A C–H oxidation approach for streamlining synthesis of chiral polyoxygenated motifs

Abstract

Chiral oxygenated molecules are pervasive in natural products and medicinal agents; however, their chemical syntheses often necessitate numerous, wasteful steps involving functional group and oxidation state manipulations. Herein a strategy for synthesizing a readily diversifiable class of chiral building blocks, allylic alcohols, through sequential asymmetric C—H activation/resolution is evaluated against the state-of-the-art. The C—H oxidation routes’ capacity to strategically introduce oxygen into a sequence and thereby minimize non-productive manipulations is demonstrated to effect significant decreases in overall step-count and increases in yield and synthetic flexibility.

Enantioselective Allylic Hydroxylation of ω‐Alkenoic Acids and Esters by P450 BM3 Monooxygenase

“…[7] The enantioselective allylic acetoxylation of terminal olefins using a combination of a Pd II /bis(sulfoxide) system with benzoquinone as the terminal oxidant and Cr III (salen) as a chiral Lewis acid cocatalyst reported by White and co-workers in 2008 was a milestone and ee values up to 63 % were achieved; the desired products were obtained in 69-89 % yield and 50-57 % ee as roughly 5:1 mixtures with the corresponding linear alcohols. [14] A P450 BM3 library of 65 variants was constructed by mutating active-site residues R47, Y51, A74, F87 and L188, all of which are known determinants of activity and selectivity of this enzyme (for details, see the Supporting Information: S2). The well-known and highly promising NADPH-dependent bacterial cytochrome P450 BM3 monooxygenase from Bacillus megaterium was the probe system of choice due to its soluble and self-sufficient character, its superior catalytic features compared to other monooxygenases, and the availability of large-scale production and purification protocols.…”

“…[8] We envisioned that a biocatalytic approach might be preferable to conventional chemistry, since enzymes ensure high selectivity by furnishing completely chiral reaction environments. [14] A P450 BM3 library of 65 variants was constructed by mutating active-site residues R47, Y51, A74, F87 and L188, all of which are known determinants of activity and selectivity of this enzyme (for details, see the Supporting Information: S2). [9,10] The native function of P450 BM3 is supposed to be the subterminal hydroxylation of fatty acids by insertion of one oxygen atom from O 2 into C À H bonds; however, the enzymes high versatility and evolvability have been proven by protein engineering.…”

“…This approach shows the highest enantioselectivity observed to date for the allylic C À H oxidation of terminal linear olefins and simultaneously addresses key issues of modern organic synthesis like the use of mild reaction conditions, aqueous media, sustainable catalysts, and O 2 as a "green" oxidant ( Figure 1). [14] A P450 BM3 library of 65 variants was constructed by mutating active-site residues R47, Y51, A74, F87 and L188, all of which are known determinants of activity and selectivity of this enzyme (for details, see the Supporting Information: S2). [9a, 15] This set of mutants served as a versatile catalyst pool for assaying the ability of P450 BM3 to catalyze the allylic hydroxylation of the model substrate ethyl 6-heptenoate (1 a).…”

Regio- and stereoselective hydroxylation of 10-undecenoic acid with a light-driven P450 BM3 biocatalyst yielding a valuable synthon for natural product synthesis

“…35 The chirality of the active site of the P450 BM3 enzyme is well documented leading often exclusively to the R enantiomer for the monooxygenated long chain fatty acids. 26 We have then investigated the stereochemistry of the enzymatically hydroxylated 10-UA.…”

Enantioselektive allylische Hydroxylierung von ω‐Alkensäuren und ‐estern mittels der P450‐BM3‐Monooxygenase

“…Dieser Ansatz ermçglicht die hçchsten bislang erreichten Enantioselektivitäten hinsichtlich der allylischen C-H-Oxidation terminaler linearer Olefine und erfüllt gleichzeitig viele Schlüsselkriterien der modernen organischen Synthese wie die Verwendung milder Reaktionsbedingungen, wässri-ger Medien, nachhaltiger Katalysatoren und O 2 als einem "grünen" Oxidationsmittel (Abbildung 1). [14] Eine vielseitige P450-BM3-Enzymbibliothek aus 65 Varianten wurde durch Mutation der Aminosäuren R47, Y51, A74, F87 und L188 aufgebaut, wobei alle diese Positionen im aktiven Zentrum lokalisiert sind und als essentielle Faktoren der Aktivität und Selektivität dieses Enzyms gelten (siehe die Hintergrundinformationen: S2). [9a, 15] Diese Biokatalysatoren wurden anschließend zur Durchmusterung der Fähigkeit von P450 BM3 für die allylische Hydroxylierung von 6-Heptensäureethylester (1 a) als Modellsubstrat herangezogen.…”