Resumen de Stereoselective reactions of N-acyl thiazolidinethiones with trimethyl orthoformate, acetals and diarylmethyl ethers catalyzed by nickel(II) complexes
Juan Manuel Romo Fernández
In this Doctoral Thesis a new stereoselective Ni(II)–mediated catalytic system for the SN1–like addition of chiral Nacyl thiazolidinethiones to electrophiles able to deliver cationic species under acidic conditions has been developed. Importantly, the nickel(II) complexes used along our studies are structurally simple, commercially available and easy to handle. These complexes coordinate to thioimides to generate an intermediate that, after deprotonation, afford a putative nickel(II) enolate, which is the real nucleophile. In Chapter 1, a totally stereoselective addition of Nacyl thiazolidinethiones to trimethyl orthoformate activated by TESOTf has been optimized. The use of this Lewis acid is also crucial for the activation of the catalyst. For Narylacetyl thiazolidinethiones, reactions with 2.5 mol% of (Ph3P)2NiCl2 and a temperature between –20 ºC and 0 ºC was required. Instead, when other Nacyl groups were used, up to 20 mol% of (Ph3P)2NiCl2 was necessary. Alternatively, a 2.5–5 mol% of (Me3P)2NiCl2 can be used, as long as the reaction temperature is –20 ºC to avoid the appearance of byproducts. The resultant adducts are obtained between 71–94% yield and they can be converted easily in enantiomerically pure compounds with a wide array of different functional groups. This method has been applied successfully to the stereoselective synthesis of the side chain of (–)pyridovericin and the C11–C19 fragment of (+)peloruside A, with overall yields of 44% and 4%, respectively. In Chapter 2, the Ni(II)mediated catalytic system was next applied to commercially available cationic salts such as 1,3benzodithiolylium tetrafluoroborate, the Eschemoser’s salt and the tropylium tetrafluoroborate. Although the results were not highly satisfactory, the obtention of the corresponding adducts support a SN1 mechanism. Furthermore, a new stereoselective Ni(II) catalyzed alkylation reaction with diarylcarbenium methyl ethers has been developed. The reaction proceeds smoothly provided that the carbocationic intermediate is stable enough. The Mayr’s scale of electrophilicity accounts for this evidence. In Chapter 3, the catalytic system has been applied to acetals, which involved the challenging construction of two new stereocenters in a single reaction. The reaction provides the corresponding anti adducts with aromatic, a,ßunsaturated and Co–propargylic acetals in low to moderate yields. The stereoselectivity of these additions strongly depends on the structure of the acetal. Particularly, acetals that furnish stable oxonium cations give the best stereocontrol, up to 83:17 diastereomeric ratio. Finally, Chapter 4 refers to our studies on the use of chiral Nglycolyl thiazolidinethiones in the Ni(II) catalyzed reaction to prepare antia,ßdihydroxycarboxyl compounds from aromatic, a,ßunsaturated cobalt–derived propargylic acetals in moderate to high yields. Therefore, this method provides a new method towards enantiomerically pure 1,2,3trioxygenated systems. The diastereomeric ratios observed in these reactions resulted to be from good (75:25) to excellent (94:6). A thorough analysis of the reaction conditions uncovered that acetals difficult to be activated require an excess of Lewis acid or acetal. All together, these results proved that the Lewis acid–mediated addition of chiral Nacyl thiazolidinethiones to a wide range of electrophiles catalyzed by structurally simple, commercially available and easy to handle nickel(II) complexes is a very efficient method for the stereoselective construction of carbon–carbon bonds. Likely, such a transformation proceeds through a SN1–like mechanism in which a putative nickel(II) enolate adds to a cationic intermediate generated in situ from orthoesters, acetals or ethers. The chiral auxiliary can be removed easily to afford an important number of enantiomerically pure compounds. The synthetic potential of this new method has been demonstrated in the preparation of the side chain of pyridovericin and the C11–C19 fragment of peloruside A.
