Expanding the Scope of Primary Amine Catalysis: Stereoselective Synthesis of Indanedione-Fused 2,6-Disubstituted trans-Spirocyclohexanones

Abstract

A cinchona-alkaloid-derived chiral primary-amine-catalyzed enantioselective method for the synthesis of the thermodynamically less stable indanedione-fused 2,6-trans-disubstituted spirocyclohexanones is demonstrated. Both the enantiomeric forms of the trans isomer are obtained in excellent yields and enantioselectivities. Furthermore, one of the enantiopure trans-spiranes bearing an additional α-substitution on the cyclohexanone ring was then epimerized into its thermodynamically stable cis counterpart, with little loss of enantioselectivity to demonstrate the feasibility of such a transformation. Mechanistic investigations revealed two competing pathways, a concerted Diels-Alder reaction and a stepwise Michael addition, for the formation of corresponding products.

Enantioselective Construction of Tetrahydroquinolin-5-one-Based Spirooxindole Scaffold via an Organocatalytic Asymmetric Multicomponent [3 + 3] Cyclization

“…To test the feasibility of our hypothesis, the reaction of dimedone-derived enaminone 1a , N -benzyl-substituted isatin 2a , and malononitrile 3 was used as a model reaction in the presence of chiral cinchona alkaloid catalyst 5a , which smoothly afforded the desired tetrahydroquinolin-5-one-based spirooxindole 4aa but in a moderate yield and with low enantioselectivity (Table , entry 1). A series of bifunctional catalysts, 5b – i , derived from various cinchona alkaloids were screened (entries 2–9). Although the yields were still unsatisfactory, cinchona alkaloid derivatives 5b and 5d bearing two hydroxyl groups were superior to others in controlling the enantioselectivity (entries 2 and 4 vs entries 1, 3 and 5–9), which may be attributed to the action of the two hydroxyl groups in forming multiple hydrogen bonds with enaminone 1 and intermediate A .…”

Asymmetric Synthesis of Nature‐Inspired Bioactive Spiro Compounds through Organocatalytic Diels–Alder Reactions

“…In summary, we have described, for the first time, the highly asymmetric 4 a / 5 b ‐catalyzed ATCDA reaction of arylideneacetones, aryl aldehydes and 1,3‐indandione by a Barbas dienamine strategy under ambient conditions. The ATCDA reaction proceeds in good yields with high exo ‐selectivity using a synergistic combination of primary amine 4 a with simple Brønsted acid 5 b . Furthermore, we have demonstrated the direct application of the ATCDA reaction in the asymmetric synthesis of anticancer products anti ‐(−)‐ 6 an and anti ‐(−)‐ 6 ao through two sequences of Suzuki–ATCDA or ATCDA–Suzuki reactions.…”

Michael Addition‐Elimination and [4+1] Annulation of Sulfonylphthalide with Hydroxychalcones for the Synthesis of Alkylidenephthalides and Indanediones

“…The indanedione moiety is an integral part of several natural products and bioactive compounds, for instance, the anti‐tumor agent Fredericamycin A [9–10] . Methodologies for the construction of 1,3‐indanediones, including 2‐substituted 1,3‐indanediones, involve selective C‐alkylation of 2‐( o ‐bromomethyl)benzylidene‐1,3‐ indandione, [11] rhodium(II) acetate catalyzed decomposition of 2‐diazo‐1,3‐indanedione, [12] tin(II) chloride catalyzed reaction of α ‐diazoketones with aldehydes, [13] palladium chloride catalyzed oxidation and cyclization of 2‐(2‐arylethynylphenyl) acetonitrile, [14] Pd(II) catalyzed reaction of t BuNC with o ‐bromoarylketones, [15] organocatalyzed reaction of 2‐arylideneindanedione with conjugated enones etc [16] …”

“…[9][10] Methodologies for the construction of 1,3-indanediones, including 2-substituted 1,3-indanediones, involve selective C-alkylation of 2-(o-bromomethyl)benzylidene-1,3-indandione, [11] rhodium(II) acetate catalyzed decomposition of 2-diazo-1,3-indanedione, [12] tin(II) chloride catalyzed reaction of α-diazoketones with aldehydes, [13] palladium chloride catalyzed oxidation and cyclization of 2-(2-arylethynylphenyl) acetonitrile, [14] Pd(II) catalyzed reaction of t BuNC with obromoarylketones, [15] organocatalyzed reaction of 2-arylideneindanedione with conjugated enones etc. [16] Phthalides bearing a stabilizing group at the benzylic position are excellent donors in conjugate additions, especially in the first step of Hauser-Kraus (HÀ K) annulation. [17][18][19][20] Hauser-Kraus (HÀ K) annulation is a widely employed synthetic method for the construction of naphthoquinones via [4 + 2] annulation of stabilized phthalides with Michael acceptors and thereby synthesis of a variety of bioactive molecules, including natural products (Scheme 1a).…”