Chemical Hybridizing Agents - ACS Symposium Series (ACS

Chapter 34 Chemical Hybridizing Agents Synthesis of Racemic cis- and trans-Methanoproline 1

Willy D. Kollmeyer , S. K. Barrett, and D. H. Flint

1

Downloaded by UNIV LAVAL on May 9, 2016 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch034

Biological Sciences Research Center, Shell Agricultural Chemical Company, P.O. Box 4248, Modesto, CA 95352

Chemicals that affect pollen v i a b i l i t y have potential value to plant breeders for production of F hybrids and seed. The non-protein amino acid [1R- (1α, 2β, 5α) ]-3-azabicyclo[3.1.0]-hexane -2-carboxylic acid, otherwise known as cis-3, 4 -methano-L-proline, is such a material. It was originally isolated from the seeds of Aesculus parviflora, and the sole literature synthesis involved methylenation of a dihydroproline derivative with hazardous diazomethane. In this work, a new and convenient method capable of yielding multigram amounts of both c i s - and trans-methanoproline isomers as racemic hydrochloride salts has been devised. This route, which starts from 1,2cyclopropanedicarboxylic acid and proceeds via 3azabicyclo [3.1.0] hexane derivatives, is described. 1

In p l a n t b r e e d i n g programs t h e search f o r improved h y b r i d s involves crossing different parental l i n e s and evaluating the r e s u l t i n g progeny. C o n t r o l o f male f e r t i l i t y i s an i m p o r t a n t s t e p i n t h i s p r o c e s s (1). F o r e x a m p l e , a c o r n p l a n t canbe emasculated mechanically with ease, because the male f l o w e r s a r el o c a t e d i nt h e upper p a r t o f t h e p l a n t a t a s u i t a b l e d i s t a n c e above t h e female f l o w e r s . Detasseling prevents any s e l f - p o l l i n a t i o n , and a plant a l t e r e d i n t h i s way c a n o n l y f u n c t i o n a s a f e m a l e p a r e n t . Then, b y r e l y i n g upon n a t u r a l c r o s s - p o l l i n a t i o n , t h e breeder c a n u s e an u n a l t e r e d p l a n t i nan a d j a c e n t row as the male parent.

1

Current address: Experimental Station, Ε. I. du Pont de Nemours & Co., Wilmington, DE 19898 0097-6156/87/0355-0401$06.00/0 © 1987 American Chemical Society

Baker et al.; Synthesis and Chemistry of Agrochemicals ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

402


T h i s s i m p l e but b a s i c t e c h n i q u e has been u s e d t o g r e a t a d v a n t a g e i n t h e development and p r o d u c t i o n o f s u p e r i o r corn hybrids. Even though c y t o p l a s m i c male s t e r i l i t y supplanted d e t a s s e l i n g f o r a time, mechanical c o n t r o l of male f e r t i l i t y i s c u r r r e n t l y the method o f c h o i c e i n h y b r i d c o r n s e e d p r o d u c t i o n (JL). Cytoplasmic Male S t e r i l i t y . Unfortunately, large-scale m e c h a n i c a l e m a s c u l a t i o n c a n n o t be a p p l i e d t o a l l c r o p s o f interest. In wheat, f o r example, the p o l l e n - b e a r i n g a n t h e r s and female s t i g m a s l a y s i d e by s i d e w i t h i n e a c h f l o r e t of a spikelet. Removal of anthers w i t h s m a l l , h a n d - h e l d i n s t r u m e n t s o b v i o u s l y has u t i l i t y o n l y f o r small-scale h y b r i d i z a t i o n experiments. N e v e r t h e l e s s , by c r o s s i n g a f e m a l e p a r e n t endowed w i t h c y t o p l a s m i c male s t e r i l i t y w i t h a male p a r e n t t h a t has fertility-restoring g e n e s , one c a n a c h i e v e h y b r i d w h e a t s e e d p r o d u c t i o n . This t e c h n o l o g y , however, has l i m i t a t i o n s : compared t o d e t a s s e l i n g i n c o r n , i t i s much more t i m e c o n s u m i n g a n d d o e s n o t a l l o w a l l e x i s t i n g l i n e s t o be e x a m i n e d a s experimental parents (1). Chemical H y b r i d i z i n g Agents. For these reasons chemical c o n t r o l o f male f e r t i l i t y has been a l o n g s o u g h t g o a l , e s p e c i a l l y f o r crops t h a t are normally s e l f - p o l l i n a t i n g such as wheat . An e f f e c t i v e c h e m i c a l h y b r i d i z i n g agent c o u l d have p o t e n t i a l v a l u e not o n l y f o r p l a n t b r e e d i n g r e s e a r c h s t u d i e s , but a l s o f o r commercial p r o d u c t i o n o f F]_ h y b r i d s . R e c e n t l y , t h e n o n - p r o t e i n a m i n o a c i d [ 1 R - ( 1 a, 2 3, 5 a) ] 3 - a z a b i c y c l o [ 3 . 1 . 0 ] h e x a n e - 2 - c a r b o x y l i c a c i d , commonly known as c i s - 3 4 - m e t h a n o - L - p r o l i n e , was p a t e n t e d a s a chemical h y b r i d i z i n g agent f o r s m a l l g r a i n c e r e a l crops Q). T h i s c o m p o u n d was o r i g i n a l l y i s o l a t e d f r o m t h e s e e d s o f Aesculus p a r v i f l o r a (1£), a n d t h e s o l e l i t e r a t u r e synthesis i n v o l v e d methylenation of a c h i r a l dihydrop r o l i n e d e r i v a t i v e with hazardous diazomethane (H). Unfortunately, n e i t h e r o f t h e s e s o u r c e s was s u i t a b l e f o r p r o v i d i n g large q u a n t i t i e s of methanoproline for plant b r e e d i n g f i e l d s t u d i e s . To t h i s e n d , we d e v i s e d a new s y n t h e s i s c a p a b l e of p r o v i d i n g m u l t i g r a m amounts o f c i s and t r a n s - m e t h a n o p r o l i n e i s o m e r s as r a c e m i c , hydrochloride salts. This route, which s t a r t s from 1,2-cyclop r o p a n e d i c a r b o x y l i c a c i d and p r o c e e d s v i a 3 - a z a b i c y c l o [3.1.0]hexane d e r i v a t i v e s , i s r e p o r t e d here. Experimental d e t a i l s are given i n the patent l i t e r a t u r e (1Z, 11) . f

Synthesis of

Methanoproline

F o l l o w i n g t h e g e n e r a l p r o c e d u r e o f M c C o y ( 1 £ ) , we s u b j e c t e d a m i x t u r e o f e t h y l c h l o r o a c e t a t e and e t h y l a c r y l a t e t o


34.

KOLLMEYER ET AL.

Chemical Hybridizing Agents

base-catalyzed cyclocondensation (see F i g u r e 1 ) . This reaction provided diethyl 1,2-cyclopropanedicarboxylates 1 a s a m i x t u r e c o n s i s t i n g prédominently o f t h e c_is.-isomer. F u r t h e r e n h a n c e m e n t o f t h e c i s p r o d u c t was a c h i e v e d by s a p o n i f i c a t i o n of the r e a c t i o n mixture t o the isomeric m i x t u r e o f 1 , 2 - c y c l o p r o p a n e d i c a r b o x y l i c a c i d s 2. a n d s u b s e q u e n t t r e a t m e n t w i t h t h i o n y l c h l o r i d e . As a c o n s e q u e n c e vacuum d i s t i l l a t i o n c o u l d be u s e d t o c l e a n l y separate the r e s u l t i n g mixture of c_is_-l 2-cyclopropaned i c a r b o x y l i c a c i d a n h y d r i d e 2. a n d t r a n s - 1 2 - c y c l o p r o p a n e d i c a r b o x y l i c a c i d c h l o r i d e 4. (2Λ) . I n t h i s way the a n h y d r i d e 2. was o b t a i n e d r e a d i l y i n 3 5 - 4 0 g b a t c h e s s t a r t i n g f r o m one m o l e e a c h o f e t h y l c h l o r o a c e t a t e a n d e t h y l a c r y l a t e ( c a . 35% y i e l d o v e r a l l ) . The n e x t s e q u e n c e i n v o l v e d c o n v e r s i o n o f t h e anhydride 2. t o 3 - a z a b i c y c l o [ 3 . 1 . 0 ] h e x a n e 2. a s s h o w n i n F i g u r e 2. A l t h o u g h t h e H NMR s p e c t r u m o f t h i s b i c y c l i c amine has b e e n d e s c r i b e d i n t h e l i t e r a t u r e (1ϋ) , d e t a i l s o f i t s p r e p a r a t i o n have not been g i v e n . I n t h i s work treatment o f t h e a n h y d r i d e 2. w i t h b e n z y l a m i n e a t e l e v a t e d t e m p e r a t u r e gave good y i e l d s o f the c o r r e s p o n d i n g b i c y c l i c imide 5.. B y a l t e r i n g t h e r e a c t i o n c o n d i t i o n s , we i s o l a t e d t h e i n t e r m e d i a t e a c i d a m i d e 1 a n d i t s b e n z y l a m m o n i u m s a l t £. R e d u c t i o n o f t h e b i c y c l i c i m i d e .5. t o t h e N - b e n z y l b i c y c l i c amine £ w i t h t h e s o l u b l e r e a g e n t sodium b i s ( 2 - m e t h o x y e t h o x y ) a l u m i n u m h y d r i d e ( R e d a l ) was essentially quantitative. A l t h o u g h a m i n e £ c o u l d be d i s t i l l e d , c r u d e p r o d u c t was s u f f i c i e n t l y p u r e f o r t h e n e x t s t e p . Thus, palladium-catalyzed hydrogenolysis of e i t h e r m a t e r i a l a f f o r d e d t h e d e s i r e d b i c y c l i c a m i n e 2L. Even though t h i s c o n v e r s i o n was e s s e n t i a l l y q u a n t i t a t i v e , a l o w e r i s o l a t e d y i e l d r e s u l t e d from c a r r y o v e r of amine H w i t h the e t h a n o l i c f o r e r u n i n t h e workup by d i s t i l l a t i o n . This i n c o n v e n i e n c e was c i r c u m v e n t e d b y a d d i n g t o t h e s o l u t i o n one e q u i v a l e n t o f h y d r o c h l o r i c a c i d b e f o r e r e m o v a l o f ethanol. T h e n t h e w e l l - b e h a v e d h y d r o c h l o r i d e 1Ώ. was o b t a i n e d i n q u a n t i t a t i v e y i e l d as a c r y s t a l l i n e mass by removing solvent at reduced pressure. When p r e p a r e d a c c o r d i n g t o F i g u r e 2, t h e b i c y c l i c a m i n e 2L a f f o r d e d a NMR spectrum t h a t compared f a v o r a b l y w i t h t h e l i t e r a t u r e spectrum (1£). A n o t h e r r o u t e t o a m i n e 1Q. u s e d t h e i s o m e r i c a l l y - m i x e d 1 , 2 - c y c l o p r o p a n e d i c a r b o x y l i c a c i d 2. d i r e c t l y w i t h o u t r e c o u r s e t o t h e a n h y d r i d e 2.. T h u s , c a . one m o l e o f c r u d e a c i d 2 was t r e a t e d w i t h b e n z y l a m i n e a t 180°C t o a f f o r d a c r y s t a l l i n e s a m p l e o f i m p u r e i m i d e ϋ (72%) . Nevertheless, when t h i s i m p u r e m a t e r i a l was r e d u c e d 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 , t h e a m i n e & (68%) was i s o l a t e d b y d i s t i l l a t i o n i n a high state of p u r i t y . As b e f o r e , c a t a l y t i c hydrogenolysis of the N-benzyl group l e d t o a q u a n t i t a t i v e y i e l d o f t h e b i c y c l i c amine h y d r o c h l o r i d e In t h i s A

F


403

1



404

NaH

CQ>Et

EtOaC

CQ2B

CQ>Et

CQ>Et

EO2C

8:2 cis:trans 1) NaOH


99%

SOCI

coc'

2

84%

coa

2) HCI

HO2C

CQ>H

4 F i g u r e 1. S y n t h e s i s o f A c i d and D e r i v a t i v e s

1,2-Cyclopropanedicarboxylic

1) Pd/Hg/EtOH

R = Benzyl

2) HCI Ν

100%

R

â ,10. (HCI) LAH or

68-98%

NaAIH (OC H OCH ) 2

RNH

2

0Q>H

3

2

RNH,

2

_180° HQ2C

4

180°

72%

78% NT R

2

81%

N

o

180°

HCI/CH CI 2

CONHR

HQ2C Ζ Figure

2.

Synthesis

RNH,>/Et

100%

91o

/ o

2

RNH Q>C

CONHR

3

£ of

3-Azabicylo[3.10]hexane


2


34.

KOLLMEYER ET AL.


405

way, a m i n e 10 was o b t a i n e d i n 27% o v e r a l l y i e l d s t a r t i n g from e t h y l c h l o r o a c e t a t e and e t h y l a c r y l a t e . B y com p a r i s o n , t h e p r e p a r a t i o n o f a m i n e 10. v i a a n h y d r i d e ϋ a f f o r d e d a n o v e r a l l y i e l d o f 30%. The n e x t s t a g e o f t h e m e t h a n o p r o l i n e s y n t h e s i s made use o f t h e c h e m i s t r y o f p i p e r i d i n e and p y r r o l i d i n e t o w h i c h t h e c h e m i s t r y o f b i c y c l i c a m i n e ϋ. i s c l e a r l y related. The l i t e r a t u r e t e a c h e s t h e N - c h l o r i n a t i o n a n d dehydrochlorination of piperidine or pyrrolidine t o afford s o l u t i o n s o f t h e r e a c t i v e c y c l i c i m i n e s 1 - p i p e r i d e i n e (12, 18) a n d 1 - p y r r o l i n e (12.) . T h e s e e l e c t r o p h l i c i m i n e s r e a d i l y a d d h y d r o g e n c y a n i d e (20-22); a n d h y d r o l y s e s o f the r e s u l t i n g α-cyano a m i n e s c o n s t i t u t e s t r a i g h t f o r w a r d r o u t e s t o p i p e c o l i c a c i d (21) a n d p r o l i n e (22.) respec tively. T h e r e f o r e , t h e m o d e l r e a c t i o n s shown i n F i g u r e 3 were c a r r i e d o u t f o r a p p l i c a t i o n t o t h e c h e m i c a l c o n v e r s i o n o f b i c y c l i c a m i n e 2.. (At t h e time o f t h i s w o r k , R e f e r e n c e 22 h a d n o t y e t a p p e a r e d . ) Of s p e c i a l note was t h e t w o s t a g e u s e o f s o d i u m b i s u l f i t e f o l l o w e d b y sodium cyanide: i n t h i s way, h a n d l i n g h y d r o g e n c y a n i d e p e r .s_e_ was a v o i d e d . W i t h t h i s e x p e r i e n c e i n hand, t h e amine h y d r o c h l o r i d e 10. w a s t r a n s f o r m e d i n t o t h e a m i n o n i t r i l e 14. a s s h o w n i n F i g u r e 4. T h i s e n t i r e s e q u e n c e was c a r r i e d o u t o n a n a p p r o x i m a t e 0.5 m o l e s c a l e v i a f i v e s e p a r a t e r e a c t i o n s w i t h o u t i s o l a t i o n o f i n t e r m e d i a t e s t o g i v e a 67% o v e r a l l y i e l d o f a m i n o n i t r i l e 14 b a s e d o n a m i n e 10. Thus, t h e a m i n e h y d r o c h l o r i d e 1Q. was n e u t r a l i z e d w i t h c o n c e n t r a t e d p o t a s s i u m h y d r o x i d e , a n d t h e l i b e r a t e d f r e e a m i n e j£ w a s t a k e n up i n e t h e r . Treatment o f t h i s s o l u t i o n w i t h N - c h l o r o s u c c i n i m i d e (NCS) g a v e a s o l u t i o n o f t h e N - c h l o r o a m i n e 11. Further a d d i t i o n of e t h a n o l i c potassium h y d r o x i d e e f f e c t e d d e h y d r o c h l o r i n a t i o n . The r e s u l t a n t b i c y c l i c i m i n e 12. i n e t h a n o l i c e t h e r was s e q u e n t i a l l y t r e a t e d w i t h aqueous sodium b i s u l f i t e and then s o l i d sodium cyanide. T h e d e s i r e d a m i n o n i t r i l e 14. w a s i s o l a t e d as a d i s t i l l a b l e l i q u i d . A f u r t h e r m o d i f i c a t i o n ( n o t s h o w n i n F i g u r e 4) eliminated t h e need f o r a separate n e u t r a l i z a t i o n o f a m i n e s a l t 10 a n d r e p l a c e d t h e p r e v i o u s c h l o r i n a t i n g a g e n t N-chlorosuccinimide with ordinary household bleach. Thus, s a l t 1Q. was a d d e d d i r e c t l y t o a n a q u e o u s m i x t u r e o f s o d i u m b i c a r b o n a t e a n d s o d i u m h y p o c h l o r i t e . The r e s u l t i n g N - c h l o r o a m i n e 1 1 was t a k e n u p i n e t h e r a n d p r o c e s s e d a s b e f o r e t o g i v e n i t r i l e 14. i n a n o v e r a l l y i e l d o f 64%. T h i s c o m p a r e d f a v o r a b l y w i t h t h e p r e v i o u s y i e l d o f 67% f o r t h e c o n v e r s i o n o f a m i n e h y d r o c h l o r i d e 1£L t o n i t r i l e 14.. The l a s t s t e p , b a r i u m h y d r o x i d e - c a t a l y z e d h y d r o l y s i s o f t h e a m i n o n i t r i l e 14. f o l l o w e d b y s u l f u r i c a c i d n e u t r a l i z a t i o n , gave a racemic m i x t u r e o f c i s - and t r a n s methanoproline. A f t e r removal o f barium s u l f a t e and solvent, t r i t u r a t i o n of the residue with ethanol afforded r


406

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS (CH )n

U. 2

(CH )n

f

NCS

CI

pyrrolidine

n=1,

(CH )n

KOH KOH EtOH

ο

Ν Η

n=o,

2

~ \

2

" \

u

—

NaHS0

piperidine

3

H 0 2

(CH )n

1)Ba(OH)

2


Γ

2)H SQ

Ί

2

NaCN

(, C H ) n 2

2

Γ

4

(CH )n 2

Η,Ο

"1

Γ

^ "SOsNa Η

n=0,

proline, 7 9 %

n=0, 3 3 %

n=1,

pipecolic a c i d , 6 5 %

n=1, 63%

ο

F i g u r e 3. α - C a r b o x y l a t i o n Piperidine

o f P y r r o l i d i n e and

Η

1) K O H

1Q.

2) N C S / E t 0 2

(HCI)

KOH

NaHS0

EtOH

Η,Ο

3

Η

ι CI

11

12. NaCN 1) B a ( O H ) 2) H S 0 2

r^O 2

4

3) ion e x c h a n g e H Η

la F i g u r e 4, hexane

^ N T ^ O C g H Η

15. α-Carboxylation

95%

C^CN Η

14 of 3-Azabicyclo[3.1.0]•


34. KOLLMEYER ET AL.


407

a trans-enriched crystalline material (ca. 1.5:1 trans :cis by H NMR). Concentration of the mother liquor gave a tacky solid enriched in the cis-isomer (ca. 2.2:1). The combined crude product (95%) had an overall trans :cis isomer ratio of 55:45. The cis-enriched fraction was purified in 5 g batches by ion exchange chromatography on Dowex 50-X8 resin with 1.5 Ν hydrochloric acid as eluent. Under these condi tions, the cis-isomer eluted first (11) . Both amino acids 15 and 1£ were obtained as analytically pure, crystalline hydrochlorides upon evaporation of the acid eluates. No evidence (^H NMR) of any cyclopropyl ring opening was noted. The cis and trans isomers of methanoproline, either individually (H) or as a mixture, are easily recognized and distinguished from one another by H NMR. The methine proton of the NCHCO2 group occurs as a doublet at δ 4.3 (D2O) in the cis isomer, whereas the trans isomer has a singlet at 6 4.1. The hydrochloride salts UL and UL_show a similar splitting pattern, but the signals occur at slightly lower fields: cis, 6 4.4, doublet; trans, 64.2, singlet. These splitting patterns, which arise from coupling with the adjacent cyclopropyl proton, are in qualitative agreement with the Karplus rule (23.) . On this basis the precursor aminonitrile 14. appeared to be a trans isomer, because the NCHCN proton resonance was a singlet at 6 3.9. However, GCMS analysis revealed two components, each having an appropriate parent ion with m/z 108. The isomeric composition of nitrile 14 was, therefore, unclear. Further improvements to this route to methanoproline and the syntheses of related amino acids have been reported elsewhere (24). In this way, chemical manipu lation of 3-azabicyclo[3.1.0]hexane has allowed the preparation of multi-kilogram quantities of both cis- and trans-methanoprolines (24) .


1

1

LITERATURE CITED 1. Poehlman, J . M. "Breeding Field Crops", 2nd ed.; Avi Publishing Company, Inc.: Westport, Connecticut, 1979; Chapters 6 and 11. 2. Hoaglund, A. R.; Elliot, F. C.; Rasmussen, L. W. Agron. J. 1953, 45, 468-472. 3. Chopra, V. L . ; Jain, S. K.; Swaminathan, M. S. Indian J . Genet. Plant Breed. 1960, 20, 188-199. 4. Porter, Κ. B.; Wiese, A. F. Crop Science 1961, 1, 381-382. 5. Kaul, C. L . ; Singh, S. P. Indian J . Plant Physiol. 1967, 10, 112-118. 6. Rowell, P. L . ; Miller, D. G. Crop Science 1971, 11, 629-631. 7. Fairey, D. T.; Stoskopf, N. C. ibid 1975, 15, 29-32.



408 8. 9. 10. 11. 12. 13. 14. 15.


16. 17. 18. 19. 20. 21. 22. 23.

24.

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