An efficient synthetic route was developed to prepare substituted d-lactones 1 and 2 in enantiopure forms which are potentially useful for biosynthetic studies with genetically engineered modular polyketide synthase (PKS). The key step to prepare the target epimeric lactones involves the samarium(II) iodide-mediated Reformatsky reaction.Modular polyketide synthases (PKSs) are giant multienzyme complexes to produce structurally diverse natural products by successive cycles of chain extension. 1 'Nonnatural' natural products from the hybrid modular PKSs have attracted much attention in connection with natural product drug discovery and development by so-called 'Combinatorial Biosynthesis'. Smaller hybrid PKS systems such as DEBS1 (DEBS = 6-deoxyerythronolide B synthase)+TE (thioesterase), 2 or DEBS1-TE 3 truncated versions of the erythromycin PKS, both of which containing the first two modules of 6-deoxyerythronolide B fused to the TE domain, have been extensively utilized in order to facilitate the detailed investigations on the biosynthesis of 6-deoxyerythronolide B. These hybrid PKSs are responsible for producing smaller lactones. 4In connection with the generation of hybrid PKSs derived from the pikromycin PKS system, 5 we are interested in the following d-lactones 1 and 2. The synthesis of these lactones would facilitate the identification and isolation of the lactones produced by hybrid PKSs. Herein, we wish to report a successful and practical synthetic route to prepare both enantiopure lactones 1 and 2 utilizing aldol and the Reformatsky reactions as key synthetic steps to secure the desired stereochemical relationships. Although both lactones has been reported to be isolated in connection with the study on the bimodular polyketide synthase based on domain or modular exchanges, they have not been chemically prepared yet. 6 Synthesis of both lactones could be achieved by coupling between the fragments A and B shown in the retrosynthetic scheme (Scheme 1). The synthetic scheme for the aldehyde fragment (Scheme 2) is quite straightforward and involves boron enolate aldol reaction 7 with the known propionate oxazolidinone 3 to produce the required two stereogenic centers. After protection of the OH group, reduction to remove the chiral auxiliary followed by the Swern oxidation gave the desired known aldehyde 7 in good yield overall. 4f
AIMTo investigate the clinical utility of biological age (BA) measurement in screening colonoscopy for the detection of colorectal adenomas in the average-risk population.METHODSA consecutive series of asymptomatic subjects aged ≥ 30 years who underwent colonoscopy in routine check-ups were enrolled. Colorectal adenoma was classified according to size, number, and location. BAs were calculated using the MEDIAGETM Biological Age Measurement System.RESULTSA total of 2696 subjects were investigated (1876 men and 820 women). The mean chronological age (CA) was 46.0 years and the mean BA was 44.7 years. Metabolic syndrome (MS) was diagnosed in 218 subjects (8.1%). The prevalence of overall colorectal adenoma was 23.1% (622/2,696). When the subjects were divided into four groups based on BA (≤ 39 years; 40-49 years; 50-59 years; ≥ 60 years), the prevalence of colorectal adenoma was increased as BA increased (P < 0.001). Colorectal adenoma located in the proximal colon was more prevalent in the BA-dominant group (BA-CA ≥ 5 years) than the CA-dominant group (CA-BA ≥ 5 years) (P = 0.034). When the subjects were categorized into four groups according to MS and age gap between BA and CA, the incidence of colorectal adenoma increased with MS and BA-dominance (P < 0.05).CONCLUSIONMeasurement of BA may help to assess the risk of colorectal adenoma in screening colonoscopy.
To accomplish minimizing feature size to sub 100nm, new light sources for photolithography are emerging, such as ArF(193nm), F2(157nm), and EUV(13nm). However as the pattern size decreases to sub 100nm, a new obstacle, that is pattern collapse problem, becomes most serious bottleneck to the road for the sub 100 nm lithography. The main reason for this pattern collapse problem is capillary force that is increased as the pattern size decreases. As a result there were some trials to decrease this capillary force by changing developer or rinse materials that had low surface tension. On the other hands, there were other efforts to increase adhesion between resists and sub materials (organic BARC).In this study, we will propose a novel approach to solve pattern collapse problems by increasing contact area between sub material (organic BARC) and resist pattern. The basic concept of this approach is that if nano-scale topology is made at the sub material, the contact area between sub materials and resist will be increased. The process scheme was like this. First after coating and baking of organic BARC material, the nano-scale topology (3~10nm) was made by etching at this organic BARC material. On this nano-scale topology, resist was coated and exposed. Finally after develop, the contact area between organic BARC and resist could be increased. Though nano-scale topology was made by etching technology, this 20nm topology variation induced large substrate reflectivity of 4.2% and as a result the pattern fidelity was not so good at 100nm 1:1 island pattern. So we needed a new method to improve pattern fidelity problem. This pattern fidelity problem could be solved by introducing a sacrificial BARC layer. The process scheme was like this. First organic BARC was coated of which k value was about 0.64 and then sacrificial BARC layer was coated of which k value was about 0.18 on the organic BARC. The nano-scale topology (1~4nm) was made by etching of this sacrificial BARC layer material and then as the same method mentioned above, the contact area between sacrificial layer and resist could be increased. With this introduction of sacrificial layer, the substrate reflectivity of sacrificial BARC layer was decreased enormously to 0.2% though there is 20nm topology variation of sacrificial BARC layer. With this sacrificial BARC layer, we could get 100nm 1:1 L/S pattern. With conventional process, the minimum CD where no collapse occurred, was 96.5nm. By applying this sacrificial BARC layer, the minimum CD where no collapse occurred, was 65.7nm. In conclusion, with nano-scale topology and sacrificial BARC layer, we could get very small pattern that was strong to pattern collapse issue.
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