Catalytic enantioselective intramolecular Tishchenko reaction of meso-dialdehyde: synthesis of (S)-cedarmycins

The first successful example of a catalytic enantioselective intramolecular Tishchenko reaction of a meso-dialdehyde in the presence of a chiral iridium complex is described. Chiral lactones were obtained in good yields with up to 91% ee. The obtained enantioenriched lactones were utilized for the first synthesis of (S)-cedarmycins A and B.

The first successful example of a catalytic enantioselective intramolecular Tishchenko reaction of a meso-dialdehyde in the presence of a chiral iridium complex is described.

The catalytic dimerization of aldehydes giving the corresponding esters was first discovered by Claisen in 1887,¹ and is now well known as the “Tishchenko reaction” (Scheme 1).Open in a separate windowScheme 1Tishchenko reaction.Claisen''s method utilizing sodium alkoxides, however, could only be applied to nonenolizable aldehydes like benzaldehyde, because enolizable aldehydes undergo aldol reactions when treated with strong bases such as sodium alkoxides.¹ In 1906, a Russian chemist, Tishchenko, reported that aluminum alkoxides were superior to sodium alkoxides in the reaction, because they were more Lewis acidic and less basic.² The transformation of acetaldehyde into ethyl acetate is the representative application of the Tishchenko reaction in the chemical industry.³ So far, a number of homogeneous catalysts exhibiting high catalytic performance for the Tishchenko reaction have been developed to compensate for the drawback of the classical aluminum alkoxide catalysts.⁴ In 2005, we reported a mild Tishchenko dimerization using a Ir catalyst.⁵ The reaction proceeds at room temperature and is effective with a wide range of aldehydes. We also reported the enantioselective oxidative lactonization⁶ of meso-diols for the preparation of chiral lactones.⁷ Although asymmetric aldol-Tishchenko reactions⁸ for chiral 1,3-diols are known, there is no report of an asymmetric intramolecular Tishchenko reaction of meso-dialdehydes for chiral lactones. We envisaged that the asymmetric borrowing hydrogen methodology⁹ could be applied to achieve an enantioselective intramolecular Tishchenko reaction of meso-dialdehydes (Scheme 2).Open in a separate windowScheme 2Strategies for enantioselective intramolecular Tishchenko reaction.The initial enantioselective reduction of meso-dialdehyde 1 could occur by a chiral 18 electron Ir hydride complex to afford chiral hydroxy aldehyde 2. The hydroxy aldehyde-lactol equilibrium would generate lactol 3. Finally, irreversible oxidation of 3 would produce the desired lactone 4.With this hypothesis in mind, we began the investigation of the intramolecular Tishchenko reaction using o-phthalaldehyde as a model substrate (10ⁱPrOH, and K₂CO₃ (6a : 5a : ⁱPrOH : K₂CO₃ = 100 : 1 : 20 : 20 mol ratio) was stirred at 30 °C for 7 h, lactone (7a) was obtained in 97% yield (entry 1). The reaction did not proceed at all in the absence of Ir catalyst (entry 2). Interestingly, the reaction without the additional hydrogen donor, ⁱPrOH, also gave the lactone, but the yield was low (entry 3). To enhance the reactivity, the addition of a base was necessary.^5a Without base or with a lower amount of base, the reaction proceeded in less than 28% yield (entries 4, 5). The reaction of 2,3-naphthalene dicarboxaldehyde 6b also proceeded similarly under optimized conditions (entry 6).Intramolecular Tishchenko reaction of aromatic dialdehydes^a

Severe Acute Cholangitis and Bacteremia Due to Campylobacter jejuni: A Case Report and Review of the Literature

Campylobacter jejuni is common cause of enteritis, but biliary infection rarely reported. An 82-year-old woman with pancreatic head cancer underwent endoscopic biliary drainage for malignant biliary obstruction. She was subsequently admitted for management of diarrhea. C. jejuni was identified in stool culture. Her symptoms resolved temporarily without antibiotics but flared up with a fever a few days later. She was diagnosed with acute cholangitis and bacteremia with C. jejuni. Endoscopic biliary drainage and antimicrobial administration improved her symptoms. As complications of C. jejuni diarrhea are rare, antibiotics are not necessarily indicated but sometimes are needed to prevent complications.     

Motor and learning dysfunction during postnatal development in mice defective in dopamine neuronal transmission

Mice lacking expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme of the catecholamine biosynthetic pathway, in dopaminergic neuronal cell types were generated by a transgenic rescue approach to clarify the role of dopamine signaling during postnatal development. Introduction of the TH transgene directed by the dopamine β-hydroxylase gene promoter into TH knockout mice restored noradrenaline and adrenaline synthesis, preventing perinatal lethality and cardiac dysfunction in the knockout mice. Lack of TH expression in the cells that normally express the dopaminergic phenotype resulted in a marked reduction of dopamine accumulation in the tissues, which led to multiple behavioral abnormalities at the juvenile stage. These abnormalities were characterized by a reduction in spontaneous locomotor activity, blockade of methamphetamine-induced hyperactivity, cataleptic behavior, and defects in active avoidance learning. In contrast, development of the pituitary gland as well as production and secretion of the pituitary peptide hormones dependent on hypothalamic dopaminergic control were normally maintained, despite defective dopamine synthesis. These results demonstrate that dopamine neurotransmission is essential for controlling spontaneous and voluntary movement and associative learning during postnatal development through the nigrostriatal and mesocorticolimbic pathways. J. Neurosci. Res. 54: 450–464, 1998. © 1998 Wiley-Liss, Inc.     

Prospects for safety testing: Initial consideration for use of transgenic mutation assays in a regulatory submission

As an initial consideration for use of TM assays in a regulatory submission, we focus here especially on the following questions: (1) What conditions would trigger the performance of a TM assay? (2) What data set is sufficient to support a negative result? and (3) What increase in mutation frequency is considered to be a positive result? In the first question, we discuss outcomes from traditional tests such as RM, CA, GM, and MN assays. In the second question, we propose a provisional data set including several items, i.e., experimental size [number of animals per group, number of plaques per animal (tissue)], tissue selection, route of administration, top dose level, number of dosings (single vs. multiple), sampling time, number of samples, dose levels, and positive and negative controls. Some statistical and biological considerations are needed for the third question. © 1996 Wiley-Liss, Inc.     

Hepatocyte growth factor stimulates cell growth and enhances the expression of transforming growth factor α mRNA in AsPC-1 human pancreatic cancer cells

We investigated the effects of hepatocyte growth factor (HGF) and transforming growth factor α (TGF α) on cell growth in four human pancreatic cancer cell lines. Changes in the expression of mRNAs of HGF, c-met, TGF α, and epidermal growth factor receptor (EGFR) by treatment with HGF and TGF α were observed. Cell growth with growth factors was assessed with the MTT assay and compared with basal growth without growth factors. Although HGF stimulated cell growth in AsPC-1, COLO-357, and T3M4 cells, Panc-1 cells showed no response to HGF. TGF α stimulated the growth of all the above cells. The expression of c-met mRNA under nonstimulated conditions was detected with Northern blotting in all cells. Treatment with HGF slightly enhanced the expression of c-met mRNA only in COLO-357 cells. The intensity of EGFR expression was consistent, and HGF mRNA was not detected during induction experiments in any cell type. Concomitant treatment with HGF and TGF α exerted an effect that was additive or less on the growth of all cells. Expression of TGF α was enhanced by HGF treatment only in AsPC-1 cells. These results suggested that HGF and TGF α stimulated cell growth through a final common pathway of signal transduction. Received: November 11, 1998 / Accepted: December 18, 1998     

Aberrant production of gliostatin/platelet-derived endothelial cell growth factor in rheumatoid synovium

Objective. To purify a protein inhibitor from rheumatoid arthritis (RA) synovial fluids which suppresses the apparent incorporation of ³H-thymidine into fibroblasts and synovial cells, and to define its biochemical features that have clinical relevance to the pathogenesis of RA. Methods. Several standard chromatographic techniques were employed for the purification of the protein. Immunochemical methods with monoclonal antibody were used to quantify and visualize the protein in sera, synovial fluids, and tissues from RA patients. Results. The chemical properties of purified inhibitor from RA synovial fluids confirmed its identity as gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF), a potent angiogenic factor. The gliostatin/ PD-ECGF level in synovial fluid and serum was higher in RA patients than in osteoarthritis controls. Conclusion. These findings strongly suggest that gliostatin/PD-ECGF might play an important role in the aberrant neovascularization of rheumatoid synovium.     

Water immersion delays the oxygen uptake response to sitting arm-cranking in humans

We investigated the effect of central hypervolaemia during water immersion up to the xiphoid process on the oxygen uptake (V˙O₂) and heart rate (HR) response to arm cranking. Seven men performed a 6-min arm-cranking exercise at an intensity requiring a V˙O₂ at 80% ventilatory threshold both in air [C trial, 29 (SD 9)?W] and immersed in water [WI trial, 29 (SD 11)?W] after 6 min of sitting. The V˙O₂ (phase 2) and HR responses to exercise were obtained from a mono-exponential fit [f(t)=baseline+gain·(1?e^{?( t ? TD )/})]. The response was evaluated by the mean response time [MRT; sum of time constant () and time delay (TD)]. No significant difference in V˙O₂ and HR gains between the C and WI trials was observed [V˙O₂ 0.78 (SD 0.1) vs 0.80 (SD 0.2) l?·?min^?1, HR 36 (SD 7) vs 37 (SD 8) beats?·?min^?1, respectively]. Although the HR MRT was not significantly different between the C and WI trials [17 (SD 3), 19 (SD 8)?s, respectively), V˙O₂ MRT was greater in the WI trial than in the C trial [40 (SD 6), 45 (SD 6)?s, respectively; P<0.05]. Assuming no difference in V˙O₂ in active muscle between the two trials, these results would indicate that an increased oxygen store and/or an altered response in muscle blood distribution delayed the V˙O₂ response to exercise.     

Behavioural assessment as substance P antagonists in mice

A series of eleven undeca- and four hexapeptide antagonists of substance P (SP) have been assayed by the SP-induced behavioural test in mice. When 2 nmol of [D-Arg1, D-Pro, D-Trp, Leu]-SP (SP 1-11 I) was intrathecally injected together with SP (0.1 nmol), SP-induced response which consists of scratching, biting and licking was markedly inhibited. [D-Trp, Leu]-SP 6-11 (SP 6-11 I) given in a dose of 2 nmol was also inhibited the SP-induced response to the same degree as SP 1-11 I. Some of SP 1-11 or SP 6-11 analogues substituted with fluorine in positions 7 and/or 8 maintained the antagonistic effect of SP 1-11 I or SP 6-11 I, though the others were weaker. Intrathecal administration of SP 1-11 I and SP 6-11 I resulted in long-lasting antinociceptive effects as measured by the tail-flick test. Fluorine-containing SP analogues were less potent than the above two analogues in producing antinociception. These results suggest that the antagonistic effect of SP analogues on the SP-induced nociceptive response do not necessarily relate to antinociceptive activity at the spinal cord level.