a convergent total synthesis of the michellamines

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A Convergent Total Synthesis of the Michellamines|

G e r h a r d B r in g ma n n , *, Rola nd G ot z, P aul A. Keller, Rainer Walter, Michael R. Boyd,

F e n g r ui L a n g , Alberto G ar cia, J ohn J . Walsh, Imanol Tellitu, K . Vija y a B h a s k a r , a n dT. Ross Kelly* ,

I n s t i t u t f u r Organi sche Chemi e, U ni versi t a t Wu r z b u r g , A m H u b l a n d , D - 9 7 07 4 W u rzburg, Germany,Laborat ory of Dr ug D i scovery Research and Devel opment , N at i onal Cancer I n st i t ut e, B ui l di n g 1052,

Room 121, Frederi ck, M aryl an d 21702-1201, and Depart m ent of Chemi st ry, E ugene F. M erk ert Chemi st ryCenter, B oston Col lege, Chestn ut H il l, M assachusetts 02167-3860

Received August 12, 1997

A convergent tota l synt hesis of the a nti-HI V michellamines (1) is described. The tetra a ryl skeletonof the michellam ines wa s constructed by forma tion f irst of the inner (nonstereogenic) biaryl a xisan d subsequently of the t wo other (stereogenic) axes in a highly convergent ma nner. The keytra nsforma tion feat ures a double S uzuki-type cross-coupling reaction between binaphtha leneditr i f late 26 a nd isoquinolineboronic acid 35. D i t r i f l a t e 26 is synthesized in six steps starting fromdiene 6 a nd 2,6-dibromobenzoquinone (9) in 21%overall yield. For lar ge scale production of 26, asubstantially shortened version of an existing procedure for the preparation of bisnaphthoquinone13 wa s a lso developed, which a l lows for t he prepar at ion of 13 from benzoquinone and diene 6 inf ive steps and 67%overall yield. B inaphthoquinone 13 wa s subsequently converted into di tr i f lat e26 in three steps an d 67%overall yield. B y th e described synt hetic strat egy, michellam ines A (1a)a n d B (1b) are produced (1a:1b ) 1:2.5) in 24.6%overall yield from diene 6. Curiously, none ofthe nonnatura l ly occurring at ropoisomer 1c is formed.

Introduction

The lack of effective drugs for the treatment of AIDSled t h e U n it ed S t a t e s N a t ion a l C a n cer I n st i tu t e t oinitia te in t he lat e 1980s a ma jor effort to discover novelHIV (human immunodeficiency virus) inhibitory agentsfrom natural sources.1 In 1991, Boyd et al .2,3 reportedthe isolation of two anti-HIV alkaloids, michellamines Aand B, f rom the tropical plant Ancistroclad us k orupensisnat ive to Ca meroon. Michellam ine B, the more potentand abunda nt of the na tura l ly occurring michellamines,aborted viral replicat ion an d virus-induced cell ki l l inga c r o s s a n u n u s u a l l y b r o a d r a n g e o f H I V s t r a i n s a n disolates in diverse human host-cell types. 3

B y a co mb i n a t i on of s p ec t r os cop ic a n d d e gr a d a t i v estudies2-6 michellamines A and B were assigned struc-tures 1a a nd 1b, r e s p e c t i v e l y , w i t h t h e r e l a t i v e a n dabsolute configurations shown. Init ial ly, the third pos-

sible a tropisomer n amed michellamine C (1c) w a s a l soi s o l a t e d , b u t w a s l a t e r f o u n d t o b e a n a r t i f a c t f o r m e dunder too harsh isolation conditions.3,7

The isolat ion of michellam ine C (1c) a pparently resultsf r om t h e f a c t t h a t t h e m i ch e ll a m i n es c a n b e i n t e r con -verted by epimerizat ion under basic conditions.3 Atequilibrium the ra tio of michellamines A, B, an d C is 3:3:1. Alth ough michellam ine C (1c) is t hermodynam ically

| P ar t 102 in th e series Acetogenic Naphthy lisoquinoline Alkaloids(from the U niversity of Wurzburg). For part 101, see: Br ingma nn, G .;Sa eb, W.; Wenzel, M.; Fra nc ois, G .; S chlauer, J . Ph a r m . Ph a r m a c ol .Lett., s u b m i t t ed . P a r t 4 7 in t h e s e r i es : H I V -I n h i bi t or y N a t u r a lP r o d u ct s (f r om t h e N a t i on a l C a n c er I n s t i t ut e ). F o r p a r t 4 6, s e e:Ha llock, Y. F.; Ca rdellina , J . H., II ; Scha ffer, M.; Br ingman n, G .; Boyd,M. R. Bi oMed. Chem. Lett., submi t ted.

Inst itute fu r Orga nische Chemie. N ati onal Canc er I nst i tute. Boston College.(1) Boyd, M. R. In AIDS Etiology, Diagnosis, Treatment and Preven-

t ion; De Vita, V. T., J r., Hellman, S., Rosenberg, S. A., Eds.; Lippin-cott: Ph iladelphia, 1988, p 305.(2 ) Manfredi , K. P . ; B l unt , J . W.; Ca rdel li na, J . H . , I I ; Mac Mahon,

J . B . ; Pa nnel l, L . L . ; G ordon, M. C . ; Boy d, M. R. J. M ed. Chem. 1991,34, 3402.

(3 ) Boy d, M. R. ; Ha l l oc k, Y. F. ; Ca rdel li na, J . H . , I I ; Manfredi , K.P. ; B l unt , J . W.; Ma c Mahon, J . B . ; B uc khei t , R. W.; Bri ngma nn, G . ;Schaffer, M.; Cra gg, G . M.; Thoma s, D . W.; J ato, J . G. J. M ed. Chem.1994, 37, 1740.

(4) B r i n g m a n n , G . I n T h e A l k a l oi d s ; Brossi , A., E d. ; Ac ademi cPr ess: New York, 1986; Vol. 29, pp 141-184.

(5) Bringma nn, G .; Zagst , R.; Schaffer, M.; H allock, Y. F.; Ca rdellina,J . H. , I I ; B oy d, M. R. An g ew . C h e m ., I n t . Ed . En g l . 1993, 32, 1190.

(6 ) Bri ngma nn, G . ; G ul den, K .-P. ; Ha l l oc k, Y. F. ; Man fredi, K. P. ;C a r d e ll in a , J . H . , I I ; B o y d , M . R . ; K r a m e r , B . ; F l ei s ch h a u e r , J .Tetrahedron 1994, 50, 7807.

(7) Br ingma nn, G.; Ha rmsen, S.; H olenz, J .; Geuder, T.; Gotz, R.;Keller, P. A.; Walt er, R.; Ha llock, Y. F.; Car dellina, J . H., II ; B oyd, M.R. Tetrahedron 1994, 50, 9643.

1090 J . O r g . C h em . 1998, 63 , 1090-1097

S0022-3263(97)01495-3 CCC : $15.00 1998 American C hemical SocietyP ubl ish ed on Web 01/27/1998


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less stable than the other two atropisomers, the reasonf o r t h e a p p a r e n t t o t a l a b s e n c e o f 1c i n n a t u r e i s u n -known.

Th e p r on ou n ce d b i ol og i ca l a c t i vi t y a s w e l l a s t h e

s t r u c t u r a l n o v e l t y o f t h e m i c h e l l a m i n e s h a s a t t r a c t e dmuch interest f rom synthetic chemists, especial ly af tert h e U . S . N a t i o n a l C a n c e r I n s t i t u t e p u b l i s h e d 8 a n a n -n ou n ce m en t e n cou r a g i n g t h e r e se a r ch co mm u n i t y t op u rs u e s y n t h e t i c a n d /or ot h e r s t u d ie s a i m e d a t t h eproduction of michella mine B . In principle, the michel-lamines can be most ef ficiently dissected retrosyntheti-ca l l y i n t w o m a n n e r s (S c h em e 1 ). O n e r e t r os y n t h e s isl ea d s t o a b iom i m et i c p a t h w a y (A) t h a t i n vol ve s t h econst ruction of th e naph th a lene/isoquinoline bonds pr i or to the forma tion of the centra l napht ha lene/na phtha leneaxis. By contra st, the complementa ry pathw a y (B ) wouldh a v e t h e c e n t r a l a x i s e s t a b l i s h e d f i r s t , w i t h t h e t w oisoquinoline moieties being added subsequently.

The first synthesis of the michellamines was achievedin 1994 following the biomimetic concept.7,9,10 I n t h i sapproach, the monomeric halves of t he m ichellam ines,korupensa mines A (2, R ) H , X ) H, axis, P-configured)a n d B (3, R ) H , Y ) H, axis, M-configured), which alsooccur in A. korupensis,11 were synthesized 9,10 a n d t h enhomo- or cross-coupled by biomimetic oxidative dimer-ization of a ppropriately protected 2 a n d/or 3 usingsilver(I) oxide.7,10

The second synthesis,12 which was completed only afew months later , fol lows the complementary pathway(B), by f irst esta blishing the centra l bond to result in adimeric napht halene unit , w hich is t hen connected w iththe corresponding isoquinoline parts by a double Suzuki-type cross-coupling rea ction.

Since then, a ddit ional syntheses ha ve been publishedfrom the la borat ories of Hoye13 a n d D a w s on 14 followingp a t h w a y A , t h e c e n t r a l a x i s a g a i n b e i n g b u i l t u p b yoxidative dimerizat ion using Ag2O13 or by Suzuki-typecross-couplings.14 These a nd oth er 15-17 synthetic effortsto build up both m ono- a nd dimeric napht hylisoquinolinealkaloids strongly underline the worldwide interest inthis promising field of research.

We origina lly reported t he present synt hesis in a briefcommu nicat ion in 1994.12 We now provide greater det ailand experimental procedures and also describe some oft h e a n c il la r y s t u di es t h a t f a ci li t a t e d t h e s y n t he si ssachievement.

Results and Discussion

The f irst sta ge of the synth esis required the prepara -tion of the binaphthalene synthon 5. To t h a t e n d, w eundertook the synthesis of bromona phthoquinone 11since dimerization of 11, or derivatives thereof , wouldafford access to the carbon skeleton of 5.

B r a s s a r d 18 reported that chloronaphthoquinone 8 ca n

be prepared r egioselectively in 74%overall yield from th eknown diene 618,19 a nd 2,6-dichloro-1,4-benzoqu inone (7)b y a D i e ls-Alder reaction followed by aromatization ofthe a dduct on silica gel an d final O-methy lat ion (Scheme2).

S i n ce b r om i de s a r e g en er a l ly m or e r ea c t iv e t h a nchlorides in met a l-cat a lyzed coupling reactions, t he bro-m o a n a l og u e 11 w a s p re pa r e d f rom 9. U s in g 2 ,6-dibromo-1,4-benzoqu inone (9)20 a s t h e d i e n o p h i l e a n d618,19 a s diene, bromoquinone 10 wa s synt hesized in 70%

(8) Anon . J . N a t . Pr o d . 1992, 55 , 1018.(9) Bringma nn, G .; Gotz, R.; Keller, P . A.; Walter, R.; Henschel, P .;

Scha f fer, M.; S ta b lein, M.; K elly, T. R.; B oyd, M. R. H eterocycles1994,39, 503.

(10) Br ingma nn, G.; Gotz, R.; Ha rmsen, S .; Holenz, J .; Walter, R.Liebigs Ann. Chem. 1996, 2045.

(11) Hallock, Y. F.; Ma nfredi, K. P .; Blun t, J . W.; Ca rdellina, J . H.,II ; S chaffer, M.; G ulden, K.-P .; Br ingma nn, G .; Lee, A. Y.; Clar dy, J .;F r a n cois, G . ; Boy d, M. R. J. Org. Chem. 1994, 59, 6349.

(12) Kelly, T. R.; Garca, A.; Lang, F.; Walsh, J . J . ; Bhaskar, K. V.;

B o y d , M . R . ; G ot z , R . ; K e l le r , P . A. ; W a l t er , R . ; B r i n gm a n n , G .Tetrahedron Lett . 1994, 35, 7621.(13) Hoye, T. R.; Chen, M.; Mi, L.; Priest, O. P. Tetrahedron Lett.

1994, 35, 8747.(14) Hobbs, P. D.; Upender, V.; Liu, J .; Pollart, D. J .; Thomas, D.

W.; Da wson, M. I . J. Chem. Soc., Chem. Commu n. 1996, 923. Hobbs,P. D . ; U pender, V.; Daw son, M. I . Synlett 1997, 965.

(15) (a) Hoye, T. R.; Mi, L. Tetrahedron Lett. 1996, 37, 3097. (b)Hoye, T. R.; Chen, M.; Tetrahedron Lett. 1996, 37, 3099.

(16) Upender, V.; Pollar t, D . J .; Liu, J .; Hobbs, P . D.; Olsen, C.; C ha o,W.; B owden, B. ; C rase, J . L . ; Thomas, D. W.; P andey , A.; L aw son, J .A.; Daw son, M. I . J . H eterocyc. Chem. 1996, 33, 1371.

(1 7) (a) Rama Rao, A. V.; Gurjar, M. K.; Ra mana , D. V.; Cheda , A.K . H eterocycles1995, 43, 1. (b) Gable, R. W.; Mar tin, R. L.; Rizza casa ,M. A. Aust. J. Chem. 1995, 48, 2013. (c) Wat an abe, T.; Kamika wa , K.;U e m u r a , M . Tetrahedron Lett. 1995, 36, 6695.

(1 8) Savard, J . ; Br assa rd, P . Tetrahedron 1984, 40, 3455.(19) Casey, C . P .; J ones, C. R.; Tukeda, H. J. Org. Chem. 1981, 46,

2089.

Scheme 1 Scheme 2

Convergent Total Synthesis of the Michellamines J. Org. Chem., Vol. 63, No. 4, 1998 1091


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yield (Scheme 3). Methylat ion of 10 by ref luxing in

methy l iodide in the presence of silver (I) oxide ga ve thedesired methy l ether 11 in 97%yield.

Bromoquinone 11 wa s converted into sta nnane deriva-tive 12 in 71%yield by heating at 100 C in dioxane withB u 6S n 2 and bis(triphenylphosphine)palladium(II) chlo-ride.21 A second palladium-promoted reaction,21 utilizingt h e s a m e ca t a l ys t , cou pl ed s t a n n a n e 12 a n d b r om o-quinone 11 to a f ford binaphthoquinone 13. B e ca u s e 13i s l ig h t s en s it i ve , i t w a s u s ua l l y con v er t e d w i t h ou tpurification to 14 by reductive a cetylat ion. The yield of14 from 12 is 65%(Scheme 4).

Since t he tw o consecutive coupling reactions lead ingt o 13 use th e sa me rea ction conditions, it proved possiblet o m a k e 13 in a s in g le s t ep. Th us , w h e n h a lf a n

equivalent of Bu 6S n 2 wa s used in the reaction of 11, af terreductive peracetylat ion, tetra acetat e 14 wa s isolated in40%yield. We previously reported 12 t h a t t h e d i m er i za -

tion of 11 t o 13 could be rea lized in a simila r yield (43%)by a n U llmann coupling rea ction w ith copper bronze inthe presence of tetrakis(triphenylphosphine)palladium-(0) in DMF ,22 but the current Stille-type23 coupling routeis preferred (Scheme 4).

The binapht hoquinone 13 ha d been synthesized before

b y L a a t s c h 24,25 v ia a n ox id a t i v e c ou p li n g a s s h ow n i nScheme 5. Although our four-step synt hesis of 13 isseveral st eps shorter t ha n t he one in S cheme 5, we a lsoexplored th e possibility of improving t he la tt er route. Tothat end, we f irst developed an improved synthesis of19.24-26 The new synthesis sta r ts w ith the D iels-Alderreaction between diene 618,19 a n d b en z oq u i n on e (16),which af fords the adduct 24 cleanly. Desilylat ion of 24i n m e t h a n o l w i t h a q u e ou s H C l a n d s u b se q u en t a r o m a -tiza tion gave th e desired product 19 in 41%overall yield.When excess benzoquinone (16) was used in the Diels-Alder rea ction, t he leftover 16 could serve as t he oxida ntfor the aromatization, which avoided the use of PCC inthe original procedure.

We were plea sed wit h th is modified synt hesis beca usei t w a s s h o r t er t h a n t h e l i t e r a t u r e s e q ue n ce , b ut i t w a sn ot a p er f ect s ol u t io n. F o r a l t h o u g h t h e D i el s-Alderreaction w as fast an d clean, the cleava ge of ketal 24 onlyaf forded na phthoquinone 19 i n a m o d er a t e y i e ld . An dan O-methylat ion step w as st i l l needed for th e prepara -tion of 20.

(20) P repared in 52%yield using the procedure of Hodgson, H. H.;Nixon, J . J. Chem. Soc. 1930, 1085. The crude product was purifiedb y p a s s in g a C H 2C l2 solution of it through a column of silica gel. Anumber of preparations of 9 have been reported i n the l i terature, butwe found this m ethod (the oxidat ion of 2,4,6-tribr omophenol using 90%fuming nitric acid) to be the most reliable one.

(2 1) F or r e ce n t r e vi ew s , s e e: (a ) F a r i n a , V. I n ComprehensiveOrganometall ic Chemistry II ; Abel, E. W., St one, F. G. A., Wilkinson,G. , Eds.; P erga mon: Oxford, 1995; Vol. 12 (Hegedus, L. S ., Ed.), p 161.(b) Knight, D. W. In Comprehensive Or ganic Synthesis; Trost, B. M.,Fl eming, I . , E ds. ; P ergamon P ress: O xford, 1 99 1; Vol. 3 ( Pat tenden,G., Ed.), Chapter 2.3. (c) Bringmann, G.; Walter, R.; Weirich, R. Angew.C h em . , I n t . Ed . E n g l . 1990, 29, 977.

(2 2) Shi mi z u, N .; Ki tamura , T.; Wata nabe, K. ; Yamaguc hi , T.;Shigyo, H.; Ohta, T. Tetrahedron Lett. 1993, 34, 3421.

(23) St ille, J . K . An g ew . C h e m ., I n t . E d . En g l . 1986, 25, 508.(24) Laa tsch, H . Liebigs Ann. Chem. 1980, 1321.(25) (a) Krohn , K . Tetrahedron Lett. 1980, 21, 3557. (b) Krohn, K.;

Broser, E . J. Org. Chem. 1984, 49, 3766.(26) Ros ner, A.; Tolkiehn, K.; Kr ohn, K. J. Chem. R es. (M) 1978,

3831.

Scheme 3

Scheme 4

Scheme 5

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To further improve the synthesis, w e sought to opti-mize the cleavage of ketal 24. Since an a cid milder tha nHCl might give a clean er reaction, a cetic acid wa s testeda n d t h e r e su lt w a s m os t r e w a r d i n g. Th u s, a f t er t h eDiels-Alder rea ction betw een diene 6 and benzoquinone(16) i n C H 2C l2 w a s c om p le t e, a ce t i c a ci d w a s a d d ed t othe reaction solution. Eva pora tion of the solvent ga ve,surprisingly, the desired methyl eth er 20 instead of theexpected phenol 19 a s t h e p r od u ct (S c h em e 6 ). Th er e a s o n w h y 20 is formed instead of 19 is unclear , butthe one-pot rea ction provides 20 in 85% overall yieldbased on diene 6.

Compound 20 w a s t h e n c o n v e r t e d t o 13 u s i n g t h epreviously reported24 procedures (Scheme 5). The syn -thesis of 13 vi a 20 s t i ll h a s m o r e s t e ps t h a n t h e r o u t evi a 11, b u t t h e s y n t h e s is o f 13/14 vi a 20 i s e a s i er a n dfaster, and better suited for large-scale production.

As a l r e a d y m e n t ion e d , q u i n on e d i m er 13 i s l ig h ts en s i t iv e, s o i t w a s u s u a l ly n ot p u r if ie d b u t i n s t ea dreductively peracetylat ed27 directly to af ford t etraa ceta te14. The tra nsforma tion is conveniently carr ied out a troom tempera ture by st irring a m ixture of crude 13, zincp ow d e r , a c e t ic a n h y d r i d e , s o d iu m a c e t a t e , a n d 4 -(d i -methylamino)pyridine (DMAP) in CH 2C l2 overnight. Theconversion of 13 t o 14 proceeds cleanly: With a puresample of 13, 14 was obtained in 95%yield.

Tetraacetate 14 cont a ins the ent ire ca rbon skeleton oft h e b i n a p h t h a l e n e s y n t h o n 5, b u t i t i s n o t p rop er lyfunctionalized for biaryl coupling with the isoquinolineunits. Refunctionalization began with a selective bis-d e a c e t y l a t i o n a t t h e l e s s h i n d e r e d s i t e s w i t h D B U i n

methanol 28 to give diacetat e 25; without purification, 25was subsequently converted 29 i n t o d i t r if la t e 26 usingtrifluoromethanesulfonic anhydride (Tf2O) an d 2,6-luti-dine in CH 2C l2. The tw o-step sequence gave 26 in 70%yield from 14 (Scheme 7). Ditr i f late 26 w a s a l s o c o n -verted into the distannanes 27a a n d 27b an d diiodide30

28 (Scheme 7) so that three dif ferent types of binaph-thalene units were available for coupling with various

isoquinoline synthons.We a n t i ci pa t e d s t e r ic h i n d r a n ce31 t o b e t h e m a j o robsta cle in t he coupling reaction between the napht ha -l e n e a n d i s o q u i n o l i n e u n i t s t o g i v e t h e m i c h e l l a m i n eskeleton. The isoquinoline unit 4 can be considered abenzene ring with t wo substit uents orth o to the couplingposition, w hile naphth alene 5 () 26-28) can be regardeda s a b en z en e r i n g w i t h o n e s u b st i t u en t or t h o t o t h ecoupling posit ion. I t is very congested a t the couplingpositions. For elabora tion of the best coupling conditions,we decided to carry out model coupling studies in orderto save the precious enantiomerically pure isoquinolineunit 34.

Orcinol derivatives 29, 30, a n d 31 were used a s models

because they are similar to the isoquinoline unit in bothsteric a nd electronic respects. The sta nna ne derivatives30 were prepared30 by first lithiation of the correspondingbromide 29 fol lowed by reacting with Bu 3SnC l (Scheme8). The boronic a cids32 31 were prepared by lithiation of29 and subsequent reaction with tr i isopropyl borate ass h ow n i n S ch em e 8. Af t er v a r iou s p er m u t a t ion s ofpotential coupling partners were examined (26-28 w i t h

(27) For a lead ing reference, see: Ulrich, H.; Richter, R. In M eth odende Organische Chemie (Houben-Weyl) : C h i n o n e ; Georg Thieme Ver-lag: Stu ttg ar t, 1977; Teil I , p 652.

(28) Ba ptistella, L. H. B .; dos San tos, J . F.; Ba llabio, K. C .; Marsa ioli ,A. J . Synthesis 1989, 436.

(2 9) Stang, P . J . ; Han ac k, M.; Subraman i an, L . R. Synthesis 1982,85.

(30 ) I n g h a m , R . K . ; R os e n be r g, S . D . ; G i l m a n , H . Chem. Rev.(Washin gton, D.C.) 1960, 60, 459.

(31) (a) Thompson, W. J .; G a udino, J . J. Or g. Chem. 1984, 49, 5237.(b) Saa , J . M.; Ma rtorell , G.; Ga rcia-Ra so, A. J. Org. Chem. 1992, 57,678. (c) Fu, J .-m.; Sn ieckus, V. Tetrahedron Lett. 1990, 31, 1665.

(3 2) For a l eadi ng reference, see: Hevesi, L . I n ComprehensiveO r g a n i c F u n c t i o n a l G r ou p T r a n s f or m a t i o n s ; Ka tri tz ky , A. R. , Meth-Cohn, O., Rees, C. W., Eds.; P erga mon: Oxford, 1995; Vol. 2 (Ley, S.V., Ed.), p 899.

Scheme 6 Scheme 7



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29-31), i t w a s d e t er m i n ed t h a t S u z u k i-t y p e33,34

cross-coupling reactions between ditriflate 26 and boronic acids31 ga ve the best yield for th e desired coupling. Couplingreactions between ditriflate 26 a nd boronic a cids 31 werecarr ied out in the presence of tetrakis(tr iphenylphos-phine)pallad ium(0) a nd bar ium hy droxide34 to a fford 32aa nd 32b in 88%and 94%yields, respectively.

With a method established for ma king the f inal biarylbonds, w e turned t o the synt hesis of the m ichellam inesthemselves. P repara tion of the specifica lly protected keyheterocyclic building block 34 (S c h em e 9 ) in a s t e r e-ochemically homogeneous form, was done as describedpreviously. 9,10,35

The subsequent conversion of 34 into th e isoquinolineboronic a cid 35 was achieved in 89%yield by the samemethod used above for preparation of the orcinol-derivedboronic acids 31 (Scheme 10). B oronic acid 35 w a s t h encoupled with di tr i f late 26 u n d e r t h e s a m e c o n d i t i o n selaborat ed for t he m odel compounds to give 36 a s am i xt u r e of a t r op is om e r s. D e p ro t ec t ion of t h e b en z y lgroups wa s ca rried out by cat alyt ic hydrogenat ion; all sixbenzyl protecting groups were removed by hydrogenationw i t h 1 0% p a l la d i u m on ch a r c oa l i n e t h a n ol a t a t m o-

s ph er ic p r es s ur e f or 14 h . Th e t w o a c et a t e s i n t h enaphthalene unit were f inal ly taken of f in the last stepof the synth esis using meth an olic HCl.

The result ing mixture of a tropisomers w as separ at edby preparative HPLC to give michellamine A (1a) a n dmichellamine B (1b) (1a: 1b ) 1:2.5). The synth etic 1aa nd 1b were show n t o be identical, by d irect comparison,to authentic, na tura l ly derived ma terials. However , we

w e r e u n a b l e t o d e t e c t a n y m i c h e l l a m i n e C (1c) i n t h esynthetic mixture even though we ha d a sample of 1c a sa TLC/HP LC sta nda rd. The question of why 1c is notdetecta ble in ei ther t he na tura l source or our synt heticmixture is intr iguing. Atropisomer 1c is a stable com-pound 3 (al though sl ightly underrepresented in a ther-modynamically dictated mixture of 1a, 1b, a n d 1c) a n dhas been synthesized previously. 10 While its a bsence inp la n t m a t e r ia l p re su m a b ly h a s t o d o w i t h t h e h i g hspecificity of the dimeriza tion enzyme, w hich ha s recent lybeen isolated,36 at least one of the tw o coupling steps inour synthesis must proceed w ith a high dia stereoselec-tivi ty. Of great interest w ould be the a xial configurationof the intermediate monocoupled product, which would

i nd ica t e t h e d eg r ee of a s y m m et r ic i nd u ct i on b y t h estereocenters present in 35 a n d w o u l d t h u s a l l o w a nestimation of the additional degree of asymmetric induc-t i o n e x e r t e d b y t h e f i r s t - g e n e r a t e d b i a r y l a x i s o n t h esecond coupling step. Regreta bly, a ll a tt empts to isola teor at least detect such a monocoupled intermediate inthe reaction of 35 a n d 26 failed.

Biological Evaluation of Synthetic 1a/1b. Thea n t i v i r a l a c t i v i t y o f t h e s y n t h e t i c m i c h e l l a m i n e s w a sindistinguisha ble from tha t previously reported 2,3 for th enatural compounds (data not shown).(33) Miya ura , N.; Ya na gi, T.; Suzuki, A. Synth. Commun. 1981, 11,

513.(34) (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.

(b) Suzuki, A. Pu r e Ap p l . C h em . 1994, 213.(3 5) Bri ngman n, G. ; Wei ric h, R. ; Reuscher, H.; J ansen, J . R. ;

Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877.

(36) Schla uer, J .; Wiesen, B .; R uckert, M.; AkeAssi, L.; H a ller, R.D.; B ar , S.; Frohlich, K.-U.; Br ingma nn, G. Arch. Biochem. Biophys.1998, 350, 87.

Scheme 8

Scheme 9

Scheme 10



6/8

Conclusion. The convergent synthesis describedherein provides the michellamines in an overall yield of24.6%from diene 6.

Experimental Section37

2-Bromo-8-hydroxy-6-methyl-1,4-naphthoquin-one (10). To a solution of 2,6-dibromobenzoquinone20 (9)(11.65 g, 43.8 mmol) in 70 mL of dry THF a t 0 C undera n itrogen at mosphere was a dded dropwise via a syr ingepump over 1 h a solution of diene 6 (9.07 g, 48.7 mmol)in 40 mL of dry THF . The resulting solution wa s stirredat room t empera ture for 3 h. Then 250 g of 230-400mesh si l ica gel was added, and the mixture was shakenunti l i t appeared homogeneous and al lowed to stand atroom t empera ture for 48 h. Subsequently, the reactionmixture w a s put directly onto a silica gel column (4 in. x10 in.) a nd purified by elut ing w ith pet roleum ether/ethy la ceta te (7:3) to give 8.18 g (70%) of bromoquin one 10 a san orange red solid, mp 186-187 C : I R (K B r ) 3438,1638 cm -1; 1H N M R ( C D C l3, 400 MHz) 2.45 (3H, s),7.10 (1H, s), 7.45 (1H, s), 7.46 (1H, s), 11.69 (1H, s); 13CNMR (CDCl3, 100 MHz) 22.9, 112.6, 122.0, 125.0, 132.1,140.2, 141.6, 150.0, 163.0, 182.6, 182.9. Ana l. Ca lcd forC 11H 7O3B r: C, 49.47; H, 2.64. Found: C, 49.40; H, 2.57.In a ddit ion, 1.27 g (10%) of met hyl ether 11 was obtainedas a yellow solid.

2-Bromo-8-methoxy-6-methyl-1,4-naphthoquin-one (11). A mixture of 5.38 g of 10 (20 mmol), 6.98 g ofAg2O powder, an d 100 mL of iodometha ne w as ref luxedfor 1 h. Then the mixture wa s f i ltered through Celitea n d t h e C e li t e a n d t h e s ol id w e r e w a s h e d w i t h C H 2C l2.The filtrate and the wash were combined and evaporatedto give 5.49 g (97%) of br omona phthoquinone 11 a s ayellow solid. The crude product w as used in th e nextr e a ct i on w i t h o ut f u r t h er p u ri fi ca t i on . An a n a l y t i ca lsample of 11 w a s ob t a i n e d b y r e cr y s t a l l iz a t i o n f r o metha nol as a yellow solid, mp 175-177 C: IR (CH 2C l2) 1667, 1597 cm -1; 1H NMR (CDCl3, 400 MHz) 2.48 (3H,s), 4.00 (3H, s), 7.10 (1H, s), 7.41 (1H, s), 7.54 (1H, s);13C N M R ( C D C l3, 100 MHz) 23.0, 57.1, 117.1, 119.2,121.1, 134.4, 138.8, 143.5, 147.9, 161.3, 176.5, 183.5;HRMS calcd for C 12H 9B rO 3 279.9735, found: 279.9767.An a l . C a l c d for C 12H 9B rO3: C, 51.27; H, 3.23. Found:C, 51.17; H, 3.15.

2-(Tributylstannyl)-8-methoxy-6-methyl-1,4-naph-thoquinone (12). A solution of bromonaphthoquinone11 (370 mg, 1.31 mmol), hexabutylditin (0.730 mL, 1.45mmol), a nd bis(triphenylphosphine)palla dium(II) chloride(Aldrich, 138 mg, 15 mol %) in 25 mL of a nhydrousd i o x a n e w a s h e a t e d a t r e f l u x u n d e r a n i t r o g e n a t m o -sphere for 1 h. After cooling, the solution wa s evaporat ed

under vacuum to yield a brown oil which was purif iedby flas h column chroma togra phy on silica gel (petroleumether /ethy l a ceta te ) 7:3) to a fford 12 a s a yellow oil (495mg , 71 %): 1H NMR (CDCl3, 400 MHz) 0.85 (9H, t, J )7.2 Hz), 1.10 (6H, t , J ) 7.2 Hz ), 1.28-1.36 (6H, m), 1.48-1.51 (6H, m), 2.47 (3H, s), 3.99 (3H, s), 7.07 (1H, s), 7.10(1H, s), 7.53 (1H, s). St an na ne 12 was converted to 13a nd 14 without further characterization.

5-Methoxy-7-methyl-1,4-naphthoquinone (20). Toa solution of diene 618,19 (2.37 g, 12.7 mmol) in 100 mL ofC H 2C l2 under an argon a tmosphere at room t emperature

wa s a dded solid benzoquinone 16(2.61 g, 24.0 mmol) over5 min. The result ing da rk greenish solution wa s st irreda t room temperat ure for 18 h. An aliquot of the solutionw a s e v a p or a t e d t o d r y n e ss a n d a n a l y z ed b y N M R s p ec-troscopy, which showed t he format ion of the D iels-Alderadduct 24. 24: 1H N M R ( C D C l3, 400 MHz) 0.20 (9H,s), 1.79 (3H, s), 2.01 (1H, dd, J ) 5.7, 12.8 Hz), 2.85 (1H,d, J ) 12.8 Hz), 3.04 (3H, s), 3.12 (1H, d, J ) 5.7 Hz),3.23 (1H, m), 5.53 (1H, s), 6.62 (1H, d, J ) 8.4 Hz), 6.74

(1H, d, J ) 8.4 Hz). Then 1.5 mL of a cetic a cid wa s ad dedto the reaction mixture and the solvent wa s evapora tedto dryness a t room t emperat ure under reduced pressureovernigh t. A da rk, greenish-yellow solid wa s formed. Thesolid was mixed with 100 mL of MeOH, and a yellow solidwa s observed a t the bottom of the flas k. The solvent wa sevapora ted to dryness a nd t he residue purif ied by f lashcolumn chromatography on silica gel (petroleum ether/e t h y l a c e t a t e ) 3:2) to a fford 2.18 g (85%) of 20 a s ayellow solid, m p 164-166 C (lit.24 mp 166 C).

2,2-Bis(1,4-diacetoxy-8-methoxy-6-methylnaph-thalene) (14). (A) From Coupling of 11 and 12. I na s e a l ed t u b e c ov er e d w i t h a l u m i n um f oi l (13 is l ightsensitive), a solution of 11 (210 m g, 0.76 m mol), tribu-t y l s t a n n a n e 12 (373 mg, 0.76 mmol), and (PPh 3)2P d C l2(80 mg, 15 mol %) in 10 mL of an hydr ous dioxane w a sheated under a rgon at 110 C overnight. After cooling,the mixture w a s poured onto a stirred mixture of Zn dust(497 mg, 7.60 mm ol), 4-(dimeth yla mino)pyridin e (371 mg,3.04 mmol), NaOAc (623 mg, 7.60 mmol), and Ac 2O (2mL) in 35 mL of CH 2C l2, and the new reaction mixturew a s s t i r r ed i n t h e d a r k o ve r n ig h t . F o r t h e w o r ku p , t h esolution was f irst f i l tered through Celi te, washed withH 2O (3 25 mL), dried over Na 2S O4, and concentratedunder vacuum to af ford, af ter chromatography (petro-leum ether/ethy l aceta te ) 1:1), tetraacetate 14 as a l ightbrow n oil (283 mg, 65%).

(B) From Dimerization of 11. I n a s e a l a b l e t u b ecovered with aluminum foil, bromoquinone 11 (438 mg ,

1.56 mmol), Sn 2B u 6 (0.39 mL, 0.78 mmol), and (PPh 3)2-P d C l2 (164 mg, 15% mol) w ere dissolved in 15 mL ofa n h y d r o u s d iox a n e u n d e r a r g o n . Th e t u b e w a s s e a l e dan d hea ted a t 110 C for 24 h. After being cooled to roomt e m pe r a t u r e , t h e m i x t u r e w a s p ou r e d o n t o a s t i r r edmixture of Zn dust (1.02 g, 15.6 mmol), 4-(dimethylami-no)pyridine (762 mg, 6.24 mmol), Na OAc (1.28 g, 15.6mmol), an d Ac2O ( 3 m L ) in 5 0 m L o f C H 2C l2, a n d t h en e w r e a c t i o n m i x t u r e w a s s t i r r e d i n t h e d a r k a t r o o mtemperature for 15 h. For the workup, the solution w asfiltered through Celite, wa shed with H 2O, dried over Na 2-S O4, a n d c on c en t r a t e d u n d e r v a c uu m . F l a s h c ol u m nchromat ography on si l ica gel (petroleum ether/ethyla c e t a t e ) 1:1) afforded 14 (178 mg, 40%) as a light brow n

oil.(C) From Pure 13. A mixture of binaphthoquinone

13 (2.01 g, 5.00 mmol), dichloromethane (200 mL), zincdust (10 g), sodium acetate (10 g), acetic anhydride (10m L ), a n d D M AP (6 g ) w a s s t i r r ed i n t h e d a r k a t r oomt e m pe r a t u r e f or 2 0 h . Th e n t h e m i xt u r e w a s f il t e re dthrough Celi te and the solids were washed with dichlo-rometha ne (100 mL). The f i ltra te a nd w ash were com-bined and evaporated at reduced pressure and elevatedt em per a t u re (u p t o 80 C ) t o g et r id of t h e a cet i ca n h y d r i d e. Th e c r u d e p r od u ct w a s f il t e re d t h r o u g h as h or t col u m n o f s i l ica g e l u s i n g d i ch l or om e t h a n e a seluent. The f il trat e wa s evapora ted to dryness, giving2.72 g (95%) of 14 a s a n of f-w h i t e s o li d , w h i ch w a s

(37) For genera l procedures a nd protocols, see: (a) Kelly, T. R.; La ng,F. J . O r g . C h em . 1996, 61, 4633. (b) Referen ce 10.



7/8

suff iciently pure for carrying out th e next st ep withoutfurther purification.

Crystal l ization of partial ly purif ied 14 f rom CH 2C l2/h e xa n e s g a v e 14 a s a w h i t e s o li d , m p 2 28-230 C : I R(C H 2C l2) 1759 cm -1; 1H NMR (CDCl3, 400 MHz) 2.10(6H, br s), 2.44 (6H, s), 2.49 (6H, s), 3.89 (6H, s), 6.73(2H, s), 7.11 (2H, br s), 7.22 (2H, s); 13C N M R ( C D C l3,100 MHz) 21.3, 21.7, 23.0, 56.8, 110.0, 113.7, 119.3,121.3, 122.5, 126.7, 130.4, 138.2, 142.2, 143.7, 156.4,

1 69 .9 ; H R M S c a l cd f or C 32H 30O 10 574.1839, found574.1820. Ana l. Ca lcd for C32H 30O10: C, 66.89; H, 5.26.Found: C, 66.54; H, 5.20.

2,2-Bis((1-acetoxy-8-methoxy-6-methyl-4-trifluo-romethanesulfonyl)oxy)naphthalene) (26). To a so-lution of tetraacetate 14 (2.80 g, 4.90 mm ol) in 65 mL ofC H 2C l2 a nd 65 mL of MeOH wa s ad ded 1,8-dia za bicyclo-[5.4.0]undec-7-ene (3.50 mL, 23.4 mmol) at room tem-p er a t u r e . Af t e r 15 m i n , t h e s ol ve n t w a s e va p o ra t e d a treduced pressure and 50 mL of water was added to themixture. The mixture was th en extra cted with C H 2C l2,and t he organ ic layer wa s separa ted and dried over Na 2-S O4. Eva porat ion of the solvent ga ve crude diaceta te 25wh ich wa s used without purificat ion in the next rea ction.The crude 25 wa s dissolved in 80 mL of CH 2C l2 a t 0 C ,2,6-lutidine (1.0 mL, 8.5 mmol) was added, and thentrifluorometha nesulfonic anhy dride (1.26 mL, 7.50 mmol)wa s a dded dropwise over 3 min. The reaction mixturewa s stirred at room temperat ure for 10 min. The solventwa s evaporat ed under vacuum, an d the result ing oi l waspurif ied by f lash column chromatography on si l ica gel(C H 2C l2) to give 2.55 g (70% from 14) of 26 a s a w h it es ol id . An a n a l y t i ca l s a m pl e o f 26 w a s ob t a i n ed b yrecrysta llizat ion from CH 2C l2/hexa ne a s w hite fla kes, mp190-191 C : I R (C H 2C l2) 1766, 1421, 1205 cm -1; 1HNMR (CDCl3, 400 MHz) 2.07 (6H, br s), 2.56 (6H, s),3.93 (6H, s), 6.83 (2H, s), 7.40 (2H, br s), 7.48 (2H, s); 13CNMR (CDCl3, 100 MHz) 21.0, 23.1, 56.9, 110.9, 113.4,119.4 (q, J ) 320 Hz) 119.6, 120.7, 121.9, 125.9, 130.3,140.5, 142.7, 144.7, 156.3; HRMS calcd for C 30H 24S 2O12F 6754.0613, found 754.0608. Anal. Calcd for C 30H 24S 2O12F 6:C, 47.75; H, 3.21. Found: C, 47.66; H, 3.18.

(1R,3R)-N-Benzyl-6,7-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-5-boronic Acid (35).A solution of 120 mg (0.22 mmol) of bromoisoquinoline349,10,35 in 10 mL of dry THF under a rgon wa s cooled to-78 C. Over th e cours e of 10 min , 0.16 mL (0.24 mm ol)of a 1.5 M solution of n-B u L i i n h e x a n e s w a s a d d e d a n dthe reaction mixture w as st irred 50 min, result ing in a nor a n g e s ol u t i on . F r e s h ly d i s t il le d (f r om s od i u m ) t r i -methyl borat e (0.12 mL, 1.11 mmol) was ad ded, and thereaction mixture was al lowed to warm to room temper-at ure overnight. Ten mill i li ters of wa ter wa s added, an d

the mixture w as extracted five times with 10-mL portionso f C H 2C l2. The combined organ ic extracts were driedover MgS O4 a nd eva pora ted under vacuum. The residuewa s chroma tographed on deactiva ted (7.5%NH 3)37b silicagel using 4:1 petroleum et her/ethy l a cetat e to give, a fterrecrysta llization from etha nol/petroleum ether, 100 mg(89%) of boroni c a cid 35 as a colorless solid, mp 106-108 C : [R]23D ) +49.3 (c ) 1.5 in MeOH); IR (KBr) 3600-3100, 3010, 2920, 2910, 2840 cm-1; 1H N MR(CDCl3, 200.1 MHz) 1.30 (3H, d, J ) 6.6 Hz ), 1.35 (3H,d, J ) 6.7 Hz), 2.79 (1H, d d, J ) 18.0, 11.3 Hz), 3.13 (1H,dd, J ) 18.0, 4.6 Hz), 3.33 (1H, d, J ) 14.1 Hz), 3.45-3.56 (1H, m), 3.85 (1H, d, J ) 14.1 Hz), 4.08 (1H, q, J )6.7 Hz), 5.02 (2H, s), 5.04 (2H, s), 5.92 (2H, s), 6.42 (1H,

s), 7.19-7 .3 1 (1 5H , m ) . An a l . C a l c d f or C 32H 34B NO4(HB r salt ): C, 65.33; H, 6.00; N, 2.38. Found: C, 64.93;H, 6.02; N, 2.36.

5,5-O-Diacetyl-N,N-dibenzyl-6,6,8,8-tetra-O-benzylmichellamine (36). I n t o a d r y S c h l e n k f l a s kwere placed under argon 60.0 mg (0.11 mmol) of iso-quinolineboronic a cid 35, 37.8 mg (0.050 mmol) of ditri-f l a t e 26, 6.0 mg (0.003 mmol) of tetrakistriphenylphos-p h in e pa l l a d i u m (0 ), 2 9. 0 m g (0 .1 6 m m o l) o f b a r i u m

h y d r ox id e , 3 m L o f d i m et h o xy e t h a n e , a n d 1 .5 m L ofdegassed wa ter . The reaction was heat ed at 80 C for 8h and cooled to room temperature, and volati les wereremoved under vacuum. The residue was subjected t opreparative thin-layer chromatography on deactivated 37b

silica gel plates using a 2:1 mixture of petroleum ether/eth yl a ceta te a s eluent to give 51.0 mg (74%) of 35 in theform of a l ight brown solid. Eva luation of the 1H N M Rs pe ct r u m i s n ot w o rt h w h i le d u e t o s u bs t a n t i a l p ea kbroad ening (due to hindered rota tion) and overlap: IR(K B r , H B r s a l t ) 3500-3200, 2940, 2900, 1700, 1650,1570 cm -1. An a l . C a l c d f or C92H 88N 2O10 (H B r sa l t ): C ,79.97; H, 6.42; N, 2.03. Foun d: C, 79.34; H, 6.44; N, 2.16.

Michellamines A (1a) and B (1b). The mixture 36(50 mg) wa s dissolved in 2 mL of absolute etha nol andhydr ogenat ed over 5.0 mg of 10%Pd /C for 14 h a t roomt em per a t u re a n d 1 a t m of h y d r og en . C a t a l y st w a sremoved by f i l trat ion through a short pad of si l ica gel ,a n d t h e f i l t r a t e w a s h e a t e d a t r e f l u x f o r 8 h i n M e O Ht h a t h a d b e e n s a t u r a t e d i n t h e c o l d w i t h g a s e o u s H C l .After evaporation of the f i l trate, the residue was takenup in MeOH and chromatographed on LH-20 Sephadex,eluting w ith MeOH. The fractions conta ining mixturesof 1a a n d 1b were combined and evaporated. The twoat ropoisomers w ere separa ted on an H P LC equipped wit ha 254 mm detector, using a 2.1 25 cm Rainin Dynama xa m i n e p h a s e co lu m n . Th e c r u d e 1a/1b m i x t u r e w a sdissolved in 7 mL of 87:13 chloroform/met ha nol, a nd 0.25-m L a l i q u o t s w e r e i n j e c t e d a n d e l u t e d w i t h t h e s a m e

solvent mixture a t a f low rat e of 12 mL/min t o give atota l of 6.6 mg (21%) of michellamine A (1a) and 16.5mg (53%) of michellamine B (1b) which were identicalwith authentic samples of natural ly derived 1a a n d 1b.

1a: [R]23D ) -8.3 (c ) 0.4 in M eOH) (lit.2 -10.5, c )0.83 in MeOH ); CD 209 -98.3, 242 +24.6, 258 +17.4;IR (KB r, diaceta te) 3550-3100, 2960, 2910, 1690, 1600cm -1; 1H NMR (d4-MeOH , 500.1 MHz) 1.21 (6H, d, J )6.5 Hz), 1.63 (6H, d, J ) 6.5 Hz), 2.12 (2H, m), 2.34 (6H,s), 2.81 (2H, m) 3.64 (2H, m), 4.10 (6H, s), 4.74 (2H, q, J) 6.5 Hz), 6.43 (2H, s), 6.75 (2H, s), 6.85 (2H, s), 7.30(2H, s); 13C N M R (d4-MeOH, 125.0 MHz) 18.4, 19.3,22.1, 33.1, 45.1, 49.4, 57.0, 102.0, 108.0, 113.1, 115.2,119.1, 120.4, 124.2, 133.1, 134.7, 136.7, 137.5, 152.2,

155.5, 156.9, 159.1.1b:[R]23D ) -16.2 (c) 0.72 in MeOH) (lit.2 -14.8, c)

0.74 in MeOH); CD 209 -53.8, 214 -53.8; IR (KBr,H B r s a l t ) 3600-3150, 2960, 2910, 1600 cm -1; 1H NMR(d4-MeOH, 500.1 MHz) 1.16 (3H, d, J ) 6.0 Hz), 1.19(3H, d, J ) 6.5 Hz), 1.59 (3H, d, J ) 6.5 Hz), 1.63 (6H, d,J ) 6.5 Hz), 2.03 (1H, dd, J ) 18.5, 11.5 H z), 2.25 (1H,dd, J ) 18.5, 4.5 Hz), 2.33 (3H, s), 2.36 (3H, s), 2.42 (1H,dd, J ) 18.5, 11.3 Hz), 2.69 (1H, dd, J ) 18.5, 4.0 Hz),3.48-3.55 (2H, m), 4.09 (3H, s), 4.10 (3H, s), 4.62 (1H, q,J ) 6.0 Hz), 4.66 (1H, q, J ) 6.0 Hz), 6.41 (2H, s), 6.75(1H, s), 6.84-6.85 (3H, m), 7.26 (1H, s), 7.30 (1H, s); 13CNMR (d4-MeOH, 125.0 MHz, diacetate) 13.1, 19.1, 20.1,20.2, 22.1, 22.2, 30.7, 30.7, 33.9, 34.9, 44.5, 44.6, 56.9,



8/8

57.0, 101.8, 101.9, 108.3, 114.8, 115.1, 115.2, 118.9, 119.0,119.2, 119.3, 120.3, 120.4, 124.4, 124.5, 134.6, 134.7,135.1, 135.2, 136.6, 136.7, 137.4, 137.5, 152.1, 152.2,155.5, 155.6, 156.3, 156.4, 158.0, 158.1, 180.2, 180.2.

Acknowledgment. This work w a s supported by t heNat iona l Inst itutes of H ealth (G ra nt CA65093 to T.R.K.),the D eutsche Forschungsgemeinscha ft (SFB 251 Okol-og ie , P h y s iolog ie u n d B ioc h emie p f la n zl ic h er u n dtierischer Leistung unter Stress) , and the Fonds derChemischen Industr ie (financial support a nd fellowsh ipto R.G.) . A.G. and P.A.K. thank NATO and the Alex-

an der von H umboldt Founda tion, respectively, for post-doctora l fellowships.

Supporting Information Available: Experimental de-tails concerning model studies and other compounds (19, 27a,27b, 28, 29b, 30a, 30b, 31a, a n d 31b) not directly relat ed tot he f inal sy nt he t i c seq ue nce (6 pag e s). Thi s m a t e r ial i scontained in libraries on microfiche, immediately follows thisar t i c l e i n t he m i c r of i l m ve r si on of t he jour nal , and c an b eor d e r e d fr om t he AC S ; se e any c ur r e nt m ast he ad pag e for

ordering informa tion.

J O971495M


a convergent total synthesis of the michellamines

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