Stereoselective Synthesis of Functionalized Cyclic Amino Acid Derivatives via a [2,3]-Stevens Rearrangement and Ring-Closing Metathesis

Abstract

Unnatural cyclic amino acids are valuable tools in biomedical research and drug discovery. A two-step stereoselective strategy for converting simple glycine-derived aminoesters into unnatural cyclic amino acid derivatives has been developed. The process includes a palladium-catalyzed tandem allylic amination/[2,3]-Stevens rearrangement followed by a ruthenium-catalyzed ring-closing metathesis. The [2,3]-rearrangement proceeds with high diastereoselectivity through an exo transition state. Oppolzer's chiral auxiliary was utilized to access an enantiopure cyclic amino acid by this approach, which will enable future biological applications.

Olefin Metathesis Reactions with Fluorinated Substrates, Catalysts, and Solvents

“…Besides the industrial application in ring-opening metathesis polymerization (ROMP) and acyclic diene metathesis polymerization (ADMET), olefin metathesis is used for the preparation of low molecular weight organic compounds by cross metathesis (CM) or by ring-closing metathesis (RCM). The latter variation is one of the most frequently used methods of C–C-bond formation in the synthesis of carbocyclic and heterocyclic compounds bearing numerous endocyclic functions. − , Also, cyclic amino acids, peptides and peptidomimetics, polycyclic alkaloids, as well as carbohydrates have been synthesized. Particularly medium sized and macrocyclic compounds and other thermodynamically less favored ring systems and those bearing special substituent patterns including tetrasubstituted alkenes can be more easily prepared by RCM than by classical methods, making this type of reaction one of the most frequently applied methods for elegant syntheses of carbo- and heterocyclic natural products …”

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides

“…Analysis was carried out using Shimadzu IRsolution v1.50 and only characteristic peaks are reported. 1 H, 13 C{ 1 H}, 19 F{ 1 H} and 19 F NMR spectra were acquired on either a Bruker Avance 300 {δ H (300 MHz), δ C (75 MHz), δ F (282 MHz)}, a Bruker Avance II 400 {δ H (400 MHz), δ C (100 MHz), δ F (376 MHz)}, a Bruker Ultrashield 500 {δ H (500 MHz), δ C (126 MHz), δ F (471 MHz)}, a Bruker Ascend 400 {δ H 400 MHz, δ C (100 MHz), δ F (471 MHz)} or a Bruker Avace III 700 {δ H (700 MHz), δ C (179 MHz), δ F (659 MHz)} spectrometer at ambient temperature (unless otherwise stated) in the deuterated solvent stated. Chemical shifts, δ, are quoted in parts per million (ppm) and are referenced to the residual solvent peak.…”

“…in THF at 60 °C, gave 42 in modest yield (46% yield) but with retention of diastereomeric purity. Subsequent N-benzyl protection to give 43, followed by treatment with Hoveyda-Grubbs 2 nd generation catalyst (HG-II) (5 mol%) in the presence of p-toluenesulfonic acid 19 (1.5 equiv.) in toluene at 80 °C gave ring-closed product 44 in good yield and as a single diastereoisomer after purification.…”

Catalytic Stereoselective [2,3]-Rearrangement Reactions

“…Tambar and co-workers reported the diastereoselective synthesis of cyclic α-amino acid derivatives through a tandem allylic amination-[2,3]-rearrangement followed by ring-closing metathesis. 108 For example, reacting homoallyl amino ester 254 with allylic carbonate 255 under the previously optimized conditions followed by ring-closing metathesis of the intermediate [2,3]-rearrangement product using Hoveyda−Grubbs II gave cyclic α-amino acid 256 in 85% yield and 89:11 dr (Scheme 61). The methodology was applied to a range of aryl and alkyl substituted allylic carbonates, forming the cyclic products in generally good yields and high diastereoselectivity over the two steps.…”