KeywordsClaisen rearrangement; organocatalysis; asymmetric catalysis; Density-functional calc; H bonding The selective construction of contiguous quaternary stereogenic centers, a motif found in many complex natural products, represents a significant synthetic challenge. We reported recently that the achiral guanidinium ion 1, bearing a non-coordinating tetraarylborate counterion, is a viable catalyst for the [3,3]-sigmatropic rearrangement of a wide range of substituted allyl vinyl ethers. [6] Rearrangements that proceed through highly dipolar transition structures were found to be particularly amenable to acceleration by ** This work was supported by the NIH (GM-43214). We acknowledge Matthew Rienzo for experimental assistance and Dr. Richard Staples for X-ray analysis.

Glycosyl phosphates are shown to be activated to stereospecific nucleophilic substitution reactions by precisely tailored bis-thiourea catalysts. Enhanced reactivity and scope is observed with phosphate relative to chloride leaving groups. Stronger binding (Km) to the H-bond donor and enhanced reactivity of the complex (kcat) enables efficient catalysis with broad functional group compatibility under mild, neutral conditions.

The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described. Part 1 of this two-part series details the design and execution of a classical resolution to generate atropisomer M-1 from a racemic precursor (rac-1). In parallel, the team sought to develop a racemization process to enable recycling of the classical resolution waste stream and maximize productivity and sustainability. Computational and experimental methods revealed a high barrier to rotation (ca. 42 kcal/mol) prompting the design of a high-temperature (>300 °C) racemization protocol for recovery of the racemic compound. Described herein are the determination of the barrier to rotation, optimization of conditions to enable racemization, proof-of-concept for a continuous-flow process to execute the process, and kilogram-scale demonstration, including (1) recovery of the undesired atropisomer as a crystalline solid from the classical resolution waste stream, (2) thermal racemization by a high-temperature continuous-flow process, and (3) isolation of the racemic compound by crystallization directly from the reaction stream.

The selective construction of contiguous quaternary stereogenic centers, a motif found in many complex natural products, represents a significant synthetic challenge. [1] Among the limited number of approaches for the formation of bonds between such sterically congested carbon atoms, intramolecular processes such as polyene cyclizations, [2a,b] intramolecular cycloadditions, [2c] and sigmatropic rearrangements [2d,e] have been particularly effective. For addressing vicinal quaternary carbons, these transformations have only been applied in a diastereocontrolled manner using substrates containing pre-existing stereogenic centers, either as part of cleavable auxiliaries or structural features of the target molecule. The development of catalytic asymmetric methods for the direct and selective formation of such stereochemical arrays represents a highly desirable and challenging goal.Since its discovery in 1912, [3] the [3,3]-sigmatropic rearrangement of allyl vinyl ethers (the Claisen rearrangement) has emerged as a proven strategy for the formation of carboncarbon bonds between vicinal stereogenic centers. [4] Diastereoselectivity is generally predictable and high in these processes because of the concerted nature of the C À O bond-breaking and CÀC bond-forming events as well as the large energetic preference for chair-like over boat-like transition states. Furthermore, important examples of enantioselective methods for Claisen rearrangements involving Lewis acid catalysis [5] have been identified recently for select substrates with chelating functional groups.We reported recently that the achiral guanidinium ion 1, bearing a non-coordinating tetraarylborate counterion, is a viable catalyst for the [3,3]-sigmatropic rearrangement of a wide range of substituted allyl vinyl ethers. [6] Rearrangements that proceed through highly dipolar transition structures were found to be particularly amenable to acceleration by hydrogen-bond donors. Substrates that meet this requirement possess either electron-donating substituents on the allyl group or electron-withdrawing substituents on the vinyl group in order to stabilize developing charge. In accord with this observation, the addition of 1 at 5 mol % loading induces rearrangement of b-ketoester derivative 3 to high levels of conversion. Notably, the diastereoselectivity is also enhanced under the guanidinium-catalyzed conditions (Scheme 1).Here we report the discovery of chiral guanidiniumcatalyzed Claisen rearrangements of cyclic O-allyl b-ketoesters as a method of broad scope for the formation of branched allylation products with both enantio-and diastereocontrol. While direct catalytic enantioselective allylations of bketoester nucleophiles, such as by phase-transfer alkylation [7a,b] or p-allyl metal chemistry, [7c-e] are highly effective with simple unsubstituted allyl electrophiles, regioselectivity for branched allylation and diastereoselectivity using more substituted electrophiles have proven to be difficult to achieve and highly dependent on the identity of t...

The last decade of small-molecule process development has witnessed a trend of increasing molecular complexity for clinical candidates. The continued advance of novel catalytic methods and subsequent translation to efficient and scalable processes has enabled process chemists to overcome the challenges associated with increasing complexity. This Account highlights several examples from the process chemistry laboratories at Amgen.1 Introduction2 The Evolution of Molecular Complexity3 Catalysis as a Lever to Build Complexity4 Ru(II)-Catalyzed Dynamic Kinetic Resolution Enabling the Manufacture of AMG 2325 Application of Enzymatic Desymmetrization toward Scale-Up of the MCL-1 Inhibitor AMG 1766 Synthesis of Fucostatin 1: Catalytic Asymmetric Transfer Hydrogenation7 Manganese-Catalyzed Asymmetric Epoxidation To Prepare a Carfilzomib Intermediate8 Asymmetric Reduction Strategies: Novel Apelin Receptor Agonists and AMG 9869 Conclusions