Enantioselective Total Synthesis of Cotylenin A

Abstract

A convergent enantioselective total synthesis of cotylenin A is described. The A-ring fragment, prepared via the catalytic asymmetric intramolecular cyclopropanation developed in our laboratory, and the C-ring fragment, prepared from a known chiral compound via a modified acyl radical cyclization, were successfully assembled by the Utimoto coupling reaction. The formidable carbocyclic eight-membered ring of cotylenin A was efficiently constructed by a palladium-mediated cyclization. All the hydroxy groups in the scaffold were stereoselectively introduced, and a modified reducing reagent, Me 4 NBH(O 2 C i Pr) 3 , has been developed. The sugar moiety fragment was prepared via three consecutive carbon−oxygen bond-forming reactions, and the glycosylation was accomplished using Wan's protocol.C otylenin A (Figure 1) was initially isolated as a plant growth regulator; 1 however, biological studies later revealed that it induces the differentiation of murine and human myeloid leukemia cells and the apoptosis of a wide range of human cancer cell lines by combined treatment with interferon-α. 2 The crystal structure of cotylenin A in a complex with 14-3-3 protein and a phosphopeptide of H + -ATPase (QSYpTV-COOH) has been reported 3 to confirm that cotylenin A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259 but not the activating interaction site, pSer621. Moreover, the combined treatment of cotylenin A with an anti-epidermal growth factor receptor antibody is reported to synergistically suppress tumor growth in vitro and in vivo, which provides a novel pharmacologic strategy for treatment of RAS mutant cancers. 4

Recent Advances in the Total Synthesis of Natural Products Containing Eight-Membered Carbocycles (2009–2019)

“…Despite the great success in methodology development, the use of transition metal-catalyzed carbocyclization in the total synthesis of complex cyclooctanoid natural products has not been fully explored. In this regard, the Nakada’s synthesis of taxol ( 1 ) via Pd-catalyzed alkenylation, the Yu’s total synthesis of asteriscanolide ( 4 ) via Rh-catalyzed [(5+2)+1]-cycloaddition, the Herzon’s total synthesis of pleuromutilin ( 3 ) via Ni-catalyzed reductive cyclization, and the Yang’s total synthesis of pre-schisanartanin C ( 11 ) via Au-catalyzed enyne cyclization, respectively, are especially remarkable.…”

Total Synthesis of ent-Plagiochianin B

“…13 A modification of the Wittig olefination was employed to furnish exomethylene 15. 6,7 Lastly, dihydroxylation, with potassium osmate dihydrate and NMO, 14 provided a 1:3 mixture of diastereomers favoring the undesired diastereomer of ent-plagiochianin B (16). 15 Separation of the diastereomers allowed for comparison of NOESY data which supported the isolation chemist's proposed relative stereochemistry of plagiochianin B.…”

“… Based on previous success, we turned to the iron-catalyzed Wacker-type oxidation to produce ketone 13 which, with this substrate, was accompanied by a mixture of diastereomeric alcohols ( 14 ) that were isolated and converted to 13 via a Swern oxidation . A modification of the Wittig olefination was employed to furnish exomethylene 15 . , Lastly, dihydroxylation, with potassium osmate dihydrate and NMO, provided a 1:3 mixture of diastereomers favoring the undesired diastereomer of ent -plagiochianin B ( 16 ) . Separation of the diastereomers allowed for comparison of NOESY data which supported the isolation chemist’s proposed relative stereochemistry of plagiochianin B.…”

Stereoselective Convergent Synthesis of Carbon Skeleton of Cotylenin A Aglycone

“…To date, in addition to a synthetic study by Shoji, Sugai, and co-workers, 8 the synthesis of cotylenin A aglycone (i.e., cotylenol) by Kato and co-workers 9 and a total synthesis of cotylenin A by Nakada and co-workers 10 have been reported. Each of these approaches used a convergent synthetic strategy.…”