有机合成++第6章+有机合成中的选择性

第七章有机合成中的选择性•现代有机合成中涉及的反应底物通常会带有多个官能团或多个可能发生反应的部位。•即使只在某个特定官能团或特定部位进行反应，还有可能生成不止一个的异构体产物。OH有机合成中的选择性控制至关重要一、概念反应的选择性(Selectivity)

：是指一个反应可能在底物的不同部位和方向进行，从而形成几种产物时的选择程度。paracetamol31%t-BuOK28%73%二、分类(-)按选择方式大致分为三种：1、化学选择性(Chemoselectivity)2、区域选择性(Regioselectivity

)3、立体选择性(Stereoselectivity)1、化学选择性(Chemoselectivity)不同官能团或处于不同化学环境中的相同官能团,在不利用保护或活化基团时区别反应的能力。excess

Ac?O100toluene,

refluxparacetamol不同官能团ketone

is

more

electrophilic

than

esterreactivity

towards

nucleophilesaldehydeketone不同官能团不同官能团hydrogen

adsorbedon

to

catalyst

surfacePd

metal

catalystaromatic

ring

coordinatesto

catalystreduced

by

NaBH4not

reduced

by

NaBH4amidecarboxylic

acid>

>reduced

by

LiAIH4NaBH4REtOHLIBH4EtOHstill

a

reducing

agenttriacylboratefastreactive处于不同化学环境中的相同官能团(I)(II)(III)非共辗的多烯煌的氢化受到取代基的影响，随着取代基数目的增多，反应变得比较困难，因而可以在多烯分子中有选择性地还原其中的一个双键。例如柠檬烯(I)

用氧化钳催化氢化时，在只吸收一摩尔的氢就停止反应时，能得到接近定量产率的(II)

,进一步氢化生成薄荷烷(III)

。2、区域选择性(Regioselectivity)O在一个具有两个不等同反应部位的底物上反应，试剂进攻两个可能部位及生成二个可能异构体的选择情况。如通常涉及的不对称涉基二侧a位、不对称双键或环氧两侧位置上的选择反应、a,

加不饱和体系的1,2或1,4加成以及烯丙基离子的1,3选择反应等。（注意烯胺与烯醇反应区域选择性的区别）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澳代醋酸烯丙酯的区域选择性反应Br+

NaCH(CO2Me)23、立体选择性(Stereoselectivity)是指反应在可能生成多种立体异构体时的选择情况。这个选择性又可分为两类：一类是相对立体化学或非对映选择性(diastereoselectivity

)另一类是绝对立体化学或对映选择性(enantioselectivity

)消除反应的立体化学two

stereo

isorneric

alkenes

possible95%

E-alkenesrerecisomers(geometncal

isomers)5%

ZalkeneD-A反应的立体化学dimethyi

maleateCOzMeCO^MeSimmons-Smith反应的立体化学Sininiori^Smith反应受到底物烯炸中某些位置的羟基的影响。当底物中含有烯丙基和高烯丙醇或酸的结构时•反应的速率会大大提高。五元或六元环的烯丙醇与卡宾反应后可立体专一性地得到环丙基处于与羟基顺式位的产物。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看马酸项两个可能产物为对映异构体，且其中的一个是过量的，为对映选择性反应。三、（能够进行）选择性反应的底物1、被选择的两方面有质的不同elimination

of

diastereoisomer

B不同异构体的反应性差别：反应活性不同；反应的区域选择性不同。为什么？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.有机合成中的选择性1、化学选择性(Chemoselectivity)2、区域选择性(Regioselectivity)3、立体选择性(Stereoselectivity)•在一个结构较为复杂的有机分子合成中，由于合成过程涉及的中间体常是多官能团的，而目标化合物又都是具有特定结构的，所以往往会涉及到三种选择性问题。•除了本身允许进行选择性反应的部分底物外，最理想的实现高选择性合成的途径是采用高选择性反应，因此寻找高选择性的有机反应（试剂）是当前有机合成方法学研究的主要课题。•另外，合成中也存在不少缺乏有效选择性反应的场合，于是不得不采用迂回的方法，如采用保护基团、潜在官能团或合成等当体的方法，甚至改变合成路线采用其它合适原料等。四、（能够实现）选择性反应（的试剂）1.羟基的选择性反应烯丙基及节基位羟基的选择性氧化MnO2

（新制）1.1.2

Ag2CO31.2

伯羟基的选择性氧化伯羟基和仲羟基同时存在时，可选择性被氧化。例如在祐存在下氧气即可选择性氧化伯羟基为竣酸，上例子中在氧化后又随即发生内酯化反应生成最后的产物。2.

粉基的选择性反应在一般条件下，醛基的活性要高，通常优先发生反应；但某些情况下也可以获得相反的选择性。通常认为，在这些条件下，醛基作为水合物被保护起来，这种水合物通过与铀离子络合而被稳定。在分离出产物后可以使醛基再释放出来。3.双键顺反式的选择性控制3.1

通过快煌的立体控制性还原通常,顺式烯煌主要通过非均相催化氢化获得；而化学还原法则大都以反式选择性为主。Na.

NH3(I)tBuOH80-90%,all

E反式烯烧的生成与反应历程有关:Zselective

reduction

ofalkynes

uses

Lindlar's

catalyst79%

yield,

all

ZH

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

surface3.2

Wittig型反应醛经Wittig反应生成烯煌的立体化学与ylide的性质有关,稳定ylide以E式产物为主，而不稳定ylide主要生成Z式产物。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产物例四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、通过加入活化官能团实现选择性反应i.ho*/h9o2.H，.heat>

TM(7)邻二醇类化合物在酸催化下，失去一分子水重排生成醛或酮的反应，称为Pinacol重排反应。pinacolHOOH0MMepinacolone70%

yield反应机理:oxygen*s

lone

pair・•a

HO：becomes

involved,stabilizing

the

newpositive

charge加Memethylmigration1black

bond

breaksgreen

bond

forms对于不对称二醇，倾向于生成更稳定的碳正离子中间体: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