Total synthesis of natural products is an important part of organic chemistry and has an impact on life sciences. Utilization of natural products in combating against human diseases has a long history and total synthesis has become an essential approach to get access to limited supply of rare natural products and its derivatives nowadays. Besides, total synthesis enables exploration and discovery of many unprecedented and novel reactivities and efficient synthetic strategies. This thesis research deals with total synthesis studies on two different types of natural products. The first target molecule is the proposed structure of iriomoteolide-2a, whose C6–C18 fragment has been synthesized in this thesis work. The second type of target molecule is 4β-acetoxyprobotryane-9β,15α-diol and the...[ Read more ]

Total synthesis of natural products is an important part of organic chemistry and has an impact on life sciences. Utilization of natural products in combating against human diseases has a long history and total synthesis has become an essential approach to get access to limited supply of rare natural products and its derivatives nowadays. Besides, total synthesis enables exploration and discovery of many unprecedented and novel reactivities and efficient synthetic strategies. This thesis research deals with total synthesis studies on two different types of natural products. The first target molecule is the proposed structure of iriomoteolide-2a, whose C6–C18 fragment has been synthesized in this thesis work. The second type of target molecule is 4β-acetoxyprobotryane-9β,15α-diol and the congeners, which contain a strained trans-[3.3.0]octane core. A novel methodology for the construction of the strained core was explored and total synthesis 4β-acetoxyprobotryane-9β,15α-diol has been accomplished.

Iriomoteolide-2a was the first 23-membered macrolide with significant bioactivity and structural novelty. But its bioactivity was limited as increasing dosage did not give a better activity, suggesting the demand for structural modifications. In Chapter 1, a brief background of iriomoteolides family of marine macrolides, including isolation, bioactivity, and reported synthetic studies, is provided.

Chapter 2 presents the results of the synthesis of the C6–C18 bis-tetrahydrofuran (bis-THF) fragment of the proposed structure of iriomoteoldie-2a via stepwise double S_N2 cyclization reaction. The C9–C12 THF ring was first constructed through an AD–S_N2 cascade sequence while the C13–C16 THF ring was then installed via an intramolecular S_N2 reaction of a chiral propargylic mesylate. Asymmetric transfer hydrogenation of propargylic ketones was demonstrated as a powerful synthetic tool to secure the stereogenic centers of the C16-propargylic carbon and the C11-allylic carbon after Red-Al reduction. The established synthetic sequence is easily amendable for the synthesis of the revised bis-THF fragment possessing (9S,11R,12S)-C9–C12 THF ring.

Chapter 3 gives a brief introduction of botryane family compounds. Among them, 4β-acetoxyprobotryane-9β,15α-diol is the key metabolite from botrytis cinerea, which produces botrydial as the ultimate metabolite to affect many plants and cause economic losses. Isolation, bioactivity, and reported synthetic studies of botryanes are discussed. Structurally, this family of compounds possesses a trans-[3.3.0]octane core that stands as a synthetic challenge over two decades. The current solution was limited to ring contraction using Wolff and pinacol rearrangements with only two successful examples in application to complex natural product synthesis. An overview of the known synthetic studies toward trans-[3.3.0]octane core is briefly covered.

The results of an unprecedented benzilic acid-type rearrangement toward the assembly of trans-[3.3.0]octane core are compiled in Chapter 4. The trans-[4.3.0]nonane core was synthesized from the 5/6 bicyclic skeleton of botryane from Rh^I catalyzed [4+2], and it underwent a TBAF–O₂–meditated benzilic acid-type rearrangement to give the desired trans-[3.3.0]octane core. Further transformations provided 4β-acetoxyprobotryane-9β,15α-diol. Moreover, synthetic study toward the total synthesis of 4β-acetoxy-9β,l0β,15α-trihydroxyprobotrydial was also described.

The main experimental procedures, the characterization data of major compounds, and the cited references are found at the end of the thesis. And tables for comparisons of our ¹³C NMR data for the synthetic fragment and natural products were given in the related chapter. Copies of the original ¹H and ¹³C NMR spectra of key compounds are given in the Appendix.