Chiral lactone intermediates

The enzyme-mediated Baeyer-Villiger oxidation to chiral lactone intermediates has received considerable attention in recent years as it offers several advantages in chemo-, regio-, and stereoselectivity compared to other catalytic strategies... 

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

Wu and co-workers (Wu et al., 1999) have demonstrated a novel chiral lactone enolate-imine process to access 2-azetidinone diols such as 35 (Scheme 13.10). Treatment of 34 with LDA at — 25°C in THF followed by addition of imine 3, afforded only trace product. Addition of HMPA or the less toxic DMPU during the lithium enolate formation step improved the yield and the trans cis diastereoselectivity ( 90 10). Recrystallization improved the purity to >95 5 trans cis 2-azetidinone. Addition of an equivalent of lithium bromide accelerates the rate of ring closure, presumably by destabilizing the intermediate lithium aggregates. Side-chain manipulation of 35 was accomplished by sodium... 

The chiral lactone alcohol derivative (178)181) can be readily prepared from natural (S)-glutamic acid, the cheapest chiral a-amino acid. Lactone (178) was alkylated to yield optically active 3-substituted lactone alcohol derivatives, (179) and (180), which were intermediates in the stereoselective synthesis of various natural products 182). 

As pointed out earlier, cycloalkylation reactions can also result from the reaction of arenes with bifunctional alkylating agents or in cases where bifunctional intermediates are involved. An example of the former is shown in equation (114), where a chiral, lactone-substituted alkene cyclizes with the arene to produce a chiral tetrahydronaphthalene derivative. 

Other syntheses of the tetracyclic intermediates 434 and 436 that merit mention, and thus constitute additional formal syntheses of (-1-)-quebrachamine, have been contributed by Fuji et aL and by Asaoka and Takei. Fuji s approach (279) starts with the chiral lactone 446, which is readily available from 2-ethyl-5-valerolactone. Partial reduction to the aldehyde stage, followed by acetal formation, gave 447, which on condensation and reduction (lithium aluminum hydride) gave a mixture of C-3 epimers 434, the late intermediate in the (+)-quebrachamine synthesis (Scheme 41). 

Route II Carbohydrates are endowed with a number of chiral centers and are available in various chain lengths. o-Mannitol is an inexpensive commodity chemical endowed with a C2 axis of symmetry. A synthesis of the key intermediate y-butyrolactone (7) from d-mannitol was envisaged in which chiral centers at C2 and C5 are correlated with C2 of the lactone intermediate (Scheme 30.27). This would, in effect, provide two molecules of the lactone from one molecule of D-mannitol. 

A similar methodology has been applied in the synthesis of various useful chiral synthetic intermediates. Representative examples include the syntheses of alduronic acid lactone 603 [637,638], chiral dispiroacetals 605 and 606 [639] and a-iodoalkyl ester 608 from respective carbohydrate derivatives 602, 604 and 607 (Scheme 3.237) [640]. 

Allenic esters readily react with dialkylzinc reagents in the presence of DIFLUORPHOS-complexed copper (from Cu(OAc)2) in THF at -20 While this initial adduct bears no new central chirality, the intermediate nonracemic copper/zinc enolate can then add in a stereocontrolled 1,2-fashion to unsymmetrical ketones. Ring closure to the resulting S-lactone completes the sequence. Both 4 A molecular sieves and 20 mol% Lewis basic Ph2S=0 (or DMSO, hexamethylphosphoramide [HMPA]) are required to direct attack at the y-position rather than the otherwise reversible aldol event at the a-site, thereby facilitating conversion to cyclic products. 

Jagodzinski PW, Peticolas WL (1981) Resonance enhanced Raman identification of the zinc-oxygen bond in a horse liver alcohol dehydrogenase-nicotinamide adenine dinucleotide-aldehyde transient chemical intermediate. J Am Chem Soc 103 234-236 Jakovac IJ, Goodbrand HB, Lok KP, Jones JB (1982) Enzymes in organic synthesis. 24. Preparations of enantiomerically pure chiral lactones via stereospecific horse liver alcohol dehydrogenase... 

A chiral, nonracemic lactone intermediate is prominent in the conversion of... 

Chiral 1,5-diols (153) have been efficiently accessed by iridium-catalysed asymmetric hydrogenation of 6-aryl-5-ketoesters (152). A gas chromatographic study indicates 0 initial ketone reduction, to the hydroxyl-ester. Loss of ethanol gives a 5-lactone intermediate, which is reductively reopened this sequence is confirmed by generation of (153) when an authentic sample of the lactone is treated under the same conditions. 

Lactonization of a hydroxy-acid to a butyrolactone is achieved, using dimethyl-formamide dineopentyl acetal, during a synthesis of oxygenated nor-heliango-lides. The chiral lactone (164) is prepared from (iJ)-malic acid, its dianion is alkylated at carbon to give the /ra/i5-disubstituted lactone (165) in moderate yield, and this is used in a synthesis of (—)-aplysistatin (Scheme 94). An independent, biogenetically patterned synthesis of this natural product, using tetronic acid intermediates, has been described. ... 

There are other simple transformations that can be performed on the hydrolyzed ketone adduct. One of them is the regioselective Baeyer-Villiger oxidation (Scheme 23a) [23, 33]. This methodology gives access to chiral lactones, which are key intermediates in the preparation of valuable intermediates. Another one is the oxidative ozonolysis (Scheme 23b), which gives access to chiral aldehydes [33]. Finally, there is also the ketone reduction to a primary alcohol (Scheme 23c) [59]. 

Scheldt and coworkers also reported an enantioselective desymmetrization reaction of 1,3-diketones 62 in the presence of triazolium salt 61. This new process combines an intramolecular aldol reaction followed by a decarboxylation process of P-lactone intermediates, giving chiral cyclopentenes 63 in moderate yields and with high ees. Notably, with aliphatic diketones 64 or 66, p-lactone products 65 or 67, respectively, were obtained (Scheme 36.17) [23]. 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

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