Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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A General Biomimetic Hetero-Diels−Alder Approach to the Core Skeletons of Xenovulene A and the Sterhirsutins A and B Pei-Jun Li, Gerald Dräger, and Andreas Kirschning* Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz Universität Hannover, Schneiderberg 1 B, 30167 Hannover, Germany
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S Supporting Information *
ABSTRACT: A biomimetic, regio- and stereoselective approach to the 5,6,11-tricyclic core skeleton of xenovulene A, as well as sterhirsutins A and B, is described. The key steps are a biomimetic inverse-electron-demand hetero-Diels−Alder cycloaddition of α-humulene and a ribose-derived vinyl ketone, followed by acid-catalyzed rearrangement of the 1,3dioxolane that neighbors the resultant cyclic enol ether.
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chemical consideration that further suggests a biosynthetic origin via hetero-DA union. In continuation of our recent work on biomimetic Diels− Alder cycloadditions in the synthesis of the elansolids,5 we now disclose a regio- and stereoselective approach to the tricyclic core skeleton of xenovulene A (1) and the sterhirsutins A (2) and B (3) by means of a hetero-Diels−Alder cycloaddition. Our retrosynthetic analysis of xenovulene A and sterhirsutins A and B is depicted in Scheme 1. We envisioned that advanced diastereomeric hetero-Diels−Alder products 5a and 5b, accessible from vinyl ketone 6 and α-humulene (7),6 would serve as key intermediates to access the three natural products 1−3 via enone 4.7 We planned to prepare ketone 6 by a short
enovulene A (1), an oxygenated humulene-containing meroterpene, was isolated from Acremonium strictum in 1995 (Figure 1).1 It was found to be an inhibitor of
Scheme 1. Retrosynthetic Analysis of Key Intermediates 4 and 5 en Route to Xenovulene A (1) and Sterhirsutins A (2) and B (3)
Figure 1. Structures of xenovulene A (1), sterhirsutins A (2) and B (3).
benzodiazepine binding to the human γ-aminobutyric acid (GABA) receptor with an IC50 value of 40 nM. Additionally, antidepressant effects were encountered for 1.2 Structurally related to xenovulene are sterhirsutin A and B (2 and 3), which were isolated by Liu and co-workers from Stereum hirsutum in 2014. Both diastereoisomers exhibit moderate antiproliferative activities against human myelogenous leukemia (K562) cells with IC50 values of 13 and 16 μg/mL, respectively.3 Although these meroterpenes originate from different fungal species, they all share a similar 5,6,11-tricyclic core structure. Biosynthetically, this core structure may be constructed through an inverse hetero-Diels−Alder cycloaddition (heteroDA) between an α,β-unsaturated ketone fragment and the sesquiterpene α-humulene.3,4 Notably, the two diastereomeric forms, sterhirsutins A and B, also appear to be the endo- and exo-products of a possible Diels−Alder reaction, a stereo© XXXX American Chemical Society
Received: December 14, 2018
A
DOI: 10.1021/acs.orglett.8b04003 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
ditions.6a,b,12 Related to these findings, the groups of Liu6c and George6d utilized highly reactive diene precursors, such as o-quinone methides in the synthesis of (rac) guajadiol B and hyperjapones A−E, respectively. In the present case, we rely on an α,β-unsaturated ketone as diene in the transformation with α-humulene (7), which lacks the reactivity of quinone methides.12 To our delight, we found that heating a solventfree mixture of 16 with an excess of 7, followed by TBAFmediated TBS deprotection, afforded the desired cycloadducts 18a and 18b in 2:1 diastereomeric ratio and 51% combined yield over two steps (Scheme 3 and Table 1, entry 5). The
sequence through 1,4-addition and methenylation of cyclopentenone 8, which itself can be prepared from D-ribose (9).8 A key issue points to the regioselectivity of the cycloaddition with respect to the dienophile, α-humulene (7), as the sterically least congested double bond at C-1/C-2 has to react exclusively.9 The synthesis of vinyl ketones 16 and 17 commenced with protection of the C2 and C3 positions of D-ribose (9) as an acetonide, followed by treatment with vinylmagnesium bromide to give triol 10 in 80% yield (Scheme 2).8 Oxidative Scheme 2. Synthesis of Vinyl Ketone 5a
Scheme 3. Hetero-Diels−Alder Cycloaddition, Synthesis and X-ray Analysis (Graphical Representation) of Silyl Ether 19a, and Acid-Catalyzed Rearrangement of Acetonide 18a−b (a)
a
TBAF = tetra-n-butylammonium fluoride.
Table 1. Studies on the Hetero-Diels−Alder Cycloaddition a
Cy = cyclohexyl, TBS = tert-butylsilyl, DMAP = 4-dimethylaminopyridine, LDA = lithium diisopropyl.
cleavage of the remaining 1,2-diol with sodium metaperiodate followed by Wittig olefination with triphenylphosphonium methylidene provided diene 12 in good yield and selectivity.10 Ring-closing metathesis of diene 12 using the Grubbs catalyst type I gave the corresponding cyclopentenol, which was directly oxidized with MnO2 to afford cyclopentenone 8 in 60% yield over two steps. Photochemical activation of methanol and 1,4-addition to cyclopentenone 8 then furnished alcohol 13 in 65% yield.8a After protection as TBS-ether (90% yield), the resulting ketone 14 was treated with lithium diisopropylamide (LDA) and Eschenmoser’s salt (Me2N = CH2I) followed by iodomethane to afford enone 16 in 70% yield after Hofmann elimination.11c Alternatively, enone 17 was prepared from 8 by 1,4-addition with (t-BuOCH2)2CuLi and subsequent Eschenmoser methenylation in 65% yield over two steps.11 With methyl vinyl ketone 16 in hand, we turned our attention to the hetero-Diels−Alder cycloaddition using αhumulene (7), the biomimetic key reaction. A seminal study by Baldwin et al. on the Diels−Alder cycloaddition with humulene utilized a quinone methide benzotropolone as the diene, which was generated in situ under thermal con-
entry 1 2 3 4 5 6 7
conditions 16/7 16/7 16/7 16/7 16/7 16/7 17/7
time/h b
(1:10), solvent (1:10), additivec (1:20), 150 °Cd (1:20), 150 °Cd (1:20), 150 °Cd (1:5), 150 °Cd (1:5), 150 °Cd
48 24 48 120 240 120 120
yielda (%)
dra
20 50 51 50
1:1 2:1 2:1 2:1
a Yields and dr refer to the isolated and purified products after two steps. bToluene, xylene, nitrobenzene; refluxing. cAlCl3, SnCl4, Sc(OTf)3; refluxing in toluene. dSealed tube.
isomers were separable by column chromatography (18a: Rf = 0.6; 18b: Rf = 0.55; ethyl acetate/petroleum ether 1:1); however, NMR analysis, including NOE experiments, was not sufficient to unequivocally prove the configuration of the newly formed stereogenic centers. Final confirmation only came after TBS protection of diastereoisomer 18a, which provided compound 19a as a crystalline solid and permitted X-ray diffraction analysis. B
DOI: 10.1021/acs.orglett.8b04003 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters This hetero-Diels−Alder cycloaddition of 16 with αhumulene (7), however, required some optimization, which is summarized in Table 1. Initially, the reaction was carried out in several high-boiling-point solvents (toluene, xylene, and nitrobenzene) with heating at reflux temperature for 48 h. Under these conditions, an inseparable mixture of homodimers derived from 16 was detected by high-resolution mass spectrometry (entry 1). Addition of Lewis acids such as AlCl3, SnCl4, and Sc(OTf)3 only led to the decomposition of 16 (entry 2).13 When enone 16 was heated in α-humuleme (7) as solvent in a sealed tube at 150 °C for 48 h, and following treatment of the crude material with TBAF, the desired cycloaddition products 18a,b were isolated in 20% yield over the two steps (entry 3). Subsequently, the yield could be raised to 50% (dr = 2:1) by extending the reaction time to 5 days. Longer reaction times did not lead to a significant improvement (entry 5); however, the excess of 7 could be decreased to five equivalents under these conditions without loss of yield (entry 6). In all cases, vinyl enone 16 was consumed by a [4 + 2]-hetero Diels−Alder dimerization as detected by LCMS.13a,14 However, efforts to purify and isolate the mixture of dimers led to complete decomposition. Finally, the reaction of enone 17 with αhumulene (7) yielded a complex and inseparable product mixture (entry 7). The diastereoselectivity of the hetero-Diels−Alder cycloaddition of 16 with α-humulene (7) is moderate. Two transition states A and B can be proposed, that explain the observed facial selectivity (Scheme 4). These are based on two
state B is less favored due to an interaction of the acetonide group (concave hemisphere) with the other methyl group in 7. Finally, acid-catalyzed rearrangement of acetonides 18a and 18b provided enones 20a and 20b, respectively (Scheme 3). This transformation was not initially expected, but to our delight, it provided a desirable advanced intermediate in one step, which is poised for late-stage modification to the full structure of xenovulene A (1) and sterhirsutene A (2). A plausible mechanism for this unique transformation is summarized in Scheme 5. Supported by the oxygen atom Scheme 5. Proposed Mechanism for the Acid-Catalyzed Rearrangement of Acetonide 18 to Enone 20
that neighbors the acetonide ring, proton-mediated migration of the tetrasubstituted olefin of 18 gives rise to enol ether 21. Further protonation and opening of the 1,3-dioxolan ring leads to diene 22, which collapses with loss of acetone to yield enone 20. In summary, we have developed a concise synthetic approach to the 5,6,11-tricyclic core skeleton of xenovulene A (1) and the sterhirsutins A (2) and B (3). A novel biomimetic hetero-Diels−Alder cycloaddition, involving αhumulene and a ribose-derived vinyl ketone, was used to construct the central dihydropyran motif, and acid-catalyzed rearrangement of the remaining 1,3-dioxolane provided a useful late-stage intermediate en route to compounds 1−3. Our study paves the way to rapidly access the full structure of xenovulene A and the sterhirsutins. Further studies on the total synthesis of xenovulene A as well as sterhirsutins A and B are currently underway.
Scheme 4. Proposed Transition States of the Hetero-Diels− Alder Cycloaddition of 16 with α-Humulene (7)
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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.8b04003.
principal considerations. The vinyl ketone 16 is characterized by a convex and a concave face. As a result, the siloxymethyl substituent is oriented into a pseudoaxial position partly filling the space of the convex face. Second, Shirahama and coworkers15 carried out a molecular mechanics calculation analysis on the preferred conformations of α-humlenene (7). They suggested two conformations which differ in a ring flip of the macrocycle with the methyl groups of the trisubstituted alkenes being oriented anti to each other and pseudoaxially. Therefore, one face of the π-bond at C-1/C-2 is shielded by the macrocycle. As a result a re- and si-face approach with respect to enone 16 can be postulated, leading to the two diastereomeric cycloaddition products 19a and 19b. Transition
Detailed experimental procedures, spectral data, and Xray crystallography (PDF) Accession Codes
CCDC 1884756 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. C
DOI: 10.1021/acs.orglett.8b04003 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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(14) (a) Heravi, M. M.; Ahmadi, T.; Ghavidel, M.; Heidari, B.; Hamidi, H. RSC Adv. 2015, 5, 101999−102075. (b) Palasz, A. Top. Curr. Chem. (Z) 2016, 374, 24. (15) (a) Shirahama, H.; Arora, S. H.; Osawa, E.; Matsumoto, T. Tetrahedron Lett. 1983, 24, 2869−2872. (b) Neuenschwander, U.; Czarniecki, B.; Hermans, I. J. Org. Chem. 2012, 77, 2865−2869.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Andreas Kirschning: 0000-0001-5431-6930 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS P.-J.L. is thankful to the Hannover School of Biomolecular Drug Research (HSBDR) doctoral training center for financial support. Helpful discussions from Dr. Michael Wolling (Boehringer Ingelheim AG & Co. KG, Germany) and Dr. Matthew D. Norris (Leibniz Universität Hannover) are kindly acknowledged.
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DOI: 10.1021/acs.orglett.8b04003 Org. Lett. XXXX, XXX, XXX−XXX
