Total synthesis cascade reactions

Nicolaou, K.C., Edmonds, D.J., Bulger, P.G. (2006) Cascade Reactions in Total Synthesis. Angewandte Chemie International Edition, 45, 7134-7186. 

A very impressive multiple cationic domino reaction was used in the enan-tioselective total synthesis of (-)-gilbertine (1-190), described by Blechert and coworkers [50]. When the tertiary alcohol 1-184 is treated with TFA, a carbocation is formed which undergoes a cascade of cyclizations to afford 1-190 in very good yield (61 %) (Scheme 1.44). The cations 1-185 to 1-189 can be assumed as intermediates. 

Another very new radical/radical domino procedure was used in the total synthesis of the alkaloid lennoxamine by Ishibashi and coworkers. Here, a 7-endo cycliza-tion/homolytic aromatic substitution reaction cascade led to the target compound in 41% yield [75]. 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

C-H activation at a primary benzylic site was the key step in very short syntheses of lig-nans 206 and 207 (Scheme 14.27) [138]. Even though both the substrate 203 and the vinyl-diazoacetate 204 contain very electron-rich aromatic rings, C-H activation to form 205 (43% yield and 91% ee) is still possible because the aromatic rings are sterically protected from electrophilic aromatic substitution by the carbenoid. Reduction of the ester in (S)-205 followed by global deprotection of the silyl ethers completes a highly efficient three-step asymmetric total synthesis of (-i-)-imperanene 206. Treatment of (R)-205 in a more elaborate synthetic sequence of a cascade Prins reaction/electrophilic substitution/lacto-nization results in the total synthesis of a related lignan, (-)-a-conidendrin 207. 

Bowman et al. reported the total synthesis of ellipticine (228) involving an imidoyl radical cascade reaction (730). For this key step, the required imidoyl radical was generated from the imidoyl selanide 1290, which was obtained from ethyl 2-(4-pyridyl)acetate (1286). Reaction of 1286 with LDA, followed by addition of methyl iodide, led to the corresponding methyl derivative 1287. Treatment of 1287 with 2-iodoaniline (743) in the presence of trimethylaluminum (AlMes) afforded the amide 1288. Using Sonogashira conditions, propyne is coupled with the amide 1288 to afford the aryl acetylene 1289. The aryl acetylene 1289 was transformed to the... 

The total synthesis of litseaverticillols D, F and G (172 and 173), which are natural products with anti-HIV activity, was achieved recently via a singlet oxygen initiated cascade proposed to be biomimetic (Scheme 64). Finally, allylic alcohols 174a and 174b (Scheme 64) were isolated in a 4/1 ratio via a stereoselective singlet oxygen ene reaction. Stereoisomer 174a is an intermediate in the synthetic route of staurosporine, which is a bioactive alkaloid with hypotensive, antimicrobial and cell cytotoxic properties. 

Ring closure to an episulfide is a feasible reaction for thiocarbonyl ylides. In most cases, the sulfur is further extruded under the reaction conditions to afford an olefin as the final product. This cascade transformation has been utilized by Danishefsky and co-workers in their total synthesis of ( )-indolizomycin (Scheme 16)." In the Danishefsky s approach, diazo ketone 137 is treated with a catalytic amount of Rh2(OAc)4 to generate thiocarbonyl ylide 138, which cyclizes to give episulfide 139. This episulfide isomerizes to mercaptan 140, which is then desulfurized by partially deactivated W-2 Raney nickel. 

Fig. 39 Examples for biomimetic cascade reactions in total synthesis...

Aldehydes undergo a Mukaiyama-aldol reaction followed by a Prins cyclization with the highly reactive allylsilane 329 to afford jy -2,6-tetrahydropyrans 330 that feature an oeo-methylene group at C-4 (Equation 140, Table 12). This Mukaiyama-aldol-Prins (MAP) cascade cyclization has been used to form a key bis-tetrahydropyran intermediate during the total synthesis of leucascandrolide A <2001JA8420>. Similarly, titanium tetrabromide mediated MAP reactions afford 4-bromo tetrahydropyrans <20030L3163>. 

Nicolaou KC, Montagnon T, Snyder SA (2003) Tandem reactions, cascade sequences, and biomimetic strategies in total synthesis. Chem Commun 5 551... 

Nicolaou KC, Edmonds DJ, Bulger PC (2006) Cascade reactions in total synthesis. Angew Chem Int Ed Engl 45 7134—7186... 

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