Synthesis of β2,2-Amino Acids by Stereoselective Alkylation of Isoserine Derivatives Followed by Nucleophilic Ring Opening of Quaternary Sulfamidates

Chiral bicyclic N,O-acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem N,O-acetalization/intramolecular transcarbamoylation reaction between conveniently protected l-isoserine and 2,2,3,3-tetramethoxybutane. The delicate balance of the steric interactions between the different functional groups on each possible diastereoisomer controls their thermodynamic stability and hence the experimental product distribution. These chiral isoserine derivatives undergo diastereoselective alkylation at the α position, proceeding with either retention or inversion of the configuration depending on the relative configuration of the stereocenters. Quantum mechanical calculations revealed that a concave-face alkylation is favored due to smaller torsional and steric interactions at the bicyclic scaffold. This synthetic methodology gives access to chiral β2,2-amino acids, attractive compounds bearing a quaternary stereocenter at the α position with applications in peptidomimetic and medicinal chemistry. Thus, enantiopure α-alkylisoserine derivatives were produced upon acidic hydrolysis of these alkylated scaffolds. In addition, α-benzylisoserine was readily transformed into a five-membered ring cyclic sulfamidate, which was ring opened regioselectively with representative nucleophiles to yield other types of enantiopure β2,2-amino acids such as α-benzyl-α-heterofunctionalized-β-alanines and α-benzylnorlanthionine derivatives.


Additional tables to follow the text of the manuscript
. Formation of chiral N,O-acetals 2, 3 and 4 from Boc-L-isoSer-OMe (1) and TMB.  Only the conditions of entry 15 gave good results when we tried to scale up the reaction. For this reason, other entries such as 5, 7 and 13 were not considered.

Diastereomeric purity determination
Purity of building blocks 2 and 3.
After an easy purification by column chromatography, compound 2 was used as starting material with a 98:2 diastereomeric ratio with respect to diastereomer 3. In the case of compound 3 the diastereomeric ratio after column chromatography was 99:1 with respect to diastereomer 2. Figure S1. Overlapping of 1 H NMR spectra corresponding to compounds 2 and 3. Figure S2. 1 H NMR zoom corresponding to spectra of starting materials after purification by column chromatography: compound 2 (A) and compound 3 (B). Taking into account the starting purity of compound 2 (98% of 2 and 2% of 3), and that alkylation of the minor isomer (3) gives the enantiomer of the alkylated compound (6a), subsequent hydrolysis to obtain the amino acid gives compound 7a with an ee = 96%. Similar features occurred for amino acid 8a, which was obtained with an ee = 94%.
2) The diastereomeric ratio for alkylation reaction of compound 2 with ethyl triflate to give 5b is 85/15 measured by 1 H NMR of the crude reaction mixture. Figure S5. Ratio of diastereomers extracted from the 1 H NMR spectrum of the crude alkylation reaction mixture of 2 with EtOTf.
After purification by column chromatography, the corresponding compound 5b has a diastereomeric purity of 95:5 with respect to the minor diastereomer. Taking into account the starting purity of compound 2 (98% of 2 and 2% of 3), and that alkylation of the minor isomer (3) gives the enantiomer of the alkylated compound, subsequent hydrolysis to obtain the amino acid gives compound 7b with an ee = 86%.
3) The diastereomeric ratio for alkylation reaction of compound 2 with benzyl iodide to give 5c is 80/20. In the same way, the ratio of diastereoisomers for alkylation of compound 3 with benzyl iodide to give 6c (enantiomer of 5c) as the major compound is 80/20. In both cases, these ratios were measured by 1  After purification by column chromatography, in the 1 H NMR spectrum of the corresponding compound 5c, used as starting material for sulfamidate chemistry, the minor diastereomer was not observed. In the same way, after purification by column chromatography the corresponding compound 6c was obtained in a 98:2 ratio respect to its diastereomer. Figure S8. In red the mixture 80:20 of diastereoisomers. In blue the purified compounds 5c (A) and 6c (B). Compound 5b appears as a pure compound and 6c in a 98:2 ratio.

S8 / S93
Taking into account the starting purity of compound 2 (98% of 2 and 2% of 3), and that alkylation of the minority isomer gives the enantiomer of the alkylated compound, enantiomeric excess of 5c is ee = 96%. Subsequent hydrolysis to obtain the amino acid gives compound 7c with an ee = 96%. The same enantiomeric excess was obtained for the sulfamidate 10 and the amino acid derivatives, which undergo reactions without loss of enantiomeric purity (ring-opening and hydrolysis reactions).

4)
The diastereomeric ratio for alkylation reaction of compound 2 with allyl iodide to give 5c is 87/13 measured by 1 H NMR of the crude reaction mixture. Figure S9. Ratio of diastereoisomers extracted from the 1 H NMR spectrum of the crude alkylation reaction mixture of 2 with allyl iodide.
After purification by column chromatography, in the 1 H NMR spectrum of the corresponding compound 5d, the minor diastereomer was not observed.
Figure S10. In red de mixture 87:13 of diastereoisomers. In blue the pure compound 5d. Compound 6a is the enantiomer of 5a and its spectral data are in good agreement 1

H NMR 400 MHz in CDCl 3
Compound 7a (α−MeisoSer) is the enantiomer of 8a and their spectral data are in good agreement and match with previously published data (reference 24 in the manuscript).   S64 / S93

Computational details
All possible conformers and ring isomers were investigated. Some structures converged to the same stationary point upon optimization; redundant isomers were discarded and only the unique structures were included in the Boltzmann distribution of Gibbs free energies, summarized in the following table. Bold entries are the minimum energy structures for each diastereomer. The index in last position of each structure names corresponds to the approximate value of dihedral angle formed between Me 7 -C 7 -O 7 -OMe 7 .

Acid-catalyzed elimination to form enecarbamates 4
Protonation at O1 in all the conformers calculated for I (compound 3) and III (compound 2) led to the spontaneous cleavage of the O1-C7a bond and formation of enammonium cations (4 H ) upon optimization of the corresponding structures. Only one structure of each diastereoisomers (2 H and 3 H ) kept these atoms bonded to each other. Potential energy scan along the O1-C7a bond revealed a barrierless (ΔE ‡ < 0.2 kcal mol -1 ) and highly exergonic process (ΔE ≈ -15.0 kcal mol -1 ) for both diastereomers.

X-Ray diffraction analysis
Details of the X-ray analyses are summarized in Table S6. Compound 2 was dissolved in dichloromethane and n-hexane was added carefully creating an interphase. The colourless crystal block was obtained by slow diffusion at 4 °C. Compound 10 was dissolved in dichloromethane and crystal needle was obtained at 4 °C. The formed crystals were analysed by X-ray diffraction.
The diffraction data were collected using graphite-monochromatic Mo-K a radiation with a Bruker APEX-II diffractometer at a temperature of 298 K using the APEX3 software. The absorption correction was performed using MULTI-SCAN. S1 The structures were solved with the WINGX program suite S2 and refined by full-matrix least squares with SHELXL. S3 Hydrogen atoms were located by mixed methods (electron-density maps and theoretical positions).
Mercury diagram of compounds 2 and 10 are represented in the Figure S16.

Enantiomeric purity determination of 7c and 8c by NMR chiral shift reagents
Following a recent but slightly modified procedure, S4,S5 the corresponding β-amino acid 7c, 8c or a mixture of known amounts of both was dissolved in D2O to generate a 0.05 M solution. The pH of these three solutions was adjusted to 10 using 1 M KOH solution in D2O. Then, a solution of 8 mg/mL of samarium(III) complex with (S,S)-ethylenediamine-N,N'disuccinate in D2O was prepared and 0.2 mL of this solution were added to each of the corresponding NMR tubes containing 0.5 mL of a solution of the amino acids 7c, 8c or the mixture of both. The 1 H NMR experiments were registered in a 400 MHz spectrometer. [