Total Synthesis of Nakadomarin

The formation of 8- and 15-membered rings was achieved by sequential RCM on compounds 184 and 187 utilizing Grubb s catalyst, which provided bislactam 188. Reduction of bislactam 188 with Red-Al completed the total synthesis of ( )-nakadomarin A. 

EtOH vi, NaOH, MeOH vii, AcCI, MeOH viii, LiBH4, MeOH, THF ix, HCIO4, DCM X, DHP, CSA xi, LiN(TMS)2, THF, then PhNTfj xii, 197, PdCljldppf), K3PO4 xiii, H2, Pd-C, MeOH, then PPTS, EtOH, then DHP, CSA xiv, LiBH4, MeOH,THE xv, Li, liq.NH3 xvi, PhS02CI, aq. NaHCO, xvii, (Boc)20, TEA, DMAP  

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The asyrrunetric total synthesis of nakadomarin A, a marine manzamine alkaloid 05Y200. 

Scheme 111 Cinchona alkaloid-derived bifunctional urea catalyst 507 in the total synthesis of (-)-nakadomarin (506)...

Jakubec P, Kyle AF, Calleja J, Dixon DJ (2011) Total Synthesis of (-)-Nakadomarin A Alkyne Ring-Closing Metaftesis. Tetrahedron Lett 52 6094... 

The diastereoselective Michael addition of P-amidoester 47 to nitroalkene 48, catalyzed by the bifunctional urea derived from cinchona alkaloid (49), was one of the key-steps in the total synthesis of nakadomarin A (Scheme 34.15) reported by Dixon et al. [47, 48]. The same catalytic system was employed successfully in the synthesis of two anti-depressant molecules. Rolipram and Paroxetine , by this group [49]. 

For interest into the total synthesis of Nakadomarin A using the methodology described, refer to the relevant review by Carson and Kerr [34]. 

Total synthesis of (—)-nakadomarin A 31, a marine alkaloid of the manzamine family, " was reported by Dixon and co-workers In their synthesis, a bifunctional organocatalyst derived from cinchonidine was effective for the Michael addition reaction of 27 and 28, and stereochemistries at C7 and C8 were efficiently controlled. In this reaction, low selectivity or decomposition of the nitroolefin was observed with the stoichiometric use of lithium 1,1,1,3,3,3-hexamethyIdisiIazide, (or lithium bis(trime-thylsilyl)amide) (LHMDS), potassium 1,1,1,3,3,3-hexam-ethyldisilazide [potassium bis(trimethylsilyl)amide] (KHMDS), or I,4-diazabicycIo[2.2.2]octane (DABCO) (Scheme 27.5). 

Nakagawa, M., Nagata, T., Ono, K., and Nishida, A. (2005) The asymmetric total synthesis of nakadomarin A, a marine manzamine alkaloid. J. Synth. Org. Chem. Japan, 63, 200-210. 

Nilson, M.G. and Funk, R.L. (2006) Generation of N-acyliminium ions via intramolecular conjugate addition reactions a strategy for the total synthesis of nakadomarin A. Org. Lett., 8, 3833-3836. 

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