Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

Abstract A general and powerful method for the stereo‐controlled Pd‐catalyzed N‐allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid‐derived C 2‐symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N‐allylated products with highest levels of enantio‐ or diastereoselectivity in a fully catalyst‐controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo‐divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide‐inspired bioactive compounds.


Asymmetric N-allylation: Ligand Screening
[a] Reactions were performed on a 1 mmol scale using 2 equiv. of 5a. [b] concentration of rac-4a; [c] the conversion was determined by means of GC; [d] The enantiomeric ratio was determined by means of GC using a chiral stationary phase; configurational assignments are based on the X-ray crystal structure analysis of the ProM-15 derivative 7a. [a] Reactions were performed on a 1 mmol scale using 2 equiv. of 5a. [b] concentration of rac-4a; [c] the conversion was determined by means of GC; [d] The enantiomeric ratio was determined by means of GC using a chiral stationary phase; configurational assignments are based on the X-ray crystal structure analysis of the ProM-15 derivative 7a.

Optimization of the peptide coupling between trans-N-Boc-3-vinyl-proline (2) and N-allylated amino esters (3)
While the glycine derivatives rac-3a and 3b afforded the expected product (6, R = H) using either PyBOP in acetonitrile or HATU in NMP as a solvent in the presence of DIPEA (Table S2, entries 1 and 2) the sterically more bulky amines (such as 3e) derived from other amino acids required the search for more powerful coupling conditions. Reactions were generally performed on a 0.3 (±0.05) mmol scale. Yields refer to the purified product after chromatography.

General information
All moisture sensitive reactions were carried out under argon atmosphere using Schlenk technique. Glassware was flame-dried under vacuum (<1 mbar) and allowed to cool down under argon atmosphere. Syringes, needles and transfer cannulas were dried in an oven at 100 °C and were flushed with argon directly prior to use. Flash chromatography was performed using silica 60 (0. 035 -0.07 mm) supplied by Acros.
The assignments of 1 H NMR are supported by H, H-COSY, HMQC(HSQC), and HMBC spectra. Carbon multiplicity assignment is based on APT or DEPT spectra. Fourier transform infrared spectroscopy (FT-IR): IR spectra were recorded on a Perkin Elmer FT-IR Paragon 1000 spectrometer using Fourier transform infrared (FTIR) multiplepoint attenuated total reflection (ATR) technique. Absorption bands are given in wave numbers (ṽ, cm -1 ). Intensive bands are marked with (s), medium with (m), weak with (w). Broad bands are marked as (br).

GC-MS
experiments were carried out on Agilent 6890 system with mass detector (MSD) 5937 N. Separation was accomplished using an  Accent column by Macherey-Nagel. For the detection TIC as well as FID was used. Hydrogen was used as carrier gas with a flow of 1.7 ml/min. The column temperature was first hold at 50 °C for 2 min and then increased to 300 °C at 25 °C/min.
For the determination of enantiomeric ratios an Agilent 6890 system with FID detection was used. The separation was performed using a CP-Chiral-Dex CB column by Varian. The carrier gas was nitrogen with a flow of 0.9 ml/min.
Alternatively a Hewlett Packard 6890 system with FID detection was used with hydrogen as carrier gas and a flow of 1.5 ml/min. The used temperature programs are specified in the analytical data of the respective substance as well as the used column.

General procedure 2: Peptide coupling using Ghosez reagent
Under inert conditions 1.1 eq. Ghosez reagent was added to a solution 1.0 eq. Zaminer's acid (2) in CH2Cl2 (0.95 ml/mmol) at 0 °C over 1 h. Afterwards 1.1 eq. DIPEA and a solution of 1.1 eq. of amine 3 in CH2Cl2 (0.85 ml/mmol) was added simultaneously to the solution at 0 °C. The reaction solution was then stirred at r.t. over night. During this process the yellow solution turned to orange. After completion the solution was washed with citric acid solution (10 vol%, 22 ml/mmol Zaminer's acid) and the aqueous phase was extracted three times using CH2Cl2.
The combined organic phases were washed with sat. NaHCO3 solution and sat. NaCl solution and dried over MgSO4. After filtration the solvent was removed under reduced pressure and the resulting yellow raw product was purified by flash column chromatography.

General procedure 3: Ru-catalyzed ring closing metathesis
Under inert conditions a solution of 1.0 eq. of the dipeptide and 4 mol% of the Hoveyda-Grubbs II catalyst (9) in C6F6 (10 ml/mmol, 0.1 M) was warmed to 70 °C and stirred for 3.5 h before another 2 mol% of Hoveyda-Grubbs II catalyst (9) were added. (Note: the mixture turns dark upon heating). After complete conversion the solution was allowed to cool down before the solvent was removed under reduced pressure. The resulting dark green oil was purified by flash column chromatography. The resulting oily product was dissolved in little CH2Cl2 and stirred over QuadraSil AP for 15 min to remove residual ruthenium. After filtration the solvent was removed under reduced pressure and the product was dried in high vacuum to afford the desired bicyclic product.
The resulting oily product was dissolved in little CH2Cl2 and stirred over QuadraSil AP for 15 min to remove residual ruthenium. After filtration the solvent was removed under reduced pressure and the product was dried in high vacuum to afford 90 mg (0.203 mmol, 71%) of the bicyclic product (S,R,S,S)-7b as a colorless viscous oil.
The resulting oily product was dissolved in little CH2Cl2 and stirred over QuadraSil AP for 15 min to remove residual ruthenium. After filtration the solvent was removed under reduced pressure and the product was dried in high vacuum to afford 66 mg (0.149 mmol, 62%) of the bicyclic product (S,R,R,R)-7b as a colorless viscous oil.