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4 Asymmetric Transformation of α-Substituted Carbonyl Compounds Via Enamine or Iminazoline Formation

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S. YOSHIKAWA Department of Synthetic Chemistry, University of Tokyo, Tokyo 113, Japan H. MATSUSHITA and S. SHIBATA Central Research Institute, The Japan Tobacco & Salt Public Corporation, 6-2-Umegaoka, Midori-ku, Yokohama, Kanagawa 227, Japan Acid hydrolysis of iminium salts of enamines composed of optically active secondary amines and racemic α-substituted carbonyl compounds yielded correspond­ ing optically active compounds. During these experi­ ments, 1-(ß-methylstyryl)-2-methylpiperidinium chloride was isolated and characterized. This enammonium salt was found to exchange deuterium and then change easily to the corresponding iminium salt. The relationships of chirality and deuteration are characterized. By analogy, the asymmetric transformation mechanisms of the above reaction was extended to iminazoline ring formation. (S)- and (R)-alanine were converted into optically labile iminazoline derivatives. When (S)-amino methylpyrrolidine was used as a diamine component, (S)-alanine was converted to (R)-alanine in an optical yield of 93.8% (e.e.). Optical Activation via Enamine Hydrolysis Using Optically Active Acid We observed optical rotation in the recovered carbonyl compound when an enamine, as the salt of an optically active acid, was hydrolyzed. An example of this is illustrated in Figure 1 (I), where the racemic carbonyl compound must be chiral. D-10-camphorsulfonic acid is added to a benzene solution of the pyrrolidine enamine of a-phenylpropionaldehyde. Then water is 0-8412-0514-0/80/33-191-049$05.00/0 © 1980 American Chemical Society

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

50

o

H Q

Q I

2

CHO

BIOMIMETIC CHEMISTRY

-

CH(CH ) 3

CH + C(CHj)

H0 SH C ° 3

2

H C^ 3

II

CHO

+H 0

CH CH(CHj)

2

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Figure 1. Hydrolysis of the enamine salt of an optically active acid added dropwise and hydrolysis is carried out by vigorously stirring the mixture. The original compound is found in the benzene layer, which exhibits optical rotation. Illustrated in Figure 2 are chiral a-carbonyl compounds formed by this method. These compounds usually produce optically active isomers, as illustrated in Table I. The optical yield depends upon the combination of enamine components. The secondary amines of a five-membered ring and six-membered ring are used as the amine component. Since 2-methylpiperidine is chiral, this piperidine is believed to form diastereomeric iminium salts with chiral carbonyl compounds. (See section entitled "Asymmetric Transformation via Iminazoline Formation" for further discussion.) No optical rotation is found in the recovered substances when achiral phenyl acetaldehyde or cyclohexanone is the carbonyl compound used. CHO CH-CH

CHO i CH-C H 2

3

5

O

A a)

(3) R = C H (4) R = CH CH CN (5) R = CH CH COOCH

(2)

3 2

2

2

2

3

O ii (6) R = GH CH CN (7) R = CH CH COOCH 2

2

2

2

3

Bulletin of the Chemical Society of Japan

Figure 2. Chiral a-carbonyl compounds from the hydrolysis of enamines (1)

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

4.

YOSHIKAWA E T A L .

Table I. Carbonyl Compounds 1

2

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3

4 5 6 7 Phenylacetaldehyde Cyclohexanone

51

Carbonyl Compound Transformations Enamine Hydrolysis Products (I)

Recovery

Amines

[«]?

piperidine pyrrolidine 2-methylpiperidine piperidine pyrrolidine 2-methylpiperidine piperidine pyrrolidine 2-methylpiperidine pyrrolidine pyrrolidine pyrrolidine pyrrolidine piperidine pyrrolidine piperidine pyrrolidine

+ 16.2 (c3.67) + 13.8 (c7.10)

89.6 84.1

+ 15.9 (cl.15) +0.22 (c55.1) +0.18 (c20.5)

92.0 82.5 62.8

+0.11 (c28.8) +0.63 (c2.30) +0.39 (cl0.8)

78.0 73.1 88.8

+0.89 (c20.1) +0.058(neat) +0.085(neat) +0.018(neat) +0.011(neat) +0.000(cll.5) +0.000(c22.4) +0.000(cl8.1) +0.000(c57.1)

80.0 51.5 39.1 42.2 38.8 80.7 68.9 62.3 71.2

Bulletin of the Chemical Society of Japan

Illustrated in Table II are the effects of different optically active acids used for producing the piperidine enamine salt of a-phenylpropionaldehyde. Based on the rate of hydrolysis and the asymmetric transformation of the recovered substances, a strong acid is most effective. Illustrated in Table III are the solvent effects. The carbonyl compound used is a-phenylpropionaldehyde and the optically active acid is D-camphorsulfonic acid. The figure reveals that when hydrolysis is carried out, less miscible solvents are more effective suggesting that interfacial reactions are effective for stereoselectivity of asymmetric transformations. Table II. Results of Acid Hydrolysis to Form the Piperidine Enamine Salt of a-Phenylpropionaldehyde (1) Acids

Time (min)

L-Tartaric acid D-Camphoric acid D-Quinic acid D-10-Camphorsulfonic acid

80 75 80 35

[a]f

Recovery (%)

-0.93(c7.3) +2.61(c3.4) +0.56(c3.2) +16.2(c3.67)

97.8 53.3 29.8 89.6

Bulletin of the Chemical Society of Japan

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

Pyrrolidine enamine

Piperidine enamine

Recovery (%)

[a»

Recovery (%)

[a]

2 3 D

Table III.

+ 1.08 (cll.3) 38.1

+ 11.8 (c3.88) 32.7

+18.3 (c6.77) 84.1

+2.81 (c2.10) 42.3

+ 10.0 (cl.81) 28.0

+16.2 (c3.67) 89.6

3

Dioxane

Benzene

CH CN

Solvent Effect on Optical Purity (I EtOH

+0.082 (c41.3) 58.9

+0.100 (c31.9) 78.0

McOH

+0.000 (c67.1) 92.3

+0.000 (c50.8) 89.7

2

H0

Bulletin of the Chemical Society of Japan

+0.026 (c35.5) 49.9

+0.091 (c23.3) 61.7

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4.

Carbonyl Compound Transformations

YOSHIKAWA E T A L .

53

Optical Activation via Achiral Acid Hydrolysis ofEnamines Containing Optically Active Secondary Amines Next, illustrated in Figure 3, is the case when optically active (+)2-methylpiperidine is used and hydrolysis is carried out with an achiral hydrochloric acid solution (2).

Q^H,

n ,

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« " CHO I CH

solvent

\

H

V

o h c

3

H

H

V'-»

*°

^0

23

...CH

HC

HC

3

3

3

solvent

C

0 -80.8°

0 -71.6°

CHC1

3

-51.1°

H 0

EtOH

2

-1.12°

-2.07°

Figure 3. Acid hydrolysis of enamines derived from {+)2-methylpiperidine

The solvent effects show almost the same tendencies as when hydrolysis is effected by optically active acids. The absolute value of the optical rotation of the recovered a-phenylpropionaldehyde is much larger in these examples. This indicates that the use of an optically active amine is more effective for asymmetric transformation than the use of an optically active acid. In addition, this method has been proved very effective for each type of carbonyl compound previously mentioned (3). If a proton is added to enamine, diastereomers are possible products when an optically active secondary amine is used, assuming the iminium salt has been produced. To investigate this matter, the series of reactions shown in Figure 4 is performed. The salt is made from the acid using HC1, and D 0 hydrolysis of the resultant salt is carried out. Since deuterium is not incorporated into the recovered a-phenylpropionaldehyde, chirality is believed to be induced before the hydrolysis (4). Illustrated in Figure 5 is the *!! N M R spectra of two types of iminium salt together with that of the enamine. The resonance signal shown in Figure 5(b) denotes two types of chemical shift, which reveals the existence of diastereomers whose concentration ratio is different than one. The resonance signal in Figure 5(c) is the iminium salt that is made with DC1, then hydrolyzed with H 0 . 2

2

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

54

BIOMIMETIC CHEMISTRY

H / CH—C R?/ W

R1 CH R :CsH5 R : CH(CH ) :

A

HN

X

3

2

3

0

R3 H

3 2

X : O.(CH ) 2

01

H0 2

,H /

\

N

X

Enamine (cis, trans)

R H Downloaded by DICLE UNIV on November 7, 2014 | http://pubs.acs.org Publication Date: December 10, 1980 | doi: 10.1021/ba-1980-0191.ch004

3

CH—CH=H*

D0

X

2

R R CH-CHO 1

(Iminium)

2

R3 H

Figure 4. Formation and hydrolysis of an enamine in the presence ofD 0 2

(0)

7 > n 'CH?

(b)

Oi

CHf

(c) n

11

\ nh^ n

CH

a

3

B

Crr * J il4.«it ,ii,.iA ^> W.>^i. 6j 5 4 3 C H

J*JMHH*XW»«AI'»^CH Nr^^ H (7) 2

2

0 CHo A >>CHOCNH-CHC^ /

CH

H

2

(9)

Figure 11. Cyclization of S-aminopyrrolidine to form an iminazole ring

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

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4.

YOSHIKAWA E T A L .

Carbonyl Compound Transformations

59

In Table V, the yields of hydrolysis and optical purity of amino acids that are recovered from iminazoline are shown. These iminazolines are isolated from the reaction mixture of the scheme shown in Figure 11. Differences were observed with the types of diamine used. In the case of aminomethylpyrrolidine, iminazoline yield is 86%, from which approximately 90% alanine is recovered; its optical purity is approximately 93% R-enantiomeric excess regardless of whether S-alanine or R-alanine is the starting material. Thus, we are confident that the alanine has been transformed asymmetrically (10). On the other hand, in the case of isopropylpropylene diamine, the configuration of the recovered alanine is retained. Also, the hydrolysis is difficult and the iminazoline yield is very low. To ascertain the presence of asymmetric transformation, mutarotation in solution was determined. Figure 12 shows the mutarotation of the above products of alanyl iminazolines in methanol solution. Table V. Asymmetric Transformation via Iminazoline Chirality of starting Alanine

Diamine Component

N H

r

CH NH,

CH

2

3

i

H N—C—CH NHCH(CH ) 2

i i

2

3

2

Recovered Alanine Chirality

e.e. %

yield

R

93.8

89.2

R

R

93.2

90.1

S

S

91.9

5.6

R

R

91.8

4.3

H In the case of S-aminopyrrolidine, equilibrium is established when the R content reaches 35.5 (e.e.)%, regardless of whether S-alanine or R-alanine is the starting material. The S-propylene diamine derivative of S-alanine is almost a racemate (see Figure 12). It follows from this that although epimerization occurs in the methanol solution, the activation energy to change the chirality of the alanine methine carbon is very different. The mutarotation when an amino-acid component is changed from alanine to proline is illustrated in Figure 13. In the case of amino pyrrolidine, mutarotation occurs, whereas with N-isopropylpropylene diamine, no mutarotation is observed. The deuterium-incorporation velocity of the methine proton in heavy methanol ( C H O D ) parallels the mutarotation velocity. 3

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

60

BIOMIMETIC CHEMISTRY

0

CH

3

Y

Z-NH-CH^dTl_ S

-50

S

0%

-

a

?3 n h

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-100

Z-NH-CH-C RorS^

1

Figure 12. Mutarotation of iminazolines

10

20 30°C

35.5%

30

in C H O H 3

Figure 13. Mutarotation of imisazoline derivatives of proline; imidazoline derivatives were refluxed in isopropanol. For these reactions to occur, we believe that an iminazoline ring and an a-branched carbon must be coplanar. A reaction sequence is depicted in Figure 14. An environment conductive to asymmetric transformation is required.

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

4.

YOSHIKAWA E T AL.

Carbonyl Compound Transformations

^J_J H

\

Z - H N ^

„.

,

"

./

N _

61

7

H C 3

| crystallized

© R

J

H

Z—HN H C

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3

r

N

) -

c

^ CH

(

N

o

t

f o r m e d )

3

Figure 14. Mutarotation of an iminazoline: (a) removal from the system by crystallization; (b) asymmetric transformation, but no preferential crystallization; (c) racemization; and (d) no epimerization The optical purity of the iminazoline consisting of alanine and 2-aminopiperidine can be increased to 93.8 (e.e.)% by crystallizing it. In Figure 14(a), once a crystal is removed to the outside of the system, it forms the solution in which asymmetric transformation is carried out; the second-order asymmetric transformation where further transformation develops is obtained. In the case of crystallization of a diastereomer, 100 (e.e.)% might be possible. In this instance, the alanine appears to be racemized when the iminazoline ring is decomposed with strong acid. In Figure 14(b), the combination of proline and 2-aminomethyl pyrrolidine, the asymmetric transformation was observed but no preferential crystallization occurred. In Figure 14(c) only racemization was observed. Moreover, in Figure 14(d), non-coplanarity of the iminazoline and a-branched carbon prevented the double-bond shift and epimerization did not occur. Table VI is a summarization of our results; amino acid and amine components are arranged into four representative cases. In the mutarotation experiment of iminazoline from alanine and isopropylpropylenediamine, the recovered alanine residue racemized entirely in methanol solution. Why, then, can the iminazoline containing the optically retained amino acid residue be synthesized? To answer this question, the iminazole mutarotation was measured in various achiral solvents. Figure 15 and 16 show progressive mutarotation in solvents from which iminazole derivatives are isolated as solids.

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

62

BIOMIMETIC CHEMISTRY

Table VI.

Results of Mutarotation Experiments Using an Amino Acid and an Iminazoline Diamine CH NH 2

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Amino Acid

N' H

CH

2

3

(CH ) CHNH—CH —CH—NH 3

2

2

Alanine

Second-order asymmetric transformation

Racemization

Proline

First-order asymmetric transformation

No reaction

2

Figure 15. Progressive mutarotation of an iminazole In methylene dichloride solution, no mutarotation was observed. Methanol has moderate ability in regard to mutarotation. Amine solutions used in this experiment are all one molar (in methylene dichloride). In both instances, the mutarotation velocity with pyrrolidine was faster than with the other amines. When iminazoline synthesis was conducted between alanyliminoether and 2-aminomethylpyrrolidine, excess pyrrolidine in the reaction media probably accelerated the epimerization reaction. Racemization is faster than crystallization of this, diastereomer, which is less soluble than the other diastereomers. In the case of isopropylpropylenediamine, the excess amine racemizes poorly, so the crystallization was faster than the racemization. Figure 17 shows the results of this experiment with ce-phenylbutyric acid replacing alanine. In this reaction, the asymmetric transformation is first order.

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

4.

YOSHIKAWA E T AL.

Carbonyl Compound Transformations

63

CH(CH ) I

3 2

CH

3

Z - W - C H - C ^ X , CH

3

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S

(CH)CHNH|CH2)2WH2

\

-20

32

H -40

20

40

Time (h)

Figure 16. Progressive mutarotation of an iminazole

* 2H r

usual

5

C H 2

5

o

r

„

0 - ^ H C O O H

6" H C I no°c40h

H O O C

V

i ^ V

M

s

\ C 2 H s

3

Q

g

%

(

e

e

}

yield 41.2%

Figure 17. Asymmetric transformation using a-phenylbutyric acid

Acknowledgments This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Japan (No. 335211). Literature Cited 1. Matsushita, H.; Noguchi, M.; Saburi, M.; Yoshikawa S. Bull. Chem. Soc. Jpn. 1975, 48, 3715. 2. Matsushita, H.; Noguchi, M.; Yoshikawa, S. Chem. Lett. 1975, 1313. 3. Matsushita, H.; Tsujino, Y.; Noguchi, M.; Yoshikawa, S. Bull. Chem. Soc. Jpn. 1976, 49, 3629. 4. Matsushita, H.; Noguchi, M.; Yoshikawa, S. Bull. Chem. Soc. Jpn. 1976, 49, 1928. 5. Matsushita, H.; Tsujino, Y.; Noguchi, M.; Yoshikawa, S. Chem. Lett. 1976; 1087.

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.

64

BIOMIMETIC CHEMISTRY

6. Matsushita, H.; Tsujino, Y.; Noguchi, M.; Yoshikawa, S. Bull. Chem. Soc. Jpn. 1977, 50, 1513. 7. Matsushita, H.; Tsujino, Y.; Noguchi, M.; Saburi, M.; Yoshikawa, S. Bull. Chem. Soc. Jpn. 1978, 51, 862. 8. Matsushita, H.; Tsujino, Y.; Noguchi, M.; Saburi, M.; Yoshikawa, S. Bull. Chem. Soc. Jpn. 1978, 51, 201. 9. Koningsberg, W.; Hill, R. H.; Craig, L. C. J. Org. Chem. 1961, 26, 3867. 10. Shibata, S.; Matsushita, H.; Noguchi, M.; Saburi, M.; Yoshikawa, S. Chem. Lett. 1978, 1305. 1979.

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R E C E I V E D May 21,

In Biomimetic Chemistry; Dolphin, D., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1980.