ANALOGUES OF (-)-PICROPODOPHYLLIN, SYNTHESIS AND USES THEREOF

Analogs of (-)-Picropodophyllin, synthesis thereof, and uses in pharmaceuticals as inhibitors of IGF1RK

A Convenient Synthesis of L-α-Vinylglycine from L-Homoserine Lactone

A procedure for the synthesis ofL-IX-vinylglycine from L-homoserine lactone is described. The route developed is convenient (only one chromatography step is required) and efficient (72 %; ≥ 95 % optical yield over 4 steps). Key features include the use of acid-labile protecting groups for the amino (Boc) and carboxyl (diphenylmethyl ester) groups, and the use of the phenylselenolate equivalent derived from sodium borohydride and diphenyl diselenide for L-homoserine lactone cleavage

Free α-Oxiranyl Amino Acids

Analogues of natural amino acids, in which the α-proton is replaced by an unsubstituted epoxide ring, are potential mechanism-based inhibitors for pyridoxal phosphate dependent enzymes.1 Yet, free α-oxiranyl amino acids have remained elusive until now. The synthesis of an α-(phenyl-substituted)oxiranyl amino ester has been reported. However, the accessibility and stability of the corresponding free, zwitterionic α-oxiranyl amino acid remained an open question.

Enantiomerically Enriched α-Methyl Amino Acids. Use of an Acyclic, Chiral Alanine-Derived Dianion with a High Diastereofacial Bias.

Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (−)-isopinocampheol; (2) (−)-trans-2-phenylcyclohexanol and (3) (−)-8-phenylmenthol. Sequential treatment of these esters with LDA (1.2 equiv.) and n-butyllithium (2.4 equiv.) at −78°C in THF generates the corresponding chiral dianions. Alkylation of each of these with benzyl bromide reveals that only the (−)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upon its derivative dianion. In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides. If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6. Of particular note, the alkylation with 3,4-bis(tert-butyldimethylsilyloxy)benzyl bromide (18) (94:6 diast. ratio, 72% yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched from. In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10% HMPA to the reaction milieu. The (−)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation. Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation. This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion

METHOD FOR THE SYNTHESIS OF α-OXRANYL AMINO ACIDS

The present invention is related to a novel class of decar-boxylase enzyme inhibitors consisting of α-oxiranyl amino acids and derivatives thereof and a method of synthesizing Such compounds

Synthesis of Higher α-Chlorovinyl and α-Bromovinyl Amino Acids: The Amino Protecting Group Determines the Reaction Course

N-Trifluoroacetyl α-vinyl amino esters are smoothly converted to the corresponding α-chlorovinyl or α-bromovinyl amino esters through the agency of phenyselenyl chloride or phenylselenyl bromide, respectively, followed by oxidation and pyrolysis. Exclusively the (E)-extemal halovinyl isomer and the internal halovinyl isomer are observed. The amino protecting group is a critical determinant of the reaction course (alkene addition vs. 5-exo-trig-like cyclization)

α-VINYLLYSINE AND α-VINYLARGININE ARE TIME-DEPENDENT INHIBITORS OF THEIR COGNATE DECARBOXYLASES

(±)-α-Vinyllysine and (±)-α-vinylarginine display time-dependent inhibition of L-lysine decarboxylase from B. cadaveris, and L-arginine decarboxylase from E. coli, respectively. A complete Kitz-Wilson analysis has been performed using a modification of the Palcic continuous UV assay for decarboxylase activity

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for \u3ci\u3eβ\u3c/i\u3e-elimination function

There is currently great interest in human serine racemase, the enzyme responsible for producing the NMDA co-agonist D-serine. Reported correlation of D-serine levels with disorders including Alzheimer’s disease, ALS, and ischemic brain damage (elevated D-serine) and schizophrenia (reduced D-serine) has further piqued this interest. Reported here is a structure/activity relationship study of position Ser84, the putative re-face base. In the most extreme case of functional reprogramming, the S84D mutant displays a dramatic reversal of β-elimination substrate specificity in favor of L-serine over the normally preferred L-serine-O-sulfate (~1200-fold change in kcat/Km ratios) and L (L-THA; ~5000-fold change in kcat/Km ratios) alternative substrates. On the other hand, the S84T (which performs L-Ser racemization activity), S84A (good kcat but high Km for L-THA elimination), and S84N mutants (nearly WT efficiency for L-Ser elimination) displayed intermediate activity, all showing a preference for the anionic substrates, but generally attenuated compared with the native enzyme. Inhibition studies with L-erythro-β-hydroxyaspartate follow this trend, with both WT serine racemase and the S84N mutant being competitively inhibited, with Ki = 31 ± 1.5 μM and 1.5 ± 0.1mM, respectively, and the S84D being inert to inhibition. Computational modeling pointed to a key role for residue Arg-135 in binding and properly positioning the L-THA and L-serine-O-sulfate substrates and the L-erythro-β-hydroxyaspartate inhibitor. Examination of available sequence data suggests that Arg-135 may have originated for L-THA-like-β-elimination function in earlier evolutionary variants, and examination of available structural data suggests that a Ser84-H2O-Lys114 hydrogen-bonding network in human serine racemase lowers the pKa of the Ser84 re-face base

Use of a Robust Dehydrogenase from an Archael Hyperthermophile in Asymmetric Catalysis–Dynamic Reductive Kinetic Resolution Entry into (S)-Profens

Hyperthermophilic archaea are of great interest in evolutionary microbiology, owing to their ability to withstand high temperatures, and often extremes of pressure, pH and salinity. Enzymes from these organisms1 may offer particular opportunities for asymmetric synthesis, complementary to approaches with mesophilic enzymes,2 or those involving enzyme3 and pathway4 reengineering. However, perhaps due to a bias that hyperthermophilic enzymes have “narrow substrate specificities,”5 archaeal extremophiles remain a largely untapped resource in asymmetric synthesis.6 Herein, we disclose a remarkably general Dynamic Reductive Kinetic Resolution (DYRKR) entry into (S)-profens, including several important NSAIDs. The enzyme employed is alcohol dehydrogenase (ADH)-10, one of 13 annotated ADHs in the hyperthermophile Sulfolobus solfataricus. Protein phylogenetic analysis of this paralogous family indicates SsADH-10 is most closely related to homologues in distant taxa (Fig. 1). The highest identity between SsADH-10 and any other SsADHs is only 34%, suggesting that the SsADH family was established prior to the emergence of other archaeal lineages. Though not described as such, the SsADH-10 appears to be the only SsADH isozyme for which structural information is available in the pdb.

Use of a Robust Dehydrogenase from an Archael Hyperthermophile in Asymmetric Catalysis–Dynamic Reductive Kinetic Resolution Entry into (S)-Profens

Hyperthermophilic archaea are of great interest in evolutionary microbiology, owing to their ability to withstand high temperatures, and often extremes of pressure, pH and salinity. Enzymes from these organisms1 may offer particular opportunities for asymmetric synthesis, complementary to approaches with mesophilic enzymes,2 or those involving enzyme3 and pathway4 reengineering. However, perhaps due to a bias that hyperthermophilic enzymes have “narrow substrate specificities,”5 archaeal extremophiles remain a largely untapped resource in asymmetric synthesis.6 Herein, we disclose a remarkably general Dynamic Reductive Kinetic Resolution (DYRKR) entry into (S)-profens, including several important NSAIDs. The enzyme employed is alcohol dehydrogenase (ADH)-10, one of 13 annotated ADHs in the hyperthermophile Sulfolobus solfataricus. Protein phylogenetic analysis of this paralogous family indicates SsADH-10 is most closely related to homologues in distant taxa (Fig. 1). The highest identity between SsADH-10 and any other SsADHs is only 34%, suggesting that the SsADH family was established prior to the emergence of other archaeal lineages. Though not described as such, the SsADH-10 appears to be the only SsADH isozyme for which structural information is available in the pdb.