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P e r g a m o nT e t r a h e d r o n 5 4 (1 9 9 8 ) 1 5 6 7 3 - 1 5 6 7 8

T E T R A H E D R O N

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 th e A n t i f u n g a l A n t ib io t i c ( + ) - P r e u s s in ~

G. Veeresa and Apurba Datta*

O r g a n i c I I I , I n d i a n I n s ti t ut e o f C h e m i c a l T e c h n o l o g y , H y d e r a b a d - 5 0 0 0 0 7 , I n d i a

R e c e i v e d 6 A u g u s t 1 9 9 8 ; r e v i s e d 6 O c t o b e r 1 9 9 8 ; a c c e p t e d 2 2 O c t o b e r 1 9 9 8

Abstract: A concise total synthesis of enantiopure (+)-preussin (1) from L-phenylalanine (3) isdescribed. The key steps involve i) syn-selective formation of the 1,2-amino alcohol fragment 2, via

chelation controlled addition of allylmagnesium bromide to N-Boc-ph enylalaninal, and ii) L-selectride®mediated stereoselective reduction of the ketone 8 to the alcohol derivative 9 with the required

stereochemistry for final cyclization. © 1998 Elsevier Science Ltd. All r ights reserved.

Keywords : antibiotic; chelation control; G rignard reaction; stereoselection.

T h e n a t u r a l l y o c c u r r i n g p y r r o l i d i n e a l k a l o i d ( + ) - p r e u s s i n 1 ( L 6 5 9 , 3 9 8 ) w a s i s o l a t e d f r o m t h e

f e r m e n t a t i o n b r o t h s o f Pr e us s i a s p . and As pe r g i l l u s oc hr ac e us . ~ P r e u s s i n a n d i t s a c y l d e r i v a t i v e s e x h i b i t

s i g n i f i c a n t a c t i v i ty a s b r o a d - s p e c t r u m a n t i b i o t i c s a g a i n s t b o t h f i l a m e n t o u s f u n g i a n d y e a s t s . T h e i m p r e s s i v e

b i o l o g i c a l a c t i v i t y a n d i n t e r e s t i n g s t r u c t u ra l f e a t u r e s h a v e t h u s m a d e p r e u s s i n a n a t t r a c t i v e t a r g e t f o r s y n t h e s is , 2

C h e l a t i o n c o n t r o l l e d a d d i t i o n o f G r i g n a r d r e a g e n t s t o c h ir a l ~ t - a m i n o a l d e h y d e s , r e s u l t i n g i n

s y n - s e l e c t i v e f o r m a t i o n o f 1 , 2 - a m i n o a l c o h o l s , 3 h a s b e e n s h o w n t o b e a v e r s a t i le t o o l f o r t h e a s y m m e t r i c

s y n t h e s i s o f t h i s i m p o r t a n t s t r u c tu r a l m o t i f o f w i d e o c c u r r e n c e . R e c e n t w o r k f r o m o u r l a b o r a t o r y h a s

d e m o n s t r a t e d t h e u t il i t y o f t h e a b o v e a p p r o a c h f o r th e s y n t h e s i s o f b i o l o g i c a l l y im p o r t a n t h y d r o x y a m i n o a c i d s ,

s t a t i n e , ~ p o l y o x a m i c a c i d , 4b a n d 3 - h y d r o x y g l u t a m i c a c i d . ~ I n c o n t i n u a t i o n o f t h e s e s t u d i e s w e u n d e r t o o k a

t o t a l s y n t h e s i s o f p r e u s s i n , f o l l o w i n g t h e r e t r o s y n t h e ti c s t r a t e g y a s s h o w n i n S c h e m e 1 . W e c o n t e m p l a t e d

t h a t , a p p l y i n g th e a f o r e m e n t i o n e d p r o t o c o l , a n a d v a n c e d i n t e r m e d i a t e 2 , c o m p r i s i n g t h e a m i n o a l c o h o l

f u n c t i o n a l i t e s o f r e q u i r e d s t e r e o c h e m i s t r y a s p r e s e n t i n 1, c a n b e e a s i l y a s s e m b l e d b y r e a c t i n g L - N - B o c -

p h e n y l a l a n i n a l w i t h a l l y l m a g n e s i u m b r o m i d e . S u b s e q u e n t tr a n s fo r m a t i o n s in v o l v i n g t h e a l k e n e m o i e t y w o u l d

t h e n l e a d t o t h e t i t l e c o m p o u n d . D e t a i l s o f t h e s t u d ie s t h u s i n i t ia t e d a r e d e s c r i b e d h e r e i n .

, ~ P n ~ , , , "

C 9 H 1 9 H C )

(+ ) -Preussin (1) 2 3 (L-Phenylalanine)

S c h e m e 1

0 0 4 0 - 4 0 2 0 / 9 8 / $ - s e e f ro n t m a t t e r © 1 9 9 8 E l s e v i e r S c i e n c e L t d . A l l f i g h t s re s e r v e d .

PII: S 0 0 4 0 - 4 0 2 0 ( 9 8 ) 0 0 9 8 1 - 8

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15674 G. Veeresa , A. Dat ta /Tetrahedron 54 (1998) 15673-15678

R e s u l t s a n d D i s c u s s i o n

N - Boc - phenyla lan ino l ( 4) w as pr epared in a one- pot r eact ion by l ith ium a luminium hyd r ide

reduction and der ivat izat ion o f L-phenylalanine 3 (Sche me 2). Sw ern oxidat ion o f 4 fol low ed by in-s i tu

reac don o f the result ing aldeh yde with al lylm agne sium bromide, fol lowin g an es tablished pro ced ure, 3a yielded

the hom oallyl ic a lcoho l 2 with goo d diastereoselect ion (6:1, dias tereoisomers separated by c olum n

c h r o m a t o g r a p h y ) i n f a v o u r o f t h e s y n isomer , 5 whic h is in agreem ent with the repo r ted observ ations . 3 '4

~H 2 I~HBoc I~HBoc" a : b " c

R I ' " / ~ C O 2 (78%)" ~ H (56"/o)" ~ (83"/°f

(3 H3 4 2

B o c B O R ~

-" d m, ~ C e(90%) (89%)D-H O H

5 6 7 C9H19

B o c B o o(80"1o) (84%)

Ms L.~,,OM s

C9H19 C9H19 C9H198 9 10

( 9 : 1 0 = 9 : 1 )

e. LiAIH4 he n Boc2O. b. S wern oxidation h en H2C=CH-CH2MgBr. c. M e2C(OMe)2, PPTS.d. O sO4 , NM O, the n NalO4 (on silica gel ). e. H19C9MgBr, Et20 . f. 2-10doxybenzoic c i d .

g. L-Selectride (1M soln. in TH F). h. MsC I,Et3N.

S c h e m e 2

Hav ing synthe sized the pivotal amino alcohol intermediate, introduction of the n ony l s ide chain

was nex t invest igated. Acetonide protect ion o f the amino alcohol functionality o f 2 af forded the

corre spo ndin g oxazo lidine der ivat ive 5. Sub sequ ent oxidat ive cleavage of the olef in to aldehyde 6 a nd i ts

r eac t ion w i th the G r ignar d r eagent de r ived f r om 1- br omon onane r esu lted in the co r r esponding a lcohol 7 as an

inseparab le mix tur e of i somer s ( 7 :3 , by H P LC ) a t the new ly f or med cente r. H o w ev er , ox ida t ion of th is

a lcohol to it s cor r espondin g ke tone 8 , f o l low ed by s te reose lec tive r educ t ion of the ca r bonyl gr o up us ing L-selectr ide® ( l i thium t r i - sec - bu ty l - bor ohyd r ide ) and subsequent mesyla t ion of the hydr oxy gr oup thus f or m ed,

yield ed the me sylate s 9 and 10 in a 9:1 rat io of dias tereoisomers wh ich could be eas i ly separated by co lum n

chr om atogr aphy . T he ass igned s te r eochemis t ry f or the i somer s 9 and 10 w as conf i r med by the subsequent

r eac t ions . Thus , ace tonide depr o tec t ion of the ma jor pr oduc t 9 under s tandar d condi t ions d i r ec tly a f f or ded the

pyroll idine der ivat ive 11 (Schem e 3) , a kn ow n precursor of (+) -preuss in . 28 Spec troscop ic data and the

spec if ic rotat io n o f l l{ [a ] D = -56.9 (c = 1.1, CH2CI2~r l it . 2g [Ct]D= -56.6 (C = 1.0, CH2C12)} were in goo d

agreem ent with the l i terature repo r ted values , whic h also conclusively proved the s tereochemical ass ign men ts

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G. Veeresa, A. Datta Tetrahedron 54 (1998) 15673-15678 15675

f o r t h e m e s y l a t e s 9 a n d 1 0 . F i n a l l y , tr e at m e n t o f t h e N - B o c - p y r r o l i d i n e 1 1 w i t h l i th i u m a lu m i n i u m h y d r i d e

u n d e r r e p o r t e d c o n d i t i o n s2~ comp le ted the in t ended s yn the s i s o f (+ ) -p reus s in (1 ) , t he s pec t ra l da ta ~s and the

spe cif ic rota t ion o f whic h {[ a ] D = +21 .6 (c = 0 .7 , CHCI3) : Natur a l 1 ab [c t ]o -- +22.0 (c = 1 .0 , CHCI3)} are

in exce l l en t ag reemen t w i th the repor t ed va lue s .

R•• i i . Na HC O3 UAIH4,,,

, ~ , / D M s (77% ) CgH19 (63% ) 9H 19

130c I~le

9 C 9H 19 11 (+)-Preuss in (1 )

S c h e m e 3

In conc lu s ion , a conc i s e s yn the s i s o f na tu ra l (+ ) -p reus s in was accom pl i s hed in t en s t eps (8 .7%

ove ra l l y i e ld ) , s t a r t ing f rom the read i ly ava i l ab le amino ac id L -pheny la l an ine , fo l low ing a s imp le an d e f f i c ien t

reac t ion s equence . The s yn the s i s demon s t ra t e s the u t i l it y o f che la t ion con t ro l l ed Gr igna r d reac t ions on ch i ra l

a -a mi no a ldehy des fo r the s t e reos e lect ive fo rma t ion o f the syn-1,2-aminoalcohol un i t . The s t ra t egy and the

approa ch de s c r ibed can a ls o be ea s i ly adap ted to s yn the s ize va r ious C -1 and C - 4 mo d i f i ed ana logues o f

p reus s in . The a bove rou te thus o f fe r s a v i ab le a lt ema t ive to the ex i s t ing me tho do log ie s fo r s yn the s iz ing th i s

b io lo g ica l ly impo r tan t t i tl e com poun d and i t s mod i f i ed ana logues in s ea rch o f impro ved ac t iv i ty .

Experimental Section

G e n e r a l . R e a g e n t s a n d s o lv e n t s w e r e o b t a in e d f r o m c o m m e r c ia l s u p p l i e r s a n d u s e d a s r e c e i v e d , u n l e s s

o the rwis e no ted . M o is tu re o r a i r s ens i t ive reac t ions we re conduc ted unde r a n i t rogen a tmos phe re in oven d r i ed

( 1 20 ° C ) g l a s s ap p a r a t u s. D i e t h y l e t h e r a n d T H F w e r e d i s ti l le d f r o m s o d i u m b e n z o p h e n o n e k e t y l p r i o r t o u s e .

T o l u e n e w a s d r i e d o v e r s o d i u m , w h e r e a s d i c h lo r o m e t h an e a n d t r ie t h yl a m i n e w e r e d i s t il l e d f r o m C a l l 2 a nd

s to red ove r mo lecu la r s i eves and anhyd rous KO H re s pec t ive ly . A l l y i e lds repor t ed re fe r to i s o la t ed ma te r i a l

j u d g e d to b e h o m o g e n e o u s b y tl c a n d N M R s p e c t r o s c o p y . C o l u m n c h r o m a t o g r a p h y w a s p e r f o r m e d o n s i li c a

ge l 60 (60 -12 0 me s h) , u s in g e thy l a ce ta te /hexane mix tu re a s e luen t , un le s s s pec i f i ed o the rwis e . The NM R

s pec t ra we re reco rded in C D C I 3 on a 200 M Hz s pec t rom e te r w i th TM S a s the in t e rna l s t anda rd . E lemen ta l

ana lys e s w e re ca r r i ed ou t in the In d ian As s oc ia t ion fo r the C u l t iva t ion o f Sc ience , J adavpur , C a lcu t t a .

(S)-2-[(tert-Butoxycarbonyl)amino]-3-phenyl-l-propanoi (4 ) . L-Phe ny la lan ine (6 .3 g , 38 .13

re too l ) was adde d in s ma l l po r t ions to a s us pens ion o f li t h ium a lumin ium hydr ide (2 .89 g , 76 .26 mm ol ) in

re f lux ing THF (125 mL ) and re f lux ing con t inued fo r .ano the r 7 h . The reac t ion mix tu re was then coo led to0°C ( i c e -ba th ) and exces s reagen t quenched by ca re fu l add i t ion o f an aqueous 15% NaO H s o lu t ion (3 mL) and

wa te r (9 mL ) . Af te r s t i r r ing a t room temp e ra tu re fo r 10 min , a s o lu t ion o f di-tert- bu ty l d i ca rbona te (8 .31 g ,

38 .13 mm ol ) in C H2C I 2 (40 m L) w as a dded to the mix tu re and s t ir r ed a t 60°C fo r 6 h , coo led to room

tempera tu re , f i l t e red th rough a p ad o f anhydro us Na2SO 4 and the f i l t r at e concen t ra t ed unde r vacuum .

Pur i f i c a t ion o f the o i ly re s idue by co lumn c h roma tograp hy (e thy l a ce ta te /hexane = 1 /3 ) a f fo rded the pu re N -

B oc - amin o a lcoho l 4 (6 .72 g , 70% ) a s a wh i t e s o l id , s im i l a r in a l l r e s pec t s to the comm erc ia l ly ava i l ab le

s a m p l e ( A l d r i c h C h e m i c a l C o m p a n y , I n c . ).

( 4 S , 5S)-5.[(tert-Butoxycarbonyl)amino]-4-hydroxy-6-phenyl-l-hexene (2 ) . To a s t i r r ed

s o l u ti o n o f o x a l y l c h lo r i d e ( 2 .4 m L , 2 7 . 88 m m o l ) a n d C H 2 C I : (5 0 m L ) a t - 7 8° C u n d e r n i t r o g en a t m o s p h e r e

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w as added D M SO ( 2 .26 m L, 31 .86 mm ol) d r opw ise . A f te r s ti rr ing f or 30 min , a so lu t ion of the amino

a lcohol 4 ( 4 g , 15 .93 mm ol) in CH 2CI2 ( 100 mL) w as added over 30 min . The m ix tur e w as w ar med to - 35°( 2

and s t ir red fo r 30 min at this temperature, fol low ed by addit ion o f di isopropylethy l amine (19 m L, 111 .55

mm ol) over 5 min . The r eac t ion mix tur e w as then w an ned to 0° C in 15 ra in and tr ans fe rr ed th r ough a cannu lato a roo m temperature solut ion of aUylmagnesium brom ide [prepared f rom M g (5 g, 0.2 mo l) and al lyl

brom ide (10.1 m L, 0.12 tool) in ether (100 mL)] over 30 rain. Af ter s t ir ring for 2 h at room temperature the

r eac t ion mix tur e w as pour ed in to aqueous sa tur ated N H 4CI so lu t ion ( 100 mL) and ac id i f ied to p H 4 by adding

10% aqueous H CI so lu tion . The or ganic l ayer w as separa ted , aqeous layer ex t r ac ted w i th CH C13 ( 3x100 mL )

and the combin ed or ganic ex t rac t s w er e w ashed sequentia lly w i th w a te r and br ine . A f te r d r y ing ove r N a2SO 4,

so lvent w as r emoved under vacuum and the r es idue pur i f ied by f la sh co lumn chr omatogr aphy ( e thy l

acetate/hexane = 1/12 ) to yield the amino alcoh ol 2 (2.6 g, 56% ) as a viscou s semi sol id: [c t]o = -2 6.4 (c =l ,

CH CI 3); I R ( nea t) 3443 , 3401 , 1690 cm- ' ; ' H N M R 6 1 .39 ( br s , 9H ) , 2 . 15- 2 .3 ( m, 2H ) , 2 . 8- 2 .92 ( m,

2H ) , 3 .49- 3 .61 ( m, 1H ) , 3 . 64- 3 .80 ( m, 1H ) , 4 . 8 (d , J = 8 .8 H z , 1H ) , 5 .1 ( b r d , J = 13 .3 H z , 2H ) , 5 . 62 -

5.85 (m, 1H) , 7.1-7 .35 (m, 5H ); '3C N M R 6 178.3, 156.0, 138.3, 134.4, 129.3, 128.3, 126.2, 118 .2,

79 .2 , 70 .1 , 55 .1 , 39 .2 , 38 .7 , 28 .2 ; H R M S ( CI ) ca lcd , f o r CITH E6N O 292.19 12 ( M H +) ; f oun d 292 .18 92;

A na l . Ca lcd f or CI7H 25N O ( 291 .4) : C , 70 .07 ; H , 8 .65 ; N , 4 .81 . Fou nd : C , 69 .81 ; H , 8 .28 ; N , 4 .78 .

( 4 S • 5 S ) - 2 • 2 - D i m e t h y l - 3 - ( t e r t - b u t • x y • a r b • n y l ) - 4 • b e n z y l - 5 - ( 2 - p r • • e n y l ) - • • 3 - • x a z • l i t l • n e ( 5 )

A so lu t ion of 2 ( 3 g , 10 .3 mm ol) , 2 , 2- d imethoxypr op ane ( 19 .5 mL , 123 .7 mm ol) and a ca ta lyt ic amo unt of

pyr idin ium p- toluenesu lfonate (50 rag) in toluene (35 mL) was s t ir red at 80°C for 4 h. Re mo val of solvent

und er vacuu m and purification of the res idue b y column chrom atog raph y (ethyl acetate/hexane = 1/19)

af ford ed the pure ox azo lidin e 5 (2.83 g, 83% ) as a l ight yel low visc ous l iquid: [c t]o = -10.3 (c = 1.1, CHCI3) ;

I R( n ea t ) 169 8cm - ' ; ~H N M R 8 1 .46 ( s, 3H ) , 1 .54 (br s , 12H ) , 1 . 97- 2 .18 ( m, 2H ) , 2 . 18 ( m, 2H ) , 2 . 60-

2 .89 ( m, 1H ) , 3 . 23 (dd , J = 4 .5 and 12 .7 H z , 1H ) , 3 . 68- 3 .86 ( m, 1H ) , 3 . 9 ( dd , J = 5 .3 and 11 .2 H z , I H ) ,

4.8-5 .0 (m, 2H) , 5.42-5 .68 (m , 1H), 7.1-7.35 (m , 5H); '3C NM R ~ 170.2, 137.7, 133.7, 129.7, 1 29.3,

128.4, 126.4, 117.4, 79.7, 77.8, 62.6, 39.2, 39.1, 37.5, 28.5, 26.9 ; HR M S (FA B+ ) calcd , for C20H3oNO

332.222 5 ( MH *) ; f ound 332 .2233; A na l. Ca lcd f or Cz0H 29N O ( 331 .46) : C , 72 .47 ; H , 8 .82 ; N , 4 .23 .

Fou nd : C , 72 .51 ; H , 8 .57 ; N , 4 .51 .

( 4 S • 5 S ) - 2 • 2 - D i m e t h y l - 3 - (t e r t - b u t •x y c a r b • n y l ) - 4 - b e n z y l- 5 - f • rm y l m e t h y l - • • 3 • • x a z •l i d i • e

(6) . To a s t ir red so lut ion of the al lyl oxazolidine 5 (1.35 g, 4.08 retool) and N-m ethy lmo rpho line-N -oxid e

( 2 .38 g , 20 .35 m mo l) in ace tone ( 10 mL) and w a te r ( 2 mL) a t r oom tempera tur e w as added a ca ta lyt ic amoun t

o f O s O 4 solut ion in toluene (5% solut ion , 5 mo l%) . Af ter s t ir r ing for 8 h, a saturated aque ous solut ion of

Na2SO 3 5 m L) was a dded to the mixture and extracted w ith ethylacetate (3x 50 m L) . The co mb ined extracts

w er e dr ied over N a2SO 4 and so lvent remo ved thor oughly under vacuum af f or d ing the c r ude d ihydr oxyla ted

com pou nd ( 1 .5 g) w hich w as d i s so lved in CH 2C12 ( 20 m E) and add ed in on e lo t to a v igo ur ous ly s t ir red

s u s p e ns i o n o f N a I O4 supp or ted in s i l ica gel (8 g, 20% NaIO4) 6 in CH2C1 (20 m L) maintained at 0°C. Af ter

s t ir r ing at the same temperature for 1 h, the sol id w as re mo ved by f i l tra tion, wa shed with C HC13 (3x2 5 mL ) ,

com bined f il tr ate concent r a ted under vac uum an d the r esidue puri fied by co lumn chr om atogr aph y ( ethyl

acetatehaexane = 1/6) yield ing the pure alde hyd e 6 (1.23 g, 90% two s teps) as a viscou s l iquid: [~t]D = - 3 .4 ( c

= l , CH CI 3) ; I R (nea t ) 1725 , 1694 cm " ; ' H N M R 6 1 .42 ( br s , 15H ) , 2 . 13 ( dd , J = 5 .4 and 12 .1 H z , I H ) ,

2.45 (m, IH ) , 2.73 (br s , IH) , 3.32 (br d, J = 12.4 Hz, lH) , 3.37 (br s , 1H) , 4.40 (m, 1H) , 7.22 (m, 5H ) ,

9 .64 ( br s , 1H ); MS ( FA B +) 334 (MH *) ; A na l . Ca lcd f or C ,gH 27N O ( 333 .43) : C , 68 .44 ; H , 8 .16 ; N , 4 .20 .

Found : C , 68 .79 ; H , 8 .03 ; N , 4 .44 .

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( $ • 5 • ) • 2 • 2 • D • m e t h y • • 3 • ( t e r t • b u t • x y c a r b • n y • ) • 4 • b e n z y • • 5 • ( 2 • h y d r • x y u n d e c y • ) • 1 • 3 • • x a z • • i •

d i n e ( 7 ) . T o a n i c e -c o o le d o l u ti o n f n o n y l m a g n e s i u m b r o m i d e ( 5 . 9 3 r e to ol ) p r e p a r ed r o m M g ( 0 . 2 9 g ,

I . 9 r e t oo l ) n d n o n y l b r o m i d e ( 1 . 1 3 L , 5 . 9 3 r e to o l) ] n e t h e r 5 0 m L ) w a s a d d e d d r o p w i s e o v e r 1 5 r ai n ,

so lu t ion of the a ldehyde 6 ( lg , 2 . 98 m mol) in e the r ( 15 mL) under n i tr ogen a tmospher e . The m ix tur e w asthen s t ir red at ro om temperature for 4 h and poured into a saturated aqu eou s NH4CI solut ion (50 mL ) . The

or ganic l ayer w as separ a ted , aqueou s layer ex tr ac ted w i th e thylace ta te ( 2x50 mL ) , com bined ex t r ac t s w ashe d

w i th br ine , d r ied (N a2SO 4) and so lvent r emo ved under vacuum . The r esidue on co lum n chr omatog r aphy

(ethyl acetate/hexane = 1/7) af forde d 7 (1.09 g, 89% ) as a colou r less oil : IR (neat) 34 77, 170 0 crn ' l ; ~H

N M R 8 0.85 (br t , J - - - 6.8 Hz, 3H) , 1.2 (br s , 18H), 1.34-1.61 (m, 13H) , 1.73-1.9 2 (m , 2H) , 2 .61-2 .9 (br

s , 1H ) , 3 . 18- 3 .22 ( m , I H ) , 3 . 42- 3 .82 ( m , 3H ) , 3 . 95- 4 .18 ( m , 1H ) , 7 . 1- 7 .32 ( m , 5H ) ; MS ( FA B +) 462

( MH +) ; A na l . Ca lcd f or C28H 47N O ( 461 .69) : C , 72 .84 ; H , 10 .26; N , 3.03. Fou nd : C , 73 .02 ; H , 9 .97 ; N ,

3 . 2 8 .

( 4S •5S )- 2•2-D•meth y•- 3 -( ter t-b ut • x y ca rb •n y• )- 4 -b en z y•- 5-( 2-• x •u nd ec y • )- • •3-• xaz•••d•ne

( 8) . To a r oom temper a tur e so lu t ion of 2 - iodoxyb enzoic ac id ( 1 .21 g , 4 . 33 mm ol) in D M SO ( 6 mL ) w as

added a so lu t ion of the second ar y a lcohol 7 ( I g , 2 . 16 r e too l ) in TH F ( 10 m L) and s t ir red f or 2 h . Th e r eac t ion

wa s que nch ed by addit ion of water (10 mL) , the precipi tated sol id w as f i l tered, f i lt rate extracted with ether

( 3x50 m L) and the co mb ined ex t r ac t s d ried over N a~SO4. Evapor a t ion of so lvent and pur i f ica t ion of the c r ude

pr oduc t by co lum n chr omato gr aphy ( e thy l acetate /hexane = 1 /8) a f f or ded the pure ke tone 8 ( 796 mg , 80% ) as

a co lor les s o i ly l iqu id : [ cO o= -2.3 (c = 1.1, CHC13) ; IR (neat) 1693 (br ) cm~; ~H N M R 8 0.86 (br t, J =

6.1 Hz, 3H ) , 1.2 (br s , 1 4H) , 1.31-1.62 (m, 15H ) , 2.1 (dd ,J = 4.25 and 10.6 Hz, 1H ) , 2.2 (br t , J = 6.8

H z , 2H ) , 2 .51 ( dd , J = 7 .6 and 8 .9 H z , 1H ) , 2 . 63- 2 .84 ( m , 1H ) , 3 .25 ( br d , J = 13 .1 H z , lH ) , 3 . 66 - 3 .78

(m, 1H ) , 4.28 -4.37 (m , 1H) , 7.1-7.3 (m, 5H); ~3C N M R 8 207 .9, 168.2, 137.3, 129.5, 128.4, 126 .5, 80.0,

63 .1 , 47 .8 , 43 .2 , 31 .7 , 29 .2 , 28 .4 , 26 .6 , 23 .3 , 22 .5 ; 14 .0 ; MS ( FA B +) 459 ( M÷) ; A na l . Ca lcd f or

C2sH45NO4 ( 459 .68) : C , 73 .16 ; H , 9 .87 ; N , 3 .05 . Fou nd : C , 73 .07 ; H , 9 .73 ; N , 3 .15 .

( 4 S , 5S) -2• `2-Dime thy• -3- ( te r t -b• t •xycarb•ny• ) -4-benzy • -5- [ (2S) -2- (me thanesu• f •ny • •xy ) -

u n d e c y l ] - l , 3 - o x a z o l i d i n e (9 ) a n d ( 4 S , 5 S ) . 2 , 2 .D i m e t h y l . 3 , ( te r t . b u t o x y c a r b o n y l )- 4 - b e n z y l -

5 - [ ( 2 R ) - 2 - ( m e t h a n e s u l f o n y l o x y ) u n d e c y l ] - l , 3 - o x a z o l i d i n e ( 10 ). T o a s olu tio n o f th e k eto ne 8

( 500 mg, 1 .08 mm ol) in TH F ( 10 mL) a t - 78° C w as added dr op w ise L- select ride * (1 M so ln . in TH F, 2 .16

mL , 2 .16 mmo l) and s t ir r ed f or 45 m in . The r eac t ion w as quench ed by sequentia l addi t ion of M eO H ( 1 .5 mL)

and aqu eous 10% N a O H ( 2mL) . A f te r st ir ring a t r oom temper a tur e f or 10 min , the mix tur e w as ex t r ac ted w i th

e the r ( 3x40 m L) , com bined ex tr act s w ashed w i th sa tur ated aqueous N H 4 C1 and br ine , d r ied ( N a~SO 4) and

s o l v e n t w a s r e m o v e d t h o r o u g h l y u n d e r v a c u u m . T h e c r u d e a l c o h o l (5 0 0 m g ) t h u s o b t a in e d w a s d i s s o lv e d i n

CH 2C1 ( 15 mL ) , coo led to 0° C (ice - ba th) and a ca ta ly t ic am ount of D M A P ( 20 mg) and E t3N ( 1 .5 mL , 10 .8

mm ol) added to i t f o l low ed by dr op w ise addit ion of me thanesu l f onyl ch lor ide ( 0 .42 mL , 5 .42 mm ol) . A f te r

s t i rr ing f or 15 min a t 0° C and 14 h a t r oom tempera tur e, the r eac tion mix tur e w as d i lu ted w i th CH zCI2 ( 3 0 m L )

and w ashe d sequent ia lly w i th w a te r , sa tur ated aqueo us N aH CO 3 and br ine . D r y ing ( N a2SO 4) , r emova l o f

so lvent and co lum n chr om atogr ap hy ( e thy l ace ta te /hexane = 1 /9 - - -> 1 /7) o f the c r ude mix tur e y ie lded the pur e

mesy la tes 9 ( 452 mg, 77% ) and 10 ( 43 mg, 7%) as co lor les s l iqu ids : 9 ( major i somer) : [C~]D= -1 2 .1 (C -----

1, CHCI3) ; IR (neat) 1697, 116 1 cm-~; ~H N M R 8 0.9 (br t , J = 6.4 H z, 3H ) , 1.28 (br s , 14 H) , 1.35-1 .71

( m, 18H ) , 1 . 80- 1 .97 (m , I H ) , 2 . 63- 2 .71 ( m , I H ) , 2 . 88 (s , 3H ) , 3 .29 ( br d , J = 11 .3 H z , I H ) , 3 . 69- 3 .84

( m, I H ) , 3 . 88- 4 .0 ( m , I H ) , 4 . 59- 4 .75 ( m , 1H ) , 7 . 09- 7 .36 ( m , 5H ) ; MS ( FA B+ ) 541 ( M ÷) . 10 (min or

isomer) : [c t]D = -3.81 (c = 1.1, CHCI3) ; ~H N M R 6 0.85 (br t , J = 6.5 H z, 3H ) , 1.20 (br s , 14H) , 1.35-

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15678 G. Veeresa, A. D atta / Tetrahedron 54 (1998) 15673-1567 8

1 . 68 ( m , 1 8 H) , 1. 8 0- 2 .0 1 ( m , I H) , 2 . 7 2 ( b r s , I H ) , 2 . 8 6 ( s , 3 H) , 3 . 0 7 - 3 . 2 8 ( m , 1 H) , 3 . 6 1 - 3 . 8 0 ( m , I H ) ,

3 . 8 4 - 4 . 0 2 ( m , 1 H ) , 4 . 5 3 - 4 . 7 2 ( m , 1 H ) , 7 .0 6 - 7 . 3 ( m , 5 H ) . T h e a b o v e m e s y l a t e s w e r e f o u n d to d e c o m p o s e

o n s t o r a g e a n d w e r e u s e d i m m e d i a t e l y f o r t h e n e x t r ea c t io n .

( 2 S , 3 S , 5 R ) , 2 - B e n z y l - l- ( t e r t- b n t o x y e a r b o n y l ) - 5 -n o n y l - 3 - p y r r o l i d in o l ( 1 1 ) . A s o l u t io n o f 9( 4 0 0 m g , 0 . 7 4 m m o l ) i n 8 0 % a q u e o u s A c O H ( 3 0 m L ) w a s s ti r re d a t r o o m t e m p e r a t u r e f o r 2 4 h . T h e r e a c t io n

m i x t u r e w a s d i l u t e d w i t h C H 2 C I 2 ( 1 0 0 m L ) , c o o l e d t o 0 ° C a n d n e u t r a l i z ed t o p H 7 b y a d d i n g s o l i d N a H C O 3 i n

s m a l l p o r ti o n s . T h e l a y e r s w e r e t h e n s e p a r at e d , a q u e o u s l a y e r e x tr a c te d w i t h C H 2 C I 2 ( 2 x 2 5 m L ) a n d th e

c o m b i n e d o rg a n i c e x t r a c ts w e r e w a s h e d s e q u e n t i al l y w i t h w a t e r a n d b ri n e . A f t e r d ry i n g o v e r N a 2 S O 4 a n d

r e m o v a l o f s o l v e n t u n d e r v a c u u m , t h e r e s id u e w a s c o l u m n c h r o m a t o g r a p h e d ( et h y l a c e t at e /h e x a n e = 1 /4 ) t o

a f f o r d th e p u r e p r o d u c t 1 1 ( 2 3 0 m g , 7 7 % ) a s a c o lo r l e s s l iq u id , th e s p e c t r a l a n d a n a ly t i c a l d a ta o f wh ic h a r e in

g o o d a g r e e m e n t w i t h t h e r e p o r t e d v a l u e s. 2g

( 2 S , 3 S , 5 R ) - 2 - B e n z y l - l - m e t h y l - 5 - n o n y l - 3 - p y r r o l i d i n o l ( 1) . T o a s ol ut io n o f th e N - B o c -

p y r r o l id i n e 1 1 ( 1 0 0 m g , 0 . 2 4 m m o l ) i n T H F ( 8 m L ) w a s a d d e d l i th i u m a lu m i n i u m h y d r i d e ( 9 5 m g , 2 . 4

r e to o l ) a n d th e mix tu r e r e f lu x e d f o r 7 h . Af te r c o o l in g to 0 °C , s a tu r a te d a q u e o u s N H4 C I (1 5 m L ) a n d w a te r

( 3 0 m L ) w a s a d d e d t o t h e re a c t io n m i x t u r e , t he r e s ul t in g s o l u t i o n e x t ra c t e d w i t h e t h e r ( 3 x 5 0 m L ) , c o m b i n e d

e x t r a ct w a s h e d w i t h b r i n e , d r i e d o v e r N a 2 S O 4 , s o l v e n t r e m o v e d u n d e r v a c u u m a n d t h e r e s id u e p u r i f ie d b y

c o l u m n c h r o m a t o g r a p h y ( e t h y l a c e ta t e /h e x a n e = 1 / 3 ) t o y ie l d ( + ) - p r e u s si n ( 1 ) ( 51 m g , 6 3 % ) a s a c o l o r l e s s

wa x y s o l id , th e s p e c t r a l a n d a n a ly t i c a l d a ta o f wh ic h i s c o n s i s t e n t w i th th o s e r e p o r te d in th e l i t e r a tu r e . 2g

A c k n o w l e d g m e n t s : W e t h a n k D r . M . K . G u r j a r f o r h i s s u p p o r t an d e n c o u r a g e m e n t . G V a l s o th a n k s

C S I R , N e w D e l h i , f o r a r e s e a r c h f e l l o w s h i p ( S R F ) .

#

1 .

2 .

3 .

4 .

5 .

6 .

R e f e r e n c e s a n d N o t e s

I I C T c o m m u n i c a t i o n N o . 3 9 59( a ) S c h w a r t z , R . E . ; L i e s c h , J .; H e n s e n s , O . ; Z i ta n o , L . ; H o n e y c u t t , S . ; G a r r i t y , G . ; F r o m t l i n g ,R . A . ; O n i s h i , J .; M o n a g h a n , R . J . Antibiot. 1 9 8 8 , 41 , 1 7 7 4 - 1 7 7 9 . ( b ) J o h n s o n , J . H . ; P h i l l i p s o n ,D . W . ; K a h l e , A . D . J . Antibiot. 1 9 8 9 , 42 , 1 1 8 4 - 1 1 8 5 . ( c ) S c h w a r t z , R . E . ; O n i s h i , J . ; M o n a g h a n , R; L i e s c h , J. ; H e n s e n s , O . US Patent 4 , 8 4 7 , 2 8 4 , 1 9 8 9 .F o r t h e re p o r t e d s y n t h e s e s se e : ( a ) K a n a z a w a , A . ; G i l l et , S . ; D e l a ir , P . ; G r e e n e , A . E . J . Org.Chem. 1 9 9 8 , 6 3 , 4 6 6 0 - 4 6 6 3 . ( b ) A r m a s , P . D . ; T e l l a d o - G a r c i a , F . ; T e l l a d o - M a r r e r o , J . J . ; R o b l e s ,J. Tetrahedron Lett. 1 9 9 8 , 39, 1 3 1 - 1 3 4 . ( c ) K a d o t a , I . ; S a y a , S . ; Y a m a m o t o , Y . Heterocycles,1 9 9 7 , 4 6 , 3 3 5 - 3 4 8 . ( d ) S c h a u m a n n , E . ; B e i e r , C . Synthesis, 1 9 9 7 , 1 2 9 6 - 1 3 0 0 . ( e) V e r m a , R . ;G h o s h , S . K . J . Chem. Soc . ,Chem.Commun. 1 9 9 7 , 1 6 0 1 - 1 6 0 2 . ( f) Y o d a , H . ; Y a m a z a k i , H . ;T a k a b e , K . Tetrahedron Asymm. 1 9 9 6 , 7 , 3 7 3 - 37 4 . ( g ) O v e r h a n d , M . ; H e c h t , S . M . J . Org.Chem.1994,59 , 4 7 2 1 - 4 7 2 2 . ( h ) D e n g , W . ; O v e r m a n , L . E . J . Am. Chem. Soc . 1994,116 , 1 1 2 4 1 -1 1 2 5 0 . ( i ) M c G r a n e , P . L . ; L i v i n g h o u s e , T . J . Am. Chem. Soc. 1 9 9 3 , 115, 1 1 4 8 5 - 1 1 4 8 9 . ( j )

S h i m a z a k i , M . ; O k a z a k i , F . ; N a k a j i m a , F . ; I s h i k a w a , T . ; O h t a , A . Heterocycles, 1 9 9 3 , 36, 1 8 2 3 -1 8 36 . ( k ) P a k , C . S . ; L e e , G . H . J . Org. Chem. 1 9 9 1 , 56, 1128.( a ) D e n i s , J - N . ; C o r r e a , A . ; G r e e n e , A . E . J . Org. Chem. 1 9 9 1 , 5 6, 6 9 3 9 - 6 9 4 2 . ( b ) J a y a s i n g h e ,L . R . ; D a t t a , A . ; A l i , S . M . ; Z y g m u n t , J .; V a n d e r V e l d e , D . G . ; G e o r g , G . I . J . Med. Chem. 1 9 9 4 ,37 , 2 9 8 1 - 2 9 8 4 . ( c ) A l i , S .M . ; H o e m a n n , M . Z . ; A u b e , J. ; M i t s c h e r , L . A . ; G e o r g , G . I . ; M c C a l l , R . ;J a y a si n g h e , L . R . J . Med. Chem. 1 9 9 5 , 38, 3 8 2 1 - 3 8 2 8 .( a ) Ve e r e s a , G . ; Da t t a , A . Tetrahedron Lett. 1 9 9 7 , 38 , 5 2 2 3 - 5 2 2 4 . ( b ) V e e r e s a , G . ; D a t t a , A .

Tetrahedron Lett. 1 9 9 8 , 39, 1 1 9 - 1 2 2 . ( c ) Ve e r e s a , G . ; Da t t a , A . Tetrahedron Left. 1 9 9 8 , 39,3 0 6 9 - 3 0 7 0 .A s s i g n m e n t o f syn s t e r e o c h e m is t r y to th e m a jo r i s o m e r 2 , in it ia l ly b a s e d o n a n a lo g y ( r e f . 3 , 4 ) , w a sp r o v e d c o n c lu s iv e ly b y c o m p a r in g th e s p e c t r a l a n d a n aly ti c al d a ta o f th e s u b s e q u e n t r e a c t io np r o d u c t s 1 1 a n d I w i th th e i r l i t e r a tu r e r e p o r te d v a lu e s (vide infra).Z h a n g , Y . L . ; S h i n g , T . K . M . J . Org. Chem. 1 9 9 7 , 62 , 2 6 2 2 - 2 6 2 4 .