Asymmetric Carbon-Carbon Bond Forming Reactions via Chiral

6 Asymmetric Carbon-Carbon Bond Forming Reactions via Chiral Oxazolines

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A L B E R T I. MEYERS Colorado State University, Department of Chemistry, Fort Collins, CO 80523

The use of chiral oxazolines as auxiliaries in C-C bond forming reactions continues to provide chiral compounds in high enantiomeric excess. Conjugate addition-alkylation of α,β-unsaturated oxazolines leads to 2,3-disubstituted alkanoic acids in high ee's. Boron enolates of oxazolines, where the chirality resides in the oxazoline or boron sub stituents, react with aldehydes to give β-hydroxy esters in high erythro or threo selectivity with good ee's. Aromatic chiral oxazolines containing o-acyl groups react with οrganometallics furnish ing, after hydrolysis, phthalides in high ee's. A further extension using aryl oxazolines leads to chiral binaphthyls in 70-100% ee's. 2,3-Disubstituted

Carboxylic

Acids

In our continuing program to u t i l i z e c h i r a l oxazolines (1-7) as a u x i l i a r y reagents i n asymmetric s y n t h e s i s , s e v e r a l novel routes to c h i r a l compounds have been developed. The p r e v i o u s l y reported (3) conjugate a d d i t i o n ( F i g . 1) to v i n y l oxazolines 1 (pure £ enantiomer) by organolithium reagents f u r n i s h i n g the adduct 2 and subsequent h y d r o l y s i s gave 3 , 3 - d i s u b s t i t u t e d c a r b o x y l i c acids _3 i n 95-99% ee. We have r e c e n t l y extended t h i s methodology to provide an a d d i t i o n a l c h i r a l center i n c a r b o x y l i c a c i d s ( F i g . 1 ) . Thus, the intermediate l i t h i o adduct 2 could be t r e a t e d w i t h an a l k y l h a l i d e t o give the a l k y l a t e d oxazoline 5> which a f t e r h y d r o l y s i s a f f o r d s the 2 , 3 - d i s u b s t i t u t e d acids 6^ i n 77-82% diastereomeric p u r i t y . HPLC examination of the d i a s t e r e o meric oxazolines _5 p r i o r to h y d r o l y s i s i n d i c a t e s that the a l k y l a t i o n o f 2: occurred with >99% s t e r e o s e l e c t i v i t y . Thus, v i r t u a l l y no presence of diastereomeric i m p u r i t i e s was observed. I t may, t h e r e f o r e , be concluded that t h e observed diastereomeric p u r i t y f o r 6_ was the r e s u l t o f p a r t i a l racemization during the h y d r o l y s i s 0097-6156/82/0185-0083$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.

84

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

R


Me

Ph

OMe

(-)-3 Figure

1.

Formation

of 2,3-disubstituted alkanoic acids by conjugate addition alkylation of α,β-unsaturated oxazolines.


and


6.

Chiral Oxazolines

MEYERS

85

o f J5. S e v e r a l examples of t h i s tandem d i a l k y l a t i o n are given i n Table I . With regard to the absolute c o n f i g u r a t i o n of the acids J6, they are assigned on the b a s i s of both known compounds and previous p r e d i c t i o n s described i n e a r l i e r work (1). I t i s i n t e r e s t i n g to note that quenching adduct 2^ to give the 2-alkyloxazol i n e 4^ and then metalation back to _2 followed by a l k y l a t i o n gave the 2 , 3 - d i s u b s t i t u t e d acids j3 o f the same c o n f i g u r a t i o n as that obtained from 1_ i n the s e q u e n t i a l d i a l k y l a t i o n process. This confirms that the same l i t h i o azaenolate 2^ i s formed both by con jugate a d d i t i o n (1^2) and metalation (4*2). Since both processes have been performed as separate methods, l e a d i n g e i t h e r to c h i r a l 2 - s u b s t i t u t e d c a r b o x y l i c a c i d s or 3 - s u b s t i t u t e d c h i r a l a c i d s , the absolute c o n f i g u r a t i o n of the 2 , 3 - d i s u b s t i t u t e d acids 6^ i s c o n s i s tent with these e a r l i e r f i n d i n g s .

Table I.

R ( i n 1)

2,3-Disubstituted C a r b o x y l i c Acids 6^

f

R Li

Diastereomeric Ratio .5

Yield 5

a-C

Diastereomeric R a t i o , 6^

%

e-c

Me

Et

99

65

77

(R)

99

(R)

Me

n-Bu

99

80

82

(R)

99

(R)

t-Bu

n-Bu

99

82

80

(S)

99

(R)

n-Bu

t-Bu

99

75

79

(R)

99

(R)

A l d o l Products

v i a Boron

Azaenolate

The use of c h i r a l oxazolines as reagents f o r a l d o l type products ( F i g . 2) r i c h i n e r y t h r o or threo β-hydroxy a c i d s has a l s o been accomplished. In e a r l i e r work i n our l a b o r a t o r y (8) we described the formation of β-hydroxyesters _7 from l i t h i o oxazo l i n e s and v a r i o u s aldehydes i n 20-25% ee. The absence of an aa l k y l group was considered the major reason f o r the poor ee's of the product which lacked s t r i n g e n t stereochemical requirements i n the t r a n s i t i o n s t a t e . The process was repeated with the 2 - e t h y l o x a z o l i n e and gave 8^ i n much h i g h e r s e l e c t i v i t y mainly as the threo-isomer and i n 75% enantiomeric p u r i t y (7). We have now i n v e s t i g a t e d t h i s a l d o l process u s i n g the boron " e n o l a t e s " of oxazolines £-and'10 ( F i g . 3) ( 9 ) . I t should be noted that boron azaenolate 9. contains the c h i r a l center on the organoborane, whereas 10 contains the c h i r a l center on the o x a z o l i n e .


86

REACTIONS

AND

PROCESSES


ASYMMETRIC

IN

CHEMISTRY

OH 7 (^20% e e )

8 {82% t h r e o , 75% e e ) Figure

2.

Chiral

oxazolines used as reagents for aldol-type erythro or threo β-hydroxy acids.

products


rich

in

6.

MEYERS

Chiral Oxazolines


Me

87

Λ

Ph

M û

I

Me

''.

I

ι

A

OMe

10

1) RCHO 2) H 0

1) RCHO I 2) H 0 3) C H N

+

+

3

3

3) C H N 2

2

2

Me

Me

Ok

C0 Me

11 ( 9 0 - 9 5 %

k

2

C0 Me 2

HO

HO

Figure 3.

2

threo)

12 ( 9 7 - 9 8 %

erythro)

Formation of β-hydroxyesters with an a-alkyl group by the aldol using boron enolates of oxazolines 9 and 10.


process

88

ASYMMETRIC

REACTIONS

A N D PROCESSES

IN

CHEMISTRY

Treatment o f with v a r i o u s aldehydes gave the threo-β-hydroxye s t e r JL1 a f t e r h y d r o l y s i s and e s t e r i f i c a t i o n , i n 90-95% d i a s t e r e o s e l e c t i v i t y with enantiomeric excess o f 77-85% (Table I I ) . On the other hand, the boron enolate 10, when t r e a t e d s i m i l a r l y with aldehydes now gave the e r y t h r o β-hydroxy e s t e r s 12 i n 97-98% d i a s t e r e o s e l e c t i v i t y though i n somewhat poorer e e s (40-60%, Table I I I ) . C NMR spectroscopy employing £ and 10 with C enriched methyl groups confirmed that only a s i n g l e enolate was fomp.d a t -78° under the c o n d i t i o n s o f k i n e t i c c o n t r o l . Equili b r a t i o n o f 9 or 10 took p l a c e by warming t h e i r ether s o l u t i o n s t o -25° showing a steady i n c r e a s e i n a second methyl s i g n a l u n t i l e q u i l i b r i u m was reached a t 2:1. Unfortunately, which enolate i s formed a t -78° i s not known a t t h i s time. When the condensation f


1 3

Table I I .

1 3

C h i r a l threo-hydroxyesters 11 from £

RCHO

% threo-erythro

% ee

Conf'n. Major Isomer [ a ]

(CHCl^)

D

EtCHO

92:8

77

2R,3R

-9.9

PrCHO

91:9

77

2R,3R

-2.5

n-PentCHO

90:10

77

2R,3R

-3.1

Me CHCH0

91:9

85

2R,3R

-12.5

CyclohexCHO

95:5

84

2R,3R

-8.1

t-BuCHO

94:6

79

2R,3S

-21.2

2

Table I I I .

RCHO

Chiral

erythro-hydroxyesters 12 from 10

% erythro-threo

Conf'n. % ee Major Isomer [ot] (CHC1 ) D

1.4

98:2

40

2S,3R

Me CHCH0

98:2

41

2S,3R

-2.3

t-BuCHO

97:3

60

2S,3S.

-6.6

EtCHO 2


3


6.

MEYERS

Chiral Oxazolines

89

with aldehydes was c a r r i e d out w i t h e q u i l i b r a t e d 9_ or 10, the d i a s t e r e o s e l e c t i v i t y i n 11 and 12 decreased, as expected, to ^80:20. Since the stereochemistry of the boron enolates 9_ and 10 i s not known, i t i s d i f f i c u l t to advance a reasonable mechanism except to p o s t u l a t e a c h a i r - t y p e six-membered t r a n s i t i o n s t a t e based on the Zimmerman model (10). This c o r r e c t l y p r e d i c t s the stereochemistry of the product provided the Ζ boron enolates of 9_ and 10 are employed ( F i g . 4) . A v a r i e t y o f other oxazolines was i n v e s t i g a t e d ( F i g . 5) to probe the nature of s t r u c t u r a l parameters i n determining the e r y t h r o threo r a t i o s of 3-hydroxy e s t e r s . Thus, r e a c t i o n of boron enolates of 13-16 and 9-BBN a l s o gave h i g h e r y t h r o s e l e c t i v i t y of JL2 (R = i - P r ) when t r e a t e d with isobutyraldehyde. It i s interest i n g to note that JL3 gave high threo s e l e c t i v i t y (Table I I ) when diisopinocampheyl borane enolate 9_ was employed while g i v i n g high e r y t h r o s e l e c t i v i t y o f _12 (R = i - P r ) u s i n g 9-BBN enolate. This i m p l i e s a major e f f e c t on the product due to the nature of the boron s u b s t i t u e n t s . F u r t h e r work should help c l a r i f y t h i s p o i n t .

C h i r a l Phthalides Aromatic oxazolines have a l s o been u t i l i z e d ( F i g . 6) as v e h i c l e s f o r asymmetric s y n t h e s i s . Thus the c h i r a l oxazoline 17, used as i t s l i t h i o or magnesiohalide d e r i v a t i v e 17b (from the bromo compound 17a) was t r e a t e d w i t h s e v e r a l carbonyl compounds to give the adducts 18, whose diastereomer r a t i o s were assessed by ^H-nmr or HPLC (Table IV). The extent of s t e r e o s e l e c t i o n was r a t h e r poor i n d i c a t i n g a s t e r i c a l l y undemanding t r a n s i t i o n s t a t e .

Table

IV. % Yield

Diast. Ratio

PhCOMe

71

64:31

PhCHO

60

57:43

o-MeOPhCHO

63

59:41

n-BuCHO

64

51:49

a) Assessed

on

a

18


90

ASYMMETRIC

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

min'm. l , 3 - 1 n t ' n . MeO


Ρ

I

Me

/

L

Ην 0-° " ^ < ^ ^
c o n f i g u r a t i o n ) . Pure enantiomers of 1£ were obtained by MPLCa s s i s t e d r e s o l u t i o n s o f JL8 followed by h y d r o l y s i s with a c i d . We next turned to r e v e r s a l of the n u c l e o p h i l e - e l e c t r o p h i l e combination by p r e p a r i n g o_-acylaryl oxazolines 21 and t r e a t i n g them with οrganometallies ( F i g . 8). A d d i t i o n of o r g a n o l i t h i u m or Grignard reagent gave the adducts 22. which smoothly rearranged to the iminolactones T5. HPLC analyses of 23. showed the r a t i o of diastereomers to be r a t h e r low again suggesting that a d d i t i o n o f organolithium reagents to 21 was perhaps too f a s t with a low ΔΔ(?*\ However, when methylmagnesium c h l o r i d e was t r e a t e d with the Qr benzoyloxazoline 24, the r e a c t i o n proceeded more slowly and, a f t e r h y d r o l y s i s , the p h t h a l i d e 2j> was recovered almost e n a n t i o m e r i c a l l y pure ( F i g . 9) (12). Future e f f o r t s w i l l now be d i r e c t e d to Grignard a d d i t i o n s to ketooxazolines i n the hope that the above r e a c t i o n possesses some g e n e r a l i t y . The complexities o f t h i s system and f a c t o r s a f f e c t i n g the t r a n s i t i o n s t a t e w i l l have to be more c a r e f u l l y addressed b e f o r e a general s y n t h e t i c approach to c h i r a l p h t h a l i d e s can be achieved.


f

C h i r a l Binaphthyls An asymmetric s y n t h e s i s of c h i r a l binaphthyls has been accom p l i s h e d u t i l i z i n g naphthyloxazolines. The method i s based on the f a c i l e displacement o f an o-methoxyl group i n a r y l o x a z o l i n e s by v a r i o u s n u c l e o p h i l e s (13). The aromatic s u b s t i t u t i o n process has now a l s o been found to proceed with o-methoxynaphthyloxazolines ( F i g . 10). A number o f n u c l e o p h i l i c reagents smoothly d i s p l a c e d the methoxyl group to 26 and a f t e r h y d r o l y s i s l e d to 1-substituted2-naphthoic a c i d s 27^. U t i l i z a t i o n of t h i s e f f i c i e n t coupling r e a c t i o n with c h i r a l oxazolines was examined i n an attempt to reach c h i r a l b i n a p h t h y l s . Thus, 28 was t r e a t e d with the Grignard reagent of l-bromo-2-methoxynaphthalene at room temperature i n THF to give the b i n a p h t h y l adduct 29_ ( F i g . 11) . Nmr a n a l y s i s showed that the r a t i o o f diastereomers i n 2£ was greater than 95:5 i n d i c a t i n g a high degree of s t e r e o s e l e c t i o n i n the coupling r e a c t i o n . H y d r o l y s i s o f 29 followed by hydride r e d u c t i o n of the intermediate e s t e r gave the c h i r a l b i n a p h t h y l 30 i n VL00% ee (confirmed by LISR-nmr techniques). Two a d d i t i o n a l naphthyl Grignard reagents were examined ( F i g . 12) which l e d to products whose r a t i o s were not as high as i n the methoxy naphthyl system, but,nevertheless, were s t i l l formed i n 60-70% ee. The c r y s t a l l i n e nature of 29


92

REACTIONS

AND

PROCESSES

IN

CHEMISTRY


ASYMMETRIC

20 Figure

88% e e 7.

Asymmetric

synthesis using proline

derivative

20.

(11)


6.

Chiral Oxazolines

MEYERS


OMe

93

R'L1 -78°

22

D i a s t e r e o m e r i c R a t i o s o f 23 R

R' L i

* Yield

Ratio

t-Bu

Ph

94

2:1

Ph

Me

85

2:1

Ph

n-Bu

86

1.2:1 23

Figure 8. Synthesis of iminolactones, 23, by reaction of o-acylaryloxazolines with organolithium or Grignard reagent and rearrangement of product, 22.

1) MeMgCl, - 4 5 ° , T H F ir

\ OMe 2) O x a l i c A c i d

25, S, 24 Figure

[a]

D

+68.4°

99% ee 9.

Preparation of phthalide, 25, by treatment of o-benzoyloxazoline, with Grignard reagent followed by hydrolysis.


24,


94

ASYMMETRIC

Figure

10.

REACTIONS

AND

PROCESSES

Synthesis of l-substituted-2-naphthoic acids by aromatic of o-methoxynaphthyloxazolines followed by hydrolysis.

IN

CHEMISTRY

substitution



Chiral Oxazolines


95

ASYMMETRIC


96

REACTIONS

AND

PROCESSES

IN

CHEMISTRY

Ph

CH

3

68.0

75:25 (PMR)

0CH

3

71.0

>95:5 (PMR)

Figure

12.

Asymmetric synthesis of chiral binaphthyls, 29, by reaction naphthyl Grignard reagents. Ratios of diastereomers are given.


with


6.

MEYERS

Chiral

97

Oxazolines

(R = H, Me, MeO) r e s u l t e d i n very easy p u r i f i c a t i o n to s i n g l e diastereomers by simple c r y s t a l l i z a t i o n . However, s i n c e t h i s was not the current aim o f the study, care was taken to avoid inadvertent r e s o l u t i o n during the workup and p u r i f i c a t i o n o f _29. The most convenient method to reach c h i r a l binaphthyls was to c a r r y out a tandem h y d r o l y s i s - r e d u c t i o n to the hydroxymethyl group ( F i g . 13). Thus, the b i n a p h t h y l o x a z o l i n e s 29 were only p a r t i a l l y hydrol y z e d to the aminoesters 31 and then subjected to hydride reduct i o n to the a l c o h o l 30. The absolute c o n f i g u r a t i o n o f the c h i r a l binaphthyls was determined by c o r r e l a t i o n methods to known d e r i v a t i v e s as w e l l as CD s p e c t r a l c h a r a c t e r i s t i c s .

Figure

13.

Hydrolysis of binaphthyloxazolines, 29, to aminoesters, reduction to alcohol producing chiral binaphthyls.

31,


and

98

ASYMMETRIC REACTIONS AND PROCESSES IN CHEMISTRY


Literature Cited 1. Meyers, A. I. Accounts of Chem. Res., 1978, 11, 375. 2. Meyers, A. I. Pure & Appl. Chem., 1979, 51, 1255. 3. Meyers, A. I.; Smith, R. K.; Whitten, C. E. J. Org. Chem., 1979, 44, 2250. 4. Meyers, A. I.; Smith, R. K. Tet. Lett., 1979, 2749. 5. Meyers, A. I.; Slade, J.; J. Org. Chem., 1980, 45, 2785. 6. Meyers, A. I.; Yamamoto, Y.; Mihelich. E. D.; Bell, R. A. J. Org. Chem., 1980, 45, 2792. 7. Meyers, A. I.; Reider, P. J. J. Am. Chem. Soc., 1979, 101, 2501. 8. Meyers, A. I.; Knaus, G. Tet. Letters, 1974, 1333. 9. Meyers, A. I.; Yamamoto, Y. J. Am. Chem. Soc., 1981, 103, 4278. 10. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc., 1957, 79, 1920. 11. Asami, M. and Mukaiyama, T. Chem. Lett., 1980, 17. 12. Meyers, A. I.; Hanagan, Μ. Α., research in progress. 13. Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem., 1978, 43, 1372. RECEIVED December 14, 1981.


Asymmetric Carbon-Carbon Bond Forming Reactions via Chiral

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