In 1997, Kobayashi and co-workers disclosed the isolation of (À)-nakadomarin A (1, Scheme 1) from an Okinawan marine sponge Amphimedon sp. Its unique 8/5/5/5/15/6 hexacyclic full-ring structure containing four stereogenic centers and an imbedded furan was shown with extensive NMR spectroscopic analyses including NOE and proton coupling data.[1a] The biological properties of 1 range from prominent cytotoxicity against murine lymphoma L1210 cells to outstanding antimicrobial and CDK4 inhibitory activities. [1b] Since 2003, elegant total and formal syntheses [2] of 1 have been accomplished by the laboratories of Nishida, [2a, b] Kerr, [2c] Dixon, [2d] Mukai, [2e] and Funk, [2f] and relevant synthesis studies have been reported by an array of research teams. [3] Having communicated a rapid construction of the tetracyclic core (ABCD rings) of ent-1 by showcasing the power of a Pt II -promoted cascade reaction sequence, [3i] we report herein a novel total synthesis of (À)-nakadomarin A with higher practicality and efficiency. The synthesis features: 1) the assembly of the tetracyclic core through the PtCl 2 -catalyzed cascade cyclization strategy [3i] (4!3, Scheme 1) followed by saturation [3i] of the C8=C9 double bond (3!2), and 2) CSA-assisted[2d] Z-selective olefin ringclosing metathesis (RCM; within 2!1) involving a monoamine precursor (17, Scheme 2) used to replace Dixons more polar diamine substrate (19 b) [2d] for the F ring generation. For the rest of our synthesis plan (Scheme 1), the E ring can be forged by typical olefin RCM [2a-c, e] (within 2! 1) prior to the F ring formation. Enyne 4 can be obtained through Sonogashira coupling of terminal alkyne 5 with iodofuran 7. While reductive amination of aldehyde 6 can be implemented to form alkyne 5, furan 7 can be accessible from cyclization/iodination of conjugated ynone 8 in the presence of hydriodic acid. Finally, ketone 8 can be prepared from 9 and 10.The synthesis of disubstituted furan 7 is described in Scheme 3. Propargyl alcohol THP ether [4] (9) was deprotonated and then treated with g-butyrolactone (10) in the presence of BF 3 ·OEt 2 to give ynone 8, treatment [5] of which with hydriodic acid (3 m) effected the desired cyclization/iodination to afford a mixture containing alcohol 11 and its THP ether (generated due to THP migration). Subjecting the above mixture to TsOH in MeOH led to 11 (52 %, from 9) as the sole product, which was silylated to furnish iodofuran 7 in 89 % yield.Unsaturated aldehyde 6[6] was converted into compound 5 (54 %, overall yield) by stepwise [3i] reductive amination (propargylamine . HCl, TEA, tBuOH, evaporation, NaBH 4 , MeOH) followed by N-sulfonylation (BsCl, TEA, DCM).[PdA C H T U N G T R E N N U N G (PPh 3 ) 2 Cl 2 ]/CuI-catalyzed Sonogashira coupling of terminal alkyne 5 with furan 7 in degassed TEA/DMF at room temperature gave rise to the key molecule 4 (87 %), in which the enecarbamate, alkyne and furan functionalities [7] By adopting our modified procedure, [3i] treatment of 4 (introduced to the r...