Nucleophilic displacement reactions in carbohydrates

Carhohydrare Resarch EIsevier Publishing Company. Amsterdam Printed in Belgium

NUCLEOPHILIC PART

IV*.

423

DISPLACEMENT

THE

SOLVOLYSIS

OF

REACTIONS

IN CARBOHYDRATES

3-ACETAhfIDO-3-DEOXY-1,2-~-ISOPROPYL~E~-~,6-

D~-U-~~~N~~U~.PH~NYL-~D-GLUCOF~R~~~E**

J. S.

BRMACOMBE

AND

Chemistry Department,

(Received

J.

G.

H.

BRYAN

The University, Birmingham

i5 (Great Britain)

October 24th, 1967)

ABSTRACT

of 3-acetamido-3-deoxy-1,2-O-isopropylidene-5,6-di-O-methaneSolvolysis sulphonyl-rr-D-glucofuranose (3) in either 95% 2-methoxyethanol or N,N-dimethylformamide, in the presence of sodium acetate, gives 3,6-(acetylepimino)-3,6-dideoxy1,2-0-isopropylidene-P-r_-idofuranose (6) as the product. The structure is assigned on the basis of chemical and spectroscopic evidence. The mechanism of the solvolysis, which involves neighbouring-group participation by the amide group, is discussed. INTRODUCTION

We have recently reported’ on a facile synthesis of 3-acetamido-3-deoxy-1,2:5,6di-0-isopropylidene-a-D-glucofuranose (1) and its conversion into 3-acetamido-3deoxy-D-glucose and 3-amino-3-deoxy-D-xylose. Graded, acid hydrolysis of compound 1 removed the 5,6-O-isopropylidene group*, and the resulting diol (2) was converted into 3-acetamido-3-deoxy-l,2-O-isopropylidene-5,6-di-O-methanesulphonyl-a-D-glucofuranose (3) on methanesulphonylation. Disulphonate 3 is of interest, since it contains sulphonic ester groups that are two and three carbon atoms removed from an acetamido group, which could conceivably participate2 in their removal; 3 is, therefore, of potential value in the synthesis of diamino sugars of biological interest.

1

R=Ac

2 R=

5

R=H

3 R = MS;

H;

R’=

4

R’= COCDB

R = MS;

R’=COCHx COCH,

*Part III: J. S. Brirnacombe, (Miss) P. A. Gent, and M. Stacey, J. Chenr. Sot. C, (1968) 567. **This work was presented, in part, at the 4th International Symposium on Carbohydrate Chemistry, Kingston, Ontario, July, 1967. Carbohyd. Res., 6 (1968) 423-430

424

J. S. BRIMACOMBE, J. G. H. BRYAN

Amides are ambident nucIeophiles, and examples of nucleophilic participation involving attack by the oxygen and nitrogen atoms of the amide group are known2”. The carbohydrate field is particularly rich in examples of neighbouring amide-group participation, which have proved of immense value in amino-sugar syntheses3. In most of the cases examined, the participating and departing groups have been located on vicinal carbon atoms, and there are comparatively few reports on amide-group participation where this relationship is not found. One example was recorded by Meyer ZI.IReckendorf4, who observed that solvolysis of methyl 2,6-dibenzamido-2,6dideoxy-4-O-methanesulphonyl-3-O-methyl-~-B-D-glucopyranoside, with ethanolic sodium ethoxide, occurred with inversion of cotiguration at C-4 to give a sixmembered dihydro-oxazine derivative. A second case was described by Hanessian’ during the course of this investigation. Thus, treatment of 5-acetamido-5-deoxy1,2-O-isopropylidene-bO-methanesulphonyl-8_~-arabinofuranose with sodium benafforded S-acetamido-5-deoxy- 1,2-O-isoprozoate in iVJ%dimethylformamide pylidene+&yxofuranose, by breakdown of the intermediate dihydro-oxazinium ion. We now report on the solvolysis of disulphonate 3. DISCUSSION

Solvolysis of dimethanesulphonate 3, with boiling 95% 2-methoxyethanol (Methyl Cellosolve) in the presence of sodium acetate, for 24 h gave a crystalline product (A), in moderate yield, following chromatography of the reaction mixture on silica gel. Attempts to follow the course of the reaction by thin-layer chromatography were made difficult by the fact that the various components were not well-separated, and the presence of compound A in the reaction mixture was best judged by the reddish spot produced on spraying the chromatogram with the vanillin-sulphuric acid reagent6. Product A was also formed when the solvolysis was carried out in NJV-dimethylformamide-sodium acetate. Compound A had a molecular weight of 243 (by mass spectrometry) and elemental analyses corresponding to the moIecular formula C, I H, 7N05. The absence of sulphonic ester groups in A was confirmed by infrared spectroscopy, which also indicated the presence of an isopropylidene group and a hydroxyl group. The spectrum showed only one absorption band in the region 1500-1700 cm-r, signifying that the acctamido group had been modified in some way during the solvolysis. The n.m.r. spectrum of compound A (Fig. 1) established the presence of an isopropylidene group, but the most significant feature of the spectrum was the appearance of a pair of doublets at r 4.16 and 4.27 (J 3.5 Hz), corresponding to one proton, which could be ascribed to the anomeric proton. Integration showed that these signals were in an approximate ratio of 1:2.5, and the pair of singlets at ca. r 8.00, corresponding to three protons, had the same ratio. The spectrum simplified when the temperature was raised to 100” and, noticeably, the doublets at low field and the pair of singlets at r cu. S-00 each coalesced; the process was reversed on cooling. This behaviour is characteristic of sugars in which the ring oxygen atom is replaced Curbohyd

Res., 6 (1968) 423-430

425

NUCLEOPHILIC DISPLACEMENT REACTIONS. IV

by the ) NCOCH,

group and is attributable to hindered internal rotation about

the nitrogen-acetyl spectroscopy?

bond, which allows the rotamers to be distinguished

by n.m.r.

l HCPS

1....l..~..I....~....I....~....I....~....I....~....I....~....~....~..~.~....~....l...,

2

3

4

5

6

7

8

9

z

Fig. 1. N.m.r. spectrum (100 MHz) of compound A, subsequently identified as 3,6-(acetylepimino)3,6-dideoxy-I .2-U-isopropylidene-/I-r-idofuranose (6).

The presence of the )NCOCHs group in compound A was also inferred from mass spectrometry. Fragmentation of acetamido sugars invariably gives rise’ to a peak in the spectrum at m/e 43, attributable to the MeC =h ion. With A, however, this ion will also result from fragmentation of the isopropylidene groupg. These fragmentation modes were distinguished by examining the product resulting from the of 3-deoxy-1,2-O-isopropylidene-S,6-di-O-methanesulphonyl-3-(trideusolvolysis terioacetamido)-a-D-glucofuranose (4). Compound 4 was obtained by N-trideuterioacetylation of 3-amino-3-deoxy-1,2:5,6-di-O-isopropylidene-cr-p glucofuranose (5), followed by selective removal of the cr-acetal group with acid, and methanesulphonylation. The mass spectrum of the product from the solvolysis of compound 4 showed peaks, inter alia, at m/e 43 (M&Z&) and 46 (CD,C=d), which were considered to arise by fragmentation of an isopropylidene and an > NCOCD, group, respectively. Acetylation and methanesulphonylation of compound A gave a mono-ester, in each case, signifying the presence of a single hydroxyl group. The methanesulphonyloxy group was not exchanged on treatment with sodium iodide in either butanone or NJV-dimethylformamide, so that it is uulikely’” to be present at a primary position. Carbohyd. Res., 6 (1968) 423430

426

J. S. BRIMACOMBE,

The

foregoing

evidence

points

to

J. G. H. BRYAN

a 3,6-(acetylepimino)-3,6-dideoxy-1,2-O-

isopropylideneglycofuranose as the basic structure for compound A, leaving the stereochemistry at C-5 undecided for the moment. Although mechanistic considerations imply an L-ido configuration (6) for compound A, it seemed desirable to confirm the stereochemistry at C-5 by independent means, particularly

as desulphonylation,

resuhing from O-S bond cleavage,

has been

observed’ under conditions comparable to those used for the solvolysis. The methanesulphonate, derived from compound A, was also found to be resistant to nucleophilic attack by either benzoate or azide ions, although thin-layer chromatography indicated that other reactions were occurring in both cases. The unreactivity of the sulphonic ester towards bimolecular nucieophilic displacement signified that it had an exo (Le., L-ido) configuration (7) with respect to the oxa-azabicyclo[3.3.0]octane ring system. This argument is enhanced by the knowledge that the endosulphonyloxy group of 3,6-anhydro-1,2-U-isopropylidene-5-O-(toluene-p-sulphonyl)a-D-glucofuranose is smoothly displaced by azide” and benzoate** ions. Moreover, with the closely related, bicyclic ring-system present in the 1,4:3,6_dianhydrohexitols, it has been establishedI that S,2 displacement of exo-sulphonates is sterically hindered, whereas displacement of an endo-substituent is facile. On this evidence, compound A can be assigned as 3,6-(acetylepimino)-3,6-dideoxy-1,2O-isopropylideneB-L-idofuranose (6).

dc 6

R=H

7

t?=t”ls

IO

Carbohydrate sulphonic esters are relatively stable under acidic and neutral conditions”, but are readily solvolysed in the presence of a group capable of rendering anchimeric assistance. Of relevance to the present discussion, it has been observed14 that 3-O-acetyl-1,2-O-isopropylidene-5,6di-O-(toluene-g-sulphonyl)-a-D-glucofuranose is solvolysed, in 95% 2-methoxyethanol-sodium acetate, to give 3,6-anhydro1,2-O-isopropylidene-5-U-(toluene-p-sulphonyl)-cr-D-gIucofuranose, with deacetylation but without cleavage of the sulphonic ester group at C-5. Thus, the first step in Carbohyd. Res.,6 (1968) 323-430

428

J. S. BRIMACOMBE,

J. G. H. BRYAN

The solution was extracted with chloroform (6 x 100 ml), and the combined and dried (MgSO,) extracts were concentrated to ca. 2 ml, and chromatographed on silica gel by elution with chloroform-ethanol (20:l). Combination and evaporation of the appropriate fractions gave 3,6-(acetylepimino)-3,6-dideoxy-1,2-O-isopropylidene-p-r_-idofuranose (6) (0.285 g, 45%), m.p. 169-I 70” (from acetone-light petroleum), [a]b -75” (c 0.4,chloroform) (Found: C, 54.6; H, 7.0; N, 5.9. C, ,H,,NO, talc.: C, 54.3; H, 7.0; N, 5.8%). The mass spectrum of the product showed the highest peak at m/e 228 (M-15)‘, corresponding to a molecular weight of 243; it also contained a peak at m/e 43. Its infrared spectrum exhibited absorptions at 3500 (OH) and 1380 cm-’ (isopropylidene group); the amide II band, present in the spectrum of compound 3, had disappeared while the amide I band (1650 cm-‘) persisted. The n.m.r. spectrum of compound 6 is shown in Fig. 1. (b) Using sodium acetate in N,N-dimethylfornzami. A solution of compound 3 (0.2 g) and sodium acetate (0.13 g) in dry NJV-dimethylformamide (16.8 ml) was heated under reflux for 3 h. The solvent was then removed, the residue was dissolved in water (20 ml), and the solution was extracted with chloroform (6 x40 ml). The combined and dried (MgSO,) extracts were concentrated to ca. 2 ml; t.1.c. (chloroform-ethanol, 2O:l) revealed the presence of two components (RF 0.1 and 0.6). Chromatography, as in (a), gave the faster-moving component (40 mg, 32%) which proved to be identical with compound 6, m.p. and mixed m-p. 169-170”. The chromatographic properties and infrared spectra of the two compounds were indistinguishable. 3 - Deoxy - I, 2 - 0 - isopropylidene - 5,6 - di- 0 - methanesulphonyl- 3 - (triderrterioacefamido)-cr-D-gkofuranose (4). This compound, m.p. l23-124”, mixed m.p. 123-124” with compound 3, was obtained by methanesulphonylation of 3-deoxyI ,2-O-isopropylidene-3-(trideuterioacetamido)-a-Dglucofuranose, essentially as described above. The latter compound was prepared by trideuterioacetylation of 3-amino-3-deoxy-1,2:5,6-di-O-isopropylidene-cr-D-glucofuranose (5), followed by graded hydrolysis with acid, as described elsewhere’. Solvolysis of compound 4, as detailed in (a), gave 3,6-dideoxy-l,2-O-isopropylidene-3,6-[(trideuterioacetyl)epimino]-~-L-idofuranose, m.p. l69-170”, [c& - 75” (c 0.45, chloroform); no depression of melting point was observed on admixture with the product from (a). The mass spectrum of the deuterated product exhibited, irrtera&a, the following peaks, m/e 231 (M-15), 46 (CD,C =b),

and 43 (CH,C=b).

5-0-Acet~~l-3,6-(acetyZepi?nino)-3,6-dideo.u)I,2-O-isopropyIidene-p-L-id~furatIose.

This compound, m-p. 126-127” (from chloroform-light petroleum), was obtained by acetylation of compound 6, with acetic anhydride in pyridine, in the normal way (Found: C, 54.1; H, 6.7. C,,HrgNO, talc.: C, 54.2; H, 6.6%). N.m.r. data: r 4.13, 4.25 (doublets, .i, ,? 3.5 Hz, anomeric proton); 7.85,7.96 (singlets, 3-proton, integrated ratio ca. 1:2.5, NAc); 7.95 (3-proton singlet, OAc); 8.50, 8.70 (3-proton singlets, CMe,). -

Carboiryd.

Res.,

6 (1968)

423430

NUCLEOPHILIC

DlSPLACEhiENT

REACTIONS.

429

IV

idofuranose (7). - A solution of compound 6 (0.1 g) and methanesulphonyl chloride (0.05 ml) in pyridine (0.5 ml) and benzene (0.2 mi) was set aside overnight, water was then added, and the solution was concentrated. The syrupy residue was dissolved in chloroform (25 ml), and the solution was washed with dilute, aqueous cadmium chloride, dried (MgSO,), and concentrated. Chromatography of the residue on silica gel by elution with ethanol-chloroform (1:20) gave sulphonate 7 (0.11 g), m.p. 144-145” (from chloroform-light petroleum) (Found: C, 44.7; H, 5.7; N, 4.0; S, 10.2. ClaH,sN07S talc.: C, 44.9; H, 5.9; N, 4.4; S, 10.0%). Attempted displacement reactions with compound 7. -

(a) With sodium iodide.

A solution of compound 7 (20 mg) and sodium iodide (30 mg) in dry N,Wdimethylformamide (1 ml) was heated in a sealed tube overnight at 95-100”. The solvent was removed, the residue was dissolved in water (10 ml), and the solution was extracted with chloroform (5 x 20 ml). Starting material (13 mg), m.p. and mixed m-p. 144-145” (from chloroform-light petroieum), was recovered on removal of the solvent. T.1.c. indicated that no other components were present. Starting material was also recovered when the displacement was attempted in butanone. (b) With sodium berrzoate. A solution of compound 7 (50 mg) and sodium benzoate (0.1 g) in N,IV-dimethylformamide (3.75 ml) was heated under reflux for 5 h. The solution was processed in the usual manner, and the residue was chromatographed on silica gel with ethanol-chloroform (1:20). This gave two unidentified components, neither of which showed an appreciable absorption attributable to benzoic ester in its infrared spectrum. (c) Wit/z sodium azide. A solution of compound 7 (0.1 g), sodium azide (23 mg), and urea (3 mg) in water (0.05 ml), contained in a sealed tube, was heated for 36 h at 115” and then processed in the usual way. The residue was shown by t.1.c. (ethyl acetate) to contain at least five components, but its infrared spectrum showed insignificant absorption at ca. 2100 cm-’ attributable to azide groups. In a parallel experiment, 3,6-anhydro-1,2-O-isopropylidene-5-O-(toluene-p sulphonyl)-cr-D-ghrcofuranose was smoothly converted into the azido derivative in high yield (cl: Ref. 1I). ACKNOWLEDGMENTS

The authors thank Professor M. Stacey, C.B.E., F.R.S., for his interest, Dr. L. D. Hall for measuring some of the n.m.r. spectra, and Dr. J. R. Majer for mass measurements. The award of a studentship (to J.G.H.B.) by the Science Research Council is gratefully acknowledged. REFERENCES 1 J. S. BRIMACOMBE,J. G. H. BRYAN, A. HUSAIN, M. STACEY,AND M. %TOLLEY, Carbohyd. Res., 3 (1967) 318. 2 (a) S. WIN~TEIN,L.GOODMAN,AND R.BOSCHAN,J. Am Chen~.Soc.,72(1950)2311;S. WINSTEIN (b) B. CAPON, Quarr.Reo. (London), 18 (1964) 45. AND R. BOSCHAN, ibid., 72 (1950) 4669; Carbohyd. Res.. 6 (1968)

423430

430

J. S. BRIMACOMBE,

J. G. H. BRYAN

3. See, for example, B. R. BAKER AND R. E. SCHAUB, J. Org. Clrem., 19 (1954) 646; B. R- BAKE% R. E. SCHAUB, J. P. JOSEPH,AND J. B. WILLIAMS, J. Am. Chem. Sot., 76 (1954) 4044; B. R. BAKER, R. E. SCHAUB, AND J_ H. WILLLAMS, ibid., 77 (1955) 7; E. J. REIST, L. GOODMAN, AND B. R. BAKER, ibid., 80 (1958) 5775; A.‘C. RICHARDSON, J. Chem. SOL, (1964) 5364, and references cited therein; C. F. GIBBS, L. HOUGH, AND A. C. RICHARDSON, Carbahyd. Res., I (1965) 290, and references cited therein. 4 W. MEYER zu RECKENDOW, Ber., 96 (1963) 2019. 5 S. HANESSIAN, J. Org. Chem., 32 (1967) 163. 6 Chromatography, E. Merck A. G., Danmtadt, 2nd edn., p. 30. 7 W. A. SZAREK, S. Wo~m, AND J. K. N. JONES, Tetrahedron Letters, (1964) 2743; H. PAULSEN, Angew. Chem., Intern. Ed. Engi., 5 (1966) 495. 8 See, for example, K. HEYNS, G. Kms~mc, AND D. MUELLER,Carbohyd. Res., 4 (1967) 452. 9 D. C. DJZJONGHAND K. BIEMANN, J. Am. Chem. SOL, 86 (1964) 67. 10 R. S. TIPSON, Adtian. Carbohydrate Chem., 8 (1953) 107. 11 M. L. WOLIXOM, J. BERNSMANN, AND D. HORTON, J. Org. Chem., 27 (1962) 4505. 12 J. G. BUCHANAN AND I. Corm, .I. Chem. Sot., (1965) 201. 13 S. J. ANGYAL AND N. K. MATHESON, J. Chem. Sot., (1952) 1133; A. C. COPE AND T. Y. SHEN, J. Am. Chem. Sot., 78 (1956) 3 177; J. A. MILLS, Adcan. Carbohydrare Chem., 10 (1955) I. 14 D. H. Buss, L. D. HALL, AND L. HOUGH, J. Chem. Sot., (1965) 1616. 15 J. G. BUCHANAN AND R. FLETCHER, J. Cfrem. Sac., (1965) 6316; (1966) 1926. Carbohyd. Res., 6 (1968) 423430