Total Synthesis of A54145 Factor D

Abstract

An efficient total synthesis of A54145 factor D (A5D), a member of the A54145 family of cyclic lipodepsipeptide antibiotics, is reported. The peptide was constructed by attaching the peptide to the 2′-chlorotrityl polystyrene resin via Sar5 and developing conditions that avoided diketopiperazine formation upon subsequent elaboration using 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis. This route allowed for facile formation of the crucial depsi bond. A branched acyclic precursor was cyclized off-resin and then globally deprotected to obtain A5D. Consistent with recent studies by others, we found that the MeOAsp residue has the 2S,3R configuration. We also established that the configuration of the stereocenter in the anteiso-undecanoyl lipid tail does not affect biological activity.

Solid-Phase Total Synthesis of Dehydrotryptophan-Bearing Cyclic Peptides Tunicyclin B, Sclerotide A, CDA3a, and CDA4a using a Protected β-Hydroxytryptophan Building Block

“…For example, both the Taylor group and the Li group have reported the synthesis of a closely related cLPA named A54145D. 103,104 Both groups were able to access analogs of this peptide through Fmoc SPPS approaches as well.…”

“…115 A structurally similar amino acid, L-erythro-MeOAsp, was prepared during the synthesis of A54145D in which a Mitsunobu reaction was used to invert the stereochemistry of the -hydroxy group from threoto the desired erythro-configuration. 103 We anticipated a similar method could be used to prepare D-erythro-…”

“…The route outlined in Scheme 3.10 was initially used and was based upon our synthesis of Fmoc-D-threo-HOAsn(Trt)-OH. 103,116 The route outlined in Scheme 3.13 was used for the large-scale synthesis of 3.9 which is based upon the procedures of Moeller et al 120 and Guzman-Martinez. 121 (50 mL), dried over MgSO4, evaporated and purified by FC (30 % EtOAc/70 % hexanes then 60 % EtOAc/38 % hexanes/2 % AcOH) to give 3.9 as an amorphous white solid (0.30 g, 60 % yield).…”

“…Compound 3.22. A solution of 3.21 103 (2.70 g, 5.50 mmol), p-nitrobenzoic acid (1.38 g, 8.26 mmol, 1.5 equiv) and triphenylphosphine (2.17 g, 8.27 mmol, 1.5 equiv) in THF (28 mL), cooled to 0 o C, was treated with diisopropyl azodicarboxylate (1.6 mL, 8.15 mmol, 1.5 equiv). The resulting mixture was left to stir for 21 h at room temperature before being evaporated in vacuo.…”

Synthesis of Azido Acids and Their Application in the Preparation of Complex Peptides

“…Scheme 47 Albericio's synthesis of aza-kahalalide analogues using AABA as a synthon Taylor and co-workers used Fmoc-protected AABA to synthesize aza-analogues of daptomycin and A54145D to determine the impact of both the ester bond and the stereochemistry at the side chain of Thr on the antimicrobial activity. 86,171 For example, in their synthesis of daptomycin analogue 256 (Scheme 48), the AABA residue was incorporated into the linear peptide 254, which was then reduced to the corresponding peptide amine 255 using DTT/DIPEA/DMF. Trp was coupled on to the -amino group and the remaining amino acids (Glu and Ser) were appended…”