Double Cycloisomerization as a Novel and Expeditious Route to Tricyclic Heteroaromatic Compounds: Short and Highly Diastereoselective Synthesis of (±)-Tetraponerine T6

Cu-Assisted double cycloisomerization of bis-alkynylpyrimidines afforded the 5−6−5 tricyclic heteroaromatic skeleton. This transformation was used as a key step in the highly diastereoselective total synthesis of (±)-tetraponerine T6

Selective Partial Reduction of Various Heteroaromatic Compounds with Bridgehead Nitrogen via Birch Reduction Protocol

For the first time various heteroaromatic compounds with bridgehead nitrogen, including indolizines, bispyrrolopyrimidines, pyrroloquinolines, pyrroloisoquinolines, and bispyrrolopyrazines, were selectively partially reduced under Birch reduction conditions. It was found that the double bond in the fused heterocycles which possesses the highest LUMO density can be selectively reduced under these conditions. Indolizine 6, containing an ester group at C-6, was reductively alkylated to give dihydroindolizines 8 and 9 possessing a quaternary carbon center in good yield. It was found that ambident substrate 12, under Birch reduction conditions, underwent smooth partial reduction to give 4,5-dihydroquinoline 14 as a sole product with no evidence of reduction of the side chain olefin. It was also shown that electron-rich pyrroloisoquinoline 15, which cannot be reduced via catalytic hydrogenation conditions, was efficiently transformed into its dihydrocounterpart 16 by using the Birch reduction protocol. Finally, it was shown that various fused diazines were smoothly and stereoselectively reduced under Birch reduction conditions to give trans-4,5-disubstituted dihydropyrimidines 30 and 32 in virtually quantitative yields

Total Synthesis of Microtubule-Stabilizing Agent (−)-Laulimalide¹

An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C3−C16 segment 4 and C17−C28 segment 5 by Julia olefination. The sensitive C2−C3 cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner−Emmons olefination between the C19-phosphonocetate and C3-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photoisomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C20-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C13-exo-methylene unit. The sensitive epoxide at C16−C17 was introduced in a highly stereoselective manner by Sharpless epoxidation at the final stage of the synthesis

Highly Diastereoselective Approach toward (±)-Tetraponerine T6 and Analogues via the Double Cycloisomerization−Reduction of Bis-alkynylpyrimidines

A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomerization−reduction of bis-alkynylpyrimidines 3a−m, has been developed. The requisite bis-alkynylpyrimidines 3a−m were readily prepared via regioselective sequential Sonogashira coupling reactions of dibromopyrimidines 1. Bis-alkynylpyrimidines 3a−m were converted into the 5−6−5 tricyclic heteroaromatic cores 4a−m via the Cu(I)-assisted double cycloisomerization reaction. The reaction proceeded stepwise, which was confirmed by the isolation of the mono-pyrrolization intermediate 5. The structure of 5 was assigned by 2D NMR and by independent synthesis. Cycloisomerization of 5 under standard conditions afforded tricyclic 4g in 89% yield. The PtO2-catalyzed hydrogenation of bis-pyrrolopyrimidines 4d, 4g, and 4i in acidic media afforded stable amidinium derivatives, 11a, 11b, and 11c. Further reduction of the latter with LiAlH4 allowed for the highly diastereoselective total synthesis of (±)-tetraponerine T6 and its analogues

Total Synthesis of Microtubule-Stabilizing Agent (−)-Laulimalide¹

An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C3−C16 segment 4 and C17−C28 segment 5 by Julia olefination. The sensitive C2−C3 cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner−Emmons olefination between the C19-phosphonocetate and C3-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photoisomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C20-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C13-exo-methylene unit. The sensitive epoxide at C16−C17 was introduced in a highly stereoselective manner by Sharpless epoxidation at the final stage of the synthesis

Total Synthesis of Microtubule-Stabilizing Agent (−)-Laulimalide¹

An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C3−C16 segment 4 and C17−C28 segment 5 by Julia olefination. The sensitive C2−C3 cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner−Emmons olefination between the C19-phosphonocetate and C3-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photoisomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C20-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C13-exo-methylene unit. The sensitive epoxide at C16−C17 was introduced in a highly stereoselective manner by Sharpless epoxidation at the final stage of the synthesis

Catalytic Enantioselective Cr-Mediated Propargylation: Application to Halichondrin Synthesis

A catalytic enantioselective propargylation in the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E furnishes homopropargyl alcohol 8 in 78% yield with 90% ee. Coupled with the workup based on Amano-lipase, this method provides a practical synthesis of optically pure 8 on a multigram scale. With maintenance of its optical purity, 8 has been converted to 1b, the C14−C19 building block of halichondrins and E7389, in two steps

Catalytic Enantioselective Cr-Mediated Propargylation: Application to Halichondrin Synthesis

A catalytic enantioselective propargylation in the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E furnishes homopropargyl alcohol 8 in 78% yield with 90% ee. Coupled with the workup based on Amano-lipase, this method provides a practical synthesis of optically pure 8 on a multigram scale. With maintenance of its optical purity, 8 has been converted to 1b, the C14−C19 building block of halichondrins and E7389, in two steps

New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Double-Inversion Approach

With sequential use of catalytic asymmetric Cr-mediated coupling reactions, E7389 C14−C35 and halichondrin C14−C38 building blocks have been stereoselectively synthesized. The C19−C20 bond is first formed via the catalytic asymmetric Ni/Cr-mediated coupling, i.e., 8 + 9 → 10 (90%; dr = 22:1), in which vinyl iodide 8 is used as the limiting substrate. The C23−C24 bond is then formed via the catalytic asymmetric Co/Cr-mediated coupling, i.e., 13 + 14 → 4 (82%; dr = 22:1), in which the alkyl−iodide bond in 14 is selectively activated over the vinyl−iodide bond. The catalytic asymmetric Ni/Cr-mediated reaction is employed to couple C14−C26 segment 19 with E7389 C27−C35 segment 20 (91%; dr = >55:1). In this synthesis, the C23−O bond is stereoselectively constructed via a double-inversion process, i.e., 21 → 22, to furnish E7389 C14−C35 building block 22 in 84% yield. The same synthetic sequence has been employed to synthesize halichondrin C14−C38 building block 18b, i.e., 16a + 19 → 18b

Metal-Catalyzed 1,2-Shift of Diverse Migrating Groups in Allenyl Systems as a New Paradigm toward Densely Functionalized Heterocycles

A general, mild, and efficient 1,2-migration/cycloisomerization methodology toward multisubstituted 3-thio-, seleno-, halo-, aryl-, and alkyl-furans and pyrroles, as well as fused heterocycles, valuable building blocks for synthetic chemistry, has been developed. Moreover, regiodivergent conditions have been identified for C-4 bromo- and thio-substituted allenones and alkynones for the assembly of regioisomeric 2-hetero substituted furans selectively. It was demonstrated that, depending on reaction conditions, ambident substrates can be selectively transformed into furan products, as well as undergo selective 6-exo-dig or Nazarov cyclizations. Our mechanistic investigations have revealed that the transformation proceeds via allenylcarbonyl or allenylimine intermediates followed by 1,2-group migration to the allenyl sp carbon during cycloisomerization. It was found that 1,2-migration of chalcogens and halogens predominantly proceeds via formation of irenium intermediates. Analogous intermediate can also be proposed for 1,2-aryl shift. Furthermore, it was shown that the cycloisomerization cascade can be catalyzed by Brønsted acids, albeit less efficiently, and commonly observed reactivity of Lewis acid catalysts cannot be attributed to the eventual formation of proton. Undoubtedly, thermally induced or Lewis acid-catalyzed transformations proceed via intramolecular Michael addition or activation of the enone moiety pathways, whereas certain carbophilic metals trigger carbenoid/oxonium type pathway. However, a facile cycloisomerization in the presence of cationic complexes, as well as observed migratory aptitude in the cycloisomerization of unsymmetrically disubstituted aryl- and alkylallenes, strongly supports electrophilic nature for this transformation. Full mechanistic details, as well as the scope of this transformation, are discussed