Asymmetric Synthesis of Functionalized Chromans via a One-Pot Organocatalytic Domino Michael-Hemiacetalization or -Lactonization and Dehydration Sequence

Abstract

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...

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[181] Polyfunctionalized chromand erivatives 469, 471,a nd 473 were obtained with good yields and stereoselectivities via ad omino Michael/hemiacetal formation/ dehydration reactionsequence.…”

“…[182] Similar to Endersa pproachp resented in Scheme 121, [181] ortho-hydroxychalcones 477 were used as the Michaela cceptors (Scheme122). Nonetheless, instead of 1,3-dicarbonyl compounds, azlactones 475 were useda st he nucleophiles.U sing the same thioureac atalyst 438,t he desired products 476 were obtained in good yieldsa nd high stereoselectivities via ad omino Michael/transesterification reaction.…”

Chiral Primary Amine Catalyzed Asymmetric α‐Benzylation with In Situ Generated ortho‐Quinone Methides

“…As illustrated below (Scheme ), exposure the mixtures of 4 a and 4 f to a catalytic amount of p‐ toluenesulfonic acid at elevated temperature yielded the medicinally important dihydrocoumarins 10 and 11 in high yields without erosion of enantioselectivity. In addition, the ring‐fused chromanes 12 and 13 with a quaternary stereocenter could be obtained with high enantioselectivity via dehydration or reduction of the semi‐ketal moiety, respectively . These types of heterocyclic cores have been found in many natural products with promising biological profiles…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…By deployment of cyclic β‐keto esters in these reactions the corresponding tricyclic nitro‐chromans are obtained with high degrees of diastereo‐ and enantioselectivities 269…”

“…[268] By deployment of cyclic b-keto esters in these reactions the corresponding tricyclic nitro-chromans are obtained with high degrees of diastereo-and enantioselectivities. [269] When used with a-nitro ketones and b,g-unsaturated keto esters as substrates in a Michael/hemiketalization/retro-Henry cascade an access to d-amino-a-keto acids is given. This sequence is catalyzed by chiral thiourea ent-66 (Scheme 139).…”