Carbasugar analogues of galactofuranosides: β-O-linked derivatives and towards β-S-linked derivatives

DOI: 10.1016/j.carres.2011.04.032

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Carbohydrate Research p. 1277 - 1290 (2011)

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Frigell, Jens

Eriksson, Lars

Cumpstey, Ian

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Article abstract of DOI:10.1016/j.carres.2011.04.032

A selectively protected carbasugar analogue of β-galactofuranose was synthesised from glucose using ring-closing metathesis as the key step. The carbasugar was converted into an α-galacto configured 1,2-epoxide, which was an effective electrophile in Lewis acid catalysed coupling reactions with alcohols. The epoxide was opened with regioselective attack at C-1 to give β-galacto configured C-1 ethers. Using carbohydrates as nucleophiles, we synthesised a number of pseudodisaccharides. The epoxide was also regioselectively opened at C-1 with a sulfur nucleophile under basic conditions to give a β-galacto configured C-1 thioether.

Full text of DOI:10.1016/j.carres.2011.04.032

Carbohydrate Research 346 (2011) 1277–1290

Contents lists available at ScienceDirect

Carbohydrate Research

journal homepage: w ww.elsevier.com/locate/carres

Carbasugar analogues of galactofuranosides: b-O-linked derivatives and towards

b-S-linked derivatives ^q

Jens Frigell ^a, Lars Eriksson ^b, Ian Cumpstey ^a,c,

⇑

^aDepartment of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden

^bDivision of Structural Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden

^cInstitut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette CEDEX, France

a r t i c l e i n f o

a b s t r a c t

Article history:

A selectively protected carbasugar analogue of b-galactofuranose was synthesised from glucose using

Received 17 March 2011

Received in revised form 16 April 2011

Accepted 25 April 2011

ring-closing metathesis as the key step. The carbasugar was converted into an

a-galacto conﬁgured

1,2-epoxide, which was an effective electrophile in Lewis acid catalysed coupling reactions with alcohols.

The epoxide was opened with regioselective attack at C-1 to give b-galacto conﬁgured C-1 ethers. Using

carbohydrates as nucleophiles, we synthesised a number of pseudodisaccharides. The epoxide was also

regioselectively opened at C-1 with a sulfur nucleophile under basic conditions to give a b-galacto con-

ﬁgured C-1 thioether.

Available online 5 May 2011

Keywords:

Carbasugars

Galactofuranose

Pseudodisaccharides

Glycomimetics

Ring-closing metathesis

Epoxide-opening

1. Introduction

Carba-aldohexofuranoses have not been extensively described

in the literature. Vasella and Huber synthesised a protected carbah-

Carbohydrates are found in nature as components of glycocon-

jugates: poly- or oligosaccharides linked to proteins, lipids and

other molecules.³The carbohydrate structures are species-

dependent: some structures, such as galactofuranose (the subject

of this work), are not found in mammals, but they are widespread

in numerous other organisms. Galactofuranose is found as a com-

ponent of oligo- or polysaccharides in some bacteria, fungi and

protozoa.^4,5It has been proposed that interfering with the biosyn-

thesis of galactofuranose and galactofuranose-containing

structures could be a potential route to antimicrobial therapies.⁶

Hydrolytically stable analogues of galactofuranose, including

C-glycosides,⁷thioglycosides,⁸thiosugars,⁹iminosugars¹⁰and gly-

cosyl amides,¹¹have been synthesised before (Fig. 1). We

considered the carbasugar 1 and its derivatives, in which the endo-

cyclic oxygen is replaced by methylene.^12,13Carbasugars have the

attractive feature that other moieties may be linked to the

carbasugar by carbon–heteroatom bond formation at C-1 to give

hydrolytically stable carbaglycoconjugates.

exofuranose from mannose by Horner–Wadsworth–Emmons chem-

istry.¹⁴The Lundt group has synthesised some carbahexofuranoses,

including 4a-carba-b-^D-glucofuranose and 4a-carba-a-L-glucofura-

nose.^15,16Ghosh et al. reported the synthesis of a number of diaste-

reomers by using ring-closing metathesis to form the C-2–C-3

bond;¹⁷only the b-D-allo compound was obtained deprotected.

Meanwhile, very recently, two syntheses of C-4@C-4a unsaturated

carbahexofuranoses have been achieved starting from carbohy-

drates: Nguyen van Nhien et al. used an alkylidenecarbene to close

the ring,¹⁸and Schneller et al. used an ene-yne metathesis strat-

egy.¹⁹The synthesis of a modiﬁed carbagalactofuranose with a fused

cyclopropane ring has also recently been reported.²⁰Carbadisaccha-

rides containing carba-(hexo or pento)-furanosides do not appear to

have been described before.^2,21,22Considering the scarce results in

the carbahexofuranose ﬁeld and the great biological signiﬁcance of

galactofuranose, both the synthesis and potential biological applica-

tions are of interest.

One possible disconnection for the synthesis of carbadisaccha-

rides is shown in Scheme 1: the carbasugar ether linkage (in I) is

put in place by attack of carbohydrate alcohol nucleophiles on an

electrophilic carbasugar C-1 (II). This approach is versatile in that

Presented in part at the 15th European Carbohydrate Symposium, Vienna, July

2009. Preliminary published reports, Refs. 1,2.

⇑

Corresponding author. Tel.: +33 (0)1 69 82 30 78; fax: +33 (0)1 69 07 72 47.

E-mail addresses: ian.cumpstey@icsn.cnrs-gif.fr, ian.cumpstey@sjc.oxon.org

Whereas all but two of the 16 possible carbapentofuranose stereoisomers have

been synthesised: 4a-carba-

been described, see Ref. 13.

a-D-ribofuranose and 4a-carba-a-L-lyxofuranose have not

(I. Cumpstey).

doi:10.1016/j.carres.2011.04.032

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J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

by ring-closing metathesis.²⁶The required diene precursor V

would be obtained in a few steps from a gluco hemiacetal VI via

Grignard addition, regioselective protection, Swern oxidation and

Wittig methylenation. Using the hemiacetal with OH-2 free (IV)

should give a carbocycle with the correct protecting group pattern

to allow 1,2-epoxide formation; we might also expect good diaste-

reoselectivity in a 1,2-chelation-controlled Grignard reaction, and

also be able to take advantage of regioselective protection of the

resulting triol to give only OH-4 free. We may use glucose as the

starting material, despite the fact that the target molecule has

the galacto conﬁguration, as the conﬁguration at C-4 is lost during

the synthesis. Related approaches to carbapentofuranose deriva-

tives have been described before.^27–35

galactofuranoside

(natural glycoside)

thiosugar

thioglycoside

2. Results and discussion

NHC(O)R

The hemiacetal 2 was synthesised in three steps from diacetone

glucose according to literature procedures.^36–38Addition of vinyl-

magnesium bromide to the hemiacetal 2 in THF gave a mixture

(6:1) of epimers 3a and 3b, separable by column chromatography,

in 87% yield (Scheme 2). When vinylmagnesium chloride in THF

was used instead, the stereoselectivity improved to ca. 20:1. The

C-1 conﬁguration of the products was not assigned at this stage,

but we later conﬁrmed that triol 3a was indeed the major product

(see below). A 1,2-chelation model³⁹accounts for the formation of

the major diastereomer. The reason why the chloride reagent gives

better selectivity than the bromide reagent is unclear, but similar

behaviour has been observed before in related systems.⁴⁰Triol 3a

was treated with 2,2-dimethoxypropane and catalytic camphorsul-

fonic acid, giving the ﬁve-membered ring acetonide 4 in a poor 33%

yield along with two more products, which were identiﬁed as the

six-membered (5) and seven-membered (6) ring isomers, respec-

tively (4:5:6; 10:2:5). The regiochemical assignment of 4–6 was

made based on ¹³C NMR chemical shifts of the acetonide methyl

groups and quaternary carbons.⁴¹When we ran the reaction under

kinetic control, treating triol 3a with 2-methoxypropene and

pyridinium tosylate in dichloromethane, the ﬁve-ring acetonide 4

was formed as essentially the only product after 15 min, and iso-

lated in 94% yield. The remaining free alcohol in 4 was oxidised un-

der Swern conditions to give ketone 7 in 80% yield. Wittig

methylenation of ketone 7 using the ylid derived from Ph₃PMeBr

and t-BuOK gave diene 8 in a moderate 49% yield. The low yield

was due to competing elimination. Ylid formation using n-BuLi

gave much better results, and yields of diene 8 of up to 81% were

obtained.

glycosyl amide

iminosugar

C-glycoside

carbasugar 1

Figure 1. Galactofuranose and modiﬁed synthetic analogues.

many readily accessible carbohydrate alcohols, or indeed other

nucleophiles, could be used to attack a single carbasugar C-1 elec-

trophile. Galactofuranose is found in microorganisms glycosidi-

cally linked to miscellaneous saccharides,⁴so a more general

route to carbagalactofuranose-containing carbadisaccharides

would be advantageous. Ether- or amine-linked carbadisaccharides

derived from carbapyranoses have been synthesised by nucleo-

philic ring-opening of 1,2-epoxides under Lewis acidic or basic

conditions.^23–25

We required a partially protected carbagalactofuranose deriva-

tive with OH-1 and OH-2 free (III), and planned to synthesise this

from a carbohydrate starting material.¹Protected carbagalactof-

uranose III should be accessible by diastereoselective reduction

of a C-4@C-4a unsaturated precursor IV, which would be made

OR'

III

+ alcohol, R'OH

Scheme 1. A retrosynthesis of carbagalactofuranosides.

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

1279

BnO

(ii)

(i)

BnO

(iii)

BnO

(v)

(iv)

BnO

OBn OBn OH

BnO

Scheme 2. Reagents and conditions: (i) vinylmagnesium chloride (4 equiv), THF, rt, 17 h, 87% (3a:3b, ca. 20:1); (ii) 2-methoxypropene (2.8 equiv), PPTS (0.1 equiv), CH₂Cl₂, rt,

15 min, 94%; (iii) DMSO (2 equiv), oxalyl chloride (2 equiv), CH₂Cl₂, ꢀ60 °C; then Et₃N (5 equiv), rt, 80%; (iv) Ph₃PMeBr (5 equiv), n-BuLi (4.5 equiv), toluene, rt, then 7, ꢀ78 °C,

81%; (v) AcOH, H₂O, (2:1), 75 °C, 2 h, quant.

BnO

(iv)

(v)

BnO

(i)

(viii)

(iii)

BnO

(vii)

OAc

(ii)

OAc

BnO

OAc

(vi)

(ix)

AcO

BnO

OAc

AcO

OAc

BnO

OAc

Scheme 3. Reagents and conditions: (i) Ac₂O, py, 14 h, quant.; (ii) Grubbs’ 2nd complex (0.035 equiv), toluene, 60 °C, 48 h; then DMSO (1.75 equiv), 24 h, 87%; (iii) NaOMe,

MeOH, rt, 90 min, quant.; (iv) Hoveyda–Grubbs 2nd complex (0.05 equiv), toluene, 60 °C, 1 h, 43%; (v) H₂, Pd/C, Et₃N (4 equiv), EtOAc, rt, 1.5 h, 91%; (vi) H₂, Pd/C, Et₃N

(5 equiv), EtOAc, rt, 1.5 h, 49%; (vii) Ac₂O, py, 72%; (viii) H₂, Pd/C, EtOAc, EtOH, rt, 1.5 h, quant.; (ix) Ac₂O, py, rt, 2 h, 69%.

We found that to get the best results in the ring-closing metath-

esis reaction, a protecting group swap at C-1 and C-2 was neces-

sary. Thus, the acetonide of 8 was removed by acidic hydrolysis

to give diol 9, which was then acetylated to give diacetate 10 in

excellent yield (Scheme 3). This compound underwent the ring-

closing reaction with Grubbs’ 2nd generation complex in toluene

at 60 °C to give cyclopentene 11 in 87% yield. As the reaction rate

dropped considerably after a few hours, the catalyst was added

portionwise over 18 h. A total of 3.5 mol % catalyst was added to

ensure complete consumption of the starting material.

1280

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

Attempts to induce ring-closure of acetonide 8 (Grubbs’ 2nd

generation complex (5 mol %), toluene, 60 °C, 21 h) resulted in no

reaction, which is not unexpected as the product from this reaction

would contain a trans-fused 5,5-ring system. Attempted ring-

closure of diol 9 did give cyclopentene 12 in 43% yield with the

Hoveyda–Grubbs 2nd generation complex in toluene at 60 °C,

and in lower yield (24–36%) when Grubbs’ 2nd generation complex

was used. These reactions with 1,2-diol 9 gave rapid consumption

of starting material and formation of unidentiﬁed by-products in

addition to the ring-closed product 12.

The acetate protection was removed from the cyclopentene 11

by methanolysis to give diol 12 in quantitative yield. The C@C bond

in 12 was reduced diastereoselectively by catalytic hydrogenation

over palladium on carbon in the presence of Et₃N to preserve the

benzyl ether protection,⁴²and the saturated diol 13 was formed

in 91% yield as a single diastereomer (see below for stereochemical

assignment). The benzyl ethers were removed from 13 by catalytic

hydrogenolysis over palladium on carbon gave the deprotected

carbasugar 1, which was also characterised as its peracetate 15.

The diastereoselectivity of the C@C reduction is possibly coun-

terintuitive, as hydrogen adds cis to both neighbouring ring substit-

uents (i.e., at C-1 and C-3). Similarly good diastereoselectivity was

observed by Lowary in a pseudoenantiomeric system, resulting in

exclusive formation of an

a-L-arabinoside from hydrogenation of

Figure 2. Crystal structure of 12. Ellipsoids are shown at 50% probability.

the corresponding C-4@C-4a unsaturated carbapentofuranose,³⁰

but the catalyst used in that reaction (viz. Wilkinson’s catalyst)

should not necessarily show the same behaviour as palladium on

carbon as used by us. We also investigated the reduction of C@C

bonds in some related compounds, all of which appeared to give

similarly good diastereoselectivity: Firstly, hydrogenation of the

cyclopentene diacetate 11 over palladium on carbon in the pres-

ence of Et₃N gave the saturated diacetate 14 also with excellent dia-

stereoselectivity (only one diastereomer was observed) but in a

disappointing isolated yield of 49%. The diastereoselectivity in the

hydrogenation of diacetate 11 had the same sense as in the hydro-

genation of diol 12, which was proved by acetylation of the satu-

rated diol 13 to give the saturated diacetate 14. The low yield in

the hydrogenation of diacetate 11 can be rationalised as we saw a

by-product formed in 46% yield that showed m/z 497 (M+Na⁺) in

its mass spectrum, and that had ﬁve high-ﬁeld protons and only

one acetate singlet in its ¹H NMR spectrum. This would be consis-

tent with reduction of the C–O bond at C-1, resulting in the nett loss

of acetate. Secondly, removal of the benzyl ethers from 12 by Birch

reduction gave the unsaturated pentaol, which was hydrogenated

over palladium on carbon to give the same b-galacto carbasugar 1

with excellent diastereoselectivity; the alternative b-gluco diaste-

reomer was not detected. Thirdly, an attempted one-pot reduc-

tion–deprotection reaction of diol 12 by hydrogenation over

palladium on carbon without Et₃N was not a clean reaction, giving

a low yield of 1 along with many by-products. Possibly this was due

to concomitant hydrogenolysis of allylic C–O bonds: it has been

shown that addition of Et₃N to the palladium-catalysed hydrogena-

tion of acarbose suppresses allylic C–N bond cleavage.⁴³Regarding

the diastereoselectivity of the reduction–deprotection of 12, we

only isolated and characterised the b-galacto carbasugar 1 but the

possibility that some of the by-products had b-gluco stereochemis-

try (or the corresponding C-4 conﬁguration) cannot be ruled out.

During the synthesis of carbasugar 1, two new stereogenic cen-

tres are formed; one from the Grignard addition to give triol 3a (C-

1 conﬁguration) and the other from the C@C reduction to form sat-

urated compound 13 (C-4 conﬁguration). Assuming ﬁxed conﬁgu-

rations at the remaining stereogenic centres, C-2, C-3 and C-5, the

in six-membered rings using ¹H NMR spectroscopy. It has been ob-

served empirically for cyclopentanes that ³J ¹H,¹H coupling con-

stants less than 5 Hz are indicative of

a trans relationship

between the protons, whereas higher coupling constants are

non-diagnostic.⁴⁴A similar observation for furanosides (for cou-

pling constants below 2 Hz) has been rationalised by evaluating

the dihedral angles in accessible ring-conformational trajectories

in the context of the Karplus equation.⁴⁵For the saturated carbah-

exofuranosides discussed in this paper,^àthe values of J_1,2were quite

diverse, ranging from 3.1 to 7.1 Hz, whereas J_3,4values were in the

range 7.5–9.0 Hz, which was not helpful in determining the relative

conﬁguration.

Lundt has reported the synthesis of carba-

a-L-glucofuranose

and carba-b-

-glucofuranose.^15,16The non-identity of the reported

¹H NMR and ¹³C NMR spectral data of either of these two com-

pounds with NMR data from carbasugar 1 suggested that 1 was

not a carbaglucofuranose and hence must be a carbagalactofura-

nose. We solved the crystal structure of the unsaturated diol 12

(Fig. 2), which was thus proved to have a b-D-xylo conﬁguration,

corresponding to a b-conﬁguration at C-1 of 1. Taken together, this

suggested that carbasugar 1 had the b-galacto conﬁguration, but

we planned to prove the relative conﬁguration of 1 by degradation,

cleaving the C-5–C-6 bond of our carbasugar to form a carbapen-

tose;¹⁵all four possible carbapentose diastereomers have been

synthesised previously.

We protected OH-1 and OH-2 of diol 13 as 2-naphthoate esters,

giving the fully protected compound 16 (Scheme 4). The benzyl

ethers of 16 were removed by catalytic hydrogenation, which

was followed by oxidative cleavage of the C-5–C-6 bond and reduc-

tion of the resulting C-5 aldehyde in situ with sodium borohydride.

The naphthoate protecting groups were then removed using so-

dium methoxide to give carbapentose 17 in 80% yield over three

steps. The carbapentose 17 was unambiguously identiﬁed as 4a-

carba-a-L

-arabinofuranose^46,47by comparison of the ¹H NMR and

¹³C NMR spectra with those of the known carbapentoses (and bear-

ing in mind the known absolute stereochemistry at C-2 and C-3);

carbasugar products should have one of the four possible

a or b D-

gluco or -galacto conﬁgurations. The inherent ﬂexibility of ﬁve-

membered rings means that it is more difﬁcult to determine the

conﬁguration of stereogenic centres in ﬁve-membered rings than

Based on assigned NMR data from 27 carba-b-D-galactofuranoses from this paper,

and also from derivatives in Refs. 21,22.

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

1281

BnO

(i)

(ii) (v)

BnO

, R = 2-naphthoyl

BnO

Scheme 4. Reagents and conditions: (i) 2-naphthoyl chloride, DMAP (0.06 equiv), pyridine, 50 °C, 24 h, 90%; (ii) H₂, Pd/C, 1 M HCl, EtOAc, 5 days, 50%; (iii) NaIO₄, H₂O, 0 °C,

1 h; (iv) NaBH₄, H₂O, rt, 2 h; (v) NaOMe, MeOH, 3 h, 50 °C, 80% (three steps).

BnO

(i), ref 22

BnO

(ii)

BnO

(iii)

BnO

OAc

BnO

20a f

19a f

R = Bu

b R = Pr

R = Et

18 19: 75%

19 20: 98%

18 19: 82%

19 20: 87%

18 19: 61%

19 20

: 48%

OMe

OBn

BnO

OMe

18 19: 65%

19 20

OMe

18 19: 77%

19 20

: 89%

18 19

: 52%

: 99%

19 20: 86%

Scheme 5. Reagents: (i) see Ref. 22; (ii) ROH (equiv: a–c, 10; d, 3.2; e,f, 5.0), BF₃ꢁEt₂O (0.1–0.2 equiv), CH₂Cl₂; (iii) Ac₂O, py, DMAP.

BnO

OEt

(i)

(ii)

BnO

OEt

BnO

19a

Scheme 6. Reagents and conditions: (i) EtBr (10 equiv), NaH, DMF, rt, 5 d, 45%; (ii) EtBr (10 equiv), NaH, DMF, rt, 4 h, 46%.

the optical rotation conﬁrmed the assignment. This means that diol

13 can indeed be assigned the b- -galacto stereochemistry.

gave the respective ethers 19a–c in high yields. In all three reac-

tions, epoxide 18 suffered nucleophilic attack at C-1 exclusively,

giving the product ethers with OH-2 free. The regiochemistry of

substitution was proved by acetylation of the coupling products

19a–c; 2D-COSY ¹H,¹H NMR spectroscopy showed a large down-

ﬁeld shift for H-2 in the acetates 20a–c, proving that OH-2 had

been acetylated.

To unambiguously prove the stereochemistry of the products

19, diol 13, with known relative conﬁguration, was alkylated with

ethyl bromide to give diethyl derivative 21. Ether 19a, resulting

from epoxide opening by ethanol, was also alkylated with ethyl

bromide and gave the same product 21, showing that the product

of epoxide opening has the b-galacto stereochemistry, consistent

We then turned to the synthesis of pseudodisaccharides based

on carbagalactofuranose. Treatment of diol 13 with DIAD and tri-

phenylphosphine resulted in 1,2-epoxide 18, formed as a single

diastereomer by intramolecular Mitsunobu type reaction.²²The

stereochemistry of epoxide 18 was apparent as a two-step proce-

dure from diol 13 via an isolated C-1 tosylate gave the same prod-

uct 18.²²

We investigated the epoxide-opening reaction with simple

model alcohol nucleophiles (10 equiv) in the presence of BF₃ꢁEt₂O

as a Lewis acid catalyst (Scheme 5). Opening with primary (etha-

nol), secondary (isopropanol), or tertiary (tert-butanol) alcohols

1282

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

OMe

BnO

(i)

BnO

25d

BnO

OBn

Scheme 7. Reagents and conditions: (i) AcOH, H₂O, 70 °C, 54%.

with C-1 attack with inversion of conﬁguration in the epoxide-

opening reaction (Scheme 6).

nethiol in MeOH under basic conditions, a thioether product 27

was formed as a single regioisomer (Scheme 8). The identity of thi-

oether 27 was conﬁrmed by acetylation of the free hydroxyl group.

Examination of the ¹H NMR spectra of acetate 28 indicated that O-

2 had been acetylated, and that, therefore, nucleophilic attack had

occurred at C-1 during the epoxide-opening reaction in this case

also. The assignment of b-galacto stereochemistry to 27 is based

on the assumption that nucleophilic attack at C-1 by EtS^ꢀwill oc-

cur with inversion of conﬁguration. In the epoxide-opening reac-

tion, we used excess base (15 equiv NaOMe, 10 equiv EtSH),

meaning that both MeO^ꢀand EtS^ꢀwere present as potential nucle-

ophiles in the reaction mixture. Only attack by the sulfur nucleo-

phile was observed.

Some issues regarding regioselectivity in epoxide formation and

opening are worthy of comment. In the epoxide-opening reactions

of 18, the fact that C-1 has an unsubstituted neighbour (C-4a),

while C-2 is linked to a carbon bearing a bulky substituent (the

benzyl ether on C-3) provides a steric argument for the preferential

nucleophilic attack at C-1 over C-2 that applies both in Lewis acidic

(O-nucleophile) and basic (S-nucleophile) conditions. In Lewis acid

mediated epoxide-opening reactions, an electronic inﬂuence on

regioselectivity can be explained in terms of the relative stability

of partial positive charges on the two epoxide carbons. A build-

up of positive charge would be less favourable at C-2 than at C-1

due to the proximity of the electron-withdrawing benzyl ether at

C-3; the carbon ﬂanking C-1, i.e., C-4a, does not bear any elec-

tron-withdrawing functionality, so the electronic argument would

also favour attack at C-1 over C-2. Under basic conditions, the b-

oxygen effect that deﬁnes the low reactivity of carbohydrate

electrophiles in S_N2 reactions applies. Hence, C-2 (which has a b-

oxygen at C-3) is less electrophilic than C-1 (which has no b-oxy-

gen at C-4a). The Fürst–Plattner guideline (or the principle of

microscopic reversibility) predicting trans-diaxial opening in six-

membered rings may be used to explain the good regioselectivity

observed by Ogawa in related carbapyranose pseudodisaccharide

formation,^50,51but it is not useful to explain our results, this differ-

ence being due to the more ﬂexible nature of ﬁve-membered

rings.²¹Indeed, we have found that the diastereomeric b-talo epox-

ide 29 (Fig. 3) was also opened with very good regioselectivity for

attack at C-1 under Lewis acidic conditions.²¹

Epoxide 18 was also opened using primary and secondary car-

bohydrate alcohols (3–5 equiv) as nucleophiles (viz. Rha OH-4

22,^48aMan OH-3 23,^48bMan OH-6 24^48c) under BF₃ꢁEt₂O catalysis,

resulting in the formation of carbadisaccharides 19d–f. Unreacted

excess alcohol starting materials were recovered. The regioselec-

tivity of the reaction was again excellent in all cases, and the prod-

ucts of nucleophilic attack at C-2 were not observed. Again, the

sense of regioselectivity was proved by acetylation of the coupling

products to give C-2^IIacetates 20d–f.

The reaction products 19 contain a secondary alcohol (OH-2^II),

which could feasibly act as a nucleophile, consuming epoxide

and product and forming pseudotrisaccharides (where the original

alcohol was a carbohydrate) or pseudodisaccharides (where it was

not).⁴⁹This scenario is to be avoided not only because the valuable

starting materials and products are consumed to form undesired

by-products, but also because separation of the desired carbasugar

ether from its homologue by chromatography may not be straight-

forward. For example, in the reaction forming pseudodisaccharide

19d, we did observe formation of a pseudotrisaccharide (25d)

whose identity was suggested by MS, with a peak seen at m/z

1101 (M+Na⁺). However, removal of impurities from this com-

pound by ﬂash chromatography was difﬁcult. The isopropylidene

group was cleaved from 25d by acidic hydrolysis to give a triol that

was puriﬁed and characterised as pseudotrisaccharide 26

(Scheme 7).

Hence the best results in the coupling reactions were obtained

by using an excess of the alcohol (which should be recovered after

the consumption of the epoxide). Using excess epoxide with an

alcohol of low nucleophilicity such as a secondary carbohydrate

alcohol can only result in low yields of the monocoupled product.

Ogawa has described ring-opening of carbapyranose 1,2-epox-

ides by alcohol nucleophiles to give

a-carbamannopyranosides.

He found that while a primary carbohydrate alcohol coupled with

the epoxide under Lewis acid catalysis, more hindered secondary

alcohol nucleophiles failed to give coupling products under these

conditions, and he instead used basic conditions.⁵⁰We tried to

open carbafuranose epoxide 18 under basic conditions (NaH, 15-

crown-5, DMF, 70–100 °C) without success; no reaction was seen

with alcohols Rha OH-4 (22) and Man OH-3 (23), even after several

days.

Two possible explanations for the excellent regioselectivity in

the Mitsunobu (epoxidation) reaction are considered. The higher

nucleophilicity of OH-1 than OH-2 could explain the outcome if

formation of the activated alcohol (RO–P⁺Ph₃) is rate-determining.

Alternatively, if there is a rapid equilibrium between the two reg-

We then examined the reactivity of the epoxide 18 towards a

sulfur nucleophile for the synthesis of carbagalactofuranose C-1

thioethers. When the epoxide 18 was treated with excess etha-

BnO

SEt

(ii)

(i)

BnO

OAc

BnO

Scheme 8. Reagents and conditions: (i) EtSH (10 equiv), NaOMe (15 equiv), MeOH, 68%; (ii) Ac₂O, pyridine, 92%.

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

1283

complex (CAS No.: 246047-72-3) was bought from Sigma–Aldrich

and coated in wax (complex 12% by weight) before use. Hoveyda–

Grubbs second generation complex (CAS No.: 301224-40-8) was

bought from Sigma–Aldrich and used as supplied. Dichlorometh-

ane was distilled from calcium hydride. Diethyl ether and THF

were dried over molecular sieves and dispensed from a solvent

puriﬁer by VAC. Toluene was distilled from sodium. Reactions per-

formed under an atmosphere of hydrogen, nitrogen or argon were

maintained by an inﬂated balloon.

BnO

Figure 3.

ioisomeric activated alcohols (RO¹–P⁺Ph₃and R⁰O²–P⁺Ph₃), possibly

via a discrete ﬁve-membered ring intermediate,⁵²before rate-

determining ring-closure, the regioselectivity may be explained

by the higher electrophilicity of C-1 than C-2. Bearing in mind

our other results on the relative nucleophilicity of OH-1 and OH-

2 in 13 (moderate–good regioselectivity with TsCl as electro-

phile)^22,21and epoxide-opening of 18 (excellent regioselectivity),

the latter explanation seems more likely.

3.2. (2R,3R,4R,5S,6R)-1,2,4-Tri-O-benzyl-1,2,3,4,5,6-hexahydroxy-

oct-7-ene (3a)

Hemiacetal 2 (11.0 g, 24.4 mmol) was dissolved in THF (45 mL)

and cooled to 0 °C under N₂. Vinylmagnesium chloride (1.6 M in

THF, 62.6 mL, 100.2 mmol) was added at 0 °C and the reaction mix-

ture was stirred at rt for 17 h. The reaction was then quenched by

slow addition of NH₄Cl (satd aq) at 0 °C until a neutral pH was ob-

tained. Et₂O (45 mL) was added and the reaction mixture was

washed with water (45 mL) and brine (2 ꢂ 45 mL). The combined

aqueous phases were extracted with Et₂O (3 ꢂ 45 mL). The organic

phases were combined and dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was puriﬁed by ﬂash column chroma-

tography to give triol 3a (10.1 g, 87%) as a yellow oil (R_f0.3,

To conclude, we have synthesised 4a-carba-b-D-galactofuranose

from glucose in 13 steps via a diastereoselective Grignard addition

to hemiacetal 3, ring-closing metathesis for carbocycle formation,

and highly diastereoselective hydrogenation of the double bond

in cyclopentene 15. Carbagalactofuranosides have been formed

by Lewis acid catalysed opening of a carbasugar 1,2-epoxide 18

using carbohydrate-derived and non-carbohydrate alcohols as

nucleophiles, with excellent regioselectivity for attack at C-1 in

all cases. The reaction appears to be generally applicable. The use

of excess nucleophile minimises competitive attack on the epoxide

by the secondary alcohol in the coupling product. Attempted ring-

opening under basic conditions failed to give any reaction with

oxygen nucleophiles, but this approach seems to hold some prom-

ise with sulfur nucleophiles, as a thiolate opened the epoxide with

excellent regioselectivity for attack at C-1.

CH₂Cl₂–Et₂O, 4:1); ½a _D²⁵

ꢃ

ꢀ28.3 (c 1.0, CHCl₃); IR (Film)

m 3400

(OH) cm^ꢀ^{1 1}H NMR (300 MHz, CDCl₃) d_H3.67–3.73 (2H, m, H-2,

;

H-5), 3.75 (1H, dd, J_1,24.7 Hz, J_1,110.2 Hz, H-1), 3.86 (1H, dd, J_{1 ,2}

3.9 Hz, J_1,110.2 Hz, H-1⁰), 3.91 (1H, dd, J_3,41.9 Hz, J_4,54.7 Hz, H-

4), 3.99 (1H, m, H-3), 4.35 (1H, m, H-6), 4.47, 4.74 (2H, 2 ꢂ d, J

11.5 Hz, PhCH₂), 4.52 (2H, s, PhCH₂), 4.58 (2H, s, PhCH₂), 5.21

(1H, dat, J_cis10.6 Hz, J 1.6 Hz, H-8_cis), 5.33 (1H, dat, J_trans17.3 Hz,

J 1.6 Hz, H-8_trans), 5.84 (1H, ddd, J_6,75.5 Hz, J_cis10.6 Hz, J_trans

17.3 Hz, H-7), 7.22–7.37 (15H, m, Ar-H); ¹³C NMR (100 MHz,

CDCl₃) d_C69.9 (t, C-1), 70.8 (d, C-3), 70.9 (d, C-6), 72.0, 73.7, 74.1

(3 ꢂ t, 3 ꢂ PhCH₂), 73.3, 77.8 (2 ꢂ d, C-2, C-5), 77.2 (d, C-4), 116.8

(t, C-8), 127.8, 127.9, 128.1, 128.1, 128.5, 128.5, 128.6 (7 ꢂ d, Ar-

CH), 137.7, 137.9, 138.2 (d, 2 ꢂ s, C-7, 3 ꢂ Ar-C); HRESIMS calcd

for C₂₉H₃₄O₆Na (MNa⁺) 501.2248; found 501.2239.

3. Experimental

3.1. General methods

Melting points were measured using a Gallenkamp melting

point apparatus and are uncorrected. Proton nuclear magnetic res-

onance (¹H) spectra were recorded on Bruker Avance II 500

(500 MHz), Bruker Avance II 400 (400 MHz), Varian Mercury 400

(400 MHz) or Varian Mercury 300 (300 MHz) spectrometers; mul-

tiplicities are quoted as singlet (s), doublet (d), doublet of doublets

(dd), doublet of doublet of doublets (ddd), triplet (t), apparent trip-

let (at), doublet of apparent triplets (dat), doublet of doublet of

apparent triplets (ddat), quartet (q), apparent quartet (aq), appar-

ent quartet of doublets (aqd) and multiplet (m). Carbon nuclear

magnetic resonance (¹³C) spectra were recorded on Bruker Avance

II 500 (125 MHz), Bruker Avance II 400 (100 MHz) or Varian Mer-

cury 400 (100 MHz) spectrometers. ¹H and ¹³C spectra and ¹³C

multiplicities were assigned using COSY, HSQC, DEPT experiments.

All chemical shifts are quoted on the d-scale in parts per million

(ppm). Residual solvent signals or TMS were used as an internal

reference. Low- and high-resolution (HRESIMS) electrospray (ESI)

mass spectra were recorded using a Bruker Microtof instrument.

Infra-red spectra were recorded on a Perkin–Elmer Spectrum One

FT-IR spectrometer using the thin ﬁlm method on NaCl plates.

Optical rotations were measured on a Perkin–Elmer 241 polarime-

ter with a path length of 1 dm; concentrations are given in g/

100 mL. Thin layer chromatography (TLC) was carried out on

Merck Kieselgel sheets, pre-coated with 60F₂₅₄silica. Plates were

visualised with UV light and developed using 10% sulfuric acid,

or an ammonium molybdate (10% w/v) and cerium (IV) sulfate

(2% w/v) solution in 10% sulfuric acid. Flash column chromatogra-

3.3. (2R,3R,4S,5S,6R)-1,2,4-Tri-O-benzyl-5,6-O-isopropylidene-

1,2,3,4,5,6-hexahydroxy-oct-7-ene (4)

Triol 3a (4.93 g, 10.3 mmol) was dissolved in CH₂Cl₂(100 mL) at

rt, and 2-methoxypropene (2.70 mL, 28.9 mmol) and PPTS

(259 mg, 1.03 mmol) were added. The reaction mixture was stirred

at rt for 15 min, after which time TLC (pentane–EtOAc, 2:1) showed

complete consumption of starting material (R_f0.2) and the forma-

tion of a product (R_f0.9). The reaction was quenched by addition of

Et₃N (5 mL) and then concentrated in vacuo. The residue was puri-

ﬁed by ﬂash column chromatography (CH₂Cl₂–Et₂O, 10:1 + 0.5%

Et₃N) to afford acetonide 4 (5.04 g, 94%) as a colourless oil; ½a _D²⁵

ꢃ

ꢀ15.1 (c 1.0, CHCl₃); IR (Film)

m ;

3468 (OH) cm^{ꢀ1 1}H NMR

(400 MHz, CDCl₃) d_H1.45 (3H, s, CH₃), 1.47 (3H, s, CH₃), 2.75 (1H,

br s, 3-OH), 3.65–3.74 (2H, m, H-1, H-2), 3.81 (1H, d, J 7.6 Hz, H-

3), 3.87–3.90 (2H, m, H-1⁰, H-4), 4.06 (1H, dd, J_4,55.7 Hz, J_5,6

8.2 Hz, H-5), 4.35 (1H, at, J 7.4 Hz, H-6), 4.39, 4.77 (2H, 2 ꢂ d, J

11.3 Hz, PhCH₂), 4.42, 4.73 (2H, 2 ꢂ d, J 11.7 Hz, PhCH₂), 4.58 (2H,

s, PhCH₂), 5.26 (1H, dat, J_cis10.3 Hz, J 1.3 Hz, H-8_cis), 5.37 (1H,

dat, J_trans17.2 Hz, J 1.2 Hz, H-8_trans), 5.85 (1H, ddd, J_cis10.3 Hz J_trans

17.3 Hz, J_6,77.3 Hz, H-7), 7.24–7.36 (15H, m, Ar-H); ¹³C NMR

(100 MHz, CDCl₃) d_C27.1, 27.1 (2 ꢂ q, C(CH₃)₂), 69.7 (t, C-1), 70.9,

78.0 (2 ꢂ d, C-4, C-5), 72.0, 73.6, 74.2 (3 ꢂ t, 3 ꢂ PhCH₂), 76.6 (d,

C-2), 79.0 (d, C-3), 82.5 (d, C-6), 109.3 (s, C(CH₃)₂), 119.4 (t, C-8),

127.7, 127.8, 127.9, 127.9, 128.1, 128.1, 128.5, 128.5, 128.5

(9 ꢂ d, Ar-CH), 135.6 (d, C-7), 138.4, 138.5 (2 ꢂ s, 3 ꢂ Ar-C); HRE-

SIMS calcd for C₃₂H₃₈O₆Na (MNa⁺) 541.2561; found 541.2549.

phy was carried out on silica gel (35–70

lm, Grace). CMAW means

CHCl₃–MeOH–AcOH–H₂O, 60:30:3:5. Grubbs’ second generation

1284

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

NMR data for regioisomeric acetonides 5 and 6. The six-mem-

the reaction was allowed to reach rt, and after an additional 1 h,

TLC (pentane–EtOAc, 4:1) showed product formation (R_f0.5) and

no remaining starting material (R_f0.4). The reaction mixture was

ﬁltered through Celite and concentrated in vacuo. The crude prod-

uct was then puriﬁed by ﬂash column chromatography (toluene–

EtOAc, 12:1?8:1), giving alkene 8 (1.60 g, 81%) as a yellowish

bered ring acetonide 5: ¹H NMR (300 MHz, CDCl₃) d_H1.43, 1.47

(6H, 2 ꢂ s, 2 ꢂ CH₃), 2.84 (1H, d, J 0.9 Hz, OH), 3.64–3.69 (3H, m,

H-5), 3.83–3.87 (2H, m), 4.06 (1H, d, J 9.0 Hz), 4.35–4.40 (2H, m,

PhCHH⁰, H-6), 4.51–4.79 (5H, m, 2 ꢂ PhCH₂, PhCHH⁰), 5.25 (1H,

dat, J_cis10.6 Hz, J_at1.3 Hz, H-8_cis), 5.37 (1H, dat, J_trans17.2 Hz, J_at

1.5 Hz, H-8_trans), 5.76 (1H, ddd, J_6,76.5 Hz, H-7), 7.24–7.36 (15H,

m, Ar-H); ¹H NMR (100 MHz, CDCl₃) d_C19.4, 29.7 (2 ꢂ q,

C(CH₃)₂), 67.5, 70.3, 71.2, 71.3, 72.0, 73.6, 73.8, 76.4, 76.5 (4 ꢂ t,

5 ꢂ d, 3 ꢂ PhCH₂, C-1, C-2, C-3, C-4, C-5, C-6), 99.7 (s, O₂C(CH₃)₂),

118.9 (t, C-8), 127.2, 127.5, 127.7, 127.8, 127.9, 127.9, 128.4,

128.5, 128.5 (9 ꢂ d, 9 ꢂ Ar-CH), 135.5 (d, C-7), 138.4, 138.5, 138.7

(3 ꢂ s, 3 ꢂ Ar-C). The seven-membered ring acetonide 6: ¹H NMR

(300 MHz, CDCl₃) d_H1.34, 1.37 (6H, 2 ꢂ s, 2 ꢂ CH₃), 2.38 (1H, d, J

9.4 Hz, OH-5), 3.59–4.09 (6H, m, H-1, H-1⁰, H-2, H-3, H-4, H-5),

4.30–4.77 (7H, m, 3 ꢂ PhCH₂, H-6), 5.18 (1H, dat, J_at1.7 Hz, J_cis

10.6 Hz, C-8_cis), 5.29 (1H, dat, J_at1.7 Hz, J_trans17.2 Hz, H-8_trans),

5.80 (1H, m, H-7), 7.24–7.35 (15H, m, Ar-H); ¹H NMR (100 MHz,

CDCl₃) d_C24.4, 25.2 (2 ꢂ q, C(CH₃)₂), 68.2, 68.6, 69.1, 71.0, 71.9,

72.9, 73.5, 76.3, 78.3 (4 ꢂ t, 5 ꢂ d, 3 ꢂ PhCH₂, C-1, C-2, C-3, C-4,

C-5, C-6), 101.5 (s, O₂C(CH₃)₂), 116.3 (t, C-8), 127.6, 127.7, 127.8,

127.9, 127.9, 128.4, 128.5, 128.5, 128.5 (9 ꢂ d, 9 ꢂ Ar-CH), 136.7

(d, C-7), 138.4, 138.6, 138.8 (3 ꢂ s, 3 ꢂ Ar-C).

oil; ½a ³_D⁰

ꢃ

+53.0 (c 1.0, CHCl₃); ¹H NMR (300 MHz, CDCl₃) d_H1.40

(3H, s, CH₃), 1.40 (3H, s, CH₃), 3.62 (1H, dd, J_1,24.4 Hz, J_1,1

10.6 Hz, H-1), 3.65 (1H, dd, J_{1 ,2}6.4 Hz, J_1,110.7 Hz, H-1⁰), 3.74

(1H, dd, J_4,52.7 Hz, J_5,68.1 Hz, H-5), 3.84 (1H, d, J_4,52.6 Hz, H-4),

4.22 (1H, dd, J_1,24.3 Hz, J_{1 ,2}6.4 Hz, H-2), 4.30, 4.61 (2H, 2 ꢂ d, J

12.1 Hz, PhCH₂), 4.42 (1H, at, J 7.7 Hz, H-6), 4.53, 4.68 (2H, 2 ꢂ d,

J 11.9 Hz, PhCH₂), 4.55, 4.69 (2H, 2 ꢂ d, J 12.1 Hz, PhCH₂), 5.01

(1H, dat, J_trans17.2 Hz, J 1.3 Hz, H-8_trans), 5.10 (1H, dat, J_cis

10.3 Hz, J 1.4 Hz, H-8_cis), 5.50 (1H, s, H-3a), 5.60 (1H, s, H-3a⁰),

5.68 (1H, ddd, J_6,77.4 Hz, J_trans17.4 Hz, J_cis10.4 Hz, H-7), 7.26–

7.39 (15H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃) d_C26.9, 27.2

(2 ꢂ q, 2 ꢂ CH₃), 70.9, 71.2, 73.4 (3 ꢂ t, 3 ꢂ PhCH₂), 73.8 (t, C-1),

76.0 (d, C-4), 78.1 (d, C-2), 78.4 (d, C-6), 81.8 (d, C-5), 109.4 (s,

C(O)₂(CH₃)₂), 116.3 (t, C-3a), 118.8 (t, C-8), 127.6, 127.7, 127.8,

127.8, 128.1, 128.4, 128.5, 128.5, 128.7 (9 ꢂ d, Ar-CH), 135.7 (d,

C-7), 138.2, 138.5, 138.8 (3 ꢂ s, Ar-C), 144.0 (s, C-3); HRESIMS calcd

for C₃₃H₃₈O₅Na (MNa⁺) 537.2611; found 537.2632.

3.4. (2R,4R,5S,6R)-1,2,4-Tri-O-benzyl-5,6-O-isopropylidene-

3.6. (2S,4S,5S,6R)-1,2,4-Tri-O-benzyl-3-methylene-oct-7-ene-

1,2,4,5,6-pentahydroxy-oct-7-en-3-one (7)

1,2,4,5,6-pentaol (9)

A cold (ꢀ60 °C) solution of DMSO (362

L, 5.10 mmol) in CH₂Cl₂

Alkene 8 (3.64 g, 7.08 mmol) was suspended in acetic acid/

water 7:4 (220 mL). 1 M HCl (20 mL) was added, and the reaction

was left to stir at 80 °C. After 2.5 h, TLC (pentane–EtOAc, 10:1)

showed formation of a product (R_f0.1) and complete consump-

tion of starting material (R_f0.5). The reaction mixture was co-

evaporated with toluene to give diol 9 (3.46 g, quantitative) as a

(5 mL) was transferred to a solution of oxalyl chloride (217

lL,

2.53 mmol) in CH₂Cl₂(5 mL) under N₂at ꢀ60 °C. The reaction mix-

ture was stirred for 30 min. Alcohol 4 (600 mg, 1.16 mmol) was

dissolved in CH₂Cl₂(15 mL) and transferred to the reaction vessel.

The reaction was left to stir for 45 min at ꢀ60 °C. Et₃N (806

lL,

5.79 mmol) was then added, and the reaction was allowed to reach

rt and was left to stir for another 30 min. CH₂Cl₂(20 mL) was

added and the reaction mixture was washed with water (25 mL)

and brine (2 ꢂ 25 mL) and the aqueous phases were extracted with

CH₂Cl₂(3 ꢂ 20 mL). The combined organic phases were dried on

Na₂SO₄and concentrated in vacuo. The crude product (R_f0.4, tolu-

ene–EtOAc, 9:1) was puriﬁed by ﬂash column chromatography

(toluene–EtOAc, 9:1) to give ketone 7 (481 mg, 80%) as an oil;

colourless oil; ½a _D²⁵

ꢃ

+65.6 (c 1.0, CHCl₃); IR (Film) m 3437 (OH)

cm^ꢀ^{1 1}H NMR (300 MHz, CDCl₃) d_H2.83 (1H, d, J_OH,63.8 Hz,

;

OH-6), 2.88 (1H, d, J_OH,55.5 Hz, OH-5), 3.45 (1H, dat, J_4,53.8 Hz,

J_at5.5 Hz, H-5), 3.61 (1H, dd, J_1,24.9 Hz, J_1,110.2 Hz, H-1), 3.72

(1H, dd, J_{1 ,2}6.6 Hz, J_1,110.2 Hz, H-1⁰), 4.02 (1H, d, J_4,53.7 Hz,

H-4), 4.13 (2H, m, H-2, H-6), 4.24, 4.61 (2H, 2 ꢂ d, J 11.5 PhCH₂),

4.52, 4.53 (2H, 2 ꢂ d, J 11.8 Hz, PhCH₂), 4.59, 4.67 (2H, 2 ꢂ d, J

12.1 Hz, PhCH₂), 5.11–5.18 (2H, m, H-8_cis, H-8_trans), 5.51 (1H, s,

H-3a), 5.59 (1H, s, H-3a⁰), 5.70 (1H, ddd, J_6,77.1 Hz, J_cis10.3 Hz,

J_trans17.2, H-7), 7.25–7.37 (15H, m, Ar-H); ¹³C NMR (100 MHz,

CDCl₃) d_C71.1, 71.3, 73.6 (3 ꢂ t, 3 ꢂ PhCH₂), 73.2, 78.5 (2 ꢂ d, C-

2, C-4), 73.2 (t, C-1), 74.5 (d, C-5), 79.6 (d, C-6), 117.4 (t, C-8),

117.5 (t, C-3a), 127.8, 127.9, 127.9, 128.2, 128.3, 128.5, 128.7

(7 ꢂ d, Ar-CH), 136.1 (d, C-7), 137.2, 137.6, 138.1 (3 ꢂ s, Ar-C),

143.5 (s, C-3); HRESIMS calcd for C₃₀H₃₄O₅Na (MNa⁺) 497.2298;

found 497.2282.

a ²_D⁵

ꢃ

+19.8 (c 1.0, CHCl₃); IR (Film)

m ;

1729 (C@O) cm^{ꢀ1 1}H NMR

(300 MHz, CDCl₃) d_H1.32 (3H, s, CH₃), 1.37 (3H, s, CH₃), 3.76 (1H,

dd, J_1,110.7 Hz, J_1,26.0 Hz, H-1), 3.83 (1H, dd, J_{1 ,2}3.8 Hz, J_1,1

10.7 Hz, H-1⁰), 4.10 (1H, dd, J_4,52.6 Hz, J_5,68.3 Hz, H-5), 4.20 (1H,

d, J_4,52.7 Hz, H-4), 4.25, 4.69 (2H, 2 ꢂ d, J 11.9 Hz, PhCH₂), 4.40–

4.44 (2H, m, H-2, H-6), 4.52 (2H, s, PhCH₂), 4.58, 4.63 (2H, 2 ꢂ d,

J 11.9 Hz, PhCH₂), 5.02 (1H, dd, J_trans17.0 Hz, J 1.0 Hz, H-8_trans),

5.09 (1H, dd, J_cis10.3 Hz, J 0.8 Hz, H-8_cis), 5.66 (1H, ddd, J_6,7

7.3 Hz, J_cis10.4 Hz, J_trans17.2 Hz, H-7), 7.24–7.33 (15H, m, Ar-H);

¹³C NMR (100 MHz, CDCl₃) d_C26.7, 27.1 (2 ꢂ q, 2 ꢂ CH₃), 70.6 (t,

C-1), 72.8, 73.2, 73.6 (3 ꢂ t, 3 ꢂ PhCH₂), 78.0, 82.0 (2 ꢂ d, C-2, C-

6), 79.3 (d, C-4), 80.0 (d, C-5), 109.8 (s, C(O)₂(CH₃)₂), 119.3 (t, C-

8), 127.3, 127.8, 128.1, 128.2, 128.2, 128.3, 128.5, 128.6, 128.6

(9 ꢂ d, Ar-CH), 134.8 (d, C-7), 137.2, 137.6, 137.9 (3 ꢂ s, 3 ꢂ Ar-

3.7. (2S,4S,5S,6R)-1,2,4-Tri-O-benzyl-5,6-di-O-acetyl-3-

methylene-oct-7-ene-1,2,4,5,6-pentaol (10)

Diol 9 (3.28 g, 6.92 mmol) was dissolved in a 1:1 mixture of

Ac₂O and pyridine (200 mL) and stirred for 18 h. TLC (toluene–

EtOAc, 7:1) showed complete consumption of starting material

(R_f0) and the formation of a product (R_f0.4). The solvents were re-

moved in vacuo and co-evaporated with toluene (2 ꢂ 100 mL). The

crude product was ﬁltered through a plug of silica (EtOAc) to give

C), 207.1 (s, C@O); HRESIMS calcd for

539.2404; found 539.2397.

₃₂H₃₆O₆Na (MNa⁺)

3.5. (2S,4S,5S,6R)-1,2,4-Tri-O-benzyl-5,6-O-isopropylidene-3-

methylene-oct-7-ene-1,2,4,5,6-pentaol (8)

diacetate 10 (3.86 g, quant.) as a yellowish oil; ½a _D²⁵

ꢃ

+39.2 (c 1.0,

CHCl₃); IR (Film)

1747 (C@O) cm^ꢀ1

;

¹H NMR (300 MHz, CDCl₃)

CH₃PPh₃Br (6.89 mg, 19.3 mmol) was suspended at 0 °C in tolu-

ene and n-BuLi (1.6 M in hexane, 10.8 mL, 17.3 mmol) was added,

after which the mixture was allowed to reach rt and stirred for 1 h.

The reaction mixture was cooled to ꢀ78 °C, after which ketone 7

(1.99 g, 3.85 mmol) was added by cannula under N₂. After 2 h,

d_H2.00 (3H, s, CH₃), 2.04 (3H, s, CH₃), 3.60 (1H, dd, J_1,110.4 Hz,

J_1,24.4 Hz, H-1), 3.69 (1H, dd, J_{1 ,2}6.2 Hz, J_1,110.3 Hz, H-1⁰), 4.05

(1H, dd, J_1,24.3 Hz, J_{1 ,2}6.0 Hz, H-2), 4.10 (1H, d, J_4,53.5 Hz, H-4),

4.13, 4.60 (2H, 2 ꢂ d,

J 11.7 Hz, PhCH₂), 4.54–4.56 (4H, m,

2 ꢂ PhCH₂), 5.09–5.17 (2H, m, H-8_cis, H-8_trans), 5.20 (1H, dd, J_4,5

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

1285

3.5 Hz, J_5,67.3 Hz, H-5), 5.43–5.52 (3H, m, H-7, H-3a, H-3a⁰), 5.61

(1H, m, H-6), 7.26–7.38 (15H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃)

d_C20.9, 21.1 (2 ꢂ q, 2 ꢂ CH₃), 70.9, 71.5, 73.6 (3 ꢂ t, 3 ꢂ PhCH₂),

73.3, 73.4 (t, d, C-1, C-5), 73.9 (d, C-6), 76.8 (d, C-4), 79.2 (d, C-2),

116.9 (t, C-3a), 120.0 (t, C-8), 127.6, 127.8, 127.8, 127.9, 128.0,

128.4, 128.5, 128.5 (8 ꢂ d, Ar-CH), 132.3 (d, C-7), 137.9, 138.2,

138.6 (3 ꢂ s, 3 ꢂ Ar-C), 142.8 (s, C-3), 169.8, 170.4 (2 ꢂ s,

2 ꢂ C@O); HRESIMS calcd for C₃₄H₃₈O₇Na (MNa⁺) 581.2510; found

581.2503.

3.9.2. Method 2: ring-closing metathesis of diene 9

Diene 9 (94 mg, 0.198 mmol) and Hoveyda–Grubbs 2nd gener-

ation complex (6 mg, 0.01 mmol) were dissolved in toluene (5 mL)

under N₂at 60 °C. After 1 h, TLC (pentane–EtOAc, 2:1) showed that

all the starting material (R_f0.5) had been consumed and that a ma-

jor product was formed (R_f0.3). The reaction mixture was concen-

trated in vacuo. The crude product was puriﬁed by ﬂash column

chromatography (toluene–EtOAc, 3:2) to give unsaturated carba-

sugar 12 (38 mg, 43%) as white crystals identical to those described

above.

3.8. 1,2-Di-O-acetyl-3,5,6-tri-O-benzyl-4a-carba-b-D-xylo-hex-

4(4a)-enofuranose (11)

3.10. 3,5,6-Tri-O-benzyl-4a-carba-b-D-galactofuranose (13)

Diacetate 10 (2.99 g, 5.36 mmol) was dissolved in toluene

(225 mL) under N₂at 60 °C. Grubbs⁰2nd generation complex

(23 mg, 0.027 mmol) was added and the reaction mixture was

stirred at 60 °C. The formation of product (R_f0.3) and consump-

tion of starting material (R_f0.4) was followed by TLC (pentane–

Unsaturated cyclopentene diol 12 (510 mg, 1.14 mmol) was dis-

solved in EtOAc (13 mL), and Et₃N (90 L, 0.65 mmol) and Pd/C

(10%, 56 mg, 0.053 mmol) were added. The mixture was degassed

and stirred under H₂. The reaction was followed by TLC

(pentane–EtOAc, 4:5), but starting material and product had simi-

lar R_fvalues (0.4). After 2 h, the reaction mixture was ﬁltered

through Celite and concentrated in vacuo to give the saturated

EtOAc, 9:1). Further catalyst was added,

a total amount of

161 mg (0.19 mmol) was added in seven portions (including the

initial addition) over 47 h. The problem of coloured ruthenium

residues co-eluting with the product was solved by adding DMSO

after completion of the reaction. The complex formed between

DMSO and ruthenium was immobile on silica during the normal

cyclopentadiol 13 (467 mg, 91%) as an oil; ½a _D²⁵

ꢀ24.2 (c 1.0,

ꢃ

CHCl₃); IR (Film)

3401 (OH) cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

d_H1.78 (1H, m, H-4a), 2.04 (1H, ddd, J 6.0 Hz, J 7.8 Hz, J_4a,4a

13.7 Hz, H-4a⁰), 2.48 (1H, m, H-4), 3.48 (1H, dd, J_5,65.1 Hz, J_6,6

chromatographic puriﬁcation.⁵³DMSO (670

lL, 9.4 mmol) was

9.9 Hz, H-6), 3.62 (1H, dd, J_6,610.0 Hz, J_5,66.0 Hz, H-6⁰), 3.65 (1H,

m, H-3), 3.78 (1H, m, H-5), 3.97–4.00 (2H, m, H-1, H-2), 4.45,

4.75 (2H, 2 ꢂ d, J 11.4 Hz, PhCH₂), 4.48, 4.52 (2H, 2 ꢂ d, J 11.8 Hz,

PhCH₂), 4.53, 4.59 (2H, 2 ꢂ d, J 11.9 Hz, PhCH₂), 7.26–7.37 (15H,

m, Ar-H); ¹³C NMR (100 MHz, CDCl₃) d_C30.4 (t, C-4a), 44.4 (d, C-

4), 71.8 (t, C-6), 72.2, 73.0, 73.6 (3 ꢂ t, 3 ꢂ PhCH₂), 77.5, 80.5

(2 ꢂ d, C-1, C-2), 77.8 (d, C-5), 87.0 (d, C-3), 127.7, 127.9, 128.0,

128.0, 128.1, 128.4, 128.6, 128.6 (8 ꢂ d, Ar-CH), 137.9, 138.1,

138.1 (3 ꢂ s, 3 ꢂ Ar-C); HRESIMS calcd for C₂₈H₃₂O₅Na (MNa⁺)

471.2142; found 471.2134.

added to the solution and stirred for 24 h. The mixture was then

concentrated in vacuo, and the residue puriﬁed by ﬂash column

chromatography (pentane–EtOAc, 8:1) to give cyclopentene 11

(2.46 g, 87%) as an oil; IR (Film)

cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃) d_H2.09 (3H, s, CH₃), 2.10 (3H,

s, CH₃), 3.71 (1H, dd, J_6,610.5 Hz, J_5,66.9 Hz, H-6), 3.85 (1H, dd,

m 1732 (C@O), 1739 (C@O)

;

J_6,610.5 Hz, J_5,63.6 Hz, H-6⁰), 4.32 (1H, m, H-5), 4.43 (1H, d,

J_2,32.9 Hz, H-3), 4.52, 4.68 (2H, 2 ꢂ d, J 11.7 Hz, PhCH₂), 4.54–

4.63 (4H, m, 2 ꢂ PhCH₂), 5.35 (1H, at, J 2.9 Hz, H-2), 5.54 (1H,

br s, H-1), 5.91 (1H, br s, H-4a), 7.26–7.39 (15H, m, Ar-H); ¹³C

NMR (100 MHz, CDCl₃) d_C21.1 (q, 2 ꢂ CH₃), 72.1, 72.3, 73.5

(3 ꢂ t, 3 ꢂ PhCH₂), 72.2 (t, C-6), 75.0 (d, C-5), 80.0 (d, C-1), 83.4

(d, C-2), 85.7 (d, C-3), 127.7, 127.8, 127.8, 127.9, 127.9, 128.1,

128.5, 128.5, 128.6 (9 ꢂ d, Ar-CH, C-4a), 137.9, 138.4, 138.5

(3 ꢂ s, 3 ꢂ Ar-C), 146.2 (s, C-4), 170.2, 170.7 (2 ꢂ s, 2 ꢂ C@O);

3.11. 1,2-Di-O-acetyl-3,5,6-tri-O-benzyl-4a-carba-b-D-

galactofuranose (14)

3.11.1. Method 1: acetylation of diol 13

Diol 13 (14 mg, 0.031 mmol) was dissolved in a 1:1 mixture of

Ac₂O and pyridine (1 mL), and stirred at rt for 3 h. TLC (pentane–

EtOAc, 1:1) showed complete consumption of starting material

(R_f0.2). The reaction mixture was co-evaporated with toluene

and ﬁltered through a plug of silica to give diacetate 14 (12 mg,

HRESIMS calcd for

553.2182.

₃₂H₃₄O₇Na (MNa⁺) 553.2197; found

3.9. 3,5,6-Tri-O-benzyl-4a-carba-b-D-xylo-hex-4(4a)-

enofuranose (12)

72%) as an oil; IR (Film) m ;

1741 (C@O) cm^{ꢀ1 1}H NMR (400 MHz,

CDCl₃) d_H1.76 (1H, m, H-4a), 2.01, 2.05 (6H, 2 ꢂ s, 2 ꢂ C(O)CH₃),

2.13 (1H, ddd, J_1,4a6.8 Hz, J_4,4a11.0 Hz, J_4a,4a14.2 Hz, H-4a⁰),

3.9.1. Method 1: deprotection of diacetate 11

Diacetate 11 (604 mg, 1.14 mmol) was dissolved in MeOH

(25 mL). A solution of NaOMe made from Na (20 mg, 0.87 mmol)

and MeOH (20 mL) was added, and the reaction was left to stir at

rt for 1 h. Dowex resin HCR-W2 was added until pH 4 was reached,

after which the solution was ﬁltered and concentrated in vacuo.

The crude product was ﬁltered through silica (EtOAc) to give diol

12 (514 mg, quant.) as white crystals; mp 74–76 °C (EtOAc–

2.42 (1H, ddat, J_at8.1 Hz, J_4,53.4 Hz, J_{4a ,4}11.3 Hz, H-4), 3.51 (1H,

dd, J_5,64.7 Hz, J_6,610.0 Hz, H-6), 3.59 (1H, dd, J_5,66.2 Hz, J_6,6

10.0 Hz, H-6⁰), 3.75 (1H, m, H-5), 3.83 (1H, dd, J_2,34.8 Hz, J_3,4

8.2 Hz, H-3), 4.31, 4.71 (2H, 2 ꢂ d, J 11.6 Hz, PhCH₂), 4.33, 4.56

(2H, 2 ꢂ d, J 11.7 Hz, PhCH₂), 4.48, 4.53 (2H, 2 ꢂ d, J 12.1 Hz,

PhCH₂), 5.00 (1H, dat, J_at3.0 Hz, J_1,4a6.8 Hz, H-1), 5.22 (1H, ddd,

J_1,23.2 Hz, J_2,34.7 Hz, J_4a,21.3 Hz, H-2), 7.27–7.38 (15H, m, Ar-H);

¹³C NMR (100 MHz, CDCl₃) d_C21.2, 21.3 (2 ꢂ q, 2 ꢂ CH₃), 28.7 (t,

C-4a), 44.7 (d, C-4), 72.3, 72.4, 73.0, 73.5 (4 ꢂ t, 3 ꢂ PhCH₂, C-6),

76.5 (d, C-5), 76.8 (d, C-1), 82.3 (d, C-2), 83.6 (d, C-3), 127.7,

127.7, 127.8, 127.9, 127.9, 128.2, 128.4, 128.5, 128.6 (9 ꢂ d, Ar-

CH), 138.2, 138.3, 138.9 (3 ꢂ s, 3 ꢂ Ar-C), 170.0, 170.5 (2 ꢂ s,

2 ꢂ OC@O); HRESIMS calcd for C₃₂H₃₆O₇Na (MNa⁺) 555.2353;

found 555.2368.

pentane); IR (Film)

3380, 3305 (OH) cm^ꢀ1; ½a _D²⁵

ꢃ

+9.6 (c 0.5,

CHCl₃); ¹H NMR (300 MHz, CDCl₃) d_H2.03 (2H, br s, OH-1, OH-2),

3.66 (1H, dd, J_6,610.7 Hz, J_5,67.1 Hz, H-6), 3.79 (1H, dd, J_6,6

10.6 Hz, J_5,63.6 Hz, H-6⁰), 4.07 (1H, br s, H-2), 4.25 (1H, m, H-3),

4.29 (1H, m, H-5), 4.39 (1H, br s, H-1), 4.52, 4.66 (2H, 2 ꢂ d, J

12.2 Hz, PhCH₂), 4.56–4.61 (4H, m, 2 ꢂ PhCH₂), 5.84 (1H, s, H-4a),

7.23–7.33 (15H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃) d_C71.9,

72.3, 73.5 (3 ꢂ t, 3 ꢂ PhCH₂), 72.3 (t, C-6), 75.0 (d, C-5), 79.8 (d,

C-1), 87.0 (d, C-3), 87.4 (d, C-2), 127.8, 127.9, 127.9, 128.0, 128.4,

128.5, 128.6 (7 ꢂ d, Ar-CH), 130.5 (d, C-4a), 138.3, 138.4, 138.5

(3 ꢂ s, 3 ꢂ Ar-C), 142.9 (s, C-4); HRESIMS calcd for C₂₈H₃₀O₅Na

(MNa⁺) 469.1985; found 469.1988.

3.11.2. Method 2: reduction of cyclopentene 11

Cyclopentene diacetate 11 (29 mg, 0.055 mmol) was dissolved

lL, 0.14 mmol) was added. Pd/C

(10%, 5 mg, 0.005 mmol) was added and all air in the reaction

in EtOAc (5 mL) and Et₃N (20

1286

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

vessel was removed by evacuation using N₂before adding H₂via

balloon. The reaction was followed by TLC (pentane–EtOAc, 7:1),

but the starting material and the major product had similar R_fval-

ues (0.3). After 1.5 h, the reaction mixture was ﬁltered through Cel-

ite and concentrated in vacuo. The crude product was puriﬁed by

ﬂash column chromatography (CH₂Cl₂–Et₂O, 15:1) to give cyclo-

pentane diacetate 14 (14 mg, 49%) as an oil, identical to that de-

scribed above.

column chromatography (toluene–EtOAc 2:1) to give the unsatu-

rated pentaacetate (18 mg, 69%) as an oil; ½a _D²⁵

ꢀ17.9 (c 1.0, CHCl₃);

ꢃ

IR (Film)

1744 (s, C@O) cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) d_H2.06,

2.07, 2.08, 2.08, 2.09 (15H, 5 ꢂ s, 5 ꢂ CH₃), 4.11 (1H, dd, J_5,67.3 Hz,

J_6,612.0 Hz, H-6), 4.48 (1H, dd, J_5,63.3 Hz, J_6,612.0 Hz, H-6⁰), 5.30

(1H, at, J_at3.9 Hz, H-2), 5.55 (2H, m, H-1, H-5), 5.83 (1H, m, H-3),

5.95 (1H, s, H-4a); ¹³C NMR (100 MHz, D₂O) d_C20.9, 20.9, 20.9,

21.0 (4 ꢂ q, CH₃), 63.7 (t, C-6), 67.0, 78.2 (2 ꢂ d, C-1, C-5), 78.4

(d, C-3), 82.9 (d, C-2), 129.8 (d, C-4a), 141.4 (s, C-4), 170.0, 170.1,

170.3, 170.4, 170.7 (5 ꢂ s, 5 ꢂ C@O).

Also a reduced product (12 mg, 46%); ¹H NMR (400 MHz, CDCl₃)

d_H1.53–2.14 (5H, m), 1.97 (3H, s, C(O)CH₃), 3.52 (1H, dd, J 4.4 Hz, J

10.0 Hz), 3.58 (1H, dd, J 6.4 Hz, J 10.0 Hz), 3.70 (1H, m), 3.77 (1H,

dd, J 3.3 Hz, J 7.1 Hz), 4.36, 4.74 (2H, 2 ꢂ d, J 11.7 Hz, PhCH₂),

4.40, 4.62 (2H, 2 ꢂ d, J 12.0 Hz, PhCH₂), 4.47, 4.53 (2H, 2 ꢂ d, J

12.1 Hz, PhCH₂), 5.08 (1H, dat, J_at3.4 Hz, J 6.7 Hz), 7.24–7.36

(15H, m, Ar-H); HRESIMS calcd for C₃₀H₃₄O₅Na (MNa⁺) 497.2298;

found 497.2305.

Na (2 mg, 0.09 mmol) was added to MeOH (2 mL), and a solu-

tion of the unsaturated pentaacetate (18 mg, 0.047 mmol) in

MeOH (1 mL) was added. The mixture was stirred at rt. After 2 h,

the reaction was quenched by the addition of acidic Dowex resin

HCR-W2. The resin was ﬁltered off and all the solvent was removed

in vacuo to afford the pentaol (8 mg, quantitative) as an oil.

The pentaol (8 mg, 0.045 mmol) was dissolved in EtOH/H₂O

[3:1] (4 mL). Pd/C (10%, 5 mg, 0.005 mmol) was added to the solu-

tion. All air was evacuated and the reaction was put under H₂. After

1.5 h, the mixture was ﬁltered through Celite and all solvent was

removed in vacuo to give the unprotected carbasugar 1 (8 mg,

quant.) identical to that described above.

3.12. 4a-Carba-b-D-galactofuranose (1)

3.12.1. Method 1: debenzylation of cyclopentane 13

Cyclopentanediol 13 (432 mg, 0.963 mmol) was dissolved in

MeOH (7 mL), and Pd/C (10%, 70 mg, 0.066 mmol) was added.

The mixture was degassed and stirred under H₂. After 7 h, TLC

(CMAW) showed formation of a single product (R_f0.2), and the

reaction mixture was ﬁltered through Celite and puriﬁed by ﬂash

3.13. 1,2,3,5,6-Penta-O-acetyl-4a-carba-b-D-galactofuranose (15)

column chromatography (CMAW) to give 4a-carba-b-

-galactofu-

Unprotected carbasugar 1 (2 mg, 0.011 mmol) was suspended

in a 1:1 mixture of Ac₂O and pyridine (1 mL) and stirred for 2 h,

after which TLC (pentane–EtOAc, 1:1) showed consumption of

starting material (R_f0) and formation of a major product (R_f0.6).

The reaction mixture was concentrated in vacuo and puriﬁed by

ﬂash column chromatography (pentane–EtOAc, 2:1) to give perac-

ranose 1 (179 mg, quant.) as an oil; ½a _D²⁵

ꢀ15.6 (c 1.0, CH₃OH);

ꢃ

¹H NMR (400 MHz, CD₃OD) d_H1.67 (1H, m, H-4a), 1.96–2.05 (2H,

m, H-4, H-4a⁰), 3.51 (1H, dd, J_5,67.8 Hz, J_6,611.7 Hz, H-6), 3.62

(1H, dd, J_5,64.2 Hz, J_6,611.7 Hz, H-6⁰), 3.71–3.79 (3H, m, H-2, H-

3, H-5), 3.90 (1H, m, H-1); ¹³C NMR (100 MHz, CD₃OD) d_C30.5 (t,

C-4a), 45.1 (d, C-4), 66.4 (t, C-6), 73.5, 78.4, 85.5 (3 ꢂ d, C-2, C-3,

C-5), 75.5 (d, C-1); HRESIMS calcd for C₇H₁₄O₅Na (MNa⁺)

201.0733; found 201.0728.

etate 15 (3 mg, 69%) as an oil; IR (Film)

NMR (400 MHz, CDCl₃) d_H1.90 (1H, ddd, J_1,4a2.4 Hz, J_4,4a8.6 Hz,

m ;

1743 (C@O) cm^{ꢀ1 1}H

J_4a,4a14.5 Hz, H-4a), 2.05, 2.06, 2.06, 2.07, 2.10 (15H, 5 ꢂ s,

5 ꢂ CH₃), 2.17 (1H, m, H-4a⁰), 2.54 (1H, ddat, J 4.6 Hz, J_at8.6 Hz, J

3.12.2. Method 2: hydrogenation of cyclopentene 12

11.2 Hz, H-4), 4.01 (1H, dd, J_5,66.5 Hz, J_6,611.9 Hz, H-6), 4.21

Unsaturated diol 12 (57 mg, 0.128 mmol) was dissolved in

EtOH/EtOAc 1:1 (25 mL) and Pd/C (10%, 25 mg, 0.023 mmol) was

added. The mixture was degassed and stirred under H₂. After

18 h, TLC (pentane–EtOAc, 1:2) showed complete consumption of

starting material (R_f0.25) and product formation (R_f0). TLC

(CMAW) also showed formation of several by-products (R_f0.5–

0.9) as well as product formation (R_f0.4). The reaction mixture

was ﬁltered through Celite, concentrated in vacuo and puriﬁed

(1H, dd, J_5,64.2 Hz, J_6,611.9 Hz, H-6⁰), 5.02 (1H, m, H-3), 5.04

(1H, m, H-1), 5.17 (1H, m, H-5), 5.20 (1H, m, H-2); ¹³C NMR

(100 MHz, CDCl₃) d_C20.9, 21.0, 21.0, 21.0, 21.2 (5 ꢂ q, 5 ꢂ CH₃),

29.5 (t, C-4a), 41.8 (d, C-4), 64.0 (t, C-6), 69.4 (d, C-5), 75.3 (d, C-

1), 76.6 (d, C-3), 81.1 (d, C-2), 170.3, 170.5, 170.7 (3 ꢂ s, 5 ꢂ C@O);

HRESIMS calcd for C₁₇H₂₄O₁₀Na (MNa⁺) 411.1262; found 411.1251.

3.14. 3,5,6-Tri-O-benzyl-1,2-di-O-(2-naphthoyl)-4a-carba-b-D-

by column chromatography (CMAW) to give 4a-carba-b-

-galacto-

galactofuranose (16)

furanose 1 (11 mg, 48%) identical to that described above.

Cyclopentanediol 13 (183 mg, 0.408 mmol) was suspended in

pyridine (10 mL) and 2-naphthoyl chloride (311 mg, 1.63 mmol)

was added at rt. A catalytic amount of DMAP (3 mg, 0.024 mmol)

was added and the reaction was heated to 50 °C. After 18 h, TLC

(toluene–EtOAc, 10:1) showed formation of a major product (R_f

0.6) but no starting material (R_f0). The reaction mixture was co-

evaporated with toluene and puriﬁed by ﬂash column chromatog-

raphy (toluene–EtOAc, 10:1) to give dinaphthoate 16 (279 mg,

3.12.3. Method 3: hydrogenation of the unsaturated pentaol

Unsaturated diol 12 (30 mg, 0.067 mmol) was dissolved in THF

(1 mL) and the reaction was cooled to ꢀ78 °C. NH_3(l)(10 mL) was

condensed into the ﬂask, after which Na (54 mg, 2.3 mmol) was

added in portions until a sustained deep blue colour was seen.

After 20 min, MeOH (110 lL) was added and after a further

30 min, the reaction was quenched by the addition of NH₄Cl_(s)

(186 mg, 3.45 mmol). The solvent was allowed to slowly evaporate

by allowing the mixture to reach rt. The crude product was parti-

tioned between EtOAc and water, and the aqueous phase was

evaporated. In order to remove salts, the residue was dissolved in

EtOH and ﬁltered through a plug of cotton wool. The solvent was

removed in vacuo and the residue dissolved in pyridine/Ac₂O

[1:1] (1 mL) with a catalytic amount of DMAP. After 18 h, TLC (tol-

uene–EtOAc 1:1) showed formation of a major product (R_f0.8). The

reaction mixture was washed with 1 M HCl (3 ꢂ 5 mL) and the

combined aqueous phases were extracted with EtOAc

(3 ꢂ 10 mL). The organic extracts were then dried (Na₂SO₄), ﬁltered

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

90%); IR (Film)

1717 (C@O) cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃) d_H

2.07 (1H, dd, J_4,4a7.9 Hz, J_4a,4a14.2 Hz, H-4a), 2.41 (1H, ddd, J_4,4a

11.3 Hz, J_{4a ,1}6.1 Hz, J_4a,4a14.2 Hz, H-4a⁰), 2.68 (1H, ddat, J_at

7.8 Hz, J_4,53.4 Hz, J_4,4a11.3 Hz, H-4), 3.57 (1H, dd, J_5,64.8 Hz, J_6,6

10.0 Hz, H-6), 3.66 (1H, dd, J_5,66.2 Hz, J_6,610.0 Hz, H-6⁰), 3.87

(1H, m, H-5), 4.11 (1H, dd, J_2,34.0 Hz, J_3,47.7 Hz, H-3), 4.46, 4.85

(2H, 2 ꢂ d, J 11.6 Hz, PhCH₂), 4.53, 4.84 (2H, 2 ꢂ d, J 11.7 Hz,

PhCH₂), 4.57, 4.63 (2H, 2 ꢂ d, J 12.1 Hz, PhCH₂), 5.50 (1H, dat, J_at

3.0 Hz, J_{4a ,1}6.1 Hz, H-1), 5.75 (1H, m, H-2), 7.20–7.31 (15H, m,

Ar-H), 7.52–7.64 (4H, m, Ar-H), 7.87–7.95 (6H, m, Ar-H), 8.06

(1H, dd, J 1.7 Hz, J 8.6 Hz, Ar-H), 8.08 (1H, dd, J 1.7 Hz, J 8.6 Hz,

Ar-H), 8.60 (1H, s, Ar-H), 8.64 (1H, s, Ar-H); ¹³C NMR (100 MHz,

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

1287

CDCl₃) d_C29.5 (t, C-4a), 45.6 (d, C-4), 72.3, 72.4 (2 ꢂ t, C-6, PhCH₂),

73.1, 73.5 (2 ꢂ t, 2 ꢂ PhCH₂), 76.7 (d, C-5), 77.8 (d, C-1), 82.4 (d, C-

2), 84.2 (d, C-3), 125.4, 125.5, 126.2, 126.7, 126.8, 127.1, 127.2,

127.4, 127.6, 127.7, 127.7, 127.8, 127.9, 127.9, 128.0, 128.2,

128.3, 128.4, 128.4, 128.5, 128.5, 128.9, 129.1, 129.3, 129.5,

129.6, 129.7, 131.5, 132.5, 132.6 (30 ꢂ d, s, Ar-CH, Ar-C), 135.7,

135.7, 138.1, 138.2, 138.8 (5 ꢂ s, Ar-C), 165.6, 166.0 (2 ꢂ s,

2 ꢂ C@O); HRESIMS calcd for C₅₀H₄₄O₇Na (MNa⁺) 779.2979; found

779.2979.

13.5 Hz, H-4a⁰), 2.28 (1H, ddat, J_at7.7 Hz, J_4,53.1 Hz, J_4,4a10.4 Hz,

H-4), 3.44–3.52 (3H, m, H-6, CH₂CH₃), 3.56–3.61 (2H, m, H-1, H-

6⁰), 3.66 (1H, at, J 7.3 Hz, H-3), 3.74 (1H, ddd, J 4.7 Hz, J_4,53.1 Hz,

J 6.3 Hz, H-5), 4.00 (1H, at, J 6.4 Hz, H-2), 4.40, 4.73 (2H, 2 ꢂ d, J

11.6 Hz, PhCH₂), 4.49 (1H, d, J 12.1 Hz, PhCHH⁰), 4.51 (1H, d, J

12.1 Hz, PhCHH⁰), 4.54 (1H, d, J 12.7 Hz, PhCHH⁰), 4.62 (1H, d, J

11.9 Hz, PhCHH’), 7.27–7.35 (15H, Ar-H); ¹³C NMR (100 MHz,

CDCl₃) d_C15.6 (q, CH₂CH₃), 26.9 (t, C-4a), 42.8 (d, C-4), 64.8 (t,

CH₂CH₃), 72.4, 72.5 (2 ꢂ t, C-6, PhCH₂), 73.0, 73.5 (2 ꢂ t,

2 ꢂ PhCH₂), 77.1 (d, C-5), 82.3 (d, C-2), 82.7 (d, C-1), 84.4 (d, C-

3), 127.7, 127.7, 127.7, 127.8, 128.0, 128.1, 128.5, 128.5, 128.5

(9 ꢂ d, Ar-CH), 138.4, 138.8, 138.9 (3 ꢂ s, 3 ꢂ Ar-C); HRESIMS calcd

for C₃₀H₃₆O₅Na (MNa⁺) 499.2455; found 499.2461.

3.15. 4a-Carba-a-L-arabinofuranose (17)

Dinaphthoate 16 (270 mg, 0.357 mmol) was dissolved in EtOAc/

EtOH (6:1, 7 mL) and Pd/C (10%, 60 mg, 0.056 mmol) was added.

HCl (1 M, 0.1 mL) was added, and the mixture was degassed and

stirred under H₂. The reaction mixture was allowed to stir at rt

for 5 days as the deprotection was very slow. Product formation

(R_f0) was followed by TLC (toluene–EtOAc, 10:1). When all starting

materials (R_f0.8) had been fully debenzylated, the mixture was ﬁl-

tered through Celite and concentrated in vacuo to afford a crude

product that was puriﬁed by ﬂash column chromatography (tolu-

ene–EtOAc, 1:1) to give a triol (87 mg, 50%).

3.17. Methyl 3,5,6-tri-O-benzyl-4a-carba-b-

D-galactofuranosyl-

(1?4)-2,3-O-isopropylidene- -rhamnopyranoside (19d)

a-L

Epoxide 18 (133 mg, 0.309 mmol) and rhamnose alcohol 22

(217 mg, 0.994 mmol) were dissolved in CH₂Cl₂(1.25 mL) at rt un-

der N₂. BF₃ꢁEt₂O (39

L, 0.309 mmol) was dissolved in dry CH₂Cl₂

(1.25 mL) and 125

lL (30.9

mol BF₃ꢁEt₂O) of this solution was

transferred to the colourless reaction mixture. After 30 min, TLC

(toluene–EtOAc, 3:1) showed complete consumption of the epox-

ide (R_f0.9) and formation of a major product (R_f0.5) as well as

remaining alcohol (R_f0.1). The reaction was quenched by addition

of Et₃N (1 mL) and the mixture was concentrated in vacuo. The

crude product was puriﬁed by ﬂash column chromatography (tol-

uene–EtOAc, 4:1) to give pseudodisaccharide 19d (105 mg, 52%) as

The triol (87 mg, 0.179 mmol) was dissolved in dioxane/H₂O

(2:1) (6 mL) and cooled to 0 °C. The reaction mixture was protected

from light by aluminium foil.

A solution of NaIO₄(76 mg,

0.357 mmol) in H₂O (0.5 mL) was added and the reaction was stir-

red for 1 h at 0 °C. TLC (EtOAc) showed formation of a possible

aldehyde (R_f0.9) and no starting material (R_f0.2). NaBH₄(27 mg,

0.72 mmol) in H₂O (0.5 mL) was added and the reaction was stirred

at rt. After 2 h, TLC (EtOAc) showed formation of a new product (R_f

0.7). The white/grey reaction mixture was quenched at 0 °C by

addition of AcOH (1 mL), after which the solution turned yellow

then deep orange. All solvents were removed in vacuo to afford a

white solid. The crude product was stirred with NaOMe (from

MeOH (9 mL) and Na (82 mg, 3.6 mmol)) at 50 °C for 3 h to com-

pletely remove the naphthoates. The reaction was quenched by

the addition of Dowex Resin HCR-W2 and the crude product (R_f

0.4, CMAW) was puriﬁed by ﬂash column chromatography

an oil; ½a ²_D⁵

ꢃ

ꢀ48.9 (c 1.0, CHCl₃); IR (Film)

m ;

3455 (OH) cm^{ꢀ1 1}H

NMR (400 MHz, CDCl₃) d_H1.23 (3H, d, J_5,66.3 Hz, CH₃-6), 1.37,

1.56 (6H, 2 ꢂ s, C(CH₃)₂), 1.62 (1H, ddd, J_1,4a7.0 Hz, J_4,4a10.5 Hz,

J_4a,4a13.5 Hz, H-4a^II), 2.10 (1H, ddd, J 6.9 Hz, J 8.5 Hz, J_4a,4a

13.6 Hz, H-4a⁰), 2.22 (1H, ddat, J_at7.1 Hz, J 3.3 Hz, J_4,4a11.0 Hz,

H-4^II), 3.11 (1H, dd, J 7.2 Hz, J 9.9 Hz, H-4^I), 3.36 (3H, s, OCH₃),

3.48 (1H, dd, J_5,64.7 Hz, J_6,610.0 Hz, H-6^II), 3.54–3.58 (2H, m, H-

5^I, H-6⁰), 3.68–3.75 (3H, m, H-1^II, H-3^II, H-5^II), 4.07 (1H, at, J

7.1 Hz, H-2^II), 4.13–4.21 (2H, m, H-2^I, H-3^I), 4.37, 4.71 (2H, 2 ꢂ d,

J 11.6 Hz, PhCH₂), 4.48, 4.53 (2H, 2 ꢂ d, J 12.1 Hz, PhCH₂), 4.50,

4.82 (2H, 2 ꢂ d, J 11.7 Hz, PhCH₂), 4.84 (1H, s, H-1^I), 7.24–7.26

(15H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃) d_C17.5 (q, C-6^I), 26.2,

27.9 (2 ꢂ q, C(CH₃)₂), 27.6 (t, C-4a^II), 41.9 (d, C-4^II), 54.9 (q,

OCH₃), 64.7 (d, C-5^I), 72.2, 72.5, 73.0, 73.5 (4 ꢂ t, 3 ꢂ PhCH₂, C-

6^II), 76.1, 78.6 (2 ꢂ d, C-2^I, C-3^I), 77.4, 83.3, 87.1 (3 ꢂ d, C-1^II, C-

3^II, C-5^II), 84.3, 84.5 (2 ꢂ d, C-4^I, C-2^II), 98.0 (d, C-1^I), 109.7 (s,

C(CH₃)₂), 127.6, 127.6, 127.7, 127.7, 127.9, 128.0, 128.1, 128.4,

128.5 (9 ꢂ d, Ar-CH), 138.4, 139.0, 139.0 (3 ꢂ s, Ar-C); HRESIMS

calcd for C₃₈H₄₈O₉Na (MNa⁺) 671.3191; found 671.3166.

(CMAW) to afford 4a-carba-a-L-arabinofuranose 17 (21 mg, 80%

over three steps; 40% from 16); ½a _D²⁵

ꢃ

ꢀ39.8 (c 1.0, MeOH), lit.⁴⁷

a ¹_D⁶

ꢃ

ꢀ40.5 (c 0.84, MeOH); ¹H NMR (400 MHz, CD₃OD) d_H1.74

(1H, ddd, J 6.2 Hz, J 10.0 Hz, J_4a,4a13.7 Hz, H-4a), 1.86 (1H, dat, J_at

7.8 Hz, J_4a,4a13.7 Hz, H-4a⁰), 2.05 (1H, m, H-4), 3.52 (2H, m, H-3,

H-5), 3.65 (2H, m, H-2, H-5⁰), 3.83 (1H, dat, J_at6.3 Hz, J_1,4a8.0 Hz,

H-1); ¹³C NMR (100 MHz, CD₃OD) d_C33.2 (C-4a), 45.1 (C-4), 64.7

(C-5), 75.6 (C-1), 78.8 (C-3), 85.7 (C-2).

3.16. 3,5,6-Tri-O-benzyl-1-O-ethyl-4a-carba-b-

galactofuranose (19a)

Also obtained was the pseudotrisaccharide 25d (30 mg, ca.

18%), but this was not obtained completely pure; HRESIMS calcd

for C₆₆H₇₈O₁₃Na (MNa⁺) 1101.5335; found 1101.5317.

Epoxide 18 (12 mg, 0.028 mmol) was dissolved in CH₂Cl₂

(2 mL), and EtOH (16 L, 0.28 mmol) was added under N₂at rt.

BF₃ꢁEt₂O (14 L, 0.11 mmol) was dissolved in dry CH₂Cl₂(10 mL)

and 0.5 mL (5.5

mol BF₃ꢁEt₂O) of this solution was transferred to

Pseudotrisaccharide 25d (25 mg, 0.023 mmol) was dissolved in

80% AcOH and heated to 70 °C. After 4 h, TLC (toluene–EtOAc, 3:1)

showed complete consumption of starting material (R_f0.6) and for-

mation of a major product (R_f0.1). The reaction mixture was co-

evaporated with toluene to yield a residue that was puriﬁed by

ﬂash column chromatography (toluene–EtOAc, 1:1) to give pseu-

dotrisaccharide triol 26 (13 mg, 54%) as an oil; ¹H NMR

the colourless reaction mixture, which then immediately turned

yellow and within minutes dark orange. The reaction was stirred

under N₂for 18 h, after which time TLC (toluene–EtOAc, 6:1)

showed complete consumption of starting material (R_f0.7) and for-

mation of a major product (R_f0.2). The reaction was quenched by

addition of NaHCO₃(satd aq, 2 mL) and washed with NaHCO₃(satd

aq, 3 ꢂ 10 mL), extracted with CH₂Cl₂(3 ꢂ 10 mL), dried (Na₂SO₄),

ﬁltered and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography (toluene–EtOAc, 10:1) to give ethyl

ether 19a (10 mg, 75%) as an oil; ¹H NMR (400 MHz, CDCl₃) d_H

1.18 (3H, t, J 7.0 Hz, CH₂CH₃), 1.60 (1H, ddd, J_1,4a5.8 Hz, J_4,4a

(400 MHz, CDCl₃) d_H1.26 (3H, d, J_5,66.3 Hz, CH₃-6^I), 1.62–1.70

(2H, m, H-4a^x, H-4a^y), 1.93 (1H, dat, J_at6.4, J_4a,4a13.4 Hz, H-4a⁰),

2.11 (1H, dat, J_at7.8 Hz, J_4a,4a13.5 Hz, H-4a⁰), 2.25 (1H, m, H-4 ),

2.34 (1H, m, H-4^x), 3.24 (1H, at, J_at9.3 Hz, H-4^I), 3.33 (3H, s,

OCH₃), 3.43–3.49 (2H, m, H-6^x, H-6^y), 3.54–3.67 (5H, m, H-5^I, H-

5^x, H-5^y, H-6⁰, H-6⁰), 3.69–3.98 (8H, m, H-2^I, H-3^I, H-1^x, H-1^y, H-

2^x, H-2^y, H-3^x, H-3^y), 4.35–4.72 (12H, m, 6 ꢂ PhCH₂), 4.63 (1H, m

(obs), H-1^I), 7.23–7.36 (30H, m, Ar-H); ¹³C NMR (125 MHz, CDCl₃)

d_C17.9 (q, C-6^I), 27.1 (t, C-4a^y), 28.8 (C-4a^x), 42.4 (d, C-4^y), 43.4 (d,

10.2 Hz, J_4a,4a13.5 Hz, H-4a), 2.03 (1H, dat, J_at7.8 Hz, J_4a,4a

1288

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

C-4^x), 54.9 (q, OCH₃), 66.8 (d, C-5^I), 71.1 (d, C-2^I), 71.5 (d, C-3^I),

71.8, 72.2, 72.4, 72.6, 72.6, 73.0, 73.5, 73.5 (8 ꢂ t, 6 ꢂ PhCH₂, C-

6^x, C-6^y), 77.2, 78.0, 82.9, 83.3, 83.4, 83.5, 84.9, 87.2 (8 ꢂ d, C-1^x,

C-1^y, C-2^x, C-2^y, C-3^x, C-3^y, C-5^x, C-5^y), 81.7 (d, C-4^I), 100.4 (d, C-

1^I), 127.7, 127.7, 127.8, 128.1, 128.1, 128.2, 128.4, 128.5, 128.5,

128.6, 128.6, 129.2 (12 ꢂ d, Ar-CH), 137.5, 138.2, 138.4, 138.7,

138.8, 138.9 (6 ꢂ s, 6 ꢂ Ar-C); HRESIMS calcd for C₆₃H₇₄O₁₃Na

(MNa⁺) 1061.5022; found 1061.4981.

C(CH₃)₂), 127.5, 127.7, 127.7, 127.8, 128.3, 128.4, 128.5 (7 ꢂ d,

Ar-CH), 138.4, 138.5, 139.1 (3 ꢂ s, 3 ꢂ Ar-C), 170.0 (s, C@O); HRE-

SIMS calcd for C₄₀H₅₀O₁₀Na (MNa⁺) 713.3296; found 713.3274.

3.21. 3,5,6-Tri-O-benzyl-1,2-di-O-ethyl-4a-carba-b-D-

galactofuranose (21)

3.21.1. Method 1: alkylation of alcohol 19a

The descriptor ‘x’ refers arbitrarily to one of the carbasugars ‘II’

or ‘III’; ‘y’ refers to the other.

Alcohol 19a (35 mg, 0.073 mmol) was dissolved in DMF (2 mL)

at rt under N₂. At 0 °C, NaH (60% in oil, 33 mg, 0.83 mmol) was

added and stirred for a few minutes after which bromoethane

3.18. General procedure for acetylation

(67 lL, 0.90 mmol) was added at rt. The reaction was left to stir un-

der N₂at rt. After 4 h, TLC (toluene–EtOAc, 7:1) showed complete

consumption of alcohol (R_f0.4) and the formation of a major prod-

uct (R_f0.8). The reaction was quenched by the addition of EtOH

(5 mL) at 0 °C and the mixture was concentrated in vacuo until a

slurry remained. The mixture was partitioned between Et₂O

(10 mL) and brine (3 ꢂ 10 mL). The aqueous phases were extracted

with Et₂O (2 ꢂ 10 mL) and the combined organic phases were dried

(Na₂SO₄), ﬁltered and concentrated in vacuo. The crude product

(50 mg) was puriﬁed by ﬂash column chromatography (toluene–

EtOAc, 12:1) to give ether 21 (17 mg, 46%) as an oil; ¹H NMR

(400 MHz, CDCl₃) d_H1.18 (3H, t, J 7.0 Hz, CH₂CH₃), 1.23 (3H, t, J

Alcohol 19 was dissolved in a mixture of Ac₂O and pyridine, and

stirred at rt. After TLC (toluene–EtOAc, 8:1) showed complete con-

sumption of starting material and formation of a single product

(typically up to 3 h), the reaction mixture was concentrated by

co-evaporating all solvent with toluene (2 ꢂ 10 mL). The residue

was puriﬁed by ﬂash column chromatography to give the acetate

20.

3.19. 2-O-Acetyl-3,5,6-tri-O-benzyl-1-O-ethyl-4a-carba-b-D-

galactofuranose (20a)

7.0 Hz, CH₂CH₃), 1.66 (1H, ddd, J_1,4a3.6 Hz, J_4,4a8.5 Hz, J_4a,4a

Ethyl ether 19a (24 mg, 0.050 mmol) was converted with Ac₂O/

pyridine [1:1] (5 mL) into its acetate 20a (23 mg, 89%), an oil (R_f

0.5, toluene–EtOAc, 8:1), according to the general procedure; IR

(Film)

(3H, t, J 7.0 Hz, CH₂CH₃), 1.75 (1H, ddat, J_at1.8 Hz, J_4,4a7.8 Hz,

13.6 Hz, H-4a), 1.92 (1H, ddd, J_1,4a7.2 Hz, J_4,4a10.2 Hz, J_4a,4a

13.6 Hz, H-4a⁰), 2.27 (1H, m, H-4), 3.43–3.74 (10H, m, 2 ꢂ CH₂CH₃,

H-1, H-2, H-3, H-5, H-6, H-6⁰), 4.37, 4.70 (2H, 2 ꢂ d, J 11.7 Hz,

PhCH₂), 4.45, 4.67 (2H, 2 ꢂ d, J 11.7 Hz, PhCH₂), 4.48, 4.53 (2H,

2 ꢂ d, J 12.1 Hz, PhCH₂), 7.25–7.32 (15H, m, Ar-H); ¹³C NMR

(100 MHz, CDCl₃) d_C15.7, 15.9 (2 ꢂ q, 2 ꢂ CH₂CH₃), 27.8 (t, C-4a),

43.2 (d, C-4), 64.4, 65.6 (2 ꢂ t, 2 ꢂ CH₂CH₃), 72.1, 72.9, 73.1, 73.5

(4 ꢂ t, 3 ꢂ PhCH₂, C-6), 77.4, 81.8, 83.9, 90.4 (4 ꢂ d, C-1, C-2, C-3,

C-5), 127.5, 127.6, 127.7, 127.7, 128.0, 128.1, 128.4, 128.4, 128.5

(9 ꢂ d, Ar-CH), 138.6, 139.0, 139.2 (3 ꢂ s, 3 ꢂ Ar-C); HRESIMS calcd

for C₃₂H₄₀O₅Na (MNa⁺) 527.2768; found 527.2786.

m ;

1724 (C@O) cm^{ꢀ1 1}H NMR (400 MHz, CDCl₃) d_H1.18

J_4a,4a13.5 Hz, H-4a), 1.90 (1H, ddd, J_1,4a6.0 Hz, J_4,4a11.4 Hz,

J_4a,4a13.5 Hz, H-4a⁰), 2.03 (3H, s, C(O)CH₃), 2.42 (1H, ddat, J_4,5

3.4 Hz, J_at7.9 Hz, J_4,4a11.4 Hz, H-4), 3.40–3.61 (4H, m, CH₂CH₃,

H-6, H-6⁰), 3.64 (1H, m, H-1), 3.75 (1H, dat, J_at4.0 Hz, J 6.2 Hz, H-

5), 3.79 (1H, dd, J_2,34.0 Hz, J_3,48.2 Hz, H-3), 4.32, 4.75 (2H, 2 ꢂ d,

J 11.7 Hz, PhCH₂), 4.34, 4.56 (2H, 2 ꢂ d, J 11.8 Hz, PhCH₂), 4.49,

4.53 (2H, 2 ꢂ d, J 12.0 Hz, PhCH₂), 5.16 (1H, m, H-2), 7.24–7.35

(15H, m, Ar-H); ¹³C NMR (100 MHz, CDCl₃) d_C15.6 (q, CH₂CH₃),

26.9 (t, C-4a), 42.8 (d, C-4), 64.8 (t, CH₂CH₃), 72.4, 72.5 (2 ꢂ t, C-

6, PhCH₂), 73.0, 73.5 (2 ꢂ t, 2 ꢂ PhCH₂), 77.1 (d, C-5), 82.3 (d, C-

2), 82.7 (d, C-1), 84.4 (d, C-3), 127.7, 127.7, 127.7, 127.8, 128.0,

128.1, 128.5, 128.5, 128.5 (9 ꢂ d, Ar-CH), 138.4, 138.8, 138.9

3.21.2. Method 2: alkylation of diol 13

Diol 13 (14 mg, 0.031 mmol) was dissolved in DMF (2 mL) and

NaH (60% in oil, 8 mg, 0.2 mmol) was added at 0 °C under N₂. Bro-

moethane (23 lL, 0.31 mmol) was added. The reaction was stirred

at rt for 5 d, after which time TLC (toluene–EtOAc, 7:1) showed that

all starting material (R_f0) was consumed and that a major product

(R_f0.7) had been formed. The reaction was quenched by the addi-

tion of NH₄Cl (satd aq, 2 mL). Et₂O (10 mL) was added, and the or-

ganic phase was washed with brine (3 ꢂ 10 mL). The organic phase

was dried (Na₂SO₄), ﬁltered and concentrated in vacuo. An impure

crude product was puriﬁed by ﬂash column chromatography (tol-

uene–EtOAc, 7:1) to give ether 21 (7 mg, 45%) as an oil, identical to

that described above.

(3 ꢂ s, 3 ꢂ Ar-C); HRESIMS calcd for

₃₂H₃₈O₆Na (MNa⁺)

541.2561; found 541.2551.

3.20. Methyl 2-O-acetyl-3,5,6-tri-O-benzyl-4a-carba-b-D-

galactofuranosyl-(1?4)-2,3-O-isopropylidene-a-L-

rhamnopyranoside (20d)

Pseudodisaccharide 19d (12 mg, 0.018 mmol) was converted

with Ac₂O/pyridine (4 mL) and DMAP (1 mg, 0.008 mmol) into its

acetate 20d (11 mg, 86%), an oil (R_f0.7, toluene–EtOAc, 6:1),

3.22. 3,5,6-Tri-O-benzyl-1-deoxy-1-S-ethyl-1-thio-4a-carba-b-D-

according to the general procedure; ½a _D²⁵

ꢃ

ꢀ56.6 (c 1.0, CHCl₃); ¹H

galactofuranose (27)

NMR (400 MHz, CDCl₃) d_H1.24 (3H, d, J_5,66.3 Hz, CH₃-6^I), 1.30,

1.50 (6H, 2 ꢂ s, C(CH₃)₂), 1.81–1.90 (2H, m, H-4a^II, H-4a⁰), 2.05

Na (80 mg, 3.49 mmol) was added to MeOH (4 mL) at rt under

N₂. Ethanethiol (172 L, 2.33 mmol) was added via syringe. Epox-

(3H, s, C(O)CH₃), 2.39 (1H, ddat, J_at7.9 Hz, J 3.7 Hz, J 11.1 Hz, H-

4^II), 3.21 (1H, dd, J 6.9 Hz, J 9.8 Hz, H-4^I), 3.34 (3H, s, OCH₃), 3.50

ide 18 (100 mg, 0.233 mmol) was dissolved in MeOH (2 mL) and

added to the reaction mixture by syringe. After 5 days, TLC (tolu-

ene–EtOAc, 6:1) showed a complete consumption of epoxide (R_f

0.6) and formation of a major product (R_f0.4). NaHCO₃(satd aq,

5 mL) was added, and the mixture was extracted with CH₂Cl₂

(3 ꢂ 15 mL). The combined organic phases were washed with NaH-

CO₃(satd aq 2 ꢂ 10 mL). The combined aqueous phases were acid-

iﬁed by addition of 1 M HCl (5 mL) and then once again extracted

with CH₂Cl₂(2 ꢂ 5 mL). The combined organic phases were dried

(Na₂SO₄), ﬁltered and concentrated in vacuo. The crude product

was puriﬁed by column chromatography (toluene–EtOAc, 12:1)

(1H, dd, J_5,64.4 Hz, J_6,610.0 Hz, H-6^II), 3.55–3.61 (2H, m, H-5^I, H-

6⁰), 3.70–3.76 (2H, m, H-3^II, H-5^II), 4.07–4.13 (3H, m, H-2^I, H-3^I,

H-1^II), 4.30, 4.72 (2H, 2 ꢂ d, J 11.7 Hz, PhCH₂), 4.33, 4.63 (2H,

2 ꢂ d, J 11.8 Hz, PhCH₂), 4.48, 4.53 (2H, 2 ꢂ d, J 12.1 Hz, PhCH₂),

4.83 (1H, s, H-1^I), 5.28 (1H, br s, H-2^II), 7.24–7.32 (15H, m, Ar-H);

¹³C NMR (100 MHz, CDCl₃) d_C17.9 (q, C-6^I), 21.4 (q, C(O)CH₃),

26.4, 28.1 (2 ꢂ q, C(CH₃)₂), 28.5 (t, C-4a^II), 45.3 (d, C-4^II), 54.9 (q,

OCH₃), 64.6 (d, C-5^I), 71.9, 73.1, 73.5 (3 ꢂ t, 3 ꢂ PhCH₂), 73.0 (t,

C-6^II), 76.1, 78.3, 81.8 (3 ꢂ d, C-2^I, C-3^I, C-1^II), 77.4, 84.4 (2 ꢂ d, C-

3^II, C-5^II), 79.9 (d, C-4^I), 82.2 (d, C-2^II), 98.2 (d, C-1^I), 109.2 (s,

J. Frigell et al. / Carbohydrate Research 346 (2011) 1277–1290

1289

to give thioether 27 (78 mg, 68%) as an oil; ¹H NMR (400 MHz,

References

CDCl₃) d_H1.26 (3H, t, J 7.3 Hz, CH₃), 1.72 (1H, m, H-4a), 2.19–

2.28 (2H, m, H-4, H-4a⁰), 2.57 (2H, m, CH₂CH₃), 2.89 (1H, aq, J

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8.3 Hz, H-1), 3.51 (1H, dd, J_5,64.4 Hz, J_6,69.9 Hz, H-6), 3.61 (1H,

dd, J_5,66.2 Hz, J_6,69.8 Hz, H-6⁰), 3.71–3.76 (2H, m, H-3, H-5), 3.91

(1H, at, J 7.4 Hz, H-2), 4.41 (1H, d, J 11.6 Hz, PhCHH⁰), 4.50–4.58

(3H, m, PhCH₂, PhCHH⁰), 4.71–4.76 (2H, m, 2 ꢂ PhCHH⁰), 7.28–

7.39 (15H, m, Ar-H); ¹H NMR (100 MHz, CDCl₃) d_C15.2 (q, CH₃),

25.1 (t, CH₂CH₃), 28.7 (t, C-4a), 43.2 (d, C-4), 48.1 (d, C-1), 72.2,

72.3, 72.9, 73.4 (4 ꢂ d, 3 ꢂ PhCH₂, C-6), 77.4, 85.4 (2 ꢂ d, C-3, C-

5), 82.3 (d, C-2), 127.6, 127.7, 127.7, 128.0, 128.1, 128.4, 128.5,

128.5 (8 ꢂ d, Ar-CH), 138.3, 138.7, 138.7 (3 ꢂ s, 3 ꢂ Ar-C); HRE-

SIMS calcd for C₃₀H₃₆O₄NaS (MNa⁺) 515.2227; found 515.2229.

Thioether 27 (3 mg, 6 mol) was dissolved in a mixture of Ac₂O

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CH₂CH₃), 1.74 (1H, ddd, J_1,4a5.0 Hz, J_4,4a8.4 Hz, J_4a,4a13.3 Hz, H-

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