Stereoselective Diazoalkane Cycloadditions to Chiral 5-Alkylidene-1,3-dioxan-4-ones and 3-Benzylidene-β-lactones

Abstract

Stereoselective 1,3-dipolar cycloaddition of diazoalkanes to ( E )-5-alkylidene-1,3-dioxan-4-ones 1 and the ( Z) -isomers (Z)-1 afforded spiropyrazolines 3 and 10 , respectively. The optically active 2-benzylidene-3-methyl-β -lactone (8) was synthesized from the corresponding 5-benzylidene-1,3-dioxan-4-one 1f by hydrolysis and recyclization and added diazomethane with opposite stereodifferentiation. Photochemical elimination of nitrogen from spiropyrazolines 3 gave enantiomerically pure spirocyclopropanes 12 that could be further transformed to cyclopropanecarboxylic acids 13 and derivatives 14 .Recently, the cycloaddition of diazomethane to 5-alkylidene-1,3-dioxan-4-ones 1 , derivatives of the naturally occurring polyhydroxybutyrates (PHB), was reported in a short communication. 1 Spiropyrazolines 3 were obtained with complete stereoselectivity, which could then lose N 2 affording spirocyclopropanes 12 or 5-alkylidene-1,3-dioxan-4-ones 15 by irradiation or thermolysis, respectively. In addition to detailed investigations and extension of these reactions to substituted diazoalkanes 2 (R 3 ≠ H) and chemical transformations of the spirocyclopropanes 12 , we report here the possibility of changing the stereochemistry of the diazomethane cycloaddition (α versus β -attack) by the application of a corresponding 3-alkylidene-β -lactone 8 . The addition of diazomethane to ( E )-5-alkylidene-1,3-dioxan-4-ones 1 gave β -products 3 (Scheme 1 and Table 1) with high stereoselectivity. 1 The same holds true for the addition of diazomethane to the ( Z )-5-alkylidene-1,3-dioxan-4-one ( Z ) -1a (R 1 = Me, R 2 = t -Bu) affording the diastereomer 10a (Scheme 2 and Table 1). In the case of the less reactive 5-arylidene-1,3-dioxanones 1 and ( Z ) -1 (R 1 =Ph, 3-MeOC 6 H 4 ) long reaction times were necessary (1 week) and mixtures of the diastereomeric spiropyrazolines 3 and 4 or 10 and 11 were obtained (Schemes 1 and 2), that could be separated by chromatography affording at least the major isomer in analytically pure state (Table 1). The configuration and constitution of the pyrazolines 3 , 4, 10 and 11 were elucidated by NMR spectroscopy (NOE-investigations included), and in some cases by their transformation to cyclopropanes 12 (vide infra). In addition, the structure of the cycloadduct 10b was proved by X-ray crystal analysis ( Figure).In order to check the scope of the dipolar cycloaddition of diazoalkanes to 5-alkylidene-1,3-dioxan-4-ones 1 , diazoethane (R 3 = Me), trimethylsilyldiazomethane (R 3 = TMS) and ethyl diazoacetate (R 3 = CO 2 Et) were included in reactions with the ethylidene compound 1a . Whereas diazoethane gave comparable results to diazomethane, reactions with trimethylsilyldiazomethane and ethyl diazoacetate proved more difficult to realize. Finally, high pressure conditions (10 kbar) or heating in benzene at 80 o C afforded complete cycloadditions (Table 1) to the corresponding 1-pyrazolines 3 or 2-pyrazoline 6a , respectively. The stereoselectivity was somewhat lower in these cases.Since most of the spiropyr...

1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with diazoalkanes

“…7,29,30 The decomposition is usually achieved photochemically as the thermally-induced process leads to lower stereoselectivity and smaller amounts of cyclopropanes. [31][32][33] Although the thermal extrusion of nitrogen mainly gives alkenes, there have been a few examples reported in the literature in which cyclopropanes are the main products from the thermal process. 7,34,35 As there was literature precedent for the thermolysis of pyrazolines to afford cyclopropanes, it was decided to explore the thermal decomposition of a pyrazoline synthesised during the current work to determine if the cyclopropane would be the major product isolated.…”

Structural Remodeling of Cocaine: Design and Synthesis of Trisubstituted Cyclopropanes as Selective Serotonin Reuptake Inhibitors

“…The first step of this project involved a literature search for methods of synthesis of the required cyclopropane scaffold. Although the synthesis of this particular scaffold has been reported,30, 31 there is a general lack of detailed procedures, and little substantive biological activity has been reported for such ligands. The chemistry that we developed to gain access to compounds 7 a – h is illustrated in Scheme 1.…”

Ligand‐Controlled Palladium‐Catalyzed Carbonylation of Alkynols: Highly Selective Synthesis of α‐Methylene‐β‐Lactones

“…Considering the value of α‐alkylidene‐β‐lactones in organic synthesis, significant interest in their preparation exists [4] . Because of the dense functionalization, mainly special synthetic methods have been developed for this class of compounds including [2+2]‐cycloaddition of ketenes, [3n, 4a–c] lactonization of β‐hydroxycarboxylic acids or derivatives, [3d, 4d–g] elimination of selenoxide from α‐methyl‐substituted lactones, [3b] and deoxygenation of β‐peroxylactones [3f, 4g–h] …”