Glenn C. Micalizio

Three-Component Coupling Sequence for the Regiospecific Synthesis of Substituted Pyridines

A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control.

A biomimetic polyketide-inspired approach to small-molecule ligand discovery

The discovery of new compounds for the pharmacological manipulation of protein function often embraces the screening of compound collections, and it is widely recognized that natural products offer beneficial characteristics as protein ligands. Much effort has therefore been focused on “natural product-like” libraries, yet the synthesis and screening of such libraries is often limited by one or more of the following: modest library sizes and structural diversity, conformational heterogeneity, and the costs associated with the substantial infrastructure of modern high-throughput screening centers. Here, we describe the design and execution of an approach to this broad problem by merging principles associated biologically-inspired oligomerization and the structure of polyketide-derived natural products. A novel class of chiral and conformationally-constrained oligomers is described (termed “chiral oligomers of pentenoic amides” – COPAs) that offers compatibility with split-and-pool methods and can be screened en masse in a batch mode. We demonstrate that a COPA library containing 160,000 compounds is a useful source of novel protein ligands by identifying a non-covalent synthetic ligand to the DNA-binding domain of the p53 transcription factor.

Convergent and stereospecific synthesis of complex skipped polyenes and polyunsaturated fatty acids

Skipped polyenes (that is, 1,4-dienes and higher homologues) are stereodefined components of a vast array of biologically important natural products, including polyunsaturated fatty acids. Although widespread in nature, these architectures are generally considered to represent significant barriers to efficient chemical synthesis. Partial reduction of skipped poly-ynes provides a pathway to a subset of such structures, but general chemical methods for the preparation of skipped polyenes that contain varied stereochemistries and substitution patterns are lacking. Here, we describe a metal-promoted reductive cross-coupling reaction between vinylcyclopropanes and alkynes (or vinylsilanes) that provides stereoselective access to a diverse array of skipped polyenes through a process that establishes one C?C bond, generates up to three stereodefined alkenes, and can be used to introduce stereogenic centres at the central positions of the skipped polyene motif. We also demonstrate the significance of the present bond construction by preparing substituted and stereodefined polyunsaturated synthetic fatty acids. A convergent route to stereodefined skipped polyenes, which proceeds through the direct union of vinylcyclopropanes with alkynes, is described. Overall, C?C bond formation occurs in concert with the establishment of up to three stereodefined alkenes, through a tandem stereoselective metallacycle-mediated coupling/stereospecific fragmentation sequence.

Complex Allylation by the Direct Cross-Coupling of Imines with Unactivated Allylic Alcohols†

Regioselective, stereoselective: The convergent coupling of allylic alcohols with imines to deliver stereodefined homoallylic amines is described (see scheme). The process proceeds with net allylic transposition without the intermediacy of allylic organometallic reagents. Two stereodefined centers and a geometrically defined di- or trisubstituted alkene are forged with high selectivity.

Metallacycle-mediated cross-coupling with substituted and electronically unactivated alkenes

This perspective surveys the history of- and recent advances in- metallacycle-mediated coupling chemistry of substituted alkenes. While the reaction of preformed metal-π complexes with ethylene was reported nearly 30 years ago, the generalization of this mode of bimolecular C-C bond formation to the regio- and stereoselective union of complex substrates has only recently begun to emerge. This perspective discusses early observations in this area, the challenges associated with controlling such processes, the evolution of a general strategy to overcome these challenges, and a summary of highly regio- and stereoselective convergent coupling reactions that are currently available by metallacycle-mediated cross-coupling with substituted alkenes.

Preparation of Stereodefined Homoallylic Amines from the Reductive Cross-Coupling of Allylic Alcohols with Imines

Regio-, diastereo-, and enantioselective coupling reactions between imines and allylic alcohols have been developed. These coupling reactions deliver complex homoallylic amine products through a convergent C-C bond forming process that does not proceed through intermediate allylic organometallic reagents. In general, convergent coupling, by exposure of an allylic alkoxide to a preformed Ti-imine complex, occurs with allylic transposition in a predictable and stereocontrolled manner. While simple diastereoselection in these reactions is high, delivering anti-products with ≥20:1 selectivity, the organometallic transformation described is compatible with a diverse range of functionality and substrates (including aliphatic and aromatic imines, allylic silanes, trisubstituted alkenes, vinyl- and aryl halides, trifluoromethyl groups, thioethers, and aromatic heterocycles). Alkene geometry of the products is a complex function of the allylic alcohol structure and is consistent with a mechanistic proposal based on syn-carbometalation followed by syn-elimination by way of a boat-like transition state geometry. Single asymmetric coupling reactions provide a means to translate the stereochemical information of the allylic alcohol to the homoallylic amine or to control diastereoselection in the coupling reactions of achiral allylic alcohols with chiral imines. Double asymmetric coupling reactions are also described that afford a unique means to control stereoselection in these complex convergent coupling processes. Finally, empirical models are proposed that are consistent with the observed stereochemical course of these coupling reactions en route to chiral homoallylic amines possessing di- or trisubstituted alkenes and anti- or syn- relative stereochemistry at the allylic and homoallylic positions.

Total Synthesis and Structure Elucidation of (+)-Phorbasin C

The first total synthesis and structure elucidation of a member of the phorbasin class of natural products is described.

[(E)-γ-(Dimethylphenylsilyl)allyl]diisopinocampheylborane: a highly enantioselective reagent for the synthesis of anti-β-hydroxyallylsilanes ☆

Abstract anti -β-Hydroxyallylsilanes are prepared with 88–95% e.e. via the asymmetric allylboration reactions of aldehydes and [( E )-γ-(dimethylphenylsilyl)allyl]diisopinocampheylborane ( 7 ).

Total Synthesis of Lehualide B by Allylic Alcohol–Alkyne Reductive Cross-Coupling

The total synthesis of anticancer marine natural product lehualide B is described. Overall, the synthesis proceeds in just eight steps from a simple gamma-pyrone, does not require the use of protecting groups, and delivers each nonconjugated trisubstituted alkene with high levels of stereoselection. The challenging C12-C16 bis-trisubstituted 1,4-diene was installed with a complex reductive cross-coupling reaction between a preformed Ti-alkyne complex and a pyrone-containing allylic alcohol.

Chemoselective Reductive Cross-Coupling of 1,5-Diene-3-ols with Alkynes: A Facile Entry to Stereodefined Skipped Trienes

A convergent synthesis of highly substituted and stereodefined skipped polyenes is described from the reductive cross-coupling of substituted 1,5-diene-3-ols with alkynes. The control of site selectivity in functionalization of the substituted diene is a central feature of this complex fragment union reaction.