Crystallization-Induced Dynamic Resolution toward the Synthesis of (S)-7-Amino-5H,7H-dibenzo[b,d]-azepin-6-one: An Important Scaffold for γ-Secretase Inhibitors

Abstract

An enantioselective synthesis of (S)-7-amino-5H, 7H-dibenzo[b,d]azepin-6-one (S-1) is described. The key step in the sequence involved crystallization-induced dynamic resolution (CIDR) of compound 7 using Boc-D-phenylalanine as a chiral resolving agent and 3,5-dichlorosalicylaldehyde as a racemization catalyst to afford S-1 in 81% overall yield with 98.5% enantiomeric excess.

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…Dibenzodiazepinone ( S )‐ 103 is a core structure of several γ‐secretase inhibitors and potential anticancer agents and a group from Bristol‐Myers Squibb sought options for its cost‐effective resolution by means of CIDT (Scheme 38). [89] …”

“…Brigaud et al found that a fluorinated oxazolidine trans-Fox, used as a chiral auxiliary, can be conveniently prepared by means of CIDT (Scheme 33). [85] Initially, a pyridinium p-toluenesulfonate catalyzed condensation reaction of fluoral ethyl hemiacetal 88 and (R)-phenylglycinol (89) provided Fox as a 62:38 trans/cis diastereomeric mixture. With the aim of increasing the ratio of trans-Fox, a large screening of epimerization conditions was performed, eventually leading to discovery of a CIDT process.…”

“…Dibenzodiazepinone (S)-103 is a core structure of several γ-secretase inhibitors and potential anticancer agents and a group from Bristol-Myers Squibb sought options for its cost-effective resolution by means of CIDT (Scheme 38). [89] The procedure was carefully optimized. A screening of several aromatic aldehydes helped to identify electron-deficient 3,5-dichlorosalicylaldehyde (105) as the best performing racemization catalyst.…”

Stereoselective Synthesis of the IDO Inhibitor Navoximod

“…We discovered that ( S )- 14 racemized upon heating at 80 °C, presumably via a retro-aza-Michael manifold promoted by protonation of the imidazole moiety. The observation of this dynamic behavior paved the way for development of a more efficient crystallization-induced dynamic resolution (CIDR) …”

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 …”