Carbocyclic core

Ziegler and Saprong described a stoichiometric cyclization onto an alkyne for the synthesis of the carbocyclic core of entecavir from diacetone glucose. Inverse addition was required to minimize deoxygenation. The highly diastereoselective reaction is tolerant to silylethers [101]. 

In contrast to the efficient reactions illustrated above, the use of 1,2-disubstituted aikenes as the 2n -components in the [5-1-2] cycloaddition has resulted, thus far, in low cycloadduct yields and complex mixtures, putatively arising from an intermediate metal-lacycle through competitive yS-hydride elimination. This limits access to the carbocyclic cores of some large and medicinally interesting natural product families (for example, those in Scheme 13.3). Introduction of an allene substrate, however, circumvents this limitation by installing the needed carbon-carbon bond while simultaneously leaving a handle for further functionalization (Scheme 13.10). For example, reduction of the exo-... 

The convenient generation of bicyclo[2.2.2]octenones through the use of ortho-quinol derivatives in Diels-Alder reactions recently inspired Wood and co-workers in their studies toward the total synthesis of CP-263,114 (110) [148]. They relied on the Wessely-Yates tandem oxidative acetoxylation/intramolecular Diels-Alder sequence to build bicyclo[2.2.2]octenones such as 114 en route to advanced isotwistane intermediates such as 111b, which could eventually be fragmented to furnish the carbocyclic core of 110 (i.e. 111a —> 110, Figure 29) [149-153],... 

J. Marco-Contelles, C. Destabel, P. Gallego, J. L. Chiara, and M. Bemabe, A new synthetic approach to the carbocyclic core of cyclopentane-type glycosidase inhibitors Asymmetric synthesis of amino-cyclopentitols via free radical cycloisomerization of enantiomerically pure alkyne-tethered oxime ethers derived from carbohydrates, J. Org. Chem., 61 (1996) 1354-1362. 

Scheme 18 Synthesis of a protected carbocyclic core of entecavir from D-diacetone glucose [99]...

In connection with a program on developing free radical methodology, Praser-Reid described several approaches to densely functionalized carbocycles. This led to the construction of the carbocyclic core of tetrodotoxin [326]. The synthesis of cyclophellitol 414 and its epi derivative, described here, illustrates the principles of this strategy [327]. 

Alonso, R A, Burgey, C S, Rao, B V, Vite, G D, Vollerthun, R, Zottola, M A, Fraser-Reid, B, Carbohydrates to carbocycles — synthesis of the densely functionalized carbocyclic core of tetrodotoxin by radical cyclization of an anhydro sugar precursor, J. Am. Chem. Soc., 115, 6666-6672, 1993. 

Sato, I. Akahori, Y. lida, K. Hirama, M. Efficient synthesis of a carbocyclic core moiety with the stereochemistry of the C-1027 chromophore. Tetrahedron Lett. 1996, 37, 5135 5138. 

Perrier [102] showed that 1,6-anhydropyranoses may undergo regioselective photobromination at C-6. This observation was exploited by Gallagher [103] during the synthesis of herbicidin glycoside 160 and by Fraser-Reid [104] during the preparation of a precursor 161 to the carbocyclic core of tetrodotoxin (Scheme 26). 

If the oxidation is performed in the presence of an external dienophile, the respective products of [4+2] cycloaddition are formed [351-356]. Typical examples are illustrated by a one-pot synthesis of several silyl bicyclic alkenes 283 by intermolecular Diels-Alder reactions of 4-trimethylsilyl substituted masked o-benzoquinones 282 generated by oxidation of the corresponding 2-methoxyphenols 281 [351] and by the hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade reaction of phenols 284 with allyl alcohol affording polycyclic acetals 285 (Scheme 3.118) [352]. This hypervalent iodine-promoted tandem phenolic oxidation/Diels-Alder reaction has been utilized in the stereoselective synthesis of the bacchopetiolone carbocyclic core [353]. 

At this juncture, with the entire carbocyclic core of aspidophytine established, an advanced staging area had been reached from which the total synthesis could hopefully be completed after a few finishing touches. Specifically, what remained was the fusion of the y-lac-tone and the excision of the unwanted carbon atom with the introduction of a double bond inside the adjacent cyclohexane ring. 

As part of our program exploring the (4+3)-cycloaddition/quasi-Favorskii reaction sequence, we undertook a formal total synthesis of spatol fFigure 7.9T an interesting natural product possessing a unique diepoxide, a 5-4-5 ring-fused carbocyclic core, and antitumor... 

Ghosh and co-workers used olefin metathesis as a key step in their synthesis of the carbocyclic core of e /-bacillariolide II, an oxylipin. Oxylipins are densely fiinctionalized naturally occurring bicyclic systems... 

Castle and co-workers used a ring-closing metathesis strategy in their synthesis of the carbocyclic core of ( )-hasubanonine, a member of the hasubanan alkaloid family." Hasubanan alkaloids are of interest due to their structural similarity to morphine alkaloids. Treatment of diene 220 with a catalytic amount of 4 in refluxing dichloromethane furnished the desired phenanthrene core 221 in quantitative yield. Six additional steps were required to obtain the desired natural product. 

Olefin metathesis was also used as a key step in Wicha and coworkers synthesis of the carbocyclic core of several di- and sesqui-terterpenes. Reaction of 277 with 5 mol % of 4 in refluxing benzene gave the corresponding bicyclic system 278 in 60% overall yield. 

Clark and co-workers used the olefin metathesis strategy pioneered by Rodriquez and co-workers for the synthesis of eight and nine-membered ring carbocycles, in their synthesis of the nine-membered carbocyclic core of a class of herbicidial nonadrides known as the comextins. Treatment of diene 381 with either catalytic 3 in refluxing dichloromethane, or 4 in... 

Nakata and co-workers recently employed a ring-closing metathesis strategy to construct the 14-membered carbocyclic core of methyl... 

Completion of the formal total synthesis of platensimycin enhanced our scope of furan Diels-Alder reactions with TBCP and simple substituted furans. Extension of this formal [4+3]-cycloaddition to annulated furans such as 46 would be necessary for access to the [5.4.0]undecane carbocyclic core of fron-dosin A. Although the analogous reaction between annulated furans and oxyallyl cations are known to be difficult, with simple electrophilic substitution... 

Xue H, Yang J, Gopal P. Toward the synthesis of norzoanth-amine building carbocyclic core by a transannular Michael reaction cascade. Org. Lett. 2011 13 5696-5699. 

Kurti L, Czako B, Corey EJ. A short, scalable synthesis of the carbocyclic core of the anti-angiogenic cortistatins from (+)-estrone by B-ring expansion. Org. Lett. 2008 10 (22) 5247-5250. 

Baumgartner, C., Ma, S., Liu, Q., and Stoltz, B.M. (2010) Efforts toward rapid construction of the cortistatin A carbocyclic core via enyne-ene metathesis. Org. Biomol. Chem., 8, 2915-2917. 

---