Lactones, reaction with lithium amides

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Because direct glycosidation of 4 with phenols is not possible, indirect methods must be used for the preparation of aryl D-glucofuranosidurono-6,3-lactones (29). In addition, aryl 2,5-di-O-acetyl-D-glucofuranosidurono-6,3-lactones (30), obtained35-37 from the reaction of 1,2,5-tri-0-acetyl-D-glucofuranurono-6,3-lactones with phenols, can only be deacetylated by such multi-step procedures as (1) ammonolysis of 30 to afford aryl D-glucofuranosiduronamides (31), followed by amide hydrolysis and lactonization, 35,37 or (2) reduction of 30 with lithium aluminum hydride, and subsequent oxidation of the intermediate aryl D-glucofuranosides38 (32) (see Scheme 1). 

Intramolecular alkylations of y-lactone enolates are merely variants of the examples mentioned in the previous sections (Section 1.1.1.3.2.2.1.). A striking feature of these reactions is their efficiency with mild bases such as l,8-diazobicyclo[5.4.0]undec-7-ene (DBU) or potassium er -butoxide instead of the lithium amides. 

In the laboratory of E.J. Corey, the first synthesis of nicandrenones (NIC), a structurally complex steroid-derived family of natural products, was accomplished. The side chain of NIC-1 was constructed from the known six-membered lactone which was converted to the Weinreb s amide by treating it with excess MeNH(OMe) HCI and trimethyl-aluminum. The resulting primary alcohol was protected as the TBS ether. The ethynylation of this amide was carried out by reaction with two equivalents of lithium trimethylsilylacetylide to afford an ynone, which was reduced enantioselectively to the corresponding propargylic alcohol using CBS reduction. 

Successful approaches to the stereoselective total synthesis of AI-77-B (28) have been reported recently by several groups. The first total synthesis was reported by Hamada et al (ref.125,126). The aminodihydroisocoumarin (42) was prepared from ethyl 6-methyIsalicylate and W-protected (S)-leucinal by a process involving diastereoselective 1,2-addition of the benzylic anion followed by spontaneous lactone formation (Scheme 4). Briefly, the methoxymethyl (MOM) methyl ester (61) was prepared from ethyl 6-methylsalicylate in the usual manner. The benzylic anion (62) was then generated in situ, by reaction of (61) with lithium diisopropy1 amide (LDA) in the presence of tetramethylethylenediamine (TMEDA) in THF (-78°C/lhr), and reacted with Boc-(S)-leucinal (63). This afforded a separable mixture of diastereomers (64a and 64b) in 32% yield. Upon use of excess LDA (2.6 equiv.) and (63) (1.4 equiv.) an 81 19 stereoselectivity was... 

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

The sulfenylation of esters,lactones, carboxylic acids,amides and lactams may be effected by reaction of the corresponding lithium enolates in THF at -78 to 0 C with dimethyl or diphenyl disulfides, or, less commonly, with methyl or phenyl sulfenyl halides. The enolates of ketones, however, are insufficiently nucleophilic to react wiA dialkyl sulfides unless HMPA is added to the reaction mixture, although they do react smoothly with diaryl sulfides. This difference allows the selective sulfenylation of esters in the presence of ketones (entry 5, Table 3). ... 

Lithium aminoborohydrides.1 The reagent 1 is a typical member of a number of lithium aminoborohydrides, prepared by reaction of BuLi with amine borancs in quantitative yields. These reagents can be stored at 25" under N2 for at least six months they are not pyrophoric. They are comparable to LiAIH4 as rcductants. Thus 1 reduces carbonyl compounds (including esters) in high yield. lactones and anhydrides are reduced, but carboxylic acids are not reduced. In addition 1 reduces amides, epoxides, oximes, nitriles, and even halides. 

Base-catalyzed alkylations of simple esters require strongly basic catalysts. Relatively weak bases such as alkoxides promote condensation reactions (Chapter 2). The techniques for successful formation of ester enolates which have been developed typically involve amide bases, most commonly lithium diisopropylamide, at low temperature. The resulting enolates can be successfully alkylated with alkyl bromides or iodides. Some examples of the alkylation of enolates of esters and lactones are presented in Scheme 1.8. 

Neurokinin-1 receptor antagonists such as 120 (Scheme 2.19) have been identified as potential antiinflammatory agents by researchers at Merck Research Laboratories. To access the tra 5-3,4-disubstituted 8-lactone 119, a key intermediate in the synthesis of 120, an asymmetric conjugate addition strategy was developed. As depicted in Scheme 2.19, reaction of the lithium enolate derived from the amide 115 with enoate 116 afforded... 

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