Polyamine-Chelated Alkali Metal Compounds - ACS Publications

14 Asymmetric Synthesis via Lithium Chelates

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on October 15, 2015 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/ba-1974-0130.ch014

THOMAS A. WHITNEY and ARTHUR W. LANGER, JR. Corporate Research Laboratories, Esso Research and Engineering C o . , L i n d e n , N . J . 07036

Reactions of a variety of prochiral carbonyl substrates with Chel* · LiR, where Chel* = trans-N.N,N',N'-tetramethyl1,2-cyclohexanediamine (TMCHD), were studied. Optically active carbinols were obtained and had an enantiomeric excess of up to 30% without sacrificing one asymmetric center to create a new one. Either of the absolute configurations of the product can be readily obtained by changing the absolute configuration of the chewing agent or by interchanging the R groups in the reaction of Chel* · LiR + R'COR". For example: ( - ) - T M C H D · LiC4H9

+ C H C H O --> ( - ) - C 6 H 5 C H ( O H ) C 4 H 9

( - ) - TMCHD·LiC6H5

+ C H C H O --> ( + ) - C H C H ( O H ) C H

6

4

5

9

6

5

4

9

trans-1,2-Diaminocyclohexane (DACH) is a particularly attractive entry into optically active chelating agents for lithium reagents. Both enantiomers were obtained readily by an improved resolution procedure.

A symmetric synthesis has been investigated since Emil Fischer's classic publication on sugar chemistry in 1894 (I) and has since been the subject of numerous studies (2, 3). Marckwald (4) defined asymmetric synthesis as "those reactions which produce optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all other analytical processes." A broader definition of asymmetric synthesis is "a process which converts a prochiral unit into a chiral unit so that unequal amounts of stereoisomeric products result" (see Ref. 3, p. 5). Of the various schemes for achieving asymmetric syntheses in reactions other than polymerizations, two have received considerable atten270 In Polyamine-Chelated Alkali Metal Compounds; Langer, A.; Advances in Chemistry; American Chemical Society: Washington, DC, 1974.

14.

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AND

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Lithium Chelates

LANGER

t i o n : e n z y m a t i c reactions ( 5 )

a n d reactions i n v o l v i n g h y d r i d e transfer

f r o m the a l p h a or b e t a p o s i t i o n of a n o p t i c a l l y a c t i v e

organometallic

reagent:


• Biochemical methods Y e a s t f e r m e n t a t i o n or > Purified enzyme system

A) R-CT

(±)

X I R—C—Y I Ζ

X Enzyme |* • R—C—Y I Ζ

OH |* R - C - D | H

5 0 % y i e l d generally stereospecific

• H y d r i d e transfer A l ( O R * ) or R * M g X + 3

R1CR2

•

Ο

Η I* Rx—C—R I OH

2

+

ketone or olefin

B o t h methods, h o w e v e r , h a v e disadvantages.

B i o c h e m i c a l transfor

mations c a n h a v e l i m i t e d a p p l i c a t i o n , a n d there is a l w a y s the p r o b l e m of finding

the p r o p e r b a c t e r i a , a n i m a l p r e p a r a t i o n , or e n z y m e a n d c u l t u r e

m e d i u m to effect a n e w synthesis. I n a d d i t i o n , p r o d u c t i s o l a t i o n — s u c h as i n t h e p r o d u c t i o n of a n o p t i c a l l y active a - d e u t e r o a l c o h o l , w h e r e a s m a l l a m o u n t of p r o d u c t m u s t be i s o l a t e d f r o m a large q u a n t i t y of spent f e r m e n t a t i o n l i q u o r — c a n present f o r m i d a b l e separation p r o b l e m s .

Product

i s o l a t i o n f r o m e n z y m e systems, e s p e c i a l l y i m m o b i l i z e d e n z y m e s , c o u l d be m u c h simpler, however. Hydride-transfer

reactions

suffer

from

the

several

shortcomings.

First, a conventional optical resolution must usually be performed

to

o b t a i n a n o p t i c a l l y active c a r b i n o l , w h i c h is t h e n c o n v e r t e d to the h a l i d e w h e n the G r i g n a r d m e t h o d is to be used.

T h e a c t u a l r e d u c t i o n is g e n

e r a l l y not the o n l y r e a c t i o n p a t h w a y ; h e n c e c a r b i n o l b y - p r o d u c t is p r o duced.

M o r e undesirable, however,

is the fact

that t h e

asymmetric

center of the o r g a n o m e t a l l i c reagent is sacrificed w h e n the n e w center is created.

chiral

U n l e s s the r e a c t i o n is stereospecific, w h i c h is r a r e l y

the case, a net o v e r a l l decrease i n c h i r a l i t y results.

In Polyamine-Chelated Alkali Metal Compounds; Langer, A.; Advances in Chemistry; American Chemical Society: Washington, DC, 1974.

272

POLYAMINE-CHELATED

ALKALI

M E T A L

COMPOUNDS

W h i l e this w o r k w a s i n progress a n alternate m e t h o d of a s y m m e t r i c synthesis via h y d r i d e transfer w a s r e p o r t e d , i n w h i c h the a s y m m e t r i c c e n ter of the c h i r a l m o i e t y is not sacrificed (3, p. 2 0 4 ) . T h i s m e t h o d uses the r e a c t i o n p r o d u c t of L i A l H

a n d v a r y i n g amounts of o p t i c a l l y a c t i v e a m i n o

4

c a r b i n o l s , s u c h as ( — ) - q u i n i n e , ( + ) - c i n c h o n i d i n e , a n d ( — ) - e p h e d r i n e , to r e d u c e p r o c h i r a l substrates. I n this system the h y d r i d e a n i o n species


is s i g m a b o n d e d to the o p t i c a l l y a c t i v e r e s i d u e , a n d a m a x i m u m of t h r e e h y d r i d e s are a v a i l a b l e for f u r t h e r r e a c t i o n .

T h e aminocarbinols

could

sometimes b e r e c o v e r e d for reuse. I n t h e instant system the c h i r a l c h e l a t i n g agent forms c o o r d i n a t e b o n d s to the l i t h i u m cation, a n d f o u r h y d r i d e s are a v a i l a b l e for subsequent r e a c t i o n . Conceptually, a n optically active, asymmetric l i t h i u m

compound,

C h e l * · L i R ( w h e r e C h e l * denotes the o p t i c a l l y a c t i v e , c h e l a t i n g a g e n t ) s h o u l d i n d u c e stereoselective reactions at the L i - R b o n d .

This should

o c c u r since r e a c t i o n c a n p r o c e e d via t w o d i a s t e r e o m e r i c t r a n s i t i o n states of u n e q u a l energy. be achieved, 1 0 0 %

I f a n e n e r g y difference of a b o u t 2 k c a l / m o l e c o u l d o p t i c a l bias c o u l d b e r e a l i z e d .

Nevertheless, the

o p t i c a l l y active chelates c o u l d thus b e u s e d to p r e p a r e o p t i c a l l y active p r o d u c t s i n e l e c t r o p h i l i c reactions w i t h o u t d e s t r o y i n g one center to create a n e w one as t h e c h e l a t i n g agent c o u l d be

asymmetric recovered

unchanged and recycled:

* Chel-LiR +

Ο

OH

II R'—C—R'

* R^-C—R" +

Chel*

LiR Chel*

Precursor

B e f o r e a t t e m p t i n g a s y m m e t r i c syntheses via the a b o v e scheme, c a r e f u l t h o u g h t w a s g i v e n to t h e c h o i c e of the C h e l * precursor. It w a s d e e m e d t h a t ( a ) the c o m p o u n d s h o u l d b e a r a c e m i c m i x t u r e ( 6 ) ;

(b)

resolution

s h o u l d b e e a s y — t h a t is, v e r y h i g h o p t i c a l p u r i t y s h o u l d b e o b t a i n e d f r o m o n l y one c r y s t a l l i z a t i o n of a n a p p r o p r i a t e salt; ( c )

inexpensive resolving

agents

the C h e l *

{e.g., t a r t a r i c a c i d )

s h o u l d be u s e d ;

(d)

precursor

s h o u l d b e easily resolvable e v e n w h e n grossly c h e m i c a l l y i m p u r e ; ( e )

both

enantiomers s h o u l d b e o b t a i n a b l e i n v e r y h i g h o p t i c a l p u r i t y ; a n d ( f ) a b solute c o n f i g u r a t i o n of the c o m p o u n d s h o u l d b e k n o w n . T h e s e considerations l e d to the c h o i c e of i r a n s - l , 2 - d i a m i n o c y c l o h e x ane ( D A C H ) as t h e o p t i m u m i n i t i a l C h e l * p r e c u r s o r since b o t h

(R,R)-

( — ) - D A C H a n d ( S , S ) - ( + ) - D A C H m a y be o b t a i n e d f r o m the r a c e m i c m i x t u r e via the ( + )-tartrate a n d ( + ) - b i t a r t r a t e salts, r e s p e c t i v e l y


(7,

14.

WHITNEY

8, 9 ) .

AND

273

Lithium Chelates

LANGER

T h e l i t e r a t u r e p r o c e d u r e s w e r e f o l l o w e d i n i t i a l l y to separate

a n d trans-OACH

(10)

cis-

a n d to resolve the latter. V a r i a t i o n s of the p u b -

l i s h e d p r o c e d u r e ( 8 ) w e r e s t u d i e d to d e t e r m i n e the effect o n o p t i c a l y i e l d of the ( — ) -antipode.

T h e best results w e r e o b t a i n e d w h e n the r e a c t i o n

w a s r u n w i t h no s p e c i a l precautions.

P u r i f i c a t i o n of the D A C H

was

( S , S ) - ( + ) - D A C H is less r e a d i l y a v a i l a b l e t h a n ( - ) - D A C H .

The


f o u n d to be

unnecessary.

f o r m e r is i n i t i a l l y o b t a i n e d f r o m the m o t h e r l i q u o r as a n o p t i c a l l y i m p u r e ( + ) - b i t a r t r a t e , w h i c h is c o n v e r t e d to the d i h y d r o c h l o r i d e ; the latter salt is f r a c t i o n a l l y c r y s t a l l i z e d r e p e a t e d l y f r o m w a t e r a n d , finally t h e ( + ) D A C H - 2 H C 1 salt is m e c h a n i c a l l y separated f r o m the f e a t h e r l i k e aggregates of t h e r a c e m i c salt ( 8 ) .

T h i s c u m b e r s o m e p r o c e d u r e was f o u n d to

be unnecessary to secure ( - f ) - D A C H of h i g h o p t i c a l p u r i t y . B y t a k i n g advantage

of the r a c e m i c m i x t u r e p r o p e r t y of D A C H , less t h a n

50%

c h e m i c a l l y a n d o p t i c a l l y p u r e ( - f ) - D A C H is r e a d i l y u p g r a d e d b y f r a c t i o n a l c r y s t a l l i z a t i o n f r o m the m e l t or h y d r o c a r b o n

solution.

Further-

more, ( + ) - D A C H of v e r y h i g h o p t i c a l p u r i t y c o u l d b e o b t a i n e d b y a single c r y s t a l l i z a t i o n of the n e u t r a l salt of u n n a t u r a l ( — ) - t a r t a r i c a c i d . T h u s f a c i l e p r o c e d u r e s w e r e d e v e l o p e d for p r e p a r i n g b o t h D A C H

anti-

podes i n e x p e n s i v e l y a n d i n q u a n t i t y . E s c h w e i l e r - C l a r k e (11) ( R,R ) - ( - ) -

and

[( + ) - a n d ( - ) - T M C H D ] Results and Previous

m e t h y l a t i o n of ( + ) - a n d ( — ) - D A C H gave

( S,S ) - ( - f ) - N ^ ^ ^ N ' - t e t r a m e t h y l c y c l o h e x a n e d i a m i n e in high yield.

Discussion investigations

have

shown

that

chelated

organolithium

reagents are h i g h l y reactive a n d s y n t h e t i c a l l y v e r s a t i l e (12, a d d i t i o n , the c h e m i s t r y of c h e l a t e d

In

13, 14).

c o m p l e x m e t a l h y d r i d e s has

been

i n v e s t i g a t e d , i n c l u d i n g t h e i r use for r e d u c i n g c a r b o n y l c o m p o u n d s

(15).

T h e results of this i n v e s t i g a t i o n of the r e a c t i o n of o p t i c a l l y active c h e l a t e d l i t h i u m c o m p o u n d s a n d p r o c h i r a l c a r b o n y l substrates are s u m m a r i z e d i n T a b l e I. T h e results s u m m a r i z e d i n t h e table w e r e o b t a i n e d w i t h o u t our t r y i n g to o p t i m i z e r e a c t i o n c o n d i t i o n s f o r m a x i m u m stereospecificity. the reactions w e r e b e g u n at — 7 5 ° to — 8 0 ° C . combined,

Generally,

A f t e r a l l reactants w e r e

the r e a c t i o n m i x t u r e w a s h e l d at t h a t t e m p e r a t u r e

m i n u t e s , t h e n a l l o w e d to w a r m to r o o m temperature.

for

30

This procedure

was f o l l o w e d m a i n l y to s t u d y the effect of ketone structure o n the o p t i c a l y i e l d of the c a r b i n o l p r o d u c t . r e a c t i o n stereospecificity

A l t h o u g h the effect of t e m p e r a t u r e

was not s t u d i e d i n d e t a i l , c o m p a r i s o n

results of runs 6 a n d 9 suggest that l o w e r temperatures

of

should


on the give

274

POLYAMINE-CHELATED

Table I.


Run

ALKALI

M E T A L

COMPOUNDS

Summary of Reactions of Optically Active Chelate

Substrate

1

(-)-TMCHD-LiC H

9

C H CHO

2

(-)-TMCHD.LiC H

5

C H CHO

3

(—)-TMCHD-LiAlH

4

C H COCH »

4

(—) - T M C H D ·LiAlH

4

C H

5

(—)-TMCHD ·LiAlH

4

C H COC H

6

(+)-TMCHD-LiAlH

7

(—)-TMCHD ·LiAlH

8

(—)-TMCHD-LiAlH

9

( — ) - T M C H D ·L i A l H

10

(—)-TMCHD · LiAlD

4

6

6

4

6

6

d

9

1 3

6

4

5

1 3

3

COCH

5

C H 6

4

1 3

COCH

c

3

9

3

c

a-Tetralone*

4

4

β-Tetralone

C H

4

e

4

1 3

COCBV

CeH CH0 5

6


14.

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Lithium Chelates

275

Chelated Lithium Compounds and Prochiral Substrates [OL]25

Product OH I

Purity

- 2 . 6 8 ° ( C , 14.3, B )

8.65

+ 2 . 9 8 ° ( C , 13.3, B « )

9.5

3

- 1 . 0 7 ° ( C , 13.5, Β · )

10.7

3

- 1 . 1 7 ° ( C , 13.5, B " )

9

+ 1 . 7 5 ° ( C , 13.7, Β · )

5.6

3

+ 1 . 0 6 ° ( C , 14.4, Β · )

10.6

α-Tetralole

- 0 . 9 7 ° ( C , 2.50, C )

3.9

β-Tetralole

- 2 . 3 2 ° ( C , 7.8, C O

8.2

- 0 . 4 0 ° ( C , 13.3, Β · )

4.0

C6H5C-C4H9 1 Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on October 15, 2015 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/ba-1974-0130.ch014

Optical

589 e

H OH

I C H CC H9 e

5

4

H OH

I C H 6

CCH

1 3

H OH

I C H e

1 3

CCH

11.7

H OH

I C H CC H 6

5

4

H OH

I C H 6

l 3

CCH H

C H 6

1 3

OH CCH

e

3

6

H OH C H C-D 6

6

- 0 . 1 6 ° (Neat)

10.3

H


%

276

POLYAMINE-CHELATED

ALKALI

M E T A L

COMPOUNDS

Table I.


Run

Substrate

Chelate

11

(—)-TMCHD«LiAlH

4

CeHsCOCHCM

12

( — ) - T M C H D ·L i A l H

4

13

(—) - T M C H D · L1AIH4

HO(CH ) COCH

14

( — ) - T M C H D · L1AIH4

C H COCH i

HOCH CH COCH 2

2

2

e

6

3

3

3

f c

f c

3

Β = benzene. Molar ratio of chelate to subtrate = 1:2. Molar ratio of chelate to substrate = 1:4. " T h e (+) - T M C H D had [ ]* 89 + 51.4° (C, 5.35, 95% E t O H ) or 97%opticai;purity. Rotation taken at 17°C.

α

b c

a

5

e

h i g h e r o p t i c a l y i e l d s . P a r t i c u l a r a t t e n t i o n w a s p a i d to c o m p l e t e r e m o v a l of the r e s i d u a l o p t i c a l l y a c t i v e c h e l a t i n g agent f r o m the p r o d u c t . C o m p a r i s o n of the results f r o m runs 1, 2, a n d 5 shows that the abso l u t e c o n f i g u r a t i o n of the p r o d u c t c a n b e v a r i e d w i t h o u t c h a n g i n g the absolute c o n f i g u r a t i o n of the c h e l a t i n g agent. T h e same result is a c h i e v e d w i t h the latter c h a n g e chelated

(cf. r u n 3 w i t h 6 ) .

L1AID4 constitutes

deuteroalcohols

(run 10).

T h e use of o p t i c a l l y active

a v e r y f a c i l e route to o p t i c a l l y a c t i v e

p a r e d b y r e d u c t i o n of d e u t e r o a l d e h y d e s

i n actively fermenting media

w i t h i s o l a t e d e n z y m e systems, a n d b y a s y m m e t r i c r e d u c t i o n s

(16),

«-

α-Deuteroalcohols h a v e p r e v i o u s l y b e e n p r e

a l d e h y d e s b y c h i r a l G r i g n a r d reagents via h y d r i d e transfer (17).

of

Both

m e t h o d s suffer f r o m the disadvantages discussed at the b e g i n n i n g of this paper. T h e size of the R groups i n R ' C O R " influences the degree of stereospecificity of these reactions, as the results of runs 5 , 1 0 , a n d 14 s h o w w h e n


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WHITNEY

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277

Lithium Chelates

LANGER

(Continued) [OL]25

Product

Optical

589

Punty

%

OH

I C H CCH OH Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on October 15, 2015 | http://pubs.acs.org Publication Date: June 1, 1974 | doi: 10.1021/ba-1974-0130.ch014

6

5

+ 4 . 9 1 ° ( C , 4.03, Ε )

8.3

Λ

2

Η OH HOCH CH CCH 2

2

3

+ 3 . 3 4 ° ( C , 4.03, E )

~30

A

Ή OH

I

HO(CH ) CCH 2

3

I

3

+0.257° (Neat)

Η

OH

I

C H -CCH 6

5

I

3

+ 2 . 9 4 ° ( C , 13.14, Β · )

7.4

Η C = chloroform. Reaction run at room temperature. Ε = 95% ethanol. * Molar ratio of chelate to substrate = 3.2. » Runs 1 and 2 were in pentane; all others were in toluene. f

0

h

R " is v a r i e d f r o m Η to C H

3

to n - C H . 4

9

seems that the greater the difference greater w i l l b e the stereospecificity.

F r o m these l i m i t e d results i t

i n size b e t w e e n

R ' a n d R " , the

H o w e v e r , other v a r i a b l e s — s u c h as

the structure of the a s y m m e t r i c c h e l a t i n g a g e n t — a l s o h a v e a n i m p o r t a n t influence o n r e a c t i o n stereospecificity.

T h i s v a r i a b l e is u n d e r study.

T h e difference i n t h e o p t i c a l y i e l d u p o n r e d u c t i o n of α-tetralone vs. β-tetralone w i t h ( — ) - T M C H D · L i A l

4

indicates that the s t e r e o c h e m i c a l

o u t c o m e of a g i v e n r e a c t i o n m a y be v e r y sensitive to s m a l l changes i n the steric e n v i r o n m e n t a r o u n d t h e p r o c h i r a l center.

N o t e w o r t h y is the

result of r u n 12, w h e r e 3 0 % o p t i c a l p u r i t y w a s a c h i e v e d , w h i c h is c o n s i d e r a b l y h i g h e r t h a n t h a t of a l l the other runs ( w i t h the possible excep t i o n of r u n 1 3 ) . T h e result of r u n 12 suggests t h a t w h e n other f u n c t i o n a l groups c a p a b l e of r e a c t i n g w i t h C h e l * · L i R are present i n the substrate, t h e y c a n h a v e a strong influence o n the o v e r a l l stereochemical o u t c o m e . I n the r e d u c t i o n of l - h y d r o x y - 3 - b u t a n o n e the r e a c t i o n c a n b e


en-

278

POL YAMINE-CHELATED

ALKALI

M E T A L

COMPOUNDS

v i s i o n e d as p r o c e e d i n g i n t r a m o l e c u l a r l y via a s i x - m e m b e r e d r i n g i n t e r m e d i a t e f o r m e d b y a n e a r l i e r r e a c t i o n of the h y d r o x y l g r o u p w i t h A 1 H ~ , 4

giving a H A 1 0 C H 3

2

species.

T h e a c t i v a t i o n energy difference

between

t h e t w o d i a s t e r e o m e r i c t r a n s i t i o n states f o r i n t r a m o l e c u l a r c a r b o n y l r e d u c t i o n m i g h t t h e n be greater t h a n that for d i r e c t attack o n the c a r b o n y l in an intermolecular reduction.


A n a t t e m p t to o b t a i n e v i d e n c e for this hypothesis w a s m a d e . t i o n of

l-hydroxyl-4-pentanone

m i g h t p r o c e e d via a

Reduc

stereochemically

less f a v o r a b l e , s e v e n - m e m b e r e d r i n g i n t e r m e d i a t e , a n d the p r o d u c t pentanediol)

of

much

less

than 3 0 %

(1,4-

o p t i c a l l y p u r i t y m i g h t result.

A l t h o u g h o p t i c a l l y active d i o l was o b t a i n e d , n o assignment of o p t i c a l p u r i t y c o u l d be m a d e since the d i o l c o u l d not b e t r a n s f o r m e d

stereo-

specifically, despite several attempts, i n t o 2 - m e t h y l - t e t r a h y d r o t h i o p h e n e 1-dioxide, w h o s e m a x i m u m r o t a t i o n is k n o w n (18).

T h e v a l i d i t y of the

a b o v e hypothesis thus r e m a i n s moot. O n e r e a c t i o n i n the l i t e r a t u r e w i t h w h i c h the T M C H D chelates c a n b e d i r e c t l y c o m p a r e d i n terms of o p t i c a l y i e l d is t h a t s t u d i e d b y N o z a k i (19), i n w h i c h sparteine · L i - n - C H r e a c t e d w i t h b e n z a l d e h y d e . 4

9

1-Phenyl-

1-pentanol w a s o b t a i n e d i n 6 % o p t i c a l p u r i t y . T h e o p t i c a l y i e l d s o b t a i n e d i n the present s t u d y w e r e g e n e r a l l y h i g h e r .

I n a d d i t i o n , sparteine is

a n a t u r a l p r o d u c t o c c u r r i n g i n a p l a n t c a l l e d " b r o o m t o p s " a n d is a v a i l a b l e i n o n l y one absolute c o n f i g u r a t i o n , t h e r e b y l i m i t i n g its u t i l i t y . Summary T h e results of this s t u d y suggest t h a t o p t i c a l l y active c h e l a t e d l i t h i u m reagents m a y be u s e d g e n e r a l l y for a s y m m e t r i c synthesis a c c o r d i n g

to

the s c h e m e : Ε

II

Chel*-LiR +

R'-C-R'

R H+

1

R-C*-EH +

Chel*

R" T h e c h e l a t i n g agent m a y t h e n b e r e c o v e r e d u n c h a n g e d a n d r e u s e d , as w a s d o n e m a n y times d u r i n g this w o r k . E i t h e r of the absolute c o n f i g u artions of the c h i r a l p r o d u c t m a y b e o b t a i n e d at w i l l , either b y v a r y i n g t h e a b s o l u t e c o n f i g u r a t i o n of C h e l * or b y v a r y i n g t h e m o d e of synthesis. As

a d d i t i o n a l results are a c c u m u l a t e d o n a v a r i e t y of substrates

types of reactions, i t m a y b e possible to p r e d i c t w i t h confidence

and the

s t e r e o c h e m i c a l o u t c o m e of a p a r t i c u l a r r e a c t i o n . A s a d d i t i o n a l i n s i g h t is g a i n e d into the factors c r i t i c a l to stereospecificity, p e r h a p s o p t i c a l y i e l d s approaching enantiomeric purity w i l l be realized.


14.

WHITNEY

AND

279

Lithium Chelates

LANGER


Experimental Resolution of trans-1,2 -Diaminocyclohexane ( D A C H ) . A t o t a l of 1000 grams (8.76 m o l e s ) D A C H ( A d a m s C h e m i c a l C o . ) , 1323 grams (8.76 m o l e s ) ( + ) - t a r t a r i c a c i d , a n d 6 liters w a t e r w e r e u s e d w i t h the A s p e r g e r p r o c e d u r e ( 8 ) . C r o p 1 tartrate separated, 542 grams, u p o n c o o l i n g to 0 ° C . T h e m o t h e r l i q u o r w a s c o n c e n t r a t e d to a b o u t 4.5 liters, a n d c r o p 2 separated, 267 grams. F u r t h e r c o n c e n t r a t i o n of the m o t h e r l i q u o r to a b o u t 2.5 liters gave c r o p 3, 180 grams. O p t i c a l l y active ( — ) - D A C H was r e c o v e r e d f r o m the tartrate salt b y a d d i n g the latter to a n excess of a q u e o u s N a O H a n d c o n t i n u o u s l y e x t r a c t i n g t h e m i x t u r e w i t h b e n z e n e u n d e r n i t r o g e n . C r o p 1 g a v e 216 grams d i s t i l l e d ( - ) - D A C H , b p 7 1 ° - 7 3 ° C / 8 m m , [ a ] 9 -40.3° (C, 5.23, b e n z e n e ) , c o r r e s p o n d i n g to 9 7 % o p t i c a l p u r i t y as d e t e r m i n e d f r o m a s a m p l e of o p t i c a l l y p u r e ( - ) - D A C H · 2 H C 1 h a v i n g [ α ] 9 -15.6° ( C , 0.20 g r a m p e r m l H 0 ) (8). T h e m o t h e r l i q u o r r e m a i n i n g after c r o p 3 ( — ) - D A C H tartrate sepa r a t e d w a s t r e a t e d as d e s c r i b e d for c r o p 1 tartrate, a n d 540 grams of d i s t i l l e d ( + ) - D A C H w e r e r e c o v e r e d [a] M O + 20.3° ( C , 5.05, b e n z e n e ) . T h e m a t e r i a l w a s p l a c e d i n a S c h l e n k t u b e , w h i c h was t h e n p l a c e d i n a constant t e m p e r a t u r e b a t h at 20 ° C . T h e t e m p e r a t u r e of t h e b a t h w a s l o w e r e d s l o w l y to 9 ° C o v e r 19 days as crystals g r e w . T h e t u b e was i n v e r t e d , a n d t h e solids w e r e f i l t e r e d f r o m t h e m o t h e r l i q u o r . T h e a r m of the S c h l e n k t u b e c o n t a i n i n g t h e solids w a s h e a t e d , a n d the m o l t e n ( + ) - D A C H w a s r e m o v e d f r o m the t u b e w i t h a p i p e t t e . It d i s p l a y e d [ + 8.22° ( C , 5.09, b e n z e n e ) . Preparation of ( + )- and ( — ) - 2 V , N , N ' , ] V ' - T e t r a m e t h y l - l , 2 - c y c l o hexanediamine (( + )- and ( — ) - T M C H D ) . The Eschweiler-Clarke (11) p r o c e d u r e was u s e d w i t h f o r m a l d e h y d e a n d f o r m i c a c i d . A 9 0 % y i e l d of ( + ) a n d ( - ) - T M C H D w a s o b t a i n e d , h a v i n g [ « L s o ± 17.2° ( n e a t ) , d = 0.888; [ « L e o ± 20.0 ( C , 5.06, b e n z e n e ) . Asymmetric Syntheses ( R u n 14). A c h a r g e of 0.19 g r a m ( 5 m m o l e s ) L i A l H , 25 m l t o l u e n e , a n d 0.85 g r a m ( 5 m m o l e s ) ( - ) - T M C H D , [ a ] . ™ — 17.2° ( n e a t ) ( 1 0 0 % o p t i c a l l y p u r e ) w a s s t i r r e d i n a b e a k e r for one h o u r at r o o m t e m p e r a t u r e . T h e t u r b i d g r a y m i x t u r e was c o o l e d to — 80 ° C , a n d a s o l u t i o n of 1.20 grams (10 m m o l e s ) a c e t o p h e n o n e i n 10 m l of toluene w a s a d d e d d r o p w i s e w h i l e t h e r e a c t i o n m i x t u r e w a s m a i n t a i n e d at — 7 0 ° to — 8 0 ° C . W h e n a c e t o p h e n o n e a d d i t i o n w a s c o m p l e t e , t h e r e a c t i o n m i x t u r e w a s m a i n t a i n e d at —70° to — 8 0 ° C for a b o u t 30 m i n u t e s , t h e n a l l o w e d to w a r m to 0 ° C . W a t e r , 5 m l , w a s a d d e d , f o l l o w e d b y 30 m l of I N H C 1 . T h e l i q u i d phases w e r e separated, a n d the a q u e o u s phase w a s e x t r a c t e d w i t h 15 m l p e n t a n e . T h e c o m b i n e d o r g a n i c p h a s e w a s t h e n e x t r a c t e d w i t h 15 m l IN H C 1 , 15 m l 1 0 % N a H C 0 s o l u t i o n , 15 m l H 0 , d r i e d o v e r N a S 0 , a n d f i n a l l y c o n c e n t r a t e d o n a r o t a r y evaporator. B y 5 8

2 5

Δ 8

2 5

2

2 5

25

5

R

2 5

2 5

25

2 5

2 5

2 5

4

3

2

4


2

280

POLY AMINE-CHELATED

ALKALI

M E T A L

COMPOUNDS

V P C analysis, the p r o d u c t w a s 9 2 % 1 - p h e n y l - l - e t h a n o l a n d 7.4% t o l u e n e ; n o ( — ) - T M C H D w a s present. T h e o p t i c a l a c t i v i t y o f t h e p r o d u c t w a s m e a s u r e d w i t h a P e r k i n E l m e r m o d e l 141 p o l a r i m e t e r : [ a ] 9 + 2.94° ( C , 13.14, b e n z e n e ) , c o r r e s p o n d i n g t o 7 . 4 % o p t i c a l p u r i t y b y d i r e c t c o m p a r i s o n w i t h a n a u t h e n t i c sample o f o p t i c a l l y p u r e 1 - p h e n y l - l - e t h a n o l . T h e other reactions s u m m a r i z e d i n the t a b l e w e r e r u n s i m i l a r l y , w i t h n o a t t e m p t m a d e t o o p t i m i z e r e a c t i o n c o n d i t i o n s t o o b t a i n m a x i m u m stereo specificity. 2 5


5 8

Literature Cited 1. Fischer, E., Ber. (1894) 27, 3231. 2. Ritchie, P. D., "Asymmetric Synthesis and Asymmetric Induction," Oxford University Press, London, 1933. 3. Morrison, J. D., Mosher, H . S., "Asymmetric Organic Reactions," PrenticeHall, Englewood Cliffs, N.J.,1971. 4. Marckwald, W., Ber. (1904) 37, 1368. 5. Bentley, R., "Molecular Asymmetry in Biology," Academic, New York, Vol. I, 1969; Vol. II, 1970. 6. Eliel, E . L . , "Stereochemistry of Carbon Compounds," McGraw-Hill, New York, 1962. 7. Jaeger, F . M., Bijkerk, L . , Proc. Kon. Ned. Akad. Wetensch. (1937) 40, 12. 8. Asperger, R. G., Liu, C. F., Inorg. Chem. (1965) 4, 1492. 9. Woldbye, F., Rec. Chem. Progr. (1964) 24, 197. 10. Smith, A. J., U.S. Patent 3,163,675 (1964). 11. Clarke, H . T., Gillespie, H . B., Weisshaus, S. Z., J. Amer. Chem. Soc. (1933) 55, 4571. 12. Langer, Jr., A. W., Trans. N.Y. Acad. Sci. (1965) 27 (7), 741. 13. Langer, Jr., A. W., U.S. Patent 3,451,988 (1969); 3,541,149 (1970). 14. Rausch, M . D., Sarnelli, A. J., ADVAN. C H E M . SER. (1973) 130, 248. 15. Langer, Jr., A. W., Whitney, Τ. Α., U.S. Patent 3,734,963 (1973). 16. Althouse, V. E . , Feigl, D. M . , Sanderson, W. Α., Mosher, H . S.,J.Amer. Chem. Soc. (1966) 88, 3595. 17. Clark, D. R., Ph.D. Thesis, Stanford University, D. A. No. 71-19,662 (1970). 18. Cram, D. J., Whitney, Τ. Α., J. Amer. Chem. Soc. (1967) 89, 4651. 19. Nozaki, H . , Aratani, T., Toraya, T., Tetrahedron Lett. (1968) 4097. RECEIVED February 12, 1973.


Polyamine-Chelated Alkali Metal Compounds - ACS Publications

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