A convergent, enantioselective synthesis of the proposed structure of kedarcidin chromophore (1) is described. The route is 24 steps in the longest linear sequence (beginning with the commercial reagent 2,3-O-isopropylidene-D-erythronolactone) with an average yield of 75% per step (overall yield: 0.1%). Our 1 H NMR data for 1 do not coincide with the data reported for kedarcidin chromophore. We have re-analyzed the original data and here propose a stereochemical revision at position C10, the site of attachment of the L-mycarose carbohydrate residue to the chromophore core (structure 2).
Process
research and development of the first fully synthetic broad
spectrum 7-fluorotetracycline in clinical development is described.
The process utilizes two key intermediates in a convergent approach.
The key transformation is a Michael–Dieckmann reaction between
a suitable substituted aromatic moiety and a key cyclohexenone derivative.
Subsequent deprotection and acylation provide the desired active pharmaceutical
ingredient in good overall yield.
Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.
Four components, each prepared in multigram amounts, have been assembled in the convergent (25 steps in the longest linear sequence), enantioselective synthesis of the differentially protected kedarcidin chromophore aglycon (1). In addition to the enantioselective synthesis of each of the four components, the route features a transannular anionic cyclization to form the bicyclo[7.3.0]dodecadienediyne core in the presence of an ansa‐bridged macrolactone. MOM=methoxymethyl, TIPS=triisopropylsilyl, TES=triethylsilyl.
A robust, cost effective and high yielding manufacturing process for enantiomerically enriched (S)-allylic amine 3, a key intermediate for fully synthetic tetracyclines have been developed.Two novel and scalable asymmetric vinylations resulting in high to excellent stereoselectivity have been developed for the key step. The final product is purified by an efficient crystallization of a L-tartaric salt. The process described has been used to manufacture ~350 kg of the tartaric salt of 3 with 99.0% ee in 8 steps (35% overall yield) from cheap and readily available dimethyl maleate.
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