The phase-transfer methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone by MeCl in 50% NaOH/toluene using substituted N-benzylcinchoninium halides has provided the methylated indanone 2 in ee's up to 94%. The effects of solvent, alkylating agent, temperature, and catalyst were investigated: nonpolar solvents gave higher ee's than polar solvents; MeCl gave a higher ee than did MeBr and Mel; and temperature had little effect on the reaction. A Hammett plot of log ee/ee0 vs. a for the N-benzylcinchoninium halide catalysts gave a reaction constant p of 0.21 with an ee range of 60% to 94%, demonstrating that substituents with increasing electronwithdrawing power improve catalyst selectivity. A kinetic and mechanistic study of the reaction has revealed several unusual features. In 50% NaOH/toluene these include the following: (1) the indanone 1 is deprotonated at the interface to form the sodium enolate as a separate solid phase; (2) the substituted IV-benzylcinchoninium catalysts are extracted into the organic layer as dimers; and (3) the kinetic order in MeCl is 0.7 and in catalyst is 0.55. In 30% NaOH/toluene the following obtain: (1) no solid enolate is formed; (2) an order in catalyst of 0.5 was found for the chiral methylation pathway, while an order of 1.0 was found for the racemic methylation pathway.

The cycloacylation of aniline derivatives to 4-quinolones in the presence of Eaton's reagent is described. This high-yielding methodology is applicable to a wide variety of functionalized anilines and requires milder conditions than those traditionally employed. This cyclization protocol is used to prepare a host of heterocycles and bis-quinolones and is characterized by relatively low reaction temperature and ease of product isolation.

Addition of the amino acids threonine, serine, proline, and arginine to fermentations of the fungus Glarea lozoyensis influenced both the pneumocandin titer and the spectrum of analogues produced. Addition of threonine or serine altered the levels of the "serine analogues" of pneumocandins B(0) and B(5) and allowed for their isolation and identification. Proline supplementation resulted in a dose-dependent increase in the levels of pneumocandins B(0) and E(0), whereas pneumocandins C(0) and D(0) decreased as a function of proline level. Moreover, proline supplementation resulted in an overall increase in the synthesis of both trans-3- and trans-4-hydroxyproline while maintaining a low trans-4-hydroxyproline to trans-3-hydroxyproline ratio compared to the unsupplemented culture. Pneumocandin production and the synthesis of hydroxyprolines was also affected by addition of the proline-related amino acid arginine but not by the addition of glutamine or ornithine. Zinc, cobalt, copper, and nickel, trace elements that are known to inhibit alpha-ketoglutarate-dependent dioxygenases, affected the pneumocandin B(0) titer and altered the levels of pneumocandins B(1), B(2), B(5), B(6), and E(0), analogues that possess altered proline, ornithine, and tyrosine hydroxylation patterns.

An improved protocol for N-acetyl enamine formation is disclosed which involves LiBr-mediated addition of MeLi to substituted nitriles. The resulting enamides are isolated in high yields and excellent purity which permits subsequent hydrogenation at very low catalyst loading.

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-1-indanone with methyl chloride in 50% sodium hydroxide/toluene using N-(p-trifluoromethylbenzyl)cinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation employing 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7-dichloro-5-methoxy-2-propyl-1-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydroxy-5-methoxy-2-propyl-1-inden-1-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an interme diate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. Efficient asymmetric alkylations have been a long-sought goal in organic synthesis.In the recent literature three different approaches have been used for asymmetric alkylations of ketones: 1) chiral alkylating reagents (2, 3); 2) chiral auxiliaries (4-9); and 3) chiral catalysts (10-12). Two examples of the first approach are shown in Figure 1. Murphy observed an asymmetric induction of 8% during the alkylation of 2,4,6-trimethylphenol with allyl (+)-camphor-10-sulphonate. Duhamel methylated the Schiff base of methyl glycinate with l,2,4,6~bis-(0-isopropylidene)~3-methoxy-sulfonyl-α-D-glucose (A*) and produced S-alanine in 65% yield, 40% enantio meric excess (ee).The use of chiral auxiliaries has been developed into elegant three-step sequences to achieve high ee's ( Figure 2). In the general scheme a ketone is derivatized with a chiral amine. Low temperature lithiation and alkylation followed by hydrolysis pro duces the alkylated ketone in moderate to excellent ee's. The auxiliaries most often used are (S)-valine tert-butyl ester (Koga), l-amino-2-methoxymethylpyrrolidine (Enders) and (S)-2-amino-l-