Oxetanone derivatives

Utility Lipase Inhibitors for Lowering Serum Cholesterol 

4S-[2- (Chitosan-g-6-hexanoylamido -4-methylvaleryloxy]-2-hexyl-hexdecanoic 1,3-lactone 

The product was Step 1 (9g) was dissolved in 200 ml THE and IH-benzotriazolium-l-[bis(dimethylamino)methylene]hexafluoro-phosphate(l-)-3-oxide) (10 mmol) dissolved in 10 ml DMF and added over 10 minutes. Tetrahydrostatin L-leucine ester (525 mg) dissolved in 100 ml THE was added, the reaction pH adjusted to 8.5 using diisopropylethy-lamine, and the mixture stirred overnight. Thereafter, the reaction volume was reduced by 50% and the product precipitated in 500 ml hexane. The crude product was washed 3 times with ethyl alcohol/water, 3 1, and dried under a lyophilizer. 

The polymer substrate consisted of low viscosity chitosan, poly(D-glucosamine), (I), which had a Brookfield viscosity of a 120-200 cps in 1% acetic acid solution. 

The author also prepared a second derivative by hydroxymethylating chitosan with paraformaldehyde and post-reacting with the lipase inhibitor tetrahydrosterastin. Other graft polymer derivatives of the current invention are described (1). 

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The cycloaddition of aldehydes and ketones with ketene under the influence of quinine or quinidine produce chiral 2-oxetanones [46,47]. Solvolytic cleavage of the oxetanone, derived from chloral, and further solvolysis of the trichloromethyl group leads to (5)- and (R)-malic acids with a 98% ee [46] (the chirality of the product depends on the configuration of the catalyst at C-8 and, unlike other alkaloid-induced reactions, it is apparently independent of the presence of the hydroxyl group). No attempts have been made to catalyse the reaction with chiral ammonium salts. 

As already mentioned, applications of the Mitsunobu reaction in lactone formation are significantly less common. Like so many other applications of the Mitsunobu reaction, the application of the Mitsunobu reaction for the preparation of lactones was first reported by Mitsunobu s group.Later on, Mitsunobu s group used the reaction to prepare colletodiol. Since then the scope of the reaction has been expanded to include the well known application of the Mitsunobu reaction for the preparation of amine protected (5)-3-amino-2-oxetanones derived from the correspondingly protected serine precursor this protocol was initially discovered by Vederas and... 

Thietane imines 26 are also obtained fi om 2-oxetanone derivatives 25 and phenyl isothiocyanate at —78°C. This reaction is an example of the conversion of one... 

The method outlined here competes well with the method developed earlier by Danheiser, et al.618 Its superiority is based on the fact that phenyl ester enolates give almost the same results as the S-phenyl thiolester enolates. However, handling the malodorous benzenethiol for the preparation of the active acid derivative and during workup of the p-lactone can be avoided. In addition, phenol is much cheaper than benzenethiol. The method is well suited for the preparation of p-lactones from symmetrical and unsymmetrical ketones. In addition to 3,3-dimethyM-oxaspiro[3.5]nonan-2-one, ( )-3-ethyl-1-oxaspiro[3.5]nonan-2-one and (3R, 4R )- and (3R, 4S )-4-isopropyl-4-methyl-3-octyl-2-oxetanone were prepared by this procedure in high yields (Notes 11 and 12). In the case of unsymmetrical ketones the less sterically crowded diasteroisomer is formed preferentially. With aldehydes as the carbonyl component the yields are unsatisfactory, because of the competitive formation of 1,3-dioxan-4-ones.6... 

Methylene-2-oxetanone, or diketene (37), does not decarboxylate on heating but cleaves to form ketene at 250 °C. A thermal rearrangement of 3-aryl-4-benzal-2-oxetanones (38) to form naphthalene derivatives appears to involve this type of pyrolysis, followed by a [ 2 + 4] cycloaddition (78JOC1146, 72LA(765)15>. 

In the present review the ring systems containing one heteroatom are considered first, except for P-lactams which are given a special section at the end. Interest in azetidines continues to be stimulated by the discovery of the potentially useful trinitro derivative. The requirements for the stereoselective synthesis of substituted oxetane are being explored and derivatives of aluminium are useful in the stereoselective routes to oxetanones. The preparation and subsequent pyrolysis of oxetanones is suggested as an alternative to the Wittig route to olefins. Stereoselective routes to thietanes and thietane 1 -oxides are mentioned. 

The structure, synthesis and biological activity of natural 2-oxetanones and their derivatives has been reviewed (95S729). The synthesis of some novel 3-(hydroxymethyl)-4-(2-substituted ethyl)-2-oxetanones and their biological activity as 3-hydroxy-3-methyl-glutaryl coenzyme-A inhibitors has been reported (94CPB1272, 94CPB2097). 

The biological and pharmaceutical properties of oxetanes have been highlighted throughout the chapter when other aspects such as their synthesis is described. For example, as discussed in Section 2.05.11, oxetanones form part of the structure of potent inhibitors of lipases and other enzymes. The naturally occurring amino acid oxetin is used as an antibiotic, and foldamers derived from analogues of oxetin have other potential therapeutic uses. The antiobesity drug tetrahydrolipstatin 119 was described in Section 2.05.11 and the /3-lactone F-244 (1223 A) has been reported with antibiotic properties <1998BMC1255>. 

Oxetanones ( -lactones) are useful synthetic intermediates which have been most often prepared by cyclization of p-halo or p-hydroxy acid derivatives or by addition of ketenes " to carbonyl compounds. They are starting materials for useful polymers and copolymers and have been used for the synthesis of alkenes and carboxylic acid derivatives. P-Lactones possessing antimicrobial activity have recently been found in bacterial cultures. ... 

Suitable derivatives to render most steroids more stable and volatile for gas chromatography and to improve their mass spectrometric properties have been developed. The trimethylsilyl ethers [206] or the methoxime-trimethylsilyl ethers of hydroxy keto steroids [207] have been widely used and their mass spectra extensively studied [204], A comparison of the GC-MS behaviour of several derivatives of some of the adrenocortical hormones has been made [208], including methoxime-trimethylsilyl ethers, dimethylsiliconides, methyl boronates, oxetanones and acetonides. The recently described improved preparation of enol-trimethylsilyl ethers of corticoids [209] should also prove of value. 

The alternative procedure for chiral 4-substituted-2-oxetanones is the ring closure of optically active 3-hydroxycarboxylic acid derivatives [49]. 

Other cycloadditions. A [3+2]-cycloaddition involving a benzoquinone and an alkene to give 2,3-dihydrobenzofuran derivatives, and an intramolecular [4+3]-cycloaddition to provide functionalized polycyclic compounds, are further demonstrations of the utility of LiClQj-OEtj. The reaction of aromatic or a,p-unsaturated aldehydes with acid chlorides proceeds via ketenes and then 2-oxetanones. ... 

Nature produces obviously not only interesting /1-lactams as in the antibiotics, but also structurally correspon ding jS-lactones. The high reactivity of the oxetanone system is crucial to the irreversible enzyme inhibition The oxetanone acylates a serine residue (Ser-152) in the active centre of the pancreas-lipase and thereby blocks its function (Fig. 5.110). [256] Some derivatives, e.g. tetrahydrolipstatin, also inhibit the thioesterase domain of the human fatty acid synthase. [257]... 

When the aldol product contains a highly reactive carboxyhc acid derivative, a spontaneous lactonization to furnish P-lactones (2-oxetanones) may follow immediately. 

Ramiandrasoa, P, Guerin, P, Girault, J.P., Bascou, P, Hammouda, A., Gammas, S. and Vert, M. (1993) Poly(d-maic acid alkvl esters) derived from 4-alkyloxycarbonyl-2-oxetanones obtained via the ketene route. Polyrn. Bull, 30, 501-508. 

As well as yielding a mixture of epimeric ketoacetates, in which the epimer required for the synthesis of lincosamine derivatives is a minor component, acetolysis of the diazoketone also gave the 3-oxetanone (112) (19% yield), a product of pyranose-ring opening. 

Leboucher-Durand, M.A., Langlois, V., and Guerin, Ph., 1996,4-Carboxy-2-oxetanone as a new chiral precursor in the preparation of functionalized racemic or optically active poly(P-malic acid) derivatives. Polym. Bull. 36 35-41. 

In this chapter we review the basic principles of polyester synthesis produced from 2-oxetanone-type monomers (named P-lactones), including details of pertinent mechanistic aspects and the general properties of the resultant polymeric materials. Before discussing the ROP of P-lactones, however, we provide a brief overview of the synthesis of P-lactone key derivatives. 

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