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

Catalytic enantioselective transformations usually rely upon optimal enantioselectivity being observed in kinetically controlled reaction processes, with energy differences between diastereoisomeric transition state energies translating to stereoisomeric product ratios. Herein, stereoselectivity resulting from an unusual reversible Michael addition of an aryl ester to 2-benzylidene malononitrile electrophiles using an isothiourea as a Lewis base catalyst is demonstrated. Notably, the basicity of the aryloxide component and reactivity of the isothiourea Lewis base both affect the observed product selectivity, with control studies and crossover experiments indicating the feasibility of a constructive reversible Michael addition from the desired product. When this reversible addition is coupled with a crystallisation-induced diastereomer transformation (CIDT) it allows isolation of products in high yield and stereocontrol (14 examples, up to 95 : 5 dr and 99 : 1 er). Application of this process to gram scale, plus derivatisations to provide further useful products, is demonstrated.


Introduction
Over the last decade, methods for the generation and controlled reactivity of C(1)-ammonium enolates have signicantly expanded, with the use of isothioureas alongside cinchona alkaloids pivotal in these advances. 1 In recent work, the use of electron-decient 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 aer a constructive enantioselective reaction is key to this strategy. 3 In these processes the aryloxide is required to full 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 pK 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 2a-d to Michael additions, 2e as well as dual catalytic methods that involve transition metal 2f-m or Brønsted acid co-catalysts. 2n 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 afunctionalised products containing two contiguous tertiary stereogenic centres in excellent yield and stereoselectivity (all $99 : 1 er, Scheme 1A). 2e The stereoselectivity observed in these processes using C(1)-ammonium enolates is usually considered to rely upon irreversible nucleophilic addition under kinetic control of the reaction, with energy differences between diastereoisomeric transition states translating to stereoisomeric product ratios. In certain circumstances, post reaction equilibration at an acidic position within the product can result in epimerisation, as for example has been observed at the C(3)position of b-lactones (Scheme 1B). 4 To the best of our knowledge, stereoselectivity that occurs in a reaction process that involves reversible addition of a C(1)-ammonium enolate to an electrophile generated using isothioureas has not been demonstrated to date. In this manuscript, the expansion of the scope of the base-free enantioselective Michael addition of aryl ester pronucleophiles to include 2-benzylidene malononitrile electrophiles is reported (Scheme 1C). Signicantly, judicious choice of aryl ester, solvent, and isothiourea proved crucial for optimal yield and stereoselectivity. Mechanistic investigation demonstrated the ability of both the aryloxide and the isothiourea catalyst to promote retro-Michael addition, a process previously unknown for isothiourea-catalysed Michael additions. In some cases, the reversibility of the Michael addition was harnessed alongside a crystallisation-induced diastereomer transformation (CIDT), giving products with enhanced diastereoselectivity (up to 95 : 5 dr) and with excellent enantioselectivity (up to 99 : 1 er).
Isolated enantioenriched TeFP products anti-14 (>95 : 5 dr, 98 : 2 er) and syn-15 (>95 : 5 dr, 94 : 6 er) were treated analogously with (R)-BTM and NBu 4 OTeFP (Scheme 3A). Treatment with (R)-BTM resulted in increased retro-Michael addition compared to PNP products anti-4 and syn-5 (46% and 56% vs. 23% and 49%). Moreover, treatment of syn-15 with 2,3,5,6-tet-rauorophenoxide showed four times less epimerisation than syn-5 with p-nitrophenoxide (1% vs. 4%), consistent with our hypothesis that the basicity of aryloxide was important for both yield and stereoselectivity. To further probe the selectivity observed in the TeFP ester series, the evolution of product diastereoselectivity with time under these reaction conditions was monitored by 1 H NMR spectroscopic analysis in CD 2 Cl 2 (Scheme 3B). At low conversions and short reaction times the dr of anti-14 : syn-15 was moderate (55 : 45 dr) but increased with time (anti-14 : syn-15 65 : 35 dr aer 24 hours), consistent with the retro-Michael control studies. Interestingly, attempted separation of the diastereoisomeric products by chromatographic purication on silica oen led to signicant variation in isolated product er (ranging from 92 : 8 to 99 : 1 er). Extensive studies indicated this to be due to the phenomenon of selfdisproportionation of enantiomers (SDE) 12 with the er of a given sample not representative of the entire reaction mixture. To ensure that spurious product enantiomeric ratios were not reported during further optimisation of reaction conditions, the products were therefore purposefully isolated as a mixture of diastereoisomers.

Reaction optimisation
The reaction conditions were further optimised using TeFP ester 9 (Table 2). Increasing the reaction concentration to 1.0 M led to improved yield (72%) with similar levels of diastereo-and enantiocontrol (entry 1). Doubling the catalyst loading to 10 mol% improved diastereoselectivity (85 : 15 dr) but reduced enantioselectivity, particularly of syn-15 (83 : 17 er syn , entry 2). Attempting to improve conversion, the reaction was carried out at 40°C (entry 3) but this led to decreased yield and stereoselectivity. Variation of the reaction solvent indicated that in both EtOAc and dimethyl carbonate (DMC) the product anti-14 : syn-15 precipitated from the reaction mixture with an accompanied increase in yield (78% and 76%, entries 4 and 5). Precipitation was also observed in Et 2 O, giving anti-14 : syn-15 with improved yield and stereoselectivity (entry 6). Increasing the reaction time in Et 2 O to 48 h gave anti-14 in quantitative yield (entry 7). Simple ltration of the reaction mixture afforded anti-14 as a single diastereoisomer (>95 : 5 dr), indicating the feasibility of a CIDT. 13 While a range of highly selective CIDT processes have been developed, these processes are generally underutilised as a strategy for enantioselective synthesis. 13a When demonstrated, CIDT processes oen provide routes to a single product diastereoisomer by crystallisation from an equilibrating mixture of isomers. For example, Johnson and coworkers recently harnessed a doubly stereodivergent CIDT process that involved a chiral bifunctional iminophosphorane catalysed enantioselective conjugate addition process between a nitroalkane and a Michael acceptor. This procedure gave gnitro-b-ketoamides containing three contiguous stereogenic centres in excellent yield and stereoselectivity (typically >95 : 5 dr, >95 : 5 er) due to catalyst-controlled epimerisation and subsequent CIDT. 14 In the case described herein, the diastereoisomeric products interconvert through reversible Michaeladdition, and to the best of our knowledge is the rst CIDT process of its kind, with precipitation of the product benecial as it can no longer participate in the retro-Michael addition. Building upon these results, various isothiourea catalysts were next screened to improve product enantioselectivity in this protocol. When (S)-TM 16 was used the reaction rate signicantly decreased, giving only 45% yield aer 168 h (entry 8). The use of (2S,3R)-HyperBTM 17 allowed the reaction time to be reduced to 24 h whilst maintaining the excellent yield and diastereoselectivity, but with reduced 79 : 21 er (entry 9

Scope and limitations of the reversible Michael addition
With the optimised reaction conditions established the scope and limitations of the Michael addition process was investigated using (4bR,11aS)-fused-BTM 19 (Scheme 4). The relative and absolute conguration of (2R,3S)-14 was conrmed by single crystal X-ray crystallography, with the conguration within all other products assigned by analogy. 17 A variety of TeFP esters were synthesised from the corresponding a-aryl, a- without a CIDT process in operation. Ortho-substitution was also tolerated, giving product 23 but with reduced yield and enantioselectivity (41%, 91 : 9 er, 76 : 24 dr). Extension to incorporate 3-thiophenyl and prop-1-enyl substituents gave the corresponding products 24 and 25 in good yields (76% and 52%) with excellent enantioselectivity (97 : 3 and 99 : 1 er). Consistent with our previous studies, 2e,n,2p a notable limitation of this process showed that an a-alkyl substituent was not tolerated, with Me-substituted TeFP ester 33 proving unreactive and returning only starting material. The scope and limitations with respect to the vinyl dinitrile Michael acceptors was next investigated, with a small selection synthesised by Knoevenagel condensation of malononitrile with the requisite aldehyde. Electron-withdrawing 4-F 3 CC 6 H 4 and 4-O 2 NC 6 H 4 substituents gave products 26 and 27 respectively in high yields (69% and 81%) with excellent enantioselectivity (98 : 2 and 99 : 1 er). Halogen containing 4-FC 6 H 4 and 4-ClC 6 H 4 substituents were also well tolerated giving products 28 and 29 in good yields (65% and 63%), again with excellent enantioselectivity (both 99 : 1 er). CIDT of product 28 allowed its isolation in good yield by direct ltration (57%, >95 : 5 dr, 99 : 1 er), while alternatively concentration of the reaction mixture followed by purication still gave 28 produced with excellent diastereoselectivity (92 : 8 dr). 3-F 3 CC 6 H 4 substitution gave product 30 in very high yield (86%) with excellent enantioselectivity (97 : 3 er). 2-F 3 CC 6 H 4 substitution gave product 31 in reduced 58% yield, presumably due to increased steric hindrance biasing the equilibrium, with the excellent enantioselectivity (99 : 1 er) maintained. Incorporation of an electron-donating 4-MeOC 6 H 4 substituent led to reduced conversion to product reecting the assumed reduced electrophilicity of the Michael acceptor containing this conjugating donor substituent, giving product 32 with excellent enantioselectivity (99 : 1 er) but in low 33% yield. Consistent with this observation, incorporation of the stronger electrondonating 4-Me 2 NC 6 H 4 substituent within 34 was not tolerated, returning only starting material. Attempted replacement of the b-aryl substituent within either cinnamyl 35 or ethyl 36 substituted vinyl dinitrile Michael acceptors again returned only starting material and so represent limitations of this methodology.

Scale-up and derivatisation
The isothiourea-catalysed Michael addition was successfully implemented on gram-scale to give 1.10 g (81%) of anti-14 (Scheme 5). Recrystallisation of the crude reaction mixture allowed a chromatography-free preparation of anti-14 as a single stereoisomer (>95 : 5 dr, >99 : 1 er). Anti-14 was then derivatised to allyl amide 37 and methyl ester 38 in good yields (61% and 67%) and as single stereoisomers (>95 : 5 dr, >99 : 1 er) despite competing retro-Michael addition being observed in both cases. Interestingly, control studies indicated that the derivatised ester and amide products 37 and 38 were stable to retro-Michael addition.

Reversible Michael addition control reaction and proposed mechanism
Further conclusive evidence of the reversible nature of the Michael addition process was sought. Unambiguous demonstration of the feasibility of this process was observed through treatment of racemic Michael addition product anti-14 (>95 : 5 dr) under the standard reaction conditions using the isothiourea (4bR,11aS)-fused-BTM 19 (5 mol%) in CPME at RT in the presence of 4-MeOC 6 H 4 -substituted TeFP ester 40 (Scheme 6A). Aer 24 hours, 13% of Michael addition product 20 (>95 : 5 dr, 99 : 1 er) was isolated, indicating that constructive Michael addition of the dinitrile acceptor arising from retro-Michael addition of product 14 was feasible. Based on previous studies 2e and the observations reported herein, a catalytic cycle for this transformation can be proposed (Scheme 6B). (4bR,11aS)-Fused-BTM 19 is reversibly acylated by a TeFP ester to form acyl ammonium ion pair 41. Reversible deprotonation by the aryloxide then generates selectively the (Z)-C(1)-ammonium enolate 42 which is stabilised by a 1,5-O/S chalcogen bonding interaction ðn O to s * SÀC Þ. [19][20][21] Michael addition to vinyl dinitrile generates the acyl ammonium intermediate 43 that is subsequently protonated by the 2,3,5,6-tetrauorophenol to give acyl ammonium ion pair 44. The aryloxide subsequently effects catalyst turnover to afford product 45 with excellent enantioselectivity, with CIDT leading to enhanced diastereoselectivity in specic examples.
Based on this catalytic cycle and control studies, retro-Michael addition could in principle occur from both the acyl ammonium intermediate 43 and the ester product 45 and we currently cannot distinguish unambiguously between both possibilities. Since our studies have demonstrated that aryloxide turnover to give a,a-difunctionalised ester products is irreversible in the presence of an isothiourea, 22 it seems likely that the isothiourea acts as a Brønsted base to promote retro-Michael addition from product 45.

Conclusions
In conclusion, the scope and limitations of the base-free enantioselective Michael addition of 2,3,5,6-tetrauorophenyl Scheme 5 Gram-scale catalytic demonstration and product derivatisations.
Scheme 6 Proposed catalytic cycle.
[a] Yield determined by 1 H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene internal standard. esters to 2-benzylidene malononitriles have been demonstrated. Variation of the substitution on both electrophilic and nucleophilic reaction partners was tolerated giving generally good yields and diastereoselectivity with excellent enantioselectivity. Mechanistic investigation determined that retro-Michael addition is promoted by both isothiourea (4bR,11aS)-fused-BTM 19 and nucleofuge 2,3,5,6-tetrauorophenoxide. In three examples the reversible nature of the Michael addition was exploited to achieve excellent product diastereoselectivity through a novel CIDT. The reaction can be readily carried out upon a gram scale and derivatised to allow access to a variety of stereodened products. Further applications of the reversible Michael addition process are currently under investigation in this laboratory.

Data availability
The research data supporting this publication can be accessed at: Author contributions AJN carried out all experimental studies in consultation with JB and CMY. CM carried our preliminary work that led to this project. ADS, AJN and CMY wrote the manuscript. AMZS and DBC carried out single crystal X-ray analysis. All authors agreed on the nalised version of the manuscript.

Conflicts of interest
There are no conicts to declare.