Asymmetric amination of cyclic β-keto esters catalyzed by amine-thiourea bearing multiple hydrogen bonding donors

Highly efficient asymmetric amination of cyclic β-keto esters with dialkyl azodicarboxylates has been achieved by bifunctional amine-thiourea bearing multiple hydrogen bond donors. Catalyst 1d showed excellent results for this transformation and provide optically active α-amino acid derivatives in up to 96% ee. Multiple hydrogen bond donors play a significant role in accelerating reactions and improving enantioselectivities.


Introduction
Optically active α-amino acid derivatives are prevalent in many natural alkaloids, compounds of pharmaceutical significance, and biologically important building blocks in organic synthesis. 1he asymmetric amination of β-keto esters with azodicarboxylates provides an efficient approach for the construction of α,α-disubstituted amino acid derivatives containing a nitrogensubstituted quaternary stereocenter, 2 and much attention has been paid to developing enantioselective catalytic protocols for this reaction over the past decade.Highly efficient Cu II /Ph-BOX and Cu II /trisoxazoline complexes catalyzed amination reaction of β-keto esters has been reported by Jørgensen and Gade. 3 Shibasaki developed a Ln III /amide catalytic system to carry out this reaction with high reactivity and excellent enantioselectivity. 4Recently, asymmetric organocatalysis becomes a powerful and environmentally friendly methodology for the catalytic production of the valuable synthetic building blocks and has received much attention. 5Cinchona alkaloid derivatives perform good to excellent reactivities and enantioselectivities for asymmetric amination of β-keto esters, β-keto lactones 6 and αcyanoesters. 7Takemoto's bifunctional thiourea catalyst exhibited excellent catalytic activity for this amination reaction. 8Axially chiral guanidines and quaternary phosphonium phase-transfer catalysts have also been designed and applied successfully for this transformation by Terada and Maruoka. 9Recently, we reported a new class of bifunctional amine-thiourea catalysts 1 bearing multiple hydrogen bond donors, which showed excellent performances in catalytic asymmetric Michael addition and nitro-Mannich reaction. 10Extending the interest of these organocatalysts in asymmetric catalysis, herein we report that oganocatalyst 1d shows excellent results for asymmetric amination of cyclic β-keto esters with azodicarboxylates and provides optically active α,α-disubstituted amino acid derivatives in up to 97% ee.' 2 ' 1 2 1 ' 2 ' * * * *

Results and Discussion
Our initial investigation began with the amination of methyl 2-oxo-cyclopentanecarboxylate 2a and diethyl azodicarboxylate 3a, and the representative results are summarized in Table 1.
To our delight, the reaction was finished in less than 10 min at room temperature in the presence of 10 mol% fine-tunable multiple-hydrogen-bond-donor catalysts 1a-d (Table 1, entries 1-4).Among the catalysts tested, (1R,2R,1'R,2'R)-1d bearing two electron-withdrawing CF 3 groups on the aromatic ring of sulfonamide NHSO 2 Ar revealed to be the most efficient catalyst (Table 1, entry 4), which was consistent with the results achieved in the study of the Michael addition and the nitro-Mannich reaction. 10Much lower enantioselectivity was observed by the methylated (1R,2R,1'R,2'R)-1e as the catalyst further demonstrated the significant importance of the multiple hydrogen bond donors embedded in the catalysts on the reactivity and enantioselectivity (Table 1, entry 6).The catalyst loading is crucial for the reproducibility of the experiment.The enantioselectivity decreased from 81% to 54% when the catalyst loading was reduced from 10mol% to 5 mol% (Table 1, entrie 4 and 5). 11A preliminary screening of solvent effects showed that EtOAc, THF and ether were the solvents of choice; other solvents such as DCM, PhMe, CH 3 CN, DMSO gave lower enantioselectivities (Table 1, entries 4 and 7-12).Protic solvents such as i PrOH or EtOH produced almost racemic adducts (Table 1, entries 13 and 14), which could be ascribed to the unfavorable background reaction 6 or the competitive activation of 3a between catalyst 1d and the protic solvent.Reducing the temperature to -78 o C led to a complete reaction with a remarkable improvement of enantioselectivity (Table 1, entries 15 and 16).Unless otherwise noted, the reaction was performed with 0.10 mmol of 1a and 0.125 mmol of 2a in 0.5 mL of solvent.b Isolated yield.c Enantiomeric excesses were determined by chiral HPLC analysis.d The absolute configurations of the product was determined as S by comparing the optical rotation and HPLC retention time with the reported date.7e 5 mol% catalyst was used.
1d (10 mol%) Unless otherwise noted, the reaction was performed with 0.10 mmol of 2, 0.125 mmol of 3 in 0.5 mL of EtOAc.b Isolated yield.c Enantiomeric excesses were determined by chiral HPLC analysis.d The absolute configurations of the product was determined as S by comparing the optical rotation and HPLC retention time with the reported date. 7aving established the optimal reaction conditions, the scope of this amination reaction was investigated, and the results are summarized in Table 2. First, we examined the effect of the ester substituent of the azodicarboxylates.The results show that the steric hindrance of the ester groups has no influence on the enantioselectivities, and excellent ee ranging from 95% to 96% were observed for all the tested azodicarboxylates, which was opposite to the trend exhibited by Takemoto's thiourea catalyst (Table 2, entries 1-3).Subsequently, the effect of the ester functional group of 2-oxo-cyclopentanecarboxylate 2 was also investigated for this transformation.Although no obvious differentiation of enantioselectivity was observed when the ester functional group of 2 switched from methyl to ethyl, iso-propyl or tert-butyl, the bulky ester functional group such as iso-propyl and tert-butyl has a detrimental effect on the reactivity and renders an extended reaction time (Table 2, entries 2 and 4-6).Catalyst 1d could also affect the asymmetric amination of both six-an seven-membered ring substrates 2e and 2f, although moderate enantioselectivities were achieved (Table 2, entries 9 and 10).Bicyclic β-keto esters 2g and 2h were also tolerated in this reaction, and the corresponding adducts could be obtained in high yields with 76% and 69% ee, respectively (Table 2, entries 11 and 12).The results for asymmetric amination of cyclic β-keto esters are comparable to those obtained with chiral metal catalysts or organocatalysts. 3 The asymmetric amination of 2-acetylcyclopentanone was also investigated.As shown in scheme 1, the desired adduct 4ia was generated in 95% yield with 80% ee under the optimized reaction condition.However, only 10% ee was achieved when acyclic β-keto ester 2jc was applied in this system.

Conclusions
In summary, we have described a highly efficient asymmetric amination of cyclic β-keto esters with dialkyl azodicarboxylates catalyzed by bifunctional amine-thiourea catalyst bearing multiple hydrogen bond donors.Catalyst 1d exhibits the best performance for this transformation and provides optically active α-amino acid derivatives in up to 96% ee.Multiple hydrogen bond donors play a significant role in accelerating reactions and improving enantioselectivities. Future investigation of those bifunctional organocatalyst in other asymmetric reactions is ongoing in our laboratory and will be reported in due course.

Experimental Section
General. 1 H NMR spectra were recorded on a VARIAN Mercury 300 MHz spectrometer in chloroform-d 3 .Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard.The data are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, brs = broad singlet, coupling constant(s) in Hz, integration). 13C NMR spectra were recorded on a VARIAN Mercury 75 MHz spectrometer in chloroform-d 3 .Chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard.Commercially obtained reagents were used without further purification.All reactions were monitored by TLC with silica gel-coated plates.Enantiomeric ratios were determined by HPLC, using a chiralpak AS-H column, a chiralpak AD-H column or a chiralcel OD-H column with hexane and i-PrOH as solvents.