On the Synergism Between H₂O and a Tetrahydropyran Template in the Regioselective Cyclization of an Epoxy Alcohol

Abstract

A regioselective epoxy alcohol cyclization promoted by the combination of neutral water and a tetrahydropyran template was investigated through a series of mechanistic experiments carried out on an epoxy alcohol containing a tetrahydropyran ring (1a) and its carbocyclic congener (1b). In contrast to 1a, cyclizations of 1b were unselective and displayed significantly faster reaction rates suggesting that the tetrahydropyran oxygen in 1a is requisite for regioselective cyclization. Reactions for both substrates were shown to occur in solution and under kinetic control without significant influence from hydrophobic effects. Kinetic measurements carried out in water/dimethyl sulfoxide mixtures suggest that 1b reacts exclusively through an unselective pathway requiring one water molecule more than what is required to solvate the epoxy alcohol. Similar experiments for 1a suggest a competition between an unselective and a selective pathway requiring one and two water molecules in excess of those required to solvate 1a, respectively. The selective pathway observed for 1a but not in 1b is rationalized by electronic and conformational differences between the two compounds.

We previously reported¹ that the combination of a template² and water provided a means to conduct highly regioselective epoxide-opening cascades reminiscent of Nakanishi’s proposed biogenesis of the ladder polyether natural products.³ With the aid of mechanistic studies carried out on the original template (tetrahydropyran 1a) and its carbocyclic analog 1b, we now provide a molecular explanation for these phenomena. In short, the data support two competing pathways for 1a: one that is unselective and first order in water and another that is highly selective with a second-order water dependence. Moreover, the differences observed between 1a and 1b demonstrate unequivocally the essential role of the tetrahydropyran ring oxygen in 1a in regioselective epoxy alcohol cyclizations.

Consistent with our earlier findings, cyclizations of 1a in water (eq 1) proceeded selectively to form the six-membered ring product, 2a (Table 1).⁴ The reaction operates under kinetic control as accumulation of the five-membered ring product (3a) was not observed in situ, and purified 3a did not isomerize to 2a when resubjected to the original (20 °C, pH 7, 3 d) or more vigorous reaction conditions (60 °C, pH 7, 7 d).

Table 1.

Epoxy alcohol cyclizations with various additives.

entry	X	time (h)	additive	% conversiona	2:3a
1	O (1a)	33	none	58 (4)	11:1 (1)
2	O (1a)	33	CTABrb	67 (1)	12:1 (2)
3	O (1a)	33	LiCl (4M)	88 (2)	15:1 (1)
4	O (1a)	33	LiClO4 (4M)	73 (3)	12:1 (1)
5	O (1a)	33	pH 7 (1M)c	81 (2)	10:1 (1)
6	CH2 (1b)	2	none	80 (12)	1:1.3 (0.1)
7	CH2 (1b)	2	CTABrb	71 (7)	1:1 (0.2)
8	CH2 (1b)	2	LiCl (4M)	93 (4)	1:1.3 (0.1)
9	CH2 (1b)	2	LiClO4 (4M)	81 (2)	1:1.3 (0.1)
10	CH2 (1b)	2	pH 7 (1M)c	82 (6)	1:1.2 (0.3)

^aAverage of three measurements; average error in parentheses.

^bcetyl trimethyl ammonium bromide, 2 equiv.

^cK₂HPO₄/KH₂PO₄ buffer.

Several experiments also suggest that the reaction occurs in solution rather than on the surface of water⁵ or in micelles (Table 1).⁶ Reaction mixtures appeared homogeneous, and more importantly, qualitative reaction rate and selectivity were only minimally affected by surfactants (entry 2). Hydrophobic effects⁷ also do not seem important as similar behavior was observed in the presence of salting-out (LiCl) or salting-in (LiClO₄) additives (entries 3-4). Ionic strength effects may account for the small rate and selectivity increases in these cases and in those carried out in phosphate buffer (entry 5).

To gain further insight into the role of the tetrahydropyran template, we next conducted a similar set of experiments with a closely related cyclohexyl cognate (1b). To our surprise, this seemingly minor structural change (O to CH₂) had profound effects on rate and selectivity (Table 1). Cyclization of 1b was significantly faster and occurred to give a nearly equimolar mixture of 2b and 3b. Once again, the reaction was shown to operate under kinetic control (i.e., no isomerization of pure 3b to 2b) in solution with little evidence for contributions from hydrophobic effects (Table 1, entries 6-10).

Solution ¹H NMR analysis of 1a and 1b in D₂O indicated chair conformations for the six-membered rings in both cases (Scheme 1). The epoxide moiety, however, appears to be situated differently for the two compounds. Coupling constants (³J) between methine and the exocyclic methylene protons ( and ) of 1a suggest a strong preference for an unproductive conformation that situates the epoxide away from the hydroxyl nucleophile (eq 2).⁸ Analogous resonances for 1b display no discernible coupling constants, suggesting a more flexible alkyl chain.

Scheme 1.

Selected low energy conformations of 1a and 1b (¹H NMR, D₂O).

The conformational differences between 1a and 1b may contribute to the observed rate differences, but it is less obvious how such preferences would bias selectivity. Kinetic experiments (¹H NMR) have aided in addressing this issue. Reactions of 1a and 1b display pseudo-first-order kinetics (pD 7, KP_i buffer), and consistent with the batch reactions, observed rates for the cyclization of 1a were more than an order of magnitude slower than for 1b (k_obs = 4.69 × 10⁻⁵ s⁻¹ and 7.16 × 10⁻⁴ s⁻¹ at 45 °C, respectively). Both reactions also display small normal solvent isotope effects (k_H2O/k_D2O = 1.33 and 1.47, respectively), consistent with a proton-transfer event that occurs in or preceding the rate-determining step.

Critical differences between the two substrates were observed for kinetic measurements made in DMSO-d₆/D₂O mixtures. Binary solvent mixtures have previously been used to determine the kinetic order of water in many reactions⁹ including epoxide hydrolysis reactions.^9b–c While this practice has become less common because solvent properties such as polarity and hydrogen-bond donor/accepting ability often complicate analysis,¹⁰ in water-rich DMSO mixtures these properties vary little thereby minimizing their effect.¹¹

In the event, both substrates displayed pseudo first-order kinetics with rates that decreased with [D₂O] (55–35 M). The effect of decreasing [D₂O] upon selectivity, however, was different for the two substrates with selectivity decreasing slightly for 1a (2a:3a = 11–8), while remaining nearly constant for 1b (2b:3b = 0.7). Using these selectivities apparent rate constants for the formation of 2 (k₂) and 3 (k₃) could be extracted from the observed rate constants. Linear plots of k₂ and k₃ vs. [D₂O] were obtained for 1b (Figure 1). For 1a, however, only k₃ displayed a linear water dependence. Most striking of all was that the plot of k₂ vs. [D_2O] for 1a contained significant polynomial character (Figure 2).

Figure 1.

k₂ and k₃ vs. [D₂O] (pD 7) for 1b at 45 °C.

Figure 2.

k₂ and k₃ vs. [D₂O] (pD 7) for 1a at 70 °C.

We hypothesize that the epoxy alcohols 1a and 1b exist as a rapidly equilibrating mixture of solvated conformers.^9b,12 Cyclization occurs when intermediates situate the epoxy alcohol appropriately for proton transfer and subsequent nucleophilic attack. The number of water molecules that organize the substrate appropriately and that serve to stabilize intermediates or transition states in excess of those required to solvate the epoxy alcohol then become kinetically relevant.

For the cyclohexane template (1b), it is apparent that there is at least one intermediate that requires only one additional water molecule for productive reaction (by virtue of the linear k₂ and k₃ vs. [D₂O] plots). Moreover, it is likely, but not necessary, that both products are formed from a common intermediate in an unselective reaction (Scheme 2).

Scheme 2.

Proposed mechanisms for epoxy alcohol cyclizations in water. Proton transfer steps omitted for clarity.

The situation is more complicated for the tetrahydropyran template (1a). Similar to 1b, a linear plot of k₃ vs. [D₂O] suggests that formation of 3a is first order in water (Figure 2). Considering the structural similarities between 1a and 1b, it is likely that this process resembles the pathway observed in 1b. The polynomial character observed in the k₂ vs. [D₂O] plot, on the other hand, suggests that 2a is formed at least in part by a second reaction mechanism with a higher order water dependence. Plots of k₂/[D₂O] vs. [D₂O] are linear with a non-zero slope, suggesting that the competing pathway is second order in water (Figure 3). A similar plot for k₃ is also linear but displays a slope that is comparatively small, indicating that 3a is formed with minimal contributions from a pathway that is second-order in water (Scheme 2).¹³

Figure 3.

k₂/[D₂O] and k₃/[D₂O] vs. [D₂O] (pD 7) for 1a at 70 °C.

These observations are consistent with two different but not mutually exclusive interpretations. In addition to affecting the ground state conformation (vide supra), the electron-withdrawing oxygen atom in the template likely decreases the nucleophilicity of 1a relative to 1b. The more nucleophilic 1b may be sufficiently reactive such that only one water molecule is required to activate the epoxide for productive cyclization. Slower reaction rates for 1a result in a competition between pathways requiring one and two water molecules. Formation of the larger ring is preferred for 1a because the electronegative oxygen in the template discourages buildup of charge on the epoxide carbon proximal to the template. The availability of a pathway that is second-order in water for 1a further stabilizes charge in the transition state, thus enhancing the effect of the tetrahydropyran oxygen and encouraging a later transition state, both of which increase selectivity for 2a.

An alternative interpretation of these data relies on a conformational difference between the intermediates that lead to unselective and selective reaction (i.e. 4a/4b and 5a). The most likely intermediate common to 1a and 1b (i.e., the pathway that is first order in water), is a chair-like intermediate such as 4a/4b (Figure 4). On the other hand, a reactive intermediate with the tetrahydropyran ring in a twist conformation, such as 5a, satisfies all of the requirements for a proposed intermediate for the selective pathway (Figure 4).

Figure 4.

Possible intermediates for epoxy alcohol cyclizations. The red and blue water molecules indicate the number and not necessarily the identity of water molecules that are kinetically relevant. The black water molecules generically represent the waters of solvation.

The second-order water dependence is explained because 5a is ideally situated for hydrogen bonding from exogenous water molecules.¹⁴ Although three explicit water molecules are depicted for 5a in Figure 4, we propose that one of these molecules originates from the solvated ground state. It is also possible that there is a more extensive hydrogen-bonding network involving additional waters of solvation. The kinetic accessibility of 5a is also feasible as the formation of twist conformers are estimated to require ca. 10 kcal/mol,¹⁵ while ΔG^‡ determined for the cyclization of 1a is greater than 20 kcal/mol. Thirdly, a pathway involving a twist conformation may favor 2a because the nucleophile trajectory in 5a differs significantly from that in 4a. Computations suggest that this factor is most important in determining the regioselectivity for epoxy alcohol cyclizations.¹⁶ Finally, selectivity differences between 1a and 1b can be explained by 5a because the carbocyclic 1b does not have a H-bond acceptor to accommodate the additional water molecules required for the selective pathway via an analogous twist conformation.

It is important to note that the two competing pathways proposed for 1a are of different kinetic order. This point is particularly relevant for explaining why a selective pathway is not observed for 1b. A twist-boat intermediate analogous to 5a but without involvement of an additional water molecule is indeed kinetically accessible for 1b,¹⁵ but the absence of the extra [water] factor in the rate law for such a pathway apparently provides for cyclization rates that do not compete with the pathway proceeding through 4b.

Further experimentation is needed to delineate how the factors outlined above contribute to selectivity in epoxy alcohol cyclizations in water, but in all likelihood product distribution is dictated by both electronic and conformational considerations.

In summary, analysis of the cyclization of 1a and its carbocyclic analog 1b in neutral water suggest that both reactions occur in solution but through mechanistically distinct pathways. This study illustrates the intimate connection between the template structure and the special properties of water; variation of either leads to an unselective reaction. We are currently elucidating the details of this interplay further and hope that the lessons learned from these studies will not only provide clues for the development of new templates and catalysts for regioselective cyclizations of epoxy alcohols, but also augment our understanding of related, consecutive epoxide openings (“cascade” reactions).¹