ChemInform Abstract: Syntheses via Isoxazolines. Old Concepts and Recent Results on Stereoselection at Isoxazoline Ring and Adjacent Centres (I)

Jaeger, V.; Mueller, Ingrid A.; Schohe, R.; Frey, Moritz; Ehrler, R.; Haefele, B.; Schroeter, D.

doi:10.1002/chin.198619362

Cited by 2 publications

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“…44 Cleavage of their weak N-O bonds is one of the most suitable transformations of 1,2-oxazine and isoxazole derivatives making these heterocycles valuable amino alcohol precursors. 45 With the two 3,6-dihydro-2H-1,2-oxazines syn-73 and anti-73, we discovered an interesting stereodivergent behavior when they were subjected to different reduction conditions leading to a set of four diastereomeric amino alcohol derivatives. 46 An alternative cleavage mode of 3,6-dihydro-2H-1,2-oxazines is depicted in Scheme 18 with syn-73 as an exemplary substrate.…”

Section: Amino Polyols Novel Carbohydrate Mimetics and More From 12-o...mentioning

confidence: 95%

Sugars, Alkaloids, and Heteroaromatics: Exploring Heterocyclic Chemistry with Alkoxyallenes

2008

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As master craftsmen, modern synthetic chemists are challenged to achieve remarkable feats of efficiency and elegance toward molecular targets. The nature of this pursuit necessitates the collection of synthetic repertoires that are tried and true. With methodologies and pathways increasingly scrutinized, the adept chemist must seek out propitious tools to incorporate into the arsenal. With this in mind, this Account highlights the versatility of alkoxyallenes as precursors to valuable heterocyclic building blocks for such efforts as natural product synthesis. Accessed by the etherification of either propargyl alcohols or propargylic halides, alkoxyallenes are obtained after base-catalyzed isomerizations of the propargylic ethers. A host of umpolung synthons are available through this scheme after metalation, generating C(3) nucleophiles synthetically equivalent to vital anionic and zwitterionic synthons. Reactions with a diverse set of heteroatomic electrophiles yield carbohydrates, spiroketals, alkaloids, and heteroaromatics via [3 + 2] or [3 + 3] cyclizations. By employing lithiated alkoxyallenes into transformation routes, the natural product chemist can utilize this methodology as a viable resource in stereoselective synthesis. A survey of our own utilization of alkoxyallenes along synthetic pathways toward natural product targets reveals their suitability for generating advantageous precursors. A set of four stereoisomeric 2,6-dideoxyhexoses were stereoselectively obtained after an initial lithiated alkoxyallene and lactaldehyde cyclization, followed by the oxidative ring opening of the dihydrofurans. Through the addition of a lithiated alkoxyallene to a functionalized benzaldehyde, an essential spiroketal diastereomer was rapidly achieved in a few steps. We greatly benefitted from alkoxyallenes in the construction of complex nitrogen-containing synthetic targets, whether pyrrolidine alkaloids, substituted imidazole derivatives, or functionalized pyridines. A pinnacle example of their utility came from the coupling of alkoxyallenes to nitrones affording 1,2-oxazines, which served as a gateway to an array of novel polyfunctionalized compounds such as aminopolyols, hydroxylated pyrrolidines, or carbohydrate mimetics. Alkoxyallenes have proven themselves to be powerful C(3) building blocks toward complex molecular targets, revealing novel pathways to a variety of desirable highly functionalized heterocycles. In our view, the full extent of their synthetic utility has yet to be truly realized.

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Section: Amino Polyols Novel Carbohydrate Mimetics and More From 12-o...mentioning

confidence: 95%

Sugars, Alkaloids, and Heteroaromatics: Exploring Heterocyclic Chemistry with Alkoxyallenes

2008

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“…The synthesis of trifluoromethyl substituted oxazines 88 and 89 (Scheme ) required a different strategy. Ready access to CF 3 substituted 3-amino-propan-1-ol derivatives 80 and 81 is achieved using a dipolar cycloaddition reaction of a nitrile oxide and an olefin as the key step. Utilizing carefully optimized conditions, the nitrile oxide was slowly generated in situ from 2-chloro-2-hydroxy-imino ester 71 in a heterogeneous mixture of NaHCO 3 in ethyl acetate in the presence of 3,3,3-trifluoropropene ( 72 ) to give the 4,5-dihydro-isoxazole ester 73 in quantitative yield.…”

Section: Chemistrymentioning

confidence: 99%

β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease

Hilpert¹,

et al. 2013

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An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

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ChemInform Abstract: Syntheses via Isoxazolines. Old Concepts and Recent Results on Stereoselection at Isoxazoline Ring and Adjacent Centres (I)

Cited by 2 publications

References 0 publications

Sugars, Alkaloids, and Heteroaromatics: Exploring Heterocyclic Chemistry with Alkoxyallenes

Sugars, Alkaloids, and Heteroaromatics: Exploring Heterocyclic Chemistry with Alkoxyallenes

β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease

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