Oxidative Asymmetric Formal Aza-Diels–Alder Reactions of Tetrahydro-β-carboline with Enones in the Synthesis of Indoloquinolizidine-2-ones

Ru-catalyzed tandem amine oxidative dehydrogenation/formal aza-Diels–Alder reaction for enantio- and diastereoselective synthesis of indoloquinolizidine-2-ones from tetrahydro-β-carbolines and α,β-unsaturated ketones is described. The reaction proceeds via tandem ruthenium-catalyzed amine dehydrogenation using tert-butyl hydroperoxide (TBHP) as the oxidant and a chiral thiourea-catalyzed formal aza-[4 + 2] cycloaddition, providing a step-economical strategy for the synthesis of these valuable heterocyclic products.


Results and Discussion
At the beginning of this work, we evaluated the model reaction of tetrahydro-β-carboline 4 with enone 5a, in the presence of acetic acid, using tert-butyl hydroperoxide (TBHP) in decane as the oxidant and primary amine-thiourea T as the bifunctional catalyst which allows dual activation of the reaction components by the hydrogen bond donor and primary amine (Table 1). [18,19,36] In the presence of the oxidant alone, the desired formal aza-Diels−Alder product 6 could not be obtained (entry 1). In the presence of Cu salt, the diastereoisomers 6aa and 7aa were obtained in 22% yield with poor diastereomeric ratio (dr) and enantioselectivities (entry 2). Ruthenium complexes exhibit cytochrome P450-like activity to catalyze selective oxidative demethylation of tertiary methyl amines in the presence of peroxides or molecular oxygen [40][41][42]. When several r4uthenium catalysts were employed in the reaction system, the desired products could be obtained in moderate yields with moderate dr and ee (entries 3−5). Among these, RuCl2(PPh3)3 gave the best enantioselectivety (69% ee of 6aa and 66% ee of 7aa) albeit in lower yield and poorer dr (entry 5). Interestingly, when the amount of acetic acid decreased to 15 mol %, the ee values increased significantly to 87% and 83% respectively and the yield and dr were both improved slightly (entry 6 vs. entry 5). Compared to PhCOOH, o-F-PhCOOH or the absence of acid, CH3CO2H gave the best results in the reaction (entry 6 vs. entries 7-9). Several oxidants were further investigated, among them only TBHP could afford the desired products effectively (entry 6 vs. entries [10][11][12]. Final evaluation of the solvents showed that toluene was the most suitable medium to give the best results (entry 6 vs. entries [13][14][15][16]. When the reaction solution was diluted to 0.2 M in toluene, the best yield (73%) and enatioselectivities (94% ee of 6aa and 90% ee of 7aa) were obtained with moderate diastereomeric ratio (entry 17).

Results and Discussion
At the beginning of this work, we evaluated the model reaction of tetrahydro-β-carboline 4 with enone 5a, in the presence of acetic acid, using tert-butyl hydroperoxide (TBHP) in decane as the oxidant and primary amine-thiourea T as the bifunctional catalyst which allows dual activation of the reaction components by the hydrogen bond donor and primary amine (Table 1). [18,19,36] In the presence of the oxidant alone, the desired formal aza-Diels−Alder product 6 could not be obtained (entry 1). In the presence of Cu salt, the diastereoisomers 6aa and 7aa were obtained in 22% yield with poor diastereomeric ratio (dr) and enantioselectivities (entry 2). Ruthenium complexes exhibit cytochrome P450-like activity to catalyze selective oxidative demethylation of tertiary methyl amines in the presence of peroxides or molecular oxygen [40][41][42]. When several r4uthenium catalysts were employed in the reaction system, the desired products could be obtained in moderate yields with moderate dr and ee (entries 3−5). Among these, RuCl2(PPh3)3 gave the best enantioselectivety (69% ee of 6aa and 66% ee of 7aa) albeit in lower yield and poorer dr (entry 5). Interestingly, when the amount of acetic acid decreased to 15 mol %, the ee values increased significantly to 87% and 83% respectively and the yield and dr were both improved slightly (entry 6 vs. entry 5). Compared to PhCOOH, o-F-PhCOOH or the absence of acid, CH3CO2H gave the best results in the reaction (entry 6 vs. entries 7-9). Several oxidants were further investigated, among them only TBHP could afford the desired products effectively (entry 6 vs. entries [10][11][12]. Final evaluation of the solvents showed that toluene was the most suitable medium to give the best results (entry 6 vs. entries [13][14][15][16]. When the reaction solution was diluted to 0.2 M in toluene, the best yield (73%) and enatioselectivities (94% ee of 6aa and 90% ee of 7aa) were obtained with moderate diastereomeric ratio (entry 17). Scheme 1. Asymmetric formal aza-Diels-Alder reaction for the synthesis of Indoloquinolizidine-2-ones.

Results and Discussion
At the beginning of this work, we evaluated the model reaction of tetrahydro-β-carboline 4 with enone 5a, in the presence of acetic acid, using tert-butyl hydroperoxide (TBHP) in decane as the oxidant and primary amine-thiourea T as the bifunctional catalyst which allows dual activation of the reaction components by the hydrogen bond donor and primary amine (Table 1) [18,19,36]. In the presence of the oxidant alone, the desired formal aza-Diels-Alder product 6 could not be obtained (entry 1). In the presence of Cu salt, the diastereoisomers 6aa and 7aa were obtained in 22% yield with poor diastereomeric ratio (dr) and enantioselectivities (entry 2). Ruthenium complexes exhibit cytochrome P450-like activity to catalyze selective oxidative demethylation of tertiary methyl amines in the presence of peroxides or molecular oxygen [40][41][42]. When several r4uthenium catalysts were employed in the reaction system, the desired products could be obtained in moderate yields with moderate dr and ee (entries 3−5). Among these, RuCl 2 (PPh 3 ) 3 gave the best enantioselectivety (69% ee of 6aa and 66% ee of 7aa) albeit in lower yield and poorer dr (entry 5). Interestingly, when the amount of acetic acid decreased to 15 mol %, the ee values increased significantly to 87% and 83% respectively and the yield and dr were both improved slightly (entry 6 vs. entry 5). Compared to PhCOOH, o-F-PhCOOH or the absence of acid, CH 3 CO 2 H gave the best results in the reaction (entry 6 vs. entries 7-9). Several oxidants were further investigated, among them only TBHP could afford the desired products effectively (entry 6 vs. entries [10][11][12]. Final evaluation of the solvents showed that toluene was the most suitable medium to give the best results (entry 6 vs. entries [13][14][15][16]. When the reaction solution was diluted to 0.2 M in toluene, the best yield (73%) and enatioselectivities (94% ee of 6aa and 90% ee of 7aa) were obtained with moderate diastereomeric ratio (entry 17).  Having established the optimal reaction conditions, the generality of this oxidative formal aza-Diel−Alder reaction for enones was then investigated. A variety of aryl-substituted enones 5b-n reacted smoothly with tetrahydro-β-carboline 4 under the optimized conditions to afford products 6ab-an in moderate to satisfactory yields with good diastereoselectivities and high enantioselectivities ( Table 2). Regardless of the position of the methyl group on the phenyl ring, moderate yields and high ee values were obtained (entries 2-4). Electron-withdrawing groups in the different positions of the phenyl ring afforded the corresponding products 6af-ai with good results (entries 5-8). Interestingly, substrate 5j with five fluorine atoms on the phenyl ring or the substrates 5k and 5l with two substituents on the phenyl rings gave the desired products with excellent diastereoselectivities (>10:1) in moderate yields. Moreover, α,β-unsaturated ketones bearing 2thiophene or 2-furan also performed well and led to the products with good stereochemical outcomes (6am and 6an). Importantly, linear alkyl group subtituted enone 5o could also undergo the reaction smoothly and afford the product 6ao with excellent diastereoselectivities (>10:1) and good enantioselectivity, albeit the yield was low relatively, even prolonging reaction time to 96 h. Some other enones such as 5-methyl-3-methylenehexan-2-one and (E)-1-phenylpent-1-en-3-one have been   Having established the optimal reaction conditions, the generality of this oxidative formal aza-Diel-Alder reaction for enones was then investigated. A variety of aryl-substituted enones 5b-n reacted smoothly with tetrahydro-β-carboline 4 under the optimized conditions to afford products 6ab-an in moderate to satisfactory yields with good diastereoselectivities and high enantioselectivities ( Table 2). Regardless of the position of the methyl group on the phenyl ring, moderate yields and high ee values were obtained (entries 2-4). Electron-withdrawing groups in the different positions of the phenyl ring afforded the corresponding products 6af-ai with good results (entries 5-8). Interestingly, substrate 5j with five fluorine atoms on the phenyl ring or the substrates 5k and 5l with two substituents on the phenyl rings gave the desired products with excellent diastereoselectivities (>10:1) in moderate yields. Moreover, α,β-unsaturated ketones bearing 2-thiophene or 2-furan also performed well and led to the products with good stereochemical outcomes (6am and 6an). Importantly, linear alkyl group subtituted enone 5o could also undergo the reaction smoothly and afford the product 6ao with excellent diastereoselectivities (>10:1) and good enantioselectivity, albeit the yield was low relatively, even prolonging reaction time to 96 h. Some other enones such as 5-methyl-3-methylenehexan-2-one and (E)-1-phenylpent-1-en-3-one have been employed in the reaction, unfortunately, no desired products were obtained (see Supplementary Materials). The absolute configuration of 6 and 7 was established according to the retention time in HPLC using chiral columns and comparison with the data obtained for the same known products reported by Jacobsen et al. [18].
Similar to the results of the 1,2,3,4-tetrahydroisoquinolines [36], under oxidative conditions, tetrahydro-β-carbolines afforded corresponding (4R,12bS)-6 as the major stereoisomer having a cis-H/H relationship which is different from the outcomes of the formal aza-Diels-Alder reaction of imines with enones [18]. Therefore, the same plausible mechanism can be proposed (Figure 2). Intermediate imine B (dihydro-β-carboline) can be formed through the oxidation of 4 by oxoruthenium (IV) intermediate A which is generated from the Ru(II) catalyst in the presence of TBHP. Then, imine B enters another catalytic cycle and undergoes a formal aza-Diels-Alder reaction with enone, which is similar to the pathway hypothesized by Jacobsen's group. Finally, the Ru complex present in the reaction mixture promotes epimerization at C-4, leading to the thermodynamic (4R,12bS)-adducts (6) after liberation from the thiourea catalyst T. The epimerization can take place by either retro-Mannich/Mannich or amine β-elimination/conjugated addition sequences [18]. Table 2. Scope of various α,β-unsaturated ketones *.
Molecules 2018, 23, x 4 of 8 employed in the reaction, unfortunately, no desired products were obtained (see Supplementary  Materials). The absolute configuration of 6 and 7 was established according to the retention time in HPLC using chiral columns and comparison with the data obtained for the same known products reported by Jacobsen et al. [18].  Similar to the results of the 1,2,3,4-tetrahydroisoquinolines [36], under oxidative conditions, tetrahydro-β-carbolines afforded corresponding (4R,12bS)-6 as the major stereoisomer having a cis-H/H relationship which is different from the outcomes of the formal aza-Diels−Alder reaction of imines with enones [18]. Therefore, the same plausible mechanism can be proposed (Figure 2). Intermediate imine B (dihydro-β-carboline) can be formed through the oxidation of 4 by oxoruthenium (IV) intermediate A which is generated from the Ru(II) catalyst in the presence of TBHP. Then, imine B enters another catalytic cycle and undergoes a formal aza-Diels−Alder reaction with enone, which is similar to the pathway hypothesized by Jacobsen's group. Finally, the Ru complex present in the reaction mixture promotes epimerization at C-4, leading to the thermodynamic (4R,12bS)-adducts (6) after liberation from the thiourea catalyst T. The epimerization can take place by either retro-Mannich/Mannich or amine β-elimination/conjugated addition sequences [18].

Materials and Methods
NMR spectra were recorded on Aglient-600 MHz (Agilent Technologies, PaloAlto, CA, USA) or Brucker-400 MHz spectrometer (Bruker, Billerica, MA, USA) using CDCl3 as solvent and TMS as internal standard unless otherwise stated. Mass spectra were recorded on a Thermo LTQ Orbitrap

Conclusions
In conclusion, we have presented the diastereo-and enantioselective oxidative formal aza-Diels-Alder reaction of tetrahydro-β-carboline and α,β-unsaturated ketones under the cooperative catalysis of Ru(II) salt and chiral aminothiourea in the presence of TBHP, yielding functionalized (4R,12bS)-indoloquinolizidine-2-ones. The practical protocol of asymmetric oxidative formal aza-Diels-Alder enlarges the substrate scope and offers interesting new opportunities to synthesize the natural products and pharmaceutical compounds further.