An intramolecular copper-mediated reductive Castro-Stephens reaction furnished a key macrocyclic triene intermediate for the total synthesis of oximidine II. Herein we describe the total synthesis of the natural product as well as studies to deduce the mechanism of this unprecedented reaction.
A “turn-on” bispyrenyl sensor for lipopolysaccharide detection with unique molecular conformations exhibits excimer emission with sensitivity down to nanomolar.
Oximidine II (1, Figure 1) was isolated in 1999 by Hayakawa and co-workers and displays cytotoxicity at the ng mL À1 level in mutant rat fibroblasts. [1] Oximidine II belongs to the benzolactone enamide family of natural products, [2] which exert their biological activity through selective inhibition of mammalian vacuolar-type H + -ATPases (V-ATPases). [3] Intrigued by its promise as an anticancer agent, our group sought a feasible synthetic route towards oximidine II.The major challenge in the synthesis of oximidine II is the formation of its strained 12-membered macrolactone core, which contains nine contiguous sp 2 -hybridized carbon atoms. The two previous total syntheses of oximidine II by the Porco [4a] and Molander [4b] groups demonstrated this difficulty. Joining C9 and C10 of the macrocyclic core of 1 through either ring-closing metathesis (Porco) or a Suzuki-Miyaura coupling (Molander) proceeded with yields of 48 % and 42 %, respectively. Other groups have reported similar challenges in forming this strained macrocycle in model systems. [5] Our retrosynthesis in Figure 1 utilizes an intramolecular Castro-Stephens reaction, [4, 5b] in which intermediate 4 is employed to form the C9-C10 bond; a chemo-and stereoselective reduction of the alkyne unit in the cyclization product 3 generates the triene macrocyclic core 2. The cyclization precursor 4 would be derived from the chiral aliphatic fragment 5 and aryl acetonide 6.The synthesis of precursor 4 (Scheme 1) began with an asymmetric Brown allylation [4,7] of aldehyde 7 with alkene 8, followed by TBS protection of the newly formed secondary hydroxy group to furnish the enantioenriched product 9 in 81 % yield as a single diastereoisomer ( 1 H NMR analysis) with 94:6 e.r. as determined by Mosher ester analysis. [8] Ozonolysis of intermediate 9 yielded aldehyde 10, which was treated with the lithium anion of 1,3-bis(TIPS)-propyne [9] to afford the Peterson olefination product with a Z/E ratio of 10:1. Desilylation and reprotection of the alcohol as its monosilyl ether provided the aliphatic building block 5. Reaction of aryl acetonide 6 [10] with the sodium alkoxide [4] of 5, followed by quenching of the resultant phenolate with Figure 1. Retrosynthesis for oximidine II (1). TBS = tert-butyldimethylsilyl, TBDPS = tert-butyldiphenylsilyl, MOM = methoxymethyl.Scheme 1. Synthesis of 4: a) sBuLi, (+)-Ipc 2 BOMe, BF 3 ·OEt 2 , À78 to 0 8C, 81 %, 94:6 e.r.; b) TBSOTf, 2,6-lutidine, CH 2 Cl 2 , quantitative; c) O 3 , CH 2 Cl 2 , À78 8C, then Me 2 S; d) 1,3-bis(TIPS)-propyne, nBuLi, THF À78 8C; e) TBAF, THF; 51 % over three steps; f) TBDPSCl, imidazole, DMAP, DMF, 80 %; g) NaHMDS, THF, 0 8C, then 5, then Me 2 SO 4 , 89 %; Ipc = isopinocampheyl, OTf = trifluoromethanesulfonate, TIPS = triisopropylsilyl, THF = tetrahydrofuran, TBAF = tetra-nbutylammonium fluoride, DMAP = 4-dimethylaminopyridine, DMF = N,N-dimethylformamide, HMDS = hexamethyldisilazane.[*] Dr.
Epoxides and episulfides react stereospecifically with Tp′ReO 2 , generated in situ from Tp′ReO 3 and PPh 3 (Tp′ ) hydrido-tris(3,5-dimethylpyrazolyl)borate). A combination of direct atom transfer, resulting in alkene, and ring expansion, resulting in a five-member rhenacycle, is observed. When epoxides cis-and trans-cyclooctene oxide are used, the ring-expanded product is exclusively the corresponding Re(V) diolate. However, when an episulfide such as ethylene sulfide or cis-or trans-cyclooctene sulfide is used, the predominant observed rhenium product is a dithiolate. Retention of initial stereochemistry is observed in all cases. Selectivity between atom transfer and ring expansion is measured for each substrate, and a mechanistic model is proposed to account for the reaction outcome.Atom transfer reactions have gained recognition as a particularly useful class of transformations. Catalyzed atom transfer reactions such as epoxidations in particular represent a particularly efficient means of utilizing inexpensive, readily available reagents for making highly versatile functional groups such as epoxides and vicinal diols. 1 In a broader view, atom transfer to or from organic substrates can have other applications; removal of oxygen from an epoxide "deprotects" the alkene product; 2 utilizing carbohydrates for fine chemical synthesis usually requires removal of an oxygenated functionality. 3 Removal of sulfur from organic compounds is key to hydrodesulfurization reactions in the petrochemical industry. 4 In the course of investigating the mechanism of a rhenium-catalyzed O atom transfer from epoxides to phosphines, both direct observation and indirect measurement of kinetics demonstrated that the reactive Re-(V) intermediate interacting with epoxide led to two competitive processes: 5 one led to alkene via what was apparently direct atom transfer, while the second was an unusual stereospecific ring expansion to give a diolate complex. While the diolate was known to generate alkene on thermolysis, 6 measurement of kinetic behavior rigorously demonstrated that this latter fragmentation was responsible for only a fraction of the alkene formed. Stoichiometric reaction of precursors to Tp′ReO 2 (Tp′Re(O)(OH) 2 , 1, or Tp′Re(O)(OH)(OEt), 2) in the absence of PPh 3 under conditions of minimal diolate cycloreversion (eq 1) also gave a mixture of alkene and diolate.The ring expansion is unusual in two respects. First, it proceeds with a high degree of stereoselectivity with retention of configuration at the migrating carbon. The substrates used in the earlier study (styrene oxide and cis-stilbene oxide) are more prone to Lewis-or Bronstedacid-catalyzed heterolysis of the C-O bond than most epoxides, but it could be that rapid trapping by the Red O group occurs more rapidly than single bond rotation occurs in a putative carbocation intermediate. We thus wished to rigorously test the capacity for maintaining high stereospecificity in this reaction. Another unusual facet was that it occurred to give the less thermodynamica...
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