Asymmetric Synthesis of 2‐Thiocyanato‐2‐(1‐aminoalkyl)‐substituted 1‐Tetralones and 1‐Indanones with Tetrasubstituted Carbon Stereogenic Centers via Cooperative Cation‐Binding Catalysis

Abstract

In this study, the concept of cooperative cation‐binding catalysis was applied for direct generation of two contiguous trisubstituted and tetrasubstituted stereogenic centers. Using the readily accessible chiral oligoethylene glycol (oligoEG) as a cation‐binding catalyst, asymmetric Mannich reactions of α‐thiocyanato cyclic ketones as Mannich donors were performed with α‐amidosulfones as the bench‐stable imine precursors in the presence of potassium fluoride as the base, affording 2‐thiocyanato‐2‐(1‐aminoalkyl)‐substituted 1‐tetralones and 1‐indanones possessing fully substituted C–SCN centers. The salient features of this process include (i) a transition metal‐free and operationally simple procedure, (ii) direct use of α‐amidosulfones as bench‐stable precursors of sensitive imines, (iii) direct enolization of racemic cyclic α‐thiocyanato ketones and (iv) excellent stereoselectivity with up to 99% ee and >20:1 diastereoselectivity (anti:syn). This protocol is easily scalable and provides a new approach for the syntheses of some biologically relevant products possessing fully substituted C–SCN centers.magnified image

Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide

“…When the catalyst loading was increased to 10 mol%, the enantioselectivity increased to 87:13 er, and the diastereoselectivity decreased to 71:29 dr. (Table 1, entry 26); therefore, we decided to still use 5 mol% catalyst loading. We also tried to lower the temperature to 0, −10, and −20 • C (Table 1, entries [27][28][29]. Fortunately, when the temperature was lowered to −10 • C, the er value could be increased to 90:10 er.…”

“…1a ‒ 1m were prepared according to the literature report [ 32 , 33 ]. 2a ‒ 2i were prepared according to the literature [ 29 ]. The chiral organocatalysts were prepared by following the reported procedures [ 34 , 35 , 36 , 37 ].…”

“…To the best of our knowledge, there are few reports on the asymmetric catalytic reaction of α-thiocyanoindanones. In 2017, Yu and coworkers used α-thiocyanoindanones and α-aminosulfones to undergo a Mannich reaction, which obtained a series of optically active 2-thiocyanato-2-(1-aminoalkyl)-substituted 1-tetralones and 1-indanones ( Scheme 1 a) [ 29 ]. Regrettably, there has been no report about a series of optically active thiocyanate compounds by using α-thiocyanoindanone as a Michael donor to undergo a 1,4-addition asymmetric reaction.…”

Palladium-catalyzed enantioselective linear allylic alkylation of vinyl benzoxazinanones: An inner-sphere mechanism

“…Thiocyanates are a kind of important compounds found in naturally occurring marine sponges and alkaloids, some of which are reported to display good anti-fungal and anti-fouling activity [38][39][40][41][42][43]. However, the efficient method to prepare chiral compounds bearing thiocyanato-attached stereocenters remains scarce [44][45][46]. In our recent work, α-thiocyanato ketones were proven to be efficient nucleophiles in the asymmetric reaction with o-QM [47].…”

Enantioselective Organocatalyzed Direct α-Thiocyanation of Cyclic β-Ketoesters by N-Thiocyanatophthalimide

“…Tremendous effort has been devoted to developing the formation of C­( sp 2 )–SCN and C­( sp 3 )–SCN bonds by nucleophilic thiocyanate sources with different oxidants or via the formation of a thiocyano radical . For the asymmetric version, chiral quaternary α-cyanatoketones were prepared by the asymmetric Mannich reaction of thiocyanato-preassembled substrates (Scheme a) . Meanwhile, there have been few reports on the direct oxidative α-thiocyanation reactions − or biomimetic SCN transfer, , and the asymmetric ring-opening thiocyanation of epoxides to form a C­( sp 3 )–SCN bond. − To the best of our knowledge, there is only one example of asymmetric electrophilic α-thiocyanation by Evans’ protocol .…”