STEREOSELECTIVE SYNTHESIS OFSECOPODOPHYLLOTOXINS

a th e s is presented by GRAHAM ANDREW CROSS

in p a r tia l fu lfilm en t of the requirements for the award of the degree of

DOCTOR OF PHILOSOPHY OF THE

UNIVERSITY OF LONDON

Department of Chemistry, November, 1985Imperial C ollege,London SW7 2AY

1

Acknowledgements

A syn th etic organic chemist can only be as productive as the a n a ly tica l and tech n ica l serv ices around him w il l allow . I would lik e to thank those serv ices both a t Imperial C ollege, London and a t P fizer Central Research, Sandwich, Kent for th e ir contribution to th is research.

In addition to th is , I would l ik e to thank my colleagues in the research groups, in Sandwich, headed by Dr. R. J. Bass and in London, headed by Dr. D. A. Widdowson for th e ir blend of humour, cynicism and sometimes even " in te llec t" which has made these three years o f research an experience which I sh a ll never forget.

I thank my w ife , fam ily and friends for th e ir support and encouragement throughout my stay a t Imperial C ollege.

2

Abstract

In Chapter One the chemistry of lignans i s reviewed. Their b io lo g ic a l a c t iv i t ie s are discussed with respect to structure /a c t iv i ty re la tion sh ip s and a b r ie f account of th e ir b io sy n th etic or ig in i s included. Synthetic s tr a te g ie s towards lignans are surveyed in considerable d e ta il and are subdivided in to biomimetic syntheses, syntheses v ia biphenyl coupling reaction s, syntheses v ia the eno lates of Y~butyrolactones and syntheses v ia p e r ic y c lic reaction s.

In Chapter Two the r e su lts of the present study are described. A syn th etic strategy towards secopodophyllotoxins v ia tra n s it io n metal catalysed cross-coupling reaction s has been explored. The r eq u is ite cross-coupling process has produced diphenylmethanes from a wide range of oxygenated aromatic compounds by the reaction s of benzylzinc reagents with aryl iod id es in the presence of a number of palladium(O) c a ta ly s ts even for benzyl h a lid es containing /3-hydrogens.

D ia s te r e o se le c t iv ity in the a ld o l condensation of Y-butyro- lactone with benzaldehyde has been studied over a wide range of con d ition s. Considerable e f fo r t to convert the so formed benzylic alcohol in to a halide for use in cross-coupling reaction s led only to /3-elim ination.

The development of e f f ic ie n t p ro tective groups for the lactone fu n c tio n a lity has been achieved. 2-(Hydroxybenzyl)-Y-butyro- lactone was s i ly la te d and the lactone reduced to the hemi-

3

a c e ta l. D irect a lk y la tiv e or a cy la tiv e protection of th is led to compounds which were not sy n th e tica lly v iab le once the benzylic alcohol was unmasked. R eversible ring opening and protection of the so formed 4-hydroxybutyraldehyde by th io k e ta lisa tio n of the carbonyl function and e th e r if ic a tio n or e s te r if ic a t io n of the a lcohol was e f f ic ie n t . These compounds have been su c ce ssfu lly d es ily la te d and converted e f f ic e n t ly in to the required benzylic h a lid es . Despite exten sive study these m aterials have not taken part u se fu lly in palladium(O) catalysed cross-coupling reaction s.

Chapter three contains experimental d e ta i ls .

4

Contents Pa9e

Acknowledgements 2Abstract 3Abbreviations 6Chapter One - Lignans 7

Introduction and d e fin it io n s 8B iosynthesis of lignans 11B io log ica l a c t iv i t ie s of lignans 14S tra teg ies in lignan synth esis 20

(a) Biomimetic syn th esis 21(b) Synthesis v ia biphenyl coupling reactions 31(c) Synthesis v ia monolactone enolates 45(d) Synthesis v ia p e r ic y c lic reaction s 67

Conclusion 80Chapter Two - R esults and d iscu ssion 83

Introduction 84R etrosynthetic a n a lysis 86The synth esis of diphenylmethanes/palladium 90catalysed coupling reactionsAldol condensation reactions 106Synthetic stu d ies towards secopodophyllotoxins 117 Conclusion 156

Chapter Three - Experimental 158References 205

5

Abbreviations

DIBALH - DiisobutylaluminiumhydrideDMAP - 4-N,N-DimethylaminopyridineTBAI - Tetranbutylammonium iodideTBAF - Tetranbutylammonium flu orid eLDA - Lithium diisopropylamidecy - cyclohexylIm - ImidazoleTMS - T rim eth ylsily lTBDMS - ^B utyld im ethylsilylTBDPS - ^B utyld iphenylsilylMEM - MethoxyethoxymethylDMAD - Dim ethylacetylenedicarboxylate

NOE - Nuclear Overhauser E ffect

6

CHAPTER ONE Lignans

7

Introduction and d e fin itio n s

Lignans are defined as the natu rally occurring dimers ofphenylpropanoid (C.C-) un its linked by the c e n tr a l((3) carbonsb Jof th e ir sid e chains (Diagram 1).

There a lso e x is t naturally occurring phenylpropanoid dimers which do not have the CQ-CQ, primary linkage and th ese areca lled neolignans.

The regular is o la t io n from natural sources of new lignans serves to confirm th e ir large number and breadth of phylogen etic d is tr ib u tio n and i t i s with th is group of compounds th at th is review i s expressly concerned. Neolignans, by contrast are considerably more lim ited in number and occurrence.

I t has been widely assumed th at lignan b iosyn thesis involves the combination of two phenylpropanoid un its by ox id ative dim- e r isa tio n of phenols. The v a lid ity of th is assumption w ill be d iscussed sh ortly however, for now, i t serves w ell to rein force our d e fin itio n s of lignans and neolignans and to d istin g u ish between them.

Diagram 1

8

H3C O ^

J )H O ^ f H C r y

R R

(D x = c h 2oh ' U ) R =

(2) X = COOH(3) X= CH3 J

r = h , o c h 3

9

Consideration of the phenoxy rad ica ls (A-E) generated by the oxidation of cinnamyl a lcoh ols and propenyl phenols (1-4) shows c lea r ly that d im erisation of two canonical forms of type E leads a fter m odification to lignans, whereas other combinations and m odifications of the canonical forms lead to n eolignans.

The range of structu ral var ia tion in lignans i s very broad however the common fam ilies can be e a s ily d istingu ish ed by a number of simple structu ral m odifications to the jft-jS' -phenyl- propanoid dimers.

The incorporation of oxygen in to the basic lignan skeleton leads to four lin ear stru ctu ra l groups. These are lignans or d er iv a tives of butane (5 ), lig a n o lid es or d er iv a tiv es of butanolide (6 ), monoepoxylignans or d er iv a tiv es of te tr a - hydrofuran (7) and bisepoxylignans or d er iv a tiv es of 3 ,7 - d ioxab icyclo [3 .3 .0 ]octan e (8 ).

A

A '

(8)In addition to th is the p o s s ib i l i ty of further c y c lisa tio n s of the phenylpropanoid dimers e x is t s . The formation of a C-7 to C-6' linkage affords the large and important c la ss of compounds known as cy c lo lig n a n s. These can occur as tetrahydro- naphthalenes (or a r y lt e tr a l in s , 9) or naphthalene d er iv atives

10

(10). An a ltern a tiv e C-6 to C-6* linkage leads to a further very important group of lign an s, the bisbenzocyclo-octadiene lignans (11).

B iosynthesis of lignans

That lignans are very widely d istr ib u ted in the p lant kingdom and th at they have been iso la te d from a l l parts of plants suggests that they play an important ro le in p lant evolu tion . Well over 200 compounds in th is general c la ss have been id e n tif ie d with great d iv e r s ity in the chemical assembly of the two ch a ra c ter is tic phenylpropanoid u n its , the degree of oxidation and types of su b stitu en ts . Despite the abundance of lignans in nature b iosyn th etic pathways to th ese compounds remain poorly in vestig a ted and l i t t l e d e f in it iv e information i s a v a ila b le .

The hypothesis, used previously to aid in the d e fin it io n of lign an s, that phenolic ox id ative coupling of monomers v ia free rad ica l or equivalent two electron processes i s important in lignan b io syn th esis, f a i l s to explain the production in nature of o p t ic a lly a c tiv e lignan dimers. That lignans occur in non-racemic form i s in d ic a tiv e of enzyme controlled

11

reactions rather than random free rad ical couplings.

H3CO

HO

OH

(12)OCH3

(13)

From structu ral an a lysis however most lignans do appear to be derived from the same CrC0 monomer un its co n ifery l a lcohol(12) and/or sinapyl alcohol (13) although there i s l i t t l e evidence that coupling occurs a t the alcohol rather than acid or aldehyde oxidation le v e ls .

There have been r e la t iv e ly few sp e c if ic radiochemical feeding experiments d irected towards lignan b iosyn th esis.

2Ayres has reported the incorporation of d l-phenylalanine 0 14(p- C) in to podophyllotoxin (14) in Podophyllum hexandrum and

confirmed by p a r tia l degradation stu d ies the incorporation of two CgĈ monomers in to the lignan dimer (Scheme 1).

Recently further feeding experiments in Podophyllum hexandrum showed th at phenylalanine, cinnamic acid and fe r u lic acid (15) are good precursors of podophyllotoxin (14) and 4'-dem ethyl- podophyllotoxin (14, C-4' OH). I t was shown that sinap ic acid(see 13) and 3 ,4 ,5-trimethoxycinnamic acid are poorly incorporated, implying that the pendant C-ring i s b u ilt up a fter the coupling of the two phenylpropane u n its . Degradation stu d ies on podophyllotoxin (14) derived from [3-OCH ,̂ 4̂C] fe r u lic

6 3

12

acid (15) showed that the two halves of the lignan molecule are equally la b e lled supporting a b iosyn th etic sequence involving the oxid ative coupling of two fe r u lic acid type phenylpropane u n its .

Scheme 1 OH

13

These observations, along with the need for the p-hydroxyl function (as in fe r u lic acid) in the phenylpropanoid monomer, strongly suggest the involvement of the p-hydroxyl group in the coupling process whether or not i t occurs by a stereocon- tr o lle d free rad ica l or a two e lectron reaction .

B io lo g ica l a c t iv i t ie s of lign an s. S tru c tu re /a c tiv ity r e la tio n sh ip s^

Much as the stru ctu ra l range of natu rally occurring lignans i sbroad then so i s the scope of th e ir b io lo g ica l a c t iv ity . Therehas been considerable e ffo r t in recent years to understand andthereby harness the p h ysio log ica l and to x ic o lo g ic a l propertiesof these compounds and the recent id e n tif ic a tio n of lignans inhuman urine and blood w il l serve to in te n s ify e ffo r ts to

4understand th e ir p ossib le ro les in man.

Various lignans are known to have antitumour, a n tim ito tic and a n tiv ir a l a c t iv ity , to show s p e c if ic in h ib itio n of certa in enzymes and to be to x ic to fungi, in se c ts and verteb rates.

(a) Antitumour a c t iv ity

Many lignans, p articu lar ly of the podophyllotoxin (14) group, have been shown to have antitumour a c t iv ity . E lucidation of s tr u c tu r e /a c tiv ity re la tion sh ip s has led to the follow ing conclusions. The methylenedioxyphenyl group i s a common feature in nearly a l l of the a c tiv e compounds and appears to be very important to c y to s ta t ic a c t iv ity . The 3 ,4 ,5-trim eth- oxyphenyl group i s of considerably le s s e r importance,

14

4 ' -demethylpodophyllotoxin (16) reta in s the a c t iv ity of podo- phyllotoxin (14). The configuration of the C-4 hydroxyl group has a marked a f fe c t on a c t iv ity , podophyllotoxin (14) being 10 times as a c tiv e as i t s C-4 epimer epipodophyllotoxin (17) and yet /5 -p elta tin (18) with a C-5 (A-ring) hydroxyl group i s even more a c tiv e than podophyllotoxin (14) i t s e l f .

(1/J Rt = CH3,R2=X=HiY=0H

(16) R2=X=H,Y = 0H(17) R1 = CH3,R2=Y=H,X=OH

(18) R1 = CH3jR2=0H jX=Y=H

(19) R1 = CH3.R2=X = Y=H

Curiously the complete absence o f a hydroxyl group a t C-4, as in deoxypodophyllotoxin (19) does not s ig n if ic a n t ly reduce a c t iv ity . The configuration a t C-2 plays a s ig n if ic a n t ro le in determining antitumour a c t iv ity . Picropodophyllotoxin (20) has marked attenuation in potency compared to podophyllotoxin (14) but i t i s in te r e st in g that there i s not a complete lack of a c t iv ity in (20 ). I t has been shown that a t equilibrium in mild base (p hysio log ica l cond itions) (14) and (20) are present in the ra tio 2.5 : 97.5 resp ec tiv e ly r e f le c t in g the high

15

energy of the strained trans lactone system of podophyllotoxin(14) and in d icatin g a p o ss ib le mode of b io d e to x ica tio n .6

(b) A ntim itotic a c t iv ity

Many compounds of the podophyllotoxin (14) group have beenshown to arrest cultured c e l l s a t metaphase and to bind to

5p u rified tubulin preparations.r-0

(21) (22)There i s evidence th at podophyllotoxin (14) competes with about twice the binding a f f in i t y for the same binding s i t e on tubulin as co lch ic in e (21). Steganacin (22), one of the bisbenzocyclo-octadiene lignans a lso binds com petitively with co lch ic in e (21) to tubulin . There i s evidence which suggests th at the compounds have a common binding s i t e which i s sp e c if ic for the trimethoxyphenyl ring. However for each there i s believed to be another point of attachment to the receptor s i t e . The presence of a trans fused lactone in podophyllotoxin (14) and steganacin (22) i s cru cia l to a n tim ito tic a c t iv ity , the picro se r ie s showing v ir tu a lly no d etectab le a f f in ity for tubulin . /3 -P e lta tin (18) shows a moderately greater a f f in ity than podophyllotoxin (14) for tubulin and i t has been

16

suggested th at sin ce 4 ' -demethylpodophyllotoxin (16) i s equally as a c tiv e as (14) then i t might be the A-ring of (14) which i s involved with the same a c tiv e s i t e as the C-ring of co lch ic in e (21).

(c) A n tiv ira l a c t iv ity

The pharmacopoeias of Western, Asian and American c i v i l isa t io n s have, for many years, included podophyllum for the treatment of condyloma acuminata (venereal w arts), measles and herpes simplex types I and I I . That podophyllum owes i t s a c t iv ity to podophyllotoxin (14), j3-peltatin (18), deoxypodo- phyllotoxin (19) and a -p e lta t in (23) i s a more recent d isco very. A n tiv ira l a c t iv ity f a l l s o ff rapidly for the picro and epi s e r ie s of compounds.

(d) In h ib ition of enzyme a c t iv ity

A very wide range of lign an s, including podophyllotoxins, l ig a n o lid e s , monoepoxylignans and bisepoxylignans have been shown to be involved in s p e c if ic enzyme in h ib itio n . The common wood con stitu en t m atairesinol (24) i s p a r ticu la r ly a c tiv e as i s syrin garesin ol (25). In the la t te r compound and i t s fam ily

17

the stereochem istry of the furan-phenyl junction i s important to b io lo g ica l a c t iv ity .

(e) Other a c t iv i t ie s

In addition to the other a c t iv i t ie s already described, lign an s, p articu larly of the podophyllotoxin group, have been ex ten sive ly screened, with success, for ca th a rtic , cardiovascular, a lle rg e n ic , in s e c t ic id a l , p is c ic id a l, mammalian to x ic , antim icrobial, fu n g is ta t ic , germination in h ib itory , cen tra l nervous system, antihepatoxin and s tr e ss reducing a c t iv i t i e s .

Recently the d etection of enterolactone (26) and enterodiol (27) in man and primates, in le v e ls comparable to those of stero id m etabolites, and the observation of c y c lic a l var ia tion of concentration with time in females has in s t i l l e d new ur

18

3gency in to the study of the b io lo g ic a l a c t iv i t ie s of lign an s. Peak le v e ls were detected during the lu te a l phase of the menstrual cycle and during pregnancy but the ex c itin g possi b i l i t y that these lignans might possess hormonal a c t iv ity has been thrown in to question by the suggestion that they are probably metabolic products of the m icroflora of the gut.

Lignans c lea r ly d isp lay a broad range of b io lo g ica l act i v i t i e s . They have frequently found c l in ic a l ap p lication and, by su b tle structu ral m odification , th e ir to x ic ity /e f f ic ie n c y ra tio has been reduced to acceptable le v e ls . For example, 4 ' - dem ethyl-1- 0 - [ 4 ,6 -0 (2-thienylm ethylene)-/3-D-glucopyranosyl] - epipodophyllotoxin, VM-26 (28) and 4 '-d em eth y l-1 -0 -[4 ,6 -0 -(ethylidene)-/3-B -glucopyranosyl]epipodophyllotoxin, VP-16-213(29) show acceptable to x ic ity le v e ls and have u sefu l therapeu-

7t i c e f fe c ts aga inst Hodgkins d isea se . Testing has shown (28) and (29) to be u sefu l cancer chemotherapeutic agents e ith er alone or in combination with other a n ti-n eo p la stic agents.

H

OH

19

The nature of the in tera c tio n between host (b io lo g ic a l receptor) and guest (a c tiv e compound) in vivo i s one not e a s ily discerned.

Extensive and system atic in v estig a tio n i s needed to further the understanding of the stru ctu ra l p rereq u isites (in three dimensions) for b io lo g ica l a c t iv ity and to d iscern any common modes of action which may underlie the apparently d iverse natural responses.

I t i s the task of the syn th etic organic chemist to provide the wide range of frequently complex and stereochem ically pure molecular systems which lignans p ossess.

S tra teg ies in lignan syn th esis

The synth esis of lignans has provided organic chemists with a considerable challenge for many years now.

I n i t ia l ly many syntheses were carried out as much to f a c i l i t a t e unambiguous structu ral id e n tif ic a tio n of the ever increasing number o f iso la te d natural products as to make q u a n tities ava ila b le for b io lo g ic a l assays. Frequently degradation of the natural products and correla tion of the fragments with sy n th etic compounds has been the method of choice in th is work.

Recently the syn th esis of b io lo g ic a lly ac tiv e or p o ten tia lly b io lo g ic a lly a c tiv e compounds by s te r e o se le c t iv e procedures has received much a tten tion and i t i s with the s tr a te g ie s so developed that the present review p rin cip a lly addresses

20

itse lf .* *

In many ways some of the c la s s ic a l routes to the 18-carbonbasic lignan skeleton remain unsurpassed, however the frequentneed for example, to syn th esise s p e c if ic a lly the thermodyna-*m ically le s s sta b le stereoisom ers of compounds has required the development of elegant and sop h istica ted s tr a te g ie s .

Many lignans can be sy n th e tica lly derived from common in te r m ediates. I t i s therefore more appropriate to ca tegorise the sy n th etic chem ist's work in terms of the key reactions employed to produce th ese interm ediates than the f in a l products derived from them.

(a) Biomimetic syn th esis - syn th esis v ia 2 ,6 -d ia ry l-3 ,7 -d io x a - b ic y c lo [3 .3 .0 ]octanes

The long held hypothesis that phenolic oxid ative coupling of two Cg u n its i s the b iosyn th etic route to lignans gained much of i t s c r e d ib il ity from many su ccessfu l syntheses of th ese compounds by oxidative combination of cinnamyl precursors .

To th is day phenolic ox id ative coupling remains a powerful sy n th etic to o l for the lignan chem ist. The technique has been developed to afford a wide range of lign an s.

In i t s sim plest form phenolic oxidation of fe r u lic acid (15) gives the 2 ,6 -d ia r y l-3 , 7 -d iox ab icyclo [3 .3 .0]octane d ilacton e(30) in 30% y ie ld .^

21

(15)

These compounds have considerable b io lo g ica l a c t iv ity of th e ir own and have been widely studied as key interm ediates in lignan synthesis.**

Rearrangement in methanolic acid leads to the aryldihydro- naphthalene (31) which i s read ily convertib le to arylnaph- thalene lignans (32) and (33). Hydrogenation and dehydration of (30) affords the anhydride (34) which by a further reductive sequence can be converted in to m atairesinol (24).

(32) Y=0,X = H2 (34)(33) X = 0,Y = H2

22

A ltern atively the acylated compound (35) can be reduced by LAH to (36) which forms the bisepoxylignan p inoresinol (37) on acid treatment. (37) Can a lso be reached v ia p a r tia l lactone reduction with DIBALH and then a tosy la tion /h yd rid e d isp la cement sequence on (38).

(36) (37) X = H2

(38) X=H,OH

The anodic oxidation of fe r u lic acid (15) and sinap ic acid (see 13) lead s, instead of coupling of type E phenoxy ra d ica ls , to coupling of type C rad ica ls and the formation of resp ec tiv e ly the asatone type compound (39) and the isoasatone

23

Fortunately the fe r r ic chloride/oxygen type phenolic oxidation procedure i s widely app licab le and e f f ic ie n t . Thus sinap ic acid (see 13) leads in 80% y ie ld to the d ilacton e (41) which as before rearranges in methanolic acid to the d iester dihydronaphthalene (42) and in aqueous acid to the corresponding d iacid (43). The dimethyl ether of (42) can be hydrogenated to the mixture of a r y lte tr a lin s (44) one of which has

11been converted to ly o n ires in o l dimethyl ether (45).

0C H 3 (41) (42) R=CH3(43) R=H

H,CCLX ^C O O C H g Y=m C00CH3

h 3c q ^ y Y ^ yh 3co n s rh 3cct

Y=M1 CH20HY ^ 0 C H 3

o c h 3

In terestin g ly phenolic oxidation of methyl sinapate g ives4-hydroxyaryltetralins which can be subsequently dehydrated toy ie ld (42).

24

Diversion of the course of the acid catalysed rearrangementsof 2 ,6 -d ia r y l-3 , 7 -d ioxab icyclo [3 .3 .0]octane lignans, to affordother lignans, can be achieved by the use of halogenated

12arom atics. For example the dibromide (46) rearranges to the monoepoxylignan (47) which affords ga lb elg in (48) a fte r reductive debromination with LAH, to sy la tio n and hydride displacem ent.

(46) X=Br

m x=ci(48) X=H;R=CH3 (50)X=Cl,R=COOCH3

The d ilacton e (49) can e ith er be s im ila r ly converted to (50) or the chloride can be used under d iffe r e n t conditions (HC1- MeOH-CHCl )̂ to red irect the normal acid rearrangement of these compounds. The usual p osition of c y c lisa tio n being blocked(49) g ives the unusual oxygenation pattern in the dihydronaphthalene (51). Hydrogenation, reduction and m ethylation g ives dehalogenated a r y lte tr a lin s (52).

25

Cl

Chemical or enzymic oxidation of E 2 ,6-dimethoxypropenyl- phenol (53) g ives a mixture of epoxylignans (54), the methylethers of which rearrange to the aryldihydronaphthalene (55)

. , 13 m acid .

The importance of 2 ,6 -d ia r y l-3 , 7 -d iox ab icyclo [3 .3 .O]octane lign an s, both in th e ir own r igh t (e .g , m atairesinol (24)) and as interm ediates in lignan syn th esis (e .g , (30)) has aroused considerable in te r e s t in th e ir preparation.

26

Sniekus proposed th e ir syn th esis using N,N,n ;n ' - te tr a -alkylsuccinamide dianions as four carbon synthons. The approach i s short and conceptually elegant (Scheme 2),pred icting sequentia l d ia s te r e o se le c t iv e d ia lk y la tio n of the succinimide dianion (Diagram 2) which, when E+ i s aldehyde, should c y c lise s te r e o sp e c if ic a lly to the required d ilacton es by v irtu e of the con stra in ts of forming the 5-5 fused ring system.

14

Scheme 2

(CH3)2N

0 0J1 \\

Y Y ^ N IC H 3̂E E

Diagram 2 Li

N(CH3)2

In p ractice the stepw ise hydroxyalkylation i s not e f f ic ie n t with benzaldehydes and the reaction i s therefore only usefu l for the preparation of symmetrical systems (E* = E^). Also the

27

threo d ia stereo se lec tio n (see Diagram 2) on hydroxyalkylationi s not high and, sin ce only one diastereomer can c y c l is e to the required d ila cto n es, the strategy becomes in e f f ic ie n t .

N evertheless monolactones are conveniently prepared in ahighly s te r e o se le c tiv e manner when simple benzylation of thedianion i s employed. Thus diamide (56) i s formed in 50% y ie ldand can be p a r tia lly reduced and lacton ised to dimethyl-m atairesinol (57). The sequence has been su ccessfu lly used to

14synth esise hinokinin, se c o la r c ir e sm o l, dihydrocubebm, enterolactone and en terod io l, a l l in high y ie ld s .

ArL 0II ArL*s• ^ n (c h 3)2 l)L iE t3BH >Q°

Ar 0r > ^N (C H 3)2 2)TsOH,PhHAr

II0 re flu x

(56) (57)

A r= 3 ,£ -d im e th o xyp h e n y l

15Brownbndge and Chan proposed b is (tr im e th y ls ilo x y )- 2 ,5-furan(58) as a precursor to 2 ,6 -d ia r y l-3 , 7 -d iox ab icyclo [3 .3 .0 ] - octane lignans. Treatment of (58) with benzaldehydes in the presence of titanium tetrach lorid e leads d ir e c t ly to the target compounds (59) in high y ie ld s with mainly the required d iequatorial configuration .

TMSO

(58)

n^ 00 ^ / ° \ ^ \ A r

OTMS ■l2eqArCH0 » hui)— OiiH 2)2eq.IiCU A(. ^ Q(59)

28

Ward has recen tly developed an elegant new four carbon synthon which allow s r e g io sp e c ific d ia lk y la tio n v ia stepwise anion formation. His retrosyn th etic an a lysis (Scheme 3) in d ica tes the need for the immediate precursor to (60) to be of the type (61) which can only a lk y la te a to the lactone carbonyl and which can i t s e l f be generated v ia the dianion (62) which should form a carbanion only a t the ter tia ry centre. I t was not only an tic ip ated that the thiomethyl group would give r e g io sp e c ific anion formation but a lso that i t would d irec t the second a lk y la tion c is to the methoxycarbonyl group.

16

Scheme 3

H ,C 00C

H3CS C00H

(63)

In practice the dianion of monoester (63) i s treated with benzaldehydes to g ive a mixture of diastereom eric monolactones (64) and (65) in 2 : 1 ra tio resp ec tiv e ly and in 50% y ie ld . Only (64) can be su ccessfu lly r e lith ia te d and quenched with piperonal to g ive the desired (66) in 58% y ie ld . Removal of the methylthio group can only be achieved via reduction to the

29

d ila c to l and methylation to the d ia ce ta l (67). Although Raney n ick el then removes the thiom ethyl group c lean ly , reversion to the desired compounds by h yd rolysis, then reduction or o x idation, cannot be achieved. Demethoxylation i s only e ffected by tr ie th y ls ila n e /tr if lu o r o b o r a n e /d ie th y l ether and th is r e su lts in benzylic eq u ilib ration and the m ethylthio group d irec ts the adjacent aryl group (Ar^) trans to i t s e l f even though the la t te r i s then in an a x ia l p o sitio n . Raney n ickel clean ly removes the m ethylthio group to give the lignans (68) in good y ie ld .

3)H30* (64) (65)

Ar^ = veratryl

(66) (67) (68)A r2= 3,4-m ethylenedioxy phenyl

30

(b) Synthesis v ia biphenyl coupling reactions

(-)-S tegan acin (22) and the group of antileukaem ic bisbenzo-cyclo-octad iene lignans possess a p ivo ta l biphenyl bond.

17B iaryl skewing i s always trans but Koga showed thermodynamic eq u ilib ration of (-)- iso s te g a n e (69) to (+ )-stegane (70) to be e s s e n t ia lly complete.

R etrosynthetic an a lysis suggests that the formation of the biphenyl bond la te in a sequence i s unfavourable sin ce the c la s s ic a l methods for such coupling involve harsh reaction conditions which would not be to lera ted w ell by the C-5 to C-7 fu n c tio n a lity of (22).

31

The Gomberg-Bachmann reaction (Scheme 4) in which a diazonium group i s replaced by an aromatic sp ecies involves free radical coupling and although i t can be used for the synth esis of unsymmetrical biphenyls the required compounds are usually not e f f ic ie n t ly formed.

Scheme U -G om berg-Bachm ann, ArH +A r N2X — ► A r- A rUllmann, 2 A r l ------------ ^ A r - A r

Cu o rC u 20

A

Scheme 5

n 0

18The c la s s ic a l Ullmann reaction (Scheme 4) i s tr a d itio n a lly used for the syn th esis of symmetrical unhindered biphenyls but in 1977 Brown and Robin reported major advances with the preparation of unsymmetrical biphenyls even with bulky o-sub- s t itu e n ts by a modified procedure. They la te r completed a to ta l synth esis of (±)-steganone (74) by including in th e ir Ullmann coupled product (Scheme 5) (71) the necessary funct io n a l ity to afford the bisbenzocyclo-octadiene framework by base induced a ld o l condensation to (72). Benzylic oxidation

32

followed by lactone cleavage and decarboxylation g ives (73)20which i s read ily converted to (±)-steganone (74).

o c h 3 o c h 3 o c h 3

(72) (73) (IDThis strategy has been used to synth esise ( ± )-p icro steg a n e ,

21( ± )-iso p icro steg a n e and (± )-isostegan e and was la te r developed in to a ch ira l synth esis by the Ullmann coupling of an o p tic a lly a c tiv e iodide (75). Thus (+)-isosteganone (76) i s obtained and thermally isom erised to (-)-stegan on e (77),correcting the absolute stereochem istry of the la t te r which

• • 22 was o r ig in a lly assigned by Kupchan.

(75) (76) (77)

33

In the b isbenzocyclo-octadiene s e r ie s the trans lactone junction i s thermodynamically sta b le hence la c to n isa tio n la te in a syn th etic sequence i s acceptab le. By contrast in podo- phyllotoxins f a c i le lactone epim erisation to the picro se r ie s must be ca re fu lly avoided.

23The Ullmann reaction was further improved by Z iegler who, having shown intram olecular Ullmann coupling to be f r u it le s s , developed an ambient temperature interm olecular process. He attempted to generate an intram olecularly heteroatom s ta b il is e d arylcopper sp ecies from the appropriate aryllith ium reagent and to react th is with an aromatic iodide having a sim ilar p o ten tia l heteroatom ligand.

Thus oxothiolane (78) i s converted to the copper reagent by nbutyllith ium metal-halogen exchange and treatment with CuI.PfOEt)^ and then reacted a t room temperature with an aryl iod ide (79) to g ive the coupled product (80) in an e x ce llen t (82%) y ie ld . Conversion to (±)-steganone however, proved to be d i f f i c u l t and in e f f ic ie n t .

o c h 3

34

The elaboration of biphenyls, once formed, to bisbenzocyclo- octadiene lignans has received considerable a tten tio n .

The biphenyls have been prepared by the Ullmann coupling methods already described and by the oxidative cleavage of phenanthrenes.

Scheme 6

Thus the d ib en zy lic dibromide (81) can be intram olecularly coupled (Scheme 6) using malonic e ster s and a racemic steganone syn th esis has been completed by a sim ilar base- induced c y lisa t io n reaction on (82) (Scheme 7 ) . ^

35

Scheme 7

(82)

steganone

Ghera has reported several syntheses from su itab ly substitu ted phenanthrenes.

25A W ittig coupling route to the stilb en e (83) followed by photochemical c y c lisa tio n g ives the phenanthrene (84) which i s oxidised to the o-quinone (85) in which the ketone groups can be clean ly d istinguish ed from each other by s e le c t iv e k eta l- isa t io n which only occurs fu rth est from the bromine giving ( 86 ) .

(83) (84)

This C-14 skeleton i s extended to the lignan C-18 framework by sequential a lk y la tio n , d ek eta lisa tio n and d iffe r e n t a lk y lation to (87).

36

r °\C) 1rTi ^Brr~o

° xM Xf-Y (86) X ,Y = = 0h3C0^Ln̂ 0 h3cô L /n rAB a ,b= - o c h £ h 2o -

H3c o " A yo c h 3

h3c o ^ yo c h 3 (87)

x =c h 3Y=A=0H

(85) b = - c h 2c h 2c h =c h

Oxidative cleavage, a-brom ination and coupling with z in c / s i lv e r couple g ives the required bisbenzocyclo-octadiene skeleton which can be manipulated to steganone in many step s. Syntheses of the schizandrin and kadsurin lignans have been sim ila r ly completed.

The pyrrolid ine enamine of cyclohexanone read ily undergoes double ring expansion with a ce ty len ic e sters to y ie ld highly fu n ction alised cyclo-octad ien es with the la te n t 7-oxo funct io n a l ity required in the stegane lignans.

(88) (89)

37

Raphael developed th is reaction in to a highly e f f ic ie n t syn th etic strategy by analoguous double ring expansion of phenanthrenes. Thus the enamine (88) affords the ring expanded C-18 system (89) in 91% y ie ld . This i s simply converted to (± )-isosteganone (76) and thence to (±)-steganone (77).

In terms of syn th etic strategy c la s s ic a l or sem i-c la ss ica l Ullmann biphenyl coupling i s not good sin ce i t requires the formation early in the sy n th etic sequence of biphenyls which, in the event, demand exten sive and non-convergent elaboration to the natural products.

The development of coupling procedures which can be applied la te in syn th etic sequences has received much a tten tion in recent years. Moreover the sy n th etic operations so derived have become standard transform ations in the preparation of lignans and are u ltim ately h eav ily r e lie d on by many elegant and modern sy n th etic s tr a te g ie s .

27Meyers has used a s tr a te g ic a lly elegant chela tion controlled r e g io sp e c ific biphenyl coupling reaction to produce 1-phenyl- naphthalene lactones from naphthalenes.

Thus the chinensin analogue (91) i s prepared (Scheme 8) when the oxazoline (90) i s treated with 1 -lith io -3 ,4 -d im eth oxy-benzene. The oxazoline group further d irec ts hydroxymethyl- ation to afford the lactone on a c id ic work-up.

That the 18-carbon skeleton of tra n s-2 -(3 " ,4 " ,5 “-trim ethoxy- b e n z y l)-3 -(3 ‘ ,4 ' -m ethylenedioxy)-7-butyrolactone (92) i s a

26

38

p oten tia l precursor to both the a r y lte tr a lin and the bisbenzo- cyclo-octad iene lignans i s very c lea r .

Scheme 8

(90)

R eg iose lec tive intram olecular c y c lisa tio n of such sp ecies has been achieved under a var ie ty of cond itions.

39

Treatment of (93) with vanadium oxyfluoride gave Sch les- sin ger28 isostegane (69) in 70% y ie ld . He proposed the intermediacy of a spirodienone (94) which p re feren tia lly undergoes "bM type phenyl migration as a r e su lt of c o n figurational in te r a c tio n s .

(93)

-i*

(94)

29 30 . . .Magnus and Kende have a lso observed th is r eg io sp e c ificnon-phenolic coupling and Koga showed i t to be completely

. . . . 34s te r e o sp e c if ic m h is syn th esis of ( - ) -iso stega n e (69).

(95)

Thermal isom erisation to (+)-stegane (70) i s followed by se le c t iv e benzylic oxidation and the to ta l synth esis of unnatural (+)-steganacin (95). The absolute stereochem istry of the natural product ( - ) -steganacin was corrected to (22) as a

-(69)

40

r e su lt of th is work.

Kende30 and Ward31 a lso envisaged the io n ic or radical c y c lisa tio n s of a hypothetical quinonemethide (96) a t s i t e s "aM or “b" as a b iogen etic model leading to the podophyllin and stegane ring systems.

0(96)

R=H

(97)

Treatment of the monophenol (97) with thallium t r i s tr if lu o r o - aceta te g iv es , in 55% y ie ld a fte r b isu lp h ite reduction and m ethylation, the a r y lte tr a lin (98). P artia l ox id ative demeth- y la tio n leading to o-quinone formation and prototropic eq u ilib ration (Scheme 9) i s b elieved to g ive r is e to the interm ediate which undergoes acid catalysed c y c lisa tio n .

Scheme 9

(98) R=COOEt

A further element of control in these c y c lisa tio n reactions32 23has been observed independently by Ward and Z iegler. Later

the s tr a teg ie s w il l be described which afford the pre-coupling compounds (99) and (100).

RfS SR"

(99) R=H,R = Ph

(100) R=0CH3,RR'= -(CH2)3-

Raney n ick el desulphurisation of (100) g ives (93) which, as previously described, can be e f f ic ie n t ly manipulated to the stegane systems by vanadium oxyfluoride non-phenolic coupling. A ltern atively d irec t treatment of (100) with V0F3 or Mn(acac)3 y ie ld s the aryldihydronaphthalene (101). When Ward treated(99) with mercury(II) sim ilar c y c lisa tio n led v ia heavy metal a ss is te d elim ination to the naphthalene (102) in 59% y ie ld .

The benzylic oxygen su b stitu en ts a t C-4 in the podophyllin lignans and at C-5 in the stegane lignans are of prime

42

importance in determining the mode of b io lo g ica l action of these compounds.

The in clu sion of such fu n c tio n a lity or masked equivalent a tthe pre-coupling stage (99, 100) has always d irected coupling

33to afford a r y lte tr a lm s . Thus Ad}angba found that acid catalysed c y c lisa tio n of (103) y ie ld s the a r y lte tr a lin (104).

As w il l be seen la te r the f a c i le formation in acid of benzylic cations from benzylic a lcoh ols and arylcyclopropyl ketones and th e ir intram olecular trapping by appropriately disposed e lec tro n -r ich aromatics has provided a most v e r s a t ile route to the podophyllum lignans.

34 29Koga and Magnus have recen tly reported elegant and e f f ic ie n t so lu tion s to achieving C-5 oxygenation in steganes.

34Koga found that while (-)- iso s te g a n e (69) i s not u se fu lly oxid ised by DDQ in a c e tic ac id , (+ )-stegane (70) in which he predicted that one of the C-5 hydrogens might be perpendicular to the adjacent aryl ring undergoes stereo - and reg io - s e le c t iv e benzylic oxidation to (t)-steg an ac in (95) in 11% y ie ld .

43

Magnus' synthesis met the challenge of the steganacm system with greater s tr a teg ic ingenuity.

Thallium tr is tr if lu o r o a c e ta te intram olecular non-phenolic oxid ative coupling of the W ittig product (105) g ives the key biphenyl (106) in 70% y ie ld . Treatment of th is with LAH and Simmons-Smith cyclopropanation from the most a ccess ib le face of (106) affords a cyclopropanemethanol (107) which on exposure to AcOH/AcONa/HClO ̂ g ives in high y ie ld a s in g le diastereomer of the ring-expanded benzylic acetate (108) with C-8 inversion .

29

r~ 0 r 0

(107) (108)

44

The correct stereochem istry of C-6 r e la t iv e to the b iary l tw is t i s estab lish ed by hydroboration and h yd rolysis. Oxidation and e s te r if ic a t io n g iv es , a fter conventional la c to n isa tio n (±)-steganone (74) in 9% y ie ld from piperonal.

(c) Synthesis v ia monolactone enolates

Many syn th etic approaches to lignans have u t i l i s e d the additio n of e lec tro p h ile s to Y-butyrolactone eno lates or th e ir eq u iva len ts.

Scheme 10

(113)

The approaches outlined here (Scheme 10) have a l l been e f f i c ie n t ly rea lised but they remain a t the focus of considerable

45

atten tio n today.

S tra te g ic a lly the enolate (110) i s id e a lly designed for the preparation of podophyllum and stegane lignans. A lkylation of (110) i s expected to afford a trans re la tion sh ip between the adjacent a and /3 su b stitu en ts in (112) and (113) and subsequent c y c lisa tio n to a r y lte tr a lin s or bisbenzocyclo-octadienes should produce a trans fused lactone.

Much synth etic work has been d irected towards the construction of systems such as (109). In p articu lar, the Stobbe condensa tion in which benzyl carbonyl compounds are condensed with d ia lk y lsu ccin ates in the presence of base, has been the nub of many synth etic schemes.

. 35Crombie has synthesised o p tic a lly ac tiv e (-)-h in ok in m and (-)-cubebin v ia Stobbe condensation of piperonal to g ive (114). This i s hydrogenated, e s te r if ie d and subjected to a second Stobbe reaction giving the d iacid (115) which can be resolved and o p tic a lly pure m aterial reduced with LAH a fte r e s te r if ic a t io n g iv in g (116).

A lly l ic oxidation affords (-)-h ib a la cton e (117) which i s hydrogenated to the c is lactone (+ )-isoh in ok in in (118). This

(1U) X=H(115) X = 3.^-m ethylenedioxybenzyl

46

can in turn be epimerised in base to the trans lactone (-)-h in ok in in (119), the la c to l of which i s (-)-cubeb in (120).

(117) (118) X=0,Y=-«H(119) X=0,Y=i i i H(120) X =H ,0H ,Y =m H

36Kirk reported the f i r s t to ta l syntheses of enterolactone (26) and enterodiol (27) v ia th is double Stobbe condensation approach. Thus the benzyl ether (121) g ives diene (122) which on c a ta ly t ic hydrogenation affords the trans d ie ster (123). This can be simply converted to the natural products.

(123)

HO OH

Stevenson has a lso developed routes to lignans v ia the Stobbe condensation. Thus treatment of veratraldehyde with d ieth y lsu ccin ate in the presence of base g ives the benzylidene h a lf ester (124). This i s reduced to the benzyl h a lf e ster and lacton ised with calcium borohydride in 86% y ie ld (125).

37

The lithium enolate of (125) i s treated with piperonal and then d ir ec tly with tr if lu o r o a c e t ic acid to y ie ld the cy c lised a l l - trans a r y lte tr a lin (126) in 90% y ie ld .

This has become a standard preparative method for ary l- t e t r a l in s . Treatment of (126) with LAH g ives , a fte r methyl- ation ( ± ) - l in t e t r a l in (127) or a fte r to sy la tio n and LAH treatment (± )-iso g a la c tin (128). When the lith ium enolate of (125) i s s im ila r ly treated with veratraldehyde and the same procedure followed (± )-p h y lte tra lin (129) i s produced.

48

Further development of th is general synth etic route i s needed38in order to e f f e c t a synthesis of (±)-hypophyllanthin. When

the lactone (130) i s treated , as i t s lithium enolate with piperonal and then cy c lised in the usual manner the ( ± ) - n i r - te tr a lin (132) skeleton i s produced (131) s e le c t iv e ly . Clearly in (130) the vacant p osition ortho to the methoxyl group i s the most activated to e le c tr o p h ilic su b stitu tio n . Accordingly (130) can be e le c tr o p h ilic a lly brominated to (133) and sim ilar a lk y la tiv e treatment of th is g ives a fte r c y c lisa tio n the hypo- phyllanthin oxygenation pattern (134). Reductive debromination and routine elaboration affords (±)-hypophyllanthin (135).

49

Br

The use of /3-benzyl-Y-butyrolactone equivalents generated byStobbe condensations has been the basis for the many lignan

39preparations reported by Brown and Robin. Thus, so derived jSpiperonyl-T-butyrolactone (136) g ives (±)-podorhizone (1 3 7 )^ and (± )-a ttenu ol (1 3 8 ) .41

50

A OBanerji recen tly prepared (± )-g a d a in (139) by a ld o l condensation of piperonal, d irec t elim ination and eq u ilib ration in acid to the trans system.

/3-Veratryl-7-butyrolactone (125) g ives c is (140) and trans 43 nartigen in (141) and p-(2-alkoxy-3,4-m ethylenedioxybenzyD -T-

butyrolactones (142) are e x c e lle n t precursors to iso-/3- 44p e lta tin (143) and i t s methyl ether.

45 . 46 47Koga , Robin and Achiwa have independently developed routes to o p tic a lly pure /3-benzyl-7-butyrolactones and v ia th e ir enolates enantom erically pure lignans have been synthesised .

The sim plest r o u te ^ involves the asymmetric hydrogenation of the Stobbe condensation product (144). Thus (144) on rhodium catalysed hydrogenation in the presence of a ch ira l bidentate

51

phosphine ligand (BPPM-Rh), followed by carefu l LAH reduction and la cto n isa tio n g ives the lactone (145) in 78% o p tica l y ie ld .

0

1147) (148) (149) X=H,OH(150) X = 0

Pure (148) i s ox id a tiv e ly cleaved to the hem i-acetal (149) which undergoes C ollins oxidation to o p tic a lly pure (R)—(150). The (S) enantiomer (145) i s le s s e f f ic ie n t ly prepared from(146) by hydroxyalkylation and elim ination to (151) followed by c a ta ly t ic hydrogenation. An enantiomeric excess of 50% corresponding to p referen tia l hydrogenation from the opposite face to the t r i t y l group g ives (145) a fter removal of the o r ig in a l ch ira l center.

. 46Robin found greater d ia ste r eo se lec tio n on a lk y la tion of (146) with 3 ,4 ,5-trimethoxybenzyl bromide and moreover the diastereomers are read ily separated by c r y s ta ll is a t io n . Thus (152) can be prepared in high o p tica l y ie ld .

These o p tic a lly pure jft-benzyl-Y-butyrolactones have been su ccessfu lly used with complete retention of stereochem ical purity to prepare lign an s. The w ell estab lish ed hydroxy-

53

a lk y la tio n /c y c lisa tio n sequence (Scheme 12) has been thoroughly studied and i s exem plified by Koga's to ta l syn th esis of (-)-isodeoxypodophyllotoxin (96% y ie ld ) .

Scheme 12

(-H so d e o xyp o d o p h y llo to x in

The stegane fam ily of lignans has a lso been synthesised viaY-butyrolactone en o la tes. Many syntheses p r in cip a lly by Brown

19-20and Robin have generated, by modified Ullmann coupling,biphenyls containing a butyrolactone or i t s equivalent which has been used v ia i t s enolate to e f f e c t c y c lisa tio n onto an appropriately disposed benzaldehyde and to so form the bisbenzocyclo-octadiene framework. These methods have been described previously .

The Stobbe condensation on unsymmetrical benzophenonesfeatures heavily in the a ltern a tiv e approaches of Gensler andH orii. F riedel-C rafts reaction derived benzophenone (153)undergoes Stobbe condensation to a mixture of isom eric

48ita co n ic ac id s. Separated from i t s double bond isomer, (154) i s c a ta ly t ic a l ly c is hydrogenated and dehydrated to the anhydride (155). Treatment of th is with stannic chloride in nitrobenzene g ives a s in g le c y c lisa tio n product (156) corres-

54

ponding to su b stitu tio n a t the vacant s i t e para to an oxygen of the methylenedioxyphenyl ring.

(153) (154)

0

H3C O '^ y ^ 'O C H 3o c h 3

(155)

^ -S ta b ilisa t io n of the c a tio n ic interm ediate of su stitu tio n was proposed to be b etter for th is ring than for the t r i - methoxyphenyl r ing. In the former the oxygen p o r b ita ls are perpendicular to the aromatic ring and can 7T-bond more e f f i c ie n tly than the oxygens of the la t te r ring, in which the p o rb ita ls cannot be so disposed because of s te r ic in tera c tio n s.

Also, sin ce the electron withdrawing e f fe c t of oxygen i s a ctiv e through the a-framework then in the absence of good

7T-bonding in the trimethoxyphenyl ring the net e f f e c t of such

55

su b stitu en ts might be to disfavour ca tion ic interm ediates. In addition to th is , product (156) corresponds to c y c lisa tio n (Diagram 3) of apparently the most stab le configuration of the startin g anhydride (155).

Routine transform ations on (156) give the c is lactone p icro-podophyllin (20) to which the Gensler^ epim erisation sequencecan be applied . The thermodynamic preference forpicropodophyllin (20) over podophyllin (14) has been mentionedpreviously.^ In the la tte r the trans fused lactone system i svery strained and the C-ring does not fre e ly ro ta te on an nmr

49time sc a le . Picropodophyllin i s much le s s r ig id and under conditions of thermodynamic eq u ilib ration (14) i s converted e s se n tia lly com pletely to (20). However, (14) and (20) have a common enolate (157) which on ir r ev e r s ib le reprotonation affords a mixture determined not by the thermodynamic equilibrium constant between (14) and (20) but by the r e la tiv e rates of protonation of i t s top and bottom fa ces .

56

Examination of Dreiding models predicted that such k in e tic reprotonation should afford considerably more podophyllin than i s present in the thermodynamic equilibrium mixture.

Accordingly the enolate can be formed with trity lsod ium and quenched with a c e tic acid g iv ing a 51% recovery of (20) and 38% of (14). Recycling a fter separation improves the sequence.

50Kende la te r attempted further improvement by low temperature k in e tic protonation of the enolate of the TBDMS ether of picropodophyllin (158).

OTBDMS

D esily la tio n r e lib era te s (14) but no real improvement over G ensler's method i s achieved. Rodrigo has developed an e f f i c ien t a ltern a tiv e to th is procedure which w il l be discussed la te r .

. . 51Horn showed that the hydroxymethylene e ster (159) can be lacton ised to the arylnaphthalenes taiwanin E (160) and j u s t i - c id in F (1 6 1 ).. A ltern a tiv e ly v ia protection as an isoxazo le(162) the ethyl e ster can be reduced and ju s t ic id in D (163) prepared.

57

(159) (160) R=H

(161) R=CH3

Much as the enolate (110) i s the product of base treatment of the /3-benzyl-7-butyrolactone (109) i t i s a lso the interm ediate product of M ichael-type conjugate addition of a benzylic anion onto butenolide (111). The p oten tia l for trapping of the enolate by e lec tro p h ile s has been amply demonstrated and the method therefore c o n stitu te s a very powerful route to the2 ,3-d isubstituted-Y -butyrolactone lig n a n s.In 1978 Z iegler showed that th io a ce ta l carbanions e f f e c t Michael addition to butenolides and th at the so formed enolates can be trapped with benzyl h a lid es or aldehydes to

58

give ex c lu siv e ly trans- 2 , 3 -d isu b stitu tio n . Thus the l i t h io -1 ,3 -d ith ian e (164) reacts with butenolide and 3 ,4 ,5-trim eth- oxybenzyl chloride (Scheme 13) to g ive the trans adduct (165) which as previously described affords aryldihydronaphthalenes on d irec t non-phenolic oxid ative coupling and ( ± )- iso s te g a n e on sim ilar coupling a fte r Raney n ickel desulphurisation . I f the d ith iane (165) i s d eth iok eta lised to the ketone then a fter reduction, acid catalysed c y c lisa tio n i s d irected towards e le c tr o p h ilic su b stitu tio n on the trimethoxyphenyl ring giving(166).

Scheme 13

0

(165)

59

A ltern ativ ely i f e le c tr o p h ilic trapping of the enolate (110) i s performed with a benzaldehyde then acid catalysed c y c lisa tio n occurs onto the piperonyl ring leading to deoxyisopodophyllotoxin (167) and isopodophyllotoxone (168) (Scheme 14).

Schem e'll

60

Brown recen tly used a sim ilar strategy in h is synth esis of52conindendrine (169).

14In 1980 Sniekus showed that the conDugate addition of sim ilar anions onto crotonamides affords predominantly threo adducts which undergo acid catalysed c y c lisa tio n to a ry l- t e t r a l in s . He thus completed a to ta l synth esis of ga lactin (170) (Scheme 15).

Scheme 15

r ^ i

61

The l i t h io d er iv atives of arylbis(phenylthio)m ethanes have32a lso been used to e f fe c t lignan sy n th esis . Ward showed that

under non a c id ic conditions treatment of benzylic geminal d ith ioa ry l compounds (99) with heavy metal s a lt s g ives access to s ta b il ise d cations which undergo c y c lisa tio n and e lim ination d ir e c tly to arylnaphthalenes (102). He a lso showed that th e ir desulphurisation provides a highly e f f ic ie n t route toenterolactone (26) and enterodiol (27), a r e su lt recen tly

. 5 3v e r if ie d by Kirk.50In 1981 Kende described an elegant construction of 0 4

oxygenated a r y lte tr a lin s (171) by intram olecular e le c tr o p h ilic trapping of a conjugate addition derived eno late . Thus (Scheme 16) and by otherwise standard methods he formed the racemic k eto-acid (156) in very high y ie ld . This however affords only the picro se r ie s of lactones and the in e ff ic ie n c y of epimer- isa t io n to podophyllotoxin (14) produced the la t te r in 4.5% overa ll y ie ld from piperonal.

Scheme 16

(171) 88%

62

Continuing h is study of self-im m olative s te r e o se le c t iv e34syn th esis of 2 ,3-d isubstituted-Y -butyrolactones Koga has

developed a very highly en a n tio se lec tiv e syn th esis of lign an s.This strategy (Scheme 17) was previously used to en a n tio se l-e c t iv e ly construct /3-benzyl-Y-butyrolactones which weresubsequently eno lised and alkylated in a separate step . Thesyn th esis of the key o p tic a lly a c tiv e butenolide (172) has

34received much a tten tio n . Koga prepared i t with completeretention of stereochem ical purity by phenylselenation ,oxidation and elim ination of (146) which i s read ily derived

54from L-glutamic acid . More recen tly Font used D-ribono-lactone as a source of c h ir a lity (Scheme 18) and obtained (172) in comparable y ie ld .Scheme 17

Scheme 18

HOv ^0t;oR

HC(OEt) 02-E tO —<0

0

^0 ----- - ------(172)HQ

R = CH2OCPh3

E ssen tia lly complete d ia stereo se lec tio n i s observed on performing the q u an tita tive conjugate addition of (173) to (172) and e le c tr o p h ilic trapping with piperonyl bromide. Though (174) can be desulphurised and then converted to lignan lactones v ia Koga's usual lactone carbonyl transp osition procedure with complete stereoreten tion the chemical y ie ld s are low.

I t was found to be b etter to carry out the e le c tr o p h ilic a lk y la tion as a separate step a fter desulphurisation of the butyrolactone (175). Thus Koga has prepared o p tic a lly pure (+)-deoxypodorhizon (176) and, v ia the previously described non-phenolic ox id ative coupling procedures, (t)-steg a n a c in(95).

(175)

64

(176)

Posner has a lso developed an en a n tio se lec tiv e Michael acceptor and him self prepared o p tic a lly a c tiv e (-)-podorhizon (177) in high y ie ld by the conjugate addition of Grignard reagents to i t (Scheme 19). The method c o n stitu te s a further preparation of (S)-(145) and i t s use in lignan sy n th esis .

Scheme 19

0

55

h 3c

The intermediacy of benzylic cations and th e ir intram olecular e le c tr o p h ilic addition to aromatics has been w ell exem plified as a method of forming a r y lte tr a lin s .

Murphy^ has shown th at in the presence of Lewis acids arylcyclopropyl ketones c y c l is e to a r y lte tr a lin s in high y ie ld s . Thus cyclopropanation of (178) followed by reaction with stannic ch loride leads eventually to podophyllotoxin (Scheme 20).

W'0

llZnB r? , ,P ------- 2— M S H V .5 )2) A3) Raney Ni

A = 3 A -m e th y le n e d io xyb e n zy l m agnesium b ro m id e

65

Scheme 20

57Snider showed that the addition of formaldehyde to styrenes in the presence of Lewis acids a lso generates benzylic cations which are intram olecularly trapped affording a r y lte tr a lin s . In addition to th is C-2 and C-3 hydroxymethylation can be carried out in the same step leading d ir e c t ly to (179) from E or Z1,4-diphenyl-2-butene (Scheme 21).

Scheme 21

lCH20)n(CH3)2AlCl

1179) 50%

66

(d) Synthesis v ia p e r ic y c lic reactions

Arylnaphthalene and a r y lte tr a lin lignans have frequently been18constructed by the D iels-A lder and other related reaction s.

C OThe observation in 1895 that phenylpropiolic acid undergoes dim erisation with dehydration to form 1-phenylnaphthalene-2,3- dicarboxylic acid anhydride (180) during heating in a c e tic anhydride (Scheme 22) provided the basis for a syn th etic methodology which i s to th is day of considerable value in the laboratory preparation of lignans.

Scheme 22

In the sim plest extension of th is the a cety len ic anhydride59(181) undergoes D iels-A lder c y c lisa tio n and affords the

naphthalene anhydride (182) which v ia reduction and p a r tia l reoxidation can be converted to ju s t ic id in E (183) and taiwanin C (184).

In order to syn th esise helioxanthin (186), otobain (187) and dehydro-otobain (188) Stevenson^ used a bromide blocking group which d ir ec ts c y c lisa tio n and i s read ily red u ctively removed a fter the D iels-A lder reaction (Scheme 23).

67

X

0

(183) X = 0 ,Y = H 2(184) X =H2,Y=0

Scheme 23

68

Access to naphthalene, dihydronaphthalene and tetrahydro- naphthalene lactones can be made d ir e c tly by the D iels-A lder c y c lisa tio n of doubly unsaturated e s te r s .

In the case of the doubly a ce ty len ic e ster (189) both p ossib le isom eric naphthalene lactones are obtained from D iels-A lder c y c lisa tio n .

(189) (190) X = 0 ,Y = H z(191) X =H 2 ,Y = 0

t s te r s synthesised , e ith er by the combination of cinnamyla lcoh ols and a cety len ic acid chlorides**^ or from sodium s a lt s

61of acids with cinnamyl ch lor id es, provide d ir e c t access to dihydronaphthalene lacton es.

Thus intram olecular D iels-A lder reaction of the e ster (192)affords the dihydronaphthalene (193) which g ives the c is

62lactone on c a ta ly t ic hydrogenation (194).

A ltern atively (194) can be formed d ir ec tly by D iels-A lder reaction of the e ster (195). In these reactions i t i s the double bond adjacent to the carbonyl group which acts as dienophile and the cinnamyl moiety as diene.

69

0 0

(196) (197)

64Rodrigo has looked at the ap p lication of the D iels-A lder reaction to lignan synth esis with particu lar a tten tion to esta b lish in g the correct r e la t iv e stereochem istries of the four adjacent ch ira l centres in podophyllotoxin and to the introduction of C-4 oxygenation.

He generated in s itu an isobenzofuran (199, o-quinodimethane equivalent) which undergoes D iels-A lder reaction with DMAD and in the presence of PTSA forms dehydropodophyllotoxin (200) a fter la c to n isa tio n in 35% overa ll y ie ld (Scheme 24).

71

Scheme 24OH

A=D M A D /TsO H

B =B H 3.DMS

I f the D iels-A lder reaction i s carried out in the presence ofa weaker acid (a c e tic acid) then the i n i t i a l adduct can beiso la te d (201) and ca re fu lly reduced to (202). C-3 Smoothlyepim erises in base and the exo ester can be s e le c t iv e lyreduced to afford , a fte r Raney n ick el hydrogenation, methyl-

64epipodophyllate (203). Rodrigo has developed an e x ce llen t a ltern a tiv e to the Gensler epim erisation and a route to podophyllotoxin (14).

In order to complete the syn th esis the 1 ,2 -c is re la tion sh ip must be preserved d esp ite the need for e ster sap on ifica tion in

72

order to e f fe c t la c to n isa tio n . In addition to th is C-4 epim erisation i s required. Rodrigo found that k e ta lisa tio n ofthe 1 ,3 -d io l (203) affords a benzocisdecalin (204) which confers considerable s t a b i l i t y to epim erisation on C-2. Saponification e f fe c ts no epim erisation. Furthermore acid treatment of the carboxylic acid r e su lts in clean .C-4 inversion and the formation of podophyllotoxin (14) in high y ie ld .

The in s itu generation of o-quinodimethanes and th e ir trapping with d ienophiles has been ex ten sive ly studied in recent years.

photochemical e n o lisa tio n on u ltr a v io le t irra d ia tio n (Scheme 25) and sin ce that time considerable e ffo r t has been expended on the d e ta i ls of the energy and geometry changes involved in the process and on the nature of the tra n sien t interm ediates. Evidence suggests that both the E and the Z isomers do form but that the c is form i s considerably shorter liv ed than the trans due to rapid in tern a l rek eton isation . The E isomer can be read ily trapped by d ien op h iles.

<

In 1961 Yang65 reported that o-alkylbenzophenones undergo

73

Scheme 25

Z E

Stevenson^ showed th at trapping with butenolide affords a ry l- te tr a lin s d ir ec tly and with the simultanious formation of three adjacent ch ira l centres in a controlled manner. The r e la tiv e stereochem istries of C-2 and C-3 can be controlled by appropriate choice of d ienophile geometry (Scheme 26).

Scheme 26

74

A ltern atively formyldiphenylmethanes undergo a sim ilargophotoenolisation and Durst has completed a to ta l syn th esis

of epiisopodophyllotoxin (205) in th is way (Scheme 27).

Scheme 27 ,

The c lear advantage and elegance of th is technique i s the incorporation of C-4 oxygenation and stereochem ical control in the formation of four adjacent ch ira l centres in one syn th etic step . The synth esis of (205) was completed using Rodrigo's k e ta lisa tio n sequence.

69Recently Takana used a benzyl equivalent of the Peterson o le fin a tio n reaction to generate an o-quinodimethane and trapped i t with maleic anhydride.

75

He completed a to ta l syn th esis of ( ±)-deoxypodophyllotoxin(167) by standard means (Scheme 28).

(167)

He has a lso shown that the 1 ,3 -d ith ian e (206) affords cyc lo adducts with maleic anhydride which are read ily converted in to

70naphthalene lignan lactones (Scheme 29).

Scheme 29

0

- lig n a n s

The ch eletrop ic exclusion of carbon dioxide and sulphur dioxide from lactones and sulphones resp ec tiv e ly has e f f i c ie n t ly afforded o-quinodimethanes.

71Thus Das showed that cycloaddition occurs when the lactone(207) i s heated with N-phenylmaleimidef the geometry of theo-quinodimethane interm ediate being apparently pure trans

76

(208) as only one D iels-A lder adduct i s formed (209). The elegance of the scheme i s lo s t sin ce basic hydrolysis of (209) resu lts in C-2 epim erisation but nevertheless the dimethoxy analogue of deoxyisopodophyllotoxin (210) i s e f f ic ie n t ly formed.

(208)

Durst anch eletrop ic extrusion of sulphur dioxide to form o-quino- dimethanes and have trapped them with a variety of d ienophiles to afford lign an s.

77

F in a lly , in a recent highly elegant strategy marred only byextreme d i f f ic u l t i e s in the preparation of s ta r tin g m aterials

74Jung has developed a s te r e o se le c tiv e intram olecular D ie ls - Alder cycloaddition reaction which leads to deoxypodophyllo- tox in .

0

(213) C - 2 111COOCH3(214) C - 2 -C O O C H 3

He reasoned that therm olysis of the mixed carbonate (211)

78

should produce specifically the trans, trans-o-quinodimethane

(212) which should undergo intram olecular D iels-A lder cycloaddition to give the a r y lte tr a lin s (213) and (214). The endo product (213) should predominate and could be simply converted to podophyllotoxin (14) by known chemistry.

In p ractice (211) was never made.

The strategy was however te s ted on (215) which forms the endo product (216) in threefo ld excess over the exo product.

(215) (215) 22%This strategy once fu lly developed should lead to the preparation of podophyllotoxin (14) with the formation of a l l four ch ira l centres in a s in g le chemical reaction .

79

Conclusion

The discovery of the wide ranging b io lo g ica l properties of lignans has inspired many organic research chemists to develop syn th etic routes to them. Also the a v a ila b il ity of r e la t iv e ly large numbers of lignans from a much sm aller number of key interm ediates has permitted ju st a few schools of research to make large contributions to the f ie ld of lignan chemistry.

Many of the le s s recent syntheses of cyclolignans re lie d on carefu l control over the d irection of e le c tr o p h ilic aromatic su b stitu tu ion during the acid catalysed rearrangements of 2 ,6 - d ia ry l-3 ,7 -d io x a b icy c lo [3 .3 .0 ]o c ta n e lign an s. S tereo se lec tiv e syntheses by Sniekus^ and Ward^ have made the la t te r compounds a ttr a c tiv e syn th etic interm ediates and control over th e ir rearrangement has la rge ly been achieved by the use of appropriately oxygenated aromatic rings and by the blocking of “normal" su b stitu tio n p o sitio n s by e le c tr o p h ilic halogenation. As a general syn th etic methodology however the rearrangement techniques o ffer much greater regiocontrol than stereocon trol and remain e f f ic ie n t only for the synth esis of unsaturated (B ring) cyclo lign an s.

Biphenyl coupling and ring expansion reactions have featured h eavily in the reported syntheses of b isbenzocyclo-octadiene lign an s. The basic 18-carbon skeleton has thus been e legan tly constructed but the techniques have fa ile d to provide the means for control over the r e la t iv e stereochem istries of the

80

su b stitu en ts in the saturated portion of the systems (C-5 toC-7, structure 22). Reported stereochem ical adjustments have,

64with the noteable exception of the contribution by Rodrigo , been in elegan t and highly in e f f ic ie n t .

This review n ecessa r ily r e f le c t s the large number of lignansyntheses which have exp lo ited the addition of benzylice le c tro p h ile s to 7-butyrolactone en o la tes. These enolates havethemselves been generated by the additon of benzylicnucleophiles to butenolides and the resu ltin g ol, (3 -dibenzyl-Y _butyrolactones have proved to be e x ce llen t precursors to

23a r y lte tr a lin s . The many reported syntheses by Z iegler , Kende^ and Brown^ 22 ,40 ,41 ,44 ,52 jjave e f f ic ie n t ly afforded awealth of lignan lactones and the self-im m olative ch ira l

34 45 46varia tion s on th is work inspired by Koga ' Robin and47 . . .Achiwa have led to the preparation of b io lo g ic a lly a c tiv e

a r y lte tr a lin s in high o p tica l purity .

F in a lly i t i s perhaps appropriate that one of the mostfundamental chemical reactions known today, the D iels-A lderreaction , should o ffer an e f f ic ie n t route to arylnaphthaleneand a r y lte tr a lin lign an s. The synth esis of D iels-A lderreaction precursors was read ily achieved when unsaturatedtargets were sought, however th e ir design with respect to moreso p h istica ted goals remains an area of in tense a c t iv ity today.

64Rodrigo has completed a syn th esis of podophyllotoxin (14) but the p oten tia l a b i l i ty of the D iels-A lder reaction to e sta b lish the correct r e la t iv e stereochem istries of the four ch ira l centres in the target was not fu lly r e a lise d . This

81

challenge was recen tly addressed by Jung but extreme d i f f i c u l t i e s in the preparation of an appropriate cyc lo addition reaction precursor allowed only the preparation of deoxypodophyllotoxin. The establishm ent of the four ch ira l centres in podophyllotoxin (14) together with the construction of the 18-carbon lignan skeleton in a s in g le chemical reaction i s a goal which w il l be keenly sought in the coming years.

82

CHAPTER TWOR esults and D iscussion

83

Introduction

Lignans are a widely occurring group of natural products and the study of both th e ir b io lo g ic a l a c t iv i t ie s and synth esis has received considerable a tten tio n in recent years. Lignans occur p rin cip a lly as three fam ilies of compounds, the b is - epoxylignans, b isbenzocyclo-octadiene lignans and a ry l-te tr a lin s and the h is to r ic a l syn th esis of a l l three groups of compounds has been discussed in Chapter One.

The podophyllum lignans have been shown to possess broad range3b io lo g ica l a c t iv ity and, for example, a number of them are

u sefu l c l in ic a l cancer chemotherapeutic agents. Extensivestu d ies in to s tr u c tu r e /a c t iv ity re la tion sh ip s for thesecompounds have revealed a number of structu ral p rereq u isitesfor a c t iv ity and have raised many questions as to the nature

5of the binding s i t e s with which they are involved.

Podophyllotoxin (14), in p articu lar , has been suggested to be involved with the same binding s i t e on tubulin as co lch ic in e (21) and sin ce both possess a trimethoxy su b stitu ted benzene ring th is has been proposed as the common binding s i t e .

This view i s apparently corroborated by the fa c t that when large su b stitu en ts, for example g lyco sid es, are present in these s i t e s then b io lo g ic a l a c t iv ity i s grea tly reduced. However th is might be the r e su lt of gross changes in l ip o - p h il ic i ty rather than s te r ic e f f e c t s .5

84

C olchicine (21) has been s e le c t iv e ly demethylated and the ro leof the methoxy groups in binding has been elu cid ated . I t i sfound that the optimum oxygenation pattern i s 1 ,2 . The 1,3 and2,3 systems have reduced a f f in it y for tubu lin . By con trast,s e le c t iv e demethylation of podophyllotoxin (14) has shown noreduction in a c t iv ity for the 1 ,3-dimethoxy compound ascompared to (14) i t s e l f . I t seems l ik e ly from th is thereforethat the C rings of podophyllotoxin (14) and co lch ic in e (21)

76do not share binding c h a r a c te r is tic s .

The observation however that /3 -p elta tin (18) binds to tubulin more e f f ic ie n t ly than does podophyllotoxin (14) suggests th at i t i s th is A ring trioxygenation pattern which corresponds to the C ring trioxygenation in co lch ic in e (21) and that th is might be the common binding s i t e .^

85

The aim of th is project was to develop syn th etic s tr a te g ie s towards a r y lte tr a lin lignans and secopodophyllotoxins, th at i s , analogues of podophyllotoxin (14) where oxygenation has been removed from the phenyl (C) ring and from C-4, and with an uncompleted ring (B ).

R etrosynthetic an a lysis

In Chapter One many su ccessfu l syn th etic s tr a te g ie s which have afforded a wide range of a r y lte tr a lin lignans have been described.

In the present study a general syn th etic procedure which might provide a wide range of stru ctu ra lly sim ilar a r y lte tr a lin s with stereochem ical control over the three contiguous ch ira l centres present in , for example, deoxypodophyllotoxin (19), was sought.

I t was envisaged that deoxypodophyllotoxin (19) should be produced by treatment of the primary iodide (217) with s i l v e r ( I ) .

86

(19)

C yclisation should be s p e c if ic for the raethylenedioxyphenyl48ring in accordance with the observations of Gensler and

should not su ffer from com petitive attack on the lactone ring which might r e su lt i f simple Lewis acid induced c y c lisa tio n were employed. The iodide should be read ily preparable from the corresponding alcohol (218).

(19)I OR

(218) R = H(219) R = Si R3

The key disconnection in the syn th etic strategy corresponds to construction of the diphenylmethane moiety of (219) by the tra n s it io n metal catalysed cross-coupling reaction of an aryl iodide (220) with a benzyl halide (2 2 1 ) .^

87

(219)

OCH, (221)

In order for the scheme to be su ccessfu l the coupling process would have to f u l f i l a number of requirements. I t would have to proceed v ia organom etallic sp ecies which are neither basic enough to e n o lise the lactone carbonyl group and thereby epimerise C-2, nor n u cleop h ilic enough to attack th is e le c tr o p h ilic centre.

In addition to t h is , control over the stereochem ical outcome of the coupling reaction could be anticip ated only i f the organom etallic reagent retained , under the reaction cond it io n s , the diastereom eric purity of the halide from which i t was formed. I f the organom etallic sp ecies were to rapidly epim erise a t the b enzylic carbon then the ra tio of d ia - stereomers in the product mixture would probably r e f le c t the r e la tiv e thermodynamic s t a b i l i t i e s of the diastereom eric organom etallic precursors.

Grignard reagents are known to be stereochem ically non-rigid^® and th is la b i l i t y has been sy n th e tica lly used via k in e tic epimeric reso lu tion by ch ira l palladium(O) complexes to e f f e c t en a n tio sp ec ific coupling reaction s. In addition to th is

88

Grignard reagents are generally reactive towards e ster s and would not be compatible with the lactone group in the required system.

The stereochem ical r ig id ity of organozinc compounds however,i s le s s studied and i s worthy of in v e stig a tio n . As w il l bedescribed sh ortly , the coupling process can be performed in anumber of ways, and i f a benzylzinc reagent should, in theevent, be s te r e o la b ile then there i s considerable precedentthat the corresponding benzylpalladium (II) reagent would notbe, and that the coupling process could be performed in as te r e o se le c t iv e manner. Organozinc compounds are r e la t iv e lyto lera n t of e le c tr o p h ilic functional groups such as n i t r i l eand e ster and should not in ter fer e with the lactone group in

79( 221 ) . 73

The retrosyn th etic a n a lysis further sim p lified the immediate target by considering that the de-/3-alkoxymethyl lactone (222) was a reasonable model on which to carry out i n i t i a l s tu d ie s . Thus th is became the sy n th etic target and might be formed from the corresponding benzylic alcohol which i s i t s e l f (223) ava ila b le from the a ld o l condensation of 7-butyrolactone with an appropriate benzaldehyde (224). I f the a ldo l condensation could be performed in a d ia s te r e o se le c t iv e manner then conversion of (223) to the benzyl halide should afford the r eq u is ite m aterials for cross-coupling in d iastereom erica lly pure form.

89

n 0

H3COOCH3

OCH3

0

OCH3 OCH3(222) (223) (224)

The synth esis of diphenylmethanes; palladium(0) catalysed coupling reactions

S e lec tiv e carbon-carbon bond formation v ia tra n s itio n metal catalysed coupling reactions i s an area of organom etallic chemistry which has a ttracted particu lar a tten tio n in the la s t two decades.

80 81In 1972 i t was discovered by Kumada and Corriu that the reactions of Grignard reagents with organic h alid es can be markedly catalysed by nickel-phosphine complexes and sin ce th at time cross-coupling reactions using these and palladium- phosphine complexes have been developed in to highly e f f ic ie n t s te r e o - , reg io - and chem o-selective processes.

A sim p lified generally accepted mechanism for n ickel and palladium catalysed cross-coupling reactions i s given here (Scheme 30).

There are believed to be three key steps in the mechanisms of these reaction s.

90

Scheme 30

RmXmX2L= Ligand. M = Ni.Pd. m= Mg. Zn. Al.Zr.B.Sn.Li.

R'= alkyl, benzyl.aryl. R"= aryl.alkenyl.X = Cl.Br.I.OR.SR.SeR.O P(0)(0R)2.

The oxidative addition of a c a ta ly t ic a l ly a c tiv e metal sp ecies to an aryl halide i s generally believed to occur a fter the m etal(0) sp ecies has become coord inatively unsaturated and

This reaction step i s u sually regarded as being rate lim itin g and the presence of bulky o -su b stitu en ts on the aryl halide i s known to disfavour i t due to s te r ic hindrance. Aromatic iod ides and bromides take part in the reaction , the la tte r compounds being much le s s reactive and frequently requiringthe use of elevated temperatures. The in flu en ce of e lectron

10converts a metal complex such as a zerovalent d -palladium82(I»nPd) to an organom etallic adduct (Scheme 31).

Scheme 31

X

91

withdrawing/donating su b stitu en ts on the aryl halide i s a lso important sin ce they can resp ec tiv e ly d e s ta b ilis e or s t a b i l is e the ox id ative addition complex.

In the second reaction step transm etallation of a preformedorganom etallic compound onto the oxid ative adduct occurs.Organometallic compounds containing highly e le c tr o p o s it iv em etals, for example lith ium , show lower r e a c t iv ity in th isstep than those of metals of interm ediate e le c tro n eg a tiv ity ,

77for example zin c, aluminium and zirconium.

In the f in a l step a 1 ,1 -reductive elim ination occurs whichforms the new carbon-carbon bond and regenerates coor-

83d in a tiv e ly unsaturated c a ta ly s t .

In the present study the chem oselective formation of diphenyl- methanes was in v estig a ted .

Two d is t in c t approaches to diphenylmethanes have been con si-79dered (Scheme 32). These are Type 1, the treatment of a

benzyl organom etallic reagent with an aryl halide in the79 84presence of a tra n s it io n metal c a ta ly s t and Type 2, ' the

treatment of an ary lz in c reagent with a benzyl halide in the presence of a sim ilar c a ta ly s t . In the f i r s t approach, control of the stereochem istry (R contains a ch ira l centre) of the coupling reaction would depend heavily on the s te r e o la b il i ty of the benzyl organom etallic sp ecies whereas in the second, the outcome should r e f le c t only the diastereochem ical purity of the benzyl halide a t the time of ox id ative addition to palladium(O), the remaining reaction steps being known to

92

r e su lt in no epim erisation. 78

Scheme 32

Type 1 Type 2

Ar-C H -X A r-Z n -X

R

The p rincipal c a ta ly s t employed was tetrak is(tr ip h en y lp h os- phine)palladium(O), (Pd°[PPh3] 4) , which was conveniently prepared in high y ie ld by standard means from palladium (II) ch loride and read ily stored in the cold and in a deoxygenated nitrogen atmosphere.®®

Type 1 coupling reactions

Benzylzinc reagents were optim ally prepared by s t ir r in g the bromide with fresh ly f i le d m eta llic zinc in THF a t room temperature for two hours during which time the zinc was consumed. The a c t iv ity of the metal used here was apparently higher than that of conventional acid-washed zinc powder and for small sca le sy n th etic work was more convenient. Rieke88 has reported the preparation of very highly a c tiv e , f in e ly

93

divided metals by the potassium reduction of th e ir h alid es (Scheme 33). For zinc he reports a p a r tic le s iz e of 17m/x and the formation of an in ten se black suspension of the metal in THF.Scheme 33

9 i/Zn + Br-C H 2-CH2- B r --------- * -Z n B r2 -------- ► Z n + 2 KBr

- c 2ha17m ii

Scheme 34

Addition of benzyl bromide to th is produced, a t room temperature, an almost immediate colour change to grey, and a t 0°, a sim ilar change occurred in 30min.. Benzyl ch loride showed no appreciable reaction even with th is very a c tiv e form of zinc metal, ru ling out the a p p lic a b ility of the scheme to the cross-coupling of such halides with aryl h a lid es .

94

The so formed benzylzinc reagents were treated (Scheme 34)with Pd^P P hJ, and iodobenzene and refluxed in THF overnight. 3 4The r e su lts of these experiments are summarised in Table 1.

Table 1

Organozinc formation

fresh ly f i le d , 2h ., room temperature "Rieke" zinc, 15min., room temperature "Rieke" zin c, 30min., room temperature

on% y ie ld of (225)0/

99

77

74

When the benzylzinc bromide generated from zinc f i l in g s wass t ir r e d alone a t room temperature the slow formation of 1 ,2 -

88diphenylethane was noted. This continued a fter a l l o f the zinc was consumed implying i t s formation then, by homolysis of the zinc-carbon bond and coupling, rather than by the reaction 6f the benzylzinc reagent with the sta r tin g halide which could, of course, occur only while some of the sta r tin g m aterial remained. On aqueous work-up th is so lu tion of benzylzinc bromide afforded not only bibenzyl but a lso traces of toluene and benzaldehyde.

In lignans high le v e ls of oxygenation in the aromatic rings

95

are frequently encountered. To demonstrate the a p p lic a b ility of th is coupling process to th e ir synth esis a number of oxygenated benzyl h alid es and iodoarenes were su c ce ssfu lly coupled.

The benzylic bromides were synthesised (Scheme 35) from the corresponding acids or aldehydes by LAH reduction, which generally occurred in over 95% y ie ld , followed by bromination of the so formed a lcoh ols with hydrogen bromide gas which was sim ila r ly e f f ic ie n t . For highly oxygenated b enzylic halides i t was necessary to purify the halide immediately before use.

Scheme 35

The iodides were a l l commercial except for 4-iodoveratrole which was synthesised by iod in ation of vera tro le in high

In Table 2 the r e s u lts , which are unoptimised, show that the coupling process i s applicable to a range of oxygenation patterns, being le s s e f f ic ie n t only when e ith er the sta r tin g b enzylic halide i s p articu lar ly unstable or when the diphenylmethane product i s too h ighly oxygenated. Thus attempts to prepare 3 ,4 ,5 ,3 ,' 4' -pentamethoxydiphenylmethane were thwarted by the a ir s e n s it iv i t y of the product mixture.

ArCOOH

ArCHO

y ie ld . 89

96

Table 2

1—1& i—i

ocr

OR

Br0̂ 8799% (225) 9071% (226) 88% (227)Br

&' - 0 86% (228) — 60% (229)Br■v

OR

49% (230) — 55% (231)

Br

R O ' ^ ^ O ROR

65% (232) — —

Br

R O - ^ ^ O ROR

— — unstab le

R=CH3

9 7

The crude mixture appeared to contain the required compound as judged by the H nmr spectrum but rapidly became dark red and was unstable to chromatography.

In a Type 1 coupling procedure which afforded the88diphenylmethane (227) in 73% y ie ld , 1 ,2-diphenylethane was

iso la te d in 15% y ie ld .93Triphenylmethane was formed m 40% y ie ld when bromodiphenyl-

methane was coupled with iodobenzene in a Type 1 procedure exem plifying the a p p lic a b ility of the scheme to a doubly benzylic and secondary bromide.

. . 79 .I t was v e r ifie d that lower cross-/hom o-coupling ra tio sr e su lt from the use of benzyl Grignard reagents whenbenzylmagnesium bromide was coupled with 4 -iod oan iso le , g iving

90 .(226) in 67% y ie ld and th is was accompanied by the formationD Oof bibenzyl in 26% y ie ld .

Type 2 coupling reaction s

The treatment of phenyllithium with anhydrous zinc chloride i sreported to r e su lt in smooth metal exchange in 1h. a t room

79temperature m THF.

When so formed phenylzinc chloride was reacted overnight withPd°[PPh3l 4 and benzyl bromide in refluxing THF, diphenyl-

8 7methane (225) was formed in e s se n tia lly q u an tita tive y ie ld (Scheme 36).

98

Scheme 36

Ph-Li . ZnC[2_ ^ P h -Z nC l Typg 2 ^ Ph-CH2-Ph(225) 99%

The systems considered u n til now have contained no protons /3 to the benzylic halide and have thus not been su scep tib le to /3-elim ination.

In the required system (221) a /3-proton i s not only present but a lso i s rendered moderately ac id ic by the adjacent carbonyl group and, for the coupling procedures to beapplicable to i t , the presence of /3-protons must be reasonably w ell to lera ted .

1-Phenyl-1-bromoethane contains three /3-protons and i t i stherefore a good model on which to t e s t the coupling process.I t was treated (Scheme 37) in a Type 1 coupling reaction withzinc f i l in g s , which were rapidly consumed and then with4-iod oan iso le and Pd^PPh^]^. Overnight reflu x in g in THF

94afforded the required diphenylmethane (233) in 50% y ie ld a fte r chromatography along with considerable amounts of polymeric m aterial. When the bromide was refluxed overnight with zinc f i l in g s alone the homo-coupling product (234) formed in 45% y ie ld as a 1 : 1 mixture of d iastereom ers, as indicated by g lc an a lysis and the reaction was again accompanied by exten sive polym erisation. /3-Elimination of the sta r tin g halide i s presumably responsib le for th is since i t seems u n lik ely

99

that elimination would occur after the formation of the

benzylzinc sp ec ies .Scheme 37

polymers

Type 2 coupling of 1-phenyl-1-bromoethane with phenylzincchloride (Scheme 38) gave a 39% y ie ld of the diphenylmethane

96(235) and th is reaction a lso resu lted m the formation of styrene as v e r if ie d by i t s presence in the crude m aterial which was analysed by H nmr spectroscopy. In th is reaction /3-elim ination could occur v ia d ir ec t thermal lo s s of HBr from the sta r tin g halide or by elim ination of a hydridopalladium sp ecies for which there i s considerable precedent (Diagram

100

Scheme 38

Diagram U

(236) dppf

For many years the ready /3-hydride elim ination of secondary alk y l Grignard reagents was a severe r e s tr ic t io n to the scope of chem oselective tra n s it io n metal catalysed cross-coupling reaction s. A number of b identate phosphine ligands have been shown to greatly increase chem oselectiv ity in these reactions and, for example, the use of d ic h lo r o [1 ,1 '-b is(d iphenylphos-

101

phino)ferrocene]palladium (0), (dppf), (236), as a c a ta ly s t allow s the sp e c if ic coupling of isopropylmagnesium ch