Copper-Catalyzed Enantioselective Borylative Allyl–Allyl Coupling of Allenes and Allylic gem-Dichlorides

A catalytic asymmetric reaction between allenes, bis(pinacolato)diboron, and allylic gem-dichlorides is reported. The method involves the coupling of a catalytically generated allyl copper species with the allylic gem-dichloride and provides chiral internal 1,5-dienes featuring (Z)-configured alkenyl boronate and alkenyl chloride units with high levels of chemo-, regio-, enantio-, and diastereoselectivity. The synthetic utility of the products is demonstrated with the synthesis of a range of optically active compounds. DFT calculations reveal key noncovalent substrate–ligand interactions that account for the enantioselectivity outcome and the diastereoselective formation of the (Z)-alkenyl chloride.

C atalytic asymmetric transformations that provide control over several stereochemistry elements in a single operation are among the most important challenges in modern organic chemistry. 1 Asymmetric allyl−allyl coupling of unsymmetrical allyl compounds represents an especially challenging type of reaction since, besides control over the enantioselectivity, many different regio-and stereoisomers can originate from coupling at either the α or γ position of both allylic reagents (Scheme 1a). Enantioselective allyl−allyl coupling has been achieved through Pd-, 2 Cu-, 3 and Ir-catalyzed 4 coupling of stoichiometric allyl metal reagents with several allylic electrophiles. However, these methods are typically confined to the introduction of simple allyl fragments from allyl metal reagents, and are limited to the synthesis of terminal 1,5-dienes (Scheme 1b). 5, 6 An interesting alternative to the stoichiometric use of allyl metal reagents in cross-coupling reactions is the catalytic generation of an allyl copper nucleophile by allene elementcupration. 7 By using this strategy, Hoveyda et al. reported a regio-and enantioselective borylative allyl−allyl coupling between allenes and primary allylic phosphates (Scheme 1c). 8 Additionally, Xiong et al. 9 and Hoveyda et al. 10 described the reductive version of this coupling by using copper hydride catalysis. Despite these efforts, the use of secondary 1,3disubstituted allyl electrophiles in enantioselective allyl−allyl cross-coupling, which imposes an extra selectivity challenge since the geometry of the resulting internal double bond must be controlled, is elusive. 5 As far as we are aware, only one racemic example of a borylative allyl−allyl coupling involving a 1,3-disubstituted allyl phosphate has been reported. 11 Within our ongoing interest in developing enantioselective multicomponent couplings of allylic gem-dichlorides, 12,13 we envisioned that an enantioselective allene allylboration based on this type of allylic substrates would afford an unprecedented chiral 1,5-diene structure bearing two orthogonal stereodefined functionalities (Scheme 1d). This high degree of functionalization would provide a useful tool to significantly expand the range of accessible molecules bearing the important and synthetically versatile 1,5-diene core. 14 Moreover, it would represent a new synthetic application among the few catalytic methods available for the stereoselective synthesis of acyclic alkenyl chlorides. 15 The envisioned transformation is highly demanding since it requires a chemo-, regio-, and stereoselective Cu-Bpin addition to the allene, followed by a regio-and enantioselective coupling of the resulting allylcopper species with the allylic gem-dichloride in a process where the geometry of the alkenyl chloride must be also controlled. Here, we report the successful realization of this idea through an enantioselective copper-catalyzed borylative allyl−allyl cross-coupling between allenes and allylic gem-dichlorides that efficiently provides chiral, densely functionalized internal 1,5-dienes bearing both (Z)-configured alkenyl chloride and alkenyl boronate units with high levels of chemo-, regio-, and stereoselectivity.
Initial chiral ligand screening revealed that the use of catalysts bearing a chiral bisphosphine (entry 1) or aminoalcohol-derived N-heterocyclic carbene (NHC) ligands (entries 2−3) led to nearly equimolar mixtures of stereoisomers 3-Z,Z and 3-Z,E in low yield with almost negligible enantioselectivity. A significant improvement in stereoselectivity was observed when sulfonate-bearing NHC ligands 16 were employed. Chiral copper complexes derived from L4 and L5, which feature a 2,6-dimethylphenyl and a mesityl group, respectively, proved to be the most efficient catalysts and provided 1,5-diene 3 as a single (Z,Z)-isomer with very good enantiomeric ratio (entries 4 and 5). Changes on the N-aryl group had a negative impact since bulkier substituents at the ortho position led to diminished enantioselectivity (entry 6), while a 3,5-disubstitution pattern produced a complete loss of efficiency (entry 7). Further evaluation of different solvents and reaction stoichiometry (entries 8−11) provided the optimal set of conditions, which comprises the use of L5 as ligand, KO t Bu as base, and toluene as solvent. Under these conditions, product 3 was obtained as a single isomer in 71% yield with 96:4 er (entry 11). Notably, no formation of other isomers arising either from coupling at the γ position of the allylcopper intermediate or from S N 2-type substitution of the allylic gem-dichloride could be detected. Interestingly, in sharp contrast with our previously reported borylative coupling between alkynes and allylic gem-dichlorides, 12 the use of alkoxide bases bearing smaller metal cations led to a significant decrease of both efficiency and stereoselectivity (entries 12− 13).
Once the optimized conditions were identified, the scope of the reaction was explored (Scheme 2). The method proved to be remarkably effective for a wide range of allenes and provided solely the corresponding (Z,Z)-configured 1,5-dienes in good yield with excellent levels of chemo-, regio-, and enantioselectivity. Allenes bearing simple alkyl groups (3,4), or aliphatic chains bearing functionalities, such as aryl rings (5,6), silyl ether (7), ester (8), ether (9), or carbamate (10), were well tolerated. Heterocyclic-substituted allenes were also amenable for this transformation, as illustrated with the synthesis of piperidine and tetrahydropyran derivatives 11 and 12. 1-Phenylallene still provided the corresponding product 13 as a single (Z,Z)-isomer with perfect regioselectivity, albeit with slightly diminished enantiomeric ratio. 17 Importantly, scalability of the reaction was demonstrated through the 1 mmol-scale synthesis of 3 using lower catalyst loading (5 mol %).
Different allylic gem-dichlorides were also evaluated for this enantioselective borylative allyl−allyl cross-coupling. Substrates with aryl rings bearing alkyl (14) or trifluoromethyl (15) groups proved to be efficient for this transformation. Halogenated aromatic substrates also furnished the corresponding 1,5-dienes (16−19) with good yield and excellent selectivities. Remarkably, the use of a hindered ortho-bromosubstituted substrate was well tolerated and provided products 18 and 19 without selectivity erosion. A substrate featuring another sterically demanding unit, such as a naphthalene group, could also be used with very high selectivity (20). Aliphatic gem-dichlorides were not suitable for the described enantioselective borylative allyl−allyl coupling. 18 Absolute stereochemistry of the products was determined by X-ray diffraction analysis of product 11, which revealed the

ACS Catalysis
pubs.acs.org/acscatalysis Letter configuration of the carbon stereogenic center to be (S), and confirmed the (Z)-configuration of both double bonds. The combination of the high level of functionality of the products and their stereochemistry makes them versatile building blocks for the synthesis of a range of chiral structures (Scheme 3). Stereodefined 1,5-dienyl chlorides 21 and 22 could be accessed by chemoselective intermolecular Suzuki− Miyaura cross-coupling. Because of the remaining alkenyl chloride, the 1,5-diene structure can be further functionalized as shown with the formation of 23. The presence of an orthobromo-substituted aryl ring in products 18 and 19 provides an extra handle to perform an intramolecular coupling, as illustrated with the synthesis of indane derivative 24. Notably, the alkenyl boronate and the alkenyl chloride functionalities could be efficiently combined through intramolecular Pdcatalyzed cross-coupling to provide chiral cyclopentene 25. Oxidation of the alkenyl boronate unit allows for the preparation of chiral alkenyl chloride-containing ketones (i.e., 26−30). Finally, chiral borylated 1,5-enyne 31 could be obtained with full stereochemical retention by LDA-mediated dehydrochlorination.
To analyze the factors that control the stereoselectivity of this enantioselective borylative allyl−allyl coupling, DFT calculations were performed (see the Supporting Information for details). Two lowest-energy structures (Ia and Ib), which rapidly interconvert (ΔG sol = 0.5 kcal·mol −1 ), were found for the σ-allyl-Cu(I) intermediate. Among the different investigated coordination modes for the stereodetermining oxidative addition step in the formation of 3-Z,Z, 19 the one featuring the allyl gem-dichloride opposite to the N-arylsulfonate group (i.e., coordination to Ia), led to the most favorable pathway to the major (S)-enantiomer, while the preferred pathway to the minor (R)-enantiomer arises from coordination to Ib where the allyl substrate is opposite to the N-mesityl (NMes) unit ( Figure 1a). The relative energy for transition state TS OA -Z,S was 2.7 kcal·mol −1 lower than for TS OA -Z,R, which is in good agreement with the observed 96:4 er. In order to account for this energy difference, analysis of non-covalent interactions (NCI) was performed. NCI plots of both transition state structures showed no significant differences in terms of repulsive interactions (see the Supporting Information). However, analysis of the attractive interactions revealed that the coordination mode in TS OA -Z,S allows for the establishment of a double potassium cation bridge interaction between the NHC's sulfonate group and both chloride units. In contrast, only one K···Cl interaction is present in TS OA -Z,R (Figure 1b). This difference in attractive interactions may suggest that the origin of enantioselectivity arises from the extra stabilization in TS OA -Z,S, which originates from the double substrate−ligand cation bridge interaction. In this line, analysis of the optimized structures for the transition states using a lithium cation instead of potassium showed that the extra stabilization given by the second cation bridge interaction of the second chlorine atom is missing in TS OA -Z,S-Li ( Figure  1c). This leads to a higher-energy transition state and, thus, to a smaller energy difference with TS OA -Z,R-Li. 20 The lack of the second stabilizing interaction may be due to the smaller size of the Li cation and might explain the lower enantioselectivity observed when LiO t Bu is used instead of KO t Bu (see Table 1, entries 11 vs 13).
To evaluate the factors that govern the diastereoselective formation of the (Z)-alkenyl chloride, we calculated the optimized structure for transition state TS OA -E,S that leads to the formation of diastereomer 3-Z,E. 21 In accordance with the experimental results, TS OA -E,S resulted in higher energy than  the preferred TS OA -Z,S (ΔG ‡ = 30.7 kcal·mol −1 vs ΔG ‡ = 23.0 kcal·mol −1 ). NCI plot analysis revealed that a new repulsive interaction between the Bpin unit and the N-arylsulfonate group appears in TS OA -E,S when compared with TS OA -Z,S ( Figure 2). Moreover, repulsive interactions between the cyclohexyl ring and the phenyl and NMes units of the NHC ligand become larger in TS OA -E,S. Analysis of TS OA -E,S geometry shows that in order to establish the stabilizing double-cation bridge interaction the system has to adopt a structural reorganization, which involves a decrease on the dihedral angle displayed between NHC carbenic carbon and C6 of the arylsulfonate ring (60.5°in TS OA -E,S vs 68.2°in TS OA -Z,S). This angle modification pushes the N-arylsulfonate ring closer to the Bpin unit, thereby engendering the new repulsive interaction. Consequently, the σ-allyl substituent adopts a new spatial disposition that enhances the repulsive interactions between the cyclohexyl group and the NHC's phenyl and mesityl rings. This set of repulsive interactions would result in a higher-energy transition state and would explain the origin of the (Z)-selectivity.
In summary, we have disclosed an enantioselective borylative allyl−allyl cross-coupling between allenes and allylic gem-dichlorides to provide optically active (Z,Z)-configured internal 1,5-dienes. Remarkable features of the method are the observed excellent chemo-, regio-, and enantioselectivity, the stereoselective formation of two orthogonally functionalized alkenyl units, and the synthetic versatility of the resulting chiral