Total Synthesis of (±)-Prostratin

Abstract

•Concise total synthesis of prostratin, a complex anti-HIV and anti-tumor agent•Modular synthesis of a polycyclic molecule with potentials in peripheral variations•Stereocontrolled construction of highly functionalized cyclohexane from phenol•Acid- and solvent-controlled stereoselective photochemical cyclopropane synthesis Natural molecules have been continuously offering drug leads for treatment of human diseases. However, searching for the optimal drugs can be often challenging because of the complexity of structural modifications. In this regard, efficient and flexible chemical synthesis routes to the relevant molecules can provide unparalleled opportunities. Prostratin and its structural relatives are complex plant-derived molecules that have shown diverse potential as drug candidates. Prostratin itself is a promising lead for developing a long-sought-after cure for human immunodeficiency virus (HIV) infection and an anti-cancer drug. In this work, we report a short and modular synthetic route to prostratin from very simple chemicals. Because of its high efficiency and flexibility, this route enables full structural optimization of the molecule and also provides a chemical foundation for exploring its derivatives' potential as medical agents. Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products. Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products. Tiglianes and daphnanes are two biogenetically correlated large families of diterpenoids isolated from plants such as Euphorbiaceae and Thymelaeaceae.1Liao S.-G. Chen H.-D. Yue J.-M. Plant orthoesters.Chem. Rev. 2009; 109: 1092-1140Crossref PubMed Scopus (159) Google Scholar, 2Wang H.-B. Wang X.-Y. Liu L.-P. Qin G.-W. Kang T.-G. Tigliane diterpenoids from the Euphorbiaceae and Thymelaeaceae families.Chem. Rev. 2015; 115: 2975-3011Crossref PubMed Scopus (130) Google Scholar Structurally, they are highly oxidized compact polycyclic compounds as shown by the representative members in Figure 1. These molecules share a densely substituted [5,7,6] tricyclic core that features C4,C10 and C8,C9 double trans configurations at ring junctions and multiple contiguous stereocenters including three tertiary alcohols. Prostratin (1), phorbol (2), and phorbol 12-myristate 13-acetate (PMA, 3), belonging to tigliane diterpenes, have an additional gem-dimethyl substituted cyclopropane ring. Degradation of phorbol (2) under acidic conditions produces crotophobolone (4), the simplest daphnane, by opening the cyclopropane ring. In contrast, however, most daphnane diterpenes present themselves with a caged orthoester substructure as exemplified by resiniferatoxin (RTX, 5). Many members within these two families have exhibited significant biological functions including anti-cancer,3Mackay H.J. Twelves C.J. Targeting the protein kinase C family: are we there yet?.Nat. Rev. Cancer. 2007; 7: 554-562Crossref PubMed Scopus (321) Google Scholar anti-viral,4Kaur P. Chu J.J.H. Chikungunya virus: an update on antiviral development and challenges.Drug Discov. Today. 2013; 18: 969-983Crossref PubMed Scopus (81) Google Scholar immunomodulatory properties.5Isakov N. Altman A. Regulation of immune system cell functions by protein kinase C.Front. Immunol. 2013; 4: 384Crossref PubMed Scopus (18) Google Scholar Phorbol (2) and PMA (3) are potent tumor promoters through activation of protein kinase C (PKC) and have been long used as biomedical tools. RTX (5) is currently in phase I trial for treatment of severe pain associated with advanced cancer. Among these members, prostratin (1) is unique because it does not show tumor-promoting related toxicity, rather behaving as a promising anti-HIV and anti-cancer agent. The current clinically used antiretroviral therapy (ART) for HIV infection can only control the levels of plasma viremia but cannot affect the latently infected cells that will lead to rebound. 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In 2015, the first total synthesis of crotophorbolone (4) was disclosed by the Inoue group (33 steps).55Asaba T. Katoh Y. Urabe D. Inoue M. Total synthesis of crotophorbolone.Angew. Chem. Int. Ed. 2015; 54: 14457-14461Crossref PubMed Scopus (56) Google Scholar An alkoxy bridgehead radical reaction was used to forge the key C9–C10 bond. Furthermore, the first total synthesis of resiniferatoxin (5) was achieved by the Wender group in 1997 (44 steps).56Wender P.A. Jesudason C.D. Nakahira H. Tamura N. Tebbe A.L. Ueno Y. The first synthesis of a daphnane diterpene: the enantiocontrolled total synthesis of (+)-resiniferatoxin.J. Am. Chem. Soc. 1997; 119: 12976-12977Crossref Google Scholar Very recently, the Inoue group has also reported a total synthesis of 5 by employing well-designed tandem radical reactions (41 steps).57Hashimoto S. Katoh S. Kato T. Urabe D. Inoue M. Total synthesis of resiniferatoxin enabled by radical-mediated three-component coupling and 7-endo cyclization.J. Am. Chem. Soc. 2017; 139: 16420-16429Crossref PubMed Scopus (68) Google Scholar Despite its close relevance to anti-HIV and anti-cancer research and development, a total synthesis of prostratin (1) has not been reported. In 2008, Wender and co-workers described an elegant preparation of 1 in four steps from crotophorbolone (4) or in five steps from phorbol (2).58Wender P.A. Kee J.-M. Warrington J.M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV.Science. 2008; 320: 649-652Crossref PubMed Scopus (166) Google Scholar Using the semi-synthetic approach, they prepared a series of prostratin analogs with modification at C13 and found that the single-site mutation already had dramatic effects on expression of latent HIV; some analogs exhibited up to 100-fold increase in activity compared with 1.59Beans E.J. Fournogerakis D. Gauntlett C. Heumann L.V. Kramer R. Marsden M.D. Murray D. Chun T.-W. Zack J.A. Wender P.A. Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo.Proc. Natl. Acad. Sci. U S A. 2013; 110: 11698-11703Crossref PubMed Scopus (115) Google Scholar Therefore, it would be of great value to access a broad spectrum of prostratin analogs and fully investigate the structure-activity relationship in order to find optimal drug candidates. This would then in turn require a flexible and efficient de novo synthetic strategy. To meet this need, herein we wish to report a total synthesis of (±)-prostratin (1) that is concise and highly modular. There are two important facts in the chemistry and biology of tigliane and daphnane natural products. The [5,7,6] tricyclic core and the five contiguous stereocenters (C4, C8–C10, and C11) are ubiquitous; the oxidation state and substituents, particularly on the C ring, have great effects on biological activities. Therefore, our synthetic plan was designed to rapidly and controllably assemble the core structure while at the same time to maximize the possibilities of peripheral modifications. As shown in the retrosynthetic analysis of prostratin (1) (Figure 2), whereas the B ring should be formed by ring-closing olefin metathesis reaction from diene 6, the A-ring and C-ring skeletons were to be introduced directly from diol 10 and Grignard reagent 11 at the early stage.60Tong G. Liu Z. Li P. Stereocontrolled construction of the tricyclic framework of tiglianes and daphnanes by an oxidative dearomatization approach.Org. Lett. 2014; 16: 2288-2291Crossref PubMed Scopus (30) Google Scholar Diol 10 was known to be readily available in either racemic or enantiopure form in three or four steps from simple commercially available chemicals.61An G.-i. Rhee H. 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Protection of the two hydroxyl groups in 10 with standard acetonide group followed by one-pot epoxidation with m-CPBA furnished the epoxide (see SI-1 in the Supplemental Information; Figures S1 and S2) as a single diastereomer in 75% yield. Copper(I) iodide-catalyzed epoxide opening reaction of the above intermediate with 4-methoxyphenylmagnesium bromide (11) delivered alcohol 12 (Figures S3 and S4) in 77% yield again as the only stereoisomer. Treatment of 12 with tert-butyldimethyl chlorosilane to cover the C4 hydroxyl group followed by demethylation using lithium diphenylphosphide64Ireland R.E. Walba D.M. Demethylation of methyl aryl ethers: 4-ethoxy-3-hydroxybenzaldehyde.Org. Synth. 1977; 56: 44-48Crossref Google Scholar cleanly unveiled phenol 9 (Figures S5 and S6) in 95% yield over two steps. Consequently, 9 could be prepared in decagrams in a short sequence, setting the stage for the planned controlled manipulation of the C ring. 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Different from standard protocols for this type of reaction, no reductant was needed in this case since the expected intermediate peroxy quinol was directly decomposed to quinol 8. In principle, a single nucleophilic addition to 8 could take place at the diastereotopic C8 and C11 positions (1,4-addition) or at C13 (1,2-addition), generating six possible regio- and/or diastereoisomers. Stimulated by the ligand assisted nucleophilic addition (LANA) method by Liotta and co-workers,66Solomon M. Jamison W.C.L. McCormick M. Liotta D. Cherry D.A. Mills J.E. Shah R.D. Rodgers J.D. Maryanoff C.A. Ligand-assisted nucleophilic additions. Control of site and face attack of nucleophiles on 4-oxido enones.J. Am. Chem. Soc. 1988; 110: 3702-3704Crossref Scopus (73) Google Scholar we first treated 8 with lithium hexamethyldisilazide (LiHMDS) to deprotonate the newly generated C9-hydroxyl group and then added methylmagnesium chloride to achieve the alkoxide-guided face selective 1,4-addition. Two separable diastereomers (∼1:1 ratio, 73%) were isolated after silica gel column chromatography.67Attempts in copper-catalyzed conjugate addition reactions of the hydroxyl-protected substrates were unsuccessful most likely because of the γ-steric hindrance and the proneness to rearomatization. Single-crystal X-ray diffraction analysis confirmed the cis configuration of the desired diastereomer 13 (Figures S9 and S10; Table S9) and its 9,11-epimer (see SI-2 in the Supplemental Information; Figures S11 and S12; Table S10). To install the C15–C17 side chain, Johnson iodination (iodine/pyridine) of 13 led to an α-iodoenone (see SI-3 in the Supplemental Information; Figures S13 and S14) in 85% yield, which then underwent palladium-catalyzed Suzuki-Miyaura coupling with 2-isopropenyl boronic acid pinacol ester, providing the cross-conjugated dienone 14 (Figures S15 and S16) in excellent yield (93%). Next, we attempted to introduce a vinyl group at C8 again employing the LANA method with vinyl Grignard reagent. However, only 14 was recovered, likely due to the high steric hindrance around C8 (see Table S7 for more details). Inspired by Yamamoto's work in super bulky Lewis acids,68Maruoka K. Shimada I. Imoto H. Yamamoto H. Conjugate addition of reactive carbanions to α,β-unsaturated ketones in the presence of ATPH.Synlett. 1994; 1994: 519-520Crossref Scopus (49) Google Scholar we reasoned that a suitable bulky Lewis acid might block C13 site by coordination with the carbonyl oxygen while at the same time activate the C8 site. Indeed, when 2 equiv of aluminum tris(2,6-diphenylphenoxide) (ATPH) were added before addition of vinylmagnesium chloride (5 equiv) to a solution of 14 in toluene, exclusive 1,4-addition was observed. With concomitant double bond migration, the α,β-unsaturated enone 7 (Figures S17 and S18) could thus be obtained in 81% yield. The configuration was again unambiguously confirmed by X-ray diffraction analysis of a single crystal of 7 (Table S11). Attempts in copper-catalyzed conjugate addition reactions of the hydroxyl-protected substrates were unsuccessful most likely because of the γ-steric hindrance and the proneness to rearomatization. Next, we tested formation of the gem-dimethyl cyclopropane D ring through photochemical nitrogen extrusion of a cyclic diazene (Figure 4).58Wender P.A. Kee J.-M. Warrington J.M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV.Science. 2008; 320: 649-652Crossref PubMed Scopus (166) Google Scholar, 69Freeman J.P. A synthesis of cyclopropyl acetates.J. Org. Chem. 1964; 29: 1379-1382Crossref Scopus (41) Google Scholar Simple treatment of 7 with hydrazine hydrate in ethanol formed a pyrazoline intermediate (Intcis, observed with nuclear magnetic resonance [NMR]) that could be oxidized using lead(IV) acetate to diazene 15 (Figures S19 and S20) after removal of the silyl group. However, the key configuration of 15 was identified by coupling constant (3JH8–H14 = 8.3 Hz) and X-ray diffraction of a single crystal to be 8,14,13-cis,cis (Table S12). Denitrogenative cyclopropanation of 15 under UV irradiation (254 nm) and successive one-pot oxidation generated 16 (Figures S21 and S22) as single isomer but with wrong configuration of the cyclopropane as evidenced by X-ray crystallography (Table S13). This result indicated the challenge in building the desired C14 stereocenter in pyrazoline formation and its necessity in following cyclopropanation, since no epimerization at C14 was observed. Notably, in Wender's semi-synthesis work from crotophorbolone (4), C14 center was preset.58Wender P.A. Kee J.-M. Warrington J.M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads a