Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides

Abstract

The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides at up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).

Isothiourea‐Catalyzed Enantioselective Functionalisation of Glycine Schiff Base Aryl Esters via 1,6‐ and 1,4‐Additions

“…The asymmetric 1,6‐addition of glycine Schiff base alkyl esters to para‐quinone methides (p‐QMs, 7 ) [27,28] has previously been demonstrated utilizing chiral ammonium salt phase transfer catalysts and Cu‐catalysts [29] . Considering the structural diversity of β‐ functionalized α‐AA derivatives that should be accessible by reacting aryl ester Schiff base 1 with p‐QMs 7 , [30] and the potential of the products to undergo further transesterifications or transaminations, the addition of 1 to p‐QM 7 a utilizing established Lewis base catalysts (Figure 1) was investigated [31] …”

Chiral Lewis Base‐Catalysed Asymmetric Syntheses of Benzo‐fused ϵ‐Lactones

“…Interestingly, cyclization towards the trans isomer was found to be faster than towards the cis, however this aspect could not be utilized in a practically useful manner as separation of trans‐ 6 a from a mixture of cis‐ 6 a and intermediate O‐deprotected 5 a was found to be difficult. It should be noted that rather low diastereoselectivities have recently also been observed for ITU‐catalysed additions of esters 3 to classical p‐QMs, [17a] thus representing a more general limitation when this covalent activation principle is used for QM addition reactions. The dr itself remained constant over the progress of the reaction and unfortunately attempts to improve the dr by means of a base‐mediated epimerization of either intermediate 5 a or a post‐cyclization epimerization of product 6 a failed.…”

Enantioselective isothiourea-catalysed reversible Michael addition of aryl esters to 2-benzylidene malononitriles

“… 1 In recent work, the use of electron-deficient aryl esters as C(1)-ammonium enolate precursors in conjunction with isothiourea catalysts has been developed to broaden the electrophiles traditionally compatible with these intermediates ( Scheme 1A ). 2 The ability of the aryl ester to acylate the Lewis basic isothiourea, liberating the corresponding aryloxide, that can subsequently act as a nucleophile to turn over the Lewis base catalyst after a constructive enantioselective reaction is key to this strategy. 3 In these processes the aryloxide is required to fulfil the role of a Brønsted base to generate the C(1)-ammonium enolate as well as a Brønsted acid to protonate the post reaction acyl-ammonium species.…”

“…The amphoteric aryloxide must therefore possess a delicate balance of p K a , nucleophilicity, and nucleofugality for a reaction to be successful. This approach has allowed a range of enantioselective processes to be developed, ranging from [2,3]-sigmatropic rearrangements 2 a – d to Michael additions, 2 e as well as dual catalytic methods that involve transition metal 2 f – m or Brønsted acid co-catalysts. 2 n As a representative example of this approach, in previous work we demonstrated the enantioselective base-free isothiourea-catalysed Michael addition of aryl ester pronucleophiles to vinyl bis-sulfones, generating α-functionalised products containing two contiguous tertiary stereogenic centres in excellent yield and stereoselectivity (all ≥99 : 1 er, Scheme 1A ).…”