C-Terminal peptide cyanosulfur ylides are readily converted to C-terminal peptide alpha-ketoacids, poised for chemoselective amide-forming reactions with hydroxylamines. These easily prepared and bench stable ylides are quickly and selectively oxidized with aqueous Oxone without the need for protection of most peptide side chains and with minimal epimerization. This approach offers the first method for preparing enantiomerically enriched, side chain unprotected alpha-ketoacids.
Cyclic peptides are important synthetic targets due to their constrained conformation, enhanced metabolic stability and improved bioavailability, which combine to make them promising lead compounds for drug candidates. They are typically synthesized by a multi-step sequence of carefully orchestrated protecting group manipulations and cyclization of side-chain protected linear precursors. In the present manuscript we disclose an alternative approach to the synthesis of peptide macrocycles by the α-ketoacid-hydroxylamine (KAHA) ligation. This reaction allows readily prepared linear peptides to be cyclized without reagents or side-chain protecting groups and delivers a native backbone amide bond at the ligation site. The precursors are prepared with Fmoc-based solid phase peptide synthesis using reagents that we have previously disclosed. No post-cyclization manipulations or deprotections other than purification are required. This protocol was applied to five different cyclic peptide natural products of varying ring sizes and side chain functionalities.
A new cyanosulfur-ylide based linker makes possible the synthesis of C-terminal peptide α-ketoacids by solid phase synthesis. The preparation of the requisite linker and its application to a variety of C-terminal peptide α-ketoacids with unprotected side chains is reported.As part of the intense interest in the development of new methods for native amide bond formation via chemoselective ligation reactions, 1,2 our group has identified a novel and unexpectedly simple amide-forming ligation reaction that enables the coupling of the peptide fragments by decarboxylative condensation between α-ketoacids and N-alkyl hydroxylamines. 3 This reaction offers great promise as a general method for the chemoselective ligation of two unprotected peptide fragments, but is currently limited by the lack of practical methods for the preparation of ligation partners bearing the requisite Cterminal α-ketoacids 4 and N-terminal hydroxylamines. 5 In addressing this, we have recently reported a robust, chemos-elective method to produce peptide α-ketoacids with minimal epimerization via oxidation of cyanosulfur ylides. 6 This method is operationally friendly, high yielding and provides peptide α-ketoacids in high enantiopurity. It is also compatible with all unprotected amino acid side chains save cysteine and methionine. To extend this strategy further in preparing larger peptide derived ketoacids, we now report the synthesis and utility of a solid-supported cyanosulfur ylide that makes possible the preparation of C-terminal α-ketoacids using standard Fmoc-based solid phase peptide synthesis (Scheme 1). 7 Inspired by Rademann et al.'s work, 8 which performed Wasserman et al.'s elegant phosphorus ylide 9 chemistry on a solid support, we hoped to enable the acylation of a cyanosulfur ylide moiety and elongation of the peptide chain on a standard solid support. We were encouraged by our previous results that the cyanosulfur ylides could tolerate the standard procedures employed for Fmoc-based N-terminal deprotection and extension of the peptide chain in the C to N direction. 6 This finding anticipated an alkyl sulfide-containing linker as a precursor to peptide cyanosulfur ylides for synthesis on a suitable solid support.Tetrahydrothiophene-derived linker 5 was prepared in five steps from commercially available tetrahydrothiophen-3-one (Scheme 2). It contains a free acid for loading onto an amine or alcohol derivatized solid support, and a four atom-spacer from the acid to the tetrahydrothiophene core. Horner-Wadsworth-Emmons reaction 10 provided α,β-unsaturated † Electronic supplementary information (ESI) ester 1, which was subjected to 1,4-conjugate reduction to afford 2. All attempts at metal catalyzed hydrogenation (Pd, Pt, Rh) failed due to catalyst poisoning by the sulfur. 11 We found that the conjugated ester could be reduced by in situ generated nickel boride, 12 accompanied with a small amount of desulfurization as a side reaction. Subsequent reduction of the ester with LiAlH 4 provided alcohol 3. 13 Elaboration ...
A novel one-pot efficient synthesis of 2,5-dihydro-1H-benzo[c]azepines and 10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a]azepines from α-amino acids and aromatic aldehydes containing an ortho-Michael acceptor is reported via decarboxylative annulations without metal catalysts in yields of 52-91%. Under microwave irradiation, this protocol provides rapid access to polycyclic ring systems (only 5 min in most cases).
We report a novel organocatalytic one-pot cascade bromination-Michael-type Friedel-Crafts alkylation dearomatization-nucleophilic rearrangement aromatization cascade process for the direct α-indolylation of unfunctionalized enals from readily available indoles with good yields and high E selectivity. The simplicity and practicality of its high efficiency for formation of a new C(sp(2))-C(sp(2)) bond constitute the most attractive advantage of this reaction.
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