Catalytic asymmetric synthesis of pyrrolidine derivatives bearing heteroatom-substituted quaternary stereocenters

Zhi-Peng Wang , Qi Wu , Jia Jiang , Zi-Rui Li , Xiao-Jiao Peng , Pan-Lin Shao * and Yun He *
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing 401331, P.R. China. E-mail:;

Received 4th August 2017 , Accepted 17th September 2017

First published on 18th September 2017

An enantioselective [3 + 2] cycloaddition of heteroatom-substituted alkenes with α-substituted isocyanoacetates has been developed. The resulting cycloadducts could be further transformed to access a number of structurally diverse and biologically important pyrrolidine derivatives which bear sulfur- or oxygen-substituted quaternary stereocenters. Excellent reactivity and enantioselectivity were obtained for a broad range of substrates.


Isocyanoacetates and their derivatives are widely used in organic, inorganic, coordination, polymeric, combinatorial, and medicinal chemistry.1 Moreover, their unique chemical reactivity renders them as versatile building blocks for the synthesis of biologically active molecules and natural products, and makes them very attractive for investigations.2 Our recent efforts have been devoted to using functionalized 1,3-dipole enolate derived from isocyanoacetate under chiral Brønsted base conditions.3 We have developed several asymmetric [3 + 2] cyclizations of isocyanoacetates with α-imino esters,3a allenoates,3b and methyleneindolinones3c with the aid of chiral silver(I) complexes developed by the Dixon group4 to synthesize oxazole-imidazolines, 3H pyrroles and spirooxindoles, respectively. While the nature of these reaction profiles necessitates further investigation, it provided more possibilities for our methodology to produce structurally diverse compounds for biological screening (Scheme 1).
image file: c7qo00692f-s1.tif
Scheme 1 Representative [3 + 2] cycloaddition of isocyanoacetates.

For several years, we have been pursuing the development of asymmetric synthesis of heterocyclic compounds, especially nitrogen-containing heterocycles,3,5 such as pyrrolidines and their analogues. Chiral pyrrolidine has been considered a “privileged scaffold” and exists in many biologically active natural products, organocatalysts and synthetic materials.6 In particular, pyrrolidine derivatives bearing heteroatom-substituted quaternary stereocenters may present more opportunities to these applications,7 especially for small-molecule drug design.8 Therefore, the development of catalytic enantioselective methods to construct such moieties would be highly desired. Herein we describe the asymmetric [3 + 2] cyclization of heteroatom-substituted alkenes9 with α-substituted isocyanoacetates to synthesize pyrrolidine derivatives bearing sulfur as well as oxygen substituted quaternary stereocenters via a sequential [3 + 2] cycloaddition and hydrogenation (Fig. 1).

image file: c7qo00692f-f1.tif
Fig. 1 Catalytic asymmetric synthesis of pyrrolidines bearing heteroatom-substituted quaternary stereocenters.

Results and discussion

As shown in Table 1, the readily available methyl 2-(tert-butylthio)acrylate 1a and methyl 2-isocyano-2-phenylacetate 2a were chosen as the model substrates to investigate the feasibility of the [3 + 2] cycloaddition/reduction. Inspired by the recent reports from the Dixon group4 and based on our development on enantioselective isocyanoacetate cycloaddition catalyzed by silver(I) complexes,3 we tested the related cinchona-derived amino phosphine precatalysts for this process. To our great delight, the use of precatalyst 3a with Ag2O led to excellent yield (92%) and enantioselectivity (trans: 96% ee, cis: 93% ee) at ambient temperature, using THF as a solvent, albeit with poor diastereoselectivity (trans[thin space (1/6-em)]:[thin space (1/6-em)]cis = 65[thin space (1/6-em)]:[thin space (1/6-em)]35) (entry 1). Lowering the temperature didn't significantly impact the cyclization (entries 5–8). A survey of solvents identified CHCl3 as the most suitable media (99% yield, trans[thin space (1/6-em)]:[thin space (1/6-em)]cis = 75[thin space (1/6-em)]:[thin space (1/6-em)]25, trans: 98% ee, cis: 96% ee) (entries 9–14). A series of optimizations were conducted, although higher diastereoselectivity was not obtained, the diastereomers bearing Cγ-tetrasubstituted α-thioether acid moieties could be easily separated by chromatography. Thus, we identified the following optimal protocol: the reaction of 1a and 2a with a molar ratio of 1.0[thin space (1/6-em)]:[thin space (1/6-em)]1.2 in the presence of Ag2O (10 mol%) and precatalyst 3a (20 mol%) in CHCl3 (1 mL) at −20 °C. It is worth noting that all the reactions were set up in open air without the need for exclusion of air or moisture.
Table 1 Optimization of the reaction conditionsa

image file: c7qo00692f-u1.tif

Entry Precatalyst Solvent Temp. Yieldb [%] trans[thin space (1/6-em)]:[thin space (1/6-em)]cisc eed [%] (trans, cis)
a Reaction conditions: Ag2O (0.01 mmol), precatalyst 3 (0.02 mmol), 1a (0.10 mmol), 2a (0.12 mmol), solvent (1.0 mL), 24 h. b Total yields of the isolated trans and cis-isomer. c Determined by 1H NMR spectroscopy (400 MHz) of the reaction mixture. d Determined by HPLC analysis using a chiral stationary phase. See the ESI for details.
1 3a THF 25 °C 92 65[thin space (1/6-em)]:[thin space (1/6-em)]35 96, 93
2 3b THF 25 °C 88 83[thin space (1/6-em)]:[thin space (1/6-em)]17 −95, −81
3 3c THF 25 °C 91 84[thin space (1/6-em)]:[thin space (1/6-em)]16 −91, −76
4 3d THF 25 °C 90 83[thin space (1/6-em)]:[thin space (1/6-em)]17 −92, −55
5 3a THF 0 °C 93 66[thin space (1/6-em)]:[thin space (1/6-em)]34 97, 95
6 3a THF −10 °C 93 68[thin space (1/6-em)]:[thin space (1/6-em)]32 98, 95
7 3a THF −20 °C 95 68[thin space (1/6-em)]:[thin space (1/6-em)]32 98, 96
8 3a THF −40 °C 95 69[thin space (1/6-em)]:[thin space (1/6-em)]31 95, 95
9 3a CHCl3 −20 °C 99 75[thin space (1/6-em)]:[thin space (1/6-em)]25 98, 96
10 3a DCM −20 °C 95 67[thin space (1/6-em)]:[thin space (1/6-em)]33 98, 97
11 3a Toluene −20 °C 98 56[thin space (1/6-em)]:[thin space (1/6-em)]44 95, 95
12 3a EA −20 °C 97 69[thin space (1/6-em)]:[thin space (1/6-em)]31 98, 95
13 3a Et2O −20 °C 96 67[thin space (1/6-em)]:[thin space (1/6-em)]33 96, 95
14 3a TBME −20 °C 95 68[thin space (1/6-em)]:[thin space (1/6-em)]32 93, 88

To study the utility of this catalytic regime, the effect of substituents in isocyanoacetates 2 with different acidity of the α-hydrogen atoms was investigated under the optimized conditions. To our delight, the [3 + 2] cyclization products 4 were obtained in uniformly high yields and enantioselectivities (Table 2). The substrates, bearing electron-neutral (4a), electron-rich (4b), electron-deficient (4c) and bulky (4d, 4e) aryl groups, participated in the reaction and proved to be suitable substrates, thus furnishing the corresponding products in excellent yields (86–99%) and enantioselectivities (trans: 94%–98% ee, cis: 92%–97% ee). Different substitution patterns on the isocyanoacetates, benzyl (4f), methyl (4g), butyl (4h), ester (4i), isopropyl (4j) and cyclohexyl (4k) groups were well tolerated. The relative and absolute configuration of 4g were established as (2S,4R) by single crystal X-ray analysis, and those of other products 4 were assigned by analogy.10 Notably, the formation of 4 highlighted the versatility of our method to prepare pyrrolidine derivatives possessing two quaternary stereocenters. This process represents an advancement of operational simplicity, synthetic efficiency and atom economy.

Table 2 Substrate scope with respect to α-substituted isocyanoacetatesa
a Unless otherwise noted, reactions were carried out with Ag2O (0.01 mmol), precatalyst 3a (0.02 mmol), 1a (0.10 mmol), 2 (0.12 mmol) in CHCl3 (1.0 mL) at −20 °C for 24 h. The dr values were determined by 1H NMR spectroscopy (400 MHz) of the reaction mixture. The yields given are those of the isolated of diastereoisomers. The enantiomeric excesses were determined by chiral HPLC analysis. See the ESI for details.
image file: c7qo00692f-u2.tif

Using this catalytic protocol, α-thioacrylates 1 with alkyl or aryl groups were then examined for the [3 + 2] cyclization and the representative results are summarized in Table 3. These substituents at the α-thioacrylates (R1 = butyl, benzyl, phenyl) have no significant effect on the reactivity and selectivity. All the reactions went smoothly, providing products 4l–n in uniformly high yields (91%–93%) and excellent enantioselectivities (trans: 92%–98% ee, cis: 88%–96% ee).

Table 3 Substrate scope with respect to α-thioacrylatea
a See Table 2 and the ESI for details.
image file: c7qo00692f-u3.tif

Then, we turned our attention to determine the scope of this process with other heteroatom substituents, with the goal to provide a versatile approach for drug leads. As expected, the same reaction conditions could be utilized for the sequential asymmetric [3 + 2] cycloaddition/reduction of α-tosyloxyacrylate 5 with α-substituted isocyanoacetates 2 to produce pyrrolidine derivatives 6, which bear Cγ-tetrasubstituted α-hydroxy acid moieties. Pyrrolidine derivatives with 2-methyl (6a), benzyl (6b), and phenyl (6c) groups were all produced in excellent yields (90%–96%) and enantioselectivities (trans: 97%–99% ee, cis: 83%–94% ee) from the corresponding α-substituted isocyanoacetates (Table 4).

Table 4 Substrate scope with respect to α-substituted isocyanoacetatesa
a See Table 2 and the ESI for details.
image file: c7qo00692f-u4.tif

With respect to nitrogen-substituted alkenes, such as α,β-dehydroamino acids (7), which are reasonably reactive in Michael addition and cycloadditions,11 turned out to be difficult substrates using this catalytic system. Nevertheless, during the process employing the cinchona-derived bifunctional squaramide catalyst 8, methyl 2-(4-methylphenylsulfonamido)-acrylate 7 was transformed to methyl 2-(tosylimino)propanoate 9, which served as a ketimine in the reaction with isocyanoacetate 2a. This Mannich-type reaction proceeded smoothly, affording imidazoline 10 containing two quaternary stereocenters in excellent yield (98%) with high diastereoselectivity (cis[thin space (1/6-em)]:[thin space (1/6-em)]trans = 88[thin space (1/6-em)]:[thin space (1/6-em)]12) and enantioselectivity (90% ee) (Scheme 2). The imidazoline moiety could be reduced to yield the masked α,β-diamino ester 11, whose relative and absolute configuration were confirmed by X-ray analysis.10

image file: c7qo00692f-s2.tif
Scheme 2 Organocatalytic [3 + 2] cyclization of 7 and 2a. See the ESI for details.


We have developed a catalytic enantioselective synthesis of the structurally diverse and biologically important pyrrolidine derivatives bearing two heteroatom-substituted quaternary stereocenters via a sequential [3 + 2] cycloaddition/reduction of α-substituted isocyanoacetates with heteroatom-substituted olefins, providing the corresponding cycloadducts in high yields (up to 99%) and excellent enantioselectivities (up to >99% ee). The high efficiency of this process, coupled with the operational simplicity, makes it an attractive method for pyrrole synthesis. Application of this protocol in drug discovery is ongoing in our laboratory.

Experimental section

General procedure for the synthesis of pyrrolidine derivatives

To a 10 mL tube charged with 3a (12.3 mg, 0.02 mmol) and Ag2O (2.3 mg, 0.01 mmol) was added CHCl3 (1 mL). The mixture was stirred at −20 °C for 5 minutes, then α-thioacrylate 1a (17.4 mg, 0.10 mmol) and isocyanoacetate 2a (21.0 mg, 0.12 mmol) were added. The reaction mixture was stirred at −20 °C until 1a was consumed, and then filtered through a pad of silica gel and washed with ethyl acetate. The solvent was removed under reduced pressure and then the residue was dissolved in MeOH (1 mL), and then NaCNBH3 (12.6 mg, 0.20 mmol) and HOAc (12 mg, 0.20 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 0.5 h, concentrated and then purified by flash chromatography on silica gel (hexanes/ethyl acetate, 2[thin space (1/6-em)]:[thin space (1/6-em)]1) to afford product 4a.

Conflicts of interest

There are no conflicts to declare.


The authors gratefully acknowledge the National Natural Science Foundation of China (no. 21402150, 21372267, 21572027) and Chongqing University for financial support. The authors thank Dr Yong-Liang Shao (Lanzhou University) and Xiangnan Gong (Chongqing University) for the X-ray crystallographic analysis.

Notes and references

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Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data, copies of 1H and 13C NMR spectra. CCDC 1538775 (4g) and 1538777 (11). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7qo00692f

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