6
7/27/2019 1-s2.0-S0040402098009818-main-1 http://slidepdf.com/reader/full/1-s20-s0040402098009818-main-1 1/6 Pergamon Tetrahedron 54 (1998) 15673-15678 TETRAHEDRON Stereoselective Synthesis of the Antifungal Antibiotic (+)-Preussin ~ G. Veeresa and Apurba Datta* Organic III, Indian Institute of Chemical Technology, Hyderabad - 500 007, India Received 6 August 1998; revised 6 October 1998; accepted 22 October 1998 Abstract : A concise total synthesis of enantiopure (+)-preussin (1) from L-phenylalanine (3) is described. 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-phenylalaninal, 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 rights reserved. Keywords : antibiotic; chelation control; Grignard reaction; stereoselection. The naturally occurring pyrrolidine alkaloid (+)-preussin 1 (L659, 398) was isolated from the fermentation broths of Preussia sp. and Aspergillus ochraceus. ~ Preussin and its acyl derivatives exhibit significant activity as broad-spectrum antibiotics against both filamentous fungi and yeasts. The impressive biological activity and interesting structural features have thus made preussin an attractive target for synthesis, 2 Chelation controlled addition of Grignard reagents to chiral ~t-aminoaldehydes, resulting in syn-selective formation of 1,2-aminoalcohols, 3 has been shown to be a versatile tool for the asymmetric synthesis of this important structural motif of wide occurrence. Recent work from our laboratory has demonstrated the utility of the above approach for the synthesis of biologically important hydroxy aminoacids, statine, ~ polyoxamic acid, 4b and 3-hydroxyglutamic acid. ~ In continuation of these studies we undertook a total synthesis of preussin, following the retrosynthetic strategy as shown in Scheme 1. We contemplated that, applying the aforementioned protocol, an advanced intermediate 2, comprising the aminoalcohol functionalites of required stereochemistry as present in 1, can be easily assembled by reacting L-N-Boc- phenylalaninal with allylmagnesium bromide. Subsequent transformations involving the alkene moiety would then lead to the title compound. Details of the studies thus initiated are described herein. , ~ P n ~ , ,, " C9H19 H C) (+)-Preussin (1) 2 3 (L-Phenylalanine) Scheme 1 0040-4020/98/$ - see front matter © 1998 Elsevier Science Ltd. All fights reserved. PII: S0040-4020(98)00981-8

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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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15676 G. V eeresa, A. Datta / Tetrahedron 54 (1998) 15673-15 678

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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G. Veeresa, A. D atta / Tetrahedron 54 (1998) 15673-1567 8 15677

( $ • 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 .