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Synthesis and structure of selected terpenoids

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I am indebtec~ to · 'rofessor _\.J. Birch, F ._:. :, ,

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the biflorin structure. ~he relationshi" bet .7een cembrene o,nd

the ter ene nasutene is discussed else-~ere in this the~is.

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r"

0

,··

C.

r 1

I

I

o::

0 r )

-

..

'0

of ' ... , t:""\

)

--'

(13)

It

,as G, !:l ... 1 -" "IC, ~ re ·nt. ~ J a-_, -_r i· -_1_

~ the early :::l::..n.n in- of the

synthetic sche e that the

a

ihyc roinrl..--none _2 'O 1-ld be a 1:rey

interrin.ediate arid the obtention of an acce:0t2,ble ,. re~,ai"atio:n

of this compo1 n.d :,as re~arfl eel as the · ·t:.·:st synthetj_c 02,l.

The initial attempts to ol)t2.in th_is com~~ound y, eTe co:n.ceivec

as -)roc eedin{._; throue:;h the knoun 6 7-hydrozyindan-1-one. r,,o

this end, L1-chrol""a11011e 12 ·.7as pre::ared in r_ ood yield accord.int;

to the reported cyclisation 7 of 3-phei'l.OJDJ~>ropionic acid _11_,

r:rhich vras itself obtained. by cyanoethylation of phenol vri th

acryloni ~rile end Tri ton ·3 catalyst8 , fo 1 J oued by aci(_ic

b.ydroJ.ysis of the 3-pheno::-J:pro~ ionitri le 10 ( 'Jcheme I 1

N

OOH

>

>

>

10

.L1

-

1?

~ .)cneme , I

~01·1erer,·:r>:en the 4-c _ro~2.no~1e ~:.'8.'1 t:..~e2ted ·Jith a_u:riini1.1_--:

chloride 1.,1_,_YJ.cey, t:1e x·enorted6 rearrance--:ent cond_i tions, the

ste2:.D-vo_atile fr2ction fl"O"'l the ::. eactio·1 ni.:_t1,-i_re ·12,~ sho··n

·1nmelv tho c:t·r,a-rti11 1~--1-e-,-,ir.i~ ..1-11e cles-i--."lr 7 ·--ra-:ro-r-:--!nc:-,....,1 1 0·1e

-~G~ ---..: -~v O .JC'..- , _ - _ . C, u - _<.,, __ ' 1.J___ , .... 1. - -.i.-,._ c J_y J.. . a l -

-2,na. c. further 1,111ic.e_.1.tifiec'" component. 11.'his res 1 ~,tor-ether

- u

-,ith the ra::;her 1017 yield of the prod ,ct nixture led to the

aba..nn onrrient of t 1e ror-:e.

~he second cethoc to be i·vesticated ~i_ised t· e

repo::cte-9 ' 10 :yrolysis of 3-but-3 ' -enyJ.cycJohex:::none 13,nhic·1

V ao COllVG:i.lient y ~ re.i:_)ar~cl- b3r COp e- -catalyseci. conjur·ate

addition 11 of but-3-ei;.yl ma' nesiur1 o:ror1ide to c:rclohez-2-enone.

(14)

:mae_nesi UI!l, :follo ·1e

~

by ethylene oxio e 12 anrl_ • RS conve:ctec to

the bromide by

t

1e method of J vala 13 • r.ihe conju~ ate rrri g-1.2rd

acl.di tion nroceec1ed smoothlv v,i tl: no ~ etect2ble form2,tj_o:.1. of

- V

the 1,

2-a

(

i tion !)roduct. ~he keto-olefin \T9 s ~.,rro_yse -, 1 ut

0

contrary to the initial report- the crude !~rolysRte co1~ai1ed

three rroducts . -)ecause of tr,is result a-id a_ so bec'"',use it

tee 0.ique:=-: at an ea,rly star·e of ths s3rnthesis, the ~yroJytic

aprroach was dj_sca.rdecl. HoFeV·":)~·,

it

is noted ths.t the recent

fulJ rei)ort 1 O ol this - rork PJ_so i·1dic2.tes th2,t th:-c'ee products

· rere obtaine(1.,namely the ci s and 1.J-"::ill.~ hydrtnd.::1.nones 14 c,nd 15

toe;ethe_ Pi th the trj_cyclic keto:1.e 1_~.

I

I

R

12.

1

The third and successful route to the ketone.?.. is

outlined i-". '"'~ch.eme I1. 'J'he [1J dol co~1densntio 1 of

m-hydI'OJ0J-ben'7ial(ehyfl e ancl. ncetone to afford ,D-hydro:r:ybensfl,laceJ:o e 20

is the subject of confJ ictin~ re:_)O~_-.-·~s i-1 the litr::; _'ature. Ja~,.·1:r

rro1.··} ers c1escribed 14 an 11..11.successful attempt at the renction

but a later c-:conp c:iaimea 15 to have obtai,1ec1- 20 by this rrie2.ns,

ouch the yield as not Sl)ecif'ied. ~Lesults in the -,-r,"esent

study :parc1leled those of -:-;he earlier investicators and it

became :necesciary to ·1rotect t:1e :0henolic f11 1ct:i_on RA i ·;n

readily-formed methoxy~r.ethyl et;her. hen this 12,s do·1e, t',e

(15)

1

c-;enuence of protectio·11 c, conr, ens'l.tio· 17 a· r

next s v e of ..L.

,Jne

JChe e ,·~ic~ re_rese~ts En obstacle to the

ef:l'.·iciency of

t

1'C; synthesis,, ras effectet ·,./ 1- irarot_·e:n--:tior o:f

• 1 8 .,:, 1 . - b • -, J • f ..L I

the '1ro1natic rinr: _,_ o ___ o veo y o·pio.?J cion o · ,.,_:e ~ roe 1, c·c

chror. j_c acid i:1. ac.c;··-one 1

S'.

TJ1,-?o~tl1natel.,r, :J,=1.thonch

it

..

1ag

R

-11

R

18 )

-

·

9

HO

1i

R

>

rtH -'· -? Q ,' .. 1-'

l.r-;,

- J

Schene

19-20

23

2~:

Q

I I

>

") e-~

c e

...

r

'.21

I. ,, · 2 -'--3

-"")

'-I..

-

E 22

~r

..--01

r

erfo:rmec1 under sta11dardised co::.~a it ions, the hydroc en2tion

·ri th

ste: r.ro.s re,ther cqpricious E~Pd \7hi::1 s~; some r1J_ns r~ave e,cceyitable

overe,l yields of the di.ketone

~1,

others proved re:ther YJoor.

Cften the h:rdrocenation had -~o be repeated because of i nco· plete reduction and in e. -trene c2.ses the u1)t2ke of

hydrot:,en ce,.., sed a,fter the olefinic bo·1d of ?.O :12,d been

sa,turat ed. 1rj.or reduction of thi r-.; bond m1d er 1.0i7-,"ressure

co·1.di tions fai. ed to brin(; about r:.·,1 i..r1~_rovement. It 1r.2y be

note·.1ort·1~r that the autoclave e 1.p2-o~red for these x·e2.ctio11s ···as

i·1 use by ;' 1'1.lJILber of other ,orkers, so thRt th J }Ossi."rliJ.ity

~hat tr~ ce ?. 1ou_nts of cata.Jy,st poi.so:1.s .. 1ere ... :ce,sent c:=u1:.1.ot be

(16)

1 1

' 7 ( '

3-methyl-Ll.J' - - · Jdrin · en-4-one 22 :v:~ s been :L"evi ousl~- reI1or~ea

l. :0 _ ..._ n-l. ... e11· ·u. 11· ""'"\~-L, .t..L ... -r J fo- .... .L ··,1h 21 T ·n t, r) 1· 0 ·o r 1,.. J. t , Ji' ,...., e =':'-·f e c + e c·1 _i

-• J ~::, ' .1 - \ : 4, - u

excellent yield b:· t11.e use of rito· ;) as a c:1-1-aJyst,P1i~e

e2,rlier exneri11e 1ts - 'i tl Equeous ethano· ic notassil12:t1 h rclro~:ide

- • V

,:ere only slishtly less e~fective22 • Tt h2,d ini tialJ_y been

honed tho..t it micht have bee 1. )Ossible to C'·use a direct

ison1eri satio:n of 22 to the r'3quiref keto~"le ~' bnt no11e of

~-\\ride v2riety of potential iso:-neriE"Ja.tior. a~ents vrhich · .ere

t:. iec1 rave any inrlication of perforini·-:~ this ch?.nce. Co11 fli tio·1.s

em~Jl oyecl inc uli ed re:fluYinc - i t'1 12-toluenes1,1_l~1honi c acia. i·ri

acetone,~~eQtrent at roan teIT~ereture 1dth potassi,w

t -huto 7"ide in either t-butanol or dir,1eth:rl sulpho~ride,e~'"~nosure

of a c·~1oro::or:m so __ ution to dry hyc1ro._;e:n chloride,refluxinc

the ethylene ketal follov1er1 by deketal isation. V:;_"'om all these

e::periments the startinr materi2.l 1-ras ::cecovere(1 u:1chnnGed.

~ ttentio:1 Vvc. ,S then L i_ve11 to the :"osc3ibili ty of a

• • ..0 .L J... • 1 J... • 2~ 1 • • I • n

re.:_,iospecii.ic, or aL -,orsL re'iose ecLiive ~ ,e in1r.r-c101.1 t r om a

sui tabJ y fu_nctione,~_isea derj_vati ve of t:1e saturrted ke-Lo~1e

hvdro .c-e·l1atiou of 22 . Direct 6.ehT<.),rr1ror'enet ion. with di

c.hloro-t.., '-- - - - '

-r icyanobenzoq_ui110-1e i refl uxi:::~r dio · ane cave n2.te:i."ie.J. , f;.,L.!__ch

·,11tJ·-1·oe-,.., _ 'J .L of . b..,....o-Yli· ·1,...1...1· .. i'.L C. lJ 0·1 .J. n~'"'ocer1,,- .. 2s J. .,. .., ...,w. ~ • ·ere

hycrotribromide,the use of J h . ' icn as 2,

t

,:J 'b ?/.

as rec en .y 1...• escr er ·, F !J~)er're i:1 tl'is CP-se to

0 ent,'"'11

(17)

-•I

,_

of t _e .i:2:'oc.v.ct Ol")t2.i~ cd after c~e JC ro"b~coni· ation v:ith ca:~j_,111

ca:rbon::>te i_-1 a_j_methylace-carn.i,. .. e~5 . 0,1 the ot'1eT h,..,n,.~, ·hoth

carbo· tet1" "l,c,.,~lori e r·a,Ve fair_ y hor 0L-eneo1.,1_s i::.1i tiFJl _ roe.net

q,

rs h

··;hich -rere deh., oro-,:ro inater by either senicarbc?.''iide~:::> or l)y

calcium carbonate i '1 din.ethylacetarnide to yieJ.d substo.ntieJ Jy

the

a

e '"'Ji:rer keto-1.e 5:_, L .thour·h smalJ_ ~ro~)ort ions ol the

aJ t ern8.tive elinin,_,_tio-,,_ 1 rorluct .22 were 0.etec table .. -.,.o_ ·ever,

the cruc e bronoketone

-

24 was rather 1r1stable anC oui -r;e ...

ra:)idly became deepJ.y c0Jo11red ancl evo]_ved hydrocen broF1.j_(l e,

so th'"~t bro~1j_nation Has event1.,1.al 1 :- abandon.ed i ·1 f9vour of

chlorination Hit 1 sulphux:rl chlori

~

2 26 , ,:hich snoothly afforn ea

the chloroketone

_g_~.

1ehydroc·1.1orination eY.11eriments r."Jei-·e

c a .. "rierl out i'/i th a varietv of V rea,.r J ent s ,, rhicr1 incl nrled. hot

col].ir~ine26 , lithj_u.m bromide in cli--1ethy-lr C";tamide 27 anf hot

, J.. - 1 1 h . _,_ . . ..:J ?8

r1e.:came1..,11v_·,1tosr) V ~.. _:., oric 1..,r1.a.:r11u_e-.

11 t"

t

C'"" ~ d q t1 . . d l . t.h. · 1

a __ nese rea,,::_·en s a:c:i..orcte ..::.. as _1e 111aJor isomer 2n __ i., lUJ•.

bronide in dimethyl-acetamide was finally seJ ecterl £:i,s t" e

t '"' ,_ . It . h

t ,

' :,

.J , ' ., h 1 · · · ·

~ eage1r OI c.aoice. . mig__ oe no-cect cn2:i:: c e e 1n1n2.--::;1on rith

1

1ex:1met1

'.lylrhos~horic triamide could be effected DJ.1.cer rat11er

J.esfJ severe co 1di tions th211 '. rere ernr- oyed in the ini t:i.al

Y'el'.)OrJ-- .!.. l,. _1t:1ou~h it u-::i,s po~C"jible to se:-:arate the isomeJ.-·ic

ketoneri lJy f~c2ctiono.l disti] =1_ation, the route , rhich ·-·as

f inalJ y adopted rend ere( this se:,aration llj'lnece ,-is2.-~y.

/ith an acceptable r:re,aration of the

rl.ihyclro-ind~none ~ now :tn hand, at~en·';io:n v,as shifted ..:co t~1e

constructio-1 of the tricyc-_·i c system, so as to L fforc1. a

ui t" b] y fuJ1ctio:1aJ ised 0.eri.v2ti ve of the :::eneraJ tyi;e 26.

(18)

1 j

ch of ~his · ·or1c ··r,s cP::c·:.ied o

t

o v2:.,to 1s 1ode] com- oui1.r s

2nd in m2ny cases ]eel. to ne~ative resl1.lts, so tb.<.t

it

ht\S

bee-n re· ortecJ. only in out}_i·1e .

e"" risa ·ed the for·ratio 1 of the ske] e~~on of 26 ( ~~

=

er,

CHO or

COO~t) in

a

sinlle ste~ base6 on consecutive· ichael adcitions

e,s sho TD belo',7. Trie,l expe ... "iments u1ere carried out ri th

3-~.ydro::ynethy:'...ene-_:-r'J.e:nth-6-en-2-one 27 anc senecioni ~rile,

either j_n the absence of any hase or 11i th the adf.i tion of 20.

triethyl2:n1ine ~, or sodiuL1 hyc.ricl.e, but i n alJ easer.; 011.ly the

ste.rt·i.n,:· nateriRls could be c1etectec. i·"l the re2.ction 't!li::t11;·es.

'L'o elii in2-ce the ~0'1<:3ibi}_ity th2,t the bulky iso!_-ro::_--yl _ronp

:JP,S nreventinc; any re2.ctio:1 an alterne,tive ~1orlel r:as erntloyec~,

namely 2-hydro-:;:,rmethylene-9-nethyl-A4-oct2,l- ='5-one30 28.

HOH

Base

>

{chene

i:rr

HOC

28

!.S be.core, se:necioni trile rrc1s not 2,·ctacked

e,nc

·when the

t t . 11 t . . 1 · ~ ... · · · ... 3 1

po ·en ia y more reac ive iso:1ro~y idenemaJ_ononi~.~ri_· e r:as

usea, ·i th a .vider variety

o:::

bases T-rhich i: clu~_ecl_ -)o~1i1u1

tb ·

a

..

·

- , -

·

:,

t

·

.L b J. • d

3

~ d

G _o:;~i _e, soc1u1n nya.ri e, o as aw1 u- nco::::i e an

(19)

-trietnyl, o _1er

t

,

-cna:.1

'

,

material c-. a eare( to be tauto1 )e:cic (ir1e-· de ... -:_7ecl froc the

.L ~

ni-'criJ e. "he rlimeri e:tion of iso~;:eo!)yJiclene11Rlononitri • e lmder

asic COi'.Jf i t ions i S , ·e]_ - knO' rn

33' 34 . '

he f2.i. 1D.'C Of th , r:e

re2ctio· s 1;1as not esr eciPl~ ,r renarkable, c.S 1Jotr1 the do::.1.or e.ncl

acceptor s ... 1eci0s are quite bulky, so that their ap·1roach vronld

s1Jffer fron"' considerable steric hi:.:1dra.nce. -.:ve:r. · d. -L~'1 auite ...

simnle donors ,11an..,r

(3

,

(3

-disubsti tuter"i acce·ntors ,r;ive veTy rioor

yie:~s of conCensation pTo{uc~s, ,iliile the self-condensation

of certain such acce·)tors .J. is also kno~-ri135 •

11he next ·)ossible a~)proach to be explored lay

i·1

the conj1 t·ate ad.di tion of ,._ suitable or.~c1.nomet2,1·1 j_c reade::.1t

t o the ketone

9

, a:s

'3 1 O\n.1 i ·1 )cheme IV.

1 ,

4-·

ar~ cii ti o·-i

>

(Ro)c:>=<

2

(RO)CH

2

<

n2se

CHO

r;cheme

IV

m the o

,:.y

occasio 1. on l'ticr1

it

\VP,'"J trie(, the

rzC

reportedJo ~reparc1:;io:L1 of 2-bromosenccialdeh~roe dj_eth:rJ_ e..cetal

yie_ .ded a 1<1-i_:7:tur~ of at least three corrn.1J.1c1 s. r;:h ,Se ~ 1e:r.e

not i 1vesti qted,but furtheT transformRtions of t~~s 2ceta_

'"? 6

unrter basic co·1.a.i tion : have ·been o1)servedJ . Tn orcler to

obtain an i:..1dicat·i..on of -c~1e viabiJi ~y of -·;he ]cheri1e, '1ttentio,1

1.·ras transferred to -i-he rt1ore rec'"'.Cl., l0

_l_-r ~ -; r b 2 ~ 0 ·10

l.J , ,va ____ c __ e -or 1

(20)

:roceec e( o rever, atte ts to

for:.-Gri na:cd r'J ent ei--'c ,.er nor·tr 11~r o ., b-- e trci-i_n e· t,

the

• --!- , l ,

1 _.

1 , ~-dib:ro oet-... ane3G r,ere lWsnccessfv1, --hie·, -;[l,C-J ·1ot

esneni'"'..L-:7 sur_risi:.r in vieiJ o::· the k:ro·r1.39 ~es~ab-i.Jisj_-~

e·"fnct of f., --3,J 1-o~r s1 J~sti -tuticn. ni1e recent re ... ort

40

of the

s11ccessful l i thj_a,tio·1 at low tenperatu~:·e of this ty _ _Je of

com 01r

c ·,

s ...,_lso invesi[ ate~ briefl:.,., r 11t t e cr1 c1.e :ngteria_

v1hic 'HG obtai-.1ed. by J~re2,tment of the 1.i t11icrtio·1 mixture "1i th

c1rl)ro11s iodide 11 fol]o" ef. by cyclohe :::-2-eno· _e eyJli.hi ted

neither hydroxy. nor carbonyl infrarer absorption and this

i_ thirrl )O~-d.hiJ.ity ·va: sour;:ht in Jche re2ay fornt")·cio·1

::.::1: ... 011 ketones of trine+,hylsilyl enol ethers4 1 • If a:,:,Jied to

an

ex, ~ - unsat1 rt.,tea... ketone, this reE~ctio:1 wouJ...a be 0Ypected to

., 8ctd

to

a conj, cateci diene sy1s~evi1, ·rh.;_ch it shouJ.d tbe:.r. be

reactio 1 ,:as o.pplied to cyclohe::-":-2-e11one, q rn.i -:tnre of 1- 9,11a

2 trl. - --1t'.·'·byl ll. v , - - ·_, ,...,1· 1y10"7,rcycl ohe - J>...) - -~ C.: - 1 '

3

- 0.,1. enes ·- 1r.1ris .' C, obt~i C,____ r1eo~ ' -i -:1 . , '1.1.· - ch .

not ... tble that the sor11e-wha:t simil2,r C8,se of t11.e fo::-r1Htio '°'. of

clienamines fron

ex

,

f,

-1r1s0,tur<1te<~ ketones ::>,lso lends to g

. t ..., . Lt?

mi;: ure o:c isoriers · ~ o

further sche:rie e'1visa:-·ed the attachment of P,n

isonro--)vlidene ..,_ - V rrou. to .J - . t18 dil1vc''roind:-'none l.l . : : . q to ..L nroduce -C!lA

cro.ss- conjucated dienone

29.

It ,

ras hoped

that

t

1

1j_s syste1:1

rn.._,lononi trJle or ethyl cyanoacetate and the,t this addition

~~i1oulri be fol- owed b~r ?. further intranol8cu_ar e,drlition ·:rnich

woul( cener'.te the tricyc-i i...c system. 1eactions of this

are ~nolm to rroceed very eff~ctively for such Rcyc]ic cases

Ll~

(21)

>

?

xv

"( --

.

~-..,,

'

,~.

t

' ' l J

AL1 }

r

.

-

b

·. ul e PO . ~ e · · -_, '=l_ ~ )

e

e11 ,..,

c

1 J

eve

c1 ,

-

.

-- I... -- c;~ .., C:, 1. . - J 'TO Ce Ul' '} : .. ~ 1.c

i ·TvO _Ve•; C0 1"[)0e~-l,10-...,-.;yl a+··Lo·1 ,,.eJ-r-, i S!'.:1T,1 ·i Q""\ +y,e:-i -:-11P,1t. ,.·:ri -l-:~1

C',_., '.J l .,l'.-' - J • .... ' lJ L - - - I L., J ~..l... - ... ' _._. U .., ,r ...L. ..,

~ethJl~ .. ' _r -Qe ...;i 1l.T lOClCe . 1 . .. 8.11(~.

- JrP. -:e-1 .., l.. ·t C C,~..,,;, ,.., p , ·Lhc v • ._.,

of

:rovet t~o~blesone

~

, e·J..one 0

- - l, - .:.:..

the

"-'I "1 I f

• ' Cl U i · ·er' . P J.G O O c, --r::i • ,

- .!. . -- __ ..., .,,;) lJ .,_

I 'l .e

~ . -, , . Ll.5

C : .-- ( . ..) 0 r, ~ l C ( ---1 --, l. . e ::::i _, C -: -, 0 - - Y'\ '

J. l. o:~

,r..; P., rl "

<..I -.I- ._, - - ... ) +, P.

V _.,

-.. ere . 0 b

t '

l ,J_nec • l ' t. i, _er. 1 "1

t

'!-_..., I P. 1 .c..e r ...i... 1) 0" J18 ,...,("I .i-,,,,o"'..t.8,.'.J t,·jJ-1-, 11c,.+,_nv1r,,. ~)() ,'Ll • • .J _1 lJ -- t:; , V t_· • - ... G J. ,.. .. .,_v - _,

L1 )

C!:)r•1,on!lJL,. C, - . C.., ') r fol· o e<~ by dj_R:30F1et}:ar1e., 11j_f/i cnlt-Les err-; 2.lFJO

enco1u tered

it

C!O lve11-:"'. .., - V L 'lVP C.., .._.,

no

.dth

cyclohe=~none

(

iscP.rc1er'-, ' Ll.8

C C., !:'I -, •) t

on ·

.,

-

' ~ P. · a

vie d b

t

the

V _eto 1:Lc

2.nc_

I-·,pr;·j ,...) __ _, c_,.JL,_t:)d V . . C011j" .., .. p·tp ...-, .... ..., ke' i. JCJ-· .. !":'! i r « ) _ , +1..· QY1 ~-L {~ r..-v-A"l c; _ ,::·o _ on' ed

re·.ct:Lo 1 , l" i () f' ·~

h ec3.J1e av2,:L 2; . 1 } 1 __ e LlO · - ' 1"

.,

' · i· Jl-,1.1 eJ·hvl C"F"'"l.O' CP."1

"'-'J.r:::,

- U -v ~ • v ~ C · I; c~ l, ~

(Y''"P, Vl_ r Q:('011 ,...

r1 -'-r- ~ ... -!-·i Y) r

(22)

--fo:rr ulated 8,8

3~

011 t:_e bas~_ r_, of its i11f'rared 0..:.1<~

.,,7

j I

,:-, or- -, ec-c'·r ...

C,.:J :-)..i. - · •

com ... ound could have arisen by lr:rclr tion of the iso·,':'o~"':-J.ia e:vie

of the liberatecl j-:.::ethylcycJ ohex-2-enone ri th etl1_3rl

cy8,noacet2.te.. ~his result and aJso the c1if~:icult \:et2,~.is!<ticE1

of

tr

e l:etoeste:c 30 ~-ed to t~1? nba~-idonnent o:f this ro11te.

ri~he final , succescjfn1 scheme 178 . .S base·l. uyion the

;iels- _l.der re8.ctio!1. ''he ketone 9 \12.S converted to its

r)-·co:-i_1.:i.ene sul Y)l1011vJJ1vc~:..,nzone and t ·1.ence bv treP..trnent 1 ~i -l-11

.... -'- u V V · - V

-methyJ lithium

50

to the conj1J.[.'2,ted ciiene

J.3

.,

i1.0r"")e st:·:--110,tu:ce

£' ave a sernicrystalline maleic anhydric1e

ao

(-:i_uct, \rb.ic·t v1as

coi1ve1: .. to6 to tJ,e hono ~,en,~ous ,N-r,henylsuccinimide

34.

,

the 1 ikely

stereochernistry of .. hich is as shO\JJ1. rrhe assit-:n.ed methyl

3

stereochemistry Has bc1serl. on the -rr·obab1e steric re·--iulsj_o·1 of

the dieno, ,_~i .. _e bv t"1a,t cTou , , rhiJ e th~ as ~i ~1.nent of

t

1,.e endo

"""' t., \. .) ,.

~ 1 r-?

conf iruratio:o '1;::i,c; n1..1: erol1.S k:no- 1:1 ana~.or-ies...,. ' ".J - 0

·~

(23)

1

adr i tion , ri th eiJ:her se:.1ecioni trile or nethy~ senecioc1te, n'')-i_ch

lt' - .L .J...

a__ ~ou _n unI or l, una ,, e

th_,t

(3

-substi tutj_on of the ,, i.eno:,"1i .,_e severely J 017era the

r.4

yieJa.s of -)ieJ s-- · 1der adn.ucts-> . 1.'he mos.j~ satisfgctory

alterne,tive clie·1ophile c,:;:;__)e2red to be o< - ce·;oxyf'cry~onitri e

55,

11hich 'TP,S :?irst 8I1I)10yecl Hl8.11Y ye2,rs aco i11 a ";y::.1thesis of

cl ehydro11orcc1x1!)hor56 . r11·1e nsA of this

a

ie""lorihiJ e a1\_1eer"1 to be

preferaole to t·1e use of ac:;_..,yloni trile, fo 110 re~ by

c11.lorinE1,tion of the adduct and hydroJysis57 in c::ises ,.1here

the diene is the v2,luc.ole cornponent of the :r0Eu;tj_on.

ihen ··he diene

22.

8,nd o(-ace+o:;:yLcry:_o;li tri] e s·rere

heE:terl to r;ethe~· in benzene so]_ution, a mi::.·ture of 2,dducts ·--2.s

obt2.inea.. TTpo~ sal onification of t:ie cy2x1.ohyd~'.:'in acetr__,l,te

fn ,ctio~1, the nK•:terioJ_ still aI're2,red to be qui..:~e com-nl_ex

\~1he:1 e:-:::2mine6 by

c

.

l • c., ana. as a nea.sure to reduc8 this

compJe:zity it ·7as trented 1,7i th eth2J101ic hydro:·on clrtJ oride

j_n order to micr[-.te the dour.:::.e bond i~1to the tetrs,subs-Li tuted

~ osition. This re2.ction is t}')e same as that 11hich is k11.01·m to

occur in the conversio1.1. of eremolnctone to isoereri10J r-i.cto·1e 1•

The effect of the isorieri.c;ation i s .j~o e:.1 i11i·1c1te the

dj_aste_·eoisonerism en:_:endered in the ini-~j_al 1y-for1red e,clrluct

by ·s:he seco·1.c-;ary methJl gToup on the five-r1embe:ced rin ;o \fter

t .. e re11oval of so111e no~J.-ketonic i 11. urity vi2: the irard.' s

de-,.,ivative,the material obtB.ine6 1w-.,.3 shO\'"il by,' J..c. 2nalysis

vrhich uere evici e 1tJ y the isomeric ke·cones

2..2.

2,nd

J.£.

3

7

8

35

(24)

, ee:-' .1,

'

.

,

:.c . ·; t,' pr

- - ·' ...,I

,

.

' ,

2.

-r-,....

-·~hat -

.

-~or r-

(3

,

~ r i ....

t.,,-rr

t:e.,

... reto

_,, \.. o· 'JO ,:i

e . ec e 11 e

- ...) - c.. .. J ... ...

irt .,

,tr-

I

i_ "") J~c11e~- o ', :_"'8 0 .J. ' c- ·';~_o

.J.. 1e1· - :re sr. e ,_.,,.~ :-) e l

of

t

1e i '10

en r: r, J. ; w. on 1 ., ~ , ~inc e 2, t ')-_f_ l o,-_el_ri) s11r• pr,-:..p

' - L< ~ J ~

nd c,C et O :_v r :t'Ol1.

s :..n

.I ~'. ' - '

-2 s · r1e '\J0

01." .. ,,.._e+o e To· revr-,-, i ·'- R 0.e,,-' r)i 1 +;1-,;:.-:.. 0 1 e0t·ror1··, C

- - V o ~ _,,_ ' - lJ ... , .. ..; - L . - - ... L•-- ., I ' - ' - -..;,1 - - - ...

ef·'cc~s "',l so co tri b

1-t

e 'Jt:_ ... o_ r .., ,r

- u -:~o

t he Ol''i011t2-tior: Of ~,(rl i t~_O""l. 2::_1d tl~2:c in ener2.1 ~~

c( -· Ct1 ) ,_,+ -j •1·11 c,•1 ·l- on -lne r,] ,..,.,,,e 8i(P" ... , .. Q "

o . : . J J - U (::;.\J - ·.L v -Vlt.~ - ~ -.. J•..-J

-~ - sl1b 'TC j_·cnent . i\J_rthe:::1 D:r:'e , a::1 e J.ectron-:re J e q si·· ,... o( -srh sti c1.1.ent

rener;-11--.:r ci· ., p0ts -l-11e 8(1 i·+i on r-.o -'L,· ,ri-'- -'-11e e.,pr,·'--ro·1-;:Je-:--1.· r.1e·1+

< - c,_ v • - _,._, . v c.,-1. , _ . .:, .... c, v.... _ ,v t.,_ _ \..., , _ ...,__ v

t',e di.ene, 1~1.iJ_e

'""' .Lh 11c1· _._, a

- - u _ 0 . ·c..., - v . ...,

con side~"c::.tio:n of t' n di: o~ e

l • I • - n 1

c;.c...:•:r _OY1.1_·c .• J ___ e 2..11C. o:_ IJ."Il"'J-- :::.ce-L

j_n b e:.1zene

1 '70

I .,,

ne

r

)

OluJ..i o '"'t

.:> ___ L,_ - _,

'.1L 11 l 8 il ...L.-- . . . i - 8 0 .._.,1.,., -'-1· 0 '" S () J.J ·f --

t

1,"' J_~::,...; 0 ,..., P

.e '"'.cry:.o n:L triJ.e . _o ~-e cu. . . e <.., r

0

r-i-~· L,- .

10 e 1.t C'l

r-, -i,!'\ ,_ - · ' ....,,

C.,

-[ .JL,_ i Cl • 0 c-, -L'

...

-

...) ~ ~ ' , lJ .J.. ·t , 1-i .u. n J r ... _ _ . . . i - 0 • e

c• --b T,

of

J • _.. -, I ~ , I •

l -,-,...i e .... .,..lO"ll 1 c.-'t,:i.i1_,

\J •• - - ) , .. U - V 1

,.., .. r,·

(25)

)

die·10 hile ui th c E nsy111L1etricfl J diene is the :re o:rt of

!harton an _11162,, rho l1-sed 1-iso})ro~ e 1ylcyclolieze1.e 8.l1C--_

ob served a ver: hig12. iJ.."edorr:i1 ,...nce of the isomer nre( icte'l oy

t

·

·

il

t ·

mh ·

elec .~onJ.c consi. ATa ions. --~eir CP,Se j_s hor.e-re:-c :"8.ther mo1~e

sim~1~ e, ;:is there is on_y a oin~,le terninal su1)stit1 ent i 11 tl1e

Ac

+

• •

diene a·1d t · o interna: substi t1.1e'1.ts --,hose ef-~ects C3hou d

effectively cancelo In t:1e rresent case, there e.re three

ter .. 1inal and one int ,rnHJ. substitue:nts. r:'he orients:cive

effects of

t

r.10 of the ter~·ni·"al substi t1,1ents sl!.ould C'"',ncel 8}1C.

1eqve o_: osi

1c

te:cni~ al e.nd internal snbsti tue·1.ts, of '.7-:ri.ich

the terriinal substituent should dominate the orientation of

additio·1. r.:hi1s is indeed the observec. resu:t, 1

nt beccuse of

the rather delicate balance of effects, it is u11remarkable t 11P.t

the overalJ selectiv· t;y is r2ther J.es<-1 then that observed · rtt'1.

Tt a·-.nearea. rather dif-fi cult to se~1c1,rate the

ketones 35 nnd 36 at t 1

1is sta: e anc1- it · 12."""' decic.eC: to

introduce tbe cr.e111inaJ. methyl .:.ro1r s into the mixture of

ketones. ' he est ah- ishnent of experiment2.l co-"1.c1i tion s fo-,:-- this

methyl2tion wcs so~ 1e,.rhat tron-:.)le sorrie. C:-eneratio ~ of -'_,he

eno. ote -1ith sodi 1rr.o. hydride in cl.i ..,,et·10:-~retb ane, folJ o,·re., by

ad ., i tio '"1 of nethyl ioc:irle Jed to i1J.-c~efined ..L rod.nets,, ,hile

refluzinc; t- butQIJOl fo~ = Oi Jed by +.he 2.r1d.i tion of methyl

iodirle yielcled o·:ly recovered starti:1. __ 1ateTi als. 1ene2,te~.

(26)

' 1 . .

_e-t; .... f _ ior_io e

~ ro{ ct but

8,C O' te i _vo2.. red ref: u~in' OI .... i:;ne ' , ~et one i. -:t, - e ·.ri th

t

·

b + · - · ., _..; r

~t-

t"

....

1 ..,

o · PS ;1 :rri "t -.l.Jo __ l .e in o-y-e r..a2.1e, :ro __ o .re

_ he rni ::-cl 1-.:." e oot2.i11:; fro~ 1

1

.L, .

t,.D.l s

V

- ,J

racer

1.re co .1c. re2di y be se~ :?,rate(

o:r

1'"1 1 ti __ e-ae-.reJ O rient

r , .,_ C',_ ""'-r~--J·ve C, :., - -c· 1 c -1-o l a_,:>fo-_rd_ - - .LL·n· e l_·e·1-.or:i_P. - . - _) .... 7.

conversio:.1 of the ketone

37

to the al cl.eh..,-c.e J8) ·7~1ic!"l ·72.s

e::· ected to be a sui tao_e interne "'ie.te Ior ,, --cne

.

,

e.

~e s11lt of steric hin(r2.:nce anrl a f2.ci __ e :..ntrori_,._,_ction of 2,

:, _j_t~

b e o:.-ie-c2rbon l"C

it

col1.ld not he :=oun -.• ~he -:o::_:.o··rin

'b -' 1 ' . , 1 - 6L 1 • J , 1 .., i.... •

.el, _OX'iJ=-:.e G--:'- ene-cj_"l~1 __ enJ-~ l'losr-~1orc:;·1e ·; o.lPle cny _o::osuJ __ i.:.on:i..uri

65 r ~ 6~

J_ h r 1 · ri • i i ,.. -hr l - ·, h .,., · , · r -'-h--1 · - - / ' '.) • ., · .1.., • - · · , I

ne l, __ tJ 1 ... e , c_ ___ e :.J--• . / _s ___ ... _o.!.!lt_ ... el,_;; _ice , __ i L,.tll(ll.

r7 en

r ethyle:.1e bromi e0 ; methylene· ri>he:..,_:-1~·hosphor'""ne0 c; ::.2, :1e3iun

, - .., • • ;J 6 0, ., • h Cl • -,

t

n .l...h

8,1.12, 81 ne~.t1v-_1_ene :::..oc l\18 _. ano_ -C e sor_rr:.r1 sa_1 or :...l:; v y

--'vt e ~--- - ---p-to- - ene s-i 1- ·no·",Tl C

-- - -l. • L.. _ .L -•-:J

- - ~ - - t.,

- O"'r1· ' l ·1.p 70 r r o·-·0 ve-, ... .,--,-0 -Lh V

- - ... _. _I'\., - - '-' e - - V ...i.. ' \,,., / ... V -re , , Q.,l. - v ' - C:., "."l..t. lJ ' !-8 ,C. ,...8 Q Cl J ~... '1e :-e+o-~e +o 8 __ u v ...,L·1.-0 0•"d-..._ ~h_c, ~ _ ~e,'"'+l· - ...._ u - · .ci . .1-..,v-r

.

xt

.

,...,

....

d . ,

mi 1.,

xe

i:;o ar-· or . ·:ne

0·1 · --- V 2. J.:; ·ace

o=:

t __

e cl e sire

(27)

) )

reactio·: mi -cture i., as less colo !_rt:;d but c"'- ai·1. cont2.i·10,(., very

little of

cr-.e

olefin

40.

ben r,hosphoi-·yJ c lo:ride v,as

su J stituted for thionyj_ chlorj.de, the t ertiary a~ coho- ·""1 - rere

re covered from co.Ld re2ction nixt1,;j:1es, .-~ii::1 e

t:

1_e u.se of

temnerFcc1J..res 1

'1i.r 1

~ e::.1onrr1 to brin1• about a ren,ction 8.ve onJ-r

-L ~ V

tr8,Ce ...,_nouHts of the desiTe- olefi:n. 1 hot di1·ethyJ. sul· 1.0"':j.de

soJ1.1tion

73

of the ,,1 cohol n-:_:;:t1rre rras auic_:lv co·1ve::.."-ced. to ..I.. V

~

darkc tar which cont?-inec1 no detectFJ))1e 2;:rro111t of t11e rtiene.

T--:ov,eve:."', fairJ.y brief e:: .... "'osu:re to hot ne1,1tral aJ urnj_nc.7 4 '"'Ve

a.

)roduct in_ vrhicl1 the FJ.aj or sin le con~,onent ·f\S t:11.e ren1.1..ired

re· ated hyd1"'oca:r.:bon · 1hich had also be8n detected i:1 the

nrevio s deh\·fr 0:l~ioris. The ';!'O"')Ortion of this conta11i11ant

-I. u .L. ..l.

co-,J. .,_ be reducer:! by .i: rioi .... treatrne 1t of t:1e 2.1nninc. -it',

!)yridine 75 or r~ore co:-.1venientl:r lJy ·che use of baslc 0,l1-,uni P

alone. rr111e diene

.4.0

could then be read.i 1y obtai·1ed in

:,ure

nitrate. Al tl1oue,h a.11_1.rnina }:1.ar1 lonr, rJeen l::nc..,·n1 to c2,talyse

elir i·"' 0:cio::.'1. of 1ot er ron alcoho::i s, conditions rrevio · sly

employed have boo 1 2,ener2, '-1:7 r1evere 75 ' 76 . ':1he reJ 0,tively nild.

t

err)eI·ature useo_ in this Cc,,se

bee"' 0 0 of ste::.:'ic con •. .._1re ~sion in tbe e)inc-,ic a] co'i.o., s, · ·hic~l

lfJ relieved as

_;9

moves tor·ard sr,2 hybridis"".tion.

?ith tJ1 e dier ~

40

i11 hc1:JcL,

it

hc1,0 l:ieeP .. e--~ ectec1 tti2t

(28)

_)

fro i ic·l tl,e l''equirecl L.1c.ehyde 38 · ovl( be ::1ccessible .

.,. 0 reve-r, r J t11011 h it ·r S ~..,OS Jib' e to re~ rod1. ce C011di·'~iOi18 for

selective ·1.yr11·oborc1.tio 1, as demonstrate,· by co·'1versio·1 of

- ir1onene to _rimary te1'"'pineo177 , repe2.ted 2t·~e-1_

·cs

to ef::ec

-the - S ri1 , e ..t..y,-=i·,, - c-.w._ ... 0,J. ·0 0I"'

when 0,xcess clisia nylbor' .ne vn1s en~loyecl, consia.~-··able a: 1ou.11.ts

8. co11 )- e·: mixture of .,._;olar subst2:n.ces,iron hie}, the :--rin1ary

alcohol 41 could not be isole,ted i·1 suf· 'icj_ent quantity to

)OrVii t further 1)11rsui t of tho synthesis.

'(o

r1--) ~t., 3

"- l"OS 'lib le o.lter:native route .1onlcl. be to introduce

at CS a cyano c.,roup, the:i..'by afforrl inc

.~:.2.

which co1.1.ld then "he

conver-':.ed to t,1e :,J de~1.ycl.e

Jf'.

'·:he ketone 37 1.ras reduced by

42a (.£.cl!. 1: 1 ratio ,1, ·rhich \Yere conve:.."ted t(J the corr es~)ono.in{

metha:nesulrlhonates 42b. :~011ever, attempted dis1)l2.cer1.ent of the

7,-,

1 b 1 :J • ., • , 1 1 ,

·a

0

mesy_ o 'Jr <Toup y soo.1u:;11 cyanioe in c.1mei:; .. 1y_ s11 -~-10-~i .e

an 1arently CP.used deep-seated der r2,dc ... tion, since no sin;i1e

corn:901,nd other theJ1 sorri.e recoverer·

m

;By late coii.Jd be

a.et

ect ed

a .. 1onc the rePction prod1_1cts . i"~eve::,:-'theles :, t' e r8actio:ns r,e:"Ved

the usef 1 :--u..r~o se of confir· 1i "1.,... the r,ro s s strncture s of the

r~tones 35 and 36, q}lich T7ere previously

the basi.s of the u1 trr-1,violet e,bsorrtion of 35 ~ · 1t101\~h roth

compo LYJ.r1s 42a and 42b , rere e· j_rne~ .... ic at "!9, the . :r·oton

attacher to this cn.r"1on :ce ·o· oted a.G a si·r1• let i:1 their ·1.r .r.

(29)

)

-

.

S 8C\,_ , S..!l,-- , , .L '-'·'-' r-t,,-. L, _, __ ~ C.., ::) ) , ~(:<i· -, _ e- l, ;:_) L(".1 of -'·hC'\ I - '-p+one"' - • v - - )

-)6 8!'8

si-t1.1_a.ter_ ~.!- ;8 °:nd .. ou=:..{ be e-r~ ectecl, becb.:use of counlin..., 1rLt

the brid'"'el-ie~ d _ :roto- ,-to r0so:c.2.te '-J a do1::."blet. inc e

t

i R •

·e

s

T-1 _1 s· ,i· ..!-e o·f l; " -- ~he se failu.:res, t0.'3re is 0,t leP.st one

other scher:ie, outlined b e1o·.,, ~ rh "ich cou}.d be e--... cct e0 to Bf +'ore"'

the aldehyde .3_§. he r-:011ome _,hyl l'"etone 4L'.- c-<hould 1:)e obtain2ble

>

35

<

38

3cherne V

>

<

45

~s

'

-by one of a nu.rn.ber of i--or.tes and. could

t:

en be ccn-rer·Lecl Vl8.

t_1e cya:10 1ydri11 45 to t~le

°'

,

(3

-n ·srtu:rated "1:i.trj_] e 46.

1

t

;J • .J ~ :J O t

n I i 1 J O ! 0

79'

so

.Jop ,er-promo ea. conJ1.1.,c·2.c ch1.(1i · i o n OI me·cny J.·c __ i11 to

46 ou .... h·t to afford the ~ revionsly soucht :.1itri1e

43.

Because of the overa.ll len ·th of c:-ny sche-'1e ~1ich

'OU ... d seem lj_:ely to af_::'ord the aJ e~1yde 38,·it seened

desi1 ... ~ble thc1.t this corJ.po1,_>1.d, j_f ·111.d 1 ·"1.en obtaine<"i, snou~.d be

e· •)Y to conve ..

t

to isoe::_,emolqc+;one. - o eve:-',~, '1e ... ,.:;:c'1 of the

l i te1:ature reve2lecl that the -:no .n ·uethods :for thn syn:theF.1is

of r.lk~rlicJ.ene bute10Ji les of the r0.q_uired ty~-e re-l.8T'['~_JJ

(30)

es eciaJ. V v at~: rc<:;ive. o ·eve-... ,.:.

·'1_ vie

r

.. ,

to ef _·ect

t

1 e ~- eq _i ~ea. conversi 0-1. 70Ul6

T' ,--,....

~ ' (

>

essence,

e.

vinylo[ ous forn of o( - ( ~ -h1.1.tyrol2..cto tylic1ene

:-triphe11yl1 hosphor2.ne, 17hich 1·1~s used sane :re,.1''8 ~so i1-1 °ore

hic;h1J ef::·ee, tive syntheses of 0( -benz~rlide-11e-

o

-b1xty1"ol::--ctoi1es81 •

nhe rio st obvio11.s route for the syn-l;hesis of

±11

is sho vn 11e __ o 1.

>

>

-->~

47

-+

-PPh3Br 51

-2-1 ethylbnt-2-enolide

.±2

is kno--_,..1, 1)u·i:; the repor-1-ed

S? 8~

synt 1eses ·' 5 are very inefficient, ',7h:Lle nore : er1era:.

syn·';heses84 2.re ine,pi, icr-,ble to 3-lmsursti tutec. b te-10.., ides

end

it

,

·a.s tJ,erefore of sane i'1teTest to clevi.se a·1 efficient

rep2,1·-.r .tio·1

o-::

t_1.e reauireo co1r,· 011 '.6. . :he e.0.1,,l~r ef:':or-· 3 ·e_ e

ini j_atec3- by ti1e reyior+~a_85 r:.cid-cn:ta1~rse( co:1.versio·1 of

trRn~-3-~:orrnylcroto:1ic acic1 to the rine-c.1 osed cis i~-lo~·~er,

2-Ill8 ~ ,yl l. SO' 18-.t"' <:<110-,"" d I"8,.. r:t Sl. rni l :::i-/,-. -r.r l0

-i-s '0..,.L,...8Cl1u-,.,qo-.... o·i-},..,,rl - - .. J... ...::., .... _ .. 1.-- .. ~ • .i....-- (,....L . . .

v,

.Jt ...1..--.., ·~ _,....,J . . . L v

-1ris fo1.u1rl_ to hyd::'o~ ..,rse 2,nd isor1erise ·':o

.. ., . ., . ,

References

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