New nonhydrolyzable mimetics of sialyl Lewis x and their binding affinity to P-selectin

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Helvetica Chimica Acta Vol. 87 (2004)

New Nonhydrolyzable Mimetics of Sialyl Lewis X and Their Binding

Affinity to P-Selectin

by Fre¬de¬ric Carrel^a), Sylvain Giraud^b), Olivier Spertini^b), and Pierre Vogel*^a)

a

¬

¬ ¬

) Institut des sciences et ingenerie chimiques, Ecole Polytechnique Federale de Lausanne, BCH,

CH-1015 Lausanne-Dorigny

) Institut d×hematologie, Centre hospitalier universitaire vaudois, CH-1011 Lausanne

b

¬

Wittig olefination of (2S,3R,5S,6R)-5-(acetyloxy)-tetrahydro-6-[(methoxymethoxy)methyl]-3-(phenylthio)-

2H-pyran-2-acetaldehyde (()-10) with {2-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-

2H-pyran-2-yl]ethyl}triphenylphosphonium iodide ((À)-11) gave a (Z)-alkene derivative ()-12 that was

converted into (aR,2R,3S,4R,5R,6S)-tetrahydro-a,3-dihydroxy-2-(hydroxymethyl)-5-(phenylthio)-6-{(2Z)-4-

[(2S,3S,4R,5S,6S)-tetrahydro-3,4,5-trihydroxy-6-methyl-2H-pyran-2-yl]but-2-enyl}2H-pyran-4-acetic acid (8),

(aR,2R,3S,4R,6S)-tetrahydro-a,3-dihydroxy-2-(hydroxymethyl)-6-{4-[(2S,3S,4R,5S,6S)-tetrahydro-3,4,5-trihy-

droxy-6-methyl-2H-pyran-2-yl]butyl}-2H-pyran-4-acetic acid (9), and simpler analogues without the hydroxy-

acetic side chain such as (2S,3S,4R,5S,6S)-tetrahydro-6-methyl-2-{(2Z)-4-[(2S,3R,5S,6R)-tetrahydro-5-hydroxy-

6-(hydroxymethyl)-3-(phenylthio)-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3,4,5-triol (30), (2S,3S,4R,5S,6S)-tet-

rahydro-6-methyl-2-{[(2S,5S,6R)-tetrahydro-5-hydroxy-6-(hydroxymethyl)-2H-pyran-2-yl]butyl}-2H-pyran-3,4,5-

triol ((À)-41) and (2S,3S,4R,5S,6S)-tetrahydro-6-methyl-2-{(2Z/E))-4-[(2R,5S,6R)-tetrahydro-5-hydroxy-6-(hy-

droxymethyl)-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3,4,5-triol (43). The key intermediates ()-10 and (À)-11

were derived from isolevoglucosenone and from l-fucose, respectively. The following IC₅₀values were

measured in a ELISA test for the affinities of sialyl Lewis x tetrasaccharide, 8, 9, 30, (À)-41, and 43 toward

P-selectin: 0.7, 2.5 2.8, 7.3 8.0, 5.3 5.9, 5.0 5.2, and 3.4 4.1 mm, respectively.

Introduction. The selectins are a family of cell-adhesion proteins that mediate the

tethering and the rolling of leucocyte endothelial cells through the recognition of the

tetrasaccharide epitope sialyl Lewis x (sLe^x) [1]. Control of the leucocyte endothelial

cell adhesion process may prove useful in cases where excess recruitment of leucocytes

can contribute to acute diseases such as stroke and reperfusion injury and chronic

diseases such as psoriasis and rheumatoid arthritis. The development of molecules that

block the interactions between sLe^xand the selectins has become an active area of

research [2 13]. Among the most promising sialyl Lewis x mimetics are compounds 2

and 3 [3] that are more potent than sLe^x-glycoside 1 in a E-selectin binding assay. They

can be prepared from commercially available starting materials in good yield [3]. These

systems contain two glycosidic acetal moieties that are readily hydrolyzed by the

stomach acidity and by ubiquitous glycosidases of the blood stream. This has stimulated

synthetic efforts to generate nonhydrolyzable mimetics of the sialyl Lewis x epitope, in

particular compounds containing a-C-fucopyranoside [2][4][5][7] or b-C-mannoside

moieties [2][5][6]. Wong and co-workers have found that compound 4, which contains

the most essential functions of sLe^xnecessary in the selectin recognition (the carboxylic

group of sialic acid, the 4-OH and 6-OH groups of the galactopyranosyl unit, the three

OH groups of the a-l-fucopyranosyl moiety [2]) is ca. 30times less potent than sLe ^xin

binding E-selectin [4]. Our studies on the synthesis of C-linked oligosaccharides (see,

Helvetica Chimica Acta Vol. 87 (2004)

1049

e.g., [14]) prompted us to prepare analogues of 4. In particular, ketones of type 5 were

targeted as potential partners in cross-aldol reactions with sialic acid mimics such as 6

[15] with the hope to be able to generate yet unknown C,C,C-linked tetrasaccharides of

type 7 that can be seen as mimics of sLe^x(1). This goal has not been reached yet. In the

meantime, our exploratory synthetic studies incited us to prepare compounds 8 and 9

that are mimics of 4. These compounds, and simpler derivatives, were assayed for their

binding of P-selectin. We found that 8, which contains a 2-deoxy-2-(phenylthio)-b-d-

glucopyranosyl moiety instead of a b-d-galactopyranosyl unit, is almost as potent as the

sLe^xtetrasaccharide in its binding with P-selectin. Simpler analogs without any

substituents at C(2) and C(3) of the b-d-glucopyranosyl moiety of 9 are also

recognized by P-selectin. This work suggests that sLe^xmimics with their b-

galactopyranosyl moiety modified widely may retain good P-selectin affinity.

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Helvetica Chimica Acta Vol. 87 (2004)

Synthesis of the New sLe^xMimics. Following the pioneering work of Wong and co-

workers [2][4], we coupled (2S,3R,5S,6R)-5-(acetyloxy)-tetrahydro-6-[(methoxymeth-

oxy)methyl]-3-(phenylthio)-2H-pyran-2-acetaldehyde (()-10) with the l-fucose-de-

rived phosphonium iodide (À)-11 via a Wittig olefination that gave the (Z)-alkene

derivative ()-12, the precursor of the sLe^xmimics prepared in this work (Scheme 1).

The salt (À)-11 was derived from the known −3-(a-l-fucopyranosyl)prop-1-ene×

(À)-13 [4]. Its OH groups were protected as methoxymethyl (MOM MeOCH₂)

i

ethers (Bu₄NI, Pr₂NEt, MeOCH₂Cl, 0 20 8) giving (À)-14 (96%). Ozonolysis of

(À)-14 and subsequent treatment with Me₂S and NaBH₄in CH₂Cl₂/MeOH

provided alcohol (À)-15 (99%). It was converted into iodide (À)-16 on treat-

ment with Ph₃P/1H-imidazole and I₂(79%) and then into the phosphonium iodide

(À)-11 (Ph₃P, benzene; 64% overall yield based on l-fucose) applying classical

procedures.

Aldehyde ()-10 was derived from isolevoglucosenone (17) [16] in 52% overall

yield (Scheme 1). Conjugated addition of PhSH to 17 (Et₃N as catalyst) afforded (À)-

18 quantitatively. The high exo stereoselectivity of this addition was expected for both

kinetic and thermodynamic reasons (steric factor) [17]. The 2-(phenylthio) substituent

was introduced to insure stereoselective b-C-glycosidation (see below). The C-

glycosidation of allyltrimethylsilane with ketone (À)-18 failed as treatment of (À)-18

under Lewis acid conditions led to the bis-allylated product. Ketone (À)-18 was thus

reduced into a mixture of alcohols 19 and 20. The diastereoselectivity (product ratio 19/

20) was poor with NaBH₄in MeOH at 08 (1:1), with LiBH₄in THFat À 788 (1:2), and

with LiAlH(O^tBu)₃in THF at À 788 (1:1.2). With K-Selectride (K^sBu₃BH), L-

Selectride (Li^sBu₃BH), and Super-H (LiEt₃BH) in THF at À 788, 20 was the major

product of reduction, with diastereoselectivities of 1:5, < 1:10, and < 1:10,

respectively. In contrast, with DIBAL-H (ⁱBu₂AlH) in THF at À 788, reduction of

(À)-18 gave alcohol 19 predominantly with a diastereoselectivity better than 7:1.

Alcohols 19 and 20 were acetylated separately under standard conditions, giving

acetate (À)-21 (56%) and (À)-22 (88%), respectively.

Attempts to promote the C-glycosidation of (À)-22 with allyltrimethylsilane in

CH₂Cl₂by Me₃SiOSO₂CF₃alone, by BF₃¥ OEt₂alone, or by both Lewis acids

simultaneously led only to products of decomposition (08). When CH₂Cl₂was

exchanged for MeCN as solvent, traces of C-glycosides ()-24 and 25 were formed

besides glycal ()-23 that was isolated in 70% yield (Scheme 1). To our delight, we

found that, when nitromethane was used as solvent and in the presence of a large

amount of allyltrimethylsilane, a 10:1 mixture of ( )-24 and 25 could be isolated in

81% yield. For success, both Lewis acid Me₃SiOSO₂CF₃and BF₃¥ OEt₂were necessary

in equimolar ratio (À208). Pure ()-24 was obtained by flash chromatography (FC;

silica gel). Its structure was deduced from its ¹H-NMR spectrum that showed typically

large ³J(H,H) (axial/axial H) coupling constants of a b-d-glucopyranosyl system. The 6-

OH group of crude ()-24 was protected as a MOM ether, giving ()-26 (82%, based

on (À)-22; < 10% of 27). Dihydroxylation of ()-26 with N-methylmorpholine N-

oxide (NMO) and a catalytical amount of OsO₄yielded a mixture 28 of diols that was

oxidized by Pb(OAc)₄in benzene/pyridine to furnish aldehyde ()-10 (96%).

Treatment of phosphonium salt (À)-11 with BuLi in THF (À 788) followed by addition

of aldehyde ()-10 led to a mixture of ()-12 and its product of saponification (À)-29.

Helvetica Chimica Acta Vol. 87 (2004)

1051

Scheme 1

MOM MeOCH₂

This crude mixture, upon treatment with K₂CO₃/MeOH at 208, produced pure (À)-29 in

63 76% yield after FC (silica gel; removal of Ph₃PO).

Cleavage of the MOM protective group of (À)-29 was realized by treatment with

MeOH and thionyl chloride (20equiv.) at 0 8. This gave 30 in 30% yield only

(Scheme 1). Swern oxidation of (À)-29 ((COCl)₂, DMSO, CH₂Cl₂, À 788, then Et₃N)

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Helvetica Chimica Acta Vol. 87 (2004)

furnished ketone (À)-31, (Scheme 2), an unstable compound that eliminated PhSH on

storing at room temperature under diluted conditions. Treatment of crude (À)-31 with

DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) at 08 provided enone ()-32 (89%, based

on (À)-29). Reaction of 0.1m ()-32 with 2 equiv. of PhSH in CH₂Cl₂at 208 (Et₃N as

catalyst promoted) equilibration with (À)-31, which could be isolated by low-temper-

ature FC in 65% yield. Crude (À)-31 (obtained by Swern oxidation) was used directly

in its cross-aldol condensation with ethyl glyoxylate. This led to a complex mixture of

products from which pure aldol (À)-33 and enones ()-34 and ()-32 could be isolated

in 29%, 32%, and 22% yield, respectively. Reduction of aldol (À)-33 with

(Me₄N)BH(OAc)₃[18] in AcOH (208) provided the glucopyranosyl derivative (À)-

1

35. Its structure was established by its H-NMR spectrum (typical vicinal coupling

3

constants J(2,3) 9.6 Hz and J(3,4) 9.9 Hz). The configuration of the secondary-

Scheme 2

MOM MeOCH₂

Helvetica Chimica Acta Vol. 87 (2004)

1053

alcohol moiety of the 3-(hydroxyacetate) group was determined by the NMR data

1

(³J(H,H) and 2D-NOESY H-NMR) of acetonide (À)-36, obtained by treatment of

(À)-35 with acetone and (MeO)₂CMe₂under acidic conditions (TsOH) [19]. The

¹³C-NMR spectrum for the gem-dimethyl moiety of (À)-36 (d(C) 19.8 and 29.7) is

typical of the chair conformation imposed by the substitution of the 1,3-dioxane system

[20]. This result confirmed that the aldol condensation (À)-31 EtOCOCHO follows

the ZimmermanÀTraxler model [21]. Attemps to obtain the b-d-galactopyranoside

analogue of (À)-35 all failed. Reductions of (À)-33 with NaBH₄in excess, ⁱBu₂AlH, L-

Selectride, K-Selectride, or Et₂BOMe/NaBH₄[22] all gave (À)-35 and by-products

containing alcohol (À)-29 resulting from a retro-aldol reaction of (À)-33 with formation

of ketone (À)-31 and subsequent reduction.

Treatment of (À)-35 with MeOH and SOCl₂(08) gave hexahydroxy ester (À)-37

(48%). Saponification of (À)-37 (0.1m NaOH/H₂O) furnished the sialyl Lewis x

mimetic 8 that was isolated in 48% yield (Scheme 2).

Reductive desulfurization of (À)-35 with Raney-Ni in EtOH afforded (À)-38 (63%,

based on (À)-33) (Scheme 3). Hydrogenation of the alkene moiety could not be

avoided. Acidic methanolysis of (À)-38 with SOCl₂/MeOH gave hexahydroxy ester

(À)-39 (70%). Saponification of (À)-39 produced 9 in 86% yield. In a similar way, (À)-

29 was converted into (À)-40 (99%) and then deprotected into (À)-41 (60%). To avoid

hydrogenation of the CC bond of (À)-29, we carried out the desulfurization of (À)-29

with Bu₃SnH and AIBN (2,2'-azabis[2-methylpropanenitrile]) (toluene, 808). This led

to a 1:2 mixture of (Z)- and (E)-alkene derivatives (À)-42 (83%). Deprotection

(SOCl₂, MeOH, 08) provided 43 ((Z)/(E) 1:2). All the new substances described here

were characterized by the spectral data (see Exper. Part).

Scheme 3

MOM MeOCH₂

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Helvetica Chimica Acta Vol. 87 (2004)

Affinity of the New sLe^xMimetics toward P-Selectin by an ELISA Test.

Evaluation of the affinity for P-selectin of 8, 9, 30, (À)-41, and 43 relative to sLe^xwere

carried out following a protocol already described [23], which implied solutions of the

ligands with a concentration varying between 1 mm to 10m m. The results are given in

the Table. The Figure displays the fitted curve for each product used in the biological

testing.

Table. IC₅₀[mm] Values for Some Synthesized Products Obtained as Described in the Exper. Part. The IC₅₀

values are given as 90% confidence intervals, obtained from the curve fitting, and with the R²for each curve fitting.

8

9

30

5.2 5.0

0.9903

(À)-41

3.3 4.1 .7

0.9968

43

sLe^xa

)

IC₅₀

R²

2.4 2.8

0.9954

7.3 8.05.3 5.9

0.9874

0

0.9890

^a) IC₅₀ 8 mm for a P-selectin ELISA-based assay by Kaila and co-workers [6].

Figure. Curve fitting from the measurements obtained in the ELISA test with 8, 9, 30, (À)-41, and 43. For each

product, every set of concentration was tested between two and six times. All inhibitions were calculated as

described in the Exper. Part.

Discussion. All new sialyl Lewis x mimetics 8, 9, 30, (À)-41, and 43 are recognized

by P-selectin at low mm concentration. The best ligand is 8, which is only four times

weaker than sLe^xitself. Removal of the 2-(phenylthio) substituent group in 8 and

Helvetica Chimica Acta Vol. 87 (2004)

1055

reducing its alkene moiety gives ligand 9, which shows a diminished (by a factor of 3)

binding affinity. Recent results by Thoma and Schwarzenbach [3] with mimetics 2 and 3

have shown that the 2-OH group of the b-d-galactopyranosyl moiety of 2 can be

esterified without loss of the binding affinity. In fact, the 2-(benzoyloxy) derivative 3 is

three times better than 2 for binding E-selectin. Thus, our observations made with 8 and

9, are parallel to those made with 2 and 3. It is surprising that our mimetics 8 and 9,

which have a b-d-glucopyranosyl moiety instead of the b-d-galactopyranoside unit of

sLe^x, and analogues such as 2 and 3 should maintain a binding affinity almost as good as

sLe^xassays with P-selectin. This might not be the case with E-selectin. A second

surprise is the observation that the simpler analogues of 8 and 9, which are devoid of

any carboxylic moiety, are in fact as active as 9. As expected for entropy reasons,

mimetics with the (Z)-alkene moiety that imitates the GlcNAc unit of sLe^xshould be

better ligands than the correponding alkanes. The greater binding activity of 43 (IC₅₀

3.7 mm) compared with that of (À)-41 (IC₅₀5.1 mm) is in agreement with this

hypothesis, although the difference in binding affinity is relatively small!

Conclusion. Compound (À)-41, which links a 2,3-dideoxy-b-d-erythro-hexopyr-

anosyl moiety with an a-l-fucopyranosyl moiety through a butane-1,4-diyl spacer,

realizes a simple nonhydrolyzable mimetic of sLe^xas it binds to P-selectin with an

affinity only eight times lower than that of sLe^x! If the butane-1,4-diyl spacer is replaced

by a less flexible (2Z)-but-2-en-1,4-diyl moiety, as in 43, the binding affinity is slightly

improved. Decoration of the 2,3-dideoxy-b-d-erythro-hexopyranosyl unit with a 2-

(phenylthio) substituent or/and a 3-(2-hydroxyacetic acid) group might enhance the

binding affinity to P-selectin. We suggest that other simple analogues (other stereo-

isomers) of (À)-41 and 43 with further substituents that could vary widely should be

made and tested for their binding affinity to the selectins.

¬

We are grateful to the Swiss National Science Foundation and the Office Federal de l×Education et de la

Science (Bern, COST D13/0001/99) for financial support. We thank also Mr. Martial Rey and Mr. Francisco

Sepulveda for their technical help, and Prof. Inmaculada Robina, University of Seville (SOCRATES EPFL-

Seville), for helpful discussions and assistance in the high-resolution mass spectroscopy.

Experimental Part

General. See [24].

Antibodies and Chimeric Proteins. The anti-P-selectin antibody able to block almost all P-selectin

interactions (WAPS 12.2) is produced from hybridoma-cell (ATCC number HB-299) culture medium and

purified by using the MAPP II kit (Bio-Rad Laboratories, Glattbrugg, Switzerland) or are from private

industries (Dako, Glostrup, Danemark, and Amersham Pharmacia Biotech, D¸bendorf, Switzerland). The P-

selectin/m chimera is obtained from the culture medium of CHO cells transfected with a plasmid containing the

corresponding DNA as described previously [23].

Determination of Products Concentration Giving 50% of Inhibition (IC₅₀) by ELISA. At 378, 0.15 mg of

sLe^x-BSA (Oxford GlycoSystems, Oxford, United Kingdom) diluted in carbonate buffer (pH 9.4) is coated

overnight in a 96-well high-binding ELISA plate (Costar, Cambridge, MA). The plate is then washed (3 times

with 200 ml of PBS 0.1% BSA 0.05% Tween-20) and blocked (200 ml of PBS 1% BSA) for 2 h at 378. P-

Selectin/m chimera is diluted to a final concentration of 2 mg/ml with or without inhibitor, then preincubated for

1 h at 208 with a biotin-labeled anti-human IgM antibody (goat anti-human IgM biotin; Catlag, Bulingame, CA)

and peroxydase-linked streptavidin (Amersham Bioscience, Uppsala, Sweden). The inhibitors are diluted from

1 mm to 10n m. All these mixtures are then incubated for 4 h at 208 in the wells of the ELISA plate. The plate

revelation is made with OPD (0.67 mg/ml; Sigma, Steinheim, Germany) in a citrate/phosphate buffer (pH

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Helvetica Chimica Acta Vol. 87 (2004)

5.0) 0.16 (v/v) H₂O₂, and the reaction is blocked with 50 ml of 3m H₂SO₄. The absorbance for each plate well is

read at 490nm with a plate reader (model MR-500; Dynatech, Microtec Produkte, Embrach-Embraport,

Switzerland). The noise corresponding to the absorbances from the detection complex is subtracted from all

absorbances of the plates. For each concentration and all products, relative inhibitions are calculated by Eqn. 1

and the absorbances obtained without inhibitors and the one obtained with the anti-P-selectin antibody WAPS.

Then, for each product, the inhibitions are plotted against the concentrations, and the IC₅₀is calculated with the

¾

GraphPad program from Prism, following the manual instructions.

ꢀAbsꢀw=o inhib À Absꢀproduct

Inhibition%

Á 100

(1)

ꢀAbsꢀw=o inhibAbsꢀWAPS

(aR,2R,3S,4R,5R,6S)-Tetrahydro-a,3-dihydroxy-2-(hydroxymethyl)-5-(phenylthio)-6-{(2Z)-4-[(2S,3S,4R,

5S,6S)-tetrahydro-3,4,5-trihydroxy-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-pyran-4-acetic Acid (8). A mixture

of (À)-37 (15 mg, 0.028 mmol) and 0.1m aq. NaOH (1 ml, 0.1 mmol) was stirred at 208 for 6 h. The mixture was

neutralized with 0.1m aq. HCl (1.2 ml) and the solvent evaporated. The residue was purified by reversed-phase

HPLC (Vydac Protein C4, 15 ! 45% MeCN/H₂O): 7 mg (48%) of pure 8. White powder. IR (film): 3420, 2925,

1720, 1635, 1440, 1385, 1240, 1125, 1070, 875, 840, 750, 690, 660. ¹H-NMR (400 MHz, CD₃OD): 7.57 7.53, 7.36

7.26 (2m, 5 arom. H); 5.60( ddd, ³J(2',3') 10.8, ³J(2',1') 6.8, 6.8, HÀC(2')); 5.46 (ddd, ³J(3',2') 10.8,

³J(3',4') 6.8, 6.8, HÀC(3')); 5.04 (s, HÀC(a)); 3.92 (ddd, ³J(2'',4'') 10.5, ³J(2'',3'') 5.4, ³J(2'',4') 5.4,

HÀC(2'')); 3.89 (dd, ³J(3'',4'') 8.6, ³J(3'',2'') 5.4, HÀC(3'')); 3.80( qd, ³J(6'', MeÀC(6'')) 6.5, ³J(6'',5'') 1.9,

HÀC(6'')); 3.77 (dd, ²J 11.9, ³J(CH₂ÀC(2),2) 1.9, 1 H, CH₂ÀC(2)); 3.73 (dd, ³J(3,4) 10.8, ³J(3,2) 9.7,

HÀC(3)); 3.71 3.69 (m, HÀC(5'')); 3.66 (dd, ³J(4'',3'') 8.6, ³J(4'',5'') 3.5, HÀC(4'')); 3.58 (dd, ²J 11.9,

³J(CH₂ÀC(2),2) 6.0, 1 H, CH₂ÀC(2)); 3.36 3.28 (m, HÀC(6), overlapped by solvent); 3.10( ddd, ³J(2,3)

3

9.7, J(2, CH₂ÀC(2)) 6.0, J(2, CH₂ÀC(2)) 1.9, HÀC(2)); 3.01 (dd, ³J(5,4) 11.8, J(5,6) 10.6, HÀC(5));

2.85 (ddm, ²J 14.8, ³J(1',2') 6.8, 1 HÀC(1')); 2.45 2.23 (m, 2 HÀC(4'), 1 HÀC(1')); 2.18 (dd, ³J(4,5) 11.9,

³J(4,3) 10.8, HÀC(4)); 1.20( d, ³J(MeÀC(6''),6'') 6.5, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CD₃OD): 178.7

(s, COOH); 135.1 (s, arom. C), 133.9 (2 arom. C); 130.2 (2 arom. C); 129.1 (C(3')); 128.7 (arom. C); 128.4

(C(2')); 82.7 (C(2)); 82.5 (C(6)); 76.3 (C(2'')); 72.6 (C(5'')); 72.2 (C(4'')); 69.9 (C(3'')); 69.0(C(6 '')); 69.0(C( a));

65.9 (C(3)); 63.1 (CH₂ÀC(2)); 52.0(C(4)); 52.0(C(5)); 32.5 (C(1 ')); 24.5 (C(4')); 16.7 (MeÀC(6'')). ESI-MS:

1029.34 (92, [2M] ), 536.83 (6, [M Na] ), 532.32 (12, [M H₂O] ), 515.32 (100, [M H] ). FAB-MS: 537

(30, [M Na] ), 237 (100). HR-FAB-MS: 537.1768 (C₂₄H₃₄NaO₁₀S , [M Na] ; calc. 537.1770).

(aR,2R,3S,4R,6S)-Tetrahydro-a,3-dihydroxy-2-(hydroxymethyl)-6-{4-[(2S,3S,4R,5S,6S)-tetrahydro-3,4,5-

trihydroxy-6-methyl-2H-pyran-2-yl]butyl}-2H-pyran-4-acetic Acid (9). As described for 8, with (À)-39 (50mg,

0.118 mmoles): 41 mg (86%) of pure 9. White powder. IR (film): ca. 3500, 2935, 1720, 1640, 1385, 1230, 1080.

¹H-NMR (CD₃OD, 400 MHz): 4.26 (d, ³J(a,4) 2.6, HÀC(a)); 3.95 3.88 (m, HÀC(2''), HÀC(3'')); 3.84

(dd, ²J 12.0, ³J(CH₂ÀC(2),2) 2.2, 1 H, CH₂ÀC(2)); 3.80( qd, ³J(6'', MeÀC(6'')) 6.5, ³J(6'',5'') 1.8,

HÀC(6'')); 3.74 3.69 (m, HÀC(5''), HÀC(4'')); 3.64 (dd, ²J 12.0, ³J(CH₂ÀC(2),2) 6.0, 1 H, CH₂ÀC(2));

3.55 (dd, ³J(3,4) 10.0, ³J(3,2) 9.5, HÀC(3)); 3.50 3.42 ( m, HÀC(6)); 3.24 (ddd, ³J(2,3) 9.5, ³J(2,

CH₂ÀC(2)) 6.0, 2.2, HÀC(2)); 2.15 (dddd, ³J(4,5ax) 11.8, ³J(4,3) 10.0, ³J(4,a) 2.6, ³J(4,5eq) 2.4,

HÀC(4)); 1.82 (dm, H_eqÀC(5)); 1.75 1.24 (m, 2 HÀC(1'), 2 HÀC(2'), 2 HÀC(3'), 2 HÀC(4'), H_axÀC(5));

1.20( d, ³J(MeÀC(6''),6'') 6.5, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CD₃OD): 177.7 (s, COOH); 82.9

(d, ¹J(C,H) 141, C(2)); 78.2 (d, ¹J(C,H) 139, C(6)); 76.5 (d, ¹J(C,H) 148, C(2'')); 72.8 (d, ¹J(C,H) 145,

C(5'') or C(4'')); 71.7 (d, ¹J(C,H) 145, C(a)); 71.5 (d, ¹J(C,H) 140, C(4'') or C(5')); 69.5 (d, ¹J(C,H) 142,

C(3'')); 68.1 (d, ¹J(C,H) 129, C(6'')); 66.8 (d, ¹J(C,H) 135, C(3)); 62.9 (t, ¹J(C,H) 143, CH₂ÀC(2)); 47.5

(t, ¹J(C,H) 129, C(4)); 36.3 (t, ¹J(C,H) 125, C(1')); 34.4 (t, ¹J(C,H) 129, C(5)); 26.7 (t, ¹J(C,H) 129, C(2')

or C(3')); 26.1 (t, ¹J(C,H) 128, C(3') or C(2')); 24.8 (t, ¹J(C,H) 125, C(4')); 16.7 (q, ¹J(C,H) 127,

MeÀC(6'')). ES: 839.3 (36, [2M Na] ), 430.86 (100, [M Na] ), 356.87 (34, product of retro-ene reaction).

HR-FAB-MS: 431.1883 (C₁₈H₃₂NaO₁₀, [M Na] ; calc. 431.1893).

(2S,3R,5S,6R)-5-(Acetyloxy)-tetrahydro-6-[(methoxymethoxy)methyl]-3-(phenylthio)-2H-pyran-2-acetal-

dehyde (()-10). A mixture of crude diol ()-28 (8.05 g, 20.1 mmol) and Pb(OAc)₄(10.1 g, 22.8 mmol) in

benzene (200 ml) and anh. pyridine (200 ml) was stirred at 208 for 40min. After evaporation, the residue was

25

purified by FC (silica gel, AcOEt): 7.114 g (96%) of ()-10. Colorless oil. a 31, a 32, a 34,

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a 53, a 60( c 1.0, CHCl₃). UV (MeCN): 254 (5000), 221 (4900). IR (film): 2940, 2885, 1735,

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1580, 1475, 1440, 1375, 1235, 1150, 1090, 1040, 920, 805, 750. ¹H-NMR (400 MHz, CD₂Cl₂): 9.76

(dd, ³J(CHO,a) 2.7, ³J(CHO,a) 1.1, CHO); 7.50 7.30 ( m, 5 arom. H); 4.75 (ddd, ³J(5,4ax) 11.0,

³J(5,6) 9.8, ³J(5,4eq) 4.8, HÀC(5)); 4.57, 4.54 (2d, ²J 6.5, MeOCH₂); 3.88 (ddd, ³J(2,3) 10.2,

Helvetica Chimica Acta Vol. 87 (2004)

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³J(2,a) 9.2, ³J(2,a) 2.8, HÀC(2)); 3.57 3.55 (m, CH₂ÀC(6)); 3.88 (ddd, ³J(6,5) 9.8, ³J(6,CH₂ÀC(6)) 7.3,

3.8, HÀC(6)); 3.28 (s, MeOCH₂); 3.08 (ddd, ²J 16.7, ³J(a,2) 2.8, ³J(a,CHO) 1.1, 1 HÀC(a)); 3.03

(ddd, ³J(3,4ax) 12.4, ³J(3,2) 10.2, ³J(3,4eq) 4.1, HÀC(3)); 2.58 (ddd, ²J 16.7, ³J(a,2) 9.2,

³J(a,CHO) 2.7, 1 HÀC(a)); 2.58 (ddd, ²J 12.4, ³J(4eq,5) 4.8, ³J(4eq,3) 4.1, H_eqÀC(4)); 2.02 (s, Me-

3

CO); 1.60( ddd, ²J 12.4, J(4ax,3) 12.4, J(4ax,5) 11.0, H_axÀC(4)). ¹³C-NMR (100.6 MHz, CD₂Cl₂): 200.5

(d, ¹J(C,H) 175, CHO); 170.0 (s, MeCO); 133.7 (d, ¹J(C,H) 161, 2 arom. C); 132.5 (s, arom. C); 129.6

(d, ¹J(C,H) 161, 2 arom. C); 128.5 (d, ¹J(C,H) 161, arom. C); 96.9 (t, ¹J(C,H) 163, MeOCH₂); 79.0

(d, ¹J(C,H) 141, C(6)); 77.1 (d, ¹J(C,H) 144, C(2)); 67.8 (d, ¹J(C,H) 152, C(5); 66.6 (t, ¹J(C,H) 142,

CH₂ÀC(6)); 55.2 (q, ¹J(C,H) 142, MeOCH₂; 47.3 (d, ¹J(C,H) 141, C(3)); 47.3 (td, ¹J(C,H) 128, J 25,

C(a)); 37.1 (t, ¹J(C,H) 133, C(4)); 21.2 (q, ¹J(C,H) 130, MeCO). CI-MS (NH₃): 386 (100, [M NH₄] ), 369

(37, [M H] ), 368 (34, M ), 337 (39, [M À OMe] ), 324 (8, [M H À MeOCH₂] ), 307 (4, [M À

MeOCH₂O] ), 276 (11, [M À Ph À Me] ). Anal. calc. for C₁₈H₂₄O₆S (368.35): C 58.68, H 6.57, S 8.70; found:

C 58.62, H 6.49, S 8.69.

{2-[(2S,3R,4R,5R,6S)-Tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]ethyl}triphenyl-

phosphonium Iodide ((À)-11). A mixture of iodide (À)-16 (5 g, 11.5 mmol) and PPh₃(6.38 g, 23.0mmol) in

benzene (50ml) was stirred at 20 8 for 10min and then heated under reflux for 24 h. After evaporation, the

residue was taken up in CH₂Cl₂(10ml), and this soln. was poured dropwise into Et ₂O (200 ml). The precipitate

was recovered. The filtrate was evaporated and the residue dissolved in CH₂Cl₂(10ml). This soln. was added

dropwise to Et₂O (200 ml) giving a second fraction of crude (À)-11. Both precipitates were dissolved in CH₂Cl₂

(8 ml), and the soln. was poured into Et₂O (200 ml) (elimination of residual PPh₃). The precipitate was

collected and dissolved in CH₂Cl₂(20ml) and the soln. evaporated again: 7.73 g of ( À)-11 (containing 10% of

25

PPh₃; converted mass (yield), 7.67 g (96%). White foam. a À1.1, a À0.8, a À0.8, a À0.7,

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a À1.1 (c 1.0, CHCl₃). UV (MeCN): 231 (17400). IR (film): 2895, 1630, 1585, 1480, 1440, 1365, 1320,

1

1215, 1150, 1110, 1030, 990, 915, 810, 750, 690. H-NMR (400 MHz, CD₂Cl₂): 7.92 7.73 (m, 15 arom. H); 4.78,

4.64 (2d, ²J 6.8, 1 MeOCH₂); 4.71, 4.67 (2d, ²J 6.8, 1 MeOCH₂); 4.64, 4.58 (2d, ²J 6.8, 1 MeOCH₂); 4.14 (br.

ddd, ³J(2',2) 9.7, ³J(2',2) 3.0, ³J(2',3') 3.0, HÀC(2')); 3.90 3.81 ( m, HÀC(3'), HÀC(4'), HÀC(5'),

HÀC(6')); 3.66 3.43 (m, 2 HÀC(1)); 3.38, 3.36, 3.19 (3s, 3 MeOCH₂); 2.11 1.92 (m, 2 HÀC(2)); 1.33

(d, ³J(MeÀC(6'),6') 6.5, MeÀC(6')). ¹³C-NMR ((100.6 MHz, CD₂Cl₂): 135.7, 135.7 (2d, ¹J(C,H) 166 163,

3 arom. C); 134.0, 133.9, 131.0, 130.8 (4d, ¹J(C,H) 166 163, 12 arom. C); 118.6, 117.8 (2s, 3 arom. C); 97.7, 97.0,

96.7 (3t, ¹J(C,H) 162, 3 MeOCH₂); 75.9 (d, ¹J(C,H) 147, C(3', 4', 5', or 6')); 74.7 (d, ¹J(C,H) 145, C(3', 4', 5',

or 6')); 73.8 (d, ¹J(C,H) 142, C(3', 4', 5', or 6')); 70.7 (d, ¹J(C,H) 143, C(2')); 69.7 (d, ¹J(C,H) 141, C(3', 4',

5', or 6')); 56.1, 56.0, 55.9 (3q, ¹J(C,H) 143, 3 MeOCH₂); 21.7 (t, ¹J(C,H) 130, C(2)); 20.2 (t, ¹J(C,H) 135,

C(1)); 15.6 (q, ¹J(C,H) 127, MeÀC(6')). CI-MS (NH₃): 570(7, [ M À I H] ), 569 (8, [M À I] ), 279 (44,

[PPh₃ NH₃] ), 263 (77, [PPh₃ H] ), 183 (26), 83 (100).

(2R,3S,5R,6S)-Tetrahydro-2-[(methoxymethoxy)methyl]-5-(phenylthio)-6-{(2Z)-4-[(2S,3R,4R,5R,6S)-tet-

rahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3-ol Acetate (()-12). At

À 788, 1.6m BuLi in hexane (1.05 ml, 1.68 mmol) was added dropwise to a stirred soln. of (À)-11 (1.033 g,

1.48 mmol) in anh. THF (15 ml). After 20min at À 788, a soln. of ()-10 (364 mg, 0.99 mmol) in anh. THF

(5 ml) was added dropwise under stirring at À 788. After stirring at À 788 for another 20min, solvents were

evaporated at À 208. The residue was purified by FC (silica gel, Et₂O): Fr. 1 containing 341 mg (53%) of ()-12,

39 mg (6%) of Fr. 2 containing ()-12 and (À)-29, and Fr. 3 of (À)-29 (100 mg, 17%), all as colorless oils.

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Data of ()-12: a 16, a 17, a 19, a 33, a 42 (c 1.0, CHCl₃). UV

(MeCN): 256 (5900), 205 (9500). IR (film): 2935, 1740, 1440, 1375, 1235, 1150, 1110, 1035, 990, 805, 740, 695.

¹H-NMR (400 MHz, CDCl₃): 7.42 7.28 (m, 5 arom. H); 5.65 (ddd, ³J(2'',3') 10.9, ³J(2',1') 6.8, 6.8, HÀC(2'));

5.54 (ddd, ³J(3',2') 10.9, ³J(3',4') 6.8, 6.8, HÀC(3')); 4.87, 4.67 (2d, ²J 6.9, 1 MeOCH₂); 4.74, 4.64 (2d, ²J

6.9, 1 MeOCH₂); 4.78 4.71 (m, HÀC(3), 1 MeOCH₂); 4.63, 4.60(2 d, ²J 6.9, 1 MeOCH₂); 4.09 4.03

(m, HÀC(2'')); 3.96 3.89 (m, HÀC(3''), HÀC(4''), HÀC(5''), HÀC(6'')); 3.60 3.58 ( m, CH₂ÀC(2)); 3.46

3.30( m, HÀC(2), HÀC(6)); 3.42, 3.39, 3.35, 3.22 (4s, 4 MeOCH₂); 3.03 (ddd, ³J(5,4ax) 12.5, ³J(5,6) 10.2,

³J(5,4eq) 4.3, HÀC(5)); 2.78 (ddm, ²J 14.6, ³J(1',2') 6.8, HÀC(1')); 2.51 (ddd, ²J 12.5, ³J(4eq,3) 4.5,

3

³J(4eq,5) 4.5, H_eqÀC(4)); 2.48 (m, 2 HÀC(4'), 1 HÀC(1')); 2.02 (s, MeCO); 1.54 (ddd, ²J 12.5, J(4ax,5)

12.5, ³J(4ax,3) 11.1, H_axÀC(4)); 1.31 (d, ³J(MeÀC(6''),6'') 6.4, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CD₂Cl₂):

169.8 (s, MeCO); 133.1 (d, ¹J(C,H) 162, 2 arom. C); 132.7 (s, arom. C); 129.1 (d, ¹J(C,H) 162, 2 arom. C);

127.9 (d, ¹J(C,H) 162, C(3')); 127.8 (d, ¹J(C,H) 161, arom. C); 126.9 (d, ¹J(C,H) 155, C(2')); 97.5, 96.9, 96.8,

96.5 (4t, ¹J(C,H) 167, 4 MeOCH₂); 81.0( d, ¹J(C,H) 140, C(6)); 78.7 (d, ¹J(C,H) 142, C(2)); 75.6

(d, ¹J(C,H) 141, C(3'', 4'', 5'', or 6'')); 75.2 (d, ¹J(C,H) 144, C(3'', 4'', 5'', or 6'')); 74.4 (d, ¹J(C,H) 145,

C(3'', 4'', 5'', or 6'')); 71.6 (d, C(2'')); 68.4 (d, ¹J(C,H) 140, C(3'', 4'', 5'', or 6'')); 68.0( d, ¹J(C,H) 152, C(3));

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Helvetica Chimica Acta Vol. 87 (2004)

66.6 (t, ¹J(C,H) 142, CH₂ÀC(2)); 55.8, 55.8, 55.6, 55.2 (4q, ¹J(C,H) 143, 4 MeOCHH₂); 46.5 (d, ¹J(C,H)

139, C(5)); 37.0( t, ¹J(C,H) 131, C(4)); 30.9 (t, ¹J(C,H) 125, C(1')); 25.5 (br. t, ¹J(C,H) ꢁ 120, C(4')); 21.0

(q, ¹J(C,H) 129, MeCO); 15.7 (q, ¹J(C,H) 129, MeÀC(6'')). CI-MS(NH₃): 678 (75), 677 (100), 676 (76,

[M NH₄] ), 659 (1.5, [M H] ), 658 (1.3, M ), 644 (1, [M H À Me] ), 627 (12, [M À OMe] ), 600 (5, [M

H À OAc] ), 551 (13), 365 (13). Anal. calc. for C₃₂H₅₀O₁₂S (658.81): C 58.34, H 7.54; found: C 58.08, H 7.72.

(2S,3R,4R,5R,6S)-Tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2-(prop-2-enyl)-2H-pyran ((À)-14).

Bu₄NI (500 mg) was added to a stirred soln. of (À)-13 [4] (4.43 g, 23.5 mmol) in CH₂Cl₂(235 ml). After

cooling at 08, ⁱPr₂NEt (24.2 ml, 141 mmol) and MeOCH₂Cl (7.15 ml, 94.2 mmol) were added successively. The

mixture was stirred at 208 for 2 h, and more ⁱPr₂NEt (24.2 ml) and MeOCH₂Cl (7.15 ml) were added

i

successively. After stirring at 208 for 3 h, more Pr₂NEt (24.2 ml) and MeOCH₂Cl (7.15 ml) were added. After

stirring at 208 for 69 h, the mixture was poured into a vigourously stirred mixture of CH₂Cl₂(200 ml) and sat. aq.

NaHCO₃soln. (50ml). If the pH was lower than 7, solid NaHCO ₃was added until the aq. layer became basic.

The aq. phase was extracted with CH₂Cl₂(300 ml, 4 Â ), the combined org. extract washed with sat. aq. NaHCO₃

soln. (50ml), dried (MgSO ₄), and evaporated, and the residue subjected to fast FC (silica gel (height 5 cm),

25

light petroleum ether/AcOEt 1:1): 7.24 g (96%) of (À)-14. Colorless oil. a À20, a À24, a À26,

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a À42, a À50( c 1.0, CHCl₃). UV (MeCN): 295 (100), 194 (1000). IR (film): 2935, 2895, 2825,

1640, 1465, 1445, 1380, 1360, 1300, 1215, 1150, 915. ¹H-NMR (400 MHz, CDCl₃): 5.87 (dddd, ³J(2',3'trans) 17.0,

³J(2',3'cis) 10.1, ³J(2',1') 6.9, 6.9, HÀC(2')); 5.09 (ddd, ³J(3'trans,2') 17.0, ⁴J(3'trans,1') 3.2, 1.4,

HtransÀC(3')); 5.05 (dm, ³J(3'cis,2') 10.1, H_cisÀC(3')); 4.83, 4.64 (2d, ²J 6.6, 1 MeOCH₂); 4.74, 4.64

(2d, ²J 6.6, 1 MeOCH₂); 4.73, 4.70(2 d, ²J 6.6, 1 MeOCH₂); 4.07 (ddd, ³J(2,3) 5.2, ³J(2,1') 8.9, 3.5,

HÀC(2)); 3.97 3.87 (m, HÀC(3), HÀC(4), HÀC(5), HÀC(6)); 3.39, 3.38, 3.37 (3s, 3 MeOCH₂); 2.47 2.30

(m, 2 HÀC(1')); 1.29 (d, ³J(MeÀC(6),6) 6.3, MeÀC(6)). ¹³C-NMR (100.6 MHz, CDCl₃): 135.1 (d, ¹J(C,H)

153, C(2')); 116.6 (t, ¹J(C,H) 156, C(3')); 97.5, 96.7, 96.5 (3t, ¹J(C,H) 163, 3 MeOCH₂); 75.6 (d, ¹J(C,H)

144, C(3, 4, 5, or 6)); 75.1 (d, ¹J(C,H) 145, C(3, 4, 5, or 6)); 74.2 (d, ¹J(C,H) 141, C(3, 4, 5, or 6)); 71.0

(d, ¹J(C,H) 151, C(2)); 68.4 (d, ¹J(C,H) 141, C(3, 4, 5, or 6)); 55.8, 55.7, 55.5 (3q, ¹J(C,H) 142, 3 MeOCH₂);

31.9 (t, ¹J(C,H) 126, C(1')); 15.4 (q, ¹J(C,H) 127, MeÀC(6)). CI-MS (NH₃): 338 (100, [M NH₄] ), 321 (1.4,

[M H] ), 289 (32, [M À OMe] ), 245 (20), 243 (22), 213 (39), 203 (43), 161 (52). Anal. calc. for C₁₅H₂₈O₇

(320.38): C 56.23, H 8.81; found: C 56.21, H 8.74.

(2S,3R,4R,5R,6S)-Tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-ethanol ((À)-15). Ozone

(3% O₃in O₂) was bubbled through a soln. of (À)-14 (4.37 g, 13.6 mmol) in CH₂Cl₂(40ml) and MeOH (10ml)

cooled at À 788 and containing NaHCO₃(100 mg). When the blue color of O₃persisted, O₂was bubbled

through the soln. for 10min. Me ₂S (2.5 ml, 34.1 mmol) was added, and the mixture was stirred at À 788 for

30min. Then NaBH ₄(1.55 g, 40.9 mmol) was added and the mixture stirred at 208 for 210min. AcOEt (150ml)

and 1n aq. HCl (50ml) were added. The aq. phase was extracted with AcOEt (150ml, 3 Â ), the combined org.

extract washed with sat. aq. NaHCO₃soln. (50ml, 2 Â ) and brine (50ml), dried (MgSO ₄), and evaporated:

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577

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4.36 g (99%) of (À)-15. Colorless oil. a À0.6, a À2.1, a À1.8, a À2.4, a À1.9 (c

1.0, CHCl₃). UV (MeCN): 265 (200), 223 (700), 196 (1600). IR (film): 3475, 2940, 2895, 1640, 1445, 1365, 1215,

1150, 1110, 1035, 915, 665. ¹H-NMR (400 MHz, CDCl₃): 4.86, 4.67 (2d, ²J 6.9, 1 MeOCH₂); 4.77, 4.66 (2d, ²J

6.9, 1 MeOCH₂); 4.75, 4.72 (2d, ²J 6.9, 1 MeOCH₂); 4.26 (dm, ³J(2,1') 10.7, HÀC(2)); 4.01

(qd, ³J(6,MeÀC(6)) 6.6, ³J(6,5) 3.2, HÀC(6)); 3.95 3.90( m, HÀC(5), HÀC(4), HÀC(3)); 3.80

(m, 2 HÀC(2')); 3.41, 3.40, 3.38 (3s, 3 MeOCH₂); 2.39 (br. s, OHÀC(2')); 2.07 1.96 (m, 1 HÀC(1')); 1.82

1.70( m, 1 HÀC(1')); 1.33 (d, ³J(MeÀC(6),6) 6.6, MeÀC(6)). ¹³C-NMR (100.6 MHz, CDCl₃): 97.5, 96.8, 96.4

(3t, ¹J(C,H) 164, 3 MeOCH₂); 75.6 (d, ¹J(C,H) 149, C(3) or C(4)); 74.9 (d, ¹J(C,H) 143, C(3) or C(4));

74.0( d, ¹J(C,H) 145, C(5)); 71.3 (d, ¹J(C,H) 145, C(2)); 68.8 (d, ¹J(C,H) 142, C(6)); 61.5 (d, ¹J(C,H) 145,

C(2')); 55.8, 55.7, 55.5 (3q, ¹J(C,H) 142, 3 MeOCH₂); 29.5 (t, ¹J(C,H) 125, C(1')); 15.6 (q, ¹J(C,H) 128,

MeÀC(6)). CI-MS (NH₃): 342 (17, [M NH₄] ), 325 (9, [M H] ), 310(8, [ M H À Me] ), 293 (26, [M À

OMe] ), 261 (100), 217 (49), 161 (57). Anal. calc. for C₁₄H₂₈O₈(324.37): C 51.84, H 8.70; found: C 51.72, H 8.52.

(2S,3R,4R,5R,6S)-Tetrahydro-2-(2-iodoethyl)-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran ((À)-16). A

mixture of (À)-15 (5.97 g,18.4 mmol), Et₂O (45 ml), MeCN (15 ml), 1H-imidazole (3.76 g, 55.2 mmol), and

PPh₃(7.24 g, 27.6 mmol) was stirred at 08 for 30min, then at 20 8 for 20h. Et ₂O (200 ml) was added, then 1m aq.

Na₂S₂O₃until complete decoloration of the soln. The aq. phase was extracted with Et₂O (100 ml, 5 Â ), the

combined org. extract washed with sat. aq. NaHCO₃soln. (20ml), dried (MgSO ₄), and evaporated, and the

residue subjected to FC (silica gel, Et₂O/light petroleum ether 2 :1): 6.29 g (79%, based on (À)-14) of (À)-16.

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Colorless oil. a À26, a À29, a À30, a À49, a À59 (c 1.0, CHCl₃). UV (MeCN):

254 (500), 197 (1600). IR (film): 2935, 2895, 2825, 1740, 1465, 1440, 1370, 1300, 1245, 1215, 1150, 1110, 1035, 990,

920. ¹H-NMR (400 MHz, CDCl₃): 4.82, 4.64 (2d, ²J 6.9, 1 MeOCH₂); 4.74, 4.62 (2d, ²J 6.9, 1 MeOCH₂); 4.73,

Helvetica Chimica Acta Vol. 87 (2004)

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4.70(2 d, ²J 6.9, 1 MeOCH₂); 4.17 (ddd, ³J(2,1') 10.6, 3.2, ³J(2,3) 3.2, HÀC(2)); 3.96 3.82 (m, HÀC(6),

HÀC(5), HÀC(4), HÀC(3)); 3.39, 3.38, 3.37 (3s, 3 MeOCH₂); 3.33 3.17 (m, 2 HÀC(2')); 2.23 2.12

(m, 1 HÀC(1')); 2.06 1.95 (m, 1 HÀC(1')); 1.32 (d, ³J(MeÀC(6),6) 6.6, MeÀC(6)). ¹³C-NMR (100.6 MHz,

CDCl₃): 97.3, 96.6, 96.4 (3t, ¹J(C,H) 164, 3 MeOCH₂); 75.4 (d, ¹J(C,H) 151, C(3, 4, 5, or 6)); 75.1

(d, ¹J(C,H) 153, C(3, 4, 5, or 6)); 73.9 (d, ¹J(C,H) 132, C(3, 4, 5, or 6)); 70.9 (d, ¹J(C,H) 147, C(2)); 68.6

(d, ¹J(C,H) 142, C(3, 4, 5, or 6)); 55.9, 55.8, 55.6 (3q, ¹J(C,H) 141, 3 MeOCH₂); 31.4 (t, ¹J(C,H) 127, C(1'));

15.5 (q, ¹J(C,H) 127, MeÀC(6)); 2.9 (t, ¹J(C,H) 151, C(2')). CI-MS (NH₃): 452 (16, [M NH₄] ), 403 (4,

[M À OMe] ), 357 (16, [M À 2 OMe À Me] ), 327 (65, [M À 3 OMe À Me] ), 315 (100), 267 (68), 161 (79).

Anal. calc. for C₁₄H₂₇IO₇(434.27): C 38.72, H 6.27, I 29.22; found: C 38.83, H 6.30, I 29.11.

(1R,4R,5R)-4-(Phenylthio)-6,8-dioxabicyclo[3.2.1]octan-2-one ((À)-18). Thiophenol (5 ml, 48.97 mmol)

and Et₃N (1.14 ml, 8.16 mmol) were added to a soln. of 17 (5.15 g, 40.8 mmol) in CH₂Cl₂(125 ml). The mixture

was stirred at 208 for 24 h and then evaporated: 9.99 g (quant.) of (À)-18. Yellow oil. An anal. sample of (À)-18

25

was obtained by FC (silica gel, AcOEt/light petroleum ether 1:2). a À61, a À63, a À76,

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a À170, a À238 (c 1.0, CHCl₃). UV (MeCN): 252 (5200), 217 (5800). IR (KBr): 2990, 1735, 1585,

1480, 1440, 1240, 1120, 1010, 950, 895, 795, 745. ¹H-NMR (400 MHz, CDCl₃): 7.48 7.41, 7.38 7.28 (2m, 5 arom.

H); 5.69 (s, HÀC(5)); 4.58 (d, ³J(1,7exo) 5.5, HÀC(1)); 3.97 (d, ²J 8.1, H_endoÀC(7)); 3.87 (dd, ²J 8.1,

³J(7exo,1) 5.5, H_exoÀC(7)); 3.55 (ddd, ³J(4,3) 7.8, ³J(4,3) 4.9, ³J(4,5) 0.9, HÀC(4)); 2.86 (dd, ²J 17.6,

³J(3endo,4) 7.8, H_endoÀC(3)); 2.57 (dddd, ²J 17.6, ³J(3exo,4) 4.9, ⁴J(3exo,1) 0.9, ⁴J(3exo,1) 0.9,

H_exoÀC(3)). ¹³C-NMR (100.6 MHz, CDCl₃): 204.3 (s, C(2)); 133.0( s, arom. C); 132.2 (d, ¹J(C,H) 161,

2 arom. C); 129.3 (d, ¹J(C,H) 161, 2 arom. C); 127.9 (d, ¹J(C,H) 161, arom. C); 103.0 (d, ¹J(C,H) 178,

C(5)); 79.2 (d, ¹J(C,H) 162, C(1)); 67.2 (t, ¹J(C,H) 154, C(7)); 47.3 (d, ¹J(C,H) 147, C(4)); 38.7

(t, ¹J(C,H) 133, C(3)). CI-MS (NH₃): 236 (21, M ), 218 (4, [M À O] ), 194 (2), 167 (2), 136 (100), 126 (6),

109 (29, PhS ). Anal. calc. for C₁₂H₁₂O₃S (236.29): C 61.00, H 5.12, S 13.57; found: C 60.92, H 5.17, S 13.65.

(1R,2R,4R,5R)-4-(Phenylthio)-6,8-dioxabicyclo[3.2.1]octan-2-ol (19). To a soln. of crude (À)-18 (31 mg,

i

0.13 mmol) in anh. THF (1.3 ml) at À 788, 1m Bu₂AlH in CH₂Cl₂(0.262 ml, 0.262 mmol) was added dropwise

under stirring. After 30min at À 788, CH₂Cl₂(10ml) and 1 m aq. HCl (3 ml) were added, and the mixture was

extracted with CH₂Cl₂(10ml, 3 Â ). The combined org. extract was washed with a sat. NaHCO₃soln. (5 ml),

dried (MgSO₄), and evaporated: 19/(À)-20 7:1 (25 mg, 80%). An anal. sample of 19 was obtained by FC (silica

gel, AcOEt/light petroleum ether 2 :1). IR (film): 3420, 2960, 2900, 1745, 1585, 1480, 1440, 1345, 1300, 1215,

1125, 1070, 1025, 985, 955, 915, 850, 795, 745, 690, 670. ¹H-NMR (400 MHz, CDCl₃): 7.43 7.22 (m, 5 arom. H);

5.50(br. s, HÀC(5)); 4.45 (br. dd, ³J(1,7exo) 4.9, ³J(1,2) 4.0, HÀC(1)); 4.27 (ddd, ³J(2,3endo) 10.5,

³J(2,3exo) 5.8, ³J(2,1) 4.0, HÀC(2)); 4.18 (d, ²J 7.7, H_endoÀC(7)); 3.75 (dd, ²J 7.7, ³J(7exo,1) 4.9,

H_exoÀC(7)); 3.36 (br. d, ³J(4,3endo) 5.7, HÀC(4)); 2.17 (ddq, ²J 13.9, ³J(3exo,2) 5.8, ⁴J(3exo,5) 0.9,

⁴J(3exo,1) 0.9, ³J(3exo,4) 0.9, H_exoÀC(3)); 2.01 (ddd, ²J 13.9, ³J(3endo,4) 10.5, ³J(3endo,2) 5.7,

H_endoÀC(3)). ¹³C-NMR (100.6 MHz, CDCl₃): 131.2 (d, ¹J(C,H) 161, 2 arom. C); 129.1 (d, ¹J(C,H) 161,

2 arom. C); 127.1 (s, arom. C); 127.1 (d, ¹J(C,H) 162, arom. C); 101.1 (d, ¹J(C,H) 178, C(5)); 76.3

(d, ¹J(C,H) 156, C(1)); 63.8 (t, ¹J(C,H) 153, C(7)); 63.8 (d, ¹J(C,H) 143, C(2)); 48.9 (d, ¹J(C,H) 144,

C(4)); 31.4 (t, ¹J(C,H) 132, C(3)). CI-MS (NH₃): 252 (28, [M NH₄] ), 239 (84, [M H] ), 238 (83, M ), 221

([M À OH] ), 203 (40), 192 (26), 136 (100).

(1R,2S,4R,5R)-4-(Phenylthio)-6,8-dioxabicyclo[3.2.1]octan-2-ol ((À)-20). A mixture of isolevoglucose-

none [16] (17; 5.15 g, 40.8 mmol), thiophenol (5 ml, 49.0 mmol), and Et₃N (1.14 ml, 8.16 mmol) in CH₂Cl₂

(125 ml) was stirred at 208 for 24 h. Evaporation gave 9.98 g of ketone (À)-18 that was dissolved in THF

(200 ml) and rapidly cooled to À 788. Super-H (1m LiEt₃BH in THF; 61.2 ml, 61.2 mmol) was added dropwise

under stirring at À 788. After 30min at À 788, the mixture was poured into CH₂Cl₂(300 ml) and 1m aq. HCl

(200 ml). The aq. phase was extracted with CH₂Cl₂(200 ml, 3 Â ), the combined org. extract washed with sat.

NaHCO₃soln. (50ml, 2 Â ), dried (MgSO₄), and evaporated: 8.75 g (90%, based on 17) of (À)-20. Colorless

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solid. M.p. 59 618. a À63, a À65, a À75, a₄₃₅À 124, a À146 (c 1.0, CHCl₃). UV

(MeCN): 249 (3400), 221 (3000). IR (KBr): 3495, 3055, 2960, 2895, 1585, 1480, 1400, 1355, 1310, 1235, 1185,

1130, 1100, 1060, 1025, 1000, 950, 910, 865, 775, 745, 690. ¹H-NMR (400 MHz, CDCl₃): 7.48 7.28 (m, 5 arom. H);

5.52 (br. s, HÀC(5)); 4.60( m, HÀC(1)); 3.87, 3.86 (2s, 2 HÀC(7)); 3.67 (br. s, HÀC(2)); 3.29 (br.

d, ³J(4,3endo) 5.9, HÀC(4)); 2.26 (ddd, ²J 15.7, ³J(3endo,4) 5.7, ³J(3endo,2) 4.3, H_endoÀC(3)); 1.97

(dm, ²J 15.7, H_exoÀC(3)). ¹³C-NMR (100.6 MHz, CDCl₃): 132.3 (d, ¹J(C,H) 161, 2 arom. C); 129.3

(d, ¹J(C,H) 161.4, 2 arom. C); 127.8 (s, arom. C); 127.8 (d, ¹J(C,H) 162, arom. C); 101.5 (d, ¹J(C,H) 177,

C(5)); 78.1 (d, ¹J(C,H) 158, C(1)); 67.3 (d, ¹J(C,H) 145, C(2)); 66.4 (t, ¹J(C,H) 150, C(7)); 46.1

(d, ¹J(C,H) 146, C(4)); 28.0( t, ¹J(C,H) 132, C(3)). CI-MS (NH₃): 239 (19, [M H] ), 238 (42, M ); 221

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Helvetica Chimica Acta Vol. 87 (2004)

(1, [M À OH] ), 203 (7), 192 (8), 136 (100). Anal. calc. for C₁₂H₁₄O₃S (238.31): C 60.48, H 5.92, S 13.45; found:

C 60.41, H 5.91, S 13.41.

(1R,2R,4R,5R)-4-(Phenylthio)-6,8-dioxabicyclo[3.2.1]octan-2-ol Acetate ((À)-21). N,N-Dimethylpyridin-

4-amine (20mg) was added to a soln. of 19 (44 mg, 0.185 mmol) in pyridine (1 ml) and Ac₂O (1 ml). After

stirring at 208 for 30min, CH ₂Cl₂(20ml) and 1 m aq. HCl (5 ml) were added. The mixture was extracted with

CH₂Cl₂(10ml, 3 Â ), the combined org. extract washed with a sat. aq. NaHCO₃soln. (5 ml), dried (MgSO₄),

and evaporated, and the residue subjected to FC (silica gel, AcOEt/light petroleum ether 1:3): 29 mg (56%) of

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(À)-21. Colorless solid. M.p. 69 708. a À87, a À92, a À105, a À187, a À230( c

1.0, CHCl₃). UV (MeCN): 251 (6700), 216 (6000). IR (KBr): 2965, 2900, 1730, 1585, 1485, 1400, 1370, 1315,

1240, 1210, 1130, 1090, 1045, 1025, 990, 965, 910, 875, 800, 745, 695. ¹H-NMR (400 MHz, CDCl₃): 7.44 7.22

(m, 5 arom. H); 5.53 (br. s, HÀC(5)); 5.25 (ddd, ³J(2,3endo) 10.9, ³J(2,3exo) 6.0, ³J(2,1) 3.9, HÀC(2));

4.56 (br. dd, ³J(1,7) 5.0, J(1,2) 3.9, HÀC(1)); 4.13 (d, ²J 7.8, H_endoÀC(7)); 3.76 (dd, ²J 7.8, J(7exo,1)

5.0, H_exoÀC(7)); 4.13 (br. d, ³J(4,3endo) 5.7, HÀC(4)); 2.21 (ddddd, ²J 13.7, ³J(3exo,2) 6.0, ³J(3exo,4)

1.2, ⁴J(3exo,5) 1.2, ⁴J(3exo,1) 1.2, H_exoÀC(3)); 2.08 (ddd, ²J 13.7, ³J(3endo,2) 10.9, ³J(3endo,4) 5.7,

H_endoÀC(3)); 2.01 (s, MeCO). ¹³C-NMR (100.6 MHz, CDCl₃): 169.7 (s, MeCO); 134.6 (s, arom. C); 131.6

(d, ¹J(C,H) 162, 2 arom. C); 129.1 (d, ¹J(C,H) 161, 2 arom. C); 127.3 (d, ¹J(C,H) 161, arom. C); 101.4

(d, ¹J(C,H) 177, C(5)); 73.5 (d, ¹J(C,H) 154, C(1)); 66.0( d, ¹J(C,H) 154, C(2)); 64.4 (t, ¹J(C,H) 149,

C(7)); 49.0( d, ¹J(C,H) 146, C(4)); 28.0( t, ¹J(C,H) 136, C(3)); 20.9 (q, ¹J(C,H) 130, MeCO). CI-MS

3

(NH₃): 298 (55, [M NH₄] ), 281 (100, [M H] ), 280(41, M ), 221 (11, [M À OAc] ), 203 (5, [M À Ph] ),

171 (7), 136 (19). Anal. calc. for C₁₄H₁₆O₄S (280.34): C 59.98, H 5.76, S 11.42; found: C 59.89, H 5.83, S 11.33.

(1R,2S,4R,5R)-4-(Phenylthio)-6,8-dioxabicyclo[3.2.1]octan-2-ol Acetate ((À)-22). A mixture of crude (À)-

20 (8.75 g, 40.8 mmol), pyridine (200 ml), Ac₂O (200 ml), N,N-dimethylpyridin-4-amine (500 mg) was stirred at

208 for 1 h. The mixture was poured into Et₂O (400 ml) and sat. aq. NaHCO₃soln. (200 ml) under vigorous

stirring. Solid NaHCO₃was added until neutralization. The mixture was extracted with Et₂O (400 ml, 4 Â ), then

with AcOEt (300 ml, 2 Â ), the combined org. extract washed with sat. aq. NaHCO₃soln. (100 ml), dried

(MgSO₄), and evaporated, and the residue recrystallized from light petroleum ether (150ml)/Et ₂O (150ml):

4.21 g of (À)-22. The mother liquor was evaporated and the residue recrystallized as above: (À)-22 (2.25 g). The

mother liquor was evaporated and the residue (5.3 g) purified by FC (silica gel, AcOEt/light petroleum ether

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1:2.5): (À)-22 (1.53 g). Total yield: 7.99 g (70%, based on (À)-18) of (À)-22. White solid. M.p. 92 948. a

25

À25, a À26, a À30, a À50, a À60( c 1.0, CHCl₃). UV (MeCN): 253 (6900), 213 (6500).

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IR (KBr): 2960, 2895, 1725, 1580, 1485, 1445, 1430, 1365, 1255, 1130, 1110, 1040, 1020, 980, 965, 935, 920, 890,

785, 750, 715, 690, 675. ¹H-NMR (400 MHz, CDCl₃): 7.44 7.21 (m, 5 arom. H); 5.53 (br. s, HÀC(5)); 4.76 4.72

(m, HÀC(2)); 4.66 4.62 (m, HÀC(1)); 3.91 (dd, ²J 7.9, ³J(7endo,1) 0.8, H_endoÀC(7)); 3.85 (dd, ²J 7.9,

³J(7exo,1) 5.4, H_exoÀC(7)); 3.25 (br. d, ³J(4,3endo) 6.8, HÀC(4)); 2.52 (ddd, ²J 16.1, ³J(3endo,4) 6.8,

³J(3endo,2) 4.8, H_endoÀC(3)); 2.21 (s, MeCO); 2.06 (dm, ²J 16.1, H_exoÀC(3)). ¹³C-NMR (100.6 MHz,

CDCl₃): 170.7 (s, MeCO); 135.4 (s, arom. C); 131.1 (d, ¹J(C,H) 161, 2 arom. C); 129.1 (d, ¹J(C,H) 161,

2 arom. C); 127.0( d, ¹J(C,H) 161, arom. C); 101.9 (d, ¹J(C,H) 177, C(5)); 74.8 (d, ¹J(C,H) 160, C(1)); 67.8

(d, ¹J(C,H) 150, C(2)); 66.1 (t, ¹J(C,H) 151, C(7)); 45.7 (d, ¹J(C,H) 144, C(4)); 26.9 (t, ¹J(C,H) 131,

C(3)); 21.3 (q, ¹J(C,H) 130, MeCO). CI-MS (NH₃): 298 (23, [M NH₄] ), 281 (100, [M H] ), 280(55, M ),

220(11, [ M À H À OAc] ), 203 (12, [M À Ph] ), 171 (11), 136 (47). Anal. calc. for C₁₄H₁₆O₄S (280.34): C 59.98,

H 5.76, S 11.42; found: C 59.95, H 5.87, S 11.37.

(2R,3S)-3-(Acetyloxy)-3,4-dihydro-5-(phenylthio)-2H-pyran-2-methanol (()-23). Allytrimethylsilane

(52 ml, 0.321 mmol), BF₃¥ OEt₂(41 ml, 0.321 mmol), and Me₃SiOSO₂CF₃(58 ml, 0.321 mmol) were added

successively to a soln. of (À)-22 (30 mg, 0.107 mmol) in MeCN (300 ml) stirred at 08. After 15 min at 08, CH₂Cl₂

(5 ml) and 1m aq. HCl (1 ml) were added. The aq. phase was extracted with CH₂Cl₂(5 ml, 3 Â ), the combined

org. extract washed with sat. aq. NaHCO₃soln. (3 ml, 2 Â ), dried (MgSO₄), and evaporated, and the residue

25

subjected to FC (silica gel, AcOEt/light petroleum ether 1:1): ()-23 (21 mg, 70%). Colorless oil. a 128,

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a 133, a 152, a 268, a 331 (c 0.5, CHCl₃). IR (film): 3415, 1735, 1630, 1585,

1475, 1435, 1375, 1240, 1160, 1025, 740, 690. UV (MeCN): 245 (8900), 219 (7800). ¹H-NMR (400 MHz, CDCl₃):

7.30 7.16 ( m, 5 arom. H); 6.94 (br. s, HÀC(6)); 5.16 (ddd, ³J(3,2) 7.3, ³J(3,4) 7.1, 5.8, HÀC(3)); 3.99

(ddd, ³J(2,3) 7.3, ³J(2,CH₂ÀC(2)) 5.2, 3.3, HÀC(2)); 3.82 (ddd, ²J 12.3, ³J(CH₂ÀC(2),OH) 7.9,

³J(CH₂ÀC(2),2) 3.3, 1 H, CH₂ÀC(2)); 3.74 (ddd, ²J 12.3, ³J(CH₂ÀC(2),OH) 5.7, ³J(CH₂ÀC(2),2) 5.2,

1 H, CH₂ÀC(2)); 2.54 (ddd, ²J 16.8, ³J(4,3) 5.8, ⁴J(4,6) 1.5, 1 HÀC(4)); 2.30( ddd, ²J 16.8, J(4,3) 7.1,

3

⁴J(4,6) 1.5, 1 HÀC(4)); 2.19 (dd, ³J(OH,CH₂ÀC(2)) 5.2, 3.3, CH₂OH); 2.10( s, MeCO). ¹³C-NMR

(100.6 MHz, CDCl₃): 170.3 (s, MeCO); 148.7 (d, C(6)); 135.8 (s, arom. C); 129.1 (d, 2 arom. C); 127.7

(d, 2 arom. C); 126.0( d, arom. C); 102.2 (s, C(5)); 76.5, 65.5, 61.1 (C(2), C(3), CH₂ÀC(2)); 30.8 (t, C(4)); 20.9

Helvetica Chimica Acta Vol. 87 (2004)

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(q, MeCO). CI-MS (NH₃): 298 (100, [M NH₄] ), 281 (88, [M H] ), 263 (5, [M À OH] ), 238 (4, [M H À

Ac] ), 221 (31, [M À OAc] ), 220(31, [ M À Ac À OH] ), 203 (25, [M À Ph] ), 171 (53). Anal. calc. for

C₁₄H₁₆O₄S (280.34): C 59.98, H 5.76, S 11.42; found: C 59.92, H 5.85, S 11.39.

(2R,3S,5R,6S)-3-(Acetyloxy)-tetrahydro-5-(phenylthio)-6-(prop-2-enyl)-2H-pyran-2-methanol (()-24).

BF₃¥ OEt₂(1.34 ml, 10.7 mmol) and Me₃SiOSO₂CF₃(1.93 ml, 10.7 mmol) were added simultaneously and

dropwise to a vigorously stirred mixture (two phases) of (À)-22 (1 g, 3.57 mmol) in MeNO₂(28 ml) and

allyltrimethylsilane (7 ml) at À 208. After stirring at À 208 for 3.5 h, the mixture was poured onto a vigorously

stirred mixture of Et₂O (350ml) and 1 m aq. HCl (50ml). The aq. phase was extracted with AcOEt (150ml, 3

Â

), the combined org. extract washed with sat. aq. NaHCO₃soln. (50ml), dried (MgSO ₄), and evaporated, and

the residue subjected to FC (silica gel, AcOEt/light petroleum ether 1:2): 531 mg (46%) of pure ()-24, then

350mg (30%) of ( )-24/25 10:1, and 55 mg (5%) of pure 25, all as colorless oils.

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Data of ()-24: a 24, a 26, a 31, a 52, a 66 (c 0.5, CHCl₃). IR

(film): 3470, 3075, 2935, 2865, 1740, 1640, 1585, 1480, 1440, 1375, 1240, 1085, 1040, 1000, 915, 800, 750, 695.

¹H-NMR (100.6 MHz, CDCl₃): 7.46 7.29 (m, 5 arom. H); 5.87 (dddd, ³J(2',3'trans) 16.9, ³J(2',3'cis) 10.8,

³J(2',1') 10.8, 7.3, HÀC(2')); 5.12 5.05 (m, 2 HÀC(3')); 4.70( ddd, ³J(3,4ax) 10.8, J(3,2) 9.7, J(3,4eq)

3

4.8, HÀC(3)); 3.68 (br. ddd, ²J 12.1, ³J(CH₂ÀC(2),OH) 7.7, ³J(CH₂ÀC(2),2) 2.5, 1 H, CH₂ÀC(2)); 3.37

(br. ddd, ²J 12.1, J(CH₂ÀC(2),2) 5.7, J(CH₂ÀC(2),OH) 5.4, 1 H, CH₂ÀC(2)); 3.37 (ddd, ³J(6,5) 10.3,

3

³J(6,1') 7.7, 2.8, HÀC(6)); 3.31 (ddd, ³J(2,3) 9.7, ³J(2,CH₂ÀC(2)) 5.7, 2.5, HÀC(2)); 2.98 (ddd, ³J(5,4ax)

12.6, J(5,6) 10.3, J(5,4eq) 4.2, HÀC(5)); 2.81 (ddddd, ²J 15.0, J(1',2') 6.5, J(1',6) 2.8, J(1',3') 1.3,

1.3, 1 HÀC(1')); 2.50( ddd, ²J 12.5, ³J(4eq,3) 4.8, ³J(4eq,5) 4.2, H_eqÀC(4)); 2.805 (br. ddd, ²J 15.0,

³J(1',6) 7.7, ³J(1',2') 7.3, 1 HÀC(1')); 2.15 (br. dd, ³J(OH,CH₂ÀC(2)) 7.7, 5.4, CH₂OH); 2.05 (s, MeCO);

1.61 (ddd, ²J 12.5, ³J(4ax,5) 12.6, ³J(4ax,3) 10.8, H_axÀC(4)). ¹³C-NMR (100.6 MHz, CDCl₃): 170.2

(s, MeCO); 134.1 (d, ¹J(C,H) 155, C(2')); 133.5 (d, ¹J(C,H) 162, 2 arom. C); 132.4 (s, arom. C); 129.1

(d, ¹J(C,H) 161, 2 arom. C); 127.9 (d, ¹J(C,H) 161, arom. C); 117.5 (t, ¹J(C,H) 156, C(3')); 80.3

(d, ¹J(C,H) 145, C(6)); 79.3 (d, ¹J(C,H) 144, C(2)); 67.7 (d, ¹J(C,H) 152, C(3)); 62.1 (t, ¹J(C,H) 142,

CH₂ÀC(2)); 46.6 (d, ¹J(C,H) 149, C(5)); 36.8 (2t, ¹J(C,H) 134, C(1'), C(4)); 21.0( q, ¹J(C,H) 130, MeCO).

3

4

CI-MS (NH₃): 323 (11, [M H] ), 281 (17, [M À allyl] ), 263 (4, [M À OAc] ), 203 (10), 163 (20), 135 (60), 109

(54), 81 (100). Anal. calc. for C₁₇H₂₂O₄S (322.46): C 63.33, H 6.88, S 9.94; found: C 63.22, H 6.84, S 9.98.

(2R,3S,5R,6S)-Tetrahydro-2-[(methoxymethoxy)methyl]-5-(phenylthio)-6-(prop-2-enyl)-2H-pyran-3-ol

Acetate (()-26). The crude reaction mixture obtained above (before chromatography; see ()-24) was

dissolved in CH₂Cl₂(35 ml). After cooling at 08, Bu₄NI (200 mg), ⁱPr₂NEt (3.6 ml, 21.4 mmol), and MeOCH₂Cl

(1.35 ml, 17.9 mmol) were added successively under stirring at 08. After stirring at 08 for 2 h, the same quantities

i

of Pr₂NEt and MeOCH₂Cl were added, and the mixture was stirred for another 2 h at 08. Then the same

amounts of ⁱPr₂NEt and MeOCH₂Cl were added again, and the mixture was stirred at 208 for 18 h. The mixture

was poured into a vigorously stirred soln. of CH₂Cl₂(100 ml) and 1m aq. HCl (30ml). The aq. phase was

extracted with CH₂Cl₂(100 ml, 3 Â ), the combined org. extract washed with sat. aq. NaHCO₃soln. (25 ml),

dried (MgSO₄), and evaporated, and the residue subjected to FC (silica gel, AcOEt/light petroleum ether 1:3):

1.075 g (82%) of ()-26 containing less than 10% of the anomer 27. Colorless oil.

25

589

25

577

25

546

25

435

25

405

Data of ()-26: a 27, a 29.5, a 35, a 62, a 66 (c 1.0, CHCl₃). UV

(MeCN): 251 (3200), 223 (2900). IR (film): 2945, 1740, 1640, 1585, 1480, 1440, 1375, 1235, 1150, 1110, 1045, 920,

850, 800, 750, 695. ¹H-NMR (400 MHz, CDCl₃): 7.45-7.27 (m, 5 arom. H); 5.90( dddd, ³J(2',3'trans) 17.0,

³J(2',3'cis) 10.4, ³J(2',1') 6.9, 6.9, HÀC(2')); 5.10 5.03 ( m, 2 HÀC(3')); 4.73 (ddd, ³J(3,4ax) 10.8,

³J(3,2) 9.9, ³J(3,4eq) 4.6, HÀC(3)); 4.63, 4.61 (2d, ²J 6.6, MeOCH₂); 3.61 3.58 (m, CH₂ÀC(2)); 3.43

(ddd, ³J(2,3) 9.9, ³J(2,CH₂ÀC(2)) 4.6, 3.1, HÀC(2)); 3.34 (ddd, ³J(6,5) 10.3, ³J(6,1') 7.4, 2.8, HÀC(6));

3.33 (s, MeCH₂O); 3.00 (ddd, ³J(5,4ax) 12.6, ³J(5,6) 10.3, ³J(5,4eq) 4.2, HÀC(5)); 2.78 (ddm, ²J 14.8,

³J(1',2') 6.8, 1 HÀC(1')); 2.53 (ddd, ²J 12.4, J(4eq,3) 4.6, J(4eq,5) 4.6, H_eqÀC(4)); 2.385 (br. ddd, ²J

3

14.8, J(1',6) 7.4, J(1',2') 6.9, 1 HÀC(1')); 2.10( s, MeCO); 1.55 (ddd,²J 12.4, J(4ax,5) 12.6, J(4ax,3)

10.8, H_axÀC(4)). ¹³C-NMR (100.6 MHz, CDCl₃): 169.8 (s, MeCO); 134.3 (d, ¹J(C,H) 155, C(2')); 133.6

(s, arom. C); 133.4 (d, ¹J(C,H) 162, 2 arom. C); 129.0( d, ¹J(C,H) 161, 2 arom. C); 127.8 (d, ¹J(C,H) 161,

arom. C); 117.2 (t, ¹J(C,H) 156, C(3')); 96.6 (t, ¹J(C,H) 163, MeOCH₂); 80.6 (d, ¹J(C,H) 142, C(6)); 78.6

(d, ¹J(C,H) 141, C(2)); 67.9 (d, ¹J(C,H) 151, C(3)); 66.4 (t, ¹J(C,H) 143, CH₂ÀC(2)); 55.1 (q, ¹J(C,H)

142, MeOCH₂); 46.4 (d, ¹J(C,H) 142, C(5)); 36.9, 36.8 (2t, ¹J(C,H) 133, C(1'), C(4)); 21.0( q, ¹J(C,H) 129,

3

MeCO). CI-MS (NH₃): 384 (100, [M NH₄] ), 367 (52, [M H] ), 335 (73, [M À OMe] ), 325 (21, [M À

CH₂CHCH₂] ). Anal. calc. for C₁₉H₂₆O₅S (366.48): C 62.27, H 7.15, S 8.75; found: C 62.30, H 7.18, S 8.70.

(2R)- and (2S)-3-{(2S,3R,5S,6R)-5-(Acetyloxy)-tetrahydro-6-[(methoxymethoxy)methyl]-3-(phenylthio)-

2H-pyran-2-yl}propane-1,2-diol (1:1 mixture; 28). N-Methylmorpholine N-oxide (4.07 g, 30.1 mmol) was added

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Helvetica Chimica Acta Vol. 87 (2004)

to a stirred soln. of ()-26 (7.357 g, 20.1 mmol) in acetone (178 ml) and H₂O (22 ml) at 208. Then 0.1m OsO₄in

CCl₄(10ml, 1 mmol) was added dropwise. After stirring at 20 8 for 3 h, AcOEt (275 ml) and Na₂S₂O₃(27.5 g)

were added. After stirring at 208 for 1 h, the mixture was filtered through a pad of Celite (height 5 cm), which

was washed with AcOEt (150ml, 5 Â ). The solvents were evaporated and the residue (10.5 g) purified by FC

(silica gel, MeOH/CH₂Cl₂1:9): 7.99 g (96%) of crude 28 used directly in the next step. An anal. sample was

25

589

25

577

25

546

25

435

obtained after purification by a second FC (silica gel, AcOEt). a 15, a 16, a 19, a

25

405

31, a 36 (c 1.0, CHCl₃). UV (MeCN): 255 (5500), 217 (6800). IR (film): 3445, 2930, 1740, 1440, 1375,

1235, 1150, 1040, 920, 735, 695. ¹H-NMR (400 MHz, CDCl₃): 7.45 7.28 (m, 5 arom. H, 2 diast.); 4.79 4.65

(m, HÀC(5'), 2 diast.); 4.63, 4.59 (2d, ²J 6.8, MeOCH₂, 2 diast.); 4.02 3.87 (m, HÀC(2), 2 diast.); 3.65 3.40

(m, HÀC(2'), HÀC(1), HÀC(6'), CH₂ÀC(6'), OHÀC(1), OHÀC(2), 2 diast.); 3.33 (2s, MeOCH₂, 2 diast.);

3.03 (ddd, ³J 14.5, ³J 10.5, ³J(3',4'eq) 4.0, HÀC(3'), diast. 1); 2.96 (ddd, ³J 14.2, ³J 10.2, ³J(3',4'eq)

4.0, HÀC(3'), diast. 2); 2.60 2.49 ( m, HÀC(4'), 2 diast.); 2.36 (br. d, ²J 14.8, HÀC(3), diast. 2); 2.26

(ddd, ²J 14.8, J 8.9, ³J 2.5, HÀC(3), diast. 1); 2.03 (s, MeCO, 2 diast.); 1.70( ddd, ²J 14.8, ³J 8.6, ³J

3

3.4, HÀC(3), diast. 1); 1.68 1.58 (m, HÀC(3), diast. 2); 1.56 (ddd, ²J ꢁ 12.3, 12.3, 12.3, HÀC(4'), 2 diast.).

¹³C-NMR (100.6 MHz, CDCl₃): 169.8, 169.8 (2s, MeCO); 133.5, 133.5 (2d, ¹J(C,H) 162, 162, 2 arom. C); 132.3,

131.9 (2s, arom. C); 129.2, 129.1 (2d, ¹J(C,H) 162, 162, 2 arom. C); 128.2, 128.1 (2d, ¹J(C,H) 161, 161, arom.

C); 96.7, 96.6 (2t, ¹J(C,H) 163, 163, MeOCH₂); 81.7, 79.0(2 d, ¹J(C,H) 143, 146, C(2')); 78.4, 78.1

(2d, ¹J(C,H) 142, C(6')); 71.7, 69.0(2 d, ¹J(C,H) 141, 144, C(2)); 67.8, 67.7 (2d, ¹J(C,H) 130, 130, C(5'));

67.0, 66.7, 66.6, 66.5 (4t, ¹J(C,H) 142, CH₂ÀC(6'), C(1)); 55.4, 55.3 (2q, ¹J(C,H) 142, 142, MeOCH₂); 47.3,

46.7 (2d, ¹J(C,H) 141, 141, C(3')); 36.8, 36.8 (2t, ¹J(C,H) 132, 133, C(4')); 35.7, 35.4 (2t, ¹J(C,H) 125, 128,

C(3)); 21.0, 21.0 (2q, ¹J(C,H) 129, 129, MeCO). CI-MS (NH₃): 418 (95, [M NH₄] ), 401 (64, [M H] ), 386

(51, [M H À Me] ), 369 (100, [M À OMe] ), 363 (59), 340(9), 309 (14), 261 (11).

(2R,3S,5R,6S)-Tetrahydro-2-[(methoxymethoxy)methyl]-5-(phenylthio)-6-{(2Z)-4-[(2S,3R,4R,5R,6S)-tet-

rahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3-ol ((À)-29). Crude (À)-12

(4.54 g, 6.89 mmol) was dissolved in MeOH (200 ml). After the addition of anh. K₂CO₃(4.76 g, 34.5 mmol), the

mixture was stirred at 208 for 1 h and then evaporated. The residue was dissolved in AcOEt (200 ml), and H₂O

(50ml) and 1m aq. HCl were added until pH 4. The aq. phase was extracted with AcOEt (200 ml, 5 Â ), the

combined org. extract washed with sat. aq. NaHCO₃soln. (50ml), dried (MgSO ₄), and evaporated, and the

residue subjected to FC (silica gel, AcOEt/light petroleum ether 3 :1): 2.86 g (67%, based on ()-10) of (À)-29

25

as yellowish oil and 217 mg (5%) of (À)-29 contaminated by Ph₃PO. a À13, a À14, a À16,

589

577

546

25

435

25

405

a À28, a À34 (c 1.0, CHCl₃). UV (MeCN): 256 (5400), 200 (12900). IR (film): 3455, 2935, 2890,

1650, 1585, 1475, 1440, 1405, 1360, 1320, 1305, 1270, 1215, 1150, 1110, 1030, 990, 920, 875, 850, 805, 735, 695.

¹H-NMR (400 MHz, CDCl₃): 7.44 7.24 (m, 5 arom. H); 5.62 (ddd, ³J(2',3') 10.8, ³J(2',1') 6.8, 6.8, HÀC(2'));

5.53 (ddd, ³J(3',2') 10.8, ³J(3',4') 6.8, 6.8, HÀC(3')); 4.87, 4.67 (2d, ²J 6.9, 1 MeOCH₂); 4.74, 4.72 (2d, ²J

6.9, 1 MeOCH₂); 4.73 (d, ²J 6.9, 1 H, MeOCH₂); 4.65 4.63 (m, 3 H, MeOCH₂); 4.08 4.02 (m, HÀC(2''));

3.95 3.88 (m, HÀC(3''), HÀC(4''), HÀC(5''), HÀC(6'')); 3.77 (dd, ²J 10.6, ³J(CH₂ÀC(2),2) 4.8, 1 H,

CH₂ÀC(2)); 3.70( dd, ²J 10.6, J(CH₂ÀC(2),2) 5.1, 1 H, CH₂ÀC(2)); 3.60( ddd, ³J(3,4ax) 10.8, J(3,2)

3

9.5, J(3,4eq) 4.6, HÀC(3)); 3.41, 3.39, 3.36, 3.35 (4s, 4 MeOCH₂); 3.28 (ddd, ³J(6,5) 10.3, ³J(6,1') 7.9, 7.2,

3

HÀC(6)); 3.23 (ddd, ³J(2,3) 9.5, ³J(2,CH₂ÀC(2)) 5.1, 4.8, HÀC(2)); 2.95 (ddd, ³J(5,4ax) 12.6, ³J(5,6)

10.3, ³J(5,4eq) 4.1, HÀC(5)); 2.76 (br. dd, ²J 14.8, ³J(1',2') 6.8, 1 HÀC(1')); 2.49 2.27 (m, H_eqÀC(4),

1 HÀC(1'), 2 HÀC(4')); 1.52 (ddd, ²J 12.6, ³J(4ax,5) 12.6, ³J(4ax,3) 10.8, H_axÀC(4)); 1.30

(d, ³J(MeÀC(6''),6'') 6.3, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CDCl₃): 133.4 (d, ¹J(C,H) 162, 2 arom. C);

132.7 (s, arom. C); 129.0( d, ¹J(C,H) 161, 2 arom. C); 127.7 (d, ¹J(C,H) 161, arom. C); 127.7 (d, C(3')); 127.1

(d, C(2')); 97.4, 96.8, 96.8, 96.4 (4t, ¹J(C,H) 167, 4 MeOCH₂); 80.7 (d, ¹J(C,H) 143, C(6)); 79.6 (d, ¹J(C,H)

141, C(2)); 75.5 (d, ¹J(C,H) 145, C(3'', 4'', 5'', 6'', or 3)); 75.2 (d, ¹J(C,H) 145, C(3'', 4'', 5'', 6'', or 3)); 74.4

(d, ¹J(C,H) 141, C(3'', 4'', 5'', 6'', or 3)); 71.6 (d, ¹J(C,H) 141, C(2'')); 68.7 (t, ¹J(C,H) 142, CH₂ÀC(2)); 68.6

(d, ¹J(C,H) 145, C(3'', 4'', 5'', 6'', or 3)); 68.3 (d, ¹J(C,H) 141, C(3'', 4'', 5'', 6'', or 3)); 55.8, 55.8, 55.6, 55.4

(4q, ¹J(C,H) 142, 4 MeOCH₂); 46.7 (d, ¹J(C,H) 142, C(5)); 39.8 (t, ¹J(C,H) 131, C(4)); 30.9 (t, ¹J(C,H)

126, C(1')); 25.4 (br. t, ¹J(C,H) 121, C(4')); 15.7 (q, ¹J(C,H) 127, MeÀC(6'')). CI-MS (NH₃): 635 (100), 634

(73, [M NH₄] ), 616 (2, M ), 603 (3), 586 (16, [M H À OMe] ), 554 (9, [M À 2 OMe] ), 509 (12), 477 (12).

Anal. calc. for C₃₀H₄₈O₁₁S (616.77): C 58.42, H 7.84, S 5.20; found: C 58.42, H 7.89, S 5.19.

(2S,3S,4R,5S,6S)-Tetrahydro-6-methyl-2-{(2Z)-4-[(2S,3R,5S,6R)-tetrahydro-5-hydroxy-6-(hydroxymeth-

yl)-3-(phenylthio)-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3,4,5-triol (30). Freshly distilled SOCl₂(165 ml,

2.27 mmol) was added to a stirred soln. of (À)-29 (70mg, 0.114 mmol) in anh. MeOH (2.25 ml) at 0 8. The

mixture was stirred at 08 for 5 min, then at 208 for 2 h. Evaporation gave a residue (50mg) that was purified by

HPLC (Nucleosil 100-5 (Macherey-Nagel), MeOH/CH₂Cl₂1:9, 5 ml/min, 45 bar): 15 mg (30%) of 30. Colorless

Helvetica Chimica Acta Vol. 87 (2004)

1063

oil. UV (MeOH): 256 (3300), 216 (5100). IR (film): 3405, 2930, 1680, 1440, 1205, 1140, 1085, 800, 725. ¹H-NMR

(400 MHz, CD₃OD): 7.48 7.26 (m, 5 arom. H); 5.65 (ddd, ³J(3',2') 10.8, ³J(3',4') 7.2, 6.9, HÀC(3')); 5.50

(ddd, ³J(2',3') 10.8, ³J(2',1') 7.3, 7.0, HÀC(2')); 3.95 (ddd, ³J(2,3) 5.5, ³J(2,1') 10.6, 5.0, HÀC(2)); 3.89

(dd, ³J(3,4) 8.8, ³J(3,2) 5.5, HÀC(3)); 3.80( qd, ³J(6,MeÀC(6)) 6.6, ³J(6,5) 2.0, HÀC(6)); 3.80( dd, ²J

11.8, ³J(CH₂ÀC(6''),6'') 2.4, 1 H, CH₂ÀC(6'')); 3.70( dd, ³J(5,4) 3.4, ³J(5,6) 2.0, HÀC(5)); 3.67

(dd, ³J(4,3) 8.8, ³J(4,5) 3.4, HÀC(4)); 3.62 (dd, ²J 11.8, ³J(CH₂ÀC(6''),6'') 5.8, 1 H, CH₂ÀC(6'')); 3.45

(ddd, ³J(5'',4''ax) 10.9, ³J(5'',6'') 9.7, ³J(5'',4''eq) 4.7, HÀC(5'')); 3.25 (ddd, ³J(2'',3'') 10.0, ³J(2'',4') 8.2,

2.4, HÀC(2'')); 3.06 (ddd, ³J(6'',5'') 9.7, ³J(6'',CH₂ÀC(6'')) 5.8, 2.4, HÀC(6'')); 3.02 (ddd, ³J(3'',4''ax) 11.8,

³J(3'',2'') 10.0, ³J(3'',4''eq) 4.0, HÀC(3'')); 2.74 (ddm, ²J 14.7, ³J 6.5, 1 HÀC(4')); 2.44 2.25

(m, H_eqÀC(4''), 1 HÀC(4'), 2 HÀC(1')); 1.47 (ddd, ²J 12.5, ³J(4''ax,3'') 11.8, ³J(4''ax,5'') 10.9, H_axÀC(4''));

1.21 (d, ³J(MeÀC(6),6) 6.6, MeÀC(6)). ¹³C-NMR (100.6 MHz, CD₃OD): 134.8 (s, arom. C); 133.9

(d, ¹J(C,H) 161, 2 arom. C); 130.2 (d, ¹J(C,H) 161, 2 arom. C); 129.2 (d, ¹J(C,H) 157, C(2')); 128.6

(d, ¹J(C,H) 161, arom. C); 128.3 (d, ¹J(C,H) 159, C(3')); 84.0( d, ¹J(C,H) 138, C(6'')); 82.6 (d, ¹J(C,H)

141, C(2'')); 76.3 (d, ¹J(C,H) 149, C(2)); 72.6 (d, ¹J(C,H) 144, C(4) or C(5)); 72.2 (d, ¹J(C,H) 141, C(5) or

C(4)); 69.9 (d, ¹J(C,H) 143, C(3)); 69.0( d, ¹J(C,H) 141, C(6)); 67.2 (d, ¹J(C,H) 144, C(5'')); 63.0

(t, ¹J(C,H) 141, CH₂ÀC(6'')); 47.8 (d, ¹J(C,H) 142, C(3'')); 41.6 (t, ¹J(C,H) 129, C(4'')); 32.1

(t,¹J(C,H) 128, C(4')); 24.5 (t, ¹J(C,H) 128, C(1')); 16.7 (q, ¹J(C,H) 125, MeÀC(6)). CI-MS (NH₃): 458

(100, [M NH₄] ), 441 (42, [M H ] ), 348 (5), 279 (8), 256 (6), 206 (21), 186 (20). ESI-MS: 441.35 (100, M);

881 (24, 2 M). FAB-MS: 463 (50, [M Na] ), 150(100). HR-FAB-MS: 441.1947 (C ₂₂H₃₃O₇S , [M H] ; calc.

441.1947).

(2R,5R,6S)-5,6-Dihydro-2-[(methoxymethoxy)methyl]-5-(phenylthio)-6-{(2Z)-4-[(2S,3R,4R,5R,6S)-tetra-

hydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3(4H)-one ((À)-31). A mix-

ture of oxalyl chloride (167 ml, 1.98 mmol), DMSO (288 ml, 3.95 mmol), and CH₂Cl₂(7 ml) was stirred at À 788

for 15 min. A soln. of (À)-29 (300 mg, 0.49 mmol) in CH₂Cl₂(3 ml) was added dropwise under stirring at À 788.

After stirring at À 788 for 30min, Et ₃N (827 ml, 5.93 mmol) was added dropwise, and the mixture was stirred at

À 788 for 90min. After evaporation, the residue was extracted Et ₂O (10ml, 3 Â ) and the combined org. extract

dried (MgSO₄) and evaporated: (À)-31 (314 mg, quant.), pure enough for the next step. An anal. sample was

25

obtained by FC (silica gel, Et₂O). Yellowish oil. a À5, a À7.2, a À13 (c 0.5, CHCl₃). UV

589

577

546

(MeCN): 256 (4800), 207 (10600). IR (film): 2935, 2825, 1730, 1585, 1475, 1440, 1405, 1380, 1360, 1305, 1215,

1150, 1110, 1035, 990, 920, 845, 810, 750, 695. ¹H-NMR (400 MHz, CDCl₃): 7.44 7.30( m, 5 arom. H); 5.66

(ddd, ³J(2',3') 11.1, ³J(2',1') ꢁ 6.8, 6.8, HÀC(2')); 5.61 (ddd, ³J(3',2') 11.1, ³J(3',4') ꢁ 6.1, 6.1, HÀC(3')); 4.87,

4.67 (2d, ²J 6.8, 1 MeOCH₂); 4.76, 4.66 (2d, ²J 6.8, 1 MeOCH₂); 4.76, 4.73 (2d, ²J 6.8, 1 MeOCH₂); 4.625,

4.605 (2d, ²J 6.8, 1 MeOCH₂); 4.11 4.01 (m, HÀC(2'')); 4.00 3.89 (m, HÀC(3''), HÀC(4''), HÀC(5''),

HÀC(6''), HÀC(2)); 3.85 (dd, ²J 11.1, ³J(CH₂ÀC(2),2) 3.1, 1 H, CH₂ÀC(2)); 3.815 (dd, ²J 11.1,

³J(CH₂ÀC(2),2) 4.9, 1 H, CH₂ÀC(2)); 3.64 (ddd, ³J(6,5) ꢁ 7.5, ³J(6,1') ꢁ 7.5, 4.1, HÀC(6)); 3.53

(ddd, ³J(5,6) ꢁ 7.5, ³J(5,4ax) 6.9, ³J(5,4eq) 6.2, HÀC(5)); 3.42, 3.40, 3.37, 3.33 (4s, 4 MeOCH₂); 2.94

(ddd, ²J 15.8, ³J(4eq,5) 6.2, H_eqÀC(4)); 2.77 (ddd, ²J 14.4, ³J ꢁ 5.2, ³J ꢁ 4.1, 1 HÀC(1')); 2.48 (ddd, ²J

15.8, ³J(4ax,5) 6.9, H_axÀC(4)); 2.39 (ddd, ²J 15.1, ³J(4',3') ꢁ 5.3, ³J(4',2'') ꢁ 5.3, 1 HÀC(4')); 2.57 2.35

(m, 1 HÀC(1'), 1 HÀC(4')); 1.31 (d, ³J(MeÀC(6''),6'') 6.2, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CD₂Cl₂):

206.5 (s, C(3)); 133.8 (d, ¹J(C,H) 161, 2 arom. C); 131.9 (s, arom. C); 129.25 (d, ¹J(C,H) 161, 2 arom. C);

128.9 (d,¹J(C,H) 156, C(3') or C(2')); 128.35 (d, ¹J(C,H) 161, arom. C); 128.9 (d, ¹J(C,H) 157, C(3') or

C(2')); 97.5, 96.8, 96.6, 96.5 (4t, ¹J(C,H) 164, 4 MeOCH₂); 82.4 (d, ¹J(C,H) 140, C(2)); 79.7 (d, ¹J(C,H) 145,

C(6)); 75.7 (d, ¹J(C,H) 145, C(3'', 4'', 5'', or 6'')); 75.2 (d, ¹J(C,H) 143, C(3'', 4'', 5'', or 6'')); 74.4 (d, ¹J(C,H)

139, C(3'', 4'', 5'', or 6'')); 71.4 (d, ¹J(C,H) 145, C(2'')); 68.6 (d, ¹J(C,H) 141, C(3'', 4'', 5'', or 6'')); 66.0

(t, ¹J(C,H) 145, CH₂ÀC(2)); 55.9, 55.9, 55.6, 55.2 (4q, ¹J(C,H) 142, 4 MeOCH₂); 46.95 (d, ¹J(C,H) 145,

C(5)); 43.5 (t, ¹J(C,H) 132, C(4)); 32.1 (t, ¹J(C,H) 126, C(1')); 25.7 (t, ¹J(C,H) 127, C(4')); 15.6

(q, ¹J(C,H) 126, MeÀC(6'')). CI-MS (NH₃): 633 (100), 632 (79, [M NH₄] ), 587 (9), 584 (4, [M H À

OMe] ), 583 (4, [M À OMe] ), 523 (10). HR-FAB-MS: 637.2625 (C₃₀H₄₆NaO₁₁S , [M Na] ; calc. 637.2659).

Anal. calc. for C₃₀H₄₆O₁₁S (614.76): C 58.61, H 7.54; found: C 57.37, H 7.65.

(2R,6S)-2-[(Methoxymethoxy)methyl]-6-{(2Z)-4-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(methoxymeth-

oxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3(6H)-one (()-32). DBU (50 ml, 0.335 mmol) was added

to a stirred soln. of crude (À)-31 (41 mg, 0.067 mmol) maintained at 08. After stirring at 208 for 15 min, CH₂Cl₂

(5 ml) and sat. aq. NaHCO₃soln. (3 ml) were added. The aq. phase was extracted with CH₂Cl₂(5 ml, 4 Â ), the

combined org. extract dried (MgSO₄) and evaporated and the residue subjected to FC (silica gel, Et₂O): ()-32

25

589

25

577

25

546

25

435

25

405

(39 mg, 89% based on (À)-29). Yellowish oil. a 3.0, a 3.2, a 3.5, a 14.5, a

19.6 (c 1.0, CHCl₃). UV (MeCN): 227 (4300). IR (film): 2935, 2835, 1745, 1695, 1440, 1385, 1260, 1215, 1150,

1064

Helvetica Chimica Acta Vol. 87 (2004)

1110, 1030, 920, 805, 755. ¹H-NMR (400 MHz, CDCl₃): 6.97 (dd, ³J(5,4) 10.3, ³J(5,6) 1.2, HÀC(5)); 6.12

(dd, ³J(4,3) 10.3, ⁴J(4,6) 2.2, HÀC(4)); 5.64 (ddd, ³J(3',2') 11.2, ³J(3',4') 7.0 , 7.0 , ÀHC(3')); 5.56

(ddd, ³J(2',3') 11.2, ³J(2',1') 7.2, 7.2, HÀC(2')); 4.84, 4.65 (2d, ²J 6.8, 1 MeOCH₂); 4.75, 4.65 (2d, ²J 6.8,

1 MeOCH₂); 4.74, 4.71 (2d, ²J 6.8, 1 MeOCH₂); 4.67 (s, 1 MeOCH₂); 4.42 (m, HÀC(6)); 4.215

(ddd, ³J(2,CH₂ÀC(2)) 5.9, 2.6, J 2.3, HÀC(2)); 4.08 4.03 (m, HÀC(2'')); 4.02 (dd, ²J 11.3,

³J(CH₂ÀC(2),2) 2.6, 1 H, CH₂ÀC(2)); 3.94 3.90( m, HÀC(3''), HÀC(4''), HÀC(5''), HÀC(6'')); 3.89

(dd, ²J 11.3, ³J(CH₂ÀC(2),2) 5.9, 1 H, CH₂ÀC(2)); 3.40, 3.39, 3.37, 3.36 (4s, 4 MeOCH₂); 2.55 2.31

(m, 2 HÀC(1'), 2 HÀC(4')); 1.31 (d, ³J(MeÀC(6''),6'') 6.2, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CDCl₃):

194.1 (s, C(3)); 150.9 (d, ¹J(C,H) 161, C(5)); 129.7 (d, ¹J(C,H) 154, C(3')); 127.1 (d, ¹J(C,H) 167, C(4));

125.0( d, ¹J(C,H) 157, C(2')); 97.5, 96.7, 96.6, 96.4 (4t, ¹J(C,H) 164, 4 MeOCH₂); 80.2 (d, ¹J(C,H) 137,

C(2)); 75.7 (d, ¹J(C,H) 149, C(3'', 4'', 5'', or 6'')); 75.0( d, ¹J(C,H) 140, C(3'', 4'', 5'', or 6'')); 74.1 (d, ¹J(C,H)

148, C(3'', 4'', 5'', or 6'')); 73.7 (d, ¹J(C,H) 137, C(6)); 71.4 (d, ¹J(C,H) 146, C(2'')); 68.5 (d, ¹J(C,H) 142,

C(3'', 4'', 5'', or 6'')); 65.8 (t, ¹J(C,H) 143, CH₂ÀC(2)); 55.8, 55.8, 55.6, 55.2 (4q, ¹J(C,H) 142, 4 MeOCH₂);

32.7 (t, ¹J(C,H) 127, C(1')); 25.6 (t, ¹J(C,H) 121, C(4')); 15.5 (q, ¹J(C,H) 126, MeÀC(6'')). CI-MS (NH₃):

522 (100, [M NH₄] ), 473 (1.1, [M À OMe] ), 397 (8), 296 (28), 224 (15). HR-FAB-MS: 527.2481

(C₂₄H₄₀O₁₁Na , [M Na] ; calc. 527.2468).

Ethyl (aR,2R,4S,5R,6S)-Tetrahydro-a-hydroxy-2-[(methoxymethoxy)methyl]-3-oxo-5-(phenylthio)-6-

{(2Z)-4-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl])but-2-enyl}-2H-

pyran-4-acetate ((À)-33) and Ethyl (aR,2R,6S)-3,6-Dihydro-a-hydroxy-2-[(methoxymethoxy)methyl]-3-oxo-6-

{(2Z)-4-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-

pyran-4-acetate (()-34). A 1 :1 mixture of ethyl glyoxylate and toluene (4 ml, 20mmol) was added to a soln. of

crude (À)-31 (0.615 g, 1 mmol) in anh. THF (10 ml) stirred at À 788. Then 1m (Me₃Si)₂NLi in THF (2 ml,

2 mmol) was added dropwise under stirring at À 788. More (Me₃Si)₂NLi in THF (up to 10mmol) was added

until completion of the reaction (TLC control). After stirring at À 788 for 30min, the mixture was poured into

CH₂Cl₂(50ml) and 1 n aq. HCl (10ml), the aq. phase extracted with CH ₂Cl₂(50ml, 4 Â ), the combined org.

extract washed with sat. aq. NaHCO₃soln. (10ml), dried (MgSO ₄), and evaporated and the residue subjected to

FC (silica gel, Et₂O): 208 mg (29%) of (À)-33, 110mg (22%) of ( )-32 (yellowish oil), and (eluent: MeOH/

CH₂Cl₂1:9) 193 mg (32%) of ()-34).

25

Data of (À)-33: Yellowish oil. a À3.7, a À3.8, a À4.2 (c 1.0, CHCl₃). UV (MeCN): 246

589

577

546

(5200), 205 (13600). IR (film): 3455, 2935, 2825, 1740, 1470, 1440, 1365, 1260, 1215, 1150, 1110, 1035, 915, 860,

805, 735, 695, 665. ¹H-NMR (400 MHz, CDCl₃): 7.55 7.30( m, 5 arom. H); 5.64 (ddd, ³J(2',3') 10.8, ³J(2',1')

6.8, 6.8, HÀC(2')); 5.56 (ddd, ³J(3',2') 10.8, ³J(3',4') 6.8, 6.8, HÀC(3')); 4.87, 4.675 (2d, ²J 6.8, 1 MeOCH₂);

4.86 (d, ³J(a,4) 2.0, HÀC(a)); 4.76, 4.74 (2d, ²J 6.8, 1 MeOCH₂); 4.74, 4.64 (2d, ²J 6.8, 1 MeOCH₂); 4.60

(s, 1 MeOCH₂); 4.35 4.21 (m, MeCH₂O); 4.10 4.01 ( m, HÀC(2'')); 3.98 3.88 (m, HÀC(3''), HÀC(4''),

HÀC(5''), HÀC(6''), HÀC(2)); 3.855 (dd, ²J 11.4, ³J(CH₂ÀC(2),2) 3.3, 1 H, CH₂ÀC(2)); 3.71

(ddd, ³J(6,5) 10.8, ³J(6,1') 8.0, 2.0, HÀC(6)); 3.68 (dd, ²J 11.4, ³J(CH₂ÀC(2),2) 5.9, 1 H, CH₂ÀC(2));

3.58 (dd, ³J(5,4) 11.5, ³J(5,6) 10.8, HÀC(5)); 3.42, 3.40, 3.36, 3.33 (4s, 4 MeOCH₂); 3.06 2.97

3

(m, 1 HÀC(1')); 3.02 (dd, ³J(4,5) 11.5, J(4,a) 10.8, HÀC(4)); 2.50 2.30( m, 1 HÀC(1'), 2 HÀC(4')); 1.32

(d, ³J(MeÀC(6''),6'') 6.8, MeÀC(6'')); 1.25 (t, ³J 7.1, MeCH₂O). ¹³C-NMR (100.6 MHz, CDCl₃): 203.0

(s, C(3)); 173.4 (s, COO); 133.8 (d, ¹J(C,H) 162, 2 arom. C); 131.6 (s, arom. C); 129.3 (d, ¹J(C,H) 162,

2 arom. C); 128.5 (d, ¹J(C,H) 162, arom. C, C(3')); 126.4 (d, ¹J(C,H) 156, C(2')); 97.5, 96.7, 96.7, 96.5

(4t, ¹J(C,H) 164, 4 MeOCH₂); 81.7 (d, ¹J(C,H) 138, C(2)); 80.4 (d, ¹J(C,H) 144, C(6)); 75.6 (d, ¹J(C,H)

138, C(3'', 4'', 5'', or 6'')); 75.1 (d, ¹J(C,H) 144, C(3'', 4'', 5'', or 6'')); 74.2 (d, ¹J(C,H) 138, C(3'', 4'', 5'', or 6''));

71.4 (d, ¹J(C,H) 148, C(2'')); 68.5 (d, ¹J(C,H) 139, C(3'', 4'', 5'', or 6'')); 67.8 (d, ¹J(C,H) 145, C(a)); 65.4

(t, ¹J(C,H) 147, CH₂ÀC(2)); 62.0( t, ¹J(C,H) 148, MeCH₂O); 56.2 (d, ¹J(C,H) 126, C(4)); 55.8, 55.8, 55.6,

55.3 (4q, ¹J(C,H) 142, 4 MeOCH₂); 51.3 (d, ¹J(C,H) 141, C(5)); 32.1 (t, ¹J(C,H) 127, C(1')); 25.6

(t, ¹J(C,H) 126, C(4')); 15.6 (q, ¹J(C,H) 127, MeÀC(6'')); 14.1 (q, ¹J(C,H) 127, MeCH₂O). CI-MS (NH₃):

716 (100, [M NH₄] ), 624 (58, [M À PhSH] ).

25

589

25

577

25

546

25

435

25

405

Data of ()-34: Orange oil. a 11, a 12, a 15, a 39, a 45 (c 0.25,

CHCl₃). UV (MeCN): 223 (1750), 194 (4000). IR (film): 3440, 2940, 2895, 2825, 1740, 1690, 1465, 1445, 1370,

1300, 1260, 1215, 1150, 1110, 1030, 995, 920, 870, 805. ¹H-NMR (400 MHz, CDCl₃): 7.06 (m, HÀC(5)); 5.71 5.62

(dm, ³J(3',2') 11.0, HÀC(3')); 5.61 5.53 (m, HÀC(2')); 4.90 4.87 ( m, HÀC(a)); 4.85, 4.67 (2d, ²J 6.7,

1 MeOCH₂); 4.76, 4.73 (2d, ²J 6.7, 1 MeOCH₂); 4.76, 4.66 (2d, ²J 6.8, 1 MeOCH₂); 4.67 (s, 1 MeOCH₂);

4.54 4.46 (m, HÀC(6)); 4.26 4.18 (m, HÀC(2)); 4.23 (q, ³J 7.0, MeCH₂O); 4.10 4.05 ( m, HÀC(2'')); 4.03

(dd, ²J 11.3, ³J(CH₂ÀC(2),2) 2.6, 1 H, CH₂ÀC(2)); 3.97 3.84 (m, HÀC(3''), HÀC(4''), HÀC(5''),

HÀC(6''), 1 H of CH₂ÀC(2)); 3.41, 3.41, 3.39, 3.37 (4s, 4 MeOCH₂); 2.62 2.30( m, 2 HÀC(1'), 2 HÀC(4'));

Helvetica Chimica Acta Vol. 87 (2004)

1065

1.31 (d, ³J(MeÀC(6''),6'') 6.2, MeÀC(6'')); 1.25 (t, ³J 7.0, MeCH₂O). ¹³C-NMR (100.6 MHz, CDCl₃): 192.8

(s, C(3)); 172.3 (s, COO); 148.4 (d, ¹J(C,H) 159, C(5)); 135.2 (s, C(4)); 129.9 (d, ¹J(C,H) 154, C(3')); 124.9

(d, ¹J(C,H) 155, C(2')); 97.6, 96.7, 96.7, 96.5 (4t, ¹J(C,H) 164, 4 MeOCH₂); 80.2 (d, ¹J(C,H) 138, C(2)); 75.8

(d, C(3'', 4'', 5'', or 6'')); 75.1 (d, ¹J(C,H) 138, C(3'', 4'', 5'', or 6'')); 74.1 (d, ¹J(C,H) 146, C(3'', 4'', 5'', or 6''));

73.7 (d, ¹J(C,H) 135, C(6)); 71.1 (d, ¹J(C,H) 141, C(2'')); 68.6 (d, ¹J(C,H) 144, C(3'', 4'', 5'', or 6'')); 68.1

(d, ¹J(C,H) 149, C(a)); 66.0( t, ¹J(C,H) 145, CH₂ÀC(2)); 62.3 (t, ¹J(C,H) 148, MeCH₂O); 55.9, 55.8, 55.6,

55.3 (4q, ¹J(C,H) 142, 4 MeOCH₂); 32.6 (t, ¹J(C,H) 134, C(1')); 25.8 (t, ¹J(C,H) 127, C(4')); 15.5

(q, ¹J(C,H) 128, MeÀC(6'')); 14.0( q, ¹J(C,H) 127, MeCH₂O). CI-MS (NH₃): 624 (100, [M NH₄] ), 608

(4, [M D] ), 578 (39, [M 1 À Et] ), 522 (7), 484 (12), 340(13), 279 (11), 164 (28). HR-FAB-MS: 629.2776

(C₂₈H₄₆O₁₄Na , [M Na] ; calc. 629.2785).

Ethyl (aR,2R,3S,4R,5R,6S)-Tetrahydro-a,3-dihydroxy-2-[(methoxymethoxy)methyl]-5-(phenylthio)-6-

{(2Z)-4-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-

pyran-4-acetate ((À)-35). A mixture of (À)-33 (100 mg, 0.14 mmol), AcOH (2.8 ml), and (Me₄N)BH(OAc)₃

(731 mg, 2.78 mmol) was stirred at 208 for 2 h and then evaporated. The residue was taken up with CH₂Cl₂

(10ml) and sat. aq. NaHCO ₃soln. (3 ml). The aq. phase was neutralized with NaHCO₃and extracted with

CH₂Cl₂(10ml, 5 Â ), the combined org. extract dried (MgSO₄) and evaporated, and the residue subjected to FC

25

(silica gel, CH₂Cl₂/MeOH 97:3): 55 mg (55%) of (À)-35. Colorless oil. a À10, a À11, a À13,

589

577

546

25

a À21, a À24 (c 1.0, CHCl₃). UV (MeCN): 257 (5200), 204 (9800). IR (film): 3440, 2960, 2925,

435

405

1730, 1440, 1380, 1265, 1215, 1150, 1110, 1030, 915. ¹H-NMR (400 MHz, CDCl₃): 7.52 7.48, 7.32 7.22

(2m, 5 arom. H); 5.58 (ddd, ³J(2',3') 11.1, ³J(2',1') 6.8, 6.8, HÀC(2')); 5.48 (ddd, ³J(3',2') 11.1, ³J(3',4')

6.8, 6.8, HÀC(3'')); 5.09 (br. d, ³J(a,OHÀC(a)) 4.0, HÀC(a)); 4.87, 4.67 (2d, ²J 6.7, 1 MeOCH₂); 4.75, 4.73

(2d, ²J 6.7, 1 MeOCH₂); 4.72, 4.63 (2d, ²J 6.7, 1 MeOCH₂); 4.61 (s, 1MeOCH₂); 4.31, 4.18 (2dq, ²J 10.8,

³J 7.1, MeCH₂O); 4.04 3.99 (m, HÀC(2'')); 3.97 3.88 (m, HÀC(3''), HÀC(4''), HÀC(5''), HÀC(6''),

HÀC(3)); 3.76 (dd, ²J 10.8, ³J(CH₂ÀC(2),2) 4.3, 1 H, CH₂ÀC(2)); 3.68 (dd, ²J 10.8, ³J(CH₂ÀC(2),2)

4.6, 1 H, CH₂ÀC(2)); 3.41, 3.40, 3.35, 3.34 (4s, 4 MeOCH₂); 3.42 3.33 (HÀC(6), overlapped by 4 MeOCH₂);

3.29 (d, ³J(OHÀC(a),a) 4.0, OHÀC(a)); 3.23 (ddd, ³J(2,3) 9.6, J(2,CH₂ÀC(2)) 4.6, 4.3, HÀC(2)); 3.04

3

(dd, ³J(5,4) 11.7, ³J(5,6) 10.8, HÀC(5)); 2.90(br. d, ³J(OHÀC(3),3) 4.3, OHÀC(3)); 2.92 2.84

(m, 1 HÀC(1')); 2.44 2.22 (m, 2 HÀC(4'), 1 HÀC(1')); 2.14 (ddm, ³J(4,5) 11.7, J(4,3) 9.9, HÀC(4)); 1.32

3

(t, ³J 7.1, MeCH₂O); 1.29 (d, ³J(MeÀC(6''),6'') 6.5, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CDCl₃): 173.4

(s, COO); 133.5 (s, arom. C); 132.6 (d, ¹J(C,H) 164, 2 arom. C); 129.0( d, ¹J(C,H) 161, 2 arom. C); 127.7

(d, ¹J(C,H) ꢁ 152, C(3')); 127.5 (d, ¹J(C,H) ꢁ 160, arom. C); 127.3 (d, ¹J(C,H) ꢁ 151, C(2')); 97.5, 97.1, 96.8, 96.5

(4t, ¹J(C,H) 162, 4 MeOCH₂); 81.0( d, ¹J(C,H) 145, C(6)); 78.1 (d, ¹J(C,H) ꢁ 140, C(2)); 75.5 (d, ¹J(C,H) ꢁ

146, C(3, 3'', 4'', 5'', or 6'')); 75.2 (d, ¹J(C,H) 144, C(3, 3'', 4'', 5'', or 6'')); 74.4 (d, ¹J(C,H) 141, C(3, 3'', 4'', 5'',

or 6'')); 71.6 (d, ¹J(C,H) ꢁ 152, C(2'')); 68.9 (t, ¹J(C,H) 146, CH₂ÀC(2)); 68.4 (d, ¹J(C,H) 142, C(3, 3'', 4'', 5'',

or 6'')); 67.7 (d, ¹J(C,H) 145, C(a)); 66.8 (d, ¹J(C,H) 148, C(3, 3'', 4'', 5'', or 6'')); 61.8 (t, ¹J(C,H) 150,

MeCH₂O); 55.9, 55.9, 55.6, 55.6 (4q, ¹J(C,H) 142, 4 MeOCH₂); 50.4 (d, ¹J(C,H) 146, C(5)); 50.3

(d, ¹J(C,H) 126, C(4)); 31.3 (t, ¹J(C,H) ꢁ 126, C(1')); 25.4 (t, ¹J(C,H) 128, C(4')); 15.7 (q, ¹J(C,H) 124,

MeÀC(6'')); 14.1 (q, ¹J(C,H) 127, MeCH₂O). CI-MS (NH₃): 736 (100, [M NH₄] ). HR-FAB-MS: 741.3133

(C₃₄H₅₄NaO₁₄S , [M Na] ; calc. 741.3132).

Ethyl (4R,4aR,5R,6S,8R,8aS)-Hexahydro-8-[(methoxymethoxy)methyl]-2,2-dimethyl-5-(phenylthio)-6-

{(2Z)-4-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}pyra-

no[3,4-d][1,3]dioxin-4-carboxylate ((À)-36). A mixture of (À)-35 (51 mg, 0.071 mmol), TsOH (10 mg), acetone

(0.35 ml), and 2,2-dimethoxypropane (0.35 ml) was stirred at 208 for 90min. CH ₂Cl₂(3 ml) and sat. aq.

NaHCO₃soln. (1 ml) were added. The aq. phase was extracted with CH₂Cl₂(5 ml, 4 Â ), the combined org.

extract dried (MgSO₄) and evaporated, and the residue subjected to FC (silica gel, Et₂O/light petroleum ether

25

4 :1): 31 mg (58%) of (À)-36. Colorless oil. a À14, a À18, a À20, a À35, a À44

589

577

546

435

405

(c 0.3, CHCl₃). UV (MeCN): 257 (7200), 205 (12100). IR (film): 2935, 1745, 1585, 1475, 1440, 1405, 1380,

1260, 1205, 1150, 1105, 1040, 990, 920, 865, 745, 720, 695, 670. ¹H-NMR (400 MHz, C₆D₆): 7.62 7.59, 7.11 7.06,

7.00 6.95 (3m, 5 arom. H); 5.78 (ddd, ³J(2',3') 10.8, ³J(2',1') 6.5, 6.5, HÀC(2')); 5.71 (ddd, ³J(3',2') 10.8,

³J(3',4') 6.5, 6.5, HÀC(3')); 4.80, 4.53 (2d, ²J 6.8, 1 MeOCH₂); 4.70, 4.68 (2d, ²J 6.8, 1 MeOCH₂); 4.64, 4.49

(2d, ²J 6.8, 1 MeOCH₂); 4.62, 4.59 (2d, ²J 6.8, 1 MeOCH₂); 4.47 (d, ³J(4,4a) 10.0, HÀC(4)); 4.25

(ddd, ³J(2'',4') 9.6, ³J(2'',4') 4.8, ³J(2'',3'') 4.8, HÀC(2'')); 4.15 (dd, ³J(3'',4'') 7.7, ³J(3'',2'') 4.3,

HÀC(3'')); 4.09 (dd, ³J(4'',3'') 7.7, ³J(4'',5'') 2.7, HÀC(4'')); 4.06, 3.97 (2dq, ²J 11.1, ³J 7.1, MeCH₂O);

3

3.95 (dd, ³J(5'',4'') 2.7, J(5'',6'') 2.7, HÀC(5'')); 3.84 (qd, ³J(6'',MeÀC(6'')) 6.5, J(6'',5'') 2.7, HÀC(6''));

3.76 (dd, ³J(8a,4a) 9.9, ³J(8a,8) 9.5, HÀC(8a)); 3.73 (d, ³J(CH₂ÀC(8),8) 3.4, CH₂ÀC(8)); 3.35

(ddd, ³J(6,5) 9.9, ³J(6,1') 8.3, 2.5, HÀC(6)); 3.30( dt, ³J(8,8a) 9.5, ³J(8,CH₂ÀC(8)) 3.4, HÀC(8)); 3.25,

1066

Helvetica Chimica Acta Vol. 87 (2004)

3.22, 3.20, 3.16 (4s, 4 MeOCH₂); 2.95 (ddm, ²J 14.8, ³J(1',2') 6.5, 1 HÀC(1')); 2.74 (dd, ³J(5,4a) 12.0,

³J(5,6) 9.9, HÀC(5)); 2.62 2.45 (m, 2 HÀC(4')); 2.52 (ddd, ³J(4a,5) 12.0, ³J(4a,4) 10.0, ³J(4a,8a) 9.9,

HÀC(4a)); 2.52 (ddd, ²J 14.8, ³J(1',6) 8.3, ³J(1',2') 6.5, 1 HÀC(1')); 1.46 (s, MeÀC(2)); 1.39

(d, ³J(MeÀC(6''),6'') 6.5, MeÀC(6'')); 1.46 (s, 2 MeÀC(2)); 0.93 (t, ³J 7.1, MeCH₂O). ¹³C-NMR

(100.6 MHz, C₆D₆): 169.7 (s, COO); 134.5 (s, arom. C); 132.9 (d, ¹J(C,H) 161, 2 arom. C); 129.4

(d, ¹J(C,H) 161, 2 arom. C); 128.7 (d, C(3')); arom. C, overlapped by C₆D₆; 127.4 (d, C(2')); 99.8 (s, C(2));

97.5, 97.0, 96.9, 96.3 (4t, ¹J(C,H) 163, 4 MeOCH₂); 82.1 (d, ¹J(C,H) 145, C(6)); 78.7 (d, ¹J(C,H) 140, C(8));

75.9 (d, ¹J(C,H) 147, C(3'')); 75.5 (d, ¹J(C,H) 147, C(4)); 75.2 (d, ¹J(C,H) 142, C(4'') or C(5'')); 75.0

(d, ¹J(C,H) 140, C(5'') or C(4'')); 72.1 (d, ¹J(C,H) 146, C(2'')); 69.6 (d, ¹J(C,H) 144, C(8a)); 68.5

(d, ¹J(C,H) 142, C(6'')); 66.0( t, ¹J(C,H) 143, CH₂ÀC(8)); 61.4 (t, ¹J(C,H) 147, MeCH₂O); 55.5, 55.5,

55.3, 54.8 (4q, ¹J(C,H) 141, 4 MeOCH₂); 49.6 (d, ¹J(C,H) 136, C(5)); 44.8 (d, ¹J(C,H) 132, C(4a)); 31.2

(t, ¹J(C,H) 126, C(1')); 29.7 (q, ¹J(C,H) 128, MeÀC(2)); 26.0( t, ¹J(C,H) ꢁ 126, C(4')); 19.8 (q, ¹J(C,H)

125, MeÀC(2)); 16.2 (q, ¹J(C,H) 127, MeÀC(6'')); 13.7 (q, ¹J(C,H) 127, MeCH₂O). CI-MS (NH₃): 776 (6,

[M NH₄] ), 727 (2, [M À OMe] ), 697 (2, [M À MeOCH₂O] ), 593 (11), 335 (12), 203 (18), 110 (100,

PhSH ). HR-FAB-MS: 781.3436 (C₃₇H₅₈NaO₁₄S , [M Na] ; calc. 781.3435).

Methyl (aR,2R,3S,4R,5R,6S)-Tetrahydro-a,3-dihydroxy-2-(hydroxymethyl)-5-(phenylthio)-6-{(2Z)-4-

[(2S,3S,4R,5S,6S)-tetrahydro-3,4,5-trihydroxy-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-pyran-4-acetate ((À)-

37). A mixture of (À)-35 (60 mg, 0.084 mmol), anh. MeOH (1.7 ml), and freshly distilled SOCl₂(121 ml,

1.67 mmol) was stirred at 08 for 5 min, then at 208 for 16 h. Evaporation and FC (silica gel, CH₂Cl₂/MeOH 6 :1)

25

gave 21 mg (48%) of (À)-37. White solid. a À27, a À39, a À44, a À56, a À68 (c

589

577

546

435

405

0.3, MeOH). IR (film): 3435, 2925, 1735, 1645, 1440, 1240, 1125, 1065, 1000, 875, 750, 695. UV (MeCN): 260

(4100), 216 (5500), 211 (5650). ¹H-NMR (400 MHz, CD₃OD): 7.55 7.51, 7.37 7.26 (2m, 5 arom. H); 5.60(br.

3

ddd, ³J(2',3') 10.8, J(2',1') 6.8, 6.8, HÀC(2')); 5.46 (ddd, ³J(3',2') 10.8, J(3',4') 6.8, 6.8, HÀC(3')); 5.08

(d, ³J(a,4) 1.5, HÀC(a)); 3.92 (dd, ³J(2'',4') 10.6, ³J(2'',3'') 5.5, HÀC(2'')); 3.89 (dd, ³J(3'',4'') 8.4,

³J(3'',2'') 5.5, HÀC(3'')); 3.81 (qd, ³J(6'',MeÀC(6'')) 6.5, ³J(6'',5'') 1.8, HÀC(6'')); 3.76 (dd, ²J 11.9,

³J(CH₂ÀC(2),2) 2.4, 1 H, CH₂ÀC(2)); 3.73 3.65 (m, MeO, HÀC(3), HÀC(4''), HÀC(5'')); 3.58 (dd, ²J

11.9, ³J(CH₂ÀC(2),2) 5.8, 1 H, CH₂ÀC(2)); 3.37 3.29 (m, overlapped by solvent, HÀC(6)); 3.08

(ddd, ³J(2,3) 9.7, ³J(2,CH₂ÀC(2)) 5.8, 2.4, 1 H, CH₂ÀC(2)); 3.04 (dd, ³J(5,4) 11.9, ³J(5,6) 10.6,

HÀC(5)); 2.85 (ddm, ²J 14.7, ³J(1',2') 6.8, 1 HÀC(1')); 2.44 2.22 (m, 2 HÀC(4'), 1 HÀC(1')); 2.11

(ddd, ³J(4,5) 11.9, ³J(4,3) 10.1, ³J(4,a) 1.5, HÀC(4)); 1.20( d, ³J(MeÀC(6''),6'') 6.5, MeÀC(6'')).

¹³C-NMR (100.6 MHz, CD₃OD): 177.4 (s, COO); 135.1 (s, arom. C), 133.8 (d, ¹J(C,H) 164, 2 arom. C);

130.2 (d, ¹J(C,H) 163, 2 arom. C); 129.1 (d, ¹J(C,H) 155, C(3')); 128.7 (d, ¹J(C,H) 163, arom. C); 128.3

(d, ¹J(C,H) 154, C(2')); 82.7 (d, ¹J(C,H) 139, C(6)); 82.4 (d, ¹J(C,H) 141, C(2)); 76.4 (d, ¹J(C,H) 147,

C(2'')); 72.6 (d, ¹J(C,H) 143, C(5'')); 72.1 (d, ¹J(C,H) 140, C(4'')); 69.8 (d, ¹J(C,H) 144, C(3'')); 68.9

(d, ¹J(C,H) 143, C(6'')); 68.9 (d, ¹J(C,H) 143, C(a)); 65.6 (d, ¹J(C,H) 145, C(3)); 63.1 (t, ¹J(C,H) 141,

CH₂ÀC(2)); 52.4 (q, ¹J(C,H) 148, MeOCH₂); 52.2 (d, ¹J(C,H) 130, C(4)); 51.8 (d, ¹J(C,H) 138, C(5)); 32.4

(t, ¹J(C,H) 126, C(1')); 24.5 (t, ¹J(C,H) 126, C(4')); 16.7 (q, ¹J(C,H) 127, MeÀC(6'')). ESI-MS: 529.05 (100,

M ). FAB-MS: 551 (100, [M Na] ). HR-FAB-MS: 529.2116 (C₂₅H₃₇O₁₀S , [M H] ; calc. 529.2107).

Ethyl (aR,2R,3S,4R,6S)-Tetrahydro-a,3-dihydroxy-2-[(methoxymethoxy)methyl]-6-{4-[(2S,3R,4R,5R,6S)-

tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]butyl}-2H-pyran-4-acetate ((À)-38). A mixture

of (À)-35 (crude obtained from 166 mg (0.23 mmol) of (À)-33), EtOH (4.6 ml), and Raney-Ni (1 g) was stirred

at 208 for 2 h. More Raney-Ni (1 g) was added and the mixture stirred at 208 for 15 h. The precipitate was filtered

off over Celite (height 2 cm), which was washed with EtOH (5 ml, 4 Â ). The filtrate was evaporated, the residue

taken up in CH₂Cl₂(10ml), the soln. dried (MgSO ₄) and evaporated, and the residue subjected to FC (silica gel,

25

CH₂Cl₂/MeOH 96 :4): 89 mg (63%, based on (À)-33) of pure (À)-38. Colorless oil. a À16, a À17,

589

577

25

546

25

a À19, a À31, a À37 (c 1.0, CHCl₃). UV (MeCN): 194 (2200). IR (film): 3460, 2940, 2825,

435

405

1730, (ꢁ1650), 1465, 1445, 1370, 1260, 1215, 1150, 1110, 1040, 920, 870, 805, 730, 665. ¹H-NMR (400 MHz,

CDCl₃): 4.87, 4.66 (2d, ²J 6.8, MeOCH₂); 4.75, 4.64 (2d, ²J 6.8, MeOCH₂); 4.75, 4.72 (2d, ²J 6.8, MeOCH₂);

4.65 (s, MeOCH₂); 4.29, 4.22 (2dq, ²J 10.8, ³J 7.1, MeCH₂O); 4.10( dd, ³J(a,OHÀC(a)) 4.6, ³J(a,4)) 3.7,

HÀC(a)); 3.98 (ddd, ³J(2'',4') 10.2, ³J(2'',4') 3.7, ³J(2'',3'') 3.7, HÀC(2'')); 3.95 3.84 (m, HÀC(3''),

HÀC(4''), HÀC(5''), HÀC(6'')); 3.80( dd, ²J 10.5, ³J(CH₂ÀC(2),2) 4.6, 1 H, CH₂ÀC(2)); 3.74 (dd, ²J

10.5, ³J(CH₂ÀC(2),2) 4.3, 1 H, CH₂ÀC(2)); 3.72 (ddd, ³J(3,4) 9.9, ³J(3,2) 9.3, ³J(3,OHÀC(3)) 3.7,

HÀC(3)); 3.41, 3.40, 3.38, 3.37 (4s, 4 MeOCH₂); 3.42 3.36 (HÀC(6), overlapped by 4 MeOCH₂); 3.31

(ddd, ³J(2,3) 9.3, J(2,CH₂ÀC(2)) 4.6, 4.3, HÀC(2)); 3.26 (d, ³J(OHÀC(a),a) 4.6, OHÀC(a)); 2.98 (br.

3

d, ³J(OHÀC(3),3) 3.7, OHÀC(3)); 2.13 (dddd, ³J(4,5ax) 12.6, ³J(4,3) 9.9, ³J(4,a) 3.7, ³J(4,5eq) 3.7,

HÀC(4)); 1.77 1.35 (m, 2 HÀC(1'), 2 HÀC(2'), 2 HÀC(3'), 2 HÀC(4'), 2 HÀC(5)); 1.32 (t, ³J 7.1,

Helvetica Chimica Acta Vol. 87 (2004)

1067

MeCH₂O); 1.29 (d, ³J(MeÀC(6''),6'') 6.5, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CDCl₃): 174.8 (s, COO); 97.4,

97.0, 96.9, 96.4 (4t, ¹J(C,H) 162, 4 MeOCH₂); 79.9 (d, ¹J(C,H) 140, C(2)); 76.9 (d, C(6)); 75.7 (d, ¹J(C,H) ꢁ

145, C(3'', 4'', 5'', or 6'')); 75.1 (d, ¹J(C,H) ꢁ 145, C(3'', 4'', 5'', or 6'')); 74.6 (d, ¹J(C,H) ꢁ 142, C(3'', 4'', 5'', or 6''));

72.1 (d, ¹J(C,H) 147, C(a)); 72.0( d, C(2'')); 69.0( t, ¹J(C,H) 145, CH₂ÀC(2)); 68.3 (d, ¹J(C,H) 140, C(3));

67.9 (d, ¹J(C,H) 141, C(3'', 4'', 5'', or 6'')); 61.8 (t, ¹J(C,H) 148, MeCH₂O); 55.9, 55.8, 55.6, 55.5

(4q, ¹J(C,H) 142, 4 MeOCH₂); 45.6 (d, ¹J(C,H) 127, C(4)); 35.6 (t, ¹J(C,H) 123, C(1')); 33.7

(d, ¹J(C,H) 127, C(5)); 26.6 (t, ¹J(C,H) 127, C(4')); 25.9 (t, ¹J(C,H) ꢁ 124, C(2') or C(3')); 25.6

(t, ¹J(C,H) ꢁ 127, C(3') or C(2')); 15.8 (q, ¹J(C,H) 127, MeÀC(6'')); 14.1 (q, ¹J(C,H) 127, MeCH₂O). CI-

MS (NH₃): 630(1, [ M NH₄] ), 473 (13), 315 (16), 244 (82), 142 (100). FAB-MS: 635 (100, [M Na] ), HR-

FAB-MS: 613.3394 (C₂₈H₅₃

O

₁₄, [M H] ; calc. 613.3435).

Methyl (aR,2R,3S,4R,6S)-Tetrahydro-a,3-dihydroxy-2-(hydroxymethyl)-6-{4-[(2S,3S,4R,5S,6S)-tetrahy-

dro-3,4,5-trihydroxy-6-methyl-2H-pyran-2-yl]butyl}-2H-pyran-4-acetate ((À)-39). A mixture of (À)-38 (44 mg,

0.072 mmol), anh. MeOH (1.5 ml), and freshly distilled SOCl₂(105 ml, 1.44 mmol) was stirred at 08 for 5 min,

then at 208 for 16 h. Evaporation and FC (silica gel, CH₂Cl₂/MeOH 4 :1) gave 21 mg (70%) of (À)-39. Colorless

25

solid. a À62, a À67, a À71, a À113, a À134 (c 0.3, MeOH). UV (MeOH): 209

589

577

546

435

405

1

(450). IR (film): 3420, 2935, 2860, 1735, 1635, 1440, 1385, 1230, 1120, 1085, 1015, 870, 800, 750, 670. H-NMR

(400 MHz, CD₃OD): 4.21 (d, ³J(a,4) 1.9, HÀC(a)); 3.91 3.84 (m, HÀC(2''), HÀC(3'')); 3.81 (dd, ²J 11.8,

³J(CH₂ÀC(2),2) 2.4, 1 H, CH₂ÀC(2)); 3.78 (qd, ³J(6'',MeÀC(6'')) 6.5, ³J(6'',5'') 1.8, HÀC(6'')); 3.72

(s, MeO); 3.68 (dd, ³J(5'',4'') 3.3, ³J(5'',6'') 1.8, HÀC(5'')); 3.65 (dd, ³J(4'',3'') 8.4, ³J(4'',5'') 3.3,

HÀC(4'')); 3.61 (dd, ²J 11.8, ³J(CH₂ÀC(2),2) 5.9, 1 H, CH₂ÀC(2)); 3.49 (dd, ³J(3,4) 10.5, ³J(3,2) 9.8,

HÀC(3)); 3.44 3.37 (m, HÀC(6)); 3.16 (ddd, ³J(2,3) 9.8, J(2,CH₂ÀC(2)) 5.9, 2.4, 1 H, CH₂ÀC(2)); 2.11

3

(dddd, ³J(4,5ax) 12.7, ³J(4,3) 10.5, ³J(4,5eq) 3.9, ³J(4,a) 2.7, HÀC(4)); 1.74 (ddd, ²J 13.2, ³J(5eq,4)

3.9, ³J(5eq,6) 1.6, H_eqÀC(5)); 1.71 1.25 (m, 2 HÀC(1'), 2 HÀC(2'), 2 HÀC(3'), 2 HÀC(4'), H_axÀC(5)); 1.21

(d, ³J(MeÀC(6''),6'') 6.5, MeÀC(6'')). ¹³C-NMR (100.6 MHz, CD₃OD): 176.2 (s, COO); 83.2 (d, ¹J(C,H)

139, C(2)); 78.2 (d, ¹J(C,H) 136, C(6)); 76.3 (d, ¹J(C,H) 144, C(2'')); 72.7 (d, ¹J(C,H) 145, C(5'')); 72.2

(d, ¹J(C,H) 145, C(a)); 72.15 (d, ¹J(C,H) 138, C(4'')); 70.0 (d, ¹J(C,H) 145, C(3'')); 68.5 (d, ¹J(C,H) 144,

C(6'')); 66.8 (d, ¹J(C,H) 142, C(3)); 63.4 (t, ¹J(C,H) 141, CH₂ÀC(2)); 52.4 (q, ¹J(C,H) 147, MeO); 47.9

(t, ¹J(C,H) ꢁ 125, C(4)); 36.8 (t, ¹J(C,H) 126, C(1')); 34.9 (t, ¹J(C,H) 126, C(5)); 27.1 (t, ¹J(C,H) 125, C(2')

or C(3')); 26.5 (t, ¹J(C,H) 128, C(3') or C(2')); 25.4 (t, ¹J(C,H) 120, C(4')); 16.7 (q, ¹J(C,H) 127,

MeÀC(6)). ESI-MS: 422.88 (100, M ), 844.85 (100, [2 M] ). FAB-MS: 445 (90, [M Na] ), 288 (100). HR-

FAB-MS: 423.2227 (C₁₉H₃₅

O

₁₀, [M H] ; calc. 423.2230).

(2R,3S,6S)-Tetrahydro-2-[(methoxymethoxy)methyl]-6-{4-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(meth-

oxymethoxy)-6-methyl-2H-pyran-2-yl]butyl}-2H-pyran-3-ol ((À)-40).

A

mixture of (À)-29 (200 mg,

0.32 mmol), THF (6.5 ml), and Raney-Ni (1 g) was stirred at 208 for 30min. More Raney-Ni (1 g) was added

(until disappearence of (À)-29, TLC control), and the mixture was stirred at 208 for 90min. The precipitate was

filtered off on a pad of Celite (height 3 cm), which was washed with AcOEt (25 ml, 5 Â ). The soln. was dried

25

(MgSO₄) and evaporated: 163 mg (99%) of (À)-29. Colorless oil. a À3.4, a À3.6, a À4.9,

589

577

546

25

435

25

405

a À8.1, a À8.6 (c 1.0, CHCl₃). UV (MeCN): 194 (2000). IR (film): 3460, 2935, 1445, 1365, 1215,

1150, 1105, 1035, 915. ¹H-NMR (400 MHz, CDCl₃): 4.86, 4.66 (2d, ²J 6.8, 1 MeOCH₂); 4.74, 4.64 (2d, ²J 6.8,

1 MeOCH₂); 4.74, 4.72 (2d, ²J 6.8, 1 MeOCH₂); 4.67 (s, 1 MeOCH₂); 3.98 (d, ³J(2'',4') 10.2, 3.7, J(2'',3'')

3

3.7, HÀC(2'')); 3.94 3.84 (m, HÀC(3''), HÀC(4''), HÀC(5''), HÀC(6'')); 3.80( dd, ²J 10.2,

³J(CH₂ÀC(2),2) 4.8, 1 H, CH₂ÀC(2)); 3.73 (dd,²J 10.2, ³J(CH₂ÀC(2),2) 5.0, 1 H, CH₂ÀC(2)); 3.59

3.50( m, HÀC(3)); 3.41, 3.39, 3.39, 3.36 (4s, 4 MeOCH₂); 3.31 3.23 (m, HÀC(2), HÀC(6)); 2.65

(d, ³J(OHÀC(3),3) 2.8, OHÀC(3)); 2.14 2.07 (m, H_eqÀC(4)); 1.74 1.24 (m, 2 HÀC(5), 2 HÀC(1'),

2 HÀC(2'), 2 HÀC(3'), 2 HÀC(4'), H_axÀC(4)); 1.28 (d, ³J(MeÀC(6''),6'') 6.2, MeÀC(6'')). ¹³C-NMR

(100.6 MHz, CDCl₃): 97.4, 96.8, 96.8, 96.4 (4t, ¹J(C,H) 162, 4 MeOCH₂); 79.8 (d, ¹J(C,H) 140, C(2) or

C(6)); 77.5 (d, ¹J(C,H) ꢁ 155, C(2) or C(6)); 75.7 (d, ¹J(C,H) ꢁ 145, C(3'', 4'', 5'', or 6'')); 75.1 (d, ¹J(C,H) ꢁ 143,

C(3'', 4'', 5'', or 6'')); 74.7 (d, ¹J(C,H) ꢁ 144, C(3'', 4'', 5'', or 6'')); 71.8 (d, ¹J ꢁ 147, C(2'')); 69.2 (t, ¹J 144,

CH₂ÀC(2)); 68.8 (d, ¹J(C,H) 143, C(3)); 67.9 (d, ¹J(C,H) 139, C(3'', 4'', 5'', or 6'')); 55.9, 55.8, 55.6, 55.4

(4q, ¹J(C,H) 142, 4 MeOCH₂); 35.6 (t, ¹J(C,H) 124, C(1')); 32.2 (t, ¹J(C,H) 130, C(4)); 30.6 (t, ¹J(C,H)

130, C(5)); 26.5 (t, ¹J(C,H) ꢁ 128, C(4')); 25.9 (t, ¹J(C,H) 129, C(2') or C(3')); 25.6 (t, ¹J(C,H) 125, C(2') or

C(3')); 15.8 (q, ¹J(C,H) 126, MeÀC(6'')). CI-MS (NH₃): 528 (100, [M NH₄] ), 511 (1.4, [M H] ), 496 (1.2,

[M 1 À Me]), 403 (7), 341 (4), 246 (2.5), 161 (15), 83 (15). Anal. calc. for C₂₄H₄₆O₁₁(510.62): C 56.45, H 9.08;

found: C 56.30, H 9.04.

(2S,3S,4R,5S,6S)-Tetrahydro-6-methyl-2-{4-[(2S,5S,6R)-tetrahydro-5-hydroxy-6-(hydroxymethyl)-2H-pyr-

an-2-yl]butyl}-2H-pyran-3,4,5-triol ((À)-41). A mixture of (À)-40 (77 mg, 0.15 mmol), anh. MeOH (3 ml), and

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Helvetica Chimica Acta Vol. 87 (2004)

freshly distilled SOCl₂(0.2 ml, 3 mmol) was stirred at 08 for 5 min, then at 208 for 2 h. Evaporation and FC

25

589

25

577

25

546

(silica gel, CH₂Cl₂/MeOH 4 :1) gave 25 mg (60%) of (À)-41. Colorless oil. a À58, a À61, a

25

435

25

405

À68, a À102, a À118 (c 0.3, MeOH). UV (MeOH): 268 (650), 195 (600). IR (film): 3385, 2935,

2860, 1650, 1455, 1380, 1260, 1155, 1070, 985, 875, 800, 750. ¹H-NMR (400 MHz, CD₃OD): 3.90 3.84

(m, HÀC(2), HÀC(3)); 3.82 (dd, ²J 11.7, ³J(CH₂ÀC(6''),6'') 2.7, 1 H, CH₂ÀC(6'')); 3.78

(qd, ³J(6,MeÀC(6)) 6.5, ³J(6,5) 1.9, HÀC(6)); 3.68 (dd, ³J(5,4) 3.4, ³J(5,6) 1.9, HÀC(5)); 3.64

(dd, ³J(4,3) 8.5, ³J(4,5) 3.4, HÀC(4)); 3.62 (dd, ²J 11.7, ³J(CH₂ÀC(6''),6'') 6.0, 1 H, CH₂ÀC(6'')); 3.36

(ddd, ³J ꢁ 10, ³J 9.4, ³J(5'',4''eq) 4.9, HÀC(5'')); 3.30 3.27 ( m, HÀC(2'')); 3.12 (ddd, ³J(6'',5'') 9.0,

³J(6'',CH₂ÀC(6'')) 6.0, 2.6, HÀC(6'')); 2.05 (dddd, ²J 12.3, ³J ꢁ 4.5, 3.8, 3.8, H_eqÀC(4'')); 1.75 1.26

(m, H_axÀC(4''), 2 HÀC(3''), 2 HÀC(1'), 2 HÀC(2'), 2 HÀC(3'), 2 HÀC(4')); 1.21 (d, ³J(MeÀC(6),6) 6.5,

MeÀC(6)). ¹³C-NMR (100.6 MHz, CD₃OD): 83.9 (d, ¹J(C,H) 136, C(6'')); 78.7 (d, ¹J(C,H) 137, C(2'')); 76.2

(d, ¹J(C,H) 140, C(2)); 72.7 (d, ¹J(C,H) 144, C(5)); 72.2 (d, ¹J(C,H) 140, C(4)); 70.0 (d, ¹J(C,H) 143,

C(3)); 68.5 (d, ¹J(C,H) 144, C(6)); 67.7 (d, ¹J(C,H) 144, C(5'')); 63.6 (t, ¹J(C,H) 142, CH₂ÀC(6'')); 36.8

(t, ¹J(C,H) 129, C(4')); 33.7 (t, ¹J(C,H) 132, C(4'')); 32.1 (t, ¹J(C,H) 131, C(3'')); 27.2 (t, ¹J(C,H) 124,

C(2') or C(3')); 26.6 (t, ¹J(C,H) 124, C(3') or C(2')); 25.4 (t, ¹J(C,H) 120, C(1')); 16.7 (q, ¹J(C,H) 127,

MeÀC(6)). CI-MS (NH₃): 335 (19, [M H] ), 281 (11), 267 (9), 217 (44), 131 (46), 81 (100). ESI-MS: 356.85

(100, [M Na] ). FAB-MS: 357 (100, [M Na] ). HR-FAB-MS: 335.2077 (C₁₆H₃₁O₇, [M H] ; calc.

335.2070).

(2R,3S,6R)-Tetrahydro-2-[(methoxymethoxy)methyl]-6-{(2Z/E)-4-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-

tris(methoxymethoxy)-6-methyl-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3-ol ((À)-42).

A

mixture of (À)-29

(182 mg, 0.295 mmol), Bu₃SnH (15 ml), AIBN (10 mg, 0.059 mmol), and toluene (15 ml) was stirred at 808

for 2 h. More AIBN (10mg) was added every 2 h until disappearance of ( À)-29. After stirring at 808 for 26 h, the

mixture was poured into pentane/MeCN 1:1 (40ml). The pentane fraction was extracted with MeCN (10ml,

5 Â ) The combined MeCN phase was washed with pentane (10ml, 2 Â ) and evaporated and the residue

25

subjected to FC (silica gel, AcOEt): 125 mg (83%; (Z)/(E) 1:2) of (À)-42. Colorless oil. a À9.8, a

589

577

25

À0.3, a À11.3, a À19.8, a À23.2 (c 3, CHCl₃). UV (MeCN): 198 (4700). IR (film): 3465,

546

435

405

2935, 1650, 1440, 1370, 1215, 1150, 1035, 990, 920, 810. ¹H-NMR (400 MHz, CDCl₃): 5.55 5.42 (m, J_trans 15.7,

J_cis 11.7, J 6.8, HÀC(2')_transcis, HÀC(3')_transcis); 4.85, 4.65 (2d, ²J 6.8, 1 MeOCH_2cis); 4.84, 4.65 (2d, ²J 6.8,

1 MeOCH_2trans); 4.74, 4.72 (2d, ²J 6.8, 1 MeOCH_2cis); 4.74, 4.71 (2d, ²J 6.8, 1 MeOCH_2trans); 4.74, 4.64

(2d, ²J 6.8, 1 MeOCH_2cis); 4.74, 4.64 (2d, ²J 6.8, 1 MeOCH_2trans); 4.67 (s, MeOCH_2transcis); 4.05 3.98

(m, HÀC(2'')_transcis); 3.96 3.86 (m, HÀC(3'')_transcis, HÀC(4'')_transcis, HÀC(5'')_transcis, HÀC(6'')_transcis); 3.79

(dd, ²J 10.5, ³J(CH₂ÀC(2),2) 4.8, 1 H of CH₂ÀC(2)_cis); 3.79 (dd, ²J 10.5, ³J(CH₂ÀC(2),2) 4.8, 1 H of

CH₂ÀC(2)_trans); 3.74 (dd, ²J 10.5, ³J(CH₂ÀC(2),2) 4.9, 1 H of CH₂ÀC(2)_trans); 3.73 (dd, ²J 10.5,

³J(CH₂ÀC(2),2) 4.9, 1 H of CH₂ÀC(2)_cis); 3.55 (ddd, ³J(3,4ax) 10.5, ³J(3,2) 10.5, ³J(3,4eq) 5.2,

HÀC(3)_cis); 3.54 (ddd, ³J(3,4ax) 10.5, ³J(3,2) 10.5, ³J(3,4eq) 5.2, HÀC(3)_trans); 3.40, 3.39, 3.38, 3.37

((4s, 4 MeOCH_2cis); 3.40, 3.38, 3.38, 3.37 ((4s, 4 MeOCH_2trans); 3.34 3.24 (m, HÀC(6)_transcis, HÀC(2)_transcis);

2.64 (br. s, OHÀC(3)_transcis); 2.44 2.06 (m, 2 HÀC(4')_transcis, 2 HÀC(1')_transcis, HÀC(4)_transcis); 1.77 1.68

(m, HÀC(5)_transcis); 1.51 1.30( m, HÀC(4)_transcis, HÀC(5)_transcis); 1.28 (d, ³J(MeÀC(6''),6'') 6.2, MeÀ

C(6'')_transcis). ¹³C-NMR (100.6 MHz, CDCl₃): 128.7 (d, ¹J(C,H) 154, C(2' or 3')_trans); 128.4 (d, ¹J(C,H) 153,

C(3' or 2')_trans); 127.6 (d, ¹J(C,H) 157, C(2' or 3')_cis); 127.1 (d, ¹J(C,H) 158, C(3' or 2')_cis); 97.5, 97.4, 96.75, 96.7,

96.5, 96.4 (6t, ¹J(C,H) 163, 4 MeOCH_2transcis); 79.9 (d, ¹J(C,H) 141, C(2)_transcis); 77.4 (d, ¹J(C,H) ꢁ 143,

C(6)_trans); 77.2 (d, C(6)_cis); 75.5 (d, ¹J(C,H) 143, C(3'', 4'', 5'', or 6'')_transcis); 75.1 (d, ¹J(C,H) 144, C(3'', 4'', 5'',

or 6'')_transcis); 74.2 (d, ¹J(C,H) 145, C(3'', 4'', 5'', or 6'')_transcis); 71.3 (d, ¹J(C,H) ꢁ 160, C(2'')_transcis); 69.0( t,

J(C,H) 142, CH₂ÀC(2)_transcis); 68.5 (d, ¹J(C,H) 144, C(4, 3'', 4'', 5'', or 6''))_transcis); 68.3 (d, C((3'', 4'', 5'', or 6''

or 4)_transcis); 55.8, 55.8, 55.5, 55.3 4 (4q, ¹J(C,H) 142, 4 MeOCH_2transcis); 38.9 (t, ¹J(C,H) 124, C(1')_trans); 33.8

(t, ¹J(C,H) 131, C(1')_cis); 32.05 (t, ¹J(C,H) 129, C(4)_transcis); 30.6 (t, ¹J(C,H) 126, C(4')_trans); 30.2

(t, ¹J(C,H) 124, C(5)_cis); 30.0 (t, ¹J(C,H) 128, C(5)_trans); 25.3 (t, ¹J(C,H) 127, C(4')_cis); 15.5 (q, ¹J(C,H)

128, MeÀC(6'')_cis); 15.4 (q, ¹J(C,H) 128, MeÀC(6'')_trans). CI-MS (NH₃): 526 (100, [M NH₄] ), 477 (1.4, [M À

OMe] ). FAB-MS: 531 (100, [M Na] ). HR-FAB-MS: 509.2943 (C₂₄H_{45 11}, [M H] ; calc. 509.2962).

O

(2S,3S,4R,5S,6S)-Tetrahydro-6-methyl-2-{(2Z/E)-4-[(2R,5S,6R)-tetrahydro-5-hydroxy-6-(hydroxymethyl)-

2H-pyran-2-yl]but-2-enyl}-2H-pyran-3,4,5-triol (43). A mixture of (À)-42 (68 mg, 0.134 mmol), anh. MeOH

(2.7 ml) and freshly distilled SOCl₂(195 ml, 2.67 mmol) was stirred at 08 for 5 min, then at 208 for 2 h.

Evaporation and FC (silica gel, CH₂Cl₂/MeOH 4 :1) gave 38 mg (86%; (Z)/(E) 1:2) of 43. Colorless oil. IR

(film): 3380, 2935, 1650, 1445, 1245, 1155, 1070, 875, 800. UV (MeCN): 205 (800). ¹H-NMR (400 MHz,

CD₃OD): 5.62 5.45 (m, J_trans 15.2, J_cis 10.3, J 6.8, HÀC(2')_transcis

,

HÀC(3')_transcis); 3.96 3.78

(m, HÀC(2)_transcis, HÀC(3)_transcis, 1 H of CH₂ÀC(6'')_transcis, HÀC(6)_transcis); 3.72 3.67 (m, HÀC(5)_transcis);

Helvetica Chimica Acta Vol. 87 (2004)

1069

3.66 (dd, ³J(4,3) 8.4, ³J(4,5) 3.5, HÀC(4)_transcis); 3.62 (dd, ²J 11.6, ³J(CH₂ÀC(6''),6'') 6.0, 1 H of

CH₂ÀC(6×')_transcis); 3.40 3.31 ( m, HÀC(2'')_transcis

,

HÀC(5'')_transcis); 3.13 (ddd, ³J(6'',5'') 9.2,

³J(6'',CH₂ÀC(6'')) 6.0

,

2.7, ÀHC(6'')_transcis); 2.45 2.01 (m, 2 HÀC(1')_transcis

,

2 HÀC(4')_transcis

,

HÀC(4'')_transcis); 1.78 1.70( m, HÀC(3'')_transcis); 1.51 1.26 (m, HÀC(4'')_transcis, HÀC(3'')_transcis); 1.21 (d, ³J

(MeÀC(6),6) 6.5, MeÀC(6)_cis); 1.20( d, ³J(MeÀC(6),6) 6.5, MeÀC(6)_trans). ¹³C-NMR (100.6 MHz,

CD₃OD): 130.4 (d, ¹J(C,H) 154, C(2' or 3')_trans); 129.4 (d, ¹J(C,H) 154, C(3' or 2')_trans); 129.1 (d, ¹J(C,H)

155, C(2' or 3')_cis); 128.2 (d, ¹J(C,H) 155, C(3' or 2')_cis); 84.0( d, ¹J(C,H) 137, C(6'')_transcis); 78.6 (d, ¹J(C,H)

140, C(2'')_transcis); 76.2, 76.1 (2d, ¹J(C,H) ꢁ 147, C(2)_transcis); 72.6, 72.5 (2d, ¹J(C,H) 145, C(4 or 5)_transcis); 72.2,

72.1 (2d, ¹J(C,H) 140, C(5 or 4)_transcis); 69.9, 69.8 (2d, ¹J(C,H) 145, C(3)_transcis); 68.8, 68.6 (2d, ¹J(C,H)

142, C(6)_transcis); 67.6 (d, ¹J(C,H) ꢁ 145, C(5'')_trans); 67.5 (d, ¹J(C,H) ꢁ 145, C(5'')_cis); 63.6 (t, ¹J(C,H) 141,

CH₂ÀC(6'')_trans); 63.5 (t, ¹J(C,H) 141, CH₂ÀC(6'')_cis); 40.1 (t, ¹J(C,H) 126, C(4')_trans); 34.8 (t, ¹J(C,H) 124,

C(4')_cis); 33.7, 33.5 (2t, ¹J(C,H) ꢁ 130, C(4'')_transcis); 31.4 (t, ¹J(C,H) 124, C(3'')_transcis); 29.5 (t, ¹J(C,H) 125,

C(1')_trans); 24.4 (t, ¹J(C,H) ꢁ 126, C(1')_cis); 16.6, 16.5 (2q, ¹J(C,H) 127, MeÀC(6)_transcis). ESI-MS: 354.83 (100,

[M Na] ); 333.34 (ca. 10 , [M H] ). FAB-MS: 355 (100, [M Na] ). HR-FAB-MS: 333.1911 (C₁₆H₂₉O₇,

[M H] ; calc. 333.1913).

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Received August 26, 2003

Article Doi

New nonhydrolyzable mimetics of sialyl Lewis x and their binding affinity to P-selectin

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