(Diisopinocampheyl)borane-Mediated Reductive Aldol Reactions of Acrylate Esters: Enantioselective Synthesis of <i>Anti</i>-Aldols

The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters <b>4</b> is described. Isomerization of the kinetically formed <i>Z</i>(O)<i>-</i>enolborinate <b>5</b><i><b>Z</b></i> to the thermodynamic <i>E</i>(O)-enolborinate <b>5</b><i><b>E</b></i> via 1,3-boratropic shifts, followed by treatment with representative achiral aldehydes, leads to <i>anti</i>-α-methyl-β-hydroxy esters <b>9</b> or <b>10</b> with excellent diastereo- (up to ≥20:1 dr) and enantioselectivity (up to 87% ee). The results of double asymmetric reactions of <b>5</b><i><b>E</b></i> with several chiral aldehydes are also presented

(Diisopinocampheyl)borane-Mediated Reductive Aldol Reactions of Acrylate Esters: Enantioselective Synthesis of <i>Anti</i>-Aldols

The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters <b>4</b> is described. Isomerization of the kinetically formed <i>Z</i>(O)<i>-</i>enolborinate <b>5</b><i><b>Z</b></i> to the thermodynamic <i>E</i>(O)-enolborinate <b>5</b><i><b>E</b></i> via 1,3-boratropic shifts, followed by treatment with representative achiral aldehydes, leads to <i>anti</i>-α-methyl-β-hydroxy esters <b>9</b> or <b>10</b> with excellent diastereo- (up to ≥20:1 dr) and enantioselectivity (up to 87% ee). The results of double asymmetric reactions of <b>5</b><i><b>E</b></i> with several chiral aldehydes are also presented

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 S_NAr 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

Early Process Development of Two Vanin‑1 Inhibitors: Solid Form Challenges and Control of Ambident Reactivity

Discovery chemistry efforts within Pfizer identified a new vanin-1 inhibitor, (S)-1, bearing a chiral methyl substituent, which exhibited an excellent profile as a potential drug-candidate selection except for the propensity to exist as an amorphous solid. Based on an improved solid form proposition, the project team chose to prioritize 2, the corresponding des-methyl compound. Both compounds were scaled to supply toxicology studies in preclinical species, and kilograms of compound 2 were manufactured to support the preclinical development work. The development of our synthetic chemistry and solid form work on this program are described in the paper. Included are computational studies to rationalize both an expected TBD-mediated epimerization as well as the control of ambident reactivity of activated 2-chloro-pyrimidine-5-carboxylic acid

Synthesis of Nirmatrelvir: Development of an Efficient, Scalable Process to Generate the Western Fragment

Nirmatrelvir (1), a novel and specific inhibitor of the SARS-CoV-2 3C-like protease, was developed by Pfizer scientists in mid 2020. Efforts to develop a scalable process to manufacture nirmatrelvir were undertaken with a great sense of urgency, as there were no effective treatments available for the worldwide patient population at that time. We used a convergent approach to generate this molecule. The first two steps used to generate the western fragment of nirmatrelvir from l-tert-leucine, ethyl trifluoroacetate, and a [3.1.0] bicyclic proline derivative are described here. This is the first of a series of four papers describing the commercial process of the development of nirmatrelvir