Utilization of the Thorpe-Ingold Effect in the Synthesis of Cyclooctanoid Ring Systems via Anionic 6-exo-dig Cyclization/Claisen Rearrangement Sequence.

We demonstrate a facile approach for the synthesis of gem-disubstituted cyclooctanoids, a motif found in several biologically active compounds. Appropriately substituted 1-alkenyl-5-pentyn-1-ols bearing gem-dialkyl substituents at either the C2, C3, or C4 position serve as useful precursors to a number of cyclooct-4-enone derivatives via a tandem, microwave-assisted oxyanionic 6-exo-dig cyclization/Claisen rearrangement reaction. gem-Dialkyl activation is necessary for these reactions to occur, as unactivated 1-alkenyl-5-pentyn-1-ols fail to undergo 6-exo-dig cyclization under the conditions employed. Further application of the methodology to the corresponding gem-dialkoxy system was also explored to facilitate access to more complex carbocycles.

Facile Access to Cyclooctanoid Ring Systems via Microwave-Assisted Tandem 6-exo dig Cyclization-Rearrangement Sequence.

Appropriately substituted 5-alkyn-1-ol systems bearing a nitrile moiety at the triple bond serve as versatile precursors to a variety of cyclooctenone derivatives via a "one-pot" base-catalyzed oxyanionic 6-exo dig cyclization/Claisen rearrangement sequence under microwave irradiation. It was found that the initially formed cyclic intermediate consists of a mixture of endo and exocyclic isomers, which appear to be in equilibrium under the reaction conditions. However, the only observed products from these reactions are α-cyano substituted cyclooctenones, derived from the exocyclic dihydrofuran intermediates.

Synthesis of cycloheptanoid natural products via tandem 5-exo cyclization/Claisen rearrangement process.

This article describes the development of microwave-assisted oxyanionic 5-exo-dig cyclization-Claisen rearrangement sequence as a convenient "one-pot" route to a variety of seven-membered carbocyclic ring systems. This process was used as the key transformation for the construction of several natural products, including frondosins A, B, and C.

Asymmetric synthesis of seven-membered carbocyclic rings via a sequential oxyanionic 5-exo-dig cyclization/claisen rearrangement process. Total synthesis of (-)-frondosin B.

Appropriately substituted nonracemic allyl alcohols, readily prepared from the corresponding enones by application of the CBS methodology, were converted to optically active cycloheptenone derivatives with almost complete transfer of chirality via an efficient "one-pot", cycloisomerization/Claisen rearrangement process. This methodology was directly applied to the expedient total synthesis of (-)-frondosin B.

Studies toward frondosin A and its analogues. Formal total synthesis of (+/-)-frondosin A.

Two reaction sequences commencing with different starting materials were successfully employed for the synthesis of frondosin A analogues, including (+/-)-frondosin A dimethyl ether. Construction of the bicyclo[5.4.0]undecane core in each case was achieved through an expedient microwave-assisted tandem 5-exo cyclization--Claisen rearrangement process.

Evolution of a synthetic strategy: total synthesis of (+/-)-welwitindolinone A isonitrile.

An efficient and highly stereoselective total synthesis of the natural product (+/-)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI2-LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties.

Intramolecular thermal allenyne [2 + 2] cycloadditions; facile construction of the 5-6-4 ring core of sterpurene.

A variety of 1-allenyl-2-propargyl-substituted cyclopentanol derivatives were found to undergo facile intramolecular microwave-assisted 2+2 alleneyne cycloaddition reactions to generate tricyclic 5-6-4 ring systems present in the sterpurenes.

Total synthesis of (+/-)-frondosin B.

An expeditious reaction sequence featuring a microwave-assisted tandem 5-exo cyclization-Claisen rearrangement process was used to assemble the A/B ring system of frondosin B. Completion of the target natural product was achieved in 38.2% yield over an eight-step linear sequence.

Synthesis of seven-membered carbocyclic rings via a microwave-assisted tandem oxyanionic 5-exo dig cyclization-claisen rearrangement process.

Appropriately substituted 1-alkenyl-4-pentyn-1-ol systems, readily prepared from simple starting materials, serve as useful precursors to a number of substituted cyclohept-4-enone derivatives via a microwave-assisted tandem oxyanionic 5-exo cyclization/Claisen rearrangement sequence. The reactions involving terminally substituted 4-pentyn-1-ols were found to be highly stereoselective, with the alpha and beta groups in the final product showing a strong preference for the trans orientation.

Progress toward the total synthesis of frondosin C.

A straightforward approach toward the total synthesis of frondosin C is described. This strategy involves a key one-pot, microwave-assisted 5-exo cyclization-Claisen rearrangement sequence that was used for the expedient assembly of the frondosic C scaffold. Subsequent manipulation of the tetracyclic core allowed the synthesis of an advanced intermediate bearing the characteristic diene moiety in the B ring. [reaction: see text]

First approach to the frondosin C ring system via a tandem cyclization/Claisen rearrangement sequence.

[reaction: see text] A one-pot tandem 5-exo cyclization/Claisen rearrangement strategy is utilized as the key step in the straightforward construction of the tetracyclic ring system of frondosin C. This reaction is done under microwave irradiation in the presence of catalytic MeLi.

Acetylenic Vinyllithiums: Consecutive Cycloisomerization-[4 + 2] Cycloaddition Reactions.

Acetylenic vinyllithiums (2), which were generated from the corresponding acetylenic vinyl bromides (3) by low-temperature lithium-bromine exchange, cyclize on warming to give, following quench with water, isomerically pure conjugated bis-exocyclic 1,3-dienes (1) in good to excellent yield. Both five-membered and six-membered outer-ring dienes may be prepared: 5-exo closure of an acetylenic vinyllithium, which proceeds with total stereocontrol via syn-addition to give the E-isomer of a five-membered outer-ring diene, tolerates aryl-, silyl-, or alkyl-substituents at the distal acetylenic carbon; the corresponding 6-exo process is less facile and seems to be confined to substrates bearing an anion-stabilizing substituent, such as phenyl or trimethylsilyl, at the terminal acetylenic carbon. The highly reactive bis-exocyclic 1,3-dienes serve as precursors to polycyclic materials through subsequent Diels-Alder reaction with a wide variety of dienophiles. The consecutive exchange-cyclization-cycloaddition methodology, which can be conducted in one pot without isolation of intermediates, provides an efficient, operationally simple, and diastereoselective route to diverse polycyclic ring systems.