Enantioselective 5‐endo‐dig Carbocyclization of β‐Ketoesters with Internal Alkynes Employing a Four‐Component Catalyst System

Abstract

The Conia-ene reaction of acetylenic b-dicarbonyl compounds represents one of the most direct methods for the formation of carbocycles, [1] and is particularly attractive for the preparation of cyclopentane derivatives. Although the classical method of the Conia-ene reaction has some limitations in its application because of the harsh experimental conditions [1,2] such as high temperature, strong base, strong acid, or photochemical activation, recent advances in the use of transition-metal catalysis [3] and organocatalysis [4] have dramatically expanded the diversity of this reaction. In 2005, the first enantioselective intramolecular Conia-ene reaction of b-ketoesters was reported by Toste and coworkers using a palladium(II)/ytterbium(III) catalyst system. [5] This work brought the enantioselective Conia-ene reaction to the attention of a number of organic chemists worldwide, and two more methods have since appeared. [6] However, all the enantioselective methods are limited to the 5-exo-dig cyclization of b-dicarbonyl compounds with terminal alkynes. An endocyclic variant of the Conia-ene reaction, that is, 5-endo-dig cyclization of b-dicarbonyl compounds with internal alkynes, is still a challenge (Scheme 1), although the transition-metal-catalyzed 5-endo-dig addition of heteroatom nucleophiles to internal alkynes are common. [7] In 2004, Toste and co-workers achieved a rare example of the gold(I)-catalyzed 5-endo-dig carbocyclization of 1,3dicarbonyl compounds with internal alkynes to provide cyclopentene adducts in high yields. [8] They surveyed several cationic group 11 metal triflates including copper(I) and silver(I) triflates as catalysts for the cyclization of b-ketoesters with internal alkynyl substituents, but only triphenylphosphine/gold(I) triflate gave the desired cyclization products. The gold(I)-catalyzed 5-endo-dig carbocyclization reported by Toste and co-workers is amenable to a wide range of b-ketoesters having an alkynyl unit, however, the corresponding asymmetric variants are difficult and give racemic products. [5] Meanwhile, we have been engaged for several years in the development of enantioselective a-functionalization of bdicarbonyl compounds as represented by enantioselective fluorination and hydroxylation reactions using nickel(II), zinc(II), or copper(II) complexes with a chiral 4,6-dibenzofurandiyl-2,2'-bis(4-phenyloxazoline) (DBFOX-Ph) or a 2,2'isopropylidinebis(4-phenyl-2-oxazoline) (Box-Ph) ligand. [9,10] As a part of this research program for the metal-catalyzed enantioselective functionalization of 1,3-dicarbonyls, we started to investigate the enantioselective 5-endo-dig cyclization of b-dicarbonyl compounds with internal alkynes. Before the completion of our work, a single example of an enantioselective 5-endo-dig cyclization of a substrate bearing an internal alkyne was reported (65 % yield with 52 % ee) in a paper focusing on an asymmetric exocyclic Conia-ene reaction of b-dicarbonyl compounds using a La/Ag heterobimetallic catalyst. [6b] On the basis of the work by T...

3,5-Bis(pentafluorosulfanyl)phenylboronic acid: A new organocatalyst for Conia-ene carbocyclization of 1,3-dicarbonyl compounds having terminal alkynes

“…These results indicate that the SF 5 function can be used as a lipophilic and sterically demanding alternative to the NO 2 group in catalyst design. Further use of 1 for asymmetric Conia-ene carbocyclization of 1,3-dicarbonyl compounds is under investigation [19].…”

“…Column chromatography was carried out on a column packed with silica-gel 60N spherical neutral size 63-210 mm. The 1 H NMR (300 MHz), 19 F NMR (282 MHz) and 13 C NMR (150.9 MHz) spectra for solution in CDCl 3 were recorded on a Buruker-600, a Varian Gemini-300. Chemical shifts (d) are expressed in ppm downfield from internal TMS, CHCl 3 , CD 3 CN and d 4 -MeOH.…”

Recent developments in enantioselective lanthanide-catalyzed transformations

“…Catalyst 85, generated through self-assembly performed in the presence of MWNT, gave the optimal result in comparison with that was self-assembled before adding MWNT. When 1 mol% of catalyst 85 was used to promote the Henry reaction of aldehydes 77h-l with nitroalkanes 9a-c, it led to the corresponding products 86a-g as major antidiastereomers in moderate to quantitative yields (52-99%), good to excellent anti/syn ratios of 83:17 to >98:2, and uniformly high enantioselectivities of [87][88][89][90][91][92][93][94][95][96][97][98][99]. This reusable confined catalyst exhibited higher catalytic efficiency that the corresponding unconfined catalyst.…”

“…Earlier, Shibata et al investigated the first enantioselective 5-endo-dig cyclization of b-ketoesters 181 with internal alkynes catalyzed by a combination of 20 mol% of Yb(OTf) 3 and 10 mol % of Zn(OAc) 2 in the presence of 11 mol% of chiral bisoxazoline 182 as ligand, and one equivalent of hexafluoroisopropyl alcohol (HFIP) as a stoichiometric additive (Scheme 57) [98]. Indeed, this four-component catalytic system was optimal to deliver the corresponding chiral endo-cyclized products 183 in good to quantitative yields (70-99%) and high enantioselectivities (82-98% ee).…”

“…The Ir-C6 bond in intermediate Scheme 58. Hydrogenation of pyrimidines catalyzed by ytterbium and iridium catalysts [98]. through a sequence composed by an oxidative addition followed by a reductive elimination.…”