Understanding the mechanisms, regioselectivies and enantioselectivities of the DMAP-catalyzed [2 + 4] cycloaddition of γ-methyl allenoate and phenyl(phenyldiazenyl)methanone

Abstract

The mechanisms, regioselectivities and enantioselectivities of the DMAP-catalyzed [2 + 4] cycloaddition reaction between γ-methyl allenoate R₁ and phenyl(phenyldiazenyl)methanone R₂ have been theoretically studied using density functional theory (DFT) calculations. Various possible reaction pathways are analyzed and discussed. The results of the DFT calculations show that the preferred mechanism (mechanism A) includes four steps: the nucleophilic addition of DMAP to R₁ to form the zwitterionic intermediate 1 (first step), the γ-addition of 1 to R₂ to generate intermediates γ-2(R&S) (second step), the intramolecular Michael addition to give the six-membered ring intermediates γ-3(RS&SR) (third step), and the catalyst DMAP liberation from γ-3(RS&SR) to generate the final product γ-P(R&S) (fourth step). The addition of DMAP to R₁ is calculated to be the rate-determining step. The reaction of 1 with R₂ is both the regioselective- and enantioselective-determining step. The calculated results are in good agreement with experimental findings. The present study may provide a useful guide not only for understanding other analogous reactions but also for designing new reactions in the future.

---

1. Introduction

Functionalized six-membered carbocyclic and heterocyclic compounds as structural motifs are often found in many pharmaceuticals, natural products and bioactive molecules.^1–5 Consequently, the construction of these compounds has received considerable attention. At present, Diels–Alder (DA) reactions are a powerful tool for the synthesis of various compounds with six-membered rings.^6–8 However, drawbacks such as unsatisfactory reactivity and regioselectivity have limited the application of these approaches.⁹

Allenes are versatile intermediates in organic synthesis, because of their rich structural and reactive properties.¹⁰ Under Lewis base catalysis, allenoates can undergo cycloaddition reactions with various unsaturated substrates, which provide alternative ways to synthesis six-memberd carbo- and heterocyclic molecules. In 2003, Kwon et al. reported the first PBu₃-catalyzed formal [4 + 2] cycloaddition reaction of α-alkyl allenoates with imines.¹¹ Since then, Lewis base catalyzed allenoate-based cycloaddition reactions to form six-membered cyclo- and heterocycles have attracted increasing interest in organic synthesis. Up to now, a large number of experimental studies have been reported on allenoates reactions with various unsaturated compounds, such as alkenes,^12–20 imines,^21–25 ketones,^26–28 aziridines,²⁹ dithioesters,³⁰ enynals and enynones,³¹ indoles,³² and oxo dienes.³³ Theoretical studies of allenoates with alkenes,^20,34 ketones and aldimines,³⁵ and enones^36,37 have also been reported.

1,3,4-Oxadiazine is an important frameworks found frequently in a series of natural products and designed materials.^38–41 The development of novel and facial methods to produce 1,3,4-oxadiazine is therefore highly desirable. Recently, Wang and co-workers reported a nucleophilic DMAP-catalyzed [2 + 4] cycloadditions of γ-methyl allenoate with phenyl(phenyldiazenyl)methanone to prepare 1,3,4-oxadiazines, in which six-membered ring with three heteroatoms is generated in a single step (Scheme 1).⁴²

Scheme 1 DMAP-catalyzed [2 + 4] cycloaddition reaction.

Based on the experimental observations, Wang and co-workers proposed a possible mechanism (Scheme 2),⁴² which includes the activation of γ-methyl allenoate by DMAP to form the zwitterionic intermediate A, γ-addtion of A to phenyl(phenyldiazenyl)methanone affords the intermediate B, intramolecular Michael addition to form the six-membered ring intermediate C, and DMAP elimination yielding the final product.

Scheme 2 The proposed mechanism for the DMAP-catalyzed [2 + 4] cycloaddition reaction in experiment.

Although the mechanism of the current [2 + 4] cycloaddition reaction has been proposed, a detailed atomistic account of it is still lacking. How does the catalytic process happened? Which step is the rate-determining step? Which step is the regioselectivity-controlling step? Why the possible five- or seven-membered ring products are not observed in experiment? A better understanding of the mechanistic details would certainly help develop more efficient experiments. However, to the best of our knowledge, there is no theoretical study on the mechanism of this novel reaction reported by Wang and co-workers.

In this study, we investigated the mechanism of the DMAP-catalyzed [2 + 4] cycloaddition between γ-methyl allenoate and phenyl(phenyldiazenyl)methanone by using density functional theory calculations and try to answer the above issues. The remainder of this paper is organized as follows: the computational method is described in Section 2, followed by the results and discussion in Section 3. Finally, we finish with some concluding remarks in Section 4.

2. Computational method

All calculations were carried out using the Gaussian 09 program package.⁴³ Geometry optimizations were carried out using the M06-2X⁴⁴ method in conjunction with 6-31+G(d,p) basis set. M06-2X provides a better description of kinetics and thermodynamics.^45–50 Moreover, the inclusion of a diffuse function in the basis set is important to deal with zwitterionic species.⁵¹ Frequency calculations were performed at the same level of theory, to check whether the obtained species was a minimum (with all real frequencies) or a transition state (with only one imaginary frequency), as well as to obtain zero point energy (ZPE) and thermodynamic corrections at 298.15 K and 1 atm. The connections of the transition state between designated isomers, were confirmed by intrinsic reaction coordinate (IRC) calculations.⁵² Single point energy calculations were performed at the M06-2X/6-311++G(d,p) level of theory. The solvation effects of toluene were considered during geometry optimization, frequency calculation and single point energy calculation by using the SMD model.⁵³ The dielectric constant of toluene was taken as 2.37. To account for dispersion effect, Grimme's DFT-D3 dispersion corrections were calculated using the DFT-D3 program.⁵⁴ Moreover, additional corrections for the Gibbs free energies were performed using the roto-harmonic approximation using the free code developed by Dr Robert Paton and Ignacio Funes-Ardois. The above two corrections were added to the M06-2X Gibbs free energies in solution. The Gibbs free energies after correction were used to discuss the reaction mechanisms. The natural bond orbital (NBO) analysis was applied to calculate the wiberg bond indices and charge distributions.^55–57

3. Results and discussion

3.1 Reaction mechanism

Based on the experimental studies reported by Wang and co-workers (Scheme 1), we have suggested and explored the detailed mechanisms (mechanism A and mechanism B) for the DMAP-catalyzed annulation reaction of γ-methyl allenoate with phenyl(phenyldiazenyl)methanone, which is depicted in Scheme 3. In the present paper, the reactants γ-methyl allenoate and phenyl(phenyldiazenyl)methanone are abbreviated with R₁ and R₂, respectively.

Scheme 3 The reaction mechanisms A and B.

As shown in Scheme 3, mechanism A proposed by Wang and co-workers⁴² includes four reaction steps: (1) the nucleophilically attack of catalyst DMAP on R₁ forms the zwitterionic adduct 1, (2) the γ-addition of 1 to R₂ generates γ-2, (3) intermediate γ-2 undergoes an intramolecular Michael addition affords intermediate γ-3 and (4) the catalyst elimination from γ-3 yielding the final product γ-P. Whereas mechanism B comprises three steps: (1) the nucleophilic addition of catalyst DMAP to R₁ generates intermediate 1, which is the same as that in mechanism A, (2) α-addition of 1 to R₂ affords intermediate α-2, and (3) intermediate α-2 transforms to the final product α-P via a concerted intramolecular cyclization and catalyst elimination process. It should be noted that the prefix “γ-” represents the γ-addition mode, while the prefix “α-” represents the α-addition mode.

As depicted in Scheme 3, both mechanism A and mechanism B starts from the intermediate 1. To simplify the presentation, the potential energy profile for the formation of intermediate 1 is shown in Fig. 1. The potential energy profile for mechanism A (associated with the γ-addition mode) is depicted in Fig. 2, and the corresponding structures are summarized in Fig. 3. The potential energy profile and optimized structures for mechanism B (associated with the α-addition mode) are presented in Fig. 4. In the following section, we will first present and discuss the reaction pathways associated with mechanism A, and then the results associated with mechanism B.

Fig. 1 Free energy profiles for the formation of 1. The solvation-corrected relative free energies at SMD(toluene)/M06-2X/6-311++G(d,p) level are given in kcal mol⁻¹. Distances at SMD(toluene)/M06-2X/6-31+G(d,p) level are given in Å.

Fig. 2 Free energy profile of the reaction mechanism A (associated with γ-addition). The solvation-corrected relative free energies at SMD(toluene)/M06-2X/6-311++G(d,p) level are given in kcal mol⁻¹.

Fig. 3 Optimized geometries involved in mechanism A. Distances at SMD(toluene)/M06-2X/6-31+G(d,p) level are given in Å.

Fig. 4 Optimized structures and free energy profile of the reaction mechanism B (associated with α-addition). The solvation-corrected relative free energies at SMD(toluene)/M06-2X/6-311++G(d,p) level are given in kcal mol⁻¹. Distances at SMD(toluene)/M06-2X/6-31+G(d,p) level are given in Å.

3.1.1 Mechanism A.
First step. As shown in Scheme 3, the reaction initiates with the nucleophilic addition of DMAP catalyst to R₁ to form the DMAP·allenoate adducts 1. It should be noted that the two isomers of R₁ (cis-R₁ and trans-R₁) have similar energies (ΔΔG = 0.5 kcal mol⁻¹, see the left-hand side of Fig. 1). The N1 atom of DMAP attacks the electron-deficient C2 atom of cis-R₁ leads to the formation of the intermediates 1 and 1′, depending on the approaching direction of DMAP and cis-R₁. The addition of DMAP to trans-R₁ proceeds via a similar way to form the intermediates 1a and 1a′. As shown in Fig. 1 (see the lower half of Fig. 1), the N1–C2 bond distance is shortened from 2.028 Å in TSR₁/1, 2.014 Å in TSR₁/1′, 1.998 Å in TSR₁/1a, and 1.999 Å in TSR₁/1a′ to 1.466 Å in 1, 1.468 Å in 1′, 1.485 Å in 1a and 1.472 Å in 1a′. Moreover, the NBO charge analyses indicate that the Wiberg bond indices change from 0.3163 in TSR₁/1, 0.3188 in TSR₁/1′, 0.3397 in TSR₁/1a, and 0.3280 in TSR₁/1a′ to 0.8853 in 1, 0.8731 in 1′, 0.8612 in 1a, and 0.8623 in 1a′. The above results imply that N1–C2 bond is formed via the nucleophilic attack of DMAP to R₁. As shown in Fig. 1, the activation energy barrier associated with the nuclophilic addition process is calculated to be 24.0 kcal mol⁻¹ for TSR₁/1, 25.3 kcal mol⁻¹ for TSR₁/1′, 24.9 kcal mol⁻¹ for TSR₁/1a, and 25.6 kcal mol⁻¹ for TSR₁/1a′, which are similar to each other. Among the four DMAP·allenoate adducts, 1 and 1′ are more stable than the other two intermediates (1a and 1a′). Thus, we expect that the formation of 1 and 1′ should be more favorable than the formation of 1a and 1a′. Moreover, our calculated results show that the conversion between 1 and 1a (or between 1′ and 1a′) is impossible because of the high energy barriers (19.8 and 20.6 kcal mol⁻¹ for 1 → 1a, and 1′ → 1a′ respectively, see Fig. S1 in the ESI†). In the following part, we first present and discuss the reaction pathways starting from 1. Then we briefly discuss the reaction pathways initiated from 1′. Intermediate 1 is calculated to be 8.4 kcal mol⁻¹ higher than the energy of DMAP + cis-R₁, indicating that the transformation of DMAP + cis-R₁ to 1 is endergonic, which implies that this step is not thermodynamically favorable.

Since at the very beginning of the reaction, R₁ and R₂ may compete each other to react with DMAP, we also examined an alternative pathway in which the catalyst DMAP reacts with R₂. To simplify the presentation, the potential energy profile for the association of catalyst DMAP and R₂ is also shown in Fig. 1 (see the right-hand side of Fig. 1). As depicted in Fig. 1, the N1 atom of DMAP attacks the N5 atom of R₂ leads to the formation of 1b and 1b′. The calculated activation energy barrier for the association of DMAP with R₂ (31.7 kcal mol⁻¹ for TSR₂/1b and 29.4 kcal mol⁻¹ for TSR₂/1b′) is much higher than that for the reaction of DMAP with R₁ via TSR₁/1 (24.0 kcal mol⁻¹). Moreover, 1 is more stable than 1b and 1b′ (see Fig. 1). The calculated results indicate that the association of catalyst DMAP with R₂ is not energetically favorable. Hence, we will focus our attention on the reaction of 1 and R₂.

Second step. Based on our calculations, the dipole moment of 1 is 12.22 D, which implies that 1 has zwitterionic characteristics. Therefore, once the zwitterionic intermediate 1 is formed, both the γ-carbon (C4) and α-carbon (C3) can nucleophilically attack the N5 atom of R₂. In the following part of this section, we will present and discuss the reaction pathways associated with the γ-addition, the reaction pathways associated with the α-addition will be discussed in Section 3.1.2 Mechanism B.

The nucleophilic addition of the γ-carbon (C4) in zwitterionic intermediate 1 to the N5 atom in R₂ forms intermediate γ-2(R&S) via transition states γ-TS1/2(R) and γ-TS1/2(S). The R and S in parentheses represent the chirality/prochirality of C4. The activation energy barrier for this step are calculated to be 9.1 kcal mol⁻¹ for γ-TS1/2(R) and 9.0 kcal mol⁻¹ for γ-TS1/2(S). It is noteworthy that this step is an exergonic process because the energy of γ-2(R) and γ-2(S) are respectively 10.5 kcal mol⁻¹ and 7.8 kcal mol⁻¹ lower than the energy of 1 + R₂.

As shown in Fig. 3, the distance of C4–N5 bond is shortened from 2.143 Å in γ-TS1/2(R), 2.134 Å in γ-TS1/2(S) to 1.460 Å in γ-2(R) and 1.460 Å in γ-2(S). In the mean time, N5–N6 bond is elongated from 1.239 Å in R₂, to 1.311 Å in γ-TS1/2(R) and 1.312 Å in γ-TS1/2(S), then to 1.414 Å in γ-2(R) and 1.413 Å in γ-2(S). N6–C7 bond is shorten from 1.443 Å in R₂ to 1.378 Å in γ-TS1/2(R), 1.386 Å in γ-TS1/2(S), then to 1.322 Å in γ-2(R) and 1.316 Å in γ-2(S). C7–O8 bond is elongated from 1.208 Å in R₂ to 1.233 Å in γ-TS1/2(R), 1.233 Å in γ-TS1/2(S), then to 1.265 Å in γ-2(R) and 1.266 Å in γ-2(S). The above results indicate that during the transformation of 1 + R₂ to 2, the C4–N5 bond is formed, while the conjugated double bond N5=N6–C7=O8 becomes the N5–N6=C7–O8 bond. The negative charge values of O8 increased from −0.552e in R₂, to −0.690e in γ-TS1/2(R) and −0.702e in γ-TS1/2(S), then to −0.814e in γ-2(R) and −0.832e in γ-2(S). This means the interaction of 1 with R₂ increases the negative charge on the O8 atom, and therefore facilitate the subsequent intramolecular Michael addition of O8 to C2.

Third step. The intramolecular Michael addition of oxygen anion (O8) to C2 affords the six-membered ring intermediates γ-3(RS&SR). It should be pointed out that once the O8–C2 bond is formed, the C2 atom becomes chiral. The two letters in parentheses represent the chirality of C4 and C2 atom, respectively. Due to the fact that only the Re face of the C2 atom in γ-2(R) and the Si face of the C2 atom in γ-2(S) can be attacked by the oxygen anion (O8) during the cyclization process, only two intermediates γ-3(RS) and γ-3(SR) are located. The corresponding transition states are γ-TS2/3(RS) and γ-TS2/3(SR), respectively. As shown in Fig. 3, the distance of O8–C2 is shortened from 1.920 Å in γ-TS2/3(RS) and γ-TS2/3(SR), to 1.443 Å in γ-3(RS) and 1.440 Å in γ-3(SR). The changes of bond distance imply that the O8–C2 bond is formed. The activation free energy barrier associated with the intramoecular Michael addition step is calculated to be 8.4 kcal mol⁻¹ for γ-TS2/3(RS) and 5.7 kcal mol⁻¹ for γ-TS2/3(SR).

To better understand why the possible five- or seven-membered ring products were not observed in experiment, besides the formation of six-membered ring intermediate γ-3(RS&SR), we also calculated reaction pathways to form five- or seven-membered ring intermediate. To simplify our discussion, the reaction pathways associated with the formation of five-, six- and seven-membered ring intermediates are denoted as the “five-, six- and seven-membered ring channel”, respectively. As shown in Fig. 2, to form five-membered ring intermediate γ-4(RS&SR), the N6 atom would attack the C3 atom. With the formation of N6–C3 bond, the C3 atom becomes chiral. The two letters in parentheses represent the chirality of C4 and C3 atom, respectively. The free energy barrier for this step is calculated to be 22.2 kcal mol⁻¹ for γ-TS2/4(RS) and 19.8 kcal mol⁻¹ for γ-TS2/4(SR), and the free reaction energies for intermediates γ-4(RS) and γ-4(SR) are 21.8 kcal mol⁻¹ (with respect to γ-4(R)) and 20.2 kcal mol⁻¹ (with respect to γ-4(S)), respectively. The results indicate that this step is easily reversible. On the other hand, the addition of the anionic O8 on C3 would generate the seven-membered ring intermediate γ-5(RS&SR), which is also an endergonic process (the reaction free energies for γ-5(R) and γ-5(S) are 24.8 kcal mol⁻¹ and 22.5 kcal mol⁻¹, respectively). It should be noted that, with the formation of O8–C3 bond, the C3 atom becomes a stereogenic center. The two letters in parentheses represent the chirality of C4 and C3 atom, respectively. The free energy barrier for this step is calculated to be 25.4 kcal mol⁻¹ for γ-TS2/5(RS), and 22.4 kcal mol⁻¹ for γ-TS2/5(SR).

Obviously, the free energy barriers associated with the five- or seven-membered ring transition states γ-TS2/4(RS&SR) and γ-TS2/5(RS&SR) are much higher than those for the six-membered ring transition state γ-TS2/3(RS&SR) (Fig. 2). Furthermore, the reaction free energies of γ-4(RS&SR) and γ-5(RS&SR) are much higher than that of γ-3(RS&SR). Therefore, based on both kinetical and thermodynamical considerations, the six-membered ring channel is much more competitive than the five- and seven-membered ring channel. This is consistent with experimental results that only the six-membered ring product was observed in experiment. The reaction pathways starting from γ-4(RS&SR) and γ-5(RS&SR) are thus not considered.

Fourth step. Catalyst DMAP eliminates from γ-3(RS&SR) leads to the final product γ-P(R&S). It should be noted that after catalyst DMAP release, the chirality of C2 atom disappears, while the chirality of C4 atom remains. Take γ-P(R) as an example, the letter in parentheses represents the chirality of C4. As shown in Fig. 2, the free energy barrier is calculated to be 0.7 kcal mol⁻¹ for γ-TS3/P(R) and 0.4 kcal mol⁻¹ for γ-TS3/P(S), which means that this step could happen very easily. The small free energy barriers also indicate that the DMAP is a very good leaving group. Moreover, the final product γ-P(R&S) lies 23.0 kcal mol⁻¹ and 23.2 kcal mol⁻¹ lower than intermediates γ-3(RS) and γ-3(SR), respectively, indicating that this step could proceed irreversibly. As depicted in Fig. 3, the distance of C2–N1 bond is elongated from 1.443 Å in γ-3(R) and 1.440 Å in γ-3(S) to 1.800 Å in γ-TS3/P(R&S). Meanwhile, C2–C3 bond is gradually shortened from 1.452 Å in γ-3(R) and 1.453 Å in γ-3(S), to 1.410 Å in γ-TS3/P(R&S), then to 1.342 Å in γ-P(R&S). This means that with the elimination of catalyst DMAP, the C2–C3 becomes a double bond.

As can be seen from Fig. 2, the calculated free energy barrier for the nucleophilic addition process R₁ + DMAP → 1 (first step) is much higher than those of the other steps (1 → γ-2, γ-2 → γ-3, and γ-3 → γ-P) in mechanism A. Considering that the high-energy barrier step controls the reaction rate in a pathway, the first step (R₁ + DMAP → 1, ΔG = 24.0 kcal mol⁻¹) can be viewed as the rate-determining step in mechanism A.

Now let us discuss the reaction pathways initiated from 1′. As shown in Fig. 1, TSR₁/1 is 1.3 kcal mol⁻¹ lower than TSR₁/1′, and 1 is 2.2 kcal mol⁻¹ stabler than 1′. Thus the formation of 1′ is much less competitive, but also feasible. Consequently, the reaction pathways starting from 1′ may also contribute to the final product. To examine this possibility, we searched for the pathways initiated from 1′, and found they are much less favorable than the reaction pathways proceeded via 1 (for details see the ESI Fig. S2†), and are thus not detailed here.

3.1.2 Mechanism B. The first step is the formation of zwitterionic intermediate 1, which is the same as that in mechanism A.

In the second step, the α-carbon (C3) of 1 nucleophilically attacks the N5 atom of R₂ affords the α-addition intermediate α-2(R&S), as depicted in Scheme 3. Note that the R and S in parentheses represent the chirality/prochirality of C4. The free energy barrier is calculated to 10.1 kcal mol⁻¹ for α-TS1/2(R) and 14.6 kcal mol⁻¹ for α-TS1/2(S), and the reaction free energy is −11.7 kcal mol⁻¹ for α-2(R) and −5.6 kcal mol⁻¹ for α-2(S). As shown in Fig. 4, the distance of C3–N5 bond is shortened from 2.082 Å in α-TS1/2(R) and 2.360 Å in α-TS1/2(S), to 1.444 Å in α-2(R) and 1.473 Å in α-2(S), indicating the C3–N5 bond is formed.

In the third step, intermediate α-2(R) undergoes a concerted O8–C2 bond formation and C2–N1 bond dissociation process leads to the final product α-P(R) via transition state α-TS2/P(R). The distance of O8–C2 bond is shortened from 1.555 Å in α-TS2/P(R) to 1.380 Å in α-P(R), while the C2–N1 bond gradually elongated from 1.454 Å in α-2(R) to 1.649 Å in α-TS2/P(R). The IRC calculations show that the formation of O8–C2 bond occurs along with the dissociation of C2–N1 bond. The free energy barrier for this step amounts to 35.6 kcal mol⁻¹, which is inaccessibly high. It should be noted that, we are unable to find the transition state connecting α-2(S) and the final product α-P(S) despite numerous attempts. Checking back to Fig. 2, we can clearly see that the transition state α-TS2/P(S) is higher in energy than those associated with γ-addition, we easily conclude that the reaction pathways associated with α-addition are energetically unfavorable.

3.2 Regioselectivity and enantioselectivity implications

The α- versus γ-addition regioselectivity of the current reaction can be rationalized by analyzing the potential energy surface of the [2 + 4] cycloaddition process. According to Fig. 2 and 4, the transition states γ-TS1/2(R&S), γ-TS2/3(RS&SR) and γ-TS3/P(RS&SR), in the γ-addition mode are lower in energy than those transition states involved in the α-addition mode. Consequently, the pathways leading to the γ-addition products should be more favorable than the pathways leading to the α-addition products, which is in good agreement with experimental results that only the γ-addition product was observed.

Since the γ-addition mode is much competitive than α-addition mode, we only discuss the enantioselectivity associated with γ-addition mode. For the current DMAP catalyzed [2 + 4] cycloaddition reaction, the reactants are not chiral, the experimental observed product has only one chiral center. However, the several intermediates and transition states have one (or two) chiral carbon, which implies that they can exist more than one possible conformers. The crucial step that affects the enantioselectivity is expected to be the association of 1 with R₂ to generate intermediates γ-2(R&S). On the basis of our calculations, the transition states γ-TS1/2(R) and γ-TS1/2(S) have comparable stabilities, the intermediate γ-2(R) is slightly more stable than γ-2(S). Consequently, the two enantiomers of the final product γ-P(R&S) may have comparable contribution to the current DMAP-catalyzed [4 + 2] cycloaddition reaction of γ-methylallenoate with phenyl(phenyldiazenyl)methanone.

4. Conclusions

The mechanisms, regioselectivities and enantioselectivities of DMAP-catalyzed [2 + 4] cycloaddition of γ-methyl allenoate R₁ with phenyl(phenyldiazenyl)methanone R₂ have been investigated at the M06-2X/6-311++G(d,p)//M06-2X/6-31+G(d,p) level in toluene solvent using the SMD solvation model. Two possible mechanisms (mechanism A and B) have been explored. The calculated results demonstrate that the catalytic cycle can be characterized by four processes (mechanism A): (I) nucleophilic attack of DMAP on R₁ to form the zwitterionic intermediate 1; (II) γ-addition of 1 to R₂ leads to intermediate γ-2(R&S), (III) γ-2 undergoes an intramolecular Michael addition to form the six-membered ring intermediate γ-3(RS&SR), and (IV) elimination of catalyst completes the catalytic cycle and yields the final product γ-P(R&S). The calculated results show that the first step is the rate-determining step, the energy barriers via the transition states TSR₁/1 is 24.0 kcal mol⁻¹. The second step is calculated to be both the regio- and enantioselectivity-determining step.

To understand the regioselectivity of the reaction, we also examined an alternative mechanism (mechanism B) which involves three steps: the first step is the same as that of mechanism A, the second step is the α-addition of 1 to R₂ to form α-2(R&S), and the last step is the concerted C2–O5 bond formation and catalyst elimination process. The energy barrier calculated for the last step amounts to 35.6 kcal mol⁻¹ via α-TS2/P(R), indicating that mechanism B should be not favorable in comparison with mechanism A. Our calculation results are in good agreement with the experimental observations, and we expect that our results may provide useful information for understanding other analogous reactions.

Acknowledgements

This work is supported by the National Natural Science Foundation of China (No. 21403024).

Notes and references

1. M. C. Elliott, J. Chem. Soc., Perkin Trans. 1, 1998, 4175–4200.
2. J. C. Conway, P. Quayle, A. C. Regan and C. J. Urch, Tetrahedron, 2005, 61, 11910–11923.
3. E. L. Larghi and T. S. Kaufman, Synthesis, 2006, 2, 187–220.
4. R. H. Liu, W. D. Zhang, Z. B. Gu, C. Zhang, J. Su and X.-K. Xu, Nat. Prod. Res., 2006, 20, 866–870.
5. M. Shoji and Y. Hayashi, Eur. J. Org. Chem., 2007, 23, 3783–3800.
6. D. L. Boger and S. M. Weinreb, Hetero Diels-Alder Methodology in Organic Synthesis, Academic Press, San Diego, 1987.
7. K. A. Jorgensen, Angew. Chem., Int. Ed., 2000, 39, 3558–33588.
8. K. A. Jorgensen, Eur. J. Org. Chem., 2004, 10, 2093–2102.
9. T. Wang and S. Ye, Org. Lett., 2010, 12, 4168–4171.
10. Modern Allene Chemistry, ed. N. Krause and A. S. K. Hashmi, Wiley-VCH, Weinheim, 2004.
11. X. F. Zhu, J. Lan and O. Kwon, J. Am. Chem. Soc., 2003, 125, 4716–4717.
12. Y. S. Tran and O. Kwon, J. Am. Chem. Soc., 2007, 129, 12632–12633.
13. X. Meng, Y. Huang, H. Zhao, P. Xie, J. Ma and R. Chen, Org. Lett., 2009, 11, 991–994.
14. F. Zhong, X. Han, Y. Wang and Y. Lu, Chem. Sci., 2012, 3, 1231–1234.
15. J. Zheng, Y. Huang and Z. Li, Org. Lett., 2013, 15, 5064–5067.
16. E. Li, Y. Huang, L. Liang and P. Xie, Org. Lett., 2013, 15, 3138–3141.
17. E. Li, P. Jia, L. Liang and Y. Huang, ACS Catal., 2014, 4, 600–603.
18. M. Gicquel, C. Gomez, P. Retailleau, A. Voituriez and A. Marinetti, Org. Lett., 2013, 15, 4002–4005.
19. W. Yao, X. Dou and Y. Lu, J. Am. Chem. Soc., 2015, 137, 54–57.
20. F. Wang, C. Yang, X. S. Xue, X. Li and J. P. Cheng, Chem.–Eur. J., 2015, 21, 10443–10449.
21. R. A. Villa, Q. Xu and O. Kwon, Org. Lett., 2012, 14, 4634–4637.
22. Y. S. Tran and O. Kwon, Org. Lett., 2005, 7, 4289–4291.
23. R. P. Wurz and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 12234–12235.
24. H. Xiao, Z. Chai, H. F. Wang, X. W. Wang, D. D. Cao, W. Liu, Y. P. Lu, Y. Q. Yang and G. Zhao, Chem.–Eur. J., 2011, 17, 10562–10565.
25. R. S. Na, C. F. Jing, Q. H. Xu, H. Jiang, X. Wu, J. Y. Shi, J. C. Zhong, M. Wang, D. Benitez, E. Tkatchouk, W. A. Goddard, H. C. Guo and O. Y. Kwon, J. Am. Chem. Soc., 2011, 133, 13337–13348.
26. R. P. Wurz and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 12234–12235.
27. Z. Shi and T. P. Loh, Angew. Chem., Int. Ed., 2013, 52, 8584–8587.
28. E. Q. Li, M. J. Chang, L. Liang and Y. Huang, Eur. J. Org. Chem., 2015, 4, 710–714.
29. H.-C. Guo, Q.-H. Xu and O. Kwon, J. Am. Chem. Soc., 2009, 131, 6318–6319.
30. H.-B. Yang, Y.-C. Yuan, Y. Wei and M. Shi, Chem. Commun., 2015, 51, 6430–6433.
31. A. L. S. Kumari and K. C. K. Swamy, J. Org. Chem., 2015, 80, 4084–4096.
32. F. Wang, Z. Li, J. Wang, X. Li and J.-P. Cheng, J. Org. Chem., 2015, 80, 5279–5286.
33. Y. T. Gu, F. L. Li, P. F. Hu, D. H. Liao and X. F. Tong, Org. Lett., 2015, 17, 1106–1109.
34. L. L. Zhao, M. W. Wen and Z. X. Wang, Eur. J. Org. Chem., 2012, 19, 3587–3597.
35. Y. Qiao and K. L. Han, Org. Biomol. Chem., 2012, 10, 7689–7706.
36. G. T. Huang, T. Lankau and C. H. Yu, J. Org. Chem., 2014, 79, 1700–1711.
37. G. T. Huang, T. Lankau and C. H. Yu, Org. Biomol. Chem., 2014, 12, 7297–7309.
38. M. A. Dekeyser, D. S. Mitchell and R. G. H. Downer, J. Agric. Food Chem., 1994, 42, 1783–1785.
39. D. L. Trepanier, P. E. Krieger and J. N. Eble, J. Med. Chem., 1965, 8, 802–807.
40. H. A. Shindy, M. A. El-Maghraby and F. M. Eissa, Dyes Pigm., 2006, 70, 110–116.
41. M. Bakavoli, M. Bakavoli, A. Shiri, H. Eshghi, S. Vaziri- Mehr, P. Pordeli and M. Pordeli, Heterocycl. Commun., 2011, 17, 49–52.
42. Q. Zhang, L. G. Meng, J. F. Zhang and L. Wang, Org. Lett., 2015, 17, 3272–3275.
43. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr, J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, R. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, J. Cossi, N. Rega, J. M. Millam, M. Klene, M. Knox, J. B. Cross, V. Bakken, V. Adamo, J. Jaramillo, J. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, R. L. Morokuma, V. G. Zakrzewski, G. A. Voth, G. A. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox, Gaussian 09 (revision B. 01), Gaussian, Inc., Wallingford, CT, 2009.
44. Y. Zhao and D. G. Truhlar, Theor. Chem. Acc., 2007, 120, 215–241.
45. E. H. Krenske, E. C. Davison, I. T. Forbes, J. A. Warner, A. L. Smith, A. B. Holmes and K. N. Houk, J. Am. Chem. Soc., 2012, 134, 2434–2441.
46. H. Yang and M. W. Wong, J. Am. Chem. Soc., 2013, 135, 5808–5818.
47. H. Yang and M. W. Wong, J. Org. Chem., 2011, 76, 7399–7405.
48. M. W. Wong and A. M. E. Ng, Aust. J. Chem., 2014, 67, 1100–1109.
49. Y. Zhao and D. G. Truhlar, Acc. Chem. Res., 2008, 41, 157–167.
50. H. Xue, D. Jiang, H. Jiang, C. W. Kee, H. Hirao, T. Nishimura, M. W. Wong and C. H. Tan, J. Org. Chem., 2015, 80, 5745–5752.
51. W. J. Hehre, L. Radom, R. V. R. Schleyer and J. A. Pople, Ab initio Molecular Orbital Theory, Wiley, New York, 1986.
52. C. Gonzalez and H. B. Gonzalez, J. Phys. Chem., 1990, 94, 5523–5527.
53. A. V. Marenich, C. J. Cramer and D. G. Truhlar, J. Phys. Chem. B, 2009, 113, 6378–6396.
54. S. Grimme, J. Antony, S. Ehrlich and H. Krieg, J. Chem. Phys., 2010, 132(1–19), 154104.
55. E. D. Glendening, A. E. Reed, J. E. Carpenter and F. Weinhold, NBO Version 3.1, Theoretical Chemistry Institute, University of Wisconsin, Madison, WI, 1996.
56. A. E. Reed, L. A. Curtiss and F. Weinhold, Chem. Rev., 1988, 88, 899–926.
57. J. P. Foster and F. Weinhold, J. Am. Chem. Soc., 1980, 102, 7211–7218.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra16321a

---