Alkyne Metathesis: An Enantioselective

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Rhodium-Catalyzed Nitrene/Alkyne Metathesis: An Enantioselective Process for the Synthesis of N‑Heterocycles Kemiao Hong,† Han Su,† Chao Pei,† Xinxin Lv,‡ Wenhao Hu,‡ Lihua Qiu,*,† and Xinfang Xu*,†,‡ †

College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China

‡

Org. Lett. Downloaded from pubs.acs.org by IDAHO STATE UNIV on 04/17/19. For personal use only.

S Supporting Information *

ABSTRACT: A chiral dirhodium-carboxylates-catalyzed asymmetric nitrene/ alkyne metathesis (NAM) cascade reaction of alkyne-tethered sulfamates has been developed, which provides a general access to the synthesis of tricyclic N-heterocycles in good yields and excellent enantioselectivity. The chiral dirhodium catalyst not only promotes the nitrene/alkyne metathesis (NAM) to generate the key α-imino metal carbene intermediate but also is responsible for the observed asymmetric induction in the terminating [2,3]-sigmatropic rearrangement of oxonium ylide species. Scheme 1. Catalytic Alkyne Functionalization via Metal Carbene Intermediate

C

atalytic nitrene transfer reaction represents a powerful and direct method for the construction of a C−N bond and has shown broad applications in modern organic synthetic chemistry.1,2 Since the amino species and N-heterocycles are prevalent in naturally occurring molecules and pharmaceutical agents, the development of catalytic selective nitrene transformation has large application potential and has attracted much attention over the past decades.3 In this context, intensive efforts have been invested exploring a variety of metal catalysts, including Rh,4 Ru,5 Ag,6 Mn,7 Cu,8 Co,9 and Fe.10 Despite these advances, the chemistry of the metal nitrene intermediate remains limited to C−H amination,2,4−11 alkene aziridination,12 and a few others.13 Further work in this direction was disclosed by Blakey through a catalytic nitrene/ alkyne metathesis (NAM) process that has shown extraordinary efficiency for the multibond formation and rapid construction of complex heterocyclic architectures in one operation.14,15 The resultant α-imino carbene intermediates were reported to be intercepted by metal carbene reactions that include [2,3]-sigmatropic rearrangement,15a,b electrophilic aromatic substitution, and cyclopropanation (Scheme 1a).15c Later, the analogous cascade reactions terminated by a Buchner reaction and migration process were reported by Panek16a and Shi,16b,c respectively. In contrast to the luxuriant chemistry of metal carbene species, the utilization of the resultant α-imino carbenes intermediate through the NAM process remains underdeveloped,17 especially the asymmetric version, and no example of catalytic enantioselective nitrene/ alkyne metathesis (NAM) cascade reaction has been disclosed so far.18,19 On the other hand, the analogous metal carbene/ alkyne metathesis (CAM) process has been well studied recently,20,21 and various asymmetric cascade reactions of the in situ generated vinyl carbene species via CAM process have been developed (Scheme 1b).22 For example, May22a and our22d group have reported a CAM process which is © XXXX American Chemical Society

terminated by asymmetric C−H bond insertion reaction for the construction of chiral polycyclic frameworks, independently. Inspired by these advances and in continuation of our interest in carbene/alkyne metathesis reactions,20 we envisioned that the asymmetric nitrene/alkyne metathesis cascade reaction could be enabled through an enantioselective terminating metal carbene reaction in the presence of an appropriate chiral dirhodium carboxylate. Herein, we report Received: March 27, 2019

A

DOI: 10.1021/acs.orglett.9b01074 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Substrate Scopea

the first example of a catalytic asymmetric nitrene/alkyne metathesis (NAM) cascade reaction of alkyne-tethered sulfamates for the highly enantioselective synthesis of tricyclic N-heterocycles in good to high yields. It is worth mentioning that the only catalyst involved in this cascade transformation is a chiral dirhodium catalyst, which is responsible for the in situ generation of the α-imino rhodium carbene intermediate and subsequent asymmetric induction (Scheme 1c).23 After optimization, the best results in terms of yields and selectivity were obtained using a mixed solvent, CF3C6H5/ TBME = 10:1, providing 2a in 77% yield with 92% ee after running the reaction for 60 h (see Table S1, entry 22 in SI), and the substrate scope was explored (Scheme 2). We first investigated the linkage part of 1: substrates with phenyl (1a) or substituted aryl (1b and 1c) as the tether smoothly reacted to give the corresponding products in >63% yields with 92%− 94% ee (2a−2c). The phenyl allyl ether (1d), instead of benzyl allyl ether, was also tolerated in this cascade transformation, providing the benzofurane derivate 2d in 81% yield with 90% ee. After recrystallization, the optically pure product 2d with >99% ee was obtained (see footnote b), which was subjected to single-crystal X-ray diffraction analysis, and the absolute configuration of 2d was determined to be (S) (CCDC 1886681). The absolute configurations of the other products were assigned by analogy. Next, we investigated the allyl component (1e−1w). A series of sulfamate esters bearing electron-neutral, -rich, or -deficient substituents on the aromatic ring of the styryl moiety were well tolerated to give moderate to good yields with excellent enantioselectivities (2e−2k, 90%−99% ee). The para-, meta-, and orthosubstitutions on the aryl group showed little effect on the both reactivity and selectivity, and good yields with >92% ee were obtained in these reactions (2k−2m). Notably, the terminal allyl substrates containing a variety of functional groups, including alkynyl (1n), alkyl (1o−1r), bromo (1s), iodo (1t), and ester (1u), all led to the desired products in moderate to high yields with 86%−95% ee (2n−2u). In the cases with internal allyl ethers (1v and 1w), the yields were diminished due to the increased steric hindrance, while the excellent enantioselectivty remained (2v and 2w,24 >90% ee). Notably, the intermolecular version of this cascade transformation also worked well under current conditions, generating the cyclized product 2x in 51% yield with 75% ee.25 To demonstrate the synthetic utility of the current method, a gram-scale reaction of bromo-substrate 1s was conducted in the presence of 0.5 mol % catalyst loading, generating 1.40 g of 2s in 75% isolated yield with 91% ee (Scheme 3a). Further transformations of product 2s (91% ee) were conducted. The reduction product 3 was obtained in 91% yield with 91% ee,24 followed by N-methylation to give 4 in 92% yield with 91% ee (Scheme 3b). Moreover, addition with methyl magnesium bromide led to the corresponding seven-membered Nheterocycles with two contiguous tertiary stereocenters in >90% yields with the excellent enantioselectivity maintained (Scheme 3c, 5s and 5q).24 The analogous addition of 2d (>99% ee) with allyl magnesium bromide could also be employed and provided the chiral dihydrobenzofuran derivative 6 in 84% yield with 94% ee (Scheme 3d). A general reaction mechanism is proposed in Scheme 4 according to the reported literature,14−16 which is initiated by the rhodium-catalyzed metal nitrene formation in the presence of an oxidant, followed by nitrene/alkyne metathesis processes to form the α-imino carbene intermediate C, and terminated

a

Reaction conditions: to Rh2(S-TCPTTL)4 (3.6 mg, 1.0 mol %), PhI(OAc)2 (70.8 mg, 1.1 equiv), and 4 Å MS (100 mg) in mixed solvent (CF3C6H5/TBME = 10:1, 0.5 mL) was added 1 (0.2 mmol) in the same mixed solvent (1.0 mL) via a syringe pump over 1 h at 0 °C under an argon atmosphere. The yields are given in isolated yields, and the enantiomeric excess was determined by chiral HPLC analysis. b The data in the parentheses are the results after recrystallization. c The reaction was carried out at −20 °C for 7 days. dThe reaction was carried out at −30 °C for 10 days.

by an enantioselective [2,3]-sigmatropic rearrangement through the oxonium ylide intermediate D to give the final product 2.23 B

DOI: 10.1021/acs.orglett.9b01074 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 3. Scale Up and Derivatizations

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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.9b01074. Experimental procedure, the 1H and 13C NMR spectra and HPLC analysis figures of all the products (PDF) Accession Codes

CCDC 1886681 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

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

Wenhao Hu: 0000-0002-1461-3671 Xinfang Xu: 0000-0002-8706-5151 Notes

Scheme 4. Proposed Reaction Mechanism

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Support for this research from the National Natural Science Foundation of China and Jiangsu province (21602148), National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” of China (2018ZX09711002-006), the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (No. 2016ZT06Y337), and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions is greatly acknowledged.

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REFERENCES

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In summary, we have described the first example of a catalytic asymmetric nitrene/alkyne metathesis (NAM) cascade reaction of sulfamate esters, which provides general access to chiral tricyclic N-heterocycles in good yields and excellent enantioselectivity. It is worth mentioning that the only catalyst involved in this four-step cascade transformation is a chiral dirhodium catalyst, which is responsible for the in situ generation of α-imino carbene intermediate via a NAM process and subsequent asymmetric induction. The salient features of this reaction include mild conditions, broad substrate generality, high bond formation efficiency, and ease in further transformations. Investigations on further applications of these catalytic cascade reactions for the construction of chiral polycyclic frameworks are underway in our laboratory. C

DOI: 10.1021/acs.orglett.9b01074 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b01074 Org. Lett. XXXX, XXX, XXX−XXX