Syntheses of β‐Lactones, 6. One‐Step Synthesis of β‐Lactones by Aldolization of Ketones or Aldehydes with 1‐Acylbenzotriazoles

Abstract

Benzotriazolides 1 of alkanoic acids with one hydrogen atom in a-position to the carboxamide group can be deprotonated with lithium diisopropylamide or lithium hexamethyldisilazanide to amide enolates 2 which condense at -90 to -95°C with ketones or aldehydes 3 to afford benzotriazolides of 0-lithiated P-hydroxylalkanoic acids 4. These reactive carboxamide derivatives cyclize with elimination of lithium benzotriazolide to the corresponding di-and trisubstituted p-lactones. With regard to the formation of P-monosubstituted 0-lactones from aldehydes the use of benzotriazolides as active carboxylic acid derivatives proved to be superior to the application of the corresponding phenyl esters. An a-unsubstituted P-lactone 6 was obtained from l-acetylbenzotriazole only with cyclohexanone. The other carbonyl compounds 3 did not provide the corresponding a-unsubstituted 0-lactones 6.The decarboxylation of p-lactones to olefin~ ['-~], the stereoselective reactions of p-lactones with a variety of electrophiles ['-6], and the regioselective fission of (3-lactones by many different n u c l e~p h i l e s [~~~~ make these highly reactive compounds versatile intermediates for organic syntheses ['O]. But at least after the detection of the (3-lactone moiety in a series of biologically active natural products like lipstatin["], lupeolactone[I2], or valilact~ne['~I the interest in efficient syntheses of this class of strained four-membered rings has gained new attention.One of the most versatile procedures for the synthesis of (3-lactones consists in the addition of ketones or aldehydes to doubly lithiated alkanoic acids and subsequent cyclization of the thus obtained (3-hydroxyalkanoic acids with benzenesulfonyl chloride in pyridine['l. Later on, it was found that p-lactones can be prepared directly in a one-pot reaction when lithium ester enolates of S-phenyl alkan e t h i o a t e~ [~, '~I or phenyl alkanoates[151 are used instead of the doubly lithiated alkanoic acids for the aldolization with ketones or aldehydes. In these one-prot reactions the intermediately formed 0-lithiated P-hydroxy esters cyclize spontaneously with elimination of lithium benzenethiolate and lithium phenolate, respectively. A common feature of these procedures is the fact that the benzenethiolate and the phenolate residue are suitable leaving groups. They facilitate the attack of the electrophilic carbon atom of the activated ester group on the lithiated (3-hydroxy group of the inter- mediate and enable in this way the observed intramolecular acylation. In this connection the question arose whether there exist other active carboxylic acid derivatives, which are superior to the phenyl or S-phenyl esters with regard to the yield of the obtained p-lactone and the diastereoselectivity of the carbon-carbon bond formation. Here we report on the results of the aldolization of ketones or aldehydes with 1 -acylbenzotriazoles.N-Acyl derivatives of imidazole are known as powerful acylating agents and have found widespread application in organic synthesis [16%17]. ...

Assay and inhibition of diacylglycerol lipase activity

“…The shorter chain separable trans - 10 and cis - 11 β-lactones were prepared according to the reported method. 32 Also, a new series of racemic ether lipids derived from lead compounds RHC80267 1 and O-3841 2 was prepared (see Supplementary data). …”

Synthesis of Long‐Chain β‐Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

“…After reaction with commercial butyraldehyde, the corresponding β‐hydroxy acids 3 a – c were obtained in 30–85 % yields. Finally, cyclization of the intermediate α,β‐disubstituted β‐hydroxy acids 3 a – c by treatment with p ‐toluenesulfonyl chloride led to α,β‐disubstituted β‐lactones VM001–3 in 42–67 % yields (Scheme ) . Both β‐hydroxy acids 3 a – c and β‐lactones VM001–3 were obtained as mixtures of diastereomers whose ratio was determined by 1 H NMR spectroscopy, and, in particular, by the relative peak integration of the characteristic α‐ and/or β‐methinic protons (see the Supporting Information for a detailed analysis on the diastereomeric ratio).…”

Benzotriazole-Mediated Synthesis of Oxygen-Containing Heterocycles

“…In all cases involving aldehydes and their reactions with the amide enolates 42, both diastereoisomers of the corresponding α,β-disubstituted β-lactones 44 were formed. The trans-configurated diastereoisomers predominated in all cases [24].…”

“…Shick and colleagues reported an interesting procedure for the preparation of β-lactones from N-acylbenzotriazoles 41 with one hydrogen atom in α-position to the carboxamide group [24]. N-Acylbenzotriazoles 41 were deprotonated with lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LiHMDS) to furnish enolates 42.…”