DielsAlder Cycloaddition to Unsaturated Sugars - American Chemical

Chapter 5

Diels—Alder Cycloaddition to Unsaturated Sugars Stereocontrol as a Function of Structure and Stereochemistry

Downloaded by UNIV MASSACHUSETTS AMHERST on August 2, 2012 | http://pubs.acs.org Publication Date: June 2, 1992 | doi: 10.1021/bk-1992-0494.ch005

Derek Horton, Dongsoo Koh, Yasushi Takagi, and Takayuki Usui Department of Chemistry, Ohio State University, Columbus, OH 43210 D i r e c t W i t t i g r e a c t i o n of Ph PCHCO Me with the four u n s u b s t i t u t e d D-aldopentoses followed by a c e t y l a t i o n provides convenient p r e p a r a t i v e access t o a c y c l i c seven-carbon t r a n s - 2 , 3 unsaturated sugar d e r i v a t i v e s . These products served as d i e n o p h i l e s f o r a d e t a i l e d comparative study i n D i e l s — A l d e r c y c l o a d d i t i o n with cyclopentadiene. Related syntheses a f f o r d e d analogous c i s - d i e n o p h i l e s . C y c l o a d d i t i o n under uncatalyzed thermal c o n d i t i o n s gave mixtures of the four p o s s i b l e s t e r e o i s o m e r i c norbornene adducts. The endo, exo r a t i o s , and diastereofacial selectivities of the adducts were determined by NMR spectroscopy and by chemical t r a n s f o r m a t i o n s , supplemented by s e l e c t e d X - r a y c r y s t a l l o g r a p h i c analyses. Different d i s t r i b u t i o n s of isomers were encountered when a Lewis a c i d was used t o c a t a l y z e the cycloaddition. The r e a c t i o n can be c o n t r o l l e d t o p r o v i d e p r e p a r a t i v e access t o s e l e c t e d isomers and thus c o n s t i t u t e s a v e r s a t i l e method f o r chirality t r a n s f e r from the p r e c u r s o r sugar to four new asymmetric centers i n a c a r b o c y c l i c framework. 3

2

As p a r t o f a general program ( 1 — 4 ) on s y n t h e t i c t r a n s f o r m a t i o n s o f sugars having p o t e n t i a l v a l u e f o r access t o e n a n t i o m e r i c a l l y pure, p o l y s u b s t i t u t e d c a r b o c y c l e s , we have made a systematic study o f the r e a c t i o n s o f v a r i o u s dienes with sugar-derived alkenes s e r v i n g as d i e n o p h i l e s . Here we present t h e r e s u l t s o f r e a c t i o n s between cyclopentadiene and a complete s t e r e o i s o m e r i c s e t o f seven-carbon trans-2. 3-unsaturated a l d o n i c e s t e r s d e r i v e d from the D-aldopentoses. Comparative r e s u l t s with corresponding seven-carbon c i s - d i e n o p h i l e s are a l s o i n c l u d e d . The work allows 0097-6156/92/0494-0066$06.00/0 © 1992 American Chemical Society

In Cycloaddition Reactions in Carbohydrate Chemistry; Giuliano, R.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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Cycloaddition to Unsaturated Sugars

p r e d i c t i v e understanding o f t h e s t e r i c f a c t o r s d i c t a t i n g the product d i s t r i b u t i o n i n t h e r e a c t i o n . F u r t h e r , i t p r o v i d e s a p o t e n t i a l methodology f o r u s i n g r e a d i l y a v a i l a b l e sugars as c h i r a l p r e c u r s o r s f o r o b t a i n i n g t e t r a C - s u b s t i t u t e d cyclopentane d e r i v a t i v e s , with each s u b s t i t u e n t capable o f d i f f e r e n t i a l chemical e l a b o r a t i o n , e n a n t i o m e r i c a l l y pure i n a l l s i x t e e n p o s s i b l e s t e r e o i s o m e r i c forms.


Synthesis o f t h e t r a n s D i e n o p h i l e s The f o u r D-aldopentoses (D-ribose, 1, D-arabinose, 2, Dlyxose, 3, and D-xylose, 4) were converted i n t o t h e corresponding methyl (E)-4,5,6,7-tetra-0-acetyl-2,3dideoxyhept-2-enonates (5—8).

0

HoQ""

„

O

OH OH

C0 CH 2

0

"

W

H

^

0

"

OH

C0 CH 2

3

C0 CH 2

a

C0 CH 2

3

3

H

H

S

A

H

H--OAC H--OAC H-j-OAc CH OAc 2

S ^ H AcO Η H-f-OAc H-]-OAc CH OAc 2

AcO--H AcO--H H-]-OAc CH OAc 2

H--OAC AcO--H H-|-OAc CH OAc 2

8

6

The pentoses may be converted by t h e c o n v e n t i o n a l sequence (5) o f d i t h i o a c e t a l formation, a c e t y l a t i o n , and demercaptalation i n t o the r e s p e c t i v e aldehydo-pentose 2,3,4,5-tetraacetates, which a f f o r d by W i t t i g c h a i n extension (2) t h e d e s i r e d d i e n o p h i l e s . Thus aldehydo-Darabinose 2,3,4,5-tetraacetate r e a c t e d with Ph PCHC0 Me i n b o i l i n g benzene t o g i v e 90% o f t h e pure, c r y s t a l l i n e Eunsaturated sugar d e r i v a t i v e 6, and t h e corresponding enantiomer was l i k e w i s e prepared from L-arabinose. However, t h e p r e p a r a t i o n r e q u i r e d s e v e r a l steps and t h e net y i e l d from arabinose was only 23%. 3

2

A s i g n i f i c a n t p r e p a r a t i v e improvement was r e a l i z e d by conducting the W i t t i g r e a c t i o n d i r e c t l y (6) on t h e f r e e


68

CYCLOADDITION REACTIONS IN CARBOHYDRATE CHEMISTRY

aldopentose (2) with t h e y l i d Ph PCHC0 Me i n b o i l i n g THF. The i n i t i a l heterogeneous mixture became a c l e a r s o l u t i o n . A c e t y l a t i o n o f t h e r e s u l t a n t mixture o f products and f l a s h chromatography a f f o r d e d t h e pure alkene 6 i n 26% y i e l d as the fastest-moving product. T h i s y i e l d c o u l d be boosted to 50% by i n c o r p o r a t i o n o f Cu(OAc) i n t h e i n i t i a l r e a c t i o n medium. Other products formed i n t h e r e a c t i o n r e s u l t from i n t e r n a l Michael a d d i t i o n from t h e C alkene p r i o r t o t h e a c e t y l a t i o n step, and t h e i r formation i s s i g n i f i c a n t l y attenuated when the copper s a l t i s i n c o r p o r a t e d i n the r e a c t i o n medium. 3

2

2


7

The same d i r e c t r e a c t i o n o f the aldopentose w i t h PhoPCHCO^Me allowed conversion o f D-ribose (1) i n t o 5 i n 25% y i e l d ; here the use o f Cu(0Ac) suppressed r a t h e r than enhanced conversion i n t o t h e alkene. The d i r e c t W i t t i g r e a c t i o n with D-lyxose (3) was t h e most s u c c e s s f u l among the f o u r pentoses and a f f o r d e d the alkene 7 i n 61% y i e l d as t h e major product; i t s y i e l d was depressed t o 40% when Cu(OAc) was present. With D-xylose (4) the d i r e c t r e a c t i o n gave the alkene 8; the y i e l d o f 43% was i n c r e a s e d to 49% when Cu(0Ac) was present i n the r e a c t i o n mixture. 2

2

2

R e l a t e d t r a n s d i e n o p h i l e s were prepared by the same d i r e c t W i t t i g r e a c t i o n on the f r e e aldopentoses but w i t h an a c e t o n a t i o n step i n p l a c e o f a c e t y l a t i o n ; thus prepared were t h e 4,5:6,7-di-0-isopropylidene analogue (9) o f 5 ( y i e l d 29%), t h e analogue 10 o f 6 (20%), t h e analogue 11 of 7 (34%), and t h e analogue 12 o f 8 (18%).

A d d i t i o n a l t r a n s d i e n o p h i l e s were prepared by t h e d i r e c t W i t t i g r e a c t i o n from f r e e and from p a r t i a l l y p r o t e c t e d aldopentoses. 2-Deoxy-D-erythro-pentose (13) gave 73% o f an 11:1 separable mixture o f t h e Ε and Ζ C alkenes (14 and 15, r e s p e c t i v e l y ) , with no accompanying c y c l i z e d products. 7



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K i n e t i c a c e t o n a t i o n (7) of D-ribose (1) t o g i v e 3,4-O-isopropylidene-D-ribopyranose (16), f o l l o w e d by the d i r e c t W i t t i g r e a c t i o n gave mainly (85%) the Ε product 17. In c o n t r a s t , the thermodynamic a c e t o n a t i o n product, 2,3-0i s o p r o p y l i d e n e - D - r i b o f u r a n o s e (18) a f f o r d e d mainly (-70%) the Ζ ( c i s ) e s t e r , i s o l a t e d as i t s 6,7-diacetate 19.

S y n t h e s i s of the c i s D i e n o p h i l e s In a d d i t i o n t o compounds 15 and 19, other d i e n o p h i l e s having the c i s c o n f i g u r a t i o n were obtained from aldehydo-D-arabinose 2,3,4,5-tetraacetate by Horner—Emmons a l k e n a t i o n with (CF^CH^O)^POC^CO^Me, which a f f o r d e d the c r y s t a l l i n e Ζ alkene 20 i n 91% y i e l d . The r e a c t i o n of 2,3 ;4,5-di-O-isopropylidene-aldehvdo-Darabinose with Ph^PCHC0 Me i n methanol a t room temperature gave a 1:4 Ε.Ζ mixture of alkenes which, on treatment with TsOH i n methanol f o l l o w e d by a c e t y l a t i o n a f f o r d e d i n 39% net y i e l d the c r y s t a l l i n e b u t e n o l i d e 21. 2


7#


H

-

AcOHH-

"

"C0 Me 2

H OAc OAc CH OAc


2

20 R e a c t i o n o f t h e t r a n s D i e n o p h i l e s w i t h Cyclopentadiene General. A l l o f t h e alkenes prepared as d i e n o p h i l e s r e a c t e d with cyclopentadiene under thermal c o n d i t i o n s (2.3) t o a f f o r d i n h i g h net y i e l d a mixture o f D i e l s — A l d e r adducts. Four stereoisomers (A—D) a r e , i n p r i n c i p l e , p o s s i b l e i n each i n s t a n c e through t r a n s i t i o n s t a t e s l e a d i n g t o endo o r exo c a r b o x y l a t e norbornene products and from s i o r r e face a t t a c k by t h e diene on t h e d i e n o p h i l e . The d e s i g n a t i o n s i o r r e r e f e r s t o t h e C a h n — I n g o l d — P r e l o g p r i o r i t i e s a t t h e double bond (lowest-numbered asymmetric p o s i t i o n i n t h e s t a r t i n g sugar d e r i v a t i v e ) of the dienophile.

R A (exo)

C0 Me Β (endo)

C0 Me

R

2

C(exo)

2

D(endo)

The observed products from t h e t r a n s d i e n o p h i l e s g e n e r a l l y comprised mixtures o f a l l four p o s s i b l e isomers, which c o u l d be d e t e c t e d i n most i n s t a n c e s by d i f f e r e n c e s i n TLC m o b i l i t y , and be q u a n t i t a t e d by NMR i n t e g r a t i o n o f key s i g n a l s (the proton α t o the c a r b o x y l a t e group and t h e methyl resonance o f t h a t group). In some cases d i r e c t s e p a r a t i o n o f a l l four isomers was perfomed by c a r e f u l chromatography. A general f e a t u r e i n a l l o f t h e r e a c t i o n s was t h a t t h e exo-carboxylate product i s favored, and t h e f a c i a l s e l e c t i v i t y i s t h a t corresponding t o o r i e n t a t i o n o f the a l l y l i c oxygen atom o f the d i e n o p h i l e toward t h e diene i n t h e t r a n s i t i o n s t a t e o f a concerted process (see f o l l o w i n g scheme). The products a r e t h e r e s u l t o f a k i n e t i c a l l y c o n t r o l l e d process, as evidenced by the f a c t t h a t s i n g l e i s o l a t e d isomers from the r e a c t i o n s , when


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71

s u b j e c t e d t o the same c o n d i t i o n s used f o r the D i e l s — A l d e r r e a c t i o n , were recovered unchanged. re-face attack

si- face attack

po Me


2

5 (D-ribo)

6 (D-arabino)

8 (D-xyfo)

7 (D-/yxo)

D i a s t e r e o f a c i a l S e l e c t i v i t i e s of A o e t y l a t e d

Dienophiles

Preparative U t i l i t y . Because of the ready a v a i l a b i l i t y of both enantiomers of arabinose, the r e a c t i o n s of the d e r i v e d Cy d i e n o p h i l e s were evaluated i n p a r t i c u l a r d e t a i l f o r p o t e n t i a l p r e p a r a t i v e u t i l i t y , with emphasis on the a b i l i t y t o separate by c r y s t a l l i z a t i o n the major isomer from the r e a c t i o n . Thus d i e n o p h i l e 6 r e a c t e d t o g i v e , by d i r e c t i s o l a t i o n , a 40% y i e l d of pure, c r y s t a l l i n e methyl (5S,6g)-6-endo-(1,2,3,4-tetra-O-acetvl-D-arabino-tetritoll-yl)bicyclo[2.2.1]hept-2-eno-5-gxo-carboxylate (22) , mp 1 0 3 . 5 — 1 0 4 . 5 ° , [α]π +73°, and l i k e w i s e the L enantiomer of 6 gave methyl (5R,bR)-6-endo-(1,2,3,4-tetra-O-acetyl-Larabino-tetritol-l-vl)bicyclo[2.2.l]hept-2-eno-5-exoc a r b o x y l a t e (23). Hanti

H syn

Hysyn^Hyanti

7

7

0~T r^l^^^

.C0 Me 2

«Ί

3

AcO+H H-j-OAc H + OAc CH OAc 2

22

COoMe

H + OAc AcO- •H AcO-j-H CH OAc 2

23

Proof of S t r u c t u r e . S t r u c t u r a l and stereochemical i d e n t i f i c a t i o n of the products was achieved by NMR, by chemical t r a n s f o r m a t i o n s , and was f u r t h e r s u b s t a n t i a t e d by X-ray c r y s t a l l o g r a p h y of s e l e c t e d products. Thus the norbornene d e r i v a t i v e 22 was i d e n t i f i e d as an exo


72


c a r b o x y l a t e d e r i v a t i v e by t h e r e l a t i v e l y h i g h - f i e l d l o c a t i o n o f t h e endo disposed H-5 s i g n a l (proton α t o t h e c a r b o x y l a t e group). Sequential O-deacetylation t o the t e t r o l 24, p e r i o d a t e degradation o f t h e polyhydroxy c h a i n t o t h e aldehydo e s t e r 25, and r e d u c t i o n with L i A l H a f f o r d e d a product (26) i d e n t i f i e d as (5S,6S)-2norbornene-5,6-dimethanol (2.8). [ a ] - 2 3 , thus e s t a b l i s h i n g t h e c h i r a l i t y o f 22 as 5S,6S. 4

e


D

CH OH 2

24

25

26

The X-ray c r y s t a l s t r u c t u r e (1) o f 22, taken i n c o n j u n c t i o n with t h e known D-arabino stereochemistry o f the s t a r t i n g sugar, provided independent a f f i r m a t i o n o f the absolute stereochemistry o f t h e product (and thus a l s o of i t s enantiomer 23) as w e l l as assurance t h a t no stereochemical a l t e r a t i o n o f t h e c h i r a l c e n t e r s i n t h e o r i g i n a l sugar c h a i n had taken p l a c e , and provided a f i r m point of reference f o r assigning structures t o a l l of the remaining isomers formed i n the c y c l o a d d i t i o n r e a c t i o n . By extension, t h e NMR parameters f o r the f o u r isomers from t h i s reaction established a basis for structural a t t r i b u t i o n o f t h e products from c y c l o a d d i t i o n o f cyclopentadiene t o t h e other d i e n o p h i l e s i n t h i s study. Lewis A c i d - C a t a l y z e d C y c l o a d d i t i o n . When t h e c y c l o a d d i t i o n t o t h e D-arabinose-derived d i e n o p h i l e 6 was performed i n t h e presence o f a Lewis a c i d c a t a l y s t ( A I C I 3 ) , both t h e geometric and t h e f a c i a l s e l e c t i v i t i e s were reversed and the major product, i s o l a t e d c r y s t a l l i n e i n 36% y i e l d was methyl (5R.6R)-5-exo-(1.2.3.4-tetra-0acetyl-D-arabino-tetritol-l-yl)bicyclo[2.2.l]hept-2-eno-6endo-carboxylate (27), t h e endo-carboxvlate product r e s u l t i n g from a t t a c k on t h e face o f the diene opposite the a l l y l i c acetoxy group. S i m i l a r r e a c t i o n o f t h e La r a b i n o s e - d e r i v e d d i e n o p h i l e correspondingly gave methyl (5S,6S)-5-exo-(1.2,3,4-tetra-O-acetyl-L-arabino-tetritol1-yl)bicycloΓ2.2.11hept-2-eno-6-endo-carboxvlate (28).


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In consequence, thus, by u s i n g both enantiomers of arabinose and r e a c t i o n under e i t h e r thermal o r Lewis a c i d c a t a l y z e d c o n d i t i o n s , i t i s p o s s i b l e t o prepare the f o u r p o s s i b l e 5.6-trans norbornene products i n e n a n t i o m e r i c a l l y pure form. These can be used, i n t u r n , t o prepare t e t r a - C - s u b s t i t u t e d cyclopentane d e r i v a t i v e s i n which a l l of the four carbon s u b s t i t u e n t s are capable o f d i f f e r e n t i a l s y n t h e t i c e l a b o r a t i o n . D e t a i l s of such t r a n s f o r m a t i o n s are documented i n a separate r e p o r t (4). Q u a n t i t a t i v e D i s t r i b u t i o n o f Adducts as a F u n c t i o n o f D i e n o p h i l e Stereochemistry. For accurate q u a n t i t a t i o n of the isomer d i s t r i b u t i o n i n the products o f c y c l o a d d i t i o n t o each of the d i e n o p h i l e s 5 — 8 , the e n t i r e mixtures o f the f o u r s t e r e o i s o m e r i c products i n each i n s t a n c e were f i r s t s u b j e c t e d t o s e q u e n t i a l O - d e a c e t y l a t i o n and p e r i o d a t e o x i d a t i o n t o a f f o r d a mixture o f two aldehydo e s t e r s 29 and 30, which upon r e d u c t i o n with L i A l H a f f o r d e d trans-2-norbornene-5,6-dimethanol as an unequal mixture o f the two enantiomers (only the 5S,6S enantiomer i s shown). NMR a n a l y s i s o f the mixture o f 29 and 30 showed d i s t i n c t i v e resonances f o r the CH 0 and CHO groups i n exo and endo o r i e n t a t i o n s , p e r m i t t i n g a c c u r a t e determination of the endo/exo r a t i o of the products i n the mixture. The observed s p e c i f i c r o t a t i o n of the d i o l , i n comparison w i t h t h a t (+23°) determined f o r the e n a n t i o m e r i c a l l y pure 5S,6S d i o l 26 (and i t s enantiomer), provided a q u a n t i t a t i v e measure of the s i . r e diastereofacial selectivity. 4

3

The r e s u l t s f o r the f o u r d i e n o p h i l e s 5 — 8 , t o g e t h e r with t h a t f o r the 2-deoxy-D-erythro-pentose-derived d i e n o p h i l e 14, are shown i n Table I . Table I . S t e r e o s e l e c t i v i t y i n the r e a c t i o n of a c e t y l a t e d d i e n o p h i l e s w i t h cyclopentadiene Dienophile 5 6 7 8 14

Conf i g u r a t i o n

D-ribo D-arabino D-lyxo D-xylo (4--deoxy)-D-erythro

Yield 86 92 97 72 93

(%)

endo/exo 31:69 31:69 37:63 29:71 41:59


si/re 30:70 64:36 60:40 38:62 53:47


74


5, 6, 7, 8

CH OH 2


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I t i s evident from these r e s u l t s t h a t t h e thermal r e a c t i o n f a v o r s t h e exo c a r b o x y l a t e products throughout. As regards d i a s t e r e o f a c i a l s e l e c t i v i t y , two o f t h e d i e n o p h i l e s (5 and 8 ) , which have t h e same S c o n f i g u r a t i o n at t h e a l l y l i c center, show the same tendency f o r favored a t t a c k a t t h e r e f a c e . In c o n t r a s t , t h e other two d i e n o p h i l e s (6 and 7, R c o n f i g u r a t i o n a t t h e a l l y l i c center) show, as expected, favored s i - f a c e a t t a c k . The d i e n o p h i l e 14, having no c h i r a l group a t t h e a l l y l i c p o s i t i o n , showed n e g l i g i b l e f a c i a l s e l e c t i v i t y . The r e l a t i v e l y low d i a s t e r e o f a c i a l s e l e c t i v i t i e s e x h i b i t e d by t h e a c y c l i c sugar-chain enonates 5 — 8 may be a s c r i b e d t o t h e conformational m o b i l i t y o f t h e c h a i n . These chains a r e d e p i c t e d i n t h e i r F i s c h e r p r o j e c t i o n s r a t h e r than as conformational r e p r e s e n t a t i o n s f o r t h e s p e c i f i c reason t h a t t h e p l a n a r z i g z a g o r i e n t a t i o n o f t h e c h a i n i s c l e a r l y favored o n l y i n chains having t h e arabino stereochemistry ( 9 ) . For the other c o n f i g u r a t i o n s , t h e conformational preference i s f o r non-extended conformations t h a t may be conformational mixtures separated by low e n e r g y - b a r r i e r s . I t i s c l e a r l y naive t o d e p i c t exact molecular o r i e n t a t i o n s f o r p u t a t i v e t r a n s i t i o n s t a t e s i n such r e a c t i o n s . Nevertheless, t h e model d e p i c t e d here f o r i n t e r p r e t i n g the course of t h e r e a c t i o n , which i s i n accord with t h e g e n e r a l model proposed by T r o s t (10) f o r d i a s t e r e o f a c i a l s e l e c t i v i t y i n a d d i t i o n s t o alkenes having an adjacent asymmetric c e n t e r , has p r e d i c t i v e u t i l i t y i n these r e a c t i o n s . The i s o p r o p y l i d e n a t e d enonates 9—12 have l e s s conformational freedom than t h e t e t r a a c e t a t e s 5 — 8 and were thus expected t o show higher d i a s t e r e o f a c i a l s e l e c t i v i t i e s i n t h e D i e l s — A l d e r r e a c t i o n . T h i s was borne out i n t h e experimental data. The D-lyxo enonate 11 i n p a r t i c u l a r gave a r e a d i l y separable mixture a f t e r r e a c t i o n w i t h cyclopentadiene under thermal c o n d i t i o n s , and a f f o r d e d a 55% i s o l a t e d y i e l d of the c r y s t a l l i n e s i exo product, mp 8 8 — 8 9 ° , along with 30% of t h e si-endo product. The s t r u c t u r e s o f these products were confirmed as b e f o r e by degradative sequences. The d i a s t e r e o f a c i a l s e l e c t i v i t y was >9:1 i n favor of s i - f a c e a t t a c k . For the other i s o p r o p y l i d e n a t e d d i e n o p h i l e s 9, 10, and 12, s e p a r a t i o n of the product isomers was more d i f f i c u l t , but determination o f the r a t i o s o f t h e f o u r p o s s i b l e products as before gave t h e r e s u l t s shown i n Table I I .


76


Table I I . S t e r e o s e l e c t i v i t y i n t h e Reaction o f I s o p r o p y l i d e n a t e d Dienophiles with Cyclopentadiene


Dienophile

Configuration

Yield

9 D-ribo 10 D-arabino 11 D-lyxo 12 D-xylo Methyl (E)-2,3-dideoxy-4,5-0isopropylidene-D-glyceropent-2-enonate (11)

(%)

endo/exo

si/re

86 98 97 96

31:69 35:65 40:60 43:57

18:82 62:38 86:14 32:68

87

40:60

32:68

The preference f o r formation o f exo products i s again e v i d e n t throughout. As f o r d i a s t e r e o f a c i a l s e l e c t i v t y , the p a t t e r n shown with t h e a c e t y l a t e d d i e n o p h i l e s 5 — 8 was again evident, with favored r e - f a c e a t t a c k f o r those compounds (9 and 12) having the R c o n f i g u r a t i o n a t t h e a l l y l i c center and s i - f a c e a t t a c k f o r those (10 and 11) having t h e S c o n f i g u r a t i o n a t the a l l y l i c c e n t e r . However, with these i s o p r o p y l i d e n a t e d d i e n o p h i l e s , t h e d i a s t e r e o f a c i a l s e l e c t i v i t y was much higher than with t h e a c e t y l a t e d analogues, e s p e c i a l l y i n the r i b o and lyxo isomers, a f a c t o r o f importance i n any proposed application i n c h i r a l synthesis. These r e s u l t s again accord with p r e d i c t i o n s based on the T r o s t model (10), and t h e f o l l o w i n g schematic i l l u s t r a t i o n s a t i f a c t o r i l y i n t e r p r e t s the observed behavior o f compounds 9—12 as w e l l as t h a t o f the 5carbon lower homologue a l s o l i s t e d i n Table I I and t h e s u b j e c t o f a r e c e n t independent study (11).

1

2

9 R=lso, R =H (D-ribo) 12 R=H, R =lso (D-xyb) 1

2

1

11

2

R «H, R =lso (D-arabino) R=lso, R =H (D-lyxo)

10

1

2

D i a s t e r e o f a c i a l S e l e c t i v i t i e s o f Acetonated

Dienophiles



5. HORTON ET AL


Reaction of the c i s D i e n o p h i l e s w i t h

77

Cyclopentadiene

A very h i g h degree of asymmetric i n d u c t i o n was e v i d e n t i n the thermal r e a c t i o n of the D-arabinose-derived c i s d i e n o p h i l e 20 with cyclopentadiene, and the c r y s t a l l i n e adduct i s o l a t e d i n 95% y i e l d was i d e n t i f i e d as methyl (5R,6S)-6-endo-(1,2,3,4-tetra-O-acetyl-D-arabino-tetritol1-vl)bicvclor2.2.11hept-2-eno-5-endo-carboxvlate (31), mp 103° by NMR spectroscopy and a l s o by X-ray c r y s t a l l o g r a p h y . Use of the same sequence s t a r t i n g from L-arabinose gave the enantiomer (32) of 31.

C0 Me H-j-OAc AcO-f H AcO+H CH OAc 2

Me0 C AcO-j-H H+OAc H-|-0Ac CH 0Ac 2

2

2

32

31

A very s m a l l p r o p o r t i o n of a second isomer i s o l a t e d from the r e a c t i o n with 20 was i d e n t i f i e d as the exo 5R,6S isomer of 31. The observed high d i a s t e r e o f a c i a l s e l e c t i v i t y i s a t t r i b u t a b l e t o conformational r e s t r i c t i o n a t the a l l y l i c c e n t e r i n d i e n o p h i l e 20. The s t e r i c bulk of the sugar c h a i n and the a c e t y l group e f f e c t i v e l y l i m i t the C-3—C-4 rotamers t o a s i n g l e conformer, as shown i n the f o l l o w i n g scheme. The diene a t t a c k s almost e x c l u s i v e l y from the same s i d e as the a l l y l i c oxygen atom ( s i - f a c e f o r the Denonate 20), where the s t e r i c hindrance i s lowest.

20A favored

20B disfavored



78


The b u t e n o l i d e 21 p r o v i d e s an o p p o r t u n i t y t o t e s t t h e f o r e g o i n g hypothesis i n t h a t t h e l a c t o n e r i n g l o c k s t h e d i e n o p h i l e i n t h e conformation t h a t i s d i s f a v o r e d f o r t h e a c y c l i c d i e n o p h i l e 20· The r e s u l t s o f t h e c y c l o a d d i t i o n r e a c t i o n with cyclopentadiene a r e e n t i r e l y s u p p o r t i v e i n t h a t t h e observed products a r e e x c l u s i v e l y those o f r e f a c e a t t a c k . The r e a c t i o n gave two products o n l y . The major one was (5S.6R)-6-endo-(2.3.4-tri-O-acetvl-Darabino-tetritol-l-yl)bicyclo[2.2.l]hept-2-ene-5-endoc a r b o x y l i c 1,4-lactone (33), i s o l a t e d c r y s t a l l i n e i n 70% y i e l d , mp 149°. The minor product, obtained i n 11% y i e l d , was t h e exo (5S,6R) isomer 34.

R =

H-4-OAc H-4-OAc CHgOAc 33

(70%)

34(11%)

S t r u c t u r e s o f t h e products were again e s t a b l i s h e d by NMR spectroscopy, and t h a t o f 33 f i r m l y c o n s o l i d a t e d by X-ray c r y s t a l l o g r a p h y . The l a c t o n e r i n g i n b u t e n o l i d e 21 c o n s t r a i n s t h e groups adjacent t o t h e double bond i n t o t h e arrangement d e p i c t e d as t h e unfavorable conformation i n the a c y c l i c c i s d i e n o p h i l e 20, and consequent approach by cyclopentadiene from t h e exposed f a c e r e s u l t s i n e x c l u s i v e re-face attack. The c o n s i s t e n c y i n t h e d i a s t e r e o f a c i a l s e l e c t i v i t i e s f o r 20 and 21 supports t h e hypothesis o f conformational r e s t r i c t i o n i n t h e a c y c l i c d i e n o p h i l e 20 and i t s analogues.

The cis-enonate 15, which i s deoxygenated a t t h e a l l y l i c p o s i t i o n , r e a c t e d with cyclopentadiene t o g i v e a mixture o f a l l f o u r p o s s i b l e adducts. The d i a s t e r e o f a c i a l s e l e c t i v i t y was n e g l i g i b l e and t h e endo.exo r a t i o (6.5:1) was s i m i l a r t o t h a t observed with b u t e n o l i d e 21. T h i s


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79


r e s u l t demonstrates t h a t the s t e r e o c e n t e r a t the a l l y l i c p o s i t i o n alone determines the d i a s t e r e o f a c i a l s e l e c t i v i t y of the D i e l s — A l d e r r e a c t i o n with these a c y c l i c c i s dienophiles. Although t h i s r e p o r t has focused p r i n c i p a l l y on d i e n o p h i l e s not c o n s t r a i n e d by a r i n g system, one f i n a l example i s the a d d i t i o n of cyclopentadiene t o a 6-membered d i e n e o p h i l e , 4-0-acetyl-2,3,6-trideoxv-L-ervthro-hex-2enonate 1,5-lactone (35, 12). Reaction of 35 w i t h cyclopentadiene gave p r i n c i p a l l y the two endo products 36 and 37 i n 31 and 38% y i e l d s , r e s p e c t i v e l y , w i t h o n l y 12% of a mixture of the two exo products being formed.

Re- Face

S/-Face

The very low d i a s t e r e o f a c i a l s e l e c t i v i t y observed with l a c t o n e 36 may be a s c r i b e d t o the competing e f f e c t s of two c h i r a l c e n t e r s , the a l l y l i c oxygen atom 0-4 (favored s i - f a c e attack) and the C-5 methyl group (favored re-face attack). Summary and Conclusions These s t u d i e s of asymmetric D i e l s — A l d e r r e a c t i o n s w i t h α,β-unsaturated sugar enonates permit the f o l l o w i n g generalizations. The d i a s t e r e o f a c i a l s e l e c t i v i t i e s are mainly c o n t r o l l e d by the a l l y l i c c o n f i g u r a t i o n . Compounds having the same c o n f i g u r a t i o n a t the a l l y l i c p o s i t i o n undergo a t t a c k on the d i e n o p h i l e a t the same f a c e .


80

CYCLOADDUION REACTIONS IN CARBOHYDRATE CHEMISTRY

The c i s d i e n o p h i l e s g e n e r a l l y e x h i b i t g r e a t e r d i a s t e r e o f a c i a l s e l e c t i v i t y than the t r a n s analogues. The d i a s t e r e o f a c i a l s e l e c t i v i t i e s observed a r e s a t i s f a c t o r i l y r a t i o n a l i z e d by T r o s t ' s s t e r i c model.


The r e a c t i o n has broad p o t e n t i a l i n s y n t h e s i s o f e n a n t i o m e r i c a l l y pure, p o l y s u b s t i t u t e d c a r b o c y c l e s by c h i r a l i t y t r a n s f e r from sugar p r e c u r s o r s .

Literature Cited 1. Horton, D . ; Machinami, T . ; Takagi, Y . ; Bergmann, C. W.; Christoph, G. D . , J. Chem. Soc., Chem. Commun., 1983, 1164—1166. 2. Horton, D . ; Machinami, T . ; Takagi, Υ . , Carbohydr. Res., 1983, 121, 135—161. 3. Horton D , ; Usui, T . , Carbohydr. Res., 1991, 216, 33—49. 4. Horton, D . ; Usui, T . , Carbohydr. Res., 1991, 216. 51—59. 5. Wolfrom, M. L.; Weisblat, D. I . ; Zophy, W. H.; Waisbrot, S. W., J. Am. Chem. Soc., 1941, 63, 201—203. 6. For early work on Wittig extension of sugar chains, see Zhdanov, Yu A.; Alexeev, Yu. E.; Alexeeva, V. G . , Adv. Carbohydr. Chem. Biochem., 1972, 27, 227—299. 7. Gelas, J.; Horton, D . , Heterocycles, 1981, 16, 1587—1601. 8. Takano, S.; Kurotaki, Α . , Synthesis. 1987, 1075—1078. 9. Blanc-Muesser, M . ; Defaye, J.; Horton, D . , Carbohydr. Res., 1980, 87, 71—86 and e a r l i e r papers cited therein. 10. Trost, B . M . ; Lynch, J.; Renaut, P . , Tetrahedron Lett., 1985, 26, 6313—6316; compare Tripathy, R.; Franck, R. W.; Onan, K . D . , J. Am. Chem. Soc., 1988, 110, 3257—3262. 11. Krief, Α . ; Dumont, W.; Pasau, P , ; Lecomte, P . , Tetrahedron. 1989, 45, 3039—3052. 12. J a r g l i g , P . ; Lichtenthaler, F. W., Tetrahedron Lett., 1982, 3781—3784. RECEIVED

February4,1992


DielsAlder Cycloaddition to Unsaturated Sugars - American Chemical

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