Catalyst‐ and Solvent‐Dependent Stereodivergence in the Intramolecular Et₂Zn/Pd⁰‐Promoted Carbonyl Propargylation: Mechanistic Implications

Abstract

Carbonyl-tethered propargylic benzoates undergo intramolecular carbonylpropargylation upon treatment with Et2 Zn in the presence of a catalytic amount of Pd(0) with the formation of 2-alkynylcyclopentanol products. A ligand/solvent effect on the cis/trans selectivity (referring to the relative positions of alkynyl and OH groups) of ring-closure has been found. In a non-coordinating solvent (benzene), increasing the electron-donating ability of the phosphine ligand (while decreasing its dissociation ability) leads to an increased tendency towards the trans product. On the other hand, the combination of a coordinating solvent (THF) and PPh3 , an easily dissociated phosphine, results in the exclusive formation of cis products. Experimental and computational results are compatible with a divergent behavior of an allenylethylpalladium intermediate that partitions between competitive carbonyl-addition and transmetalation pathways, each leading to a different diastereoisomer. These results also suggest that the dissociating ability of the phosphine regulates that behavior.

Stereodivergent Catalysis

“…For instance, benzoate 634 gave cis -cyclopentanol 635 using Pd­(PPh 3 ) 4 , whereas Pd­(OAc) 2 /P n Bu 3 afforded trans - 635 (Scheme ). Solvent and temperature effects have also been observed, so in a noncoordinating solvent such as benzene with electron-donating phosphines an increased tendency toward the trans -product was observed. On the other hand, the combination of a coordinating solvent such as THF and triphenylphosphine (an easily dissociated phosphine) afforded cis -products.…”

Synthesis of bicyclic alcohols by palladium-catalyzed Et2Zn-mediated intramolecular carbonylpropargylation

“…Starting from esters 1, the expected bicyclic products 2 were obtained in moderate to good yields upon treatment with Et2Zn in benzene, in the presence of a catalytic amount of Pd(PPh3)4 (Table 1). The alternative use of THF as solvent or P(nBu3) as ligand 21 led to very low yielding reactions with substantial substrate degradation. Remarkably, under the conditions indicated in Table 1, the cyclization took place with high stereoselectivity, affording usually a single isomer.…”

“…Simple monocyclic 2alkynylcyclopentanols have been similarly prepared from the corresponding acyclic propargylic esters. 21 In that case, the cisor trans-relationship between the alkynyl and hydroxyl functionalities was shown to depend on the choice of phosphine and solvent, and for simple aldehyde substrates, this particular combination of Pd(PPh3)4 as catalyst and benzene as solvent had led to low stereoselectivities. It is likely that the high levels of stereocontrol observed in the present cyclizations, particularly in the case of [3.3.0] ring fusion, are due to the rigidity of the newly generated bicyclic system.…”

“…1,2 This variant, proceeding through the corresponding allenylzinc intermediates IIIb, has been applied both inter-and intramolecularly, albeit only with linear acyclic substrates in the latter case. 20,21 We now report the application of the Pd(0)/Et2Znpromoted intramolecular propargylation of carbonyl compounds to the preparation of bicyclic alkynylcyclopentanols from aldehyde-tethered propargylic ester substrates, whereupon previous limitations of the use of these substrates are overcome.…”

Stereocontrol in Palladium‐Catalyzed Propargylic Substitutions: Kinetic Resolution to give Enantioenriched 1,5‐Enynes and Propargyl Acetates

“…While a number of methods have capitalized on these features resulting in catalytic carbon-carbon and carbon-heteroatom bond forming reactions, [2-4] there are few asymmetric variants. [3d, 5] This deficit is likely due to two issues: (1) unlike structurally similar (allyl)Pd intermediates that are configurationally dynamic, [6] both B and C are chiral and configurationally static, reflecting the configuration of the starting material after stereospecific S N 2′ addition of Pd; [7] (2) in the absence of significant steric bias, bond formation generally occurs from the (allenyl)Pd complex B to furnish chiral allene products of type D , [8,9] which are known to be susceptible to racemization by Pd even under mild conditions. [10] To address these issues, asymmetric Pd-catalyzed propargyl substitutions have relied on stereospecific couplings with optically enriched propargyl electrophiles, and are limited in scope to allene products that are biased against racemization based on electronics or sterics.…”