Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives

The scope and limitations of a tandem N-allylation/[2,3]-rearrangement protocol are investigated through the incorporation of a variety of functional groups within an allylic phosphate precursor. This method uses readily accessible N,N-dimethylglycine aryl esters and functionalized allylic phosphates, forming quaternary ammonium salts in situ in the presence of a palladium catalyst. Subsequent enantioselective [2,3]-sigmatropic rearrangement, promoted by the chiral isothiourea tetramisole, generates α-amino acid derivatives with two contiguous stereocenters. The incorporation of electron-withdrawing ester and amide groups gave the best results, furnishing the desired products in moderate to good yields (29–70%), with low diastereocontrol (typically 60:40 dr) but high enantioselectivity (up to 90:10 er). These results indicate that substrate–catalyst interactions in the proposed transition state are sensitive to the substitution pattern of the substrates.

Mass spectrometry (m/z) data were acquired by either electrospray ionisation (ESI) or nanospray ionisation (NSI) at either the University of St Andrews Mass Spectrometry Facility or at the EPSRC UK National Mass Spectrometry Facility at Swansea University.

General Procedure for the Synthesis of Allylic Phosphates
Following the procedure of Smith and co-workers 2 , allylic alcohol (1.0 eq) was added to a flame dried round bottom flask and dissolved in anhydrous CH2Cl2 (0.1 M) under argon atmosphere. Et3N (1.5 eq) and DMAP (0.25 eq) were added, the mixture was cooled to 0 °C and diethyl chlorophosphate (1.5 eq) was added dropwise. Stirring was continued at rt until TLC analysis indicated complete conversion. The reaction mixture was quenched with sat. aq. NaHCO3 (equal volume), the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3 × equal volume). The combined organic phases were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude residue was purified by flash silica chromatography as specified.
General Scheme for the Synthesis of Amide containing Allylic Alcohols

General Procedure for Amide Coupling
Adapting the procedure of Snaddon and co-workers, 5 monoethyl fumarate (1.0 eq) and amine (1.1 eq) were dissolved in CH2Cl2 (0.4 M), followed by the addition of EDCIHCl (1.1 eq) and DMAP (0.1 eq) at 0 °C. The reaction mixture was allowed to warm to room temperature overnight and subsequently washed with 1 M HCl (2 × equal volume) and brine (2 × equal volume). The organic phase was dried over MgSO4, filtered and the solvent removed under reduced pressure to yield the corresponding amide ester, which was used without further purification.

General Procedure for Ester Hydrolysis with LiOH
Adapting the procedure of Smith and co-workers, 6 LiOH·H2O (1.1 eq) was added in portions to a stirred solution of ethyl ester (1.0 eq) in H2O : THF 1:1 (1.0 M). The reaction was stirred overnight at room temperature followed by acidification with 2 M HCl to pH 2 and extraction with CH2Cl2 (3 ×). The combined organic phases were dried over MgSO4 and the solvent removed under reduced pressure to yield the corresponding acid.

General Procedure for the Reduction of unsaturated Acids
Adapting the procedure of Jacobi and co-workers, 7 to a stirred solution of unsaturated acid (1.0 eq) and Et3N (1.1 eq) in anhydrous THF (0.4 M) under inert atmosphere at 0 °C was added dropwise ethyl chloroformate (1.1 eq). The resulting suspension was stirred at 0 °C for 1 h, filtered and the solid washed twice with anhydrous THF. The combined filtrates were added dropwise to a vigorously stirred solution of NaBH4 (2.5 eq) in H2O (0.7 M) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred until TLC indicated complete conversion. The mixture was adjusted to pH 5 with 1 M HCl, extracted with EtOAc (4 ×) and the combined organic phases dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified by silica column chromatography as specified.

General Procedure for Tandem Pd/ITU Relay Catalysis
A Schlenk tube was charged with PdFurCat (5 mol%) or Pd2(dba)3CHCl3 (2.5 mol%) and P(2-furyl)3 (10 mol%), (S)-TMHCl (10 mol%) and PNP Ester (1.0 eq). The tube was then evacuated and flushed with argon three times, degassed MeCN (0.06 M) was added and the mixture stirred for 10 min at room temperature. Subsequently phosphate or mesylate (1.0 -2.0 eq) and iPr2NEt (2.4 eq) were added in this order and the reaction mixture stirred at room temperature for 16 h. An aliquot was taken, the solvent removed under reduced pressure and 1 H NMR spectroscopy of the crude mixture used to determine the dr. The reaction S7 mixture was then filtered over a short plug of silica with MeCN and the filtrate concentrated under reduced pressure. The residue was purified by flash silica chromatography as specified or directly derivatised with NaOBn.
Derivatisation with NaOBn: The crude reaction mixture was dissolved in anhydrous THF (6.0 mL), freshly prepared NaOBn (1 M in anhydrous THF, 0.45 mL, 0.45 mmol, 1.5 eq) added dropwise at room temperature and the reaction monitored by TLC. After complete conversion (ca. 3h) the reaction was quenched with sat. NaHCO3 solution (equal volume) and diluted with EtOAc.
The phases were separated, the aqueous phase extracted with EtOAc (3 × equal volume) and the combined organic phases washed with sat. NaHCO3 (2 × equal volume) and brine (equal volume). The organic phase was dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the crude product, which was purified by silica column chromatography as specified.

2-Phenylprop-2-en-1-ol (SI-5)
Following the procedure from Snaddon and co-workers, 15 in a flame dried three necked flask Mg turnings (1.46 g, 60.0 mmol, 3.0 eq) were covered with anhydrous Et2O under an inert atmosphere. Bromobenzene (5.32 mL, 50.0 mmol, 2.5 eq) was dissolved in 40 mL anhydrous Et2O and added dropwise in the presence of a small amount of iodide to help start the reaction. The rate of addition was adjusted to keep a constant reflux. After complete addition the reaction mixture was heated at reflux for 1 h and subsequently allowed to cool to rt. CuI

2-Phenylallyl methanesulfonate (17)
Following the procedure of Snaddon and co-workers, 15 in a flame dried round bottom flask methanesulfonic anhydride (2.05 g, 11.8 mmol, 2.0 eq) was added to a stirred solution of alcohol SI-5 (5.88 mmol, 790 mg, 1.0 eq) in anhydrous CH2Cl2 (15 mL). The mixture was cooled to 0 °C and iPr2NEt (2.05 mL, 11.8 mmol, 2.0 eq) added dropwise. The reaction mixture was allowed to warm to rt and stir until TLC (Petrol : EtOAc 4:1) indicated complete conversion. The solvent was removed under reduced pressure and the crude product purified by silica column chromatography (Petrol : Et2O 5:1 to 2:1) to yield the title compound as a yellow liquid (748 mg, 60%). Data in accordance with literature. 15
The solvent was removed under reduced pressure, the residue diluted with H2O (20 mL) and S14 brine (20 mL) and extracted with CH2Cl2 (4 × 30 mL). The combined extracts were washed with 1 M HCl (40 mL) and brine (40 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was recrystallised from CH2Cl2 to afford the title compound as yellow solid (2.74 g, 33%). m.p. (CH2Cl2) 129 -131 °C.
After cooling to room temperature, the reaction was quenched with sat. NH4Cl solution (40 mL), the phases separated and the aqueous phase extracted with Et2O (3 × 60 mL). The

S53
Proposed Mechanism for the Formation of 44 coordinates to the unsubstituted allylic fragment (A6, Path B). As the nucleophilic substitution step is reversible, Pd-π-allyl complex A8 can form. This step also produces A7 as an unproductive side product, however, this could not be isolated. The unsubstituted Pd-πallyl complex A8 can react with another molecule of PNP ester A5, giving ammonium salt A9 bearing two unsubstituted allyl fragments. It is also conceivable that A9 can be obtained from an uncatalyzed nucleophilic substitution of ammonium salt A4 with a molecule of PNP ester A5 (Path C). [2,3]-rearrangement of ylide A10 formed from ammonium salt A9 will lead to PNP ester A11, which upon derivatization with NaOBn gives the observed side product 44.