Efficient asymmetric synthesis of (R)-3-hydroxy- and alkanoyloxytetradecanoic acids and method for the determination of enantiomeric purity

Keegan, David S.; Hagen, Steven R.; Johnson, David A.

doi:10.1016/s0957-4166(96)00464-8

Cited by 32 publications

(26 citation statements)

References 16 publications

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“…A number of other reaction conditions led to the formation of mixtures of regioisomeric benzyl ethers. For example, the use of BH 3 .NHMe 2 in DCM, which is the conventional solvent for this reagent, 30 gave a mixture of products .Glycosyl donor 4 31 and fatty acids 6 ,26 7 and 8 32,33 were prepared by reported procedures.…”

Section: Chemical Synthesismentioning

confidence: 99%

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

2007

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LPS from Rhizobium sin-1 (R. sin-1) can antagonize the production of tumor necrosis factor alpha (TNF-α) by E. coli LPS in human monocytic cells. Therefore these compounds provide interesting leads for the development of therapeutics for the prevention or treatment of septic shock. Detailed structure activity relationship studies have, however, been hampered by the propensity of these compounds to undergo β-elimination to give biological inactive enone derivatives. To address this problem, we have chemically synthesized in a convergent manner a R. sin-1 lipid A derivative in which the β-hydroxy ester at C-3 of the proximal sugar unit has been replaced by an ether linked moiety. As expected, this derivative exhibited a much-improved chemical stability. Furthermore, its ability to antagonize TNF-α production induced by enteric LPS was only slightly smaller than that of the parent ester modified derivative demonstrating that the ether-linked lipids affect biological activities only marginally. Furthermore, it has been shown for the first time that R. sin-1 LPS and the ether modified lipid A are also able to antagonize the production of the cytokine interferoninducible protein 10, which arises from the TRIF-dependent pathway. The latter pathway was somewhat more potently inhibited than the MyD88-dependent pathway. Furthermore, it was observed that the natural LPS possesses much greater activity than the synthetic and isolated lipid As, which indicates that di-KDO moiety is important for optimal biological activity. It has also been found that isolated R. sin-1 LPS and lipid A agonize a mouse macrophage cell line to induce the production of TNF-α and interferon beta in a Toll-like receptor 4-dependent manner demonstrating species specific properties.

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Section: Chemical Synthesismentioning

confidence: 99%

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

2007

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“…The synthesis of the requisite (R)-3-hydroxy-and alkanoyloxytetradecanoic acid starting materials 8 and 9 was initially achieved by Ru(II)-Binap-catalyzed hydrogenation of keto ester 10 in the key step and subsequent enantiomeric enhancement by crystallization of the dicyclohexylammonium (DCHA) salt of 11 (Scheme 2) [27]. Reproducibility problems with commercial Ru(II) catalysts as well as difficulties in removing the DCHA-HBr by-product in the preparation of p-bromophenacyl (PAc) ester 12 were overcome by using Genet's in-situ-Ru(II) asymmetric hydrogenation method [28] and e.e.…”

Section: IImentioning

confidence: 99%

Synthetic TLR4-active Glycolipids as Vaccine Adjuvants and Stand-alone Immunotherapeutics

Johnson¹

2008

CTMC

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The design of vaccine adjuvants and stand-alone immunotherapeutics has historically been a mix of alchemy and accident partly because of the complex nature of the molecular mechanisms involved in immune system function. The recent discovery of pattern recognition receptors and toll-like receptors (TLRs) in particular on cells of the immune system has shown the important role that stimulation of these cell receptors by microbial products plays in both innate and adaptive immune responses. Considerable effort has been directed at developing pharmaceutically acceptable mimetics of many TLR-active natural products, including the main cell-surface component of Gram-negative bacteria: lipopolysaccharide (LPS). LPS and its active principle, lipid A, are potent stimulators of host defense systems via their interaction with TLR4. However, the profound pyrogenicity and lethal toxicity of LPS and lipid A have precluded their medicinal use. Structure/activity investigations on natural S. minnesota R595 lipid A and its derivatives have led to the development of a novel class of synthetic lipid A mimetics known as aminoalkyl glucosaminide phosphates (AGPs). This review discusses the evolution of the AGPs and related TLR4-active glycolipids with emphasis on structure/activity relationships in the AGP series and pre-clinical/clinical development of selected AGPs, including the potent vaccine adjuvant RC-529.

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“…The Noyori catalyst, RuCl 2 [(R)-BINAP], can be used for the catalytic reduction of esters of 3-oxo carboxylic acids with H 2 [43]. A high yield and ee >98% can be achieved with H 2 pressures of 100 atm (Scheme 9, entry ii) [44].…”

Section: Chemical Reductionmentioning

confidence: 99%

Asymmetric Synthesis of α-Unsubstituted β-Hydroxy Acids

Alberício¹

2008

COS

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Efficient asymmetric synthesis of (R)-3-hydroxy- and alkanoyloxytetradecanoic acids and method for the determination of enantiomeric purity

Cited by 32 publications

References 16 publications

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

Synthetic TLR4-active Glycolipids as Vaccine Adjuvants and Stand-alone Immunotherapeutics

Asymmetric Synthesis of α-Unsubstituted β-Hydroxy Acids

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Efficient asymmetric synthesis of (R)-3-hydroxy- and alkanoyloxytetradecanoic acids and method for the determination of enantiomeric purity

Cited by 32 publications

References 16 publications

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

Synthetic TLR4-active Glycolipids as Vaccine Adjuvants and Stand-alone Immunotherapeutics

Asymmetric Synthesis of &#945;-Unsubstituted &#946;-Hydroxy Acids

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Asymmetric Synthesis of α-Unsubstituted β-Hydroxy Acids