Lanthanides have provided many exciting opportunities in the metal-catalyzed reactions and reductive chemistry in organic chemistry area, with samarium diiodide (SmI₂) being the most popular reagent. This thesis research deals with the acrylates and crotonates possessing an electron-withdrawing achiral or chiral aryloxy group for the SmI₂-mediated reductive coupling with aliphatic aldehydes. The products, α,γ-trans- and β,γ-cis-disubstituted y-butyrolactones, obtained in high stereoselectivity and yields, are the versatile precursors to trisubstituted tetrahydrofurans and other stereochemically defined building blocks. Applications in diverted total synthesis of natural macrolides and designed analogues are demonstrated.

A brief overview is given in Chapter 1 about target-orient...[ Read more ]

Lanthanides have provided many exciting opportunities in the metal-catalyzed reactions and reductive chemistry in organic chemistry area, with samarium diiodide (SmI₂) being the most popular reagent. This thesis research deals with the acrylates and crotonates possessing an electron-withdrawing achiral or chiral aryloxy group for the SmI₂-mediated reductive coupling with aliphatic aldehydes. The products, α,γ-trans- and β,γ-cis-disubstituted y-butyrolactones, obtained in high stereoselectivity and yields, are the versatile precursors to trisubstituted tetrahydrofurans and other stereochemically defined building blocks. Applications in diverted total synthesis of natural macrolides and designed analogues are demonstrated.

A brief overview is given in Chapter 1 about target-oriented synthesis (TOS), diversity-oriented synthesis (DOS), and diverted total synthesis (DTS), and selective examples of the SmI₂-mediated reductive coupling reactions used in total synthesis. It is followed by the structural analysis of apratoxin A, palmyrolide A, and laingolides consisting of a unique 1,3-anti-Me/t-Bu subunit, and the progress in total synthesis of apratoxin A and palmyrolide A.

Chapter 2 summarizes in more details the representative types of reductive carbon-carbon bond-forming reactions mediated by SmI₂ and the two proposed single-electron transfer pathways for reductive coupling of acrylates/crotonates with carbonyl compounds. Our new results on SmI₂-mediated reductive coupling reactions of α-substituted acrylates in achiral and chiral forms are then complied for efficient formation of trans-α,γ-disubstituted γ-butyrolactones in high stereoselectivity and high chemical yields. Particularly, racemic or chiral form of trans-5-tert-butyl-3-methyldihydrofuran-2-one serves as the synthetic precursor to 1,3-anti-Me/t-Bu subunit.

Usefulness of the SmI₂-mediated reductive coupling of the chiral crotonate consisting of an axially chiral naphthyloxy group with a non-branched aldehyde, (S)-citronellal, is illustrated in the diverted total synthesis of the designed analogues of amphidinolide T congeners. The cis-5-alkyl-4-methyldihydrofuran-2-one is readily transformed into the C1-C11 trisubstituted tetrahydrofuran-containing acid fragment and incorporation of this acid fragment into the designed macrolactones of 17- to 19-membered rings affords the analogues showing the same cytotoxicity against mouse lymphocytic leukemia cell line L1210.

Chapters 4 and 5 present the main results of this thesis research on diverted total synthesis of palmyrolide A and laingolide A using the pentamodule synthesis strategy in which trans-5-tert-butyl-3-methyldihydrofuran-2-one and its cis isomer, in both racemic and enantioenriched forms, are used as the key building blocks for the 1,3-anti- and 1,3-syn-Me/t-Bu subunits, respectively. The Pd(OAc)₂-Aphos-Y-catalyzed "9-MeO-9-BBN variant" of B-alkyl Suzuki-Miyaura cross-coupling reaction and the Negishi cross-coupling reaction with a chiral organozinc reagent are employed for the key fragment assembly. The 15-membered macrocyclic ring consisting of the trans-enamide moiety is constructed through sequential RCM/olefin isomerization protocol. These efforts result in diverted total synthesis of (-)-palmyrolide A and its 5,7-epimer, and all four C7 ,C9-diastereoisomers of laingolide A. By comparing the ¹³C NMR data of four C7,C9-diastereoisomers of laingolide A with those of the natural form, it allows us to assign the relative configuration of laingolide A as (2R*,7R*,9S*). Therefore, for the first time, we have revealed that the 1,3-syn-Me/t-Bu relationship does exist in Nature.

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