The Pd-catalyzed cross coupling of terminal allylic carbonates and allylB(pin) is described. The regioselectivity of this reaction is sensitive to the bite angle of the ligand with small bite angle ligands favoring the branched substitution product. This mode of regioselection is consistent with a reaction that operates by a 3,3′ reductive elimination reaction. In the presence of appropriate chiral ligands, this reaction is rendered enantioselective and applies to both aromatic and aliphatic allylic carbonates.The Pd-catalyzed cross-coupling of organic electrophiles with organometallic reagents, especially organoboron derivatives, is broadly developed and has made a significant impact on the way complex molecules are prepared.1 One exception to this generalization is the cross-coupling of substituted allylmetal reagents. This reaction has received less attention but holds significant promise for asymmetric synthesis;2 recently reported Pd-catalyzed enantioselective couplings of crotyl boronates and aryl electrophiles are illustrative.3 Similarly, the cross coupling of allylmetal reagents with allyl electrophiles is attractive because it has the capacity to establish two new stereocenters with concomitant formation of an sp3-sp3 carbon-carbon bond.4 This catalytic reaction is also not well developed, perhaps because of the propensity for π-allyl intermediates to undergo β-hydride elimination5 (delivering 1,3-dienes) and perhaps because these reactions often lack regioselectivity or favor achiral products. Indeed, unlike the isoelectronic decarboxylative allylation of allyl enol carbonates6 and Tsuji-Trost reaction with preformed enolates,7 the allyl-allyl coupling does not benefit from an inherent regiocontrol bias. In this report, we present a paradigm for regiocontrol in allyl-allyl coupling reactions and use it to establish highly regio-and enantioselective catalytic variants.Recent studies in our laboratory have focused on the transition metal catalyzed enantioselective addition of allylboronates to unsaturated carbonyls.8 These reactions proceed by way of oxygenated bis(allyl)metal species with a 3,3′-reductive elimination being responsible for construction of the C-C bond. The 3,3′-reductive elimination mechanism, as put forward by Echavarren, operates when coordination of a ligand to a bis(allyl)metal species causes both allyl groups to adopt the η1 bonding mode (B , Scheme 1) instead of the more common η3 mode (as in A).4j , 9 We surmised that in the case of simple allyl-allyl cross coupling, bidentate ligands would be most effective at prompting the bis(η1-morken@bc.edu. Supporting Information Available: Characterization and procedures. This information is available free of charge through the internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2011 August 11. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript allyl) bonding mode and that, if the allyl groups are able to rapidly isomerize at some point on th...

The palladium catalyzed allyl-allyl cross-coupling was investigated with substituted prochiral allylic boronates. These reactions deliver products bearing adjacent stereocenters and the issue of diastereocontrol is therefore paramount. Under appropriately modified conditions, this allyl-allyl coupling strategy was found to apply to a range of substrates, generally occurring with high enantioselectivity (92:8 – >99:1 er) and good diastereoselection (4:1 – 14:1 dr).

The use of unsaturated methylidene ketones in catalytic conjugate allylations allows for a significant expansion in substrate scope and, with appropriate chiral ligands, occurs in a highly enantioselective fashion.Catalytic enantioselective conjugate addition of organometallic reagents to unsaturated carbonyls is an important method in asymmetric synthesis. These reactions are usually accomplished under the aegis of late transition metal catalysts and occur with a broad variety of organometallic reagents. 1 While significant successes have been recorded with aryl, alkyl, vinyl, and alkynyl nucleophiles, reactions of allylmetal reagents are much less developed. In recent studies, we have addressed this limitation and have introduced an enantio-and regioselective catalytic conjugate addition of allylB(pin) (2 , Scheme 1) to arylidene alkylidene ketones (1). 2 Mechanistic studies suggest that this reaction proceeds by way of Lewis acid-induced oxidative addition of the metal to the less hindered alkylidene enone (to give I), followed by transmetallation and 3,3′-reductive elimination 3 via transition state II. 4 Thus for substrate 1, the hexylidene group functions as an activator for allylation of an aryl-substituted enone. While this strategy is effective, it leaves a gap in technology for the selective allylation of alkyl-substituted enones. 5 In this manuscript, we address this issue and describe a general strategy that is effective for the regio-and enantioselective allylation of both aromatic and aliphatic substituted enones.Under the paradigm described above, it appeared plausible that a general catalytic allylation of both aryl-and alkyl-substituted enones might arise from reactions of methylidenesubstituted enones such as 3 (Table 1). In this scenario, oxidative addition of the transition metal to the less hindered methylidene site would be favored, and subsequent 3,3′ reductive elimination would deliver the allyl group to the adjacent internal prochiral alkene. An initial experiment probing this strategy was conducted with Taddol-derived phosphonite ligand L1 6 (Taddol = trans-4,5-Bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane), the most effective ligand for conjugate allylation of arylidene alkylidene ketones (1). In the event, morken@bc.edu. Supporting Information Available. Complete experimental procedures and characterization data ( 1 H and 13 C NMR, IR, and mass spectrometry). This material is free of charge via the internet at http://pubs.acs.org. (Table 1) in the presence of 5 mol % Ni(cod) 2 , 6 mol % ligand L1 and 1.2 equiv of allylB(pin), provided addition product 4 with high regioselectivity and moderate enantiocontrol (entry 1). This encouraging result prompted further study. Examination of ligand structure L1 with Pd 2 (dba) 3 (entry 2) revealed that the regioselectivity was slightly enhanced with Pd relative to Ni; however, the enantioselectivity was diminished. To improve enantioselection a number of other Taddolderived phosphorus ligands were examined, and a selection of results ...

Catalytic enantioselective allyl-allyl cross-coupling of a borylated allylboronate reagent gives versatile borylated chiral 1,5-hexadienes. These compounds may be manipulated in a number of useful ways to give functionalized chiral building blocks for asymmetric synthesis.

Catalytic Enantioselective Allyl-Allyl Cross-Coupling with a Borylated Allylboronate. -Highly enantioselective cross-coupling reactions between the borylated allylboronate (I) and various allylic chlorides are described. Different chiral ligands are required for the cross-coupling reaction of allylic chlorides bearing cycloaliphatic or aromatic substituents on the one hand and aliphatic substituted allyl chlorides on the other hand. The latter tend toward predominant elimination reactions otherwise. -(LE, H.; KYNE, R. E.; BROZEK, L. A.; MORKEN*, J. P.; Org. Lett. 15 (2013) 7, 1432-1435, http://dx.