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Exploring the relative reactivities of the hydroxyl groups of monosaccharides by molecular modeling and molecular mechanics
Journal of Molecular Structure 516 (2000) 203–214 www.elsevier.nl/locate/molstruc
Exploring the relative reactivities of the hydroxyl groups of monosaccharides by molecular modeling and molecular mechanics V.G.S. Box*, T. Evans-Lora Department of Chemistry, City College of the City University of New York, Convent Avenue @ 138th Street, New York, NY 10031, USA Received 10 March 1999; accepted 6 April 1999
Abstract The molecular modeling program STR3DI.EXE, and its molecular mechanics module, QVBMM, were used to simulate, and evaluate, the stereo-electronic effects in the mono-alkoxides of the 4,6-O-ethylideneglycopyranosides of allose, mannose, galactose and glucose. This study has confirmed the ability of these molecular modeling tools to predict the regiochemistry and reactivity of these sugar derivatives, and holds considerable implications for unraveling the chemistry of the rare monosaccharides. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Molecular mechanics; Nucleophilicity; Monosaccharide alkoxide; Quantized valence bonds’ molecular mechanics
1. Introduction The monosaccharides are probably the most densely functionalized naturally occurring organic molecules, and are undoubtedly among the most important organic molecules in the biochemistry of all living things. The chemistry of the monosaccharides has been developed, over many decades, by exhaustive empirical experimentation, and today there is a very broad base of knowledge about the chemical reactions of the monosaccharides. To a large degree, theoretician have not been able to propose congruent models to rationalize the various aspects of the chemistry of these monosaccharides. The theoretical models that have been put forward are usually quite limited in their scope, and/or have stimulated significant controversy about their theoretical underpinnings, thus preventing their * Corresponding author. Tel.: 1 1-212-650-8266. E-mail address: [email protected] (V.G.S. Box).
uniform acceptance. The development of the quantized valence bonds’ molecular mechanics (QVBMM) force field represents a successful effort to provide organic chemists with a new theoretical tool for addressing some of the structure-reactivity problems found in carbohydrate chemistry, particularly the modeling and assessment of the stereoelectronic effects that are due to a sugars hydroxyl groups [1]. One of the experimentally well defined aspects of monosaccharide chemistry is the fact that the hydroxyl groups of these molecules are not equally reactive as nucleophiles [2]. The patterns of nucleophilic reactivity of these hydroxyl groups vary from sugar to sugar, even changing with changes in the structure (functionalization) of a given sugar [2]. This aspect of carbohydrate chemistry is well suited for theoretical study since the vast quantity of empirically gained knowledge in this area will tightly control the development of theoretical rationalizations for these phenomena.
0022-2860/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S0022-286 0(99)00191-X
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Scheme 1.
2. The mono-esterification of diol mono-alkoxides 2.1. Mechanistic possibilities It is well known that simple alcohols, and diols, undergo esterification by acyl halides and anhydrides, in the presence of pyridine (or other tertiary amines), via termolecular transition states, as is shown in Scheme 1 [3–6]. These reactions are typical “general base catalyzed” reactions. In contrast, the alkoxides of alcohols, or the monoalkoxides of diols, generated in their “specific base catalyzed” esterification reactions, engage in bimolecular transition states with these acylating agent, as is shown in Scheme 2 [7–9]. These bimolecular alkoxide esterification reactions are encountered under phase transfer reaction conditions, and are usually much faster than the termolecular reactions of the corresponding alcohol. In phase transfer reactions the alkoxides are usually unsolvated (“naked”) and free since the associated cation is usually a large organic quaternary ammonium or phosphonium ion. These “naked” anions are better (more available nucleophilic electron density) nucleophiles, the transition states are less crowded, and the entropic
requirements for the formation of the bimolecular transition states are significantly smaller than those for the termolecular transition states. While the possible mechanisms for the reactions of monohydric alcohols are uncomplicated, there are four distinct, and experimentally plausible, mechanisms by which a given diol’s mono-alkoxide can react with an electrophilic acylating, or alkylating, agent. These are shown in the Scheme 3, below. Two of these mechanisms, Paths A and B, will be accessible by mono-alkoxides that have an intramolecular O–H hydrogen bond between the alkoxidic oxygen and the hydroxyl group, and the other two mechanisms, Paths C and D, will be accessible by the non-O–H hydrogen bonded conformers. Path A would require the attack of the intramolecularly O–H hydrogen bonded alkoxidic oxygen on the electrophile. This pathway would only be regioselective if the isomeric intramolecularly hydrogen bonded alkoxide was less stable. Otherwise, the hydrogen could shift onto the alkoxidic oxygen, hence changing the site of the alkoxidic nucleophilic center, and reducing the regioselectivity of the reaction. Path B appears to be quite similar to Path A, but
Scheme 2.
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Scheme 3.
would involve the alcoholic oxygen acting as the nucleophilic center, and the alkoxidic oxygen acting as an internal base, in a “termolecular-like” approach to the transition state. The intramolecular nature of this pathway would bypass most of the entropic and steric disadvantages of the intermolecular termolecular analogue, Scheme 1, but would result in the non-alkoxidic oxygen becoming the site of the esterification reaction. This pathway would be possible if the alcoholic oxygen possessed the highest energied, hence most nucleophilic [10], lone pair. Path C would require the direct attack of the nonhydrogen bonded alkoxidic oxygen on the electrophile. This pathway would be available if intramolecular O–H hydrogen bonding was geometrically unfavorable, or if the C–H hydrogen-bonded alkoxide was more stable than the O–H hydrogen bonded conformer. Path D would involve the direct attack of the nonhydrogen bonded alcoholic oxygen on the electrophile. This pathway would also be available if intramolecular O–H hydrogen bonding was geometrically unfavorable, or if the C–H hydrogen-bonded alkoxide was more stable than the O–H hydrogen bonded conformer, and if the alkoxidic oxygen was so effectively stabilized by intramolecular hydrogen bonding
that its lone pairs were less energetic than those of the hydroxyl group. This path would also be possible if the alkoxidic oxygen was simply sterically hindered. Note that the through-space electrostatic stabilization of the developing positive charge on the alcoholic oxygen by the negatively charged alkoxidic oxygen should steadily increase through the transition state, and crest into the intermediate, and would require that the alkoxidic oxygen be reasonably close to the hydroxyl oxygen. While the pathways A, B and C would proceed via the transition states in which the alkoxidic negative charge should steadily decrease in size as the reaction progressed through the transition state, the pathway D would involve the retention of the alkoxidic negative charge and the generation of a positive charge on the neighboring alcoholic oxygen. There are many organic reactions that show this feature. Indeed, the reactions of ylides with carbonyl compounds, among several others, are facilitated, and accelerated, by this kind of developing stabilizing electrostatic interaction [10–12]. Thus, Path D cannot logically be excluded from consideration. It is very important to recognize that the favored reaction pathway will determine the regiochemistry of the reaction.
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Scheme 4.
3. Lone pair energy, basicity and nucleophilicity Since the QVBMM force field can be regarded as a quantitative expression of the ideas embodied in VSEPR theory, the lone pair orbitals of alkoxides and alcohols are treated as sp 3 hydrid orbitals in order to maximize the distances between these sites of high electron density on their host atoms. As has been describe before [10], let us briefly consider the possible consequences of the through space—not resulting in bonding—interactions of a lone pair of electrons with an electrophile (an “empty” orbital), a positive charge (or the positive end of a dipole), another pair of electrons, or a negative charge. Using a simple molecular orbital picture, we can qualitatively describe the energetic outcomes of these events, as is shown in the diagram below in Scheme 4. Thus, the interaction of a lone pair with an electrophile or positive charge should lower the lone pairs’ energy, making it more stable and hence less nucleophilic. In the presence of several of these interactions, it might be possible for the lone pair to become very stable, so as to become a very poor nucleophile. However, the interaction of a lone pair with another pair of electrons or a negative charge should cause the energy of the lone pair to be increased, and the lone pair should become a better nucleophile. Several of these interactions could increase the nucleophilicity of the lone pair quite considerably. This molecular orbital model has successfully been used to rationalize the greater nucleophilicities of banomeric oxygen atoms, over their a-anomeric counterparts, and hence to rationalize the mechanistic
descriptions of a number of intriguing monosaccharide reactions [10]. Another interesting correlation that gives credibility to these ideas is the congruence of the trend in the lone pair energies of the simple monohydric alkoxides (bearing in mind their symmetry properties) and the known basicities of these alkoxides. Alkoxide Methoxide Ethoxide 2-propoxide tert-butoxide
QVBMM lone pair energy kcal 20.66 20.66, 1.41, 1.41 1.49, 1.49, 3.08 3.40
The lone pairs that were flanked dihedrally by hydrogens were considerably lower in energy in comparison to those that were similarly flanked by carbons. While the lone pair energies do predict the trend in the basicities of these alkoxides, any attempt to correlate these lone pair energies to the nucleophilicities of these alkoxides would also require a discussion of the steric factors in the transition states of their nucleophilic attacks. These steric factors must significantly be more important than those in the acid-base reactions. However, it could logically be concluded that the alkoxide having the higher energied lone pair—the more basic lone pair—should also be a better nucleophile if the contributing steric factors are similar for both molecules. The application of this fundamental concept to the present study will take the form of allowing the QVBMM force field to calculate the sizes of the intramolecular interactions of the lone pairs of the diol monoalkoxides with other lone pairs, bonding pairs, and the partial charges from dipoles. Since hydrogen
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bonding and favorable interactions with positively charged sites will stabilize—deactivate—a lone pair, then lone pairs that experience the largest total repulsions will be better candidates for nucleophilic activity than the other lone pairs, and certainly more than lone pairs that are stabilized. It will be seen, below, that the QVBMM data completely support this concept, resulting in a perfect congruence of the calculated data with the experimental facts.
4. The diols The methyl 4,6-O-alkylideneglycohexopyranosides of glucose, (1) and (5), mannose, (2) and (6), allose, (3) and (7), and galactose, (4) and (8), should be able to utilize any of these four pathways in the reactions of their mono-alkoxides with acylating or alkylating agents.
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A discussion of the actual mechanism of the nucleophilic behavior of each of these molecules will therefore require a rigorous, and quantitative, assessment of the factors that could bias each reaction towards one of the pathways outlined above. Thus, for each 4,6-O-ethylidene derivative (R CH3) of the molecules 1–8, the QVBMM structure energy minimizations and stereo-electronic evaluations should allow us to establish: 1. The structure of the most stable isomer of its possible mono-alkoxides, since this entity will be the most abundant nucleophile in the reaction. 2. Whether a particular mono-alkoxide has several isomers/conformers that are also close in enthalpy to the most stable isomer, and can interconvert rapidly enough, to warrant invoking the Curtin–Hammett principle in the discussion of the relative reactivities of the entire
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array of isomers, rather than just considering the lowest energied isomer. 3. Whether the highest energied lone pair is present on the alkoxidic oxygen, or not, as this lone pair should be the nucleophilic agent.
5. The Curtin–Cammett principle The Curtin–Hammett principle [13] states that if a given reactive molecule has two (or more) isomers or conformers that interconvert in a rapid equilibrium under the reaction conditions, then ratios of the products from the various reacting isomers/conformers will be proportional to the ratios of the reaction rates of these isomers/conformers. The principle is true only when the equilibrium interconversions of the isomers/conformers is significantly greater than the reaction rates, and this situation usually occurs when the enthalpy difference between the two isomers/conformers is relatively quite small (less than 3 kcal/mol in this study). Further, for reactions that are governed by the Curtin–Hammett principle, if the transition states of the reactions of the various isomers/conformers are nearly equivalent in energy, then the highest energy isomer/conformer will react faster, and the major product of the reaction will be derived from that isomer/conformer. It is known [3–6] that equatorial hydroxyl groups of cyclohexanols are normally esterified more rapidly their axial isomers, suggesting that the transition states for the reactions of the axial isomers are higher in energy. We shall assume that the transition states for the reactions of the equatorial oxygens are equivalent in energy, as would also be the case for the axial oxygens, and that the transition states for the reactions of the axial oxygens will be higher in energy than those for the equatorial oxygens. Most phase transfer esterifications and alkylations are done using an aqueous basic solution as one phase. The organic phases of these reactions must therefore be saturated with, albeit a very small concentration of, water. However, the presence of traces of water in the organic phase forces one to recognize that neither the isomerization of one alkoxide to another, nor the change of one C–OH conformer to another, needs to be an intramolecular event, since water could facilitate the rapid exchange of protons between the lone
pair (basic) sites, in an intermolecular process. Thus, the interconversions of isomeric alkoxides, or conformers, could be quite rapid in these reactions, so justifying the application of the Curtin–Hammett principle to this problem.
6. The STR3DI molecular modeler The STR3DI 1 molecular modeling programs use the new QVBMM module for performing structure energy minimizations [1]. This molecular mechanics force field can be regarded as a quantitative expression of the well-known valence shell electron pair repulsion (VSEPR) theory. The QVBMM force field not only treats lone pairs as discrete, very small, negatively charged, “atom-like” entities, but it also invokes, and uses, all of the possible bond polarizations present in the molecule, even those of aliphatic C–H bonds [1]. The STR3DI molecular modeling programs have been shown to efficiently, and faithfully, simulate the structures of most organic molecules, and especially those that contain heteroatomic lone pairs. Indeed, it is well known that most molecular mechanics force fields cannot reliably simulate complex, lone pair interaction phenomena like the anomeric effects found in acetals and glycosides, but, as will be seen from the results of the calculations performed by this force field, even these anomeric effects are efficiently simulated by the STR3DI programs [1,14]. The QVBMM force field reliably calculates the stereo-electronic and strain energy present in unsolvated molecules by assuming that the molecules are either in the gas phase, or are dissolved in a non-polar hydrocarbon solvent. Thus, the QVBMM calculations do not take their solvation energies into consideration. However, since structurally similar, isomeric molecules that have the same number and types of bonds will normally be similarly solvated, the force field does gives reliable estimates of the enthalpy differences between these molecules, regardless of the 1 Information about the STR3DI molecular Modeler and the QVBMM force field can be obtained from Exorga, Inc., P.O. Box 56, Colonia, NJ 07067, USA, and at the INTERNET web-site— http://ourworld.compuserve.com/homepages/exorga
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solvent in which they are dissolved, since the solvation energies will cancel out. The phase transfer alkylation/acylation reactions of the mono-alkoxides to be discussed are performed under conditions in which the reactive nucleophilic alkoxides are dissolved in non-polar organic solvents. The possible solvation and entropy factors are assumed to be nearly equivalent for each isomeric alkoxide of a given sugar, because these isomers are very closely related in structures and geometries. Any comparison of the enthalpies of these isomers will therefore effectively cancel out the contributions due to these solvation, and entropy, factors. Thus, the data generated by the QVBMM force field should be credible in this study. The unique ability of the STR3DI programs to calculate the energies of the lone pairs of electrons in a molecule (due to n–n, n–s, n–p and n–dipole interactions) allows us to determine which lone pairs at the nucleophilic reaction site possesses the highest repulsive electronic energy and is very likely to be the initiator of the nucleophilic attack [1,10]. This assessment cannot be made by any other molecular mechanics program in existence. Thus, we were confident that the QVBMM force field, and the STR3DI molecular modeling program, would provide the data we needed to rationally discuss the details of the nucleophilic attack of the glycosidic alkoxides on acylating agents in the nonpolar environment of a phase transfer reaction. 6.1. The QVBMM calculations There are two possible isomeric mono-alkoxides for each of the molecules 1–8, and each monoalkoxide has nine primary staggered conformers, since there are three possible conformations for the C–OH moiety, and three possible conformations for the anomeric/glycosidic methoxyl group. These nine conformers, for each isomeric mono-alkoxide, were constructed, and their energies repeatedly minimized to assure us that the resulting structures were indeed very close to their minimum energies. The lowest energied mono-alkoxide isomer and any others of similar energy were then selected for further scrutiny. We also inquired if the stereo-electronic interactions in these molecules, when they were a few kcals above their energy minima, were similar to
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those found at the minima. This was done to assure us that the profile of energies present during the minimization of any given molecule was one that changed smoothly towards the minimum, and did not involve significant energetic and structural dislocations. In fact, this notion was indeed correct, and it considerably reinforced our confidence in the data, since we recognized that valid conclusions could be arrived at even if we examined the stereo-electronic profile a molecule that was close to, but not at, its energy minimum. 6.2. Identifying the conformations A system was developed to enable us to rapidly identify the conformers, and was based on: 1. The anomeric configuration of the sugar. 2. The site of the alkoxidic oxygen (so also revealing the site of the non-alkoxidic oxygen). 3. The conformation about the C-1–O-1 bond. 4. The conformation of the hydroxyl group—ring carbon moiety. The glycosidic conformation was identified by assigning the number 1 to the conformer in which the aglycone was anti to C-2, the most stable conformers. The number 2 for conformations of a-anomers in which the aglycone was anti to O-5, or for conformations of b-anomers in which the aglycone was anti to H-1, the next more stable conformers. The number 3 to the least favorable conformers—when the aanomeric aglycone was anti to H-1, or when the banomeric aglycone was anti to O-5. The letter A was assigned to the hydroxyl group’s conformation if the hydrogen was “pointing towards” C-1, the letter B if it was anti to the neighboring C–H bond, and the letter C if the hydrogen was “pointing away from” the anomeric center, C-1. The prefixes were the first three letters of the sugar’s name. Anomers were then designated by their first letters (A for a-, and B for b-). These letters were followed by the numbered site of the alkoxidic oxygen. Followed by the number for the glycosidic conformation. Then followed the hydroxyl group conformation designator. Thus GLUA31A would be the 4,6-O-ethylidenea-d-glucopyranoside, in which the alkoxidic oxygen was O-3, the aglycone was in the most stable,
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Table 1 QVBMM structure energy data for the methyl 4,6-O-ethylidineglycopyranosidic alkoxides. (H represents the site of a hydrogen that is bonded to the respective atom, 2 or 3) Initial isomer
Final isomer
Allopyranosides A31B A31B A22A A21A A21B A21B B22C B22C B21C B21C Galactopyranosides A31B A31B A21B A21B B31A B31A B32A B32A Glucopyranosides A21C A21C A31C A31C A21A A21A B31C B31C B21A B21A B32C B32C B22A B22A Mannopyranosides A21C A21C A31C A31C A31B A31B A21B A21B A21A A21A A31A A31A B31A B31A B22C B22C B22B B22B B32C B32C B32B B32B B22A B22A B31B B31B
Strain energy
Lone pair energies 2A
2B
2C
3A
55.395 57.117 58.023 55.129 55.604
20.622 20.562 21.671 21.358 20.719
H 22.007 1.615 0.464 0.323
20.43 21.516 20.182 0.292 0.413
21.079 H 0.877 20.36 20.403
52.450 54.94 58.261 60.245
20.579 20.794 H H
H 1.247 0.557 0.489
20.216 21.217 20.094 20.179
20.921 0.216 20.83 20.979
50.098 52.458 52.753 56.862 57.246 58.193 58.702
20.825 20.484 20.584 0.454 20.108 0.856 0.122
1.015 1.694 1.237 0.042 0.032 20.037 20.109
21.278 H 23.363 H 23.123 H 22.684
49.41 49.682 49.688 50.089 51.172 52.573 54.194 54.273 54.29 54.777 56.467 56.682 57.353
21.526 20.725 20.925 21.127 21.151 H H 21.025 21.253 21.246 21.395 21.088 0.333
0.722 0.488
20.957 H 0.104 20.933 21.023 20.696 20.644 20.435 20.345 H 0.538 20.368 0.888
exo-anomeric position 1 (anti to C-2), and the 2hydroxyl group’s hydrogen was “pointing towards” C-1. A quick study of the bit-mapped images will facilitate an acquaintanceship with the system. Notice that in this series of compounds, the nomenclature allows one to quickly decide if O–H hydrogen bonding could be present in the conformer. Thus, for example, the 31A, the 32A (3nA) and the 21C (2nC) conformers cannot have O–H hydrogen bonds, while the 3nB, the 3nC, the 2nA and the 2nB conformers can possibly have O–H hydrogen bonds.
H 20.114 0.203 20.018 20.601 20.766 20.967 20.457 H 20.596 H
3B
2.046 2.507 H 21.258 21.409 0.725
3C 20.893 20.731 0.734 H H
0.661 0.931
0.427 0.262 0.545 0.373
20.247 20.685 H 22.918 H 23.028 H
0.475 0.554 0.488 0.552 0.516 0.637 0.568
H 20.516 20.031 20.373 0.24 20.135 0.365
0.096 0.492 0.783 0.448
0.777 0.624 0.545
H 20.61 20.271 0.518 0.624 20.463 20.549 H 0.302 20.714 20.916 20.438 21.187
H
H
H 0.59 0.587 0.174 0.301 0.342 0.565 H 0.613
0.537 0.519 0.53 0.775 H 0.618 0.748 0.618 0.754
7. Analyzing the QVBMM data 7.1. Hydrogen bonding Most organic chemists would intuitively assume that the O–H hydrogen bonded mono-alkoxides would be more stable than their non-O–H hydrogen bonded isomers/conformers. However, the QVBMM calculations revealed that this notion would only be valid if one ignored the significant contributions of the C–H dipoles in stabilizing the alkoxidic negative charge by C–H hydrogen bonding. Indeed, the
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Table 2 Molecular geometry at the anomeric centers of some selected pyrans (Table 1) (The exo-anomeric dihedral angle encompassed O-5–C-1–O-1– C-7, where C-7 is the aglycone carbon) Bond lengths
Bond angles
Exo-anomeric dihedral angle
Molecule
O-5–C-1
C-1–O-1
O-2–O-3
O-5,C-1,C-2
O-5,C-1,O-1
C-2,C-1,O-1
C-1,O-1,C-7
ALLA31B ALLB22C GALA31B GALB31A GLUA21C GLUA31C GLUA32C GLUB31C MANA31B MANA21C MANB31A MANB32C MANB32B
1.419 1.427 1.421 1.425 1.422 1.422 1.425 1.424 1.422 1.424 1.424 1.423 1.423
1.424 1.428 1.423 1.424 1.426 1.424 1.427 1.425 1.422 1.424 1.423 1.422 1.422
2.893 2.916 2.929 2.880 2.922 2.872 2.867 2.874 2.939 2.928 2.882 2.814 2.978
108.5 110.1 109.5 113.7 107.1 106.0 104.9 106.9 108.8 112.4 110.4 114.3 110.4
114.1 113.0 112.8 113.7 112.6 114.0 115.8 111.5 114.5 112.5 114.8 115.2 115.5
114.7 114.9 112.7 109.1 115.0 114.9 112.7 115.2 110.7 111.0 110.3 112.3 113.5
112.4 113.9 112.9 113.4 112.8 113.0 113.7 113.7 112.8 112.8 113.4 114.8 115.0
QVBMM calculations clearly showed that it is necessary to consider all of the lone pair interactions— including those with dipoles and repulsions from torsional interactions—in order to validly arrive at an assessment of a mono-alkoxide’s stability. Thus, the non-quantitative assumptions traditionally used in assessing the relative reactivities of the mono-alkoxides have all been severely flawed. An examination of Table 1 will show that C–H hydrogen bonded mono-alkoxides were frequently found to be more stable than their O–H hydrogen bonded isomers. Indeed, while several of these mono-alkoxides were initially constructed in conformations that had alkoxide—H–O hydrogen bonds, during the process of energy minimization these conformations were changed into more stable conformations in which the O–H hydrogen bonding interaction was replaced by C–H hydrogen bonding.
80.9 72.1 68.9 59.9 64.0 58.3 140.4 52.1 67.3 68.8 58.5 46.1 41.3
certainly highlight the fact that ester migration can totally mislead the experimenter’s analysis of the outcome of the reaction if the regiochemistry of the reaction is not observed in its very early stages. In our analyses of these reactions, we have decided that the trends shown in ester migration during the acylation of a sugar should be logically extrapolated to the beginning of that reaction, in order to assess the initially observable regiochemistry of that reaction. For example, if during the course of an acylation reaction, especially at its midpoint, the ratio of 2-ester to 3-ester is about 1-1, and that ratio decreases as the reaction progresses, then the reaction must have initially shown a regioselectivity for the 2-ester. This pattern of changing apparent regioselectivity is quite commonly observed in the phase transfer, and other, acylations of sugar vicinal diols [7–9].
7.2. Ester migration
7.3. Reactivity and regiochemistry from the QVBMM data
A discussion of the regiochemistry of the selective acylations of sugars must be approached with great caution because of the tremendous facility with which esters migrate along the sugar backbone. This is particularly true when these esterifications are done under phase transfer conditions [7–9]. These studies of the relative rates of formation of the esters from 4,6-Oalkylidene, or benzylidene, glycopyranosides
The structure energy minimization of each of the possible conformations of the mono-alkoxides from each sugar were performed using the QVBMM force field. Then, for each sugar anomer, we selected from the data the lowest enthalpied alkoxide, since this molecule would obviously be the most abundant nucleophile present in their phase transfer reactions. If a particular mono-alkoxide had several conformers/
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isomers whose enthalpies were within 3.5 kcals of that mono-alkoxide’s lowest energied isomer, then these conformers/isomers were also selected for inclusion in the analysis, described below, since we intended to apply the Curtin–Hammett principle to the relative reactivities of these similar-enthalpied molecules. The QVBMM structure energy data for the lone pair interactions are presented in Table 1 and the calculated geometry about the anomeric center of some of the alkoxides are presented in Table 2. 7.4. Reactivity and lone pair stereo-electronic energy It is well known that a-glucopyranosides react much more rapidly at O-2 than do corresponding the b-glucopyranosides either at O-2 or O-3 [3–9]. If we examine the lone pair energies of these glucopyranosides, in Table 1, we see that the highest energied lone pair of the reactive a-glucopyranoside is on O-2 in GLUA31C and has 1.69 kcal of repulsive electronic energy, while the highest energied lone pairs, on O-2 and O-3, of the b-glucopyranoside GLUB32C have energies of 0.85 and 0.63 kcal, respectively. Negative lone pair energies suggests that these lone pairs are stabilized and deactivated, rather than repulsively activated, relative to the other lone pairs. The hydrogen bonded lone pairs in the glucopyranosidic 2C–3A duets are illustrative. Thus, the lone pair electronic energies do reflect their relative nucleophilic reactivities. 7.5. Regiochemistry of reactions of the glucopyranosides 7.5.1. The a -anomer The a-glucopyranoside (1) had its most stable isomeric mono-alkoxides close enough in energy to warrant the use of the Curtin–Hammett principle in the discussion of the mechanistic pathway most used. The most stable isomers, A21C, A31C and A21A, were all within 3 kcal/mol of each other, and would be expected to equilibrate rapidly with each other. Notice that the most stable isomer, A21C, did not possess a O–H hydrogen bond, while the other two did. These isomers all had their most energetic lone pairs on O-2. However, the O–H hydrogen bonded isomer A31C clearly had the highest energied, hence most nucleophilic, lone pair on its alcoholic oxygen O-2. This clearly suggested that the
mechanistic pathway available to the A31C isomer was Path B, Scheme 3, while the isomer A21C—no O–H hydrogen bond—should react via Path C, and the isomer A21A—O–H hydrogen bonded—should react via Path A. The QVBMM data therefore predicts the dominant nucleophilicity of the O-2, which is consistent with the experimental data. The a-glucopyranosides are known to be preferentially esterified under phase transfer conditions at O-2 [7–9,15–17]. 7.5.2. The b -anomer The b-glucopyranoside (5) had four low energied, O–H hydrogen bonded, mono-alkoxides. The isomer B32C had the highest energied lone pair on the alcoholic O-2. Thus this molecule should also be esterified under phase transfer conditions at O-2, by the mechanistic pathway B. The most stable isomer, B31C, had lone pairs of similar energies, 0.45 and 0.55, on O-2 and O-3, respectively, and the rates of their reactions might be similar. Thus, the QVBMM data predicted that this molecule should also be preferentially esterified under phase transfer conditions at O-2, via Path B. This is consistent with the experimental data [7–9,15–17]. 7.6. Regiochemistry of reactions of the allopyranosides 7.6.1. The a -anomer The a-allopyranoside (3) had three low energied mono-alkoxide isomer, A31B, A22A and A21B. Their O-3 had a 1,3-diaxial relationship with the anomeric O-1, enabling any lone pair in the 3B position to interact fiercely with one of the lone pairs of O1. Thus, with the exception of isomer A21B—which had a hydrogen in the 3B position that was strongly hydrogen bonded to O-1—the highest energied lone pairs resided on this oxygen, O-3, of the isomers A31B and A22A. However, this O-3 lone pair was the most hindered since it was directly beneath the pyran ring, and was the lone pair closest to the axial O-1. It was therefore quite easy to decide that steric factors would severely hinder the transition state of reactions involving this high energied loner pair of the axial O-3 of isomers A31B and A22A, and that the molecule ought to react at the lone pair of the next highest energy. Note also that the isomer A21B had its highest energied lone pair on O-2.
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Thus, while it was obvious that isomer A21B would dominate the nucleophilic chemistry of the a-allopyranosides, and be most nucleophilic at O-2, the steric factor discussed above also would require the isomers A31B and A22A to react at O-2, since these isomers had their next highest energied lone pairs on their O-2. Isomer A31B did not have a O–H hydrogen bond and hence must react slowly by Path D, isomer A22A had an O–H hydrogen bond and would react via Path A, and isomer A21B did not have an O–H hydrogen bond and must react via Path C. Thus, the QVBMM data predicted that this molecule should be preferentially esterified under phase transfer conditions at O-2. This is consistent with the experimental data [7–9]. 7.6.2. The b -anomer The b-allopyranoside (7) had two low energied mono-alkoxide isomers, the non-O–H hydrogen bonded conformers B22C and B21C. Their highest energied lone pair were attached to the alkoxidic O2. It was logical to conclude that these alkoxides should react via Path C, to give predominantly the 2-ester, under phase transfer conditions. 7.7. Regiochemistry of reactions of the galactopyranosides 7.7.1. The a -anomer The a-galactopyranoside (4) had two low energied mono-alkoxide isomers, the non-O–H hydrogen bonded isomers A31B and A21B. The isomer A21B had a significantly higher energied lone pair on its O-2 than isomer A31B had on its O-3. This factor should allow the O-2 oxygen to be a better, more available, nucleophile, and to react via Path C. Thus, the QVBMM data predicted that this molecule should be preferentially esterified under phase transfer conditions at O-2, and this is consistent with the experimental data [7–9,15–17]. 7.7.2. The b -anomer The b-galactopyranoside 8 had two low energied, non-O–H hydrogen bonded, mono-alkoxide isomers, B31A and B32A. Both had their highest energied lone pair attached to O-3, and these lone pair energies were undoubtedly large enough to allow an unequivocal conclusion that this alkoxide should react at O-3, via
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Path C. The QVBMM data predicted that this molecule should be preferentially esterified under phase transfer conditions at O-3. This is consistent with the experimental data [7–9]. 7.7.3. Regiochemistry of reactions of the mannopyranosides The esterifications of the 4,6-di-O-substituted amannopyranosides have been closely investigated. The reactions that were done in pyridine clearly favor reaction at O-3 over O-2, even though Kong, Du and Wu [9] have reported that their attempts at the benzoylation of 4,6-di-O-benzyl-a-d-mannopyranosides, using benzoyl chloride in pyridine favored the formation of the 2-benzoate ester. In contrast, the phase transfer esterification reactions seemed uniformly to favor the formation of the 2-O esters. 7.7.4. The a -anomer The a-mannopyranoside (2) had six low energied mono-alkoxide conformers, of which A21C—with the alkoxide at O-2—was the most stable. All of these conformers had their highest energied lone pair on O-3, and only A21C had a lone pair on O-2 almost equal in energy to that on O-3 (0.722 and 0.777, respectively). Since O-2 is axially oriented, it ought to be esterified more slowly that the equatorially oriented O-3, even if these two atoms had lone pairs of similar energy. Thus the QVBMM generated data suggests that esterification ought to occur largely at O-3, as is observed in the reactions in pyridine. However, the experimental fact of preferential esterification on O-2 under phase transfer catalyzed conditions suggests that there is either a yet-undiscovered (by us) lower energied conformation than A21C that has its highest energied lone pair on O-2 (that must also be considerably higher in energy that any on O3), or that the a-mannopyranoside is undergoing phase transfer esterification by a mechanism that we have not taken into account. We have searched the available boat and twist-boat conformations and have, so far, been unable to uncover any lower energied conformer than A21C. We shall continue to explore the possibility of neighboring group participation, particularly involving the ring oxygen O-5 (which has lone pairs of considerably high energies) as the source of the regioselectivity
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observed in the phase transfer esterification of the amannopyranosides. 7.7.5. The b -anomer The b-mannopyranoside (6) also had seven low energied mono-alkoxide conformers, of which B31A, B22C and B22B were the most stable. Once again all of these conformers had their highest energied lone pair on the O-3, even though B22C and B22B are alkoxidic at O-2. Thus, the QVBMM data suggests that the b-mannopyranoside should be preferentially esterified at O-3 (as they do when esterified in pyridine), while the experimental data indicated that these b-mannopyranosides undergo esterification preferentially on O-3. Our conformational searches have also not uncovered a conformer lower in energy than B31A, B22C or B22B, and we continue to examine the possibility of neighboring group participation, particularly involving the ring oxygen O-5 (which again has lone pairs of considerably high energies) as the source of the regioselectivity observed in the phase transfer esterification of the b-mannopyranosides.
the a-anomeric mono-alkoxides were clearly more stable than their b-anomeric mono-alkoxides. 8. Conclusion The QVBMM force field calculations of the structures and energies of the mono-alkoxides of the 4,6-Oethylideneglycopyranosides have allowed us to accurately predict the regiochemistry of their reactions with simple electrophiles. The data also have enabled us to predict, quantitatively, the relative reactivities of the monosaccharide alcoholic and alkoxidic oxygens. This dramatic accomplishment then suggests that the QVBMM force field should be useful in predicting the nucleophilic regiochemistry and reactivity of other sugar derivatives and of other molecules that have several nucleophilic sites. Indeed, we are conducting a similar study on the rarer, and much more expensive, glycohexopyranosides (gulose, talose, idose and altrose) and will present our findings as soon as we have gathered enough relevant experimental data with which to compare the calculated data.
7.8. The anomeric effects It must be noted that the anomeric effects have never been measured experimentally for the monosaccharide alkoxides discussed in this paper. Indeed, the compositional complexity of a solution of a given monosaccharide’s monoalkoxide would either defy the validity of such measurements, or make the process one requiring considerable effort. While it was not a stated goal of this work to examine the anomeric effects [14–17] in these mono-alkoxides, this data naturally fell out of the results shown in the tables, and were completely congruent with what would have been predicted from first principles. Note that in all instances, the known experimental trends in anomeric enthalpy differences are corroborated by the QVBMM data for these monoalkoxides. Thus, only the allopyranoside had a b-anomeric mono-alkoxide that was lower in energy than its a-anomeric mono-alkoxide (as would be expected), while in the other molecules,
References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
V.G.S. Box, J. Mol. Model. 3 (1997) 124. J. Lehrfeld, Carbohydr. Res. 39 (1975) 364. A.H. Haines, S.A. Abbas, Carbohydr. Res. 39 (1975) 358. H. Honig, H. Weidmann, Carbohydr. Res. 39 (1975) 374. A.H. Haines, Adv. Carbohydr. Chem. Biochem. 33 (1976) 11. V.G.S. Box, Heterocycles 20 (1983) 1641. V.G.S. Box, Heterocycles 20 (1983) 677. L.L. Box, V.G.S. Box, E.V. Roberts, Carbohydr. Res. 119 (1983) 273. F. Kong, J. Du, H. Wu, Carbohydr. Res. 147 (1986) 337. V.G.S. Box, Heterocycles 19 (1982) 1939. J. Hine, Y. Chou, J. Org. Chem. 46 (1981) 649. J. Hajdu, G.M. Smith, J. Am. Chem. Soc. 103 (1981) 6192. E.L. Eliel, L.N. Mander, S.H. Wilen, Stereochemistry of Organic Compounds, Wiley, New York, 1994. V.G.S. Box, Heterocycles 48 (1998) 2389. I. Tvaroska, T. Bleha, Adv. Carbohydr. Chem. Biochem. 47 (1989) 45. V.G.S. Box, Heterocycles 31 (1990) 1157. V.G.S. Box, Heterocycles 32 (1991) 795.
Exploring the relative reactivities of the hydroxyl groups of monosaccharides by molecular modeling and molecular mechanics V.G.S. Box*, T. Evans-Lora Department of Chemistry, City College of the City University of New York, Convent Avenue @ 138th Street, New York, NY 10031, USA Received 10 March 1999; accepted 6 April 1999
Abstract The molecular modeling program STR3DI.EXE, and its molecular mechanics module, QVBMM, were used to simulate, and evaluate, the stereo-electronic effects in the mono-alkoxides of the 4,6-O-ethylideneglycopyranosides of allose, mannose, galactose and glucose. This study has confirmed the ability of these molecular modeling tools to predict the regiochemistry and reactivity of these sugar derivatives, and holds considerable implications for unraveling the chemistry of the rare monosaccharides. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Molecular mechanics; Nucleophilicity; Monosaccharide alkoxide; Quantized valence bonds’ molecular mechanics
1. Introduction The monosaccharides are probably the most densely functionalized naturally occurring organic molecules, and are undoubtedly among the most important organic molecules in the biochemistry of all living things. The chemistry of the monosaccharides has been developed, over many decades, by exhaustive empirical experimentation, and today there is a very broad base of knowledge about the chemical reactions of the monosaccharides. To a large degree, theoretician have not been able to propose congruent models to rationalize the various aspects of the chemistry of these monosaccharides. The theoretical models that have been put forward are usually quite limited in their scope, and/or have stimulated significant controversy about their theoretical underpinnings, thus preventing their * Corresponding author. Tel.: 1 1-212-650-8266. E-mail address: [email protected] (V.G.S. Box).
uniform acceptance. The development of the quantized valence bonds’ molecular mechanics (QVBMM) force field represents a successful effort to provide organic chemists with a new theoretical tool for addressing some of the structure-reactivity problems found in carbohydrate chemistry, particularly the modeling and assessment of the stereoelectronic effects that are due to a sugars hydroxyl groups [1]. One of the experimentally well defined aspects of monosaccharide chemistry is the fact that the hydroxyl groups of these molecules are not equally reactive as nucleophiles [2]. The patterns of nucleophilic reactivity of these hydroxyl groups vary from sugar to sugar, even changing with changes in the structure (functionalization) of a given sugar [2]. This aspect of carbohydrate chemistry is well suited for theoretical study since the vast quantity of empirically gained knowledge in this area will tightly control the development of theoretical rationalizations for these phenomena.
0022-2860/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S0022-286 0(99)00191-X
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Scheme 1.
2. The mono-esterification of diol mono-alkoxides 2.1. Mechanistic possibilities It is well known that simple alcohols, and diols, undergo esterification by acyl halides and anhydrides, in the presence of pyridine (or other tertiary amines), via termolecular transition states, as is shown in Scheme 1 [3–6]. These reactions are typical “general base catalyzed” reactions. In contrast, the alkoxides of alcohols, or the monoalkoxides of diols, generated in their “specific base catalyzed” esterification reactions, engage in bimolecular transition states with these acylating agent, as is shown in Scheme 2 [7–9]. These bimolecular alkoxide esterification reactions are encountered under phase transfer reaction conditions, and are usually much faster than the termolecular reactions of the corresponding alcohol. In phase transfer reactions the alkoxides are usually unsolvated (“naked”) and free since the associated cation is usually a large organic quaternary ammonium or phosphonium ion. These “naked” anions are better (more available nucleophilic electron density) nucleophiles, the transition states are less crowded, and the entropic
requirements for the formation of the bimolecular transition states are significantly smaller than those for the termolecular transition states. While the possible mechanisms for the reactions of monohydric alcohols are uncomplicated, there are four distinct, and experimentally plausible, mechanisms by which a given diol’s mono-alkoxide can react with an electrophilic acylating, or alkylating, agent. These are shown in the Scheme 3, below. Two of these mechanisms, Paths A and B, will be accessible by mono-alkoxides that have an intramolecular O–H hydrogen bond between the alkoxidic oxygen and the hydroxyl group, and the other two mechanisms, Paths C and D, will be accessible by the non-O–H hydrogen bonded conformers. Path A would require the attack of the intramolecularly O–H hydrogen bonded alkoxidic oxygen on the electrophile. This pathway would only be regioselective if the isomeric intramolecularly hydrogen bonded alkoxide was less stable. Otherwise, the hydrogen could shift onto the alkoxidic oxygen, hence changing the site of the alkoxidic nucleophilic center, and reducing the regioselectivity of the reaction. Path B appears to be quite similar to Path A, but
Scheme 2.
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Scheme 3.
would involve the alcoholic oxygen acting as the nucleophilic center, and the alkoxidic oxygen acting as an internal base, in a “termolecular-like” approach to the transition state. The intramolecular nature of this pathway would bypass most of the entropic and steric disadvantages of the intermolecular termolecular analogue, Scheme 1, but would result in the non-alkoxidic oxygen becoming the site of the esterification reaction. This pathway would be possible if the alcoholic oxygen possessed the highest energied, hence most nucleophilic [10], lone pair. Path C would require the direct attack of the nonhydrogen bonded alkoxidic oxygen on the electrophile. This pathway would be available if intramolecular O–H hydrogen bonding was geometrically unfavorable, or if the C–H hydrogen-bonded alkoxide was more stable than the O–H hydrogen bonded conformer. Path D would involve the direct attack of the nonhydrogen bonded alcoholic oxygen on the electrophile. This pathway would also be available if intramolecular O–H hydrogen bonding was geometrically unfavorable, or if the C–H hydrogen-bonded alkoxide was more stable than the O–H hydrogen bonded conformer, and if the alkoxidic oxygen was so effectively stabilized by intramolecular hydrogen bonding
that its lone pairs were less energetic than those of the hydroxyl group. This path would also be possible if the alkoxidic oxygen was simply sterically hindered. Note that the through-space electrostatic stabilization of the developing positive charge on the alcoholic oxygen by the negatively charged alkoxidic oxygen should steadily increase through the transition state, and crest into the intermediate, and would require that the alkoxidic oxygen be reasonably close to the hydroxyl oxygen. While the pathways A, B and C would proceed via the transition states in which the alkoxidic negative charge should steadily decrease in size as the reaction progressed through the transition state, the pathway D would involve the retention of the alkoxidic negative charge and the generation of a positive charge on the neighboring alcoholic oxygen. There are many organic reactions that show this feature. Indeed, the reactions of ylides with carbonyl compounds, among several others, are facilitated, and accelerated, by this kind of developing stabilizing electrostatic interaction [10–12]. Thus, Path D cannot logically be excluded from consideration. It is very important to recognize that the favored reaction pathway will determine the regiochemistry of the reaction.
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Scheme 4.
3. Lone pair energy, basicity and nucleophilicity Since the QVBMM force field can be regarded as a quantitative expression of the ideas embodied in VSEPR theory, the lone pair orbitals of alkoxides and alcohols are treated as sp 3 hydrid orbitals in order to maximize the distances between these sites of high electron density on their host atoms. As has been describe before [10], let us briefly consider the possible consequences of the through space—not resulting in bonding—interactions of a lone pair of electrons with an electrophile (an “empty” orbital), a positive charge (or the positive end of a dipole), another pair of electrons, or a negative charge. Using a simple molecular orbital picture, we can qualitatively describe the energetic outcomes of these events, as is shown in the diagram below in Scheme 4. Thus, the interaction of a lone pair with an electrophile or positive charge should lower the lone pairs’ energy, making it more stable and hence less nucleophilic. In the presence of several of these interactions, it might be possible for the lone pair to become very stable, so as to become a very poor nucleophile. However, the interaction of a lone pair with another pair of electrons or a negative charge should cause the energy of the lone pair to be increased, and the lone pair should become a better nucleophile. Several of these interactions could increase the nucleophilicity of the lone pair quite considerably. This molecular orbital model has successfully been used to rationalize the greater nucleophilicities of banomeric oxygen atoms, over their a-anomeric counterparts, and hence to rationalize the mechanistic
descriptions of a number of intriguing monosaccharide reactions [10]. Another interesting correlation that gives credibility to these ideas is the congruence of the trend in the lone pair energies of the simple monohydric alkoxides (bearing in mind their symmetry properties) and the known basicities of these alkoxides. Alkoxide Methoxide Ethoxide 2-propoxide tert-butoxide
QVBMM lone pair energy kcal 20.66 20.66, 1.41, 1.41 1.49, 1.49, 3.08 3.40
The lone pairs that were flanked dihedrally by hydrogens were considerably lower in energy in comparison to those that were similarly flanked by carbons. While the lone pair energies do predict the trend in the basicities of these alkoxides, any attempt to correlate these lone pair energies to the nucleophilicities of these alkoxides would also require a discussion of the steric factors in the transition states of their nucleophilic attacks. These steric factors must significantly be more important than those in the acid-base reactions. However, it could logically be concluded that the alkoxide having the higher energied lone pair—the more basic lone pair—should also be a better nucleophile if the contributing steric factors are similar for both molecules. The application of this fundamental concept to the present study will take the form of allowing the QVBMM force field to calculate the sizes of the intramolecular interactions of the lone pairs of the diol monoalkoxides with other lone pairs, bonding pairs, and the partial charges from dipoles. Since hydrogen
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bonding and favorable interactions with positively charged sites will stabilize—deactivate—a lone pair, then lone pairs that experience the largest total repulsions will be better candidates for nucleophilic activity than the other lone pairs, and certainly more than lone pairs that are stabilized. It will be seen, below, that the QVBMM data completely support this concept, resulting in a perfect congruence of the calculated data with the experimental facts.
4. The diols The methyl 4,6-O-alkylideneglycohexopyranosides of glucose, (1) and (5), mannose, (2) and (6), allose, (3) and (7), and galactose, (4) and (8), should be able to utilize any of these four pathways in the reactions of their mono-alkoxides with acylating or alkylating agents.
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A discussion of the actual mechanism of the nucleophilic behavior of each of these molecules will therefore require a rigorous, and quantitative, assessment of the factors that could bias each reaction towards one of the pathways outlined above. Thus, for each 4,6-O-ethylidene derivative (R CH3) of the molecules 1–8, the QVBMM structure energy minimizations and stereo-electronic evaluations should allow us to establish: 1. The structure of the most stable isomer of its possible mono-alkoxides, since this entity will be the most abundant nucleophile in the reaction. 2. Whether a particular mono-alkoxide has several isomers/conformers that are also close in enthalpy to the most stable isomer, and can interconvert rapidly enough, to warrant invoking the Curtin–Hammett principle in the discussion of the relative reactivities of the entire
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array of isomers, rather than just considering the lowest energied isomer. 3. Whether the highest energied lone pair is present on the alkoxidic oxygen, or not, as this lone pair should be the nucleophilic agent.
5. The Curtin–Cammett principle The Curtin–Hammett principle [13] states that if a given reactive molecule has two (or more) isomers or conformers that interconvert in a rapid equilibrium under the reaction conditions, then ratios of the products from the various reacting isomers/conformers will be proportional to the ratios of the reaction rates of these isomers/conformers. The principle is true only when the equilibrium interconversions of the isomers/conformers is significantly greater than the reaction rates, and this situation usually occurs when the enthalpy difference between the two isomers/conformers is relatively quite small (less than 3 kcal/mol in this study). Further, for reactions that are governed by the Curtin–Hammett principle, if the transition states of the reactions of the various isomers/conformers are nearly equivalent in energy, then the highest energy isomer/conformer will react faster, and the major product of the reaction will be derived from that isomer/conformer. It is known [3–6] that equatorial hydroxyl groups of cyclohexanols are normally esterified more rapidly their axial isomers, suggesting that the transition states for the reactions of the axial isomers are higher in energy. We shall assume that the transition states for the reactions of the equatorial oxygens are equivalent in energy, as would also be the case for the axial oxygens, and that the transition states for the reactions of the axial oxygens will be higher in energy than those for the equatorial oxygens. Most phase transfer esterifications and alkylations are done using an aqueous basic solution as one phase. The organic phases of these reactions must therefore be saturated with, albeit a very small concentration of, water. However, the presence of traces of water in the organic phase forces one to recognize that neither the isomerization of one alkoxide to another, nor the change of one C–OH conformer to another, needs to be an intramolecular event, since water could facilitate the rapid exchange of protons between the lone
pair (basic) sites, in an intermolecular process. Thus, the interconversions of isomeric alkoxides, or conformers, could be quite rapid in these reactions, so justifying the application of the Curtin–Hammett principle to this problem.
6. The STR3DI molecular modeler The STR3DI 1 molecular modeling programs use the new QVBMM module for performing structure energy minimizations [1]. This molecular mechanics force field can be regarded as a quantitative expression of the well-known valence shell electron pair repulsion (VSEPR) theory. The QVBMM force field not only treats lone pairs as discrete, very small, negatively charged, “atom-like” entities, but it also invokes, and uses, all of the possible bond polarizations present in the molecule, even those of aliphatic C–H bonds [1]. The STR3DI molecular modeling programs have been shown to efficiently, and faithfully, simulate the structures of most organic molecules, and especially those that contain heteroatomic lone pairs. Indeed, it is well known that most molecular mechanics force fields cannot reliably simulate complex, lone pair interaction phenomena like the anomeric effects found in acetals and glycosides, but, as will be seen from the results of the calculations performed by this force field, even these anomeric effects are efficiently simulated by the STR3DI programs [1,14]. The QVBMM force field reliably calculates the stereo-electronic and strain energy present in unsolvated molecules by assuming that the molecules are either in the gas phase, or are dissolved in a non-polar hydrocarbon solvent. Thus, the QVBMM calculations do not take their solvation energies into consideration. However, since structurally similar, isomeric molecules that have the same number and types of bonds will normally be similarly solvated, the force field does gives reliable estimates of the enthalpy differences between these molecules, regardless of the 1 Information about the STR3DI molecular Modeler and the QVBMM force field can be obtained from Exorga, Inc., P.O. Box 56, Colonia, NJ 07067, USA, and at the INTERNET web-site— http://ourworld.compuserve.com/homepages/exorga
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solvent in which they are dissolved, since the solvation energies will cancel out. The phase transfer alkylation/acylation reactions of the mono-alkoxides to be discussed are performed under conditions in which the reactive nucleophilic alkoxides are dissolved in non-polar organic solvents. The possible solvation and entropy factors are assumed to be nearly equivalent for each isomeric alkoxide of a given sugar, because these isomers are very closely related in structures and geometries. Any comparison of the enthalpies of these isomers will therefore effectively cancel out the contributions due to these solvation, and entropy, factors. Thus, the data generated by the QVBMM force field should be credible in this study. The unique ability of the STR3DI programs to calculate the energies of the lone pairs of electrons in a molecule (due to n–n, n–s, n–p and n–dipole interactions) allows us to determine which lone pairs at the nucleophilic reaction site possesses the highest repulsive electronic energy and is very likely to be the initiator of the nucleophilic attack [1,10]. This assessment cannot be made by any other molecular mechanics program in existence. Thus, we were confident that the QVBMM force field, and the STR3DI molecular modeling program, would provide the data we needed to rationally discuss the details of the nucleophilic attack of the glycosidic alkoxides on acylating agents in the nonpolar environment of a phase transfer reaction. 6.1. The QVBMM calculations There are two possible isomeric mono-alkoxides for each of the molecules 1–8, and each monoalkoxide has nine primary staggered conformers, since there are three possible conformations for the C–OH moiety, and three possible conformations for the anomeric/glycosidic methoxyl group. These nine conformers, for each isomeric mono-alkoxide, were constructed, and their energies repeatedly minimized to assure us that the resulting structures were indeed very close to their minimum energies. The lowest energied mono-alkoxide isomer and any others of similar energy were then selected for further scrutiny. We also inquired if the stereo-electronic interactions in these molecules, when they were a few kcals above their energy minima, were similar to
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those found at the minima. This was done to assure us that the profile of energies present during the minimization of any given molecule was one that changed smoothly towards the minimum, and did not involve significant energetic and structural dislocations. In fact, this notion was indeed correct, and it considerably reinforced our confidence in the data, since we recognized that valid conclusions could be arrived at even if we examined the stereo-electronic profile a molecule that was close to, but not at, its energy minimum. 6.2. Identifying the conformations A system was developed to enable us to rapidly identify the conformers, and was based on: 1. The anomeric configuration of the sugar. 2. The site of the alkoxidic oxygen (so also revealing the site of the non-alkoxidic oxygen). 3. The conformation about the C-1–O-1 bond. 4. The conformation of the hydroxyl group—ring carbon moiety. The glycosidic conformation was identified by assigning the number 1 to the conformer in which the aglycone was anti to C-2, the most stable conformers. The number 2 for conformations of a-anomers in which the aglycone was anti to O-5, or for conformations of b-anomers in which the aglycone was anti to H-1, the next more stable conformers. The number 3 to the least favorable conformers—when the aanomeric aglycone was anti to H-1, or when the banomeric aglycone was anti to O-5. The letter A was assigned to the hydroxyl group’s conformation if the hydrogen was “pointing towards” C-1, the letter B if it was anti to the neighboring C–H bond, and the letter C if the hydrogen was “pointing away from” the anomeric center, C-1. The prefixes were the first three letters of the sugar’s name. Anomers were then designated by their first letters (A for a-, and B for b-). These letters were followed by the numbered site of the alkoxidic oxygen. Followed by the number for the glycosidic conformation. Then followed the hydroxyl group conformation designator. Thus GLUA31A would be the 4,6-O-ethylidenea-d-glucopyranoside, in which the alkoxidic oxygen was O-3, the aglycone was in the most stable,
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Table 1 QVBMM structure energy data for the methyl 4,6-O-ethylidineglycopyranosidic alkoxides. (H represents the site of a hydrogen that is bonded to the respective atom, 2 or 3) Initial isomer
Final isomer
Allopyranosides A31B A31B A22A A21A A21B A21B B22C B22C B21C B21C Galactopyranosides A31B A31B A21B A21B B31A B31A B32A B32A Glucopyranosides A21C A21C A31C A31C A21A A21A B31C B31C B21A B21A B32C B32C B22A B22A Mannopyranosides A21C A21C A31C A31C A31B A31B A21B A21B A21A A21A A31A A31A B31A B31A B22C B22C B22B B22B B32C B32C B32B B32B B22A B22A B31B B31B
Strain energy
Lone pair energies 2A
2B
2C
3A
55.395 57.117 58.023 55.129 55.604
20.622 20.562 21.671 21.358 20.719
H 22.007 1.615 0.464 0.323
20.43 21.516 20.182 0.292 0.413
21.079 H 0.877 20.36 20.403
52.450 54.94 58.261 60.245
20.579 20.794 H H
H 1.247 0.557 0.489
20.216 21.217 20.094 20.179
20.921 0.216 20.83 20.979
50.098 52.458 52.753 56.862 57.246 58.193 58.702
20.825 20.484 20.584 0.454 20.108 0.856 0.122
1.015 1.694 1.237 0.042 0.032 20.037 20.109
21.278 H 23.363 H 23.123 H 22.684
49.41 49.682 49.688 50.089 51.172 52.573 54.194 54.273 54.29 54.777 56.467 56.682 57.353
21.526 20.725 20.925 21.127 21.151 H H 21.025 21.253 21.246 21.395 21.088 0.333
0.722 0.488
20.957 H 0.104 20.933 21.023 20.696 20.644 20.435 20.345 H 0.538 20.368 0.888
exo-anomeric position 1 (anti to C-2), and the 2hydroxyl group’s hydrogen was “pointing towards” C-1. A quick study of the bit-mapped images will facilitate an acquaintanceship with the system. Notice that in this series of compounds, the nomenclature allows one to quickly decide if O–H hydrogen bonding could be present in the conformer. Thus, for example, the 31A, the 32A (3nA) and the 21C (2nC) conformers cannot have O–H hydrogen bonds, while the 3nB, the 3nC, the 2nA and the 2nB conformers can possibly have O–H hydrogen bonds.
H 20.114 0.203 20.018 20.601 20.766 20.967 20.457 H 20.596 H
3B
2.046 2.507 H 21.258 21.409 0.725
3C 20.893 20.731 0.734 H H
0.661 0.931
0.427 0.262 0.545 0.373
20.247 20.685 H 22.918 H 23.028 H
0.475 0.554 0.488 0.552 0.516 0.637 0.568
H 20.516 20.031 20.373 0.24 20.135 0.365
0.096 0.492 0.783 0.448
0.777 0.624 0.545
H 20.61 20.271 0.518 0.624 20.463 20.549 H 0.302 20.714 20.916 20.438 21.187
H
H
H 0.59 0.587 0.174 0.301 0.342 0.565 H 0.613
0.537 0.519 0.53 0.775 H 0.618 0.748 0.618 0.754
7. Analyzing the QVBMM data 7.1. Hydrogen bonding Most organic chemists would intuitively assume that the O–H hydrogen bonded mono-alkoxides would be more stable than their non-O–H hydrogen bonded isomers/conformers. However, the QVBMM calculations revealed that this notion would only be valid if one ignored the significant contributions of the C–H dipoles in stabilizing the alkoxidic negative charge by C–H hydrogen bonding. Indeed, the
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Table 2 Molecular geometry at the anomeric centers of some selected pyrans (Table 1) (The exo-anomeric dihedral angle encompassed O-5–C-1–O-1– C-7, where C-7 is the aglycone carbon) Bond lengths
Bond angles
Exo-anomeric dihedral angle
Molecule
O-5–C-1
C-1–O-1
O-2–O-3
O-5,C-1,C-2
O-5,C-1,O-1
C-2,C-1,O-1
C-1,O-1,C-7
ALLA31B ALLB22C GALA31B GALB31A GLUA21C GLUA31C GLUA32C GLUB31C MANA31B MANA21C MANB31A MANB32C MANB32B
1.419 1.427 1.421 1.425 1.422 1.422 1.425 1.424 1.422 1.424 1.424 1.423 1.423
1.424 1.428 1.423 1.424 1.426 1.424 1.427 1.425 1.422 1.424 1.423 1.422 1.422
2.893 2.916 2.929 2.880 2.922 2.872 2.867 2.874 2.939 2.928 2.882 2.814 2.978
108.5 110.1 109.5 113.7 107.1 106.0 104.9 106.9 108.8 112.4 110.4 114.3 110.4
114.1 113.0 112.8 113.7 112.6 114.0 115.8 111.5 114.5 112.5 114.8 115.2 115.5
114.7 114.9 112.7 109.1 115.0 114.9 112.7 115.2 110.7 111.0 110.3 112.3 113.5
112.4 113.9 112.9 113.4 112.8 113.0 113.7 113.7 112.8 112.8 113.4 114.8 115.0
QVBMM calculations clearly showed that it is necessary to consider all of the lone pair interactions— including those with dipoles and repulsions from torsional interactions—in order to validly arrive at an assessment of a mono-alkoxide’s stability. Thus, the non-quantitative assumptions traditionally used in assessing the relative reactivities of the mono-alkoxides have all been severely flawed. An examination of Table 1 will show that C–H hydrogen bonded mono-alkoxides were frequently found to be more stable than their O–H hydrogen bonded isomers. Indeed, while several of these mono-alkoxides were initially constructed in conformations that had alkoxide—H–O hydrogen bonds, during the process of energy minimization these conformations were changed into more stable conformations in which the O–H hydrogen bonding interaction was replaced by C–H hydrogen bonding.
80.9 72.1 68.9 59.9 64.0 58.3 140.4 52.1 67.3 68.8 58.5 46.1 41.3
certainly highlight the fact that ester migration can totally mislead the experimenter’s analysis of the outcome of the reaction if the regiochemistry of the reaction is not observed in its very early stages. In our analyses of these reactions, we have decided that the trends shown in ester migration during the acylation of a sugar should be logically extrapolated to the beginning of that reaction, in order to assess the initially observable regiochemistry of that reaction. For example, if during the course of an acylation reaction, especially at its midpoint, the ratio of 2-ester to 3-ester is about 1-1, and that ratio decreases as the reaction progresses, then the reaction must have initially shown a regioselectivity for the 2-ester. This pattern of changing apparent regioselectivity is quite commonly observed in the phase transfer, and other, acylations of sugar vicinal diols [7–9].
7.2. Ester migration
7.3. Reactivity and regiochemistry from the QVBMM data
A discussion of the regiochemistry of the selective acylations of sugars must be approached with great caution because of the tremendous facility with which esters migrate along the sugar backbone. This is particularly true when these esterifications are done under phase transfer conditions [7–9]. These studies of the relative rates of formation of the esters from 4,6-Oalkylidene, or benzylidene, glycopyranosides
The structure energy minimization of each of the possible conformations of the mono-alkoxides from each sugar were performed using the QVBMM force field. Then, for each sugar anomer, we selected from the data the lowest enthalpied alkoxide, since this molecule would obviously be the most abundant nucleophile present in their phase transfer reactions. If a particular mono-alkoxide had several conformers/
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isomers whose enthalpies were within 3.5 kcals of that mono-alkoxide’s lowest energied isomer, then these conformers/isomers were also selected for inclusion in the analysis, described below, since we intended to apply the Curtin–Hammett principle to the relative reactivities of these similar-enthalpied molecules. The QVBMM structure energy data for the lone pair interactions are presented in Table 1 and the calculated geometry about the anomeric center of some of the alkoxides are presented in Table 2. 7.4. Reactivity and lone pair stereo-electronic energy It is well known that a-glucopyranosides react much more rapidly at O-2 than do corresponding the b-glucopyranosides either at O-2 or O-3 [3–9]. If we examine the lone pair energies of these glucopyranosides, in Table 1, we see that the highest energied lone pair of the reactive a-glucopyranoside is on O-2 in GLUA31C and has 1.69 kcal of repulsive electronic energy, while the highest energied lone pairs, on O-2 and O-3, of the b-glucopyranoside GLUB32C have energies of 0.85 and 0.63 kcal, respectively. Negative lone pair energies suggests that these lone pairs are stabilized and deactivated, rather than repulsively activated, relative to the other lone pairs. The hydrogen bonded lone pairs in the glucopyranosidic 2C–3A duets are illustrative. Thus, the lone pair electronic energies do reflect their relative nucleophilic reactivities. 7.5. Regiochemistry of reactions of the glucopyranosides 7.5.1. The a -anomer The a-glucopyranoside (1) had its most stable isomeric mono-alkoxides close enough in energy to warrant the use of the Curtin–Hammett principle in the discussion of the mechanistic pathway most used. The most stable isomers, A21C, A31C and A21A, were all within 3 kcal/mol of each other, and would be expected to equilibrate rapidly with each other. Notice that the most stable isomer, A21C, did not possess a O–H hydrogen bond, while the other two did. These isomers all had their most energetic lone pairs on O-2. However, the O–H hydrogen bonded isomer A31C clearly had the highest energied, hence most nucleophilic, lone pair on its alcoholic oxygen O-2. This clearly suggested that the
mechanistic pathway available to the A31C isomer was Path B, Scheme 3, while the isomer A21C—no O–H hydrogen bond—should react via Path C, and the isomer A21A—O–H hydrogen bonded—should react via Path A. The QVBMM data therefore predicts the dominant nucleophilicity of the O-2, which is consistent with the experimental data. The a-glucopyranosides are known to be preferentially esterified under phase transfer conditions at O-2 [7–9,15–17]. 7.5.2. The b -anomer The b-glucopyranoside (5) had four low energied, O–H hydrogen bonded, mono-alkoxides. The isomer B32C had the highest energied lone pair on the alcoholic O-2. Thus this molecule should also be esterified under phase transfer conditions at O-2, by the mechanistic pathway B. The most stable isomer, B31C, had lone pairs of similar energies, 0.45 and 0.55, on O-2 and O-3, respectively, and the rates of their reactions might be similar. Thus, the QVBMM data predicted that this molecule should also be preferentially esterified under phase transfer conditions at O-2, via Path B. This is consistent with the experimental data [7–9,15–17]. 7.6. Regiochemistry of reactions of the allopyranosides 7.6.1. The a -anomer The a-allopyranoside (3) had three low energied mono-alkoxide isomer, A31B, A22A and A21B. Their O-3 had a 1,3-diaxial relationship with the anomeric O-1, enabling any lone pair in the 3B position to interact fiercely with one of the lone pairs of O1. Thus, with the exception of isomer A21B—which had a hydrogen in the 3B position that was strongly hydrogen bonded to O-1—the highest energied lone pairs resided on this oxygen, O-3, of the isomers A31B and A22A. However, this O-3 lone pair was the most hindered since it was directly beneath the pyran ring, and was the lone pair closest to the axial O-1. It was therefore quite easy to decide that steric factors would severely hinder the transition state of reactions involving this high energied loner pair of the axial O-3 of isomers A31B and A22A, and that the molecule ought to react at the lone pair of the next highest energy. Note also that the isomer A21B had its highest energied lone pair on O-2.
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Thus, while it was obvious that isomer A21B would dominate the nucleophilic chemistry of the a-allopyranosides, and be most nucleophilic at O-2, the steric factor discussed above also would require the isomers A31B and A22A to react at O-2, since these isomers had their next highest energied lone pairs on their O-2. Isomer A31B did not have a O–H hydrogen bond and hence must react slowly by Path D, isomer A22A had an O–H hydrogen bond and would react via Path A, and isomer A21B did not have an O–H hydrogen bond and must react via Path C. Thus, the QVBMM data predicted that this molecule should be preferentially esterified under phase transfer conditions at O-2. This is consistent with the experimental data [7–9]. 7.6.2. The b -anomer The b-allopyranoside (7) had two low energied mono-alkoxide isomers, the non-O–H hydrogen bonded conformers B22C and B21C. Their highest energied lone pair were attached to the alkoxidic O2. It was logical to conclude that these alkoxides should react via Path C, to give predominantly the 2-ester, under phase transfer conditions. 7.7. Regiochemistry of reactions of the galactopyranosides 7.7.1. The a -anomer The a-galactopyranoside (4) had two low energied mono-alkoxide isomers, the non-O–H hydrogen bonded isomers A31B and A21B. The isomer A21B had a significantly higher energied lone pair on its O-2 than isomer A31B had on its O-3. This factor should allow the O-2 oxygen to be a better, more available, nucleophile, and to react via Path C. Thus, the QVBMM data predicted that this molecule should be preferentially esterified under phase transfer conditions at O-2, and this is consistent with the experimental data [7–9,15–17]. 7.7.2. The b -anomer The b-galactopyranoside 8 had two low energied, non-O–H hydrogen bonded, mono-alkoxide isomers, B31A and B32A. Both had their highest energied lone pair attached to O-3, and these lone pair energies were undoubtedly large enough to allow an unequivocal conclusion that this alkoxide should react at O-3, via
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Path C. The QVBMM data predicted that this molecule should be preferentially esterified under phase transfer conditions at O-3. This is consistent with the experimental data [7–9]. 7.7.3. Regiochemistry of reactions of the mannopyranosides The esterifications of the 4,6-di-O-substituted amannopyranosides have been closely investigated. The reactions that were done in pyridine clearly favor reaction at O-3 over O-2, even though Kong, Du and Wu [9] have reported that their attempts at the benzoylation of 4,6-di-O-benzyl-a-d-mannopyranosides, using benzoyl chloride in pyridine favored the formation of the 2-benzoate ester. In contrast, the phase transfer esterification reactions seemed uniformly to favor the formation of the 2-O esters. 7.7.4. The a -anomer The a-mannopyranoside (2) had six low energied mono-alkoxide conformers, of which A21C—with the alkoxide at O-2—was the most stable. All of these conformers had their highest energied lone pair on O-3, and only A21C had a lone pair on O-2 almost equal in energy to that on O-3 (0.722 and 0.777, respectively). Since O-2 is axially oriented, it ought to be esterified more slowly that the equatorially oriented O-3, even if these two atoms had lone pairs of similar energy. Thus the QVBMM generated data suggests that esterification ought to occur largely at O-3, as is observed in the reactions in pyridine. However, the experimental fact of preferential esterification on O-2 under phase transfer catalyzed conditions suggests that there is either a yet-undiscovered (by us) lower energied conformation than A21C that has its highest energied lone pair on O-2 (that must also be considerably higher in energy that any on O3), or that the a-mannopyranoside is undergoing phase transfer esterification by a mechanism that we have not taken into account. We have searched the available boat and twist-boat conformations and have, so far, been unable to uncover any lower energied conformer than A21C. We shall continue to explore the possibility of neighboring group participation, particularly involving the ring oxygen O-5 (which has lone pairs of considerably high energies) as the source of the regioselectivity
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observed in the phase transfer esterification of the amannopyranosides. 7.7.5. The b -anomer The b-mannopyranoside (6) also had seven low energied mono-alkoxide conformers, of which B31A, B22C and B22B were the most stable. Once again all of these conformers had their highest energied lone pair on the O-3, even though B22C and B22B are alkoxidic at O-2. Thus, the QVBMM data suggests that the b-mannopyranoside should be preferentially esterified at O-3 (as they do when esterified in pyridine), while the experimental data indicated that these b-mannopyranosides undergo esterification preferentially on O-3. Our conformational searches have also not uncovered a conformer lower in energy than B31A, B22C or B22B, and we continue to examine the possibility of neighboring group participation, particularly involving the ring oxygen O-5 (which again has lone pairs of considerably high energies) as the source of the regioselectivity observed in the phase transfer esterification of the b-mannopyranosides.
the a-anomeric mono-alkoxides were clearly more stable than their b-anomeric mono-alkoxides. 8. Conclusion The QVBMM force field calculations of the structures and energies of the mono-alkoxides of the 4,6-Oethylideneglycopyranosides have allowed us to accurately predict the regiochemistry of their reactions with simple electrophiles. The data also have enabled us to predict, quantitatively, the relative reactivities of the monosaccharide alcoholic and alkoxidic oxygens. This dramatic accomplishment then suggests that the QVBMM force field should be useful in predicting the nucleophilic regiochemistry and reactivity of other sugar derivatives and of other molecules that have several nucleophilic sites. Indeed, we are conducting a similar study on the rarer, and much more expensive, glycohexopyranosides (gulose, talose, idose and altrose) and will present our findings as soon as we have gathered enough relevant experimental data with which to compare the calculated data.
7.8. The anomeric effects It must be noted that the anomeric effects have never been measured experimentally for the monosaccharide alkoxides discussed in this paper. Indeed, the compositional complexity of a solution of a given monosaccharide’s monoalkoxide would either defy the validity of such measurements, or make the process one requiring considerable effort. While it was not a stated goal of this work to examine the anomeric effects [14–17] in these mono-alkoxides, this data naturally fell out of the results shown in the tables, and were completely congruent with what would have been predicted from first principles. Note that in all instances, the known experimental trends in anomeric enthalpy differences are corroborated by the QVBMM data for these monoalkoxides. Thus, only the allopyranoside had a b-anomeric mono-alkoxide that was lower in energy than its a-anomeric mono-alkoxide (as would be expected), while in the other molecules,
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