Stereoselective Synthesis,Characterization, and Antibacterial Activities of Novel Isosteviol Derivatives with D‐Ring Modification

Considerable interests have been attracted by isosteviol and its derivatives because of their large variety of bioactivities. In this project, a series of novel 15‐ and 16‐substituted isosteviol derivatives were stereoselectively prepared by means of functional interconversions in ring D of the tetracyclic diterpene isosteviol. All compounds synthesized were characterized by analysis of NMR, IR, HR‐MS data, and the configurations of 33 and 37 were confirmed by X‐ray crystallographic analysis. The antibacterial activities in vitro of these isosteviol derivatives were investigated; the synthetic compounds were more active against Gram‐positive than Gram‐negative bacteria, and were especially active against Bacillus subtilis. Among them, compound 27 (MIC=1.56 μg/ml) exhibited the highest antibacterial activity and thus may be exploitable as a lead compound for the development of potent antibacterial agents.     

Catalytic Stereoinversion of L‐Alanine to Deuterated D‐Alanine

A combination of an achiral pyridoxal analogue and a chiral base has been developed for catalytic deuteration of L ‐alanine with inversion of stereochemistry to give deuterated D ‐alanine under mild conditions (neutral pD and 25 °C) without the use of any protecting groups. This system can also be used for catalytic deuteration of D ‐alanine with retention of stereochemistry to give deuterated D ‐alanine. Thus a racemic mixture of alanine can be catalytically deuterated to give an enantiomeric excess of deuterated D ‐alanine. While catalytic deracemization of alanine is forbidden by the second law of thermodynamics, this system can be used for catalytic deracemization of alanine with deuteration. Such green and biomimetic approach to catalytic stereocontrol provides insights into efficient amino acid transformations.     

Photofragmentation of 2‐Deoxy‐D‐Ribose Molecules in the Gas Phase

We have measured the synchrotron‐induced photofragmentation of isolated 2‐deoxy‐D ‐ribose molecules (C₅H₁₀O₄) at four photon energies, namely, 23.0, 15.7, 14.6, and 13.8 eV. At all photon energies above the molecule′s ionization threshold we observe the formation of a large variety of molecular cation fragments, including CH₃⁺, OH⁺, H₃O⁺, C₂H₃⁺, C₂H₄⁺, CH_xO⁺ (x=1,2,3), C₂H_xO⁺ (x=1–5), C₃H_xO⁺ (x=3–5), C₂H₄O₂⁺, C₃H_xO₂⁺ (x=1,2,4–6), C₄H₅O₂⁺, C₄H_xO₃⁺ (x=6,7), C₅H₇O₃⁺, and C₅H₈O₃⁺. The formation of these fragments shows a strong propensity of the DNA sugar to dissociate upon absorption of vacuum ultraviolet photons. The yields of particular fragments at various excitation photon energies in the range between 10 and 28 eV are also measured and their appearance thresholds determined. At all photon energies, the most intense relative yield is recorded for the m/q=57 fragment (C₃H₅O⁺), whereas a general intensity decrease is observed for all other fragments— relative to the m/q=57 fragment—with decreasing excitation energy. Thus, bond cleavage depends on the photon energy deposited in the molecule. All fragments up to m/q=75 are observed at all photon energies above their respective threshold values. Most notably, several fragmentation products, for example, CH₃⁺, H₃O⁺, C₂H₄⁺, CH₃O⁺, and C₂H₅O⁺, involve significant bond rearrangements and nuclear motion during the dissociation time. Multibond fragmentation of the sugar moiety in the sugar–phosphate backbone of DNA results in complex strand lesions and, most likely, in subsequent reactions of the neutral or charged fragments with the surrounding DNA molecules.     

Enzyme‐Catalyzed Stereoselective Synthesis of Two Novel Carbasugar Derivatives

Enzymatic resolution of racemic 1,4,5,6‐tetrachloro‐2‐(hydroxymethyl)‐7,7‐dimethoxybicyclo[2.2.1]hept‐5‐ene (rac‐ 1 ) using various lipases in vinyl acetate as acetyl source was studied. The obtained enantiomerically enriched (+)‐(1,4,5,6‐tetrachloro‐7,7‐dimethoxybicyclo[2.2.1]hept‐5‐en‐2‐yl)methyl acetate ((+)‐ 2 ; 94% ee), upon treatment with Na in liquid NH₃, followed by Amberlyst‐15 resin in acetone, provided (−)‐5‐(hydroxymethyl)bicyclo[2.2.1]hept‐2‐en‐7‐one ((−)‐ 7 ), which is a valuable precursor for the synthesis of carbasugar derivatives. Subsequent Baeyer–Villiger oxidation afforded a nonseparable mixture of bicyclic lactones, which was subjected to LiAlH₄ reduction and then acetylation. The resultant compounds (−)‐ 11 and (+)‐ 12 were submitted to a cis‐hydroxylation reaction, followed by acetylation, to afford the novel carbasugar derivatives (1S,2R,3S,4S,5S)‐4,5‐bis(acetoxymethyl)cyclohexane‐1,2,3‐triyl triacetate ((−)‐( 13 )) and (1R,3R,4R,6R)‐4,6‐bis(acetoxymethyl)cyclohexane‐1,2,3‐triyl triacetate ((−)‐( 14 )), respectively, with pseudo‐C₂‐symmetric configuration. The absolute configuration of enantiomerically enriched unreacted alcohol (−)‐ 1 (68% ee) was determined by X‐ray single‐crystal analysis by anchoring optically pure (R)‐1‐phenylethanamine. Based on the configurational correlation between (−)‐ 1 and (+)‐ 2 , the absolute configuration of (+)‐ 2 was determined as (1R,2R,4S).     

Stereoselective Synthesis of D‐ and L‐Carbocyclic Nucleosides by Enzymatically Catalyzed Kinetic Resolution

An efficient synthesis of (S)‐ or (R)‐3‐(benzyloxy‐methyl)‐cyclopent‐3‐enol was developed by appling an enzyme‐catalyzed kinetic‐resolution approach. This procedure allowed the syntheses of the enantiomeric building blocks (S)‐ and (R)‐cyclopentenol with high optical purity (>98 % ee). In contrast to previous approaches, the key advantage of this procedure is that the resolution is done on the level of enantiomers that only contain one stereogenic center. Owing to this feature, it was possible to chemically convert the enantiomers into each other. By using this route, the starting materials for the syntheses of carbocyclic D ‐ and L ‐nucleoside analogues were readily accessible. 3′,4′‐Unsaturated D ‐ or L ‐carbocyclic nucleosides were obtained from the condensation of various nucleobases with (S)‐ or (R)‐cyclopentenol. Functionalization of the double bond in 3′‐deoxy‐3′,4′‐didehydro‐carba‐D ‐thymidine led to a variety of new nucleoside analogues. By using the cycloSal approach, their corresponding phosphorylated metabolites were readily accessable. Moreover, a new synthetic route to carbocyclic 2′‐deoxy‐nucleosides was developed, thereby leading to D ‐ and L ‐carba‐dT. D ‐Carba‐dT was tested for antiviral activity against multidrug‐resistance HIV‐1 strain E2‐2 and compared to the known antiviral agent d4T, as well as L ‐carba‐dT. Whilst L ‐carba‐dT was found to be inactive, its D ‐analogue showed remarkably high activity against the resistant virus and significantly better than that of d4T. However, against the wild‐type virus strain NL4/3, d4T was found to be more‐active than D ‐carba‐dT.     

Stereoselective Total Synthesis of Decytospolides A and B Starting from D‐Mannitol

The stereoselective total synthesis of decytospolides A and B, two naturally occurring pyran derivatives, has been achieved using D ‐mannitol as the starting material. The intramolecular oxa‐Michael reaction has been employed to construct the tetrahydropyran ring of the molecules and Weinreb amide formation to generate their side chain with a keto function.     

Stereoselective Total Synthesis of Mangiferaelactone using D‐Mannose as a Chiral Pool

A convergent total synthesis of mangiferaelactone has been accomplished in a highly stereoselective manner from readily available D ‐mannose. The following methods like organocatalytic enantioselective epoxidation, ring‐closing metathesis, and Steglich esterification have been employed as key steps, which make this approach more attractive.     

Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D‐Printed Mesoreactors

3D‐printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D‐printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best‐performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee . The method was applied to the continuous‐flow synthesis of biologically active chiral 1,2‐amino alcohols (norephedrine, metaraminol, and methoxamine) through a two‐step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.     

Stereoselective Synthesis of Phosphoryl Derivatives

The reaction of dialkylphosphonites with N-(bromomethyl)phthalimide furnishes alkyl phenyl hydrogenphosphinates, dialkyl phenylphosphonates, and N-[(bromomethyl)phthalimido)]-phosphinates. The stereoselectivity of the primary product of the reaction appears to increase with the increasing size of the groups attached to the phosphorus atom.     

An Efficient and Simple Method for Stereoselective Synthesis of N‐Substituted Iminosugars from D‐Xylose Derivative

A series of new N‐substituted iminosugars were successfully synthesized through a general synthetic route from D‐xylose derivative. This approach provided a convenient access to the synthesis of N‐alkylated iminosugars as potential glucosidase inhibitors, which included a reaction of reductive amination. Various N‐alkylated iminosugars were prepared in good yields with high stereoselectivity.     

Synthesis of Well‐Defined Adenosine Diphosphate Ribose Oligomers

The post‐translational modification of proteins that is known as adenosine diphosphate ribosylation (ADPr) regulates a wide variety of important biological processes, such as DNA‐damage repair and cellular metabolism. This modification is also involved in carcinogenesis and the process of aging. Therefore, a better understanding of the function of ADP‐ribosylation is crucial for the development of novel therapeutics. To facilitate the elucidation of the biology of ADPr, the availability of well‐defined fragments of poly(ADP‐ribose) is essential. Herein we report a solid‐phase synthetic approach for the preparation of ADP‐ribose oligomers of exactly defined length. The methodology is exemplified by the first reported synthesis of an ADP‐ribose dimer and trimer.     

Studies on the Synthesis and Structure of New Urea‐Linked Sugar Podando‐Coronand Derivatives

With the aim to develop direct, simple, and efficient coupling procedures involving saccharides and cyclodextrins (CDs), the modified Staudinger method, the phosphine imide method, was chosen as a promising versatile way to reach the goals. Thus, the new cyclam derivatives 6 – 9 were obtained in good yields (see Scheme). In the case of β‐cyclodextrin, the method also allowed the synthesis of the icosa‐O‐acetyl‐6^A‐isocyanato‐6^A‐deoxy‐β‐CD sugar isocyanate 11 and of symmetrical or unsymmetrical carbohydrate carbodiimides 12 and 17 under smooth conditions and in a simple way. Structural, theoretical, and experimental investigations on several urea‐like cyclams revealed the fundamental role played by permanent strong H‐bonds between urea functions in the conformational equilibrium of the molecules.     

Asymmetric Synthesis and Antitumor Activity of Spiro‐Oxadiazole Derivatives from 1,4:3,6‐Dianhydro‐D‐fructose

A series of spiro‐oxadiazoles were synthesized from 1,4:3,6‐dianhydro‐D ‐fructose and hydrazides via a stereo‐ selective two‐step reaction sequence. The structures of newly synthesized compounds were established by spectral analysis. The absolute configuration of compound 2a was further confirmed by single crystal X‐ray analysis. All the synthesized compounds were screened for their in vitro antitumor activity, showing that these compounds have poor inhibitory activities against A549, MGC‐803 tumor cells.