Synthesis of Angularly Substituted trans‐Fused Decalins through a Metallacycle‐Mediated Annulative Cross‐Coupling Cascade

Abstract

Ac onvergent coupling reaction is described that enables the stereoselective construction of angularly substituted trans-fused decalins from acyclic precursors.T he process builds on our alkoxide-directed titanium-mediated alkynealkyne coupling and employs a1 ,7-enyne coupling partner. Overall, the reaction is thought to proceed through initial formation of at etrasusbstituted metallacyclopentadiene,s tereoselective intramolecular [4+ +2] cycloaddition, elimination, isomerization, and regio-and stereoselective protonation. Distinct from our early studies directed at the synthesis of trans-fused hydrindanes,t he current annulative coupling reveals an important effect of TMSCl in controlling the final protonation-the event that establishes the stereochemistry of the ring fusion.

Catalytic Enantioselective Formal (4+2) Cycloaddition by Aldol–Aldol Annulation of Pyruvate Derivatives with Cyclohexane‐1,3‐Diones to Afford Functionalized Decalins

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The decalin structure is found in bioactive molecules.W eh ave developed catalytic enantioselective formal (4+ +2) cycloaddition reactions via aldol-aldol cascade reactions between pyruvate-derived diketoester derivatives and cyclohexane-1,3-dione derivatives that affordh ighly functionalized decalin derivatives.The reactions were performed using aq uinidine-derived catalyst under mild conditions.D ecalin derivatives bearing up to six chiral carbon centers including tetrasubstituted carbon centers were synthesized with high diastereo-and enantioselectivities.F ive to six stereogenic centers were generated from achiral molecules with the formation of two C À Cb onds in as ingle transformation resulting in the formation of the decalin system. [2][3][4][5] Construction of the decalin ring system has been performed using cycloadditions, [2] cross coupling, [3] polyene cyclizations and related ene-involved annulations, [4] Robinson annulations [2c,d, 5] and related Michael-aldol reactions, [6] in which the reactions start from Michael additions to a,b-unsaturated ketones.H ere we report organocatalytic enantioselective aldol-aldol annulation cascade reactions to afford functionalized decalin derivatives (Scheme 1).In our strategy,C2symmetric starting materials pyruvatederived diketoester derivatives (dihydropyran derivatives) 1 [7] and cyclohexane-1,3-diones 2 are used for the aldol-aldol annulation cascade reactions to construct new cyclohexane rings,r esulting in the formation of decalin derivatives 3 or 4 (Scheme 1). [1] Decalin derivatives often have antiinflammatory,a nti-bacterial, and anti-tumor activities.

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“…[1] Decalin derivatives often have antiinflammatory,a nti-bacterial, and anti-tumor activities. [2][3][4][5] Construction of the decalin ring system has been performed using cycloadditions, [2] cross coupling, [3] polyene cyclizations and related ene-involved annulations, [4] Robinson annulations [2c,d, 5] and related Michael-aldol reactions, [6] in which the reactions start from Michael additions to a,b-unsaturated ketones.H ere we report organocatalytic enantioselective aldol-aldol annulation cascade reactions to afford functionalized decalin derivatives (Scheme 1). [2][3][4][5] Construction of the decalin ring system has been performed using cycloadditions, [2] cross coupling, [3] polyene cyclizations and related ene-involved annulations, [4] Robinson annulations [2c,d, 5] and related Michael-aldol reactions, [6] in which the reactions start from Michael additions to a,b-unsaturated ketones.H ere we report organocatalytic enantioselective aldol-aldol annulation cascade reactions to afford functionalized decalin derivatives (Scheme 1).…”

“…[1] Therefore,s ynthesis of functionalized decalin derivatives is of interest in drug discovery efforts and in related research. [2][3][4][5] Construction of the decalin ring system has been performed using cycloadditions, [2] cross coupling, [3] polyene cyclizations and related ene-involved annulations, [4] Robinson annulations [2c,d, 5] and related Michael-aldol reactions, [6] in which the reactions start from Michael additions to a,b-unsaturated ketones.H ere we report organocatalytic enantioselective aldol-aldol annulation cascade reactions to afford functionalized decalin derivatives (Scheme 1).In our strategy,C2symmetric starting materials pyruvatederived diketoester derivatives (dihydropyran derivatives) 1 [7] and cyclohexane-1,3-diones 2 are used for the aldol-aldol annulation cascade reactions to construct new cyclohexane rings,r esulting in the formation of decalin derivatives 3 or 4 (Scheme 1). Ther eaction is expected to generate five or six stereogenic centers,d epending on the substituent of 2.W e hypothesized that appropriate catalysts and conditions would accelerate the reactions of 1 with 2 to afford decalin derivatives 3 and 4 with high diastereo-and enantioselectivities.…”

“…[1] Therefore,s ynthesis of functionalized decalin derivatives is of interest in drug discovery efforts and in related research. [2][3][4][5] Construction of the decalin ring system has been performed using cycloadditions, [2] cross coupling, [3] polyene cyclizations and related ene-involved annulations, [4] Robinson annulations [2c,d, 5] and related Michael-aldol reactions, [6] in which the reactions start from Michael additions to a,b-unsaturated ketones.H ere we report organocatalytic enantioselective aldol-aldol annulation cascade reactions to afford functionalized decalin derivatives (Scheme 1).…”