Enantioselective Synthesis of Polycyclic Carbocycles via an Alkynylation–Allylation–Cyclization Strategy

Abstract

ABSTRACT:A new general three-stage strategy to access polycyclic ring systems bearing all-carbon quaternary centers with high enantioselectivity is reported. The required starting materials were readily accessed in racemic form through the -alkynylation of ketoesters with EBX (Ethynyl BenziodoXolone) hypervalent iodine reagents. A Pd-catalyzed asymmetric decarboxylation allylation was then achieved in high yields and enantioselectivities with Trost's biphosphine ligands. Finally, transition-metal catalyzed cyclization of the obtained chiral enynes gave access to fused and spiro polycyclic ring systems constituting the core of many bioactive natural products.The fascinating structure of natural products is the result of millions of years of evolution in interaction with biological targets. Particularly striking is the high occurrence of complex polycyclic ring systems with numerous stereocenters. An interesting substructure present in natural products is constituted by a benzene ring fused to at least two further saturated carbocycles. Both fused and spiro ring systems can be found in important bioactive compounds such as steroids like estradiol or alkaloids like buprenorphine.1 The presence of all-carbon quaternary centers embedded in the polycyclic core of many of these molecules represents a formidable challenge for synthetic chemistry.2 In this context, we envisioned that ketone 1 bearing a 1,5 enyne substructure around an all-carbon quaternary center would be an ideal precursor for both fused and spiro ring systems (Scheme 1). Addition of an allyl Grignard reagent, followed by olefin ring-closing metathesis (RCM) would give an easy access to fused ring systems. The 1,5-enyne itself can be used to access spiro or rearranged ringsystems based on transition-metal catalysis.3 Whereas RCM is now a mature method, cyclisomerization reactions to access spiro ring systems have been much less investigated. Indeed, there are only two examples of such transformations so far, both occurring on unsubstituted alkane rings. 3h,3k Nevertheless, the main challenge with the proposed strategy resided in the enantioselective synthesis of enyne 1. Most synthetic methods known to access 1,5 enynes take advantage of the reactivity of a propargylic cation generated through either catalytic or stoichiometric Lewis acid activation, allowing access only to racemic material. 4 Morken and co-workers showed recently that a Pd-catalyzed enantiospecific crosscoupling reaction gave 1,5-enynes with high enantiomeric excess starting from enantioenriched activated propargylic alcohols and allyl boronic esters. 5a In this report only one example leading to all-carbon quaternary centers in a non-cyclic product was presented. In 2013, the same group reported a kinetic resolution of racemic propargylic esters using chiral ligands. Clearly, none of the reported methods to access 1,5-enynes appeared promising in the context of our synthetic goal, and we decided to developed a new strategy based on the enantioselective decarboxylative allylation...

Cyclic Hypervalent Iodine Reagents for Atom‐Transfer Reactions: Beyond Trifluoromethylation

“…[73] Alpha alkynyl β-allyl keto esters were obtained in high yields using DBU or TMG as stoichiometric bases with TIPS-EBX (5) or TBDPS-EBX. The silyl protected -alkynyl -allyl ketoesters were then subjected to palladium catalysis using the Trost ligand naphthyl-DACH to yield -alkynyl -allyl ketones with up to 97% enantioselectivity.…”

“…[19a] In 2014, Waser and co-workers developed an indirect approach to access a-alkynyl indanones and tetralones with high enantiopurities through an alkynylation/palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) sequence (Scheme 34). [73] a-Alkynyl b-allyl keto esters were obtained in high yields on using diazabicyclo [5.4.0]undec-7ene (DBU) or tetramethylguanidine (TMG) as stoichiometric bases with TIPS-EBX (5)o rT BDPS-EBX. Thes ilyl-protected a-alkynyl b-allyl ketoesters were then subjected to palladium catalysis using the Tr ost ligand naphthyl-DACHto yield a-alkynyl a-allyl ketones with up to 97 %ee.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…formation of 1232 from enyne 1229) culminating in an alkyl migration event (e.g. the conversion of 1230 to 1231) was also reported [1180]. Epiglobulol and aromadendranediols were prepared using a gold-catalyzed cyclization of diene-yne derivatives (e.g.…”

Palladium‐Catalyzed Decarboxylative Asymmetric Allylic Alkylation: Development, Mechanistic Understanding and Recent Advances

“…Waser reported the first successful application of DAAA for indanone and tetralone substrates with α‐alkynyl substituents in 2014 (Scheme A) . Hypervalent iodine reagents were employed to access the α‐alkynyl keto esters 48 under benign conditions.…”