Synthesis of the Core Structure of Daphnimacropodines | Organic Letters

May 29, 2019 - Daphniphyllum alkaloids daphnimacropodines A–C possess a highly congested ring system and share a common tetracyclic ring skeleton...
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Cite This: Org. Lett. 2019, 21, 4309−4312

Synthesis of the Core Structure of Daphnimacropodines Yuye Chen,†,‡,∥ Jingping Hu,†,§,∥ Lian-Dong Guo,† Peilin Tian,† Tianyue Xu,† and Jing Xu*,† †

Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China ‡ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau 999078, China § School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang 150006, China Downloaded via EAST CAROLINA UNIV on August 3, 2019 at 15:10:14 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: Daphniphyllum alkaloids daphnimacropodines A−C possess a highly congested ring system and share a common tetracyclic ring skeleton. To access the challenging chemical structure of daphnimacropodines, a divergent synthetic approach toward their total synthesis is described. A stereoselective synthesis of the core structure of daphnimacropodines has been achieved from a simple diketone building block. Our approach features an intramolecular carbamate aza-Michael addition and a hydropyrrole synthesis via a Au-catalyzed alkyne hydration followed by an aldol condensation, whereas all the other attempts failed.

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wing to their intriguing pharmacological potential, the genus Daphniphyllum has long been used in traditional Chinese medicine. Promising biological profiles, such as antiHIV, antitubulin polymerization, anticarcinogenic, antioxidant, vasorelaxant, neurotrophic, and cytotoxic activities, have also been identified from many Daphniphyllum alkaloids.1,2 The challenging chemical architectures and interesting bioactivities of these alkaloids have attracted much attention from the synthetic community.3 To date, about 20 complex Daphniphyllum alkaloids have been impressively accomplished by Heathcock,4 Carreira,5 Smith,6 Li,7 Hanessian,8 Fukuyama,9 Zhai,10 Dixon,11 Qiu,12 our,13 Gao,14 and Sarpong15 groups. Daphnimacropodines A−C were isolated in 2007 by Hao et al. (Figure 1).16 Structurally, these alkaloids possess tetra-, penta-, and hexacyclic congested ring systems with two adjacent quaternary centers, thus posing a remarkable synthetic challenge. Related synthetic studies have been reported by Hanessian17 and Gao3k groups. By analyzing the structural backbones of daphnimacropodines, a tetracyclic 5/6/7/5 ring skeleton was recognized as a common feature (Figure 1, highlighted in blue). Therefore, a divergent synthetic strategy based on this common ring system would be desirable to efficiently access the total synthesis of daphnimacropodines. From a retrosynthetic perspective, daphnimacropodines could be synthesized from the core structure 1, through a cyclopropane opening reaction and formation of the cyclopentene motif. The hydropyrrole of 1 was envisaged to be © 2019 American Chemical Society

Figure 1. Daphnimacropodines and their retrosynthesis.

constructed from compound 2, employing a Au-catalyzed alkyne hydration followed by an aldol condensation. Moreover, intermediate 2 could be achieved from diketone 3 via an Received: April 28, 2019 Published: May 29, 2019 4309

DOI: 10.1021/acs.orglett.9b01486 Org. Lett. 2019, 21, 4309−4312

Letter

Organic Letters Scheme 1. Synthesis of the Core Structure of Daphnimacropodines

Information for details). The intermolecular Michael additions, using various nitrogen sources, were not successful, most likely due to the significant steric hindrance at the C-1 position. Moreover, owing to the presence of the adjacent quaternary centers, the desired intermolecular aza-Michael addition would be required to occur from the concave face, which would also be very difficult. Therefore, we envisioned that converting the C-9 hydroxyl group into a carbamate functionality might allow a desired intramolecular aza-Michael addition from the carbamate nitrogen atom. To this end, carbamate derivative 10 was synthesized from enone 9 and carbonyl diimidazole followed by treatment of propynylamine (Scheme 1). Subjecting carbamate 10 to a sodium-hydride-promoted intramolecular Michael addition successfully formed the desired C1−N bond to give the key intermediate 2 (Scheme 1). The identity of 2 was unambiguously confirmed via singlecrystal X-ray diffraction. On the other hand, carbamates 12−14 were synthesized in order to access the desired C1−N bond as well as the hydropyrrole moiety (Scheme 2; see Supporting Information for details). A palladium-catalyzed coupling reaction21 using carbamate 12 failed to give any desired product. A radical-type cyclization using N-chlorocarbamate 13 under Stockdill’s conditions22 gave no reaction. Moreover, the radical-type cyclization23 using bromoketone 14 gave only very messy results. Next, we sought to employ a Conia-ene-type reaction7,24−27 to construct the pivotal tetrahydropyrrole motif, using silyl enol ether 15, which was synthesized from 2 in one step (see Supporting Information). Unfortunately, all of the conditions attempted including Au(I),7a,b,24 Ag(I),7c,e Cu(I),25 and tungsten-catalyzed26 Conia-ene-type reactions using compound 15 resulted in no reaction (Table 1). No trace of the desired compound 16 or compound 1 could be detected (LC-MS and NMR) from the aforementioned attempts. The failure of these attempts might be attributed to the rapid hydrolysis of the sensitive enol silyl ether. Considering that

intramolecular carbamate aza-Michael addition and a cyclopropanation reaction as well as certain redox manipulations. Recently, we have accomplished a concise total synthesis of (−)-himalensine A, using a similar diversified synthetic strategy from an analogue of diketone 3.13 Here, we wish to describe our recent efforts toward the total synthesis of daphnimacropodines, in which the core structure of these intriguing alkaloids has been successfully synthesized. Our synthesis commenced from the Wieland−Miescher-type diketone 3, which was synthesized in a racemic form from 1,3cycloheptanedione 4 in two steps, including a reductive alkylation18 and an aldol condensation (Scheme 1). The enone moiety of 3 was converted into its enol methyl ether form, thus allowing subsequent reduction of the remaining ketone functionality in a stereoselective manner. An oxone-mediated γ-oxidation19 followed by tert-butyldimethylsilyl protection of the less hindered secondary hydroxyl group afforded compound 5. For constructing the adjacent quaternary centers, Luche’s alkylzinc condition20 failed to give any conjugate addition product. Alternatively, a diastereoselective 1,2reduction of the enone motif, followed by an OH-directed cyclopropanation, was employed to successfully produce compound 6, which contains the desired, critical adjacent quaternary centers. A TEMPO-mediated oxidation successfully converted compound 6 into ketone 7. A diacetate derivative 8 was produced from 7 in two steps (desilylation with TBAF and diacylation with acetic anhydride). Through a single-crystal Xray diffraction of diacetate 8, all five stereogenic centers were unambiguously confirmed. Subsequently, a Saegusa−Ito oxidation smoothly furnished enone 9 from ketone 7. The TMS group that was concomitantly introduced into the C-9 hydroxy group during the enol silyl ether formation was cleaved upon acidic workup. At this stage, various trials to form the C1−N bond and the tetrahydropyrrole moiety were attempted (see Supporting 4310

DOI: 10.1021/acs.orglett.9b01486 Org. Lett. 2019, 21, 4309−4312

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Organic Letters ORCID

Scheme 2. Synthetic Attempts toward Compound 16

Jing Xu: 0000-0002-5304-7350 Author Contributions ∥

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from SZSTI (KQJSCX20170728154233200, JCYJ20170817110515599, KQTD20150717103157174), National Natural Science Foundation of China (21772082), SZDRC (Discipline Construction Program), and the Shenzhen Nobel Prize Scientists Laboratory Project (C17783101) is greatly appreciated.

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Table 1. Attempted Conia-ene-Type Reaction Conditions entry 1 2 3 4 5 6

catalyst Au(PPh3) NTf2 Au(PPh3) NTf2 Au(PPh3) NTf2 AgNTf2 CuI W(CO)6

additive

TTBP TTBP, 4 Å MS Et3N H2O

solvent

2/11/16 (%)

DCM/H2O (10:1)

82/7/0

PhMe/MeOH (10:1) PhMe/MeOH (10:1) DCM/iPrOH (1:1) MeCN THF (hν)

12/61/0 83/12/0 62/0/0 0/0/0 52/0/0

diketone 11 could act as the precursor for an aldol condensation reaction, compound 2 was subjected to the Au-catalyzed hydration conditions to yield intermediate 11, which subsequently underwent an aldol condensation using sodium methoxide conditions to finally produce compound 1 with the desired hydropyrrole moiety (Scheme 1). In summary, we have successfully synthesized the core structure of the complex Daphniphyllum alkaloids daphnimacropodines in 15 steps, from the commercially available 1,3cycloheptanedione. Encouraged by this endeavor, further efforts toward the diversified total synthesis of daphnimacropodines are currently underway in our laboratory and will be reported in due course.

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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.9b01486. Experimental procedures and compound characterization data (PDF) Accession Codes

CCDC 1912037−1912038 contain 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 Author

*E-mail: [email protected]. 4311

DOI: 10.1021/acs.orglett.9b01486 Org. Lett. 2019, 21, 4309−4312

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DOI: 10.1021/acs.orglett.9b01486 Org. Lett. 2019, 21, 4309−4312