Abstract
In this article, we report the total synthesis of 6-deoxydihydrokalafungin (DDHK), a key biosynthetic intermediate of a dimeric benzoisochromanequinone antibiotic, actinorhodin (ACT), and its epimer, epi-DDHK. Tricyclic hemiacetal with 3-siloxyethyl group was subjected to Et3SiH reduction to establish the 1,3-cis stereochemistry in the benzoisochromane, and a subsequent oxidation/deprotection sequence then afforded epi-DDHK. A bicyclic acetal was subjected to AlH3 reduction to deliver the desired 1,3-trans isomer in an approximately 3:1 ratio, which was subjected to a similar sequence to that used for the 1,3-cis isomer that successfully afforded DDHK. A semisynthetic approach from (S)-DNPA, an isolable biosynthetic precursor of ACT, was also examined to afford DDHK and its epimer, which are identical to the synthetic products.
Highlights
Actinorhodin (ACT, 1) is an aromatic polyketide belonging to the dimeric benzoisochromanequinone (BIQ) family [1] and is produced by Streptomyces coelicolor A3 (2), which is among the most genetically studied actinomycetes [2]
To resolve the ambiguity regarding the intermediacy of DDHK (3) in ACT biosynthesis, we established a semisynthetic method for obtaining DDHK (3) and its epimer epi-DDHK (7) by the reduction of (S)-DNPA (6), an isolable biosynthetic precursor of ACT, and successfully clarified the function of the
We we report the total synthesis of DDHK (3) and its epimer 7 using various reduction contotal synthesis of DDHK (3) and its epimer 7 using various reduction conditions for the ditions for the stereoselective construction of the benzoisochromane moiety
Summary
Actinorhodin (ACT, 1) is an aromatic polyketide belonging to the dimeric benzoisochromanequinone (BIQ) family [1] and is produced by Streptomyces coelicolor A3 (2), which is among the most genetically studied actinomycetes [2]. DDHK (3) is presumed to be produced from (S)-DNPA (6) via reduction by ActVI-2, but has not yet been isolated from any biosynthetic strains of S. coelicolor or their mutants because of conversion to the shunt product actinoperylone [4]. DDHK (3) is composed of a benzoisochromane skeleton with two hydroxy groups on the C-9 and C-10 positions [6] and incorporates a disubstituted dihydropyran ring with 1,3-trans stereochemistry. In previous reports concerning the synthesis of the Molecules 2021, 26, 6397 groups on the C-9 and C-10 positions [6] and incorporates a disubstituted dihydropyran ring with 1,3-trans stereochemistry. We we report the total synthesis of DDHK (3) and its epimer 7 using various reduction contotal synthesis of DDHK (3) and its epimer 7 using various reduction conditions for the ditions for the stereoselective construction of the benzoisochromane moiety.
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