Total synthesis of hyacinthacine A2: stereocontrolled 5-aza-cyclooctene photoisomerization and transannular hydroamination with planar-to-point chirality transfer

Abstract

The total synthesis of hyacinthacine A2 is reported via a novel transannular hydroamination in which planar chirality of a 5-aza-trans-cyclooctene precursor is transferred to point chirality in the product. Key to the success of this strategy was the development of a method for establishing absolute planar chirality via stereocontrolled photoisomerization of a 5-aza-cis-cyclooctene. This was accomplished by constructing a 5-aza-cis-cyclooctene precursor with a trans-fused acetonide. The improved diastereoselectivity observed upon photoisomerization of this derivative is attributed to the conformational strain of the eight-membered ring in the minor diastereomer.

Computationally guided discovery of a reactive, hydrophilic trans-5-oxocene dienophile for bioorthogonal labeling

“…41,42 Here we report the computational design and synthesis of a trans -5-oxocene (“oxoTCO”, 3 ) – a small, hydrophilic, and highly reactive dienophile for use in the bioorthogonal tetrazine ligation reaction. The reaction of 3 (2.2 : 1 d.r.)…”

Chromatography with silver nitrate: part 2

“…During the synthetic campaign that resulted in the total synthesis of hyacinthacine A2 (130) Fox et al 74 …”

“…In pursuit of 6-membered ring alkaloids Beauchemin et al 74 systematically evaluated the utility of a Cope-type hydroamination approach. Results from this study presented an opportunity to attempt the total synthesis of coniine (126), which was eventually successful starting from pyranone 127.…”

“…55 The crude target molecule (74), however, was found to contain a number of impurities, presenting a considerable purification challenge unassisted by its volatile and nonpolar nature. Panaginsene (74) was finally purified using SNIS (Scheme 8).…”

Synthetic Strategies towards the Azabicyclo[3.3.0]-Octane Core of Natural Pyrrolizidine Alkaloids. An Overview

“…195 Hyacinthacine A 2 has been also acquired via transannular hydroamination. 196 Scheme 14 Transannulation Protocol towards Australine. An oxidative transannular approach was employed to prepare a pyrrolizidine skeleton in the synthesis of UCS1025A, an anti-tumor antibiotic of natural origin.…”