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The HR2331-M06 fragment developed by Hiray Pharma Solutions is a critical structural component of the non-peptidic GLP-1 receptor agonist orforglipron. Following extensive research, the Lilly team has developed a scalable and industrially viable process route for HR2331-M06: the key intermediate HR2331-M04（CAS：3047292-99-6）was constructed via an Evans auxiliary-controlled asymmetric 1,4-selective allylic alkylation via conjugate addition；Subsequently following reduction, removal of the Evans chiral auxiliary, and cyclization to form a saturated pyran ring, the key HR2331-M06 fragment was successfully synthesized. The stereochemical control in the construction of the HR2331-M06 fragment via Evans auxiliary-mediated asymmetric allylic alkylation through conjugate addition is critically dependent on the suppression of the diastereomeric impurity ent-M04 generated during the synthesis of HR2331-M04.

Research has demonstrated that the diastereomeric impurity ent-M04 must be controlled below 1.5% at this stage to effectively limit the formation of enantiomeric impurities in HR2331-M06 during subsequent derivatization and transformation steps. To achieve such control, a preliminary investigation into the formation mechanism of ent-M04 was conducted.

The reaction of BL2331-M04 involves a 1,4-addition of an organocopper reagent to an α,β-unsaturated carbonyl compound, facilitated by a benzyl oxazolidinone-based Evans chiral auxiliary.

The challenge associated with its chiral induction lies in the difficulty of achieving high stereoselectivity under the given reaction conditions:

1. In contrast to the rigid framework of cyclic α,β-unsaturated carbonyl compounds, the α-carbonyl moiety in the BL2331-M03 substrate exhibits free rotation, giving rise to both S-trans and S-cis conformers, thereby presenting challenges for effective chiral induction.

2. The indole N-H moiety in HR2331-M03 exhibits moderate acidity, with a pKa value of approximately 16. In the 1,4-chiral induction addition reaction converting M03 to M04 using an allyl Turbo Grignard reagent in the presence of CuCl, the reaction environment is highly basic, leading to deprotonation of the indole N-H group. The resulting negative charge can be delocalized through conjugation to the α,β-unsaturated carbonyl system of the activated carbonyl moiety, thereby reducing the double-bond character of the α,β-unsaturated bond and rendering it effectively freely rotatable. This conformational flexibility presents a significant challenge to stereocontrol, as interconversion between the S-trans and S-cis conformers becomes feasible. The S-trans conformation reacts selectively with the allyl copper species to afford the desired product, whereas the S-cis conformation leads to the formation of the undesired diastereomer of M04. 

3.The initial reaction conditions for synthesizing HR2331-M04 were as follows: Substrate BL2331-M03 was pretreated with LiHMDS in THF, followed by reaction with the organocopper reagent derived from allylmagnesium chloride Turbo Grignard reagent at temperatures below -40 °C. There is reason to believe that the structural state of the Turbo Grignard reagent in solution also has a very direct impact on the chiral induction addition reaction.

In addition to organolithium compounds, Grignard reagents RMgX are among the most widely used reactive reagents in synthesis. It is therefore not surprising that much effort has been devoted to structural elucidation both in the solid state and in solution, since knowing the structure of highly reactive reagents is of essential importance when it comes to understanding the principles governing the high reactivity. When the structural characteristics of these compounds are understood, tuning of the reactivity becomes possible. This holds especially true for the “turbo Grignard” reagent iPrMgCl·LiCl (1(iPr)·LiCl), introduced by Knochel et al., which possesses a high kinetic basicity, favoring halogen/magnesium exchange on substituted aromatic and heteroaromatic halides over nucleophilic attack on sensitive functional groups such as cyano, ester, etc. Furthermore, the solubility of the resulting arylmagnesium species is improved, due to the presence of LiCl.

However, up to now only a suggestion of the mode of action of LiCl on the Grignard reagent has been made in the literature: namely, deaggregation of RMgX oligomers and coordination of LiCl with formation of a four-membered MgCl-LiCl ring.

Schlenk Equilibrium of Turbo Grignard Reagents

Similarly, in solution, a complex Schlenk equilibrium is also present for Grignard reagents.

Schlenk Equilibrium of Grignard Reagents

Therefore, controlling the Schlenk equilibrium of both the conventional Grignard reagents and Turbo Grignard reagents presents significant challenges. Factors such as temperature, concentration, and the presence of additives can influence the equilibrium, resulting in poor process reproducibility and compromising the overall robustness of the reaction system.

Benn and co-workers21a demonstrated that the Schlenk equilibrium between EtMgBr and Et₂Mg in Et₂O favored the solvent-coordinated monoalkylmagnesium species EtMgBr-OEt₂. By contrast, in THF, R₂Mg and MgBr₂ are the dominant species present in solution. Furthermore, it is known that the Schlenk equilibrium can be driven, partially, toward the formation of R₂Mg in any solvent by the addition of dioxane to a solution of the Grignard reagent.

Copper-promoted asymmetric reactions frequently attain high enantioselectivity through reduction in substrate conformational mobility via two-point binding, as in the general copper(I) cuprates 1a,b or by η²-binding at chiral Cu^II complexes, generalized by 2. As copper(II) does not form organometallic species, and readily undergoes reduction to Cu^I .

Generalized binding modes for Cu-promoted activation of prochiral substrates where MR is a main group organometallic, X is a halogen, D is a generalized two electron donor, and ‘‘bridge’’ is a generalized anionic ligand. Of course, Extension to analogous isoelectronic fragments (e.g., NRfor O, etc.) is possible.

Our research findings indicated that the reactions of monoalkyl Grignard reagents (RMgBr) and dialkyl Grignard reagents (R₂Mg) with cuprous ions generated distinct active copper species, which led to alterations in the mechanism of the 1,4-asymmetric addition reaction. Neutral alkylcopper reagents resulted in a substantial decrease in both regioreactivity and enantiomeric excess (e.e.) value.

Given the aforementioned challenges, extensive research has led to the identification of an optimal control strategy. Diastereomeric formation was effectively suppressed during the reaction (diastereomeric ratio <1.5%), and process robustness was significantly enhanced, enabling successful pilot-scale amplification.