1364705-39-4

Upstream product

• 70277-02-0 3-iodo-L-tyrosine methyl ester 
• 15761-38-3 L-N-Boc-Ala 
• 100-39-0 benzyl bromide 
• 79677-58-0 2-amino-3-(3-iodo-4-hydroxyphenyl)propionic acid methyl ester hydrochloride 
• 60-18-4 L-tyrosine 
• 70-78-0 3-Iodo-L-tyrosine 
• 71400-64-1 (S)-methyl 2-amino-3-(4-(benzyloxy)-3-iodophenyl)propanoate hydrochloride 

Downstream Products

• 1364706-18-2 Ac-(cyclo-m,m)-[(3-Cl)FAAAY]-CO₂Me 

Relevant academic research and scientific papers

Stereocontrolled Synthesis of Arylomycin-Based Gram-Negative Antibiotic GDC-5338

We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic GDC-5338. The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.

Initial Analysis of the Arylomycin D Antibiotics

The arylomycins are a class of natural product antibiotics that inhibit bacterial type I signal peptidase and are under development as therapeutics. Four classes of arylomycins are known, arylomycins A-D. Previously, we reported the synthesis and analysis of representatives of the A, B, and C classes and showed that their spectrum of activity has the potential to be much broader than originally assumed. Along with a comparison of the mechanism of acquired and innate resistance, this led us to suggest that the arylomycins are latent antibiotics, antibiotics that once possessed broad-spectrum activity, but which upon examination today, have only narrow spectrum activity due to prior selection for resistance in the course of the competition with other microorganisms that drove their evolution in the first place. Interestingly, actinocarbasin, the only identified member of the arylomycin D class, has been reported to have activity against MRSA. To confirm and understand this activity, several actinocarbasin derivatives were synthesized. We demonstrate that the previously reported structure of actinocarbasin is incorrect, identify what is likely the correct scaffold, confirm that scaffold has activity against MRSA, and determine the origin of this activity.

PROCESS FOR MAKING ARYLOMYIN RING ANALOGS

Methods for making an arylomycin ring of formula t or salts or solvates thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R5, R10 and Pg1 are as defined herein.

Biaryl-bridged macrocyclic peptides: Conformational constraint via carbogenic fusion of natural amino acid side chains

A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki-Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta-meta, meta-ortho, and ortho-meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation. Suzuki-Miyaura macrocyclizations were successfully achieved both in solution and on solid phase for all three sizes of peptide. This approach constitutes a means of constraining peptide conformation via direct carbogenic fusion of side chains of naturally occurring amino acids such as phenylalanine and tyrosine, and so is complementary to strategies involving non-natural, for example, hydrocarbon, bridges.