Oxazolines Intermediates

Hartwig and Whaley suggested that when substituents are placed in the 4-position of the ethylamine side chain, an oxazoline intermediate (7) is formed a side reaction that was first mentioned by Krabbe in 1940. However, Hartwig and Whaley did not isolate the putative intermediate. 

In 1977 Fitton et al. conducted the first detailed study that shed light on the true mechanism of the Pictet-Gams reaction. It was postulated that all Pictet-Gams reactions create an oxazoline intermediate (15) by the mechanism shown below ... 

Once the oxazoline intermediate was formed, the reaction could undergo one of two paths or both - depending upon the type of substituent present in the 4-position of the phenylethylamine side chain. It was observed that when Ry was methyl or ethyl, the products obtained were from path A ... 

Benzyl ethers are amongst the easiest to cleave by Lewis acids (20). Significant clipping of such bonds, with consequent loss of functionality, resulted during attempted HCl-catalyzed hydrolyses of polystyrene-supported oxazoline intermediates (21, 22) and chiral supports (23, 24). 

The same synthetic scheme was applied to synthesize nucleoside analogues with natural or modified base, starting from a- and p-D-xylo-17 and p-D-ura/uHO-derivatives.105 Grouiller also used the procedure with p-D-fructose to prepare nucleoside derivatives.18 However, the fragility of the oxazoline intermediate and low yields obtained limited the methodology. 

Since under these conditions elimination of mesyloxy groups can only occur with participation of the vicinal acetamido group via oxazoline intermediates presupposing iraws-arrangements of the mesyloxy and acetamido moieties, the configuration of (12) and its precursors is unequivocally established. 

An alternative mechanism to form thiazoles and oxazoles is through oxidation of a dipeptide followed by cyclization from an enolate or thienolate precursor and subsequent dehydration (Scheme 7.2). This represents a higher-energy pathway and there is no accumulation of thiazoline or oxazoline intermediates [22-24]. 

Phosphorous oxychloride (POCI3) can also be used without further activation. For the synthesis of the antidepressant (/ )-(—)-rolipram 24, cyclization of the (3-hydroxy amide 21 with POCI3 gave the oxazoline intermediate 22. Diastereo-selective conjugate addition of cyanide gave the cyano derivative 23, which was further transformed to (/ )-( )-rolipram (Scheme 8.11). 

Because of the mild and essentially neutral reaction conditions, Burgess reagent was applied for the construction of the oxazoline intermediates 60 required by Pattendon and co-workers " " for their syntheses of thiangazole 61 and lissoclin-... 

The same isothiocyanate 5 was obtained when 6 was used as the starting material.32 For this 0- N acyl migration, a mechanism has been proposed that involves the oxazoline intermediate 8, which results after dehydration of the initially formed l,2-(orthoacetyl)amide (7). The oxazoline derivative subsequently reacts with the thiocyanate ion at C-l, with Walden inversion. 

Functionalization of a pyrrolidine a-position has been observed on photolysis of 44.36 Naphthoquinone 46 formed via an oxazoline intermediate (45), which is structurally similar to intermediate 42. 

Figure 12. Proton-NMR spectra of the oxazoline intermediates 44 and 45. Key to formulas same as for Figure 1.

The presence of an oxazoline intermediate was proved in the mechanism of C-2-amidoglycosidation of glycals <02JA9789>. 

Several 0-GlcNAcase inhibitors have been described, the most popular are streptozotocin (STZ) and PUGNAc. Both of these compounds are substrate mimetics that inhibit 0-GlcNAcase activity by resembling the natural substrate s ox-azoline transition state after its entrance into the active site (50, 51). Unfortunately, the above inhibitors are nonselective and can inhibit other glycosyl hydrolases therefore, they are a detriment to a multitude of cell pathways. Another, more potent transition state analog, A-acetylglucosamine-thiazoline (NAG-thiazoline), has been described recently (5). The increased potency likely is because the compound already resembles the oxazoline intermediate before it is exposed to the enzyme. Macauley et al. 

Yohino, T, Sato, K, Wanme, F, Takai, I, Ishido, Y, Efficient catalysis by pyridinium sulfonate in glycosylation involving an oxazoline intermediate derived from per-O-acetyl-iV-acetyllactosamine and A,V-diacetylchitobiose, Glycoconjugate J., 9, 287-291, 1992. 

A recent paper on the Pictet-Gams synthesis of isoquinolines (Scheme 44) describes the use of oxazoline intermediates for an improved method of preparing the starting materials. or/ o-Halogenated A -alkyl-A -acyl-benzylamines (67) can be cyclized to dihydroisoquinolones (68) by their reaction with KNH2 in liquid ammonia or with LiNPr 2 in THF under thermal... 

Evidence for existence of the oxazoline intermediate is found in the ability of GlcNAc-thiazoline, which mimics the oxazoline structure, to inhibit these enzymes. " Structural analyses of hexosaminidases in complex with these inhibitors have yielded useful mechanistic insights." In the case of SpHex and 0-GlcNAcase, the structures of the two transition states flanking the oxazoline intermediate have been investigated through substrate structure-function studies, including a-deuterium xiEs. " ""... 

Enzymes classified into oxazoline intermediate type are typically chitinase and hyaluronidase. Chitinase from Bacillus sp. (EC 3.2.1.14) belonging to the glycoside hydrolase family 18 primarily catalyzes hydrolysis of (1— 4)-jff-A-acetylglucosaminide linkage in chitin (30,32,33). The hydrolysis mechanism is postulated to proceed through the substrate-assisted mechanism as follows (Figure 3). 

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