Automatic retrosynthetic route planning using template-free models

Retrosynthetic route planning can be considered a rule-based reasoning procedure. The possibilities for each transformation are generated based on collected reaction rules, and then potential reaction routes are recommended by various optimization algorithms. Although there has been much progress in computer-assisted retrosynthetic route planning and reaction prediction, fully data-driven automatic retrosynthetic route planning remains challenging. Here we present a template-free approach that is independent of reaction templates, rules, or atom mapping, to implement automatic retrosynthetic route planning. We treated each reaction prediction task as a data-driven sequence-to-sequence problem using the multi-head attention-based Transformer architecture, which has demonstrated power in machine translation tasks. Using reactions from the United States patent literature, our end-to-end models naturally incorporate the global chemical environments of molecules and achieve remarkable performance in top-1 predictive accuracy (63.0%, with the reaction class provided) and top-1 molecular validity (99.6%) in one-step retrosynthetic tasks. Inspired by the success rate of the one-step reaction prediction, we further carried out iterative, multi-step retrosynthetic route planning for four case products, which was successful. We then constructed an automatic data-driven end-to-end retrosynthetic route planning system (AutoSynRoute) using Monte Carlo tree search with a heuristic scoring function. AutoSynRoute successfully reproduced published synthesis routes for the four case products. The end-to-end model for reaction task prediction can be easily extended to larger or customer-requested reaction databases. Our study presents an important step in realizing automatic retrosynthetic route planning.

Retrosynthetic pathway planning using a template-free model coupled with heuristic Monte Carlo tree search.     

CoPc在八面沸石笼中的原位合成及性能研究

采用苯酐－尿素路线，对CoPc金属配合物在八面沸石超笼中原位合成进行了考察，并采用多种物化手段和催化反应对所制备的CoPcY进行了详细的表征。结果表明，该制备路线是一简便有效的合成路线，采用该路线可在八面沸石超笼中原位合成CoPc金属配合物并将之固定于八面沸石中。在该制备方法中合成温度、离子交换所采用的盐类型及催化剂对CoPc金属配合物在八面沸石超笼中的合成及所制备的CoPcY在环己烷氧化反应中的催化性能有很大的影响，其中180 ℃为最佳合成温度，氯化钴较适合作为交换的盐类。在八面沸石超笼中原位合成的CoPc金属配合物在温和的反应条件下对环己烷氧化具有良好催化活性，转化数TON最高可达5 000以上。     

中枢神经兴奋药物莫达非尼的合成新方法

提出了两步法合成中枢神经兴奋药物莫达非尼的新路线。合成路线简捷,得到的产品易纯化,缩短了反应时间,适合于工业化生产,莫达非尼总产率高达97.5%。第一步,二苯甲醇∶硫脲∶氢溴酸∶氢氧化钠∶氯乙酰胺的摩尔比为1.0∶1.2∶2.0∶3.5∶1.8,水为溶剂,温度恒定70℃;第二步,温度40℃,用过氧化氢氧化。     

Towards the development of synthetic routes using theoretical calculations: an application of in silico screening to 2,6-dimethylchroman-4-one

This study describes an attempt to develop a synthetic route using theoretical calculations, i.e., in silico synthesis route development. The KOSP program created four potential synthetic routes for generating 2,6-dimethylchroman-4-one. In silico screening of these four synthetic routes was then performed. In silico screening involves theoretical analysis of synthetic routes prior to actual experimental work. A synthetic route using the Mitsunobu reaction had already been reported by Hoddgets et al. Theoretical investigations were also conducted on two S(N)Ar reactions as well as a Michael reaction before they were examined experimentally. In silico screening using DFT calculations indicated that only the Michael reaction was likely to produce the target. Experimental work confirmed that the target was obtained in a yield of 76.4% using the Michael reaction. The other two routes, except for the Mitsunobu reaction, failed to generate the target. Our results demonstrate that theoretical calculations can be used to narrow down the number of experiments that need to be conducted when developing novel synthetic routes.     

紫草素类似物全合成研究

以1,4-二氢基萘醌为原料,经过甲基化、甲酰化、NHK(Nozaki-Hiyama-Kishi)反应、硝酸铈铵(cAN)和AgO/HNO3氧化脱甲氧基等5步反应,完成了一条紫草素类似物新的合成路线.该路线能够简便、快速地合成紫草素类似物.     

Synthesis of Organic-Inorganic Hybrid Particles by Sol-Gel Chemistry

The synthesis of ORganically MOdified SILica (ORMOSIL) particles has been carried out using both the hydrolytic and non-hydrolytic sol-gel routes. The hybrid (nano)composites are organically modified with an alkyl or aryl group covalently bonded to silicon. Hybrids have been synthesised in an aqueous sol-gel process by a modified Stöber route, producing spherical nanoparticles with diameters in the range 50–300 nm. The size of the particles can be controlled by control of certain reaction parameters. Smaller ormosil nanoparticles can be synthesised by a base-catalysed emulsion polymerisation route, by varying the type and concentration of surfactant and precursor feed rate. In this case, particles in the size range 3.5–10 nm can be obtained. Hybrids have been synthesised from hyperbranched polyesters by encapsulation in a silica matrix using the hydrolytic sol-gel route. Optimisation of the reaction conditions allows the hybrids to be produced as isolated sub-micron spherical particles. Ormosil particles have also been synthesised using the non-hydrolytic sol-gel route, which may lead to products of different morphologies because of the different polarity of the reaction medium. Different reaction conditions were studied in order to optimise the size and shape of the particles, including choice of solvent, use of surfactants and addition of polystyrene. Dimethylsulfoxide acts as a novel oxygen donor for the catalyst-free formation of colourless silsesquioxanes.     

Enhanced Conversion Efficiency Enabled by Species Migration in Direct Solar Energy Storage

Solar energy can be stored via either an indirect route in which electricity is involved as an intermediate step, or a direct route that utilizes photogenerated charge carriers for direct solar energy conversion. In this study, we investigate the fundamental difference between the direct and indirect routes in solar energy conversion using a new photoelectrochemical energy storage cell (PESC) as a model device. This PESC centers on a liquid junction that utilizes CH₃NH₃PbI₃ perovskite to drive photoelectrochemical reactions of Benzoquinone (BQ) and Ferrocene (Fc) redox species. The experimental studies show that the equilibrium redox potentials are 0.1 V and −0.78 V (vs Ag/AgNO₃) for Fc⁺/Fc and BQ/BQ^.−, respectively, which would produce a theoretical open-circuit voltage of 0.88 V for the storage device. The physics-based computational analysis shows a relatively flat reaction rate distribution in the electrode for the indirect route; however, in the direct route the photoelectrochemical reaction rate is critically affected by electron concentration due to strong light absorption of the perovskite material, which has been shown to vary by at least 10-fold in the transverse direction across the photoelectrode. The drastic variation of reaction rate in the photoelectrode creates an electric field that is 7.5 times stronger than the bulk electrolyte, which causes the photo-converted reaction product (i. e., BQ^.−) to drift away from the photoelectrode thereby creating a constant reaction driving force. As a result, it has been shown that the intrinsic solar to chemical conversion (ISTC) efficiency improves by ∼40 % for the direct route compared to the indirect route at 0.05 mA/cm².     

Total Synthesis of (+)-Cornexistin

Herein, we describe the first total synthesis of (+)-cornexistin as well as its 8-epi-isomer starting from malic acid. The robust and scalable route features a Nozaki–Hiyama–Kishi reaction, an auxiliary-controlled syn-Evans-aldol reaction, and a highly efficient intramolecular alkylation to form the nine-membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a β-keto nitrile. The developed route enabled the synthesis of 165 mg (+)-cornexistin.     

Linear total synthetic routes to beta-D-C-(1,6)-linked oligoglucoses and oligogalactoses up to pentaoses by iterative Wittig olefination assembly

Two complementary routes, A and B, have been followed for the stepwise iterative assembly of beta-D-(1,6)-glucopyranose and galactopyranose residues through methylene bridges. In route A the building block was constituted by 2,3,4-tri-O-benzyl-6-O-tert-butyldiphenylsilyl (O-TBDPS) beta-linked galactosylmethylenephosphorane, while in route B the building block was a beta-linked formyl C-glycopyranoside with a similar orthogonal protection of hydroxy groups. In route A each cycle consisted of the reaction of the phosphorane building block with a sugar residue bearing a formyl group at the C-5 carbon atom (coupling) and transformation of the O-TBDPS-protected primary alcohol into the formyl group (arming). Accordingly, route A is defined as the aldehyde route. On the other hand, each cycle in route B involved the coupling of the sugar aldehyde building block with a substrate bearing a phosphorus ylide at C-6 and introduction of the phosphonium group in the arming step as a precursor of the ylide functionality. Accordingly, route B is defined as the ylide route. The efficiency of route A proved to be seriously hampered by the 1,2-elimination of BnOH under the basic reaction conditions of the Wittig olefination, giving rise to the formation of substantial amounts of enopyranose. On the other hand, the ylide route B proved to be more efficient since very good yields (70-93%) of the isolated Wittig products were obtained throughout four consecutive cycles. Individual olefins and polyolefins obtained by routes A and B using gluco and galacto substrates were reduced and debenzylated in one pot by H(2)/Pd(OH)(2) to give the corresponding beta-D-C-(1,6)-linked oligosaccharides up to the pentaose stage. The latter compounds were fully characterized by high-field NMR spectroscopy (500 MHz).     

Novel synthesis method of ester free trimethylene carbonate derivatives

Ester free poly(trimethylene carbonate) (PTMC) derivatives show biocompatibility and biodegradability and do not generate any acidic compounds after decomposition. Their syntheses methods are limited however, hampering their material application. Herein, we established a novel synthesis route of ester free trimethylene carbonate (TMC) derivatives. The novel synthesis route was described using six aldehydes and one ketone as starting compounds. The key reaction is the selective deprotection from two protected hydroxyl groups in the cyclic acetal structure by diisobutylaluminium hydride. This novel synthesis route means that it is possible to convert aldehyde group to ether groups in the side chain of TMC. Conventionally, only a substituent derived from a primary alcohol was introduced into the side chain. We therefore succeeded in decreasing the number of reaction steps from five to three, compared with the conventional route. Furthermore, the development of a novel synthesis route enabled the introduction of substituents derived from secondary alcohols, anticipating the creation of further types of ester free TMC derivatives.     

Total Synthesis of (+)‐Cornexistin

Herein, we describe the first total synthesis of (+)‐cornexistin as well as its 8‐epi‐isomer starting from malic acid. The robust and scalable route features a Nozaki–Hiyama–Kishi reaction, an auxiliary‐controlled syn‐Evans‐aldol reaction, and a highly efficient intramolecular alkylation to form the nine‐membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a β‐keto nitrile. The developed route enabled the synthesis of 165 mg (+)‐cornexistin.     

Selectivity of Intramolecular Radical Addition Reactions Cyclization of ω-Alkenyl Radicals

Small ω-alkenyl radicals are known to cyclize exclusively via the unexpected Anti-Markownikow pathway which leads to cycloalkyl-methyl radicals as the observed reaction products. The strong kinetic preference diminishes, as the linking methylene chain becomes larger. Semiempirical calculations using MINDO/3-UHF allow to classify the observed reaction pathways as individual probes between allowed (n = 1, route A ) and electronically favourable (n = ∞, route M ) routes of reactions.     

A flexible synthesis of C-6 and N-1 analogues of a 4-amino-1,3-dihydroimidazo[4,5-c]pyridin-2-one core

A flexible route which enables access to derivatives of 4-amino-1,3-dihydroimidazo[4,5-c]pyridin-2-ones is described. Issues of selectivity, reaction safety, and low yields in original routes are overcome with the key improvements to the route, including a Negishi cross-coupling and use of a carbamate as a protecting group and intrinsic carbonyl source. The new route enables variation of C-6 and N-1 substituents.     

A DFT Study on the Reaction Mechanism Involved in the Synthesis of Sodium Azide via Hydrazine Hydrate Method

Sodium azide is a widely used inorganic compound. Besides the commonly used method of "Wislicenus process" which uses ammonia, nitrous and sodium as materials, the hydrazine hydrate route is also employed for the preparation of sodium azide particularly in laboratory. However, because many species are involved in the reaction system, the reaction details for the hydrazine hydrate route are still unclear. A comprehensive understanding of the reaction mechanism may provide meaningful help for optimizing the production process. In this work, the reaction mechanism for the synthesis of sodium azide by hydrazine hydrate route has been studied using density function theory(DFT) method. On the basis of our calculations, the reaction details, including the energetics of ten elementary steps, the structures of intermediates and transition states as well as the influence of inorganic acids and alcohols, were illuminated at the atomistic level. Both the two steps, the generation of key intermediate(NH_2-NH-NO) and the trans-cistransformation of NH_2-NH-NO, are suggested to be the possible rate-limiting step, corresponding to the energy barriers of 20.3 and 22.7 kcal/mol, respectively. In the early reaction steps to generate NH_2-NH-NO, the main role of sulphuric acid is to donate proton, which can be replaced by nitric acid or hydrochloric acid. From the energy point of view, isopropanol has similar reactivity as methanol and ethanol.     

Stereoselective Synthesis of cis-2 and trans-2-(Indol-3-yl) Cyclopropyl Amines,Carboxylic Acids,and Esters

We report a general route for the synthesis of E and Z isomers of indol-3-yl cyclopropyl amines, carboylic acids, and esters. These cyclopropane containing molecules are of interest as conformationally constrained analogues of tryptamine and indole propionic acid, biologically active indoles. The route involves reaction of vinyl indole with ethyl diazoacetate, chromatographic separation of the E and Z stereoisomers of the resulting cyclopropane esters, hydrolysis to form the E and Z cyclopropane acids, and formation of amines by the Curtius reaction.     

Total synthesis of an antitumor antibiotic,Fostriecin (CI-920)

The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin, corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C, was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the former route is basically the same as those reported by other groups, the latter route is novel and more effective than the former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin, but also its various analogues including stereoisomers.     

Formation of the active species of cytochrome p450 by using iodosylbenzene: a case for spin-selective reactivity

The generation of the active species for the enzyme cytochrome P450 by using the highly versatile oxygen surrogate iodosylbenzene (PhIO) often produces different results compared with the native route, in which the active species is generated through O(2) uptake and reduction by NADPH. One of these differences that is addressed here is the deuterium kinetic isotope effect (KIE) jump observed during N-dealkylation of N,N-dimethylaniline (DMA) by P450, when the reaction conditions change from the native to the PhIO route. The paper presents a theoretical analysis targeted to elucidate the mechanism of the reaction of PhIO with heme, to form the high-valent iron-oxo species Compound I (Cpd I), and define the origins of the KIE jump in the reaction of Cpd I with DMA. It is concluded that the likely origin of the KIE jump is the spin-selective chemistry of the enzyme cytochrome P450 under different preparation procedures. In the native route, the reaction proceeds via the doublet spin state of Cpd I and leads to a low KIE value. PhIO, however, diverts the reaction to the quartet spin state of Cpd I, which leads to the observed high KIE values. The KIE jump is reproduced here experimentally for the dealkylation of N,N-dimethyl-4-(methylthio)aniline, by using intra-molecular KIE measurements that avoid kinetic complexities. The effect of PhIO is compared with N,N-dimethylaniline-N-oxide (DMAO), which acts both as the oxygen donor and the substrate and leads to the same KIE values as the native route.     

Total synthesis of peridinin and related C37-norcarotenoid butenolides

As an extension of our synthesis of symmetrical carotenoids, the preparation of the highly functionalized C37-norcarotenoid butenolide peridinin (1), its 6'-epi- and 11'Z stereoisomers has been completed. Featuring a central dihalogenated C8 linchpin unit 6, two synthetic routes, differing in the ordering of the last three steps were explored by using the C3,C3'-bisdehydroxylated target as the model system. The first route uses the combination of a modified Z-selective Julia reaction and two sequential Stille couplings, the last one producing the isomerisation of the polyene Z double bond. The second route inverts these steps and makes the isolation of the 11'Z stereoisomers as major products possible. An efficient Z to E isomerisation of the final carotenoid skeleton simply uses the Stille reaction conditions at ambient temperature. As the reaction of bromoallene 12 with alkenylstannane 11 occurs with inversion of configuration, 6'-epi-peridinin could also be prepared by route A. The advantages and limitations of the sequential Stille cross-coupling approach to carotenoids are highlighted.     

Reaction of 1-Amino-3-propoxy-2-propanol with Aldehydes

The reaction of 1-amino-3-propoxy-2-propanol was examined as a route to the corresponding 1,3-oxazolidines.     

担载型贵金属催化剂上甲烷直接羰基化反应

利用程序升温脉冲反应、恒温脉冲反应及探针分子表面反应技术较系统地考察了担载型贵金属催化剂上甲烷直接羰基化制乙醛的反应，研究发现通过采用总反应分解法操作后，能够克服甲烷直接羰基化反应的热力学限制，将总反应转化为两个可在较温和条件发生的反应，首次实现了CH4＋CO→CH3CHO的反应即首先进行甲烷的分解，然后引入CO与甲烷分解所产生的表面物种直接反应生成乙醛．本文还探讨了甲烷吸附条件，CO与甲烷分解所产生的表丙碳物种间的作用等反应的影响因素、探针分子CH3I的表面反应结果显示甲烷分解产生的CHx（ad）（x≤3）物种可能是该反应的活性中间体