A scalable, asymmetric synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo3,4-cisoxazole, a key intermediate in the synthesis of LY2886721, is reported. ...Highlights of the synthesis include the development of an asymmetric 3 + 2 intramolecular cycloaddition facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.
To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the ...conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer–Bergs reaction to give a hydantoin with the targeted l-glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.
A synthesis of cryptophycin 52 (2) is reported using a Sharpless asymmetric dihydroxylation (AD) strategy to install the epoxide moiety. The high stereoselectivity of the AD reaction that allows for ...an efficient means of preparing the epoxide is in contrast to the standard direct epoxidation of cryptophycin substrates, which proceeds with poor diastereoselectivity. Methodology for conversion of the diol AD product to the requisite epoxide is disclosed. The transformation has been optimized to proceed in high yield in the presence of base sensitive functionality.
A pilot-plant scale desymmetrization of the cyclic meso-epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in ...high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, (R)-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.
A synthesis of cryptophycin 52 is reported using a Shi epoxidation strategy to install the epoxide moiety in a diastereoselective fashion. Several epoxidation results for cryptophycin substrates are ...disclosed followed by a discussion of the details relating to the preparation of cryptophycin 52 in two synthetic steps from one of the intermediate epoxides.
The asymmetric synthesis and biological activity of (2S,1‘S,2‘R,3‘R)-2-(2‘-carboxy-3‘-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3‘ substituted carboxy cyclopropyl glycine ...is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.
The synthesis of unit A of the cryptophycins from (S)-trans-3-penten-2-ol and from (S)-trans-4-hexen-3-ol has been completed. The key stereodetermining step is a 2,3-Wittig rearrangement of a ...propargyl ether. Elaboration of the rearrangement product was accomplished by means of a selective hydroboration−oxidation of a terminal alkyne, Horner−Emmons homologation of the derived aldehyde, followed by selective ozonolytic cleavage and Wittig olefination. This synthesis provides easy access to the series of cryptophycin analogues that incorporate a modified aromatic ring in unit A.
We demonstrate a link between preschoolers’ quantitative competencies and their school-entry knowledge of the relations among numbers (number-system knowledge). The quantitative competencies of 141 ...children (69 boys) were assessed at the beginning of preschool and throughout the next 2 years of preschool, as was their mathematics and reading achievement at the end of kindergarten and their number-system knowledge at the beginning of first grade. A combination of Bayes analyses and standard regressions revealed that the age at which the children had the conceptual insight that number words represent specific quantities (cardinal value) was strongly related to their later number-system knowledge and was more consistently related to broader mathematics than to reading achievement, controlling for intelligence, executive function, and parental education levels. The key implication is that it is not simply knowledge of cardinal value but the age of acquisition of this principle that is central to later mathematical development and school readiness.
A simple three-step preparation of (R)-(−)-1-piperidino-3,3-dimethylbutan-2-ol (amino alcohol catalyst for the Noyori asymmetric alkylation of aldehydes) based on a classical resolution of the ...racemate is described. Use of this catalyst in a detailed study of the asymmetric ethylation of trans-crotonaldehyde producing trans-(S)-4-hexen-3-ol is also described. The impact of catalyst enantiopurity and loading on the product enantiopurity and yield is studied, which led to optimized conditions for reaction scale-up.
