Organocatalytic Asymmetric Formal [3+2] Cycloaddition as a Versatile Platform to Access Methanobenzo[7]annulenes

Abstract

Pharmaceutically and structurally important methanobenzo[7]annulenes were synthesized in very good yields with excellent enantio- and diastereoselectivities through an unprecedented organocatalytic formal [3+2] cycloaddition from readily available 2-alkyl-3-hydroxynaphthalene-1,4-diones and alkyl vinyl ketones.

Organocatalyzed Synthesis of [3.2.1] Bicyclooctanes

“…Recently, Ramachary et al have achieved a versatile method to obtain methanobenzo[7]annulenes by organocatalytic asymmetric formal [3 + 2] cycloaddition, as can be seen in Scheme 21 [41]. …”

Construction of 2‐Thiabicyclo[3.3.1]nonanes by Organocatalytic Asymmetric Formal [3+3] Cycloaddition

“…Recently, we have discovered an organocatalytic three‐component reductive alkylation (TCRA) or reductive coupling reaction for the green high‐yielding synthesis of 2‐alkylcyclic‐1,3‐diones from cyclic‐1,3‐diones, aldehydes/ketones, and Hantzsch esters . Later, this method was well recognized and practiced for the synthesis of a library of 2‐alkylcyclic‐1,3‐diones, which are suitable starting materials for the synthesis of a large number of natural products as well as medicinally relevant compounds , .…”

“…Given the recent discovery of the TCRA reaction, we envisioned that l ‐proline 3a could catalyze the TCRA reaction of thiane‐3,5‐dione 1 , aldehydes 2 , and Hantzsch ester 4 to furnish the alkylation products 5 in very good yields (Scheme ); followed by organocatalytic formal [3+3] cycloaddition between the resulting 4‐alkyl‐thiane‐3,5‐diones 5 with alkyl vinyl ketones 6 to yield the desired 2‐thiabicyclo[3.3.1]nonanes 10 in a highly stereoselective and product specific manner, overcoming competition with two other ring‐closing cyclizations (products 8 – 9 , Scheme ).…”

Organocatalytic Asymmetric Formal [3+2] Cycloaddition as a Versatile Platform to Access Methanobenzo[7]annulenes

“…Heteroaryl-substituted hydroxydiones (5n-p)a lso participated in the domino reaction with 6a in the presence of 2k at 20 8 8Cfor 5-9 hours to furnish 8na-pa in 70-91 %y ields with 84-93 % ee,a nd 10:1-16:1 d.r. [10] Moreover,t he scope of either the 2j-o r2k-catalyzed domino reaction was extended further by developing alibrary of optically pure methanobenzo[7]annulenes (8ab-ae)bythe reaction of various hydroxydiones (5a-u)with different alkyl vinyl ketones (6b-e;T able 3). Correspondingly,t he hydroxydiones 5q-u,c ontaining five different alkyl groups also underwent reaction with 6a under 2k catalysis at 20 8 8C for 2-6 hours to furnish the chiral products 8qa-ua in very good yields and ee values with good to excellent d.r.values (entries 16-20).…”

“…Taken together, the resulsts conclusively show that the strength of the hydrogen bonding between 5b-u, possessing 2-alkyl substituents,a nd the catalyst 2k dictates the result of the reaction rate and selectivity.W e established the structure of the domino products 8 by NMR analysis and absolute stereochemistry was confirmed by Xray structure analysis on (À)-8da and (À)-8ea(see Figures S1 and S2). [10] Moreover,t he scope of either the 2j-o r2k-catalyzed domino reaction was extended further by developing alibrary of optically pure methanobenzo[7]annulenes (8ab-ae)bythe reaction of various hydroxydiones (5a-u)with different alkyl vinyl ketones (6b-e;T able 3). Notably,t he domino reaction of ethyl vinyl ketone (6b)with 5aunder the catalysis of either 2j or 2k in trifluorotoluene at 0-3 or 20 8 8Cf or 72 hours furnished 8ab in very poor conversions.H owever,t he same reaction at 40 8 8Cfor 13 hours furnished (+ +)-8ab in 80 %yield with 74 % ee and 90:1 d.r.and (À)-8abin 80 %yield with 76 % ee and 25:1 d.r.…”