Total Synthesis of (+)‐Omphadiol

Abstract

Omphadiol (1) is a sesquiterpene isolated from the basidiomycete omphalotus illudens and the edible fungus clavicorona pyxidata (Scheme 1).[1] As a member of the africanane family of sesquiterpenes, which all possess a 5-7-3 tricyclic core, omphadiol contains six contiguous stereogenic centers, which makes it a challenging synthetic target. Comparison with structurally similar terpenoids, including pyxidatol (2) and africanol (not shown), [2] reveals a large family of sesquiterpenes and diterpenes that share a common tetrasubstituted cyclopentane ring (highlighted in red). Notably, many of these natural products display potent biological activities. For example, rossinone B (3) shows anti-inflammatory, antiviral, and antiproliferative activities [3] while chinesin (4) possesses antimicrobial and antiviral activity.[4] Tomoeone F (5) displays significant cytotoxicity against KB cells.[5] While synthetic studies toward members of this family including a recent biomimetic synthesis of (AE )-rossinone B have appeared, [6] no further biological studies have been described. Full biological evaluation of omphadiol was precluded owing to insufficient quantities isolated from natural sources.[1a] As part of a program to demonstrate the utility of b-lactones as synthetic intermediates, we set out to develop a scaleable route to the common cyclopentane core (highlighted in red) found in these terpenoids as a prelude to biological studies and investigations into their likely biosynthetic interconnectivity. Herein we report a three-step synthesis of a versatile, carvone-derived bicyclic b-lactone, which constitutes the key intermediate for the described ten-step synthesis of (+)-omphadiol. This total synthesis also features several efficient CÀC bond-forming reactions, novel single-pot, sequential and tandem processes, and the highly stereocontrolled introduction of all six stereogenic centers.Our synthetic strategy was premised on a late-stage facially selective cyclopropanation of the C2 À C4 double bond governed by the topology of the [5.3.0] bicycle 6 (Scheme 2). The cycloheptenone would in turn be constructed by ring-closing metathesis (RCM) of diene 7, which could be derived from bromide 8 by a sequential one-pot intra-/ intermolecular dialkylation. The key intermediate for the synthesis of omphadiol and related terpenes was identified as the bicyclic b-lactone 9. We anticipated that this versatile intermediate could be constructed by the reorganization of the carbon skeleton of (R)-carvone through a nucleophilepromoted aldol lactonization process of a derived keto acid.The synthesis of (+)-omphadiol commenced with a [Mn III (dpm) 3 ]-catalyzed (dpm = dipivaloylmethanato) formal hydration of the enone moiety of (R)-carvone to afford the hydroxy ketone 11 in a chemo-and regioselective manner and as an inconsequential mixture of diastereomers (d.r. 2:1; Scheme 3).[7] Subsequent oxidative cleavage of the a-hydroxyketone by periodic acid delivered ketoacid 12. Upon activation of the carboxylic acid with tosyl chloride, and...

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…434 Furthermore, some of the syntheses discussed herein are quite efficient in terms not only of step count, but yield and material throughput as well. 46,49,136,435 Some have overall yields approaching 20%, 64,95 and one has produced gram quantities of the target in a single synthetic pass. 114 However, much work remains to be able to accomplish this on a consistent basis, particularly owing to the highly variable structures of terpenes and the lack of a universal synthetic strategy.…”

“…94 In 2011, the Romo research group reported the inaugural total synthesis of this natural product starting from (−)-carvone. 95 …”

Ring Expansions of β-Lactams and β-(thio)lactones

“…However, β-lactones substituted with aryl groups gave compounds 189 in lower yields along with some by-products. The total synthesis of the sesquiterpene (+)-omphadiol has been achieved using bicyclic β-lactone 195 as key intermediate [66]. In order to achieve this goal,…”

Conformational Design Principles in Total Synthesis

“…Omphadiol contains a trans-fused 5/7-bicyclic core whose LEC is usually predictable (Scheme 17). [50] Theauthors found that when olefin 17-2 was treated under the cyclopropanation conditions,5 -epi-omphadiol was obtained. It is not difficult to understand that the b-selective cyclopropanation could be aresult of either the rigid conformation of the trans-fused 5/7 ring or the direction of the 5-b-OH group.H owever,w hen compound 17-4 bearing a 5-a-OH group was treated with the same conditions,t he b-selective cyclopropanation still occurred to afford omphadiol.…”

“…Scheme 17. Total synthesis of omphadiol via LEC-controlled cyclopropanation by Liu and Romo [50] (DIBAL-H = diisobutylaluminium hydride).…”