A Carbohydrate Approach for the First Total Synthesis of Cochliomycin C: Stereoselective Total Synthesis of Paecilomycin E, Paecilomycin F and 6′‐epi‐Cochliomycin C

Abstract

The first total synthesis of the chlorinated resorcylic acid lactone cochliomycin C is achieved starting from the readily available sugar D‐lyxose. The strategy has also lead to the total synthesis of natural resorcylic acid lactones paecilomycin E, paecilomycin F and a synthetic analogue 6‐epi‐cochliomycin C. The key reactions include Ohira–Bestmann alkynylation, ring closing metathesis and regioselective methylation under Mitsunobu conditions.

Applications of Mitsunobu Reaction in total synthesis of natural products

“…have demanded considerable attention for novel 14‐membered benzannulated macrolides. RALs are initially isolated from a series of fungi . fascinatingly, numerous compounds of this class are showed extensive range of bio‐properties such as anti‐malarial, antifungal, antiparasitic, and antiviral activities.…”

“…At first, Wang et al . isolated and reported three new RALs named cochliomycins A, B and C from the marine fungus Cochliobolus lunatus (M351) related to the gorgonian Dichotellagemmacea in the South China Sea area …”

“…Furthermore, the total synthesis of paecilomycin F ( 164 ) was achieved and reported by Mahankali in 2015. The total synthesis of 164 started with 2,4,6‐trihydroxybenzoic acid (THBA) ( 165 ) which upon treatment with trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) in acetone as solvent under Danishefskys conventional conditions gave the corresponding acetonide 166 . The latter was subjected to classical Mitsunobu conditions providing methyl ether 167 , regioselectively compound 167 was transformed into ester 168 after several steps (76% yield) The latter was then converted to the desired natural product 164 via multi‐step synthesis (Scheme ).…”

“…RALs are initially SCHEME 29 The total synthesis of (3R,5S)-5-hydroxy-de-O-methyllasipdiplodin 141 isolated from a series of fungi. [222] fascinatingly, numerous compounds of this class are showed extensive range of bio-properties such as anti-malarial, [223] antifungal, [224] antiparasitic, and antiviral [225] activities. At first, Wang et al [226] isolated and reported three new RALs named cochliomycins A, B and C from the marine fungus Cochliobolus lunatus (M351) related to the gorgonian Dichotellagemmacea in the South China Sea area.…”

Stereoselective total synthesis of the antiplasmodial resorcylic acid lactone paecilomycin F

“…The product obtained after allylation was a mixture of diastereomers, which were inseparable and were directly treated with MOM-Cl to get the corresponding MOM ethers (9:1) which were easily separable by column chromatography. Based on the earlier experience for the allylation reaction, 19,21 we proceeded further with the major diastereomer 18. Thus, treatment of the major diastereomer 18 with TBAF resulted in the formation of 8, the key side chain fragment with the required stereochemistry.…”