Conformational Equilibria of Acylated Aldopentopyranose Derivatives

9

Conformational Equilibria of

Acylated

Aldopentopyranose Derivatives and

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on March 7, 2016 | http://pubs.acs.org Publication Date: June 1, 1973 | doi: 10.1021/ba-1971-0117.ch009

Conformations of

Acyclic

Favored

Sugar Derivatives

P. L. DURETTE, D. HORTON, and J. D. WANDER The Ohio State University, Columbus, Ohio 43210

By using low-temperature NMR spectroscopy and averaging of spin couplings, the relative proportions of the two chair conformers in solution were determined for various configurational series of acylated aldopentopyranosyl halides, glycosides, esters, and thioesters. The effects on these equilibria of solventpolorityand the nature of the aglycon in the glycosides have been examined and are discussed in terms of steric and electronic interactions between substituent groups in their influence on conformational equilibria and rate of conformational inversion. In acyclic systems, NMR-spectral studies show that the extended, planar, zigzag arrangement of the carbon atoms in the sugar chain is the favored conformation in solution except when such an arrangement would generate a parallel, 1,3-interaction between substituents. In the latter situation, the interaction is alleviated by rotation about a C—C bond to give a bent (sickle) form as the favored conformation.

'Tphe conformational studies ( I ) on acyclic sugar derivatives and on aldopentopyranose derivatives that have been conducted i n our labo ratories during the last few years are surveyed, and some of our more recent results in each of these areas are introduced. For each aspect the sugar derivatives were examined i n solution by proton magnetic reso nance ( P M R ) spectroscopy, and the data obtained were used to provide conformational information. Acyclic systems w i l l be treated first. 147 Isbell; Carbohydrates in Solution Advances in Chemistry; American Chemical Society: Washington, DC, 1973.

148


Acyclic

CARBOHYDRATES IN SOLUTION

Systems

It has long been supposed that a hydrocarbon chain favors an ex tended conformation i n which the carbon atoms lie i n an approximate plane in a zigzag arrangement that results from maximum separation of the largest groups along each carbon—carbon bond. This rationale for unsubstituted chains has been widely used to express conformational formulas for acyclic sugar derivatives by simple extension of the prin ciple of assigning favored conformations that agree with the maximum staggering of small-medium-large sets of groups along each carbon—car bon bond i n the chain (2). However, direct chemical or physical evi dence for such assignments until recently has been largely lacking, except for a few experiments on reactivity of acyclic sugar derivatives that are not necessarily valid as a direct measure of the conformation i n the ground state. A point that is particularly questionable is the conforma tional behavior of extended-chain systems i n which there would be two substituent groups, separated by one intervening carbon atom, on the same side of an extended chain—namely, a parallel 1,3-relationship of sub stituent^. Such an arrangement bears a formal resemblance to the syndiaxial disposition of these substituents on a six-membered ring, a situation that is conformationally unstable. To test experimentally the validity of the planar, zigzag rationaliza tion of conformation i n acyclic-sugar systems, various types of derivatives having acyclic sugar-chains present were examined by P M R spectroscopy. To obtain satisfactory dispersion of the signals of the methine and methyl ene protons on the chain, acyclic sugar derivatives having dissimilar end-groups were utilized. In each instance these spectra were recorded at a field strength sufficient to allow reliable spin-couplings to be deter mined, either by first-order approximation or by appropriate calculation, and the spin couplings are accurate to within ± 0 . 3 H z or better. The first example illustrated (Figure 1) is a quinoxaline derivative, having a four-carbon, acetylated carbohydrate chain attached to it. The

H

Figure 1. 2-(O~3Lrabino-Tetrahydroxybutyl)quinoxaline ],>,,.

]f,y J,..*.'

3.0

Hz

8.5 HZ 3.0 Hz

J,., . ih

5.5

Hz

Jia'.ib' 12.0 Hz

Isbell; Carbohydrates in Solution Advances in Chemistry; American Chemical Society: Washington, DC, 1973.


9.

DURETTE ET AL.

Conformational Equilibria

149

chain has the arabino stereochemistry, and from the small coupling of the protons at positions 1' and 2' of the side chain, it can be inferred that these protons are i n gauche disposition, whereas protons 2' and 3', which show a large spin coupling of 8.5 H z , are evidently i n antiparallel dis position. Consideration of these and the other couplings for the com pound i n chloroform solution leads to the conclusion that the favored conformation of the chain is as shown in Figure 1 and corresponds to a planar, zigzag arrangement of the carbon atoms i n the chain, resulting from maximum staggering of large-medium-small sets of groups along each carbon—carbon bond (3). Before this rationalization obtained with one example is extended to other systems, it should be remembered that this compound has the arabino stereochemistry, and in the extended conformation it has no par allel 1,3-interaction between acetoxyl groups. To make generalizations on the conformational behavior of such derivatives and obtain data that might be extended to other systems, it is important to study systems having other configurations. This was performed initially with a series of triazole derivatives having a sugar chain attached, by varying the stereochemistry in the side chain (4).

favored

Figure 2.

Destabilization by 1 ^-interactions

In the triazole derivatives having a tetrahydroxybutyl side-chain, the behavior of the L-xt/Zo derivative is noteworthy. Figure 2 shows that the observed spin-coupling of H - l with H-2 on the side chain is 5.6 H z . However, the fully extended conformation of the carbon chain in such a system would bring H - l and H-2 into gauche disposition, and for this arrangement a small value of Ji would be expected. The magnitude actually observed indicates that there is a substantial contribution from 2



H

H

H

w

SEt H

rib o

lyxo

xylo

SEt

OAr H H SEt

H AcO H

H OAc H

H

H

Figure 3.

SEt

v

N%

H

a

H

H

*S

%

H

H

AcO

\Τ

V

SEt

SEt

SJEt^H

OAC

S E t JH

OAc "H

manno

H'

H AcO

galacto

Ή

H AcO

OAc

\J

H AcO S E t

arabino

AcO yH C

HI

w/

X

AcO

x

AcO

AcO

AcO

SEt

OAc

H

SEt

Conformations of dithioacetal peracetates

favored

H

EtS'

favored

AcO

AcO'

H

favored

AcO,


ο

I

ο

ο

9.

DURETTE ET AL.


151


a conformation having H - l and H-2 antiparallel, as shown in the lower part of the figure; such a bent conformation is called a sickle conformation since the chain of carbon atoms is bent around so that, in this example, the carbon atom of the aryl system can be considered as the point of the sickle and C-3 and C-4 of the side chain constitute the handle. Results entirely analogous to these have been observed with the corresponding acetylated derivatives of these substituted triazoles (5). Extending these studies to systems not having a heterocycle at the end of the chain, a series of dithioacetal peracetates was examined (6). Generally, (Figure 3) these derivatives adopt favored conformations having the fully extended, planar zigzag chain only when such an ar rangement would not lead to a parallel 1,3-interaction between substit uent groups. Extended zigzag conformations are indicated by the spincouplings in the arabino, galacto, and manno series. However, the coupling data for the ribo, xylo, and lyxo derivatives were not consistent with the fully extended arrangement. For example, in the ribo series, the / , 4 coupling was small, corresponding to a gauche disposition of H-3 and H-4 and not to the antiparallel arrangement required i n the extended conformation. The favored conformation shown is a sickle form derived from the extended form by rotating C-5 out of the plane of the other carbon atoms so that it becomes the point of the sickle. Likewise, i n the xylo series a sickle conformation is adopted. In this instance it is C - l that is rotated out of the plane of the other carbon atoms. This operation gives rise to the conformation shown in which the protons at C-2 and C-3 are essentially antiparallel, which agrees with the large coupling con stants observed; the extended arrangement would have led to a small value for / , . In the lyxo series it is one of the end groups that is in 1,3interaction with the acetoxyl group at C-3 in the fully extended conforma tion, and the value observed for J agrees with a favored conformation in which there is rotation about the C - l - C - 2 bond to alleviate this interaction without generating another similar one. 3

2

3

lt2

Closely similar results were obtained with various diphenyl dithio acetal acetates (7), with the unsubstituted diethyl dithioacetals (8), and with the aldehydo-pentose peracetates (9) and the tetra-O-acetylaldopentose dimethyl acetals (10). Subsequent work in other laboratories has shown the same general principles for the methyl 5-hexulosonates (11) and the pentononitrile tetraacetates (12), two examples where a full series of stereoisomers has been studied. Other workers have investigated isolated examples or partial series (13, 14, 15, 16, 17, 18), and parallel work by x-ray crystallography (19, 20, 21, 22) on acyclic sugar deriva tives in the solid state has shown excellent correlation with the general principles outlined here for the molecules in solution. Some results of a recent collaborative study (10) on the tetraacetates of the aldopentose dimethyl acetals are shown in Table I. The arabino


152

C A R B O H Y D R A T E S IN SOLUTION

Table I.


Compound

Configuration

1

ribo

2

arabino

3

xylo

4

lyxo

HC(OMe)

3

6

The 2,3,4,5-Tetra-O-Acetylpentose Dimethyl

b

2

3a

From 220-MHz spectrum at ambient temperature, measured in chloroform-d.

derivative favors the fully extended form, whereas the ribo and xylo derivatives adopt sickle conformations as the favored forms. The lyxo derivative adopts a favored conformation derived from the fully extended form by rotation about C - l - C - 2 to a rotamer having H - l and H - 2 antiparallel as the favored, but not exclusive, form. These conformational tendencies have also been correlated with the ease of irreversible cyclization of various acyclic derivatives (23, 24).


9.

Conformational

DURETTE E T AL.

Acetals i n Solution

153

Equilibria

0


Coupling Constants, Hz Jl,2

J2.3

J3.4

J4.5

J4.6'

J

6.5

3.9

5.5

2.5

6.3

12.2

6.7

2.6

8.3

2.9

5.1

12.3

5.5

4.7

5.4

4.3

5.9

12.0

5.6

6.5

3.3

4.4

6.3

11.6

HC(OMe)

I

AcO

2

5.5'

Η

Ην

OAc

OAc

HCOAc

OMe

I AcOCH

I

H''

^ H H / ^ M e O '

>H

AcOCH

I

2a

CH OAc 2

HC(OMe)

I

H

2

v

AcO

OAc

η

OAc

AcOCH I AcOCH

I HCOAc

I CH OAc 2

a

4

From 100-MHz spectra at ambient temperature, unless otherwise stated.

Thus, when the aldopentose diethyl dithioacetals are treated with 1 mole of p-toluenesulfonyl chloride i n pyridine, cyclization to form a 2,5-anhydride is observed i n each instance except i n the arabino series, where a 5-O-p-tolylsulfonyl derivative can be isolated. It may be supposed (23) that the energy of activation for the cyclization reaction, being the differ ence between the ground-state and the transition-state energies, is smaller in those stereoisomers where conformational factors bring 0 - 2 into close



154


proximity with C-5 in a low-energy conformation. In the arabino series, extra energy has to be expended to bring the molecule from its favored, extended conformation into an orientation in which 0-2 approaches C-5 from its rear side to permit displacement of the p-tolylsulfonyloxy group. For the arabino derivative there is an additional elevation of the transitionstate energy for cyclization because of the necessity to develop the a l l syn arrangement of three substituents at the ring-closure step. A related study on ring closure (24), this time under conditions of acid-catalyzed methanolysis, is illustrated in Figure 4, which shows a recent collaborative effort. The four stereoisomeric 1,2-O-isopropylidene5-O-p-tolylsulfonylaldopentofuranoses were refluxed in methanolic hydro gen chloride. W i t h i n a few minutes each starting material had become converted into an anomeric mixture of methyl 5-O-p-tolylsulfonylaldopentofuranosides. Further refluxing of this mixture for 5 hours led, as illustrated in the lyxo series, to the corresponding 2,5-anhydropentose dimethyl acetals. A high yield of this product was obtained in the lyxo series after 5 hours, and the xylo series behaved likewise; in the ribo series a similar result was observed although the yield of product was somewhat lower. However, in the arabino series the product after 5 hours was exclusively the mixture of pyranosides, and none of the 2,5-anhydride could be detected. In the arabino series it was necessary to extend the period of reflux to 72 hours to obtain the 2,5-anhydro dimethyl acetal, even in very low yield. This observed difference in behavior as a func tion of configuration can again be interpreted in conformational terms. In this instance the relative transition-state energies for ring-closure are presumably the most significant. Since, in at least two of these examples, it would be impossible for the anhydride ring to form from the furanose precursor directly, it can be supposed that the small proportion of d i methyl acetal statistically present in equilibrium with the more favored furanoside undergoes irreversible ring-closure to form the 2,5-anhydride, and that the steric requirements for the ring closure are particularly unfavorable for the arabinose derivative. Cyclic

Systems

Our studies on cyclic systems set out to answer questions such as the following, with respect to multisubstituted tetrahydropyran rings: (a) What effect does the heteroatom have on the conformational behavior? (b) Are sugars and their derivatives in rapid conformational equi librium in solution? (c) Are steric effects additive? The general type of molecule studied is shown i n Figure 5. In the 2,3,4,5-tetrasubstituted, tetrahydropyran ring-system the anomeric sub-


9.

DURETTE ET AL.

Conformational

155

Equilibria

stituents ( R ) were systematically varied by the groups O A c , O B z , O M e , halogen, and SAc while the substituents at the other three positions were acetoxyl or benzoyloxyl groups. Again the key tool was P M R spectroscopy, and particular emphasis was placed on comparing behavior throughout various whole series of stereoisomeric examples.


MeOH, HCI 5min. TS0H2C] HO

[0

OMe TsOH, HO

0-CM82

HC(OMe) 2

MeOH, HCI 5hr.*

OH

OH

(lyxo)

Fost

Fast

Slow

Very Slow

Figure 4. Ring closure of the four stereoisomeric l,2-0-isopropylidene-5-0-ptolylsulfonyhldopentofuranoses

OAc

Figure 5. 2,3,4,5-Tetrasubstituted, tetrahydropyran ring-system


156


First, the anomeric equilibria of the aldopentopyranose tetraacetates were examined by N M R spectroscopy and by optical rotation (25). Each of the acetylated anomeric forms of the aldopentopyranose tetraacetates was allowed to attain equilibrium in a 1:1 mixture of acetic anhydride and acetic acid containing perchloric acid as a catalyst (Table I I ) . The


Table II. Anomeric Equilibria of D-Aldopentopyranose Tetraacetates at 2 7 ° C in 1 : 1 Acetic Anhydride-Acetic Acid, 0.1 Ai in Perchloric Acid Equilibrium constant Κ = β/α

AG°, kcal mole' , for a A c O > A c S ) , it was interesting to retain the same atom directly attached to the anomeric position and to vary the nature of the attached substituent. Table X shows the conformational behavior of the analog of β-D-xylopyranose tetraacetate in which the 1-acetoxyl group has been replaced by a benzoyloxyl group (46). The data (46) indicate that 3 9 % of the mole cules exist in the all-axial conformation, as compared with only 2 8 % i n this conformation for β-D-xylopyranose tetraacetate. It can be inferred that the axial-directing effect of the benzoyloxyl group is higher than that of the acetoxyl group, and for the series of derivatives having a β-D-xylopyranose structure, the relative order of axial-directing effects of the 1-substituent falls i n the order halogen > O B z > O A c « SAc. Such a trend is not necessarily adopted for other configurations. In the next example (Table X I ) the effect of changing the substit uents at the secondary positions on the ring is examined. The compound has the same overall structure as that in Tables I X and X , except that now all of the four substituents are benzoyloxyl groups. The equilibrium data indicate that the all-axial I C (D) conformer is present in an approxi mate 1:1 equilibrium with the all-equatorial CI form. Since the all-axial form occurs to the extent of 5 1 % , as compared with only 3 9 % for the corresponding tri-O-acetyl 1-benzoate and only 2 8 % for the correspond ing tetraacetate (25), this indicates that the replacement of acetate groups around the ring by benzoate groups correlates with an enhancement of




ic

^

ci

Figure 11.

Conformational equilibria for the


9.

DURETTE E T AL.

Conformational

1C


169

Equilibria

Cl fi

-ο

-ribo

1C

Cl /B-O-orobino

H

OAc

1C

H

Cl S

-0-//XO

eight Ό-aldopentopyranose tetraacetates


170

CARBOHYDRATES

Table VII.

Configuration

SOLUTION

Conformational Equilibria of D-Aldopentopyranose Tetraacetates in Acetone-rfe at 31°C Equilibrium AG°T, Constant kcal mole~ , for Κ = C1/1C 1C(D))

Configuration

(cis)

Joe, 5a

Q-D-arabino

1.0

-13.2

0.04

(χ-Ό-arabino

2.0

-13.0

0.26

$-O-lyxo

3.3

-12.4

0.63

$-O-ribo

3.4

-12.4

0.74

(x-O-lyxo

4.4

-11.6

2.5

Q-v-xylo

4.9

-11.8

2.6

(x-O-ribo

4.7

-11.2

3.4

50


9.


Table IX.

171


DURETTE ET AL.

Temperature Dependence of the Conformational Equilibrium for β-D-Xylopyranose Tetraacetate in Acetone-tie

$-O-Xylopyranose Tetraacetate J 1,2, Hz 7.5 7.3 7.1 7.0 6.6 6.4 6.3

Temperature*, degrees C -65 -49 -25 -16 +37 +62 +68 a 6

b

Within ±2°C. Within dzO.l Hz.

Table X .

2,3,4-Tri-O-Acetyl-1 -0-Benzoyl-/?-D-Xylopyranose Η

OBz

Η

1Ç

Coupling Constants, Hz ~r

]

'

Jl 2

Α

5.9

Cl

Equilibrium

7~

'

δ

Αδ

4.5

7.7

β

κ K

Constant 0

1

"le 1.6

AG° (kcal)

J^ôïë)

-0.28

Order of size of axial-directing effect for various aglycons in the §-xylo series : Halogen > O B z > OAc « SAc a

100 M H z , (CD ) CO, 31°C. 3

2


172

CARBOHYDRATES


Table XI.

IN

SOLUTION

β-D-Xylopyranose Tetrabenzoate"

Coupling Constants, Hz

Equilibrium

Constant

AG° (kcal) (mole)

5.1 a

6.7

4.0

6.6

+0.01

0.98

100 M H z , (CD ) CO, 31°C. 3

2

the axial-directing effect of the substituent at C - l . In related studies some other examples of the same general effect i n which the axial-directing effect of the 1-substituent seems greater when the ring substituents are changed from acetates to benzoates have been noted. Such instances include the acylated methyl aldopentopyranosides (47) and various halides (29). F o r example, tri-0-benzoyl-/?-D-xylopyranosyl chloride exists in chloroform-d to greater than 9 5 % i n the all-axial form, as compared with about 8 0 % with the tri-O-acetyl analog (29). W h e n the equilibrium positions for the peracetylated aldopentopyranoses are compared with those for their perbenzoylated analogs ( Table X I I ) , a general overall correlation suggests that the syn-diaxial arrangeTable XII.

Comparison of Equilibrium Positions for the Peracetylated and Perbenzoylated Aldopentopyranoses

(a)

$-O-xylo, §-O-ribo, and perbenzoates

(b) (χ-Ό-arabino and

Conformational Equilibria of Acylated Aldopentopyranose Derivatives

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