Asymmetric Reactions Toward the Synthesis of Carbohydrates

Chapter 16

Asymmetric Reactions Toward the Synthesis of Carbohydrates Koichi Narasaka

Downloaded by MONASH UNIV on May 21, 2013 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch016

Department of Chemistry, Faculty of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

By the use of chiral oxazolidines derived from a chiral norephedrine and methyl ketones, an asymmetric aldol reaction proceeds in a highly enantioselective manner. In the case of ethyl or α-methoxy ketones, the corresponding anti aldol products were obtained with high diastereo- and enantioselectivities. A chiral titanium reagent, generated from dichlorodiisopropoxytitanium and a chiral 1,4-diol, prepared from dimethyl tartrate, is found to be an effective catalyst for asymmetric Diels-Alder reactions. 1,3-Oxazolidin-2-one derivatives of α,β-unsaturated carboxylic acids react with dienes in the presence of a 10% molar equivalents of the chiral titanium reagent, giving the adducts in high optical purity. The chiral titanium reagent is also applied to the hydrocyanation of aldehydes successfully.

Asymmetric Aldol Reaction The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2) W i t h this in mind, t h e asymmetric aldol r e a c t i o n o f chiral o x a z o l i d i n e s 1, p r e p a r e d from chiral n o r e p h e d r i n e and methyl ketones was i n v e s t i g a t e d . The g e n e r a l pathway o f this asymmetric aldol r e a c t i o n is outlined in t h e f o l l o w i n g scheme. I t would be e x p e c t e d t h a t t h e t r e a t m e n t o f a chiral o x a z o l i d i n e w i t h 2 molar amounts o f lithium d i i s o p r o p y l a m i d e (LDA) would g e n e r a t e a lithiated enamine, which would be c o n v e r t e d t o t h e cyclic m e t a l l o enamine 2_ by t h e a d d i t i o n o f a m e t a l s a l t . As a r i g i d 5-membered c h e l a t e i s formed i n t h e c y c l i c m e t a l l o - e n a m i n e 2_, h i g h asymmetric i n d u c t i o n would be e x p e c t e d i n t h e s u c c e s s i v e r e a c t i o n w i t h an a l d e h y d e t h r o u g h a [ 4 . 3 . 0 ] - b i c y c l i c t r a n s i t i o n s t a t e 2· Removal o f t h e c h i r a l a u x i l i a r y from t h e adduct 4_, p e r f o r m e d by a c i d treatment, w i l l g i v e a corresponding a l d o l product

c

0097-6156/89/0386-0290$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.

Asymmetric Reactions Toward Carbohydrate Synthesis

16. NARASAKA

Ph

W

0

R

2

NH

X

u

Γ Ph

Me LDA

Li

0

Me 1

R

R'CHO

Λ

η-2

2

Ph

Me

0

N^M^'^L

OH

R>0

Η .

R ^ V

PhlÔ


Me

M

MXn

J M ^ U

1 Me

Ph

Me

5

Based on t h i s assumption, t h e asymmetric a l d o l r e a c t i o n o f c h i r a l 1 , 3 - o x a z o l i d i n e s 1^ o f methyl ketones was examined. I t was found t h a t t h e c o r r e s p o n d i n g a l d o l p r o d u c t s were o b t a i n e d i n good o p t i c a l p u r i t y when d i v a l e n t t i n c h l o r i d e was used as an a d d i t i v e metal s a l t . The t y p i c a l e x p e r i m e n t a l p r o c e d u r e i s as f o l l o w s : The o x a z o l i d i n e 1^ was p r e p a r e d from ( + ) - n o r e p h e d r i n e and acetone, and p u r i f i e d by d i s t i l l a t i o n . To a THF (2 mL) s o l u t i o n o f LDA (2.1 mmol) was added a THF s o l u t i o n o f l a (1 mmol) a t 0 °C and t h e m i x t u r e was s t i r r e d f o r 2 h r . Then a THF (4 mL) s o l u t i o n o f SnCl (1.05 mmol) was added a t 0 °C and s t i r r e d f o r 30 min. To t h i s m i x t u r e was added a THF (2 mL) s o l u t i o n o f 2 , 2 - d i m e t h y l p r o p a n a l ( 1 . 2 mmol). A f t e r s t i r r i n g f o r 20 min a t 0 °C, t h e m i x t u r e was quenched w i t h aq. 4% NaHCO^. The crude r e a c t i o n m i x t u r e was t r e a t e d w i t h a c e t o n e i n t h e p r e s e n c e o f a c a t a l y t i c amount o f BF^ t ^ t o remove t h e c h i r a l a u x i l i a r y . The crude p r o d u c t s were p u r i f i e d by c h r o m a t o g r a p h i c p r o c e d u r e t o g i v e t h e corresponding 3-hydroxy ketone 5a w i t h 86% ee. 2

0

E

Ph Me V-(

°

ΝΗ

Χ

Me Me

1) 2LDA

ιττ^Γ

3) ~)

'BuCTO

0 OH Bu

H 0* 3

5a

86°/ ee 0

1a In T a b l e 1, t h e y i e l d s and t h e o p t i c a l p u r i t i e s o f t h e a l d o l p r o d u c t s between some methyl ketones and a l d e h y d e s a r e summarized. I t i s a p p a r e n t t h a t t h e a l d o l p r o d u c t s o f methyl ketones were o b t a i n e d i n good t o e x c e l l e n t o p t i c a l p u r i t y . ( 3 ) Furthermore, t h i s r e a c t i o n was a p p l i e d t o t h e a l d o l r e a c t i o n of 3-pentanone. When t h e c h i r a l o x a z o l i d i n e £ was p r e p a r e d from 3-pentanone and t h e a l d o l r e a c t i o n was c a r r i e d o u t by t h e same p r o c e d u r e , t h e a, 3 - a n t i 3-hydroxy ketones 7. were produced p r e d o m i n a n t l y o v e r t h e syn-isomer J3 w i t h e x c e l l e n t o p t i c a l p u r i t i e s . ( 5 ) (See T a b l e 2.)


291

292

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

Ph Me }—\

0

1) 2LDA

NH

2) 5 n C l

X

* 2

3)

R'CHO

A)

H 0

>

5) acetone Et 0-BF

2

2

> 3

R Me ]_b R=Ph 1c

R= B u f

T a b l e 1.


RCOCH

Asymmetric A l d o l R e a c t i o n o f M e t h y l Ketones R'CHO

3

PhCOCH

Yield/%

Ph(CH ) CHO n-PrCHO c-C H CHO t-BucAo Ph(CH ) CHO c-C H CHO t-BucAo

3

t-BuCOCH 3

Optical

68 69 64 66 64 54 56

70 76

Purity/%ee 3

ιί 85

a

a

95

a) Determined by Η ΝMR o r F NMR measurement o f i t s MTPA ester{4) i n the presence o f E u ( f o d > . b) Determined by H NMR measurement i n t h e p r e s e n c e o f Eu(hfc) . 3

3

Me

Ph

1) 2LDA 2) SnCI

»

2

T a b l e 2. entry 1 2 3

* A) acetone BF -OEt 3

H-6

0

3) RCHO

0

QH

OH

R

2

Asymmetric A l d o l R e a c t i o n o f E t h y l Ketones RCHO

Ph(CH ) CHO c-C H CHO t-BucAo

Yield/% 77 75 56

antirsyn 7:1 9:1 6:1

Optical

Purity/%ee

92 92 95°

a) The r e l a t i v e s t e r e o c h e m i s t r y i n e n t r y 1 and 2 i s a s s i g n e d by t h e c o u p l i n g c o n s t a n t between t h e p r o t o n s on C-4 and C5.(6) I n t h e c a s e s o f e n t r y 2 and 3, i t was a l s o d e t e r m i n e d by t h e chemicaj. s h i f t ^ g f t h e methyl c a r b o n on C-4. ( 7 ) b) Determined by H and F NMR measurement o f i t s MTPA ester i n the pjesence of Eu(fod)^. c) Determined by H NMR measurement i n t h e p r e s e n c e o f Eu(hfc) . 3


16. NARASAKA


In o r d e r t o determine t h e a b s o l u t e s t e r e o c h e m i s t r y o f t h e a n t i - a l d o l ]_, a d i a s t e r e o i s o m e r o f t h e i n s e c t pheromone, (3S,4R)4-methylheptan-3-ol j l l was s y n t h e s i z e d from t h e ( + ) - o x a z o l i d i n e 6, The r e a c t i o n o f (+)-£ and p r o p a n a l gave a l d o l s 9a and 10a i n 61% y i e l d ( a n t i : s y n = 7.3:1). They were c o n v e r t e d t o t h e c o r r e s p o n d i n g a c e t a t e s 9 b 1 0 b and s e p a r a t e d by column chromatography. The o p t i c a l p u r i t y o f t h e a n t i - a c e t a t e 9b was determined as 95% ee u s i n g a c h i r a l s h i f t r e a g e n t . The a n t i a c e t a t e 9b was then c o n v e r t e d t o t h e a c e t a t e o f t h e d e s i r e d isomer o f t h e pheromone 1_1 as shown below. The a b s o l u t e c o n f i g u r a t i o n (3S,4R) and t h e o p t i c a l p u r i t y ( 95% ee) were p r o v e d by comparison w i t h t h o s e o f t h e l i t e r a t u r e . ( 8 ) Highly e n a n t i o s e l e c t i v e s y n t h e s i s o f a n t i - a l d o l s has remained as a f o r m i d a b l e s y n t h e t i c problem. The p r e s e n t asymmetric a l d o l r e a c t i o n a f f o r d s a u s e f u l method f o r t h e i r p r e p a r a t i o n .


f

Ph

Me " Ζ " * 2) S n C U

Λ

O ,NH v

3 ) E1CH0 A) acetone BF -OEt 3

^

X

A _

A

X „

—

.

H

?

Et

2

For t h e p r e p a r a t i o n o f o p t i c a l l y a c t i v e p o l y h y d r o x y compounds, such as s y n t h e t i c i n t e r m e d i a t e s o f monosaccharides, t h e

asymmetric a l d o l r e a c t i o n o f 1,3-dimethoxy-2-propane (Table 3) by Ph

Me

^ ^

W

a

12

OMe

4 BFa-EijO-

13

~

T a b l e 3. entry 1 2 3 4

OMe

acetone

Asymmetric A l d o l R e a c t i o n o f α-Methoxy Ketone RCHO

Ph(CH ) CHO n-C H CHO 9 19 c-C Η CHO t-BuCHO in

Y i e l d / ?S 72 74 64 45

a a n t i :: syn 7 9 7 10

:: :: :: ::

2 1 1 0

Optical Purity/%ee

< 95 95 95° C

a) The r e l a t i v e s t e r e o c h e m i s t r y i s a s s i g n e d by t h e c o u p l i n g c o n s t a n t between t h e p r o t o n s on C-3 and C-4 i n e n t r y 1 and 2, and i n t h e cases o f e n t r y 3 and 4 t h e s t e r e o c h e m i s t r y i s a s s i n g e d by t h e c o u p l i n g c o n s t a n t between t h e p r o t o n s on C-3 and C-4 o f ^ t h e i r a c e t a t e s . ( 6 ) b) Determined by H NMR measurement o f i t s a c e t a t e i n t h e presence of Eu^hfc) . c) Determined by H NMR measurement i n t h e p r e s e n c e o f Eu(hfc) . 3


293

294


t h i s methodology was examined. As i n t h e c a s e o f 3-pentanone, t h e r e a c t i o n o f a c h i r a l o x a z o l i d i n e 12^ w i t h a l d e h y d e s a f f o r d e d p r e d o m i n a n t l y t h e c o r r e s p o n d i n g a n t i - a l d o l a d d u c t s 13. Q u i t e h i g h e n a n t i o s e l e c t i v i t y was o b s e r v e d and i n p a r t i c u l a r one enantiomer was o b t a i n e d a l m o s t e x c l u s i v e l y i n t h e r e a c t i o n w i t h s e c o n d a r y and t e r t i a r y a l d e h y d e s . ( 9 ) The L - l y x o s e d e r i v a t i v e 14_ was p r e p a r e d from t h e a n t i - a d d u c t 13a o f 3 - p h e n y l p r o p a n a l as o u t l i n e d below, and t h e a b s o l u t e c o n f i g u r a t i o n was d e t e r m i n e d by comparison w i t h t h e o p t i c a l r o t a t i o n o f an a u t h e n t i c s a m p l e ( l O ) d e r i v e d from D - l y x o s e . 0

OH

Γι

0

τ"

MeOsJÂ^Ph

1 ) A c

H

0

OH OH

H

Μ θ Ο \ Λ Λ |

2) Dl BAL

OMe


20 'V ^

Ν

^

Ph

•

OMe

OMe

6

13a

15 1) H0" 2) A c 0 /

1 )(lmd) CO 2

2 ) separation of isomers

3) Β

2

Br3

V. OAc OAc Br

Q

AcON/\A^Ph ,

3) N B S

6 A 7. EtS

AgF /

Û

MeOÂvÂ^wPh

OAc OAc Ac0> OAc

1) 0s04-Nal0 2) E t S H , H

A

OAc

SEt

H +OAc •OAc H AcO ·

51 7. ( 96 7. e.e. )

4

CH 0Ac 2

U±

65 /. e

MeO.

R e l a t i v e c o n f i g u r a t i o n s o f A and Β a r e d e t e r m i n e d by c o u p l i n g c o n s t a n t o f H NMR. As mentioned, t h e p r e s e n t methodology a f f o r d s an e f f e c t i v e means f o r t h e s y n t h e s i s o f o p t i c a l l y a c t i v e a l d o l s . A high l e v e l o f asymmetric i n d u c t i o n was o b s e r v e d w i t h a wide range o f ketones such as m e t h y l , e t h y l and α-methoxy. Furthermore, when (1S,2R)n o r e p h e d r i n e i s employed as a c h i r a l a u x i l i a r y , i t i s always t h e s i - f a c e o f a l d e h y d e s t h a t i s a t t a c k e d by t h e t i n ( I I ) enamine. Asymmetric D i e l s - A l d e r R e a c t i o n In t h e above asymmetric a l d o l r e a c t i o n , t h e i n t r o d u c t i o n and t h e removal o f t h e c h i r a l a u x i l i a r y a r e c a r r i e d o u t by s i m p l e p r o c e d u r e s , and h i g h asymmetric i n d u c t i o n i s a c h i e v e d even a t i c e - b a t h temperature. However, a t l e a s t a s t o i c h i o m e t r i c amount of a c h i r a l a u x i l i a r y i s r e q u i r e d i n such a s t e r e o d i f f e r e n t i a t i n g reaction ( c h i r a l a u x i l i a r y i s attached t o the reactant.).



16. NARASAKA


In o r d e r t o p e r f o r m asymmetric r e a c t i o n s more e f f i c i e n t l y , i t i s d e s i r a b l e t h a t a l a r g e amount o f an o p t i c a l l y a c t i v e compound s h o u l d be produced w i t h o n l y a s m a l l i n v e s t m e n t of c h i r a l a u x i l i a r y i n a c a t a l y t i c process. T h i s use o f asymmetric c a t a l y s t s i s an a r e a of i n v e s t i g a t i o n t h a t has d e v e l o p e d r a p i d l y i n the l a s t two decades, from which v e r y e f f i c i e n t methods have been d e v e l o p e d . Most of them, however, a r e c o n c e r n e d w i t h asymmetric f u n c t i o n a l group t r a n s f o r m a t i o n s , and l i t t l e has been done f o r the c o n s t r u c t i o n of o p t i c a l l y a c t i v e carbon skeletons.(11) In o r g a n i c s y n t h e s i s , Lewis a c i d s have been a p p l i e d t o a wide v a r i e t y of c a r b o n - c a r b o n bond f o r m i n g r e a c t i o n s . Therefore, i t i s e x p e c t e d t h a t i f we c o u l d d e s i g n an e f f e c t i v e c h i r a l Lewis a c i d , v a r i o u s c a r b o n - c a r b o n bond f o r m i n g r e a c t i o n s c o u l d be w e l l c o n t r o l l e d i n an e n a n t i o s e l e c t i v e manner. As i t i s w e l l known t h a t t i t a n i u m r e a g e n t s can be a p p l i e d t o a v a r i e t y o f c a r b o n carbon bond f o r m i n g r e a c t i o n s as Lewis a c i d s , the e x p l o r a t i o n of c h i r a l t i t a n i u m r e a g e n t s was i n i t i a l l y i n v e s t i g a t e d . One o f t h e e f f i c i e n t method f o r c o n s t r u c t i n g c a r b o h y d r a t e s i s t h e D i e l s - A l d e r r e a c t i o n , which g i v e s a v a r i e t y o f i m p o r t a n t s y n t h e t i c intermediates f o r the s y n t h e s i s of c y c l i t o l derivatives. We t h e r e f o r e were i n t e r e s t e d i n the development o f asymmetric D i e l s - A l d e r r e a c t i o n by t h e use o f c h i r a l t i t a n i u m reagents. Recent p r o g r e s s i n t h i s a r e a has l e d t o the development o f v a r i o u s , h i g h l y s e l e c t i v e , asymmetric r e a c t i o n s by employing c h i r a l d i e n e s and d i e n o p h i l e s i n the p r e s e n c e of Lewis a c i d s . ( 1 2 ) On the o t h e r hand, l i t t l e work has been done on asymmetric D i e l s A l d e r r e a c t i o n s promoted by c h i r a l Lewis a c i d s . ( 1 3 ) F i r s t l y , we m o d i f i e d the 01, (3-unsaturated a c i d s t o be used as d i e n o p h i l e s by c o n v e r t i n g them i n t o the c o r r e s p o n d i n g 1,3oxazolidin-2-one ( a b b r e v i a t e d as o x a z o l i d o n e ) d e r i v a t i v e s 15. T h i s m o d i f i c a t i o n i s based on the c o n s i d e r a t i o n t h a t such b i d e n t a t e d i e n o p h i l e s would form r i g i d complexes w i t h a c h i r a l Lewis a c i d , r e s u l t i n g i n h i g h r e a c t i v i t y and a good l e v e l of ïïf a c i a l s e l e c t i v i t y d u r i n g the c y c l o a d d i t i o n r e a c t i o n . As t h e c h i r a l Lewis a c i d s , c y c l i c d i a l k o x y d i c h l o r o t i t a n i u m s ( I V ) were chosen and p r e p a r e d i n s i t u from v a r i o u s c h i r a l 1,2- o r 1 , 4 - d i o l s and d i c h l o r o d i i s o p r o p o x y t i t a n i u m ( I V ) a c c o r d i n g t o the a l k o x y exchange method.(14)

r-0

r-OH

*(R) L-OH

+

TiCI (0-'Pr) 2

2

N

> *( R )

L-O'

TiCU +

2*ΡΓΟΗ

L

The r e a c t i o n o f 3 - c r o t o n o y l o x a z o l i d o n e 15a and c y c l o p e n t a d i e n e was examined i n t o l u e n e i n the p r e s e n c e o f an e q u i m o l a r amount of v a r i o u s c h i r a l a l k o x y titanium(IV) derivatives. I t was found t h a t the c o r r e s p o n d i n g endo-adduct 18a was o b t a i n e d i n 55% ee when the c h i r a l 2,3-0-isopropylidene1,1,4,4-tetraphenylbutanetetraol 17a(15) was i n t r o d u c e d as a chiral auxiliary. In t h i s t i t a n i u m c a t a l y s t , the c o n f o r m a t i o n o f


295

296


t h e 7-membered r i n g of t h e a l k o x y t i t a n i u m i s thought t o be important i n c o n t r o l l i n g the e n a n t i o s e l e c t i v i t y along with the c o n f o r m a t i o n o f t h e 5-membered a c e t a l r i n g . The r e a c t i o n was, t h e r e f o r e , examined f u r t h e r by u s i n g 1,1,4,4t e t r a p h e n y l b u t a n e t e t r a o l d e r i v a t i v e s which have v a r i o u s s u b s t i t u e n t s on t h e a c e t a l c e n t e r , and t h e t i t a n i u m r e a g e n t

ο ο

V7 - T i C l ( O i - P r ) 2

Me^Vo

+

Ο

.Me

2

0

toluene

A

CON 0

15a


18a Ph

Ph 5 5 % ee.

Me

Ο

VOH Ph Ph

Ph

^

Ph 757oe.e.

P

\ ° Y ^

Me

Ο

0

H

92%ee.

VOH Ph

Ph

17b

( 1 molar amounts of 17b )

d e r i v e d from 2 , 3 - O - p h e n y l e t h y l i d e n e d e r i v a t i v e 17b was found t o promote t h e asymmetric c y c l o a d d i t i o n r e a c t i o n i n a s e l e c t i v e manner y i e l d i n g 18a w i t h 75% o p t i c a l p u r i t y . Moreover, by t h e use o f 2 molar amounts o f t h e t i t a n i u m r e a g e n t , t h e p r o d u c t 18b was o b t a i n e d i n 92% ee.(15) The ( R ) - ( + ) - c h i r a l 1 , 4 - d i o l 17b was e a s i l y p r e p a r e d from L(+)-dimethyl t a r t r a t e . D i m e t h y l t a r t r a t e was c o n v e r t e d t o t h e c o r r e s p o n d i n g p h e n y l e t h y l i d e n e d e r i v a t i v e by t r e a t m e n t w i t h 1,1d i m e t h o x y - l - p h e n y l e t h a n e and c a t . p - t o l u e n e s u l f o n i c a c i d i n r e f l u x i n g benzene, f o l l o w e d by c o n v e r s i o n t o t h e d i o l 17b w i t h e x c e s s phenylmagnesium bromide. The d i o l was p u r i f i e d by column chromatography on s i l i c a g e l (hexane : e t h y l a c e t a t e = 5 : 1 ) , and r e c r y s t a l i z a t i o n from a m i x t u r e o f hexane and 2 - p r o p a n o l . The c r y s t a l s were o b t a i n e d as a adduct o f 17b and 2 - p r o p a n o l (mp 111-114 ° C ) . The a z e o t r o p i c removal o f 2 - p r o p a n o l w i t h benzene a f f o r d e d t h e d i o l 17b as a w h i t e amorphous s o l i d . S i n c e h i g h e n a n t i o s e l e c t i v i t y was a c h i e v e d by employing two molar e q u i v a l e n t s o f t h e c h i r a l t i t a n i u m r e a g e n t g e n e r a t e d from 17b, t h e asymmetric D i e l s - A l d e r r e a c t i o n o f v a r i o u s o x a z o l i d o n e d e r i v a t i v e s o f a, (3-unsaturated a c i d s JJ> and c y c l o p e n t a d i e n e was studied. The r e s u l t s a r e l i s t e d i n T a b l e 4. With the exception o f t h e a c r y l o y l d e r i v a t i v e 15b, v a r i o u s d i e n o p h i l e s r e a c t e d w i t h c y c l o p e n t a d i e n e t o g i v e t h e endo-adducts 18^ i n h i g h o p t i c a l purity.


Asymmetric Reactions Toward Carbohydrate Synthesis297

16. NARASAKA

Ph Ph

T a b l e 4.


R

Asymmetric D i e l s - A l d e r R e a c t i o n o f _15 w i t h Cyclopentadiene React. Temp./ °C

Me H Ph n-Pr CH CH=CH

Yield/%

-15 -78 0 -15 rt

3

endo:exo

Optical Purity/%ee

90:10 86:14 92: 8 90:10 92: 8

92° (2S,3R) 38^ (2S) 81 90 82

93 69 97 82 77

d

β

θ

a) These isomers were s e p a r a t e d by s i l i c a g e l chromatography. b) Those o f endo i s o m e r s . c) The p r o d u c t s were c o n v e r t e d t o t h e c o r r e s p o n d i n g b e n z y l e s t e r s by Evans' p r o c e d u r e , ( 1 6 ) and t h e a b s o l u t e c o n f i g u r a t i o n and t h e o p t i c a l p u r i t y were determined by t h e o p t i c a l r o t a t i o n . ( 1 2 d ) d) The p r o d u c t was reduced t o an a l c o h o l w i t h l i t h i u m ^ a l u m i n u m h y d r i d e , and t h e o p t i c a l p u r i t y was determined by F NMR a n a l y s i s o f t h e c o r r e s p o n d i n g c h i r a l MTPA e s t e r . ( 4 ) e) The p r o d u c t s were reduced t o a l c o h o l s w i t h l i t h i u m aluminum h y d r i d e , and t h e o p t i c a l p u r i t y was determined by HPLC a n a l y s i s o f t h e c o r r e s p o n d i n g P i r k l e ' s carbamates.(17)

H i g h e n a n t i o s e l e c t i v i t y was a l s o a t t a i n e d upon a d d i t o n o f the c h i r a l t i t a n i u m reagent t o t h e r e a c t i o n o f a c y c l i c dienes w i t h o x a z o l i d o n e s o f 2 - b u t e n o i c a c i d 15a and f u m a r i c a c i d 19. The p r e s e n t t i t a n i u m r e a g e n t was n o t e d t o e x h i b i t a wide a p p l i c a b i l i t y t o t h e asymmetric D i e l s - A l d e r r e a c t i o n o f v a r i o u s p r o c h i r a l d i e n e s and d i e n o p h i l e s . p

M e ^ N O ^ 15a

4

M

h

Ph Ph O ^ O H

X J

V S

-

TTCyO+Prfe

>

46 7oy., 9 2 7*e.e.

Ph Ph

Me

o,c^N o+ ζ

PÔH χ«τ

n

u

_ ricyo-i-POa

A

Me

0 CON 0

v

toluene, r.t.

Ph

XX

toluene,r.t.

>

(J,

9

CON 0

19 86°/ey. 85 7oe.e. f


298



Next we i n v e s t i g a t e d t h e e f f e c t o f a l t e r i n g t h e r a t i o o f t h e t i t a n i u m r e a g e n t t o d i e n o p h i l e s . I t was found, however, t h e use o f two molar e q u i v a l e n t s o f t h e c h i r a l t i t a n i u m r e a g e n t i s i n d i s p e n s a b l e f o r a h i g h degree e n a n t i o s e l e c t i o n . That i s , when a c a t a l y t i c amount (10-17%) of t h e t i t a n i u m r e a g e n t i s used i n t h e r e a c t i o n o f 15a and c y c l o p e n t a d i e n e , t h e endo-adduct 18a i s o b t a i n e d i n h i g h y i e l d but i n low e n a n t i o s e l e c t i v i t y .

To improve t h i s p r o c e d u r e a h i g h l y e n a n t i o s e l e c t i v e p r o c e s s employing o n l y a t r u l y c a t a l y t i c amount o f t h e c h i r a l Lewis a c i d was d e s i r a b l e . I t was found t h a t t h e p r e s e n c e o f M o l e c u l a r S i e v e s 4A (MS 4A) i n t h e r e a c t i o n m i x t u r e enhances t h e e n a n t i o s e l e c t i v i t y i n the c h i r a l t i t a n i u m - c a t a l y z e d r e a c t i o n . ( 1 8 ) The c h i r a l t i t a n i u m a l k o x i d e was p r e p a r e d by t h e a l k o x y exchanging method, removing i s o p r o p a n o l a z e o t r o p i c a l l y from t h e r e f l u x i n g toluene s o l u t i o n . However, t h e same h i g h l e v e l o f asymmetric i n d u c t i o n was o b s e r v e d by t h e use o f t h e c h i r a l t i t a n i u m s p e c i e s g e n e r a t e d _in s i t u by m i x i n g t h e c h i r a l 1 , 4 - d i o l 17b and d i c h l o r o d i i s o p r o p o x y t i t a n i u m i n t o l u e n e a t room temperature i n t h e p r e s e n c e o f MS 4A. F o r example, t h e c h i r a l c a t a l y s t was p r e p a r e d from a 10.5% molar amount ( t o t h e d i e n o p h i l e ) o f t h e 1 , 4 - d i o l 17b and a 10% molar amount o f d i c h l o r o d i i s o p r o p o x y t i t a n i u m i n t o l u e n e a t room temperature, and then powdered MS 4A, 3 - c r o t o n o y l o x a z o l i d o n e 15a and c y c l o p e n t a d i e n e were added s u c c e s s i v e l y a t 0 °C. A f t e r b e i n g s t i r r e d f o r 24 hr, t h e endo-adduct 18a was produced i n 91% ee w i t h t h e same a b s o l u t e c o n f i g u r a t i o n (2S,3R) as t h a t o b s e r v e d i n the o r i g i n a l procedure. As can be seen i n T a b l e 5, v a r i o u s o x a z o l i d o n e s o f a c r y l i c a c i d d e r i v a t i v e s lj> r e a c t w i t h c y c l o p e n t a d i e n e t o a f f o r d t h e endo-adducts JL8 i n good t o h i g h (64-91%) e n a n t i o s e l e c t i v i t y by t h e combined use o f a c a t a l y t i c amount o f t h e c h i r a l t i t a n i u m r e a g e n t and MS 4A. Compared t o t h e p r e v i o u s p r o c e d u r e i n which 2 molar e q u i v a l e n t s o f t h e c h i r a l t i t a n i u m was employed, almost t h e same l e v e l o f e n a n t i o s e l e c t i v i t y was a t t a i n e d i n t h e D i e l s - A l d e r r e a c t i o n o f 15a, and t h e o p t i c a l p u r i t y o f t h e c y c l o a d d u c t 18b was improved s i g n i f i c a n t l y . On the o t h e r hand, t h e r e a c t i o n o f t h e o x a z o l i d o n e d e r i v a t i v e o f f u m a r i c a c i d 19_ and b u t a d i e n e was found t o p r o c e e d i n poor e n a n t i o s e l e c t i v i t y as compared w i t h t h e r e a c t i o n c a r r i e d out i n t h e p r e s e n c e o f e x c e s s amounts o f t h e c h i r a l t i t a n i u m r e a g e n t , and t h e c y c l o h e x e n e d i c a r b o x y l i c a c i d d e r i v a t i v e 20_ was o b t a i n e d i n 32-45% ee. In o r d e r t o a c h i e v e wide a p p l i c a b i l i t y f o r t h e c a t a l y t i c p r o c e d u r e , t h e r e a c t i o n c o n d i t i o n s were


16. NARASAKA

Asymmetric Reactions Toward Carbohydrate Synthesis 0.1

0

Ph Ph Ph O^-OH ^ Τ ' O^VOH Ph Ph

MB

0

mol TTCyO+Prfe

toluene M.S. A A


Table

5.

R Me Η n-Pr Ph

Asymmetric D i e l s - A l d e r R e a c t i o n of T i t a n i u m Reagent React. Temp./°C 0 -40 0 rt

endo: exo

a

U s i n g C a t a l y t i c Amount

Yield/%

92: 8 96: 4 91: 9 88: 12

b Optical

87 93 79 72

Purity/%ee

91 (2S,3R) 64 (2S) 72 64

a) These isomers were s e p a r a t e d by s i l i c a g e l chromatography. b) Determined by t h e same p r o c e d u r e s d e s c r i b e d i n t h e T a b l e 4.

examined i n d e t a i l . The r e a c t i o n o f 19_ and b u t a d i e n e was examined i n v a r i o u s s o l v e n t s i n t h e p r e s e n c e o f a 10% molar e q u i v a l e n t s o f t h e c h i r a l t i t a n i u m a l k o x i d e and powdered MS 4A. The e n a n t i o s e l e c t i v i t y d i s p l a y e d by t h e r e a c t i o n s i n v a r i o u s s o l v e n t s a r e summarized i n T a b l e 6. I t was n o t e d t h a t t h e e n a n t i o s e l e c t i v i t y i s i n f l u e n c e d s t r o n g l y by t h e s o l v e n t , and t h a t a l k y l s u b s t i t u t e d benzenes a r e v e r y s u i t a b l e s o l v e n t s f o r t h e p r e s e n t r e a c t i o n . The e n a n t i o s e l e c t i v i t y i s dependent on t h e number o f methyl groups on t h e benzene r i n g and t h e o p t i c a l p u r i t y o f t h e adduct 2_0 was g r e a t l y i n c r e a s e d i n t h e o r d e r o f t o l u e n e , x y l e n e s and t r i m e t h y l b e n z e n e s . Furthermore, r a t h e r h i g h e n a n t i o s e l e c t i v i t y was a t t a i n e d by employing h e x y l b e n z e n e as t h e s o l v e n t , and t h e t r a n s - 4 - c y c l o h e x e n e - l , 2 - d i c a r b o x y l i c a c i d d e r i v a t i v e 20 was o b t a i n e d i n 98% y i e l d w i t h 85% ee.(19)

phPh

Ν

01-

^

M

S

4 A , r.t.

0.1 mol

Ι Λ ρ η κ Λ

CON

19

0 \ /

20


299

300


T a b l e 6.

S o l v e n t E f f e c t on t h e E n a n t i o s e l e c t i v i t y a

a

Solvent

Solvent

Optical Purity/%ee 22 32-45 67 68 74

benzene toluene o-xylene g-xylene cumene

Optical Purity/%ee

CCI 4 b 1,2,3-TMB 1,3,5-TMB 1,3,5-TIPB hexylbenzene C

58 77 81 85 85

a) Determined by t h e NMR a n a l y s i s o f t h e c o r r e s p o n d i n g d i m e t h y l e s t e r (Mg(OMe) u s i n g c h i r a l s h i f t r e a g e n t E u i h f c ) ^ . b) TMB=trimethylbenzene. c) T I P B = t r i i s o p r o p y l b e n z e n e .


2

The g e n e r a l i t y o f t h e s o l v e n t e f f e c t on t h e e n a n t i o s e l e c t i v i t y was examined i n t h e f o l l o w i n g examples u s i n g 1,3,5t r i m e t h y l b e n z e n e (1,3,5-TMB) as t h e common s o l v e n t (under unoptimized r e a c t i o n c o n d i t i o n s ) . The r e a c t i o n o f 19_ w i t h i s o p r e n e was a l s o found t o p r o c e e d smoothly i n 1,3,5-TMB t o a f f o r d t h e 4 - m e t h y l c y c l o h e x e n e - l , 2 d i c a r b o x y l i c a c i d d e r i v a t i v e 2_1 i n 92% ee. PhPh

Ph P V ^ O H X J

M

e

0

2

c ^ l

N

X

0

P

. γ

h

m

P

-

T i C ,

o.1 m o l 2(0-

O H

U

" Ph Ph

TiCI (0-i-Pr) 2

2

1

1,3,5-TMB , 0°C 15


T a b l e 7. ~

R

Reaction Yield/%

Me Ph n-Pr

90 97 75

o f 15 w i t h

Cyclopentadiene

endo:exo 91: 9 92: 8 91: 9

a

b Optical Purity/%ee 91 82 75

a) These isomers were s e p a r a t e d by s i l i c a g e l chromatography. b) Determined by t h e p r o c e d u r e s d e s c r i b e d i n T a b l e 4.

As shown by T a b l e 7 above, t h e c h i r a l t i t a n i u m c a t a l y s t MS 4A system i s w i d e l y a p p l i c a b l e t o t h e r e a c t i o n s o f a v a r i e t y of d i e n o p h i l e s and d i e n e s when a s u i t a b l e a l k y l s u b s t i t u t e d benzene i s employed a s a s o l v e n t , and s y n t h e t i c a l l y i m p o r t a n t D i e l s - A l d e r a d d u c t s a r e p r e p a r e d i n h i g h e n a n t i o s e l e c t i v i t y by the present c a t a l y t i c process. Asymmetric H y d r o c y a n a t i o n R e a c t i o n The c h i r a l t i t a n i u m r e a g e n t p r e p a r e r d i n s i t u from t h e c h i r a l 1 , 4 - d i o l and d i c h l o r o d i i s o p r o p o x y t i t a n i u m i s e x p e c t e d t o be a p p l i c a b l e t o v a r i o u s r e a c t i o n s c a t a l y z e d by L e w i s a c i d s . We, t h e r e f o r e , i n v e s t i g a t e d t h e asymmetric s y n t h e s i s o f c y a n o h y d r i n s from a l d e h y d e s and c y a n o t r i m e t h y l s i l a n e employing t h e c h i r a l t i t a n i u m reagent.(20) Asymmetric s y n t h e s i s o f c y a n o h y d r i n s i s an i m p o r t a n t p r o c e s s i n o r g a n i c s y n t h e s i s because c y a n o h y d r i n s can be e a s i l y c o n v e r t e d i n t o a v a r i e t y o f v a l u a b l e s y n t h e t i c i n t e r m e d i a t e s such as 01hydroxy a c i d s , α-hydroxy ketones, and (3-amino a l c o h o l s . O p t i c a l l y a c t i v e c y a n o h y d r i n s a r e o b t a i n e d i n good s e l e c t i v i t y by the n u c l e o p h i l i c a t t a c k of cyanating reagents t o c h i r a l acetals.(21) However, t h e c h i r a l a u x i l i a r i e s a r e d e s t r o y e d , and not r e c o v e r e d . In c a t a l y t i c processes with c h i r a l b o r y l compounds,(22) D - o x y n i t r i l a s e , ( 2 3 ) and s y n t h e t i c p e p t i d e s , ( 2 4 ) t h e o p t i c a l p u r i t i e s of the r e s u l t i n g cyanohydrins are g e n e r a l l y not sufficient. F i r s t l y , we examined t h e asymmetric h y d r o c y a n a t i o n o f 3phenylpropanal. When 3 - p h e n y l p r o p a n a l was t r e a t e d w i t h c y a n o t r i m e t h y l s i l a n e using the c h i r a l t i t a n i u m a l k o x i d e prepared from d i c h l o r o d i i s o p r o p o x y t i t a n i u m and t h e c h i r a l 1 , 4 - d i o l 17b i n t o l u e n e a t room temperature, o n l y a t r a c e amount o f t h e



302

c y a n o h y d r i n 23a was g e n e r a t e d a f t e r 2 days. On t h e o t h e r hand, by t h e a d d i t i o n o f MS 4A t o t h i s s o l u t i o n , t h e r e a c t i o n p r o c e e d e d smoothly a t -65 °C t o g i v e 2 - h y d r o x y - 4 - p h e n y l b u t a n e n i t r i l e , which was i s o l a t e d i n 89% y i e l d w i t h 74% ee. The h y d r o c y a n a t i o n o f p r i m a r y , s e c o n d a r y and a r y l a l d e h y d e s was examined w i t h c y a n o t r i m e t h y l s i l a n e to g i v e the o p t i c a l l y a c t i v e cyanohydrins i n good o p t i c a l p u r i t y . In p a r t i c u l a r , benzaldehyde i s c o n v e r t e d i n t o ( R ) - m a n d e l o n i t r i l e 23b i n 96% ee. (See T a b l e 8.) PhPh

li r^ ao ! \. -, ™ - ™* ^ h

ο Downloaded by MONASH UNIV on May 21, 2013 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch016

R

X .

H

+ Me S.CN 3

HO

— —

•

R

' C

X

N

23

toluene, -65 *C, 2 days

T a b l e 8.

H

Asymmetric H y d r o c y a n a t i o n o f Aldehydes Cyanotrimethylsilane

with

a R

R e a c t i o n Time/h

Ph PhCH PhCH CH c-C H 6 11 C H,/ 8 17 f t

12 12 12 48 24

Yield/% 79 66 89 77 66

Optical 96 77 74

Purity/%ee

(R)£

Asymmetric Reactions Toward the Synthesis of Carbohydrates

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