Natural products synthesis, strained alkenes

However, from the outset of this field, the limitations as well as the potentials of this cycloaddition were also apparent. For instance, the efficiency of this cycloaddition in an intermolecular manner was typically low unless strained olefins were used. Moreover, the use of unsymmetrical alkenes led to a mixture of the cyclopentenone regioisomers. Synthetic utility of this reaction is considerably expanded by the emergency of the intramolecular reaction. Schore introduced the first intramolecular version forming several rings simultaneously, which is now the most popular synthetic strategy in natural product synthesis because of its conceptual and operational simplicity. Additionally, the regiochemistry is no longer the problem in this variation. 

Strained alkenes in natural product synthesis 13AG(E)4078. Supramolecular construction of optoelectronic biomaterials 13ACR1527. Suzuki reaction in total synthesis 12T9145. 

Two illustrations that show the power of this reaction for the preparation of strained cycloalkenes are the contractions of 102 to the propellane 103 , an application that has been reviewed , and of 104 to the bicyclo[2.1.1]hexene 105 . The utility of the Ramberg-Backlund rearrangement in the preparation of various natural products such as steroids , terpenoids and pheromones has been demonstrated. In addition to the synthetic applications mentioned in the previous subsection, several selected examples taken from the recent literature are given in equations 66-69. These examples further demonstrate the potential of this method for alkene synthesis in general. 

In 2004, Kozmin et al. reported the total synthesis of bistramide A (69), a marine natural product with potent cytotoxicity [67]. In this synthesis (Fig. 21) the authors developed a novel approach featuring a sequential ring opening/selective alkene cross metathesis of highly strained cyclopropenone ketal (70) with terminal alkenes (71) and (72). After extensive reaction optimization, this process was successfully achieved using Grubbs II catalyst. For the cross metathesis reaction, a remarkable regioselectivity was observed in the presence of two different alkene moieties. 

The last example in this section is the total synthesis of RK-397 (83) by Sammakia et al. [71]. RK-397 (83) is an oxopolyene macrolide, which was isolated from a strain of soil bacteria. This natural product presents several synthetic challenges, including particularly the installation of the highly sensitive polyene moiety. Sammakia and coworkers successfully tackled this obstacle through a selective alkene cross metathesis reaction at a late stage (Fig. 24). By screening a number of reaction conditions, they found that treatment of alkene (84) and 2,4,6-hexatrienal with Grubbs I catalyst smoothly afforded polyene product (85) in 72% yield as a 4 1 mixture of /Z isomers. 

The aldol reaction plays a key role in biosynthesis of poly-ketide natural products. It is also one of the most used transformations for stereoselective C—C bond formation. Deslongchamps and co-workers described one of the early examples of transannular aldol reactions in the synthesis of (it)-ryanodol, a compact and highly functionalized polycyclic diterpenoid isolated from Ryania speciosa The 1,5-diketone 48 that was requisite for the transannular aldol reaction was generated in situ from 47 by ozonolysis of its alkene (Scheme 20.14). Conformational equilibration of 48 to the less strained conformer B was followed by a transannular aldol reaction to give 49 in 90% yield. The polycyclic molecular framework provided the conformational bias for stereoselective formation of 49, which was converted to ryanodol after additional transformations. 

---