Abstract
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 (3 S,4 S)- and (3 R,4 R)-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.
Highlights
Fluorination of organic molecules has proven to be a highly useful tool for the manipulation of their conformational and electronic properties with minimal steric effects.[1−7] Fluorination of the L-proline ring has been heavily exploited for conformational control of its ring pucker.[8]
Our retrosynthetic analysis of 3,4-difluoroprolines is outlined in Scheme 2
While the epoxides and diols would be accessed from 3,4-dehydroderivatives 25a−c, direct functionalization of 25a−c such as vicinal difluorination or a halofluorination/fluoride halide displacement could lead to the desired 3,4-difluoroprolines. 3,4-Dehydroproline is a commercially available building block but can be obtained by a well-described elimination process involving 26a−c starting from cheap (4R)-4-hydroxyproline
Summary
Fluorination of organic molecules has proven to be a highly useful tool for the manipulation of their conformational and electronic properties with minimal steric effects.[1−7] Fluorination of the L-proline ring has been heavily exploited for conformational control of its ring pucker.[8]. The rotational energy barrier is decreased and accelerated cis/trans isomerization is observed.[11−13] The same effect renders fluorinated prolines less basic[11,13,14] and the carboxylic acid group more acidic.[15]. The combination of both conformational and dynamical effects make fluoroprolines valuable tools for determining the significance of proline’s unique structural properties within proteins or peptides.[8,14] the first syntheses of (4R)-FPro 1 and (4S)-FPro 2 date back to 1965,16 it took until the late 1990s for this potential to be fully recognized. In a landmark study investigating the mechanism behind collagen stability,[9,17,18] Raines and co-workers applied fluoroprolines to revise the origins behind the extraordinary
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