Synergistic catalysis for cascade allylation and 2-aza-cope rearrangement of azomethine ylides

The efficient construction of enantiomerically enriched molecules from simple starting materials via catalytic asymmetric synthesis strategies is a key challenge in synthetic chemistry. Metallated azomethine ylides are commonly-used synthons for the preparation of N-heterocycles and α-amino acids. Remarkably, to date, the utilization of azomethine ylides for the facile access to chiral amines has proven elusive. Here, we report that a synergistic Cu/Ir-catalytic system combined with careful tuning of the steric congestion can be used to convert aldimine esters to a variety of chiral homoallylic amines via a cascade allylation/2-aza-Cope rearrangement. The elucidation of the distinct effects of each stereogenic center of the allylation intermediates on the stereochemical outcome and chirality transfer in the rearrangement further guided the selection of catalysts combination.

S5 stirring for 0.5 h, 2 N NaOH (1 mL) and Boc2O (88 mg, 0.4 mmol) was then added and stirring at rt for 3 h. The layers were separated, and the aqueous layer was extracted with DCM (5 mL x 2). The combined organic components were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtration and evaporated in vacuum. The residue was purified by column chromatography to give the desired product, which was then directly analyzed by HPLC to determine the enantiomeric excess.

tert-butyl (R)-(1-(4-chlorophenyl)-3-phenylbut-3-en-1-yl)carbamate (Figure 7)
Following (Z)-geometry 3s was isolated as major product, and the Z/E ratio was 13:1 according to the crude 1 HNMR. We proposed a possible transition state to rationalize the stereoselectivity. However, this interesting phenomenon for the synthesis of (Z)geometry of homoallylic amines with high Z/E ratio are not suitable for allylic carbonates other than crotyl carbonate (when n-propyl, cyclohexyl and 2-phenylethyl substituted allylic carbonates was conducted, a mixture of Z/E products with 1.5:1 to 3:1 Z/E ratio were obtained).

Synthesis of 7
A suspension of Pd/C (0.15 g) and 6 (1.43 g) in 10 mL EtOH and H2 was stirred at 30 o C under 30 atm hydrogen atmosphere. After being stirred for 6 h, the mix was filtered through a pad of Celite to remove the Pd/C powder. The organic solvent was then removed by rotary evaporation to give the desired product DL-methyl leucine 7 in >98% purity (1.43 g, 99%).

Synthesis of (S)-10
A

S37
Cope rearrangement: The reaction was performed following general reaction procedure A without further work up. (2S,3S)-3z' was isolated as single isomer, which was diluted in CD2Cl2, and taken a 1 H NMR spectrum using CH2Br2 as internal standard.
(2S,3S)-3z' (0.2 mmol) and CH2Br2 (0.2 mmol) were dissolved in a mixed solution of CD2Cl2 (250 µL) and d8-toluene (250 µL) and transferred to a dry NMR tube. The and transferred to a dry NMR tube. The NMR tube was sealed up, heated to 50 o C for the specified time and submitted to the NMR analysis.

Investigation on steric effect of 2-aza-Cope rearrangement
The screening of aldimine esters with different substituents strongly indicated that the steric effect is the key fact for 2-aza-Cope rearrangement (Table S1). For instance, aldimine esters with less bulky -substituents such as benzyl and methyl group provide the allylated intermediates without sufficient steric congestion, and therefore The iridium complex was prepared according to Hartwig's method. 7 Dissolved the complex (10 µmol) with 500 µL CD2Cl2 and transferred to a dried NMR tube for NMR analysis.

Preparation of a mixed complex solution
To a dried NMR tube were successively added the solution of iridium complex (10 µmol, prepared as mentioned before) in 300 µL CD2Cl2 and the solution of Cu(I)-L3 complex (40.0 µmol, prepared as mentioned before) in 300 µL CD2Cl2 at room temperature under argon atmosphere, and the resulting mixture was shaken up for 30 sec. The 31 P NMR spectra were recorded at 25 o C at 3 h after the two solutions were mixed. No new peak was observed according to the 31 P NMR spectra, indicated that the ligand scrambling was negligible or absent in this reaction ( Figure S1). The reaction was performed as the general procedure A described except to use L2 instead of L3 as the chiral ligand for copper(I) complex. After reacted at room temperature for 18 h, only trace amount of desired product formed. The result indicated