We describe herein a catalytic, enantioselective process for the synthesis of 4H-chromenes which are important structural elements of many natural products and biologically active compounds. A sequence comprising a conjugate addition of β-diketones to in situ generated ortho-quinone methides followed by a cyclodehydration reaction furnished 4-aryl-4H-chromenes in generally excellent yields and high optical purity. A BINOL-based chiral phosphoric acid was employed as a Brønsted acid catalyst which converted ortho-hydroxy benzhydryl alcohols into hydrogen-bonded ortho-quinone methides and effected the carbon-carbon bond-forming event with high enantioselectivity.

A full account of the Brønsted acid catalyzed, enantioselective synthesis of 4H-chromenes and 1H-xanthen-1ones from o-hydroxybenzyl alcohols and β-dicarbonyl compounds is provided. The central step of our strategy is the BINOL− phosphoric acid catalyzed, enantioselective cycloaddition of βdiketones, β-keto nitriles, and β-keto esters to in situ generated, hydrogen-bonded o-quinone methides. Upon acid-promoted dehydration, the desired products were obtained with generally excellent yields and enantioselectivity. Detailed mechanistic studies including online-NMR and ESI-MS measurements were conducted to identify relevant synthetic intermediates. A reversible formation of a dimer from the starting alcohol and the reactive o-quinone methide in an off-cycle equilibrium was observed, providing a reservoir from which the o-quinone methide can be regenerated and introduced into the catalytic cycle again. Reaction progress kinetic analysis was utilized to determine kinetic profiles and rate constants of the reaction uncovering o-quinone methide formation as the rate-limiting step. In combination with Hammett plots, these studies document the relationship between o-quinone methide stabilization by electronic effects provided by the substituents and the reaction rate of the described process. In addition, DFT calculations reveal a concerted yet highly asynchronous [4 + 2]-cycloaddition pathway and an attractive CH−π interaction between the catalyst's tBu group and the o-quinone methide as an important stereochemical control element.

A highly stereocontrolled and flexible access to biologically relevant polydeoxypropionates in optically pure form has been developed. Taking advantage of our previously established strategy for the asymmetric and stereodivergent synthesis of trideoxypropionate building blocks, we have now been able to assemble large polydeoxypropionate chains with defined configuration in a highly convergent manner. Central steps of this approach include two Suzuki-Miyaura cross-coupling reactions with subsequent highly diastereoselective hydrogenations to join three advanced synthetic intermediates in excellent yield and with full stereochemical control. We have applied this strategy successfully towards the asymmetric synthesis of glycolipid membrane components phthioceranic acid and hydroxyphthioceranic acid, the latter of which was synthesized on a half-gram scale.

4H-Chromene sind wichtige Strukturelemente vieler Naturstoffe und biologisch aktiver Verbindungen. Mithilfe einer enantioselektiven konjugierten Addition von b-Diketonen an in situ erzeugte ortho-Chinomethide gelingt nach dehydratisierender Cyclisierung eine breit anwendbare und hochselektive Synthese wertvoller 4-Aryl-4H-chromene. Eine Binol-basierte chirale Phosphorsäure wird zur In-situ-Erzeugung der ortho-Chinomethide aus ortho-Hydroxybenzhydrylalkoholen eingesetzt und katalysiert den C-C-bindungsbildenden Schritt. Ortho-ChinomethidesindhochreaktiveIntermediateinderorganischen Chemie, die in jüngerer Vergangenheit zunehmend genutzt werden, vor allem in der Synthese von Chromansystemen. Sie lassen sich auf vielfältige Weise aus einfachen Vorläufern in situ erzeugen und reagieren als polarisierte elektronenarme 1-Oxabutadiene bevorzugt mit elektronenreichen [2 p]-Komponenten in Hetero-Diels-AlderReaktionen mit inversem Elektronenbedarf oder mit Nucleophilen in konjugierten 1,4-Additionen jeweils unter Rückbildung des aromatischen p-Systems.

Broensted Acid Catalyzed, Conjugate Addition of -Dicarbonyls to in situ Generated ortho-Quinone Methides-Enantioselective Synthesis of 4-Aryl-4H-chromenes. -Optimized conditions which need only little excess of dicarbonyl reactant render possible the access to various title compounds with good to excellent yields and high enantioselectivity. In the case of (VI) and (XII), spontaneous cyclization takes place without the addition of TosOH. -(EL-SEPELGY, O.; HASELOFF, S.; ALAMSETTI, S. K.; SCHNEIDER*, C.; Angew. Chem., Int. Ed. 53 (2014) 30, 7923-7927, http://dx.