Synthesis of a building block for phosphonate analogues of moenomycin A12 from D-tartaric acid

TETRAHEDRON

Pergamon

Tetrahedron 57 82001) 9437±9452

Synthesis of a building block for phosphonate analogues of

moenomycin A₁₂from d-tartaric acid

Jalal Zahra,^aLothar Hennig,^aMatthias Findeisen,^aSabine Giesa,^aPeter Welzel,^a,p

b

Dietrich Muller and William S. Sheldrick

b

È

a

È È

Fakultat fur Chemie und Mineralogie, Universitat Leipzig, Johannisallee 29, D-04103 Leipzig, Germany

Institut fur Analytische Chemie, Ruhr-Universitat Bochum, D-44780Bochum, Germany

È

b

È

Received 27 June 2001; revised 6 September 2001; accepted 28 September 2001

AbstractÐAn approach for the synthesis of moenomycin A₁₂C-glycoside partial structures is reported based on allyltin chemistry. q 2001

1. Introduction

pyrophosphate bridge.²The formation of the polymeric

peptidoglycan from this precursor at the outer face of the

cytoplasmic membrane requires two enzymatic activities, a

glycosyl transferase and an acyl serine transferase 8trans-

peptidase).³The high molecular weight penicillin binding

proteins of E. coli combine in a single polypeptide chain the

required transglycosylase and transpeptidase activities. The

transpeptidation reaction is inhibited by the b-lactam anti-

biotics. Most of the antibiotics that inhibit the trans-

glycosylation step seem to interfere with the substrate8s)

of this reaction.^4,5The only class of compounds known

with certainty to inhibit the enzyme of this reaction, the

transglycosylase,⁶are the moenomycins 8see, for example,

moenomycin A₁₂81),⁷8Scheme 1). A mechanism for their

mode of action has been proposed.^8,9It is assumed that they

are anchored to the cytoplasmic membrane via the lipid part

Infectious diseases continue to be a leading cause of

morbidity and mortality worldwide. Especially the increas-

ing frequency of resistance to existing antibiotics represents

a serious public health treat.¹Thus, there is an urgent need

for discovery and development of new agents active against

resistant strains. Human cells lacka cell wall but bacteria

are surrounded by a cell wall that is crucial for survival. This

feature of bacteria is an attractive target for antibiotic action.

The biosynthesis of peptidoglycan, the main structural

component of the bacterial cell wall, occurs successively

in three cell compartments, in the cytoplasm, at the inner

face and at the outer face of the cytoplasmic membrane.

The immediate precursor of peptidoglycan is lipid II, a

disaccharide peptide linked to a C₅₅lipid carrier via a

Scheme 1.

Keywords: carbohydrates; antibiotics; tin compounds; cyclization; rearrangements.

Corresponding author. Tel.: 149-341-97-36551; fax: 149-341-97-36599; e-mail: welzel@organik.chemie.uni-leipzig.de

p

PII: S0040-4020801)00951-6

9438

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

Scheme 2.

and bind then highly selectively to the active site of the

enzyme via the C±E±F trisaccharide. Units A, B, and D

have been shown to be of minor importance for the anti-

biotic activity.¹⁰The moenomycins do not induce resistance

readily. However, a weakpoint in this respect may be the

phosphate bond at unit F. Its cleavage by a yet poorly

characterized enzyme is the only enzymatic degradation

reaction of the moenomycins that is known to-date.¹¹

Furthermore, some analogues which we expected to be

antibiotically active, were devoid of antibiotic activity. It

has been speculated, that these compounds are used as

substrates by the transglycosylase.¹²With this in mind we

embarked on a programme aimed at synthesizing tri-

saccharide analogues of moenomycin A₁₂in which the

phosphate oxygen at C-1 of unit F is replaced by a CH₂

group.¹³It seemed important to retain all other functional

groups in ring F as present in moenomycin since they are

known to be of major importance as far as antibiotic activity

is concerned.^10,14Some mono- and disaccharide phos-

phonate models of moenomycin A have already been

prepared but obviously their structures were too simple to

elicit antibiotic activity.¹⁵

formula 2 to give a precursor of type 3 8Scheme 2). 2

would be available from 3 by an Arbuzov reaction. Further

disconnection of 3 leads to 6. Electrophilic cyclizations of

type 6 compounds is another important route to C-glyco-

sides. The most important disconnection is that of 6 which

yields the two precursors 4 and 5. Compound 4 should be

easily available from d-tartaric acid. Reagents of type 5 can

be made from allyl alcohol by silyl ether formation, depro-

tonation with butyllithium and trapping the organometallic

intermediate with tri-n-butyltin chloride.¹⁷

3. Attempted synthesis of 10via 8

We ®rst tried to prepare 10 by assembling 8 with the known

8Z)-substituted g-silyloxyallyl stannane 9 8Scheme 3).¹⁷

Thus, 7 was reduced with sodium borohydride to provide

1

8 in 41% yield. According to the H NMR spectrum which

displayed two singlets for the NH protons at 6.54 and 6.58

8no coupling to the adjacent proton, as shown by a homo

decoupling experiment), 8 was a 1:1 mixture of two stereo-

isomers. Under the conditions employed 8MgBr₂´OEt₂and

BF₃´OEt₂, respectively) 8 turned out to be stable. This

means that neither the open-chain aldehyde tautomer of 8

nor a Speckamp N-acyl iminium ion¹⁸could be trapped by 9.

2. Synthetic planning

For the synthesis of C-glycosides many methods exist.

Carbocation, carbanion and radical chemistry can be used

to add carbon appendages to C-1 of the starting sugar.¹⁶We

decided to disconnect the target structure as indicated in

4. Reaction of 12 with 9

After the failure with 8 we turned to the addition of 9 to

aldehyde 12 8Scheme 4). This aldehyde was obtained from

Scheme 3.

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

9439

Scheme 4.

the known¹⁹d-tartaric acid derivative 11a by selective ester

hydrolysis 811a!11b, KOH 81 equiv.) in methanol,²⁰73%),

amide formation using Staab's procedure²¹891%) and

DIBAH reduction in dichloromethane 894%). The missing

three carbons could be introduced by coupling 12 with 9.¹⁷

The yield and the stereoselectivity of this addition was

strongly dependent on the activating Lewis acid.²²Best

results were obtained using magnesium dibromide

etherate.²³Under these conditions a heptonic acid amide

A was obtained in 50% yield as a single stereoisomer. A

second isomer B was formed when the addition was, for

example, catalyzed by zinc bromide 8CH₂Cl₂, 2308C).

The total yield was lower in this case 823%), however.

compounds is C-1. We were unable to deduce the relative

con®guration at the newly formed stereogenic centers from

the ¹H NMR spectra. In an attempt to overcome this

problem the free OH-group of the heptonamide was

oxidized to furnish a ketone C that on Luche reduction

furnished a stereoisomer D of the original addition product

of 12 with 9. But again, attempts to establish the relative

con®guration proved fruitless. Thus, we decided to

determine the con®guration after electophilic cyclization.

Selective cleavage of the acetonide ring leaving the silyl

ether intact was unsuccessful. Acetic acid, ferric chloride,

or cupric chloride removed the silyl group whereas the

acetonide was stable under these conditions. Thus, all the

protecting groups were removed from A on re¯uxing an

ethanol±water solution in the presence of Dowex 50-H¹

to afford the completely deprotected product in quantitative

yield. Good quality ¹H- and ¹³C NMR spectra were obtained

for this compound. They did not show any signals for

The heptonamide A obtained from 12 with 9 contains two

new stereogenic centers at C-4 and C-5. Thus, it could be

either the l-galacto, l-gluco, d-altro or d-ido isomer 8see

13a±13d, Scheme 4). Note, that the amide carbon in these

9440

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

Figure 1.

acetonide or TBDMS groups. The ¹H NMR spectra

displayed a broad singlet at 7.64 for the CONH₂group.

However, it was very complicated to obtain reasonable

MS spectra. FAB MS was unsuccessful and the ESI MS

spectra of deprotected A did not show a signal for the

molecular ion. Instead a signal at m/z 347.09769 8calculated

for [2M22NH₃±H]²: 347.10565, difference0.00796)

indicated the removal of ammonia. We conclude that

under the ESI conditions the amide had been converted to

a lactone. Electrophilic mercuric tri¯uoroacetate-mediated

was isolated. Cyclization under the conditions detailed

above furnished the two furanoid cyclization products 18a

and 18b. The con®guration at C-6 could not be determined

by NMR.

The outcome of the addition of the allylstannane 9 to 12 can

be explained on the basis of a transition state geometry as

indicated in formula 19 in which it is assumed that the

MgBr₂-promoted addition involves chelation control and

that the CvO and CvC bonds are in an antiperiplanar

relationship as suggested previously²³8Scheme 5).

cyclization of deprotected

A

followed by HgX!I

exchange¹⁶produced two stereoisomeric compounds

which according to the NMR spectra were methyl esters.

After crystallization of one of them from methanol an X-ray

analysis yielded structure 15a 8see Fig. 1) con®rming the

presence of a methyl ester and demonstrating the lability of

the amide group in this system. Not unexpectedly, a

furanoid cyclization product had been formed. Most

importantly, the X-ray structure proved that the addition

of allyl stannane 9 to aldehyde 12 had given the l-galacto

product 13a 8compound A) exactly as desired and as present

in unit F of moenomycin A₁₂. The second isomer in the

cyclization reaction was then 15b. The oxidation product

of 13a must be 16 8compound C) and the isomer of 13a

obtained by reduction of 16 is the l-gluco compound 13b

8D). The second isomer 8compound B) in the zinc bromide-

mediated reaction of 12 with 9 was not identical with 13b

and has, thus, either structure 13c or 13d.

5. Attempted synthesis of 26 via 22a

In order to achieve the desired cyclization to a pyranoid

ring, functional group manipulations blocking the 3-OH

group and liberating the OH group at C-2 became necessary

8Scheme 6). The 4-OH group of 13a was converted into a

urethane via the phenyl carbonate 813a!20a!20b). The

silyl protecting group was removed to give 20c. Attempts

to convert this compound into a trisaccharide on reaction

with the oxazoline derived from chitobiose octaacetate

failed completely.²²The reason for the low nucleophilicity

of 20c originates most probably from the electron-with-

drawing substituent at C-4. It is known that the Beau±

Jacquinet oxazolines 8formed from 21) are much more

reactive than the normal oxazolines.²⁴And indeed, disac-

charide 22a was formed on reaction of 20c with 21. But

even in this reaction the yield was low 820%). Unfortu-

nately, all of the known methods that we tried failed to

remove the acetonide group from 22a.

We also removed the protecting groups from 13b by

hydrolysis in the presence of Dowex 50-H¹. In this case,

too, the amide group was hydrolyzed and the free acid 17

6. Synthesis of 26 via 14a

In order to circumvent these problems, the silyl protecting

group was cleaved from 13a with TBAF in THF. The result-

ing 14a was glycosylated via the Beau±Jacquinet

procedure. When 0.2 equiv. of TMS±OTf were used we

obtained 22b and 23b which we were unable to separate.

The mixture was converted into the corresponding phenyl

carbonates which could be separated to give 1:3 mixture of

23c and 23d 876%). Again, we were unable to remove the

acetonide group selectively.²²When the reaction of 14a and

Scheme 5.

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

9441

Scheme 6.

21 was performed in the presence of 0.45 equiv. of TMS±

OTf disaccharide 22b was obtained in 32% yield. In

addition, the 1!4 disaccharide 23e 84%) and the tri-

saccharide 23a 810%) were isolated. The ¹H and ¹³C signals

of compounds 22b and 23e were assigned with the help of

lactone bond in 24a. The FAB MS showed parent ion peaks

corresponding to [M1H]¹and [M1Na]¹, respectively.

In principle, the lactone is a very nice compound since it

contains the 4-OH group in a protected form. Thus, protect-

ing the 3-OH group and opening the lactone ring with

ammonia would set the stage for the 6-exo-trig cyclization.

Attempts to protect the 3-OH group directly failed. Either

both OH groups were protected under the reaction condi-

tions 8see 24b and 24e) or the 2-OH group reacted

selectively 8see 24c and 24f). 24c was obtained from 24a

with 1 equiv. of phenyl chloroformate in 70% yield. ¹H and

¹³C signals of 24c were assigned with the help of 2D NMR

experiments. HMBC spectra showed a long-range coupling

between 2-H and the CO of the phenyl carbonate group

indicating that the phenyl carbonate group was at C-2.

1

2D experiments. The H NMR spectrum of 22b showed

³J_1E,2E8.1 Hz con®rming the b-glycosidic bond, which

was also indicated by the ¹³C chemical shift 8d100.00)

of C-1^E. HMBC spectra showed a long-range coupling

between 5-H and C-1^E, also a long-range coupling between

1^E-H and C-5 was identi®ed. The ¹H NMR spectrum of 23e

indicated the presence of a trimetyl silyl group 8singlet at

d0.067), which was also seen by the ¹³C chemical shift

1

3

0

8d0.39). The H NMR coupling constant J_{1 ,2}8.1 Hz

13

and the C chemical shift 8d99.34) of C-1⁰con®rmed

the b-glycosidic bond formation. HMBC spectra showed a

long-range coupling between 4-H and C-1⁰, and a long-

range coupling between 1⁰-H and C-4 was identi®ed. The

FAB MS spectrum was in accord with structure 23e.

1

Acetylation of 24c yielded 24d in 75% yield. In the H

NMR spectrum of 24d the signal of 3-H was shifted to

higher frequency 81.0 ppm) while no signi®cant shift for

2-H was observed compared to 24a. HMBC showed a

long-range coupling between 2-H and the CO of the phenyl

carbonate, also a long-range coupling was identi®ed

between 3-H and the acetyl group attached to C-3.

Attempts to remove the carbonate group from 24d proved

fruitless.²²

On removing the acetonide protecting group from 22b using

cupric chloride dihydrate in acetonitrile²⁵lactone 24a was

obtained 894%) demonstrating once again the lability of the

amide group 8Scheme 7). No signals for acetonide or amide

1

groups were observed in the H NMR spectrum. The FAB

MS displayed parent ion peaks at m/z 606.0 and 628.0 which

correspond to [M1H]¹and [M1Na]¹, respectively. The

structural assignment of 22b rests mainly on a careful analy-

sis of the NMR spectra of its diacetyl derivative 24b. Both

¹H- and ¹³C NMR spectra of 24b indicated the presence of

®ve acetyl groups 8three for the sugar and two for the

As a consequence of these observations a two-step protocol

was used for the protection of the 3-OH group. Silyl ether

24f obtained from 24a in 89% yield was acetylated to give

24g 894%). HMBC showed a long-range coupling between

3-H and the CO of the acetyl group in accord with structure

24g. Silyl group removal with TBAF gave 24h 898%). After

successful protection of the 3-OH group, opening of the

lactone ring with NH₃in THF furnished two products,

3-acetate 25b and the 4-isomer 25c 882% total yield). The

1

lactone). In the H NMR spectra of 24b the signals of 2-H

and 3-H were shifted to higher frequencies 8by 1.3 and

0.8 ppm, respectively) while no signi®cant shift for 4-H

was observed compared to that of 24a. HMBC spectra

showed a long-range coupling between 2-H and 3-H and

the CO of the acetyl groups attached to C-2 and C-3, respec-

tively. This is an indication that the 4-OH in 22b formed the

1

presence of the amide group in 25b was indicated by H

NMR 8broad singlets at 6.00 and 6.79 for the CONH₂group

which disappeared after D₂O treatment). 2-H gave a singlet

9442

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

Scheme 7.

at 4.46 which is unusual in this system. That the acetate was

at C-3 was obvious from the long range coupling 8HMBC)

between 3-H and the acetyl CO. In 25c, the amide was

can be explained by the migration of the acetyl group

8C-3!C-4).

1

apparent from the H NMR spectra 8two singlets at 5.91

When the lactone opening was performed at the stage of

24g, amide 25a was obtained in 94% yield without acetyl

group migration.²⁶The formation of the amide in 25a was

indicated by ¹H NMR 8two broad singlets at 5.92, and 6.57

for the CONH₂group). HMBC spectra showed a long-range

coupling between 3-H and the CO of the 3-acetoxy group.

However, when the silyl group was removed from 25a with

TBAF in THF the same mixture of 25b 846%) and 25c

838%) resulted as above.

and 6.87 for the CONH₂group which disappeared after

D₂O treatment). The signal of 2-H gave a doublet-type

signal with a coupling constant of ³J6.3 Hz for the

coupling with 2-OH as shown in a COSY experiment and

also by D₂O exchange. A second splitting with J1.4 Hz

8for the coupling of 2-H with 3-H) was observed upon

recording the spectrum after treatment with D₂O. Similarly,

the signal of 3-H could only be fully analyzed after D₂O

exchange. The coupling constant J_3,4was 9.9 Hz. HMBC

spectra showed a long-range coupling between 4-H and

the CO of the acetate attached to C-4. The formation 25c

The last step in this synthesis was the ring closure of 25b.

Electrophilic cyclization [8i)Hg8OCOCF₃)₂in THF, 8ii) KCl

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

9443

in water, 8iii) I₂] afforded 26 in 28% yield. The acetyl group

had again migrated to the equatorial position at C-4. The ¹H

NMR spectra proved the C-glycoside structure. The

methylene protons 7^F-H 8dd), 7^F-H⁰8dd), and 6^F-H 8ddd)

formed an ABX system. The coupling constant

³J_5F,6F5.9 Hz con®rmed the a position of iodo methyl

was warmed to room temperature during 1 h. The precipi-

tated boron complex was removed from the reaction

mixture, and the ®ltrate was concentrated at room tempera-

ture. The crude product was puri®ed by FC eluting with

CHCl₃±MeOH 90:10, to furnish after solvent evaporation

solid 8 80.82 g, 41%). IR 8KBr): 3436 8br), 1748, 1374,

3

1

group at C-6. The coupling constant J_4F,5F9.8 Hz is in

1244, 1059 cm²¹. H NMR 8200 MHz, [D₆]DMSO, homo-

agreement with the galacto-con®guration of unit F. The

primary amide group gave rise to two broad singlets in the

¹H NMR spectrum 8at 7.79 and 8.60). The ¹³C NMR spec-

trum showed the C-7 signal at d3.60. The HMBC spectra

indicated a long-range coupling between 4-H and the CO of

the acetate attached to C-4. This is an evidence for the

migration of the acetyl group. The cyclization of 25c

decoupling): d2.01 8s, 6H, CH₃), 5.00 8m, 2H, CH), 5.26

8d, 1H, CHOH), 6.54, 6.58 8NH, NH), 8.85 8s, OH). ¹³C

NMR 850 MHz, [D₆]DMSO): d20.62, 20.77 8COCH₃),

73.84 8CHOH), 79.27, 80.29 8CH), 167.41, 169.75, 169.98

8CO). C₈H₁₁NO₆8217.17, 217.06), FAB MS: m/z 218.0

[M1H]¹, 240.0 [M1Na]¹.

1

furnished 27 in 44% yield. Again, the H NMR spectra of

27 showed a C-glycoside structure 8ABX system for CH₂-7

8.2. Attempted addition of 9 to 8

3

and 6^F-H. The coupling constant J_4,52.6 Hz indicated a

Hydroxylactam 8 80.10 g, 0.46 mmol) and magnesium

bromide etherate 80.12 g, 0.46 mmol) were dissolved in

anhydrous CH₂Cl₂815 mL) under an argon atmosphere in

an ice-bath. 1-tert-Butyl-dimethylsilyloxy-3-tri-n-butyl-

stannyl-1-propene 89) 80.21 g, 0.46 mmol) in anhydrous

CH₂Cl₂82 mL) was added. The reaction was monitored by

TLC 8CHCl₃±MeOH 90:10). After 2 h the reaction mixture

was removed from the ice-bath and stirred at room tempera-

ture for 48 h. No reaction was observed.

furanoid ring formation instead of a pyranoid ring as in 25b.

The con®guration at C-6 was not assigned. The amide group

1

was indicated by H NMR 8two broad singlets at 8.23, and

8.49 for the CONH₂group). The 2-H proton was up®eld

shifted to 4.85 while that of 4-H was down®eld shifted to

6.24. This is evidence that the acetoxy group was linked to

C-4 and not to C-2. The ¹³C NMR spectrum showed the C-7

signal at d3.67 ppm. The FAB MS displayed parent ion

peaks at m/z 789.8 and 812.8 which correspond to [M1H]¹

and [M1Na]¹, respectively.

In another experiment, BF₃´OEt₂843 mL, 50 mg,

0.34 mmol) was added to a mixture of hydroxylactam 8

850 mg, 0.23 mmol) and allystannane

9

80.14 g,

7. Conclusion

0.30 mmol) in 3 mL of anhydrous CH₂Cl₂under an argon

atmosphere at 2108C. The reaction was monitored by TLC

8CHCl₃±MeOH 90:10). After 24 h no reaction was

observed.

The results reported above demonstrate 8i) that d-tartaric

acid can nicely be converted into l-galactoheptonamides

8d-galactohepturonamides), i.e. into a structural moiety

that is present in moenomycin analogues of type 2, 8ii)

that the amide group in this type of compounds is very

labile, and 8iii) that the acetonide protecting group used

for the protection of the OH groups at C-2 and C-3 causes

severe problems at later stages of the synthesis. It was found

that replacement of acetonide by cyclopentylidene protec-

tion did not solve the problems.²²

8.2.1. 2,3-O-Isopropylidine-d-tartaric acid methyl ester

amide .11c). A solution of N,N-carbonyldiimidazole

82.19 g, 13.3 mmol) in anhydrous THF 825 mL) was added

dropwise to a solution of methylhydrogen-2,3-isopropyl-

idene-d-tartrate 811b)²⁰82.21 g, 10.8 mmol) in anhydrous

THF 850 mL) during 10 min. The reaction mixture was

stirred for further 20 min. Gaseous ammonia was bubbled

through the reaction mixture at a slow rate for 2 h. The

reaction progress was followed by TLC 8CHCl₃±MeOH

90:10). The solvent was removed, the crude product was

puri®ed by FC eluting with CHCl₃±MeOH 90:10, to afford

after solvent evaporation pure 11c 82.00 g, 91%) as a color-

less oil. R_f: 0.40 8CHCl₃±MeOH 90:10). IR 8®lm): 3455

8br), 3376 8br), 3223 8br), 1869, 1750, 1380, 1255, 1213,

1104 cm²¹. ¹H NMR 8200 MHz, CDCl₃): d1.43, 1.45 82s,

6H, CH₃), 3.77 8s, 3H, OCH₃), 4.70 8s, 2H, CH), 6.54, 6.90

82s, 2H, CONH₂). ¹³C NMR 850 MHz, CDCl₃, APT):

d26.54, 26.94 8C8CH₃)₃), 53.29 8OCH₃), 77.70, 77.98

8CH), 113.97 8C8CH₃)₂), 171.09, 173.32 8CO). C₈H₁₃NO₅

8203.19, 203.08), FAB MS: m/z 204.0 [M1H]¹, 226.0

[M1Na]¹.

8. Experimental

8.1. General

NMR: GEMINI 200 8Varian), GEMINI 2000 8Varian),

GEMINI 300 8Varian), DRX 400 8Bruker), DRX 600

8Bruker); chemical shifts are given in d values. HMBC

and HMQC experiments were performed using the

DRX 400 and the DRX 600. Mass spectrometry: FAB

MS: VG Autospec 8Fisons, 3nitrobenzylalcohol matrix),

ESI MS: FT-ICR-MS Apex II 8Bruker Daltonics, water±

methanol, negative ion mode). For other methods, see

Ref. 27

8.2.2. .4S,5S)-5-Formyl-2,2-dimethyl-[1,3]dioxolane-4-

carboxylic acid amide .12). A solution of diisobutyl-

aluminium hydride 810 mL, 1.0 M in CH₂Cl₂) was added

dropwise over 1 h at 2788 to a solution of 11c 80.81 g,

3.99 mmol) in anhydrous CH₂Cl₂83 mL). The reaction

was monitored by TLC 8CHCl₃±MeOH 90:10). After

stirring for additional 8 h, isopropanol 86 mL) was added

8.1.1. .3S,4S)-3,4-Diacetoxy-5-hydroxy-2-pyrrolidinone

.8). Sodium borohydride was added to 83S,4S)-3,4-di-

acetoxy-2,5-pyrrolidinedione 87)²⁸82.0 g, 9.3 mmol)

dissolved in THF 840 mL) and water 82 mL) at 2408C.

The reaction progress was followed by TLC 8CHCl₃±

MeOH 90:10). After stirring for 5 h, the reaction mixture

9444

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

dropwise to the reaction mixture. After 20 min citric acid

815% aq., 10 mL) was added to the vigorously stirred

mixture. The mixture was warmed gradually to room

temperature, the pH was adjusted to 3.5 by the citric acid

solution. The reaction mixture was stirred until the two

phases had separated, the aqueous phase was extracted

with CH₂Cl₂85£50 mL), the combined organic extracts

were dried over sodium sulfate. The solvent was removed

at room temperature yielding 12 80.64 g, 94%) as an oil

which became solid after precipitation from an PE±ethyl

acetate mixture. R_f: 0.36 8CHCl₃±MeOH 90:10). IR

After stirring the reaction mixture overnight at room

temperature, the solvent was removed under reduced

pressure. The product was puri®ed by FC eluting with

CHCl₃±MeOH 95:5, to yield after solvent evaporation

14a 813.1 mg, 78%) as colorless solid. IR 8KBr): 3436

8br), 1675, 1379, 1255, 1218, 1071 cm²^{1 1}H NMR

.

8200 MHz, CDCl₃, HH COSY): d1.46, 1.50 82s, 6H,

C8CH₃)₂), 3.41 8d, 1H, 5-OH), 3.78 8ddd, 1H, 4-H), 4.12

8dd, 1H, 3-H), 4.30±4.38 8m, 2H, 5-H, 4-OH), 4.46 8d,

1H, 2-H), 5.24 8ddd, 1H, 7-H_a), 5.40 8ddd, 1H, 7-H_b), 6.01

8ddd, 1H, 6-H), 6.13, 6.76 82s, 2H, CONH₂). J_2,38.1 Hz,

J_3,46.8 Hz, J_5,OH8.4 Hz, J_5,65.1 Hz, J_6,7a10.3 Hz,

J_6,7b17.4 Hz. ¹³C NMR 8100 MHz, CDCl₃, HMQC,

HMBC): d26.23, 27.18 8C8CH₃)₂), 71.84 8C-5), 74.61

8C-4), 77.58 8C-2), 79.15 8C-3), 111.46 8C8CH₃)₂), 116.29

8C-7), 138.46 8C-6), 175.62 8CONH₂). C₁₀H₁₇NO₅8231.24,

231.11), FAB MS: m/z 232.1 [M1H]¹.

1

8KBr): 3451 8br), 1678, 1382, 1257, 1218, 1089 cm²¹. H

NMR 8200 MHz, [D₅]pyridine, HH COSY): d1.41±1.58

8singlets for CH₃), 4.14±5.85 8many multiplets, CH), 7.21,

8.27, 8.34, 8.83 8unassigned signals), 10.0 8s, CHO). ¹³C

NMR 850 MHz, [D₅]pyridine, HETCOR): 22.25, 24.29

26.32, 26.61, 26.69, 26.76, 26.90, 27.02, 27.35, 27.49

8C8CH₃)₃signals), 69.51, 76.84, 76.93, 79.45, 81.90,

82.94, 83.80 8CH signals), 90.67, 94.13, 95.93, 111.51,

111.58, 111.73 8C8CH₃)₂signals), 113.33, 113.71

8unassigned signals), 172.91, 173.13, 174.75, 175.13,

175.62 8CONH₂signals), 199.54 8CHO). C₇H₁₁NO₄

8173.17, 173.06), FAB MS: m/z 174.2 [M1H]¹, 196.0

[M1Na]¹.

8.2.5. 6,7-Dideoxy-l-galacto-hept-6-enonamide .14b). A

mixture of 13a 842 mg, 0.12 mmol), Dowex 50 W X 8H¹

form, ,1.0 g) in ethanol±water 2:1 83 mL) was heated

under re¯ux. The reaction progress was followed by TLC

8CHCl₃±MeOH 90:10). After 1 h the solution was ®ltered,

the resin was washed with ethanol, and solvents were

removed from the combined ®ltrates. The crude solid

product was washed several times with CH₂Cl₂to afford

14b 821 mg, 91%) as colorless solid. R_f: 0.44 8CHCl₃±

8.2.3. 5-O-.tert-Butyldimethylsilyl)-6,7-dideoxy-2,3-O-

isopropylidene-l-galacto-hept-6-enonamide .13a). The

aldehyde 12 80.46 g, 2.7 mmol) and magnesium bromide

etherate 80.70 g, 2.7 mmol) were dissolved in anhydrous

CH₂Cl₂815 mL) under an argon atmosphere in an ice-

bath. 9 81.25 g, 2.7 mmol) in anhydrous CH₂Cl₂85 mL)

was added. The reaction was monitored by TLC 8CHCl₃±

MeOH 90:10). After 1 h the reaction mixture was removed

from the ice-bath and stirred at room temperature for 48 h

until all reactants were consumed. The reaction was stopped

by the addition of 5 mL of water, then acidi®ed with a few

drops of diluted HCl to remove the MgCl₂suspension and

stirred until the two phases had separated. The organic phase

were removed and the aqueous phase was extracted several

times with CH₂Cl₂. The combined organic extracts were

dried over Na₂SO₄and the solvent was removed. The

crude product was puri®ed by FC eluting with CHCl₃±

MeOH 95:5, to yield after solvent evaporation 13a

80.46 g, 50%). R_f: 0.35 8CHCl₃±MeOH 90:10). IR 8KBr):

1

MeOH 70:30). H NMR 8200, 300 MHz, [D₅]pyridine, HH

COSY): d4.67 8dd, 1H, 4-H), 4.88 8ddd, 1H, 5-H), 5.11 8d,

1H, 2-H), 5.23±5.32 8m, 2H, 3-H, 7-H_a), 5.65 8ddd, 1H,

7H_b), 6.42 8ddd, 1H, 6-H), 7.64 8bs, 2H, CONH₂).

J_2,38.8 Hz, J_3,48.1 Hz, J_4,53.1 Hz, J_5,65.5 Hz, J_6,7a

10.3 Hz, J_6,7b16.8 Hz. ¹³C NMR 850.3 MHz, [D₅]pyridine,

HETCOR):70.87 8C-5), 74.54 8C-3), 75.83 8C-2), 84.21

8C-4), 115.90 8C-7), 139.02 8C-6), 175.96 8CO). C₇H₁₃NO₅

8191.18, 191.079373). ESI MS: calculated for [2M22NH₃±

H]²: 347.10565, found: 347.09769 8lactone). A mass spec-

trum in the positive mode or a FAB MS could not be

obtained.

8.3. Ring closure of 13a

8a) Trying NIS: Tri¯uoromethanesulfonic acid 817.4 mL,

0.13 mmol) was added to a mixture of 13a 815.4 mg,

0.44 mmol) and NIS 849 mg, 0.22 mmol) in anhydrous

benzene 85 mL) under an argon atmosphere at 58C. The

resulting mixture was stirred for 3 h. The reaction was

monitored by TLC 8CHCl₃±MeOH 80:20). No reaction

was observed.

3391 8br), 3271 8br), 1683, 1654, 1378, 1253, 1084 cm²¹

.

¹H NMR 8200 MHz, CDCl₃, homodecoupling): d0.05,

0.07 82s, 6H, Si8CH₃)₂), 0.89 8s, 9H, C8CH₃)₃), 1.40, 1.46

82s, 6H, C8CH₃)₂), 3.50 8ddd, 1H, 4-H), 3.72 8d, 1H, 4-OH),

4.14 8dd, 1H, 3-H), 4.35 8dd, 1H, 5-H), 4.43 8d, 1H, 2-H),

5.18 8d, 1H, 7-H_a), 5.29 8d, 1H, 7-H_b), 5.97 8ddd, 1H, 6-H),

6.57, 6.62 82s, 2H, CONH₂). J_2,37.0 Hz, J_3,47.3 Hz,

J_4,52.6 Hz, J_4,OH5.5 Hz, J_5,66.6 Hz, J_6,7a10.6 Hz,

J_6,7b17.2 Hz. ¹³C NMR 850 MHz, CDCl₃, APT,

HETCOR): d24.43, 23.63 8Si8CH₃)₂), 18.68 8C8CH₃)₃),

26.38 8C8CH₃)₃), 27.27, 27.51 8C8CH₃)₂), 73.75 8C-5), 76.55

8C-4), 78.01 8C-3), 78.41 8C-2), 111.58 8C8CH₃)₂), 116.75

8C-7), 138.99 8C-6), 175.10 8CO). C₁₆H₃₁NO₅Si 8345.51,

345.20), FAB MS: m/z 346.1 [M1H]¹, 368.1 [M1Na]¹.

8b) Trying iodine: Iodine 824 mg, 0.094 mmol in 0.8 mL of

THF) was added to 13a 811.0 mg, 0.0032 mmol in 0.2 mL

of THF) and phthalate buffer 81.0 mL, pH4). The reaction

was monitored by TLC 8CHCl₃±MeOH 90:10). The reac-

tion mixture was stirred at room temperature for 72 h. After

stirring for 120 h the reaction was stopped by the addition of

sodium thiosulfate dissolved in a minimum amount of

water. After stirring until the solution became colorless,

solvents were removed under reduced pressure. The residue

was puri®ed by FC eluting with CHCl₃±MeOH 90:10, to

afford after solvent evaporation compound 14a 84.8 mg,

65%).

8.2.4. 6,7-Dideoxy-2,3-O-isopropylidene-l-galacto-hept-

6-enonamide .14a). Acetic acid 810% in water, 1 mL)

was added to 13a 825.0 mg, 0.072 mmol in 2 mL of THF).

The reaction was monitored by TLC 8CHCl₃±MeOH 95:5).

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

9445

8.4. Ring closure of 14b

8C-5), 82.46 8C-6), 85.48 8C-3), 173.82 8C-1). C₈H₁₃IO₆

8332.09, 331.97569), ESI MS: m/z calculated for

[2M2H]²: 662.95138, found 662.94368.

Compound 14b 80.27 g, 1.4 mmol) and mercuric tri¯uoro-

acetate 80.65 g, 1.5 mmol) were dissolved in anhydrous

THF 85 mL) under an argon atmosphere. The resulting

mixture was stirred at room temperature for 60 h, the reac-

tion was monitored by TLC 8CHCl₃±MeOH 80:20). KCl

80.11 g, 1.4 mmol) dissolved in a minimum amount of

water was added. The reaction mixture was stirred for

90 min, until all reactants were consumed as indicated by

TLC 8CHCl₃±MeOH 90:10). Solvents were removed under

reduced pressure, and the residue was puri®ed by FC eluting

with ethyl acetate±MeOH 90:10, to afford after solvent

evaporation 0.35 g of mercury containing compounds. The

produced mixture and I₂80.36 g, 1.4 mmol) were dissolved

in anhydrous THF 85 mL) under an argon atmosphere, the

reaction was monitored by TLC 8CHCl₃±MeOH 95:5).

After stirring for 5 h the reaction was stopped by the addi-

tion of sodium thiosulfate in a minimum amount of water.

After stirring until the solution became colorless, solvents

were removed under reduced pressure. The residue was

puri®ed by FC eluting with CHCl₃±MeOH 95:5, to afford

after solvent evaporation compound 15a 8130 mg, 29%) and

compound 15b 812 mg, 3%).

8.4.3. 5-O-.tert-Butyldimethylsilyl)-6,7-dideoxy-2,3-O-

isopropylidene-l-xylo-hept-6-en-4-ulosonamide .16). Com-

pound 13a 8135 mg, 0.39 mmol) was dissolved in a mixture of

anhydrous DMSO 80.75 mL) and acetic anhydride 80.5 mL)

under an argon atmosphere. The mixture was stirred at room

temperature. Progress of the reaction was followed by TLC

8CHCl₃±MeOH 94:6). After 5 h the reactants were consumed.

The reaction mixture was diluted with CH₂Cl₂830 mL) and

washed successively with water, saturated sodium bicarbonate

and water 85 mL each). The organic phase was dried over

sodium sulfate and concentrated under reduced pressure.

The crude product was puri®ed by FC eluting with CHCl₃±

MeOH 94:6, to afford after solvent evaporation 16 891 mg,

68%). R_f: 0.69 8CHCl₃±MeOH 90:10). IR 8KBr): 3475, 3344,

1

2954, 2927, 2858, 1730, 1685, 1381, 1254, 1088 cm²¹. H

NMR 8200 MHz, CDCl₃, HH COSY): d0.08, 0.12 8s, 6H,

Si8CH₃)₂), 0.92 8s, 9H, C8CH₃)₃), 1.46, 1.47 82s, 6H,

C8CH₃)₂), 4.67 8d, 1H, [2-H or 3-H]), 4.98 8m, 1H, 5-H),

4.99 8m, 1H, [2-H or 3-H]), 5.31 8ddd, 1H, 1H, 7-H_a), 5.47

8ddd, 1H, 7-H_b), 5.93 8ddd, 1H, 6-H), 6.57, 6.62 82s, 2H,

CONH₂). J_2,36.2 Hz, J_5,65.9 Hz, J_6,7a10.3 Hz, J_6,7b

16.1 Hz. ¹³C NMR: 8100 MHz, CDCl₃, APT, HMQC):

d24.55, 24.36 8Si8CH₃)₂), 18.81 8C8CH₃)₃), 26.21

8C8CH₃)₃), 26.90 8C8CH₃)₂), 77.07, 78.93, 78.99 8C-2, C-3,

C-5), 113.47 8C8CH₃)₂), 118.88 8C-7), 134.92 8C-6), 173.10

8CONH₂), 205.21 8C-4). C₁₆H₂₉NO₅Si 8343.49, 343.18), FAB

MS: m/z 344.1 [M1H]¹, 366.1 [M1Na]¹.

8.4.1. Methyl 3,6-anhydro-7-deoxy-7-iodo-d-glycero-l-

galacto-heptonate .15a). Mp 146±1478C. R_f: 0.17

8CHCl₃±MeOH 90:10). H NMR 8200 MHz, [D₅]pyridine,

1

homodecoupling, HH COSY): d3.54 8dd, 1H, 7-H), 3.67

8s, 3H, OCH₃), 3.73 8dd, 1H, 7-H⁰), 4.63 8broad, 1H, 5-H),

4.81 8ddd, 1H, 6-H), 4.89 8d, 1H, 2-H), 4.93 8dd, 1H, 3-H),

4.97 8broad, 1H, 4-H). J_2,32.9 Hz, J_3,42.6 Hz, J_6,7

6.2 Hz, J_6,77.8 Hz, J_7,79.5 Hz. ¹H NMR 8200 MHz,

[D₅]pyridine1D₂O): d3.43 8dd, 1H, 7-H), 3.62 8s, 3H,

OCH₃), 3.63 8dd, 1H, 7-H⁰), 4.62 8dd, 1H, 5-H), 4.63±

4.72 8m, 1H, 6-H), 4.83 8d, 1H, 2-H), 4.86 8m, 1H, 3-H),

4.94 8m, 1H, 4-H). J_2,32.8 Hz, J_4,51.9 Hz, J_5,63.4 Hz,

0

8.4.4. 5-O-.tert-Butyldimethylsilyl)-6,7-dideoxy-2,3-O-

isopropylidene-l-gluco-hept-6-enonamide .13b). Sodium

borohydride 82.5 mg, 0.066 mmol) was added in one portion

to a solution of 16 822.4 mg, 0.065 mmol) and CeCl₃´6H₂O

826.1 mg, 0.069 mmol) dissolved in methanol 82.5 mL).

After stirring at room temperature for 15 min the reactants

were consumed as indicated by TLC 8CHCl₃±MeOH 95:5).

Acetone 83 mL) was added to stop the reaction. The solvent

was removed under reduced pressure and the remaining oil

was dissolved in CH₂Cl₂830 mL), and washed with water

82£5 mL). The organic phase was dried over sodium sulfate.

The crude product was puri®ed using FC eluting with

CHCl₃±EtOH 93:7 to furnish after solvent evaporation

13b 819 mg, 86%). R_f: 0.34 8CHCl₃±MeOH 90:10). IR

8KBr): 3534 8br), 3411 8br), 3319 8br), 1688, 1658, 1383,

1255, 1083 cm²¹. ¹H NMR 8200 MHz, CDCl₃, homodecou-

pling, HH COSY): d0.03, 0.06 8s, 6H, Si8CH₃)₂), 0.88 8s,

9H, C8CH₃)₃), 1.43, 1.48 82s, 6H, C8CH₃)₂), 2.24 8d, 1H,

4-OH), 3.65 8ddd, 1H, 4-H), 4.12 8m, 1H, 5-H), 4.37 8dd,

1H, 3-H), 4.47 8d, 1H, 2-H), 5.21 8m, 1H, 7- H_a), 5.31 8m,

1H, 7-H_b), 5.91 8ddd, 1H, 6-H), 6.18, 6.55 82s, 2H, CONH₂).

J_2,38.4 Hz, J_3,41.1 Hz, J_4,OH9.5 Hz, J_4,57.7 Hz, J_5,6

J_6,76.3 Hz, J_6,77.5 Hz, J_7,78.9 Hz. ¹³C NMR 875 MHz,

[D₅]pyridine, HETCOR): d2.53 8C-7), 51.72 8OCH₃),

71.95 8C-2), 77.98 8C-5), 79.37 8C-4), 83.35 8C-6), 88.46

8C-3), 172.88 8C-1). C₈H₁₃IO₆8332.09, 331.98), FAB MS:

m/z 333.0 [M1H]¹, 355.0 [M1Na]¹. Crystal data for

C₈H₁₃IO₆: Siemens P4 diffractometer, Mo Ka radiation,

orthorhombic, space group P2₁2₁2₁; a6.28382), b

0

Ê

Ê ³

8.48183), c20.44088) A, U1089.286) A , F8000)648,

Z4, D_c2.025 g cm²³, R0.029[I.2s8I)], wR₂0.072

for 1831 unique re¯ections 82u_max608), Flackabsolute

structure parameter 0.0183). Full crystallographic details

have been deposited with the Cambridge Crystallographic

Data Center 8CCDC 150778). Copies may be obtained

free of charge on application to the Director, CCDC, 12

Union Road, Cambridge CB2 1EZ, UK 8e-mail: deposit

@c.ck.cam.ac.uk).

1

6.6 Hz, J_6,710.3 Hz, J_6,7b17.0 Hz. H NMR 8200 MHz,

8.4.2. Methyl 3,6-anhydro-7-deoxy-7-iodo-l-glycero-l-

galacto-heptonate .15b). R_f: 0.20 8CHCl₃±MeOH 90:10).

¹H NMR 8600 MHz, [D₅]pyridine, HH COSY): d3.62 8dd,

1H, 7-H), 3.67 8s, 3H, OCH₃), 3.69 8m, 1H, 7-H⁰), 4.20 8m,

1H, 6-H), 4.68 8dd, 1H, 5-H), 4.92±4.96 8m, 2H, 2-H, 3-H),

5.29 8dd, 1H, 4-H). J_3,46.7 Hz, J_4,56.7 Hz, J_5,66.1 Hz,

CDCl₃1D₂O): Similar to the previous data but the signal

at 2.24 was reduced and the signal at 3.65 became a dd. ¹³C

NMR 850 MHz, CDCl₃, APT, HETCOR): d24.56, 23.66

8Si8CH₃)₂), 18.58 8C8CH₃)₃), 26.23 8C8CH₃)₃), 26.58, 27.35

8C8CH₃)₂), 72.82 8C-4), 75.35 8C-5), 76.14 8C-2), 78.15

8C-3), 111.09 8C8CH₃)₂), 117.57 8C-7), 139.45 8C-6),

174.26 8CO). C₁₆H₃₁NO₅Si 8345.51, 345.20), FAB MS:

m/z 346.1 [M1H]¹, 368.1 [M1Na]¹.

J_6,74.9 Hz, J_6,76.4 Hz, J_7,710.6 Hz. ¹³C NMR

8150 MHz, [D₅]pyridine, HMQC, HMBC): d10.90

8C-7), 51.86 8OCH₃), 71.77 8C-2), 77.65 8C-4), 81.68

0

9446

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

8.4.5. 6,7-Dideoxy-l-gluco-hept-6-enoic acid .17).

Following the procedure used to deprotect 13a, 13b

864 mg, 0.19 mmol) gave 17 833.5 mg 94%) as a colorless

solid. R_f: 0.44 8CHCl₃±MeOH 70:30). ¹H NMR 8200,

300 MHz, [D₅]pyridine, HH COSY): d5.00±5.22 8m,

4H, 2-H, 3-H, 4-H, 5-H), 5.68 8ddd, 1H, 7-H_a), 5.67 8ddd,

1H, 7H_b), 6.42 8ddd, 1H, 6-H). J_5,65.7 Hz, J_6,7a10.4 Hz,

J_6,7b16.7 Hz. ¹³C NMR 850 MHz, [D₅]pyridine, HMQC):

d71.27, 74.78, 74.97, 83.99 8C-2, C-3, C-4, C-5), 116.11

8C-7), 139.56 8C-6), 177.06 8CO). C₇H₁₂O₆8192.17,

192.063388), ESI MS: m/z calculated for [M2H]²:

191.06339, found 191.05561.

d3.20 8C-7), 70.21, 73.33, 82.43 8C-2, C-3, C-4), 71.96

8C-5), 82.09 8C-6), 173.04 8C-1). C₇H₁₁IO₆8318.07,

317.960040), ESI MS: m/z calculated for [M2H]²:

316.96004, found 316.95255, calculated for [2M2H]²:

634.92008, found: 634.91289.

8.5.3. 5-O-.tert-Butyldimethylsilyl)-6,7-dideoxy-2,3-O-

isopropylidene-4-O-phenoxycarbonyl-l-galacto-hept-6-

enonamide .20a). Phenyl chloroformate 8135 mL, 0.17 g,

1.0 mmol) was injected into a solution of 13a 80.29 g,

0.84 mmol) and anhydrous pyridine 80.3 mL) in CH₂Cl₂

83 mL) under an argon atmosphere at 08C. The reaction

progress was followed by TLC 8CHCl₃±MeOH 95:5).

After stirring the reaction mixture for 1 h the reactants

were consumed. The reaction was stopped by adding

water 85 mL). After extraction with CH₂Cl₂83£30 mL),

the combined phases were dried with sodium sulfate. The

solvent was removed under reduced pressure. The crude

product was puri®ed by FC eluting with PE±ethyl acetate

1:1, to furnish after solvent evaporation 20a 80.24 g, 60%).

8.5. Ring closure of 17

Compound 17 833.5 mg, 0.18 mmol) and mercuric tri¯uoro-

acetate 875 mg, 0.18 mmol) were dissolved in 2 mL of

anhydrous THF under an argon atmosphere. The resulting

mixture was stirred at room temperature for 8 h, the reaction

was monitored by TLC 8CHCl₃±MeOH 90:10). KCl

813.4 mg, 0.18 mmol) dissolved in a minimum amount of

water was added to the reaction mixture. The reaction

mixture was then stirred for 90 min until all reactants

were consumed as indicated by TLC 8ethyl acetate±

MeOH 90:10). The solvent was removed under reduced

pressure, and the residue was puri®ed by FC eluting with

ethyl acetate±MeOH 90:10, to afford after solvent evapora-

tion compounds A 823.0 mg) and B 812.2 mg). Compound A

and I₂82.5 mg, 0.010 mmol) were dissolved in anhydrous

THF 81 mL) under an argon atmosphere. The reaction was

monitored by TLC 8CHCl₃±MeOH 95:5). After 4 h the

reaction was stopped by the addition of a solution of sodium

thiosulfate in a minimum amount of water. After stirring

until the solution became colorless, the solvents were

removed under reduced pressure. The residue was puri®ed

by FC eluting with ethyl acetate, to afford after solvent

evaporation compound 18a 812.7 mg, 22%). The same

procedure was used for compound B, to afford 18b

83.0 mg, 5.3%) after puri®cation by FC eluting with

CHCl₃±MeOH 95:5.

1

R_f: 0.6 8CHCl₃±MeOH 95:5). H NMR 8200 MHz, CDCl₃,

HH COSY): d0.08, 0.13 8s, 6H, Si8CH₃)₂), 0.92 8s, 9H,

C8CH₃)₃), 1.44, 1.50 82s, 6H, C8CH₃)₂), 4.41 8dd, 1H, 3-H),

4.53±4.62 8m, 1H, 2-H, 5-H), 5.01 8dd, 1H, 4-H), 5.27 8m,

1H, 7-H_a), 5.46 8m, 1H, 7-H_b), 5.98 8ddd, 1H, 6-H), 6.20,

6.53 82s, 2H, CONH₂), 7.18±7.45 8m, 5H, Ar±2-H, Ar±2⁰-

H, Ar±4-H, Ar±3-H, Ar±3⁰-H). J_2,37.0 Hz, J_3,44.0 Hz,

J_4,57.0 Hz, J_5,66.2 Hz, J_6,7a10.6 Hz, J_6,7b17.0 Hz. ¹³

C

NMR: 850 MHz, CDCl₃, APT, HETCOR): d24.46,

23.90 8Si8CH₃)₂), 18.67 8C8CH₃)₃), 26.30 8C8CH₃)₃),

26.52, 26.33 8C8CH₃)₂), 72.16 8C-5), 76.73 8C-2), 77.79

8C-3), 80.70 8C-4), 111.11 8C8CH₃)₂), 118.76 8C-7),

121.57 8Ar±C-2, Ar±C-2⁰), 126.35 8Ar±C-4), 129.85

8Ar±C-3, Ar±C-3⁰), 137.32 8C-6), 151.83 8OCOO),

154.10 8Ar±C-1), 173.72 8CONH₂). C₂₃H₃₅NO₇Si 8465.62,

465.22), FAB MS: m/z 466.4 [M1H]¹, 488.3 [M1Na]¹.

8.5.4. 5-O-.tert-Butyldimethylsilyl)-6,7-dideoxy-2,3-O-

isopropylidene-4-O-carbamoyl-l-galacto-hept-6-enon-

amide .20b). In a pressure reactor 8BuÈchi AG MiniClave)

compound 23a 852.3 mg, 0.11 mmol) was dissolved in

CH₂Cl₂84 mL). Gaseous ammonia was bubbled for

10 min into the reaction mixture while the apparatus was

cooled down using liquid nitrogen. Then the solution was

allowed to warm to room temperature. The reaction mixture

was stirred at room temperature at ,5 bar for 13 h, by this

time all reactants were consumed as indicated by TLC 8ethyl

acetate). The solvent was removed under reduced pressure.

The crude product was puri®ed by FC eluting with ethyl

acetate, to afford after solvent evaporation solid 20b

839.3 mg, 90%). R_f: 0.50 8ethyl acetate). IR 8KBr): 3425

8.5.1. 3,6-Anhydro-7-deoxy-7-iodo-J-glycero-l-gluco-

heptanoic acid .18a). R_f: 0.17 8CHCl₃±MeOH 90:10). H

1

NMR 8200, 600 MHz, [D₅]pyridine, homodecoupling, HH

COSY): d3.58 8dd, 1H, 7-H), 3.75 8dd, 1H, 7-H⁰), 4.42

8ddd, 1H, 6-H), 4.61 8dd, 1H, 5-H), 5.13 8dd, 1H, 3-H), 5.23

8d, 1H, 2-H), 5.28 8dd, 1H, 4-H), 8.34 8s, 1H, OH).

J_2,34.8 Hz, J_3,48.1 Hz, J_4,54.2 Hz, J_5,62.8 Hz, J_6,7

6.5 Hz, J_6,77.7 Hz, J_7,79.3 Hz. ¹³C NMR 850,

150 MHz, [D₅]pyridine, APT, HMQC, HMBC): d2.43

8C-7), 69.84 8C-5), 75.01 8C-2), 80.97 8C-4), 84.41 8C-6),

85.74 8C-3), 178.00 8C-1). C₇H₁₁IO₆8318.07, 317.960040),

ESI MS: m/z calculated for [M2H]²: 316.96004, found

316.95206, calculated for [2M2H]²: 634.92008, found:

634.91064.

0

1

8br), 3379 8br), 1722, 1688, 1380, 1254 cm²¹. H NMR

8200 MHz, CDCl₃. HH COSY): d0.04, 0.07 8s, 6H,

Si8CH₃)₂), 0.89 8s, 9H, C8CH₃)₃), 1.41, 1.45 82s, 6H,

C8CH₃)₂), 4.38 8dd, 1H, 3-H), 4.45 8d, 1H, 2-H), 4.46 8dd,

1H, 5-H), 4.90 8dd, 1H, 4-H), 5.16 8bs, 2H, OCONH₂), 5.19

8m, 1H, 7-H_a), 5.33 8ddd, 1H, 7-H_b), 5.88 8ddd, 1H, 6-H),

6.22, 6.49 82d, 2H, CONH₂). J_2,36.6 Hz, J_3,45.9 Hz,

J_5,66.2 Hz, J_6,7a10.4 Hz, J_6,7b17.2 Hz, J_NH,NH2.8 Hz.

¹³C NMR 850 MHz, CDCl₃, APT, HETCOR): d24.47,

23.86 8Si8CH₃)₂), 18.70 8C8CH₃)₃), 26.31 8C8CH₃)₃),

26.59, 27.51 8C8CH₃)₂), 72.83, 77.57, 77.62 8C-2, C-3,

C-5), 76.84 8C-4), 111.33 8C8CH₃)₂), 117.70 8C-7), 137.74

8.5.2. 3,6-Anhydro-7-deoxy-7-iodo-J-glycero-l-gluco-

heptanoic acid .18b). R_f: 0.95 8CHCl₃±MeOH 90:10). H

1

NMR 8200, 600 MHz, [D₅]pyridine, HH COSY): d3.49

8dd, 1H, 7-H), 3.72 8dd, 1H, 7-H⁰), 4.30 8ddd, 1H, 6-H), 4.43

8dd, 1H, 5-H), 4.90±5.03 8m, 3H, 2-H, 3-H, 4-H).

0

J_4,54.0 Hz, J_5,63.3 Hz, J_6,76.2 Hz, J_6,77.9 Hz, J_7,7

9.3 Hz. ¹³C NMR: 875 MHz, [D₅]pyridine, HMQC):

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

9447

8C-6), 157.18 8OCONH₂), 173.93 8CONH₂). C₁₇H₃₂N₂O₆Si

8388.53, 388.20), FAB MS: m/z 389.2 [M1H]¹, 411.2

[M1Na]¹.

calculated for [2M1H]¹: 1411.22123, found 1411.22892,

calculated for [2M1Na]¹: 1433.21104, found 1433.20709.

8.6. Glycosylation of acceptor 14a

8.5.5. 6,7-Dideoxy-2,3-O-isopropylidene-4-O-carbamoyl-

l-galacto-hept-6-enonamide .20c). Acetic acid 825% in

water, 2.5 mL) was added to 20b 80.10 g, 0.26 mmol).

The reaction was followed by TLC 8ethyl acetate). After

stirring the reaction mixture at 608C for 2 h, the reactants

were consumed. The solvent was removed 8codistillation

with toluene) under reduced pressure. The resulting solid

was washed many times with CH₂Cl₂to afford 20c

870 mg, 97%). R_f: 0.30 8ethyl acetate), 0.20 8CHCl₃±EtOH

90:10). IR 8KBr): 3471 8br), 3438 8br), 1724, 1672, 1613,

A mixture of 14a 8162 mg, 0.70 mmol), 21 80.53 g,

Ê

0.89 mmol), and activated 3 A molecular sieves 81.0 g) in

anhydrous acetonitrile 82 mL) was stirred for 1 h at room

temperature under an argon atmosphere, then cooled to

2208C. Trimethylsilyl tri¯ate 827 mL, 0.15 mmol) was

injected into the reaction ¯askin portions during 1 h. The

reaction was monitored by TLC 8CHCl₃±ethyl acetate 1:1).

The reaction mixture was stirred at 2208C for additional 5 h

until all reactants were consumed. The reaction was stopped

by the addition of triethylamine 80.1 mL), the mixture was

®ltered, the molecular sieves were washed with CH₂Cl₂. The

solvents were removed under reduced pressure. The crude

product was puri®ed by FC eluting with CHCl₃±EtOH 94:6,

to give a mixture of 22b and 23b 80.11 g, 22% in a ratio 3:1),

and 23a 80.1739 g, 22%). 22b and 23b were not separable at

this stage.

1

1378, 1088 cm²¹. H NMR 8200 MHz, [D₅]pyridine, HH

COSY): d1.46, 1.53 82s, 6H, C8CH₃)₂), 4.96 8m, 1H,

5-H), 5.10 8dd, 1H, 3-H), 5.25 8d, 1H, 2-H), 5.25 8m, 1H,

7-H_a), 5.76 8m, 1H, 7-H_b), 5.81 8dd, 1H, 4-H), 6.40 8ddd, 1H,

6-H), 7.61 8bs, 2H, OCONH₂), 8.35, 8.82 82s, 2H, CONH₂).

J_2,36.0 Hz, J_3,43.8 Hz, J_5,64.8 Hz, J_6,7a10.4 Hz,

J_6,7b17.1 Hz. ¹³C NMR 850 MHz, [D₅]pyridine,

HETCOR): d26.37, 27.54 8C8CH₃)₂), 71.82 8C-5), 75.65

8C-4), 76.97 8C-2), 80.47 8C-3), 110.84 8C8CH₃)₂), 115.83

8C-7), 139.56 8C-6), 158.37 8OCONH₂), 176.11 8CONH₂).

C₁₁H₁₈N₂O₆8274.27, 274.12), FAB MS: m/z 275.1

[M1H]¹, 297.1 [M1Na]¹.

The reaction was repeated using the same procedure but the

ratio of TMS±OTf was increased 80.21!0.45 equiv.). 14a

80.40 g, 1.73 mmol), 21 81.03 g, 1.73 mmol), acetonitrile

82 mL), TMS±OTf 8140 mL, 0.45 equiv.) afforded after

puri®cation by FC 8eluting with CHCl₃±EtOH 94:6): 22b

80.36 g, 32%), 23e 852 mg, 4.1%), and 23a 80.18 mg, 9.6%).

8.5.6. 4-O-Carbamoyl-5-O-[3,4,6-tri-O-acetyl-2-deoxy-2-

.2,2,2-trichloroacetamido)-b-d-glucopyranosyl]-6,7-di-

deoxy-2,3-O-isopropylidene-l-galacto-hept-6-enonamide

.22a). A mixture of 20c 822 mg, 0.080 mmol) and 21

8.6.1. 5-O-[3,4,6-Tri-O-acetyl-2-deoxy-2-.2,2,2-trichloro-

acetamido)-b-d-glucopyranosyl]-6,7-dideoxy-2,3-O-iso-

propylidene-l-galacto-hept-6-enonamide .22b). R_f: 0.45

8CHCl₃±EtOH 90:10). IR 8KBr): 3341 8br), 1748, 1677,

Ê

857 mg, 0.10 mmol) and activated 3 A molecular sieves

81.0 g) in anhydrous CH₂Cl₂85 mL) was stirred for 1 h at

room temperature under an argon atmosphere, then cooled

to 08C. Trimethylsilyl tri¯ate 85 mL, 0.027 mmol) was

injected into the reaction ¯askand the reaction was moni-

tored by TLC 8PE±ethyl acetate 1:1). After stirring the

mixture for 2 h the reactants were consumed. Triethylamine

80.1 mL) was added to stop the reaction and the mixture was

®ltered, the molecular sieves were washed with CH₂Cl₂, the

solvent was removed under reduced pressure. The crude

product was puri®ed by FC eluting with PE±ethyl acetate

1:1, to afford after solvent evaporation 22a 811.2 mg, 20%).

R_f: 0.22 8CHCl₃±EtOH 90:10). ¹H NMR 8400 MHz, CDCl₃,

HH COSY): d1.39 8s, 6H, C8CH₃)₂), 1.97 8s, 6H, COCH₃),

2.06 8s, 3H, COCH₃), 3.67 8m, 1H, 5^E-H), 3.86 8m, 1H,

2^E-H), 4.07 8dd, 1H, 6^E-H), 4.19 8dd, 1H, 6^E-H⁰), 4.38 8m,

2H, 3-H, 5-H), 4.52 8d, 1H, 2-H), 4.78±4.86 8m, 2H, 4-H,

1^E-H), 5.04 83H, 4^E-H, OCONH₂), 5.21 8d, 1H, 7-H_a), 5.79

8d, 1H, 7-H_b), 5.41 8dd, 1H, 3^E-H), 5.76, 6.50 82s, 2H,

CONH₂), 5.86 8m, 1H, 6-H), 7.51 8d, 1H, NH^E).

J_2,35.0 Hz, J_6,7a11.3 Hz, J_6,7b17.0 Hz, J_1E,2E8.1 Hz,

1530, 1375, 1238, 1042 cm²¹

.

¹H NMR 8400 MHz,

CDCl₃, HH COSY): d1.39 8s, 6H, C8CH₃)₂), 1.956,

1.964, 2.02 83s, 9H, COCH₃), 3.62 8dd, 1H, 4-H), 3.66

8ddd, 1H, 5^E-H), 3.90 8ddd, 1H, 2^E-H), 4.03±4.09 8m, 2H,

3-H, 6^E-H), 4.07 8dd, 1H, 3-H), 4.16 8dd, 1H, 6^E-H⁰), 4.25

8dd, 1H, 5-H), 4.41 8d, 1H, 2-H), 4.90 8d, 1H, 1^E-H), 5.01

8dd, 1H, 4^E-H), 5.18 8d, 1H, 7-H_a), 5.32 8d, 1H, 7-H_b), 5.38

8dd, 1H, 3^E-H), 5.97 8ddd, 1H, 6-H), 6.26, 6.62 82s, 2H,

CONH₂), 7.52 8d, 1H, NH^E). J_2,37.1 Hz, J_3,46.7 Hz,

J_4,54.6 Hz, J_5,67.4 Hz, J_6,7a10.6 Hz, J_6,7b17.7 Hz,

J_1E,2E8.1 Hz, J_2E,3E10.6 Hz, J_2E,NH8.1 Hz, J_3E,4E

0

9.5 Hz, J_4E,5E9.9 Hz, J_5E,6E2.5 Hz, J_{5E,6 E}5.3 Hz,

J_{6E,6 E}11.9 Hz. ¹³C NMR 850 MHz, CDCl₃, HMQC,

0

HMBC): d20.76, 20.88 8COCH₃signals), 26.53, 27.15

8C8CH₃)₂), 56.73 8C-2^E), 62.37 8C-6^E), 68.93 8C-4^E),

71.93, 71.96 8C-3^E, C-5^E), 75.33 8C-4), 77.50 8C-2, C-3),

82.19 8C-5), 92.61 8CCl₃), 100.00 8C-1^E), 111.55 8C8CH₃)₂),

118.82 8C-7), 135.57 8C-6), 162.39 8COCCl₃), 169.61,

170.82,

C₂₄H₃₃Cl₃N₂O₁₃8663.89, 662.10), FAB MS: m/z 663.0

170.93

8COCH₃),

174.50

8CONH₂).

J_2E,3E9.5 Hz, J_2E,NH7.1 Hz, J_3E,4E9.9 Hz, J_4E,5E

6.7 Hz, J_5E,6E,1 Hz, J_{5E,6 E}4.4 Hz, J_{6E,6 E}11.8 Hz. ¹³C

NMR 850 MHz, CDCl₃, HMQC): d21.12, 21.25

8COCH₃signals), 27.14, 27.64 8C8CH₃)₂), 57.13 8C-2^E),

62.34 8?), 62.68 8C-6^E), 69.14 8C-4^E), 71.80 8C-5^E), 72.36

8C-3^E), 75.33 8C-4), 76.71 8C-2), 77.31, 81.05 8C-3, C-5),

92.88 8CCl₃), 99.59 8C-1^E), 111.87 8C8CH₃)₂), 118.84 8C-7),

134.92 8C-6), 156.91 8OCONH₂), 162.72 8COCCl₃), 170.02,

171.07, 171.17, 174.04 8COCH₃) and 8CONH₂).

C₂₅H₃₄Cl₃N₃O₁₄8706.92, 705.110636), ESI MS: m/z

calculated for [M1Na]¹: 728.10041, found 728.09966,

[M1H]¹, 685.0 [M1Na]¹.

0

8.6.2. 5-O-.Trimethylsily)-4-O-[3,4,6-tri-O-acetyl-2-deoxy-

2-.2,2,2-trichloroacetamido)-b-d-glucopyranosyl]-6,7-

dideoxy-2,3-O-isopropylidene-l-galacto-hept-6-enon-

amide .23e). R_f: 0.38 8CHCl₃±EtOH 90:10). IR 8KBr): 3449

8br), 3359 8br), 1750, 1688, 1529, 1374, 1239, 1040 cm²¹

.

¹H NMR 8400 MHz, CDCl₃, HH COSY): d0.07 8s, 9H,

Si8CH₃)₃), 1.40, 1.44 82s, 6H, C8CH₃)₂), 1.988, 2.008, 2.063

83s, 9H, COCH₃), 3.70 8ddd, 1H, 5⁰-H), 3.76 8dd, 1H, 4-H),

9448

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

3.80 8m, 1H, 2⁰-H), 4.16 8dd, 1H, 6⁰-H), 4.26 8dd, 1H,

6⁰-H⁰), 4.29 8dd, 1H, 3-H), 4.41 8m, 1H, 5-H), 4.62 8d,

1H, 2-H), 5.02 8d, 1H, 1⁰-H), 5.08 8dd, 1H, 4⁰-H), 5.20 8d,

1H, 7-H_a), 5.31 8d, 1H, 7-H_b), 5.44 8dd, 1H, 3⁰-H), 5.88 8m,

1H, 6-H), 5.94, 6.52 82s, 2H, CONH₂), 7.34 8d, 1H, NH⁰).

triethylamine 30:70:0.1, to furnish after solvent evaporation

23c 814.6 mg, 21%) and 23d 836 mg, 53%).

8.7.1. 4-O-[3,4,6-Tri-O-acetyl-2-deoxy-2-.2,2,2-trichloro-

acetamido)-b-d-glucopyranosyl]-6,7-dideoxy-2,3-O-iso-

propylidene-5-O-phenoxycarbonyl-l-galacto-hept-6-

enonamide .23c). R_f: 0.21 8PE±ethyl acetate±TEA

30:70:1). IR 8KBr): 3450 8br), 3257 8br), 1752, 1689,

J_2,36.4 Hz, J_3,47.7 Hz, J_4,52.5 Hz, J_5,65.7 Hz, J_6,7a

0

10.2 Hz, J_6,7b17.1 Hz, J_{1 ,2}8.1 Hz, J_{2 ,NH}8.1 Hz,

0

J_{2 ,3}10.6 Hz, J_{3 ,4}9.5 Hz, J_{4 ,5}9.9 Hz, J_{5 ,6}2.5 Hz,

J_{5 ,6}4.6, Hz J_{6 ,6}12.2 Hz. ¹³C NMR 874 MHz, CDCl₃,

APT, HMQC, HMBC): d0.39 8Si8CH₃)₃), 20.65, 20.70,

20.74 8COCH₃), 26.13, 27.26 8C8CH₃)₂), 56.75 8C-2⁰),

61.79 8C-6⁰), 68.66 8C-4⁰), 71.07 8C-3⁰), 71.96 8C-5⁰),

73.01 8C-5), 76.81 8C-3), 77.74 8C-2), 81.36 8C-4), 92.36

8CCl₃), 99.34 8C-1⁰), 111.40 8C8CH₃)₂), 117.03 8C-7),

138.28 8C-6), 162.11 8COCCl₃), 169.54, 170.67, 170.74

8COCH₃), 173.68 8CONH₂). C₂₇H₄₁Cl₃N₂O₁₃Si 8736.07,

734.14), FAB MS: m/z 757.0 [M1Na]¹.

.

1374, 1243, 1080, 1043 cm²^{1 1}H NMR 8400 MHz,

0

0 0

0

0 0

CDCl₃, HH COSY): d1.42, 1.46 82s, 6H, C8CH₃)₂),

2.01, 2.02, 2.07 83s, 9H, COCH₃), 3.75 8ddd, 1H, 5⁰-H),

3.94 8ddd, 1H, 2⁰-H), 4.11 8m, 1H, 4-H), 4.19 8dd, 1H,

6⁰-H), 4.29 8dd, 1H, 6⁰-H⁰), 4.42 8dd, 1H, 3-H), 4.63 8d,

1H, 2-H), 5.06 8d, 1H, 1⁰-H), 5.14 8dd, 1H, 4⁰-H), 5.25±

5.46 8m, 3H, 3⁰-H, 5-H, 7-H_a), 5.51 8narrow m, 1H, 7-H_b),

5.76 8d, 1H, CONH), 5.91 8ddd, 2H, 6-H), 6.55 8d, 1H,

CONH⁰), 7.15±7.42 8m, 6H, Ar±H's, NH⁰). J_2,36.2 Hz,

J_3,45.5 Hz, J_5,66.91 Hz, J_6,7a10.3 Hz, J_6,7b17.2 Hz,

8.6.3. 4,5-Di-O-[3,4,6-tri-O-acetyl-2-deoxy-2-.2,2,2-tri-

chloroacetamido)-b-d-glucopyranosyl]-6,7-dideoxy-2,3-

O-isopropylidene-l-galacto-hept-6-enonamide .23a). R_f:

0.45 8CHCl₃±EtOH 90:10). IR 8KBr): 3448 8br), 3366

0

J_NH,NN2.5 Hz, J_{1 ,2}8.2 Hz, J_{3 ,4}9.5 Hz, J_{4 ,5}9.9 Hz,

J_{5 ,6}2.7 Hz, J_{5 ,6}4.3 Hz, J_{6 ,6}12.4 Hz. ¹³C NMR

850 MHz, CDCl₃, HMQC, HMBC): d20.94, 20.99,

21.06 8COCH₃), 26.61, 27.47 8C8CH₃)₂), 56.91 8C-2⁰),

62.09 8C-6⁰), 68.79 8C-4⁰), 71.62 8C-3⁰), 72.44 8C-5⁰),

77.07 8C-2), 77.69 8C-3), 79.02 8C-5), 79.20 8C-4), 92.59

8CCl₃), 100.08 8C-1⁰), 112.13 8C8CH₃)₂), 121.35 8C-7),

121.43 8Ar±C-2, Ar±C-2⁰), 126.61 8Ar±C-4), 130.03

8Ar±C-3, Ar±C-3⁰), 132.36 8C-6), 151.56 8Ar±C-1),

152.89 8OCOO), 162.69 8COCCl₃), 169.95, 171.16,

171.29 8COCH₃), 173.88 8CONH₂). C₃₁H₃₇Cl₃N₂O₁₅

8784.00, 782.13), FAB MS: m/z 804.9 [M1Na]¹.

0

0 0

0

0 0

8br), 1750, 1527, 1374, 1235, 1042 cm²^{1 1}H NMR

.

8600 MHz, CDCl₃, HH COSY): d1.41, 1.43 82s, 6H,

C8CH₃)₂), 1.993 8s, 6H, COCH₃), 1.998, 2.004, 2.070,

2.075 84s, 12H, COCH₃), 3.64 8m, 1H, 5^E-H), 3.75 8m,

2H, 2^E-H, 5⁰-H), 3.85 8dd, 1H, 4-H), 3.89 8m, 1H, 2⁰-H),

4.02 8d, 1H, 6^E-H), 4.16 8m, 2H, 6^E-H⁰, 6⁰-H), 4.26 8d, 1H,

6⁰-H⁰), 4.30 8dd, 1H, 5-H), 4.44 8dd, 1H, 3-H), 4.73 8d, 1H,

2-H), 4.91 8d, 1H, 1^E-H), 4.96 8dd, 1H, 4^E-H), 5.04 8m, 2H,

1⁰-H, 4⁰-H), 5.20 8d, 1H, 7-H_a), 5.28 8d, 1H, 7-H_b), 5.52 8dd,

1H, 3⁰-H), 5.61 8dd, 1H, 3^E-H), 6.03 8m, 1H, 6-H), 6.55 8bs,

2H, CONH₂), 7.73 8d, 1H, NH^E), 7.94 8bs, 1H, NH⁰).

8.7.2. 5-O-[3,4,6-Tri-O-acetyl-2-deoxy-2-.2,2,2-trichloro-

acetamido)-b-d-glucopyranosyl]-6,7-dideoxy-2,3-O-iso-

propylidene-4-O-phenoxycarbonyl-l-galacto-hept-6-

enonamide .23d). R_f: 0.29 8PE±ethyl acetate±TEA

30:70:1). IR 8KBr): 3441, 1751, 1688, 1374, 1245, 1078,

J_2,35.2 Hz, J_3,46.5 Hz, J_4,52.6 Hz, J_5,68.4 Hz, J_6,7a

10.5 Hz, J_6,7b17.2 Hz, J_1E,2E8.4 Hz, J_2E,3E9.9 Hz,

J_2E,NH8.4 Hz, J_3E,4E9.4 Hz, J_4E,5E9.4 Hz, J_5E,6E

1045 cm²^{1 1}H NMR 8200 MHz, CDCl₃, HH COSY):

.

0

2.1 Hz, J_{6E,6 E}12.0 Hz, J_{2 ,3}9.9 Hz, J_{3 ,4}9.9 Hz,

J_{5 ,6}5.5 Hz, J_{6 ,6}12.0 Hz. ¹³C NMR 850 MHz, CDCl₃,

HMQC, HMBC): d20.91, 21.02, 21.15 8COCH₃signals),

27.40, 28.27 8C8CH₃)₂), 57.03, 57.10 8C-2^E, C-2⁰), 62.46,

62.65 8C-6^E, C-6⁰), 69.15, 69.42 8C-4^E, C-4⁰), 70.89, 71.14

8C-5^E, C-5⁰), 71.95, 72.36 8C-3^E, C-3⁰), 77.31 8C-2), 78.14

8C-3), 81.61 8C-4), 82.67 8C-5), 92.55, 92.77 8CCl₃), 99.86

8C-1^E, C-1⁰), 112.15 8C8CH₃)₂), 118.64 8C-7), 136.94 8C-6),

162.07, 163.28 8COCCl₃), 164.48 8?), 169.93, 170.31,

170.89, 171.09, 171.15, 171.21 8COCH₃), 174.77

8CONH₂). C₃₈H₄₉Cl₆N₃O₂₁81096.53, 1093.10), FAB MS:

m/z 1116.2 [M1Na]¹.

0

0 0

0

0 0

d1.44, 1.46 82s, 6H, C8CH₃)₂), 2.01, 2.02, 2.08 83s, 9H,

COCH₃), 3.72 8ddd, 1H, 5^E-H), 3.83 8m, 1H, 2^E-H), 4.10

8dd, 1H, 6^E-H), 4.24 8dd, 1H, 6^E-H⁰), 4.46 8dd, 1H, 3-H),

4.56 8dd, 1H, 5-H), 4.68 8d, 1H, 2-H), 4.99 8d, 1H, 1^E-H),

5.03±5.12 8m, 2H, 4^E-H, 4-H), 5.32 8d, 1H, 7-H_a), 5.46 8d,

1H, 7-H_b), 5.54 8dd, 1H, 3^E-H), 5.95 8m, 2H, 6-H, CONH),

6.56 8d, H, CONH⁰), 7.16±7.41 8m, 5H, Ar±H's), 7.52 8d,

1H, NH^E). J_2,36.6 Hz, J_3,44.9 Hz, J_5,66.8 Hz, J_6,7a

10.3 Hz, J_6,7b17.3 Hz, J_NH,NH2.9 Hz, J_1E,2E8.4 Hz,

J_2E,NH8.1 Hz, J_3E,4E9.5 Hz, J_4E,5E9.9 Hz, J_5E,6E

2.3 Hz, J_{5E,6 E}4.9 Hz, J_{6E,6 E}12.3 Hz. ¹³C NMR

875 MHz, CDCl₃, HMQC, HMBC): d22.60, 22.65,

22.74 8COCH₃), 28.42, 28.93 8C8CH₃)₂), 58.79 8C-2^E),

64.11 8C-6^E), 70.74 8C-4^E), 73.11 8C-3^E), 73.90 8C-5^E),

78.61 8C-2), 79.28 8C-3), 80.56 8C-4), 81.67 8C-5), 94.4

8CCl₃), 100.85 8C-1^E), 113.05 8C8CH₃)₂), 121.79 8C-7),

123.09 8Ar±C-2, Ar±C-2⁰), 128.03 8Ar±C-4), 131.40

8Ar±C-3, Ar±C-3⁰), 136.06 8C-6), 153.20 8Ar±C-1),

155.55 8OCOO), 163.99 8COCCl₃), 171.52, 172.43,

172.62 8COCH₃), 175.11 8CONH₂). C₃₁H₃₇Cl₃N₂O₁₅

8784.00, 782.13), FAB MS: m/z 805 [M1Na]¹.

0

8.7. Phenyl carbonate protection of the mixture 22b and

23b

Phenyl chloroformate 818 mL, 22 mg, 0.14 mmol) was

added to the mixture of 22b and 23b 857 mg, 0.086 mmol)

in anhydrous CH₂Cl₂83 mL) and anhydrous pyridine

80.1 mL) at 08C under an argon atmosphere. The reaction

was followed by TLC 8PE±ethyl acetate±triethylamine

30:70:0.1). After stirring for 1 h, the reactants were

consumed. The reaction was stopped by addition of water

85 mL). After extraction with CH₂Cl₂83£30 mL), the

combined organic phases were dried over sodium sulfate.

Solvents were removed under reduced pressure. The crude

product was puri®ed by FC eluting with PE±ethyl acetate±

8.7.3. 6,7-Dideoxy-5-O-[3,4,6-tri-O-acetyl-2-deoxy-2-.2,

2,2-trichloroacetamido)-b-d-glucopyranosyl]-l-galacto-

hept-6-enono-1,4-lactone .24a). CuCl₂´2H₂O 80.40 g,

2.4 mmol) was added to 22b 80.23 g, 0.35 mmol) in

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

9449

acetonitrile 85 mL). A heavy darkred precipitate was

observed immediately. The reaction progress was followed

by TLC 8CHCl₃±EtOH 93:7). After heating the reaction

mixture under re¯ux for 5 h the reactants were consumed.

The solvent was removed under reduced pressure, the resi-

due was taken up into ethyl acetate 860 mL) and extracted

several times with a solution of half-saturated NaHCO₃until

the aqueous phase became colorless. The organic phase was

dried over sodium sulfate. The solvent was removed under

reduced pressure and the residue was puri®ed by FC eluting

with CHCl₃±EtOH 93:7, to afford after solvent evaporation

24a 8197 mg, 94%). R_f: 0.21 8CHCl₃±EtOH 90:10). IR

8KBr): 3463 8br), 3374 8br), 1748, 1531, 1372, 1237,

Phenyl chloroformate 813.2 mL, 16.4 mg, 0.11 mmol) was

added to 24a 860.4 mg, 0.10 mmol) and anhydrous pyridine

80.1 mL) in anhydrous CH₂Cl₂84 mL) at 2208C under an

argon atmosphere. The reaction progress was followed by

TLC 8CHCl₃±MeOH 90:10). After stirring the reaction

mixture for 2 h, the reactants were consumed. The reaction

was stopped by adding water 85 mL). After extraction with

CH₂Cl₂83£30 mL), the combined organic phases were

dried over sodium sulfate, and the solvent was removed

under reduced pressure. The crude product was puri®ed

by FC eluting with CHCl₃±MeOH 90:10, to furnish 24c

850.1 mg, 70%). R_f: 0.29 8CHCl₃±EtOH 90:10). IR 8KBr):

3425 8br), 1796 8s), 1751, 1372, 1239, 1043 cm²¹. ¹H NMR

8400 MHz, CDCl₃, HH COSY): d1.95, 1.96, 2.01 83s, 9H,

COCH₃), 3.63 8ddd, 1H, 5^E-H), 3.99 8m, 1H, 2^E-H), 4.04

8dd, 1H, 6^E-H), 4.18 8dd, 1H, 6^E-H⁰), 4.23 8dd, 1H, 4-H),

4.30 8dd, 1H, 5-H), 4.60 8dd, 1H, 3-H), 4.80 8d, 1H, 1^E-H),

5.02 8dd, 1H, 4^E-H), 5.22±5.40 8m, 4H, 2-H, 7-H_a, 7-H_b,

3^E-H), 5.91 8ddd, 1H, 6-H), 7.13±7.35 8m, 6H, Ar±H's,

NH^E). J_2,38.1 Hz, J_3,47.8 Hz, J_4,55.0 Hz, J_5,67.4 Hz,

J_6,7a10.6 Hz, J_6,7b17.7 Hz, J_1E,2E8.1 Hz, J_3E,4E9.5 Hz,

.

1042 cm²^{1 1}H NMR 8600 MHz, [D₅]pyridine, HH

COSY): d1.99, 2.00, 2.09 83s, 9H, COCH₃), 3.90 8m,

1H, 5^E-H), 4.32 8d, 1H, 6^E-H), 4.50±4.56 8m, 2H, 2^E-H,

6^E-H⁰), 4.68 8dd, 1H, 4-H), 4.77 8dd, 1H, 5-H), 4.91 8dd,

1H, 3-H), 5.02 8d, 1H, 2-H), 5.30 8d, 1H, 7-H_a), 5.46 8dd,

1H, 4^E-H), 5.56 8m, 2H, 7-H_b, 1^E-H), 6.09 8dd, 1H, 3^E-H),

6.35 8ddd, 1H, 6-H), 10.75 8d, 1H, NH^E). J_2,38.5 Hz,

J_3,47.7 Hz, J_4,56.2 Hz, J_5,67.4 Hz, J_6,7a10.2 Hz,

J_5E,6E2.5 Hz, J_{5E,6 E}5.0 Hz, J_{6E,6 E}12.4 Hz. ¹³C NMR:

875 MHz, CDCl₃, HMQC, HMBC): d20.46, 20.47,

20.63 8COCH₃), 55.81 8C-2^E), 61.80 8C-6^E), 68.18 8C-4^E),

71.45 8C-3), 71.62 8C-3^E), 72.02 8C-5^E), 78.39 8C-2), 79.48

8C-5), 82.07 8C-4), 92.13 8CCl₃), 99.89 8C-1^E), 120.58

8C-7), 120.69 8Ar±C-2, Ar±C-2⁰), 126.54 8Ar±C-4),

129.52 8?), 129.57 8Ar±C-3, Ar±C-3⁰), 132.33 8C-6),

150.67 8Ar±C-1), 153.13 8OCOO), 162.28 8COCCl₃),

168.11 8C-1), 169.26 8COCH₃at C-4^E), 170.76 8COCH₃at

C-6^E), 170.97 8COCH₃at C-3^E). C₂₈H₃₀Cl₃NO₁₅8726.90,

725.07), FAB MS: m/z 748.0 [M1Na]¹.

0

J_6,7b17.4 Hz, J_NH,2E8.2 Hz, J_3E,4E9.7 Hz, J_5E,6E

2.3 Hz, J_{5E,6 E}5.2 Hz, J_{6E,6 E}11.8 Hz. ¹³C NMR

850 MHz, [D₅]pyridine, HMQC, HMBC): d18.94, 19.01,

19.04 8COCH₃), 55.60 8C-2^E), 60.85 8C-6^E), 68.19 8C-4^E),

70.58 8C-5^E), 70.85 8C-3^E), 73.11 8C-3), 73.90 8C-2), 80.34

8C-5), 81.75 8C-4), 92.38 8CCl₃), 99.19 8C-1^E), 117.21

8C-7), 133.53 8C-6), 161.83 8COCCl₃), 168.30 8COCH₃at

C-4^E), 168.89, 168.94 8COCH₃at C-3^Eand C-6^E), 173.98

8C-1). C₂₁H₂₆Cl₃NO₁₃8606.79, 605.05), FAB MS: m/z 606.0

[M1H]¹, 628.0 [M1Na]¹.

0

8.7.4. 2,3-Di-O-acetyl-6,7-dideoxy-5-O-[3,4,6-tri-O-acetyl-

2-deoxy-2-.2,2,2-trichloroacetamido)-b-d-glucopyrano-

syl]-l-galacto-hept-6-enono-1,4-lactone .24b). Acetic

anhydride 80.5 mL) was added to 24a 819 mg,

0.031 mmol) dissolved in a minimum amount of anhydrous

pyridine. After stirring the reaction mixture overnight, the

solvent was removed under reduced pressure and the residue

was puri®ed by FC eluting with ethyl acetate±PE 1:1, to

afford after solvent evaporation pure 24b 815.2 mg, 70%).

8.7.6. 3-O-Acetyl-6,7-dideoxy-2-O-phenoxycarbonyl-5-O-

[3,4,6-tri-O-acetyl-2-deoxy-2-.2,2,2-trichloroacetamido)-

b-d-glucopyranosyl]-l-galacto-hept-6-enono-1,4-lactone

.24d). Acetic anhydride 80.5 mL) was added to 24c

860.4 mg, 0.083 mmol) dissolved in a minimum amount of

anhydrous pyridine. After stirring the reaction mixture over-

night, the solvent was removed under reduced pressure and

the residue was puri®ed by FC eluting with ethyl acetate±

PE 1:1, to afford after solvent evaporation pure 24d

847.5 mg, 75%). IR 8KBr): 3420 8br), 1752, 1372, 1235,

IR 8KBr): 3455 8br), 1799 8s), 1751, 1372, 1236, 1044 cm²¹

.

¹H NMR 8400 MHz, [D₅]pyridine, HH COSY): d1.99,

2.01, 2.06, 2.09, 2.10 85s, 15H, COCH₃), 3.92 8ddd, 1H,

5^E-H), 4.31 8dd, 1H, 6^E-H), 4.50 8dd, 1H, 6^E-H⁰), 4.61 8m,

1H, 2^E-H), 4.85 8dd, 1H, 5-H), 4.91 8dd, 1H, 4-H), 5.29 8d,

1H, 7-H_a), 5.43±5.52 8m, 3H, 1^E-H, 4^E-H, 7-H_b), 6.01±6.06

8m, 2H, 3-H, 3^E-H), 6.10 8ddd, 1H, 6-H), 6.30 8d, 1H, 2-H),

10.66 8d, 1H, NH^E). J_2,37.1 Hz, J_3,46.7 Hz, J_4,56.4 Hz,

J_5,67.4 Hz, J_6,7a10.6 Hz, J_6,7b17.0 Hz, J_NH,2E8.7 Hz,

1044 cm²^{1 1}H NMR 8400 MHz, CDCl₃, HH COSY):

.

d1.97 8s, 6H, COCH₃), 2.01, 2.05 82s, 6H, COCH₃),

3.65 8ddd, 1H, 5^E-H), 4.01 8m, 1H, 2^E-H), 4.06 8dd, 1H,

6^E-H), 4.17 8dd, 1H, 6^E-H⁰), 4.24 8dd, 1H, 5-H), 4.34 8dd,

1H, 4-H), 4.84 8d, 1H, 1^E-H), 5.04 8dd, 1H, 4^E-H), 5.25±5.40

8m, 3H, 7-H_a, 7-H_b, 3^E-H), 5.39 8d, 1H, 2-H), 5.61 8dd, 1H,

3-H), 5.81 8ddd, 1H, 6-H), 7.10±7.38 8m, 6H, Ar±Hs, NH^E).

J_5E,6E2.5 Hz, J_{5E,6 E}5.3 Hz, J_{6E,6 E}12.4 Hz. ¹³C NMR:

850 MHz, [D₅]pyridine, HMQC, HMBC): d20.38, 20.59,

20.62, 20.68, 20.71 8COCH₃), 57.03 8C-2^E), 62.61 8C-6^E),

69.81 8C-4^E), 72.44 8C-5^E), 72.74, 73.50 8C-3, C-3^E), 73.80

8C-2), 81.29 8C-5), 82.42 8C-4), 94.13 8CCl₃), 100.10

8C-1^E), 120.31 8C-7), 134.14 8C-6), 163.61 8COCCl₃),

169.84, 170.14, 170.38, 170.41, 170.70, 170.85 8CO).

C₂₅H₃₀Cl₃NO₁₅8690.87, 689.07), FAB MS: m/z 690.0

[M1H]¹, 712.0 [M1Na]².

J_2,37.2 Hz, J_3,46.7 Hz, J_4,55.7 Hz, J_5,67.5 Hz, J_6,7a

0

10.2 Hz, J_6,7b17.3 Hz, J_1E,2E8.1 Hz, J_4E,5E9.9 Hz,

J_5E,6E2.5 Hz, J_{5E,6 E}5.2 Hz, J_{6E,6 E}11.9 Hz. ¹³C NMR:

850 MHz, CDCl₃, HMQC, HMBC): d20.68, 20.72,

20.84 8COCH₃signals), 56.20 8C-2^E), 62.14 8C-6^E), 68.58

8C-4^E), 71.92 8C-3^E), 72.22 8C-3, C-5^E), 76.13 8C-2), 81.14

8C-4), 81.54 8C-5), 92.46 8CCl₃), 100.51 8C-1^E), 120.72 8C-

7), 120.98 8Ar±C-2, C-2⁰), 126.79 8Ar±C-4), 129.83 8Ar±

C-3, Ar±C-3⁰), 129.93 8?), 132.27 8C-6), 150.00 8Ar±C-1),

152.83 8OCOO), 162.21 8COCCl₃), 167.38 8C-1), 169.46

8COCH₃at C-4^E), 169.88 8COCH₃at C-3), 170.72 8COCH₃

at C-6^E), 170.98 8COCH₃at C-3^E). C₃₀H₃₂Cl₃NO₁₆8768.94,

767.08), FAB MS: m/z 790.0 [M1Na]¹.

0

8.7.5. 6,7-Dideoxy-2-O-phenoxycarbonyl-5-O-[3,4,6-tri-O-

acetyl-2-deoxy-2-.2,2,2-trichloroacetamido)-b-d-gluco-

pyranosyl]-l-galacto-hept-6-enono-1,4-lactone

.24c).

9450

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

8.8. Attempted phenyl carbonate cleavage from 24d

25.53 8C8CH₃)₃), 55.89 8C-2^E), 62.04 8C-6^E), 68.40 8C-4^E),

72.13, 72.18 8C-3^E, C-5^E), 72.90 8C-2), 74.52 8C-3), 80.95,

81.20 8C-4, C-5), 92.44 8CCl₃), 100.97 8C-1^E), 120.18 8C-7),

132.67 8C-6), 162.06 8COCCl₃), 169.31 8COCH₃at C-4^E),

169.68 8COCH₃at C-3), 170.57 8COCH₃at C-6^E), 170.71

8COCH₃at C-3^E), 171.28 8C-1). C₂₉H₄₂Cl₃NO₁₄Si 8763.09,

761.14), FAB MS: m/z 784.2 [M1Na]¹.

A mixture of 24d 827.8 mg, 0.036 mmol), imidazole 860 mg,

0.88 mmol) and water 840 mL) in dioxane 84 mL) was

stirred at room temperature for 24 h. Monitoring by TLC

8CHCl₃±EtOH 90:10) revealed that no reaction tookplace.

8.8.1. 2-O-.tert-Butyldimethylsilyl)-6,7-dideoxy-5-O-[3,4,

6-tri-O-acetyl-2-deoxy-2-.2,2,2-trichloroacetamido)-b-

d-glucopyranosyl]-l-galacto-hept-6-enono-1,4-lactone

.24f). TBDMS±OTf 834 mL, 1.15 mmol) was injected into a

reaction ¯askcontaining 24a 848.4 mg, 0.079 mmol) and

anhydrous pyridine 830 mL) in anhydrous CH₂Cl₂82 mL)

under an argon atmosphere at 2508C. The reaction was

followed by TLC 8toluene±acetone 1:1). After stirring at

2508C for 5 h, the reaction was stopped by the addition

of saturated aq. Na₂CO₃82 mL). After extraction with

with CH₂Cl₂83£15 mL), the combined phases were dried

over sodium sulfate, and the solvent was removed under

reduced pressure. The crude product was puri®ed by FC

eluting with ethyl acetate±PE 60:40, to afford after solvent

evaporation 24f 850.4 mg, 89%). R_f: 0.23 8PE±ethyl acetate

1:1). IR 8KBr): 3505 8br), 3421 8br), 1789 8s), 1752, 1726

8.8.3. 5-O-[3,4,6-Tri-O-acetyl-2-deoxy-2-.2,2,2-trichloro-

acetamido)-b-d-glucopyranosyl]-6,7-dideoxy-2-O-.tert-

butyldimethylsilyl)-3-O-acetyl-l-galacto-hept-6-enon-

amide .25a). Ammonia was bubbled through a solution of

24g 820 mg, 0.026 mmol) in THF 82 mL) at 08C. The reac-

tion was monitored by TLC using ethyl acetate. After 8 h

the reactants were consumed, the solvent was removed

under reduced pressure, and the crude product was puri®ed

by FC eluting with ethyl acetate to furnish after solvent

evaporation 25a 819.2 mg, 94%). R_f: 0.52 8ethyl acetate).

1

IR 8KBr): 3469, 1747, 1533, 1238, 1043 cm²¹. H NMR

8400 MHz, CDCl₃, HH COSY): d0.08, 0.12 82s, 6H,

Si8CH₃)₂), 0.85 8s, 9H, C8CH₃)₃), 1.966, 1.973, 2.03, 2.05

84s, 12H, COCH₃), 3.62 8ddd, 1H, 5^E-H), 4.02±4.09 8m, 2H,

2^E-H, 6^E-H), 4.12±4.20 8m, 3H, 4-H, 5-H, 6^E-H⁰), 4.35 8d,

1H, 2-H), 4.76 8d, 1H, 1^E-H), 5.04 8dd, 1H, 4^E-H), 5.12±5.35

8m, 4H, 3-H, 7-H_a, 7-H_b, 3^E-H), 5.82 8ddd, 1H, 6-H), 5.92,

6.57 82s, 2H, CONH₂), 7.08 8d, 1H, NH). J_2,36.7 Hz,

J_5,66.9 Hz, J_6,7a10.2 Hz, J_6,7b17.2 Hz, J_1E,2E8.5 Hz,

0

1

8s), 1236, 1154, 1042 cm²¹. H NMR 8200 MHz, CDCl₃,

HH COSY): d0.15, 0.18 82s, 6H, Si8CH₃)₂), 0.92 8s, 9H,

C8CH₃)₃), 2.03 8s, 6H, COCH₃), 2.08 81s, 3H, COCH₃), 3.69

8ddd, 1H, 5^E-H), 3.90±4.40 8m, 7H, 2-H, 3-H, 4-H, 5-H,

2^E-H, CH₂-6^E), 4.87 8d, 1H, 1^E-H), 5.09 8dd, 1H, 4^E-H),

5.26±5.48 8m, 3H, 7-H_a, 7-H_b, 3^E-H), 5.97 8ddd, 1H, 6-H),

J_2E,NH9.2 Hz, J_4E,5E9.9 Hz, J_5E,6E2.5 Hz, J_{5E,6 E}

5.0 Hz. ¹³C NMR 850 MHz, CDCl₃, HMQC, HMBC):

d25.09, 24.89 8Si8CH₃)₂), 18.28 8C8CH₃)₃), 20.75,

20.81, 20.88, 21.30 8COCH₃), 25.96 8C8CH₃)₃), 55.77

8C-2^E), 62.28 8C-6^E), 68.74 8C-4^E), 70.17, 72.04 8C-3^E,

C-5^E), 72.44 8C-2), 72.85, 73.82 8C-3, C-4), 84.38 8C-5),

92.60 8CCl₃), 101.48 8C-1^E), 118.14 8C-7), 135.66 8C-6),

162.94 8COCCl₃), 169.43, 170.16, 170.74, 171.21

8COCH₃), 175.55 8CONH₂). C₂₉H₄₅Cl₃N₂O₁₄Si 8780.13,

778.17), FAB MS: m/z 779.1 [M1H]¹, 801.1 [M1Na]¹.

7.19 8d, 1H, NH^E). J_5,67.3 Hz, J_6,7a10.3 Hz, J_6,7b

17.4 Hz, J_1E,2E8.1 Hz, J_2E,NH9.2 Hz, J_3E,4E9.5 Hz,

J_4E,5E9.9 Hz, J_5E,6E2.2, 4.8 Hz. ¹³C NMR 850 MHz,

CDCl₃, HETCOR): d24.91, 24.58 8Si8CH₃)₂), 18.39

8C8CH₃)₃), 20.66, 20.85 8COCH₃signals), 22.81 8?), 25.76

8C8CH₃)₃), 56.07 8C-2^E), 62.03 8C-6^E), 68.36 8C-4^E), 71.98,

72.32 8C-3^E, C-5^E), 74.65, 75.15, 80.35, 81.46 8C-2, C-3,

C-4, C-5), 92.37 8CCl₃), 100.37 8C-1^E), 120.64 8C-7),

132.89 8C-6), 162.43 8COCCl₃), 169.40, 170.78, 171.10,

172.55 8CO). C₂₇H₄₀Cl₃NO₁₃Si 8721.06, 719.13), FAB

MS: m/z 742.0 [M1Na]¹.

8.9. TBDMS cleavage of 25a

A solution of tetrabutylammonium ¯uoride in THF 81 M,

150 mL, 0.15 mmol) was added to 25a 8104 mg, 0.13 mmol)

in anhydrous THF 82 mL) at 2138C. The reaction progress

was followed by TLC 8CHCl₃±EtOH 90:10). After stirring

for 1 h the reactants were consumed. The reaction was

worked up by the addition of half-saturated ammonium

chloride solution 82 mL) and extraction with ethyl acetate

83£20 mL). The combined organic phases were dried over

sodium sulfate, and the solvent was removed under reduced

pressure. The crude products were puri®ed by FC eluting

with ethyl acetate to afford after solvent evaporation 25b

841.2 mg, 46%) and 25c 833.4 mg, 38%).

8.8.2. 3-O-Acetyl-2-O-.tert-butyldimethylsilyl)-6,7-dideoxy-

5-O-[3,4,6-tri-O-acetyl-2-deoxy-2-.2,2,2-trichloroaceta-

mido)-b-d-glucopyranosyl]-l-galacto-hept-6-enono-1,4-

lactone .24g). Acetic anhydride 80.5 mL) was added to 24f

8122.8 mg, 0.17 mmol) in anhydrous pyridine 80.4 mL). The

reaction mixture was stirred overnight at room temperature.

The solvent was removed under reduced pressure and the

residue was puri®ed by FC eluting with PE±ethyl acetate1:1

to afford after solvent evaporation 24g 8121 mg, 94%) R_f:

0.47 8CHCl₃±EtOH 90:10). IR 8KBr): 3499 8br), 1802 8s),

1

1750, 1529, 1371, 1235, 1043 cm²¹. H NMR 8400 MHz,

CDCl₃, HH COSY): d0.08, 0.11 82s, 6H, Si8CH₃)₂), 0.85

8s, 9H, C8CH₃)₃), 1.96, 1.97, 2.02, 2.05 84s, 12H, COCH₃),

3.62 8ddd, 1H, 5^E-H), 4.02±4.09 8m, 2H, 2^E-H, 6^E-H), 4.13±

4.20 8m, 3H, 4-H, 5-H, 6^E-H⁰), 4.35 8d, 1H, 2-H), 4.76 8d,

1H, 1^E-H), 5.03 8dd, 1H, 4^E-H), 5.21±5.34 8m, 4H, 3-H,

7-H_a, 7-H_b, 3^E-H), 5.28 8ddd, 1H, 6-H), 7.04 8d, 1H,

8.9.1. 3-O-Acetyl-5-O-[3,4,6-tri-O-acetyl-2-deoxy-2-.2,2,

2-trichloroacetamido)-b-d-glucopyranosyl]-6,7-dideoxy-

l-galacto-hept-6-enonamide .25b). R_f: 0.42 8CHCl₃±

EtOH 90:10). IR 8KBr): 3436, 1793 8s), 1749, 1530, 1373,

1235, 1043 cm²¹. ¹H NMR 8600 MHz, CDCl₃, HH COSY):

d1.96 8s, 6H, COCl₃), 2.01, 2.02 82s, 6H, COCH₃), 3.64

8m, 1H, 5^E-H), 3.86 8dd, 1H, 4-H), 3.98 8dd, 1H, 5-H), 4.01±

4.08 8m, 2H, 2^E-H, 6^E-H), 4.17 8dd, 1H, 6^E-H⁰), 4.46 8bs, 1H,

2-H), 4.75 8d, 1H, 1^E-H), 5.02 8dd, 1H, 4^E-H), 5.17±5.35 8m,

4H, 3-H, 7-H_a, 7-H_b, 3^E-H), 5.90 8ddd, 1H, 6-H), 6.00, 6.79

NH^E). J_2,36.7 Hz, J_5,67.2 Hz, J_6,7a10.5 Hz, J_6,7b

17.5 Hz, J_1E,2E8.1 Hz, J_2E,NH9.2 Hz, J_5E,6E2.5 Hz,

J_{5E,6 E}5.2 Hz, J_{6E,6 E}12.2 Hz. ¹³C NMR 850 MHz,

CDCl₃, HMQC, HMBC): d25.35, 24.75 8Si8CH₃)₂),

18.21 8C8CH₃)₃), 20.66, 20.71, 20.84 8COCH₃signals),

0

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

9451

1

82s, 2H, CONH₂), 7.61 8d, 1H, NH). J_4,55.0 Hz,

J_5,67.6 Hz, J_6,7a10.2 Hz, J_6,7b17.5 Hz, J_1E,2E8.4 Hz,

1042 cm²¹. H NMR 8200, 400 MHz, CDCl₃, HH COSY):

d1.95, 1.96, 2.03, 2.06 84s, 12H, COCH₃), 3.66 8ddd, 1H,

5^E-H), 3.97±4.12 8m, 3H, 2^E-H, CH₂-6^E), 4.18±4.26 8m, 2H,

4-H, 5-H), 4.47 8d, 1H, 2-H), 4.82 8d, 1H, 1^E-H), 5.02 8dd,

1H, 4^E-H), 5.22±5.36 8m, 4H, 7-H_a, 7-H_b, 3^E-H, 3-H), 5.85

J_2E,NH7.8 Hz, J_3E,4E9.4 Hz, J_4E,5E9.9 Hz, J_5E,6E

2.6 Hz, J_{5E,6 E}5.2 Hz, J_{6E,6 E}12.0 Hz. ¹H NMR

8400 MHz, CDCl₃1D₂O): Similar to the previous data,

but there was no signal at d6.00, 6.79 and 7.61. ¹³C

NMR 850 MHz, CDCl₃, HMQC, HMBC): d20.77,

20.91, 21.12 8COCH₃signals), 56.50 8C-2^E), 62.18 8C-6^E),

68.53 8C-4^E), 71.33 8C-2), 72.06, 72.12 8C-3^E, C-5^E), 72.42,

73.20 8C-3, C-4), 82.66 8C-5), 92.37 8CCl₃), 100.18 8C-1^E),

119.97 8C-7), 134.85 8C-6), 163.29 8COCCl₃), 169.53,

170.38, 170.84, 171.16 8COCH₃), 174.13 8CONH₂).

C₂₃H₃₁Cl₃N₂O₁₄8665.86, 664.08), FAB MS: m/z 665.1

[M1H]¹, 687.1 [M1Na]¹.

0

8ddd, 1H, 6-H), 7.26 8d, 1H, NH). J_5,67.4, Hz J_6,7a

10.6 Hz, J_6,7b17.7 Hz, J_1E,2E8.1 Hz, J_2E,NH9.2 Hz,

J_4E,5E9.9 Hz, J_5E,6E2.5, 4.6 Hz. ¹³C NMR 850 MHz,

CDCl₃, HMQC, HMBC): d20.74, 20.89, 21.10, 21.19

8COCH₃), 56.13 8C-2^E), 62.15 8C-6^E), 68.59 8C-4^E), 72.06,

72.17 8C-3^E, C-5^E), 72.80 8C-2), 75.73 8C-3), 81.42, 81.55

8C-4, C-5), 92.45 8CCl₃), 100.57 8C-1^E), 120.49 8C-7),

132.93 8C-6), 162.47 8COCCl₃), 169.53, 170.87, 170.91,

171.21, 172.50 8C-1). C₂₃H₂₈Cl₃NO₁₄8648.83, 647.06),

FAB MS: m/z 648.1 [M1H]¹, 670.1 [M1Na]¹.

8.9.2. 4-O-Acetyl-5-O-[3,4,6-tri-O-acetyl-2-deoxy-2-.2,2,

2-trichloroacetamido)-b-d-glucopyranosyl]-6,7-dideoxy-

l-galacto-hept-6-enonamide .25c). R_f: 0.37 8CHCl₃±EtOH

90:10). IR 8KBr): 3450, 1745, 1675, 1374, 1239,

8.10. Ammonia opening of 24h

Ammonia was bubbled through a solution of 24h 871 mg,

0.11 mmol) in THF 82 mL) at 08C. The reaction was moni-

tored by TLC using ethyl acetate. After 5 h the reactants

were consumed, the solvent was removed under reduced

pressure, and the crude product was puri®ed by FC eluting

with ethyl acetate to furnish after solvent evaporation 25b

and 25c 859 mg, 82%).

1043 cm²^{1 1}H NMR 8600 MHz, CDCl₃, HH COSY):

.

d1.94, 1.95, 2.00, 2.01 84s, 12H, COCH₃), 3.64 8m, 1H,

5^E-H), 3.81 8doublet-type signal, 1H, 2-H), 4.04 8dd, 1H,

6^E-H), 4.12±4.15 8m, 3H, 2^E-H, 6^E-H⁰, 2-OH), 4.25 8m,

1H, 3-H), 4.53 8d, 1H, 5-H), 4.81 8d, 1H, 3-OH), 4.86 8d,

1H, 1^E-H), 4.96±4.98 8m, 2H, 4-H, 4^E-H), 5.08 8d, 1H,

7-H_a), 5.12 8dd, 1H, 3^E-H), 5.24 8d, 1H, 7-H_b), 5.72 8ddd,

1H, 6-H), 5.91, 6.87 82s, 2H, CONH₂), 8.28 8d, 1H, NH).

J_2,2-OH6.3 Hz, J_3,3-OH7.8 Hz, J_5,65.5 Hz, J_6,7a10.5 Hz,

8.10.1. 4-O-Acetyl-2,6-anhydro-7-deoxy-7-iodo-5-O-[3,4,

6-tri-O-acetyl-2-deoxy-2-.2,2,2-trichloroacetamido)-b-

d-glucopyranosyl]-d-glycero-l-galacto-heptonamide

.26). Compound 25b 822.7 mg, 0.034 mmol) and mercuric

tri¯uoroacetate 829.19 mg, 0.068 mmol) were dissolved in

4 mL of anhydrous THF under an argon atmosphere. After

stirring the reaction mixture at room temperature for 48 h

the reactants were consumed as indicated by TLC 8CHCl₃±

MeOH 80:20). KCl 815 mg, 0.20 mmol) dissolved in a mini-

mum amount of water was added. The mixture was then

stirred for 90 min until all reactants were consumed as indi-

cated by TLC 8CHCl₃±MeOH 90:10). Solvents were

removed under reduced pressure. The residue and I₂

816.8 mg, 0.066 mmol) were dissolved in anhydrous THF

82 mL) under an argon atmosphere, the reaction was moni-

tored by TLC 8CHCl₃±EtOH 95:5). After stirring for 4 h the

reaction was stopped by the addition of sodium thiosulfate

dissolved in a minimum amount of water. After stirring until

the solution became colorless, the reaction mixture was

diluted with ethyl acetate, dried over sodium sulfate, and

the solvents were removed under reduced pressure. The

crude product was puri®ed by FC eluting with CHCl₃±

EtOH 95:5, to afford after solvent evaporation 26 87.5 mg,

J_6,7b16.7 Hz, J_1E,2E8.4 Hz, J_2E,NH9.4 Hz, J_3E,4E

1

0

9.4 Hz, J_{5E,6 E},1 Hz, J_{5E,6 E}4.7 Hz, J_{6E,6 E}11.5 Hz. H

NMR 8300 MHz, CDCl₃1D₂O, HH COSY): d2.00,

2.01, 2.06, 2.09 84s, 12H, COCH₃), 3.72 8ddd, 1H, 5^E-H),

3.89 8d, 1H, 2-H), 4.11 8dd, 1H, 6^E-H), 4.16±4.23 8m, 2H,

2^E-H, 6^E-H⁰), 4.31 8dd, 1H, 3-H), 4.61 8dd, 1H, 5-H), 4.90±

4.96 8m, 2H, 1^E-H, 3^E-H), 5.01 8dd, 1H, 4^E-H), 5.17 8dm,

1H, 7-H_a), 5.25 8dd, 1H, 4-H), 5.33 8d, 1H, 7-H_b), 5.79 8ddd,

1H, 6-H). J_2,31.4 Hz, J_3,49.9 Hz, J_4,51.4 Hz, J_5,6

5.3 Hz, J_6,7a10.8 Hz, J_6,7b16.6 Hz, J_1E,2E8.5 Hz,

0

J_2E,NH8.8 Hz, J_4E,5E9.9 Hz, J_5E,6E2.7, 5.5 Hz, J_{6E,6 E}

12.2 Hz. ¹³C NMR 850 MHz, CDCl₃, HMQC, HMBC):

d20.75, 20.81, 21.85, 21.05 8COCH₃), 55.50 8C-2^E),

62.47 8C-6^E), 68.68 8C-3), 69.34 8C-4^E), 71.77 8C-2),

72.05 8C-5^E), 72.72 8C-3^E), 74.17 8C-4), 78.68 8C-5),

92.68 8CCl₃), 101.19 8C-1^E), 117.07 8C-7), 135.56 8C-6),

162.77 8COCCl₃), 169.52, 170.77, 170.84, 172.15

8COCH₃), 174.92 8CONH₂). C₂₃H₃₁Cl₃N₂O₁₄8665.86,

664.08), FAB MS: m/z 665.0 [M1H]¹, 687.0 [M1Na]¹.

8.9.3. 3-O-Acetyl-6,7-dideoxy-5-O-[3,4,6-tri-O-acetyl-2-

deoxy-2-.2,2,2-trichloroacetamido)-b-d-glucopyranosyl]-

l-galacto-hept-6-enono-1,4-lactone .24h). Tetrabutyl-

ammonium ¯uoride trihydrate 895 mg, 0.12 mmol) in THF

82 mL) was added to 24g 895 mg, 0.12 mmol) in THF

82 mL) at 2138C. The reaction progress was followed by

TLC 8ethyl acetate). After stirring for 20 min, the reactants

were consumed. The reaction was stopped by the addition of

half-saturated NH₄Cl solution 82 mL), then extracted

several times with ethyl acetate. The combined organic

phases were dried over sodium sulfate, the solvent was

removed under reduced pressure, the residue was puri®ed

by FC eluting with ethyl acetate to afford after solvent

evaporation 24h 876.4 mg, 98%). R_f: 0.40 8CHCl₃±EtOH

90:10). IR 8KBr): 3436 8br), 1764, 1373, 1238,

1

28%). R_f: 0.53 8CHCl₃±EtOH 90:10). H NMR 8300 MHz,

CDCl₃, HH COSY): d2.01, 2.05, 2.12, 2.16 84s, 12H,

COCH₃), 3.92 8dd, 1H, 7^F-H), 4.00 8ddd, 1H, 5^E-H), 4.14

8dd, 1H, 7^F-H⁰), 4.29 8m, 1H, 2^E-H), 4.36 8dd, 1H, 6^E-H),

4.50 8dd, 1H, 6^E-H⁰), 4.78 8d, 1H, 2^F-H), 4.91 8m, 1H, 6^F-H),

5.06 8dd, 1H, 5^F-H), 5.37 8m, 1H, 3^F-H), 5.53 8dd, 1H, 4^E-H),

5.68±5.72 8m, 2H, 4^F-H, 1^E-H), 6.18 8dd, 1H, 3^E-H), 7.79,

8.60 82s, 2H, CONH₂), 10.66 8d, 1H, NH). J_2F,3F1.7 Hz,

0

J_4F,5F9.8 Hz, J_5F,6F5.9 Hz, J_6F,7F3.3 Hz, J_{6F,7 F},1 Hz,

0

J_7F,7F11.3 Hz, J_NHF,NHF2.2 Hz, J_1E,2E10.2 Hz, J_2E,NH

8.0 Hz, J_2E,3E10.6 Hz, J_3E,4E9.2 Hz, J_4E,5E9.9 Hz,

J_5E,6E2.5 Hz, J_{5E,6 E}4.7 Hz, J_{6E,6 E}12.1 Hz. ¹³C NMR:

875 MHz, CDCl₃, HMQC, HMBC): d3.60 8C-7^F), 20.10,

20.19, 20.42, 21.07 8COCH₃), 56.98 8C-2^E), 61.92 8C-6^E),

0

9452

J. Zahra et al. / Tetrahedron 57 52001) 9437±9452

67.47 8C-3^F), 69.24 8C-4^E), 71.22 8C-3^E), 71.84 8C-5^E),

72.66, 72.71 8C-2^F, C-4^F), 74.68 8C-5^F), 76.43 8C-6^F),

93.33 8CCl₃), 100.40 8C-1^E), 162.70 8COCCl₃), 169.48,

170.01, 170.10, 170.13 8COCH₃), 171.45 8CONH₂).

C₂₃H₃₀Cl₃IN₂O₁₄8791.76, 789.98), FAB MS: m/z 789.9

[M1H]¹, 812.9 [M1Na]¹.

6. van Heijenoort, J.; van Heijenoort, Y.; Welzel, P. In Antibiotic

Inhibition of Bacterial Cell Wall Surface Assembly and

Function, Actor, P., Daneo-Moore, L., Higgins, M. L., Salton,

M. R. J., Shockman, G. D., Eds.; American Society for Micro-

biology: Washington, 1988; pp. 549±557.

È

7. Donnerstag, A.; Marzian, S.; MuÈller, D.; Welzel, P.; Bottger,

D.; Stark, A.; Fehlhaber, H.-W.; Markus, A.; van Heijenoort,

È

8.10.2. 4-O-Acetyl-3,6-anhydro-7-deoxy-7-iodo-5-O-[3,4,

6-tri-O-acetyl-2-deoxy-2-.2,2,2-trichloroacetamido)-b-

d-glucopyranosyl]-J-glycero-l-galacto-heptonamide

.27). Following the procedure used to prepare 26,

compound 25c 833.1 mg, 0.050 mmol), mercuric tri¯uoro-

acetate 830 mg, 0.070 mmol), anhydrous THF 84 mL) and I₂

817.0 mg, 0.067 mmol) afforded 27 817.2 mg, 44%). R_f: 0.44

Y.; van Heijenoort, J. Tetrahedron 1995, 51, 1931±1940.

8. Ritzeler, O.; Hennig, L.; Findeisen, M.; Welzel, P.; MuÈller, D.;

Markus, A.; Lemoine, G.; Lampilas, M.; van Heijenoort, J.

Tetrahedron 1997, 53, 1675±1694.

9. Terrak, M.; Ghosh, T. K.; van Heijenoort, J.; Van Beemen, J.;

Lampilas, M.; Aszodi, J.; Ayala, J. A.; Ghuysen, J.-M.;

Á

Nguyen-Desteche, M. Mol. Microbiol. 1999, 34, 350±364.

1

8CHCl₃±EtOH 90:10). H NMR 8400 MHz, CDCl₃, HH

10. For leading references, see: El-Abadla, N.; Lampilas, M.;

Hennig, L.; Findeisen, M.; Welzel, P.; MuÈller, D.; Markus,

A.; van Heijenoort, J. Tetrahedron 1999, 55, 699±722.

11. Metten, K.-H.; Hobert, K.; Marzian, S.; Hackler, U. E.; Heinz,

U.; Welzel, P.; Aretz, W.; BoÈttger, D.; Hedtmann, U.; Seibert,

G.; Markus, A.; Limbert, M.; van Heijenoort, Y.; van

Heijenoort, J. Tetrahedron 1992, 48, 8401±8418.

12. Kosmol, R.; Hennig, L.; Welzel, P.; Findeisen, M.; MuÈller, D.;

Markus, A.; van Heijenoort, J. J. Prakt. Chem. 1997, 339,

340±358.

COSY): d1.98, 2.01, 2.04, 2.10 84s, 12H, COCH₃), 3.56

8dd, 1H, 7-H), 3.68 8dd, 1H, 7-H⁰), 3.97 8ddd, 1H, 5^E-H),

4.39 8dd, 1H, 6^E-H), 4.44 8dd, 1H, 6^E-H⁰), 4.52 8m, 1H, 6-H),

4.65 8m, 1H, 2^E-H), 4.72 8dd, 1H, 3-H), 4.78 8dd, 1H, 5-H),

4.85 8d, 1H, 2-H), 5.50 8dd, 1H, 4^E-H), 5.61 8d, 1H, 1^E-H),

6.00 8dd, 1H, 3^E-H), 6.24 8dd, 1H, 4-H), 8.23, 8.49 82s, 2H,

CONH₂), 10.62 8d, 1H, NH). J_2,35.8 Hz, J_3,44.5 Hz,

0

J_4,52.6 Hz, J_5,64.7 Hz, J_6,78.9 Hz, J_6,74.7 Hz, J_7,7

9.9 Hz, J_1E,2E8.4 Hz, J_2E,NH8.9 Hz, J_2E,3E10.2 Hz,

0

J_3E,4E9.4 Hz, J_4E,5E9.9 Hz, J_5E,6E2.1 Hz, J_{5E,6 E}

13. Nicotra, F. In Carbohydrate Mimics, Chapleur, Y., Ed.; ;1998;

pp. 67±85 and references therein. See also: Thatcher, G. J. R.;

Cambell, A. S. J. Org. Chem. 1993, 58, 2272±2281.

14. For a preliminary communication, see: Zahra, J.; Hennig, L.;

Findeisen, M.; Welzel, P.; MuÈller, D.; Sheldrick, W. S.

Tetrahedron Lett. 2001, 42, 2969±2972.

4.7 Hz, J_{6E,6 E}12.0 Hz. ¹³C NMR: 875 MHz, CDCl₃,

HMQC, HMBC): d3.67 8C-7), 20.79, 20.88, 21.03,

21.11 8COCH₃), 56.84 8C-2^E), 62.61 8C-6^E), 69.92 8C-4^E),

72.63 8C-5^E), 73.08, 73.19 8C-2, C-3^E), 78.92 8C-4), 82.19,

82.33 8C-5, C-6), 84.74 8C-3), 94.11 8CCl₃), 99.60 8C-1^E),

163.72 8COCCl₃), 170.14, 170.74, 170.80, 170.86

8COCH₃), 175.60 8CONH₂). C₂₃H₃₀Cl₃IN₂O₁₄8791.76,

789.98), FAB MS: m/z 789.8 [M1H]¹, 812.8 [M1Na]¹.

0

15. Brooks, G.; Edwards, P. D.; Hatto, J. D.; Smale, T. C.; South-

gate, R. Tetrahedron 1995, 51, 7999±8014. Vederas, J. C.;

Quiao, L. J. Org. Chem. 1993, 58, 3480±3482.

16. Levy, D. E.; Tang, C. The Chemistry of C-glycosides; Elsevier

Science: Oxford, 1995. Postema, M. H. D. Tetrahedron 1992,

48, 8545±8599.

Acknowledgements

17. Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett.

1987, 28, 139±142.

The Leipzig group gratefully acknowledges ®nancial

support by the Deutsche Forschungsgemeinschaft

8Innovationskolleg `Chemisches Signal und biologische

Antwort'), BC Biochemie GmbH, and the Fonds der

Chemischen Industrie.

18. Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,

3817±3856.

19. McKew, J. C.; Kurth, M. J. Org. Prep. Proced. Int. 1993, 25,

125±130.

20. Musich, J. A.; Rapoport, H. J. Am. Chem. Soc. 1978, 100,

4865±4872.

21. Staab, H. H. Angew. Chem. 1959, 71, 194±195.

References

È

22. See Zahra, J. Dissertation, Universitat Leipzig, 2001.

1. Cohen, M. L. Nature 2000, 406, 762±781 and references

therein.

23. Review: Marshall, J. A. Chem. Rev. 1996, 96, 31±47.

24. Blatter, G.; Beau, J.-M.; Jacquinet, J.-C. Carbohydr. Res.

1994, 260, 189±202.

2. Review: Bugg, T. H. D. Comprehensive Natural Products

Chemistry; Barton, D., Nakanishi, K., Eds.; Elsevier Science:

Amsterdam, 1999; Vol. 3.

25. Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K.

Tetrahedron Lett. 1998, 39, 3091±3092.

3. Gof®n, C.; Ghuysen, J.-M. Microbiol. Mol. Biol. Rev. 1998,

62, 1079±1093.

26. Overkleeft, H. S.; van Wiltenburg, J.; Pandit, U. K.

Tetrahedron 1994, 50, 4215±4224.

4. Review: Goldman, R. C.; Gange, D. Curr. Med. Chem. 2000,

7, 801±820.

27. Behnke, D.; Hennig, L.; Findeisen, M.; Welzel, P.; MuÈller, D.;

Thormann, M.; Hofmann, H.-J. Tetrahedron 2000, 56, 1081±

1095.

5. Lo, M.-C.; Men, H.; Branstrom, A.; Helm, J.; Yao, N.;

Goldman, R.; Walker, S. J. Am. Chem. Soc. 2000, 122,

3540±3541 and references therein.

28. Dener, J. M.; Hart, D. J.; Ramesh, S. J. Org. Chem. 1998, 53,

6022±6030.

Article Doi

Synthesis of a building block for phosphonate analogues of moenomycin A12 from D-tartaric acid

DOI: 10.1016/S0040-4020(01)00951-6

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0040-4020(01)00951-6

Full text of DOI:10.1016/S0040-4020(01)00951-6

Products guided by the article

R&D Labs maybe for 403709-24-0

Relevant to this article

Hot Product