J Mol Model (2014) 20:2173 DOI 10.1007/s00894-014-2173-0

ORIGINAL PAPER

Mechanistic aspects of the lycopodine Michael-Claisen domino cyclization Wilhelm A. Eger & Ernst Anders & Craig M. Williams

Received: 4 December 2013 / Accepted: 7 February 2014 / Published online: 16 March 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract The Michael-Claisen domino (MCD) cyclization used in the lycopodine synthesis by Stork, was evaluated mechanistically using DFT calculations. Calculations suggest that a dianion is not formed, which conforms to classical dianion formation normally requiring strong kinetic bases. Instead ethoxide in ethanol produces a monoanionic species driving the MCD cyclization. This endeavor has opened up potential to expand the scope of this unique reaction and provide educational clarity. Keywords Density functional theory . Lycopodine . Michael-Claisen cyclization

Introduction In 1968 Stork et al. reported the first synthesis of dl-lycopodine (1) [1], which is the most widely occurring of the Lycopodium alkaloids. In the course of the synthesis access to the quinolone advanced intermediate 2 was required, which could be obtained from cyclohexadione 3. To access dione 3 a Michael-Claisen domino cyclization involving acrylate 4 and This paper belongs to a Topical Collection on the occasion of Prof. Tim Clark’s 65th birthday Electronic supplementary material The online version of this article (doi:10.1007/s00894-014-2173-0) contains supplementary material, which is available to authorized users. W. A. Eger : C. M. Williams (*) School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Queensland, Australia e-mail: [email protected] W. A. Eger : E. Anders Institut für Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universität Jena, Humboldtstrasse 10, 07743 Jena, Germany

ethyl acetoacetate 5 was employed giving the cyclic ester 6, which was later decarboxylated affording 3 (Scheme 1). On review of this reaction sequence, we were immediately drawn to the unique Michael-Claisen domino (MCD) cyclization. This particular reaction involving 4 and 5, generates a useful six membered ring (i.e., 6), which surprisingly has never been further explored, although, there is one five membered ring case reported in a prostaglandin synthesis, but a strong kinetic base was required to effect cyclization [2, 3]. There are, in addition, closely related examples by Ishikawa [4, 5] and Das [6], using acetone units instead of ethyl acetoacetate (5), but these systems lack the ability to incorporate the additional ester functional group if so desired. In the view that this reaction has potential for wider application, and that the Stork lycopodine synthesis is used as a teaching tool in Designing Organic Syntheses [7], we felt that this Michael-Claisen domino (MCD) cyclization warranted mechanistic investigation using DFT.

Computational methods Calculations were carried out using a hybrid meta-GGA DFT functional at the M06 level [8]. This functional has been optimized for non-metal atoms and gives good results overall, especially when weak interactions are involved. All reported energies and structures were obtained using the software package Gaussian09, revision D.01 [9]. For all atoms, the 6 −31+G(d,p) basis set as implemented in Gaussian09 was used throughout. This basis set describes the second row atoms by the McLean-Chandler basis [10, 11], the basis set of McGrath and Curtiss for third row atoms [12–14], and the WatchersHay basis set [15, 16] for the first row of transition metals using the scaling factors of Raghavachari and Trucks [17]. All stationary points were characterized with a frequency analysis, where minima must have no imaginary frequencies

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Scheme 1 Reaction sequence yielding dl-lycopodine

and the saddle points exactly one imaginary frequency. All given energies are free Gibbs energies (in kJ mol−1) relative to the first encounter complex C-1 of the reactants, i.e., acrylate and sodiated acetoacetate, which are zero point and thermally corrected. Therefore, all reported energetic values refer to standard conditions such as 298 K and 1 atm pressure. Solvent corrected geometries and energies were calculated with C-PCM as implemented in Gaussian09 [18–20]. In this model, the species of interest are embedded in a cavity of molecular shape surrounded by a polarizable continuum, whose field modifies the energy and physical properties of the solute. The solvent reaction field is described by polarization charges distributed on the cavity surface. This procedure is known to reproduce experimental solvation energies quite well. Parameters for methanol were chosen, since this solvent

Scheme 2 Proposed reaction mechanism

closely matches ethanol used in the experimental procedure reported by Stork. Structure numbering: To distinguish between calculated species and structures given in Schemes 1 and 2, a ‘C-’ (for calculated) has been placed in front of the structure numbers.

Results and discussion The MCD cyclization sequence opens up a number of interesting mechanistic questions after the initial addition of sodiated acetoacetate 7 to acrylate 4, which gives tricarbonyl 8 (Scheme 2). If the reaction path follows that of A, two deprotonations from positions 4 (i.e., 9) and then position 6 (i.e., 10) are required to facilitate cyclization to 12 (after protonation of 11). Although from a synthetic practitioners

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Scheme 3 Conjugated Michaeltype addition reaction of the acrylate and the sodiated acetoacetate species. Numbers in brackets are Gibbs free energies relative to C-1 in kJ mol−1

perspective path A is plausible, it is not consistent with traditional carbonyl dianion formation. For example, to doubly deprotonate ethyl acetoacetate a strong base, such as nbutyl lithium [21–23], or LDA, is required for the second deprotonation step. Alternatively, if calculations suggest ethoxide is able to establish an equilibrium position between 9 and 10 driving the reaction to the thermodynamic sink (i.e., 11) this would be of significant value for expanding the scope of the reaction. Path B, although at first glance is unlikely because the formation of a nonstabilized enolate over a stabilized enolate is counter intuitive, required investigation to determine the potential for direct deprotonation of 8 (via position 6). This pathway may be a possibility based on steric grounds, thus leading to 12 (Scheme 2).

Scheme 4 Intramolecular proton shift via three possible pathways via C-6, C-4, and C-10. Numbers in brackets are Gibbs free energies relative to C-1 in kJ mol−1

To begin this study the initial conjugate addition (Michael addition) step between the sodiated acetoacetate 7 and acrylate 4 was investigated (Scheme 2). Interestingly, it was discovered that precoordination by the sodium ion (C–1, Scheme 3) is the most important process for intrinsic regioselectivity, and a transitional barrier of 61 kJ mol−1 (i.e., C-2) is required to access the addition product C-3. This observation was in agreement with calculations performed by Ishikawa [5] who used potassium bases to effect MCD reactions with nonstabilized enolates. With the Michael addition secured, a starting point for both pathway A and B in the Claisen cyclization could be ascertained by determining the energetics of single anion formation, which results in either the non-stabilized enolate 9 or stabilized enolate 13 (Scheme 2). Thus, mono-

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Fig. 1 Selected geometries of the competing transition states involved in the intra- and intermolecular proton shift reaction. Dashed bonds indicate the proton transfer mode. Thin lines indicate interactions between the sodium ion and oxygen atoms. Hydrogen atoms—white carbon atoms— gray, oxygen atoms—red, sodium ions—purple

deprotonation by ethoxide needed to be explored, and considering C-3 (Scheme 3) is proposed to be in solution, the equivalent intramolecular proton shift required investigation.

Three intramolecular proton shift pathways leading to sodiated C-5 were found (Scheme 4). Firstly, a one-step transition state (TS) directly leading from C-3 to C-5

Scheme 5 The two competing pathways for the second deprotonation step. Numbers in brackets are Gibbs free energies relative to C-1 in kJ mol−1

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Scheme 6 Cyclization reaction pathways; mono- (top) or disodiated (bottom). Numbers in brackets are Gibbs free energies relative to C-1 in kJ mol−1

involving a proton shift from the methyl group to the methine carbon alpha to the ester moiety (i.e., TS C-4). Two, more or less, equivalent pathways could lead to C-5. Essentially a proton shift (via C-6) from the ester group bearing carbon atom to the ester enolate (i.e., C-7) with a subsequent shift of a proton from the methyl group to the stabilized enolate carbon atom via C-8 arriving at C-5. The third pathway is almost identical to that via C-7, the only difference is that it is intermolecularly catalyzed by the proton shuttle methanol. Somewhat surprisingly, however, was that intramolecular deprotonation at position 4, the most acidic, was a higher energy process compared to deprotonation at the less acidic site at position 6, which we attribute to strain. Details about the reasons for the energetics can be found below. Overall however, the one-step intramolecular conversion of C-3 to C-5 (via C-4) is the most favorable pathway compared to the methanol catalyzed two-step intermolecular process (e.g., via C-10 and C-13), and the uncatalyzed relative (e.g., via C-6 and C-8) (Scheme 4). The significant differences in energies observed when comparing transition states C-4, C-6, C-8, C-10, and C-13 can be attributed mainly to ring strain effects. Corresponding snapshots of the geometries are illustrated in Fig. 1. In the first row, the one-step pathway transition state via C-4 is shown. The second row shows the methanol-catalyzed two-step pathway via C-10 and C-13, while the third row depicts the most unfavorable pathway via C-6 and C-8. The latter becomes obvious, illustrated by the high ring strain gained by the fourmembered ring character of the proton transition, which leads to increased activation barriers. Furthermore, the difference between the one-step pathway via C-4 and the methanolcatalyzed two-step pathway via C-10 and C-13 is the

formation of a significant chair configuration within the proton transfer cluster. It is clearly evident that transition state C-4 forms a chair along the proton transfer mode. In view of the flattened geometries in the case of C-10 and C-13, the comparably high activation energies are reasonable. Reasons for the flattened geometries of C-10 and C-13 are most likely due to a combination of steric hindrance of the bulkier residues, which force the hydrogen atom into an unfavorable position. The sodium-oxygen interactions impart the same effects. Both these steric influences are missing in the geometry of C-4. Having found a viable reaction profile leading to C-5 (Scheme 4) it remained to unmask a profile for the doubly deprotonated (disodiated) species C-18 (Schemes 5 and 6). This by default will have a significant difference in energy and be potentially less favored. As a comparison, to doubly deprotonate ethyl acetoacetate a strong base, such as n-butyl lithium [21–23], is required for the second deprotonation step. Although, the system being studied herein is under equilibrium control. That is, formation of only a small amount of the dianion C-18 may be enough to drive the reaction to completion. On this premise there are two pathways, which can lead to C-18 (Scheme 5). Firstly, deprotonation of C-7, leading to C18, was evaluated. In this process the 6-membered TS C-20 was observed along with inclusion complexes C-19 and C-21. Of note is the observation that intermediate (C-21, −61), subsequent to TS C-20 (−67) is 6 kJ mol−1 higher in energy. While this difference is still within the error of the method used, and thus a potential method artefact, it further indicates that C-20 is a very late transition state, which has equivalent energy compared to its subsequent intermediate C-21. Moreover, the back reaction leading from C-21 to C-7 (via C-20) has nearly no

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Fig. 2 Comparison of transition state C-20 and C-16 geometries for the competing pathways to the disodiated species including intermediate C21. Hydrogen atoms—white, carbon atoms—gray, oxygen atoms—red, sodium ions—purple

activation barrier and therefore the reaction from C-7 to C-21 occurs only if there is a subsequent reaction, which readily consumes newly formed C-21. This finding was somewhat fortuitous for comparison reasons, because this transition state (i.e., C-20) had a rather low activation energy (54 kJ mol−1),

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which competes with the ring closure transition state C-22 (22 kJ mol−1) (see below Results and discussion and Scheme 6). In addition to the unfavorably higher activation energy, C-20 has nearly no back-reaction barrier as explained above, whereas the back-reaction barrier of C-22 is at least feasible (6 kJ mol−1, in relation to C-23). The second pathway involving the second deprotonation step via TS C-16 and associated inclusion complexes (C-15 and C-17) has a far too large activation barrier (92 kJ mol−1). Thus, from these results it can be concluded that the second deprotonation step of Scheme 4 is unlikely to occur, but due to the relatively moderate difference in activation energies it cannot be completely excluded (Scheme 5). However, taking into account that the transition states potentially leading to C-7 (i.e., C-6 and C-10) are clearly unfavorable in comparison with the transition state leading to C-5 (i.e., C-4); it becomes clear that if the double deprotonation step would occur at all it would be via the first reaction pathway seen in Scheme 5. The difference in reaction activation energies stem from the differently stained ring structures. Pertinent structures are shown in Fig. 2. Even though transition state C-16 has a favored six-membered ring mode, for shuttling the proton and the sodium atom, it is circumvented by the pendant residues that prevent full relaxation. Whereas transition state C-20 can form an angled geometry, where the carbon atom based part forms a flat structure, which forms an angle of about 100° to the plane spanned by the sodium atom and the methanol moiety. This relaxation gives C-20 a lower activation barrier in comparison to C-16. Intermediate C-21, which results from transition state C-20, has nearly the same geometry as C-20. In view of these two geometry considerations, it becomes obvious that C-20 is a late transition state being located very close to C-21 on the energetic hyper surface, and thus has a very low back reaction activation energy. When comparing the energies of the ring closure step in both pathways A and B, a critical factor in judging path A over path B lies in understanding which sodiated species is the final product produced from the reaction. To detail this further, two questions need to be answered. Firstly, is a neutral species [i.e., product (C-30)] a direct output of the reaction sequence? That is, in the view that excess ethoxide is present in solution, does this result in a sodiated species waiting in solution for acid work up? Secondly, is a specific sodiated species (e.g., tetrahedral intermediate) produced as part of the reaction sequence that waits in solution for acid work up? To address these points the two cyclization modes were calculated stopping at the first ring-closed sodiated species, see Scheme 6. In the case of the mono-deprotonated pathway (path B) TS C-22 leads to mono-sodiated species C-23, but this process is uphill. The dianion C-18 gives the ring-closed dianion C-25, via TS C-24, which suggests that path A is

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Scheme 7 Desodiation pathways following the cyclization step; mono- (top) and disodiated species (bottom). Numbers in brackets are Gibbs free energies relative to C-1 in kJ mol−1

thermodynamically favored. However, the number of unfavorable transformations involved to arrive at C-25 (see Schemes 4 and 5) far out weights the concise, potentially kinetically favored, process leading to C-23 (Scheme 6). It should be noted that the low energies of the di-sodiated species need to be interpreted with caution, as in solution the sodium ions strongly interact with solvent molecules and for this study the energy gain by the oxygen-sodium interactions found are in the gas phase, and could be quite artificially high. Thus, it is more instructive to consider activation energies, as these are relative and could compensate systematic errors. Such activation energies can be found in pathway A from C-18 to C-24 and in pathway B from C-5 to C-22. Therefore, when compared, pathway B has nearly half the height in activation barrier, namely 22 kJ mol−1, compared to pathway A, 39 kJ mol−1. This suggests that pathway B is favored even in view of the fact that unfavorable transition states precede pathway A. What is the case if the overall reaction sequence for both processes (mono and dianion) does not stop at the first cyclization step? We subsequently calculated desodiation (sodium ion removal) to give the neutral product C-30, for pathway A and B (Scheme 7), however, in both cases this led to high energy processes. These results suggest it is a reasonable conclusion that the reaction sequence stops at the sodiated tetrahedral intermediates as drawn in Scheme 6. It should also

Scheme 8 Tautomers of product C-30. Numbers in brackets are Gibbs free energies relative to C-1 in kJ mol−1

be kept in mind, however, that these calculations have an artificial aspect. Even though the reaction could follow such a mechanism, the effect of the solvent medium, in particular of additional ethanol and ethoxide molecules, has been neglected to save computational time. Such molecules could lower activation energies with the help of very complicated long chained reaction mechanisms, which are outside the scope of this work. Thus, the high activation barriers of the desodiation reaction transition states C-28 and C-33 can be attributed to the unfavorable four-membered ring transition state structures involved in the desodiation process. To complete this overall investigation in the gas phase, energies of the tautomers C-30, C-36, and C-37 were calculated and found to behave as expected (Scheme 8). The keto structure C-30 is the most stable, while the enol structures show higher energies. Enol C-37 is higher in energy, because the double bond connects to the carbon atom bearing the ester group. This is in agreement with that previously reported [24]. With the gas phase calculations completed solvent corrections using methanol where evaluated for the most preferable pathway (mono-sodiated, B). In general the energetic values shifted only slightly (Fig. 3), which was also found to be the case for the geometries. More specifically most of the transition states, i.e., C-2, C-4, C-22, and C-28, were observed to be less stable in methanol. Only transition state C-26 profited from the solvated environment. A sodium ion bound to two oxygen atoms seemed to be a common structural motif of the solvated transition states, which most likely originates from the solvent forcing the constellation involving the sodium ion and two bound oxygen atoms into less favorable positions. This was not observed for C-26, as in this structure, the sodium ion is bound to one oxygen atom only. Overall, the dominant reaction pathway B remains the most favored as calculated in a methanol environment.

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Fig. 3 Comparison of Gibbs free energies relative to C-1 for the preferred reaction pathway calculated in the gas phase (blue graph) and methanol corrected (C-PCM, red graph). Explicit values given for the methanol corrected calculations (red graph)

Conclusions In conclusion, a gas phase investigation into the Stork Michael-Claisen domino (MCD) reaction has been performed. This reaction has not been investigated previously in a computational sense and has not seen further application in the synthetic literature. The results found through our investigation suggest that mono-sodiated pathway B is preferred. Although most chemists would lean toward dianion formation, they are reminded that ethoxide in ethanol struggles to generate such species, which usually require strong kinetic bases such as LDA and butyl lithium. Acknowledgments The University of Queensland and the FriedrichSchiller-Universität Jena for financial support, and computational time. CMW thanks the Australian Research Council for a Future Fellowship.

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