Cycloaddition of enediynes

Decahydro-4a,5b-dimethylphenanthrene (3).5 This very air-sensitive hydrophen-anthrene nucleus is obtained by a [2 + 2 + 2] cycloaddition of enediyne (1) mediated by CpCo(CO)2. This cyclization is noteworthy because it involves cyclization of a tetra-... 

Scheme 7.5 Rhodium-catalyzed stereoselective [2-1-2-1-2] cycloaddition of enediyne.

Shibata, T, Kurokawa, H., Kanda, K. (2007) Enantioselective intramolecular [2+2+2] cycloaddition of enediynes for the synthesis of chiral cyclohexa-1,3-dienes. Journal of Organic Chemistry, 72, 6521-6525. 

Continuing their work on the [2+2+2] cycloaddition of enediynes, Gan-don and Aubert discovered that replacement of PPh3 by the NHC ligand IPr... 

Bennacer, B., Fujiwara, M., Lee, S.-Y. and Ojima, I. (2005) Silicon-initiated car-bonylative carbotricyclization and [24-24-24-1] cycloaddition of enediynes catalyzed by rhodium complexes. 7o r a/ of the American Chemical Society, 127(50), 17756-17767. 

Scheme 5.11 [2+2+2] Cycloaddition reactions of enediynes in presence of a NHC-Co complex...

Bicyclic cis- and frans-isoxazolidinyldiynes have been prepared by intramolecular nitrone cycloaddition of the two side chains of an acyclic enediyne-nitrone precursor (Scheme 2.233) (731). 

Cycloaddition of cncdiynes. Photolysis of the enediyne 1 in the presence of catalytic quantities of CpCo(CO)2 in refluxing toluene results in the tricyclic diene 2. The reaction involves a diene rearrangement in the expected product (a).1... 

Estrones. An A —> BCD approach to estrones involves a cobalt catalyzed intramolecular 2 + 2 -y 2] cycloaddition of the enediyne 1 to form the B, C. and D rings in one step. The high stereoselectivity suggests that the cyclization involves a Dicls-Alder-type reaction of the vinyl group with a cobaltacyclopentadiene formed by coupling of the two alkyne units. The homoannular diene obtained on demetalation is isomcrized easily to the diene 3. 

Malaciia and co-workers reported an improved diastereoselectivity of the Cocatalyzed cycloaddition of substituted linear enediynes by introducing substituents such as esters, sulfoxide, or phosphine oxide at the terminal position of either the double or the triple bond [76]. 

With an appropriate precursor C-ring, dienyl steroids have been made accessible in a remarkably highly stereoselective process [77]. Intramolecular cycloaddition reactions of enediynes containing a terminal alkyne group have also been observed by Vollhardt [78] (eq. (27)). 

Slowinski, R, Aubert, C.. and Malacria, M., Highly stereoselective induction in the cobalt-mediated [2 -I- 2 -I- 2] cycloaddition of chhal phosphine oxides substituted linear enediynes. Tetrahedron Lett., 40, 5849, 1999. 

Scheme 77. Intramolecluar, metal-mediated [2 + 2 + 2] cycloaddition of an enediyne to form polycycles of medical interest.

During the study on the scope and limitations of CO-SiCaT reactions, it was found that in the absence of hydrosilane, the reaction of 1-substituted endiynes 525 catalyzed by [Rh(cod)Cl]2 afforded carbonylative tricyclization products 526 in good yield via a novel [2+2+2+1] cycloaddition, accompanied by a small amount of noncarbonylative product (527) via a [2+2+2] cycloaddition (Scheme 2-77). The reaction of 525 under the CO-SiCaT conditions gave noncarbonylated product 527 exclusively. Also, it should be noted that the attempted reaction of enediynes 525 with a terminal acetylene moiety under the standard [2+2+2+1] conditions did not take place. 

Interestingly, the reaction of unsubstituted dodec-ll-ene-l,6-diyne 218 under the optimized [2+2+2+1] cycloaddition conditions proceeded slowly (3 days) to give the tricyclic adduct 219 in 51% yield. In sharp contrast, the CO-SiCaT of enediyne 218 gave 219 in 91% isolated in 24 h (Scheme 98). Thus, the two carbonylation reactions are complimentary with respect to the substrate type. 

When the core chromophore is changed to pyrazine (Scheme 30.23, bottom), interaction of enediyne moiety with 1,4-cyclohexadiene proceeds as a cycloaddition [40]. The latter change in reactivity is attributed to the particularly fast formation of an electrophilic triplet state that attacks the jc-bond of 1,4-CHD. In the presence of an ortho-amide functionahty, the same chromophore undergoes either a 7-endo-dig cyclization or photohydration [41]. 

Cycloaddition of an enediyne leads to the corresponding cyclohexadiene along with the possibility of creating one to two consecutive stereogenic centers, depending on the substitution of the alkene inserted. Cobalt, albeit stoichiometric, is a reactant of choice to perform these reactions [8], Thus, the presence of a chiral motif on the enediyne substrate is crucial to achieve a satisfactory level of diastereoselectivity (Scheme 7.4). Stereoselective catalytic versions were also achieved by switching to cationic rhodium in the presence of atropisomeric ligands [9]. Various enan-tioenriched cyclohexadienes were obtained with enantioselectivities up to 97% (Scheme 7.5). 

Slowinski, R, Aubert, C., Malacria, M. (2003). Diastereoselective cobalt-mediated [2+2+2] cycloadditions of substituted linear enediynes phosphine oxides scope and limitations. Journal of Organic Chemistry, 68, 378-386. 

CpCo(C0>2 catalyses the dimerisation of Me SiC=CSiMe to the butaaiene, and the C2+2+23 cycloaddition of silylated enediynes to give the A ring of... 

Strategies for the Synthesis of Steroid Systems by Co-catalyzed [2-I-2-I-2] Cycloaddition of Nonconjugated Enyne-Allenes and Enediynes... 

The cobalt-catalyzed [2+2+2] cycloaddition of 4-hydroxy-substituted enediynes [152] that has been implemented in the synthesis of 2-hydroxy substituted decahydrophenanthrenes [153] has shown that the hydroxy group in the propargyl position tolerates the chosen reaction conditions. So, this approach could be an appropriate route to hydrogenated trans-phenanthrenes, which are the ABC cores of ergosterin and lumisterin steroids. This was a reason to consider the diastereoselective synthesis of (3S)-hydroxyandrosta-5,7-diene-17-ones 2.307, the precursors of vitamin D, via a D ABCD approach. 

Intramolecular Cycloaddition of Nonconjugated Enediynes of a Higher Order as a Route to Functionalized Condensed Polycyclic Systems... 

The first attempt to construct a condensed core was a unique silicon-initiated (CO-SiCaT) reaction of carbonylated carbotricyclization of enediynes 2.314 [154, 161]. The 5-7-5 fused tricyclic products can be produced from the same type enediynes and CO through also by the rhodium-catalyzed intramolecular [2+2+2+1] cycloaddition [154, 160]. Reaction of dodeca-ll-ene-l,6-diyne 2.314 or heteroatomic analogues with a hydrosilane catalyzed by Rh(acac)(CO)2 at ambient temperature and pressure affords the corresponding fused 5-7-5 tricyclic system with a seven-membered lactone ring, 5-oxo-l,3a,4,5,7,9-hexahydro-6H-cyclopenta[e]azulenes 2.315 or related heteroanalogs in a yield from good to excellent (50-98%) (Scheme 2.104) [154]. 

Cycloaddition reaction of two molecules of alkyne and alkene is a direct route for the synthesis of substituted cyclohexadiene derivatives, which are important components of the Diels-Alder reaction. Therefore, the reaction cycloisomerization of enediyne azamacrocycles represents a pathway to the synthesis of highly functionalized tetra-condensed cyclo-hexadienes in a single step. The synthetic variety of such reactions is... 

The effect of changing the substituents at the doubie bond on the [2+2+2] cycloaddition reaction of enediyne macrocydes at the application of this methodology, were investigated the macrocydes 2.385 and 2.386 with unsubstituted double bond (entries 7 and 8, Table 2.20), and comparing them with the cycloisomerization of various macrocydes 2.389-2.391. The main trend observed for enediyne macrocydes was the preferred formation of 5,6,6-membered rings fused with cyclo-hexadiene core (2.398) over 5,5,6 ring systems (compounds 2.389 and 2.390), which in turn formed more readily than 5,5,5-tetracondensed structures (2.392 and 2.393) (entries 9-11 in Table 2.20) [183]. 

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