Amplification of Anti-Diastereoselectivity via Curtin−Hammett Effects in Ruthenium-Catalyzed Hydrohydroxyalkylation of 1,1-Disubstituted Allenes: Diastereoselective Formation of All-Carbon Quaternary Centers

Abstract

Under the conditions of ruthenium catalyzed transfer hydrogenation, 1,1-disubstituted allenes 1a-1c and alcohols 2a-2g engage in redox-triggered generation of allylruthenium-aldehyde pairs to form products of hydrohydroxyalkylation 3a-3g, 4a-4g and 5a-5g with complete branched regioselectivity. By exploiting Curtin-Hammett effects, good to excellent levels of antidiastereoselectivity (4:1 ->20:1) are obtained. Thus, all carbon quaternary centers are formed in a diastereoselective fashion upon carbonyl addition from the alcohol oxidation level in the absence of pre-metallated nucleophiles or stoichiometric byproducts. Exposure of allene 1b to equimolar quantities of alcohol 2a and aldehyde 6b under standard reaction conditions delivers adducts 4a and 4b in a 1:1 ratio. Similarly, exposure of allene 1b to equimolar quantities of aldehyde 6a and alcohol 2b provides adducts 4a and 4b in an identical equimolar ratio. Exposure of allene 1b to d 2 -para-nitrobenzyl alcohol, deuterio-2a, under standard reaction conditions delivers the product of hydrohydroxymethylation deuterio-4a, which incorporates deuterium at the carbinol position (>95% 2 H) and the interior vinylic position (34% 2 H). Competition experiments involving exposure of allene 1b to equimolar quantities of benzylic alcohols 2a and deuterio-2a reveal no significant kinetic effect. The collective data corroborate rapid, reversible alcohol dehydrogenation, allene hydrometallation and (E)-, (Z)-isomerization of the transient allylruthenium in advance of turn-over limiting carbonyl addition. Notably, analogous allenealdehyde reductive C-C couplings employing isopropanol as the terminal reductant display poor levels of anti-diastereoselectivity, suggesting carbonyl addition is not turn-over limiting in reactions conducted from the aldehyde oxidation level.

Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis

“…Although good levels of anti -diastereo- and enantioselectivity were observed, the use of multiple stoichiometric metallic reagents and manganese metal diminish the appeal of this method, especially given the earlier disclosure of related alcohol-allene couplings that provide identical products with complete atom-efficiency. 100 …”

Ruthenium-Catalyzed Asymmetric Hydrohydroxyalkylation of Butadiene: The Role of the Formyl Hydrogen Bond in Stereochemical Control

“…15–17 After C-C bond formation, the resulting homoallylic ruthenium alkoxide exchanges with a reactant alcohol to release the product. The catalytic cycle is closed by dehydrogenation to form the aldehyde and regenerate the ruthenium hydride.…”

Alkynes as Allylmetal Equivalents in Redox-Triggered C–C Couplings to Primary Alcohols: (Z)-Homoallylic Alcohols via Ruthenium-Catalyzed Propargyl C–H Oxidative Addition

“…2). 4 Such branched products of allylation are formed in related iridium 5a and ruthenium 5b catalyzed C-C couplings of primary alcohols and allenes, suggesting alkyne-to-allene isomerization is evident in this process. These observations, in combination with our ongoing studies of the ruthenium catalyzed C-C coupling of alkynes and primary alcohols or aldehydes to form allylic alcohols or enones, 6 prompted us to explore the use of alkynes as allyl donors 7 under the conditions of ruthenium catalysis.…”