Synthesis of Orthogonally Protected Thioamide Dipeptides for Use in Solid-Phase Peptide Synthesis

Orthogonally protected thioamide-containing dipeptides were efficiently and cleanly prepared from the precursor dipeptides using Curphey’s method (P4S10, hexamethyldisiloxane (HMDO), reflux, DCM) in 67-96% isolated yield. This was in contrast to the use of Lawesson’s or Berzelius’ reagents where significant issues with reaction non-completion, decomposition and purification were observed. Subsequent clean removal of the dipeptides’ t-butyl ester protecting groups gave thioamide dipeptide acids which were suitable for use in solid-phase peptide synthesis (SPPS)

Spirobicyclic Diamines 1: Synthesis of Proline-derived Spirolactams via Thermal Intramolecular Ester Aminolysis

Proline derived [4.4]-spirolactams have been synthesised in good yields by a reductive-amination reaction followed by thermal cyclisation of the resulting amine onto the proline ester group in refluxing toluene. The synthesis of the corresponding [4.5]-spirolactams by the same method gave much reduced yields

Spirobicyclic Diamines 2: Synthesis of Homochiral Diastereoisomeric Proline Derived [4,4]-Spirolactams

L-Proline derived diastereoisomeric [4.4]-spirolactams have been prepared by a reductive-amination reaction of (R)- or (S)-alanine methyl ester followed by thermal cyclisation of the resulting amine onto the proline ester group in refluxing toluene. Under similar conditions (R)- or (S)-phenylalanine methyl ester gave no cyclisation products, while R- or S-a-methylbenzylamine required treatment with NaNH2 in refluxing toluene to induce cyclisation giving diastereoisomeric [4.4]-spirolactam

Synthesis of Orthogonally Protected 1,2-diaminopropanoic Acids by Ring-Opening of 3-Unsubstituted N-Activated Aziridine 2-Carboxylates with Para-Methoxybenzylamine: a Study of the Regioselectivity of the Reaction

Orthogonally protected 1,2-diaminopropanoic acids (DAPs) have been synthesised in good yields by the ring-opening of 3-unsubstituted N-activated aziridine 2-carboxylates with para-methoxybenzylamine. The choice of both the N-activating group and ester alkyl group had a significant influence on the ratio of attack at the a or b positions of the aziridine. However, the regiochemical outcome is not predictable

Use of the Mitsunobu Reaction in the Synthesis of Orthogonally Protected a,b-Diaminopropionic Acids

Orthogonally protected a,b-diaminopropionic acids have been synthesised in good yields by the reaction of N-trityl L-serine esters with N-substituted sulfonamides under Mitsunobu reaction conditions (DEAD, PPh3, THF). The best isolated yields were obtained when N-Boc p-toluenesulfonamide was used as the nitrogen nucleophile precursor in the Mitsunobu reaction. Subsequently, the N-trityl group was efficiently replaced with the more stable allyloxycarbonyl (alloc) group

Spirobicyclic Diamines. Part 3: Synthesis and Metal Complexation of Proline-Derived [4,4]-Spirodiamines.

The syntheses of racemic and homochiral [4.4]-spirolactams, starting from L-proline, in good yields are described. Reduction of the lactam carbonyl group of spirolactams, containing chiral substituents on the lactam nitrogen, with lithium aluminium hydride, gives a series of homochiral [4.4]-spirodiamines. The crystal structure of one of these spirodiamines on complexation with zinc chloride was obtained. Interestingly it showed a hydrogen-bonded dimeric structure, where the monomers are diastereoisomeric diamines

Assessing the Correlation of Microscopy-based and Volumetry-based Measurements for Resin Swelling in a Range of Potential Greener Solvents for SPPS

The degree of resin swelling in a particular solvent system is one of the critical parameters for SPPS, and for solid phase synthesis, in general. Methods used for measuring the degree of resin swelling include microscopy-based and volumetry-based methods. This study describes, and compares, the use of both methods for a number of commercially available resins commonly used in SPPS, with a range of solvents which have been identified in the literature as “greener” than DCM, DMF and NMP. The results were analysed by statistical methods and a significant correlation between the two distinct methods has been demonstrated for the first time. The results will likely be used, in conjunction with other literature methods, to help in choosing both the resin and solvent system for greener SPPS (GSPPS), as well as for continuous flow SPPS, which is of growing importance

Solid-Phase Peptide Synthesis of Analogues of the N-Terminus A-ring Fragment of the Lantibiotic Nisin: Replacements for the Dehydroalanine (Dha) Residue at Position 5 and the First Incorporation of a Thioamide Residue

A number of A-ring analogues of the lantibiotic nisin, containing replacements for the Dha at position 5, have been successfully prepared by solid-phase peptide synthesis. The Dha replacements include glycine, alanine, phenylalanine, serine and 1-aminocyclopropyl carboxylic acid (ACCa). The incorporation of a thioamide-isoleucine residue at position 4 is also described and is the first report of the preparation of a lantibiotic ring fragment containing a thioamide link

Studies on the Synthesis of Orthogonally Protected Azalanthionines, and of Routes towards b-Methyl Azalanthionines, by Ring-Opening of N-Activated Aziridine-2-Crboxylates

Orthogonally protected azalanthionines were successfully synthesised by the ring-opening of N-activated aziridine-2-carboxylates with protected diaminopropanoic acids (DAPs). The required DAPs were also prepared by ring-opening of N-activated aziridine-2-carboxylates with para-methoxybenzylamine, but it was found that the choice of aziridine protecting groups dictated both the success of the reaction as well as the regioselectivity of the isolated products. Attempts to extend the methodology to the preparation of the more sterically demanding b-methyl azalanthionines have, so far, been unsuccessful

Synthesis of Orthogonally Protected Azalanthionines (Lanazanines) by Sequential Ring-Opening of N-Substituted Aziridine 2-Carboxylates

Orthogonally protected azalanthionines (lanazanines, 4-azadiaminopimelic acids or b-aminoalaninoalanines) have been synthesised in good yields by the ring-opening of N-protected aziridine 2-carboxylates with suitably protected diaminopropanoic acids (DAPs). The required DAPs were also synthesised by ring-opening of N-protected aziridine 2-carboxylates with para-methoxybenzylamine