Diene-transmissive Diels-Alder Research Articles

Diene-Transmissive Enantioselective Diels-Alder Reactions and Sequences Involving Substituted Dendralenes.

Readily available and stable substituted [3]dendralenes undergo highly chemo-, regio-, diastereo-, and enantioselective organocatalyzed Diels-Alder reactions with acrolein to form enantiomerically enriched cycloadducts. These monocycloadducts carry semicyclic dienes that undergo a second, substrate-controlled diastereoselective Diels-Alder reaction with a different dienophile to form 2-fold cycloadducts. Overall, annulated, functional group rich, chiral Δ1(9)-octalin building blocks are accessed in one-pot operations that significantly extend the preparative value of diene-transmissive Diels-Alder sequences since they offer products of regio- and stereochemistry complementary to those generated from the parent, unsubstituted [3]dendralene.

Diene-Transmissive Diels-Alder Sequences with Benzynes.

Diene-transmissive Diels-Alder (DTDA) sequences are extraordinarily powerful processes for the generation of fused bicyclic systems. Nonetheless, only stable dienophiles have previously been deployed. Herein we report DTDA sequences with a variety of substituted [3]dendralenes in the first study to deploy arynes as dienophiles. We demonstrate the one-flask generation of complex, aromatic-ring-containing, multicyclic systems of relevance to medicinal chemistry. These synthetic operations provide numerous successful examples of the otherwise challenging and rarely reported intermolecular Diels-Alder reaction of acyclic 1,3-butadienes with arynes, which is made possible due to the exalted reactivity of dendralenic dienes.

3]Dendralenes: Synthesis, Reactivity Studies and Employment in Diversity-Oriented Synthesis of Complex Polycyclic Scaffolds

[3]Dendralenes are exquisite molecules as they exhibit enormous potential for the rapid generation of architecturally esoteric scaffolds when subjected to tandem Diels–Alder reactions, but their synthesis is a tall order. In conjunction with diversity-oriented synthesis, [3]dendralenes satisfy the potential demand for simultaneous and efficient synthesis of intricate collections of molecules that exhibit a range of activities for lead generation in drug discovery. This account chronicles our roller-coaster journey and systematic approach beginning from the synthesis of extremely unstable, non-isolable [3]dendralenes through moderately stable examples and then finally, highly functionalized, stable [3]dendralenes via sequential methylenation (using dimethylsulfonium methylide) and Horner–Wadsworth–Emmons olefination. It also describes the study of the attributes affecting their stability and reactivity with various dienophiles. In addition, it reports on how these dendralenes, upon astute maneuvering, can be engaged in a diene-transmissive Diels–Alder (DTDA) sequence, thus harnessing their full potential by construction of a small but diverse library of complex frameworks in a quick and efficient manner, with step and atom economy.1 Introduction2 Literature Methods for [3]Dendralene Synthesis3 Our Tryst with [3]Dendralenes3.1 Serendipitous Olefination with the Corey–Chaykovsky Ylide3.2 Synthesis of [3]Dendralenes and Reactivity/Stability Studies3.3 Diels–Alder Reactions of [3]Dendralenes3.4 Tuning of [3]Dendralenes for the DTDA Reactions3.5 Diversity-Oriented Synthesis with [3]Dendralenes3.6 Rationalization of Factors Governing the Stability and Reactivity of [3]Dendralenes4 Conclusions

Tuning the Stability and the Reactivity of Substituted [3]Dendralenes for Quick Access to Diverse Copiously Functionalized Fused Polycycles with Step and Atom Economy.

This is the first comprehensive study that details the synthesis of stable acyclic trisubstituted [3]dendralenes and deciphers their structural requisite for a successful diene transmissive Diels-Alder (DTDA) reaction by employing two different dienophiles and eventually generating a small repository of complex molecules, thus exemplifying how substituted [3]dendralenes could be deployed in diversity-oriented synthesis with high selectivities. A balance of reactivity and stability was struck by prudent selection of the position and nature of functional groups on these [3]dendralenes. Upon tandem Diels-Alder reactions with several symmetrical as well as unsymmetrical dienophiles, these dendralenes afforded diversity-oriented quick access to many polycyclic complex motifs possessing several functional groups and multiple stereogenic centers. Thus, the full potential of the dendralenes could be harnessed. The reactions proceeded under mild conditions with step and atom economy and were highly regio- and stereoselective besides being excellent yielding. The DTDA sequence resulted in the generation of four new carbon-carbon bonds, two new rings, and 3-7 stereogenic centers. The key feature of the method is that we could rapidly generate complexity along with functional and structural diversity from a trivial acyclic substrate with no stereogenic centers.

Ruthenium-catalyzed synthesis of 2,3-cyclo[3]dendralenes and complex polycycles from propargyl alcohols.

Ruthenium-catalyzed cascade transformations for the synthesis of 2,3-cyclo[3]dendralenes and multicomponent processes based thereon to generate complex polycycles are presented. The combination of allylation-cyclization sequences with diene-transmissive Diels-Alder reactions allows the rapid and selective construction of natural-product-like motifs from easily accessible starting materials in a one-pot process and provides a new method to access potential drug candidates.

ChemInform Abstract: Dendralenes Branch Out: Cross‐Conjugated Oligoenes Allow the Rapid Generation of Molecular Complexity

AbstractReview: about 300 refs.

Dendralenes Branch Out: Cross‐Conjugated Oligoenes Allow the Rapid Generation of Molecular Complexity

Twenty-seven years ago, H. Hopf published the only previous comprehensive review on branched oligoenes that had the title "Dendralenes: A Neglected Family of Hydrocarbons". The dendralenes are no longer neglected. Research into the synthesis, properties, and applications of dendralenes is rapidly gaining momentum and this Review summarizes important recent findings. From significant fundamental properties (the first demonstration of alternating behavior since the annulenes) through to unparalleled complexity-generating synthetic transformations, this fundamental oligoene family is coming of age. Effective synthetic approaches to cyclic and acyclic dendralene systems are analyzed and classified. The most powerful synthetic transformations of the dendralenes, diene-transmissive Diels-Alder reactions, are surveyed in detail.

Diene-Transmissive Cycloadditions: Control of Monocycloaddition by Self-Assembly on a Lewis Acid Template

The sequential control of diene-transmissive Diels-Alder reactions to expand their versatility for natural product synthesis and the preparation of diversity oriented libraries is described. Self-assembly of the components (trienol 5 and methyl acrylate) via a Lewis acid template proceeds with regio-, diastereo-, and enantioselective [(S)-BINOL added] control to the monoadduct. In contrast, no cycloaddition reaction occurred at 22 degrees C in the absence of catalyst. This protocol obliterates the necessity of tether installation for an intramolecular cyclization. [reaction: see text].

A Triple Diene-Transmissive Diels−Alder Strategy To Build the Quassinoid Framework

[chemical reaction: see text]. An advanced intermediate to the highly oxygenated triterpene quassinoids was prepared in 14 steps from tetrahydrofuran. The key steps are three diene-transmissive Diels-Alder cycloadditions. Several features of this synthesis are noteworthy, including a successful Mitsunobu reaction on an allenylic alcohol, a rare [4 + 2] cycloaddition involving an enethiol ether dienophile, and complete control over all 10 chiral centers created.

( η2-Propene)Ti(O- i-Pr) 2-mediated cyclization of allenynol derivatives which leads to a stereoselective preparation of cyclic cross-conjugated trienes

Treatment of allenynol derivatives with ( η 2-propene)Ti(O- i-Pr) 2 afforded the title compounds which are a possible starting material for the diene-transmissive Diels-Alder reaction.

The Diene-Transmissive [4 + 2]-Cycloaddition Strategy: Stereoselective Synthesis of Advanced Intermediates to Quassinoids

Complex intermediates to quassinoids, some optically active and containing many functional groups, were synthesized via a diene-transmissive Diels-Alder strategy. The stereochemistry of the key inter- and intramolecular cycloadditions was controlled by stereodefined groups on the preexisting C ring and on the tether

Enantioselective synthesis of an advanced intermediate to quassinoids

An optically pure advanced intermediate to the quassinoids was prepared via the diene-transmissive Diels-Alder cycloaddition strategy. The absolute stereochemistry of the intramolecular cycloaddition was controlled by a methyl and a t-butyldimethylsilyloxy group via a chair-like endo transition state.

A stereoselective diene-transmissive [4 + 2]-cycloaddition strategy for the construction of the tetracyclic quassinoid framework

The tetracyclic quassinoid framework was stereoselectively constructed using a diene-transmissive Diels-Alder reaction between the cyclic formyl-diene 13 and ethyl vinyl ether

ChemInform Abstract: Diene‐Transmissive Diels‐Alder Reactions and Their Related Reactions

A new process of multiple sequence of the Diels-Alder reaction, referred to as “diene-transmissive Diels-Alder reaction”, of cross-conjugated trienes, and a stepwise sequence of double Diels-Alder reaction of cross-conjugated triene equivalents are presented. Bis (silyoxy) cross-conjugated trienes, 1 and 2, undergo two sequential Diels-Alder reactions with a variety of dienophiles giving hydronaphthalene rings. Some characteristics of this reaction have been discussed in terms of stereo-, regio-, and chemoselectivity.Next, cross type of diene-transmissive Diels-Alder reaction has been demonstrated by using trienes, 1 and 2. The first cycloaddition stage of cross reaction, which has to be highly selective in the formation of mono-cycloadducts, has been performed by the reaction of active triene 2 with cyclic olefins or both the trienes, 1 and 2, with acyclic olefins. The second cycloadditions with a variety of dienophiles afforded cross type of bis-adducts. In the similar reactions of 2-ethoxy substituted 34 and 1-methyl substituted cross-conjugated triene 36, the initial cycloaddition selectively occurs across mono-substituted diene part in 34 and disubstituted one in 36, respectively.Finally, cross types of stepwise sequential Diels-Alder reactions in a one-pot procedure are presented using the triene equivalents, 33, 35, 55, and 63. Among them, diene-alcohols, 55 and 63, are very useful triene equivalents, as they are readily available from the Grignard reaction of chloroprene. It is particularly noteworthy that the sequential Diels-Alder reaction using 63 provides a new method for the two six-membered rings annelation to cyclic ketones : Naphtho-annelated cycloalkanes with a variety of unsaturation are obtained by choosing the kind of dienophiles, the order of their use, and dehydrogenation.

Synthesis and Consecutive Double Diels–Alder Cycloadditions of 3-Methylene-5-phenylsulfinyl-1-pentene as a Synthetic Equivalent of Parent Cross-conjugated Triene, 3-Methylene-1,4-pentadiene

Abstract 3-Methylene-5-phenylsulfinyl-1-pentene undergoes stepwise double Diels–Alder cycloadditions with two different dienophiles to afford hydronaphthalene skeletons. This sequence corresponds to cross type of diene-transmissive Diels-Alder cycloaddition of parent 3-methylene-1,4-pentadiene.

ChemInform Abstract: Diene‐transmissive Diels ‐ Alder Reaction Using 2‐Ethoxy‐3‐methylene‐1,4‐pentadiene and 2‐(2‐Bromo‐1‐ethoxyethyl)‐1,3‐butadiene.

AbstractA new cross‐conjugated triene (IV) und a triene equivalent (III) [the precursor of(IV)] have been synthesized and their diene‐transmissive Diels‐Alder Cycloadditions are investigated; the mechanism is discussed thoroughly.

ジエン伝達Ｄｉｅｌｓ‐Ａｌｄｅｒ反応および関連反応

A new process of multiple sequence of the Diels-Alder reaction, referred to as “diene-transmissive Diels-Alder reaction”, of cross-conjugated trienes, and a stepwise sequence of double Diels-Alder reaction of cross-conjugated triene equivalents are presented. Bis (silyoxy) cross-conjugated trienes, 1 and 2, undergo two sequential Diels-Alder reactions with a variety of dienophiles giving hydronaphthalene rings. Some characteristics of this reaction have been discussed in terms of stereo-, regio-, and chemoselectivity.Next, cross type of diene-transmissive Diels-Alder reaction has been demonstrated by using trienes, 1 and 2. The first cycloaddition stage of cross reaction, which has to be highly selective in the formation of mono-cycloadducts, has been performed by the reaction of active triene 2 with cyclic olefins or both the trienes, 1 and 2, with acyclic olefins. The second cycloadditions with a variety of dienophiles afforded cross type of bis-adducts. In the similar reactions of 2-ethoxy substituted 34 and 1-methyl substituted cross-conjugated triene 36, the initial cycloaddition selectively occurs across mono-substituted diene part in 34 and disubstituted one in 36, respectively.Finally, cross types of stepwise sequential Diels-Alder reactions in a one-pot procedure are presented using the triene equivalents, 33, 35, 55, and 63. Among them, diene-alcohols, 55 and 63, are very useful triene equivalents, as they are readily available from the Grignard reaction of chloroprene. It is particularly noteworthy that the sequential Diels-Alder reaction using 63 provides a new method for the two six-membered rings annelation to cyclic ketones : Naphtho-annelated cycloalkanes with a variety of unsaturation are obtained by choosing the kind of dienophiles, the order of their use, and dehydrogenation.

Diene-transmissive Diels-Alder Reaction Using 2-Ethoxy-3-methylene-1,4-pentadiene and 2-(2-Bromo-1-ethoxyethyl)1,3-butadiene

Abstract A new cross-conjugated triene, 2-ethoxy-3-methylene-1,4-pentadiene, and a triene equivalent, 2-(2-bromo-1-ethoxyethyl)-1,3-butadiene, have been synthesized and their diene-transmissive Diels-Alder cycloadditions are investigated. The initial Diels-Alder reaction selectively occurs not across the diene part substituted with the alkoxyl moiety but the monosubstituted diene. Some cross types of diene-transmissive Diels-Alder reaction are demonstrated using the triene equivalent and two different dienophiles.

Cross Diene-transmissive Diels-Alder Cycloaddition Reaction of Bis(silyloxy) Cross-conjugated Trienes

Abstract Cross type of diene-transmissive Diels-Alder cycloaddition has been demonstrated by using two bis-silyloxy cross-conjugated trienes. The first cycloaddition stage of cross reaction, which has to be highly selective in the formation of mono-cycloadducts, has been performed by the reactions of an activated triene with cyclic olefins or those of trienes with acyclic olefins.The secod cycloadditions with a variety of dienophiles provide cross types of bis-adducts. The characteristics of these cross reactios are discussed.

Diene-transmissive Diels-Alder Cycloaddition Reaction of Bis(silyloxy) Cross-conjugated Trienes

Abstract Multiple Diels-Alder reaction of bis(silyloxy) cross-conjugated trienes is presented. Two trienes, 3-benzylidene- and 3-(methoxymethylene)-2,4-bis(trimethylsilyloxy)-1,4-pentadiene, undergo two sequential Diels-Alder cycloadditions with a variety of dienophiles forming hydronaphthalene rings. Some characteristics of this reaction have been discussed in terms of stereo-, regio-, and chemoselectivity. It is proposed that this process is referred to as “diene-transmissive Diels-Alder reaction”.