Dongyeol Lim

Rapid and efficient solid phase syntheses of cyclic peptides with endocyclic biaryl ether bonds

Solid phase syntheses of the OF4949 derivs. I (R = H, CH2CONH2) and II (R1 = H, R2 = H, NH2; R1 = NH2, R2 = H) were performed via protection/deprotection of tyrosine side chains on a support, and SNAr macrocyclization reactions. [on SciFinder (R)]

Total synthesis of halicylindramide A.

A rapid and efficient Fmoc solid-phase synthesis of halicylindramide A is described. The strategy comprises resin attachment of the first amino acid via the side chain of aspartic acid, stepwise solid-phase synthesis of the linear peptide analog up to the cysteine residue, on-resin head-to-tail cyclization and linear peptide synthesis of the N-terminal region, and finally cysteine oxidation and formylation. The stereochemistry of the halicylindramide A was confirmed by comparison of NMR and RP-HPLC data with the natural molecule. A distinctive conformational change was observed from the CD spectra of the halicylindramide A in sodium dodecyl sulfate.

Resin type can have important effects on solid phase asymmetricalkylation reactions

A new N-propionylated oxazolidinone 1 is prepared; asymmetric nalkylations of this auxiliary proceed with varying yields and nenantioselectivities when supported on Merrifield, Wang and TentaGel R PHB nresins.

Comparisons of the conformational biases imposed by trans-2,3-methanomethionine and alpha-methylmethionine.

A comparative study of four peptidomimetics of the sequence Phe‐Met‐Arg‐Phe‐amide (FMRFa) was performed to compare the conformational bias caused by trans‐2,3‐methanomethionine and α‐methylmethionine stereoisomers. The specific compounds studied were F[(2S,3S)‐cyclo‐M] RFa, F[(2R,3R)‐cyclo‐M]RFa, F[(S)‐α‐MeM]RFa, and F[(R)‐α‐MeM]RFa. Molecular simulations based on CHARMm 22 indicate that γ‐turn, inverse γ‐turn, and α‐helical conformations about the cyclo‐M residue are accessible to the two F[cyclo‐M]RFa stereoisomers. Similar calculations for F[(S)‐α‐MeM]RFa, and F[(R)‐α‐MeM]RFa indicate that the α‐methylamino acids tend to favor α‐helical conformations. The nmr data is presented for the four peptidomimetics. Most informative were the rotating frame nuclear Overhauser effect cross peaks between the NH protons proximal to the methionine surrogates, and the Cβ hydrogens. Overall, these nmr data indicate F[(2S,3S)‐cyclo‐M]RFa and F[(2R,3R)‐cyclo‐M]RFa preferentially adopt inverse γ‐turn and γ‐turn conformations, respectively, whereas F[(S)‐α‐MeM]RFa and F[(R)‐α‐MeM]RFa tend to form partial left‐ and right‐handed helical structures (although energy differences between the two turn structures, and between the two helical structures are likely to be small). It is suggested that the wider NH‐Cα‐CO angle of cyclopropane amino acids and their more severe steric requirements around the Cβ carbons force the peptidomimetic N‐ and C‐termini into the same region of conformational space. This favors C7 turns in the cyclopropane amino acid series relative to the less constrained α‐methyl derivatives.

Solid-Phase Synthesis of Triostin A Using a Symmetrical Bis(diphenylmethyl) Linker System

Triostin A is a symmetric bicyclic depsipeptide with very potent antitumoral activity because of its bisintercalation into DNA. In this study, we report a new synthetic strategy that exploits a structural symmetry of triostin A. First, we prepared a novel symmetric linker molecule that is labile under mildly acidic conditions and suitable for a solid-phase synthesis procedure. Two Cys units were attached to a linker-resin conjugate via their free thiol groups, and double deprotection and double coupling reactions were then applied to synthesize linear tetradepsipeptides. Subsequently, the key biscyclization of the tetradepsipeptides was performed on the resin, and the resulting cyclic octapeptide was detached from the linker-resin conjugate to give a peptide with two free thiols. Finally, triostin A was obtained by oxidizing the free thiols in solution to produce a disulfide. The yield was improved through exploration of two different solid-phase synthetic approaches under similar strategy. Mainly, this strategy was developed to enable the ease and rapid preparation of libraries of symmetric bicyclic depsipeptides. It also addresses several synthetic problems with our synthesis, including diketopiperazine (DKP) formation, poor cyclization yields and preparation of noncommercial N-methyl amino acids in good yields.

2,3-Methanoamino acid analogs of Arg stabilize secondary structures of a 13 amino acid peptide in aqueous solution

Peptidomimetics 1 and 2 of RN24 (an RNase A C-peptide analog) in which the Arg+-10 residue is replaced by 2R,3S-cyclo-Arg′ and by 2S,3S-cyclo-Arg′, respectively, show less temperature dependence in CD studies than the parent peptide.