Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

A dipeptide-based urea-amide tertiary amine (DP-UAA) was shown to be an effective Brønsted base catalyst for the first asymmetric annulation reaction between 5H-thiazol-4-ones and N-itaconimides. High levels of enantioselectivity (up to 99% ee) and diastereoselectivity (>19:1 dr) were obtained for a series of spirocyclic 1,4-sulfur-bridged piperidinone-based succinimides.

Recently, we described an organocatalytic asymmetric [4 + 2] cyclization of 5H-thiazol-4-ones with a series of activated alkenes, including nitroalkenes, 4-oxo-4-arylbutenones, 4-oxo-4-arylbutenoates and methyleneindolinones [10].This work elucidated the feasibility of the electrophilic addition to the C2 position of 5H-thiazol-4-ones.More importantly, it provided a direct and convenient approach to synthesize three kinds of biologically important chiral 1,4-sulfur-bridged piperidinones and a The reaction was performed in a 0.05 mmol scale; b yield was isolated by flash column; c ee was determined by HPLC.

Results and Discussion
Our studies were initiated by examining a model reaction between 5H-thiazol-4-one 1a and N-phenyl itaconimide 2a (Table 1).The reaction was first evaluated in toluene at 25 °C and using L-tert-leucine-based thiourea−tertiary amine I as the catalyst (Table 1, entry 1), with excellent catalytic efficacy as demonstrated in a series of asymmetric reactions [18].It was found that the reaction was completed after 48 hours, affording the desired [4 + 2] annulation adduct 3a in 55% yield with 64% ee.A significant amount of conjugate addition adduct led to the unsatisfactory chemoselectivity and thus the moderate yield.When the H-bond donor was changed from thiourea to urea (catalyst II), it did not provide better results (Table 1, entry 2) [17,19].In the [4 + 2] annulation of 5H-thiazol-4-ones with nitroalkenes, dipeptide-based thiourea−amide−tertiary amine III (DP-TAA) was devised and demonstrated as a competent catalyst to furnish excellent chemo-and stereoselectivity [10].Therefore, we examined catalyst III for this reaction (Table 1, entry 3); annulation adduct 3a was obtained in 60% yield with 70% ee.The increased in enantioselectivity indicates the potential of dipeptide-based tertiary amine for this type of reaction.By modifying the thiourea moiety of III to urea lead us to catalyst DP-UAA IV, which could further increase the enantioselectivity (Table 1, entry 4).Subsequently, we screened the solvent effect with IV as the catalyst (Table 1, entries 5-7), and the results revealed that chloroform was the best reaction medium regarding the enantioselectivity (Table 1, entry 7).By changing the reaction temperature (Table 1, entries 8 and 9), we found that the yield of 3a was decreased to 60% but the ee value was increased to 92% at −10 °C (Table 1, entry 9).To improve the chemoselectivity, we synthesized a series of DP-UAAs through tuning of the substituent groups of the urea.We were pleased to find that the reaction rate could be tremendously increased by utilizing DP-UAA V as the catalyst, and 3a was obtainable with high enantioselectivity, high chemoselectivity and excellent yield of 98% (Table 1, entry 10).
Through an analysis of the absolute configuration of adduct 3, it is proposed that a plausible reaction mechanism should be similar to the DP-TAA-catalyzed [4 + 2] annulation between 5H-thiazol-4-ones and nitroalkenes [10].In this stepwise process, the use of 3,5-dichlorophenyl as the substituent group of the urea in catalyst V would remarkably increase the free energy difference between Rand S-selection in the first Michael addition step, and also decreases the free energy of the second formal Mannich reaction, thus improving the reaction rate and chemoselectivity of the [4 + 2] cycloaddition.
To extend the usefulness of this reaction, we demonstrate that the adduct can be efficiently reduced with borane.As shown in Scheme 2, 3a was readily reduced to afford a spirocyclic sulfurbridged N-heterocycle 4 in 70% yield and without compromising its ee value.

Conclusion
In conclusion, we have developed the first asymmetric reaction of 5H-thiazol-4-ones with N-itaconimides.By employing a DP-UAA catalyst, the reaction undergoes a [4 + 2] annulation process with excellent chemoselectivity and with a broad substrate scope, affording a series of valuable chiral spirocyclic 1,4-sulfur-bridged piperidinone-based succinimides in high yields (up to 98%) and excellent enantio-and diastereoselectivities (up to 99% ee and >19:1 dr).Further investigations involving new [4 + 2] annulation of 5H-thiazol-4-ones DP-TAAs and DP UAAs currently ongoing and will be reported in due course.

Table 1 :
Optimization of reaction conditions a .