Construction of Optically Active Isotwistanes and Aminocyclitols Using Chiral Cyclohexadiene as a Common Intermediate

Abstract

We have developed a new method for synthesizing chiral isotwistane and homoisotwistane skeletons as well as aminocyclitols in a highly stereoselective manner. These results were achieved through the use of a common intermediate, which was derived from the ytterbium-catalyzed asymmetric Diels-Alder reaction of Danishefsky diene.Key words isotwistane; homoisotwistane; aminocyclitol; Diels-Alder; asymmetric catalysis; hetero-DielsAlder Many biologically active compounds possess a cyclic skeleton with center chirality in their structure. Therefore, the stereoselective synthesis of optically active carbon frameworks is in high demand for synthetic and medicinal chemists. The Diels-Alder reaction has been widely used for this purpose to construct six-membered carbocycles, and the catalytic and enantioselective variant of this reaction has been studied for decades. 1) Our group reported the first example of the catalytic and asymmetric Diels-Alder reaction of Danishefsky diene (1) 2,3) (Chart 1). Functionalized cyclohexene 3 was obtained in optically pure form, and 3 could be transformed to cyclohexenone 4 in quantitative yield. Both functionalized compounds could be potential synthetic intermediates, and we have previously demonstrated the synthetic utility of this reaction. 4-7)In the present study, silyloxy-substituted cyclohexadiene 7 derived from 4 was shown to be a key intermediate for two types of synthetically useful chiral building blocks, i.e., the tricyclo[4.3.1.0 3,7 ] decane (isotwistane 8, n=1) and tricyclo[5.3.1.0 3,8 ] undecane (homoisotwistane 8, n=2) skeletons via the intramolecular Diels-Alder reaction, and aminocyclitol 10 via the intermolecular hetero-Diels-Alder reaction with nitrosobenzene (Chart 2). Results and DiscussionConstruction of Isotwistane and Homoisotwistane Skeletons Isotwistane is an all-carbon tricyclic compound, and its structural motif is found in natural products such as pupukeananes, [8][9][10][11][12] palhinines, [13][14][15] and seychellene. [16][17][18] These types of compounds with (homo) isotwistane skeleton were attracted by their potential for perfumery, and the difference of scent derived from their chirality could be an important research target. Due to the unique structure of isotwistanes, the total syntheses of biologically active compounds with isotwistane skeletons have been studied by many research groups. [19][20][21][22][23] Most of these studies have used the intramolecular DielsAlder reaction to build the fused structure of isotwistane. Based on these previous studies, we planned the synthesis of a chiral isotwistane skeleton by two Diels-Alder reactions: our asymmetric Diels-Alder reaction and a sequential intramolecular Diels-Alder reaction.Dienophiles 2a-d with an olefin in the side chain (R) were prepared. We expected that Lewis acidic activation of the dienophile would occur site-specifically only at the acyloxazolidinone moiety, and the Diels-Alder reaction would take place at the adjacent olefin. With the application of our ytterbium catalyst, 3) the asy...

Catalytic and Enantioselective Diels‐Alder Reaction of Siloxydienes

“…Nishida derivatized the adduct to chiral isotwistane skeletons and aminocyclitols . The intramolecular Diels‐Alder reaction of cyclohexadiene 20 having alkene in its side chain was used to give the corresponding isotwistane (n=1) and homoisotwistane (n=2) skeletons 22 (Scheme ).…”

Pd-Catalyzed Cascade Reactions of Aziridines: One-Step Access to Complex Tetracyclic Amines

“…The cycloaddition step was seen to occur under conditions substantially milder than those of similar IMDA reactions. 14 Indeed, substrates lacking an activated dienophile (i.e., 12a–c ) reacted at 70 °C, and we chose to investigate this further. As observed above, t Bu system 12a proved to be less reactive than amide 12c ( k = 6.8 × 10 –6 s –1 vs k = 5.5 × 10 –5 s –1 at 75 °C).…”

“…The cycloaddition step was seen to occur under conditions substantially milder than those of similar IMDA reactions . Indeed, substrates lacking an activated dienophile (i.e., 12a–c ) reacted at 70 °C, and we chose to investigate this further.…”