Allyl protecting group mediated intramolecular aglycon delivery (IAD): Synthesis of α-glucofuranosides and β-rhamnopyranosides

Tetrahedron 60 (2004) 9061–9074

Allyl protecting group mediated intramolecular aglycon delivery

(IAD): synthesis of a-glucofuranosides and b-rhamnopyranosides

b

Ian Cumpstey,^aAntony J. Fairbanks^a,and Alison J. Redgrave

*

^aChemistry Research Laboratory, Oxford University, Mansﬁeld Road, Oxford OX1 3TA, UK

^bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK

Received 8 June 2004; revised 6 July 2004; accepted 28 July 2004

Available online 27 August 2004

Abstract—The use of allyl protecting group mediated intramolecular aglycon delivery (IAD) as a strategy for intramolecular glycosylation

has been extended to allow the stereoselective synthesis of a-glucofuranosides and b-rhamnopyranosides, in a totally stereoselective fashion.

The efﬁciency of intramolecular glycosylation is dependent on the protecting group pattern of the glycosyl donor, and on the steric bulk of the

glycosyl acceptor.

1. Introduction

Aglycon Delivery (IAD), wherein the aglycon is delivered

to the same face of the glycosyl donor as the C-2 hydroxyl,

hence forming a 1,2-cis linkage. The most notable

applications of IAD to the synthesis of b-mannosides have

arisen from the laboratories of Hindsgaul,³Stork,⁴and

Ogawa,⁵whilst Bols extended the Stork ‘silicon tether’

approach to the synthesis of a-glucosides.⁶Following

on from methodological developments⁷of the original

Hindsgaul IAD approach,³we recently reported the

development of an IAD strategy based on the use of glyco-

syl donors possessing allyl protection of the 2-hydroxyl

group.⁸Herein the 2-O-allyl protecting group is isomerised

to yield an enol ether, which can then undergo iodonium ion

mediated tethering of a range of aglycon alcohols.

Subsequent intramolecular glycosylation then yields the

1,2-cis glycoside product, with complete control of

The formal sub-division of glycosidic linkages into two

categories depending on whether the 2-hydroxyl group is

formally cis or trans to the anomeric substituent is

strategically useful when planning the synthesis of a

particular oligosaccharide. The use of participating protect-

ing groups on the 2-hydroxyl of a glycosyl donor readily

allows the stereoselective formation of 1,2-trans glycosidic

linkages,¹and therefore the construction of glycosides and

oligosaccharides containing 1,2-trans linkages may be

readily achieved by employing monosaccharide building

blocks which posses 2-O-acyl protection. However, the

stereoselective synthesis of glycosides and oligosaccharides

containing 1,2-cis linkages is considerably more difﬁcult. At

the very least, the presence of such 1,2-cis linkages neces-

sitates the use of glycosyl donors with non-participating

protecting groups at the 2-position. However, in general,

intermolecular glycosylation reactions of such donors are

very rarely completely stereoselective,²and the undesired

anomer must be separated, if possible, and discarded.

One of the most ingenious approaches to overcome this

problem of stereoselectivity is to temporarily attach, or

‘tether’, the glycosyl acceptor to the C-2 hydroxyl of the

glycosyl donor. This process can then be followed by a

stereospeciﬁc intramolecular glycosylation, or Intramolecular

Keywords: Carbohydrates; Glycosylation; Stereocontrol; Thioglycosides;

Intramolecular aglycon delivery (IAD).

* Corresponding author. Tel.: C44-1865-275-647; fax: C44-1865-275-

674; e-mail: antony.fairbanks@chem.ox.ac.uk

Figure 1.

doi:10.1016/j.tet.2004.07.083

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I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

anomeric stereochemistry (Fig. 1). This strategy has been

applied to allow the synthesis of a variety of b-mannno-

pyranosides and a-glucopyranosides, using either thioglyco-

sides⁹or glycosyl ﬂuorides¹⁰as donors, and in addition,

both steps have also been achieved in a one-pot reaction.⁹

peracetylated using acetic anhydride in combination with

iodine¹⁴to give a tetraacetate which was then directly

treated with para-thiocresol and BF₃$OEt₂to give thio-

glycosides 3a/3b as a separable 3.6:1 a/b mixture (76%

yield over two steps, Scheme 1). Zemplen deacetylation of

the pure a-anomer 3a gave the triol 4 (97% yield).

Treatment of triol 4 with butanedione and trimethyl ortho-

formate in methanol, in the presence of an acid catalyst as

described by Ley,^13bafforded the selectively 3,4-protected

derivative 5 (74% yield). Allylation with sodium hydride

and allyl bromide gave the fully protected sugar 1 (83%

yield). Finally, isomerisation of the allyl group by treatment

with Wilkinson’s catalyst¹⁵yielded the enol ethers 6 as

substrates for tethering and glycosylation of aglycon

alcohols (95% yield).

Despite considerable methodological investigation into the

development of IAD, this type of intramolecular glycosyla-

tion approach has not yet become a widely and generally

used approach for glycoside and oligosaccharide synthesis.

This is perhaps in part due to the limited number of

examples of the different types of 1,2-cis glycosidic

linkages that have so far been prepared by this strategy.¹¹

In particular, the vast majority of work published to date¹²

has focused on the synthesis of the notorious b-manno

linkage, which, although it forms part of the core N-glycan

pentasaccharide, does not otherwise have particularly

widespread occurrence in nature. In order to begin to

address this problem, and hopefully expand the utility of

IAD as a method for stereoselective glycosylation in a more

general context, we detail herein extensions of the allyl IAD

approach to other 1,2-cis glycosides, namely a-glucofurano-

sides and b-rhamnopyranosides.

Protection by 1,2-diacetal groups, such as BDA, is known to

reduce the reactivity of a glycosyl donor, and indeed such

torsional deactivation has been successfully applied in a

reactivity tuning approach to one-pot oligosaccharide

synthesis.¹⁶In order to investigate any potential effect of

BDA protection on the efﬁciency of the intramolecular

glycosylation reaction inherent in the IAD approach,

glycosyl donor 1 was also elaborated into the dibenzylated

donor 7. Thus, BDA protected donor 1 was treated with

aqueous triﬂuroacetic acid to afford the diol 8 (95% yield),

which was then benzylated by treatment with sodium

hydride and benzyl bromide to give the benzyl-protected

donor 7 (88% yield). Finally, 7 was isomerised by treatment

with Wilkinson’s catalyst, as before, to give the required

enol ethers 9 as substrates for subsequent tethering and

glycosylation (80% yield, Scheme 1).

2. Results and discussion

2.1. Synthesis of b-rhamnopyranosides

2.1.1. Synthesis of glycosyl donors. The allyl IAD

approach requires selective access to the 2-hydroxyl of the

glycosyl donor. As rhamnose is a 6-deoxy sugar, any

protecting group strategy therefore only requires differen-

tiation of the axial 2-hydroxyl from the equatorial 3- and

4-hydroxyl groups, and this may be most readily achieved

by the use of a butane diacetal (BDA) protecting group.¹³

The BDA protected rhamnose thioglycoside 1 was therefore

chosen as an initial donor for study. ^L-Rhamnose 2 was

2.1.2. Tethering and intramolecular glycosylation reac-

tions. Investigations initially focused on the use of the more

readily available BDA protected donors. Enol ethers 6 were

treated with N-iodosuccinimide (NIS) and methanol, and the

desired mixed acetals 10 were obtained in good yield

Scheme 1. (i) I₂, Ac₂O, rt; (ii) TolSH, BF₃$OEt₂, DCM, rt, 76% over 2 steps (3a:3b, 3.6:1); (iii) Na, MeOH, rt, 97%; (iv) CH₃C(O)C(O)CH₃, CH(OMe)₃,

CSA, MeOH, 75 8C, 74%; (v) allyl bromide, DMF, NaH, 0 8C, 83%; (vi) Wilkinson’s catalyst, BuLi, THF, 70 8C, 95%; (vii) TFA/H₂O (9:1), 95%; (viii) BnBr,

DMF, NaH, 0 8C, 88%; (ix) Wilkinson’s catalyst, BuLi, THF, 70 8C, 80%.

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

9063

Scheme 2. (i) NIS, MeOH, DCE, K40 8C/rt, 96%; (ii) NIS, DTBMP, AgOTf, DCE, 50 8C, 29%; (iii) NIS, methyl 2-O-benzyl-4,6-O-benzylidene-a-D-

mannopyranoside, DTBMP, CH₂Cl₂, K40 8C/rt, 60%; (iv) NIS, DTBMP, AgOTf, DCE, rt, 70%.

(Scheme 2). However, when tethered material 10 was

treated under a range of reaction conditions commonly

used for the activation of thioglycosides, the desired methyl

b-rhamnoside 11 was only obtained in poor yield: the best

yield (30%) was obtained by the use of NIS and silver

triﬂate in the presence of di-tert-butylmethyl pyridine

(DTBMP) in dichloroethane (DCE) as solvent, at 50 8C;

all reactions required heating to proceed at an appreciable

rate indicating torsional deactivation of the glycosyl donor.

In all reactions in which NIS was used as activator,

succinimide-trapped products, such as 12, were observed to

a varying degree, which was found to be concentration

dependent. Despite the disappointing efﬁciency of this

intramolecular glycosylation process, it was noted that no

a-rhamnoside products were observed in any reaction, and

the low yields were perplexing as no other major products

were isolated. This observation that allyl-mediated IAD

does not work efﬁciently for BDA-protected donors in the

rhamno series, is particularly interesting in light of results

obtained by Ogawa which indicated that para-methoxy-

benzyl (PMB) mediated IAD worked more efﬁciently for

glycosyl donors that possessed cyclic 4,6-protection,^5cand

which could therefore also be considered as torisionally

deactivated. It was therefore thought prudent at this juncture

to investigate if allyl-mediated IAD was actually compatible

with cyclic 4,6-protection of the glycosyl donor. To this end,

the enol ethers 13¹⁷were tethered to a secondary

carbohydrate alcohol to give mixed acetals 14. Intramole-

cular glycosylation of 14, mediated by NIS and silver tri-

ﬂate, proceeded smoothly to give the a-gluco disaccharide

15 in good yield as the sole product (Scheme 2). This result

therefore indicates that whilst allyl mediated IAD is

apparently not compatible with 3,4-BDA protection of the

donor, it is indeed compatible with 4,6-benzylidene

protection.

alternatively by using iodine, silver triﬂate and DTBMP,

and good yields of the mixed acetals 16aKd were obtained

in all cases (Scheme 3). Intramolecular glycosylation of the

methanol (16a) and the primary carbohydrate (16b) tethered

materials, mediated by NIS and silver triﬂate, cleanly

furnished the desired b-rhamnosides¹⁸17a and 17b in good

yield in a totally stereoselective fashion. Attempted

alternative activation of 16b with MeOTf resulted in no

appreciable glycosylation, indicating that in this system

NIS/AgOTf is a more potent activator. In contrast to the

BDA-protected glycosylations outlined above, which

required heating in order for efﬁcient reaction to be seen,

these reactions did proceed at an appreciable rate at room

temperature, in line with the expected higher reactivity of

these ‘armed’ benzylated donors over the torsionally

deactivated BDA-protected counterparts. However, when

the steroid-tethered material 16d was treated under the

same conditions, only a relatively poor 29% yield of the

In light of the failure of the BDA protected donor to undergo

efﬁcient intramolecular glycosylation, the enol ethers 9,

derived from the benzylated donor 7, were investigated.

Iodonium-mediated tethering of a range of aglycon alcohols

with the enol ethers 9 was undertaken either using NIS or

Scheme 3. (i) ROH, NIS, DCE, K40 8C/rt; 16a, 88%; 16b, 75%; (ii)

ROH, I₂, AgOTf, DTBMP, CH₂Cl₂, K78 8C/rt; 16c, 82%; 16d, 69%; (iii)

NIS, DTBMP, AgOTf, DCE, 50 8C; 17a, 54%; 17b, 62%; 17c, –; 17d, 29%.

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b-rhamnoside 17d was obtained. Moreover for the case of

the tethered material derived from the secondary carbo-

hydrate alcohol 16c, only decomposition and no appreciable

glycosylation was observed.

2.2. Synthesis of a-glucofuranosides

2.2.1. Synthesis of the glycosyl donor. Investigations

required access to a glucofuranosyl donor bearing 2-O-allyl

protection, which was readily available from diacetone

glucose via the known diacetate 18.¹⁹Treatment of

diacetate 18 with para-thiocresol at room temperature in

the presence of BF₃$OEt₂gave the desired thioglycoside

19a/b as a disappointing anomeric mixture (1.3:1,

19b:19a,²⁰in a poor overall yield (31%). However,

conducting the reaction at lower temperature (K30 8C)

increased both the yield and selectivity (58%, 50:1

19b:19a, Scheme 4). Subsequent studies focused on the

major b-product as a donor for IAD.²¹Amine-mediated

deacetylation of 19b gave the alcohol 20 (91% yield).

Subsequent allylation with sodium hydride and allyl

bromide gave the glycosyl donor 21 (94% yield) and ﬁnally

Wikinson’s catalyst mediated isomerisation gave the

required enol ethers 22 (96% yield, Scheme 4).

Scheme 5. (i) ROH, NIS, DCE, K40 8C/rt; 23a, 75%; 23b, 53%; (ii)

ROH, I₂, AgOTf, DTBMP, CH₂Cl₂, K78 8C/rt; 23b, 64%; 23c, 88%; (iii)

NIS, DTBMP, AgOTf, DCE, rt; 24a, 70%; 24b, 39%; (iv) MeOTf, Me₂S₂,

DTBMP, CH₂Cl₂, rt; 24c, 32%.

DTBMP resulted in the formation of the desired a-gluco-

furanoside 24a, as a single anomer,²²in a good 75% yield.

When mixed acetals 23b, derived from the more hindered

primary manno alcohol, were treated under the same

conditions again only a single a anomer of the desired

glycosylated product 24b was formed, but in a rather poor

35% yield. Moreover, treatment of mixed acetals 23c,

derived from the hindered secondary manno alcohol with

NIS, siver triﬂate and DTBMP resulted in a complex

mixture of products.²³However, the use of dimethyl(thio-

methyl)sulfonium triﬂate (DMTST) as an alternative

activator^11cgave a much cleaner glycosylation reaction,

and the 1,2-cis disaccharide 24c was isolated without any

formation of the aglycon alcohol, albeit in a very modest

overall yield (32%, Scheme 5).

3. Summary and conclusion

The potential of allyl-mediated IAD as a tool for the

synthesis of a-glucofuranosyl and b-rhamnosyl bonds has

been investigated with a range of substrates. In all cases,

tethering reactions of aglycon alcohols to enol ethers

derived from 2-O-allyl protected glycosyl donors by

Wilkinson’s catalyst mediated isomerisation has been

efﬁciently achieved. However the efﬁcacy of the subsequent

intramolecular glycosylation reaction has been demon-

strated to depend markedly both on the protecting group

pattern of the glycosyl donor, and on the steric bulk of the

glycosyl acceptor. Importantly, intramolecular glycosyla-

tion was completely stereoselective in all cases, and only the

1,2-cis isomer of glycosylated product was isolated from all

glycosylation reactions. However, in the rhamnopyranose

series, butane diacetal protection (BDA) of the 3- and 4-

hydroxyls of the donor is seen to be currently incompatible

with high yielding intramolecular glycosylation. Since

efﬁcient intramolecular glycosylation of a 4,6-O-benzylidene

Scheme 4. (i) HSTol, BF₃$OEt₂, CH₂Cl₂, K30 8C, 58%, 19b:a, 50:1; (ii)

ⁿPrNH₂, MeOH, THF, rt, 91%; (vi) allyl bromide, DMF, NaH, 0 8C, 94%;

(vii) Wilkinson’s catalyst, BuLi, THF, 70 8C, 96%.

2.2.2. Tethering and intramolecular glycosylation reac-

tions. Iodonium ion-mediated tethering reactions of a

selection of carbohydrate aglycon alcohols to the b-gluco-

furanose enol ethers 22 were undertaken, both using NIS as

a source of I^C, and also by the use of iodine, silver triﬂate

and di-tert-butylmethylpyridine, to form mixed acetals

23a–c in good yield in all cases (Scheme 5).

Treatment of the mixed acetals derived from diacetone

galactose 23a with NIS and silver triﬂate in the presence of

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

9065

protected gluco donor was observed using identical reaction

conditions, this implies that the effect may not be simply due

to torsional deactivation of the glycosyl donor. In the

glucofuranose series, intramolecular glycosylation of mixed

acetals derived from a simple unhindered primary alcohol

aglycon is efﬁcient. However, the yield of intramolecular

glycosylation is seen to decrease with increasing bulk of the

aglycon alcohol, and only low yields were achieved for a

hindered secondary carbohydrate alcohol. It is clear that in

order for allyl IAD to become a useful and widely

applicable technique for the stereoselective synthesis of

di- and higher oligosaccharides, the efﬁciency of the

intramolecular glycosylation step requires substantial

improvement. Investigations into the improvement and

optimisation of allyl mediated IAD in the cases of hindered

secondary carbohydrate alcohols are currently in progress,

and the results will be reported in due course.

Chemistry Laboratory using solid probe temperature

programmed ﬁeld ionisation (TOF FI) on a Micromass

GCT Tof spectrometer. Optical rotations were recorded on a

Perkin–Elmer 241 polarimeter with a path length of 1 dm.

Concentrations are given in g/100 ml. Microanalyses were

performed by the microanalytical services of Elemental

Microanalysis Ltd., Devon. Thin layer chromatography

(TLC) was carried out on Merck Kieselgel 0.22–0.25 mm

thickness glass-backed sheets pre-coated with 60F₂₅₄silica.

Plates were developed using 5% w/v ammonium molybdate

in 2 M sulfuric acid. Flash column chromatography was

carried out using Sorbsil C60 40/60 silica. Solvents and

reagents were dried and puriﬁed before use according to

standard procedures; dichloromethane was distilled from

CaH₂immediately before use; methanol was distilled from

NaH or anhydrous methanol was purchased from Acros;

THF and ether were distilled from solutions of sodium

benzophenone ketal immediately before use; anhydrous

DMF and anhydrous dichloroethane were purchased from

Aldrich or Acros. Petrol refers to the fraction of light

petroleum ether boiling in the range 40–60 8C. Reactions

performed under an atmosphere of argon or hydrogen gas

were maintained by an inﬂated balloon.

4. Experimental

4.1. General

Melting points were recorded on a Koﬂer hot block and are

uncorrected. Proton nuclear magnetic resonance spectra

were recorded on Bruker DPX 400 or AV 400 (400 MHz),

Bruker AMX 500 or DRX 500 (500 MHz) or Bruker DPX

200, AC 200 or Varian Gemini 200 (200 MHz) spectro-

meters. Spectra were assigned using COSY, edited HSQC,

HMQC and/or HMBC experiments. Carbon nuclear mag-

netic resonance spectra were recorded on Bruker DPX 400

or AV 400 (100.6 MHz), Bruker AMX 500 or DRX 500

(125.7 MHz) or Bruker DPX 200, AC 200 or Varian Gemini

200 (50.3 MHz) spectrometers. Multiplicities were assigned

using APT or DEPT sequence. Proton-carbon coupling

constants were measured either from proton-coupled carbon

spectra (125.7 MHz) or from carbon-coupled HSQC spectra

(400 MHz). Fluorine nuclear magnetic resonance spectra

were recorded on a Bruker DPX 250 (235 MHz) spectro-

meter. All chemical shifts are quoted on the d scale in ppm

and coupling constants are quoted once. Residual signals

from the solvents were used as an internal reference.

Infrared spectra were recorded on a Perkin–Elmer 150

Fourier transform spectrophotometer. Low resolution mass

spectra were obtained by atmospheric pressure chemical

ionisation (APCI) on a Micromass Platform 1 APCI

spectrometer; or by electrospray ionisation (ES) on a Micro-

mass Platform 1 APCI spectrometer, or on a Micromass

LCT spectrometer, or on a VG BioQ spectrometer, or by on

a Micromass ZMD spectrometer, or by the EPSRC Mass

Spectrometry Service Centre, Department of Chemistry,

University of Wales, Swansea, on a Micromass Quattro II

spectrometer; or using chemical ionisation (CI) on a

Micromass AutoSpec-oa Tof spectrometer, or by the

EPSRC Mass Spectrometry Service Centre on a Micromass

Quattro II spectrometer; or using solid probe temperature

programmed ﬁeld ionisation (TOF FI) on a Micromass GCT

Tof spectrometer by the Inorganic Chemistry Laboratory,

Oxford University, UK. High-resolution mass spectra were

performed on a Waters 2790-Micromass LCT electrospray

ionisation mass spectrometer, or by the EPSRC Mass

Spectrometry Service Centre on a MAT900 XLT electro-

spray ionisation mass spectrometer, or by the Inorganic

4.1.1. para-Tolyl 2,3,4-tri-O-acetyl-1-thio-a-^L-rhamno-

pyranoside 3a and para-tolyl 2,3,4-tri-O-acetyl-1-thio-

b-^L-rhamnopyranoside 3b. L-Rhamnose 2 (10.0 g,

61 mmol) was suspended in acetic anhydride (40 ml).

Iodine (250 mg, 0.98 mmol) was dissolved in acetic

anhydride (10 ml). The mixture was warmed until an

exothermic reaction was initiated, then added to the sugar

suspension. The reaction mixture was kept cool in a water

bath. After 10 min, TLC (petrol/ethyl acetate, 1:1) indicated

formation of major (R_f0.5) and minor (R_f0.45) products and

the absence of starting material (R_f0). The reaction was

diluted with CH₂Cl₂(200 ml), washed with Na₂S₂O₃

(200 ml of a 10% aqueous solution) and NaHCO₃(200 ml

of a saturated aqueous solution), dried (MgSO₄), ﬁltered and

concentrated in vacuo to afford the crude tetraacetate

(20.1 g, 99%) as a pale yellow oil which was used without

further puriﬁcation. Crude tetraacetate (18.7 g, 56 mmol)

and para-thiocresol (10.7 g, 86.2 mmol) were dissolved in

CH₂Cl₂(50 ml). BF₃$OEt₂(9.1 ml, 74.7 mmol) was added

and the reaction mixture stirred at rt under Ar. After 3 h,

TLC (petrol/ethyl acetate, 3:2) indicated formation of two

products (R_f0.5 and 0.45) complete consumption of starting

materials (R_f0.35 and 0.3). The reaction mixture was

diluted with CH₂Cl₂(300 ml) and washed with NaHCO₃

(300 ml of a saturated aqueous solution), dried (MgSO₄),

ﬁltered and concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography (petrol/ethyl acetate, 4:1)

and recrystallised from ether/petrol to afford thioglycoside 3

(a/b ratio 3.6:1 determined by ¹H NMR spectroscopy)

(17.0 g, 76%). Separation of the anomers by ﬂash column

chromatography gave pure a-thioglycoside 3a as white

crystals, mp 112–114 8C (ether/petrol); [a]²_D⁵ZK87.2 (c,

3.4 in CHCl₃); n_max1749 (s, CZO) cm^K1; d_H(400 MHz,

CDCl₃) 1.23 (3H, d, J_5,6Z6.1 Hz, CH₃-6), 2.00, 2.07, 2.13

(9H, 3!s, 3!COCH₃), 2.32 (3H, s, ArCH₃), 4.36 (1H, dq,

J_4,5Z9.7 Hz, H-5), 5.13 (1H, at, JZ10.0 Hz, H-4), 5.28

(1H, dd, J_2,3Z3.5 Hz, J_3,4Z10.1 Hz, H-3), 5.32 (1H, d,

J_1,2Z1.3 Hz, H-1), 5.48 (1H, dd, H-2), 7.11, 7.35 (4H, 2!

d, JZ8.1 Hz, Ar-H); d_C(100.6 MHz, CDCl₃) 17.3 (q, C-6),

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I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

20.6, 20.8, 20.9, 21.1 (4!q, ArCH₃, 3!COCH₃), 67.6,

69.3, 71.1, 71.2(4!d, C-2, C-3, C-4, C-5), 86.0(d, ¹J_C-1,H-1

(c, 1.0 in CHCl₃); n_max3410 (br, OH) cm^K1; d_H(400 MHz,

CDCl₃) 1.27 (3H, d, J_5,6Z6.5 Hz, CH₃-6), 1.32, 1.34 (6H,

2!s, 2!C(O)₂CH₃), 2.33 (3H, s, ArCH₃), 2.69 (1H, d,

J_OH,2Z1.8 Hz, OH-2), 3.25, 3.31 (6H, 2!s, 2!OCH₃),

3.78 (1H, at, JZ9.7 Hz, H-4), 3.99 (1H, dd, J_2,3Z3.1 Hz,

J_3,4Z10.0 Hz, H-3), 4.18 (1H, br s, H-2), 4.26–4.30 (1H, m,

H-5), 5.43 (1H, s, H-1), 7.11, 7.35 (4H, 2!d, JZ8.0 Hz,

Ar-H); d_C(125.7 MHz, CDCl₃) 16.3, 17.5, 17.7 (3!q, 2!

C(O)₂CH₃, C-6), 21.0 (q, ArCH₃), 47.6, 48.0 (2!q, 2!

OCH₃), 67.5, 68.5, 68.6, 71.2 (4!d, C-2, C-3, C-4, C-5),

88.0 (d, C-1), 99.7, 100.1 (2!s, 2!C(O)₂CH₃), 129.7,

131.9 132.0 (3!d, Ar-CH), 130.2, 137.5 (2!s, Ar-C); m/z

(ES^C) 786 (2MCNH₄^C, 5), 402 (MCNH₄^C, 41), 353 (MK

OMe, 100%). (HRMS calcd for C₁₉H₃₂NO₆S (MNH^C₄)

402.1950. Found 402.1949).

Z

168.2 Hz, C-1), 129.3, 138.2 (2!s, Ar-C), 129.9, 132.4

(2!d, Ar-CH), 169.9, 170.0, 170.0 (3!s, 3!CZO); m/z

(CI^C) 414 (MCNH^C₄, 76), 273 (M-STol, 100%). (HRMS

calcd for C₁₉H₂₈NO₇S (MNH^C₄) 414.1586. Found

414.1581). (Found: C, 57.49; H, 6.27. C₁₉H₂₄O₇S requires

C, 57.56; H, 6.10%); and pure b-thioglycoside 3b as white

crystals, mp 103–107 8C (ether/petrol); [a]²_D⁵ZC23.5 (c,

1.5 in CHCl₃); n_max1749 (s, CZO) cm^K1; d_H(400 MHz,

CDCl₃) 1.30 (3H, d, J_5,6Z6.1 Hz, CH₃-6), 1.98, 2.04, 2.21

(9H, 3!s, 3!COCH₃), 2.34 (3H, s, ArCH₃), 3.52 (1H, dq,

J_4,5Z9.6 Hz, H-5), 4.83 (1H, d, J_1,2Z1.2 Hz, H-1), 4.99

(1H, dd, J_2,3Z3.5 Hz, J_3,4Z10.1 Hz, H-3), 5.11 (1H, at, JZ

9.8 Hz, H-4), 5.64 (1H, dd, H-2), 7.13, 7.40 (4H, 2!d, JZ

8.0 Hz, Ar-H); d_C(100.6 MHz, CDCl₃) 17.7 (q, C-6), 20.6,

4.1.4. (2⁰S, 3⁰S) para-Tolyl 2-O-allyl-3,4-O-(2⁰,3⁰-

dimethoxybutan-2⁰,3⁰-diyl)-1-thio-a-L-rhamnopyrano-

side 1. Alcohol 5 (118 mg 0.31 mmol) was dissolved in

anhydrous DMF (2 ml) and cooled to 0 8C. Allyl bromide

(0.053 ml, 0.62 mmol) then sodium hydride (60% in

mineral oil) (25 mg, 0.62 mmol) were added. After 2 h,

TLC (petrol/ethyl acetate, 3:1) indicated formation of a

single product (R_f0.6) and almost complete consumption of

starting material (R_f0.3). The reaction was quenched with

water (50 ml) and extracted with ether (50 ml). The organic

layer was dried (MgSO₄), ﬁltered and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy (petrol/ethyl acetate, 8:1) to afford the BDA

protected donor 1 (108 mg, 83%) as a colourless oil;

[a]²_D⁵ZK289 (c, 0.25 in CHCl₃); n_maxno signiﬁcant peaks;

d_H(400 MHz, CDCl₃) 1.29 (3H, d, J_5,6Z6.3 Hz, CH₃-6),

1.32, 1.33 (6H, 2!s, 2!C(O)₂CH₃), 2.33 (3H, s, ArCH₃),

3.26, 3.31 (6H, 2!s, 2!OCH₃), 3.81 (1H, at, JZ9.9 Hz,

H-4), 3.89 (1H, dd, J_1,2Z1.3 Hz, J_2,3Z3.0 Hz, H-2), 3.97

20.6, 20.7, 21.1 (4!q, ArCH₃, 3!COCH₃), 70.2, 70.9,

Z

1

71.8, 74.9 (4!d, C-2, C-3, C-4, C-5), 85.7 (d, J_C-1,H-1

153.4 Hz, C-1), 129.4, 138.4 (2!s, Ar-C), 129.9, 132.7

(2!d, Ar-CH) 169.8, 170.2, 170.3 (3!s, 3!CZO); m/z

(CI^C) 414 (MCNH^C₄, 100), 273 (M-STol, 96%). (HRMS

calcd for C₁₉H₂₈NO₇S (MNH^C₄) 414.1586. Found

414.1586). (Found: C, 57.65; H, 6.30. C₁₉H₂₄O₇S requires

C, 57.56; H, 6.10%).

4.1.2. para-Tolyl 1-thio-a-^L-rhamnopyranoside 4. Pure

a-thioglycoside 3a (9.4 g 23.7 mmol) was suspended in

methanol (70 ml). Sodium (60 mg, 2.6 mmol) was dissolved

in methanol (10 ml) and then added to the sugar solution.

The reaction mixture was stirred at rt. After 1 h 40 min, TLC

(petrol/ethyl acetate, 1:1) indicated formation of a major

product (R_f0.1) and no remaining starting material (R_f0.7).

The reaction mixture was concentrated in vacuo and the

residue puriﬁed by ﬂash column chromatography (ethyl

acetate/methanol, 9:1) to afford the triol 4 (6.23 g, 97%) as a

white solid which was recrystallised from ether to give

white crystals, mp 95–96 8C (ether); [a]²_D⁵ZK207 (c, 0.25

in CHCl₃); n_max3342 (br, OH) cm^K1; d_H(400 MHz, CDCl₃)

1.32 (3H, d, J_5,6Z6.2 Hz, CH₃-6), 2.34 (3H, s, ArCH₃), 3.57

(1H, dd, J_3,4Z10.2 Hz, H-3), 4.16 (1H, ddat, J_gem

13.5 Hz, JZ5.8, 1.4 Hz, OCHH⁰CHZCH₂), 4.20–4.29

(2H, m, H-5, OCHH⁰CHZCH₂), 5.16 (1H, dd, J_gem

Z

1.7 Hz, J_ZZ10.4 Hz, CHZCH_EH_Z), 5.29 (1H, daq, JZ

1.7 Hz, J_EZ17.3 Hz, CHZCH_EH_Z), 5.42 (1H, d, H-1), 5.92

(1H, ddat, CHZCH₂), 7.11, 7.34 (4H, 2!d, JZ8.1 Hz,

Ar-H); d_C(100.6 MHz, CDCl₃) 16.6, 17.7, 17.8 (3!q, 2!

C(O)₂CH₃, C-6), 21.1 (q, ArCH₃), 47.6, 47.9 (2!q, 2!

OCH₃), 67.9, 68.9, 68.9, 77.5 (4!d, C-2, C-3, C-4, C-5),

71.7 (t, OCH₂CHZCH₂), 87.2 (d, C-1), 99.5, 99.8 (2!s,

2!C(O)₂CH₃), 117.1 (t, CHZCH₂), 129.7, 131.7 (2!d,

Ar-CH), 131.0, 135.0 (2!s, Ar-C) 137.4 (d, CHZCH₂);

m/z (ES^C) 483 (MCNH₄^CCMeCN, 15), 442 (MCNH^C₄,

40), 425 (MCH^C, 100), 393 (MKOMe, 81%). (HRMS

calcd for C₂₂H₃₆NO₆S (MNH^C₄) 442.2263. Found

442.2265).

(1H, at, JZ9.4 Hz, H-4), 3.81 (1H, dd, J_2,3Z2.9 Hz, J_3,4

Z

9.3 Hz, H-3), 4.12–4.19 (1H, m, H-5), 4.22 (1H, d, H-2),

5.41 (1H, s, H-1), 7.04, 7.30 (4H, 2!d, JZ8.0 Hz, Ar-H);

d_C(100.6 MHz, CDCl₃) 17.5 (q, C-6), 21.0 (q, ArCH₃),

69.3, 72.1, 72.5, 73.2 (4!d, C-2, C-3, C-4, C-5), 88.2

(d, C-1), 129.8, 131.9 (2!d, Ar-CH), 130.1, 137.4 (2!s,

Ar-C); m/z (CI^C) 288 (MCNH^C₄, 42), 271 (MCH^C, 4%).

(HRMS calcd for C₁₃H₂₂NO₄S (MNH^C₄) 288.1270. Found

288.1269). (Found: C, 57.61; H, 6.71. C₁₃H₁₈O₄S requires

C, 57.76; H, 6.71%).

4.1.3. (2⁰S, 3⁰S) para-Tolyl 3,4-O-(2⁰,3⁰-dimethoxybutan-

2⁰,3⁰-diyl)-1-thio-a-L-rhamnopyranoside 5. Triol 4

(145 mg 0.54 mmol) was suspended in anhydrous methanol

(5 ml). 2,3-Butanedione (0.15 ml, 1.72 mmol), trimethyl

orthoformate (0.50 ml, 4.62 mmol) and camphorsulfonic

acid (15 mg, 0.064 mmol) were added and the reaction

mixture stirred under Ar at 75 8C. After 16 h, TLC (petrol/

ethyl acetate, 1:1) indicated formation of a major product

(R_f0.6) and no remaining starting material (R_f0.1).

Triethylamine (4 ml) was added and the mixture was

concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ethyl acetate, 3:1) to afford

alcohol 5 (153 mg, 74%) as a colourless oil; [a]²_D⁵ZK262

4.1.5. (2⁰S, 3⁰S) para-Tolyl 3,4-O-(2⁰,3⁰-dimethoxybutan-

2⁰,3⁰-diyl)-2-O-prop-1⁰⁰-enyl-1-thio-a-L-rhamnopyrano-

side 6. Wilkinson’s catalyst (471 mg, 0.51 mmol) was

dissolved in freshly distilled THF (6 ml) and degassed.

Butyl lithium (1.6 M solution in hexanes) (0.48 ml,

0.76 mmol) was added and the mixture stirred for 10 min.

BDA protected donor 1 (2.16 g, 5.09 mmol) was dissolved

in freshly distilled THF (6 ml) and heated to 70 8C. The

catalyst solution was added by cannula under Ar. After

30 min, TLC (petrol/ether, 8:1) indicated formation of two

products (R_f0.2 and R_f0.25) and complete consumption of

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

9067

starting material (R_f0.1). The reaction was allowed to cool

then diluted with CH₂Cl₂(20 ml) and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy (petrol/ether, 8:1) to afford enol ethers 6 (2.04 g,

95%) as a colourless oil. (Z/E, 1.8:1). The isomers were

separated by ﬂash column chromatography (petrol/ether,

8:1) for characterisation purposes. E isomer, a colourless

71.9, 74.2, 79.2 (4!d, C-2, C-3, C-4, C-5), 71.3 (t,

OCH₂CHZCH₂), 85.1 (d, C-1), 118.3 (t, CHZCH₂), 129.8,

132.0, 133.8 (3!d, Ar-CH, CHZCH₂), 130.4, 137.7 (2!s,

Ar-C); m/z (TOF FI^C) 310 (M^C, 100%). (HRMS calcd for

C₁₆H₂₂O₄S (M^C) 310.1239. Found 310.1237).

4.1.7. para-Tolyl 2-O-allyl-3,4-di-O-benzyl-1-thio-a-^L-

rhamnopyranoside 7. The triol 8 (500 mg 1.61 mmol)

was dissolved in anhydrous DMF (15 ml) and cooled to

0 8C. Benzyl bromide (0.57 ml, 4.84 mmol) then sodium

hydride (60% in mineral oil) (258 mg, 6.44 mmol) were

added. After 14 h 30 min, TLC (petrol/ethyl acetate, 4:1)

indicated formation of a single product (R_f0.6) and

complete consumption of starting material (R_f0.1). The

reaction mixture was quenched with methanol (4 ml) and

partitioned between ether (100 ml) and water (100 ml). The

aqueous layer was re-extracted with ether (50 ml) and the

combined organic extracts were washed with brine (50 ml),

dried (MgSO₄), ﬁltered and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography

(petrol/ether, 8:1) to afford the benzylated donor 7

(693 mg, 88%) as a colourless oil; [a]²_D⁵ZK120.7 (c, 0.75

in CHCl₃); n_maxno signiﬁcant peaks; d_H(400 MHz, CDCl₃)

1.35 (3H, d, J_5,6Z6.3 Hz, CH₃-6), 2.34 (3H, s, ArCH₃), 3.63

oil; [a]²_D⁵ZK254 (c, 0.5 in CHCl₃); n_max1673 (CZC) cm^K1

;

d_H(400 MHz, CDCl₃) 1.29 (3H, d, J_5,6Z6.3 Hz, CH₃-6),

1.32, 1.35 (6H, 2!s, 2!C(O)₂CH₃), 1.52 (3H, dd, JZ1.5,

6.8 Hz, OCHZCHCH₃), 2.34 (3H, s, ArCH₃), 3.27, 3.31

(6H, 2!s, 2!OCH₃), 3.80 (1H, at, JZ9.9 Hz, H-4), 4.03

(1H, dd, J_2,3Z3.1 Hz, J_3,4Z10.1 Hz, H-3), 4.18 (1H, d,

H-2), 4.25 (1H, dq, J_4,5Z9.6 Hz, H-5), 4.88 (1H, dq, J_EZ

12.7 Hz, OCHZCH), 5.49 (1H, s, H-1), 6.14 (1H, dd,

OCHZCH), 7.12, 7.36 (4H, 2!d, JZ8.1 Hz, Ar-H); d_C

(100.6 MHz, CDCl₃) 12.4 (q, CHZCHCH₃), 16.6, 17.7,

17.8 (3!q, 2!C(O)₂CH₃, C-6), 21.0 (q, ArCH₃), 47.6, 47.9

(2!q, 2!OCH₃), 67.7, 67.8, 68.8, 77.6 (4!d, C-2, C-3,

C-4, C-5), 85.6 (d, C-1), 99.6, 100.2 (2!s, 2!C(O)₂CH₃),

102.5 (d, OCHZCH), 129.8, 131.9 (2!d, Ar-CH), 130.6,

137.6 (2!s, Ar-C) 144.7 (d, OCHZCH); Z isomer, a

colourless oil; [a]²_D⁵ZK366 (c, 1.0 in CHCl₃); n_max1668

(CZC) cm^K1; d_H(400 MHz, CDCl₃) 1.30 (3H, d, J_5,6

Z

6.1 Hz, CH₃-6), 1.32, 1.34 (6H, 2!s, 2!C(O)₂CH₃), 1.61

(3H, dd, JZ1.7 Hz, JZ6.7 Hz, OCHZCHCH₃), 2.33 (3H,

s, ArCH₃), 3.27, 3.32 (6H, 2!s, 2!OCH₃), 3.86 (1H, at,

JZ9.9 Hz, H-4), 4.03 (1H, dd, J_2,3Z3.1 Hz, J_3,4Z10.1 Hz,

H-3), 4.08 (1H, d, H-2), 4.26 (1H, dq, J_4,5Z9.6 Hz, H-5),

4.58 (1H, aquint, JZ6.7 Hz, OCHZCH), 5.38 (1H, s, H-1),

5.96 (1H, dd, J_ZZ6.0 Hz, OCHZCH), 7.12, 7.35 (4H, 2!

d, JZ8.1 Hz, Ar-H); d_C(100.6 MHz, CDCl₃) 9.5 (q, CHZ

CHCH₃), 16.7, 17.7, 17.8 (3!q, 2!C(O)₂CH₃, C-6), 21.1

(q, ArCH₃), 47.6, 48.0 (2!q, 2!OCH₃), 67.9, 68.1, 68.9,

79.5 (4!d, C-2, C-3, C-4, C-5), 86.8 (d, C-1), 99.6, 100.0

(2!s, 2!C(O)₂CH₃), 105.6 (d, OCHZCH), 129.8, 132.1

(2!d, Ar-CH), 130.5, 137.7 (2!s, Ar-C) 143.8 (d, OCHZ

CH); For the E/Z mixture; m/z (ES^C) 483 (MCNH₄^CC

MeCN, 27), 442 (MCNH^C₄, 29), 425 (MCH^C, 64), 393

(MKOMe, 100%). (HRMS calcd for C₂₂H₃₆NO₆S

(MNH^C₄) 442.2263. Found 442.2261).

(1H, at, JZ9.4 Hz, H-4), 3.85 (1H, dd, J_2,3Z3.2 Hz, J_3,4

9.3 Hz, H-3), 3.95 (1H, dd, J_1,2Z1.6 Hz, H-2), 4.09–4.20

(3H, m, OCH₂CHZCH₂, H-5), 4.65, 4.97 (2H, ABq, J_AB

10.9 Hz, PhCH₂), 4.73 (2H, s, PhCH₂), 5.20 (1H, dd, J_gem

Z

1.6 Hz, J_ZZ10.2 Hz, CHZCH_EH_Z), 5.28 (1H, daq, JZ

1.5 Hz, J_EZ17.2 Hz, CHZCH_EH_Z), 5.43 (1H, d, H-1), 5.92

(1H, ddat, CHZCH₂), 7.11–7.42 (14H, m, Ar-H); d_C

(100.6 MHz, CDCl₃) 17.8 (q, C-6), 21.1 (q, ArCH₃), 69.1,

76.4, 77.2, 79.8 (4!d, C-2, C-3, C-4, C-5), 71.5, 72.2, 75.5

(3!t, OCH₂CHZCH₂, 2!PhCH₂), 86.1 (d, C-1), 118.0 (t,

CHZCH₂), 127.6, 127.7, 127.9, 128.0, 128.3, 128.4, 129.8,

131.8, 134.7 (9!d, Ar-CH, CHZCH₂), 130.9, 137.4,

138.1, 138.5 (4!s, Ar-C); m/z (APCI^C) 546 (MC56,

100), 508 (MCNH^C₄, 5), 491 (MCH^C, 10%); (CI^C) 508

(MCNH^C₄, 100%). (HRMS calcd for C₃₀H₃₈NO₄S

(MNH^C₄) 508.2522. Found 508.2524). (Found: C, 73.60;

H, 7.12. C₃₀H₃₄O₄S requires C, 73.44; H, 6.98%).

4.1.6. para-Tolyl 2-O-allyl-1-thio-a-^L-rhamnopyranoside

8. The BDA protected donor 1 (159 mg 0.38 mmol) was

dissolved in triﬂuoroacetic acid (1.8 ml) and water (0.2 ml)

and stirred at rt. After 10 min, TLC (petrol/ethyl acetate,

3:1) indicated formation of a single product (R_f0.2) and

disappearance of starting material (R_f0.7). The reaction

mixture was concentrated in vacuo and the residue puriﬁed

by ﬂash column chromatography (petrol/ethyl acetate,

5:2/1:1) to afford the triol 8 (110 mg, 95%) as a colourless

oil; [a]²_D⁵ZK289 (c, 0.25 in CHCl₃); n_max3392 (br, OH),

1646 (w, CZC) cm^K1; d_H(400 MHz, CDCl₃) 1.34 (3H, d,

J_5,6Z6.2 Hz, CH₃-6), 2.34 (3H, s, ArCH₃), 2.70 (2H, br s,

4.1.8. para-Tolyl 3,4-di-O-benzyl-2-O-prop-1⁰-enyl-1-

thio-a-^L-rhamnopyranoside 9. Wilkinson’s catalyst

(120 mg, 0.13 mmol) was dissolved in freshly distilled

THF (3 ml) and degassed. Butyl lithium solution in hexanes

(0.12 ml, 0.20 mmol) was added and the mixture stirred for

10 min. Benzylated donor 7 (640 mg, 1.31 mmol) was

dissolved in freshly distilled THF (3 ml) and heated to

75 8C. The catalyst solution was added by cannula under Ar.

After 1 h 30 min, TLC (petrol/ether, 4:1) indicated for-

mation of two products (R_f0.5 and R_f0.55) and complete

consumption of starting material (R_f0.45). The reaction was

allowed to cool then diluted with CH₂Cl₂(4 ml) and

concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ether, 8:1) to afford the enol

ethers 9 (513 mg, 80%) as a colourless oil; n_max1671 (CZ

C) cm^K1; partial data: d_H(400 MHz, CDCl₃) (E/Z, 1.4:1), E

isomer 1.35 (3H, d, J_5,6Z6.1 Hz, CH₃-6), 1.54 (3H, dd, JZ

1.6, 6.9 Hz, OCHZCHCH₃), 3.63 (1H, at, JZ9.3 Hz, H-4),

4.92 (1H, dq, J_EZ12.5 Hz, OCHZCHCH₃), 5.45 (1H, d,

J_1,5Z1.5 Hz, H-1), 6.09 (1H, dq, OCHZCHCH₃); Z isomer

1.36 (3H, d, J_5,6Z6.2 Hz, CH₃-6), 1.65 (3H, dd, JZ1.5,

OH), 3.50 (1H, at, JZ9.5 Hz, H-4), 3.77 (1H, dd, J_2,3

Z

3.7 Hz, J_3,4Z9.5 Hz, H-3), 3.92 (1H, dd, J_1,2Z1.2 Hz,

H-2), 4.00 (1H, ddat, J_gemZ12.6 Hz, JZ6.2 Hz, JZ1.2 Hz,

OCHH⁰CHZCH₂), 4.12 (1H, dq, J_4,5Z9.4 Hz, H-5), 4.19

(1H, ddat, JZ5.5, 1.4 Hz, OCHH⁰CHZCH₂), 5.21 (1H, dd,

J_gemZ1.4 Hz, J_ZZ10.3 Hz, CHZCH_EH_Z), 5.29 (1H, daq,

JZ1.5 Hz, J_EZ17.3 Hz, CHZCH_EH_Z), 5.50 (1H, d, H-1),

5.90 (1H, ddat, CHZCH₂), 7.13, 7.36 (4H, 2!d, Ar-H); d_C

(100.6 MHz, CDCl₃) 17.4 (q, C-6), 21.1 (q, ArCH₃), 68.9,

9068

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

6.7 Hz, OCHZCHCH₃), 3.67 (1H, at, JZ9.3 Hz, H-4), 4.10

(1H, dd, J_1,2Z1.8 Hz, J_2,3Z2.8 Hz, H-2), 4.58 (1H, aquin,

JZ6.6 Hz, OCHZCHCH₃), 5.37 (1H, d, H-1), 5.91 (1H,

dq, J_ZZ6.1 Hz, OCHZCHCH₃); d_C(100.6 MHz, CDCl₃) E

isomer 12.4 (q, OCHZCHCH₃), 17.8 (q, C-6), 21.1 (q,

ArCH₃), 72.2, 75.5 (2!t, 2!PhCH₂), 85.4 (d, C-1), 102.4

(d, OCHZCHCH₃), 144.0 (d, OCHZCHCH₃); Z isomer

9.5 (q, OCHZCHCH₃), 17.9 (q, C-6), 21.1 (q, ArCH₃),

72.2, 75.5 (2!t, 2!PhCH₂), 86.3 (d, C-1), 104.8 (d,

OCHZCHCH₃), 144.9 (d, OCHZCHCH₃); m/z (APCI^C)

546 (MC56, 100), 491 (MCH^C, 11%); (CI^C) 508 (MC

NH^C₄, 100), 491 (MCH^C, 17%). (HRMS calcd for

C₃₀H₃₈NO₄S (MNH^C₄) 508.2522. Found 508.2526).

(Found: C, 73.56; H, 7.11. C₃₀H₃₄O₄S requires C, 73.44;

H, 6.98%).

27.1 (q, CHICH₃), 47.6, 47.9 (2!q, 2!OCH₃), 54.8 (q,

OCH₃), 68.0, 68.4, 68.7, (3!d, C-3, C-4, C-5), 74.4 (d,

C-2), 88.0 (d, C-1), 99.6, 99.9 (2!s, 2!C(O)₂CH₃), 105.1

(d, (O)₂CHCHI), 129.9, 132.3 (2!d, Ar-CH), 130.5, 137.8

(2!s, Ar-C); Diastereomer 4 (50%): d_H(400 MHz, CDCl₃)

1.28 (3H, d, J_5,6Z6.0 Hz, CH₃-6), 1.29, 1.31 (6H, 2!s, 2!

C(O)₂CH₃), 1.81 (3H, d, JZ6.8 Hz, CHICH₃), 2.34 (3H, s,

ArCH₃), 3.24, 3.32, 3.55 (9H, 3!s, 3!OCH₃), 3.85 (1H,

at, JZ9.5 Hz, H-4), 3.98–4.02 (2H, m, H-2, H-3), 4.06 (1H,

dq, JZ4.0 Hz, CHI), 4.24 (1H, dq, J_4,5Z9.7 Hz, H-5), 4.78

(1H, d, (O)₂CHCHI), 5.36 (1H, s, H-1), 7.12–7.14, (2H, m,

Ar-H), 7.34–7.36 (2H, m, Ar-H).

4.1.10. (2⁰S, 3⁰S) Methyl 3,4-O-(2⁰,3⁰-dimethoxybutan-

2⁰,3⁰-diyl)-b-L-rhamnopyranoside 11. Mixed acetals 10

(114 mg, 0.25 mmol), were dissolved in anhydrous

dichloroethane (9 ml). 2,6-Di-tert-butyl-4-methylpyridine

(138 mg, 0.67 mmol), N-iodosuccinimide (227 mg,

1.0 mmol) and silver triﬂuoromethanesulfonate (87 mg,

0.34 mmol) were added. The reaction mixture was stirred

at 50 8C under Ar. After 19 h, TLC (petrol/ethyl acetate,

1:1) indicated the formation of a product (R_f0.2). The

reaction mixture was partitioned between CH₂Cl₂(60 ml)

and Na₂S₂O₃(50 ml of a 10% aqueous solution). The

organic layer was dried (MgSO₄), ﬁltered and concentrated

in vacuo. The residue was puriﬁed by ﬂash column

chromatography (petrol/ethyl acetate, 1:2) to afford the

b-rhamnoside 11 (21 mg, 29%) as a colourless oil;

[a]²_D⁵ZK122.7 (c, 1.0 in CHCl₃); n_max3472 (br, OH)

cm^K1; d_H(400 MHz, CDCl₃) 1.30, 1.35 (6H, 2!s, 2!

C(O)₂CH₃), 1.33 (3H, d, J_5,6Z6.1 Hz, CH₃-6), 2.46 (1H, br

s, OH-2), 3.25, 3.27 (6H, 2!s, 2!OCH₃), 3.46 (1H, dq,

J_4,5Z9.3 Hz, H-5), 3.55 (3H, s, OCH₃-1), 3.66 (1H, dd,

J_2,3Z3.0 Hz, J_3,4Z10.1 Hz, H-3), 4.01 (1H, br s, H-2), 3.75

(1H, at, JZ9.6 Hz, H-4), 4.41 (1H, d, J_1,2Z0.8 Hz, H-1); d_C

(125.7 MHz, CDCl₃) 16.4, 17.5, 17.7 (3!q, 2!C(O)₂CH₃,

C-6), 47.5, 47.9 (2!q, 2!OCH₃), 56.8 (q, OCH₃-1), 67.8,

69.4, 70.0, 70.4 (4!d, C-2, C-3, C-4, C-5), 99.6, 100.1 (2!

4.1.9. (2⁰S, 3⁰S) para-Tolyl 3,4-O-(2⁰,3⁰-dimethoxybutan-

2⁰,3⁰-diyl)-2-O-(2-iodo-1-methoxypropyl)-1-thio-a-L-

rhamnopyranoside 10. N-Iodosuccinimide (239 mg,

˚

1.1 mmol) and 4 A molecular sieves were added to

anhydrous dichloroethane (2 ml) and cooled to K40 8C

under Ar. (2⁰S, 3⁰S) Enol ethers 6 (150 mg, 0.35 mmol, E/Z,

68:32) and methanol (0.022 ml, 0.53 mmol) were dissolved

in anhydrous dichloroethane (2 ml) and added to the

reaction vessel by cannula under Ar. The reaction was

allowed to warm to 0 8C over 55 min. After this time, the

reaction was quenched with sodium thiosulfate (30 ml of a

10% aqueous solution) then extracted with CH₂Cl₂(2!

30 ml). The combined organic extracts were dried (MgSO₄),

ﬁltered and concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography (petrol/ether, 8:1) to afford

mixed acetals 10 (197 mg, 96%) as a colourless oil. m/z

(ES^C) 641 (MCNH₄^CCMeCN, 12), 600 (MCNH^C₄, 3),

583 (MCH^C, 3%). (HRMS calcd for C₂₃H₃₉NO₇SI

(MNH^C₄) 600.1492. Found 600.1496). Data for the

individual 4 diastereomers (relative %): Diastereomer 1

(17%): d_H(400 MHz, CDCl₃) 1.27 (3H, d, J_5,6Z6.0 Hz,

CH₃-6), 1.31, 1.34 (6H, 2!s, 2!C(O)₂CH₃), 1.87 (3H, d,

JZ6.9 Hz, CHICH₃), 2.33 (3H, s, ArCH₃), 3.24, 3.32, 3.37

(9H, 3!s, 3!OCH₃), 3.74 (1H, at, JZ10.0 Hz, H-4), 3.99

(1H, dd, J_2,3Z2.5 Hz, J_3,4Z10.3 Hz, H-3), 4.07 (1H, dd,

J_1,2Z1.4 Hz, H-2), 4.24 (1H, dq, J_4,5Z9.6 Hz, H-5), 4.65

(1H, d, JZ2.6 Hz, (O)₂CHCHI), 4.67 (1H, dq, CHI), 5.46

(1H, d, H-1), 7.11–7.13, (2H, m, Ar-H), 7.34–7.36 (2H, m,

Ar-H); Diastereomer 2 (8%): d_H(400 MHz, CDCl₃) 1.29

(3H, d, J_5,6Z6.2 Hz, CH₃-6), 1.29, 1.31 (6H, 2!s, 2!

C(O)₂CH₃), 1.92 (3H, d, JZ6.8 Hz, CHICH₃), 2.33 (3H, s,

ArCH₃), 3.27, 3.31, 3.33 (9H, 3!s, 3!OCH₃), 3.79 (1H,

1

s, 2!C(O)₂CH₃), 100.8 (d, J_C-1,H-1Z156.6 Hz, C-1); m/z

(ES^C) 315 (MCNa^C, 14), 310 (MCNH₄^C, 62), 261 (MK

OMe, 100%). (HRMS calcd for C₁₃H₂₈NO₇(MNH^C₄)

310.1866. Found 310.1867).

4.1.11. Phenyl 4,6-O-benzylidene-2-O-(2-iodo-1-(methyl

2-O-benzyl-4,6-O-benzylidene-a-^D-mannopyranosid-3-

O-yl)propyl)-3-O-pivaloyl-1-thio-b-^D-glucopyranoside

14. N-Iodosuccinimide (163 mg, 0.23 mmol), 2,6-di-tert-

butyl-4-methyl pyridine (99 mg, 0.48 mmol), methyl 2-O-

benzyl-4,6-O-benzylidene-a-^D-mannopyranoside (90 mg,

at, JZ10.0 Hz, H-4), 3.98 (1H, dd, J_2,3Z2.6 Hz, J_3,4

Z

˚

10.4 Hz, H-3), 4.17 (1H, dd, J_1,2Z1.3 Hz, H-2), 4.24 (1H,

dq, J_4,5Z9.7 Hz, H-5), 4.42 (1H, d, JZ5.7 Hz,

(O)₂CHCHI), 4.51 (1H, dq, CHI), 5.44 (1H, d, H-1), 7.11–

7.13, (2H, m, Ar-H), 7.34–7.36 (2H, m, Ar-H); Diaster-

0.282 mmol) and 4 A molecular sieves were added to

anhydrous dichloromethane (2 ml) and cooled to K40 8C

under Ar. Phenyl 4,6-O-benzylidene-3-O-pivaloyl-2-O-

prop-1⁰-enyl-1-thio-b-D-glucopyranoside 13 (234 mg,

0.484 mmol) was dissolved in anhydrous dichloromethane

(2 ml) and added to the reaction vessel by cannula under N₂.

The reaction was allowed to warm to rt. After 16 h, TLC

(cyclohexane/ethyl acetate, 4:1) indicated the complete

consumption of starting material (R_f0.7). After a further

24 h, the solvent had all evaporated off. TLC (cyclohexane/

ethyl acetate, 4:1) indicated the formation of two major

products (R_f0.45 and 0.5), plus some remaining starting

alcohol (R_f0.4). The reaction was quenched with Et₃N

(2 ml) and stirred for 5 min. Sodium thiosulfate (50 ml of a

eomer 3 (25%): d_H(400 MHz, CDCl₃) 1.29 (3H, d, J_5,6

Z

6.2 Hz, CH₃-6), 1.28, 1.30 (6H, 2!s, 2!C(O)₂CH₃), 1.88

(3H, d, JZ7.2 Hz, CHICH₃), 2.34 (3H, s, ArCH₃), 3.23,

3.31, 3.50 (9H, 3!s, 3!OCH₃), 3.82 (1H, at, JZ9.9 Hz,

H-4), 3.98 (1H, dd, J_2,3Z3.0 Hz, J_3,4Z10.3 Hz, H-3), 4.18

(1H, dd, J_1,2Z1.2 Hz, H-2), 4.20 (1H, dq, JZ5.8 Hz, CHI),

4.25 (1H, dq, J_4,5Z9.7 Hz, H-5), 4.31 (1H, d, (O)₂CHCHI),

5.41 (1H, s, H-1), 7.11–7.14, (2H, m, Ar-H), 7.34–7.37 (2H,

m, Ar-H); d_C(100.6 MHz, CDCl₃) 16.5, 17.6, 17.8 (3!q,

2!C(O)₂CH₃, C-6), 21.1 (q, ArCH₃), 23.0 (q, CHICH₃),

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

9069

10% aqueous solution) was added and the mixture extracted

with CH₂Cl₂(2!50 ml). The combined organic extracts

were dried (MgSO₄), ﬁltered and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography

(cyclohexane/ethyl acetate, 6:1) to afford mixed acetals 14.

(142 mg, 60%) as a white foam. m/z (ES^C) 1000 (MC

NH^C₄, 53%), which was used directly in the next step

without further characterisation.

4.1.14. para-Tolyl 3,4-di-O-benzyl-2-O-(2-iodo-1-(methyl

2,3,4-tri-O-benzyl-a-^D-glucopyranosid-6-O-yl)propyl)-

1-thio-a-^L-rhamnopyranoside 16b. N-Iodosuccinimide

˚

(138 mg, 0.61 mmol) and 4 A molecular sieves were

added to anhydrous dichloroethane (2 ml) and cooled to

K40 8C under Ar. Methyl 2,3,4-tri-O-benzyl-a-^D-gluco-

pyranoside (189 mg, 0.41 mmol) was dissolved in anhy-

drous dichloroethane (2 ml) and added to the reaction vessel

by cannula under Ar. Vinyl ethers 9 (99 mg, 0.20 mmol)

were dissolved in anhydrous dichloroethane (2 ml) and

added to the reaction vessel by cannula under Ar. The

reaction was allowed to warm to rt. After 21 h, TLC (petrol/

ether, 4:1) indicated complete consumption of the enol ether

(R_f0.5). TLC (petrol/ethyl acetate, 3:1) indicated formation

of a major (R_f0.7) and two minor (R_f0.6 and 0.4) products

and remaining aglycon (R_f0.3). The reaction was quenched

with sodium thiosulfate (30 ml of a 10% aqueous solution)

then extracted with CH₂Cl₂(2!30 ml). The combined

organic extracts were dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (petrol/ether, 3:1) to afford mixed acetals

16b (164 mg, 75%) as a colourless oil; m/z (APCI^C) 1136

(MC56, 20%); (ES^C) 1139 (MCNH^C₄CMeCN, 11), 1098

(MCNH^C₄, 14%). (HRMS calcd for C₅₈H₆₉NO₁₀SI

(MNH^C₄) 1098.3687. Found 1098.3678).

4.1.12. Methyl 4,6-O-benzylidene-3-O-pivaloyl-a-^D-

glucopyranosyl-(1/3)-2-O-benzyl-4,6-O-benzylidene-

a-^D-mannopyranoside 15. The mixed acetals 14 prepared

above (133 mg, 0.136 mmol) were dissolved in anhydrous

dichloroethane (4 ml). 2,6-Di-tert-butyl-4-methylpyridine

(56 mg, 0.272 mmol), silver triﬂuoromethanesulfonate

(35 mg, 0.136 mmol) and N-iodosuccinimide (92 mg,

0.409 mmol) were added. After 14 h 30 min, TLC (petrol/

ethyl acetate, 4:1) indicated the formation of a major

product (R_f0.3) and the absence of starting material (R_f0.4).

The reaction mixture was partitioned between CH₂Cl₂(2!

50 ml) and Na₂S₂O₃(50 ml of a 10% aqueous solution). The

organic layer was dried (MgSO₄), ﬁltered and concentrated

in vacuo. The residue was puriﬁed by ﬂash column

chromatography (petrol/ethyl acetate, 3:1) to afford the

a-gluco disaccharide 15 (67 mg, 70%) as a colourless oil;

[a]²_D²ZC40.6 (c, 0.65 in CHCl₃); d_H(400 MHz, CDCl₃)

1.23 (9H, s, C(CH₃)₃), 2.56 (1H, d, J_OH,2Z11.5 Hz, OH-2_b),

3.37 (3H, s, OCH₃), 3.59 (1H, at, JZ9.6 Hz, H-4_b), 3.67

(1H, ddd, J_1,2Z3.8 Hz, J_2,3Z9.7 Hz, H-2_b), 3.72 (1H, at,

JZ10.3 Hz, H-6_b), 3.79–3.90 (3H, m, H-2_a, H-5_a, H-5_b),

3.89 (1H, at, JZ10.3 Hz, H-6_a), 4.20–4.26 (3H, m, H-3_a,

4.1.15. para-Tolyl 3,4-di-O-benzyl-2-O-(2-iodo-1-(methyl

2-O-benzyl-4,6-O-benzylidene-a-^D-mannopyranosid-3-

O-yl)propyl)-1-thio-a-^L-rhamnopyranoside 16c. Iodine

(61 mg, 0.24 mmol), silver triﬂuoromethanesulfonate

(61 mg, 0.24 mmol), 2,6-di-tert-butyl-4-methylpyridine

(100 mg, 0.48 mmol), methyl 2-O-benzyl-4,6-O-benzyli-

H-4_a, H-6⁰_b), 4.28 (1H, dd, J_5,6Z4.5 Hz, J_6,6Z9.9 Hz,

H-6⁰_a), 4.74 (1H, d, J_1,2Z1.4 Hz, H-1_a), 4.77 (2H, s,

PhCH₂), 5.28 (1H, d, H-1_b), 5.42 (1H, at, JZ9.7 Hz, H-3_b),

5.50, 5.62 (2H, 2!s, 2!PhCH), 7.27–7.48 (15H, m, Ar-H);

d_C(100.6 MHz, CDCl₃) 27.6 (q, C(CH₃)₃), 37.8 (s, C(CH₃)₃),

55.4 (q, OCH₃), 63.9, 64.3, 72.1, 72.2, 75.7, 77.8, 78.9, 79.3

(8!d, C-2_a, C-3_a, C-4_a, C-5_a, C-2_b, C-3_b, C-4_b, C-5_b), 69.1,

69.3, (2!t, C-6_a, C-6_b), 73.9 (t, PhCH₂), 100.1, 101.2, 101.5,

101.9 (4!d, C-1_a, C-1_b, 2!PhCH), 126.4, 126.7, 127.9,

128.4, 128.5, 128.7, 129.1, 129.3, 129.5 (9!d, Ar-CH),

136.4 (s, Ar-C), 176.9 (s, CZO); m/z (ES^C) 729 (MCNa^C,

30), 724 (MCNH^C₄, 100%). (HRMS calcd for C₃₉H₅₀NO₁₂

(MNH^C₄) 724.3333. Found 724.3331).

0

˚

dene-a-^D-mannopyranoside (72 mg, 0.19 mmol) and 4 A

molecular sieves were added to freshly distilled CH₂Cl₂

(2 ml) and cooled to K78 8C under Ar. Vinyl ethers 9

(90 mg, 0.18 mmol) were dissolved in freshly distilled

CH₂Cl₂(3 ml) and added to the reaction vessel by cannula

under Ar. The reaction was allowed to warm to rt. After 6 h

30 min, TLC (petrol/ethyl acetate, 4:1) indicated complete

consumption of starting material (R_f0.8) and formation of a

major product (R_f0.7). The reaction was quenched with

sodium thiosulfate (30 ml of a 10% aqueous solution) then

extracted with CH₂Cl₂(2!30 ml). The combined organic

extracts were dried (MgSO₄), ﬁltered and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy (petrol/ether, 3:1) to afford mixed acetals 16c

(148 mg, 82%) as a white foam; m/z (ES^C) 1027 (MC

K^C, 62), 1011 (MCNa^C, 100), 1006 (MCNH^C₄, 65%).

4.1.13. para-Tolyl 3,4-di-O-benzyl-2-O-(2-iodo-1-meth-

oxypropyl)-1-thio-a-^L-rhamnopyranoside 16a. N-Iodo-

˚

succinimide (138 mg, 0.61 mmol) and 4 A molecular

sieves were added to anhydrous dichloroethane (2 ml) and

cooled to K40 8C under Ar. Vinyl ethers 9 (100 mg,

0.20 mmol) and methanol (0.013 ml, 0.30 mmol) were

dissolved in anhydrous dichloroethane (2 ml) and added to

the reaction vessel by cannula under Ar. The reaction was

allowed to warm to rt over 1 h. After this time, the reaction

was quenched with sodium thiosulfate (30 ml of a 10%

aqueous solution) then extracted with CH₂Cl₂(2!30 ml).

The combined organic extracts were dried (MgSO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ether, 8:1) to afford mixed

acetals 16a (117 mg, 88%) as a colourless oil; m/z (APCI^C)

704 (MC56, 100), 666 (MCNH^C₄, 10%); (ES^C) 671 (MC

Na^C, 100%). (HRMS calcd for C₃₁H₄₁NO₅SI (MNH^C₄)

666.1750. Found 666.1760).

4.1.16. para-Tolyl 3,4-di-O-benzyl-2-O-(1-(cholestan-3-

b-yloxy)-2-iodopropyl)-1-thio-a-^L-rhamnopyranoside

16d. Iodine (57 mg, 0.22 mmol), silver triﬂuoromethane-

sulfonate (57 mg, 0.22 mmol), 2,6-di-tert-butyl-4-methyl-

pyridine (91 mg, 0.44 mmol), cholestan-3-b-ol (70 mg,

˚

0.18 mmol) and 4 A molecular sieves were added to freshly

distilled CH₂Cl₂(1 ml) and cooled to K78 8C under Ar.

Vinyl ethers 9 (90 mg, 0.18 mmol) were dissolved in freshly

distilled CH₂Cl₂(2 ml) and added to the reaction vessel by

cannula under Ar. The reaction was allowed to warm to rt.

After 6 h 45 min, TLC (petrol/ethyl acetate, 4:1) indicated

complete consumption of starting material (R_f0.8) and

formation of a major product (R_f0.9). The reaction was

quenched with sodium thiosulfate (30 ml of a 10% aqueous

9070

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

solution) then extracted with CH₂Cl₂(2!30 ml). The com-

bined organic extracts were dried (MgSO₄), ﬁltered and

concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ether, 11:1) to afford mixed

acetals 16d (118 mg, 69%) as a white foam; m/z (ES^C) 1027

(MCNa^C, 22%).

8.7 Hz, H-5_b), 3.37 (3H, s, OCH₃), 3.49–3.56 (3H, m, H-2_a,

H-3_b, H-4_b), 3.64 (1H, at, JZ9.5 Hz, H-4_a), 3.71–3.76 (2H,

m, H-5_a, H-6_a), 4.00 (1H, at, JZ9.3 Hz, H-3_a), 4.14 (1H, br

0

d, JZ1.9 Hz, H-2_b), 4.23 (1H, dd, J_5,6Z3.6 Hz, J_6,6

Z

11.5 Hz, H-6⁰_a), 4.44 (1H, s, H-1_b), 4.61 (1H, d, J_1,2

3.5 Hz, H-1_a), 4.64, 4.96 (2H, ABq, J_ABZ10.8 Hz, PhCH₂),

4.66, 4.82 (2H, ABq, J_ABZ12.5 Hz, PhCH₂), 4.69, 4.77

(2H, ABq, J_ABZ11.5 Hz, PhCH₂), 4.76, 4.87 (2H, ABq,

4.1.17. Methyl 3,4-di-O-benzyl-b-^L-rhamnopyranoside

17a. Mixed acetals 16a (114 mg, 0.18 mmol) was dissolved

in anhydrous dichloroethane (3 ml). 2,6-Di-tert-butyl-4-

methylpyridine (73 mg, 0.35 mmol), N-iodosuccinimide

(119 mg, 0.53 mmol) and silver triﬂuoromethanesulfonate

(46 mg, 0.18 mmol) were added. The reaction mixture was

stirred at rt for 30 min under Ar and then heated to 50 8C.

After 3 h, TLC (petrol/ether, 4:1) indicated the absence of

starting material (R_f0.5). TLC (petrol/ethyl acetate, 3:1)

indicated formation of several products (R_f0.55, 0.5 and

0.1). The reaction mixture was allowed to cool and then

triﬂuoroacetic acid (2 ml) and water (1 ml) were added, and

the mixture stirred further. After 2 h, TLC (petrol/ethyl

acetate, 3:1) indicated formation of a major product (R_f0.1).

The reaction mixture was partitioned between NaHCO₃

(30 ml of a saturated aqueous solution) and CH₂Cl₂(2!

30 ml). The combined organic extracts were washed with

sodium thiosulfate (30 ml of a 10% aqueous solution) dried

(MgSO₄), ﬁltered and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (petrol/ethyl

acetate, 2:1) to afford b-rhamnoside 17a (34 mg, 54%) as a

colourless oil; [a]_D²⁵ZC27.0 (c, 1.5 in CHCl₃); n_max3480

J_ABZ10.3 Hz, PhCH₂), 4.87, 5.00 (2H, ABq, J_AB

Z

10.7 Hz, PhCH₂), 7.27–7.40 (25H, m, Ar-H); d_C

(125.7 MHz, CDCl₃) 17.8 (q, C-6_b), 55.1 (q, OCH₃), 66.9,

71.0, 73.3, 75.0, 75.4, 75.6 (6!t, 5!PhCH₂, C-6_a), 68.2,

69.7, 71.4, 77.2, 79.5, 79.6, 81.0, 81.9 (8!d, C-2_a, C-3_a,

1

C-4_a, C-5_a, C-2_b, C-3_b, C-4_b, C-5_b), 98.1 (d, J_C-1,H-1

Z

167.9 Hz, C-1_a), 99.3 (d, ¹J_C-1,H-1Z157.1 Hz, C-1_b), 127.5,

127.6, 127.7, 127.8, 127.8, 127.9, 127.9, 128.0, 128.1,

128.2, 128.3, 128.3, 128.3 (13!d, Ar-CH), 137.7, 138.0,

138.2, 138.3, 138.7 (5!s, Ar-C); m/z (APCI^C) 846 (MC

56, 12), 808 (MCNH₄^C, 7%); (APCI^K) 825 (MCCl^K, 32),

699 (MKBn, 95%). (HRMS calcd for C₄₈H₅₈NO₁₀

(MNH^C₄) 808.4061. Found 808.4069).

4.1.19. Cholestan-3⁰-b-yl 3,4-di-O-benzyl-b-L-rhamno-

pyranoside 17d. Mixed acetals 16d (102 mg, 0.10 mmol)

were dissolved in anhydrous dichloroethane (9 ml). 2,6-Di-

tert-butyl-4-methylpyridine (42 mg, 0.20 mmol), N-iodo-

succinimide (69 mg, 0.31 mmol) and silver triﬂuoromethane-

sulfonate (26 mg, 0.10 mmol) were added and the mixture

stirred under Ar at rt. After 2 h 20 min, TLC (petrol/ethyl

acetate, 3:1) indicated the absence of starting material (R_f

0.9) and the formation of a various products (R_f0.5–0.9).

The reaction mixture was partitioned between CH₂Cl₂(2!

40 ml) and sodium thiosulfate (40 ml of a saturated aqueous

solution). The combined organic extracts were dried

(MgSO₄), ﬁltered and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (petrol/ethyl

acetate, 4:1) to afford b-rhamnosyl steroid 17d (21 mg,

29%) as a colourless oil; [a]²_D⁴ZC25.4 (c, 0.8 in CHCl₃);

n_max3469 (br, OH) cm^K1; d_H(400 MHz, CDCl₃) 0.65, 0.80

(6H, 2!s, 2!steroid CH₃), 0.86 (3H, d, JZ6.3 Hz, steroid

CH₃), 0.90 (3H, d, JZ6.9 Hz, steroid CH₃), 0.90 (3H, d, JZ

6.4 Hz, steroid CH₃), 0.93–1.99 (31H, m, steroid CH, CH₂),

1.34 (3H, d, J_5,6Z6.2 Hz, CH₃-6), 2.44 (1H, br s, OH-2),

3.30 (1H, dq, J_4,5Z8.8 Hz, H-5), 3.51–3.57 (2H, m, H-3,

H-4), 3.63–3.69 (1H, m, steroid OCH), 4.05 (1H, br s, H-2),

4.52 (1H, s, H-1), 4.65, 4.95 (2H, ABq, J_ABZ10.9 Hz,

PhCH₂), 4.68, 4.78 (2H, ABq, J_ABZ11.9 Hz, PhCH₂),

7.27–7.40 (10H, m, Ar-H); d_C(125.7 MHz, CDCl₃) 12.0,

12.3, 18.6, 22.5, 22.8 (5!q, 5!steroid CH₃), 17.9 (q, C-6),

21.2, 23.8, 24.2, 27.7, 28.2, 28.7, 32.1, 35.8, 36.1, 36.8,

39.5, 40.0 (12!t, 12!steroid CH₂), 28.0, 35.5, 35.8, 44.9,

54.4, 56.3, 56.5 (7!d, 7!steroid CH), 35.6, 42.6 (2!s,

2!steroid C), 69.0, 71.3, 77.7, 79.6, 81.5 (5!d, C-2, C-3,

C-4, C-5, steroid OCH), 71.2, 75.5 (2!t, 2!PhCH₂), 97.2

(br, OH) cm^K1; d_H(400 MHz, CDCl₃) 1.37 (3H, d, J_5,6

6.2 Hz, CH₃-6), 2.39 (1H, br s, OH-2), 3.33 (1H, dq, J_4,5

Z

9.2 Hz, H-5), 3.51–3.60 (2H, m, H-3, H-4), 3.55 (3H, s,

OCH₃), 4.11 (1H, br s, H-2), 4.31 (1H, d, J_1,2Z1.0 Hz, H-1),

4.66, 4.95 (2H, ABq, J_ABZ10.9 Hz, PhCH₂), 4.69, 4.78

(2H, ABq, J_ABZ12.2 Hz, PhCH₂), 7.28–7.41 (10H, m,

Ar-H); d_C(125.7 MHz, CDCl₃) 17.7 (q, C-6), 56.7 (q,

OCH₃), 68.2, 71.3, 79.6, 81.3 (4!d, C-2, C-3, C-4, C-5),

1

71.3, 75.3 (2!t, PhCH₂), 100.5 (d, J_C-1,H-1Z156.0 Hz,

C-1), 127.6, 127.7, 127.8, 128.0, 128.3, 128.4 (6!d, Ar-CH),

137.7, 138.2 (2!s, Ar-C); m/z (ES^C) 739 (2MCNa^C, 7),

734 (2MCNH^C₄, 11), 417 (MCMeCNCNH^C₄, 46), 381

(MCNa^C, 15), 376 (MCNH^C₄, 100%). (HRMS calcd for

C₂₁H₃₀NO₅(MNH^C₄) 376.2124. Found 376.2124).

4.1.18. Methyl 3,4-di-O-benzyl-b-^L-rhamnopyranosyl-

(1/6)-2,3,4-tri-O-benzyl-a-^D-glucopyranoside 17b.

Mixed acetals 16b (70 mg, 0.065 mmol) were dissolved in

anhydrous dichloroethane (3 ml). 2,6-Di-tert-butyl-4-

methylpyridine (27 mg, 0.13 mmol), N-iodosuccinimide

(44 mg, 0.20 mmol) and silver triﬂuoromethanesulfonate

(17 mg, 0.065 mmol) were added and the mixture stirred

under Ar at rt. After 17 h 30 min, TLC (petrol/ethyl acetate,

3:1) indicated the complete consumption of starting material

(R_f0.6) and the formation of a major product (R_f0.1). The

reaction was quenched with sodium thiosulfate (30 ml of a

10% aqueous solution) and extracted with CH₂Cl₂(2!

30 ml). The organic extracts were dried (MgSO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ethyl acetate, 3:1/1:1) to

afford b-rhamno disaccharide 17b (32 mg, 62%) as a

colourless oil; [a]_D²⁴ZC32.6 (c, 1.4 in CHCl₃); n_max3452

1

(d, J_C-1,H-1Z158.3 Hz, C-1), 127.7, 127.8, 127.9, 128.1,

128.4, 128.4 (6!d, Ar-CH), 137.9, 138.6 (2!s, Ar-C); m/z

(ES^C) 737 (MCNa^C, 24), 732 (MCNH^C₄, 100%). (HRMS

calcd for C₄₇H₇₄NO₅(MNH₄^C) 732.5567. Found 732.5563).

4.1.20. para-Tolyl 2-O-acetyl-3,5,6-tri-O-benzyl-1-thio-

a-^D-glucofuranoside 19a and para-tolyl 2-O-acetyl-

3,5,6-tri-O-benzyl-1-thio-b-^D-glucofuranoside 19b.

Method 1 (reaction carried out at 0 8C). Diacetate 18

(br, OH) cm^K1; d_H(400 MHz, CDCl₃) 1.32 (3H, d, J_5,6

6.4 Hz CH₃-6_b), 2.26 (1H, br s, OH-2_b), 3.32 (1H, dq, J_4,5

Z

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

9071

(1.0 g, 1.87 mmol) and para-thiocresol (348 mg,

2.81 mmol) were dissolved in freshly distilled CH₂Cl₂

(5 ml) and cooled to 0 8C. BF₃$OEt₂(0.3 ml, 2.43 mmol)

was added and the mixture stirred under Ar. After 45 min,

TLC (petrol/ethyl acetate, 2:1) indicated complete con-

sumption of starting material (R_f0.5) and formation of two

major products (R_f0.6 and 0.65). After a further 2 h, the

reaction mixture was partitioned between CH₂Cl₂(2!

100 ml) and NaHCO₃(100 ml of a saturated aqueous

solution). The combined organic extracts were dried

(MgSO₄), ﬁltered and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (petrol/ethyl

acetate, 5:1) to afford a-thioglycoside 19a (154 mg, 13%)

as a colourless oil; [a]²_D⁴ZC60.5 (c, 1.0 in CHCl₃); n_max

1749 (s, CZO) cm^K1; d_H(400 MHz, CDCl₃) 2.16 (3H, s,

combined organic extracts were dried (MgSO₄), ﬁltered and

concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ethyl acetate, 5:1) to afford

a-thioglycoside 19a (37 mg, 1%) as a colourless oil

identical to that described above, and b-thioglycoside 19b

(1.93 g, 58%) as a colourless oil identical to that described

above.

4.1.21. para-Tolyl 3,5,6-tri-O-benzyl-1-thio-b-^D-gluco-

furanoside 20. b-Thioglycoside 19b (195 mg, 0.33 mmol)

was dissolved in methanol (5 ml), THF (10 ml) and

n-propylamine (5 ml) and stirred at rt. After 14 h, TLC

(petrol/ethyl acetate, 2:1) indicated complete consumption

of starting material (R_f0.7) and formation of a major

product (R_f0.6). The reaction mixture was concentrated in

vacuo and the residue puriﬁed by ﬂash column chromato-

graphy (petrol/ethyl acetate, 4:1/3:1) to afford alcohol 20

(2.10 g, 91%) as a colourless oil; [a]²_D⁵ZK132.2 (c, 1.25 in

CHCl₃); n_max3406 (br, OH) cm^K1; d_H(400 MHz, CDCl₃)

2.34 (3H, s, ArCH₃), 2.40 (1H, d, J_OH,2Z3.8 Hz, OH-2),

COCH₃), 2.34 (3H, s, ArCH₃), 3.71 (1H, dd, J_5,6Z5.5 Hz,

0

J_6,6Z10.6 Hz, H-6), 3.91 (1H, dd, J_5,6Z1.8 Hz, H-6 ),

4.06 (1H, ddd, J_4,5Z9.3 Hz, H-5), 4.15 (1H, dd, J_2,3

Z

0.6 Hz, J_3,4Z3.4 Hz, H-3), 4.42 (1H, dd, H-4), 4.49, 4.80

(2H, ABq, J_ABZ11.2 Hz, PhCH₂), 4.56, 4.76 (2H, ABq,

J_ABZ11.6 Hz, PhCH₂), 4.62 (2H, s, PhCH₂), 5.54 (1H, dd,

J_1,2Z4.6 Hz, H-2), 5.72 (1H, d, H-1), 7.09–7.40 (19H, m,

Ar-H); d_C(100.6 MHz, CDCl₃) 20.7, 21.1 (2!q, ArCH₃,

COCH₃), 71.0, 72.0, 72.7, 73.4 (4!t, 3!PhCH₂, C-6),

75.5, 77.2, 78.8, 81.5 (4!d, C-2, C-3, C-4, C-5), 89.6 (d,

C-1), 127.4, 127.5, 127.6, 127.7, 127.7, 127.7, 127.8, 128.3,

128.3, 128.4, 129.7, 131.9 (12!d, Ar-CH), 131.1, 137.3,

137.4, 138.4, 138.6 (5!s, Ar-C), 169.8 (s, CZO); m/z

(ES^C) 657 (MCNH^C₄CMeCN, 34), 621 (MCNa^C, 21),

616 (MCNH^C₄, 100), 599 (MCH^C, 3%). (HRMS calcd

for C₃₆H₄₂NO₆S (MNH^C₄) 616.2733. Found 616.2727); and

b-thioglycoside 19b (213 mg, 18%) as a colourless oil;

0

3.75 (1H, dd, J_5,6Z5.2 Hz, J_6,6Z10.7 Hz, H-6), 3.91 (1H,

0

dd, J_5,6Z2.0 Hz, H-6 ), 4.04 (1H, dd, J_2,3Z1.2 Hz, J_3,4

Z

4.3 Hz, H-3), 4.17 (1H, ddd, J_4,5Z9.0 Hz, H-5), 4.37 (1H,

br s, H-2), 4.39 (1H, dd, H-4), 4.46, 4.62 (2H, ABq, J_AB

Z

11.6 Hz, PhCH₂), 4.50, 4.76 (2H, ABq, J_ABZ11.2 Hz,

PhCH₂), 4.61 (2H, s, PhCH₂), 5.19 (1H, d, J_1,2Z2.4 Hz,

H-1), 7.09–7.40 (19H, m, Ar-H); d_C(100.6 MHz, CDCl₃)

21.1 (q, ArCH₃), 70.6 (t, C-6), 72.0, 72.6, 73.4 (3!t, 3!

PhCH₂), 76.3 (d, C-5), 79.5 (d, C-2), 80.7 (d, C-4), 83.2 (d,

C-3), 93.2 (d, C-1), 127.4, 127.6, 127.7, 128.2, 128.3, 128.4,

129.7, 131.4 (8!d, Ar-CH), 131.8, 137.1, 137.7, 138.5,

138.7 (5!s, Ar-C); m/z (ES^C) 615 (MCNH₄^CCMeCN, 8),

574 (MCNH^C₄, 18), 557 (MCH^C, 6%). (HRMS calcd for

C₃₄H₄₀NO₅S (MNH^C₄) 574.2627. Found 574.2627).

[a]²_D⁴ZK88.9 (c, 1.0 in CHCl₃); n_max1748 (s, CZO) cm^K1

;

d_H(400 MHz, CDCl₃) 2.09 (3H, s, COCH₃), 2.33 (3H, s,

0

ArCH₃), 3.73 (1H, dd, J_5,6Z4.8 Hz, J_6,6Z10.7 Hz, H-6),

0

3.90 (1H, dd, J_5,6Z1.9 Hz, H-6 ), 4.11 (1H, d, J_3,4Z3.8 Hz,

4.1.22. para-Tolyl 2-O-allyl-3,5,6-tri-O-benzyl-1-thio-b-

D-glucofuranoside 21. Alcohol 20 (2.1 g, 3.78 mmol) was

dissolved in anhydrous DMF (10 ml) and cooled to 0 8C.

Allyl bromide (0.65 ml, 7.55 mmol) then sodium hydride

(60% in mineral oil) (300 mg, 7.55 mmol) were added.

After 1 h, TLC (petrol/ethyl acetate, 3:1) indicated for-

mation of a single product (R_f0.5) and little remaining

starting material (R_f0.2). The reaction mixture was

partitioned between ether (100C50 ml) and water

(100 ml). The combined organic layers were dried

(MgSO₄), ﬁltered and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (petrol/ether,

4:1) to afford glycosyl donor 21 (2.12 g, 94%) as a

colourless oil; [a]²_D³ZK99.9 (c, 2.0 in CHCl₃); n_maxno

signiﬁcant peaks; d_H(400 MHz, CDCl₃) 2.34 (3H, s,

H-3), 4.18 (1H, ddd, J_4,5Z9.3 Hz, H-5), 4.30 (1H, dd, H-4),

4.44, 4.71 (2H, ABq, J_ABZ11.1 Hz, PhCH₂), 4.53, 4.85

(2H, ABq, J_ABZ11.5 Hz, PhCH₂), 4.61, 4.65 (2H, ABq,

J_ABZ12.4 Hz, PhCH₂), 5.34 (1H, d, J_1,2Z1.4 Hz, H-1),

5.44 (1H, d, H-2), 7.09–7.42 (19H, m, Ar-H); d_C

(100.6 MHz, CDCl₃) 20.9, 21.1 (2!q, ArCH₃, COCH₃),

70.1, 71.8, 72.5, 73.7 (4!t, 3!PhCH₂, C-6), 75.8, 80.2,

80.7, 81.2 (4!d, C-2, C-3, C-4, C-5), 91.0 (d, C-1), 127.4,

127.5, 127.6, 127.7, 127.8, 128.2, 128.3, 128.3, 129.6,

129.7, 131.9 (11!d, Ar-CH), 131.5, 137.4, 137.5, 138.5,

138.6 (5!s, Ar-C), 169.8 (s, CZO); m/z (ES^C) 657 (MC

NH^C₄CMeCN, 33), 616 (MCNH^C₄, 60%). (HRMS calcd

for C₃₆H₄₂NO₆S (MNH^C₄) 616.2733. Found 616.2732),

together with a further a/b mixture (223 mg, 19%) as a

colourless oil.

0

ArCH₃), 3.74 (1H, dd, J_5,6Z5.3 Hz, J_6,6Z10.7 Hz, H-6),

0

3.93 (1H, dd, J_5,6Z2.0 Hz, H-6 ), 3.97–4.00 (2H, m,

OCHH⁰CHZCH₂), 4.10–4.12 (2H, m, H-2, H-3), 4.20 (1H,

ddd, J_4,5Z9.1 Hz, H-5), 4.31 (1H, dd, J_3,4Z3.8 Hz, H-4),

4.52, 4.62 (2H, ABq, J_ABZ11.6 Hz, PhCH₂), 4.52, 4.80

(2H, ABq, J_ABZ11.6 Hz, PhCH₂), 4.62 (2H, s, PhCH₂),

5.20 (1H, dq, J_ZZ10.4 Hz, JZ1.5 Hz, CHZCH_EH_Z), 5.26

(1H, dq, J_EZ17.3 Hz, JZ1.7 Hz, CHZCH_EH_Z), 5.30 (1H,

d, J_1,2Z1.7 Hz, H-1), 5.84 (1H, ddt, JZ5.5 Hz, CHZCH₂),

7.09–7.42 (19H, m, Ar-H); d_C(100.6 MHz, CDCl₃) 21.1 (q,

ArCH₃), 70.6, 70.8, 72.0, 72.5, 73.4 (5!t, C-6, 3!PhCH₂,

OCH₂CHZCH₂), 76.2, 81.2, 81.3, 86.3 (4!d, C-2, C-3,

C-4, C-5), 91.0 (d, C-1), 117.6 (t, CHZCH₂), 127.4, 127.4,

Method 2 (reaction carried out at K30 8C). Diacetate 18

(2.99 g, 5.61 mmol) and para-thiocresol (836 mg,

6.74 mmol) were dissolved in freshly distilled CH₂Cl₂

(15 ml) in a ﬂame-dried ﬂask and cooled to K30 8C under

Ar. BF₃$OEt₂(1.04 ml, 8.42 mmol) was added and the

mixture stirred under Ar. After 40 min, the mixture had

warmed to K20 8C. At this time, TLC (petrol/ethyl acetate,

2:1) indicated little remaining starting material (R_f0.5) and

formation of a major product (R_f0.6). The reaction was

quenched with Et₃N (2 ml), and the mixture partitioned

between CH₂Cl₂(120C60 ml) and water (100 ml). The

9072

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

127.6, 127.6, 127.7, 127.8, 128.2, 128.3, 128.4, 129.6,

131.4, 133.9 (12!d, Ar-CH, CHZCH₂), 131.9, 137.0,

137.7, 138.6, 138.9 (5!s, Ar-C); m/z (ES^C) 619 (MCNa^C,

33), 614 (MCNH^C₄, 100), 597 (MCH^C, 7%). (HRMS

calcd for C₃₇H₄₄NO₅S (MNH^C₄) 614.2940. Found

614.2938).

(methyl 2,3,4-tri-O-benzyl-a-^D-mannopyranosid-6-O-

yl)propyl)-1-thio-b-^D-glucofuranoside 23b. Iodine

(55 mg, 0.22 mmol), silver triﬂuoromethanesulfonate

(56 mg, 0.22 mmol), 2,6-di-tert-butyl-4-methylpyridine

˚

(116 mg, 0.57 mmol) and 4 A molecular sieves were added

to freshly distilled CH₂Cl₂(1 ml) and cooled to K78 8C

under Ar. Methyl 2,3,4-tri-O-benzyl-a-^D-mannopyranoside

(82 mg, 0.18 mmol) was dissolved in freshly distilled

CH₂Cl₂(2 ml) and added by cannula under Ar. Enol ethers

22 (100 mg, 0.17 mmol) were dissolved in freshly distilled

CH₂Cl₂(2 ml) and added to the reaction vessel by cannula

under Ar. The reaction was allowed to warm to rt. After

18 h, TLC (petrol/ethyl acetate, 6:1) indicated formation of

a single major product (R_f0.7), and little remaining starting

material (R_f0.8). The reaction was quenched with sodium

thiosulfate (40 ml of a 10% aqueous solution) then extracted

with CH₂Cl₂(2!40 ml). The combined organic extracts

were dried (MgSO₄), ﬁltered and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography

(petrol/ethyl acetate, 7:1) to afford mixed acetals 23b

(128 mg, 64%) as a colourless oil; m/z (ES^C) 1245 (MC

NH^C₄CMeCN, 55), 1209 (MCNa^C, 100), 1204 (MC

NH^C₄, 92%).

4.1.23. para-Tolyl 3,5,6-tri-O-benzyl-2-O-prop-1⁰-enyl-1-

thio-b-^D-glucofuranoside 22. Wilkinson’s catalyst (320 mg,

0.35 mmol) was dissolved in anhydrous THF (6 ml) and

degassed. Butyl lithium (1.6 M solution in hexanes)

(0.32 ml, 0.52 mmol) was added and the mixture stirred

for 10 min. Glycosyl donor 21 (2.07 g, 3.47 mmol) was

dissolved in anhydrous THF (6 ml) and heated to 70 8C. The

catalyst solution was added by cannula under Ar. After 2 h,

TLC (CH₂Cl₂/petrol, 4:1) indicated formation of a two

products (R_f0.45 and 0.5) and complete consumption of

starting material (R_f0.4). The reaction was allowed to cool

then diluted with CH₂Cl₂(ca 5 ml) and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy (petrol/ethyl acetate, 8:1) to afford enol ethers 22

(1.99 g, 96%) as a colourless oil. Partial data: d_H(400 MHz,

CDCl₃) (E/Z, 1:1.7), E isomer 1.50 (3H, dd, JZ1.5 Hz, JZ

6.7 Hz, OCHZCHCH₃), 2.33 (3H, s, ArCH₃), 4.83 (1H, dq,

J_EZ12.5 Hz, OCHZCH), 5.31 (1H, d, J_1,2Z1.2 Hz, H-1),

5.97 (1H, daq, JZ1.5 Hz, OCHZCH); Z isomer 1.53 (3H,

dd, JZ1.9 Hz, JZ6.7 Hz, OCHZCHCH₃), 2.33 (3H, s,

ArCH₃), 5.30 (1H, d, J_1,2Z1.8 Hz, H-1), 5.84 (1H, daq,

J_ZZ6.2 Hz, JZ1.7 Hz, OCHZCH); d_C(100.6 MHz,

CDCl₃) E isomer 12.4 (q, OCHZCHCH₃), 21.1 (q,

ArCH₃), 90.8 (d, C-1), 102.6 (d, OCHZCH), 143.8 (d,

OCHZCH); Z isomer 9.3 (q, OCHZCHCH₃), 21.1 (q,

ArCH₃), 91.1 (d, C-1), 104.4 (d, OCHZCH), 142.9 (d,

OCHZCH); m/z (ES^C) 619 (MCNa^C, 100), 614 (MC

NH^C₄, 67), 597 (MCH^C, 23%). (HRMS calcd for

C₃₇H₄₁O₅S (MH^C) 597.2675. Found 597.2674).

4.1.26. para-Tolyl 3,5,6-tri-O-benzyl-2-O-(2-iodo-1-

(methyl 2-O-benzyl-4,6-O-benzylidene-a-^D-mannopyra-

nosid-3-O-yl)propyl)-1-thio-b-^D-glucofuranoside 23c.

Iodine (55 mg, 0.22 mmol), silver triﬂuoromethanesulfonate

(56 mg, 0.22 mmol), 2,6-di-tert-butyl-4-methylpyridine

˚

(116 mg, 0.57 mmol) and 4 A molecular sieves were

added to freshly distilled CH₂Cl₂(1 ml) and cooled to

K78 8C under Ar. Methyl 2-O-benzyl-4,6-O-benzylidene-

a-^D-mannopyranoside (65 mg, 0.18 mmol) was dissolved in

freshly distilled CH₂Cl₂(2 ml) and added by cannula under

Ar. Enol ethers 22 (100 mg, 0.17 mmol) were dissolved in

freshly distilled CH₂Cl₂(2 ml) and added to the reaction

vessel by cannula under Ar. The reaction was allowed to

warm to rt. After 17 h, TLC (petrol/ethyl acetate, 3:1)

indicated formation of a two major products (R_f0.55 and

0.5), and little remaining starting material (R_f0.6). The

reaction was quenched with sodium thiosulfate (40 ml of a

10% aqueous solution) then extracted with CH₂Cl₂(2!

40 ml). The combined organic extracts were dried (MgSO₄),

ﬁltered and concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography (petrol/ethyl acetate,

7:1/3:1) to afford mixed acetals 23c (161 mg, 88%) as a

colourless oil; m/z (ES^C) 1153 (MCNH₄^CCMeCN, 22),

1117 (MCNa^C, 58%).

4.1.24. para-Tolyl 3,5,6-tri-O-benzyl-2-O-(1-(1,2:3,4-di-

O-isopropylidene-a-^D-galactopyranos-6-O-yl)-2-iodo-

propyl)-1-thio-b-^D-glucofuranoside 23a. N-Iodosuccini-

˚

mide (68 mg, 0.30 mmol), and 4 A molecular sieves were

added to anhydrous dichloroethane (1 ml) and cooled to

K40 8C under Ar. 1,2:3,4-Di-O-isopropylidene-a-^D-

galactopyranose (52 mg, 0.20 mmol) was dissolved in

anhydrous dichloroethane (1.5 ml) and added to the reaction

vessel by cannula under Ar. Vinyl ethers 22 (60 mg,

0.1 mmol) were dissolved in anhydrous dichloroethane

(1.5 ml) and added to the reaction vessel by cannula under

Ar. The reaction was stirred and allowed to warm to rt.

After 1 h 35 min, TLC (petrol/ethyl acetate, 6:1) indicated

formation of a major product (R_f0.2), and complete

consumption of starting material (R_f0.5). The reaction

was quenched with sodium thiosulfate (30 ml of a 10%

aqueous solution) then extracted with CH₂Cl₂(2!30 ml).

The combined organic extracts were dried (MgSO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ethyl acetate, 5:1 with 1%

Et₃N) to afford mixed acetals 23a (107 mg, 75%) as a

colourless oil. m/z (ES^C) 1005 (MCNa^C, 41), 1000 (MC

NH^C₄, 5), 877 (M-STolCNH^C₄, 25%). (HRMS calcd for

C₄₉H₆₃NO₁₁SI (MNH^C₄) 1000.3167. Found 1000.3170).

4.1.27. 3,5,6-Tri-O-benzyl-a-^D-glucofuranosyl-(1/6)-

1,2:3,4-di-O-isopropylidene-a-^D-galactopyranose 24a.

Mixed acetals 23a (85 mg, 0.087 mmol) were dissolved in

anhydrous dichloroethane (7 ml). 2,6-Di-tert-butyl-4-

methylpyridine (35 mg, 0.17 mmol), N-iodosuccinimide

(59 mg, 0.26 mmol) and silver triﬂuoromethanesulfonate

(22 mg, 0.087 mmol) were added and the mixture stirred

under Ar at rt. After 6 h, TLC (petrol/ethyl acetate, 3:1)

indicated the complete consumption of starting material (R_f

0.6) and the formation of a major product (R_f0.3). The

reaction was quenched with sodium thiosulfate (30 ml of a

10% aqueous solution) and extracted with CH₂Cl₂(2!

30 ml). The organic extracts were dried (MgSO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by ﬂash

4.1.25. para-Tolyl 3,5,6-tri-O-benzyl-2-O-(2-iodo-1-

I. Cumpstey et al. / Tetrahedron 60 (2004) 9061–9074

9073

column chromatography (petrol/ethyl acetate, 2:1) to afford

a-gluco disaccharide 24a (44 mg, 75%) as a colourless oil;

100%). (HRMS calcd for C₅₅H₆₄NO₁₁(MNH^C₄) 914.4479.

Found 914.4467).

[a]²_D²ZK18.2 (c, 0.55 in CHCl₃); n_max3467 (br, OH) cm^K1

d_H(400 MHz, CDCl₃) 1.33, 1.34, 1.46, 1.53 (12H, 4!s, 4!

;

4.1.29. Methyl 3,5,6-tri-O-benzyl-a-^D-glucofuranosyl-

(1/3)-2-O-benzyl-4,6-O-benzylidene-a-^D-mannopyra-

noside 24c. Dimethyl disulﬁde (24 ml, 0.26 mmol) and

methyl triﬂuoromethanesulfonate (30 ml, 0.26 mmol) were

dissolved in freshly distilled CH₂Cl₂(1 ml) and stirred

under Ar at rt. After 5 min, 2,6-di-tert-butyl-4-methylpyri-

dine (68 mg, 0.33 mmol) was added and the mixture cooled

to 0 8C. Mixed acetals 23c (72 mg, 0.066 mmol) was

dissolved in freshly distilled CH₂Cl₂(2 ml) and added by

cannula under Ar. After 5 h, TLC (petrol/ethyl acetate, 3:1)

indicated very little remaining starting material (R_f0.6) and

the formation of major (R_f0.4) and minor (R_f0.4–0.5)

products. The reaction was quenched with Et₃N and the

mixture partitioned between ether (40 ml) and brine (40 ml).

The aqueous layer was re-extracted with ether (20 ml) and

the combined organic extracts dried (MgSO₄), ﬁltered and

concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ethyl acetate, 7:2) to afford

a-gluco disaccharide 24c (17 mg, 32%) as a colourless oil;

0

CH₃), 3.68 (1H, dd, J_5,6Z6.1 Hz, J_6,6Z10.5 Hz, H-6_b),

0

3.79 (1H, dd, J_5,6Z7.9 Hz, J_6,6Z10.0 Hz, H-6_a), 3.86–3.90

(2H, m, H-6⁰_a, H-6⁰_b), 4.03 (1H, ddd, J_4,5Z8.4 Hz, J_5,6

2.0 Hz, H-5_b), 4.06–4.11 (2H, m, H-5_a, H-3_b), 4.27–4.29

Z

0

(2H, m, H-4_a, H-2_b), 4.33 (1H, dd, J_1,2Z5.1 Hz, J_2,3

Z

2.3 Hz, H-2_a), 4.37 (1H, dd, J_3,4Z4.3 Hz,, H-4_b), 4.52, 4.70

(2H, ABq, J_ABZ11.8 Hz, PhCH₂), 4.54, 4.80 (2H, ABq,

J_ABZ11.6 Hz, PhCH₂), 4.58 (2H, s, PhCH₂), 4.58–4.61

(1H, m, H-3_a), 5.21 (1H, d, J_1,2Z4.4 Hz, H-1_b), 5.52 (1H, d,

H-1_a), 7.16–7.37 (15H, m, Ar-H); d_C(100.6 MHz, CDCl₃)

24.4, 24.9, 25.9, 26.1 (4!q, 4!CH₃), 65.5 (d, C-5_a), 67.1

(t, C-6_a), 70.5, 70.5, 70.8, 75.5 (4!d, C-2_a, C-3_a, C-4_a,

C-2_b), 71.3, 71.7, 72.6, 73.3 (4!t, 3!PhCH₂, C-6_b), 76.0

(d, C-5_b), 78.2 (d, C-4_b), 83.7 (d, C-3_b), 96.3 (d, C-1_a), 102.4

(d, C-1_b), 108.9, 109.3 (2!s, 2!C(CH₃)₂), 127.3, 127.4,

127.4, 127.5, 127.5, 127.6, 128.2, 128.3, 128.3 (9!d,

Ar-CH), 137.9, 138.6, 138.9 (3!s, Ar-C); m/z (ES^C) 751

(MCNH^C₄CMeCN, 22%), 715 (MCNa^C, 26), 710 (MC

NH^C₄, 100%). (HRMS calcd for C₃₉H₅₂NO₁₁(MNH^C₄)

710.3540. Found 710.3541).

[a]²_D²ZC12.8 (c, 0.5 in CHCl₃); n_max3498 (br, OH) cm^K1

;

d_H(500 MHz, CDCl₃) 3.37 (3H, s, OCH₃), 3.67 (1H, dd,

0

J_5,6Z5.7 Hz, J_6,6Z10.8 Hz, H-6_b), 3.78–3.89 (4H, m, H-2_a,

H-5_a, H-6_a, H-6⁰_b), 4.00 (1H, ddd, J_4,5Z8.0 Hz, J_5,6

Z

4.1.28. Methyl 3,5,6-tri-O-benzyl-a-^D-glucofuranosyl-

(1/6)-2,3,4-tri-O-benzyl-a-^D-mannopyranoside 24b.

Mixed acetals 23b (103 mg, 0.087 mmol) were dissolved

in anhydrous dichloroethane (7 ml). 2,6-Di-tert-butyl-4-

methylpyridine (35 mg, 0.17 mmol), N-iodosuccinimide

(59 mg, 0.26 mmol) and silver triﬂuoromethanesulfonate

(22 mg, 0.087 mmol) were added and the mixture stirred

under Ar at rt. After 5 h, TLC (petrol/ethyl acetate, 3:1)

indicated the complete consumption of starting material (R_f

0.7) and the formation of a major product (R_f0.3). The

reaction was quenched with sodium thiosulfate (30 ml of a

10% aqueous solution) and extracted with CH₂Cl₂(2!

30 ml). The organic extracts were dried (MgSO₄), ﬁltered

and concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography (petrol/ethyl acetate, 2:1) to afford

a-gluco disaccharide 24b (30 mg, 39%) as a colourless oil;

0

2.1 Hz, H-5_b), 4.04 (1H, dd, J_2,3Z2.3 Hz, J_3,4Z4.5 Hz,

H-3_b), 4.14 (1H, at, JZ9.5 Hz, H-4_a), 4.23–4.28 (3H, m,

H-3_a, H-6⁰_a, H-2_b), 4.35 (1H, dd, H-4_b), 4.48, 4.67 (2H,

ABq, J_ABZ12.0 Hz, PhCH₂), 4.52, 4.75 (2H, ABq, J_AB

Z

11.6 Hz, PhCH₂), 4.52, 4.56 (2H, ABq, J_ABZ12.0 Hz,

PhCH₂), 4.59, 4.67 (2H, ABq, J_ABZ12.0 Hz, PhCH₂), 4.67

(1H, d, J_1,2Z1.3 Hz, H-1_a), 5.28 (1H, d, J_1,2Z4.5 Hz,

H-1_b), 5.59 (1H, s, PhCH), 7.23–7.47 (25H, m, Ar-H); d_C

(125.7 MHz, CDCl₃) 54.8 (q, OCH₃), 63.8 (d, C-5_a), 68.7 (t,

C-6_a), 70.7 (t, C-6_b), 71.4, 72.3, 73.2, 73.8 (4!t, 4!

PhCH₂), 75.2 (d, C-3_a), 75.9, 76.0 (2!d, C-2_b, C-5_b), 78.0,

(d, C-2_a, C-4_a, C-4_b), 83.4 (d, C-3_b), 100.2 (d, C-1_a), 101.5

(d, PhCH), 102.8 (d, C-1_b), 125.9, 127.2, 127.3, 127.3,

127.4, 127.5, 127.7, 128.1, 128.1, 128.2, 128.3, 128.9 (12!

d, Ar-CH), 137.2, 137.7, 137.9, 138.5, 138.8 (5!s, Ar-C);

m/z (ES^C) 827 (MCNa^C, 46), 822 (MCNH^C₄, 100%).

(HRMS calcd for C₄₈H₅₆NO₁₁(MNH^C₄) 822.3853. Found

822.2863).

[a]²_D²ZC35.6 (c, 0.5 in CHCl₃); n_max3383 (br, OH) cm^K1

;

d_H(400 MHz, CDCl₃) 3.31 (3H, s, OCH₃), 3.63 (1H, dd,

0

J_5,6Z6.7 Hz, J_6,6Z10.5 Hz, H-6_b), 3.68–3.71 (1H, m, H-5_a),

0

3.79–3.82 (2H, m, H-2_a, H-6_a), 3.84 (1H, dd, J_5,6Z1.9 Hz,

H-6⁰_b), 3.89 (1H, dd, J_2,3Z2.9 Hz, J_3,4Z9.6 Hz, H-3_a),

4.01–4.07 (2H, m, H-4_a, H-5_b), 4.09 (1H, dd, J_2,3Z2.0 Hz,

0

Acknowledgements

J_3,4Z4.4 Hz, H-3_b), 4.18 (1H, dd, J_5,6Z3.6 Hz, J_6,6

Z

11.3 Hz, H-6⁰_a), 4.25 (1H, dd, J_1,2Z4.3 Hz, H-2_b), 4.34 (1H,

dd, J_4,5Z8.0 Hz, H-4_b), 4.46 (2H, s, PhCH₂), 4.49, 4.67

(2H, ABq, J_ABZ12.0 Hz, PhCH₂), 4.55, 4.81 (2H, ABq,

J_ABZ11.6 Hz, PhCH₂), 4.63 (2H, s, PhCH₂), 4.67, 4.93

(2H, ABq, J_ABZ10.8 Hz, PhCH₂), 4.69, 4.77 (2H, ABq,

J_ABZ12.2 Hz, PhCH₂), 4.70 (1H, s, H-1_a), 5.28 (1H, d,

H-1_b), 7.23–7.38 (30H, m, Ar-H); d_C(100.6 MHz, CDCl₃)

54.8 (q, OCH₃), 67.6 (t, C-6_a), 71.3 (d, C-5_a), 71.7, 72.1,

72.1, 72.7, 72.8, 73.2, 75.1 (7!t, 6!PhCH₂, C-6_b), 74.4,

74.5 (2!d, C-2_a, C-4_a), 75.6 (d, C-2_b), 76.3 (d, C-5_b), 78.4

(d, C-4_b), 79.9 (d, C-3_a), 83.7 (d, C-3_b), 99.0 (d, C-1_a), 102.6

(d, C-1_b), 127.2, 127.3, 127.4, 127.5, 127.5, 127.5, 127.6,

127.7, 127.8, 127.9, 128.1, 128.2, 128.3, 128.3 (14!d,

Ar-CH), 138.0, 138.1, 138.4, 138.4, 138.6, 139.0 (6!s,

Ar-C); m/z (ES^C) 919 (MCNa^C, 54), 914 (MCNH^C₄,

We gratefully acknowledge ﬁnancial support from the

EPSRC and GlaxoSmithKline (Quota and CASE Awards to

I.C.). We also gratefully acknowledge the use of the EPSRC

Mass Spectrometry Service (Swansea, UK) and the

Chemical Database Service (CDS) at Daresbury, UK.

References and notes

¨

1. Wulff, G.; Rohle, G. Angew. Chem. Int. Ed. Engl. 1974, 13,

157–170.

2. For a recent review on 1,2-cis glycosylation focusing on

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Chem. 2003, 7, 35–79.

by the IAD approach, see: (a) Packard, G. K.; Rychnovsky,

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173–197, and references contained therein.

17. Cumpstey, I. D. Phil. Thesis, University of Oxford, 2002.

18. The b-stereochemistry of rhamnoside products was assigned

by measurement of ¹J_C-1,H-1, which was found to be !160 Hz

in all cases. See Bock, K.; Pedersen, C. J. Chem. Soc. Perkin

Trans. 2 1974, 293–297.

6. (a) Bols, M.; Hansen, H. C. Chem. Lett. 1994, 1049–1052.

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20. The stereochemistry of 19a and 19b was determined by NOE

experiments which showed mutual enhancements between

H-1 and H-4 only for 19b. In addition ³J_1,2for 19a was 4.6 Hz,

3

whereas J_1,2for 19b was 1.4 Hz conﬁrming these assign-

8. For a recent review of the allyl IAD approach, which also

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gations detailed in this paper, see: Fairbanks, A. J. Synlett

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21. Studies were in fact also carried out on the minor a-anomer

19a, which was carried through an analogous reaction

sequence to that undertaken for 19b (Scheme 4). However,

all subsequent IAD experiments on tethered materials derived

from the a-donor, in which the leaving group is syn to the

2-hydroxyl group, revealed that whilst intramolecular glyco-

sylation did occur that this was substantially less efﬁcient than

for the epimeric donor, in which the anomeric leaving group is

anti to the 2-hydroxyl.

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Redgrave, A. J.; Fairbanks, A. J. Chem. Commun. 2000,

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2001, 3, 2371–2374. (b) Cumpstey, I.; Fairbanks, A. J.;

Redgrave, A. J. Monatsh. Chem. 2002, 133, 449–466.

11. For work detailing the synthesis of other 1,2-cis furanosides by

the IAD approach, see: (a) Sanchez, S.; Bamhaoud, T.; Prandi,

J. Tetrahedron Lett. 2000, 41, 7447–7452. (b) Krog-Jensen, C.;

Oscarson, S. J. Org. Chem. 1996, 61, 4512–4513.

(c) Krog-Jensen, C.; Oscarson, S. J. Org. Chem. 1998, 63,

1780–1784.

22. The anomeric stereochemistry of the a-glucofuranose dis-

3

accharides 24a–c was determined by the J_H1,H2coupling

constant, which was between 4.3 and 4.5 Hz in all cases. See

Ref. 19.

23. Whilst the desired 1,2-cis disaccharide 24c was formed, as

evidenced by ¹H NMR spectroscopy, this material could not be

efﬁciently separated from the also-formed manno aglycon alco-

hol. In addition the overall reaction yield was low (!31%),

and many other unidentiﬁed products were also observed.

12. For work detailing the synthesis of other 1,2-cis pyranosides

Article Doi

Allyl protecting group mediated intramolecular aglycon delivery (IAD): Synthesis of α-glucofuranosides and β-rhamnopyranosides

DOI: 10.1016/j.tet.2004.07.083

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Full text of DOI:10.1016/j.tet.2004.07.083

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