Anomeric α-azido acid (2-azido-2-deoxy-hept-2-ulopyranosonic acid) derivatives en route to peptides incorporating sugar amino acids

Tetrahedron:

Asymmetry

Tetrahedron: Asymmetry 16 (2005) 127–141

Anomeric a-azido acid

(2-azido-2-deoxy-hept-2-ulopyranosonic acid) derivatives

en route to peptides incorporating sugar amino acids

*

´ ´ ´ ´ ´ ´

Katalin Czifrak, Peter Szilagyi and Laszlo Somsak

Department of Organic Chemistry, University of Debrecen, H-4010, POB 20, Debrecen, Hungary

Received 25 October 2004; accepted 23 November 2004

Available online 25 December 2004

Abstract—Per-O-acylated 2,6-anhydro-aldoheptonic acids of D-glycero-D-gulo and D-glycero-L-manno conﬁguration obtained by

nitrosation of the corresponding aldonamides were transformed into methyl-, tert-butyl-, 2,2,2-trichloroethyl-, and pentachlorophe-

nyl esters, acid chlorides and glycinamides by standard procedures. Radical-mediated bromination either by bromine in boiling

CHCl₃under illumination, or NBS in reﬂuxing CCl₄in the presence of Bz₂O₂or AIBN, or Na₂S₂O₄–KBrO₃in CH₂Cl₂–water

biphasic solvent mixture at rt gave axial anomers of the 2-bromides of the above esters and acid chlorides (2-bromo-2-deoxy-a-

D-hept-2-ulopyranosonic acid derivatives), while a glycinamide was split along the –H₂C–NH– bond. Anomeric bromides of the

glycinamides were obtained by N-acylation of a glycine ester with the pentachlorophenyl 2-bromo-2-deoxy-ulosonates. In this reac-

tion the axial anomeric bromide proved stable. Sodium azide in DMSO or DMF was used for the substitution of the anomeric bro-

mides. These reactions proceeded with inversion in the case of each ester and glycinamide to produce equatorial azides (2-azido-2-

deoxy-b-^D-hept-2-ulopyranosonic acid derivatives). The azide substitution in 2-bromo-2-deoxy-a-D-galacto-hept-2-ulopyranosonic

acid chloride gave 2-azido-2-deoxy-a-^D-galacto-hept-2-ulopyranosonic acid azide with retention of the anomeric conﬁguration. This

acid azide was coupled with a glycine ester to give an axial anomeric azide. These transformations represent highly stereoselective

routes to both anomers of dipeptides incorporating anomeric a-azido acids.

1. Introduction

chemistry N-glycosides of 2-ulosonic acid derivatives)

have been reviewed recently.^3,5

Hybrids of sugars and amino acids have received consid-

erable attention over the past decade because, in the

form of O- and N-glycosides of amino acid side chains,

such compounds are crucial elements of glycopro-

teins.^1,2In order to obtain hydrolytically stable counter-

parts of the above linking moieties a plethora of

synthetic methods for C-glycosyl amino acids have been

elaborated.³Amino acids on various carbohydrate scaf-

folds have been widely investigated in drug design, and

in building up artiﬁcial glycopeptides as well as unnatu-

ral biopolymers.^4–6A unique combination of an a-ami-

no acid and a sugar arises in the anomeric a-amino acid

type compounds, also called fused sugar glycines,³

where the anomeric carbon of the sugar is the asymmet-

ric centre of the amino acid (I, Scheme 1). Preparative

methods to obtain various derivatives of anomeric a-

amino acids (from the point of view of carbohydrate

a

C

O

COOH

NH₂

I

b

N

(RO)_n

OR

II

a

b

C

N

C

N

O

(RO)_n

OR

δ

N

C

δ

O

Br

(RO)_n

OR

III

IV

O

C

H

O

N

H

OR

*

Corresponding author. Tel.: +36 52 512 900x2348; fax: +36 52 453

836; e-mail: somsak@tigris.unideb.hu

Scheme 1.

doi:10.1016/j.tetasy.2004.11.064

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

128

Stepwise introduction of the carbon and nitrogen func-

tionalities to the anomeric carbon can among other

ways be designed along disconnections a and b in the

generalised formula II in Scheme 1. In such reaction se-

quences the formation of substrates III and IV for the

last nucleophilic substitution is of prime importance.

While compounds of type III could not be prepared in

radical-mediated halogenations of N-glycosyl deriva-

tives,⁷various bromides of type IV have been described

in the literature. The main preparative procedures in-

volve radical-mediated bromination⁸of acyl-,^9–12iso-

propylidene-,^13–16or silyl^13,14,16,17protected 2,5-^14–17or

2,6-^9–13anhydro-aldonic acid esters,^12–15-amides,^10–12

and -nitriles,^9,11,12and ionic bromination of a benzyl-

ated 2,6-anhydro-aldonic ester.¹⁸In a speciﬁc oxidation

of dichloro exoglycals furanoid 2-chloro-2-deoxy-ulo-

sonic esters analogous to IV were obtained.¹⁹A pyra-

noid 2-bromo-2-deoxy-ulosonic ester was prepared by

conventional HBr–AcOH treatment of the parent ano-

meric O-acetate.²⁰

tions to obtain 2-bromo- and 2-azido-2-deoxy-ulosonic

acid derivatives (IV and II, respectively), which can be

suitable for further manipulations to incorporate them

into peptides.

2. Results and discussion

The starting 2,6-anhydro-heptonic acids 1–3 were pre-

pared by nitrosation of the corresponding heptonamides

according to a literature protocol.²⁷Standard proce-

dures were used for the transformations of these acids,

and the prepared derivatives are collected in Table 1.

Formation of methyl esters 4 and 5 was straightforward

using diazomethane. For the preparation of tert-butyl

esters 6–8 several known methods were tried, however,

only acid catalysed transesteriﬁcation with tBuOAc

proved satisfactory. The trichloroethyl esters 9–11 were

obtained by a DCC-DMAP mediated coupling of tri-

chloroethanol with the corresponding acid. Pentachlo-

rophenol in the presence of DCC yielded active esters

12–14. Acylated glycines 15–17 were prepared from

12–14, respectively, because direct DCC coupling of

acids 1–3 with glycine methyl ester gave large amounts

of by-products. Acid chlorides 18 and 19 were made

with PCl₅as described.²⁸

Several of these products were subjected to azide

substitution reactions to yield the corresponding fura-

noid^14–17,19and pyranoid^{13,18,21–23}2-azido-ulosonic

esters,^13–19,23amides^21,22and nitriles.²¹Both furanoid

and pyranoid 2-azido-ulosonic esters were prepared

from thiazolyl ketol acetate precursors.²⁴Oxidative

transformations of ulosyl azides were also applied to

obtain furanoid^25,26and pyranoid²⁶2-azido-ulosonic

acid derivatives.

For brominations of the prepared acid derivatives

(Table 2) three methods were investigated: bromine in

CHCl₃in the presence K₂CO₃(method G¹¹); NBS in

CCl₄in the presence of Bz₂O₂or AIBN (method H⁸);

Na₂S₂O₄–KBrO₃in CH₂Cl₂–water biphasic solvent mix-

ture (method I¹²). Each of these methods resulted in

Herein the aim is to investigate the feasibility of radical-

mediated brominations and subsequent azide substitu-

Table 1. Preparation of 2,6-anhydro-aldonic acids and their derivatives

O

Gly

O

Gly

O

Gly

COOH

CONH₂

COR

Method (see below)

NO₂

CH₂Cl₂

4-19

1-3

Gly (Method: yield [%])

AcO

OAc

OBz

O

OAc

O

AcO

BzO

AcO

OAc

BzO

OAc

Starting acid

1 (82; lit.²⁷87)

2 (72; lit.²⁷86)

3 (76)

R

–OMe

–OtBu

4^a(A: 99)

6 (B: 77)

9 (C: 78)

5 (A: 99)

8 (B: 73)

7 (B: 42)

10 (C: 70 )

13 (D: 71)

16 (E: 57)

–OCH₂CCl₃

–OC₆Cl₅

–NHCH₂COOMe

–Cl

11 (C: 76)

14 (D: 89)

17 (E: 72)

19 (F: 75)

12 (D: 75)

15 (E: 76)

18 (F: 75; lit.²⁸80)

Method A: CH₂N₂, Et₂O, acetone, rt, 5 min

B: tBuOAc, 60% aq HClO₄, rt, 3 d

C: CCl₃CH₂OH, DCC, DMAP, CH₂Cl₂, rt, 2–4 h

D: C₆Cl₅OH, DCC, CH₂Cl₂, rt, 4–6 h

E: Gly-COOC₆Cl₅(12–14), MeOOCCH₂NH₂ÆHCl, Et₃N, abs. 1,4-dioxane, rt

F: PCl₅, Et₂O, reﬂux, 3 h

^aThis compound was prepared earlier by transformation of acetylated C-glucopyranosyl nitromethane²⁹or glucopyranosyl cyanide derivatives.³⁰

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K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

129

Table 2. Bromination reactions of 2,6-anhydro-aldonic acid derivatives

O

Gly

O

Gly

R

Method (see below)

Br

20-30

R

Gly (Method: yield [%])

AcO

OAc

OBz

O

OAc

O

AcO

BzO

AcO

BzO

AcO

–COOH

Decomposition with

methods G, H and I

20 (G: 75^a)

Not investigated

–COOMe

21 (G: 80 )

(H: 68)

(I: 77^b)

(I: 54 + 21 32)

23 (G: decomposition)

(H: 83^b)

–COOtBu

22 (G: decomposition)

(H: clean reaction)

(I: 85^b)

(I: 72^b)

–COOCH₂CCl₃

–COOC₆Cl₅

24^c(I)

25 (I)

28 (G: 99)

26^d(I)

29 (G: 89)

27 (G: 99)

(I: 91)

–CONHCH₂COOMe

–COCl

See text and Scheme 3

30 (H: not isolated)

See also Scheme 4

Not investigated

Decomposition

Method G: Br₂, abs. CHCl₃, K₂CO₃, reﬂux

H: NBS, Bz₂O₂, or AIBN, abs. CCl₄, reﬂux

I: Na₂S₂O₄, KBrO₃, CH₂Cl₂, H₂O, rt

^aTraces of 35 were separated by column chromatography.

^bCrude product suﬃciently pure for further transformation.

^cFormed together with an unidentiﬁed bromine containing by-product and not isolated in a pure state (see text also).

^dFormed together with 33 which was isolated after the azide substitution reaction.

multicomponent product mixtures when tried with acid

1. Methyl esters 4 and 5 gave brominated products 20

and 21, respectively, under each condition in 70–80%

yields, except method I with 5 when ulosonic ester 32

was formed in signiﬁcant proportion. Formation of 31

was not observed during transformation of 4 by method

I. Ulosonic esters 31 and 32 were also obtained by silver

oxide promoted hydrolysis of bromides 20 and 21 in sep-

arate experiments (Scheme 2).

sponding ulosonic acids (or those of the anomeric bro-

mides 24 and 25), which might arise from bromination

of the methylene group (–COOCH₂CCl₃) with a capto-

dative substitution pattern.⁸Bromination of 11 gave

26, and the by-product isolated after the azide substitu-

tion reaction proved to be ulosonic ester 33. Active

esters 12–14 were brominated by methods G or I to give

high yields of 27–29, respectively. A modiﬁed Hell–

Vollhard–Zelinsky reaction of acid chloride 18 under

conditions H resulted in bromide 30. Unfortunately,

several attempts at brominating 19 proved unsuccessful,

only formation of complex reaction mixtures was ob-

served. Similarly, bromination of 15 under conditions

of each method G, H and I failed to give the expected

bromide 35, only 2-bromo-ulosonamide 34¹⁰could be

isolated from the multicomponent mixture (Scheme 3).

Therefore, the targeted bromides 35–37 were prepared

by substitution with glycine methyl ester in the bromi-

nated active esters 27–29, respectively, whereby the ano-

meric bromides remained untouched.

OR

RO

1 eq H₂O,

1 eq Ag₂O

RO

a

O

e

COOMe

COOR'

OH

RO

DMSO, r. t.

Br

20

21

a, R = Ac (

e, R = Bz (

D

-galacto)

-gluco)

31 (74 %) R' = Me

32 (52 %) R' = Me

33

R' = CH₂CCl₃

Scheme 2.

tert-Butyl esters 6 and 8 decomposed when brominated

with method G, but were transformed via clean reac-

tions into bromides 22 and 23, respectively, by methods

H and I. By method I trichloroethyl esters 9 and 10 each

gave two bromine containing products, which were not

separated, but immediately subjected to azide substitu-

tion. NMR spectra showed a ꢀ10:1 ratio for the two

compounds, and evidenced that the main products were

24 and 25. We speculated that the minor products could

be 1-bromo-2,2,2-trichloroethyl esters of the corre-

Azide substitutions in the bromo derivatives were per-

formed with NaN₃in DMSO or DMF solutions as de-

scribed previously.²¹With the exception of bromides

of active esters 27 and 29, which decomposed under

these conditions, the transformations gave azides 38–

47 in good yields without diﬃculties (Table 3).

Reaction of 30 with excess NaN₃produced 2-azido-ulo-

sonic azide 48 with retained anomeric conﬁguration

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K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

130

AcO

OAc

O

OAc

O

OAc

O

AcO

OAc

O

AcO

I

NBS, AIBN

abs. CCl₄, reflux

CONH₂

COCl

CONHCH₂COOMe

COCl

AcO

Br

15

34 (46 %)

18

30

4 eq NaN₃,

abs. DMF,

r. t.

method I: Na₂S₂O₄, KBrO₃, CH₂Cl₂, H₂O, r. t.

OR

OAc

O

RO

a

OAc

O

AcO

35 (71 %)

36 (71 %)

37 (58 %)

a, R = Ac (

e, R = Ac (

e, R = Bz (

D-galacto)

D-gluco)

O

e

CONHCH₂COOMe

CON₃

KOH

DMF, r. t.

COOH

RO

AcO

Br

N₃

48

49 (38 %)

MeOOCCH₂NH₂.HCl

Et₃N, abs. 1,4-dioxane, r. t.

(60 % for the two steps)

MeOOCCH₂NH₂.HCl,

Et₃N,

abs. 1,4-dioxane, r. t.

OR

O

RO

a

27

a, R = Ac (

e, R = Ac (

e, R = Bz (

D-galacto)

D-gluco)

e

COOC₆Cl₅

28

RO

29

Br

OAc

AcO

O

Scheme 3.

CONHCH₂COOMe

AcO

N₃

50 (32 %)

(Scheme 4). Although mechanistic features were not

studied in detail this unexpected result can be explained

in two plausible ways. First, chloride ions liberated by

azide from the acid chloride moiety (which must be

more reactive than the anomeric bromide in this partic-

ular compound) invert conﬁguration of the anomeric

carbon which, in a second inversion during the azide

substitution, gives the retention product. A similar pro-

cess could be elicited by external chloride in the case of

2-bromo-2-deoxy-ulosononitriles.²¹Second, substitu-

tions by azide ions may have some radical nucleophilic

character (S_RNor SET reactions) that was demonstrated

with 2-bromo-ulosononitriles, as well.²¹This would im-

ply the appearance of glycosyl radicals on the reaction

pathway, which are known to exhibit axial selectivity

in their reactions.³¹As the azide substitution of 30 per-

formed in the presence of radical traps (1,4-dinitrobenz-

ene, galvinoxyl) resulted in mixtures of unidentiﬁed

products, among which 48 could not be detected, the

understanding of the stereoselectivity of this reaction

in this way can also be relevant. Acylation of glycine

methyl ester with 48 gave 50, which is the epimer of 45.

Scheme 4.

2-Azido-ulosonic azide 48 was also transformed into

anomeric a-azido acid 49 by KOH in DMF (Scheme

4). In order to obtain the epimer of 49 the hydrolysis

of tert-butyl ester 40 was investigated ﬁrst, however, sev-

eral established methods brought about no change at all

or resulted in decomposition. Deprotection of trichloro-

ethyl ester 42 (Scheme 5) under the usual Zn/AcOH con-

ditions gave anomeric a-amino acid 52, while Zn dust in

the presence of 1-methylimidazole (NMI) left the azido

group unchanged to yield 51.³²

Structural elucidation of the new compounds was

straightforward by established NMR methods. The con-

ﬁguration of the anomeric carbons lacking hydrogens

was deduced from the three bond coupling between H-

2 (parent carbohydrate numbering) and the carbon at-

tached to the anomeric centre as described earlier.^9,21

The presence of the azide group was shown by the IR

spectra as expected (see Experimental).

Table 3. Azide substitutions in the brominated 2,6-anhydro-aldonic acid derivatives

O

Gly

O

Gly

R

N₃

R

NaN₃

Br

DMSO, r. t.

38-47

Gly (Yield [%])

R

OAc

O

OBz

O

AcO

OAc

O

AcO

BzO

AcO

–COOMe

–COOtBu

38 (84)

40 (69)

39 (75)

41 (56)

44 (59^a)

–COOCH₂CCl₃

–COOC₆Cl₅

–CONHCH₂COOMe

42 (59^a)

43 (60^a)

46 (69)

Decomposition

45 (65)

Decomposition

47 (66)

^aYield refers to two steps: bromination and azide substitution.

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K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

131

˚

OAc

O

DMSO) were dried by storage over 4 A molecular

sieves. Organic solutions were dried over anhydrous

MgSO₄and concentrated in vacuo at 40–50 ꢁC (water

bath).

OAc

O

AcO

N₃

COOCH₂CCl₃

Zn, NMI

EtOAc, reflux

N₃

AcO

COOH

42

51(59 %)

4.2. General procedure I

Zn, AcOH

r. t.

For the preparation of per-O-acylated C-(b-^D-glycopyr-

anosyl)formic acids (2,6-anhydro aldonic acids) 1–3

(adapted from Ref. 27): A per-O-acylated 2,6-anhydro

aldonamide (5.5 g) was dissolved in abs. CH₂Cl₂

(50mL) and a solution of NO ₂(obtained by heating

PbNO₃) in abs. CH₂Cl₂(10mL, saturated at ꢁ20 ꢁC)

was added dropwise. The reaction mixture was stirred

at room temperature and monitored by TLC (eluent:

toluene–acetone 1:1). After completion of the transfor-

mation the solvent was evaporated, and the crude prod-

uct puriﬁed by crystallisation from Et₂O.

OAc

AcO

Me

N

O

NH₂

NMI

=

AcO

COOH

N

52(45 %)

Scheme 5.

3. Conclusion

Investigation of the radical-mediated bromination of

several derivatives of per-O-acylated C-(b-^D-glycopyr-

anosyl)formic acids (2,6-anhydro-^D-hept-2-ulopyrano-

sonic acids) revealed that bromine can be introduced

in an axial position at the anomeric carbon of methyl-,

tert-butyl-, 2,2,2-trichloroethyl-, and pentachlorophenyl

esters and acid chlorides. Similar bromination of glyci-

namides gave only C-(1-bromo-1-deoxy-b-^D-glycopyr-

anosyl)formamides. This cleavage showed similar

reactivity of the amino acid moiety and the anomeric

centre. Bromo derivatives of glycinamides could be ob-

tained by acylation of glycine esters by the bromide of

pentachlorophenyl esters. In this reaction the anomeric

bromide was not substituted.

4.2.1. C-(2,3,4,6-Tetra-O-acetyl-b-^D-galactopyranosyl)-

formic acid (3,4,5,7-tetra-O-acetyl-2,6-anhydro-^D-gly-

cero-^L-manno-heptonic acid) 1. Prepared from 3,4,5,7-

tetra-O-acetyl-2,6-anhydro-^D-glycero-L-manno-hepton-

amide²⁷according to general procedure I. Yield: 82%

(lit.²⁷86%) white crystalline product; mp: 132–134 ꢁC;

(lit.²⁷132–134 ꢁC). The NMR data were identical with

the published ones.

4.2.2. C-(2,3,4,6-Tetra-O-acetyl-b-^D-glucopyranosyl)for-

mic acid (3,4,5,7-tetra-O-acetyl-2,6-anhydro-^D-glycero-D-

gulo-heptonic acid) 2. Prepared from 3,4,5,7-tetra-

O-acetyl-2,6-anhydro-^D-glycero-D-gulo-heptonamide²⁷

according to general procedure I. Yield: 72% (lit.²⁷85%)

white crystalline product; mp: 129–131 ꢁC (lit.²⁷138–

140 ꢁC). The NMR data were identical with the pub-

lished ones.

Replacement of the anomeric bromide with azide ion

took place with inversion in the esters and the glycin-

amides to yield equatorial azides. On the other hand,

retention at the anomeric centre and formation of an

acid azide was observed in the reaction of the acid chlo-

ride derivative. Acylation of glycine methyl ester by this

latter acid azide opened up a route to a glycinamide with

an axial azide group. In this way highly selective syn-

thetic sequences have been found for both anomers of

dipeptides containing anomeric a-azido acids.

4.2.3. C-(2,3,4,6-Tetra-O-benzoyl-b-^D-glucopyranosyl)-

formic acid (2,6-anhydro-3,4,5,7-tetra-O-benzoyl-^D-gly-

cero-^D-gulo-heptonic acid) 3. Prepared from 2,6-

anhydro-3,4,5,7-tetra-O-benzoyl-^D-glycero-D-gulo-hep-

tonamide¹¹according to general procedure I. Yield:

4.18 g (76%) white crystalline product; mp 181–184 ꢁC;

[a]_D= +14 (c 0.41, CHCl₃); m_max(KBr): 3328–2840,

1732, 1490, 1270, 1070, 708; ¹H NMR (CDCl₃) d

(ppm): 8.01–7.81 (20H, m, Ph), 5.94 (1H, s, COOH),

5. 94 (1H, pseudo t, J = 9.4, 9.0Hz, H-2), 5.75–5.67

(2H, m, H-3, H-4), 4.64 (1H, dd, J = 12.0, 4.2 Hz, H-

6), 4.5 (1H, dd, J = 12.0, 2.1 Hz, H-6⁰), 4.35 (1H, d,

J = 9.0Hz, H-1), 4.22 (1H, ddd, J = 12.0, 4.2, 2.1 Hz,

H-5); ¹³C NMR (CDCl₃) d (ppm): 165.7 (COOH),165.4,

165.1 (3) (CO), 133.4–128.3 (aromatics), 76.3 (C-1),

76.3, 73.7, 69.9, 69.1 (C-3 to C-5), 63.2 (C-6). Anal.

Calcd for C₃₅H₂₈O₁₁(624.61): C, 67.30; H, 4.52. Found:

C, 67.35; H, 4.49.

4. Experimental

4.1. General methods

Melting points were measured in open capillary tubes or

on a Koﬂer hot stage and are uncorrected. Optical rota-

tions were determined on a Perkin–Elmer 241 polarime-

ter at room temperature. IR spectra were taken with a

Perkin–Elmer 16 PC FT-IR spectrometer. NMR spectra

were recorded with Bruker WP 360SY (360/90MHz for

¹H/¹³C) and Varian UNITYINOVA 400 WB (400/

100 MHz for ¹H/¹³C) spectrometers. Chemical shifts

are referenced to internal Me₄Si (¹H) or the residual sol-

vent signal (¹³C). TLC was performed on DC Alurolle

4.3. Method A: preparation of per-O-acylated methyl C-

(b-^D-glycopyranosyl)formates (methyl 2,6-anhydro-aldo-

nates) 4 and 5

Kieselgel 60F

(Merck), the plates were visualised

254

by gentle heating. For column chromatography Kie-

selgel 60 (Merck, particle size 0.063–0.200 mm) was

used. Distilled solvents (CH₂Cl₂, CHCl₃, 1,4-dioxane,

A per-O-acylated 2,6-anhydro-aldonic acid (1 or 3, 3 g)

was dissolved in acetone (50mL) and diazomethane in

Et₂O solution was added. After disappearance of the

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K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

132

starting material (TLC, ethyl acetate–hexane 1:1) the

solvent was removed in vacuo, and the residue was crys-

tallised from Et₂O.

1750, 1372, 1214, 1020; ¹H NMR (CDCl₃) d (ppm):

5.43 (1H, dd, J = 3.7, <1 Hz, H-4), 5.38 (1H, dd,

J = 10.8, 9.6 Hz, H-2), 5.07 (1H, dd, J = 9.6, 3.7 Hz,

H-3), 4.18–4.15 (2H, m, H-6, H-6⁰), 3.95 (1H, ddd,

J = 7.5, 7.5, <1 Hz, H-5), 3.90(1H, d, J = 10.8 Hz, H-

1), 2.18, 20.5, 2.04, 1.98 (12H, 4 · s, OAc), 1.45 (9H, s,

C(CH₃)₃); ¹³C NMR (CDCl₃) d (ppm): 170.3, 170.0,

169.0(CO), 166.0( COOC(CH₃)₃), 82.9 (COOC(CH₃)₃),

77.1 (C-1), 74.2, 71.7, 67.0, 66.4 (C-2 to C-5), 61.4 (C-6),

27.7 (COOC(CH₃)₃), 20.6, 20.5 (CH₃). Anal. Calcd for

C₁₉H₂₈O₁₁(432.42): C, 52.77; H, 6.53. Found: C,

52.69; H, 6.61.

4.3.1. Methyl C-(2,3,4,6-tetra-O-acetyl-b-^D-galactopyr-

anosyl)formate (methyl 3,4,5,7-tetra-O-acetyl-2,6-anhy-

dro-^D-glycero-L-manno-heptonate) 4. Prepared from 1

according to Method A. Yield: 3.09 g (99%) white crys-

talline product; mp: 146–148 ꢁC; [a]_D= +17 (c 1.17,

1

CHCl₃); m_max(KBr): 3904, 1760, 1376, 1240, 1070; H

NMR (CDCl₃) d (ppm): 5.45 (1H, dd, J = 3.7, 1.2 Hz,

H-4), 5.37 (1H, t, J = 9.9, 9.8 Hz, H-2), 5.11 (1H, dd,

J = 9.9, 3.7 Hz, H-3), 4.17–4.12 (2H, m, H-6, H-6⁰),

3.99 (1H, d, J = 9.8 Hz, H-1), 3.95 (1H, ddd, J = 6.7,

6.7, 1.2 Hz, H-5), 3.76 (3H, s, OCH₃), 2.23, 2.11, 2.10,

2.06 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d (ppm):

170.2, 170.1, 169.8, 169.4 (CO), 167.4 (COOCH₃), 76.8

(C-1), 74.6, 71.3, 67.1, 66.6 (C-2 to C-5), 61.5 (C-6),

52.8 (OCH₃), 20.5, 20.4 (CH₃). Anal. Calcd for

C₁₆H₂₂O₁₁(390.35): C, 49.23; H, 5.68. Found: C,

48.90; H, 5.88.

4.4.2. tert-Butyl C-(2,3,4,6-tetra-O-acetyl-b-^D-glucopyr-

anosyl)formate (tert-butyl 3,4,5,7-tetra-O-acetyl-2,6-

anhydro-^D-glycero-D-gulo-heptonate) 7. Prepared from

2 (0.20 g, 0.53 mmol) according to Method B. Yield:

0.09 g (42%) white crystalline product; mp: 101–

103 ꢁC; [a]_D= ꢁ5 (c 1.02, CHCl₃); m_max(KBr): 2972,

1760, 1376, 1220, 1026; ¹H NMR (CDCl₃) d (ppm):

5.26–5.18 (2H, m, H-2, H-3), 5.10(1H, dd, J = 9.4,

9.2 Hz, H-4), 4.26 (1H, dd, J = 12.5, 4.6 Hz, H-6), 4.15

0

4.3.2. Methyl C-(2,3,4,6-tetra-O-benzoyl-b-^D-glucopyr-

anosyl)formate (methyl 2,6-anhydro-3,4,5,7-tetra-O-ben-

zoyl-^D-glycero-D-gulo-heptonate) 5. Prepared from 3

according to Method A. Yield: 3.03 g (99%) white crys-

talline product; mp: 149–150 ꢁC; [a]_D= +14 (c 1.22,

CHCl₃); m_max(KBr): 3850, 3066, 1732, 1490,

(1H, dd, J = 12.5, 2.0Hz, H-6 ), 3.91 (1H, d,

J = 9.8 Hz, H-1), 3.70(1H, ddd, J = 12.5, 4.6, 2.0Hz,

H-5), 2.09, 2.03, 2.01 (12H, 4 · s, OAc), 1.45 (9H, s,

C(CH₃)₃); ¹³C NMR (CDCl₃) d (ppm): 170.5, 170.1,

169.2, 168.8 (CO), 165.7 (COOC(CH₃)₃), 82.9

(COOC(CH₃)₃), 77.0(C-1), 75.7, 73.7, 69.2, 67.9 (C-2

to C-5), 61.9 (C-6), 27.7 (COOC(CH₃)₃), 20.6, 20.5

(CH₃). Anal. Calcd for C₁₉H₂₈O₁₁(432.42): C, 52.77;

H, 6.53. Found: C, 52.61; H, 6.41.

1

1270, 1070, 708; H NMR (CDCl₃) d (ppm): 8.02–7.25

(20H, m, Ph), 5.96 (1H, t, J = 10.0, 9.8 Hz, H-3), 5.69

(1H, t, J = 9.8, 9.8 Hz, H-4), 5.71 (1H, t, J = 10.0,

9.9 Hz, H-2), 4.64 (1H, dd, J = 11.7, 4.9 Hz, H-6), 4.52

(1H, dd, J = 11.7, 3.1 Hz, H-6⁰), 4.36 (1H, d,

J = 9.9 Hz, H-1), 4.18 (1H, ddd, J = 9.8, 4.9, 3.1 Hz,

H-5), 3.68 (3H, s, OCH₃); ¹³C NMR (CDCl₃) d (ppm):

167.2 (COOCH₃), 165.9, 165.6, 165.0, 164.9 (CO),

133.3–128.1 (aromatics), 76.7 (C-1), 76.2, 73.4, 70.2,

69.1 (C-2 to C-5), 63.1 (C-6), 52.7 (OCH₃). Anal. Calcd

for C₃₆H₃₀O₁₁(638.63): C, 67.71; H, 4.73; O, 27.56.

Found: C, 67.68; H, 4.74; O, 27.60.

4.4.3. tert-Butyl C-(2,3,4,6-tetra-O-benzoyl-b-^D-gluco-

pyranosyl)formate (tert-butyl 2,6-anhydro-3,4,5,7-tetra-

O-benzoyl-^D-glycero-D-gulo-heptonate)

8. Prepared

from 3 (0.30 g, 0.69 mmol) according to Method B.

Puriﬁed by column chromatography (eluent: ethyl ace-

tate–hexane 1:2), conversion 95%. Yield: 0.229 g (73%)

white crystalline product; mp: 119–121 ꢁC; [a]_D= +29

(c 1.05, CHCl₃); m_max(KBr): 3062, 2978, 1740, 1492,

1

1096, 708; H NMR (CDCl₃) d (ppm): 8.18–7.22 (20H,

4.4. Method B: preparation of per-O-acylated tert-butyl

C-(b-^D-glycopyranosyl)formates (tert-butyl 2,6-anhydro

aldonates) 6–8

m, Ph), 5.94 (1H, dd, J = 9.8, 9.2 Hz, H-2), 5.76 (1H,

t, J = 10.5, 10.5 Hz, H-4), 5.72 (1H, dd, J = 10.5,

9.8 Hz, H-3), 4.64 (1H, dd, J = 12.5, 3.3 Hz, H-6), 4.54

(1H, dd, J = 12.5, 5.2 Hz, H-6⁰), 4.48 (1H, d,

J = 9.8 Hz, H-1), 4.18 (1H, ddd, J = 12.5, 5.2, 3.3 Hz,

H-5), 2.05 (9H, s, C(CH₃)₃); ¹³C NMR (CDCl₃) d

(ppm): 166.1, 165.7, 165.1 (CO), 164.8 (COOC(CH₃)₃),

133.3–128.2 (aromatics), 83.0(COO C(CH₃)₃), 76.0(C-

1), 73.9, 69.9, 69.3, 63.2 (C-2 to C-5), 27.5

(COOC(CH₃)₃). Anal. Calcd for C₃₉H₃₆O₁₁(680.11):

C, 68.81; H, 5.33. Found: C, 68.96; H, 5.43.

A per-O-acylated 2,6-anhydro-aldonic acid 1 or 2 or 3

was dissolved in tert-butyl acetate (6 mL/mmol) and

60% HClO₄(0.1 equiv) was added to the solution. The

reaction mixture was stirred at room temperature for

3 days. After completion of the reaction (TLC, ethyl ace-

tate–hexane 1:1) the solution was diluted with CH₂Cl₂

(10mL) 4 · and washed with water (10mL), satd. aque-

ous NaHCO₃(2·10mL) and water (10mL). After dry-

ing the solvent was evaporated in vacuo, and the crude

product crystallised during standing at 4 ꢁC or was puri-

ﬁed by column chromatography in the case of 8.

4.5. Method C: preparation of per-O-acylated 2,2,2-

trichloroethyl C-(b-^D-glycopyranosyl)formates (2,2,2-tri-

chloroethyl 2,6-anhydro-aldonates) 9–11

4.4.1. tert-Butyl C-(2,3,4,6-tetra-O-acetyl-b-^D-galacto-

pyranosyl)formate (tert-butyl 3,4,5,7-tetra-O-acetyl-2,6-

A per-O-acylated 2,6-anhydro-aldonic acid 1 or 2 or 3

was dissolved in abs. CH₂Cl₂(10mL/mmol), and

3 equiv 2,2,2-trichloroethanol, 1 equiv DCC, and

0.1 equiv DMAP were added. The reaction mixture

was stirred at room temperature until TLC (ethyl ace-

tate–hexane 1:1) showed complete transformation

anhydro-^D-glycero-D-manno-heptonate)

6. Prepared

from 1 (0.30 g, 0.70 mmol) according to Method B.

Yield: 0.26 g (77%) white crystalline product; mp: 74–

77 ꢁC; [a]_D= +12 (c 1.1, CHCl₃); m_max(KBr): 2976,

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

133

(ꢀ4 h). After ﬁltration the solvent was removed in va-

cuo, and the residue puriﬁed by column chromatogra-

phy (eluent: ethyl acetate–hexane 1:1).

ics), 93.5 (COOCH₂CCl₃), 76

4

(C-1), 74.9

(COOCH₂CCl₃), 76.4, 73.5, 70.2, 69.0 (C-2 to C-5),

62.9 (C-6). Anal. Calcd for C₃₇H₂₉Cl₃O₁₁(756.00): C,

58.79; H, 3.87; Cl, 14.07. Found: C, 58.60; H, 3.71;

Cl, 13.88.

4.5.1. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-acetyl-b-^D-

galactopyranosyl)formate (2,2,2-trichloroethyl 3,4,5,7-

tetra-O-acetyl-2,6-anhydro-^D-glycero-L-manno-heptonate)

9. Prepared from 1 (0.30 g, 0.80 mmol) according to

Method C. Yield: 0.30 g (75%) colourless oil

(R_f= 0.39, ethyl acetate–hexane 1:1); [a]_D= ꢁ6 (c 0.20,

CHCl₃); m_max(CHCl₃): 2968, 1756, 1370, 1236, 1070,

4.6. Method D: preparation of per-O-acylated pentachlo-

rophenyl C-(b-^D-glycopyranosyl)formates (pentachloro-

phenyl 2,6-anhydro-aldonates) 12–14

A per-O-acylated 2,6-anhydro-aldonic acid 1 or 2 or 3

was dissolved in abs. CH₂Cl₂(15 mL/mmol), and

3 equiv pentachlorophenol and 1 equiv DCC were

added. The reaction mixture was stirred at rt and mon-

itored by TLC (ethyl acetate–hexane 1:1). When the

reaction was completed, the solvent was evaporated in

vacuo, and the crude product puriﬁed by column chro-

matography (eluent: ethyl acetate–hexane 1:1).

1

700; H NMR (CDCl₃) d (ppm): 5.47 (1H, dd, J = 2.9,

<1 Hz, H-4), 5.41 (1H, dd, J = 10.3, 9.6 Hz, H-2), 5.15

(1H, dd, J = 9.6, 2.9 Hz, H-3), 4.90(1H, d,

J = 11.8 Hz, CH₂), 4.66 (1H, d, J = 11.8 Hz, CH₂), 4.20

(1H, d, J = 9.6 Hz, H-1), 4.19–4.17 (2H, m, H-6, H-6⁰),

4.02 (1H, ddd, J = 5.9, 6.0, <1 Hz, H-5), 2.18, 2.06,

2.05, 2.04 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d

(ppm): 170.3, 170.2, 169.8, 169.5 (CO), 165.6

(COOCH₂CCl₃), 94.1 (COOCH₂CCl₃), 76.1 (C-1), 74.8

(COOCH₂CCl₃), 74.4, 71.3, 66.9, 66.5 (C-2 to C-5),

61.3 (C-6), 20.7, 20.5, 20.4 (CH₃). Anal. Calcd for

C₁₇H₂₁Cl₃O₁₁(507.71): C, 40.22; H, 4.17; Cl, 20.95.

Found: C, 40.02; H, 3.98; Cl, 20.80.

4.6.1. Pentachlorophenyl C-(2,3,4,6-tetra-O-acetyl-b-^D-

galactopyranosyl)formate (pentachlorophenyl 3,4,5,7-

tetra-O-acetyl-2,6-anhydro-^D-glycero-L-manno-heptonate)

12. Prepared from 1 (0.5 g, 1.33 mmol) according to

Method D. Yield: 0.62 g (75%) white crystalline product

from Et₂O; mp: 130–132 ꢁC; [a] = +21 (c 1.02, CHCl₃);

m_max(KBr): 3436, 1754, 1364, 1226, 1096, 600; ¹H

NMR (CDCl₃) d (ppm): 5.66 (1H, t, J = 9.8, 9.8 Hz,

H-2), 5.49 (1H, dd, J = 3.3, <1 Hz, H-4), 5.16 (1H, dd,

J = 9.8, 3.3 Hz, H-3), 4.44 (1H, d, J = 9.8 Hz, H-1),

4.26 (1H, dd, J = 11.2, 6.6 Hz, H-6), 4.19 (1H, dd,

J = 11.2, 6.6 Hz, H-6⁰), 4.10(1H, ddd, J = 6.6, 6,6,

<1 Hz, H-5), 2.21, 2.07, 2.04, 2.02 (12H, 4 · s, OAc);

¹³C NMR (CDCl₃) d (ppm): 170.3, 170.2, 170.0, 168.8

(CO), 162.8 (COOC₆Cl₅), 143.2–127.3 (aromatics), 76.3

(C-1), 75.0, 71.8, 66.9, 65.9 (C-2 to C-5), 61.1 (C-6),

20.6, 20.5 (CH₃). Anal. Calcd for C₂₁H₁₉Cl₅O₁₁

(624.64): C, 40.38; H, 3.07; Cl, 28.38. Found: C, 40.18;

H, 2.92; Cl, 28.20.

4.5.2. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-acetyl-b-^D-

glucopyranosyl)formate (2,2,2-trichloroethyl 3,4,5,7-

tetra-O-acetyl-2,6-anhydro-^D-glycero-D-gulo-heptonate)

10. Prepared from 2 (0.40 g, 1.06 mmol) according

to Method C: Yield: 0.38 g (70%) white crystalline

product from Et₂O; mp: 115–117 ꢁC; [a]_D= ꢁ2 (c

0.21, CHCl₃); m_max(KBr): 2980, 1738, 1270, 1090,

1

640; H NMR (CDCl₃) d (ppm): 5.29 (1H, t, J = 9.4,

9.2 Hz, H-2), 5.25 (1H, t, J = 9.2, 9.2 Hz, H-3), 5.14

(1H, t, J = 9.2, 9.2 Hz, H-4), 4.85 (1H, d,

J = 11.9 Hz, CH₂), 4.69 (1H, d, J = 12.0 Hz, CH₂),

4.27 (1H, dd, J = 11.8, 5.2 Hz, H-6), 4.22 (1H, d,

J = 9.4 Hz, H-1), 4.11 (1H, dd, J = 11.8, 6.2 Hz, H-

6⁰), 3.77 (1H, ddd, J = 11.8, 6.2, 5.6Hz, H-5), 2.10,

2.05, 2.03 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d

(ppm): 170.7, 170.2, 169.4, 169.3 (CO), 165.5

(COOCH₂CCl₃), 93.9 (COOCH₂CCl₃), 76.0(C-1),

74.8 (COOCH₂CCl₃), 75.9, 73.4, 69.4, 67.7 (C-2 to C-

5), 61.8 (C-6). Anal. Calcd for C₁₇H₂₁Cl₃O₁₁

(507.71): C, 40.22; H, 4.17; Cl, 20.95. Found: C,

39.96; H, 4.29; Cl, 20.85.

4.6.2. Pentachlorophenyl C-(2,3,4,6-tetra-O-acetyl-b-^D-

glucopyranosyl)formate (pentachlorophenyl 3,4,5,7-tetra-

O-acetyl-2,6-anhydro-^D-glycero-D-gulo-heptonate)

13.

Prepared from (0.2 g 0.53 mmol) 2 according to Method

D. Yield: 0.23 g (71%) white crystalline product from

Et₂O; mp: 148–150 ꢁC; [a]_D= ꢁ15 (c 1.03, CHCl₃); m_max

(KBr): 3420, 1752, 1370, 1220, 1056, 600; ¹H NMR

(CDCl₃) d (ppm): 5.48 (1H, pseudo t, J = 10.5, 9.8 Hz,

H-2), 5.30(1H, pseudo t, J = 9.8, 9.2 Hz, H-4), 5.22

(1H, pseudo t, J = 9.8, 9.2 Hz, H-3), 4.46 (1H, d,

J = 10.5 Hz, H-1), 4.34 (1H, dd, J = 12.5, 4.6 Hz, H-6),

4.5.3. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-benzoyl-b-

D-glucopyranosyl)formate (2,2,2-trichloroethyl 2,6-anhy-

dro-3,4,5,7-tetra-O-benzoyl-^D-glycero-D-gulo-heptonate)

11. Prepared from 3 (0.30 g, 0.48 mmol) according

to Method C. Yield: 0.28 g (76%) white crystalline

product from ethyl acetate–hexane; mp 163–164 ꢁC;

[a]_D= +15 (c 0.42, CHCl₃); m_max(KBr): 3060, 2980,

1732, 1270, 1090, 708, 640; ¹H NMR (CDCl₃) d

(ppm): 8.08–7.22 (20H, m, Ph), 6.00 (1H, t, J = 9.6,

9.6 Hz, H-2), 5.80–5.70 (2H, m, H-3, H-4), 4.85 (1H,

d, J = 11.8 Hz, CH₂), 4.68 (1H, dd, J = 12.5, 2.2 Hz,

H-6), 4.58 (1H, d, J = 11.8 Hz, CH₂), 4.54 (1H, d,

J = 9.6 Hz, H-1), 4.52 (1H, dd, J = 12.5, 5.1 Hz,

H-6⁰), 4.23 (1H, ddd, J = 12.5, 5.1, 2.2 Hz, H-5);

¹³C NMR (CDCl₃) d (ppm): 166.0( COOCH₂CCl₃),

165.7, 165.5, 165.2, 165.1 (CO), 133.5–128.3 (aromat-

0

4.22 (1H, dd, J = 12.5, 2.0Hz, H-6 ), 3.86 (1H, ddd,

J = 12.5, 4.6, 2.0 Hz, H-5), 2.10, 2.05, 2.00, 1.95 (12H,

4 · s, OAc); ¹³C NMR (CDCl₃) d (ppm): 170.5, 170.2,

169.2, 168.8 (CO), 162.7 (COOC₆Cl₅), 143.1–127.2 (aro-

matics), 76.3 (C-1), 75.9, 73.8, 68.9, 67.6 (C-2 to C-5),

61.7 (C-6), 20.6, 20.5 (CH₃). Anal. Calcd for

C₂₁H₁₉Cl₅O₁₁(624.64): C, 40.38; H, 3.07; Cl, 28.38.

Found: C, 40.09; H, 3.17; Cl, 28.12.

4.6.3. Pentachlorophenyl C-(2,3,4,6-tetra-O-benzoyl-b-^D-

glucopyranosyl)formate (pentachlorophenyl 2,6-anhydro-

3,4,5,7-tetra-O-benzoyl-^D-glycero-D-gulo-heptonate) 14.

Prepared from 3 (0.50 g, 0.80 mmol) according to

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

134

Method D. Yield: 0.63 g (89%) white crystalline product

from Et₂O; mp: 171–173 ꢁC; [a]_D= +24 (c 1.01, CHCl₃);

2), 5.15 (1H, dd, J = 10.0, 9.5, H-3), 5.09 (1H, dd,

J = 10.0, 9.5 Hz, H-4), 4.29 (1H, dd, J = 12.6, 5.3 Hz,

H-6), 4.21 (1H, dd, J = 12.6, 2.1 Hz, H-6⁰), 4.17 (1H,

dd, J = 18.4, 5.3 Hz, CH₂), 3.97 (1H, d, J = 9.5 Hz, H-

1), 3.95 (1H, dd, J = 18.4, 5.3 Hz, CH₂), 3.78 (1H,

ddd, J = 12.6, 5.3, 2.1, Hz, H-5), 3.76 (3H, s, OCH₃),

2.12, 2.05, 2.03, 1.99 (12H, 4 · s, OAc); ¹³C NMR

(CDCl₃) d (ppm): 170.5 (COOCH₃), 169.9, 169.6,

169.3, 169.2 (CO), 166.8 (CONH), 75.7 (C-1), 75.7,

73.3, 69.2, 68.0(C-2 to C-5), 61.7 (C-6), 52.3

(COOCH₃), 40.7 (CH₂), 20.6, 20.5 (CH₃). Anal. Calcd

for C₁₈H₂₅N₁O₁₂(447.70): C, 48.32; H; 5.63; N, 3.13.

Found: C, 48.42; H, 5.46; N, 3.26.

m

_max(KBr): 3904, 1742, 1584, 1492, 1270, 1070, 708, 620;

¹H NMR (CDCl₃) d (ppm): 8.18–7.25 (20H, m, Ph), 6.04

(1H, dd, J = 9.8, 9.2 Hz, H-2), 5.96 (1H, pseudo t,

J = 9.8, 9.2 Hz, H-3), 5.78 (1H, pseudo t, J = 9.8,

9.2 Hz, H-4), 4.82 (1H, d, J = 9.8 Hz, H-1), 4.72 (1H,

dd, J = 12.5, 3.3 Hz, H-6), 4.55 (1H, dd, J = 12.5,

5.9 Hz, H-6⁰), 4.31 (1H, ddd, J = 12.5, 5.9, 3.3 Hz,

H-5); ¹³C NMR (CDCl₃) d (ppm): 165.9, 165.7, 165.1,

164.6 (CO), 162.7 (COOC₆Cl₅), 143.1–127.3 (aromat-

ics), 76.8 (C-1), 76.6, 73.9, 69.4, 69.1 (C-2 to C-5), 62.8

(C-6). Anal. Calcd for C₄₁H₂₇Cl₅O₁₁(872.92): C,

56.41; H, 3.12; Cl, 20.31. Found: C, 56.10; H, 2.95; Cl,

20.20.

4.7.3. N-[(2,3,4,6-Tetra-O-benzoyl-b-^D-glucopyranosyl)-

carbonyl]glycine methylester (N-(2,6-anhydro-3,4,5,7-

tetra-O-benzoyl-^D-glycero-D-gulo-heptonoyl)glycine meth-

ylester) 17. Prepared from 14 (0.20 g, 0.23 mmol)

according to Method E. Yield: 0.11 g (72%) colourless

oil (R_f= 0.33, ethyl acetate–hexane 1:1); [a]_D= +10( c

0.96, CHCl₃); m_max(CHCl₃): 3648, 2950, 1736, 1522,

1492, 1268, 1070, 708; ¹H NMR (CDCl₃) d (ppm):

8.12–7.22 (20H, m, Ph), 7.07 (1H, t, J = 5.3, 5.3 Hz,

NH), 5.95 (1H, t, J = 9.2, 9.2 Hz, H-2), 5.71 (1H, dd,

J = 9.8, 9.2, H-3), 5.69 (1H, dd, J = 9.8, 9.2 Hz, H-4),

4.73 (1H, dd, J = 12.5, 2.6 Hz, H-6), 4.53 (1H, dd,

J = 12.5, 4.6 Hz, H-6⁰), 4.34 (1H, d, J = 9.2 Hz, H-1),

4.23 (1H, ddd, J = 9.2, 4.6, 2.6 Hz, H-5), 4.09 (1H, dd,

J = 18.4, 5.3 Hz, CH₂), 3.96 (1H, dd, J = 18.4, 5.3 Hz,

CH₂), 3.71 (3H, s, OCH₃); ¹³C NMR (CDCl₃) d

(ppm): 166.8 (COOCH₃), 166.8, 166.1, 165.6, 165.2

(CO), 165.1 (CONH), 133.5–128.2 (aromatics), 76.2

(C-1), 76.2, 73.6, 69.9, 69.0(C-2 to C-5), 62.7 (C-6),

52.2 (COOCH₃), 40.8 (CH₂). Anal. Calcd for

C₃₈H₃₃NO₁₂(695.68): C, 65.61; H, 4.78; N, 2.01. Found:

C, 65.41; H, 4.56; N, 2.26.

4.7. Method E: preparation of N-(per-O-acyl-2,6-anhy-

dro-aldonoyl)glycine methylesters 15–17, and N-(per-O-

acyl-2-substituted-2-deoxy-hept-2-ulopyranosonoyl)-

glycine methylesters 35–37 and 50

An acid derivative 12–14, or 27–29, or 48 was dissolved

in abs. 1,4-dioxane (3 mL/mmol), and MeO₂CCH₂-

NH₂ÆHCl (2 equiv) followed by Et₃N (2 equiv) were

added. The mixture was stirred at rt and monitored

by TLC (ethyl acetate–hexane 1:1) until the starting

material disappeared. The solvent was then evaporated

in vacuo, and the residue puriﬁed by column chroma-

tography (eluent: ethyl acetate–hexane 1:1). The product

crystallised during standing at rt.

4.7.1. N-[(2,3,4,6-Tetra-O-acetyl-b-^D-galactopyranosyl)-

carbonyl]glycine methylester (N-(3,4,5,7-tetra-O-acetyl-

2,6-anhydro-^D-glycero-L-manno-heptonoyl)glycine methyl-

ester) 15. Prepared from 12 (0.25 g 0.40 mmol)

according to Method E. Yield: 0.14 g (76%) white crys-

talline product; mp: 114–117 ꢁC; [a]_D= +27 (c 0.98,

CHCl₃); m_max(KBr): 3370, 2950, 1752, 1370, 1230,

1070, 720; ¹H NMR (CDCl₃) d (ppm): 7.20(1H, t,

J = 5.3, 5.3 Hz, NH), 5.48 (1H, dd, J = 3.7, 1.0Hz, H-

4), 5.34 (1H, t, J = 10.0, 10.0, H-2), 5.12 (1H, dd,

J = 10.0, 3.7 Hz, H-3), 4.24 (1H, dd, J = 11.0, 6.8 Hz,

H-6),4.15 (1H, dd, J = 18.4, 5.3 Hz, CH₂), 4.12 (1H,

dd, J = 11.0, 3.2 Hz, H-6⁰), 4.06 (1H, ddd, J = 6.8, 6.8,

1.0Hz, H-5), 3.98 (1H, d, J = 10.0 Hz, H-1), 3.94 (1H,

dd, J = 18.4, 5.3 Hz, CH₂), 3.78 (3H, s, OCH₃), 2.18,

2.08, 1.98 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d

(ppm): 170.2 (COOCH₃), 169.9, 169.8, 169.7, 169.6

(CO), 167.0( CONH), 76.0(C-1), 74.3, 71.2, 67.0, 66.3

(C-2 to C-5), 61.3 (C-6), 52.2 (COOCH₃), 40.6 (CH₂),

20.6, 20.5, 20.4 (CH₃). Anal. Calcd for C₁₈H₂₅NO₁₂

(447.40): C, 48.32; H, 5.63; N, 3.13. Found: C, 48.01;

H, 5.70; N, 3.36.

4.8. Method F: preparation of per-O-acylated C-(b-^D-

glycopyranosyl)formyl chlorides (2,6-anhydro-aldonoyl

chlorides) 18 and 19

(Adapted from Ref. 28): A per-O-acylated 2,6-anhydro-

aldonic acid 1 or 3 was suspended in abs. Et₂O (10mL/

mmol), and treated with PCl₅(1.1 equiv). The mixture

was boiled under reﬂux until a clear solution was ob-

tained (ꢀ3 h). After cooling hexane (15 mL/mmol) was

added to the mixture to induce crystallisation at

ꢁ20 ꢁC in the case of 18, or the volatiles were removed

to yield a pure crude product.

4.8.1. C-(2,3,4,6-Tetra-O-acetyl-b-^D-galactopyranosyl)-

formyl chloride (3,4,5,7-tetra-O-acetyl-2,6-anhydro-^D-

glycero-^L-manno-heptonoyl chloride) 18. Prepared from

1 (0.20 g, 0.53 mmol) according to Method F. Yield:

0.20 g (75%, lit.²⁸80%) colourless crystalline product

from hexane; mp: 105–106 ꢁC (lit.²⁸100 ꢁC).

4.7.2.

N-[(2,3,4,6-Tetra-O-acetyl-b-^D-glucopyranosyl)-

carbonyl]glycine methylester (N-(3,4,5,7-tetra-O-acetyl-

2,6-anhydro-^D-glycero-D-gulo-heptonoyl)glycine methyl-

ester) 16. Prepared from 13 (0.15 g, 0.24 mmol)

according to Method E. Yield: 0.06 g (57%) white crys-

talline product; mp: 111–113 ꢁC; [a]_D= +10( c 0.97,

CHCl₃); m_max(KBr): 3368, 2972, 1760, 1370, 1230,

1070, 720; ¹H NMR (CDCl₃) d (ppm): 6.92 (1H, t,

J = 5.3, 5.3 Hz, NH), 5.27 (1H, t, J = 9.5, 9.5 Hz, H-

4.8.2. C-(2,3,4,6-Tetra-O-benzoyl-b-^D-glucopyranosyl)-

formyl chloride (2,6-anhydro-3,4,5,7-tetra-O-benzoyl-^D-

glycero-^D-gulo-heptonoyl chloride) 19. Prepared from 3

(0.50 g, 0.80 mmol) according to Method F. Yield:

0.50 g (99%), yellowish oil (R_f= 0.10, ethyl acetate–

hexane 3:1); [a]_D= +10( c 0.42, CHCl₃); m_max(CHCl₃):

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

135

3672, 1754, 1552, 1492, 1380, 1270, 1094, 708; ¹H NMR

(CDCl₃) d (ppm): 8.06–7.22 (20H, m, Ph), 5. 97 (1H, t,

J = 9.6, 9.6 Hz, H-2), 5.78–5.66 (2H, m, H-3, H-4),

4.65 (1H, dd, J = 12.5, <1 Hz, H-6), 4.52 (1H, dd,

J = 12.5, 4.4 Hz, H-6⁰), 4.40(1H, d, J = 9 6 Hz, H-1),

4.22 (1H, ddd, J = 12.5, 4.4, <1 Hz, H-5); ¹³C NMR

(CDCl₃) d (ppm): 169.8 (COCl), 166.3, 165.7, 165.3,

165.1 (CO), 133.5–128.3 (aromatics), 76.2 (C-1), 76.0,

73.5, 69.8, 69.0(C-2 to C-5), 63.1 (C-6). Anal. Calcd

for C₃₅H₂₇ClO₁₁(643.05): C, 65.37; H, 4.23; Cl, 5.51.

Found: C, 65.15; H, 4.49; Cl, 5.35.

1:1); [a]_D= +150( c 1.02, CHCl₃); m_max(CHCl₃):

3904, 1764, 1378, 1270, 1080; ¹H NMR (CDCl₃) d

(ppm): 5.52 (1H, dd, J = 3.6, 1.6 Hz, H-4), 5.46 (1H,

d, J = 10.5 Hz, H-2), 5.34 (1H, dd, J = 10.5, 3.6 Hz, H-

3), 4.53 (1H, ddd, J = 6.8, 6.3, 1.6 Hz, H-5), 4.26 (1H,

dd, J = 11.6, 6.8 Hz, H-6), 4.19 (1H, dd, J = 11.6,

6.3 Hz, H-6⁰), 3.85 (3H, s, OCH₃), 2.16, 2.10, 2.07,

1.99 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d (ppm):

170.2, 169.8, 169.7, 169.1 (CO), 164.7 (COOCH₃,

³J_COOMe,H-2= 2.4 Hz), 94.4 (C-1), 72.8, 69.8, 66.7, 66.3

(C-2 to C-5), 60.4 (C-6), 53.8 (OCH₃), 20.7, 20.5, 20.4

(CH₃). Anal. Calcd for C₁₆H₂₁BrO₁₁(469.16): C,

40.96; H, 4.52; Br, 17.03. Found: C, 41.24; H, 4.48;

Br, 17.25.

4.9. Brominations

4.9.1. Method G. A per-O-acylated 2,6-anhydro-aldo-

nic acid ester was dissolved in abs. CHCl₃(15 mL/

mmol), and bromine (3.5 equiv) and some K₂CO₃(acid

scavenger) were added. The mixture was placed in an

Erlenmeyer ﬂask above a heat lamp (375 W, distance

from the lamp ꢀ2–3 cm, height of the solution 1–

2 cm), and reﬂuxed. If the mixture decolourised bromine

(0.5 equiv) was added again. When TLC (ethyl acetate–

hexane, 1:1) showed complete transformation CHCl₃

(10mL/mmol) was added, and the mixture washed with

1 M aq Na₂S₂O₃satd. aq NaHCO₃(2·) and water.

After drying the solvent was removed in vacuo, and

the residue puriﬁed by crystallisation or column chro-

matography if necessary.

Compound 20 was obtained by Method I in 77% yield.

4.9.5. Methyl C-(2,3,4,6-tetra-O-benzoyl-1-bromo-1-

deoxy-b-^D-glucopyranosyl)formate (methyl 3,4,5,7-tetra-

O-benzoyl-2-bromo-2-deoxy-a-^D-gluco-hept-2-ulopyrano-

sonate) 21. Prepared from 5 (1.50g, 2.35 mmol)

according to Method G. Yield: 1.35 g (80%) white crys-

talline product; mp: 188–190 ꢁC; [a]_D= +129 (c 1.19,

CHCl₃); m_max(KBr): 3854, 3650, 1742, 1492, 1378,

1

1270, 1096, 708; H NMR (CDCl₃) d (ppm): 8.09–7.26

(20H, m, Ph), 6.17 (1H, dd, J = 10.0, 9.5 Hz, H-3),

5.85 (1H, dd, J = 10.5, 10.0 Hz, H-4), 5.84 (1H, d,

J = 9.5 Hz, H-2), 4.77 (1H, ddd, J = 10.5, 4.2,

2.6 Hz, H-5), 4.69 (1H, dd, J = 12.6, 4.2 Hz, H-6),

4.58 (1H, dd, J = 12.6, 2.6 Hz, H-6⁰), 3.77 (3H, s,

OCH₃); ¹³C NMR (CDCl₃) d (ppm): 165.9 (COOCH₃,

³J_{COOMe, H-2}= 2.4 Hz), 165.4, 164.9, 164.6 (2) (CO),

133.5–128.3 (aromatics), 94.0(C-1), 74.3, 72.1, 7.06,

67.8 (C-2 to C-5), 61.9 (C-6), 53.9 (OCH₃). Anal. Calcd

for C₃₆H₂₉BrO₁₁(717.53): C, 60.26; H, 4.07; Br, 11.14.

Found: C, 59.98; H, 4.10; Br, 11.35.

4.9.2. Method H. A per-O-acylated 2,6-anhydro-aldo-

nic acid ester was dissolved in abs. CCl₄or abs. CHCl₃

(10mL/mmol), NBS (1 equiv), and AIBN or Bz ₂O₂

(0.1 equiv) were added. The mixture was reﬂuxed until

the starting material disappeared (TLC, ethyl acetate–

hexane 1:1). It was then diluted with CHCl₃(15 mL/

mmol) and washed with 1 M aq Na₂S₂O₃, satd. aq

NaHCO₃(2·), and water, then dried. After ﬁltration

and removal of the solvent in vacuo the residue was

puriﬁed by crystallisation or column chromatography

if necessary.

By using Method I the crude mixture contained com-

pound 36 as a by-product. Column chromatography

(eluent: ethyl acetate–hexane, 1:2) gave 21 in 54% yield.

4.9.3. Method I. A per-O-acylated-2,6-anhydro-aldo-

nic acid ester was dissolved in CH₂Cl₂(3 mL/mmol),

and KBrO₃(6 equiv) and Na₂S₂O₄(6 equiv) in aqueous

solutions (3 mL of each) were added in one portion (in

case of larger scale reactions the Na₂S₂O₄solution was

added dropwise to the other components). The mixture

was stirred at rt until disappearance of the starting mate-

rial (TLC), then diluted with CH₂Cl₂(6 mL/mmol). Aq

Na₂S₂O₃(1 M) was added, shaken well, and then sepa-

rated. The organic phase was further washed with satd.

aq NaHCO₃(2·), and water, then dried. After ﬁltration

and removal of the solvent in vacuo the residue was

puriﬁed by crystallisation or column chromatography

if necessary.

By Method H 21 was obtained in 68% yield.

4.9.6. tert-Butyl C-(2,3,4,6-tetra-O-acetyl-1-bromo-1-

deoxy-b-^D-galactopyranosyl)formate (tert-butyl 3,4,5,7-

tetra-O-acetyl-2-bromo-2-deoxy-a-^D-galacto-hept-2-ulo-

pyranosonate) 22. Prepared from 6 (0.1 g, 0.23 mmol)

according to Method I. Yield: 0.1 g (85%) yellowish

crude syrup (R_f= 0.5, ethyl acetate–hexane 1:1) suﬃ-

ciently pure for the next transformation. Spectroscopic

characterisation could not be carried out because of easy

decomposition of the compound.

4.9.7. tert-Butyl C-(2,3,4,6-tetra-O-benzoyl-1-bromo-1-

deoxy-b-^D-glucopyranosyl)formate (tert-butyl 3,4,5,7-

tetra-O-benzoyl-2-bromo-2-deoxy-a-^D-gluco-hept-2-ulo-

pyranosonate) 23. Prepared from 8 (0.1 g, 0.14 mmol)

according to Method H. Yield: 0.092 g (83%) yellowish

crude syrup (R_f= 0.46, ethyl acetate–hexane 1:1) suﬃ-

ciently pure for the next transformation. Spectroscopic

characterisation could not be carried out because of easy

decomposition of the compound. By using Method I the

yield was 72%.

4.9.4.

Methyl

C-(2,3,4,6-tetra-O-acetyl-1-bromo-1-

deoxy-b-^D-galactopyranosyl)formate (methyl 3,4,5,7-

tetra-O-acetyl-2-bromo-2-deoxy-a-^D-galacto-hept-2-ulo-

pyranosonate) 20. Prepared from 4 (1.50g, 3.83 mmol)

according to Method G, puriﬁed by column chromato-

graphy (eluent: ethyl acetate–hexane 1:1). Yield: 1.16 g

(65%) colourless oil (R_f= 0.57, ethyl acetate–hexane

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

136

4.9.8. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-acetyl-1-

bromo-1-deoxy-b-^D-galactopyranosyl)formate (2,2,2-tri-

chloroethyl 3,4,5,7-tetra-O-acetyl-2-bromo-2-deoxy-a-^D-

galacto-hept-2-ulopyranosonate) 24. Prepared from 9

(0.96 g, 1.89 mmol) according to Method I. Yield:

0.88 g colourless oil (R_f= 0.41, ethyl acetate–hexane

1:1) (crude product contaminated with an unidentiﬁed

bromine containing by-product, R_f= 0.45, ethyl ace-

tate–hexane 1:1). This was used for the azide substitu-

(CO), 160.2 (COOC₆Cl₅, ³J_COOC6Cl5,H-2= <1 Hz),

142.7–127.3 (aromatics), 93.1 (C-1), 73.1, 69.8, 66.5,

66.2 (C-2 to C-5), 60.2 (C-6), 20.6, 20.5, 20.3 (CH₃).

Anal. Calcd for C₂₁H₁₈BrCl₅O₁₁(703.54): C, 35.85; H,

2.58; Br, 11.30; Cl, 25.20. Found: C, 35.62; H, 2.28;

Br, 11.25; Cl, 24.96.

By using Method I 27 was obtained in 91% yield.

1

tion to give 42. H NMR (CDCl₃) d (ppm): 5.54 (1H,

4.9.12. Pentachlorophenyl C-(2,3,4,6-tetra-O-acetyl-1-

bromo-1-deoxy-b-^D-glucopyranosyl)formate (pentachloro-

dd, J = 2.9, 1.5 Hz, H-4), 5.50(1H, d, J = 10.3 Hz, H-

2), 5.37 (1H, dd, J = 10.3, 2.9 Hz, H-3), 4.89 (1H, d,

J = 11.8 Hz, CH₂), 4.79 (1H, d, J = 11.8 Hz, CH₂),

4.55 (1H, ddd, J = 5.9, 5.1, 1.5 Hz, H-5), 4.26–4.21

(2H, m, H-6, H-6⁰), 2.17, 2.11, 2.06, 2.00 (12H, 4 · s,

OAc).

phenyl

3,4,5,7-tetra-O-acetyl-2-bromo-2-deoxy-a-^D-

gluco-hept-2-ulopyranosonate) 28. Prepared from 13

according to Method G. Yield: 0.11 g (97%) colourless

oil (R_f= 0.52, ethyl acetate–hexane 1:1); [a]_D= +49

(c 1.11, CHCl₃); m_max(CHCl₃): 3438, 1756, 1368, 1230,

1056, 600; ¹H NMR (CDCl₃) d (ppm): 5.55 (1H, t,

J = 9.5, 9.5 Hz, H-3), 5.48 (1H, d, J = 9.5 Hz, H-2),

5.34 (1H, dd, J = 9.5, 8.9 Hz, H-4), 4.47–4.37 (2H,

m, H-5, H-6), 4.28 (1H, dd, J = 13.7, 3.7 Hz, H-6⁰),

2.11, 2.08, 2.07, 2.02 (12H, 4 · s, OAc); ¹³C NMR

(CDCl₃) d (ppm): 170.3, 169.8, 169.1, 168.6 (CO),

4.9.9. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-acetyl-1-

(2,2,2-tri-

bromo-1-deoxy-b-^D-glucopyranosyl)formate

chloroethyl 3,4,5,7-tetra-O-acetyl-2-bromo-2-deoxy-a-^D-

gluco-hept-2-ulopyranosonate) 25. Prepared from 10

(0.20 g, 0.39 mmol) according to Method I. Yield:

0.23 g colourless oil (R_f= 0.43, ethyl acetate–hexane

1:1) (crude product contaminated with an unidentiﬁed

by-product (R_f= 0.28, ethyl acetate–hexane 1:1) in 5:1

ratio). This was used for the azide substitution to give

43. ¹H NMR (CDCl₃) d (ppm): 5.52 (1H, t, J = 9.2,

9.2 Hz, H-3), 5.34 (1H, d, J = 9.2 Hz, H-2), 5.26 (1H,

t, J = 10.6, 9.2 Hz, H-4), 4.89 (1H, d, J = 11.9 Hz,

CH₂), 4.79 (1H, d, J = 11.9 Hz, CH₂), 4.39 (1H, dd,

J = 13.2, 4.0Hz, H-6), 4.34 (1H, ddd, J = 13.2, 4.0,

2.6 Hz, H-5), 4.19 (1H, dd, J = 13.2, 2.6 Hz, H-6⁰),

2.11 (2), 2.05, 2.01.

3

160.2 (COOC₆Cl₅, J_COOC6Cl5,H-2= 2.2 Hz), 142.7–

132.3 (aromatics), 91.8 (C-1), 74.0, 71.8, 69.6, 66.4

(C-2 to C-5), 60.5 (C-6), 20.5, 20.4 (CH₃). Anal. Calcd

for C₂₁H₁₈BrCl₅O₁₁(703.54): C, 35.85; H, 2.58; Br,

11.30; Cl, 25.20. Found: C, 35.71; H, 2.40; Br, 11.18;

Cl, 25.26.

4.9.13. Pentachlorophenyl C-(2,3,4,6-tetra-O-benzoyl-1-

bromo-1-deoxy-b-^D-glucopyranosyl)formate (pentachloro-

phenyl

3,4,5,7-tetra-O-benzoyl-2-bromo-2-deoxy-a-^D-

gluco-hept-2-ulopyranosonate) 29. Prepared from 14

according to Method G. Yield: 0.19 g (89%) yellowish

oil (R_f= 0.52, ethyl acetate–hexane 1:2); [a]_D= +39

(c 1.03, CHCl₃); m_max(CHCl₃): 3650, 2962, 1736,

1522, 1490, 1378, 1264, 1090, 708, 610; ¹H NMR

(CDCl₃) d (ppm): 8.08–7.25 (20H, m, Ph), 6.24 (1H, t,

J = 9.5, 9.5 Hz, H-3), 6.04 (1H, d, J = 9.5 Hz, H-2),

5.95 (1H, dd, J = 10.5, 9.5 Hz, H-4), 4.90–4.80 (2H, m,

H-5, H-6), 4.60(1H, dd, J = 12.6, 3.7 Hz, H-6⁰); ¹³C

NMR (CDCl₃) d (ppm): 165.7, 165.5, 164.9, 164.3

4.9.10. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-benzoyl-1-

(2,2,2-tri-

bromo-1-deoxy-b-^D-glucopyranosyl)formate

chloroethyl 3,4,5,7-tetra-O-benzoyl-2-bromo-2-deoxy-a-

D-gluco-hept-2-ulopyranosonate) 26. Prepared from 11

(0.30 g, 0.40 mmol) according to Method I. Yield:

0.30 g yellowish oil (R_f= 0.41, ethyl acetate–hexane

1:2), which contained the corresponding hydroxy deriv-

1

ative 33 in 5:1 ratio; H NMR (CDCl₃) d (ppm): 8.08–

3

7.24 (20H, m, Ph), 6.20 (1H, dd, J = 9.6, 9.2 Hz, H-3),

5.88 (1H, d, J = 9.2 Hz, H-2), 5.84 (1H, dd, J = 9.6,

9.2 Hz, H-4), 4.85 (1H, d, J = 11.9 Hz, CH₂), 4.79 (1H,

ddd, J = 11.9, 3.9, 2.6 Hz, H-5), 4.73 (1H, d,

J = 11.9 Hz, CH₂), 4.72 (1H, dd, J = 11.9, 2.6 Hz, H-

6), 4.57 (1H, dd, J = 11.9, 3.9 Hz, H-6⁰).

(CO), 160.2 (COOC₆Cl₅, J_COOC6Cl5,H-2= 3.2 Hz),

142.7–126.1 (aromatics), 92.6 (C-1), 74.6, 72.0, 70.4,

67.6 (C-2 to C-5), 61.4 (C-6). Anal. Calcd for

C₄₁H₂₆BrCl₅O₁₁(951.83): C, 51.74; H, 2.75; Br,

8.39; Cl, 18.62. Found: C, 51.71; H, 2.60; Br, 8.18; Cl,

18.36.

4.9.11. Pentachlorophenyl C-(2,3,4,6-tetra-O-acetyl-1-

(penta-

4.10. General procedure II

bromo-1-deoxy-b-^D-galactopyranosyl)formate

chlorophenyl 3,4,5,7-tetra-O-acetyl-2-bromo-2-deoxy-a-

D-galacto-hept-2-ulopyranosonate) 27. Prepared from

12 (0.30 g, 0.48 mmol) according to Method G. Yield:

0.33 g (99%) yellowish oil (R_f= 0.58, ethyl acetate–hex-

ane 1:1); [a]_D= +57 (c 1.02, CHCl₃); m_max(CHCl₃):

For the preparation of per-O-acylated methyl C-(1-hy-

droxy-b-^D-glycopyranosyl)formates (methyl hept-2-ulo-

pyranosonates) 31 and 32: A methyl per-O-acyl-2-

bromo-2-deoxy-a-^D-glyco-hept-2-ulopyranosonate 20

or 21 was suspended in DMSO (5 mL/mmol), Ag₂O

(1 equiv) and water (1 equiv) were added. The reaction

mixture was stirred at rt in the dark and monitored by

TLC (ethyl acetate–hexane 5:4). After disappearance

of the starting bromide it was ﬁltered on Celite, the ﬁl-

trate was diluted with water (25 mL/mmol), washed with

Et₂O (5·). After drying the solvent was removed

in vacuo to give a clean product.

1

3430, 1760, 1370, 1230, 1026, 600; H NMR (CDCl₃)

d (ppm): 5.64 (1H, d, J = 10.5 Hz, H-2), 5.58 (1H, dd,

J = 3.3, 1.3 Hz, H-4), 5.41 (1H, dd, J = 10.5, 3.3 Hz,

H-3), 4.63 (1H, ddd, J = 6.6, 6.6, 1.3 Hz, H-5), 4.31

(1H, dd, J = 11.2, 6.6 Hz, H-6), 4.27 (1H, dd, J = 11.2,

6.6 Hz, H-6⁰), 2.20, 2.08, 2.00 (12H, 3 · s, OAc); ¹³C

NMR (CDCl₃) d (ppm): 170.1, 169.8, 169.7, 168.5

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

137

4.10.1. Methyl C-(2,3,4,6-tetra-O-acetyl-1-hydroxy-b-D-

galactopyranosyl)formate (methyl 3,4,5,7-tetra-O-acetyl-

4.10.4. N-[(2,3,4,6-Tetra-O-acetyl-1-bromo-1-deoxy-b-^D-

galactopyranosyl)carbonyl]glycine methylester (N-(3,4,5,

7-tetra-O-acetyl-2-bromo-2-deoxy-a-^D-galacto-hept-2-

ulopyranosonoyl)glycine methylester) 35. Prepared

from 27 (0.30 g, 0.43 mmol) according to Method E.

Yield: 0.18 g (71%) colourless oil (R_f= 0.22, ethyl

acetate–hexane 1:1); [a]_D= +96 (c 0.79, CHCl₃); m_max

a-^D-galacto-hept-2-ulopyranosonate)

31. Prepared

from 20 (0.25 g, 0.53 mmol) according to general proce-

dure II. Yield: 0.15 g (74%) colourless oil (R_f= 0.53,

ethyl acetate–hexane 5:4); [a]_D= +55 (c 1.26, CHCl₃);

m_max(CHCl₃):3658, 3440, 1758, 1362, 1232, 1050; ¹H

NMR (CDCl₃) d (ppm): 5.59 (1H, d, J = 10.6 Hz, H-

2), 5.49 (1H, dd, J = 3.2, 1.3 Hz, H-4), 5.35 (1H, dd,

J = 10.6, 3.2 Hz, H-3), 4.56 (1H, s, OH), 4.48 (1H,

ddd, J = 6.9, 6.9, 1.3 Hz, H-5), 4.16 (1H, dd, J = 11.5,

6.9 Hz, H-6), 4.06 (1H, dd, J = 11.5, 6.9 Hz, H-6⁰),

3.86 (3H, s, OCH₃), 2.18, 2.03, 2.02, 1.97 (12H, 4 · s,

OAc); ¹³C NMR (CDCl₃) d (ppm): 170.4, 170.3, 170.0,

1

(CHCl₃): 3378, 2960, 1754, 1680, 1370, 1260, 1070; H

NMR (CDCl₃) d (ppm): 7.02 (1H, t, J = 5.3, 5.3 Hz,

NH), 5.55 (1H, dd, J = 3.2, 1.0Hz, H-4), 5.43 (1H, d,

J = 10.5 Hz, H-2), 5.33 (1H, dd, J = 10.5, 3.2 Hz, H-3),

4.56 (1H, ddd, J = 6.8, 6.6, 1.0Hz, H-5), 4.31 (1H,

dd, J = 12.1, 6.8 Hz, H-6), 4.22 (1H, dd, J = 12.1,

6.3 Hz, H-6⁰), 4.12 (1H, dd, J = 18.4, 5.3 Hz, CH₂),

4.03 (1H, dd, J = 18.4, 5.3 Hz, CH₂), 3.79 (3H, s,

OCH₃), 2.17, 2.13, 2.10, 1.99 (12H, 4 · s, OAc); ¹³C

NMR (CDCl₃) d (ppm): 170.4 (COOCH₃), 169.8,

3

169.5 (CO), 168.6 (COOCH₃, J_COOCH3,H-2= 2.2 Hz),

94.6 (C-1), 68.7, 68.6, 67.9, 67.7 (C-2 to C-5), 61.4 (C-

6), 54.1 (COOCH₃), 20.7, 20.6 (CH₃). Anal. Calcd for

C₁₆H₂₂O₁₂(406.26): C, 47.30; H, 5.47. Found: C,

47.54; H, 5.65.

3

169.3 (CO), 164.9 (CONH, J_CONH,H-2= 2.2 Hz), 94.0

(C-1), 73.5, 69.7, 66.5, 66.5 (C-2 to C-5), 60.7 (C-6),

52.5 (COOCH₃), 41.1 (CH₂), 20.8, 20.5, 20.4 (CH₃).

Anal. Calcd for C₁₈H₂₄N₁BrO₁₂(526.30): C, 41.08; H,

4.60; N, 2.66; Br, 15.18. Found: C, 41.20; H, 4.58; N,

2.56; Br, 15.08.

4.10.2. Methyl C-(2,3,4,6-tetra-O-benzoyl-1-hydroxy-b-

D-glucopyranosyl)formate (methyl 3,4,5,7-tetra-O-ben-

zoyl-a-^D-gluco-hept-2-ulopyranosonate) 32. Prepared

from 21 (0.35 g, 0.49 mmol) according to general

procedure II. Yield: 0.17 g (52%), white crystalline

product from diethylether; mp: 147–151 ꢁC; [a]_D= +52

(c 1.14, CHCl₃); m_max(KBr): 3652, 3648, 2962,

4.10.5. N-[(2,3,4,6-Tetra-O-acetyl-1-bromo-1-deoxy-b-^D-

glucopyranosyl)carbonyl]glycine methylester (N-(3,4,5,7-

tetra-O-acetyl-2-bromo-2-deoxy-a-^D-gluco-hept-2-ulopy-

ranosonoyl)glycine methylester) 36. Prepared from 28

(0.56 g, 0.80 mmol) according to Method E. Yield:

0.30 g (71%), colourless oil (R_f= 0.16, ethyl acetate–hex-

ane 1:1); [a]_D= +76 (c 1.12, CHCl₃); m_max(CHCl₃):

3376, 2954, 1758, 1670, 1354, 1252, 1040; ¹H NMR

(CDCl₃) d (ppm): 7.06 (1H, t, J = 5.3, 5.3 Hz, NH),

1

1736, 1520, 1496, 1372, 1264, 1088, 708, 610; H NMR

(CDCl₃) d (ppm): 8.07–7.24 (20H, m, Ph), 6.20

(1H, dd, J = 10.2, 9.8 Hz, H-3), 5.90 (1H, d, J =

10.2 Hz, H-2), 5.83 (1H, t, J = 9.9, 9.8 Hz, H-4), 4.72

(1H, ddd, J = 9.9, 4.7, 3.0Hz, H-5), 4.71 (1H, s, OH),

4.61 (1H, dd, J = 12.4, 4.7 Hz, H-6), 4.49 (1H, dd,

J = 12.4, 3.0Hz, H-6 ), 3.86 (3H, s, OCH₃); ¹³C NMR

5.50(1H, t,

J = 10.0, 9.5 Hz, H-3), 5.24 (1H, d,

0

3

(CDCl₃) d (ppm): 168.7 (COOCH₃, J_COOCH3,H-2

=

J = 10.0 Hz, H-2), 5.22 (1H, t, J = 10.0, 9.5 Hz, H-4),

4.38–4.32 (3H, m, H-5, H-6, H-6⁰), 4.09 (1H, dd,

J = 18.4, 3.1 Hz, CH₂), 4.02 (1H, dd, J = 18.4, 3.1 Hz,

CH₂) 3.78 (3H, s, OCH₃), 2.14, 2.12, 2.07, 2.01 (12H,

4 · s, OAc); ¹³C NMR (CDCl₃) d (ppm): 170.8

(COOCH₃), 169.8, 169.3, 169.2 (CO), 164.8 (CONH,

³J_CONH,H-2= <1 Hz), 92.5 (C-1), 74.2, 71.6, 69.6, 66.5

(C-2 to C-5), 60.5 (C-6), 52.5 (COOCH₃), 41.1 (CH₂),

20.6, 20.4 (CH₃). Anal. Calcd for C₁₈H₂₄NBrO₁₂

(526.30): C, 41.08; H, 4.60; N, 2.66; Br, 15.18. Found:

C, 41.10; H, 4.62; N, 2.60; Br, 15.06.

2.1 Hz), 166.2, 165.7, 165.2, 165.1 (CO), 133.6–128.3

(aromatics), 94.4 (C-1), 71.4, 71.4, 70.0, 69.4 (C-2 to

C-5), 61.4 (C-6), 54.1 (COOCH₃). Anal. Calcd for

C₃₆H₃₀O₁₂(654.54): C, 66.06; H, 4.63. Found: C,

65.74; H, 4.68.

4.10.3. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-benzoyl-1-

hydroxy-b-^D-glucopyranosyl)formate (2,2,2-trichloroethyl

3,4,5,7-tetra-O-benzoyl-a-^D-gluco-hept-2-ulopyranoson-

ate) 33. Isolated by column chromatography as a

by-product from the preparation of 44. Yield: 0.03 g

(14% for two steps from 11) colourless oil (R_f= 0.26,

ethyl acetate–hexane 1:2); [a]_D= +45 (c 0.40, CHCl₃);

¹H NMR (CDCl₃) d (ppm): 8.06–7.26 (20H, m, Ph),

6.18 (1H, t, J = 9.2, 8.8 Hz, H-3), 5.92 (1H, d,

J = 9.2 Hz, H-2), 5.87 (1H, t, J = 9.8, 8.8 Hz, H-4),

4.87 (1H, d, J = 12.0Hz, CH ₂), 4.83 (1H, d,

J = 12.0Hz, CH ₂), 4.72–4.61 (3H, m, H-5, H-6, OH),

4.46 (1H, dd, J = 11.8, 2.2 Hz, H-6⁰); ¹³C NMR (CDCl₃)

d (ppm): 166.8, 166.0, 165.7, 165.1 (CO), 164.9

(COOCH₂CCl₃, ³J_{COOCH2CCl3,H-2}= <1 Hz.), 133.5–

128.2 (aromatics), 93.5 (C-1), 84.6 (COOCH₂CCl₃),

75.7 (COOCH₂CCl₃), 71.2, 71.1, 70.1, 68.9 (C-2 to C-

5), 62.2 (C-6). Anal. Calcd for C₃₇H₂₉Cl₃O₁₂(772.00):

C, 57.57; H, 3.79; Cl, 13.78. Found: C, 57.17; H, 3.60;

Cl, 13.50.

4.10.6. N-[(2,3,4,6-Tetra-O-benzoyl-1-bromo-1-deoxy-b-

D-glucopyranosyl)carbonyl]glycine methylester (N-(3,4,5,

7-tetra-O-benzoyl-2-bromo-2-deoxy-a-^D-gluco-hept-2-

ulopyranosonoyl)glycine methylester) 37. Prepared

from 29 (0.11 g, 0.11 mmol) according to Method E.

Yield: 0.05 g (53%) yellowish oil (R_f= 0.34, ethyl ace-

tate–hexane 1:1); [a]_D= +79 (c 0.77, CHCl₃); m_max

1

(CHCl₃): 3650, 2654, 1736, 1600, 1270, 1092, 708; H

NMR (CDCl₃) d (ppm): 8.18–7.24 (20H, m, Ph), 7.20

(1H, t, J = 5.3, 5.3 Hz, NH), 6.15 (1H, t, J = 9.5,

9.5 Hz, H-3), 5.82 (1H, t, J = 10.0, 9.5 Hz, H-4), 5.78

(1H, d, J = 9.5 Hz, H-2), 4.84 (1H, dd, J = 12.6,

2.1 Hz, H-6), 4.78 (1H, ddd, J = 12.6, 4.2, 2.1 Hz, H-

5), 4.56 (1H, dd, J = 12.6, 4.2 Hz, H-6⁰), 4.07 (1H, dd,

J = 17.9, 5.3 Hz, CH₂), 4.02 (1H, dd, J = 17.9, 5.3 Hz,

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

138

CH₂), 3.72 (3H, s, OCH₃); ¹³C NMR (CDCl₃) d (ppm):

169.2 (COOCH₃), 165.5 (CONH, ³J_{CONH, H-2}= 4.4 Hz),

165.0, 164.5 (CO), 133.8–128.3 (aromatics), 93.0 (C-1),

74.8, 71.9, 70.3, 67.7 (C-2 to C-5), 61.5 (C-6), 52.4

(COOCH₃), 41.2 (CH₂). Anal. Calcd for C₃₈H₃₂NBrO₁₂

(774.58): C, 58.93; H, 4.16; N, 1.81; Br, 10.32. Found: C,

58.63; H, 4.32; N, 1.85; Br, 10.06.

(679.54): C, 63.63; H, 4.31; N, 6.18. Found: C, 63.54;

H, 4.36; N, 6.00.

4.11.3. tert-Butyl C-(2,3,4,6-tetra-O-acetyl-1-azido-1-

deoxy-a-^D-galactopyranosyl)formate (tert-butyl 3,4,5,7-

tetra-O-acetyl-2-azido-2-deoxy-b-^D-galacto-hept-2-ulo-

pyranosonate) 40. Prepared from 22 (0.12 g, 0.23 mmol

crude product) according to general procedure III. Puri-

ﬁed by column chromatography (eluent: ethyl acetate–

hexane, 1:1): Yield: 0.09 g (69%) colourless oil

(R_f= 0.37, ethyl acetate–hexane 1:1); [a]_D= +65 (c

0.77, CHCl₃); m_max(CHCl₃): 2978, 2128, 1754, 1372,

4.11. Azide substitutions

General procedure III for the preparation of derivatives of

per-O-acylated C-(1-azido-1-deoxy-a-^D-glycopyranosyl)-

formic acids (2-azido-2-deoxy-b-^D-glyco-hept-2-ulopyr-

anosonic acids) 38–47: A per-O-acylated 2-bromo-2-

deoxy-a-^D-glyco-hept-2-ulopyranosonic acid derivative

was dissolved in abs. DMSO (2 mL/mmol) unless stated

otherwise, and NaN₃(2 equiv) was added. The mixture

was stirred at room temperature. When the starting

material disappeared (TLC, ethyl acetate–hexane 1:1),

water (10mL/mmol) was added and the aqueous phase

washed with Et₂O (5·). The organic phase was washed

with water, dried, and the solvent evaporated in vacuo.

The crude product was puriﬁed by crystallisation or by

column chromatography if necessary.

1

1214, 1024; H NMR (CDCl₃) d (ppm): 5.67 (1H, dd,

J = 10.5, 3.7 Hz, H-3), 5.49 (1H, dd, J = 3.7, 1.6 Hz,

H-4), 5.31 (1H, d, J = 10.5 Hz, H-2), 4.53 (1H, ddd,

J = 6.3, 6.3, 1.6 Hz, H-5), 4.18–4.13 (2H, m, H-6, H-

6⁰), 2.18, 2.06, 2.05, 1.97 (12H, 4 · s, OAc), 1.58 (9H,

s, C(CH₃)₃); ¹³C NMR (CDCl₃) d (ppm): 170.2, 170.0,

3

169.8, 168.9 (CO), 164.0( COOC(CH₃)₃, J_{COOtBu, H-2}

=

6.6 Hz), 90.6 (C-1), 85.4 (COOC(CH₃)₃), 72.0, 68.9,

68.7, 66.8 (C-2 to C-5), 61.4 (C-6), 27.8 (C(CH3)₃),

20.5 (CH₃). Anal. Calcd for C₁₉H₂₇N₃O₁₁(473.44): C,

48.20; H, 5.75; N, 8.88. Found: C, 48.10; H, 5.66; N,

8.56.

4.11.1. Methyl C-(2,3,4,6-tetra-O-acetyl-1-azido-1-de-

oxy-a-^D-galactopyranosyl)formate (methyl 3,4,5,7-tetra-

O-acetyl-2-azido-2-deoxy-b-^D-galacto-hept-2-ulopyrano-

sonate) 38. Prepared from 20 (0.50 g, 1.06 mmol)

according to general procedure III. Yield: 0.45 g (84%)

white crystalline product from diethylether; mp: 95–

97 ꢁC; [a]_D= +55 (c 1.61, CHCl₃); m_max(KBr): 3904,

4.11.4. tert-Butyl C-(1-azido-2,3,4,6-tetra-O-benzoyl-1-

deoxy-a-^D-glucopyranosyl)formate (tert-butyl 2-azido-

3,4,5,7-tetra-O-benzoyl-2-deoxy-a-^D-gluco-hept-2-ulo-

pyranosonate) 41. Prepared from 23 (0.09, 0.12 mmol

crude product) according to general procedure III. Puri-

ﬁed by column chromatography (eluent: ethyl acetate–

hexane,1:2): Yield: 0.05 g (46%) colourless oil

(R_f= 0.46, ethyl acetate–hexane 1:1); [a]_D= +37

(c 1.18, CHCl₃); m_max(CHCl₃): 3064, 2978, 2130, 1736,

1

2122, 1762, 1378, 1240, 1216, 1076; H NMR (CDCl₃)

d (ppm): 5.58 (1H, dd, J = 11.1, 3.6 Hz, H-3), 5.49

(1H, d, J = 11.1 Hz, H-2), 5.35 (1H, dd, J = 3.6,

<1 Hz, H-4), 4.53 (1H, ddd, J = 6.6, 6.6, <1 Hz, H-5),

4.18 (1H, dd, J = 12.5, 6.6 Hz, H-6), 4.16 (1H, dd,

1

1268, 1092, 708; H NMR (CDCl₃) d (ppm): 8.10–7.22

(20H, m, Ph), 6.44 (1H, dd, J = 9.8, 9.2 Hz, H-3), 5.73

(1H, t, J = 9.8, 9.2 Hz, H-4), 5.62 (1H, d, J = 9.8 Hz,

H-2), 4.72–4.62 (2H, m, H-5, H-6), 4.50(1H, dd,

J = 12.6, 6.3 Hz, H-6⁰), 1.60(9H, s, C(CH ₃)₃); ¹³C

NMR (CDCl₃) d (ppm): 166.0, 165.5, 165.1, 164.7

J = 12.5, 6.6 Hz, H-6⁰), 3.90(3H, s, OCH ), 2.18, 2.06,

3

2.04, 1.97 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d

(ppm): 170.0, 169.8, 169.5, 168.8 (CO), 165.8 (COOCH₃,

³J_COOMe,H-2= 4.1 Hz), 90.6 (C-1), 72.0, 68.7, 68.3, 66.7

(C-2 to C-5), 61.0(C-6), 53.2 (O CH₃), 20.4, 20.3, 20.2

(CH₃). Anal. Calcd for C₁₆H₂₁N₃O₁₁(431.36): C,

44.55; H, 4.91; N, 9.74. Found: C, 44.10; H, 5.06; N,

9.56.

3

(CO), 164.0( COOC(CH₃)₃, J_COOtBu,H-2= 4.4 Hz),

133.5–128.2

(aromatics),

90.3

(C-1),

85.6

(COOC(CH₃)₃), 73.2, 72.0, 71.2, 69.0 (C-2 to C-5),

62.8 (C-6), 27.9 (C(CH₃)₃). Anal. Calcd for

C₃₉H₃₅N₃O₁₁(721.73): C, 64.90; H, 4.89; N, 5.82.

Found: C, 64.64; H, 4.76; N, 5.80.

4.11.2. Methyl C-(1-azido-2,3,4,6-tetra-O-benzoyl-1-

deoxy-a-^D-glucopyranosyl)formate (methyl 2-azido-

3,4,5,7-tetra-O-benzoyl-2-deoxy-b-^D-gluco-hept-2-ulopyr-

anosonate) 39. Prepared from 21 (1.20g, 1.67 mmol)

according to general procedure III. Yield: 0.90 g (80%)

colourless oil, which crystallised from methanol (57%);

mp: 121–123 ꢁC; [a]_D= +41 (c 1.22, CHCl₃); m_max

(KBr): 3854, 3064, 2128, 1736, 1492, 1452, 1270, 1094,

4.11.5. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-acetyl-1-

azido-1-deoxy-a-^D-galactopyranosyl)formate (2,2,2-tri-

chloroethyl 3,4,5,7-tetra-O-acetyl-2-azido-2-deoxy-b-^D-

galacto-hept-2-ulopyranosonate) 42. Prepared from 24

(1.35 g, 2.30mmol crude product) according to general

procedure III. Puriﬁed by column chromatography (elu-

ent, ethyl acetate–hexane, 1:1): Yield: 1.01 g (75% for

two steps from 9) colourless oil (R_f= 0.53, ethyl ace-

tate–hexane 1:2); [a]_D= +51 (c 0.24, CHCl₃); m_max

1

708; H NMR (CDCl₃) d (ppm): 8.01–7.20 (20H, m,

Ph), 6.36 (1H, dd, J = 10.5, 9.5 Hz, H-3), 5.81 (1H, dd,

J = 9.5, 9.4 Hz, H-4), 5.70(1H, d, J = 10.5 Hz, H-2),

4.70–4.60 (2H, m, H-6, H-6⁰) 4.51 (1H, ddd, J = 11.6,

5.2, 2.3 Hz, H-5), 3.90(3H, s, OCH ₃); ¹³C NMR

(CDCl₃) d (ppm): 165.3, 164.9, 164.5 (CO), 165.9

(COOCH₃, ³J_COOMe,H-2= 4.1 Hz), 133.5–128.2 (aromat-

ics), 90.1 (C-1), 73.3, 71.9, 71.0, 68.8 (C-2 to C-5), 62.5

(C-6), 53.4 (OCH₃). Anal. Calcd for C₃₆H₂₉N₃O₁₁

1

(CHCl₃): 2968, 2128, 1754, 1370, 1230, 1068, 722; H

NMR (CDCl₃) d (ppm): 5.67 (1H, dd, J = 10.3,

3.7 Hz, H-3), 5.53 (1H, dd, J = 3.7, 2.2 Hz, H-4), 5.43

(1H, d, J = 10.3 Hz, H-2), 5.01 (1H, d, J = 11.8 Hz,

CH₂), 4.92 (1H, d, J = 11.8 Hz, CH₂), 4.55 (1H, ddd,

J = 6.6, 5.9, 2.2 Hz, H-5), 4.19–4.15 (2H, m, H-6, H-

6⁰), 2.20, 2.07, 2.04, 1.98 (12H, 4 · s, OAc); ¹³C NMR

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

139

(CDCl₃) d (ppm): 170.2, 169.9, 169.6, 168.9 (CO),

163.9 (COOCH₂CCl₃, J_{COOCH2CCl3,H-2}= 8.3 Hz), 93.6

CHCl₃); m_max(KBr): 3370, 2958, 2134, 1744, 1680,

1370, 1252, 1068; ¹H NMR (CDCl₃) d (ppm): 7.08

(1H, t, J = 5.9, 5.9 Hz, NH), 5.84 (1H, dd, J = 10.5,

3.3 Hz, H-3), 5.55 (1H, dd, J = 3.3, 1.3 Hz, H-4), 5.51

(1H, d, J = 10.5 Hz, H-2), 4.87 (1H, ddd, J = 6.6, 2.6,

1.3 Hz, H-5,), 4.16 (1H, dd, J = 12.5, 2.6 Hz, H-6),

4.15 (1H, dd, J = 18.4, 5.9 Hz, CH₂), 4.10(1H, dd,

J = 12.5, 6.6 Hz, H-6⁰), 3.95 (1H, dd, J = 18.4, 4.6 Hz,

CH₂), 3.78 (3H, s, OCH₃), 2.17, 2.10, 2.04, 1.97 (12H,

4 · s, OAc); ¹³C NMR (CDCl₃) d (ppm): 170.3

(COOCH₃), 169.8, 169.7, 169.5, 169.2 (CO), 165.3

3

(COOCH₂CCl₃), 90.7 (C-1), 75.1 (COOCH₂CCl₃),

72.5, 68.7, 68.3, 66.7 (C-2 to C-5), 61.2 (C-6), 20.6,

20.5, 20.4 (CH₃). Anal. Calcd for C₁₇H₂₀Cl₃N₃O₁₁

(548.72): C, 37.21; H, 3.67; Cl, 19.38; N, 7.66. Found:

C, 37.10; H, 3.60; Cl, 19.30; N, 7.56.

4.11.6. 2,2,2-Trichloroethyl C-(2,3,4,6-tetra-O-acetyl-1-

azido-1-deoxy-a-^D-glucopyranosyl)formate (2,2,2-trichlo-

roethyl 3,4,5,7-tetra-O-acetyl-2-azido-2-deoxy-b-^D-gluco-

hept-2-ulopyranosonate) 43. Prepared from 25 (0.20 g,

0.34 mmol crude product) according to general proce-

dure III. Puriﬁed by column chromatography (eluent,

ethyl acetate–hexane, 1:1): Yield: 0.09 g (60% for two

steps from 10) yellowish oil (R_f= 0.50, ethyl acetate–

hexane 1:1); [a]_D= +36 (c 0.20, CHCl₃); m_max(CHCl₃):

2968, 2128, 1754, 1370, 1230, 1068, 722; ¹H NMR

(CDCl₃) d (ppm): 5.74 (1H, dd, J = 10.6, 9.2 Hz, H-3),

5.23 (1H, dd, J = 10.6, 9.2 Hz, H-4), 5.21 (1H, d,

J = 9.2 Hz, H-2), 5.02 (1H, d, J = 11.9 Hz, CH₂), 4.93

(1H, d, J = 11.9 Hz, CH₂), 4.31–4.24 (2H, m, H-5, H-

6), 4.16 (1H, dd, J = 10.6, <1 Hz, H-6⁰) 2.10, 2.06,

2.04, 1.99 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d

(ppm): 170.5, 169.7, 169.3, 168.8 (CO), 163.8

3

(CONH, J_CONH,H-2= 6.5 Hz), 89.3 (C-1), 72.4, 69.1,

68.0, 67.3 (C-2 to C-5), 61.3 (C-6), 52.5 (COOCH₃),

40.8 (CH₂), 20.6, 20.5 (CO). Anal. Calcd for

C₁₈H₂₄N₄O₁₂(488.41): C, 44.27; H, 4.95; N, 11.47.

Found: C, 44.15; H, 4.76; N, 11.50.

4.11.9. N-[(2,3,4,6-Tetra-O-acetyl-1-azido-1-deoxy-a-^D-

glucopyranosyl)carbonyl]glycine methylester (N-(3,4,5,7-

tetra-O-acetyl-2-azido-2-deoxy-b-^D-gluco-hept-2-ulopy-

ranosonoyl)glycine methylester) 46. Prepared from 36

(0.14 g, 0.26 mmol) according to general procedure III.

Yield: 0.09 g (69%) oil, which crystallised on standing

at 4 ꢁC to give white crystals; mp: 97–99 ꢁC; [a]_D= ꢁ5

(c 1.04, CHCl₃); m_max(KBr): 3372, 2954, 2136, 1752,

1684, 1350, 1242, 1068; ¹H NMR (CDCl₃) d (ppm):

7.20(1H, t, J = 5.3, 5.3 Hz, NH), 5.87 (1H, t, J = 8.8,

8.8 Hz, H-3), 5.30–5.24 (2H, m, H-2, H-4), 4.64 (1H,

ddd, J = 10.0, 3.7, 2.2 Hz, H-5,), 4.26 (1H, dd,

J = 12.1, 2.2 Hz, H-6), 4.18 (1H, dd, J = 12.5, 3.7 Hz,

H-6⁰) 4.13 (1H, dd, J = 18.4, 5.3 Hz, CH₂), 4.02 (1H,

dd, J = 18.4, 5.3 Hz, CH₂), 3.78 (3H, s, OCH₃), 2.10,

2.05, 2.01 (12H, 3 · s, OAc); ¹³C NMR (CDCl₃) d

(ppm): 170.5 (COOCH₃), 169.6, 169.5, 169.1 (CO),

(COOCH₂CCl₃,

³J_{COOCH2CCl3,H-2}= 6.0Hz),

93.5

(COOCH₂CCl₃), 89.1 (C-1), 75.1 (COOCH₂CCl₃),

73.0, 71.3, 70.9, 67.5 (C-2 to C-5), 61.4 (C-6), 20.6,

20.5 (CH₃). Anal. Calcd for C₁₇H₂₀Cl₃N₃O₁₁(548.72):

C, 37.21; H, 3.67; Cl, 19.38; N, 7.66. Found: C, 37.15;

H, 3.65; Cl, 19.28; N, 7.49.

4.11.7. 2,2,2-Trichloroethyl C-(1-azido-2,3,4,6-tetra-O-

benzoyl-1-deoxy-a-^D-glucopyranosyl)formate (2,2,2-tri-

chloroethyl 2-azido-3,4,5,7-tetra-O-benzoyl-2-deoxy-b-^D-

gluco-hept-2-ulopyranosonate) 44. Prepared from 26

(0.23 g, 0.27 mmol crude product) according to general

procedure III. Puriﬁed by column chromatography (elu-

ent, ethyl acetate–hexane: 1:3): Yield: 0.10 g (59% for

two steps from 11) white crystalline product from meth-

anol; mp: 177–179 ꢁC; [a]_D= +45 (c 0.41, CHCl₃); m_max

(KBr): 3904, 3066, 2132, 1740, 1584, 1570, 1490, 1374,

3

164.9 (CONH, J_CONH,H-2= 4.1 Hz), 88.6 (C-1), 72.6,

71.1, 70.8, 67.5 (C-2 to C-5), 61.3 (C-6), 52.4

(COOCH₃), 40.8 (CH₂), 20.4, 20.3 (CO). Anal. Calcd

for C₁₈H₂₄N₄O₁₂(488.41): C, 44.27; H, 4.95; N, 11.47.

Found: C, 44.35; H, 4.56; N, 11.26.

4.11.10. N-[(1-Azido-2,3,4,6-tetra-O-benzoyl-1-deoxy-a-

D-glucopyranosyl)carbonyl]glycine methylester (N-(2-

azido-3,4,5,7-tetra-O-benzoyl-2-deoxy-b-^D-gluco-hept-2-

ulopyranosonoyl)glycine methylester) 47. Prepared

from 37 (0.07 g, 0.09 mmol) according to general proce-

dure III. Yield: 0.04g (66%) colourless oil (R_f= 0.44,

ethyl acetate–hexane 1:1); [a]_D= ꢁ13 (c 0.77, CHCl₃);

m_max(CHCl₃): 3648, 2954, 2128, 1732, 1600, 1522,

1

1270, 1070, 708; H NMR (CDCl₃) d (ppm): 8.05–7.25

(20H, m, Ph), 6.46 (1H, dd, J = 10.4, 9.6 Hz, H-3),

5.82 (1H, dd, J = 10.4, 9.6 Hz, H-4), 5.77 (1H, d,

J = 10.4 Hz, H-2), 5.05 (1H, d, J = 12.0Hz, CH ₂), 5.00

(1H, d, J = 12.0Hz, CH ₂), 4.71–4.68 (2H, m, H-5, H-

6), 4.52 (1H, dd, J = 12.2, 5.3 Hz, H-6⁰); ¹³C NMR

(CDCl₃) d (ppm): 165.9, 165.3, 165.0, 164.5 (CO),

1

1264, 1092, 708; H NMR (CDCl₃) d (ppm): 8.20–7.24

163.9

(COOCH₂CCl₃,

³J_{COOCH2CCl3,H-2}= 4.0Hz),

(20H, m, Ph), 7.20 (1H, t, J = 5.3, 5.3 Hz, NH), 6.64

(1H, t, J = 9.5, 9.5 Hz, H-3), 5.86 (1H, dd, J = 10.0,

9.5 Hz, H-4), 5.78 (1H, d, J = 9.5 Hz, H-2), 5.10(1H,

ddd, J = 12.6, 3.7, 2.6 Hz, H-5,), 4.71 (1H, dd,

J = 12.6, 2.6 Hz, H-6), 4.45 (1H, dd, J = 12.6, 3.7 Hz,

H-6⁰) 4.14 (1H, dd, J = 17.9, 5.3 Hz, CH₂), 4.0(1H,

dd, J = 17.9, 5.3 Hz, CH₂), 3.54 (3H, s, OCH₃); ¹³C

NMR (CDCl₃) d (ppm): 168.9 (COOCH₃), 166.0

133.7–128.3 (aromatics), 93.5 (COOCH₂CCl₃), 90.3

(C-1), 75.3 (COOCH₂CCl₃), 73.6, 71.8, 70.9, 68.8 (C-2

to C-5), 62.5 (C-6). Anal. Calcd for C₃₇H₂₈Cl₃N₃O₁₁

(797.01): C, 55.76; H, 3.54; Cl, 13.34; N, 5.27. Found:

C, 55.66; H, 3.60; Cl, 13.30; N, 5.26.

4.11.8. N-[(2,3,4,6-Tetra-O-acetyl-1-azido-1-deoxy-a-^D-

galactopyranosyl)carbonyl]glycine methylester (N-(3,4,

5,7-tetra-O-acetyl-2-azido-2-deoxy-b-^D-galacto-hept-2-

ulopyranosonoyl)glycine methylester) 45. Prepared

from 35 (0.18 g, 0.34 mmol) according to general proce-

dure III. Yield: 0.11 g (65%) white crystalline product

from diethylether; mp: 135–136 ꢁC; [a]_D= +1 (c 0.93,

3

(CONH, J_CONH,H-2= 6.5 Hz), 165.2, 165.1, 164.9

(CO), 133.6–128.2 (aromatics), 89.1 (C-1), 73.4, 71.6,

71.1, 68.6 (C-2 to C-5), 62.2 (C-6), 52.4 (COOCH₃),

41.1 (CH₂). Anal. Calcd for C₃₈H₃₂N₄O₁₂(736.70): C,

69.96; H, 4.38; N, 7.61. Found: C, 69.85; H, 4.45; N,

7.36.

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

140

4.11.11. C-(2,3,4,6-Tetra-O-acetyl-1-azido-1-deoxy-b-D-

galactopyranosyl)formic acid azide (3,4,5,7-tetra-O-acet-

yl-2-azido-2-deoxy-a-^D-galacto-hept-2-ulopyranosonoyl

azide) 48. Prepared from 30 according to general pro-

cedure III with 4 equiv NaN₃in dry DMF. Puriﬁed by

column chromatography (eluent: ethyl acetate–hexane

1:1): Yield: 0.07 g (60% for two steps from 18) colourless

oil (R_f= 0.58, ethyl acetate–hexane 2:1); [a]_D= +110( c

0.20, CHCl₃); m_max(CHCl₃): 2948, 2152, 1754, 1370,

J = 18.9, 5.1 Hz, CH₂), 3.79 (3H, s, OCH₃), 2.18, 2.13,

2.10, 1.99 (12H, 4 · s, OAc); ¹³C NMR (CDCl₃) d

(ppm): 170.4 (COOCH₃), 169.8, 169.3 (CO), 165.0

3

(CONH, J_CONH,H-2= 2.8 Hz), 94.0(C-1), 73.6, 73.4,

69.7, 66.5 (C-2 to C-5), 60.7 (C-6), 52.5 (COOCH₃),

41.1 (CH₂), 20.9, 20.8, 20.7, 20.6 (CO). Anal. Calcd

for C₁₈H₂₄N₄O₁₂(488.41): C, 44.27; H, 4.95; N, 11.47.

Found: C, 44.19; H, 4.78; N, 11.55.

1

1220, 1084; H NMR (CDCl₃) d (ppm): 5.53 (1H, dd,

4.11.14. C-(2,3,4,6-Tetra-O-acetyl-1-azido-1-deoxy-a-^D-

galactopyranosyl)formic acid (3,4,5,7-tetra-O-acetyl-2-

azido-2-deoxy-b-^D-galacto-hept-2-ulopyranosonic acid)

51. Trichloroethyl ester 42 (0.05 g, 0.09 mmol) was

suspended in abs. ethyl acetate (5 mL) and Zn dust

(0.023 g, 3.3 equiv, activated by washing with 2 M HCl

(2·), water (2·), acetone (2·) and diethylether (2·), then

air dried on a glass ﬁlter) and 1-methylimidazole (NMI,

0.021 mL, 3 equiv) were added. The reaction mixture

was stirred and reﬂuxed till TLC (ethyl acetate–hexane

1:1) showed complete disappearance of the starting

material. After ﬁltration on a Celite bed EtOAc

(5 mL) was added, and the ﬁltrate washed by satd. aque-

ous NaHCO₃(2·5 mL). The aqueous phase was acidi-

ﬁed with 2 M HCl to pH ꢀ2–3 and extracted with

Et₂O (5 · 5 mL). After drying and removal of the sol-

vent 0.03 g (59%) chromatographically uniform yellow-

ish oil (R_f= 0.70, CHCl₃–MeOH 1:1) was obtained;

[a]_D= +17 (c 0.20, CHCl₃); m_max(CHCl₃): 3200–2800,

2130, 1746, 1372, 1222, 1064, 954, 714; ¹H NMR

(CDCl₃) d (ppm): 5.66 (1H, dd, J = 10.3, 2.9 Hz, H-3),

5.53 (1H, dd, J = 2.9, <1 Hz, H-4), 5.40(1H, d,

J = 10.3 Hz, H-2), 5.19 (1H, s, COOH), 4.62 (1H, ddd,

J = 3.7, <1 Hz, H-4), 5.49 (1H, d, J = 10.3 Hz, H-2),

5.32 (1H, dd, J = 10.3, 3.7 Hz, H-3), 4.51 (1H, ddd,

J = 6.6, 6.6, <1 Hz, H-5), 4.24 (1H, dd, J = 11.8,

6.6 Hz, H-6), 4.19 (1H, dd, J = 11.8, 6.6 Hz, H-6⁰),

2.18, 2.12, 2.07, 1.99 (12H, 4 · s, OAc); ¹³C NMR

3

(CDCl₃) d (ppm): 171.4 (CON₃, J_CON3,H-2= <1 Hz),

170.1, 169.8, 169.7, 168.9, (CO), 95.0 (C-1), 73.2, 69.8,

66.4, 66.2 (C-2 to C-5), 60.3 (C-6), 20.7, 20.5, 20.4

(CH₃). Anal. Calcd for C₁₅H₁₈N₆O₁₀(442.34): C,

40.73; H, 4.10; N, 19.00. Found: C, 40.70; H, 4.16; N,

19.25.

4.11.12. C-(2,3,4,6-Tetra-O-acetyl-1-azido-1-deoxy-b-^D-

galactopyranosyl)formic acid (3,4,5,7-tetra-O-acetyl-2-

azido-2-deoxy-a-^D-galacto-hept-2-ulopyranosonic acid)

49. Compound 48 (0.05 g, 0.11 mmol) and KOH

(0.01 g, 0.18 mmol) were stirred in abs. DMF at rt for

21 h. The mixture was then diluted with water

(10mL), acidiﬁed to pH ꢀ1 with 2 M HCl, and ex-

tracted with Et₂O (5 · 4 mL). After drying and removal

of the solvent the residue was puriﬁed by column chro-

matography (eluent: CHCl₃–MeOH 7:3) to give 18 mg

(38%) white crystals. Mp 155–158 ꢁC; [a]_D= +33

(c 0.24, MeOH); m_max(CHCl₃): 3904, 3420–2900 2130,

J = 6.9, 6.6, <1 Hz, H-5), 4.20(1H, dd,

J = 11.8,

6.6 Hz, H-6), 4.16 (1H, dd, J = 11.8, 6.9 Hz, H-6⁰),

2.20, 2.10, 2.07, 1.99 (12H, 4 · s, OAc); ¹³C NMR

1

1752, 1230, 724; H NMR (MeOD) d (ppm): 5.96 (1H,

3

dd, J = 10.6, 4.0 Hz, H-3), 5.46 (1H, dd, J = 4.0,

<1 Hz, H-4), 5.24 (1H, d, J = 10.6 Hz, H-2), 4.89 (1H,

ddd, J = 6.6, 6.6, <1 Hz, H-5), 4.59 (1H, s, COOH),

4.18 (1H, dd, J = 11.9, 6.6 Hz, H-6), 4.10(1H, dd,

J = 11.9, 6.6 Hz, H-6⁰), 2.16, 2.02, 2.01, 1.92 (12H,

4 · s, OAc); ¹³C NMR (MeOD) d (ppm): 172.1 (COOH,

³J_COOH,H-2= <1 Hz), 172.0(2), 171.7, 171.4 (CO), 93.7

(C-1), 72.8, 71.4, 70.5, 69.1 (C-2 to C-5), 62.9 (C-6),

20.7, 20.6 (2), 20.5 (CH₃). Anal. Calcd for

C₁₅H₁₉N₆O₁₁(417.33): C, 43.17; H, 4.59; N, 10.07.

Found: C, 42.96; H, 4.16; N, 9.80.

(CDCl₃) d (ppm): 170.8 (COOH, J_COOH,H-2= 5.5 Hz),

170.2, 169.3, 167.1 (CO), 90.5 (C-1), 72.0, 69.0, 68.2,

66.9 (C-2 to C-5), 61.3 (C-6), 20.7, 20.6 (CO). Anal.

Calcd for C₁₅H₁₉N₃O₁₁(417.33): C, 43.17; H, 4.59; N,

10.07. Found: C, 43.22; H, 4.57; N, 10.00.

4.11.15. C-(2,3,4,6-Tetra-O-acetyl-1-amino-1-deoxy-^D-

galactopyranosyl)formic acid (3,4,5,7-tetra-O-acetyl-2-

amino-2-deoxy-^D-galacto-hept-2-ulopyranosonic

acid)

52. Trichloroethyl ester 42 (0.18 g, 0.33 mmol) was

suspended in glacial acetic acid (1 mL) and Zn dust

(0.18 g, 10 equiv) was added. The mixture was stirred

at rt until disappearance of the starting material, then

diluted with water and ﬁltered on a Celite bed. The ﬁl-

trate was acidiﬁed with 2 M HCl to pH ꢀ 3 and ex-

tracted with Et₂O (5 · 5 mL). The organic phase was

dried, the solvent removed to give 0.06 g (45%) yellowish

oil; [a]_D= +31 (c 0.21, CHCl₃); R_f= 0.59 (CHCl₃–

MeOH 1:1); m_max(CHCl₃): 3200–2800, 1746, 1372,

4.11.13. N-[(2,3,4,6-Tetra-O-acetyl-1-azido-1-deoxy-b-^D-

galactopyranosyl)carbonyl]glycine methylester (N-(3,4,

5,7-tetra-O-acetyl-2-azido-2-deoxy-a-^D-galacto-hept-2-

ulopyranosonoyl)glycine methylester) 50. Prepared

from 48 (0.09 g, 0.20 mmol) according to Method E.

Puriﬁed by column chromatography (eluent: ethyl ace-

tate–hexane 1:1): Yield: 0.03 g (32%) colourless oil

(R_f= 0.33, ethyl acetate–hexane 3:1); [a]_D= +42 (c

0.38, CHCl₃); m_max(CHCl₃): 3398, 2956, 2135, 1754,

1698, 1372, 1220, 1084; ¹H NMR (CDCl₃) d (ppm):

7.02 (1H, t, J = 5.1, 5.1 Hz, NH), 5.55 (1H, dd,

J = 2.9, 1.5 Hz, H-4), 5.43 (1H, d, J = 9.5 Hz, H-2),

5.33 (1H, dd, J = 9.5, 2.9 Hz, H-3), 4.57 (1H, ddd,

J = 6.6, 6.7, 1.5 Hz, H-5), 4.31 (1H, dd, J = 11.8,

6.6 Hz, H-6), 4.21 (1H, dd, J = 11.8, 5.9 Hz, H-6⁰),

4.13 (1H, dd, J = 18.9, 5.1 Hz, CH₂), 4.03 (1H, dd,

1

1222, 1064, 954, 714; H NMR (CDCl₃): d (ppm): 7.10

(3H, very broad s, COOH, NH₂), 5.67 (1H, d,

J = 10.6 Hz, H-2), 5.51 (1H, dd, J = 1.3, <1 Hz, H-4),

5.38 (1H, dd, J = 10.6, 4.0 Hz, H-3), 4.52 (1H, ddd,

J = 6.6, 6.6, <1 Hz, H-5), 4.21–4.08 (2H, m, H-6, H-6⁰)

2.20, 2.06 (2), 1.99 (12H, 3 · s, OAc); ¹³C NMR

(CDCl₃): d (ppm): 170.9 (COOH), 170.6, 170.3, 170.2,

169.3 (CO), 94.4 (C-1), 68.8, 68.5, 67.9, 67.6 (C-2 to

C-5), 61.4 (C-6), 20.6, 20.5 (CH₃). Anal. Calcd for

´

K. Czifrak et al. / Tetrahedron: Asymmetry 16 (2005) 127–141

141

14. Brandstetter, T. W.; Fuente, C.; Kim, Y.-h.; Cooper, R. I.;

Watkin, D. J.; Oikonomakos, N. G.; Johnson, L. N.;

Fleet, G. W. J. Tetrahedron 1996, 52, 10711–10720.

15. Estevez, J. C.; Saunders, J.; Besra, G. S.; Brennan, P. J.;

Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 1996,

7, 383–386.

C₁₅H₂₁NO₁₁(391.33): C, 46.04; H, 5.41; N, 3.58. Found:

C, 46.22; H, 5.57; N, 3.36.

Acknowledgements

16. Smith, M. D.; Long, D. D.; Martin, A.; Campbell, N.;

´

17. Long, D. D.; Smith, M. D.; Martin, A.; Wheatley, J. R.;

Watkin, D. G.; Muller, M.; Fleet, G. W. J. J. Chem. Soc.,

Perkin Trans. 1 2002, 1982–1998.

18. Bichard, C. J. F.; Mitchell, E. P.; Wormald, M. R.;

Watson, K. A.; Johnson, L. N.; Zographos, S. E.; Koutra,

D. D.; Oikonomakos, N. G.; Fleet, G. W. J. Tetrahedron

Lett. 1995, 36, 2145–2148.

This work was supported by the Hungarian Scientiﬁc

Research Fund (Grants: OTKA T32124 and T43550).

Compounds 31 and 32 were prepared during a stay of

P.S. as an Erasmus exchange student in the laboratory

of Dr. J.-P. Praly (University Claude Bernard Lyon 1,

ESCPE, Lyon, France).

Bleriot, Y.; Fleet, G. W. J. Synlett 1999, 1151–1153.

19. Lakhrissi, M.; Chapleur, Y. Tetrahedron Lett. 1998, 39,

4659–4662.

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Article Doi

Anomeric α-azido acid (2-azido-2-deoxy-hept-2-ulopyranosonic acid) derivatives en route to peptides incorporating sugar amino acids

DOI: 10.1016/j.tetasy.2004.11.064

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Full text of DOI:10.1016/j.tetasy.2004.11.064

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