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. 2021 Mar 1;60(10):5162-5167.
doi: 10.1002/anie.202014238. Epub 2021 Jan 21.

Convergent Total Synthesis of Yaku'amide A

Yu Cai  1 , Zhiwei Ma  1 , Jintao Jiang  1 , Concordia C L Lo  1 , Shi Luo  1 , Ankur Jalan  1 , Joseph M Cardon  1 , Alexander Ramos  1 , Diego A Moyá  1 , Daniel Joaquin  1 , Steven L Castle  1
Affiliations

Convergent Total Synthesis of Yaku'amide A

Yu Cai et al. Angew Chem Int Ed Engl. .

Abstract

Total synthesis of the anticancer peptide natural product yaku'amide A is reported. Its β-tert-hydroxy amino acids were prepared by regioselective aminohydroxylation involving a chiral mesyloxycarbamate reagent. Stereospecific construction of the E- and Z-ΔIle residues was accomplished through a one-pot reaction featuring anti dehydration, azide reduction, and O→N acyl transfer. Alkene isomerization was negligible during this process. These methods enabled a highly convergent and efficient synthetic route to the natural product.

Keywords: O→N acyl transfer; aminohydroxylation; natural products; peptides; total synthesis.

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Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Yaku’amides A (1) and B (2). ΔAAs are shown in red, β-OHAAs are shown in blue, and configurations assigned by Inoue are shown in green.
Scheme 1.
Scheme 1.
Retrosynthesis of 1. Boc = tert-butoxycarbonyl, TES = triethylsilyl.
Scheme 2.
Scheme 2.
Aminohydroxylation-based synthesis of β-OHAAs present in 1. Tf = trifluoromethanesulfonyl, Ms = methanesulfonyl.
Scheme 3.
Scheme 3.
Synthesis of right-hand tetrapeptide 8. EDC•HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, HOBt = 1-hydroxybenzotriazole, THF = tetrahydrofuran, DMF = N,N-dimethylformamide.
Scheme 4.
Scheme 4.
Syntheses of dipeptide 6 and tripeptide 7. Stereocenters marked with asterisks show relative, not absolute, stereochemistry. DMP = Dess–Martin periodinane.
Scheme 5.
Scheme 5.
Synthesis of nonapeptide 5.
Scheme 6.
Scheme 6.
Synthesis of pentapeptide 4. Stereocenters marked with asterisks show relative, not absolute, stereochemistry.
Scheme 7.
Scheme 7.
Synthesis of NTA carboxylic acid 3. AZADO = 2-azaadamantane N-oxyl, TMS = trimethylsilyl.
Scheme 8.
Scheme 8.
Completion of the total synthesis of 1. COMU = 1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate.
See this image and copyright information in PMC

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