Studies on the synthesis of unsaturated nucleoside analogs

Carbohydrate

Rese4rch

97

ElscvierPublishingCompany.Amsterdam

Printed in Belgium

STUDIES

ON

THE

SYNTHESIS

OF UNSATURATED

NUCLEOSIDE

ANALOGS* KONOSHINONODERAANDTOSHINORIYAJIMA Loborcrorv

of Biological Chemisrry, Department of Agriculrural Chemistry, Kyoro Universiry, Kyoro

(Received October 13th, 1969; in revised form, December 3Oth, 1969)

ABSTRACT

An unsaturated 6-deoxy-L-hexopyranosyltheophylline diacetate was synthesized, starting from L-rhamnopyranose tetraacetate (l),by the fusion procedure with the use of p-toluenesulfonic acid, and also through dehydration with phosphorus pentaoxide by way of 2,3,4-tri-0-acetyk-rhamnopyranose (2) in NJV-dimethylformamide. It was found that 2,3,4-tri-U-acetyl-l,5-anhydro-l,6-dideoxy-L-arabinohex-1-enitol (2,3,4-tri-0-acetyl-2-hydroxy-L-rhamnal) (3) was involved as an intermediate. The following glycal derivatives were condensed with theophylline by the fusion procedure: 2-hydroxy-D-glucal tetraacetate, D-galactal triacetate, 2-hydroxyD-glucal tetraacetate, D-galactal triacetate, 2-hydroxy-D-galactal tetraacetate (6), 2-hydroxy-D-xylal triacetate, L-rhamnal diacetate, and 1,2,4,6-treta-0-acetyl-3deoxy-D-fhreo-hex-2-enopyranose (‘7). The unsaturated nucleoside analogs thus synthesized are described. INTRODUCTION

The synthesis of an unsaturated nucleoside has been reported by Bowles et al. 1 who utilized various glycal derivatives in an acid-catalyzed, fusion reaction. In a similar fashion Leutzinger et aL2 synthesized 9-(2,3-dideoxy-D-erytilro-hex-2enopyranosyl)guanine. The introduction of 2’,3’-unsaturation has also been described in the synthesis of pyrimidine3m4 and purine’ nucleosides, based largely on the intermediate formation of a 2’,3’-anhydronucleoside or an oxetane ring in a basecatalyzed, elimination reaction_ McCarthy et ~1.~~~ synthesized angustmycin A (decoyinine) from 1’,3’,4’-O-orthoformylpsicofuranine. In the course of our studies on the synthesis of nucleosides’, it was found that a double bond was formed in the sugar moiety of the products obtained when theophylline was condensed with the tetraacetate 1 by the fusion procedure or when the triacetate 2 reacted with theophylline by the dehydrating procedure. The present paper describes a new reaction for the synthesis of 7-(2,4-di-0-acetyl-3,6-dideoxy-x-r_erythro-hex-Zenopyranosyl)theophylline (5) and the synthesis of several theophylline nucleoside derivatives having 2’,3’-unsaturation. *Dedicated to the memory of Professor M. L. Woifrom. Carbohyd.

Res., 13 (1970) 97-104

IL ONODERA,

98 RESULTS

T. YAJIMA

AND DISCUSSION

Condensation of 1 with theophylline was effected by fusion in the presence of p-toluenesulfonic acid. White, fine needles were obtained in 2.5% yield. The n.m.r. spectrum of the product showed signals for two acetoxy groups, two N-methyl groups, and four protons attributable to the sugar moiety, indicating absence of a proton at C-2’. The anomeric configuration was tentatively assigned on the basis of the observed negative optical rotation and the negative, plain o.r.d. curve. The position of substitution on the theophylline residue was determined to be N-7 by U.V. spectroscopy. The Jvalues (J3r,4t 2.7 Hz, J4S,5. 7.5 Hz) obtained by n.m.r. spectroscopy on 5, as reported in the previous paperg, suggest that the double bond is probably between C-2’ and C-3’, and that the acetoxy group is attached to C-2’ (compare the n.m.r. data obtained with 1,2,4-tri-U-acetyl-3,6-dideoxy-a-D-erythrohex-2-enopyranose”). The analytical results aIso supported this suggestion. Consequently, the product was identified as 7-(2,4-di-0-acetyl-3,6-dideoxy-a-L-erythrohex-2-enopyranosyl)theophylline (5). The best yield of 5 in the fusion procedure was obtained by heating the mixture for 30 min at 160-170” under diminished pressure. Deacetylation of the product with methanolic ammonia caused fission of the glycosidic bond and theophylline was recovered. Compound 5 did not undergo hydrogenation over platinum oxide in methanol, possibly because of steric reasons. Other addends such asp-nitrophenol and 6-benzamidopurine were used in place of theophylline, but no unsaturated condensation products were detected in the reaction mixture. The use of acetylated hexopyranoses in place of 1 gave the usual condensation products and no unsaturated products were detected.

Me OAc

AcO

I

4

?

-C 1

AcO

R=

OAC

2

Theaphyllin-7-yl

(A) By

thefusion

OAc

AcO

procedure,

(B) By

the

dehydration procedure

Condensation of 2 with theophylline occurred on heating in N,N-dimethylformamide for 140 h at 60-70”, with phosphorus pentaoxide as a dehydrating agent. Curbohyd. Res., 13 (1970) 97-104

UNSATURATED

SUGAR

NUCLEOSIDES

99

The reaction product was an unsaturated L-hexopyranosyltheophylline, obtained in 4.5% yield; the product was proved to be identical with 5 produced by the fusion procedure described above. In order to verify the structure of 5 and to deduce the mechanism of these reactions, some related reactions were investigated. The reaction of 1,2,3,4-tetra-Oacetyl-6-deoxy-L-mannopyranose with theophylline by the fusion procedure did not give an unsaturated product, but instead produced a saturated compound 7-(2,3,4tri-0-acetyM-deoxy-L-mannopyranosyl)theophylline in 61% yield. The structure of this product was determined from the signals of three acetoxy groups and five protons attributed to the sugar moiety in the n.m.r. spectrum, and from elementary analytical data. It was considered that the substituent at C-5’ took little or no part in the formation of a double bond in the reaction product. 7-(2,3,4-Tri-O-acetyl-6-deoxy-a-L-galactopyranosyl)theophy~ne was prepared by condensation of 2,3,4-tri-0-benzoyE6-deoxy-cr-L-galactopyranosyl bromide1 ’ with chloromercuritheophylline in boiling xylene, with subsequent removal of the protecting groups followed by acetylation in pyridine”. Although this compound was treated under the same reaction conditions as those used for synthesis of 5, the compound was recovered unchanged. Therefore, it was considered that the unsaturation was formed in the sugar moiety before N-glycosylation. Subsequently, 1 was heated for 15 min at 130-140” in presence of p-toluenesulfonic acid under diminished pressure. Two spots [RF 0.44 (A) and RF 0.69 (B)] were observed by t.1.c. on KieselgelG with 1:9 (v/v) ethyl acetate-benzene as the developer. The two fractions were isolated as syrups by column chromatography with use of the same solid phase and eluting solvent. The n.m.r. spectrum of the product from fraction A showed the signals of three acetoxy groups and four other protons, and the existence of a double bond was indicated by the appearance of u-v. absorption at A::,“” 228 nm. It was also found that no specific absorption appeared at 3200-3300 cm- ’ that could be assigned to a hydroxyl group in the i.r. spectrum. The product showed the same mobility as that of synthetic 2-hydroxy-L-rhamnal triacetate (2,3,4-tri-0-acetyl-1,5-anhydro-1,6dideoxy-L-arabino-hex-1-enitol, 3). The syrup obtained from fraction B was considered to be 2,4-di-O-acetyl-3,6dideoxy-L-eryflzro-hex-2-enopyranose (4), as shown by n.m.r., i-r., and U.V. spectral measurements. The n.m.r. spectrum showed that two acetoxy groups and four other protons were present. A hydroxyl group was indicated by the i.r. spectral absorption at 3200-3300 cm- ‘. A broad absorption at jlK;zH 228 nm indicated the presence of a double bond in the product. These results suggest that the double bond in 5 is formed in the sugar moiety before Wglycosylation. Theophylline was condensed with 3 under the same conditions. Apparently degradation of 3 took place to a large extent, and the uncrystallized reaction product was subjected to t.1.c. on Kieselgel-G with 80% butyl alcohol (i) and 3:7 (v/v) ethyl acetate-benzene (ii) as the developer. The RF value of the product was 0.66 with solvent (i) and 0.54 with solvent (ii), respectively. These values are the same as those carb0hyd. Res., 13 (1970) 97-104

K. ONODERA,

loo

T.

YAJIMA

of 5 synthesized by the fusion procedure, suggesting, therefore, that N-glycosylation takes place between the unsaturated sugar molecule and theophylline. Me

ctl,oAc

AcoQR Acoe AcoaR 9

Aco&qR OAc

OAC 10

11

12

R = Theophyllin-7-yl

In order to investigate further the structure of the product from 3, and to attempt to explain the mechanism of formation of a double bond in the sugar molecule, some unsaturated nucleoside analogs were synthesized, by using glycal derivatives. Theophylline was condensed in presence of a catalytic amount of p-toluenesulfonic acid with the fully acetylated derivatives of following glycals: 2-hydroxy-D-galactal (6), 2-hydroxy-D-glucal, D-galactal, L-rhamnal, 2-hydroxy-D-xylal, and 1,2,4,6-tetra0-acetyl-3-deoxy-o-threo-hex-2enopyranose (7); to give 7-(2,4,6-tri-0-acetyl-3deoxy-/3-D-three-hex-Zenopyranosyl)theophylline (S), 7-(2,4,6-tri-0-acetyl-3-deoxya-z)-erythro-hex-2-enopyranosyl)theophylline (9), 7-(4,6-di-0-acetyl-2,3-dideoxy-p-nthree-hex-2-enopyranosyl)theophylline (IO), 7-(4O-acetyl-2,3,6-trideoxy-/3-L-erythr& hex-2-enopyranosyl)theophylline

(ll), 7-(2,4-di-0-acetyl-3-deoxy-a-D-glyceru-pent-2-

enopyranosyl)theophylline (12), and 8, respectively. Further investigations on the mechanism for the formation the acetylated

t_-rhamnopyranose

molecule

of unsaturation

in

are desirable.

EXPERIMENTAL

General methods. - Melting points were measured on a hot stage. Specific rotations were determined with Yanagimoto direct-reading polarimeter. N.m.r. spectra were observed with a Varian A-60 spectrometer at ca. 30”. Tetramethylsilane in chloroform-d was used as internal standard. Chemical shifts are expressed on the r scale in p_p.m_ and the coupling constants in Hz were obtained by direct measurement of spacings of the spectral lines. Multiplet spacings were measured at a sweepwidth of 250 Hz. The concentration of the sample solutions’ was about 10%. 1.r. Carbalzyd. Rex.

13 (1970)

97-104

UNSATURATED

SUGAR

spectra were measured with a Yanagimoto multipurpose

101

NUCLEOSIDES

with Shimadzu

ORD-185

spectrometer.

Ar-7 spectrometer.

instrument_ T.1.c.

U.V. spectra

was performed

curves were obtained

on Kieselgel-G

alcohol-water, or 1:9 and 3:7 ethyl acetate-benzene detection was performed with 50% sulfuric acid. 2,3.4-Tri-O-acetyI-6-cleoxy-a-r_-n1~nnopyrmrose (2). by acetylation of L-rhamnopyranose

1 (10g),prepared

0.r.d.

were measured as developing -

with Hitachi

with

86:14

solvents,

The syrupy monohydrate

butyl and

tetraacetate with acetic

anhydride-pyridine, was dissolved in a mixture of acetic acid (4 ml) and acetic anhydride (4 ml) at 0”. To the solution was added 30 ml of acetic acid saturated at 0” with hydrogen bromide, and the reaction mixture was kept for 3 h at 16”. The reddish solution was poured dropwise into ice-water with vigorous stirring during 1 h. The reaction product was extracted twice with 50 ml of chloroform_ The chloroform layer was washed with an aqueous solution of sodium hydrogen carbonate and water, dried over calcium chloride and evaporated in cacao to a syrup. Ether (80 ml) was added to the syrup and the resultant solution was decoiorited with activated carbon. Refrigeration of the solution and recrystallization from ether gave fine needles; yield 5.6 g (64%); m.p. 90-91”, [a]h6 - 130” (c 0.5, chloroform); n.m.r. data (chloroform-n): r 4.83 (3 protons, H-l, H-2, H-3), 5.85 (quartet, H-4), 6.5 (quartet, H-5), 7.85, 7.93, 8.0 (9 protons, OAc), 8.76 (3 protons, doublet, H-6), ;izti 3430 (OH), 173O(C=O), 1225 cm-‘(OAc). Anal. Calc. for CltHIgOs: C, 49.65; H, 6.25. Found: C, 49.30; H. 6.61.

Fusiotl reaction of I,2,3,4-tetra-O-acetyl-6-deoxy-L-nzannop~~ra/zose (1)to give (3) and (4). - Compound 1 (3 g) was heated for 15 min at 130-140” with a catalytic amount of p-toluenesulfonic acid under diminished pressure. The reaction mixture was dissolved in a small volume of 1:9 (v/v) ethyl acetate-benzene and subjected to column chromatography (monitored by t.1.c.) to give two fractions. Evaporation of the first fraction gave 3 as a syrup; n.m.r. data (chloroform-d): z 5.29 (doublet, H-l), 4.8 (doublet, H-3), 4.68 (quartet, H-4), 6.32 (octet, H-5), 7.9, 7.99, 8.05 (9 protons, OAc), 8.72 (3 protons, H-6); vzX 1780 (C=O), 1225 cm- ’ 2~;~” 228 nm. The second fraction gave 4, also as a syrup; n.m.r. data (GAc); (chloroform-n): r 4.9 (singlet, H-l), 4.3 (doublet, H-3), 4.8 (quartet, H-4), 6.2 (octet, H-5), 7.83,7.95 (6 protons, OAc), 8.70 (3 protons, H-6); v$& 3450 (OH), 1740 (C = 0), 1225 (OAc), 835 cm- r (C=C); ,I:::” 228 nm.

7-(2,4-Di-O-acetyl-3,6-dideo~y-a-L-erythro-he~-2-enopyra~zos~~~theophyllirze

(5).

Syrupy l(5 g) and 2.7 g of theophylline were heated at 160-l 70” in an oil bath. To the molten mixture 0.1 g of p-toluenesulfonic acid was added with vigorous stirring. After 30 min at 160-170” under diminished pressure, the mixture was dissolved in a small volume of ethanol, decolorized with active carbon and kept overnight in a refrigerator. The crystalline product was recrystallized twice from ethanol to afford fine needles; yield 1.5 g (25%); m-p. 192-193”, [a]2 - 121” (c 0.55, chloroform); JEtoH 7 2.12 (1 proton, H-8), -mnx 274 nm, %zEH 244 nm; n.m.r. data (chloroform-6): 3.25 (broadened singlet, H-l’), 3.90 (quartet, H-3’), 4.69 (octet, H-4’), 6.21 (octet, H-5’), 6.40, 6.59 (MeN-1 and -3), 7.86, 7.91 (6 protons, OAc), 8.76 (3 protons,

-

C’orhl~yd. Res., 13 (1970) 9?-104

K. ONODERA,

102

T. YAJIMA

doublet, H-6’), ?z 1770 (C=O), 1695,1717 (C=O), 1560 (C=C), 1225 (OAc), 840, 835 cm-’ (C=C); o.r.d. data (c 0.1, chloroform, 20”): negative plain curve. Anal. Calc. for C1,H2,,N40,: C, 52.54; H, 5.11; N, 14.28. Found: C, 52.04; H, 5.12; N, 14.29. Compound 2 (5 g) and theophylline (4.5 g) were dissolved in 100 ml of N,Ndimethylformamide containing 2.5 g of phosphorus pentaoxide. The mixture was heated for 140 h at O-70” with exclusion of moisture, and the reaction mixture was poured into separatory funnel containing equal volumes of chloroform and ice-water. The chloroform layer was washed with ice-water three times, dried over anhydrous sodium sulfate and evaporated under diminished pressure. The residual syrup was dissolved in a small volume of hot ethanol. After decolorization, the ethanolic solution was kept overnight in a refrigerator. The crystalline product obtained was recrystallized from ethanol; yield 350 mg (4.5%), m.p. 192-193”, [a]? - 121.3” (c 0.55, chloroform); A!$gH244 nm. Anal. Calc. for C,,H2cN407 : C, 52.04; H, 5.11; N, 14.28. Found: C, 51.95; H, 5.05; N, 14.26. The n.m.r., i.r., u.v., and o.r.d. data for this compound wereidentical with those of 5 produced by the fusion procedure. 7-(2,4,6-Tri-O-acefyZ-3-deoxy-8_D-threo-hex-2-enopyr~osy~)theophyiZine (8). Compound 6 (7.8 g) and 4.0 g of theophylline were condensed by heating for 20 min at 180-200” in the presence of p-toluenesulfonic acid. After treatment of the reaction mixture as described above, white crystals were obtained in 23% yield; m.p. 203-205", 1,,, EtoH 275 nm, Neil” 246 nm; o.r.d. data (c 0.1, bl f: -10.7” (c 0.28, chloroform); chloroform, 20”): a negative plain curve; n.m.r. data: r 2.27 (1 proton, H-S), 3.12 (doublet, H-l’), 3.67 (quartet, H-3’), 4.57 (quartet, H-4’), 5.97 (octet, H-5’), 5.78 (quartet, H-6’), 6.40,6.58 (MeN-1 and -3), 7.89,7.93,8.05 (9 protons, 0Ac); I$$ 1775, 1723 (C=O), 1560 (C=C), 1225 (OAc), 835 (C=C) cm-‘. Compound 7 (5 g) and theophylline (2.8 g) were condensed as described above. The product was obtained in 33% yield and its physical properties were identical with those of compound 8 prepared by the condensation of 6 with theophylline. Anal. Cab for CIgH,,N,09: C, 50.66; H, 4.92; N, 12.44. Found: C, 50.53; H, 5.03; N, 12.53. 7-(2,4,6-Tri-O-acefyZ-3-deo~-a-D-erythre (9). - 2-Hydroxy-D-glucal tetraacetate (3 g) and theophylline (2 g) were melted at 130” in an oil bath. After the addition of 0.1 g of p-toluenesulfonic acid, condensation was performed for 20 min at 130-140” under diminished pressure. To the reaction mixture was added 10 ml of ethanol and the mixture was then decolorized with active carbon. A crystalline product was obtained, yield 1.7 g (42%); m-p. 8688”, [a]h6 f80” (c 1.0, chloroform); AgtH 276 run, A,,, “cH 245 nm; n.m.r. data (chloroform-d): z 2.08 (1 proton, H-S), 3.17 (singlet, H-l’), 3.84 (quartet, H-3’), 4.39 (octet, H-4’), 5.80 (2 protons, H-6’), 6.13 (octet, H-5’), 6.40, 6.60 (MeN-1 and -3), 7.83, 7.85, 7.96 (9 protons, OAc); ~2: 1750,171O (C=O), 1550 (C=C), 1220 (OAc), 840,835 cm-’ (C=C); or-d. data (c 0.1, chloroform, 20’): a positive plain curve. Carbohyd.KS.,

13 (1970) 97-104

UNSATURATED

SUGAR

103

NUCLEOSIDES

Anal. Calc. for C,aH,,N,O, C, 49.83; H,5.13; N, 12.39.

-0.5 H,O):

C, 49.64; H, 5.05; N, 12.20. Found:

7-(4,6-Di-O-acetyZ-2,3-dideoxy-P_D-threo-~zex-2-enopyranosyl)tlreophylline

(IO).

Condensation of D-galactal triacetate (4.9 g) with theophylline (3.9 g) was effected for 30 min at 140-150” in the presence ofp-toluenesulfonic acid and under diminished pressure. The reaction mixture was dissolved in 22 ml of ethanol and the crystalline product that formed was recrystallized from ethanol; yield, 12%; m-p. 208-210”, [a]: 0” (c 0.25, chloroform); AzEH 274 nm, AEgH 245 nm; o.r.d. data (c 0.1, chloroform, 20”): a negative plain curve, n.m.r. data (chloroform-d): z 2.22 (1 proton, H-8), 3.09 (H-l’), 4.98 (H-2’), 4.73 (H-3’), 4.55 (1 proton, H-4’), 5.80 (2 protons, H-6’), 6.02 (1 proton, H-5’), 6.42,6.60 (MeN-1 and-3), 7.82,7.94 (6 protons, OAc); vE:i 1750, 171O(C=O), 155O(C=C), 1220(OAc),835 cm-‘(C=C). Anal. Calc. for C,,H2eN407: C, 52.04; H, 5.14; N, 14.28. Found: C, 51.80; H, 4.93; N, 14.13. -

7-(#-0-Acetyll-2,3,6-trideoxy-P_L-erythro-hex-2-enopy~~osy~theophyl~ine

(11).

condensation reaction was performed for 15 min at 130-140” in the presence of p-toluenesulfonic acid with 1 g of L-rhamnal diacetate and 0.9 g of theophylline; yield, 23.4%; m.p. 85-86”, [or];” +71.7” (c 0.55, chloroform); AzgH 274 nm AEvz 247 nm; o.r.d. data (c 0.1, chloroform, 20”): a positive plain curve; mm.;. data (chloroform&): z 2.22 (1 proton, H-8), 3.30 (H-l’), 5.12 (H-2’), 4.22 (H-3’), 4.67 (H-4’), 5.86 (H-5’), 6.40, 6.60 (MeN-1 and -3), 8.10 (3 protons, OAc), 8.66 (H-6’); vrf; 1720, 1690 (C=C), 1220 cm-’ (OAc). Anal. Calc. for C,5H,8N40s: C, 53.88; H, 5.43; N, 16.76. Found: C, 53.88; H, 5.67; N, 16.65. -The

7-(2,4-Di-O-acetyyl-3-deoxy-a-~glycero-pent-2-enopyranosy~theophyZZine

(12). -

Condensation of 2-hydroxy-D-xylal triacetate (1.9 g) with theophylline (1.35 g) was performed for 20 min at 140” under diminished pressure_ The product was obtained amorphous; [a]$” _t 15” (c 0.1, chloroform); r-‘,‘Fz 276 nm, Agg,” 247 run; 0-r-d. data (c 0.1, chloroform, 20”): a positive plain curve; n.m.r. data (chloroform-d): r 2.23 (1 proton, H-S), 3.18 (H-l’), 3.80 (H-3’), 4.61 (H-4’), 6.18 (2 protons, H-5,, 5’), 6.40, 6.60 (MeN-1 and -3), 7.87,7.89 (6 protons, OAc); v=z 1770,1710(C =O), 1550 (C = C), 1230 cm- r (OAc). ACKNOWLEDGMENT

The authors are grateful to Dr. T. Shingu (Department Kyoto University) for measurement of n.m.r. spectra.

of Pharmacolo,T,

REFERENCES 1 W.A. BOWL= AND R.K. ROBINS, J. Amer. Chem. Sot.,86 (1964)1252. 2 E.E. LEIJTZINGER, R.K. ROBINS, AND L.B. TOWNSEND, TerruhedronLert.,(1968)4475. 3 C. L. STEVENS,N.A.NIEE.EN, AND P. BLU~ERGS,J. Amer. Chem. Sot., 86 (1964)2725. 4 J.P. HORWITZ, J. CHUA, M-A. DA ROOGE, AND M. NOEL, Tetrahedron L&t., (1964) 2125. 5 J. P. HORWITZ, J. CXIJA,AND M. NOEL, Tetrahedron Letr., (1966) 1343.

Curbohyd.

Res., 13 (1970) 97-104

104

K. ONODERA, T. YAJIMA

6 J. R. MCCARTHY, JR., M. J. ROBINS, L. B. TOWNSEND, AND R. K. ROBINS, J. Amer. Chcm. Sot., 88 (1966) 1549.

7 J. R. MCCARTY, JR., R. K. ROBINS, AND M. J. ROBINS, J. Amer. Chem. Sot., 90 (1968) 4993. 8 K. ONODERA, S. HIRANO, H. FUKIJMI, AND F. MASIJDA, Curbohyd. Res., 7 (1965) 254. K. ONODERA, S. HIRANO, N. KAsHrhfuti, F. MASUDA, T. YAJIMA, AND N. MIYAZAKI, J. Org. Chem., 31 (1966) 1291. 9 K. ONODERA, S. HIRANO, F. MASUDA, AND T. YAJIMA, Chem. Commun., (1968) 1538. 10 R. J. FERXIER AND G. H. SANKEY, J. Chem. Sot. (C), (1966) 2345. 11 R. K. NESS, H. G. FLETCHER, JR., AND C. S. HUDSON, J. Amer. Chem. Sot., 73 (1951) 296. 12 B. R. BAIEER,K. HEWSON, H. J. THOMAS, AND J. A. JO~INSON,JR., J. Org. Chem., 22 (1957) 954. Curbohyd. Res., 13 (1970) 97-104