Asymmetric Total Synthesis of (−)‐Nakadomarin A

Abstract

A key intermediate in the first asymmetric synthesis of the marine alkaloid (−)‐nakadomarin A (1), isolated from the marine sponge Amphimedon sp., was the optically active hydroisoquinoline 2. Two separate ring‐closing‐metathesis reactions were crucial to the construction of the 15‐ and 8‐membered rings.

Efficient and Selective Formation of Macrocyclic Disubstituted Z Alkenes by Ring‐Closing Metathesis (RCM) Reactions Catalyzed by Mo‐ or W‐Based Monoaryloxide Pyrrolide (MAP) Complexes: Applications to Total Syntheses of Epilachnene, Yuzu Lactone, Ambrettolide, Epothilone C, and Nakadomarin A

“…The earlier approaches utilized olefin metathesis to prepare the larger ring structure of nakadomarin A, albeit with relatively low efficiency (15–30 mol % Ru complex) and minimal or stereoselectivity in favor of the undesired isomer (~2:1–1:2 E : Z ). 38 Due to the ineffective stereochemical control in the macrocyclic ring formation, as with epilachnene and epothilone C, strategies involving alkyne RCM/partial hydrogenation sequence have been introduced. 22,39 We demonstrated in our initial disclosure 6 that in the presence of W alkylidene 13 , macrocyclic RCM reactions with tetracyclic substrate 16 as well as the more strained pentacyclic 18 proceed efficiently and with exceptional Z selectivity (90% yield and 97% Z and 63% yield and 94% Z , respectively); these advances are summarized in Scheme 7.…”

“…38d The difficult nature of the latter RCM process originates largely from the relatively high ring strain associated with the Z alkene-containing macrocycle. Hence, it is the less active first-generation Ru carbene (vs the more active 2c and 2d ), which must be added at a slow rate to the reaction mixture, that preserves the small kinetic preference for the Z alkene isomer.…”

“…Moreover, significantly more dilute conditions (0.3 vs 5.0 mM) and 300 mol % of camphorsulfonic acid are needed (60–70% conv, 27% yield and 60% E , otherwise). It is worthy of note that, in spite of the fact that formation of the cyclooctene moiety in the majority of the formerly reported total syntheses of nakadomarin A was implemented in the absence of the rigidifying macrocyclic alkene, 38,39c 20–100 mol % of a Ru-based carbene proved necessary for achieving a reasonably efficient cyclization. 38a–c,e …”

Development of Environmentally Benign Organometallic Catalysis for Drug Discovery and Its Application

“…For more than ten years, we have been exploring a synthetic methodology for nitrogen-containing heterocycles using these ruthenium carbene catalysts and applying them to the synthesis of biologically active natural products. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] Here, we describe our synthetic study of nitrogen-containing heterocycles using ring-closing metathesis (RCM), such as chiral bicyclic lactams, azacycloundecenes, axially chiral macrolactams, 1,2-dihydroquinolines and indoles, including the development of silyl-enol ether ene metathesis and selective isomerization of terminal olefin, and its application to the synthesis of the natural products, (Ϫ)-coniceine, (S)-pyrrolam A and angustureine.…”

N-Heterocyclic carbenes as highly efficient ancillary ligands in homogeneous and immobilized metathesis ruthenium catalytic systems

“…Also, stereospecific synthesis of the pair of natural macrolides, cis-and trans-resorcylide, 164 and 165, both acting as plant growth inhibitors, was performed by Couladuros et al Asymmetric total synthesis of (-)-nakadomarin A (166), a natural compound of the class of ircinal and manzamine alkaloids 167 and 168, having cytotoxic activity against murine lymphoma cells as well as antimicrobial activity, has been performed recently by means of ringclosing metathesis of the diene precursors, with complexes 32 and 34 in the key reaction steps. 88 In this process, the difference in reactivity between the bisphosphane and NHC/phosphane precatalysts was significant, the former leading to the 15-membered azacycle in 26% yield whereas the latter gave the 8-membered azacycle, in 83% yield. Spongidepsin, 169, a remarkable natural compound with cytotoxic and antiproliferative activities against several cancer cell lines, has been synthesized recently through a stereodivergent ring-closing strategy.…”