PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (ß6 Glu → Val) on the ß-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

Chemoselective Preparation of Clickable Aryl Sulfonyl Fluoride Monomers: A Toolbox of Highly Functionalized Intermediates for Chemical Biology Probe Synthesis.

Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide-alkyne cycloaddition). The monomers can be used either as fragments to prepare clickable SF analogues of drugs (biologically active compounds) bearing an aryl ring or, alternatively, attached to drugs as minimalist clickable aryl SF substituents.

An Effective Bifunctional Aldehyde Linchpin for Type II Anion Relay Chemistry: Development and Application to the Synthesis of a C16-C29 Fragment of Rhizopodin.

The design, synthesis, and validation of a new bifunctional aldehyde linchpin for Type II anion relay chemistry have been achieved. For this linchpin, the initial nucleophilic addition proceeds under Felkin-Anh control to generate the syn-alkoxide, which undergoes a 1,4-Brook rearrangement to relay the negative charge, thus leading to the formation of a dithiane-stabilized carbanion. Subsequent trapping with an electrophile furnishes a tricomponent adduct with an embedded propionate subunit, a ubiquitous structural motif found in polyketides. The utility of this new linchpin is demonstrated with the construction of a potential C16-C29 fragment for the synthesis of rhizopodin, an actin-binding macrolide.

Visible-Light-Driven Photocatalytic Initiation of Radical Thiol-Ene Reactions Using Bismuth Oxide.

A nontoxic and inexpensive photocatalytic initiation of anti-Markovnikov hydrothiolation of olefins using visible light is reported. This method is characterized by low catalyst loading, thereby enabling a mild and selective method for radical initiation in thiol-ene reactions between a wide scope of olefins and thiols.

Access to Highly Substituted 7-Azaindoles from 2-Fluoropyridines via 7-Azaindoline Intermediates.

A versatile synthesis of 7-azaindoles from substituted 2-fluoropyridines is described. C3-metalation and 1,4-addition to nitroolefins provide substituted 2-fluoro-3-(2-nitroethyl)pyridines. A facile oxidative Nef reaction/reductive amination/intramolecular SNAr sequence furnishes 7-azaindolines. Finally, optional regioselective electrophilic C5-substitution (e.g., bromination or nitration) and subsequent in situ oxidation delivers highly functionalized 7-azaindoles in high overall efficiency.

Through-bond/through-space anion relay chemistry exploiting vinylepoxides as bifunctional linchpins.

The development of new bifunctional linchpins that permit the union of diverse building blocks is essential for the synthetic utility of anion relay chemistry (ARC). The design, synthesis, and validation of three vinylepoxide linchpins for through-bond/through-space ARC are now reported. For negative charge migration, this class of bifunctional linchpins employs initial through-bond ARC by an SN 2' reaction, followed by through-space ARC exploiting a 1,4-Brook rearrangement. The trans-disubstituted vinylepoxide linchpin yields a mixture of E/Z isomers, whereas the cis-disubstituted and the trans-trisubstituted vinylepoxide linchpins proceed to deliver three-component adducts with excellent E selectivity.

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,ß-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.

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.

Regioselective Reductive Cross-Coupling Reactions of Unsymmetrical Alkynes.

The present microreview summarizes our progress over the last few years in defining regioselective reductive cross-coupling reactions of unsymmetrical alkynes with terminal- and internal alkynes, aldehydes, and imines. We begin with a brief historical perspective of metal-mediated reductive dimerization reactions of aromatic alkynes and discuss the challenges associated with "crossed" versions of this mode of reactivity. Next, a collection of available methods that allow for regioselective reductive cross-coupling of internal alkynes with terminal and internal alkynes, aldehydes, and imines is summarized. After an examination of the requirements for regioselectivity in these cases, the logic behind our design of alkoxide-directed titanium-mediated reductive cross-coupling reactions is presented. A nomenclature is introduced to delineate the presumed mechanistic origin of regioselection associated with each reaction design, and a presentation of alkoxide-directed regioselective reductive cross-coupling reactions of alkynes follows. Throughout, principal issues related to reactivity and selectivity are discussed to assess scope and limitations of available methods and to describe the broad challenges that exist for defining complex fragment union reactions based on reductive cross-coupling chemistry.

Convergent synthesis of piperidines by the union of conjugated alkynes with imines: a unique regioselective bond construction for heterocycle synthesis.

A two-step process is described for the union of aromatic imines, conjugated alkynes, and aldehydes that results in a stereoselective synthesis of highly substituted piperidines. This synthetic process has been made possible by defining a unique regioselective functionalization of conjugated alkynes that establishes a suitably functionalized substrate for subsequent heterocycle-forming cationic annulation. Given the flexibility of the coupling process, heterocycles can be accessed through a process that establishes up to four stereogenic centers and four fused rings.