RCM/hydrogenation

Scheme 18 Synthesis of the phenanthroindolizine alkaloid antofine (95) by a sequence of RCM, hydrogenation, and Pictet-Spengler cyclomethylenation [67]...

The strategic sequential RCM/hydrogenation reactions have been used for the synthesis of (R)-(+)-muscopyridinc. The RCM of the protonated pyridine bearing two alkene chains was performed with an indenylidene-ruthenium catalyst that also allows hydrogenation under 50 atm of hydrogen, and mus-copyridine was obtained in 57% yield [84] (Scheme 38). Normuscopyridine was similarly prepared in 68% yield [84],... 

It has been demonstrated that these ruthenium complexes are also effective precatalysts for hydrogenation reactions. In 2001, Louie et al. reported the first example of ruthenium-catalyzed tandem RCM/hydrogenation and RCEM/hydrogenation (Scheme 5.1) [1]. Tandem RCM/isomerization [2], RCM/Kharasch addition [3], RCM/dihydroxylation [4], enyne metathesis/Claisen rearrangement [5], enyne metathesis/cyclopropanation [6], ROMP/hydrogenation [7], and CM/aza-Michael addition [8] have also been developed successfully. 

SCHEME 5.1 Ru-catalyzed cascade RCM/hydrogenation and RCEM/hydrogenation. 

The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

The synthesis of an epothilone model system via an alternative C9-C10 disconnection was first examined by Danishefsky in 1997. However, extension of this C9-C10 strategy to a fully functionalized epothilone intermediate was not successful, demonstrating the limitations of RCM with the early catalysts A and B [116]. In 2002, Sinha and Sun disclosed the stereoselective total syntheses of epoA (238a) and epoB (238b) by the RCM of epoxy compounds 242 in the presence of catalyst C (Scheme 50) [117]. The reaction furnished an inconsequential mixture of isomers 243 (E/Z 1 1) in high yield. Subsequent selective hydrogenation of the newly formed double bond followed by deprotection led to epothilones A and B. 

Thus far, chemists have been able to influence the stereoselectivity of macro-cyclic RCM through steric and electronic substrate features or by the choice of a catalyst with appropriate activity, but there still exists a lack of prediction over the stereochemistry of macrocyclic RCM. One of the most important extensions of the original metathesis reaction for the synthesis of stereochemi-cally defined (cyclo)alkenes is alkyne metathesis, followed by selective partial hydrogenation. 

Coplen, T.B. (2011). Guidelines and recommended terms for expression of stableisotope-ratio and gas-ratio measurement results. Rapid Gommunications in Mass Spectrometry, 25, 2538-2560. DOl 10.1002/rcm.5129 Cormie, A.B., Luz, B., Schwarcz, H.P. (1994a). Relationship between the hydrogen and oxygen isotopes of deer bone and their use in the estimation of relative humidity. Geochimica et Cosmochimica Acta, 58, pp. 3439-49. 

In a formal synthesis of quinolizidine 233A 296, the 2,6-m-disubstituted piperidine 292, as a mixture of dia-stereomers, was transformed into 293 by N-acylation with but-3-enoyl chloride. An RCM afforded 294, which was transformed into 295 by hydrogenation of the double bonds and hydride reduction of the lactam, thereby completing a formal synthesis <2000JOC8908> of quinolizidine 233A 296 (Scheme 65) <2004JA4100>. 

Scheme 19. Mo-catalyzed RCM in tandem with catalytic hydrogenation allows the control of C2-C6 relative stereochemistry in the macrolactam region of Sch 38516...

Scheme 21. Mo-catalyzed RCM is carried out on the fully functionalized diene subsequent hydrogenation delivers the protected form of Sch 38516...

Also in macrocyclizations the conformation of the starting diene has an influence on the RCM/ADMET ratio. Substituents on the diene which form hydrogen bonds between each other or with the intermediate carbene complex, or external Lewis acids can have an important effect on the course of the reaction. Such effects, often subtle, might explain the variable results sometimes obtained in macrocyclizations [842], but make synthesis-planning and the formulation of general guidelines difficult. 

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