Hon Wai Lam

Catalyst-Controlled Divergent C–H Functionalization of Unsymmetrical 2-Aryl Cyclic 1,3-Dicarbonyl Compounds with Alkynes and Alkenes

Achieving site-selective, switchable C-H functionalizations of substrates that contain several different types of reactive C-H bonds is an attractive objective to enable the generation of different products from the same starting materials. Herein, we demonstrate the divergent C-H functionalization of unsymmetrical 2-aryl cyclic 1,3-dicarbonyl compounds that contain two distinct, nonadjacent sites for initial C-H functionalization, where product selectivity is achieved through catalyst control. By use of a palladium-N-heterocyclic carbene complex as the precatalyst, these substrates undergo oxidative annulation with alkynes to provide spiroindenes exclusively. In contrast, a ruthenium-based catalyst system gives benzopyrans as the major products. Examples of divergent, oxidative C-H alkenylations of the same substrates are also provided.

Enantioselective Rhodium-Catalyzed Addition of Arylboronic Acids to Alkenylheteroarenes

In the presence of a rhodium complex containing a newly developed chiral diene ligand, alkenes activated by a range of π-deficient or π-excessive heteroarenes engage in highly enantioselective conjugate additions with various arylboronic acids.

Enantioselective Rhodium‐Catalyzed Addition of Potassium Alkenyltrifluoroborates to Cyclic Imines

Chiral α-branched allylic amines are important building blocks for organic synthesis, and several catalytic asymmetric methods have been developed for their synthesis. For example, enantioselective metal-catalyzed amination of allylic electrophiles 1 , 2 , 3 ] and rearrangement of allylic imidates have proven to be highly effective. An alternative approach to chiral allylic amines that can be advantageous from the viewpoint of convergency is the catalytic enantioselective union of an alkenyl nucleophile with an imine. In view of the widespread success of enantioselective Rh(I)-catalyzed additions of arylboron reagents to imines as a means to access chiral α-aryl branched amines, development of the corresponding reactions of alkenylboron reagents to prepare chiral α-branched allylic amines should be an attractive goal. Surprisingly however, only very limited precedent exists for this transformation. Brak and Ellman have developed highly diastereoselective Rh(I)-catalyzed additions of alkenylboron reagents to N-tertbutanesulfinyl aldimines (Scheme 1A). The only existing enantioselective variant is that of Shintani, Hayashi, and coworkers who, as part of a study involving additions of potassium aryltrifluoroborates to N-sulfonyl ketimines, also described one example using an alkenyltrifluoroborate (Scheme 1B). Also of relevance is a single example of an enantioselective Rh(I)-catalyzed addition of an alkenylsilane to an N-sulfonyl aldimine. 18 ] Therefore, a general enantioselective Rh(I)-catalyzed addition of alkenylboron reagents to imines remains undeveloped. Herein, we demonstrate that cyclic imines are highly effective substrates for enantioselective Rh(I)-catalyzed additions of potassium alkenyltrifluoroborates, providing products in excellent enantioselectivities and generally good yields. The cyclic structure of these imines, where the C=N bond is constrained in the Z-geometry, appears to be N

Functionalization of C sp 3H and C sp 2H Bonds: Synthesis of Spiroindenes by Enolate‐Directed Ruthenium‐Catalyzed Oxidative Annulation of Alkynes with 2‐Aryl‐1,3‐dicarbonyl Compounds

The metal-catalyzed oxidative annulation of alkynes with aryl or alkenyl substrates bearing various heteroatom-containing functional groups has proven to be a versatile, efficient, and atom-economic strategy to access a range of valuable heterocyclic products. These processes generally rely upon coordination of the metal center to the heteroatomcontaining functional group, which directs site selective Csp2 H bond cleavage to form the metallacycle A (Scheme 1a). Coordination and migratory insertion of the alkyne and subsequent C X (X = heteroatom) reductive elimination then forms the heterocyclic product. These alkyne oxidative annulations have been complemented by variants that result in the functionalization of two Csp2 H bonds, with or without the assistance of directing groups (Scheme 1b). While these reactions are effective in forming aromatic carboand azacycles, the scope and utility of the general process would be considerably enhanced if variants involving the functionalization of Csp3 H bonds could be developed, thus resulting in partially saturated cyclic products. However, progress in this area has been limited. To our knowledge, the only existing report comes from Nakao, Hiyama and co-workers, who recently described the oxidative annulation of formamides with alkynes, in which an extra equivalent of alkyne acts as the stoichiometric oxidant (Scheme 1c). Herein, we report a new mode of catalytic alkyne oxidative annulation involving the (formal) functionalization of one Csp3 H bond and one Csp2 H bond (Scheme 1d). This ruthenium-catalyzed process results in the formation of indenes, which are important structures in various biologically active compounds and functional materials. A notable feature of this process is the formation of an all-carbon quaternary center, which has not been described previously in alkyne oxidative annulations. At the outset of this work, we hypothesized that aarylcarbonyl compounds might be suitable substrates for alkyne oxidative annulations by virtue of the acidic nature of the a protons, that is, deprotonation would generate an enolate which could serve as an efficient directing group for Csp2 H bond cleavage. 2-Aryl cyclic 1,3-dicarbonyl compounds were selected for investigation on the basis of their high acidity and the permanent close proximity of the aryl and carbonyl groups. This latter feature renders these substrates conformationally predisposed for cyclometallation, thus forming a six-membered metallacycle in readiness for migratory insertion of the alkyne and spiroindene formation. 2-Aryl-1,3-diketones, which exist predominantly in the enol tautomer, were investigated first, and we began with a study of the reaction of 3-hydroxy-2-phenyl-2-cyclohexenone (1a) with 1-phenyl-1-propyne (2a ; Table 1). The Scheme 1. a)–d) Metal-catalyzed oxidative annulation of alkynes.

Catalytic 1,4-rhodium(III) migration enables 1,3-enynes to function as one-carbon oxidative annulation partners in C-H functionalizations.

1,3-Enynes containing allylic hydrogens cis to the alkyne are shown to act as one-carbon partners, rather than two-carbon partners, in various rhodium-catalyzed oxidative annulations. The mechanism of these unexpected transformations is proposed to occur through double C–H activation, involving a hitherto rare example of the 1,4-migration of a RhIII species. This phenomenon is general across a variety of substrates, and provides a diverse range of heterocyclic products.

Stereoselective Synthesis of Multisubstituted Enamides via Rhodium-Catalyzed Carbozincation of Ynamides

A new rhodium-catalyzed carbozincation of ynamides has been developed, using diorganozinc reagents or functionalized alkylzinc halides. The reactions are highly regio- and stereoselective, allowing access to a wide range of multisubstituted enamides, which are increasingly important building blocks for organic synthesis. Utilization of the alkenylzinc intermediates in further carbon-carbon bond-forming reactions to form trisubstituted enamides is also possible.

Aromatic Heterocycles as Activating Groups for Asymmetric Conjugate Addition Reactions. Enantioselective Copper-Catalyzed Reduction of 2-Alkenylheteroarenes

The versatility of chiral copper hydride catalysis has been demonstrated through development of highly enantioselective 1,4-reductions of 2-alkenylheteroarenes, substrates that have been rarely considered for asymmetric conjugate addition reactions. Both azoles and azines serve as efficient activating groups for this process.

Enantioselective Copper(I)‐Catalyzed Borylative Aldol Cyclizations of Enone Diones

The in situ trapping of metal enolates generated by the catalytic hydrometalation of a,b-unsaturated carbonyl compounds has proven to be a mild and versatile method for carbon–carbon bond construction. Not only does this strategy allow precise control of the site of enolization of substrates containing several acidic sites, the use of chiral metal/ligand complexes can also enable products to be formed with high levels of diastereoand enantiocontrol. In this context, we and others have developed various copper(I)catalyzed or copper(I)-mediated reductive aldol, Mannich, and Michael reactions to furnish products with high diastereoand enantioselectivities. While these processes are effective, the development of related transformations in which metal enolate generation is initiated not by the formation of a carbon–hydrogen bond, but by a carbon–heteroatom bond which can then be exploited in subsequent functionalizations, should also be of high value. Given the recent developments in enantioselective copper(I)catalyzed conjugate boration reactions, 9] we envisaged a domino conjugate boration/aldol cyclization sequence in which a copper enolate generated from the initial conjugate boration is trapped by a pendant ketone to deliver cyclic products containing multiple stereocenters (Scheme 1). Relevant precedent for such a process is relatively limited. Hoveyda and co-workers have described racemic N-heterocyclic-carbene-catalyzed conjugate boration of a cyclic enone with subsequent in situ trapping of the resulting boron enolate with benzaldehyde, whereas Kanai, Shibasaki, and co-workers reported a similar enantioselective process catalyzed by a chiral copper/bisphosphine complex. Recently, Riant and co-workers developed a racemic copper-catalyzed conjugate boration/intermolecular aldol sequence of acyclic or cyclic a,b-unsaturated carbonyl compounds. However, analogous processes in which the aldol reaction occurs in an intramolecular fashion have not, to our knowledge, been reported, despite the potential for the generation of useful functionalized cyclic building blocks. In view of the precedent set by Krische and co-workers, who described highly diastereoand enantioselective rhodium-catalyzed conjugate arylation/aldol cyclizations of enone diones, we wondered whether a related process involving copper-catalyzed conjugate boration could be developed. Herein, we report the enantioselective coppercatalyzed domino conjugate boration/aldol cyclization of enone diones to give a range of highly functionalized bicyclic products. This desymmetrization process results in the formation of one boron–carbon bond, one carbon–carbon bond, and four contiguous stereocenters, two of which are quaternary, with high levels of diastereoand enantioselection. Our studies commenced with evaluation of various common chiral bisphosphine ligands (L1–L4 ; 5.5 mol%) in the domino conjugate boration/aldol cyclization of the enone dione 1a with B2(pin)2 (1.1 equiv) in the presence of CuCl (5 mol%) and NaOtBu (7.5 mol%) in THF (0.1m) at room temperature (Table 1, entries 1–4). Although the desired bicyclic product 3a was formed in greater than 95:5 d.r. [(major isomer):( other isomers)] in several cases, appreciable quantities of the product 2a resulting from conjugate boration without cyclization were often observed (Table 1, entries 1, 2, and 4). With the Taniaphos ligand L3, 2a was the sole product (Table 1, entry 3). Regarding enantioinduction, the Josiphos ligand L4 provided the best results, furnishing 3a as the major product (3a/2a = 93:7) in 85 % ee (Table 1, entry 4). Additional optimization revealed that the inclusion of MeOH (2.0 equiv; Table 1, entry 5) and halving the concentration of the reaction (Table 1, entry 6) led to further increases in enantioselectivity, albeit with a lower ratio of 3a/ 2a (Table 1, entry 6). Fortunately, the use of more-hindered alcohol additives improved this ratio without sacrificing enantioselectivity (Table 1, entries 7 and 8), with iPrOH providing the best results (entry 7). It should be noted that there is the potential for enantioenrichment of 3 a through a ligand-controlled double asymmetric process, in which the copper enolate containing the minor stereogenicity formed in Scheme 1. Proposed conjugate boration/aldol cyclization.

Enantioselective Synthesis of Allylboronates and Allylic Alcohols by Copper‐Catalyzed 1,6‐Boration

Chiral secondary allylboronates are obtained in high enantioselectivities and 1,6:1,4 ratios by the copper-catalyzed 1,6-boration of electron-deficient dienes with bis(pinacolato)diboron (B2(pin)2). The reactions proceed efficiently using catalyst loadings as low as 0.0049 mol %. The allylboronates may be oxidized to the allylic alcohols, and can be used in stereoselective aldehyde allylborations. This process was applied to a concise synthesis of atorvastatin, in which the key 1,6-boration was performed using only a 0.02 mol % catalyst loading.

Diastereo- and enantioselective Pd(II)-catalyzed additions of 2-alkylazaarenes to N-Boc imines and nitroalkenes.

A chiral Pd(II)-bis(oxazoline) complex was found to be highly effective in promoting the first direct diastereo- and enantioselective addition of alkylazaarenes to N-Boc aldimines and nitroalkenes under mild conditions. Deprotection of Boc-protected products proceeded readily to provide amines in high yields.