Eine kurze enantioselektive Totalsynthese von (−)‐Englerin A

Abstract

Selektive Oxidationen des Dienons 2 sowie eine Ringschlussmetathese zum Hydroazulengerüst ermöglichten die 12‐stufige Synthese der Titelverbindung 1 aus (−)‐Photocitral A (3), das seinerseits rasch mittels dualer Katalyse aus (−)‐Isopulegol erhältlich ist.

A concise enantioselective synthesis of the guaiane sesquiterpene (−)-oxyphyllol

“…Recently, we developed an efficient access to the anticancer guaiane (−)-englerin A ( 5 ) starting from (−)-photocitral A ( 6 ), which in turn can be prepared in only 2 steps from commercially available (−)-isopulegol through dual catalysis [6]. Due to the structural similarity of the hydroazulene core in (−)-oxyphyllol ( 1 ) and 5 , we decided to use a modification of our route to 5 for the synthesis of 1 that would also constitute a formal synthesis of the related guaiane (+)-orientalol E ( 2 ) [4,7].…”

“…The acetyl group of 3 can be utilized to generate the isopropyl group, and a regioselective transannular epoxide opening would construct the oxygen-bridged bicyclic hydroazulene framework. Alcohol 3 was traced back to the known epoxy enone 4 that already served as an intermediate for the total synthesis of 5 [6]. …”

“…As shown in Scheme 2, we first planned to use the known diol 7 , which is available by diastereoselective dihydroxylation of 4 [6]. Since a chemoselective deoxygenation of the secondary alcohol of 7 would give rise to the desired intermediate 3 , we investigated a radical defunctionalization strategy [8].…”

“…a) 1 mol % K 2 OsO 4 , NMO, acetone, water, THF, rt, 97%, diastereomeric ratio = 2:1 (ref. [6]); b) PhOC(S)Cl, pyridine, CH 2 Cl 2 , 0 °C to rt, 42% 9 . NMO = N -methylmorpholine N -oxide.…”

“…To our delight, a direct regio- and diastereoselective Co(II)-catalyzed hydration [12] of the olefin in 4 succeeded to give the required α-stereoisomer 3 in 58% isolated yield after chromatographic separation of the minor β-alcohol. Compared to the envisaged deoxygenation route (Scheme 2), this key transformation saved 2 steps and paved the way for a final reaction sequence that was based on our synthesis of (−)-englerin A ( 5 ) [6]. Thus, Wittig olefination of the acetyl group in 3 afforded the sensitive vinyl epoxide 10 along with some cyclized product 11 .…”