A Highly Diastereo‐ and Enantioselective Reaction for Constructing Functionalized Cyclohexanes: Six Contiguous Stereocenters in One Step

Abstract

Organic motifs with contiguous multiple stereocenters exist in numerous natural and unnatural products that exhibit important biological activity.[1] The number of possible stereoisomers increases exponentially with the number of stereocenters, thus the highly stereoselective synthesis of chiral compounds with multiple stereocenters from simple starting materials is a challenge. Nature has developed many efficient ways to construct such structures from simple starting materials, as demonstrated by the production of chiral carbohydrates, proteins, and alkaloids. Inspired by nature, the asymmetric domino process, which generates more than one chemical bond concomitantly with the creation of multiple stereocenters in a one-pot fashion, has emerged as a promising way to achieve these aims.[2] Despite the fact that a number of structurally diverse compounds with contiguous multiple stereocenters have been synthesized using this strategy, to the best of our knowledge, a domino process which generates six or more stereocenters by one intermolecular reaction of two simple compounds in an asymmetric fashion has not been reported. [3,4] The identification of a reactive species that triggers a domino process is a prerequisite for the successful establishment of an efficient tandem reaction. As active species, enolates are considered to be the most powerful and reliable cornerstones for establishing many classical transformations.[5] a-Ketoesters could be recognized as latent enolates since the keto-to-enol tautomerization could easily take place in these compounds in the presence of suitable Lewis acids. [6] With this in mind, we envisaged that the reactive enolate species derived from an a-ketoester would be useful to trigger a formal [2+2+2] cycloaddition through an asymmetric Michael [7] /Michael/Henry [8] tandem sequence with nitroalkenes as electrophiles (Scheme 1). Mechanistically, a chiral Lewis acid catalyst would activate the a-ketoester to give rise to the intermediate enolate A which would then add to nitroalkene 2 by a conjugate addition to yield intermediate B.The intermediate B would further react with nitroalkene 2 to generate the intermediate C under appropriate reaction conditions. Ring closure through the Henry reaction would lead to the desired six-membered annulation product 3 with six stereogenic centers (Scheme 1). The challenge of designing such an efficient catalytic asymmetric strategy mainly depends on the necessity of stereoselectively generating the stable reactive species B and highly reactive intermediate C in situ. To address this challenge, we need to identify a chiral transition metal catalyst to generate the metal enolate A with stereodefined geometry, thus guaranteeing that the first conjugate Michael addition proceeds with high diastereoand enantioselectivity. A chiral Lewis acid catalyst with the appropriate steric and electronic properties is crucial for the successful implementation the above strategy. Given that a conformationally rigid structure would have good chiral induction ab...

Catalytic Enantioselective [3 + 2] Cycloaddition of α-Keto Ester Enolates and Nitrile Oxides

“…Along with others, we have noted that reactions involving transition-metal enolates display enhanced rates in alcoholic solvent. 6h,21 In fact, the use of i PrOH gave a >20:1 preference for the desired product 3a (Table 1, entry 11: 77% yield, 70% ee, 11:1 dr). The protic solvent may promote fragmentation of less-active catalyst oligomers, 22 or catalyst turnover from the Cu(II)-alkoxide intermediate proceeding [3 + 2]-cycloaddition via protonolysis.…”

Stereoselective Multiple Bond‐Forming Transformations (MBFTs): The Power of 1,2‐ and 1,3‐Dicarbonyl Compounds

“…In the same vein, two years later, Huang and co‐workers demonstrated that 1,2‐ketoesters could efficiently participate in an closely related domino pseudo‐three‐component enantioselective Michael/Michael/Henry sequence with nitroalkenes as electrophiles catalyzed by a new copper(II) complex incorporating a rigid chiral diamine (Scheme ) 54. The acetate counter anion was found to be crucial for good reactivity and high stereoselectivities.…”

Domino Reaction of Naphthoquinone and β‐Arylpyruvic Acids: Synthesis of 3‐(Naphthoquinonyl)naphthofuran‐2(3H)‐ones

“…For instance, organocatalyzed aldol reactions of enamines derived from α‐keto acids with aldehydes, followed by esterification of the carboxylic group with the resulting carbinol gave access to highly substituted furan‐2( 5H )‐ones (Scheme ) . Domino sequences involving conjugate addition of α‐keto esters with nitroalkenes have been also described to synthesize highly substituted cyclohexane units stereoselectively (Scheme ) . Moreover, α‐keto carboxylic acid derivatives can undergo decarboxylative reactions, generating a valuable acyl anion intermediate, through the extrusion of CO 2 .…”