The identification of new asymmetric tandem reactions that allow the rapid and atom-economic generation of enantioenriched complex molecules from simple starting materials remains a key goal of modern organic synthesis. These tandem reactions allow multiple C-C or C-O bond-forming events to occur in a single vessel and,as a consequence,significantly increase the efficiency for the overall process  and frequently serve as a fundamental platform for the construction of the special skeletons in a predictable one-pot style and have always been in great demand.
Catalytic asymmetric inverse-electron-demand Diels-Alder reaction (IEDDAR),one of the most powerful tools,is provoking continuous interest of chemists ,and has been partially addressed in the elegant work including the activation of dienes through the LUMO-lowering strategy with the aid of Lewis acidic metal complexes  or organic molecules  as well as the catalytic approach involving enamine-activated HOMO of the electron-rich dienophiles by Jøgensenet al.  and Chen et al. . However,reactions that simultaneously activate both the LUMO and HOMO are still challenging.
For these reasons,considerable effort has been devoted to the development of catalytic asymmetric Diels-Alder reaction cascades,which has been recognized as one of the most useful approaches . Among these achievements,organocatalysis, especially bifunctional chiral thiourea-catalyzed transformations, exhibited extraordinary value and aroused wide interest [7, 8, 9]. Jian Wang  reported an asymmetric organocatalytic cascade involving Michael/hemiketalization/retro-Henry reaction of b,gunsaturated ketoesters  witha-nitroketones. Rui Wang  recently developed a new class of thiourea bifunctional catalysts based on rosin and successfully applied them to several asymmetric transformations.
Encouraged by these elegant advancements,we hoped to extend the application of organocatalysts (Fig. 1) and improve the efficiency of the related tandem transformations. Fortunately,an unprecedented result was found in the application of a chiral rosinderived bifunctional thiourea catalyst in the reaction of α-nitro ketones with β,γ-unsaturated a-ketoesters,which gave better stereoselectivity and yields than the similar transformations reported by others . Furthermore,experimental and theoretical investigations suggested that the reaction maybe proceeded through a different process including a tandem cascade involving an IEDDAR and a retro-Henry reaction. The IEDDAR occurred through a simultaneous activation of LOMO and HOMO. These reactions gave versatile synthetic building blocks for further transformations .2. Experimental
A mixture of 1c (0.01 mmol,10.0 mol%) and b,g-unsaturated ketoester 2 (0.15 mmol) in dry toluene (1.0 mL) was stirred at -15°C for 30 minutes. Thena-nitro ketone 3 (0.10 mmol) was added. After the reaction was completed (monitored by TLC analysis),the resulting mixture was concentrated under reduced pressure and the residue was purified through column chroma-tography on silica gel using petroleum ether/ethyl acetate (1:8,v/v) as an eluent to give the optically pure product 4-6. 3. Results and discussion
Our initial investigation began by screening organocatalysts (Fig. 1) to evaluate their ability to promote the tandem reaction of b,g-unsaturateda-ketoester (2a)witha-nitro acetophenone (3a) in the presence of 10 mol% catalyst loading at 10°C in toluene. As shown in Table 1,in the presence of catalyst 1a,the reaction proceeded smoothly to yield the desired product 4a in high yield (90%) and promising enantioselectivity (73%ee,entry 1 in Table 1). Subsequently,a brief survey of other catalysts was conducted.Notably,tertiary amine containing thioureas 1a-1e gave adducts in almost the same high yields (entries 1-5 in Table 1),but 1c furnished the products with the best enantioselectivity (89% ee, entry 3 in Table 1). Furthermore,catalyst 1f and 1g could also prompt the reactions,albeit in lower yields and selectivity. It was found that the configuration of 4a was determined by the chiral center in the cyclohexanediamine moiety and both chiral moieties in 1c were responsible for theeevalues. The two chiral moieties in 1c were additive and 1c gave the best enantioselectivity. By comparison,there appeared a mismatch between the chirality of the quinine part and the rosin part in 1e,leading to the worst result. As a reference,a previously reported thiourea 1h that has only one stereogenic center without the positive or negative influence from the second chiral center gave a moderate result.
Further optimization of the solvents was carried out using catalyst 1c (entries 6-9 in Table 1) and the effect of the reaction temperature was also examined (entries 10-13 in Table 1). To our delight,toluene was still the best solvent in terms of chemical yield and enantioselectivity. The side-reactions were effectively inhibited and the yields were further improved when the reaction temperature was lowered. The best result was observed (92% yield, and 97%ee,entry 12 in Table 1) when the reaction was performed in the presence of the tertiary amine-thiourea 1c at -15°C in toluene. Besides,the enantiomeric excess can be maintained by using 5 mol% of catalyst1cbut with a slight decrease in the chemical yield (entry 14 in Table 1).
Having established the optimal conditions,a range ofb,gunsaturateda-ketoesters was then surveyed to determine the scope and limitations of this reaction. As shown in Table 2,the rosin-derived thiourea catalyst lc was highly effective in promoting the IEDDAR/retro-Henry reaction cascades. It also appeared that the electronic properties and the position of the substituents on the phenyl ring inb,g-unsaturateda-ketoesters had a limited influence on the enantioselectivity of the reaction (entries 1-11 in Table 2),the products 4 were formed in high yields (86%-92%) and excellent enantioselectivies (90%-98%ee). Notably,b,g-unsaturateda-ketoesters bearing 2-naphthyl,2-thienyl also afforded their corresponding products in high yields and excellent enantioselectivity (98% and 95%ee,respectively,entries 12 and 13 in Table 2). The expansion of the protocol to other b,g-unsaturated aketoesters with different substituents on the ester moiety gave the desired products ineevalues ranging from 93% to 97% (entries 14-19 in Table 2),which are obviously superior to those of reported cases .
The reaction ofa-nitro acetone 3b withb,g-unsaturated aketoesters with different substituents on the aromatic ring or the ester moiety also gave high enantioselectivity and yields. Gratifyingly,some of the reactions produced almost optically pure adducts.
The relative and absolute configurations of the products were determined by X-ray crystal structure analysis of 4s (see the Supporting information and Fig. 2) and the X-ray structure of 4s has been deposited in the Cambridge Crystallographic Data Center with a code of CCDC 822960.
Encouraged by the good results obtained above,more challenging substrate,a-nitro propiophenone 3c,was synthesized and applied in the reaction with 2a. To our delight,the enhanced steric hindrance of 3c had limited effect on the result. The reaction proceeded smoothly and completed within 48 h,affording the product 6a in 6:1 drand 99%ee(Scheme 1).
According to literature ,the mechanism of this transformation catalyzed by 1h should follow the Path A in Scheme 2,where Michael adduct 10 was the key intermediate,and 10 was enolized to 11 followed by a cyclization to produce 12 subsequently. However,no Micheal adduct 10 was observed in our cases monitored by NMR and thin layer chromatography analyses. In fact,Hais more acidic than Hbin 10,so the enolation of 10would have favored the formation of 13 rather than11and product 14 rather than 12 should have been obtained (Scheme 2).
In Wang and co-worker’s report ,controlled experiments have performed with 2a and 7a/7b as shown in Scheme 3. Under the catalysis of quinine,2a reacted with 7a and 7b,respectively, formed Micheal adduct 15 and 16 through Path B as shown in Scheme 2,but no tandem product 17 was observed. In order to clarify the intermediates involved,our controlled experiments were done with 2a and 7a/7b using 1c as a catalyst,too. However, we observed neither the Micheal adducts 10 nor 12. In fact,no Micheal adducts were found during the entire process of the reactions of 2 and 3 catalyzed by 1c(Scheme 3).
Elsewhere,catalyst 1c has succeeded in a direct IEDDAR  and no Michael adducts were observed either.
The above theoretical analysis,literature research and experimental verification showed that our transformation catalyzed by 1c proceeded via different intermediates from those reported . Accordingly,a new mechanism,a tandem process of IEDDAR and retro-Henry,was proposed as shown in Scheme 4. Initially,a-nitro ketone 3 was enolized to form enol 9,which reacted with 2 as a dienophile under the catalysis of thiourea and yielded the IEDDAR product 10. Then the basicity of the catalyst prompted the retro-Henry reaction of 10 leading to the formation of 4-6.4. Conclusion
In conclusion,we disclosed a more efficient asymmetric reaction cascade of a-nitroketones with b,g-unsaturated aketoesters catalyzed by rosin-derived thiourea catalysts. The improvement on the see value depends on the additive effect of the two chiral moieties in the catalyst. A new tandem IEDDAR/ retro-Henry process was proposed by theoretical analyses, literature research and experimental verifications,which allows the formation of multiple C-C and C-O bonds in one pot. The IEDDAR proceeded via a dual HOMO (dienophiles) and LUMO (dienes) activation pathway,which represents a new utility of bifunctional catalysts. Excellent yields and excellent stereoselectivity were obtained in all substrates tested. This work found a more efficient catalyst for the tandem IEDDAR/retro-Henry reactions,along with a deep investigation on the additive and subtractive effects between the multiple chiral moieties in organocatalysts. Acknowledgments
We are grateful for the grants from the National Natural Science Foundation of China (Nos. 21071068 and 21372107) and the Fundamental Research Funds for the Central Universities (No. lzujbky-2012-k08). Appendix A. Supplementary data
Supplementary material related to this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2013.12.024.
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