The asymmetric organocatalytic one‐pot synthesis of polyfunctionalized cyclohexanes is described. Starting from β‐keto esters, nitroalkenes and α,β‐unstaturated aldehydes and employing a bifunctional norephedrine‐based thiourea catalyst, six contiguous stereocenters including one quarternary center are generated. The one‐pot protocol follows a Michael/Michael/aldol addition sequence and affords the highly substituted cyclohexanes in moderate to very good yields (22–70%), diastereomeric ratios of dr>95:5 and excellent enantioselectivities of 91–99% ee.
A s y m m e t r i c O r g a n o c a t a l y t i c S y n t h e s i s o f C h r o m a n s Abstract: Starting from 2-(nitrovinyl)phenols and various cyclic dicarbonyl nucleophiles, a one-pot thiourea-catalyzed diastereoand enantioselective synthesis of polyfunctionalized chroman derivatives via a domino Michael-hemiacetalization and dehydration sequence as well as via a domino Michael-lactonization reaction is reported. Cyclopenta[b]chromenes, tricyclic spirochromans, and tetrahydro-1H-xanthenes bearing a variety of functional groups can be synthesized in this way in good to excellent yields (56-91%) and with very good diastereo-(88-99% de) and enantioselectivities (83-99% ee).In recent years, great progress has been made in the asymmetric organocatalytic synthesis of stereochemically defined complex molecular structures via the concept of multi-component domino reactions. 1 Owing to the importance of the benzopyran framework, its construction has attracted considerable attention, and various synthetic methods have been reported. 2 Chiral benzopyrans represent a privileged structural motif that is found in a range of natural products and drug candidates with broad biological implications ( Figure 1). 3 Thus, it is crucial to develop asymmetric strategies to construct highly enantioenriched scaffolds like dihydrocoumarins and chromenes. For the stereoselective synthesis of these oxygen-containing heterocycles, (nitrovinyl)phenols are important starting materials. During our investigations of new reactive species for developing new organocatalytic cascade reactions, we decided to expand the potential ability of 2-(2-nitrovinyl)phenols 1 to participate in the thiourea amine-catalyzed domino Michaelhemiacetalization reaction 4 with easily enolizable nucleophiles like cyclic b-keto esters 2 as well as cyclic 1,3-diketones 3,4. Quite recently, we have developed a novel bifunctional thiourea catalyst, which promotes the asymmetric Michael addition of acyclic b-keto esters to (nitrovinyl)phenols as well as nitrostryrenes with great efficiency. On the basis of this observation we envisaged that polycyclic chromanols, versatile intermediates to complex chromenes, spirochromans and tetrahydro-1H-xanthenes, could be generated by Michael addition and subsequent intramolecular hemiacetalization if 2-(2-nitrovinyl)phenol served as substrate. The phenolic hydroxy group participates in this process through carbonyl addition and makes this sequence a powerful tool among the existing annulation methodologies. Hemiacetals can be subsequently transformed into many useful chroman core structures. However, different pathways are possible if prochiral nucleophiles bear more than one carbonyl group and thus the chemoselectivity of the reaction becomes an important issue. Cyclization would either afford chromenes or xanthenes 5, 6, and 9 or spiranes 7 and 8 as shown in Scheme 1. Herein, we report our findings regarding these sequential one-pot reactions.The studies of the domino Michael-hemiacetalization reactions were started by screening t...
A highly stereoselective one-pot organocatalytic procedure involving a Michael–Michael–1,2-addition sequence provides an efficient access to fully substituted cyclohexanes bearing five contiguous stereocenters in good yields and excellent stereoselectivities.
A s y m m e t r i c S y n t h e s i s o f 4 H -C h r o m e n e sAbstract: A one-pot thiourea-catalyzed enantioselective synthesis of polyfunctionalized 4H-chromenes via a domino Michael-hemiacetalization reaction and subsequent dehydration is reported. Starting from 2-nitrovinylphenols and b-keto esters, the new protocol affords the 4H-chromenes bearing a variety of functional groups with good to excellent yields (76-95%) and enantioselectivities ranging from 30-99% ee. Both enantiomers are available at will depending on the ephedrine or pseudoephedrine-based thiourea catalyst used.
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