Francesco De Sarlo

1,3-Aminoalcohols by reductive cleavage of isoxazolidines with molybdenum hexacarbonyl

Abstract Isoxazolidines are reductively cleaved to 1,3-aminoalcohols by reacting with Mo(CO) 6 and water. Reaction conditions are simple, mild and selective giving good yields of highly functionalized products with complete retention of configuration of the stereocenters. The reduction fails when steric hindrance is experienced by the nitrogen atom.

Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats.

Some activities of retinoids on cellular and humoral immunity have been described, but the available data are conflicting or obtained at concentrations that are toxic in vivo. In this study, we demonstrate that 13-cis-retinoic acid (13-cRA), a retinoid well tolerated in human therapy, can suppress T cell-mediated immunity in rats. Treatment with pharmacological concentrations of 13-cRA prevented active as well as passive transfer experimental autoimmune encephalomyelitis (EAE) and suppressed lymphocyte responsiveness to T cell mitogens, suggesting that the drug activity included suppression of an effector T cell response. In addition, mitogen- and antigen-induced lymphocyte proliferation was inhibited in vitro in the presence of concentrations of 13-cRA equivalent to or less than those achieved in vivo, further suggesting that the prevention of EAE was due to a suppressive activity on T cell-mediated immunity. The immunosuppressive activity of 13-cRA included suppression of interleukin 2, whose production was inhibited in splenocytes. These data indicate that, in an in vivo mammalian system, 13-cRA exerts a suppressive activity on T cell-mediated immunity intensive enough to suppress an ongoing immune response, and that this effect can be achieved at nontoxic concentrations that may also be attained in human therapy.

Synthesis of 4,5‐Dihydroisoxazoles by Condensation of Primary Nitro Compounds with Alkenes by Using a Copper/Base Catalytic System

A new procedure for the synthesis of 4.5-dihydroisoxazoles by condensation of primary nitro compounds with olefins by using a copper/base catalytic system is described. The catalytic effect of copper(II) salts is evidenced by comparison of the reaction rates. Thus, activated nitro compounds react faster than with organic catalysis by tertiary amines, whereas nitroalkanes, unable to condense with dipolarophiles in the presence of the base alone, undergo the reaction on addition of a copper(II) catalyst. The observed occurrence of induction periods in most reactions is ascribed to an equilibrium preceding the rate-determining step, and gives a hint as to the proposed reaction mechanism. The results indicate that this method might be of practical and general utility for synthetic practice.

Highly efficient and mild synthesis of nitrones by catalytic oxidation of hydroxylamines with tetra-n-propylammonium perruthenate

Abstract Oxidation of N,N-disubstituted hydroxylamines by N-methylmorpholine N-oxide (NMO) and catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) at room temperature occurs very rapidly to give the corresponding nitrones, which can be trapped by dipolarophiles present in the reaction mixture, in excellent yields. A competitive experiment in the presence of a primary alcohol gave a > 50:1 nitrone to aldehyde ratio.

Suppression of experimental allergic encephalomyelitis by retinoic acid

Administration of retinoic acid (RA) prevented the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. RA suspended in corn oil was given for 3 days before the expected onset of the disease to rats immunized with myelin and to controls. The drug suppressed the neurological symptoms as well as the perivascular infiltrates observed in vehicle-treated animals. The results indicate that under these experimental conditions, RA has immunosuppressive activity by interfering with the efferent phase of the immune response.

A new synthesis of (2S)-4-oxopipecolic acid by thermal rearrangement of enantiopure spirocyclopropaneisoxazolidine

Abstract A novel synthesis of (2S)-4-oxo-pipecolic acid is reported. The synthetic route employs as a key step the diastereoselective cycloaddition of the N-glycosylnitrone 7 to methylenecyclopropane followed by thermal rearrangement of the spirocyclopropaneisoxazolidine 8a . Stereoselective reduction of the N-BOC methyl ester of 4-oxopipecolic acid by L-selectride ® gives the protected cis-4-hydroxy-pipecolic acid 14 .

Michael Additions versus Cycloaddition Condensations with Ethyl Nitroacetate and Electron‐Deficient Olefins

Ethyl nitroacetate (1) reacts with electron-poor olefins in the presence of a base to give either the Michael adducts 3 or the isoxazoline cycloadducts 4, resulting from water elimination. The proportions of the two products depend on the reaction conditions and change in the course of the process. Kinetic profiles for the two reactions show that the cycloaddition-condensations require long induction times that dramatically decrease upon addition of a copper salt to the catalytic system: the drops in the induction time cause increases in the proportion of cycloadducts 4, which are often the sole reaction products. This is the first report on the selective formation of products 3 and 4 from primary nitro compounds through modulation of the catalytic system.

The regioselectivity of nitrone and nitrile oxide cycloadditions to alkylidenecyclopropanes

Abstract The 1,3-dipolar cycloaddition of nitrile oxides and a nitrone to alkylidencyclopropanes 1–5 ,used as model for methylenecyclopropanes substituted with aryl group ( 1 ), electron-releasing groups ( 2 and 3 ) and electron-attracting groups ( 4 and 5 ) is reported. The cycloaddition to alkylidenecyclopropanes 1–3 gives prevalently or exclusively adducts bearing the cyclopropane ring on the C4 position of the isoxazoline (isoxazol idine) ring, whereas methoxycarbonyl substituted methylenecyclopropanes 4 and 5 give adducts with the opposite regiochemistry. The high regioselectivity observed in the case of dialkyl substituted methylenecyclopropanes raises the question of the role played by the cyclopropylidene ring in these cycloadditions. A FMO approach based both on semiempirical and ab initio calculations is unable to explain this “cyclopropylidene effect”.

Rearrangement of isoxazoline-5-spiro derivatives. Part 7. Thermal rearrangement of 4,5-dihydro and tetrahydroisoxazole-5-spirocyclobutanes to azepin-4-one derivatives☆

Abstract Some representative 4,5-dihydro and tetrahydroisoxazole 5-spirocyclobutanes have been synthesized by 1,3-dipolar cycloaddition of alkylidenecyclobutanes to nitrile oxides and nitrones, respectively. When subjected to flash vacuum thermolysis conditions, the spiranic cycloadducts rearranged to afford mainly the desired azepin-4-one derivatives. In addition, the isoxazoline cycloadducts gave unexpected by-products, which were identified as 1-alkenyl-2-pyrrolidinones. Analogies and differences with respect to the lower homologue cyclopropanes are evidenced in both cycloaddition and rearrangement reactions.

Baker's yeast reduction of prochiral γ-nitroketones. II.1 straightforward enantioselective synthesis of 2,7-dimethyl-1,6-dioxaspiro[4.4]nonanes

Abstract The bakers yeast reduction of 5-nitro-2,8-nonanedione 2 afforded the corresponding (2 S ,8 S )-5-nitro-2,8-nonanediol 3 with complete diastereoselectivity and high enantioselectivity. The conversion of 3 into the thermodynamic (E,E) (Z,Z) (3:1) mixture of optically active (95% e.e.) 2,7-dimethyl-1,6-dioxaspiro[4.4]nonanes 5 was then achieved by spontaneous cyclization under the acidic conditions of the Nef reaction.