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T E T R A H E D R O N

L E T T E R SP erg am on T e t r ahedron L e tt er s 40 (1999) 3077-3080

A S h o r t C h e m o e n z y m a t i c S y n t h e si s o f (+ ) - N a r c i c la s i n e

D a v i d G o n z a l e z , i T h e o d o r e M a r t i n ot ," a n d T o m a s H u d l i c k y * 'i"

Chem istry Departm ent, University of Florida, Gainesville, FL 32611Rec eived 16 Decemb er 1998; accepted 9 February 1999

Abstract: The t i tle alkaloid has bee n synthesized in eight operations fr om dibromobenzene and o-

vanillin, via enzymatic oxidation of the former compound, Suzuki coupling and a Bisehler-Napieralski

type cyclization as the key transformations. © 1999 Elsevier Science Ltd. All rights reserved.

N arc i c l a s ine (1 ) , t he l a s t o f t he an t i t um or A m ary l l i daceae a lka lo ids t o y i e ld t o t o t a l syn thes i s , t i s f ound i n

the ex t r ac t o f Lycoris radiate, 2 Pancratium litorale, 3 and Pancratium maritimum, 4 as w e l l a s i n s eve ra l Narcissus

spec i e s , s O f t he fou r w e l l -kn ow n c om poun ds (panc ra t i s ta t i n , 7 -deoxy panc ra t i s t a t i n , l yco r i c id ine , and na rc i c l a s ine )

tha t have a t t r ac t ed a t t en t i on a s po t en t i a l an t i neop l a s t i c agen t s , 6 na rc i c l a s ine i s t he on ly one w ho se m ode o f ac t i v i t y

has been b r i e f l y i nves t i ga t ed . 9cOH

21 3 OH

9 10 I I I~ " ~0 ~ . Jo , . , ] L . .M

( ~ ~r"Ob" ~4b'OH

OH 0

1 Narciclasine

Su zuk i ~ OR enzymat ic Brc ou plin g,. < O ~ . ~ 1 2O R . oxidation ,, / 0

Bischler- - BrO I ~ Y " Y . "O RNapieralski OM e \ NH

2 3 R= Ac , M e2C 4

S che m e 1 . D es ign o f na rc i c l a s ine syn thes is .

T he c lose ly r e l a t ed and m ore abundan t l yco r i c id ine l acks t he 7 -hydroxy l g rou p be l i ev ed t o be im por t an t i n

the b io log i ca l ac t i v i t y o f na rc i c la s ine . 2 P anc ra t i s ta t i n ( lR -hyd roxy-1 0bc tH de r iva t i ve o f 1 ) , and 7 -deoxypanc ra t i s t a t i n a r e r e l a t ed i n t he s am e w ay , bu t t he l a t t e r subs t ance i s abou t 10 t im es l e s s ac t i ve t han t he

fo rm e r i n i den t i ca l ce l l l i ne s c r eens . 7 A n a t t em pt t o con ve r t t he m ore abundan t cong ene r s t o panc ra t i s t a ti n by

hydra t i on o f t he C I -C 10 b o l e f i n w as unsucces s fu l . 8 T o d a t e a t r u ly p rac ti ca l syn thes i s o f I o r i t s conge ne r s has no t

m a te r i a l i zed . T hus , t he supp ly -and -dem a nd i s sue o f an t i t um or sc r een ing o f t hese a lka lo ids has no t been a l l ev i a t ed .

S eve ra l syn theses o f t hese a lka lo ids have been r epo r t ed ; 1"9~ and t he va r iou s syn the t i c s t r a t eg i e s w ere r ecen t l y

sum m ar i zed i n tw o ex ce l l en t r ev i e w s ) 2 In 1995, a chem oe nzym at i c s t r a t egy f rom th i s l abora to ry l ed to t he fi r s t

( and , a t 13 s t eps , s t il l t he shor t e s t ) enan t i ose l ec t i ve syn thes i s o f panc ra t i s t a ti n . 9~ In subsequen t s t ud i e s , w e

addres sed seve ra l m a jo r im provem en t s t o shor t en fu r the r t he syn the t i c s equence and t o p rov ide a fu l l y gene ra l and

h igh ly e f f i c i en t rou t e to a l l f ou r a lka lo ids . I n t h i s r epor t , w e desc r ibe a b r i e f rou t e ( e igh t ope ra t i ons ) t o t he t i tl e

c o m p o u n d v i a a n e n z y m a t i c d i h y d r o x y l a t io n o f m - d i b r o m o b e n z e n e .

m - D i b r o m o b e n z e n e w a s s u b j e c t e d t o t h e w h o l e - c e l l f e r m e n t a t i o n w i t h E. coli J M 1 0 9 ( p D T G 6 0 1 A ) , a n

o r g a n i s m d e v e l o p e d b y G i b s o n 1 315 f o r t h e o v e r e x p r e s s i o n o f t o lu e n e d i o x y g e n a s e ( T D O ) , w h o s e s t ru c t ur e h a s

r ecen t l y been so lved. 16 B ioox ida t i on y i e lded t he new m e tabo l i t e 5 (4 g /L , > 99 % ee ) t ha t p r e sen t s un ique sym m et ry

a n d t w o c h e m i c a l l y d i ff e r e n t v i n y l i c b ro m i n e a t o m s ( C 3 b r o m i n e i s h y d r o g e n b o n d e d t o C 2 O H ) , S c h e m e 2 . T h e

' [email protected]" [email protected]"' hudlicky@ chem.ufl.edu

0040-403 9/99/$ - see f ront mat ter © 1999 E lsevier Science L td. A l l rights reserved.

PH: S 0040-4039(99)00433-5



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rota t ion of the sym me try axis tha t takes place during the t ransform at ion of 4 in to 5 , pos i t ion s the brom ine a toms in

different p lanes . ~ This sy mm etry rota t ion wil l la te r a l low the se lec t ive incorpora t ion of the arom atic fragment of

narc ic las ine . Diol 5 was t ransformed in a one-pot opera t ion to bicycl ic oxazine 6 in 70% yie ld , as shown in

Schem e 2, Reduct ion o f th is mater ia l un der K eck 's condi t ions R7:8 to yie ld the condu ramin e oxidat ion s ta te as

previou s ly reported, 1°¢ 'a :9 gave p redom inant ly the fu l ly dehalogen ated conduram ine d eriva t ive 7b.

We s tud ied the pos s ib i l i t y o f r educ ing the oxaz ine to uns a tu rat ed ke tone 8 . Tr ibu ty l tin hydr ide o r tris-

t r imeth yls i ly ls i lane (TT MS S) are sui ted for th is t ransforma t ion but cannot be app l ied to oxazine 6 s ince

overreduc t ion of the vinyl ic bromine is unavoida ble under such condi t ions . Conv erse ly , Mo(CO)62° c leanly

reduced d ib romina ted oxaz ine 6 to the co r re s pond ing b romo ke tone 8 w i th concom i tan t ( and in t e re st ing ) c l eavage

of the ace ton ide p ro tec t ing g roup . Wi th th i s r e s u l t in hand , w e exp lo red the pos s ib i l i t y o f d i rec ted hydr ide

reduct ion b y m eans of Zn(BH4)221 or Na(AcO)3BH4. 22 To date th is reac t ion has prov ided t r io l 9 in only a

d i s appo in t ing 10% d ia s t e romer ic exces s (HPLC ) . To c i rcumven t the p rob lem o f ove r t ' educ tion o f the b romine

a tom, we d ec ided to coup le the a rom a t i c po r t ion o f the a lka lo id d i rec t ly to ox az ine 6 and pos tpone the b r idge

opening to a la ter s tage in the synthes is . Surpris ingly , oxazine 10 was res is tant to a luminum ama lgam reduct ion,

while s t ronger reducing agents led to ful ly sa tura ted products . This resul t c losed the direc t reduct ion pa thway tothe c t -hydroxy com pound ; therefore , we chose to t ransform 10 in to unsa tura ted ke tone 12 with TT MS S.

In te res t ing ly , a cons ide rab le amoun t o f 11 (10 -15%) was fo rmed du r ing Suzuk i cou p l ing o f b romide 6 w i th

bora te 2 (prepared from o-vani l l in in four s teps and 20% overa l l y ie ld 23) prob ably through a Pd inser t ion-type

mechan i s m. Gu ided by th i s obs e rva t ion we d ec ided to add ace ton i t ri l e and M o(C O)6 d i rec t ly to the Suzuk i r e ac tion

mixture af te r the coupl ing was f in ished. Heat in g of th is mixture for 10 hours afforded ke tone 11 in 45% yie ld ,

reaching the advanc ed in termed ia te 11 in only three s teps from m-dibrom obenzen e .

In order to se t the s te reochemis try a t C2 (n arc ic las ine num bering) , we app l ied the kno wn NaBH4 redu ct ion

fol lowed by M itsunobu invers ion sequence as repo rted by Ch ida in his lyco ric idine prep ara t io n) °b'c This proced ure

gave c l ean ly the de s i red a -benzoa te 14 in 50% ( f rom 12).

A mod i f i c a t ion o f the B i s ch le r -Nap ie ra ls k i r e ac t ion repor t ed by B anwe l lTM

and app l i ed wi th s ucces s by thesame author in s impli f ied mode ls of phenanthridone a lka loids , 4b was cho sen to c lose r ing B of the ta rge t a f te r the

required manipula t ion of ace tonide 14 in to diace ta te 15 (30% ov er the three s teps) . Fina l ly , rem oval of the es ter

and m e thy l e the r p ro tec tive g roups in 16 (Am ber lys t ba s i c , M eOH and LiC I , DM F re s pec t ive ly ) 5 rende red

synthet ic narc ic las ine (1) whose ~H NM R and opt ica l ro ta t ion matched the reported da ta for the a lka loid .26

Overa l l , we have comple ted a to ta l synthes is of narc ic las ine in 12 s teps carr ied out as only 8 individual

chemica l ope ra t ions f rom m -d ib romobenzene (14 f rom o -van i l li n ) . A comple te de s c r ip t ion o f the rou te s dep ic t ed in

Schem e 2, wi th focus on the resul ts obta ined in the reduct ion of the oxazin e sys tem un der different condi t ions as

wel l as the Zn(BH4)2 reduct ion o f d ihydro xy ketones , wi l l appear in an upcom ing ful l account .

A c k n o w l e d g m e n t

We thank Dr . Dav id T . G ibs on fo r p rov id ing us w i th a s ample o f E. coli J M 109(pDTG601A) , Dr . M ary Ann

Endoma fo r he r a s s i s tance in the b io t rans fo rma t ion expe r imen t s , and Dr . Ion G h iv i r iga fo r NM R s upport .

F inanc ial s uppor t by TDC R es ea rch Fo unda t ion (Fe l lows h ip to TM ) , N a t iona l Sc ience Founda t ion (C HE-9315684

and CHE-9521489), and U.S. Environm enta l Protec t ion Ag ency (R826133) are gra teful ly ackno wledg ed.



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Br Br Br Q,H

i' i ~ ........ Br" 5 ~" I~OH" BrO ~ O M e NHCO2Me4 S i v : v / \

o°e po , / . t \ v'vl \

0 ~ Br t O,

0 v i /k~~ . ~ O...~O_Me Br ~HcoOHe('0~ 1 ~ NHCO2Me

O M e 1 1 O M e 1 0 8

viii

t O H .O , z

~0~ . ~ NHCO,Me ~ 0 ~ NHCO=Me

O M e O M e

1 2 1 3

x ii

7=,;X : Br (1%)7b ; X=H 99%)

vii OH

~Br OHNHCO2Me

OBzi

: - ~ , ~ O A c

~ 0 - ~ J N H C O 2M e

O M e

1 4 I x i

O B z

-~.,..~OAc

O ~ NH

O M e 0

1 5

i) E. coil JM I09 (pDTG601A), 4 g/L; i i ) DM P, acetone, TsOH, r t ; then NHCO 2Me, NalO4, rt , 70%; i i i) AI(Hg) ,

THF, 80%; iv) borate 2, Pd(PPh3)4, aq. Na2CO3, Phil , reflux, 30%; v) Mo(CO)6, M eCN -H20 , ref lux, 75%; vi)

TTM SS, AIB N, Ph il, reflux, 80%; vii) Zn(BI-h)2, DM E, -10 °C, 70% ; viii) NaBH 4, CeCI3, MeO H, 0 °C, 80% ; ix)

BzOH, B u3P, DEA D, THF, r t, 65%; x) Dow ex 50X8-100, MeOH , r t ; then Ac20 , py, DM AP, r t, 70%; xi) Tf20,

DMA P, CH2CI2, 0 °C, 40%; xi i) Amb er lys t A21, M eOH, r t ; then LiCI , DMF, 120 °C, 20%.

Scheme 2. Sum mary of the narciclas ine synthesis.

R e f e re n c e s a n d n o t e s

§ We can designate these planes as "prochemotopic", in addition to "proenantiotopic", since the vinylic bromine

atom s will bec om e chemically d ifferent after the next operation. Th e Diels-Alder cyc load dition transformed

the bromine at C3 into an allylic one.

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2 5 . W e th a n k Dr . S . P u l l e y ( U . o f M is s o u r i ) a n d P r o f . B . M . T r o s t ( S ta n d f o r d U . ) f o r s u p p ly in g th e c o r r e c t

condi t ion s for the f ina l dem ethyla t io n . In the or ig ina l pap er by these au tho rs ( re f . 9d ) the use o f LiI is r eported .

2 6 . W e th a n k P r of . J . H . R ig b y a n d th e Na t io n a l C a n c e r I n st itu te f o r p ro v id in g th e NM R a n d TL C d a ta a s we l t a s a

sam ple o f na tura l narc ic lasine .

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