Versatile enantiocontrolled synthesis of (+)-fostriecinElectronic supplementary information (ESI) available: experimental section. See http://www.rsc.org/suppdata/cc/b2/b209742g/

Abstract

Fostriecin, a potent protein phosphatase inhibitor and antitumor agent, has been enantioselectively synthesized in naturally occurring form via a versatile route, which also allows one to secure all possible stereoisomeres of the C1-C13 fragment including the C11 stereocenter and the geometry of the delta 12-double bond.

Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster

“…Cloning of the PLM biosynthetic gene cluster and creation of a strain producing only PLM-B also set the stage for the generation of novel compounds with improved stability, activity, and selectivity. As such, this work represents a complementary approach to the widespread synthetic approaches directed toward this class of compounds (5,(17)(18)(19)(20)(21). One of the key structural differences between PLMs and fostriecin is the C-8 ethylamine substituent, which may contribute to less potent activity (15).…”

“…Phase I clinical trials of fostriecin were suspended before either dose-limiting toxicities or therapeutic plasma levels were attained because of inherent drug instability and unpredictable purity in the clinical supply of the natural product (1,4). In an attempt to address these limitations and further develop this class of novel antitumor agents, no less than six elegant total syntheses of fostriecin have been developed over a short 2-year period (5,(17)(18)(19)(20)(21). A complementary approach for developing these agents can come through gene manipulation of the natural biosynthetic process.…”

Total Synthesis of Biologically Active Natural Products Based on Highly Selective Synthetic Methodologies

“…Previously, we demonstrated 41,51,52) that ynones 19 and 20 effectively served as pivotal intermediates for the synthesis of 17 and 18 as well as their various isomers via Z-or Eselective conjugate addition of hydroiodic acid, C9-hydroxydirected anti-or syn-selective reduction of the C11-carbonyl group, Stille coupling, and phosphorylation as major transformations (Chart 7). From the retrosynthetic perspective, we envisioned epoxide 22 as a common precursor of 19 and 20 by the disconnection via ethynylation, ring-closing metathesis, and asymmetric allylation or pentenylation.…”

The chemistry of the carbon–transition metal double and triple bond: annual survey covering the year 2002

“…99) for laulimalide total synthesis [306-310]; (7) formation of six-membered ring oxacycles fused to a ribonucleoside ring (e.g. 100) [311]; (8) formation of six-membered ring lactones for fostriecin total synthesis [312,313]; (9) diastereoselective formation of bicyclic six-membered ring containing oxygen heterocycles (e.g. 101) [314,315]; (10) formation of six-membered ring ␣,␤-unsaturated lactones [316][317][318][319][320]; (11) formation of six-membered ring ␣,␤-unsaturated lactones for total synthesis of methynolide [321], goniodiol (see 102) [322], and osmundalatone [323]; (12) formation of ␤,␥-unsaturated six-membered ring lactones [324]; (13) formation of six-membered ring cyclic ethers for total synthesis of ambruticin [325]; (14) tandem alkene-isomerization and RCM to form various cyclic enol ethers (e.g.…”