methods and design in organic synthesisdiposit.ub.edu/dspace/bitstream/2445/134177/6/4.3. fg... ·...
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methodsanddesigninorganicsynthesis
2018-19Master Course
PereRomea
inOrganicChemistry
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4.3.Functionalgroups
Rubik’scube
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JustONEfunctionalgroupdisconnectionR X
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NR2
Amine
OR
AlcoholEther
SR
ThiolThioether
N3
Azide
NR
Imine
O
AldehydeKetone
N
Nitrile
Asingleheteroatomboundtothebackbone
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R
OH
R
O
H R
O
OH
oxidation oxidation
reductionreduction
primaryalcohol aldehyde carboxylicacid
R R
OH
R R
O
R OR
Ooxidation oxidation
reductionreduction
secondaryalcohol ketone ester
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alcohols?
OHNH2
amines?
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OHNaturalchargedistribution
Alkylad0
OHOH
Alkylda3
OH OHR
Alkylad2
OH OHAlkylda1
OHOH
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OHNaturalchargedistribution
OHOH
X
X:halide,sulfonate
OH OR
OH O X
X:halideEnolate
OHO
HHM
X:Li,MgCl
SN2
IonicAdditionstoCarbonyls
AlkylationofEnolates(orEnamines)
Michael
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OHNaturalchargedistribution
OHOH
X
X:halide,sulfonate
OH OR
OH O X
X:halideEnolate
OHO
HHM
X:Li,MgCl
SN2
IonicAdditionstoCarbonyls
AlkylationofEnolates(orEnamines)
Michael
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?Ph HN O O PhJabbatheHuttStarWars
ICI-D7114 intermediate anti-obesity treatment
SeeChapter2.Concepts(II)
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route A
problem
Chemoselectivity
PhHN O
O Ph
PhHN O
O Pha
SN2
PhHN
O
OH
PhHN
O
O
PhHN
O
O Ph
Base
Br Ph
-
route B
PhHN O
O Ph
PhHN O
O Phb
StabilityChemoselectivity
problem(s)
SN2
OH
HO HO
O PhBr Ph
Base O
O PhBr Ph
Base
PhHN
O
O Ph
PhHN
Cl
-
route C
PhHN O
O Phc
Ph NH O
O Ph
Polyalkylation?
OH
HO HO
O PhBr Ph
Base Base
BrBr
PhHN
O
O Ph
BrO
O Ph
Ph NH2
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route D
PhHN O
O Phd
Ph HN O
O Ph
O
O PhNH3BECAREFUL!LONGWAY
Aminesarealwayssensitivefellows
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REVIEW: Synthesis of Amines
Apparently,SN2MEDIATEDALKYLATION
ofammonia,primary,secondary,ortertiaryamines
isthemostappropriatewaytoprepareamines.
HOWEVER,POLYALKYLATIONHAMPERSSUCHANAPPROACH
HN
HH
HN
HR
HN
RR
RN
RR
RN
R RR
– HX
R X
– HX
R X
– HX
R X
– HX
R X
SN2 SN2 SN2 SN2
So,keepinminddifferentoptions…
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REVIEW: Synthesis of Amines
PRIMARYAMINES
Alkyl azidesAlkyl halides Primary aminesSN2
R XN3 R N3
H2 R NH2
Reduction
N
O
OR X N
O
O
R R NH2N2H4 or OH
Alkyl halides SN2 Hydrolysis Primary amines
GabrielSynthesis
R NO2H2 R NH2
LiAlH4 R CH2NH2R C N
Reduction Reduction Primary aminesNitrilesPrimary aminesNitro
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REVIEW: Synthesis of Amines
SECONDARYAMINES
R R
ORNH2
R R
N RNaBH4
R R
N RH
ReductionImines Secondary Amines
R Cl
ORNH2 LiAlH4
R N
OR
HR N R
H
ReductionAmides Secondary Amines
TERTIARYAMINES
R Cl
OR2NH LiAlH4
R N
OR
RR N R
R
ReductionAmides Tertiary Amines
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?Ocfentanil (or A-3217) painkiller NNMeO OF Ph
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Don’tdisconnectthisnitrogen:heterocycleBUILDINGBLOCK
N
NMeOO
F
Ph
-
N
NMeOO
F
PhN
HNF
PhClMeO
O
N
NF
Ph
FGA
NH2F
N
O
PhN-Phenylethylpiperidone
a1 d0
N
H2N
F PhHowever,payattentiontotheBuchwald-Hartwigreaction
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OHNaturalchargedistribution
OHOH
X
X:halide,sulfonate
OH OR
OH O X
X:halideEnolate
OHO
HHM
X:Li,MgCl
SN2
IonicAdditionstoCarbonyls
AlkylationofEnolates(orEnamines)
Michael
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?Terfenadine derivative treatment of allergyHO PhPh N OH CO2H
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Thedisconnectionofthisalcoholproducestwofragmentsofsimilarcomplexity:
TWOOPTIONS
NHO
PhPh
OH
CO2H
a b
-
NHO
PhPh
OH
CO2H
a
NHO
PhPh
H
O
CO2H
b
NHO
PhPh
H
O CO2H
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FourindependentFG
HO
PhPh
NOH
CO2H
-
HO
PhPh
NOH
CO2H
HO
PhPh
N H
O
CO2H
Br
CN
Br
Br
CN
HO
PhPh
NH Cl O
O
NH
O
EtO2 x Ph
-
NH
O
EtO Protection
NCbz
O
EtO 2 PhMgBr HO
PhPh
NCbz
Cl O
O
NHO
O
O
PhPh
HO
PhPh
NH
Deprotection
Br
CN1) Base
2) MeI
Br
CNNaOH
Br
CO2H1) NaH
2) BuLi
Li
CO2Na
Li
CO2Na HO
PhPh
NOH
CO2H
NHO
H
O
PhPh
H3O+
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OHNaturalchargedistribution
OHOH
X
X:halide,sulfonate
OH OR
OH O X
X:halideEnolate
OHO
HHM
X:Li,MgCl
SN2
IonicAdditionstoCarbonyls
AlkylationofEnolates(orEnamines)
Michael
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?trans-Clerodane diterpenoids
antibacterial, antitumor, antifeedant activity
H
OO
H
OO
OH
H
O
Annonene Solidagolactone PL3
-
a5
Alkyl-d
H
OO
H
OO
: ORGANOCUPRATES
1) LDDB, THF, –78 °CSPhH2) CuBr·SMe2, –78 °C
3) TMSCl,O
O
4) DBU, CH2Cl2, rt,
–78 °C to rt
H
OO
43%
Overman,L.E.JACS2015,137,660
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Non-Naturalchargedistribution
d1
OH
UMPOLUNG
a1
OHX
S
S S S
d1 aldehyde
S
S
OH
OH
OH
S SO
X:halide,sulfonate
d1epoxide
OOHOHS SS
S OH
Smith,A.B.III,ACR1998,31,35;2004,37,365
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Non-Naturalchargedistribution
d1
OH
UMPOLUNG
a1
d1epoxide
d1 aldehyde
OHX
S
S S S
S
S
OH
OH
OH
S SO
X:halide,sulfonate
OOHOHS SS
S OH
Smith,A.B.III,ACR1998,31,35;2004,37,365
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?Mycoticin A antifungi agent
OH OH OHOH OH OH
HO
HO
O
O
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Theconstructionofthepolyolfragmenttakesadvantageofthesymmetry
OH OH OHOH OH OH
HO
HO
O
O
OHOH OH OHOH OH OH
HO
…andTACTICSmaybebasedontheUMPOLUNGconcept
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S S
TBS
S S
TBSTBS OBn
SS Ot-BuLiEt2O Et2O
OBnO
Et2O, HMPA
O O
BnO OBnTBSO OHOHSS SS OTBS
59%
Brookrearrangement
S OBnOTBSS
HO OTBSO OO OO O
Smith,A.B.,III.OL1999,1,2001;JACS2003,125,14445
FournewC–Cbondsinoneflask
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Non-NaturalchargedistributionOH
UMPOLUNG
a2d2organocuprate
OH O O
OH O OX
a3 d3 X:#halide,#sulfonate
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TWOfunctionalgroupswhichdisconnection?Y Cn X
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one-groupdisconnection
R O R R O R
d0 alkyl-a
two-groupdisconnection
R O R
OH
R OR
OHd0 a2
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Relationshipsbetweentwoheteroatoms
1,1-RelationshipX
O
1
YX
1
X
Y
O
Y
O
O1
21
21
21,2-Relationship
X Y
1 3
O Y
1 3
O O
1 31,3-Relationship
X
Y
O
Y
O
O1
41
41
41,4-Relationship
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1,1-relationship?esters?
X
O
ORRO
acetals?
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Consonantrelationship
X:halide,OR,NR2,SR
X
O
d0a1
ORROOR
OR
OR
O
OR
O
d0a1
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Consonantrelationship
X:halide,OR,NR2,SR
X
O
Cl
O
O
O O
SR
O
OR
O
N3
O
NH
+ N
O
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1,2-relationship?1,2-diols?
α-hydroxyketones?OH
OH1
2
O
OH12
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Dissonantrelationship
X,Y:halide,OR,NR2
X
Y
OH
OH
O
O
OBr
Br
OsO4oxidationPinacolcoupling
EpoxideopeningSN2
Epoxidesplayacrucialroleinthesynthesisof1,2-diols
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Dissonantrelationship
X,Y:halide,OR,NR2
X
Y
OH
OH
O
O
OBr
Br
OsO4oxidationPinacolcoupling
EpoxideopeningSN2
Epoxidesplayacrucialroleinthesynthesisof1,2-diols
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?O OHO
OH
RouteAone-groupdisconnection
OOH
RouteBtwo-groupdisconnection
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OOH
RouteA
problem
Siteselectivity
HOOH
Br
RouteB
OH OTACTICReactivityofepoxides
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?Propranolol high blood pressure O NOH
-
O NOH
O OH N
1,2-di
O O
C–X
OHCl O
Payattentiontothissystem
-
Cl O
Threeelectrophilicsites
13
2
C1isthemostreactiveone
HO O
O O O O
O OH
PAYNEREARRANGEMENT
-
OOCl O O OCl
O
X
OXOH
Theconfigurationofthechiralcentercanbedramaticallyaffected
Cl O O OO
X
OXOH
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Dissonantrelationship
X,Y:halide,OR,NR2
X
Y
OHO
BrO O
BrominationSN2
Inageneralway,
O OOH
O
Oxidationofenolates,enols,orenamines
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1,3-relationship?ß-hydroxycarbonyl?
ß-aminocarbonyl?
O OH
12
3
O NH21
23
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Consonantrelationship
X,Y:O,N
YX
O OH O OH
d2 a1
O OH OOR
a3 d0
-
Consonantrelationship
X,Y:O,N
YX
Aldol
O OH O O
Enolate Aldehyde
O OH OOR Oxa-Michael
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?Doxpicomine analgesic ON O
-
N O
N
O
N OH
N
OH
ACETALasourceofinstability
N O
N
ORO
OR
SYMMETRYtakeadvantage
N O
ORO
OROH
FGI
N O
ORO
OR
1,3-ConsonantAZAMICHAEL
13
Conversionofanalkeneintoanalcoholisveryuseful
FGI
O
ORO
ORN H
O
ALDOL
1,3-Consonant1
3
-
? Atropine treatment of certain nerve agents and pesticide poisoningN OO OH
-
N
O
O
OH
N
HO
HO
O
OH
ON
3
31
3
31
AHIGHLYSYMMETRICALß-aminoketone
N
O
FGI
HO
O
O
H H
1
3
ACHIRALß-HYDROXYACID
1,3-Consonant
-
ON ON
CO2H
CO2H
ON
CO2H
CO2H
1
3
3
a1 d2
FGI
Keepinmindbidirectionalsyntheses
CHO
CHO+ MeNH2
Mannichreactioncouplingofanenolizablecarbonylwithformaldehydeanda1aryor2aryamine
R
OR
R
OR
R2N
H
O
HR2NH
ß-AminocarbonylSeeChapter7
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CHO
CHO+ MeNH2 N
OH
CO2H
CO2H
OH
N
CO2H
HO2COH
N
HO
CO2H
HO2CO
N
CO2H
HO2CO
ON
-
1,4-relationship?1,4-dicarbonylcompounds?
O
O1
2
34
-
HO OHOH
HOOHHO
HO OHO
OHO OH
O
Osuccinic acid fumaric acid
OHO
Olevulinic acid
O OO
maleic anhydride
O
furan
-
DissonantrelationshipX
Y
O
O
O
CH2
FGI
O
CH2d2alkyla
O
NO2
FGI
O
NO2a3d1
X,Y:O,N
-
?from Gymnomitrion obtusumOH O
-
O O O
OH
FGI
13
1
4
BrBr
O
1) LDA, –78 to 0 °C
2) BrBr
OBr
OO
Hg(OAc)2
HCOOH
1,3-Consonant
OOO
O1,4-Dissonant
a2
Ot-BuOK
t-BuOHO
Me2CuLi
-
1,5-relationship?1,5-dicarbonylcompounds?
O O
12
3
45
-
Consonantrelationship
X,Y:O,N
X Y
O O O O
d2 a3
Enolate
OMichael
-
?Rogletimide sedative N NHOO
-
N
NH
O
O NCO2Et
CO2Et
1
5
1,5-consonantN
CO2Et
CO2Et
a3
d2
NCO2Et
NCN
FGI
NBr
CN
d1a1
NCO2Et
CO2Et
-
?Steroid skeletonO ROH
H
H HO
testosterone
H
H HO
O
progesterone
H
H HHO
Hcholesterol
HO
H
Hlanosterol
-
O
R
O
O
RobinsonannulationMichaeladditionofacarbonyltoanenone
followedbyanintramolecularaldolcondensation
O
BaseO
O
Wieland-MiescherKetoneOHO
O
1 5
1,3-consonant
O
OO
1 3
O
OO
1,5-consonant