Solvent-controlled diastereodivergent cascade synthesis of trisubstituted tetrahydrothiophenes utilizing polystyrene-supported amine

An efficient and solvent – controlled diastereodivergent thia-Michael/aldol cascade synthesis of tetrahydrothiophenes (THTs) has been developed. The cascade reaction is catalyzed by polystyrene-supported amine to afford trisubstituted tetrahydrothiophene derivatives in excellent yields and diastereoselectivities. A broad range of substrate tolerance is examined under two different solvents to access a library of diastereomeric THTs. Moreover, the polymer-supported amines can be recovered and reused for the cascade reaction.


Introduction
3][4][5][6][7] For examples; biotin, a water-soluble B vitamin A, which plays an essential role in many biological processes; a potent-glucosidase inhibitor salacinol B and kotalanol C, isolated from several Salacia species; a highly efficient and specific A3 adenosine receptor antagonist 4′-thioadenosine derivative D; 4′thiocytidine nucleoside E is shown to have activity against HSV-1 and HSV-2; (R)-tetrahydrothiophene-3-ol F is an essential intermediate to the synthesis of potent antibacterial sulopenem G and other penem-based antibiotics; and tetronothiodin H is a cholecystokinin type-B receptor antagonist.][10][11][12] Adsorption of THT on gold has also been recognized as a crucial technique for producing self-assembled monolayers (SAMs), which are useful for controlling the physical and chemical characteristics of surfaces for various technological applications. 13Over the past few decades, much effort has been made to synthesize THT derivatives due to their synthetic utilities and potent biological activities. 14,15gure 1.Selective bioactive compounds having tetrahydrothiophene core.
Several methods have been accomplished to reduce the tedious workup and purification processes during organic synthesis. 16Despite overwhelming advancement, the development of efficient and sustainable methodologies still continues as a challenging and an attractive field of research.The utilization of solidsupported catalysts is one of the most fascinating ways to overcome waste generation and time-consuming purification.][24]

Results and Discussion
Our recent findings on the synthesis of trisubstituted THTs indicated that DABCO was an appropriate catalyst for the thia-Michael/aldol reaction. 47We move towards the solid-supported catalyst to make the methodologies more sustainable, eco-friendly and to reduce the purification time.We initiate our investigation with the 5 mol % of polystyrene-supported 1,4-diazabicyclo[2.2.2]octane (PS-DABCO) (I) as a catalyst for the cascade reaction of -keto ester 1a and 1,4-dithiane-2,5-diol 2 in toluene at room temperature.The reaction was not fully completed after 48 h and the diastereoselectivity was quite low (Table 1, entry 1).Next, the reaction was performed with higher catalyst loadings and 20 mol % of PS-DABCO was found to be efficient enough to afford a synthetically viable yield and moderate dr (Table 1, entry 3).Pleasingly, the dr was enhanced by performing the reaction at 0 °C.However, lowering the reaction temperature had a detrimental effect on yield (Table 1, entry 5).
Further, we have explored several polymer-supported catalysts.The reaction was much faster in polystyrene-supported 4-(dimethylamino)pyridine (PS-DMAP) (II) than PS-DABCO (I) (Table 1, entry 6).Gratifyingly, diisopropylaminomethyl-polystyrene (III) afforded the desired product 3a in excellent yield and diastereoselectivity (Table 1, entry 7).When the reaction was carried out with diethylaminomethylpolystyrene (IV), an almost similar yield was observed (Table 1, entry 8).In the presence of a stronger base like bicyclic nitrogen-containing catalyst polystyrene-supported 1,8-diazabicyclo[5.4.0]undec-7-ene (PS-DBU) (V), the reactants consumed much faster.However, diastereoselectivity was very poor (Table 1, entry 9).Diisopropylaminomethyl-polystyrene (III) was used as an organocatalyst for further optimization of reaction condition.Several solvents were tested.In general, non-polar solvents yielded 3a as the major diastereomer.Toluene was the best-suited solvent among others to provide 3a in high yield and dr (Table 1, entry 7).Surprisingly, it was found that the presence of ethanol as a solvent led to the different diastereoisomer 4a as a major isomer (Table 1, entry 16).Serendipitously, complete switching of diastereoisomer was observed in the presence of acetonitrile as a reaction solvent.After seeing the reversal of diastereoselectivity, we again investigate all polymer-supported catalysts in the presence of acetonitrile solvent.Diisopropylaminomethylpolystyrene was indeed found to be efficient for forming both diastereoisomers in the presence of different solvent systems ( a Reaction conditions: 1a (81.7 mg, 0.4 mmol), 2 (33.5 mg, 0.22 mmol), PS-Cat.(I-V), toluene (0.5 mL), unless specified.b Diastereomeric ratio for all entries was determined by 1 H NMR analysis of crude reaction mixture.c Isolated yield.
Having the optimized reaction conditions, we explored the substrate generality for solvent-controlled diastereodivergent synthesis of trisubstituted tetrahydrothiophenes. Firstly, substrate scope under the © AUTHOR(S) condition A (in the presence of toluene as a solvent, Table 2) was investigated leading to 2,3-anti-3,4-syn isomer (3).
−Ketoesters bearing para-halos (F, Cl, Br) on aryl led to the formation of desired products (3a-d) in excellent yield and diastereoselectivity.Both electron-withdrawing (cyano-and nitro-) and donating groups (tert-butyl-and methoxy-) on the para-position of the phenyl ring were well tolerated under the optimized reaction conditions, affording the tetrahydrothiophene products (3e-h).Excellent yield and dr were obtained with dihalo-substitution on several positions of the phenyl ring of unsaturated ketoesters (1i-l).
Noteworthy, heteroaryl substituted, namely 2-thiophenyl, tetrahydrothiophene (4o) was prepared efficiently.Next, aliphatic Michael acceptor (R 1 = Me) was used.Although, the reaction was relatively slow, the desired THT (4r) was isolated in 81% yield with 13:1 dr.Gram-scale reactions were carried out to demonstrate the synthetic potential of the developed solvent-controlled diastereodivergent methodology.The cascade thia-Michael/aldol reactions at the gram scale under both conditions proceeded efficiently to afford desired diastereoisomers in excellent yield and selectivity.

AUTHOR(S)
Further, the supported catalyst was recovered and recycled up to 10 cycles under both optimized conditions (Scheme 1).Notably, after each cycle, the isolated yield decreased slightly.However, diastereoselectivity remained unaffected.In addition, the hydroxyl group of trisubstituted tetrahydrothiophenes 3a and 4a was transformed into hydrogen sulfate (5a and 6a) group by treating with pyridine•SO3 (Scheme 2).

Conclusions
In summary, we have successfully established a diastereodivergent synthesis of trisubstituted tetrahydrothiophenes via thia-Michael/aldol reaction of 1,4-dithiane-2,5-diol to activated olefins.The © AUTHOR(S) diastereo-switch was achieved by altering solvents in the presence of a solid-supported amine catalyst giving excellent yield and dr.In addition, the synthetic utilities of the developed method were examined by gram scale reaction and by recycling of supported catalyst for the synthesis of both diastereoisomers.Also, the hydroxyl group of products THT was transformed into THT-hydrogen sulfate derivatives.

Experimental Section
General.Unless otherwise noted, all reactions were carried out in closed vial. 1 H NMR spectra were recorded on a 500 MHz or 400 MHz spectrometers (125 MHz or 100 MHz for 13C NMR).The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet.TLC was performed with silica gel GF254 precoated on aluminium plates and spots were visualized with UV.Flash column chromatography was performed on silica gel.HPLC analysis was performed on an HPLC instrument equipped with a UV-Vis detector.IR spectra were recorded on an FT-IR spectrometer and only major peaks were reported in cm −1 .High-resolution mass spectra (HRMS) were obtained by the ESI-TOF method.Optical rotations were measured on a commercial automatic polarimeter and reported as follows: [α]25 D (c = g/100 mL, solvent).Melting points were recorded on a digital melting point apparatus.α,β-Unsaturated ketone 1 derivatives. 24All the other chemicals, reagents, catalysts II-V, and solvents were purchased from commercial sources and used as received unless specified.4-(Dimethylamino)pyridine, polymer-bound extent of labelling: ~3.0 mmol/g DMAP loading, matrix crosslinked with 2% DVB purchased from Sigma Aldrich.Diisopropylamine, polymer-bound -100-200 mesh, extent of labelling: 2.0-3.5 mmol/g loading, 1% cross-linked with divinylbenzene purchased from Sigma Aldrich.Diethylaminomethyl-polystyrene extent of labelling: ~3.2 mmol/g loading, 200 -400 MESH purchased from Sigma Aldrich.1,8-Diazabicyclo[5.4.0]undec-7-ene, polymer-bound, 100-200 mesh, extent of labelling: 1.5-2.5 mmol/g loading, 1 % cross-linked with divinylbenzene purchased from Sigma Aldrich.Chloromethyl Polystyrene Resin crosslinked with 1% DVB (100-200mesh) (2.0-3.0mmol/g)purchased from TCI chemicals.Diastereoisomeric ratio mentioned in the manuscript table 2, 3, and 4 is calculated by crude reaction mixture.Diastereoisomeric ratio mentioned on the proton NMR spectra is calculated after purification of products.

Table 1 .
Initial optimization of cascade thia-Michael/aldol reaction a