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J. C,.!.._ IJ c..~ l, - .U. o
I am indebtec~ to · 'rofessor _\.J. Birch, F ._:. :, ,
• . -·, for the nrovi sion of facilities a.nd ~or his ~~1,,_ic
a:o.ce
and enco1.,1..r0_., e- ~e:1.t throue,hout this · rorl: .
I am [-:2:~e~ul tony colleac1,,1es,in ·0c=t:ticrlar .Jr.
G
1.,...
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.
_1..i_sse]_J_ forma,ny e-1j o~rable che! J_icc.l an( social conversations, c ,~•.G. to
C11ool esne,-·i· ::il lv --.oferic.•01" ·, ·
.) •·- - !) , -L. v C,----v .,_ .L :J >-.) - U O • O
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ro1.1..:.n·c
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I a::..t1 ,.leasec. to ack_nonled·· e t:1e hel- > of the
..,I.. ' - " " ....L
tec ... 1.nicLl staff of t~1e -Jchoo2., es::_--eci::·,lly that of .
1.re.njelov:Lc and~ 1 ... _\_., •• ("oLt_j_:,..
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stace
· )e,uben.
~/:i_nally, I am .:_r2;t ·.:fu.l to ·b.1e Jo _ '011.0:1eal th 'Jcie1ltific
and ll'ldustrial ~e.search Or:._anisation for the austrc~ of 8.
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z~re r ade .1hic .. .!. ~o,y a=..10·.1 a Juccessfnl co. J.~e 'Jio~-o
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5
Introduction • • • • • • 6
Discussion • • • • • • • • 8
~~xperimental 0 • • • 0 •
29
· __ ef erences • • • • • 0 • •
67
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"
74
~·iscussion • • • 0 0 • 0 •
75
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al 0 0 • • 0 084
~ef ere:n.ce s ~ 0 • • 0 0 • • 02 .I
'
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the re2,ctivi ty of or~aY1ic conpou.1."1.ds e.,nd i.:t their structural
elucidatio:1 have brought ·:1i th the1:1 a bu_r~~eoninc of s3rnthetic
endeavour. .A.s the variety of too ls ave,ilable to the synt~1etic
che1.1ist he,s increased., so has his , ·il2-incnesn to ap)roach the construction of e-':rer iore coi
1:
lex 11olect:.les, often i:1d ~J_l . . '"·.h. _-'i:;-I'"'11 __ 1_ly PJ'l
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1i2.a f:t·eelin,ii
-the novel Jacto-1.ic di ter--)ene ere olacto.1e 1.
-
:1"eniccldegTadatio:1 failed to e_i_ucidate the struct11re of the cori1:,01r1d,
but i::.1 a later --ray sturly, < h EL1r1 , 2,s in 2 c1.educed the
struct 1.re of isoeremole,ctone ?, 1l1ic11 may be obt;- inc· b~r l"'rief trentment of erenolactone 1·1i th hot anueo11.s et·1r ·'lo 1 ic - i::.1era:i
..,_
acid. S<nbsequently, 13,S8 s:1ectrorn.etric data have been aovRncer
3
i 1 fv..rther s :i.:9~'"'ort of str:1-cttrre s 1 0J.1d 2.
In a survey of the fielc. u:1 to 1
S63,
J.iche.,rclsanr1-:i • l LL .J t th . 1
eno.:ric cson ' s ca e at al~ thC; .J.: 10 ~1 ;: ite::;_"'")e·"les ca!l be
.J..
de~. ived, in --)ri11ci11l e, from the ./
20 head-to-tail i so:1·-.enoid
[_,eranyJ.eeTanyl ~.,yrophosphate
3.
!-:o rever, fl,] tviou~,}i erenolactoneappe2.rs to contain i ntact isoprene u-11.its .1,it is c:i_ear~y an
exception to
t
1"e { ene:ral cl2~sn . .. '\. later revie1.v
5
a does :1ote 2linitec n.11: ber of other biosynthetica1~.y al::J:O.OI'rnal ~:
20
com1)ot1nds,na1YJ.ely ryanodo:
.2.,
biflorill.§.,
cemb:. ... ene 7 2::.10. t:1e(J_Uassj_n § croup. r he latter c_ rour is kno\m. to a1~ise by
decradatio:1 of t:{·iterr>en.e stx·uct1.,1..re ",·.'hi e the fina1 structure
obtained for ryanoo oJ.. cl oe s, i·1. fa.ct, cont2,j_·1 e..:.~ 1r1rearran.~ed,
a~11ei t highly O"'~icli '"Jec1, {·er2,11:y-1~ere,,niol skel eto ,Sh , :- s does
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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synthetic sche e that the
a
ihyc roinrl..--none _2 'O 1-ld be a 1:reyinterrin.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.
:mae_nesi UI!l, :follo ·1e
~
by ethylene oxio e 12 anrl_ • RS conve:ctec tothe bromide by
t
1e method of J vala 13 • r.ihe conju~ ate rrri g-1.2rdacl.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 ut0
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 recentfulJ 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.
1The 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
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 theef: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.thonchit
..
1agR
-11
R18 )
-
·
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
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
-•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 theaJ 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 eathe chloroketone
_g_~.
1ehydroc·1.1orination eY.11eriments r."Jei-·ec 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. · 1a __ 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.
1 j
ch of ~his · ·or1c ··r,s cP::c·:.ied o
t
o v2:.,to 1s 1ode] com- oui1.r s2nd in m2ny cases ]eel. to ne~ative resl1.lts, so tb.<.t
it
ht\Sbee-n re· ortecJ. only in out}_i·1e .
e"" risa ·ed the for·ratio 1 of the ske] e~~on of 26 ( ~~
=
er,
CHO orCOO~t) in
a
sinlle ste~ base6 on consecutive· ichael adcitionse,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 thet 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~1i1u1tb ·
a
..
·
- , -
·
:,
t
·
.L b J. • d3
~ dG _o:;~i _e, soc1u1n nya.ri e, o as aw1 u- nco::::i e an
-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:ere2ctio· 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 riooryie:~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
<
n2seCHO
r;cheme
IV
m the o
,:.y
occasio 1. on l'ticr1it
\VP,'"J trie(, therzC
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
: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 thes11ccessful 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. bereactio 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 hopedthat
t
11j_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~
>
?
xv
"( --.
~-..,,
'
,~.
t
' ' l J
AL1 }
r
.
-
b·. ul e PO . ~ e · · -_, '=l_ ~ )
e
e11 ,..,c
1 Jeve
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 "1t
'!-_..., 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
.dthcyclohe=~none
(
iscP.rc1er'-, ' Ll.8
C C., !:'I -, •) t
on ·
.,-
' ~ P. · avie d b
t
theV _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' edre·.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
--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 ciieneJ.3
.,
i1.0r"")e st:·:--110,tu:ce£' ave a sernicrystalline maleic anhydric1e
ao
(-:i_uct, \rb.ic·t v1ascoi1ve1: .. to6 to tJ,e hono ~,en,~ous ,N-r,henylsuccinimide
34.
,
the 1 ikelystereochernistry 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
~·
·~
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 ther.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 bepreferaole 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·rereheE: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 thiscompJe: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,ndJ.£.
3
7
8
35
2£
, ee:-' .1,
'
.
,:.c . ·; t,' pr
- - ·' ...,I
,
.
' ,2.
-r-,....
-·~hat -
.
-~or r-(3
,
~ r i ....t.,,-rr
t:e.,... reto
_,, \.. o· 'JO ,:ie . ec e 11 e
- ...) - c.. .. J ... ...
irt .,
,tr-
Ii_ "") J~c11e~- o ', :_"'8 0 .J. ' c- ·';~_o
.J.. 1e1· - :re sr. e ,_.,,.~ :-) e l
of
t
1e i '10en 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 ·'- 1· 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 • ec• --b T,
of
• J • _.. -, I ~ , I •l -,-,...i e .... .,..lO"ll 1 c.-'t,:i.i1_,
\J •• - - ) , .. U - V 1
,.., .. r,·
)
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
·
·
ilt ·
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.ichthe 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~.
' 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 rientr , .,_ 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.se::· 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"Cit
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...h8,1.12, 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 . ·:ne0·1 · --- V 2. J.:; ·ace
o=:
t __
e cl e sire) )
reactio·: mi -cture i., as less colo !_rt:;d but c"'- ai·1. cont2.i·10,(., very
little of
cr-.e
olefin40.
ben r,hosphoi-·yJ c lo:ride v,assu 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 oftemnerFcc1J..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..iredre· 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,,sebee"' 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_)
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 "heconver-':.ed to t,1e :,J de~1.ycl.e
Jf'.
'·:he ketone 37 1.ras reduced by42a (.£.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
0mesy_ 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 bea.et
ect eda .. 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.
)
-
.
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
sT-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 thel 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
es eciaJ. V v at~: rc<:;ive. o ·eve-... ,.:.
·'1_ vie
r
.. ,
to ef _·ect
t
1 e ~- eq _i ~ea. conversi 0-1. 70Ul6T' ,--,....
~ ' (
>
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-edS? 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 efficientrep2,1·-.r .tio·1
o-::
t_1.e reauireo co1r,· 011 '.6. . :he e.0.1,,l~r ef:':or-· 3 ·e_ eini 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
.. ., . ., . ,