Glycomimetics: Modern Synthetic Methodologies - American Chemical

Chapter 2

Synthesis of Stable Carbohydrate Mimetics Maarten H. D. Postema, Jared L. Piper, Lei Liu, Venu Komanduri, and Russell L. Betts

Downloaded by FUDAN UNIV on March 11, 2017 | http://pubs.acs.org Publication Date: January 10, 2005 | doi: 10.1021/bk-2005-0896.ch002

Department of Chemistry, 243 Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202

The synthesis of a variety of stable carbohydrate mimetics using a R C M approach is discussed. An esterification-ringclosing metathesis (RCM) approach has been utilized for the preparation of a variety of alkyl and aryl C-glycosides. The synthesis of a number of C-saccharides will also be addressed. Yield optimization studies and the synthesis of the substrates will also be discussed.

© 2005 American Chemical Society

Roy; Glycomimetics: Modern Synthetic Methodologies ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

23

24

Introduction


The goal at the outset of our synthetic carbohydrate program was to develop a unified approach to the synthesis of stable carbohydrate mimetics. CGlycosides, compounds in which the interglycosidic oxygen had been replaced by a carbon atom (Figure 1), are a well known class of stable carbohydrate mimics. Herein, we wish to present a unified and convergent method to gain access to alkyl and aryl β-C-glycosides as well as a variety of β-C-saccharides.

HO

HO

HO HO

HOHO\

H 0

OMe

Acetal linkage Susceptible to acid hydrolysis and enzymatic cleavage (1 ->4)-JJ-0-Disaccharide

HOHOHQOMe

Carbon-carbon bond Stable to acid and enzymatic cleavage β-(1 -^-P-C-Disaccharide

Figure 1. Structures of O- and C-Glycosides

An esterification-RCM protocol is rather well-suited to fulfill this goal. The central scheme in Figure 2 illustrates the strategy. Esterification of olefin alcohol 1 with generic acid 2 should deliver ester 3, which is subsequently converted to the glycal 4, via a two-step protocol. Functionalization of the formed double bond of 4 delivers the target β-C-glycoside 5. The convergence of this approach is obvious and the generality of access to various substrates is only limited by the availability of the required carboxylic acids. There have been several reviews written on the synthesis of C-glycosides (7). The author has made some contributions to this area as well (2-5). This chapter is a summary of an award lecture given by the author at the Fall 2003 A C S meeting held in New York City (6). We consider the esterification reaction to be the cornerstone of our methodology. It is a convergent step that reliably produces the ester in a single and easy to perform step (Scheme 1). This approach would neither be possible, nor conceivable, without the advent of modern olefin metathesis catalysts. Figure 3 shows a few of the most commonly used catalysts. In this work, we initially relied upon Schrock's Molybdenum catalyst 6 (7) to effect the ring closures, but now exclusively rely upon the second generation Grubbs ruthenium catalyst 7 (8). The required olefin alcohols were prepared via a slight adaptation of the literature protocols (9). Kinetic furanoside formation was followed by benzylation (10a —> 11a) and hydrolysis produced the lactols 12a that were subsequently purified by column chromatography. Wittig olefination then



Figure 2. Our Program Plan

C-Glycoglyceroilpfde



26

^ R l

OH

'~*—^

+

H0 C 2

s

Scheme J. Esterification Reaction

I 7-Pr

i-Pr W

T

( F a C f e M e C O ' M o ^ - lMe Me (F C) MeC0 3

k A

2

Mes'

\ Mes

Τ

Mes

CI/,. C l

I Ph PCy 3

PCy

3

6

Figure 3. RCM Catalysts


27 OH H 0

OBn

MeOH, HCl

^ î l . O H ± BnBr, NaH

B ΓgΙ ΟS- Λ^̶& C H s 11a

OH

10a

HCI/H 0 2

OBn

Ph P=CH 3

BnO A _ 1

a

^ '

7

1

T

"ΒηΟ"--\^7 . ΒηΟ-Λ^νΟΗ 0

-

F

Δ

12a 46% over 3 steps

%

BnO


H

OBn 2

/

BnO /

lA^-OH

U\ÔH

1b, 61%

1c, 57%

Scheme 2. Olefin Alcohol Synthesis

afforded the target alkenols l a (Scheme 2). Olefin alcohols l b and l c were prepared in a similar fashion by starting with the approriate pentose sugar. Access to derivatives with protecting groups other than benzyl was also desired. Tri-O-acetyl-D-glucal (13) was deacetylated and benzylated with pmethoxybenzyl chloride to give 14. Cleavage of the olefin in 14 gave formate aldehyde 15. Hydrolysis of the formate ester led to lactol 16 and Wittig olefination then furnished the P M B protected olefin alcohol Id (Scheme 3).

PMBO-^ " ϊ λ

Ο

Q

S

°

4

(

C

a

t

—

R

9>7X^% ROA 1

3

1 4

:

R

:R

=

A

=

ΡΜΒΟΛ

*

Nal0

1. NaOMe, MeOH I 2. N a H , P M B C I , D M F U

Ρ Μ Β Ο - Λ ^ Ο -

)

c

PMB,72%

PMBO*^ PMBO---\ Λ

5. O s O f , N a l 0 -

RO~ 6.NaCI0 [0]

Bnd 3

4

'

7

6

/

θ

4

ROj..

2

3. N a O M e , M e O H

ρ

32:

4. N a H , B n B r , D M F L _

3 3 :

R = A c , 64% R s s B

n,75%

Scheme 9. Keck Allylation Approach to the C-4 Acid

T i C I Z n dust, « — 35: X = 0 , 8 2 % TMEDA, CH Br , PbCI (cat.) »—»*36: X = C H , 5 1 % 4 l

2

2

2

2

Scheme 10. A Low Yielding Sequence


36

1

!

v e b 0

H i toluene, 9 ° -60°C -

2. BH »THF; NaOH, H2O2

RO^ RORO~

_ RO


3

One-Pot Protocol

RO^ ROI OMe

38: R = Bn, R = H, 64% over 2 steps

1. H ,Pd/C I 2. AcgO.pyr.l

1

2

u

39: R = R' = Ac, 94% over 2 steps

Scheme 11. Implementation of the One-Pot Protocol

TiCI , Z n dust, ι — 40: w X = 0 , 92% TMEDA, CH Br , PbCI (cat.) L - * 4 1 X = C H , 67% 4

2

2

2

2

42, 40% with 6 74% with 7

1. ( 7 ) toluene 60 ° C 2. B H - T H F ; H 0 NaOH 3

2

2 l

•

BnO BnO HO 43. 57%

«

Scheme 12. Contrasting Results with Catalysts 6 and 7


37 F Cv.OH 3

X

H C^

Ο

3

F 3

44

20 mol%

BnO-

-α

BnOBnO-

toluene 60 °C

BnO BnO BnO

ο

42 F

3

C

CH

3

45, 18% plus baseline decomposition


Scheme 13. A Possible Explanation

Cyclization of an example with no linking atoms demonstrates the power of this methodology to furnish direct linked or Ι,Γ-linked-C-disaccharides such as 47 (Scheme 14).

BnO-^ Β η θ Λ _ BnO""

46

BnO 0

B

n

OBn

47, 77%

Scheme 14. Synthesis of the Direct-Linked Disaccharide 47

A variety of carbohydrate-based acids were then prepared via the free radical allylation route as shown below in Table 3 (18). These acids were coupled to the appropriate olefinic alcohols and subsequent cyclization produced a small library of differentially-linked β-D-Cdisaccharides (Table 4). The yields for the two-step procedure are good and entry 1 gives a side-by-side yield comparison of both catalysts. In essence, we were able to "walk around the ring" and install acid functionality at any carbon atom and selectively prepare the corresponding C-disaccharide (18).


38 Table 3. Synthesis of the Pyranose Acids entry

alcohol

radical precursor

OAc H O

allyl derivatives '

acid**

11 6

OR

OAc

-^\ô RO. OMe R = Ac, 64% R = Bn, 75%

OMe

A c 0

85%

BnO-X*-Â

RO

AcO-A—Â AcOX OMe

OM@

76%

H

2

Bn

° °\

P

B n O - ^ - ^ A BnOj OMe

R0

OMe

77%


R = Ac, 11% R a Bn, 75%

2 ^ ο

χ

P n - V o ^

P h ^ V o - ^

Ρ Η Ο Ο ( Ι ) θ Λ ^ Λ HΟ O-- Χ ^ Λ ΒζΟ' ΒζΟ» OMe OMe 85%

^

^

^ Λ RO' OMe R = Bz, 62% R = Bn, 94%

κ

b

A c: O *. . 0— AcOA cΟO - Λ

AcO-*.

^

1

A

c

O

I ^

R

O

AcO-XÂ

—

V

P

Λ

RO O -—

χ

^

°

-

OMe

h

^ ^ o

Η 0

2

Glycomimetics: Modern Synthetic Methodologies - American Chemical

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