Aplysin synthesis

A number of oxacyclic natural products were synthesized via carbocycle-forming radical reaction of oxacyclic intermediates. An early example is the synthesis of (-)-dihydroagarofuran (170) by Biichi [109] (Scheme 58). The bridgehead chloride 168 obtained from the corresponding hydroxy ketone was amenable to radical cycliza-tion, and the tricyclic ether 169 was duly obtained. The aplysin synthesis [110] provides another example, and (—)-karahana ether (173) was synthesized via radical cyclization of the substrate 171 [111] (Scheme 59). Lactonic natural products (-1-)-eremantholide A [112], alliacolide [113], and (-)-anastrephin [114] were prepared via a variety of carbocycle-forming radical cyclization reactions. In the total synthesis of spongian-16-one (176) [115] (Scheme 60), the butenolide moiety in the substrate 174 served as the final radical acceptor for three consecutive 6-endo-. rig cyclizations. 

Provided that the silanolate elimination proceeds with anti selectivity, it must be concluded, that the intermediate homoallylic alcohol has an anti configuration, and thus the reagent has an ( -configuration. Acidic hydrolysis of the enol ether leads to enones the overall sequence consists of a nucleophilic acroylation. This has also been applied in the total synthesis of the marine diterpene ( )-aplysin-2067. 

Harrowven DC, Lucas MC, Howes PD (2001) The Synthesis of a Natural Product Family From Debromoisolaurinterol to the Aplysins. Tetrahedron 57 791... 

This three-carbon homologation was used in a synthesis of the diterpene (— )-aplysin-20 (4) from nerolidol (equation 1). ... 

Ethyl diazoacetate has been used extensively in the homologation of ketones to 3-keto esters. Lewis acid is required for the reaction (equation 23). ° There is a tendency for the least-substituted group to migrate, particularly if one group is fully substituted (equation 24). In a total synthesis of ( )-aplysin (20) this selective rearrangement was applied (Scheme 9), and a similar approach was used in a synthesis of (+)-hirsutic acid. Ethyl diazoacetate has also been used in the homologation of acyclic... 

The complete chemical and. ST-ray studies of laurinterol (140) have been published. In addition to laurinterol, debromolaurinterol and isolaurinterol (141) are also found in Laurencia intermedia Yamada. Aplysin (142), isolated from Aplysia kurodai Baba, can be derived from laurinterol by acid-catalysed cyclisation. A synthesis of both aplysin and debromoaplysin, involving suitable elaboration of the alcohol (143) has been reported.The synthesis of the methyl... 

Cyclobutanones. Epoxidation of an allylic methylene cyclopropane is followed by Lewis acid-catalyzed rearrangement of the strained oxaspiranes in situ. Such cyclobutanones are valuable for the synthesis of certain natural products (e.g., aplysin). 

Both (-)-aplysin (117) and (-)-debromoaplysin (116) have been synthesized (Scheme 8). The initial step involves the coupling of the chlorocyclopentenone (114) with the optically active metalated bromo-ether (113), which was derived from (-l-)-a-pinene. This reaction produces (115) together with the diastereoisomeric chlorohydrin. In another synthesis of aplysin (117) (Scheme 9) the key step is the acid-catalysed rearrangement of the trichothecane-type... 

An analogous strategy using a palladium-catalyzed ring-expansion reaction of 1-vinylcyclobutanols was also employed in the synthesis of (-)-aplysin [29], (-1-)-equilenin [30], ( )-deoxyverrucarol [31], and ( )-scirpene [32]. 

Directed lithiation of (36) is the first step in a new synthesis of aplysin. Lithiation of the methyl groups of 3-methylquinoline and methylbenzonitriles is accomplished with LDA at —78 °C. When direct lithiation does not occur at the desired site, aryl lithium compounds can often be obtained by the action of RLi on ArBr at low temperatures. In this way the isomeric cyanopheny 1-lithiums and the quinone carbanion equivalent (37) can be obtained. Reaction of an aryl-lithium with CF2=CCl2 gives (38), which is converted into (39) by the action of Bu"Li at low temperature. ... 

Yamaguchi, Y, Uyehara, T., and Kato, T. (1985) Biogenetic type synthesis of ( )-condnndiol and ( )-aplysin-20. Tetrahedron Lett., 26, 343-346. 

Yoshida, M., Shoji, Y., and Shishido, K. (2010) Fnantioselertive formal total synthesis of aplysin utilizing a palladium-catalyzed addition of an alkylboronic acid to an aHenic alcohol—Eschenmoser/Claisen rearrangement. Tetrahedron, 66, 5053-5058. 

Ghosh, A., Biswas, S, and Venkateswaran, R,V. (1988) Stereo-controlled synthesis of ( )-debromoaplysin and ( )-aplysin. J. Chem. Soc. Chem. Commun., 1421. 

Laronze, J.Y., Boukili, R.E., Cartier, D., Laronze, J, and Levy, J. (1989) The Sheradsky rearrangement of a,a-disubstituted cyclopentenone aryloximes a synthesis of the sesquiterpenes ( )-aplysin and ( )-filiformin. Tetrahedron Lett., 30, 2229-2232,... 

Nath, A., Ghosh, A., and Venkateswaran, R.V. (1992) Rapid high-yield synthesis of the marine sesquiterpenes debromoaplysin and aplysin via the acid catalysed rearrangement of a cyclobutachromanol. J. Org. Chem., 57, 1467-1472. 

Harrowven, D.C., Lucas, M.C., and Howes, P.D. (1999) Total synthesis of aplysin and debromoaplysin using a diastereoselective, sulfur mediated radical cyclisation strategy. Tetrahedron Lett., 40, 4443 444. 

The titanium- ate complexes of a-methoxy allylic phosphine oxides, generated in situ by reaction of the corresponding lithium anion and Ti(0-i-Pr)4, condense with aldehydes exclusively at the a-position to produce homoallylic alcohols in a diastereose-lective fashion. The overall result is the three-carbon homologation of the original aldehyde, and this protocol has been used in a synthesis of (-)-aplysin-20 from nerolidol. The titanium- ate complex produced by reaction of the chiral lithium anion of an ( )-crotyl carbamate with Ti(0- -Pr)4 affords -y-condensation products (homoaldols) on reaction with aldehydes. Allyl anions produced by the reductive metalation of allyl phenyl sulfides condense with a,p-unsaturated aldehydes in a 1,2-manner at the more substituted (a) allyl terminus in the presence of Ti(0-i-Pr)4. 1,2-Addition of dialky Izincs to a,p-unsaturated aldehydes can be achieved with useful levels of enantiocontrol when the reaction is conducted using a chiral titanium(IV) catalyst in the presence of Ti(0- -Pr)4 (eq 20). Higher ee values are observed when an a-substituent (e.g. bromine) is attached to the substrate aldehyde, but a -substituent cis-related to the carbonyl group has the opposite effect. 

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