Mechanistic Considerations of Biomimetic Asymmetric Reductions

16 Mechanistic Considerations of Biomimetic Asymmetric Reductions

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 5, 2018 | https://pubs.acs.org Publication Date: April 28, 1982 | doi: 10.1021/bk-1982-0185.ch016

ATSUYOSHI OHNO Kyoto University, Institute for Chemical Research, Kyoto, Japan

As shown in Table 1, the reduction of ethyl benzoylformate by a 1-substituted-1,4-dihydronicotinamide, a model of NADH or NADPH, in acetonitrile occurs in the presence of a bivalent metal ion such as magnesium(II) or zinc(II)(1)(Scheme 1). When one of the amide-hydrogens is substituted by a chiral group, asymmetric reduction takes place. The stereospecificity of this reduction is also affected by magnesium ion as shown in Table 2 (2,3). Although it is not clear why such a remote chiral center affects the stereochemistry of the reduction, the presence of a nitrogen atom on the side chain appears to play an important role in the stereospecificity, as shown in Table 3(4). The optical yield is still unsatisfactory compared with the enzymic reductions. Expecting that the enantioselectivity would be improved with a model compound having the chiral center and reacting hydrogen at the same position, we synthesized all four possible optical iso mers of N-α-methylbenzyl-1-propyl-2,4-dimethyl-1,4-dihydronicotin amide (MePNPH, Scheme 1) . Results for the reduction of various substrates with some of these model compounds are sum marized in Table 4. 1

2

I

I

Pr PNPH

I

Pr Me PNPH

R R = Pr: PNAH R = PhCH : BNAH

0

2

1

Hereafter, the author will denoteXY-MePNPHfor an isomer of MePNPH which has configurations X at the ring C and Y at the benzylic carbon. 2

4

0097-6156/82/0185-0219$05.00/0 © 1982 American Chemical Society

Eliel and Otsuka; Asymmetric Reactions and Processes in Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

2

ASYMMETRIC

220 Table 1.

REACTIONS A N D PROCESSES IN CHEMISTRY

Reduction of E t h y l Benzoylformate by l - B e n z y l - l , 4 - d i a

hydronicotinamide (BNAH) ^


BNAH, mmol

Metal i o n , mmol

1.06

Isolated Y i e l d , % Ethyl Recovered mandelate Keto e s t e r

b )

none 2 +

Mg 2+

1.11 1.09

Mg 2 +

Zn

1.09

Li

1.09

+

1.08 1.13 1.25

90

0

6

86

0

ioo

8

66

92

2

C)

e)

1.25

d )

The r e a c t i o n s were r u n with 1 mmol o f keto e s t e r i n 15 mL of a c e t o n i t r i l e f o r 17 h r a t room temperature c

chlorate.

)

Reaction time: 44 h r .

was i s o l a t e d i n 90% y i e l d .

Table 2.

d

)

i n the dark.

^ Per+

Oxidized BNAH (BNA )

' Hydrated s a l t was used.

Asymmetric Reduction of E t h y l Benzoylformate by

O p t i c a l l y Active N-a-Methylbenzyl-l-propyl-l,4-dihydronicotinamide (PNPH) Config. of PNPH, mmol R

S

a

)

Mg

, mmol

2+

[Mg ]/[PNPH]

E t h y l mandelate Y i e l d , % e.e.,%

1.00

0.26

0.3

86

6.6

1.02

0.52

0.5

82

8.6

2.05

1.05

0.5

95

9.9

0.99

1.04

1.1

94

19.6

0.98

1.99

2.0

95

18.1

96

-18.6

1.14

0.96

0.8

C)

Reactions were run with 1 mmol o f the keto e s t e r i n 15 mL o f a c e t o n i t r i l e f o r 44 h r a t room temperature i n the dark. c) chlorate. 5-Mandelate was obtained i n excess.

^ Per-


16.

OHNO

Biomimetic

Asymmetric

221

Reductions

Table 3.

E f f e c t o f Substituent on the S t e r e o s p e c i f i c i t y of the a) Reduction of E t h y l Benzoylformate E t h y l mandelate

X i n Model


I s o l a t e d , ^ e.e.,% 26

NH CH

9

2

2

0

' Reaction c o n d i t i o n s are the same as described i n Table 2. s t r u c t u r e of the model i s :

The

I Pr Chemical y i e l d s are q u a n t i t a t i v e .

Table 4.

Reduction by C h i r a l N-a-methylbenzyl-l-propyl-2,4-di-

dimethyl-l,4-dihydronicotinamide . , _

„

Substrate

C o n f i g . of G

Me PNPH ν' 2

(Me PNPH)

.

2

w/

b)

Product

Conv.,%

RR RR

100 100

U

DDC) RR >

inn 100

Π

RR

95

BR 57? HRC) 57?>

60 56 68 79

Structure Y i e l d , % e.e.,% j

^v

S| C 0

' C>

f ^ l iyjL.C0 Me ^ j f 0 9

2

c

2

M e

H ^ ^ Or H

2 OH

Η

lyJL.C0.Me ^ T X 2

H

0

H

100 100 100

97.6 (i?) 96.5(5) 94.7(5)

100

52.5 (i?)

9

9

>

9

9

100 92.0(7?) 100 92.0(5) 68 71.3(7?) 66 41.4(5)


ASYMMETRIC

REACTIONS A N D PROCESSES IN

CHEMISTRY

Table 4 Continued

MeO. RR"'


CF, '^3

V

97 "

|^1 ^CF. ^ *>< 3 S

>

>

H

C F

3

x OT

F

S 3

9 5

S

7 5 C

)

iiff

CF

H

^

©

99

RR

C)

3

O\^

74

ffî

OH

3

RR

77

3

*K

C )

99

SS

85

3

-

Î

O.N

100

> 9 5

( 5 )

52.5 82.2(i?)

OH

C F

C F

95 (Λ)

55.3 82.5(if)

B r - ^ Î X 3

100

90

(i?)

OH

C F

% < 3

58.0 85.9(i?)

OH

J• ^ Se^ Su^ ' Η

RR

0

C F

Η

CF3

0

n

Η

C F

80.2(Λ)

4

33.6 76.4(Λ)

1

Η

C F

·

100

CF

'^'^^X 3

100

8

OH

^ " 3 -^ „ Η OH

u

7

C F

CF

3

1

0

0

> 9 9

( 5 )

OH

^ J ^ X ^ 50.1 62.8(Λ) H OH


16.

OHNO

Biomimetic

Asymmetric

Reductions

223

Table 4 Continued


45.2 52.1(i?)

78.3

-0

40.3 43.4(i?)

43.3 53.5(5)

39.4 30.3(5)

35.7 16.5(5)

See Note 5 f o r the n o t a t i o n .

Amount of substrate consumed.

Reaction without magnesium p e r c h l o r a t e .


A S Y M M E T R I C REACTIONS A N D PROCESSES

224

IN CHEMISTRY

The r e s u l t s show s e v e r a l i n t e r e s t i n g c h a r a c t e r i s t i c s ; 1. I n t r o d u c t i o n of two methyl groups on the d i h y d r o p y r i d i n e r i n g (Me2PNPH) enhances the r e a c t i v i t y compared to PNPH, as e x h i b i t e d by the r e d u c t i o n o f α,α,α-trifluoroacetophenone without magnesium ion. 2. The predominant enantiomer of the product i s determined by the c o n f i g u r a t i o n a t the C ^ - p o s i t i o n of Me2?NPH i n the presence of M g . However, i n the absence of magnesium i o n , the c o n f i g u r a t i o n a t the b e n z y l i c carbon exerts a secondary e f f e c t on the s t e r e o chemistry. For enzymic r e a c t i o n s , i t was proposed that the carbonyl oxygen o f the substrate points toward the d i h y d r o p y r i d i n e r i n g n i t r o g e n of NAD(P)H i n the t r a n s i t i o n s t a t e ( 6 ) . Based on the same assumption the stereochemistry of the product i n the mimetic r e d u c t i o n can be p r e d i c t e d as shown i n 1_.


2+

HC 3

.H

R : polar substituent R: n

nonpolar s u b s t i t u e n t

R CONHR

HC"

C

J

κ

R p

\S Π δ

The r e l a t i v e bulk of the s u b s t i t u e n t s i n the substrate exerts no c o n t r i b u t i o n , a t l e a s t not a primary one. In order to o b t a i n i n f o r m a t i o n on the t r a n s i t i o n - s t a t e stereochemistry, we s t u d i e d the r e d u c t i o n o f camphoroquinone (CQ) with Me PNPH. Products from the r e d u c t i o n of (-)- and (+)-CQ s are shown i n Scheme 2 and the r e s u l t s are l i s t e d i n Table 5. ,

2

Scheme 2

OH D-2a

OH Z>-3a



16.

OHNO

Biomimetic

Asymmetric

Reductions

225

OH X-3b

£-3b

Scheme 3

D-2

X-2

b


2

Product Yield, %>

Product Ratio

c)

c

X-2a

D-2a

*-3a

Z?-3a

(-)-CQ

RR

57.7

40.6

8

19

68

5

(-)-CQ

SS

36.2

67.6

20

16

6

58

X-2b

D-2b_

X-3b

Z?-3b

(+)-CQ

RR

53.1

47.3

21

14

7

58

(+)-CQ

SS

50.9

58.7

7

21

62

10

X-2 (±)-CQ

SS

d)

X-3

e)

e)

D-3

e)

43

27

16

14

54.1

46.0

Z)-2

e)

' Reaction was run f o r 52 h r w i t h each 1 mmol o f reagent. b

)

C

Isolated y i e l d s .

^

^ R e l a t i v e i n t e n s i t i e s o f ^"H-NMR s i g n a l s .

Racemic camphoroquinone.

e

^ A mixture o f a^ and b^.

Table 6.

Reduction of Camphoroquinone w i t h

Substrate

Model

ν T, h r * '

,, C

7

Product f$> Y i e

NAD(P)H-Models ν Product Ratio

X-2a

Z?-2a

X-3a

D-3a

(-)-CQ

BNAH

235

42.3

7.3

14

13

16

57

(-)-CQ

PNAH

48

65.6

4.3

13

11

24

52

9

14

62

(-)-CQ

(+)-CQ a )

i?-PNPH

91

i?-PNPH

Reaction time. of ^-H-NMR s i g n a l s .

91 b

)

50.2

61.6 Isolated y i e l d s .

15

8.6

6.8 C

)

X-2b

D-2b

X-3b

Z?-3b

8

10

20

62

Relative i n t e n s i t i e s


16.

OHNO

Biomimetic Asymmetric Reductions

227


Based on the above r e s u l t s , s t e r i c and e l e c t r o n i c e f f e c t s of the s u b s t i t u e n t s of a substrate have been s t u d i e d f u r t h e r . Results from the r e d u c t i o n of a s e r i e s of 2 - f l u o r o a c y l p y r i d i n e s and 2 - a c y l p y r i d i n e s i n d i c a t e that s u b s t i t u e n t e f f e c t s are such that the s t e r e o s p e c i f i c i t y of the r e d u c t i o n i s mainly governed by electronic effects. However, the s t e r i c bulk of the s u b s t i t u e n t s exerts a c e r t a i n e f f e c t on the conformation of these substrates(7

" U). The s t e r e o s p e c i f i c i t y remains almost constant (>90% e.e.) f o r the r e d u c t i o n of s u b s t i t u t e d and unsubstituted α,α,α-trifluoroacetophenones i n the presence of magnesium i o n . On the other hand, the s p e c i f i c i t y changes with a change i n e l e c t r o n i c e f f e c t of the s u b s t i t u e n t f o r the r e d u c t i o n without magnesium i o n . Both e l e c t r o n - r e l e a s i n g and -withdrawing s u b s t i t u e n t s increase the specificity. The r e s u l t s cannot be accounted f o r by simple s t e r i c or e l e c t r o n i c s u b s t i t u e n t e f f e c t s i n a one-step r e a c t i o n . However, a m u l t i - s t e p mechanism with an i n i t i a l e l e c t r o n - t r a n s f e r process(12, 13) e x p l a i n s the v a r i a t i o n of the s p e c i f i c i t y . An e l e c t r o n - r e l e a s i n g s u b s t i t u e n t reduces the e l e c t r o n - a f f i n i t y of a substrate and the e l e c t r o n - t r a n s f e r to a substrate of t h i s s o r t r e q u i r e s a high a c t i v a t i o n energy, as i l l u s t r a t e d i n Scheme 4a. A substrate i n t h i s category would form an e l e c t r o n - t r a n s f e r complex with Me2PNPH, which i s unstable. The subsequent protont r a n s f e r takes place almost spontaneously. The stereochemistry of the net r e d u c t i o n w i l l be d e f i n e d i n the i n i t i a l e l e c t r o n t r a n s f e r step. The s e l e c t i v i t y - r e a c t i v i t y r e l a t i o n s h i p p r e d i c t s that the l e s s the e l e c t r o n - r e l e a s i n g power o f a s u b s t i t u e n t on the subst r a t e , or the l e s s the a c t i v a t i o n energy f o r the e l e c t r o n - t r a n s f e r process, the l e s s the d i f f e r e n c e i n energy between p r e f e r r e d and other conformations. Consequently, the r e d u c t i o n becomes l e s s stereospecific. With a s t r o n g l y electron-withdrawing s u b s t i t u e n t on a subst r a t e , on the other hand, the e l e c t r o n - t r a n s f e r takes place q u i t e r a p i d l y and the intermediate e l e c t r o n - t r a n s f e r complex becomes more s t a b l e than the reactant system as shown i n Scheme 4c. The p r e f e r e n t i a l course of r e d u c t i o n i n t h i s category i s , t h e r e f o r e , c o n t r o l l e d by the thermodynamic s t a b i l i t y of the intermediate, which makes s t r o n g l y electron-demanding substrates more s t e r e o s p e c i f i c than weakly electron-demanding ones. The s t e r e o chemistry of the net r e d u c t i o n i s now d e f i n e d i n the second step. Scheme 4b represents the intermediate category, i n which both the i n i t i a l and second steps a f f e c t the s t e r e o s p e c i f i c i t y of the reduction. In Scheme 4, f u l l l i n e s i n d i c a t e the r e d u c t i o n without magnesium i o n and dotted l i n e s represent the r e d u c t i o n with magnesium i o n . Since magnesium i o n c a t a l y z e s the i n i t i a l e l e c t r o n - t r a n s f e r process, the stereochemistry of the net reduc t i o n i n the presence of magnesium i o n i s c o n t r o l l e d by e n e r g e t i c s of-the second step.


ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY

228


Scheme 4

\ I I

(a)

(b)

(c)

Literature Cited 1. Ohnishi, Y.; Kagami, M.; Ohno, A. J. Am. Chem. Soc. 1975, 97, 4766 2. Ohnishi, Y.; Numakunai, T.; Ohno, A. Tetrahedron Lett. 1975, 3813. 3. Ohnishi, Y.; Numakunai, T.; Kimura, T.; Ohno, A. Tetrahedron Lett. 1976, 2699. 4. Ohno, Α.; Yamamoto, H.; Kimura, T.; Oka, S. Tetrahedron Lett. 1977, 4585. 5. Bentley, R. "Molecular Asymmetry in Biology", Vol2, Academic Press, New York, 1970; pp 36 - 39. 6. Ohno, Α.; Yasui, S.; Oka, S. Bull. Chem. Soc. Jpn. 1980, 53, 2651. 7. Barassin, J . ; Queguiner, G.; Lumbroso, H. Bull. Soc. Chim. Fr. 1967, 4707. 8. Osborne, R. R.; McWhinnie, W. R. J. Chem. Soc., A 1967, 2075. 9. Kidani, Y.; Noji, M.; Koike, H. Bull. Chem. Soc. Jpn. 1975, 48, 239. 10. Gase, R. Α.; Pandit, U. K. J . Am. Chem. Soc. 1979, 101, 7059. 11. Ohno, Α.; Yamamoto, H.; Oka, S. J. Am. Chem. Soc. 1981, 103, 2041. 12. Ohno, Α.; Shio, T.; Yamamoto, H.; Oka, S. J. Am. Chem. Soc. 1981, 103, 2044. RECEIVED December 14, 1981.


Mechanistic Considerations of Biomimetic Asymmetric Reductions

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