Stereoselective Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters via

Letter Cite This: Org. Lett. 2018, 20, 6564−6568

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Stereoselective Allylic Alkylation of 1‑Pyrroline-5-carboxylic Esters via a Pd/Cu Dual Catalysis Penglin Liu,†,§ Xiaohong Huo,†,§ Bowen Li,† Rui He,† Jiacheng Zhang,† Tianhong Wang,† Fang Xie,*,† and Wanbin Zhang*,†,‡ †

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, and ‡School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China

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S Supporting Information *

ABSTRACT: The asymmetric allylation of 1-pyrroline-5-carboxylic esters has been accomplished through a synergistic Pd/Cu catalyst system under mild reaction conditions. The mechanistic studies suggested that (1) nucleophilic attack is the enantiodiscriminating step; (2) the cooperative action of two chiral reactive species, N-metalated azomethine ylides and πallylpalladium, is most likely responsible for its high reactivity and excellent enantioselectivity (up to >99% ee); and (3) the steric hindrance and electronic factors of the allylic electrophiles and imino ester substrates are crucial for the formation of the linear products. A series of 3,4-2H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high yields and with high to excellent regioselectivity and enantioselectivity.

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catalysis. While organocatalysts can activate a range of functional groups,7 metal catalysts possess a greater number of activation modes.8 It is expected that this bimetallic catalysis strategy would enable a much broader range of asymmetric reactions. Indeed, enantioselective reactions with α-hydroxyketones compounds, amino acid derivatives, α-CF3 amides, and azaaryl acetamides as nucleophiles have recently been reported.9 It is believed that the combination of this bimetallic catalysis strategy and the allylic chemistry will provide a great opportunity for the enantioselective synthesis of natural products and important bioactive compounds. Recently, the enantioselective transformation of cyclic imino esters has attracted much attention, as they serve as versatile synthetic intermediates for the preparation of many natural and biologically active compounds, for example, cis-5-phenylproline, spirocyclic scaffolds, and pyrrolizidine (Scheme 1).10 Among various methodologies, the Pd-catalyzed asymmetric allylic alkylation of readily available cyclic imino esters are most promising in terms of operational simplicity, starting material availability, and convenience of derivation. However, this transformation has not been reported previously, mainly due to (1) its low reactivity or need for harsh reaction conditions, (2) the challenging stereocontrol of prochiral nucleophiles, and (3) the regioselective formation of either the branched or linear product. Herein, we implement a bimetallic catalysis strategy for the enantioselective allylic alkylation of cyclic imino esters and explore the specific performance of this strategy in allylic substitution reactions from the viewpoint of

ince the pioneering work of Tsuji and Trost, Pd-catalyzed asymmetric allylic substitution has long been the focus of asymmetric catalysis research and has become an important synthetic tool among chemists.1 This methodology not only provides access to a number of enantiopure bioactive molecules but also provides an opportunity for understanding the mechanism of the stereocontrol of the enantioselective catalysis.1,2 These are mainly due to the obvious advantages of allylic chemistry, including: (1) the ease of derivatization of target compounds containing an isolated double bond; (2) the ability to produce enantiomerically pure products from either achiral or chiral racemic substrates; and (3) the compatibility with a large variety of nucleophiles and, thus, the enantioselective catalytic formation of multiple types of bonds. Accordingly, much effort has been devoted to this area, and considerable progress has been achieved. However, several issues still exist: (1) the scope of nucleophiles remains limited;3 (2) problems associated with the stereocontrol of prochiral nucleophiles owing to the long distance between the stereogenic and catalytic centers; and (3) the regioselective control of either the branched or linear products.4 Thus, the development of catalytic strategies to address these issues are highly desired. Recently, synergistic catalysis has attracted increasing attention due to its advantages over traditional catalytic methodologies for reactivity and selectivity.5 By introducing a second organocatalyst to this process, a series of uncommon nucleophiles (e.g., simple aldehydes and ketones) could be successfully applied in the asymmetric allylic alkylation under mild conditions through the combined use of palladium/ enamine.6 Meanwhile, a second metal catalyst is introduced to this process for the realization of synergistic bimetallic © 2018 American Chemical Society

Received: September 11, 2018 Published: October 10, 2018 6564

DOI: 10.1021/acs.orglett.8b02902 Org. Lett. 2018, 20, 6564−6568

Letter

Organic Letters Scheme 3. Substituent Effects on Regioselectivitya

Scheme 1. Bimetallic Catalysis Strategy for the Asymmetric Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters

a Reaction conditions: see Table 1, entry 4. Isolated yield of the linear products. b24 h.

Table 2. Substrate Scope of the Allylic Acetatesa

Table 1. Optimization of Reaction Conditionsa

entry

1

T (°C)

yieldb (%)

1 2e 3f 4 5 6

1a 1a 1a 1a 1b 1c

rt rt rt 50 50 50

67 6 0 93 93 94

l/b

ee of 3ac

dr of 4d

ee of 4 (%)c

1:1.8 1:4.3

94 6

1.7:1 1.3:1

98/95 3/44

1:1.4 1:1.4 1:1.3

93 94 93

2.2:1 2.2:1 2.2:1

96/93 96/93 97/94

a

Reaction conditions: 2a (0.25 mmol), 1 (1.4 equiv), Pd/L (5 mol %), Cu/L (5 mol %), K2CO3 (1.0 equiv), THF (1.5 mL), 16 h. b Isolated yield of the mixture of the linear and branched products. c The ee values were determined by HPLC using chiral columns, and the absolute configuration was determined by comparison of the sign of the optical rotation with that in the reported data.10a dDetermined by 1H NMR integration of the crude reaction mixtures. eWithout Cu catalyst. fWithout Pd catalyst.

Scheme 2. Proposed Mechanism for the Asymmetric Allylic Alkylation of 1a−c

a Reaction conditions: see Table 1, entry 4. bIsolated yield of the linear products. cSee Table 1, footnote c. dFor 1b. eFor 1c. f24 h.

were mainly formed via the attack of the carbon nucleophiles at the phenyl substituted position (l/b = 1:1.8) and the enantioselectivity of the linear and branched products are both satisfactory (94% ee and 98%/95% ee, respectively). Subsequently, control experiments were conducted to probe the cooperative interplay of the bimetallic catalyst system. Only a trace amount of the substituted product was obtained in the

reactivity, regioselectivity, and stereocontrol of the prochiral nucleophiles (Scheme 1). Initially, cinnamyl acetate 1a was selected as an electrophilic precursor for the asymmetric allylation of the cyclic imino ester 2a in the presence of K2CO3 using a [Pd/L + Cu/L] catalyst combination (Table 1). We found that the branched products 6565

DOI: 10.1021/acs.orglett.8b02902 Org. Lett. 2018, 20, 6564−6568

Letter

Organic Letters Table 3. Substrate Scope of Cyclic Imino Estersa

The linear E substrate 1a usually forms a syn-configured allyl complex that may produce the linear E and/or the branched product. The linear Z substrate 1c will initially form an anticonfigured allyl complex, which may react directly with the nucleophile to generate the Z linear and/or the branched product. As for the branched allylic substrate 1b, these are expected to give a mixture of the syn and anti-configured allyl intermediates (Scheme 2).4a Accordingly, reactions with two linear (E and Z) and the branched allylic precursors were conducted under the optimal reaction conditions. Similar results, including the l/b ratio, yield, and enantioselectivity of both the linear and branched products were obtained (Table 1, entries 4−6). It can be concluded that the rate of nucleophilic attack is slower than that of anti-syn equilibration, which may be suggested by the result that the reaction of the linear Z substrate gave only the linear E product without any the linear Z product (Table 1, entry 6). Oxidative addition of the three different isomers 1a−c is expected to give the same monosubstituted π-allyl complex. High stereoselectivity of the linear products suggested that π−σ−π equilibration is fast compared to nucleophilic substitution and the chiral catalysts may allow preferential attack of the nucleophile to one of the two rapidly equilibrating π-allyl intermediates (Table 1, entries 4−6). That is to say that the nucleophilic attack is the enantiodiscriminating step.13 We then attempted to regulate and control the regioselectivity of this reaction by (1) changing the steric environment or electronic factors, such as charge separation on the two allylic termini of the allylic electrophiles, and (2) changing the steric environment of the cyclo imino ester nucleophiles (Scheme 3). To test the feasibility of our hypothesis, nonconjugated alkyl group allylic precursors were first screened. To our delight, the ratio of l/b could be reversed using the crotyl esters (5:1 vs 1:1.4). Furthermore, the l/b ratio increased rapidly when the steric hindrance of the substituent group was increased. These results indicate that the regioselectivity is sensitive to the steric environment and electronic factors of the two allylic termini. Indeed, the linear products were also smoothly obtained when the methyl ester was replaced with a butyl ester (9:1 vs 1:1.4). The allylic electrophile scope was explored using the cyclic imino tert-butyl ester 2b as a representative substrate (Table 2). At first, two linear (E and Z) and the branched allyl precursors were subjected to the reaction conditions, providing almost identical results (entries 1−3). A series of allylic substrates substituted with arenes bearing electron-withdrawing and electron-donating substituents all furnished the corresponding products with high reactivities and satisfactory regioselectivities and enantioselectivities (5b−p). To our delight, simple allyl acetate, crotyl acetate, and trans-2-hexenyl acetate proved to be good substrates, affording the corresponding products in high yields and enantioselectivities (5q,r). Furthermore, 1,3-diphenyl-substituted substrate 1s is also compatible with the reaction conditions, providing the product 5s in 81% yield, 7:1 dr, and 98% ee. The scope of the cyclic imino esters was next investigated (Table 3). Various aryl substituted cyclic imino esters bearing electron-deficient or electron-rich groups were all tolerated in this reaction (6a−i), giving the desired products in good yields and with excellent stereoselectivities. Reactions involving naphthyl-, furyl-, 2-methoxypyridinyl-, and alkyl-substituted cyclic imino esters also proceeded well to deliver the desired

a Reaction conditions: see Table 1, entry 4. bIsolated yield of the linear products. cSee Table 1, footnote c.

Scheme 4. Gram-Scale Experiments with 1a

absence of the Cu catalyst and the ee decreased rapidly from 94% to 6% (entry 2). The results indicate that the chiral copper complex is indispensable to the reactivity and enantioselectivity. Additionally, none of the target product was obtained in the absence of the Pd catalyst (entry 3). These results suggest that the combined use of two chiral metal catalysts seems to be important for the reactivity and stereochemical control of this reaction. To improve the regioselectivity, the effects of other parameters, including temperature, base, and ligands were carefully screened.11 Only negligible effects of these factors on the regioselectivity were found. Pd-catalyzed allylic substitution reactions with monosubstituted allylic electrophiles typically give linear products in which the nucleophile adds to the least hindered terminus and the regioselective formation of a branched product is particularly difficult.1 In contrast, the formation of the branched product is usually found in Ir-catalyzed allylic substitution reactions.9g,12 Interestingly, the branched products are mainly produced in our present Pd/Cu catalyst system. To obtain the linear products, it is necessary to gain insight into the mechanism of this dual catalysis (Scheme 2). 6566

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Organic Letters

2687. (n) Grange, R. L.; Clizbe, E. A.; Evans, P. A. Synthesis 2016, 48, 2911. (2) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis; Springer: New York, 1999; Vols. I−III, Suppl. I−II. (b) Zhou, Q.-L. Privileged Chiral Ligands and Catalysts; WileyVCH: Weinheim, 2011. (c) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. (d) Halpern, J.; Trost, B. M. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5347. (3) For selected examples, see: (a) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846. (b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (c) Tao, Z.-L.; Zhang, W.-Q.; Chen, D.-F.; Adele, A.; Gong, L.-Z. J. Am. Chem. Soc. 2013, 135, 9255. (d) Zhou, H.; Yang, H.; Liu, M.; Xia, C.; Jiang, G. Org. Lett. 2014, 16, 5350. (e) Turnbull, B. W. H.; Evans, P. A. J. Am. Chem. Soc. 2015, 137, 6156. (f) Lin, H.-C.; Wang, P.-S.; Tao, Z.-L.; Chen, Y.-G.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2016, 138, 14354. (g) Wright, T. B.; Evans, P. A. J. Am. Chem. Soc. 2016, 138, 15303. (4) For examples of branched regioselectivity control, see: (a) Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990, 31, 1743. (b) Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997, 561. (c) Prétôt, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323. (d) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471. (e) Faller, J. W.; Wilt, J. C. Org. Lett. 2005, 7, 633. (f) Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc. 2005, 127, 17516. (g) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007, 46, 7259. (h) Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc. 2007, 129, 14172. (i) Wang, X.; Guo, P.; Han, Z.; Wang, X.; Wang, Z.; Ding, K. J. Am. Chem. Soc. 2014, 136, 405. (5) (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (c) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015, 13, 8116. (6) For selected reviews, see: (a) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2010, 2999. (b) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365. (c) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272. (d) Afewerki, S.; Cordóva, A. Chem. Rev. 2016, 116, 13512. For selected examples, see: (e) Ibrahem, I.; Cordóva, A. Angew. Chem., Int. Ed. 2006, 45, 1952. (f) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (g) Zhao, X.; Liu, D.; Guo, H.; Liu, Y.; Zhang, W. J. Am. Chem. Soc. 2011, 133, 19354. (h) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065. (i) Huo, X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Angew. Chem., Int. Ed. 2014, 53, 6776. (j) Huo, X.; Quan, M.; Yang, G.; Zhao, X.; Liu, D.; Liu, Y.; Zhang, W. Org. Lett. 2014, 16, 1570. (k) Krautwald, S.; Schafroth, M. A.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020. (l) Zhou, H.; Zhang, L.; Xu, C.; Luo, S. Angew. Chem., Int. Ed. 2015, 54, 12645. (m) Leth, L. A.; Glaus, F.; Meazza, M.; Fu, L.; Thøgersen, M. K.; Bitsch, E. A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 15272. (n) Schwarz, K. J.; Amos, J. A.; Klein, J. C.; Do, D.; Snaddon, T. N. J. Am. Chem. Soc. 2016, 138, 5214. (o) Meng, J.; Fan, L.-F.; Han, Z.-Y.; Gong, L.-Z. Chem. 2018, 4, 1047. (7) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Dalko, P. I. Enantioselective Organocatalysis: Reactions and Experimental Procedures; Wiley-VCH: Weinheim, 2007. (c) List, B. Chem. Rev. 2007, 107, 5413. (8) (a) Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH, New York, 2009. (b) Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to Catalysis; University Science Books, Sausalito, 2010. (9) (a) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928. (c) Jia, T.; Cao, P.; Wang, B.; Lou, Y.; Yin, X.; Wang, M.; Liao, J. J. Am. Chem. Soc. 2015, 137, 13760. (d) Saito, A.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2017, 56, 5551. (e) Huo, X.; He, R.; Fu, J.; Zhang, J.; Yang, G.; Zhang, W. J. Am. Chem. Soc. 2017, 139, 9819. (f) Wei, L.; Xu, S.-M.; Zhu, Q.; Che, C.; Wang, C.-J. Angew. Chem., Int. Ed. 2017, 56, 12312. (g) Huo, X.; Zhang, J.; Fu, J.; He, R.; Zhang, W. J. Am. Chem. Soc. 2018, 140, 2080.

products in good to high yields and with high enantioselectivities (6j−n). To confirm the scalability of the present methodology, we performed a larger scale synthesis of 4a using the standard reaction conditions, and comparable results were obtained with higher regioselectivity (Scheme 4). In summary, we have developed a synergistic Pd/Cu catalyst system for the asymmetric allylation of 1-pyrroline-5-carboxylic esters. A series of 3,4-2H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high yields and with high to excellent enantioselectivity and regioselectivity under mild conditions. Mechanistic studies revealed that the cooperative action of the two chiral metal complexes is most likely responsible for its high reactivity and excellent enantioselectivity; the steric hindrance and electronic factors of the electrophiles and the nucleophiles are crucial for the formation of the linear products. Further applications of this bimetallic catalysis strategy for use in other asymmetric transformations are ongoing in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02902.

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Experimental procedures, full spectroscopic data for all new compounds, and 1H and 13C NMR and HPLC spectra (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wanbin Zhang: 0000-0002-4788-4195 Author Contributions §

P.L. and X.H. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NSFC (Nos. 21472123, 21620102003, 21572129, and 21831005), the SHMEC (No. 201701070002E00030), and the STCSM (No. 18ZR1431700) for financial support.

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REFERENCES

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