Synthesis of (2S,3R)- and (2S,3S)-[3-2H1]-proline via highly stereoselective hydrolysis of a silyl enol ether

Barraclough, P.; Spray, Caroline A.; Young, Douglas W.

doi:10.1016/j.tetlet.2005.04.126

Cited by 9 publications

(4 citation statements)

References 8 publications

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“…The synthesis of trans -4-fluoro- l -proline ( 13 ) began with the oxidation of (2 S ,4 R )-Boc-protected hydroxyproline ( 8 ) (Scheme ), which resulted in compound 9 . The reduction of the ketone moiety was readily carried out using NaBH 4 . However, this reaction resulted in a modest 92:4 dr (84% de) selectivity for the desired diastereomer 10 , which could not be used in the following steps without chromatographic purification.…”

Section: Resultsmentioning

confidence: 99%

“…The reduction of the ketone moiety was readily carried out using NaBH 4 . 14 However, this reaction resulted in a modest 92:4 dr (84% de) selectivity for the desired diastereomer 10, which could not be used in the following steps without chromatographic purification. We next explored keto reductase (KRED) transformation and expected that it might give a much-improved stereoselectivity.…”

Section: Synthesis Of Trans-4-fluoro-l-proline (13)mentioning

confidence: 99%

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Practical Asymmetric Synthesis of a Bicyclic Pyrrolidinol

Guo¹,

Gharbaoui

Lizza³

et al. 2022

Org. Process Res. Dev.

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The “butterfly-shaped” bicyclic pyrrolidinol ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1) is a key building block for drug candidates, and its practical chemical synthesis remains elusive. As such, an asymmetric synthesis for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1) that is amenable for scale-up has been developed. The newly optimized process utilizes readily available N-Boc-trans-4-hydroxy-l-proline methyl ester (8) to establish the challenging stereogenic center bearing the fluoride. Subsequent diastereoselective α-alkylation was achieved by leveraging Seebach’s self-regeneration of stereochemistry (SRS) methodology, which has been exploited for the synthesis of proline derivatives. Finally, intramolecular cyclization/deprotection cascade and carbonyl reduction afford the bicyclic pyrrolidinol 1 in nine linear steps from compound 8. This process significantly reduces the overall production sequence and allows the preparation of product 1 on a multikilo scale with a 40% overall yield and perfect control of chirality (>99% ee and de).

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Trans-4-fluoro-l-proline (13)mentioning

confidence: 99%

Practical Asymmetric Synthesis of a Bicyclic Pyrrolidinol

Guo¹,

Gharbaoui

Lizza³

et al. 2022

Org. Process Res. Dev.

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“…With no straightforward access to other 3,4-dihydroxyproline diastereoisomers as substrates for bis-deoxyfluorination, investigations turned toward an electrophilic fluorination approach. Barraclough et al had demonstrated the regioselective conversion of a 4-ketoproline derivative to the corresponding silyl enolether, , which was used to stereoselectively introduce deuterium at C3. Hence, formation of the silyl enol ether 49a was achieved upon treatment of 29a , − synthesized by Dess–Martin periodinane oxidation of 26a in 94% yield (not shown), with LDA and TMSCl, and subsequently fluorinated with SelectFluor (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Conformational Properties of 3,4-Difluoro-l-prolines

et al. 2019

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Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/trans isomerization) are introduced. With fluorination at both 3- and 4-positions, matching or mismatching effects can occur depending on the relative stereochemistry. Here we report, in full, the syntheses and conformational properties of three out of the four possible 3,4-difluoro-l-proline diastereoisomers. The yet unreported conformational properties are described for (3S,4S)- and (3R,4R)-difluoro-l-proline, which are shown to bias ring pucker and cis/trans ratios on the same order of magnitude as their respective monofluorinated progenitors, although with significantly faster amide cis/trans isomerization rates. The reported analogues thus expand the scope of available fluorinated proline analogues as tools to tailor proline’s distinct conformational and dynamical properties, allowing for the interrogation of its role in, for instance, protein stability or folding.

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“…The research groups of Young and Nishiyama have used pyroglutamate analogs as precursors for the synthesis of a range of isotopically labeled a-amino acids such as leucine, isoleucine, valine, and proline [49][50][51][52][53][54][55][56][57]. Their strategy utilizes the pyroglutamate ring to introduce additional functionality, followed by facile ring-opening 480j 11 Synthesis of Isotopically Labeled a-Amino Acids reactions for the synthesis of linear amino acids.…”

Section: Chiral Pool Approachmentioning

confidence: 99%