Frontiers in Modern Carbohydrate Chemistry - American Chemical

Chapter 4

Iodoamidation of Glycals: A Facile Preparation of 2-Deoxy-N-glycosylamides Downloaded by PENNSYLVANIA STATE UNIV on May 18, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch004

Cecilia H. Marzabadi and Michael DeCastro Department of Chemistry and Biochemistry, Seton Hall University, 400 South Orange Avenue, South Orange, N J 07079

2-Deoxy-2-iodo-N-glycosylamides have been prepared in high yields and with good selectivities by a one step process starting from glycals. The resultingtrans-configured2-deoxy2-iodo-N-glycosylamides are readily converted to the 2-deoxyN-glycosylamides by tin hydride mediated reductive deiodination. Aliphatic and aromatic primary amides, substituted ureas and amino acids were added to glycals in this fashion. The stereoselectivity and yields in these reactions were governed by a variety of factors including the nature of the solvent used in the addition reaction, the types of protecting groups on the glycal, and the nature of the R group on the amide.

Dedicated to the memory of Professor Jacques van Boom 50

© 2007 American Chemical Society

In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

Downloaded by PENNSYLVANIA STATE UNIV on May 18, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch004

51 In recent years the essential role of glycoproteins in important biological processes such as cellular recognition, adhesion, differentiation and metastasis has been recognized (7). Furthermore, because of the role glycoproteins play in bacterial infections, in facilitating inflammation and host immune responses to these organisms, this has lead toward important advances in the development of vaccines for the prevention of diseases (2). Glycopeptides are characterized by the formation of a bond between the anomeric position of a sugar and an OH or N H group on an amino acid. Naturally-occurring O-linked glycopeptides are usually formed between a hydroxyl group of a serine or threonine residue with CI of the sugar. N-Linked glycopeptides generally occur between the amino group of an asparagine residue and the anomeric position (3). In contrast to O-linked glycopeptides, N-linked glycopeptides are relatively robust to a variety of reaction conditions (e.g. acid, base) thereby making them easier to handle in synthetic transformatioms (4). In recent years, even relatively simple glycosylamides have been shown to possess important biological properties. Heterocyclic glycosylamides have shown moderate activity as potential inhibitors of chitinases (5). N retinoylamides have been prepared and tested as anti-tumor agents (6). Likewise, N-(P-D-glucopyranosyl)propanoamide was prepared as a simple mimic of the C7-C10 fragment of the anti-tumor sponge metabolites, the mycalamides (7). Murphy and coworkers reported that some glycosylamide analogs inhibit the binding of fibroblast growth factor (FGF-2) to heparin (8). Cyclodextrin polyamides and "peptidodisaccharides" have been synthesized and their binding to lectins determined (9). Other uses for glycosylamides have also been described in the literature. Amphiphilic glycosylamides have been demonstrated to be a valuable class of non-ionic biosurfactants (70). Also, Kunz has used N-glycosylamides as an anomeric protecting group in glycosylation sequences (4). Previous methods reported for the synthesis of these glycoconjugates include: 1) from glycosylamines by coupling with a carboxylic acid moiety (77) (most common) or by coupling with an acyl chloride or anhydride (72); the problem with these methods is that anomerization frequently occurs during synthesis. The coupling with acids can also be done photochemically (75); 2) via a Staudinger reaction with anomeric azides. Both a and P-selective ligation reactions have been realized depending on the phosphine employed (14, 15). With acid chlorides, triphenylphosphine can be used as a ligand. However, problems with purification of the resulting amides due to contamination with triphenylphosphine oxide can occur. To avoid this cross-contamination, polystyrene conjugated triphenylphosphine has been successfully employed in this protocol (76); 3) from anomeric isothiocyanates by reaction with carboxylic acids (N,N-bisglycosylthiourea formation also competes) (77); 4) from the Ritter



52 reaction of pentenyl glycosides and carboxylic acids (18); and 5) by coupling of TMS-amides with anomeric sulfoxides (19). All of these methods suffer from undesired side reactions, the need to do difficult purification sequences, the need to synthesize the anomeric azide or amine, low yields of product or a loss of anomeric stereocontrol in the reaction. Reported methods for the synthesis of 2-deoxyglycosylamides are even more sparse. Although most naturally-occuring 2-deoxy-N-glycopeptides are the P-anomers, a-linked 2-deoxy-N-glycopetides have also been isolated (20) and this has spurred great interest in developing methods for their synthesis. For example, Thiem and coworkers reported the synthesis of an asparaginesmodified-2-deoxy-ct-N-glycopeptide as a potential inhibitor of the reninangiotensin system using a 2-deoxy-2-iodo-N-succinimidylglycoconjugate (21). This was accomplished by ring opening of the succinimidyl moiety, peptide coupling and subsequent reductive deiodination. Recently, 2-deoxyglycosyl azides also were prepared from glycals and were used in the synthesis of 2deoxy-p-N-glycopeptides via their corresponding glycosylamines (22). We were also interested in using glycals as precursors for the synthesis of 2-deoxyglycopetides. We thought that it may also be possible to obtain the otlinked N-glycosylamide linkage directly using a variation of some chemistry first reported nearly thrity years ago by Lemieux (23) and Thiem (24); the haloglycosylation reaction.. The haloglycosylation reaction has been used extensively for the preparation of /raws-configured 2-haloglycosides from glycals and alcohols. The greatest selectivity in addition occurs when, the bulky, participating halogen, iodine is used. The ot-manno products are obtained preferentially from protected Dglucals and axial, bridging, iodonium ion intermediates have been proposed. Subsequent reductive deiodination of the 2-iodoglycosides with trialkylstannanes leads to the formation of 2-deoxy-a-glycosides . Other anomeric functionalities have been incorporated using this approach, such as: esters (25), the hydroxyl group of amino acids (26), water (27), isocyanates (28) and isothiocyanates (29). N-halosulfonamides have also been added directly to glycals (30). This elegant procedure afforded 2-amino-2-deoxy-P-glycosides from glycals in a two step sequence. Aziridinium ions were proposed as reactive intermediates to account for the regiochemistry and excellent stereoselectivity observed. Other weakly nucleophilic nitrogen species were aso reported to add to glycals. Thiem described the isolation of anomeric succinimides from the haloglycosylation reactions of glycals with poorly nucleophilic alcohols. Interestingly, the glycosyl imides were shown to exist preferentially in the alternate C chair conformation, presumably because of the reverse anomeric effect (57). These last two studies led us to investigate the possibility of using halonium ions to mediate the reactions of simple alkyl and arylamides with glycals. !

4


53


Towards this end, iodoamidation reactions were carried out on a variety of protected glucals: tri-O-acetyl-D-glucal, tri-O-benzyl-D-glucal and tris-O-tertbutyldimethylsilyl-D-glucal (Scheme 1, 1) with several primary alkyl and aryl amides (32). The addition reactions of substituted ureas and protected amino acids were also investigated.

RO-W

R'CONHR"

R

°

J,,

R O - * 7 ^

?

c=o I 1

a R = Ac b Bn c TBDMS

R' 2(aM)

2

G

(P >

R' = alkyl = aryl = N-alkyl - N,N-dialkyl

Scheme 1. Iodoamidation Reactions of Protected D-Glucals

As representative data in Table 1 shows, diastereomeric mixtures of gluco and manno iodoamides 2-9 were obtained from the reactions of these nitrogen nucleophiles with protected glucals. The major diastereomers observed in all cases, were the trans addition products, the ct-manno and (3-gluco isomers. This polar addition reaction likely proceeds via the initial formation of the N-haloamide from the reaction of the amide with N-iodosuccinimide. Iodonium ion is then transferred to the glycal from the N-iodoamide and the resulting amide nitrogen attacks to effect a Markovnikov-like addition to the vinyl ether. The high facial selectivity in this reaction occurs because of :1) the preference of the bulky halogen to add in the less sterically-hindered axial plane of the glucal and 2) the bulky, polarizable iodonium ion is capable of effectively stabilizing the developing oxocarbonium ion through a bridging species. Therefore, the nucleophilic amidic nitrogen can only then be trapped at CI by attacking from the opposite face of the molecule. For the addition reactions with simple amides, low temperatures were used (-78° C for 2 hr, then -78° - 25° C over 4 hr) and propionitrile was employed as the solvent (25). The mixtures were allowed to stir for 24-48 hr before extractive workup and subsequent column chromatography (Si0 , gradients of hexane/ethyl acetate). Variations in the halonium species (e.g. C1+ or Br+), the reaction solvent (diethyl ether, THF, or DMF) or the reaction temperature gave less favorable product distributions. For the simple amides, the highest yields and greatest diasteroselectivities were obtained when benzamide was used as the nucleophile (Table 1, Entries 1-3). 2


54 Table 1. ' H - N M R Ratios" and Isolated Yields of Diastereomeric Iodoamides from Protected D-GIucals Entry

Iodoamide


1 2 3 4

2a 2b 2c 3c

Sugar R= Ac Bn TBDMS TBDMS

Amide R'=

Ph Ph Ph CH

amanno (oM) 6 2 1" 1

3

Pgluco (PG) 10 1 0 0

Isolated yield c

(%) 42 85 82 50

('c ) 4

10 4

5

4c

TBDMS

6

5c

TBDMS

7

6c

TBDMS

8 9 10

7c 8c 9c

TBDMS TBDMS TBDMS

( c,)

JO O

NHCH CH N(CH ) BocGlnOMe 2

3

l

b

0

82

l

k

1

85

l

b

0

90

d

0 95 90

Nd l l

3

b

2

b

d

Nd 0 0

integration of anomeric resonances; NMRs run in CDC1 with 0.03% added TMS 3

indicates only product in the ' C conformation was observed. 4

c

Purified material following column chromatography (Si0 ). 2

^ o product was detected.

In the reactions with benzamide, the benzyl protected sugar afforded primarily the a-manno addition product, whereas the acetyl protected glucal gave mainly the P-gluco product. Furthermore, the electron poor acetylated glucal reacted more sluggishly than the benzyl protected precursor and gave lower yields of product. Interestingly, the tert-butyldimethylsilyl (TBDMS) protected glucal afforded only a single addition product in high yield when reacted with NIS and benzamide. Analysis of the proton NMR spectrum of the /ra-tertbutyldimethylsilylated product suggested that the compound isolated from the reaction mixture existed in the alternate *C chair conformer (Figure 1). Similar diastereoselectivities were observed with the TBDMS- protected glucal and other primary amides. However, with acetamide a higher proportion of the alternate C i conformer was observed (Table 1, Entry 4). 4

4


55 TBDMSCK

9 IOTBDMS p

,


Figure 1. TBDMS-Substituted lodobenzamides

This reaction was successful for a variety of primary amides (31), however, when the secondary amide, N-methylbenzamide was used in the reaction with triO-benzyl-D-glucal under the same conditions, none of the desired adducts were obtained. Instead, only the diequatorial succinimide adduct (70%) and starting materials were recovered. The addition reaction also worked with other glycals. For example, reaction with tri-O-benzyl-D-galactal 10 and benzamide afforded a 2:1 ratio of diaxiakdiequatorial addition products in 80% yield (Scheme 2). Based on the observed J values for the ring protons, it appeared as if there was no distortion from the normal Ci conformation of the chair in this addition reaction. 4

BnO

QBn

BnO .OBn

CH CH CN 3

10

2

AH

Bn

Frontiers in Modern Carbohydrate Chemistry - American Chemical

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