One‐Pot Two‐Step Chemoenzymatic Cascade for the Synthesis of a Bis‐benzofuran Derivative

Abstract

Chemoenzymatic cascades enable reactions with the high productivity of chemocatalysts and high selectivity of enzymes. Nevertheless, the combination of these different fields of catalysis is prone to mutual deactivation of metal‐ and biocatalysts. In this study, a one‐pot sequential two‐step catalytic cascade reaction was successfully implemented for the synthesis of a methylene‐bridged bis(2‐substituted benzofuran). In the first step, a palladium‐free Sonogashira reaction is used for the synthesis of a benzofuran derivative. In the subsequent step, the formed 2‐substituted benzofuran is hydroxylated by the monooxygenase P450 BM3 variant (A74S‐F87V‐L188Q) and undergoes further elimination reactions. The study proofs that combination of Cu scorpionate catalyzed Sonogashira cross‐coupling and P450 mediated oxidation is possible and results in up to 84 % yield of the final product. The oxidation reaction is boosted by capturing inhibiting reaction components.

Enzymatic Late‐Stage Modifications: Better Late Than Never

“…[42] Chemoenzymatic synthesis has also been demonstrated in ao ne-pot, two-step cascade,w here the first step was apalladium-free Sonogashira cross-coupling to abenzofuran (9), followed by hydroxylation using aB M3 variant facilitating the loss of formaldehyde and affording the bis-2substituted product (11). [43] Furthermore,t he chemoenzymatic regio-and stereochemical diversification of the macrocyclic skeleton of pikromycin (12 a/b)w as initiated via ac ombination of click chemistry and esterification prior to hydroxylation catalysed by the engineered P450 PikC (Figure 4). [44] This study emphasised how aP 450 triple mutant derived from abiosynthetic pathway could be evolved into as ynthetically viable biocatalyst permitting late-stage diversification of cyclic motifs.…”

Enzymkatalysierte späte Modifizierungen: Besser spät als nie

“…Ein entsprechendes chemoenzymatisches Verfahren wurde von Rentmeister et al entwickelt. [76] Für die selektive Zwei-Schritt-Fluorierung niedermolekularer organischer Verbindungen katalysiert eine optimierte P450-BM3-Variante zunächst eine selektive Hydroxylierung, wobei die Cyclopentenon-Derivate (41)(42)(43) Außerdem wurde die Desoxyfluorierung auf sterisch anspruchsvolle Terpenoide angewendet, z. B. für die Sesquiterpenlacton-Derivate (7R)-Fluorartemether ( 52) und (7R)-Fluorartersunat (53).…”

“…Zudem wurde die chemoenzymatische Synthese in einer Zwei‐Schritt‐Eintopfkaskade gezeigt, wobei der erste Schritt eine Palladium‐freie Sonogashira‐Kreuzkupplung zum Benzofuran ( 9 ) war. Dieser schloss sich eine Hydroxylierung mithilfe einer BM3‐Variante an, sodass nach Freisetzung von Formaldehyd das bis‐2‐substituierte Produkt ( 11 ) entstand [43] . Außerdem wurde die chemoenzymatische regio‐ und stereochemische Diversifizierung des Makrozyklus des Pikromycins ( 12 a / b ) via Click‐Chemie und Veresterung mit nachfolgender Hydroxylierung durch eine optimierte Variante des P450‐Enzyms PikC ermöglicht (Abbildung 4).…”

Merging Whole‐cell Biosynthesis of Styrene and Transition‐metal Catalyzed Derivatization Reactions

“…[7][8][9][10][11] Over the last decade this approach has been expanded to include a wide variety of other reaction classes. [12] Compatible transition-metal and enzyme catalyzed reactions now include palladium catalyzed cross-couplings, [13][14][15][16] copper catalyzed Sonogashira cross-couplings, [17] ruthenium catalyzed metathesis reactions, [18][19][20] ruthenium and iridium catalyzed hydride transfer reactions, [21][22][23] gold and palladium catalyzed cycloisomerizations, [24] enzymatic hydrogenations, [14,22,24] P450catalyzed epoxidations [19,20] and hydroxylations, [17] and dehalogenations. [21,25] Being able to use cell free extracts or whole microbial cells for biocatalysis would be attractive because it negates the need to purify enzymes, and in addition, the use of whole microbial cells would enable the cell to regulate the use and regeneration of any required co-factors.…”

“…Over the last decade this approach has been expanded to include a wide variety of other reaction classes [12] . Compatible transition‐metal and enzyme catalyzed reactions now include palladium catalyzed cross‐couplings, [13–16] copper catalyzed Sonogashira cross‐couplings, [17] ruthenium catalyzed metathesis reactions, [18–20] ruthenium and iridium catalyzed hydride transfer reactions, [21–23] gold and palladium catalyzed cycloisomerizations, [24] enzymatic hydrogenations, [14,22,24] P450‐catalyzed epoxidations [19,20] and hydroxylations, [17] and dehalogenations [21,25] …”