Total synthesis cobalt mediated cycloaddition

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. 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

Cobalt-mediated [2-I-2-I-2] cycloaddition of an alkyne to the double bond of an enamide has been found to give spontaneously the lycorane ring system 127). Thus, a formal total synthesis of ( )--y-lycorane (100) has been achieved by this methodology. Also, ( )-y-lycorane (100) has been synthesized starting with pyrrole 128) or homophthalimide 129). 

Eichberg Ml, Dorta RL et al (2000) The formal total synthesis of ( )-strychnine via a cobalt-mediated [2+2+2] cycloaddition. Org Lett 2 2479-2481... 

The sequential [2+2+2] cycloaddition enabled the synthesis of long helicenes. The total syntheses of [7]hehphenes and [9]hehphenes were achieved via the cobalt-mediated double and triple [2+2+2] cycloadditions (Scheme 21.28) [32]. 

The total synthesis of (+)-complanamide A relies on two cobalt-mediated [2 + 2 + 2] cycloadditions to give pyridine rings (Scheme 1.34) [67fj. This cycUzation... 

For a long period the formation of a strained benzocyclobutane moiety was thought of as being a special feature of cobalt-mediated [2 - - 2 - - 2] cycloaddition reactions, as shown in the synthesis of <7Z-estrone (5) or as mentioned in the case of the pro-toilludanes 37 to 39. However, as a part of the total synthesis of the furanosteroide viridin 47, a potent antifungal metabolite of Gliocladium virens, a truly catalytic formation of the benzocyclobutane 44, could be realized in 86% yield with the help of Wilkinson s complex (Scheme 7.10) [18]. 

Vollhardt et al. reported the total synthesis of [7]heliphenes via the cobalt-mediated intramolecular double [2 + 2 + 2] cycloaddition as a key step (Scheme 10.6) [9a]. In addition, [9]heliphenes were also synthesized via cobalt-mediated intramolecular triple [2 + 2 + 2] cycloaddition (Scheme 10.7) [9b]. 

Vollhardt s total synthesis of strychnine successfully demonstrated the power of the cobalt-mediated [2+2+2]cycloaddition (111) for the construction of complex polycyclic molecules (Scheme 11). This key reaction was originally developed by his group in the 1970s, and widely utilized for the syntheses of complex natural and unnatural products (112-116). Here, this reaction was used for the simultaneous closure of the E and G rings with formation of the C7 quaternary center (117-119). To accomplish total synthesis, five synthetic approaches were investigated, but only the successful one is shown here. 

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