Organocatalytic Asymmetric Direct α-Alkynylation of Cyclic β-Ketoesters

The first organocatalytic enantioselective direct α-alkynylation of β-ketoesters and 3-acyl oxindoles
is described. It is demonstrated that activated β-halo-alkynes undergo nucleophilic acetylenic substitution
catalyzed by chiral phase-transfer compounds to afford the alkynylated products in high yields and excellent
enantioselectivities. The potential of the reaction is first demonstrated for various alkynylating reagents
having chloride and bromide as the leaving groups and substituents such as allyl and alkyl esters, amides,
ketones, and sulfones. These reactions proceed with 74−99% yield and 88−97% ee. Then the scope in
nucleophile is demonstrated for a large number of cyclic β-ketoesters with various ring-sizes and for oxindoles
as well. The corresponding optically active products are formed in high yields and with enantioselectivities
up to 98% ee. The procedure allows for the stereocontrolled attachment of an ethynyl unit in the α-position
to the carbonyl compound by facile removal of the activating group, and this has been demonstrated for a
number of the optically active allyl esters. Furthermore, the synthesis of optically active 1,4-enynes is also
shown. The isolation and characterization by X-ray analysis of the catalyst with p-nitrophenolate as the
counterion allowed us to propose a model of the catalyst−substrate intermediate which might account for
the observed enantioselectivity of the organocatalytic enantioselective α-alkynylation reaction. Furthermore,
it is suggested that this intermediate is also the reactive species for a number of other electrophiles adding
to β-ketoesters giving enantioselectivities in the range of 90−98% ee.

本文首次报道了β-酮酸酯(β-ketoesters)与3-酰基氧化吲哚(3-acyl oxindoles)的有机催化对映选择性直接α-炔基化反应。研究证实，活化的β-卤代炔烃(activated β-halo-alkynes)在手性相转移化合物(chiral phase-transfer compounds)催化下发生亲核炔基取代反应(nucleophilic acetylenic substitution)，可高产率、高对映选择性地得到炔基化产物。本文首先针对以氯、溴为离去基团(leaving groups)，且带有烯丙基酯、烷基酯、酰胺、酮及砜等取代基的各类炔基化试剂(alkynylating reagents)，验证了该反应的应用潜力。此类反应的收率可达74%~99%，对映体过量值(Enantiomeric Excess, ee)为88%~97%。随后，本文考察了该反应的亲核试剂适用范围，涵盖多种环尺寸的环状β-酮酸酯(cyclic β-ketoesters)以及氧化吲哚(oxindoles)类底物。相应的手性产物(optically active products)均可获得较高收率，对映选择性最高可达98% ee。该方法可通过简便脱除活化基团(activating group)，实现炔基单元(ethynyl unit)在羰基化合物α位的立体可控引入，这一点通过多例手性烯丙基酯(allyl esters)产物得到了验证。此外，本文还展示了手性1,4-烯炔(1,4-enynes)的合成路径。本文通过X射线衍射分析(X-ray analysis)分离并表征了以对硝基苯酚盐为抗衡离子(counterion)的催化剂，据此提出了催化剂-底物中间体(catalyst−substrate intermediate)模型，该模型可合理解释该有机催化对映选择性α-炔基化反应所观测到的对映选择性结果。进一步研究表明，该中间体同样是多种其他亲电试剂(electrophiles)与β-酮酸酯发生加成反应的活性物种，此类反应的对映选择性可达90%~98% ee。