Iridium-catalyzed asymmetric cyclization of alkenoic acids leading to γ-lactones

Asymmetric cyclization of alkenoic acids was realized by the use of an iridium/chiral bisphosphine catalyst, giving high yields of the corresponding γ-lactones with good enantioselectivity.

The results obtained for the iridium-catalyzed asymmetric cyclization of alkenoic acids are summarized in Table 2. Several 2,2-disubstituted 4-pentenoic acids 1 underwent the cyclization to give the corresponding lactones 2 (entries 1-7).The reaction of 2,2-diaryl-4-pentenoic acids 1b and 1c, having electrondonating substituents on the aromatic rings, proceeded to give 2b and 2c in high yields with 85 and 83% ee, respectively (entries 2 and 3).The reaction of 1d and 1e, having electronwithdrawing fluoro and chloro groups, gave 2d and 2e with modest enantioselectivity, 70 and 61% ee, respectively (entries 4 and 5).The modest yield (53%) of 2e is due to the loss of 1e by decarboxylation, which was proven to proceed without the iridium catalyst under the reaction conditions: heating of 1e in NMP at 100 1C for 20 h gave 4,4-di(4-chlorophenyl)-1-butene in 56% yield (66% conversion of 1e).2,2-Dialkyl-4-pentenoic acids 1f and 1g are also good substrates to give corresponding lactones 2f and 2g in good yields with 86 and 89% ee, respectively (entries 6 and 7).The substituents at the 2-position of carboxylic acids 1 are essential for the present reaction: 2-pentenioc acid did not undergo the cyclization. 20On the other hand, the reaction of 2-vinylbenzoic acid 1h proceeded at 120 1C to give 2h with a moderate enantioselectivity (entry 8). 21) The stereochemistry of the lactone formed in the present catalytic conditions was estimated by the reaction of enantiomerically pure carboxylic acids 1i.The reaction of (R)-1i in the presence of the Ir/(R)-DTBM-segphos catalyst gave lactone 2i in 68% yield with very high diastereoselectivity (eqn (1)).The absolute configuration of the lactone 2i was determined to be 3R,5R, which was assigned by comparison of the optical rotation ([a] D = À27, c 0.74 in CHCl 3 ) with the reported one ([a] D = À45.3,c 1.17 in CHCl 3 for (3R,5R)-2i). 22On the other hand, a lower diastereoselectivity 81 : 19 was observed in the reaction of (S)-1i (eqn (2)), indicating that the face-selectivity of the cyclization is influenced by the substituents at the a-position of the carboxylic acids 1. (3) The reaction of 2,2-diallylphenylacetic acid (1j) proceeded well to give the corresponding lactones in good yields, where the lactones contained double bond isomers and they were hydrogenated in the presence of [Ir(cod)(PCy 3 )(py)]PF 6 23 (Cy = cyclohexyl, py = pyridine, eqn (3)).The saturated lactones trans-2j 0 and cis-2j 0 were formed in moderate diastereoselectivity and good enantioselectivity.
Scheme 1 shows three possible reaction pathways for the Ir-catalyzed cyclization.One involves the oxidative addition of the carboxylic acid 1a to the Ir(I) giving a hydridoiridium(III) species, and a sequential alkene insertion into the Ir(III) leads to the formation of lactone 2a via reductive elimination (5 mol% Ir) and (R)-DTBM-segphos in NMP (0.80 mL) at 100 1C for (Scheme 1a).Another reaction pathway is associated with the formation of an Ir(I) carboxylate species (Scheme 1b).In consideration of a weak basicity of NMP, the Ir(I) carboxylate species could be formed by deprotonation and the species undergoes the alkene insertion.Scheme 1c shows the other pathway initiated by an electrophilic activation of the alkene moiety with the Ir(I) species, where the subsequent attack of the carboxyl group to the alkene forms the C-O bond.Mashima and co-workers reported the synthesis of hydridoiridium(III) carboxylate complexes via oxidative addition of carboxylic acids to an Ir(I)/binap complex. 24Krische and co-workers reported an iridium-catalyzed addition of carboxylic acids to allenes, 3c where it is proposed that oxidative addition is the initial step of the reaction.To gain some insight into the mechanism, a stoichiometric reaction of 1a with [IrCl(coe) 2 ] 2 and (R)-DTBM-segphos in benzene-d 6 was conducted.Treatment of [IrCl(coe) 2 ] 2 , (R)-DTBMsegphos, and carboxylic acid 1a in benzene-d 6 at room temperature for 24 h brought about the formation of hydridoiridium complexes as a mixture of two isomers (73 : 27).The major isomer showed a virtual triplet at À27.1 ppm (J P-H = 22 Hz) in the1 H NMR analysis, which was tentatively assigned to be a hydride at a cis-position to two phosphorous atoms. 25The result indicates that the reaction pathway (a) initiated by the oxidative addition of the carboxylic acid is plausible in the present cyclization.The possible intermediacy of the iridium(I) carboxylate species was also investigated by the use of a hydroxoiridium(I) complex as a catalyst precursor.The reaction of 1a was conducted in the presence of [Ir(OH)(cod)] 2 and (R)-DTBM-segphos, which is expected to react with 1a to form the iridium(I) carboxylate.The reaction gave the lactone in 20% yield accompanied by decarboxylation products in 62% yield as a mixture of the double bond isomers. 26The result indicates that the iridium(I) carboxylate is not likely to be the intermediate in the present reaction, because the formation of such decarboxylation products was not observed in the reaction of 1a catalyzed by the IrCl/(R)-DTBM-segphos complex.
Determining the stereochemistry of the addition using deuterated carboxylic acids would be helpful in distinguishing pathway (c) from others; pathway (c) leads to an anti-addition product while others lead to a syn-addition product.Unfortunately, however, the reactions of carboxylic acids containing internal alkenes were unsuccessful, and thus, the pathway (c) could not be excluded at this stage. 26e results of deuterium-labeling experiments are shown in eqn (4) and (5).In the reaction of deuterated carboxylic acid 1a-d 1 , deuterium incorporation into a methyl group of 2a was low (0.15D/3H, eqn (4)).The low content of the deuterium is probably due to an incorporation of hydrogen atoms from solvent NMP via the C-H activation of a methyl group on NMP. 27A 5% of deuterium incorporation at the g-position was also observed.On the other hand, in the reaction of 1a-d 2 , which is substituted at the alkene terminus with two deuterium atoms, a significant amount of a migration of deuterium into the g-position of 2a was observed (0.44D, eqn (5)).A migration of deuterium from the terminal position to the internal one was also detected in a recovered 1a-d 2 .
(4) In summary, we have developed an asymmetric cyclization of alkenoic acids using an Ir/(R)-DTBM-segphos catalyst that gives lactones with good enantioselectivity.
This work was supported by JSPS KAKENHI Grant No. 15H03810.M.N. thanks the JSPS for a Research Fellowship for Young Scientists.We thank Prof. K. Maruoka and Prof. T. Kano (Kyoto University) for HRMS analysis and Takasago International Corporation for the gift of (R)-DTBM-segphos.
the results of the stoichiometric reaction and deuterium-labeling experiments, the catalytic cycle is postulated as illustrated in Scheme 2. Oxidative addition of O-H bond to Ir(I) forms (carboxylato)iridium(III) hydride B. The alkene insertion into the Ir-H bond in an exo-fashion forms alkyliridium(III) C and the successive reductive elimination gives lactone 2a and regenerates the Ir(I) species.The migration of deuterium observed as shown in eqn (5) can be explained by reversible insertion and b-hydride elimination of intermediate C 0 , which is formed via the alkene insertion in an endo-fashion.

Table 1
Ir-catalyzed asymmetric cyclization of alkenoic acid 1a a