Lactonization/benzylic method

The efficient stereocontrol observed in the benzylic lactone hydro-genolyses described in the section on Lactonization/Benzylic Lactone Reduction prompted an investigation into methods for preparing analogous fused bicyclic lactones from enamides 89, 92, 94, and 96. The possible intermediacy of benzylic carbocation 123 in the triethylsilane... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Azetidine-2-carboxylic acid (2) is commercially available. It is readily prepared as the racemate by refluxing 2,4-dibromobutyric acid ester with benzhydrylamine in acetonitrile. If benzyl 2,4-dibromobutyrate is treated with benzhydrylamine, the resulting benzyl TV-benz-hydryl-D,L-azetidine-2-carboxylate is hydrogenolytically processed to D,L-azetidine-2-car-boxylic acid in a one-step reaction. 101,107 Resolution of the racemate can be performed by the method of Vogler 108 via fractional crystallization of the Z-D,L-Aze-OH-H-Tyr-N2H3 salt thereby the salt of the D-imino acid precipitates first from methanol. 96 A stereoselective synthesis of A-tosyl-L-azetidine-2-carboxylic acid can be achieved by a two-step reaction from N-tosyl-L-homoserine lactone. 94 ... 

Most stereoselective alkylations to the lactone intermediates are accomplished using the method reported by Kleinman and co-workers.1201 The dianion form is prepared by treating the lactone with lithium or sodium hexamethyldisilanazide. Then, the reaction between the dianion and an alkyl halide produces the 2-alkylated lactone (Scheme 11, Section 10.6.2). Kleinman and co-workers reported that the ratio of the trans- and ds-lactone is 47 3. When a doubly protected a-amino aldehyde [e.g., dibenzylamino aldehyde, (/ert-butoxycarbonyl)-benzylamino aldehyde] is used, the c/.v-lactone is not obtained. As an example, the alkylation of (55,1 5)-5-[l -[/V-(/< rt-butoxycarbonyl)benzylamino]-2 -phenylethyl]dihydrofuran-2(3/7)-one to produce (3/ ,55,l 5)-3-benzyl-5-[1 -[/V-(/ert-butoxycarbonyl)benzylamino]-2 -phenyl-ethyl]dihydrofuran-2(3//)-one is described in this section. 

Cleavage of esters and lactones (8,447-448).1 SN2-Cleavage of esters and lactones with NaSeC6H5in HMPT-THF is considered to be the most effective known method. The order of reactivity of related reagents is NaSeC6H5-18-crown-6-THF > LiSe(, H5 HMPT THF > LiSeC6H5 THF. Methyl esters are cleaved more readily than ethyl esters benzyl, isoamyl, and isopropyl esters are cleaved in high yield, but more slowly. Methyl esters are cleaved easily, irrespective of steric hindrance. Amides are completely inert. 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

Analogues of 70 have been prepared by various methods including nucleophilic displacement of triflate esters attached directly to the oxetane ring (see Section 2.05.7.2) <2001TL4247>, from xylose, 145, via the benzyl-idene-protected oxetane, 146 (Scheme 24) <2004TA2667>, or from L-rhamnose, 147, via a l,4-lactone-2-O-triflate, 148 (and key oxetane 149 (Scheme 25)) <2004TA2681>. The /3-azidoester monomers formed by these methods were converted to the /3-amino acids and subsequently to /3-peptides by reduction of the azide and ester hydrolysis. 

Dirhodium caprolactamate [Rh2(cap)4] is reported to be an effective catalyst with tert-butyl hydrogen peroxide for benzylic oxidation of chromans, for example, 490, 492, and 495 under mild conditions to give lactones 491, 493, and 496, along with peroxide 494 (Scheme 89). This method has been applied to a synthesis of Palmarumycin CP2 <20050L5167>. 

Methylenation of tri-O-benzyl-D-arabinolactone 335 (Scheme 115) with BT methyl sulfone gave [148] the expected adduct (not shown in the scheme) under the standard conditions in 78% yield. However, the rearrangement step was retarded. Methylene exoglycal 337 was eventually obtained in 66% yield when the reagents were treated first with LHMDS in THF at - 78 °C and then with DBU at rt. The method was applied to various sugar lactones with pyra-nose or furanose rings to give the respective methylene derivatives in 46- 74% yields. 

The nucleophilicity of the aromatic system can alternatively be increased by using organometallic aromatic compounds, which also solves the problem of regioselectivity. This method was applied by Sulikowski et al., who reacted a variety of sugar lactones with aryl lithiums to afford intermediate lactols which were subsequently reduced to the C-glycosides by cyanoboro hydride [137]. For example, selective orfho-bromination of monobenzylated napthalene diol 174 affords the bromide 175 which is converted into the dianion with three equivalents of n-BuLi. Treatment with the benzylated lactone 176 afforded lactol 177 (Scheme 45, the D-dideoxygluconolactone 176 was erroneously drawn as the... 

Acid-Catalyzed Benzylation. Benzyl trichloroacetimidate, Cl3CC(=NH)OBn, reacts with hydroxyl groups under acid catalysis to give the con-esponding benzyl ethers in good yield. The method is particularly useful for the protection of base-sensitive substrates (i.e., alkoxide-sensitive), such as hydroxy esters or hydroxy lactones, as exemplified below. 

During the synthesis of n-apiose, 3-0-benzyl-n-fructose was treated in the same way (Kiliani method), and a crystalline 3-0-benzyl lactone was formed (m.p. 150-152°). Reduction by means of sodium borohydride gave the branched-chain heptitol (75), showing that this method provides an interesting tool for the synthesis of branched-chain sugars. - ... 

Fontaine and coworkers have recently reported the synthesis of a supported aza-lactone via atom radical transfer polymerization (ATRP) [9]. This method involved the preparation of a Wang resin-supported initiator, followed by subsequent ATR polymerization between 2-vinyl-4,4-dimethyl-5-oxazolone (VAZ) and styrene to generate several macroporous, aza-lactone functionalized resins with different architectures. These were shown to scavenge benzyl amines in a highly efficient fashion (Scheme 8.5). 

Benzyl 3-(9-benzyl-2-deoxy-4,6-0-isopropyhdene-a,p-D-arabino-hexopyranoside (32) and methyl 3-(9-benzyl-2-deoxy-4,6-0-isopropylidene-a-D-ribohexopyranoside were prepared from D-glucose and used as precursors for the syntheses of 13 and its analogue 39, respectively (Scheme 3). The crucial step was the formation of the pyrrohdine ring in 35 from 34, which was effected by sodium borohydride reduction followed by alkaline treatment. The pyrrolidine 35 was then coupled with benzyloxycarbonyl-L-vahne via an active ester or by the DCC method to give 36, which was converted to the lactone 37 by acid hydrolysis followed by oxidation with pyridinium chlorochromate. Finally, the lactone 37 was hydrogenated to give 38, a precursor for 13. 

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