Enantioselective nickel-catalyzed anti -arylmetallative cyclizations onto acyclic electron-deficient alkenes †

Enantioselective nickel-catalyzed reactions of (hetero)arylboronic acids or alkenylboronic acids with substrates containing an alkyne tethered to various acyclic electron-deficient alkenes are described. The metal-catalyzed addition of an arylboron reagent to an alkyne, followed by enantioselective intramolecular nucleophilic addition of the resulting alkenylmetal species onto a tethered electrophile, is a versatile domino reaction sequence for the synthesis of diverse chiral carbo- and heterocycles. 1 We 2 and others 3 have recently described nickel-catalyzed variants of these reactions in which reversible E / Z isomerization of the intermediate alkenylnickel species enables enantioselective arylative cyclizations to proceed that would otherwise be impossible because of geometric constraints. Variants of these reactions that give achiral products, 4 and several related processes, 5–7 have also been described. We have previously enantioselective desymmetrizing nickel-catalyzed arylative cyclizations onto cyclohexa-2,5-dienones, which give fused bicyclic products with high diastereo- and enantioselectivities (Scheme 1A). 2 a However, the use of a broader range of acyclic electron-deficient, conjugated alkenes in cyclizations be valuable in providing less complex, non-fused products, the synthetic of Herein, we demonstrate that acyclic enones, nitroalkenes, a , b -unsaturated esters, and a , b

The metal-catalyzed addition of an arylboron reagent to an alkyne, followed by enantioselective intramolecular nucleophilic addition of the resulting alkenylmetal species onto a tethered electrophile, is a versatile domino reaction sequence for the synthesis of diverse chiral carbo-and heterocycles. 1 We 2 and others 3 have recently described nickel-catalyzed variants of these reactions in which reversible E/Z isomerization of the intermediate alkenylnickel species enables enantioselective arylative cyclizations to proceed that would otherwise be impossible because of geometric constraints. Variants of these reactions that give achiral products, 4 and several related processes, [5][6][7] have also been described.
We have previously described enantioselective desymmetrizing nickel-catalyzed arylative cyclizations onto cyclohexa-2,5-dienones, which give fused bicyclic products with high diastereo-and enantioselectivities (Scheme 1A). 2a However, the use of a broader range of acyclic electron-deficient, conjugated alkenes in cyclizations would be valuable in providing less complex, non-fused products, and would substantially increase the synthetic utility of this methodology. Herein, we demonstrate that acyclic enones, nitroalkenes, a,b-unsaturated esters, and a,b-unsaturated nitriles can be used as electrophiles in the enantioselective preparation of various non-fused chiral carbo-and heterocycles (Scheme 1B). Collectively, these results represent a substantial increase in the scope of nickel-catalyzed anti-carbometallative cyclizations.
The results of evaluating different boronic acids in reactions with substrates 1g or 1p are shown in Table 2. Substituted phenylboronic acids with various groups at the para (2t), meta (2q), or ortho (2r) positions successfully underwent the reaction to give products with reasonable to high yields and high enantioselectivities, as did 3,4-dichlorophenylboronic acid (2u) and 3-thienylboronic acid (2s). Various alkenylboronic acids also reacted with 1p to give products 2v-2x in 499% ee but in low yields because of competitive protodeboronation.
Further investigations into the scope of these reactions revealed some interesting findings. For example, the reaction of 2fluorophenylboronic acid with substrate (E)-1q, which contains an a,b-unsaturated t-butyl ketone, gave the arylative cyclization product 2y in only 25% yield but in 499% ee (eqn (1)). This reaction also gave the alkyne hydroarylation products 3 in 30% yield, which were isolated as a 0.7 : 1 mixture of inseparable E-and Z-isomers, respectively. Evidently, the steric hindrance imparted by the t-butyl group had a negative effect on the efficiency of arylative cyclization. Interestingly, however, the analogous reaction with the stereoisomeric substrate (Z)-1q gave 2y in 90% yield and 499% ee (eqn (2)). The markedly different propensity of (E)-1q and (Z)-1q to undergo the desired reaction is reminiscent of our prior work in enantioselective nickel-catalyzed intramolecular allylic alkenylations, where Z-allylic phosphates gave arylative cyclization products but the corresponding E-isomers did not. 2b The reasons for the differing results obtained from (E)-1q and (Z)-1q are not clear, but perhaps the lower thermodynamic stability of (Z)-1q is manifested in greater reactivity toward nucleophilic attack, and/or the steric requirements of the reaction are better accommodated by (Z)-1q. Moreover, the major enantiomer of 2y is identical for both reactions (see the ESI † for tentative stereochemical models). These results contrast with several other examples of enantioselective 1,4-additions of carbon nucleophiles to electron-deficient alkenes where E-and Z-isomers of the substrates give opposite enantiomers of the products. 11 However, reactions where E-and Z-isomers give the same major enantiomers of 1,4-addition products are also known. 1j,11b (2) Thus far, only enones or nitroalkenes had been used as electrophiles. Interestingly, use of an a,b-unsatured ester gave other types of products (eqn (3)). Substrate 1r reacted with PhB(OH) 2 (2.0 equiv.) in the presence of 10 mol% each of Ni(OAc) 2 Á4H 2 O and (S)-t-Bu-NeoPHOX (L1) to give the arylative cyclization product 2z (14%, 499% ee), conjugated dienes 5 (23% yield) and 6 (15% yield) resulting from Heck-type cyclizations, 12,13 and what appeared to be the reductive cyclization product 4, which could not be isolated cleanly. These results can be  explained by considering the mechanism of nickel-catalyzed anticarbometallative cyclizations that we have proposed previously (Scheme 2). 2,4c Reaction of 1r and PhB(OH) 2 would, after arylnickelation and reversible E/Z isomerization, 2,4c lead to alkenylnickel species 7. A syn-stereospecific migratory insertion of the alkene 2b would then give the C-bound nickel enolate 8. Protodenickelation of 8 by TFE gives the arylative cyclization product 2z. However, the low yield of 2z suggests that this step is slow compared with substrates containing ketones or nitro groups (Tables 1 and 2). 14 In competition with protodenickelation of 8, bond rotation to give 8 0 and stereospecific syn-b-hydride elimination gives diene 5 and a nickel hydride species 9. The nickel hydride 9 can then enter analogous reaction pathways with substrate 1r but via alkyne hydronickelation to give 10 and eventually, the reductive cyclization product 4 and diene 6.
Given the results shown in Schemes 3 and 4, it was not surprising that substrate 16b (see eqn (6)), which contains an a,b-unsaturated ester rather than an a,b-unsaturated ketone, did not provide the desired arylative cyclization product when it was reacted with PhB(OH) 2 using L1 as the chiral ligand. However, unlike for substrates 13 and 16a, it was interesting to observe that (S)-t-Bu-PHOX (L3) was an effective chiral ligand in the arylative cyclization of 16b, which reacted smoothly with PhB(OH) 2 (2.0 equiv.) in the presence of 10 mol% each of Ni(OAc) 2 Á4H 2 O and L3 to give tetrahydropyridine Scheme 2 Mechanistic rationale of the formation of 2z and 4-6.
In summary, we have reported enantioselective nickelcatalyzed anti-carbometallative cyclizations of (hetero)arylboronic acids and alkenylboronic acids with acyclic substrates containing an alkyne tethered to an enone, nitroalkene, a,b-unsaturated ester, or a,b-unsaturated nitrile. The products are various non-fused chiral carbo-and heterocycles, and the enantioselectivities are excellent in most cases (often Z99% ee). These results represent a substantial increase in the scope over our previous work. 2 Interesting findings comparing the efficiencies of E/Z stereoisomers of certain substrates, and the isolation of products resulting from b-hydride eliminations and reductive cyclizations have also been described (eqn (1)- (5)). 16 This work was supported by the Engineering and Physical Sciences Research Council and AstraZeneca [Industrial CASE Studentship, grant number EP/S513854/1]; the University of Nottingham; and GlaxoSmithKline.

Conflicts of interest
There are no conflicts to declare.