Bioisosteric Tactics in the Discovery of Tetflupyrolimet: A New Mode-of-Action Herbicide.

The last new herbicidal modes-of-action with commercial significance were introduced to the marketplace multiple decades ago. Serious weed resistance to most herbicidal classes have since emerged with widespread use. Aryl pyrrolidinone anilides represent an entirely new mode-of-action class of herbicides that interfere with de novo pyrimidine biosynthesis in plants via inhibition of dihydroorotate dehydrogenase. The chemical lead for this new herbicide class discovery was identified from high-volume sourced greenhouse screening that required structural reassignment of the hit molecule followed by an extensive synthetic optimization effort. With excellent grass weed control and pronounced safety on rice, the selected commercial development candidate has a proposed common name of tetflupyrolimet and represents the first member of the new HRAC (Herbicide Resistance Action Committee) Group 28. This paper describes the discovery path to tetflupyrolimet with an added focus on the bioisosteric modifications pursued in optimization, including replacements of the lactam core itself.

Silyl glyoxylates. Conception and realization of flexible conjunctive reagents for multicomponent coupling.

This Perspective describes the discovery and development of silyl glyoxylates, a new family of conjunctive reagents for use in multicomponent coupling reactions. The selection of the nucleophilic and electrophilic components determines whether the silyl glyoxylate reagent will function as a synthetic equivalent to the dipolar glycolic acid synthon, the glyoxylate anion synthon, or the α-keto ester homoenolate synthon. The ability to select for any of these reaction modes has translated to excellent structural diversity in the derived three- and four-component coupling adducts. Preliminary findings on the development of catalytic reactions using these reagents are detailed, as are the design and discovery of new reactions directed toward particular functional group arrays embedded within bioactive natural products.

Palladium-catalyzed 1,1-aryloxygenation of terminal olefins.

This paper describes the 1,1-arylacetoxylation of diverse α-olefins using organostannanes and hypervalent iodine oxidants. The reaction provides a convergent approach for generating a C-C and a C-O bond as well as a new stereocenter in a single catalytic transformation.

Palladium-catalyzed oxidative arylhalogenation of alkenes: synthetic scope and mechanistic insights.

This article describes the development of a Pd-catalyzed reaction for the arylhalogenation (halogen = Cl or Br) of diverse alpha-olefins by oxidatively intercepting Mizoroki-Heck intermediates. These transformations afford synthetically useful 1,2- and 1,1-arylhalogenated products in good yields with good to excellent selectivities that can be modulated by changing the nature of the halogenating reagent and/or the reaction conditions. The selectivity of these reactions can be rationally tuned by (i) controlling the relative rates of oxidative functionalization versus beta-hydride elimination from equilibrating Pd(II)-alkyl species and (ii) stabilization of organometallic Pd(II) intermediates through the formation of pi-benzyl adducts. These arylhalogenations exhibit modest to excellent levels of stereoselectivity, and the key carbon-halogen bond-forming step proceeds with predominant retention of stereochemistry at carbon.

Self-consistent synthesis of the squalene synthase inhibitor zaragozic acid C via controlled oligomerization.

Despite the prevalence of repeating subunits in chiral natural products, stereocontrolled oligomerization is a largely unexplored strategy for construction of carbon skeletal frameworks. This report describes the use of silyl glyoxylates as dipolar glycolic acid synthons in a controlled oligomerization reaction for the efficient construction of the squalene synthase inhibitor zaragozic acid C. This new methodology allows rapid, stereocontrolled formation of the carbon skeleton with a desirable protecting group scheme while minimizing functional group repair and oxidation state manipulations.

Mild and adaptable silver triflate-assisted method for trityl protection of alcohols in solution with solid-phase loading applications.

Trityl ethers were prepared in solution in a matter of minutes by treating trityl chloride with silver triflate in the presence of alcohols. Yields were comparable or better than known literature methods. The method was compatible with the base-labile Fmoc protecting group of amino alcohols and adapted for trityl protection of halo-containing alcohols. These base- and nucleophile-sensitive intermediates were anchored on trityl resin and further functionalized, displaying the utility of this approach for future combinatorial applications.

Symbiotic reagent activation: Oppenauer oxidation of magnesium alkoxides by silylglyoxylates triggers second-stage aldolization.

The treatment of silylglyoxylates with magnesium alkoxides at ambient temperature results in symbiotic Oppenauer oxidation of the alkoxide and Meerwein-Ponndorf-Verley reduction of the silylglyoxylate. The reduced silylglyoxylate undergoes subsequent [1,2]-Brook rearrangement and aldol reaction with the carbonyl oxidation product. The magnesium alkoxide may be accessed via deprotonation of primary or secondary alcohols with EtMgBr, via addition of Grignard reagents to aldehydes, or via CuI-catalyzed alkylation of epoxides. For aliphatic primary alkoxides, moderate levels of anti diastereoselection are observed. A crossover experiment reveals that dissociation of the nascent aldehyde from the magnesium center is faster than [1,2]-Brook rearrangement and aldolization.