Complex tetrahydrofurans from carbohydrate lactones: THF amino acids as building blocks for unnatural biopolymers

Article abstract of DOI:10.1039/b111258a

The multi-gram syntheses of two epimeric six-carbon tetrahydrofurancarboxylates based upon a D-arabinofuranose template are described. An approach to 3-O-benzyl protected derivatives is also detailed. Introduction of nitrogen at C-6 of these scaffolds leads to the generation of building blocks suitable for the generation of oligomers which possess well defined secondary structures. Radical bromination facilitates introduction of nitrogen at C-2, to afford anomeric α-amino acid derivatives which are elaborated to two unnatural diastereomers of the potent herbicidal natural product hydantocidin. X-Ray crystal structures of N-methyl-2-azido-2-deoxy-α-D-arabino-hex-2-ulofuranosonamide and N-dodecyl-2-azido-2-deoxy-β-D-arabino-hex-2-ulofuranosonamide are also disclosed.

Full text of DOI:10.1039/b111258a

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Complex tetrahydrofurans from carbohydrate lactones: THF amino
acids as building blocks for unnatural biopolymers
Daniel D. Long,a Martin D. Smith,a Angeles Martín,a Joseph R. Wheatley,a David G. Watkin,b
Mattaius Müllerb and George W. J. Fleet*a
1
a Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford, UK OX1 3QY.
E-mail: gwjf@ermine.ox.ac.uk
b Chemical Crystallography Laboratory, Oxford University, 9 Parks Road, Oxford,
UK OX1 3QU
Received (in Cambridge, UK) 11th December 2001, Accepted 22nd April 2002
First published as an Advance Article on the web 6th August 2002
The multi-gram syntheses of two epimeric six-carbon tetrahydrofurancarboxylates based upon a -arabinofuranose
template are described. An approach to 3-O-benzyl protected derivatives is also detailed. Introduction of nitrogen
at C-6 of these scaffolds leads to the generation of building blocks suitable for the generation of oligomers which
possess well defined secondary structures. Radical bromination facilitates introduction of nitrogen at C-2, to
afford anomeric α-amino acid derivatives which are elaborated to two unnatural diastereomers of the potent
herbicidal natural product hydantocidin. X-Ray crystal structures of N-methyl-2-azido-2-deoxy-α--arabino-
hex-2-ulofuranosonamide and N-dodecyl-2-azido-2-deoxy-β--arabino-hex-2-ulofuranosonamide are also
disclosed.
Introduction
Carbohydrates bearing both an amino and a carboxylic acid
functionality have been extensively investigated, and proposed
both as combinatorial building blocks1 and as peptido-
mimetics.2–5 Syntheses of α-amino acids that incorporate the
anomeric centre of a carbohydrate have been described6–9 and
α,α-disubstituted amino acids that incorporate the anomeric
centres of glucofuranose and glucopyranose have been shown
to be inhibitors of glycogen phosphorylase.10–12 The anomeric
amino acid motif 1 is also found as a component of the natural
herbicide hydantocidin 2.13,14 In addition, anomeric amino
acids as exemplified by 1 (and their pyranose analogues) have
aspects of this work have been published in a preliminary
been incorporated into short peptide sequences with a view to
form.32
influencing secondary structural propensities.15–17 Unnatural
oligomers which possess well defined secondary structure
(foldamers)18 have the potential for novel catalytic or selective
recognition properties and this has initiated efforts directed
toward their design and synthesis. The potential of THF
Results and discussion
Synthesis of the THF Nucleus
amino acids in this regard has been demonstrated through the
homo-oligomerisation of 5-(azidomethyl)-tetrahydrofuran-2-
carboxylates such as 3; both turns19 and helices20 have been
reported for these carbopeptoids. It has been shown that an
isomeric unit of 3 is an effective isostere for gly–gly in enkeph-
alins through the synthesis of analogues with much the same
biological activity as that of the natural products.21 A similar
approach has been adopted for the generation of somatostatin
analogues22 and β-hairpin peptides.23 Recent reports24–28 detail-
ing the strong propensity of relatively short β-peptides to adopt
secondary structures have also prompted the synthesis of
3-azidotetrahydrofuran-2-carboxylates 429 and oligomeric
oxetane β-amino acids which populate a 10-helical conform-
ation.30,31
This paper describes the generation of α- and β--arabino-
furanose C-glycosyl derivatives, including two previously
unreported stereoisomers of hydantocidin 2. The syntheses of
monomeric building blocks that have been utilised in the
synthesis of homo-oligomeric THF amino acids that adopt
well-defined secondary structures are also reported.19 Certain
2-O-Trifluoromethanesulfonates of carbohydrate γ- and
δ- lactones in basic33 or acidic34 methanol give good to excel-
lent yields of highly substituted tetrahydrofurancarboxylates.
Such a procedure has been utilised for the synthesis of
C-glycosyl derivatives of glucofuranose,35 which have provided
scaffolds for the generation of glucofuranose libraries.36,37
Although the corresponding tosyl38,39 and mesyl40 esters also
form tetrahydrofurans, triflates consistently produce the
optimum yields of tetrahydrofurancarboxylates.
1. From D-mannonolactone 5. Application of this method-
ology to the synthesis of 3 indicated that the key intermediate 7
was required [Scheme 1]; in order to introduce the triflate at C-2,
it is necessary to protect the primary hydroxy group at C-6 in
-mannono-1,4-lactone 5. Kinetic acetonation of the side-
chain diol in 5 by 2-methoxypropene in dimethylform-
amide (DMF) in the presence of toluene-p-sulfonic acid acid
(p-TsOH) gave the monoacetonide 6 [89% yield]; this represents
a modification of the published procedure.41 Treatment of 6
with trifluoromethanesulfonic anhydride in dichloromethane in
1982
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b111258a

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Scheme 1 (i) 2-Methoxypropene, DMF, p-TsOH; (ii) Tf2O, CH2Cl2,
Pyridine, Ϫ40 ЊC; (iii) 1% HCl in MeOH.
the presence of pyridine effected a highly regioselective esteri-
fication of the more nucleophilic hydroxy group α- to the
lactone, to give the stable triflate 7 which could be isolated in
85% yield; however, treatment of the crude triflate 7 with
hydrogen chloride in methanol gave the required ester 8 in an
overall yield of 84% from 6.
Formation of the triflate 7 has been previously reported but
in significantly poorer yield.42 Thus, multi-gram amounts of 8
may readily be prepared from 5 in an overall yield of 76%.
Structural proof of the stereochemistry of the carboxylate in 8
is given later in the paper. The formation of 8 from 7 proceeds
with hydrolysis of the side-chain acetonide, methanolysis of the
lactone and subsequent intramolecular SN2 closure of the
resulting open-chain hydroxy triflate 9 with inversion of con-
figuration at C-2 [Scheme 2]. No C-glycopyranosides (arising
Scheme 3 (i) Acetone, (CH3)2C(OMe)2, p-TsOH, MeOH; (ii) Tf2O,
CH2Cl2, pyridine, Ϫ40 ЊC; (iii) 1% HCl in MeOH.
triflate 14 [89% yield], as previously described.46 Treatment of
14 with hydrogen chloride in methanol effected clean, quanti-
tative conversion to the α-arabinofuranoside 15 via hydrolysis
of the 3,4- and 5,6-O-isopropylidene groups and SN2 displace-
ment of the C-2 triflate by the C-5 hydroxy group. Thus, large
quantities of 15 is easily prepared from 10 in only three steps
and an overall yield of 70%.
c. From 3-O-benzyl-D-glucose 16. An alternative approach to
a 3-hydroxy-protected gluconolactone derivative is shown in
Scheme 4, starting from 3-O-benzylglucose 16.47–49 Oxidation of
the lactol 16 with bromine water buffered by barium carbonate
gave the lactone 17 in 79% yield; the structure ascribed to 17 as
the γ- rather than the δ-lactone is on the basis of the carbonyl
stretch at 1780 cmϪ1. Reaction of the lactone 17 with acetone in
the presence of camphorsulfonic acid (CSA) afforded the
acetonide 18 [80% yield], which upon esterification with triflic
anhydride in dichloromethane in the presence of pyridine at
Ϫ40 ЊC gave the unstable triflate 19 [86% yield]. Treatment
of the triflate 19 with hydrogen chloride in methanol gave
the tetrahydrofuran 20 in 98% yield. Thus, the overall yield
of the protected α--arabinofuranosecarboxylate 20 from
3-O-benzylglucose 16 is 52%. It is noteworthy that none of the
epimeric methyl ester 8 is formed under these conditions, since
it might have been anticipated that the trans-triflate 19 would
undergo rapid equilibration to the more stable cis-epimer.50
Hydrogenation of 20 in methanol gave the unprotected
α-arabinofuranose derivative 15 in 89% yield, identical in all
respects to that described earlier.
Structural proof of the configuration at C-2 of the methyl
carboxylate in 20 was provided by its conversion to 24. Thus,
reaction of 20 with toluene-p-sulfonyl chloride in dichloro-
methane in the presence of pyridine gave the corresponding
tosyl derivative 21 [60% yield, together with 26% of recovered
20], which with sodium iodide in butanone gave the iodide 22
[77% yield]. Hydrogenation of the iodide 22 in methanol in the
presence of sodium acetate and 10% palladium on charcoal
gave 23 [98% yield], from which the benzyl protecting group was
removed by further hydrogenation in methanol containing a
few drops of acetic acid with palladium black as the catalyst to
give 24 [89% yield].
Scheme
2
Mechanistic rationale for generation of the THF-
carboxylate 8.
from attack of the C-6 rather than the C-5 hydroxy group) were
isolated; ring closures to C-glycopyranoses by nucleophilic
displacement at C-2 of a sugar are rare.43
2. From D-gluconolactone 10. A similar sequence to that
described above could be applied to the -glucono-1,4-lactone
acetonide 11 – and might allow similarly easy access to the
corresponding carboxylate 15. However, all attempts to prepare
12 – either as an isolable compound or as an intermediate for
direct conversion to 15 – were unsuccessful [Scheme 3]. It is
frequently the case that triflates of cis-diol structures on rings
without protection of the neighbouring hydroxy function are
useful intermediates (such as 7), but triflates derived from
trans-1,2-diols are not easily handled, presumably because of
the ready formation of epoxides. It is thus necessary to protect
the C-3 hydroxy group of a suitable gluconolactone derivative
and this can readily be achieved by using an open-chain triflate.
Thus, reaction of the readily available -glucono-1,5-lactone
10 with a mixture of acetone, 2,2-dimethoxypropane and
methanol in the presence of toluene-p-sulfonic acid gave
the diisopropylidene derivative 1344,45 in which only C-2 is
unprotected [79% yield]; esterification of 13 gave the stable
The C-2 epimer 31 of 24 was prepared by generation of the
3-O-benzyl mannonolactone derivative 25. Comparison with
31, prepared below, showed that the ring contraction of the
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1983

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Scheme 4 (i) Br2, H2O, BaCO3; (ii) acetone, CSA; (iii) Tf2O, pyridine, CH2Cl2; (iv) HCl, MeOH; (v) H2, Pd–C, MeOH; (vi) TsCl, pyridine, CH2Cl2;
(vii) NaI, EtCOMe; (viii) H2, Pd–C, NaOAc, MeOH; (ix) H2, Pd-black, AcOH, MeOH.
yield]; sequential hydrogenation of 29 in the presence of
palladium catalysts gave first the benzyl ether 30 [83% yield]
and then the required methyl ester 31 [97% yield]. The proper-
ties of 31, other than its specific rotation, were identical to those
of a sample of its enantiomer, the structure of which has been
determined by X-ray crystallographic analysis.51
The structural relationship of the tetrahydrofurans reported
in this paper to the enantiomer of 31 provides unequivocal
evidence for the structures proposed.
Synthesis of ꢀ-azido acid building blocks
The generation of THF α-amino acid derivatives requires func-
tionalisation at C-2; suitably protected carbohydrate carboxyl-
ates are susceptible to selective captodative radical formation52
and readily undergo radical bromination at this position.53
Persilylation of carboxylates 8 and 15 with tert-butyl-
dimethylsilyl chloride (TBSCl) in DMF in the presence of
imidazole at 85 ЊC afforded the trisilyl derivatives 32 (97%) and
33 (84%), respectively [Scheme 6]. Reaction of either 32 or 33
with N-bromosuccinimide in tetrachloromethane at 80 ЊC in the
presence of catalytic benzoyl peroxide afforded an unstable
bromide mixture 34, which upon treatment with sodium azide
in DMF yielded an identical, inseparable mixture of epimeric
anomeric amino acid derivatives 35 in an overall yield of 89%
(from 32) and 59% (from 33), respectively.
Azide displacement of bromide at the ‘anomeric’ position of
Scheme 5 (i) CF3CO2Na, DMF; H2O; (ii) Tf2O, pyridine, CH2Cl2;
a C-glycosyl carboxylate has been shown to proceed with inver-
(iii) HCl, MeOH; (iv) H2, Pd–C, MeOH; (v) TsCl, pyridine, CH2Cl2;
sion of configuration via an SN2 mechanism.54 Thus, loss of the
(vi) NaI, EtCOMe; (vii) H2, Pd–C, NaOAc, MeOH; (viii) H2, Pd-black,
stereointegrity at the anomeric position of the carboxylates
32 and 33 occurs during the bromination step rather than the
azide displacement. Stereoselective bromination is most often
observed with substrates possessing a 3,4-O-isopropylidene-
protected cis-diol function.6 Removal of the silyl protection
of the epimeric azido ester mixture 35 with methanolic HCl
allowed for ready separation of the products 36 (46%) and 37
(47%) by silica gel chromatography. The 1 : 1 ratio of these
materials implies that the bromination of the carboxylates 32
and 33 proceeds in a non-stereoselective fashion.
The THF α-amino acid derivatives 36 and 37 were each
treated with a series of primary amines in methanol in an
attempt to prepare crystalline derivatives. This afforded the
amido derivatives 38a–c (78–89% yield) and 39a,b (94, 95%
yield), respectively [Scheme 7].
AcOH, MeOH.
triflate 19 to give 15 had occurred with clean inversion of
configuration at C-2, [Scheme 5].
Initial reaction of 19 with sodium trifluoroacetate in di-
methylformamide, followed by aqueous work-up with concomit-
ant hydrolysis of the resulting trifluoroacetate ester, gave the
inverted manno-alcohol 25 [93% yield]. Esterification of the free
hydroxy group in 25 with trifluoromethanesulfonic anhydride
gave the triflate 26 [87% yield]. Treatment of the triflate 26 with
methanolic hydrogen chloride afforded the target tetrahydro-
furan 27 [100% yield]. Hydrogenation of 27 in methanol in the
presence of palladium on charcoal caused removal of the
benzyl ether to give 8, demonstrating that both the benzylated
26 and unbenzylated 7 triflates give the tetrahydrofurans 27 and
8 respectively, with inversion of configuration at C-2. Structural
proof for 27 was obtained by conversion to 31. Tosylation of
27 gave 28 [70% yield], which with sodium iodide gave 29 [90%
The absolute stereochemistry of the azide derivatives in this
synthetic sequence was established via the X-ray crystal-
structure determination of both the methylamide 38a and the
1984
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998

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Fig. 1 X-Ray crystal structures of N-methyl-2-azido-2-deoxy-α--
arabino-hex-2-ulofuranosonamide 38a and N-dodecyl-2-azido-2-
deoxy-β--arabino-hex-2-ulofuranosonamide 39b, showing crystallo-
graphic numbering scheme.
Scheme 6 (i) TBSCl, DMF, imidazole; (ii) NBS, CCl4, (PhCOO)2;
(iii) NaN3, DMF; (iv) HCl in MeOH.
Scheme 7 (i) RNH2, MeOH where R = (a) Me, (b) nBu, (c) CH3(CH2)11
(ii) RNH2, MeOH where R = (a) nBu, (b) CH3(CH2)11.
dodecylamide 39b [Fig. 1]. The azide substituent of the methyl-
amide 38a is clearly on the opposite side of the molecule to its
adjacent hydroxy group at C-3. In contrast, the azide group of
the dodecylamide 39b (found to contain two asymmetric units
in the unit cell), derived from the ester 36, is on the same face of
the molecule as the adjacent C-3 hydroxy group.
Formation of hydantocidin analogues
The successful formation of the THF α-amino acid derivatives
35 facilitated conversion to the remaining two diastereomers of
hyantocidin 2 which have yet to be described in their depro-
tected forms.55,56 Using established methodology for the con-
struction of a spiro-hydantoin ring, the epimeric mixture 35
was first subjected to palladium-catalysed hydrogenation in
methanol to afford the epimeric amino esters 40 and 41 in a
total yield of 99% (with a variable diastereoisomeric ratio)
[Scheme 8]. Separation of the epimers on a silica gel column
was possible but it was found that both the pure products 40
and 41 slowly epimerised in solution, presumably via an open-
chain imine. Thus, a mixture of the amines 40 and 41 was
treated with potassium cyanate in acetic acid to afford the con-
figurationally stable, separable ureas 42 (46%) and 43 (18%)
together with an N-acylated side product as an anomeric mix-
ture (31%). Hydantoin-ring formation from ureido esters has
Scheme 8 (i) H2, Pd-black, MeOH (ii) KOCN, AcOH (iii) TBAF,
THF.
previously been accomplished under both acidic and basic
conditions57,58 and both approaches appeared compatible with
concomitant silyl removal. Treatment of either pure urea 42 or
43 with aqueous TFA resulted in hydantoin-ring formation in
high yield and complete silyl ether cleavage. However, in all
cases the reaction was accompanied by significant epimeris-
ation at C-2 to give an inseparable mixture of final compounds
44 and 45. Epimerisation of ureido esters and the hydantoin
ring itself has been observed in strongly acidic or basic condi-
tions. Employing tetrabutylammonium fluoride (TBAF) in
THF resulted in formation of the deprotected hydantoins 44
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1985

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and 45 in quantitative yield from their respective ureido esters
42 and 43. Inspection of the 500 MHz H NMR spectrum of
the crude tosylester 46 with sodium azide afforded the THF
amino acid derivative 3 in an improved yield of 71% over
1
each sample of 44 and 45 prepared by the TBAF method
revealed that both were very slightly contaminated with their
C-2 epimer (less than 5% epimerisation in each case). A pure
sample of the hydantoin 45 was obtained by crystallisation. The
stereochemical assignment at C-2 of the ureas 42 and 43 was
determined from NOE studies, and by analogy the absolute
configuration of the hydantoins 44 and 45 was established. The
NH of the urea moiety of ureido ester 42 showed a very strong
NOE to H-3 and a weak NOE to the tert-butyl of the silyl
group on OH-3 [Fig. 2]. This is consistent with the urea being
the two steps (8
46
3). Through a modification of this
procedure, ester 15 reacted with methanesulfonyl chloride
in pyridine in the presence of 4-(dimethylamino)pyridine
(DMAP) to yield the mesyl derivative 51 in 72%, which was
subsequently displaced with azide to afford the azido com-
pound 52 in 98% yield [Scheme 10].
Fig. 2 Significant NOE enhancements observed for the epimeric ureas
42 and 43 (s = strong, w = weak).
found on the same side of the ring as the H-3 proton. Ureido
ester 43 showed a weak NOE between the urea NH and H-3,
H-4 and H2-6. This is indicative of the urea being orientated on
the same side of the ring as the methylene C-6. The strong NOE
between the NH and the tert-butyl of the silyl group on OH-3
further supported this assertion.
Scheme 10 (i) MsCl, pyridine, DMAP; (ii) NaN3, DMF; (iii) K2CO3,
IPA; (iv) NaOH(aq.); then IPA, H2SO4; (v) TsCl, pyridine, 3 Å sieves.
The 6-azido methyl carboxylates 3 and 52 each represent a
THF amino acid derivative in which both the amino and carb-
oxylic acid function are present in a protected form. Differential
deprotection of such frameworks allows isolation of amino and
acid components.59 Reduction of the azide functionality of the
methyl ester 3 through catalytic hydrogenation conditions
afforded the bicyclic lactam 50, presumably via spontaneous
intramolecular closure of a non-isolable C-6 amine onto the
ester across the tetrahydrofuran. Hydrogenation of 52, in which
the azide functionality is trans to the methyl ester, resulted in
complex mixtures, probably arising from uncontrolled inter-
molecular condensations. It was envisaged that a more hin-
dered, less reactive ester could (in both cases) facilitate isolation
of a 6-amino component. Transesterification of 3 and 52 was
best achieved with propan-2-ol (IPA) in the presence of potas-
sium carbonate at 70 ЊC to afford the isopropyl esters 49 and 55
in 78% and 85% yield, respectively. An alternative route could
be envisaged through formation of the isopropyl ester prior
to the introduction of azide at C-6. It was found that trans-
esterification of the methyl esters 8 and 15 was best achieved via
a two-step protocol; initial hydrolysis with aqueous sodium
hydroxide and subsequent treatment with IPA and conc. sul-
furic acid at 80 ЊC afforded the isopropyl esters 47 and 53 in
97% and 90% yield, respectively. Esterification of the C-6
hydroxy groups of 47 and 53 with toluene-p-sulfonyl chloride in
pyridine in the presence of 3Å molecular sieves gave the tosyl
esters 48 (83%) and 54 (62%), which both underwent efficient
displacement by sodium azide in DMF at 90 ЊC to yield the
azides 49 (78%) and 55 (99%), respectively.
ꢁ-Amino acid building blocks: dipeptide isosteres
Elaboration of the methyl carboxylates 8 and 15 to THF
amino derivatives necessitated selective introduction of nitro-
gen at C-6. Accordingly, the ester 8 was treated with toluene-
p-sulfonyl chloride in pyridine in the presence of 3Å molecular
sieves at 0 ЊC to afford the C-6 tosyl ester 46 in 79% yield
[Scheme 9].
Reaction of the sulfonate ester 46 with sodium azide in DMF
at 90 ЊC gave the 6-azido compound 3 in 85% yield. Reaction of
Conclusions
The generation of THF carboxylates from carbohydrate
lactones has been demonstrated to be a short and efficent
process. Elaboration of these intermediates through function-
alisation at either C-2 or C-6 provides access to THF amino
acid derivatives; this prompted the total syntheses of two
unknown diastereoisomers of the natural herbicide hydanto-
cidin and also provided monomeric components suitable for
oligomerisation to the carbopeptoid class of foldamers.
Scheme 9 (i) TsCl, pyridine, 3 Å sieves; (ii) NaN3, DMF; (iii) H2, Pd,
MeOH; (iv) K2CO3, IPA; (v) NaOH(aq.); then IPA, H2SO4.
1986
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998

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mannono-1,4-lactone 6 (425 mg, 1.95 mmol) in dichloro-
Experimental
methane (20 mL) containing dry pyridine (0.63 mL, 7.80 mmol)
at Ϫ30 ЊC, under an atmosphere of nitrogen. The reaction mix-
ture was stirred at Ϫ30 ЊC for 30 min. TLC (ethyl acetate–
hexane 1 : 1) indicated complete conversion of the starting
material (Rf 0.1) to a major product (Rf 0.6). Three drops of
water were added and the reaction mixture was passed through
a silica plug (ethyl acetate–hexane 1 : 1) topped with MgSO4.
The solvent was removed in vacuo (co-evaporation with tolu-
ene) and the residue was purified by flash chromatography
(ethyl acetate–hexane 1 : 2) to yield 5,6-O-isopropylidene-2-O-
Hexane refers to petroleum ether boiling in the range 60–80 ЊC,
distilled before use; CH2Cl2 was distilled from calcium hydride.
All other solvents were used as supplied (AR or HPLC grade).
Reagents were used as supplied. Aqueous orthophosphate solu-
tion buffering to pH 7 (pH 7 buffer) was prepared through the
dissolution of 85 g of KH2PO4 and 14.5 g of NaOH in 950 mL
of distilled water. TLC was performed on aluminium or plastic
sheets coated with silica gel 60 F254, visualisation being effected
using 0.2% w/v cerium() sulfate and 5% ammonium molyb-
date() in 2 M sulfuric acid. Column chromatography was
performed on Sorbsil C 60 40/60 silica. Melting points were
recorded on a Kofler hot block and are uncorrected. Optical
rotations were recorded on a Perkin–Elmer 241 polarimeter
with a path length of 1 dm; concentrations are quoted in g (100
mL) and [α]D-values are in units of 10Ϫ1 deg cm2 gϪ1. 1H NMR
spectra were recorded, unless otherwise stated, on either a
Bruker AM 500 or an AMX 500 spectrometer (500 MHz) or,
where stated, on a Varian Gemini 200 or a Bruker AC 200
spectrometer (200 MHz). 13C NMR spectra were recorded,
unless otherwise stated, on a Bruker AM 500 or an AMX 500
spectrometer (125.3 MHz) or, where stated, on a Varian Gemini
200 or a Bruker AC 200 spectrometer (50.3 MHz), and multi-
plicities were assigned using DEPT sequence. Chemical shifts
(δ) are quoted in ppm and coupling constants (J) in Hz.
Residual signals from solvents were used as internal reference,
and 13C NMR spectra in D2O were referenced to 1,4-dioxane
(δC 67.4). The following abbreviations were used to explain
multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; b, broad; a, apparent. IR spectra were recorded on a
Perkin–Elmer Paragon 1000 spectrophotometer using either
thin films on NaCl plates (thin film) or KBr discs (KBr). Low-
resolution mass spectra were recorded on either a VG MASS
LAB 20–250 using desorption chemical ionisation (DCI; NH3),
chemical ionisation (CI, NH3) or fast atom bombardment
(FAB), or on a VG Platform using atmospheric pressure chem-
ical ionisation (APCI). High-resolution mass spectra (HRMS)
were recorded on a VG Autospec spectrometer. A solution of
HCl in MeOH was generated by the addition of acetyl chloride
to dry methanol. Elemental analyses were carried out by the
microanalysis service of the Dyson Perrins Laboratory or
the Oxford University Inorganic Chemistry Laboratory.
trifluoromethylsulfonyl--mannono-1,4-lactone
7 (580 mg,
85%) as a white solid (Found: C, 34.59; H, 3.67. C10H13O8F3S
requires C, 34.29; H, 3.74%); m.p. 109–110 ЊC (decomp.); [α]2D1
ϩ13.6 (c, 1.00 in CHCl3); νmax (KBr): 3375 (OH), 1775 (C᎐O,
᎐
lactone) cmϪ1; δH (CDCl3; 200 MHz): 1.38, 1.46 (6H, 2 × s,
C(CH3)2), 2.94 (1H, b–s, OH), 4.08 (1H, dd, J6,5 3.6, J6,6Ј 9.3,
H-6), 4.21 (1H, dd, J6Ј,5 5.8, H-6Ј), 4.31 (1H, dd, J4,3 2.8, J4,5 8.4,
H-4), 4.47 (1H, ddd, H-5), 4.80 (1H, a–dd, H-3), 5.38 (1H, d,
J2,3 4.7, H-2); δC (CDCl3; 50.3 MHz): 24.2, 25.9 (2 × q,
C(CH3)2), 65.5 (t, C-6), 68.1, 72.1, 79.8, 80.8 (4 × d, C-2, C-3,
C-4, C-5), 109.3 (s, C(CH ) ), 115.4 (q, SO CF ), 168.6 (s, C᎐O);
᎐
3
2
2
3
ϩ
m/z (CI; NH3): 368 (M ϩ NH4 , 100), 351 (M ϩ Hϩ, 30%).
Methyl 2,5-anhydro-D-gluconate 8
Method (i). Trifluoromethanesulfonic anhydride (11.3 mL,
67.1 mmol) was added to a stirred solution of 5,6-O-isopropyl-
idene--mannono-1,4-lactone 6 (11.25 g, 51.6 mmol) in a mix-
ture of dichloromethane (180 mL) and dry pyridine (16.7 mL,
206.4 mmol) at Ϫ30 ЊC, under an atmosphere of nitrogen. The
reaction mixture was stirred at Ϫ30 ЊC for 1 h. TLC (ethyl
acetate–hexane 1 : 1) indicated complete conversion of the
starting material (Rf 0.1) to a major product (Rf 0.6). Water
(0.6 mL) was added and the reaction mixture was passed
through a silica plug (ethyl acetate–hexane 1 : 1) topped with
MgSO4. The solvent was removed in vacuo (co-evaporation
with toluene) to give 5,6-O-isopropylidene-2-O-trifluoromethyl-
sulfonyl--mannono-1,4-lactone 7 as an off-white solid, which
was used without further purification. The crude 5,6-O-
isopropylidene-2-O-trifluoromethylsulfonyl--mannono-1,4-
lactone 7 was stirred in a 1% v/v solution of hydrogen chloride
in methanol (65 mL), at room temperature, under an atmos-
phere of nitrogen. After 20 h, TLC (chloroform–methanol
7.5%) indicated complete conversion of the starting material
(Rf 0.8) to a major product (Rf 0.2). Sodium hydrogen carbon-
ate (6.5 g, excess) was added and the reaction mixture was
stirred for 2 h and then filtered through Celite. The solvent was
removed in vacuo and the residue was pre-adsorbed onto silica
and purified by flash chromatography (chloroform–methanol
7.5%) to yield methyl 2,5-anhydro--gluconate 8 (8.28 g, 84%
over two steps) as a yellow oil which solidified upon prolonged
drying (Found: C, 43.70; H, 6.39. C7H12O6 requires C, 43.75; H,
6.29%); m.p. 97–98 ЊC; [α]2D1 ϩ27.8 (c, 1.00 in MeOH); νmax (thin
film): 3371 (OH), 1742 (C᎐O, ester) cmϪ1; δ (CD3CN; D2O
5,6-O-isopropylidene-D-mannono-1,4-lactone 6
Toluene-p-sulfonic acid monohydrate (100 mg, catalytic)
was added to a stirred solution of -mannono-1,4-lactone 5
(10.89 g, 61.2 mmol) in DMF (40 mL) at 0 ЊC, under an atmos-
phere of nitrogen. 2-Methoxypropene (7.25 mL, 73.4 mmol)
was added dropwise at 0 ЊC and the stirred solution was allowed
to warm to room temperature. After 20 h, TLC (ethyl acetate)
indicated conversion of the starting material (Rf 0.0) to a major
product (Rf 0.5). Sodium carbonate (5 g, excess) was added and
the reaction mixture stirred for 2 h and then filtered through
Celite. The solvent was removed in vacuo (co-evaporation with
toluene). The residue was pre-adsorbed onto silica and purified
by flash chromatography (ethyl acetate–hexane 4 : 1) to yield
5,6-O-isopropylidene--mannono-1,4-lactone 6 (11.82 g, 89%)
as a white solid; m.p. 136–137 ЊC (ethyl acetate) [Lit.,60 m.p.
138–139 ЊC]; [α]2D1 ϩ58.5 (c, 1.00 in H2O) {Lit.,60 [α]2D0 ϩ59.0
(c, 1.20 in H2O)}; δH (CD3CN; D2O shake): 1.33, 1.39 (6H,
2 × s, C(CH3)2), 3.92 (1H, dd, J6,5 4.9, J6,6, 8.9, H-6), 4.09 (1H,
dd, J6Ј,5 6.1, H-6Ј), 4.33–4.39 (3H, m, H-3, H-4, H-5), 4.47 (1H,
d, J2,3 4.3, H-2).
᎐
H
shake): 3.64 (1H, dd, J6,5 3.7, J6,6Ј 11.9, H-6), 3.70 (1H, dd, J6Ј,5
3.4, H-6Ј), 3.71 (3H, s, CO2CH3), 3.87 (1H, a–dd, H-5), 4.02
(1H, a–t, H-4), 4.12 (1H, dd, J3,2 4.2, J3,4 1.7, H-3), 4.60 (1H, d,
H-2); δC (CD3CN): 54.0 (q, CO2CH3), 61.9 (t, C-6), 78.0, 78.8,
82.6, 88.3 (4 × d, C-2, C-3, C-4, C-5), 174.4 (s, C᎐O); m/z (CI;
᎐
ϩ
NH3): 210 (M ϩ NH4 , 100), 193 (M ϩ Hϩ, 60%).
Method (ii). A solution of methyl 2,5-anhydro-3-O-benzyl--
gluconate 27 (see below) (180 mg, 0.64 mmol) in methanol
(10 mL) was stirred under an atmosphere of hydrogen in the
presence of 10% palladium on activated carbon (10 mg). After
10 h, TLC (ethyl acetate) indicated complete conversion of the
starting material (Rf 0.3) to a single product (Rf 0.0; Rf 0.2,
chloroform–methanol, 37 : 3). The reaction mixture was filtered
through Celite (eluted with MeOH) and the solvent was
5,6-O-Isopropylidene-2-O-trifluoromethylsulfonyl-D-mannono-
1,4-lactone 7
Trifluoromethanesulfonic anhydride (426 µL, 2.53 mmol)
was added to a stirred solution of 5,6-O-isopropylidene--
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1987

View Article Online
removed in vacuo. The residue was purified by flash chromato-
graphy (chloroform–methanol, 37 : 3) to yield methyl 2,5-
anhydro--gluconate 8 (84 mg, 69%). Data identical to those of
product formed by method (i).
Sodium hydrogen carbonate (5 g, excess) was added and the
reaction mixture was stirred for 1 h and then filtered through
Celite. The solvent was removed in vacuo and the residue was
purified by flash chromatography (ethyl acetate) to yield methyl
2,5-anhydro--mannonate 15 (5.0 g, 100%) as a colourless oil;
(HRMS ϩ Hϩ: 193.070494. C7H13O6 requires m/z, 193.071213);
[α]2D3 ϩ47.2 (c, 1.00 in MeOH); νmax (thin film): 3402 (OH), 1742
(C᎐O, ester) cmϪ1; δ (D2O): 3.69 (1H, dd, J6,5 5.0, J6,6Ј 12.3,
Methyl 3,4:5,6-di-O-isopropylidene-D-gluconate 13
Toluene-p-sulfonic acid monohydrate (150 mg, catalytic)
was added to a stirred suspension of -glucono-1,5-lactone 10
(10.0 g, 56.0 mmol) in a mixture of 2,2-dimethoxypropane
(20 mL), acetone (6 mL) and methanol (2 mL). The reaction
mixture was stirred at room temperature for 50 h, under an
atmosphere of nitrogen. TLC (ethyl acetate–methanol 10%)
indicated complete conversion of the starting material (Rf 0.2)
to a major product (Rf 0.9). Sodium hydrogen carbonate (1 g,
excess) was added and the reaction mixture was stirred for
1 h and then filtered through Celite. The solvent was removed
in vacuo and the residue was dissolved in dichloromethane
(50 mL) and washed with water (10 mL). The aqueous phase
was extracted with dichloromethane (40 mL) and the combined
organic extracts were dried (MgSO4), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography
(ethyl acetate–hexane 1 : 3) to yield methyl 3,4:5,6-di-O-
isopropylidene--gluconate 13 (12.9 g, 79%) as a colourless oil;
[α]2D1 Ϫ2.3 (c, 1.00 in CHCl3) [Lit.,44,45 [α]2D0 ϩ10.3 (c, 1.00 in
CHCl3) after distillation, Ϫ1.7 (c, 1.18 in CHCl3) after silica
gel column]; δH (CDCl3): 1.34, 1.35, 1.38, 1.42 (12H, 4 × s,
2 × C(CH3)2), 3.05 (1H, a–dd, OH), 3.83 (3H, s, CO2CH3), 3.98
(1H, dd, J6,5 3.9, J6,6Ј 8.4, H-6), 4.05 (1H, m, H-4), 4.09 (1H, m,
H-5), 4.14 (1H, dd, J6Ј,5 5.8, H-6Ј), 4.22 (1H, a–dd, H-3), 4.34
(1H, dd, J2,OH 9.1, J2,3 1.3, H-2); δC (CDCl3): 25.2, 26.4, 26.6,
27.1 (4 × q, 2 × C(CH3)2), 52.6 (q, CO2CH3), 67.8 (t, C-6), 69.4,
76.4, 77.2, 80.8 (4 × d, C-2, C-3, C-4, C-5), 109.8, 110.0 (2 × s, 2
᎐
H
H-6), 3.76 (1H, m, H-6Ј), 3.77 (3H, s, CO2CH3), 4.04–4.07 (2H,
m, H-4, H-5), 4.35 (1H, at, H-3), 4.51 (1H, d, J2,3 4.0, H-2);
δC (D2O; 50.3 MHz): 53.6 (q, CO2CH3), 61.7 (t, C-6), 76.9, 80.2,
82.2, 85.8 (4 × d, C-2, C-3, C-4, C-5), 173.9 (s, C᎐O); m/z
᎐
(APCIϩve): 193 (M ϩ Hϩ, 100%).
Method (ii). A solution of methyl 2,5-anhydro-3-O-benzyl--
mannonate 20 (see below) (133 mg, 0.47 mmol) in methanol
(10 mL) was stirred under an atmosphere of hydrogen in the
presence of 10% palladium on activated carbon (10 mg). After
17 h, TLC (ethyl acetate) indicated complete conversion of the
starting material (Rf 0.3) to a single product (Rf 0.1; Rf 0.3, ethyl
acetate–methanol, 9 : 1). The reaction mixture was filtered
through Celite (eluted with MeOH) and the solvent was
removed in vacuo. The residue was purified by flash chromato-
graphy (ethyl acetate–methanol, 9 : 1) to yield methyl 2,5-
anhydro--mannonate 15 (81 mg, 89%). Data identical to those
of product formed by method (i).
3-O-Benzyl-D-glucono-1,4-lactone 17
Bromine (1.14 mL, 22.37 mmol) was slowly added to a stirred
solution of 3-O-benzyl--glucopyranose 16 (5.00 g, 18.60
mmol) and barium carbonate (5.52 g, 27.97 mmol) in water (50
mL) at 0 ЊC in the dark. The reaction mixture was allowed to
warm to room temperature and was stirred for 4 h. TLC (ethyl
acetate–methanol, 9 : 1) indicated complete conversion of the
starting material (Rf 0.3) to a single product (Rf 0.5). The reac-
tion mixture was filtered through Celite (eluted with water and
ethyl acetate), and air was bubbled through the filtrate until the
excess of bromine was removed. The solvent was removed in
vacuo to give a white slurry. Ethyl acetate (100 mL) was added
to the slurry and the mixture was refluxed for 30 min. The
solution was decanted and this extraction procedure was
repeated a further three times. The combined organic extracts
were filtered, the solvent was removed in vacuo, and the residue
was purified by flash chromatography (ethyl acetate–hexane, 7 :
3) to yield 3-O-benzyl--glucono-1,4-lactone 17 (3.93 g, 79%)
(Found: C, 57.97; H, 6.33. C13H16O6 requires C, 58.20; H,
6.01%); [α]2D0 ϩ34.4 (c, 1.15 in CH3OH); νmax (thin film): 3401
× C(CH ) ), 172.9 (s, C᎐O).
᎐
3
2
Methyl 3,4:5,6-di-O-isopropylidene-2-O-trifluoromethylsulfonyl-
D-gluconate 14
Trifluoromethanesulfonic anhydride (8.60 mL, 51.1 mmol) was
added to a stirred solution of methyl 3,4:5,6-di-O-isopropyl-
idene--gluconate 13 (11.4 g, 39.3 mmol) in dichloromethane
(100 mL) containing dry pyridine (9.54 mL, 0.12 mol)
at Ϫ10 ЊC, under an atmosphere of nitrogen. The reaction mix-
ture was stirred at Ϫ10 ЊC for 15 min. TLC (ethyl acetate–
hexane 1 : 3) indicated complete conversion of the starting
material (Rf 0.3) to a major product (Rf 0.5). The reaction mix-
ture was diluted with dichloromethane (100 mL) and washed
successively with 2M hydrochloric acid (50 mL) and pH 7
buffer (50 mL). The organic phase was dried (MgSO4), filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (ethyl acetate–hexane 1 : 4) to yield methyl
3,4:5,6-di-O-isopropylidene-2-O-trifluoromethylsulfonyl--
gluconate 14 (14.7 g, 89%) as a white solid; m.p. 67–68 ЊC (ethyl
acetate–hexane) [Lit.,46 m.p. 66–67 ЊC]; [α]2D2 ϩ49.8 (c, 1.00 in
CHCl3) {Lit..44,45 [α]2D0 ϩ44.2 (c, 1.10 in CHCl3)}; δH (CDCl3):
1.36, 1.40, 1.41 (12H, 3 × s, 2 × C(CH3)2), 3.87 (1H, dd, J4,3 7.5,
J4,5 8.4, H-4), 3.91 (1H, dd, J6,5 5.8, J6,6Ј 8.8, H-6), 3.91 (3H, s,
CO2CH3), 4.07 (1H, m, H-5), 4.22 (1H, dd, J6Ј,5 6.3, H-6Ј), 4.55
(1H, dd, J3,2 1.9, H-3), 5.33 (1H, d, H-2); δC (CDCl3): 25.0, 26.0,
27.2 (3 × q, 2 × C(CH3)2), 53.5 (q, CO2CH3), 68.1 (t, C-6),
76.9, 79.2, 80.4 (3 × d, C-2, C-3, C-4, C-5), 110.1, 111.4 (2 × s,
(br, OH), 1780 (C᎐O) cmϪ1; δ (CD OD): 3.69 (1H, dd, J6,5 5.9,
᎐
H
3
J6,6Ј 11.5, H-6), 3.77 (1H, dd, J6Ј,5 3.9, H-6Ј), 4.00 (1H, m, H-5),
4.27 (1H, dd, J3,2 4.8, J3,4 5.7, H-3), 4.49 (1H, d, H-2), 4.64 (1H,
a–t, H-4), 4.69–4.76 (2H, AB-q, J 11.6, CH2Ar), 7.27–7.51 (5H,
m, Ar); δC (CD3OD; 50.3 MHz): 62.9 (t, C-6), 70.4, 71.6, 79.1,
80.8 (4 × d, C-2, C-3, C-4, C-5), 72.3 (t, CH2Ar), 127.7, 128.1,
128.3 (3 × d, Ar), 137.8 (s, Ar), 175.8 (s, C᎐O); m/z (DCI; NH ):
᎐
3
ϩ
286 (M ϩ NH4 , 100), 269 (M ϩ Hϩ, 20%).
3-O-Benzyl-5,6-O-isopropylidene-D-glucono-1,4-lactone 18
2 × C(CH ) ), 118.3 (q, J 19.7, SO CF ), 165.4 (s, C᎐O).
᎐
3
2
2
3
-Camphor-iso-sulfonic acid (CSA) was added to a stirred
solution of 3-O-benzyl--glucono-1,4-lactone 17 (3.93 g,
14.60 mmol) in acetone (100 mL) until the solution reached pH
2. The reacion mixture was stirred at room temperature for
17 h, under an atmosphere of nitrogen. TLC (ethyl acetate–
methanol, 9 : 1) indicated complete conversion of the starting
material (Rf 0.5) to a major product (Rf 0.8). Sodium hydrogen
carbonate (500 mg, excess) was added and the reaction mixture
was stirred for 1 h and then filtered through Celite. The solvent
Methyl 2,5-anhydro-D-mannonate 15
Method (i). Methyl 3,4:5,6-di-O-isopropylidene-2-O-tri-
fluoromethylsulfonyl--gluconate 14 (11.0 g, 26.1 mmol) was
stirred in a 1% v/v solution of hydrogen chloride in methanol
(40 mL), at room temperature, under an atmosphere of nitro-
gen. After 15 h, TLC (ethyl acetate) indicated complete conver-
sion of the starting material (Rf 0.9) to a major product (Rf 0.1).
1988
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998

View Article Online
was removed in vacuo and the residue was dissolved in ethyl
acetate (70 mL) and washed successively with water (15 mL)
and brine (10 mL). The organic phase was dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (ethyl acetate–hexane, 1 : 2) to yield
4.63–4.79 (2H, AB-q, J 11.7, CH2Ar), 4.64 (1H, d, J2,3 2.2, H-2),
7.27–7.51 (5H, m, Ar); δC (CDCl3; 50.3 M): 52.5 (q, CO2CH3),
62.0 (t, C-6), 72.1 (t, CH2Ar), 76.1, 80.9, 86.4, 87.9 (4 × d, C-2,
C-3, C-4, C-5), 128.1, 128.2, 128.7 (3 × d, Ar), 137.3 (s, Ar),
ϩ
172.5 (s, C᎐O); m/z (DCI; NH ): 300 (M ϩ NH , 40), 283 (M
᎐
3
4
3-O-benzyl-5,6-O-isopropylidene--glucono-1,4-lactone
18
ϩ Hϩ, 10%).
(3.62 g, 80%) as an oil (Found: C, 62.44; H, 6.36. C16H20O6
requires C, 62.33; H, 6.54%); [α]2D0 ϩ54.7 (c, 1.00 in CHCl3);
νmax (thin film): 3401 (br, OH), 1789 (C᎐O) cmϪ1; δ (CDCl3;
Methyl 2,5-anhydro-3-O-benzyl-6-O-p-tolylsulfonyl-D-
mannonate 21
᎐
H
500 MHz): 1.39, 1.45 (6H, 2 × s, 2 × C(CH3)2), 3.97 (1H, dd, J6,5
6.2, J6,6Ј 8.7, H-6), 4.12 (1H, dd, J6Ј,5 6.4, H-6Ј), 4.28 (1H, dd, J3,2
4.2, J3,4 5.7, H-3), 4.42 (1H, b–d, H-2), 4.46 (1H, m, H-5), 4.71
(1H, dd, J4,5 6.3, H-4), 4.69–4.71 (2H, AB-q, J 11.6, CH2Ar),
7.31–7.38 (5H, m, Ar); δC (CDCl3; 50.3 M): 25.3, 26.5 (2 × q,
C(CH3)2), 66.1 (t, C-6), 71.9, 73.0, 79.6, 80.6 (4 × d, C-2, C-3,
C-4, C-5), 72.6 (t, CH2Ar), 109.9 (s, C(CH3)2), 128.0, 128.3,
128.7 (3 × d, Ar), 137.2 (s, Ar), 175.4 (s, Ar); m/z (CI; NH3): 326
Toluene-p-sulfonyl chloride (85 mg, 0.45 mmol) was added to a
stirred solution of methyl 2,5-anhydro-3-O-benzyl--mannon-
ate 20 (105 mg, 0.37 mmol) in dichloromethane (2 mL) contain-
ing and dry pyridine (0.09 mL, 1.11 mmol) at 0 ЊC. The reaction
mixture was allowed to warm to room temperature and was
stirred for 22 h, under an atmosphere of nitrogen. TLC (ethyl
acetate) indicated partial conversion of the starting material
(Rf 0.3) to a single product (Rf 0.65). The reaction mixture was
acidified with 2M hydrochloric acid, diluted with ethyl acetate
(40 mL), and washed successively with water (10 mL) and brine
(10 mL). The organic phase was dried (MgSO4), filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (ethyl acetate–hexane, 1 : 1), to yield recovered
methyl 2,5-anhydro-3-O-benzyl--mannonate 20 (27 mg,
26%), and methyl 2,5-anhydro-3-O-benzyl-6-O-p-tolylsulfonyl-
-mannonate 21 (98 mg, 60%) as a white crystalline solid
(Found: C, 57.88; H, 5.59. C21H24O8S requires C, 57.79; H,
5.54%); m.p. 103–106 ЊC (diethyl ether–hexane); [α]2D0 ϩ49.2 (c,
ϩ
(M ϩ NH4 , 45), 309 (M ϩ Hϩ, 55%).
3-O-Benzyl-5,6-O-isopropylidene-2-O-trifluoromethylsulfonyl-D-
glucono-1,4-lactone 19
Trifluoromethanesulfonic anhydride (1.94 mL, 11.48 mmol)
was added to a stirred solution of 3-O-benzyl-5,6-O-isopropyl-
idene--glucono-1,4-lactone 18 (2.36 g, 7.65 mmol) in dichloro-
methane (15 mL) containing and dry pyridine (1.81 mL, 23.00
mmol) at Ϫ40 ЊC, under an atmosphere of nitrogen. The reac-
tion mixture was stirred at Ϫ40 ЊC for 2 h. TLC (ethyl acetate–
hexane, 1 : 1) indicated complete conversion of the starting
material (Rf 0.5) to a major product (Rf 0.6). The reaction mix-
ture was diluted with diethyl ether (40 mL) and washed succes-
sively with water (5 mL) and 2M hydrochloric acid (11.5 mL).
The aqueous phase was extracted with diethyl ether (40 mL)
and the combined organic extracts washed with brine (10 mL),
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (ethyl acetate–hexane,
1 : 4) to yield 3-O-benzyl-5,6-O-isopropylidene-2-O-trifluoro-
methylsulfonyl--glucono-1,4-lactone 19 (2.88 g, 86%), as an
unstable oil (Found: C, 46.17; H, 4.62. C17H19SO8F3 requires C,
46.37; H, 4.35%); [α]2D0 ϩ9.2 (c, 1.15 in CHCl3); νmax (thin film):
1810 (C᎐O), 1375, 1142 (S᎐O) cmϪ1; δ (CDCl ): 1.39, 1.46 (6H,
1.00 in CHCl3); νmax (thin film): 1741 (C᎐O) 1361, 1177 (S᎐O)
᎐
᎐
cmϪ1; δH (CDCl3): 2.44 (3H, s, ArCH3), 3.77 (3H, s, CO2CH3),
4.14 (1H, a–t, H-3), 4.17 (2H, a–d, H2-6), 4.24 (1H, m, H-4),
4.30 (1H, dt, J4,5 3.4, J5,6 = J5,6Ј = 5.9, H-5), 4.54 (1H, d, J2,3 2.2,
H-2), 4.57–4.63 (2H, AB-q, J 11.8, CH2Ar), 7.30–7.39 (7H, m,
Ar), 7.78–7.79 (2H, m, Ar); δC (CDCl3; 50.3 MHz): 21.5 (q,
ArCH3), 52.6 (q, CO2CH3), 68.4 (t, C-6), 72.1 (t, CH2Ar), 76.1,
81.4, 83.7, 87.5 (4 × d, C-2, C-3, C-4, C-5), 127.9, 128.2, 128.7,
130.1 (4 × d, Ar), 137.2, 132.7, 145.3 (3 × s, Ar), 172.1 (s, C᎐O);
᎐
ϩ
m/z (CI; NH3): 454 (M ϩ NH4 , 35%).
Methyl 2,5-anhydro-3-O-benzyl-6-deoxy-6-iodo-D-mannonate 22
᎐
᎐
H
3
Sodium iodide (119 mg, 0.80 mmol) was added to a
stirred solution of methyl 2,5-anhydro-3-O-benzyl-6-O-p-
tolylsulfonyl--mannonate 21 (69 mg, 0.16 mmol) in butanone
(3 mL). The reaction mixture was stirred for 7 h at reflux, under
an atmosphere of nitrogen. TLC (diethyl ether) indicated con-
version of the starting material (Rf 0.4) to a single product (Rf
0.6). The solvent was removed in vacuo and the residue was
dissolved in diethyl ether (40 mL) and washed successively with
water (20 mL) and brine (10 mL). The organic phase was dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (diethyl ether–hexane, 3 : 2)
to yield recovered methyl 2,5-anhydro-3-O-benzyl-6-O-p-
tolylsulfonyl--mannonate 21 (5 mg, 7%), and methyl 2,5-
anhydro-3-O-benzyl-6-deoxy-6-iodo--mannonate 22 (48 mg,
77%) as an oil (Found: C, 42.89; H, 4.23. C14H17O5I requires C,
42.88; H, 4.37%); [α]2D0 ϩ14.8 (c, 0.9 in CHCl3); νmax (thin film):
2 × s, C(CH3)2), 4.03 (1H, dd, J6,5 5.6, J6,6Ј 8.8, H-6), 4.14 (1H,
dd, J6Ј,5 6.6, H-6Ј), 4.44–4.48 (2H, m, H-3, H-5), 4.61 (1H, dd,
J4,3 5.2, J4,5 6.8, H-4), 4.70–4.75 (2H, AB-q, J 11.6, CH2Ar),
5.31 (1H, d, J2,3 3.7, H-2), 7.34–7.41 (5H, m, Ar); δC (CDCl3;
50.3 MHz): 25.1, 26.5 (2 × q, C(CH3)2), 66.2 (t, C-6), 72.6, 76.9,
80.2, 80.5 (4 × d, C-2, C-3, C-4, C-5), 73.3 (t, CH2Ar), 110.5
(s, C(CH3)2), 128.4, 128.7, 128.9 (3 × d, Ar), 135.9 (s, Ar), 166.5
ϩ
(s, C᎐O); m/z (CI; NH ): 458 (M ϩ NH , 10), 441 (M ϩ Hϩ,
᎐
3
4
5%).
Methyl 2,5-anhydro-3-O-benzyl-D-mannonate 20
3-O-Benzyl-5,6-O-isopropylidene-2-O-trifluoromethylsulfonyl-
-glucono-1,4-lactone 19 (2.52 g, 0.57 mmol) was stirred in a
1% v/v solution of hydrogen chloride in methanol (8 mL), at
room temperature, under an atmosphere of nitrogen. After 2 h,
TLC (ethyl acetate–hexane, 1 : 1) indicated complete conversion
of the starting material (Rf 0.6) to a major product (Rf 0.05), (Rf
0.3 in ethyl acetate). The reaction mixture was diluted with ethyl
acetate (40 mL) and washed successively with water (10 mL)
and brine (10 mL). The organic phase was dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography (ethyl acetate–hexane, 4 : 1) to yield
methyl 2,5-anhydro-3-O-benzyl--mannonate 20 (1.16 g, 98%),
as a white solid (Found C, 59.39; H, 6.12. C14H18O6 requires C,
59.57; H, 6.43%); m.p. 79–85 ЊC (diethyl ether–hexane); [α]2D0
3463 (br, OH), 1741 (C᎐O) cmϪ1; δ (CDCl ): 3.33 (1H, dd, J
᎐
H
3
6,5
5.7, J6,6Ј 10.1, H-6), 3.38 (1H, dd, J6Ј,5 8.2, H-6Ј), 3.79 (3H, s,
CO2CH3), 4.19 (1H, a–t, H-3), 4.29–4.33 (2H, m, H-4, H-5),
4.62–4.69 (2H, AB-q, J 11.8, CH2Ar), 4.71 (1H, d, J2,3 2.1, H-2),
7.32–7.40 (5H, m, Ar); δC (CDCl3; 50.3 MHz): 5.1 (t, C-6), 52.7
(q, CO2CH3), 72.3 (t, CH2Ar), 78.9, 81.9, 86.7, 87.8, (4 × d,
C-2, C-3, C-4, C-5), 128.1, 128.4, 128.8 (3 × d, Ar), 137.2 (s,
ϩ
Ar), 172.3 (s, C᎐O); m/z (CI; NH ): 410 (M ϩ NH , 40), 393
᎐
3
4
(M ϩ Hϩ, 10%).
ϩ56.0 (c, 1.0 in CHCl3); νmax (thin film): 1741 (C᎐O) cmϪ1;
᎐
Methyl 2,5-anhydro-3-O-benzyl-6-deoxy-D-mannonate 23
δH (CDCl3): 3.77 (1H, dd, J6,5 5.0, J6,6Ј 11.8, H-6), 3.79 (3H, s,
CO2CH3), 3.84 (1H, dd, J6,5 3.6, J6,6Ј 11.9, H-6), 4.19 (1H, a–t,
H-3), 4.23 (1H, a–q, H-5), 4.28 (1H, dd, J4,3 2.3, J4,5 3.8, H-4),
Sodium acetate (64 mg, 0.79 mmol) was added to a solution of
methyl 2,5-anhydro-3-O-benzyl-6-deoxy-6-iodo--mannonate
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1989

View Article Online
22 (77 mg, 0.20 mmol) in methanol (4 mL) and the mixture was
stirred under an atmosphere of hydrogen in the presence of
10% palladium on activated carbon (5 mg). After 6 h, TLC
(diethyl ether) indicated complete conversion of the starting
material (Rf 0.6) to a single product (Rf 0.5). The reaction mix-
ture was filtered through Celite (eluted with MeOH) and the
solvent was removed in vacuo. The residue was dissolved in
ethyl acetate (40 mL), acidified with 2M hydrochloric acid and
washed successively with water (20 mL) and brine (10 mL). The
organic phase was dried (MgSO4), filtered, and concentrated
in vacuo. The residue was purified through a silica plug
(chloroform) to yield methyl 2,5-anhydro-3-O-benzyl-6-deoxy-
-mannonate 23 (51 mg, 98%) as an oil (Found: C, 62.95; H,
6.74. C14H18O5 requires C, 63.15; H, 6.81%); [α]2D0 ϩ37.1 (c, 1.5
3-O-Benzyl-5,6-O-isopropylidene-2-O-trifluoromethylsulfonyl-D-
mannono-1,4-lactone 26
Trifluoromethanesulfonic anhydride (0.16 mL, 0.96 mmol) was
added to a stirred solution 3-O-benzyl-5,6-O-isopropylidene--
mannono-1,4-lactone 25 (228 mg, 0.74 mmol) in dichloro-
methane (3 mL) containing dry pyridine (0.18 mL, 2.22 mmol)
at Ϫ40 ЊC, under an atmosphere of nitrogen. The reaction mix-
ture was stirred at Ϫ40 ЊC for 2 h. TLC (ethyl acetate–hexane,
1 : 1) indicated complete conversion of the starting material (Rf
0.4) to a major product (Rf 0.7). The reaction mixture was
diluted with diethyl ether (40 mL) and washed successively with
water (5 mL) and 2M hydrochloric acid (1 mL). The aqueous
phase was extracted with diethyl ether (40 mL) and the com-
bined organic extracts washed with brine (10 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (ethyl acetate–hexane, 1 : 5)
to yield 3-O-benzyl-5,6-O-isopropylidene-2-O-trifluoromethyl-
sulfonyl--mannono-1,4-lactone 26 (282 mg, 87%) as an
unstable oil (Found: C, 46.43; H, 4.44. C17H19SO8F3 requires C,
in CHCl3); νmax (thin film): 3435 (OH), 1739 (C᎐O) cmϪ1;
᎐
δH (CDCl3; 200 MHz): 1.36 (3H, d, J6,5 6.5, CH3), 3.78 (3H, s,
CO2CH3), 3.94 (1H, dd, J4,3 3.0, J4,5 4.6, H-4), 4.14 (1H, a–t,
H-3), 4.18 (1H, m, H-5), 4.61–4.72 (2H, AB-q, J 11.8, CH2Ar),
4.60 (1H, d, J2,3 2.7, H-2), 7.34–7.38 (5H, m, Ar); δC (CHCl3;
50.3 MHz): 18.5 (q, C-6), 52.9 (q, CO2CH3), 72.4 (t, CH2Ar),
80.9, 81.3, 82.1, 88.8 (4 × d, C-2, C-3, C-4, C-5), 128.1, 128.2,
46.37; H, 4.35%); νmax (thin film): 1811 (C᎐O), 1375, 1142 (S᎐O)
᎐
᎐
cmϪ1; δH (CDCl3; 200 MHz): 1.40, 1.46 (6H, 2 × s, C(CH3)2),
4.05 (1H, dd, J6,5 4.0, J6,6Ј 9.2, H-6), 4.14 (1H, dd, J6Ј,5 5.9, H-6Ј),
4.21 (1H, dd, J4,3 2.9, J4,5 8.6, H-4), 4.42 (1H, m, H-5), 4.55 (1H,
dd, J3,2 4.7, H-3), 4.67–4.92 (2H, m, CH2Ar), 5.36 (1H, d, H-2),
7.27–7.56 (5H, m, Ar); δC (CDCl3; 50.3 MHz): 24.9, 26.8 (2 × q,
C(CH3)2), 66.5 (t, C-6), 71.5, 74.9, 78.8, 79.8 (4 × d, C-2, C-3,
C-4, C-5), 74.8 (t, CH2Ar), 110.2 (s, C(CH3)2), 128.6, 128.7,
128.8 (3 × d, Ar), 137.6 (s, Ar), 172.9 (s, C᎐O); m/z (CI; NH ):
᎐
3
ϩ
284 (M ϩ NH4 , 60), 267 (M ϩ Hϩ, 20%).
Methyl 2,5-anhydro-6-deoxy-D-mannonate 24
A
solution of methyl 2,5-anhydro-3-O-benzyl-6-deoxy--
mannonate 23 (46 mg, 0.17 mmol) and acetic acid (4 drops) in
methanol (4 mL) was stirred under an atmosphere of hydrogen
in the presence of palladium-black (10 mg). After 6 h, TLC
(diethyl ether) indicated complete conversion of the starting
material (Rf 0.5) to a single product (Rf 0.1). The reaction mix-
ture was filtered through Celite (eluted with MeOH) and the
solvent was removed in vacuo to yield methyl 2,5-anhydro-6-
deoxy--mannonate 24 (27 mg, 89%) as an oil; [α]2D0 ϩ41.2 (c,
129.0 (3 × d, Ar), 136.3 (s, Ar), 167.1 (s, C᎐O); m/z (CI; NH ):
᎐
3
458 (M ϩ NH4 , 55), 441 (M ϩ Hϩ, 5%).
ϩ
Methyl 2,5-anhydro-3-O-benzyl-D-gluconate 27
3-O-Benzyl-5,6-O-isopropylidene-2-O-trifluoromethylsulfonyl-
-mannono-1,4-lactone 26 (282 mg, 0.64 mmol) was stirred in a
1% v/v solution of hydrogen chloride in methanol (8 mL), at
room temperature, under an atmosphere of nitrogen. After 6 h,
TLC (ethyl acetate–hexane, 1 : 1) indicated complete conversion
of the starting material (Rf 0.6) to a single product (Rf 0.05; Rf
0.6 in ethyl acetate). The reaction mixture was diluted with ethyl
acetate (40 mL) and washed successively with water (10 mL)
and brine (10 mL). The organic phase was dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (ethyl acetate–hexane, 4 : 1) to yield
methyl 2,5-anhydro-3-O-benzyl--gluconate 27 (180 mg, quant)
as an oil (Found: C, 59.50; H, 6.25. C14H18O6 requires C, 59.57;
H, 6.43%); [α]2D5 Ϫ48.3 (c, 1.15 in CHCl3); νmax (thin film): 1743
(C᎐O) cmϪ1; δ (CDCl3): 3.75 (3H, s, CO2CH3), 3.78 (1H, m,
0.95 in CH3OH); νmax (thin film): 3401 (br, OH), 1738 (C᎐O)
᎐
cmϪ1; δH (CD3OD; 500 MHz): 0.86 (3H, d, J6,5 6.4, CH3) 3.20
(1H, dd, J4,3 4.1, J4,5 5.9, H-4), 3.30 (3H, s, CO2CH3), 3.54 (1H,
m, H-5), 3.77 (1H, a–t, H-3), 3.87 (1H, d, J2,3 3.9, H-2);
δC (CD3OD; 50.3 MHz): 17.4 (q, C-6), 51.1 (q, CO2CH3), 80.7,
81.0, 82.0, 82.1 (4 × d, C-2, C-3, C-4, C-5), 172.8 (s, C᎐O); m/z
᎐
(DCI; NH3): 194 (M ϩ NH4 , 100), 177 (M ϩ Hϩ, 35%).
ϩ
3-O-Benzyl-5,6-O-isopropylidene-D-mannono-1,4-lactone 25
Sodium trifluoroacetate (2.39 g, 17.50 mmol) was added to
a stirred solution of 3-O-benzyl-5,6-O-isopropylidene-2-O-tri-
fluoromethylsulfonyl--glucono-1,4-lactone 19 (772 mg, 1.75
mmol) in dimethylformamide (5 mL). The reaction mixture was
stirred for 17 h at room temperature, under an atmosphere of
nitrogen. TLC (ethyl acetate–hexane, 1 : 1) indicated complete
conversion of the starting material (Rf 0.7) to a single product
(Rf 0.4). The solvent was removed in vacuo and the residue was
dissolved in ethyl acetate (70 mL), filtered, and washed succes-
sively with water (30 mL) and brine (10 mL). The organic phase
was dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (ethyl acetate–
hexane, 1 : 2) to yield 3-O-benzyl-5,6-O-isopropylidene--
mannono-1,4-lactone 25 (503 mg, 93%) as a white solid
(Found: C, 62.49; H, 6.62. C16H20O6 requires C, 62.33; H,
6.54%); m.p. 68–70 ЊC (diethyl ether–hexane); [α]2D5 ϩ7.3 (c,
᎐
H
H-6), 3.88 (1H, dd, J6Ј,5 3.1, J6Ј,6 12.2, H-6Ј), 3.99 (1H, ddd, J5,4
5.9, J5,6 5.9, H-5), 4.28 (1H, dd, J3,2 6.8, J3,4 5.1, H-3), 4.45 (1H,
a–t, H-4), 4.64–4.79 (2H, AB-q, J 11.7, CH2Ar), 4.78 (1H, d,
H-2), 7.29–7.49 (5H, m, Ar); δC (CDCl3; 50.3 MHz): 52.3 (q,
CO2CH3), 61.5 (t, C-6), 72.4 (t, CH2Ar), 74.0, 78.9, 85.2, 86.0
(4 × d, C-2, C-3, C-4, C-5), 127.8, 128.1, 128.6 (3 × d, Ar), 137.5
ϩ
(s, Ar), 171.9 (s, C᎐O); m/z (CI; NH ): 300 (M ϩ NH , 100),
᎐
3
4
283 (M ϩ Hϩ, 25%).
Methyl 2,5-anhydro-3-O-benzyl-6-O-p-tolylsulfonyl-D-gluconate
28
Toluene-p-sulfonyl chloride (139 mg, 0.73 mmol) was added to
a stirred solution of methyl 2,5-anhydro-3-O-benzyl--glucon-
ate 27 (175 mg, 0.61 mmol) in dichloromethane (2 mL) contain-
ing dry pyridine (0.15 mL, 1.28 mmol) at 0 ЊC. The reaction
mixture was allowed to warm to room temperature and was
stirred for 22 h, under an atmosphere of nitrogen. TLC (ethyl
acetate) indicated partial conversion of the starting material
(Rf 0.3) to a single product (Rf 0.65). The reaction mixture was
acidified with 2M hydrochloric acid, diluted with ethyl acetate
(40 mL), and washed successively with water (10 mL) and brine
(10 mL). The organic phase was dried (MgSO4), filtered, and
1.0 in CHCl3); νmax (thin film): 3436 (br, OH), 1790 (C᎐O) cmϪ1;
᎐
δH (CDCl3; 500 MHz): 1.40, 1.46 (6H, 2 × s, C(CH3)2), 4.05 (1H,
dd, J6,5 4.6, J6,6Ј 9.1, H-6), 4.18 (1H, dd, J6Ј,5 6.0, H-6Ј), 4.27 (1H,
dd, J4,3 2.9, J4,5 8.3, H-4), 4.36 (1H, dd, J3,2 4.9, H-3), 4.42 (1H,
ddd, H-5), 4.46 (1H, d, H-2), 4.78–4.89 (2H, AB-q, J 11.3,
CH2Ar), 7.33–7.51 (5H, m, Ar); δC (CDCl3; 50.3 MHz): 25.1,
26.8 (2 × q, C(CH3)2), 66.8 (t, C-6), 70.8, 72.0, 76.1, 79.6 (4 × d,
C-2, C-3, C-4, C-5), 74.5 (t, CH2Ar), 109.9 (s, C(CH3)2), 128.4,
128.8, 129.9, 131.8 (3 × d, Ar), 137.3 (s, Ar), 175.3 (s, C᎐O); m/z
᎐
ϩ
(CI; NH3): 326 (M ϩ NH4 , 100), 309 (M ϩ Hϩ, 55%).
1990
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998

View Article Online
concentrated in vacuo. The residue was purified by flash chro-
matography (ethyl acetate–hexane, 1 : 1), to yield recovered
methyl 2,5-anhydro-3-O-benzyl--gluconate 27 (12 mg,
7%), and methyl 2,5-anhydro-3-O-benzyl-6-O-p-tolylsulfonyl-
-gluconate 28 (185 mg, 70%) as an oil (Found: C, 58.03; H,
5.33. C21H24O8S requires C, 57.79; H, 5.54%); [α]2D0 ϩ34.3 (c, 1.2
in CHCl3); νmax (thin film): 1746 (C᎐O) 1361, 1177 (S᎐O) cmϪ1;
C-5), 127.8, 128.1, 128.6 (3 × d, Ar), 137.8 (s, Ar), 170.5 (s,
ϩ
C᎐O); m/z (CI; NH ): 284 (M ϩ NH , 100), 267 (M ϩ Hϩ,
᎐
3
4
25%).
Methyl 2,5-anhydro-6-deoxy-D-gluconate 31
solution of methyl 2,5-anhydro-3-O-benzyl-6-deoxy--
A
᎐
᎐
gluconate 30 (81 mg, 0.30 mmol) and acetic acid (5 drops) in
methanol (2 mL) was stirred under an atmosphere of hydrogen
in the presence of palladium-black (10 mg). After 9 h, TLC
(diethyl ether) indicated complete conversion of the starting
material (Rf 0.5) to a single product (Rf 0.1). The reaction mix-
ture was filtered through Celite (eluted with MeOH) and the
solvent was removed in vacuo (co-evaporation with toluene).
The residue was pre-adsorbed onto silica and purified by flash
chromatography (ethyl acetate–hexane, 3 : 2) to yield methyl
2,5-anhydro-6-deoxy--gluconate 31 (52 mg, 97%) as a white
crystalline solid (Found: C, 47.53; H, 6.86. C7H12O5 requires C,
47.73; H, 6.87%); m.p. 81–82 ЊC; [α]2D5 ϩ10.5 (c, 1.00 in CH3CN)
{Lit.,33 for enantiomer m.p. 83–84 ЊC; [α]2D0 Ϫ12.4 (c, 1.00
δH (CDCl3): 2.30 (1H, b–s, OH), 2.43 (3H, s, ArCH3), 3.70 (3H,
s, CO2CH3), 4.14 (1H, m, H-5), 4.19 (1H, dd, J3,2 5.4, J3,4 2.7,
H-3), 4.20 (1H, dd, J6,5 5.5, J6,6Ј 10.2, H-6), 4.25 (1H, dd, J6Ј,5
8.0, H-6Ј), 4.38 (1H, b–s, H-4), 4.53–4.60 (2H, AB-q, J 11.8,
CH2Ar), 4.77 (1H, d, H-2), 7.24–7.37 (7H, m, Ar), 7.76–7.79
(2H, m, Ar); δC (CDCl3; 50.3 MHz): 21.5 (q, ArCH3), 52.0
(q, CO2CH3), 69.2 (t, C-6), 72.4 (t, CH2Ar), 75.0, 80.3, 83.5,
84.8 (4 × d, C-2, C-3, C-4, C-5), 127.8, 128.0, 128.1, 128.2,
128.6, 130.2 (6 × d, Ar), 132.5, 137.4, 145.3 (3 × s, Ar), 169.9 (s,
ϩ
C᎐O); m/z (DCI; NH ): 454 (M ϩ NH , 100), 437 (M ϩ Hϩ,
᎐
3
4
5%).
Methyl 2,5-anhydro-3-O-benzyl-6-deoxy-6-iodo-D-gluconate 29
in CH3CN)}; νmax (KBr): 3436 (OH), 1747 (C᎐O) cmϪ1;
᎐
Sodium iodide (225 mg, 1.50 mmol) was added to a
stirred solution of methyl 2,5-anhydro-3-O-benzyl-6-O-p-
tolylsulfonyl--gluconate 28 (131 mg, 0.30 mmol) in butanone
(3 mL). The reaction mixture was stirred for 7 h at reflux, under
an atmosphere of nitrogen. TLC (diethyl ether) indicated con-
version of the starting material (Rf 0.4) to a single product (Rf
0.6). The solvent was removed in vacuo and the residue was pre-
adsorbed onto silica and purified by flash chromatography
(diethyl ether–hexane, 1 : 1) to yield methyl 2,5-anhydro-3-O-
benzyl-6-deoxy-6-iodo--gluconate 29 (106 mg, 90%) as an oil
(Found: C, 42.99; H, 4.39. C14H17O5I requires C, 42.88; H,
4.37%); [α]2D0 Ϫ48.3 (c, 1.20 in CHCl3); νmax (thin film): 3468
(OH), 1746 (C᎐O) cmϪ1; δ (CDCl3): 1.98 (1H, d, J 4.0, OH,
D2O exchanges), 3.41 (1H, dd, J6,5 5.7, J6,6Ј 9.8, H-6), 3.47 (1H,
a–t, H-6Ј), 3.75 (3H, s, CO2CH3), 4.16 (1H, ddd, J5,4 3.1,
J5,6Ј 9.2, H-5), 4.23 (1H, dd, J3,2 5.7, J3,4 2.9, H-3), 4.40 (1H, b-q,
H-4, collapses to a–t upon D2O exchange), 4.61–4.64 (2H,
AB-q, J 11.8, CH2Ar), 4.82 (1H, d, H-2), 7.28–7.38 (5H, m, Ar);
δC (CDCl3; 50.3 MHz): 5.2 (t, C-6), 52.2 (q, CO2CH3), 72.8 (t,
CH2Ar), 77.5, 80.8, 85.1, 86.5 (4 × d, C-2, C-3, C-4, C-5), 127.9,
δH (CDCl3; 500 MHz): 1.45 (3H, d, J6,5 6.3, CH3), 2.08 (1H, d,
J 3.8, OH-4, D2O exchanges), 2.54 (1H, d, J 5.4, OH-3, D2O
exchanges), 3.38 (3H, s, CO2CH3), 3.92 (1H, m, H-5), 3.94 (1H,
dt, J4,3 2.6, H-4), 4.36 (1H, m, H-3), 4.61 (1H, d, J2,3 4.9, H-2);
δC (CD3CN; 50.3 MHz): 18.2 (q, C-6), 51.2 (q, CO2CH3),
78.9, 80.4, 81.3, 82.2 (4 × d, C-2, C-3, C-4, C-5), 170.4 (s, C᎐O);
᎐
m/z (CI; NH3): 194 (M ϩ NH4 , 100), 177 (M ϩ Hϩ, 50%).
ϩ
These properties are identical to those of a sample of the
enantiomer.51
Methyl 2,5-anhydro-3,4,6-tris-O-tert-butyldimethylsilyl-D-
gluconate 32
᎐
H
tert-Butyldimethylsilyl chloride (8.48 g, 56.3 mmol) was added
to a stirred solution of methyl 2,5-anhydro--gluconate 8
(3.00 g, 15.6 mmol) and imidazole (7.98 g, 117.2 mmol) in
DMF (25 mL). The reaction mixture was stirred at 85 ЊC for
20 h, under an atmosphere of nitrogen. TLC (ethyl acetate–
hexane 1 : 2) indicated complete conversion of the starting
material (Rf 0.0) to a single product (Rf 0.9). The solvent was
removed in vacuo (co-evaporation with toluene). The residue
was dissolved in ethyl acetate (100 mL) and washed successively
with water (40 mL) and pH 7 buffer (40 mL). The aqueous
phase was extracted with ethyl acetate (25 mL) and the
combined organic phases were dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (diethyl ether–hexane, 1 : 10) to yield methyl
2,5-anhydro-3,4,6-tris-O-tert-butyldimethylsilyl--gluconate 32
(8.10 g, 97%) as a colourless oil (Found: C, 55.96; H, 10.53.
C25H54O6Si3 requires C, 56.13; H, 10.17%); [α]2D1 ϩ13.6 (c, 1.00
128.3, 128.7 (3 × d, Ar), 137.3 (s, Ar), 170.4 (s, C᎐O); m/z (DCI;
᎐
ϩ
NH3): 410 (M ϩ NH4 , 70), 393 (M ϩ Hϩ, 15%).
Methyl 2,5-anhydro-3-O-benzyl-6-deoxy-D-gluconate 30
Sodium acetate (89 mg, 1.08 mmol) was added to a solution of
methyl 2,5-anhydro-3-O-benzyl-6-deoxy-6-iodo--gluconate 29
(106 mg, 0.27 mmol) in methanol (4 mL) and the mixture was
stirred under an atmosphere of hydrogen in the presence of
10% palladium on activated carbon (5 mg). After 17 h, TLC
(diethyl ether) indicated complete conversion of the starting
material (Rf 0.6) to a single product (Rf 0.5). The reaction
mixture was filtered through Celite (eluted with MeOH)
and the solvent was removed in vacuo. The residue was dis-
solved in ethyl acetate (40 mL), acidified with 2M hydrochloric
acid, and washed successively with water (20 mL) and brine
(10 mL). The organic phase was dried (MgSO4), filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (diethyl ether–hexane, 2 : 3) to yield recovered
methyl 2,5-anhydro-3-O-benzyl-6-deoxy-6-iodo--gluconate 29
(17 mg, 16%), and methyl 2,5-anhydro-3-O-benzyl-6-deoxy--
gluconate 30 (60 mg, 83%) as an oil (Found: C, 62.91; H, 6.66.
C14H18O5 requires C, 63.15; H, 6.81%); [α]2D5 Ϫ27.7 (c, 0.9
in CHCl3); νmax (thin film): 1746 (C᎐O, ester) cmϪ1; δ (CDCl ):
᎐
H
3
0.06, 0.06, 0.11, 0.11, 0.12 (18H, 5 × s, 3 × Si(CH3)2), 0.86, 0.90,
0.90 (27H, 3 × s, 3 × SiC(CH3)3), 3.71 (1H, a–t, H-5), 3.75 (3H,
s, CO2CH3), 3.84 (1H, dd, J6,5 9.7, J6,6Ј 5.5, H-6), 3.94 (1H, dd,
J6Ј,5 10.0, H-6Ј), 4.18 (1H, s, H-4), 4.21 (1H, a–d, H-3), 4.71
(1H, d, J2,3 3.4, H-2); δC (CDCl3; 50.3 MHz): Ϫ5.6, Ϫ5.5,
Ϫ5.4, Ϫ4.8, Ϫ4.6 (5 × q, 3 × Si(CH3)2), 17.8, 18.2 (2 × s,
3 × SiC(CH3)3), 25.5, 25.6, 25.8 (3 × q, 3 × SiC(CH3)3), 51.7
(q, CO2CH3), 63.1 (t, C-6), 78.3, 80.0, 81.8, 88.3 (4 × d, C-2,
ϩ
C-3, C-4, C-5), 169.7 (s, C᎐O); m/z (CI; NH ): 552 (M ϩ NH ,
᎐
3
4
11), 535 (M ϩ Hϩ, 100%).
Methyl 2,5-anhydro-3,4,6-tris-O-tert-butyldimethylsilyl-D-
mannonate 33
in CHCl3); νmax (thin film): 3472 (OH), 1747 (C᎐O) cmϪ1;
᎐
δH (CDCl3): 1.44 (3H, d, J6,5 6.4, CH3), 1.53 (1H, d, J 4.3, OH,
D2O exchanges), 3.76 (3H, s, CO2CH3), 3.91 (1H, m, H-5), 4.00
(1H, m, H-4), 4.17 (1H, dd, J3,2 6.0, J3,4 3.6, H-3), 4.61–4.66
(2H, AB-q, J 11.9, CH2Ar), 4.72 (1H, d, H-2), 7.29–7.38 (5H,
m, Ar); δC (CDCl3; 50.3 MHz): 18.7 (q, C-6), 52.0 (q, CO2CH3),
72.4 (t, CH2Ar), 79.4, 79.9, 81.5, 85.9 (4 × d, C-2, C-3, C-4,
tert-Butyldimethylsilyl chloride (3.73 g, 24.7 mmol) was added
to a stirred solution of methyl 2,5-anhydro--mannonate 15
(1.32 g, 6.9 mmol) and imidazole (3.71 g, 51.5 mmol) in DMF
(11 mL). The reaction mixture was stirred at 85 ЊC for 14 h,
under an atmosphere of nitrogen. TLC (ethyl acetate–hexane,
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1991

View Article Online
1 : 2) indicated complete conversion of the starting material
(Rf 0.0) to a single product (Rf 0.9). The solvent was removed
in vacuo (co-evaporation with toluene). The residue was dis-
solved in ethyl acetate (40 mL) and washed with water (15 mL).
The organic phase was dried (MgSO4), filtered, and concen-
trated in vacuo. The residue was purified by flash chromato-
graphy (ethyl acetate–hexane, 5 : 95) to yield methyl 2,5-
anhydro-3,4,6-tris-O-tert-butyldimethylsilyl--mannonate 33
(3.07 g, 84%) as a colourless oil (Found: C, 56.26; H, 10.40.
C25H54O6Si3 requires C, 56.13; H, 10.17%); [α]2D1 ϩ16.0 (c, 1.00
(36 mL). The reaction mixture was degassed and stirred at
reflux (80 ЊC) for 2 h 30 min, under an atmosphere of nitrogen.
TLC (diethyl ether–hexane, 1 : 8) indicated complete conversion
of the starting material (Rf 0.3) to a major product (Rf 0.55).
The reaction mixture was cooled, filtered, and the solvent
removed in vacuo. The crude residue was used without further
purification.
Sodium azide (323 mg, 4.97 mmol) was added to a stirred
solution of the crude residue in DMF (24 mL). The reaction
mixture was stirred at room temperature for 20 h, under
an atmosphere of nitrogen. TLC (diethyl ether–hexane, 1 : 8)
indicated conversion of the starting material (Rf 0.55) to
a single product (Rf 0.6). The reaction mixture was concen-
trated in vacuo (co-evaporation with toluene) and the resi-
due was purified by flash chromatography (diethyl ether–
hexane, 1 : 18) to give an inseparable mixture of methyl
2-azido-2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-α/β--
arabino-hex-2-ulofuranosonate 35 (1.30 g, 59% over two steps)
as a colourless oil identical to the compound mixture previously
described.
in CHCl3); νmax (thin film): 1735 (C᎐O, ester) cmϪ1; δ (CDCl ):
᎐
H
3
0.05, 0.06, 0.07, 0.14 (18H, 4 × s, 3 × Si(CH3)2), 0.85, 0.90, 0.91
(27H, 3 × s, 3 × SiC(CH3)3), 3.68 (1H, a–t, H-5), 3.73 (3H, s,
CO2CH3), 3.74 (1H, dd, J6,5 9.7, J6,6Ј 5.5, H-6), 4.09 (1H, s,
H-4), 4.12 (1H, dd, J6Ј,5 9.5, H-6Ј), 4.39, 4.42 (2H, 2 × s, H-2,
H-3); δC (CDCl3): Ϫ5.7, Ϫ5.6, Ϫ5.2, Ϫ5.1, Ϫ5.0 (5 × q,
3 × Si(CH3)2), 17.5, 17.7, 18.1 (3 × s, 3 × SiC(CH3)3), 25.4, 25.5,
25.8 (3 × q, 3 × SiC(CH3)3), 51.9 (q, CO2CH3), 63.2 (t, C-6),
78.4, 82.6, 84.7, 88.8 (4 × d, C-2, C-3, C-4, C-5), 171.4 (s, C᎐O);
᎐
ϩ
m/z (APCIϩve): 552 (M ϩ NH4 , 26), 535 (M ϩ Hϩ, 100%).
Methyl 2-azido-2-deoxy-ꢀ-D-arabino-hex-2-ulofuranosonate 37
and methyl 2-azido-2-deoxy-ꢂ-D-arabino-hex-2-ulofuronosonate
36
Methyl 2-azido-2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-ꢀ/ꢂ-
D-arabino-hex-2-ulofuranosonate 35
Method 1. N-Bromosuccinimide (2.95 g, 16.6 mmol) was
added to a stirred solution of methyl 2,5-anhydro-3,4,6-tris-O-
tert-butyldimethylsilyl--gluconate 32 (8.09 g, 15.1 mmol)
and benzoyl peroxide (80 mg, catalytic) in tetrachloromethane
(100 mL). The reaction mixture was degassed and stirred at
reflux (80 ЊC) for 30 min, under an atmosphere of nitrogen.
TLC (diethyl ether–hexane 1 : 8) indicated complete conversion
of the starting material (Rf 0.3) to a major product (Rf 0.55).
The reaction mixture was cooled, filtered, and the solvent was
removed in vacuo. The crude residue was used without further
purification.
Sodium azide (1.28 g, 19.7 mmol) was added to a stirred
solution of the crude residue in DMF (50 mL). The reaction
mixture was stirred at room temperature for 18 h, under an
atmosphere of nitrogen. TLC (diethyl ether–hexane, 1 : 8) indi-
cated conversion of the starting material (Rf 0.55) to a single
product (Rf 0.6). The reaction mixture was concentrated to
15 mL and then diluted with ethyl acetate (150 mL) and washed
with water (2 × 30 mL). The aqueous phase was extracted with
ethyl acetate (100 mL) and the combined organic phrases
were dried (MgSO4), filtered, and concentrated in vacuo (co-
evaporation with toluene). The residue was purified by flash
chromatography (diethyl ether–hexane, 1 : 19) to give an
inseparable mixture of methyl 2-azido-2-deoxy-3,4,6-tris-O-
tert-butyldimethylsilyl-α/β--arabino-hex-2-ulofuranosonate 35
(7.74 g, 89% over two steps) as a colourless oil (HRMS Ϫ N2 ϩ
Hϩ: 548.326991. C25H54O6NSi3 requires m/z, 548.325899); νmax
A mixture of methyl 2-azido-2-deoxy-3,4,6-tris-O-tert-butyl-
dimethylsilyl-α/β--arabino-hex-2-ulofuranosonate 35 (3.5 g,
6.09 mmol) was stirred in a 3% v/v solution of hydrogen
chloride in methanol (50 mL) at room temperature, under an
atmosphere of nitrogen. After 21 h, TLC (diethyl ether–hexane,
1 : 8) indicated complete conversion of the starting material (Rf
0.6) to two major products (Rf 0.3 and Rf 0.25 in chloroform–
methanol, 9 : 1). Sodium hydrogen carbonate (3 g, excess) was
added and the reaction mixture was stirred for 2 h and then
filtered through Celite. The solvent was removed in vacuo and
the residue was pre-adsorbed onto silica and purified by flash
chromatography (chloroform–methanol, 4% to 8% to 10%) to
yield methyl 2-azido-2-deoxy-α--arabino-hex-2-ulofuranoson-
ate 37 as a colourless oil (667 mg, 47%) (Found: C, 35.47;
H, 4.94; N, 18.09. C7H11O6N3 requires C, 36.06; H, 4.75;
N, 18.02%) (HRMS Ϫ N2 ϩ Hϩ: 206.066961. C7H12O6N
requires m/z, 206.066462); [α]2D3 ϩ108.9 (c, 1.03 in MeOH);
νmax (thin film): 3368 (OH), 2120 (N ), 1748 (C᎐O, ester) cmϪ1;
᎐
3
δH (CD3CN): 3.45 (1H, a–t, OH-6, exchanges with D2O), 3.65–
3.69 (2H, m, H-6, OH-4, exchanges with D2O), 3.67 (1H, ddd,
J6Ј,5 3.2, J6Ј,6 12.0, J6Ј,OH 4.5, H-6Ј), 3.78 (3H, s, CO2CH3), 4.03
(1H, dd, J3,4 2.8, J3,OH 8.1, H-3), 4.09 (1H, m, H-4), 4.20
(1H, a–dd, H-5), 4.42 (1H, d, OH-3, exchanges with D2O);
δC (CD3OD): 52.1 (q, CO2CH3), 61.5 (t, C-6), 76.3, 82.4, 86.9
(3 × d, C-3, C-4, C-5), 99.1 (s, C-2), 167.7 (s, C᎐O); m/z
᎐
(APCIϩve): 206.36 (M Ϫ N2 ϩ Hϩ, 40), 104 (100%); and
methyl 2-azido-2-deoxy-β--arabino-hex-2-ulofuranosonate 36
(652 mg, 46%) as a colourless oil (Found: C, 35.88; H, 4.98, N,
18.19. C7H11O6N3 requires C, 36.06; H, 4.75; N, 18.02%); [α]2D1
Ϫ36.0 (c, 1.08 in MeOH); νmax (thin film): 3368 (OH), 2129 (N3),
(thin film): 2128 (N ), 1773 (C᎐O, ester), 1753 (C᎐O, ester)
᎐
᎐
3
cmϪ1; δH (CDCl3): 0.07, 0.08, 0.08, 0.13, 0.13, 0.14, 0.17, 0.18
(36H, 8 × s, 6 × Si(CH3)2), 0.86, 0.86, 0.90, 0.92, 0.95 (54H,
5 × s, 6 × SiC(CH3)3), 3.70 (1H, a–t), 3.74–3.81 (2H, m), 3.77,
3.79 (6H, 2 × s, 2 × CO2CH3), 3.88 (1H, dd, J 10.0, J 5.5), 4.08
(1H, ddd, J 1.2, J 5.4, J 6.7), 4.20 (2H, m, H-3), 4.24 (1H, b–s),
4.30 (1H, b–dd, J 5.5, J 9.5), 4.41 (1H, b–d, J 1.7); δC (CDCl3;
50.3 MHz): Ϫ5.5, Ϫ5.2, Ϫ5.1, Ϫ5.0, Ϫ4.9, Ϫ4.7, Ϫ4.6 (7 × q,
6 × Si(CH3)2), 17.6, 17.7, 18.0, 18.2 (4 × s, 6 × SiC(CH3)3),
25.4, 25.6, 25.8 (3 × q, 6 × SiC(CH3)3), 51.7, 52.8 (2 × q,
2 × CO2CH3), 62.3, 62.8 (2 × t, 2 × C-6), 77.0, 78.1, 82.2, 83.6,
1742 (C᎐O, ester) cmϪ1; δ (CD CN; D O shake): 3.60 (1H, dd,
᎐
H
3
2
J6,5 4.8, J6,6Ј 12.3, H-6), 3.73 (1H, dd, J6Ј,5 3.0, H-6Ј), 3.80 (3H, s,
CO2CH3), 3.89 (1H, ddd, J5,4 6.8, H-5), 4.02 (1H, a–t, H-4), 4.32
(1H, d, J3,4 6.7, H-3); δC (CD3OD): 52.2 (q, CO2CH3), 61.9 (t,
C-6), 74.0, 79.7, 83.8 (3 × d, C-3, C-4, C-5), 94.6 (s, C-2), 168.4
(s, C᎐O); m/z (APCIϩve): 206.34 (M Ϫ N ϩ Hϩ, 57), 104
᎐
2
(100%).
87.4, 91.2 (6 × d, 2 × (C-3, C-4, C-5)), 96.9, 99.0 (2 × s, 2 × C-2),
ϩ
N-Methyl-2-azido-2-deoxy-ꢀ-D-arabino-hex-2-ulofuranoson-
amide 38a
166.4, 167.8 (2 × s, 2 × C᎐O); m/z (DCI; NH ): 593 (M Ϫ NH ,
᎐
3
4
19), 548 (M Ϫ N2 ϩ Hϩ, 74%).
A solution of methylamine (33% w/w in industrial methylated
spirits) (0.27 mL, 20.6 mmol) was added to a stirred solution of
methyl 2-azido-2-deoxy-α--arabino-hex-2-ulofuranosonate 37
(48 mg, 0.206 mmol) in methanol (1 mL). The reaction mix-
ture was stirred at room temperature for 30 min, under an
Method 2. N-Bromosuccinimide (748 mg, 4.20 mmol) was
added to a stirred solution of methyl 2,5-anhydro-3,4,6-tris-O-
tert-butyldimethylsilyl--mannonate 33 (2.04 g, 3.82 mmol)
and benzoyl peroxide (25 mg, catalytic) in tetrachloromethane
1992
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998

View Article Online
atmosphere of nitrogen. TLC (ethyl acetate–methanol, 9 : 1)
indicated complete conversion of the starting material (Rf 0.6)
to a major product (Rf 0.3). The solvent was removed in vacuo
and the residue was purified by flash chromatography (ethyl
acetate–methanol, 9 : 1) to yield N-methyl-2-azido-2-deoxy-α-
-arabino-hex-2-ulofuranosonamide 38a (43 mg, 84%) as a
colourless oil which later crystallised (Found: C, 35.98; H, 5.14;
N, 23.81. C7H12O5N4 requires C, 36.21; H, 5.21; N, 24.13%);
m.p. 130–131 ЊC (ethyl acetate–hexane); [α]2D1 ϩ170.8 (c, 0.25
in MeOH); νmax (KBr disc): 3369 (OH, NH), 2118 (N3), 1669
N-Butyl-2-azido-2-deoxy-ꢂ-D-arabino-hex-2-ulofuranosonamide
39a
nButylamine (0.20 mL, 2.06 mmol) was added to a stirred solu-
tion of methyl 2-azido-2-deoxy-β--arabino-hex-2-ulofurano-
sonate 36 (48 mg, 0.206 mmol) in methanol (1 mL). The reac-
tion mixture was stirred at room temperature for 35 min, under
an atmosphere of nitrogen. TLC (ethyl acetate–methanol, 10%)
indicated complete conversion of the starting material (Rf 0.6)
to a major product (Rf 0.5). The solvent was removed in vacuo
and the residue was purified by flash chromatography (ethyl
acetate–methanol, 5%) to yield N-butyl-2-azido-2-deoxy-β--
arabino-hex-2-ulofuranosonamide 39a (53 mg, 94%) as a
colourless oil (HRMS Ϫ N2 ϩ Hϩ: 247.130027. C10H19O5N2
requires m/z, 247.129397); [α]2D3 Ϫ40.0 (c, 0.78 in MeOH);
(C᎐O, amide I), 1541 (amide II) cmϪ1; δ (CD OD): 2.79 (3H, s,
᎐
H
3
NCH3), 3.73 (1H, dd, J6,5 5.3, J6,6Ј 12.5, H-6), 3.81 (1H, dd, J6Ј,5
3.3, H-6Ј), 4.01 (1H, dd, J4,3 2.7, J4,5 4.6, H-4), 4.09 (1H, d, J3,4
2.7, H-3), 4.15 (1H, ddd, H-5); δC (CD3OD): 26.2 (q, NCH3),
62.4 (t, C-6), 78.3, 83.2, 89.1 (3 × d, C-3, C-4, C-5), 101.1
νmax (thin film): 3340 (OH, NH), 2124 (N ), 1669 (C᎐O, amide
᎐
(s, C-2), 169.2 (s, C᎐O); m/z (APCIϪve): 231.10 ([M Ϫ H]Ϫ
3
᎐
I), 1540 (C᎐O, amide II) cmϪ1; δ (CD OD): 0.95 (3H, t, J 7.4,
᎐
H
3
100%).
CH2CH3), 1.33–1.40 (2H, m, CH2), 1.49–1.55 (2H, m,
CH2CH3), 3.21–3.24 (2H, m, NHCH2), 3.67 (1H, dd, J6,5 6.0,
J6,6Ј 12.0, H-6), 3.79 (1H, dd, J6Ј,5 3.4, H-6Ј), 3.95 (1H, ddd,
H-5), 3.99 (1H, a–t, H-4), 4.20 (1H, d, J3,4 6.3, H-3); δC (CD3-
OD): 12.6 (q, CH2CH3), 19.5, 31.0, 38.7 (3 × t, 3 × CH2), 62.0
(t, C-6), 74.9, 81.0, 83.9 (3 × d, C-3, C-4, C-5), 95.3 (s, C-2),
N-Butyl-2-azido-2-deoxy-ꢀ-D-arabino-hex-2-ulofuranosonamide
38b
nButylamine (0.21 mL, 2.15 mmol) was added to a stirred
solution of methyl 2-azido-2-deoxy-α--arabino-hex-2-ulo-
furanosonate 37 (50 mg, 0.215 mmol) in methanol (1 mL). The
reaction mixture was stirred at room temperature for 20 min,
under an atmosphere of nitrogen. TLC (ethyl acetate–
methanol, 10%) indicated complete conversion of the starting
material (Rf 0.6) to a major product (Rf 0.5). The solvent was
removed in vacuo and the residue was purified by flash
chromatography (ethyl acetate–methanol, 5%) to yield N-butyl-
2-azido-2-deoxy-α--arabino-hex-2-ulofuranosonamide 38b (58
mg, 89%) as a colourless oil (HRMS Ϫ N2 ϩ Hϩ: 247.129242.
C10H19O5N2 requires m/z, 247.129397); [α]2D1 ϩ94.1 (c, 0.80
in MeOH); νmax (thin film): 3338 (OH, NH), 2115 (N3), 1663
(C᎐O, amide I), 1544 (C᎐O, amide II) cmϪ1; δ (CD OD): 0.93
169.0 (s, C᎐O); m/z (APCIϪve): 273.30 ([M Ϫ H]Ϫ, 100%).
᎐
N-Dodecyl-2-azido-2-deoxy-ꢂ-D-arabino-hex-2-ulofuranoson-
amide 39b
A solution of dodecylamine (211 mg, 1.12 mmol) in methanol
(0.5 mL) was added to a stirred solution of methyl 2-azido-2-
deoxy-β--arabino-hex-2-ulofuranosonate 36 (26 mg, 0.112
mmol) in methanol (0.5 mL). The reaction mixture was stirred
at room temperature for 30 min, under an atmosphere of nitro-
gen. The crude infared spectrum indicated loss of the ester peak
(1748 cmϪ1) and formation of an amide peak (1667 cmϪ1). The
solvent was removed in vacuo and the residue was purified by
flash chromatography (ethyl acetate) to yield N-dodecyl-2-
azido-2-deoxy-β--arabino-hex-2-ulofuranosonamide 39b (41
mg, 95%) as a yellow oil which later crystallised (Found: C,
55.97; H, 9.11; N, 14.10. C18H34O5N4 requires C, 55.94; H, 8.87;
N, 14.50%) (HRMS Ϫ N2 ϩ Hϩ 359.254632. C18H35O5N2
requires m/z, 359.254598); m.p. 64–65 ЊC (ethyl acetate–
hexane); [α]2D1 Ϫ27.9 (c, 0.58 in MeOH); νmax (KBr disc): 3401
᎐
᎐
H
3
(3H, t, J 7.4, CH2CH3), 1.33–1.41 (2H, m, CH2), 1.49–1.55 (2H,
m, CH2CH3), 3.21–3.29 (2H, m, NHCH2), 3.74 (1H, dd, J6,5 5.1,
J6,6Ј 12.1, H-6), 3.82 (1H, dd, J6Ј,5 3.1, H-6Ј), 4.02 (1H,
dd, J4,3 2.9, J4,5 4.8, H-4), 4.09 (1H, d, H-3), 4.15 (1H, ddd,
H-5); δC (CD3OD): 12.6 (q, CH2CH3), 19.5, 30.9, 38.7 (3 × t, 3
× CH2), 60.8 (t, C-6), 76.6, 81.8, 87.4 (3 × d, C-3, C-4, C-5),
99.8 (s, C-2), 167.5 (s, C᎐O); m/z (APCIϪve): 273.51 ([M Ϫ
᎐
H]Ϫ, 100%).
(OH, NH), 2126 (N ), 1653 (C᎐O, amide I), 1541 (C᎐O, amide
᎐
᎐
3
II) cmϪ1; δH (CD3OD): 0.89 (3H, t, J 7.0, CH2CH3), 1.29–1.32
(18H, m, (CH2)9), 1.51–1.54 (2H, m, CH2CH3), 3.19–3.23 (2H,
m, NHCH2), 3.66 (1H, dd, J6,5 6.1, J6,6Ј 12.0, H-6), 3.78 (1H,
dd, J6Ј,5 3.4, H-6Ј), 3.94 (1H, ddd, H-5), 3.99 (1H, a–t, H-4),
4.19 (1H, d, J3,4 6.3, H-3); δC (CD3OD): 12.9 (q, CH2CH3),
22.2, 26.4, 28.6, 29.0, 29.2, 31.6, 39.0 (7 × t, 11 × CH2), 62.0 (t,
C-6), 74.9, 81.0, 83.9 (3 × d, C-3, C-4, C-5), 95.3 (s, C-2), 169.0
N-Dodecyl-2-azido-2-deoxy-ꢀ-D-arabino-hex-2-ulofuranoson-
amide 38c
A solution of dodecylamine (244 mg, 1.29 mmol) in methanol
(0.5 mL) was added to a stirred solution of methyl 2-azido-2-
deoxy-α--arabino-hex-2-ulofuranosonate 37 (30 mg, 0.129
mmol) in methanol (0.5 mL). The reaction mixture was stirred
at reflux (65 ЊC) for 1 h, under an atmosphere of nitrogen.
The crude infrared spectrum indicated loss of the ester peak
(1748 cmϪ1) and formation of an amide peak (1667 cmϪ1). The
solvent was removed in vacuo and the residue was purified by
flash chromatography (ethyl acetate–hexane, 5 : 1) to yield
N-dodecyl-2-azido-2-deoxy-α--arabino-hex-2-ulofuranoson-
amide 38c (39 mg, 78%) as a yellow oil (Found: C, 55.96; H,
9.27; N, 14.94. C18H34O5N4 requires C, 55.94; H, 8.87; N,
14.50%) (HRMS) Ϫ N2 ϩ Hϩ: 359.254870. C18H35O5N2
requires m/z, 359.254598); [α]2D1 ϩ80.2 (c, 0.58 in MeOH); νmax
(s, C᎐O); m/z (APCIϪve): 385.59 ([M Ϫ H]Ϫ, 100%).
᎐
Methyl 2-amino-2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-ꢀ-
D-arabino-hex-2-ulofuranosonate 40 and methyl 2-amino-2-
deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-ꢂ-D-arabino-hex-2-
ulofuranosonate 41
A solution of methyl 2-azido-2-deoxy-3,4,6-tris-O-tert-butyl-
dimethylsilyl-α/β--arabino-hex-2-ulofuranosonate 35 (1.414 g,
2.46 mmol) in methanol (25 mL) was stirred under an
atmosphere of hydrogen in the presence of palladium black
(100 mg, catalytic). After 18 h, TLC (diethyl ether–hexane,
1 : 1) indicated complete conversion of the starting material
(Rf 0.9) to two products (Rf 0.4, Rf 0.3). The reaction mix-
ture was filtered through Celite (eluted with methanol) and
the solvent was removed in vacuo. The residue was purified
by flash chromatography (diethyl ether–hexane, 1 : 1) to
yield a mixture of methyl 2-amino-2-deoxy-3,4,6-tris-O-tert-
butyldimethylsilyl-α--arabino-hex-2-ulofuranosonate 40 and
methyl 2-amino-2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-β-
(KBr disc): 3401 (OH, NH), 2116 (N ), 1667 (C᎐O, amide I),
᎐
3
1549 (C᎐O, amide II) cmϪ1; δ (CD3OD): 0.89 (3H, t, J 7.0,
᎐
H
CH2CH3), 1.28–1.32 (18H, m, (CH2)9), 1.51–1.55 (2H, m,
CH2CH3), 3.19–3.29 (2H, m, NHCH2), 3.73 (1H, dd, J6,5 5.2,
J6,6Ј 12.1, H-6), 3.82 (1H, dd, J6Ј,5 3.2, H-6Ј), 4.02 (1H, dd,
J4,3 2.9, J4,5 4.7, H-4), 4.09 (1H, d, H-3), 4.16 (1H, ddd, H-5);
δC (CD3OD): 12.9 (q, CH2CH3), 22.2, 26.4, 28.8, 29.0, 29.3,
31.6, 39.0 (7 × t, 11 × CH2), 60.8 (t, C-6), 76.7, 81.8, 87.5 (3 × d,
C-3, C-4, C-5), 99.9 (s, C-2), 167.5 (s, C᎐O); m/z (APCIϪve):
᎐
385.60 ([M Ϫ H]Ϫ, 100%).
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1993

View Article Online
-arabino-hex-2-ulofuranosonate 41 (1.391 g, 99%) as a colour-
less oil. Further flash chromatography (diethyl ether–hexane,
3 : 4) of the mixture 40 and 41 (which epimerises in solu-
tion) gave pure methyl 2-amino-2-deoxy-3,4,6-tris-O-tert-
butyldimethylsilyl-α--arabino-hex-2-ulofuranosonate 40 as a
white solid (Found: C, 54.79; H, 10.21; N, 2.23. C25H55O6NSi3
requires C, 54.60; H, 10.08; N, 2.55%); m.p. 70–71 ЊC (ethyl
acetate–hexane); νmax (KBr disc): 3405, 3324 (OH, NH), 1749
(C᎐O, ester) cmϪ1; δ (C6D6): 0.06, 0.08, 0.13, 0.15, 0.16,
(4 × s, 2 × CO2CH3, 2 × CH3CONH); m/z (APCIϩve): 592.3
(M ϩ Hϩ, 100%); methyl 2-deoxy-3,4,6-tris-O-tert-butyl-
dimethylsilyl-2-ureido-α--arabino-hex-2-ulofuranosonate 42
(568 mg, 46%) as a white solid (Found: C, 52.53; H, 9.81; N,
4.37. C26H56O7N2Si3 requires C, 52.66; H, 9.52; N, 4.72%); m.p.
73–74 ЊC (ethyl acetate–hexane); [α]2D1 ϩ60.6 (c, 1.00 in CHCl3);
νmax (KBr disc): 3381 (NH), 1750 (C᎐O, ester), 1684 (C᎐O, urea
᎐
᎐
I), 1523 (C᎐O, urea II) cmϪ1; δ (C6D6): 0.06, 0.06, 0.08, 0.08,
᎐
H
0.15, 0.16, (18H, 6 × s, 3 × Si(CH3)2), 0.87, 0.90, 0.93 (27H,
3 × s, 3 × SiC(CH3)3), 3.67 (1H, a–t, H-6), 3.79 (3H, s,
CO2CH3), 3.90 (1H, dd, J6Ј,5 5.4, J6Ј,6 9.9, H-6Ј), 4.15–4.18 (3H,
m, H-3, H-4, H-5), 4.46 (2H, b–s, NH2), 6.13 (1H, b–s, NH);
δC (CDCl3; 50.3 MHz): Ϫ5.6, Ϫ5.1, Ϫ4.7 (3 × q, 3 × Si(CH3)2),
17.5, 18.2 (2 × s, 3 × SiC(CH3)3), 25.4, 25.6, 25.8 (3 × q,
3 × SiC(CH3)3), 52.6 (q, CO2CH3), 63.3 (t, C-6), 78.8, 83.1, 88.3
(3 × d, C-3, C-4, C-5), 94.6 (s, C-2), 157.3 (s, NH2CONH),
168.0 (s, CO2CH3); m/z (ES): 637 (M ϩ HCOOϪ, 100%); and
methyl 2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-2-ureido-β-
-arabino-hex-2-ulofuranosonate 43 (244 mg, 18%) as a white
solid (Found: C, 52.60; H, 9.71; N, 4.46. C26H56O7N2Si3 requires
C, 52.66; H, 9.52; N, 4.72%); m.p. 65–67 ЊC (ethyl acetate–
hexane); [α]2D1 Ϫ22.0 (c, 0.25 in CHCl3); νmax (KBr disc): 3435
᎐
H
0.19, (18H, 6 × s, 3 × Si(CH3)2), 0.95, 0.96, 0.97 (27H, 3 × s,
3 × SiC(CH3)3), 2.21 (2H, b–s, NH2), 3.43 (3H, s, CO2CH3),
3.82 (1H, dd, J6,5 7.4, J6,6Ј 10.2, H-6), 3.86 (1H, dd, J6Ј,5
5.0, H-6Ј), 4.14 (1H, ddd, J5,4 2.8, H-5), 4.31 (1H, a–t, H-4),
4.73 (1H, d, J3,4 2.5, H-3); δC (C6D6, 50.3 MHz): Ϫ5.1, Ϫ4.6,
Ϫ4.5, Ϫ4.3 (4 × q, 3 × Si(CH3)2), 18.1, 18.4, 18.6 (3 × s,
3 × SiC(CH3)3), 26.0, 26.1, 26.2 (3 × q, 3 × SiC(CH3)3), 51.9 (q,
CO2CH3), 64.0 (t, C-6), 78.9, 80.9, 85.3 (3 × d, C-3, C-4, C-5),
94.3 (s, C-2), 171.3 (s, C᎐O); m/z (APCIϩve): 550.74 (M ϩ Hϩ,
᎐
100%); and methyl 2-amino-2-deoxy-3,4,6-tris-O-tert-butyl-
dimethylsilyl-β--arabino-hex-2-ulofuranosonate 41 (contam-
inated with 40); δH (C6D6): 0.07, 0.12, 0.14, 0.14, 0.14 (18H,
5 × s, 3 × Si(CH3)2), 0.92, 0.95, 0.96 (27H, 3 × s, 3 × SiC(CH3)3),
2.20 (2H, b–s, NH2), 3.44 (3H, s, CO2CH3), 3.92 (1H, dd,
J6,5 8.0, J6,6Ј 10.2, H-6), 3.97 (1H, dd, J6Ј,5 5.6, H-6Ј), 4.22 (1H,
d, J3,4 2.2, H-3), 4.29 (1H, ddd, J5,4 2.4, H-5), 4.33 (1H, a–t,
H-4); δC (C6D6, 50.3 MHz): Ϫ5.1, Ϫ4.6, Ϫ4.5, Ϫ4.3 (4 × q,
3 × Si(CH3)2), 18.1, 18.4, 18.6 (3 × s, 3 × SiC(CH3)3), 26.0, 26.1,
26.2 (3 × q, 3 × SiC(CH3)3), 51.6 (q, CO2CH3), 64.5 (t, C-6),
79.3, 84.8, 87.0 (3 × d, C-3, C-4, C-5), 97.3 (s, C-2), 169.8 (s,
(NH), 1747 (C᎐O, ester), 1687 (C᎐O, urea I), 1505 (C᎐O, urea
᎐
᎐
᎐
II) cmϪ1; δH (C6D6): 0.05, 0.08, 0.09, 0.17, 0.17, (18H, 5 × s,
3 × Si(CH3)2), 0.87, 0.89, 0.96 (27H, 3 × s, 3 × SiC(CH3)3), 3.64
(1H, dd, J6,5 8.3, J6,6Ј 10.2, H-6), 3.76 (1H, dd, J6Ј,5 5.4, H-6Ј),
3.79 (3H, s, CO2CH3), 4.10 (1H, ddd, J5,4 2.3, H-5), 4.15 (1H,
a–t, H-4), 4.27 (1H, d, J3,4 2.2, H-3), 4.82 (2H, b–s, NH2), 5.60
(1H, b–s, NH); δC (CDCl3; 50.3 MHz): Ϫ5.4, Ϫ5.1, Ϫ4.8, Ϫ4.7
(4 × q, 3 × Si(CH3)2), 17.7, 18.0, 18.3 (3 × s, 3 × SiC(CH3)3),
25.6, 25.7, 25.8 (3 × q, 3 × SiC(CH3)3), 53.0 (q, CO2CH3),
63.0 (t, C-6), 77.4, 83.0, 86.9 (3 × d, C-3, C-4, C-5), 90.7 (s,
C-2), 157.2 (s, NH2CONH), 170.2 (s, CO2CH3); m/z (ES): 637
(M ϩ HCOOϪ, 100%).
C᎐O).
᎐
Methyl 2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-2-ureido-ꢀ-
D-arabino-hex-2-ulofuranosonate 42, methyl 2-deoxy-3,4,6-tris-
O-tert-butyldimethylsilyl-2-ureido-ꢂ-D-arabino-hex-2-ulo-
furanosonate 43 and methyl 2-acetamido-2-deoxy-3,4,6-tris-O-
tert-butyldimethylsilyl-ꢀ/ꢂ-D-arabino-hex-2-ulofuranosonate
(2R,3S,4S,5R)-3,4-Dihydroxy-2-hydroxymethyl-7,9-dioxo-1-
oxa-6,8-diazaspiro[4.4]nonane 44
Potassium cyanate (554 mg, 6.83 mmol) was added to a stirred
solution of methyl 2-amino-2-deoxy-3,4,6-tris-O-tert-butyl-
A solution of tetrabutylammonium fluoride (1.0M in THF)
(0.59 mL, 0.59 mmol) was added to a stirred solution of methyl
2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-2-ureido-α--
arabino-hex-2-ulofuranosonate 42 (116 mg, 0.20 mmol) in THF
(4 mL). The reaction mixture was stirred for 24 h at room
temperature, under an atmosphere of nitrogen. TLC CMAW
(chloroform–methanol–acetic acid–water 60 : 30 : 3 : 5) indi-
cated complete conversion of the starting material (Rf 1.0) to a
single product (Rf 0.6). The solvent was removed in vacuo
and the residue was purified by flash chromatography CMAW
(chloroform–methanol–acetic acid–water 60 : 30 : 3 : 5) and
reversed-phase chromatography (H2O) to yield (2R,3S,4S,5R)-
3,4-dihydroxy-2-hydroxymethyl-7,9-dioxo-1-oxa-6,8-diaza-
spiro[4.4]nonane 44 (43 mg, 100%, contaminated with <5% of
its epimer) as a white solid. A pure sample was obtained by
crystallisation (EtOH–H2O) (Found: C, 38.44; H, 4.66; N,
12.73. C7H10O6N2 requires C, 38.54; H, 4.62; N, 12.84%);
m.p. 198–200 ЊC (EtOH–H2O); [α]2D2 Ϫ5.95 (c, 0.19 in MeOH);
dimethylsilyl-α--arabino-hex-2-ulofuranosonate
40
and
methyl 2-amino-2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-β-
-arabino-hex-2-ulofuranosonate 41 (1.25 g, 2.28 mmol) in
acetic acid (30 mL). The solution was stirred at room temper-
ature, under an atmosphere of nitrogen for 1h 45 min. TLC
(diethyl ether–hexane, 1 : 1) indicated complete conversion of
the starting material mixture (Rf 0.4, Rf 0.3) to three major
products (Rf 0.1, Rf 0.0 and Rf 0.0). The solvent was removed in
vacuo (co-evaporation with toluene) and the residue was dis-
solved in ethyl acetate (100 mL) and washed with water (2 × 30
mL). The aqueous phase was extracted with ethyl acetate (50
mL) and the combined organic phases were dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography (diethyl ether–hexane 1 : 2; then diethyl
ether; then ethyl acetate–hexane, 5 : 4) to yield methyl 2-
acetamido-2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-α/β--
arabino-hex-2-ulofuranosonate (420 mg, 31%) as a colourless
oil (HRMS ϩ Hϩ: 592.351016. C27H58O7NSi3 requires m/z,
νmax (KBr disc): 3382 (NH), 1777, 1723 (C᎐O, hydantoin) cmϪ1;
᎐
δH (CD3OD): 3.71 (1H, dd, J2a,2 6.9 J2a,2b 12.0 H-2a(CHHOH)),
3.77 (1H, dd, J2b,2 2.7 H-2b(CHHOH)), 3.92 (1H, ddd, J2,3 8.3
H-2), 4.13 (1H, d, J4,3 8.7 H-4), 4.26 (1H, at, H-3); δC (D2O: 50.3
MHz): 62.3 (t, CH2OH), 72.9, 79.3, 82.2 (3 × d, C-2, C-3, C-4),
93.7 (s, C-5), 158.7 (s, C-7), 174.5 (s, C-9); m/z (APCIϪve):
217.1 ([M Ϫ H]Ϫ, 100%).
592.352114); νmax (KBr disc): 3428 (NH), 1746 (C᎐O, ester),
᎐
1707 (C᎐O, amide) cmϪ1; δ (CDCl3): 0.05, 0.08, 0.09, 0.12,
᎐
H
0.17, 0.20, 0.23 (36H, 7 × s, 6 × Si(CH3)2), 0.87, 0.87, 0.89,
0.94, 0.99 (54H, 5 × s, 6 × SiC(CH3)3), 1.94, 1.98 (6H, 2 × s,
2 × CH3CONH), 3.57, 3.67 (2H, 2 × a–t, 2 × H-6), 3.78, 3.79
(2H, 2 × dd, 2 × H-6Ј), 3.78, 3.79 (6H, 2 × s, 2 × CO2CH3),
4.10–4.16 (3H, m), 4.18–4.20 (3H, m), 6.60, 7.22 (2H, 2 × s,
2 × NH); δC (CDCl3; 50.3 MHz): Ϫ5.7, Ϫ5.4, Ϫ5.2, Ϫ4.8,
Ϫ4.7 (5 × q, 6 × Si(CH3)2), 17.5, 17.6, 17.9, 18.2 (4 × s,
6 × SiC(CH3)3), 23.0 (q, 2 × CH3CONH), 25.4, 25.5, 25.8
(3 × q, 6 × SiC(CH3)3), 52.5, 52.8 (2 × q, 2 × CO2CH3), 63.2
(t, 2 × C-6), 77.6, 78.7, 82.8, 83.4, 87.6, 88.6 (6 × d, 2 × (C-3,
C-4, C-5), 90.4, 93.5 (2 × s, 2 × C-2), 167.4, 169.5, 169.6, 170.2
(2R,3S,4S,5S)-3,4-Dihydroxy-2-hydroxymethyl-7,9-dioxo-1-
oxa-6,8-diazaspiro[4.4]nonane 45
A solution of tetrabutylammonium fluoride (1.0M in THF)
(0.40 mL, 0.40 mmol) was added to a stirred solution of methyl
2-deoxy-3,4,6-tris-O-tert-butyldimethylsilyl-2-ureido-β--
arabino-hex-2-ulofuranosonate 43 (79 mg, 0.13 mmol) in THF
1994
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998

View Article Online
(3 mL). The reaction mixture was stirred for 24 h at room tem-
perature, under an atmosphere of nitrogen. TLC CMAW
(chloroform–methanol–acetic acid–water 60 : 30 : 3 : 5) indi-
cated complete conversion of the starting material (Rf 1.0) to
a single product (Rf 0.6). The solvent was removed in vacuo
and the residue was purified by flash chromatography CMAW
(chloroform–methanol–acetic acid–water 60 : 30 : 3 : 5) and
reversed-phase chromatography (H2O) to yield (2R,3S,4S,5S)-
3,4-dihydroxy-2-hydroxymethyl-7,9-dioxo-1-oxa-6,8-diaza-
spiro[4.4]nonane 45 (29 mg, 100%, contaminated with <5% of
its epimer) as a white solid; δH (CD3OD): 3.60 (1H, dd, J2a,2 5.1
J2a,2b 12.2 H-2a(CHHOH)), 3.75 (1H, dd, J2b,2 2.6 H-2b-
(CHHOH)), 3.83 (1H, ddd, J2,3 8.0, H-2), 3.94 (1H, at, H-3),
4.28 (1H, d, J4,3 8.2, H-4); δC (D2O; 50.3 MHz): 60.3 (t,
CH2OH), 72.8, 76.4, 81.3 (3 × d, C-2, C-3, C-4), 91.2 (s, C-5),
159.3 (s, C-7), 176.6 (s, C-9); m/z (APCIϪve): 217.1 ([M Ϫ H]Ϫ,
100%).
reaction mixture was warmed to room temperature, filtered
through Celite (eluent: dichloromethane), and washed with
buffer (pH 7; 10 mL) and the aqueous layer was extracted
with ethyl acetate (3 × 50 mL). The combined organic phases
were dried (MgSO4), filtered, and concentrated in vacuo to
give methyl 2,5-anhydro-6-O-p-tolylsulfonyl--gluconate 46 as
white solid which was used without further purification.
Sodium azide (1.56 g, 24.1 mmol) was added to a stirred solu-
tion of crude methyl 2,5-anhydro-6-O-p-tolylsulfonyl--glucon-
ate 46 in DMF (30 mL), under an atmosphere of nitrogen. The
mixture was heated at 90 ЊC for 18 h, when TLC (ethyl acetate–
hexane, 2 : 1) indicated the presence of a major product (Rf 0.3)
and no starting material (UV-visible, Rf 0.2). The reaction
mixture was cooled to room temperature, concentrated to
approximately 5 mL, diluted with ethyl acetate (100 mL), and
washed with buffer (pH 7; 40 mL). The aqueous layer was
extracted with ethyl acetate (2 × 100 mL) and the combined
organic phases were dried (MgSO4), filtered, and concentrated
in vacuo to give a residue, which was purified by flash chrom-
atography (ethyl acetate–hexane, 2 : 1) to afford methyl 2,5-
anhydro-6-azido-6-deoxy--gluconate 3 as a white crystalline
solid (2.495 g, 71% over two steps) (Found: C, 39.00; H, 5.16; N,
18.77. C7H11O5N3 requires C, 38.71; H, 5.11; N, 19.35%); m.p.
77–78 ЊC; [α]2D4 ϩ48.8 (c, 1.0 in methanol); νmax (KBr disc) 3420
Methyl 2,5-anhydro-6-O-p-tolylsulfonyl-D-gluconate 46
Toluene-p-sulfonyl chloride (1.21 g, 6.4 mmol) was added to a
stirred solution of methyl 2,5-anhydro--gluconate 8 (1.25 g,
6.5 mmol) and 3Å molecular sieves (1.2 g) in pyridine (15 mL)
at Ϫ10 ЊC under an atmosphere of nitrogen. After 3 h, TLC
(ethyl acetate) indicated the presence of a major compound (Rf
0.5) and no starting material (Rf 0.1). The reaction mixture was
warmed to room temperature, filtered through Celite (eluent:
dichloromethane), and washed with buffer (pH 7; 20 mL) and
the aqueous layer was extracted with ethyl acetate (3 × 60 mL).
The combined organic extracts were dried (MgSO4), filtered,
and concentrated in vacuo to give a white solid, which was pre-
adsorbed onto silica and purified by flash chromatography
(ethyl acetate–hexane, 2 : 1) to afford methyl 2,5-anhydro-6-O-
p-tolylsulfonyl--gluconate 46 as a white crystalline solid (1.78
g, 79%) (Found: C, 48.60; H, 5.19. C14H18O8S requires C, 48.55;
H 5.24 %); m.p. 136–138 ЊC; [α]2D4 ϩ62.5 (c, 0.20 in methanol);
νmax (KBr disc): 3508 (br, OH), 1744 (s, COOCH3) cmϪ1;
δH (CD3CN): 2.45 (3H, s, CH3Ar), 3.67 (3H, s, COOCH3), 3.91
(1H, a–t, J 2.7, H-4), 3.95 (1H, ddd, J5,4 2.9, J5,6 5.6, J5,6Ј 6.5, H-
5), 4.13 (1H, dd, J5,6Ј 6.6, J6,6Ј 10.3, H-6Ј), 4.15 (1H, dd, J6,5 5.5,
J6,6Ј 10.3, H-6), 4.22 (1H, dd, J3,4 2.2, J2,3 4.8, H-3), 4.59 (1H, d,
J3,2 4.8, H-2), 7.44 (2H, d, J 8.2, 2 × ArH), 7.80–7.82 (2H, m,
2 × ArH); δC (CD3CN; 50.3 MHz): 12.7 (1 × q, CH3Ar), 52.3
(1 × q, COOCH3), 71.1 (1 × t, C-6), 78.4, 78.6, 81.9, 84.1 (4 × d,
C-2, C-3, C-4, C-5), 128.8, 131.1 (2 × d, 4 × Ar–CH), 133.6,
(br, OH), 2126, 2099 (N ), 1740 (C᎐O) cmϪ1; δ (D2O; 500
᎐
3
H
MHz): 3.57 (2H, d, J6,5 5.7, H2-6), 3.77 (3H, s, COOCH3), 4.02
(1H, dt, J5,4 3.6, J5,6 5.7, H-5), 4.07 (1H, dd, J4,3 2.3, J4,5 3.6,
H-4), 4.42 (1H, dd, J3,4 2.3, J3,2 4.9, H-3), 4.79 (1H, d, J2,3 4.9,
H-2); δC (D2O; 50 MHz): 52.6 (1 × t, C-6), 53.4 (1 × q,
COOCH3), 78.2, 78.5, 81.4, 85.0 (4 × d, C-2, C-3, C-4, C-5),
ϩ
172.1 (1 × s, C᎐O); m/z (CINH ): 235 (M ϩ NH , 100), 218
᎐
3
4
(M ϩ Hϩ, 18), 192 (59), 190 (M ϩ Hϩ Ϫ N2, 60%).
6-Amino-2,5-anhydro-6-deoxy-D-glucono-1,6-lactam 50
A solution of methyl 2,5-anhydro-6-azido-6-deoxy--gluconate
3 (100 mg, 0.46 mmol) in methanol (5 mL) was stirred under an
atmosphere of hydrogen, in the presence of 10% palladium on
carbon (25 mg). After 1 h, TLC (ethyl acetate–methanol, 9 : 1)
indicated conversion of the starting material (Rf 0.8) to a major
product (Rf 0.1). The reaction mixture was filtered through
Celite (eluted with methanol) and the solvent was removed
in vacuo. The residue was purified by flash chromatography
CMAW (chloroform–methanol–acetic acid–water 60 : 30 : 3 : 5)
to yield 6-amino-2,5-anhydro-6-deoxy--glucono-1,6-lactam 50
(34 mg, 46%) as an orange, amorphous solid; m.p. 221–225 ЊC;
[α]2D1 Ϫ22.2 (c, 0.95 in MeOH); νmax (thin film): 3500, 3152 (OH,
NH), 1689 (C᎐O, amide) cmϪ1; δ (D2O): 3.26 (1H, m, H-6),
146.5 (OSO C, CH –ArC), 170.5 (1 × s, C᎐O). m/z (APCIϩve):
᎐
2
3
369 (M ϩ Naϩ, 13), 347 (M ϩ Hϩ, 85%).
᎐
H
Methyl 2,5-anhydro-6-azido-6-deoxy-D-gluconate 3
3.59 (1H, dd, J6Ј,5 12.8 J6Ј,6 12.8, H-6Ј), 4.12 (1H, a–dd, H-4),
4.30 (1H, m, H-5), 4.35 (1H, m, H-3), 4.41 (1H, d, J2,3 7.0);
δC (D2O; 50.3 MHz): 44.8 (t, C-6), 79.6, 80.6, 81.9, 82. (4 × d,
Method 1. Sodium azide (374 mg, 5.7 mmol) was added to a
stirred solution of methyl 2,5-anhydro-6-O-p-tolylsulfonyl--
gluconate 46 (1.33 g, 3.8 mmol) in DMF (10 mL), under an
atmosphere of nitrogen. The mixture was heated at 90 ЊC for 18
h, when TLC (ethyl acetate) indicated the presence of a major
product (Rf 0.6) and no starting material (UV-visible, Rf 0.5).
The reaction mixture was cooled to room temperature, diluted
with ethyl acetate (25 mL), and washed with water (10 mL). The
aqueous layer was extracted with ethyl acetate (3 × 25 mL) and
the combined organic phases were dried (MgSO4), filtered, and
concentrated in vacuo to give a residue, which was purified by
flash chromatography (ethyl acetate–hexane, 2 : 1) to afford
methyl 2,5-anhydro-6-azido-6-deoxy--gluconate 3 as a white
crystalline solid (706 mg, 85%).
C-2, C-3, C-4, C-5), 190.9 (s, C᎐O); m/z (APCIϪve): 158
᎐
([M Ϫ H]Ϫ, 96%).
Isopropyl 2,5-anhydro-D-gluconate 47
Sodium hydroxide solution (0.5M aq; 25 mL, 12.5 mmol) was
added to a stirred solution of methyl 2,5-anhydro--gluconate 8
(2.4 g, 12.5 mmol) in 1,4-dioxane (10 mL) at room temperature.
After 10 min, TLC (ethyl acetate) indicated the presence of a
single product (Rf 0.0) and no starting material (Rf 0.1). The
mixture was concentrated in vacuo (co-evaporation with tolu-
ene), suspended in propan-2-ol (25 mL) and cooled to 0 ЊC.
Concentrated sulfuric acid (0.2 mL) was added dropwise and
the mixture was heated at 80 ЊC for 18 h, when TLC (ethyl
acetate–methanol, 19 : 1) indicated the presence of a single
product (Rf 0.5) and no starting material (Rf 0.0). Sodium
hydieyescarbonate (4 g) was added and the mixture was stirred
for 2 h when pH 7 was reached. The reaction mixture was fil-
tered through Celite (eluent: propan-2-ol) and concentrated in
vacuo. The residue was purified by flash chromatography (ethyl
Method 2. Toluene-p-sulfonyl chloride (3.058 g, 16.0 mmol)
was added to a stirred solution of methyl 2,5-anhydro--
gluconate 8 (1.3 g, 16.0 mmol) and 3Å molecular sieves (2 g) in
pyridine (20 mL) at Ϫ10 ЊC, under an atmosphere of nitrogen.
After 3 h, TLC (ethyl acetate) indicated the presence of a major
compound (Rf 0.5) and no starting material (Rf 0.1). The
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1995

View Article Online
acetate–methanol, 19 : 1) to afford isopropyl 2,5-anhydro--
gluconate 47 as a white crystalline solid (2.643 g, 97%); (Found:
C, 48.82; H, 7.27. C9H16O6 requires : C, 49.09; H, 7.32%); m.p.
98 ЊC (ethyl acetate); [α]2D5 ϩ38.4 (c, 1.0 in methanol); νmax (thin
film): 3369 (br, OH), 1732 (s, C᎐O) cmϪ1; δ (CD3OD; 500
MHz): 1.27 (6H, a–t, J 6.3, (CH3)2CH), 3.72 (2H, d, J6,5 2.8, H2-
6), 3.90 (1H, dt, J5,6 2.8, J 4.4, H-5), 4.02 (1H, a–t, J 2.5, H-4),
4.19 (1H, dd, J 2.1, J3,2 4.5, H-3), 4.58 (1H, d, J2,3 4.5, H-2),
5.08 (1H, septet, J 6.3, (CH3)2CH ); δC (CD3OD; 50 MHz): 21.0
(1 × q, 2 × (CH3)2CH), 61.9 (1 × t, C-6), 69.0, 77.6, 78.1, 80.8,
of a single product (Rf 0.4) and no starting material (Rf 0.3).
The reaction mixture was filtered through Celite and concen-
trated in vacuo to give a residue, which was purified by flash
chromatography (ethyl acetate–hexane, 2 : 1) to afford iso-
propyl 2,5-anhydro-6-azido-6-deoxy--gluconate 49 as a white
crystalline solid (70 mg, 78%).
᎐
H
Method 3. Toluene-p-sulfonyl chloride (1.126 g, 5.9 mmol)
was added to a stirred solution of isopropyl 2,5-anhydro--
gluconate 47 (1.3 g, 5.9 mmol) and 3Å molecular sieves (1 g) in
pyridine (10 mL) at Ϫ10 ЊC, under an atmosphere of nitrogen.
After 18 h, TLC (ethyl acetate) indicated the presence of a
major compound (Rf 0.7) and no starting material (Rf 0.2). The
reaction mixture was warmed to room temperature, filtered
through Celite (eluent: dichloromethane), and washed with buf-
fer (pH 7, 50 mL) and the aqueous layer was extracted with
ethyl acetate (3 × 50 mL). The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo to give iso-
propyl 2,5-anhydro-6-O-p-tolylsulfonyl--gluconate 48 as white
solid which was used without further purification. Sodium
azide (576 mg, 8.9 mmol) was added to a stirred solution of
crude isopropyl 2,5-anhydro-6-O-p-toluylsulfonyl--gluconate
48 in DMF (15 mL), under an atmosphere of nitrogen. The
mixture was heated at 90 ЊC for 18 h, when TLC (ethyl acetate–
hexane, 2 : 1) indicated the presence of a major product (Rf 0.3)
and no starting material (UV visible, Rf 0.4). The reaction
mixture was cooled to room temperature, concentrated to
approximately 5 mL, diluted with ethyl acetate (50 mL), and
washed with buffer (pH 7; 30 mL). The aqueous layer was
extracted with ethyl acetate (3 × 60 mL) and the combined
organic phares were dried (MgSO4), filtered, and concentrated
in vacuo to give a residue, which was purified by flash chrom-
atography (ethyl acetate–hexane, 2 : 1) to afford isopropyl 2,5-
anhydro-6-azido-6-deoxy--gluconate 49 as a white crystalline
solid (1.09 g, 74% over two steps) (Found: C, 44.35; H, 6.16; N,
17.00. C9H15O5N3 requires C, 44.08; H, 6.16; N, 17.13%); m.p.
88–91 ЊC (ethyl acetate); [α]2D5 ϩ61.9 (c, 1.0 in methanol);
νmax (KBr disc): 3444 (br, OH), 2113 (N ), 1733 (C᎐O) cmϪ1;
86.9 (5 × d, C-2, C-3, C-4, C-5, (CH ) CH), 170.3 (1 × s, C᎐O);
᎐
3
2
m/z (APCIϩve): 243 (M ϩ Naϩ, 9%), 221 (M ϩ Hϩ, 55%),
179.0 (100%).
Isopropyl 2,5-anhydro-6-O-p-tolylsulfonyl-D-gluconate 48
Toluene-p-sulfonyl chloride (86 mg, 0.45 mmol) was added
to a stirred solution of isopropyl 2,5-anhydro--gluconate 47
(100 mg, 0.45 mmol) and 3Å molecular sieves (100 mg) in pyrid-
ine (3 mL) at Ϫ10 ЊC, under an atmosphere of nitrogen. After
18 h, TLC (ethyl acetate) indicated the presence of a major
compound (Rf 0.7) and no starting material (Rf 0.2). The reac-
tion mixture was warmed to room temperature, filtered through
Celite (eluent: dichloromethane), and washed with buffer (pH
7; 30 mL) and the aqueous layer was extracted with ethyl acet-
ate (3 × 35 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo to give a white
solid, which was pre-adsorbed onto silica and purified by flash
chromatography (ethyl acetate–hexane, 2 : 1) to afford isopropyl
2,5-anhydro-6-O-p-tolylsulfonyl--gluconate 48 as a white
crystalline solid (140 mg, 83%) (Found: C, 51.33; H, 5.93.
C16H22O8S requires C, 51.33; 5.84%); m.p. 148–151 ЊC (ethyl
acetate); [α]2D3 ϩ41.0 (c, 0.81 in methanol); νmax (thin film): 3455,
3399 (OH), 1730 (C᎐O) cmϪ1; δ (acetone-d6, 500 MHz): 1.19
᎐
H
(3H, d, J 6.3, (CH3)2CH), 1.20 (3H, d, J 6.3, (CH3)2CH), 2.46
(3H, s, CH3Ar), 4.00–4.03 (1H, m, H-5), 4.07–4.09 (1H, m,
H-4), 4.20 (1H, dd, J6,5 6.8, J6,6Ј 10.1, H-6), 4.25 (1H, d, J6Ј,5 5.8,
J6,6 10.1, H-6Ј), 4.35 (1H, a–dt, J 2.7, J3,2 5.1, H-3), 4.56 (1H, d,
J2,3 5.1, H-2), 4.69 (1H, JOH,4 4.3, exchanges with D2O, OH-4),
᎐
3
δH (CD3OD, 500 MHz): 1.27 (6H, a–t, J 6.2, (CH3)2CH), 3.38
(1H, dd, J6Ј,5 4.7, J6Ј,6 12.7, H-6Ј), 3.62 (1H, dd, J6,5 7.5, J6,6Ј 12.7,
H-6), 3.91–3.94 (1H, m, H-5), 3.95 (1H, dd, J4,3 3.0, J4,5 5.7,
H-4), 4.26 (1H, dd, J3,4 2.7, J3,2 5.1, H-3), 4.61 (1H, d, J2,3 5.1,
H-2), 5.07 (1H, septet, J 6.2, (CH3)2CH ): δC (CD3OD; 50
MHz): 20.6, 20.7 (2 × q, (CH3)2CH), 52.2 (1 × t, C-6), 68.5,
77.8, 78.1, 80.9, 84.9 (5 × d, C-2, C-3, C-4, C-5, (CH3)2CH),
4.71 (1H, d, JOH, 5.0, exchanges with D2O, OH-3), 5.07 (1H,
3
septet, J 6.3, (CH3)2CH), 7.48 (2H, d, J 8.2, 2 × ArH), 7.82–7.85
(2H, m, 2 × ArH); δC (CD3CN, 50 MHz): 20.3, 20.6, 20.7 (3 × q,
CH3Ar, (CH3)2CH), 69.7 (1 × t, C-6), 68.7, 77.5, 81.0, 83.3
(4 × d, (CH3)2CH), C-2, C-3, C-4, C-5), 127.7, 129.7 (2 × d,
4 × Ar–CH), 132.8, 145.1 (2 × s, OSO2C, CH3–ArC), 169.5
(1 × s, C᎐O); m/z (APCIϩve), 397 (M ϩ Naϩ, 8), 375 (M ϩ Hϩ,
᎐
169.6 (1 × s, C᎐O); m/z (APCIϩve): 268 (M ϩ Naϩ, 6), 246
᎐
35), 333 (100%).
(M ϩ Hϩ, 5), 218 (M ϩ Hϩ Ϫ N2, 100), 182 (35), 140 (37%).
Isopropyl 2,5-anhydro-6-azido-6-deoxy-D-gluconate 49
Methyl 2,5-anhydro-6-O-methylsulfonyl-D-mannonate 51
Method 1. Sodium azide (29 mg, 0.44 mmol) was added to a
stirred solution of isopropyl 2,5-anhydro-6-O-p-tolylsulfonyl-
-gluconate 48 (see also method 3, below), (110 mg, 0.29 mmol)
in DMF (3 mL), under an atmosphere of nitrogen. The mixture
was heated at 90 ЊC for 18 h, when TLC (ethyl acetate–hexane,
2 : 1) indicated the presence of a major product (Rf 0.3) and no
starting material (UV-visible, Rf 0.4). The reaction mixture was
cooled to room temperature, diluted with ethyl acetate (20 mL),
and washed with water (10 mL). The aqueous layer was
extracted with ethyl acetate (3 × 25 mL) and the combined
organic phases were dried (MgSO4), filtered, and concentrated
in vacuo to give a residue, which was purified by flash chromato-
graphy (ethyl acetate–hexane, 2 : 1) to afford isopropyl 2,5-
anhydro-6-azido-6-deoxy--gluconate 49 as a white crystalline
solid (62 mg, 86%).
Methanesulfonyl chloride (300 µL, 3.94 mmol) was added
dropwise to a stirred solution of methyl 2,5-anhydro--
mannonate 15 (445 mg, 2.32 mmol) and 4-(dimethylamino)-
pyridine (28 mg, 0.23 mmol) in pyridine (6 mL) at Ϫ20 ЊC,
under an atmosphere of nitrogen. After 2.5 h, TLC (ethyl acet-
ate) indicated the presence of a major compound (Rf 0.4) and
no starting material (Rf 0.2). Buffer solution (pH 7; 1 mL) was
added and the mixture was concentrated in vacuo to give a resi-
due, which was purified by flash chromatography (ethyl acetate–
hexane, 9 : 1) to afford methyl 2,5-anhydro-6-O-methylsulfonyl-
-mannonate 51 (450 mg, 72%) as a white crystalline solid
(Found: C, 35.73; H, 5.03. C8H14O8S requires C, 35.55; H,
5.22%); m.p. 74–75 ЊC; [α]2D1 ϩ41.7 (c, 1.02 in methanol); νmax
(thin film): 3466 (OH) 1738 (C᎐O), 1349, 1173 (OSO Me) cmϪ1;
᎐
2
δH (CD3CN; 500 MHz): 3.07 (3H, s, COOCH3), 3.63 (1H, d,
J 4.6, OH), 3.71 (3H, s, OSO2CH3), 3.82 (1H, d, J 4.7, OH), 3.94
(1H, a–q, J 4.5, H-4), 4.15 (1H, ddd, J5,6Ј 4.0, J5,4 4.6, J5,6 6.6,
H-5), 4.24 (1H, a–q, J 3.6, H-3), 4.28 (1H, dd, J6,5 6.5, J6,6Ј 11.0,
H-6), 4.34 (1H, dd, J6Ј,5 3.8, J6Ј,6 11.0, H-6Ј), 4.38 (1H, d, J2,3 3.4,
H-2); δC (CD3CN; 125 MHz): 37.8 (1 × q, OSO2CH3), 52.7
Method 2. Potassium carbonate (51 mg, 0.37 mmol) was
added to a stirred solution of methyl 2,5-anhydro-6-azido-6-
deoxy--gluconate 3 (80 mg, 0.37 mmol) in propan-2-ol (5 mL).
The reaction mixture was stirred at room temperature for 18 h,
when TLC (ethyl acetate–hexane, 2 : 1) indicated the presence
1996
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998

View Article Online
(1 × q, COOCH3), 70.7 (1 × t, C-6), 78.1, 81.3, 83.7, 83.8 (4 × d,
Isopropyl 2,5-anhydro-D-mannonate 53
C-2, C-3, C-4, C-5), 172.2 (1 × s, C᎐O); m/z (APCIϩve): 293
᎐
A solution of methyl 2,5-anhydro--mannonate 15 (9.8 g,
51.0 mmol) in 0.5M aqueous sodium hydroxide (103 mL,
51.5 mmol) was stirred at room temperature for 1 h, when TLC
(ethyl acetate–methanol, 19 : 1) indicated the presence of a
single compound (Rf 0.0) and no starting material (Rf 0.4). The
mixture was concentrated in vacuo by co-evaporation with tolu-
ene to afford an amorphous white solid. The mixture was sus-
pended in propan-2-ol (140 mL), conc. sulfuric acid (3 mL) was
added, and the suspension was heated to 80 ЊC. After 14 h, TLC
(ethyl acetate–methanol, 9 : 1) indicated the presence of a single
compound (Rf 0.5). Sodium dydrogen carbonate (10 g) was
added and the mixture was stirred for 1 h before being filtered,
and concentrated in vacuo to give a residue, which was purified
by flash chromatography (ethyl acetate–methanol, 19 : 1) to
afford isopropyl 2,5-anhydro--mannonate 53 as a white solid
(10.1 g, 90%), m.p. 61–65 ЊC (ethyl acetate) (Found: C, 48.81; H,
7.32. C9H16O6 requires C, 49.09; H, 7.32%); [α]2D5 ϩ44.1 (c, 1.0
(M ϩ Naϩ, 40), 271 (M ϩ Hϩ, 100%).
Methyl 2,5-anhydro-6-deoxy-6-azido-D-mannonate 52
Sodium azide (142 mg, 2.19 mmol) was added to a stirred solu-
tion of methyl 2,5-anhydro-6-O-methylsulfonyl--mannonate
51 (422 mg, 1.56 mmol) in DMF (12 mL) and the mixture was
heated to 65 ЊC. After 23 h, TLC (ethyl acetate) indicated the
presence of a major product (Rf 0.5) and no starting material
(Rf 0.3). The mixture was concentrated in vacuo, suspended in
ethyl acetate (30 mL), washed with buffer solution (pH 7; 5
mL), and extracted with ethyl acetate (2 × 20 mL). The com-
bined organic extracts were dried (MgSO4), filtered, and con-
centrated in vacuo to give a residue, which was purified by flash
chromatography (ethyl acetate–hexane, 3 : 2) to afford methyl
2,5-anhydro-6-deoxy-6-azido--mannonate 52 as a colourless
oil (329 mg, 98%) (Found: C, 38.67; H, 5.43; N, 19.21.
C7H11O5N3 requires C, 38.71; H, 5.10; N, 19.35%); [α]2D1 ϩ70.2
(c, 0.88 in methanol); νmax (thin film) 3401 (OH), 2104 (N3),
1737 (C᎐O) cmϪ1; δ (D2O; 500 MHz): 3.52 (1H, dd, J6,5 6.4,
in methanol); νmax (thin film) 3399 (br, OH), 1729 (C᎐O) cmϪ1;
᎐
δH (CD3OD; 500 MHz): 1.26 (6H, d,J 6.3, (CH3)2CH), 3.64
(1H, dd, J6,5 4.7, J6,6Ј 11.8, H-6), 3.72 (1H, dd, J6Ј,5 3.9, J6Ј,6 11.8,
H-6Ј), 3.98 (1H, a–t, H-4), 4.04 (1H, a–q,J 4.2, H-5), 4.24 (1H,
a–t,J 3.0, H-3), 4.33 (1H, d, J2,3 3.0, H-2), 5.04 (1H, septet,
J 6.3, (CH3)2CH ); δC (CD3OD, 125 MHz): 21.9 (2 × q,
(CH3)2CH), 63.0 (1 × t, C-6), 70.2, 78.7, 82.0, 84.4, 87.7 (5 × d,
᎐
H
J6,6Ј 13.4, H-6), 3.64 (1H, dd, J6Ј,5 3.8, J6Ј,6 13.5, H-6Ј), 3.80 (3H,
s, COOCH3), 4.09 (1H, dd, J4,3 4.2, J4,5 4,7, H-4), 4.16 (1H, ddd,
J5,6Ј 3.9, J5,4 4.8, J5,6 6.4, H-5), 4.40 (1H, a–t, J 4.0, H-3), 4.58
(1H, d, J2,3 4.0, H-2); δC (125 MHz; D2O) 51.3 (1 × t, C-6), 52.7
(1 × q, COOCH3), 76.8, 79.3, 81.4, 83.4 (4 × d, C-2, C-3, C-4,
C-2, C-3, C-4, C-5, (CH ) CH), 172.6 (1 × s, C᎐O); m/z
᎐
3 2
ϩ
C-5), 173.1 (1 × s, C᎐O); m/z (CI; NH ): 235 (M ϩ NH ,
(APCIϪve): 219.1 (20%, [M Ϫ H]ϩ).
᎐
3
4
100%), 218 (M ϩ Hϩ, 19%).
Isopropyl 2,5-anhydro-6-O-p-tolylsulfonyl-D-mannonate 54
Isopropyl 2,5-anhydro-6-azido-6-deoxy-D-mannonate 55
Toluene-p-sulfonyl chloride (1.08 g, 5.66 mmol) was added to a
stirred solution of isopropyl 2,5-anhydro--mannonate 53
(1.09 g, 4.95 mmol) and 3Å molecular sieves (1 g) in pyridine
(15 mL) at Ϫ10 ЊC, under an atmosphere of nitrogen. After
24 h, TLC (ethyl acetate) indicated the presence of a major
product (Rf 0.5) and no starting material (Rf 0.1). The mixture
was filtered through Celite (eluent–acetonitrile) and concen-
trated in vacuo. The residue was diluted with ethyl acetate
(40 mL), washed with buffer (pH 7; 20 mL), and the aqueous
layer was extracted with ethyl acetate (2 × 40 mL). The com-
bined organic phases were dried (MgSO4), filtered, and concen-
trated in vacuo to give a residue, which was purified by flash
chromatography (ethyl acetate–hexane, 5 : 1) to afford isopropyl
2,5-anhydro-6-O-p-tolylsulfonyl--mannonate 54 as a white
crystalline solid (1.31 g, 62%); (Found C, 51.33; H, 5.84.
C16H22O8S requires C, 51.33; H, 5.84 %); m.p. 120–123 ЊC; [α]2D4
ϩ46.6 (c, 0.85 in methanol); νmax (thin film): 3422 (OH), 1716
(COOCH3) cmϪ1; δH (acetone-d6, 400 MHz): 1.23 (3H, d, J 6.2,
(CH3)2CH), 1.24 (3H, d, J 6.2, (CH3)2CH), 4.01 (1H, m, H-4),
4.13–4.20 (2H, m, H-6, H-5), 4.23 (1H, m, H-6Ј), 4.27 (1H, d,
J2,3 2.9, H-2), 4.32–4.35 (1H, m, H-3), 4.58 (1H, d, JOH,4 4.3,
OH-4), 4.79 (1H, d, JOH,3 4.6, OH-3), 5.00 (1H, septet, J 6.2,
(CH3)2CH ), 7.51 (2H, d, J 8.0, 2 × ArH), 7.84–7.86 (2H, m,
2 × ArH); δC (CD3OD; 50 MHz): 21.8 (1 × q, CH3–Ar), 22.1
(2 × q, (CH3)2CH), 70.8 (1 × t, C-6), 70.5, 78.4, 81.7, 83.4, 84.5
(5 × d, C-2, C-3, C-4, C-5, (CH3)2CH), 129.2, 131.2 (2 × d,
4 × Ar–CH), 134.1, 146.7 (2 × s, OSO2C, CH3–ArC), 172.2
Method 1. Sodium azide (26 mg, 0.4 mmol) was added to a
stirred solution of isopropyl 2,5-anhydro-6-O-p-tolylsulfonyl-
-mannonate 54 (see below) (100 mg, 26 mmol) in DMF (3 mL)
and the mixture was heated to 80 ЊC. After 18 h, TLC (ethyl
acetate–hexane, 3 : 1) indicated the presence of a major product
(Rf 0.6) and no starting material (Rf 0.5, UV-visible). The mix-
ture was cooled, concentrated in vacuo, suspended in ethyl acet-
ate (50 mL), washed with buffer solution (pH 7; 10 mL), and
extracted with ethyl acetate (2 × 20 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated in vacuo
to give a residue, which was purified by flash chromatography
(ethyl acetate–hexane, 3 : 1) to afford isopropyl 2,5-anhydro-6-
deoxy-6-azido--mannonate 55 as a white crystalline solid
(58 mg, 99%).
Method 2. Potassium carbonate (658 mg, 4.77 mmol) was
added to a stirred solution of methyl 2,5-anhydro-6-azido-6-
deoxy--mannonate 52 (950 mg, 4.34 mmol) in propan-2-ol
(5 mL). The reaction mixture was stirred at room temperature
for 26 h, when TLC (ethyl acetate–hexane, 3 : 1) indicated the
presence of a single product (Rf 0.6) and no starting material
(Rf 0.5). The reaction mixture was filtered through Celite and
concentrated in vacuo to give a residue, which was purified by
flash chromatography (ethyl acetate–hexane, 2 : 1) to afford
isopropyl 2,5-anhydro-6-azido-6-deoxy--mannonate 55 as a
white crystalline solid (900 mg, 85%) (Found: C, 44.16; H, 6.01;
N, 17.13 . C9H15O5N3 requires C, 44.08; H, 6.16; N, 17.13%);
m.p. 47–53 ЊC (ethyl acetate); [α]2D3 ϩ58.6 (c, 1.0 in methanol);
νmax (thin film): 3362 (br, OH), 2100 (N ), 1728 (C᎐O) cmϪ1;
(1 × s, C᎐O); m/z (APCIϩve): 397 (M ϩ Naϩ, 10), 333.1 (50),
᎐
(287.1, 50%).
᎐
3
X-Ray determination†
δH (CD3OD; 500 MHz): 1.26 (6H, d, J 6.3, (CH3)2CH), 3.42
(1H, dd, J6,5 6.3, J6,6Ј13.1, H-6Ј), 3.47 (1H, dd, J6Ј,5 4.3, J6Ј,6Ј 13.1,
H-6Ј), 3.92 (1H, dd, J4,3 3.5, J4,5 4.7, H-4), 4.09 (1H, a–dt, J 4.5,
J5,6Ј 6.3, H-5), 4.25 (1H, a–t, J 3.4, H-3), 4.33 (1H, d, J2,3 3.4,
H-2), 5.05 (1H, septet, J 6.3, (CH3)2CH); δC (CD3OD, 50 MHz):
22.0 (2 × q, (CH3)2CH), 53.3 (1 × t, C-6), 70.3, 79.3, 82.1, 84.2,
Crystal structure determination of 39b. Crystals of 39b were
recrystallised from ethyl acetate–hexane.
Crystal data. C18H34O5N4, Mr 772.52 g molϪ1 (2 asymmetric
units in the unit cell), Monoclinic, a (Å) 18.382, b (Å) 8.655,
c (Å) 27.054, V (Å3) 4201.35, T (K) 293, Space group: C121,
85.7 (5 × d, C-2, C-3, C-4, C-5, (CH ) CH), 172.5 (1 × s, C᎐O);
᎐
3
2
m/z (APCIϪve): 244 ([M Ϫ H]ϩ, 10%), 216 ([M Ϫ H Ϫ N2]ϩ,
5%), 129 (100%). (APCIϩve): 218.1 (M ϩ Hϩ Ϫ N2, 60), 200.1
(100), 176 (50), 157.9 (70%).
† CCDC reference number(s) 182246–182247. See http://www.rsc.org/
suppdata/p1/b1/b111258a/ for crystallographic files in .cif or other
electronic format.
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998
1997

View Article Online
Z = 8, ZЈ = 2, µ = 0.70 mmϪ1, No. of independent reflections:
4202, Rint: 0.013, No. of reflections used: 3762, R 0.0745, wR
0.0971.
26 D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo, L. Oberer,
U. Hommel, R. Amstutz and H. Widmer, Helv. Chim. Acta, 1996,
79, 2043.
27 D. Seebach, J. V. Schreiber, P. I. Arvidsson and J. Frackenpohl,
Helv. Chim. Acta, 2001, 84, 271.
28 R. P. Cheng, S. H. Gellman and W. F. DeGrado, Chem. Rev., 2001,
101, 3219.
29 M. P. Watterson, L. Pickering, M. D. Smith, S. J. Hudson,
P. R. Marsh, J. E. Mordaunt, D. J. Watkin, C. J. Newman and
G. W. J. Fleet, Tetrahedron: Asymm., 1999, 10, 1855.
30 S. F. Barker, D. Angus, C. Taillefumier, M. R. Probert, D. J. Watkin,
M. P. Watterson, T. D. W. Claridge, N. L. Hungerford and G. W. J.
Fleet, Tetrahedron Lett., 2001, 42, 4247.
Crystal- structure determination of 38a. Crystals of 38a were
recrystallised from ethyl acetate–hexane.
Crystal data. C7H12O5N4, Mr 232.20 g molϪ1, Monoclinic,
a (Å) 7.147, b (Å) 6.349, c (Å) 11.384, V (Å3) 496.46, T (K) 293,
Space group: P1211, Z = 2, µ = 1.10 mmϪ1, No. of independent
reflections: 3127, Rint: 0.019 No. of reflections used: 1978 R
0.0275, wR 0.0230.
31 T. D. W. Claridge, J. M. Goodman, A. Moreno, D. Angus,
S. F. Barker, C. Taillefumier, M. P. Watterson and G. W. J. Fleet,
Tetrahedron Lett., 2001, 42, 4251.
32 M. D. Smith, D. D. Long, D. G. Marquess, T. D. W. Claridge and
G. W. J. Fleet, Chem. Commun., 1998, 2039.
33 S. M. S. Choi, P. M. Myerscough, A. J. Fairbanks, B. M. Skead,
C. J. F. Bichard, S. J. Mantell, J. C. Son, G. W. J. Fleet, J. Saunders
and D. Brown, J. Chem. Soc., Perkin Trans. 1, 1992, 1605.
34 J. R. Wheatley, C. J. F. Bichard, S. J. Mantell, J. C. Son, D. J. Hughes,
G. W. J. Fleet and D. Brown, J. Chem. Soc., Perkin Trans. 1, 1993,
1065.
35 C. J. F. Bichard, T. W. Brandstetter, J. C. Estevez, G. W. J. Fleet,
D. J. Hughes and J. R. Wheatley, J. Chem. Soc., Perkin Trans. 1,
1996, 2151.
Acknowledgements
Support from EPSRC, GlaxoWellcome and the European
Community (for a postdoctoral fellowship [contract no.
ERBFMBICT961664]) is gratefully acknowledged.
References
1 J. P. McDevitt and P. T. Lansbury, J. Am. Chem. Soc., 1996, 118,
3818; F. Schweizer, Angew. Chem., Int. Ed., 2002, 41, 230.
2 M. D. Smith and G. W. J. Fleet, J. Pept. Sci., 1999, 5, 425; S. A. W.
Gruner, E. Locardi, E. Lohof and H. Kessler, Chem. Rev., 2002, 102,
491.
3 E. G. vonRoedern and H. Kessler, Angew. Chem., Int. Ed. Engl.,
1994, 33, 687.
4 E. G. vonRoedern, E. Lohof, G. Hessler, M. Hoffmann and
H. Kessler, J. Am. Chem. Soc., 1996, 118, 10156.
5 L. Poitout, Y. Le Merrer and J. C. Depezay, Tetrahedron Lett., 1995,
36, 6887.
6 M. D. Smith, D. D. Long, A. Martin, N. Campbell, Y. Bleriot and
G. W. J. Fleet, Synlett, 1999, 1151.
36 T. W. Brandstetter, C. de la Fuente, Y. H. Kim, R. I. Cooper,
D. J. Watkin, N. G. Oikonomakos, L. N. Johnson and G. W. J. Fleet,
Tetrahedron, 1996, 52, 10711.
37 T. W. Brandstetter, C. de la Fuente, Y. H. Kim, L. N. Johnson,
S. Crook, P. Lilley, D. J. Watkin, K. E. Tsitsanou, S. E. Zographos,
E. D. Chrysina, N. G. Oikonomakos and G. W. J. Fleet, Tetrahedron,
1996, 52, 10721.
38 H. Frank and I. Lundt, Tetrahedron, 1995, 51, 5397.
39 H. B. Sinclair, Carbohydr. Res., 1984, 127, 146.
40 S. J. Mantell, G. W. J. Fleet and D. Brown, J. Chem. Soc., Perkin
Trans. 1, 1991, 1563.
7 M. Lakhrissi and Y. Chapleur, Tetrahedron Lett., 1998, 39, 4659.
8 A. Dondoni, M. C. Scherrmann, A. Marra and J. L. Delepine,
J. Org. Chem., 1994, 59, 7517.
9 V. Gyollai, L. Somsak and L. Szilagyi, Tetrahedron Lett., 1999, 40,
3969.
41 J. A. J. M. Vekemans, J. Boerekamp, E. F. Godefrei and G. J. F.
Chittenden, Recl. Trav. Chim. Pays-Bas, 1985, 104, 266.
42 I. Kalnwish, K. H. Mette and R. Bruckner, Heterocycles, 1995, 40,
939.
43 J. C. Estevez, A. J. Fairbanks, K. Y. Hsia, P. Ward and G. W. J. Fleet,
Tetrahedron Lett., 1994, 35, 3361.
44 C. Taillefumier, S. Colle and Y. Chapleur, Carbohydr. Lett., 1996, 2,
39.
45 H. Regeling, E. de Rouville and G. J. F. Chittenden, Recl. Trav.
Chim. Pays-Bas, 1987, 106, 461.
10 C. J. F. Bichard, E. P. Mitchell, M. R. Wormald, K. A. Watson,
L. N. Johnson, S. E. Zographos, D. D. Koutra, N. G. Oikonomakos
and G. W. J. Fleet, Tetrahedron Lett., 1995, 36, 2145.
11 T. M. Krulle, K. A. Watson, M. Gregoriou, L. N. Johnson,
S. Crook, D. J. Watkin, R. C. Griffiths, R. J. Nash, K. E. Tsitsanou,
S. E. Zographos, N. G. Oikonomakos and G. W. J. Fleet, Tetrahedron
Lett., 1995, 36, 8291.
12 T. W. Brandstetter, Y. H. Kim, J. C. Son, H. M. Taylor, P. M. D.
Lilley, D. J. Watkin, L. N. Johnson, N. G. Oikonomakos and
G. W. J. Fleet, Tetrahedron Lett., 1995, 36, 2149.
46 R. Csuk, M. Hugener and A. Vasella, Helv. Chim. Acta, 1988, 71,
609.
13 H. Haruyama, T. Takayama, T. Kinoshita, M. Kondo, M. Nakajima
and T. Haneishi, J. Chem. Soc., Perkin Trans. 1, 1991, 1637.
14 M. Nakajima, K. Itoi, Y. Takamatsu, T. Kinoshita, T. Okazaki,
K. Kawakubo, M. Shindo, T. Honma, M. Tohjigamori and T.
Haneishi, J. Antibiot., 1991, 44, 293.
15 J. C. Estevez, R. J. Estevez, H. Ardron, M. R. Wormald, D. Brown
and G. W. J. Fleet, Tetrahedron Lett., 1994, 35, 8885.
16 J. C. Estevez, H. Ardron, M. R. Wormald, D. Brown and G. W. J.
Fleet, Tetrahedron Lett., 1994, 35, 8889.
47 M. H. Adams, R. I. Reeves and W. F. Goebel, J. Biol. Chem., 1941,
140, 653.
48 K. Freudenberg, H. Hochstetter and H. Engels, Ber. Dtsch. Chem.
Ges., 1925, 58, 666.
49 C. J. F. Bichard, J. R. Wheatley and G. W. J. Fleet, Tetrahedron:
Asymm., 1994, 5, 431.
50 T. M. Krulle, B. Davis, H. Ardron, D. D. Long, N. A. Hindle,
C. Smith, D. Brown, A. L. Lane, D. J. Watkin, D. G. Marquess and
G. W. J. Fleet, Chem. Commun., 1996, 1271.
17 J. C. Estevez, J. W. Burton, R. J. Estevez, H. Ardron, M. R.
Wormald, R. A. Dwek, D. Brown and G. W. J. Fleet, Tetrahedron:
Asymm., 1998, 9, 2137.
18 S. H. Gellman, Acc. Chem. Res., 1998, 31, 173; D. J. Hill, M. J. Mio,
R. B. Prince, T. S. Hughes and J. S. Moore, Chem. Rev., 2001, 101,
3893.
51 S. J. Mantell, P. S. Ford, D. J. Watkin, G. W. J. Fleet and D. Brown,
Tetrahedron, 1993, 49, 3343.
52 H. G. Viehe, Z. Janousek, R. Merenyi and L. Stella, Acc. Chem.
Res., 1985, 18, 148.
53 L. Somsak and R. J. Ferrier, Adv. Carbohydr. Chem. Biochem., 1991,
49, 37.
19 M. D. Smith, T. D. W. Claridge, G. E. Tranter, M. S. P. Sansom and
G. W. J. Fleet, Chem. Commun., 1998, 2041.
20 T. D. W. Claridge, D. D. Long, N. L. Hungerford, R. T. Aplin,
M. D. Smith, D. G. Marquess and G. W. J. Fleet, Tetrahedron Lett.,
1999, 40, 2199.
54 S. Choi, D. R. Witty, G. W. J. Fleet, P. L. Myers, R. Storer,
C. J. Wallis, D. Watkin and L. Pearce, Tetrahedron Lett., 1991, 32,
3569.
55 S. Mio, M. Ueda, H. Harayuma, K. Kitagawa and S. Sugai,
Tetrahedron, 1991, 47, 2145.
21 T. K. Chakraborty, S. Jayaprakash, P. V. Diwan, R. Nagaraj, S. R. B.
Jampani and A. C. Kunwar, J. Am. Chem. Soc., 1998, 120, 12962.
22 S. A. W. Gruner, G. Keri, R. Schwab, A. Venetianer and H. Kessler,
Org. Lett., 2001, 3, 3723.
23 B. Aguilera, G. Siegal, H. S. Overkleeft, N. J. Meeuwenoord,
F. Rutjes, J. C. M. van Hest, H. E. Schoemaker, G. A. van der Marel,
J. H. van Boom and M. Overhand, Eur. J. Org. Chem., 2001, 1541.
24 D. H. Appella, L. A. Christianson, I. L. Karle, D. R. Powell and
S. H. Gellman, J. Am. Chem. Soc., 1996, 118, 13071.
25 D. H. Appella, J. J. Barchi, S. R. Durell and S. H. Gellman, J. Am.
Chem. Soc., 1999, 121, 2309.
56 S. Mio, M. Shiraishi, H. Harayuma and S. Sato, Tetrahedron, 1991,
47, 2121.
57 T. W. Brandstetter, M. R. Wormald, R. A. Dwek, T. D. Butters,
F. M. Platt, K. E. Tsitsanou, S. E. Zographos, N. G. Oikonomakos
and G. W. J. Fleet, Tetrahedron: Asymm., 1996, 7, 157.
58 J. C. Estevez, M. D. Smith, M. R. Wormald, G. S. Besra,
P. J. Brennan, R. J. Nash and G. W. J. Fleet, Tetrahedron: Asymm.,
1996, 7, 391.
59 D. E. A. Brittain, M. P. Watterson, T. D. W. Claridge, M. D. Smith
and G. W. J. Fleet, J. Chem. Soc., Perkin Trans. 1, 2000, 3655.
60 E. H. Goodyear and W. N. Haworth, J. Chem. Soc., 1927, 3136.
1998
J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998