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Synlett 2019; 30(08): 869-874
DOI: 10.1055/s-0037-1612078
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© Georg Thieme Verlag Stuttgart · New York

Asymmetric Transformations of α-Hydroxy Enamides Catalyzed by Chiral Brønsted Acids

Subramani Rajkumar ◊
,
Jiawen Wang ◊
,
Xiaoyu Yang  *
School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, P. R. of China   Email: yangxy1@shanghaitech.edu.cn
› Author Affiliations

We gratefully acknowledge financial support from NSFC (Grant No. 21702138), the Shanghai Pujiang Program, Thousand Talents Plan youth program, and ShanghaiTech University startup funding.
Further Information

Publication History

Received: 27 November 2018

Accepted after revision: 20 December 2018

Publication Date:
22 January 2019 (online)

 
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◊ These authors contributed equally to this work.

Dedicated to Professor Yong-Zheng Hui on the occasion for his 80th birthday

Abstract

2-Aminoallyl cations are reactive intermediates that undergo diverse reactions, such as cycloadditions, direct nucleophilic additions, Nazarov electrocyclizations, and rearrangements. We review recent development in asymmetric catalytic reactions (nucleophilic additions and Nazarov electrocyclizations) based on chiral counteranion-paired 2-aminoallyl cation intermediates generated through activation of α-hydroxy enamides in the presence of chiral Brønsted acid catalysts. With an understanding of their asymmetric catalysis modes and mechanisms, we expect more asymmetric catalytic reactions will be developed on the basis of this strategy in the near future.


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Key words

aminoallyl cations - hydroxy enamides - chiral anion catalysis - Brønsted acids - indole addition - Nazarov electrocyclization

2-Oxyallyl cations are versatile reactive intermediates that have been applied in a wide spectrum of chemical transformations.[1] In particular, the [4+3] cycloadditions of 2-oxyallyl cations with dienes or furans deliver a variety of seven-membered complex cyclic products in one step. The efficiency of such transformations has encouraged chemists to develop asymmetric catalytic versions, and a range of different catalytic systems have been obtained.[2] Recently, MacMillan and co-workers reported the first asymmetric nucleophilic addition of indoles to an 2-oxyallyl cation in the presence of an organocatalyst,[3] which further expanded the scope of asymmetric reactions based on 2-oxyallyl cations.

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Xiaoyu Yang(middle) was born in Jiangsu Province of the People’s Republic of China in 1984, and obtained his B.Sc. in Chemistry from Nanjing University in 2007. He then moved to Shanghai Institute of Organic Chemistry and he obtained his Ph.D. under the supervision of Professor Biao Yu in 2012, working on the total synthesis of bioactive naturally occurring glycoconjugates. He then spent three years as a postdoctoral researcher with Professor Dean Toste at The University of California, Berkeley, ­focusing on developing novel methods for asymmetric catalysis and ­selective protein modification. In 2016, he began his independent ­researches at ShanghaiTech University, and he was selected in the 13th Thousand Talents Plan youth program in 2017. His current research interests include the development of new methodologies for asymmetric catalysis and bioconjugation. Rajkumar Subramani (right) obtained his B.Sc. and M.Sc. in Chemistry from University of Madras (India) in 2007 and 2009, respectively. He then moved to VIT University (India) to pursuit his Ph. D under the supervision of Professor G. Thirumanavelan, working on Ru(II)-catalyzed C–H activation reactions. In 2017, he joined professor Yang’s group at ShanghaiTech University as a postdoctoral fellow, working on asymmetric catalysis based on chiral Brønsted acids catalysts. Jiawen Wang (left) was born in Anhui Province, People’s Republic of China in 1993. He obtained his B.Sc. in Chemistry from Xiamen University (China) in 2016. Later, he joined Professor Yang’s group at ShanghaiTech University as a graduate student, working on the development of novel asymmetric catalytic reactions based on the concept of chiral anion catalysis.

Unlike the successful developments involving the use of 2-oxyallyl cations, the use of their 2-aminoallyl analogues in syntheses of functionalized imines and enamines derivatives has received little attention. Most existing examples involve [4+3], [3+3], or [3+2] cycloadditions (Scheme [1]).[4] On the other hand, transformations based on the Nazarov electrocyclization have proved to be efficient route to cyclopentenamide derivatives.[5] The nucleophilic capture of 2-aminoallyl cations has recently become a viable method for synthesizing highly functionalized enamides. Kartika and co-workers[6] and Schlegel and Schneider[7] have reported the nucleophilic addition of in-situ-generated 2-aminoallyl cations by a variety of nucleophiles in the presence of achiral Brønsted or Lewis acid catalysts. Driven by the high synthetic value of 2-aminoallyl cations, we were particularly interested in developing related asymmetric catalysis, which had not been realized before 2018.

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Scheme 1 Diverse reactivities of 2-aminoallyl cations

One of the challenges of asymmetric catalysis is the lack of efficient protocols that provide good stereoselectivity control of highly reactive 2-aminoallyl cations. Here, we summarize existing strategies for the generation of 2-aminoallyl cations, as illustrated in Scheme [2]. The classical ­approach for generating 2-aminoallyl cations relies on the activation of 2-chloroimines or enamines promoted by a stoichiometric amount of a Ag(I) salt.[4c] [4e] [4f] Shipman and co-workers developed the first catalytic methodology through activation of 2-methyleneaziridines by a Lewis acid catalyst.[4b,8] Blakey and Robertson and their respective co-workers reported a new route that involves the introduction of allenes to electrophilic metallonitrenes in an intramolecular fashion.[4d] [9] Kartika and co-workers recently reported a novel method for generating nonsymmetrical 2-aminoallyl cations through Brønsted acid-catalyzed dehydration of α-hydroxycyclopentenamides; the cations were then trapped by various nucleophiles (C-nucleophiles or heteroatom nucleophiles) in high yields with complete control of regioselectivity at the less-substituted side.[6]

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Scheme 2 Developed methods for generation of 2-aminoallyl cations

In attempts to establish an asymmetric protocol involving the use of 2-aminoallyl cations, we investigate their counteranions as potent sources of chirality for further asymmetric induction in chiral Brønsted acid catalysis. It is noteworthy that chiral anion catalysis or asymmetric counteranion-directed catalysis, which is based on the ionic interaction between the cationic intermediate and the chiral conjugate base of the catalyst, has become a reliable strategy for a wide range of asymmetric transformations.[10] Moreover, after the pioneering works of Akiyama et al.[11] and of Uraguchi and Terada,[12] the last decade has witnessed an explosive growth in chiral Brønsted acid catalysis, especially catalysis by chiral phosphoric acids.[13] Various novel scaffolds for chiral phosphoric acid catalysts, as well new types of chiral Brønsted acids with increased acidity have been continually developed, which has enriched the arsenal of chiral anion catalysts. In the same line of research interest, we decided to establish a new type of asymmetric Brønsted acid catalysis through dehydration of α-hydroxy enamides to form chiral-anion-paired 2-aminoallyl cations for further enantioselective transformations (Scheme [3]).

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Scheme 3 Asymmetric catalytic transformations based on chiral ­anion-paired 2-aminoallyl cation intermediate

We began our studies by conducting the reaction of 1H-indole (1a) with the α-hydroxycyclopentenamide 2a in the presence of the popular chiral phosphoric acid catalyst (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (TRIP) in toluene. Surprisingly, we obtained a mixture of the α′-addition product 4a [6] and the unexpected indole β-addition product 3a, which was un­ambiguously identified by X-ray crystallography (Scheme [4]; upper).[14] In this case, poor regioselectivity (68:32) between 3a and 4a, as well as a low level of enantioselectivity toward the major 3a isomer (er = 62.5:37.5), were observed (Scheme [4]). Upon further careful optimization of the reaction conditions, the SPINOL-derived chiral phosphoric acid cat A was identified as the optimal catalyst, which gave the β-indolyl cyclopentenamide 3a in 87% yield with a high regioselectivity (3a/4a = 86:14) as well as an excellent enantio­selectivity (er = 95:5). To better understand the origin of the regioselectivity toward the β-isomer, we performed a set of experiments with various phosphoric acid catalysts (Scheme [4]; lower). Achiral diphenyl hydrogen phosphate DiPh-PA afforded 3a and 4a in ratio of 63:37 favoring the α′-addition product, whereas BINOL-derived BINOL-PA gave approximately 1:1 mixture of the α′-and β-addition products. Furthermore, the regioselectivity was also strongly dependent on the choice of solvent, and the selectivity was almost eliminated by the use of MeCN (3a/4a = 43:57). These results indicated that different steric factors were encountered in the key 2-aminoallyl cation intermediate paired with the corresponding counteranions. On increasing the steric bulkiness of the phosphoric acid catalyst (Di-PA → BINOL-PA → cat A), a bulkier counteranion paired with the 2-aminoallyl cation shields the reactive center from nucleophilic addition of indole, thereby favoring the competitive β-H elimination reaction and subsequent β-addition. On the other hand, a polar solvent such as MeCN stabilizes the 2-aminoallyl cation and loosens the electronic pairing between the 2-aminoallyl cation and the counteranion, thereby favoring the direct α′-addition product.

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Scheme 4 Optimization of the reaction conditions and investigation of regioselectivity

With the optimal conditions in hand, we next explored the substrate scope of this reaction with a range of cyclopentenamides and indoles (Scheme [5]). Substituents with various electronic properties at the 4-, 5-, 6-, or 7-position of indole were well tolerated (3a–f). With respect to the scope of cyclopentenamide, alkyl groups other rather than the methyl group installed on the nitrogen atom of enamides were also compatible with the standard conditions, yielding the corresponding products 3g and 3h with high enantioselectivities. In addition, the tolerance toward various groups at the α-position of cyclopentenamide was also investigated. A range of substituted arenes and hetarenes were well tolerated under the optimized conditions (3i–m), whereas the alkyl-substituted substrate 2n afforded the desired 3n with significantly less enantioselectivity.

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Scheme 5 Substrate scope for asymmetric synthesis of β-indolyl ­cyclopentenamides

Next, we wished to address the formation of the unexpected regioisomer 3a by studying the reaction mechanism (Scheme [6]). A preliminary report[6] indicated that direct ­activation of α-hydroxy enamide 2a with a Brønsted acid catalyst should generate the 2-aminoallyl cation intermediate INT A, which is further converted into the α′-substituted product 4a upon direct addition of the nucleophile at the less-substituted side. On the other hand, when the chiral phosphoric acid cat A was used, this nucleophilic addition was inhibited, probably due to the bulkiness of the corresponding anion of this chiral catalyst. Instead, a competing β-H elimination reaction was observed in the absence of the indole nucleophile, affording a mixture of dienamides 5a, 5a′, and 5a′′, identified by 1H NMR spectroscopy. In addition, we and our collaborators performed a density functional theory (DTF) calculation study to achieve a better understanding of the reaction mechanism.[14] Eventually, the computational results suggested that the step of direct nucleophilic addition to the 2-aminoallyl cation INT A involved overcoming a higher energy barrier than that involved in the β-H elimination step in the presence of the chiral phosphate anion. Therefore, we rationalized that subsequent reprotonation of the mixture of dienamides at the α′-position should yield the key α,β-unsaturated phosphate-paired iminium intermediate INT B, permitting the subsequent asymmetric addition event to occur with high enantioselectivity. The reaction between the racemic β-hydroxycyclopentenamide 6a and indole under the standard conditions afforded the same product 3a with an almost identical ­enantiomeric excess, indicating that the key intermediate INT B is also generated by direct dehydration of 6a under our conditions of Brønsted acid catalysis.

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Scheme 6 Proposed reaction mechanism

The synthetic value of the developed reaction was further demonstrated by the facile derivatization of the chiral enamide 3a (Scheme [7]). The β-indolyl cyclopentanone 7a and the β-indolyl cyclopentylamine 8a were readily obtained by simple hydrolysis or catalytic hydrogenation of 3a, respectively, without any erosion of the enantioselectivity.

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Scheme 7 Further transformations of 3a

With similar research interests, Kartika and co-workers also reported parallel work on asymmetric additions of indoles to α-hydroxy cyclopentenamides catalyzed by chiral phosphoric acids, at the same time as our work was published.[15] Compared with our results, they obtained better reaction outcomes for α-alkyl-substituted enamides (Scheme [8]). Their substrate-scope studies also demonstrated that various substituted indoles were well tolerated under the optimal conditions (10 mol% cat B, DCE, –10 °C), whereas α-methyl or α-aryl substitution gave the β-indolyl cyclopentenamides 9 with high enantioselectivities (9a–d). On the other hand, the enantioselectivities of the products decreased when α-alkyl substituents other than a methyl group were present (e.g., Et or All; 9e and 9f).

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Scheme 8 Substrate scopes for asymmetric synthesis of β-indolyl ­cyclopentenamides by Kartika and co-workers

Interestingly, in addition to asymmetric addition of nucleophiles to α-hydroxy enamides, Chan and co-workers employed chiral Brønsted acid catalysis to developed a new asymmetric Nazarov-type electrocyclization of α-hydroxy enamides.[16] The reaction mechanism and chiral induction design for this reaction are briefly illustrated in Scheme [9]. Chiral Brønsted acid-mediated dehydration generated the chiral-anion-paired 2-aminoallyl cation intermediate. In the presence of electron-rich arene or hetarene groups at the α-position, a subsequent 4π conrotatory electrocyclization as the stereodetermining step delivers the enantiomerically enriched arenium ion intermediate. Finally, hydrogen abstraction and aromatization provide the product and regenerate the chiral Brønsted acid catalyst.

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Scheme 9 Proposed strategy for a chiral Brønsted acid-catalyzed asymmetric Nazarov-type electrocyclization

With respect to the scope of this asymmetric 4π-conrotatory electrocyclization reaction, α-aryl or -thienyl α-hydroxy enamides 10 were converted into cyclized products 11 with excellent enantiomeric excesses by using the chiral N-triflyl phosphoramide catalyst cat C (Scheme [10]). A range of electron-rich aryl groups and substituted alkynyl groups were well tolerated at the α-position of the enamide, yielding the corresponding 1H-indene products 11a–e with high enantioselectivities. A α-(2-thienyl)-substituted enamide was also a compatible substrate under the optimal conditions, generating the 4H-cyclopenta[b]-fused heterocycle 11f with a high enantiomeric excess. A detailed DFT calculation explained the origin of the observed product enantioselectivities.

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Scheme 10 Substrate scope for asymmetric Nazarov-type electro­cyclization of α-hydroxy enamides

Although chiral phosphate anions were proposed to be responsible for the chirality induction in these reactions, a further study indicated that single-anionic interaction between the 2-aminoallyl cation intermediate and the chiral anion was insufficient to provide high stereoselectivity control. In our work, we observed that N-methylindoles showed a low reactivity under the optimal conditions, yielding the corresponding products in <10% yield. In the work of Kartika and co-workers, an N-methylindole afforded the product 9g (Figure [1]) in both low yield and low ­enantiomeric ratio. In the work of Chan and co-workers, an N,N-disubstituted enamide showed good reactivity under the standard conditions, but gave the corresponding 1H-indene 11g in completely racemic form. All these results suggested the additional hydrogen bonding between the substrate and the chiral phosphate anion should be taken into account. Therefore, the authors proposed that the high levels of enantioselectivites in these examples were achieved through a bifunctional activation mode or a dual activation mode,[13c] in which the chiral phosphate anion not only interacts with the cationic intermediate through ionic interaction, but also through hydrogen bonding with the acidic proton (–NH) (Figure [1]; bottom).

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Figure 1 Proposed catalysis modes for asymmetric indole addition ­reaction and Nazarov-type cyclization

In conclusion, recent research results demonstrate that α-hydroxy enamides are versatile substrates for diverse transformations that proceed through reactive 2-aminoallyl cation intermediates upon catalysis by Brønsted acids. Here, we have described some recent advances in asymmetric catalytic nucleophilic addition reactions and asymmetric Nazarov-type electrocyclizations of α-hydroxy enamides in the presence of chiral Brønsted acid catalysts. The chiral phosphate anion-paired 2-aminoallyl species has been ­proposed as a key intermediate for downstream asymmetric events. With the understanding of their asymmetric ­catalysis modes and detailed reaction mechanisms by DFT calculation studies, we expect that further development of useful asymmetric reactions based on α-hydroxy enamides substrates in combination with chiral Brønsted acid catalysts should prove fruitful.


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Acknowledgment

We thank Miss Sujuan Zheng and Professor Qian Peng (Naikan University, China) for work on the DFT calculations on the reaction mechanism of our work. Professor Baihua Ye (ShanghaiTech University) was acknowledged for manuscript proofreading.



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Xiaoyu Yang(middle) was born in Jiangsu Province of the People’s Republic of China in 1984, and obtained his B.Sc. in Chemistry from Nanjing University in 2007. He then moved to Shanghai Institute of Organic Chemistry and he obtained his Ph.D. under the supervision of Professor Biao Yu in 2012, working on the total synthesis of bioactive naturally occurring glycoconjugates. He then spent three years as a postdoctoral researcher with Professor Dean Toste at The University of California, Berkeley, ­focusing on developing novel methods for asymmetric catalysis and ­selective protein modification. In 2016, he began his independent ­researches at ShanghaiTech University, and he was selected in the 13th Thousand Talents Plan youth program in 2017. His current research interests include the development of new methodologies for asymmetric catalysis and bioconjugation. Rajkumar Subramani (right) obtained his B.Sc. and M.Sc. in Chemistry from University of Madras (India) in 2007 and 2009, respectively. He then moved to VIT University (India) to pursuit his Ph. D under the supervision of Professor G. Thirumanavelan, working on Ru(II)-catalyzed C–H activation reactions. In 2017, he joined professor Yang’s group at ShanghaiTech University as a postdoctoral fellow, working on asymmetric catalysis based on chiral Brønsted acids catalysts. Jiawen Wang (left) was born in Anhui Province, People’s Republic of China in 1993. He obtained his B.Sc. in Chemistry from Xiamen University (China) in 2016. Later, he joined Professor Yang’s group at ShanghaiTech University as a graduate student, working on the development of novel asymmetric catalytic reactions based on the concept of chiral anion catalysis.
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Scheme 1 Diverse reactivities of 2-aminoallyl cations
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Scheme 2 Developed methods for generation of 2-aminoallyl cations
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Scheme 3 Asymmetric catalytic transformations based on chiral ­anion-paired 2-aminoallyl cation intermediate
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Scheme 4 Optimization of the reaction conditions and investigation of regioselectivity
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Scheme 5 Substrate scope for asymmetric synthesis of β-indolyl ­cyclopentenamides
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Scheme 6 Proposed reaction mechanism
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Scheme 7 Further transformations of 3a
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Scheme 8 Substrate scopes for asymmetric synthesis of β-indolyl ­cyclopentenamides by Kartika and co-workers
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Scheme 9 Proposed strategy for a chiral Brønsted acid-catalyzed asymmetric Nazarov-type electrocyclization
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Scheme 10 Substrate scope for asymmetric Nazarov-type electro­cyclization of α-hydroxy enamides
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Figure 1 Proposed catalysis modes for asymmetric indole addition ­reaction and Nazarov-type cyclization