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"Retrosynthetic (or antithetic) analysis is a problem-solving

technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively:' simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule. to a synthetic precursor is accomplished by the application of a transform, the exact reverse of a synthetic reaction, to a target structure. Each structure derived antithetically front a TGT then itself becomes a TC]: for further analysis. Repetition of this process eventually produces a tree of intermediates having chemical structures as nodes and pathways from bottom to top corresponding to possible synthetic routes to the rGT "

E.l. Corey

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• Some defInitions of terms used in synthesis,

1; ~

r- . i

o. target molecule (or TM) the molecule to be synthesized

. " . : ....

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• . retrosynthetic analysis or retrosynthesis

• retrosynthetic arrow

.

• disconnection

.-synthon

• reagent

j "

.:- ....

. .

disconnection

..

-_

product or target 11101 ecu I e amelfolide

:;.

the process of mentally breaking-down a molecule into starting materials

an open-ended ·;3.T_fOW, ~ ) used to indicate the reverse of? synthetic reaction

. .

an imaginary bond cleavage, corresponding to the reverse of a real reaction

idealized fragments resulting from a disconnec-

. tion, Synthons need to be replaced by reagents in a suggested synthesis

.a;~~al chemical compound ~~ed as theequiva-

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,

o

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proposed st8l'ting. rllflteri<lls

r:-

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H

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?

CH3-CH2-CH2-OH CH3-CH2-COOR CH3 .. CH2-CH=O

CH2=CH-CH2-OH CH2=CH-COOH CH2=CH-CH=O

F

_HC-C-COOR

HC=C-CH=O

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C-C-C-C-C-C 'n = 6

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Compound Functional group Heteroatom Hybridisation
CH3-CHrOH -OH -OR sp3
CH3-CH2-NH2 -NH2 -NH2 sp3
CH3-CHrCl -CI -Cl ..,
sp?
CH3-CO-CH3 C=O =0 sp2
CH3-C:::::;N -CN =N sp (+)

(-)

C-E

F

C-G

-~

-OH, -OR =0

-NR2' =NR X (halogen)

metals of groups 1, 2 and 12 -AIR2' -SiR3

(+)

C-A

(+) -N02, =NOH, =N-NHR, =N(O)R, .,-N(R)-NO, =Nz, =N, -NR3

(+)

-SR, -S(O)R, -S02R, -SR2' (and the corresponding Se derivatives)

(+)

-PR2, -P(O)R2, -PR3 . -BRj, =CR2, ~CR

- '

.~

.-~

.~

. '.!

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transition metals

.. ~ ... -,~

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C+) (-) (+) (-) (+) (-)

C - C -c - E

C-C-C-G

(+) (+) (+) C-C-C-A

(+) (-) (+) CH3-CHz-CHz-Cl (+) (-) C+) CH2=CH-C02CH3

(+) (-) (+) CH3-CHz-CH=O

(+) (-) (+) (-) CH3-CH2-CH2-CH2-Li

(+) (-) (+)

CHt:=CH-CHrOMs (-) (+) (-) CH2::::CH-CHrMgBr

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Bifunctional relationship

n even

n odd

!;

-E - (C)n- E'

dissonant

consonant

dissonant

consonant

consonant

dissonant

consonant

dissonant

dissonant

consonant

... :~~:~~~;~~~~~' -:

~j

.. '~

:~

Bifunctional relationship

Example

Notation

.! 0
E 0
E'
(- ) (-)
0 1.5-C E E'

~(+) .

(-) .

(-) (+)0(+) (-) 0

C+)

E (-)~(-) C+)VC+) (-)

(+) (-)0-)

(+) (+)

E E'

o 0

~

o NR

~

Cl OMe

~OMe

o

6

Clo

. -~.

1,3-C

C-ring

,

. ..• ~ .... ~~ "'_- .. ~·;:: .... :i?~'1.-..i..-_>r-.- ........... _::::':~:;'~ .-;._....};_;;_ ....... >"c_'·.c_· ~P';;" __ ,.,~ '. '.,":':~'- .... ,:'b~;,;,-

Bifunctional relationship

Example

Notation

G Li
(±)t-E I i.i-o
H2C-Cl
/.
E' 0
~ ~g
HO • t, 1,2-D
E NH2
E 0
~ l,4-D
E'
0
(-)
c+)a~ HNQ 1,2-D; 1,4-D
(+) E'
(+)' 0
'" (-)
C±)oc+)
_.;"r-
(+) (-)
E OH
(-) D-rings -r
,
'"
-,
. ,
(+)
.•.
/E~ 'i
/O~ Y ...
e:

(+) t (+)
f JJ'.t Q11 o.Jn ~.~.''Z.l.-\ La ~(y\~(a_ ~ry.V~~ ~V<L~ 1... .. (.c..l..CgIU ~ u.Qa.l: 0 v;. ~l ~ tv.; 0 fhQ e_,; .. ~t"Y) ~ "{;co(b.u JW.Q ~ cl.j

RELA ~tON"\ C(l~f"I Af'J'T I .Ji.." t..Jqo,.f:t_ 4(j"yy\ r-

d..o.~~ck .L 0- <Io'\.,(!). ~~t;;. ~~~. ;

o

~OR +

o 0

~

o

~

-

1.3-C

o

~

J) OH

~

o

~

+

1.3-C

o

~+

o

II

H

o NR..,

~-H

l,3-C

-;

1

$..) c,;,rn~ ~OA.-~" j

,

o

~

1.S-C

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~ F ~ 'Com4"'olu.an.:l.Orn.t..

•

. ,-

5\S1:eHI t{O NO \!UN:tL.ONAU

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alkynes

consider R

disconnecting ~ - -=- <: - here---~R or hero _. - _. - - - - - - - _

o

/+

o

MgBr

ipso

>

o

~

o

~R

aromatic rings

o

~ + R,CuLi

ipso

~ 1,1 C-C OH 0
: .> 8 @r A
p~ + -use
-use Grignard synthon reagent consider

- - - - disconnecting here

P~

,r. .,

j.

~:

O~< a.

I 1.,1 C-C

.Ph~a OH· _. c. Ph~

_ . c: >

_ b 1.,1 C-C

EtMgBr

Ph~

e Me

b ij1,:1 C-C

Ph~

o

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ANAU itt f.fTftO SI tJfe 1:l C A

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-use ===:--:H + base -use Br~

reagents

5INT€~(

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H2, lindlar

R-,-1 _;:::::::::~R2

Na, NH3(1)

~ R2

R1~

trans (E)-alkene •

.; -r; ~. .~

. Z)-alkene

... _ .. ,~

~_~.. --~....._.~~--.~..o.:--.--- ....... _.__._- ·_' ._~___._. . .___.. .......... __ ._~_~. "~ .. _.r~_ -------~.~--~-...-----

,~ .r _ .' ~ • •

-

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SR

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(Ys~ c-s sulfide

CI~

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SINTO {III

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-'t

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~o =====>

Cl

~o

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>

o

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H R1~N~R2

C-N amine

H

R1~N ............... R2

secondary amine is more reactive than primary amine

~ ALf 1:>( AH~ Nt 0 &'V,ATcettv'.AR40

sterlc hindrance OEt prevents further reaction

X ..

OEt

o

"v- .~--.

- __ , ~ . _- _

+ O~OMe CI

+Y'oMe CI

~OMe""

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.~'

}.: ~ .• -"""""",.~~- . ~~- •• '''--Q~--">-~-~' .----:'~------.

.s\5T~\-t\ e:,tFvNltoNAL\ 6" POLl~V"Ji3lONALl

?.fJ\.. ~W.l~: c.orrn~....x-· s C9l'lVR.~-Vr.\J. _ur:L\MA-{'(\,Q!u 'l\il.tG.. J..,.. ~".,'ln.'~' CDn-:~ ot: ~if ~1:lQ"'&"! .A. r-m.J1 u. ~ .wcclt~ J.t 'U.~·OVA·

CD N'2,oN.A NT, J.,! 0 a 'S9P:> (\fA NT ,

Retro-Claisen:

o _) 0

~=>~+

RO-

o

RO~

1.3-C

Retro-aldol:

H

o _j '-..0

~=>~+ ~

1,3-C

Retro-Mannich:

Retro-Michael:

H

OMe

OMe

>

_use~CHO

OH

OH

~ GI N("€ R.O CD

:.,II,

.~

1 L ~m""r~o ~&~ o\.,f(9o

t 1w..J:fAo l.llmtb~ oH~'~~s) bond to be formed

aldehyde must act by aldol reaction

as electrophile h~re I

~.

A -------------4

ketone must not act as electrophile here

, ,

aldehyde must not enolizs here

ketone must enotiza here

ketone must not

enolize here

OSiMe3

OMe

OH

(LiJ.( ttb 5 \

\..) r

Me3Si/ <, SiMe3

OSiMe3

OMe

MeaSiCI

OH

OH

o

, .' .i

,"" -r o

.~

OMe

gingerol, 92% yield

OH

CHO FGI

~ dehydrate

i-

J. 5lN'TE Sl .~

~~CHO

base

.~-

~ .~

11

iJ. 'U .Qa1A"Of'(ll·

.!_'; ~ ~

~ANA-Ll ~\ ReTflOSlNTETtC4 <kU' ilJnQ.~&",-~ bQi>lCO NIIV"€" ~

.;:.__

C-O acetal

FGI

reduction

OH

. N Me"'" 'Me

3

/N,

Me' , Me

0+

~~CHO

1. LlAIH4 _---..,~ ~PI{o/f11 C02Et

N

ME(""'" 'Me

CI

gel

+~Me2

00 ~h~ 0
0 P~
P~ -use
N
H
synthon reagent
blNL€~1 00
0 80-90%
Ph~ yield
+ Ph
H ~. ~

Wi.3-hydroxy carbonyls and a,~-unsaturated carbonyls: use the aldol reaction

r ,-1(_

>

o /CHO A R1

e R2

-use enolate equivalent

a,J3 . ." D

<¢~===R~R2

3-amino ketones and alcohols: use Mannich or nitrile aJdol

o

R1'N~R'

acid catalyst (often Hel)

-enollze

FGJ (reduction)

l,3-diketones: use the Claisen condensation 000

Rl.~R2 R1)0

2 .

-use acyl chloride or ester

o

eA2

R

-use enolate equivalent

.60 _Et_0_~ __ C_02_E_t Et00

-use malonate

,

-use en one

1.KOH

2. H+, heat

St 5TEf'.t1 Dl5S0NANT(

Vf..{A· h.. .. ~t_rm.,,:. ol'/¥l 0 mo-rn""(' ~ s: to~~~~..e... ¥Ca."lJ -i' 0..1 ti 1tnQ.,c"01a- ol' f 0 Oast. tsC _.Q.. rn ~ rroo "n') V'tI t 10 ~ ~ • /h d.uJ.l r'Gtd.t.u. 0.. ol.c.& OL'4c.o(),\f"Y\~\AI.· ~\"Mo -4-"

.cluJ!. 'V\,'co1JU1..l o.~ Co...,...'o[olt.f-e.t btSCoNN€~~(o.AJl

lLtDG-lCt{~ ~~'"'t.<A.t-hrodo ro ... · Olt..l' ~l~O)rO~' ..l.ylA.,...\v~Q1t;

\

cl.t._ .1\.." otr .ttn~t'l\O ~m IN \/6 R. ~l 0 N f J;?st. R€ ATTl \It ~

A A

I I

R'-X + R-C:- R'-C-R

1
"equivalent synthon"
j
E ,.
!
Rt+ + R-C:- FGI A--E

illogical disconnecti on

E

,

R'-C-R

II logical

D- disconnection

E

I

R' + +C-R

- St,51E Kt bl SSON ~N\ t ?lv- CON V AI l

-~.Q. .Atu-m~(),L u M PO LO N G-d..tl-\',(Q. d.o..e. Aj.d.t4.to .(... v~ ol·:u

- ,POlA~lTA-' IHve~~A Jl.o\ ~o\,,·CJ:l_~v..L~ SlNTONI LA CVl NATuR..A-Lt

EtcA"'C\lVl'lk"" L Nn"ut~ , J 1).Q.,~~. ".MrMro.te.oL 'I Ao",,-O hI-' ~o .t.. c.\...v;Q./t. v.:Mkt:\lo- Mt~ ~. "",tJ.;\..' c:J.... M,'AU ~ ol" ~s.o mOA1t::~

..

1,2-D system

illogical disconn,

Umpolung

E

Jy

E'

E

)""r·

E'

E

)C+l

r

E'

or

1,4- D system

. illogical disconn.

E

)'·"r

'£' Umpolung

E

)C+) _ .r>: /' . ),., .

,C~) r T - c+/:"y

E' E'

E'

or

E

./(+) ~/

(-)- T

E'

E E

A C-) 'A H

'·'.Y '" Y

E' E'

1,6-D system

illogical disconn,

Umpolung

E

E

~(+) -<. /'

(+)~ I

E'

E'

among other possibilities

E

~(-) (+)~

SlNTO N l 'IVHP>OL€t::>11 Et> \ LO£.o FR.A-MH..eNl"\ E Q.Ul VA Lt::A)Tl Co,.'" ?a..AR,\'1'A'" lNNATV~Al\

Synthon

Umpoled synthon

equivalent to

Umpoled synthon

0 NO:! NH~
~(-) ~- ~(-~
0
)1<-) HC=C o

)1(-)

o

)1(-)

N=C=S N=C:

_j_ or ._j_

OH

_J<-)

BR~

~- -

x

~(-)

o -RO) (-)

o

~(-)

(+)

o

~(-)

(+)

o

~(-)

o

~(+)

NO,

~

i:_ 2- __ ~

NHJ

(-) ~

(+)

SR "

I~ .

RS~

H015CQ

°

n-CnH:n ;: 0

H

SLN1eS(

;

HODCCl:,. CH20-0H 1. pels

2. KH n-CnHo7

. - = Q

H

H0J:5=Cc\'... .

. °

n-CJ1Ho7 ~

. - :; ° H

..u.u ~J..Wr~O dn' ~vW>;:o\.U ct 'b.otLVl.to: .z 06..10 olo.lli ,:roUIh- oW. C.IS - ,JA.s'H(_, NG I ,,~o\o~ ~~ Jw.2,r ~~OJ Co~'tica...

o

INve Rr'i,I.ON€: ):it R.€A-TT!VnA -~EJ...t 9c.!c.t' o

CIS-.JA-SkoN6

~.

III

o

-

j-N02

. £I-L~"": '<a-&u.U ~'mt._~'c:o ~Q.1fo

" crotonisarion"

~ 1 aldol condensation

o

-0

1 "Net-type reaction"

o

o

o

o

o

__ -..._. __ ;~_+_:_.~_~ :-+. _:"_r~~_ ._: :"" ":~ _ ~ __ ."'" _.~~~r_~.">~.r. . ; ~~~_~ ~ __ > ~ __ -:_ ~ _~ _ ~ • • •• _'~_':

~ .... : .... ~ ... ~ ... ~ ... ~. -~ ... ~ .. ~ ... .: -~.

'O"ih'ii,-t1.4lGi.-~-~--c:.hZ~~::w..1Q.:"':O .M....\1ohd~ 1l ~ .'~.ol.i",c;$'ib-!-o:

. . . . . ~ . .

: C:liJ : R~,:Q,Q 6"Nii1.,Ar"t.p: :Q..; .~ ::::t:t~~.~.,: ... : ... : ... : ... : .... :.,,; .... : .... : .... : .. ': .... : .... : .... : .... :

:Jr:l::L"r.IHTL:+_+--H~:-:T~Hcr.TTT

: : . . Ri' . c.J.;f .. : ~L .. :J\tLO~ ((, : : .. ((,.1: :.. .03" . R.' C' i(' : : .

. : ... :.. .: . :. -. ~ . : . : " . .

~ ... - ...... _,.,_.- .. -:.._. -~ ....... ~

. .

. . .

_~~___:_ __ , _:___ ~_._.~,~ ~:-'"..._, .... ~_.~_.~>~:~c-'~ .. .-,~ .. "-+ > ,_. ~, ~ .. .,. _~~ _~~---.~ __

. . .

'. • ~ + • •• I. •• . • • .. • • • • • • •

. , . j .. -c~-~.,---.c_i_l__i_-· .. LL_~'-~·t~-~-rr~-- --.:_-'-~-c---.~'~-c-c--,-----~-c-.

++. .: '. .... ~ .. ~.+.~ .~._'.: ... :r "":.. .

. . . . -_. -"'-'-- .. -- _.-. - .... _._- . .......,_.- .... ,--~~ .. _--- <---~- .. ~

;_ __ ~ . .:._-.~. __ . ~_..:_ ~ .... ~.~; __ ~ .. -:''''_+ .. '__..~~ __ , ,:____.____.~'.:v~.__.,-:----~ ..... ~~· _~ ...... ~~~~ ,_--:.-------:~ _ .... _ ... OT"._:L __ ._:~ _." • ..- __ ~~ __ n.~ .. __ ~ ~_~«. __ .~_

. . . .

-._.' -- --~-- .. -- .... :-- .. --- - ~-- ... ----:-- .. ---- :--7~ ~- ~:- -.-. --~- ~r~ - ~ ~ ...:._ .:...-..:-~- - - ----- -.-_..._.:_~ ._.

...

~--~"- ... ----.~~~. -'~- ~ ,_ .. _ ..... -. -" ... ~. ---.- ... ---.~.--<

,4NA Ll"t R..cT so ~l NT~T l c.A

OH

H~Ph

OH ®APh

r O~l,. t"o- ~atM. ~ o rm.L pf-'o ....f ~..td>0~""ol.o

v-,

5lNTES\

_:1_" N_aH__.. [~081 2. ~Ph

- ,

, .-..

Phn1 ~

N N

H

OH

phenyramidol

SLNTf".5( - ~

Ph,,~ + ~u~

- """-......h H2N ~N

:1,2-dIX

Ph"<l o

70% yield

....... -"':.

_ •• _ . .c.~. __ ;J.~_-:".'r~'

. 0 21N~

cO~ i.2-<liX

OH >

-

C-:-O ether

OHCI~

~O

VU

:t..base

. ....-~

~~~

OH

OH

2. ~_./1

cr "-....J

o

CPlC. LOA.O I bR,t N A-

1,2-dIX

>

synthon

o

a

Ci HO

HOAe

IJ A:- F I /of. { sa III 1;ANAl'Sf R.clllo.sl NT~1'lCA.. oW. tuw.e~'!QlQv..1A" FeNAG-LI cat:olo

CI

CI CI CI BeN
FGI 1
~02Et > CN > 0
OH OH 1. NaCN

CI

excess MeMgBr

0----

2_ EtOH, W

OH

OH Ff"NA.crt..t co wLo

S\~\"tN' 1, J... \) \ fv Nc~ 0 N .A.L\. l:A. ssoNA-NT.\

cl,: ~~~ /tfIt"oo'" A. c:JAJ .R.,_~ \AU. ~ tlJio

L ~ 4 ...-R2 11

R~/ l~) ~ Rl~0

2 0 natural polarity -use enol(ate)

umpolung - special t ..-

@ yR' reagent n"ded '( R'

o 0

synthesis of 1,4-diketone yR' e
~R2 0
yR2 R2NH yR2 <±l
H ~R2
+ Rl./ --- R·· r. '
0 NR2 0 H2O
en amine 0 0 )°1 R2 R2

1 e + e~ -use~ ROO umpolung

-use

umpolung

..... '.

8

use

==>

()J:

b

enamine

o

o

l~(a ('rd9J., t'- b.J:I 0-«. ~ .. obJ . ~ fl"i10- .At fA L

~~~f;h ~~-!:-

o

4 FGI

3 C02Et:::=::::;>

4 Frledel-crafts 0 0

2 3 C02H ======::> I #. + O~O

:_,'

. ·_~-'_·.:r·:-_~-,·

J "-,,Xi, t~ "I..I.IUI.: ~ ol' MM- f<'"'- ~ . ~ Q....o£..

FGI

CH3-CH(OH)-CHrCH2-OH . > CH3-CH(OH)-CHrCH=O

retro-aldol

======:;» 2 CHrCHO

. 0

6

o

~o~

U COOCH~

J.3-C

~; .. ----: -~ _ ..

-<~.,....._.,__ --...".~ .~.- -. ~~~ -e--r" ;=J",~" _: -...., .. '"':'""""'c,.....,...,.~...- .. _"'.~ • ..,-

I I - CH-CH-OH --- -C=C- _ .. -- .. -o=C-

I I

-C::::O O=G-

t

I t /! '" /0",

-CH-C~O '" /

___ A ,

r \

r I 1 1 "'--1 ----'1

OH OB X OH NH2 OH

~. .

~J1"~

o ::::::::::> @ ( II

cO

H

H

o

(0