Polycyclic frameworks, synthesis

The synthetic route to the prostaglandins developed by Kelly and his colleagues at Upjohn similarly depends on a rigid polycyclic framework for establishment of the stereochemistry. The synthesis differs significantly from that above in that a rearrangement step is used to attain the stage comparable to 23. 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

Although the above-mentioned electrocyclization reactions were well studied prior to the discovery of the endiandric acids, their utilization in the total synthesis of complex molecules had not been demonstrated. The endiandric acids, therefore, offered an irresistible opportunity to explore the utility of electrocyclization reactions in synthesis. The successful studies disclosed below demonstrate that these reactions can provide concise solutions to the challenge presented by complex polycyclic frameworks. 

With the polycyclic framework of the natural product intact, the completion of the total synthesis only requires a short sequence of reactions. At this juncture, the decision was made to address the problem of reconstituting the A-ring lactone. It was hoped that a selective oxidation of the A-ring allylic ether could be achieved. 

The synthesis of enantiomerically pure compounds is the challenging problem for organic chemists. The synthesis becomes obsolete if the intermediates produce racemic mixtures. The problem is particularly acute when the asymmetric centers do not reside in a rigid cyclic or polycyclic framework. To be able to carry out efficient syntheses of complex molecules, chemists have to control the sense of chirality at each chiral center as it is introduced in the course of synthesis. Monoalkyl- or dialkyl-boranes exhibit a remarkable chemo-, stereo-, and regioselectivity for the hydroboration of unsaturated compounds. This property, coupled with the capability for asymmetric creation of chiral centers with chiral hydroboration agents, makes the reaction most valuable for asymmetric organic synthesis. In some of the cases, however, this has been achieved by diborane itself as shown in the synthesis of monensin by Kishi et al. A stereospecific synthesis of its seven carbon. component has been accomplished by two hydroboration reactions (Eq. 129) 209. ... 

The validity of the conceived retrosynthetic plan was proven in its truly brilliant synthetic implementation. In fact, the synthesis of a rather complicated polycyclic framework containing three adjacent quaternary centers was achieved with record-breaking simplicity and efficiency (Scheme 3.26) in only... 

Surprisingly few examples in this category of nine-membered ring radicals are devoted to the synthesis of polycyclic frameworks through a radical cascade involving transannular closures. We have previously mentioned the capacity of the car-yophyllene radical to cyclize transannularly (Scheme 28), but this example of a unique radical cyclization step was not applied in cascade strategies [45]. 

The intramolecular Diels-Alder (IMDA) or hetero Diels-Alder (IMHDA) cydoad-dition reactions are often the key step in the synthesis of functionalized bicyclic bridged and polycyclic systems with high regio and stereoselectivity. The application of microwave irradiation to IMDA and IMHDA reactions may have significant advantages compared with conventional heating methods. Early examples of microwave activation in these reactions for synthesis of polycyclic frameworks, have been extensively reviewed by de la Hoz and will not be discussed herein [3jj. 

The beauty of this method is that iterative processes can proceed and that polycyclic frameworks can be constructed. In the formal synthesis of (-)-brevisin, compound 36 was obtained by using a rhodium-catalyzed e do-selective epoxide-opening cascades. Thus, when THP 35 was treated with [Rh(CO)2Cl]2, compound 36 was formed and then transformed to primary alcohol 37 which is a precursor of (-)-brevisin (Scheme 20) (2015JA6941). 

A different strategy and very elegant approach combines the palladium insertion into an aryl halide, subsequent Heck reaction, and an intramolecular arylation through C—H activation. In 2004, Larock published the synthesis of various polycycles by utilizing such a tandem protocol [131]. The sequence leading to tetracycle 217 is shown in Equation 12.40-1, Scheme 12.40. The sequential palladium-catalyzed reactions allow the efficient elaboration of complex polycyclic frameworks, which are commonly observed in natural products. 

Although this synthesis provides the most direct entry into the twistane polycyclic structure, the adequate balance between the problem of framework construction and the subsequent functional group manipulations, required by the "principle of maximum simplicity", is missed. However, the synthesis represents without doubt an outstanding contribution to the synthesis of polycyclic non-natural products. 

This unique C-C bond-forming reaction has been applied to the synthesis of natural products [480,481]. In the examples reported, intramolecular C-H insertion into R3C-H groups was used for the construction of more elaborate, polycyclic carbon frameworks. Representative examples are listed in Table 3.7. 

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