Conjugated polyenes in linear and cyclic forms represent a large and diverse group of natural products and synthetic molecules which play significant roles in biology, medicine, and material sciences. The conjugated polyene motif, featured by two or more carbon-carbon double bonds linked through a single bond, is derived from a variety of natural sources. The side chain of mycolactone E produced by a frog pathogen and the proposed intermediates of polyketide synthases SgcE in biosynthesis of the C-1027 enediyne core are the linear conjugated polyenes which are synthesized in this thesis research for structural assignment.

A brief introduction of polyenes, enediynes and mycolactones is given in Chapter 1. The structures of enediyne antibiotics and the current development in biosy...[ Read more ]

Conjugated polyenes in linear and cyclic forms represent a large and diverse group of natural products and synthetic molecules which play significant roles in biology, medicine, and material sciences. The conjugated polyene motif, featured by two or more carbon-carbon double bonds linked through a single bond, is derived from a variety of natural sources. The side chain of mycolactone E produced by a frog pathogen and the proposed intermediates of polyketide synthases SgcE in biosynthesis of the C-1027 enediyne core are the linear conjugated polyenes which are synthesized in this thesis research for structural assignment.

A brief introduction of polyenes, enediynes and mycolactones is given in Chapter 1. The structures of enediyne antibiotics and the current development in biosynthesis of the 9- and 10-membered enediyne cores are described. An emphasis is put on Buruli ulcer (BU) and the mycolactones which are produced by a group of very closely related pathogenic mycobacteria. The mycolactones share a common 12-membered macrolactone core with various conjugated polyene side chains. Mycolactone E, produced by M liflandii, is related to Buruli ulcer-like disease of frogs. The reported strategies for total synthesis of mycolactones are discussed.

The results on synthesis of the three proposed polyene intermediates related to biosynthesis of the C-1027 enediyne core are presented in Chapter 2. General synthetic methods have been developed for accessing three types of linear polyenes. The indium-mediated allylation of 3-chloro-2-( ethoxymethoxy)prop-1-ene is used as a synthetic equivalent of an acetone enolate to react with a number of polyene aldehydes to produce 4-substituted 4-hydroxybutan-2-ones. The aldol reaction of acetoacetate with the polyene aldehydes followed by lactonization is employed for assembling 6-substituted 5,6-dihydro-4-hydroxy-2H-pyran-2-ones. The aldol-type reaction of a dianion species derived from 4-hydroxy-6-methyl-2H-pyran-2-one with the polyene aldehydes is adopted for construction of 6-substituted 4-hydroxypyran-2-ones. NMR profiles of 6-substituted 5,6-dihydro-4-hydroxy-2H-pyran-2-ones in CDCl₃, DMSO-d₆ and CD₃OD provide useful reference for structural assignment. Moreover, HPLC profiles reveal that (5E,7E,9E,11E,13E,15E)-4-hydroxyheptadeca-5,7,9,11,13,15-hexaen-2-one is not relevant to the biosynthesis while 5,6-dihydro-4-hydroxy-6-[(1E,3E,5E,7E,9E,11E)-trideca-1,3,5,7,9,11-hexaen-1-yl]-2H-pyran-2-one and 4-hydroxy-6-[(3E,5E,7E,9E,11E,13E)-2-hydroxypentadeca-3,5,7,9,11,13-hexaen-1-yl)]-2H-pyran-2-one might be the two polyene intermediates associated with biosynthesis of the C-1027 enediyne core. Furthermore, two aberrant pyrone products, i.e. 4-hydroxy-6-[(1E,3E)-penta-l,3-dien-1-yl]-2H-pyran-2-one and 6-[(1E,3E,5E)-hepta-1,3,5-trien-1-yl]-4-hydroxy-2H-pyran-2-one, generated by CalE8 in the biosynthesis of the calicheamicin enediyne core have been synthesized and the structures confirmed.

The novel synthesis of the side chain of mycolactone E via the Aphos-Y-Pd(OAc)₂-catalyzed Suzuki-Miyaura cross-coupling reaction of alkenyl halides with alkenyl boronates is summarized in Chapter 3. The required triene bromide fragment is synthesized by the Wittig and HWE reactions while the chiral alkenyl boronate fragment is assembled by the Cu(I)-catalyzed highly regioselective borylation of an internal alkyne. The two stereogenic centers are installed by the known asymmetric hydrogenation and oxa-Michael reaction of benzaldehyde hemiacetal alkoxide, respectively. The synthesized side chain in an isomeric pure form has been used in total synthesis of mycolactone E in our laboratory.

The main experimental procedures, the characterization data for the key compounds and the cited references are found at the end of the thesis. Copies of original ¹H and ¹³C NMR spectra are given in the Appendix.