JACS: Zhang Liming group, University of California, Santa Barbara, realizes asymmetric isomerization of alkynes and asymmetric synthesis of 2,5-dihydrofuran catalyzed by chiral bifunctional phosphine ligands / gold

The direct isomerization of alkynes to chiral propadiene is the simplest and most atom economical method However, the literatures focus on alkynes with acid propargylic hydrogen, and the asymmetric isomerization of other alkynes is rarely reported Zhang Liming's group at the University of California, Santa Barbara, previously reported the method of isomerization of arylalkyne into 1-aryl-1,3-diene via propadiene intermediate (scheme 1a), which can be realized by bifunctional phosphine ligands L1 and L2 with distal aniline In order to overcome the internal balance between alkyne and propadiene during isomerization, the author proposes to capture the in-situ generated chiral propadiene (scheme 1b) by stereospecific cyclization of propadienyl methanol In this way, chiral propargyl alcohol can be directly converted into chiral 2,5-dihydrofuran Chiral 2,5-disubstituted 2,5-dihydrofuran and its analogues widely exist in various bioactive natural products (scheme 1c) However, due to the need to introduce two necessary chiral centers in advance or derive from the existing chiral elements through stereoselectivity (scheme 1D), the method of constructing chiral 2,5-dihydrofuran does not have the characteristics of increasing the stereochemistry complexity Recently, Zhang Liming's group has realized asymmetric isomerization of alkynes and asymmetric synthesis of 2,5-dihydrofuran catalyzed by chiral bifunctional phosphine ligand / gold The research results are published in J am Chem SOC (DOI: 10.1021 / JACS 8b12833) (photo source: J am Chem SOC.) the synthesis of L2 usually requires the use of a diaryl skeleton (scheme 2a) with a stable chiral axis However, the yield of the reaction is very low (~ 14%) when a large steric hindrance pad 2 group is introduced around the crowded chiral axis Therefore, we have designed a scheme 2B with variable axial direction, which has a chiral center at C1 position of 1,2,3,4-tetrahydroisoquinoline ring The orientation of the R substituents in (a r, R) - L4 is far away from the catalytic site, which will not affect the catalytic activity of Au + complexes On the other hand, L4 is turned 180 ° axially to obtain (as, R) - L4, which has an R group pointing to the catalytic site The large steric hindrance R group has a space shielding effect to prevent the nitrogen lone pair electrons from participating in the deprotonization Therefore, similar to the stable axial chirality in L3, the central chirality can only involve the distal tertiary amino group in deprotonation Since (a r, R) - L4 Au + and (a s, R) - L4 Au + cannot be converted to each other, (a s, R) - L4 Au + will be wasted due to catalytic deactivation (photo source: J am Chem SOC.) based on the above strategy, the author prepared a series of chiral ligands and studied the cycloisomerization reaction with (R) - dodecyl-3-alkyne-2-ol (5a) as the substrate (Table 1) It was found that when the ligand was (R) - L4 - 4, the yield (76%) and the enantioselectivity (trans: CIS = 93:7) were better Later, the author found that when the reaction temperature was 80 ℃, the solvent was DCE, and the substrate concentration was 0.05 M, the yield of the reaction was better (85%), and the lower loading of NABAR F4 or the addition of 3 μ MS would lead to a slightly lower yield (photo source: J am Chem SOC.) through the optimized reaction conditions, the author studied the application scope of the reaction (Table 2) Firstly, a series of chiral secondary propargylic alcohols (5, R1 = me, R2 = h) were screened When C = C, phenyl, benzyloxy, phthalimide and chlorine are contained in R3, the reaction has good yield and enantioselectivity; when cyclopentyl, cyclohexyl and 1-adamantyl with large steric hindrance are introduced in R3, the enantioselectivity of the reaction is improved and the yield is good The introduction of n-amyl, isopropyl or phenyl in R1 gave excellent yield and enantioselectivity, while the introduction of tert butyl reduced the yield, but the trans / CIS selectivity remained good In addition, all four stereoisomers of 2,5-disubstituted 2,5-dihydrofuran can be obtained by using different combinations of l4-4 and substrate enantiomers (photo source: J am Chem SOC.) next, the author turned his attention to the chiral propargyl alcohol substrate 6, which can be enantioselective cycloisomerized In general, chiral TERT propargyl alcohol derivatives have good tolerance to steric hindrance, and excellent yield and enantioselectivity can be obtained However, due to steric hindrance, the reaction of estrone derivatives is slow, and the catalyst loading and reaction time need to be increased, but its cycloisomerization has enantioselectivity (> 50:1) In order to study the role of ligands, the author first separated two kinds of pre catalyst's resistance to transfer isomers, and confirmed their differential isomer structure (scheme 3a) by single crystal X-ray diffraction For [(a s, R) - L4 - 4] AuCl, cyclohexyl competes for the space occupied by Cl and blocks the binding with π - substrate during the catalytic process; for [(a r, R) - L4 - 4] AuCl, the direction of cyclohexyl is far away from the metal When the mixture of [(a r, R) - l4-4] AuCl and [(a s, R) - l4-4] AuCl (1:1.7) is heated at 80 ℃ for 1 h, its proportion does not change, indicating that the axial configuration of the ligand is stable after coordination with AuCl The mixture (1:1) of [(a r, R) - l4-4] AuCl and [(a s, R) - l4-4] AuCl can be completely converted to [(a r, r-l4-4] AuCl (scheme 3b, EQ 1) under suitable conditions, which shows that the diaryl axis of the ligand can rotate at 80 ℃, which is thermodynamically advantageous to asymmetric catalysis In addition, the stability of the axial isomer of the pre catalyst had no significant effect on the conversion and yield (scheme 3b, EQ 2) DFT calculation results show that the reaction undergoes the process of CIS near plane deprotonation Therefore, the author can construct two competing models (scheme 3C) to produce opposite allene configuration Model II experienced the spatial interaction of R 3 and the instability of aromatic ring, while model I did not Therefore, deprotonization will benefit model I The predicted products are consistent with the experimental results, and the subsequent proton depolarization has stereoselectivity (photo source: J am Chem SOC.) conclusion: Zhang Liming's research group has realized the asymmetric isomerization of alkynes catalyzed by chiral bifunctional phosphine ligands / gold, and synthesized chiral propadiene In addition, chiral 2,5-dihydrofuran compounds can be obtained directly from chiral or non chiral propargylic alcohols in good yields, and the new stereocenters have good to excellent stereoselectivity.