Anhydrides as a , b-unsaturated acyl ammonium precursors : isothiourea-promoted catalytic asymmetric annulation processes †

Asymmetric organocatalysis has developed tremendously as a synthetic strategy within the last decade and a range of methodologies and catalysts have emerged that provide functionalised products with high levels of stereocontrol. Ideally a given organocatalyst architecture should be able to participate in a range of reaction processes and display diverse modes of reactivity, while showing good catalytic efficiency and delivering products with high levels of enantioselectivity. Within this area, isothioureas, initially employed by Birman and Okamoto as efficient O-acyl transfer reagents, have been utilised in a range of kinetic resolution, asymmetric desymmetrisation, C-acylation and C-carboxylation processes, as well as O-silylation reactions. Recent advances have showcased the utility of isothioureas to generate ammonium enolates from carboxylic acids and their applications in aldoland Michael-lactonisation processes (Fig. 1A). Building upon these precedents, this work demonstrates the previously unexplored ability of isothioureas to generate asymmetry by promoting the addition of a range of nucleophiles to a stereodened a,b-unsaturated acyl ammonium species (Fig. 1B). While Peters and Ye have invoked a,b-unsaturated acyl ammoniums as precursors to dienolate formation, to the best of our knowledge there are currently no processes that form C–C bonds directly via such intermediates. Related work in the literature has shown that NHCs can catalytically generate a,bunsaturated acyl azolium intermediates through an internal redox process from alkynals, from enals using a stoichiometric


Introduction and background
Asymmetric organocatalysis has developed tremendously as a synthetic strategy within the last decade and a range of methodologies and catalysts have emerged that provide functionalised products with high levels of stereocontrol. 1 Ideally a given organocatalyst architecture should be able to participate in a range of reaction processes and display diverse modes of reactivity, while showing good catalytic efficiency and delivering products with high levels of enantioselectivity.Within this area, isothioureas, 2 initially employed by Birman and Okamoto as efficient O-acyl transfer reagents, 3 have been utilised in a range of kinetic resolution, 4 asymmetric desymmetrisation, 5 C-acylation and C-carboxylation processes, 6 as well as O-silylation reactions. 7Recent advances have showcased the utility of isothioureas to generate ammonium enolates 8 from carboxylic acids and their applications in aldol-9 and Michael-lactonisation processes (Fig. 1A). 10 Building upon these precedents, this work demonstrates the previously unexplored ability of isothioureas to generate asymmetry by promoting the addition of a range of nucleophiles to a stereodened a,b-unsaturated acyl ammonium species (Fig. 1B).While Peters and Ye have invoked a,b-unsaturated acyl ammoniums as precursors to dienolate formation, 11 to the best of our knowledge there are currently no processes that form C-C bonds directly via such intermediates.Related work in the literature has shown that NHCs 12 can catalytically generate a,bunsaturated acyl azolium intermediates through an internal redox process from alkynals, 13 from enals using a stoichiometric oxidant, 14 directly from a,b-unsaturated acyl uorides or enol esters, 15 or alternatively from a-bromoenones. 16The oxidative approach from enals has been applied to a range of asymmetric C-C bond-forming reactions including aza-Claisen, 17 Coates-Claisen, 18 cyclopropanation 19 and Michael addition processes. 20iven the recognised difficulties in accessing a wide variety of ynals and enals for such NHC-catalysed approaches and limitations associated with the scope and generality of such processes, 21 we envisaged a direct strategy to generate an a,bunsaturated acyl ammonium species from readily available a,bunsaturated carboxylic acids or their anhydrides.Described herein are our results concerning isothiourea-promoted asymmetric addition of 1,3-diketones, b-ketoesters and azaaryl ketones to a,b-unsaturated acyl ammonium intermediates for the preparation of a range of functionalised esters, stereo-dened dihydropyranones and dihydropyridones in highly enantioenriched form (up to 97% ee).Proof of concept and reaction optimisation: annulations using diketone nucleophiles Initial investigations focused upon generation of an a,b-unsaturated acyl ammonium directly from cinnamic acid 1 (Scheme 1A), via in situ activation using 4-methoxybenzoic anhydride (PMBA) and isothiourea HBTM 2.1 5 (20 mol%). 22Employing diketone 4 as the nucleophile provided dihydropyranone 2 in modest 25% isolated yield, albeit with an encouraging 95% ee.Cinnamic anhydride 3 was next evaluated as an alternative acyl ammonium precursor, 23 giving dihydropyranone 2 in improved 49% yield and 95% ee (Scheme 1B).These initial ndings served as a benchmark for further optimisation with the aim to lower catalyst loadings and improve isolated yields. 24rther studies showed that in situ ring opening of dihydropyranone 2 with MeOH led to consistently higher isolated yields of the functionalised ester product 6 (Table 1).Variation of the base showed that EtN(iPr) 2 , DBU or PS-BEMP (polymersupported 2-t-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine) could be used in this process, although DBU gave 6 with reduced enantioselectivity (entry 5). 25 The use of PS-BEMP proved optimal, allowing the catalyst loading of HBTM 2.1 5 to be reduced to 1 mol% without compromising product enantioselectivity, albeit with reduced product yields (entry 11).Performing the reaction in THF led to a reduced yield (entries 4 and 9).While catalytic asymmetric Michael additions to nitro-olens and enones are well documented, 26 this strategy formally allows the asymmetric Michael addition of diketones to a,b-unsaturated carboxylic acid derivatives for which there is only limited precedent. 27

Reaction scope and generality
The generality of this process was next probed, initially through variation of the a,b-unsaturated anhydride component (Table 2).Using HBTM 2.1 5 (5 mol%) and a number of symmetrical diketones, this protocol tolerates a range of 2-, 3-, and 4-substituted b-aryl groups containing either electronwithdrawing or electron-donating groups, as well as heteroaryl Scheme 1 Initial proof of concept studies.a Isolated yield of 2; b determined by HPLC analysis.substituents, giving the corresponding functionalised esters in good yield (up to 86%) and high enantioselectivity (90-97% ee, 6-14).Notable reactivity trends within this series indicate that anhydrides containing electron decient b-aryl units give higher product conversion and isolated yields than their electron rich b-aryl counterparts (product 9).b-Alkyl substituents within the anhydride are also tolerated (a signicant advantage over the NHC-catalysed systems that typically exhibit low enantioselectivity in similar transformations), 20b although low temperatures are necessary to achieve optimal enantioselectivity, resulting in only moderate reaction efficiency and reduced product yields (15 and 16).Variation of the diketone functionality was next investigated (Table 2, 17-21).A range of substituted aryl and heteroaryl diketones participate in this reaction process, giving functionalised esters 17-21 in moderate to good yield and high enantioselectivity. 28urther investigations probed the stereospecicity of this asymmetric annulation protocol (Scheme 2).While (E,E)-cinnamic anhydride 3 gave functionalised ester (S)-6 in 83% yield and 96% ee (Scheme 2A), (Z,Z)-cinnamic anhydride 22 gave (R)-6 in reduced 41% yield and only 30% ee (Scheme 2B), 29 indicating the necessity of the (E)-conguration for maximum enantiocontrol.
The generality of this process was next examined (Table 3), with b-aryl and b-heteroaryl substituents within the anhydride tolerated, in all cases giving the corresponding dihydropyranones 27-32 in acceptable yield (46-70%) and high ee (89-96%). 31aving probed the viability of this process, our attention turned to 1,3-dicarbonyl systems that are not tolerated in related NHC-catalysed processes.For example, aliphatic cyclic Michael donors such as 1,3-cyclohexanedione 33 have been reported by Bode to be ineffective in NHC-catalysis using a,b-unsaturated acyl azoliums. 21However, in this organocatalysed process, diketone 33 demonstrated favourable reactivity and provided 34 in high yield and good enantioselectivity (Scheme 4).

Beyond 1,3-dicarbonyls: azaaryl ketones as nucleophiles
Encouraged by the novel and complementary reactivity of the isothiourea catalysis, the scope of this asymmetric annulation was extended beyond the use of 1,3-dicarbonyl nucleophiles.Gratifyingly, azaaryl ketone 35 proved a competent nucleophile and displayed improved reactivity compared with simple 1,3dicarbonyls.This increased reactivity allows bench grade solvents in an open ask atmosphere to be employed, PS-BEMP can be replaced with more cost efficient EtN(iPr) 2 and a lower catalyst loading of 1 mol% could be routinely employed.The use of this nucleophile led to intriguing regioselectivity.Cyclisation occurs preferentially through the benzothiazole nitrogen, generating dihydropyridone 36a as the major product, in addition to dihydropyranone 36b as the minor product (88 : 12 regioisomeric ratio).These heterocycles were readily separable by chromatography, with the major product 36a obtained in excellent yield and high enantioselectivity (97% ee aer a single recystallisation, Scheme 5).
Next, the substrate scope with this nucleophile was examined with respect to the anhydride component (Table 4).The increased reactivity of the azaaryl ketone 35 provided a wide range of enantioenriched heterocycles in excellent yields and enantioselectivities.For example, while anhydrides bearing electron-rich and aliphatic substituents were modestly tolerated using diketone 4 (Table 2) in terms of both reactivity and enantioselectivity, the use of azaaryl ketone 35 with the same anhydrides leads to enantioenriched products in high yields under our reaction conditions (Table 4).

Mechanistic investigations
In related NHC-catalysed processes involving a,b-unsaturated acyl azolium intermediates two potential mechanistic pathways have been proposed; a Michael addition-lactonisation process with dicarbonyls, ketene acetals and enamines (favoured by Studer and Mayr) 32 or alternatively an initial 1,2-addition followed by a [3,3]-Claisen rearrangement with Kojic acid and enamine derivatives (favoured by Bode) 21 to facilitate the formation of enantioenriched products.Similarly, in our isothiourea-promoted annulation, related catalytic cycles depicted in Fig. 2(a) and (b), could potentially be responsible for the generation of the annulation products with high enantiocontrol.Both cycles involve an initial N-acylation of HBTM 2.1 5 with an anhydride to generate the corresponding a,b-unsaturated acyl ammonium 41.The s-cis conformation of ammonium 41 is presumably favoured, with the carbonyl oxygen hypothesised to adopt a syn-conformation with respect to the isothiourea S atom due to a stabilising non-bonding O-S interaction (n o to s * C-S ). 33In pathway (a), Michael addition 31 of diketone enolate 42 to the Re face of the a,b-unsaturated acyl ammonium 41 gives intermediate 43, 34   To gain insight into the favoured mechanistic pathway, potential intermediates were synthesised and subjected to the reaction conditions.Interestingly, Lupton has previously shown that 1,2-addition of NHCs to enol esters such as 47 facilitates formation of dihydropyranone 49 in the presence of NHC catalyst 48, albeit with moderate enantioselectivity (Scheme 6A).In this regard, 50 was prepared from cinnamoyl chloride and dicarbonyl 4.This potential [3,3]-rearrangement precursor was examined under the reaction conditions, resulting in no conversion into dihydropyranone 2 (Scheme 6B) 15a-c aer 24 h at room temperature.While this result does not rule out either mechanistic pathway, it indicates that 50 is not a likely intermediate in this process.Additionally the absence of any 1,2addition products such as 50 in the 1 H NMR of all unpuried reaction mixtures provides further evidence to support this view.
Evidence supporting the intermediacy of an acyl ammonium species was next obtained.Treatment of trans-cinnamoyl chloride 51 with HBTM 2.1 5 in CH 2 Cl 2 gave the a,b-unsaturated acyl ammonium salt 52 that was isolated in high yield (Scheme 7). 35X-ray crystallography conrmed the structure of 52 and provided further support for the syn geometry of the carbonyl oxygen and the isothiourea S atom, presumably due to the previously hypothesised stabilising non-bonding O-S interaction (n o to s * C-S ).The isolated acyl ammonium salt 52 was next examined as a precatalyst, employing cinammic anhydride 3 and diketone 4 under our optimised reaction conditions (Scheme 8).The functionalised ester 6 was isolated in similar yield and enantioselectivity (82% yield, 91% ee) compared with the use of organocatalyst HBTM 2.1 5 (83% yield, 95% ee) in this process, consistent with acyl ammonium salt 52 being an intermediate in this asymmetric annulation.
At this juncture we cannot rule out any plausible mechanistic pathway that involves an a,b-unsaturated acyl ammonium ion, although we currently favour a catalytic cycle involving a Michael addition-lactonisation sequence, described in Fig. 2(a).Further mechanistic investigations and DFT calculations to provide insight into the pathway in operation are underway and will be reported in due course.

Conclusions
To conclude, HBTM 2.1 5 promotes the asymmetric annulation of a range of nucleophiles including 1,3-diketones, b-ketoesters and azaaryl ketones to (E,E)-a,b-unsaturated anhydrides, giving either functionalised esters (upon ring opening), dihydropyranones, or dihydropyridones in good yields (up to 86%) and high enantioselectivity (up to 97% ee) via a postulated a,b-unsaturated acyl ammonium intermediate.Current research from this laboratory is directed toward developing alternative uses of isothioureas and other Lewis bases in asymmetric catalysis, and exploiting a,bunsaturated acyl ammonium intermediates for a range of synthetic procedures.

Fig. 1
Fig. 1 Proposed access to enantioenriched annulation products via an unexplored a,b-unsaturated acyl ammonium species.

Scheme 2
Scheme 2 Stereospecificity of asymmetric annulation process.a Isolated yield of 6; b determined by HPLC analysis.
Scheme 5 Asymmetric addition of azaaryl ketone 35. a Isolated yield; b determined by HPLC analysis; c determined from 1 H NMR of unpurified reaction mixture; d following a single recrystallisation.

1, 2 -
addition to the a,b-unsaturated acyl ammonium 42 to generate intermediate 46 followed by a [3,3]-rearrangement and subsequent proton transfer/lactonisation process would lead to the same enantioenriched products.

Table 1
Optimisation studies 1 Isolated yield of 6. b Determined by HPLC analysis.cConversiondeterminedby1HNMR spectroscopic analysis of the unpuried reaction mixture.dReactionconducted in THF.

Table 2
Substrate scope a Isolated yield of 6-21.b Determined by HPLC analysis.c 10 mol% catalyst.d Reaction carried out at À78 C. e Reaction conducted in THF.