Asymmetric Functional Organozinc Additions to Aldehydes Catalyzed by 1,1′-Bi-2-naphthols (BINOLs)

Abstract

ConspectusChiral alcohols are ubiquitous in organic structures. One efficient method to generate chiral alcohols is the catalytic asymmetric addition of a carbon nucleophile to a carbonyl compound since this process produces a C–C bond and a chiral center simultaneously. In comparison with the carbon nucleophiles such as an organolithium or a Grignard reagent, an organozinc reagent possesses the advantages of functional group tolerance and more mild reaction conditions. Catalytic asymmetric reactions of aldehydes with arylzincs, vinylzincs, and alkynylzincs to generate functional chiral alcohols are discussed in this Account.Our laboratory has developed a series of 1,1′-bi-2-naphthol (BINOL)-based chiral catalysts for the asymmetric organozinc addition to aldehydes. It is found that the 3,3′-dianisyl-substituted BINOLs are not only highly enantioselective for the alkylzinc addition to aldehydes, but also highly enantioselective for the diphenylzinc addition to aldehydes. A one-step synthesis has been achieved to incorporate Lewis basic amine groups into the 3,3′-positions of the partially hydrogenated H8BINOL. These H8BINOL–amine compounds have become more generally enantioselective and efficient catalysts for the diphenylzinc addition to aldehydes to produce various types of chiral benzylic alcohols. The application of the H8BINOL–amine catalysts is expanded by using in situ generated diarylzinc reagents from the reaction of aryl iodides with ZnEt2, which still gives high enantioselectivity and good catalytic activity. Such a H8BINOL–amine compound is further found to catalyze the highly enantioselective addition of vinylzincs, in situ generated from the treatment of vinyl iodides with ZnEt2, to aldehydes to give the synthetically very useful chiral allylic alcohols.We have discovered that the unfunctionalized BINOL in combination with ZnEt2 and Ti(OiPr)4 can catalyze the terminal alkyne addition to aldehydes to produce chiral propargylic alcohols of high synthetic utility. The reaction was conducted by first heating an alkyne with ZnEt2 in refluxing toluene to generate an alkynylzinc reagent, which can then add to a broad range of aldehydes at room temperature in the presence of BINOL and Ti(OiPr)4 with high enantioselectivity. It was then found that the addition of a catalytic amount of dicyclohexylamine (Cy2NH) allows the entire process to be conducted at room temperature without the need to generate the alkynylzincs at elevated temperature. This BINOL–ZnEt2–Ti(OiPr)4–Cy2NH catalyst system can be used to catalyze the reaction of structurally diverse alkynes with a broad range of aldehydes at room temperature with high enantioselectivity and good catalytic activity.The work described in this Account demonstrates that BINOL and its derivatives can be used to develop highly enantioselective catalysts for the asymmetric organozinc addition to aldehydes. These processes have allowed the efficient synthesis of many functional chiral alcohols that are useful in organic synthesis.

Rhodium(III)-Catalyzed [4+2] Annulation via C-H Activation: Synthesis of Multi-Substituted Naphthalenone Sulfoxonium Ylides

“…Substituted naphthols have been characterized as crucial organic motifs and are embedded in various pharmaceuticals and natural products such as rifampicin [1,2,3], gossypol [4,5,6], dioncophylline A [7,8,9], propranolol [10,11,12,13], and naftopidil [14,15,16] (Figure 1). As a result, the development of efficient methods to synthesize multi-substituted naphthols is important [17,18,19,20]. Over the past few years, transition-metal-catalyzed C–H activation has been demonstrated to be a convenient strategy to establish aromatic and heteroaromatic skeletons [21,22,23,24].…”

Chiral Lithium Amido Zincates for Enantioselective 1,2‐Additions: Auto‐assembling Reagents Involving a Fully Recyclable Ligand

“…This is assigned to the dramatic change of reactivity when going from "unreactive" sp linear R 2 Zn to "reactive" sp 2 or sp 3 zinc complexes formed thanks to coordinative interactions between lone pairs of ac hiral ligand and empty orbitals of the zinc atom in R 2 Zn. [9] Given that literature is extremelyp rofuse about examples of chiral s-donor coordinating entities( such as diamines) providing dative covalent zinc complexes, [10] it appears necessary to make it clear at this point that we are not aiming to propose "one more" chiral s-donor ligandf or neutral organozincs pecies. The work and resultsr eported here are related to afully different goal and consistsin:i.…”

Development of Ar‐BINMOL‐Derived Atropisomeric Ligands with Matched Axial and sp3 Central Chirality for Catalytic Asymmetric Transformations

“…The 1,2‐addition of organometallic reagents to carbonyl compounds is one of the most fundamental carbon–carbon bond‐forming reactions in the enantioselective construction of optically active secondary alcohols . Especially since the seminal work reported by Ohno and co‐workers in 1989, extensive studies on the enantioselective 1,2‐addition of organometallic reagents to carbonyl compounds have been carried out based on the bis‐sulfamide‐, TADDOL‐, or BINOL‐derived ligands .…”