One-pot synthesis of multivalent arrays of mannose mono- and disaccharides

Tetrahedron 59 (2003) 7983–7996

One-pot synthesis of multivalent arrays of mannose mono-

and disaccharides

a

b

Wayne Hayes,^aHelen M. I. Osborn,^aSadie D. Osborne, Robert A. Rastall

,

*

and Barbara Romagnoli^a

^aSchool of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK

^bSchool of Food Bioscience, University of Reading, Whiteknights, Reading RG6 6AP, UK

Received 11 March 2003; revised 14 July 2003; accepted 7 August 2003

Abstract—The synthesis of a selection of multivalent arrays of mannose mono- and disaccharides, that are of potential use as anti-infective

agents against enterobacteria infections, is described.

1. Introduction

binding sites on the bacteria are typically within the micro- to

millimolar range it is essential that multivalent arrays of the

disease associated carbohydrates are administered. In particu-

lar,ﬂexiblemultivalentarraysanddendritic⁶arraysofreceptor

carbohydrates are of current interest, as a result of their

enhanced activity resulting from the cluster effect.⁷

It is now accepted that glycoproteins and glycolipids are

widely expressed on cell surfaces and participate in many

molecular recognition and binding processes in both healthy

and diseased states.¹In particular, some bacterial surface

proteins show speciﬁc binding for carbohydrates expressed

on human cells, and such interactions form an essential part

of the infection pathway. It has been demonstrated that

administration of synthetic or natural carbohydrate deriva-

tives can disrupt this infective pathway, so long as the

administered derivatives have high afﬁnities for the

bacterial lectins.²In such cases, the bacteria are no longer

able to interact with the host, and therefore pass through the

body without initiating infection. These therapeutic agents

have been termed anti-infective agents. A number of anti-

infective agents occur naturally, for example, human breast

milk contains numerous soluble oligosaccharides that

provide newborn babies with a mechanism for diverting

infection processes.³However, there is also considerable

interest in the design of synthetic, multivalent carbohydrate

based anti-infective agents as alternatives to traditional

antiobiotic therapies.⁴It has been postulated that since anti-

infective agents rely on disrupting carbohydrate–lectin

interactions, any mutations that render the bacteria resistant

to the anti-infective carbohydrate agents should also

produce bacteria that are incapable of binding to the host’s

carbohydrates.⁵This is particularly useful given the

evolution of multi-drug resistant microbial pathogens.

2. Results and discussion

As part of a programme directed towards the inhibition of

infections caused by enterobacteria (for example some E.

coli and S. suis strains), that naturally adhere via type 1

ﬁmbriae to highly-branched mannose chains,⁸we required

access to multivalent arrays of mannose saccharides.

Although the natural hosts display complex mannose

saccharides, it has already been demonstrated that arrays

of mannose monosaccharides,⁹as well as Man a-1,2-Man

and Man a-1,3-Man disaccharides,¹⁰are effective for

inhibiting the carbohydrate–lectin interactions. The

ultimate aim of this programme was to devise method-

ologies that would allow efﬁcient entry to multivalent

mannose anti-infective agents in a concise manner. Initial

studies aimed to assess the suitability of forming these

targets by condensation of fully protected mannopyranoside

donors with a range of alcohol or thiol linkers. However, it

is evident from Scheme 1 and Table 1 that access to

relatively simple divalent derivatives via such an approach

proved problematic, with the reactions only being syntheti-

cally useful when more than two carbon units were

incorporated within the linker: when shorter linkers such

as ethylene glycol, ethane 1,2-dithiol or mercaptoethanol

were utilised it generally proved difﬁcult to access

synthetically useful quantities of the divalent targets.

(Scheme 1, Table 1). This effect was observed presumably

Since the afﬁnity of individual carbohydrate sequences for the

Keywords: anti-infective; E. coli; S. suis; mannose; ﬁmbriae; dendrimer.

*

Corresponding author. Fax: þ44-0-1189316331;

e-mail: h.m.i.osborn@rdg.ac.uk

doi:10.1016/j.tet.2003.08.011

7984

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

Scheme 1. (i) R¼OAc, BF₃·OEt₂; R¼SEt or SePh, NIS, TfOH.

Table 1.

R

Linker

Ethylene glycol

Ethane 1,2-dithiol

Ethanol mercaptan

Butane 1,4-diol

Divalent derivative (%)

Monovalent derivative (%)

OAc

SEt

SePh

OAc

(1) 11

(3) 0

(2) 15

(4) 15

(6) 12

–

(5) 39

(7) 46

(8) 72

(9) 54

(10) 49

(11) 63

Octane 1,8-diol

Bis(4-hydroxyphenyl)methane

4,4⁰-Biphenol

1,3-Propanedithiol

Scheme 2. (i) K₂CO₃, MeOH.

yields.¹²However, this strategy has not been extended to

allow synthesis of higher valent derivatives through reaction

of more highly functionalised amine clusters with reducing

sugars. This strategy was considered particularly attractive

for entry to multivalent carbohydrate anti-infective agents

since it circumnavigates the need for time consuming

protection/deprotection steps and offers equal potential for

derivatisation of both mannose mono- and disaccharide

units. Initial studies concentrated on the condensation

reaction of ^D-(þ)-mannose with ethylene diamine, in

methanol, at 508C. Pleasingly this approach allowed direct

access to the target divalent derivative (16) in 77% yield,

and the target crystallized out of the solution when left at

48C overnight (Scheme 3).¹³

Table 2.

Acetylated derivative

Deprotected target

Yield (%)

(1) X¼O, Y¼O, n¼1

(7) X¼O, Y¼O, n¼3

(9) X¼OPh, Y¼OPh, n¼0

(11) X¼S, Y¼S, n¼2

(12)

(13)

(14)

(15)

94

86

83

89

as a result of disfavoured steric interactions that occur

between the carbohydrate residues within the short linker

targets.

Conversion of the protected intermediates to the deprotected

divalent targets proved possible in excellent yield by simple

treatment with potassium carbonate and methanol

(Scheme 2, Table 2). However, the limited success of the

methodology for accessing derivatives derived from short

linkers, and the need for conventional carbohydrate

protection/deprotection manipulations, sought us to

investigate an alternative approach for accessing derivatives

of higher valency with greater efﬁciency.

Moreover, it also proved possible to extend this method-

ology to allow access to a library of multivalent mannose

monosaccharides (16–24), by incorporation of the

multivalent amines illustrated in Figure 1 (Table 3).

Thus linkers of different lengths, ﬂexibility and valency

were easily incorporated with each allowing one-pot entry

to the desired targets in synthetically useful yields. The

anomeric conﬁgurations of the glycosylamines were

Preparation of glycosylamines by condensation of amines

with reducing sugars is well described in the literature¹¹and

condensation of a small range of reducing sugars with

diamines has also been previously reported to allow efﬁcient

access to divalent carbohydrate derivatives in excellent

1

determined by measuring J[¹³CH(1)] coupling constants

for representative targets. Comparison of these with values

reported in the literature¹⁵indicated that the glycosylamines

were of the a-conﬁguration.

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

7985

Scheme 3. (i) Anhydrous methanol, room temperature, then 48C, 77%.

Figure 1.

In some cases the multivalent amines utilised in the

reactions were commercially available. However, some

amines necessitated synthesis. For example, pentaerythritol

tetraamine (29) was prepared by reduction of azide (30)

utilising hydrogen and 10% Pd/C. The azide (30) was itself

prepared in excellent yield by treatment of pentaerythrityl

tetrabromide with sodium azide in DMF at 808C (Scheme 4).

Amines (31) and (32) were prepared by de-O-acetylation

of amines (33) and (34), respectively, with potassium

carbonate and methanol with the amines themselves

being prepared from azides (35) and (36) respectively.

The azides (35) and (36) were easily prepared in two

steps from 1,2,3,4,6-penta-O-acetate mannopyranoside

by initial condensation with 2-bromoethanol or 3-bromo-

propan-1-ol, under Lewis acid mediated conditions

(Scheme 5).

Table 3.

Saccharide

Amine

Ethylenediamine

1,2-Propanediamine

1,3-Propanediamine

1,4-Butanediamine

Tris(2-aminoethyl)amine

Pentaerythrityl tetraamine (29)

Hexavalent dendrimer¹⁴

Amine (31)

Amine (32)

Ethylenediamine

Hexavalent dendrimer¹⁴

Yield (%)

Extension of the methodology to allow condensation of

multivalent amines with the disaccharides Man-a-1,2-

Man¹⁶and Man-a-1,3-Man¹⁷also proved straightforward.

The disaccharides were prepared via chemical or enzymatic

pathways according to literature methods^16,17and were then

reacted in their deprotected forms with ethylene diamine or

the hexavalent dendrimer¹⁴under the one-pot reaction

conditions outlined above. Pleasingly this approach allowed

entry to the multivalent disaccharide targets (25–28) in

good to excellent yields.

D-Mannose

Man a-1,3-Man

Man a-1,2-Man

Man a-1,3-Man

Man a-1,2-Man

(16) 77

(17) 64

(18) 68

(19) 53

(20) 56

(21) 47

(22) 56

(23) 43

(24) 38

(25) 43

(26) 39

(27) 37

(28) 35

In order to gain preliminary data concerning the stability of

the multivalent derivatives in aqueous solutions, divalent

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W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

Scheme 4. (i) NaN₃, DMF, 808C, 81%; ii) Pd/C, H₂, MeOH, 91%.

Scheme 5. (i) CH₂Cl₂, BF₃·OEt₂; (ii) NaN₃, DMF; (iii) H₂, Pd/C; (iv) K₂CO₃, MeOH.

derivative (16) was stirred under aqueous conditions at 238C

1

for 4 h and the solution analysed by TLC and H NMR for

evidence of decomposition. Pleasingly no hydrolysis

products were detected during this time suggesting that

the targets have suitable half lives to be of interest as

potential anti-infective agents.

s, d, t, m, denoting singlet, doublet, triplet and multi-

plet, respectively. All coupling constants (J) are quoted

in Hertz.

Infra red spectra were recorded on either a Perkin–

Elmer Paragon 1000 FT-IR spectrometer, or a Perkin–

Elmer 1720-X spectrometer. Spectra were analysed as

either a thin oil ﬁlm between sodium chloride plates or

as a potassium bromide disc. All absorptions are quoted

3. Conclusions

in cm²¹

.

A range of multivalent mannose mono- and disacchar-

ides have been prepared in an efﬁcient manner using a

range of different methodologies. Of particular interest

is the development of a one-pot methodology that

allows entry to multivalent derivatives without any need

for protecting group strategies. The utility of the

derivatives as anti-infective agents against infections

caused by enterobacteria is currently being evaluated in

our laboratories.

High-resolution mass-spectrometric data, both low-

resolution mass spectra (m/z) and accurate mass spectra

(HRMS), were recorded on a Fisons VG Autospec mass

spectrometer. All spectra were recorded using either

chemical ionisation, with either methane or ammonia gas

as the ionising source, fast-atom bombardment using

caesium ions as the ion source and glycerol as the matrix,

or electrospray ionisation.

All melting points were recorded using a Kofﬂer heated

stage microscope and are uncorrected.

4. Experimental

4.1. General

Speciﬁc optical rotations ([a]²_D⁰) were recorded at the

sodium D line (589.3 nm) in chloroform, methanol or water

and are quoted in units of 10²¹deg cm²g²¹. Solution

NMR spectra were recorded on a Bruker AC250

(250 MHz), a Bruker DPX250 (250 MHz), and a Bruker

AMX400 (400 MHz) spectrometer. All spectra were

recorded in either chloroform-d, methanol-d, or in

deuterated water and are referenced to residual solvent

peaks or to an internal standard, tetramethylsilane. Peak

positions were recorded in d ppm with the abbreviations

concentrations (c) are given in units of 10²²g cm²³

.

Measurements were obtained using a Perkin–Elmer 341

polarimeter.

Elemental analyses were performed by Medac Ltd, Brunel

Science Centre, Surrey.

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

7987

All reactions were monitored by thin layer chromatography

(TLC) using Merck aluminium backed plates coated with

0.2 mm silica 60 F₂₅₄. Product spots were visualised using

UV irradiation (254 nm) and by staining the plate with an

ethanol/sulfuric acid (25:1, v/v) dip.

3.75 (3H, m, 2£H_b, H_a), 3.56–3.60 (1H, m, H_a), 3.14 (1H, br

s, OH), 2.09 (3H, s, OAc), 2.03 (3H, s, OAc), 1.98 (3H, s,

OAc), 1.92 (3H, s, OAc); d_C(62.5 MHz, CDCl₃) 171.0

(CvO), 170.3 (2£CvO), 170.0 (CvO), 98.1 (CH), 70.3

(CH₂OH), 69.7 (CH), 69.4 (CH), 68.8 (CH), 66.3 (CH), 62.7

(CH₂), 61.6 (CH₂O), 21.1 (CH₃), 21.0 (2£CH₃), 20.9 (CH₃);

m/z (CI) 410 (MþNH^þ₄, 57%), 331 (98), 169 (38), 73 (100);

Found 410.1642, C₁₆H₂₈O₁₁N requires 410.1662.

Flash column chromatography was performed using Merck

60 silica gel (particle size 0.040–0.063 nm, 230–400 mesh

ASTM) using head pressure by means of hand bellows.

4.1.2. 2⁰-Thioethyl 2,3,4,6-tetra-O-acetyl-1-a-D-manno-

pyranoside (4). 1,2,3,4,6-Penta-O-acetyl-a-^D-manno-

pyranoside (1.700 g, 4.36 mmol) was dissolved in distilled

CH₂Cl₂(20 cm³) and 1,2-ethane dithiol (1.10 cm³,

13.08 mmol) was added followed after 30 min by the

addition of boron triﬂuoride etherate (1.60 cm³,

13.08 mmol) at 08C. The reaction mixture was warmed up

to room temperature and stirred under an argon atmosphere.

The reaction was followed by TLC analysis, using ethyl

acetate/hexane (1:1, v/v) as the solvent system. After 12 h

saturated sodium bicarbonate solution was added (20 cm³)

and the organic layer extracted with dichloromethane

(3£30 cm³). The combined organic layers were dried over

magnesium sulfate, ﬁltered and concentrated to dryness

under reduced pressure. The resulting yellow oil was

puriﬁed using column chromatography on silica gel (ethyl

acetate/hexane, 1:1, v/v). The relevant fractions were

collected and combined to give 2⁰-thioethyl 2,3,4,6-tetra-

O-acetyl-a-D-mannopyranoside (4) as a colourless solid

(0.46 g, 15%). Mp 39.4–41.28C; [a]²_D⁰¼þ42.06 (c 0.68,

CHCl₃); d_H(250 MHz, CDCl₃) 5.23–5.29 (4H, m, H-1, H-

2, H-3, H-4), 4.27 (1H, m, H-5), 4.20–4.23 (1H, m, H-6),

4.03–4.08 (1H, m, H-6), 2.70–2.85 (4H, m, 2£H_a, 2£H_b),

2.11 (3H, s, OAc), 2.06 (3H, s, OAc), 2.01 (3H, s, OAc),

1.94 (3H, s, OAc), 1.63 (1H, t, J¼8.0 Hz, SH); d_C

(62.5 MHz, CDCl₃) 170.9 (CvO), 170.2 (CvO), 170.1

(CvO), 170.0 (CvO), 83.3 (CH), 71.3 (CH), 69.6 (2£CH),

66.6 (CH), 62.8 (CH₂), 36.1 (CH₂SH), 25.0 (CH₂S), 21.2

(CH₃), 21.1 (CH₃), 21.0 (2£CH₃); m/z (CI) 442 (MþNH^þ₄,

18%), 331 (12), 245 (21), 213 (100), 153 (47), 97 (40);

Found 442.1209, C₁₆H₂₈O₉NS requires 442.1206.

Anhydrous solvents were supplied in ‘sure seal’ bottles by

Aldrich. All reactions were performed under an inert

atmosphere of argon or nitrogen unless otherwise stated.

Solvents were evaporated under aspirator vacuum (ca.

20 mmHg) at approximately 358C, unless otherwise stated

or when coevaporating using toluene.

4.1.1. 1,2-Bis[O-2,3,4,6-tetra-O-acetyl-a-^D-mannopyrano-

syl]ethane-1,2-diol(1)and2⁰-hydroxyethyl 2,3,4,6-tetra-O-

acetyl-a-^D-mannopyranoside (2). 1,2,3,4,6-Penta-O-acetyl-

a-^D-mannopyranoside (0.965 g, 2.47 mmol) was dissolved

in distilled CH₂Cl₂(10 cm³) and ethylene glycol (0.41 cm³,

7.41 mmol) was added followed, after 30 min, by the

addition of boron triﬂuoride etherate (0.91 cm³, 7.41 mmol)

at 08C. The reaction mixture was warmed up to room

temperature and stirred under an argon atmosphere. The

reaction was followed by TLC analysis, using ethyl acetate/

hexane (1:1, v/v) as the solvent system. After 14 h saturated

sodium bicarbonate solution was added (20 cm³) and the

organic layer extracted with CH₂Cl₂(3£30 cm³). The

combined organic layers were dried over magnesium

sulfate, ﬁltered and concentrated to dryness under reduced

pressure. The resulting yellow oil was puriﬁed using column

chromatography on silica gel (ethyl acetate/hexane, 1:1, v/v).

The relevant fractions were collected and combined to give

2,3,4,6-tetra-O-acetyl-a-D-mannose as a yellow oil (0.16 g,

19%), 2⁰-hydroxyethyl 2,3,4,6-tetra-O-acetyl-a-D-manno-

pyranoside (2) as a colourless oil (0.45 g, 15%), and 1,2-

bis[O-2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyl]ethane-

1,2-diol (1) as a colourless oil (0.19 g, 11%). Data for (1):

[a]²_D⁰¼þ7.42 (c 1.20, CHCl₃); n_max(NaCl, cm²¹) 1747 (s,

CvO str), 1436 (s, as CH₃), 1373 (s, s CH₃), 1232 (s,

CC(vO)–O str); d_H(400 MHz, CDCl₃) 5.28 (2H, dd,

J¼10.0, 3.5 Hz, H-3, H-3⁰), 5.19–5.21 (4H, m, H-2, H-2⁰,

H-4, H-4⁰), 4.80 (2H, d, J¼1.5 Hz, H-1, H-1⁰), 4.17–4.24

(2H, m, H-6), 4.02–4.08 (2H, m, H-6⁰), 3.94–3.98 (2H, m,

H-5, H-5⁰), 3.64–3.83 (4H, m, 2£H_a, 2£H_b), 2.09 (6H, s,

2£OAc), 2.03 (6H, s, 2£OAc), 1.98 (6H, s, 2£OAc), 1.93

(6H, s, 2£OAc); d_C(100 MHz, CDCl₃) 170.5 (2£CvO),

169.9 (2£CvO), 169.8 (2£CvO), 169.6 (2£CvO), 97.5

(2£CH), 69.3 (2£CH), 68.8 (2£CH), 68.5 (2£CH), 66.0

(2£CH), 65.9 (2£CH₂), 62.3 (2£CH₂), 20.7 (2£CH₃), 20.6

(6£CH₃); m/z (CI) 740 (MþNH^þ₄, 5%), 331 (43), 229 (11),

168 (26), 87 (100); Found 740.2640, C₃₀H₄₆O₂₀N requires

740.2613.

4.1.3. 1,2-Bis[O-2,3,4,6-tetra-O-acetyl-a-^D-mannopyrano-

syl] ethane-1-hydroxy-2⁰-thiol (5) and 2⁰-hydroxythioethyl

2,3,4,6-tetra-O-acetyl-a-^D-mannopyranoside(6).1,2,3,4,6-

Penta-O-acetyl-a-^D-mannopyranoside (2.73 g, 7.01 mmol)

was dissolved in anhydrous CH₂Cl₂(20 cm³) and 2-mer-

captoethanol (1.37 cm³, 21.02 mmol) was added. The

reaction mixture was cooled to 08C and treated with boron

triﬂuoride etherate (2.58 cm³, 21.02 mmol). The reaction

mixture was warmed up to room temperature and stirred

under a nitrogen atmosphere for 5 h. An ice-cold solution of

saturated sodium bicarbonate (30 cm³) was added to the

reaction mixture and then this mixture was diluted with

CH₂Cl₂(40 cm³). The organic layer was washed with a

saturated solution of sodium bicarbonate (3£40 cm³) and

dried over magnesium sulfate. The resulting solution was

ﬁltered and concentrated to dryness in vacuo and then

puriﬁed using column chromatography on silica gel (ethyl

acetate/hexane (2:1, v/v)). The relevant fractions were

collected, combined and concentrated to dryness under

reduced pressure to yield 1,2-bis[O-2,3,4,6-tetra-O-acetyl-

a-D-mannopyranosyl] ethane-1-hydroxy-2⁰-thiol (5) as a

colourless solid (0.20 g, 39%) and 2⁰-hydroxythioethyl

Data for (2): [a]_D²⁰¼þ36.83 (c 0.52, CHCl₃); n_max(NaCl,

cm²¹) 3521 (m, OH str), 2940 (m, OH str), 1746 (s, CvO

str), 1439 (m, as CH₃), 1372 (s, s CH₃), 1228 (s, CC(vO)–

O str), 1138 (s, C–O–C str), 1047 (s, C–O–C str), 980 (s,

C–O–C str); d_H(250 MHz, CDCl₃) 5.16–5.25 (3H, m,

H-2, H-3, H-4), 4.82 (1H, d, J¼1.5 Hz, H-1), 4.20 (1H, dd,

J¼5.5 Hz, 12.5, H-6), 4.00–4.08 (2H, m, H-5, H-6), 3.69–

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W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (6) as

a

170.3 (2£CvO), 170.1 (2£CvO), 98.0 (2£CH), 70.0

(2£CH), 69.4 (2£CH), 68.9 (2£CH), 68.3 (2£CH₂), 66.6

(2£CH), 62.9 (2£OCH₂CH₂), 25.8 (2£OCH₂CH₂), 21.4

(2£CH₃), 21.3 (4£CH₃), 21.1 (2£CH₃); m/z (CI) 768

(MþNH^þ₄, 6%), 577 (13), 438 (80), 331 (80), 289 (100),

229 (64), 169 (16), 115 (28); Found 768.2936, C₃₂H₅₀O₂₀N

requires 768.2930.

colourless solid (0.33 g, 12%). Data for (5). Mp 68.5–

70.28C; [a]²_D⁰¼þ57.65 (c 0.52, CHCl₃); d_H(250 MHz,

CDCl₃) 5.17–5.27 (7H, m, H-2, H-3, H-4, H-1⁰, H-2⁰, H-3⁰,

H-4⁰), 4.78 (1H, d, J¼1.5 Hz, H-1), 4₀.19–4.31 (3H, m, H-5,

H-6), 3.98–4.07 (3H, m, H-5⁰, H-6 ), 3.58–3.92 (2H, m,

CH₂O), 2.66–2.90 (2H, m, CH₂S), 2.09 (3H, s, 2£OAc),

2.04 (3H, s, 2£OAc), 2.00 (3H, s, 2£OAc), 1.93 (3H, s,

2£OAc); d_C(62.5 MHz, CDCl₃) 169.6 (2£CvO), 169.0

(2£CvO), 168.8 (4£CvO), 96.7 (CH), 91.2 (CH), 69.8

(CH), 68.4 (CH), 68.2 (CH), 67.9 (CH), 67.8 (CH), 66.3

(CH₂O), 65.2 (CH), 65.0 (CH), 61.4 (CH₂), 29.2 (CH₂S),

19.9 (2£CH₃), 19.7 (3£CH₃), 19.6 (3£CH₃); m/z (CI) 756

(MþNH^þ₄, 79%), 331 (100), 169 (34); Found 756.2352,

C₃₀H₄₆O₁₈NS requires 756.2385.

4.1.5. 1,8-Bis[O-2,3,4,6-tetra-O-acetyl-a-^D-mannopyrano-

syl]octane-1,8-diol (8). Ethyl 2,3,4,6-tetra-O-acetyl-1-thio-

a-^D-mannopyranoside (0.615 g, 1.57 mmol) and 1,8-octa-

nediol (0.274 g, 1.89 mmol) were dissolved in anhydrous

acetonitrile (15 cm³), added to activated molecular sieves

˚

(4 A) and stirred at 08C for 30 min under a nitrogen

atmosphere. To this solution were added N-iodosuccinimide

(0.705 g, 3.14 mmol) and triﬂic acid (catalytic amount), the

reaction mixture was then allowed to warm to room

temperature and stirred for 10 min. TLC analysis of the

reaction was performed, using ethyl acetate/hexane (3:1, v/v)

as the solvent system, and showed that the reaction had gone

to completion (starting material R_f0.73, product R_f0.57).

The reaction mixture was diluted with CH₂Cl₂(40 cm³) and

ﬁltered through a pad of Celite^wwith the aid of CH₂Cl₂

(20 cm³). The ﬁltrate was then washed with an aqueous 10%

sodium thiosulfate solution (2£20 cm³) to quench any

unreacted N-iodosuccinimide. The combined organic layers

were then washed with a saturated aqueous sodium

bicarbonate solution (2£20 cm³) and then dried over

magnesium sulfate, ﬁltered and concentrated to dryness in

vacuo to produce a brown oil. The resulting oil was then

puriﬁed using column chromatography on silica gel (ethyl

acetate/hexane (3:1, v/v)). The relevant fractions were

collected, combined and concentrated to dryness under

reduced pressure to yield 1,8-bis[O-2,3,4,6-tetra-O-acetyl-

a-D-mannopyranosyl]octane-1,8-diol (8) as a yellow oil

(0.91 g, 72%). [a]_D²⁰¼þ28.55 (c 0.42, CHCl₃); n_max(NaCl,

cm²¹) 1748 (s, CvO str), 1433 (w, as CH₃), 1374 (s, s

CH₃), 1198 (s, CC(vO)–O str), 1135 (m, C–O–C str),

1074 (s, C–O–C str), 1056 (s, C–O–C str), 980 (w, C–O–

C str); d_H(400 MHz, CDCl₃) 5.35 (2H, dd, J¼3.5, 10.0 Hz,

H-3, H-3⁰), 5.27 (2H, t, J¼10.0 Hz, H-4, H-4⁰), 5.23 (2H, dd,

J¼1.5, 3.5 Hz, H-2, H-2⁰), 4.81 (2H, d, J¼1.5 Hz, H-1,

H-1⁰), 4.28 (2H, dd, J¼5.5, 12.0 ₀Hz, H-6, H-6⁰), 4.11

(2H, dd,₀J¼2.5, 12.0 Hz, H-6, H-6 ), 3.95–4.01 (2H, m,

H-5, H-5 ), 3.44–3.72 (4H, m, 4£H_a), 2.16 (6H, s, 2£OAc),

2.11 (6H, s, 2£OAc), 2.06 (6H, s, OAc), 2.00 (6H, s, OAc),

1.51–1.63 (2H, m, 2£H_b), 1.28–1.40 (10H, m, 2£H_b, 4£H_c,

4£H_d); d_C(100 MHz, CDCl₃) 170.8 (2£CvO), 170.2

(2£CvO), 170.1 (2£CvO), 169.8 (2£CvO), 97.5

(2£CH), 69.7 (2£CH), 69.2 (2£CH), 68.5 ((OCH₂CH₂CH₂-

CH₂)₂), 68.4 (2£CH), 66.2 (2£CH), 62.5 (2£CH₂), 29.2

((OCH₂CH₂CH₂CH₂)₂), 26.0 ((OCH₂CH₂CH₂CH₂)₂), 25.7

((OCH₂CH₂CH₂CH₂)₂), 20.9 (2£OAc), 20.7 (6£OAc); m/z

(CI) 824 (MþNH^þ₄, 10%), 331 (100), 229 (17), 169 (15);

Found 824.3577, C₃₆H₅₈O₂₀N requires 824.3209.

Data for (6). Mp 101.3–102.88C; [a]²_D⁰¼þ75.00 (c 1.31,

CHCl₃); n_max(NaCl, cm²¹) 3484 (m, O–H str), 2944 (m,

O–H str), 1746 (s, CvO str), 1433 (m, as CH₃), 1373 (s, s

CH₃), 1229 (s, CC(vO)–O str), 1052 (s, C–O–C str), 976

(m, C–O–C str); d_H(250 MHz, CDCl₃) 5.31 (1H, d,

J¼1.5 Hz, H-2), 5.15–5.26 (3H, m, H-1, H-3, H-4), 4.34–

4.39 (1H, m, H-5), 4.21 (1H, dd, J¼6.0, 12.0 Hz, H-6),

4.04–4.09 (1H, m, H-6), 3.69–3.76 (2H, m, CH₂OH),

2.72–2.92 (2H, m, CH₂S), 2.44 (1H, br s, OH), 2.10 (3H, s,

OAc), 2.04 (3H, s, OAc), 1.95 (3H, s, OAc), 1.93 (3H, s,

OAc); d_C(62.5 MHz, CDCl₃) 171.0 (CvO), 170.4 (CvO),

170.2 (CvO), 170.1 (CvO), 83.5 (CH), 71.5 (CH), 69.7

(CH), 69.6 (CH), 66.7 (CH), 62.9 (CH₂), 62.1 (CH₂OH),

35.6 (SCH₂), 21.3 (CH₃), 21.1 (CH₃), 21.0 (2£CH₃); m/z

(CI) 426 (MþNH^þ₄, 67%), 331 (100), 289 (70), 229 (72),

169 (89), 109 (47).

4.1.4. 1,4-Bis[O-2,3,4,6-tetra-O-acetyl-a-^D-manno-

pyranosyl]butane-1,4-diol (7). 1,2,3,4,6-Penta-O-acetyl-

a-^D-mannopyranoside (0.503 g, 1.28 mmol) was dissolved

in distilled CH₂Cl₂(15 cm³) and 1,4-butanediol (56.8 mL,

0.64 mmol) was added at 08C, followed by the addition of

boron triﬂuoride etherate (0.40 cm³, 3.84 mmol). The

reaction was warmed up to room temperature under an

argon atmosphere. The reaction was followed by TLC

analysis, using diethyl ether as the solvent system. After

16 h saturated sodium bicarbonate solution was added

(30 cm³) and the organic layer extracted with dichloro-

methane (3£40 cm³). The combined organic layers were

dried over magnesium sulfate, ﬁltered and concentrated to

dryness under reduced pressure. The resulting brown oil was

puriﬁed using column chromatography on silica gel eluting

with diethyl ether/hexane (3:1, v/v). The relevant fractions

were collected and combined to give 1,4-bis[O-2,3,4,6-

tetra-O-acetyl-a-D-mannopyranosyl]butane-1,4-diol (7) as

a yellow oil (0.23 g, 46%). [a]²_D⁰¼þ55.00 (c 0.07, CHCl₃);

n_max(NaCl, cm²¹) 1750 (s, CvO str), 1436 (w, as CH₃),

1370 (s, s CH₃), 1230 (s, CC(vO)–O str), 1135 (m, C–O–

C str), 1084 (s, C–O–C str), 1049 (s, C–O–C str), 979 (w,

C–O–C str); d_H(250 MHz, CDCl₃) 5.21–5.26 (4H, m,

H-3, H-3⁰, H-4, H-4⁰), 5.16–5.18 (2H, dd,₀J¼2.0, 3.0 Hz,

H-2, H-2⁰), 4.74 (2H, d, J¼1.5 Hz, H-1, H-1 ), 4.22 (2H, dd,

J¼5.5,₀12.0 Hz, 2£H-6), 4.04 (2H, ₀dd, J¼3.0, 12.0 Hz,

2£H-6 ), 3.87–3.91 (2H, m, H-5, H-5 ), 3.37–3.68 (4H, m,

4£H_a), 2.09 (6H, s, OAc), 2.04 (6H, s, 2£OAc), 1.98 (6H, s,

2£OAc), 1.93 (6H, s, 2£OAc), 1.60–1.67 (4H, m, 4£H_b);

d_C(62.5 MHz, CDCl₃) 171.0 (2£CvO), 170.5 (2£CvO),

4.1.6. Bis(4-hydroxyphenyl)methane bis(2,3,4,6-tetra-O-

acetyl-a-^D-mannopyranoside) (9). Bis(4-hydroxyphenyl)-

methane (0.309 g, 1.55 mmol) and phenyl 2,3,4,6-tetra-O-

acetyl-1-seleno-a-^D-mannopyranoside (1.832 g, 3.76 mmol)

were dissolved in anhydrous DCM (40 cm³), added to

˚

activated molecular sieves (4 A) and stirred at 08C for

30 min under a nitrogen atmosphere. To this solution were

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

7989

added N-iodosuccinimide (0.696 g, 3.09 mmol) and triﬂic

acid (catalytic amount), the reaction mixture was allowed to

warm to room temperature and stirred for 20 min. TLC

analysis of the reaction was performed, using ethyl acetate/

hexane (1:1, v/v) as the solvent system, and showed that the

reaction had gone to completion (starting material R_f0.61,

product R_f0.32). The reaction mixture was diluted with

CH₂Cl₂(40 cm³) and ﬁltered through a pad ofCelite^wwith the

aid of CH₂Cl₂(20 cm³). The ﬁltrate was then washed with an

aqueous 10% sodium thiosulfate solution (2£40 cm³) to

quench any unreacted N-iodosuccinimide. The combined

organic layers were then washed with a saturated aqueous

sodium bicarbonate solution (2£40 cm³) and then dried over

magnesium sulfate, ﬁltered and concentrated to dryness in

vacuo to produce a brown oil. The resulting oil was then

puriﬁed using column chromatography on silica gel (ethyl

acetate/hexane (1:1, v/v)). The relevant fractions were

collected, combined and concentrated to dryness under

reduced pressure to yield bis(4-hydroxyphenyl)methane

bis(2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside) (9) as a

colourless foam (0.72 g, 54%). [a]²_D⁰¼þ66.30 (c 1.13,

CHCl₃); n_max(NaCl, cm²¹) 3026 (m, ArCH str), 2961 (m,

ArCH str), 1746 (s, CvO str), 1609 (m, ArCvC–C–O–C

str), 1589 (w, ArCvC–C–O–C str), 1505 (s, ArCvC str),

1433 (s, as CH₃), 1371 (s, s CH₃), 1319 (w, CC(vO)–O str),

1215 (s, CC(vO)–O str), 1176 (m, CC(vO)–O str), 1127

(m, C–O–C str), 1036(m, C–O–C str), 983 (m, C–O–C str);

d_H(250 MHz, CDCl₃) 7.06 (4H, d, J¼8.5 Hz, 4£o-ArH), 6.97

(4H, d, J¼8.5 Hz, 4£m-ArH), 5.55 (2H, dd, J¼10.0, 3.0 Hz,

H-2, H-2⁰), 5.48 (2H, s, H-1, H-1⁰), ₀5.43 (2H, br s, H-4, H-4⁰),

5.36 (2H, t, J¼10.0 Hz, H-3, H-3 ), 4.28 (2H,₀dd, J¼12.0,

5.0 Hz, H-6, H-6⁰), 4.03–4.12 (4H, m, H-5, H-5 , H-6, H-6⁰),

3.84 (2H, s, ArCH₂), 2.19 (6H, s, 2£OAc), 2.05 (6H, s,

2£OAc), 2.03 (6H, s, 2£OAc), 2.02 (6H, s, 2£OAc); d_C

(62.5 MHz, CDCl₃) 170.9 (2£CvO), 170.3 (4£CvO), 170.1

(2£CvO), 154.6 (2£ArCOSug), 136.2 (2£ArC(CH₂)CAr),

130.2 (4£o-ArC), 116.9 (4£m-ArC), 96.3 (2£CH), 69.8

(2£CH), 69.4 (2£CH), 69.3 (2£CH), 66.3 (2£CH), 62.4

(2£CH₂), 40.6 (CH₂Ar), 21.3 (2£CH₃), 21.2 (2£CH₃), 21.0

(4£CH₃); m/z (CI) 878 (MþNH^þ₄, 49%), 331 (100), 169 (86),

109 (78); Found 878.3101, C₄₁H₅₂O₂₀N requires 878.3082.

vacuo to produce a brown oil. The resulting oil was then

puriﬁed using column chromatography on silica gel (ethyl

acetate/hexane (1:1, v/v)). The relevant fractions were

collected, combined₀and reduced to dryness under reduced

pressure to yield 4,4 -biphenol bis(2,3,4,6-tetra-O-acetyl-a-

D-mannopyranoside) as two rotamer isomers, both as

colourless foams (10a: 0.36 g, 28%, 10b: 0.27 g, 21%).

Data for 10a: [a]_D²⁰¼þ66.64 (c 1.44, CHCl₃); n_max(NaCl,

cm²¹) 3456 (s, ArCH str), 3025 (s, ArCH str), 2963 (s,

ArCH str), 1741 (s, CvO str), 1607 (m, ArCvC–C–O–C

str), 1495 (m, ArCvC str), 1439 (s, as CH₃), 1367 (s, s

CH₃), 1239 (s, CC(vO)–O str), 1215 (s, CC(vO)–O str),

1127 (m, C–O–C str), 1037 (s, C–O–C str), 978 (m,

C–O–C str); d_H(400 MHz, CDCl₃) 7.41 (4H, d, J¼8.5 Hz,

4£o-ArH), 7.08 (4H, d, J¼8.5 Hz, 4£m-ArH), 5.55 (2H, d,

J¼1.5 Hz, H-1, H-1⁰), 5.45 (2H, dd, J¼1.5, 3.5 Hz, H-2,

H-2⁰), 5.41 (2H, dd, J¼3.5, 10.0 Hz, H-3, H-3⁰), 5.24 (2H,

ddd, J¼2.0, 3.5, 10.₀0 Hz, H-4, H-4⁰, 4.25 (2H, dd, J¼5.₀0,

12.0 Hz, H-6, H-6 ), 4.09–4.14 (2H, m, H-5, H-5 ),

4.03–4.08 (2H, m, H-6, H-6⁰), 2.15 (6H, s, 2£OAc), 2.09

(6H, s, 2£OAc), 2.04 (6H, s, 2£OAc), 1.99 (6H, s, 2£OAc);

d_C(100 MHz, CDCl₃) 170.8 (2£CvO), 170.2 (2£CvO),

170.0 (2£CvO), 169.8 (2£CvO), 154.9 (2£ArCOSug),

135.3 (2£ArCCAr), 127.9 (4£o-ArC), 116.8 (4£m-ArC),

96.2 (2£CH), 69.8 (2£CH), 69.2 (2£CH), 68.8 (2£CH),

66.5 (2£CH), 63.0 (2£CH₂), 21.3 (4£CH₃), 21.2 (2£CH₃),

21.1 (2£CH₃); m/z (CI) 864 (MþNH^þ₄, 21%), 331 (100),

169 (47), 109 (28); Found 864.2941, C₄₀H₅₀O₂₀N requires

864.2926.

Data for 10b. [a]_D²⁰¼þ65.82 (c 1.32, CHCl₃); n_max(NaCl,

cm²¹) 3475 (s, ArCH str), 3025 (m, ArCH str), 2956 (m,

ArCH str), 1741 (s, CvO str), 1645 (w, ArCvC–C–O–C

str), 1604 (w, ArCvC–C–O–C str), 1495 (m, ArCvC str),

1432 (m, as CH₃), 1370 (s, s CH₃), 1224 (s, CC(vO)–O

str), 1124 (m, C–O–C str), 1074 (m, C–O–C str), 1043 (s,

C–O–C str), 978 (m, C–O–C str); d_H(400 MHz, CDCl₃)

7.41 (4H, dd, J¼8.5, 19.0 Hz, 4£o-ArH), 6.91 (4H, dd,

J¼8.5, 84.5 Hz, 4£m-ArH), 5.60 (2H, dd, J¼3.5, 10.0 Hz,

H-3, H-3⁰), 5.56 (2H, d, J¼2.0 Hz, H-1, H-1⁰), 5.48 (2H, d₀d,

J¼2.0, 3.5 Hz, H-2, H-2⁰), 5.36–5.42₀(2H, m, H-4, H-4 ),

4.30 (2H,₀dd, J¼5.0, 12.5 Hz, H-6, H-6 ), 4.10–4.16 (4H, m,

H-5, H-5 , H-6, H-6⁰), 2.22 (6H, s, 2£OAc), 2.08 (6H, s,

2£OAc), 2.04 (6H, s, 2£OAc); d_C(100 MHz, CDCl₃) 171.2

(2£CvO), 170.6 (4£CvO), 170.3 (2£CvO), 128.4

(ArCOSug), 128.2 (ArCOSug), 117.1 (ArCCAr), 116.1

(ArCCAr), 96.2 (2£CH), 69.9 (2£CH), 69.5 (2£CH), 69.4

(2£CH), 66.4 (2£CH), 62.5 (2£CH₂), 21.3 (4£CH₃), 21.1

(4£CH₃); m/z (CI) 864 (MþNH^þ₄, 22%), 534 (49), 331 (52),

186 (100); Found 864.2941, C₄₀H₅₀O₂₀N requires

864.2926.

4.1.7. 4,4⁰-Biphenol bis(2,3,4,6-tetra-O-acetyl-a-D-manno-

pyranoside) (10). 4,4⁰-Biphenol (0.2878 g, 1.55 mmol)

and phenyl 2,3,4,6-tetra-O-acetyl-1-seleno-a-^D-manno-

pyranoside (1.810 g, 3.71 mmol) were dissolved in

anhydrous CH₂Cl₂(40 cm³), added to activated molecular

˚

sieves (4 A) and stirred at 08C for 30 min under a nitrogen

atmosphere. To this solution were added N-iodosuccinimide

(0.696 g, 3.09 mmol) and triﬂic acid (catalytic amount), the

reaction mixture was allowed to warm to room temperature

and stirred for 20 min. TLC analysis of the reaction was

performed, using ethyl acetate/hexane (1:1, v/v) as the

solvent system, and showed that the reaction had gone to

completion (starting material R_f0.61, product R_f0.35). The

reaction mixture was diluted with CH₂Cl₂(40 cm³) and

ﬁltered through a pad of Celite^wwith the aid of CH₂Cl₂

(20 cm³). The ﬁltrate was then washed with an aqueous 10%

sodium thiosulfate solution (2£40 cm³) to quench any

unreacted N-iodosuccinimide. The combined organic layers

were then washed with a saturated aqueous sodium

bicarbonate solution (2£40 cm³) and then dried over

magnesium sulfate, ﬁltered and concentrated to dryness in

4.1.8. 1,3-Bis[S-2,3,4,6-tetra-O-acetyl-a-^D-mannopyrano-

syl]propane-1,3-dithiol (11). 1,2,3,4,6-Penta-O-acetyl-a-

D-mannopyranoside (5.790 g, 14.83 mmol) was dissolved in

distilled CH₂Cl₂(40 cm³) and 1,3-propanedithiol (0.74 cm³,

7.42 mmol) was added followed by boron triﬂuoride

etherate (1.88 cm³, 14.83 mmol). The reaction was stirred

at room temperature under an argon atmosphere. The

reaction was followed by TLC analysis, using diethyl ether/

ethyl acetate (1:1, v/v) as the solvent system. After 24 h

saturated sodium bicarbonate solution was added (40 cm³)

and the organic layer extracted with CH₂Cl₂(3£30 cm³).

7990

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

The combined organic layers were dried over magnesium

sulfate, ﬁltered and concentrated to dryness under reduced

pressure. The resulting yellow oil was puriﬁed using column

chromatography on silica gel eluting with diethyl ether/

ethyl acetate (1:1, v/v). The relevant fractions were

collected and combined to give 1,3-bis[S-2,3,4,6-tetra-O-

acetyl-a-D-mannopyranosyl]propane-1,3-dithiol (11) as a

colourless solid (3.57 g, 63%). Mp 77.8 – 79.58C;

[a]²_D⁰¼þ78.06 (c 1.47, CHCl₃); n_max(NaCl, cm²¹) 1742

(s, CvO str), 1432 (w, as CH₃), 1368 (m, s CH₃), 1225 (s,

CC(vO)–O str), 1136 (w, C–C–O str), 1048 (s, C–O–C

str), 976 (w, C–O–C str); d_H(250 MHz, CDCl₃) 5.23–5.30

(2H, m, 2£H-3, 2£H-4), 5.17–5.21 (2H, m, 2£H-1, 2£H-2),

4.25–4.32 (2H, m, 2£H-5, 2£H-6), 4.18–4.423 (1H, m,

2£H-6⁰), 2.65–2.78 (4H, m, H_a), 1.89–1.99 (2H, m,

SCH₂CH₂CH₂S), 2.09 (6H, s, 2£OAc), 2.03 (6H, s,

2£OAc), 1.98 (6H, s, 2£OAc), 1.91 (6H, s, 2£OAc); d_C

(62.5 MHz, CDCl₃) 170.4 (2£CvO), 170.0 (2£CvO),

169.8 (2£CvO), 169.6 (2£CvO), 82.4 (2£CH), 70.4

(2£CH), 69.3 (2£CH), 69.1 (2£CH), 66.2 (2£CH), 62.3

(2£CH₂), 29.8 (2£CH₂S), 28.6 (SCH₂CH₂CH₂S), 20.7

(2£CH₃), 20.6 (4£CH₃), 20.5 (2£CH₃); m/z (CI) 786

(MþNH^þ₄, 30%), 331 (100), 213 (40), 169 (36); Found

786.2333, C₃₁H₄₈O₁₈NS₂requires 786.2313.

with methanol and then added to and stirred with the

reaction mixture for 30 min. The resin was then ﬁltered off

under gravity and the resulting solution concentrated to

dryness in vacuo to yield 1,2-bis[O-a-D-mannopyranosyl]-

ethane-1,2-diol (13) as a colourless oil (0.07 g, 86%) which

was puriﬁed on a G-15 Sephadex size exclusion column.

[a]_D²⁰¼þ27.08 (c 0.07, H₂O), (lit.¹⁸[a]²_D²¼þ76.00 (c 1.00,

H₂O); n_max(NaCl, cm²¹) 3328 (s, O–H str), 2954 (m, O–H

str), 1134 (m, C–O–C str), 1107 (m, C–O–C str), 1056 (s,

C–O–C str); d_H(400 MHz, D₂O) 4.82 (2H, d, J¼1.5 Hz,

H-1, H-1⁰), 3.89 (2H, dd, J¼1.5, 3.5 Hz, H-2, H-2⁰), 3.84

(2H, dd,₀J¼1.5, 12.0 Hz, H-6, H-6⁰), 3.68–3.77 (6H, m,

0

H-3, H-3₀, H-6, H-6 , H_a, H_a), 3.57–3.61 (4H, m, H-4, H-4 ,

0

H-5, H-5 ), 3.49–3.55 (2H, m, H_a, H_a), 1.53–1.65 (4H, m,

0

2£H_b, 2£H_b); d_C(100 MHz, D₂O) 100.0 (2£CH), 73.1

(2£CH), 70.9 (2£CH), 70.4 (2£CH), 67.9 (2£CH₂O), 67.1

(2£CH), 61.2 (2£CH₂), 28.5 (OCH₂CH₂), 25.4

(OCH₂CH₂).

4.1.11. Bis(4-hydroxyphenyl)methane bis(a-^D-manno-

pyranoside) (14). A ﬂask was charged with bis(4-hydroxy-

phenyl)methane

bis(2,3,4,6-tetra-O-acetyl-a-D-

mannopyranoside) (9) (0.50 g, 0.58 mmol) dissolved in

anhydrous methanol (20 cm³). To this solution a catalytic

amount of anhydrous potassium carbonate (0.006 g,

0.06 mmol) was added and the reaction mixture was stirred

at room temperature under a nitrogen atmosphere. TLC

analysis using ethyl acetate/hexane (1:1, v/v), showed that

after 4 h the reaction had gone to completion (starting

material R_f0.32, product R_f0.00). Amberlite IR-120

(PLUS) ion-exchange resin was washed with methanol

and then added to and stirred with the reaction mixture for

30 min. The resin was then ﬁltered off under gravity and the

resulting solution concentrated to dryness in vacuo to yield

bis(4-hydroxyphenyl)methane bis(a-D-mannopyranoside)

(14) as a colourless foam (0.25 g, 83%) which was not

puriﬁed further. n_max(KBr, cm²¹) 3256 (s, ArCH str), 2920

(m, ArCH str), 2835 (m, O–H str), 1545 (m, ArCvC–O–C

str), 1056 (s, C–O–C str), 1022 (s, C–O–C str), 970 (s,

C–O–C str); d_H(400 MHz, D₂O) 7.18 (4H, d, J¼8.5 Hz,

4£o-ArH), 7.08 (4H, d, J¼8.5 Hz, 4£m-ArH), 5.52 (2H, s,

H-1, H-1⁰), 4.08 (2H, br s, H-2, H-2⁰), 3.89 (2H, dd, ₀J¼5.0,

12.0 Hz, H-6, ₀H-6⁰), 3.67–3.85 (6H, m, H-3, H-3 , H-4,

H-4⁰, H-6, H-6 ), 3.58–3.65 (2H, m, H-5, H-5⁰), 2.71–2.76

(2H, m, ArCH₂Ar); d_C(100 MHz, D₂O) 154.5 (2£

ArCOSug), 135.0 (2£ArC(CH₂)CAr), 129.7 (4£o-ArCH),

116.8 (4£m-ArCH), 99.8 (2£CH), 74.2 (2£CH), 72.2

(2£CH), 71.2 (2£CH), 66.8 (2£CH), 60.5 (2£CH₂), 38.7

(ArCH₂Ar).

4.1.9. 1,2-Bis[O-a-^D-mannopyranosyl]ethane-1,2-diol

(12). A ﬂask was charged with 1,2-bis[O-2,3,4,6-tetra-O-

acetyl-a-D-mannopyranosyl]ethane-1,2-diol (1) (0.367 g,

0.51 mmol) dissolved in anhydrous methanol (15 cm³). To

this solution a catalytic amount of anhydrous potassium

carbonate (0.007 g, 0.05 mmol) was added and the reaction

mixture was stirred at room temperature under a nitrogen

atmosphere. TLC analysis using ethyl acetate/hexane (1:1,

v/v), showed that after 3 h the reaction had gone to

completion (starting material R_f0.36, product R_f0.00).

Amberlite IR-120 (PLUS) ion-exchange resin was washed

with methanol and then added to and stirred with the

reaction mixture for 30 min. The resin was then ﬁltered off

under gravity and the resulting solution concentrated to

dryness in vacuo to yield 1,2-bis[O-a-D-mannopyranosyl]-

ethane-1,2-diol (12) as a colourless oil (0.18 g, 94%) which

was puriﬁed on a G-15 Sephadex size exclusion column.

[a]²_D⁵¼þ18.95 (c 0.01, H₂O); n_max(NaCl, cm²¹) 3362 (s,

O–H str), 2926 (m, O–H str), 1454 (w, as CH₃), 1373 (m, s

CH₃), 1132 (m, C–O–C str), 1094 (m, C–O–C str), 1054

(s, C–O–C str), 1033 (s, C–O–C str); d_H(400 MHz, D₂O)

4.51 (2H, d, J¼1.5 Hz, H-1, H-1⁰), 3.57–3.98 (10H, m, H-5,

H-5⁰, 2£H-6, 2£H-6⁰, 2£CH₂O), 3.37–3.50 (4H, m, H-3,

H-3⁰, H-4, H-4⁰), 3.30 (2H, t, J¼1.5 Hz, H-2, H-2⁰); d_C

(100 MHz, D₂O) 84.6 (2£CH), 72.2 (2£CH), 70.0 (2£CH),

69.5 (2£CH), 68.0 (2£CH₂), 66.2 (2£CH), 60.0 (2£CH₂O).

4.1.12. 1,3-Bis[S-a-^D-mannopyranosyl]propane-1,3-

dithiol (15). A ﬂask was charged with 1,3-bis[S-2,3,4,6-

tetra-O-acetyl-a-D-mannopyranosyl]propane-1,3-dithiol

(11) (0.411 g, 0.53 mmol) dissolved in anhydrous methanol

(15 cm³). To this solution a catalytic amount of anhydrous

potassium carbonate (0.007 g, 0.05 mmol) was added and

the reaction mixture was stirred at room temperature under a

nitrogen atmosphere. TLC analysis using ethyl acetate/

hexane (1:1, v/v), showed that after 3 h the reaction had

gone to completion (starting material R_f0.41, product R_f

0.00). Amberlite IR-120 (PLUS) ion-exchange resin was

washed with methanol and then added to and stirred with the

reaction mixture for 30 min. The resin was then ﬁltered off

4.1.10. 1,4-Bis[O-a-^D-mannopyranosyl]butane-1,4-diol

(13). A ﬂask was charged with 1,4-bis[O-2,3,4,6-tetra-O-

acetyl-a-D-mannopyranosyl]butane-1,4-diol (7) (0.147 g,

0.20 mmol) dissolved in anhydrous methanol (15 cm³). To

this solution a catalytic amount of anhydrous potassium

carbonate (0.002 g, 0.02 mmol) was added and the reaction

mixture was stirred at room temperature under a nitrogen

atmosphere. TLC analysis using ethyl acetate/hexane (1:1,

v/v), showed that after 3 h the reaction had gone to

completion (starting material R_f0.36, product R_f0.00).

Amberlite IR-120 (PLUS) ion-exchange resin was washed

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

7991

under gravity and the resulting solution concentrated to

dryness in vacuo to yield 1,3-bis[S-a-D-mannopyranosyl]-

propane-1,3-dithiol (15) as a colourless oil (0.21 g, 89%)

which was puriﬁed on a G-15 Sephadex size exclusion

2895 (s, O–H str), 1664 (m, N–H bend), 1466 (s, as CH₃),

1248 (s, s CH₃), 1162 (s, C–O–C str), 967 (s, C–O–C str),

700 (m, N–H wagging); d_H(400 MHz, D₂O) 4.09 (1H, s,

H-1), 4.00 (1H, s, H-1⁰), 3.61–3.69 (4H, m, H-2, H-2⁰, H-6,

H-6⁰), 3.46 (2H, dd, J¼6.5, 11.5 Hz, H-6, H-6⁰), 3.38 (2H,

dd, J¼3.5, 10.0 Hz, H-3, H-3⁰), 3.29 (2H, t, J¼10.0 Hz, H-4,

H-4⁰), 3.07–3.10 (2H, m, H-5, H-5⁰), 2.78 (1H, q, J¼4.5,

12.5 Hz, H_bor CHMeN), 2.60 (1H, dd, J¼4.5, 12.5 Hz, H_a

or CH₂N), 2.49 (1H, dd, J¼9.0, 12.5 Hz, H_aor CH₂N), 0.81

(3H, dd, J¼6.5, 9.0 Hz, CH₃); d_C(100 MHz, D₂O) 89.3

(CH), 86.6 (CH), 79.9 (2£CH), 76.6 (2£CH), 74.0 (2£CH),

69.9 (2£CH), 63.9 (2£CH₂), 55.2 (CH₂N), 48.8 (CHMeN),

column. [a]²_D⁰¼þ38.25 (c 1.47, H₂O); n_max(NaCl, cm²¹

)

3334 (s, O–H str), 2928 (m, O–H str), 1137 (m, C–O–C

str), 1093 (m, C–O–C str), 1052 (s, C–O–C str); d_H

(400 MHz, D₂O) 4.97 (2H, d, J¼1.0 Hz, H-1, H-1⁰), 3.72

(2H, dd, J¼1.5, 3.0 Hz, H-2, H-2⁰), 3.63–3.67 (2H, m, H-5,

H-5⁰), 3.54 (2H, dd, J¼2.5 Hz, 12.5 Hz, H-6, H-6⁰), 3.43–

3.49 (4H, ₀m, H-4, H-4⁰, H-6, H-6⁰), 3.34 (2H, t, J¼10.0 Hz,

H-3, H-3 ), 2.38–2.54 (4H, m, SCH₂), 1.65 (2H, q,

J¼7.0 Hz, SCH₂CH₂CH₂S); d_C(100 MHz, D₂O) 85.1

(2£CH), 73.5 (2£CH), 72.6 (2£CH), 72.1 (2£CH), 71.4

(2£CH), 67.3 (2£CH), 61.1 (2£CH₂), 29.9 (2£SCH₂), 28.8

(SCH₂CH₂CH₂S).

1

20.4 (CH₃); J[¹³CH(1)]¼165 Hz; m/z (ES^þ) 399 (MþH^þ,

100%); Found 399.1970, C₁₅H₃₁O₁₀N₂requires 399.1980.

4.1.15. N,N⁰-Di-a-D-mannopyranosyl 1,3-propane-

diamine (18). 1,3-Propanediamine (0.57 cm³, 6.48 mmol),

was dissolved in anhydrous methanol (10 cm³) and the

mixture stirred at room temperature. To this was added

D-(þ)-mannose (2.10 g, 11.66 mmol) and the resulting

solution stirred under a nitrogen atmosphere. After 5 min

the ^D-(þ)-mannose dissolved and after 4 h a colourless solid

precipitated from the solution. After 6 h a colourless

precipitate had formed in the reaction mixture. The reaction

mixture was stored for 24 h at 48C, and then the precipitate

was ﬁltered off, washed with ice-cold methanol and then

dried in vacuo (using a drying piston) for 48 h at 40 8C. This

yielded N,N⁰-di-a-D-mannopyranosyl 1,3-propanediamine

(18) as a colourless powder (1.76 g, 68%). Mp 134.7–

4.1.13. N,N⁰-Di-a-D-mannopyranosyl ethylenediamine

(16). Ethylenediamine (0.39 cm³, 6.48 mmol), was dis-

solved in anhydrous methanol (7 cm³) and the mixture

heated to 508C. To this was added ^D-(þ)-mannose (2.10 g,

11.66 mmol) and the resulting solution stirred under a

nitrogen atmosphere at 508C. After 5 min the ^D-(þ)-

mannose dissolved and after 1 h a colourless solid

precipitated from the solution. Another aliquot of anhydrous

methanol (7 cm³) was added in order to ensure complete

dissolution of the reaction mixture. After 3 h a colourless

precipitate had formed in the reaction mixture. The reaction

mixture was stored for 24 h at 48C, and then the precipitate

was ﬁltered off, washed with ice-cold methanol and then

dried in vacuo (using a drying piston) for 48 h at 408C. This

yielded N,N⁰-di-a-D-mannopyranosyl ethylenediamine (16)

as a colourless powder (1.77 g, 77%). Mp 152.8–153.48C;

[a]²_D⁰¼210.74 (c 3.55, H₂O); n_max(KBr, cm²¹) 3510 (s, as

N–H str), 3311 (s, s N–H str), 2931 (s, O–H str), 2885 (s,

O–H str), 2841 (s, O–H str), 1618 (m, N–H bend), 1136 (s,

C–O–C str), 995 (s, C–O–C str), 696 (s, ₀N–H wagging);

d_H(400 MHz, D₂O) 4.03 (2H, s, H-1, H-1 ), 3.71 (2H, dd,

J¼2.5, 12.0 Hz, H-6, H-6⁰), 3.68 (2H, d, J¼3.5 Hz, H-2, H-2⁰),

3.49 (2H, dd, J¼6.5, 12.0 Hz, H-6, H-6⁰), 3.42 (2H, dd, J¼3.5,

9.5 Hz, H-3, H-3⁰), 3.32 (2H, t, J¼9.5 Hz, H-4, H-4⁰), 3.10–

3.14 (2H, m, H-5, H-5⁰), 2.61–2.81 (4H, m, 2£H_a, 2£H_b); d_C

(100 MHz, D₂O) 89.5 (2£CH), 80.0 (2£CH), 76.6 (2£CH),

73.6 (2£CH), 69.9 (2£CH), 64.0 (2£CH₂), 47.1 (2£CH₂);

¹J[¹³CH(1)]¼166 Hz; m/z (FAB) 385 (MþH^þ, 22%); Found

385.1832, C₁₄H₂₉O₁₀N₂requires 385.1822.

135.68C; [a]²_D⁰¼229.39 (c 0.40, H₂O); n_max(KBr, cm²¹

)

3374 (s, s N–H str), 2929 (s, O–H str), 1654 (w, N–H

bend), 697 (m, N–H wagging); d_H(400 MHz, D₂O) 3.87

(2H, s, H-1, H-1⁰), 3.56 (2H, dd, J¼2.0, 12.0 Hz, H-6, H-6⁰),

3.49–3.52 (2H, m, H-2, H-2⁰), 3.33–3.42 (2H, m, H-6,

H-6⁰), 3.28 (2H, dd, J¼₀3.5, 10.0 Hz, H-3, H-3⁰), 3.18 (2H,₀t,

J¼10.0 Hz, H-4, H-4 ), 2.97–2.99 (2H, m, H-5, H-5 ),

2.77–2.81 (2H, m, 2£H_aor CH₂N), 2.39–2.47 (2H, m, 2£H_a

or CH₂N), 1.15–1.19 (2H, m, 2£H_bor NCH₂CH₂CH₂N); d_C

(100 MHz, D₂O) 89.2 (2£CH), 79.9 (2£CH), 76.6 (2£CH),

73.8 (2£CH), 69.9 (2£CH), 63.9 (2£CH₂), 46.9 (2£CH₂N),

28.5(NCH₂CH₂CH₂N); ¹J[¹³CH(1)]¼ 166 Hz; m/z (ES^þ) 399

(MþH^þ, 100%); Found 399.1971, C₁₅H₃₁O₁₀N₂requires

399.1980; Found: C, 43.58; H, 7.69; N, 6.46. Calc. for

C₁₅H₃₀O₁₀N₂(M_r398.19): C, 43.27; H, 7.70; N, 6.73%.

4.1.16. N,N⁰-Di-a-D-mannopyranosyl 1,4-butanediamine

(19). 1,4-Butanediamine (0.65 cm³, 6.48 mmol), was

dissolved in anhydrous methanol (20 cm³) and the mixture

stirred at room temperature. To this was added ^D-(þ)-

mannose (2.10 g, 11.66 mmol) and the resulting solution

stirred under a nitrogen atmosphere. After 30 min the

D-(þ)-mannose dissolved e and after 5 h a colourless solid

precipitated from the solution. After 8 h a colourless

precipitate had formed in the reaction mixture. The reaction

mixture was stored for 24 h at 48C, and then the precipitate

was ﬁltered off, washed with ice-cold methanol and then

dried in vacuo (using a drying piston) for 48 h at 408C. This

yielded N,N⁰-di-a-D-mannopyranosyl 1,4-butanediamine

(19) as an off-white powder (1.30 g, 53%). Mp 125.7–

4.1.14. N,N⁰-Di-a-D-mannopyranosyl 1,2-propane-

diamine (17). 1,2-Propanediamine (0.54 cm³, 6.48 mmol),

was dissolved in anhydrous methanol (10 cm³) and the

mixture stirred at room temperature. To this was added

D-(þ)-mannose (2.10 g, 11.66 mmol) and the resulting

solution stirred under a nitrogen atmosphere. After 5 min

the ^D-(þ)-mannose dissolved and after 4.5 h a colourless

solid precipitated from the solution. After 7 h a colourless

precipitate had formed in the reaction mixture. The reaction

mixture was stored for 24 h at 48C, and then the precipitate

was ﬁltered off, washed with ice-cold methanol and then

dried in vacuo (using a drying piston) for 48 h at 40 8C. This

yielded N,N⁰-di-a-D-mannopyranosyl 1,2-propanediamine

(17) as a colourless powder (1.66 g, 64%). Mp 138.1–

127.28C; [a]²_D⁰¼229.97 (c 1.00, H₂O); n_max(KBr, cm²¹

)

3303 (s, s N–H str), 2918 (m, O–H str), 2864 (m, O–H str),

1650 (w, N–H bend), 687 (m, N–H wagging); d_H

(400 MHz, D₂O) 4.24 (2H, s, H-1, H-1⁰), 3.94 (2H, dd,

139.38C; [a]²_D⁰¼221.06 (c 0.93, H₂O); n_max(KBr, cm²¹

)

3331 (s, s N–H str), 2952 (s, O–H str), 2921 (s, O–H str),

7992

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

J¼2.0, 12.0 Hz, H-6, H-6⁰), 3.89 (2H, d, J¼3.0 Hz, H-2,

H-2⁰), 3.73 (2H, dd, J¼6.5, 12.0 Hz, H-6, H-6⁰), 3.66 (2H,

dd, J¼3.0, 10.0 Hz, H-3, H-3⁰), 3.55 (₀2H, t, J¼10.0 Hz, H-4,

H-4⁰), 3.34–3.38 (2H, m, H-5, H-5 ), 2.95–2.97 (2H, m,

CH₂N or H_a), 2.68–2.71 (2H, m, CH₂N or H_a), 1.54–1.55

(4H, m, 2£CH₂CH₂N or NCH₂CH₂CH₂CH₂N or 4£H_b); d_C

(100 MHz, D₂O) 89.3 (2£CH), 80.0 (2£CH), 76.6 (2£CH),

73.7 (2£CH), 69.7 (2£CH), 63.9 (2£CH₂), 47.2 (2£CH₂N),

(0.071 g, 47.6 mmol) was dissolved in anhydrous methanol

(10 cm³) and the mixture stirred at room temperature. To

this was added freshly distilled triethylamine (0.08 cm³,

0.57 mmol) and the resulting solution stirred under a

nitrogen atmosphere for 30 min. ^D-(þ)-Mannose (0.103 g,

0.57 mmol) was added to the reaction mixture. After 30 min

the ^D-(þ)-mannose dissolved and after 8 h a colourless solid

precipitated from the solution. After 16 h a white precipitate

had formed in the reaction mixture. The reaction mixture

was stored for 24 h at 48C, and then the precipitate was

ﬁltered off, washed with ice-cold methanol and then dried in

vacuo (using a drying piston) for 48 h at 408C. This yielded

the desired mannose-based dendrimer (22) as an off-white

powder (0.05 g, 56%). Mp 179.0–181.18C; [a]²_D⁰¼250.00

(c 0.01, H₂O); n_max(KBr, cm²¹) 3323 (s, s N–H str), 3238

(s, ArCH str), 2955 (m, ArCH str), 2854 (m, O–H str), 1650

(m, N–H bend), 1640 (s, CvO str), 1558 (m, N–H bend

and C–N str), 1543 (m, ArCvC–O–C str), 1199 (w, N–H

bend, C–N str), 1054 (s, C–O–C str), 1023 (s, C–O–C str),

970 (s, C–O–C str), 798 (s, N–H wagging); d_H(400 MHz,

D₂O) 7.48–7.65 (12H, m, ArCH), 5.27 (3H, s, CH(CH₂)₂),

4.03 (6H, dd, J¼1.5, 3.5 Hz, 6£H-2), 3.98 (6H, d,

J¼1.5 Hz, 6£H-1,), 3.94 (6H, dd, J¼3.5, 10.0 Hz,

6£H-3), 3.73–3.92 (18H, m, 3£CH(CH₂NH)₂,6£H-6),

3.83 (6H, dd, J¼6.0, 11.5 Hz, 6£H-6), 3.67 (6H, t,

J¼10.0 Hz, 6£H-4), 3.56–3.61 (6H, m, C(O)NHCH₂),

3.45–3.50 (6H, m, 6£H-5), 2.84–2.93 (6H, m,

C(O)NHCH₂CH₂N); d_C(100 MHz, D₂O) 169.6

(3£CvO), 169.3 (3£CvO), 136.4 (3£ArC), 136.2

(3£ArC), 127.5 (12£ArCH), 94.3 (3£CH(CH₂NH)₂), 77.5

(6£CH), 73.3 (6£CH), 71.5 (6£CH), 71.0 (6£CH), 67.1

(3£(CH(CH₂NH)₂), 66.9 (6£CH), 61.3 (6£CH₂), 54.2

(3£C(O)NHCH₂), 38.0 (3£C(O)NHCH₂CH₂N).

1

29.3 (2£CH₂CH₂N); J[¹³CH(1)]¼165 Hz; m/z (FAB) 413

(MþH^þ, 87%); Found 413.2134, C₁₆H₃₃O₁₀N₂requires

413.2135; Found: C, 46.56; H, 7.98; N, 6.55. Calc. for

C₁₆H₃₂O₁₀N₂(M_r412.21): C, 46.60; H, 7.82; N, 6.79%.

4.1.17. Tris{N,N-a-^D-mannopyranosyl-2-aminoethyl}-

(2.69 cm³,

amine

(20).

Tris(2-aminoethyl)amine

17.97 mmol), was dissolved in anhydrous methanol

(20 cm³) and the mixture stirred at room temperature. To

this was added ^D-(þ)-mannose (2.160 g, 11.99 mmol) and

the resulting solution stirred under a nitrogen atmosphere.

After 30 min the ^D-(þ)-mannose dissolved and after 16 h

the reaction mixture was stored for 24 h at 48C, the reaction

mixture was concentrated in vacuo to dryness, and then the

resulting oil was dried in vacuo (using a drying piston) for

48 h at 408C. This yielded tris{N,N-a-D-mannopyranosyl-2-

aminoethyl}amine (20) as a yellow oil (6.37 g, 56%). [a]²_D⁰¼

221.88 (c 0.16, H₂O); n_max(KBr, cm²¹) 3248 (m, s N–H str),

3034 (m, O–H str), 2951 (w, O–H str), 1661 (w, N–H bend),

695 (s, N–H wagging); d_H(400 MHz, D₂O) 3.96 (3H, s, H-1,

H-1⁰, H-1⁰⁰), 3.66 (3H, d, J¼12.0 Hz, H-6, H-6⁰, H-6⁰⁰), 3.60

(3H, d, J¼3.0 Hz, H-2₀,₀H-2⁰, H-2⁰⁰), 3.44 (3H, dd, J¼3.0,

10.0 Hz, H-3, H-3⁰, H-3 ), 3.26 (3H, t,₀J¼10.0 Hz, H-4, H-4⁰,

H-4⁰⁰), 3.04–3.09 (3H, m, H-5, H-5 , H-5⁰⁰), 2.46 (6H, t,

J¼6.5 Hz, 3£CH₂N), 2.30 (6H, t, J¼6.5 Hz, N(CH₂)₃); d_C

(100 MHz, D₂O) 88.1 (CH), 78.9 (CH), 75.4 (CH), 72.6 (CH),

68.7 (CH), 62.7 (CH), 57.7 (3£CH₂N), 39.3 (N(CH₂)₃).

4.1.20. 1,2-Bis[O-a-^D-mannopyranosyl] ethane-1-

hydroxy-2⁰-amine (23). 2⁰-Aminoethyl-O-a-D-manno-

pyranoside (31) (0.17 g, 0.81 mmol), was dissolved in

anhydrous methanol (10 cm³) and the mixture stirred at

room temperature. To this was added ^D-(þ)-mannose

(0.29 g, 1.62 mmol) and the resulting solution stirred

under a nitrogen atmosphere. After 30 min the ^D-(þ)-

mannose dissolved and after 4 h the reaction mixture was

stored for 24 h at 48C, the reaction mixture was concentrated

in vacuo to dryness, and then the resulting foam was dried

in vacuo (using a drying piston) for 48 h at 408C.

This yielded 1,2-bis[O-a-D-mannopyranosyl] ethane-1-

hydroxy-2⁰-amine (23) as a colourless foam (0.13 g, 43%).

[a]²_D⁰¼þ35.95 (c 0.19, H₂O); n_max(KBr, cm²¹) 3328 (s, s

N–H str), 3258 (s, O–H str), 2928 (s, O–H str), 1657 (m,

N–H bend), 702 (m, N–H wagging); d_H(400 MHz, D₂O)

4.94 (1H, s,₀H-1), 4.04 (1H, d, J¼1.5 Hz, H-2⁰₀), 3.80–3.98

(7H, m, H-1 , H-2, H-3⁰, CH₂O, H-4⁰, H-5, H-6 ), 3.61–3.73

(7H, m, H-3, CH₂O, H-4, H-5⁰, H-6⁰, 2£H-6), 2.90–3.01

(2H, m, CH₂N); d_C(100 MHz, D₂O) 100.2 (CH), 74.2 (CH),

73.1 (CH), 71.4 (CH), 70.9 (CH), 70.8 (CH), 70.3 (CH),

68.0 (CH₂O), 67.5 (CH), 67.4 (CH), 67.1 (CH), 61.3

(2£CH₂), 47.6 (CH₂N); Found: C, 40.08; H, 7.51; N, 3.30.

Calc. for C₁₄H₂₇O₁₁N.2 H₂O (M_r421.18): C, 39.90; H, 7.41;

N, 3.32%; m/z (ES^þ) 386.2 (MþH^þ, 100%).

4.1.18. Pentaerythrityl tetra{N,N-a-^D-manno-

pyranosyl}amine (21). Pentaerythrityl tetraamine (29)

(0.087 g, 0.66 mmol), was dissolved in anhydrous methanol

(10 cm³) and the mixture stirred at room temperature. To

this was added ^D-(þ)-mannose (0.472 g, 2.62 mmol) and

the resulting solution stirred under a nitrogen atmosphere.

After 30 min the ^D-(þ)-mannose dissolved and after 3.5 h a

colourless solid precipitated from the solution. After 6 h a

colourless precipitate had formed in the reaction mixture.

The reaction mixture was stored for 24 h at 48C, and then the

precipitate was ﬁltered off, washed with ice-cold methanol

and then dried in vacuo (using a drying piston) for 48 h at

408C. This yielded pentaerythrityl tetra{N,N-a-D-manno-

pyranosyl}amine (21) as a colourless solid (0.24 g, 47%).

Mp 60.3–61.88C; n_max(KBr, cm²¹) 3254 (m, s N–H str),

2934 (w, O–H str), 2851 (w, O–H str), 1665 (w, N–H

bend), 702 (s, N–H wagging); d_H(400 MHz, D₂O) 3.59–

3.76 (8H, m, H-1, H-1⁰, H-1⁰⁰,₀H-1⁰⁰⁰, H-2,₀H₀₀-2⁰, H-2⁰⁰,₀H-2⁰⁰⁰),

3.44–3.56 (20H, m, H-3, H-₀3₀₀, H-3⁰⁰, H-3 , H-4, H-4 , H-₀₀₀4⁰⁰,

H-4⁰⁰⁰, H-5, H-5⁰, H-5⁰⁰, H-5 , 2£(H-6, H-6⁰, H-6⁰⁰, H-6 )),

2.37–2.55 (8H, m, 4£CH₂); d_C(100 MHz, D₂O) 71.4

(4£CH), 71.0 (4£CH), 69.9 (4£CH), 69.5 (4£CH), 69.2

(4£CH), 63.6 (4£CH₂), 51.9 (CCH₂), 51.8 (CCH₂), 49.2

(C(CH₂)₄), 47.4 (2£CCH₂).

4.1.21. 1,3-Bis[O-a-^D-ma₀nnopyranosyl] propane-1-

hydroxy-3⁰-amine (24). 3 -Aminopropyl-O-a-D-manno-

pyranoside (32) (0.42 g, 1.77 mmol), was dissolved in

4.1.19. Mannopyranoside based hexavalent glyco-

dendrimer (22). The hexafunctional dendrimer core¹⁴

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

7993

anhydrous methanol (20 cm³) and the mixture stirred at

room temperature. To this was added ^D-(þ)-mannose

(0.64 g, 3.54 mmol) and the resulting solution stirred

under a nitrogen atmosphere. After 30 min the ^D-(þ)-

mannose dissolved and after 4 h the reaction mixture was

stored for 24 h at 48C, the reaction mixture was then

concentrated in vacuo to dryness, and then the resulting

foam was dried in vacuo (using a drying piston) for 48 h at

408C. This yielded 1,3-bis[O-a-D-mannopyranosyl] pro-

pane-1-hydroxy-3⁰-amine (24) as a colourless foam (0.27 g,

38%). [a]²_D⁰¼þ6.53 (c 0.38, H₂O); n_max(KBr, cm²¹) 3320

(s, s N–H str), 3264 (s, O–H str), 2954 (s, O–H str), 1653

(m, N–H bend), 699 (m, N–H wagging); d_H(400 MHz,

D₂O) 4.93 (1H, s, H-1), 3.49–3.95 (11H, m, H-2, H-3, H-4,

H-5, 2£H-6, H-1⁰, H-2⁰, H-3⁰, H-4⁰, CH₂O), 3.26–3.43 (4H,

m, H-5⁰, 2£H-6⁰, CH₂O), 2.50–2.60 (2H, m, CH₂N), 1.58–

1.62 (2H, m, OCH₂CH₂CH₂N); d_C(100 MHz, D₂O) 94.3

(CH), 94.0 (CH), 76.4 (CH), 73.3 (CH), 72.6 (CH), 71.5

(CH), 71.0 (CH), 70.5 (CH), 67.1 (CH), 66.9 (CH), 65.8

(CH₂O), 61.3(2£CH₂),46.0(CH₂N), 27.7(OCH₂CH₂CH₂N);

m/z (ES^þ) 400.2 (MþH^þ, 20%).

4.1.22. N,N⁰-Di-[3-O-a-D-mannopyranosyl-D-mannose]

ethylenediamine (25). Ethylenediamine (0.02 cm³,

0.32 mmol), was dissolved in anhydrous methanol

(10 cm³) and the mixture stirred at room temperature. To

this was added 3-O-a-^D-mannopyranosyl-D-mannose

(0.198 g, 0.52 mmol) and the resulting solution stirred

under a nitrogen atmosphere. After 5 min the 3-O-a-^D-

mannopyranosyl-^D-mannose dissolved and after 3 h a

colourless solid precipitated from the solution. After 8 h a

colourless precipitate had formed in the reaction mixture.

The reaction mixture was stored for 24 h at 48C, and then the

precipitate was ﬁltered off, washed with ice-cold methanol

and then dried in vacuo (using a drying piston) for 48 h at

408C. This yielded N,N⁰-di-[3-O-a-D-mannopyranosyl-D-

mannose]ethylenediamine (25) as a colourless powder

(0.09 g, 43%). [a]²_D⁰¼þ16.78 (c 0.10, H₂O), m.p. 99.0–

101.1 8C; n_max(KBr, cm²¹) 3318 (s, s N–H str), 3198 (s,

O–H str), 2918 (s, O–H str), 1655 (m, N–H bend), 698 (m,

N–H wagging); d_H(400 MHz, D₂O) 4.95 (2H, 2£H-1),

4.03–4.06 (2H, m, 2£H-1⁰), 3.83–3.89 (4H, m, 2£H-2,

2£H-2⁰), 3.65–3.73 (6H, m, 2£H-3, 2₀£H-4⁰, 2£H-6), 3.55–

3.61 (6H, m, 2£H-3⁰, 2£H-4, 2£H-6 ), 3.34–3.50 (4H, m,

2£H-5, 2£H-5⁰), 2.47–2.90 (4H, m, 2£NCH₂); d_C

(100 MHz, D₂O) 102.5 (2£CH), 87.3 (2£CH), 81.5

(2£CH), 77.4 (2£CH), 73.6 (2£CH), 71.1 (2£CH), 70.7

(2£CH), 70.3 (2£CH), 67.0 (2£CH), 66.9 (2£CH), 61.2

(4£CH₂), 41.1 (2£NCH₂).

40 8C. This yielded N,N⁰-di-[2-O-a-D-mannopyranosyl-D-

mannose]ethylenediamine (26) as a colourless powder

(0.06 g, 39%). Mp 91.2–92.88C; [a]²_D⁰¼þ26.40 (c 0.12,

H₂O); n_max(KBr, cm²¹) 3324 (s, s N–H str), 3198 (s, O–H

str), 2856 (s, O–H str), 1655 (m, N–H bend), 701 (m, N–H

wagging); d_H(400 MHz, D₂O) 5.13 (2H, d, J¼1.5 Hz, 2£H-

1⁰), 4.16 (2H, dd, J¼2.0, 3.0 Hz, 2£H-2⁰), 4.04–4.07 (2H,

m, 2£H-3⁰), 4.03 (2H, s, 2£H-1), ₀3.71–4.01 (18H, ₀m, 2£H-

2, 2£H-3, 2£H-4, 4£H-6, 2£H-4 , 2£H-5⁰, 4£H-6 ), 3.60–

3.70 (2H, m, 2£H-5), 2.52–2.64 (2£(NCH₂)₂); d_C

(100 MHz, D₂O) 93.2 (2£CH), 79.6 (2£CH), 73.6

(2£CH), 72.8 (2£CH), 71.6 (2£CH), 70.7 (2£CH), 70.4

(2£CH), 70.0 (2£CH), 67.4 (2£CH), 67.1 (2£CH), 61.3

(2£CH₂), 61.1 (2£CH₂), 33.0 (NCH₂), 32.4 (NCH₂).

4.1.24. General method for the preparation of a-1,3- and

a-1,2-mannobioside based hexavalent glycodendrimers

(27 and 28). The hexavalent dendrimer core¹⁴(1 equiv.)

was dissolved in anhydrous methanol (5 cm³) and the

mixture stirred at room temperature. To this was added

freshly distilled triethylamine (12 equiv.) and the resulting

solution stirred under a nitrogen atmosphere for 30 min.

a-1,3- or a-1,2-Mannobioside (12 equiv.) was added to the

reaction mixture, after 2 h the mannobiosides dissolved and

after 8 h a colourless solid precipitated out of the solution.

After 16 h a colourless precipitate had formed in the

reaction mixture. The reaction mixture was stored for 24 h

at 48C, and then the precipitate was ﬁltered off, washed with

ice-cold methanol and then dried in vacuo (using a drying

piston) for 48 h at 408C. This yielded both the a-1,2- and

a-1,3-mannobioside-based dendrimers (27 and 28) as

off-white powders.

According to the above procedure the hexavalent dendrimer

core¹⁴(0.090 g, 60.10 mmol) was treated with triethylamine

(0.10 cm³, 0.72 mmol), and then 3-O-a-D-mannopyranosyl-

D-mannose was added (0.247 g, 0.72 mmol) to yield

compound (27) as a colourless solid (0.06 g, 37%). Mp

166.8–168.0 8C; [a]²_D⁰¼þ16.75 (c 0.21, H₂O); n_max(KBr,

cm²¹) 3310 (s, s N–H str), 3254 (s, ArCH str), 2938 (m,

ArCH str), 2849 (m, O–H str), 1652 (s, N–H bend), 1642 (s,

CvO str), 1553 (m, N–H bend and C–N str), 1541 (m,

ArCvC–O–C str), 1204 (w, N–H bend, C–N str), 1053 (s,

C–O–C str), 1017 (s, C–O–C str), 980 (s, C–O–C str),

799 (s, N–H wagging); d_H(400 MHz, D₂O) 7.15–7.26

(12H, m, ArCH), 4.85 (3H, s, CH(CH₂)₂), 4.84 (6H, d,

J¼1.5 Hz, 6£H-1⁰), 3.77 (6H, dd, J¼1.5, 3.5 Hz, 6£H-2⁰),

3.65 (6H, dd, J¼3.5, 10.0 Hz, 6£H-3⁰), 3.31–3.62 (72H, m,

6£H-1, 6£H-2, 6£H-3, 6£H-4, 12£H-6, 6£H-4⁰, 6£H-5⁰,

12£H-6⁰, 3£CH(CH₂NH)₂), 3.22–3.29 (6H, m,

C(O)NHCH₂), 3.08–3.14 (6H, m, 6£H-5), 2.52–2.57 (6H,

m, C(O)NHCH₂CH₂N); d_C(100 MHz, D₂O) 170.1

(6£CvO), 138.0 (3£ArC), 136.5 (3£ArC), 127.6

(12£ArCH), 102.7 (6£CH), 94.5 (3£CH(CH₂NH)₂), 78.3

(6£CH), 76.3 (6£CH), 73.7 (6£CH), 72.8 (6£CH), 70.8

(6£CH), 70.7 (6£CH), 70.4 (6£CH), 67.1 (3£CH(CH₂NH)₂),

66.6 (6£CH), 66.4 (6£CH), 61.3 (6£CH₂), 61.2 (6£CH₂),

53.5 (3£C(O)NHCH₂), 37.1 (3£C(O)NHCH₂CH₂N).

4.1.23. N,N⁰-Di-[2-O-a-D-mannopyranosyl-D-mannose]

ethylenediamine (26). Ethylenediamine (0.01 cm³,

0.20 mmol), was dissolved in anhydrous methanol

(10 cm³) and the mixture stirred at room temperature. To

this was added 2-O-a-^D-mannopyranosyl-D-mannose

(0.125 g, 0.36 mmol) and the resulting solution stirred

under a nitrogen atmosphere. After 5 min the 2-O-a-^D-

mannopyranosyl-^D-mannose dissolved and after 3 h a

colourless solid precipitated from the solution. After 8 h a

colourless precipitate had formed in the reaction mixture.

The reaction mixture was stored for 24 h at 48C, and then the

precipitate was ﬁltered off, washed with ice-cold methanol

and then dried in vacuo (using a drying piston) for 48 h at

According to the above procedure the hexavalent dendrimer

core¹⁴(0.029 g, 36.20 mmol) was treated with triethylamine

(0.10 cm³, 0.43 mmol), and then 2-O-a-D-mannopyranosyl-

D-mannose was added (0.149 g, 0.43 mmol) to yield

7994

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

compound (28) as a colourless solid (0.06 g, 35%). Mp

159.5–161.08C; [a]²_D⁰¼þ20.45 (c 0.11, H₂O); n_max(KBr,

cm²¹) 3313 (s, s N–H str), 3240 (s, ArCH str), 2925 (m,

ArCH str), 2850 (m, O–H str), 1654 (s, N–H bend), 1638 (s,

CvO str), 1561 (m, N–H bend and C–N str), 1545 (m,

ArCvC–O–C str), 1204 (w, N–H bend, C–N str), 1052 (s,

C–O–C str), 1022 (s, C–O–C str), 973 (s, C–O–C str),

802 (s, N–H wagging); d_H(400 MHz, D₂O) 7.18–7.32

(12H, m, ArCH), 5.17 (3H, s, CH(CH₂)₂), 4.84 (6H, d,

J¼1.5 Hz, 6£H-1⁰), 3.87 (6H, dd, J¼1.5, 3.0 Hz, 6£H-2⁰),

3.42–3.75 (78H, m, 6£H-1,₀6£H-2, 6£H-3, 6£H-4, 12£H-

6, 6£H-3⁰, 6£H-4⁰, 6£H-5 , 12£H-6⁰, 3£CH(CH₂NH)₂),

3.32–3.41 (6H, m, C(O)NHCH₂), 3.21–3.31 (6H, m, 6£H-

5), 2.53–2.61 (6H, m, C(O)NHCH₂CH₂N); d_C(100 MHz,

D₂O) 171.0 (3£CvO), 168.1 (3£CvO), 136.4 (3£ArC),

136.1 (3£ArC), 127.5 (12£ArCH), 102.5 (6£CH), 93.0

(3£CH(CH₂NH)₂), 79.5 (6£CH), 73.5 (6£CH), 72.8

(6£CH), 71.6 (6£CH), 70.6 (12£CH), 70.5 (6£CH), 70.3

(6£CH), 67.3 (3£CH(CH₂NH)₂), 67.1 (6£CH), 61.3

(6£CH₂), 61.2 (6£CH₂), 52.5 (3£C(O)NHCH₂), 45.0

(3£C(O)NHCH₂CH₂N).

4.1.27. 2⁰-Bromoethyl 2,3,4,6-tetra-O-acetyl-a-D-manno-

pyranoside (37). Boron triﬂuoride etherate (11.60 cm³,

94.32 mmol) was added to a solution of 1,2,3,4,6-penta-O-

acetyl-a-^D-mannopyranoside (10.834 g, 27.76 mmol) and

2-bromoethanol (1.96 cm³, 27.65 mmol) in dry CH₂Cl₂

(100 cm³). The reaction mixture was stirred in the dark

under a nitrogen atmosphere for 3 h. TLC analysis, using

ethyl acetate/hexane (1:1, v/v), showed that the reaction had

gone to completion (starting material R_f0.53, product R_f

0.63). CH₂Cl₂(200 cm³) was added, the reaction mixture

was neutralised by adding saturated sodium bicarbonate

solution (200 cm³) and the resulting solution was washed

with deionised water (2£200 cm³). The combined organic

layers were dried over magnesium sulfate, ﬁltered and

concentrated to dryness under reduced pressure. The

resulting oil was then puriﬁed using column chromato-

graphy on silica gel (ethyl acetate/hexane (1:1, v/v)). The

relevant fractions were collected, combined and concen-

trated to dryness under reduced pressure to yield 2⁰-

bromoethyl-2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside

(37) as a colourless powder (5.17 g, 41%). Mp 115.1–

117.28C, (lit.¹⁹118–1198C); [a]²_D⁰¼þ42.09 (c 0.53,

CHCl₃), (lit.¹⁹[a]_D²³¼þ45.00 (c 0.60, CDCl₃)); n_max

(NaCl, cm²¹) 1745 (s, CvO str), 1733 (s, CvO str),

1435 (w, as CH₃), 1381 (m, s CH₃), 1367 (m, s CH₃), 1291

(w, s CH₃), 1230 (s, CC(vO)–O str), 1137 (m, C–O–C

str), 1086 (m, C–O–C str), 1051 (s, C–O–C str), 1006 (m,

C–O–C str), 979 (m, C–O–C str), 683 (m, C-Br str); d_H

(250 MHz, CDCl₃) 5.25–5.33 (3H, m, H-2, H-3, H-4), 4.87

(1H, s, H-1), 4.27 (1H, dd, J¼11.5, 5.5 Hz, H-6), 4.10–4.15

(2H, m, H-5, H-6), 3.87–3.96 (2H, m, CH₂O), 3.52 (2H, app

t, J¼5.5 Hz, CH₂Br), 2.15 (3H, s, OAc), 2.10 (3H, s, OAc),

2.00 (3H, s, OAc), 1.99 (3H, s, OAc); d_C(62.5 MHz,

CDCl₃) 171.0 (CvO), 170.4 (CvO), 170.2 (CvO), 170.1

(CvO), 98.1 (CH), 69.8 (CH), 69.4 (CH), 69.3 (CH), 68.9

(CH₂O), 66.4 (CH), 62.8 (CH₂), 30.0 (CH₂Br), 21.3 (CH₃),

21.1 (3£CH₃); m/z (CI) 472 (MþNH^þ₄, 50%), 331 (100),

169 (23), 81 (18); Found 472.0806, C₁₆H₂₇O₁₀N⁷⁹Br

requires 472.0818.

4.1.25. Pentaerythrityl tetraazide (30). Pentaerythrityl

tetrabromide (2.747 g, 7.08 mmol) and sodium azide

(5.615 g, 86.40 mmol) were dissolved in anhydrous DMF

(50 cm³) and stirred at 808C for 4 h under a nitrogen

atmosphere. TLC analysis of the reaction mixture was

performed, using hexane/ethyl acetate (3:1, v/v) as the solvent

system, and this showed that the reaction had gone to

completion (starting material R_f0.88, product R_f0.80).

The reaction mixture was concentrated to dryness under

reduced pressure, dissolved in CH₂Cl₂(50 cm³) and then

washed with deionised water (4£50 cm³). The combined

organic layers were then dried over magnesium sulfate,

ﬁltered azeotroped with toluene (3£50 cm³) and then

concentrated to dryness in vacuo. The resulting oil was

then puriﬁed using column chromatography on silica gel

(hexane/ethyl acetate, 3:1, v/v). The relevant fractions were

collected and combined to give pentaerythrityl tetraazide (30)

as a colourless solid (1.36 g, 81%). Mp 50.2–51.68C; n_max

(NaCl, cm²¹) 2100 (s, CNvN^þvN²str), 1445 (m, as CH₃),

1348 (s, s CH₃), 1256 (s, CC(vO)–O str), 1149 (m, as C–C–O

str); d_H(250 MHz, CDCl₃) 3.27 (8H, s, 4£CH₂); d_C

(63 MHz, CDCl₃) 51.8 (4£CH₂), 44.3 (C); m/z (CI) 296

(MþNH^þ₄, 91%), 169 (46); Found 236.1972, C₅H₁₂N₁₃

requires 236.1979.

4.1.28. 3⁰-Bromopropyl 2,3,4,6-tetra-O-acetyl-a-D-manno-

pyranoside (38). Boron triﬂuoride etherate (4.06 cm³,

33.01 mmol) was added to a solution of 1,2,3,4,6-penta-O-

acetyl-a-^D-mannopyranoside (3.338 g, 8.55 mmol) and

3-bromo-1-propanol (0.85 cm³, 9.40 mmol) in dry CH₂Cl₂

(40 cm³). The reaction mixture was stirred in the dark under

a nitrogen atmosphere for 4 h. TLC analysis, using ethyl

acetate/hexane (1:1, v/v), showed that the reaction had gone

to completion (starting material R_f0.43, product R_f0.57).

CH₂Cl₂(80 cm³) was added, the reaction mixture was

neutralised by adding saturated sodium bicarbonate solution

(80 cm³) and the resulting solution was washed with

deionised water (2£80 cm³). The combined organic layers

were dried over magnesium sulfate, ﬁltered and concen-

trated to dryness under reduced pressure. The resulting oil

was then puriﬁed using column chromatography on silica

gel (ethyl acetate/hexane (1:1, v/v)). The relevant fractions

were collected, combined and concentrated to dryness under

reduced pressure to yield 3⁰-bromopropyl-2,3,4,6-tetra-O-

acetyl-a-D-mannopyranoside (38) as a pale yellow oil

(1.60 g, 39%). [a]_D²⁰¼þ39.10 (c 1.95, CHCl₃); n_max(NaCl,

cm²¹) 1746 (s, CvO str), 1435 (m, as CH₃), 1370 (s, s

CH₃), 1224 (s, CC(vO)–O str), 1137 (s, C–O–C str), 1088

4.1.26. Pentaerythrityl tetraamine (29). A solution of

pentaerythrityl tetraazide (30) (0.470 g, 1.99 mmol) in dry

methanol (15 cm³) containing 10% palladium-on-charcoal

(0.50 g) was exposed to hydrogen at room temperature for

10 h. TLC analysis of the reaction mixture was performed,

using hexane/ethyl acetate (3:1, v/v) as the solvent system,

and this showed that the reaction had gone to completion.

The catalyst was ﬁltered off through Celite^wand washed

with methanol. The ﬁlterate was concentrated in vacuo to

yield pentaerythrityl tetraamine (29) as a colourless oil

(0.24 g, 91%) which was not puriﬁed further. n_max(NaCl,

cm²¹) 3489 (s, as N–H str), 3362 (s, s N–H str), 1648 (m,

N–H bend), 1576 (s, N–H bend), 1484 (m, as CH₃), 1324

(s, s CH₃), 682 (m, N–H wagging); d_H(250 MHz, CDCl₃)

4.26 (8H, s, 4£NH₂), 2.45 (8H, s, 4CH₂); d_C(62.5 MHz,

CDCl₃) 44.6 (C), 43.6 (4£CH₂).

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

7995

(s, C–O–C str), 1050 (s, C–O–C str), 981 (m, C–O–C str),

688 (m, C-Br str); d_H(400 MHz, CDCl₃) 5.27–5.29 (2H, m,

H-3, H-4), 5.23–5.24 (1H, m, H-2), 4.84 (1H, d, J¼1.5 Hz,

H-1) 4.28 (1H, dd, J¼5.5, 12.5 Hz, H-6), 4.13 (1H, dd,

J¼2.5, 12.5 Hz, H-6), 4.00–4.04 (1H, m, H-5), 3.88–3.94

(1H, m, CH₂O), 3.53–3.62 (3H, m, CH₂O, CH₂Br), 2.06–

2.19 (2H, m, OCH₂CH₂CH₂Br) 2.16 (3H, s, OAc), 2.11 (3H,

s, OAc), 2.06 (3H, s, OAc), 2.00 (3H, s, OAc); d_C

(62.5 MHz, CDCl₃) 170.8 (CvO), 170.2 (CvO), 170.1

(CvO), 170.0 (CvO), 97.9 (CH), 69.7 (CH), 69.3 (CH),

68.9 (CH), 66.3 (CH), 65.8 (CH₂O), 62.7 (CH₂), 32.3

(OCH₂CH₂CH₂Br), 30.5 (CH₂Br), 21.1 (CH₃), 21.0

(2£CH₃), 20.9 (CH₃); m/z (CI) 488 (MþNH^þ₄, 22%), 331

(100); Found 488.0973, C₁₇H₂₉O₁₀N⁸¹Br requires

488.0955.

gone to completion (starting material R_f0.57, product R_f

0.47). The reaction mixture was concentrated to dryness

under reduced pressure, dissolved in CH₂Cl₂(50 cm³) and

then washed with deionised water (4£50 cm³). The

combined organic layers were dried over magnesium

sulfate, ﬁltered, azeotroped with toluene (3£50 cm³) and

then concentrated to dryness under reduced pressure. The

resulting oil was then puriﬁed using column chromato-

graphy on silica gel (ethyl acetate/hexane (1:1, v/v)). The

relevant fractions were collected, combined and concen-

trated to dryness under reduced pressure to yield 3⁰-

azidopropyl 2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside

(36) as a colourless solid (0.85 g, 71%). Mp 50.2–51.98C;

[a]²_D⁰¼þ46.02 (c 1.08, CHCl₃); n_max(NaCl, cm²¹) 2101 (s,

CNvN^þvN^-str), 1745 (s, CvO str), 1444 (w, as CH₃),

1366 (m, s CH₃), 1232 (s, CC(vO)–O str), 1136 (m, C–O–

C str), 1052 (m, C–O–C str); d_H(400 MHz, CDCl₃) 5.25–

5.34 (2H, m, H-3, H-4), 5.24 (1H, d, J¼2.0, 3.0 Hz, H-2),

4.82 (1H, d, J¼1.5 Hz, H-1),4.29 (1H, dd, J¼5.5, 12.0 Hz,

H-6), 4.12 (1H, dd, J¼2.5, 12.0 Hz, H-6), 3.95–3.99 (1H,

m, H-5), 3.79–3.85 (1H, m, CH₂O), 3.51–3.56 (1H, m,

CH₂O), 3.44 (2H, t, J¼6.5 Hz, CH₂N₃), 2.16 (3H, s, OAc),

2.11 (3H, s, OAc), 2.05 (3H, s, OAc), 2.00 (3H, s, OAc),

1.87–1.94 (2H, m, OCH₂CH₂CH₂N₃); d_C(62.5 MHz,

CDCl₃) 171.0 (CvO), 170.4 (CvO), 170.3 (CvO), 170.1

(CvO), 98.0 (CH), 69.8 (CH), 69.4 (CH), 69.0, (CH), 66.5

(CH), 65.2 (CH₂O), 62.9 (CH₂), 48.5 (CH₂N₃), 29.0 (OCH₂-

CH₂CH₂N₃), 21.3 (2£CH₃), 21.1 (2£CH₃); m/z (CI) 449

(MþNH^þ₄, 20%), 331 (100); Found 449.1904, C₁₇H₂₅O₁₀N₃

requires 449.1884; Found: C, 47.49; H, 5.88; N, 9.66. Calc. for

C₁₇H₂₉O₁₀N₄(M_r431.16): C, 47.33; H, 5.84; N, 9.74%.

4.1.29. 2⁰-Azidoethyl 2,3,4,6-tetra-O-acetyl-a-D-manno-

pyranoside (35). A solution of 2⁰-bromoethyl 2,3,4,6-tetra-

O-acetyl-a-D-mannopyranoside (37) (0.228 g, 0.50 mmol)

in anhydrous DMF (20 cm³) was treated with sodium azide

(0.198 g, 3.05 mmol) and the reaction mixture stirred at

608C for 1 h. TLC analysis, using ethyl acetate/hexane (2:1,

v/v), showed that the reaction had gone to completion

(starting material R_f0.69, product R_f0.60). The reaction

mixture was concentrated to dryness under reduced

pressure, dissolved in CH₂Cl₂(50 cm³) and then washed

with deionised water (4£50 cm³). The combined organic

layers were dried over magnesium sulfate, ﬁltered and

concentrated to dryness under reduced pressure. The

resulting oil was then puriﬁed using column chromato-

graphy on silica gel (ethyl acetate/hexane (2:1, v/v)). The

relevant fractions were collected, combined and concen-

trated to dryness under reduced pressure to yield 2⁰-

4.1.31. 2⁰-Aminoethyl 2,3,4,6-tetra-O-acetyl-a-D-manno-

pyranoside (33). A solution of 2⁰-azidoethyl 2,3,4,6-tetra-

O-acetyl-a-D-mannopyranoside (35) (0.772 g, 1.85 mmol)

in dry methanol (30 cm³) containing 10% palladium-on-

charcoal (0.235 g) was exposed to hydrogen at room

temperature for 16 h. TLC analysis of the reaction mixture

was performed, using ethyl acetate/hexane (1:1, v/v) as the

solvent system, and showed that the reaction had gone to

completion (starting material R_f0.60, product R_f0.00). The

catalyst was ﬁltered off through Celite^wand washed wit₀h

methanol. The ﬁltrate was concentrated in vacuo to yield 2 -

aminoethyl 2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside

(33) as a yellow oil (0.62 g, 85%) which was not puriﬁed

further. n_max(NaCl, cm²¹) 3509 (s, as N–H str), 3373 (s, s

N–H str), 1749 (s, CvO str), 1734 (s, CvO str), 1653 (s,

N–H bend), 680 (s, N–H wagging); d_H(400 MHz, CDCl₃)

5.26–5.36 (3H, m, H-2, H-3, H-4), 4.87 (1H, d, J¼1.5 Hz,

H-1), 4.31 (1H, dd, J¼5.0, 12.0 Hz, H-6), 4.11 (1H, dd,

J¼2.5, 12.0 Hz, H-6), 4.00–4.05 (1H, m, H-5), 3.80–3.85

(1H, m, CH₂O), 3.57–3.62 (1H, m, CH₂O), 2.89 (2H, t,

J¼5.5 Hz, CH₂NH₂), 2.16 (3H, s, OAc), 2.11 (3H, s, OAc),

2.05 (3H, s, OAc), 1.99 (3H, s, OAc); d_C(100 MHz, CDCl₃)

170.7 (CvO), 170.1 (CvO), 169.9 (CvO), 97.8 (CH),

69.5 (CH), 69.1 (CH), 68.5 (CH), 67.9 (CH₂O), 66.1 (CH),

62.4 (CH₂), 48.6 (CH₂NH₂), 20.9 (2£CH₃), 20.7 (2£CH₃);

m/z (FAB) 392 (MþH^þ, 100%), 350 (20), 72 (22); Found

392.1572, C₁₆H₂₆O₁₀N requires 392.1557.

azidoethyl

2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside

(35) as colourless crystals (0.15 g, 73%). Mp 81.8–

82.18C; [a]²_D⁰¼þ37.39 (c 0.55, CHCl₃), (lit.¹⁸

[a]²_D⁰¼þ50.2 (c 0.75, CHCl₃)); n_max(NaCl, cm²¹) 2106

(s, CNvN^þvN^-str), 1745 (s, CvO str), 1732 (s, CvO

str), 1435 (w, as CH₃), 1379 (m, s CH₃), 1365 (m, s CH₃),

1228 (s, CC(vO)–O str), 1135 (m, C–O–C str), 1108 (w,

C–O–C str), 1074 (m, C–O–C str), 1050 (s, C–O–C str),

979 (s, C–O–C str); d_H(400 MHz, CDCl₃) 5.37 (1H, dd,

J¼10.0, 3.5 Hz, H-3), 5.33 (1H, app t, J¼10.0 Hz, H-4),

5.28 (1H, dd, J¼3.5, 2.0 Hz, H-2), 4.88 (1H, d, J¼2.0 Hz,

H-1), 4.30 (1H, dd, J¼12.5, 5.5 Hz, H-6), 4.13 (1H, dd,

J¼12.5, 2.5 Hz, H-6), 4.05 (1H, m, H-5), 3.65–3.91 (2H, m,

CH₂O), 3.42–3.54 (2H, m, CH₂N₃), 2.17 (3H, s, OAc), 2.11

(3H, s, OAc), 2.06 (3H, s, OAc), 2.00 (3H, s, OAc); d_C

(62.5 MHz, CDCl₃) 171.0 (CvO), 170.4 (CvO), 170.2

(2£CvO), 98.1 (CH), 69.8 (CH), 69.2 (2£CH), 67.4

(CH₂O), 66.4 (CH), 62.8 (CH₂), 50.7 (CH₂N₃), 21.3

(CH₃), 21.1 (3£CH₃); m/z (CI) 435 (MþNH^þ₄, 96%), 390

(35), 331 (100); Found 435.1717, C₁₆H₂₇O₁₀N₄requires

435.1727. Found: C, 46.47; H, 5.54; N, 9.52. Calc. for

C₁₆H₂₃O₁₀N₃(M_r417.14): C, 46.04; H, 5.55; N, 10.07%.

4.1.30. 3⁰-Azidopropyl 2,3,4,6-tetra-O-acetyl-a-D-man-

nopyranoside (36). A solution of 3⁰-bromopropyl 2,3,4,6-

tetra-O-acetyl-a-D-mannopyranoside

(38)

(1.311 g,

2.72 mmol) in anhydrous DMF (40 cm³) was treated with

sodium azide (1.077 g, 16.56 mmol) and the reaction

mixture stirred at 608C for 1.5 h. TLC analysis, using

ethyl acetate/hexane (1:1, v/v), showed that the reaction had

4.1.32. 3⁰-Aminopropyl-2,3,4,6-tetra-O-acetyl-a-D-man-

nopyranoside (34). A solution of 3⁰-azidopropyl 2,3,4,6-

tetra-O-acetyl-a-D-mannopyranoside

(36)

(1.991 g,

7996

W. Hayes et al. / Tetrahedron 59 (2003) 7983–7996

4.62 mmol) in dry methanol (20 cm³) containing 10%

palladium-on-charcoal (0.425 g, wet weight) was exposed

to hydrogen at room temperature for 12 h. TLC analysis of

the reaction mixture was performed, using ethyl acetate/

hexane (1:1, v/v) as the solvent system, and showed that the

reaction had gone to completion (starting material R_f0.47,

product R_f0.00). The catalyst was ﬁltered off through

Celite^wand washed with methanol. The ﬁltrate was

concentrated in vacuo to yield 3⁰-aminopropyl-2,3,4,6-

tetra-O-acetyl-a-D-mannopyranoside (34) as a colourless

foam (0.67 g, 61%) which was not puriﬁed further. n_max

(NaCl, cm²¹) 3509 (s, as N–H str), 3373 (s, s N–H str),

3341 (s, O–H str), 3324 (s, O–H str), 2897 (s, O–H str),

1653 (s, N–H bend), 1228 (w, as C–C–O str), 1094 (m,

C–O–C str), 680 (s, N–H wagging); d_H(250 MHz,

CD₃OD) 4.77 (1H, d, J¼1.5 Hz, H-1), 3.46–3.83 (8H, m,

H-2, H-3, H-4, H-5, 2£H-6, OCH₂CH₂CH₂NH₂), 2.70–2.84

(2H, m, OCH₂CH₂CH₂NH₂), 1.79–1.86 (2H, m, OCH₂-

CH₂CH₂NH₂); d_C(62.5 MHz, CD₃OD) 101.9 (CH), 75.1

(CH), 73.0 (CH), 72.5 (CH), 69.0 (CH), 67.3 (OCH₂CH₂-

CH₂NH₂or OCH₂CH₂CH₂NH₂), 63.3 (CH₂), 48.3 (OCH₂-

CH₂CH₂NH₂or OCH₂CH₂CH₂NH₂), 30.6 (OCH₂-

CH₂CH₂NH₂); m/z (ES^þ) 238.1 (MþH^þ, 47%).

4.1.33. 2⁰-Aminoethyl-O-a-D-mannopyranoside (31). A

ﬂask was charged with 2⁰-aminoethyl 2,3,4,6-tetra-O-

acetyl-a-D-mannopyranoside (33) (0.51 g, 1.30 mmol) dis-

solved in anhydrous methanol (15 cm³). To this solution a

catalytic amount of anhydrous potassium carbonate (0.005 g,

0.05 mmol) was added and the reaction mixture was stirred at

room temperature under a nitrogen atmosphere. TLC analysis

using methanol: CH₂Cl₂(5:95, v/v), showed that after 1.5 h

the reaction had gone to completion (starting material R_f0.98,

product R_f0.32). Amberlite IR-120 (PLUS) ion-exchange

resin was washed with methanol and then added to and stirred

with the reaction mixture for 30 min. The resin was then

ﬁltered off under gravity and the resulting solution concen-

trated to dryness in vacuo to yield 2⁰-aminoethyl-O-a-D-

mannopyranoside (31) as a colourless foam (0.24 g, 87%)

which was used directly in the next reaction.

Research Endowment Trust Fund (S. D. O and B. R.) for

their ﬁnancial support of this work. The assistance of Mr

Peter Heath for NMR analysis of the compounds is also

acknowledged.

References

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acetyl-a-D-mannopyranoside (34) (1.2 g, 2.4 mmol) dis-

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catalytic amount of anhydrous potassium carbonate

(0.005 g, 0.05 mmol) was added and the reaction mixture

was stirred at room temperature under a nitrogen atmos-

phere. TLC analysis using methanol: CH₂Cl₂(5:95, v/v),

showed that after 1.5 h the reaction had gone to completion

(starting material R_f0.8, product R_f0.32). Amberlite IR-120

(PLUS) ion-exchange resin was washed with methanol and

then added to and stirred with the reaction mixture for

30 min. The resin was then ﬁltered off under gravity and the

resulting solution concentrated to dryness in vacuo to yield

3⁰-aminopropyl-O-a-D-mannopyranoside (32) as a colour-

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¨

We gratefully acknowledge the University of Reading’s

Article Doi

One-pot synthesis of multivalent arrays of mannose mono- and disaccharides

DOI: 10.1016/j.tet.2003.08.011

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