A new radical-based coupling method has been developed for the single-step generation of various γ-amino acids and α,β-diamino acids from α-aminoacyl tellurides. Upon activation by Et3 B and O2 at ambient temperature, α-aminoacyl tellurides were readily converted into α-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (-)-manzacidin A.
Hikizimycin (1), which exhibits
powerful anthelmintic
activity, has the most densely functionalized structure among nucleoside
antibiotics. A central 4-amino-4-deoxyundecose of 1 possesses
10 contiguous stereocenters on a C1–C11 linear chain and is
decorated with a cytosine base at C1 and a 3-amino-3-deoxyglucose
at C6-OH. These distinctive structural features of 1 make
it an extremely challenging target for de novo construction. Herein,
we report a convergent total synthesis of 1 from four
known components: 3-azide-3-deoxyglucose derivative 4, bis-TMS-cytosine 5, d-mannose 9, and d-galactose derivative 10. We first designed
and devised a novel radical coupling reaction between multiply hydroxylated
aldehydes and α-alkoxyacyl tellurides. The generality and efficiency
of this process was demonstrated by the coupling of 7c and 8, which were readily accessible from two hexoses, 9 and 10, respectively. Et3B and O2 rapidly induced decarbonylative radical formation from α-alkoxyacyl
telluride 8, and intermolecular addition of the generated
α-alkoxy radical to aldehyde 7c yielded 4-amino-4-deoxyundecose 6-α with installation of the desired C5,6-stereocenters.
Subsequent attachments of the cytosine with 5 and of
the 3-azide-3-deoxyglucose with 4 were realized through
selective activation of the C1-acetal and selective deprotection of
the C6-hydroxy group. Finally, the 3 amino and 10 hydroxy groups were
liberated in a single step to deliver the target 1. Thus,
the combination of the newly developed radical-coupling and protective-group
strategies minimized the functional group manipulations and thereby
enabled the synthesis of 1 from 10 in only
17 steps. The present total synthesis demonstrates the versatility
of intermolecular radical addition to aldehyde for the first time
and offers a new strategic design for multistep target-oriented syntheses
of various nucleoside antibiotics and other bioactive natural products.
Polyoxins J (1 a) and L (1 b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1 a and 1 b contain thymine and uracil nucleobases, respectively. Herein we report the unified total synthesis of 1 a, 1 b, and their artificial analogues 1 c and 1 d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between α-alkoxyacyl tellurides and a chiral glyoxylic oxime ether led to chemo- and stereoselective construction of the ribonucleoside α-amino acid structures of 1 a-d without damaging the preinstalled nucleobases. The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1 a-d. The two amino acid fragments were connected and elaborated into 1 a-d (longest linear sequence: 11 steps). Compounds 1 a and 1 b assembled in this way exhibited potent activity against true fungi, while only 1 d was active against Gram-positive bacteria.
A new radical-based coupling method has been developed for the single-step generation of various g-amino acids and a,b-diamino acids from a-aminoacyl tellurides. Upon activation by Et 3 B and O 2 at ambient temperature, a-aminoacyl tellurides were readily converted into a-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (À)-manzacidin A.
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