多肽合成中困难序列的缩合研究进展(5)

发布时间:2021-06-08

非常详细的综述性文章

HANXiang.etal:Recent

progress

intheimprovementofthecouplingefficiencyof‘‘difficultsequences’’in

peptidesynthesis

methane)一polarsolvents

clearly

indicatedthatthe

solubilityofpeptides,such

as

Boc—Leu9-OBzl,with

卢-sheet

structure

in

organicsolventswasindependentof

thepolarityofsolventsbutwasstronglydependenton

theirhydrogen

donating

and

accepting

ability.The

hydrogenbonding

between

peptide(P)and

solvents

(S)suchas(P)N—H…O=C(S),(P)N—H…O=S(S),(P)N—H…O=P(S),and(P)C=O…H—O(S)

shouldbethebase

on

which

8.sheetstructureis

formed.Inthesubsequentstudy.Cilli

et

al[24]

demonstrate

that

the

8-sheet

structure—disrupting

potentialofhydrogen -donorand--acceptorsolventsisingoodrelationship

with

theirelectron—acceptor

and

—donor

numbers(ANand

DN)respectively.They

foundthattheANorderofhydrogendonorsolventsisarranged

as:HFIP(hexanuoroisopropan01)

>PhOH

(phen01)>TFE(2,2,2-trifluoroethan01)>AcOH

(aceticacid)>MeOH(methan01)>EtOH(ethan01)>

nBuOH(凡一butan01)>iPrOH(isopropan01),and

in

theDN

order

of

hydrogen

acceptor

solvents,HMPA

(hexamethylphosphoramide)>DMSO>TMP(1,1,

1一tri(hydroxymethyl)propane)>NMP(N—methyl一2一

pyrrolidone)>DMF(N,N—dimethylformamide),and

thetendenciesofANandDNwerelarger,theirp—sheet

structure

disrupting

potential

become

higher.Among

the

solvent

systemstested[22I.amixture

of

TFE

or

HFIPand

TCM(trichloromethane)or

DCMwasfound

to

bemostpowerfulfordissolvingthesparingly—soluble

protectedpeptides.

It

is

obvious

thatcombinationsof

homogenous

solvents(all

are

AN

or

DN)areonlysuitable

for

solubility

improvement,and

those

ofheterogeneous

(AN+DN)oneswould

not

beeffective.Asa

matter

offact,theprincipleof

usinghomogeneous

mixed

solventsforsolubility

improvingwas

employed

years

beforein

the

synthesis

of

BovinePancreaticRNase

A[25|.TheeffectofchaotropicsaltsPossibly

chaotropic

salts[26j

decrease

secondary

formationin

growingpeptide

chainandalso

perturbpotentialinteractionsbetweenthe

peptideandresin,exposing

the

N—terminal

to

the

coupling

ideahasbeentestedfirstbyusing

urea.

thegrowingpeptidechaininthelength

rangeof

residues

from

the

resin,thecompleteness

of

Boc—Glnas

thecarboxyliccomponent,via

an

ester,wasenhanced

from

70%(nourea)to

100%(with1.5mol L—ureainDMF).But

carbodiimide)coupling

procedure.Recently,Kliset

alcomparedtheeffectofthreekindsofchaotropicsalts

KSCN,NaCl04and

LiBr,on

the

coupling

reaction

between

Boc Thr(Bzl)and

NH2一Ala—Ala—Ala—Lys

(C1Z)一Phe—Leu—Arg(Tos)一Ala—His(Bom)一Ala—MBHA

resin.Theyfoundthatcouplingrunningin0.4mol

L“KSCN(orNaCl04)in

DMFwascompletein1h.

Whileunderstandardcondition(nochaotropicsalt)

thereaction

rate

wasvery

slow,andcouplingwas

not

complete(Table1).

Table1The

effectofchaotropic

additive+on

the

complete

coupling(%)一ofBoc—T(Bzl)to

AAAK

(C1Z)FLR(Tos)AH(Bom)A-MBHAresin

‘0.4mol L。1Additivein

DMF/DCM(1:1);一Estimated

byquantitativeninhydrin

test

In

Alacoupling,LiBrwas

as

effective

as

KSCN.They

declared

that

for

difficultcouplings

of

other

residuestheeffectofaddingchaotropicsaltsduringor

precedingthecouplingstepwas

even

moreclearer.

SwellingstateimprovementoftheresinAnumber

of

factors

affect

the

resin

swelling.

Somelabsfoundthatelevatedtemperaturecouldforcecoupling

to

completion。2“.Itis

conceivablethatthe

higherthetemperature

is,thelargerthespaceinthe

resinmatrixshouldbe.Solvation

isanother

essentialfactor

to

affeetthe

swellingstateofresin[28].

Itwas

foundthatthe

swellingratioofBoc--Glu--Glu.-Glu--Leu--

Leu—Trp(Nps)一Phe—OCH2一polystyrene

in20%TFE/

DCMwas2timesofthatinDCMalone,andthatthe

average

couplingcompleteness

of

five

followingLys

residueswerequitedifierent:99.7%(in20%TFE/

DCM)and98.3%(inDCM).The

effectofthe

peptideloadingandsolvent

system

in

SPPShasbeenstudiedbyHRMAS—NMR(high

resolutionmagic

anglespinningnuclear

magnetic

resonance)[29.

Strong

peptide

chain

aggregationwas

observed

mainly

in

highlypeptide

loadedresinswhensolvatedin

CDCl3.

Conversely,dueto

thebetter

swellingofthesehighly

loaded

resins

in

DMSO,the

relevant

sequence—

dependentconformationalalterationswere

detected.Tayloret

al。”。investigated

the

relationshipbetween

solvent

properties

and

solvationof

the

resin

and

structurethe

reaction.ThisWhen6—1couplingactivenear

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