Cyclohexylalanine

Modification of the amino acid residues located on the N-terminal side of Pro was shown to have a major influence on the rate of cyclic dipeptide formation. For the series of dipeptide analogues of X-Pro-/>NA, the half-lives of cyclic dipeptide formation in 0.5 molG phosphate buffer (pH 7) at 37 °C were reported as follows X = Gly 5.1 days, X = Val 2.5 days, X = Ala 1.1 days, X = /3-cyclohexylalanine 0.8 days, X = Arg 0.7 days, and X = Phe 0.5 days. Increased bulkiness of alkyl and aryl substituents have been previously shown to increase the rate of cyclization due to intramolecular reactions. This however does not seem true for the series studied by Goolcharran and Borchardt as the Ala analogue cyclized twice as fast as the bulkier analogue. From the study it is evident that simple steric bulk of substituents alone cannot be used to effectively explain the effects involved in the formation of cyclic dipeptides from various peptide precursors. 

The intense interest in y - am i n o - (i -hydroxy acid related peptides has led to a great deal of effort devoted to their synthesis. Statine analogues Ahppa (11), Achpa (12), and Dahoa (13) (Scheme 2), which correspond to the replacement of the chain equivalent of leucine in statine by those of phenylalanine, cyclohexylalanine, and lysine, respectively, were used to synthesize inhibitors of pepsin, renin, and penicillinopepsinJ1314] With the objective of developing highly specific inhibitors, C2-substituted analogues have also been introduced into short, substrate-derived inhibitors, e.g. the a,a-difluoro statine 14 in renin inhibitors,1151 and N -substituted statine derivatives like 15 in HIV-1 protease inhibitors.[16]... 

Thus, our studies examined the effect of these incorporations on H3 receptor affinity by making ligands that could be envisioned synthetically by modifying the two structural features A and B of 29 illustrated in figure 18 A 2-carbon straight chain vs trans cyclopropyl ring and B amide-oxime array vs the other spacers depicted in figure 17. For the purpose of these SAR studies, we used the cyclohexyl or phenyl tail which were available from commercially available (S)-N-Boc-cyclohexylalanine or (S)-N-Boc-phenylalanine. 

The cyclopropyl analogs of GT-2140 (Table 1), GT-2163 37 and GT-2164 38 (figure 21), were prepared by coupling 34 and 35 with (S)-N-BOC-cyclohexylalanine followed by deprotection. The binding affinities obtained for these derivatives... 

Cyclopropane compounds containing the olefin isostere replacement for the amide bond were prepared using Julia olefination chemistry. Aldehydes 39 and 40 were obtained by LAAIH4 reduction of the chiral w-butyl esters of 32 and 33, respectively, followed by swera oxidation of the corresponding alcohols (Figure 22). Condensation of the (S)-N-BOC-cyclohexylalanine sulfone 41 with aldehyde 39 gave after treatment with 2% Na(Hg) and deprotection, the trans and cis olefin-amines... 

In the laboratory of E.B. Pedersen, several 2-methylsulfanyl-1H-imidazoles were prepared and tested for their activity against HIV-1 These compounds can be regarded as novel non-nucleoside reverse transcriptase inhibitors. The required a-aminoketone hydrochloride building blocks were prepared using the Dakin-West reaction. L-Cyclohexylalanine was dissolved in excess pyridine and propionic anhydride and was kept at reflux overnight. The resulting a-propionylamino ethyl ketone was hydrolyzed with concentrated hydrochloric acid and the a-aminoketone hydrochloride was heated with one equivalent of potassium thiocyanate in water to afford 4-cyclohexylmethyl-5-ethyl-1,3-dihydroimidazole-2-thione. This material was then advanced to 4-cyclohexylmethyl-1-ethoxymethyl-5-ethyl-2-methylsulfanyl-IH-imidazole. 

CoA) reductase] are prescribed chronically to the elderly (162). The initial success of statins was impressive and the FDA approved six of them (22-27,Fig. 13.7) (163).Although all approved statins have been associated with a very low incidence of rhabdomyolysis, only one, cerivastatin (27), was withdrawn from the U.S. market because of it (164,165). The ability of statins to reduce the levels of A/3s in vitro and in vivo was reported (85, 86, 166, 167) but at doses exceeding the approved human dosage. A cyclohexylalanine-based statin... 

Cha5, Cha6, Cha9, Cha10 [-AA (Cha = Cyclohexylalanine) Perhydro-antamanide 2x 103 >10... 

Synthesis of the perfluoroalkyl P-amino alcohol 5 (70) required for the preparation of the perfluoroalkyl ketone VI as shown in Scheme 2 is illustrative of the method used to prepare analogous compounds. Tm-butyloxycarbonyl-L-cyclohexylalaninal 4 was condensed with perfluoroethyl or perfluoropropyl lithium which was generated in situ by the addition of methyllithium-lithium bromide complex to the corresponding perfluoroalkyl iodide. The alcohol 5 was isolated as an epimeric mixture which was used in the preparation of peptide IV. Oxidation using the Dess-Martin periodinane reagent (9) yielded the fluoroketone VI. 

Cotton effect is detected in the n-n transitions at 334 nm, but the maximum at 252 nm, which is probably related to the n-n intramolecular charge-transfer band, is optically active. Most dansyl-L-amino acids show a positive Cotton effect centered at about 260 nm in methanol, but four derivatives (phenylalanine, jS-cyclohexylalanine, methionine, and leucine) exhibit negative Cotton effects (Polonski et a/., 1974). It is assumed that the reversal of the... 

The occurrence of numerous secondary metabolites and the unusual structural elements l-a-aminobutyric acid, D-alanine, and the C9-amino acid (2S,3/(,4/(,6 )-2-amino-3-hydroxy-4-methyl-6-octenoic acid [(4/ )-4-(( )-2-butenyl)-4-methyl-L-threonine=Bmt] indicate that this peptide is not produced ribosomally but rather post-translationally by a multi-enzyme complex. Additionally offered foreign amino acids are incorporated, e.g., further cyclosporins are obtained in directed biosyntheses by replacement of the a-aminobutyric acid in position 2 by D- or L-allylglycine, of d-alanine in position 8 by D-setine or 3-fluoroalanine, and of butenylmethylthreonine in position 1 by L-/S-cyclohexylalanine... 

Incorporation of foreign amino acids into various positions can also be attained, as illustrated by the formation of [L AIlylgly jCyA when DL-ot-allylglycine is fed as precursor. Exogenously supplied L-3-cyclohexylalanine results in a predominant production of [MeCyclohexylalai]CyA (replacement of MeBmt). It is noteworthy that DL-threo-3-cyclohexylserine, a closer mimetic to Bmt, was not incorporated into cyclosporins by the organism only the usual pattern of cyclosporins A, B, and C was observed. 

An improved preparation of (S)-N-(Boc)-cyclohexylalaninal by application of the Moffatt-Swern oxidation of a-amino alcohols has been described [1346]. MofFatt-Swern oxidation of protected (S)-alcohol 1803 with DMSO/(COCl)2/Et3N/... 

Af-a-(9-fluorenylmethoxycarbonyl)--(D,L)-valine -(D,L)-phenylalanine -(D,L)-Ieucine -(D,L)-norleucine -(D,L)-proline -(D,L)-norv aline -(D, L)-try ptophan -(D,L)-alanine -(D,L)-/3-cyclohexylalanine -(D,L)-methionine Tryptophan Tryptophanamide a-methyltry ptophan 1 -methy Itryptophan 4-melhyltryptophan... 

L-Cyclohexylalanine(C7) L-Asparagioe (C8) L-Glutamine (C9) L-t-Bulylglycine (CIO) L-Glutamic acid (ClI) L-Serine(C12)... 

Fig. 10. CD spectra of poly-cyclohexylalanine in 59.1% methanesulfonic acid, immediately after the preparation of the solution (curve 1) and 2 hr after the preparation of the solution (curve 2) from ref. [32a]). See the original paper for the experimental details.

Figure 13.27 Reductive amination of cyclohexyl pyruvate to D-cyclohexylalanine (a precursor to inogatran) by engineered amino acid dehydrogenase.

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