JACS: the enantioselective phosphination of diene and phosphine oxide

Conjugated diene is the key structure of many natural products and drug molecules In recent years, the research of hydrogenation functionalization of dienes has been booming However, compared with other hydrogenated functionalization (such as borohydride and hydroformylation), the study of phosphine acylation is only in its infancy In 1982, Hirao first reported the preparation of allylphosphonate by coupling isoprene and diethyl phosphonate The reaction needs to be carried out at 150 ℃ and the yield is only 10% Tanaka later improved the reaction by using a more active pinacol phosphonate ester to achieve the hydrophosphonylation of 1,3-diene However, this strategy is still limited to the generation of enantiomers or racemic mixtures Considering the application of chiral phosphine in catalysis, medicine and agricultural chemistry, it is necessary to develop more efficient enantioselective phosphine acylation (source: J am Chem SOC.) recently, the research team of vy M Dong, University of California, Irvine, USA, reported for the first time the palladium catalyzed hydrophosphorylation of diene and phosphine oxide, which has high regioselectivity and enantioselectivity Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 8b1150) Firstly, the reaction conditions were screened with 1-phenylbutadiene (1a) and diphenylphosphine (2a) as substrates (Table 1) It is found that the occlusal angle of the chiral diphosphonate ligands can affect the efficiency of the reaction When PD 2 (DBA) 3 and bis (diphenyl phosphine) ferrocene (dppf) are combined to catalyze the reaction, the efficiency of phosphine acylation is the best Through further optimization, the author found that the target product 3AA could be synthesized with high yield (91%) and selectivity (> 20:1 RR, 95:5 ER) at the scale of gram when the catalyst loading was reduced to 0.50 mol% In addition, the addition of acid can accelerate the reaction rate After (source: J am Chem SOC.), the author investigated the hydroformylation of various 1,3-dienes with 2A (Table 2) All kinds of aryl substituted dienes can be converted into the chiral product 3ba - 3ja with medium to good yield and excellent selectivity The reactivity of chlorinated aromatic dienes (3CA, 3HA, 3ia) is higher than that of brominated aromatic dienes (3DA) Butadiene and isoprene can be coupled with 2a to obtain chiral 3mA and 3Na, respectively (source: J am Chem SOC.) next, the author studied the hydrophosphorylation of 1A with various phosphines oxide (Table 3) In general, the reactions showed high reactivity (3AB - 3AM, 51-88%), regioselectivity (> 20:1rr) and enantioselectivity (74:26-98:2er) The coupling can withstand all kinds of substituted aryl (3AB - 3AI), heterocyclic (3aj) and alkyl (3AK) phosphine oxide (source: J am Chem SOC.) in order to verify whether the control catalyst can selectively obtain the diastereomers, the author prepared the phosphine oxide 2n containing tert butyl and phenyl, and obtained (R, R) - diastereomer 3an and (R, s) - diasterer 3an '(Figure 2) respectively through the enantiomeric control of ligand L3 (source: J am Chem SOC.) finally, the author proposed the transformation mechanism of the reaction (Figure 3) First, Pd (0) precatalyst was substituted with diphosphonic acid to form chiral monomer species I, and then oxidized with diphenylphosphinic acid (HX) to form pd-h species II After that, II can obtain the main product 3 (path a) and the secondary product 4 (path B) through two different reaction paths In pathway a, III undergoes ligand exchange with phosphine oxide 2 via the key PD - π - allyl intermediate IV to form species v Then, allyl phosphine oxide 3 was eliminated by V reduction and Pd catalyst was regenerated (source: J am Chem SOC.) conclusion: the research team of vy M Dong, University of California Irvine, has developed the enantioselective hydrophosphonylation of dienes for the first time, which provides a supplementary method for the preparation of chiral allyl products The mechanism study shows that the coupling is carried out by reversible palladization of 1,3-diene, and then irreversible reduction elimination is carried out to obtain chiral allylic phosphine oxide.