Stereoselective Glycosylations Using Chiral Auxiliaries - American

Chapter 6

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Stereoselective Glycosylations Using Chiral Auxiliaries Jin-Hwan Kim, Hai Yang, and Geert-Jan Boons* Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602

The stereoselective introduction of a glycosidic bond presents the greatest challenge to complex oligosaccharide synthesis. Important developments such as automated polymer supported oligosaccharide synthesis will not realize their full potential until this problem is addressed. We have developed a novel approach for stereoselective glycosylations whereby a chiral auxiliary at C-2 of a glycosyl donor controls the anomeric outcome of a glycosylation.

Introduction Glycoconjugates are the most functionally and structurally diverse compounds in Nature and it is now well established that protein- and lipid-bound saccharides play essential roles in many molecular processes impacting eukaryotic biology and disease. * Examples of such processes include fertilization, embryogenesis, neuronal development, hormone activities, the proliferation of cells and their organization into specific tissues. Remarkable changes in the cell-surface carbohydrates occur with tumor progression, which 1

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© 2007 American Chemical Society In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

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74 appears to be intimately associated with the dreaded state of metastasis. Furthermore, carbohydrates are capable of inducing a protective antibody response, which is a major contributor to the survival of an organism during infection. Oligosaccharides have also been found to control the development and defense mechanisms of plants. The increased appreciation of the role of carbohydrates in the biological and pharmaceutical sciences has resulted in a revival of interest in carbohydrate chemistry. A major obstacle to advances in glycobiology is the lack of pure and structurally well-defined carbohydrates and glycoconjugates. These compounds are often found in low concentrations and in microheterogeneous forms, greatly complicating their isolation and characterization. In many cases, well-defined oligosaccharides can only be obtained by chemical- or enzymatic synthesis. Although these approaches for obtaining complex oligosaccharides are plagued with problems, synthetic compounds are increasingly used to address important problems in glycobiology research and for vaccine and drug discovery.

Recent Progress in the Synthesis of Complex Oligosaccharides Despite complex oligosaccharides synthesis is plagued by problems, significant improvements have been made during the past decade. " New leaving groups for the anomeric center have been developed, which can be introduced under mild reaction conditions and are sufficiently stable for purification and storage for a considerable period of time. The most commonly employed glycosyl donors include anomeric fluorides, trichloroacetimidates, and thioglycosides. The glycal assembly strategy, the use of anomeric sulfoxides and dehydrative glycosylation protocols are also emerging as attractive tools for the assembly of complex oligosaccharides. Convergent synthetic strategies that allow the convenient assembly of complex oligosaccharides from properly protected building units involving a minimum number of synthetic steps have become available. Methods for solid phase oligosaccharide synthesis have been reported and these procedures shorten oligosaccharide synthesis by removing the need to purify intermediate derivatives. Recently, automated solid-phase synthesis was used for the preparation a branched dodecasaccharide. For this purpose, an automated peptide synthesizer was re-engineered to allow repetitive chemical manipulations at variable temperatures. An acceptor substrate was attached to a 1% cross-linked polystyrene resin that was modified by an octenediol linker. Trichloroacetimidates were employed as glycosyl donors in combination with acetyl esters as temporary protecting groups. At the end of the coupling cycles, the linker could easily be cleaved by an olefin cross metathesis to give a protected saccharide as a pentenyl glycoside. The need for increasingly 4

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In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

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efficient methods for oligosaccharide synthesis has stimulated the development of enzymatic methods. " These enzymatic methods bypass the need for protecting groups since the enzymes control both the regio- and stereoselectivity of glycosylation. 4

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The Problem of Anomeric Control in Glycosylations The stereoselective introduction of a glycosidic linkage is one of the most challenging aspects in complex oligosaccharide synthesis. The nature of the protecting group at C-2 of a glycosyl donor is a major determinant of the anomeric selectivity. A protecting group at C-2, which can perform neighboring group participation during a glycosylation, will give 1,2-trans glycosides. On die other hand, 1,2-cis glycosides can be obtained when a non-assisting functionality is present at C-2. In these glycosylations, the reaction conditions (e.g. solvent, temperature, and promoter) as well as the constitution of the glycosyl donor and acceptor (e.g. type of saccharide, leaving group at the anomeric center, protection and substitution pattern) will determine the anomeric selectivity. In general, efforts to introduce 1,2-cw glycosides lead to mixtures of anomers. Separation of these anomers requires time-consuming purification protocols resulting in loss of material. It also limits the use of one-pot multi-step glycosylations ' and automated polymer-supported synthesis. ' The stereoselective formation of 1,2-c/s glycosides is one of the principal challenges of complex oligosaccharide synthesis. The next section will provide a brief overview of the most important methods for controlling anomeric selectivity in glycosylations. The most reliable method for the introduction of 1,2-trans glycosidic linkages is based on neighboring group participation of a 2-O-acyl functionality. In these glycosylations, a promoter (A) activates an anomeric-leaving group, which results in its departure and the formation of an oxacarbenium ion. Subsequent, neighboring group participation by a 2-O-acyl protecting group leads to the formation of a more stable dioxolenium-ion. Attack of an alcohol at the anomeric centre of the dioxolenium-ion results in the formation of a 1,2trans glycoside (Scheme la). Thus, in the case of glucosyl-type donors, p-linked products will be obtained while mannosides will give a-glycosides. The neighboring group assisted glycosylation procedures are compatible with many different glycosylation protocols and anomeric leaving groups. In some glycosylations, the alcohol may attack at the C-2 position of the dioxolane-ring of the dioxolenium-ion, resulting in the formation of an undesired ortho-ester. Ortho-ester formation may be prevented by the use of a C-2 benzoyl- or pivaloyl group. In some cases, the glycosylation may also proceed via the oxacarbenium ion leading to mixtures of anomers. 19,20

21

22 23

15,24 25


76 1,2-cw-Glycosides can be synthesized when a non-assisting functionality is present at C-2 of a glycosyl donor. In general, these glycosylations require optimization of reaction conditions such as solvent, temperature, and promoter to achieve acceptable anomeric selectivities. The first procedure for the selective formation of 1,2-cis glycosides such as a-glucosides and a-galactosides was introduced by Lemieux and coined 'the in-situ anomerization procedure' (Scheme lb). In this type of glycosylation, an activator catalyzes an equilibration between an a- and p-halide. This equilibrium is shifted strongly towards the ahalide since this compound is stabilized by an endo-anomeric effect. However, the energy barrier for nucleophilic attack by an alcohol is lower for the P-halide leading to the formation of an a-glycoside. An important requirement of this reaction is that the rate of equilibration is much faster than that of glycosylation. High a-anomeric selectivities have been obtained with other anomeric leaving groups. Although the reaction mechanisms of these glycosylations have not been studied in detail, it is reasonable to assume that they proceed via an in-situ anomerization process and probably a- and P-ion pairs are formed as reactive intermediates. P-Linked mannosides are another class of cw-glycosides that are difficult to introduce in a stereoselective manner. These glycosidic linkages have been introduced by the activation of a-halides with insoluble silver salts (Scheme lc). In this case, anomerization of the halide is restricted because of the absence of nucleophiles in the reaction mixture. Therefore, these glycosylations proceed with inversion of configuration. Silver silicate and silver silicatealuminate have been applied as heterogeneous catalyst. Recently, P-mannosides have been prepared in a highly stereoselective manner by an intramolecular aglycon delivery approach (Scheme Id). ' In this approach, the sugar alcohol (ROH) is first linked via an acetal or silicon tether (Y = C H , methoxybenzylidene or SiMe ) to the C-2 position of a mannosyl donor. Subsequent activation of the anomeric centre of this adduct forces the aglycon to be delivered from the P-face of the glycosyl donor. The research group of Crich has pioneered an attractive approach for the introduction of P-mannosides by the in-situ formation of an anomeric triflate (Scheme le). " This triflate is only formed as an a-anomer because of a strong endo-anomeric effect. An S 2 likedisplacement of the a-triflate by a sugar hydroxyl will result in the formation of a P-mannoside. A prerequisite of p-mannoside formation is that the mannosyl donor is protected by a 4,6-O-benzylidene acetal, which opposes oxacarbenium because of torsional strain engendered on going to the sofa conformation of this intermediate. This method has been extended to the introduction of prhamnosides. ' A participating solvent can also control the stereochemical outcome of a glycosylation. A marked example is the use of acetonitrile, which in many cases leads to the formation of mainly equatorial glycosidic bonds (e.g. P-glucosides and P-galactosides). Several groups have independently proposed that this


26

7,27

28 31

2

2

32

36

N

37 38

6


77 reaction proceeds via an a-nitrilium ion. Nucleophilic substitution of the nitrilium ion by an alcohol will lead to mainly, but not exclusively, p-glycosides (Scheme If). The use of diethyl ether as a solvent is known to increase the aanomeric selectivity of glycosylations. 39


(a) Preparation of 1,2-trans glycosides by neighbouring group participation

?

O

X

to

(b) Preparation of a-glycosides by in situ anomerization ROH

\

ROH

-0

.Br

B n OOR L

BnO

Br

(c) Preparation of p-mannosides by using insoluble silver salts BnO^

BnO Br

BnO

HOR

Q

Br,

(d) Synthesis of p-mannosides by intra molecular aglycon delivery Y

0' X)R .OR

(e) Introduction of p-mannosidic linkage by in-situ formation of an a-triflate BnO

BnO

Tf 0 2

OR S(0)Ph

QTf

(f) Preparation of p-glycosides by participation of the solvent acetonitrile CH CN 3

-O

^

O

N=C-CH

3

Scheme 1. Methods for the stereoselective formation ofglycosidic linkages.


78

Stereoselective Glycosylations Using Chiral Auxiliaries We have developed a novel approach for stereoselective glycosylations using a chiral auxiliary at C-2 of a glycosyl donor (Schemes 2a, b). The auxiliary is a C - l substituted ethyl moiety that contains a nucleophilic group (Nu). Upon formation of an oxacarbenium ion, the nucleophilic moiety of the auxiliary will participate, leading to the formation of either a trans- or cisdecalin system. It is expected that an auxiliary with S-stereochemistry will lead only to the formation of /rara-decalin since the alternate cw-fused system will place the phenyl-substituent in an axial position inducing unfavorable steric interactions (Scheme 2a). Subsequent displacement of the anomeric moiety of the fraras-decalin intermediate will lead to the formation of a 1,2-cw glycoside. Alternatively, the use of an auxiliary with #-stereochemisty will lead to the formation of a l,2-/ra«,s-glycoside because in this case the /raw-decalin system will experience unfavorable steric interactions. Therefore glycosylation will only take placefromthe cw-decalin intermediate (Scheme 2b). Ethyl mandelate was explored as a first generation chiral auxiliary because both enantiomers of this compound are readily available. Furthermore, esters are


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(a) Neighboring group participation by an S auxiliary at C-2 leading to 1,2-c/s glycosides

0

- A

Prr—i

0 R

ph< —Nu 1,2-c/s glycoside

ROH

X

(b) Neighboring group participation by an R auxiliary at C-2 leading to 1,2-trans glycosides ROH

act* PlK

Ph LA

>—Nu

-Nu R-configuration

P h

" N

— -Nu

O

1,2-trans glycoside

HJT

A

V—10 Ph

A = activator, Nu = nucleophile, L = leaving group

Scheme 2. New approaches for stereoselective glycosylation


79 well-established as appropriate participating functionalities in glycosylations and the benzylic nature of the auxiliary will make it possible to remove it under reductive conditions. Glucosyl donors 5R and 5S, containing a (/?)- or (S)ethoxycarbonylbenzyl moiety, xould be prepared by an efficient procedure starting from the readily available epoxide l . Thus, reaction of 1 with ethyl Rmandelate in the presence of BF -OEt led to a fraw-diaxial opening of the epoxide to give 2R in a yield of 48%. Next, acetolysis of the 1,6-anhydro-bridge of 2R with acetic anhydride and catalytic amount of TMSOTf gave compound 3R in an almost quantitative yield. The anomeric acetyl group of 3R could be selectively removed with hydrazinium acetate to give hemiacetal 4R, which could be converted into trichloroacetimidate 5R using trichloroacetonitrile in the presence of DBU. Glycosyl donor 5S could be prepared by a similar protocol using ethyl 5-mandelate as the starting material (Scheme 3). 4 1


3

2

8

°v

^OAc

lH

Ph

OBn

OB

TMSOTf

pS7

(48%) 2R/S

J p

B n O ^ ,

(93%)

Q

R

1 C0 Et

n

2

H NNH HOAc (95%) 2

2

CI CCN/DBU (92%) 3

£

Z

R

/

S

R

=

A

c

4R/S: R = H U s f V S : R = C(NH)CCI

3

Bn = benzyl, DBU = 1,8-diazabicydo[5.4.0]undec-7-ene, TMSOTf = trimethylsilyl trifluoromethanesulfonate.

Scheme 3. Preparation ofglycosyl donors 5R/S Coupling of 5S with 9 using a catalytic amount of TMSOTf in dichloromethane at -78°C gave disaccharide 14S mainly as the a-glycoside in an almost quantitative yield. As expected, coupling of 5R with 9 under similar reaction conditions gave 14R mainly as the 0-anomer. The fact that an inversion of configuration of the asymmetric center of the auxiliary led to a reversal of the stereochemical outcome of the glycosylation provided strong support for the proposed mode of participation. In order to demonstrate the generality of the approach, a range of glycosyl acceptors was glycosylated with 5R and 5S. In each case, a glycosylation with glycosyl donor 5S gave mainly an a-anomer whereas the use of 5R led to the formation of p-anomers. It is well known that the protecting group pattern of a glycosyl donor can influence the anomeric outcome of a glycosylation. Therefore, the glucosyl donors 6R/S, 7R/S and 8R/S were prepared which have a benzoyl ester, an allyloxycarbonate or an allyl ether at C-3, respectively. These glycosyl donors


80 were expected to be convenient for complex oligosaccharide synthesis because the C-6 acetyl ester can be removed in the presence of a benzoyl group whereas the allyl- or allyloxycarbonyl protecting group can be cleaved without affecting the acetyl group at C-6. These glycosyl donors could easily be prepared from the key intermediates 2R/S.


Table 1. Stereoselective glycosylations with glucosyl donors 5R/S, 6R/S, 7R/S and 8 R/S OAc

OAc

-OAc

BnO Bzi

X

o

BnO AIIO-*-^^

BnO , AllocO

cr "cci

0

Phy-

3

C C ,

Ph^/°

3

CO 0 Et

C0 Et

C0 Et

6R/S

7R/S

8R/S

2

C C

°

'

3

2

2

^OH ^ O B n / \ ^ ^ M

OH

OH BnO Bn

Stereoselective Glycosylations Using Chiral Auxiliaries - American

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