Differently glycosidated 2-amino-2-deoxy-D-glucopyranosiduronic acids as building blocks in peptide synthesis

Helvetica Chimica Acta Vol. 88 (2005)

2375

Differently Glycosidated 2-Amino-2-deoxy-d-glucopyranosiduronic Acids as

Building Blocks in Peptide Synthesis¹)

by Andreas Kyas and Martin Feigel*

Fakult‰t f¸r Chemie, Ruhr-Universit‰t Bochum, Universit‰tsstrasse 150, D-44780 Bochum

(fax: 49-(0)2343214497; e-mail: feigel@indi-f.nsc.ruhr-uni-bochum.de)

Seven differently glycosidated sugar amino acids (SSAs) derived from glucosamine have been prepared.

Following standard solution-phase peptide-coupling procedures, the glycosidated 2-amino-2-deoxy-d-glucopyr-

anosiduronic acids were condensed with natural amino acids to furnish useful heterodi- and -trimeric building

blocks to be used in peptide synthesis. Combinations of these building blocks yielded hetero-oligomeric peptides

with two sugar amino acid units in different distances to each other. These were prepared to evaluate the

influence of glycosidic side chains on the peptide backbone. Conformations of selected examples were examined

by means of ROESY spectroscopy in combination with molecular dynamics (MD) simulations and circular-

dichroism (CD) studies.

Introduction. Artificial building blocks for the synthesis of artificial peptides have

gained widespread interest. Sugar amino acids (SAAs) constitute a very interesting

class amongst artificial building blocks, offering attractive features like mimicking of

carbohydrate structures, modification of polarity, introduction of stereochemically

defined H-bond donors, and introduction of conformationally rigid elements [1 13].

The majority of studies published so far have focused on the conformational influence

of pyranoid and furanoid rings bearing carboxyl and amine groups at different

positions. The diversifying possibilities of different functionalization at the anomeric C-

atom have not been explored so far, although similar approaches to broaden the

synthetic range have been suggested [14][15]. Beside the glycosyl nucleic acids

developed in the groups of Goodnow and Tam [16 18], little use has been made of the

possibility to achieve a spectrum of diverse building blocks simply by varying the

glycosyl moiety of the sugar amino acids. This paper reports an optimized synthetic

route of known reactions to prepare a variety of differently glycosidated alkyl 2-amino-

2-deoxy-d-glucopyranosiduronic acids (see Table below), and demonstrates their use in

the synthesis of artificial peptides.

Results and Discussion. The synthetic approach to alkyl 2-{[(benzyloxy)carbo-

nyl]amino}-2-deoxy-b-d-glucopyranosiduronic acids is summarized in the Scheme

below. Starting from glucosamine hydrochloride (1), 1,3,4,6-tetra-O-acetyl-2-{[(benzyl-

oxy)carbonyl]amino}-2-deoxy-b-d-glucopyranose (2) was prepared in anomerically

pure form using the anchimeric influence of the temporary anisylidene protecting

group. Compound 2 is a starting material for the synthesis of glycosyl halides, glycosyl

1

)

Part of this work was presented at the 11th European Carbohydrate Symposium, Lisbon, Portugal,

September 2 7, 2001 (PA082).

¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

2376

Helvetica Chimica Acta Vol. 88 (2005)

Scheme 1. Synthetic Route to the Differently Glycosidated Alkyl 2-{[(benzyloxy)carbonyl]amino}-2-deoxy-d-

glucopyranosiduronic Acids 10 16

i) Anisaldehyde (1 equiv.), NaOH (1.1. equiv.). ii) Ac₂O, pyridine, r.t., 2 4 h. iii) acetone, HCl (1.1. equiv),

reflux. iv) ZCl (1.5 equiv.), NaHCO₃(2.5 equiv.), CHCl₃/H₂O 1:2, r.t., 3 24 h. v) RÀOH, TMSTf, mol. sieves,

anh. CH₂Cl₂, 48, 15 46 min. vi) 1. Na (s), MeOH, 0.5 3 h; 2. Dowex WX4-100 (H ), evaporation; 3. TEMPO

(cat.), NaClO, NaClO₂, MeCN/Borax (pH 9.0) 1:1.

trichloroacetimidates, or other glycosyl donors, and can be used directly as a glycosyl

donor in Lewis acid catalyzed glycosidation reactions.

With trimethylsilyl 1,1,1-trifluoromethanesulfonate (TMSTf) as a catalyst [19],

various primary and secondary alcohols were introduced as aglycones in good-to-

excellent yields. The alcohols used comprise primary alcohols with branched or

unbranched side chains, unsaturated alcohols, and sterically hindered secondary

alcohols like fenchol or menthol (compounds 3 9; Scheme and Table).

After O-deacetylation following standard procedures, IBX/NaClO₂oxidation, as

well as the usual TEMPO oxidation according to Flitsch and Davis [20], furnished the

desired uronic acids 10 16 (Table). However, these procedures were encumbered by

tedious workup and moderate yields; furthermore, aromatic groups and unsaturated

bonds were not left intact when using the two-phase variant of the TEMPO oxidation.

Therefore, the deacetylated glycosides were oxidized according to a homogenous

variant of the TEMPO oxidation described by Zhao [21], which afforded the

differently glycosidated 2-{[(benzyloxy)carbonyl]amino}-2-deoxy-d-glucopyranosidur-

onic acids in good to excellent yields.

The (benzyloxy)carbonyl-protected (Z-protected) compounds 10 16 can be used

as building blocks for peptide synthesis in solution. In solid-phase peptide synthesis, Z-

protection is unfavorable, owing to the lack of on-bead hydrogenolytic-cleavage

methods. This problem might be overcome by simply altering the amino protection in a

final step; yet another problem is the close distance of unprotected OH and NH₂

groups, giving rise to O- and N-acylation. This problem is worse in solid-phase peptide

synthesis due to the strong activation conditions usually employed, and due to the lack

of monitoring possibilities. Instead of introducing additional protection/deprotection

steps, we decided to react the SAAs in solution to higher building blocks. Flanking the

amino uronic acids I C- and/or N-terminally with standard amino acids yields the di-

and trimeric building blocks II IV (Fig. 1), which enlarges the distance between the

desired coupling sites and the unprotected OH groups.

Helvetica Chimica Acta Vol. 88 (2005)

2377

Table. Total Yields of the Glycosides 3 9 and the Corresponding Alkyl 2-{[(Benzyloxy)carbonyl]amino}-2-

deoxyglucopyranosiduronic Acids 10 16

Glycosyl residue (R)

Acetylated glycoside (yield [%])

Uronic acid (yield [%)]

3 (94)

10 (71 95)

4 (90)

11 (94)

5 (43)

6 (60)

12 (60)

13 (92 99)

7 (91)

14 (53)

b-15 (95)

a-15 (68)

8 (59)

9 (17)

16 (40)

The obvious advantage of this approach is that every single step can be controlled,

and that the products can be readily purified and characterized. With the N-terminally

(II) and C-terminally (III, IV) deprotected compounds, standard peptide coupling

between amino acids is possible.

In a first step, the glycosidated compounds 10 16 were coupled with amino acid

methyl ester hydrochlorides (Gly, Ala or Val) via EDC/HOBt activation to afford the

resulting heterodimeric compounds 17 25 (Fig. 2). The latter can, after appropriate

deprotection, be used as building blocks II and III in peptide synthesis. Following

hydrogenolytic cleavage of the Z-group and coupling with Boc-protected amino acids

2378

Helvetica Chimica Acta Vol. 88 (2005)

Fig. 1. Types of building blocks used forsolution-phase peptide synthesis . All compounds are derived from the

uronic acids 10 16 (type I). Saponification or N-deprotection (Z group) of 17 25 yields the dimeric building

blocks II and III. Coupling of II with Boc-protected amino acids, followed by saponification, leads to the

trimeric building blocks IV.

(EEDQ activation), the Boc- and ester-protected heterotrimeric building blocks 26

32 were obtained (Fig. 2).

To evaluate the feasibility of the building blocks described, peptide oligomers with

two different SAAs moieties were prepared, in which none, one, or two inner amino

acid residues are present, respectively. These compounds were synthesized to evaluate

the influence of sterically demanding aglycones on the coupling behavior of the

building blocks I IV, as well as to study the conformation of the resulting oligomers.

For the synthesis of oligomers 33 35, couplings were performed in solution via

EDC/HOBt or EEDQ activation, with equally good results. The latter method has the

advantage of generating no detectable amounts of O-acylation products, whereas in

EDC/HOBt activation, O-acylation and EDC-adduct formation were observed as side

reactions to some extent. In one case, quantitative 3-O-acylation was observed in EDC/

HOBt-mediated fragment condensation of an amino-deprotected type-II building

block with a trimeric peptide fragment [22] (data not shown). Usually, the slightly

Helvetica Chimica Acta Vol. 88 (2005)

2379

stronger activating EDC/HOBt variant was used for the activation of the uronic acid

COOH group, whereas EEDQ was used for the activation of COOH groups to

predominantly attack the SAA amino group.

Monomeric menthyl ( 5-methyl-2-(1-methylethyl)cyclohexyl) 2-{[(benzyloxy)-

carbonyl]amino}-2-deoxy-b-d-glucopyranosiduronic acid (b-15) was reacted with

amino-deprotected 17 to give b-33 in 41% yield. Two dimeric building blocks,

carboxy-deprotected a-22 and amino-deprotected 17 were condensed to give tetra-

meric a-34 in 17% yield after flash chromatography, the low yield being attributed to

very strong adsorption on normal-phase silica gel. Two trimeric building blocks,

carboxy-deprotected 29 and amino-deprotected 28, were coupled to give the

oligohexamer 35, which was isolated, after reverse-phase HPLC, in 42% yield.

The oligomers 33 35 were fully characterized by NMR and MS. The NMR spectra

of 35 showed two clearly distinguishable sets of signals, referred here as −major× and

−minor× form, which varied in chemical shift d with respect to the linkage region of the

fenchyl (1,3,3-trimethylbicyclo[2.2.1]hept-2-yl) substituent to the carbohydrate

moiety and the N-terminal Boc-d-Phe moiety. As both forms showed equivalently

large coupling constants for the anomeric H-atoms of the fenchyl glycoside, which is

typical for b-anomers, simple anomerization could be ruled out. Judging by ROESY

spectroscopy, the most-likely explanation is sterically restricted rotation of the fenchyl

ring along the glycosidic linkage. A similar set of signals was already present in the

spectra of trimer 29. Racemization of the adjacent Boc-d-Phe residue during the

preparation of 29 was ruled out, as all heterotrimeric components were prepared from

one single batch of Boc-d-Phe-OH, so that contamination by Boc-l-Phe-OH or

racemization during COOH activation should have been observed at least for

compound b-30, bearing both a sterically demanding and optically active aglycone. The

same holds true for the theoretical endo/exo epimerization of the norborneol OH

group, resulting in a different glycoside; a similar behavior should have been observed

in the case of menthol.

For selected compounds, distance information was obtained by ROESY experi-

ments in (D₆)DMSO. Using these information as distance restraints in molecular

dynamics (MD) simulations (MM2, Polak Ribierre conjugate gradient), structures

were derived that suggested a helical conformation. In the case of 34 (Fig. 3) and 35

(Fig. 4), the pyranose planes were found to be twisted against each other by ca. 908.

An ordered conformation of the SAA peptide chain is in accordance with the

circular dichroism (CD) spectra of selected compounds (Fig. 5). The CD curves of the

subunits 28 and 29 are −reproduced× by the CD curves of the larger peptide 35 corrected

by the number of amide bonds adjacent to stereogenic centers. This suggests that the

local environment at the amide bonds is similar in the measured compounds. However,

more-detailed structural information could not be derived, as reference spectra for

oligo-amides of this type are not known.

Conclusions.

Starting from a simple reaction sequence, a set of differently

glycosidated 2-amino-2-deoxy-d-glucopyranosiduronic acids (SAAs), compounds 10

16, were generated. These were coupled with standard amino acids to higher building

blocks, which are well-suited for solution-phase peptide synthesis. The possibility to

generate differently glycosidated SAAs in good yields using reliable reactions on a

2380

Helvetica Chimica Acta Vol. 88 (2005)

Fig. 2. Structures and yields of heterodimeric and heterotrimeric building blocks derived from the corresponding

sugaramino acids

Helvetica Chimica Acta Vol. 88 (2005)

2381

Fig. 2 (cont.)

gram scale should be especially interesting for combinatorial purposes, thus broadening

the repertoire of carbohydrate-based building blocks.

Experimental Part

1. General. Solvents and chemicals were obtained from Acros, J. T. Baker, Biosolve, Fluka, NovaBiochem,

Riedel-de Hae»n, or Sigma-Aldrich in at least synthesis-grade quality. Solvents and alcohols for reactions

performed under anh. conditions were dried according to standard methods, and stored under Ar in the

presence of activated molecular sieves (3 or 4 ä). CH₂Cl₂and DMF used for peptide couplings were obtained

from Biosolve in peptide-synthesis grade. Glycosidation reactions were carried out under anh. conditions under

Ar atmosphere. Reactions were monitored by TLC (pre-coated silica gel plates; Merck 60 F₂₅₄). Chromato-

graphic separations were performed on flash silica gel 32 63 (60ä; ICN Biomedicals). CD Spectra were

recorded in MeOH (Uvasol; Merck) at sample concentrations of 0.4 mm (28, 29) or 0.075 mm (35) on a Jasco

J-715 apparatus in the range of 190 300nm; De values were converted to molar ellipticity [V] with the Jasco

Spectra Analysis V1.0 software. NMR Spectra were recorded on Bruker DPX-200 (200.13 (¹H) or 50.33 MHz

(¹³C)), Bruker DRX-400 (400.13 or 100.61 MHz, resp.), and Bruker DRX-600 (600.13 or 150.90 MHz, resp.) in

2382

Helvetica Chimica Acta Vol. 88 (2005)

Fig. 3. Calculated conformation of 34. NOEs used as geometrical restraints are depicted as arrows, their

intensities being represented in arrow thickness.

CDCl₃, CD₃CN, or (D₆)DMSO; d in ppm, J in Hz. Mass spectra (FAB) were recorded on a VG Instruments

Autospec mass spectrometer, in m/z. Elemental analyses were carried out on a Vario EL (Elementar/Hanau).

2. General Procedures. 2.1. Glycosidation Reactions (GP 1). Glycosidation reactions were performed under

strictly anh. conditions. Compound 2 and 1.1 5.0equiv. of glycosyl acceptor were dissolved in anh. CH ₂Cl₂in

the presence of ground Drierite and ground molecular sieves (3 ä), and stirred at r.t. for ca. 30min. under

continuous Ar flow. Then, 1.1 1.5 equiv. of TMSTf were added dropwise via a Teflon septum. The mixture was

stirred for 30 60min (TLC control), passed through a bed of Celite, and diluted with AcOEt. The filtrate was

extracted with sat. NaHCO₃soln., washed with brine, and dried (Na₂SO₄). After removal of the drying reagent

and concentration under reduced pressure, the crude product was either crystallized from a suitable solvent

(EtOH, AcOEt/hexanes, Et₂O) or subjected to column chromatography (CC).

2.2. Oxidation Reactions (GP 2). Deacetylation was carried out by adding a cat. amount of Na to a soln. or

suspension of the respective acetylated glycoside in anh. MeOH. After a reaction time of 30 180min (TLC

control) at r.t., the resulting clear soln. was neutralized with Dowex 50 WX4-100 (H form), filtered, and

evaporated to dryness. The crude product was usually very pure by NMR and FAB-MS (data not shown) and

was, therefore, processed without further purification. The deacetylation product was dissolved in a 1:1 mixture

of MeCN and Borax buffer (pH 9.0; at least 5 ml of MeCN per mmol of starting material) in the presence of

TEMPO (15 mg). Oxidation solns. A (2.2 equiv. of NaClO₂in 15 ml H₂O per mmol starting material) and B

(9 ml bleach soln. 2 ml sat. NaHCO₃soln. 4 ml brine) were simultaneously added dropwise at 48 (ice bath)

and vigorous stirring. After completed addition, stirring was continued for ca. 30min. Then, the pH of the soln.

was raised to ca. 12 by adding 0.1m aq. NaOH soln. The mixture was extracted with Et₂O, and the org. phase was

washed with 0.1m aq. NaOH soln (2Â). The aq. layers were combined, carefully acidified to pH 1.5 2.0, and

Helvetica Chimica Acta Vol. 88 (2005)

2383

Fig. 4. Calculated major (a) and minor (b) conformations of 35. Arrows indicate backbone NOEs used as

geometrical restraints for MD simulations, which were equivalent for both the major and minor form. In the

MD structures, individual NOEs of the major and minor form are indicated, their intensities being represented

in arrow thickness.

2384

Helvetica Chimica Acta Vol. 88 (2005)

Fig. 5. CD Spectra of 35 and the parent trimeric type-IV building blocks 28 and 29. The corrected (corr.) curve

of 35 represents that of 35 divided by the number of amide bonds adjacent to stereogenic centers (i.e., four).

repeatedly extracted with AcOEt. The org. phase was dried (Na₂SO₄) and evaporated under reduced pressure to

afford the crude products (intensively smelling glassy films), which were precipitated from ether/hexanes.

2.3. Solution-Phase Peptide Coupling. 2.3.1. With EDC/HOBt (GP 3a). The carboxy component (1 equiv.)

and the amino component (1.0 1.3 equiv.) were dissolved in CH ₂Cl₂in the presence of HOBt (1.5 equiv.) and

EDC hydrochloride (1.5 equiv.). After addition of Et(i-Pr)₂N or Et₃N, the mixture was stirred at r.t. for 3 12 h,

concentrated to dryness under reduced pressure, and suspended in AcOEt. The crude product was precipitated

from Et₂O or Et₂O/hexanes.

2.3.2. With EEDQ (GP 3b). The carboxy component (1.0equiv.) and the amino component (1.0 1.3

equiv.) were dissolved in CH₂Cl₂and treated with EEDQ (1.2 1.5 equiv.). After stirring at r.t. for 12 36 h, the

mixture was concentrated under reduced pressure, suspended in AcOEt, and extracted with 10% (w/v) aq. citric

acid soln., sat. NaHCO₃soln., and brine. The org. layer was dried (Na₂SO₄), filtered, and concentrated under

reduced pressure, and the remaining crude product was precipitated from Et₂O or Et₂O/ hexanes.

3. Synthesis of the Glycosyl Donor 2. 3.1. 2-Deoxy-2-{[(4-methoxyphenyl)methylidene]amino}-d-glucopyr-

anose. Glucosamine hydrochloride (1; 20g, 92.77 mmol) was dissolved in 5 n aq. NaOH soln. (20.4 ml,

102.05 mmol; 1.1 equiv.) and treated with anisaldehyde (11.28 ml, 92.77 mmol, 1.0 equiv.). After brief shaking,

the soln. solidified and was kept at 48 overnight. The crystalline slurry was suction-filtered, and rinsed with H₂O

and small portions of Et₂O/hexanes 2 :1 to afford, after drying, a creamy colorless solid (26.64 g, 89.6 mmol) in

97% yield. ¹H-NMR (400 MHz, (D₆)DMSO): 8.11 (s, ArCHN); 7.69 (d, J 8.5, 2 arom. H); 6.99 (d, J 8.5, 2

arom. H); 6.51 (d, J 6.5, 1-OH); 4.90( d, J 5.0, 4-OH); 4.79 (d, J 6.0, 3-OH); 4.70 (dd, J 7.3, 7.3,

HÀC(1)); 4.53 (dd, J 5.8, 5.8, 6-OH); 3.79 (s, MeO); 3.74 (ddd, J 11.5, 5.5, 2.0, HÀC(6)); 3.47 (ddd, J

11.5, 6.3, 6.3, H'ÀC(6)); 3.41 (dd, J 9.5, 9.0, HÀC(3)); 3.23 (ddd, J 9.2, 6.3, 2.0, HÀC(5)); 3.14 (ddd, J 9.0,

9.2, 5.0, HÀC(4)); 2.80( dd, J 8.5, 9.5, HÀC(2)). ¹³C-NMR (100 MHz, (D₆)DMSO): 161.43 (ArÀCHN);

161.23, 129.80, 129.28, 114.07 (arom.); 95.91 (C(1)); 78.34 (C(2)); 77.03 (C(5)); 74.78 (C(3)); 70.56 (C(4)); 61.48

Helvetica Chimica Acta Vol. 88 (2005)

2385

(C(6)); 55.45 (MeO). FAB-MS: 298.1 ([M H] ), 280.1 ([M À H₂O] ). Anal. calc. for C₁₄H₁₉NO₆: C 56.56, H

6.44, N 4.46; found: C 55.93, H 6.25, N 4.49.

3.2. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-{[(4-methoxyphenyl)methylidene]amino}-d-glucopyranose. The

above (Sect. 3.1) compound (26.6 g, 89.47 mmol) was dissolved in anh. pyridine (150ml) and cooled in an ice

bath, and Ac₂O (75 ml) was added in small portions under continuous stirring. The cooling bath was removed,

and the mixture was stirred at r.t. for 2 4 h. After adding toluene, the solvents were removed under reduced

pressure, the remaining oil being repeatedly co-evaporated with toluene. The resulting yellowish solid was

crystallized from EtOH to afford the title compound (31 g, 66.6 mmol) in 72% yield. ¹H-NMR (400 MHz,

(D₆)DMSO): 8.27 (s, ArÀCHN); 7.64 (d, J 8.5, 2 arom. H); 6.98 (d, J 8.5, 2 arom. H); 6.05 (d, J 8.0,

HÀC(1)); 5.43 (dd, J 9.8, 9.8, HÀC(3)); 4.96 (dd, J 9.5, 9.5, HÀC(4)); 4.26 (m, HÀC(5), HÀC(6)); 4.01

(dd, J 12, 2, H'ÀC(6)); 3.78 (s, MeO of Ar); 3.43 (dd, J 9.8, 8.0, HÀC(2)); 3.28 (s, Ac); 2.0 1 (s, 2 Ac); 1.97 (s,

Ac). ¹³C-NMR (100 MHz, (D₆)DMSO): 170.14 (6-OCOMe); 169.54 (4-OCOMe); 169.08 (3-OCOMe); 168.68

(1-OCOMe); 164.57 (ArÀCH N); 161.98, 130.03, 128.41, 114.34 (arom.); 92.69 (C(1)); 72.51 (C(3)); 72.37

(C(2)); 71.69 (C(5)); 68.00 (C(4)); 61.81 (C(6)); 55.51 (MeO of Ar); 20.64 (OCOMe); 20.57 (2 OCOMe); 20.31

(OCOMe). FAB-MS: 488.0([ M Na] ), 466.0([ M H] ), 406.0 ([M À Ac] ), 346.0([ M À 2Ac] ), 286.0

([M À 3Ac] ). Anal. calc. for C₂₂H₂₇NO₁₁: C 56.77, H 5.85, N 3.01; found: C 56.53, H 5.89, N 2.89.

3.3. 1,3,4,6-Tetra-O-acetyl-b-d-glucosamine Hydrochloride. The above (Sect. 3.2) compound (20g,

42.97 mmol) was dissolved in hot acetone, and treated with conc. HCl (3.8 ml, 1.1 equiv.) under vigorous

stirring. The immediately solidifying mass was cooled to r.t., stirred with Et₂O/hexanes, and kept overnight at 48.

After suction-filtration, the crystalline mass was washed with cold Et₂O/hexanes and then hexanes to yield a

colorless solid (16.5 g, 42.90mmol) in nearly quant. yield. ¹H-NMR (400 MHz, (D₆)DMSO): 5.54 (d, J 8.5,

HÀC(1)); 5.04 (dd, J 9.8, 9.8, HÀC(3)); 4.80( dd, J 9.5, 9.5, HÀC(4)); 4.14 (dd, J 12.8, 5.3, HÀC(6));

3.94 (m, H'ÀC(6), HÀC(5)); 2.77 (dd, J 10.0, 8.5, HÀC(2)); 2.10( s, Ac); 1.98 (s, 2 Ac); 1.95 (s, Ac); the signal

of the NH₂group was broadened due to exchange with water. ¹³C-NMR (100 MHz, (D₆)DMSO): 94.7 (C(1));

74.56 (C(3)); 71.53 (C(5)); 68.49 (C(4)); 62.43 (C(6)); 55.12 (C(2)); 20.84 (OCOMe); 20.62 (2 OCOMe); 20.53

(OCOMe). FAB-MS: 384.3 ([M H] ), 348.2 ([M À Cl] ), 370.2 ([M À Cl Na] ), 289.1 ([M À Cl À Ac] ).

Anal. calc. for C₁₄H₂₂ClNO₉: C 43.81, H 5.78, N 2.91; found: C 40.94, H 6.33, N 4.29.

3.4. 1,3,4,6-Tetra-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranose (2). The above

(Sect. 3.3) compound (7.7 g, 20mmol) was dissolved in CHCl ₃(40ml) and H ₂O (80ml) in the presence of

solid NaHCO₃(2.5 equiv.) and benzylchlorocarbonate (ZCl; 1.5 equiv.). The mixture was stirred for 3 24 h,

while maintaining the pH at 8.0, until TLC showed the disappearance of the starting material. The mixture was

acidified to pH 1.5 2.0, and then extracted several times with CHCl₃. The combined org. layers were washed

with diluted HCl, sat. NaHCO₃soln., and brine, dried (Na₂SO₄), and concentrated in vacuo. The remaining

creamy-colorless product was crystallized from cyclohexane to yield 2 as a colorless solid (8.03 g) in 83% yield.

¹H-NMR (600 MHz, (D₆)DMSO): 7.44 (d, J 8.7, NH); 7.34 (m, 2 arom H of Z); 7.28 (m, 3 arom. H of Z); 5.69

(d, J 8.5, HÀC(1)); 5.16 (dd, J 9.7, 9.5, HÀC(3)); 5.03 (d, J 12.6, CH₂of Z); 4.88 (dd, J 9.7, 9.7,

HÀC(4)); 4.19 (dd, J 12.3, 4.3, HÀC(6)); 3.98 (d, J 12.3, H'ÀC(6)); 3.67 (m, HÀC(5)); 3.67 (m, HÀC(2));

1.99 (s, 2 Ac); 1.96 (s, Ac); 1.86 (s, Ac). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.03 (OCOMe); 169.52

(OCOMe); 169.28 (OCOMe); 155.92 (CO of Z); 137.19, 128.40, 127.85, 127.47 (arom.); 91.98 (C(1)); 72.42

(C(3)); 71.67 (C(5)); 68.25 (C(4)); 65.49 (CH₂of Z); 61.58 (C(6)); 54.31 (C(2)); 20.51 (OCOMe); 20.50

(OCOMe); 20.43 (OCOMe); 20.30 (OCOMe). FAB-MS: 504.2 ([M Na] ), 481.2 (M ), 422.2 ([M À Ac] ).

Anal. calc. for C₂₂H₂₇NO₁₁: C 54.88, H 5.65, N 2.91; found: C 54.68, H 5.75, N 2.85.

4. Preparation of Glycosides 3 16. 4.1. 3-Methylbutyl 3,4,6-Tri-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-

2-deoxy-b-d-glucopyranoside (3). Compound 2 (2.006 g, 4.17 mmol) was treated with isoamyl alcohol (2.27 ml,

20.8 mmol, 5 equiv.) according to GP 1. The crude product was crystallized from EtOH to yield 3 (2.002 g) in

94.4% yield as a colorless solid. ¹H-NMR (400 MHz, (D₆)DMSO): 7.25 (m, 5 arom H); 4.94 (m, CH₂of Z,

HÀC(5)); 4.74 (dd, J 9.5, 9.5, HÀC(4)); 4.47 (d, J 8.0, HÀC(1)); 4.10( dd, J 12.1, 4.5, HÀC(6)); 3.93 (dd,

J 12.1, 2.0, H'ÀC(6)); 3.67 (m, HÀC(3), 1 H of isoamyl); 3.37 (m, HÀC(2), 1 H of isoamyl)); 1.93 (s, Ac);

1.88 (s, Ac); 1.78 (s, Ac); 1.54 (dq, J 20, 6.7, 1 H of isoamyl); 1.28 (ddd, J 20, 13, 7, 2 H of isoamyl); 0.75 (2d,

J 6.7, 2 Me of isoamyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 170.15 (OCOMe); 169.66 (OCOMe); 169.40

(OCOMe); 156.00 (NCOOBn); 137.33, 128.40, 127.83, 127.46 (arom.); 100.62 (C(1)); 72.88 (C(5)); 70.80 (C(3));

68.86 (C(4)); 67.53 (1 C of isoamyl); 65.31 (CH₂of Z); 61.97 (C(6)); 55.39 (C(2)); 37.89 (1 C of isoamyl); 24.35

(1 C of isoamyl); 22.54, 22.36 (2 Me of isoamyl); 20.60 (OCOMe); 20.51 (OCOMe); 20.40 (OCOMe). FAB-MS:

532.2 ([M Na] ), 510.2 ([M H] ), 422.1 ([M À isoamyl] ). Anal. calc. for C₂₅H₃₅NO₁₀: C 58.93, H 6.92, N

2.75; found: C 58.65, H 7.14, N 2.71.

2386

Helvetica Chimica Acta Vol. 88 (2005)

4.2. Prop-2-enyl 3,4,6-Tri-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranoside (4).

Compound 2 (1.0g, 2.08 mmol) was treated with allyl alcohol (355 ml, 5.2 mmol, 2.5 equiv.) according to

GP 1. The crude product was precipitated from Et₂O to yield 4 (896.5 mg) as a colorless solid in 90% yield.

¹H-NMR (600 MHz, (D₆)DMSO): 7.34 (m, NH, 2 arom H of Z); 7.29 (m, 3 arom. H of Z); 5.83 (ddd, J 17.1,

10.5, 5.2, 1 H of allyl); 5.22 (dd, J 17.1, 1.5, 1 H of allyl); 5.10( dd, J 10.5, 1.1, 1 H of allyl); 5.05 (m, 1 H of CH₂

of Z, HÀC(3)); 4.99 (d, J 12.5, 1 H of CH₂of Z); 4.82 (dd, J 9.7, 7.6, HÀC(4)); 4.60( d, J 8.0, HÀC(1));

4.21 (dd, J 13.2, 5.2, 1 H of allyl); 4.17 (br. d, J 12.3, HÀC(6)); 4.02 (m, 1 H of allyl, H'ÀC(6)); 3.75 (m,

HÀC(5)); 3.50( dd, J 9, 9, 8, HÀC(2)); 2.01 (s, Ac); 1.95 (s, Ac); 1.85 (s, Ac). ¹³C-NMR (150MHz,

(D₆)DMSO): 170.13 (OCOMe); 169.62 (OCOMe); 169.37 (OCOMe); 155.90(C O of Z); 137.32 (arom.),

134.33 (allyl); 128.39, 127.81, 127.48 (arom.); 116.70 (allyl); 100.00 (C(1)); 72.84 (C(3)); 70.85 (C(5)); 69.42

(C(6)); 68.83 (C(4)); 65.33 (CH₂of Z); 61.92 (allyl); 55.41 (C(2)); 20.59 (OCOMe); 20.49 (OCOMe); 20.37

(OCOMe). FAB-MS: 502.2 ([M Na] ), 480.2 ([M H] ), 422.2 ([M À allyl] ).

4.3. 2-Phenylethyl 3,4,6-Tri-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranoside (5).

Compound 2 (2.5 g, 5.2 mmol) was reacted with 2-phenylethanol (653 ml, 5.45 mmol 1.05 equiv.) according to

GP 1 for 15 min. Standard workup and crystallization from i-PrOH yielded 5 (1.2 g) in 43% yield as a colorless

solid. ¹H-NMR (600 MHz, (D₆)DMSO): 7.40 7.26 ( m, 5 arom. H of Z, NH); 7.26 7.13 (m, 5 arom. H of

phenethyl); 5.07 (m, 1 H of CH₂of Z, HÀC(3)); 4.97 (d, J 12.6, 1 H of CH₂of Z); 4.82 (dd, J 9.7, 9.3,

HÀC(4)); 4.63 (d, J 7.9, HÀC(1)); 4.17 (dd, J 12.3, 4.7, HÀC(6)); 4.03 (dd, J 12.3, 1.7, H'ÀC(6)); 3.89

(ddd, J 9.8, 6.9, 1 H of phenethyl); 3.77 (br. d, HÀC(5)); 3.67 (m, J 9.8, 6.9, 1 H of phenethyl); 3.49 (ddd,

J 9.3, 7.9, HÀC(2)); 2.79 (ddd, J 10, 6.9, 6.9, 2 H of phenethyl); 2.0 (s, OCOMe); 1.95 (s, OCOMe); 1.84 (s,

OCOMe). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.9 (OCOMe); 170.4 (OCOMe); 170.1 (OCOMe); 156.7

(CO of Z); 139.5, 138.1, 129.7, 129.2, 129.0, 128.6, 128.2, 126.9 (arom.); 101.1 (C(1)); 73.7 (C(3)); 71.9 (C(5));

71.3 (CH₂of phenethyl); 69.5 (C(4)); 66.1 (CH₂of Z); 63.1 (C(6)); 56.1 (C(5)); 36.2 (CH₂of phenethyl); 21.4

(3 OCOMe). FAB-MS: 566.2 ([M Na] ), 544.3 ([M H] ), 422.2 ([M À phenethyl] ). Anal. calc. for

C₂₈H₃₃NO₁₀: C 61.87, H 6.12, N 2.58; found: C 61.85, H 6.86, N 2.50.

4.4. Hexyl 3,4,6-Tri-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranoside (6). Com-

pound 2 (2.5 g, 5.2 mmol) was reacted with hexan-1-ol (973 ml, 7.8 mmol, 1.5 equiv.) according to GP 1 for

30min. Workup furnished a colorless solid, which was crystallized from EtOH to yield the title compound

(1.57 g) in 60.4% yield. ¹H-NMR (600 MHz, (D₆)DMSO): 7.4 7.3 (m, NH, 2 arom. H of Z); 7.29 (br. dd, 2 arom.

H of Z); 5.06 (dd, J 10 , 10 , HÀC(3)); 5.04 (d, J 12.8, 1 H of CH₂of Z); 4.96 (d, J 12.8, 1 H of CH₂of Z);

4.81 (dd, J 10 , 10 , HÀC(4)); 4.54 (d, J 8.3, HÀC(1)); 4.16 (dd, J 12, 5, HÀC(6)); 4.0( dd, J 12, 1.5,

H'ÀC(6)); 3.75 (br. m, HÀC(5)); 3.69 (ddd, J 9.8, 6.5, 6.5, 1 H of hexyl); 3.45 (br. ddd, J 9.2, 9.2, 8.3,

HÀC(2)); 3.42 (ddd, J 9.8, 6.5, 6.5, 1 H of hexyl); 2.00 (s, Ac); 1.95 (s, Ac); 1.85 (s, Ac); 1.45 (ddd, J 14, 7, 6.5,

CH₂of hexyl); 1.23 (br. m, 6 H of hexyl); 0.83 (dd, J 7, 7, Me of hexyl). ¹³C-NMR (150MHz, (D ₆)DMSO):

170.1, 169.6, 169.4 (3 OCOMe); 155.9 (CO of Z); 137.3, 128.4, 127.8, 127.4 (arom. C of Z); 100.6 (C(1)); 72.9

(C(3)); 70.8 (C(5)); 69.1, (CH₂of hexyl); 68.9 (C(4)); 65.3 (CH₂of Z); 62.0 (C(6)); 55.4 (C(2)); 31.0, 29.0, 25.0,

22.1 (4 CH₂of hexyl); 20.6, 20.5, 20.4 (3 OCOMe); 14.0(Me of hexyl). FAB-MS: 546.2 ([ M Na] ), 524.2

([M H] ), 422.1 ([M À hexyl] ). Anal. calc. for C₂₆H₃₇NO₁₀: C 59.64, H 7.12, N 2.68; found: C 59.35, H 7.41, N

2.60.

4.5. 1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl 3,4,6-Tri-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-2-deoxy-b-

d-glucopyranoside (7). Compound 2 (1.62 g, 3.37 mmol) was reacted with (1R)-endo-()-fenchol (624 mg,

4.05 mmol, 1.2 equiv.) according to GP 1 for 45 min. Crystallization from EtOH yielded 7 (1.14 g) in 58.6% yield

as colorless needles. ¹H-NMR (600 MHz, (D₆)DMSO): 7.35 (m, 2 arom. H of Z, NH); 7.28 (m, 3 arom. H of Z);

5.11 (dd, J 10.1, 10.1, HÀC(3)); 4.99 (s, CH₂of Z); 4.77 (dd, J 9.6, 9.6, HÀC(4)); 4.41 (d, J 8.1, HÀC(1));

4.07 (s, CH₂(6)); 3.71 (br. m, HÀC(5)); 3.48 (ddd, J 10, 10, 8.1, HÀC(2)); 3.01 (s, 1 H of fenchyl); 1.98, 1.96,

1.88 (3s, 3 Ac); 1.59 (s, 1 H of fenchyl); 1.54 (br. d, 2 H of fenchyl); 1.40( d, 1 H of fenchyl); 1.31 (m, 1 H of

fenchyl); 1.01 (d, 1 H of fenchyl); 0.97, 0.94 (2s, 2 Me of fenchyl); 0.82 (m, 1 H of fenchyl); 0.76 (s, Me of

fenchyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.07, 169.67, 169.52 (3 OCOMe); 155.98 (CO of Z), 137.25,

128.39, 127.91, 127.58 (arom.); 102.75 (C(1)); 93.75 (C(2) of fenchyl); 72.52 (C(3)); 70.54 (C(5)); 69.33 (C(4));

65.36 (CH₂of Z); 62.38 (C(6)); 55.76 (C(2)); 48.80(C(4) of fenchyl); 47.62 (C(1) of fenchyl); 40.24 (C(7) of

fenchyl); 29.53 (3-Me of fenchyl); 25.84 (C(5) of fenchyl); 25.40(C(6) of fenchyl); 21.58 (1-Me of fenchyl);

20.62, 20.56, 20.49 (3 OCOMe); 19.31 (3-Me of fenchyl). FAB-MS: 598.3 ([M Na] ), 576.3 ([M H] ), 422.2

([M À fenchyl] ). Anal. calc. for C₃₀H₄₁NP₁₀: C 62.59, H 7.18, N 2.43; found: C 65.52, H 7.64, N 2.38.

4.6. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 3,4,6-Tri-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-

2-deoxy-b-d-glucopyranoside (8). Compound 2 (3 g, 6.22 mmol) was reacted with (2.917 g, 18.67 mmol,

Helvetica Chimica Acta Vol. 88 (2005)

2387

3 equiv.) of (À)-menthol and TMSTf (1.2 equiv.)²) according to GP 1 for 45 min. Crystallization from EtOH

yielded 8 (3.28 g) in 91% yield. ¹H-NMR (400 MHz, (D₆)DMSO): 7.31 (m, 4 arom. H of Z, NH); 5.10( dd, J

9.8, 9.8, HÀC(3)); 5.01 (s, CH₂of Z); 4.78 (dd, J 9.8, 9.8, HÀC(4)); 4.62 (d, J 8.0, HÀC(1)); 4.09 (dd, J

12, 5.5, HÀC(6)); 3.99 (dd, J 12, 2.3, H'ÀC(6)); 3.72 (ddd, J 9.8, 5.5, 2.3, HÀC(5)); 3.38 (dd, J 8.0, 9.8,

HÀC(2)); 3.31 (m, 1 H of menthyl); 2.15 (m, 1 H of menthyl); 2.03 (br. d, 1 H of menthyl); 1.97, 1.95, 1.85 (3s,

3 Ac); 1.56 (br. dt, 2 H of menthyl); 1.29 (br. m, 1 H of menthyl), 1.06 (br. dd, 1 H of menthyl); 0.91 (m, 1 H of

menthyl); 0.82 (br. d, 2 Me of menthyl); 0.69 (d, Me of menthyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 170.09,

169.66, 169.47 (3 OCOMe); 155.95 (CO of Z); 137.42, 128.37, 127.81, 127.50(arom.); 98.83 (C(1)); 78.20(C(1)

of menthyl); 72.85 (C(3)); 70.58 (C(5)); 69.26 (C(4)); 65.21 (CH₂of Z); 62.41 (C(6)); 55.56 (C(2)); 47.30(C(2)

of menthyl); 40.34 (C(6) of menthyl); 33.98 (C(4) of menthyl); 30.94 (C(5) of menthyl); 24.70 (Me₂CH); 22.71

(C(3) of menthyl); 22.26 (Me of menthyl); 20.91 (Me of menthyl); 20.55 (2 OCOMe); 20.44 (OCOMe); 15.47

(Me of menthyl). FAB-MS: 578.2 ([M H] ), 600.2 ([M Na] ), 422.1 ([M À menthyl] ), 156 (menthyl ).

Anal. calc. for C₃₀H₄₃NO₁₀: C 62.38, H 7.5, N 2.42; found: C 62.14, H 7.7, N 2.31.

4.7. Methyl 6-O-(3,4,6-Tri-O-acetyl-2-{[(benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranosyl)-2,3,4-

tri-O-benzyl-a-d-glucopyranoside (9). Compound 2 (523 mg, 1.09 mmol) was reacted with methyl 2,3,4-tri-O-

benzyl-a-d-glucopyranoside (505 mg) and TMSTf (1.5 equiv.) according to GP 1 for 60min. The crude product

was subjected to CC (SiO₂), but the fractions still showed trace impurities of methyl 2,3,4-tri-O-benzyl-a-d-

glucopyranoside. To obtain an anal. sample, a part of the purified material was recrystallized from i-PrOH/

pentane to afford 9 (141 mg ) in 14.6% yield as a colorless solid. ¹H-NMR (600 MHz, (D₆)DMSO): 7.49 (d, J

9.4, 2'-NH); 7.39 7.17 (m, 18 arom. H); 7.13 (m, 2 arom. H); 5.10( dd, J 9.9, 9.9, HÀC(3')); 4.98 (d, J 12.5,

1 H of CH₂of Z); 4.84 (dd, J 9.5, 9.5, HÀC(4')); 4.81 (d, J 11.2, 1 H of CH₂of Bn); 4.77 (m, HÀC(1), 1 H of

CH₂of Z); 4.68 (d, J 11.2, 1 H of CH₂of Bn); 4.65 (m, 3 H of 2 CH₂of Bn); 4.60( d, J 8.3, HÀC(1')); 4.56 (d,

J 10.8, 1 H of CH₂of Bn); 4.2 (dd, J 12, 4.3, HÀC(6')); 3.98 (d, J 12, H'ÀC(6')); 3.95 (d, J 10.4, HÀC(6));

3.77 (m, HÀC(5')); 3.72, (dd, J 9.3, 9.3, HÀC(3)); 3.64 (dd, J 10.4, 3.6, H'ÀC(6)); 3.58 (m, HÀC(5)); 3.53

(ddd, J 9.5, 9.5, 8.5, HÀC(2')); 3.43 (m, HÀC(2), HÀC(4)); 3.25 (s, 1-MeO); 1.99, 1.95, 1.86 (3s, 3 Ac);

¹³C-NMR (150MHz, (D ₆)DMSO): 170.2, 169.7, 169.4 (3 OCOMe); 155.9 (CO of Bn); 139.0, 138.7, 138.6 (3

arom. C of Bn); 136.9 (arom. C of Z); 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6, 127.4 (8 arom. C); 100.9

(C(1')); 97.0(C(1)); 81.3 (C(3)); 79.9 (C(2)); 77.1 (C(4)); 74.7, 74.2 (2 CH of Bn); 72.7 (C(3')); 71.6 (CH₂of

2

Bn); 70.8 (C(5')); 69.3 (C(5)); 68.7 (C(4')); 67.8 (C(6)); 65.6 (CH₂of Z); 61.9 (C(6')); 55.4 (C(2')); 54.7 (1-

MeO); 20.7, 20.6, 20.5 (3 OCOMe). FAB-MS: 908.3 ([M Na] ), 886.3 ([M H] ), 854.3 ([M À MeO] ),

746.2 ([M À MeO À BnO] ), 663.1 ([M À MeO À 2BnO Na] ), 639.1 ([M À MeO À 2BnO] ), 422.1. Anal.

calc. for C₄₈H₅₅NO₁₅¥ H₂O: C 64.04, H 6.58, N 1.52; found: C 64.60, H 6.42, N 1.56.

5. Preparation of Pyranosiduronic Acids 10 16. 5.1. 3-Methylbutyl 2-{[(Benzyloxy)carbonyl]amino}-2-

deoxy-b-d-glucopyranosiduronic Acid (10). Compound 3 (1.03 g) was oxidized with TEMPO according to GP 2.

The remaining crude glassy film became crystalline after prolonged standing at r.t. or by trituration with Et₂O/

pentane. Yield of 10: 1.057 g (92%). ¹H-NMR (400 MHz, (D₆)DMSO): 7.3 (m, 5 arom. H); 7.07 (d, J 8.5,

NH); 4.98 (d, J 12.3, CH₂of Z); 4.29 (d, J 8.0, HÀC(1)); 3.72 (ddd, J 9.4, 6.4, 6.4, 1 H of isoamyl); 3.53 (d,

J 9.0, HÀC(5)); 3.37 (ddd, J 9.4, 6.4, 6.4, 1 H of isoamyl); 3.33 (dd, J 9.0, 9.0, HÀC(4)); 3.30( dd, J 9.0,

8.5, HÀC(3)); 1.62 (ddd, J 6.4, 6.4, 6.4, 1 H of isoamyl); 1.33 (dddd, J 13.6, 6.5, 6.5, 6.5, CH₂of isoamyl);

0.82 (d, J 6.5, Me of isoamyl); 0.81 (d, J 6.5, Me of isoamyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 170.35

(COOH); 156.09 (CO of Z); 137.31 (arom. C); 128.20(3 arom. C); 127.59 (2 arom. C); 101.83 (C(1)); 75.73

(C(5)); 73.49 (C(3)); 72.21 (C(4)); 67.31 (CH₂of Z); 65.15 (C(1) of isoamyl); 57.13 (C(2)); 37.96 (C(2) of

isoamyl); 24.29 (C(3) of isoamyl); 22.54 (Me of isoamyl); 22.25 (Me of isoamyl). FAB-MS: 420.1 ([M Na] ),

398.1 ([M H] ), 310.1 ([M À isoamyl] ). Anal. calc. for C₁₉H₂₇NO₈: C 57.42, H 6.85, N 3.52; found: C 56.37, H

6.83, N 3.49.

5.2. Prop-2-enyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranosiduronic Acid (11). Com-

pound 4 (421.4 mg, 1.2 mmol) was oxidized according to GP 2. Extractive workup and removal of solvents under

reduced pressure yielded 11 (415 mg) in 94% yield as a colorless solid. ¹H-NMR (600 MHz, (D₆)DMSO): 7.34

(br. m, 4 arom. H of Z); 7.29 (m, 1 arom H of Z); 7.1 (br. m, NH); 5.8 (ddd, J 17.4, 10.4, 5.2, 1 H of allyl)); 5.22

(dd, J 17.4, 1.5, 1 H of allyl); 5.1 4.9 (br. m, 4 H, 2 H of allyl, CH₂of Z); 4.35 (d, J 7.5, HÀC(1)); 4.18 (dd,

J 13.6, 4.9, 1 H of allyl); 3.96 (dd, J 13.6, 5.2, 2 H of allyl); 3.54 (d, J 9, HÀC(5)); 3.36 (dd, J 9, 9,

HÀC(4)); 3.3 (br. m, H₂O, HÀC(3), HÀC(2)). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.01 (C(6)); 156.08 (CO

2

)

With 2.0equiv. of TMSTf of a freshly opened (and, therefore, probably more-reactive) batch, and after

prolonged reaction time (3 h), the a-epimer of 8 was isolated quantitatively (data not shown).

2388

Helvetica Chimica Acta Vol. 88 (2005)

of Z); 137.40(arom. C); 134.52 (C(2) of allyl); 128.28, 128.25, 127.61 (3 arom. C); 116.13 (C(3) of allyl); 101.22

(C(1)); 75.84 (C(5)); 73.42 (C(3)); 72.13 (C(4)); 69.12 (C(1) of allyl); 65.08 (CH₂of Z); 57.10(C(2)). FAB-MS:

368.4 ([M H] ), 390.4 ([M Na] ), 310.3 ([M À allyl] ).

5.3. 2-Phenylethyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranosiduronic Acid (12). Com-

pound 5 (839.1 mg, 2.01 mmol) was oxidized according to GP 2. An anal. sample was precipitated from Et₂O to

afford 12 (339 mg) in 39% yield (first crop). Repeated crystallization of the mother liquor afforded two more

crops, amounting to 60% overall yield. ¹H-NMR (600 MHz, (D₆)DMSO): 12.6 (br. s, COOH); 7.44 6.98 (m_c, 5

arom H of phenethyl, 5 arom. H of Z, NH); 5.23 (br. s, OH); 5.0 2 (s, OH, CH₂of Z); 4.38 (d, J 7.4, HÀC(1));

3.86 (ddd, J 9.5, 7, 7, 1 H of phenethyl); 3.59 (ddd, J 9.5, 7, 7, 1 H of phenethyl); 3.56 (d, J 9.3, HÀC(5));

3.36 (dd, J 9.3, 9.3, HÀC(4)); 3.29 (m, HÀC(3)); 3.25 (br. s, H₂O, HÀC(2)); 2.75 (ddd, J 13.9, 7, 7, 2 H of

phenethyl). ¹³C-(NMR) (150MHz, (D ₆)DMSO): 170.2 (C(6)); 156.2 (CO of Z); 138.9 (arom. C of

phenethyl); 137.4 (arom. C of Z); 129.4, 129.0, 128.7, 128.4, 128.2, 127.7, 126.7, 126.1 (8 arom. C); 101.6 (C(1));

76.0(C(5)); 73.6 (C(3)); 72.2 (C(4)); 69.6 (CH of phenethyl); 65.2 (CH₂of Z); 57.1 (C(2)); 35.5 (CH₂of

2

phenethyl). FAB-MS: 454.1 ([M Na] ), 432.1 ([M H] ), 298.1 ([M À Z] ), 310.1 ([M À phenethyl] ).

Anal. calc. for C₂₂H₂₅NO₈¥ H₂O: C 58.79, H 6.06, N 3.12; found: C 59.59, H 6.03, N 3.15.

5.4. Hexyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranosiduronic Acid (13). Compound 6

(1.54 g) was deacetylated according to standard procedures (85% yield; data not shown), and the resulting

product (1.06 g) was oxidized according to GP 2. The org. extract of the acidified aq. layer furnished 13 (1.085 g)

in 98% yield as an off-white foam. ¹H-NMR (600 MHz, (D₆)DMSO): 12.6 (br. s, COOH); 7.33 (m, 4 arom. H of

Z); 7.29 (m, 1 arom H. of Z); 7.08 (br. d, NH); 5.01 (br. m, 2 OH, CH₂of Z); 4.3 (d, J 7, H ÀC(1)); 3.67 (ddd,

J 9.6, 6, 6, 1 H of hexyl); 3.53 (d, J 9.4, HÀC(5)); 3.34 (m, HÀC(4), 1 H of hexyl); 3.29 (br. dd, HÀC(3));

3.19 (br. m, HÀC(2)); 1.42 (ddd, J 13.7, 6.8, 6.8, 2 H of hexyl); 1.32 1.13 (m, 6 H of hexyl); 0.83 (dd, J 6.8,

6.8, Me of hexyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.1 (C(6)); 156.1 (CO of Z); 137.4, 128.3, 127.7, 127.6

(arom. C of Z); 101.8 (C(1)); 75.9 (C(5)); 73.5 (C(3)); 72.2 (C(4)); 68.9 (CH₂of hexyl); 65.1 (CH₂of Z); 57.2

(C(2)); 31.0, 29.1, 25.0, 22.1, 13.9 (4 CH₂and 1 Me of hexyl)). FAB-MS: 412.2 ([M H] ), 434.2 ([M Na] ),

310.1 ([M À hexyl] ). Anal. calc. for C₂₀H₂₉NO₈¥ H₂O: C 55.93, H 7.28, N 3.26; found: C 57.15, H 6.88, N 3.29.

5.5. 1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranosi-

duronic Acid (14). Compound 7 (753 mg, 1.675 mmol) was oxidized according to GP 2. Extractive workup

yielded 14 (0.412 g) in 53% yield. ¹H-NMR (600 MHz, (D₆)DMSO): 7.32 (m, 4 arom. H of Z); 7.29 (m, 1 arom H

of Z); 7.12 (d, J 9.3, NH); 5.23 (br. s, OH); 5.04 (d, J 12.5, 1 H of CH₂of Z); 4.99 (br. s, OH); 4.93 (d, J

12.5, 1 H of CH₂of Z); 4.15 (d, J 8.3, HÀC(1)); 3.49 (d, J 9.5, HÀC(5)); 3.36 (dd, J 9.2, 9.2, HÀC(4));

3.30(br. m, H₂O, HÀC(3)); 3.23 (m, HÀC(2)); 2.95 (s, 1 H of fenchyl); 1.60(br. m, 1 H of fenchyl); 1.57 (br. m,

1 H of fenchyl); 1.53 (br. m, 1 H of fenchyl); 1.39 (d, J 9.4, 1 H of fenchyl); 1.30(br. m, 1 H of fenchyl); 1.00

(m, 1 H of fenchyl); 0.98 (s, Me of fenchyl); 0.89 (s, Me of fenchyl); 0.80 (br. m, 1 H of fenchyl); 0.75 (s, Me of

fenchyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.2 (C(6)); 156.1 (CO of Z); 137.5, 128.3, 127.7, 125.4 (4 arom.

C); 104.0 (C(1)); 93.2 (C(2) of fenchyl); 75.7 (C(5)); 73.3 (C(3)); 72.2 (C(4)); 65.1 (CH₂of Z); 57.6 (C(5)); 48.8

(C(4) of fenchyl); 47.6 (C(1) of fenchyl); 40.6 (C(7) of fenchyl); 29.6 (Me of fenchyl); 25.9 (C(6) of fenchyl);

25.3 (C(5) of fenchyl); 21.7 (Me of fenchyl); 19.4 (Me of fenchyl). FAB-MS: 464.1 ([M H] ), 486.1 ([M

Na] ), 310.0 ([M À fenchyl] ). Anal. calc. for C₂₄H₃₃NO₈¥ H₂O: C 59.61, H 7.71, N 2.90; found: C 59.93, H 8.04,

N 2.84.

5.6. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-b-d-gluco-

pyranosiduronic Acid (b-15). Compound 8 (455.3 mg) was oxidized according to GP 2. Both the Et₂O extract of

the basified aq. phase and the AcOEt extract of the acidified aq. phase contained, as the single product, the title

compound. Yield: 463.5 mg (97%). Colorless foam. ¹H-NMR (400 MHz, (D₆)DMSO): 12.6 (br. s, COOH); 7.3

(m, 5 arom. H of Z); 7.09 (d, J 9.5, NH); 5.09 (d, J 12.5, 1 H of CH₂of Z); 5.05 (br. s, OH); 4.92 (d, J 12.5,

1 H of CH₂of Z); 4.39 (d, J 8.0, HÀC(1)); 3.50( d, J 9.5, HÀC(5)); 3.3 (br. m, H₂O, HÀC(3), HÀC(4), 1 H

of menthyl); 3.09 (m, HÀC(2))); 2.1 (m, 1 H of menthyl); 1.98 (br. d, J 12, 1 H of menthyl); 1.55 (br. d, J

12.8, 2 H of menthyl); 1.3 (m, 1 H of menthyl); 1.04 (m, 1 H of menthyl); 0.9 (dd, J 12.7, 1 H of menthyl); 0.81

(br. d, 2 Me of menthyl); 0.74 (m, 1 H of menthyl); 0.65 (d, J 7, Me of menthyl); 0.63 (br. d, J 12, 1 H of

menthyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 170.2 (C(6)); 156.2 (CO of Z); 137.7, 128.3, 127.7, 127.6 (4 arom.

C); 99.8 (C(1)); 77.7 (C(1) of menthyl); 75.9 (C(5)); 73.6 (C(4)); 72.2 (C(3)); 64.9 (CH₂of Z); 57.5 (C(2)); 47.5

(C(2) of menthyl); 40.4 (C(6) of menthyl); 34.1 (C(4) of menthyl): 30.9 (C(5) of menthyl); 24.7 (Me₂CH of

menthyl); 23.2 (C(3) of menthyl); 22.7 (Me of menthyl); 22.3 (Me of menthyl); 15.6 (Me of menthyl). FAB-

MS: 510.0 ([M 2Na] ), 488.0([ M Na] ), [M À menthyl] ), 310.0. Anal. calc. for C₂₄H₃₅NO₈¥ H₂O: C 59.61,

H 7.71, N 2.90; found: C 59.93, H 8.05, N 2.84.

Helvetica Chimica Acta Vol. 88 (2005)

2389

5.7. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-a-d-gluco-

pyranosiduronic Acid (a-15). Compound a-8 (2.043 g, 4.523 mmol) was oxidized according to GP 2. Extractive

workup yielded the title compound (1.9 g) in 90.5% yield. ¹H-NMR (600 MHz, (D₆)DMSO): 12.45 (br. s,

COOH); 7.35 (m, 4 arom. H of Z); 7.31 (m, 1 arom. H of Z); 7.01 (d, J 7.2, NH); 5.24 (br. s, OH); 5.0 2 (d, J

12.5, 1 H of CH₂of Z); 4.98 (d, J 12.5, 1 H of CH₂of Z); 4.89 (d, J 3.2, HÀC(1)); 4.73 (br. s, OH); 3.93 (d,

J 9, HÀC(5)); 3.47 (dd, J 9, 9, HÀC(3)); 3.38 (dd, J 9, 9, HÀC(4)); 3.34 (m, HÀC(2)); 3.20( m, 1 H of

menthyl); 2.26 (dt, J 6.8, 1 H of menthyl); 2.07 (br. d, J 12.3, 1 H of menthyl); 1.58 (br. d, J 11.3, 1 H of

menthyl); 1.53 (br. d, J 12.7, 1 H of menthyl); 1.35 (m, 1 H of menthyl); 1.18 (m, 1 H of menthyl); 0.95 (d, J

12.3, 1 H of menthyl); 0.88 (m, J 12.7, 1 H of menthyl); 0.83 (d, J 6.8, Me of menthyl); 0.77 (d, J 7, Me of

menthyl); 0.74 (m, 1 H of menthyl); 0.59 (d, J 7; Me of menthyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.9

(C(6)); 156.0(C O of Z); 137.1 (arom. C); 128.4 (arom. CH); 127.9 (arom. CH); 127.9 (arom. CH); 99.3 (C(1));

80.9 (C(1) of menthyl); 72.2 (C(5)); 72.2 (C(4)); 69.8 (C(3)); 65.5 (CH₂of Z); 56.5 (C(2)); 48.4 (C(2) of

menthyl); 42.8 (C(6) of menthyl); 39.9 (C(4) of menthyl); 31.1 (C(5) of menthyl); 24.2 (CH of menthyl); 22.3

(Me of menthyl); 21.2 (C(3) of menthyl); 21.1, 15.6 (2 Me of menthyl). FAB-MS: 510.0 ([M 2Na] ), 488.0

([M Na] ), 310.0 ([M À menthyl] ).

5.8. Methyl 6-O-(2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-b-d-glucopyranuronosyl)-2,3,4-tri-O-benzyl-a-

d-glucopyranoside (16). Compound 9 (269.4 mg, 304 mmol) was deacetylated according to standard procedures.

An anal. sample (data not shown) was purified by precipitation from Et₂O/pentane. The deacetylated product

(230mg, 303 mmol) was oxidized according to GP 2. The org. extract of the acidified aq. layer furnished the title

compound as a colorless solid (170mg crude), which was precipitated from ether/pentane to yield 16 (95 mg) in

1

41% yield. H-NMR (600 MHz, CD₃CN): 7.7 6.9 (m, 20arom. H); 5.72 (br. d, NH); 5.0 1 (d, J 11.7, 1 H of

CH₂of Z); 4.88 (m, 1 H of CH₂of Z, 1 H of CH₂of Bn); 4.78 (d, J 3, HÀC(1)); 4.74 (d, J 11, 1 H of CH₂of

Bn); 4.72 (d, J 10.8, 1 H of CH₂of Bn); 4.66 (s, CH₂of Bn); 4.57 (d, J 10.8, 1 H of CH₂of Bn); 4.45 (d, J

8.1, HÀC(1')); 4.02 (d, J 10.8, HÀC(6)); 3.77 (m, HÀC(5'), HÀC(3)); 3.69 (dd, J 10.8, 3.4, H'ÀC(6)); 3.63

(br. d, HÀC(5)); 3.53 (dd, J 9, 9, HÀC(4')); 3.51 (dd, J 9.4, 9.4, HÀC(4)); 3.45 (m, HÀC(3'), HÀC(2));

3.39 (m, HÀC(2')); 3.31 (s, MeO). ¹³C-NMR (150MHz, CD ₃CN): 170.3 (C(6')), 157.3 (CO of Z); 140.2, 139.8,

139.7 (3 arom. C of Bn); 137.9 (1 arom. C of Bn); 129.4, 129.3, 129.25, 129.2, 128.9, 128.8, 128.6, 128.5, 128.4 (9

arom. C); 102.8 (C(1')); 98.6 (C(1)); 82.5 (C(3)); 81.2 (C(2)); 78.4 (C(4)); 75.9 (CH₂of Bn); 75.5 (CH₂of Bn);

75.2 (C(5')); 74.5 (C(3')); 73.2 (CH₂of Bn); 73.1 (C(4')); 70.5 (C(5)); 68.9 (C(6)); 67.3 (CH₂of Z); 58.3 (C(2'));

55.5 (MeO). FAB-MS: 818.3 ([M 2Na] ), 796.3 ([M Na] ), 758.9 ([M À MeO H₂O] ), 487.2, 310.1.

6. Syntheses of Heterodimeric Building Blocks 17 25. 6.1. 3-Methylbutyl 2-{[(Benzyloxy)carbonyl]amino}-

2-deoxy-N-{[(methoxy)carbonyl]methyl}-b-d-glucopyranosiduronamide (17). Compound 10 (1.695 g,

4.26 mmol) and glycine methylester hydrochloride (1.34 g, 10.66 mmol, 2.5 equiv.) were subjected to EDC

coupling according to GP 3a. The resulting colorless solid was precipitated to afford 17 (1.71 g) in 86% yield.

¹H-NMR (600 MHz, CD₃CN): 7.39 7.30( m, 5 arom. H); 7.28 (m, NH of Gly); 5.63 (br. s, 2-NH); 5.05 (d, J

12.7, CH₂of Z); 4.46 (d, J 8.1, HÀC(1)); 4.33 (s, 4-OH); 3.96 (d, J 6, NCH₂); 3.90( ddd, J 9.8, 6.4, 6.4, 1 H

of isoamyl); 3.73 (d, J 9.4, HÀC(5)); 3.69 (s, MeO); 3.52 (ddd, J 9.8, 6.4, 1 H of isoamyl); 3.44, (br. m,

HÀC(3), HÀC(4), 3-OH); 3.32 (ddd, J 9, 9, 8, HÀC(2)); 1.67 (ddd, J 6.8, 6.4, 6.4, 1 H of isoamyl); 1.42

(dddd, J 13.5, 6.8, 6.8, 6.8, CH₂of isoamyl); 0.88 (d, J 6.4, Me of isoamyl); 0.87 (d, J 6.4, Me of isoamyl)).

¹³C-NMR (150MHz, CD ₃CN): 172.3 (6-CONH); 170.9 (COOMe); 157.5 (CO of Z); 138.4, 129.5, 128.9, 128.7

(4 arom C. of Z); 102.5 (C(1)); 74.9 (C(3)); 74.0 (C(5)); 73.9 (C(4)); 69.1 (C(1) of isoamyl); 67.1 (CH₂of Z);

58.2 (C(2)); 52.8 (COOMe); 41.4 (CH₂NH); 39.1 (C(2) of isoamyl); 25.7 (C(3) of isoamyl); 23.0(C(4) of

isoamyl); 22.7 (C(5) of isoamyl). FAB-MS: 859.4 ([2M Na] ), 491.2 ([M Na] ), 469.2 ([M H] ), 381.1

([M À isoamyl] ). Anal. calc. for C₂₂H₃₂N₂O₉: C 56.40, H 6.88, N 5.98; found: C 56.31, H 6.61, N 5.85.

6.2. Prop-2-enyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{[(methoxy)carbonyl]methyl}-b-d-glucopyr-

anosiduronamide (18). Compound 11 (280mg) and glycine methylester hydrochloride (143 mg, 1.14 mmol,

1.5 equiv.) were condensed according to GP 3a to afford a glassy solid. Yield: 219.4 mg (66.5%) of 18. ¹H-NMR

(400 MHz, (D₆)DMSO): 8.35 (t, J 5.8, NH of Gly); 7.43 7.22 (m, 5 arom. H of Z); 7.17 (d, J 8.5, 2-NH);

5.82 (dddd, J 17, 10, 5, 5, 1 H of allyl)); 5.23 (br. d, J 17, 1 H of allyl); 5.16 4.92 (m, 1 H of allyl, CH₂of Z, 3-

OH, 4-OH); 4.37 (d, J 8, HÀC(1)); 4.24 (dd, J 13.5, 5, 1 H of allyl); 3.98 (dd, J 13.5, 5, 1 H of allyl); 3.88

(d, J 5.8, NCH₂); 3.63 (s, MeO); 3.3 (br. m, H₂O, HÀC(2), HÀC(3), HÀC(4)). ¹³C-NMR (100 MHz,

(D₆)DMSO): 170.2 (C(6)); 169.3 (COOMe); 156.2 (CO of Z); 137.5 (arom. C of Z); 134.6 (C(2) of allyl);

128.5, 128.4, 127.8, 127.7 (4 arom. C. of Z); 116.2 (C(3) of allyl); 101.1 (C(1)); 75.2 (C(5)); 73.6 (C(3)); 72.3

(C(4)); 69.1 (C(1) of allyl); 65.2 (CH₂of Z); 57.1 (C(2)); 51.9 (COOMe); 40.6 (NCH₂). FAB-MS: 461.2 ([M

Na] ), 381.1 ([M À allyl] ).

2390

Helvetica Chimica Acta Vol. 88 (2005)

6.3. 2-Phenylethyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{[(methoxy)carbonyl]methyl}-b-d-gluco-

pyranosiduronamide (19). Compound 12 (318.3 mg, 738 mmol) and glycine methylester hydrochloride

(185 mg, 1.475 mmol, 2.0equiv.) were coupled according to GP 3a to furnish a crude product, which was

1

purified by precipitation from Et₂O/hexanes to afford 19 (307 mg) in 82% yield as a colorless solid. H-NMR

(600 MHz, (D₆)DMSO): 8.27 (t, J 6, NH of Gly); 7.35 (m, 4 arom. H); 7.29 (d, 1 arom. H); 7.22 (m, 4 arom.

H); 7.16 (m, 1 arom. H); 7.11 (br. d, 2-NH); 5.02 (br. s, CH₂of Z, 3-OH); 4.96 (d, J 4, 4-OH); 4.41 (d, J 7.6,

HÀC(1)); 3.92 (m, J 9.7, 7, 1 H of phenethyl); 3.88 (d, J 6, NCH₂); 3.61 (m, MeO, HÀC(5), 1 H of

phenethyl); 3.35 (ddd, J 8.5, 8.5, 4, HÀC(4)); 3.32 (m, HÀC(3)); 3.27 (br. m, HÀC(2)); 2.77 (m, J 14, 7, 1 H

of phenethyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.0 (C(6)); 169.3 (COOMe); 156.1 (CO of Z); 138.8

(arom. C of phenethyl); 137.4 (arom. C of Z); 128.9, 128.3, 128.2, 127.7, 126.0(5 arom. C); 101.4 (C(1)); 75.2

(C(5)); 73.7 (C(3)); 72.2 (C(4)); 69.4 (CH₂of phenethyl); 65.2 (CH₂of Z); 51.7 (C(2)); 40.6 (NCH₂); 35.5 (CH₂

of phenethyl). FAB-MS: 525.2 ([M Na] ), 503.2 ([M H] ), 381.1 ([M À 2(phenethyl)] ). Anal. calc. for

C₂₅H₃₀N₂O₉¥ H₂O: C 57.80, H 6.01, N 5.39; found: C 57.94, H 5.66, N 5.25.

6.4. Hexyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{[(methoxy)carbonyl]methyl}-b-d-glucopyranosi-

duronamide (20). Compound 13 (1.076 g, 2.42 mmol) and glycine methylester hydrochloride (608 mg,

4.84 mmol, 2.0equiv.) were coupled according to GP 3a to afford, after precipitation from Et₂O, 20

(998.4 mg) in 86% yield as a colorless solid. ¹H-NMR (400 MHz, (D₆)DMSO): 8.32 (t, J 6, NH of Gly);

7.33 (m, 5 arom. H of Z); 7.12 (d, J 9, 2-NH); 5.06 (m, 3-OH); 5.01 (m, CH₂of Z, 4-OH); 4.32 (d, J 8.5,

HÀC(1)); 3.87 (dd, J 6, 2, NCH₂); 3.73 (ddd, J 9.7, 6.4, 6.4, 1 H of hexyl); 3.63 (s, MeO); 3.59 (d, J 9,

HÀC(5)); 3.4 3.3 (m, 1 H of hexyl, HÀC(4), HÀC(3)); 3.21 (dd, J 9, 9, 8.5, HÀC(2)); 1.44 (m, 2 H of

hexyl); 1.2 (br. m, 6 H of hexyl); 0.83 (t, J 6.8, Me of hexyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 170.2 (C(6));

169.4 (COOMe); 156.2 (CO of Z); 137.5, 128.4, 127.8, 127.7 (4 arom. C of Z); 101.7 (C(1)); 75.3 (C(5)); 73.6

(C(3)); 72.3 (C(4)); 68.9 (CH₂of hexyl); 65.2 (CH₂of Z); 57.1 (C(2)); 51.8 (COOMe); 40.6 (NCH₂); 31.2, 29.1,

25.1, 22.2 (4 CH₂of hexyl); 14.0(Me of hexyl). FAB-MS: 505.2 ([ M Na] ), 483.1 ([M H] ), 381.1 ([M À

hexyl] ), 349.1 ([M 2 À COOBn] ). Anal. calc. for C₂₃H₃₄N₂O₉: C 57.25, H 7.10, N 5.81; found: C 56.04, H

6.70, N 5.47.

6.5. 1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{[(methoxy)carbo-

nyl]methyl}-b-d-glucopyranosiduronamide (21). Compound 14 (891.2 mg, 1.92 mmol) and glycine methylester

hydrochloride (353 mg) were coupled according to GP 3a to afford 21 (903 mg) in 88% yield as a colorless solid.

¹H-NMR (600 MHz, (D₆)DMSO): 8.09 (br. t, J 5.5, NH of Gly); 7.44 7.25 (m, 5 arom. H of Z); 7.07 (d, J

8.7, 2-NH); 5.1 4.8 (m, CH₂of Z, 3-OH, 4-OH); 4.19 (d, J 8, HÀC(1)); 3.95 3.85 (dd, J 17, 5.5, NCH₂);

3.61 (s, MeO); 3.55 (d, J 9, HÀC(5)); 3.42 (br. m, HÀC(4)); 3.38 (br. m, HÀC(3)); 3.25 (ddd, J 9, 9, 8,

HÀC(2)); 3.01 (s, 1 H of fenchyl); 1.61 (br. m, 1 H of fenchyl); 1.57 (s, 1 H of fenchyl); 1.55 (br. m, 1 H of

fenchyl); 1.40( d, 1 H of fenchyl); 1.30(br. m, 1 H of fenchyl); 1.00 (s, Me and 1 H of fenchyl); 0.92 (s, Me of

fenchyl), 0.81 (br. m, 1 H of fenchyl); 0.78 (s, Me of fenchyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 169.9 (C(6));

169.2 (COOMe); 156.0(C O of Z); 137.4, 128.2, 127.6 (3 arom. C of Z); 103.8 (C(1)); 93.1 (C(2) of fenchyl);

75.5 (C(5)); 73.4 (C(3)); 72.0(C(4)); 65.0(CH ₂of Z); 57.5 (C(2)); 51.6 (COOMe); 48.8 (C(1) of fenchyl); 48.7

(C(3) of fenchyl); 47.6 (C(4) of fenchyl); 40.6 (C(7) of fenchyl); 38.8 (NCH₂); 29.6 (Me of fenchyl); 25.8 (C(6)

of fenchyl); 25.3 (C(5) of fenchyl); 21.6, 19.4 (2 Me of fenchyl). FAB-MS: 557.2 ([M Na] ), 535.2 ([M H] ),

381.1 ([M À fenchyl] ). Anal. calc. for C₂₇H₃₈N₂O₉¥ EtOH: C 59.98, H 7.64, N 4.82; found: C 60.15, H 7.01, N

4.44.

6.6. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{[(meth-

oxy)carbonyl]methyl}-b-d-glucopyranosiduronamide (b-22). Compound b-15 (336 mg, 722 mmol) and glycine

methylester hydrochloride (145 mg, 1.23 mmol, 1.7 equiv.) were coupled according to GP 3a to afford b-22

(345.8 mg) in 89% yield as a colorless solid. ¹H-NMR (600 MHz, (D₆)DMSO): 8.12 (m, NH of Gly); 7.39 (s, 4

arom. H of Z); 7.25 (m, 1 arom. H of Z); 7.09 (d, J 9, 2-NH); 5.09 (d, J 12.7, 1 H of CH₂of Z); 5.02 (d, J 3,

4-OH); 4.97 (d, J 3, 3-OH); 4.93 (d, J 12.7, 1 H of CH₂of Z); 4.40( d, J 8.5, HÀC(1)); 3.87 (m, NCH₂);

3.61 (s, MeO); 3.55 (d, J 9, HÀC(5)); 3.35 (br. m, HÀC(4), HÀC(3)); 3.31 (br. m, 1 H of menthyl); 3.11 (ddd,

J 9, 9, 8.5, HÀC(2)); 2.19 (m, 1 H of menthyl); 2.00 (br. d, J 11.7, 1 H of menthyl); 1.56 (br. m, 2 H of

menthyl); 1.29 (br. s, 1 H of menthyl); 1.04 (m, 1 H of menthyl); 0.90 (m, J 12, 1 H of menthyl); 0.81 (d, 2 Me

of menthyl); 0.75 (m, J 12, 1 H of menthyl); 0.67 (m, 1 Me and 1 H of menthyl). ¹³C-NMR (150MHz,

(D₆)DMSO): 170.0 (C(6)); 168.9 (COOMe); 156.1 (CO of Z); 137.6, 128.3, 127.7, 127.6 (4 arom. C. of Z); 99.7

(C(1)); 77.7 (C(1) of menthyl); 75.5 (C(5)); 73.7 (C(4)); 72.1 (C(3)); 64.9 (CH₂of Z); 57.3 (C(2)); 52.0

(COOMe); 47.5 (C(2) of menthyl); 40.4 (NCH₂); 40.2 (C(6) of menthyl); 34.1 (C(4) of menthyl); 30.9 (C(6) of

menthyl); 24.7 (C(7) of menthyl); 22.6 (C(3) of menthyl); 22.3 (Me of menthyl); 21.1 (Me of menthyl); 15.6

Helvetica Chimica Acta Vol. 88 (2005)

2391

(Me of menthyl). FAB-MS: 582.2 ([M 2Na] ), 559.2 ([M Na] ), 537.2 ([M H] ), 381.2 ([M À

menthyl] ). Anal. calc. for C₂₇H₄₀N₂O₉: C 60.43, H 7.51, N 5.22; found: C 60.11, H 7.52, N 5.16.

6.7. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{[(meth-

oxy)carbonyl]methyl}-a-d-glucopyranosiduronamide (a-22). Compound a-15 (1.43 g, 3.07 mmol) and glycine

methylester hydrochloride (771 mg, 5.14 mmol, 2.0equiv.) were coupled according to GP 3a to furnish, after

precipitation from Et₂O/hexanes, a-22 as a colorless solid in 88% yield. ¹H-NMR (600 MHz, (D₆)DMSO): 8.27

(t, J 6, NH of Gly); 7.35 (m, 4 arom. H of Z); 7.31 (m, 1 arom. H of Z); 6.96 (d, J 7, 2-NH); 5.00 (d, J 12.8,

CH₂of Z); 4.97 (d, J 4.3, 4-OH); 4.94 (d, J 3.6, HÀ(1)); 4.73 (d, J 3.6, 3-OH); 3.93 (d, J 9.8, HÀC(5));

3.86 (dd, J 17, 6, NCH₂); 3.62 (s, MeO); 3.51 (m, HÀC(3)); 3.38 (ddd, J 7, 9, 3.5, HÀC(2)); 3.35 (dd, J 9,

9, 4.3, HÀC(4)); 3.20( m, 1 H of menthyl); 2.28 (m, 1 H of menthyl); 2.05 (br. d, J 11.9, 1 H of menthyl); 1.59

(br. d, J 12.3, 1 H of menthyl); 1.54 (br. d, J 13, 1 H of menthyl); 1.34 (br. m, 1 H of menthyl); 1.20( m, 1 H of

menthyl); 0.99 (m, J 11.9, 1 H of menthyl); 0.90 (m, 1 H of menthyl); 0.85 (d, J 6.8, Me of menthyl); 0.79 (br.

d, J 7, Me and 1 H of menthyl); 0.60 (d, J 6.8, Me of menthyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.1

(C(6)); 170.0 (COOMe); 156.1 (CO of Z); 137.0, 128.3, 127.9, 127.8 (4 arom. C. of Z); 99.1 (C(1)); 81.1 (C(1) of

menthyl); 72.7 (C(4)); 71.6 (C(5)); 69.8 (C(3)); 65.5 (CH₂of Z); 56.3 (C(2)); 51.7 (COOMe); 48.3 (C(2) of

menthyl); 42.5 (C(6) of menthyl); 40.5 (NCH₂); 33.9 (C(4) of menthyl); 31.2 (C(2) of menthyl); 24.2 (1 C of

menthyl); 22.3 (C(3) of menthyl); 22.1, 21.2, 15.5 (3 Me of menthyl). FAB-MS: 582.2 ([M 2Na] ), 559.2

([M Na] ), 537.2 ([M H] ), 381.2 ([M À menthyl] ). Anal. calc. for C₂₇H₄₀N₂O₉: C 60.43, H 7.51, N 5.22;

found: C 60.11, H 7.52, N 5.16.

6.8. Methyl 6-O-((5S)-2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-5-[({[(methoxy)carbonyl]methyl}ami-

no)carbonyl]-b-d-xylopyranosyl)-2,3,4-tri-O-benzyl-a-d-glucopyranoside (23). Compound 16 (161.2 mg,

0.208 mmol) and glycine methylester hydrochloride (78.5 mg, 0.625 mmol, 3.0 equiv.) were coupled according

to GP 3a. The crude product was precipitated from Et₂O to yield 23 (48 mg) in 27% yield as a colorless solid.

FAB-MS: 867.4 ([M Na] ), 845.4 ([M H] ), 734.3 ([M À Z Na] ), 711.3 ([M À Z] ), 662.3 ([M À

2(benzyl)] ), 634.4 ([M 3 À 2(benzyl) À MeO] ), 487.2, 464.2, 381.3.

6.9. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{(S)-

[(methoxy)carbonyl](1-methylethyl)methyl}-b-d-glucopyranosiduronamide (24). Compound b-15 (310.6 mg,

667 mmol) and valine methylester hydrochloride (134 mg, 800 mmol, 1.2 equiv.) were coupled according to

GP 3b to yield 24 (373.5 mg) in 97% yield as a colorless solid. ¹H-NMR (600 MHz, CDCl₃): 7.32 (m, 4 arom. H

of Z); 7.30( m, 1 arom. H of Z); 6.97 (d, J 9, NH of Val); 5.17 (d, J 5, 2-NH); 5.09, 5.03 (2d, J 11 each, CH₂

of Z); 4.78 (d, J 7.2, HÀC(1)); 4.54 (dd, J 9, 5, a-H of Val); 4.00 (br. m, HÀC(3)); 3.76 (d, J 9, HÀC(5));

3.71 (s, MeO); 3.55 (dd, J 9, 9, HÀC(4)); 3.43 (br. m, 1 H of menthyl); 3.21 (m, J 7.2, HÀC(2)); 2.23 (m,

1 H of menthyl); 2.16 (m, b-H of Val); 1.92 (m, 1 H of menthyl); 1.61 (d, 2 Â 1 H of menthyl); 1.30(br. m, 1 H of

menthyl); 0.94 (m, 1 H of menthyl); 0.91 (d, J 9.8, Me of Val); 0.88 (d, J 6.8, Me of Val); 0.87 (d, J 7.2, Me

of menthyl); 0.84 (d, J 6.6, Me of menthyl); 0.81 (d, J 7, Me of menthyl); 0.78 (br. m, 2 Â 1 H of menthyl).

¹³C-NMR (150MHz, CDCl ₃): 171.4 (C(6)); 170.9 (COOMe); 156.2 (CO of Z); 136.1, 128.5, 128.2, 128.1 (4

arom. C of Z); 98.0(C(1)); 78.5 (C(1) of menthyl); 73.1 (C(4)); 72.3 (C(3)); 71.9 (C(5)); 66.9 (CH ₂of Z); 57.3

(C(2)); 56.4 (a-H of Val); 52.3 (COOMe); 47.2 (C(2) of menthyl); 40.2 (C(6) of menthyl); 34.0 (C(4) of

menthyl); 31.2 (C(5) of menthyl); 31.1 (b-H of Val); 25.2 (CH of menthyl); 22.8 (C(3) of menthyl); 22.2, 20.8 (2

Me of menthyl); 18.9, 17.5 (2 Me of Val); 16.0(Me of menthyl). FAB-MS: 601.2 ([ M Na] ), 579.2 ([M

H] ), 423.1 ([M À menthyl] ).

6.10. 3-Methylbutyl 2-{[(Benzyloxy)carbonyl]amino}-2-deoxy-N-{(S)-[(methoxy)carbonyl](methyl)meth-

yl}-b-d-glucopyranosiduronamide (25). Compound 10 (513.0mg, 1.3 mmol) and alanine methylester hydro-

chloride (270.3 mg) were coupled according to GP 3a to afford 25 (492 mg) as a colorless solid in 79% yield.

¹H-NMR (400 MHz, (D₆)DMSO): 8.30( d, J 7, NH of Ala); 7.41 7.23 (m, 5 arom. H of Z); 7.11 (d, J 9, 2-

NH); 5.26 4.83 (br. m, CH₂of Z); 4.34 (dq, J 7, 7, a-H of Ala); 4.29 (d, J 8.0, HÀC(1)); 3.73 (m, J 9.8, 8.0,

1 H of isoamyl); 3.62 (s, MeO); 3.56 (d, J 9.5, HÀC(5)); 3.39 (m, J 9.8, 6.8, 1 H of isoamyl); 3.38 (dd, J

9.5, 9.5, HÀC(4)); 3.3 (br. m, H₂O, HÀC(3)); 3.22 (ddd, J 9, 9, HÀC(2)); 1.62 (m, 1 H of isoamyl); 1.36 (m,

2 H of isoamyl); 1.29 (d, J 7, a-Me of Ala); 081 ( d, 6 H of isoamyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 172.9

(C(6)); 168.4 (COOMe); 156.2 (CO of Z); 137.5, 128.4, 127.8, 127.7 (4 arom. C of Z); 101.9 (C(1)): 75.7 (C(5));

73.7 (C(3)); 72.0(C(4)); 67.3 (C(1) of isoamyl); 65.1 (CH ₂of Z); 57.1 (C(2)); 52.0(COO Me); 47.5 (a-C of Ala);

38.0(C(2) of isoamyl); 24.3 (C(3) of isoamyl); 22.6 (C(4) of isoamyl); 22.4 (C(5) of isoamyl); 17.3 ( a-Me of

Ala). FAB-MS: 505.1 ([M Na] ), 483.1 ([M H] ), 395.1 ([M À isoamyl] ).

7. Preparation of Heterotrimeric Compounds. All heterodimers were used in the amino-deprotected form

obtained by hydrogenolytic cleavage of the Z group in the presence of 10% Pd/C in EtOH or MeOH under

1 atm of H₂for 3 12 h. After filtration and removal of the solvent under reduced pressure, the desired

2392

Helvetica Chimica Acta Vol. 88 (2005)

deprotected compounds were obtained mostly in quant. yields, and were used in the subsequent coupling

without further purification. The amino-deprotected heterodimers were characterized by NMR and MS (data

not shown).

7.1. 3-Methylbutyl 2-{[N-(tert-Butoxycarbonyl)-d-phenylalanyl]amino}-2-deoxy-N-{[(methoxy)carbonyl]-

methyl}-b-d-glucopyranosiduronamide (26). N-Deprotected 17 (605 mg, 1.81 mmol) was coupled with Boc-d-

Phe-OH (600 mg) according to GP 3b. After extractive workup and removal of solvents, the remaining residue

was precipitated from Et₂O/hexanes to afford 26 (710mg) in 68% yield as a colorless solid. ¹H-NMR (400 MHz,

(D₆)DMSO): 8.36 (t, J 5.8, NH of Gly); 7.93 (d, J 9, 2-NH); 7.25 (2d, 4 arom. H of Phe); 7.17 (m, 1 arom. H

of Phe); 6.68 (d, J 9, NH of Phe); 5.09 (d, J 3.5, 4-OH); 4.94 (d, J 4.5, 3-OH); 4.41 (d, J 8.5, HÀC(1));

4.17 (dt, J 9, 9, 3.5, a-H of Phe); 3.88 (d, J 5.8, a-CH₂of Gly); 3.75 (m, J 9.5, 6.5, 1 H of isoamyl); 3.67 (d,

J 9, HÀC(5)); 3.63 (s, MeO); 3.50( ddd, J 9, 9, 8.5, HÀC(2)); 3.44 3.34 (br. m, 3 H of isoamyl); 2.96 (dd,

J 13.5, 3.5, 1 b-H of Phe); 2.70( ddd, J 13.5, 9, 9, 1 b-H of Phe); 1.62 (m, 1 H of isoamyl); 1.26 (s, t-BuO),

0.80 (d, J 6.5, 2 Me of isoamyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 171.8 (CONH of Phe); 170.3 (C(6)); 169.5

(COOMe); 155.3 (COO^tBu); 138.5, 129.4, 128.1, 126.3 (4 arom. C of Phe); 101.5 (C(1)); 78.0 (OCMe₃); 75.4

(C(5)); 73.8 (C(3)); 72.3 (C(4)); 67.3 (C(1) of isoamyl); 55.8 (a-C of Phe); 55.4 (C(2)); 51.9 (COOMe); 40.7 (a-

C of Gly); 38.3 (b-C of Phe); 38.1 (C(2) of isoamyl); 28.3 (OCMe₃); 24.4 (C(3) of isoamyl); 22.7 (C(4) of

isoamyl); 22.5 (C(5) of isoamyl). FAB-MS: 1185.7 ([2M Na] ), 604.3 ([M Na] ), 582.3 ([M H] ), 504.3

([M À Boc Na] ), 494.3 ([M À isoamyl] ). Anal. calc. for C₂₈H₄₃N₃O₁₀¥ H₂O: C 56.08, H 7.56, N 7.01; found: C

56.54, H 7.39, N 6.89.

7.2. 2-Phenylethyl 2-{[N-(tert-Butoxycarbonyl)-l-valinyl]amino}-2-deoxy-N-{[(methoxy)carbonyl]meth-

yl}-b-d-glucopyranosiduronamide (27). N-Deprotected 19 (300 mg, 815 mmol) and Boc-l-Val-OH (253 mg)

were coupled according to GP 3b. The crude product was precipitated from Et₂O/hexanes to afford 27 (180mg)

in 40% yield. ¹H-NMR (600 MHz, CD₃CN): 7.28 (m, 2 arom. H of phenethyl, NH of Gly); 7.23 (d, 2 arom. H of

phenethyl): 7.19 (m, 1 arom. H of phenethyl); 6.66 (d, J 8.9, 2-NH); 5.49 (d, J 5.7, NH of Val); 4.61 (d, J

8.5, HÀC(1)); 4.03 (ddd, J 9.6, 7.4, 1 H of phenethyl); 3.94 (d, J 6, a-CH₂of Gly); 3.83 (dd, J 8, 5.7, a-H of

Val); 3.74 (m, 2 H of phenethyl); 3.68 (s, MeO); 3.60( dd, J 8.9, 8.5, HÀC(2)); 3.57 (d, J 3.0, 3-OH); 3.52

(dd, J 8.9, 8.9, HÀC(3)); 3.44 (dd, J 8.9, 8.9, HÀC(4)); 2.85 (br. dd, J 7.4, 6.9, 2 H of phenethyl); 2.02 (m,

b-H of Val); 1.41 (s, t-BuO); 0.93, 0.87 (2d, J 6.8 each, 2 Me of Val). ¹³C-NMR (150MHz, CD ₃CN): 173.0

(CONH of Val); 172.2 (C(6)); 170.8 (COOMe); 157.1 (COO^tBu); 139.8, 130.0, 129.4, 127.2 (4 arom. C of

phenethyl); 101.8 (C(1)); 80.0 (COOCMe₃); 75.1 (C(3)); 73.9 (C(5)); 73.8 (C(4)); 71.2 (C(1) of phenethyl ); 61.3

(a-C of Val); 56.3 (C(2)); 52.8 (COOMe); 41.3 (a-C of Gly); 36.8 (C(2) of phenethyl); 31.7 (b-C of Val); 28.6

(OCMe₃); 19.6, 18.1 (2 Me of Val). FAB-MS: 590.3 ([M Na] ), 568.3 ([M H] ), 468.2 ([M 2 À Boc] ),

446.2 ([M À 2(phenethyl)] ). Anal. calc. for C₂₇H₄₁N₃O₁₀¥ H₂O: C 55.47, H 7.28, N 7.19; found: C 55.65, H 7.13,

N 6.93.

7.3. Hexyl 2-{[N-(tert-Butoxycarbonyl)-d-phenylalanyl]amino}-2-deoxy-N-{[(methoxy)carbonyl]methyl}-

b-d-glucopyranosiduronamide (28). N-Deprotected 20 (667.6 mg, 1.996 mmol) and Boc-d-Phe-OH (635.6 mg,

2.39 mmol, 1.2 equiv.) were coupled according to GP 3b to afford 28 (1.04 g) in 87% yield as a colorless solid.

¹H-NMR (600 MHz, (D₆)DMSO): 8.31 (t, J 5.5, NH of Gly); 7.91 (d, J 8.7, 2-NH); 7.24 (m, 4 arom. H of

Phe); 7.17 (m, 1 arom. H of Phe); 6.61 (d, J 9, NH of Phe); 5.04 (d, J 3.8, 4-OH); 4.90( d, J 4.7, 3-OH);

4.42 (d, J 8.5, HÀC(1)); 4.18 (br. ddd, J 10, 9, 3, a-H of Phe); 3.90, 3.87 (2dd, J 17 and 5.5 each, a-CH₂of

Gly); 3.71 (br. m, 1 H of hexyl); 3.67 (d, J 9, HÀC(5)); 3.63 (s, COOMe); 3.51 (ddd, J 9, 9, 8.5, HÀC(2));

3.38 (br. m, HÀC(3), HÀC(4), 1 H of hexyl); 2.97 (dd, J 13.5, 3, 1 H of CH₂of Phe); 2.72 (dd, J 13.5, 10,

1 H of CH₂of Phe); 1.44 (br. m, 2 H of hexyl); 1.33 1.12 (br. m, t-BuO, 6 H of hexyl); 0.78 (t, J 6.7, Me of

hexyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 171.7 (CONH of Phe); 170.1 (C(6)); 169.4 (COOMe); 155.1

(COO^tBu); 138.4, 129.3, 128.0, 126.2 (4 arom. C of Phe); 101.3 (C(1)); 77.9 (OCMe₃); 75.3 (C(5)); 73.8 (C(3));

72.3 (C(4)); 68.9 (C(1) of hexyl); 55.7 (a-C of Phe); 55.3 (C(2)); 51.8 (COOMe); 40.6 (a-C of Gly); 38.2 (b-C of

Phe); 31.2 (C(4) of hexyl); 29.2 (C(2) of hexyl); 28.2 (OCMe₃); 25.2 (C(3) of hexyl); 22.1 (C(5) of hexyl); 14.0

(C(6) of hexyl). FAB-MS: 618.3 ([M Na] ), 1213.6 ([2M Na] ), 495.3 ([M 1 À Boc] ), 518.3 ([M À

Boc Na] ). Anal. calc. for C₂₉H₄₅N₃O₁₀¥ 4 H₂O: C 52.48, H 7.44, N 6.33; found: C 53.14, H 6.95, N 6.40.

7.4. 1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl 2-{[N-(tert-Butoxycarbonyl)-d-phenylalanyl]amino}-2-deoxy-N-

{[(methoxy)carbonyl]methyl}-b-d-glucopyranosiduronamide (29). N-Deprotected 21 (670.6 mg, 1.674 mmol)

and Boc-d-Phe-OH (555.3 mg) were coupled according to GP 3a. The resulting crude product was precipitated

from Et₂O/hexanes to yield 29 (864.9 mg) in 79.8% yield as a colorless solid. ¹H-NMR (400 MHz, (D₆)DMSO):

8.19 (t, J 5.8, NH of Gly); 7.93 (d, J 9, 2-NH); 7.23 (m, 4 arom. H of Phe); 7.16 (m, 1 arom. H of Phe); 6.70

(d, J 8.8, NH of Phe); 5.08 (d, J 5, 3-OH); 4.79 (d, J 5, 4-OH); 4.29 (d, J 8, HÀC(1)); 4.19 (m, a-H of

Phe); 3.89 (2d, J 5.8 each, a-CH₂of Gly); 3.65 3.55 (m, HÀC(5), HÀC(2), COOMe); 3.41 (m, HÀC(3),

Helvetica Chimica Acta Vol. 88 (2005)

2393

HÀC(4)); 3.04 (s, 1 H of fenchyl); 2.99 (dd, J 12.5, 3, 1 b-H of Phe); 2.70( dd, J 12.5, 12, 1 b-H of Phe); 1.62

(br. m, 1 H of fenchyl); 1.56 (br. s, 1 H of fenchyl); 1.53 (br. m, 1 H of fenchyl); 1.39 (br. d, J 9, 1 H of fenchyl);

1.30(br. m, 1 H of fenchyl); 1.25 (s, t-BuO); 1.03 (s, Me of fenchyl); 0.99 (br. m, 1 H of fenchyl); 0.92 (s, endo-Me

of fenchyl); 0.76 (s, 1 H and exo-Me of fenchyl). ¹³C-NMR (100 MHz, (D₆)DMSO): 171.6 (CONH of Phe);

170.1 (C(6)); 168.8 (COOMe); 155.2 (COO^tBu); 138.7, 129.4, 128.0, 126.1 (4 arom. C of Phe); 103.0 (C(1)); 91.7

(C(2) of fenchyl); 77.8 (OCMe₃); 75.6 (C(5)); 73.8 (C(3)); 72.1 (C(4)); 55.7 (a-C of Phe); 55.6 (C(2)); 51.8 (a-C

of Gly); 48.8 (C(1) and C(3) of fenchyl); 47.5 (C(4) of fenchyl); 40.9 (C(7) of fenchyl); 40.7 (a-C of Gly); 39.0

(b-C of Phe); 29.5 (endo-Me of fenchyl); 28.3 (OCMe₃); 25.9 (C(5) of fenchyl); 25.5 (C(6) of fenchyl); 21.7 (exo-

Me of fenchyl); 19.7 (Me of fenchyl). FAB-MS: 1317.2 ([2M Na] ), 670.2 ([M Na] ), 648.2 ([M H] ),

570.2 ([M À Boc H Na] ), 494.1 ([M À fenchyl] ), 438.1 ([M À fenchyl À Boc 2Na] ).

7.5. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[N-(tert-Butoxycarbonyl)-d-phenylalanyl]amino}-

2-deoxy-N-{[(methoxy)carbonyl]methyl}-b-d-glucopyranosiduronamide (b-30). N-Deprotected b-22 (551.6 mg,

1.37 mmol) and Boc-d-Phe-OH (472.5 mg, 1.78 mmol, 1.5 equiv.) were coupled according to GP 3a to furnish b-

1

30 (894.5 mg) in 98% yield as a yellow foam. H-NMR (600 MHz, (D₆)DMSO): 8.16 (t, J 5.8, NH of Gly);

7.91 (d, J 6.6, 2-NH); 7.24 (m, 4 arom. H of Phe); 7.17 (m, 1 arom. H of Phe); 6.59 (d, J 8.7, NH of Phe); 5.04

(d, J 4.5, 3-OH); 4.87 (d, 4-OH); 4.53 (d, J 7.2, HÀC(1)); 4.17 (m, a-H of Phe); 3.88 (d, J 5.8, a-CH₂of

Gly); 3.63 (d, J 9.4, HÀC(5)); 3.61 (s, COOMe); 3.44 3.34 (m, HÀC(2), HÀC(3), HÀC(4), 1 H of

menthyl); 3.01 (dd, J 3.4, 13.8, 1 H of b-CH₂of Phe); 2.71 (dd, J 10.3, 13.8, 1 H of b-CH₂of Phe); 2.20( m,

1 H of menthyl); 2.04 (br. d, J 12, 1 H of menthyl); 1.55 (m, 2 Â 1 H of menthyl); 1.30(br. m, 1 H of menthyl);

1.27 (s, t-BuO); 1.04 (m, 1 H of menthyl); 0.90 (m, J 13, 1 H of menthyl); 0.81 (d, J 10, Me of menthyl); 0.80

(d, J 9.4, Me of menthyl); 0.72 (br. m, 2 Â 1 H of menthyl); 0.68 (d, J 7, Me of menthyl). ¹³C-NMR

(150MHz, (D ₆)DMSO): 171.4 (CONH of Phe); 170.1 (C(6)); 169.0 (COOMe); 155.2 (COO^tBu); 138.5, 129.4,

128.0, 126.2 (4 arom. C of Phe); 98.9 (C(1)); 78.0 (OCMe₃); 77.1 (C(1) of menthyl); 75.7 (C(5)); 73.9 (C(4)); 72.1

(C(3)); 55.6 (C(2), a-C of Phe); 51.8 (COOMe); 47.5 (C(2) of menthyl); 40.7 (C(6) of menthyl); 40.6 (a-C of

Gly); 38.3 (b-C of Phe); 34.1 (C(4) of menthyl); 31.0(C(5) of menthyl); 28.3 (OC Me₃); 24.6 (1 H of menthyl);

22.7 (C(3) of menthyl); 22.3, 21.1, 15.6 (3 Me of menthyl). FAB-MS: 673.1 ([M H Na] ), 651.1 ([M

2 H] ), 494.7 ([M À menthyl] ), 395.3 ([M 2 À Boc] ). Anal. calc. for C₃₃H₅₁N₃O₁₀¥ H₂O: C 59.44, H 7.86, N

6.30; found: C 59.13, H 7.84, N 6.15.

7.6. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[N-(tert-Butoxycarbonyl)-d-phenylalanyl]amino}-

2-deoxy-N-{[(methoxy)carbonyl]methyl}-a-d-glucopyranosiduronamide (a-30). N-Deprotected a-22 (1.0604 g,

2.63 mmol) and Boc-d-Phe-OH (840mg, 3.145 mmol, 1.2 equiv.) were coupled according to GP 3a. The crude

product was purified by precipitation from CH₂Cl₂/hexanes to afford a-30 (635 mg) in 60% yield as a colorless

solid. ¹H-NMR (600 MHz, (D₆)DMSO): 8.30( t, J 6, NH of Gly); 7.6 (d, J 7, 2-NH); 7.23 (m, 4 arom. H of

Phe); 7.16 (m, 1 arom. H of Phe); 6.76 (d, J 9.3, NH of Phe); 4.92 (d, J 3.4, HÀC(1)); 4.28 (ddd, J 10.0,

9.3, 3.0, a-H of Phe); 3.98 (d, J 9.8, HÀC(5)); 3.87 (dd, J 17, 6, a-CH₂of Gly); 3.72 (br. m, HÀC(2)); 3.62 (s,

COOMe); 3.56 (br. m, HÀC(3)); 3.41 (br. m, HÀC(4)); 3.02 (dd, J 13.2, 3, 1 H of b-CH₂of Phe); 2.69 (dd,

J 13.2, 10, 1 H of b-CH₂of Phe); 2.25 (m, J 6.9, 6.9, 1 H of menthyl); 2.08 (d, J 11.6, 1 H of menthyl); 1.58

(d, J 12, 1 H of menthyl); 1.54 (d, J 13, 1 H of menthyl); 1.34 (m, 1 H of menthyl); 1.25 (s, t-BuO); 1.13 (br. s,

1 H of menthyl); 1.01 (m, J 11.6, 1 H of menthyl); 0.91 (m, J 13, 1 H of menthyl); 0.86 (d, J 6, Me of

menthyl); 0.81 (d, J 6.9, Me of menthyl); 0.76 (dd, J 12, 1 H of menthyl), 0.63 (d, J 6.9, Me of menthyl).

¹³C-NMR (150MHz, (D ₆)DMSO): 171.9 (CONH of Phe); 170.1 (C(6)); 170.0 (COOMe); 155.3 (COO^tBu);

138.3, 129.3, 128.0, 126.1 (4 arom. C of Phe); 98.7 (C(1)); 80.2 (OCMe₃); 78.1 (C(1) of menthyl); 72.8 (C(4));

71.9 (C(5)); 70.1 (C(3)); 55.5 (a-C of Phe); 54.4 (b-C of Phe); 51.7 (COOMe); 48.4 (C(2) of menthyl); 42.5

(C(6) of menthyl); 40.5 (a-C of Gly); 38.0( b-C of Phe); 33.9 (C(4) of menthyl); 31.2 (C(5) of menthyl); 28.2

(OCMe₃); 24.5 (1 C of menthyl); 22.4 (C(3) of menthyl); 22.1, 21.2, 15.7 (3 Me of menthyl). FAB-MS: 673.1

([M H Na] ), 651.1 ([M 2 H] ), 494.7 ([M À menthyl] ), 395.3 ([M 2 H À menthyl À Boc] ). Anal.

calc. for C₃₃H₅₁N₃O₁₀¥ H₂O: C 59.44, H 7.86, N 6.30; found: C 59.13, H 7.84, N 6.15.

7.7. (1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[N-(tert-Butoxycarbonyl)-d-phenylalanyl]amino}-

2-deoxy-N-{(S)-[(methoxy)carbonyl](1-methylethyl)methyl}-b-d-glucopyranosiduronamide (31). N-Depro-

tected 24 (259.6 mg, 585 mmol) and Boc-d-Phe-OH (233 mg, 878 mmol, 1.5 equiv.) were coupled according to

GP 3b. The resulting crude product was purified by precipitation from Et₂O to yield 31 (305 mg) in 75.6% yield.

¹H-NMR (600 MHz, (D₆)DMSO): 8.13 (d, J 8.7, NH of Val); 7.94 (d, J 7.9, 2-NH); 7.28 7.24 (m, 5 arom. H

of Phe); 6.63 (d, J 8.7, NH of Phe); 5.06 (d, J 5.1, 4-OH); 4.85 (d, J 5.1, 3-OH); 4.51 (d, J 7.8, HÀC(1));

4.26 (dd, J 8.7, 6.3, a-H of Val); 4.16 (ddd, J 9.4, 8.7, 3.5, a-H of Phe); 3.70( d, J 9.4, HÀC(5)); 3.63 (s,

COOMe); 3.46 (m, HÀC(4)); 3.40( m, HÀC(3), HÀC(2)); 3.35 (br. m, 1 H of menthyl); 3.01 (dd, J 13.8, 3.5,

1 H of b-CH₂of Phe); 2.71 (dd, J 13.8, 9.4, 1 H of b-CH₂of Phe); 2.15 (m, 1 H of menthyl); 2.05 (m, 1 H of

2394

Helvetica Chimica Acta Vol. 88 (2005)

menthyl); 2.01 (m, J 6.4, 6.4, b-H of Val), 1.54 (m, 2 Â 1 H of menthyl); 1.27 (br. s, 1 H of menthyl, t-BuO);

1.04 (dd, J 11, 11, 1 H of menthyl); 0.88 (m, 1 H of menthyl); 0.85 (d, J 6.4, 2 Me of Val); 0.80 (m, 2 Me of

menthyl); 0.69 (m, 2 Â 1 H of menthyl); 0.65 (d, Me of menthyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 171.9

(CONH of Ph); 171.4 (C(6)); 168.4 (COOMe); 155.2 (COO^tBu); 138.5, 129.7, 129.5, 128.3, 128.1 (4 arom. C of

Phe); 99.2 (C(1)); 80.5 (OCMe₃); 77.1 (C(1) of menthyl); 75.6 (C(5)); 74.0(C(3)); 71.4 (C(4)); 56.9 ( a-C of

Val); 55.5 (C(2)); 55.4 (a-C of Phe); 51.7 (COOMe); 47.3 (C(2) of menthyl); 40.5 (C(6) of menthyl); 38.2 (b-C

of Phe); 34.0 (C(4) of menthyl); 30.9 (C(5) of menthyl); 30.5 (b-C of Val); 28.2 (OCMe₃); 24.6 (1 C of menthyl);

22.7 (C(3) of menthyl); 22.2, 20.9 (2 Me of menthyl); 18.9, 18.2 (2 Me of Val); 15.6 (Me of menthyl). FAB-MS:

714.3 ([M Na] ), 692.3 ([M H] ), 614.2 ([M À Boc Na] ), 536.2 ([M À menthyl] ), 480.1 ([M À Boc À

menthyl 2Na] ).

7.8. 3-Methylbutyl 2-{[N-(tert-Butoxycarbonyl)-l-phenylalanyl]amino}-2-deoxy-N-{(S)-[(methoxy)carbo-

nyl](methyl)methyl}-b-d-glucopyranosiduronamide (32). N-Deprotected 25 (315 mg, 905 mmol) and Boc-l-

Phe-OH (290mg, 1.09 mmol, 1.21 equiv.) were coupled according to GP 3b. The crude product (512 mg, 94.5%)

showed residual traces of the EEDQ reagent and was, therefore, precipitated from Et₂O to afford 32 (343 mg) in

a yield of 63.6% as a colorless solid. ¹H-NMR (600 MHz, CDCl₃): 7.28 (m, 2 arom. H of Phe); 7.23 (m, 1 arom. H

of Phe); 7.20( m, 2 arom. H of Phe); 7.12 (d, J 7.4, NH of Ala); 6.44 (br. s, 2-NH); 5.17 (d, J 7.2, NH of Phe);

4.69 (br. m, HÀC(1), OH); 4.56 (dq, J 7.4, 7.2, a-H of Ala); 4.28 (dt, J 7.2, 7.2, a-H of Phe); 3.91 (dd, J 9.5,

9.5, HÀC(3)); 3.86 (ddd, J 15.7, 6.8, 6.8, 1 H of isoamyl); 3.76 (d, J 9.3, HÀC(5)); 3.74 (s, COOMe); 3.56

(dd, J 9.3, 9.3, HÀC(4)); 3.45 (m, J 15.7, 7.2, 1 H of isoamyl); 3.26 (ddd, J 9.5, 9.5, 8.5, HÀC(2)); 3.05 (dd,

J 13.6, 7.2, 1 H of b-CH₂of Phe); 2.98 (dd, J 13.6, 7.2, 1 H of b-CH₂of Phe); 1.65 (m, 1 H of isoamyl); 1.44

(br. s, 2 H of isoamyl); 1.42 (d, J 7.2, Me of Ala); 1.36 (s, t-BuO); 0.86 (d, J 6.3, 2 Me of isoamyl). ¹³C-NMR

(150MHz, CDCl ₃): 172.7 (CONH of Phe); 172.1 (C(6)); 170.2 (COOMe); 156.6 (COO^tBu); 136.5, 129.3, 128.7,

127.0 (4 arom. C of Phe); 100.0 (C(1)); 80.5 (OCMe₃); 72.5 (C(4)); 72.2 (C(3)); 72.1 (C(5)); 67.8 (C(1) of

isoamyl); 57.6 (C(2)); 56.1 (a-C of Phe); 52.7 (MeO); 47.5 (a-C of Ala); 38.0(C(2) of isoamyl, b-C of Phe); 28.2

(OCMe₃); 24.6 (C(3) of isoamyl); 22.5 (C(4) of isoamyl); 22.4 (C(5) of isoamyl); 18.1 (Me of Ala). FAB-MS:

618.3 ([M Na] ), 596.3 ([M H] ).

8. Fragment Condensations. N-Deprotection was carried out as described above, and C-deprotection was

achieved by saponification with sat. aq. LiOH soln. (1.1 equiv.) in EtOH for 3 h, followed by neutralization and

lyophilization. The respective saponification products (Li carboxylates) were obtained in quant. yields.

Complete saponification was ascertained by NMR and MS experiments (data not shown).

8.1. [(3-Methylbutyl 2-{[((1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[(Benzyloxy)carbonyl]ami-

no}-2-deoxy-b-d-glucopyranosid)uronyl]amino}-2-deoxy-b-d-glucopyranosid)uronyl]glycine Methyl Ester

(33). Compound b-15 (124.6 mg, 267.6 mmol) was pre-activated with HOBt (55 mg, 403 mmol, 1.5 equiv.) and

EDC ¥ HCl (103 mg, 535.3 mmol, 2.0equiv.) in CH ₂Cl₂(5 ml), and then reacted with N-deprotected 17 (92.0mg,

275.1 mmol, 1.03 equiv.) according to GP 3a. Extractive workup after 48 h furnished a crude product, which was

precipitated from Et₂O and then purified by gel filtration (Sephadex LH-20) to yield 33 (86.5 mg) as a colorless

solid in 41.2% yield. ¹H-NMR (600 MHz, (D₆)DMSO): 7.83 (m, NH of Gly); 7.31 7.14 (m, 5 arom. H of Z); 6.73

(m, 2-NH, 2'-NH); 5.03 (br. s, 1 H of CH₂of Z); 4.92 (br. s, 1 H of CH₂of Z); 4.79 (br. s, 2 OH); 4.71 (br. s,

2 OH); 4.48 (br. d, J 8.1, HÀC(1), HÀC(1')); 3.92 (m, a-CH₂of Gly); 3.87 3.82 (m, 1 H of isoamyl); 3.68

(br. d, HÀC(5), HÀC(5')); 3.64 (s, MeO); 3.58 3.33 (br. m, HÀC(3), HÀC(3'), HÀC(2), HÀC(2'), HÀC(4),

HÀC(4'), 1 H of isoamyl); 3.31 (dt, 1 H of menthyl); 2.23 (br. m, 1 H of menthyl); 1.56 1.47 (m, 1 H of isoamyl,

2 Â 1 H of menthyl); 1.42 1.28 (m, 2 H of isoamyl); 1.25 (br. m, 1 H of menthyl); 1.09 (br. m, 1 H of menthyl);

0.91 0.54 (br. m, 5 Me, 3 Â 1 H of menthyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 169.9 (C(6), C(6')); 169.6

(COOMe); 156.1 (CO of Z); 137.3, 128.1, 127.5, 127.2 (4 arom. C of Z); 100.8 (C(1)); 99.3 (C(1')); 77.7 (C(1) of

menthyl); 74.7 (C(5), C(5')); 73.7 (C(3), C(3')); 72.1 (C(4), C(4')); 67.3 (C(1) of isoamyl); 65.1 (CH₂of Z); 55.6

(C(2), C(2')); 54.5 (a-C of Gly); 47.3 (C(2) of menthyl); 40.4 (COOMe); 37.8 (C(6) of menthyl); 35.8 (C(2) of

isoamyl); 33.9 (C(4) of menthyl); 30.9 (C(5) of menthyl); 24.6 (1 C of menthyl); 24.3 (C(3) of isoamyl); 22.6

(C(3) of menthyl); 22.4 (Me of menthyl); 22.0(Me of isoamyl); 20.7 (Me of menthyl); 15.8 (Me of isoamyl, Me

of menthyl). FAB-MS: 804.2 ([M Na] ), 782.2 ([M H] ), 670.4 ([M À Z H Na] ). MALDI-MS (rel. to

angiotensin): 804.4 ([M Na] ), 671.6 ([M À Z 2 H Na] ).

8.2. {[3-Methylbutyl 2-({[((1S,2S,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-{[(Benzyloxy)carbonyl]ami-

no}-2-deoxy-a-d-glucopyranosid)uronyl]glycinyl}amino)-2-deoxy-b-d-glucopyranosid]uronyl}glycine Methyl

Ester (34). Saponified a-22 (Li salt; 200 mg, 378.4 mmol) was coupled with N-deprotected 17 (126.5 mg,

378.4 mmol, 1.0equiv.) according to GP 3b. Extractive workup after 48 h furnished a crude product, which was

subjected to CC (SiO₂; CHCl₃/MeOH 30:1) to afford 34 (53.9 mg) in 17% yield. ¹H-NMR (600 MHz,

(D₆)DMSO): 8.31 (t, J 5.8, NH of Gly¹); 7.88 (t, J 5.3, NH of Gly²); 7.76 (d, J 8.8, 2-NH); 7.35 (s, 4 arom.

Helvetica Chimica Acta Vol. 88 (2005)

2395

H of Z); 7.31 (m, 1 arom. H of Z); 7.04 (d, J 7.2, 2'-NH); 5.18 (d, J 3.8, 4'-OH); 5.04 (d, J 3.4, 4-OH); 5.0

(m, CH₂of Z, 3-OH); 4.93 (d, J 3.6, HÀC(1')); 4.79 (d, J 5.7, 3'-OH); 4.39 (d, J 8.3, HÀC(1)); 3.95 (d,

J 9.8, HÀC(5')); 3.88 (d, J 5.8, a-CH₂of Gly¹); 3.77 (dd, J 16, 5.3, a-CH₂of Gly²); 3.74 (m, 1 H of

isoamyl); 3.69 (dd, J 16, 5.3, 1 H of CH₂of Gly²); 3.66 (d, J 9, HÀC(5)); 3.63 (s, MeO); 3.51 (ddd, J 9, 9,

5.7, HÀC(3')); 3.45 (dd, J 9, 8.8, 8.3, HÀC(2)); 3.42 3.32 (m, HÀC(2'), HÀC(4'), HÀC(4), HÀC(3), 1 H of

isoamyl); 3.21 (dt, J 10, 4, 1 H of menthyl); 2.28 (m, 1 H of menthyl); 2.02 (br. d, J 11.9, 1 H of menthyl);

1.65 1.55 (m, Me of isoamyl, 1 H of menthyl); 1.53 (m, J 13, 1 H of menthyl); 1.42 1.28 (m, 2 H of isoamyl,

1 H of menthyl); 1.18 (br. dd, J 11, 11, 1 H of menthyl); 0.97 (ddd, J 11.9, 11, 11, 1 H of menthyl); 0.89 (m,

J 13, 1 H of menthyl); 0.84 0.83 (m, 2 Me of isoamyl, Me of menthyl); 0.78 (d, J 6.8, Me of menthyl); 0.74

(m, J 13, 1 H of menthyl); 0.60 (d, J 6.8, Me of menthyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 170.2, 169.6,

169.4, 168.3 (4 CONH); 156.1 (CO of Z); 137.1, 128.4, 127.9 (3 arom C of Z); 101.2 (C(2)); 99.2 (C(1')); 81.0

(C(1) of menthyl); 75.3 (C(5)); 73.6 (C(4')); 73.0(C(3)); 72.2 (C(4)); 71.8 (C(5 ')); 69.7 (C(3')); 67.3 (C(1) of

isoamyl); 65.6 (CH₂of Z); 56.3 (C(2')); 55.5 (C(2)); 51.8 (COOMe); 48.4 (C(2) of menthyl); 42.7 (C(6) of

menthyl); 41.9 (a-C of Gly²); 40.6 (a-C of Gly¹); 37.9 (C(2) of isoamyl); 34.0(C(4) of menthyl); 31.2 (C(5) of

menthyl); 24.4 (C(3) of isoamyl); 24.2 (1 C of menthyl); 22.7 (C(3) of menthyl); 22.4 (1 C of menthyl); 22.3

(2 Me of isoamyl); 21.3, 15.6 (2 Me of menthyl). FAB-MS: 861.4 ([M Na] ), 751.4 ([M À isoamyl] ), 595.2

([M À isoamyl À menthyl] ). Anal. calc. for C₄₀H₆₂N₄O₁₅¥ 6 H₂O: C 51.96, H 7.28, N 5.95; found: C 51.45, H 7.14,

N 5.64.

8.3. [(Hexyl 2-{[({[1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl 2-Deoxy-2-({N-[(tert-Butoxy)carbonyl]-d-phe-

nylalanyl}amino)-b-d-glucopyranosid]uronyl}glycinyl)-d-phenylalanyl]amino}-2-deoxy-b-d-glucopyranosid)-

uronyl]glycine Methyl Ester (35). C-Deprotected 29 (Li carboxylate; 64 mg, 0.1 mmol) and N-deprotected 28

(53.5 mg, 0.1 mmol) were coupled according to GP 3a. Extractive workup after 3.5 d and precipitation from

Et₂O/pentane furnished a crude product (82 mg), which was purified by prep. RP-HPLC (Si 60-10-C18; MeCN/

H₂O (pH 7) 60:40, isocratic) to afford 35 (48 mg) in 42% yield. ¹H-NMR (600 MHz, (D₆)DMSO)³): 8.32 (t, J

5.7, NH of Gly¹); 8.12 (d, J 9, NH of Phe¹); 8.03 (d, J 9, 2-NH); 7.93 (d, J 9.4, 2'-NH); 7.84 (br. t, NH of

Gly²); 7.22 (br. s, 8 arom. H of Phe); 7.16 (m, 2 arom. H of Phe); 6.68 (br. d, J 10, 0.7 NH of Phe²(major)); 6.18

(br. d, J 8, 0.3 NH of Phe²(minor)); 5.10(br. s, 0.7 OH (major)); 5.06 (br. s, 1.3 OH); 5.00 (m, OH); 4.80( m,

OH); 4.58 (dt, J 9, 3.5, a-H of Phe¹); 4.45 (d, J 7.8, 0.3 HÀC(1') (minor)); 4.36 (d, J 8.5, HÀC(1)); 4.29

(d, J 8.3, 0.7 HÀC(1') (major)); 4.19 (br. m, a-H of Phe²); 3.89 (m, J 5.7, a-CH₂of Gly¹); 3.83 (dd, J 16, 6,

1 H of a-CH₂of Gly²); 3.71 (m, J 9.5, 6.8, 1 H of hexyl); 3.67 (d, J 9, HÀC(5)); 3.63 (s, MeO); 3.62 (d, J

8, HÀC(5')); 3.58 3.55 (m, 1 H of CH₂of Gly², HÀC(2), HÀC(2')); 3.42 3.34 (br. m, HÀC(3), HÀC(3'),

HÀC(4), HÀC(4'), 1 H of hexyl); 3.07 2.96 (br. m, 1 H of b-CH₂of Phe¹and Phe², resp., 1 H of fenchyl); 2.74

2.65 (br. m, 1 H of b-CH₂of Phe¹and Phe², resp.), 1.61 (br. m, 1 H of fenchyl); 1.57 1.41 (br. m, 2 Â 1 H of

fenchyl, 2 H of hexyl); 1.36 (br. d, 1 H of fenchyl); 1.33 1.14 (br. m, 13 H, 6 H of hexyl, 0.7 OCMe₃(major));

1.12 1.05 (br. s, 3 H, OCMe₃(minor)); 1.02 (s, Me of fenchyl (major)); 0.99 (br. s, > 1 H, 1 H and Me of fenchyl

(minor)); 0.93 (s, > 1 H, Me of fenchyl (minor)); 0.87 (s, Me of fenchyl (major)); 0.78 (br. t, 1 H of fenchyl, Me

of hexyl); 0.74 (s, Me of fenchyl). ¹³C-NMR (150MHz, (D ₆)DMSO): 171.1, 170.2, 169.4, 168.7 (4 CONH); 167.9

(COOMe); 155.1 (CO of Boc)); 138.0, 129.3, 128.1, 126.3, 126.1 (5 arom. C of Phe); 102.8 (HÀC(1') (major));

101.5 (HÀC(1)); 100.6 (HÀC(1') (minor)); 91.5 (C(2) of fenchyl (major)); 89.9 (C(2) of fenchyl (minor); 77.8

(OCMe₃); 75.6 (HÀC(5)); 75.3 (HÀC(5')); 73.8 (HÀC(3), HÀC(3')); 72.4 (HÀC(4), HÀC(4')); 68.9 (C(1) of

hexyl); 55.7 (a-C of Phe¹); 55.6 (a-C of Phe²); 55.1 (HÀC(2), HÀC(2')); 48.8 (C_qof fenchyl (major)); 48.6 (C_q

of fenchyl (minor)); 47.5 (C_qof fenchyl (major)); 41.9 (a-C of Gly²); 40.9 (CH of fenchyl); 40.6 (a-C of Gly¹);

39.0( b-C of Phe); 31.4 (Me of fenchyl (major)); 31.3 (C(4) of hexyl); 29.7 (Me of fenchyl (major)); 29.3 (C(2) of

hexyl); 28.3 (OCMe₃); 25.7 (C(5) of fenchyl); 25.4 (C(6) of fenchyl); 25.3 (C(3) of hexyl); 22.2 (C(5) of hexyl);

21.7 (Me of fenchyl (major)); 21.2 (Me of fenchyl (minor)); 19.7 (Me of fenchyl (major)); 19.6 (Me of fenchyl

(minor)); 14.0(Me of hexyl). FAB-MS: 1133.5 ([ M Na] ), 1033.4 ([M À Boc] ). MALDI-MS (rel. to

angiotensin): 1133 ([M Na] ).

3

)

NMR assignments include two subsets of signals in a ratio of ca. 0.7 to 0.3, with variation in the part of the

fenchyl glycoside. Shift differences occurred in the region of the glycoside linkage and the adjacent Boc-d-

Phe substituent. The two conformers are designated as major and minor, resp.

2396

Helvetica Chimica Acta Vol. 88 (2005)

REFERENCES

[1] F. Schweizer, Angew. Chem., Int. Ed. 2002, 41, 230.

[2] M. Stoeckle, G. Voll, R. Guenther, E. Lohof, E. Locardi, S. Gruner, H. Kessler, Org. Lett. 2002, 4, 3169.

[3] A. N. Van Nhien, H. Ducatel, C. Len, D. Postel, Tetrahedron Lett. 2002, 43, 3805.

[4] T. Ziegler, D. Roseling, L. R. Subramanian, Tetrahedron: Asymmetry 2002, 13, 911.

[5] T. K. Chakraborty, A. Ghosh, R. Nagaraj, A. R. Sankar, A. C. Kunwar, Tetrahedron 2001, 57, 9169.

[6] T. K. Chakraborty, S. Ghosh, S. Jayaprakash, Curr. Med. Chem. 2002, 9, 421 435.

[7] T. K. Chakraborty, S. Ghosh, S. Jayaprakash, J. Sharma, V. Ravikanth, P. V. Diwan, R. Nagaraj, A. C.

Kunwar, J. Org. Chem. 2000, 65, 6441.

[8] T. K. Chakraborty, S. Jayaprakash, P. V. Diwan, R. Nagaraj, S. R. B. Jampani, A. C. Kunwar, J. Am. Chem.

Soc. 1998, 120, 13545.

[9] T. K. Chakraborty, S. Jayaprakash, S. Ghosh, Comb. Chem. High Throughput Screen. 2002, 5, 373.

[10] S. Gruner, E. Locardi, E. Lohof, H. Kessler, Chem. Rev. 2002, 102, 491.

[11] S. Gruner, V. Truffault, G. Voll, E. Locardi, M. Stockle, H. Kessler, Chem. Eur. J. 2002, 8, 4365.

[12] S. A. W. Gruner, E. Locardi, E. Lohof, H. Kessler, Chem. Rev. 2002, 102, 491 514.

[13] S. A. W. Gruner, V. Truffault, G. Voll, E. Locardi, M. Stockle, H. Kessler, Chemistry 2002, 8, 4366.

[14] M. J. Sofia, R. Hunter, T. Y. Chan, A. Vaughan, R. Dulina, H. Wang, D. Gange, J. Org. Chem. 1998, 63,

2802.

[15] C. M¸ller, E. Kitas, H. P. Wessel, J. Chem. Soc., Chem. Commun. 1995, 2425.

[16] R. A. Goodnow, Jr., A.-R. Richou, S. Tam, Tetrahedron Lett. 1997, 38, 3195.

[17] R. A. Goodnow, Jr., S. Tam, D. L. Pruess, W. W. McComas, Tetrahedron Lett. 1997, 38, 3199.

[18] R. A. Goodnow, S. Y.-K. Tam, Patent PCT Int. Appl., F. Hoffmann-La Roche, Switzerland, Accession

Number: An 1997:381016, 1997.

[19] T. Ogawa, K. Beppu, S. Nakabayashi, Carbohydr. Res. 1981, 93, C6.

[20] N. J. Davis, S. L. Flitsch, Tetrahedron Lett. 1993, 34, 1181.

[21] M. Zhao, J. Li, Z. Song, D. M. Tschaen, E. J. J. Grabowski, P. J. Reider, J. Org. Chem. 1999, 64, 2564.

[22] A. Kyas, Ph.D. Thesis, Ruhr-Universit‰t, Bochum, 2003.

Received February 11, 2005

Article Doi

Differently glycosidated 2-amino-2-deoxy-D-glucopyranosiduronic acids as building blocks in peptide synthesis

DOI: 10.1002/hlca.200590175

Source and publish data:

Authors:

Article abstract of DOI:10.1002/hlca.200590175

Full text of DOI:10.1002/hlca.200590175

Products guided by the article

R&D Labs maybe for 870529-34-3

Relevant to this article

Hot Product