Total synthesis of complex natural products, such as 24-demethylbafilomycins, not only serves as the purposes for confirming the structures and accessing to synthetic derivatives for SAR studies, but also provides a forum to examine the scope and generality of new reactions, new reagents, and novel synthetic tactics. 24-Demethylbafilomycin A₂ and C₁ are two new members of the Class B subgroup of the plecomacrolides, and share the same 16-membered ring macrolactone core as bafilomycin A₁, whose total synthesis has been accomplished by many groups using various Pd-catalyzed cross-coupling reactions in construction of the C10–C13 (E,E)-diene subunit. This thesis research describes a different approach to assembly of the C10–C13 (E,E)-diene subunit using the diester-tethered 1,3-diene–ene...[ Read more ]

Total synthesis of complex natural products, such as 24-demethylbafilomycins, not only serves as the purposes for confirming the structures and accessing to synthetic derivatives for SAR studies, but also provides a forum to examine the scope and generality of new reactions, new reagents, and novel synthetic tactics. 24-Demethylbafilomycin A₂ and C₁ are two new members of the Class B subgroup of the plecomacrolides, and share the same 16-membered ring macrolactone core as bafilomycin A₁, whose total synthesis has been accomplished by many groups using various Pd-catalyzed cross-coupling reactions in construction of the C10–C13 (E,E)-diene subunit. This thesis research describes a different approach to assembly of the C10–C13 (E,E)-diene subunit using the diester-tethered 1,3-diene–ene ring-closing metathesis (RCM) and subsequent transformations toward formal total synthesis of bafilomycin A₁, and total synthesis of 24-demethylbafilomycin A₁ and A₂.

Chapter 1 briefly introduces the structures and biological activity of some typical members of the plecomacrolides and the known strategies for total synthesis of bafilomycin A₁. These are followed by a brief overview on RCM, and applications of 1,3-diene–ene RCM and the temporary silicon-tethered (TST) RCM for synthesis of useful intermediates, assembly of advanced alkene fragments, and access to the challenging double bonds, such as trisubstituted (E)-alkene embedded in a macrocycles.

Discussed in details in Chapter 2 are the original results of two synthetic strategies designed for accessing the 16-membered macrolactone core of 24-demethylbafilomycins. The first strategy features a sequence of aldol reaction, 1,3-diene–ene RCM, and β-elimination, which works well but unfortunately delivers exclusively the undesired (12Z)-macrolactone in the RCM step. An alternative strategy is based on the ring contraction of the more flexible 18-membered macrolactone, which is thought to be formed in the RCM step in favor of the (12E)-isomer due to reduced ring strain. However, the undesired (12Z)-isomer is also obtained exclusively, indicating the remarkable influence of appendages and substrate stereochemistry on the outcome of RCM reactions.

A novel diester tethered-RCM protocol is then developed for general fragment assembly with formation of the thermodynamically more stable (E)-double bond by taking advantage of the flexible chain length of the diester tether. Chapter 3 presents our results of the diester-tethered 1,3-diene–ene RCM for assembling the C3–C12 and C13–C17 alcohol fragments with concomitant formation of the desired C10–C13 (E,E)-1,3diene subunit in excellent combined yields. The (12E):(12Z) ratios of 82:17–85:15 are obtained for the macrodiolides varying from 23- to 25-membered rings. By following conventional transformations, the desired (12E)-macrodiolides are converted into the known 16-membered macrolactone diol used for bafilomycin A₁ total synthesis. Moreover, from the same 16-membered macrolactone diol, 24-demethylbafilomycin A₁ is synthesized via the boron-mediated syn-selective aldol reaction of the ethyl ketone corresponding to the side chain of 24-demethylbafilomycin A₁. From the latter, 24-demethylbafilomycin A₂ and C₁ are prepared but disagreement in C19-OMe configuration with the literature ¹³C NMR data is noted while purification of 24-demethylbafilomycin C₁ is not achieved at this stage.

The main experimental procedures, the characterization data for the key intermediates and the cited references are found at the end of the thesis. Copies of original ¹H and ¹³C NMR spectra of some key intermediates and tables for comparisons of ¹H and ¹³C NMR data of our synthetic 24-demethylbafilomycins with those reported in the literature are given in the Appendix.