Mismatched Cases in Proline-Catalyzed Cascade Reactions

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Matched/Mismatched Cases in Proline-Catalyzed Cascade Reactions with Carbohydrates: A Computational Insight into the Role of D- and L‑Proline Kenta Stier,† Marek P. Checinski,† Swjatoslaw N. R. Witte,‡ and Rainer Mahrwald*,§ †

CreativeQuantum GmbH, Am Studio 2, 12489 Berlin, Germany Institute of Organic Chemistry, Leibnitz University, Hannover, Schneiderberg 1 B 30167 Hannover, Germany § Institute of Chemistry, Humboldt University Berlin, Brook-Taylor Str. 2, 12484 Berlin, Germany Downloaded via VANDERBILT UNIV on January 14, 2019 at 03:26:59 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.



S Supporting Information *

ABSTRACT: The cascade reactions of carbohydrates with methyl ketones in the presence of proline feature complex running reaction steps. By extensive quantum mechanical simulation, a coherent reaction mechanism was identified matching the experimental data. The present calculations indicate a Mannich reaction/proline hydrolysis/retro aza-Michael cascade to form an intermediate α,β-unsaturated ethyl ketone. This key precursor yields C-glycosides by a final intramolecular amine-catalyzed oxa-Michael addition. Additionally, the formation of this intermediate determines the rate and selectivity of the overall cascade reaction. Strongly matched and mismatched cases were observed when used with D- or L-proline. They are consistent with the calculated energy barriers of the corresponding transition states.



INTRODUCTION

For similar synthesis of C-glycosides of unprotected 2-N-acylaldohexoses and aldopyranoses, see ref 7. The highest yields were detected in the L-proline series using D-deoxyribose (deoxy-10, 70%), whereas the lowest yields were obtained with xylose (xylo-9, 17%). The corresponding Cglycosides of ribose, arabinose, and lyxose were isolated with nearly similar yields (rib-7, 50%; ara-8, 44%; and lyxo-11, 45%, Scheme 1). Initially, an aldol condensation of acyclic ribose 1 with methyl ethyl ketone 6 followed by an intramolecular oxaMichael reaction was assumed to be the reaction mechanism (Scheme 2). For a comprehensive overview of advances in the synthesis of C-glycosides, see refs 5 and 8. To gain a deeper insight into the mechanism of this prolinecatalyzed cascade reaction, we conducted the same reactions in the presence of D-proline. The C-glycosides of deoxyribose and lyxose were isolated with the same yields as in the L-proline series (deoxy-10, 70%, and lyxo-11, 45%). However, strong mismatched cases were observed by deployment of D-proline, when

Proline-catalyzed aldol reactions have been investigated to a great extent over the past 15 years.1 Moreover, numerous reports of computational calculations on this reaction reflect this extensive research.2 The enamine mechanism has been firmly established.3 Transition states have been calculated to explain the origins of stereoselectivities and configurations that were obtained during this reaction. Also, calculations of prolinecatalyzed Mannich-reactions have been reported.4 This strong development of important organocatalyzed transformations has enabled the development of the operationally simple protocol to synthesize C-glycosides presented in this article. Unprotected carbohydrates react with several different methyl ketones in the presence of proline and additional amounts of base to yield the corresponding C-glycosides in moderate to good yields.5 The corresponding C-glycosides were obtained by reactions with methyl ethyl ketone 6 within 72 h at room temperature in the presence of proline and diazabicycloundecene (DBU, Scheme 1). These reported cascade reactions are new and exciting, as they unexpectedly deviate from the classical Amadori pathway.6 © XXXX American Chemical Society

Received: October 1, 2018 Published: December 13, 2018 A

DOI: 10.1021/acs.joc.8b02530 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

a quantitative conversion of D-ribose into the corresponding hemiaminal II was detected within the first 2 h at room temperature. However, the enamine I of methyl ethyl ketone and proline was detected after 24 h to an extent of maximal 20% by NMR experiments (Scheme 5).9 Further investigation in this field supports these observations. A similar trend of promotion or prevention of a reaction was detected by deployment of ketohexoses with acetone and proline. NMR experiments of this series indicate the same rapid and quantitative formation of the corresponding hemiaminal of fructose and proline.10 To gain more insight into the reaction mechanism, we started a program of extensive computational calculations. Herein we present results of quantum chemical calculations of transition states of this cascade reaction.

Scheme 1. Cascade Reactions of Aldopentoses with Methyl Ethyl Ketone in the Presence of D- or L-Prolinea



COMPUTATIONAL METHODS

Reaction conditions: 1 eq DBU, 1 eq proline, 72 h, and rt. Yields are given as overall yields of α-anomers, β-anomers, hemiketals, and pyranoid C-glycosides (see ref 5).

Density functional theory (DFT) was used for the calculation of structures and energetics. The hybrid B3LYP functional for exchange and correlation11,12 was used for optimizations and combined with a recent dispersion correction of Grimme (DFT-D version 3 with BeckeJohnson damping13). Due to the experiences that B3LYP-D3 produces, precise geometries of organic molecules with hydroxyl groups, this DFT-functional was used. The B3LYP optimizations were performed using a double-ζ basis set def2-SVP.14 For all calculated structures, a vibrational analysis was done with the B3LYP-D3 hybrid functional and def2-SVP basis set. The single point calculations were performed using DSD-PBE-NL and a triple-ζ basis set def2-TZVP.13 To account for solvent effects, the single point calculations were carried out using the CPCM (conductor-like polarizable continuum model) for methanol.15 All calculations performed in this article were done using code based on the Firefly QC package.16 It was modified to match our computer infrastructure.

used with ribose or xylose. Hardly any reactions were detected in reactions of ribose or xylose (rib-7 and xylo-9, < 5%). On the other hand, an increase of yields was observed when used with arabinose in the presence of D-proline (ara-8, 59%). To prove this strong differentiation of carbohydrates by proline, an equimolar mixture of D-arabinose 2 and D-xylose 3 was reacted with methyl ethyl ketone in the presence of Dproline under the described conditions. After 72 h, the formation of the C-arabinoside 8 was observed at room temperature only. The corresponding C-xyloside 9 was not detected in these experiments (Scheme 3). These findings suggest a strong influence of the configuration of carbohydrates and proline on the outcome of this reaction. Comparable results were obtained by reactions with aldohexoses. The highest yields were observed by reactions of 2-deoxyhexoses with methyl ethyl ketone (deoxygluco-20, 50%, and deoxygalacto-21, 100%), whereas no reactions were detected with glucose (gluco-17, 0%, Scheme 4). NMR-experiments were carried out to gain a deeper understanding of the reaction mechanism. To this end, we reacted separately methyl ethyl ketone and D-ribose with Lproline in the presence of DBU. These reaction mixtures were monitored by NMR experiments and DC analyses. Surprisingly,

RESULTS AND DISCUSSION The potentially viable pathways were analyzed and described consistently and exemplarily by transformations of D-ribose with L- and D-proline. The individual reaction steps of ribose with proline and methyl ethyl ketone are depicted below to classify the dimension of activation barrier. Complete calculations of reactions of starting materials with deoxyribose, lyxose, xylose, or arabinose with D- or L-proline are collected in the Supporting Information.9 Thermodynamics of the Direct and Uncatalyzed Aldol Condensation. The focus of the following calculations is on the crucial intermediate IX. The α,β-unsaturated ethyl ketone IX is the starting material for the subsequent and final aminecatalyzed intramolecular oxa-Michael reaction to yield the corresponding C-glycosides (see Scheme 2). This ethyl ketone IX is the product of a direct aldol condensation of the acyclic structure of D-ribose 1 and methyl ethyl ketone 6. A free energy of +6.7 kJ/mol was calculated for the reaction of methyl ethyl ketone with D-ribose in the absence of proline (eq 1). Aldopentoses exist mainly in the hemiacetal form. The occurrence of acyclic structures of aldopentoses is detected in only very small amounts (∼0.05% in H20 at room temperature).17 On the basis of this data, a realization of such a direct

a



Scheme 2. Proposed Mechanism of Cascade Reaction of Methyl Ethyl Ketone with Ribose in the Presence of Proline

B

DOI: 10.1021/acs.joc.8b02530 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Competitive Cascade Reactions of Arabinose and Xylose with Methyl Ethyl Ketone

Scheme 4. Reactions of Aldohexoses with Methyl Ethyl Ketone in the Presence of L-Prolinea

Reaction conditions: 1 eq DBU, 1 eq L-proline, 72 h, and rt. Yields are given as overall yields of α-anomers and β-anomers.

a

Scheme 5. Formation of Enamine I and Hemiaminal II

and uncatalyzed aldol condensation should be considered to be unrealistic. A quite similar direct aldol condensation process of acyclic carbohydrates with methyl ketones has not been reported in the literature so far. Reactions of Starting Materials with L-Proline. On the basis of the result of an uncatalyzed direct aldol condensation

(eq 1), further investigations of the aldol addition of ribose with methyl ethyl ketone in the presence of proline were conducted. To this end, all starting materials and intermediates of this reaction were analyzed by initial calculations. The following free energies for reactions of starting materials with L-proline were calculated. They are depicted in eqs 2−5. C

DOI: 10.1021/acs.joc.8b02530 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 6. Formation of C-Glycosides via the Houk−List Pathway

Scheme 7. Transition State B for Reaction of Ribose 1 with Enamine Ia

a

Hydrogen atoms are omitted for clarity (with the exception of the green-colored one).

Figure 1. Transition state C for reaction of oxazolidinone rib-III with enamine I. Hydrogen atoms are omitted for clarity (with the exception of the green-colored ones). Distances are given in Å.

The intermediates α- and β-rib-II are stabilized by DBU, as they exist as a proline−DBU salt.9 The preferentially formed D

DOI: 10.1021/acs.joc.8b02530 J. Org. Chem. XXXX, XXX, XXX−XXX

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Figure 2. Comparison of transition state energies during the C−C bond formation processes by the direct aldol addition, Houk−List pathway, and Mannich reaction.

Scheme 8. Stereoisomers of Ethyl Ketones rib-VII and rib-VIIIa

a

The denotation 1 and 2 refers to the nomenclature of the foregoing carbohydrates.

formation of oxazolidinone rib-III or the formation of imine ribIV are observed (eqs 4 and 5). Similar intermediates were described in reactions of glucose with proteinogenic amino acids.18 To sum up, it is assumed that proline reacts with both methyl ethyl ketone and D-ribose at room temperature (eqs 2 and 3). By

hemiaminal β-rib-II is the subject of a successive dehydration, which can occur in two different ways. As a result of that, the E

DOI: 10.1021/acs.joc.8b02530 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 9. Elimination of L-Proline from α- and β-Configured Ethyl Ketone rib-VII by a Retro-Aza-Michael Reaction

Scheme 10. Elimination of D-Proline from α- and β-Configured Ethyl Ketone rib-VIII by a Retro-Aza-Michael Reaction

reacting proline with methyl ethyl ketone, the formation of the corresponding enamine I is observed (eq 2). Reaction of Dribose 1 and L-proline yields α- and β-configured hemiaminal rib-II (eq 3), which can undergo a dehydration. α- or βconfigured oxazolidinones rib-III or imine rib-IV are the results of this reaction step (eqs 4 and 5). All calculations of this reaction cascade have been done with the energetically most

favored structure as the starting material. The calculated values are in accordance with the experimental data and are supported by NMR experiments (Scheme 5).9 By further calculations, alternative transformations of reactive intermediates rib-III and rib-IV into the key intermediate ethyl ketone IX were explored. F

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Scheme 11. Chair Conformation of the Transition States during the Proline Elimination by a Retro-Aza-Michael Reactiona

a

The denotation of conformations of the 7-membered rings was carried out in analogy to conformations of carbohydrates.

Scheme 12. Transition States D and E of α- and β-rib-VII with L-Prolinea

a

Hydrogen atoms are omitted for clarity (with the exception of the green-colored ones). Distances are given in Å.

Direct Aldol Addition. In initial calculations, we evaluated the direct reaction of methyl ethyl ketone with oxazolidinone rib-III. The thermodynamical data of the keto−enol equilibrium of methyl ethyl ketone indicate that the keto form of methyl ethyl ketone is by far the more stable one (eq 6). On the basis of this fact, a possible transition state for the direct reaction of β-configured oxazolidinone (ß-rib-III) with methyl ethyl ketone 6 was investigated. The execution of this reaction requires 201.3 kJ/mol at room temperature. The corresponding calculated transition state A is depicted in eq 7.

In eq 7, hydrogen atoms are omitted for clarity (with the exception of the green-colored ones). Distances are given in Å. The calculated energy of 201.3 kJ/mol for the barrier of the transition state A is too high. On the basis of this value, such a direct reaction of methyl ethyl ketone 6 with imine rib-IV is not feasible at room temperature. Aldol Condensation/Oxa-Michael Cascade Reaction. On the basis of the initial proposal of an aldol condensation/oxaMichael cascade as the reaction mechanism (Scheme 2), the following scenario could be proposed. The C−C bond G

DOI: 10.1021/acs.joc.8b02530 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 13. Transition States N and O of α- and β-rib-VIII with D-Prolinea

a

Hydrogen atoms are omitted for clarity (with the exception of the green-colored ones). Distances are given in Å.

formation process is realized by a proline-catalyzed aldol addition step of the acyclic ribose 1 with the enamine of proline I to yield the intermediate V. Subsequent dehydration and elimination of proline generate the α,β-unsaturated ketone ribIX. A final intramolecular oxa-Michael reaction gives an access to C-glycoside rib-7 (Scheme 6). A free energy of −21.7 kJ/mol was calculated for this C−C bond formation process, and an energy barrier of +48.6 kJ/mol was calculated for the associated transition state B (Scheme 7). Mannich Reaction. As discussed above, both ribose and methyl ethyl ketone react with proline at room temperature (eqs 2 and 3). On the basis of these results, we have calculated transition states under these conditions. By the reaction of oxazolidinone (β-rib-III) with the terminal enamine of methyl ethyl ketone I, an access to the Mannich intermediate rib-VI is given. This formal Mannich reaction occurs via the intermediately formed imine rib-IV (eq 8). An energy barrier of +53.3 kJ/mol was calculated for the associated transition state C of the formation of α-rib-VI (eq 8, Figure 1). The imine rib-IV (eq 9) represents an intermediate during this transformation from rib-III to the intermediate ethyl ketone rib-VI. An access to the ethyl ketone α-rib-VI is provided by a Mannich-reaction of imine rib-IV with the enamine of methyl ethyl ketone I. For this individual reaction step, a free enthalpy of −31.8 kJ/mol at room temperature was calculated (eq 9). For investigation of relations between oxazolidinones and the

corresponding imines in proline-catalyzed reactions, see ref 19. Support for the Mannich-reaction of aldimines by both metal as well organocatalysis is given by selected reactions in ref 20. A new stereogenic center is created during the formation of ethyl ketone α-rib-V (red asterisk at the former anomeric carbon atom C-1, eqs 8 and 9). The relevance of this asymmetric carbon atom (former anomeric carbon atom of ribose) for the overall process will be discussed during the retro aza-Michael reaction (see eq 11). To compare these three different C−C bond formation steps (direct aldol addition, Houk−List mechanism, and Mannich reaction) the calculated values of these processes were depicted in the graph below (Figure 2). To this end, the energies of starting L-proline, D-ribose, and methyl ethyl ketone were set at 0 kJ/mol. The high value of transition state A (177.2 kJ/mol) indicates the inability to perform the C−C bond formation process by a direct aldol addition at room temperature (Figure 2). The energy barrier for the C−C bond formation via the Houk−List pathway was located at 80.6 kJ/mol starting from Lproline, D-ribose, and methyl ethyl ketone (transition state B, Figure 2). This value of transition state B is 19.5 kJ/mol higher than that of transition state C. Transition state C (61.1 kJ/mol) represents the C−C bond formation via the Mannich reaction of imine rib-IV with enamine I (eq 8). Additionally, the formation of transition state C is supported by the results of spectroscopic experiments (Scheme 5). For these reasons, further calculations H

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The Journal of Organic Chemistry Scheme 14. Transition States P and Q of α- and β-ara-VIII with D-Prolinea

a

Hydrogen atoms are omitted for clarity (with the exception of the green-colored ones). Distances are given in Å.

The calculations with these four diastereoisomers started with the α- and β-configured intermediates VII (L-proline). A hydrogen-bonded seven-membered ring system was located as a possible transition state (Scheme 9). Different energy barriers were calculated for these transition states depending on the configuration and conformation of these seven-membered rings. A barrier of 58.9 kJ/mol and a free energy of −8.7 kJ/mol were calculated for this proline elimination step, when α-configured ethyl ketone α-rib-VII (transition state D, Scheme 9) was used. In strong contrast, 143.9 kJ/mol was calculated for the corresponding transition state E of the proline elimination of β-configured rib-VII at room temperature. An opposing tendency was observed in the D-proline-series. A barrier of 106.9 kJ/mol was calculated for the transition state N of the elimination of D-proline, when used with α-rib-VIII. On the other hand, 86.6 kJ/mol was determined for the transition state O during the D-proline elimination of β-configured ethyl ketone rib-VIII (Scheme 10). The energy barriers of these four calculated transition states D, E, N, and O reveal the conformational and configurative properties of the transition states during the proline elimination via a retro-aza-Michael reaction. To avoid steric interactions, the 7-membered ring transition state can exist in the boat- or in the chair-conformation. For a consistent and homogeneous discussion, this fact is depicted for the chair-series with the corresponding nomenclature in Scheme 11.

of the overall process were proceeded with the Mannich-product rib-VI. Removal of the Imine−Proline. The intermediate α-ribVI can undergo a hydrolytic cleavage of proline. As a consequence, the ethyl ketone α-rib-VII is formed. Then, +23.2 kJ/mol was calculated for this process at room temperature (eq 10). A similar hydrolytic elimination of proline is described during the Morita−Baylis−Hillman reaction.21 Retro Aza-Michael Reaction. The elimination of the second proline molecule is realized by a retro-aza-Michael process, producing α,β-unsaturated ethyl ketone rib-IX (eq 11). This key intermediate IX is the base for the final intramolecular oxa-Michael addition to yield the corresponding C-glycosides. Initial calculations indicated a strong influence of the configuration of the former pseudoanomeric atom (C-1) of the Mannich products VII (L-proline) or VIII (D-proline) and the configuration of proline on this elimination step. Four stereoisomers can be formed by the Mannich-reaction of imine IV with enamine I followed by the subsequent hydrolytic fragmentation of proline (eqs 9 and 10). When used with ribose, these are α- and β-configured rib-VII (or 1.2-anti- and 1.2-synconfigured rib-VII) in the L-proline series and α- and βconfigured rib-VIII (or 1.2-anti- and 1.2-syn-configured ribVIII) in the D-proline series. These four diastereoisomers of Dribose are depicted in Scheme 8. They were individually analyzed by the following calculations. I

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The Journal of Organic Chemistry Scheme 15. Transition States T and U of α- and β-deoxy-VIII with D-Prolinea

a

Hydrogen atoms are omitted for clarity (with the exception of the green-colored ones). Distances are given in Å.

means of transition states of ribose. The conformations and configurations of the transition states of the four other pentoses (arabinose, xylose, deoxyribose, and lyxose) are discussed only shortly in analogy to transition states of ribose. For complete calculations and graphics of configurations and conformations of all transition states D−W, see Table 2 and ref 9. In reactions of ribose, the carboxylate function of L-proline utilizes the pro-S-configured hydrogen atom at C-6 to generate the 7-membered transition states D and E with a N,6C5conformation (Scheme 12). The changing from α- to β-rib-VII requires an inversion of the equatorial position of ribose at the C-5 in transition state D (58.9 kJ/mol) into an unfavorable axial position at C-5 in transition state E. A change of the conformation from transition state D to E is not observed. The N,6C5-conformation is conserved in both transition states. Thus, this operation originates a strong increase of the activation energy of transition state E (143.9 kJ/mol). On the other hand, D-proline utilizes the pro-R-configured hydrogen atom at C-6 to construct the 7-membered transition states N and O (Scheme 13). An unfavorable axial position of ribose is observed in both transition state N and O to avoid steric repulsions with D-proline. When used with α-rib-VIII, a 5CN,6conformation for transition state N (106.9 kJ/mol) is located. The changing of configuration at C-5 by changing from α-ribVIII to β-configured rib-VIII involves steric repulsions with Dproline. As a consequence, a ring flip from the 5CN,6-

Both the configuration of the former anomeric carbon atom of pentoses and the configuration of proline control the configuration and conformation of the 7-membered transition state (former C-1C-5 in the 7-membered transition states). The configuration of proline dictates the choice of one of the diastereotopic hydrogen atoms at C-6, to form a hydrogen bridge with the carboxylate function of proline (Schemes 12 and 13). This highly stereoselective operation occurs independently of the configuration at the former anomeric carbon atom (C-5) of the deployed carbohydrates by a following general way. DProline (R-proline) picks the pro-R-configured hydrogen, whereas the pro-S-configured hydrogen atom is selected by Lproline (S-proline). In addition, the configuration of the C-5 carbon atom has to be considered in the construction of the transition states (α- or β-configured intermediate VII or VIII of the D- or L-proline series). As a result of that, four diastereomeric transition states have to be considered. For ribose, these are the pro-S-5.6-syn-configured transition state D and pro-S-5.6-anticonfigured transition state E in the L-proline series and the proR-5.6-anti-configured transition state N and pro-R-5.6-synconfigured transition state O in the D-proline-series. The resulting steric interactions and strains can be compensated by a ring flip from the 5CN,6- to the N,6C5-conformation or vice versa (see transition states N and O, Scheme 13). This principle discussed above (D-proline, pro-R-configured hydrogen, and L-proline, pro-S-configured hydrogen) will be demonstrated in the following detailed and exemplarily by J

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The Journal of Organic Chemistry Scheme 16. Transition States V and W of α- and β-lyxo-VIII with D-Prolinea

a

Hydrogen atoms are omitted for clarity (with the exception of the green-colored ones). Distances are given in Å.

In general, transition states with a 5.6-anti-configuration are characterized by higher energy barriers, whereas the energetically favored transition states were identified with a 5.6-synconfiguration. This fact strongly suggests a syn-elimination of proline as the mechanism to yield the α.β-unsaturated ketone IX. These discussed relations of conformation and configuration of transition states work exactly and without fail in the L-proline series. Exceptions were noticed by calculations of reactions in the presence of D-proline. In this series, the pro-R-configured

Table 1. Comparison of Yields of Reactions in the Presence of D- or L-Proline yield (%)

ribose

arabinose

xylose

deoxyribose

lyxose

L-proline

50