Diastereoselective Synthesis of ψ[(E)-CMeCH]- and ψ[(E)-CMeCMe]- Type Dipeptide Isosteres Based on Organocopper-Mediated anti-S_N2‘ Reaction

Abstract

[reaction: see text] A straightforward synthetic route for the synthesis of diastereomerically pure psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]-type dipeptide isosteres was developed on the basis of regio- and stereoselective anti-S(N)2' alkylation of 3-(N-Boc-5-methyl-4-substituted-oxazolidin-2-on-5-yl)acrylates with organocopper reagents.

Regio- and stereoselective ring-opening of chiral 1,3-oxazolidin-2-one derivatives by organocopper reagents provides novel access to di-, tri- and tetra-substituted alkene dipeptide isosteresElectronic supplementary information (ESI) available: synthetic procedures and characterization for 4a,b, 5a,b, 7b, 8a,b, 9a,b, 10b, 11a,b, 12b,c, 13b, 14a,b, 15, 16a,b, 17a,b, 18, 19b, 20b. See http://www.rsc.org/suppdata/p1/b2/b203482d/

“…In fact, in the alkylation of the non-methylated trans-1,3-oxazolidin-2-one 10a, formation of the Z-isomer 15 of the α-alkylated product ‡ The crystal structures of 18 and 19a were presented in the preliminary communication. 14 was observed only by treatment with Pr i Cu(CN)MgClؒBF 3 ؒ 2LiCl (but not the methyl and benzyl counterparts). Bulky alkyl groups such as an isopropyl group, may lead to favourable formation of other copper-π-allyl complexes such as 21b, which can provide the Z-isomer 15.…”

“…Therefore, we sought to develop a new general synthesis of diverse ψ[(E )-CMe᎐ ᎐ CH]-and ψ[(E )-CMe᎐ ᎐ CMe]type EADIs using organocopper-mediated alkylation of new key intermediates. 14 Accordingly, 5-vinyl-1,3-oxazolidin-2-ones, having hydroxy groups protected and activated as cyclic carbamates, were subjected to various modifications using organometallic reagents with accompanying ring-opening and decarboxylation. [15][16][17][18] We had previously reported that alkylation of 5-vinyl-1,3-oxazolidin-2-ones with various organocopper reagents proceeds regio-and stereoselectively to give vinylglycine derivatives.…”

A Concise Account of Recent SN2′ Grignard Coupling Reactions in Organic Synthesis

“…Fujii and co-workers reported that the copper-catalyzed anti-S N 2¢ addition of Grignard reagents to the b-(oxazolidin-2-on-5-yl) a,b-unsaturated esters afforded (E)-allylic amines as major product (Table 21). 45 In the same year, Fujii and co-workers also reported the use of this methodology to synthesize (E)-alkene transxaa-pro dipeptide mimetics. The oxazolidinone 70, when reacted with (i-Pro)Me 2 SiCH 2 Cu(CN)MgCl•2LiCl in THF at -78 °C for 30 minutes, with additional stirring for three hours at 0 °C, proceeded in 98% yield with ring opening and decarboxylation to give exclusively the anti-S N 2¢ product 71, whereas reaction of 72 proceeded quantitatively to afford the alkylated product 73 (Scheme 20).…”

First Stereoselective Synthesis of a Pro-ProE-Alkene Dipeptide Isostere

“…RGD pseudo peptides, resulting in nearly equal or even higher biological activities compared to the parent peptide. 3 Proline as the only secondary amino acid has special properties that set it apart from the other natural amino acids. Because of both its cyclic structure and the dialkylation of the a-amino group it has specific conformational effects on the peptide and protein backbone and therefore often plays an important role in influencing the secondary structure of proteins.…”

“…7 A synthetic approach to E-alkene isosteres of type 1 containing a disubstituted double bond often relies on Wittigtype reactions (Figure 1). 2,3 The stereoselective construction of the trisubstituted double bond in an E-Pro-Pro isostere of type 2 requires a different synthetic strategy. Our approach intends to combine the stereoselective introduction of an allylic alcohol and a subsequent Ireland-Claisen rearrangement.…”