A radical-based approach for the construction of the tetracyclic structure of resiniferatoxin

The total synthesis of seven members of the lapidilectine and grandilodine family of alkaloids has been accomplished in racemic and enantiopure form without protection/deprotection of functional groups. The two key steps, an 8-endo-dig hydroarylation and a 6-exo-trig photoredox cyclization, were catalyzed using gold. A rationale for the formation of the cyclopropane ring of the lundurines is also provided.

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“…Employing allylSnBu 3 (10 equiv) as nucleophile, this one-pot procedure provided a mixture of 9 and 10 in an unsatisfactory 1:2 ratio. 28 …”

Section: Resultsmentioning

confidence: 99%

Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship

et al. 2018

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“…Upon activation with CSA, the axial C9 alcohol of 11 participated in acetal exchange with the C13′ dimethyl acetal to provide the oxabicyclo[2.2.2]octane 12 (d.r.=1:1 at C13′). The C9 O,Se‐acetal was then constructed by conversion of the C9 vinyl ether of 12 8j. Thus, the vinyl ether 12 was chemoselectively oxidized by m CPBA to the carboxylic acid 13 via the intermediacy of the hydroxy ketone.…”

Section: Methodsmentioning

confidence: 99%

Total Synthesis of Crotophorbolone

et al. 2015

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The complex ABC-tricyclic structure of crotophorbolone, a derivative of the tigliane diterpenoids, was assembled by coupling of simple fragments. The six-membered C-ring fragment, having five contiguous stereocenters, was stereoselectively constructed from (R)-carvone. After attachment of the five-membered A-ring through the π-allyl Stille coupling reaction, the α-alkoxy bridgehead radical reaction effected the endo-cyclization of the seven-membered B-ring by forming the sterically congested bond at C9 and C10 stereospecifically and stereoselectively, respectively. Finally, the functional groups on the 5/7/6-membered ring system were manipulated by rhodium-catalyzed C2 olefin isomerization, C13 decarboxylative oxidation, and C4 hydroxylation, thus completing the first total synthesis of crotophorbolone.

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“…10a and V-40 (0.2 eq) were added by syringe pump over 3 h, and the reaction mixture was stirred for an additional 1 h. b) Compound 8e was obtained as a single diastereoisomer. 71) We demonstrated that the radical-mediated three-component reactions effectively incorporated the two carbocycles and a carbon chain into the multiply functionalized compounds. Thus, we planned to integrate the three-component reaction as a key assembling reaction of the A-and C-rings of resiniferatoxin (1).…”

Section: Radical-mediated Three-component Reactionmentioning

confidence: 99%

Radical-Mediated Three-Component Reaction: A Study toward the Total Synthesis of Resiniferatoxin

Urabe

2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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This review summarizes the efforts to develop a radical-mediated three-component reaction and its application to a convergent approach to synthesize the 5/7/6-tricyclic framework (ABC-rings) of the densely functionalized dephnane diterpene, resiniferatoxin. The α-alkoxy bridgehead radical species, which was designed as the radical donor of the three-component reaction, was generated from O,Se-and O,Te-acetals under two different conditions. The generated α-alkoxy bridgehead radical effectively underwent the threecomponent reaction with α,β-unsaturated ketones and allyltributyltin/aldehyde under each of the conditions, giving rise to a wide variety of multiply functionalized 2,3-trans disubstituted cyclopentenone moieties. One of the established reactions was utilized as the key assembling reaction of the ABC-tricyclic framework of resiniferatoxin. The reaction of the bridgehead radical of the highly functionalized 6-membered C-ring, the 5-membered A-ring, and an allyltributyltin derivative effectively produced the C4-branched AC-rings. The last B-ring was constructed from the coupling adduct in two steps through the 7-endo cyclization, delivering the tricyclic framework possessing the correct C8 and 9-stereocenters of resiniferatoxin. The present methods demonstrate the power of the three-component reaction using an α-alkoxy bridgehead radical in a convergent approach to the complex architectures of daphnane diterpenes.

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A radical-based approach for the construction of the tetracyclic structure of resiniferatoxin

Cited by 41 publications

References 65 publications

Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship

Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship

Total Synthesis of Crotophorbolone

Radical-Mediated Three-Component Reaction: A Study toward the Total Synthesis of Resiniferatoxin

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