Enantioselective bifunctional iminophosphorane catalyzed sulfa-Michael addition of alkyl thiols to unactivated β-substituted-α,β-unsaturated esters

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated β-substituted-α,β-unsaturated esters catalyzed by a bifunctional iminophosphorane (BIMP) organocatalyst is described.

Unactivated b-substituted-a,b-unsaturated esters, such as methyl crotonate, methyl cinnamate and their homologues, are a class of low reactivity electrophiles that offer a wealth of untapped potential in the eld of enantioselective organocatalysis. 1 To date, these esters have remained a persistent challenge as Michael acceptors in asymmetric catalysis using both metal-rich and metal-free catalyst systems, largely due to their low inherent electrophilicity 2 and low propensity for catalyst activation and enantioface discrimination. 3,4They are commercial and cheap, or are readily prepared by a variety of standard methods and are stable.In contrast to commonly used (reactive) Michael acceptors such as nitroolens, they lie at the bottom of the Mayr electrophile reactivity (E) scale, 5,6 and unlike enal and enone Michael acceptors they cannot be activated through iminium ion formation with chiral amine catalysts. 7Related literature examples employ activated carboxylic derivatives 8 such as N-enoyl imides, N-enoyl oxazolidinones, peruorinated alkyl esters, thioamides, N-enoyl pyrroles and, most recently, aryl esters. 9Alternatively, activating substituents at the aor b-positions can also be used to gain reactivity and/or stereoselectivity.To illustrate the case in point, to date there has not been a single report of a highly enantioselective addition of a pro-nucleophilic reagent [a carbon-centered (C-H) or heteroatom-centered (X-H) acid] to unactivated alkyl cinnamate or crotonate esters under organocatalytic conditions. 10Effectively, these cheap chemical feedstocks are out of reach of existing chiral organocatalysts and accordingly are a very attractive 'simple' target class of electrophiles for new enantioselective organocatalytic reaction development (Fig. 1).
2][13] To this end, we disclosed that bifunctional iminophosphorane (BIMP) catalysts, containing a novel organosuperbase were highly efficacious in the rst general enantioselective organocatalytic ketimine nitro-Mannich reaction.12b,d Likewise, very recently, high catalyst performance (in terms of reactivity and enantioselectivity) with a second generation BIMP catalyst was also witnessed in the rst organocatalytic conjugate addition of alkyl thiols to unactivated a-substituted acrylate esters (such as methyl methacrylate).12e In both of these transformations an organosuperbase was demonstrated to be essential for reactivity.
We speculated that the reluctance of unactivated b-substituted-a,b-unsaturated esters to undergo organocatalytic Michael addition reactions could be overcome using our BIMP catalyst family.To exemplify this we chose the sulfa-Michael addition (SMA) of alkyl thiols as this is a reaction of central importance for the asymmetric construction of chiral suldes possessing a stereogenic centre at the b-carbon and no organocatalytic enantioselective version has previously been reported. 14,15We reasoned that the high Brønsted basicity of our BIMP catalysts could activate the high pK a alkyl thiol pronucleophile (pK a(DMSO) ¼ 17 for n-BuSH) 16,17 and the modular design of the catalyst family, through its variable backbone scaffold, hydrogen-bond donor group and iminophosphorane superbase would expedite optimal catalyst identication.Herein, and as part of our research program towards the development of novel asymmetric reactions with challenging electrophile/pro-nucleophile combinations, we wish to report our investigations leading to the highly enantioselective SMA reaction of alkyl thiols to unactivated b-substituted-a,b-unsaturated esters.
We chose commercially available methyl crotonate (2a) and 1-propanethiol (3a) as our model system and investigated reactivity using rst generation BIMP catalyst 1a (Table 1, entry 1).In toluene, at room temperature using 10 mol% catalyst we were delighted to observe an exceptional reactivity prole; bmercaptoester product 4a was afforded in near quantitative yield aer only 2 hours with low but signicant enantiocontrol (55 : 45 er). 18With good reactivity established we next investigated the performance of a small library of second generation BIMP catalysts featuring variations around the amide-thiourea motif that we recently reported 12e (Table 1, entries 2-6).The modular design of our BIMP catalysts allowed rapid library generation and our attention focussed on the amide-thiourea moiety as the H-bond donor group and the tris-(4-methoxyphenylphosphine) derived iminophosphorane as the Brønsted basic group (Fig. 2).
Catalysts 1b-d possessing a thiourea constructed from two (S)-congured tert-leucine derived residues, the tris-(4-methoxyphenylphosphine)-derived iminophosphorane and a variable terminal amide group gave poor enantioselectivity in all cases (Table 1, entries 2, 3, and 4).When catalyst 1ethe diastereomer of 1dwas trialled however, a signicant boost to the enantioselectivity was witnessed (Table 1, entry 5, 75 : 25 er). 19 comparison with an analogous catalyst possessing a phenylglycine and a tert-leucine residue (1g) resulted in a slight improvement to the enantioselectivity (Table 1, entry 7, 81 : 19 er).At this stage, the effect of varying the ester group of the crotonate on the enantioselectivity in the SMA was investigated.A range of simple, commercial or readily synthesized alkyl crotonate esters were trialled and a correlation between the size of the ester group and the enantioselectivity was observedpleasingly tert-butyl crotonate (2e) afforded the product 4e in 92 : 8 er albeit in a slightly increased reaction time of 8 h ( With optimized reaction conditions established, the scope of the transformation with respect to the thiol pro-nucleophile and the a,b-unsaturated ester was investigated (Fig. 3).Minimal variation to the enantioselectivity was observed across a good range of linear (propyl to decyl) or branched (cyclic and acyclic)  alkyl mercaptans.The reaction with 4-methoxybenzyl mercaptan was also well-tolerated and afforded the b-mercaptoester 4m in 99% yield and 95 : 5 er at À15 C. Following investigation into the scope of the reaction with respect to the alkyl thiol, variation to the b-substituent of the a,b-unsaturated ester was subsequently examined using 1-propanethiol or 4-methoxybenzyl mercaptan as the sulfur-centred pro-nucleophile.We were pleased to observe that the excellent reactivity and selectivities were maintained when tert-butyl cinnamate, bearing a phenyl group at the b-position, was used as the electrophile to afford the desired b-mercaptoester 4n in 98% yield and 88 : 12 er.
Similarly, excellent yields of the b-mercaptoesters 4o-r were obtained from the corresponding primary alkyl b-substituteda,b-unsaturated esters with very good levels of enantiocontrol.b-Mercaptoesters 4s and 4t containing a terminal N-Boc protected amine and TBS protected hydroxyl group respectively were also synthesized in good to excellent yields and excellent enantiomeric ratios.
Although the scope of the reaction was performed with 10 mol% catalyst loading, we were keen to demonstrate lower loadings were viable.Accordingly, and aer reoptimization of the reaction conditions, to 5 M in Et 2 O at 0 C, we were pleased to nd b-mercaptoester 4e was afforded in near quantitative yield and 95 : 6 er on 7 mmol scale of tert-butyl crotonate (2e) using 1 mol% catalyst 1g (Scheme 1).
To demonstrate synthetic utility of the b-mercaptoester products a selection of standard chemical transformations were carried out (Scheme 2).Thus b-mercaptoester 4e (95 : 5 er) was transesteried to the methyl ester 4a in a two step process; initial acidic cleavage of the tert-butyl ester and subsequent methyl ester formation under acidic conditions afforded 4a in 78% yield without compromising stereochemical integrity.Oxidation of 4e afforded sulfone 5a without any observable racemization in near quantitative yield.Finally, b-mercaptoester 4m was reduced to the alcohol in excellent yield, without appreciable loss of enantiopurity. 20n summary, we have developed the rst organocatalytic enantioselective SMA of alkyl thiols to unactivated b-substituted-a,b-unsaturated esters.Impressive reactivity and excellent levels of enantioselectivities were achieved across range of linear, branched, cyclic alkyl and benzylic thiols, in SMA reactions to various b-substituted-a,b-unsaturated esters using a novel bifunctional iminophosphorane catalyst.This work demonstrates that the high reactivity of the BIMP catalysts enables low reactivity electrophiles such as b-substituted-a,bunsaturated esters to undergo highly enantioselective conjugate addition reactions for the rst time and thus represents a signicant advance in the eld.Work to uncover further capabilities of the BIMP catalyst family is ongoing in our laboratories and the results will be disclosed in due course.

Fig. 3 Scheme 1
Fig. 3 Scope of the SMA of alkyl thiols to b-substituted-a,b-unsaturated esters.Reactions were carried out with 0.20 mmol 2 and 0.60 mmol 3. Yields are isolated yields and enantiomeric ratios were determined by HPLC analysis or GC analysis on a chiral stationary phase.a The reaction was performed at À15 C. b The reaction was quenched after 96 h.c Absolute configuration of 4n determined by chemical correlation (see ESI †).

Table 1
Catalyst screening studies and reaction optimization a