Ring-closing metathesis of allylsilanes as a flexible strategy toward cyclic terpenes. short syntheses of teucladiol, isoteucladiol, poitediol, and dactylol and an attempted synthesis of caryophyllene.
The development of a strategy consisting of allylsilane ring-closing metathesis and subsequent S(E)' electrophilic desilylation (allylsilane RCM/S(E)') to construct exo-methylidenecycloalkanes is described. Its utility is documented in short syntheses of teucladiol and poitediol. A key transformation in the synthesis of teucladiol is an aldol addition that establishes three stereochemical relationships in one step with ≥10:1 diastereoselectivity and provides a fascinating example of double stereodifferentiation/kinetic resolution with racemic reaction partners in the context of natural product synthesis. The synthesis of (±)-teucladiol required five steps from cyclopentenone and proceeded in 28% overall yield; adaptation of this route to an enantioselective synthesis of (-)-teucladiol enabled the determination of the absolute configuration of this terpene natural product. The use of fluoride-mediated conditions in the final desilylation step preserves the location of the alkene, delivering the natural product (±)-isoteucladiol (five steps and 21% yield from cyclopentenone). The synthesis of poitediol showcases the power of RCM for constructing eight-membered rings and features a highly diastereoselective epoxidation/fluoride-mediated fragmentation sequence for installing the exo-methylidene group with an adjacent hydroxyl-bearing stereocenter. The synthesis of (±)-poitediol required seven steps and proceeded in 18% overall yield. Again, fluoride-mediated desilylation of a late-stage intermediate (with retention of double-bond location) delivered the natural product (±)-dactylol (seven steps and 24% yield). Efforts directed toward incorporating the RCM/S(E)' sequence into a synthesis of caryophyllene are also disclosed. While ultimately unsuccessful, these efforts resulted in the identification of a novel metal alkylidene-promoted deallylation reaction of terminal 1,4-dienes. A possible mechanism for this unexpected deallylation reaction of 1,4-dienes is provided.
Dowling
Matthew S
MS
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, USA.
Vanderwal
Christopher D
CD
D003500:Cyclization; D003516:Cycloparaffins / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D045789:Sesquiterpenes, Guaiane; D012821:Silanes / Q000737:chemistry*; D013237:Stereoisomerism
D003516:Cycloparaffins; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D012821:Silanes; C555280:dactylol; C555281:isoteucladiol; C546806:poitediol; C546807:teucladiol; C024714:caryophyllene