The effect of stereochemistry on the oxidation of substituted hexitols

Carbohydrate

Rtsccrrrh

89

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THE

EFFECT

OF

SUBSTITUTED

STEREOCHEMISTRY

ON THE

OXIDATION

OF

HEXITOLS”

GEORGE Y. Wu**

AND

J. M.

Department of Chemistry,

SUGIHARA

North Dakota State University, Fargo, North Dakora 58102 (U. S. A.)

(Received September 29th, 1969; in revised form, December 27th. 1969)

ABSTRACT

l-O-Benzoyl-2,3:5,6-di-O-isopropylidene-D-gulitol (3) and -D-allitol. (4) were found to be inert toward oxidation by chromium trioxide in pyridine, confirming previous findings of apparent effects of 1,4-interaction. l-O-Benzoyl-2,3:5,6-di-Oisopropylidene-D-mannitol (2), though previously established to be inert toward chromium trioxide in pyridine, was smoothly oxidized to 6-0-benzoyl-1,2:4,5-di-Oisopropylidene-D-arabino-3-hexulose (5) by methyl sulfoxide in acetic However, the latter converted 1,5-di-0-benzoyl-2,4-U-benzylidene-xylitol -ribitol(7) into 3-(methylthio)methyl ethers.

anhydride. (6) and

INTRODUCTION

The reaction mechanism proposed by Westheimer’ for the oxidation of secondary alcohois to ketones by chromic acid has had general acceptance. A rapid, reversible formation of chromate ester is followed by the rate-determining abstraction of a proton from the carbinol carbon atom. However, the initial step may become rate 0 I II HC-OH + HsCr04 + H’ z=? MC-0-Cr-OH I I I OH [’ controlling

when an alcohol

i + Hz0 ---f ‘C=O+HsO++HsCrOs / 1

that is highly sterically

hindered

is applied2.

Oxidation of substituted alditols with chromic acid as a route to ketoses has given varied results. 1-0-Benzoyl-2,3:5,6-di-U-isopropylidene-DL-galactitol (1) was smoothly oxidized to the expected ketose by chromium trioxide in pyridine3. On the other hand, a stereoisomer, l-O-benzoyl-2,3:5,6-di-O-isopropylidene-D-mannitol (2), was inert4*‘. The extent of interaction of the hydroxyl group on C-4 with the benzoyloxy group on C-l was presumed4 to be the important variable. In order to understand

better

stereoisomers

this marked of

difference

in reactivity,

1 and 2 and have established

*Dedicated to the memory of Professor M. L. Wolfram. **Present U. S. A.

address: Department

we have prepared

their

reactivity

toward

of Chemistry, St. Vincent College, Latrobe,

two additional chromic

acid.

Pennsylvania

15650,

Carbohyd. Res., 13 (1970) 89-95

G. Y. WU,

90

J. M, SUGIHARA

Methyl sulfoxide in acetic anhydride and with phosphorus pentaoxide applied as additional oxidizing agents for comparative purposes.

have been

RESULTS AND DISCUSSION

Crystalline

l-O-benzoyl-2,3:5,6-di-O-isopropylidene-o-gulitol

by reduction of 2,3:5,6-di-0-isopropylidene-D-gulono-1 selective benzoy!ation of the primary hydroxyl group.

(3) was obtained

,4-lactone6, followed by The i.r. absorption of the

starting lactone near 1780 cm- ’ (I ,Uactone) supports the structural assignment made6. Acetonation of o-allono-1,4-lactone’ provided the 2,3: 5,6_diisopropylidene acetal, which exhibited i-r. absorption near 1780 cm- ‘. Reduction of the latter acetal, followed by selective benzoylation, gave crystalline l-O-benzoyl-2,3:5,6-di-Osopropylidene-D-allitol (4). h,COBZ

I_LEOBZ

Mt%C&

I HCO

,004

OCH

I I

I

HOCH

HCOH

I I H&O’

HCO

1(o-isomer1

>CMe2 HCO

1 >CMe, HCO

I I HCO

HCOH

I I

HOCH

HCO

1 )CMe2 HzCO

I

HCO

[

I

Me2C,

H,COBz

H*COE3Z

I

'CMe,

2

I

‘CMe

%CO’ 3

2

HCO,

I

H2CO’

,CMe,

4

Neither 3 nor 4 gave a ketose under reaction conditions (chromium trioxidethat gave 6-O-benzoyl-l,2:4,5-di-O-isopropylidene-~~-_~yZo-3-hexulose pyridine)3 from 1.incompounds 2,3, and 4, the hydroxyl groups on C-2 and C-3 are disposed cis in the Fischer projection formula. Thus acetonation to give the 2:3-isopropylidene acetal provides a dioxolane ring on which C-l and C-4 are cis (Fig. 1). In the galactitol derivative (l), these substituents are placed in a trajis-relationship (Fig. 2). Formation of a chromate ester would probably be hindered seriously when the substituents at CH3

I

0

/&

0

4

1

Y&--P 2

3

0

0

‘H

0 =

/ _(j Fig. 1. c&Disposition

-

\

of substituents on 2,3-acetal

Carbohyd. Res., 13 (1970) 89-95

ring.

OXIDATION

91

OF SUBSTITUTJZD HEXITOLS

Fig. 2. rrans-Disposition

of substituents

on 2,3-acetal

C-1 and C-4 are disposed cis, as compared propose that hindrance in this esterification

ring.

with the opposite configuration. We step causes the marked difference in

reactivity, since it is not evident how removal of a proton from the carbinyl carbon atom, should esterification occur, be appreciably different among the four isomers. Some comparative studies have been made by using methyl sulfoxide (MelSO) and acetic anhydride as the oxidizing agent. The mannitol derivative (2) was converted into a crystalline product. The n.m.r. spectrum showed signals assignable without ambiguity to aromatic, methine and methylene, and methyl protons in the ratio, 5:7:12, consistent with the structure of 6-O-benzoyl-1,2:4,5-di-U-isopropylideneD-arabirzo-3-hexulose (5). Hydrolysis of 5 in acetone with Amberlite IR-120 (H+) resin gave crystalline 6-O-benzoyl-D-arabitro-3-hexulose, whose n.m.r. spectrum showed no signals attributable to methyl protons. Application of the same procedure to the gulitol (3) and the allitol (4) derivatives provided syrups that have not been crystallized. H&0Bz

pi-2

M=2=\oCH

HA,/ 2

I

rfco

I

“iO\ DCHPh I

RXL

I

c=o

‘ewe,

I

kC0'

H,COaZ

H&OQZ

I

H,COBZ 5

The behavior anhydride

has

bR=H

7R=H

8 R = CH;SCH3

9 R =

Ct-$SMe

10 R = cocu3

llR=

AC

of some additional

been

determined.

substrates toward methyl sulfoxide 1,5-Di-O-benzoyl-2,4-U-methylenexylitolg Carbohyd.

and acetic and

Res., 13 (1970) 89-95

92

G. Y. WU,

J. M. SUGIHARA

1,5-di-0-benzoyl-2,4-0-metl~yleneribitol~ have previously been oxidized by chromium trioxide in acetic acid, but not in pyridine, to the same product, 1,5-di-O-benzoyl-2,40-methylene-erythvo-3-pentulose. Under the same reaction conditions, 1,5-di-Obenzoyl-2,4-0-benzylidene-xylitol(6) and -ribitol(7) were not oxidized4. Both 6 and 7, when treated with methyl sulfoxide-acetic anhydride, yielded crystalline products, presumed to be the 3-(methylthio)methyl ethers (8 and 9, respectively), based upon the presence of signals at r 7.80 in the n.m.r. spectra, assignable to methyl protons in the SCH, groups lo _ Melting points were depressed when 8 and 9 were mixed with 3-U-acetyl-l,5-di-U-benzoy1-2,4-U-benzylidenexylitol (10)and -ribitol (ll), respectively. A mechanism describing the formation of these ethers has been previously described’. No products of oxidation were obtained when 2, 3, and 4 were treated with methyl sulfoxide and phosphorus pentaoxide” in phosphoric acid. EXPERIMENTAL

General methods. - Analyses were made by the Australian Microanalytical Service. N.m.r. spectra were recorded on a Varian A-60A n.m.r. spectrometer for solutions in deuteriochloroform. 1-r. spectra of Nujol mulls or potassium bromide pellets were recorded on a Beckman IR-10 spectrophotometer. Melting points were determined on a Fisher-Johns apparatus and are not corrected. Optical rotations were taken on a Shimadzu spectropolarimeter in I-dm tubes. 2,3:5,6-Di-O-isopropylidene-D-gulitol. A solution of 2,3:5,6-di-O-isopropylidene-o-gulono-1,4-lactone6 (2 g) in 250 ml of dry ether was added dropwise during 60 min at room temperature into 100 ml of an ethereal solution of 0.80 g powdered lithium aluminum hydride. The mixture was refluxed for 2 h and the excess hydride destroyed by gradual addition of wet ether, with external cooling and stirring. The mixture was filtered through a layer of packed Celite (Johns-Manville). Concentration of the filtrate at room temperature with seeding provided a crystalline product, yield 1.4 g (70%): m-p. 72-74”, [c&’ -t-9.35” (c 0.11, ethanol). The first crystalline product was obtained by vacuum distillation of the syrup at c 150”; the i.r. spectrum showed no band at 1,790 cm-‘. An analytical sample, m.p. 75.5--76”, was prepared by three recrystallizations from ligroin. Anal. Calc. for CrzH,,O,: C, 54.95; H, 8.45. Found: C, 54.65; H, 8.66. I-O-BenzoyZ-2,3:5,6-di-O-isopropylid~ne-D-guZitol (3). To an ice-cold, vigorously stirred solution of 2.62 g (IO mmoles) of 2,3:5,6-di-O-isopropylidene-Dgulitol in 13 ml of dry pyridine was added dropwise a mixture of 1.4 ml (1.54 g, I I mmoles) of benzoyl chloride in anhydrous pyridine (13 ml). After 12 h at 0” the resulting suspension was poured with stirring into 200 ml of crushed ice. The mixture was kept overnight in the cold to give a layer of syrup, which was crystallized from ethanol giving 2.4g (70%) of 3, m-p. 98-100”. An analytical sample, m-p. 99-lOO“, [a];? - 12.5” (c 1.1, e th anol), was prepared by three additional recrystallizations from ligroin. Anal.Calc. for C,9H2607: C, 62.28; H, 7.15. Found: C, 62.26; H, 7.10. Carbohyd. Res., 13 (1970) S9-95

G. Y. wu, J. rvl. SUGIHARA

94

coid and a syrup resulted. Several washings of the syrup with ice-cold water and keeping *in the cold afforded a solid, which crystallized from absolute ethanol to give 5; yield 2,4 g (51%), m-p. 76”. An analytical sample, m-p. 74-75”, [a]G2 + 60.5” (c 0.8, ethanol), was prepared after four recrystallizations from ligroin; n.m.r. data: t 1.8-2.1 (multiplet, 2 protons, orrho-aromatic), 2.4-2.7 (multiplet, 3 protons, meta- and paraaromatic), 4.9-6.1 (multiple& 7 protons, methylene and methine), 8.4, 8.56, 8.6, 8.64 (4 three-proton singlets, methyl).

Anal. Calc. for ClgHZ407: C, 62,62; 6-0-Benzoyl-D-arabino-3-/rextrlose. isopropylidene-D-arabino-3-hexulose (1 g), Amberlite IR-120 (Hi) resin was refluxed filtrate was evaporated to provide crystalline

H, 6.64. Found: C, 62.64; H, 6.63. A mixture of 6-0-benzoyl-1,7:4,5-di-Oacetone (50 ml), water (15 ml), and 5 g of for 5 h. The mixture was filtered and the 6-O-benzoyl-D-arabino-3-hexulose (89%),

m.p. 147-148”, [a]g -82.0 (c 0.91, ethanol); n.m.r. data (in chloroform-d after exchange with deuterium oxide): 7 1.9-2.7 (multiplet, aromatic), 5.3-6.3 (multiplet, methylene and methine), no signal between r 8-9. Anal. Calc. for C,3H,607: C, 54.93; H, 5.68. Found: C,54.84; H, 5.67. 1,5-Di-O-be~lzoyl-2,4-O-berlzy~ide~e-3-O-~~~~etf~y~t~~io)~~~etl~yIxy~itoi (8). A solution

of 3.45 g (10 mmoles)

of 1,5-di-O-benzoyl-2,4-O-benzylidene-xylitol’2

(6),

30 m! of methyl sulfoxide (distilled over caicium hydride), and 20 ml of acetic anhydride was kept for 20 h at room temperature. The mixture was poured, with s;irring, onto ice-water containing potassium carbonate. The powder deposited was collected on filter paper, washed several times with cold water, and crystallized from ethanol to give 1.2g (41%) of 8, m-p. 156-157”. An analytical sample, m-p. 160-161”, was prepared by three recrystallizations from ligroin; n.m.r. data: T 7.8 (3-proton singlet, SCH,), 1.8-2.8 (multiplet, 15 aromatic protons, 4.3-6.0 (multiplet, 10 protons, methylene and methine). Anal. Calc. for C2,H,,0,S: C, 66.12; H, 5.55. Found: C, 66.00; H, 5.58. 3-0-AcetyZ-1,5-di-O-benzoyZ-2,4-O-be~z~~Zidene_~yIito~ (10). To 1,5-di-Obenzoyl-2,4-0-benzylidenexylitol 1’ (1 g) in pyridine (10 ml) was added 1 ml of acetic anhydride.

The mixture,

after being kept overnight

at room temperature,

was

poured, with stirring, into an ice-cold solution of potassium carbonate. The precipitate was filtered on paper, washed several times with cold water, and crystallized from absolute ethanol to give 1.3 g (91%) of 10,m-p. 124-127”. An analytical sample, m.p. 128-129”, was prepared by three recrystallizations from ethanol; n.m.r. data: 5 7.81 (singlet, 3 protons, acetyi methyl) 1.82-2.7 (multiplet, 15 protons, aromatic), 4.2-5.8 (multiplet, 8 protons, methylene and methine). Anal. Calc. for CzsH,,Os : C, 68.56; H, 5.X. Found: C, 68.89; H, 5.55. I,5-Di-O-benzoyl-2,4-O-bei~zyiidene-3-O-~t?~etl~yit~~io)~~~et~~y~ribitoi (9). A solution of 3.45 g (10 mmoles) of 1,5-di-O-benzoyl-2,4-0-bentylideneribito14 (7),

30 ml of methyl sulfoxide,

and 20 ml of acetic

anhydride

was kept for 42 h at room

temperature. The solution was poured into aqueous potassium carbonate with cooling and stirring. The mixture was kept in the cold for several days and the residue was filtered off, washed several times with cold water, and crystallized from ethanol to Curbolqd. Res.,

13 (1970) 89-95

OXIDATION

95

OF SUBSTITUTED HESITOLS

give 1.75 g of 9, m-p. 98”. After several recrystaliizations

from ethanol,

the compound

had m.p. 98-99”. After heating the sample in a high vacuum at 78”, the m.p. increased to 116-118”; n.m.r. data: r 7.5 (3-proton singlet, SCH,), 1.7-2.7 (multiplet, 15 aromatic protons, 4.2-6.0 jmultiplet, 10 protons, methylene and methine). Aural. Calc. for C,,H,,O,S: C, 66.12; H, 5.55. Found: C, 66.69; H, 5.96. 3-0-AcetyI-I,5-di-O-benzoyI-2,4-O-ben~yfideneribito~ (11). - To 1 g of 1,5-di-Oin pyridine (10 ml) was added 1 ml of acetic benzoyE2,P0-benzylideneribito14

anhydride.

The mixture,

after being kept overnight,

was poured,

with stirring,

into an

ice-cold solution of potassium carbonate. The precipitate deposited was filtered off and washed with cold water. An analytical sample, m.p. 108-log”, was prepared by three recrystallizations from ethanol; n.m.r. data: z 7.94 (singlet, 3 protons, acetyl methyl), 1.8-2.8 (multiple& 15 protons, aromatic), 4.1-6.0 (multiplet, 8 protons, methylene and methine). Anal. Calc. for C,,H,,O,: C, 68.56; H, 5.34. Found: C, 68.25; H, 5.50. Attempted oxidation of I-O-benzoyl-2,3:5,6-di-O-isopropyIidet~e-D-gLiIitoI and -D-allitol with chromium trioxide in pyridine. - A mixture of 1 g of the hexitol derivative, 0.4 g of chromium trioxide, and 25 ml of anhydrous pyridine was heated for 120 min at 60”. The mixture was poured with vigorous stirring into ice-water containing

sodium

hydrogen

carbonate.

The suspension

was extracted

several

times

with chloroform. The chloroform was dried (magnesium sulfate) and the starting gulitol and allitol derivatives were recovered in yields of 70% and 65%, respectively. Attempted oxidation qf I-O-benzoyl-2,3:5,6-di-O-isopropylidene-D-r?~ai~t~itol (21, -D-gulitol (31, and -D-ailitol (4) with methyl sulfoside, phosphorus pentaoside, and phosphoric acid. A solution of phosphorus pentaoxide in 85% phosphoric acid (l:l, by wt) was prepared. To 20 ml of this mixture, methyl sulfoxide (10 ml) and 1 g of the hexitol derivative were added with stirrin g. The reaction mixture was kept overnight at room temperature and then poured into an aqueous solution of potassium carbonate, cooled externally_ The precipitate obtained was crystallized from ligroin. Compounds 2, 3, and 4 were recovered in yields of 70%, 65%, and 65%, respectively. REFERENCES 1 F. H. WESTHEILIER, c/lem. Rec., 45 (1949) 419. 2 J. ROCEK, F. H. WESTHEI~IER, A. ESCHENLIOSER, 3 4 5 6

7 8 9 10 11 12

AND L. MOLDOVANY, Hek. Chim. Acra, 45 (1962) 2554. G. U. YUEN AND J. M. SUGIHARA, J. Org. C/tern., 26 (1961) 1598. S. DORRENCE, Ph. D. Thesis, University of Utah, 1964. J. W. BIRD AND J. K. N. JONES, Can. J. Chem., 41 (1963) 1877. K. IWADARE, BulI. Cheat. Sot. Japan, 18 (1943) 230. F. L. HUWOLLER, Merhods Carbohyd. Cftem., 1 (1962) 102. J. D. ALBRIGHT AND L. GOLDhlAN, J. Amer. Chem. Sot., 87 (1965) 4214; 89 (1967) 2416. A. SERA, Ball. Chem. Sot. Japan, 35 (1962) 2033. J. L. GoDhfAN AND D. HORTON, Carbohyd. Res., 6 (1968) 229. K. ONODERA, S. HIRANO, AND N. KASHIMURA. J. Amer. Chem. Sor., S7 (1965) 4651: Corboh_vd_ Res., 6 (1968) 276. R. M. HANN, A. T. NESS, AND C. S. HUDSON, J. Amer. Chem. Sot., 68 (1946) 1761.

Carbohyd.

Res.. 13 (1970) 89-95