Absolute configurations and CD spectra of axially chiral biphenyls prepared in a facile manner by crystallization‐induced configuration transformation

Abstract

Axially chiral biphenyls such as (M,S)-3k have been conveniently obtained by crystallization of their diastereomeric mixtures, which were synthesized from racemic 4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-carboxylester-2'-carboxyl-biphenyls 4 and chiral amino alcohols (R)-alaninol, (S)-alaninol, (S)-valinol, and (S)-phenylalaninol. A crystallization-induced configuration transformation of the biphenyls was thus achieved. It was found that amide formation of an (S)-valinol or (S)-phenylalaninol at the 2'-position of the biphenyl usually induced the deposition of crystals with the (M)-configuration from ethanol in yields higher than 50%. The absolute configurations (ACs) of two crystalline biphenyls have been determined by X-ray crystallographic analysis. The ACs of nine biphenyls have been assigned based on their CD spectra. Further, stability investigation of these axially chiral biphenyls revealed that the ACs could revert upon redissolution. The energy barrier to epimerization between (P,R)-3b and (M,R)-3b was measured as DeltaG(#) = 21.45 kcal/mol and the half-life in ethanol at 301 K was 17.1 h.

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…explored conformational properties of a series of 12 biphenyls 187 a – l bearing four ortho ‐substituents, including a chiral amino alcohol arm attached by carboxamide linker (Scheme 68). [32] While in ethanol solution, 187 a – l formed diastereomeric mixtures in ratios close to equimolar (dr<55:45). A half‐life of epimerization between ( M , R )‐ 187 b and ( P , R )‐ 187 b in ethanol at 301 K was determined to be 17.1 h. With the exception of ( R )‐alaninol derivatives 187 c , d , crystallization provided biphenyls 187 in high diastereomeric purities and sometimes in yields unexpectedly high for a plain separation, thus indicating that CIDT had occurred.…”

“…Due to the fact that many different terms were employed to describe CIDT, it is likely that some relevant CIDT examples are easily and repeatedly overlooked by people conducting a literature survey. Hence it is worthwhile to note that over the last years, in addition to the terms stated above, the following alternative names have been used: [29] crystallizationinduced (CI) dynamic transformation, [30] CI dynamic atroposelective resolution, [31] CI configuration transformation, [32] asymmetric transformation by dynamic crystallization, [33] deracemization by dynamic salt formation, [34] diastereoconvergent crystallization, [35] and dynamic crystallization-driven condensation. [36] In principle, AT1 is an integral part of dynamic kinetic resolutions (DKR) [37] and dynamic thermodynamic resolutions (DTR).…”

Stereoselective Synthesis of Functionalized α-Amino Acids Isolated by Filtration

“…Lately, the power of CIDT was nicely demonstrated, e.g., in the crystallization-based synthesis of the Halaven C14–C26 fragment, where “a 78% cost improvement and 80% waste reduction was achieved” or in the synthesis of L/T channel blocker ACT-280778, receiving the SCS Sandmeyer Prize, 2015. , Since a successful substrate has to contain a labile stereocenter, typical recent examples of CIDT involve base-catalyzed epimerizations, ,− tautomerism, − aldol, , Pictet–Spengler, − Mannich − and Michael reactions, − nucleophilic substitutions, , aminal and ketal formation, − atropisomerism, − or complexation , (Figure ). As well, radical-mediated racemizations might comprise a viable CIDT platform …”