From an ent-Estrane, through a nat-Androstane, to the Total Synthesis of the Marine-Derived Δ^8,9-Pregnene (+)-03219A

Abstract

The total synthesis of (+)-03219A, a rare Δ8,9-pregnene isolated from the marine-derived Streptomyces sp. SCSIO 03219, is described that is based on a series of transformations that enable progression from epichlorohydrin to an ent-estrane, then conversion to a nat-androstane, and finally establishment of the natural product target. Key to the success of these studies was implementation of two rearrangement processes to formally invert the quaternary center at C13 and establish the C10 quaternary center.

Marine natural products

“…68 As with previous reviews in this series, a number of new bacterial MNPs were claimed during 2021, but the structures presented were not fully consistent with the spectroscopic evidence provided. 7,30,31 The rst total syntheses of 22 marine bacterial compounds was reported in the literature during 2021, caprolactin C 6, 5 akazaoxime 4 and A-76356 45, 16 MA026 67, 25 xiamycins D and E, 69 bacicyclin, 70 (+)-pseudonocardide A and (+)-pseudonocardide C, 71 nocardiotide A, 72 three 2-(p-hydroxybenzyl)prodigiosin-based MNPs, along with isoheptylprodigiosin, and tambjamine MYP1, 73 (+)-spiroindimicin A, 74 nesteretal A, 75 (+)-03219A, 76 enterocin, 77 nahuoic acid A, 78 piscibactin, 79 and aldgamycin N. 80 Over 80 reviews featuring some aspect of marine bacterial chemistry or biology were published during 2021. This is the highest number of reviews ever and no doubt reects the impact that COVID-19 has had on labs around the world.…”

“…The first total syntheses of 22 marine bacterial compounds was reported in the literature during 2021, caprolactin C 6 , 5 akazaoxime 4 and A-76356 45 , 16 MA026 67 , 25 xiamycins D and E, 69 bacicyclin, 70 (+)-pseudonocardide A and (+)-pseudonocardide C, 71 nocardiotide A, 72 three 2-( p -hydroxybenzyl)-prodigiosin-based MNPs, along with isoheptylprodigiosin, and tambjamine MYP1, 73 (+)-spiroindimicin A, 74 nesteretal A, 75 (+)-03219A, 76 enterocin, 77 nahuoic acid A, 78 piscibactin, 79 and aldgamycin N. 80…”

Function-Oriented Synthesis of Pentacyclic Triterpenoids and Discovery of an ent-Estrane as a Natural Product-Inspired Androgen Receptor Antagonist

“…Consistent with our goals, we then targeted 26-norlupeol ( 3 ) and 26-norgermanicol ( 4 ) and designed a divergent synthetic pathway that proceeds by way of the tetracyclic common intermediate 7 (Figure ) through differential functionalization of the E-ring followed by installation of the common A-ring. It was recognized that 7 could be accessible from 8 , and tetracycle 8 was understood to be the product of sequential coupling and functionalization of the simple starting materials 9 , 10 , and 11 . We have previously described the asymmetric construction of 8 through simple bidirectional functionalization of epichlorohydrin ( 10 ) followed by metallacycle-mediated annulative cross-coupling with TMS-propyne and finally tandem protodesilylation and double asymmetric regio- and stereoselective Friedel–Crafts-based cyclization…”

Progress toward the De Novo Asymmetric Synthesis of Euphanes

“…In turn, I was imagined as the product of a tandem Brønsted acid mediated desilylation of the polyunsaturated hydrindane II and subsequent double asymmetric Freidel–Crafts cyclization to establish the C9 stereocenter . Finally, hydrindane II was targeted for synthesis from metallacycle-mediated annulative cross-coupling of enyne III with TMS-propyne. , While this coupling technology has been the topic of a number of recent studies, an enyne possessing the substitution and unsaturation of III has yet to be demonstrated to be compatible with this type of organometallic coupling process. In addition to describing the chemical synthesis activities that have resulted in the preparation of 1 , these efforts have also resulted in the discovery that this C14-desmethyl euphane-like system is a structurally novel agonist of the Liver X Receptor (LXR).…”