The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation

Abstract

Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically complex molecules in a single operation. In addition to generating two or more stereocentres in a single reaction, multiple asymmetric reactions also impart increased enantiomeric excess to the final product in comparison with the analogous single transformation. Furthermore, multiple asymmetric operations have the potential to independently construct several stereocentres at remote points within the same molecular scaffold, rather than relying on pre-existing chiral centres that are proximal to the reactive site. Despite the inherent benefits of multiple catalytic enantioselective reactions, their application to natural product total synthesis remains largely underutilized. Here we report the use of a double stereoablative enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F (ref. 8). By employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation, we demonstrate that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess. The stereochemical information generated by means of this catalytic transformation facilitates the easy and rapid completion of the total synthesis of this marine natural product.

Multi-Bond Forming Processes in Efficient Synthesis

“…Double alkylation (a) and independent metathesis (b) in the synthesis of (À)-cyanthiwigin F by Enquist and Stoltz. [171] (dmdba, bis(3,5-dimethoxybenzylidene)acetone.) Exhaustive cyclopropanation [8] simple question by amalgamating separate reactions into the same process, we are compelled to improve our toolkit of selective and compatible transformations.…”

“…[171] A two-directional, catalytic asymmetric approach is used to target a chiral C 2 -symmetric intermediate (Scheme 27a). Thus, a mixture of the three stereoisomers of allyl ester 49 (namely the two C 2 -symmetric enantiomers and the one achiral meso diastereomer) was converted, by the formation of two new C-C bonds in an enantioselective double Tsuji-Trost allylation, [172] into a highly enriched sample of the chiral diastereomer 50.…”

Synthesis of Natural Products Containing Medium‐Size Carbocycles by Ring‐Closing Alkene Metathesis

“…the presence of a chiral ligand gave 278, which was converted to tetraene 279 [67]. RCM of 279 followed by a one-pot cross-metathesis with vinylpinacolboronate led after oxidation to the bicyclic aldehyde 280 possessing the BC ring system of the natural product.…”

Stereoselective Formal Synthesis of (+)-Allokainic Acid <i>via</i> Thiol-Mediated Acyl Radical Cyclization

“…The mixture of trans-2 and 10 was further purified by another column chromatography (hexane/ AcOEtϭ1/1) to give trans-2, which was characterized as below. (11), (3aR,3bS,8aR)-Hexahydro-2H-furo[3,2:3,4]pyrrolo[1,2-c][1,3]oxazole-2,6-dione (12), and Methyl (S)-3-Methyl-2-oxooxazolidine-4-propionate To an ice-cooled and stirred suspension of LiAlH(Ot-Bu) 3 (890 mg, 3.5 mmol) in THF (8 ml), a solution of the 10 : 1 mixture of trans-2 and 10 (543 mg, 2.35 and 0.23 mmol, respectively) in THF (2 ml) was added. After 30 min, the reaction mixture was poured into water (20 ml).…”

“…40) The mixture of trans-2 and 10 was treated with LiAlH(Ot-Bu) 3 to give trans-alcohol 11 in 33% yield along with lactone 12 (1%), which was probably produced by spontaneous cyclization of the cis-isomer of 11 (Chart 6). At the same time, deformylation product 10 was converted into the corresponding saturated ester and removed at this stage by silica gel column chromatography.…”