Niobium Pentachloride Activation of Enone Derivatives: Diels-Alder and Conjugate Addition Products

The Zoanthus alkaloids, exemplified by (-)-norzoanthamine 3a and zoanthamine 3b, show promising activity against osteoporosis. Susumu Kobayashi of the Tokyo University of Science assembled (Angew. Chem. Int. Ed. 2009, 48, 1400; Angew. Chem. Int. Ed. 2009, 48, 1404) the challenging tricyclic core of 3a employing the intramolecular Diels-Alder cyclization of 1 to 2. The cyclopentane of 1 served as useful scaffolding, even though it was cleaved en route to 3a. The cyclohexane ring of 1 has five of its six positions substituted, including three that are alkylated quaternary centers. The starting point for the preparation of 1 was the enantiomerically-pure Hajos-Parrish ketone 4, containing the first of the those quaternary centers. Conjugate addition of MeLi established the second quaternary center. The less stable endo alkyl branch of 1 was installed by conjugate addition to the more reactive α-methylene ketone of the cross-conjugated 5, followed by kinetic quench. Addition of vinyl cuprate across the open face of the enone 7 then established the final quaternary center, setting the stage for the intramolecular Diels-Alder reaction. The silyl enol ether from the cyclization of 1 was not stable, so it was directly oxidized to the enone 2. The keto phosphonate 16 for the last two rings of 3a was prepared from the previously-reported crystalline glutamic acid-derived mesylate 12. Reduction and homologation delivered the ester 14, that was condensed with the phosphonate anion 15 to give 16. The congested cyclopentanone 17, derived from 2, was most efficiently deprotonated with n -BuLi. Exposure of the resulting silyl enol ether to ozone led to the α-hydroxylated product 18. Unexpectedly but happily, oxidative cleavage of 18 delivered, after deprotection and reprotection, the more congested aldehyde 19. This cleavage may be proceeding by tautomerization of 18 to the regioisomeric keto alcohol. The aldehyde 19 was condensed with the keto phosphonate 16, to give, after hydrogenation, the keto lactone 20. A series of oxidation state adjustments then completed the synthesis of (-)-norzoanthamine 3a.

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ChemInform Abstract: CYTOCHALASIN SUPPORT STUDIES. 5. CONJUGATE ADDITION OF β-OXO ESTER DIANIONS TO VINYL SULFONES: A NEW PROCEDURE FOR SEVEN-RING ANNULATION. SYNTHESIS OF A CHIRAL CYTOCHALASIN C INTERMEDIATE VIA AN INTRAMOLECULAR DIELS-ALDER REACTION OF

Chemischer Informationsdienst ◽

10.1002/chin.198304367 ◽

1983 ◽

Vol 14 (4) ◽

Author(s):

S. G. PYNE ◽

D. C. SPELLMEYER ◽

S. CHEN ◽

P. L. FUCHS

Keyword(s):

Conjugate Addition ◽

Alder Reaction ◽

Diels Alder ◽

Diels Alder Reaction

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Cytochalasin support studies. 5. Conjugate addition of .beta.-oxo ester dianions to vinyl sulfones: a new procedure for seven-ring annulation. Synthesis of a chiral cytochalasin C intermediate via an intramolecular Diels-Alder reaction of a chiral Z diene

Journal of the American Chemical Society ◽

10.1021/ja00385a030 ◽

1982 ◽

Vol 104 (21) ◽

pp. 5728-5740 ◽

Cited By ~ 33

Author(s):

S. G. Pyne ◽

D. C. Spellmeyer ◽

S. Chen ◽

P. L. Fuchs

Keyword(s):

Conjugate Addition ◽

Alder Reaction ◽

Diels Alder ◽

Diels Alder Reaction

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Carbon atom insertion bicycloannulation: total syntheses of ishwarane and ishwarone

Canadian Journal of Chemistry ◽

10.1139/v84-328 ◽

1984 ◽

Vol 62 (10) ◽

pp. 1908-1921 ◽

Cited By ~ 11

Author(s):

Robert M. Cory ◽

Lester P. J. Burton ◽

Dominic M. T. Chan ◽

Fred R. McLaren ◽

Mary H. Rastall ◽

...

Keyword(s):

Carbon Atom ◽

Total Synthesis ◽

Conjugate Addition ◽

Diels Alder ◽

Magnesium Bromide ◽

Total Syntheses ◽

Tertiary Alcohols ◽

Naturally Occurring ◽

Carbene Insertion ◽

Equivalent Sequence

Insertion of a carbon atom into a methyl cyclohexene, leading in a single synthetic step to a bicyclo[3.2.1.02.7]octane by carbene addition to the double bond and carbene insertion into a methyl C—H bond, has been accomplished by treating the cyclohexene with carbon tetrabromide and methyllithium at low temperatures. This new bicycloannulation method has been employed in a total synthesis of ishwarane (1), the naturally occurring parent hydrocarbon of the ishwarane class of tetracyclic sesquiterpenes. Although this reaction was not successful with various possible precursors of ishwarone (2), this natural product was prepared in low yield by a two-step version of the carbon atom insertion bicycloannulation (CAIB) procedure involving addition of bromoform-derived dibromocarbene to the octalone (5) followed by treatment of the resulting dibromocyclopropane (56) with methyllithium. The same two-step sequence was also successful in the first synthesis of norishwarane (20), the hydrocarbon comprising the bare ring system of the ishwarane sesquiterpenoids. The Diels–Alder synthesis used in the preparation of the octalin precursor (18) of norishwarane could not be used for the terpenes themselves because of the lack of dienophilic reactivity of the required cyclohexenone (7). A regioselective Diels–Alder equivalent sequence was therefore developed, consisting of conjugate addition of lithium di(3-methyl-3-butenyl)cuprate (42) to 2,3,4-trimethylcyclohex-2-en-1-one (7), epoxidation, base-catalyzed cyclization of the resulting epoxide (47) to a mixture of primary and tertiary alcohols (50 and 49, respectively), and dehydration of 49 to give 5. In the case of ishwarane, the octalin precursor (62) was synthesized by conjugate addition of lithium dimethylcuprate to octalone 59, addition of methyl magnesium bromide to the resulting decalone (60) to give octalol 61, and dehydration.

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