Synthesis of new glycosyl-α-aminoacid derivatives for glycopeptide chemistry

TETRAHEDRON

Pergamon

Tetrahedron 57 (2001) 6215±6227

Synthesis of new glycosyl-a-aminoacid derivatives for

glycopeptide chemistry

p

Claude Grison, Frederic Coutrot and Philippe Coutrot

Â Â

Â Â Â Â

Institut Nanceien de Chimie Moleculaire, FR CNRS 1742, UMR 7565, Universite Henri Poincare, Nancy 1, BP 539,

Nancy 54506, France

Received 18 December 2000; revised 14 May 2001; accepted 29 May 2001

AbstractÐThe synthesis of new N- or C-protected glycosyl-a-aminoacids and their use to prepare new glycopeptides is described. The

overall synthetic strategy to obtain these new a-aminoacid chirons involves four distinct steps from dialdoses: (1) a diastereoselective

Darzens reaction between the potassium anion derived from isopropyl dichloroacetate and a suitable protected dialdose, (2) the one-pot

transformation of the so-obtained isopropyl glycosyl-a-chloroglycidic ester with magnesium iodide, then sodium hydrogenosul®te, into an

isopropyl glycosyl-a-ketoester, (3) the reductive amination of the a-ketoester with (S)-a-methylbenzylamine and an hydrogenating reagent,

1. Introduction

syl analogs with a C±C anomeric bond between the peptide

and the carbohydrate moiety⁸or with a C±C bond in another

glucidic position have been synthesized to improve the

metabolic stability of these potential drugs.⁹

Carbohydrate moieties of glycopeptides play different deci-

sive roles, especially in recognition phenomena.¹The

conformation²and solubility³of proteins are in¯uenced by

the oligosaccharide chain that can also prohibit the proteo-

lytic cleavage.⁴As a result, the synthesis of glycopeptides is

an attractive goal for an understanding of the mutual inter-

actions between both moieties and for their biological inter-

est. A lot of works concern the synthesis of models that

mimic the natural glycopeptides with a N-glycosidic bond

between the sugar residue and asparagine or with an O-

glycosidic bond with hydroxy-containing aminoacids.⁵

However, these compounds are sensitive towards acids or

bases and represent a challenge to the synthetic chemist

which uses acidic or basic conditions in both solution and

solid-phase peptide synthesis.⁶Moreover, such as N- or O-

glycopeptides are also subject to both chemical and enzy-

matic deglycosylation in vivo involving a limitation for

their use as potential therapeutic agents.⁷More stable glyco-

Herein we report the complete study¹⁰concerning the synth-

esis of new stable glycosyl a-aminoesters 6a±e/6⁰a±e,

where the a-C of the glycine moiety is connected to the

C-6 of a pyranose or to the C-5 of pentoses, their selective

N- and C-deprotections and their incorporation into a

peptide (Fig. 1).

Even though various synthetic approaches to furanosyl a-

aminoacid derivatives have been reported over the years

especially in the polyoxin series¹¹none of them can be

applied to the introduction of the a-C-glycine moiety at

the C-5 of a furanose (as in 6b±d/6⁰b±d that present one

C more relatively to the analogue polyoxin moiety), or at the

C-6 of a pyranose (as in 6a/6⁰a). In this context, a particu-

larly attractive strategy for the asymmetric synthesis of such

Figure 1.

Keywords: amino acids and derivatives; glycopeptides; amination; reduction.

Corresponding author. Tel.: 133-3-83-91-20-33; fax: 133-3-83-91-23-93; e-mail: claude.grison@lco2.uhp-nancy.fr

p

PII: S0040-4020(01)00600-7

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C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

Figure 2.

Scheme 1.

Table 1.

convenient to introduce a benzylamine moiety into 4a±e,

that could be selectively removed to lead to the primary

amine by hydrogenation. A ®rst attempt was achieved by

reaction between benzylamine and a-ketoester 4a in isopro-

panol, leading to the corresponding imine, followed by an

hydrogenation using Pd/C (10%) as a catalyst. The use of

any catalytic mineral or organic acid was prohibited for the

formation of the intermediate benzylimine because of the

presence of the sugar ketal groups. However, benzylamine

was a too powerful nucleophilic reagent and a side-trans-

amidi®cation of the isopropyl ester accompanying the

expected aminoproduct was observed in a proportion of

26%. As a result, the use of the more hindered (S)-a-methyl-

benzyl amine was studied to circumvent this dif®culty and

also because it seemed adaptable to realize a double asym-

metric induction with the carbohydrate moiety during the

hydrogenation step. Effectively, in these conditions any

side-transamidi®cation of the isopropylester was observed,

but the imine formation in the case of 4a was slow, as a

consequence of the steric hindrance. The best conditions to

reach 5a/5⁰a needed 2 equiv. of (S)-a-methylbenzylamine

in benzene at re¯ux, for 13 h, in the presence of crushed

molecular sieves. For the other a-ketoesters 4b±e, the

imines 5b±e were prepared in milder conditions with

2 equiv. of (S)-a-methylbenzylamine, in isopropyl alcohol,

at room temperature, for 24 h. The imines 5a±e/5⁰a±e were

not isolated, as a result of their inclination to hydrolyse into

starting a-ketoesters 4a±e, but directly submitted to hydro-

gen in the presence of palladium (10%) on charcoal for 24 h

at normal pressure in most cases (procedure A).

Entry

1

2/2⁰

Yield %^a,b

4

Yield %^a

1

2

3

4

5

1a

1b

1c

1d

1e

2a/2⁰a

2b/2⁰b

2c/2⁰c

2d/2⁰d

2e/2⁰e

87 (84/16)

79 (80/20)

99 (65/35)

86 (73/27)

89 (62/38)

4a

4b

4c

4d

4e

84

89

67

86

87

a

Yield of puri®ed products.

Diastereomer ratio.

b

systems involves the easy introduction of an a-ketoester

moiety on a suitable protected dialdose followed by an

aminoreduction and further chemoselective deprotections

before coupling (Fig. 2).

2. Results and discussion

2.1. Synthesis of glycosyl a-ketoesters 4a±e

Glycosyl-a-ketoesters have already been shown by us to be

very useful chiral building blocks to obtain bioactive mole-

cules.¹²These starting materials are prepared in two steps

from the readily available dialdoses 1a±e: a Darzens reac-

tion between 1a±e and the potassium anion derived from

isopropyl dichloroacetate cleanly afforded a diastereomeric

mixture of a-chloroglycidic esters 2a±e/2⁰a±e in high yield

(79±99% yield). The reaction of these glycidic esters 2a±e/

2⁰a±e with magnesium iodide in diethylether, followed by a

treatment with a saturated aqueous sodium hydrogenosul®te

solution cleanly afforded the a-ketoesters 4a±e (67±87%

yield) via the epimeric no-isolated b-iodo-a-ketoesters

3a±e/3⁰a±e (Scheme 1, Table 1).¹³

The best results for products 6 were obtained in the

case of the aminoreduction of the d-galacto a-ketoester

4a/4⁰a, whereas relatively poor yields were obtained in

furanic and linear series. In the case of the pyranic

series we have noted that the reduction step was far

more rapid with the hydrogen pressure increase (8 h

under a pressure of 10 bar instead of 24 h under the

normal pressure). Concurrently the yield increased up

2.2. Reductive amination of a-ketoesters 4a±e (Scheme

2, Table 2)

With the aim to further obtain N-protected a-aminoacids or

N-deprotected a-aminoesters for peptidic coupling, it was

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

6217

Scheme 2.

Table 2.

Entry

Starting material

Product

n

Solvent

T (8C)

t₁(h)

t₂(h)

Overall yield %^a

Diastereomeric ratio^b

1

2

3

4

5

6

7

8

4a

4b

4c

4d

4e

6a/6⁰a

6b/6⁰b

6c/6⁰c

6d/6⁰d

6e/6⁰e

1

2

iPrOH

AcOEt

C₆H₆

iPrOH

C₆H₆

iPrOH

20

24

13

24

H₂, 1 bar

H₂, 10 bar

H₂, 1 bar

NaBH₃CN

H₂, 10 bar

NaBH₃CN

H₂, 1 bar

NaBH₃CN

H₂, 1 bar

24

8

30

36

±

43/57

50/50

±

70

86

92

30

62

40

65

42

35

45

49/51

45/55

54/46

70/30

60/40

50/50

53/47

39/61

20

re¯ux

20

8

24

3.5

8

3.5

24

3.5

24

9

10

11

12

13

a

Yield of puri®ed products.

The diastereomeric ratio was evaluated by ¹H NMR (250 MHz) on the crude product.

b

to 86% for 6a/6⁰a. This difference was assigned to a

partial hydrogenolysis of the a-methylbenzylamine

moiety of 6a/6⁰a that occured in the reaction medium

when the reduction was too slow under normal pressure

and that led to 7a/7⁰a with a free amino group (Scheme

3). Compound 7a/7⁰a was detected only in the crude

product and was not eluted on the silicagel chromato-

graphic column during the puri®cation. In the furanic

and d-arabino linear series, the products 6b±e were

always accompanied by some quantities of the starting

a-ketoesters 4b±e having not reacted (10±20%), with

some corresponding a-hydroxyester reduction products

(4±9%). It means that imine formation was not

complete in these cases, even after 24 h. These struc-

tures obviously needed either a much longer reaction

time than in the d-galacto series or a large excess of

a-methylbenzylamine. Moreover an important loss of

product after puri®cation on a silicagel chromatographic

column (about 30%) was associated with the presence

in the crude product of the polar a-aminoesters 7b±e/

7⁰b±e resulted from the side debenzylation during the

hydrogenation step. An attempt to increase the hydrogen

pressure in the case of 5c/5⁰c with the aim to reduce the

reduction time and then to decrease this debenzylation,

as for 5a, revealed to be relatively inef®cient in the

furanic series (compare entries 9, 11, 13).

cially in the case of furanic structures. A ®rst attempt with

sodium borohydride to reduce the intermediate imine

showed no improvement, because the isopropyl ester

group was also affected and reduced into alcohol. However,

the use of the smooth reductor sodium cyanoborohydride in

isopropanol was better, and even though literature recom-

mended the reduction of imine at pH6±8,¹⁴the imines 5/5⁰

were enough reactive to be reduced under basic pH. By this

procedure, the imines 5 were reduced with 1 equiv. of

sodium cyanoborohydride, with stirring at room tempera-

ture for 3.5 h, and quenched by water (procedure B). The

crude was concentrated, extracted with chloroform, dried

with sodium sulphate, evaporated, and puri®ed on a silicagel

chromatography column.

With NaBH₃CN no side hydrogenolysis of the a-methyl-

benzyl moiety was observed and the sole noticed secondary

products were a-hydroxyesters resulted from the reduction of

the starting a-ketoesters 4b±d. The yields increased in all

cases, excepted for the d-xylo compound 6d/6⁰d, that could

be explained by a lower reactivity of the relatively hindered

carbonyl in 4d, due to the proximity of the cis methoxy at C-3.

No signi®cant diastereoisomeric excess was noted in the

products 6, that is quite surprising, because it could be

supposed, a priori, that the chiral d-sugar moieties combined

with the (S) con®guration of the N-a-methylbenzylic carbon

would involve a high diastereoselective hydrogenation of

the intermediate imines 5.

An improved method was then studied to obtain the second-

ary amines 6b±d/6⁰b±d without side hydrogenolysis, espe-

Scheme 3.

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C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

Figure 3.

Figure 4.

In fact, the ¹H NMR of the crude product 5a, as an example,

indicated the presence of two conformational diastereomers

5a/5⁰a (50/50) which differed by the Z/E conformations of

the imine moiety. A non-chelated model described by

Harada¹⁵in the case of aliphatic compounds could be

applied to the imine 5a/5⁰a and could explain the lack of

diastereoselectivity. The stereomer 5a could lead mainly to

the aminoester 6a (S), whereas 5⁰a could lead mainly to the

aminoester (R) (Fig. 3).

form. The a-carbon of the aminoester moiety appeared to be

(S) (Fig. 4).

2.3. Debenzylation and N-side coupling

Each mixture of diastereoisomeric compounds 6a±d/6⁰a±d

was hydrogenolyzed in isopropanol for 5 h in the presence

of Palladium on charcoal (10%) and under 50 bar hydrogen

pressure.¹⁷The crude products were then ®ltered on celite to

remove the catalyst, and the resulting primary a-amino-

esters 7 were directly coupled during 4 h in chloroform at

room temperature with BOC±Ala±OH, triethylamine and

benzotriazolyloxy trisdimethylaminophosphonium hexa-

¯uorophosphate (BOP) as coupling reagents (Scheme 3,

Table 3).¹⁸

Nevertheless, in the particular case of 6a/6⁰a, the two

diastereoisomers could be easily separated by selective

precipitation in diethylether, that compensated for the

non-diastereoselectivity of the hydrogenation step: 6a

was insoluble in diethylether whereas 6⁰a was comple-

tely soluble in this solvent. This interesting property

was not found again for the other a-aminoesters 6b±

e/6⁰b±e that were isolated as a mixture of diastereo-

isomers.

In these conditions the expected dipeptides 8 were obtained

with excellent yields and with exactly the same diastereo-

meric ratios as those of the starting amino synthons 7. This

indicated that coupling reactions were effected without any

racemisation and with the same rate with each diastereomer

7a±d and 7⁰a±d. Moreover, coupling conditions were

As a consequence, the structure of pure 6a was established

by X-ray crystallography¹⁶after recrystallization in chloro-

Table 3.

Entry

Starting material 6

7

Yield %^a

Dipeptide 8

Yield %^b

1

2

3

4

6a/6⁰a 98/2

6a/6⁰a 10/90^c

6c/6⁰c 60/40

6d/6⁰d 55/45

7a/7⁰a 98/2

7a/7⁰a 10/90

7c/7⁰c 60/40

7d/7⁰d 55/45

95

97

99

8a/8⁰a 98/2

8a/8⁰a 10/90

8c/8⁰c 60/40

8d/8⁰d 55/45

93

80

64

87

a

Yield of crude products.

Yield of puri®ed products.

All diastereomeric ratios were evaluated by ¹H NMR (250 MHz) on the crude product.

b

c

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

6219

Scheme 4.

Table 4.

Entry

Starting material 6

Methyl ester 9

Yield %^a

Dipeptide 11

Yield %^a

1

2

3

4

6a

9a

83

86

80

84

11a

81

61

75

85

6a/6⁰a 10/90

6c/6⁰c 60/40

6d/6⁰d 55/45

9a/9⁰a 10/90

9c/9⁰c 60/40

9d/9⁰d 55/45

11a/11⁰a 10/90

11c/11⁰c 60/40

11d/11⁰d 55/45

a

Yield of puri®ed products.

entirely compatible with ketal or ether protections of the

carbohydrate moieties.

1 equiv. of 1N potassium hydroxide, in MeOH/THF 1/3 at

re¯ux for 4 h led to the carboxylates 10a±d which were

directly coupled, in situ, with HCl, GlyOMe, in the same

coupling conditions as those explained above (Scheme 4,

Table 4).

2.4. Hydrolysis of the isopropyl ester group and C-side

coupling (Scheme 4, Table 4)

Hydrolysis of the isopropyl ester of 6 proved very dif®cult

and various hydrolysis conditions were studied with 6a/6⁰a

as model. Neither potassium carbonate in a minimum of

water (that was used by us with success for the terminal

hydrolysis of the isopropyl ester of a KDO precursor),¹²or

KOH in THF/MeOH at different temperatures, or KOH/

dicyclohexyl-18-crown-6, gave total hydrolysis. However,

the by-product methyl ester 9a/9⁰a was partly obtained

(63%) with the expected potassium carboxylate 10a/10⁰a

(13%) after 3 h at re¯ux of 6a/6⁰a with a 1N solution of

potassium hydroxide (1 equiv.) in the solvent mixture THF/

MeOH 1/2. Prolongation of the reaction time led to product

degradation. These results suggested that the isopropyl ester

6a/6⁰a was ®rst transesteri®ed into the methyl ester 9a/9⁰a

that led to the carboxylate 10a/10⁰a. As a consequence, it

seemed more convenient to obtain 10a/10⁰a from methyl

ester 9a/9⁰a as starting material instead of isopropyl ester

6a/6⁰a. Unfortunately the initial Darzens reaction was less

ef®cient with methyl dichloroacetate than with isopropyl

dichloroacetate, so that it was more convenient to adjust

the complete transesteri®cation of 9a/9⁰a from 6a/6⁰a.

This was successfully effected by stirring a mixture of

lithium methylate and isopropyl a-aminoester 6a/6⁰a in

MeOH/THF (1/2) at re¯ux during 2.5 h. In these conditions,

all the diastereomer methyl esters 9a±d were obtained and

isolated after puri®cation by chromatography on silicagel. It

was noted that these transesteri®cations were carried out

without any epimerisation and led to the expected methyl

esters in good yields whatever the nature of the carbohy-

drate moiety. Further hydrolysis of diasteromers 9a±d with

2.5. Introduction of the 2-(1⁰,2⁰;3⁰,4⁰-di-O-isopropyl-

idene-6⁰-deoxy-a-d-galactopyranosyl)glycine residue

inside a peptide (Scheme 5)

As a ®rst example to illustrate the versatility of the method,

we have chosen the inclusion of 2-(1⁰,2⁰;3⁰,4⁰-di-O-isopro-

pylidene-6⁰-deoxy-a-d-galactopyranosyl)glycine between

an alanine and a glycine residue. To prevent the classical

oxazolone formation and therefore a possible epimerisation,

the tripeptide was built from the chiron 6a/6⁰a (98/2), by

synthesizing ®rst the dipeptide 11a/11⁰a (98/2) according to

Scheme 4. Secondly, 11a/11⁰a (98/2) was debenzylated

under the same conditions as those described above to

obtain 7 from 6 (Scheme 3). Then, the so-obtained N-depro-

tected crude dipeptide 12a/12⁰a (98/2) was coupled with

(l)-BOC±Ala±OH in the presence of triethylamine and

BOP to give the tripeptide 13a/13⁰a (98/2) with an overall

yield of 69% from 11a/11⁰a, after chromatographic puri®-

cation. Any epimerisation occurred as can be observed from

the invariance of the diastereomeric ratios (Scheme 5).

Because natural glycoproteins include a lot of carbohydrate

moities in different positions, the synthesis of peptides with

the glycosyl moiety in any determined position represents

an exciting challenge. With this aim, we have also studied

the vicinal couplings, a priori the most dif®cult examples,

having steric hindrance between two glycosylated aminoa-

cid synthons. At ®rst the carboxylic partner 10a/10⁰a (98/2)

was coupled with the amino partner 7a/7⁰a (98/2) leading to

the almost pure 14aa with an excellent yield, whereas in a

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C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

Scheme 5.

second coupling, 10a/10⁰a (98/2) reacted with the amino

partner 7c/7⁰c (60/40) yielded 14ac/14⁰ac with a strict

stereospeci®city. It was noteworthy that these reactions,

carried out in the presence of BOP and triethylamine, in

chloroform, at room temperature, were rapid and lasted

only 2.5 h (Scheme 6).

4. Experimental

Â

Mass spectral data were obtained at the Faculte de Chimie,

Â

Universite Louis Pasteur, Strasbourg. H NMR and ¹³C

1

NMR were run at 250 (or 400 MHz) and 62.5 MHz, respec-

tively. Chemical shifts are given in parts per million (ppm)

using the residue solvent peaks as reference relatively to

TMS. Tetrahydrofuran (THF) was distilled from sodium-

benzophenone ketyl. Dichloromethane was distilled from

P₂O₅. Unless otherwise noted, all reactions were performed

in oven-dried glassware under an atmosphere of dry nitro-

gen. Solutions were evaporated under reduced pressure with

a rotary evaporator, and the residues were chromatogra-

phied on a silica gel column using an ethyl acetate±hexane

as eluent unless speci®ed otherwise. All puri®ed products

gave satisfactory elemental analysis.

3. Conclusion

In conclusion, we have described a convenient route to a

new class of glycosyl-a-aminoacid derivatives by reductive

amination of precursor glycosyl-a-ketoesters and we have

shown their use in peptide synthesis. This strategy offers

many possibilities for combining together different glyco-

syl-a-aminoacids or to alternate with natural residues in any

position. It allows access to an extremely varied library of

glycopeptide analogues with potent biological applications.

We are now continuing our investigations to increase the

diastereofacial selectivity of the reductive amination for the

obtention of pure diastereoisomer chirons, and at the same

time we are studying the application of these chirons in solid

phase peptide synthesis.

4.1. Procedure A for the reductive amination of glycosyl-

a-ketoesters 4

In a typical procedure, 2 equiv. of (S)-a-methylbenzylamine

(2.47 g, 20.4 mmol) were added to a solution of 1 equiv. of

4a (3.66 g, 10.2 mmol) in 50 mL of isopropanol. The

mixture was stirred at room temperature in the presence of

Scheme 6.

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

6221

crushed molecular sieves during 24 h and then ®ltered. To

the ®ltrate was added 1.8 g of palladium on charcoal 10%,

and the solution was hydrogenated for 24 h at room

temperature under normal pressure, or for 8 h at room

temperature under a 10 bar initial pressure. The catalyst

was removed by ®ltration and washed with chloroform.

The solution was evaporated to dryness and the residue

was puri®ed on a silicagel chromatographic column with

CH₂Cl₂/AcOEt (5/1) to give 6a/6⁰a (49/51) (4.08 g,

8.8 mmol, 86%).

(250 MHz, CDCl₃): d7.31±7.25 (m, 5H), 5.87 (d, 1H,

J3.8 Hz), 5.04±4.90 (m, 1H), 4.57 (d, 1H, J3.8 Hz),

4.42±4.36 (m, 1H), 3.81±3.73 (m, 1H), 3.61 (d, 1H,

J3.0 Hz), 3.45±3.35 (m, 1H), 3.32 (s, 3H), 2.04±1.70

(m, 2H), 1.52 (s, 4H), 1.33 (s, 3H), 1.33 (d, 3H,

J6.0 Hz), 1.20 (d, 3H, J6.4 Hz), 1.17 (d, 3H,

J6.4 Hz); ¹³C NMR (62.5 MHz, CDCl₃): d174.7,

145.5, 128.4, 127.2, 126.7, 111.1, 104.4, 84.8, 81.7, 77.1,

68.2, 57.5, 56.8, 56.4, 31.6, 26.7, 26.2, 25.1, 22.7, 21.9,

21.7; IR (KBr): n3430, 1722 cm²¹; MS (ESI): m/z:

408.3 (MH¹, 100%).

The diastereomers 6a and 6⁰a could be easily separated by

precipitation in diethylether.

4.1.4. Isopropyl 2-[[(1⁰S)-1⁰-phenylethyl]amino]-2,3-di-

deoxy-4,5:6,7-di-O-isopropylidene-d,l-glycero-d-arabino-

heptouronate 6e/6⁰e. The starting material 4e (600 mg,

1.82 mmol) gave 6e/6⁰e 39/61 (360 mg, 45%, colourless

oil) by procedure A; TLC (hexane/AcOEt (1/1)) R_f0.50.

4.1.1. Isopropyl 7-[[(1⁰S)-1⁰-phenylethyl]amino]-6,7-di-

deoxy-1,2:3,4-di-O-isopropylidene-l-glycero-a-d-galacto-

octopyranuronate 6a. White powder insoluble in ether.

1

TLC (CH₂Cl₂/AcOEt (5/1)) R_f0.65; mp 1788C; H NMR

1

6e: H NMR (250 MHz, CDCl₃): d7.27±7.17 (m, 5H),

(250 MHz, CDCl₃): d7.31±7.21 (m, 5H), 5.45 (d, 1H,

J5.1 Hz), 5.11±5.01 (m, 1H), 4.49 (dd, 1H, J2.6,

8.1 Hz), 4.26 (dd, 1H, J2.6, 5.1 Hz), 4.14±4.05 (m, 1H),

3.82±3.74 (m, 2H), 3.05 (dd, 1H, J5.6, 6.8 Hz), 2.01±1.88

(m, 1H), 1.83±1.71 (m, 1H), 1.63 (s, 3H), 1.56 (s, 1H), 1.39

(s, 3H), 1.34 (s, 3H), 1.33 (d, 3H, J6.8 Hz), 1.25 (d, 3H,

J5.1 Hz), 1.24 (s, 3H), 1.23 (d, 3H, J6.0 Hz); ¹³C NMR

(62.5 MHz, CDCl₃): d174.7, 145.5, 128.3, 127.1, 126.9,

109.0, 108.5, 96.5, 72.0, 70.9, 70.5, 68.0, 64.6, 56.9, 55.9,

5.09±4.99 (m, 1H), 4.10±3.95 (m, 1H), 3.95±3.78 (m,

2H), 3.71 (q, 1H, J6.4 Hz), 3.55±3.42 (m, 2H), 3.17 (dd,

1H, J6.4 Hz, J6.8 Hz), 2.12±1.91 (m, 2H), 1.91±1.72

(m, 1H), 1.32 (d, 3H, J6.4 Hz), 1.31 (s, 6H), 1.28 (s,

6H), 1.22 (d, 3H, J6.0 Hz), 1.20 (d, 3H, J6.4 Hz); ¹³C

NMR (62.5 MHz, CDCl₃): d174.6, 145.2, 128.3, 126.8,

126.7, 109.5, 109.0, 81.2, 77.5, 76.8, 68.0, 67.5, 56.8, 56.7,

37.3, 27.1, 26.8, 26.6, 25.2, 22.6, 21.9, 21.7; IR (KBr):

n3374, 1722 cm²¹; MS (ESI): m/z: 436.4 (MH¹, 100%).

33.4, 26.0, 25.9, 25.2, 25.0, 24.3, 21.9, 21.7; IR (KBr):

n3332, 1722 cm²¹

;

a_D274.8 (c0.79 g dl²¹

20

,

1

CHCl₃); MS (ESI): m/z: 464 (MH¹, 100%).

6⁰e: H NMR (250 MHz, CDCl₃₎: d7.31±7.22 (m, 5H),

5.01±4.91 (m, 1H), 4.15±3.98 (m, 2H), 3.96±3.85 (m,

2H), 3.78 (q, 1H, J6.4 Hz), 3.57±3.45 (m, 2H), 3.17 (dd,

1H, J6.4 Hz, J6.8 Hz), 1.92±1.78 (m, 2H), 1.58 (br s,

1H), 1.40 (s, 3H),1.39 (s, 3H), 1.36 (d, 3H, J6.4 Hz), 1.33

(s, 6H), 1.21 (d, 3H, J6.4 Hz), 1.19 (d, 3H, J6.4 Hz); ¹³C

NMR (62.5 MHz, CDCl₃): d174.7, 145.7, 128.3, 126.8,

126.7, 109.5, 108.9, 81.3, 77.5, 76.8, 67.9, 67.5, 56.7, 56.2,

37.1, 27.3, 26.9, 26.6, 25.2, 22.6, 21.8, 21.6; IR (KBr):

n3325, 1722 cm²¹; MS (ESI): m/z: 436.4 (MH¹, 100%).

4.1.2. Isopropyl 7-[[(1⁰S)-1⁰-phenylethyl]amino]-6,7-di-

deoxy-1,2:3,4-di-O-isopropylidene-d-glycero-a-d-galacto-

octopyranuronate 6⁰a. Orange oil soluble in ether. ¹H NMR

(250 MHz, CDCl₃): d7.32±7.21 (m, 5H), 5.57 (d, 1H,

J5.0 Hz), 4.93±4.83 (m, 1H), 4.60 (dd, 1H, J2.6,

7.7 Hz), 4.32 (dd, 1H, J2.6, 5.0 Hz), 4.23±4.18 (m, 1H),

4.07 (dd, 1H, J1.7, 7.7 Hz), 3.80±3.73 (m, 1H), 3.47 (dd,

1H, J3.0, 10.7 Hz), 2.05±1.92 (m, 2H), 1.66 (s, 3H), 1.47 (s,

1H), 1.37(s, 6H), 1.34(s, 3H), 1.23(d, 3H, J7.3 Hz), 1.18(d,

3H, J6.4 Hz), 1.12 (d, 3H, J6.0 Hz); ¹³C NMR (62.5 MHz,

CDCl₃): d175.2, 145.8, 128.2, 126.8, 126.7, 108.8, 108.3,

96.5, 73.4, 71.0, 70.4, 67.9, 64.0, 56.6, 55.5, 34.9, 26.2, 25.9,

24.9, 24.2, 22.4, 21.7, 21.6; IR (KBr): n3325, 1722 cm²¹.

4.2. Procedure B for the reductive amination of glycosyl-

a-ketoesters 4

In a typical procedure, 2 equiv. of (S)-a-methylbenzylamine

(180 mg, 1.51 mmol) were added to a solution of 1 equiv. of

a-ketoester 4a (270 mg, 0.75 mmol) in 5 mL of isopropanol

and the mixture was stirred for 24 h in the presence of

crushed molecular sieves. Then, 1 equiv. of sodium cyano-

borohydride (47 mg, 0.75 mmol) was added, and the reac-

tion was kept at room temperature during 3.5 h, quenched

by water and extracted with chloroform. The organic layer

was dried over magnesium sulphate, evaporated under

reduced pressure, and the residue was puri®ed by chromato-

graphy on a silica gel column.

4.1.3. Isopropyl 6-[[(1⁰S)-1⁰-phenylethyl]amino]-5,6-di-

deoxy-3-O-methyl-1,2-O-isopropylidene-d,l-glycero-a-d-

xylo-heptofuranuronate 6d/6⁰d. The starting material 4d

(320 mg, 1.06 mmol) gave 6d/6⁰d 50/50 (180 mg, 42%,

colourless oil) by procedure A.

6d: TLC (hexane/AcOEt (1/2)) R_f0.79; ¹H NMR (250 MHz,

CDCl₃): d7.31±7.26 (m, 5H), 5.82 (d, 1H, J3.8 Hz),

5.12±5.04 (m, 1H), 4.45 (d, 1H, J3.8 Hz), 4.4±4.3 (m,

1H), 3.69±3.61 (m, 1H), 3.17 (d, 1H, J2.6 Hz), 3.14 (s,

3H), 2.89 (dd, 1H, J5.1, 9.4 Hz), 1.90±1.80 (m, 2H), 1.54

(s, 4H), 1.32 (s, 3H), 1.29±1.22 (m, 9H); ¹³C NMR

(62.5 MHz, CDCl₃): d174.9, 145.1, 128.4, 127.2, 127.1,

111.2, 104.6, 83.8, 81.7, 77.2, 68.2, 57.5, 56.8, 56.6, 32.1,

26.7, 26.3, 25.1, 21.9, 21.8, 21.7; IR (KBr): n3430,

1722 cm²¹; MS (ESI): m/z: 408.3 (MH¹, 100%).

4.2.1. Isopropyl 6-[[(1⁰S)-1⁰-phenylethyl]amino]-5,6-di-

deoxy-1-O-methyl-2,3-O-isopropylidene-d,l-glycero-b-d-

ribo-heptofuranuronate 6b/6⁰b. The starting material 4b

(200 mg, 0.66 mmol) gave 6b/6⁰b (166 mg, 62%, colourless

oil) by procedure B; TLC (hexane/AcOEt (1/2)) R_f0.87.

1

6b: H NMR (250 MHz, CDCl₃): d7.32±7.20 (m, 5H),

6⁰d: TLC (hexane/AcOEt (1/2)) R_f0.79; ¹H NMR

5.03±4.87 (m, 1H), 4.82 (s, 1H), 4.63 (dd, 1H, J6.0,

6222

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

1

3.4 Hz), 4.53 (d, 1H, J6.0 Hz), 4.05 (ddd, 1H, J3.4, 5.6,

7.3 Hz), 3.76 (q, 1H, J6.4 Hz), 3.46 (t, 1H, J6.4 Hz),

3.29 (s, 3H), 2.09±2.01 (m, 2H), 1.51 (s, 1H), 1.45 (s,

3H), 1.35 (d, 3H, J6.4 Hz), 1.32 (s, 3H), 1.21 (d, 3H,

J6.4 Hz), 1.18 (d, 3H, J6.4 Hz); ¹³C NMR (62.5 MHz,

CDCl₃): d174.2, 145.4, 128.2, 126.9, 126.6, 112.2, 106.6,

85.0, 80.4, 76.5, 67.9, 56.6, 56.1, 54.2, 32.0, 26.0, 24.9,

White powder. H NMR (250 MHz, CDCl₃): d6.01 (br

s, 2H), 5.45 (d, 1H, J5.1 Hz), 5.07 (h, 1H, J6.0 Hz),

4.58 (dd, 1H, J2.5, 8.1 Hz), 4.29 (dd, 1H, J2.5,

5.1 Hz), 4.16 (dd, 1H, J8.1, 1.7 Hz), 4.07±3.90 (m, 2H),

2.51±2.34 (m, 1H), 2.30±2.15 (m, 1H), 1.60 (s, 3H), 1.43 (s,

3H), 1.33 (s, 3H), 1.30 (s, 3H), 1.26 (d, 6H, J6.0 Hz); ¹³C

NMR (62.5 MHz, CDCl₃): d170.7, 109.4, 108.9, 96.3,

72.2, 71.0, 70.2, 69.7, 64.4, 51.2, 30.6, 25.9, 25.8, 24.7,

22.8, 21.7, 21.5; IR (KBr): n3380, 1722 cm²¹

.

24.5, 21.6, 21.5; IR (KBr): n3409, 3233, 1743 cm²¹

;

1

6⁰b: H NMR (250 MHz, CDCl₃): d7.32±7.20 (m, 5H),

5.14±5.04 (m, 1H), 4.79 (s, 1H), 4.65 (dd, 1H, J5.6,

3.8 Hz, 1H), 4.54 (d, 1H, J5.6 Hz), 4.15 (m, 1H), 3.73

(q, 1H, J6.4 Hz), 3.20 (s, 3H), 3.16 (dd, 1H, J4.8,

9.8 Hz), 1.99±1.75 (m, 2H), 1.52 (s, 1H), 1.43 (s, 3H),

1.34 (d, 3H, J6.4 Hz), 1.32 (s, 3H), 1.27 (d, 3H,

J6.4 Hz), 1.24 (d, 3H, J6.4 Hz); ¹³C NMR (62.5 MHz,

CDCl₃): d175.1, 144.8, 128.2, 126.8, 126.6, 112.0, 106.6,

85.1, 80.8, 76.6, 67.8, 56.3, 56.2, 54.4, 32.9, 26.3, 25.2,

MS (ESI): m/z: 360.2 (MH¹, 100%).

4.3.2. Isopropyl 7-amino-6,7-dideoxy-1,2:3,4-di-O-iso-

propylidene-d-glycero-a-d-galacto-octopyranuronate 7⁰a.

The starting materials 6a/6⁰a 10/90 (300 mg, 0.65 mmol)

gave 7a/7⁰a 10/90 (226 mg, 97%).

¹H NMR (250 MHz, CDCl₃): d5.51 (d, 1H, J5.1 Hz),

5.2±5.07 (m, 1H), 4.60 (dd, 1H, J2.1, 8.1 Hz), 4.32 (dd,

1H, J2.1, 5.1 Hz), 4.12 (dd, 1H, J8.1, 1.7 Hz), 4.02±3.95

(m, 1H), 2.68±2.57 (m, 1H), 2.25±2.15 (m, 1H), 1.54 (s,

3H), 1.49 (s, 3H), 1.34 (s, 3H), 1.32 (s, 3H), 1.34±1.29 (m,

6H); ¹³C NMR (62.5 MHz, CDCl₃): d168.3, 109.8, 109.1,

96.1, 72.4, 71.0, 70.7, 70.2, 64.9, 51.4, 29.2, 26.1, 25.8,

24.7, 24.4, 21.7, 21.6; IR (KBr): n3409, 3233,

1743 cm²¹; MS (ESI): m/z: 360.2 (MH¹, 100%).

22.3, 21.8, 21.6; IR (KBr): n3380, 1722 cm²¹

.

4.2.2. Isopropyl 6-[[(1⁰S)-1⁰-phenylethyl]amino]-5,6-di-

deoxy-1-O-methyl-2,3-O-isopropylidene-d,l-glycero-a-d-

lyxo-heptofuranuronate 6c/6⁰c. The starting materials 4c

(270 mg, 0.89 mmol) gave 6c/6⁰c (235 mg, 65%, colourless

oil) by procedure B; TLC (hexane/AcOEt (1/2)) R_f0.86.

1

6c: H NMR (400 MHz, CDCl₃): d7.33±7.26 (m, 5H),

4.3.3. Isopropyl 6-amino-5,6-dideoxy-1-O-methyl-2,3-O-

isopropylidene-d,l-glycero-a-d-xylo-heptopyranuronate

7c/7⁰c. The starting materials 6c/6⁰c 60/40 (158 mg,

0.39 mmol) gave 7c/7⁰c 60/40 (115 mg, 97%, viscous

powder).

5.11±5.04 (m, 1H), 4.79 (s, 1H), 4.46 (d, 1H, J5.9 Hz),

4.34 (dd, 1H, J5.9, 3.7 Hz), 4.07 (dt, 1H, J3.7, 6.8 Hz),

3.71 (q, 1H, J6.6 Hz), 3.31 (s, 3H), 3.13 (t, 1H, J6.8 Hz),

1.95 (t, 2H, J6.8 Hz), 1.86 (br s, 1H), 1.38 (s, 3H), 1.34 (d,

3H, J6.6 Hz), 1.31 (s, 3H), 1.27 (d, 3H, J6.4 Hz), 1.23

(d, 3H, J6.4 Hz); ¹³C NMR (62.5 MHz, CDCl₃): d174.7,

145.0, 128.2, 126.8, 126.5, 112.1, 106.7, 84.9, 80.0, 76.8,

67.9, 56.7, 56.5, 54.3, 32.4, 25.9, 24.8, 24.7, 21.7, 21.6.

7c: ¹H NMR (400 MHz, CD₃CN): d5.01 (h, 1H, J6.3 Hz),

4.79 (s, 1H), 4.68±4.64 (m, 1H), 4.51 (d, 1H, J5.8 Hz),

4.11±4.05 (m, 1H), 3.63±3.56 (m, 1H), 3.27 (s, 3H), 2.59

(br s, 2H), 2.13±1.78 (m, 2H), 1.40 (s, 3H), 1.28 (s, 3H),

1.24 (d, 6H, J6.3 Hz; ¹³C NMR (62.5 MHz, CDCl₃):

d168.1, 112.7, 106.7, 85.0, 80.3, 75.4, 70.6, 55.2, 51.6,

1

6⁰c: H NMR (400 MHz, CDCl₃): d7.33±7.26 (m, 5H),

5.00±4.93 (m, 1H), 4.88 (s, 1H), 4.63 (dd, 1H, J5.9,

3.4 Hz), 4.56 (d, 1H, J5.9 Hz), 4.28±4.24 (m, 1H), 3.77

(q, 1H, J6.6 Hz), 3.50 (dd, 1H, J4.4, 9.8 Hz), 3.35 (s,

3H), 2.11±2.03 (ddd, 1H, J8.5, 14.4, 4.4 Hz), 1.86 (br s,

1H), 1.85±1.76 (ddd, 1H, J4.2, 14.4, 9.8 Hz), 1.45 (s, 3H),

1.33 (d, 3H, J6.6 Hz), 1.22 (s, 3H), 1.21 (d, 3H,

J6.4 Hz), 1.19 (d, 3H, J6.4 Hz); ¹³C NMR (62.5 MHz,

CDCl₃): d174.6, 145.7, 128.2, 126.8, 126.5, 112.1, 106.6,

85.1, 80.7, 76.5, 67.9, 56.7, 56.2, 54.2, 32.5, 26.0, 25.1,

24.7, 21.8, 21.6.

32.1, 26.1, 24.9, 21.7; IR (KBr): n3416, 1735 cm²¹

.

7⁰c: ¹H NMR (400 MHz, CD₃CN): d5.00 (h, 1H,

J6.3 Hz), 4.81 (s, 1H), 4.68±4.64 (m, 1H), 4.50 (d, 1H,

J5.0 Hz), 4.11±4.05 (m, 1H), 3.63±3.56 (m, 1H), 3.28 (s,

3H), 2.59 (br s, 2H), 2.13±1.78 (m, 2H), 1.40 (s, 3H), 1.28

(s, 3H), 1.27 (d, 6H, J6.3 Hz); ¹³C NMR (62.5 MHz,

CDCl₃): d168.5, 113.0, 107.1, 85.1, 80.3, 75.7, 70.5,

54.4, 51.2, 32.9, 26.0, 25.0, 21.5; IR (KBr): n3416,

1735 cm²¹

.

6c/6⁰c: IR (KBr): n3339, 1722 cm²¹; MS (ESI): m/z:

408.3 (MH¹, 100%), 320.2 ((M287)¹, 85%).

4.3.4. Isopropyl 6-amino-5,6-dideoxy-3-O-methyl-1,2-O-

isopropylidene-d,l-glycero-a-d-xylo-heptopyranuronate

7d/7⁰d. The starting materials 6d/6⁰d 55/45 (70 mg,

0.17 mmol) gave 7d/7⁰d 55/45 (51 mg, 99%).

4.3. Hydrogenolysis of glycosyl-a-aminoesters 6

In a typical reaction, 100 mg of palladium 10% on charcoal

was added to a solution of 6a/6⁰a (98/2) (100 mg,

0.22 mmol) in 10 mL of isopropanol. The mixture was

hydrogenated under a 50 bar pressure of hydrogen during

5 h at room temperature, then ®ltered through celite, and the

®ltrate was reduced in vacuo to yield 7a/7⁰a (98/2) (75 mg,

95%).

7d: ¹H NMR (250 MHz, CDCl₃): d5.87 (d, 1H, J3.8 Hz),

5.04 (h, 1H, J6.2 Hz), 4.56 (d, 1H, J3.8 Hz), 4.38±4.30

(m, 1H), 3.65±3.57 (m, 2H), 3.40 (s, 3H), 2.7 (br s, 1H),

2.20±1.7 (m, 2H), 1.48 (s, 3H), 1.29 (s, 3H), 1.25 (d, 6H,

J6.2 Hz); ¹³C NMR (62.5 MHz, CDCl₃): d174.8, 111.3,

104.6, 84.9, 81.6, 77.2, 68.4, 57.5, 52.0, 32.2, 26.6, 26.1,

21.8, 21.7; IR (KBr): n3455, 3403, 1728 cm²¹

.

4.3.1. Isopropyl 7-amino-6,7-dideoxy-1,2:3,4-di-O-iso-

propylidene-l-glycero-a-d-galacto-octopyranuronate 7a.

7⁰d: ¹H NMR (250 MHz, CDCl₃): d5.87 (d, 1H,

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

6223

J3.8 Hz), 5.03 (h, 1H, J6.2 Hz), 4.57 (d, 1H, J3.8 Hz),

4.38±4.30 (m, 1H), 3.65±3.57 (m, 2H), 3.41 (s, 3H), 2.7 (br

s, 1H), 2.20±1.7 (m, 2H), 1.48 (s, 3H), 1.29 (s, 3H), 1.25 (d,

6H, J6.2 Hz); ¹³C NMR (62.5 MHz, CDCl₃): d174.2,

111.3, 104.4, 84.6, 81.4, 77.8, 68.6, 57.6, 52.6, 32.4, 26.6,

8c: ¹H NMR (400 MHz, CDCl₃): d6.80 (d, 1H,

J5.9 Hz), 5.11±5.01 (m, 2H), 4.82 (s, 1H), 4.66 (dd, 1H,

J5.9, 3.6 Hz), 4.61±4.56 (m, 1H), 4.53 (d, 1H, J5.9 Hz),

4.21±4.18 (m, 1H), 3.97±3.93 (m, 1H), 3.29 (s, 3H), 2.32±

2.26 (m, 1H), 2.21±2.15 (m, 1H), 1.46 (s, 3H), 1.45 (s, 9H),

1.38 (d, 3H, J7.0 Hz), 1.33 (s, 3H), 1.28 (d, 3H,

J6.5 Hz), 1.26 (d, 3H, J6.3 Hz); ¹³C NMR (62.5 MHz,

CDCl₃): d172.2, 171.0, 155.2 112.5, 106.9, 85.0, 80.5,

80.0, 77.2, 69.2, 54.6, 50.8, 50.0, 30.7, 28.3, 26.1, 25.0,

21.8, 21.6, 18.7; IR (KBr): n3402, 1735, 1714,

26.1, 21.8, 21.7; IR (KBr): n3455, 3403, 1728 cm²¹

.

4.4. General procedure for N-side coupling

A mixture of 1 equiv. of a-aminoester 7/7⁰, 1.1 equiv. of

BOC±Ala±OH, 1.5 equiv. of triethylamine, 1.1 equiv. of

BOP, in chloroform, was stirred for 4 h at room temperature.

The reaction mixture was then washed with water, and the

aqueous layer was extracted with chloroform. The organic

layers were joined together and dried over sodium sulphate,

then evaporated, and the residue was puri®ed by chromato-

graphy on a silica gel column.

1658 cm²¹

.

8⁰c: ¹H NMR (250 MHz, CDCl₃₎: d7.11±7.05 (br d, 1H),

5.12±4.99 (m, 2H), 4.88 (s, 1H), 4.72±4.66 (m, 1H), 4.60±

4.55 (m, 1H), 4.53 (d, 1H, J6.0 Hz), 4.23±4.16 (m, 1H),

3.98±3.92 (m, 1H), 3.33 (s, 3H), 2.33±2.03 (m, 2H), 1.45 (s,

9H), 1.44 (s, 3H), 1.37 (d, 3H, J6.8 Hz), 1.31 (s, 3H), 1.26

(d, 3H, J6.4 Hz), 1.23 (d, 3H, J6.4 Hz); ¹³C NMR

(62.5 MHz, CDCl₃): d172.4, 171.0, 155.2 112.6, 106.8,

84.8, 80.5, 80.0, 76.8, 69.1, 54.5, 50.6, 50.0, 30.2, 28.3,

26.0, 24.9, 21.7, 21.5, 18.6; IR (KBr): n3402, 1735,

4.4.1. Isopropyl 7-[[(2⁰S)-2⁰-(tert-butoxycarbonylamino)-

1⁰-oxopropyl]amino]-6,7-dideoxy-1,2:3,4-di-O-isoprop-

ylidene-l-glycero-a-d-galacto-octopyranuronate 8a. The

starting materials 7a/7⁰a (98/2) (75 mg, 0.21 mmol) gave

8a/8⁰a (98/2) (103 mg, 93%).

1714, 1658 cm²¹

.

4.4.4. Isopropyl 6-[[(2⁰S)-2⁰-(tert-butoxycarbonylamino)-

1⁰-oxopropyl]amino]-5,6-dideoxy-3-O-methyl-1,2-O-iso-

propylidene-d,l-glycero-a-d-xylo-heptofuranuronate 8d/

8⁰d. The starting materials 7d/7⁰d 55/45 (51 mg,

0.17 mmol) gave 8d/8⁰d 55/45 (70 mg, 87%); TLC (hex-

ane/AcOEt (1/3)) R_f0.66.

1

TLC (hexane/AcOEt (1/3)) R_f0.69; H NMR (250 MHz,

CDCl₃): d6.90 (br s, 1H), 5.49 (d, 1H, J5.1 Hz), 5.33

(d, 1H, J6.0 Hz), 5.13±4.95 (m, 1H), 4.59 (dd, 1H, J2.6,

7.7 Hz), 4.55±4.48 (m, 1H), 4.30 (dd, 1H, J5.1, 2.6 Hz),

4.28±4.23 (m, 1H), 4.13 (dd, 1H, J1.7, 7.7 Hz), 3.84±3.80

(m, 1H), 2.31±2.17 (m, 1H), 2.14±2.04 (m, 1H), 1.51 (s,

3H), 1.45 (s, 12H), 1.38 (d, 3H, J6.8 Hz), 1.34 (s, 3H),

1.33 (s, 3H), 1.25 (d, 3H, J4.2 Hz), 1.21 (d, 3H,

J4.2 Hz); ¹³C NMR (62.5 MHz, CDCl₃): d172.4,

170.9, 155.1, 109.4, 108.7, 96.4, 77.5, 72.8, 70.9, 70.1,

69.0, 65.2, 50.9, 49.9, 30.7, 28.3, 26.0, 24.7, 24.5, 21.7,

1

8d: H NMR (250 MHz, CDCl₃₎: d7.05±6.95 (m, 1H),

5.89 (d, 1H, J4.1 Hz), 5.15±5.08 (m, 1H), 5.08±4.99

(m, 1H), 4.67±4.52 (m, 1H), 4.55 (d, 1H, J4.1 Hz),

4.22±4.16 (m, 2H), 3.59 (d, 1H, J3.3 Hz), 3.41 (s, 3H),

2.28±2.00 (m, 2H), 1.46 (s, 3H), 1.45 (s, 9H), 1.37 (d, 3H,

J6.9 Hz), 1.31 (s, 3H), 1.26 (d, 3H, J6.4 Hz), 1.24 (d,

3H, J6.4 Hz); ¹³C NMR (62.5 MHz, CDCl₃): d172.5,

170.9, 155.2, 111.5, 104.6, 84.8, 81.0, 80.0, 77.3, 69.1,

57.6, 50.5, 49.9, 29.9, 28.2, 26.6, 26.1, 21.6, 18.5; IR

21.6, 19.2; IR (KBr): n3416, 1731, 1714, 1680 cm²¹

.

4.4.2. Isopropyl 7-[[(2⁰S)-2⁰-(tert-butoxycarbonylamino)-

1⁰-oxopropyl]amino]-6,7-dideoxy-1,2:3,4-di-O-isopropyl

idene]-d-glycero-a-d-galacto-octopyranuronate 8⁰a. The

starting materials 7a/7⁰10/90 (0.217 g, 0.60 mmol) gave 8a/

8⁰a 10/90 (0.255 g, 80%).

(KBr): n3346, 1715, 1673 cm²¹

.

8⁰d: ¹H NMR (250 MHz, CDCl₃): d6.81 (d, 1H,

J7.4 Hz), 5.84 (d, 1H, J3.6 Hz), 5.15±5.08 (m, 1H),

5.09±4.98 (m, 1H), 4.67±4.52 (m, 1H), 4.57 (d, 1H,

J3.6 Hz), 4.22±4.16 (m, 2H), 3.67 (d, 1H, J3.1 Hz),

3.43 (s, 3H), 2.28±2.00 (m, 2H), 1.46 (s, 3H), 1.45 (s,

9H), 1.36 (d, 3H, J7.1 Hz), 1.29 (s, 3H), 1.26 (d, 3H,

J6.2 Hz), 1.25 (d, 3H, J6.2 Hz); ¹³C NMR (62.5 MHz,

CDCl₃): d172.5, 171.0, 155.2, 111.4, 104.6, 84.7, 81.3,

80.0, 77.1, 69.1, 57.6, 50.6, 50.0, 30.6, 28.2, 26.6, 26.0,

1

TLC (hexane/AcOEt (1/3)) R_f0.69; H NMR (250 MHz,

CDCl₃): d7.46 (br s, 1H), 5.54 (d, 1H, J5.1 Hz), 5.24

(d, 1H, J6.0 Hz), 5.08±4.94 (m, 1H), 4.58 (dd, 1H, J2.6,

8.1 Hz), 4.54±4.47 (m, 1H), 4.31 (dd, 1H, J5.1, 2.6 Hz),

4.24±4.19 (m, 1H), 4.05 (dd, 1H, J1.7, 8.1 Hz), 3.95±3.89

(m, 1H), 2.24±2.12 (m, 1H), 2.07±1.98 (m, 1H), 1.55 (s,

3H), 1.44 (s, 9H), 1.42 (s, 3H), 1.37 (d, 3H, J6.8 Hz), 1.33

(s, 3H), 1.32 (s, 3H), 1.26 (d, 3H, J6.4 Hz), 1.21 (d, 3H,

J6.4 Hz); ¹³C NMR (62.5 MHz, CDCl₃): d172.7, 170.9,

155.0, 109.3, 108.9, 95.8, 78.7, 73.1, 70.6, 70.0, 68.7, 65.2,

50.7, 49.0, 30.7, 28.2, 25.8, 25.7, 24.7, 24.3, 21.6, 18.5; IR

21.7, 18.5; IR (KBr): n3346, 1715, 1673 cm²¹

.

4.5. General procedure for the transesteri®cation of the

isopropyl glycosyl-a-aminoesters 6

(KBr): n3437, 3395, 1734, 1714, 1672 cm²¹

.

1 equiv. (1.3 mmol) of BuLi (2.5 M in hexane) was added

dropwise at 08C to 4.5 mL of methyl alcohol. Then, a solu-

tion of 1 equiv. (600 mg, 1.3 mmol) of pure 6a in 9 mL of

THF was added and the mixture was stirred at re¯ux (608C)

during 2.5 h. The crude was concentrated, washed with

water, and the aqueous layer was extracted with dichloro-

methane. The organic layer was dried over magnesium

4.4.3. Isopropyl 6-[[(2⁰S)-2⁰-(tert-butoxycarbonylamino)-

1⁰-oxopropyl]amino]-5,6-dideoxy-1-O-methyl-2,3-O-iso-

propylidene-d,l-glycero-a-d-lyxo-heptofuranuronate

8c/8⁰c. The starting materials 7c/7⁰c 60/40 (30 mg,

0.099 mmol) gave 8c/8⁰c 60/40 (30 mg, 64%); TLC (hex-

ane/AcOEt (1/1)) R_f0.42.

6224

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

sulphate, evaporated, and the residue was puri®ed on a silica

gel chromatographic column.

9c/9⁰c: IR (KBr): n3318, 1736 cm²¹

.

4.5.4. Methyl 6-[[(1⁰S)-1⁰-phenylethyl]amino]-5,6-di-

deoxy-3-O-methyl-1,2-O-isopropylidene-d,l-glycero-a-d-

xylo-heptofuranuronate 9d/9⁰d. The starting materials 6d/

6⁰d (55/45) (103 mg, 0.25 mmol) gave 9d/9⁰d (55/45)

(80 mg, 84%); TLC (hexane/AcOEt (1/1)) R_f0.68.

4.5.1. Methyl 7-[[(1⁰S)-1⁰-phenylethyl]amino]-6,7-di-

deoxy-1,2:3,4-di-O-isopropylidene-l-glycero-a-d-galacto-

octo pyranuronate 9a. The pure diastereomer 6a (370 mg,

0.8 mmol) gave 9a (289 mg, 83%, white powder); TLC

(hexane/AcOEt (1/2)) R_f0.79; mp 1518C.

1

9d: H NMR (250 MHz, CDCl₃): d7.31±7.21 (m, 5H),

¹H NMR (250 MHz, CDCl₃): d7.32±7.20 (m, 5H), 5.46

(d, 1H, J5.1 Hz), 4.48 (dd, 1H, J2.6, 8.1 Hz), 4.27

(dd, 1H, J2.6, 5.1 Hz), 4.11±4.01 (m, 1H), 3.78±3.70

(m, 2H), 3.72 (s, 3H), 3.15 (dd, 1H, J5.6, 7.3 Hz),

2.00±1.90 (m, 1H), 1.89±1.79 (m, 1H), 1.64 (s, 3H),

1.56 (s, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 1.33 (d, 3H,

J6.4 Hz), 1.26 (s, 3H); ¹³C NMR (62.5 MHz, CDCl₃):

d175.7, 145.1, 128.2, 127.0, 126.9, 108.9, 108.3, 96.5,

71.8, 70.8, 70.4, 64.5, 56.7, 55.6, 51.6, 33.6, 25.9, 25.8,

25.1, 24.9, 24.3; IR (KBr): n3320, 1733 cm²¹; MS

(ESI): m/z: 436.2 (MH¹, 100%); 376.2 ((M259)¹,

5.82 (d, 1H, J3.8 Hz), 4.45 (d, 1H, J3.8 Hz), 4.37±

4.30 (m, 1H), 3.73 (s, 3H), 3.68 (q, 1H, J6.4 Hz), 3.17

(d, 1H, J3.4 Hz), 3.13 (s, 3H), 2.98 (dd, 1H, J5.6,

8.5 Hz), 1.93±1.86 (m, 2H), 1.54 (s, 4H), 1.33 (d, 3H,

J6.4 Hz), 1.26 (s, 3H); ¹³C NMR (62.5 MHz, CDCl₃):

d175.9, 145.0, 128.4, 127.1, 126.7, 111.2, 104.6, 85.0,

83.8, 81.6, 77.2, 56.8, 56.4, 51.8, 31.7, 26.7, 25.0, 22.8;

IR (KBr): n3346, 1731 cm²¹

.

1

9⁰d: H NMR (250 MHz, CDCl₃): d7.31±7.21 (m, 5H),

5.87 (d, 1H, J3.8 Hz), 4.56 (d, 1H, J3.8 Hz), 4.45±4.40

(m, 1H), 3.77 (q, 1H, J6.4 Hz), 3.60±3.58 (m, 4H), 3.46

(dd, 1H, J4.7, 9.4 Hz), 3.33 (s, 3H), 2.08±1.95 (m, 1H),

1.83±1.71 (m, 1H), 1.52 (s, 4H), 1.31 (d, 3H, J6.0 Hz),

1.26 (s, 3H); ¹³C NMR (62.5 MHz, CDCl₃): d175.8,

145.6, 128.3, 127.0, 126.9, 111.3, 104.5, 85.0, 83.8, 81.7,

77.2, 57.5, 56.3, 51.7, 32.1, 26.3, 25.0, 22.7; IR (KBr):

55%); a_D269,3 (c2,44 g dl²¹, CHCl₃).

20

4.5.2. Methyl 7-[[(1⁰S)-1⁰-phenylethyl]amino]-6,7-di-

deoxy-1,2:3,4-di-O-isopropylidene-d-glycero-a-d-galacto-

octopyranuronate 9⁰a. The starting materials 6a/6⁰a (10/

90) (200 mg, 0.43 mmol) gave 9a/9⁰a (10/90) (160 mg,

86%); TLC (hexane/AcOEt (1/2)) R_f0.74.

n3346, 1731 cm²¹

.

¹H NMR (250 MHz, CDCl₃): d7.32±7.20 (m, 5H), 5.57

(d, 1H, J5.1 Hz), 4.61 (dd, 1H, J2.6, 8.1 Hz), 4.32 (dd,

1H, J2.6, 5.1 Hz), 4.22±4.16 (m, 1H), 4.08 (dd, 1H,

J1.7, 8.1 Hz, 3.76 (q, 1H, J6.4 Hz), 3.56 (s, 3H), 3.54

(dd, 1H, J3.4, 10.0 Hz), 2.06±1.80 (m, 2H), 1.65 (s, 3H),

1.56 (s, 4H), 1.46 (s, 3H), 1.35 (d, 3H, J6.4 Hz), 1.27 (s,

3H); ¹³C NMR (62.5 MHz, CDCl₃): d176.2, 145.6, 128.2,

127.0, 126.9, 109.0, 108.4, 96.1, 73.4, 71.0, 70.5, 64.0, 56.7,

55.3, 51.5, 35.0, 26.2, 26.0, 25.0, 24.3, 22.5; IR (KBr):

4.6. General procedure for the hydrolysis of methyl

glycosyl-a-aminoesters 9 and C-side coupling

In a typical procedure, a solution of 1 equiv. of isopropyl a-

aminoester 9 in a mixture of solvent MeOH/THF 1/3, was

added to 1 equiv. of a 1N methanolic solution of potassium

hydroxide, and stirred at re¯ux for 4 h. Then, the crude was

reduced, and directly used in C-side coupling. The a-amino-

carboxylate 10 was stirred in chloroform with 1.1 equiv. of

HCl,Gly-OMe, 1.5 equiv. of triethylamine, and 1.1 equiv. of

BOP. The mixture was washed with water, and the aqueous

layer was extracted by chloroform. The organic layers were

joined together and dried with sodium sulphate, concen-

trated, and puri®ed by chromatography on a silica gel

column to give 11/11⁰.

n3318, 1743 cm²¹

.

4.5.3. Methyl 6-[[(1⁰S)-1⁰-phenylethyl]amino]-5,6-di-

deoxy-1-O-methyl-2,3-O-isopropylidene-d,l-glycero-a-d-

lyxo-heptofuranuronate 9c/9⁰c. The starting materials 6c/

6⁰c (60/40) (260 mg, 0.64 mmol) gave 9c/9⁰c (60/40)

(194 mg, 80%); TLC (hexane/AcOEt (1/2)) R_f0.76.

4.6.1. Methyl N-[6,7-dideoxy-1,2:3,4-di-O-isopropylidene-

7-[[(1⁰S)-1⁰-phenylethyl]amino]-l-glycero-a-d-galacto-

octopyranuronoyl]-glycinate 11a. The starting materials

9a/9⁰(98/2) (250 mg, 0.57 mmol) gave 11a/11⁰a (98/2)

(193 mg, 69%); TLC (hexane/AcOEt (1/3)) R_f0.45.

1

9c: H NMR (250 MHz, CDCl₃): d7.32±7.22 (m, 5H),

4.79 (s, 1H), 4.45 (d, 1H, J5.6 Hz), 4.31 (dd, 1H, J5.6,

3.4 Hz), 4.07 (dt, 1H, J3.4, 6.8 Hz), 3.73 (s, 3H), 3.69 (q,

1H, J6.4 Hz), 3.31 (s, 3H), 3.19 (t, 1H, J6.8 Hz), 1.96 (t,

2H, J6.8 Hz), 1.61 (br s, 1H), 1.45 (s, 3H), 1.38 (s, 3H),

1.35 (d, 3H, J6.4 Hz); ¹³C NMR (62.5 MHz, CDCl₃):

d175.8, 144.9, 128.2, 126.9, 126.6, 112.1, 106.8, 84.9,

80.7, 79.9, 76.5, 56.7, 56.5, 54.3, 32.5, 25.9, 25.0, 24.7.

¹H NMR (250 MHz, CDCl₃): d7.54 (t, 1H, J5.6 Hz),

7.32±7.19 (m, 5H), 5.47 (d, 1H, J5.1 Hz), 4.49 (dd, 1H,

J2.6, 7.7 Hz), 4.25 (dd, 1H, J5.1, 2.6 Hz), 4.11±3.99 (m,

2H), 3.90 (dd, 1H, J7.7, 1.8 Hz), 3.87±3.80 (m, 1H),

3.78±3.73 (m, 1H), 3.76 (s, 3H), 3.08 (dd, J4.3, 8.5 Hz),

2.45 (br s, 1H), 2.00±1.90 (m, 1H), 1.86±1.77 (m, 1H), 1.46

(s, 3H), 1.40 (s, 3H), 1.34 (d, 3H, J7.3 Hz), 1.31 (s, 3H),

1.26 (s, 3H); ¹³C NMR (62.5 MHz, CDCl₃): d175.0,

170.3, 144.7, 128.4, 126.8, 108.9, 108.3, 96.2, 72.7, 70.6,

70.0, 67.1, 59.5, 56.7, 52.1, 40.7, 34.5, 25.9, 25.7, 24.8,

1

9⁰c: H NMR (250 MHz, CDCl₃): d7.32±7.22 (m, 5H),

4.87 (s, 1H), 4.62 (dd, 1H, J5.5, 3.4 Hz), 4.55 (d, 1H,

J5.5 Hz), 4.27±4.20 (m, 1H), 3.76 (q, 1H, J6.4 Hz),

3.62 (s, 3H), 3.50 (dd, 1H, J4.7, 9.5 Hz), 3.34 (s, 3H),

2.14±2.03 (m, 1H), 1.88±1.77 (m, 1H), 1.61 (br s, 1H),

1.45 (s, 3H), 1.33 (d, 3H, J6.4 Hz), 1.30 (s, 3H); ¹³C

NMR (62.5 MHz, CDCl₃): d175.6, 145.5, 128.2, 127.0,

126.9, 112.1, 106.7, 85.2, 80.7, 79.9, 76.5, 56.4, 56.3, 54.3,

32.5, 26.0, 25.9, 24.8.

24.3, 24.1; IR (KBr): n3346, 1743, 1673 cm²¹

.

4.6.2. Methyl N-[6,7-dideoxy-1,2:3,4-di-O-isopropylidene-

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

6225

7-[[(1⁰S)-1⁰-phenylethyl]amino]-d-glycero-a-d-galacto-

octopyranuronoyl]-glycinate 11⁰aThe starting materials

9a/9⁰a 10/90 (65 mg, 0.15 mmol) gave 11a/11⁰a 10/

90(45 mg, 61%); TLC (hexane/AcOEt (1/3)) R_f0.45.

81.1, 79.6, 77.7, 59.9, 57.7, 56.8, 40.8, 28.7, 26.5, 26.1,

24.4.

1

11⁰d: H NMR (250 MHz, CDCl₃): d7.86 (br t), 7.35±

7.20 (m, 5H), 5.93 (d, 1H, J4.1 Hz), 4.52 (d, 1H,

J4.1 Hz), 4.20 (dd, 1H, J6.7, 18.4 Hz), 4.07±4.03 (m,

1H), 3.98 (dd, 1H, J4.9, 18.4 Hz), 3.86 (q, 1H, J6.4 Hz),

3.79 (s, 3H), 3.47 (d, 1H, J3.3 Hz), 3.33 (s, 3H), 3.03 (dd,

1H, J3.6, 10.1 Hz), 1.99±1.82 (m, 2H), 1.51 (br s, 1H),

1.48 (s, 3H), 1.39 (d, 3H, J6.4 Hz), 1.34 (s, 3H); ¹³C NMR

(62.5 MHz, CDCl₃): d175.0, 170.2, 144.8, 127.1, 126.9,

126.6, 111.3, 85.5, 81.0, 79.6, 77.7, 59.9, 57.8, 57.6, 40.6,

32.4, 26.7, 26.2, 24.7.

¹H NMR (250 MHz, CDCl₃): d8.07 (t, 1H, J5.1 Hz),

7.34±7.18 (m, 5H), 5.52 (d, 1H, J5.1 Hz), 4.57 (dd, 1H,

J2.6, 8.1 Hz), 4.29 (dd, 1H, J5.1, 2.6 , 4.11 (dd, 1H,

J8.1, 1.7 Hz), 4.00±3.97 (m, 1H), 3.96±3,86 (m, 2H),

3.81±3.73 (m, 1H), 3.76 (s, 3H), 3.20 (dd, J3.9, 5.6 Hz),

2.22±2.11 (m, 1H), 1.96±1.85 (m, 1H), 1.49 (s, 6H), 1.36 (s,

3H), 1.34 (d, 3H, J5.6 Hz), 1.26 (s, 3H); ¹³C NMR

(62.5 MHz, CDCl₃): d174.2, 169.4, 144.8, 128.4, 127.0,

109.1, 108.5, 96.3, 73.3, 70.8, 70.3, 65.5, 57.3, 56.4, 51.6,

40.9, 33.5, 26.0, 25.9, 24.9, 24.4; IR (KBr): n3437, 3360,

11d/11⁰d: IR (KBr): n3438, 3353, 1750, 1673 cm²¹

.

1743, 1666 cm²¹

.

4.7. Introduction of the 2-(1⁰,2⁰;3⁰,4⁰-di-O-isopropylidene

6⁰-deoxy-a-d-galactopyranosyl)glycine residue inside a

peptide

4.6.3. Methyl N-[5,6-dideoxy-1-O-methyl-2,3-O-isopro-

pylidene-6-[[(1⁰S)-1⁰-phenylethyl]amino]-d,l-glycero-a-

d-lyxo-heptofuranuronoyl]-glycinate 11c/11⁰c. The start-

ing materials 9c/9⁰c 60/40 (117 mg, 0.29 mmol) gave 11c/

11⁰c 60/40 (95 mg, 75%); TLC (hexane/AcOEt (1/2)) R_f

0.52.

4.7.1. Methyl N-[6,7-dideoxy-1,2:3,4-di-O-isopropylidene-

7-amino-l-glycero-a-d-galacto-octopyranuronoyl]-glycinate

12a. To a solution of 11a/11⁰a (98/2) (180 g, 0.37 mmol) in

15 mL of isopropanol was added 0.20 g of palladium 10%

on charcoal. The mixture was hydrogenated at room

temperature under a 50 bar pressure of hydrogen during

5 h, then ®ltered through celite, and the ®ltrate was evapo-

rated in vacuo to yield 12a/12⁰a (98/2).

11c: ¹H NMR (250 MHz, CDCl₃): d7.71 (t, 1H,

J5.7 Hz), 7.36±7.19 (m, 5H), 4.84 (s, 1H), 4.48±4.47

(m,2H), 4.22 (dd, 1H, J6.4, 18.5 Hz), 3.99 (dd, 1H,

J5.7, 18.5 Hz), 3.97±3.91 (m, 1H), 3.78 (s, 3H), 3.74±

3.68 (m, 1H), 3.29 (s, 3H), 3.10 (dd, 1H, J3.8, 9.0 Hz),

2.38 (br s, 1H), 2.05 (ddd, 1H, J15.0, 4.2, 3.8 Hz), 1.91

(ddd, 1H, J15.0, 8.0, 9.0 Hz), 1.42 (s, 3H), 1.39 (d, 3H,

J6.4 Hz), 1.26 (s, 3H); ¹³C NMR (62.5 MHz, CDCl₃):

d174.9, 170.3, 144.8, 128.5, 127.1, 126.3, 112.3, 107.5,

84.7, 80.7, 78.8, 59.7, 57.8, 57.2, 40.8, 33.1, 26.0, 24.8,

24.2.

¹H NMR (400 MHz, CDCl₃): d8.63 (br s, 2H); 5.47 (d,

1H, J4.8 Hz), 4.52 (dd, 1H, J2.2 Hz, J7.7 Hz), 4.46±

4.38 (m, 1H), 4.25 (dd, 1H, J2.2 Hz, J4.8 Hz), 4.12±

4.05 (m, 2H), 4.03±3.98 (m, 1H), 3.98±3.86 (m, 1H), 3.67

(s, 3H), 2.32±2.14 (m, 2H), 1.50 (s, 3H), 1.38 (s, 3H), 1.27

(s, 3H), 1.25 (s, 3H); ¹³C NMR (62.5 MHz, CDCl₃):

d170.0, 169.6, 109.0, 108.5, 96.3, 72.0, 70.5, 70.1, 65.9,

52.2, 52.0, 41.2, 31.6, 25.9, 25.7, 24.7, 24.2; IR (KBr):

n3381, 3219, 1750, 1687 cm²¹; MS (ESI): m/z: 389.1

(MH¹, 100%).

11⁰c: ¹H NMR (250 MHz, CDCl₃): d8.03 (t, 1H,

J6.4 Hz), 7.36±7.19 (m, 5H), 4.88 (s, 1H), 4.62 (dd, 1H,

J3.4, 6.0 Hz), 4.52 (d, 1H, J6.0 Hz), 4.13±4.06 (m, 1H),

3.97±3.88 (m, 3H), 3.75 (s, 3H), 3.30 (s, 3H), 3.27±3.23 (m,

1H), 2.38 (br s, 1H), 2.20±2.13 (m, 2H), 1.49 (s, 3H), 1.39

(d, 3H, J6.4 Hz), 1.32 (s, 3H); ¹³C NMR (62.5 MHz,

CDCl₃): d174.3, 170.2, 144.6, 128.5, 127.2, 126.5,

112.3, 107.1, 84.9, 80.9, 79.0, 59.7, 56.9, 54.9, 40.9, 29.8,

26.2, 24.9, 23.9.

4.7.2. Methyl N-[6,7-dideoxy-1,2:3,4-di-O-isopropylidene-

7-[[(2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxo-

propyl]amino]-l-glycero-a-d-galacto-octopyranuro-

noyl]-glycinate 13a. To a solution of 12a/12⁰a (98/2)

(140 mg, 0.36 mmol) in 25 mL of chloroform were added

1.1 equiv. (75 mg, 0.39 mmol) of BOC±Ala±OH,

1.5 equiv. (54 mg, 0.54 mmol) triethylamine, 1.1 equiv.

(174 mg, 0.39 mmol) of BOP, and the mixture was stirred

for 2.5 h at room temperature. The crude was washed with

10 mL of water, and the aqueous layer was extracted with

chloroform. The organic layers were joined together and

dried over magnesium sulphate, then evaporated. The resi-

due was puri®ed by chromatography on a silica gel column

to give the colourless oil 13a/13⁰a (98/2) (139 mg, 69%

from 11a/11⁰); TLC (hexane/AcOEt(1/3)) R_f0.3.

11c/11⁰c: IR (KBr): n3339, 1740, 1670 cm²¹

.

4.6.4. Methyl N-[5,6-dideoxy-3-O-methyl-1,2-O-isopro-

pylidene-6-[[(1⁰S)-1⁰-phenylethyl]amino]-d,l-glycero-a-

d-xylo-heptofuranuronoyl]-glycinate 11d/11⁰d. The start-

ing materials 9d/9⁰d 55/45 (50 mg, 0.124 mmol) gave 11d/

11⁰d 55/45 (46 mg, 85%); TLC (hexane/AcOEt (1/3)) R_f

0.51.

11d: ¹H NMR (250 MHz, CDCl₃): d8.16 (t, 1H,

J3.4 Hz), 7.35±7.20 (m, 5H), 5.92 (d, 1H, J3.8 Hz),

4.55 (d, 1H, J3.8 Hz), 4.31±4.27 (m, 1H), 3.97 (d, 2H,

J5.9 Hz), 3.92 (q, 1H, J6.4 Hz), 3.75 (s, 3H), 3.61 (d,

1H, J3.1 Hz), 3.40 (s, 3H), 3.22 (t, J4.9 Hz), 2.20±2.12

(m, 2H), 1.51 (br s, 1H), 1.48 (s, 3H), 1.37 (d, 3H,

J6.4 Hz), 1.32 (s, 3H); ¹³C NMR (62.5 MHz, CDCl₃):

d174.3, 170.0, 144.6, 128.4, 126.9, 126.6, 111.4, 85.6,

¹H NMR (400 MHz, CDCl₃): d7.32 (d, 1H, J4.7 Hz);

7.16±7.11 (m, 1H); 5.57 (d, 1H, J4.9 Hz), 5.33 (d, 1H,

J5.4 Hz), 4.62 (dd, 1H, J2.5, 7.9 Hz), 4.51±4.45 (m,

1H), 4.34 (dd, 1H, J2.5, 4.9 Hz), 4.27±4.23 (m, 1H),

4.19 (dd, 1H, J1.7, 7.9 Hz), 4.14 (d, 1H, J6.2 Hz),

4.10 (d, 1H, J6.2 Hz), 3.90±3.84 (m, 1H), 3.75 (s, 3H),

2.20±2.09 (m, 2H), 1.48 (s, 12H), 1.47 (s, 3H), 1.40 (d, 3H,

6226

C. Grison et al. / Tetrahedron 57 (2001) 6215±6227

J7.2 Hz), 1.36 (s, 3H), 1.34 (s, 3H); ¹³C NMR (62.5 MHz,

CDCl₃): d173.6, 171.8, 170.4, 155.7, 109.3, 108.8, 96.3,

79.9, 72.9, 70.6, 70.1, 66.4, 52.7, 52.3, 50.6, 41.0, 31.3,

28.2, 25.9, 25.8, 24.8, 24.3, 17.3; IR (KBr): n3423,

3367, 1752, 1700, 1686, 1676 cm²¹; MS (ESI): m/z: 560.3

(MH¹, 18%), 582.2 (MNa¹, 100%).

60.3, 56.9, 54.4, 50.0, 33.6, 31.2, 26.1, 25.9, 24.9, 24.2,

23.8, 23.7, 21.7, 21.4.

14⁰ac: ¹H NMR (250 MHz, CDCl₃): d8.13 (d, 1H,

J8.5 Hz); 7.37±7.18 (m, 5H); 5.46 (d, 1H, J4.7 Hz),

5.15±5.02 (m, 1H), 4.91 (s, 1H), 4.70±4.64 (m, 1H),

4.63±4.60 (m, 1H), 4.57±4.45 (m, 2H), 4.33 (dd, 1H,

J4.7, 2.6 Hz), 4.07±3.71 (m, 4H), 3.32 (s, 3H), 3.16±

3.12 (m, 1H), 2.33±2.14 (m, 2H), 1.97±1.81 (m, 3H),

1.61±1.18 (m, 27H); ¹³C NMR (62.5 MHz, CDCl₃):

d174.8, 171.0, 145.0, 128.3, 126.9, 126.1, 112.6, 108.8,

106.7, 96.2, 84.8, 80.7, 76.8, 72.7, 70.8, 70.4, 68.9, 67.5,

60.0, 56.7, 54.4, 50.2, 32.5, 30.2, 26.1, 25.9, 24.9, 24.2,

23.8, 23.7, 21.7, 21.4.

4.8. Coupling between two glycosyl-a-aminoacids

4.8.1. Isopropyl 6,7-dideoxy-1,2:3,4-di-O-isopropylidene-

7-[[6,7-dideoxy-1,2:3,4-di-O-isopropylidene-7-[[(1⁰S)-1⁰-

phenylethyl]amino]-l-glycero-a-d-galacto-octopyranur-

onoyl]amino]-l-glycero-a-d-galacto-octopyranuronate

14aa. In a typical procedure, a solution of 10a/10⁰a (98/2)

(160 mg, 0.34 mmol) in 25 mL of chloroform was stirred

during 2 h at room temperature in the presence of 1 equiv.

(120 mg, 0,34 mmol) of 7a/7⁰a (98/2), 1.1 equiv. (170 mg,

0.37 mmol) of BOP, and some drops of triethylamine to ®x

the pH at 9. The crude was washed with 10 mL of water, and

the aqueous layer was extracted with chloroform. The

organic layer was dried over magnesium sulphate, evapo-

rated, and the residue was puri®ed by chromatography on a

silica gel column to give 14aa/14⁰aa (98/2) (253 mg, 98%)

as a white powder; TLC (hexane/AcOEt (1/3)) R_f0.66; mp

668C.

14ac/14⁰ac: IR (KBr): n3423, 3346, 1736, 1673 cm²¹

.

Acknowledgements

We thank Dr A. van Dorsselaer (Strasbourg University) for

the mass spectra.

References

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Synthesis of new glycosyl-α-aminoacid derivatives for glycopeptide chemistry

DOI: 10.1016/S0040-4020(01)00600-7

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