.; Neuhaus, D.; Williamson, M. P. J. Magn. Reson.
1987, 73, 45–68.
14. Box, J. M.; Harwood, L. M.; Whitehead, R. C. Synlett 1997,
571–573.
15. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508–524.
31. Bauer, W. Magn. Reson. Chem. 1996, 34, 532–537.
32. Sheldrick, G. M. Shelx86. Acta Crystallogr. sect. A 1990, 46,
467–473.
16. Suzuki, A. Acc. Chem. Res. 1982, 15, 178–184.
17. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936–3938.
33. Sheldrick, G. M. SHELXL: Program for Crystal Structure
Refinement; University of Gottingen, 1993.