Isosteres, dipeptide

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

Scheme 2.59 Synthesis of L,L-type ( )-alkene dipeptide isosteres 243 through palladium(0)-catalyzed isomerization of vinylaziridines 240.

A related palladium(O)-catalyzed epimerization of y-aziridinyl-a,P-enoates 244 was also reported by Ibuka, Ohno, Fujii, and coworkers (Scheme 2.60) [43]. Treatment of either isomer of 244 with a catalytic amount of Pd(PPh3)4 in THF yielded an equilibrated mixture in which the isomer 246 with the desired configuration predominated (246 other isomers = 85 15 to 94 6). In most cases the isomer 246 could be easily separated from the diastereomeric mixture by a simple recrystallization, and the organocopper-mediated ring-opening reaction of 246 directly afforded L,L-type (E)-alkene dipeptide isosteres 243. 

E)-alkene dipeptide isostere 48, 51, 63 alkenylepoxide 42 alkoxy carbonyl protecting group 32 P-alkoxy-a-amino esters... 

The addition of titanated 2-methylpropenamides to 2-(ter/-butoxycarbonylamino)a]dehydes was investigated during the synthesis of dipeptide isosteres and was shown to exhibit low selectivity only93,94. 

An efficient route for the synthesis of the Phe-Phe hydroxyethy-lene dipeptide isostere precursors utilized for the design of potential inhibitors of renin and HIV-protease was developed. The key step is the zinc-mediated stereoselective allylation of A-protected a-amino aldehydes in aqueous solution (Eq. 8.32).70 NaBF4/M (M = Zn or Sn) showed facilitating allylation of a variety of carbonyl compounds in water, and a-and y-addition products of crotylations could be alternatively obtained under the control of this novel mediator (Eq. 8.33).71... 

M. Clare, R. A. Mueller, and K. Houseman, Effect of hydroxyl group configuration in hydroxyethlamine dipeptide isosteres on HIV protease inhibition, J. Med. Chem. 34 1222(1991). 

In the synthesis of the azabicyclic core of the Stemona alkaloids, methyl (2/W,3.9/ ,3a/W)-2-(2-cthoxycarbonylethyl)-hexahydropyrrolo[l,2- ]isoxazole-3-carboxylate was hydrogenolyzed over 10% Pd-C in EtOAc and acetic acid at room temperature to give after cyclization the bicyclic lactam 153 <2005JOC3157> (Equation 22). This route was also used to produce pyrrozilidinone-based dipeptide isosteres <2005T8836>. 

The dipeptide isosteres with indolizin-3-one structure 271 were also synthesized using similar strategies <1998JOC7463>. 

Aziridine cleavage based on an Sn2 reaction was used for the synthesis of peptides bearing E alkene dipeptide isosteres, a novel class of potent bombesin receptor antagonists [62]. Treatment of the vinylaziridine 86 (Scheme 9.19) with isobutyl and isopentyl magnesiocyanocuprates in THF at —78 °C for 30 min. stereospecifi-cally gave the desired E alkene isosteres 87 in high isolated yields [63]. 

If the carbamate already contains a stereogenic centre, the internal chiral induction will either oppose or enforce the external induction exerted by the chiral base. In the (5 )-A,A-dibenzylphenylalaninol carbamate 89 (equation 19), i-BuLi/TMEDA removes preferently the pro-R-H to form the (25, 17 )-configured lithium compound 90a besides few 91a, ratio 90 10. However, when i-BuLi/(—)-sparteine (11) is applied, due to its high preference for /jro-i -protons, the ratio 90b/91b is inverted (10 90). The intermediates had been applied to the synthesis of several dipeptide isostere spacers. ... 

We synthesized the ketomethylene, , and hydroxyethylene,8, isosteres of a Leu-Ala dipeptide sequence in order to explore the importance of the two extra atoms in statine relative either to substrate or to the tetrahedral intermediate (Figure 1) in another aspartyl protease system. The compounds were synthesized by the routes outlined in Scheme I. This route was chosen so as to provide steric control at C-2 and C-5 of both 7 and 8 as well as to provide ready access to C-4 labeled analogs. Details of the synthesis have been described else-where.(23.24) Inhibitors were synthesized in which Leu-Ala dipeptide Isosteres replaced either Sta or Sta-Ala in known pepstatin analogs. Inhibition of porcine pepsin was determined using the reported spectrophotometric assay (Table I).(25)... 

Fluoroolefin Dipeptide isosteres Structure, Syntheses, and Appiications... 

Synthesis of funtionalized (Z)-fluoroalkene-type dipeptide isosteres (36) via Sml2-mediated reduction of y,y-difluoro-ot, -enoates 2.3.19. Reductive formation of fluoroolefins and subsequent conversion to diketopiperazine mimics (71). Nonpeptidic amide bond replacement... 

Fluoroolefin Dipeptide Isosteres Stmcture, Syntheses, and Applications 701... 

FLUOROOLEFIN DIPEPTIDE ISOSTERES 2.1. Alkenes as amide bond substitutes... 

The synthesis and utility of fluoroolefin peptide isosteres has previously been reviewed [45], The fluoroolefin isostere preparations summarized below are organized by the synthetic method employed to introduce the fluoroolefin rather than by the dipeptide isostere formed. 

The preparations of Glyi/r[CF=CH]Gly (4) and Phei/r[CF=CH]Gly (5) were described by Allmendinger and his coworkers [46,47]. The Gly-Gly fluoroolefin dipeptide isostere (4) was synthesized from cyclic acetal (6), obtained by the procedure of Dehmiow [48] involving a carbene insertion and reexpansion reaction. Further elaboration as detailed in Scheme 1 ultimately afforded the A/-protected amino acids (4). 

The Phe-Gly isostere (Z)-5 was prepared starting with the aldehyde (7b) (Scheme 2). The A/-Boc protected dipeptide isostere (Z)-5 was obtained as a racemate. 

Methyl fluoro(diethoxyphosphono)dithioacetate (34) has been prepared from difluorinated precursors [56], Fluorophosphonothioacetamides (35) derived from this dithioester, have been successfully transformed into highly functionalized fluoroalkenes (36). Judicious selection of the aldehyde coupling partner can lead expeditiously to the preparation of fluoroolefin dipeptide isosteres following elaboration of the carboethoxy group and desulfurization (Scheme 11). 

Horner-Emmons. The use of 2-fluoro-2-diethylphosphonoacetic acid (41) or acylfluorodiethylphosphonoacetate to prepare fluoroolefin dipeptide isostere precursors (42)... 

Otaka et al. reported the synthesis of (Z)-fluoroalkene dipeptide isosteres utilizing an organocopper-mediated reduction (Scheme 23) [69,70]. Reduction of 65 with Me2Cu(CN)Li2 2 LiBr-2 LiCI (4 equiv.) in THF-Et20 at -78°C for 15 min, proceeded unequivocally to yield the desired (Z)-fluoroalkene dipeptide isostere, eoc-Phei/r[(Z)-CF=CH]Gly-OEt (64) in 85% isolated yield. 

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