Synthesis of pentasaccharide fragments related to the O-specific polysaccharide of Shigella flexneri serotype 1a

DOI: 10.1002/ejoc.200600078

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European Journal of Organic Chemistry p. 2618 - 2630 (2006)

Update date:2022-07-30

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Authors:

Lemanski, Gregor

Ziegler, Thomas

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Article abstract of DOI:10.1002/ejoc.200600078

The synthesis of the pentasaccharide 5-aminopentyl glycosides α-L-Rhap-(1→3)-[α-D-Glcp-(1→4)]-β-D-GlcpNAc- (1→2)-α-L-Rhap-(1→2)-α-L-Rhap-1-O-(CH₂) ₅NH₂ (29) and α-L-Rhap-(1→3)-α-L-Rhap- (1→3)-[α-D-Glcp-(1→4)]-β-D-GlcpNAc-(1→2) -α-L-Rhap-1-O-(CH₂)₅NH₂ (28), related to the O-specific polysaccharide of Shigella ilexneri serotype 1a by coupling of the suitably protected trisaccharides α-D-Glcp-(1→4)-β-D- Glcp(1→2)-α-L-Rhap-1-O-(CH₂)₅NH₂ (23) and α-L-Rhap-(1→3)-[α-D-Glcp-(1→4)]-β-D-Glcp-1- SPh (26) with the corresponding rhamnosyl glycosides α-L-Rhap-(1→3)- α-L-Rhap-1-SEt (17) and α-L-Rhap-(1→3)-α-L-Rhap-1-O- (CH₂)₅NH₂ (13), is described. Building blocks 23 and 26 were prepared by intramolecular glycosylation of an unsymmetrically tethered cellobiosamine derivative. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600078

FULL PAPER

DOI: 10.1002/ejoc.200600078

Synthesis of Pentasaccharide Fragments Related to the O-Specific

Polysaccharide of Shigella flexneri Serotype 1a^[‡]

Gregor Lemanski^[a]and Thomas Ziegler*^[a]

Keywords: Carbohydrates / Glycosylation / Oligosaccharides / Spacers

The synthesis of the pentasaccharide 5-aminopentyl

glycosides α- -Rhap-(1Ǟ3)-[α- -Glcp-(1Ǟ4)]-β- -GlcpNAc-

(1Ǟ2)-α- -Rhap-(1Ǟ2)-α- -Rhap-1-O-(CH₂)₅NH₂(29) and

α- -Rhap-(1Ǟ3)-α- -Rhap-(1Ǟ3)-[α- -Glcp-(1Ǟ4)]-β-

GlcpNAc-(1Ǟ2)-α- -Rhap-1-O-(CH₂)₅NH₂(28), related to

the O-specific polysaccharide of Shigella flexneri serotype 1a

by coupling of the suitably protected trisaccharides α-

Glcp-(1Ǟ4)-β- -Glcp(1Ǟ2)-α- -Rhap-1-O-(CH₂)₅NH₂(23)

and α-

with the corresponding rhamnosyl glycosides α-

(1Ǟ3)-α- -Rhap-1-SEt (17) and α- -Rhap-(1Ǟ3)-α- -Rhap-1-

O-(CH₂)₅NH₂(13), is described. Building blocks 23 and 26

were prepared by intramolecular glycosylation of an unsym-

metrically tethered cellobiosamine derivative.

Germany, 2006)

-Rhap-(1Ǟ3)-[α-

-Glcp-(1Ǟ4)]-β-

-Glcp-1-SPh (26)

L-Rhap-

protein conjugates were sufficiently immunogenic in hu-

mans.^[23–25]For immunological studies of such neoglyco-

conjugates toward their application as vaccines it is desir-

able to have variations of the polysaccharide repeating unit

available. Several syntheses of di- to pentasaccharide struc-

tures, as well as an octa- and a decasaccharide fragment

related to the O-SP of Shigella flexneri serotypes 2a,^[26–32]

5a,^[33–39]and others^[40–43]were published already. We were

especially interesting in the O-SP of Shigella flexneri 1a

(Figure 1),^[13,44–46]the O-specific polysaccharide of which is

characterized by a branched pentasaccharide repeating unit

containing α-linked -rhamnose, β-linked N-acetyl--glu-

cosamine and α--glucose.

Introduction

Recently, the World Health Organization estimated that

more than one million deaths per year occur due to infec-

tions with Shigella spp. The victims are mostly young chil-

dren of the developing world but often also humans in in-

dustrialized countries.^[1–9]Shigella flexneri,^[10–13]a gram-

negative enteropathogenic bacterium, is responsible for the

endemic form of shigellosis, a highly infectious dysenteric

syndrome in humans that causes diarrheal fever, violent

cramps, and discharge of mucous membranes and bloody

stools.^[14–19]Shigellosis is characterized by a high morbidity

and mortality. It is transmitted by person-to-person contact

or indirectly through contaminated food or water. Cur-

rently, however, there are no licensed vaccines against this

pathogen available yet. Existing antimicrobial treatments

are becoming increasingly ineffective due to the growing an-

tibiotic resistance^[5,20]among Shigella spp. Therefore, the

development of novel treatments and the accelerated search

for vaccines for prevention of shigellosis is strongly advized

in order to provide protection against the most common

serotypes of Shigella spp.^[21,22]In case of non-encapsulated

gram-negative bacteria, such as Shigella, the O-specific

polysaccharides (O-SP) of their lipopolysaccharides are es-

sential virulent factors and serve as a protective antigen for

the host’s immunity. Thus, serum antibodies to the O-SP

may well provide protection against infections through vac-

cination although the O-specific polysaccharide moieties

are often not immunogenic enough. However, it has been

demonstrated for several enterobacteria that corresponding

Figure 1. Repeating unit of the O-specific polysaccharide of Shig-

ella flexneri serotype 1a antigen.

Here, we describe the syntheses of the pentasaccharide

sequences A(E)BCD and DA(E)BC – as their 5-aminopen-

tyl glycosides – of Shigella flexneri 1a O-specific polysac-

charide using our recently developed method of intramolec-

ular glycosylation through prearranged glycosides.^[47–55]

[‡] Prearranged Glycosides, XV. Part XIV: Ref.^[53]

[a] Institute of Organic Chemistry, University of Tübingen,

Auf der Morgenstelle 18, 72076 Tübingen, Germany

Fax: +49-7071-29-73035

E-mail: thomas.ziegler@uni-tuebingen.de

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Synthesis of Pentasaccharide Fragments

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In particular, we apply the intramolecular glycosylation 2-O-benzoyl-3,4-di-O-benzyl-1-thio-α--rhamnopyrano-

strategy by unsymmetrically tethered glycosides^[53,56](i.e. side^[68](9). First, coupling of the latter with 5-[(benzyloxy-

carboxybenzyl moieties) to a highly flexible synthesis of carbonyl)amino]pentanol by means of N-iodosuccinimide

Shigella flexneri 1a O-specific pentasaccharide aminopentyl (NIS) in the presence of a catalytic amount of trifluorome-

glycosides.

thanesulfonic acid (TfOH) in dichloromethane afforded the

rhamnoside 10 in 80% yield, which was then debenzoylated

with sodium methoxide in methanol to provide the rham-

nosyl acceptor 11 in a virtually quantitative yield. Next, the

rhamnosides 9 and 11 were coupled with NIS/TfOH to af-

Results and Discussion

For the synthesis of the pentasaccharide fragments re- ford the disaccharide 12 in 70% yield. Finally, Zemplén de-

lated to the O-SP of Shigella flexneri 1a a convergent block- acylation^[69]gave the desired α--Rhap-(1Ǟ2)--Rhap di-

wise approach was chosen. For both sequences A(E)BCD saccharide 13 in 95% yield (Scheme 1).

and DA(E)BC three disaccharide building blocks were

For the preparation of the α--Rhap-(1Ǟ3)--Rhap di-

needed: an α--Glcp-(1Ǟ4)--GlcpNAc disaccharide for saccharide donor related to fragment DA, the rhamnoside

fragment EB suitable for being used as donor and acceptor, 9 was first converted with NBS/water into monosaccharide

an α--Rhap-(1Ǟ2)--Rhap disaccharide acceptor for frag- 14 in 91% yield, obtained as an anomeric mixture. Next,

ment CD and an α--Rhap-(1Ǟ3)--Rhap disaccharide do- the rhamnose derivative 14 was converted into the corre-

nor for fragment DA. The required building block EB con- sponding trichloroacetimidate 15 (79%) by treatment with

tains an α--glucosyl residue which was planned to be es- Cl₃CCN and DBU. Trimethylsilyl trifluoromethanesulfon-

tablished by intramolecular glycosylation of an appropri- ate (TMSOTf) catalyzed glycosylation of ethyl 2-O-benzoyl-

ately prearranged glycoside. For that purpose, the ethyl 1- 4-O-benzyl-1-thio-α--rhamnopyranoside^[70](16) with the

thio-glucoside 1^[57]was alkylated with tert-butyl 2-(bro- imidate 15 afforded the disaccharide 17 in 76% yield.

momethyl)benzoate^[53](2) by means of NaH in DMF to

In order to construct the DA(E)BC pentasaccharide re-

afford the crystalline glucoside 3a (89%), and the tert-butyl peating unit of Shigella flexneri serotype 1a, the disaccha-

ester was hydrolyzed by treatment of the glucoside 3a with ride donor 8a was first coupled to the 2-position of the

trifluoroacetic acid (TFA) in dichloromethane to give the rhamnoside 11 using NIS and a catalytic amount of

glucoside 3b in 90% yield. The o-methylbenzoyl tether was TMSOTf as promoter. Thus, the trisaccharide 19 was ob-

chosen for linking the glucoside 3b with the known glucosa- tained in 57% yield. The NMR spectra showed a hetero-

mine 5a^[58]because similarly tethered prearranged glyco- nuclear J_C-1,1-Hcoupling constant of 163.8 Hz for the an-

sides have previously been shown to produce high α-stereo- omeric center at the glucosamine moiety which proved the

selectivities during intramolecular glycosylations.^[53]The β-linkage. Originally, it was planned to open the o-benzyl-

amino group in the glucosamine acceptor was protected as benzoate tether in the disaccharides 8a and 19 by transes-

phthalimide in order to avoid low yields and the formation terification with methanol in order to deprotect the 3-posi-

of stable oxazolines during the following glycosylation tion of the glucosamine moieties for further elongation of

steps. N-Phthalimido groups can be easily converted into the saccharide chains with the rhamnosyl donor 9 and 17,

the N-acetyl groups later on.^[59–62]Furthermore, the combi- respectively. However, treatment of the disaccharide 8a un-

nation of a phenylthio group in the glucosamine moiety and der Zemplén conditions (NaOMe in methanol) resulted in

an ethylthio group in the glucose moiety allows for a selec- extensive decomposition and afforded the acceptor 18 in

tive activation of the ethylthio group without affecting the poor 45% yield. The selective ring opening of the o-benzyl-

phenylthio group. Thus, the hydroxy group at the 3-position benzoate tether in 19 proved to be even more difficult. Un-

of glucosamine 5a was first condensed with the glucoside der Zemlpén conditions or by treatment with hydrazine hy-

3b in the presence of DCC/DMAP to yield the prearranged drate^[59]complete decomposition occurred. Saponification

bis(glycoside) 6a in 73% yield. Next, the benzylidene acetal of the ester group in 19 with sodium borohydride^[61]or hy-

of the glucosamine moiety was reductively opened with drolysis under acidic conditions failed completely. Treat-

[63,64]

NaCNBH₃

to afford the bis(glycoside) 7a in 63% ment with MeNH₂only opened the phthalimide ring and

yield. Intramolecular glycosylation of the latter with iodon- gave the trisaccharide 21 in 54% yield. Ethylenediamine^[60]

ium dicollidine perchlorate^[65–67](IDCP) as promoter in removed the phthalimide group completely but did not

dichloromethane proceeded smoothly and gave the desired cleave the ester group at all. Solely the trisaccharide 20

α--Glcp-(1Ǟ4)--GlcpNPhth-linked disaccharide 8a ster- could be isolated in poor 45% yield after reacetylation with

eoselectively in 69% yield. The anomeric configuration of acetic anhydride (Scheme 2).

the newly formed O-glycosidic linkage was unambiguously

In order to circumvent these persisting problems, other

assigned by measuring a vicinal J_1,2coupling constant of amino protecting groups were needed. However, commonly

3.4 Hz at the anomeric center of the glucose moiety which used N-protecting groups like N-dichlorophthaloyl,^[71]N-

is typical for the α--glucosidic linkages. In addition, the tetrachlorophthaloyl,^[72–74]N-chloroacetyl,^[75]N-trichlo-

related J_C-1,1-Hheteronuclear coupling constant of roacetyl,^[76,77]N-trichloroethoxycarbonyl,^[78,79]or N,N-di-

169.8 Hz also proved the α-linkage.^[92–94]

acetyl^[80]were not applicable here due to their high sensibility

The α--Rhap-(1Ǟ2)--Rhap disaccharide acceptor under conditions required for saponification of the tether.

related to fragment CD was synthesized from known ethyl The use of 2-azido-2-deoxy glucose derivatives as starting

Eur. J. Org. Chem. 2006, 2618–2630

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G. Lemanski, T. Ziegler

FULL PAPER

Scheme 1.

Scheme 2.

materials appeared impractical as well, because this avenue group appeared to be suitable here because trifluoroacet-

would require employment of triflyl azide which is, how- amides are stable during deprotection of other acyl

ever, inconvenient on a large scale.^[81]The N-acetyl-N-ben- groups,^[89–91]but are still easily removed and ensure high β-

zyl group is also not recommendable for protecting amino selectivities and good yields during glycosylation reac-

groups in glucosamine-containing oligosaccharides, because tions.^[86]Thus, the N-trifluoroacetyl-protected glucosamine

rotamers at the amide bond complicate assignment of 4^[86]was first converted into the glucoside 5b in 85% yield

NMR signals considerably.^[82–85]Solely the trifluoroacetyl by sequential deprotection with NaOMe in methanol, fol-

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Eur. J. Org. Chem. 2006, 2618–2630

Synthesis of Pentasaccharide Fragments

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lowed by reaction with benzaldehyde dimethylacetal and a THF.^[87]This way, the prearranged bis(glycoside) 6b was

catalytic amount of p-toluenesulfonic acid. Esterification of obtained in 70% overall yield. Next, the benzylidene acetal

the glucosamine 5b with the glucoside 3b and DDC turned group of the glucosamine moiety was regioselective opened

out to be sluggish though. Better results were obtained by with NaCNBH₃to give the prearranged bis(glucoside) 7b

first converting 3b into the mixed anhydride with trichloro- in 63% yield. Intramolecular glycosylation of the latter by

benzoyl chloride and Et₃N in CH₂Cl₂, followed by DMAP- promotion with IDCP in CH₂Cl₂afforded the disaccharide

catalyzed alcoholysis of the latter with the glucoside 5b in 8b in 72% yield. Once again the heteronuclear J_C-1,1-H

Scheme 3.

Scheme 4.

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G. Lemanski, T. Ziegler

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the one resonating at lower field was designated as H_aand the

one resonating at higher field was designated as H_b. Carbon signal

assignments were made by C,H correlation. Optical rotations were

measured at 20 °C with a Perkin–Elmer polarimeter, model 341.

Melting points were determined with a Büchi apparatus, model

510. FAB mass spectra were recorded with a TSQ 70 Finnigan

spectrometer. Elemental analyses were performed with a HEKA-

tech CHNS-Euro 3000 instrument.

coupling constant of 169.9 Hz in the NMR spectra of the

glucose moiety of 8b showed unambiguously an α-linkage

at the anomeric center.

Coupling of unsymmetrically tethered disaccharide block

8b with the rhamnoside 11 by activation of the donor with

NIS/TMSOTf afforded the β-linked trisaccharide 22 in 65%

yield with J_C-1,1-H= 161.0 Hz for the anomeric center of

the glucosylamino moiety. Treatment of the latter with mag-

nesium methoxide^[90,91]proceeded smoothly and gave the

desired trisccharide 23 in 77% yield. Finally, rhamnosyl-

ation to the 3-position of 23 with 1-thiorhamnoside 17 and

NIS/TfOH in dichloromethane afforded the pentasaccha-

ride 24 in 62% yield. Similarly, the tethered disaccharide

block 8b was transferred into the acceptor building block

25 by transesterification with magnesium methoxide in 76%

Ethyl

thio-α-

3,4,6-Tri-O-benzyl-2-O-(2-tert-butyloxycarbonylbenzyl)-1-

D-glucopyranoside (3a): NaH (0.21 g, 8.90 mmol) and tert-

butyl 2-(bromomethyl)benzoate (2)^[53](1.81 g, 6.68 mmol) were

added with stirring at 0 °C to a solution of 1^[57](2.20 g, 4.45 mmol)

in DMF (75 mL), and the mixture was stirred at room temp. for

40 min. MeOH was added in order to destroy excess NaH and the

mixture was poured onto ice. After extraction with CH₂Cl₂, the

organic phases were washed with brine and water. After concentra-

yield followed by glycosylation with rhamnosyl imidate 15 tion and chromatography (petroleum ether/acetone, 10:1) of the

residue, crystallization afforded 3a (2.71 g, 89%), m.p. 80–81 °C

(EtOH). [α]²_D⁰= –13.1 (c = 0.9, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 5.33 (d, J = –14.4 Hz, 1 H, PhCH₂), 5.21 (d, J =

–14.3 Hz, 1 H, PhCH₂), 4.82 (d, J = –12.2 Hz, 1 H, PhCH₂), 4.77

(d, J = –10.8 Hz, 1 H, PhCH₂), 4.61 (d, J = –12.1 Hz, 1 H, PhCH₂),

4.59 (s, 1 H, PhCH₂), 4.56 (s, J = –10.9 Hz, 1 H, PhCH₂), 4.54 (d,

J = –12.2 Hz, 1 H, PhCH₂), 4.49 (d, J_1,2= 9.6 Hz, 1 H, 1-H), 3.76

(dd, J_6a,6b= –10.9 Hz, 1 H, 6a-H), 3.72 (t, J_3,4= 8.8 Hz, 1 H, 3-

H), 3.68 (dd, 1 H, 6b-H), 3.61 (t, J_4,5= 9.2 Hz, 1 H, 4-H), 3.53

under TMSOTf catalysis to give the α-linked trisaccharide

donor 26 in 71% yield. Subsequent condensation of the lat-

ter with rhamnosyl acceptor 13 under NIS/TMSOTf acti-

vation furnished the pentasaccharide 27 in 55% yield; the

newly formed β-linkage of the glucosylamino group was

once again proven by measuring a J_C-1,1-Hcoupling con-

stant of 160.8 Hz at the anomeric center (Scheme 3).

Sequential deblocking of pentasaccharides 24 and 27 was

achieved by first converting the N-trifluoroacetyl group into

(dd, J_2,3= 8.6 Hz, 1 H, 2-H), 3.52–3.48 (m, J_5,6a= 1.9 Hz, J_5,6b

an N-acetyl group by saponification with aqueous NaOH 4.6 Hz, 1 H, 5-H), 2.79–2.69 (m, 2 H, SCH₂CH₃), 1.56 [s, 9 H,

(CH₃)₃C], 1.29 (t, J = 7.5 Hz, 3 H, SCH₂CH₃). ¹³C NMR

(100.6 MHz, CDCl₃): δ = 166.2 (CO), 86.6 (C-3), 85.0 (C-1), 82.0

(C-2), 81.3 [C(CH₃)₃], 79.2 (C-5), 78.0 (C-4), 75.7 (PhCH₂), 75.0

(PhCH₂), 73.4 (PhCH₂), 72.8 (PhCH₂), 69.2 (C-6), 28.2 [C(CH₃)₃],

in methanol, followed by N-acetylation with Ac₂O of the

intermediate amine. Benzoyl groups were also removed dur-

ing this step and final hydrogenolysis of the intermediates

furnished the deblocked 5-aminopentyl glycoside pentasac-

24.9 (SCH₂CH₃), 15.1 (SCH₂CH₃). C₄₁H₄₈O₇S (684.89): calcd. C

charides 28 and 29 in 81% and 79% yield, respectively

71.90, H 7.06; found C 71.94, H 7.08.

(Scheme 4).

Ethyl 3,4,6-Tri-O-benzyl-2-O-(2-carboxybenzyl)-1-thio-α-D-gluco-

pyranoside (3b): A solution of 3a (3.64 g, 5.32 mmol) and TFA

(5.4 mL, 53.20 mmol) in CH₂Cl₂(60 mL) was stirred at room temp.

After 2 h, the mixture was diluted twice with toluene and the sol-

vents were evaporated. Crystallization of the crude product af-

forded 3b (3.02 g, 90%), m.p. 123–124 °C (petroleum ether/ace-

tone). [α]²_D⁰= –15.7 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃):

δ = 5.31 (s, 2 H, PhCH₂), 4.83 (d, J = –11.5 Hz, 1 H, PhCH₂), 4.82

(d, J = –10.6 Hz, PhCH₂), 4.61 (d, J = –12.1 Hz, 1 H, PhCH₂),

4.57 (d, J = –12.1 Hz, 1 H, PhCH₂), 4.55 (d, J = –12.1 Hz, 1 H,

PhCH₂), 4.50 (s, 1 H, PhCH₂), 4.47 (d, J_1,2= 9.6 Hz, 1 H, 1-H),

3.78–3.70 (m, 2 H, 6a-H, 6b-H), 3.71 (t, J_3,4= 8.8 Hz, 1 H, 3-H),

3.64 (t, J_4,5= 9.2 Hz, 1 H, 4-H), 3.52–3.48 (m, J_5,6a= 1.7 Hz, 1 H,

5-H), 3.57 (t, J_2,3= 9.7 Hz, 1 H, 2-H), 2.80 –2.66 (m, 2 H,

SCH₂CH₃), 1.28 (t, J = 7.5 Hz, 3 H, SCH₂CH₃). ¹³C NMR

(100.6 MHz, CDCl₃): δ = 171.7 (COOH), 86.7 (C-3), 84.8 (C-1),

81.6 (C-2), 79.2 (C-5), 78.0 (C-4), 75.7 (PhCH₂), 75.0 (PhCH₂),

73.4 (PhCH₂), 72.7 (PhCH₂), 69.2 (C-6), 24.7 (SCH₂CH₃), 15.1

(SCH₂CH₃). C₃₇H₄₀O₇S (628.78): calcd. C 70.68, H 6.41, S 5.10;

found C 70.67, H 6.43, S 4.81.

Conclusion

In conclusion, we have successfully demonstrated the ef-

ficient construction of the α-glucosyl-containing blocks 8a,

8b by using our intramolecular glycosylation method via

unsymmetrical tethers. Furthermore, the usefulness of this

approach as a new flexible strategy for the synthesis of com-

plex oligosaccharides is impressively demonstrated.

Experimental Section

General: Thin-layer chromatography (TLC) was performed on pre-

coated plastics sheets, Polygram SIL G/UV₂₅₄, 40× 80 mm (Mach-

erey–Nagel). Spots were detected by UV light and by charring with

5% sulfuric acid in ethanol. Column chromatography (CC) was

performed by elution from columns of silica gel (Macherey–Nagel,

0.032–0.063 mm). Solutions in organic solvents were dried with an-

hydrous sodium sulfate, and concentrated at 40 °C, Ͻ200 Pa. NMR

spectra were recorded with Bruker Advance 400 Ultra Shield

(400 MHz) and Bruker AMX 400 (400 MHz) instruments and cal-

ibrated with TMS as internal standard. Proton signal assignments

were made by first-order analysis of the spectra by H,H COSY

techniques. Of two magnetically nonequivalent geminal protons,

Phenyl 4,6-O-Benzylidene-2-deoxy-1-thio-2-trifluoroacetamido-β-D-

glucopyranoside (5b): A solution of 4^[86](24.72 g, 50.10 mmol) and

NaOMe in methanol (500 mL) was stirred at room temp. for 2 h,

neutralized (ion exchange resin, H⁺form), filtered and concen-

trated. Benzaldehyde dimethylacetal (18 mL, 120.24 mmol) and p-

toluenesulfonic acid (0.95 g, 5.00 mmol) were added to the crude

compound in acetonitrile (500 mL), and the forming solution was

stirred at room temp. for 18 h. The mixture was neutralized with

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Synthesis of Pentasaccharide Fragments

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Et₃N and poured into water. The precipitate was collected by fil-

tration and recrystallization from acetone/ethanol afforded 5b

(19.45 g, 85%), m.p. 264 °C (dec.). [α]²_D⁰= –17.6 (c = 1.0, acetone).

¹H NMR (400 MHz, [D₆]acetone): δ = 8.77 (d, J = 7.8 Hz, 1 H,

NH), 5.65 (s, 1 H, PhCH₂), 5.14 (d, J_1,2= 10.1 Hz, 1 H, 1-H), 5.09

(d, J = 4.5 Hz, 1 H, OH), 4.29 (dd, J_5,6a= 5.0 Hz, J_6a,6b= –10.2 Hz,

4.38 (d, J_1,2= 9.9 Hz, 1 H, 1_E-H), 4.28–4.20 (m, J_2,3= 9.9 Hz, 1

H, 2_B-H), 4.08 (dd, J_5,6a= 4.5 Hz, J_6a,6b= –10.2 Hz, 1 H, 6a_B-H),

3.75–3.64 (m, J_5,6a= 3.4 Hz, 5 H, 3_E-H, 4_B-H, 6b_B-H, 6a_E-H, 6b_E-

H), 3.56–3.49 (m, J_4,5= 9.7 Hz, 2 H, 4_E-H, 5_B-H), 3.46–3.43 (m, 1

H, 5_E-H), 3.34 (t, J_2,3= 9.4 Hz, 1 H, 2_E-H), 2.61–2.46 (m, 2 H,

SCH₂CH₃), 1.16 (t, J = 7.3 Hz, 3 H, SCH₂CH₃). ¹³C NMR

1 H, 6a-H), 4.07–4.00 (m, J_3,4= 9.2 Hz, 2 H, 2-H, 3-H), 3.81 (t, (100.6 MHz, CDCl₃): δ = 167.8 (PhCO), 157.1 (NHCOCF₃, J_C,F

J_5,6b= 10.1 Hz, 1 H, 6b-H), 3.64 (t, J_4,5= 9.1 Hz, 1 H, 4-H), 3.56

(ddd, 1 H, 5-H). ¹³C NMR (100.6 MHz, [D₆]acetone): δ = 157.8

(NHCOCF₃, J_C,F= 36.2 Hz), 117.2 (NHCOCF₃, J_C,F= 287.6 Hz),

= 37.7 Hz), 115.6 (NHCOCF₃, J_C,F= 288.3 Hz), 101.0 (PhCH),

87.3 (C-1_B), 86.6 (C-3_E), 84.9 (C-1_E), 81.9 (C-2_E), 79.0 (C-5_E), 77.9

(2 C, C-4_E, C-5_B), 75.7 (PhCH₂), 75.0 (PhCH₂), 73.4 (PhCH₂), 73.3

102.2 (PhCH), 87.5 (C-1), 82.1 (C-4), 72.9 (C-3), 71.4 (C-5), 68.9 (C-3_B), 72.3 (PhCH₂), 70.8 (C-4_B), 69.1 (C-6_E), 68.1 (C-6_B), 53.8

(C-6), 56.7 (C-2). C₂₁H₂₀NO₅SF₃(455.45): calcd. C 55.38, H 4.43,

N 3.08, S 7.04; found C 55.37, H 4.59, N 2.99, S 6.91.

(C-2_B), 24.7 (SCH₂CH₃), 15.1 (SCH₂CH₃). C₅₈H₅₈F₃NO₁₁S₂

(1066.22): calcd. C 65.34, H 5.48, N 1.31, S 6.01; found C 65.51,

H 5.47, N 1.35, S 5.80.

Ethyl 3,4,6-Tri-O-benzyl-2-O-[(4,6-O-benzylidene-2-deoxy-1-phen-

ylthio-2-phthalimido-β-

1-thio-β-

catalytic amount of DMAP were added at room temp. to a solution

-glucopyranos-3-yloxy)-2-carbonylbenzyl]-

Ethyl 3,4,6-Tri-O-benzyl-2-O-[(6-O-benzyl-2-deoxy-1-phenylthio-2-

-glucopyranoside (6a): DCC (0.46 g, 2.23 mmol) and a phthalimido-β-D-glucopyranos-3-yloxy)-2-carbonylbenzyl]-1-thio-β-

D-glucopyranoside (7a): A solution of HCl in THF was added por-

of 3b (1.17 g, 1.86 mmol) and 5a^[58](0.91 g, 1.86 mmol) in CH₂Cl₂tionwise at room temp. to a suspension of 6a (2.68 g, 2.44 mmol),

(60 mL). After stirring for 24 h, the mixture was diluted with NaCNBH₃(1.38 g, 21.96 mmol) and molecular sieves (3 Å) in THF

CH₂Cl₂and filtered through a layer of Celite^. The filtrate was

subsequently washed with aqueous HCl and saturated aqueous

NaHCO₃solution, dried and concentrated. Chromatography (tolu-

ene/acetone, 55:1) of the residue afforded 6a (1.48 g, 73%) as color-

less foam. [α]²_D⁰= +27.6 (c = 1.1, CHCl₃). ¹H NMR (400 MHz,

(90 mL) until the evolution of gas had ceased. The mixture was

then diluted with CH₂Cl₂and filtered through a layer of Celite^.

The filtrate was washed with saturated aqueous NaHCO₃solution,

dried and concentrated. Chromatography (toluene/acetone, 25:1)

afforded 7a (1.70 g, 63%) as a colorless foam. [α]²_D⁰= +20.7 (c =

CDCl₃): δ = 6.12 (t, J_3,4= 9.5 Hz, 1 H, 3_B-H), 5.90 (d, J_1,2

1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.87 (dd, J_3,4

10.6 Hz, 1 H, 1_B-H), 5.52 (s, 1 H, PhCH₂), 5.03 (d, J = –14.8 Hz,

1 H, PhCH₂), 4.80 (d, J = –10.9 Hz, 1 H, PhCH₂), 4.77 (d, J = –

9.0 Hz, 1 H, 3_B-H), 5.79 (d, J_1,2= 10.5 Hz, 1 H, 1_B-H), 5.11 (d, J

= –13.7 Hz, 1 H, PhCH₂), 5.02 (d, J = –13.7 Hz, 1 H, PhCH₂),

14.8 Hz, 1 H, PhCH₂), 4.63 (s, 1 H, PhCH₂), 4.61 (d, J = –12.0 Hz, 4.74 (d, J = –11.0 Hz, 1 H, PhCH₂), 4.68–4.54 (m, 4 H, PhCH₂),

1 H, PhCH₂), 4.57 (s, 1 H, PhCH₂), 4.55 (d, J = –12.1 Hz, 1 H, 4.58 (d, J = –10.7 Hz, 1 H, PhCH₂), 4.51 (d, J = –11.0 Hz, 1 H,

PhCH₂), 4.54 (d, J = –12.5 Hz, 1 H, PhCH₂), 4.51 (dd, J_2,3

PhCH₂), 4.49 (d, J = –10.5 Hz, 1 H, PhCH₂), 4.41 (t, J_2,3=

9.9 Hz, 1 H, 2_B-H), 4.44 (m, 1 H, 6a_B-H), 4.30 (d, J_1,2= 9.7 Hz, 1 10.4 Hz, 1 H, 2_B-H), 4.34 (d, J_1,2= 9.5 Hz, 1 H, 1_E-H), 3.88–3.76

H, 1_E-H), 3.86–3.78 (m, 3 H, 4_B-H, 5_B-H, 6b_B-H), 3.74 (dd, J_5,6b

= 4.6 Hz, 1 H, 6a_E-H), 3.67 (dd, J_6a,6b= –10.9 Hz, 1 H, 6b_E-H),

3.56 (t, J_3,4= 8.7 Hz, 1 H, 3_E-H), 3.49 (t, J_4,5= 9.0 Hz, 1 H, 4_E-

(m, 3 H, 5_B-H, 6a_B-H, 6b_B-H), 3.65–3.58 (m, J_6a,6b= –10.9 Hz, 2

H, 4_B-H, 6b_E-H), 3.54–3.48 (m, 2 H, 3_E-H, 4_E-H), 3.44–3.40 (m,

J_5,6a= 1.8 Hz, 2 H, 2_E-H, 5_E-H), 2.73–2.59 (m, 2 H, SCH₂CH₃),

H), 3.43–3.39 (m, J_5,6a= 1.9 Hz, 1 H, 5_E-H), 3.17 (dd, J_2,3= 8.4 Hz, 1.24 (t, J = 7.4 Hz, 3 H, SCH₂CH₃). ¹³C NMR (100.6 MHz,

1 H, 2_E-H), 2.65–2.49 (m, 2 H, SCH₂CH₃), 1.18 (t, J = 7.4 Hz, 3

CDCl₃): δ = 167.8 (NCO), 167.3 (NCO), 167.0 (CO), 86.3 (C-3_E),

H, SCH₂CH₃). ¹³C NMR (100.6 MHz, CDCl₃): δ = 167.9 (NCO), 84.8 (C-1_E), 83.1 (C-1_B), 82.3 (C-2_E), 79.1, 79.0 (1 C, 1 C, C-5_B, C-

167.1 (NCO), 165.8 (CO), 101.4 (PhCH), 86.4 (C-3_E), 84.8 (C-1_E), 5_E), 77.7 (C-4_E), 75.8 (PhCH₂), 75.2 (C-3_B), 74.8 (PhCH₂), 73.5

84.1 (C-1_B), 81.7 (C-2_E), 79.1, 79.0 (1 C, 1 C, C-5_B, C-5_E), 77.8 (C-

(PhCH₂), 73.4 (PhCH₂), 73.0 (PhCH₂), 70.0 (C-4_B), 69.7 (C-6_B),

4_E), 75.5 (PhCH₂), 74.9 (PhCH₂), 73.4 (PhCH₂), 72.1 (PhCH₂), 69.0 (C-6_E), 53.5 (C-2_B), 24.6 (SCH₂CH₃), 15.0 (SCH₂CH₃).

71.0 (C-3_B), 70.6 (C-4_B), 69.1 (C-6_E), 68.5 (C-6_B), 54.3 (C-2_B), 24.7 C₆₄H₆₃NO₁₂S₂(1102.33): calcd. C 69.74, H 5.76, N 1.27; found C

(SCH₂CH₃), 15.1 (SCH₂CH₃). C₆₄H₆₁NO₁₂S₂(1100.31): calcd. C 69.93, H 5.84, N 1.33.

69.86, H 5.59, N 1.27, S 5.83; found C 69.79, H 5.66, N 1.33, S

Ethyl 3,4,6-Tri-O-benzyl-2-O-[(6-O-benzyl-2-deoxy-1-phenylthio-2-

5.96.

trifluoroacetamido-β-

thio-β- -glucopyranoside (7b): A solution of HCl in Et₂O was

added portionwise at room temp. to a suspension of 6b (2.15 g,

-glucopyranoside (6b): A solution of 3b (2.31 g, 2.02 mmol), NaCNBH₃(1.14 g, 18.18 mmol) and molecular sieves

D-glucopyranos-3-yloxy)-2-carbonylbenzyl]-1-

Ethyl 3,4,6-Tri-O-benzyl-2-O-[(4,6-O-benzylidene-2-deoxy-1-phen-

ylthio-2-trifluoroacetamido-β- -glucopyranos-3-yloxy)-2-carbonyl-

benzyl]-1-thio-β-

3.67 mmol) and triethylamine (0.51 mL, 3.67 mmol) in CH₂Cl₂

(15 mL) was added dropwise at 0 °C to a solution of 2,4,6-trichlo-

robenzoyl chloride (1.07 g, 4.40 mmol) in CH₂Cl₂(15 mL). The

mixture was stirred at room temp. for 16 h, then diluted with

CH₂Cl₂, washed with water, dried and concentrated. To the crude

anhydride in THF (20 mL) was added dropwise a solution of 5b

(3 Å) in THF (40 mL) until the evolution of gas had ceased. The

mixture was diluted with CH₂Cl₂and filtered through a layer of

Celite^. The filtrate was washed with an aqueous NaHCO₃solu-

tion, dried and concentrated. Chromatography (toluene/ethyl ace-

tate, 10:1) gave 7b (1.36 g, 63%) as a colorless foam. [α]²_D⁰= –22.2

(c = 1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.85 (d, J =

(1.66 g, 3.67 mmol) and DMAP (0.45 g, 3.67 mmol) in THF 9.6 Hz, 1 H, NHCO), 5.27 (d, J = –12.6 Hz, 1 H, PhCH₂), 5.25 (t,

(20 mL). After stirring at room temp. for 1 h, the mixture was di-

luted with CH₂Cl₂, washed with water, dried and concentrated.

Chromatography (toluene/ethyl acetate, 15:1) of the residue af-

J_3,4= 9.7 Hz, 1 H, 3_B-H), 5.11 (d, J = –13.3 Hz, 1 H, PhCH₂), 4.80

(d, J_1,2= 10.4 Hz, 1 H, 1_B-H), 4.73 (d, J = –11.1 Hz, 1 H, PhCH₂),

4.63 (d, J = –11.6 Hz, 1 H, PhCH₂), 4.58–4.49 (m, 8 H, PhCH₂),

4.39 (d, J_1,2= 9.6 Hz, 1 H, 1_E-H), 3.83 (dd, J_5,6a= 2.5 Hz, J_6a,6b

= –10.6 Hz, 1 H, 6a_B-H), 3.74 (dd, J_5,6b= 5.3 Hz, 1 H, 6b_B-H),

3.71–3.63 (m, 3 H, 5_B-H, 6a_E-H, 6b_E-H), 3.61–3.51 (m, 3 H, 3_E-H,

forded 6b (2.74 g, 70%). [α]²_D⁰= –27.6 (c = 1.1, CHCl₃). H NMR

(400 MHz, CDCl₃): δ = 5.56 (t, J_3,4= 9.7 Hz, 1 H, 3_B-H), 5.49 (s,

1 H, PhCH₂), 5.20 (d, J = –14.4 Hz, 1 H, PhCH₂), 5.12 (d, J =

–14.4 Hz, 1 H, PhCH₂), 4.85 (d, J_1,2= 10.6 Hz, 1 H, 1_B-H), 4.82 4_B-H, 4_E-H), 3.49–3.42 (m, 2 H, 2_E-H, 5_E-H), 2.73–2.61 (m, 2 H,

(d, J = –11.1 Hz, 1 H, PhCH₂), 4.78 (d, J = –11.1 Hz, 1 H, PhCH₂), SCH₂CH₃), 1.25 (t, J = 7.5 Hz, 3 H, SCH₂CH₃). ¹³C NMR

4.74 (d, J = –10.9 Hz, 1 H, PhCH₂), 4.73–4.52 (m, 3 H, PhCH₂),

(100.6 MHz, CDCl₃): δ = 169.3 (PhCO), 158.4 (NHCOCF₃, J_C,F

2623

Eur. J. Org. Chem. 2006, 2618–2630

www.eurjoc.org

G. Lemanski, T. Ziegler

FULL PAPER

= 38.1 Hz), 116.8 (NHCOCF₃, J_C,F= 287.6 Hz), 86.6 (C-3_E), 86.5 [(Benzyloxycarbonyl)amino]pentanol (0.54 g, 2.27 mmol) and mo-

(C-1_B), 85.2 (C-1_E), 82.9 (C-2_E), 79.6 (C-5_B), 79.5 (C-5_E), 78.3 (C- lecular sieves (4 Å) in CH₂Cl₂(50 mL) was cooled under argon to

4_E), 77.7 (C-3_B), 76.2 (PhCH₂), 75.3 (PhCH₂), 74.0 (PhCH₂), 73.9

(PhCH₂), 73.8 (PhCH₂), 72.3 (PhCH₂), 70.0 (C-6_B), 69.4 (2 C, C-

4_B, C-6_E), 53.4 (C-2_B), 25.2 (SCH₂CH₃), 15.4 (SCH₂CH₃).

–10 °C and stirred for 10 min. NIS (0.51 g, 2.27 mmol) and TfOH

(20 µL, 0.23 mmol) were successively added, the mixture was stirred

for 10 min, neutralized by addition of triethylamine, diluted with

C₅₈H₆₀F₃NO₁₁S₂(1068.23): calcd. C 65.21, H 5.66, N 1.31, S 6.00; CH₂Cl₂and filtered through a layer of Celite^®. The filtrate was

found C 65.43, H 5.68, N 1.41, S 5.83.

washed with aqueous Na₂S₂O₃solution, water, dried and concen-

trated. Chromatography (petroleum ether/ethyl acetate, 4:1) of the

residue afforded 10 (1.21 g, 80%) as an oil. –[α]²_D⁰= +11.7 (c = 1.8,

Phenyl 2Ј,3-O-(2-Methylenebenzoyl)-(3,4,6-tri-O-benzyl-α-

pyranosyl)-(1Ǟ4)-6-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-

-gluco-

D-glu-

copyranoside (8a): IDCP^[88](0.52 g, 1.44 mmol) was added at room

temp. under argon to a mixture of 7a (0.79 g, 0.72 mmol) and mo-

lecular sieves (4 Å) in CH₂Cl₂(40 mL). The mixture was stirred for

3 h, diluted with CH₂Cl₂and filtered. The filtrate was washed with

aqueous sodium thiosulfate solution, water, dried and concen-

trated. Chromatography (toluene/ethyl acetate, 15:1) afforded 8a

(0.52 g, 69%) as a colorless foam. [α]²_D⁰= +53.1 (c = 1.0, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 5.98 (dd, J_3,4= 9.1 Hz, 1 H, 3_B-

H), 5.88 (d, J_1,2= 10.4 Hz, 1 H, 1_B-H), 5.21 (d, J_1,2= 3.4 Hz, 1 H,

1_E-H), 5.01 (d, J = –10.4 Hz, 1 H, PhCH₂), 4.82 (d, J = –11.0 Hz,

1 H, PhCH₂), 4.66 (d, J = –12.9 Hz, 1 H, PhCH₂), 4.61 (d, J =

–12.0 Hz, 1 H, PhCH₂), 4.57 (s, 2 H, PhCH₂), 4.52 (s, 1 H, PhCH₂),

4.47 (d, J = –12.4 Hz, 1 H, PhCH₂), 4.45 (d, J = –11.1 Hz, 1 H,

CHCl₃). H NMR (400 MHz, CDCl₃): δ = 5.57 (dd, J_2,3= 3.3 Hz,

1 H, 2-H), 5.09 (br. s, 1 H, PhCH₂OCO), 4.91 (d, J = –10.8 Hz, 1

H, PhCH₂), 4.83 (d, J_1,2= 1.7 Hz, 1 H, 1-H), 4.79 (br. s, 1 H, NH),

4.77 (d, J = –11.3 Hz, 1 H, PhCH₂), 4.64 (d, J = –10.9 Hz, 1 H,

PhCH₂), 4.56 (d, J = –11.3 Hz, 1 H, PhCH₂), 4.03 (dd, J_3,4

9.3 Hz, 1 H, 3-H), 3.82–3.75 (m, J_5,6= 6.2 Hz, 1 H, 5-H), 3.70–

3.62 (m, 1 H, OCH₂), 3.53 (t, J_4,5= 9.4 Hz, 1 H, 4-H), 3.44–3.36

(m, 1 H, OCH₂), 3.23–3.16 (m, 2 H, NHCH₂), 1.63–1.47 (m, 4 H,

CH₂), 1.41–1.35 (m, 2 H, CH₂), 1.36 (d, 3 H, 6-H). ¹³C NMR

(100.6 MHz, CDCl₃): δ = 165.8 (PhCO), 156.4 (OCONH), 97.6 (C-

1, J_C-1,1-H= 169.3 Hz), 80.1 (C-4), 78.2 (C-3), 75.4 (PhCH₂), 71.5

(PhCH₂), 69.5 (C-2), 67.6 (2 C, PhCH₂, C-5), 66.6 (PhCH₂OCO),

40.9 (CH₂NH), 29.7 (CH₂), 29.0 (CH₂), 23.4 (CH₂), 18.1 (C-6).

C₄₀H₄₅NO₈(667.8): calcd. C 71.94, H 6.79, N 2.10; found C 71.75,

H 6.81, N 1.93.

PhCH₂), 4.39 (d, J = –10.5 Hz, 1 H, PhCH₂), 4.30 (t, J_2,3

10.4 Hz, 1 H, 2_B-H), 3.96 (t, J_4,5= 9.1 Hz, 1 H, 4_B-H), 3.86–3.69

(m, J_5,6a= 4.1 Hz, 4 H, 3_E-H, 5_B-H, 6a_E-H, 6b_E-H), 3.61 (dd, J_5,6b

= 1.8 Hz, 1 H, 6a_B-H), 3.53 (t, J_4,5= 9.5 Hz, 1 H, 4_E-H), 3.52 (dd,

J_6a,6b= –10.5 Hz, 1 H, 6b_B-H), 3.42 (dd, J_2,3= 9.7 Hz, 1 H, 2_E-H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 169.6 (CO), 168.1 (CO), 167.2

(CO), 100.0 (C-1_E, J_C,H= 169.8 Hz), 82.5 (C-1_B), 81.1 (C-3_E), 80.7

(C-2_E), 79.9 (C-4_B), 78.9 (C-5_E), 76.9 (C-4_E), 75.7 (PhCH₂), 74.8 (1

C, 2 C, C-3_B, PhCH₂), 73.5 (PhCH₂), 73.1 (PhCH₂), 71.5 (C-5_B),

70.9 (PhCH₂), 68.8 (C-6_E), 68.6 (C-6_B), 53.9 (C-2_B). C₆₂H₅₇NO₁₂S

(1040.20): calcd. C 71.59, H 5.52, N 1.35, S 3.08; found C 71.60,

H 5.61, N 1.40, S 3.15.

5-[(Benzyloxycarbonyl)amino]pentyl 3,4-Di-O-benzyl-α-L-rhamno-

pyranoside (11): A solution of 10 (202 mg, 0.30 mmol) and a cata-

lytic amount of NaOMe (1  in methanol) in MeOH (5 mL) were

stirred at room temp. for 24 h, neutralized with ion exchange resin

(Dowex 50 W X 8, H⁺), filtered and concentrated. Chromatog-

raphy (petroleum ether/acetone, 3:1) of the residue afforded 11

(167 mg, 98%) as a colorless foam. [α]²_D⁰= –24.6 (c = 1.0, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 5.09 (br. s, 2 H, PhCH₂OCO),

4.88 (d, J = –10.9 Hz, 1 H, PhCH₂), 4.77 (d, J_1,2= 1.5 Hz, 1 H, 1-

H), 4.68 (br. s, 3 H, PhCH₂, NH), 4.63 (d, J = –10.9 Hz, 1 H,

PhCH₂), 4.01 (dd, J_2,3= 3.5 Hz, 1 H, 2-H), 3.83 (dd, J_3,4= 9.3 Hz,

1 H, 3-H), 3.75–3.68 (m, J_5,6= 6.3 Hz, 1 H, 5-H), 3.67–3.59 (m, 1

H, OCH₂), 3.45 (t, J_4,5= 9.4 Hz, 1 H, 4-H), 3.40–3.33 (m, 1 H,

OCH₂), 3.21–3.15 (m, 2 H, CH₂NH), 1.60–1.43 (m, 1 H, CH₂),

1.39–1.34 (m, 2 H, CH₂), 1.30 (d, 3 H, 6-H). ^{1 3}C NMR

Phenyl 2Ј,3-O-(2-Methylenebenzoyl)-(3,4,6-tri-O-benzyl-α-

pyranosyl)-(1Ǟ4)-6-O-benzyl-2-deoxy-1-thio-2-trifluoroacetamido-

β- -glucopyranoside (8b): IDCP (0.77 g, 2.14 mmol) was added at

D-gluco-

0 °C under argon to a mixture of 7b (1.14 g, 1.07 mmol) and molec-

ular sieves (4 Å) in CH₂Cl₂(40 mL). The mixture was stirred for

40 min, diluted with CH₂Cl₂and filtered. The filtrate was washed

with aqueous thiosulfate solution, water, dried and concentrated.

Chromatography (toluene/ethyl acetate, 20:1) afforded 8b (0.78 g,

72%) as a colorless foam. [α]²_D⁰= +17.2 (c = 1.0, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 5.55 (t, J_3,4= 9.9 Hz, 1 H, 3_B-H), 5.18 (d,

J_1,2= 3.8 Hz, 1 H, 1_E-H), 5.04 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.88

(d, J_1,2= 10.1 Hz, 1 H, 1_B-H), 4.83 (d, J = –10.9 Hz, 1 H, PhCH₂),

4.77–4.69 (m, 2 H, PhCH₂), 4.54 (d, J = –11.1 Hz, 1 H, PhCH₂),

4.51 (d, J = –12.1 Hz, 1 H, PhCH₂), 4.44 (d, J = –10.6 Hz, 1 H,

PhCH₂), 4.42 (s, 1 H, PhCH₂), 4.36 (d, J = –12.1 Hz, 1 H, PhCH₂),

4.31 (d, J = –11.9 Hz, 1 H, PhCH₂), 4.11–4.03 (m, J_2,3= 10.0 Hz,

1 H, 2_B-H), 3.91 (t, J_4,5= 9.4 Hz, 1 H, 4_B-H), 3.82 (t, J_5,6a= 9.9 Hz,

J_6a,6b= –10.0 Hz, 6a_B-H), 3.78–3.71 (m, 4 H, 3_E-H, 5_B-H, 5_E-H,

6b_E-H), 3.60–3.54 (m, 2 H, 4_E-H, 6a_E-H), 3.48–3.43 (m, 2 H, 2_E-

H, 6b_B-H), ¹³C NMR (100.6 MHz, CDCl₃): δ = 171.4 (PhCO),

(100.6 MHz, CDCl₃): δ = 156.3 (OCONH), 98.9 (C-1, J_C-1,1-H

167.9 Hz), 80.1 (C-3), 79.9 (C-4), 75.4 (PhCH₂), 71.9 (PhCH₂), 68.5

(C-2), 67.3 (OCH₂), 67.2 (C-5), 66.5 (PhCH₂OCO), 40.9 (CH₂NH),

29.7 (CH₂), 29.0 (CH₂), 23.3 (CH₂), 17.8 (C-6). C₃₃H₄₁NO₇

(563.68): calcd. C 70.32, H 7.33, N 2.49; found C 69.99, H 7.31, N

2.51.

5-[(Benzyloxycarbonyl)amino]pentyl (2-O-Benzoyl-3,4-di-O-benzyl-

α-L-rhamnopyranosyl)-(1Ǟ2)-3,4-di-O-benzyl-α-L-rhamnopyrano-

side (12): A mixture of 9^[68](180 mg, 0.365 mmol), 11 (206 mg,

0.365 mmol) and molecular sieves (4 Å) in CH₂Cl₂(10 mL) was

cooled under argon to –10 °C and stirred for 10 min. NIS (82 mg,

0.365 mmol) and TfOH (ca. 4 µL, 37 µmol) were successively

added, the mixture was stirred for 15 min, neutralized by addition

of triethylamine, diluted with CH₂Cl₂and filtered through a layer

of Celite^®. The filtrate was washed with aqueous Na₂S₂O₃solution,

water, dried and concentrated. The crude compound was purified

by chromatography (petroleum ether/ethyl acetate, 4:1) to yield

pure 12 as colorless foam (253 mg, 70%). [α]²_D⁰= +12.8 (c = 1.3,

157.3 (NHCOCF₃, J_C,F= 37.3 Hz), 116.2 (NHCOCF₃, J_C,F

287.6 Hz), 100.7 (C-1_E, J_C,H= 169.9 Hz), 85.1 (C-1_B), 81.7 (C-3_E),

81.0 (C-2_E), 79.4 (C-4_B), 79.3 (C-5_E), 77.3 (2 C, C-3_B, C-4_E), 76.2

(PhCH₂), 75.5 (PhCH₂), 73.9 (PhCH₂), 73.4 (PhCH₂), 71.9 (C-5_B),

71. 6 (PhCH₂), 69.0 (C-6_E), 68.8 (C-6 _B) , 5 3. 2 ( C- 2_B).

C₅₆H₅₄F₃NO₁₁S (1006.10): calcd. C 66.85, H 5.41, N 1.39, S 3.19;

found C 67.11, H 5.44, N 1.40, S 3.30.

CHCl₃). H NMR (400 MHz, CDCl₃): δ = 5.76 (dd, J_2,3= 3.1 Hz,

1 H, 2_C-H), 5.13 (d, J_1,2= 1.7 Hz, 1 H, 1_C-H), 5.08 (br. s, 2 H,

PhCH₂OCO), 4.90 (d, J = –10.8 Hz, 1 H, PhCH₂), 4.82 (d, J =

–11.3 Hz, 1 H, PhCH₂), 4.78 (br. s, 1 H, NH), 4.70 (d, J_1,2= 1.6 Hz,

1 H, 1_D-H), 4.67 (s, 3 H, PhCH₂), 4.64 (d, J = –10.9 Hz, PhCH₂),

4.61 (d, J = –10.8 Hz, 1 H, PhCH₂), 4.58 (d, J = –11.3 Hz, 1 H,

5-[(Benzyloxycarbonyl)amino]pentyl 2-O-Benzoyl-3,4-di-O-benzyl-α-

-rhamnopyranoside (10): A mixture of 9^[68](1.12 g, 2.27 mmol), 5-

2624

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Eur. J. Org. Chem. 2006, 2618–2630

Synthesis of Pentasaccharide Fragments

FULL PAPER

PhCH₂), 4.08 (dd, J_3,4= 9.3 Hz, 1 H, 3_C-H), 3.98 (br. t, J_2,3

ture was concentrated in vaco and the residue was chromato-

2.9 Hz, 1 H, 2_D-H), 3.92–3.89 (m, J_5,6= 6.2 Hz, 1 H, 5_C-H), 3.85

(dd, J_3,4= 9.2 Hz, 1 H, 3_D-H), 3.68–3.58 (m, J_5,6= 6.2 Hz, 2 H,

graphed (petroleum ether/acetone, 4:1 + 0.5% Et₃N) to yield 15

(0.70 g, 79%) as colorless foam. [α]²_D⁰= –3.8 (c = 0.9, CHCl₃). H

5_D-H, OCH₂), 3.53 (t, J_4,5= 9.4 Hz, 1 H, 4_C-H), 3.44 (t, J_4,5

9.4 Hz, 1 H, 4_D-H), 3.36–3.29 (m, 1 H, OCH₂), 3.20–3.14 (m, 2 H,

CH₂NH), 1.57–1.42 (m, 4 H, CH₂), 1.36 (d, 3 H, 6_C-H), 1.34–1.30 = –10.8 Hz, 1 H, PhCH₂), 4.80 (d, J = –11.4 Hz, 1 H, PhCH₂),

(m, 2 H, OCH₂), 1.29 (d, 3 H, 6_D-H). ¹³C NMR (100.6 MHz,

4.66 (d, J = –10.8 Hz, 1 H, PhCH₂), 4.61 (d, J = –11.4 Hz, 1 H,

CDCl₃): δ = 165.4 (PhCO), 156.3 (OCONH), 99.2 (C-1_C, J_C,HPhCH₂), 4.11 (dd, J_3,4= 9.4 Hz, 1 H, 3-H), 4.03–3.98 (m, J_5,6

NMR (400 MHz, CDCl₃): δ = 8.67 (s, 1 H, CNH), 6.31 (d, J_1,2

1.9 Hz, 1 H, 1-H), 5.72 (br. t, J_2,3= 3.2 Hz, 1 H, 2-H), 4.93 (d, J

170.0 Hz), 98.7 (C-1_D, J_C,H= 168.8 Hz), 80.0 (2 C, C-4_C, C-4_D),

79.8 (C-3_D), 77.7 (C-3_C), 75.3 (2 C, PhCH₂), 74.7 (C-2_D), 72.1

(PhCH₂), 71.5 (PhCH₂), 69.4 (C-2_C), 68.2 (C-5_C), 67.8 (C-5_D), 67.2

(OCH₂), 66.5 (PhCH₂OCO), 40.9 (CH₂NH), 29.7 (CH₂),

6.2 Hz, 1 H, 5-H), 3.64 (t, J_4,5= 9.5 Hz, 1 H, 4-H), 1.39 (d, 3 H,

6-H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 165.5 (PhCO), 160.1

(CNH), 95.2 (C-1), 90.7 (CCl₃), 79.3 (C-4), 77.3 (C-3), 75.6

(PhCH₂), 71.8 (PhCH₂), 70.5 (C-2), 68.0 (C-5), 75.6 (PhCH₂), 18.1

29.0 (CH₂), 23.3 (CH₂), 18.2 (C-6_C), 18.0 (C-6_D). C₆₀H₆₇NO₁₂(C-6). C₂₉H₂₈Cl₃NO₆(592.91): calcd. C 58.75, H 4.76, N 2.36;

(994.17): calcd. C 72.49, H 6.79, N 1.41; found C 72.55, H 6.81, N

1.35.

found C 58.77, H 4.77, N 2.13.

Ethyl (2-O-Benzoyl-3,4-di-O-benzyl-α-L-rhamnopyranosyl)-(1Ǟ3)-

2-O-benzoyl-4-O-benzyl-1-thio-α-L-rhamnopyranoside (17): A mix-

5-[(Benzyloxycarbonyl)amino]pentyl (3,4-Di-O-benzyl-α-

L-rhamno-

ture of 15 (0.29 g, 0.49 mmol) and 16^[70](0.17 g, 0.41 mmol) in

CH₂Cl₂(15 mL) was cooled under argon to –10 °C and stirred for

10 min. TMSOTf (8 µL, 45 µmol) was successively added, the mix-

ture was stirred for 15 min, neutralized by addition of triethyl-

amine, diluted with CH₂Cl₂, washed with saturated aqueous

NaHCO₃solution, water and concentrated. Chromatography (pe-

troleum ether/ethyl acetate, 10:1) of the residue afforded 17 (0.26 g,

76%) as colorless foam. [α]²_D⁰= –0.7 (c = 1.6, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 5.60 (dd, J_2,3= 3.1 Hz, 1 H, 2_D-H), 5.49

(dd, J_2,3= 3.2 Hz, 1 H, 2_A-H), 5.33 (d, J_1,2= 1.5 Hz, 1 H, 1_A-H),

5.17 (d, J_1,2= 1.7 Hz, 1 H, 1_D-H), 4.87 (d, J = –10.8 Hz, 1 H,

PhCH₂), 4.79 (d, J = –11.3 Hz, 1 H, PhCH₂), 4.66 (d, J = –10.8 Hz,

1 H, PhCH₂), 4.58 (d, J = –11.3 Hz, 1 H, PhCH₂), 4.55 (d, J =

–10.1 Hz, 1 H, PhCH₂), 4.36 (d, J = –11.4 Hz, 1 H, PhCH₂), 4.23

(dd, J_3,4= 9.4 Hz, 1 H, 3_A-H), 4.16–4.08 (m, J_5,6= 6.1 Hz, 1 H,

pyranosyl)-(1Ǟ2)-3,4-di-O-benzyl-α- -rhamnopyranoside (13): A

solution of 12 (1.08 g, 1.09 mmol) and a catalytic amount of Na-

OMe (1  in methanol) in MeOH (30 mL) was stirred at room

temp. for 48 h, neutralized with ion exchange resin (Dowex

50 W X 8, H⁺), filtered and concentrated. Chromatography (petro-

leum ether/acetone, 4:1) of the residue afforded 13 (0.92 g, 95%) as

a colorless foam. [α]²_D⁰= –27.3 (c = 1.0, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 5.09 (br. d, 2 H, PhCH₂OCO), 5.08 (d, J_1,2

= 1.8 Hz, 1 H, 1_C-H), 4.88 (d, J = –10.9 Hz, 1 H, PhCH₂), 4.86 (d,

J = –10.8 Hz, 1 H, PhCH₂), 4.75 (br. s, 1 H, NH), 4.71 (s, 2 H,

PhCH₂), 4.68 (d, J_1,2= 1.7 Hz, 1 H, 1_D-H), 4.66 (s, 2 H, PhCH₂),

4.63 (d, J = –11.7 Hz, 1 H, PhCH₂), 4.59 (d, J = –11.5 Hz, 1 H,

PhCH₂), 4.13 (dd, J_2,3= 3.2 Hz, 1 H, 2_C-H), 3.98 (br. t, J_2,3

3.3 Hz, 1 H, 2_D-H), 3.88 (dd, J_3,4= 9.4 Hz, 1 H, 3_D-H), 3.85–3.77

(m, J_5,6= 6.2 Hz, 1 H, 5_C-H), 3.83 (dd, J_3,4= 9.3 Hz, 1 H, 3_C-H),

3.68–3.63 (m, J_5,6= 6.2 Hz, 1 H, 5_D-H), 3.61–3.54 (m, 1 H, OCH₂),

3.47 (t, J_4,5= 9.3 Hz, 1 H, 4_C-H), 3.38 (t, J_4,5= 9.4 Hz, 1 H, 4_D-

H), 3.36–3.28 (m, 1 H, OCH₂), 3.21–3.14 (m, 2 H, CH₂NH), 1.59–

1.31 (m, 6 H, CH₂), 1.30 (d, 3 H, 6_C-H), 1.28 (d, 3 H, 6_D-H). ¹³C

NMR (100.6 MHz, CDCl₃): δ = 156.3 (OCONH), 100.7 (C-1_C),

98.8 (C-1_D), 80.4 (C-4_D), 80.0 (C-4_C), 79.8 (C-3_D), 79.5 (C-3_C), 75.3

(2 C, PhCH₂), 74.7 (C-2_D), 72.2 (PhCH₂), 72.1 (PhCH₂), 68.7 (C-

2_C), 67.8 (2 C, C-5_C, C-5_D), 67.2 (OCH₂), 66.6 (PhCH₂OCO), 40.9

(CH₂NH), 29.8 (CH₂), 29.1 (CH₂), 23.4 (CH₂), 18.0 (C-6_C), 17.9

(C-6_D). C₅₃H₆₃NO₁₁(890.07): calcd. C 71.52, H 7.13, N 1.57; found

C 71.21, H 7.11, N 1.50.

5_A-H), 3.90 (dd, J_3,4= 9.3 Hz, 1 H, 3_D-H), 3.85–3.78 (m, J_5,6

6.2 Hz, 1 H, 5_D-H), 3.64 (t, J_4,5= 9.4 Hz, 1 H, 4_A-H), 3.47 (t, J_4,5

= 9.4 Hz, 1 H, 4_D-H), 2.70–2.56 (m, 2 H, SCH₂CH₃), 1.34 (d, 3 H,

6_A-H), 1.28 (t, J = 7.4 Hz, 3 H, SCH₂CH₃), 1.18 (d, 3 H, 6_D-H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 165.8 (PhCO), 165.6 (PhCO),

99.5 (C-1_D, J_C,H= 171.9 Hz), 82.0 (C-1_A), 80.6 (C-4_A), 79.7 (C-

4_D), 78.0 (C-3_A), 77.7 (C-3_D), 75.6 (PhCH₂), 74.7 (C-2_A), 74.6

(PhCH₂), 71.5 (PhCH₂), 69.7 (C-2_D), 68.6, 68.8 (1 C, 1 C, C-5_A,

C-5_D), 25.8 (SCH₂CH₃), 17.9, 18.0 (1 C, 1 C, C-6_A, C-6_D), 15.1

(SCH₂CH₃). C₄₉H₅₂O₁₀S (833.01): calcd. C 70.65, H 6.29; found C

70.59, H 6.39.

Phenyl O-[3,4,6-Tri-O-benzyl-2-O-(2-methoxycarbonylbenzyl)-α-

glucopyranosyl]-(1Ǟ4)-6-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-

-glucopyranoside (18): Sodium methoxide (1  in MeOH, 200 µL)

D-

2-O-Benzoyl-3,4-di-O-benzyl-α/β-L-rhamnopyranose (14): A mixture

of 9^[68](0.74 g, 1.50 mmol) in acetone/water (23 mL, 9:1 v/v) was

treated with NBS (1.07 g, 6.00 mmol). After stirring at room temp.

for 20 min, the solution was diluted with CH₂Cl₂, washed with sat-

urated aqueous NaHCO₃solution, water and dried. The reaction

solution was filtered, and the solvent was removed in vaco. The

crude product was purified by chromatography (petroleum ether/

acetone, 5:1) to yield pure 14 as a colorless foam (0.61 g, 91%) as

was added to a solution of 8a (60 mg, 58 µmol) in a mixture of

CH₂Cl₂(1 mL) and MeOH (3 mL) and stirred at 40 °C temp. for

48 h. After neutralization with ion-exchange resin (Dowex

50 W X 8, H⁺) and filtration, the solvent was evaporated and the

crude product was purified by chromatography (toluene/ethyl ace-

tate, 10:1) to afford 18 (28 mg, 45%) as a foam. [α]²_D⁰= +46.7 (c =

an anomeric mixture (α/β, 4:1). [α]²_D⁰= +51.9 (c = 2.3, CHCl₃). H

1.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.98 (d, J_1,2

NMR (400 MHz, CDCl₃; α-anomer): δ = 5.61 (dd, J_2,3= 3.2 Hz,

1 H, 2-H), 5.26 (d, J_1,2= 1.8 Hz, 1 H, 1-H), 4.11 (dd, J_3,4= 9.3 Hz,

1 H, 3-H), 4.07–4.02 (m, J_5,6= 6.2 Hz, 1 H, 5-H), 1.35 (d, 3 H, 6-

H). ¹³C NMR (100.6 MHz, CDCl₃; α-anomer): δ = 165.8 (PhCO),

92.5 (C-1), 80.0 (C-4), 77.6 (C-3), 75.3 (PhCH₂), 71.5 (PhCH₂), 69.7

(C-2), 67.9 (C-5), 18.2 (C-6). C₂₇H₂₈O₆(448.52): calcd. C 72.30, H

6.29; found C 72.38, H 6.42.

10.0 Hz, 1 H, 1_B-H), 5.23 (d, J_1,2= 3.7 Hz, 1 H, 1_E-H), 5.08 (d, J

= –10.4 Hz, 1 H, PhCH₂), 4.85 (d, J = –10.3 Hz, 1 H, PhCH₂),

4.83 (d, J = –10.9 Hz, 1 H, PhCH₂), 4.67 (d, J = –11.2 Hz, 1 H,

PhCH₂), 4.63 (d, J = –10.9 Hz, 1 H, PhCH₂), 4.55 (d, J = –11.9 Hz,

1 H, PhCH₂), 4.54 (d, J = –12.8 Hz, 1 H, PhCH₂), 4.50 (d, J =

–10.3 Hz, 1 H, PhCH₂), 4.46 (d, J = –10.5 Hz, 1 H, PhCH₂), 4.42

(d, J = –10.6 Hz, 1 H, PhCH₂), 4.28 (dd, J_3,4= 9.2 Hz, 1 H, 3_B-

H), 4.10 (t, J_2,3= 10.0 Hz, 1 H, 2_B-H), 3.91 (t, J_4,5= 9.1 Hz, 1 H,

4_B-H), 3.90–3.82 (m, J_5,6a= 4.4 Hz, J_6a,6b= –10.6 Hz, 6 H, 3_E-H,

5_B-H, 6a_B-H, OCH₃), 3.80–3.61 (m, 3 H, 5_E-H, 6a_E-H, 6b_E-H),

3.63 (dd, J_5,6b= 1.9 Hz, 1 H, 6b_B-H), 3.55 (t, J_4,5= 9.4 Hz, 1 H,

2-O-Benzoyl-3,4-di-O-benzyl-α-L-rhamnopyranosyl Trichloroacet-

imidate (15): DBU (23 µL, 0.15 mmol) was added to a stirred solu-

tion of 14 (0.67 g, 1.49 mmol) and trichloroacetonitrile (0.43 g,

2.98 mmol) in CH₂Cl₂(15 mL) at 0 °C. After 2 h at 0 °C, the mix-

Eur. J. Org. Chem. 2006, 2618–2630

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2625

G. Lemanski, T. Ziegler

FULL PAPER

4_E-H), 3.46 (dd, J_2,3= 9.7 Hz, 1 H, 2_E-H). ¹³C NMR (100.6 MHz,

PhCH₂), 4.65 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.60 (d, J = –11.6 Hz,

CDCl₃): δ = 170.0, 167.9, 167.7 (3 C, CO), 100.0 (C-1_E), 82.8 (C- 1 H, PhCH₂), 4.58 (d, J_1,2= 8.3 Hz, 1 H, 1_B-H), 4.57 (d, J =

1_B), 81.2 (C-4_B), 81.0 (C-2_E), 80.5 (C-3_E), 79.0 (C-5_E), 77.0 (C- –11.2 Hz, 1 H, PhCH₂), 4.54 (s, 2 H, PhCH₂), 4.47 (s, 2 H, PhCH₂),

4_E), 75.6 (PhCH₂), 75.0 (PhCH₂), 74.2 (C-3_B), 73.4 (PhCH₂), 73.1 4.45 (d, J = –11.5 Hz, 1 H, PhCH₂), 4.43 (d, J = –11.5 Hz, 1 H,

(PhCH₂), 71.0 (2 C, C-5_B, PhCH₂), 68.9 (C-6_E), 68.5 (C-6_B), 55.4 PhCH₂), 4.22 (dd, J_2,3= 10.0 Hz, 1 H, 2_B-H), 4.20 (d, J = –11.1 Hz,

(C-_B), 51.2 (OCH₃). C₆₃H₆₁NO₁₃S (1072.24): calcd. C 70.57, H

5.73, N 1.31, S 2.99; found C 70.61, H 5.75, N 1.33, S 2.89.

1 H, PhCH₂), 3.99 (br. s, 1 H, 2_C-H), 3.92 (t, J_4,5= 9.6 Hz, 1 H,

4_B-H), 3.90 (t, J_3,4= 9.6 Hz, 1 H, 3_E-H), 3.82–3.77 (m, 5 H, 3_C-H,

5_B-H, 6a_E-H, 6b_E-H, PhCH₂), 3.63–3.50 (m, 6 H, 4_E-H, 5_C-H, 5_E-

H, 6a_B-H, 6b_B-H, OCH₂), 3.50 (dd, J_2,3= 9.6 Hz, 1 H, 2_E-H), 3.28

(t, J_4,5= 9.6 Hz, 1 H, 4_C-H), 3.22–3.18 (m, 1 H, OCH₂), 3.18–3.10

(m, 2 H, CH₂NH), 1.84 (s, 3 H, NHCOCH₃), 1.50–1.39 (m, 4 H,

CH₂), 1.28 (d, J_5,6= 6.0 Hz, 3 H, 6_C-H), 1.26–1.21 (m, 2 H, CH₂).

¹³C NMR (100.6 MHz, CDCl₃): δ = 170.0 (CO), 165.7 (CO), 156.4

5-[(Benzyloxycarbonyl)amino]pentyl 2ЈЈ,3Ј-O-(2-Methylenebenzoyl)-

(3,4,6-tri-O-benzyl-α-

D-glucopyranosyl)-(1Ǟ4)-(6-O-benzyl-2-de-

oxy-2-phthalimido-β- -glucopyranosyl)-(1Ǟ2)-3,4-di-O-benzyl-α-L-

rhamnopyranoside (19): A mixture of 8a (54 mg, 96 µmol), 11

(120 mg, 115 µmol) and molecular sieves (4 Å) in CH₂Cl₂(6 mL)

was cooled under argon to –40 °C and stirred for 10 min. NIS

(30 mg, 115 µmol) and TMSOTf (ca. 5 µL, 30 µmol) were success-

ively added, the mixture was stirred for 1 h, neutralized by addition

of triethylamine, diluted with CH₂Cl₂and filtered. The filtrate was

washed with aqueous sodium thiosulfate solution, water, dried and

concentrated. The residue was chromatographed (toluene/acetone,

(OCONH), 102.9 (C-1_B, J_C,H= 162.9 Hz), 98.9 (C-1_E, J_C,H

169.8 Hz), 97.8 (C-1_C, J_C,H= 171.7 Hz), 81.4 (C-3_E), 80.4 (2 C, C-

4_C, C-2_E), 79.4 (2 C, C-4_B, C-3_C), 78.8 (C-5_E), 78.0 (C-2_C), 77.6 (C-

3_B), 74.8 (C-4_E), 71.4 (C-5_B), 69.3 (C-6_E), 68.3 (C-6_B), 67.7 (C-

5_C), 67.3 (OCH₂), 66.6 (OCOCH₂Ph), 58.1 (C-2_B), 29.8 (CH₂), 29.1

(CH₂), 23.4 (CH₂), 23.2 (CH₃CONH), 17.8 (C-6_C). C₈₃H₉₂N₂O₁₈

(1405.65): calcd. C 70.92, H 6.60, N 1.99; found C 71.23, H 6.55,

N 2.05.

15:1) to yield 19 (81 mg, 57%) as a colorless foam. [α]²_D⁰= +55.1 (c

= 0.8, CHCl₃). H NMR (400 MHz, CDCl₃): δ = 6.20 (dd, J_3,4

9.0 Hz, 1 H, 3_B-H), 5.54 (d, J_1,2= 8.2 Hz, 1 H, 1_B-H), 5.23 (d, J_1,2

= 3.4 Hz, 1 H, 1_E-H), 5.08 (br. s, 2 H, PhCH₂CO), 5.04 (d, J =

–10.4 Hz, 1 H, PhCH₂), 4.84 (d, J = –11.0 Hz, 1 H, PhCH₂), 4.77

(d, J_1,2= 1.5 Hz, 1 H, 1_C-H), 4.70 (br. s, 1 H, NH), 4.64 (d, J =

–11.3 Hz, 1 H, PhCH₂), 4.62 (d, J = –12.2 Hz, PhCH₂), 4.52 (d, J

= –12.2 Hz, 1 H, PhCH₂), 4.44 (d, J = –12.2 Hz, 1 H, PhCH₂),

5-[(Benzyloxycarbonyl)amino]pentyl 2ЈЈ,3Ј-O-(2-Methylenebenzoyl)-

(3,4,6-tri-O-benzyl-α-

methylaminocarbonyl)benzoyl]-6-O-benzyl-2-deoxy-β-

pyranosyl}-(1Ǟ2)-3,4-di-O-benzyl-α- -rhamnopyranoside (21): A

-glucopyranosyl)-(1Ǟ4)-{2-amino-[2-(N-

-gluco-

solution of 19 (85 mg, 59 µmol) in EtOH (1.7 mL) was treated with

MeNH₂/EtOH (3.4 mL, 33%), stirred at room temp. for 1 h and at

60 °C for 2 h. After cooling, the mixture was concentrated and the

residue was treated with pyridine (5 mL) and acetic anhydride

(1.6 mL). After 24 h, the mixture was poured onto ice and extracted

with CH₂Cl₂. The organic phase was washed with diluted aqueous

HCl solution, saturated aqueous NaHCO₃solution, water, dried

and concentrated. Chromatography (toluene/ethanol, 25:1) of the

residue afforded 21 (48 mg, 54%) as a colorless foam. [α]²_D⁰= +38.2

4.43 (s, 3 H, PhCH₂), 4.39 (s, 2 H, PhCH₂), 4.38 (br. d, J_2,3

10.7 Hz, 1 H, 2_B-H), 4.24 (d, J = –12.2 Hz, 1 H, PhCH₂), 4.00 (d,

J = –10.7 Hz, 1 H, PhCH₂), 3.94 (d, J = –11.0 Hz, 1 H, PhCH₂),

3.90–3.73 (m, 6 H, 3_E-H, 4_B-H, 4_E-H, 5_B-H, 6a_E-H, 6b_E-H), 3.73

(br. s, 1 H, 2_C-H), 3.66–3.58 (m, 4 H, 3_C-H, 5_E-H, 6a_B-H, 6b_B-H),

3.56–3.48 (m, J_5,6= 6.1 Hz, 2 H, OCH₂, 5_C-H), 3.44 (dd, J_2,3

9.6 Hz, 1 H, 2_E-H), 3.25–3.20 (m, 1 H, OCH₂), 3.15–3.10 (m, 2 H,

CH₂NH), 3.04 (t, J_4,5= 9.5 Hz, 1 H, 4_C-H), 1.44–1.36 (m, 4 H,

CH₂), 1.25–1.22 (m, 2 H, CH₂), 1.15 (d, 3 H, 6_C-H). ¹³C NMR

(100.6 MHz, CDCl₃): δ = 169.4 (CO), 168.1 (NCO), 167.7 (NCO),

156.4 (OCONH), 100.1 (C-1_B, J_C,H= 163.8 Hz), 99.7 (C-1_E, J_C,H

= 169.8 Hz), 99.0 (C-1_C, J_C,H= 171.1 Hz), 81.2 (C-3_B), 80.7, 80.6

(1 C, 1 C, C-2_E, C-4_B), 80.3 (C-4_C), 78.8 (C-5_E), 78.0 (C-2_C), 76.9

(C-3_C), 75.7 (PhCH₂), 74.9 (2 C, PhCH₂), 74.4 (C-4_E), 73.5

(PhCH₂), 73.4 (C-3_B), 73.1 (PhCH₂), 72.2 (PhCH₂), 71.5 (C-5_B),

71.0 (PhCH₂), 68.9 (C-6_E), 68.6 (C-6_B), 67.9 (C-5_C), 67.1 (OCH₂),

66.6 (OCOCH₂Ph), 55.1 (C-2_B), 40.9 (CH₂NH), 29.7 (CH₂), 29.1

(CH₂), 23.3 (CH₂), 17.7 (C-6_C). C₈₉H₉₂N₂O₁₉(1493.72): calcd. C

71.57, H 6.21, N 1.88; found C 71.35, H 6.17, N 1.85.

(c = 1.1, CHCl₃). H NMR (400 MHz, CDCl₃): δ = 7.75 (br. d, J

= 4.4 Hz, 1 H, CONHCH₃), 6.91 (br. d, J = 7.1 Hz, 1 H, NHCO),

5.32 (t, J_3,4= 10.0 Hz, 1 H, 3_B-H), 5.26 (d, J_1,2= 3.1 Hz, 1 H, 1_E-

H), 5.14 (d, J = –10.2 Hz, 1 H, PhCH₂), 5.07 (br. s, 2 H,

PhCH₂OCO), 4.86 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.79 (d, J_1,2

8.4 Hz, 1 H, 1_B-H), 4.78 (br. s, 1 H, 1_C-H), 4.31–4.25 (m, 1 H, 2_B-

H), 4.74 (br. s, 1 H, CH₂NH), 4.73 (d, J = –11.1 Hz, 1 H, PhCH₂),

4.67 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.62 (d, J = –11.9 Hz, 1 H,

PhCH₂), 4.59 (d, J = –11.1 Hz, 1 H, PhCH₂), 4.55 (s, 3 H, PhCH₂),

4.48 (d, J = –11.5 Hz, 1 H, PhCH₂), 4.47 (d, J = –10.2 Hz, 1 H,

PhCH₂), 4.46 (d, J = –11.5 Hz, 1 H, PhCH₂), 4.17 (d, J = –11.1 Hz,

5-[(Benzyloxycarbonyl)amino]pentyl 2ЈЈ,3Ј-O-(2-Methylenebenzoyl)- 1 H, PhCH₂), 4.02 (br. s, 1 H, 2_C-H), 3.94 (t, J_4,5= 9.2 Hz, 1 H,

(3,4,6-tri-O-benzyl-α-

-glucopyranosyl)-(1Ǟ4)-(2-acetamido-6-O-

4_B-H), 3.87 (t, J_3,4= 9.5 Hz, 1 H, 3_E-H), 3.83–3.79 (m, 4 H, 3_C-H,

5_B-H, 6a_E-H, 6b_E-H), 3.72 (d, J = –11.1 Hz, 1 H, PhCH₂), 3.65–

3.52 (m, J_5C,6C= 5.8 Hz, 6 H, 4_E-H, 5_C-H, 5_E-H, 6a_B-H, 6b_B-H,

OCH₂), 3.49 (dd, J_2,3= 9.7 Hz, 1 H, 2_E-H), 3.33–3.31 (m, 1 H,

OCH₂), 3.20–3.14 (m, J_4,5= 9.7 Hz, 3 H, 4_C-H, CH₂NH), 2.79 (d,

J = 4.4 Hz, 3 H, CONHCH₃), 1.53–1.45 (m, 4 H, CH₂), 1.30 (d, 1

H, 6_C-H), 1.29–1.26 (m, 2 H, CH₂). ¹³C NMR (100.6 MHz,

CDCl₃): δ = 170.7 (NHCO), 170.1 (NHCO), 167.5 (CO), 156.5

benzyl-2-deoxy-β- -glucopyranosyl)-(1Ǟ2)-3,4-di-O-benzyl-α-L-

rhamnopyranoside (20): Ethylenediamine (5 mL) was added to a

solution of compound 19 (133 mg, 92 µmol) in nBuOH (15 mL).

After stirring at 80 °C for 48 h, the mixture was concentrated and

the residue was taken up in pyridine (9 mL) and acetic anhydride

(1.4 mL). After 24 h, the solution was poured onto ice and ex-

tracted with CH₂Cl₂. The organic layer was washed successively

with diluted aqueous HCl solution and saturated aqueous

NaHCO₃solution, dried and the solvents were evaporated. The

residue was purified by chromatography (toluene/ethanol, 20:1) to

give pure 20 (58 mg, 45%) as an oil. [α]²_D⁰= +40.6 (c = 1.0, CHCl₃).

(OCONH), 102.4 (C-1_B, J_C,H= 158.3 Hz), 100.0 (C-1_E, J_C,H

165.9 Hz), 98.8 (C-1_C, J_C,H= 170.7 Hz), 80.9, 80.8, 80.7 (1 C, 2 C,

1 C, C-2_E, C-3_E, C-4_B, C-4_C), 79.7 (C-3_C), 77.5 (C-2_C), 76.7 (C-3_B),

75.6 (2 C, C-4_E, PhCH₂), 75.3 (C-5_E), 75.1 (PhCH₂), 71.5 (C-5_B),

¹H NMR (400 MHz, CDCl₃): δ = 5.50 (br. s, 1 H, NHCOCH₃), 68.7, 68.8 (1 C, 1 C, C-6_B, C-6_E), 67.8 (C-5_C), 67.2 (OCH₂), 66.6

5.25 (d, J_1,2= 3.4 Hz, 1 H, 1_E-H), 5.23 (t, J_3,4= 9.8 Hz, 1 H, 3_B- (OCOCH₂Ph), 54.9 (C-2_B), 40.9 (CH₂NH), 29.8 (CH₂), 29.1 (CH₂),

H), 5.12 (d, J = –10.4 Hz, 1 H, PhCH₂), 5.08 (br. s, 2 H,

PhCH₂CO), 4.88 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.78 (br. s, 1 H,

26.7 (NHCOCH₃), 23.4 (CH₂), 17.8 (C-6_C). C₉₀H₉₇N₃O₁₉

(1524.78): calcd. C 70.89, H 6.41, N 2.76; found C 71.15, H 6.38,

1_C-H), 4.76 (br. s, 1 H, CH₂NH), 4.74 (d, J = –11.1 Hz, 1 H, N 2.83.

2626

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Eur. J. Org. Chem. 2006, 2618–2630

Synthesis of Pentasaccharide Fragments

5-[(Benzyloxycarbonyl)amino]pentyl 2ЈЈ,3Ј-O-(2-Methylenebenzoyl)- (NHCOCF₃), 156.2 (OCONH), 115.7 (NHCOCF₃), 101.8 (C-1_B),

FULL PAPER

(3,4,6-tri-O-benzyl-α-

oxy-2-trifluoroacetamido-β-

benzyl-α- -rhamnopyranoside (22): A mixture of 11 (135 mg,

0.24 mmol), 8b (263 mg, 0.26 mmol) and molecular sieves (4 Å) in

CH₂Cl₂(15 mL) was cooled under argon to –30 °C and stirred for

10 min. NIS (59 mg, 0.26 mmol) and TMSOTf (ca. 13 µL, 70 µmol)

-glucopyranosyl)-(1Ǟ4)-(6-O-benzyl-2-de-

99.9 (C-1_E), 98.6 (C-1_C), 82.2 (C-4_B), 81.0 (C-3_E), 80.8 (C-2_E), 80.0

(C-4_C), 79.6 (C-5_E), 77.6 (C-2_C), 76.7 (C-3_C), 75.6 (PhCH₂), 75.5

(C-4_E), 75.4 (PhCH₂), 75.2 (PhCH₂), 74.6 (2 C, C-3_B, PhCH₂), 73.9

(PhCH₂), 73.4 (PhCH₂), 73.1 (PhCH₂), 71.0 (2 C, C-5_B, C-6_E), 68.7

(C-6_B), 67.9 (C-5_C), 67.2 (OCH₂), 66.4 (OCOCH₂Ph), 56.8 (C-2_B),

50.8 (OCH₃), 41.0 (CH₂NH), 29.9, 29.3, 23.6 (3 C, CH₂), 18.0 (C-

-glucopyranosyl)-(1Ǟ2)-3,4-di-O-

were successively added, the mixture was stirred for 30 min, neu- 6_C). C₈₄H₉₃F₃N₂O₁₉(1491.67): calcd. C 67.64, H 6.28, N 1.88;

tralized by addition of triethylamine, diluted with CH₂Cl₂and fil-

tered. The filtrate was washed with aqueous Na₂S₂O₃solution,

water, dried and concentrated. Chromatography (toluene/acetone,

12:1) of the residue yielded 22 (244 mg, 65%) as a colorless foam.

found C 67.90, H 6.31, N 1.95.

5-[(Benzyloxycarbonyl)amino]pentyl (2-O-Benzoyl-3,4-di-O-benzyl-

α-

pyranosyl)-(1Ǟ3)-[3,4,6-tri-O-benzyl-2-O-(2-methoxycarbonyl-

benzyl)-α- -glucopyranosyl-(1Ǟ4)]-(6-O-benzyl-2-deoxy-2-trifluo-

roacetamido-β- -glucopyranosyl)-(1Ǟ2)-3,4-di-O-benzyl-α- -rham-

L-rhamnopyranosyl)-(1Ǟ3)-(2-O-benzoyl-4-O-benzyl-α-L-rhamno-

[α]²_D⁰= +13.6 (c = 0.6, CHCl₃). H NMR (400 MHz, CDCl₃): δ =

5.26 (t, J_3,4= 10.2 Hz, 1 H, 3_B-H), 5.22 (d, J_1,2= 3.3 Hz, 1 H, 1_E-

H), 5.10 (d, J = –11.1 Hz, 1 H, PhCH₂), 5.08 (br. s, 2 H,

PhCH₂CO), 4.79 (s, 1 H, 1_C-H), 4.84 (d, J = –11.1 Hz, 1 H,

PhCH₂), 4.83 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.77 (d, J = –10.6 Hz,

1 H, PhCH₂), 4.75 (br. s, CH₂NHCO), 4.68 (d, J = –11.1 Hz, 1 H,

PhCH₂), 4.63 (d, J = –11.4 Hz, 1 H, PhCH₂), 4.59 (d, J = –12.1 Hz,

1 H, PhCH₂), 4.57 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.55 (d, J =

–12.1 Hz, 1 H, PhCH₂), 4.52 (d, J_1,2= 8.8 Hz, 1 H, 1_B-H), 4.51–

4.47 (m, 3 H, PhCH₂), 4.43 (d, J = –11.9 Hz, 1 H, PhCH₂), 4.41

(d, J = –11.4 Hz, 1 H, PhCH₂), 4.13–4.04 (m, 1 H, 2_B-H), 3.90 (br.

s, 1 H, 2_C-H), 3.90–3.75 (m, 7 H, 3_C-H, 3_E-H, 4_B-H, 4_E-H, 5_B-H,

6a_E-H, 6b_E-H), 3.66–3.56 (m, 5 H, 5_C-H, 5_E-H, 6a_B-H, 6b_B-H,

OCH₂), 3.47 (dd, J_2,3= 9.8 Hz, 1 H, 2_E-H), 3.35–3.31 (m, 1 H,

OCH₂), 3.34 (t, J_4,5= 9.5 Hz, 1 H, 4_C-H), 3.19–3.11 (m, 2 H,

CH₂NH), 1.54–1.30 (m, 6 H, CH₂), 1.30 (d, J_5,6= 6.1 Hz, 3 H,

6_C-H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 170.2 (PhCO), 157.3

(NHCOCF₃), 156.4 (OCONH), 115.8 (NHCOCF₃), 102.1 (C-1_B,

J_C,H= 161.0 Hz), 100.0 (C-1_E), 98.8 (C-1_C), 81.0 (C-3_E), 80.7 (2 C,

C-2_E, C-4_B), 80.2 (C-4_C), 79.5 (C-5_E), 77.8 (C-2_C), 76.9 (C-3_C), 75.5

(2 C, PhCH₂), 75.4 (2 C, C-4_E, PhCH₂), 75.2 (C-3_B), 75.1 (PhCH₂),

73.9 (PhCH₂), 73.5 (PhCH₂), 73.1 (PhCH₂), 71.5 (C-5_B), 71.0 (C-

6_E), 68.6 (C-6_B), 67.8 (C-5_C), 67.2 (OCH₂), 66.6 (OCOCH₂Ph), 54.7

(C-2_B), 40.9 (CH₂NH), 29.8 (CH₂), 29.1 (CH₂), 23.4 (CH₂), 17.8

(C-6_C). C₈₃H₈₉F₃N₃O₁₈(1459.62): calcd. C 68.30, H 6.15, N 1.92;

found C 68.53, H 6.17, N 1.91.

nopyranoside (24): NIS (33 mg, 147 µmol), followed by trifluorome-

thanesulfonic acid (ca. 3 µL, 34 µmol), were added under argon to

a mixture of 23 (215 mg, 144 µmol), 17 (120 mg, 144 µmol) and

molecular sieves (4 Å) in CH₂Cl₂(10 mL). The reaction mixture

was stirred at –10 °C for a period of 30 min and was then diluted

with CH₂Cl₂, filtered, washed with sodium thiosulfate solution, sat-

urated aqueous NaHCO₃solution. The organic extracts were fi-

nally washed with water, dried and concentrated in vacuo. The

crude compound was purified by chromatography (toluene/acetone,

15:1) to yield pure 24 (202 mg, 62%) as an oil. [α]²_D⁰= +35.6 (c =

1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.60 (dd, J_2,3

3.1 Hz, 1 H, 2_D-H), 5.53 (dd, J_2,3= 3.4 Hz, 1 H, 2_A-H), 5.18 (d,

J_1,2= 3.6 Hz, 1 H, 1_E-H), 5.16 (s, 1 H, 1_D-H), 5.09 (br. s, 2 H,

PhCH₂CO), 5.06 (d, J = –11.2 Hz, 1 H, PhCH₂), 4.92 (d, J_1,2

8.7 Hz, 1 H, 1_B-H), 4.88 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.86 (d, J

= –11.1 Hz, 1 H, PhCH₂), 4.80 (s, 1 H, 1_C-H), 4.79 (br. s, 1 H,

CH₂NHCO), 4.77 (d, J = –10.8 Hz, 1 H, PhCH₂), 4.75 (d, J =

–11.3 Hz, 1 H, PhCH₂), 4.69 (d, J = –12.0 Hz, 1 H, PhCH₂), 4.67–

4.50 (m, 8 H, PhCH₂), 4.48 (s, 2 H, PhCH₂), 4.46 (d, J = –12.2 Hz,

1 H, PhCH₂), 4.43 (s, 3 H, PhCH₂), 4.04–3.94 (m, 5 H, 3_A-H, 3_D-

H, 5_B-H, 6a_B-H, 6b_B-H), 4.83 (d, J_1,2= 1.8 Hz, 1 H, 1_A-H), 3.90–

3.81 (m, J_3B,4B= 9.9 Hz, 6 H, 2_C-H, 3_B-H, 3_C-H, OCH₃), 3.82–

3.75 (m, 3 H, 5_A-H, 5_D-H, 6a_E-H), 3.73–3.53 (m, 8 H, 2_B-H, 3_E-H,

4_A-H, 4_B-H, 5_C-H, 5_E-H, 6b_E-H, OCH₂), 3.53–3.48 (m, 3 H, 2_E-H,

4_D-H, 4_E-H), 3.40 (t, J_4,5= 9.7 Hz, 1 H, 4_C-H), 3.39–3.30 (m, 1 H,

OCH₂), 3.17–3.09 (m, 2 H, CH₂NH), 1.55–1.40 (m, 4 H, CH₂),

1.38–1.31 (m, 2 H, CH₂), 1.36 (d, J_5,6= 6.2 Hz, 3 H, 6_A-H), 1.34

(d, J_5,6= 6.1 Hz, 3 H, 6_D-H), 1.30 (d, J_5,6= 6.2 Hz, 3 H, 6_C-H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 169.7, 169.5, 168.9 (3 C, CO),

158.2 (NHCOCF₃), 156.5 (OCONH), 115.5 (NHCOCF₃), 100.9

5-[(Benzyloxycarbonyl)amino]pentyl [3,4,6-Tri-O-benzyl-2-O-(2-

methoxycarbonylbenzyl)-α-

deoxy-2-trifluoroacetamido-β-

benzyl-α- -rhamnopyranoside (23): A solution of 22 (0.25 g,

D-glucopyranosyl]-(1Ǟ4)-(6-O-benzyl-2-

-glucopyranosyl)-(1Ǟ2)-3,4-di-O-

0.17 mmol) in MeOH (15 mL) and Mg(OMe)₂in MeOH (1 mL)

was stirred at room temp. for 3 d. The mixture was diluted with

CH₂Cl₂, washed with aqueous HCl solution, water, dried and con-

centrated. Chromatography (toluene/acetone, 8:1) of the residue af-

forded 23 (0.19 g, 77%) as a foam. [α]²_D⁰= +10.6 (c = 1.0, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 5.20 (d, J_1,2= 3.2 Hz, 1 H, 1_E-

H), 5.10 (d, J = –11.2 Hz, 1 H, PhCH₂), 5.08 (br. s, 2 H,

(C-1_B), 100.1 (C-1_E), 99.6 (C-1_D), 98.7 (C-1_C), 97.6 (C-1_A, J_C,H

172.8 Hz), 81.2 (2 C, C-3_E, C-4_B), 80.8 (C-2_E), 80.2 (2 C, C-4_A, C-

4_C), 79.9 (C-4_D), 79.6 (C-5_E), 78.6 (C-3_B), 78.3 (C-3_A), 77.5 (2 C,

C-2_C,C-3_D), 76.6 (C-3_C), 75.7 (PhCH₂), 75.5 (C-4_E), 75.4 (PhCH₂),

75.2 (PhCH₂), 74.9 (PhCH₂), 74.6 (PhCH₂), 74.3 (PhCH₂), 74.0

(PhCH₂), 73.7 (PhCH₂), 73.1 (PhCH₂), 70.8 (C-5_B), 69.8 (C-2_A),

69.6 (C-2_D), 69.3 (C-6_B), 69.0 (C-6_E), 68.8 (C-5_D), 67.7 (3 C, C-5_A,

C-5_C, OCH₂), 66.3 (OCOCH₂Ph), 57.7 (C-2_B), 52.1 (OCH₃), 40.8

(CH₂NH), 29.5, 29.1, 23.4 (3 C, CH₂), 18.1, 17.8 (1 C, 2 C, C-6_A,

C-6_C, C-6_D). C₁₃₁H₁₃₉F₃N₂O₂₉(2262.55): calcd. C 69.54, H 6.19,

N 1.24; found C 69.73, H 6.25, N 1.30.

PhCH₂CO), 4.85 (d, J = –12.2 Hz, 1 H, PhCH₂), 4.83 (d, J_1,2

8.7 Hz, 1 H, 1_B-H), 4.81 (d, J = –11.1 Hz, 1 H, PhCH₂), 4.80 (s, 1

H, 1_C-H), 4.77 (br. s, 1 H, CH₂NHCO), 4.75 (d, J = –10.7 Hz, 1

H, PhCH₂), 4.70 (d, J = –11.2 Hz, 1 H, PhCH₂), 4.64 (d, J =

–11.3 Hz, 1 H, PhCH₂), 4.57 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.55

(d, J = –10.6 Hz, 1 H, PhCH₂), 4.53 (d, J = –12.1 Hz, 1 H, PhCH₂),

4.51–4.44 (m, 3 H, PhCH₂), 4.42 (d, J = –11.9 Hz, 1 H, PhCH₂),

Phenyl [3,4,6-Tri-O-benzyl-2-O-(2-methoxycarbonylbenzyl)-α-D-glu-

4.39 (d, J = –11.4 Hz, 1 H, PhCH₂), 3.93–3.83 (m, 7 H, 2_B-H, 2_C- copyranosyl]-(1Ǟ4)-6-O-benzyl-2-deoxy-1-thio-2-trifluoroacet-

H, 3_C-H, 5_B-H, OCH₃), 3.82–3.71 (m, J_3B,4B= 9.9 Hz, 8 H, 3_B-H, amido-β- -glucopyranoside (25): A mixture of 8b (0.50 g,

3_E-H, 4_B-H, 4_E-H, 6a_B-H, 6b_B-H, 6a_E-H, 6b_E-H), 3.63–3.55 (m, 3

H, 5_C-H, 5_E-H, OCH₂), 3.48 (dd, J_2,3= 9.6 Hz, 1 H, 2_E-H), 3.38–

0.50 mmol) in MeOH (20 mL) was treated with Mg(OMe)₂in

MeOH (2.5 mL) and stirred at 40 °C for 20 h. The solution was

3.33 (m, J_4,5= 9.6 Hz, 2 H, 4_C-H, OCH₂), 3.17–3.10 (m, 2 H, neutralized with aqueous HCl solution, extracted with CH₂Cl₂and

CH₂NH), 1.55–1.30 (m, 6 H, CH₂), 1.27 (d, J_5,6= 6.2 Hz, 3 H, 6_C- the organic phase was washed with water, dried and concentrated.

H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 168.9 (CO), 156.9

The chromatography (toluene/ethyl acetate, 10:1) of the crude prod-

Eur. J. Org. Chem. 2006, 2618–2630

www.eurjoc.org

2627

G. Lemanski, T. Ziegler

FULL PAPER

uct furnished 25 (0.39 g, 76%) as a colorless foam. [α]²_D⁰= +15.3 (c

aqueous Na₂S₂O₃solution, water, dried and concentrated. The resi-

due was chromatographed (toluene/acetone, 15:1) to afford 27

(126 mg, 55%) as a colorless oil. [α]²_D⁰= +15.6 (c = 0.7, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 5.54 (dd, J_2,3= 4.3 Hz, 1 H, 2_A-

H), 5.18 (d, J_1,2= 3.7 Hz, 1 H, 1_E-H), 5.09 (d, J = –11.2 Hz, 1 H,

= 0.8, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.17 (d, J_1,2

9.9 Hz, 1 H, 1_B-H), 5.16 (d, J_1,2= 3.6 Hz, 1 H, 1_E-H), 5.11 (d, J =

4.5 Hz, 1 H, OH), 5.06 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.90 (d, J

= –11.2 Hz, 1 H, PhCH₂), 4.83 (d, J = –11.3 Hz, 1 H, PhCH₂),

4.77 (d, J = –11.1 Hz, 1 H, PhCH₂), 4.55 (d, J = –12.1 Hz, 1 H, PhCH₂), 5.08 (br. s, 2 H, OCOCH₂Ph), 4.92 (br. s, 2 H, 1_B-H, 1_C-

PhCH₂), 4.50 (d, J = –10.6 Hz, 1 H, PhCH₂), 4.46 (d, J = –10.6 Hz, H), 4.88 (d, J_1,2= 1.6 Hz, 1 H, 1_A-H), 4.87 (d, J = –10.6 Hz, 1 H,

1 H, PhCH₂), 4.43 (s, 1 H, PhCH₂), 4.37 (d, J = –12.1 Hz, 1 H, PhCH₂), 4.86 (d, J = –11.1 Hz, 1 H, PhCH₂), 4.77 (d, J = –10.8 Hz,

PhCH₂), 4.32 (d, J = –11.9 Hz, 1 H, PhCH₂), 4.07–4.01 (m, 1 H,

3_B-H), 3.90–3.82 (m, 5 H, 2_B-H, 4_B-H, OCH₃), 3.70–3.68 (m, 3 H,

1 H, PhCH₂), 4.75 (d, J = –11.1 Hz, 1 H, PhCH₂), 4.72 (br. s, 1 H,

CH₂NHCO), 4.69 (d, J = –12.0 Hz, 1 H, PhCH₂), 4.67 (d, J =

3_E-H, 5_E-H, 6b_E-H), 3.81–3.75 (m, 3 H, 5_B-H, 6a_E-H, 6a_B-H), 3.60– –10.6 Hz, 1 H, PhCH₂), 4.64 (s, 1 H, 1_D-H), 4.59 (d, J = –12.1 Hz,

3.55 (m, 1 H, 6b_B-H), 3.52–3.47 (m, 1 H, 4_E-H), 3.49–3.45 (m, 1 1 H, PhCH₂), 4.56 (s, 2 H, PhCH₂), 4.50 (d, J = –10.8 Hz, 1 H,

H, 2_E-H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 170.1 (CO), 157.2 PhCH₂), 4.48 (s, 2 H, PhCH₂), 4.46 (d, J = –11.3 Hz, 1 H, PhCH₂),

(NHCOCF₃), 116.0 (NHCOCF₃), 100.6 (C-1_E), 84.8 (C-1_B), 81.5

(C-3_E), 81.1 (C-2_E), 80.8 (C-4_B), 79.4 (C-5_E), 77.4 (C-4_E), 76.8 (C- J = –11.2 Hz, 1 H, PhCH₂), 4.35 (d, J = –10.6 Hz, 1 H, PhCH₂),

3_B), 76.1 (PhCH₂), 75.3 (PhCH₂), 73.6 (PhCH₂), 72.9 (PhCH₂), 4.33 (d, J = –11.6 Hz, 1 H, PhCH₂), 4.31 (d, J = –10.8 Hz, 1 H,

71.5 (C-5_B), 71.4 (PhCH₂), 68.9 (2 C, C-6_B, C-6_E), 54.3 (C-2_B), 51.2 PhCH₂), 4.29 (s, 2 H, PhCH₂), 4.25 (d, J = –11.9 Hz, 1 H, PhCH₂),

4.43 (s, 2 H, PhCH₂), 4.39 (d, J = –11.9 Hz, 1 H, PhCH₂), 4.36 (d,

(OCH₃). C₅₇H₅₈F₃NO₁₂S (1038.15): calcd. C 65.95, H 5.63, N 1.35;

found C 65.88, H 5.59, N 2.85.

4.16 (d, J = –12.2 Hz, 1 H, PhCH₂), 4.10 (d, J = –10.6 Hz, 1 H,

PhCH₂), 4.03–3.99 (m, 5 H, 2_C-H, 3_A-H, 5_B-H, 6a_B-H, 6b_B-H),

3.91 (dd, J_3,4= 9.6 Hz, 1 H, 3_D-H), 3.85 (br. s, J_2,3= 2.8 Hz, 1 H,

2_D-H), 3.83–3.66 (m, J_3C,4C= 9.4 Hz, J_5C,6C= 6.1 Hz, 12 H, 2_B-H,

3_B-H, 3_C-H, 3_E-H, 4_A-H, 4_B-H, 5_A-H, 5_C-H, 6a_E-H, OCH₃), 3.63–

3.56 (m, J_5D,6D= 6.1 Hz, 3 H, 5_D-H, 5_E-H, OCH₂), 3.53–3.46 (m,

3 H, 2_E-H, 4_E-H, 6b_E-H), 3.45 (t, J_4,5= 9.4 Hz, 1 H, 4_C-H), 3.41

(t, J_4,5= 9.5 Hz, 1 H, 4_D-H), 3.33–3.28 (m, 1 H, OCH₂), 3.18–3.11

(m, 2 H, CH₂NH), 1.56–1.43 (m, 4 H, CH₂), 1.38–1.29 (m, 2 H,

CH₂), 1.36 (d, J_5,6= 6.2 Hz, 3 H, 6_A-H), 1.35 (d, 3 H, 6_C-H), 1.30

(d, 3 H, 6_D-H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 169.9, 168.7 (2

C, CO), 158.0 (NHCOCF₃), 156.3 (OCONH), 115.7 (NHCOCF₃),

101.6 (C-1_B, J_C,H= 160.8 Hz), 99.3 (C-1_C), 98.6 (C-1_D), 97.8 (C-

1_A), 81.4 (C-4_B), 80.3 (C-4_C), 80.2 (C-4_A), 80.0 (C-4_D), 78.3 (3 C,

C-2_C, C-3_A, C-3_B), 77.7 (C-3_D), 76.7 (C-3_C), 76.5 (C-2_D), 75.7

(PhCH₂), 75.5 (PhCH₂), 75.0 (PhCH₂), 74.7 (PhCH₂), 74.5

(PhCH₂), 74.0 (2 C, PhCH₂), 73.8 (PhCH₂), 73.5 (PhCH₂), 73.3

(PhCH₂), 73.0 (PhCH₂), 70.8 (C-5_B), 69.6 (C-2_A), 69.3 (C-6_B), 68.1

(C-5_C), 67.7 (C-5_A), 67.6 (C-5_D), 67.3 (OCH₂), 66.5 (OCOCH₂Ph),

56.8 (C-2_B), 52.5 (OCH₃), 41.0 (CH₂NH), 29.7 (CH₂), 29.3 (CH₂),

23.5 (CH₂), 18.2, 18.1, 17.7 (3 C, C-6_A, C-6_C, C-6_D).

C₁₃₁H₁₄₁F₃N₂O₂₈(2248.56): calcd. C 69.98, H 6.32, N 1.25; found

C 69.81, H 6.25, N 1.29.

Phenyl (2-O-Benzoyl-3,4,-di-O-benzyl-α-

(1Ǟ3)-[3,4,6-tri-O-benzyl-2-O-(2-methoxycarbonylbenzyl)-α-

pyranosyl-(1Ǟ4)]-6-O-benzyl-2-deoxy-1-thio-2-trifluoroacetamido-

β- -glucopyranoside (26): A mixture of 25 (0.25 g, 0.24 mmol) and

-rhamnopyranosyl)-

D-gluco-

15 (0.17 g, 0.29 mmol) in CH₂Cl₂(12 mL) was cooled under argon

to –10 °C and stirred for 10 min. TMSOTf (ca. 6 µL, 33 µmol) was

successively added. The mixture was stirred for 20 min, neutralized

by addition of triethylamine, diluted with CH₂Cl₂, washed with

saturated aqueous NaHCO₃solution, water, dried and concen-

trated. Chromatography (toluene/ethyl acetate, 15:1) of the residue

gave 26 (0.25 g, 71%) as a colorless foam. [α]²_D⁰= +22.3 (c = 1.0,

CHCl₃). H NMR (400 MHz, CDCl₃): δ = 5.56 (dd, J_2,3= 3.2 Hz,

1 H, 2_A-H), 5.45 (d, J_1,2= 9.9 Hz, 1 H, 1_B-H), 5.18 (d, J_1,2

3.6 Hz, 1 H, 1_E-H), 5.00 (br. s, J_1,2= 1.7 Hz, 1 H, 1_A-H), 4.85 (d,

J = –12.2 Hz, 1 H, PhCH₂), 4.82 (d, J = –11.6 Hz, 1 H, PhCH₂),

4.78 (d, J = –11.2 Hz, 1 H, PhCH₂), 4.76 (d, J = –10.7 Hz, 1 H,

PhCH₂), 4.70 (d, J = –12.2 Hz, 1 H, PhCH₂), 4.63 (d, J = –12.2 Hz,

1 H, PhCH₂), 4.58 (d, J = –10.7 Hz, 1 H, PhCH₂), 4.57 (d, J =

–10.8 Hz, 1 H, PhCH₂), 4.55 (s, 1 H, PhCH₂), 4.51 (d, J =

–12.2 Hz, 1 H, PhCH₂), 4.50–4.42 (m, 3 H, PhCH₂), 4.40 (d, J =

–12.0 Hz, 1 H, PhCH₂), 3.99–3.88 (m, 6 H, 4_B-H, 5_B-H, 6a_B-H,

OCH₃), 3.80–3.75 (m, 4 H, 3_B-H, 5_A-H, 6a_E-H, 6b_B-H), 3.70–3.62

(m, 4 H, 2_B-H, 3_E-H, 5_E-H, 6b_E-H), 3.55–3.50 (2 H, 2_E-H, 4_E-H),

3.50 (t, J_4,5= 9.5 Hz, 1 H, 4_A-H), 3.43 (dd, J_3,4= 9.4 Hz, 1 H, 3_A-

H), 1.23 (d, J_5,6= 6.3 Hz, 3 H, 6_A-H). ¹³C NMR (100.6 MHz,

CDCl₃): δ = 168.7, 166.5 (2 C, CO), 157.8 (NHCOCF₃), 115.4

(NHCOCF₃), 100.9 (C-1_E), 98.8 (C-1_A, J_C,H= 171.7 Hz), 83.9 (C-

1_B), 81.6 (C-3_E), 80.8 (2 C, C-2_E, C-3_B), 79.8 (2 C, C-4_A, C-4_B),

79.3 (C-5_E), 77.4 (2 C, C-3_A, C-4_E), 76.1 (PhCH₂), 75.7 (PhCH₂),

75.5 (PhCH₂), 74.6 (PhCH₂), 73.9 (PhCH₂), 73.3 (PhCH₂), 71.3

(C-5_B), 71.6 (PhCH₂), 70.0 (C-2_A), 69.5 (C-6_B), 68.9 (C-6_E), 68.5

5-Aminopentyl (α-

osyl)-(1Ǟ3)-[α- -glucopyranosyl-(1Ǟ4)]-(2-acetamido-2-deoxy-β-

glucopyranosyl)-(1Ǟ2)-α- -rhamnopyranoside (28): Compound 24

L-Rhamnopyranosyl)-(1Ǟ3)-(α-L-rhamnopyran-

D-

(70 mg, 31 µmol) was dissolved in MeOH (4 mL), aqueous NaOH

solution (1 , 1 mL) was added, the solution was stirred for 16 h,

neutralized with ion exchange resin (H⁺form), filtered and concen-

trated by repeated coevapoartion with toluene. The crude product

was dissolved in MeOH (3 mL), cooled to 0 °C and treated with

Ac₂O (300 µL) for 2 h. The mixture was then concentrated and

coevaporated with methanol. The residue was redissolved in

MeOH (4 mL), AcOH (3 drops) and Pd(OH)₂(20% on charcoal,

ca. 20 mg) were added and stirred under H₂at room temp. for 4 d.

Filtration of the mixture, concentration and chromatography of the

residue with water on Bio Gel P2 and lyophilization of carbo-

hydrate-containing fractions afforded 28 (23 mg, 81%). [α]²_D⁰= –8.6

(c = 1.0, H₂O). ¹³C NMR (100.6 MHz, D₂O): δ = 175.1 (CO), 102.3

(C-1_D), 102.1 (C-1_B), 101.5 (C-1_A), 100.5 (C-1_C), 100.0 (C-1_E), 82.0

(C-3_B), 80.7 (C-4_B), 79.2, 79.1 (2 C, C-2_C, C-3_A), 72.8, 72.7 (1 C, 2

C, C-3_E, C-4_C, C-4_D), 72.3 (C-4_A), 71.9 (C-2_E), 71.2 (2 C, C-5_B,

OCH₂), 71.1 (C-2_A), 70.8 (2 C, C-2_D, C-3_D), 70.4, 70.3 (2 C, C-3_C,

C-4_E), 70.0 (C-5_A), 69.6, 69.5, 69.4 (3 C, C-5_C, C-5_D, C-5_E), 61.4,

61.1 (2 C, C-6_B, C-6_E), 55.6 (C-2_B), 39.7 (CH₂NH), 28.4, 26.7 (2

C, CH₂), 22.6 (COCH₃), 22.4 (CH₂), 17.3, 17.1 (2 C, 1 C, C-6_A,

(C-5_A), 55.2 (C-2_B), 52.6 (OCH₃), 17.8 (C-6_A). C₈₄H₈₄F₃NO₁₇

(1468.65): calcd. C 68.70, H 5.77, N 0.95, S 2.18; found C 68.73,

H 5.69, N 1.01, S 2.09.

5-[(Benzyloxycarbonyl)amino]pentyl (2-O-Benzoyl-3,4-di-O-benzyl-

α-

carbonylbenzyl)-α-

trifluoroacetamido-β-

-rhamnopyranosyl)-(1Ǟ2)-3,4-di-O-benzyl-α-

-rhamnopyranosyl)-(1Ǟ3)-[3,4,6-tri-O-benzyl-2-O-(2-methoxy-

-glucopyranosyl-(1Ǟ4)]-(6-O-benzyl-2-deoxy-2-

-glucopyranosyl)-(1Ǟ2)-(3,4-di-O-benzyl-α-

-rhamnopyranoside

(27): NIS (24 mg, 107 µmol) and TMSOTf (ca. 9 µL, 51 µmol) were

added under argon to a cooled mixture (–20 °C) of 26 (150 mg,

102 µmol), 13 (91 mg, 102 µmol) and molecular sieves (4 Å) in

CH₂Cl₂(7 mL). The suspension was stirred for 35 min, neutralized

with triethylamine, diluted with CH₂Cl₂, filtered, washed with

2628

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2618–2630

Synthesis of Pentasaccharide Fragments

FULL PAPER

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D₂O): δ = 175.4 (CO), 102.3 (C-1_B), 101.5 (C-1_A), 101.3 (C-1_C),

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C, C-2_C, C-2_D), 73.1, 73.0 (2 C, C-4_C, C-4_D), 72.7 (C-3_E), 72.4 (C-

4_A), 72.0 (C-2_E), 71.2 (OCH₂), 70.9 (2 C, C-5_B, C-5_C), 70.6 (2 C,

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17.1, 17.0 (1 C, 2 C, C-6_A, C-6_C, C-6_D). C₃₇H₆₆N₂O₂₃(906.94):

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