Synthesis of all eight stereoisomeric 6-deoxy-l-hexopyranosyl donors - Trends in using stereoselective reductions or mitsunobu epimerizations

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FULL PAPER

DOI: 10.1002/ejoc.201403074

Synthesis of All Eight Stereoisomeric 6-Deoxy-

L

-hexopyranosyl Donors –

Trends in Using Stereoselective Reductions or Mitsunobu Epimerizations

Tobias Gylling Frihed,^[a]Christian Marcus Pedersen,*^[a]and Mikael Bols^[a]

Keywords: Carbohydrates / 6-Deoxy-l-sugars / Diastereoselectivity / Reduction / Nucleophilic substitution / Substituent

effects

The synthesis of all eight rare but biologically important 6-

deoxy- -hexoses as their thioglycoside glycosyl donors start-

ing from the commercially available -rhamnose or -fucose

is reported. The synthesis of all eight 6-deoxy-

which revealed some general trends. The stereoselective re-

duction of 4-oxopyranosides could be predicted by the Cram

chelation model, while Mitsunobu conditions led to elimi-

L

-hexoses was nation in some substrates.

accomplished using a variety of epimerization methods,

saccharide (i.e., 3) containing only 6-deoxy-l-talose. This

bacterium is associated with e.g., periodontitis and endo-

Introduction

The rare but biologically important 6-deoxy-l-hexoses carditis.^[4]Zorbamycin (4) is a glycopeptide containing a 6-

play important roles in nature (Figure 1).^[1]For instance, deoxy-l-gulose unit, and belongs to the bleomycin family

the naturally occurring glycomacrolide Apoptolidin A (1) of antitumor antibiotics.^[5]The sulfated glycopeptidolipid

contains an l-quinovose (6-deoxy-l-glucose) unit, and this (i.e., 5) from the opportunistic bacterial pathogen Mycobac-

compound has been reported to induce apoptosis in several terium avium has also been reported to contain both a 6-

cancer cell lines.^[2]Likewise, the lipopolysaccharide (i.e., 2) deoxy-4-O-sulfonato-l-taloside and a 3,4-di-O-methyl-l-

from the Gram-negative pathogen Yersinia pseudotuberculo- rhamnoside.^[6]6-Deoxy-l-altrose has been found in various

sis contains l-quinovose, and has been identified as the lipopolysaccharides of bacterial pathogens of the genus Yer-

major virulent factor.^[3]The lipopolysaccharide of the sinia. For instance, Yersinia enterocolitica serovars O:1.2a,3

Gram-negative bacterium Actinobacillus actinomycetemco- and O:2a,2b,3 have a trisaccharide repeating unit (i.e., 6)

mitans serotype C is reported to consist of a repeating di- consisting only of 6-deoxy-l-altrose units.^[7]The tetracyclic

Figure 1. Examples of l-hexoses in natural products.

[a] Department of Chemistry, University of Copenhagen,

triterpene Datiscoside C (7) isolated from the plant Datisca

glomerata contains a 6-deoxy-l-alloside,^[8]and 6-deoxy-l-

idose occurs in the diterpene glycoside 8 isolated from Aster

spathulifolius Maxim.^[9]l-Rhamnose (6-deoxy-l-mannose)

Universitetsparken 5, 2100 Copenhagen Ø, Denmark

E-mail: cmp@chem.ku.dk

www.ki.ku.dk/forskning/bionanochem/bols-group/

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201403074.

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and l-fucose (6-deoxy-l-galactose) are common l-sugars Synthesis from Thio-

widely present in Nature. As an example, l-fucose is a com-

L-fucoside 9β

Following a known procedure, thio-fucopyranoside 9β

was protected as its butane 2,3-diacetal (BDA) in a reaction

catalyzed by camphorsulfonic acid (CSA) to give 6-deoxy-

l-galactopyranoside 12 in 70% yield (Scheme 2).^[16]Mitsu-

nobu inversion using diisopropyl azodicarboxylate (DIAD),

triphenylphoshine, and p-nitrobenzoic acid gave 13 in 70%

yield, and subsequent Zemplén deacylation gave 6-deoxy-l-

glucopyranoside 14 in 70% yield. The use of p-nitrobenzoic

acid was important to the inversion, since no reaction was

observed with benzoic acid.^[17]

For the synthesis of the 6-deoxy-l-gulopyranoside, a

three-component reaction developed by Miethchen and co-

workers was performed.^[18]Thio-fucopyranoside 9β was

treated with chloral and N,NЈ-dicyclohexylcarbodiimide

(DCC) in refluxing dichloroethane, which gave compound

15 as an inseparable 5.5:1 exo:endo mixture after column

chromatography in 88% yield (Scheme 2). The exo isomer

could be fractionally recrystallized from Et₂O/petroleum

ether as white needles in 50% yield. Subsequently, the carb-

amate of the exo isomer of 15 was removed with NaOMe

in refluxing ethanol to give 16 in 88% yield. The use of

ethanol as the solvent was important, since methanol gave

a slow reaction and incomplete conversion. Attempted re-

moval of the trichloroethylidene by various methods was

fruitless. Iridium-catalyzed reductive dehalogenation with

ponent of sialyl Lewis X. Furthermore, digitoxin shows an

enhanced antitumor activity when its carbohydrate moiety

is substituted with a single unit of l-rhamnose.^[10]

Due to the low natural abundance of the 6-deoxy-l-

sugars, various methods for their synthesis have been ex-

plored, either using common sugars as starting materials^[11]

or in de novo^[12]approaches. Although the 6-deoxy-l-sugars

are important biological motifs that are found in natural

products, a general approach to all eight 6-deoxy-l-hexoses

as their thioglycosyl donors is, according to the best of our

knowledge, lacking. It was therefore the purpose of this

work to develop such an approach that could be ac-

complished from cheap and commercially available starting

materials. Therefore, we chose the commercially available

building blocks l-fucose and l-rhamnose as a starting

point.^[13]Early installation of the anomeric thioacetal fol-

lowed by protecting-group manipulation and stereoselective

epimerization should give all eight 6-deoxy-l-hexoses as

their thioglycoside glycosyl donors, ready for oligosacchar-

ide and glycoconjugate synthesis.

Results and Discussion

Both l-fucose and l-rhamnose were converted into their various silanes^[19]or treatment with Zn/Ac₂O in triethyl-

respective thioglycosides 9 and 11 in three steps by peracet- amine with sonication^[20]gave complex mixtures. Tin-

ylation, thioglycosylation, and Zemplén deacetylation. In hydride-mediated dehalogenation initiated by 1,1Ј-azobis-

the case of l-fucose, the peracetylated compound was di- (cyclohexanecarbonitrile) (ABCN) produced an inseparable

rectly treated with thiophenol and BF₃·OEt₂, and then the mixture of partly dehalogenated and desulfurized com-

crude product was deacetylated to give the desired thio-β- pounds.^[21]

fucopyranoside (i.e., 9β) in 80% yield over three steps, to-

Due to these difficulties, we turned our attention to the

anomer (i.e., 9α) in 18% yield selective installation of a leaving group on 3-OH in l-fucose

gether with its

α

(Scheme 1).^[14]Likewise, peracetylated l-rhamnose was thi- derivative 9β. Heating nBu₂SnO with thio-fucopyranoside

oglycosylated to give an anomeric mixture of 10 (α/β 4:1) 9β in refluxing toluene gave the tin acetal, which was treated

in 97% yield over two steps. The α anomer could be frac- at room temperature with MsCl to give the 3-O-mesylated

tionally crystallized in 67% yield. The pure α anomer was derivative (Scheme 2).^[22]To avoid any epoxide formation

deacetylated to give compound 11 in quantitative yield during the following substitution, the intermediate was

(Scheme 1).^[15]

acetylated to give 17 in 76% yield over the two steps. Unfor-

Scheme 1. Synthesis of thio-l-fucoside 9 and thio-l-rhamnoside 11.

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Synthesis of 6-Deoxy-l-hexopyranosyl Donors

Scheme 2. Synthesis of 6-deoxy-l-galacto-, 6-deoxy-l-gluco-, and 6-deoxy-l-gulopyranosides from thio-fucopyranoside.

tunately, no reaction was observed using either KOAc/18- steps.^[11h]The acyl groups were removed (84%), and the 2,3-

crown-6 in DMF at 140 °C or under Lattrell–Dax condi- cis-OH’s were isopropylidenated (88%) to give the desired

tions (nitrite mediated).^[23]Attempted installation of the 6-deoxy-l-guloside (i.e., 23). A four-step sequence starting

more reactive triflate at 3-OH via the stannylene acetal was from 20 was carried out to give 23 in 76% yield with only

unsuccessful.

one purification. Afterwards, epimerization of the 4-OH

Instead, fucoside 9β was transformed into 2,4-di-O- group to give the 6-deoxy-l-alloside was explored. A Lat-

benzoylated derivative 20 by 3,4-O-orthoester formation, trell–Dax reaction^[23a,23b]on the triflate did not give the in-

benzoylation of the free 2-OH in 19, and orthoester opening tended product, but resulted in the elimination product (i.e.,

in 79% yield over three steps (Scheme 3).^[24]Subsequent 24) in 79% yield.^[25]This can be explained by an anti E2

triflation and inversion using CsOAc with 18-crown-6 gave elimination of the antiperiplanar 5-H_axial. Interestingly, this

acylated 6-deoxy-l-guloside 21 in 79% yield over two vinylic ether slowly degraded in the NMR tube to give a

Scheme 3. Synthesis of 6-deoxy-l-gulo- and 6-deoxy-l-allopyranosides from thio-fucopyranoside; DMAP = 4-(dimethylamino)pyridine.

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complex mixture. The same elimination product (i.e., 24) benzyl groups at the 2 and 3 positions was carried out as

described by Crich and Vinogradova^[30]by naphthylmethyl

etherification of the 4-position to give 28 in 98% yield, fol-

lowed by hydrolysis of the isopropylidene to give 29 in 95%

yield. Subsequently, benzylation (98% yield) and DDQ

(2,3-dichloro-5,6-dicyanobenzoquinone) mediated oxi-

dation of the naphthylmethyl group gave 2,3-di-O-benzyl-

ated 6-deoxy-l-mannopyranoside 31 in 94% yield via fully

protected donor 30.^[30]Epimerization of the 4-hydroxy

group in 27 was carried out by Swern oxidation to give

ketone 32 in 71% yield,^[31]followed by stereoselective re-

duction using NaBH₄to give the 6-deoxy-l-talopyranoside

(i.e., 33) in 89% yield.^[32]

was observed when the alcohol was subjected to Mitsunobu

conditions, again, presumably, being formed by E2 elimi-

nation of the antiperiplanar 5-H_axialand the oxyphosphon-

ium ion intermediate.^[26]Instead, a two-step inversion was

accomplished using a Swern oxidation with trifluoroacetic

anhydride (TFAA)^[27]as the electrophile to give an 83%

yield of ketone 25, followed by stereoselective reduction

with LiH(sBu)₃(l-selectride)^[28]to form the desired 6-de-

oxy-l-alloside (i.e., 26) in 90% yield.

Synthesis from Thio-L-rhamnoside 11

Protection of the 2-OH and 3-OH groups in thio-rham-

nopyranoside 11 by isopropylidination^[29]gave 6-deoxy-l-

The synthesis of the 6-deoxy-l-altropyranoside and the

manno donor 27 in 84% yield (Scheme 4). Installation of 6-deoxy-l-idopyranoside was inspired by work by Ramesh

Scheme 4. Synthesis of 6-deoxy-l-manno- and 6-deoxy-l-talopyranosides from thio-rhamnopyranoside; Nap = 2-naphthylmethyl.

Scheme 5. Synthesis of 6-deoxy-l-altro- and 6-deoxy-l-idopyranosides from thio-rhamnopyranoside; TBS = tert-butyldimethylsilyl.

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Synthesis of 6-Deoxy-l-hexopyranosyl Donors

and Franck.^[33]An acid-catalyzed orthoester protection of reochemistry easily underwent inversion to the trans diaxial

thio-rhamnopyranoside 11 made it possible to directly sil- and diequatorial systems (Scheme 6, a and b). In contrast,

ylate the free 4-OH group to give intermediate 34 the trans diaxial diol (Scheme 6, c) underwent elimination

(Scheme 5). After the reaction was complete, acetic acid was instead of inversion.^[26]Even though the cis diol in

added to the flask, and the orthoester opened to give com- Scheme 6 (b) has two diaxial protons, H-3 and H-5, no eli-

pound 35 in 90% yield over three steps with only one purifi- mination was observed. Taking this into consideration, the

cation necessary. Afterwards, a two-step procedure for the axial protecting group at O-3 in the system shown in

synthesis of compound 37 was investigated. Swern oxi- Scheme 6 (c) sterically hampers the substitution, leaving the

dation produced ketone 36 in 91% yield, which, upon re- elimination pathway as the only option.

duction at –78 °C with NaBH₄, gave a 12:1 mixture (at 0 °C

the mixture was 4:1) in favor of the desired axial epimer

(i.e., 37) in 79% yield. Previously, Brown and Krishnamur-

thy have reported that equatorial attack by l-selectride is

particularly favored in cyclohexanones with α substituents,

and this has also been found in carbohydrates.^[28]Consist-

ently with this, reduction with l-selectride of crude ketone

36 gave only axial epimer 38 (73% yield over two steps).

During the l-selectride reduction, the benzoyl group mi-

grated from 2-OH to 3-OH, presumably via the ⁴C₁confor-

mation. Debenzoylation of 38 proved more difficult than

anticipated. Zemplén deacylation gave a complex mixture

in which the silyl group had partly migrated. Instead, deac-

ylation was accomplished without any silyl migration by

treatment with EtMgBr to give diol 39 in 87% yield.^[34]The

diol in 39 could be benzylated, and subsequent acid-medi-

ated desilylation gave 6-deoxy-l-altropyranoside 40 in 58%

yield over two steps. Inversion of 4-OH was first attempted

by a two-step oxidation/reduction protocol in which the

alcohol was oxidized under Swern conditions to give 41 in

88% yield. Unfortunately, l-selectride reduction of 41 led

to the reformation of compound 40 in 60% yield, with none

Scheme 6. Observed trend in the Mitsunobu inversion; Pg = protec-

tive group, PNB = p-nitrobenzoyl.

of the desired epimer being observed. Instead, the epimeriz-

ation was accomplished with a Mitsunobu reaction to give

The most reliable epimerization method was oxidation

42 in 98% yield. Standard Zemplén deacylation gave 6-de- followed by stereoselective reduction. First of all, the selec-

oxy-l-idopyranoside 43 in 94% yield. Interestingly, the con- tivity could be greatly enhanced by changing to l-selectride

formation of the 6-deoxy-l-idopyranoside 43 was found to and conducting the reaction at low temperature.^[27,28]Sec-

1

be a perfect C₄based on the lack of proton coupling con- ondly, the stereoselectivity can be predicted^[37]based on

stants (only J_5,6= 6.3 Hz was observed), even though this Cram’s chelate model, and is dependent on the neighboring

conformation has four axial substituents. This underlines protecting group (Scheme 7; the arrow indicates the hydride

the great influence of the equatorial 6-methyl group on the attack as observed from the experiments).^[38]Here, the

conformational preference.^[35]

metal coordinates between the carbonyl and the α oxygen

to give a staggered conformation, and the hydride is deliv-

ered from the face with the least sterically demanding sub-

stituent, i.e., the proton H-3 (Scheme 7, a and b). Since our

systems contain a cyclic ketone, rotation between the carb-

Epimerizations

In the work described above, several epimerizations were onyl and the α carbon is hampered. Therefore, the Felkin–

carried out by any of four different methods: oxidation fol- Anh model is not valid as it requires a hydride attack from

lowed by stereoselective reduction, Mitsunobu reaction, nu- the sterically crowded C-2 which also leads to an unfavor-

cleophilic substitution of a leaving group, and chloral/ able 1,3-diaxial interaction between the incoming hydride

DCC-induced inversion.^[18]This last method appears highly and C-2 substituent, as seen in 32 and 25 (Scheme 7, a and

attractive since the epimerization takes place at the same b).^[39]In the case of compound 36 (Scheme 7, c), two pos-

time as the installation of orthogonal protecting groups. sible chelations to either O-2 or O-4 are feasible. Since only

Unfortunately, removal of the trichloroethylidene group one epimer is observed after the reduction, only the Cram’s

was not compatible with the anomeric thioacetal. Nucleo- chelate model for chelation to the O-4 is decisive. The two

philic substitution worked only occasionally, making this Cram’s chelate models to either O-4 or O-2 would give op-

method less attractive.^[36]Interestingly, some trends can be posite epimers. The observation of only one product can be

seen from the Mitsunobu inversion in our 6-deoxy sugar explained by an unfavorable 1,3-diaxial interaction between

system with a free 4-OH. The substrates with a 3,4-cis ste- the hydride and the anomeric thiophenyl group (Scheme 7,

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Scheme 7. Cram’s chelate model for explaining the stereoselective outcome of the reductions (the arrow indicates the hydride attack as

observed from the experiments).

c). Furthermore, chelation to O-4, which bears a silyl pro- amples, 4-oxo glycopyranosides having benzyl or p-meth-

tecting group, is more favorable than to benzoate-protected oxybenzyl (PMB) ethers at O-3 favored attack of the

O-2, since the negative charge is more localized on O-4 than hydride from the equatorial side (Scheme 8, a). On the other

on O-2.

hand, when benzoyl esters or methoxymethyl (MOM)

The finding that an OBz group did not exert any chela- ethers were used at O-3, a preference of axial hydride attack

tion control was somewhat surprising. Turning to the litera- was observed (Scheme 8, b). This may be due to a lack of

ture, several examples were found which confirmed this ten- chelating ability of the OBz and OMOM groups. Instead,

dency although no explanation was given.^[37a]In those ex- 1,3-diaxial interaction comes into play by directing the

6

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Synthesis of 6-Deoxy-l-hexopyranosyl Donors

Scheme 8. Explanations of literature results.

hydride to attack from the less hindered axial face

(Scheme 8, b).

Experimental Section

Phenyl 1-Thio-β-

L

-fucopyranoside (9β)^[14]and Phenyl 1-Thio-α-

suspension of l-fucose (8.00 g,

L-

Taking the above observation regarding epimerization

into account, guidelines for synthesis of cis or trans diols

can be devised. Since the protecting group of the α substitu-

ent influences the stereoselective reduction, both cis and

trans diols can be synthesized by using either chelating or

nonchelating protecting groups. Chelating protecting

groups, like benzyl and silyl ethers, would give the cis diol,

whereas nonchelating protecting groups, like benzoyl esters

and methoxymethyl ethers, would give the trans diol. Alter-

natively, the trans diol could also be synthesized by a Mitsu-

nobu reaction.

fucopyranoside (9α):^[14]

A

48.7 mmol) in pyridine (20 mL) was treated with Ac₂O (41 mL,

438.6 mmol, 9 equiv.), and the mixture was heated to 100 °C for

1 h. After this time, TLC (R_f= 0.50, heptane/EtOAc, 3:2) showed

that the starting material had been converted. The mixture was

cooled to room temp., concentrated, and coevaporated twice with

toluene.

The residue was dissolved in dry CH₂Cl₂(100 mL). Then thio-

phenol (6.0 mL, 58.46 mmol, 1.2 equiv.) was added, the solution

was cooled to 0 °C, and BF₃·OEt₂(7.4 mL, 58.5 mmol, 1.2 equiv.)

was added dropwise. The reaction mixture was stirred for 2 h at

0 °C, and then for 12 h at room temp. The mixture was diluted with

CH₂Cl₂(100 mL), and washed with HCl (1 m; 75 mL), satd. aq.

NaHCO₃(75 mL), and H₂O (75 mL), and then dried (MgSO₄).

The mixture was concentrated to give a residue (R_f= 0.53, heptane/

EtOAc, 3:2).

Conclusions

We have reported a highly attractive route to all eight

important 6-deoxy-l-hexoses. To the best of our knowledge,

this is the first general method for synthesizing all eight 6-

deoxy-l-hexoses as their thioglycoside glycopyranosyl do-

nors.^[40]The thioglycoside donors were all synthesized from

cheap^[13]and commercially available l-fucose and l-

rhamnose using protecting-group manipulation and highly

selective epimerizations. This approach produces thio do-

nors ready for glycosylation to access important natural

products. The syntheses relied on several stereoselective re-

ductions which could be explained by Cram’s chelate model

provided the neighboring protecting group did not contain

a benzoyl group. This led to some trends regarding the syn-

thesis of cis and trans diols by epimerization: 1) The synthe-

sis of cis diols can be achieved using stereoselective re-

duction of a ketone when the α substituent is chelating, e.g.,

a benzyl or silyl ether. The synthesis of trans diols can be

achieved either using 2) the Mitsunobu reaction; or 3)

stereoselective reduction without a chelating α substituent

next to the ketone. With access to all the 6-deoxy-l-hexoses,

the parent l-hexoses can easily be obtained by C–H acti-

vation.^[41,42]

The residue was dissolved in MeOH (100 mL), and the mixture was

made slightly basic with NaOMe (25 wt.-% in MeOH; 2 mL). After

the reaction was complete (3 h), the solution was neutralized with

Amberlite IR-120 (H⁺) resin, filtered, and concentrated. The crude

syrup was purified by flash column chromatography (heptane/

EtOAc, 2:3Ǟ1:2) to give β product 9β (8.77 g, 70%) as a foam,

and a 2:1 α/β mixture (3.62 g, 29%) as a syrup. A second column

separated the α from the β anomer. The pure β anomer (foam) was

dissolved in hot EtOH, and the solution was cooled down. Then,

heptane was added to the solution, which resulted in the crystalli-

zation of the β anomer as white needles. The α anomer could be

crystallized from hot EtOH/petroleum ether (2.28 g, 18%).

Data for β anomer 9β: White needles. R_f= 0.26 (heptane/EtOAc,

1:10). HRMS (MALDI⁺): calcd. for C₁₂H₁₆O₄SNa⁺279.0662;

found 279.0697, m.p. 93–94 °C, lit. m.p. 91–92 °C^[3]or m.p. 91–

93 °C.^{[4] 1}H NMR (500 MHz, CDCl₃): δ = 7.55 (dd, J = 7.5, J =

2.1 Hz, 2 H, Ph), 7.34–7.29 (m, 3 H, Ph), 4.50 (d, J_1,2= 9.4 Hz, 1

H, 1-H), 3.78 (dd, J = 2.7, J = 1.2 Hz, 1 H, 3-H or 4-H), 3.69 (dt,

J = 7.3, J = 6.0 Hz, 1 H, 5-H), 3.65–3.59 (m, 2 H, 2-H and 3-H or

4-H), 1.37 (d, J_5,6= 6.4 Hz, 3 H, 6-H) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ = 132.6 (C_Ph), 132.5 (C_{Ph ipso}), 129.2 (C_Ph), 128.2 (C_Ph),

88.7 (C-1), 75.2, 74.9 (C-5), 71.7, 70.1, 16.8 (C-6) ppm.

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Data for α anomer 9α: R_f= 0.41 (heptane/EtOAc, 1:10). HRMS

(MALDI⁺): calcd. for C₁₂H₁₆O₄SNa⁺279.0662; found 279.0663, N₂, and butane-2,3-dione (0.81 mL, 9.4 mmol, 1.2 equiv.) and tri-

m.p. 159–161 °C. [α]²_D²= –344 (c = 1.0, MeOH). ¹H NMR

methyl orthoformate (3.41 mL, 31.2 mmol, 4 equiv.) were added.

(500 MHz, CDCl₃): δ = 7.50 (m, 2 H, PhS_ortho), 7.34–7.28 (m, 3 H, Then, (Ϯ)-camphorsulfonic acid (91 mg, 0.39 mmol, 0.05 equiv.)

Ph), 5.61 (d, J_1,2= 5.4 Hz, 1 H, 1-H), 4.45 (qd, J_5,6= 6.6, J_4,5was added, and the reaction mixture was heated to reflux and

1.4 Hz, 1 H, 5-H), 4.15 (dd, J_2,3= 10.1, J_1,2= 5.4 Hz, 1 H, 2-H), stirred for 15 h. The mixture was neutralized with Et₃N, and con-

3.88 (dd, J_3,4= 3.4, J_4,5= 1.3 Hz, 1 H, 4-H), 3.67 (dd, J_2,3= 10.1, centrated in vacuo. The resulting syrup was purified by flash col-

2.00 g, 7.80 mmol) was dissolved in dry methanol (100 mL) under

=

J_3,4= 3.3 Hz, 1 H, 3-H), 1.35 (d, J_5,6= 6.6 Hz, 3 H, 6-H) ppm. umn chromatography (heptane/EtOAc, 8:1Ǟ4:1) to give com-

¹³C NMR (126 MHz, CDCl₃): δ = 134.3 (C_{PhS ipso}), 131.8 (C_Ph), pound 12 (2.01 g, 70%) as a solid. The solid could be recrystallized

129.3 (C_Ph), 127.8 (C_Ph), 91.3 (C-1), 72.4 (C-3), 71.6 (C-4), 69.3 (C- from hot EtOAc/heptane. R_f= 0.31 (heptane/EtOAc, 2:1). HRMS

2), 67.7 (C-5), 16.3 (C-6) ppm.

(ESI⁺): calcd. for C₁₈H₂₆O₆SNa⁺393.1342; found 393.1337. [α]²_D²

= +159 (c = 1.0, CHCl₃), lit.^[16a][α]²_D²= +119.1 (c = 0.23, CDCl₃).

¹H NMR (500 MHz, CDCl₃): δ = 7.55 (m, 2 H, Ph), 7.27–7.22 (m,

Phenyl 2,3,4-Tri-O-acetyl-1-thio-α-L A

-rhamnopyranoside (10):^[15]

suspension of l-rhamnose (6.00 g, 32.9 mmol) in pyridine (15 mL)

was treated with Ac₂O (25 mL, 264 mmol, 8 equiv.), and the mix-

ture was heated to 100 °C for 1 h. After this time, TLC (R_f= 0.40,

heptane/EtOAc, 3:2) showed that the starting material had been

converted. The mixture was cooled to room temp., concentrated,

and coevaporated twice with toluene.

3 H, Ph), 4.72 (d, J_1,2= 10.0 Hz, 1 H, 1-H), 4.01 (t, J_1,2= J_2,3

=

9.8 Hz, 1 H, 2-H), 3.78 (dd, J_2,3= 9.7, J_3,4= 3.0 Hz, 1 H, 3-H),

3.75 (dd, J_3,4= 3.0, J_4,5= 1.2 Hz, 1 H, 4-H), 3.70 (qd, J_5,6= 6.5,

J_4,5= 1.2 Hz, 1 H, 5-H), 3.26 (s, 3 H, CH₃O), 3.17 (s, 3 H, CH₃O),

1.36 (d, J_5,6= 6.5 Hz, 3 H, 6-H), 1.33 (s, 3 H, CH₃), 1.32 (s, 3 H,

CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 134.0 (C_{Ph ipso}),

131.8 (C_Ph), 128.9 (C_Ph), 127.3 (C_Ph), 100.5 (C_acetal), 100.5 (C_acetal),

85.5 (C-1), 75.3 (C-5), 72.3 (C-3), 70.4 (C-4), 65.3 (C-2), 48.2

(C_methoxy), 48.2 (C_methoxy), 17.9 (C_methyl), 17.8 (C_methyl), 16.8 (C-6)

ppm.

The residue was dissolved in dry CH₂Cl₂(60 mL). Then, thi-

ophenol (4.1 mL, 39.5 mmol, 1.2 equiv.) was added, the solution

was cooled to 0 °C, and BF₃·OEt₂(5.0 mL, 39.5 mmol, 1.2 equiv.)

was added dropwise. The reaction mixture was stirred for 2 h at

0 °C, and then for 10 h at room temp. The mixture was diluted

with CH₂Cl₂(60 mL), and washed with HCl (1 m; 30 mL), satd.

aq. NaHCO₃(60 mL), and brine (50 mL). Purification of the crude

product by flash column chromatography (petroleum ether/Et₂O,

3:1Ǟ3:2) gave the product (12.22 g, 97%) as a anomeric mixture

(α/β, 4:1) as a white solid. Fractional crystallization from petroleum

ether/Et₂O gave the desired α anomer 10 (8.39 g, 67%) as white

crystals. R_f= 0.41 (petroleum ether/Et₂O, 3:2). HRMS (ESI⁺):

calcd. for C₁₈H₂₂O₇SNa⁺405.0978; found 405.0981. The spectra

were consistent with literature data.^{[15] 1}H NMR (500 MHz,

CDCl₃): δ = 7.47 (m, 2 H, Ph), 7.33–7.28 (m, 3 H, Ph), 5.50 (dd,

J_2,3= 3.4, J_1,2= 1.7 Hz, 1 H, 2-H), 5.41 (d, J_1,2= 1.1 Hz, 1 H, 1-

Phenyl 4-O-(4-Nitrobenzoyl)-6-deoxy-2,3-O-(2Ј,3Ј-dimethoxy-2Ј,3Ј-

dimethylbutane)-1-thio-β-L-glucopyranoside (13): Phenyl 2,3-O-

(2Ј,3Ј-dimethoxy-2Ј,3Ј-dimethylbutane)-1-thio-β-l-fucopyranoside

(12; 518 mg, 1.40 mmol), Ph₃P (2.20 g, 8.39 mmol, 6 equiv.), and p-

nitrobenzoic acid (1.40 g, 8.39 mmol, 6 equiv.) were dissolved in

toluene (10 mL), and diisopropyl azodicarboxylate (DIAD;

1.65 mL, 8.39 mmol, 6 equiv.) was added dropwise. The mixture

was stirred at room temp. under nitrogen for 3 d. Then, additional

PPh₃(337 mg, 1.40 mmol, 1 equiv.), p-nitrobenzoic acid (234 mg,

1.4 mmol, 1 equiv.), and DIAD (0.28 mL, 1.40 mmol, 1 equiv.)

were added to push the reaction further. The mixture was stirred

for another day. Then the reaction was quenched with saturated

aq. NaHCO₃, and the mixture was extracted with CH₂Cl₂(3ϫ).

The combined organic extracts were washed with water, dried

(MgSO₄), and concentrated. The residue was purified by flash

chromatography (heptane/EtOAc, 20:1, then 15:1Ǟ10:1) to give

compound 13 (462 mg, 70%) as an amorphous solid. R_f= 0.58

(heptane/EtOAc, 2:1). HRMS (ESI⁺): calcd. for C₂₅H₂₉O₉NSNa⁺

542.1455; found 542.1465. [α]²_D²= +130 (c = 1.0, CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 8.30 (m, 2 H, Ph), 8.20 (m, 2 H, Ph), 7.54

(m, 2 H, Ph), 7.30 (m, 3 H, Ph), 5.14 (t, J_3,4= J_4,5= 9.6 Hz, 1 H,

4-H), 4.81 (d, J_1,2= 10.0 Hz, 1 H, 1-H), 4.01 (t, J_2,3= J_3,4= 9.7 Hz,

H), 5.29 (dd, J_3,4= 10.1, J_2,3= 3.3 Hz, 1 H, 3-H), 5.14 (t, J_4,5

=

9.9 Hz, 1 H, 4-H), 4.36 (dqd, J_4,5= 9.8, J_5,6= 6.2, J = 0.7 Hz, 1

H, 5-H), 2.14 (s, 3 H, CH₃CO), 2.08 (s, 3 H, CH₃CO), 2.01 (s, 3

H, CH₃CO), 1.25 (d, J_5,6= 6.2 Hz, 3 H, 6-H) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ = 170.01 (C=O), 169.99 (C=O), 169.9 (C=O),

133.3 (C_{Ph ipso}), 131.8 (C_Ph), 129.2 (C_Ph), 127.9 (C_Ph), 85.7 (C-1),

71.3 (C-2), 71.2 (C-4), 69.4 (C-3), 67.8 (C-5), 20.9 (C_Methyl), 20.8

(C_Methyl), 20.7 (C_Methyl), 17.4 (C-6) ppm.

Phenyl 1-Thio-α-L

-rhamnopyranoside (11):^[15]Phenyl 2,3,4-tri-O-

acetyl-1-thio-α-l-rhamnopyranoside (10; 8.33 g, 21.8 mmol) was

dissolved in MeOH (50 mL), and the solution was made slightly

basic with NaOMe (25 wt.-% in MeOH; 0.05 mL). After the reac-

tion was complete (3 h), the solution was neutralized with Am-

berlite IR-120 (H⁺) resin, filtered, and concentrated. The crude

syrup was purified by flash column chromatography (heptane/

EtOAc, 1:1Ǟ1:6) to give compound 11 (5.53 g, 99%) as a white

solid. R_f= 0.24 (heptane/EtOAc, 1:10), m.p. 99–100 °C. HRMS

(ESI⁺): calcd. for C₁₂H₁₆O₄SNa⁺279.0662; found 279.0668. ¹H

NMR (500 MHz, CDCl₃): δ = 7.41 (m, 2 H, Ph), 7.26–7.20 (m, 3

H, Ph), 5.49 (d, J_1,2= 1.3 Hz, 1 H, 1-H), 4.24 (dd, J_2,3= 3.3, J_1,2

= 1.5 Hz, 1 H, 2-H), 4.16 (dd, J_4,5= 9.5, J_5,6= 6.2 Hz, 1 H, 5-H),

3.92 (br. s, 1 H, 4-OH), 3.82 (dd, J_3,4= 9.4, J_2,3= 3.3 Hz, 1 H, 3-

H), 3.58 (t, J_3,4= J_4,5= 9.4 Hz, 1 H, 4-H), 1.33 (d, J_5,6= 6.2 Hz,

3 H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 134.1 (C_{SPh ipso}),

131.5 (C_Ph), 129.21 (C_Ph), 127.6 (C_Ph), 88.0 (C-1), 73.5 (C-4), 72.7

(C-2), 72.4 (C-3), 69.5 (C-5), 17.6 (C-6) ppm.

1 H, 3-H), 3.79 (t, J_1,2= J_2,3= 9.7 Hz, 1 H, 2-H), 3.69 (dq, J_4,5

=

9.4, J_5,6= 6.2 Hz, 1 H), 3.20 (s, 3 H, CH₃O), 3.16 (s, 3 H, CH₃O),

1.33 (s, 3 H, CH₃), 1.31 (d, J_5,6= 6.2 Hz, 3 H, 6-H), 1.22 (s, 3 H,

CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 163.5 (C=O), 150.9

(C_{Bz ipso}), 135.2 (C_{Bz ipso}), 133.3 (C_{SPh ipso}), 132.1 (C_Ph), 130.9 (C_Ph),

129.0 (C_Ph), 127.7 (C_Ph), 123.8 (C_Ph), 100.4 (C_ketal), 99.9 (C_ketal),

85.3 (C-1), 75.1 (C-5), 73.9 (C-4), 72.1 (C-3), 68.5 (C-2), 48.3

(C_methoxy), 47.8 (C_methoxy), 18.1 (C-6), 17.7 (C_methyl), 17.7 (C_methyl

ppm.

)

Phenyl

thio-β-

6-Deoxy-2,3-O-(2Ј,3Ј-dimethoxy-2Ј,3Ј-dimethylbutane)-1-

-glucopyranoside (14): Phenyl 4-O-(4-nitrobenzoyl)-6-de-

L

oxy-2,3-O-(2Ј,3Ј-dimethoxy-2Ј,3Ј-dimethylbutane)-1-thio-β-l-gluc-

opyranoside (13; 429 mg, 0.90 mmol) was dissolved in MeOH

(10 mL) under nitrogen, and NaOMe (25 wt.-% in MeOH; 0.1 mL)

was added. The reaction mixture was stirred for 1 h, and then it

was quenched with Amberlite IR-120, filtered, and concentrated.

The residue was purified by dry column chromatography (heptane/

EtOAc, 8:1Ǟ4:1) to give compound 14 in (273 mg, 81%).

Phenyl

2,3-O-(2Ј,3Ј-Dimethoxy-2Ј,3Ј-dimethylbutane)-1-thio-β-L-

fucopyranoside (12):^[16a]Phenyl 1-thio-β-l-fucopyranoside (9β;

8

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Synthesis of 6-Deoxy-l-hexopyranosyl Donors

R_f

1

=

0.37 (heptane/EtOAc, 2:1). HRMS (ESI⁺): calcd. for

406.9649; found 406.9643. [α]²_D²= +75 (c = 1.0, CHCl₃). H NMR

C₁₈H₂₆O₆SNa⁺393.1342; found 393.1342. The spectra were consis-

tent with literature data.^{[16a] 1}H NMR (500 MHz, CDCl₃): δ = 7.53

(m, 2 H, Ph), 7.30–7.23 (m, 3 H, Ph), 4.77 (d, J_1,2= 9.7 Hz, 1 H,

(500 MHz, CDCl₃): δ = 7.56 (m, 2 H, Ph), 7.40–7.31 (m, 3 H, Ph),

5.49 (s, 1 H, H_{2,2,2-trichloroethylidene}), 4.80 (dd, J_2,3= 5.2, J_3,4

2.6 Hz, 1 H, 3-H), 4.65 (d, J_1,2= 9.2 Hz, 1 H, 1-H), 4.45 (dd, J_1,2

=

1-H), 3.70 (m, 1 H, 3-H), 3.62 (t, J_1,2= 9.7 Hz, 1 H, 2-H), 3.48– = 9.1, J_2,3= 5.1 Hz, 1 H, 2-H), 3.95 (td, J_5,6= 6.5, J_4,5= 1.3 Hz,

3.40 (m, 2 H, 4-H, 5-H), 3.29 (s, 3 H, CH₃O), 3.20 (s, 3 H, CH₃O), 1 H, 5-H), 3.90 (d, J_3,4= 2.9 Hz, 1 H, 4-H), 1.95 (br. s, 1 H, 4-

1.38 (d, J_5,6= 5.6 Hz, 3 H, 6-H), 1.34 (s, 3 H, CH₃), 1.34 (s, 3 H,

OH), 1.35 (d, J_5,6= 6.5 Hz, 3 H, 6-H) ppm. ¹³C NMR (126 MHz,

CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 133.7 (C_{SPh ipso}), CDCl₃): δ = 132.8 (C_{SPh ipso}), 132.4 (C_SPh), 129.2 (C_SPh), 128.3

131.8 (C_SPh), 128.9 (C_SPh), 127.5 (C_SPh), 100.2 (C_ketal), 99.8 (C_ketal), (C_SPh), 107.0 (C_{2,2,2-trichloroethylidene}), 99.2 (CCl₃), 85.0 (C-1), 78.8

85.1 (C-1), 76.6 (C-4 or C-5), 74.5 (C-3), 72.8 (C-4 or C-5), 68.2 (C-

2), 48.3 (C_methoxy), 48.1 (C_methoxy), 18.0 (C-6), 17.8 (C_methyl), 17.8

(C_methyl) ppm.

(C-3), 74.9 (C-2), 72.7 (C-5), 68.3 (C-4), 16.1 (C-6) ppm.

Phenyl 2,4-Di-O-acetyl-3-O-methylsulfonyl-1-thio-β- -fucopyranos-

L

ide (17): Phenyl 1-thio-β-l-fucopyranoside (9β; 0.30 g, 1.17 mmol)

was dissolved in toluene (20 mL), and nBu₂SnO (0.32 g, 1.29 mmol,

1.1 equiv.) was added. The flask was equipped with a Dean–Stark

apparatus, and the mixture was heated at reflux for 4 h under nitro-

gen. Subsequently, the mixture was cooled to room temp., and

MsCl (0.45 mL, 5.85 mmol, 5 equiv.) was added. The mixture was

stirred under nitrogen at room temp. for 18 h (R_f= 0.61, heptane/

EtOAc, 1:2). Then, the mixture was concentrated and passed

through a short column of silica gel (petroleum ether/EtOAc, 2:1).

Phenyl

chloroethylidene)-1-thio-β-

4-O-Cyclohexylcarbamoyl-6-deoxy-(R)-2,3-O-(2,2,2-tri-

-gulopyranoside (15): Phenyl 1-thio-β-l-

L

fucopyranoside (9β; 1.50 g, 5.85 mmol) was suspended in dry 1,2-

dichloroethane (15 mL), and chloral (2.00 mL, 20.5 mmol,

3.5 equiv.) and DCC (2.84 g, 14.6 mmol, 2.5 equiv.) were sequen-

tially added. Then, the mixture was heated at reflux with stirring

for 4 h until TLC (heptane/EtOAc, 4:1) showed that the reaction

was complete. The sugar dissolved gradually during this time. The

mixture was allowed to cool to room temp., then AcOH (10% aq.;

15 mL) was added, and the mixture was stirred for an additional

40 min to destroy the excess DCC. The precipitated N,NЈ-dicyclo-

hexylurea was removed by filtration, the organic phase was sepa-

rated, and the aqueous phase was extracted with CH₂Cl₂(3ϫ). The

combined organic extracts were washed with satd. aq. NaHCO₃,

and brine, dried (MgSO₄), and concentrated in vacuo. The residue

was purified by dry column chromatography (heptane with an in-

crement of 1.25% EtOAc) to give a mixture of the exo-H/endo-H

diastereomers (5.5:1) of compound 15 (2.63 g, 88%) as a white

powder. Fractional recrystallization from Et₂O/petroleum ether

gave the pure exo-H isomer (1.50 g, 50%) as white needles. Both

diastereomers: R_f= 0.47 (heptane/EtOAc, 4:1). exo-H: HRMS

(ESI⁺): calcd. for C₂₁H₂₆O₅NSCl₃Na⁺532.0489; found 532.0475.

[α]²_D²= +74 (c = 1.0, CHCl₃), m.p. 160–161 °C. ¹H NMR

(500 MHz, CDCl₃): δ = 7.56 (m, 2 H, Ph), 7.37–7.28 (m, 3 H, Ph),

5.48 (s, 1 H, H_{2,2,2-trichloroethylidene}), 5.13 (d, J_3,4= 2.2 Hz, 1 H, 4-

The resulting phenyl 3-O-methylsulfonyl-1-thio-β-l-fucopyranoside

was dissolved in CH₂Cl₂(5 mL), and then Ac₂O (2.2 mL,

23.41 mmol, 20 equiv.) and pyridine (1.9 mL, 23.1 mmol, 20 equiv.)

were added. The mixture was stirred under nitrogen for 18 h. Sub-

sequently, the mixture was concentrated, and the residue was puri-

fied by flash column chromatography (petroleum ether/EtOAc, 3:1)

to give compound 17 (296 mg, 76% over two steps) as a colorless

syrup. R_f= 0.53 (heptane/EtOAc, 1:1). HRMS (MALDI⁺): calcd.

for C₁₇H₂₂O₈S₂Na⁺441.0648; found 441.0651. [α]²_D²= –2 (c = 1.0,

1

CHCl₃). H NMR (500 MHz, CDCl₃): δ = 7.51 (m, 2 H, PhS_ortho),

7.34–7.28 (m, 3 H, PhS), 5.35 (dd, J_3,4= 3.6, J_4,5= 1.1 Hz, 1 H,

4-H), 5.20 (t, J_1,2= J_2,3= 9.8 Hz, 1 H, 2-H), 4.87 (dd, J_2,3= 9.7,

J_3,4= 3.5 Hz, 1 H, 3-H), 4.69 (d, J_1,2= 9.9 Hz, 1 H, 1-H), 3.80

(qd, J_5,6= 6.3, J_4,5= 1.0 Hz, 1 H, 5-H), 2.99 (s, 3 H, OSO₂CH₃),

2.15 (s, 3 H, CH₃CO), 2.13 (s, 3 H, CH₃CO), 1.24 (d, J_5,6= 6.5 Hz,

3 H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 170.6 (C=O),

169.6 (C=O), 132.8 (Ph), 132.5 (Ph_ipso), 129.0 (Ph), 128.3 (Ph), 86.3

(C-1), 77.9 (C-3), 73.2 (C-5), 70.9 (C-4), 67.2 (C-2), 39.1

(OSO₂CH₃), 21.0 (CH₃CO), 20.8 (CH₃CO), 16.5 (C-6) ppm.

H), 4.76 (d, J = 8.3 Hz, 1 H, NH), 4.69 (dd, J_2,3= 5.1, J_3,4

=

2.5 Hz, 1 H, 3-H), 4.63 (d, J_1,2= 9.5 Hz, 1 H, 1-H), 4.42 (dd, J_1,2

= 9.5, J_2,3= 5.0 Hz, 1 H, 2-H), 3.93 (qd, J_5,6= 6.6, J_4,5= 1.6 Hz,

1 H, 5-H), 3.48 (m, 1 H, CH-NH), 1.94 (dq, J = 12.6, J = 4.1 Hz,

2 H, H_cyclohexyl), 1.71 (dq, J = 12.9, J = 4.2 Hz, 2 H, H_cyclohexyl),

1.61 (dt, J = 13.0, J = 4.0 Hz, 1 H, H_cyclohexyl), 1.55 (s, 1 H,

H_cyclohexyl), 1.36 (m, 1 H, H_cyclohexyl), 1.27 (d, J_5,6= 6.5 Hz, 3 H,

6-H), 1.22–1.08 (m, 3 H, H_cyclohexyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ = 154.4 (C=O), 133.6 (C_{SPh ipso}), 131.9 (C_Ph), 129.14

(C_Ph), 128.0 (C_Ph), 106.6 (C_{2,2,2-trichloroethylidene}), 99.0 (CCl₃), 84.8

(C-1), 76.9 (C-3), 75.1 (C-2), 71.9 (C_{cyclohexyl tert.}), 68.5 (C-4), 50.3

(C_{cyclohexyl sec.}), 33.4 (C_{cyclohexyl sec.}), 25.6 (C_{cyclohexyl sec.}), 24.8

(C_{cyclohexyl sec.}), 16.0 (C-6) ppm.

Phenyl 2,4-Di-O-benzoyl-1-thio-β-L-fucopyranoside (20): Phenyl 1-

thio-β-l-fucopyranoside (9β; 1.41 g, 3.04 mmol) and triethyl ortho-

benzoate [PhC(OEt)₃; 1.21 mL, 5.33 mmol, 1.5 equiv.] were dis-

solved in CH₂Cl₂(25 mL), camphorsulfonic acid (CSA; 50 mg,

0.22 mmol, 0.05 equiv.) was added, and the mixture was stirred at

room temp. for 45 min under nitrogen (TLC of exo & endo: R_f=

0.40 & 0.45, petroleum ether/EtOAc, 2:1). Then, the reaction mix-

ture was neutralized with dry Et₃N. Subsequently, the mixture was

cooled to 0 °C, and benzoyl chloride (BzCl; 1.24 mL, 10.7 mmol,

3 equiv.), dry Et₃N (5.0 mL, 35.5 mmol, 10 equiv.), and 4-(dimeth-

ylamino)pyridine (DMAP; 43 mg, 0.36 mmol, 0.1 equiv.) were

Phenyl

6-Deoxy-(R)-2,3-O-(2,2,2-trichloroethylidene)-1-thio-β-L-

gulopyranoside (16): A solution of exo-H phenyl 4-O-cyclohexylcar- added sequentially. The mixture was stirred under nitrogen for 25 h

bamoyl-6-deoxy-(R)-2,3-O-(2,2,2-trichloroethylidene)-1-thio-β-l-gu- at room temp. (TLC of exo & endo: R_f= 0.55 & 0.68, petroleum

lopyranoside (15; 0.87 g, 1.71 mmol) in absolute EtOH (30 mL)

was heated to reflux, and NaOMe (25 wt.-% in MeOH; 0.4 mL)

was added. The reaction mixture was stirred for 5 h, then another

ether/EtOAc, 2:1). Then, the mixture was treated with satd. aq.

NaHCO₃, and extracted with CH₂Cl₂(3ϫ). The combined organic

extracts were washed with brine, dried (MgSO₄), and concentrated

portion of NaOMe was added (25 wt.-% in MeOH; 0.2 mL). The to 50 mL. Subsequently, AcOH (90% aq.; 10 mL) was added, and

reaction mixture was stirred for a further 2 h, then the reaction was

quenched with Amberlite IR-120 resin. The mixture was filtered,

and the filtrate was concentrated. The residue was purified by flash

column chromatography (heptane/EtOAc, 12:1Ǟ8:1) to give com-

pound 16 (0.53 g, 81%) as crystals. R_f= 0.41 (heptane/EtOAc, 3:1),

m.p. 115–117 °C. HRMS (ESI⁺): calcd. for C₁₄H₁₅O₄SCl₃Na⁺

the mixture was stirred for 18 h. The reaction was quenched with

satd. aq. NaHCO₃, and the mixture was extracted with CH₂Cl₂

(3ϫ). The combined organic extracts were washed with brine, dried

(MgSO₄), and concentrated. The residue was purified by flash col-

umn chromatography (petroleum ether/EtOAc, 6:1Ǟ3:1) to give

compound 20 (1.41 g, 85% over three steps) as a solid. R_f= 0.27

Eur. J. Org. Chem. 0000, 0–0

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T. G. Frihed, C. M. Pedersen, M. Bols

FULL PAPER

(petroleum ether/EtOAc, 3:1). HRMS (MALDI⁺): calcd. for

(d, J_4,OH= 6.3 Hz, 1 H, 4-OH), 1.15 (d, J_5,6= 6.6 Hz, 3 H, 6-H)

ppm. ¹³C NMR (126 MHz, CD₃CN): δ = 135.7 (PhS_ipso), 131.4

C₂₆H₂₄O₆SNa⁺487.1184; found 487.1186. [α]²_D²= –14 (c = 1.0,

1

CHCl₃), m.p. 106–110 °C. H NMR (500 MHz, CDCl₃): δ = 8.09 (C_Ph), 129.9 (C_Ph), 127.7 (C_Ph), 86.2 (C-1), 72.8 (C-4), 72.3 (C-3),

(m, 2 H, Ph), 7.94 (m, 2 H, Ph), 7.61 (m, 2 H, Ph), 7.56 (m, 2 H,

Ph), 7.50–7.44 (m, 4 H, Ph), 7.40 (m, 1 H, Ph), 7.34 (m, 2 H, Ph),

72.2 (C-5), 67.4 (C-2), 16.5 (C-6) ppm.

Phenyl 6-Deoxy-2,3-O-isopropylidene-1-thio-β-L-gulopyranoside (23)

5.51 (dd, J_3,4= 3.5, J_4,5= 1.0 Hz, 1 H, 4-H), 5.19 (t, J_1,2= J_2,3

=

Method A: Camphorsulfonic acid (CSA; 15 mg, 0.06 mmol,

0.05 equiv.) was added to a solution of phenyl 6-deoxy-1-thio-β-l-

gulopyranoside (22; 323 mg, 1.26 mmol) and 2,2-dimethoxyprop-

ane (0.77 mL, 6.30 mmol, 5 equiv.) in dry acetone (6 mL). The mix-

ture was stirred at room temp. for 1.5 h under nitrogen, then the

reaction was quenched with Et₃N, and the solution was concen-

trated. The residue was purified by flash column chromatography

(petroleum ether/EtOAc, 6:1Ǟ3:1) to give compound 23 in

(330 mg, 88%) as a white solid. R_f= 0.42 (petroleum ether/EtOAc,

2:1). HRMS (MALDI⁺): calcd. for C₁₅H₂₀O₄SNa⁺319.0975;

found 319.0975. [α]²_D²= +106 (c = 1.0, CHCl₃), m.p. 113–114 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.55 (m, 2 H, Ph), 7.31 (m, 3 H,

9.7 Hz, 1 H, 2-H), 4.87 (d, J_1,2= 9.7 Hz, 1 H, 1-H), 4.10 (dd, J_2,3

= 9.6, J_3,4= 3.5 Hz, 1 H, 3-H), 3.97 (qd, J_5,6= 6.4, J_4,5= 1.1 Hz,

1 H, 5-H), 2.72 (br. s, 1 H, 3-OH), 1.32 (d, J_5,6= 6.4 Hz, 3 H, 6-

H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 167.0 (C=O), 166.5

(C=O), 134.4 (C_Ph), 133.7 (C_Ph), 133.6 (C_Ph), 131.1 (C_Ph), 130.3

(C_Ph), 130.2 (C_Ph), 129.6 (C_Ph), 129.3 (C_Ph), 129.0 (C_Ph), 128.7

(C_Ph), 128.6 (C_Ph), 128.5 (C_Ph), 84.9 (C-1), 74.0 (C-5), 73.7 (C-3),

73.4 (C-2), 71.7 (C-4), 17.0 (C-6) ppm.

Phenyl 3-O-Acetyl-2,4-di-O-benzoyl-6-deoxy-1-thio-β-L-gulopyra-

noside (21): Phenyl 2,4-di-O-benzoyl-1-thio-β-l-fucopyranoside

(20; 146 mg, 0.31 mmol) was dissolved in pyridine (1 mL), and the

solution was cooled to 0 °C. Triflic anhydride (0.22 mL, 0.63 mmol,

2 equiv.) was added. The reaction mixture was stirred at 0 °C under

nitrogen for 1 h (R_f= 0.51, petroleum ether/EtOAc, 3:1). Then, the

reaction was quenched by the addition of methanol, and the mix-

ture was concentrated. The residue was dissolved in CH₂Cl₂, and

water was added (green solution). The aqueous phase was extracted

with CH₂Cl₂(3ϫ), and the combined organic extracts were washed

with HCl (1 m), satd. aq. NaHCO₃, and brine, dried, and concen-

trated.

Ph), 4.67 (d, J_1,2= 9.2 Hz, 1 H, 1-H), 4.37 (dd, J_2,3= 5.2, J_3,4

=

2.6 Hz, 1 H, 3-H), 4.03 (dd, J_1,2= 9.2, J_2,3= 5.2 Hz, 1 H, 2-H),

3.96 (td, J_5,6= 6.6, J_4,5= 1.3 Hz, 1 H, 5-H), 3.79 (dd, J_3,4= 2.6,

J_4,5= 1.3 Hz, 1 H, 4-H), 1.82 (br. s, 1 H, 4-OH), 1.51 (s, 3 H,

CH₃C), 1.39 (s, 3 H, CH₃C), 1.33 (d, J_5,6= 6.6 Hz, 3 H, 6-H) ppm.

¹³C NMR (126 MHz, CDCl₃): δ = 133.6 (C_{PhS ipso}), 132.1 (C_Ph),

129.1 (C_Ph), 127.9 (C_Ph), 110.3 (C_{isopropylidene ketal}), 87.6 (C-1), 77.0

(C-3), 72.9 (C-5), 72.5 (C-2), 68.8 (C-4), 28.4 (C_{Methyl isopropylidene}),

26.1 (C_{Methyl isopropylidene}), 16.2 (C-6) ppm.

Method B: Four-step sequence starting from phenyl 2,4-di-O-

The crude product was dissolved in MeCN (2 mL), and CsOAc

(241 mg, 1.26 mmol, 4 equiv.) and 18-crown-6 (332 mg, 1.26 mmol,

4 equiv.) were added. The mixture was stirred at room temp. for

18 h under nitrogen, and then it was concentrated. The residue was

purified by flash column chromatography (petroleum ether/EtOAc,

6:1Ǟ3:1) to give compound 21 (126 mg, 79%) as a syrup. R_f=

0.38 (petroleum ether/EtOAc, 3:1). HRMS (MALDI⁺): calcd. for

C₂₈H₂₆O₇SNa⁺529.1291; found 529.1288. [α]²_D²= –53 (c = 1.0,

CHCl₃). ¹H NMR (500 MHz, CD₃CN): δ = 7.95 (m, 4 H, Ph), 7.77

(m, 2 H, Ph), 7.59–7.49 (m, 6 H, Ph), 7.42–7.33 (m, 3 H, Ph), 5.53

(t, J_2,3= J_3,4= 3.6 Hz, 1 H, 3-H), 5.35 (d, J_1,2= 10.3 Hz, 1 H, 1-

benzoyl-1-thio-β-l-fucopyranoside

(20).

Triflic

anhydride

(0.46 mL, 2.74 mmol, 2 equiv.) was added to a cold (0 °C) solution

of phenyl 2,4-di-O-benzoyl-1-thio-β-l-fucopyranoside (20; 636 mg,

1.37 mmol) in pyridine (6 mL). The reaction mixture was stirred at

0 °C under nitrogen for 1 h (TLC: R_f= 0.51, petroleum ether/

EtOAc, 3:1). Then, the reaction was quenched by the addition of

methanol, and the mixture was concentrated. The residue was dis-

solved in CH₂Cl₂, and water was added (green solution). The aque-

ous phase was extracted with CH₂Cl₂(3ϫ), and the combined or-

ganic extracts were washed with HCl (1 m), satd. aq. NaHCO₃, and

brine, dried, and concentrated.

H), 5.12 (dd, J_3,4= 3.8, J_4,5= 1.4 Hz, 1 H, 4-H), 5.07 (dd, J_1,2

=

The residue was dissolved in MeCN (10 mL), and CsOAc (1.06 g,

5.50 mmol, 4 equiv.) and 18-crown-6 (1.45 mg, 5.50 mmol, 4 equiv.)

were added. The mixture was stirred at room temp. for 18 h under

nitrogen (TLC: R_f= 0.38, petroleum ether/EtOAc, 3:1), and then

water was added. The aqueous phase was extracted with CH₂Cl₂

(3ϫ). The combined organic extracts were washed with brine, dried

(MgSO₄), and concentrated.

10.3, J_2,3= 3.3 Hz, 1 H, 2-H), 4.40 (qd, J_5,6= 6.4, J_4,5= 1.4 Hz, 1

H, 5-H), 2.11 (s, 3 H, CH₃CO), 1.25 (d, J_5,6= 6.4 Hz, 3 H, 6-H)

ppm. ¹³C NMR (126 MHz, CD₃CN): δ = 170.4 (CH₃CO), 166.0

(PhCO), 165.6 (PhCO), 134.7 (C_Ph), 134.7 (C_Ph), 134.6 (C_Ph), 131.7

(C_Ph), 130.5 (C_Ph), 130.4 (C_Ph), 130.4 (C_Ph), 130.2 (C_Ph), 129.9

(C_Ph), 129.8 (C_Ph), 129.7 (C_Ph), 129.4 (C_Ph), 82.2 (C-1), 72.3 (C-5),

72.0 (C-4), 68.1 (C-3), 67.9 (C-2), 21.0 (CH₃CO), 16.6 (C-6) ppm.

The residue was dissolved in MeOH (10 mL), NaOMe (25 wt.-%

in MeOH; 0.1 mL) was added, and the reaction mixture was stirred

at room temp. overnight under nitrogen (TLC: R_f= 0.36, petroleum

ether/EtOAc, 1:9). The reaction was quenched with Amberlite IR-

120 resin, the mixture was filtered, and the filtrate was concen-

trated.

Phenyl 6-Deoxy-1-thio-β-L-gulopyranoside (22): Phenyl 3-O-acetyl-

2,4-di-O-benzoyl-6-deoxy-1-thio-β-l-gulopyranoside (21; 0.82 g,

1.62 mmol) was dissolved in MeOH (20 mL), NaOMe (25 wt.-% in

MeOH; 0.1 mL) was added, and the reaction mixture was stirred

at room temp. for 18 h under nitrogen. The reaction was quenched

with Amberlite IR-120 resin, the mixture was filtered, and the fil-

trate was concentrated. The residue was purified by flash column

chromatography (petroleum ether/EtOAc, 1:1Ǟ1:6) to give com-

pound 22 (348 mg, 84%) as a white solid. R_f= 0.36 (petroleum

ether/EtOAc, 1:9). HRMS (MALDI⁺): calcd. for C₁₂H₁₆O₄SNa⁺

279.0662; found 279.0670. [α]²_D²= +106 (c = 1.0, MeOH), m.p. 134–

135 °C. ¹H NMR (500 MHz, CD₃CN): δ = 7.51–7.46 (m, 2 H, Ph),

7.34–7.24 (m, 3 H, Ph), 4.90 (d, J_1,2= 9.9 Hz, 1 H, 1-H), 3.97 (qd,

J_5,6= 6.6, J_4,5= 1.4 Hz, 1 H, 5-H), 3.90 (t, J_2,3= J_3,4= 3.6 Hz, 1

H, 3-H), 3.61 (ddd, J_1,2= 9.9, J_2,OH= 5.5, J_2,3= 3.1 Hz, 1 H, 2-

The residue was dissolved in dry acetone (10 mL), and 2,2-dimeth-

oxypropane (0.84 mL, 6.85 mmol, 5 equiv.) and enough cam-

phorsulfonic acid (CSA; 32 mg, 0.14 mmol, 0.1 equiv.) to make the

solution acidic were added. The mixture was stirred at room temp.

for 2 h under nitrogen, then the reaction was quenched with Et₃N,

and the solution was concentrated. The residue was purified by

flash column chromatography (petroleum ether/EtOAc, 6:1Ǟ3:1)

to give compound 23 (309 mg, 76% over four steps) as a white

solid. R_f= 0.42 (petroleum ether/EtOAc, 2:1). Data as above.

H), 3.50 (ddd, J_4,OH= 6.2, J_3,4= 3.7, J_4,5= 1.4 Hz, 1 H, 4-H), 3.38 Phenyl 4,6-Dideoxy-2,3-O-isopropylidene-1-thio-β-

D-erythro-hex-4-

(br. s, 1 H, 3-OH), 3.33–3.25 (d, J_2,OH= 5.5 Hz, 1 H, 2-OH), 3.06 enopyranoside (24): Tf₂O (0.24 mL, 1.42 mmol, 2 equiv.) was added

10

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Synthesis of 6-Deoxy-l-hexopyranosyl Donors

dropwise to a cold (0 °C) solution of phenyl 6-deoxy-2,3-O-iso-

propylidene-1-thio-β-l-gulopyranoside (23; 210 mg, 0.71 mmol) in

pyridine (2 mL). The mixture was stirred at 0 °C for 1 h under ni-

trogen. Then, the reaction was quenched with MeOH, and the mix-

ture was concentrated. The residue was dissolved in CH₂Cl₂, and

water was added. The aqueous phase was extracted with CH₂Cl₂

(3ϫ). The combined organic phases were washed with HCl (1 m),

satd. aq. NaHCO₃, and brine, dried (MgSO₄), and concentrated.

was added to a solution of phenyl 6-deoxy-2,3-O-isopropylidene-

1-thio-β-l-ribo-hexopyranosid-4-ulose (25; 180 mg, 0.61 mmol) in

THF (5 mL) at –78 °C under nitrogen. The reaction mixture was

stirred at –78 °C for 1 h, then the temperature was raised to –20 °C

over a period of 1 h. Subsequently, the reaction was quenched with

water, and the mixture was extracted with CH₂Cl₂(3ϫ). The com-

bined organic extracts were washed with saturated aqueous

NaHCO₃, brine, dried (MgSO₄), and concentrated. The residue

was purified by flash column chromatography (petroleum ether/

EtOAc, 5:1Ǟ4:1) to give compound 26 (163 mg, 90%) as a syrup.

R_f= 0.42 (petroleum ether/EtOAc, 2:1). HRMS (MALDI⁺): calcd.

for C₁₅H₂₀O₄SNa⁺319.0975; found 319.0975. [α]²_D²= +65 (c = 1.0,

CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.53 (m, 2 H, Ph), 7.33–

7.27 (m, 3 H, Ph), 4.63 (d, J_1,2= 9.2 Hz, 1 H, 1-H), 4.51 (dd, J_2,3

= 5.0, J_3,4= 4.0 Hz, 1 H, 3-H), 4.03 (dd, J_1,2= 9.2, J_2,3= 5.0 Hz,

1 H, 2-H), 3.63 (dq, J_4,5= 9.6, J_5,6= 6.1 Hz, 1 H, 5-H), 3.55 (dd,

J_4,5= 9.6, J_3,4= 3.9 Hz, 1 H, 4-H), 2.06 (br. s, 1 H, 4-OH), 1.53

(s, 3 H, CH₃C), 1.40 (s, 3 H, CH₃C), 1.37 (d, J_5,6= 6.1 Hz, 3 H,

6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 133.7 (C_{Ph ipso}), 132.0

(C_Ph), 129.0 (C_Ph), 127.7 (C_Ph), 110.7 (C_{isopropylidene}), 86.2 (C-1),

75.7 (C-2), 75.5 (C-3), 74.0 (C-5), 71.2 (C-4), 29.8, 28.4, 26.2 (2

CH₃C), 18.1 (C-6) ppm.

The residue was dissolved in DMF (2 mL), and NaNO₂(0.49 mg,

7.09 mmol, 10 equiv.) and 15-crown-5 (0.70 mL, 3.54 mmol,

5 equiv.) were added. The reaction mixture was stirred at 50 °C

overnight, but no conversion was observed. Instead, CsOAc

(0.54 g, 2.83 mmol, 4 equiv.) was added, and the reaction mixture

was stirred at 50 °C overnight, which resulted in the complete con-

version of the starting material. The mixture was concentrated, and

the residue was redissolved in CH₂Cl₂and water. The aqueous

phase was extracted with CH₂Cl₂(3ϫ), and the combined organic

phases were washed with brine, dried (MgSO₄), and concetrated.

The residue was purified by flash column chromatography (petro-

leum ether/EtOAc, 15:1Ǟ 8:1) to give elimination product 24

(150 mg, 76% over two steps) as a syrup. R_f= 0.60 (petroleum

ether/EtOAc, 6:1). HRMS (MALDI⁺): calcd. for C₁₅H₁₈O₃SNa⁺

Phenyl 2,3-O-Isopropylidene-1-thio-α-L

-rhamnopyranoside (27):^[29]

301.0869; found 301.0870. [α]²_D²= +13 (c = 1.0, CHCl₃). H NMR

1

Phenyl 1-thio-α-l-rhamnopyranoside (11; 2.00 g, 7.80 mmol) was

dissolved in dry acetone (40 mL) under nitrogen, and camphorsul-

fonic acid (91 mg, 0.39 mmol, 0.05 equiv.) and then 2,2-dimeth-

oxypropane (10 mL) were added. After 2 h, TLC (heptane/EtOAc,

2:1) showed that the reaction was finished. The reaction solution

was neutralized with NaOH (1.0 m), and the solvent was removed.

The residue was dissolved in CH₂Cl₂, and this solution was washed

with water. The aqueous layer was reextracted with CH₂Cl₂(3ϫ),

and the combined organic fractions were washed with brine, dried

(MgSO₄), and concentrated. The residue was purified by flash col-

umn chromatography (heptane/EtOAc, 5:1Ǟ2:1) to give com-

pound 27 (1.94 g, 84%) as a white solid. R_f= 0.30 (heptane/EtOAc,

2:1). HRMS (ESI⁺): calcd. for C₁₅H₂₀O₄SNa⁺319.0975; found

319.0969. ¹H NMR (500 MHz, CDCl₃): δ = 7.48 (m, 2 H, Ph),

7.34–7.27 (m, 3 H, Ph), 5.75 (d, J_1,2= 0.9 Hz, 1 H, 1-H), 4.35 (dd,

(500 MHz, CDCl₃): δ = 7.56 (m, 2 H, Ph), 7.38–7.26 (m, 3 H, Ph),

4.95 (d, J_1,2= 8.2 Hz, 1 H, 1-H), 4.91 (d, J_3,4= 4.3 Hz, 1 H, 4-H),

4.51 (br. dd, J_2,3≈ 5.7, J_3,4≈ 4.3 Hz, 1 H, 3-H), 4.02 (dd, J_1,2

=

8.2, J_2,3= 5.7 Hz, 1 H, 2-H), 1.83 (s, 3 H, 6-H), 1.47 (s, 3 H, CH₃C),

1.38 (s, 3 H, CH₃C) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 154.8

(C-5), 133.0 (C_{Ph ipso}), 132.5 (C_Ph), 129.1 (C_Ph), 127.9 (C_Ph), 109.2

(C_{isopropylidene}), 96.5 (C-4), 84.6 (C-1), 72.5 (C-2), 69.3 (C-3), 28.6,

26.0 (2 CH₃C), 19.9 (C-6) ppm.

Phenyl 6-Deoxy-2,3-O-isopropylidene-1-thio-β-L-ribo-hexopyranos

id-4-ulose (25): Dimethyl sulfoxide (60 μL, 0.86 mmol, 3.5 equiv.)

was added to dry CH₂Cl₂(3 mL) under argon, and the solution

was cooled to –78 °C. Trifluoroacetic anhydride (TFAA; 90 μL,

0.62 mmol, 2.5 equiv.) was added over a 5 min period, and the mix-

ture was allowed to react for a further 15 min. Phenyl 6-deoxy-2,3-

O-isopropylidene-1-thio-β-l-gulopyranoside (23; 73 mg, 0.25 mmol)

was dissolved in dry CH₂Cl₂(3 mL), and this solution was added

to the cooled solution by cannula. The reaction mixture was stirred

at –78 °C for 2 h, after which time Et₃N (120 μL, 0.86 mmol,

3.5 equiv.) was added. The reaction temperature was allowed to rise

to –20 °C over 1 h, by which time the product had formed. Then,

the mixture was warmed quickly to room temp., and the reaction

was quenched with satd. aq. NaHCO₃. The aqueous phase was

extracted with CH₂Cl₂(3ϫ), and the combined organic phases

were washed with brine, dried (MgSO₄), and concentrated. The

remaining oil was passed through a short column of silica gel (pe-

troleum ether/EtOAc, 5:1) to give ketone 25 (60 mg, 83%) as a

syrup. R_f= 0.47 (petroleum ether/EtOAc, 3:1). HRMS (MALDI⁺):

calcd. for C₁₅H₁₈O₄SNa⁺317.0818; found 317.0819. [α]²_D²= –48 (c

= 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.54 (m, 2 H,

J_2,3= 5.5, J_1,2= 0.9 Hz, 1 H, 2-H), 4.11 (dd, J_3,4= 7.4, J_2,3

5.4 Hz, 1 H, 3-H), 4.08 (m, 1 H, 5-H), 3.48 (dd, J_4,5= 9.8, J_3,4

=

7.6 Hz, 1 H, 4-H), 1.54, 1.37 (2 s, 6 H, 2 CH₃C_{isopropylidene}), 1.24

(d, J_5,6= 6.3 Hz, 3 H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ

= 133.6 (C_{SPh ipso}), 132.0 (C_Ph), 129.2 (C_Ph), 127.8 (C_Ph), 109.9

(C_acetal), 83.9 (C-1), 78.5 (C-3), 76.7 (C-2), 75.4 (C-4), 67.1 (C-5),

28.3, 26.6 [2 C(CH₃)₂], 17.2 (C-6) ppm.

Phenyl

2,3-O-Isopropylidene-4-O-(2-naphthylmethyl)-1-thio-α-L-

rhamnopyranoside (28):^[30]NaH (60% in mineral oil; 1.08 g,

26.99 mmol, 2 equiv.) was added to a cold (0 °C) solution of phenyl

2,3-O-isopropylidene-1-thio-α-l-rhamnopyranoside (27; 4.00 g,

13.50 mmol) in DMF (40 mL), and the mixture was stirred for

30 min. Then, 2-(bromomethyl)naphthalene (3.28 g, 14.85 mmol,

1.1 equiv.) was added, and the reaction mixture was stirred at room

temp. for 1 h under nitrogen. Subsequently, the reaction was

quenched with methanol, and the mixture was concentrated. The

residue were poured into water, and the mixture was extracted with

EtOAc (3ϫ). The combined organic phases was washed with brine,

dried (MgSO₄), and concentrated. The residue was purified by dry

column chromatography (heptane with an increment of 0.5%

EtOAc) to give compound 28 (5.77 g, 98%) as a white solid. R_f=

0.50 (heptane/EtOAc, 5:1). HRMS (ESI⁺): calcd. for

C₂₆H₂₈O₄SNa⁺459.1606; found 459.1600. [α]²_D²= –194 (c = 1.0,

CHCl₃), m.p. 83–84 °C, ref.^[30][α]²_D²= –192.2 (c = 0.83, CHCl₃),

Ph), 7.33 (m, 3 H, Ph), 4.75 (d, J_1,2= 8.5 Hz, 1 H, 1-H), 4.65 (dd,

4

J_2,3= 7.9, J_3,5= 1.4 Hz, 1 H, 3-H), 4.60 (dd, J_2,3= 7.9, J_1,2

=

4

8.5 Hz, 1 H, 2-H), 4.18 (qd, J_5,6= 7.0, J_3,5= 1.4 Hz, 1 H, 5-H),

1.51 (s, 3 H, CH₃C), 1.43 (d, J_5,6= 7.0 Hz, 3 H, 6-H), 1.41 (s, 3 H,

CH₃C) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 206.7 (C=O),

132.6 (C_{Ph ipso}), 132.2 (C_Ph), 129.2 (C_Ph), 128.3 (C_Ph), 112.5

(C_{isopropylidene}), 86.8 (C-1), 79.8 (C-5), 77.8 (C-2), 77.0 (C-3), 27.3,

25.5 (2 CH₃C), 17.4 (C-6) ppm.

Phenyl

6-Deoxy-2,3-O-isopropylidene-1-thio-β-L-allopyranoside

(26): l-Selectride (1.0 m in THF; 0.90 mL, 0.92 mmol, 1.5 equiv.) m.p. 81–83 °C. The spectra were consistent with literature data. ¹H

Eur. J. Org. Chem. 0000, 0–0

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T. G. Frihed, C. M. Pedersen, M. Bols

FULL PAPER

NMR (500 MHz, CDCl₃): δ = 7.85–7.79 (m, 4 H, Ph), 7.51–7.44

(m, 5 H, Ph), 7.33–7.26 (m, 3 H, Ph), 5.74 (s, 1 H, 1-H), 5.08 [d,

²J = 11.6 Hz, 1 H, CH(H_a)Ph], 4.81 [d, ²J = 11.6 Hz, 1 H, CH(H_b)-

Ph], 4.37 (m, 2 H, 2-H, 3-H), 4.17 (dq, J_4,5= 9.7, J_5,6= 6.2 Hz, 1

(C_Ar), 128.55 (C_Ar), 128.2 (C_Ar), 128.2 (C_Ar), 128.1 (C_Ar), 127.99

(C_Ar), 127.97 (C_Ar), 127.9 (C_Ar), 127.8 (C_Ar), 127.8 (C_Ar), 127.4

(C_Ar), 126.8 (C_Ar), 126.2 (C_Ar), 126.2 (C_Ar), 124.00 (C_Ar), 86.00 (C-

1), 80.7 (C-4), 80.2 (C-3), 76.7 (C-2), 75.6 (C_Bn), 72.3 (C_Bn), 72.3

H, 5-H), 3.35 (ddd, J_4,5= 9.8, J_3,4= 5.8, J = 1.0 Hz, 1 H, 4-H), (C_Bn), 69.5 (C-5), 18.1 (C-6) ppm.

1.52, 1.40 (2 s, 6 H, 2 CH₃C_{isopropylidene}), 1.26 (d, J_5,6= 6.2 Hz, 3

Phenyl 2,3-Di-O-benzyl-1-thio-α-L

-rhamnopyranoside (31):^[30]Phenyl

H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 135.8 (C_{Ph ipso}),

133.7 (C_{Ph ipso}), 133.4 (C_{Ph ipso}), 133.2 (C_{Ph ipso}), 132.0 (C_Ph), 129.2

(C_Ph), 128.3 (C_Ph), 128.0 (C_Ph), 127.8 (C_Ph), 127.7 (C_Ph), 127.0

(C_Ph), 126.2 (C_Ph), 126.0 (C_Ph), 109.7 (C_acetal), 84.0 (C-1), 81.6 (C-

4), 78.6, 76.9 (C-2, C-3), 73.3 (C_{naphthylmethyl}), 66.4 (C-5), 28.2, 26.7

[2 C(CH₃)₂], 17.9 (C-6) ppm.

2,3-di-O-benzyl-4-O-(2-naphthylmethyl)-1-thio-α-l-rhamnopyranos-

ide (30; 1.00 g, 1.73 mmol) was dissolved in CH₂Cl₂/H₂O (20:1;

40 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ;

472 mg, 2.08 mmol, 1.2 equiv.) was added. The reaction mixture was

stirred for 1.5 h. Then, the reaction was quenched by the addition

of satd. aq. NaHCO₃, and the mixture was extracted with CH₂Cl₂

(3ϫ). The combined organic extracts were washed with satd.

NaHCO₃, and brine, dried (MgSO₄), and concentrated. The residue

was purified by flash column chromatography (heptane/EtOAc,

10:1Ǟ4:1) to give compound 31 (0.71 g, 94%) as a colorless syrup.

Phenyl 4-O-(2-Naphthylmethyl)-1-thio-α-L-rhamnopyranoside (29):

Phenyl 2,3-O-isopropylidene-4-O-(2-naphthylmethyl)-1-thio-α-l-

rhamnopyranoside (28) (5.25 g, 12.03 mmol) was dissolved in

CH₂Cl₂(50 mL), and water (1 mL) and TFA (4 mL) were added.

The reaction mixture was stirred for 4 h, then it was quenched with

saturated aqueous Na₂CO₃, and the aqueous phase was extracted

with CH₂Cl₂(3ϫ). The combined organic phases were dried

(MgSO₄), and concentrated to give a white solid. Recrystallization

from EtOAc/hexane and dry column chromatography (heptane

with an increment of 3.3% EtOAc) of the residue gave compound

29 (4.53 g, 95%). R_f= 0.24 (heptane/EtOAc, 2:1). HRMS (ESI⁺):

calcd. for C₂₃H₂₄O₄SNa⁺419.1293; found 419.1306. [α]²_D²= –225

R_f

=

0.48 (heptane/EtOAc, 3:1). HRMS (ESI⁺): calcd. for

C₂₆H₂₈O₄SNa⁺459.1601; found 459.1610. [α]²_D²= –6 (c = 1.0,

CHCl₃), ref.^[30][α]²_D²= –12 (c = 0.4, CHCl₃). The spectra were consis-

tent with literature data. ¹H NMR (500 MHz, CDCl₃): δ = 7.45–

7.42 (m, 2 H, Ph), 7.39–7.27 (m, 13 H, Ph), 5.57 (d, J_1,2= 1.5 Hz, 1

H, 1-H), 4.71 [d, ²J = 12.2 Hz, 1 H, CH(H_a)Ph], 4.56 [2 d, ²J = 11.6,

²J = 12.2 Hz, 2 H, CH(HЈ_a)Ph, CH(H_b)Ph], 4.44 [d, J = 11.6 Hz, 1

H, CH(HЈ_b)Ph], 4.12 (dq, J_4,5= 9.3, J_5,6= 6.1 Hz, 1 H, 5-H), 4.03

(dd, J_2,3= 3.0, J_1,2= 1.6 Hz, 1 H, 2-H), 3.81 (t, J_3,4= J_4,5= 9.4 Hz,

1 H, 4-H), 3.65 (dd, J_3,4= 9.5, J_2,3= 3.0 Hz, 1 H, 3-H), 2.37 (s, 1

H), 1.36 (d, J_5,6= 6.2 Hz, 3 H, 6-H) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ = 137.8 (C_{Bn ipso}), 137.8 (C_{Bn ipso}), 134.8 (C_{PhS ipso}), 131.4

(C_Ph), 129.2 (C_Ph), 128.7 (C_Ph), 128.6 (C_Ph), 128.2 (C_Ph), 128.1 (C_Ph),

128.1 (C_Ph), 128.0 (C_Ph), 127.5 (C_Ph), 85.9 (C-1), 79.8 (C-3), 75.7 (C-

2), 72.1 (C_Bn), 71.9 (C-4), 71.6 (C_Bn), 69.8 (C-5), 17.8 (C-6) ppm.

1

(c = 1.0, CHCl₃), m.p. 119–120 °C. H NMR (500 MHz, CDCl₃):

δ = 7.88–7.81 (m, 4 H, Ph), 7.52–7.45 (m, 5 H, Ph), 7.32–7.25 (m,

2

3 H, Ph), 5.48 (d, J_1,2= 1.6 Hz, 1 H, 1-H), 4.91 (dd, J = 11.5 Hz,

2 H, CH₂Ph), 4.26 (dq, J_4,5= 9.4, J_5,6= 6.3 Hz, 1 H, 5-H), 4.20

(q, J = 2.3 Hz, 1 H, 2-H), 3.97 (dd, J = 12.4, J = 3.4 Hz, 1 H, 3-

H), 3.49 (t, J_4,5= 9.2 Hz, 1 H, 4-H), 2.54 (br. d, J = 3.9 Hz, 1 H,

OH), 2.41 (br. d, J = 5.1 Hz, 1 H, OH), 1.38 (d, J_5,6= 6.3 Hz, 3

H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 135.7 (C_{Ph ipso}),

134.2 (C_{Ph ipso}), 133.5 (C_{Ph ipso}), 133.2 (C_{Ph ipso}), 131.6 (C_Ph), 129.2

(C_Ph), 128.7 (C_Ph), 128.1 (C_Ph), 127.9 (C_Ph), 127.6 (C_Ph), 127.0

(C_Ph), 126.5 (C_Ph), 126.3 (C_Ph), 125.9 (C_Ph), 87.6 (C-1), 82.0 (C-4),

75.3 (C_Bn), 72.7 (C-2), 72.1 (C-3), 68.8 (C-5), 18.2 (C-6) ppm.

Phenyl 2,3-O-Isopropylidene-6-deoxy-1-thio-α-L-lyxo-hexopyranos-

id-4-ulose (32):^[31]Dimethyl sulfoxide (0.42 mL, 5.90 mmol,

3.5 equiv.) was added to dry CH₂Cl₂(15 mL), and the solution was

cooled to –78 °C. Trifluoroacetic anhydride (TFAA; 0.60 mL,

4.22 mmol, 2.5 equiv.) was added over a 5 min period, and the mix-

ture was allowed to react for a further 15 min. Phenyl 2,3-O-iso-

propylidene-1-thio-α-l-rhamnopyranoside (27; 0.50 g, 1.69 mmol)

was dissolved in dry CH₂Cl₂(10 mL), and this solution was added

to the cooled solution. The reaction mixture was stirred at –78 °C

for 3 h, after which time Et₃N (0.82 mL, 5.90 mmol, 3.5 equiv.) was

added. The reaction temperature was allowed to rise to –20 °C over

2 h, after which time the product had formed. Then, the mixture

was warmed quickly to room temp., and the reaction was quenched

with water. The aqueous phase was extracted with CH₂Cl₂(3ϫ),

and the combined organic phases were dried (MgSO₄) and concen-

trated. The remaining oil was passed through a short column of

silica gel (heptane/EtOAc, 20:1 then 15:1) to give ketone 32 (0.35 g,

71%) as a syrup. R_f= 0.46 (heptane/EtOAc, 4:1). HRMS (ESI⁺):

calcd. for C₁₅H₁₈O₄SNa⁺317.0818; found 317.0818. The spectra

were consistent with literature data.^{[31] 1}H NMR (500 MHz,

CDCl₃): δ = 7.49 (m, 2 H, Ph), 7.36–7.29 (m, 3 H, Ph), 5.69 (d,

J_1,2= 1.5 Hz, 1 H, 1-H), 4.71 (d, J_5,6= 6.7 Hz, 1 H, 5-H), 4.67

(dd, J_2,3= 6.1, J_1,2= 1.5 Hz, 1 H, 2-H), 4.49 (d, J_2,3= 6.1 Hz, 1

Phenyl 2,3-Di-O-benzyl-4-O-(2-naphthylmethyl)-1-thio-α-L-rhamno-

pyranoside (30):^[30]NaH (60% in mineral oil; 0.82 g, 20.48 mmol,

4 equiv.) was added to a cold (0 °C) solution of phenyl 2,3-O-iso-

propylidene-1-thio-α-l-rhamnopyranoside (29; 2.00 g, 5.12 mmol)

in DMF (20 mL), and the mixture was stirred for 30 min. Then,

benzyl bromide (1.3 mL, 11.26 mmol, 2.2 equiv.) was added, and

the mixture was stirred for 3 h under nitrogen. The reaction was

quenched with methanol, and the mixture was concentrated. The

residue was poured into water, and the mixture was extracted with

EtOAc (3ϫ). The combined organic phases were washed with

brine, dried (MgSO₄), and concentrated. The residue was purified

by dry column chromatography (heptane with an increment of

2.0% EtOAc) to give compound 30 (2.89 g, 98%) as a colorless

syrup. R_f= 0.35 (heptane/EtOAc, 8:1). HRMS (ESI⁺): calcd. for

C₃₇H₃₆O₄SNa⁺599.2232; found 599.2204. [α]²_D²= –61 (c = 1.0,

CHCl₃), ref.^[30][α]²_D²= –66.8 (c = 1.54, CHCl₃). The spectra were

1

consistent with literature data. H NMR (500 MHz, CDCl₃): δ =

7.85–7.75 (m, 4 H, Ar), 7.50–7.44 (m, 3 H, Ar), 7.40–7.25 (m, 15

2

H, Ar), 5.51 (d, J_1,2= 1.7 Hz, 1 H, 1-H), 5.12 [d, J = 11.1 Hz, 1

H, 3-H), 1.48, 1.40 (2 s, 6 H, 2 CH₃C_{isopropylidene}), 1.34 (d, J_5,6

=

2

6.7 Hz, 3 H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 204.4

(C-4), 132.6 (C_{SPh ipso}), 131.6 (C_SPh), 129.4 (C_SPh), 128.1 (C_SPh),

111.7 (C_{isopropylidene}), 83.6 (C-1), 79.8 (C-2), 76.3 (C-3), 71.6 (C-4),

27.0, 26.0 [2 C(CH₃)₂], 15.2 (C-6) ppm.

H, CH(H_a)Ar], 4.84 [d, J = 11.1 Hz, 1 H, CH(H_b)Ar], 4.74 [d, J

2

= 12.4 Hz, 1 H, CH(H_a)Ar], 4.67 [d, J = 12.4 Hz, 1 H, CH(H_b)-

Ar], 4.63 (s, 2 H, CH₂Ar), 4.19 (dq, J_4,5= 9.3, J_5,6= 6.1 Hz, 1 H,

5-H), 4.02 (dd, J_2,3= 3.1, J_1,2= 1.8 Hz, 1 H, 2-H), 3.87 (dd, J_3,4

=

9.3, J_2,3= 3.1 Hz, 1 H, 3-H), 3.75 (t, J = 9.4 Hz, 1 H, 4-H), 1.39

Phenyl 6-Deoxy-2,3-O-isopropylidene-1-thio-α-L-talopyranoside (33)

(d, J_5,6= 6.2 Hz, 3 H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ

= 138.4 (C_{Ar ipso}), 138.0 (C_{Ar ipso}), 136.2 (C_{Ar ipso}), 134.8 (C_{Ar ipso}), Method 1: Phenyl 2,3-O-isopropylidene-6-deoxy-1-thio-α-l-lyxo-

133.5 (C_{Ar ipso}), 133.1 (C_{Ar ipso}), 131.5 (C_Ar), 129.2 (C_Ar), 128.6 hexopyranosid-4-ulose (32; 188 mg, 0.64 mmol) was dissolved in

12

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Synthesis of 6-Deoxy-l-hexopyranosyl Donors

MeOH/CH₂Cl₂(1:1; 2 mL), and the solution was cooled to 0 °C. rated aqueous NaHCO₃, the layers were separated, and the aque-

NaBH₄(48 mg, 1.28 mmol, 2 equiv.) was added in several portions.

The reaction mixture was stirred under nitrogen at 0 °C for 40 min,

ous phase was extracted with CH₂Cl₂(3ϫ). The combined organic

phases were washed with satd. aq. NaHCO₃, and brine, dried

and then at room temp. for 10 min, by which time the reduction (MgSO₄), and concentrated. The residue was purified by flash col-

was complete. The reaction was quenched with water, and the mix-

ture was extracted with CH₂Cl₂(3ϫ). The combined organic ex-

tracts were washed with saturated aqueous NaHCO₃, and brine,

dried (MgSO₄), and concentrated. The residue was purified by flash

column chromatography (heptane/EtOAc, 10:1 then 5:1) to give

compound 33 (167 mg, 89%) as a colorless syrup.

umn chromatography (heptane/EtOAc, 25:1Ǟ18:1) to give com-

pound 35 (7.11 g, 90% over three steps) as a white solid. R_f= 0.37

(heptane/EtOAc, 8:1). HRMS (ESI⁺): calcd. for C₂₅H₃₄O₅SiSNa⁺

497.1788; found 497.1789. [α]²_D²= –113 (c = 1.0, CHCl₃), m.p. 92–

1

93 °C. H NMR (500 MHz, CDCl₃): δ = 8.03 (m, 2 H, Ph), 7.59

(m, 1 H, Ph), 7.51–7.44 (m, 4 H, Ph), 7.33–7.27 (m, 3 H, Ph), 5.61

(dd, J_2,3= 3.4, J_1,2= 1.6 Hz, 1 H, 2-H), 5.56 (d, J_1,2= 1.6 Hz, 1

H, 1-H), 4.19 (m, 1 H, 5-H), 4.04–3.98 (m, 1 H, 3-H), 3.69 (t, J =

9.1 Hz, 1 H, 4-H), 2.04 (br. s, 1 H, 3-OH), 1.34 (d, J_5,6= 6.2 Hz,

3 H, 6-H), 0.94 (s, 9 H, 3 CH₃C), 0.16 (2 s, 6 H, 2 CH₃Si) ppm.

¹³C NMR (126 MHz, CDCl₃): δ = 166.3 (C=O), 134.1 (C_{Ph ipso}),

133.5 (C_{Ph ipso}), 132.0 (C_Ph), 129.9 (C_Ph), 129.8 (C_Ph), 129.2 (C_Ph),

128.6 (C_Ph), 127.8 (C_Ph), 86.2 (C-1), 75.6 (C-4), 75.1 (C-2), 71.6

(C-3), 70.2 (C-5), 26.1 (C_methyl), 18.5 (C_methyl), 18.3 (C_quat.), –3.7

(C_methyl), –4.3 (C_methyl) ppm.

Method 2: Dimethyl sulfoxide (0.67 mL, 9.45 mmol, 3.5 equiv.) was

added to dry CH₂Cl₂(30 mL), and the solution was cooled to

–78 °C. Trifluoroacetic anhydride (TFAA; 0.95 mL, 6.75 mmol,

2.5 equiv.) was added over a 5 min period, and the mixture was

allowed to react for a further 15 min. Phenyl 2,3-O-isopropylidene-

1-thio-α-l-rhamnopyranoside (27; 0.80 g, 2.70 mmol) was dissolved

in dry CH₂Cl₂(20 mL), and this solution was added to the cooled

solution. The reaction mixture was stirred at –78 °C for 3 h, after

which time Et₃N (1.32 mL, 9.45 mmol, 3.5 equiv.) was added. The

reaction temperature was allowed to rise to –20 °C over 2 h, by

which time the product had formed. Then, the mixture was warmed

quickly to room temp., and the reaction was quenched with water.

The aqueous phase was extracted with CH₂Cl₂(3ϫ), and the com-

bined organic phases were dried (MgSO₄) and concentrated.

Phenyl 2-O-Benzoyl-4-O-tert-butyldimethylsilyl-6-deoxy-1-thio-α-L-

arabino-hexopyranosid-3-ulose (36): Dimethyl sulfoxide (0.16 mL,

2.21 mmol, 3.5 equiv.) was added to dry CH₂Cl₂(8 mL) under

argon, and the solution was cooled to –78 °C. Trifluoroacetic an-

hydride (TFAA; 0.22 mL, 1.58 mmol, 2.5 equiv.) was added over a

5 min period, and the mixture was allowed to react for a further

15 min. Phenyl 2-O-benzoyl-4-O-tert-butyldimethylsilyl-1-thio-α-l-

rhamnopyranoside (35; 0.30 g, 0.63 mmol) was dissolved in dry

CH₂Cl₂(2 mL), and this solution was added to the cooled solution.

The reaction mixture was stirred at –78 °C for 3 h, after which time

Et₃N (0.31 mL, 2.21 mmol, 3.5 equiv.) was added. The reaction

temperature was allowed to rise to –20 °C over 2 h, by which time

the product had formed. Then, the mixture was warmed quickly to

room temp., and the reaction was quenched with water. The aque-

ous phase was extracted with CH₂Cl₂(3ϫ), and the combined or-

ganic phases were washed with brine, dried (MgSO₄), and concen-

trated. The remaining oil was passed through a short column of

silica gel (heptane/EtOAc, 30:1 then 25:1) to give ketone 36

(273 mg, 91%) as a colorless syrup. R_f= 0.40 (heptane/EtOAc,

10:1). HRMS (ESI⁺): calcd. for C₂₅H₃₂O₅SiSNa⁺495.1632; found

495.1634. [α]²_D²= –132 (c = 1.0, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 8.04 (m, 2 H, Ph), 7.61 (m, 1 H, Ph), 7.49 (m, 4 H,

Then, the residue was dissolved in in MeOH/CH₂Cl₂(1:1; 2 mL),

and the solution was cooled to 0 °C. NaBH₄(204 mg, 5.40 mmol,

2 equiv.) was added in several portions. The reaction mixture was

stirred under nitrogen at 0 °C for 30 min, and then at room temp.

for 10 min, by which time the reduction was complete. The reaction

was quenched with water, and the mixture was extracted with

CH₂Cl₂(3ϫ). The combined organic extracts were washed with

saturated aqueous NaHCO₃, and brine, dried (MgSO₄), and con-

centrated. The residue was purified by flash column chromatog-

raphy (heptane/EtOAc, 8:1Ǟ4:1) to give compound 33 (0.63 g,

79% over two steps) as a colorless syrup. R_f= 0.30 (heptane/

EtOAc, 3:1). HRMS (ESI⁺): calcd. for C₁₅H₂₀O₄SNa⁺319.0975;

found 319.0976. [α]²_D²= –169 (c = 1.0, CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 7.50 (m, 2 H, Ph), 7.33–7.27 (m, 3 H, Ph),

5.73 (d, J_1,2= 2.3 Hz, 1 H, 1-H), 4.26 (dd, J = 6.4, J_3,4= 4.7 Hz,

1 H, 3-H or 4-H), 4.21 (m, 2 H, 2-H, 5-H), 3.67 (dd, J_3,4= 4.7, J

= 1.5 Hz, 1 H, 3-H or 4-H), 2.17 (br. s, 1 H, 4-OH), 1.59, 1.40 (2

s, 6 H, 2 CH₃C_{isopropylidene}), 1.29 (d, J_5,6= 6.5 Hz, 3 H) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ = 133.5 (C_{Ph ipso}), 131.9 (C_Ph), 129.1

(C_Ph), 127.7 (C_Ph), 109.7 (C_{isopropylidene}), 83.5 (C-1), 73.8 (C-2), 73.4

(C-3 or C-4), 67.7 (C-3 or C-4), 66.7 (C-5), 26.1, 25.5 [2 C(CH₃)₂],

16.7 (C-6) ppm.

4

Ph), 7.32 (m, 3 H, Ph), 5.74 (dd, J_1,2= 2.9, J_1,5≈ 0.6 Hz, 1 H, 1-

H), 5.44 (d, J_1,2= 2.9 Hz, 1 H, 2-H), 4.45 (ddq, J_4,5= 8.3, J_5,6

=

4

6.2, J_1,5≈ 0.6 Hz, 1 H, 5-H), 4.32 (d, J_4,5= 8.3 Hz, 1 H, 4-H),

1.41 (d, J_5,6= 6.2 Hz, 3 H, 6-H), 0.92 (s, 9 H, 3 CH₃C), 0.15 (s, 3 H,

CH₃Si), 0.05 (s, 3 H, CH₃Si) ppm. ¹³C NMR (126 MHz, CDCl₃): δ

= 199.7 (C=O _ketone), 165.0 (C=O _benzoyl), 133.9 (C_Ph), 132.7 (C_Ph),

132.2 (C_{Ph ipso}), 130.0 (C_Ph), 129.3 (C_Ph), 128.9 (C_{Ph ipso}), 128.8

(C_Ph), 128.3 (C_Ph), 86.4 (C-1), 79.0 (C-4), 78.2 (C-2), 74.3 (C-5),

Phenyl 2-O-Benzoyl-4-O-tert-butyldimethylsilyl-1-thio-α-L-rhamno-

pyranoside (35): Phenyl 1-thio-α-l-rhamnopyranoside (11; 3.84 g,

15.0 mmol) was dissolved in dry CH₂Cl₂(50 mL), and triethyl

benzoate (5.1 mL, 22.5 mmol, 1.5 equiv.) was added, followed by

CSA (174 mg, 0.75 mmol, 0.05 equiv.). The reaction mixture was

stirred for 1 h under nitrogen (R_f= 0.55, heptane/EtOAc, 2:1).

Then, the reaction mixture was neutralized with Et₃N, and concen-

trated in vacuo followed by coevaporation with toluene.

25.9 (C_Methyl), 18.6 (C-6), 18.4 (C_quat.), –4.3 (C_Methyl), –5.3 (C_Methyl

ppm.

)

Phenyl 2-O-Benzoyl-4-O-tert-butyldimethylsilyl-6-deoxy-1-thio-α-

L-

altropyranoside (37): Phenyl 2-O-benzoyl-4-O-tert-butyldimethyl-

silyl-6-deoxy-1-thio-α-l-arabino-hexopyranosid-3-ulose (36;

250 mg, 0.53 mmol) was dissolved in CH₂Cl₂/MeOH (1:1; 4 mL),

and the solution was cooled to –78 °C under nitrogen. NaBH₄

(40 mg, 1.06 mmol, 2 equiv.) was added in several portions. The

reaction mixture was stirred for 1 h at –78 °C, and then the tem-

perature was raised to 0 °C over a period of 30 min. Subsequently,

the reaction mixture was stirred for 30 min at 0 °C, then the reac-

tion was quenched with water, and the mixture was extracted with

CH₂Cl₂(3ϫ). The combined organic phases were washed with sat-

urated aqueous NaHCO₃, and brine, dried (MgSO₄), and concen-

Subsequently, the crude residue was dissolved in dry DMF

(25 mL), and this solution was cooled to 0 °C. Imidazole (3.06 g,

44.9 mmol, 3 equiv.) and tert-butyldimethylsilyl chloride (3.39 g,

22.5 mmol, 1.5 equiv.) were added. The temperature of the reaction

mixture was slowly raised to room temp. over 2 h, and the mixture

was stirred for a further 18 h (R_f= 0.77, heptane/EtOAc, 4:1).

Then, AcOH (90% aq.; 50 mL) was added, and the mixture was

stirred for 2.5 h. Subsequently, the mixture was poured into satu-

Eur. J. Org. Chem. 0000, 0–0

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T. G. Frihed, C. M. Pedersen, M. Bols

FULL PAPER

trated. The ratio of 3-OH axial/3-OH equatorial was measured by

¹H NMR spectroscopy to be ca. 12:1 in favor of the desired 3-OH

axial product. The residue was purified by flash column

chromatography (CH₂Cl₂/heptane, 1:4Ǟ1:1) to give compound 37

(199 mg, 79%) as a colorless syrup. R_f= 0.49 (heptane/EtOAc, 6:1).

was added to a cold (0 °C) solution of phenyl 3-O-benzoyl-4-O-

tert-butyldimethylsilyl-6-deoxy-1-thio-α-l-altropyranoside (38;

1.05 g, 2.21 mmol) in THF (22 mL) under argon. The reaction mix-

ture was stirred for 5 h, and then it was quenched with satd. aq.

NH₄Cl. The mixture was extracted with Et₂O (3ϫ), and the com-

HRMS (ESI⁺): calcd. for C₂₅H₃₄O₅SiSNa⁺497.1788; found bined organic extracts were washed with brine, dried (MgSO₄), and

497.1790. [α]²_D²= –109 (c = 1.0, CHCl₃). ¹H NMR (500 MHz,

concentrated. The residue was purified by flash column chromatog-

CDCl₃): δ = 8.01 (m, 2 H, Ph), 7.59 (m, 1 H, Ph), 7.51 (m, 2 H, raphy (heptane/EtOAc, 10:1Ǟ5:1) to give compound 39 (0.71 g,

Ph), 7.46 (m, 2 H, Ph), 7.30–7.21 (m, 3 H, Ph), 5.56 (dd, J_2,3= 3.5,

87%) as a colorless syrup. R_f= 0.36 (heptane/EtOAc, 3:1). HRMS

J_1,2= 1.3 Hz, 1 H, 2-H), 5.45 (s, 1 H, 1-H), 4.50 (dq, J_4,5= 9.3, (ESI⁺): calcd. for C₁₈H₃₀O₄SiSNa⁺393.1526; found 393.1537.

J_5,6= 6.2 Hz, 1 H 5-H), 4.02 (t, J_2,3= J_3,4= 3.4 Hz, 1 H, 3-H), [α]²_D²= –173 (c = 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ =

3.78 (dd, J_4,5= 9.2, J_3,4= 3.3 Hz, 1 H, 4-H), 2.74 (br. s, 1 H, 3-

7.50–7.47 (m, 2 H, Ph), 7.29–7.21 (m, 3 H, Ph), 5.21 (d, J_1,2=

OH), 1.32 (d, J_5,6= 6.3 Hz, 3 H, 6-H), 0.94 (s, 9 H, 3 CH₃C), 0.16 2.6 Hz, 1 H, 1-H), 4.37 (dq, J_4,5= 8.4, J_5,6= 6.4 Hz, 1 H, 5-H),

(s, 3 H, CH₃Si), 0.13 (s, 3 H, CH₃Si) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ = 165.2 (C=O _benzoyl), 136.8 (C_{Ph ipso}), 133.6 (C_Ph), 131.3

4.16 (dd, J_2,3= 4.4, J_1,2= 2.4 Hz, 1 H, 2-H), 3.88 (t, J = 3.9 Hz, 1

H, 3-H), 3.72 (dd, J_4,5= 8.3, J = 3.3 Hz, 1 H, 4-H), 2.57 (br. s, 1

(C_Ph), 129.89 (C_Ph), 129.7 (C_{Ph ipso}), 129.0 (C_Ph), 128.6 (C_Ph), 127.3 H, OH), 2.12 (br. s, 1 H, OH), 1.27 (d, J_5,6= 6.4 Hz, 3 H, 6-H),

(C_Ph), 85.3 (C-1), 73.9 (C-2), 72.3 (C-4), 69.3 (C-3), 64.8 (C-5), 25.8 0.91 (s, 9 H, 3 CH₃C), 0.13, 0.12 (2 s, 6 H, 2 CH₃Si) ppm. ¹³C

(C_Methyl), 18.1, 18.1 (C-6, C_quat.), –4.2 (C_Methyl), –4.5 (C_Methyl) ppm. NMR (126 MHz, CDCl₃): δ = 136.5 (C_{Ph ipso}), 131.1 (C_Ph), 129.0

(C_Ph), 127.2 (C_Ph), 87.3 (C-1), 72.2 (C-2), 72.0 (C-4), 71.1 (C-3),

Phenyl 3-O-Benzoyl-4-O-tert-butyldimethylsilyl-6-deoxy-1-thio-α-L-

66.5 (C-5), 25.8 (C_Methyl), 18.1, 17.7 (C-6, C_quat.), –4.3 (C_Methyl),

–4.5 (C_Methyl) ppm.

altropyranoside (38): Dimethyl sulfoxide (1.4 mL, 19.4 mmol,

3.5 equiv.) was added to dry CH₂Cl₂(50 mL) under argon, and the

solution was cooled to –78 °C. Trifluoroacetic anhydride (TFAA;

2.0 mL, 13.9 mmol, 2.5 equiv.) was added over a 5 min period, and

the mixture was allowed to react for a further 15 min. Phenyl 2-O-

benzoyl-4-O-tert-butyldimethylsilyl-1-thio-α-l-rhamnopyranoside

(35; 2.63 g, 5.5 mmol) was dissolved in dry CH₂Cl₂(15 mL), and

this solution was added to the cooled solution. The reaction mix-

ture was stirred at –78 °C for 3 h, after which time Et₃N (2.70 mL,

19.4 mmol, 3.5 equiv.) was added. The reaction temperature was

allowed to rise to –20 °C in 2 h, by which time the product had

formed. Then, the mixture was warmed quickly to room temp.,

and the reaction was quenched with water. The aqueous phase was

extracted with CH₂Cl₂(3 ϫ), and the combined organic phases

were washed with brine, dried (MgSO₄), and concentrated.

Phenyl 2,3-Di-O-benzyl-6-deoxy-1-thio-α-L-altropyranoside (40)

Method A: Benzyl bromide (0.79 mL, 6.62 mmol, 4 equiv.) was

added to a cold (0 °C) solution of phenyl 6-deoxy-4-O-tert-butyldi-

methylsilyl-1-thio-α-l-altropyranoside (39) (0.61 g, 1.65 mmol) in

DMF (15 mL), and then NaH (60 % in mineral oil; 200 mg,

4.96 mmol, 3 equiv.) was added. The reaction mixture was stirred

under argon at 0 °C for 2 h, then the reaction was quenched with

methanol, and the mixture was concentrated (R_f= 0.64, heptane/

EtOAc, 4:1).

The crude phenyl 2,3-di-O-benzyl-6-deoxy-4-O-tert-butyldimethyl-

silyl-1-thio-α-l-altropyranoside was dissolved in methanol (50 mL),

p-toluenesulfonic acid (28 mg, 0.17 mmol, 0.1 equiv.) was added,

and the mixture was heated to reflux under nitrogen for 22 h. Sub-

sequently, the reaction mixture was neutralized with Et₃N, and con-

centrated. The residue was purified by flash column chromatog-

raphy (heptane/EtOAc, 12:1Ǟ6:1) to give compound 40 (0.42 g,

58 % over two steps) as a colorless syrup. R_f= 0.32 (heptane/

EtOAc, 4:1). HRMS (ESI⁺): calcd. for C₂₆H₂₈O₄SNa⁺459.1601;

found 459.1600. [α]²_D²= –84 (c = 1.0, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 7.41 (m, 2 H, Ph), 7.30–7.14 (m, 13 H, Ph), 5.38 (s, 1

H, 1-H), 4.70 [d, ²J = 11.4 Hz, 1 H, CH(H_a)Ph], 4.60 [d, ²J =

l-Selectride (1.0 m in THF; 8.31 mL, 8.31 mmol, 1.5 equiv.) was

added to a solution of the crude phenyl 2-O-benzoyl-4-O-tert-

butyldimethylsilyl-6-deoxy-1-thio-α-l-arabino-hexopyranosid-3-

ulose (36; 2.62 g, 5.54 mmol) in THF (40 mL) at –78 °C under ni-

trogen. The reaction mixture was stirred at –78 °C for 90 min, and

then the temperature was raised to room temp. over a period of

90 min, followed by stirring for a further 30 min. The reaction was

quenched with water, and the mixture was extracted with CH₂Cl₂

(3ϫ). The combined organic extracts were washed with saturated

aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated.

The residue was purified by flash column chromatography (hept-

ane/EtOAc, 15:1Ǟ10:1) to give compound 38 (1.93 g, 73% over

two steps) as a colorless syrup. R_f= 0.23 (heptane/EtOAc, 6:1).

HRMS (ESI⁺): calcd. for C₂₅H₃₄O₅SiSNa⁺497.1788; found

497.1787. [α]²_D²= –145 (c = 1.0, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 8.22 (m, 2 H, Ph), 7.59 (m, 1 H, Ph), 7.52–7.45 (m, 4

H, Ph), 7.31–7.25 (m, 3 H, Ph), 5.40 (t, J_2,3= J_3,4= 3.6 Hz, 1 H,

2

12.0 Hz, 1 H, CH(H_a)Ph], 4.43 [d, J = 12.0 Hz, 1 H, CH(H_b)Ph],

2

4.31 [d, J = 11.4 Hz, 1 H, CH(H_b)Ph], 4.22 (dq, J_4,5= 9.7, J_5,6

=

6.3 Hz, 1 H, 5-H), 3.96 (dd, J_2,3= 3.4, J_1,2= 1.4 Hz, 1 H, 2-H),

3.71 (td, J_2,3= J_3,4= 3.5 Hz, 1 H, 3-H), 3.55 (dd, J_4,5= 9.7, J_3,4

=

3.7 Hz, 1 H, 4-H), 2.11 (br. s, 1 H, 4-OH), 1.26 (d, J_5,6= 6.2 Hz,

3 H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 137.5 (C_{Ph ipso}),

137.4 (C_{Ph ipso}), 137.3 (C_{Ph ipso}), 130.7 (C_Ph), 129.0 (C_Ph), 128.7

(C_Ph), 128.7 (C_Ph), 128.4 (C_Ph), 128.3 (C_Ph), 128.2 (C_Ph), 128.0

(C_Ph), 127.0 (C_Ph), 85.5 (C-1), 76.3 (C-3), 76.2 (C-2), 72.9 (C_Bn),

72.3 (C_Bn), 70.0 (C-4), 66.3 (C-5), 17.8 (C-6) ppm.

3-H), 5.31 (d, J_1,2= 2.0 Hz, 1 H, 1-H), 4.60 (dq, J_4,5= 8.8, J_5,6

=

6.4 Hz, 1 H, 5-H), 4.30 (dd, J_2,3= 4.3, J_1,2= 2.0 Hz, 1 H, 2-H),

3.95 (dd, J_4,5= 8.6, J_3,4= 3.2 Hz, 1 H, 4-H), 2.59 (s, 1 H), 1.36 (d,

J_5,6= 6.4 Hz, 3 H), 0.78 (s, 9 H, 3 CH₃C), 0.09, 0.07 (2 s, 6 H, 2

CH₃Si) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 166.2 (C=

Method B: From phenyl 2,3-di-O-benzyl-6-deoxy-1-thio-α-l-arab-

ino-hexopyranosid-4-ulose (41): l-Selectride (1.0 m in THF;

1.21 mL, 1.21 mmol, 1.5 equiv.) was added dropwise to a cold (–

78 °C) solution of phenyl 2,3-di-O-benzyl-6-deoxy-1-thio-α-l-arab-

ino-hexopyranosid-4-ulose (41; 350 mg, 0.80 mmol) in THF. The

reaction mixture was stirred under nitrogen at –78 °C for 1 h, and

then the temperature was raised to room temp. over 1 h. The reac-

tion was quenched with water, and the mixture was extracted with

CH₂Cl₂(3ϫ). The combined organic extracts were washed with

saturated aqueous NaHCO₃, and brine, dried (MgSO₄), and con-

O

_benzoyl), 136.0 (C_{Ph ipso}), 133.3 (C_Ph), 131.5 (C_Ph), 130.3 (C_Ph),

129.9 (C_{Ph ipso}), 129.1 (C_Ph), 128.5 (C_Ph), 127.4 (C_Ph), 87.7 (C-1),

72.4 (C-3), 71.0 (C-2), 70.0 (C-4), 67.6 (C-5), 25.7 (C_Methyl), 17.9,

17.8 (C-6, C_quat.), –4.4 (C_Methyl), –4.8 (C_Methyl) ppm.

Phenyl 6-Deoxy-4-O-tert-butyldimethylsilyl-1-thio-α-

L-altropyrano-

side (39): EtMgBr (1.0 m in THF; 22 mL, 22.12 mmol, 10 equiv.)

14

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Pages: 17

Synthesis of 6-Deoxy-l-hexopyranosyl Donors

centrated. The residue was purified by flash column chromatog-

raphy (heptane/EtOAc, 12:1Ǟ6:1) to give compound 40 (0.21 g,

60%). Data as above.

Phenyl 2,3-Di-O-benzyl-6-deoxy-1-thio-α-L-idopyranoside (43):

Phenyl 4-O-(4-nitrobenzoyl)-2,3-di-O-benzyl-6-deoxy-1-thio-α-l-

idopyranoside (42; 200 mg, 0.34 mmol) was dissolved in MeOH

(5 mL) under nitrogen, and NaOMe (25 wt.-% in MeOH; 0.1 mL)

was added. The reaction mixture was stirred for 15 h, and then the

mixture was quenched with Amberlite IR-120, filtered, and concen-

trated. The residue was purified by flash column chromatography

(heptane/EtOAc, 12:1Ǟ10:1) to give compound 43 (140 mg, 94%)

as a colorless syrup. R_f= 0.42 (heptane/EtOAc, 4:1). HRMS

(MALDI⁺): calcd. for C₂₆H₂₈O₄SNa⁺459.1601; found 459.1602.

[α]²_D²= –95 (c = 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ =

7.50 (d, J = 7.5 Hz, 2 H, Ph), 7.39–7.24 (m, 13 H, Ph), 5.55 (s, 1

H, 1-H), 4.72–4.62 [m, 3 H, 5-H, 2 CH(H_a)Ph], 4.53 [t, J = 11.7 Hz,

2 H, 2 CH(H_b)Ph], 3.88 (s, 1 H), 3.82 (s, 1 H), 3.51 (s, 1 H), 3.16

(s, 1 H, 4-OH), 1.31 (d, J_5,6= 6.3 Hz, 3 H, 6-H) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ = 137.7 (C_{Ph ipso}), 137.5 (C_{Ph ipso}), 136.8

(C_{Ph ipso}), 130.7 (C_Ph), 129.1 (C_Ph), 128.8 (C_Ph), 128.6 (C_Ph), 128.4

(C_Ph), 128.0 (C_Ph), 127.8 (C_Ph), 127.0 (C_Ph), 86.0 (C-1), 75.6, 74.0,

72.4 (C_Bn), 72.2 (C_Bn), 69.8, 64.7 (C-5), 16.4 (C-6) ppm.

Phenyl 2,3-Di-O-benzyl-6-deoxy-1-thio-α-L-arabino-hexopyranosid-

4-ulose (41): Dimethyl sulfoxide (0.24 mL, 3.34 mmol, 3.5 equiv.)

was added to dry CH₂Cl₂(10 mL) under argon, and the solution

was cooled to –78 °C. Trifluoroacetic anhydride (TFAA; 0.46 mL,

2.39 mmol, 2.5 equiv.) was added over a 5 min period, and the mix-

ture was allowed to react for a further 15 min Phenyl 2,3-di-O-

benzyl-6-deoxy-1-thio-α-l-altropyranoside (40; 417 mg,

0.63 mmol) was dissolved in dry CH₂Cl₂(5 mL), and this solution

was added to the cooled solution. The reaction mixture was stirred

at –78 °C for 3 h, after which time Et₃N (0.47 mL, 3.34 mmol,

3.5 equiv.) was added. The reaction temperature was allowed to rise

to –20 °C in 2 h, by which time the product has formed. Then, the

mixture was warmed quickly to room temp., and the reaction was

quenched with water. The aqueous phase was extracted with

CH₂Cl₂(3ϫ), and the combined organic phases were washed with

brine, dried (MgSO₄), and concentrated. The remaining oil was

passed through a short column of silica gel (heptane/EtOAc, 30:1

then 25:1) to give ketone 41 (367 mg, 88%) as a white solid. R_f=

0.33 (heptane/EtOAc, 4:1), m.p. 78–79 °C. HRMS (MALDI⁺):

calcd. for C₂₆H₂₆O₄SNa⁺457.1444; found 457.1444. [α]²_D²= –144

Supporting Information (see footnote on the first page of this arti-

1

cle): H, ¹³C, COSY, and HSQC NMR spectra of all compounds;

materials and methods.

1

(c = 1.0, CHCl₃). H NMR (500 MHz, CDCl₃): δ = 7.47 (m, 2 H,

Acknowledgments

Ph), 7.41 (m, 2 H, Ph), 7.36–7.28 (m, 11 H, Ph), 5.58 (d, J_1,2

=

4.6 Hz, 1 H, 1-H), 4.91 [d, J = 11.5 Hz, 1 H, CH(H_a)Ph], 4.80 [d,

J = 11.3 Hz, 1 H, CH(H_a)Ph], 4.73 [d, J = 11.3 Hz, 1 H, CH(H_b)

Ph], 4.66–4.59 [m, 2 H, CH(H_b)Ph, 5-H], 4.52 (d, J_2,3= 8.9 Hz, 1

H, 3-H), 3.76 (dd, J_2,3= 8.9, J_1,2= 4.6 Hz, 1 H, 2-H), 1.35 (d, J_5,6

= 6.9 Hz, 3 H, 6-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 208.9

The Lundbeck Foundation is acknowledged for financial support.

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bohydr. Chem. Biochem. 2004, 59, 9–67.

(C-4), 137.6 (C_{Ph ipso}), 137.5 (C_{Ph ipso}), 134.1 (C_{Ph ipso}), 131.4 (C_Ph), [2] P. T. Daniel, U. Koert, J. Schuppan, Angew. Chem. Int. Ed.

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129.2 (C_Ph), 128.6 (C_Ph), 128.6 (C_Ph), 128.2 (C_Ph), 128.2 (C_Ph),

128.1 (C_Ph), 128.1 (C_Ph), 127.8 (C_Ph), 88.2 (C-1), 82.5 (C-3), 82.0

(C-2), 74.4 (C_benzyl), 74.1 (C_benzyl), 72.7 (C-5), 16.2 (C-6) ppm.

Phenyl 4-O-(4-Nitrobenzoyl)-2,3-di-O-benzyl-6-deoxy-1-thio-α-L-

idopyranoside (42): Phenyl 2,3-di-O-benzyl-6-deoxy-1-thio-α-l-al-

tropyranoside (40; 200 mg, 0.46 mmol), Ph₃P (721 mg, 2.75 mmol,

6 equiv.), and p-nitrobenzoic acid (503 mg, 2.75 mmol, 6 equiv.)

were dissolved in toluene (5 mL), and diisopropyl azodicarboxylate

(DIAD; 0.54 mL, 2.75 mmol, 6 equiv.) was added dropwise. The

mixture was stirred at room temp. under nitrogen for 15 h. Sub-

sequently, the reaction was quenched with saturated aq. NaHCO₃,

and the mixture was extracted with CH₂Cl₂(3ϫ). The combined

organic extracts were washed with water, dried (MgSO₄), and con-

centrated. The residue was purified by flash chromatography (hept-

ane/EtOAc, 12:1Ǟ10:1) to give compound 42 (262 mg, 98%) as a

pale yellow syrup. R_f= 0.52 (heptane/EtOAc, 4:1). HRMS

(MALDI⁺): calcd. for C₃₃H₃₁O₇NSNa⁺608.1713; found 608.1713.

[α]²_D²= –92 (c = 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ =

8.01 (dt, J = 2.0, J = 9.0 Hz, 2 H, Ph), 7.95 (dt, J = 2.0, J = 9.0 Hz,

2 H, Ph), 7.46 (m, 2 H, Ph), 7.34–7.06 (m, 13 H, Ph), 5.61 (d, J_1,2

= 1.4 Hz, 1 H, 1-H), 4.99 (m, 1 H, 4-H), 4.84 (qd, J_5,6= 6.7, J_4,5

= 1.8 Hz, 1 H, 5-H), 4.69 [d, J = 12.0 Hz, 1 H, CH(H_a)Ph], 4.64

[d, J = 12.0 Hz, 1 H, CH(H_b)Ph], 4.49 [d, J = 10.9 Hz, 1 H, CH(H_a)

Ph], 4.28 [d, J = 10.9 Hz, 1 H, CH(H_b)Ph], 3.84 (td, J = 3.3, J =

1.2 Hz, 1 H, 3-H), 3.74 (dt, J_2,3= 2.8, J_1,2= 1.2 Hz, 1 H, 2-H),

1.50 (br. s, 1 H, 4-OH), 1.18 (d, J_5,6= 6.6 Hz, 3 H) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ = 164.5 (C_carbonyl), 150.6 (C_{Ph ipso}), 137.5 (C_Ph

_ipso), 137.2 (C_{Ph ipso}), 136.9 (C_{Ph ipso}), 135.3 (C_{Ph ipso}), 131.1 (C_Ph),

130.8 (C_Ph), 129.0 (C_Ph), 128.7 (C_Ph), 128.4 (C_Ph), 128.2 (C_Ph),

128.1 (C_Ph), 127.8 (C_Ph), 127.1 (C_Ph), 123.4 (C_Ph), 86.0 (C-1), 75.9

(C-2), 73.2 (C-3), 72.9 (C_Bn), 72.8 (C_Bn), 71.2 (C-4), 62.9 (C-5), 16.4

(C-6) ppm.

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T. G. Frihed, C. M. Pedersen, M. Bols

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2014, DOI:10.1002/anie.201408209.

Received: August 13, 2014

Published Online: ᭿

16

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43074

/KAP1

Date: 28-10-14 13:59:35

Pages: 17

Synthesis of 6-Deoxy-l-hexopyranosyl Donors

Rare Sugar Synthesis

T. G. Frihed, C. M. Pedersen,*

M. Bols ........................................... 1–17

Synthesis of All Eight Stereoisomeric 6-De-

oxy-l-hexopyranosyl Donors – Trends in

Using Stereoselective Reductions or Mitsu-

nobu Epimerizations

The synthesis of all eight rare but biologi-

cally important 6-deoxy-l-hexoses as their

thioglycoside glycosyl donors starting from

l-rhamnose or l-fucose is reported. The

synthesis was achieved using various epi-

merization methods. The stereoselective re-

duction of 4-oxo pyranosides could be pre-

dicted by the Cram chelation model, while

Mitsunobu epimerization led to elimin-

ation in some substrates.

Keywords: Carbohydrates / 6-Deoxy-l-su-

gars / Diastereoselectivity / Reduction /

Nucleophilic substitution / Substituent ef-

fects

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

17

Article Doi

Synthesis of all eight stereoisomeric 6-deoxy-l-hexopyranosyl donors - Trends in using stereoselective reductions or mitsunobu epimerizations

DOI: 10.1002/ejoc.201403074

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Article abstract of DOI:10.1002/ejoc.201403074

Full text of DOI:10.1002/ejoc.201403074

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