Total Syntheses of a 16a'-Homoleurosidine and a 16a'-Homovinblastine

Vinblastine has been used in clinic as an anti-cancer agent. Due to its high cytotoxity, generation of vinblastine congeners as safe anti-cancer agents is always the interesting topic in medicinal chemistry. In the previous synthesis of vinblastine, it has been found that a higher energy conformation of vinblastine lacking cytotoxity and inhibition against tubulin polymerization, can be converted to its lower energy natural conformation on heating to 110 ℃. The high temperature (110 ℃) other than a physiological temperature required for the conformational inversion excludes the possibility of using the higher energy conformational isomer as a potential pro-drug for thermal activation. In the continuing of searching for thermal activated anti-cancer pro-drug, we re-designed and synthesized new vinblastine congeners with the enlarged azonine ring by inserting one carbon atom at the C-16 position of azonine ring in order to decrease the energy barrier for the conformational inversion.In this paper, we wish to report the total syntheses of 16a'-homoleurosidine and 16a'-homovinblastine, the azonine ring expanded compounds of vinblastine and leurosidine respectively. The synthesis of 16a'-homoleurosidine was achieved through enatioselective generation of a tetracyclic intermediate by a Diels-Alder reaction, followed by ring expansion of the tetracyclic intermediate by regioselective rapture of a cyclopropane ring as key steps. The synthesis of 16a'-homovinblastine was achieved through stereoselective inversion of the tertiary hydroxyl group from R configuration to the S configuration in the tetracyclic intermediate. The 16a'-homoleurosidine was obtained dominantly in its high energy conformation at room temperature and neutral condition. On protonation, a 1:1 mixture of atropisomers of 16a'-homoleurosidine was found. In contrast to 16a'-homoleurosidine, the 16a'-homovinblastine existed in the form of two atropisomers in a 1:2.3 ratio at room temperature and neutral condition, with a complete shift to the lower energy atropisomer with increasing solvent acidity. The hydrogen bond formed between the nitrogen atom and the hydroxyl group of piperidine ring played a key role in controlling the equilibrium shift between the higher energy atropisomer and the lower energy atropisomer.     

Unusual Knoevenagel condensations of 16a-substituted-16-methylene-17-keto-steroids

A Knoevenagel condensation between 3β-acetoxy-16-pyrrolidinylmethylenandrost-5-en-17-one (8c) and an excess of malononitrile led unexpectedly to 3β-acetoxyandrost-5-eno-[17,16-c]-1′,6′-dicyanoaniline (12a) as the major product and 3β-acetoxy-16-pyrrolidinylmethylen-17-dicyanomethylenandrost-5-ene (11a) as the minor product. Knoevenagel reactions of other 16a-substituted-16-methylen-17-keto steroids were studied to evaluate the scope and mechanism of the reaction.     

A highly convergent synthesis of mexiprestil: 16(R) 16-methoxy 16-methyl PGE1 methyl ester

The synthesis of optically pure mexiprostil, a PGE₁ analogue, via the three component coupling process, e.g. Michael addition of the appropriate ω-side chain onto enantiomerically pure, protected (R)-4-hydroxy-cyclopentenone, followed by in situ trapping with the a-side chain, is described.     

16th International Conference on Physical Organic Chemistry (ICPOC16)

Russian Journal of Organic Chemistry -     

The syntheses of 16a'-homo-leurosidine and 16a'-homo-vinblastine. Generation of atropisomers

The synthesis of 16a'-homo-leurosidine was achieved through enantioselective generation of a ring D'-seco-precursor 33 (without requirement of a chiral auxiliary). Its cyclization provided the N(b')-quaternary salt 35 with a configuration corresponding to the atropisomeric form 8a rather than 8b of the target product. On debenzylation, the amine 8a was obtained and found not to isomerize thermally to the anticipated atropisomer 8b (in contrast to its lower homologue, with its formation of natural leurosidine). However, on protonation, a 1:1 mixture of atropisomers of 16a'-homo-leurosidine was obtained. A synthesis of 16a'-homo-vinblastine provided two atropisomers 5a and 5b for the free base at equilibrium (1:2.3 at room temperature in CDCl(3)), with a shift to the major conformer 5b with increasing solvent acidity or decreasing temperature. The synthesis was achieved through a stereoselective inversion of the tertiary hydroxyl function in the enantioselectively generated C-20' progenitor 39.     

Oxyfluorotitanophosphate cluster [Ti10P4O16F44]16-: synthesis and characterization of K16[Ti10P4O16F44

One oxyfluorotitanophosphate cluster compound, K16[Ti10P4O16F44], has been synthesized and structurally characterized. As far as we know, it is the first cluster compound for titanophosphate.     

Facile green synthesis of 16-dehydropregnenolone acetate (16-DPA) from diosgenin

Chromium- and MnO₂-free green synthesis of industrially important steroidal drug intermediate 16-dehydropregnenolone acetate (16-DPA) starting from diosgenin is reported. The reaction sequence involves three steps: acetolysis followed by acetylation, oxidation, and hydrolysis. In the first step, Ac₂O was used both as reagent and solvent in combination with a Lewis acid (AlCl₃), which led to considerable reduction of high temperature and pressure requirements of earlier processes. The oxidation step was made catalytic with the use of KMnO₄(5 mol%) in the presence of co-oxidant NaIO₄, leading to less waste generation (of chromium, MnO₂, etc.). Minimization of the temperature, pressure, time consumption, and use of nontoxic solvents makes the process very handy and simple.     

FSM-16沸石和纳米TiO2/FSM-16沸石的合成与光谱表征

二氧化钛纳米相超细粉体由于具有独特的光电性质和良好的化学稳定性, 近年来已引起人们高度重视. 这种粉体是光催化、太阳能转换、精细陶瓷等领域的重要材料, 尤其在废水处理中已得到了普遍应用[1,2]. 但悬浮相二氧化钛具有易失活、易凝聚和难回收等弱点. 就此而言, 近期十分引人关注的分子筛主体-纳米客体复合材料为解决这个难题提供了新的途径. 特别是具有规则孔道结构的中孔沸石分子筛, 由于孔径在纳米级范围内的可调性, 被认为是纳米粒子组装理想的宿主, 为低维材料(量子点、量子线和超晶格等)的特殊物理、化学性质研究提供了有力工具.     

A further study on closo boron hydrides B16H2−16 (D2) and B16H16Td) using ab initio molecular orbital theory

Ab initio molecular orbital calculations of doubly negative charged B₁₆H^2?₁₆(D₂) and neutral B₁₆H₁₆(Td) have been done at the HF/6-31G level. They are predicted to be chemically and kinetically stable by vibrational analyses on their respective energy hypersurface of the HF/6-31G level. The geometrical structure of the species B₁₆H²₁₆ (D₂) was discussed.