Undesired Diastereomer Research Articles

Dramatic influence of ester steric hindrance on the diastereoselectivity of a Michael addition towards the synthesis of the ABC tricycle of hexacyclinic acid

During our studies toward the synthesis of the ABC ring system of hexacyclinic acid, we observed an unexpected influence of the steric bulk of the ester group of the Michael acceptor in a key conjugate addition. We propose an eight-membered ring transition state to explain the formation of the undesired diastereomer in the case of unhindered esters.

Scalable synthesis of cladosporin

Cladosporin, a secondary metabolite isolated from fungal sources like Cladosporium cladosporioides and Aspergillus flavus was found to exhibit selective nano-molar activity against malarial parasite Plasmodium falciparum by inhibiting parasitic protein biosynthesis. In addition, this natural product has a broad range of bioactivities including, antiparasitic, antifungal, antibacterial as well as plant growth inhibition. However, it has limited availability from the natural sources for further development. Herein, we report a modified and improved synthetic route which led us to produce this potent natural product in a gram scale. Conversion of the undesired diastereomer to desired one via Mitsunobu inversion of secondary alcohol and carbon monoxide insertion reaction towards the construction of isocoumarin unit are the key features of the present synthesis.

Studies on the Second-Generation Approach to Loline Alkaloids: Synthesis of N-Bus-norloline through N-tert-Butanesulfinyl Imine Based Asymmetric Vinylogous Mannich Reaction

A strategy is outlined for the synthesis of loline alkaloids. This second-generation approach features direct access to the requisite vicinal diamino motif by a Cu(OTf)₂-mediated highly <i>trans</i>-diastereoselective vinylogous Mannich reaction (VMR) of Ellman <i>N</i>-<i>tert</i>-butanesulfinyl imine derived from isopropylidene-protected (<i>S</i>)-glyceraldehyde, with <i>N</i>-Boc-2-<i>tert</i>-(butyldimethylsilyloxy)pyrrole (TBSOP). Fleming’s method was employed for the introduction of a hydroxyl group at C4 of the adduct, which gave the undesired diastereomer in 40% yield. The intramolecular S_N reaction of the pyrrolizidine derivative to build the etheral bridge proved to be difficult, and produced <i>N</i>-Bus-norloline in only 20% yield. In light of the valuable information gained during this investigation, an improved version of the second-generation approach is being investigated, which is expected to provide a concise and efficient access to the challenging loline alkaloids.

Route Development and Multikilogram GMP Delivery of a Somatostatin Receptor Antagonist

Route development and demonstration on multikilogram scale for the first GMP delivery of MK-4256 are described. Key aspects of the convergent route include a regioselective green iodination, one-pot oxadiazole synthesis, and an efficient ketone Pictet–Spengler reaction with diastereomeric upgrade via crystallization to afford 6 kg of API. A recycle procedure augmented the yield of desired diastereomer in the Pictet–Spengler reaction from a mixture of diastereomers heavily enriched in the undesired diastereomer.

ChemInform Abstract: A New Method for the Construction of the Hydroxylated Tropane Skeleton: Enantioselective Synthesis of (‐)‐Bao Gong Teng A.

AbstractThe intramolecular reductive coupling of aldehyde (IV) gives rise to a mixture which contains the undesired diastereomer (V) as main product.

Suzuki−Miyaura Approach to JNJ-26076713, an Orally Active Tetrahydroquinoline-Containing αVβ3/αVβ5 Integrin Antagonist. Enantioselective Synthesis and Stereochemical Studies

An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.

Stereoselective enzymatic reduction of keto-salinosporamide to (−)-salinosporamide A (NPI-0052)

Salinosporamide A (NPI-0052, 1), a highly potent 20S proteasome inhibitor, has been prepared from its ketone precursor ( 2) by asymmetric enzymatic reduction. The yields are quantitative with complete stereoselective conversion to the desired product, with no evidence for the undesired diastereomer. This process should lead to new synthetic strategies for the total synthesis of 1.

A Tandem Metal Carbene Cyclization—Cycloaddition Approach to the Pseudolaric Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A tandem metal carbene cyclization-cycloaddition approach to the pseudolaric acids.

An approach toward the synthesis of the antifungal and cytotoxic pseudolaric acids based on the tandem metal carbene cyclization-cycloaddition reaction is described. Using this strategy, the advanced intermediate 3a bearing three of the four stereocenters of the target molecules has been synthesized. The substrate-controlled diastereoselectivity of the tandem carbene cyclization-cycloaddition was preferential for the undesired diastereomer, but reagent control through the use of Hashimoto's chiral rhodium catalyst Rh(2)(S-BPTV)(4) reversed the selectivity in favor of 3a. Ring opening of the oxabicyclic nucleus to give a hydroxycycloheptene has been demonstrated in a model study.

Direct Liquid Chromatographic Separation of 3R-Trans, 3S-Cis, and 3R-Cis 1,1-Dimethylethyl (4R-CIS)-6-Cyanomethyl-2,2-Dimethyl-1,3-Dioxane-4-Acetate Enantiomers on a Cellulose Tris (3,5-Dimethylphenyl Carbamate) Chiral Column

Direct liquid chromatographic separation of 3R-trans, 3S-cis and 3R-cis 1,1-dimethylethyl (4R-cis)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate enantiomers on a cellulose tris (3,5-dimethylphenyl carbamate) column is described. The 3R-cis isomer is an intermediate in the synthesis of atorvastatin (a HMG-CoA reductase inhibitor). The detection limit for each of the undesired 3R-trans and 3S-cis isomers was 0.2% by area percent normalization. The separation of the undesired 3S-trans diastereomer was occasionally observed, and was found to be greatly affected by slight differences in mobile phase composition.

Hydrogenation of a Chiral 1H-Benz[de]isoquinolin-1-one and an Equilibration Using Palladium Catalyst

The catalytic hydrogenation of a chiral 1H-benz[de]isoquinolin-1-one to palonosetron and the undesired diastereomer was optimized using a variety of conditions and catalysts. The most selective catalyst for the production of palonosetron was an unreduced palladium on carbon catalyst. The (+)- and (−)-camphorsulfonic acid salts of the 1H-benz[de]isoquinolin-1-one and the complex of the 1H-benz[de]isoquinolin-1-one with Mg2+ upon catalytic hydrogenation gave the greatest preference for the undesired diastereomer. An equilibration of the undesired diastereomer from hydrogenation and palonosetron as hydrochloride salts using hydrogen-activated palladium on carbon catalyst under a nitrogen atmosphere was developed. The procedure was used to recycle the hydrochloride salt of the undesired diastereomer from hydrogenation into pure palonosetron hydrochloride.