Synthesis novel total

Each level has its merits. The ab initio level is useful for discovering new reactions by searching for new sequences of electron pushing steps. The name-reaction level is most useful for novel total synthesis whereas the reaction sequence level is useful for rapidly generating classical syntheses, but has little innovative power. 

ACS Symposium Series American Chemical Society Washington, DC, 1977. 

A linear symbolic code has been developed for this purpose. 

PRIORITY is a value representing the initial plausibility of the transform, before consideration of the reaction site context. Values range from -50 to 100. CHARACTER describes what kinds of structural modifications the transform can make, e.g., ALTERS GROUP, BREAKS RING. 

CONDITIONS are generalized classes of reaction conditions, rather than specific reagents. The advantage being that any new reagent can always be represented as belonging to a general class. These are described later in this paper. 

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An example of the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a novel total synthesis of the macrosphelides A (209) and B (208) (Scheme 41) [100]. When the PMB-pro-tected compound 204 was examined as a metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts A or C. When the reaction was carried out using equimolar amounts of catalyst C in refluxing 1,2-dichloroethane, the cyclized product 205 was obtained in 65% yield after 5 days. On the other hand, the free allylic alcohol 206 reacted smoothly at room temperature leading to the desired macrocycle 207 in improved yield. 

Imanishi, T, Yagi, N., Shin, H., Hanaoka, M. (1981) 1.6-Dihydro-3(2H)-Pyridinones as Synthetic Intermediates. A Novel Total Synthesis of ( )-Ibogamine and ( )-Epiibogamine. Tetrahedron Letters, 22, 4001-4004. 

In a novel total synthesis of the tricyclic sesquiterpene (—)-longifolene, an intramolecular diazoalkane cycloaddition to a cyclohexadienone ring followed by thermal ring contraction of the resulting pyrazoline gave the tricychc vinylcyclo-propane 261 and this constitutes the key steps in this synthesis (314) (Scheme 8.63). The interesting features of this sequence are the separation of dipole and dipolarophile by five atoms and the formation of a seven-membered ring in the cycloaddition step. 

Dysidiolide is the first compound found to be a natural inhibitor of protein phosphatase cdc25A that is essential for cell proliferation. Y. Yamada et al. develcyed a novel total synthesis of this natural product using an intramolecular Diels-Alder cycloaddition as the key step. Deoxygenation of the advanced bicyclic intermediate at the C24 position was achieved under Woiff-Kishner reduction conditions to afford the C24 methyl group. 

Hydroxyquinine 97 was prepared recently in the course of a novel total synthesis approach toward cinchona alkaloids (Scheme 12.27). Interestingly, studies on stereocontrolled synthesis of quinine, apart from that of Uskokovic [66], were not published until 2001 and 2004, again underlining the fact that cinchona alkaloid... 

The first example, reported in 1975 by Marquet, concerns a novel total synthesis of biotin, based on stereoselective alkylation of a bicyclic, cw-fused, five-membered ring sulfoxide [126,127]. 

Demeke D, Forsyth CJ. Novel total synthesis of the anticancer natural product dysidiolide. Org. Lett. 2000 2 3177 3179. 

Ito K, Suzuki F, Hamna M. Novel total synthesis of ( )-ery-sotramidine, an oxo-erythrinan alkaloid. J. Chem. Soc. Chem. Commun. 1978 (17) 733-734. 

Eiter, K. Novel total synthesis of sex attractant of Porthetria dispar (7,8-cw-epoxy-2-methyloctadecane). Angew. Chem. Int. Ed. Engl. 11, 60—61 (1972). 

Liao, C.-C. and Wei, C.-P., Synthetic applications of masked o-benzoquinones. A novel total synthesis of ( ) forsythide aglucone dimethyl ester, Tetrahedron Lett., 30, 2255,1989. 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

The total synthesis of ( )-estrone [( )-1 ] by Vollhardt et al. is a novel extension of transition metal mediated alkyne cyclotrimeriza-tion technology. This remarkable total synthesis is achieved in only five steps from 2-methylcyclopentenone (19) in an overall yield of 22%. The most striking maneuver in this synthesis is, of course, the construction of tetracycle 13 from the comparatively simple diyne 16 by combining cobalt-mediated and ort/io-quinodimethane cycloaddition reactions. This achievement bodes well for future applications of this chemistry to the total synthesis of other natural products. 

The body of chemistry described above for amphotericin B (1) allowed, for the first time, the preparation of a series of novel derivatives of this polyene macrolide antibiotic and set the stage for a total synthesis of this target molecule. Below we unfold the adventure that led to the accomplishment of this goal.910... 

Our general survey of palladium in organic synthesis must now come to an end. At the very least, we hope that our brief foray into this fascinating area conveys some of the vitality that characterizes research in this area. The remainder of this chapter will address the first total synthesis of rapamycin by the Nicolaou group. This work is predicated on a novel variant of the Stille reaction. 

Madindoline A (7) and B (ent-8) are potent inhibitors of interleukin 6. In a total synthesis [21] that also intended to determine the relative and absolute configurations of these novel antibiotics, the densely functionalized cyclopen-tene-l,3-dione ring of 7 and 8 was elaborated via RCM of diene-diol 2 (Scheme 1). 

In a recent total synthesis of the novel neurotrophic agent merrilactone A (22, Scheme 4) by Inoue and Hirama [24], key intermediate 21 with the cis-bicyclo[3.3.0] octane framework embedded within the caged pentacycle 22 was elaborated from cyclobutane 18 by a sequence of RCM and immediate cleavage of the resulting bicyclic vicinal diol 19 to raeso-diketone 20. Cyclooctenedione 20 then underwent regioselective transannular aldol reaction at low temperature (LHMDS, THF, -100 °C) to produce a 3 1 mixture of isomers in 85% combined yield. The major isomer 21 with the required stereochemistry was then converted into the racemic natural compound ( )-22 in 19 steps. 

The marine natural product dynosin A (92) is a new member of the aerugi-nosin family and a novel inhibitor of thrombin and Factor Vila. In Hanessian s total synthesis of 92 [66], both the dihydroxyoctahydroindole 88 and the A3 pyrroline moiety 91 were prepared by RCM-based routes (Scheme 17). 

Also, a novel RCM-based approach to the 6-aza[3.2.1]bicyclooct-3-ene 103, and hence a formal total synthesis of the antitumor antibiotic (-)-peduncular-ine (104) (Scheme 20), was recently disclosed by Martin s group [70]. Initial ex-... 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

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