Development of organic reactions that productively leverage physical properties

Abstract

Crystallization-induced stereoconvergent Michael additions demonstrate the potential of using physical properties to reveal unique reactivity.

Catalytic, crystallization-induced π-bond additions show that product physical properties can drive stereoconvergence.

INTRODUCTION

The discovery and development of efficient catalytic reactions for the preparation of complex molecules (1) is an area of intense focus in organic synthesis (2). Within the tremendous progress on catalytic organic reactions over the past few decades, a common trend has emerged: Reaction development in academic laboratories has understandably tended to take a “transition state” approach toward optimization studies by focusing on the interactions that guide selectivity and efficiency in the bond-forming event. This approach has enabled the discovery of powerful organic reactions for the synthesis of structurally complex small molecules; however, the user-friendliness of published methods is at times untested or murky, and difficult isolations or limited scalability can impinge on the ability for the practicing chemist to easily access the pure desired product (3). A provocative hypothesis for this bifurcation could be that the advent of flash column chromatography (4)—a reliable, robust, and undeniably enabling technology that carries inherent challenges and disadvantages on scale—de-emphasized the need during the early reaction optimization stages to concurrently develop purifications (e.g., crystallizations) that might be helpful in larger-scale applications. When merged with modern chromatographic techniques, the transition-state focus translates to product physical properties being an ignored or secondary consideration, with favorable product attributes being uncovered in an incidental manner. This circumstance need not be so, and this focus article posits that distinct advantages can be accrued by a more integrated approach.

BACKGROUND: ANALYSIS OF SKELETAL CONSTRUCTION

In many organic reactions, one can envision that the reactants and products can be divided into two distinct sections: (i) keystone atoms and bonds [e.g. the carbon-carbon (C─C) bond construction; dashed box in Fig. 1A], defined as atoms and bonds that comprise the desired skeleton and cannot be easily manipulated and (ii) peripheral appendages (e.g., protecting groups, carboxylic acid derivatives; red and blue circles in Fig. 1A), defined as functional groups on the peripheries of the compound that are ripe for further manipulation. Addition reactions such as the Michael reaction (Y = CH or CR) and Mannich reaction (Y = N) exemplify this division: The C_α─C_ß bond construction comprises the keystone atoms and bonds, while the acid derivative (blue circle) and alkene/imine activating groups (red circle) are the peripheral appendages.

Fig. 1. Modifying physical properties can be valuable during reaction development.

(A) In conventional optimization studies of organic reactions, the peripheral appendages are optimized primarily for reactivity purposes. (B) Catalytic, asymmetric Michael additions demonstrate that solubility properties can be crucial to reaction success and divergent outcomes, suggesting untapped potential in physical property optimization. (C) Merged asymmetric catalysis/CIDT approach can be extended to Mannich additions.

The peripheral appendages by definition do not constitute the critical molecular skeleton, uniquely positioning them for optimization similar to any other variable (temperature, solvent…) to achieve an ideal reaction outcome. In a transition-state focus, chemists primarily optimize these appendages and the reaction conditions for reactivity or selectivity purposes. In the hypothetical addition reactions, this workflow can consist of, inter alia, tuning the α-proton acidity by changing the acid derivative or adjusting the π-bond electrophilicity by optimizing the activating group bonded to Y.

With this backdrop, we ask the following overarching questions: Why are physical properties rarely taken into consideration when designing catalytic organic reactions in the academic laboratory and why cannot they be optimized using the peripheral appendages and/or the reaction conditions to achieve a desired reaction outcome? Do these variables contain untapped potential for physical property optimization in connection with reaction development? The optimization of physical properties, a strategy regularly deployed holistically in fields such as pharmaceutical process chemistry and polymer chemistry, could facilitate easier isolation resulting in a more efficient net overall reaction (starting materials → pure products) while also increasing the user-friendliness of the method (5, 6). Reactivity that had not been previously considered could also possibly be unlocked.

RECENT RESULTS

A recent publication reported crystallization-driven enantio- and diastereoselective Michael reactions of nitroalkane nucleophiles I to alkylidene ß-keto amide electrophiles II to establish three contiguous stereocenters (Fig. 1B) (7). Crucial to the method was the use of a physical property (solubility/crystallinity) to achieve high stereoselectivity at two of the three asymmetric centers established in the reaction. The reaction proceeds via an enantioselective C─C bond-forming reaction mediated by a Dixon bifunctional iminophosphorane catalyst (8) followed by a highly selective crystallization-induced diastereomer transformation (CIDT) (9–12) of the product P. Epimerization of both C_α and C_γ and preferential crystallization of one diastereomer P enables stereoconvergence to a single stereoisomer. Without exploiting the poor product solubility in ethereal solvents, no stereoselectivity is observed. The use of product physical properties to achieve stereocontrol is complementary to recent work pioneered by Chen, Wendlandt, Ellman, and others on selective epimerization (13) where stereoelectronic properties, typically the preference for substituents to lie in the equatorial position in a cyclic system, are used to accomplish highly efficient stereoconvergent epimerizations.

The peripheral appendages of the compounds made in this study, namely, the nitro group and amide, drove both the products’ desirable solubility profiles and requisite stereochemical lability. For example, keto ester-derived electrophiles performed poorly, in part, due to their greater solubility. In addition to the contribution to the physical properties, the appendages can be surrogates for a diverse set of functional groups (amines, ketones, carboxylic acid derivatives…), enabling conversion into a variety of valuable products. The solubility properties allowed for all products to be isolated in a simple filtration of the crude reaction mixture without the need for flash column chromatography. The ease of workup and product isolation also had implications in terms of increasing the scalability (conducted up to 25 g without loss of efficiency) and sustainability of the developed reaction due to less time and material required. The differential solubility of the product and the catalyst moreover enabled a simple catalyst recycling protocol. Last, changes in the identity of the peripheral appendage were shown to induce stereochemical changes in the crystallized product, an attribute that merits further investigation (Fig. 1B).

OUTLOOK

This work suggests that examining and optimizing physical properties early and in parallel with other variables in organic reaction development can offer distinct advantages. Several questions remain that will be crucial to further application of the strategy: (i) How general is the approach (e.g., what other systems can be adapted and how can we reliably predict which ones will or will not)? (ii) Can physical properties be used to override intrinsic or kinetic selectivity to access complimentary products or stereoisomers? (iii) What other types of useful reactivity can be revealed by leveraging physical properties? All three lines of inquiry are under active investigation. With respect to the first point, a recent paper successfully illustrates the concept in the context of enolate-based bond constructions with imine electrophiles (Mannich additions) (14). The combined use of peripheral appendage identity and judicious (ethereal/hydrocarbon) solvent selection to assure crystallinity in the product β-amino acid derivatives transmutes a reaction exhibiting negligible stereocontrol under homogenous conditions to one that is highly diastereoselective under conditions of induced crystallization (Fig. 1C).

Approaches of this type outlined here would not be universally applicable: For example, reactions directed toward late-stage functionalization rather than skeletal construction operate with different constraints and have different goals. Nonetheless, we posit that early incorporation of physical property optimization into the workflow of developing organic reactions may have positive effects in increasing their efficiency, sustainability, applicability, and user-friendliness.