Synthesis of a Ring-Expanded Bryostatin AnalogueBarry M. Trost,* Hanbiao Yang, Oliver R. Thiel, Alison J. Frontier, and Cheyenne S. BrindleDepartment of Chemistry, Stanford UniVersity, Stanford, California 94305Received October 11, 2006; E-mail: [email protected] bryostatins are a family of marine natural products thatdisplay a wide range of biological activities, most notably theiranticancer activity in vivo.1This effect is attributed to their abilityto modulate the functions of protein kinase C isozymes within cells.One of the members of this family, bryostatin 1, is currently inseveral phase I and phase II clinical trials for the treatment of severalcancers.2The syntheses of bryostatins and their analogues havebeen an active research area since the structure elucidation ofbryostatin 1 in 1982.3To date, three total and one formal syntheseshave been reported,4-7and potent bryostatin analogues8have beenidentified. In the analogue synthesis front, efforts have been centeredon the simplification of the 26-membered macrolactone backbone.Herein, we report the synthesis of a ring-expanded analogue 1(Scheme 1), which retains all the functionalities in the bryostatins,and their biological activities against several cancer cell lines.Shown in Scheme 1 is our retrosynthetic analysis. Inspired bythe B-ring and C-ring segments, we developed a Ru-catalyzedtandem process9for the synthesis of 4-methylene-cis-2,6-tetra-hydropyran and a Pd(II)-catalyzed tandem reaction10for thesynthesis of dihydropyrans. Since our Pd(II) catalysis necessitatesan early installation of the sensitive R,β-unsaturated methyl esterat C(13), we decided to evaluate a ring-closing metathesis (RCM)approach for the formation of the macrocycle.11,12The sterichindrance of the C(16)-C(17) double bond (bryostatin numbering)made this approach risky, but we were encouraged by the potentialto access ring-expanded analogues.13Our synthesis of the northern hemisphere 2 is outlined in Scheme2. The alcohol 914was converted to the hydroxyketone 12 followinga procedure5from Evans. Subsequent hydroxyl-directed anti-reduction,15lactonization,16and protection gave lactone 14. At thisstage, a β,γ-unsaturated ketone was introduced to give 5. The keyRu-catalyzed tandem coupling between enone 5 and homopropar-gylic alcohol 4 furnished tetrahydropyran 15 in 56% yield as a 9:1cis:trans diastereomeric mixture, and no double bond isomer wasobserved. Although excess 5 (2.2 equiv) was used in the reaction,1.2 equiv was recovered and recycled. Subsequent bromination anddeprotection gave the corresponding diol, which was subjected toa tandem lactone methanolysis-ketalization to afford 16. Com-pound 16 was converted to vinyl bromide 16 and then the northernhemisphere 2 in eight steps.Our synthesis of the southern hemisphere 3 commenced withD-glactonic acid 1,4-lactone (Scheme 3). Epoxide opening of 1817with methyl propionate deliver ed methyl ynoate 19, which wascoupled with alkyne 2018under our tandem Pd(II) catalysisconditions to give dihydropyran 21 in 55% yield.19At this stage,the vicinal oxygens at C(19) and C(20) were introduced via anepoxidation. Unfortunately, the stereochemistry of the newlyintroduced C(20) hydroxyl group was the opposite of that requiredfor our synthesis. This undesired selectivity was overcome by aDess-Martin oxidation20/Luche reduction21sequence. After intro-Scheme 1Scheme 2aaReagents and conditions: (a) TBSOTf, Et3N, -78 °C, 94%; (b) 9-BBN,then H2O2, NaOAc, 93%; (c) TEMPO, KBr, NaOCl, CH2Cl2/H2O; (d) Ti(O-i-Pr)2Cl2, 11, toluene, -78 °C, 69% over two steps, ∼10:1 dr at C(5); (e)Me4NBH(OAc)3, AcOH/CH3CN, -35 °C, 96%, 15:1 dr at C(3); (f) 10 mol% of Otera’s catalyst 13, hexane, reflux; (g) TBDPSCl, imidazole, DMF,50 °C, quantitative; (h) AcOH/H2O (4:1), 69%; (i) Dess-Martin oxidation;(j) allyl iodide, In, DMF, rt, 66% over two steps; (k) Dess-Martin oxidation,85%; (l) 10 mol % of [CpRu(CH3CN)3]PF6, acetone, rt, 56% yield, dr 9:1;(m) NBS, DMF, 93%; (n) BF3‚OEt2, 1,3-propanedithiol, CH2Cl2, 0 °C, 98%;(o) PPTS, CH3OH, CH(OCH3)3, reflux, 71%; (p) TESCl, DMAP, thenpyridine, Ac2O, 92%; (q) PPTS, MeOH, rt, 85%; (r) DMSO, (COCl)2, Et3N,CH2Cl2, -78 °C to rt; (s) Ph3PCH3Br, n-BuLi, 63% over two steps; (t)TBAF, THF, rt, 82%; (u) Me3SnOH, DCE, 140 °C, microwave, 82%; (v)Pd(PPh3)4, CO, DMF/CH3OH, 85 °C, 94%; (w) TESOTf, 2,6-lutidine,CH2Cl2, 68%.Published on Web 02/06/200710.1021/ja067305j CCC: $37.00 © xxxx American Chemical Society J. AM. CHEM. SOC. XXXX,XXX,9APAGE EST: 1.9ducing a terminal olefin via a Takai olefination22and a Negishicross-coupling,23the resulting triene 24 was hydrolyzed andmonosilylated to give the southern hemisphere 3, which was thencoupled with 2 in th e pre sence of 2-methyl-6-nit robenzoic acidanhydride24to give 25. Gratifyingly, treatment of 25 with Grubbs-Hoveyda catalyst25gave 31-membered lactone 26 as an inseparable1:1 E:Z mixture in 80% yield.26Final deprotection gave triols 1and 27, which were separated by preparative TLC.The compounds 1 and 27 were tested against several cancer celllines. Particularly impressive and interesting is the ability of 1 toinhibit the growth of NCI-ADRsa breast cancer cell line with addedmulti-drug-resistant pumpsswith an IC50of 123 nM.27In summary, a ring-expanded bryostatin analogue 1 with potentantitumor activity against the NCI-ADR cancer cell line wassynthesized. Notable features include a Ru-catalyzed tandemtetrahydropyran formation, a Pd-catalyzed tandem dihydropyranformation, and a ring-closing metathesis. The chemistry reportedherein should be applicable to future syntheses of the bryostatinsand their analogues.Acknowledgment. We thank NIH General Medical Science(GM 13598), NSF, and fellowships from Amgen (H.Y.), Bristol-Myers Squibb (H.Y.), the Alexander-von-Humboldt foundation(O.R.T.), NIH (A.J.F.), NSF (C.S.B.), and ARCS (C.S.B.) for theirgenerous financial support. We thank Dr. Hugo Menzella fromKosan Biosciences for testing the biological activities of compounds1 and 27, and Dr. Yong Li for helpful discussions. We thankProfessor Deryn Fogg, Jay Conrad, Professor Robert Grubbs, andDr. Tobias Ritter for providing samples of catalysts and JohnsonMatthey for a gift of Pd salts. Mass spectra were provided by theMass Spectrometry Regional Center of the UCSF, supported bythe NIH Division of Research Resources.Supporting Information Available: Experimental details andspectroscopic data (PDF). This material is available free of charge viathe
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