Rapid Construction of the Scaffold of Quorumolide A Enabled

Letter pubs.acs.org/OrgLett

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

Rapid Construction of the Scaffold of Quorumolide A Enabled by a Tandem ROM/RCM Strategy and a Tandem Oxidative Cyclization Strategy Junhong Xiang,† Xiuhe Zhao,† Jiaxin Li,† Yahui Ding,*,† Chao Wang,‡ Liang Wang,*,† and Yue Chen*,†

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†

The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China ‡ Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States S Supporting Information *

ABSTRACT: A synthetically challenging framework in the plant-derived cembranoid quorumolide A was established in a seven-step sequence featuring a ring-opening/-closing metathesis cascade reaction to construct the fused butenolide ring and the 14-membered macroring in a single step. The utilization of a tandem oxidative cyclization strategy is the key to build the tetrahydro-2H-pyran moiety.

M

arine organisms are the major resources to produce cembranoids, a large group of 14-membered carbocyclic diterpenoids,1 which mainly function as defensive tools for organisms against their natural enemies.2 Therefore, cembranoids have exhibited a broad spectrum of biological properties such as anticancer, anti-inflammatory, and antimicrobial activities.3 Thus, cembranoids have attracted great interest in chemical community.4 A few innovative and elegant synthetic work of cembranoids have been reported, exemplified by the total synthesis of (−)-Pavidolide B and (+)-Sarcophytin recently accompanied by the Yang4e and Carreira4f groups. Up to now, only a few cembranoids have been identified from a limited species of high plants.1,2,5 Among these, a highly modified cembranoid quorumolide A, together with quorumolide B and quorumolide C were isolated from the Euphorbia Antiquorum (Figure 1).2 Structurally, quorumolide A represents the first cembranoid bearing both a fused cyclic butenolide ring and a fused tetrahydro-2H-pyran moiety in the 14-membered macroring.

Notably, the stereoconfigurations of C2 (R) and C12 (S) within the pyran ring of quorumolide A are opposite to the stereoconfigurations of the marine-derived cembranoids.2,6 However, the function and the mechanism of action of these plant-derived cembranoids remains totally unknown. The scarce resources of quorumolide A pose a barrier to a deeper investigation into its function and further medicinal chemistry study. To the best of our knowledge, total synthesis of quorumolide A as well as the construction of its scaffold have not yet been reported. Herein, we provide an efficient strategy employing a ring-opening/-closing metathesis (ROM/RCM) cascade reaction and a tandem oxidative cyclization to rapidly construct the scaffold of quorumolide A. Bearing the main core of quorumolide A, 1-deisopropylquorumolide A (4) was chosen as our synthetic target (Scheme 1). Retrosynthetically, the tetrahydro-2H-pyran moiety could be constructed via a tandem oxidative cyclization reaction7 including epoxidation of the C11, C12 double bond followed by in situ nucleophilic attack of O21 at C12 to open the epoxyl ring. Next, as the key step in our route, an intramolecular ROM/RCM cascade reaction was expected to construct the fused butenolide ring and close the 14membered macroring. Developed by Grubbs and co-workers,8 this cascade reaction has subsequently served as a powerful tool for the construction of fused butenolide rings,9 and recent successful examples are Li’s strategy for the efficient synthesis

Figure 1. Structures of quorumolide A−C.

Received: July 9, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b02363 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

the main product was identified as our target molecule 4 evidenced by the fact that the 1H NMR data largely coincided with that of natural quorumolide A. The interesting cyclic structure of 4 was further verified through 2D-NMR and X-ray crystallographic analysis (Scheme 3). The formation of

Scheme 1. Retrosynthetic Analysis

Scheme 3. Completion of the Synthesis of Scaffold

of the humulanolides10 and our synthesis of the ovatodiolide scaffold.11 Intermediate 6 could be assembled through esterification and nucleophilic addition. A Mukaiyama-type aldol reaction between compounds 8 and 9 can be employed to connect C5 and C6 in a diastereoselective manner. The synthesis started with the easily prepared silyl enol ether 8, which instantly underwent an asymmetric Mukaiyama-type aldol reaction with aldehyde 9 to deliver alcohol 7 in 72% yield with high stereoselectivity.11 This reaction can be conducted on a 25-g scale. Further treatment of compound 7 with N,Odimethylhydroxylamine hydrochloride and trimethyl aluminum gave Weinreb amide 10 in 60% yield. Then, the freshly prepared Grignard reagent 11 attacked the Weinreb amide 10 to provide ketone 12 in 86% yield. Compound 12 was then treated with cyclobut-1-enecarboxylic anhydride11,12 and converted into 6 in 70% yield (Scheme 2).

tetrahydro-2H-pyran suggested the excellent spatial match of C12 and O21 for nucleophilic attack after the C11 and C12 double bond of compound 5 was epoxidated from the β-face. In summary, we have developed a concise and asymmetric synthetic route to construct the unique core of cembranoid quorumolide A in seven steps. The strategy used a ROM/ RCM cascade reaction and a tandem oxidative cyclization as key steps. The fused butenolide ring and tetrahydro-2H-pyran moiety in the 14-membered macroring were constructed efficiently without protection manipulation. Further efforts in applying this strategy to the synthesis of quorumolide A and primary biological tests of the compounds we obtained are currently ongoing and will be reported in due course.

Scheme 2. Synthesis of Ester 6

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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.9b02363. Detailed experimental procedures and spectral data (PDF)

With the intermediate 6 in hand, we attempted the key ROM/RCM cascade reaction to build the butenolide ring and close the 14-membered macroring in a single operation. The optimal condition of this transformation we identified in our previous work11 is the addition of 10% equivalents of Hoveyda−Grubbs’ second generation catalyst to the 1.5 mM of intermediate 6 in refluxing toluene. To our delight, the reaction under these optimal conditions went smoothly, and the desired product 14 was obtained as the main isolated product in 50% yield (E:Z > 10:1). No NOE correlation was found between C11−H and C20−H, suggesting the configuration of the C11, C12 double bond of 14 was E. Subsequently, reduction of compound 14 under Corey− Bakshi−Shibata (CBS)13 reaction condition afforded an inseparable mixture of alcohol 5 (d.r. = 2:1). So there is one mere chemical manipulation left toward our synthetic target. To form the tetrahydro-2H-pyran, the conditions of oxidative cyclization were attempted. Finally, we discovered that when the mixture of the alcohol 5 was subjected to epoxidation with m-CPBA, the reactant disappeared in about 0.5 h, and the main product was separated out by chromatography. To our delight,

Accession Codes

CCDC 1937896 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]. *E-mail: [email protected]. ORCID

Yue Chen: 0000-0002-1317-7097 Author Contributions

The manuscript was written through contributions of all authors. B

DOI: 10.1021/acs.orglett.9b02363 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (NSFC) (No. 81573282 to Y.C.; No. 81703350 to L.W.), the National Science Fund for Distinguished Young Scholars (No. 81625021) to Y.C., the Fundamental Research Funds for the Central Universities, and Hundred Young Academic Leaders Program of Nankai University.

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DOI: 10.1021/acs.orglett.9b02363 Org. Lett. XXXX, XXX, XXX−XXX