An enantioselective, convergent, total synthesis of (+)-acutiphycin (18 steps, longest linear sequence from commercial materials) features the first application of an alkynyl ether as a macrolactone precursor in total synthesis, as well as the first example of an intermolecular, SmI2-mediated, Reformatsky fragment coupling reaction.
Described herein is a method of stereoselective synthesis of trisubstituted allylic alcohols by alkylation of alkenyl alanates, formed in situ through treatment of propargyl alcohols with Vitride (Red-Al). This technique represents the first of its kind to feature a trans-hydrometalation, and is particularly effective for the formation of 1,4-dienes. Applications involving primary, secondary, and tertiary alcohols are discussed, as well as limitations regarding both alkyne and electrophile components.
In this article we compare and contrast the strategies and tactics used in the syntheses of the amphidinolide T family of natural products that have been reported by Fürstner, Ghosh and ourselves. Similar approaches to the trisubstituted THF ring present in the targets are utilized in all of the syntheses, but each strategy showcases a different means of macrocyclization.
(−)-Terpestacin (1, naturally occurring enantiomer) and (+)-11-epi-terpestacin (2) were prepared using catalyst-controlled, stereoselective, intermolecular reductive coupling reactions of alkyne 9 and aldehyde 10, affording allylic alcohols 42 or 11-epi-42 in a 3:1 ratio (or 1:3 depending on the enantiomer of ligand 41a used). These stereoselective fragment couplings were instrumental in confirming that “siccanol” is not 11-epi-terpestacin but, in fact, is (−)-terpestacin itself. Several intramolecular alkyne−aldehyde reductive coupling approaches to 1 and 2 were also investigated and are discussed herein.
Two nickel-catalyzed reductive coupling reactions of alkynes were instrumental in a modular, stereoselective synthesis of amphidinolide T1 (1). The C13−C21 fragment was prepared from two simple starting materials that were joined in a catalytic alkyne−epoxide fragment coupling operation, whereas an intramolecular aldehyde−alkyne reductive coupling simultaneously formed the final carbon−carbon bond of the macrocycle and established the C13 carbinol configuration with complete selectivity in the desired fashion.
(−)-Terpestacin (1a, naturally occurring enantiomer) and (+)-11-epi-terpestacin (1b) were prepared using catalyst-controlled, stereoselective intermolecular reductive couplings of alkyne 4 and aldehyde 5. Related to enantioselective methods developed in our laboratory, these stereoselective fragment couplings were instrumental in confirming that “siccanol” is not 11-epi-terpestacin, but in fact is (−)-terpestacin itself.
A trimethylsilyl (SiMe3) group is the basis of a strategy that emulates the three fundamental proposed processes in ladder polyether biosynthesis: chain homologation, stereoselective epoxidation (95% ee or 95:5 dr), and endo-selective, stereospecific (inversion) hydroxyepoxide cyclization (95:5 endo:exo, 95% dr). A tris-THP was synthesized in 18 total operations from commercial materials using this approach.
A dicobalt hexacarbonyl (Co2(CO)6) cluster is essential for the unusually broad dipolarophile scope and for the sense and degree of diastereoselection in a catalytic, three-component synthesis of tetrahydrofurans and dihydrofurans. Likely involving a new class of carbonyl ylide, these cycloadditions are stereospecific with respect to the dipolarophile and exhibit high diastereoselectivity and regioselectivity in most cases. Differentiation of all four positions of the tetrahydrofuran can thus be accomplished in a triply convergent manner.