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Total syntheses of (+)-mycotrienin I, (+)-mycotrienol, and (+)-lactacystin: An application of chiral (E)-crotylsilane bond constructions
Bibliografi
Author:
Masse, Craig Edward
;
Panek, James S.
(Advisor)
Topik:
CHEMISTRY
;
ORGANIC
Bahasa:
(EN )
ISBN:
0-599-71811-0
Penerbit:
Boston University
Tahun Terbit:
2001
Jenis:
Theses - Dissertation
Fulltext:
9967159.pdf
(0.0B;
0 download
)
Abstract
The application of chiral (
E
)-crotylsilane bond construction methodology to the asymmetric synthesis of complex molecules has been demonstrated in the total syntheses of three natural products: the macrolide antibiotics (+)-mycotrienol and (+)-mycotrienin I, and the proteasome inhibitor (+)-lactacystin. In that regard, a highly convergent asymmetric synthesis of the ansamycin antibiotics (+)-mycotrienin I and (+)-mycotrienol has been achieved through the synthesis and coupling of the C9–C16 subunit and the aromatic subunit, respectively. All four stereogenic centers were introduced using our chiral allylsilane bond construction methodology. The total synthesis is highlighted by the incorporation of the (
E, E, E
)-triene unit with simultaneous macrocyclization through a palladium-(0)-catalyzed (Stille-type) coupling/macrocyclization. Divergence from this advanced triene intermediate allows access to both natural products. A total synthesis of (+)-lactacystin has been completed which utilizes an asymmetric allylsilane bond construction for the installation of the C6–C7 stereogenic centers. This double stereodifferentiating crotylation reaction was carried out between an oxazoline aldehyde derived from hydroxyleucine and our silane reagent to install the C6–C7 stereogenic centers of (+)-lactacystin with high levels of diastereoselection. Additionally, the synthesis highlights an efficient 3-step preparation of the hydroxyleucine synthon using a modified catalytic asymmetric aminohydroxylation reaction developed in our laboratories. We have also applied this asymmetric aminohydroxylation methodology to the formal synthesis of the protein kinase C inhibitor, (−)-balanol. A new approach to the asymmetric synthesis of (
E
)-olefin dipeptide isosteres is described based on asymmetric C-N bond constructions resulting from electrophilic nitrations of chiral (
E
)-crotylsilanes and by a catalytic enantioselective amination of chiral (
E
)-crotylsilanes. The silane reagents undergo efficient
anti
-S
E
′
additions to these nitrogen-based electrophiles to give the (
E
)-olefin isosteres. The (
E
)-olefin isosteres are nonhydrolyzable, rigid analogs of the peptide linkage in biologically active peptides. An efficient approach to the asymmetric synthesis of functionalized cyclopentenols, cyclohexenols, and aminocyclopentenes is described based on a Lewis acid-mediated carbocyclization of chiral (
E
)-crotylsilanes. The silyl-aldehyde or
in situ
generated silyl-iminium ion reagents undergo a clean exo-trig cyclization to afford the chiral cycloalkenols and aminocycloalkenes.
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