Structure-Elucidating Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone C

Abstract

The (polyenoyl)­tetramic acid militarinone C (1) heads a family of seven members. Before our work, the configuration of C-5 was unknown whereas the configurations of C-8′ and C-10′ were either (R,R) or (S,S). We synthesized the four stereoisomers of constitution 1, which conform with these insights. This included cross-coupling both enantiomers of the western building block (8) with both enantiomers of the eastern building block (9). The specific rotations of the resulting 1 isomers suggested that natural 1 is configured like the coupling partners (S)-8 and (R,R)-9. This conclusion was corroborated by degrading natural 1 to alcohol 35 and by proving its configurational identity with synthetic (R,R)-35.

Stereostructure Clarifying Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone B. A Highly Acid-Labile N-Protecting Group for Amides

“…The configurations of compounds 1 – 7 were mostly unknown when first reported. ,, An exception are the syn -configurations of the methylated stereocenters (C-8′, C-10′) 2 deducible from δ 8′‑ C H 3 – δ 10′‑ C H 3 = 2.0–2.2 ppm (Figure ). Their ( R )-configurations in 1 , 5 , and 7 emerged from total syntheses − ,, and in 1 and 6 from reisolations, Lemieux–Johnson cleavage/NaBH 4 reduction tandems, and the identity of the resulting alcohol 8 with authentic ( R , R )- 8 (ref and the present work, respectively). The heterocyclic stereocenter of militarinone C ( 1 ), C-5, is ( S )-configured, according to synthesis. , Since militarinone B ( 3 ) is believed to be biosynthesized from militarinone C ( 1 ) , it should be (5 S )-configured, too.…”

“…Their ( R )-configurations in 1 , 5 , and 7 emerged from total syntheses − ,, and in 1 and 6 from reisolations, Lemieux–Johnson cleavage/NaBH 4 reduction tandems, and the identity of the resulting alcohol 8 with authentic ( R , R )- 8 (ref and the present work, respectively). The heterocyclic stereocenter of militarinone C ( 1 ), C-5, is ( S )-configured, according to synthesis. , Since militarinone B ( 3 ) is believed to be biosynthesized from militarinone C ( 1 ) , it should be (5 S )-configured, too. The ( S )-configuration of the fourth stereocenter of militarinone B ( 3 ), C-1′′, became evident after we synthesized the remaining militarinone B candidates, namely 3 and epi - 3 (Figure ), as disclosed below.…”

“…Two of them (B, C) are (polyenoyl)­tetramic acids, and five are (polyenoyl)­hydroxypyridones . Earlier total syntheses in this class of compounds led to the militarinones C ( 1 , ) and D ( 5 ,, ) and to N -deoxymilitarinone A ( 7 ). The present study describes stereoselective total syntheses of the naturally occurring (polyenoyl)­tetramic acid militarinone B 3 ( 3 ) and its unnatural diastereomer epi - 3 (formulas are shown in Figure ).…”

“…Militarinone family 1 – 7 of natural products. Full configurational assignments by experiment [ 1 , , 3 (this work), 5 , ,, 6 (this work), 7 6 ] or extrapolation ( 2 , 4 ).…”

Regioselective O/C phosphorylation of α-chloroketones: a general method for the synthesis of enol phosphates and β-ketophosphonates via Perkow/Arbuzov reaction

“…Although compared with 1chloropropan-2-one and 1-bromopropan-2-one, 1-iodopropan-2-one exhibited superior regioselectivity (25 : 1) of Arbuzov reaction, the yield of 4a was poor (entry 3 vs. entries 1 and 2) due to that 1-iodopropan-2-one would decompose under solventfree conditions. However, since higher-polar solvent of actone exhibited good regioselectivity of Arbuzov reaction (Table 1, entry 11), we hypothesized that if 1-iodoketone could be generated in situ by treatment of 2a with NaI in acetone (Finkelstein reaction [20][21][22][23] ), which may be benecial to the conversion Fig. 1 Proposed mechanistic pathway.…”