In 1997, Kobayashi and co-workers disclosed the isolation of ( )-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. The biological properties of 1 range from prominent cytotoxicity against murine lymphoma L1210 cells to outstanding antimicrobial and CDK4 inhibitory activities. Since 2003, elegant total and formal syntheses of 1 have been accomplished by the laboratories of Nishida, Kerr, Dixon, Mukai, and Funk, and relevant synthesis studies have been reported by an array of research teams. Having communicated a rapid construction of the tetracyclic core (ABCD rings) of ent-1 by showcasing the power of a Pt-promoted cascade reaction sequence, we report herein a novel total synthesis of ( )-nakadomarin A with higher practicality and efficiency. The synthesis features: 1) the assembly of the tetracyclic core through the PtCl2-catalyzed cascade cyclization strategy [3i] (4!3, Scheme 1) followed by saturation of the C8=C9 double bond (3!2), and 2) CSA-assisted Z-selective olefin ringclosing metathesis (RCM; within 2!1) involving a monoamine precursor (17, Scheme 2) used to replace Dixon s more polar diamine substrate (19b) for the F ring generation. For the rest of our synthesis plan (Scheme 1), the E ring can be forged by typical olefin RCM (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 (9) was deprotonated and then treated with g-butyrolactone (10) in the presence of BF3·OEt2 to give ynone 8, treatment [5] of which with hydriodic acid (3m) 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 was converted into compound 5 (54%, overall yield) by stepwise reductive amination (propargylamineHCl, TEA, tBuOH, evaporation, NaBH4, MeOH) followed by N-sulfonylation (BsCl, TEA, DCM). [Pd ACHTUNGTRENNUNG(PPh3)2Cl2]/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 [a] Dr. B. Cheng, F. Wu, Y. Zhou Hefei National Laboratory for Physical Science at Microscale and Department of Chemistry University of Science and Technology of China Hefei 230026 (P.R. China)