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P e rg a m o n

S0957-4166(96)00009-2

Tetrahedron:Asymmetry.Vo l. 7, No. 2. pp. 373-374, 1996Copyright© 1996 ElsevierScienceLtd

Printed in Great Britain.All rights reserved0957-4166/96 $15.00 + 0 .00

A N o v e l S t e r e o s e l e c t i v e S y n t h e s i s o f E n a n t i o m e r i c a l l y P u r e

A n t i f u n g a l A g e n t , ( + ) -P r e u s s i n

H i d e m i Yo d a ,* H i r o y a s u Ya m a z a k i , a n d K u n i h i k oT a k a b e *

Depar tment o f M olecu la r Sc ience , Facu l ty o f Engineer ing ,

Sh izuoka Univers i ty, Ham amatsu 432 , Japan

A b s t ra c t : An e ff i c ien t and nove l p rocess i s desc r ibed fo r the asymm et r ic syn thes i sof (2S , 3S , 5R ) - 1 -methy l -5 -nonyl -2- (phenylmethy l ) -3 -pyr ro l id ino l , (+) -preuss inemp loy ing reduc t ive deoxyg ena t ion o f a func t iona l ized qua te rnary c t -hydroxy N-Bo cpyrro l idine obtained b y s tereocon troUed elabo rat ion of t ri -O-benzyl-I~-D-arabino-furanose . The syn the t ic s t ra tegy invo lves no separa t ion o f st e reo i somers th rough theent i re sequence.

(+)-Preu ssin (L-657 ,398) 1 , an ant i fungal ant ibiot ic f i rs t isolated inOH

1988 f rom fe rmenta t ion b ro ths o fAspergi l lus ochraceusAT C C 2 2 9 4 7 , , ,h a s a t tr a c te d c o n s i d e ra b l e a t te n t io n s i n ce t h is c o m p o u n d w a s s h o w n t o / - ' - - k ~ f ~ ' ~

inhibi t grow th of the bacter ia , Cand/da, and f i lame ntous fungi , including C91.119,, ,"~",, ~' ' , , ,

Trichophyton mentaand Microsporum canis .1 The re la t ive and abso lu te Ic ~s te reochemis t ry o f 1 was de te rmined from 1H and 13C NMR spec t ra and

nuclear Overh auser effect experimen ts , lb Due to i ts interest ing act ivi t ies

as we l l a s un ique s t ruc tu ra l f ea tu res , to our knowledge , f ive approaches

Preussin 1

to the to ta l syn thes i s o f 1 have been e labora ted to da te ,2 som e of w hich requ i red mu l t i s tep reac t ions o r have

included a n onstereoselect ive route with s tereoisom er separat ion.

On the o ther hand , recen t ly we repor ted a nove l and shor t syn the t ic s t ra tegy fo r the p repara t ion o f

enan t iom er ica l ly pure ( - ) -an i somycin emp loy ing thecis-selectivelac tam format ion p ro toco l .4 In thisconnec t ion i t i s no tewor thy tha t (+) -preuss in 1 and i t s ace ta te es te r show a b roader spec t rum of an t i funga l

act ivi ty agains t both f i lamen tous fungi and yeasts than the s t ructural ly re la ted anisomy cin, la

Wi th these cons idera tions in m ind , we wish to com mun ica te the de ta i l s o f a nove l syn the t ic p rocess fo r theprepara tion o f 1 wi thou t separa t ion o f s t e reo i somers . Th is m ethod fea tu res the s te reocont ro l l ed e labora t ion o f

the func t iona l ized N-B oc lac tam der iva t ive accord ing to our p reced ing repor t5 in wh ich asymm et r ic

deoxygen a t ion o f the qua te rnary a -hy drox y compou nd i s an essen t ia l s t ep fo r in t roduc ing a s t e reogen ic cen te r.

As shown in Schem e 1 , func t iona l ized d ias tereomer icaUy pure N-p -me thoxy ben zy l (MPM ) lac tam 3 ,

obtained from co mm ercial ly avai lable 2 ,3 ,5- t r i-O-benzyl-I~-D-arabinofuranose2 3 ,4 ,5 in h igh y ie ld , was t rea ted

wi th CA N fo l low ed by the Boc-pro tec t ion to g ive N-B oc lac tam 4 . Af te r remova l o f the p ro tect ing g roups f rom

4 wi th Pd(b lack) , h igh ly reg iose lec t ive acy la t ion wi th PhOCSC1 fo l lowed by rad ica l deoxygena t ion wi th

373

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374 H. YODAet aL

B n O - - ] / 0 , , , , ~H

O B n 2 O B n 3 O B n 4

p oc _ , B o c / = x

5 6

i B o cH19C. N. r ~ /) f

7

Sch em e 1. Reagents and condit ions: (a) 1 MP MN H2, Benzene, M S 4A, reflux; quant.; 2BnMgC1, -78 °C, TH F; 3 PCC , MS 4A, CH2C12; 59% (2 s teps); (b) 1 Ce(NH4)2(NO3) 6, CH aCN -H2 0; 76% ; 2 (Boc)20 , Et3N, DMA P, CH2C12; quant .; (c) 1 Pd(black) , HC OO H, M eOH ; quant .;2 PhOCSC1, pyridine , D M A P, CH3C N; 3 Bu3SnH, A IBN , toluene, 9 0 °C; 72% (2 steps); (d) TBSC1,imidazole, DM F; 91 %; (e) 1 C9HxgMgBr, -78 °C, THF; 2 Et~SiH, BF3oOEt2, -4 0-- 30 °C, CH2C12;67% (2 steps); (f) 1 Bu4NF, TH F; 97% ; 2 LiA1H4, THF, 50 C; 92%.

Bu3SnH6 resulted in the preparation o f 5, [et]24D+25.1 (c 0.85, CH C13) in high yield. Th is wa s then silylated

to give 6, [ct]23D +37.9 (c 1.20, CHC13). Nucleophil ic addit ion of nony lmagn esium brom ide to the key

comp ound 6 prov ided the labi le quaternary ct-hydroxy N -Bo c intermediate. This w as readi ly submitted toreductive d eoxyg enation with Et3 Sill in the prese nce o f BF3 • OEt2, cleanly leading to the pyrrolidine derivative7, [ct]25D -46.4 (c 1.50, CHC13) as a single stereoiso mer5 in 67% yield (2 steps) with the desired R

configurat ion. 7 Ac com pany ing formation of small amoun ts of ketone (5%) derived from equilibrium of the

quatern ary intermediate wa s observed. Finally, 7 wa s reduce d effective ly with LiA1H4 in TH F in 92% yieldafter desilylation to com plete the total synthesis o f (+)-preussin 1, [ct]24D +28 .2 (c 1.00, C HC I3) [natural 1,

[ct]25D +22.0 (c 1.0, CHC 13)lb] . The spectral data of the synthet ic amorph ous sol id 1 were com pletely

identical with those of the reported natural 1 and synthetic 2 com pou nd.

This process, in w hich (+)-preussin is synth esized from 2,3,5-tri-O-benzyl-13-D-arabinofuranose, involves

no separation of stereoisomers through out the entire sequen ce and provide s a new synthetic strategy.

R e f e r e n c e s a n d n o t e sI. (a) Schw artz, R. E.; Liesch , J.; Hen sens, O.; Zitano, L.; Ho ney cutt, S.; Garrity, G.; From tling, R. A.;

Onishi, J.; Monaghan,R. J . Ant ibiot .1 9 8 8 , 41 , 1774. (b) Johnso n, J. H.; Phillipson, D. W .; Kahle, A.D . J . Antibiot .1 9 8 9 , 4 2 , 1184.

2. (a) Pal<, C. S.; Lee ,G. H. J . Org. Chem-1 9 9 1 , 56 , 1128. (b) Shimazaki, M.; Okazaki, F.; Nakajima,F. Ishikawa, T.; Ohta, A.Heterocycles1 9 9 3 , 36 , 1823. (c) McGrane, P. L. ; Livinghouse,T. J . A m .Chem- Soc.1 9 9 3 , 115 , 11485. (d) Overhand, M.; Hecht ,S. M. J. Org. Chem-1 9 9 4 , 59 , 4721. (e)Deng, W. ; Overman,L. E. J . Am . Chem. Soc.1 9 9 4 , 116, 11241.

3. Yoda, H.; Nakajima, T. ; Yam azaki , H.; Takabe, K.Heterocycles1 9 9 5 , 41 , 2423.4. (a) Lay , L.; Nicotra, F.; Pagan ini, A.; Pang razio, C.; Panza, L.Tetrahedron Lett. 1 9 9 3 , 34, 4555. (b)

Hashim oto, M.; Terashima, S.Chem. Let t .1994, 1001 .Yoda, H.; Yam azaki , H.; Kawauchi , M.; Takabe, K.Tetrahedron: Asymmetryin press.Sharma, R.; Marquez, V. E.Synth. Commun.1 9 9 4 , 24 , 1937.The absolute co nfiguration of the generated stereogenic c enter was determined based o n its spectral data ofsynthetic (+)-1.

5.

6 .7

(Received in Japan20 N o v e m b e r1995)