Construction of β 2,2-amino acids by palladium catalyzed asymmetric allylation of 4-substituted isoxazolidine-5-one

The author of the paper: Wan yanlang has been the focus of scientists' efforts since β - amino acid showed a good prospect in pharmaceutical chemistry In fact, compounds with β - amino acid fragments tend to show good biological activity and stability, especially for the common peptidases However, interestingly, although all the reported methods can obtain enantiomerized β 2 - and β 3-amino acids, the asymmetric synthesis of β 2,2-amino acids is still a challenge, especially for compounds containing four substituted carbon stereocenters (Figure 1a) Recently, the team of stellios arseniyadis and Janine cossy of Paris University of Arts and Sciences published the method of directly constructing β 2,2-amino acids by palladium catalyzed asymmetric allyl alkylation of 4-substituted isoxazolidine-5-one (DOI: 10.1002 / chem 201800641) on Chemistry - a European Journal In the past few years, the author has been committed to developing new synthesis methods and strategies and applying them to the total synthesis of active natural products In this case, palladium catalyzed asymmetric allylation has recently been applied to two new prochiral substrates, allylic dienol and allylic carbonate This method can be used to construct all kinds of chiral butene lactones and butyrolactones with α - carbon completely substituted stereocenters in a highly enantioselective way In view of the above results, it is assumed that PD AAA can synthesize corresponding α, α - disubstituted products by using 4-substituted isoxazolidine-5-one, and then N-O bond cleavage into β 2,2-amino acid (Figure 1b) (source: Chemistry - a European Journal) the author first studied 4-phenylisoxazolidine-5-one 1A as a model substrate, and the results of its reactivity and enantioselectivity under various conditions are shown in Table 1 For the first group of conditions, the author evaluated the effect of different chiral ligands Results the corresponding α, α - disubstituted isoxazolidine-5-one was obtained in good yields of 85% to 95% But interestingly, different ligands have a great influence on selectivity The results showed that the enantioselectivity of phosphine oxazoline type ligands such as phox, (s) - L4, axial chiral diphosphonate ligands such as BINAP, (R) - L5, spiro diphosphonate ligands such as (R) - SDP (L7) and phosphide amide type ligands such as (s, R, R) - L6 were poor, while C2 symmetric diphosphonate ligands (L1, L2 and L3) were the best After obtaining the best ligands, the author investigated the effect of alkali on the selectivity of the reaction (Table 1), and screened Na 2CO 3, Li 2CO 3, CS 2CO 3, nah and DBU bases Although most bases obtained allylation products in good yield (82-95%), DBU decreased the yield In order to further optimize PD AAA reaction, the author also evaluated the effect of Pd catalyst precursor on the reaction and found that PD 2 (DBA) 3 was superior to PD (allyl) Cl] 2, [PD (cinnamyll) (CL)] 2 and Pd (OAC) 2 In addition, the reduction of PD 2 (DBA) 3 from 5 mol% to 1.25 mol% resulted in a significant reduction of EE from 90% to 79% Next, the author considers whether the change of enantioselectivity can be observed if additives are added to PD AAA reaction under the same conditions However, when the stoichiometric LiCl was used, it was observed that the reaction stopped completely, and the enantioselectivity of 15-crown-5 was comparable to the previous one, but the yield was low (source: Chemistry - a European Journal) the effect of solvents on the selectivity of the reaction was investigated (Table 1) As a general trend, ether solvents such as THF, MTBE, dioxane and larger polar solvents such as NMP have the best EE value range from 82% to 90% Curiously, the alkylation products obtained by using toluene and acetonitrile have good yield but low enantioselectivity When the reaction is carried out at a lower temperature such as 0 ℃ or - 10 ℃, the EE value of the product is slightly increased, so the author finally decided to set the reaction temperature as 0 ℃ After determining the optimal reaction conditions [PD 2 (DBA) 3 (5 mol%), (R, R) - L1 (10 mol%), Na 2CO 3 (2 equivalent), THF, 0 ℃], the author screened the substrate range, and summarized the results in Table 2 (source: Chemistry - a European Journal) the results show that this method can be widely applied to 4-aryl / heteroaryl isoxazoline-5-one compounds with high yield (86-97%) and enantioselectivity (85-92%) The introduction of electron donating substituents, such as methoxy or methyl, and electron absorbing substituents, such as chlorine, bromine, fluorine or trifluoromethyl, in the aromatic ring pair position have achieved good results In addition, the optical purity of the product can be further improved after recrystallization with pentane / ether The model proposed by Trost et al Can be used to predict the absolute configuration of the newly formed total substituted carbon solid center The enolase is close to the π - allyl PD - (R, R) - L1 complex re surface to avoid the adverse steric hindrance between the "wall" of the ligand and the BOC Group of the substrate This selectivity is confirmed by single crystal X-ray analysis (see structure in Table 2) In order to expand the scope of the reaction, the author then turned his attention to substituted allyl acetate, especially 2-substituted allyl acetate The results are shown in Table 3 (source: Chemistry - a European Journal) under the above conditions, when isoxazolidine-5-one 1A reacts with a series of allyl acetate, the corresponding α - allylation products are separated with excellent enantioselectivity (EE up to 95%) In general, the effect of electron effect on stereoselectivity is more obvious than that of space effect When the volume of C2 substituent is increased, such as using methyl, trimethylsilyl or phenyl instead of hydrogen atom, the enantioselectivity of the reaction is improved However, the chlorine atom or methyl ester substituents have adverse effects on the enantioselectivity and yield of the reaction Interestingly, when 2 - [(trimethylsilyl) methyl] allyl acetate is used, the value of the allyl methylate derivative 2J is obtained in 94% yield and 90% ee; when 2-methoxy substituted allyl acetate (2O) is used, the reaction even stops completely Finally, a practical and highly enantioselective method for the synthesis of α, α - disubstituted isoxazolidine-5-one-2 was established, and a simple method was developed to convert it into corresponding β 2,2-amino acid 3 and β - lactam 4 (scheme 1) In order to achieve N-O bond breaking, the author screened various reaction conditions (Na 2S 2O 4 / EtOH / H 2O, SMI 2 / THF, Zn / AcOH), but none of them got the expected amino acids Fortunately, at - 78 ℃ in THF solvent, naphthyl sodium was used to obtain 90% yield of product 3 Then, the carboxylic acid was methylated by tmschn 2 and deprotected by TFA The cyclized product 4 was obtained under the action of ET 3N, tmscl and t-bumgcl (source: Chemistry - a European Journal) conclusion: the author has developed a novel and highly enantioselective catalytic scheme for the synthesis of α, α - disubstituted isoxazolidine-5-ketone with α - carbon completely substituted solid center by palladium catalyzed asymmetric allyl alkylation In addition, valuable β 2,2-amino acids and β - lactam can be synthesized by subsequent reaction transformation.