Endo-Selective Construction of Spiro-[butyrolactone-pyrrolidine] via Ag(I)/CAAA-Amidphos-Catalyzed 1,3-Dipolar Cycloaddition between Azomethine Ylides and α-Methylene-γ-Butyrolactone

Construction of spirocyclic pyrrolidines bearing a spiro quaternary stereocenter is an enormous challenge in synthetic organic chemistry. In this report, we introduce a Ag(I)/CAAA-amidphos-catalyzed enantioselective 1,3-dipolar cycloaddition between azomethine ylides and α-methylene-γ-butyrolactone as an effective strategy for the construction of excellent endo-selective spiro-[butyrolactone-pyrrolidine] derivatives. Meanwhile, the catalytic system was also successfully applied in the three-component one-pot reaction of azomethine ylides formed in situ under the action of N,N′-diisopropylcarbodiimide serving as a dehydrator. Under the optimal conditions, endo-pyrrolidine derivatives bearing a spiro quaternary stereocenter were obtained with high to excellent yields (up to 95% yield) and enantioselectivities (up to 93% ee).


Optimization of the 1,3-Dipole Cycloaddition Reaction Conditions
We first investigated the 1,3-dipolar cycloaddition of α-imino ester 2a and α-methylene-γbutyrolactone 3 catalyzed cooperatively by silver(I) oxide and different CAAA-Amidphos 1a−d ( Table 1, entries 1−4). Through the screening of amidophosphanes, we found that the combination of Ag2O and the amidphos 1d gave relatively satisfactory reactivity and enantioselectivity (Table 1, entry 4). In order to achieve higher enantioselectivities in the process, different metal salts, such as Ag2CO3, AgF, AgOAc, AgOTf, and Cu(OTf)2, were screening for the process (entries 5−9). Disappointingly, the yields and enantioselectivities of endo-4a adduct have not been greatly improved when compared with the catalytic system Ag2O/1d. Next, when the reaction temperature was reduced to −20 °C, the enantioselectivity was increased to 92% ee, albeit with a slightly decreased yield and a prolonged reaction time (6 h, 90% yield, entry 10). Gratifyingly, when 20 mol% H2O was added, the reaction rate was accelerated to 0.7 h with a slightly increased enantioselectivity (93% ee, entry 11). We speculated the water (H2O) reacted with silver(I) oxide (Ag2O) to produce the strong base silver(I) hydroxide (AgOH), which could promote deprotonation of the α-imino esters to generate the azomethine ylide and accelerate the reaction process. Therefore, the optimal conditions for the asymmetric 1,3-dipolar cycloaddition of α-imino ester 2 and α-methylene-γ-butyrolactone 3 were established as 2 mol% Ag2O/4 mol% 1d/20 mol% H2O in toluene at −20 °C.

Study on Substrate Adaptability
Under the optimal reaction conditions, the adaptability of substrates was explored. As shown in Scheme 2, α-imino esters 2a−n from aromatic aldehydes with different electronic properties and steric hindrance reacted with α-methylene-γ-butyrolactone 3 to provide the exclusively endo-selective spirocyclic pyrrolidines 4a−n with high to excellent yields (85%−94%) and enantioselectivities (81%−93% ee) in the presence of the catalytic Ag2O/1d. Notably, the iminoesters derived from 2substituted aromatic aldehydes afforded relatively high enantioselectivities except for the iminoester 2h. When R 1 was the heteroaromatic group, the endo-4o was also successfully obtained with 90% yield and 89% enantioselectivity in 2 h. Delightedly, the primary alkyl iminoester 2p derived from 3methylbutanal was also tolerated, affording the desired endo-4p adduct with moderate yield and enantioselectivity, albeit for requiring prolonged reaction time (4 h, 78% yield, 75% ee).

Study on the Construction of Spiro Pyrrolidines by the Three-Component One-Pot Method
We next transferred our attention to evaluate the three-component one-pot 1,3-dipolar cycloaddition of the in situ generated α-iminoesters from tert-butyl glycinate and different aromatic aldehydes under the action of N,N'-Diisopropylcarbodiimide (DIC) serving as a dehydrator with αmethylene-γ-butyrolactone 3 [29,30]. As shown in Scheme 3, arene-substituents with different electronic properties and steric hindrance were well tolerated and the desired endo-6a−6f were obtained in one-pot process with excellent yields (92%-97%) and moderate to high enantioselectivities (66%-90% ee). Notably, when Ar was 2-furyl group, the corresponding sipro endo-6g was also obtained with 89% yield and 87% enantioselectivity.

Materials
Unless noted otherwise, 1 H and 13 C NMR spectra were recorded on a Bruker AV-400 spectrometer (Bruker Biospin, Fällanden, Switzerland) in CDCl3. CDCl3 served as the internal standard (δ = 7.26) for 1 H NMR and (δ = 77.0) for 13 C NMR. Diastereomeric ratios were determined from crude 1 H NMR. Chiral HPLC was performed on a Agilent 1260 apparatus (Agilent Technologies, California, US) equipped with a spectrophotometric detector (monitoring at 205-230 nm) with Daicel chiral AS-H and AD-H columns (Daicel Chemical Industries Co., Ltd., Tokyo, Japan). All solvents are used after reevaporation. The α-methylene-γ-butyrolactone were purchased from Adamas-beta ® Co., Ltd. (Shanghai, China). Other commercially available reagents were not further purified. All reactions were monitored by thin-layer chromatography (TLC) plates (Qingdao Marine Chemistry Company, Qingdao, China). Flash column chromatography was completed by using silica gel 200-300 (particle size 0.0040-0.0750 mm) (Qingdao Marine Chemistry Company, Qingdao, China). The absolute configuration of endo-6e was determined by X-ray diffraction analysis (Bruker AXS, Karlsruhe, Germany), and those of other products were deduced on the basis of these results.

Conflicts of Interest:
The authors declare no conflict of interest.