有機合成++第6章+有機合成中的選擇性

第七章有機合成中的選擇性?現(xiàn)代有機合成中涉及的反應(yīng)底物通常會帶有多個官能團或多個可能發(fā)生反應(yīng)的部位。?即使只在某個特定官能團或特定部位進行反應(yīng)，還有可能生成不止一個的異構(gòu)體產(chǎn)物。OH有機合成中的選擇性控制至關(guān)重要一、概念反應(yīng)的選擇性(Selectivity)

：是指一個反應(yīng)可能在底物的不同部位和方向進行，從而形成幾種產(chǎn)物時的選擇程度。paracetamol31%t-BuOK28%73%二、分類(-)按選擇方式大致分為三種：1、化學(xué)選擇性(Chemoselectivity)2、區(qū)域選擇性(Regioselectivity

)3、立體選擇性(Stereoselectivity)1、化學(xué)選擇性(Chemoselectivity)不同官能團或處于不同化學(xué)環(huán)境中的相同官能團,在不利用保護或活化基團時區(qū)別反應(yīng)的能力。excess

Ac?O100toluene,

refluxparacetamol不同官能團ketone

is

more

electrophilic

than

esterreactivity

towards

nucleophilesaldehydeketone不同官能團不同官能團hydrogen

adsorbedon

to

catalyst

surfacePd

metal

catalystaromatic

ring

coordinatesto

catalystreduced

by

NaBH4not

reduced

by

NaBH4amidecarboxylic

acid>

>reduced

by

LiAIH4NaBH4REtOHLIBH4EtOHstill

a

reducing

agenttriacylboratefastreactive處于不同化學(xué)環(huán)境中的相同官能團(I)(II)(III)非共輾的多烯煌的氫化受到取代基的影響，隨著取代基數(shù)目的增多，反應(yīng)變得比較困難，因而可以在多烯分子中有選擇性地還原其中的一個雙鍵。例如檸檬烯(I)

用氧化鉗催化氫化時，在只吸收一摩爾的氫就停止反應(yīng)時，能得到接近定量產(chǎn)率的(II)

,進一步氫化生成薄荷烷(III)

。2、區(qū)域選擇性(Regioselectivity)O在一個具有兩個不等同反應(yīng)部位的底物上反應(yīng)，試劑進攻兩個可能部位及生成二個可能異構(gòu)體的選擇情況。如通常涉及的不對稱涉基二側(cè)a位、不對稱雙鍵或環(huán)氧兩側(cè)位置上的選擇反應(yīng)、a,

加不飽和體系的1,2或1,4加成以及烯丙基離子的1,3選擇反應(yīng)等。（注意烯胺與烯醇反應(yīng)區(qū)域選擇性的區(qū)別）conjugate

addition

productirreversiblethermodynamic

product:more

stableattack

is

possiblealLUMOfast

butreversiblecyanohydrinkinetic

product:forms

fasterbut

el?:trostatic

attraction

toOO

is

greaterEl

reactions

can

be

regioselectivetwo

regioisomeric

alkenes

possibletrisubstitutedalkeneregioisomersHBr.

H2Omajor

productminor

productEl reactions

give

the

more

substituted

alkeneregioselective

fofmabon

of

thepartial

doubie

bondhas

only

onesubstituent

lessstabilizedtnsubstituted

alkene

forms

fasterThe

regioselectivity

of

E2

eliminationsE2

reactions

may

give

the

more

substituted

alkene,

but

become

more

regiose?lective

for

the

less

substituted

alkene

with

more

hindered

basesmethyl

hydrogenanti-periplanar

to

ClROmethyl

hydrogens

moreaccessible:

bulky

baseprefers

to

form

lesssubstituted

alkene澳代醋酸烯丙酯的區(qū)域選擇性反應(yīng)Br+

NaCH(CO2Me)23、立體選擇性(Stereoselectivity)是指反應(yīng)在可能生成多種立體異構(gòu)體時的選擇情況。這個選擇性又可分為兩類：一類是相對立體化學(xué)或非對映選擇性(diastereoselectivity

)另一類是絕對立體化學(xué)或?qū)τ尺x擇性(enantioselectivity

)消除反應(yīng)的立體化學(xué)two

stereo

isorneric

alkenes

possible95%

E-alkenesrerecisomers(geometncal

isomers)5%

ZalkeneD-A反應(yīng)的立體化學(xué)dimethyi

maleateCOzMeCO^MeSimmons-Smith反應(yīng)的立體化學(xué)Sininiori^Smith反應(yīng)受到底物烯炸中某些位置的羥基的影響。當?shù)孜镏泻邢┍透呦┍蓟蛩岬慕Y(jié)構(gòu)時?反應(yīng)的速率會大大提高。五元或六元環(huán)的烯丙醇與卡賓反應(yīng)后可立體專一性地得到環(huán)丙基處于與羥基順式位的產(chǎn)物。例如63%

yield>99%

this

diastereoisomerOHLkidlarNracemic

Dheromoneracemic

alcoholenantiomerically

pure(/?>pherumoneunwanted

urethaneof

(S卜alcoholredraw,

rotating

aboutcentral

bond

to

putredraw=>UAIH4produced

in

a

ratio

of

3:1major

diastereoisomerMe

and

OH

antiminor

diastereoisomerMe

and

OH

synOHCOjHPhCHO+BuLiBu40%

e.e.[DIPAMP]RhL2(L

=

solvent)HjO看馬酸項兩個可能產(chǎn)物為對映異構(gòu)體，且其中的一個是過量的，為對映選擇性反應(yīng)。三、（能夠進行）選擇性反應(yīng)的底物1、被選擇的兩方面有質(zhì)的不同elimination

of

diastereoisomer

B不同異構(gòu)體的反應(yīng)性差別：反應(yīng)活性不同；反應(yīng)的區(qū)域選擇性不同。為什么？The

key

to

explaining

reactions

like

this

is

to

draw

the

conformation

of

the

molecules.

Both

willadopt

a

chair

conformation,

andgenerally

the

chair

having

thelargest

substituent

equatorial

(or

thelargest

number

of

substituents

equatorial)

is

the

more

stable.

In

these

examples

the

isopropyl

group

ismost

influential—it

is

branched

and

will

have

very

severe

1,3-diaxial

interactions

if

it

occupies

anaxial

position.

In

both

diastereoisomers,

an

equatorial

i-Pr

also

means

an

equatorialMe:

the

only

dif?ference

is

the

orientation

of

the

chlorine.

For

diastereoisomer

A,

the

chlorine

is

forced

axial

in

themajor

confdrmen

there

is

no

choice,

because

the

relative

configuration

is

fixed

in

thestarting

mater?ial.

Ifs

less

stable

than

equatorial

Cl,

but

is

ideal

for

E2

elimination

and

there

are

two

protons

that

areanti-periplanar

available

for

removal

by

the

base.

The

two

alkenes

are

formed

as

a

result

of

each

ofthe

possible

protons

with

a3:l

preference

for

the

moresubstituted

alkene

(see

below).For

diastereoisomer

B,

the

chlorine

is

equatorial

in

the

lowest-energy

conformation.

Once

again

there

is

nochoice.

But

equatorial

leaving

groups

cannot

be

eliminated

by

E2:

in

thisconformation

there

is

no

anti-periplanar

proton.

This

accounts

for

the

difference

in

rate

between

the

two

diastereoisomers.

A

has

the

chlorine

axial

virtually

all

the

time

ready

for

E2,

while

B

has

an

axial

leaving

group

only

in

the

minute

proportion

of

the

molecules

that

happen

not

to

be

in

the

lowest-energy

conformation,

but

that

have

all

three

substituents

axial.

The

all-axial

conformer

is

much

higher

in

energy,

but

only

in

this

con-fbmer

can

Cl-

be

eliminated.

The

concentration

of

reactive

molecules

is

low,

so

the

rate

is

also

low.

There

is

only

one

proton

anti-periplanar

and

so

elimination

gives

a

single

alkene.有機合成中的選擇性1、化學(xué)選擇性(Chemoselectivity)2、區(qū)域選擇性(Regioselectivity)3、立體選擇性(Stereoselectivity)?在一個結(jié)構(gòu)較為復(fù)雜的有機分子合成中，由于合成過程涉及的中間體常是多官能團的，而目標化合物又都是具有特定結(jié)構(gòu)的，所以往往會涉及到三種選擇性問題。?除了本身允許進行選擇性反應(yīng)的部分底物外，最理想的實現(xiàn)高選擇性合成的途徑是采用高選擇性反應(yīng)，因此尋找高選擇性的有機反應(yīng)（試劑）是當前有機合成方法學(xué)研究的主要課題。?另外，合成中也存在不少缺乏有效選擇性反應(yīng)的場合，于是不得不采用迂回的方法，如采用保護基團、潛在官能團或合成等當體的方法，甚至改變合成路線采用其它合適原料等。四、（能夠?qū)崿F(xiàn)）選擇性反應(yīng)（的試劑）1.羥基的選擇性反應(yīng)烯丙基及節(jié)基位羥基的選擇性氧化MnO2

（新制）1.1.2

Ag2CO31.2

伯羥基的選擇性氧化伯羥基和仲羥基同時存在時，可選擇性被氧化。例如在祐存在下氧氣即可選擇性氧化伯羥基為竣酸，上例子中在氧化后又隨即發(fā)生內(nèi)酯化反應(yīng)生成最后的產(chǎn)物。2.

粉基的選擇性反應(yīng)在一般條件下，醛基的活性要高，通常優(yōu)先發(fā)生反應(yīng)；但某些情況下也可以獲得相反的選擇性。通常認為，在這些條件下，醛基作為水合物被保護起來，這種水合物通過與鈾離子絡(luò)合而被穩(wěn)定。在分離出產(chǎn)物后可以使醛基再釋放出來。3.雙鍵順反式的選擇性控制3.1

通過快煌的立體控制性還原通常,順式烯煌主要通過非均相催化氫化獲得；而化學(xué)還原法則大都以反式選擇性為主。Na.

NH3(I)tBuOH80-90%,all

E反式烯燒的生成與反應(yīng)歷程有關(guān):Zselective

reduction

ofalkynes

uses

Lindlar's

catalyst79%

yield,

all

ZH

H%/VV\A/VVVV\/V'catalyst

surface3.2

Wittig型反應(yīng)醛經(jīng)Wittig反應(yīng)生成烯煌的立體化學(xué)與ylide的性質(zhì)有關(guān),穩(wěn)定ylide以E式產(chǎn)物為主，而不穩(wěn)定ylide主要生成Z式產(chǎn)物。bombykol92%

yield79%

yieldZ

double

bond

by

reduction

of

alkyne—Zdouble

bond

by

Wittig

reaction。乂+

10-15%

￡

isomer咨80-90%

yield.

Z

isomer

onlyIn

this

case,

the

Wittig

reaction

is

not

entirely

Z-selective,

and

it

generates

some

E-isomer,Lindlar-catalysed

reduction,

on

the

other

hand,

generates

pure

Z-alkene.例二impossible

Grignard

reagentH2Otie

benzyl

(Bn)

protecting

groupNaHOTHPHsO*1HP

removed

In

acid0n

survl^s

acidBn

survives

baseHa,

Pd/C產(chǎn)物例四Flexibilene,

found

in

a

marine

coral,

hasanunusual15-membered

ring

structure.19;

76%

yield

from

16

+

1813;

flexibilene,

52%

yield2826a30quinolinesynthesis283132合成3032OH34pyrrohdtiwAcHN例六4、通過加入活化官能團實現(xiàn)選擇性反應(yīng)i.ho*/h9o2.H，.heat>

TM(7)鄰二醇類化合物在酸催化下，失去一分子水重排生成醛或酮的反應(yīng)，稱為Pinacol重排反應(yīng)。pinacolHOOH0MMepinacolone70%

yield反應(yīng)機理:oxygen*s

lone

pair??a

HO：becomes

involved,stabilizing

the

newpositive

charge加Memethylmigration1black

bond

breaksgreen

bond

forms對于不對稱二醇，傾向于生成更穩(wěn)定的碳正離子中間體:H2s0499%

yieldthis

benzyiic

cation

is

morestable

and

is

formed

fasterthis

product

isformedItiis

product

isnot

formedChemoselectivity

by

Reagent:

The

Pinacol

RearrangementHOpinacol'pinacolone1Treatmentof

the

unsymmetrical

diol

49

with

acid

leads

to

loss

of

OH

from

what

would

be

the

more

stable

/-alkyl

cation

and

hence,by

hydrogen

shift,

to

the

ketone

51.如何得到？The

alternative,

more

interesting

rearrangement

to

give

53

can

beinitiated

by

tosylation

of

the

diol

49

in

weak

base.

It

is

impossible

totosylate

tertiaryalcohols

under

these

conditions,

asboth

the

t-alcohol

and

TsCl

are

large,

so

only

the

secondary

alcohol

becomessulfonylated

and

so

leaves,

and

the

rearranged

ketone

53

is

the

onlyproduct.In

Corey's

longifolene

synthesis,

the

fused

enone

54

was

animportant

intermediate.

Synthesis

from

the

readily

availableRobinson

annelationproduct

57

is

very

attractive,

but

this

demandsa

ring

expansion

step

such

as

the

pinacol

rearrangement

of

55

ofunknown

selectivity.1,2-Diols

such

as

55

normally

comefrom

the

hydroxylation

of

analkene,

in

this

case

the

diene

56

which

might

be

made

by

a

Wittigreaction

on

the

dione

57.Every

step

in