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...

Natural sesquiterpenoids

“…Sterostrein C 234 was shown to be an inseparable mixture of a pair of isomers. 230 The total synthesis of (+)-omphadiol has been accomplished, 231 whilst the synthesis of the proposed structure for africanan-1a-ol has been described, showing that it must be revised. 59 The elucidation of the role of the Baeyer-Villiger monooxygenase and a non-heme irondependent dehydrogenase/oxygenase in the final steps of the biosynthesis of pentalenolactone and neopentalenolactone in Streptomyces has been reported.…”

Olefin Metathesis: Catalyst Inhibition as a Result of Isomerization

“…The undesirable olefin isomerization, promoted by ruthenium speciesf ormed during the decomposition of the catalyst, was observed. [8,9] It was recently proposed that undesired double-bond isomerization can lead to accumulation of isomerst hat act as catalyst poison. Accumulation of isomerst hat can form inactiveF ischer-type alkylidene complexes,l eads to the full inhibition of the catalytic reaction.…”

“…[1] In particular, catalystd ecomposition is one of the major limiting factors for the use of ruthenium alkylidene catalysts in olefin metathesis reactions. [8,9] It was recently proposed that undesired double-bond isomerization can lead to accumulation of isomerst hat act as catalyst poison. [3, 4] Although thermald ecomposition is ac ommonw ay for catalysts to deactivate, the inhibition of the catalystd iffers from case to case, depending mostly on impurities presentedi nt he solvent and starting olefin.…”

“…[6] Identifying the catalysts inhibitors and catalyst poisons is generally not trivial in catalysis. [8,9] It was recently proposed that undesired double-bond isomerization can lead to accumulation of isomerst hat act as catalyst poison. [7] In this survey it is demonstrated how the otherwise insignificant catalyst decomposition leads to the significant accumulation of ac ompound that acts as ac atalyst inhibitor.T he double-bond isomerization, as ac ommon side-reaction in olefin metathesis, has been at opic of numerous reports.…”

“…[7] In this survey it is demonstrated how the otherwise insignificant catalyst decomposition leads to the significant accumulation of ac ompound that acts as ac atalyst inhibitor.T he double-bond isomerization, as ac ommon side-reaction in olefin metathesis, has been at opic of numerous reports. [8,9] It was recently proposed that undesired double-bond isomerization can lead to accumulation of isomerst hat act as catalyst poison. [10] Herein, cleare videncei sp rovided to support this proposal.The ring-closing metathesis (RCM) of N,N-diallyl-tosylamide 1,a so ne of the most popularb enchmarking substrates, has been the subject of numerous reports.…”