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P e r ga m on Tetrahedron: Asymmetry, Vol. 7, No. 6, pp. 1591-1594, 1996Copyright 0 1996 Elsevier Science LtdPrinted in Great Britain. All rights reservedPII : S0 95 7-4 16 6(9 6)0 01 89 -9 0957-4166/96 $15.00+ 0.00

Synthes is of En antiopure 3,4-Disubstituted Piperidines.An Asy mm etric Sy nth es i s of (+)-Paroxet ineM e r c e d e s A m t , J o s e H i da lg o , a n d J oa n B o s c h

Laboratoryof Organic~ i s t r y , F a c u l t yof Pharmacy,Universityo f Bm~elona, 08028-Barcelona,Spain.

A bs t ra c t : An asym metr ic synthes is of the 3 ,4- t rans-disubst itu ted p iper id ine der iva tive (+) -paroxe t ine f rom the chi ra l non racem ic lac tam 1 i s reported . The p- f luoroph enyl subst i tuent isin t roduced by conjuga te addi t ion to the unsa tura ted lac tams 3 whereas the a ryloxymethylsubst i tuent a t the 3-posi t ion i s assembled b y taking advantage o f the ac t iva t inga lkox ycarbo nyl group of 3 . Copyright 1996 Elsevier Science LtdParoxe t ine i s a po tent and se lec t ive inhibi tor of 5-hydrox ytryptam ine uptake , wi th a reduced

pro pen sity to cau se the side-e ffects usu ally associated with tr ic yclic antidepressants. 1 I t is anenant iomer ica l ly pu re [ ( - ) -enant iomer] t rans-3 ,4-disobst i tu ted p iperid ine , and the o nly repor ted synthes is ofth is drug involves the resolut ion o f an adv anced racem ic intermedia te . 2

I n t he c on te x t o f ou r s tud i es3 on the synthesis of diverse ly substituted enan tiopure piperidines fromthe chi ra l non- raeemic lac tam 1, we repor t he re an enant iose lec t ive synthes is of the (+) -enant iomer ofparoxetine. This requ ires the stereoselective introd uction o f substituents at the piperidine 3- and 4-posit ions.

The p- f luorop hen yl subst i tuent a t the p iper id ine 4-posi t ion was in t roduced by con juga te addi t ion tothe unsa tura ted lac tams 3a and 3b. T he a lko xycarbo nyl group in 3 not only provides an addi t iona l ac t iva t iontowards the conjuga te addi t ion4 but i s a lso the precursor of the hydroxymethyl group required for thesubsequent assembl ing o f the a ryloxym ethyl subst iment a t the p iperid ine 3-posi t ion . The synthe t ic sequenceis depic ted in Schem e 1 .

Bicyc l ic lac tam 13a was co nver ted to selenldes 2a (85%) and 2 b (77% ) (d ias te reomer ic mixtures) in aone-po t reac t ion involv ing the sequent ia l t r ea tment of 1 wi th l i th ium hexamethyldis i laz ide , m ethyl (orbe nz y l ) c h lo r o f o rm a te , a nd pheny l se l ene ny l b r om ide . 50 z on o lys i s o f s e l e uide s 2a a nd 2b ga ve thecor respond ing unsa tura ted lac tams 3 a an d 3b which, w i thout puri fica tion ,6 were a l low ed to reac t wi th l ith ium(p- f luorophenyl)eyanocupra te to g ive the t rans-3 ,4-disubst i tu ted p iper id ines 4a7 and 4b 8 in 80% a nd 70%ove r a ll y i e ld f r om 2a a nd 2b , r e spe c tive ly . On ly m inor m ou n t s ( < 5 %) o f t he cis i somers were de tec ted byNM R . I n t he s e r i es b , i t wa s de m ons t r a t ed tha t t he m ino r cis i som e r wa s t he e p im e r o f 4b a t t he C - 3 pos i ti ono f t he p ipe dd ine r i ng be c a use t he m ix tu r e o f cis-trans es te r s was conver ted to a s ingle enant iopure 4-subst itu ted p iper id ine 59 by debenz yla t ion fo l lowed b y decarboxy la t ion [ i) NI -I4+HCO2 , Pd-C, M eOH ; i i)toluene, ref lux] .

1591

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1592 M. AMAT et a l .

Se R

Se R 8eR SeR ~

i . ~ ii ~ iii 0 0 ' ivOo o 4 @seR 2 a R = Me 3b R = B n

c

0 0 0 S 0C C C7 R = H R = B o c8 R=B oc ix ~-~10 R= H (+)-ParoxetineS c h e m e 1 . R e a g e n t s a n d c o n d i t i o n s : i ) HMDSLi (2 .2 equiv) , CICO2R (1 .0 equiv) , -78oc , THF, thenC 6H 5S e B r ( 1 .4 e qu iv ) ; ii ) 03 , - 78 C to 25o c , C H2C 12; i ii ) ( p - F C 6H4) C uC N Li , - 78o c , THF ; i v ) L iA1H4-AIC13, TH F, -78 oc ; v) H2, Pd(OH )2, MeO H; vi ) H2, (Bo c)20 , Pd(OH )2, AcO Et; v i i) MsC1, pyr , 10C; v ii i)3 ,4- (methylenedioxy)phenol , NaOMe, MeOH, re f lux; ix) TFA, CH2C12.

The re la t ive conf igura t ion wi th in 4b was de te rmined by N OE exper iments , thus conf i rming tha t thecuprate additions to 31) procee d, as m ention ed earlier, 3b from the ~t face o f the piperidine r ing.Trea tment of 4a wi th a lane , genera ted in s i tu f rom A IC13 and LiA1H4, accompl ished the reduc t ion of

both the lac tam carbonyl group and the es te r func t ion as we l l a s the reduc t ive c leavage of the oxazol id iner ing to g ive the p iper id ine d io l 610 in 74% yie ld in a s ingle synthe t ic s tep . Th e sam e diol 6 was obta ined in60% yie ld s ta rt ing f rom the benz yl es te r 4b . Th e t r ans diequa tor ia l r e la tionship be tween the hydrox ym ethyland p- f luorophenyl subst i tuents was evident f rom the mul t ip l ic i ty and coupl ing constants of the p iper id inep r o tons in t he 1H - NM R spe c tr um .

The c h i ra l a ux i l ia r y wa s r e m ove d b y hydr oge no lys i s t o g ive t he s e c onda r y a m ine 7 , a l t hough f r om thesynthe t ic s tandpoint i t was more convenient to ca r ry out th is reac t ion in the presence of d i - te r t -butyld ica rbona te 11. Un der these co ndi t ions , the N-protec ted amine 8 w as ob ta ined in 73% yield . T he a ryl e therm oie ty o f pa r oxe t ine w a s i nc o r po r a te d ( 57% ove r a ll y i e ld ) by m e sy la t i on o f t he hy dr oxy g r oup o f 8 f o l lowe dby reac t ion of the resul ting mesy la te 9 w i th sodium 3,4- (methylenedioxy )phenoxide .

F ina l ly , deprotec t ion of the N-B oc der iva t ive 10 wi th T FA provided (+) -paroxe t ine 12 in 94% yield .This synthe t ic mate r ia l was ident ica l in a l l r espec ts (TLC in severa l so lvent mixtures , IR , IH-NMR, I3C-NM R) w i th an authent ic sample of pa roxe t ine ext rac ted f rom com merc ia l Seroxa t~ except for the s ign of theopt ica l ro ta tion {[CX]o z +81.7 (c 1.3, MeO H); sam ple fro m S eroxat [a ]D22 -89.4 (c 1.6, M eO H)} .

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Enan tiopure 3,4-disubsti tuted piperidines 1593

The synthes is o f (+) -paroxe t ine repor ted here fur ther i l lus t ra tes the potent ia l o f b icyc l ic lac tam 1 forthe synthes is o f d iverse ly subst i tu ted enant iopure p iperid ines.

Ac knowle dgm e n t : F ina nc i a l suppor t f r om the DG I C Y T, S pa in ( P r o j e c t P B 94- 0214) i s g r a t e f u l lyacknowledged. Thanks a re a lso due to the "Comiss iona t pe r a Univers i ta ts i Recerca" , Genera l i ta t deCata lunya , for Grant SG R95-0042 8 and to the "Minis te r io de Educac i6n y Cienc ia" for a fe llowship to J . H.R e f e r e n ce s a n d N o t e s

1 . Dru gs Fut . 198 6 ,11 , 112.2. a) Christense n, J . A. ; Squires, R. F. ,Ger . Patent 2,404,113, 1974; C h e n t A b s . 1974, 81 , 152011q. b)

Christensen, J . A. ; Squires, R. F. , U. S. Patent 4,007,196, 1977. c) Barnes, R. D. ; Wood-Kaczmar, M.W.; Richanison, J . E. ; Lynch, I . R. ; Buxton, P. C. ; Curzons, A. D. , European Patent 0 223 403, 1987.

3. (a) Am at, M.; Llor , N. ; Bosch , J . Tetrahedron Left . 1 9 9 4 , 35 , 2223. (b) Am at, M.; Llor , N. ; Hidalgo, J . ;Hern(mdez , A.; Bosch, J . T e t rah e dron : A sy m m e t r y 1996, 7, 977.4 . An a lko xycarbon yl group is necessa ry for the success of conjuga te addi t ions to unsa tura ted f ive 4a,b

a nd s ix - m e m be r e d~ lactams: (a) Meyers, A. I . ; Snyder , L. J . Org . Chent 1 9 9 2 , 57, 3814. (b) Meyers,A. I . ; Snyder , L. J. Org. Chent 1993, 58 , 36. (c) Overman, L. E. ; Robichaud, A. J . J . A nt C hent Soc.1989, 1 1 1 , 3 0 0 .

5. Al l y ie lds a re f rom mate r ia l pur i fied by column chromatography. Sa t is fac tory ana lyt ica l and/orspec t ra l da ta were ob ta ined for a ll new compou nds .

6 . Lac tam s 3 proved to be some what uns table , g iv ing the cor responding 2-pyr idones by opening o f theoxazol id ine r ing .

7. 4a: 1H-N MR (CDC13, 500 M Hz ) 5 2.33 (ddd, J= 14.5, 9.0, 5.0 Hz, 1H, H-8); 2.43 (dt, J = 14.5, 4.5 Hz,1H, H-8); 3.63 ( td, J= 9.0, 4.5 Hz, 1H, H-7); 3.64 (s, 3H, CH3); 3.64 (d, J = 9.0 Hz, 1H, H-6); 3.80 (dd,J = 8.5, 7.0 Hz, 1H, H-2); 4.50 ( t , J = 8.5 Hz, 1H, H-2); 4.90 (k J = 4.5 Hz, 1H, H-8a); 5.44 ( t , J= 8.0Hz, 1H, H-3); 6.94 ( t , J= 8.5 Hz, 1H, m-FC6 H4); 7.11 (dd, J= 8.5, 5.0 Hz, 1H, o-FC6 H4); 7.16-7.22(m, 3H, C6H 5); 7.26 (m, 2H , C6I-I5) . 13C-NM R (CDCI3, 75 M Hz ) ~ 33.1 (C-8); 37.2 (C-7); 52.2(CH3); 54.1 (C-6); 58.5 (C-3); 71.5 (C-2); 85.6 (C-8a); 115.5 (Jc_F = 21.0 Hz , m-FC 6H4); 126.0 (o-C6H5); 127.6 (p-C6H5); 128.3 (Jc.v= 7.3 Hz, o-FC6I-I4); 128.6 (m-C6H5); 136.2 (ipso-C6H5); 139.2( ip so-FC6H4) ; 161.5 (Jc_F= 2 45.0 H z, p-FC 6H 4); 165.8 (C =O ); 169.2 (C= O). [~]D 22 -37.1 (C 0.5,CH2C12).

8. 4b: 1H -NM R (CDC13, 300 M Hz ) 8 2.31 (ddd, J-- 14.5, 9.5, 5.0 Hz, 1H, H-8); 2.44 (dr, J = 14.5, 4.3 Hz,1H, H-8); 3.62 ( td, J-- 9.5, 4.3 Hz, 1H, H-7); 3.75 (d, J = 9.5 Hz, 1H, H-6); 3.81 (dd, J= 8.8, 7.5 Hz,1H, H-2 ); 4.51 ( t , J= 8.8 Hz, 1H, H-2); 4.91 ( t , J= 4.8 Hz, 1H, H-8a); 5.06 (d, J= 12.0 Hz, 1H,CH2C6I-I5); 5.10 (d, J= 12.0 Hz, 1H, C H 2C ~5 ); 5.47 ( t , J = 7.8 Hz, 1H, H-3); 6.97 ( t, J= 8.5 Hz, 1H,m-FC_oH4); 7.05-7 A0 (m, 12H, At) . 13C-NM R (CDC13, 50 M Hz ) f i 33.4 (C-8); 37.3 (C-7); 54.6 (C-6);58.6 (C-3); 67.0 (C H2C 6Hs); 71.5 (C -2); 85.7 (C-8a); 115.6 (Jc_F= 21.0 Hz , m-FC6 H4); 126.1 (o-C6H5); 135.2 (ipso-C6H5); 136.0 ( ip so-C6Hs) ; 139.3 ( ipso-FC6H4); 161.2 (Jc .F= 24 5.0 Hz, p-FC6H 4);166.1 (C =O ); 168.6 (C= O). [Ct]D 2 -52.2 (c 0.5, CH2C12).

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1594 M. AMA T et al .

9. 5: 1H-NMR (CDC13, 500 M Hz) 8 2 .17 (ddd, J= 13.5 , 6.0, 4.0 Hz , 1H , H-8 ); 2.41(ddd, 13.5, 7.5, 5.0 Hz, 1H, H-8 ); 2.75 (d, J= 5 . 5 H z , 2H, H-6); 3.43 (m, 1H, H-7); ~ ' . f---x3.69 (dd, J = 9.0 7.5 Hz, 1H, H-2); 4.48 (t , J = 8.5 Hz, 1H, H-2); 4.76 (t , J= 5.5 Hz,1H, H-8a); 5 .38 ( t, J = 7 .5 Hz , 1H, H-3) ; 7 .05 ( t, J= 8 .5 Hz , 2H, m -F C ~4 ); 7 .22 (m, L J4H, At ' ); 7.27 (m, 1H, Ar); 7.34 (m, 2H, Ar). 13C-NMR (CDCI3, 50 MHz) 8 33.67(C-7); 34.6 (C-8); 37.3 (C-6); 58.2 (C-3); 72.0 (C-2); 86.1 (C-Sa); 115.5 (Jc .F = 21.0 [ ~Hz, m-FC6H4); 125 .8 (o-C6H5); 1 27 .6 (p-C6H5); 128.1 (Jc .F= 7.3 Hz, o-FC6H4);128.8 (m-C6H5); 137.5 ( ipso-C6H5); 139.8 ( ipso-FC6H4); 161.5 (J_F= 245.0 Hz , p- cFC6I-I4); 168.8 (C =O ). [tZ]D 2 +15.1 (c 0.5, C H2C12).

10. 6: 1H -NM R (CDC13, 300 M Hz) 8 1 .65 (t , J= 11.0 Hz, 1H, H-2ax); 1.70-1.95 (m, 3H, H-3 and 2 H-5);2.14 (t , J= 11.3, 4.6 Hz, 1H, H-4ax); 2.37 (td, J= 11.5, 3.3 Hz, 1H, H-6ax); 2.39 (b r s , 2H , 2 OH); 2.95(din, J = 11.5 Hz, 1H, H-6eq); 3.09 (dd, J= 11.0, 7.3 Hz, 1H , CH 20 ); 3.18 (din, J = 11.0 Hz, 1H, H-2eq);3.30 (dd, J = 11.0, 3.2 Hz, 1H , CH 20 ); 3.63 (dd, J = 10.4, 5.0 Hz, 1H, NCHCH 2); 3.77 (dd, J = 10.4, 5.0Hz, 1H, NCH CH2); 4 .04 (t , J= 10.4 Hz , IH , NC H); 6.92 (t, J= 8.8 Hz, 2H, m-FC6H 4); 7.06 (dd, J=8.8, 5.6 H z, 2H, o-FC6I-I4); 7.19 (m , 2H, C6H 5); 7.32 (m, 2H, C6I-I5). 13C-NM R (CDC 13, 50 M Hz) 835.0 (C-5); 44.2 (C-3); 44.6 (C-4); 49.3 (C-6); 53.2 (C-2); 60.0 (CHCH2); 63.6 (CH20); 70.1 (NCH);115.2 (Jc_F 21.0 Hz, m-FC6H 4); 127.9 (p-C4~5); 128 .2 (o-C6H5); 128.6 (Jc_F 7.3 Hz, o-FC6H4);128.9 (m-C6Hs); 135.1 ( ipso-C6Hs); 139 .7 ( ipso-FC6H4); 16 1.0 (Jc_F 245.0 Hz , p-FC 6I-I4). [Ct]D 2+31.4 (C 0.5, MeOH).

11. Sai to, S.; Nak ajima, H.; Inaba, M.; Moriwake, T. Te trahed ron Le t t. 1989, 3 0 , 837.12. 11: 1H-NM R (CD CI3, 300 MH z) ~ 1.75 (qd, J= 12.0, 4.0 Hz , 1H, H-5ax); 1.80 (m, 1H, H-5eq); 2.10

(m, 1H, H-3ax); 2.60 (td, J= 12.0, 5.0 Hz, 1H, H-4ax); 2.71 (t , J= 12.0 Hz, H-2ax); 2.77 (td, J = 12.0, 3.0Hz, 1H, H-6ax); 3.21 (din, J-- 12.0 Hz, 1H, H-6eq); 3.42 (m asked, 1H, H-2eq); 3.43 (d d, J = 9.5, 7.0 Hz,1H, CH2); 3.56 (dd, J= 9.5, 3.0 Hz, 1H , CH2); 5.88 (s, 2H, OC H2 0); 6.12 (dd, J = 8.5, 2.5 Hz, 1H, H-6'); 6.33 (d, J= 2.5 Hz, 1H, H-2'); 6.61 (d, J= 8.5 Hz, 1H, H-5'); 6.98 (t , J= 8.8 Hz, 2H, m-FC6H4);7.15 (d d, J= 8.8, 5.5 H z, 2H, o-FC6H4). 13C-NM R (CDC13, 50 M Hz ) ~ 35.2 (C-5); 42.8 (C-3); 44.4(C-4); 46.8 (C-6); 50.2 (C-2); 69.3 (CH 20) ; 97.7 (C-2'); 1 00.9 (OC H2 0); 105 .3 (C-6'); 107 .6 (C-5');115.1 (J_F= 21.0 Hz , m-FC6I-I4); 128 .5 (Jc .F = 7.3 Hz, o-FC6I-I4); 139 .8 ( ip so-FC6H4) ; 141.3 (C-3');147.9 (C-4'); 154 .2 (C-1'); 160 .5 (J_F 245.0 Hz, p-FC6I-I4). M p (maleate sal0 135-136oC (EtOH-ether) [L it. 2a 136-13 8oc (EtOH -ether)].

(Rece ived in U K 17 A p r i l 1996)