Stereospecific and Stereodivergent Construction of Tertiary and Quaternary Carbon Centers through Switchable Directed/Nondirected Allylic Substitution

This study introduces the ortho‐diphenylphosphanylbenzoate (o‐DPPB)/o‐DPPB oxide system as a switchable directing/nondirecting leaving group in a copper‐mediated allylic substitution with Grignard and organozinc reagents. With this system, the regioselective, stereospecific, and stereodivergent construction of quaternary as well as tertiary carbon centers is possible in a reliable and predictable fashion. Starting from one substrate enantiomer, both optical antipodes of the substitution products are readily available. Hence, this methodology features reversed polarity in comparison to established enolate alkylation chemistry and may be an interesting alternative, particularly for the construction of quaternary stereogenic carbon centers.     

Iterative deoxypropionate synthesis based on a copper-mediated directed allylic substitution: formal total synthesis of borrelidin (C3-C11 fragment)

A new iterative strategy for the flexible preparation of any oligodeoxypropionate stereoisomer is presented which relies on an o-DPPB-directed copper mediated allylic substitution employing enantiomerically pure Grignard reagents; the reaction is working with perfect control over all aspects of the reaction selectivity. This key C--C bond-forming step features reversed polarity compared with established enolate alkylation methodology. It thus avoids existing problems of enolate alkylation strategies such as enolate reactivity as well as costs and problems associated with the chiral auxiliary. Practicability of this new method is demonstrated through application in natural product syntheses. Thus, an efficient synthesis of the northern part of the angiogenesis inhibitor borrelidin (28), the deoxypropionate building block 27, could be devised, representing a formal total synthesis.     

Stereoselective synthesis of trisubstituted olefins by a directed allylic substitution strategy

New methodology for the stereoselective synthesis of trisubstituted olefins is presented. The use of ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing leaving group for copper-mediated allylic substitution with Grignard reagents allowed for the stereoselective construction of a wide range of E olefins, without the need for an adjacent electron-withdrawing group. Our modular three-step approach toward trisubstituted alkenes commenced with geminal α-methylene aldehydes. Addition of an organometallic reagent and introduction of the o-DPPB group by esterification was followed by the o-DPPB-directed copper-mediated allylic substitution with a Grignard reagent to furnish stereodefined trisubstituted olefins. Additionally, incorporation of a stereocenter from the chiral pool allowed the preparation of an enantiomerically pure olefin that bore three alkyl substituents in high E/Z selectivity.     

o-DPPB-directed copper-mediated and -catalyzed allylic substitution with Grignard reagents

The ortho-diphenylphosphanylbenzoyl (o-DPPB) group was explored as a directing leaving group in copper-mediated and copper-catalyzed allylic substitution with Grignard reagents. Complete control of chemo-, regio- and stereoselectivity with complete syn-1,3-chirality transfer was observed as a result of the directed nature of the reaction. No excess of organometallic reagent is required and the directing group can be recovered quantitatively. Coordination studies in the solid state and in solution have shown that two substrates are bound via the phosphine function of the directing group at copper. Dynamic NMR experiments in solution are in agreement with a ligand-exchange process at copper, a prerequisite for the development of a substoichiometric process.     

A Unified Strategy for the Stereospecific Construction of Propionates and Acetate–Propionates Relying on a Directed Allylic Substitution

Flexible friends : A new strategy that relies on o‐DPPB‐directed allylic substitution has been implemented for the flexible and stereospecific construction of major polyketide and isoprenoid structural elements (see scheme; o‐DPPB=ortho‐diphenylphosphanyl benzoate; PG=protecting group).

     

Site- and enantioselective formation of allene-bearing tertiary or quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution

Catalytic enantioselective allylic substitutions that result in addition of an allenyl group (<2% propargyl addition) and formation of tertiary or quaternary C-C bonds are described. Commercially available allenylboronic acid pinacol ester is used. Reactions are promoted by a 5.0-10 mol % loading of sulfonate-bearing chiral bidentate N-heterocyclic carbene (NHC) complexes of copper, which exhibit the unique ability to furnish chiral products arising from the S(N)2' mode of addition. Allenyl-containing products are generated in up to 95% yield, >98% S(N)2' selectivity, and 99:1 enantiomeric ratio (er). Site-selective NHC-Cu-catalyzed hydroboration of enantiomerically enriched allenes and conversion to the corresponding β-vinyl ketones demonstrates the method's utility.     

Asymmetric construction of quaternary carbon stereocenter by Pd-hemilabile ligand-catalyzed allylic substitution

The catalyst comprised [PdCl(η³-C₃H₅)]₂ and a simple chiral hemilabile ferrocene ligand, 1′,2-bis(diphenylphosphinoethyl)ferrocenyl alcohol, provides synthetically acceptable results for an enantioselective Pd-catalyzed allylic alkylation of cyclohexanone derivatives bearing an electron-withdrawing group at the α-position to form the quaternary carbon with up to 90% enantioselectivity under mild reaction conditions.     

Absolute asymmetric synthesis of "chiral-at-metal" Grignard reagents and transfer of the chirality to carbon

Two new six-coordinate Grignard reagents, cis-[(p-CH(3)C(6)H(4))MgBr(dme)(2)] (1) and cis-[MgCH(3)(thf)(dme)(2)]I (2), have been synthesized and their crystal structures have been determined. Both reagents are cis-octahedral and therefore chiral. They crystallize as conglomerates and racemize rapidly in solution. By utilizing these properties, the absolute asymmetric synthesis of specifically the Delta or the Lambda enantiomer was achieved for both Grignard reagents. Enantiopure 1 and 2 were then reacted with butyraldehyde or benzaldehyde to give the corresponding alcohol in up to 22 % enantiomeric excess. At -60 degrees C, the Grignard reagents crystallize as racemic phases instead of conglomerates. Consequently, the crystal structures of rac-cis-[(p-CH(3)C(6)H(4))MgBr(dme)(2)].DME (3) and rac-cis-[MgCH(3)(thf)(dme)(2)]I (4) could be determined.     

Asymmetric Total Synthesis of (−)‐Erogorgiaene and Its C‐11 Epimer and Investigation of Their Antimycobacterial Activity

A short, nine‐step, highly enantioselective synthesis of (?)‐erogorgiaene and its C‐11 epimer is reported. The key stereochemistry controlling steps involve catalytic asymmetric crotylation, anionic oxy‐Cope rearrangement and cationic cyclisation. (?)‐Erogorgiaene exhibited promising antitubercular activity against multidrug‐resistant strains of Mycobacterium tuberculosis.