Carbohydrate Drug Design - American Chemical Society

Chapter 11

Practical Applications of Computational Studies of the Glycosylation Reaction 1

2

Downloaded by PENNSYLVANIA STATE UNIV on June 15, 2012 | http://pubs.acs.org Publication Date: June 15, 2006 | doi: 10.1021/bk-2006-0932.ch011

Dennis M. Whitfield and Tomoo Nukada 1

Institute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada The Institute for Physical and Chemical Research (RIKEN), Wako-shi, 351-01 Saitama, Japan

2

A qualitative summary of our canonical vector representation of the conformations of six membered rings and its quantitative application to sugar pyranose rings is presented first. This representation is illustrated for the results of Density Functional Theory (DFT) optimized structures of per O-methylated D-lyxo, D-manno and D-gluco-configured oxacarbenium ions where two conformers are consistently found. Nucleophilic attack modelled with methanol is found to lead to intramolecular hydrogen bonding from the hydroxylic proton to electronegative oxygens of the oxacarbenium ion. As well, the ring conformation is found to change with the C-5-O-5--C-1-C-2 torsion angle moving from nearly planar in the isolated cations to more negative values in the case of α-approach and to more positive values for βattack. This can be favorable or unfavorable depending on the protecting groups present with for example 4,6-benzylidene protection favoring β-attack with D-manno-configured ions whereas for D-gluco-configured ions α-approach is favorable. Extending the D F T studies to 2-O-acetyl analogues finds similar pairs of cations and raises the important issue of the order of ring inversion or O-2 bond rotation during the formation of ring inverted dioxolenium ions which in some cases are calculated to be very stable. Finally, an example using complex constraints is described which led to the design and development of 2,6-dimethylbenzoyl and 2,6dimethoxybenzoyl as O-2 protecting groups which greatly minimize the acyl transfer side reaction. © 2006 American Chemical Society

In Carbohydrate Drug Design; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.

265

266


Organic chemistry has a long established principle that by understanding the mechanism of a reaction it should be possible to optimize that reaction. What we wish to present in this chapter is a synopsis of our attempts to understand the mechanism of glycosylation reactions with the goal of optimizing this important reaction. Our technique is the use of modern computational methods, see experimental. Since it is not possible to investigate all aspects of the glycosylation reaction we have focussed on the role of ring conformations. It is hoped that our results will assist experimentalists like us and our collaborators to develop better glycosylation technologies. This chapter is divided into four sections. The first outlines the new algebra that we have developed to describe the conformations of 6-membered rings that dominate the chemistry of carbohydrates (1). The second section shows our current understanding of the conformations of pyranose sugars with all ether protecting groups. The third section considers the implications of section 2 when C-2 is substituted with an acyl group capable of neighboring group participation. The fourth section considers a side reaction, namely acyl transfer to the acceptor alcohol, that is a problematic side reaction associated with neighboring group participation. This is not the chronological order in which these studies were made. It is, however, a more logical choice and should provide the reader with a logical progression of our ideas.

Section 1. Quantitative Description of Pyranose Ring Conformation Following the IUPAC Nomenclature. In this communication we characterize each pyranose conformer which is derived from the output of a density functional theory (DFT) calculation by a system that uses the familiar IUPAC nomenclature. This definition is not deduced from a 3-dimensional view of a graphical representation of a molecule. In practice the differentiation of a skew conformer from a boat conformer is difficult by visual examination of graphical models. Instead, our definition is based on a numerical basis. We first introduce the concepts of our new definition method. A detailed description is given in Réf. (1), here we attempt to give a sufficiently simple explanation that all chemists can use. Why do we need a new definition? The reason follows from the ambiguities of visual examination which partly results from the fact that traditional pyranose ring conformation characterizations are qualitative (2). These traditional methods describe visual conformational changes based on symmetry elements, which are intuitively easy to understand, but it is not easy to describe conformational interconversions qualitatively with these methods. On the other hand, quantitative characterizations have been also developed (3). These quantitative methods are mathematically precise and afford a set of


267


numbers which is unique to one pyranose conformation. The basic idea of all of these methods is a projection of pyranose endocyclic torsion angles onto a trigonometric orthonormal system. Such projections use a kind of Fourier transformation and this mathematical rigor insures their preciseness. These mathematical methods are advantageous for a quantitative recognition. However, they lack the visual significances that qualitative methods have. Our new definition aims to have both the visual significance familiar to an organic chemists and the quantitative preciseness for computational purposes. In particular we aim to elucidate the mechanisms of both enzymatic and experimental glycosylations with computational chemistry. These processes involve conformational changes, of pyranose rings and so we need a robust method to calculate these changes. We also should provide conformational figures which researchers in many fields can easily understand. Therefore, we come to need a new definition having advantages both of qualitative and quantitative methods.

Quantitative description of pyranose ring conformation following the IUPAC conformational nomenclature. Since internal ring dihedral angles give the best descriptions of ring distortions, we choose to use the set of six endocyclic dihedral angles as a geometrical parameter. We use the following definitions T!(C-lC-2--C-3C-4), T ( C - 2 C - 3 - - C 4C-5), T (C-3C-4--C-50-5), T ( C - 4 C - 5 - - 0 - 5 C - Ï ) , T (C-50-5--C-1C-2) and τ ( 0 5C-1--C-2C-3). A six dimensional space containing only these sets is a closed vector space which includes torsion angle sets of all typical conformations, namely, chairs, boats, skew-boats, half-chairs, and envelopes. 2

3

4

5

6

A basic concept of Fourier transformation is a projection of XYZ-Cartesian coordinates onto another orthonormal system. We reasoned that we could use a direct projection of any set onto the vector space defined by sets of typical conformer's torsion angles. As a first step, we should make this vector space defined by typical conformers conforming to the IUPAC conformational nomenclature. This procedure amounts to making quantitative representations of visual conformational changes which chemists can intuitively understand.

Canonical vector space and redundancy vector space We define the canonical vector space (a vector space defined by typical conformers) on the basis of a 3-dimensional sphere as qualitatively analyzed by Hendrickson (4). The interrelation diagram among typical conformers can be described as in Figure 1. The two chair conformers occupy the poles and the



268

Figure 1. Spherical representation of pyranose conformations. The equatorial circle corresponds to pseudo-rotation.

pseudo-rotation plane consisting of the skew and boat conformers is situated at the mid-point between the two chairs. Any axis connected to the two chairs is orthogonal to the pseudo-rotation plane in this spherical representation. It is therefore easily realized that this canonical vector space could be represented with three basic canonical vectors. By contrast, the number of components in the set are the six dihedral angles. Note that older qualitative characterizations use two molecular symmetry elements (σ-plane or C -axis). Such qualitative figures give us several hints for making appropriate canonical vectors. That is, each conformer's canonical vector should maintain an adequate symmetry. The presence of symmetry elements means that the sum of components in a canonical vector should be 2


269 equal to 0. Based on these concepts, we define basic canonical vectors shown in Table 1. In order to precisely conform to the IUPAC convention we adopt 60° as a maximum torsion angle value according to Prelog and Cano (5). For fitting to chemist's intuition, we define a transition conformer, a half-chair, that is situated at a middle point between chair and skewboat. In a similar manner, the envelope conformers are situated at a middle point between chair and boat, see E and E in Figure 1. By definition the canonical vector space presented by these vectors is isomorphic to 3 dimensional space. This means any point of canonical vector space can be represented adequately by three fundamental vectors. We can handle canonical vectors with the methods of three dimensional Euclidean space vectors. Any point in this space can be described as in equation 1. 4


4

Ρ is a point in the canonical space. Ec is a vector among chair, envelope, or halfchair basic canonical vectors. Ea, Eb, (Ea Φ Eb, Ec^ Eb, Ec^ Ea) are two arbitrary orthogonal basic canonical vectors. fa, fb and fc are scalar coefficients. Ρ = fa-Ea + fb-Eb + fc-Ec

(1)

Since any vector in this canonical space can be presented by a linear combination of three basic canonical vectors this canonical space is a vector space. Therefore, we can define metric characters, inner product and absolute value in the same manner as those of a vector space. 2

|E| = (Ε, E), |E|>0, an absolute value of vector Ε, (E,E) inner product. We also use another metric character corresponding to an angle between two vectors of Euclidean space. F = (Ε,Ρ)/|Ε|·|Ρ|, 0 Β + f4 Redl + f5 Red2 + f6 Red3

(3)

With equation (3), one conformer is mapped uniquely to the vector space which is built by three canonical basis set vectors and three redundancy basis set vectors. A convenient method of conformational characterization is to use only the first three terms, three canonical basis set vectors in the equation (3). So, a pyranose conformation and a conformational change can be represented with XYZ-coordinates or polar coordinates. As mentioned above, we make a new definition method which has advantages both of quantitative and qualitative methods. Quantitative methods have advantages for illustrating pyranose conformational changes. Our new method inherits this strong point. Distortions from initial conformers can be visually and quantitatively understood with our method from the magnitude and type of distortion. For example we have used this canonical vector space for a constraint in molecular dynamic simulations of pyranose conformation change. Since we are interested in glycosylation reactions we need also to consider bond breaking and bond forming therefore with this quantitative formulation we can use such constraints in quantum molecular dynamics (6).

Section 2 - Permethylated Glycopyranosyl Oxacarbenium Ions - The Two Conformer Hypothesis We confine our discussion in Sections two to four, to glycosylation reactions between pyranose sugars in which one sugar acts as an electrophilic donor reacting with a nucleophilic alcohol. This encompasses most, but not all experimental methods for glycosylation. Early kinetic studies showed that, except for reactions of very strong nucleophiles where true S 2 kinetics could be observed, most glycosylation reactions have considerable S 1 character (7). This strongly implies that glycopyranosyl oxacarbenium ions are likely formed as intermediates or transitions states (TS). In all such cases the anomeric carbon must obtain appreciable sp character. In most donors before activation the anomeric carbon is sp hybridized and in the product glycosides it is also sp hybridized. Therefore as a glycosylation reaction proceeds the anomeric carbon proceeds from sp to sp and back to sp . These changes have pronounced consequences for the conformation of the 6-membered pyranose ring. N

N

2

3

3

3

2

3


273 It should be noted that the classical 5-coordinate anti S 2 TS also requires the anomeric carbon to obtain a transient planar conformation. Although the details are clearly different, the concepts are similar. To describe these ring conformational changes we use the formalism developed in Section 1.


N

In a real glycosylation reaction the donor must be activated by a promoter or catalyst in a solvent. The reaction must also be kept free of adventitious water and any other nucleophiles that could compete with the alcoholic acceptor. As well, the proton of the acceptor must be transferred and some base must ultimately take up these protons. These realities make the reaction much more complicated than our models. However, it is our goal to assess the importance of the pyranose ring conformation especially in the intermediates and TS of the reaction. The progress of glycosylation reactions is difficult to follow experimentally and usually the most one can measure is the disappearance of starting material and the appearance of products as a function of time. Importantly, it is difficult to detect transient intermediates if they are formed. In fact, in most cases all the data that is reported is the overall yield and the α:β ratio of the products. Typically, predominant or exclusive formation of one isomer is attributed to S 2 attack on a reactive intermediate and approximately 50:50 α:β mixtures attributed to non-specific attack on a free oxacarbenium ion i.e. S 1. Thus, it was a great surprise to us to discover that calculated intermediates between glycopyranosyl oxacarbenium ions and the achiral nucleophile methanol exhibited marked stereoselectivity. N

N

Furthermore, in all cases studied to date the calculated intermediate with the lowest energy corresponds to the generally preferred anomer of the product. This unanticipated result led us to completely revise our thinking about the origin of the stereochemistry of glycosylation reactions. How do we calculate these intermediates? First for these examples, we choose O-methyl substituted glycopyranosyl oxacarbenium ions by suitable in silico modifications to optimized chair conformations of the parent per O-methyl glycopyranose. With these species there are no hydroxyls and hence no intramolecular hydrogen bonding. Conformations with intramolecular hydrogen bonding are found as the lowest energy ones by gas phase calculations of neutral monosaccharides and this factor may obscure other factors influencing reactivity (8, 9). 1

Methyl is also the smallest possible protecting group and begins to address the important issue of the effect of protecting groups on reactivity. In agreement with other calculations of permethylated sugars and experimental studies with model compounds, the preferred conformation of secondary O-methyl substituents is to have the methyl carbon syn to the sugar methane (10). These


274 species with these 0-methyl conformations are then subjected to minimization using Density Functional Theory (DFT) calculations. Visual analysis of graphical images of this first optimized structure is then performed to check for side chain orientations. A l l appropriate side chain conformations are altered until a good structure is found which is then checked to be a minima by frequency calculations. These calculations include a continuum solvent (parameterized to CH C1 ) correction and energies are corrected for Zero Point Energy (ZPE). Alternatively, different conformations may be generated by in silico modifications of one of the 38 standard IUPAC conformations of tetrahydropyran followed by the D F T optimization with side chain optimization process described above. These 38 conformations are shown in Table 1 and are available via the Internet at http://www.sao.nrc.ca/ibs/6ring.html.


2

2

The D F T calculations were carried out with the Amsterdam Density Functional (ADF) program system, ADF2000 (11). The atomic orbitals were described as an uncontracted double-ζ Slater function basis set with a single-ζ polarization function on all atoms which were taken from the A D F library. The Is electrons on carbon and oxygen were assigned to the core and treated by the frozen core approximation. A set of s, p, d, f, and g Slater functions centered on all nuclei were used to fit the electron density, and to evaluate the Coulomb and exchange potentials accurately in each SCF cycle. The local part of the V potential ( L D A ) was described using the V W N parameterization (12), in combination with the gradient corrected ( C G A ) Becke's functional (13) for the exchange and Perdew's function for correlation (BP86) (14). The C G A approach was applied self-consistently in geometry optimizations. Second derivatives were evaluated numerically by a two point formula. The solvation parameters were dielectric constant ε =9.03, ball radius =2.4 angstroms, with atomic radii of C=1.7, 0=1.4 and H=1.2 angstroms. x c

As a first example consider 2,3,4-tri-O-methyl-D-lyxopyranosyl cation, 1. Two conformers were found that differ by ring inversion, see Figure 2. One conformer, BO, is the H conformation, long considered a probable conformation for such glycopyranosyl oxacarbenium ions. In terms of the C, Β and S terms (Section 1) it is C , 0.573, B 0.059 and % 0.389 i.e. approximately half a chair and half a twist boat therefore a half chair; H 0.778. The second conformer, B l , has the H conformation which is C 0.580, B 0.100 and S , 0.486 and therefore H 0.972. In this conformation the substituents at 0-3 and 0-4 are pseudo-axial whereas the substituent at 0-2 is pseudo-equatorial. The terms with small coefficients show not only how the dominant conformation is distorted but precisely measure the degree of distortion. 4

3

4

2 5

4

3

3

!

4

3

4

3

4


2 5

275 Considering that axial substituents are normally considered to be destabilizing it is surprisingly that this B l conformer is calculated to be 12.6 kJ mol" more stable than BO. This energy difference is sufficiently high that, i f the barrier separating these conformers is low enough, and the lifetime of these ions is long enough, than B l should be the dominant species present. Specific solvation, ion-pairing, nucleophile preassociation and the effects of different protecting groups are all expected to modify this intrinsic selectivity. Note, for most synthetic purposes even i f all ether protecting groups are used the stereoelectronic effects of protecting groups are expected to have an effect. This result, i.e. two conformers, does give the experimentalist a place to start their analysis from, which is our present goal. Downloaded by PENNSYLVANIA STATE UNIV on June 15, 2012 | http://pubs.acs.org Publication Date: June 15, 2006 | doi: 10.1021/bk-2006-0932.ch011

1

Figure 2. Ball and Stick Representations of2,3,4-tri-0-methyl-D-lyxopyranosyl cation, 1, in its BO andBl Conformations, showing relative energies in kJ mot

Consideration of α or β-nucleophilic attack on BO and B l of 1 leads to four cases to consider. Using methanol as model nucleophile in order to avoid most issues of the stereoelectronic effects of protecting groups of the acceptor on stereoselectivity DFT calculations of the four possible cases were made (15). Values are: l(B0)+aMeOH -19.3 kJ mol" , 1(Β0)+βΜβΟΗ -48.9 (-20.9) kJ mol" \ l ( B l ) + a M e O H -35.6 (-17.6) kJ mol" , 1(Β1)+βΜ6θΗ -64.6 (-36.6) kJ mol" (in brackets corrected for Η-bonding, see below). 1

1

1

The results are best viewed by looking at the spherical representation of the conformations of 6-membered rings, see Figure 3. This shows the changes in conformation from the isolated cation to the ion:dipole complexes. Examination of a number of such complexes has led to the recognition of two important variables (16). One factor is intramolecular hydrogen bonding between the nucleophilic hydroxyl proton and the electronegative atoms of the oxacarbenium ions especially in cases where the species have appreciable hydronium ion character. The relative energetics of this effect are over estimated because intermolecular hydrogen bonding is not considered but it still is considered to be an important factor.


276 Secondly, the change in pyranosyl ring conformation from the isolated cation to the ion:dipole complex can be favorable or unfavorable. In all the isolated cations the C-5-0-5--C-1-C-2 (τ ) torsion angle is nearly planar, for 1 BO it is 10.6° and for 1 B l it is 5.2°. For the D-sugars considered so far, this torsion angle increases for β-attack and decreases for α-attack.


5

For 1 α-attack iomdipole complexes shift the pyranosyl ring conformation by lowering the C-5-0-5--C-1-C-2 torsion angle by 9° and 44.9° for BO and B l respectively. Whereas β-attack raises it by 31.7° and 45.2° for BO and B l . Both β-complexes allow for hydrogen bonding with the BO conformer exhibiting an acutely angled Η-bond to the pseudo-axial 0-2 and for the B l conformer a nearly linear Η-bond to the pseudo-axial 0-3 was found. For α-attack on B l a Η-bond to pseudo-axial 0-4 was found, whereas for aattack on BO no hydrogen bonds were found. Ball and stick representations of these structures are shown in Figure 3. The result of these effects is to put the BO + aMeOH in a Q conformer which is close to the starting H whereas BO + βΜβΟΗ shifts to the less favourable S conformer. This BO + aMeOH conformation is favourable for α-attack but the absence of hydrogen bonding probably underestimates the stability of this complex. 4

4

3

2

0

3

On the other hand the B l + aMeOH is in the unfavourable S i conformation whereas the B l + βΜεΟΗ is in the favourable C chair as well as having a strong intramolecular hydrogen bond. Therefore it is not surprising that this is predicted to be the most stable complex and hence β-glycosides are predicted to be the preferred products. Indeed experimental results with a 2,3,4-tri-Obenzyl-D-lyxopyranosyl donor predominantly give β-glycosides (17). !

4

D-lyxopyranose has the same configurations at C-2, C-3 and C-4 as D mannopyranose and from the results with 1 could be expected to preferentially yield β-glycosides in glycosilation reactions. Since even ether protected D mannopyranosyl donors usually give predominantly α-glycosides this suggests an important stereodirecting role for the substituent at C-5 in hexopyranoses. DFT calculations on 2,3,4,6-tetra-O-methyl- mannopyranosyl cation 2 provide some support for this hypothesis (18). Again two conformers that differ by ring inversion were found for the manno cation. With BO characterized as C 0.566, B , 0.043 and S 0.397 therefore H 0.793 and the inverted B l conformations characterized as *C 0.522, °' B 0.432 and % 0.048 therefore E 0.864 (ΔΕ 1.9 kJ mol' ). The E conformation is near in configurational space to H as visualized on the planar representation of the spherical representation, Figure 4a. The calculated C-5--C-6 torsion angle defined as o (H-5C-5-C-60-6) was found to be -178.7° (gg) for BO and -50.8° (gt) for B l . This shift for B l perhaps reflects the pseudo-axial orientation of 04. 4

!

{

2

5

3

4

3

3

4

3

1

3

3

4

H



277

Figure 3. Planar Representation of the Spherical Representation of Pyranose Ring Conformations Showing the Positions of the Parent BO and Bl Conformers ofl and the results of a- or β-Attack Ball and Stick Representations of the Resulting Ion.Dipole Complexes of 1 and Methanol, showing relative energies in kJ moF . 1



278

b)

\

3,01

5

D

v . H»

^AL.,.

D,

J 4

-'àO

Figure 4ab. Planar Representation of the Spherical Representation of Pyranose Ring Conformations Showing the Positions of the Parent BO and Bl Conformers of 2 and 3 plus the Consequences of a- or β-Attack on Each. Top (a) Man 2 and Bottom (b) 3.


279 For 2 the β-face complexes are calculated to be more stable than those for α-face complexes. Values are: 2(B0)+aMeOH -21.3 kJ m o l , 2(B0)+pMeOH -51.3 (23.3) kJ mol' , 2(Bl)+aMeOH -30.9 kJ mol' , 2(Β1)+βΜβΟΗ -49.5 (-21.5) kJ mol' (in brackets corrected for Η-bonding). Most of this extra stabilization comes from hydrogen bonding to 0-6 even though this forces the ring into a B , 3 (BO) or an inverted C ( B l ) conformations, respectively. The second consequence of hydrogen bonding is a shorter O - C - l bond length. Values are: 2(B0)+aMeOH 1.860 A , 2(B0)+pMeOH 1.498 A , 2(Bl)+aMeOH 1.672 A , 2(Β1)+βΜβΟΗ 1.510 A . 1

1

1

1

0

!

4


m

Previously, we had estimated the energetic contribution of hydrogen bonding to be 28 kJ mol" by calculating for a deoxy analogue in the same conformation as the parent oxygen containing hydrogen bond accepting compound (16). These "corrected" values show the expected trend of α more favorable than β for mannopyranosyl donors. 1

Similar D F T calculations with 2,3,4,6-tetra-O-methyl-glucopyranosyl cation 3 test the effect of the configuration at C-2. Again two conformers were found with 3(B0) characterized as Q 0.507, B , 0.015 and % 0.509 therefore H 1.013 and 3(B1) characterized as *C 0.188, B , 0.117 and S , 0.779 (ΔΕ 4.8 kJ mol' ). In this case S\ is relatively far, see Figure 4b, from H . Examination of Figure 5h shows that this conformation allows 0-2 to be pseudo-equatorial while 0-3, 0-4 and C-6 are pseudo-axial. This limited selection of results suggests that having 0-2 in a pseudo-equatorial conformation stabilizes the oxacarbenium ion. This unanticipated result is a direction for future investigations. 4

4

2

5

3

5

4

1

0

3

5

3

4

Hydrogen bonding is found for 3(Β0)+βΜβΟΗ and 3(Β1)+βΜβΟΗ to 0-6 and for 3(Bl)+aMeOH to 0-4. The corresponding energies are: 3(B0)+aMeOH 43.4 kJ mol' , 3(Β0)+βΜεΟΗ -56.2 (-28.2) kJ mol' , 3(Bl)+aMeOH -55.3 (27.3) kJ mol" and 3 ( B l ) 4 f M e O H -43.0 (-15.0) kJ mol' . Thus, including H bonding shows a preference for β-glycosides whereas without it a preference for α-glycosides. The torsion angle τ is 0.3° for BO changing to -39.5° and 35.3° for a- and β-attack respectively whereas for B l τ changes from -4.6° to -38.1° and 23.3° for a- and β-attack respectively. 1

1

1

1

5

5

For 1 to 3 and for several other sugars (unpublished and below) this trend of finding two conformers for the glycopyranosyl oxacarbenium ions which differ by ring inversion appears to be general. We have named this the Two Conformer Hypothesis. This hypothesis leads to four cases to consider when examining the α:β selectivity. The resulting ion:dipole complexes with the model nucleophile methanol have as distinguishing characteristics intramolecular hydrogen bonding and ring conformational changes characterized by a decrease in C-5-0-5--C-1-C-2 (τ ) 5



280

Figure 5. Ball and Stick Representations of the Ion.Dipole Complexes of 2 (a-d) and 3 (e-h) plus Methanol.



281

Figure 5. Continued.

for α-attack and an increase for β-attack on D-sugars from nearly planar configurations in the isolated cations. These conformational changes may be favorable or unfavorable depending on the conformations involved. These changes depend on the configuration of the sugar and the protecting groups. Among other factors that could be studied, one variable that could be expected to be important is the variation of overall energy with the distance between the nucleophilic oxygen and the anomeric carbon, O — C - l . We have investigated this degree of freedom by systematically varying this "bond length" while allowing all other degrees of freedom to optimize by starting at the minima found in Figure 5 and varying this distance either forward or backward between 1.38 and 3.0 Â in small increments. Figure 6 shows one such study for the case of 3 plus βΜβΟΗ where each data point is a full constrained DFT optimization. We identified several technical problems with this study such as the discontinuities at long C - l - O bond lengths associated with changes in the ring conformation. However, in this case the complex does dissociate to the expected H conformation at long C - l - O bond lengths. Several conclusions can be made from these studies. m

m

4

3

m

In all cases including the one in Figure 6 the minima are shallow as in this case the region from about 1.42-1.68 Â is within 5 kJ mol" of the minimum. As mentioned above, this complex shows considerable hydronium ion character. Indeed at short separations the hydrogen bonded hydroxyl proton transfers to its oxygen acceptor, in this case 0-6. Since many glycosylation reactions are done in the absence of bases this type of intramolecular proton transfer is highly plausible in real reactions. 1


In Carbohydrate Drug Design; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006. 1

2

m

2

Figure 6. Variation of the Energy as a Function of the C-l~O Bond length for Glc 3 Plus β-Methanol. The minimum is set to 0.0 kJ mot . Optimizations include a continuum dielectric correction parameterized to CH Cl .



C j 0.344

C , 0.780

4

5-p

5 -a

B 0.018

B 0.629

M

0 , 3

B 0.495

M

2

% 0.266

2

° S 0.046

2

° S 0.046 4

4

2.298

-

2.222 1.645

E 0.688

-

-

1.632

-

E 0.967

-

m

m

C-1-O Â o °

-

HalfChair Envelope

1

108.1

97.9

-

96.3

107.4

-

Carbohydrate Drug Design - American Chemical Society

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