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Tetrahedron Letters ,Vol. 36. No. 21. pp . 3715-3718, 1995Elsevier ScienceLtdPrinted in G reat Britain0040-4039/95 $9.50+0.00

E n a n t i o - a n d D i a s t e r e o d iv e r g e n t S y n t h e s i s o f A l l F o u r D i a s t e r e o m e r s o ft h e 2 , 6 - D i s u b s t i t u t e d 3 - P i p e r i d i n o l C h i r a l B u i l d i n g B l o c k

N a o k i To y o o ka , Y a s uko Y o s h i da , a nd Ta ke f um i M o m o s e *

Faculty of Pharm aceutical Sciences, Toyama M edical and Pharm aceutical Universi ty , Sugitani 2630. Toyam a 930-01, Japan

A b s t r a c t : E n a n t i o - a n d d i a s t e r e o d i v e r g e n t s y n th e s i s o f a l l f o u r d i a s t e r e o m e r s o f 2 , 6 -d i subs t i t u t ed 3 -p i per i d i no l has been ach i eved . The v er sa t i l i ty o f t hese compound s as t hech i r a l bu i l d i ng b l ock fo r a l ka l o i d syn t hes i s has been dem ons t r a t ed bo t h by t o t a l syn t hes i so f i s o - 6 - c a s s i n e a n d b y f o r m a l s y n t h e s is o f p r o s o p i n i n e , c a s s in e , a n d s p e c t a li n e .

N a t u r a l l y o c c u r r i n g 2 , 6 ( c i s o r t r a n s ) - d i s u b s t i t u t e d 3-p i per i d i no l s , such a s P r o s o p i s a n d C a s s ia a l ka l o i d s ,1have r ece i v ed muc h a t t en t i on ow i ng to a var i e t y o f the i r b i o l og i ca l ac t i v i t i es . Conse quen t l y , mu ch e f fo r t hasbeen d i r ec t ed t oward t he s t e r eose l ec t i ve syn t hes i s o f t hese a l ka l o i d s to da t e .2 A m o n g th e e f f o rt s a r e o u r r e c e n t

~ / ~ , , O HO ii, A : n = 10: cassine~ n = 12: spectaline) " t ( " " M eH

~ . ,,.OH C : R = HO(CH2)2: ulitloridineR ..... Me R = MeC (O): so-6-cassineH

~ , . . , OH ER" R = Me(CHz)3(CH=CH)3:micropineR"'" / OH -" R = EtC(O)(CH2)v prosophylline

iMeX F~ OH X = O: prosopininE t . , , ~ 9 .N .,,,, j. ,,.,/O D: X= H, OH:prosopine

Hrepo r t s on t he enan t i od i ve rgen t syn t hes i s o f c i s , c i s - t r i s u b s t i tu t e d 3-p i per i d i no l ch i r a l bu i l d i ng b l ock s3 and t he i rapp l i ca t i on t o t he syn t hes i s o f 3 -p i per i d i no l and i ndo l i z i d i ne a l ka l o i d s .5

In t h i s com mun i ca t i on , we wi sh t o r epo r t an a l t e rna t ive des i gn l ead i ng to t he enan t i o - and d i as t e r eod i verge n tsyn t hes i s o f t hese 3 -p i per i d i no l a l ka l o i d s f rom a s i ng l e p recu r so r .

F i r s t, w e e x a m i n e d t h e e n a n t i o d iv e r g e n t s y n th e s i s o f t h e k e y p i p e r i d o n e 1 . 6 T h e l i p a s e 7 - c a t a l y z e dt r a n s e s t e d f i c a t i o n o f t h e h y d r o x y e s t e r ( + ) - 1 , p r e p a r e d f r o m t h e N a B H 4 r e d u c t i o n o f a [ 3- ke to e s t e r ( 2 ), 8a f f o r d e d t h e a c e ta t e o f ( + ) -1 9 i n 4 7 % y i e l d ( > 9 9 % e e ) 10 a l o n g w i t h ( - )- 1 ( 5 2 % , 9 1 % e e ) . H y d r o l y s i s o f t h eace t a t e w i t h K2 CO3 gav e (+) -1 ( [o t]26 D +64 .3 ) 11 i n 90% y i e l d . The ena n t i om er ( - ) -112 was fo und t o bed e r i v e d m o r e e f f e c t i v e l y f r o m t h e b a k e r ' s y e a s t r e d u c t i o n o f 2 in h i g h o p t i c a l y i e l d ( 98 % e e ) . l 0 D i r e c tr ecrys t a l l i za t i on o f t he c rude r educ t i on p roduc t r esu l t ed i n o b t a i n i ng t he sca l emi c ( - ) -1 ( [x]26D -64 .5 ) i n 88%yi e l d . I n add i t i on , t he hyd rox y es t e r 1 was foun d i n t e r conve r t i b l e w i t h t he s t a r t i ng 13 -ke to es t e r (2 ) by theJones ox i da t i on in 80% y i e l d .

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o ". . . . OH b a lced s e a = O l ) N a BH 4 . E tO H , ( 9 2 %) ( - ) - 1 +tap w=ta r" C O = E t ( 8 8 % ) O c o 2 E t 2 ) v i ny l c = a ~ t ipa= PS, i -Pr20 , CO2 EtB n B n J B nK z C O 3 - - R = A c( - ) - I 2 J o n ~ c ~ i d n . 8 0 ~ ) F J O H l ~ . - ( + ) - 1 : R = HN e x t , w e e xa m i ne d t he d i a s t e re od i ve r ge n t s yn t he s is o f a ll f ou r d i a s t e r e ome r s o f 2 , 6 - d is ubs t it u t e d 3 -

piper id inol s t a r t ing w i th ( - ) - I . Th e 2,6(c is)-disubsti tuted 3-piper id inol chi ra l bui ld ing b lo ck for the type Aa l ka lo i d w a s s yn t he s i z e d a s f o l low s . P r o t e c ti on o f t he hyd r oxy l i n ( - ) - I a nd s ubs e que n t r e duc t ion o f theresul t ing p iper idone ( - ) -3 ( [a ]26D - I 15.4) a f forded the a lcohol ( - ) -4 ( [a ]26 D -46.2) , which was t rans formedinto the p ipe dd on e (-)-6 ([o~]26D 6 9.4) vi a the p henylthio ether (-)-S ([cx]26D -67.1). Conv ers ion of ( - ) -6 in tothe be nzyl e ther ( - ) -7 ( [cz ]26D - 60 . 9 ) a nd s ubs e que n t hom ol oga t i on a t t he l a c ta m c a r b ony l i n ( - ) - 7 v ia th eth io lac tam ( - ) -8 ( [(Z]26D -158.6) by the Esc henm oser ' s su l f ide-cont rac tion p rotocol 13 a f forded the v inylogo usurethane (+)-914 ([~]26D+50.7) . The ca ta ly ti c hydrogen a t ion of (+) -9 fo l lowed by protec t ion of the resul tinga mi ne p r ov i de d t he p i pe r i d ine ( - ) - I 0 ( [ a ] 26D - 10 .3 ) a nd s ma l l a moun t s o f a 4 : 1 mi x t u r e o f c is ( 2 , 6 )- a ndtrans(2,6)-N-benzylpiperic~nes. Hyd rogeno lys i s of ( - ) - I0 and p rotec tion of the resul ting a lcohol provided theurethan e (-)-11 ([(Z]26D -1.3). Red uct ion of (-)-11 furnished the alcoh ol (-)-12 ([ec]26D -2 9.9 , lit. 4a [a]26D-30.7) . As the t rans format ion of (- ) -12 or it s enant iom er (+) -12 in to (+) -spec ta line 4a and ( - ) -methyl N , O -diace ty l spic iger in a te 4b or in to ( - ) -cas s ine4a had been furni shed, the absolu te s t e reochemis t ry of ( - ) - I wasde te rmined t o b e 2R, 3 S .

--a ~ ' ~ : " O M O M c ~ " " O M O M o' ~ ' ~- : i( - ) - I

O " " N " " ' R O " - N " " "C H 2 R X " h r " M eB n B n B n

b r ~ ( - )- 3 : R = C O ~ t ~ _ _ ( . ) - s : R = S P h g r . - - ( . ). 1 : R = 0~ _ , . ( . ) . 4 : R = C H 2 0 H d ( . ) . 6 : R = H L . - , -( - )- S : R = S

h [ ' ~ 1 ' ' ' O B nM e O L ~ C / " ~ I ~ ' " M e M e O 2 C ~ . . . . . . . . M e H O ~ ' " ~ N / ' ' " M e

B n C O 2 ~ C O ~ e[ ' - - ( - ) . 1 0 : R = B n ( . ) . 1 2 ( 89 % )( + ) . 9 i , a L _ , . ( . ) . H : R = M O M ( 9 3 % )8.: MO MCI, HUnigbase, CH CI3, eflux (98%); b: Super-Hydride,0 C (96%); : PhSSPh, a-Bu 3P, pyridine(95%); d: R"neyNi (W-4) 95%);e: c. HCI,McOH, eflux; : Na il, BnBr, 80 C (84% in 2 steps); g: Lawesson'sreagent (96%);h: BICH2CO2M e hen Ph3P, Et3N (83%); : H2, Pal(OH)2,MeOH; : ClCO2Me,K2CO {68%yield in 2 steps and the starting (+)-9 n 20% recovery)

An othc r 2,6(cb)-d isubst i tuted 3-piperidinol for the type B alkaloid was synthesize d as fol lows. Th e alcoho l( - )- 4 w a s t r a ns fo r me d i n t o t he be nz y l e t he r ( - )- 13 ( [ a ]26D - 50 . 4 ) , w h i c h w a s c on ve n e d i n t o t he v i ny l ogou sure thanc (+) -1514 ( [a ]26D + 10.5) v ia the th io lac tam ( - ) -14 ( [a ]26D -179.5) . The ca ta ly t i c hydrog ena t ion of(+)-15 and pro tect ion of the rcsuhin g am ine afford ed the urethane (+)-16 ([C~]26D+37.6) . The PC C oxida t iono f ( + ) - 16 ga ve t he ke t one ( + ) - 17 ( [ c t ] 26D +110 . 4 ) , w h i c h w a s s ub j e c t e d , a f t e r hyd r oge no l ys i s , t o t heNaB (OA c)3H reduc t ion to furni sh the d io l (+) -18 ( [cz]26D +8.5) a s a sole produ ct . 15

( . ) .4 ~ " . J ' ' ' ' B ~ s ~ . .. ~ . . . . . . .o B . ~ M . ~ . v O B .B n B n B n( - ) - 1 3 ( - ) - 1 4 ( + ) - I S : R = H ( 5 3 % )


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d , e F . ~ I . . O H f . 0 d , g .O H(+ )- IS - -- , .M e O ~ ..~ .. . . . .K . , .N . ~ . /O B n - - M o O 2 C , . . . . ~ ' . . . . / O B n - M e O 2 C ~ ......~ '~ ../O H

COzMe COzMe COzMe(+)-16 (+).17 ()-ISa: Nail, BnB r 96%); b: Lawesson's eagent (90%); c: BrCH2CO2Me hen Ph3P, Et3N {53%of (+ )-15 and 31% of theMOM ether (R = MO M)I; d: H2, Pd(OH)2 MeOH; e: CICO2Me,K2CO {(+)-16 n 71% yield and the startin g (+)-15in 7% recoveav}; : PCC , AcONa 96%);g: NaB(OAc)3H,AcOH 86% in 2 steps)A 2,6(trans)-disubstituted 3 - p i p e r i d i n o l f o r t h e t y p e C a l k a l o i d w a s s y n t h e s i z e d a s f o l l o w s . R e d u c t i o n o f

( + ) - 9 w i t h N a B H 3 C N i n t h e p r e se n c e o f a c i d g a v e a 1 : 14 m i x t u r e o f th e cis (2,6)- and trans(2,6)-piper idines .H y d r o g e n o l y s i s o f t h e m i x t u r e o v e r P d ( O H ) 2 f o l l o w e d b y t r e a t m e n t o f t h e r e s u l ti n g a m i n e w i t h C 1 C O 2 M ep r o v i d e d trans-piperidine ( - ) - 1 9 ( [a ] 2 6 D - 1 . 1 ) i n 6 8 % i s o l a t e d y i e l d . T h e f t r s t s y n t h e s i s o f ( - ) - i s o - 6 - c a s s i n e(22 ) 16 ([Ct]26D -1 .517 , l i t . 18 [(X]25D +3 .3) f ro m (-) -1 9 v ia t h e a l c o h o l ( - ) -2 0 ( [ (x ]2 6D - 1 4 . 2 ) a n d t h e d i e n e 2 1w a s a c c o m p l i s h e d a s d e p i c te d b e l o w .

a ~' dF ~ . . O B n b ,c ~ . . . . O B n(+ ) -9 - M, ,N / . . . . , "n C O d V l ecLt'(2,6) : Ir~z.~B2,6)= I : 14 ( .) .19

A ~ , , , , , O B n e , f , . , , ~ , . , , , O B n g ,b ,h L ~ ''~OHH O " v - N / " . M e H

( - ) - 2 0 2 1 ( - ) - 22a: NaBH3CN. TFA, 0 C (99% of combinedyield); b: H2, Pd(OH) , M eOH; c: K2CO 3, CICO2Me(68%); d: S uper-Hydride 9:2%); e: Sw ern oxidn,; f: C H2=CH (CH2)gP+Ph3Br , n-BuL l (80% in 2steps); g: W acker oxidn. (64%); h: TM SI. CHCI (58% n 2 steps)F i n a l l y , a 2 , 6 ( t r a n s ) - d i s u b s t i t u t e d 3 - p i p e r i d i n o l f o r t h e t y p e D a l k a l o i d w a s s y n t h e s i z e d a s f o l l o w s .

R e m o v a l o f t h e m e t h o x y m e t h y l i n ( - ) - 1 3 a n d P C C o x i d a t io n o f t h e r e s u l ti n g a lc o h o l g a v e t h e s c a l e m i c k e t o n e( + ) - 2 3 ( [0 t] 26 D + 1 1 8 . 6 ) i n 8 3 % y i e l d a f t e r r e c r y s t a l l i z a t i o n f r o m i - P r 2 0 . H y d r o g e n o l y s i s o f ( + ) - 2 3 a n ds u b s e q u e n t r e d u c t i o n w i t h N a B ( O A c ) 3 H p r o v i d e d t h e t r a ~ - d i o l ( - ) -2 4 ( [ a ]2 6 D -4 0 .3 ) a s a so l e p ro d u c t . 1 9P r o t e c t i o n o f ( - ) - 2 4 a f f o r d e d t h e d i b e n z y l e t h e r ( - ) - 2 5 ( [ 0t ] 26 D -4 6 . 7 ) , w h i c h w a s t r a n s f o r m e d i n t o t h ev in y lo g o u s u re th a n e (+) -2 7 1 4 ( [o ( ]2 6D + 2 3 . 5 ) v ia t h e t h io l a c t a m ( - ) -2 6 ( [ ( z]2 6D - 1 0 5 . 9 ). R e d u c t i o n o f ( + ) - 2 7w i t h N a B H 3 C N i n t h e p r es e n c e o f a c i d g a v e a 1 :8 m i x t u r e o f t h e 2,6-cis- a n d 2,6-trans-piperidine i n 8 9 %c o m b i n e d y i e l d , a n d f r a c t i o n a t i o n b y r e p e a t ed c h r o m a t o g r a p h y a f f o r d e d t h e p u r e t r a a x - p i p e d d i n e ( - ) -2 8 ( [ ct ]2 6D- 2 3 . 2 ) i n 5 3 % i s o l a t e d y i e l d . R e d u c t i o n o f ( - ) - 2 8 w i th L iA 1 H 4 p r o v i d e d t h e a l c o h o l ( - ) - 2 9 ( [0 ~]2 6D -3 7 .9 ) ,w h o s e a p p l i c a t io n i n i t s r a c e m i c f o r m t o t h e s t e r e o s e le c t iv e s y n t h e s i s o f p r o s o p i n i n e w a s r e p o r t e d b y S t i l le .2a,b

a , b( . ) - 13 O . . . . . B nB n( + ) - 23g . ~ ' F T O B n h

M eO ~ J , .~ . L , ,, ,N . . .) . .. .. I O B nB n( + ) . 2 ' I

O / O R S. .....~ , ,. / . ' ~ . . . / O B nB n B nc ~ ( - ) - 2 4 : R - H ( ) - 2 6~ ( - ) - 2 5 : R - B n, F / ~ O B n i . [ I ~ O B n

a O 2 C, ., ,. .. ,L~ N . .. .P . . .. ./ O n H O . / - , . . d , J -~ . . ) . . . . O anB n B n( - ) - 2 8 ( - ) - 2 9a: c. HCI.MeOH, reflux;b: PCC. AcONa 83% n 2 steps);c: H , Pd(OH)2, MeOH;d: Na,B(OAc)jH.AcOH 97% n2 steps); e: KOH )BnB r, MS 4A (79%); f: L awesson's eagent(94%); g: B rCH2CO2Me hen Ph3P, Et3N (92%);h:NaBH3CN.TFA,0 C; i: LiAIH , THF. eflux 84%)


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F o u r d i a s t e re o m e r s o f 2 , 6 ( c i s o r t r a n s ) - d i s u b s f i t u t e d 3 - p i p e r i d i n o l { ( - ) - 1 2 , ( + ) - 1 8 , ( - ) - 2 0 , a n d ( - ) - 2 9 } t h u so b t a i n e d a n d t h e c o u n t e r e n a n t i o m e r ( + ) - 1 w o u l d s e r v e as p r o m i s i n g e h i r a l b u i l d i n g b l o c k s f o r t h e s y n t h e s i s o fo t h e r 3 - p i p e r i d i n o l a l k a l o i d s , a n d a d d i t i o n a l s t u d i e s o n t h e s y n t h e t i c u t i li t y o f t h e s e h e t e r o c y c l e s a r e in p r o g r e s s .R E F E R E N C E S A N D N O T E S1 . S t m n z , G . M . ; F i n d l a y , J . A . I n The Alkaloids; B r o s s i , A . , E d . ; A c a d e m i c P r e s s : N e w Y o r k , 1 9 8 5 ; V o l . 2 6 , p p 8 9 - 1 8 3 .W a n g , C . - L . J. ; W u o n o l a , M . A . Org. Prep. Prec. Int. 1 9 9 2 , 24 , 5 8 5 - 6 2 1 . P i n d e r , A . R . Nat . Prod. Rep. 1 9 9 2 , 9 , 4 9 1 -5 0 4 . P i n d a r , A . R . Nat. Prod. Rep. 1 9 9 2 , 9 , 1 7 -3 5 . P i n d e r , A . R . Nat. Prod. Rep. 1 9 9 0 , 7 , 4 4 7 - 4 5 5 .2 . N o n c h i r a l s y n t h e s i s : ( a ) C o o k , G . R . ; B e h o l z , L.. G . ; S t il l e , J . R . Tetrahedron Lett . 1 9 9 4 , 3 5 , 1669 -1672 . Co) Co ok , t3 .R . ; B e h o l z , L . G . ; 8 t i l l e , J. R. J. Org. Chem. 1 9 9 4 , 5 9 , 3 5 7 5 - 3 5 8 4 . ( c ) N a t s u m e , M . ; O g a w a , M . Heterocyc l e s 1 9 8 0 ,1 4 , 1 6 9 - 1 7 3 . ( d ) N a t s u m e , M . ; O g a w a , M . H e t e r o c y c l e s 1 9 8 0 , 1 4 , 6 1 5 - 6 18 . ( e) N a t s u m e , M . ; O g a w a , M .Heterocycles 1 9 8 1 , 1 6 , 9 73 - 9 7 7 . ( t ) N a t s u m e , M . ; O g a w a , M . Heterocycles 1 9 8 3 , 20 , 6 0 1 - 6 0 5 . ( g ) H o l m e s , A . B . ;T h o m p s o n , J . ; B a x t e r , A . J . 1 3 . ; D i x o n , J. J. Chem. Se e. , Chem. C ommun. 1 9 8 5 , 3 7 - 3 9 . ( h ) B i r k i n s h a w , T . N . ;H o l m e s , A . B . Tetrahedron Lett . 1 9 8 7 , 28 , 8 1 3 - 8 1 6 . ( i ) P a t e m e , M . ; B r o w n , E. J . Chem. Res . 1 9 8 5 , 2 7 8 - 2 7 9 . ( j )H a s s e b e r g , H . - A . ; G e r l a c h , H . Ann. Chem. 1989 , 255-2 61 . Ch i r a l s yn th e s i s : (k ) I - Ia ne s sia n , 84 F re n e t te , R . TetrahedronLet t . 1 9 7 9 , 3 3 9 1 - 3 3 9 4 . ( I) $ a l t o h , Y . ; M o r i y a m a , Y . ; T a k a h a s h i , T . ; K h u o n g - H u u , Q . Tetrahedron Lett . 1 9 8 0 , 21 , 7 5 -7 8 . ( m ) S a i t o h , Y . ; M o r i y a m a , Y . ; H i r o t a , H . ; K h u o n g - H u u , Q . Bull. Chem. Soc. Jpn. 1 9 8 1 , 54 , 488 - 492 . (n )C i u f o l i n i , M . A . ; H e r m a n n , C . W . ; W h i t m i r e , K . H . ; B y r n e , N. E. J. Am. Chem. Soc. 1 9 8 9 , 1 1 1 , 3 4 7 3 - 3 4 7 5 . ( o ) L u ,

Z . - H . ; Z h o u , W . - S . Tetrahedron 1 9 9 3 , 49 , 4 6 5 9 - 4 6 6 4 . ( p ) T a d a n o , K . ; T a k a o , K . ; N i g a w a r a , Y . ; N i s h i o , E . ; T a k a g i , I . ;M a e d a , K . ; O g a w a , S . S Y N L E T T 1 9 9 3 , 5 6 5 - 5 6 7 . ( q ) T a k a o , K . ; N i g a w a r a , Y . ; N i s h i o , E . ; T a k a g i , I 4 M a e d a , K . ;T a d a n o , K . ; O g a w a , S . Tetrahedron 1 9 9 4 , 50 , 5 6 8 1 - 5 7 0 4 .3 . M o m o s e , T . ; T o y o o k a , N . ; J i n , M . Tetrahedron Lett . 1 9 9 2 , 33 , 5 3 8 9 - 5 3 9 0 .4 . ( a ) M o m o s e , T . ; T o y o o k a , N . Tetrahedron Lett . 1 9 9 3 , 34 , 5 7 8 5 - 5 7 86 . ( b ) M o m o s e , T . ; T o y o o k a , N . Heterocyc l e s1 9 9 5 , 40 , 1 3 7 - 1 3 8 .5 . M o m o s e , T . ; T o y o o k a , N. J . O rg. Chem. 1 9 9 4 , 59 , 9 4 3 - 9 4 5 .6 . T h e p i p e r i d o n e o f t y p e 1 h a s b e e n u t i l iz e d a s a k e y c o m p o u n d f o r s t e r e o s e l e c d v e s y n t h e s i s o f a l k a l o i d s i n r a c e m i c f o r m s i nt h e p i o n e e r in g w o r k b y S t i l l e. 2 a , b W e p l a n n e d t h e e f f ic i e n t a n d c o n v e n i e n t , m o r e o v e r , ch i r a l c o n s t r u c ti o n o f t h i she te rocyc le .7 . W e a re g ra t e f u l t o A m a n o P h a r m a c e u t i c a l C o . , L t d . f o r t h e g e n e r o u s g i ft o f l i p a s e P S .8 . B o n j o c h , J . ; S e r r e t, I . ; B o s c h , J . Tetrahedron 1 9 8 4 , 40 , 2 5 0 5 - 2 5 1 1 .9 . Sa t is f a cto ry a na ly t i c a l a nd s pe c t r a l da ta we re ob ta ine d fo r a l l ne w c om poun ds .1 0 . T h e v a l u e o f e e w a s d e te r m i n e d b y H P L C a n a l y si s u si n g a c o lu m n p a c k e d w i th C H I R A L P A K A S ( D a i c e l C h e m i c a l C o . ,L t d . , i - P r O H : n - h e x a n e = l : 3 ) .1 1 . O p t i c a l r o t a t i o n s w e r e t ak e n i n c h l o r o f o r m u n l e s s o t h e r w i s e s t a t ed .

1 2 . T h e r e l a t iv e s t e r e o c h e m i s t r y o f ( -) - 1 w a s d e t e rm i n e d t o b e c / s b y t h e X - r a y c r y s t a l lo g r a p h i c a n a l y s i s . C r y s t a l l o g r a p h i c d a t afo r ( - ) - I : m o noe l in ic , s pa c e g ro up 1>21 , w i th a = 7 .052 (2 ) A , b - -- 11 .937(1 ) ,~ , c = 9 .521 7(9 ) A , f l = 106 .54(1 )*V = 768 .4 (2 )A 3 , a n d Z = 2 ( d e a l e d = 1 . 19 9 g e r a ' 3 ) , # ( M o K a ) = 0 . 8 7 c m " 1 a b s o r p t i o n c o r r ec t e d b y t o s ca n s ; 1 8 5 6 u n i q u e r e f l e c t i o n s ;8 7 9 w i t h ! > 3 . 0 0 ~ ( / ) w e r e u s e d i n r e f i n e m e n t ; R = 5 . 4 % , R w = 7 . 6 % . T h e a u t h o r s h a v e d e p o s i t ed a to m i c c o o r d i n a t e f o r( - ) - 1 w i t h t h e C a m b r i d g e C r y s t a l lo g r a p h i c D a t a C e n t r e . T h e c o o r d i n a t e c a n b e o b t a i n e d , o n r e q u e s t , f r o m t h e D i r e c t o r ,C a m b r i d g e C r y s t a l l o g r a p h i c D a t a C e n t r e , 1 2 U n i o n R o a d , C a m b r i d g e , C B 2 1 E Z , I l K .1 3 . R o t h , M . ; D u b s , P . ; G t t s c h i , E . ; E s c h e n m o s e r , A. Heir. Chim. Acta 1 9 7 1 , 5 4 , 7 1 0 - 7 3 4 .1 4 . A s i n g l e i s o m e r w a s i s o l a te d , b u t t h e s t e r e o c h e m i s t ry o f t h e o l e f i n m o i e t y w a s n o t d e t e r m i n e d1 5 . A n a u t h e n t i c s a m p l e o f t h e c o r r e s p o n d i n g c / s d io l w a s p r e p a r e d f ro m t h e h y d r o g e n o l y s i s o f ( + ) - 1 6 o v e r P d ( O H ) 2 .1 6 . T h e s y n t h e t i c ( - ) - 2 2 w a s i d e n t ic a l i n i t s 1 H a n d 1 3C N M R d a t a w i t h t h e n a t u r a l p r o d u c t . 1 7 S p e c t r o s c o p i c d a t a f o rs y n t h e t i c ( - ) - 2 2 : 1 H N M R ( 5 0 0 M H z , C D C I 3 ) 8 : 1 . 0 7 ( 3 H , d , J = 6 . 5 H z ) , 1 .1 7 -1 . 38 ( 1 4 H , b r ) , 1 .4 5 - 1. 5 8 ( 4 H , m ) , 1 . 5 9-1 .73 (3H, m ) , 1 .84 (1H, t t , J = 9 .0 , 4 .3 Hz ) , 2 .13 (3H , s ) , 2 .41 (2H , t , J = 7 .5 Hz ) , 2 .81 ( IH , qu in te t - l ike , J = 3 .1 Hz ) , 3 .10( I H , q d , J = 6 . 5 , 3 .1 H z ) , 3 . 6 6 ( 1 H , q u i n t e t - l i k e , J = 3 . 1 H z ) ; 1 3 C N M R ( 7 5 . 5 M H z , C D C I 3 ) 8 : 1 5 . 8 7 , 2 3 . 8 4 , 2 6 . 6 2 ,2 7 . 7 1 , 2 9 . 1 5 , 2 9 . 3 6 , 2 9 . 4 1 , 2 9 . 5 0 , 2 9 . 5 6 , 2 9 . 6 7 , 2 9 . 8 3 , 3 3 . 0 1 , 4 3 . 8 0 , 4 9 . 6 7 , 5 0 . 0 8 , 6 9 . 2 2 , 2 0 9 . 3 9 .1 7 . T h e v a l u e o f t h e o p t i c a l ro t a t i o n o f t h e s y n t h e t i c (- ) - 2 2 w a s n o t c h a n g e d a f t e r r e c r y s t a l l i z a ti o n o f i t s h y d r o e h l o r i d e ( m p1 1 8 - 1 2 0 * C , l i t. 1 7 m p 1 2 3 * C ) f r o m E t O A c .18 . Ch r i s to f id i s , 14 W e l te r , A . ; J a do t , J . Tetrahedron 1 9 7 7 , 33 , 9 7 7 - 9 7 9 .1 9 . A n a u t h e n t i c s a m p l e o f t h e c o r r e s p o n d i n g c / s d i o l w a s p r e p a r e d fr o m t h e h y d r o g e n o l y s i s o f a n a lc o h o l w h i c h w a s o b t a i n e d b yt h e r e m o v a l o f t h e m e t h o x y m e t h y l o f ( - )- 1 3 w i t h a c i d .

( R e c e i v e d i n J a p a n 2 7 J a n u a r y 1 9 9 5 ; r e v i s e d 2 2 M a r c h 1 9 9 5 ; a c c e p t e d 2 9 M a r c h 1 9 9 5 )

1 s2.0 004040399500661u main(carbamate monomethylation)

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