Asymmetric Synthesis of -Alkyl Amino Acids through a Biocatalytic Dynamic Kinetic Resolution of PEGylated -Alkyl Amino Esters.

The first examples of a practical procedure for a lipase-catalyzed dynamic kinetic resolution of PEGylated -alkyl amino esters is reported. This method allows for the preparation of a broad range of aromatic and aliphatic enantiomerically enriched -alkyl unnatural amino acids in up to 98% yield and 99% ee. We have found that PEGylated esters have a significant solubility advantage and improved reactivity over traditional hydrophobic lipase substrates, thereby allowing for efficient and scalable dynamic kinetic resolution (DKR) under aqueous conditions.

Stereocontrolled Synthesis of Arylomycin-Based Gram-Negative Antibiotic GDC-5338.

We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic . The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.

Macrolactamization Approaches to Arylomycin Antibiotics Core.

Two practical entries to arylomycin antibiotics core structures are investigated. In route A, the activation of l-Hpg for the key macrolactamization step is achieved in 89% yield in the presence of unprotected phenol and amine functionalities. Alternatively, a propanephosphonic acid anhydride (T3P)-promoted coupling between thel-Tyr and l-Ala moieties in route B led to a facile macrolactamization in 68% yield with a marked reduction in competing oligomerization.

Construction of Polycyclic β-Ketoesters Using a Homoconjugate Addition/Decarboxylative Dieckmann Annulation Strategy.

The construction of arene-fused cyclic β-ketoesters from 2-iodoaryl esters and 1,1-cyclopropane diesters is detailed. The synthetic method takes advantage of a CuI·SMe-mediated homoconjugate addition followed by a decarboxylative Dieckmann cyclization to afford valuable polycyclic building blocks. Various iodoaryl esters and 1,1-cyclopropane diesters were evaluated, and the limitations of both reactions are discussed.

Highly Efficient Synthesis of a Staphylococcus aureus Targeting Payload to Enable the First Antibody-Antibiotic Conjugate.

A practical synthesis of the complex payload for an anti-Staphylococcus aureus THIOMAB antibody-antibiotic conjugate (TAC) is described. The route takes advantage of a delicate oxidative condensation, achieved using a semi-continuous flow procedure. It allows for the generation of kilogram quantities of a key intermediate to enable a mild nucleophilic aromatic substitution to the tertiary amine free drug.

Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates.

The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been elusive. Here we describe a bioreversible linkage based on a quaternary ammonium that can be used to connect a broad array of tertiary and heteroaryl amines to a carrier protein.

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.

Enantioselective synthesis of gamma-hydroxyenones by chiral base-catalyzed Kornblum DeLaMare rearrangement.

A cinchona-alkaloid catalyzed asymmetric Kornblum DeLaMare rearrangement has been developed. Thus, enantioenriched 4-hydroxyenones are prepared from dienes by a two-step sequence involving photochemical dioxygenation and chiral base-catalyzed desymmetrization of the resulting endoperoxides.

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.

Mechanism and scope of the cyanide-catalyzed cross silyl benzoin reaction.

In this work, cross silyl benzoin addition reactions between acylsilanes (1) and aldehydes (2) catalyzed by metal cyanides are described. Unsymmetrical aryl-, heteroaryl-, and alkyl-substituted benzoin adducts can be generated in moderate to excellent yields with complete regiocontrol using potassium cyanide and a phase transfer catalyst. From a screen of transition metal cyanide complexes, lanthanum tricyanide was identified as an improved second-generation catalyst for the cross silyl benzoin reaction.

Metallophosphites as umpolung catalysts: the enantioselective cross silyl benzoin reaction.

Carbonyl polarity reversal (umpolung) has been realized employing metallophosphites as catalysts. As a result, nonenzymatic asymmetric cross silyl benzoin reactions have been achieved, giving optically active silyl ether-protected benzoin adducts. The reaction is general with respect to aryl, alkyl, and heterocyclic substrates with good to excellent yields and good to excellent enantioselectivities.

Tandem carbon-carbon bond constructions via catalyzed cyanation/Brook rearrangement/C-acylation reactions of acylsilanes.

[reaction: see text] A tandem nucleophile-catalyzed cyanation/Brook rearrangement/C-acylation has been developed. Phase transfer cocatalysts facilitate cyanide-catalyzed reactions between acylsilanes and cyanoformates to afford protected tertiary carbinol products. A catalytic cycle is proposed involving cyanation of an acylsilane, [1,2]-Brook rearrangement, and C-acylation of the derived carbanion by a cyanoformate ester.