Synthesis of glucuronic acid derivatives via the efficient and selective removal of a C6 methyl group

Accepted Manuscript Synthesis of glucuronic acid derivatives via the efficient and selective removal of a C6 methyl group Zhuang Hou, Yang Liu, Xin-xin Zhang, Xiao-wei Chang, Mao-sheng Cheng, Chun Guo PII: DOI: Reference:

S0040-4039(16)31690-2 http://dx.doi.org/10.1016/j.tetlet.2016.12.055 TETL 48467

To appear in:

Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

24 October 2016 14 December 2016 19 December 2016

Please cite this article as: Hou, Z., Liu, Y., Zhang, X-x., Chang, X-w., Cheng, M-s., Guo, C., Synthesis of glucuronic acid derivatives via the efficient and selective removal of a C6 methyl group, Tetrahedron Letters (2016), doi: http:// dx.doi.org/10.1016/j.tetlet.2016.12.055

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1

Synthesis of glucuronic acid derivatives via the efficient and selective removal of a C6 methyl group Zhuang Hou, Yang Liu,* Xin-xin Zhang, Xiao-wei Chang, Mao-sheng Cheng, Chun Guo* Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016 China (Received , ; CL-; E-mail: [email protected] (Y. Liu), [email protected] (C. Guo))

Abstract This investigation is related to the development of a general strategy for the synthesis of certain glucuronic acid derivatives. In particular, we report exceptionally selective conditions for removing the C6 methyl protecting group by potassium hydroxide without affecting the benzoyl protecting groups on the C2, C3 and C4 hydroxyl groups in high yields (95%–99%). The present method proves to be efficient and environmentally friendly in terms of short reaction time, high yield and the single product.

Keywords: Glucuronic acid; Potassium hydroxide; Selective deprotection Introduction Glucuronic acids are ubiquitous in many biological systems and play a vital role in diverse physiological functions. What’s more, functionalized glucuronic acid derivatives are used as valuable building blocks in the synthesis of glycoproteins, glycolipids and natural products which have biological function 1-5. As a result, there are various efforts aiming at developing efficient and mild methods for the synthesis of glucuronic acid derivatives. The synthesis of glucuronic acid is traditionally achieved by the oxidation of the C6 primary alcohol of a monosaccharide to the corresponding C6 carboxylic acid 6. However, these methods are associated with several limitations such as usage of oxidant, generation of several side products, or unsatisfactory yields. Recently, Murphy and co-workers reported that glucuronic acid azide 2 can be prepared from azide 1 by saponification of all of the esters and subsequent acetylation for six days 7, 8 (Scheme 1, upper part). Although this method paved the way to prepare glycosides with similar structural features, the disadvantages of the lower yield and the generation of 3,6-lactone as the byproduct due to the longer reaction time are obvious. By inspecting the structure of compound 2, several clues were obtained for the optimization of synthetic protocol. For example, it is easy to remove C2, C3 and C4 acetyl protecting groups on glucuronic acid derivative 1 by CH3ONa/CH3OH without affecting the C6 methyl ester. Conversely, to obtain a free C6 carboxyl group by removing its methyl protecting group and keep all of the remaining acetyl groups, such as in glycosyl carboxylic acid 2, is quite difficult. The reason is that the carboxyl group and hydroxyl groups in glucuronic acid tend to be protected or deprotected together. Because glucuronic acid is quite important in the research of multiple disciplines, such as medicinal chemistry, drug metabolism, and natural product chemistry 9-11, it is necessary to find alternative protocol to fulfill the need of selective deprotection. Herein, we report an efficient method that can selectively remove the C6 methyl group from a glucuronic acid methyl ester without influencing any benzoyl protecting groups (Scheme 1, lower-left part). The resulting carboxyl group is ready to form amides or esters to afford other modified structures or as more complex donors

2

such as MBHA resin 12 (Scheme 1, lower-right part). Therefore, this procedure can be widely used for the synthesis and structural modification of glycoside relatives of glucuronic acid.

Scheme 1. Selective removal of the C6 methyl group on glucuronic acid derivatives. Results and discussion A typical example is introduced here when glucuronic acid azide 8 with O-benzoyl protecting groups on the C2, C3 and C4 hydroxyl groups was prepared (Scheme 2). First, D-glucurono-6,3-lactone 3 was hydrolyzed in a solution of CH3ONa in CH3OH to afford methyl ester 4, which was then quantitatively converted to per-Obenzoyl compound 5 by direct reaction with excess benzoyl chloride. Compound 5 was brominated under the treatment of the HBr–AcOH system in a high yield of 98% 13. To ensure a stable model compound, an azide group was introduced at the anomeric center, which resulted in a corresponding β-azide with the effect of the participation of the C2 benzoyl. Finally, the reaction proceeded with high selectivity, giving the corresponding sugar derivative with the free carboxyl group at C6 in excellent yield (Scheme 2).

Reagents and conditions: (a) CH3ONa, CH3OH, r.t., 5 h; (b) BzCl, pyridine, 5 h, 99%; (c) HBr-AcOH, DCM, r.t., 5 h, 98%; (d) NaN3, DMF, 2 h, 80%; (e) KOH (2 equiv.), acetone, r.t., 5 min, 95%. Scheme 2. Synthesis of glucuronic acid azide as a model compound

3

For the last step of demethylester reaction, we began the investigation by treatment of 7 in acetone using lithium hydroxide as the base, which formed product 8 with lower yields on different amount of base (Table 1, entry 1-3). We reasoned that if a stronger base instead of lithium hydroxide was used to remove the methyl group on compound 7 in a quick-treatment manner, the hydrolysis of benzoyl esters would not occur. Therefore, we treated 7 in acetone using sodium hydroxide (2.0 equiv.) as the base, which generated the desired product 8 in only 5 minutes with a 74% yield (Table 1, entry 4). Although this yield was not good enough, the much shorter reaction time showed advantages compared to the previous work. Further investigations were carried out to improve the product yields under various conditions. A good yield of 91% was observed by increasing the amount of sodium hydroxide to 2.5 equivalents (Table 1, entry 5). However, 3.0 molar equivalents of the base resulted in a great decrease in the yield to 23% (Table 1, entry 6). Subsequently, potassium hydroxide was applied instead as the base. To our delight, product 8 was obtained in a higher yield as high as 95% (Table 1, entry 7) when 2.0 molar equivalents of base was introduced, and the reaction time was not as crucial as expected (Table 1, entries 7–9). If the amount of the base was increased to 3.0 molar equivalents, the influence on the yield was not too serious (Table 1, entry 10). However, when the amount of the base was decreased to 1.0 molar equivalent, the results were so bad even if longer reaction times were allowed (Table 1, entry 11-12). The effects of various solvents were also investigated (Table 1, entries 13–16). The results showed that other polar aprotic solvents, such as acetonitrile, provided lower yields (Table 1, entries 13–14). As expected, polar protic solvents, such as methanol, helped hydroxylize the esters without selectivity (Table 1, entries 15–16). Therefore, all of the preliminary experiments clearly revealed that the best way to proceed with the hydrolysis of 7 is the application of potassium hydroxide (2.0 equiv.) as the base, acetone as the solvent and a reaction time of 5 min. Table 1. Optimization of the reaction conditions for selective removal of C6-methyl of glucuronic acid

Entry

Base

Solvent

Time

Equiv

Yielda

1

LiOH

acetone

5 min

2.0

42%

2

LiOH

acetone

5 min

2.5

51%

3

LiOH

acetone

5 min

3.0

14%

4

NaOH

acetone

5 min

2.0

74%

5

NaOH

acetone

5 min

2.5

91%

6

NaOH

acetone

5 min

3.0

23%

7

KOH

acetone

5 min

2.0

95%

4

a

8

KOH

acetone

10 min

2.0

93%

9

KOH

acetone

30 min

2.0

90%

10

KOH

acetone

5 min

3.0

82%

11

KOH

acetone

30 min

1.0

12%

12

KOH

acetone

3h

1.0

17%

13

KOH

acetonitrile

5 min

2.0

40%

14

KOH

acetonitrile

5 min

3.0

80%

15

KOH

methanol

5 min

2.0

46%

16

KOH

methanol

10 min

2.0

10%

Isolated yields.

To verify the applicability of this protocol, we tested different substrates (Scheme 3). First, compound 9 with acetyls as protective groups was applied. Although the yield of product 10 is not as good as product 8, it still shows some advantages compared with the reported method in terms of much shorter reaction time and higher yield. Subsequently, several glucuronide compounds with different substitutions on the anomeric center were utilized. Compound 11 is an important intermediate in the research of glycolipids. To the best of our knowledge, 11 can only be obtained in four steps from D-glucose by oxidation using TEMPO 8. This time it can be provided from intermediate 5 in a 95% yield by our method. In addition, glucuronides are interesting markers for the consumption of alcohol such as compound 13 which was obtained by use of the RuCl3–NaIO4 reagent system 14. Considering the relatively high cost of RuCl3 as well as NaIO4 used in the reaction, we apply our approach to the synthesis of such compounds. It was nice to see that compound 13 was conveniently synthesized in excellent yield by this means. The scope of this methodology was further explored in the synthesis of sugar amino acid and glucuronic acid containing coumarin. Sugar amino acids (SAAs), the carbohydrate derivatives bearing both amino and carboxylic acid functional groups, represent an important class of such new molecules that can be used to create novel materials with potential applications as glycomimetics and peptidomimetics15-18. Considering the importance of this class of compounds, we choose 15 as a model compound to explore applicability of this protocol. The new sugar amino acid 15 can be synthesized from compound 14 in excellent yield of 97%. Another example is compound 17 which is useful to the structural modification of aromatic amines and aromatic alcohols. Compound 16 could be obtained by treatment of aromatic amine with isothiocyanate intermediate in good yield (see supporting information). Conversion of 16 to 17 proceeded smoothly in 98% yield by our method. Further evaluation on complex structure, such as disaccharide 22, was also successful. The novel compound 22 was prepared in nine steps with 23% overall yield (see supporting information). To our delight, the desired disaccharide 23 was formed in 98% yield, showing broader range of application of this method.

5

We note that the hydrolysis of 20 and 22 requires great care, for even a slight excess of base leads to irreversible lactone opening. However, we found that these unique structures were still stable when dealing with potassium hydroxide to remove the C6 methyl. Highly pure 21 and 23 can be isolated in excellent yields. Moreover, this selective condition furnished the products without affecting either the sugar anomeric center or the lactone ring. OR

O AcO AcO

a

OR

O

O OAc

BzO BzO

N3

9: R=Me 10: R=H

O

O OBz

OBz

Yield=75%

a

Yield=95%

O

12: R=Me 13: R=H

OBz

O

O

O O OBz a

20: R=Me 21: R=H Yield=96%

O OBz

O O OBz

OBz

18: R=Me 19: R=H Yield=98%

OR

BzO BzO

14: R=Me 15: R=H

OR

a

Yield=97%

NHAc OBz

Yield=97%

BzO BzO

S

16: R=Me 17: R=H

a

a

BzO BzO

H N

H N

O

BzO BzO

Yield=99%

OR

BzO BzO

OCH3

OBz

O O

OR

O

O

BzO BzO

5: R=Me 11: R=H

a

OR

O

O BzO BzO

O

OR O

N N N

O

CH3 CH3

OBz a

O

22: R=Me 23: R=H Yield=98%

Reagents and conditions: (a) KOH (2.0 equiv.), acetone, 5 min. Scheme 3. Selective removal of the C6 methyl group on different glucuronic acid substrates Conclusion In summary, an efficient and reliable procedure for the synthesis of C6-carboxyl glucuronyl acid and its application in the preparation of corresponding glycosyl compounds are described. The high yields up to 99% testified the feasibility and efficiency of this protocol. Given other advantages of this protocol, including its mild conditions, short reaction time, lower cost and easy operation, it provides rapid access to biologically relevant carbohydrates in a labor-saving and economical manner. With modifications in the anomeric centre and free C6 carboxyl group, the syntheses of further saccharide compounds may be expected, and their utilization in carbohydrate chemistry can also undergo fast progress. Acknowledgments

6

This project was financially supported by National Natural Science Foundation of China (No. 81473087 and 81573292). Dr. Y. Liu wishes to express his thanks for the support by the Program for Liaoning Excellent Talents in University (LJQ2014110). Supplementary data: All the preparative procedures for the substrates descripted above and the 1H and synthesized compounds are provided in supporting information.

13

C NMR spectra of

References and notes: 1

2 3 4 5 6 7 8 9 10 11

12 13 14 15 16 17 18

(a) Yu B, Zhang YC, Tang PP. Eur J Org Chem. 2007;31:5145−5161. (b) Cai C, Li L-Y, Harvey C, Liu J, Linhardt RJ. Tetrahedron Lett. 2013;54:4471–4474. (c) Wei G-H, Kumar V, Xue J, Locke RD, Matt KL. Tetrahedron Lett. 2009;50:6543–6545. (a) Stachulski AV, Harding JR, Lindon JC, Maggs JL, Park BK, Wilson ID. J Med Chem. 2006;49:6931−6945. (b) Cao H, Yu B. Tetrahedron Lett. 2005;46:4337–4340. (a) Capila I, Linhardt R. Angew Chem Int Ed. 2002;41:391−412. (b) Shetty SS, Koyama Y. Tetrahedron Lett. 2016;57:3657–3661. (a) Van den Bos LJ, Codée JDC, Litjens REJN, Dinkelaar J, Overkleeft HS, Van der Marel GA. Eur J Org Chem. 2007;24:3963−3976. (b) Li Y-F, Yu B, Sun J-S, Wang R-X. Tetrahedron Lett. 2015;56:3816–3819. Wadouachi A, Kovensky J. Molecules. 2011;16:3933−3968. (a) Nowogrodzki M, Mlynarski J. Curr Org Chem. 2014;18:1913−1934. (b) Dhamale OP, Zong C, AlMafraji K, Boons G J. Org Biomo. Chem. 2014;12:2087−2098. Tosin M, O'Brien C, Fitzpatrick GM, Müller-Bunz H, Glass WK, Murphy PV. J Org Chem. 2005;70:4096−4106. Pilgrim W, Murphy PV. Org Lett. 2009;11:939−942. Quan, X-Q, Kang L, Zhe, Yin X-Z, Jin Z-H, Gao Z-G. Chinese Chem Lett. 2015;26: 695−699. Leu YL, Wu YJ, Chern JW. J Med Chem. 2008;51:1740−1746. (a) Baltina L, Hoever G, Michaelis M, Kondratenko R, Baltina L, Tolstikov GA, Doerr HW, Cinatl J. J Med Chem. 2005;48:1256−1259. (b) Alaoui AE, Schmidt F, Monneret C, Florent JC. J Org Chem. 2006;71:9628−9636. (a) Lindhorst TK. J Org Chem. 2004;69:4441−4445. (b) Tosin M, Murphy PV. Org Lett. 2002;21:3675−3678. (c) Malkinson JP, Falconer RA, Toth I. J Org Chem. 2000;65:5249−5252. Monch B, Gebert A, Emmerling F, Becker R, Nehls I. Carbohydr Res. 2012;352:186−190. Banerjee A, Senthilkumar S, Baskaran S. Chem Eur J. 2016;22:902–906. Tian G-Z, Wang X-L, Hu J, Wang X-B, Guo X-Q, Yin J. Chinese Chem Lett. 2015;26:922−930. Rockendorf N, Lindhorst TK. J Org Chem. 2004;69:4441−4445. Mathiselvam M, Loganathan D, Varghese B. Carbohydr Res. 2013;380:1−8. Malkinson JP, Falconer RA, Toth I. J Org Chem. 2000;65:5249−5252.

7

Graphical Abstract

A method for exceptionally selective removing the C6 methyl protecting group by potassium hydroxide without affecting the benzoyl protecting groups on the C2, C3 and C4 hydroxyl groups of certain glucuronic acid derivatives in high yields (95%–99%) was reported.

8

Highlights •

Highly effective and efficient method for synthesis of glucuronic acid derivatives.

•

Exceptionally selective removing the C6 methyl from glucuronic acid ester.

•

Mild conditions; short reaction time; lower cost; easy operation; excellent yields.

•

Rapid access to relevant carbohydrates in a labor-saving and economical manner.