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The Janus Face of Steric Effect in Lewis Acid Catalyst with Size-Exclusion Design. Steric Repulsion and Steric Attraction in Catalytic Exo-Selective Diels-Alder Reaction Mária Bakos, Zoltán Dobi, Daniel Fegyverneki, Ádám Gyömöre, Israel Fernandez, and Tibor Soós ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b02099 • Publication Date (Web): 21 Jun 2018 Downloaded from http://pubs.acs.org on June 25, 2018

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ACS Sustainable Chemistry & Engineering

The Janus Face of Steric Effect in Lewis Acid Catalyst with Size-Exclusion Design. Steric Repulsion and Steric Attraction in Catalytic Exo-Selective Diels-Alder Reaction Mária Bakos,†,⊥,§ Zoltán Dobi,†,§ Dániel Fegyverneki,† Ádám Gyömöre,† Israel Fernández,‡ Tibor Soós*† †

Institute of Organic Chemistry, Research Centre of Natural Sciences, Hungarian Academy of Sciences. Magyar tudósok körútja 2, H-1117, Budapest, Hungary. ⊥ Present address: Ximo Hungary Kft., Záhony utca 7, H-1031, Budapest, Hungary.

‡

Departamento de Química Orgánica I and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Avda. de Séneca, 2 Ciudad Universitaria 28040-Madrid, Spain.

This article is dedicated to István Tamás Horváth’s 65th birthday Supporting Information Placeholder Corresponding author: *Email:[email protected] ABSTRACT: An exo-selective catalytic Diels-Alder reaction was developed using Lewis acid catalyst with size-exclusion structural design. Exploiting the steric effect, especially the steric attraction, the Lewis acid catalyst was able to reroute the reaction along a higher energy pathway. The experimental findings were also supported by theoretical calculations. This catalyst development allows an easy and practical access to highly complex and pharmaceutically relevant compounds.

KEYWORDS: Borane, Catalysis, Exo-Selective, Steric-Tuning, Steric Attraction

The Diels-Alder reaction and its variations have become one of the most useful and powerful tools in organic chemistry,1,2 as exemplified by its broad applications in natural product synthesis.3–7 The power of this reaction is also acknowledged by industrial chemists because of the rapid and atom-economical construction of complex structures with minimal waste generation.7 As up to four new stereocenters can be generated in a single step, the value of this transformation rests upon the degree of the stereocontrol that can be exercised. Apart from some particular cases, this cycloaddition has an innate endo selectivity8-13 that can be increased further by catalysts.14 Accordingly, rerouting the reaction pathway toward disfavored exo-products constitutes one of the most challenging undertakings in Diels-Alder reactions (Scheme 1). The exo-selective Diels-Alder reaction, however, is not only a theoretical, but also a practical pursuit owing to the limited accessibility of exo-products. Two different approaches have been pursued to alter the selectivity, the substratecontrolled15-19 and catalyst-controlled strategies.20–24 Despite unequivocal progress, there is still a room for further improve-

ments in terms of selectivity and substrate scope. Herein, we show that a sterically overcrowded Lewis acid catalyst can divert the Diels-Alder reaction to exo-manifold. As theoretical calculations suggest, the enhanced steric congestion around the catalytically active site engenders steric attraction (large steric elements generated non-covalent interactions) that helps to reroute the reaction along an otherwise higher energy pathway. Albeit in Diels-Alder reaction the major application of Lewis acids is to facilitate the formation of endo product, some specific Lewis acids have been developed to reverse the endo/exo selectivity. In these efforts, a primary breakthrough was the discovery that the steric bulk was a critical structural element of the developed catalysts. It was conceived that the steric repulsion restricted the conformational possibilities of the Lewis acid-dienophile complex, reduced the number of competing transition states, and destabilized the endo-transition state. Thus, the combination of these factors together rendered the reaction exo-selective. The sterical encumbrance of the catalyst was also recognized as the causative effect for exo-selective Diels-Alder reaction of enals (Scheme 1). The bulky B(C6F5)3 Lewis acid (I), the archetypical Lewis acid component of frustrated Lewis pairs (FLP), showed inverse endo/exo selectivity as compared to common Lewis acids such as BF3·Et2O, or AlCl3.25 However, recent theoretical calculations by Fernández and coworkers26 on this reaction revealed that the observed selectivity switch is not the result of the previously envisaged steric destabilization of the endo-transition state, but the occurrence of a significant CH···F non-covalent interaction between the reactants along the exo pathway. Most importantly, the calculations suggest that fluorine atoms in ortho position have a decisive contribution to the stabilization of the exo-transition state.

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entry

diene

1c

R=H R’=TMS R=H R’=TMS R=H R’=TMS R=H R’=TBS R=H R’=TIPS R=H R’=TIPS R=H R’=TIPS R=H R’=TIPS R=H R’=TIPS R=MeO R’=TIPS R=MeO R’=TIPS R=MeO R’=TIPS R=MeO R’=TIPS

2c 3c 4c 5c 6

c

7c 8c 9c 10c 11e 12e,f 13e,g

cat II II

II II III IV IV V V V V V

R=MeO R’=TIPS R=MeO R’=TIPS

15e,g,i 16e,i

I I

h

THF

0.25

3a,o/4a,ob (conv.) 1/5.2 (99%) 1/10 (75%) 1/1.8 (82%) 1.1/1 (94%) 1.3/1 (94%) 1/3.2 (29%) 6/1 (94%) 6.5/1 (94%) 7.5/1 (99%) 9.4/1 (89%) 13/1 (85%) 7.9/1 (76%) 15/1 (99%) 7.3/1 (99%; 66%j)

0.25

0.25 0.25 0.25 0.25 0.25 1 1 1 1 1 1

Toluene

Vh h

conc [M]

Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene

II

R=MeO R’=TIPS

14e,g

solve nt DC M

1

Toluene Toluene

exo-/endob 89/11 85/15 94/6 96/4 93/7 n.d. d 93/7 87/13 84/16 83/17 26/74 17/83 90/10 85/15

1

17/1

55/45

1

3.7/1 (84%)

22/78

Lewis acid O

R1

R1

L.A. O

R2

+

COR2 R2

R1

exo transition state O O O

O OH

O

HN O

NH2

O

N

CH3

tetrahydrocannabinol

oseltamivir

stenine

Scheme 1. The trans-cyclohexene generating disfavored exo-Diels-Alder reaction and the occurrence of trans-patterns in natural products and pharmaceuticals. This alternative, steric attraction driven mechanistic rationale triggered us to exploit size-exclusion Lewis acids, that we originally developed for FLP hydrogenation,27–29 in Diels-Alder reactions. These boranes have an enhanced steric shield around the boron atom to restrict many side-reaction of FLPs, but still allow the cleavage of the small size hydrogen molecule. As we have recently reported, these specific Lewis acids significantly expanded the FLP hydrogenation in scope and practicality, including functional group and water tolerances.27–29 At the outset of our investigation, it was expected that the enhanced steric shielding (Cl instead of F atom in ortho positions, see Table 1) also results in an enhanced steric attraction around the boron center which might be translated into improved exo selectivity in Diels-Alder reaction.

Table 1. Screening of Catalyst and Reaction Conditionsa O

O

O OR' O R

1a,o a:R=MeO, o:R=H R' = TMS, TBS, TIPS

O

Et

2a

(1.2 equiv)

1) Lewis acid 2) H + /H2O

Ar

Ar

Ar O

O

Et

trans-3a,o (exo)

O

O

Et

cis-3a,o (endo)

Ar O 4a,o

a

Reaction conditions: Diene (0.5 mmol, 1.0 equiv.), dienophile (0.6 mmol, 1.2 equiv.), catalyst (0.05 mmol, 0.1 equiv.), 25°C, 24 hours. b Conversion and exo/endo selectivity of 3a,o were determined by 1H NMR from the crude reaction mixture. c The diene was purified without chromatography. d Due to low conversion, the minor diastereomer was undetectable. e The diene was purified by column chromatography. f 5 mol% CF3CH2OH was used as an additive. g 1 mol% TEA was applied as an additive. h 5 mol% catalyst load was used. i -40°C, 150 min. j Isolated yield of 3aa adduct.

Our further attempt was to expand exo-selective Diels-Alder reaction in substrate scope. We aimed to explore easily available, synthetically useful, but still challenging substrates. Previous research has shown that the substitution pattern of the diene influences the selectivity, i.e. lack of terminal substituents on the “butadiene” core typically led to endo-preferred reaction.30 As we aimed to revert this type of selectivity, we chose to examine the selectivity of silyloxy dienes 1a,o in the test reaction. (Table 1). Furthermore, ethyl acrylate (2a) was selected as dienophile because such a low reactive substrate has not been proved as a competent substrate in Lewis acid promoted exo-selective Diels-Alder reaction.31 Our initial results performed with catalyst II and using TMS protecting group were rather disappointing; as in polar solvents the desired Diels-Alder adduct, the exo-product trans-3a, were obtained as a minor products and the homo-dimerization of the diene 1a occurred and 4a was detected as a main product (Table 1, entries 1, 2). To suppress this undesired reactivity, less polar solvent toluene, and more stable silyl protecting groups (TBS or TIPS) were applied in the reaction, nevertheless, the amount of the undesired product 4a remained significant (Table 1, entries 1– 5). Interestingly, even a slight modification of the catalyst Lewis acidity had a significant impact on the cis/trans 3a product/4a dimer ratio. Whereas tempering the strength of Lewis acidity of the catalyst (e.g. III) reduced the conversion of the reaction and the desired adduct’s yield, higher Lewis acidity (IV and V) enhanced the formation of desired Diels-Alder products trans-3a and cis-3a significantly (Table 1, entries 6-9). However, within the employed acidity range, the Lewis acidity of the applied catalyst II-V had negligible impact on the exo/endo selectivity (entries 59). Catalyst V, as the best performing catalyst, showed also remarkable exo selectivity. The still high amount of homo-DielsAlder product prompted us to enhance further the reactivity of diene 1a, therefore, we employed 1o having a methoxy-group in the aryl ring. Gratifyingly, this modification gave better ratio for the desired product (Table 1, entry 10). These initial results were performed with 1a,o diene that were purified without chromatography. Surprisingly, reversed exo/endo selectivity was observed when chromatographically purified diene 1o was employed (Table 1, entry 11). We attributed this selectivity backsliding to a competing Lewis acid induced Brønsted acid-catalytic reaction,28 which was initiated by either the slight amount of silanol formed during the chromatography or the removal of amine traces remained from the enolate formation. Therefore the effect of different additives was tested on the selectivity of the reaction. Addition


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ACS Sustainable Chemistry & Engineering of CF3CH2OH alcohol, as expected, shifted even further the reaction toward endo product formation (Table 1, entries 12). Addition of triethylamine, however, not only restored both the overall yield and exo preference of the reaction, but improved them slightly further (Table 1, entry 13). The reduction of catalyst load was also investigated; the employment of 5 mol% of V only slightly altered the exo-selectivity (Table 1, entry 14). Finally and most importantly, the Diels-Alder reaction was probed with catalyst I, which is the sterically less bulky progenitor of catalyst V (Table 1, entries 15, 16). As highlighted in Table 1, the enhanced steric shielding was a critical, enabling element to secure high exo selectivity in the catalytic reaction, as sterically less crowded borane I provided poor exo/endo ratio. Additionally, a similar exo-selectivity backsliding could be observed when Lewis acid I was applied without triethylamine base additive (Table 1, entry 16). Further practical advantage of ortho F-Cl exchange in the catalyst design is that, unlike catalyst I, catalyst V is less accessible, which might be the reason that the reaction can be conducted even at ambient temperature. Having identified catalyst V as a competent, exo-selective catalyst for Diels-Alder reaction and developed a robust reaction condition, we next turned our attention to explore the scope of this reaction. A variety of electron-deficient and electron-rich dienes underwent exo-selective Diels-Alder reaction with ethyl-acrylate (Scheme 2, 3aa-3ra). Reactions with dienes having electrondonating substituents on the aromatic ring generally gave slightly higher yields. The reactions with ortho-aryl dienes revealed that ortho substituents have a deleterious effect on exo/endo selectivity (Scheme 2, 3ca, 3fa). To our delight, dienes with heteroaromatic groups (3qa, 3ra) can be also applied in this catalytic reaction.

Scheme 2. Reaction Scope of the Diels-Alder Reactiona

a

Reaction conditions: Diene (1.0 mmol, 1.0 equiv.), dienophile (1.2 mmol, 1.2 equiv.), TEA (0.01 mmol, 0.01 equiv.), catalyst (0.05 mmol, 0.05 equiv.) 1 mL abs. toluene, 25°C. bThe diastereomeric ratio in the crude reaction product was determined by 1H NMR cIsolated yields. While the previous borane-catalyzed Diels-Alder proceeded well only with enals substituted with electron-withdrawing groups at β-position,25 our aim was also to utilize less reactive enals as dienophiles. Crotonaldehyde proved to be a suitable choice for this exo-selective catalytic reaction. Dienes with both electronwithdrawing and donating substituents performed similarly. The selectivity-lowering effect of ortho substituents was also observed in these cases, although their effect was attenuated (Scheme 2, 3cb, 3fb). The scope of the suitable enals have been also exam-



ined and results showed that dienophiles with longer aliphatic side-chain gave the same selectivity for 3ac and 3ad without significant loss in yield. However, introduction of an aryl ring into dienophile decreased the exo selectivity of 3ae. To gain more insight into the exo/endo selectivity of the above discussed Diels-Alder reactions, we carried out Density Functional Theory (DFT) calculations at the dispersion-corrected SMDB3LYP-D3/def2-TZVPP//B3LYP-D3/def2-SVP level.32 To this end, the exo/endo reaction profiles involving the model methyl acrylate (where the ethyl group was replaced by a methyl group) and butadiene (R = H, R’ = SiMe3) in the presence of either catalyst I or catalyst V were explored. Moreover, among the different possible conformations adopted by the dienophile (i.e. s-trans or s-cis conformation along with the syn or anti orientation of the Lewis acid coordinated to the carbonyl group), we focused only, based on our previous report on strongly related reactions involving α,β-enals,26 on those leading to the most stable exo/endo transition states. Not surprisingly, both catalysts lead to rather similar reaction profiles. As depicted in Figure 1 for the transformation involving catalyst I, the cycloaddition reaction leading to the exocycloadduct is not concerted but proceeds stepwise through the zwitterionic intermediate INT-exo. For the endo-pathway, the corresponding transition state TS2-endo could not be located on the potential energy surface, which is not surprising considering the exergonicity of the reaction and the rather low barrier associated with the ring-closure step (ca. 2 kcal/mol for the process involving TS2-exo, see Figure 1).33 The selectivity of the transformation is therefore defined by the energy difference between

the corresponding transition states in the first step of the process according to the Curtin-Hammett principle.34 Thus, the computed free activation energy difference is 1.9 kcal/mol at 25 ºC , which is consistent with the poor exo-preference observed experimentally (see Table 1, entry 15, 16). Moreover, according to the data in Figure 1, the endo-cycloadduct is not only kinetically but also thermodynamically favored over the formation of the corresponding exo-cycloadduct (∆∆GR = 3.0 kcal/mol, at 25 ºC). The scenario involving catalyst V is markedly different to that commented above for the process involving catalyst I. As readily seen in Figure 2 (only the rate determining step is shown), the exo-cycloadduct is now thermodynamically strongly favored over the endo-cycloadduct (∆∆GR = 8.4 kcal/mol, at 25 ºC). In addition, the corresponding transition state TS1-exo is also more stable than the corresponding TS1-endo by 0.7 kcal/mol. This free activation energy difference is translated into an exo/endo ratio of ca. 77:23, which is consistent with the experimental findings (see Table 1). The combined thermodynamic and kinetic preference for the exo-pathway explains the observed exoselectivity when using catalyst V (whereas the opposite is found for catalyst I). We previously found that the exo-pathway was favored in the analogous reaction involving α,β-enals as a consequence of the occurrence of a stabilizing CH···F non-covalent interaction in the corresponding exo-transition states which is not present in the analogous endo-transition states.11 For this reason, we analyzed in detail the non-covalent interactions present in the exo-transition states for the processes involving either catalyst I or catalyst V.

Figure 1. Computed reaction profiles for the Diels-Alder reaction of methyl acrylate and butadiene (R = H, R’ = SiMe3) in the presence of B(C6F5)3 (catalyst I).Relative free energies at 25 ºC and bond distances are given in kcal/mol and angstroms, respectively. All data have been computed at the SMD(toluene)-B3LYP-D3/def2-TZVPP//B3LYP-D3/def2-SVP level.


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Figure 2. Computed reaction profiles for the Diels-Alder reaction of methyl acrylate and butadiene (R = H, R’ = SiMe3) in the presence of B(C6F5)2(C6H3Cl2) (catalyst V). Relative free energies at 25 ºC and bond distances are given in kcal/mol and angstroms, respectively. All data have been computed at the SMD(toluene)-B3LYP-D3/def2-TZVPP//B3LYP-D3/def2-SVP level. To this end, the NCIPLOT method35 was applied to directly visualize such non-covalent interactions. As shown in Figure 3, among other interactions, both species benefit from three different stabilizing CH···F interactions (green surfaces) established between the ortho-halogen atoms of the catalyst and the C–H bonds of the diene moiety (including the reactive CH bonds). This finding provides further support to the key role of CH···F interactions in these Lewis-acid catalyzed Diels-Alder reactions..26 Strikingly, the transition state involving catalyst V exhibits an additional stabilizing Cl···π∗(C=O) non-covalent interaction which is not present in the analogous saddle point involving catalyst I. The Second Order Pertubation Theory (SOPT) of the Natural Bond Orbital (NBO) method nicely agrees with this qualititatve finding as it locates a two-electron delocation from a chlorine lone-pair to the vacant p-atomic orbital of the oxygen atom with an associated stabilizing SOPT-energy, ∆E(2), of –0.99 kcal/mol. As a result, the saddle point TS1-exo involving catalyst V is further stabilized and becomes slightly more stable than the corresponding TS1-endo. This additional stabilization together with the computed much higher thermodynamic stability of the corresponding exocycloadduct render the exo-pathway the preferred reaction channel. At variance, the non-covalent CH···F interactions in the exotransition state involving catalyst I are not enough to revert the typical endo-bias of the Diels-Alder reaction.

Figure 3. Contour plots of the reduced density gradient isosurfaces (density cutoff of 0.03 a.u.) for TS1-exo (cat-V, left) and TS1exo (cat-I, right). The surface color code is blue for strongly attractive, green for weakly attractive, and red for strongly repulsive interactions. The dashed box shows the most significant CH···F interactions. In conclusion, in a dual attempt to further Diels-Alder reaction in efficiency and scope, we developed a catalytic exo-selective Diels-Alder reaction of silyloxy dienes and ethyl-acrylate using a Lewis acid with size-exclusion design. As the calculations suggest, the key to the success of exo selectivity was the enhanced steric hindrance around the catalytic center which engenders steric attraction for substrates and helps to reroute the reaction along a higher energy pathway. We anticipate that these advances might result in the further valorization of exo-selective Diels-Alder reaction and trigger to unlock even more of its potential in organic synthesis and medicinal chemistry. Further studies to explore the utility of size-exclusion design are ongoing in our laboratory and will be reported in due course.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website: Detailed synthesis of boranes with their full characterization, reaction conditions and NMR spectra, computational details and Cartesian coordinates and energies for all species discussed in the text.

AUTHOR INFORMATION Author Contributions § These authors contributed equally.

Notes



The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Research, Development and Innovation Office (K-116150 to T.S.). Financial support was also provided by the Spanish Ministerio de Economía y Competitividad (MINECO) and FEDER (Grants CTQ2016-78205-P and CTQ2016-81797-REDC to I. F.). The authors would like to thank Márk Szabó (Instrumentation Center, RCNS, Budapest) for NMR technical support. We are grateful for the financial and technical support from Servier Research Institute of Medicinal Chemistry.

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Synopsis: A novel metal-free catalyst reroutes Diels-Alder reaction along a higher energy exo-selective pathway under mild conditions

7 ACS Paragon Plus Environment

The Janus Face of Steric Effect in Lewis Acid ... - ACS Publications

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