多肽合成中困难序列的缩合研究进展(5)
发布时间:2021-06-08
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
a
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
a
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
3
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.
7
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
6
structurethe
reaction.ThisWhen6—1couplingactivenear