Trends in Synthetic Carbohydrate Chemistry - American Chemical

Chapter 9

Total Synthesis of Cyclodextrins

Downloaded by UNIV OF CALIFORNIA SAN FRANCISCO on February 18, 2015 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch009

Yukio Takahashi and Tomoya Ogawa Riken Institute of Physical and Chemical Research, Wako-shi, Saitama 351-01, Japan

An approach to the total synthesis of cyclodextrins is outlined. Intramolecular glycosylative cyclizations are investigated as the key step, using appropriately protected malto-oligosyl fluorides, for successful synthesis of completely protected cyclomalto-hexa-, hepta-, and -octaoses. Deprotection of these intermediates afforded the desired, unsubsituted cyclodextrins.

Cyclodextrins, products of the degradation of starch by an amylase of B a c i l l u s macerans(1), have been studied i n terms of chemical modifications, mainly for the purpose of developing e f f i c i e n t enzyme mimics(2). Not only their unique c y c l i c structures, but also their a b i l i t y to form inclusion complexes with suitable organic molecules, led us to investigate the t o t a l synthesis of t h i s class of molecules(3)· We describe here an approach to a t o t a l synthesis of a l p h a ( l ) , gamma(2), and "iso-alpha" cyclodextrin (3).

0097-6156/89/0386-0150$06.00/0 © 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

9. TAKAHASHI AND OGAWA


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Retrosynthetic analysis of cyclodextrins led us to design a l i n e a r , key intermediate 4 which could be suitable for a possible intramolecular g l y c o s y l a t i o n for the synthesis of alpha, gamma, and some isomeric cyclodextrins, according to the kind of protective group at C-6 of the nonreducing glucopyranosyl residue. [A] Synthesis of eyeloma1tohexaose (alpha cyclodextrin) We f i r s t describe a synthesis of alpha cyclodextrin. The synthetic plan i s shown i n Scheme 1 . An immediate precursor for 1 could be the perbenzylated precursor 5, which could be cleaved to give a l i n e a r glucohexaosyl f l u o r i d e 6. This key intermediate 6 i s obtainable from the maltose d e r i v a t i v e s 8 and 9 through the intermediacy of the glucohexaose d e r i v a t i v e 7.

Synthetic transformation of β-maltose octaacetate (10) into the g l y c o s y l acceptor 8 and g l y c o s y l donor 9 i s shown i n Scheme 2.


TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

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Compound 10 was converted into a l l y l glycoside 11 i n 73% y i e l d i n two steps, (a) Bu^SnOCH CH=CH —SnCly (^), and (b) MeONa—MeOH. Treatment of 11 with dimethoxypropane and TsOH, and then with benzyl bromide— NaH—DMF afforded compound 12 i n 51% y i e l d . S o l v o l y s i s of compound 12 i n MeOH—AcOH, and then monobenzylation by the stannylation— a l k y l a t i o n method(5) gave the desired g l y c o s y l acceptor 8 i n 67% y i e l d . Acetylation of compound 8 and then d e a l l y l a t i o n with P d C l — AcONa i n aq.AcOH(6) afforded a 93% y i e l d of hemiacetal 13, which was treated with (a) S0C1 —DMF i n dichloroethane(7) and (b) AgF— CH^CN(8) to give the desired f l u o r i d e 9 i n 73% o v e r a l l y i e l d . 2

2

2


2

13

8

Scheme 2.

9

Synthesis of the glycosyl acceptor and donor.

Having a g l u c o b i o s y l f luoride 9 and a g l y c o s y l acceptor 8 thus e f f i c i e n t l y prepared, g l y c o s y l a t i o n conditions using both compounds were examined with respect to the kind of solvent and Lewis acid to be employed. In the presence of SnCl2(9)1 AgOS0 CF^, and powdered molecular sieves i n Et 0, compounds 8 and 9 afforded a 1.8:1 mixture of 14 and 15 i n 80% y i e l d as w e l l as the 1,6-anhydro d e r i v a t i v e 16 (15%)· Other g l y c o s y l donors carrying either chlorine or trichloroacetimidate i n place of f l u o r i n e gave i n f e r i o r r e s u l t s i n t h i s p a r t i c u l a r instance. Further elongation of the glucan chain on the glucotetraose d e r i v a t i v e 14- was studied i n two ways. F i r s t , compound 14 was transformed into a g l y c o s y l acceptor 17, which was then glycosylated by use of 2 equivalents of the donor 9 under the same conditions as already described to give a 2:1 mixture of 7 and 18 i n 65% y i e l d . Second, compound H was transformed into the glucotetraosyl donor 19 i n 50% o v e r a l l y i e l d i n 3 steps, (a) PdCl —AcONa—aq.AcOH, (b) S0C1 —DMF, and (c) AgF—CH3CN. G l y c o s y l a t i o n of the g l y c o s y l acceptor 8 with 0.9 equivalent of the g l y c o s y l donor 19 afforded a 1.7:1 mixture of 7 and 20 i n 55% y i e l d . From the preparative viewpoint, the f i r s t route using glucotetraosyl acceptor 17 and 2

2

2

2





15

14

153

16

Scheme 3 ·

17

Scheme ^ . Glucohexaosyl intermediate via the glucobiosyl-donor and glucotetraosyl-acceptor route.

20

Scheme 5 · Glucohexaosyl intermediate v i a the glucotetraosyldonor and glucobiosyl-acceptor route.



154

glucobiosyl donor 9 i s more e f f i c i e n t than the second one. Conversion of the glucohexaosyl d e r i v a t i v e 7 into the desired key intermediate 6 i s shown i n Scheme 6. Treatment of 7 with (a) NaOMe— MeOH, (b) (C1CH C0) 0— pyridine afforded i n 70% y i e l d the monochloroacetyl d e r i v a t i v e 21, which was d e a l l y l a t e d with P d C l — NaOAc—aq.AcOH to give the hemiacetal 22 i n 60% y i e l d . The transformation of 22 into f l u o r i d e 23 was achieved i n 73% y i e l d i n 2 steps: (a) S0C1?—DMF and (b) AgF—CHoCN. Compound 23 was deacylated with NaOMe—MeOH—THF to give 6 i n 95% y i e l d . 2

2


2

f*Nu f*Nu f-*V ^ Ζ

21

22

0

RO-^ROO-

f

ROJ^O

W_

OMCA

JJ

C

^ ^5 R=Bn 1 R=H

Scheme 6.

(MCA = C1CH C0). 2

The c r u c i a l intramolecular g l y c o s y l a t i o n of 6 with S n C l — AgOS0 CF^ afforded a 20% y i e l d of compound 5; the l a t t e r was debenzylated with Pd-C—HC0 H—Me0H(1_0) to give cyclomaltohexaose (alpha cyclodextrin) q u a n t i t a t i v e l y . 2

2

2

[B] Synthesis of cyclomaltooctaose (gamma cyclodextrin) A synthetic approach to gamma cyclodextrin was a l s o examined by use of the technology developed i n [A]. Two routes for the preparation of a glucooctaosyl intermediate 25 were examined. In a f i r s t approach, the glucohexaosyl acceptor 24-, r e a d i l y obtained from 7 (Scheme 6) was glycosylated with 5·5 equivalents of the donor 9 to give a 21% y i e l d of the desired intermediate 25 as w e l l as a 5-4-% y i e l d of the isomeric product 26. As a second approach, the glucotetraosyl f l u o r i d e 19 was treated with an equivalent amount of the glucotetraosyl acceptor 17 to give a 27% y i e l d of a 3:1 mixture of 25 and the β-anomer. However, i n this reaction, a major product was found to be the undesired 1,6-anhydro d e r i v a t i v e 27, i s o l a t e d i n 30% y i e l d . As the y i e l d of the desired product 25 by both routes was comparable and the preparation of glucotetraosyl donor 19 requires 3





155

Scheme 8. steps from the intermediate 14 (Scheme 5), i t was more p r a c t i c a l to use an excess of the glucobiosyl donor 9> as described i n the f i r s t approach. The glucooctaosyl d e r i v a t i v e 25 was converted into the f l u o r i d e 28, i n 4.7% o v e r a l l y i e l d , i n 3 steps (a) P d C l — AcONa— aq.AcOH, (b) S0C1 —DMF, and (ç) AgF. Deacylation of 28 with MeONa— MeOH— THF afforded a 92% y i e l d of the key intermediate 29· Compound 29 was c y c l i z e d i n the presence of SnCl —AgOSO-pCF^—Ά molecular sieves i n Et 0—C1(CH ) C1 to give an 8.4% y i e l d of perbenzylated gamma cyclodextrin, which was debenzylated with 10% Pd-C i n HC0 H—MeOH— THF—H 0 to give an 80% y i e l d of gamma cyclodextrin (2). 2

2

2

2

2

2

2

2

[C] Synthesis of iso-alpha cyclodextrin In the previous section we observed that intramolecular g l y c o s y l a t i v e c y c l i z a t i o n leading to alpha cyclodextrin was 2.Λ times more e f f i c i e n t i n terms of the y i e l d obtained than that leading to gamma cyclodextrin. We have examined how r e g i o s e l e c t i v e this type of c y c l i z a t i o n i s when the 4->6-diol d e r i v a t i v e 30 is used to give 31 and 32. Product 32 may be regarded as an iso-alpha cyclodextrin derivative. The synthetic plan i s shown i n Scheme 10. When used i n combination with a g l y c o s y l acceptor 17, the glucobiosyl donor 33 (which carries different kinds of a c y l protective groups on 0-Λ and 0-6'), may be suitable for the preparation not only of 30 but a l s o of other intermediates carrying different functional groups at C-6 of the nonreducing-end glucopyranosyl residue of 30. !




156

32

Scheme 10.

D i o l 3Λ, r e a d i l y obtainable from 12 (Scheme 2), was converted into the f l u o r i d e 33 i n 5 steps i n 35% o v e r a l l y i e l d . Glycosylation of compound 17 with 4.6 equivalents of the donor 33 afforded the desired glucohexaosyl d e r i v a t i v e 35 i n 18% y i e l d , together with the β-isomer 36 i n 8.2% y i e l d .


9. H0

TAKAHASHI AND OGAWA

"-\A_-a


157

r OMCA

~

Β

„

" ^ - V - V


OMCA

35 —

Scheme 11.

36

Synthesis of a glucohexaosyl

intermediate.

The transformation of compound 35 into f l u o r i d e 30 was achieved i n 50% o v e r a l l y i e l d v i a compound 37 i n k steps: (a) PdCl —AcONa, (b) S0C1 —DMF, (c) AgF, and (d) MeONa—MeOH—THF. The c r u c i a l g l y c o s y l a t i v e ring-closure was achieved e f f i c i e n t l y i n the presence of SnCl —AgOS0 CF —4Â molecular sieves i n C1(CH ) C1 i n 65% y i e l d to give a 1:2.5 mixture of 31 and 32. The structure of 31 was r e a d i l y determined by i t s transformation into the perbenzyl d e r i v a t i v e 5, which was i d e n t i f i e d with the same compound obtained previously i n Scheme 6. The isomeric product 32 was transformed into the monoacetate 38, which showed a signal for a c e t y l methyl at δ 1.901 i n i t s ^H n.m.r. spectrum, and was a l s o debenzylated q u a n t i t a t i v e l y to give "iso-alpha cyclodextrin" 3, [O^D +81° (c 0.05, 2

2

2

2

3

2

2

H 0). 2

,OWCA

,OMCA

35

37

ο

Λ

31 R = B n R'=OH " 5 R=R'=Bn ~ /

30

Scheme 12.

32 R = B n , R ' = 0 l i 38 R = B n , R'=Ac Ί> R=R'=H

Glycosylative r i n g closure.



158

In conclusion, by employing three key intermediates 6, 29, and 30, intramolecular g l y c o s y l a t i v e ring closures were executed to afford alpha, gamma, and "iso-alpha" cyclodextrins, respectively-.^ 1 )


Acknowledgment We thank Dr. J. Uzawa and Mrs. T. Chijimatsu f o r recording and measuring the n.m.r. s p e c t r a and Dr. H. Honma and h i s s t a f f f o r the elemental analyses. We a l s o thank Ms. A. Takahashi and Ms. K. Moriwaki f o r their technical assistance.

References 1. French, D. Adv. Carbohydr. Chem. Biochem. 1957, 12, 189-60; Saenger, W. Angew. Chem., Int. Ed. Engl. 1980, 19, 344-62. 2. Breslow, R. Science 1982, 218, 532-37; Tabushi, I. Acc. Chem. Res. 1982, 15, 66-72; Croft, A. P.; Bartsch, R. A. Tetrahedron 1983, 39, 1417-74. 3. Ogawa, T.; Takahashi, Y. Carbohydr. Res. 1985, 138, C5-C9. 4. Ogawa, T.; Matsui, M. Carbohydr. Res. 1976, 51, C13-C18. 5. Ogawa, T.; Matsui, M. Carbohydr. Res. 1977, 56, C1-C6; 1978, 62, C1-C4; Tetrahedron 1981, 37, 2363-69; Veyriéres, A.J.Chem. Soc., Perkin Trans I 1981, 1626-29. 6. Ogawa, T.; Nakabayashi, S. Carbohydr. Res. 1981, 93, C1-C5; Ogawa, T.; Nakabayashi, S.; Kitajima, T. ibid. 1983,144,22536. 7. Newman, M. S.; Sujeeth, P. K. J. Org. Chem. 1978, 43, 4367-69. 8. Helferich, B.; Gootz, R. Ber. 1929, 62, 2505-07; Hall, L. D.; Manville, J. F.; Bhacca, N. S. Can. J. Chem. 1969, 47, 1-17. 9. Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431-32. 10. Amin, B. El; Anantharamaiah, G. M.; Royer, G. P.; Means, C. E. J. Org. Chem. 1979, 44, 3442-44; Rao , V. S.; Perlin, A. S. Carbohydr. Res. 1980, 83, 175-77. 11. For further discussion and experimental details, refer to; Takahashi, T.; Ogawa, T. Carbohydr. Res. 1987, 164, 277-96. RECEIVED October

14, 1988


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