Practical Asymmetric Synthesis Research Articles

Amplifying enantioselectivity in asymmetric transformations using heterogeneous chiral single-rhodium-site catalyst with sustained catalytic activity

Rhodium-catalyzed asymmetric reactions have played a pivotal role in the synthesis of functional chiral molecules. However, the ambiguous mechanism involving several plausible catalytically active species, the potential for catalyst deactivation and the need for constant reusability remain key challenges. Heterogeneous chiral Rh catalysts are highly desirable, but their performance has been hampered by low density and stability of catalytically active sites. Herein, we have devised a versatile methodology for fabricating highly efficient and robust chiral heterogeneous single-Rh-site catalysts by direct polymerization. The successful anchoring of single Rh-ligand species, the amplification of enantioselective inductive ability and the uniform distribution of atomic Rh sites within the resulting polymer matrix are identified as crucial factors contributing to their exceptional catalytic performance via comprehensive characterization and controlled experiments. In contrast to the corresponding homogeneous analogues, these chiral single-Rhodium-site catalysts exhibit outstanding performance, yielding enhanced enantioselectivity and broad applicability, even accommodating various functional groups. Remarkably, these results are achieved with just half catalyst dosage. Furthermore, their industrial potential is demonstrated through successful utilization in continuous flow processes and robust batch recycling. In future, we aim to expand the horizons of heterogeneous chiral single-metal-site catalysis, and bring us a step closer to practical asymmetric synthesis.

Practical Asymmetric Synthesis of Sulfoximines and Sulfimides from Sulfinamides

AbstractChiral sulfoximines and sulfimides are an interesting class of compounds in various areas. However, methodologies for preparing these chiral sulfur compounds in a stereoselective manner have been underdeveloped. Herein, we briefly summarize our recent studies on asymmetric synthesis of sulfoximines and sulfimides from readily available enantioenriched sulfinamides. In these studies, optically pure sulfoximines and sulfimides having various carbon substituents on their sulfur atom could be obtained.1 Introduction2 Asymmetric Synthesis of Chiral Sulfoximines3 Asymmetric Synthesis of Chiral Sulfimides4 Conclusion

Practical Asymmetric Synthesis of a Bicyclic Pyrrolidinol

The “butterfly-shaped” bicyclic pyrrolidinol ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1) is a key building block for drug candidates, and its practical chemical synthesis remains elusive. As such, an asymmetric synthesis for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)-methanol (1) that is amenable for scale-up has been developed. The newly optimized process utilizes readily available N-Boc-trans-4-hydroxy-l-proline methyl ester (8) to establish the challenging stereogenic center bearing the fluoride. Subsequent diastereoselective α-alkylation was achieved by leveraging Seebach’s self-regeneration of stereochemistry (SRS) methodology, which has been exploited for the synthesis of proline derivatives. Finally, intramolecular cyclization/deprotection cascade and carbonyl reduction afford the bicyclic pyrrolidinol 1 in nine linear steps from compound 8. This process significantly reduces the overall production sequence and allows the preparation of product 1 on a multikilo scale with a 40% overall yield and perfect control of chirality (>99% ee and de).

Practical Asymmetric Synthesis of Chiral Sulfoximines via Sulfur-Selective Alkylation.

Chiral sulfoximines have recently been considered as promising bioisosteres in medicinal chemistry. However, methods for preparing chiral sulfoximines in a stereoselective manner are underdeveloped. Herein, we demonstrate an asymmetric synthesis of chiral sulfoximines through a stereospecific S-alkylation of readily accessible chiral sulfinamides under practical conditions. A key to establishing the practical conditions was the identification of the intermediate structure in our previously reported S-alkylation by X-ray crystallographic analysis.

SPHENOL, A New Chiral Framework for Asymmetric Synthesis.

Privileged chiral catalysts have found tremendous applications and thus immensely advanced asymmetric synthesis in the past few decades. However, truly privileged chiral frameworks are still extremely limited. Thus, the search for and development of new versatile members remain in high demand but challenging. Herein we report the design, synthesis, and application of a new chiral framework, SPHENOL, which features combined advantages of BINOL and SPINOL. This unique feature enables SPHENOL to serve as a new platform for the development of chiral ligands and catalysts. Its superior performance has been demonstrated in mechanistically unrelated reactions, including asymmetric hydrogenation, hydroacylation, and spirocyclization for the practical asymmetric synthesis of SPHENOL itself. These results indicated the great potential of SPHENOL as a useful chiral framework.

Practical Asymmetric Synthesis of Fluorinated Amino Acids and Their Application to Peptide Engineering

Practical Asymmetric Synthesis of Fluorinated Amino Acids and Their Application to Peptide Engineering

Development of Hamari Ligands for Practical Asymmetric Synthesis of Tailor-Made Amino Acids.

Enantiomerically pure tailor-made amino acids are in extremely high demand in nearly every sector of the health-related industries. In particular, the rapidly growing number of amino-acid-based pharmaceuticals calls for the development of advanced synthetic approaches featuring practicality and commercial viability. Here we provide a brief summary of the development of axially chiral tridentate Hamari ligands and their application for general asymmetric synthesis of various structural types of amino acids. The methodological diversity includes: dynamic kinetic resolution and (S)-/(R)-interconversion of unprotected amino acids and homologation of nucleophilic glycine equivalents via alkyl halide alkylation reactions as well as multiple-step transformations allowing preparation of polyfunctional and cyclic derivatives. The practicality of these methods is critically discussed.

A practical asymmetric synthesis of ortho-substituted 4-pyrazolyl-2-ethylamines

A reliable three-step synthesis of ortho-substituted 4-pyrazolyl-2-ethylamines starting from a pyrazole methyl ketone and N-tert-butanesulfinylamine is described. Strongly dehydrating conditions were required to form the N-tert-butanesulfinyl ketimines, but these intermediates were stable to aqueous work-up and chromatography. Reduction of N-tert-butanesulfinyl ketimines with L-selectride®, or Super-hydride®, in THF afforded excellent yields and diastereoselectivities of the sulfinamides, which were converted into chiral amines with methanolic HCl. The 4-pyrazolyl-2-ethylamines from these investigations are attractive building blocks for medicinal chemists, as they exhibit low molecular weight, and low calculated octanol-water partition coefficient (c Log P values), while disrupting planarity with three-dimensional character. For example, the amine products were utilized in structure-activity studies of the human transient receptor potential vanilloid 1 (TRPV1/VR1).

Expedient Asymmetric Synthesis of (S)-2-Amino-4,4,4-trifluorobutanoic Acid via Alkylation of Chiral Nucleophilic Glycine Equivalent

Here we disclose a practical asymmetric synthesis of an enantiomerically 97.8% ee pure N-Fmoc derivative of (S)-2-amino-4,4,4-trifluorobutanoic acid performed on >10 g scale of the target product. The method is based on alkylation (CF3–CH2–I) of a new generation of a chiral nucleophilic equivalent conducted at ambient temperature with an excellent stereochemical outcome. The developed protocol does not require any chromatographic separations and includes only one purification step via recrystallization of the final product.

A novel and practical asymmetric synthesis of eptazocine hydrobromide.

In order to prepare eptazocine hydrobromide effectively, a novel, mild and practical asymmetric process was developed starting from 1-methyl-7-methoxy-2-tetralone under the catalysis of N-(p-trifluoromethylbenzyl)cinchonidinium bromide. The reaction conditions were optimized to obtain the product in excellent overall yield and purity.

Practical Asymmetric Synthesis of Sitagliptin Phosphate Monohydrate.

Optically pure sitagliptin phosphate monohydrate is efficiently and practically synthesized through a chiral hemiacetal as the key intermediate in 54% overall yield starting from (E)-4-(2,4,5-trifluorophenyl)but-2-enal and N-boc-protected hydroxylamine. The chiral hemiacetal fragment is constructed by a tandem aza-Michael/hemiacetal reaction catalyzed by an organocatalyst and the influence of acidity of Brønsted acid on tandem aza-Michael/hemiacetal reaction is researched in detail.

Novel and practical asymmetric synthesis of β2,3-amino esters using asymmetric Michael addition of chiral amine

A practical method for the synthesis of chiral β2,3-amino esters having various substituents was developed, which is characterized by an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. We found that a highly face-selective protonation occurred by the quick addition of water to the enolate intermediate derived from the Michael addition reaction to afford N-protected β2,3-amino esters in moderate to excellent yields. This finding was made possible by the facile preparation of geometrically pure trisubstituted (E)-α,β-unsaturated esters, which was established recently by our group. The subsequent deprotection of the amino group in the Michael adduct by using N-iodosuccinimide (NIS) efficiently provided β2,3-amino esters having various substituents.

Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor.

The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.

Practical Asymmetric Synthesis of Amathaspiramides B, D, and F.

The practical asymmetric synthesis of amathaspiramides B, D, and F has been accomplished by utilizing an aza-Barbier allylation as the key step to construct the common intermediate with two adjacent stereocenters. A kinetically controlled cyclization to build the challenging thermodynamically less stable 8R-hemiaminal moiety is also important in the synthesis of amathaspiramide D. The route is readily scalable, and gram quantity of the final product D has been prepared.

A novel and practical asymmetric synthesis of dapoxetine hydrochloride.

A novel and practical asymmetric synthesis of dapoxetine hydrochloride by using the chiral auxiliary (S)-tert-butanesulfinamide was explored. The synthesis was concise, mild, and easy to perform. The overall yield and stereoselectivity were excellent.

Synthesis of chiral trans-fused 2-methyl-5-hydroxyldecahydroquinoline

A practical asymmetric synthesis of the trans-fused 2-methyl-5-hydroxyldecahydroquinolines 8a and 8b is reported. Double Michael addition of enone 4 with (S)-phenylethylamine generated separable C2-methylated decahydroquinolinones 5a and 5b, which were converted to 8a and 8b via several functional group transformations.

Synthesis of Sitagliptin Phosphate by a NaBH4/ZnCl2-catalyzed Diastereoselective Reduction

Abstract A practical asymmetric synthesis of sitagliptin phosphate, from 1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo-[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)butane-1,3-dione, in overall 65.3% yield has been reported. The target compound was synthesized via eneamination, diastereoselective reduction, amine-deprotection, and phosphatization. The key diastereoselective reduction was performed with NaBH4 and ZnCl2, and it gave the product with almost quantitative yield and 68.5% d.e. value after simple work-up and recrystallization with IPA/PE; a high enantiopurity (d.e.% = 99.3%) can also be obtained in 57.1% yield.

Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor

AbstractA practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper‐catalyzed acylation along with the implementation of the BI‐DIME ligands for a ligand‐controlled Suzuki cross‐coupling and an unprecedented bis(trifluoromethane)sulfonamide‐catalyzed tert‐butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.

Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor.

A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.

Practical Asymmetric Synthesis of an Edivoxetine·HCl Intermediate via an Efficient Diazotization Process

A convergent synthesis of (S)-(4-benzylmorpholin-2-yl)(morpholino)methanone methanesulfonate (1), a key regulatory starting material for edivoxetine·HCl, was developed at Eli Lilly & Company. This novel synthesis utilizes d-serine as the source of chirality, which is preserved throughout the synthesis. Key features include the development of a scalable diazotization process to produce (S)-epoxy acid 7, which was optimized to improve the process safety profile. The final (S)-morpholino acid intermediate 11 was converted to the title compound using T3P with >99.9% purity in 75% yield. Life cycle analysis of the new route revealed a 69% reduction in global warming potential (GWP) for solvent usage relative to the prior route of manufacture.