Isothiourea-catalyzed formal enantioselective conjugate addition of benzophenone imines to b -fluorinated a , b -unsaturated esters

The isothiourea-catalyzed formal enantioselective conjugate addition of 2-hydroxybenzophenone imine derivatives to a , b -unsaturated para nitrophenyl esters has been developed. Investigations of the scope and limitations of this procedure showed that b -electron withdrawing substituents within the a , b -unsaturated ester component are required for good product yield, giving rise to a range of b -imino ester and amide derivatives in moderate to good isolated yields with excellent enantioselectivity (20 examples, up to 81% yield and 97:3 er).

The development of methods for the enantioselective synthesis of b-amino acid derivatives 1a is of widespread importance due to the prevalence of this structural motif in natural products and medicinally relevant compounds. 1 Among the synthetic methods that have been developed for the preparation of b-amino acid derivatives, arguably the most simple and elegant involves the asymmetric conjugate addition of an ammonia equivalent to an a,b-unsaturated carbonyl motif. As an example of this approach, the conjugate addition of enantiomerically pure lithium amide derivatives to a,b-unsaturated esters has been developed and exploited extensively by Davies and coworkers. Conjugate addition of lithium N-benzyl-N-amethylbenzylamide to an a,b-unsaturated ester gives the corresponding b-amino ester with high diastereoselectivity (495 : 5 dr), with N-deprotection through hydrogenolysis giving the corresponding b-amino ester derivatives (Scheme 1a). 2 Over the last two decades, several enantioselective organocatalytic approaches to amine conjugate addition have been introduced. To date, these successful approaches rely upon enals, 3 enones, 4 N-acyl pyrazoles, 5 and nitro-olefins 6 as Michael acceptors, with the use of bifunctional thiourea 4a,5b,7,8a-c,e or squaramide 4,5c,8a,b,e organocatalysts, or Lewis basic pyrrolidines 3,8 commonplace. Catalytic enantioselective amine conjugate additions to a,b-unsaturated esters are rare, reflecting the recognized recalcitrance of a,b-unsaturated esters as Michael acceptors (Scheme 1b). To date, the current state-of-the-art organocatalytic approach is represented by Seidel and co-workers' 9 demonstration of the conjugate addition of cyclic secondary amines to balkyl-a,b-unsaturated benzyl esters using a selenourea-thiourea catalyst 1 (Scheme 1c). Although limited to b-alkyl substituted Michael acceptors, this impressive methodology was applicable to a range of cyclic amines and the kinetic resolution of (AE)-cyclic 2-arylamines.
Our approach to enantioselective amine conjugate addition focused upon the use of imines as nucleophiles. The conjugate addition of (diphenylmethylene)amine to a,b-unsaturated esters, nitriles and ketones in racemic form has been demonstrated by de Meijere et al. MeOH was optimal as a solvent and a basic additive (such as NEt 3 ) led to effective product formation (Scheme 2a). 10 In 2018, Alemán and co-workers successfully demonstrated an enantioselective aza-Michael addition of nucleophilic imines to enals using secondary amine catalyst 2 (Scheme 2b). 11 Trapping of the resultant b-imino aldehydes with a phosphorane gave the corresponding d-imino esters in good yield and enantioselectivity. Notably, 2-hydroxybenzophenone imines showed increased reactivity and enantioselectivity compared with the parent benzophenone imine, attributed to an increase in acidity of the imine proton caused by intramolecular hydrogen bonding. 12, 13 In previous work, we and others have demonstrated a range of enantioselective Michael-addition processes of in situ generated a,b-unsaturated acyl ammonium species. 14,15 Building on these precedents, we report herein the formal isothiourea-catalyzed enantioselective addition of 2-hydroxybenzophenone imines to b-fluorinated a,b-unsaturated paranitrophenyl esters via an a,b-unsaturated acyl ammonium intermediate, giving products in up to 98 : 2 er (Scheme 2c).
The scope and limitations of the developed process was explored through variation of the nucleophilic imine reaction component (Fig. 1). Variation of the electronic bias of the 4-aryl substituent within the imine component showed that decreased product yield was observed upon changing from an electrondonating 4-MeO-(5, 70% yield) to 4-Me (9, 49% yield), 4-H (11, 36% yield) and electron-withdrawing 4-Br substituent (10, 24% yield) all with 496 : 4 er. This is consistent with increasing Scheme 2 Previous imine conjugate additions and this work. electron density within the imine component leading to increased product yield. Interestingly, comparing the yield and er of products 11 and 12 indicates that the 2-hydroxy-substituent within the imine is essential for high product er, but does not affect product yield. The incorporation of an additional electrondonating 4-MeO substituent led to product 13 in reduced yield but maintained high product er. Variation of the b-substituent within the a,b-unsaturated ester indicated that the incorporation of polyhalogenated or ester electron-withdrawing groups was necessary for reactivity as alkyl, aryl, ketone and amide substituted acceptors gave no significant product formation. For example, the introduction of halogenated (CF 2 H) and polyhalogenated substituents (CF 2 Cl, CF 2 Br, and C 2 F 5 ) led to products 14-17 in up to excellent yields with high enantioselectivity (40% to 81%; 496 : 4 er), while the incorporation of ester substituents gave 18-19 in poor 20% product yield in up to 96 : 4 er. Variation of the post catalysis nucleophilic component (Nuc-H) to incorporate alcohols as well as cyclic secondary and acyclic primary amines gave a range of ester and amide products 20-24 in good yield (42% to 64%) and excellent enantioselectivity (Z96 : 4 er).
To further demonstrate the synthetic utility of this transformation, it was applied to the gram-scale synthesis of product 5 with consistent yield and enantioselectivity (67%, 96 : 4 er, Scheme 3). Hydrolysis gave the free b-amino amide product 26 in high yield and enantioselectivity (95%, 96 : 4 er). 16 A proposed mechanism of this transformation is shown in Scheme 4. Reversible acylation of the isothiourea with the a,b-unsaturated ester 1a generates the key a,b-unsaturated acyl isothiouronium ion pair 26. An intramolecular chalcogen 1,5-SÁ Á ÁO interaction (n Os* S-C ) 17 provides a plausible stabilising effect and conformational lock. Hydrogen bonding between the 2-hydroxy-substituent and the imine N serves to conformationally restrict this functionality and facilitate deprotonation. [11][12][13] Subsequent conjugate addition to the s-cis conformation of the a,b-unsaturated acyl isothiouronium 26 anti-to the stereodirecting phenyl substituent of the isothiourea catalyst generates the ammonium enolate intermediate 27. Proton transfer generates the b-imino acyl isothiouronium intermediate 28, with catalyst turnover facilitated by the aryloxide counterion to form the product and release the isothiourea catalyst BTM 7. 18 In summary, enantioselective organocatalytic conjugate addition of 2-hydroxybenzophenone imines to a,b-unsaturated esters using the isothiourea BTM as an organocatalyst gives enantioenriched b-imino amides in modest to good yield (20-81%) and excellent enantioselectivity (typically 495 : 5 er). 19 The DOST-SEI and DOST-Foreign Graduate Scholarship Program of the Philippines are thanked for a PhD scholarship (J. E. L) and the Royal Society for a Newton Fellowship (C. S.).

Conflicts of interest
There are no conflicts of interests to declare.