Syntheses of all eight stereoisomers of conidendrin

ABSTRACT

All eight stereoisomers of conidendrin were synthesized from (1 R,2 S,3 S)-1-(4-benzyloxy-3-methoxyphenyl)-3-(4-benzyloxy-3-methoxybenzyl)-2- hydroxymethyl-1,4-butanediol ((+)-4) and its enantiomer with high optical purity. The configurations at 4-positions of the conidendrin stereoisomers were constructed by intramolecular Friedel-Crafts reaction of protected 4. After conversion to tetrahydronaphthalene intermediate 7a, the 2- and 3-position of tetrahydronaphthalene structure 7a were converted to 3a- and 9a-position of (+)-α-conidendrin (3a), respectively. By the epimerization process of 2- or 3-position of 7a, the other diastereomers were obtained. All enantiomers were also synthesized from (?)-4.     

Short-step syntheses of all stereoisomers of preussin and their bioactivities

All the eight stereoisomers of (+)-preussin (1b), an antifungal agent inhibiting the growth of fission yeast and human cancer cells, were synthesized in two steps by non-stereoselective reactions and chromatographic separation, starting from L- and D-N-protected-phenylalaninal (2). Their bioassay revealed all of the stereoisomers to be almost equally bioactive.     

Total synthesis and adjuvant activity of all stereoisomers of pinellic acid

Pinellic acid is a novel and potentially useful oral adjuvant when used in conjunction with intranasal inoculation of influenza HA vaccines. All stereoisomers of pinellic acid have been synthesized via regioselective asymmetric dihydroxylation, regioselective inversion, and stereoselective reduction, and their adjuvant activities were characterized. Among this series of isomers, 9S, 12S, 13S compound has the most potent adjuvant activity. Structure-activity relationships are discussed.     

Syntheses of sphingosine-1-phosphate stereoisomers and analogues and their interaction with EDG receptors

Sphingosine-1-phosphate (S1P) is considered to be an important regulator of diverse biological processes acting as a natural ligand to EDG receptors. As a preliminary study to develop potent and selective agonist and antagonist for EDG receptors, we report synthesis of S1P stereoisomers and analogues and their binding affinities to EDG-1, -3, and -5.     

Practical synthesis of all inositol stereoisomers from myo-inositol.

Synthesis of six inositol stereoisomers was successfully carried out via conduritol intermediates prepared from myo-inositol. Dihydroxylation and epoxidation followed by ring opening of the conduritol B, C and F derivatives gave epi-, allo-, muco-, neo-, DL-chiro- and scyllo-inositol. The cis-inositol derivative, which may not be prepared by this approach, was synthesized in 5 steps via 2-O-benzoyl-myo-inositol orthoformate as the key intermediate.     

Leucine-phenylalanine dipeptide-based N-mesyloxysuccinimides: synthesis of all four stereoisomers and their assay against serine proteases

The four stereoisomers of 3-(N-acetylleucylamino)-3-benzyl-1-[(methylsulfonyl)oxy]succinimid e have been prepared and shown to inhibit alpha-chymotrypsin and human neutrophil elastase. The structural and stereochemical features that affect the potency and selectivity of inhibition are discussed.     

Divergent syntheses of all stereoisomers of phytosphingosine and their use in the construction of a ceramide library

Sphingolipids such as ceramide and sphingosine-1-phosphate have recently attracted intense research interests because of their functional roles as signaling molecules in many important physiological processes, such as growth arrest, apoptosis, and inflammatory responses, and cell proliferation, vascular maturation and trafficking of lymphocytes. The well-defined modular structures of ceramides and related glycosylceramides are ideally amenable to library formation for medicinal chemistry investigation. We have developed divergent synthetic routes to all eight phytosphingosine stereoisomers and then proceeded to prepare phytosphingosine-based ceramide library composed of more than 500 compounds.     

Spirobiflavonoid stereoisomers from the endangered conifer Glyptostrobus pensilis and their protein tyrosine phosphatase 1B inhibitory activity

Six spirobiflavonoid stereoisomers including two new ones, spiropensilisols A (1) and B (2), were isolated from a mass-limited trunk barks of Glyptostrobus pensilis, an endangered conifer endemic to China. The new structures featuring a benzofuran-containing spirolactone and their absolute configurations were determined by extensive spectroscopic methods. All the isolates showed significant inhibitory activities against the human protein tyrosine phosphatase 1B (PTP1B) enzyme, a potential therapeutic target for diabetes and obesity, with IC₅₀ values ranging from 3.3 to 17.1 µM. A preliminary SAR analysis with assistance of the molecular modeling approach was performed for the most potent compound (i.e., 1), to understand the nature of interactions governing the binding mode of spirobiflavonids within the active site of the PTP1B enzyme.     

Total synthesis and cytotoxicity evaluation of all ochratoxin A stereoisomers

The mycotoxin ochratoxin A is a potent inhibitor of the protein biosynthesis and known to be cytotoxic in nanomolar concentrations. In order to investigate the relationship between stereochemistry and cytotoxicity of this compound, all four ochratoxin A stereoisomers have been synthesized. Using the liver cell line Hep G2, the compounds were tested for cytotoxic and apoptotic potential. It could be shown, that the l-configuration of the phenylalanine moiety of the molecule is mostly responsible for the high cytotoxicity of ochratoxin A while the stereocenter at the dihydroisocoumarine structure is of less importance.     

Asymmetric synthesis of all stereoisomers of 6-methylpipecolic acids

Summary.  Asymmetric synthesis of all four stereoisomers of 6-methylpipecolic acids with high enantiomeric purity via iterative AD reaction, starting from 1,6-heptadiene, has been described. Received March 25, 2002 Accepted June 15, 2002 Published online January 30, 2003 Authors' address: Hiroki Takahata, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan, E-mail: takahata@tohoku-pharm.ac.jp RID="*" ID="*"  The stereo-configurations of 8 and 9 in Fig. 3 and 12 in Fig. 4 show only major isomers. RID="**" ID="**"  The absolute configurations of 11 and 14     

Synthesis of all stereoisomers of 3-hydroxypipecolic acid and 3-hydroxy-4,5-dehydropipecolic acid and their evaluation as glycosidase inhibitors

A highly practicable synthesis of both enantiomers of 3-hydroxypipecolic acid derivatives 1, 2, 3, 4 is described. Screening of these molecules for glycosidase inhibition has been examined. Compound 3 was shown to be a potent inhibitor of beta-N-acetylglucosaminidase as well as Escherichia coli beta-glucuronidase.     

Syntheses of sulfated glycopolymers and analyses of their BACE-1 inhibitory activity

The glycopolymers for glycosaminoglycan mimic were synthesized, and the inhibitory effects of Alzheimer’s β-secretase (BACE-1) were examined. The regio-selective sulfation was conducted on N-acetyl glucosamine (GlcNAc), and the acrylamide derivatives were synthesized with the consequent sulfated GlcNAc. The glycopolymers were synthesized with acrylamide using radical initiator. The glycopolymer with sulfated GlcNAc showed the strong inhibitory effect on BACE-1, and the inhibitory effects were dependent on the sulfation positions. Especially, glycopolymers carrying 3,4,6-O-sulfo-GlcNAc showed the strong inhibitory effect. The docking simulation suggested that glycopolymers bind to the active site of BACE-1.     

Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin

All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration–activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.     

Synthesis of all four stereoisomers of 3-amino-2-hydroxybutanoic acids

All four stereoisomers of 3-amino-2-hydroxybutanoic acids were been obtained as single enantiomers via stereospecific reactions from D-gulonic acid gamma-lactone and D-glucono-delta-lactone.     

Syntheses of immunomodulating androstanes and stigmastanes: comparison of their TNF-alpha inhibitory activity

In a previous work our group showed that some synthetic stigmastanes may play a role in immune-mediated inflammation. In this paper we report the syntheses of a series of new steroidal compounds derived from dehydroepiandrosterone and stigmasterol, and the evaluation of their in vitro inhibitory activity of the TNF-α production by macrophages. A preliminary qualitative structure–activity relationship was established.     

A simple synthesis of four stereoisomers of roseoside and their inhibitory activity on leukotriene release from mice bone marrow-derived cultured mast cells

Four stereoisomers of roseoside (vomifoliol glucosides) were synthesized using glucose as a chiral resolving reagent. The four synthetic stereoisomers exhibited inhibitory activity on leukotriene release from mouse bone marrow-derived cultured mast cells (BMCMC). The (6S)-isomers of roseoside were about twice as active as (6R)-isomers.     

Syntheses of tetrahydroxyazepanes from chiro-inositols and their evaluation as glycosidase inhibitors

Two pairs of C(2)-symmetric tetrahydroxyazepanes [(-), (+)-1 and (-), (+)-2] have been synthesized from the enantiomeric chiro-inositols and evaluated as glycosidase inhibitors. Alternative syntheses of ido-tetrahydroxyazepanes (-)- and (+)-2 from myo-inositol were also developed. The key synthetic transformations were glycol fission and cyclization of the derived dialdehydes by double reductive amination. The D-manno-tetrahydroxyazepane [(-)-1] showed selective inhibition of alpha-L-fucosidase and beta-D-galactosidase, while the enantiomer [(+)-1] was a selective inhibitor of an alpha-D-galactosidase. In contrast, the L-ido-tetrahydroxyazepane (+)-2 was a broad spectrum hexosidase inhibitor, but showed none of the reported hexosaminidase inhibition. Its enantiomer (-)-2 is a poor hexosidase inhibitor.     

Syntheses of ferulic acid derivatives and their suppressive effects on cyclooxygenase-2 promoter activity

Novel ferulic acid derivatives in which feruloyl groups were attached to the hydroxyl groups of myo-inositol 1,3,5-orthoformate derivatives were synthesized. These feruloyl-myo-inositols suppressed the cyclooxygenase-2 (COX-2) promoter activity in a concentration-dependent manner. Among the examined compounds, compound 9 showed the highest activity. A treatment with 100 microM of compound 9 for 24 h resulted in a 50% decrease of COX-2 promoter activity without marked cytotoxicity. Both the molecular structure in which two ferulic acid moieties are facing each other and the molecular hydrophobicity may be essential for the suppression of COX-2 promoter activity.     

Efficient access to all four stereoisomers of phenylalanine cyclopropane analogues by chiral HPLC

Bonded polysaccharide‐derived chiral stationary phases were found to be useful for the preparation of the four stereoisomers of the cyclopropane analogue of phenylalanine (c₃Phe) as well as for the direct determination of the enantiomeric purity of c₃Phe derivatives by HPLC. Three chiral stationary phases, consisting of cellulose and amylose derivatives chemically bonded on allylsilica gel, were tested. The mixed 10‐undecenoate/3,5‐dimethylphenylcarbamate of cellulose, 10‐undecenoate/3,5‐dimethylphenylcarbamate of amylose and 10‐undecenoate/p‐methylbenzoate of cellulose were the starting polysaccharide derivatives for CSP‐1, CSP‐2, and CSP‐3, respectively. Using mixtures of n‐hexane/chloroform/2‐propanol as mobile phase on a semi‐preparative column (150 mm × 20 mm ID) containing CSP‐2, we separated about 1.7 g of racemic cis‐methyl 1‐tert‐butoxycarbonylamino‐2‐phenylcyclopropanecarboxylate (cis‐ 6 ) and 1.2 g of racemic trans‐methyl‐1‐tert‐butoxycarbonylamino‐2‐phenylcycloprop‐anecarboxylate (trans‐ 6 ) by successive injections. Chirality 11:583–590, 1999. © 1999 Wiley‐Liss, Inc.