[5 + 2] Cycloaddition Reactions in Organic and Natural Product Synthesis

Terpenes represent one of the largest and most diverse classes of secondary metabolites, with over 55,000 members isolated to date. The terpene cyclase enzymes used in nature convert simple, linear hydrocarbon phosphates into an exotic array of chiral, carbocyclic skeletons. Further oxidation and rearrangement results in an almost endless number of conceivable structures. The enormous structural diversity presented by this class of natural products ensures a broad range of biological properties-ranging from anti-cancer and anti-malarial activities to tumor promotion and ion-channel binding. The marked structural differences of terpenes also largely thwart the development of any truly general strategies for their synthetic construction. This review focuses on synthetic strategies directed toward some of the most complex, biologically relevant terpenes prepared by total synthesis within the past decade. Of crucial importance are both the obstacles that modern synthetic chemists must confront when trying to construct such natural products and the key chemical transformations and strategies that have been developed to meet these challenges.

Modern synthetic efforts toward biologically active terpenes

Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C–H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C–H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C–H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C–O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C–H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core. A synthesis of 6-deoxyerythronolide B is reported that uses a late-stage C–H oxidative macrocyclization reaction to forge the key macrocyclic core found in the erythromycins. By installing oxygen at a late-stage, this strategy improves synthetic efficiency by minimizing the ‘oxygen load’, and provides stereochemical versatility at the site of oxidation.

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Total synthesis and study of 6-deoxyerythronolide B by late-stage C-H oxidation

The rapid generation of molecular complexity in a relatively easy manner has made the [5+2] cycloaddition approach a highly useful tool in the synthesis of a wide number of complex natural products and important biologically active products containing seven-membered rings. Besides the common and highly efficient [5+2] cycloadditions of oxidopyrylium and oxidopyridinium ions with π-systems which offer an easy access to a wide range of novel heterocyclic seven-membered ring molecules with a oxygen or nitrogen bridge, and the less employed [5+2] photocycloadditions, the metal-catalyzed [5+2] cycloadditions have attracted a lot of attention and have become one of the most popular ways of constructing seven-membered ring products. All these cycloadducts can be synthetically manipulated easily toward a number of interesting molecular structures with high potential applications. Abbreviations: Ac: acetyl; Ar: aryl; BarF: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; BINAP: 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl; Bn: benzyl; Boc: tert-butoxycarbonyl; Bu: butyl; Bz: benzoyl; Cbz: benzyloxycarbonyl; cod: cyclooctadiene; Cp: cyclopentadienyl; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE: 1,2-dichloroethane; de: diastereomeric excess; DFT: density functional theory; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; dppb: 1,4-bis(diphenylphosphino)butane; dppe: 1,2-bis(diphenylphosphine)ethane; dppp: 1,3-bis(diphenylphosphino)propane; ee: enantiomeric excess; Et: ethyl; HFIP: hexafluoroisopropyl alcohol; L: ligand; M: metal; Me: methyl; MOM: methoxymethyl; Ms: mesyl; Ph: phenyl; PMB: para-methoxybenzoyl; Pr: propyl; Segphos: 5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole; TBDPS: tert-butyldiphenylsilyl; TBS: tert-butyldimethylsilyl; TEA: triethylamine; Tf: trifluoromethanesulfonyl; TFE: trifluoroethanol; THP: tetrahydropyran; TIPS: triisopropylsilyl; TMS: trimethylsilyl; Tol: tolyl; Tp: hydridotris(pyrazolyl)borate; Ts: 4-toluenesulfonyl (tosyl); VCP: vinylcyclopropane.

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Recent Developments in the [5+2] Cycloaddition

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Total synthesis and studyof 6-deoxyerythronolide B by late-stage C-H oxidation

Resiniferatoxin (RTX,1) is a daphnane diterpene, identified in the latex of Euphorbia resiniferaon the basis of its extraordinary irritant activity. 1 While structurally related to the potent tumor-promoting phorbol esters, 2 RTX is not a tumor promoter 3 and does not compete for the phorbol ester binding site on protein kinase C. 4 It does, however, exhibit activity in common with capsaicin ( 2), the major active constituent of red peppers. 5 In addition to its widely appreciated culinary use, capsaicin is the active ingredient in several commercial analgesic formulations and is also of interest as an antinociceptive agent and antifeedant. 6 Exhibiting potencies 10 3 to 105 times greater than capsaicin in many assays, RTX itself is of special therapeutic interest as an analgesic agent, particularly for the treatment of pain associated with diabetic polyneuropathy and postherpetic neuralgia. 7 In addition, RTX and its analogs serve as key probes for biochemical investigations of the relatively little studied vanilloid receptor. 8 Notwithstanding the remarkably long (>2000 years) continuous therapeutic use of daphnane extracts, 5a the complexity and restricted availability of daphnanes and their analogs have greatly limited studies on their molecular mode of action. 9,10

http://depa.fquim.unam.mx/amyd/archivero/ARTICULO-SINTESIS-TOTAL_30934.pdf

Yoshihide Ueno

Papers

The First Synthesis of a Daphnane Diterpene: The Enantiocontrolled Total Synthesis of (+)-Resiniferatoxin