C‐Alkylation of Sarcosine Residues in Cyclic Tetrapeptides via Lithium Enlates

Abstract

The cyclic tetrapeptides cyclo(‐Leu‐Sar‐Gly‐), cyclo(‐Val‐Sar‐Sar‐Gly‐), and cylco(‐Meleu‐Gly‐D‐Alasar‐) have been synthesized from the component amino acids (BOP‐Cl coupling), using the pentafluorophenyl esters for the cyclization step (42, 13, and 30% yield, respectively). Multiple deprotonation (LDA in THF/LiBr/DMPU) and addition of highly reactive electrophiles (CF3CO2D, MeI, CH2O, CH2CHCH2Br, PhCH2Br) produce cyclic tetrapeptides with additional substituents introduced diastereoselectively (70 to > 98% ds) in yields ranging from 20 to 90%. The C‐alkylatd products are all derived from a sarcosine‐enolate moiety adjacent to another N‐methylamino acid. The structures of the resulting products are determined by NMR spectroscopy (DNOE and ROESY techniques) and by hydrolysis to the parent amino acids, suitable derivatization, and analysis by chromatography on a chiral GC column. It was shown in two cases that the overall yield of cyclization/alkylation to give a disubstitued cyclic tetrapeptide is higher than that of a synthesis of the same product from the corresponding amino‐acid building blocks. Surprising temperature and salt effects on the yields and selectivities of the reactions of the cyclic tetrapeptide enolates are presented, and possible mechanistic interpretations are discussed.

Highly Stereoselective Peptide Modifications through Pd‐Catalyzed Allylic Alkylations of Chelated Peptide Enolates

“…For cyclic peptides, the selectivities are generally better, because one face of the reaction intermediate can be shielded by the peptide ring. [9] The most spectacular example reported so far was the modification of cyclosporine, as reported by Seebach et al [10] In this case, a single sarcosine subunit was alkylated stereoselectively. Recently, Maruoka and co-workers [11] reported the stereoselective functionalization of peptide Schiff bases [12] by chiral phase-transfer catalysis.…”

Cyclotetrapeptide Complexes of Nickel(II) and Palladium(II) by Template Synthesis from Dipeptide Esters with Functionalized Side Chains − Crystal Structure of [(cyclo‐Gly‐β‐Ala‐Gly‐β‐Ala‐4H+)Cu](PPN)2

“…First, a common ''reasonable'' isotropic thermal parameter U of 0.09 was assigned to these atoms and the site occupancies were refined. This procedure led to approximate s.o.f.s of 0.7, 0.75 and 0.55, which were fixed afterwards on these values, since they added, reasonably, to an integer (2). With these fixed s.o.f.s the thermal parameters of the three oxygen atoms were refined freely isotropic.…”

“…[20] The ester groups of complex 1 were hydrolyzed to give the tetraanionic palladium complex in 6. For possible use in diagnostics and radiotherapy [17,18] the water-soluble sodium salts 1b and 7 were prepared by the addition of water to a mixture of H-Gly-Asp(OMe) 2 , NaOMe, and metal salt. The structures of complexes 1b and 7 were verified by 2D NMR techniques.…”

“…[3] Seebach et al have pioneered studies on the synthesis, structure, and biological activity of cyclo-β-tetrapeptides. [2,4] Although some cyclotetrapeptides are difficult to synthesize, [2,4,5,6] our facile route from non-activated peptide esters on metal centres [7,8] involves the cyclocondensation of dipeptide esters at metal templates (Cu 2ϩ , Ni 2ϩ , Pd 2ϩ ) and requires neither a protecting nor an activating group or a coupling agent. Also, high dilution of the reaction mixture is not necessary.…”

“…Biologically active natural cyclic tetrapeptides [2] are promising candidates for new anticancer agents. [3] Seebach et al have pioneered studies on the synthesis, structure, and biological activity of cyclo-β-tetrapeptides.…”