synthesis of the enantiomer of the antidepresant tranylcypromine.pdf

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P e r g a m o n Tetrahedron: Asymmetry,Vol. 7, No. 12, pp. 3505-3512, 1996Copyright 1996 ElsevierScienceLtdPrinted in Grea t Britain.All rights reservedPI I: S0 95 7- 41 66 (9 6) 00 45 7- 0 0957-4166/96 $15.00 + 0.0o

S y n t h e si s o f T h e E n a n t i o m e r o f t h e A n t i d e p r e s sa n t T r a n y l c y p r o m i n eR e n ~ C s u k , * a M a g d a J . S e h a b e l b a n d Y v o n n e v o n S c h o lz b

a Institut . Organ. Chemie, Martin-LutherUniversitatHalle-Wittenberg,Kurt-Mothes Strasse2, D-06120 Halle (Saale),Germany,b Pharm.-Chemisches nstitut, Ruprecht-KarlsUniversit/ltHeidelberg, m NeuenheimerFeld 364, D-69120 Heidelberg,Germany.

A b s t r a c t : B o t h e n a n t i o m e r s o f t h e a n t i d e p re s s a n t t r a n y l c y p r o m i n e , trans 2 - p h e n y l - c y c l o p r o p y -l a m i n e 1 , w e r e p r e p a r e d i n e n a n t i o m e r i c a l ly p u r e f o r m b y a c h e m o e n z y m a t i c a p p r o a c h s t a r t i n gf rom racemic (+ ) - (1RS, 2RS)-trans e thy l 2 -pheny l -cyc loprop ane ca rbox y la t e (+ )-3 .Copyright 1996 Elsevier Science Ltd

I N T R O D U C T I O N

R a c e m i c s w i t ch e s a r e c h i r a l d r u g s t h a t a r e a lr e a d y a p p r o v e d a s r a c e m a t e s b u t h a v e b e e n r e d e v e l o p e d a ss i n g l e i s o m e r s . S o m e t i m e s t h e s i n g l e i s o m e r v e r s i o n l a c k s c e r t a in s i d e e f f e c ts t h a t t h e r a c e m a t e e x h i b i t s a n dw h e r e t h e t w o e n a n t i o m e r s a r e s u f f i ci e n t ly d i ff e r e n t in p h a r m a c o l o g i c a l e f f e c ts 1 , i t m a y b e p o s s i b l e t o g e t ap a t e n t o n o n e o r b o t h i s o m e r s .2 I n a p r o j e c t d e a l in g w i t h t h e d e v e l o p m e n t o f r ac e m i c s w i t c h e s f o r ( p r o - ) d r u g sa n d d r u g i n t e r m e d i a t e s b y c h e m o e n z y m a t i c e n a n t i o d i f f e re n t i a ti o n w e b e c a m e i n t e r es t e d i n t h em o n o a m i n o o x i d a s e i n h i b it o r ( M A O I ) t r a n y lc y p r o m i n e ( P a r n at e , J a tr o s o m N ) , ( + ) - (1 R S , 2SR)- t rans 2-p h e n y l - c y c l o p r o p y l a m i n e (_ +) -1 . T r a n y t c y p r o m i n e i s a n o r a l M A O I - t y p e a n t i d e p r e s s a n t a n d i t i s u s e d t o t r e a tm a j o r d e p r e s s i o n i n p a t i e n t s w h o h a v e n o t r e s p o n d e d t o o t h e r a n t i d e p r e s s a n t t h e r a p y a n d a r e e i t h e r c lo s e l ys u p e r v i s e d o r h o s p i t a l i z e d . 1 i s u s e d i n t h e r a p y a s a r a c e m a t e . I t h a s b e e n e s t a b l i s h e d , h o w e v e r , t h a t t h ee n a n t i o m e r s o f 1 s h o w b o t h q u a l i t a t iv e a n d q u a n t i ta t iv e d i ff e r e n ce s . T h u s ( + ) - (1 S , 2 R ) - I e x h i b i t s a f i v e - f o l dh i g h e r M A O I a c t i v i t y t h a n i t s e n a n t i o m e r , w h e r e a s t h e l a t te r i n h ib i t s s ig n i f i c a n t ly s t ro n g e r t h e r e - u p t a k e o fe a t e c h o l a m i n e s . 3 I n a d d i t i o n , t h e trans-2-phenylcyclopropyl-amine m o i e t y i s p a r t o f a n t i b a c t e r i a l a c t i v eg y r a s e i n h i b i to r s a n d a g a i n a s t r o n g d e p e n d e n c e o f t h e a n t ib a c t e r ia l ac t i v it y w i t h t h e a b s o l u t e c o n f i g u r a t i o n o ft h e t w o s t e r e o g e n ic c e n t e r s o f t h i s m o i e t y w a s e s t a b l i sh e d .4

S e v e r a l a p p r o a c h e s f o r t h e s y n t h e s i s o f t h e t w o e n a n t i o m e r s o f ( + )- 1 o r s u i t a b le p r e c u r s o r s h a v e b e e nd e v i s e d . T h u s , ( - ) - ( 1 R , 2 R)-trans 2 - p h e n y l - c y c l o p r o p a n e e a r b o x y l i c a c id ( - ) - 2 h a s b e e n o b t a i n e d f r o m t h er a c e m a t e b y c r y s t a l l i z a t i o n o f i t s ( + ) - d e h y d r o a b i e t h y l a m i n e 3 o r b r u c in e 5 s a l ts w h e r e a s f o r t h e s y n t h e s i s o f( + ) - 2 t h e d i a s t e r e o m e r i c q u i n i n e s a l t s 6 h a v e b e e n u s e d . I n a d d i t i o n , e n a n t i o s e l e c t iv e c y c l o p r o p a n a t i o n o fs t y r e n e w i t h a l k y l d i a z o a c e t a t e s h a s b e e n p e r f o r m e d i n t h e p r e s e n c e o f s e m i e o r r i n - m e t a l ( - t r i f l a t e ) 7, 8c o m p l e x e s o r o f b i s ( o x a z o l i n e ) c o p p e r c o m p l e x e s 9-1 1 t o a f f o r d ( + ) -2 o r ( - ) - 2 w i t h e e ' s o f 9 0 - 9 9 % .

R E S U L T S A N D D I S C U S S I O N

A c h e m o e n z y m a t i c r o u t e w a s p l a n e d s t a r t i n g f r o m r a c e m i c ( + ) - ( 1 RS, 2 RS)- t rans e t h y l 2 - p h e n y l -e y c l o p r o p a n e e a r b o x y l a t e ( + ) - 3 a n d ( + ) -( 1 RS, 2 RS)-trans h e x y l 2 - p h e n y l - c y c l o p r o p a n e c a r b o x y l a t e ( + ) -4 ;( + ) - 4 w a s e a s i l y o b t a i n e d f r o m ( + ) - 3 b y t r a n s e s t e r i fi c a t io n w i t h n - h e x a n o l i n t h e p r e s e n c e o f c o n e . s u l f u r ica c i d . I t w a s a n o t h e r a i m o f th i s p r o j e c t t o u s e r a t h e r in e x p e n s i v e e n z y m e s t o a l l o w a v e r y e c o n o m i c s y n t h e s i so f t h e e n a n t i o m e r s o f 1 .

3505



3506 R. CSUK e t a l .

T h e t w o e s t e rs w e r e s u b j e c t e d to e h e m o e n z y m a t i c h y d r o l y s i s r e a c ti o n s u s i n g p H - s t a t e q u i p m e n tm a i n t a i n i n g t h e p H o f t h e r e a c t i o n s c o n s ta n t a t p H = 7 t h r o u g h o u t th e r e a c t i o n b y t h e a d d i t i o n o f 0 . 1 N N a O H .Both (+ ) -3 and (_+)-4 were exce l l en t subs t ra te s fo r the en zym e p ig l i ve r e s t e ra se (PLE) , bu t unfor tuna t e ly t heseh y d r o l y s e s p r o c e e d e d w i t h o u t a n y s e l e c ti v i ty .Tab le 1 Enzy mat i c H ydro lys i s o f (_+) -3 and (+) -4E n z y m e c o n v e r s i o n e e o f ( - ) - 3 e e o f ( + ) -2 c o n v e r s io n e e o f ( - ) - 4 e e o f ( + ) - 2

o f (_+)-3 [%] [%] [%] o f (+)-4 [%] [%] [%]L i p o l a s e - p o w d e r 0 7 3 > 9 9 4 9Lipo la se L100 55 > 99 77 47 86 78Lipase P 62 92 43 68 92 50Lipase PS 72 90 32 22 32 68N o v o z y m 4 3 5 6 1 2 0 1 4 6 6 1 8 9PLE 50 0 0 58 0 0L i p a s e A Y 2 9 2 4 6 7 0L ipa se M 62 59 75 0L ipas e F 0 10 0 0

P ph,, ' j (R) ph4P (S)L i p o l a s e p o w d e r(:t:)-4 R = C6H i ~ (-)-4 ee > 99% (+)-2 ee = 49%L i p o l a s e L 1 0 0 ( + ) - 2 e e = 7 7 %

( + ) - 3 R = C 2 H 5 ~, ( - ) - 3 e e _> 9 9 %E t O H , H + L i p o l a s e L 1 0 0( + ) - 2 e e = 7 7 % ~ ( + ) - 3 e e = 7 7 % ~ ( + ) - 2 e e > 9 9 %

T h e b e s t r e s u l ts ( c f. T a b l e 1 ) w e r e o b t a i n e d w i t h t h e l i p o l a s e p o w d e r ( i m m o b i l i z e d l i p o l a s e , E .C .3 . 1 .1 . 3 ) t o a f f o r d e n a n t i o m e r i c a l l y p u r e ( - ) - 4 a n d w i t h t h e l ip o l a s e L 1 0 0 ( a s u s e d i n d e t e r g e n t s )e n a n t i o m e r i e a U y p u r e ( - ) - 3 w a s o b t a i n e d . I n t e r e s ti n g l y , ( + ) - 3 w a s a n o n - s u b s t r a t e f o r th e l i p o l a s e p o w d e rw i t h i n a r e a c t i o n t i m e o f 3 d a y s . T h i s r e p r e s e n t s a d r a m a t i c c h a n g e o f r e a c t iv i t y a s a f u n c t i o n o fi m m o b i l i z a ti o n . W o r t h w h i l e t o m e n t i o n t h a t l i p o l a s e h a s b e e n o b t a i n e d a c c o r d i n g t o G M P p r o c e d u r e s f r o m an o n - p a t h o g e n m i c r o o r g a n i s m , i t i s n o t to x i c , v e r y c h ea p d u e i ts c o m m o n - s p r e a d u s e i n s y n t h e t i c d e t er g e n t sand b iosur fae t an t s and i s comp le t e ly b iodegrada t ed .

T h e e n a n t i o m e r i c p u r i t y o f 3 w a s d e t e r m i n e d b y H P L C e i t h e r d i r e c t l y u s i n g a ( S , S ) - W h e l k O 1 c o l u m n o r a f t e r t r a n s e s te r i f ic a t i o n w i t h n - h e x a n o l a s i t s h e x y l e s t e r 4 ; t h e H P L C i n v e s t i g a ti o n o f t h e h e x y l e s t e r4 s h o w e d a c l e a n b a s e l i n e s e p a ra t i o n o f th e c o r r e s p o n d i n g e n an t i o m e r s o n a C h i r a l c e l O D - R c o lu m n . T h e e eof 2 was mea sured a f t e r i t s r e -e s t e r i f i ca t i on wi th e thano l ( ---~3) .

S a p o n i f i c a t io n o f ( - ) - 3 w i t h 2 N N a O H g a v e ( - ) - ( 1 R , 2R) - t r ans 2 - p h e n y l - c y c l o p r o p a n e c a r b o x y l i c a c i d( - ) - 2 . ( - ) - 2 w a s s u b j e c t e d t o a m o d i f i e d Cu r t iu s d e g r a d a t io n u s i n g d i p h e n y l p h o s p h o r y l a z i d e , tert. b u t a n o l a n dt r i e th y l a m i n e 12 t o a f f o r d ( - ) - 5 .1 3 A s a b y p r o d u c t t h e f o r m a t i o n o f t h e c a r b a m o y l a z i d e ( - ) - 6 w a s o b s e r v e d . 14T r e a t m e n t o f ( - ) - 5 w i t h c o n e . h y d r o c h l o r i c a c id a t ro o m t e m p e r a t u re g a v e e n a n t i o m e r i c a l ly p u r e ( - ) -t r a n y l c y p r o m i n e ( - ) - 1 .



The enan t iomer o f t r any lcypromine 3507

/CO2EtN N a O H(R)ph '' (R) ph (R)

(-)-3, ee > 99 % (-)-2

p hX,.~ (R) 0 ph i. ,( +6 ( - ) - s

Ph 0 e' (R)Ph*(+)-7 (-)-1, ee _> 99 %

ph4P (S)(+)-2

DP PA, NEt3 1t. BuOH, AH

ph g (S) 0(+)-s

I) HCI [2) NaOH

ph f (S)(+)-1, ee > 99%

A s f o r t h e s y n t h es is o f ( + ) - 1 t h e en a n t i o m er i ca ll y e n r i ch ed ( + ) - 2 ( ee = 7 7 - 7 8 % ) f r o m t h e f ir s tenzymat ic hydro lys i s was sub jec ted to a r e-es ter i f ica t ion to af fo rd (+) -3 ( ee = 77-78%) tha t was used as as tar ting mater ia l fo r a secon d enzym at ic hydro lys i s w i th l ipo lase L100 us ing a co nver s ion o f 40% to y ie ldenan t iomer ica l ly pure (+) -2 . Curt ius degradat ion o f (+) -2 fo l lowed by ac id ic hydro lys i s f ina l ly gave enan t io -merical ly pure (+)- tranylcypromine (+)-1.

Since no suitable cond it ions for a direct HP LC determination of the enantiom eric pur i ty of 1 cou ld befound, the ee was established af ter in-situ t ransformation o f 1 into i ts der ivat ive 7. A clean basel ine separat ionof the two enan t iomers cou ld be ach ieved us ing a Chi ra lce l OD -R colum n. 15Fig. 1 : HPLC inves t iga t ion o f (+) - , (+ ) - and ( - ) -3 : (S , S) -Whelk O1 , pen tane/prop-2-OH /AcOH 98/2 /05 ,1 ml /min , ~, = 27 0 n m; tR [ ( - ) -3] = 5.04 m in, tR [ (+)-3] = 5.74 m ini -~ 5 .04 l 5 . 0 45 .74 ~- ~ . ~ 5 . 7 4

Fig . 2 : HPL C inves t iga t ion o f (+ ) - , (+ ) - and ( - ) -7 : Chi ra lce l O D-R , Ac CN /H2 0 (pH=4) 50 /50 , 0 .4 ml/min ,X = 2 80 n m ; tR [ ( - ) -7] = 41 .58 rain, tR [ (+)-7] - - 46.62 rain

4 1 . 5 84 6 . 6 2

4 1 . 5 8

E X P E R I M E N T A L

~ : ~ - 4 6 . 6 2G en e r a l . - M e l t i n g p o i n t s a r e u n co r r ec t ed (R e i c h e r t hot s tage microscope) , op t ica l ro ta t ions were

ob ta ined us ing a Perk in-E lmer 243B po lar imeter (1 cm micro-cel l ) , NMR spect r a ( in ternal Me4Si ) were



3508 R. CSUK et al.

recorde d using ei ther a Bruker A M 250 or a Var ian XL30 0 instrument (8 given in ppm , J in Hz, internal M e4Si,IR spect r a ( f i lm o r KBr pel le t) on a P erk in-E lmer 298 ins t rument o r on a Perk in-E lmer 1605 FT- IR , MSspectra were taken ei ther on a M AT 311 A or a Var ian-112S instrument; fo r elemental analy sis a Foss-H eraeusVar io EL ins t rument was used . TLC was per fo rmed on s i l i ca gel (Merck 5554 , de tec t ion by d ipp ing in anethano l ic n inhydr in (1%) so lu t ion fo l lowed by gen t le heat ing , o r by t r ea tment wi th iod ine) . HPLC wasper forme d on a Merck-H i tach i L6200A /L4000/D 2500 ins trument ; the pH-s ta t equ ipm ent was ob ta ined f romM et r o h m . T h e en zy m e s w er e u s ed a s o b t a in ed : L i p o l a s e an d L i p o l a s e L 1 0 0 ( N o v o N o r d i s k ) , L i p as e P(Pseudomonas f luorescens, A m an o L t d . ) , L i p as e PS (Pseudomonas sp., A m a n o L t d .) , N o v o z y m 4 3 5(Candida antarctica,N o v o N o r d is k ), PL E (porcine liver, Boehringer Mannheim).

(+)-(1 RS , 2 RS)-trans H exyl 2-ph enyl-cyelopropane earboxylate [ (+) -4] . - A so lu t ion o f (+) -3 (5 .0g, 26.3 mmol, commercial, Lancaster, used as received) in n-hexanol (75 m/) and conc. sulfuric acid (0.5 m/) washeated for 12 h at 130 C; the ethanol forme d dur ing this react ion was disti lled of f con tinuou sly by use of adisti l lat ion head at tac hed on to the top o f a 80 C wa rm Vigreux co lumn. Af ter coo l ing to 25 C the excess o fhexanol wa s d is t i ll ed o f f under r educed pressure and the r es idue was sub jec ted to co lum n chrom atograp hy(si l ica gel , hexa ne - -~ ethyl acetate/hex ane 1:20 ---> 1:10) to afford (+)-4 (6.0 g, 93% ) as a color less oi l . A s abyprod uct d ihexy le ther (2 .3 g ; co lo r less o i l ; RF (e thy l ace ta te /hexane 1 :15) 0 .42 ; nD = 1 .4180; IR ( f ilm) v2957s , 2932s, 2859s, 1603w, 1467m, 1377w, 1120m; IH N M R (250 MH z, CDCI3) : ~ 3.39 ( t, J = 6.7, 4 H, 2 xOC H2), 1 .59-1.51 (m, 4 H, 2 x CH2), 1 .36-1.30 (m, 12 H, 6 x CH2), 0 .89 ( t , J = 6.4, 6 H, 2 x CH3); 13C N M R(63 M Hz , CDC 13): ~ 71.11 (t, 2 x OCH 2), 31.88, 29.91, 26.03, 2 2.78 (ea ch t, 2 x CH2 ), 14.14 (q, 2 x CH 3);MS (ei , 80 eV, 78 C): 186 (5.4%), 185 (35.1%), 132 (1.1%), 131 (13.2%), 113 (3.2% ), 101 (22.3% ), 86(6.3%), 85 (100.0%)) wa s formed . Da ta for 4: RF (ethyl acetate/hexane 1:15) 0.35; IR (film): v 3030m, 2956 s,2931s, 2859m, 1726s, 1605w, 1499m, 1458m, 1437m, 1409s, 1337m, 1263m, 1220m, 1175s, I078m, 1044w;IH NM R (250 M Hz, CDC13) : 6 7 .30-7 .07 (m, 5 H , H-C(phenyl ) ) , 4 .10 ( t, J= 6.7, 2 H, OCH2), 2.51 (ddd , J=9.5, 6.1, 3.9, 1 H, H-C (2)), 1.93-1.86 (m, 1 H, H-C(1)), 1.66-1.55 (m, 1 H, HA -C(3 ) and 2 H, CH2), 1.41-1.26(m, 1 H, HB -C(3) and 6 H, 3 x CH2), 0 .89 ( t, J = 6.3, 3 H, CH3); 13C NM R (63 M Hz, CD CI3) : ~ 173.48 (s ,CO ), 140.19 (s , Cq(ph enyl)) , 128.49, 126.48, 126.21 (d, C(phenyl)) , 64.95 ( t , OCH2), 31.47, 28 68 (each t ,CH2), 26.16 (d, C(2)), 24.21 (d, C(1)), 25.62, 22.56 (each t, CH2), 17.03 (t, C(3)), 14.00 (q, CH3); MS (ei, 80eV, 100 C): 248 (0.4%), 247 (2.0%), 246 (12.6%), 215 (0.8%), 191 (5.4%), 163 (33.0%), 162 (69.6%), 145(17.8%), 144 (23.6%), 117 (93.5%), 116 (23.9%), 115 (33.7%), 107 (27.1%), 91 (19.8%), 43 (100 .0% ); An al.calcd, fo r C16H 2202 (246.35): C, 78.01; H, 9.00; found: C, 77.72; H, 9.03.

( - ) - ( 1 R , 2 R ) - t r a n s ethyl 2-ph enyl-cyclopropane carboxylate ( - ) -3 and t r a n s 2-phenyl-cyclopropane carboxylic acid (2 ) . - To a so lu t ion o f (+) -3 (3 .0 g , 15 .8 mmol) in water (40 ml) at 30 Cl ipo lase L100 (100 r ag) w as added and the pH of the react ion mix ture w as kep t cons tan t in the pH-s ta tequ ipm ent a t 7 .0 by the add i t ion o f 0.1 N NaOH (86.73 m l co r r e s p o n d i n g t o a co n v e r s i o n o f 5 5 % ) . T h eaqueous so lu t ion w as d i lu ted wi th d ich loromethane (50 m /) and brought to pH ~- 1 -2 by the carefu l add i t ion o f17% aqueou s hydroch lor ic ac id . The aqueous layer was ex t r ac ted wi th d ich loromethane (4 x 40 m /) and thecombined organ ic phases were d r ied (MgSO4) , the so lven t was evapora ted and the r es idue sub jec ted toch rom ato grap hy (silica gel, ethy l acetate/hexane 1:10 ---> 1:5) to afford (-)-3 (1.14 g, 38% ) and 2 (1.25 g, 49%).

Data fo r ( - ) -3 : co lo r less l iqu id , [ a] ~- 30 8 ( c 0 .78 , CHC13) , ee >99% [ li t. : [ a ]~ -2 79 ( ee 96%) 9 ,[ a] ~+ 23 6 ( ee 75%) fo r (+) -3 16] ; RF (e thy l ace ta te/hexane 1 :15) 0 .43 ; IR (KBr) : v 3415m, 3087m ; 3065m,3030m, 2982m, 1957w, 1879w, 1718s, 1675m, 1653m, 1636m, 1617w, 1603m, 1581m, 1560m, 1545w,




1507w, 1496m, 1473m, 1457s, 1437m, 1412m, 1387m, 1366m, 1336s, 1311m, 1286m, 1219m, l190s, 1077m,1 0 4 0 m , 1 0 1 8 m ; I H N M R ( 2 5 0 M H z , C D C I 3 ) : ~ 7 .30 - 7 .0 7 ( m , 5 H , H - C ( p h en y l )) , 4 .1 6 ( q , J = 7.1, 2 H,OC H2) , 2 .51 (ddd, J = 9.4, 6 .1, 4 .1, 1 H, H-C(2)) , 1 .89 (ddd, J = 8.4, 5 .1, 4 .1, 1 H, H-C (1)) , 1 .59 (ddd, J=9.4, 5 .1, 4 .4, 1 H, H A-C (3)) , 1 .33 -1.24 (m, 1 H, HB-C(3)), 1 .27 (t , J = 7.1, 3 H, CH3); 13C N M R (63 M Hz ,CD CI3 ): ~ 173.39 (s , CO ), 140.15 (s, Cq(phenyl)), 128.47, 126.48, 126.19 (d, C(phe nyl)) , 60.68 ( t , OCH2 ),26.15 (d, C(2)) , 24.16 (d, C(1)) , 17.02 ( t , C(3)) , 14.27 (q, CH3); MS (ei , 80 eV, 30 C): 192 (0.5%), 191(6.1%), 190 (47.9%), 162 (7.6%), 145 (23.2%), 144 (20.3%), 135 (18.9%), 133 (13.7%), 117 (100 .0% ); An al.ealcd, for C12H1402 (190.24) : C, 75.76; H, 7.42; found: C, 75.44; H, 7.42. Determ ination o f the ee: 1) HPL C,co lum n W helk O1 (Merck) , pen tane/2-propanol /acet ic ac id 98 /2 /0.5 , f low 1 .0 m/ /min , p ressure 24 bar , UVdete ction a t ~, = 27 0 nm , tR [(-)- 3] = 5.04 m in, t R [(+)-3] = 5.74 min; 2) after transesterification: 3 (1 m g) w asdissolve d in n-hexano l (0.1 m/) and catalyt ic amou nts of cone. sulfur ic acid (10/. t/ ) w ere added . After warm ingto 120 C for 60 min the r eact ion mix ture was coo led to 25 C, the so lven ts were r emoved under r educedpressure and the r es idue d i sso lved in methanol (3 ml, HPLC quali ty , Merck) . After f i l t rat ion (membrane f i l ter45 Bm) th i s so lu t ion was d i r ec t ly used fo r HPL C: Chi ra lce l OD -R (Daicel) , methano l /wa ter (pH = 4 by theadd i t ion o f HC104) 80 /20 , f low 0 .4 ml/min, pressure 27 kg /cm2, UV detec t ion a t ~ , = 280 n m, tR [ ( - ) -4 ] =54.03 m in, tR [ (+)-4] = 65.76 m in.

Data fo r 2 : whi te so l id , mp 46-47 C, [ c~]~+299.0 ( c 1 .05 , CHC13), ee = 77% (by H PL C af teres ter if ica t ion : A so lu t ion o f 2 (1 m g) andp -Ts OH (cata ly t ic amounts ) in d ry e thano l (1 m/) wa s heated und erref lux for 30 min, then the solven t wa s remov ed under reduced pressure, the remaining residue wa s redissolvedin methanol (3 ml, HP LC qual i ty , Merck) , f il te red (mem brane f il te r , 45 ~m ) and th i s so lu t ion was d i r ec t lyused for the HPLC analysis) .( - ) - (1 R, 2 R)- t rans 2-phenyl-cyelopropane carboxylic acid ( - ) -2 . - A so lu tion o f ( - ) -3 (0 .5 g , 2 .63 mm ol) inan aq u eo u s s o l u ti o n o f N aO H ( 2 N , 5 ml) was heated under r eflux fo r 5 h . Af ter coo l ing to 25 C the pH wasadjusted b y the addit ion o f 17% HC1 to 1-2 and the mixture was extracted with ethyl acetate (4 x 30 ml). T h ecom bined organ ic layer s were d r ied (MgSO4), the so lven t was r em oved under r educed pressure and ( - ) -2 (0 .41g, 96% ) w as ob tained a s a white sol id; m p 36-37 C ( l it . : color less oi l 17, 51-52 C 5, 47-4 9 C 3) ; RF (ethylacetate/hexane 1:2) 0.29; [ t~]~-381.3 (c 0.96, CHC13) ( li t .: [a]~ -38 1.1 (c 1, CHC13) 3) ; ee > 9 9% (determ inedas e thy l es ter by H PLC (Wh elk O1 , vide supra); IR (KBr) : v 3032s, 2645s, 2365m , 1950w, 1874w, 1690s,1602m, 1581m, 1560w, 1498s, 1461s, 1447s, 1432s, 1338s, 1326s, 1308s, 1289s, 1236s, 1182m, l l18m,1080m, 1057m, 1048m, 1041m, 1024m; 1H NM R (250 MH z, CDC13): ~5 11.45 (br s , 1 H, OH), 7 .31-7.08 (m,5 H , H-C(phenyl ) ) , 2 .60 (ddd, J = 9.5, 6.5, 4.0, 1 H, H-C(2)), 1.90 (ddd, J = 8.3, 4.7, 4.0, 1 H, H-C (1)), 1.66(ddd, J = 9.5, 4 .7, 4 .6, 1 H, HA -C(3)) , 1 .39 (ddd, J = 8 .3 , 6 .5 , 4 .6, 1 H , HB-C(3) ) ; 13C N M R (63 M Hz ,CDC 13): ~5 180.03 (s, CO), 13 9.53 (s, Cq(phenyl)), 128.57, 126.75, 126.33 (d, C(ph eny l)), 27.13 (d, C(2 )),24 .00 (d, C(1)), 17.50 (t, C(3)); MS (ei, 80 eV , 61 C): 162 (44.0%), 161 (1.0%), 145 (3.0% ), 144 (15.6 %),118 (9.6%), 117 (100.0%); An al. calcd, for C10H 1002 (162.19): C , 74.06; H, 6.21; found : C, 73.97; H, 6.39.

( - ) - ( 1 R, 2 S - t r a n s (2-phenyl-cyclopropyl)-carbaminic acid t e r t . butyl ester ( - ) -5 and ( - ) - (1 R, 2S)- t rans (2-phenyl-eyelopropyl)-carbamoyl azide ( - ) - 6 . - T o a s o lu t io n o f ( - ) - 2 i n d r y tert. butano l (5 ml),t r i e thy larn ine (0 .22 g , 2 .18 mmol) and d iphenyl phosphory l az ide (0 .60 g , 2 .18 r e too l ) were added and themix ture was warmed to 90-95 C for 5 h . Then the so lven ts were r emoved under r educed pressure and theresidue subje cted to chro ma togra phy (ethyl acetate/hexane 1:10) to afford ( - ) -5 (0.26 g, 51%) and ( - ) -6 (0.03g, 9%).



3510 R. CSUK et al.

Data fo r ( - ) -5 : whi te so l id ; mp 81-83 C; RF (e thy l ace ta te(hexane 1 :4 ) 0 .48 ; [ a]~ -97 .6 ( c 0 .8 ,CHC13); IR (KBr) : v 3370s, 302 9w, 3011w, 2983w, 2934w, 1734w, 1688s, 1653m, 1617w , 1604w, 1560w,1512s, 1457w, 1443w, 1391w, 1365m, 1338w, 1268m, 1252m, 1226w, 1213m, 1167s, lll3w, ll02w, 1079w,1068m, 1045m, 1027w; lH NM R (250 MH z, CD CI3): ~ 7 .29-7 .10 (m, 5 H , H-C(phenyl ) ) , 4 .85 ( b r s , 1 H,NH) , 2 .72 (m, 1 H , H-C(1) ) , 2 .03 (ddd, J = 9.4, 6.5, 3.0, 1 H, H -C(2 )), 1.45 (s, 9 H, 3 x CH3(ter t . butyl) ) ,1 .18-1.11 (m, 2 H, HA,B-C (3)) ; 13C N M R (63 MH z, C DCI3) : ~ 156.35 (s , CO), 140.76 (s , Cq (phe nyl)) ,128.33, 126.51,12 6.03 (each d, C(phenyl)) , 79.64 (s , Cq(tert. butyl)), 32.57 (d, C(1)), 28.49 (q, 3 x CH3(tert .buty l)), 25.11 (d, C(2)), 16.37 (t, C(3)); M S (ei, 80 eV, 54 C): 234 (0 .1%), 23 3 (0.5% ), 219 (0.1%o), 218(0.6%), 177 (21.5%), 134 (5.4%), 133 (48.3%), 132 (28.3%), 116 (34.8%), 57 (100.0%); anal . calcd, forCI4H19NO2 (233.31): C, 72.07; H, 8.21; N, 6.00; found: C, 72.07; H, 8.17; N, 5.82.

Data for ( - ) -6: white sol id; mp 65-83 C (under decomposit ion) ; RF (ethyl acetate/hexane 1:4) 0.40;[a ]~ -1 14 .9 (c 0.74, CHC13); IR (KB r): v 3319s, 3085w, 3028m , 2172s, 2146s, 1675s, 1605m, 1546s, 1499s,1460m, 1387w, 1326m, 1281s, 1215m, 1193m, 1166m, 1090m, 1069m, 1058m, 1045m, 1033m, 1003m;IH NM R (250 M Hz, CDC13): 5 7.30-7.03 (m, 5 H, H-C(pheny l)) , 5.43 (br s , 1 H, NH), 2 .85-2.75 (m, 1 H,H-C (I)) , 2 .15-2.05 (m, 1 H, H-C(2)) , 1 .30-1.19 (m, 2 H, HA,B-C(3)) ; 13C NM R (63 M Hz, CDC I3) : ~ 157.20(s, CO), 139.80 (s, Cq(phenyl)), 128.47, 126.77, 126.63 (each d, C(phenyl)), 32.56 (d, C(1)), 25.01 (d, C(2)),15.83 (t, C(3)); MS (el, 80 eV, 59 C): 202 (0.2%), 173 (15.4%), 159 (46.6%), 130 (100.0%), 116 (51.2%),104 (42.5%), 103 (31.8%), 77 (43.7%); HR MS calcd, for C IoH10N40: 202.0856; found: 202.0856.

( - ) - (1 R, 2 S) - trans 2 - p h en y l - ey e l o p r o p y l am i n e , ( - ) - t r an y l ey p r o m i n e ( - ) - 1 . - T o a s o l ut io n o f ( - ) - 5(0.15 g, 0 .65 mmol) in THF (1 ml) aqueous hydrochlor ic acid (33%, 1 ml) was added and the mix ture waswarm ed to 40 C for 30 min. After cooling to 25 C the pH w as adjusted to 13-14 by the careful addit ion o f anaqueous so lu t ion o f NaOH (20%) and the mix ture was ex t r ac ted wi th d ie thy le ther (3 x 20 m/). The co mbine dorganic phases we re dr ied (MgSO4), f i l tered through a short pad of basic alum inium oxide, ev aporate d and ( - ) -1 (0.06 g, 68% ) rem aine d as an oi l; RE (ethyl acetate/m ethanol 3:1) 0.27; [a] ~- 13 5.4 (c 0.81, C HC t3) ( l it . :[a] ~-1 15 .8 (c 1.13, CHCI3)3) ; IR ( fi lm): v 2920s, 2728s, 2113w, 1946w, 1763w, 1735w, 1718w, 1701w,1696w, 1685w, 1636m, 1605s, 1582s, 1561s, 1496s, 1466s, 1443m, 1404w, 1346w, 1247m, l185s, 1156s,l117s , 1023s; IH NM R (300 M Hz, d4-methanol ) : ~ 7 .22-6 ,98 (m, 5 H , H-C(phenyl ) ) , 4 .82 ( s , 2 H , NH2) ,2.43 (ddd, J = 7.7, 4.4, 3.3, 1 H, H-C (1)), 1.84 (ddd, J = 9.1, 6.0, 3.3, 1 H, H-C (2)), 1.03-0.92 (m , 2 H, HA,B-C(3)) ; 13C N M R (75 MH z, d4-m ethan ol) : ~ 143.53 (s , Cq(p henyl)) , 129.22, 12 6.67, 126.45 (ea ch dC(phenyl)), 35.75 (d, C(1)), 26.36 (d, C(2)), 18.13 (t, C(3)); MS (ei, 80 eV, 300C): 134 (8.7%), 133 (100.0%o),132 (79.9%), 130 (8.1%), 118 (4.0%), 117 (19.8%), 115 (36.6%), 104 (14.4%), 91 (17.4%), 77 (20.7%); Anal.calcd , for C9H I1N (13 3.20): C, 81.16; H , 8.32; N, 10.52; found: C, 80.93; H, 8.44; N, 10.63; ee _> 99% asd e t e r m i n ed b y H PL C a f t e r d e r iv a t i za t io n w i t h p h en y l - i s o cy an a t e : ( - ) - 1 (1 m g ) w as d i s s o l ved i n d r ydiethylether (1 m/) , t r iethylamine (0.25 m/) and phenyl- isocyanate (5/z/) were added. After warming (50 C,30 min) and coo l ing to 25 C, the vo la t i le components were r em oved under r educed pressure and the r es iduewas d i sso lved in methanol (3 ml, HPL C qual i ty , Merck) . Th is so lut ion was f i l t er ed (mem brane f i l t e r, 45 g m)and the f i l t r a te was d i r ec t ly used fo r the HPLC inves t iga t ions : co lumn Chi ra lce l OD-R (Dalcel) , eluent:aceton i t r i l e /water (pH = 4 by the add i t ion o f HC104) 50 :50 , f low 0 .4 ml/min , pressure 19 kg /c m 2 , UV-dete ction a t ~, = 280 nm , tR [(-)-7] = 41.58 min, tR [(+)-7] = 46.62 rain.

(+)-(1 R S , 2 S R ) - t ra n s l - p h en y l - 3 - ( 2 - p h e n y l - cy c l o p r o p y l ) - u r ea ( + ) - 7 . - T o a s o l u t io n o f ( + )- 1 ( 0 .1 5g, 1 .13 nunol) in dry diethylether (1 m/) , t r iethylamine (0.5 m/) and phenyl- isocyanate (0.12 ml, 1.13 nunol)




were ad ded and the r eact ion mix ture was s t ir red fo r 3 h a t 25 C. The so lven t was r em oved un der r educedpressure and the res idue sub jec ted to chrom atograp hy ( e thy l ace ta te /hexane 1 :10 ~ 1 :5 ~ 1 :2 -~ e thy lacetate) to afford (+)-7 (0.24 g, 91%) as a white sol id; m p 172-174 C ; RF (ethyl acetate/hexa ne 1:3) 0.19; IR(KB r) : v 3290 m, 3057w, 2979w , 1734w, 1718w, 1695m, 1642s, 1600s, 1572s, 1496m, 1464w, 1445m, 1401w,1311m , 1244m , 1196w, 1183w, 1113w, 1076w, 1030w; 1H NM R (300 MH z, d6-DM SO) : 8 8 .37 ( s, 1 H ,NH ) , 7 .42-7 .39 (m , 2 H , H-C(pheny l ) ) , 7 .30-7 .12 (m, 7 H , H-C(phenyl ) ) , 6 .93-6 .87 (m, 1 H , H-C(phen yl ) ) ,6 .59 ( d , d = 2.7, 1 H, NH ), 2.77-2.71 (m, 1 H, H-C(1)), 1.97 (ddd, J = 9.0, 6.2, 3.0, 1 H, H-C (2)), 1.18-1.13( m , 2 H , H A ,B - C ( 3 ) ) ; 1 3C N M R ( 7 5 M H z , d 6 - D M SO ) : 6 1 5 5 .5 6 ( s , C O ) , 1 4 1 .33 , 1 4 0 .0 9 ( each s ,Cq(ph enyl)) , 128.48, 128.02, 125.77, 125.39, 121.00, 117.70 (each d, C(ph enyl)) , 32.82 (d, C(1)) , 24.59 (d,C(2)) , 15.84 ( t, C(3)) ; MS (el, 80 eV, 138 *C ): 253 (5.3%), 252 (26.8% ), 137 (45.8% ), 133 (68.9%), 132(100.0% ); Anal . c alcd, for CI6H 16N 20 (252.32) : C, 76.17; H , 6.39; found: C, 75.87; H, 6.39.

(+)-(1 S, 2 S ) - t ra n s 2 - p h e n y l - e y c l o p r o p a n e earboxy l ic ac id (+) -2 . - A so lu t ion o f 2 (1 .08 g , 6 .66m m o l , ee = 7 7 % , vide supra) in abs. ethanol (25 ml) was t r ea ted wi th ca ta ly t ic amounts o fp-TsOH and themix ture wa s heated unde r r ef lux fo r 8 h . The so lven ts were r emoved und er r educed pressure, the r es idue wasd isso lved in e thy l ace ta te (100 ml) , extracted in succession with a saturated aque ous solut ion o f NaH CO 3 (2 x5 ml) and br ine (10 m l) and dr ied (MgSO4) . The so lven t was evapora ted and the r es idue sub jec ted tochrom atograph y (s i l ica gel , hexane/e thy l ace ta te 10 :1 5 :1 ) to af fo rd 3 (1.23 g , 96%) , ee = 77% as determinedby H PL C (W helk O 1 , vide supra) . 3 (1.2 g, 6 .31 retool) w as dissolved in water (80 ml) and t r ea ted wi th theenzy me l ipo lase L1 00 (600 r ag) in the pH-s ta t equ ipment as descr ibed above (pH = 7 , 30 C) . Af ter add i t ionof a to ta l o f 25 .22 m l of 0.1 N NaO H (cor responding to a conver s ion o f 40%) the r eact ion w as s topped byex t rac t ion wi th d ich loromethane (3 x 30 ml) . The aqueous layer was ad jus ted to pH - - 1 -2 by the carefu ladd i t ion o f hydroch lor ic ac id (0 .1 N) , ex t r ac ted w i th d ich loromethane (4 x 50 ml) an d t h e co m b i n ed o r g an i cphases were d r ied (MgSO4) , the so lven t was r emoved under r educed pressure and the r es idue sub jec ted tochrom atog raphy (si l ica gel , hexane/ethyl acetate 10:1 --} ethyl acetate) to a fford 3 (0.5 g, 45%, color less l iquid;[ a ]~ = 225 .7 ( c 0 .86 , CHC13; ee = 72% (by HPLC , W helk O1 , vide supra)) and (+)-2 (0.32 g, 32%): whiteso lid, m p 46-47 C; [ a]~ +3 77 .1 ( c 1 .04 , CHC13); ee > 99% (determined as e thy l es ter by HPL C, W helkO1 ) ; RF, IR, IH N M R, 13C NM R and M S as descr ibed fo r ( - ) -2 ; Anal . ca lcd , fo r C10H1002 (162 .19) : C,74.06; H, 6.21; found: C , 73.86; H , 6.48.

(+)-(1 S, 2 R ) - t ra n s ( 2 - p h e n y l -c y c l o p r o p y l ) -e a r b a m i n i c a c i d tert. b u t y l e s t e r ( + ) - 5 . - Fo l l o w i n g t h eproce dure giv en for the preparat ion o f ( - ) -5 f ro m (+)-2 (0.18 g, 1 .09 retool) (+)-5 (0.15 g, 57%) w as obtaine dtogeth er with a small am ount o f s l ightly impure (+)-6 (11 rag) . Data for (+)-5: white sol id; m p 82-84 C; [a ]~+97 .0 ( c 0 .98 , CHC13) ; analy t ica l da ta as g iven fo r ( -) -6 ; Anal . ca lcd , fo r CI4 HI9 NO 2 (233.31) : C, 72.07; H,8.21; N, 6.00; fou nd: C, 71.93; H , 8.32; N, 6.18.

(+) - (1 S , 2 R ) - t r a n s 2 - p h e n y l - c y l o p r o p y l a m i n e , ( + ) - t r a n y l e y p r o m i n e , ( + ) - 1 .- F o l lo w i n g t heproce dure g iven for the preparat ion o f ( - ) -1 f ro m (+)-5 (0.15 g, 0 .65 retool) (+)-1 (0.06 g , 67% ) was obta inedas an oil ; [a ]~ +134 .9 (c 0.85, CHC I3); analytical data as give n for ( - ) -1; Anal . calcd, for C9H 11N (133.20) : C,81 .16 ; H , 8 .32 ; N , 10 .52 ; found: C, 80 .90 ; H , 8 .21 ; N , 10 .69 ; ee > 99% (as determined by HPLC af terder ivat iza t ion wi th phenyl - i socyana te ( ~ 7 ) on Chi ra lce l O D-R , vide supra).

A C K N O W L E D G M E N TFi n an c ia l s u p p o r t b y t h e E u r o p ean C o m m u n i ti e s ( SC 1 - C T 9 2 - 0 7 8 0 ) an d t h e Fo n d s d e r C h em i s ch en

Indus t rie i s g ra tefu l ly acknowled ged ; we are indeb ted to Prof. Dr. R. Neidle in, Ph ar m azeu t i s ch - C h em i s ch esIns t i tu t , Univer s i ta t Heidelberg , fo r h i s encouragement , to Miss A. Kersting, P h a r m a z e u t i s c h - C h e m i s c h e s



3512 R. CSUK et a l.

Ins t i tu t , Univer s i t / i t Heidelberg , fo r her sk i l l ed exper imenta l ass i s tance , to Dr. Thomas Litz , Inst i tut f .Pharmazeu t . Chemic , T U Braunschweig , fo r shar ing h i s know how on in-situ HPL C der ivat iza t ions in such agenerous way , to Novo Nor d i s k A /S , Bagsvard (Denmark) and Amano Enzyme Europe L td. , M i l t o n K ey n es(UK) fo r the generous donat ion o f enzymes , to Dr. P. Rosyk, Weinheim, fo r h i s he lp wi th the manuscr ip t andto Perkin-Elmer Ltd., Oberl ingen, for suppor t .

R E F E R E N C E S A N D N O T E S1 How ever , i t is also conceivab le that the enantiome r that is about to be discarded is mo difying

the ac t iv i ty o f the o ther enan t iomer .2 Stinson, S., C., C EN, October 9, 1995, 44-74.3 Rile y, T. N.; Brier, C. G., d. Med . Chem. 1972, 5, 1187-1188 and references cited therein.4 Mitscher , L. A.; Sharma, P. N.; Chu, D. T. W.; Shen, L. L.; Pem et, A. G. , J. Med. Chem. 1986,

29, 2044-2047.5 W alborsky , H. M.; Plonsker , L.; J . Am. C hem. Soc. 1961, 83, 2138-2144.6 Inouye , Y.; Sugita, T.; W alborsky, H. M., Tetrahedron 1964, 20, 1695-1699.7 Fr i tschi, H.; Leutene gger , U.; Pfal tz, A., Helv. Chim. Acta, 1988, 71, 1553-1565.8 Leuten egger , U.; Um bricht , G.; Fahrni , C.; von Matt , P.; Pfal tz, A., Tetrahedron 1992, 48,

2143-2156.9 Evans, D .A. ; W oe rpe l , K .A. ; Sc ot t , M .J . ,Ange w. Chem . 1992,104,439-441; ,4ngew. Chem.

Int. Ed. Engl. 1992, 31,430-432.10 Evan s, D. A.; Wo erpel , K. A.; Hinm an, M. M.; Faul , M. M., J . Am. Chem . Soc. 1991 ,113 ,

726-728.11 Lowe nthal , R. E.; Abiko, A.; Masa mune , S. , Tetrahedron Le tt. 1990, 31, 6005-6008.12 Haef ing er , W.; Kl( ippner, E., Helv. Chim. Acta 1982, 65, 1837-1852; Koskin en, A. M. P.;Munoz, L., J . Or g . Chem. 1993, 58, 879-886;13 The racem ate has already been descr ibed: Baumgarten, H. E.; Smith, H. L.; Staklis , A., d. Org.

Chem. 1975, 40, 3554-3561.14 Previously the formation of such carbam oyl azides dur ing Curtius degradat ion has been

observed: Nino miya , K.; Shioiri , T.; Yam ada, S. , Chem. Pharm. Bull . 1974, 22, 1398-1404;Nino miya , K.; Shioiri , T .; Yamada , S. , Tetrahedron 1974, 30, 2151-2157;

15 Rece ntly a sulfated cyclodextr ine chiral s tat ionary phase for HP LC has been descr ibed thusal lowing the direct determination o f 1 without the need of der ivat izat ion. U nfor tunately, thismater ial is not com merc ial available; Stalcup, A. M.; Gahrn, K. H., Anal . Chem. 1996, 68, 1369-1374.

16 Vin ce, R.; Turak hia, R. H.; Shann on, W. M.; Arnett, G., ,/..Med . Chem. 1987, 30, 2026-2030.17 Mori , A.; Arai , I . ; Yam amo to, H.; Tetrahedron 1986, 42, 6447-6458.

(Received in UK 19 September 1996)

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