Catalytic Enantioselective Carbonyl Allylation and Propargylation via Alcohol-Mediated Hydrogen Transfer: Merging the Chemistry of Grignard and Sabatier

Abstract

Conspectus Merging the characteristics of transfer hydrogenation and carbonyl addition, we have developed a new class of catalytic enantioselective C-C bond formations. In these processes, hydrogen transfer between alcohols and π-unsaturated reactants generates carbonyl-organometal pairs that combine to deliver products of addition. Based on this mechanistic paradigm, lower alcohols are converted directly to higher alcohols in the absence of premetalated reagents or discrete alcohol-to-carbonyl redox reactions. In certain cases, due to a pronounced kinetic preference for primary vs secondary alcohol dehydrogenation, diols and higher polyols are found to engage in catalytic stereo- and site-selective C-C bond formation - a capability that further enhances efficiency by enabling skeletal construction events without extraneous manipulations devoted to the installation and removal of protecting groups. While this Account focuses on redox-neutral couplings of alcohols, corresponding aldehyde reductive couplings mediated by 2-propanol were developed in parallel for most catalytic transformations reported herein. Mechanistically, two distinct classes of alcohol C-H functionalizations have emerged, which are distinguished by the mode of pronucleophile activation; specifically, processes wherein alcohol oxidation is balanced by (a) π-bond hydrometalation or (b) C-X bond reductive cleavage. Each pathway offers access to allylmetal or allenylmetal intermediates and, therefrom, enantiomerically enriched homoallylic or homopropargylic alcohol products, respectively. In the broadest terms, carbonyl addition mediated by premetalated reagents has played a central role in synthetic organic chemistry for well over a century, however, the requisite organometallic reagents pose issues of safety, require multistep syntheses and generate stoichiometric quantities of metallic byproducts. The concepts and catalytic processes described in this Account, conceived and developed wholly within the author’s laboratory, signal a departure from the use of stoichiometric organometallic reagents in carbonyl addition. Rather, they reimagine carbonyl addition as a hydrogen auto-transfer process or cross-coupling in which alcohol reactants, by virtue of their native reducing ability, drive generation of transient organometallic nucleophiles and, in doing so, serve dually as carbonyl proelectrophiles. The catalytic allylative and propargylative transformations developed thus far display capabilities far beyond their classical counterparts and their application to the total synthesis of type I polyketide natural products have evoked a step-change in efficiency. More importantly, the present data suggest that diverse transformations traditionally reliant on premetalated reagents may now be conducted catalytically without stoichiometric metals. This Account provides the reader and potential practitioner with a catalog of enantioselective alcohol-mediated carbonyl additions – a user’s guide, 10-year retrospective, and foundation for future work in this ...

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

“…The( P)-allenylzinc reagent 36 prepared from (R)-alcohol mesylate 35 reacted with the C1-C9 aldehyde 37 to give the C9-C10 anti adduct 38 as asingle diastereomer. [61,62] This methodology generates the new C À Cb ond enantio-and diastereoselectively in redox-neutral manner,w hich avoids the introduction of the aldehyde and therefore can minimize redox manipulations.E mploying this methodology in their 2015 synthesis, [51] Krische reported the asymmetric biscrotylation of 1,3-diol 50 (Scheme 6c). In their second-generation approach published in 2017, [50] the Rh-catalyzed asymmetric hydroformylation of terminal alkenes 41 and 46 was combined with asymmetric allylation and diastereoselective crotylation to give the C12-C13 syn product 45 and C6-C8 anti,syn product 49,r espectively (Scheme 6b).…”

Enantioselective Iridium‐Catalyzed Allylation of Acetylenic Ketones via 2‐Propanol‐Mediated Reductive Coupling of Allyl Acetate: C14‐C23 of Pladienolide D

“…To address these limitations, we have developed metal‐catalyzed carbonyl reductive couplings that utilize elemental hydrogen, 2‐propanol or formate as terminal reductant, as well as related hydrogen auto‐transfer processes wherein alcohols serve as hydrogen donor and carbonyl proelectrophile . While this technology has enabled diverse catalytic enantioselective aldehyde allylations and propargylations, asymmetric transfer hydrogenative allylations of ketones are restricted to vicinal dicarbonyl compounds…”

Chemische Synthesen und chemische Biologie von Carboxylpolyether‐Ionophoren: Aktuelle Entwicklungen

“…[61,62] Diese Methode erzeugt die neue C-C-Bindung enantio-und diastereoselektiv in redoxneutraler Weise,w odurch die Einführung eines Aldehyds vermieden und Redoxmanipulation minimiert werden. Krische et al entwickelten eine Ir-katalysierte asymmetrische Crotylierung unter Verwendung des Alkohols als Crotyl-Akzeptor und 3-Buten-1-ylacetat als Crotyl-Donor.…”

“…In einer Synthese von Cossy [45,46] ergab die asymmetrische Addition chiraler Allenylzink-Reagenzien an Aldehyde (von Marshall [59] In Leightons 2001 publiziertem Ansatz [49] lieferte ein einstufiger Prozess bestehend aus Rh-katalysierter intramolekularer Siloformylierung des Alkins 39, anti-Crotylierung,T amao-Fleming-Oxidation und anschließender diastereoselektiver Enol-Keton-Tautomerisierung das Produkt 40,w elches die C8-C20-anti,anti-Stereotriade enthält, in guter Ausbeute und Selektivität( Schema 6a). In ihrem 2017 publizierten Ansatz der zweiten Generation [50] wurde die Rh-katalysierte asymmetrische Hydroformylierung der terminalen Alkene 41 und [61,62] Diese Methode erzeugt die neue C-C-Bindung enantio-und diastereoselektiv in redoxneutraler Weise,w odurch die Einführung eines Aldehyds vermieden und Redoxmanipulation minimiert werden. Basierend auf dieser Methode [51] berichteten Krische et al 2015 über eine asymmetrische Bis-Crotylierung des 1,3-Diols 50 (Schema 6c).…”