Oral cancer in Taiwan: Is diabetes a risk factor?

5576 J. Org. Chem. 1993,58, 5576-5577

Differentiation of Contiguous Hydroxyl Groups by Regioselective Conversion of Acetonides

into tert-Butyl Hydroxyalkyl Ethers

Wen-Lung Cheng, Sue-Min Yeh,' and Tien-Yau Luh'

Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, Republic of China Received June 7, 1993.

Summary: Treatment of the acetonides of simple con- tiguous diols or those derived from carbohydrates with the Grignard reagent yields regioselectively the corre- sponding hydroxyalkyl ether.

Selective transformation of an acetal of a contiguous

diol into the corresponding hydroxyalkyl ether would be highly useful in synthesis because the two hydroxyl groups can thus be differentiated. T i c 4 is commonly used to promote various kinds of cross-coupling reactions of acetals? and the reaction occasionally proceeds with high stereoselectivity.s Regioselective modification of two vicinal hydroxy groups of glycerol via 1,2-0-benzylidene derivatives by reductive cleavage using DIBALH has been

r e p ~ r t e d . ~ Trimethylaluminum has also been employed

to serve this purpose, and high selectivity was achieved only when the substrate contained a neighboring hydroxyl group for chelation.s Although the reaction of a Grignard reagent with an acetal has been known for almost three

decades: not much synthetic use has been r e p ~ r t e d . ~ The

protection of vicinal hydroxy groups of carbohydrates by acetal groups is widely used. Selective deprotection of these acetals would be particularly valuable in derivati- zation of carbohydrates. Described herein are the results which demonstrate a useful regioselective ring-opening reaction of acetonides with Grignard reagents.

In the beginning of this investigation, we tested the

generality of this reaction by treating acetonides 1 with

4 equiv of Grignard reagents in refluxing benzene-ether

(5:l) for 18 h. After the usual workup procedure, the

corresponding hydroxyalkyl ethers 2 were obtained in good

yields (eq l).4 Both five- and six-membered acetonides 5 , l a R = Ph, n = 1 1 b R = C8Hl3, n = 1 l c R = Ph, n = 2 2 1 72% 2b 89% 2c 80%

behaved similarly, and the C-0 bond of the less hindered

site in 1 was cleaved regioselectively. Presumably, the

oxygen atom on this site would coordinate to magnesium ~

Abstract published in Advance ACS Abstracts, September 1,1993. (1) Recipient of the Ministry of Education scblarehip, 1992-93. (2) For a review, see: Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043.

(3) (a) Bartlett, P. A.; Johnson, W. S.; Elliott, J. D. J . Am. Chem. SOC.

1983,105,2088. (b) Mori, A.; Fujiwara, J.; Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1983, 24, 4581.

(4) (a) Takano, S.; Kurotaki, A.; Sekiguchi, Y.; Satoh, S.; Hirama, M.; Ogasawara, K. Synthesis 1986, 811. (b) Takano, S.; Akiyama, M.; Ogasawara, K. C h m . Phurm. Bull. 1984,32,791. (c) Takano, S.; Akiyama, M.; Sato, 5.; Ogasawara, K. Chem. Lett. 1983,1693.

(5) Takano, S.; Ohkawa, T.; Ogasawara, K. Tetrahedron Let). 1988, 29, 1823.

(6) (a) Blomberg, C.; Vreugdenhil, A. D.; Homsma, T.Rec. Trau. Chim.

1963,82,355. (b) Mallory, R. A.; Rovinski, S.; Scheer, 1. Roc. Chem. SOC.

London 1964,416.

0022-3263/93/1958-5576$04.00/0

preferentially, resulting in the regioselective protection of the more hindered hydroxy group of a diol.

The presence of a neighboring oxygen moiety changed the selectivity. Thus, the reaction of 3 with MeMgI

afforded the corresponding diol 4 in 78% yield (eq 2). It

seemed likely that the chelation with magnesium leading

to intermediate 5 may play a key role in controlling such

selectivity. 3 4 OBu-t X Me t-BuO H 8 5

The extension of this reaction to sugar derivatives has

been executed. Bisacetonides 6 were allowed to react with

an excess amount of the Grignard reagent in benzene-

ether a t 60 "C for 4 h to give 7 exclusively (eq 3). The

Me I Me tie 6rR'=H, R"=OMe 6b R'=OMe, R"= H 7 1 R = Ph, R'= H, R"= OMe; 53% 7b R I Me, R' P H, R" = O M ; 72?/0 7c R = Ph, R'= OMe; R"= H; 57% 7d R = Me, R'=OMe; R"= H; W/o

structures of 7 were unambiguously proven by 2D-COSY

experimente. Interestingly, both anomeric a- and @-meth-

oxy groups gave the same cleavage pattern, liberating the

2-hydroxyl derivatives 7. Again, the chelation of the OMe

group and the neighboring oxygen function at C-2 with

magnesium may explain the results. When 6a was treated

with MeMgI under refluxing toluene conditions for 36 h,

diol 8 was isolated in 71% yield. In a similar manner,

bisacetonides 9a and b were transformed, under similar

conditions at 60 OC overnight, into 10a and b in 79 and

75 % yields, respectively (eq 4). On the other hand, diols

o+

-

0 1993 American Chemical Society

101 79% b75%

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Communications J. Org. Chem., Vol. 68,

No.

dithioacetal moiety would promote the corresponding

coupling reaction of the sulfur moiety in the presence of

the nickel catalyst. Indeed, the reaction of 11 with MeMgI

in the presence of a catalytic amount of NiClz(dppe) gave

15 in 55% yield (eq 7). This result illustrates an interesting

12 and 14 were obtained in 64 and 66% yields from the

exhaustive reactions of MeMgI with 11 and 13 in refluxing

benzene, respectively (eqs 6 and 6). It is worth noting

that starting 11 wae recovered in 96 ’3% yield upon treatment with MeA.8

/..

1 1

12

14

We recently demonstrated that the aliphatic dithioacetal

group can undergo nickel-catalyzed croes-coupling reaction

by means of chelation.9 Accordingly, the presence of an oxygen function which is in close proximity with the (7) For a review, me: Trotimov, B. A.; Koroetova, S. E. RIMS. Chem. Rev. 1976,44,41.

(8) Cf. rsf 6.

(9) (a) Wong,K.-T.; Luh, T.-Y. J. Am. Chem. SOC. 1992,114,7908. (b)

SKU, L.-L.; Yu, C. C.; WOW, K.-T.; C h a , B.-L.; C h w , W.-L.; Yw, T.-M.; Luh, T.-Y. Organometallics 1908,12,1018. (c) For a review on

the coupbg reactio~ of dithioace*, we: Luh, T.-Y. Acc. Chem. Re8. 1991,

a,

/B

1 1

55% _OH i

15

one-pot transformation of acetonides-dithioacetals into

the corresponding hydroxy alkenes.

In summary, we have demonstrated a useful procedure to partially deprotect acetonides of vicinal diols to give the corresponding tert-butyl hydroxyalkyl ethers. The

application of this reaction could be particularly useful in

selective protecting-deprotecting of hydroxyl groups in carbohydrates. Further synthetic applications are in progress in our laboratory.

Acknowledgment. Support from the National Science Council of the Republic of China is gratefully acknowl- edged.

Supplementary Material Available: Experimental pro- cedures for the preparation of 2a-c, 4,7a-d, 8,10a,b, 12,14, and 16 (6 pages). This material ia contained in libraries on microfiche,

immediately follow this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information.

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