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Article Cite This: J. Phys. Chem. A 2018, 122, 1938−1947

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DFT Investigation of the Diastereoselectivity of the MX2 and MX3 Lewis-Acid-Catalyzed Mukaiyama Aldol Reaction between C,O,OTris(trimethylsilyl)ketene Acetal and Aldehydes Slim Hadj Mohamed,†,‡ Benoît Champagne,*,‡ and Mahmoud Trabelsi† †

Laboratory of Natural Substances, Faculty of Sciences, University of Sfax, 3038 Sfax, Tunisia Laboratory of Theoretical Chemistry, Theoretical and Structural Physical Chemistry Unit, Namur Institute of Structured Matter, University of Namur, rue de Bruxelles, 61, B-5000 Namur, Belgium

‡

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ABSTRACT: The kinetics and diastereoselectivity of the Mukaiyama aldol reaction between C,O,O-tris(trimethylsilyl)ketene acetal and aldehydes bearing alkyl, vinyl, and aromatic substituents is influenced by the nature of Lewis acid catalysts. A density functional theory investigation using the M06-2X exchange-correlation functional and the PCM scheme to account for solvent effects has been carried out to characterize the structure and energetics of the transition state when the Lewis acid is ZnBr2 (MX2) or GaCl3 (MX3) in comparison to the uncatalyzed reaction. The main observations are that (i) the pro-syn transition states are always more stable than the pro-anti ones; (ii) for MX2, the transition state presents a cyclic structure, whereas it is open for MX3, owing to steric interactions; (iii) the difference of activation free enthalpy between the pro-anti and pro-syn transition states decreases when the reaction is catalyzed, by either MX2 or MX3, demonstrating a reduction of the diastereoselectivity with respect to the uncatalyzed reaction; (iv) this decrease of diastereoselectivity is larger for MX3- than for MX2-catalyzed reactions; and (v) the MX3-catalyzed reactions are kinetically favored by 1−2 kcal mol−1 with respect to the MX2 ones. been used to accelerate the Mukaiyama aldol reaction.2−4,10 In general, the MX2-catalyzed Mukaiyama aldol reaction is less common than the reaction involving MX3 catalysts. Later on, Wong and Wong11 reported that MCl3 (M = B, Al, and Ga) metal chlorides are excellent Lewis acid catalysts for the Mukaiyama reaction due to the high electronaffinity of the B, Al, and Ga metals. Theoretically, the stereoselectivity of the LA-catalyzed Mukaiyama aldol reaction has been explained by using either closed cyclic transition state models10,12 (Zimmermann−Traxler transition state models13) or open transition state models3,14−16 (Figure 1). In 1994, Denmark et al.12 reported that the open transition state of the MX2 (SnCl2)-catalyzed Mukaiyama reaction can be obtained only when the carbonyl of an aldehyde is in an antiperiplanar position with respect to the CC double bond of silyl enol ether, whereas the cyclic transition state is possible when the carbonyl is in synclinal position. Open TS models of LA-catalyzed Mukaiyama aldol reactions were originally proposed by Heathcock3 when MXn, R1, R2, and R3 (Figure 1) are BF3, Ph, Me, and tBu, respectively. Then, complementary studies were published by Munoz-Muniz et

I. INTRODUCTION The Mukaiyama aldol reaction1 is an efficient way to form carbon−carbon bonds and prepare in one step products with multiple stereocenters. The reaction between the enolsilane derivative and carbonyl compounds provides a route for the stereoselective construction of β-hydroxycarbonyl units, which are important building blocks toward the synthesis of many natural products and pharmaceuticals. Since the discovery of the TiCl4-catalyzed reaction by Mukaiyama,1 a variety of Lewis acid (LA) catalysts (MX2 and MX3) with conventional metals such as aluminum,2 boron,3 zinc,4 iron,4 magnesium,4 and mercury4 have been used in organic solvents. With the development of organic chemistry in water, some researchers wanted to transpose the Mukaiyama reaction into an aqueous medium. So, Li et al.5 studied the aqueous Mukaiyama reaction and found that the Lewis acids are not good catalysts, because they favor the reaction with water rather than with the substrate (the carbonyl). Kobayashi et al.6,7 reported that the use of the Lewis acid for the Mukaiyama aldol reaction in pure water proceeds with a low yield. This problem was solved when a small amount of surfactant was added in the reaction medium. Moreover, Loh and coworkers8,9 showed that InCl3 was an efficient hydrocompatible Lewis acid catalyst in aldol reactions of silyl enol ether with aldehydes. Both MX2 and MX3 Lewis acids are considered as good activating catalysts, since they have © 2018 American Chemical Society

Received: November 12, 2017 Revised: January 29, 2018 Published: February 5, 2018 1938

DOI: 10.1021/acs.jpca.7b11186 J. Phys. Chem. A 2018, 122, 1938−1947

Article

The Journal of Physical Chemistry A

Figure 1. Open and cyclic transition states of the Mukaiyama aldol reaction between silyl enol ether and aldehyde catalyzed by MXn (n = 2, 3) Lewis acids.

Figure 2. Mukaiyama aldol reaction between the C,O,O-tris(trimethylsilyl)ketene acetal 1 and aldehydes 2a−2h.

al.,14 Lee et al.,15 and Hatanaka et al.,16 with other combinations of LA and R1−R3 substituents to analyze the transition state structures and to explain the diastereoselectivity. Munoz-Muniz et al.14 studied the InCl3-catalyzed Mukaiyama aldol reaction between silyl enol ether Z and benzaldehyde by using several levels of approximation ranging from semiempirical PM3 and ab initio HF/3-21G* to hybrid density functional theory (DFT), B3LYP/3-21G*, and B3LYP/LANL2DZ. All methods support that the syn isomer is favored and that it is generated via a chelated closed, Zimmerman−Traxler-like, transition state. By contrast, the formation of the anti isomer is predicted to occur via an open transition structure, though its energy is significantly larger than for the syn isomer formation. By employing the M06/6-311G*//B3LYP/6-31G* level of theory and accounting for solvent effects with the polarizable continuum model (PCM), Lee et al.15 investigated and rationalized the steric effects and dipole−dipole interactions on the diastereoselectivity of the BCl3-catalyzed Mukaiyama aldol reaction between (E) and (Z) isomers of silyl enol ethers bearing substituents of different size and aldehydes (acetaldehyde and benzaldehyde). They found that pro-anti pathways take place via antiperiplanar transition structures, while the prosyn pathways prefer synclinal transition structures. Their computational approach has also enabled to reproduce the pro-syn preference of the reaction between ethyl-substituted (Z)-silyl enol ether and ethyl trimethylsilyl t-butyl ketene acetal and benzaldehyde. Later on, in 2016, Lee et al.17 investigated the stereoselectivity and compared the open and closed transition structures of the (acyloxy)borane-catalyzed Mukaiyama reactions between silyl enol ether and acetaldehyde by using a combination of dispersion-corrected DFT calculations and transition state force fields (TSFF). They found that the closed transition structures are more stable than the open ones. Hatanaka et al.16 performed calculations with the dispersioncorrected B3LYP-D exchange-correlation (XC) functional together with the artificial force induced reaction (AFIR)

method18−20 to sample the large number of transition states of the Mukaiyama reaction between 1-(trimethylsiloxy)cyclohexene and benzaldehyde catalyzed by the water-tolerant lanthanide LA [Eu(H2O)8]. They found that (i) the pro-anti transition state favors a synclinal conformation, whereas the pro-syn favors the antiperiplanar conformation and that (ii) the latter is slightly favored over the former, ΔΔG‡ = ΔG‡(proanti) − ΔG‡(pro-syn) = 0.4 kcal/mol. The explanations of the diastereoselectivity of vinylogous and homologous Mukaiyama aldol reactions have also been based on open transition state models. In 2005, Lopez et al.21 studied the BF3-catalyzed vinylogous Mukaiyama aldol reaction between 2-(trimethylsiloxy)furans and aldehydes at the B3LYP/6-311++G(2d,p)//B3LYP/6-31+G(d) level of theory. They found that (i) this reaction is fairly sensitive to steric and electronic effects leading to very small differences in the activation barriers of stereodivergent pathways and that (ii) the syn-γ-hydroxyalkylbutenolides are formed preferentially following a g+ orientation of the two reactants with the aldehyde in the s-trans conformation. Recently, LeBlanc et al.22 used the M06/6-311G(d)//B3LYP/6-31G(d) method for modeling the transition state structures of the BF3-catalyzed homologous Mukaiyama reaction of enols and [(trimethylsilyl)oxy]alkenes. The main results of that investigation are that (i) among the many transition state conformations, the lowest energy transition states are those with a synclinal geometry, in which the alkene is positioned over the cyclic oxyallyl cation; (ii) the relative orientation of the alkene and oxyallyl cation is explained in terms of stabilizing intermolecular interactions, revealed by NBO analysis, between one or more fluorines of the complexed BF3 and hydrogens on the alkene moiety as well as between the oxygen on the alkene and the π-system of the oxyallyl cation, and (iii) the energy differences between the transition states is not large. In general, the Mukaiyama aldol reaction between ketene silyl acetal is less common than the reaction involving silyl enol 1939


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Structures of the transition states of the Mukaiyama aldol reaction between C,O,O-tris(trimethylsilyl)ketene acetal 1 and benzaldehyde 2a in the presence of ZnBr2 as a MX2 Lewis acid type show that the position of the Zn atom with respect to the oxygen atom of the trimethylsiloxy group of 1 is responsible for the conformation of the transition state (cyclic or open transition state). Moreover, the C,O,O-tris(trimethylsilyl)ketene acetal 1 possesses geminal OSiMe3 groups (Oα−SiMe3 and Oα′−SiMe3). These trimethylsiloxy groups have different chemical environments, because the Oα′−SiMe3 group is on the same side as the SiMe3 group attached to Cβ, whereas the Oα− SiMe3 one is on the opposite side. In this case, when the Cγ Oβ group is in gauche position with respect to the CαCβ double bond, two positions for the CγOβ−Zn carbonyl−metal group are possible: two oxygen atoms can complex the Zn atom, either that of the Oα−SiMe3 group (Tb′, Tc′) or that of the Oα′−SiMe3 group (Ta′, Td′), leading both to the formation of cyclic (closed) transition structures in chair conformation (Figure 3). On the other hand, when the CγOβ bond is in antiperiplanar position with respect to the CαCβ double bond, the Zn atom is only linked to the carbonyl oxygen of the aldehyde (Oβ), because the distance between the Zn and Oα/ Oα′ atoms of 1 are too large to allow coordination with Oα or Oα′ (the Zn−Oα distance amounts to 5.25 Å for pro-anti and 5.57 Å for pro-syn structures). The absence of this additional Zn−O complexation leads to open transition state structures, of which the energy is higher than these of the Ta′−Td′ cyclic transition states. Indeed, in comparison to the most stable closed TS structures, the relative free enthalpy of the TS1 (TS2) structures attains 21.5 kcal/mol (19.9 kcal/mol) (Table 1). The preference for the cyclic transition state over the open transition state has also been obtained in the case of the (acyloxy)borane-catalyzed Mukaiyama aldol reaction between silyl enol ether and acetaldehyde as studied by Lee et al.,17 who reported that the closed transition structure is 0.8 kcal/mol more stable than the open one due to the formation of a hydrogen bond between the hydrogen of silyl enol ether and the oxygen atom of the (acyloxy)borane Lewis acid. Still, in that work, the ΔG‡ difference is much smaller than for the reaction between 1 and 2a. Among the closed transition states, the Tb′ pro-anti structure is more stable than the Ta′ structure. Similarly, the Tc′ pro-syn structure is more stable than the Td′ structure. This leads to the conclusion that Tb′ is the favored pro-anti and Tc′ the favored pro-syn transition states. This result is in agreement with the energies of the Ta −Td cyclic transition states of the corresponding uncatalyzed reaction.25 However, in the latter case, the transition states where the carbonyl and the Cβ−SiMe3 group are on the same side are less stable than those where the carbonyl and Cβ−SiMe3 are on opposite sides. Then, Tc′ prosyn presents a lower free enthalpy than Tb′ pro-anti so that the syn diastereomer is favored over its anti analogue. By going from Tb′ to Tc′, the ØCα‑Cβ‑Cγ‑Oβ torsion angle decreases (from 47.5 to 35°) and, accordingly, the Oβ...Oα distance (from 2.91 to2.73 Å), leading to an increased interaction between the frontier orbitals where the donor and acceptor are in favorable position25,31 (see Figure S1). This explains why the Tc′ structures are more stable than the Tb′ ones. Moreover, the transition state energy differences between Tb′ and Tc′ in the ZnBr2-catalyzed reaction are smaller (ΔΔE‡ = 0.6 kcal/mol and ΔΔG‡ = 0.9 kcal/mol) than in the uncatalyzed reaction (The corresponding differences between the Tb and Tc structures are 1.8 kcal/mol for ΔΔE‡ and 1.8 kcal/mol for ΔΔG‡). So, the

ether. Bellassoued and coworkers studied the Mukaiyama aldol reaction between C,O,O-tris(trimethylsilyl)ketene acetal 1 with a variety of aldehydes 2a−h (aliphatic, vinylic, and aromatic), catalyzed by MX2 and MX34,23,24 LA catalysts. In particular, when the HgI2 Lewis acid is used at room temperature and in toluene solutions, the aldol reaction produces syn and anti βtrimethylsiloxy-α-trimethylsilyl alkanoic acid silyl esters 3 in low diastereoselectivity.24 Then, although a closed Zimmermann− Traxler transition state was proposed for the MX2-catalyzed mechanism of these reactions, the nature of the transition state was not discussed for MX3 catalysts. It should also be noted that (i) in this reaction, the silyl ketene acetal contains geminal OSiMe3 groups attached to carbon Cα (Figure 2) and that (ii) owing to the complexity of this substrate and previous mechanisms discussed above, the respective structures of the transition states for the MX2- and MX3-catalyzed reactions remain to be unraveled. This led to the present DFT quantum chemistry investigation of the kinetics of this Mukaiyama aldol reaction between ketene silyl acetal 1 and these aldehydes (2a− h) (Figure 2), where both MX2 and MX3 Lewis acid catalysts are considered. In particular, the study focuses on the diastereoselectivity of the reaction using open and cyclic transition state models (Figure 1). This work complements our previous DFT investigation25 on the uncatalyzed form of the same Mukaiyama aldol reaction, which has been shown to present a high diastereoselectivity, in favor of the syn diastereoisomer.

II. THEORETICAL AND COMPUTATIONAL ASPECTS The calculations were carried out at the DFT level using the M06-2X exchange-correlation functional.26,27 The 6-31G(d) basis set was employed for all atoms with the exception of In, which was described using the LANL2DZ basis set.28 The transition states (TSs) were fully optimized by using the Berny method. All TSs are characterized by a single imaginary vibrational frequency. To probe widely the potential energy surface and to locate the different TSs, several starting structures were considered in the geometry optimization. These transition structures were obtained by considering systematic rotations, by steps of 15°, around the Cβ−Cγ bond [ØCα‑Cβ‑Cγ‑Oβ torsion angle]. The free enthalpies were evaluated at standard temperature (298.15 K) and pressure (1 atm). In all calculations (geometry optimizations and vibrational frequency calculations), solvent effects (toluene) were taken into account by using the Integral Equation Formalism (IEF) version of the Polarizable Continuum Model (IEF-PCM).29 All calculations were performed using the Gaussian 09 package.30 III. RESULTS AND DISCUSSION MX2 (ZnBr2)-Catalyzed Mukaiyama Aldol Reaction. Table 1 lists the activation Gibbs enthalpies for the different (closed and open) transition states of the ZnBr2-catalyzed reaction between 1 and 2a−2h as well as their differences to highlight the preferred reaction path. In addition, representative geometrical parameters of these transition states are provided, (i) two dihedral angles, ØCα‑Cβ‑Cγ‑Oβ (position of the CγOβ carbonyl with respect to the CαCβ double bond) and ΘSi‑Cβ‑Cγ‑Oβ (position of the CγOβ carbonyl with respect to Cβ−SiMe3) as well as (ii) the d1(Cγ...Cβ), d2(Zn...Oβ), d3(Zn...Oα/Oα′), and d4(Oβ...Oα/Oα′) distances. For the reaction between 1 and 2a, the corresponding quantities for the uncatalyzed reaction25 are also given. 1940


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Table 1. Activation Free Enthalpy (ΔG‡, kcal/mol) and Activation Free Enthalpy Differences (ΔΔG‡, kcal/mol) As Evaluated with the IEFPCM/M06-2X/6-31G* Method (T = 298.15 K; P = 1 bar, solvent = toluene) as Well as Representative Geometrical Parameters of the Transition State Structures, the ØCα‑Cβ‑Cγ‑Oβ and ΘSi−Cβ‑Cγ‑Oβ Dihedral Angles (deg), and the d1(Cβ...Cγ), d2(Zn...Oβ), d3(Zn...Oα/Oα′), and d4(Oβ...Oα/Oα′) Distances (Å)

1/2 1/2a

1/2a...ZnBr2

1/2b...ZnBr2

1/2c...ZnBr2

1/2d...ZnBr2

1/2e...ZnBr2

1/2f...ZnBr2

1/2g...ZnBr2

1/2h...ZnBr2

TS

ΔG‡

ΔΔG‡a

Ø

Θ

d1

d2

d3

d4

Tb

pro-anti pro-anti pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti

31.0 32.8 29.3 35.0 8.0 8.7 29.5 7.1 8.9 27.1 7.8 8.5 29.9 7.0 8.9 28.2 8.0 8.6 29.0 7.2 8.9 27.1 8.1 8.8 29.7 7.2 8.9 26.8 7.8 8.7 28.3 7.1 9.0 25.3 7.6 8.5 27.4 6.8 8.5 25.4 7.7 8.2 25.8 7.1 8.3 23.4 7.5

0 (1.8) 2.2 0 5.8 0 (0.9) 0.6 21.5 0 1.8 19.9 0 (0.7) 0.8 22.1 0 1.9 21.2 0 (0.8) 0.6 21.0 0 1.6 19.9 0 (0.9) 0.7 21.6 0 1.7 19.6 0 (0.7) 0.9 20.6 0 1.9 18.1 0 (0.8) 0.9 19.8 0 1.7 18.6 0 (0.6) 0.5 18.1 0 1.2 16.3 0 (0.7)

56.3 17.7 29.2 71.5 47.5 321.4 175.2 35.0 301.3 185.3 45.7 322.1 171.7 45.1 300.9 186.4 50.8 321.7 176.2 45.4 300.8 182.6 51.8 319.1 177.7 50.4 299.3 185.0 48.5 295.2 176.9 33.1 298.4 185.8 48.0 314.1 180.8 35.5 306.6 190.9 49.1 311.3 197.2 30.2 297.8 190.8 46.2

180.0 251.9 155.9 309.3 174.0 86.7 305.9 161.7 65.9 308.6 170.8 88.1 299.3 173.6 65.2 309.1 175.8 88.0 306.8 174.6 65.3 307.6 177.0 84.5 307.1 180.5 64.6 307.7 172.9 61.5 302.2 162.4 63.4 310.9 172.4 78.7 304.9 166.7 70.30 314.8 172.1 77.0 324.5 154.6 61.2 312.4 169.7

1.96 2.21 2.15 2.14 3.02 3.15 2.14 2.88 3.15 2.24 2.98 3.12 2.16 3.23 3.15 2.22 3.11 3.19 2.15 3.11 3.16 2.24 3.13 3.18 2.14 2.88 3.10 2.22 3.09 3.16 2.15 3.00 3.12 2.22 3.11 3.22 2.16 3.14 3.21 2.23 3.00 3.21 2.17 3.18 3.20 2.24 3.00

2.06 2.04 1.93 2.01 2.05 1.95 2.07 2.05 1.99 2.06 2.06 1.94 2.08 2.05 1.94 2.06 2.06 2.01 2.05 2.04 2.00 2.05 2.05 1.94 2.05 2.06 1.99 2.06 2.04 1.98 2.05 2.03 2.00 2.05 2.04 1.99 2.10 2.06 2.00 2.08 2.06 2.00 2.07

2.10 2.09 5.25 2.19 2.10 5.57 2.12 2.09 5.35 2.09 2.10 5.56 2.10 2.09 5.29 2.08 2.10 5.55 2.10 2.09 5.36 2.09 2.10 5.55 2.11 2.08 5.27 2.07 2.11 5.38 2.11 2.11 5.27 2.07 2.11 5.86 2.11 2.08 5.31 2.07 2.10 5.76 2.12

2.57 2.47 2.43 2.60 2.91 2.87 2.73 3.13 3.11 2.87 2.90 3.15 3.21 2.89 2.90 3.13 2.99 2.87 2.81 3.13 3.10 2.80 2.92 3.06 3.10 2.94 2.96 3.18 3.14 2.99 2.89 3.08 3.17

Tb Ta Tc Td Tb′ Ta′ TS1 Tc′ Td′ TS2 Tb′ Ta′ TS1 Tc′ Td′ TS2 Tb′ Ta′ TS1 Tc′ Td′ TS2 Tb′ Ta′ TS1 Tc′ Td′ TS2 Tb′ Ta′ TS1 Tc′ Td′ TS2 Tb′ Ta′ TS1 Tc′ Td′ TS2 Tb′ Ta′ TS1 Tc′ Td′ TS2 Tb′

1941


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The Journal of Physical Chemistry A Table 1. continued 1/2

TS

ΔG‡

ΔΔG‡a

Ø

Θ

d1

d2

d3

d4

Tb

pro-anti pro-anti pro-syn pro-syn pro-syn

8.0 26.3 6.8 8.0 23.9

0.5 18.7 0 1.2 17.1

299.9 199.6 42.3 291.2 181.4

65.2 327.9 165.7 57.1 304.3

3.22 2.16 3.15 3.15 2.24

2.07 2.00 2.07 2.07 2.00

2.07 5.59 2.08 2.07 5.26

3.09 2.87 3.08 -

Ta′ TS1 Tc′ Td′ TS2

a

Relative activation free enthalpy. In parentheses are given the free enthalpy differences between the most stable pro-anti and pro-syn transition states, ΔΔ‡ = Δ‡(most stable pro-anti) − Δ‡(most stable pro-syn). bTa-Td are the transition states corresponding to the uncatalyzed reaction between 1 and 2a (Scheme 3 of ref 21); Ta′-Td′ and TS1-TS2 are the transition states correspond to the ZnBr2-catalyzed reaction between 1 and 2 (Figure 3).

Figure 3. TS1−TS2 and Ta′−Td′ transition structures of the MX2-catalyzed Mukaiyama aldol reaction between 1 and 2a.

decreases from the uncatalyzed32 to MX2-catalyzed Mukaiyama aldol reaction24 between silyl ketene acetal and aldehydes. The ΔG‡ variations as a function of the nature of the R substituent are weak. Indeed, the ΔG‡ ranges from 7.5 kcal/mol

diastereoselectivity decreases strongly from the uncatalyzed to MX2 Lewis-acid-catalyzed Mukaiyama aldol reaction. These values are in agreement with the experimental study of Bellassoued et al.,24,32 who reported that the diastereoselectivity 1942


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Table 2. Activation Free Enthalpy (ΔG‡, kcal/mol) and Activation Free Enthalpy Differences (ΔΔG‡, kcal/mol) As Evaluated with the IEFPCM/M06-2X/6-31G* Method (T = 298.15 K; P = 1 bar, solvent = toluene) as Well as Representative Geometrical Parameters of the Transition Structures, the Cβ...Cγ Distance (d, Å) and the ØCα‑Cβ‑Cγ‑Oβ Torsion Angle (Ø, deg)a

1/2...GaCl3

TS

ΔG‡

ΔΔG‡b

d

Ø

Tc

1/2a...GaCl3

pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn

6.2 6.5 7.3 5.6 6.4 7.5 6.2 6.6 7.3 5.6 6.2 7.4 6.4 6.8 7.5 5.8 6.5 7.7 6.2 6.5 7.1 5.6 6.4 7.6

0 (0.5) 0.3 1.2 0 0.8 1.9 0 (0.6) 0.4 1.1 0 0.6 1.8 0 (0.6) 0.4 1.1 0 0.7 1.8 0 (0.5) 0.3 1.0 0 0.8 1.9

2.41 2.41 2.46 2.40 2.37 2.46 2.37 2.31 2.37 2.28 2.28 2.38 2.44 2.45 2.50 2.39 2.39 2.50 2.43 2.39 2.47 2.36 2.31 2.42

41.3 175.7 321.9 111.7 187.1 298.9 51.0 174.4 321.9 106.1 189.7 299.4 41.5 176.2 321.9 113.5 187.4 298.4 40.8 178.5 322.2 100.0 187.3 297.4

T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6

1/2b...GaCl3

1/2c...GaCl3

1/2d...GaCl3

1/2...GaCl3

TS

ΔG‡

ΔΔG‡b

d

Ø

Tc

1/2e...GaCl3

pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn

6.3 6.7 7.3 5.6 6.3 7.5 6.3 6.8 7.5 5.7 6.5 7.6 6.5 7.0 7.7 6.0 7.0 7.9 6.1 6.6 7.4 5.7 6.7 7.3

0 (0.6) 0.5 1.0 0 0.6 1.8 0 (0.6) 0.5 1.2 0 0.8 1.9 0 (0.5) 0.5 1.2 0 1.0 1.9 0 (0.4) 0.5 1.2 0 1.0 1.7

2.36 2.32 2.35 2.24 2.27 2.37 2.35 2.27 2.33 2.39 2.24 2.34 2.43 2.40 2.42 2.45 2.39 2.43 2.42 2.39 2.46 2.45 2.42 2.44

41.7 177.9 319.6 105.8 191.3 300.1 40.5 183.4 320.5 86.5 191.0 304.7 133.1 195.7 321.5 88.4 188.1 301.1 118.9 194.9 319.0 93.5 186.9 285.5

T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6

1/2f...GaCl3

1/2g...GaCl3

1/2h...GaCl3

Only those TSs characterized by ΔΔG‡ < 2.0 kcal/mol16 are listed. Relative activation free enthalpy. In parentheses are given the free enthalpy differences between the most stable pro-syn and pro-anti transition states, ΔΔ‡ = Δ‡(most stable pro-anti) − Δ‡(most stable pro-syn). cTypes of transition structures, see Figure 4. a b

(R = Hep) to 8.1 kcal/mol (R = 3-thienyl) for Tb′ and from 6.8 kcal/mol (R = −CHC(Me)2) to 7.2 kcal/mol (R = 4chlorophenyl) for Tc′. For all R substituents, d2 is smaller than d3, d1 decreases by going from Ta′ to Tb′, and the same occurs from Td′ to Tc′, with two exceptions, R = {3-(PhO)C6H4, Hep}, where d1 increases slightly. MX3 (BCl3, AlCl3, GaCl3, and InCl3)-Catalyzed Mukaiyama Aldol Reaction. First, we selected GaCl3 as the Lewis acid catalyst to investigate the geometries of the transition state structures, the diastereoselectivity, and the kinetics of the Mukaiyama reactions between 1 and aldehydes 2 bearing alkyl, vinyl, or aromatic substituents. From modeling the transition states with an MX3 Lewis acid, we conclude that only the open transition states are possible owing to steric effects. Indeed, the formation of cyclic structures where the metal is complexed by both the oxygen of the carbonyl and the oxygen of one of the OSiMe3 groups leads to strong repulsive interactions between the chlorine atoms and the OSiMe3 groups. The d(Cβ...Cγ) distance, ØCα‑Cβ‑Cγ‑Oβ torsion angle, activation energy difference (ΔΔE‡), activation free energy (ΔG‡), and free energy difference (ΔΔG‡) between the pro-anti and pro-syn transition states of the GaCl3-catalyzed Mukaiyama aldol reaction are listed in Table 2. The six pro-anti or pro-syn conformations of the TS structures (T1−T6) of the GaCl3-catalyzed reaction can usually be distinguished using the ØCα‑Cβ‑Cγ‑Oβ torsion angle. T1−T3 are pro-anti, while T4−T6 are pro-syn (Table 2 and

Figure 4). T1 and T4 adopt an antiperiplanar (ap) conformation, while T2, T3, T5, and T6 are gauche conformations [synclinal (sc) and/or anticlinal (ac)]. Note that some synperiplanar (sp) transition states were also obtained, but since they are characterized by very small imaginary frequencies, they do not correspond to stable conformations due to the steric effects created by the chlorines and OSiMe3 groups. In T1 and T4, the ØCα‑Cβ‑Cγ‑Oβ angle ranges from 174.4 to 195.7°, whereas T2, T3, T5, and T6 are characterized by ØCα‑Cβ‑Cγ‑Oβ angles belonging to the [37.8, 133.1°] interval in the synclinal or anticlinal domain. In the transition state structures, the Cβ...Cγ bond lengths vary over a broad range, between 2.27 and 2.50 Å, in agreement with the results by Lee et al.15 (from 2.09 to 2.66 Å). For all substituents, in the case of the pro-anti TS, the ΔG‡ decreases slightly from the antiperiplanar T1 to the synclinal T2, whereas it is larger for the other synclinal structure (T3). Similarly, in the case of pro-syn, the antiperiplanar T4 structure presents a slightly higher energy than T5, whereas for T6, the energy is greater. The large energy differences between T3 and T2 on one side and T6 and T5 on the other side were also observed between the Ta and Tb [Td and Tc] transition states of the uncatalyzed Mukaiyama aldol reaction.25 Indeed, in the (Ta, T3) and (Td, T6) transition states, the COβ is at the same side as the CβSiMe3 group, while they are at opposite sides for (Tb, T2) and (Tc, T5), leading to less steric interactions. Therefore, 1943


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Figure 4. Conformation types (1−6) of the pro-anti and pro-syn transition states of the MCl3-catalyzed Mukaiyama aldol reaction between 1 and 2a−2h.

the Cβ−SiMe3 and OSiMe3 groups, but the COβ is on the same side as the Cβ−SiMe3 group, making their energies higher than those of T2 and T5. This leads to the conclusion that the carbonyl position has an important effect on the energy of transition states. In order to study the influence of the volume of the Lewis acid on the diastereoselectivity and on the kinetic of this reaction, the geometries of the pro-anti and pro-syn transition states have been optimized for the reaction between 1 and 2a in the presence of B, Al, Ga, and In metal chlorides (MCl3) (Table 3). The transition energy differences between the most stable pro-anti and pro-syn transition states are small and hardly vary with the metal nature. Indeed, the ΔΔE‡ (ΔΔG‡) values are equal to 0.6, 0.5, 0.5, and 0.5 (0.5, 0.6, 0.5, and 0.6) kcal/mol for BCl3, AlCl3, GaCl3, and InCl3, respectively. For the GaCl3catalyzed reaction between 1 and 2a−2h, the amplitude of ΔΔG‡ ranges from 0.5 to 0.6 kcal/mol when R is an aromatic group, from 0.6 to 0.6 kcal/mol for vinylic groups, and from 0.4 to 0.5 kcal/mol if R is aliphatic. As a consequence, for B, Al, Ga, and In metal chlorides, the activation free enthalpies differences are all positive but small, leading to a weak diastereoselectivity. Note that this lack of metal effect on the diastereoselectivity contrasts with the experimental results demonstrated by Munoz-Muniz et al.,14 who observed an inversion of diastereoselectivity when going from the InCl3 to CeCl3 LA-

for both pro-anti and pro-syn transition state structures, the variation of the carbonyl position with respect to the CαCβ double bond from +sc to −sc requires more energy than from the sc/ac to ap position. The lower energy of the (Tb, Tb′, T2) and (Tc, Tc′, T5) transition state structures leads to the conclusion that for both uncatalyzed and (MX2, MX3)catalyzed reactions, the transition states favor the situation where the carbonyl is on the opposite side to the SiMe3 substituent on the Cβ atom. For pro-anti, the most stable transition state is T2, whereas T5 is the most stable for the prosyn reactions, and it is also more stable than T2. In T5, the GaCl3 LA is further away from the rest of the structure, which creates therefore less steric effects than in T2 (Figure 3). The role of MX3-Lewis acid position on the stability of TSs was also highlighted by Heathcock et al.,3 who reported that the pro-anti synclinal conformation characterized by steric interactions between tBu (R3) and the BF3 Lewis acid (Figure 1) has been excluded.3 On the other hand, the R substituent is in interaction only with the Cβ−SiMe3 group for T2, whereas it is in interaction with both the Cβ−SiMe3 and OSiMe3 groups in T5 transition states. These two effects are antagonistic, but the former is dominant so that the T5 energies are smaller than the T2 ones. Note that this favorable position of the R substituent is also found for the TC′ transition structure (Figure 3). It should be noted that in T1, the R substituent is also between 1944


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free enthalpies of activation, ΔG‡, are systematically 1−2 kcal mol−1 smaller for the MX3-catalyzed reactions than with ZnBr2 as catalyst. To our knowledge, this effect has not yet been confirmed experimentally but could easily be verified owing to the common nature of the substrates and catalysts.

catalyzed Mukaiyama aldol reaction. Then, by going from the uncatalyzed to the MCl3 (M = B, Al, Ga, and In)-catalyzed reactions, ΔΔG‡ decreases strongly, leading to the conclusion that the role of the MCl3 Lewis acid catalyst in this aldol reaction is not limited to reducing the activation energies and accelerating the reactions, because at the same time, it decreases the diastereoselectivity in comparison to the uncatalyzed reaction.25 In the presence of ZnBr2 and MCl3 (M = B, Al, Ga, and In) metal chlorides, the pro-syn is located below the pro-anti transition states. So globally, the syn product is the kinetic diastereomer. This kinetics are in agreement with (i) the kinetics of the same reaction in the absence of catalyst,25 with (ii) the kinetics of TiCl4-catalyzed Mukaiyama aldol reaction between ketene bis(trimethylsilyl) acetals and aldehydes as experimentally studied by Dubois et al.33 and theoretically confirmed by Lee et al.,15 with (iii) the kinetics of the BCl3catalyzed Mukaiyama aldol reaction between E silyl enol ether and acetaldehyde as studied by Lee et al.,15 with (iv) the kinetics of the lanthanide-catalyzed reaction between 1(trimethylsiloxy)cyclohexene and benzaldehyde as studied by Hatanaka et al.,16 and with (v) the kinetics of the InCl3catalyzed reaction between silyl enol ether and benzaldehyde as studied by Munoz-Muniz et al.14 Figure 5 summarizes the relationship between the pro-anti versus pro-syn free enthalpy of activations for the LA-catalyzed Mukaiyama aldol reactions and those of the uncatalyzed reaction taken from ref 25. Besides a clear decrease of the proanti versus pro-syn ΔG‡ for the catalyzed reaction and a further reduction by going from ZnBr2 to GaCl3, there is no simple relationship between their amplitudes. Therefore, the diastereoselectivity of the reaction decreases when it is catalyzed by Lewis acid, and it decreases when going from MX2 to MX3 Lewis acids.

Table 3. Activation Free Enthalpy (ΔG‡, kcal/mol) and Activation Free Enthalpy Differences (ΔΔG‡, kcal/mol) As Evaluated with the IEFPCM/M06-2X/6-31G* Method (T = 298.15 K; P = 1 bar, solvent = toluene) as Well as d(Cβ...Cγ) Distances (d, Å), ØCα‑Cβ‑Cγ‑Oβ Torsion Angles (Ø, deg), and the Types of the Most Stable Pro-anti and Pro-syn Transition Structures 1/2a

TS

ΔΔE‡a

ΔG‡

ΔΔG‡a

d

Ø

Tb

1/2a...BCl3

proanti pro-syn proanti pro-syn proanti pro-syn proanti pro-syn

0.6

6.6

0.5

2.55

38.8

T2

0.5

6.1 6.4

0.6

2.43 2.50

112.1 38.7

T5 T2

0.5

5.9 6.2

0.5

2.48 2.41

115.0 41.3

T5 T2

0.5

5.6 6.7

0.6

2.40 2.39

111.7 54.2

T5 T2

2.36

112.4

T5

1/2a...AlCl3

1/2a...GaCl3

1/2a...InCl3

6.1

a

The activation energy/free enthalpy differences between the most stable pro-anti and pro-syn transition states, ΔΔ‡ = E(most stable proanti) − E(most stable pro-syn). bTypes of transition structures, T2 and T5 are shown in Figure 4.

IV. CONCLUSION Density functional theory with the M06-2X exchangecorrelation functional and the PCM scheme to account for solvent effects has been used to study the geometries of the transition states and the diastereoselectivity of MX2 and MX3 Lewis acid-catalyzed Mukaiyama aldol reaction between C,O,O-tris(trimethylsilyl)ketene acetal and aldehydes bearing alkyl, vinyl, and aromatic substituents. These DFT calculations show that cyclic transition structures are the best models to describe the diastereoselectivity of the MX2-catalyzed reaction, where the metal is coordinated with both oxygen atoms (the oxygen of the carbonyl atom and that of the siloxy group). These calculations confirm the mechanism proposed by Bellasoued et al.4 In this case, four types of cyclic transition states (Ta′−Td′) are obtained, with two pro-anti (Ta′, Tb′) and two pro-syn (Tc′, Td′) structures, Tb′ being the most stable proanti and Tc′ the most stable pro-syn structure. On the other hand, open transition structures are more suitable to rationalize the diastereoselectivity of the MX3-catalyzed reactions. In this case, six types of transition states (T1−T6) are possible, with three pro-anti (T1, T2, T3) and three pro-syn (T4, T5, T6). The T2 conformation is the most stable pro-anti and the T5 the most stable pro-syn. In all cases, the syn diastereoisomer is favored, but the difference of activation free enthalpy between the pro-anti and pro-syn transition states decreases when the reaction is catalyzed, and it is further reduced when going from MX2 to MX3 Lewis acids, demonstrating a reduction of the diastereoselectivity. Calculations have finally revealed that the

Figure 5. Relationship between the ΔΔG‡(pro-anti−pro-syn) of the catalyzed and uncatalyzed Mukaiyama aldol reactions between 1 and 2a−2h.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.7b11186. HOMO of the Tb′ and Tc′ transition states; enthalpies and free enthalpies of reaction; atomic Cartesian coordinates (Å) and enthalpies for all transition states (PDF) 1945


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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Tel: +32 81 724554 (B.C.) ORCID

Benoît Champagne: 0000-0003-3678-8875 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.H.M. thanks the Fonds Spécial de Recherche of UNamur for his PhD grant. This work was supported by funds from the Belgian Government (IUAP No P7/5 “Functional Supramolecular Systems”) and the Francqui Foundation. The calculations were performed on the computers of the Consortium des Équipements de Calcul Intensif, including those of the Technological Platform of High-Performance Computing, for which we gratefully acknowledge the financial support of the FNRS-FRFC (Conventions No. 2.4.617.07.F and 2.5020.11) and of the University of Namur.

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