A Ramberg-Baecklund approach to the synthesis of C-glycosides, C-linked disaccharides, and C-glycosyl amino acids

Article abstract of DOI:10.1002/1099-0690(200204)2002:7<1323::AID-EJOC1323>3.0.CO;2-8

Synthetic applications of exo-glycals, derived from S-glycoside dioxides using the Meyers variant of the Ramberg-Baecklund rearrangement, are described. These include a formal synthesis of a β-glycosidase inhibitor 12 and an efficient route to spirocyclic glucose derivatives 17 and 18. The synthesis of C-linked disaccharides 24, 31, and 38 and the C-glycosyl amino acid 49 using the Ramberg-Baecklund rearrangement is also reported. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200204)2002:7<1323::AID-EJOC1323>3.0.CO;2-8

FULL PAPER
A Ramberg؊Bäcklund Approach to the Synthesis of C-Glycosides, C-Linked
Disaccharides, and C-Glycosyl Amino Acids
Duncan E. Paterson,[a] Frank K. Griffin,[a] Marie-Lyne Alcaraz,[a] and
Richard J. K. Taylor*[a]
Keywords: Carbohydrates / Sulfones / Rearrangements / exo-Glycals
Synthetic applications of exo-glycals, derived from S-glyco-
18. The synthesis of C-linked disaccharides 24, 31, and 38
side dioxides using the Meyers variant of the and the C-glycosyl amino acid 49 using the
Ramberg−Bäcklund rearrangement, are described. These in-
clude a formal synthesis of a β-glycosidase inhibitor 12 and
an efficient route to spirocyclic glucose derivatives 17 and
Ramberg−Bäcklund rearrangement is also reported.
Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
(
Introduction
enation of the corresponding lactones,[3,4] it is the availabil-
ity of tri- and tetra-substituted alkenes from the
RambergϪBäcklund approach which offers an advantage
over other routes. Herein we report synthetic applications
of some of these alkenes and other more general extensions
and applications of this methodology.
Carba-analogues of glycosides and glycoconjugates have
attracted considerable interest over the last three decades
in view of their hydrolytic stability and potential enzyme
inhibitory properties. Virtually the complete repertoire of
carbonϪcarbon bond-forming reactions has been deployed
for the synthesis of this class of compound and several re-
views have been published on the subject.[1] Recent work in
our laboratory has focussed on the use of the
RambergϪBäcklund rearrangement of S-glycoside dioxides
1 as the key step in the formation of exo-glycals 2,[2a,2c]
(Scheme 1). Although the parent exo-methylenic derivatives
such as 2a are also accessible by titanium-mediated methyl-
Results and Discussion
Formal Synthesis of Glycosidase Inhibitor 12
The enol ether moiety of 2a has been extensively elabo-
rated by other groups to produce a variety of modified glu-
cose derivatives, as illustrated in Scheme 2. Dipolar cyclo-
addition using carbomethoxy nitrile oxide occurs stereose-
lectively to give isoxazoline 3[3] whereas epoxidation using
dimethyldioxirane (DMDO) produces a diastereomeric
mixture of epoxides 4.[5,6] Radical addition of thiolacetic
acid proceeds via an anomerically-stabilised axial C1-rad-
ical to give adduct 5[5] and boron trifluoride-catalysed
dimerisation produces the C-linked disaccharide 6.[7] 1-C-
Methyl-α-O-disaccharides have also been prepared from
exo-glycals by Lewis acid-catalysed reactions with glycosyl
acceptors.[8] The stereoselective 9-BBN hydroboration-ox-
idation of 2a to give exclusively the β-C-glycoside 7 was
initially described by RajanBabu and Reddy;[3] Johnson and
Johns have demonstrated that the intermediate organobo-
rane can undergo palladium-catalysed cross-coupling reac-
tions to give the aromatic C-glycoside derivatives 8.[9] We
have also recently reported the synthesis of a C-glycosyl
amino acid by the Suzuki coupling of this organoborane
with a vinyl iodide derived from the Garner aldehyde.[10] In
addition, we have carried out the dihydroxylation of exo-
glycal 2a to produce the known tetrabenzyl-α--gluco-2-
heptulopyranose 9 {m.p. 111 °C, ref.[11] 112.5Ϫ113.5 °C.
[α]D20 ϭ ϩ13.6 (c ϭ 1.4, CHCl3), ref.[11] ϩ14.7 (c ϭ 0.97,
Scheme 1. Reagents: (i) KOH, CCl4, aq. tBuOH, 60 °C; (ii) KOH/
Al2O3, CBr2F2, tBuOH, DCM, 5 °C to room temp. Bzl ϭ benzyl;
DCM ϭ dichloromethane
[a]
Department of Chemistry, University of York,
Heslington, York, YO10 5DD, UK
Fax: (internat.)ϩ44-1904/432-543
E-mail: rjkt1@york.ac.uk
Eur. J. Org. Chem. 2002, 1323Ϫ1336
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0407Ϫ1323 $ 17.50ϩ.50/0
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D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor
FULL PAPER
Scheme 2. exo-Glycals are versatile intermediates for the synthesis of more highly functionalised C-glycosides
CHCl3)}. Sigmatropic rearrangements involving the enol ration of 2b was attempted using 9-BBN, no reaction was
ether function have recently been described: a Claisen observed, presumably for steric reasons. However, hydro-
rearrangement of 6-vinyl exo-glycals[12] and
a
boration with BH3·THF followed by oxidative workup af-
ClaisenϪIreland rearrangement of 2-O-acyl exo-glycals[13] forded a separable mixture of the secondary alcohols 10
furnish cyclooctene and C-glycan derivatives, respectively. and 11; the latter, which predominates, has been converted
Exomethylenic sugars have also proved to be good sub- into the novel β-glycosidase inhibitor 12 in five steps by
strates for ring-closing olefin metathesis: derivatives of 2a Schmidt and Dietrich.[16] The formation of the major dia-
bearing an unsaturated side chain at position 2 have been stereomer 11 results from addition of borane from the lower
shown to undergo ruthenium catalysed ring closure to give face of the double bond, as shown in Scheme 3. The C1
bicyclic glycosylidene compounds.[14] Postema and Cali- configuration of 11 was established by comparison with lit-
mente have also exploited this powerful carbonϪcarbon erature data {[α]2D0 ϭ ϩ8.5 (c ϭ 1.5, CHCl3), ref.[17] ϩ7.5
bond-forming process for the preparation of C1-substituted (c ϭ 1.0, CHCl3)} and hence, due to the demands of the
glycals[15a] and C-linked disaccharides.[15b]
stereospecific syn-addition of the borane, the (Z)-geometry
The phenyl-substituted exo-glycal derivative 2b is acces- of the double bond in the substrate 2b was able to be con-
sible in high yield and good stereoselectivity from the tan- clusively assigned. The observation of NOEs between
dem halogenation-RambergϪBäcklund rearrangement of HϪC1 and HϪC3 on (Z)-2b supports this conclusion (al-
benzyl sulfone 1b (Scheme 1). We decided to explore the though insufficient quantities of the pure (E)-isomer were
elaboration of this substrate (Scheme 3). When hydrobo- available to conduct comparative experiments).
Scheme 3. HydroborationϪoxidation of exo-glycal 2b to give the known C-glycoside 11
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A RambergϪBäcklund Approach to the Synthesis of C-Glycosides
FULL PAPER
Preparation of Spirocyclic Glucose Derivatives
and yeasts and is the main carbohydrate component of the
blood of many insects.[23]
The vinyl ether moiety of exo-glycals is readily pro-
tonated at the exocyclic carbon atom to form an oxycarben-
ium intermediate, which can be trapped by a variety of nu-
cleophiles. Hence, our next aim was the synthesis of a tri-
substituted exo-glycal with a pendant hydroxyl group which
should undergo acid-catalysed intramolecular addition to
the double bond to form spirocyclic sugars 17 and 18.
These compounds, which are simplified analogues of anti-
viral natural products such as papulacandin D,[18] have been
prepared by a number of different routes including ring-
closing metathesis of unsaturated ketosides[19] and radical
cyclisation of hydroxyalkyl glycosides.[20] In our new syn-
thesis (Scheme 4), 2,3,4,6-tetra-O-benzyl-1-thio-β--glu-
cose[21] (13) was alkylated with 3-chloropropan-1-ol to give
sulfide 14, which was then oxidised to sulfone 15 with
mCPBA. Pleasingly, the unprotected alcohol 15 underwent
halogenative RambergϪBäcklund rearrangement smoothly
using Chan’s modified conditions[22] to give exo-glycal 16
in 74% yield (Z/E ϭ 80:20). Acid-catalysed cyclisation was
achieved by treatment of a methanol solution of 16 with
camphorsulfonic acid (CSA) to give a separable mixture of
the spiroacetals 17[19,20] and 18[20] (70:30) in a combined
yield of 76%, with the thermodynamically more stable
product predominating. Although the optical rotations of
the two isomers are similar, comparison of the 13C signals
of the spiro centres with literature values allowed us to con-
firm their stereochemistry: 17, δC: 107.3 (C1), ref.[20] 107.3;
18, δC: 109.8 (C1), ref.[20] 109.9.
Scheme 5. Generic representation of a RambergϪBäcklund exo-
glycal-based approach to C-disaccharide synthesis; FGI ϭ func-
tional group interconversion
C-Trehaloses have been prepared by the groups of Ki-
shi[24] and Martin,[25] and recently Schmidt and Patro have
reported the synthesis of novel isotrehalose analogues with
a functionalised linking carbon.[26] Our strategy, outlined
in Scheme 6, required the preparation of the thioglycoside-
derived intermediate 20. This compound was readily avail-
able from the coupling of the known thiol 13[21] and iodide
19, itself easily accessible from exo-glycal 2a by hydrobo-
C-Linked Disaccharide Synthesis
The natural progression of this work was towards the ration-oxidation[3] followed by iodination using the method
synthesis of C-linked disaccharides, as outlined in of Garegg and Samuelsson.[27] The corresponding sulfone-
Scheme 5. Our first target was a carba-analogue of isotre- linked disaccharide was then obtained by oxidation with
halose [β--glucopyranosyl-(1Ǟ1Ј)-β--glucopyranose], a mCPBA, providing 21 in 93% yield from 19.
member of a family of disaccharides in which residues are RambergϪBäcklund rearrangement of 21 proceeded in
linked through their anomeric centres. Trehalose [α-- moderate yield under Meyers’ conditions[28] to afford enol
glucopyranosyl-(1Ǟ1Ј)-α--glucopyranose] occurs natur- ether 22, predominantly as the (Z)-isomer (Z/E ϭ 91:9).
ally as a storage carbohydrate in certain plants, algae, fungi, Stereochemical assignment was based on the trend that the
Scheme 4. Synthesis of spirocyclic glucose derivatives; reagents: (i) Cl(CH2)3OH, K2CO3, acetone, reflux; (ii) mCPBA, Na2HPO4, DCM;
(iii) KOH/Al2O3, CBr2F2, tBuOH, DCM, 5 °C to room temp.; (iv) CSA, MeOH. mCPBA ϭ meta-chloroperoxybenzoic acid, CSA ϭ
camphorsulfonic acid
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D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor
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Scheme 6. Synthesis of C-isotrehalose; reagents: (i) 9-BBN, THF, 0 °C to room temp., then H2O2, aq. KOH; (ii) PPh3, imidazole, I2,
toluene, 70 °C; (iii) K2CO3, acetone, reflux; (iv) mCPBA, Na2HPO4, DCM; (v) KOH, CCl4, aq. tBuOH, 60 °C; (vi) H2, Pd/C, MeOH,
EtOAc; (vii) H2, Pd(OH)2/C, EtOH, EtOAc; (viii) Ac2O, pyridine; 9-BBN ϭ 9-borabicyclo[3.3.1]nonane
vinylic protons of (Z)-exo-glycals resonate at lower field in used previously. The resulting sulfone 29 underwent a hal-
the 1H NMR spectrum than those in the corresponding (E)- ogenative RambergϪBäcklund rearrangement to give exo-
isomers.[29] Hydrogenolytic O-debenzylation followed by glycal 30 as a 88:12 mixture of (Z)- and (E)-isomers in 57%
acetylation led, unintentionally, to ketal 23 as a result of yield. Subsequent reduction/debenzylation followed by
acid-catalysed addition of methanol to the vinyl ether of 22. acetylation produced the novel, ethylene-bridged disacchar-
1
However when ethanol was used as the co-solvent, double ide 31. Again the H and 13C NMR spectroscopic data re-
bond reduction and deprotection of 22 were achieved in vealed the magnetic equivalence of each sugar residue, in
good yield to give C-isotrehalose (24), which was converted agreement with a symmetrical β,β-linked structure.
into its peracetate derivative 25 for characterisation. The
We then turned our attention to the preparation of the
NMR spectroscopic data were consistent with the forma- carba-analogue of the (1Ǟ6Ј)-disaccharide methyl gen-
tion of a symmetrical β,β-linked disaccharide and also tiobioside, which was first synthesised by Rouzaud and Si-
agreed with published data.[25]
nay¨.[32] This allowed us the opportunity to widen the scope
We believe that this methodology offers a rapid, conver- of the methodology still further: instead of using an S-gly-
gent and practically simple route to β,β-(1Ǟ1Ј)-carba-di- coside-derived sulfone in the key RambergϪBäcklund re-
saccharides. Although we have shown that the intermediate arrangement we planned to prepare a more symmetrical
enol ether 22 can be elaborated further by the addition of sulfone-linked precursor in which the sulfonyl group was
alcohols, a variety of alternative synthetic elaborations positioned centrally and flanked on each side by a methyl-
could be attempted on this substrate, for example hydrobo- ene attached to a monosaccharide unit.
ration, epoxidation, dihydroxylation, or dipolar cycloaddi-
tion, in order to introduce functionality to the carbon simple thioetherificationϪoxidation routine previously de-
bridge. scribed (Scheme 8). With iodide 19 already at hand, we re-
The desired substrate was readily prepared using the
This approach is well suited to analogue synthesis simply quired only the complementary thiol 34. This was obtained
by varying the alkylating agent. Thus, the homologated from alcohol 32[33] by displacement with thiolacetic acid
(1Ǟ1Ј)-carba-disaccharide 31 containing a two-carbon under Mitsunobu conditions, followed by deacetylation. S-
bridge (‘‘homoisotrehalose’’) was readily prepared Alkylation of 34 and oxidation of the resulting sulfide gave
(Scheme 7). Lactol 26 was converted into sulfonate 27c by sulfone 36 in high yield. Treatment of 36 with KOH/Al2O3
a straightforward three-step sequence[30] involving Moffat- and CBr2F2 gave the desired unsaturated C-disaccharide 37
type C-glycosylation[31] to give ester 27a[30] followed by re- in 64% yield (Z/E ϭ 74:26). This alkene has been prepared
duction and mesylation; 27c was then coupled with thiol previously by Kishi[34] and by Dondoni[35] who also de-
13[21] in a similar alkylationϪoxidation sequence to that scribed its hydrogenation/debenzylation to furnish methyl
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A RambergϪBäcklund Approach to the Synthesis of C-Glycosides
FULL PAPER
Scheme 7. Synthesis of homoisotrehalose; reagents: (i) (EtO)2P(O)CH2CO2Et, NaH, THF;[30] (ii) LiAlH4, THF;[30] (iii) MsCl, Et3N,
DCM; (iv) K2CO3, acetone, reflux; (v) Oxone , THF, MeOH, H2O; (vi) KOH, CCl4, aq. tBuOH, 65 °C; (vii) H2, Pd(OH)2/C, EtOH,
EtOAc; (viii) Ac2O, pyridine; Ms ϭ mesyl ϭ methanesulfonyl
Scheme 8. Synthesis of methyl C-gentiobioside; reagents: (i) PPh3, DIAD, AcSH, THF, 0 °C to room temp.; (ii) NaOMe, MeOH;
(iii) K2CO3, acetone, reflux; (iv) mCPBA, Na2HPO4, DCM; (v) KOH/Al2O3, CBr2F2, tBuOH, DCM, 5 °C to room temp.; (vi) H2,
Pd(OH)2/C, MeOH, EtOAc; (vii) Ac2O, pyridine;[35] DIAD ϭ diisopropylazodicarboxylate
C-gentiobioside (38). We carried out the hydrogenation un- common sites for protein glycosylation are the amide nitro-
der the same conditions and then prepared heptaacetate 39 gen of asparagine (Figure 1, a) and the hydroxyl group of
which displayed spectroscopic data consistent with those re- serine and threonine (Figure 1, b). Replacement of the gly-
ported in the literature {[α]2D0 ϭ ϩ65.1 (c ϭ 0.45, CHCl3), cosidic nitrogen or oxygen by carbon gives the correspond-
ref.[35] ϩ63 (c ϭ 0.7, CHCl3)}.
ing C-glycoside analogues (glycopeptidomimetics), the syn-
thesis of which has been the subject of several recent pub-
lications[38] and a review article.[39] We also now report the
application of our RambergϪBäcklund methodology to the
synthesis of a carba-analogue of glucosyl serine.
C-Glycosyl Amino Acid Synthesis
Interest in the structure and function of glycoproteins has
grown enormously in recent years.[36] However, despite their
diversity in form, the core region of these molecules Ϫ the
The key starting material, iodide 19, was already at hand
covalent linkage between the carbohydrate and peptide do- from previous studies. Thiol 43 was the required coupling
mains Ϫ shows relatively little variation.[37] By far the most partner and although this useful building block had not
Eur. J. Org. Chem. 2002, 1323Ϫ1336
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D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor
FULL PAPER
rivative 49 as a single diastereoisomer whose spectroscopic
properties were fully consistent with the structure shown.
Conclusion
In summary, we have shown that RambergϪBäcklund-
derived exo-glycals can easily be transformed into func-
tionalised C-glycosides of potential biological interest, such
as enzyme inhibitor 12 and spirocyclic derivatives 17 and
18. We have also established that carba-analogues of
(1Ǟ1Ј)- and (1Ǟ6Ј)-linked disaccharides and glycosyl
amino acids can be prepared from readily available sulfone-
linked precursors using Meyers’ variant of the
RambergϪBäcklund rearrangement.
Figure 1. The two most common types of glycopeptidic linkage:
(a) N-acetylglucosamine-asparagine;
serine/threonine
(b) N-acetylgalactosamine-
Experimental Section
General Remarks: THF was distilled from sodium diphenyl ketyl
immediately prior to use. DCM was distilled from calcium hydride.
Light petroleum ether refers to the fraction boiling in the range
been reported previously, it was easily obtainable from the
Garner aldehyde (S)-40[40] by borohydride reduction fol-
lowed by Mitsunobu displacement using thiolacetic acid 40Ϫ60 °C and was redistilled before use. Alumina-supported potas-
sium hydroxide (KOH/Al2O3) was prepared according to Chan’s
procedure.[22] Reactions were monitored by TLC on silica gel 60
F254 (Merck) with detection by charring with sulfuric acid. Organic
extracts were dried over anhydrous sodium sulfate and column
and then treatment with sodium methoxide (Scheme 9). Al-
kylation of 43 with iodide 19 followed by oxidation as be-
fore produced sulfone 45, which was subjected to Chan’s
halogenative RambergϪBäcklund conditions to give (E)-al-
kene 46 (Jtrans ϭ 15.6 Hz) in 37% unoptimised yield. Alkene
reduction was efficiently achieved using diimide generated
in situ and the amino acid moiety was unmasked in a one-
pot procedure[41] using Jones’ reagent. Treatment with di-
azomethane afforded methyl ester 48 and, finally, debenzyl-
˚
chromatography was carried out using 33Ϫ64 (60 A) silica gel
(ICN). Melting points (m.p.) were determined with an Electro-
thermal IA9100 digital melting point apparatus and are uncorrec-
ted. Specific rotations were measured on a Jasco DIP-370 digital
polarimeter and are expressed in units of 10Ϫ2 deg·cmϪ2·gϪ1. Mass
spectrometry was carried out on a Fisons Analytical Autospec in-
ation followed by acetylation gave the C-glucosyl serine de- strument using either chemical ionisation (CI) or fast atom bom-
Scheme 9. Synthesis of a C-glycosyl serine analogue; reagents: (i) NaBH4, MeOH; (ii) Ph3P, DIAD, AcSH, THF; (iii) MeONa, MeOH;
(iv) K2CO3, acetone, reflux; (vi) mCPBA, Na2HPO4, DCM; (vi) KOH/Al2O3, CBr2F2, tBuOH, 60 °C; (vii) TsNHNH2, NaOAc, DME,
85 °C; (viii) 1  Jones reagent, acetone, then CH2N2, Et2O; (ix) H2, Pd(OH)2/C, EtOH, EtOAc, then Ac2O, pyridine; DME ϭ 1,2-di-
methoxyethane
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A RambergϪBäcklund Approach to the Synthesis of C-Glycosides
FULL PAPER
bardment (FAB) techniques; all high resolution mass spectral de-
terminations are within 5 ppm of the calculated value. Elemental
analyses were performed by Chemical Analytical Services Unit,
(4 ϫ CH2Ph), 74.3, 78.4, 79.0, 79.5, 81.0, 87.3 (C1ϪC6), 127.5,
127.6, 127.8 (ϫ 2), 127.9, 128.1, 128.3, 128.4 (arom. CH), 137.9,
138.0, 138.2 (ϫ 2), 140.2 (subst. arom. C); m/z (FAB): 653 (100)
University of Newcastle, UK using a Carlo Erba 1106 elemental [M ϩ Na]ϩ; found [M ϩ Na]ϩ 653.2882. C41H42O6·Na requires
analyser. NMR spectra were recorded on Jeol EX270 and Bruker 653.2879.
AMX500 spectrometers, operating at 1H frequencies of 270 and
3Ј-Hydroxyprop-1Ј-yl 2,6-Anhydro-2,3,4,6-tetra-O-benzyl-1-thio-β-
500 MHz and 13C frequencies of 67.9 and 125 MHz, respectively.
D-glucopyranoside (14): A mixture of 3-chloropropan-1-ol (0.4 mL,
0.45 g, 4.76 mmol), 2,3,4,6-tetra-O-benzyl-1-thio-β--glucose[21]
(13) (1.62 g, 2.91 mmol), potassium carbonate (4.02 g, 29.1 mmol),
and sodium iodide (0.1 g, 0.7 mmol) in dry, degassed acetone
(60 mL) was stirred under reflux for 20 h. After cooling to 0 °C,
the solids were removed by filtration and the filtrate was concen-
trated. The residue was then redissolved in DCM and washed with
water (50 mL), brine (50 mL), dried, and the solvents evaporated
in vacuo. The crude product was purified by column chromato-
graphy (light petroleum ether/EtOAc, 4:1Ǟ7:3) to give 14 as a col-
ourless oil (1.34 g, 75%); Rf ϭ 0.30 (light petroleum ether/EtOAc,
3,4,5,7-Tetra-O-benzyl-α-D-gluco-2-heptulopyranose (9): N-Methyl-
morpholine N-oxide (0.12 g, 1.0 mmol) was added to a solution of
exo-glycal 2a (0.27 g, 0.50 mmol) in a mixture of water (2 mL) and
acetone (9 mL).
A solution of osmium tetroxide (0.0013 g,
0.005 mmol) in tert-butyl alcohol (0.5 mL) was then added and the
resulting solution was stirred overnight at room temp. before being
quenched with satd. aq. NaHSO3 (10 mL) and stirred for a further
10 min. The product was extracted with EtOAc (2 ϫ 20 mL) and
the combined organic extracts washed with brine (40 mL), dried,
and the solvent removed in vacuo. The product was purified by
column chromatography (light petroleum ether/EtOAc, 4:1Ǟ1:1)
to afford the product as a solid which was recrystallised from water
to afford 9 as a fine powder (0.27 g, 94%); m.p. 110.8Ϫ111.3 °C,
ref.[11] 112.5Ϫ113.5 °C. [α]2D0 ϭ ϩ13.6 (c ϭ 1.4, CHCl3), ref.[11]
ϩ14.7 (c ϭ 0.97, CHCl3).
1:1). [α]2D0 ϭ ϩ12.9 (c ϭ 1.0, CHCl3); νmax/cmϪ1: 3500 (br., OH),
˜
3032, 2872, 1497, 1454, 1360, 1210, 1126, 1062, 1029. 1H NMR
(270 MHz, CDCl3): δ ϭ 1.79Ϫ1.90 (m, 2 H, CH2CH2OH), 2.39
(br. s, 1 H, OH), 2.73Ϫ2.83 and 2.89Ϫ2.99 (2 ϫ m, 2 H, SCH2),
3.40Ϫ3.84 (m, 8 H, 2-H, 3-H, 4-H, 5-H, 6-HA, 6-HB, CH2OH),
4.44 (d, J ϭ 9.7 Hz, 1 H, 1-H), 4.48Ϫ4.60 and 4.72Ϫ4.94 (m, 8 H,
4 ϫ CH2Ph), 7.11Ϫ7.39 (m, 20 H, 4 ϫ Ph). 13C NMR (67.9 MHz,
CDCl3): δ ϭ 27.4 (C2Ј), 32.6 (C1Ј), 60.0 (C3Ј), 69.0 (C6), 73.4,
75.0, 75.5, 75.7 (4 ϫ CH2Ph), 77.8, 78.7, 81.5, 85.6, 86.5 (C1ϪC5),
127.6, 127.7, 127.8, 128.0, 128.1, 128.3, 128.4 (arom. CH), 137.7,
137.8 (ϫ 2), 138.4 (subst. arom. C); m/z (FAB): 637 (100) [M ϩ
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-
heptitol (10) and 2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-
erythro- -talo-heptitol (11): A solution of borane in THF (1 ,
D-erythro-L-gulo-
D-
L
2.13 mL, 2.13 mmol) was added to a solution of the alkene 2b
(0.10 g, 0.163 mmol) in THF (5 mL) and the mixture was stirred
for three days. The reaction was quenched by the addition of aq.
NaOH (1 , 1 mL), followed by aq. H2O2 (ca. 30% v/v, 1 mL).
After stirring for 30 min at room temp., the mixture was partitioned
between brine (30 mL) and EtOAc (30 mL), the aqueous layer was
extracted with EtOAc (2 ϫ 20 mL) and the combined organic
phases were washed with brine (20 mL), dried, and concentrated
in vacuo. Column chromatography (light petroleum ether/EtOAc,
4:1Ǟ2:1) gave first unchanged starting material (0.012 g, 12%) fol-
lowed by 10 as a white solid (0.017 g, 17%); Rf ϭ 0.59 (light petro-
leum ether/EtOAc, 1:1); m.p. 95.5Ϫ97.5 °C. [α]2D0 ϭ ϩ22.7 (c ϭ 1.7,
CHCl3); ν˜max/cmϪ1: 3459 (br., OH), 3030, 2866, 1496, 1453, 1362,
1213, 1065. 1H NMR (270 MHz, CDCl3): δ ϭ 3.31 (br. d, J7A,7B ϭ
10.1 Hz, 1 H, 7-HA), 3.54, (dd, J7B,7A ϭ 10.1, J7B,6 ϭ 3.2 Hz, 1 H,
7-HB), 3.68Ϫ3.70 (m, 3 H, 5-H, 6-H, OH), 3.97 (dd, J3,4 ϭ 8.5,
Na]ϩ; found [M
637.2600.
ϩ
Na]ϩ 637.2601. C37H42O6S·Na requires
3Ј-Hydroxyprop-1Ј-yl S,S-Dioxo-2,6-anhydro-2,3,4,6-tetra-O-
benzyl-1-thio-β- -glucopyranoside (15): mCPBA (2.97 g, 57Ϫ86%
D
purity, 9.81Ϫ14.8 mmol) was added portionwise to a stirred mix-
ture of thioglycoside 14 (1.85 g, 3.01 mmol) and Na2HPO4 (2.19 g,
15.4 mmol) in DCM (20 mL) at 0 °C. After 15 min at 0 °C, the
reaction mixture was stirred overnight at room temp. after which
time it was diluted with ether (30 mL), aq. Na2S2O3 (0.1 , 30 mL)
was added and the mixture was stirred for a further 30 min. The
organic layer was then washed with 10% aq. NaOH (20 mL), brine
(20 mL), dried, and concentrated. The crude product was purified
by column chromatography (light petroleum ether/EtOAc,
4:1Ǟ1:1) to give 15 as a colourless syrup (1.60 g, 82%); Rf ϭ 0.25
(light petroleum ether/EtOAc, 1:1). [α]2D0 ϭ ϩ31.7 (c ϭ 1.0, CHCl3);
ν˜max/cmϪ1: 3498 (br., OH), 3030, 2917, 2873, 1497, 1454, 1361,
1330, 1309 (SO2), 1144 (SO2), 1097, 1028. 1H NMR (270 MHz,
CDCl3): δ ϭ 1.98Ϫ2.11 (m, 3 H, CH2CH2OH, OH), 3.11Ϫ3.22
and 3.32Ϫ3.41 (m, 2 H, CH2SO2), 3.46Ϫ3.69 (m, 6 H, 4-H, 5-H,
6-HA, 6-HB, CH2OH), 3.79 (t, J ϭ 8.7 Hz, 1 H, 3-H), 4.10 (t, J ϭ
9.0 Hz, 1 H, 2-H), 4.41 (d, J1,2 ϭ 9.2 Hz, 1 H, 1-H), 4.51 (A2, 2
H, CH2Ph), 4.52, 4.79 (AB, J ϭ 10.9 Hz, 2 H, CH2Ph), 4.77, 5.00
(AB, J ϭ 9.7 Hz, 2 H, CH2Ph), 4.86, 4.95 (AB, J ϭ 11.2 Hz, 2 H,
CH2Ph), 7.12Ϫ7.38 (m, 20 H, 4 ϫ Ph). 13C NMR (67.9 MHz,
CDCl3): δ ϭ 25.2 (CH2CH2OH), 48.2 (CH2SO2), 60.2 (CH2OH),
68.7 (C6), 73.4, 75.1, 75.4, 75.9 (4 ϫ CH2Ph), 77.0, 79.6, 86.0 (ϫ
2), 89.6 (C1ϪC5), 127.6, 127.8, 127.9, 128.0 (ϫ 2), 128.1, 128.4,
128.5, 128.6 (arom. CH), 137.3 (ϫ 2), 137.4, 138.0 (subst. aromatic
C); m/z (FAB): 669 (30) [M ϩ Na]ϩ, 413 (80%); found [M ϩ Na]ϩ
669.2508. C37H42O8S·Na requires 669.2498.
J3,2 ϭ 5.1 Hz, 1 H, 3-H), 4.05Ϫ4.14 (m, 2 H, 2-H, 4-H), 4.23, 4.42
(AB, J ϭ 12.1 Hz, 2 H, CH2Ph), 4.47, 4.77 (AB, J ϭ 10.9 Hz, 2
H, CH2Ph), 4.70, 4.84 (AB, J ϭ 11.4 Hz, 2 H, CH2Ph), 4.90, 4.85
(AB, J ϭ 11.2 Hz, 2 H, CH2Ph), 5.15 (d, J1,2 ϭ 9.0 Hz, 1 H, 1-H),
7.12Ϫ7.40 (m, 25 H, 5 ϫ Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ
68.6 (C7), 73.2, 74.5, 74.7, 75.0 (4 ϫ CH2Ph), 72.5, 73.5, 75.0, 77.7,
80.1, 81.8 (C1ϪC6), 127.1, 127.5, 127.8, 127.9, 128.2, 128.3, 128.4,
128.5, 128.7 (arom. CH), 137.0, 137.9 (ϫ 2), 138.3, 140.6 (subst.
arom. C); m/z (FAB) 653 (100) [M ϩ Na]ϩ; found [M ϩ Na]ϩ
653.2875. C41H42O6·Na requires 653.2879. Ϫ Further elution gave
11 as a colourless oil (0.050 g, 49%); Rf ϭ 0.48 (light petroleum
ether/EtOAc, 1:1). [α]2D0 ϭ ϩ8.5 (c ϭ 1.5, CHCl3), ref.[17] ϩ7.5 (c ϭ
1.0, CHCl3); νmax/cmϪ1: 3430 (br., OH), 3030, 2866, 1496, 1453,
˜
1
1361, 1208, 1105. H NMR (270 MHz, CDCl3): δ ϭ 2.81 (br. s, 1
H, OH), 3.36 (t, J ϭ 9.2 Hz, 1 H, 3-H), 3.46 (br. d, J6,5 ϭ 9.7 Hz,
1 H, 6-H), 3.58 (t, J ϭ 9.7 Hz, 1 H, 5-H), 3.71Ϫ3.81 (m, 4 H, 2-
H, 4-H, 7-HA, 7-HB), 4.47, 4.86 (AB, J ϭ 10.9 Hz, 2 H, CH2Ph),
4.48, 4.55 (AB, J ϭ 12.1 Hz, 2 H, CH2Ph), 4.58, 4.77 (AB, J ϭ (E,Z)-4,8-Anhydro-5,6,7,9-tetra-O-benzyl-2,3-dideoxy-D-gluco-non-
10.9 Hz, 2 H, CH2Ph), 4.80, 4.92 (AB, J ϭ 10.9 Hz, 2 H, CH2Ph), 3-enitol (16): Dibromodifluoromethane (0.5 mL, 5.5 mmol) was ad-
4.94 (d, J1,2 ϭ 3.4 Hz, 1 H, 1-H), 7.17Ϫ7.41 (m, 25 H, 5 ϫ Ph). ded dropwise over 1 min to a vigorously stirred mixture of sulfone
13C NMR (67.9 MHz, CDCl3): δ ϭ 68.9 (C7), 73.3, 74.3, 74.9, 75.4 15 (0.27 g, 0.42 mmol), KOH/Al2O3 (2.60 g), tert-butyl alcohol
Eur. J. Org. Chem. 2002, 1323Ϫ1336
1329

D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor
FULL PAPER
(6 mL) and DCM (3 mL) at 5 °C. The mixture was then stirred at tallisation from hexane prior to column chromatography (light pet-
room temp. for 3.5 h after which time it was diluted with DCM
roleum ether/EtOAc, 5:1Ǟ4:1). Iodide 19 was thus obtained as a
(20 mL) and the solids were removed by suction filtration through colourless oil which slowly crystallised on standing (0.674 g, 81%
a pad of Celite . The reaction vessel and the filter cake were rinsed
thoroughly with DCM and the combined filtrates were concen-
from 2a over 2 steps); Rf ϭ 0.34 (light petroleum ether/EtOAc, 1:1);
m.p. 55Ϫ57 °C. [α]2D0 ϭ Ϫ4.0 (c ϭ 1.0, CHCl3); ν˜max/cmϪ1: 3030,
1
trated. The crude product was then purified column chromato- 2865, 1496, 1453, 1360, 1210, 1099. H NMR (270 MHz, CDCl3):
graphy (light petroleum ether/EtOAc, 4:1Ǟ1:1) to afford 16 (Z/E ϭ
80:20) as a colourless oil (0.178 g, 73%); Rf ϭ 0.08 (light petroleum
δ ϭ 3.04 (ddd, J2,3 ϭ 9.2, J2,1A ϭ 5.0, J2,1B ϭ 2.7 Hz, 1 H, 2-H),
3.38 (dd, J1A,1B ϭ 10.8, J1A,2 ϭ 5.0 Hz, 1 H, 1-HA), 3.43Ϫ3.54 (m,
ether/EtOAc, 4:1); νmax/cmϪ1: 3405 (br., OH), 2875, 1471, 1381, 3 H, 3-H, 5-H, 6-H), 3.65 (t, J ϭ 9.5 Hz, 1 H, 4-H), 3.72Ϫ3.79 (m,
1171, 1070, 1028. 1H NMR (270 MHz, CDCl3): δ ϭ 2.05Ϫ3.21 3 H, 1-HB, 7-HA, 7-HB), 4.57Ϫ4.95 (4 ϫ AB, 8 H, 4 ϫ CH2Ph),
and 2.32Ϫ2.45 (m, 3 H, CH2CH2OH, OH), 3.60 (t, J ϭ 6.5 Hz, 2 7.17Ϫ7.40 (m, 20 H, 4 ϫ Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ
˜
H, CH2OH), 3.67Ϫ3.79 (m, 4 H, 6-H, 7-H, 9-HA, 9-HB), 3.93 (br.
d, J ϭ 6.5 Hz, 1 H, 5-H), 4.33Ϫ4.83 (m, 9 H, 8-H, 4 ϫ CH2Ph),
7.7 (C1), 68.6 (C7), 73.5, 75.0, 75.4, 75.6 (4 ϫ CH2Ph), 77.2, 78.4,
79.2, 81.5, 86.6 (C2ϪC6), 127.5, 127.7 (ϫ 2), 127.8, 127.9, 128.0,
4.98 (t, J ϭ 7.5 Hz, 1 H, 3-H, Z-isomer), 5.21 (t, J ϭ 8.7 Hz, 1 H, 128.3, 128.4, 128.5 (arom. CH), 137.8, 138.0, 138.3 (ϫ 2) (subst.
3-H, E-isomer), 7.13Ϫ7.17 and 7.24Ϫ7.36 (m, 20 H, 4 ϫ Ph). 13C arom. C); m/z (FAB): 687 (7%, [M ϩ Na]ϩ, 91 (100) [C7H7]ϩ; found
NMR (67.9 MHz, CDCl3):
28.2 (CH2CH2OH), 62.2 [M ϩ Na]ϩ 687.1609. C35H37IO5·Na requires 687.1583; found C
δ
ϭ
(CH2OH), 68.7 (C9), 72.4, 73.4, 74.1, 74.3 (4 ϫ CH2Ph), 77.8, 77.9,
79.03, 84.9 (C5ϪC8), 106.4 (C3), 127.50, 127.60, 127.64, 127.76,
127.80, 127.88, 128.04, 128.18, 128.24, 128.30 (arom. CH), 137.85,
137.95, 138.07, 138.21 (subst. arom. C), 148.6 (C4, E-isomer), 149.8
(C4, Z-isomer); m/z (FAB): 603 (100) [M ϩ Na]ϩ; found [M ϩ
Na]ϩ 603.2719. C37H40O6·Na requires 603.2723.
63.48, H 5.73. C35H37IO5 requires C, 63.26, H 5.61%.
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-S-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-
β-D-glucopyranosyl)-1-thio-β-D-glycero-D-gulo-heptitol (20): Potas-
sium carbonate (3 g, 21.7 mmol) was added to a solution of the
thiol 13[21] (0.25 g, 0.45 mmol) and iodide 19 (0.30 g, 0.45 mmol)
in acetone (10 mL) and the mixture was heated at reflux for 30 min.
(1S)-2,3,4,6-Tetra-O-benzyl-1-deoxy-
tetrahydrofuran[20] (17) and (1R)-2,3,4,6-Tetra-O-benzyl-1-deoxy-
glucopyranosyl-1-spiro-2Ј-tetrahydrofuran[20] (18): Camphorsulfonic layer was further extracted with EtOAc (2 ϫ 30 mL). The organic
D
-glucopyranosyl-1-spiro-2Ј- On cooling, the solvent was evaporated and the residue was parti-
D-
tioned between EtOAc (40 mL) and H2O (40 mL) and the aqueous
acid (0.01 g) was added to a solution of exo-glycal 16 (0.223 g,
0.4 mmol) in dry methanol (10 mL) and the resulting solution was
stirred for 5 h at room temp. after which time the methanol was
parts were washed with brine (30 mL), dried, and concentrated in
vacuo to give the crude product as a solid (0.48 g) which was used
directly in the next step. An analytical sample was purified by col-
evaporated under reduced pressure. The residue was then purified umn chromatography (light petroleum ether/EtOAc, 3:1Ǟ2:1) and
by column chromatography (light petroleum ether/EtOAc,
19:1Ǟ9:1) to afford spiroacetal 17 as a colourless oil (0.117 g,
53%); Rf ϭ 0.41 (light petroleum ether/EtOAc, 4:1). [α]2D0 ϭ ϩ26.6
then recrystallisation from hexane to give 20 as fine needles, Rf ϭ
0.27 (light petroleum ether/EtOAc, 3:1); m.p. 116.5Ϫ117 °C. [α]2D0
Ϫ31.2 (c ϭ 1.1, CHCl3); ν˜max/cmϪ1: 3006, 2907, 1497, 1454, 1360,
ϭ
(c ϭ 0.7, CHCl3); νmax/cmϪ1: 3062, 3030, 2922, 2872, 1497, 1453, 1234, 1205, 1089, 1064. 1H NMR (270 MHz, CDCl3): δ ϭ 2.82,
˜
1362, 1154, 1122, 1085, 1027. 1H NMR (270 MHz, CDCl3): δ ϭ
1.75Ϫ3.01 (m, H, CH2CH2CH2O), 3.55Ϫ3.75 (m,
3.26 (ABX, J1A,1B ϭ 14.2, J1A,2 ϭ 5.6 Hz, J1B,2 unresolved, 2 H,
4
4
H), 1-HA, 1-HB), 3.35Ϫ3.42 (m, 3 H, 2-H, 2Ј-H, 5Ј-H), 3.53Ϫ3.68 (m,
3.82Ϫ3.90 (m, 2 H), 3.96Ϫ4.00 (m, 1 H), 4.03 (t, J ϭ 9.2 Hz, 1 H), 11 H, 3-HϪ6-H, 7-HA, 7-HB, 1Ј-H, 3Ј-H, 4Ј-H, 6Ј-HA, 6Ј-HB),
4.49, 4.62 (AB, J ϭ 12.1 Hz, 2 H, CH2Ph), 4.54, 4.84 (AB, J ϭ 4.45Ϫ4.94 (m, 16 H, 8 ϫ CH2Ph), 7.14Ϫ7.39 (m, 40 H, 8 ϫ Ph).
10.9 Hz, 2 H, CH2Ph), 4.68, 4.96 (AB, J ϭ 11.4 Hz, 2 H, CH2Ph),
4.90 (A2, 2 H, CH2Ph), 7.14Ϫ7.35 (m, 20 H, 4 ϫ Ph). 13C NMR 73.3, 73.5, 74.9, 75.0 (ϫ 2), 75.1, 75.4, 75.4 (8 ϫ CH2Ph), 77.9,
(67.9 MHz, CDCl3): 24.0 (CH2CH2CH2O), 33.4 78.3, 78.9, 79.0, 79.4, 79.8, 82.0, 84.7, 86.6, 87.1 (C2ϪC6,
13C NMR (67.9 MHz, CDCl3): δ ϭ 31.1 (C1), 68.9, 69.0 (C7, C6Ј),
δ
ϭ
(CH2CH2CH2O), 68.1 (CH2CH2CH2O), 68.7 (C6), 73.3, 74.7, 75.5, C1ЈϪC5Ј), 127.5, 127.6, 127.7, 127.8 (ϫ 2), 127.9, 128.0, 128.2,
75.6 (4 ϫ CH2Ph), 71.2, 78.5, 80.0, 84.5 (C2ϪC5), 107.34 (C1), 128.3, 128.4, 128.5 (arom. CH), 138.1, 138.2, 138.6 (subst. arom.
127.5, 127.7, 127.8, 127.8, 128.0, 128.3 (ϫ 2), 128.4 (arom. CH),
C); m/z (FAB): 1115.5 (100) [M ϩ Na]ϩ, 181 (45%); found [M ϩ
138.0, 138.1, 138.4, 138.7 (subst. arom. C); m/z (CI): 598 (100) [M Na]ϩ 1115.4746. C69H72O10S·Na requires 1115.4744.
ϩ NH4]ϩ; found [M ϩ NH4]ϩ 598.3153. C37H40O6·NH4 requires
S,S-Dioxo-2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-S-(2Ј,3Ј,4Ј,6Ј-tetra-
O-benzyl-β- -glucopyranosyl)-1-thio-β- -glycero- -gulo-heptitol
598.3169. Further elution gave spiroacetal 18 as an oil which solidi-
fied on standing (0.050 g, 23%); Rf ϭ 0.33 (light petroleum ether/
EtOAc, 4:1); m.p. 69Ϫ71 °C, ref.[20] 69.8Ϫ71.3 °C. [α]2D0 ϭ ϩ29.7
(c ϭ 0.4, CHCl3), ref.[20] ϩ29.8 (c ϭ 0.4, CHCl3).
D
D
D
(21): To a solution of the crude disaccharide 20 (0.48 g) in DCM
(10 mL) was added first Na2HPO4 (0.31 g, 2.18 mmol) then
mCPBA (0.23 g, 1.33 mmol) and the reaction mixture was stirred
for 1 h. The solution was diluted with DCM (40 mL), washed suc-
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-iodo-D-glycero-D-
gulo-heptitol (19): To a solution of the heptitol 8[3] (0.695 g, cessively with satd. aq. Na2S2O3 (30 mL), aq. NaOH (1 , 20 mL),
1.25 mmol) in toluene (30 mL) at 70 °C was added first triphenyl-
brine (30 mL), and dried. The product was purified by column
phosphane (0.49 g, 1.87 mmol) followed by imidazole (0.26 g, chromatography (light petroleum ether/EtOAc, 3:1) to give sulfone
3.82 mmol) and finally iodine (0.45 g, 1.77 mmol). A black tar
21 as a foam (0.47 g, 93%); Rf ϭ 0.22 (light petroleum ether/EtOAc,
formed immediately at the bottom of the flask and the mixture was 3:1), [α]2D0 ϭ ϩ14.0 (c ϭ 1.0, CHCl3); νmax/cmϪ1: 3031, 2913, 1497,
stirred at 70 °C for 30 min. After cooling, the reaction was 1454, 1361, 1331, 1311 (SO2), 1214, 1205, 1148 (SO2), 1098, 1064.
˜
quenched by the addition of satd. aq. NaHCO3 (50 mL) and stirred
vigorously for a further 15 min. The layers were separated and the 6.8 Hz, 1 H, 1-HA), 3.40Ϫ3.48 (m, 3 H, 2-H, 3-H, 5Ј-H), 3.53Ϫ3.69
1H NMR (270 MHz, CDCl3): δ ϭ 2.30 (dd, J1A,1B ϭ 14.9, J1A,2 ϭ
aqueous was extracted again with toluene (2 ϫ 30 mL), the com-
bined organic phases were washed with brine (20 mL) and dried.
Evaporation of the solvent under reduced pressure gave the crude
product as a solid. Triphenylphosphane oxide was removed by crys-
(m, 9 H, 1-HB, 4-H, 5-H, 7-HA, 7-HB, 3Ј-H, 4ЈH, 6Ј-HA, 6Ј-HB),
3.74Ϫ3.82 (m, 1 H, 6-H), 4.02 (t, J ϭ 8.7 Hz, 1 H, 2Ј-H), 4.42Ϫ4.59
(m, 7 H, 1Ј-H, 3 ϫ CH2Ph), 4.68Ϫ4.94 (m, 10 H, 5 ϫ CH2Ph),
7.14Ϫ7.38 (m, 40 H, 8 ϫ Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ
1330
Eur. J. Org. Chem. 2002, 1323Ϫ1336

A RambergϪBäcklund Approach to the Synthesis of C-Glycosides
52.7 (C1), 68.4, 68.7 (C7, C6Ј), 73.3 (ϫ 2), 74.9, 75.0 (ϫ 2), 75.1,
FULL PAPER
(125 MHz, CDCl3): δ ϭ 20.6, 20.7, 20.8, 21.0 (COCH3), 33.6 (C7),
75.5, 75.7 (8 ϫ CH2Ph), 74.1, 77.3, 77.9 (ϫ 2), 78.7, 79.0, 80.0, 48.2 (OCH3), 62.0, 62.3 (C1, C13), 68.4 (ϫ 2), 68.7, 71.7, 71.8,
86.3, 87.0, 90.7 (C2ϪC6, C1ЈϪC5Ј), 127.5, 127.6, 127.7 (ϫ 2), 72.0, 73.3, 74.4, 75.8 (C2ϪC5, C8ϪC12), 99.6 (C6), 169.4, 169.5,
127.8, 127.9, 128.3, 128.4, 128.5 (arom. CH), 137.7, 137.8, 137.9, 169.6, 169.7, 170.1, 170.3, 170.7 (ϫ 2) (COCH3); m/z (FAB): 729
138.1, 138.2, 138.3 (subst. arom. C); m/z (FAB): 1147.5 (40) [M ϩ
(40) [M ϩ Na]ϩ, 724 (12) [M ϩ Na]ϩ; found [M ϩ Na]ϩ 729.2222.
Na]ϩ, 625.3 (45%); found [M ϩ Na]ϩ 1147.4641. C69H72O12S·Na C30H42O19·Na requires 729.2218.
requires 1147.4642.
Bis(2,3,4,6-tetra-O-acetyl-β-
D
-glucopyranosyl)methane[25]
(25):
Pearlman’s catalyst (20% w/w Pd(OH)2 on carbon, 0.025 g) was
added to a solution of alkene 22 (0.111 g, 0.105 mmol) in EtOAc
(2.5 mL) and EtOH (2.5 mL) and the resulting mixture was stirred
for 48 h under an atmosphere of H2 (balloon). The supernatant
liquid was then decanted and the remaining solids were stirred with
MeOH (5 mL) for 15 min. This process was repeated until no prod-
uct was detectable in the washings by TLC. The combined washings
were evaporated to dryness to give an oil (0.047 g) which was redis-
solved in a mixture of Ac2O (2 mL) and pyridine (5 mL). After
stirring overnight at room temp., the solution was evaporated to
dryness in vacuo and the last traces of pyridine were removed as
an azeotrope with toluene (ϫ 3). The yellow residue was purified
by column chromatography (light petroleum ether/EtOAc, 1:2) to
yield 25 as a white solid (0.049 g, 69% from 22), Rf ϭ 0.26 (light
petroleum ether/EtOAc, 1:1); m.p. 127Ϫ129 °C, ref.[25] 141.4Ϫ142.4
°C. [α]2D0 ϭ Ϫ9.1 (c ϭ 1.0, CHCl3), ref.[25] Ϫ17.2 (c ϭ 1.45, CHCl3)
[The discrepancy between our observed specific rotation and the
value quoted in this publication is thought to be due to our sample
being insufficiently dried. We learned from a personal communica-
tion with these authors that 25 is extremely hygroscopic.]; found
(Z,E)-2,6:8,12-Dianhydro-1,3,4,5,9,10,11,13-octa-O-benzyl-7-
deoxy- -glycero- -gulo- -gulo-tridec-6-enitol (22): Powdered potas-
D
D
L
sium hydroxide (3 g, 53.5 mmol) was added to a stirred mixture of
tert-butyl alcohol (6 cm) and water (1.5 mL) at 60 °C. After the
base had dissolved, a solution of sulfone 21 (0.367 g, 0.326 mmol)
in carbon tetrachloride (6 mL) was added, and the biphasic mixture
was stirred at 60 °C for 1 h. After cooling to room temp., the lower
aqueous layer was removed and the pale yellow organic phase was
washed with brine, dried, and the solvent was removed in vacuo.
Purification by column chromatography (light petroleum ether/
EtOAc, 3:1 with 1% Et3N) gave 22 as a pale yellow oil (0.167 g,
48%, Z/E ϭ 91:9); Rf ϭ 0.36 (light petroleum ether/EtOAc, 3:1),
[α]2D0 ϭ ϩ39.9 (c ϭ 1.1, CHCl3); ν˜max/cmϪ1: 3030, 2898, 1687 (Cϭ
C), 1496, 1454, 1361, 1208, 1100, 1071, 1028. 1H NMR (270 MHz,
CDCl3): δ ϭ 3.35 (t, J ϭ 9.0 Hz, 1 H), 3.48 (br. d, J ϭ 9.2 Hz, 1
H), 3.60Ϫ3.79 (m, 10 H), 3.90 (d, J ϭ 6.1 Hz, 1 H), 3.93Ϫ3.99 (m,
1 H), 4.40Ϫ4.92 (m, 14 H), 5.11 (d, J ϭ 8.7 Hz, 1 H, 7-H, Z-
isomer), 5.41 (d, J ϭ 8.7 Hz, 1 H, 7-H, E-isomer), 7.15Ϫ7.34 (40
H, 8 ϫ Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ 68.7, 69.0 (C1,
C13), 72.1, 73.3, 73.5, 73.8, 74.2, 74.6, 74.9, 75.6 (8 ϫ CH2Ph),
77.9, 78.0, 78.2, 78.7 (ϫ 2), 83.1, 84.6, 86.7 (C2ϪC5, C8ϪC12),
108.5 (C7), 127.3, 127.6, 127.7, 127.8 (ϫ 2), 127.9, 128.0, 128.1,
128.3 (arom. CH), 137.8, 138.2 (ϫ 2), 138.3, 138.4, 138.6, 138.8
(subst. arom. C), 152.6 (C6); m/z (FAB): 1081.5 (40) [M ϩ Na]ϩ,
1076.2 (35%); found [M ϩ Na]ϩ 1081.4863. C69H70O10·Na re-
quires 1081.4867.
[M ϩ Na]ϩ 699.2110. C29H40O18·Na requires 699.2112. 1H and 13
C
NMR spectroscopic data were in excellent agreement with those
reported in the literature.[25]
3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-deoxy-1-O-methanesulfonyl-
D
-glycero-D-gulo-octitol (27c): Methanesulfonyl chloride (0.20 mL,
2.58 mmol) was added slowly to a solution of octitol 27b[30] (1.12 g,
1.97 mmol) in DCM containing triethylamine (0.35 mL,
2.51 mmol) and the resulting solution stirred at room temp. for 1 h
after which the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (EtOAc/
petroleum ether, 9:1Ǟ4:1) to give 27c as colourless plates (1.09 g,
86%); Rf ϭ 0.61 (light petroleum ether/EtOAc, 1:1); m.p. 87.5Ϫ88
Methyl 8,12-Anhydro-1,3,4,5,9,10,11,13-octa-O-acetyl-7-deoxy-
D-
glycero- -gulo-α- -gulo-6-trideculopyranoside (23): Palladium on
D
L
carbon (5% w/w, 0.015 g) was added to a solution of alkene 22
(0.160 g, 0.150 mmol) in EtOAc (3 mL) and MeOH (3 mL) and the
resulting mixture was stirred for 8 h under an atmosphere of H2
(balloon). The supernatant layer was decanted and the remaining
solids were stirred with MeOH (2 mL) for 15 min. This process was
repeated until no product was detectable in the washings by TLC.
The combined washings were evaporated to dryness to give a col-
ourless oil (0.08 g) which was redissolved in a mixture of Ac2O
(2 mL) and pyridine (4 mL). After stirring overnight at room temp.,
the solution was evaporated to dryness in vacuo and the last traces
of pyridine were removed as an azeotrope with toluene (ϫ 2). The
residue was purified by column chromatography (light petroleum
ether/EtOAc, 1:2) to give first fraction as a foam (0.022 g) tentat-
ively identified as C-neotrehalose octaacetate. Further elution gave
23 as a colourless oil (0.018 g, 17% from 22); Rf ϭ 0.36 (light petro-
°C. [α]2D0 ϭ ϩ8.7 (c ϭ 1.0, CHCl3); νmax/cmϪ1: 3066, 3033, 2909,
˜
2871, 1496, 1453, 1357, 1347, 1171 (SO3), 1131, 1071, 973, 946,
736, 691. 1H NMR (270 MHz, CDCl3): δ ϭ 1.70Ϫ1.82 (m, 1 H, 2-
HA), 2.21Ϫ2.33 (m, 1 H, 2-HB), 2.86 (s, 3 H, CH3SO3), 3.25Ϫ3.41
(m, 3 H, 3-H, 4-H, 7-H), 3.58Ϫ3.73 (m, 4 H, 5-H, 6-H, 8-HA, 8-
HB), 4.27Ϫ4.41 (m, 2 H, 1-HA, 1-HB), 4.49, 4.57 (AB, J ϭ 12.1
Hz, 2 H, CH2Ph), 4.56, 4.82 (AB, J ϭ 10.9 Hz, 2 H, CH2Ph), 4.63,
4.90 (AB, J ϭ 11.2 Hz, 2 H, CH2Ph), 4.88, 4.92 (AB, J ϭ 11.2 Hz,
2 H, CH2Ph), 7.14Ϫ7.34 (20 H, 4 ϫ Ph). 13C NMR (67.9 MHz,
CDCl3): δ ϭ 31.2 (C2), 36.9 (CH3SO3), 66.6 (C1), 68.9 (C8), 73.2,
74.9, 75.2, 75.5 (4 ϫ CH2Ph), 74.8, 78.3, 78.8, 81.7, 87.1 (C3ϪC7),
127.7, 127.8, 127.9, 128.0, 128.2, 128.4, 128.5 (arom. CH), 137.8,
137.9, 138.0, 138.4 (subst. aromatic C); m/z (FAB): 669 (100) [M
ϩ Na]ϩ; found [M ϩ Na]ϩ 669.2495. C37H42O8S·Na requires
669.2498.
leum ether/EtOAc, 3:1). [α]2D0 ϭ ϩ24.3 (c ϭ 0.8, CHCl3); νmax
/
˜
1
cmϪ1: 2859, 1747 (CϭO), 1434, 1371, 1253, 1231, 1098, 1036. H
NMR (500 MHz, CDCl3): δ ϭ 1.83 (dd, J7A,7B ϭ 15.4, J7A,8 ϭ 2.6
Hz, 1 H, 7-HA), 1.96, 1.99, 2.02, 2.03 (ϫ 2), 2.07, 2.11, 2.13 (24 H, 7
ϫ s, 8 ϫ COCH3), 2.04Ϫ2.05 (m, 1 H, 7-HB), 3.27 (s, 3 H, OCH3), 3,7-Anhydro-4,5,6,8-tetra-O-benzyl-1-S-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-
3.59Ϫ3.64 (m, 2 H, 8-H, 12-H), 3.84 (ddd, J2,3 ϭ 10.3, J2,1A ϭ 2.7, β-
D
-glucopyranosyl)-2-deoxy-1-thio-β-
D-glycero-D-gulo-octitol (28):
J2,1B ϭ 4.4 Hz, 1 H, 2-H), 4.12, 4.20 (ABX, J13A,13B ϭ 12.3,
A solution of thiol 13 (2.09 g, 3.75 mmol) and mesylate 27c (1.01 g,
J13A,12 ϭ 0, J13B,12 ϭ 2.2 Hz, 2 H, 13-HA, 13-HB), 4.13, 4.24 (ABX, 1.56 mmol) in acetone (60 mL) containing anhydrous potassium
J1A,1B ϭ 12.2, J1A,2 ϭ 2.7, J1B,2 ϭ 4.4 Hz, 2 H, 1-HA, 1-HB), 4.96
carbonate (2.16 g, 15.2 mmol) was stirred under reflux for 36 h.
(t, J ϭ 9.4 Hz, 1 H, 9-H), 5.04 (t, J ϭ 9.6 Hz, 1 H, 11-H), 5.09 The reaction mixture was cooled to 5Ϫ10 °C, the solids removed
(J ϭ 9.4 Hz, 1 H, 3-H), 5.15 (t, J ϭ 9.4 Hz, 1 H, 10-H), 5.25 (d, by filtration and washed with DCM. The filtrate was then concen-
J
5,4 ϭ 9.6 Hz, 1 H, 5-H), 5.43 (t, J ϭ 9.4 Hz, 1 H, 4-H). 13C NMR trated and the residue was purified by column chromatography
Eur. J. Org. Chem. 2002, 1323Ϫ1336
1331

D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor
FULL PAPER
(EtOAc/petroleum ether 9:1Ǟ4:1) to afford 28 as a colourless oil
105.8 (C1), 127.3Ϫ128.3 (arom. CH), 138.0, 138.1, 138.2 (ϫ 2),
138.3, 138.4, 138.5, 138.7 (subst. aromatic C), 149.4 (C1Ј); m/z
(1.63 g, 94%); Rf ϭ 0.32 (light petroleum ether/EtOAc, 4:1). [α]2D0
ϭ
ϩ56.2 (c ϭ 1.6, CHCl3); νmax/cmϪ1: 3066, 3032, 2908, 2870, 1496, (FAB): 1095.5 (100) [M ϩ Na]ϩ.
˜
1453, 1359, 1210, 1138, 1124, 1083, 1047. 1H NMR (270 MHz,
1,2-Bis(2,3,4,6-tetra-O-acetyl-β-
D-glucopyranosyl)ethane
(31):
CDCl3): δ ϭ 1.75Ϫ1.90 (m, 1 H, 2-HA), 2.11Ϫ2.24 (m, 1 H, 2-HB),
2.76Ϫ2.88 (m, 1 H, 1-HA), 2.93Ϫ3.04 (m, 1 H, 1-HB), 3.27 (t, J ϭ
9.0 Hz, 1 H), 3.37Ϫ3.47 (m, 4 H), 3.58Ϫ3.72 (m, 8 H), 4.41Ϫ4.63
and 4.71Ϫ4.94 (m, 17 H, 8 ϫ CH2Ph, 1Ј-H), 7.14Ϫ7.39 (m, 40 H,
8 ϫ Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ 26.7 (CH2CH2S),
31.95, (CH2CH2S), 68.9 (C6Ј, C8), 73.3, 73.5, 73.6, 74.9, 75.0, 75.4,
75.5, 75.7 (8 ϫ CH2Ph), 77.7, 77.8, 78.3, 78.8, 79.0, 81.7, 82.1, 84.8,
86.5, 87.1 (C3ϪC7, C1ЈϪC5Ј), 127.5, 127.6, 127.7, 127.8, 127.9,
128.1, 128.2, 128.3 (arom. CH), 137.95, 138.1, 138.2, 138.5, 138.6
(subst. arom. C); found [M ϩ NH4]ϩ 1124.3102. C70H74O10S·NH4
requires 1124.3006.
Pearlman’s catalyst (20% w/w Pd(OH)2 on carbon, 0.025 g) was
added to a solution of alkene 30 (0.16 g, 0.15 mmol) in ethanol
(2 mL) and ethyl acetate (2 mL) and the mixture was stirred at
room temp. under an atmosphere of hydrogen (balloon) for 26 h.
The catalyst was then removed by filtration and the filtrate was
evaporated. The residue was then taken up in pyridine (5 mL) and
acetic anhydride (1 mL) added to it and stirred for a further 16 h.
The solvent was removed under reduced pressure and the residue
taken up in ethyl acetate (10 mL) and washed with 10% aq. hydro-
chloric acid (10 mL), 10% aq. NaOH (10 mL), water (2 ϫ 10 mL),
dried, and concentrated in vacuo. The crude product was then puri-
fied by column chromatography (light petroleum ether/EtOAc,
4:1Ǟ1:1) to give 31 as a colourless solid (0.055 g, 53%); Rf ϭ 0.23
S,S-Dioxo-3,7-Anhydro-4,5,6,8-tetra-O-benzyl-1-S-(2Ј,3Ј,4Ј,6Ј-
tetra-O-benzyl-β-D-glucopyranosyl)-2-deoxy-1-thio-β-D-glycero-D-
(light petroleum ether/EtOAc, 1:1); m.p. 56.5Ϫ57.5 °C. [α]2D0
ϭ
gulo-octitol (29): A solution of Oxone (4.43 g, 7.21 mmol) in water
(10 mL) was added to a solution of S-linked disaccharide 28
(1.55 g, 1.40 mmol) in methanol (10 mL) and tetrahydrofuran
(30 mL) and the resulting mixture stirred at 60 °C for 3.5 h. After
cooling to room temp., the mixture was diluted with ether (50 mL),
stirred for a further 0.5 h, and then the layers separated. The aque-
ous layer was extracted with ether (30 mL) and the combined ether-
eal extracts washed with water (50 mL) and brine (50 mL), and
then dried and concentrated. The crude product was purified by
column chromatography (light petroleum ether/EtOAc, 9:1Ǟ4:1)
to give 29 as a solid (1.26 g, 79%); Rf ϭ 0.41 (light petroleum ether/
Ϫ10.9 (c ϭ 0.5, CHCl3); νmax/cmϪ1: 2959, 2869, 1744 (CϭO), 1433,
1367, 1237, 1106, 1043. 1H NMR (270 MHz, CDCl3): δ ϭ 1.64 (br.
s, 4 H, CH2CH2), 2.00, 2.03, 2.05, 2.10 (4 ϫ s, 24 H, 8 ϫ COCH3),
3.41Ϫ3.51 (m, 2 H, 1-H), 3.61 (ddd, J5,4 ϭ 9.7, J5,6B ϭ 4.6, J5,6A ϭ
2.2 Hz, 2 H, 5-H), 4.09, 4.23 (ABX, J6A,6B ϭ 12.1, J6A,5 ϭ 2.2,
J6B,5 ϭ 4.6 Hz, 2 H, 6-HA, 6-HB), 4.88 (t, J ϭ 9.5 Hz, 2 H, 4-H),
5.04 (t, J ϭ 9.7 Hz, 2 H, 2-H), 5.16 (t, J ϭ 9.5 Hz, 2 H, 3-H). 13C
NMR (67.9 MHz, CDCl3): δ ϭ 20.55, 20.6, 20.7 (COCH3), 25.8
(CH2CH2), 62.1 (C6), 68.5, 71.3, 74.3, 75.6, 76.8 (C1ϪC5), 169.4,
169.6, 170.3, 170.6 (COCH3); m/z (CI): 708 (100) [M ϩ NH4]ϩ;
found [M ϩ NH4]ϩ 708.2715. C30H42O18·NH4 requires 708.2715.
˜
EtOAc, 1:1); m.p. 68Ϫ69 °C. [α]2D0 ϭ ϩ32.6 (c ϭ 0.7, CHCl3); ν˜max
/
cmϪ1: 3066, 3033, 2911, 2871, 1497, 1454, 1361, 1331, 1309, 1134,
1112 (SO2) 1069, 1028. 1H NMR (270 MHz, CDCl3): δ ϭ
1.86Ϫ1.99 (m, 1 H, 2-HA), 2.35Ϫ3.49 (m, 1 H, 2-HB), 3.15Ϫ3.37
(m, 5 H), 3.44Ϫ3.70 (m, 8 H), 3.76 (t, J ϭ 8.7 Hz, 1 H), 4.09 (t,
J ϭ 9.2 Hz, 1 H), 4.34 (d, J ϭ 9.5 Hz, 1 H, 1Ј-H), 4.43Ϫ4.63 and
4.75Ϫ5.02 (16 H, 2 ϫ m, 8 ϫ CH2Ph), 7.14Ϫ7.39 (m, 40 H, 8 ϫ
Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ 23.95 (CH2CH2SO2), 47.9
(CH2CH2SO2), 68.45, 68.8 (C8, C8Ј), 73.3, 73.35, 75.0, 75.1, 75.20,
75.3, 75.5, 75.8 (8 ϫ CH2Ph), 76.95, 77.1, 77.2, 78.3, 78.8 (ϫ 2),
81.8, 86.0, 86.9, 89.4 (C3ϪC7, C1ЈϪC5Ј), 127.6, 127.7 (ϫ 2), 127.9
(ϫ 2), 128.0, 128.1, 128.4, 128.5, 128.6 (arom. CH), 137.5, 137.65,
137.8, 137.9, 138.0, 138.05, 138.1, 138.5 (subst. arom. C); found
[M ϩ Na]ϩ 1161.4807. C70H74O12S·Na requires 1161.4799.
Methyl 6-S-Acetyl-2,3,4-tri-O-benzyl-6-thio-α-
(33): Diisopropyl azodicarboxylate (0.81 mL, 4.10 mmol) was ad-
ded dropwise to solution of triphenylphosphane (1.08 g,
D-glucopyranoside
a
4.12 mmol) in THF (30 mL) at 0 °C and the mixture was stirred
for 20 min at this temperature after which time a white precipitate
had formed. A solution of alcohol 32[33] (0.952 g, 2.05 mmol) and
thiolacetic acid (0.30 mL, 4.10 mmol) in THF (20 mL) was then
added and the reaction mixture stirred for 1 h at 0 °C and then
allowed to warm to room temp. overnight. The solvent was evapor-
ated in vacuo and the resulting red residue was purified by column
chromatography (light petroleum ether/EtOAc, 5:1Ǟ3:1) followed
by recrystallisation of the main fraction from hexane to afford 33
as a crystalline solid (0.556 g, 52%). The mother liquor was rechro-
matographed to give a further 0.167 g (67% overall yield) of 33,
Rf ϭ 0.40 (light petroleum ether/EtOAc, 2:1); m.p. 83.5Ϫ84.5 °C.
(E,Z)-3,7-Anhydro-1-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-
D-gluco-
pyranosylidene)-1,2-dideoxy-4,5,6,8-tetra-O-benzyl- -glycero-D-
D
[α]2D0 ϭ ϩ23.4 (c ϭ 1.0, CHCl3); νmax/cmϪ1: 3031, 2913, 1693 (Cϭ
˜
gulo-octitol (30): A mixture of sulfone-linked disaccharide 29
(0.35 g, 0.31 mmol) in carbon tetrachloride (5 mL), tert-butyl alco-
hol (5 mL) and water (1 mL) containing powdered potassium hy-
droxide (0.41 g, 7.32 mmol) was stirred at 65 °C for 5 h. The reac-
tion mixture was then cooled to 0 °C, diluted with DCM, filtered
through Celite , and the filtrate was dried and concentrated. The
residue was purified by column chromatography (light petroleum
ether/EtOAc, 9:1Ǟ4:1) to give 30 (Z/E ϭ 88:12) as a colourless oil
O), 1497, 1454, 1359, 1155, 1136, 1092, 1072, 1050. 1H NMR
(270 MHz, CDCl3): δ ϭ 2.32 (s, 3 H, COCH3), 3.03, 3.43 (ABX,
J6A,6B ϭ 13.6, J6A,5 ϭ 7.8, J6B,5 ϭ 3.2 Hz, 2 H, 6-HA, 6-HB), 3.30
(dd, J4,3 ϭ 9.6, J4,5 ϭ 8.7 Hz, 1 H, 4-H), 3.36 (s, 3 H, OCH3), 3.50
(dd, J2,3 ϭ 9.6, J2,1 ϭ 3.6 Hz, 1 H, 2-H), 3.72Ϫ3.79 (m, 1 H, 5-H),
3.97 (t, J ϭ 9.6 Hz, 1 H, 3-H), 4.40 (d, J1,2 ϭ 3.6 Hz, 1 H, 1-H),
4.61, 4.89 (AB, J ϭ 10.7 Hz, 2 H, CH2Ph), 4.64, 4.78 (AB, J ϭ
12.1 Hz, 2 H, CH2Ph), 4.81, 4.98 (AB, J ϭ 10.7 Hz, 2 H, CH2Ph),
7.28Ϫ7.37 (m, 15 H, 3 ϫ Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ
30.5 (SCOCH3), 30.8 (C6), 55.1 (OCH3), 73.3, 75.1, 75.7 (3 ϫ
CH2Ph), 69.3, 79.9, 80.4, 81.8 (C2ϪC5), 97.8 (C1), 127.6, 127.8,
127.9, 128.0, 128.1, 128.4 (ϫ 2) (arom. CH), 137.9, 138.0, 138.6
(subst. arom. C), 194.8, SCOCH3); m/z (CI): 540 (100) [M ϩ
NH4]ϩ, 491 (20%), 91 (20) [C7H7]ϩ; found [M ϩ NH4]ϩ 540.2421.
C30H34O6S·NH4 requires 540.2420.
(0.15 g, 57%); Rf ϭ 0.71 (light petroleum ether/EtOAc, 4:1). [α]2D0
ϭ
ϩ32.6 (c ϭ 0.7, CHCl3); νmax/cmϪ1: 3030, 3009, 2960, 2936, 1665
(CϭC), 1492, 1451, 1361. 1H NMR (270 MHz, CDCl3): δ ϭ
2.42Ϫ2.53 (m, 1 H, allylic HA), 2.84 (br. dd, 1 H, J ϭ 14.3, 7.5 Hz,
allylic HB), 3.34Ϫ3.44 (m, 3 H), 3.58Ϫ3.81 (m, 9 H), 3.94 (d, J ϭ
7.0 Hz, 1 H), 4.36Ϫ4.89 (m, 16 H, 8 ϫ CH2Ph), 5.24 (t, J ϭ 7.0
Hz, 1 H, CHϭC, Z-isomer), 7.10Ϫ7.35 (m, 40 H, 8 ϫ Ph). 13C
NMR (67.9 MHz, CDCl3): δ ϭ 26.4, (CH2CHϭC), 68.7, 69.1 (C6Ј,
C8), 72.6, 73.4 (ϫ 2), 74.3 (ϫ 2), 75.0, 75.1, 75.5 (CH2Ph), 77.7,
˜
Methyl 2,3,4-Tri-O-benzyl-6-thio-α-D-glucopyranoside (34): A meth-
78.2, 78.6, 78.7, 78.9, 79.2, 81.4, 85.1, 87.2 (C1ЈϪC5Ј, C3ϪC7), anolic solution of sodium methoxide (25% w/w, 0.04 mL,
1332 Eur. J. Org. Chem. 2002, 1323Ϫ1336

A RambergϪBäcklund Approach to the Synthesis of C-Glycosides
FULL PAPER
0.17 mmol) was added to a solution of the S-acetate 33 (0.10 g,
0.19 mmol) in degassed MeOH (5 mL) and the mixture was stirred
for 2 h. Amberlyst 15 ion-exchange resin was then added until the
pH of the solution became neutral, the resin was removed by filtra-
leum ether/EtOAc, 2:1). [α]2D0 ϭ ϩ17.5 (c ϭ 0.84, CHCl3); νmax
˜
/
cmϪ1: 3031, 2924, 1497, 1454, 1361, 1314 (SO2), 1207, 1134, 1115
(SO2), 1095, 1071. 1H NMR (270 MHz, CDCl3): δ ϭ 3.02Ϫ3.14
(m, 2 H), 3.24Ϫ3.83 (m, 11 H), 3.43 (s, 3 H, OCH3), 3.95 (t, J ϭ
tion and the filtrate evaporated in vacuo to give 34 as a colourless 9.2 Hz, 1 H, 3-H), 4.18Ϫ4.25 (m, 1 H, 5-H), 4.38Ϫ4.98 (m, 15 H,
oil (0.050 g, 55%); Rf ϭ 0.33 (light petroleum ether/EtOAc, 3:1). 1-H, 7 ϫ CH2Ph), 7.13Ϫ7.35 (m, 35 H, 7 ϫ Ph). 13C NMR
[α]2D0 ϭ ϩ57.1 (c ϭ 0.9, CHCl3); νmax/cmϪ1: 3031, 2907, 2576 (SH),
(67.9 MHz, CDCl3): δ ϭ 55.7 (OCH3), 56.4, 56.6 (C6, C1Ј), 65.3,
74.3, 78.1, 78.5, 79.4 (ϫ 2), 80.1, 81.6, 86.9 (C2ϪC5, C2ЈϪC6Ј),
˜
1496, 1453, 1360, 1270, 1186, 1155, 1137, 1070. 1H NMR
(270 MHz, CDCl3): δ ϭ 1.51 (dd, JSH,6B ϭ 8.6, JSH,6A ϭ 7.8 Hz, 69.0 (C7Ј), 73.2 (ϫ 2), 73.3, 74.7, 75.0, 75.6 (ϫ 2) (7 ϫ CH2Ph),
1 H, SH), 2.60 (dt, J6A,6B ϭ 13.3, J6A,5 ϭ J6A,SH ϭ 7.8 Hz, 1 H, 97.9 (C1), 127.4, 127.6, 127.7, 127.8 (ϫ 2), 127.9, 128.0, 128.3,
6-HA), 2.72 (ddd, J6B,6A ϭ 13.3, J6B,SH ϭ 8.6, J6B,5 ϭ 2.7 Hz,1 H, 128.4, 128.5 (arom. CH), 137.4, 137.6, 137.7, 138.0 (ϫ 2), 138.2,
6-HB), 3.40 (s, 3 H, OCH3), 3.44 (dd, J4,3 ϭ 9.7, J4,5 ϭ 9.0 Hz, 1
138.5 (subst. arom. C); m/z (FAB): 1071 (15) [M ϩ Na]ϩ, 711 (8%),
H, 4-H), 3.52 (dd, J2,3 ϭ 9.7, J2,1 ϭ 3.6 Hz, 1 H, 2-H), 3.68Ϫ3.75 271 (15%), 181 (100%); found [M
(m, 1 H, 5-H), 4.00 (t, J ϭ 9.7 Hz, 1 H, 3-H), 4.57 (d, J1,2 ϭ 3.6 C63H68O12S·Na requires 1071.4329.
Hz, 1 H, 1-H), 4.61, 4.91 (AB, J ϭ 11.2 Hz, 2 H, CH2Ph), 4.66,
ϩ
Na]ϩ 1071.4338.
(Z,E)-Methyl 8,12-Anhydro-2,3,4,9,10,11,13-hepta-O-benzyl-6,7-di-
deoxy-α- -glycero- -gulo- -gluco-tridec-6-enopyranoside (37): A
4.80 (AB, J ϭ 12.1 Hz, 2 H, CH2Ph), 4.81, 5.00 (AB, J ϭ 10.9 Hz,
2 H, CH2Ph), 7.23Ϫ7.33 (m, 15 H, 3 ϫ Ph). 13C NMR (67.9 MHz,
CDCl3): δ ϭ 26.3 (C6), 55.2 (OCH3), 73.3, 75.0, 75.7 (3 ϫ CH2Ph),
70.6, 79.6, 80.1, 81.9 (C2ϪC5), 97.9 (C1), 127.6, 127.8, 127.9,
128.0, 128.4 (ϫ 2) (arom. CH), 138.0 (ϫ 2), 138.6 (subst. arom. C);
m/z (CI): 498 (100) [M ϩ NH4]ϩ, 341 (90%), 251 (30%), 235 (45%),
91 (85) [C7H7]ϩ; found [M ϩ NH4]ϩ 498.2311. C28H32O5S·NH4
requires 498.2314.
D
D
D
solution of the sulfone 36 (0.046 g, 0.04 mmol) in DCM (0.5 mL)
was added to a stirred suspension of KOH/Al2O3 (25% w/w, 2.0 g)
in tert-butyl alcohol (3 mL) at 5 °C. CBr2F2 (0.5 mL, 5.47 mmol)
was then added over a period of 2 min and the reaction mixture
was stirred at this temperature for 2 h. More KOH/Al2O3 (1.5 g)
and CBr2F2 (0.5 mL, 5.47 mmol) was added and stirring continued
for a further 1 h at 5 °C and then for 2 h at room temp. The mixture
Methyl 2,3,4-Tri-O-benzyl-6-S-(2Ј,6Ј-anhydro-3Ј,4Ј,5Ј,7Ј-tetra-O- was diluted with DCM (40 mL), stirred for 10 min, filtered through
benzyl-1Ј-deoxy-
D
-glycero-
D
-gulo-heptitol-1-yl)-6-thio-α-
D
-gluco-
Celite , and the filtrate was evaporated under reduced pressure.
The residue was chromatographed on a silica gel column (light pet-
roleum ether/EtOAc, 4:1Ǟ3:1) to yield 37 as a white solid (0.025 g,
64%, Z/E ϭ 74:26). 1H NMR (270 MHz, CDCl3): selected data for
(Z)-isomer: δ ϭ 5.65 (dd, J ϭ 11.2 Hz, 1 H, 6.1, 6-H or 7-H), 5.70
(dd, J ϭ 11.6 Hz, 1 H, 6.3, 6-H or 7-H); selected data for (E)-
isomer, 5.96 (appt. t, J ϭ 4.1 Hz, 2 H, 6-H or 7-H). 13C NMR
pyranoside (35): Potassium carbonate (3 g, 21.7 mmol) was added
to a solution of the thiol 34 (0.094 g, 0.19 mmol) and iodide 19
(0.130 g, 0.19 mmol) in acetone (20 mL) and the mixture was
heated at reflux for 4 h. On cooling, the solvent was evaporated
and the residue partitioned between EtOAc (40 mL) and H2O
(40 mL) and the aqueous portion further extracted with EtOAc (2
ϫ 30 mL). The organic parts were washed with brine (30 mL), (67.9 MHz, CDCl3): δ ϭ selected data for (Z)-isomer, 132.9, 132.6
dried and concentrated in vacuo to give the crude product as an
(C6, C7); selected data for (E)-isomer: 130.4, 130.7 (C6, C7); m/z
oil which was chromatographed on silica (light petroleum ether/ (FAB): 1005.5 (100) [M ϩ Na]ϩ; found [M ϩ Na]ϩ 1005.4545.
EtOAc, 5:1Ǟ3:1) to give 35 as a colourless oil (0.14 g, 72%); Rf ϭ C63H66O10·Na requires 1005.4554.
0.40 (light petroleum ether/EtOAc, 2:1). [α]2D0 ϭ ϩ8.6 (c ϭ 1.0,
CHCl3); νmax/cmϪ1: 3031, 2909, 1497, 1454, 1360, 1208, 1154, 1137,
Methyl 2,3,4,9,10,11,13-Hepta-O-acetyl-8,12-anhydro-6,7-dideoxy-
˜
α- -glycero- -gulo-
D
D
D
-gluco-tridecopyranoside[35] (39): Pearlman’s
1091, 1069. 1H NMR (270 MHz, CDCl3): δ ϭ 2.71, 3.00 (ABX,
catalyst (20% w/w Pd(OH)2 on carbon, 0.02 g) was added to a solu-
tion of alkene 37 (0.10 g, 0.10 mmol) in EtOAc (2 mL) and EtOH
(2 mL) and the resulting mixture was stirred for 8 h under an atmo-
sphere of H2 (balloon). The supernatant layer was decanted and
the remaining solids were stirred with MeOH (2 mL) for 15 min.
This process was repeated until no product was detectable in the
washings by TLC. The combined washings were evaporated to dry-
ness and triturated with DCM to give a waxy solid (0.019 g), which
was redissolved in a mixture of Ac2O (1 mL) and pyridine (2 mL).
After stirring overnight at room temp., the solution was evaporated
to dryness in vacuo and the last traces of pyridine were removed
as an azeotrope with toluene (ϫ 3). The residue was purified by
column chromatography (light petroleum ether/EtOAc, 1:1) to
yield 39 as a white solid (0.008 g, 12% from 37); Rf ϭ 0.18 (light
petroleum ether/EtOAc, 1:1). [α]2D0 ϭ ϩ65.1 (c ϭ 0.45, CHCl3),
ref.[35] ϩ63 (c ϭ 0.7, CHCl3); ν˜max/cmϪ1: 3023, 2951, 1747 (CϭO),
1434, 1371, 1225, 1171, 1104, 1047, 1069; . 1H NMR (500 MHz,
J
1ЈA,1ЈB ϭ 13.6, J1ЈA,2Ј ϭ 7.5 Hz, J1ЈB,2Ј unresolved, 2 H, 1Ј-HA, 1Ј-
HB), 2.81, 3.00 (ABX, J6A,6B ϭ 13.6, J6A,5 ϭ 7.5 Hz, J6B,5 unre-
solved, 2 H, 6-HA, 6-HB), 3.36 (s, 3 H, OCH3), 3.31Ϫ3.72 (m, 9 H,
2-H, 4-H, 2Ј-H to 6Ј-H, 7Ј-HA, 7Ј-HB), 3.80 (ddd, J5,4 ϭ 7.5,
J5,6A ϭ 7.5, J5,6B ϭ 2.2 Hz, 1 H, 5-H), 3.96 (t, J ϭ 9.2 Hz, 1 H, 3-
H), 4.45Ϫ4.99 (m, 15 H, 1-H, 7 ϫ CH2Ph), 7.14Ϫ7.37 (m, 35 H,
7 ϫ Ph). 13C NMR (67.9 MHz, CDCl3): δ ϭ 34.9, 35.2 (C6, C1Ј),
55.0 (OCH3), 69.0 (C7Ј), 73.2, 73.4, 74.9, 75.0 (ϫ 2), 75.4, 75.6 (7 ϫ
CH2Ph), 70.9, 78.4, 78.9, 79.9 (ϫ 2), 80.6 (ϫ 2), 81.9, 87.0 (C2ϪC5,
C2ЈϪC6Ј), 97.7 (C1), 127.5 (ϫ 2), 127.6, 127.7, 127.8, 128.0, 128.1,
128.2, 128.3 (ϫ 2) (arom. CH), 138.0 (ϫ 2), 138.1, 138.2, 138.5,
138.6 (subst. arom. C); m/z (FAB): 1039.5 (100) [M ϩ Na]ϩ; found
[M ϩ Na]ϩ 1039.4430. C63H68O10S·Na requires 1039.4431.
Methyl S,S-Dioxo-2,3,4-tri-O-benzyl-6-S-(2Ј,6Ј-anhydro-3Ј,4Ј,5Ј,7Ј-
tetra-O-benzyl-1Ј-deoxy-
glucopyranoside (36): To a solution of the disaccharide 35 (0.132 g,
D-glycero-D-gulo-heptitol-1-yl)-6-thio-α-D-
0.13 mmol) in DCM (8 mL) was added first Na2HPO4 (0.09 g, CDCl3): δ ϭ 1.41Ϫ1.46 (m, 2 H, 6-HA, 7-HA), 1.76Ϫ1.84 (m, 2 H,
0.63 mmol) then a solution of mCPBA (0.06 g, 0.35 mmol) in 6-HB, 7-HB), 2.00 (ϫ 2), 2.03, 2.04, 2.05, 2.07, 2.09 (6 ϫ s, 21 H,
DCM (2 mL) and the reaction mixture was stirred for 3 h. The 7 ϫ COCH3), 3.36 (s, 3 H, OCH3), 3.38Ϫ3.41 (m, 1 H, 8-H), 3.62
solution was diluted with DCM (40 mL), washed with satd. aq. (ddd, J12,11 ϭ 10.0, J12,13B ϭ 5.3, J12,13A ϭ 2.2 Hz, 1 H, 12-H),
Na2S2O3 (20 mL), aq. NaOH (1 , 20 mL), brine (30 mL), and 3.72Ϫ3.76 (m, 1 H, 5-H), 4.08, 4.23 (ABX, J13A,13B ϭ 12.3,
dried. The crude product obtained on evaporation of the solvent
J13A,12 ϭ 2.2, J13B,12 ϭ 5.3 Hz, 2 H, 13-HA, 13-HB), 4.81Ϫ4.88 (m,
was chromatographed on silica (light petroleum ether/EtOAc, 2:1) 4 H, 1-H, 2-H, 4-H, 9-H), 5.03 (appt. t, J11,12 ϭ 10.0, J11,10 ϭ 9.5
to give 36 as an opaque oil (0.13 g, 95%); Rf ϭ 0.25 (light petro-
Eur. J. Org. Chem. 2002, 1323Ϫ1336
Hz, 1 H, 11-H), 5.17 (t, J ϭ 9.5 Hz, 1 H, 10-H), 5.43 (t, J ϭ 9.7
1333

D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor
FULL PAPER
Hz, 1 H, 3-H). 13C NMR (67.9 MHz, CDCl3): δ ϭ 20.59, 20.62, 21.7 mmol) was added to a solution of the thiol 43 (0.25 g,
20.66 (ϫ 2), 20.69, 20.71, 20.72 (7 ϫ COCH3), 26.81, 27.04 (C6, 1.01 mmol) and iodide 19 (0.287 g, 0.43 mmol) in acetone (25 mL)
C7), 55.23 (OCH3), 62.33 (C13), 68.41, 68.71, 70.12, 71.15, 71.81, and the mixture was heated at reflux for 4.5 h. After cooling, the
72.23, 74.29, 75.73, 77.88 (C2ϪC5, C8ϪC12), 96.48 (C1), 169.51, solids were removed by filtration, the solvent was evaporated and
169.66, 169.92, 170.01, 170.20, 170.34, 170.65 (7 ϫ COCH3); m/z the residue was partitioned between EtOAc (50 mL) and H2O
(FAB): 671 (100) [M ϩ Na]ϩ; found [M ϩ Na]ϩ 671.2155. (50 mL). The aqueous layer was further extracted with EtOAc (2
C28H40O17·Na requires 671.2163.
ϫ 25 mL) and the organic parts were washed with brine (30 mL),
dried, and concentrated in vacuo to give the crude product as an
oil. Purification by column chromatography (light petroleum ether/
EtOAc, 4:1) gave 44 as a colourless oil (0.239 g, 71%); Rf ϭ 0.23
(light petroleum ether/EtOAc, 4:1). [α]2D0 ϭ Ϫ30.7 (c ϭ 1.2, CHCl3);
(S)-S-Acetyl-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-(thiomethyl)-
1,3-oxazolidine (42): Diisopropyl azodicarboxylate (0.85 mL,
4.32 mmol) was added dropwise to a solution of triphenylphos-
phane (1.13 g, 4.31 mmol) in THF (30 mL) at 0 °C and the mixture
was stirred for 30 min at this temperature after which time a white
precipitate had formed. A solution of alcohol 41[42] (0.50 g,
2.16 mmol) and thiolacetic acid (0.31 mL, 4.34 mmol) in THF
(20 mL) was added and the resulting yellow mixture was stirred for
1 h at 0 °C. The solvent was evaporated in vacuo and the resulting
residue treated with a mixture of light petroleum ether and EtOAc
(5:1) causing triphenylphosphane to crystallise. The supernatant
was purified by column chromatography (light petroleum ether/
EtOAc, 5:1Ǟ4:1) to give a mixture of the desired product and tri-
phenylphosphane sulfide. The contaminant was removed by crys-
tallisation from hexane to leave 42 as a colourless oil (0.517 g,
83%); Rf ϭ 0.32 (light petroleum ether/EtOAc, 3:1). [α]2D0 ϭ Ϫ15.0
νmax/cmϪ1: 2978, 2871, 1695 (CϭO), 1496, 1477, 1454, 1386, 1365,
˜
1308, 1260, 1245, 1208, 1171, 1143, 1099, 1071, 1028. 1H NMR
(270 MHz, [D6]DMSO, 80 °C): δ ϭ 1.47, 1.55 [2 ϫ s, 6 H,
C(CH3)2], 1.49 [s, 9 H, OC(CH3)3], 2.55Ϫ2.69 (m, 2 H, SCH2oxaz.),
2.79 (dd, J1ЈA,1ЈB ϭ 13.7, J1ЈA,2 ϭ 6.5 Hz, 1 H, 1Ј-HA), 3.00 (br. t,
J1ЈB,1ЈA ϭ 13.7 Hz, 1 H, 1Ј-HB), 3.46Ϫ3.62 and 3.69Ϫ3.82 (2 ϫ m,
8 H, 4-H, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, 7Ј-HA, 7Ј-HB), 3.91Ϫ4.02
(2 H, 5-HA, 5-HB), 4.55Ϫ4.90 (m, 8 H, 4 ϫ CH2Ph), 7.27Ϫ7.40
(m, 20 H, 4 ϫ Ph). 13C NMR (67.9 MHz, [D6]DMSO, 80 °C):
δ ϭ 23.4 (br), 26.5 [C(CH3)2], 27.7 [OC(CH3)3], 33.6 (C1Ј), 34.7
(CH2oxaz.), 56.4 (C4), 65.7 (C5), 68.9 (C7Ј), 72.2, 73.4, 73.5, 73.9
(4 ϫ CH2Ph), 78.1 (ϫ 2), 80.2, 85.5 (ϫ 2) (C2ЈϪC6Ј), 78.9
[OC(CH3)3], 92.9 (C2), 126.9, 127.0 (ϫ 2), 127.1, 127.2, 127.7
(arom. CH), 138.0 (ϫ 2), 138.1, 138.3 (subst. arom. C), 150.7
(tBuOCON); m/z (FAB): 806 (100) [M ϩ Na]ϩ, 684 (35) [M Ϫ
(c ϭ 1.0, CHCl3); νmax/cmϪ1: 2980, 2878, 1752 (CϭO, S-acetate),
˜
1702 (CϭO, carbamate), 1479, 1456, 1384, 1367, 1295, 1260, 1208,
1174, 1133, 1097, 1079, 1050. 1H NMR (270 MHz, [D6]DMSO, 80
°C): δ ϭ 1.43, 1.54 [2 ϫ s, 6 H, C(CH3)2], 1.47 [s, 9 H, OC(CH3)3],
2.36 (s, 3 H, COCH3), 2.99Ϫ3.06 (m, 1 H, CHAHBSAc), 3.23 (br.
d, JHA,HB ϭ 12.8 Hz, 1 H, CHAHBSAc), 3.68 (br. d, J5A,5B ϭ 7.3
Hz, 1 H, 5-HA), 3.87, 3.93Ϫ4.02 (m, 2 H, 4-H, 5-HB). 13C NMR
(67.9 MHz, [D6]DMSO, 80 °C): δ ϭ 23.6 (br), 26.6 [C(CH3)2], 28.0
[OC(CH3)3], 30.3 (COCH3), 30.7 (CH2SAc), 56.1 (C4), 66.1 (C5),
79.4 [OC(CH3)3], 93.4 (C2), 151.1 (tBuOCON), 194.0 (COCH3);
m/z (CI): 290 (20) [M ϩ H]ϩ, 234 (15%), 190 (100) [M Ϫ Boc ϩ
H]ϩ; found [M ϩ H]ϩ 290.1426. C13H23NO4S.H requires 290.1426.
BocϩH]ϩ, 181 (30%); found [M
C46H57NO8S·Na requires 806.3703.
ϩ
Na]ϩ 806.3707.
(4S)-S-(2Ј,6Ј-Anhydro-3Ј,4Ј,5Ј,7Ј-tetra-O-benzyl-1Ј-deoxy-
D-
glycero- -gulo-heptitol-1Ј-yl)-N-(tert-butoxycarbonyl)-2,2-dimethyl-
D
4-(sulfonylmethyl)-1,3-oxazolidine (45): To a solution of sulfide 44
(0.554 g, 0.707 mmol) in DCM (20 mL) was added first Na2HPO4
(0.501 g, 3.53 mmol) then mCPBA (0.366 g, 2.12 mmol) and the
reaction mixture was stirred for 3 h. The solution was diluted with
DCM (50 mL), washed with satd. aq. Na2S2O3 (30 mL), aq. NaOH
(1 , 20 mL), brine (30 mL), and dried. On evaporation of the solv-
ent the crude sulfone was obtained as a gum (0.551 g, 95%) which
was Ͼ 95% pure according to 1H NMR analysis. An analytical
sample was chromatographed on silica (light petroleum ether/
EtOAc, 4:1) to give 45 as a white foam, Rf ϭ 0.09 (light petroleum
(S)-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-(thiomethyl)-1,3-oxa-
zolidine (43): A methanolic solution of sodium methoxide (25% w/
w, 0.26 mL, 1.14 mmol) was added to a solution of the S-acetate
42 (0.33 g, 1.14 mmol) in degassed MeOH (5 mL) and the mixture
was stirred for 4 h. Amberlyst 15 ion-exchange resin was then ad-
ded until the pH of the solution became neutral, the resin was
removed by filtration and the filtrate was evaporated in vacuo. Puri-
fication by column chromatography (light petroleum ether/EtOAc,
5:1Ǟ4:1) gave first 43 as a colourless oil (0.162 g, 57%); Rf ϭ 0.37
(light petroleum ether/EtOAc, 4:1). [α]2D0 ϭ Ϫ25.8 (c ϭ 1.2, CHCl3);
ether/EtOAc, 4:1). [α]2D0 ϭ Ϫ30.1 (c ϭ 0.6, CHCl3); ν˜max/cmϪ1
:
2980, 2876, 1694 (CϭO), 1497, 1454, 1387, 1314 (SO2), 1261, 1248,
1210, 1170, 1106, 1052, 1028. 1H NMR (270 MHz, [D6]DMSO, 80
°C): δ ϭ 1.44, 1.55 [2 ϫ s, 15 H, C(CH3)2, OC(CH3)3], 3.21 (dd, 1
H, JA,B ϭ 15.0, JA,4 ϭ 1.5 Hz, SO2CHAHBoxaz.), 3.39Ϫ3.58 (m, 6
H, SO2CHAHBoxaz., 1Ј-HA, 1Ј-HB, 3Ј-H, 4Ј-H, 5Ј-H), 3.70 (br. s,
2 H, 7Ј-HA, 7Ј-HB), 3.78Ϫ3.91 (m, 2 H, 2Ј-H, 6Ј-H), 4.00Ϫ4.09
(ABX, J5A,5B ϭ 9.2, J5A,4 ϭ 5.3, J5B,4 ϭ 1.5 Hz, 2 H, 5-HA, 5-HB),
4.32Ϫ4.40 (m, 1 H, 4-H), 4.48, 4.55 (AB, J ϭ 12.4 Hz, 2 H,
CH2Ph), 4.59, 4.82 (AB, J ϭ 10.7 Hz, 2 H, CH2Ph), 4.67, 4.74
(AB, J ϭ 11.4 Hz, 2 H, CH2Ph), 4.81, 4.86 (AB, J ϭ 11.4 Hz, 2
H, CH2Ph), 7.18Ϫ7.37 (m, 20 H, 4 ϫ Ph). 13C NMR (67.9 MHz,
[D6]DMSO, 80 °C): δ ϭ 23.4 (br), 26.5 [C(CH3)2], 27.7 [OC(CH3)3],
51.1 (C4), 55.6 (SO2CH2oxaz.), 55.9 (C1Ј), 66.1 (C5), 68.6 (C7Ј),
72.3, 73.4, 73.5, 73.9 (4 ϫ CH2Ph), 73.3, 77.6, 77.9, 79.5, 85.2
(C2ЈϪC6Ј), 79.4 [OC(CH3)3], 92.4 (C2), 126.9, 127.0, 127.1, 127.2,
127.5, 127.7, 127.8, 128.1 (arom. CH), 137.6 137.8 (ϫ 2), 138.1
(subst. arom. C), 150.5 (tBuOCON); m/z (FAB): 838 (100) [M ϩ
Na]ϩ; found [M ϩ Na]ϩ 838.3608. C46H57NO10S·Na requires
838.3601.
νmax/cmϪ1: 2979, 2878, 2562 (SH), 1694 (CϭO), 1478, 1456, 1386,
˜
1367, 1310, 1296, 1261, 1245, 1207, 1174, 1147, 1102, 1081, 1061.
1H NMR (270 MHz, [D6]DMSO, 80 °C): δ ϭ 1.41, 1.49 [2 ϫ s, 6
H, C(CH3)2], 1.43 [s, 9 H, OC(CH3)3], 2.24 (br. t, J ϭ 8.5 Hz, 1 H,
SH), 2.52 (dt, JHA,HB ϭ 12.6, JHA,4 ϭ JHA,SH 8.5 Hz, 1 H,
CHAHBSH), 2.72Ϫ2.81 (m, 1 H, CHAHBSH), 3.81Ϫ3.88 (m, 1 H,
4-H), 3.89, 3.95 (ABX, J5A,5B ϭ 9.2, J5A,4 ϭ 2.2, J5B,4 ϭ 5.6 Hz, 2
H, 5-HA, 5-HB). 13C NMR (67.9 MHz, [D6]DMSO, 80 °C): δ ϭ
23.3 (br), 26.4 [C(CH3)2], 25.3 (CH2SH), 27.6 [OC(CH3)3], 58.9
(C4), 65.0 (C5), 78.9 [OC(CH3)3], 93.0 (C2), 150.8 (tBuOCON);
m/z (CI): 248 (35) [M ϩ H]ϩ, 192 (65%); 148 (100) [M Ϫ Boc ϩ H]ϩ;
found [M ϩ H]ϩ 248.1322. C11H21NO3S.H requires 248.1320.
Further elution gave an oil (0.038 g) tentatively identified as the
dimeric disulfide of 43.
(4S)-S-(2Ј,6Ј-Anhydro-3Ј,4Ј,5Ј,7Ј-tetra-O-benzyl-1Ј-deoxy-
glycero- -gulo-heptitol-1Ј-yl)-N-(tert-butoxycarbonyl)-2,2-dimethyl- (E)-5,9-Anhydro-6,7,8,10-tetra-O-benzyl-1,2-N,O-isopropylidene-2-
4-(thiomethyl)-1,3-oxazolidine (44): Potassium carbonate (3 g, (tert-butoxycarbonylamino)-2,3,4-trideoxy- -erythro- -talo-dec-3-
D-
D
D
L
1334
Eur. J. Org. Chem. 2002, 1323Ϫ1336

A RambergϪBäcklund Approach to the Synthesis of C-Glycosides
FULL PAPER
enitol (46): KOH/Al2O3 (25% w/w, 5.0 g) was added to a solution (arom. CH), 138.0 (ϫ 2), 138.1, 138.4 (subst. arom. C), 150.9
of the sulfone 45 (0.46 g, 0.56 mmol) in tert-butyl alcohol (8 mL)
and the mixture was heated to 60 °C. CBr2F2 (0.5 mL, 5.47 mmol)
was added and the reaction was stirred at this temperature for
15 min. Two portions of CBr2F2 (0.5 mL, 5.47 mmol each) were
added over the next 2.5 h but some starting material still remained.
Therefore, more KOH/Al2O3 (3.0 g) was added, followed by
CBr2F2 (0.5 mL, 5.47 mmol) after 15 min. The mixture was diluted
with DCM (40 mL), stirred for 10 min, filtered through Celite ,
and the filtrate was evaporated under reduced pressure. The residue
was chromatographed on a silica column (light petroleum ether/
EtOAc, 4:1Ǟ3:1) to yield a solid which crystallised upon tritura-
tion with light petroleum ether to afford 46 as a white crystalline
solid (0.155 g, 37%), Rf ϭ 0.14 (light petroleum ether/EtOAc, 3:1);
(tBuOCON); m/z (FAB): 774.4 (100) [M ϩ Na]ϩ, 652.3 (35) [M Ϫ
Boc ϩ H]ϩ; found [M ϩ Na]ϩ 774.3979. C46H57NO8·Na requires
774.3982.
Methyl 5,9-Anhydro-6,7,8,10-tetra-O-benzyl-2-(tert-butoxycarbonyl-
amino)-2,3,4-trideoxy-D-erythro-L-talo-deconate (48): Freshly pre-
pared Jones reagent (1 , 0.26 mL, 0.26 mmol) was added dropwise
to a solution of 47 (0.051 g, 0.068 mmol) in acetone (1.5 mL) co-
oled to 5 °C and the mixture was stirred at this temperature for
15 min before being allowed to warm to room temp. Stirring was
continued for 6 h after which excess Jones reagent was quenched
by the addition of 2-propanol (0.2 mL). The solution pH was made
neutral with satd. aq. NaHCO3, ether (50 mL) was added and the
resulting solution was washed with brine (2 ϫ 10 mL), dried, and
the solvent was evaporated in vacuo. The residue (0.05 g) was redis-
solved in ether (10 mL), cooled to 5 °C, and an ethereal solution
of diazomethane (ca. 2 , 1 mL) was added in three portions over
a period of 30 min. The reaction mixture was warmed to room
temp. and excess diazomethane was quenched by the addition of
AcOH. Evaporation of the solvent gave the crude product as a
cream solid which was purified by column chromatography (light
petroleum ether/EtOAc, 4:1Ǟ3:1) afforded 48 as a white solid
(0.031 g, 62%); Rf ϭ 0.39 (light petroleum ether/EtOAc, 3:1); m.p.
m.p. 109Ϫ110 °C. [α]2D0 ϭ Ϫ11.9 (c ϭ 1.0, CHCl3); νmax/cmϪ1: 2979,
˜
2869, 1695 (CϭO), 1606 (CϭC), 1497, 1454, 1384, 1366, 1254,
1207, 1168, 1098, 1067, 1028. 1H NMR (270 MHz, [D6]DMSO, 80
°C): δ ϭ 1.36 [s, 9 H, OC(CH3)3], 1.47, 1.53 [2 ϫ s, 6 H, C(CH3)2],
3.26 (t, J ϭ 9.2 Hz, 1 H, 8-H), 3.47Ϫ3.54 (m, 2 H, 10-HA, 10-HB),
3.62Ϫ3.74 (m, 4 H, 1-HA, 1-HB, 6-H, 9-H), 3.86 (dd, J7,8 ϭ 9.5,
J7,6 ϭ 5.6 Hz, 1 H, 7-H), 4.01 (dd, J5,6 ϭ 9.0, J5,4 ϭ 6.0 Hz, 1 H,
5-H), 4.37 (br. t, J ϭ 5.8 Hz, 1 H, 2-H), 4.51, 4.56 (AB, J ϭ 12.1
Hz, 2 H, CH2Ph), 4.59, 4.76 (AB, J ϭ 11.2 Hz, 2 H, CH2Ph), 4.62,
4.69 (AB, J ϭ 11.2 Hz, 2 H, CH2Ph), 4.79, 4.84 (AB, J ϭ 11.4 Hz,
2 H, CH2Ph), 5.72 (dd, J3,4 ϭ 15.6, J3,2 ϭ 5.8 Hz, 1 H, 3-H), 5.84
(dd, J4,3 ϭ 15.6, J4,5 ϭ 6.0 Hz, 1 H, 4-H), 7.20Ϫ7.34 (m, 20 H, 4
ϫ Ph). 13C NMR (67.9 MHz, [D6]DMSO, 80 °C): δ ϭ 23.5 (br),
26.4 [C(CH3)2], 27.6 [OC(CH3)3], 57.6 (C2), 67.1 (C1), 69.1 (C10),
72.2, 73.4 (ϫ 2), 73.9 (4 ϫ CH2Ph), 77.7 (ϫ 2), 77.9, 82.0, 85.4
(C5ϪC9), 78.7 [OC(CH3)3], 92.7 [C(CH3)2], 126.8, 126.9 (ϫ 2),
127.0, 127.1, 127.2, 127.4, 127.6, 127.7 (ϫ 2), 128.2, 128.4 (arom.
CH), 128.6, 131.4 (C3, C4), 138.0 (ϫ 2), 138.1, 138.4 (subst. arom.
C), 150.9 (tBuOCON); m/z (FAB): 772.5 (100) [M ϩ Na]ϩ; found
[M ϩ Na]ϩ 772.3829. C46H55NO8·Na requires 772.3825.
134Ϫ136 °C. [α]2D0 ϭ Ϫ8.2 (c ϭ 1.5, CHCl3); νmax/cmϪ1: 3360 (NH),
˜
3031, 2903, 2863, 1757 (ester CϭO), 1682 (carbamate CϭO), 1515,
1453, 1366, 1307, 1218, 1199, 1158, 1104, 1056, 1027. 1H NMR
(500 MHz, CDCl3): δ ϭ 1.41 [s, 9 H, OC(CH3)3], 1.46Ϫ1.54 (m, 1
H, 4-HA), 1.66Ϫ1.73 (m, 1 H, 4-HB), 1.85Ϫ1.91 (m, 1 H, 3-HA),
2.01Ϫ2.10 (m, 1 H, 3-HB), 3.18Ϫ3.26 (m, 2 H, 5-H, 6-H), 3.38 (br.
d, J9,8 ϭ 9.4 Hz, 1 H, 9-H), 3.59 (t, J ϭ 9.2 Hz, 1 H, 8-H),
3.64Ϫ3.72 (m, 3 H, 7-H, 10-HA, 10-HB), 3.67 (s, 3 H, CO2CH3),
4.25Ϫ4.31 (m, 1 H, 2-H), 4.40, 4.61 (AB, J ϭ 12.2 Hz, 2 H,
CH2Ph), 4.56, 4.80 (AB, J ϭ 10.9 Hz, 2 H, CH2Ph), 4.59, 4.85
(AB, J ϭ 10.7 Hz, 2 H, CH2Ph), 4.89 (A2, C2 H, H2Ph), 5.13 (br.
d, JNH,2 ϭ 7.9 Hz, 1 H, NH), 7.15Ϫ7.17 (m, 2 H, 2 ϫ arom. H),
7.24Ϫ7.34 (m, 18 H, 18 ϫ arom. H). 13C NMR (125 MHz, CDCl3):
δ ϭ 27.6, 28.7 (C3, C4), 28.3 [OC(CH3)3], 52.1 (CO2CH3), 53.5
(C2), 68.9 (C10), 73.4, 74.9, 75.3, 75.5 (4 ϫ CH2Ph), 78.5, 78.7,
78.9, 82.0, 87.2 (C5ϪC9), 79.7 [OC(CH3)3], 127.6 (ϫ 2), 127.7 (ϫ
2), 127.9, 128.1, 128.3, 128.4 (ϫ 2), 128.5 (arom. CH), 137.9, 138.1,
138.2, 138.6 (subst. arom. C), 155.4 (tBuOCON), 173.2 (CO2CH3);
m/z (FAB): 762.5 (100) [M ϩ Na]ϩ, 706.5 (30%); found [M ϩ Na]ϩ
762.3614. C44H53NO9·Na requires 762.3618.
5,9-Anhydro-6,7,8,10-tetra-O-benzyl-1,2-N,O-isopropylidene-2-(tert-
butoxycarbonylamino)-2,3,4-trideoxy-D-erythro-L-talo-decitol (47):
A mixture of alkene 46 (0.168 g, 0.22 mmol) and freshly recrys-
tallised tosylhydrazide (0.125 g, 0.67 mol) was dissolved in DME
(10 mL) and the solution was heated to 85 °C. A solution of aq.
NaOAc (1 , 0.67 mL, 0.67 mmol) was added in three equal por-
tions over a period of 3 h and the mixture was stirred for a further
8 h, although TLC showed that some starting material remained.
More tosylhydrazide (0.042 g, 0.23 mmol) and aq. sodium acetate
(1 , 0.22 mL, 0.22 mmol) were added and stirring was continued
at 85 °C for a further 8 h. The reaction mixture was then diluted Methyl 5,9-Anhydro-6,7,8,10-tetra-O-acetyl-2-(tert-butoxycarbonyl-
with water (30 mL) and extracted with DCM (3 ϫ 20 mL), the amino)-2,3,4-trideoxy- -erythro- -talo-deconate (49): Pearlman’s
organic parts were dried and the solvents evaporated in vacuo. Col- catalyst (20% w/w Pd(OH)2 on carbon, 0.01 g) was added to a solu-
umn chromatography (light petroleum ether/EtOAc, 4:1) gave 47 tion of 48 (0.057 g, 0.077 mmol) in EtOAc (1.5 mL) and MeOH
D
L
as a colourless oil (0.138 g, 82%); Rf ϭ 0.20 (light petroleum ether/
(1.5 mL) and the resulting mixture was stirred overnight under an
atmosphere of H2 (balloon). The supernatant layer was decanted
EtOAc, 4:1). [α]2D0 ϭ Ϫ12.8 (c ϭ 1.0, CHCl3); νmax/cmϪ1: 2977,
˜
2868, 1693 (CϭO), 1497, 1454, 1389, 1365, 1257, 1208, 1171, 1100, and the remaining solids were stirred with MeOH (5 mL) for
1
1028. H NMR (270 MHz, [D6]DMSO, 80 °C): δ ϭ 1.41 [s, 9 H, 15 min. This process was repeated until no product was detectable
OC(CH3)3], 1.42, 1.50 [2 ϫ s, 6 H, C(CH3)2], 1.35Ϫ1.45, 1.64Ϫ1.81
(2 ϫ m, 4 H, 3-HA, 3-HB, 4-HA, 4-HB), 3.22Ϫ3.33 (m, 2 H, 6-H, to dryness to give an oil (0.033 g) which was redissolved in a mix-
8-H), 3.47Ϫ3.54 (m, 2 H, 5-H, 7-H), 3.60Ϫ3.74 (m, 4 H, 1-HA, 9- ture of Ac2O (1 mL) and pyridine (2 mL). After stirring overnight
in the washings by TLC. The combined washings were evaporated
H, 10-HA, 10-HB), 3.79Ϫ3.91 (m, 2 H, 2-H, 1-HB), 4.54 (A2, 2 H, at room temp., the solution was evaporated to dryness in vacuo
CH2Ph), 4.60, 4.76 (AB, J ϭ 11.2 Hz, 2 H, CH2Ph), 4.64, 4.81 and the last traces of pyridine were removed as an azeotrope with
(AB, J ϭ 11.0 Hz, 2 H, CH2Ph), 4.83 (A2, 2 H, CH2Ph), 7.21Ϫ7.34
(m, 20 H, 4 ϫ Ph). 13C NMR (67.9 MHz, [D6]DMSO, 80 °C): δ ϭ (light petroleum ether/EtOAc, 1:1) to yield 49 as a white solid
23.4 (br), 26.5 [C(CH3)2], 27.5, 28.8 (C3, C4), 27.7 [OC(CH3)3], (0.009 g, 21% from 48), Rf ϭ 0.19 (light petroleum ether/EtOAc,
56.6 (C2), 66.3 (C1), 69.1 (C10), 72.2, 73.4, 73.5, 73.8 (4 ϫ CH2Ph), 1:1); m.p. 145Ϫ146.5 °C. [α]2D0 ϭ Ϫ18.0 (c ϭ 0.45, CHCl3); νmax
77.7, 77.9, 78.3, 81.4, 85.8 (C5ϪC9), 78.4 [OC(CH3)3], 92.4
cmϪ1: 3405 (NH), 2903, 1745 (ester CϭO), 1690 (carbamate Cϭ
[C(CH3)2], 126.6, 126.8, 126.9, 127.1, 127.3, 127.4, 127.7, 127.9 O), 1558, 1506, 1382, 1259, 1227, 1158, 1034. 1H NMR (270 MHz,
toluene (ϫ 4). The residue was purified by column chromatography
˜
/
Eur. J. Org. Chem. 2002, 1323Ϫ1336
1335

D. E. Paterson, F. K. Griffin, M.-L. Alcaraz, R. J. K. Taylor
FULL PAPER
[15] [15a]
D. Calimente, M. H. D. Postema, J. Org. Chem. 1999, 64,
CDCl3): δ ϭ 1.44 [s, 9 H, OC(CH3)3], 1.50Ϫ1.80 (m, 4 H, 3-HA,
3-HB, 4-HA, 4-HB), 2.00, 2.02, 2.04, 2.10 (4 ϫ COCH3), 3.39Ϫ3.47
(m, 1 H, 5-H), 3.62 (ddd, J9,8 ϭ 9.9, J9,10B ϭ 5.1, J9,10A ϭ 2.4 Hz,
[15b]
1770Ϫ1771.
M. H. D. Postema, D. Calimente, Tetrahedron
Lett. 1999, 40, 4755Ϫ4759.
R. R. Schmidt, H. Dietrich, Angew. Chem. Int. Ed. Engl. 1991,
30, 1328Ϫ1329.
[16]
[17]
[18]
[19]
1 H, 9-H), 3.74 (s, 3 H, CO2CH3), 4.09, 4.22 (ABX, J10A,10B
ϭ
12.4, J10A,9 ϭ 2.4, J10B,9 ϭ 5.1 Hz, 2 H, 10-HA, 10-HB), 4.21Ϫ4.30
(m, 1 H, 2-H), 4.87 (t, J ϭ 9.7 Hz, 1 H, 8-H), 5.03 (t, J ϭ 9.5 Hz,
1 H, 6-H), 5.16 (t, J ϭ 9.5 Hz, 1 H, 7-H), 5.13 (br. d, JNH,2 ϭ 8.1
Hz, 1 H, NH). 13C NMR (67.9 MHz, CDCl3): δ ϭ 20.6 (ϫ 2), 20.7
(COCH3), 27.4, 28.1 (C3, C4), 28.3 [OC(CH3)3], 52.3 (CO2CH3),
53.2 (C2), 62.3 (C10), 68.6, 71.7, 74.3, 75.7 (ϫ 2) (C5ϪC9), 80.0
[OC(CH3)3], 155.3 (tBuOCON), 169.5, 169.6, 170.4, 170.7
(COCH3), 172.9 (CO2CH3); m/z (FAB): 570 (100) [M ϩ Na]ϩ, 548
(22) [M ϩ H]ϩ, 448 (80%), 706.5 (30%), 329 (35%); found [M ϩ
Na]ϩ 762.3614. C24H37NO13·Na requires 762.3618.
Prof. R. R. Schmidt, Universität Konstanz, personal commun-
1
ication. H NMR spectra were identical.
˜
A. G. M. Barrett, M. Pena, J. A. Willardsen, J. Chem. Soc., Chem.
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´
´
A. Martın, J. A. Salazar, E. Suarez, J. Org. Chem. 1996, 61,
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M. Anastasia, P. Ciuffreda, A. Fiecchi, A. Scala, J. Chem. Soc.,
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H. Ohrui, G. H. Jones, J. G. Moffat, M. L. Maddox, A. T. Christi-
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Acknowledgments
We are grateful to the University of York for a studentship
(D. E. P.), the Government of Papua New Guinea for the award of
an HEP fellowship (F. K. G.) and the Leverhulme Trust for a visit-
ing fellowship (M.-L. A.). We also thank Dr. Trevor Dransfield
(University of York) for obtaining mass spectroscopic data.
[24]
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Received August 17, 2001
[41]
[42]
[O01402]
1336
Eur. J. Org. Chem. 2002, 1323Ϫ1336