The Miharamycins and Amipurimycin: their Structural Revision and the Total Synthesis of the Latter

Abstract

The structural puzzle of amipurimycin, ap eptidyl nucleoside antibiotic,i ss olved by total synthesis and X-ray diffraction analysis,w ith the originally proposed configurations at C3' and C8' inverted and those at C6',C 2 '',a nd C3'' corrected. As imilar structural revision of the relevant miharamycins is proposed via chemical transformations and then validated by X-ray diffraction analysis.T he miharamycins bear an unusual trans-fused dioxabicyclo[4.3.0]nonane sugar scaffold, whichw as previously assigned as being in the cis configuration.

Total Synthesis of Nucleoside Antibiotics Amicetin, Plicacetin, and Cytosaminomycin A—D

“…[ 22‐26 ] Especially, the gold(I)‐catalyzed glycosylation protocol using glycosyl ortho ‐alkynylbenzoates (Abz) as donors has been successfully applied to the synthesis of highly complex natural nucleoside antibiotics, including A201A, tunicamycins, and amipurimycin. [ 27‐30 ] With this method, we also achieved total synthesis of the largest congener of the amicetin family, streptcytosine A, together with the smaller fragments plicacetin ( 2 ) and cytosamine ( 3 ). [ 18 ] However, the synthesis of amicetin was not successful due to failure in the final amidation and deprotection.…”

Solving the Structural Puzzles of Amipurimycin and Miharamycins Enabled by Stereodivergent Total Synthesis

“…To secure the required C‐3′ and C‐8′ configurations in the revised amipurimycin 5 , D‐arabinose was utilized as the starting material (Figure 15). [7b] Thus, aldol addition of D‐arabinose derived ketone 80 with methyl aminoketone 57 ( R ) could provide adduct 81 (89 %), with the C‐3 being fixed to be at S configuration. Treatment of ketone 82 with Zn(BH 4 ) 2 /CeCl 3 gave the desired 7 S ‐ol 83 in a highly stereoselective manner (dr=12.4 : 1) [31] .…”

“…In fact, we accomplished the synthesis of the four possible stereoisomers of amipurimycin ( 1 a – d ), and furthermore their C8’( R ) epimers ( 1 e – h ), but found none of them could match the analytical data of the nature product. Careful comparison of the analytical data led us to revise the structure of amipurimycin (Figure 1C, 5 ), in which the configuration of the quaternary C3’ is inverted, the stereochemistry of C8’ is changed to R , the stereochemistry of C6’ is fixed to be S , and the cis ‐3‐aminocyclopentane‐2‐carboxylic acid residue is assigned to have a 2’’ R ,3’’ S configuration [7b] . In fact, 3( S )‐aminocyclopentane‐2( R )‐carboxylic acid as a single enantiomer, named cispentacin or FR109615, has been identified from Streptomyces setonii [8] .…”

“…A similar revision of the core structure of miharamycin A/B would change the cis ‐fused dioxabicyclo[4,3,0]nonane into a conformationally restricted trans‐ fused one (Figure 1C, 6 ). Fortunately, the revised structures of these intriguing peptidyl nucleosides have finally been validated unambiguously by total synthesis of amipurimycin 5 and X‐ray diffraction analysis of the authentic samples of amipurimycin and miharamycin B [7b] …”

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

“…The guanidine system is present in structural components of biomolecules, namely in the amino acid arginine or in the nucleobase guanine. It is also embodied in the nitrogenous aromatic moiety of various bioactive compounds, such as in the 2aminopurine motif, which is contained in the antibiotic natural nucleosides amipurimycin and miharamycins [22,23], and in various synthetic nucleosides exhibiting anticancer [24] and antiviral properties [25], or in the 2-aminopyrimidine moiety, which is present in the anticancer drug imatinib [26]. On the other hand, the amidine (or imidamide) system (NH2-C=NR) contained in the guanidine group is present in the cytosine and adeninebased motifs, which are found in various nucleoside analogues used as chemotherapeutic agents [27,28].…”