6. functional group interconversion - ubdiposit.ub.edu/dspace/bitstream/2445/61063/26/6. organic...
TRANSCRIPT
2014-2015 Autumn Term
6. Functional Group Interconversion
Sky and Water IMaurits Cornelis Escher, 1938
Dr. Pere Romea Department of Organic Chemistry
Organic Synthesis
Carbon Backbone & Functional Groups
The synthesis of an organic compound must pay attention to ...
Functional groups
Functional Group Interconversion (FGI)
I. Nucleophilic Substitutions
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
III. OxidationsMechanism!!!
Carbon backbone
(Chapters 2–4 )
2Pere Romea, 2014
Nucleophilic Substitutions
The nucleophilic substitutions involve
the interconversion of functional groups bound to sp3 carbonis
Csp3
Nucleophile Leaving group
RX
Electrophile
Chap. 15
X+ Nu
Nu+ X
3Pere Romea, 2014
Nucleophilic Substitutions
Two model mechanisms, called SN1 i SN2,
are used to explain the nucleophilic substitutions
Unimolecular (SN1) or bimolecular (SN2) nucleophilic substitution?
X+ Nu
Nu+ X
A slightly different model, called SN2’, may be useful in substitutions on allylic substrates
+ Nu + XX Nu
4 Pere Romea, 2014
Nucleophilic Substitutions and FGI
5
There are three main sources to carry out FGI through nucleophilic substitutions: sulfonates, alcohols, and alkyl halides
NuR–OSO2R’ R–NuSulfonates
R–OH R–NuNu
Alcohols
R–NuR–XNuAlkyl halides
X: I, Br, Cl
Pere Romea, 2014
Nucleophilic Substitutions and FGI
A wide array of structures can be synthesized from sulfonates and alkyl halides through
nucleophilic substitution of X = OSO2R, I, Br, Cl in C–C bond forming reactions and FGI
R X
R Y
R SR
R OH
R OR
RO R
O
R SH
Y
RSHor RS
H2Sor HS
H2Oor OH
ROHor RO
O R
O
RR
NR
R N3
R NH2
NH3
N3
CN
R
6Pere Romea, 2014
Nucleophilic Substitutions and FGI
R–OSO2R’ R–NuNuSulfonates
R–OH R–NuNu
Alcohols
R–NuR–XNuAlkyl halides
X: I, Br, Cl
7
How easy is to interconvert sulfonates, alcohols, and alkyl halides?
Pere Romea, 2014
Alcohols and Sulfonic Esters
Conversion of alcohols into sulfonic esters
– Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance
– The reaction does not affect the C–O bond: the configuration of the carbon remains the same
– Mesylates and tosylates are largely employed. Triflates are the most reactive sulfonates
– Rearrangements of the carbon backbone are not frequent
OH
MeMe
H
TsCl, pyr
Me
Me
Mesyl chlorideTosyl chloride
Triflic Anhidride
MsCl
TsCl
Tf2O
MeSO2Clp-MePhSO2Cl(CF3SO2)2O
MesylateTosylateTriflate
OH+ RSO2Cl or (RSO2)2O
OSO2R
pyridine
CH2Cl2 or Et2O0 °C – rt
8 Pere Romea, 2014
Sulfonic Esters and Alkyl Halides
Conversion of sulfonate into alkyl halides
SN2
X
OH X X: Cl, Br, I
OH
Pr
1) MsCl, Et3N, CH2Cl22) LiCl, DMF
Cl
Pr83%
PhOH
1) TsCl, pyr, CH2Cl22) LiBr, DMF
89%Ph
PhBr
Ph
TBDPSO OH1) MsCl, Et3N, CH2Cl2
2) Lil, acetone
94%
TBDPSO I
9 Pere Romea, 2014
Alcohols and Alkyl Halides
Conversion of alcohols into alkyl halides
R–OH
R–OSO2R’
R–X
X–
Sulfonates
Alcohols
Alkyl halidesX: I, Br, Cl
?
R’SO2Cl
10 Pere Romea, 2014
Alcohols and Alkyl Halides
Conversion of alcohols into alkyl halides
OH X X: Cl, Br, I
11
HCl conc
HCl/ZnCl2 (Lucas reagent)PCl3SOCl2, 1,4-dioxaneSOCl2, non nucleophilic solvent
Tert
Prim & SecPrim & SecPrim & SecPrim & Sec
SN1 (racemization)
SN2 (inversion)SN2 (inversion)SN2 + SN2 (retention)SN2 (inversion)
HBr conc
HBr conc, ∆PBr3
Tert
PrimPrim & Sec
SN1 (racemization)
SN2 SN2 (inversion)
P/I2 Prim & Sec SN2 (inversion)
Reagents & Conditions Alcohols Mechanism
Pere Romea, 2014
Alcohols and Alkyl Halides
Problem! Too harsh experimental conditions: mixture of mechanisms and transpositions
SN1
H
Br
OH OH2
Br
Br
Br86% 14%
OHH
OH2Br
BrsingleSN2
OHH
OH2Cl
Cl
single12Pere Romea, 2014
Alcohols and Alkyl Halides
More selective transformations are required …
The most used options are based on the conversion of alcohols into alkoxyphosphonium salts,
highly reactive in SN2 substitutions
Ph3P + E–Nu Ph3PNu
EPh3P E + Nu
Ph3P E + Ph3P + HE
Alkoxyphosphonium salt
HHO
HO
Ph3PH
O + Nu Ph3P=O +H
Nu
Alkoxyphosphonium salt13 Pere Romea, 2014
Alcohols and Alkyl Halides
Ph3P / X2 : Ph3P / I2, Ph3P / Br2, Ph3P / Cl2
Ph3P + Br–Br Ph3PBr
BrPh3P Br
+ Br
– Br
HHOPh3P Br Ph3P
– HBr
HO+
Br
– Ph3P=O
HBr
SN2
OHBrPBr3Br
Br
+ +
11% 26% 63%
Ph3P/Br2Br
90%
This transformation is very useful for secondary alcohols and those systems that easily produce transpositions, as neopentylic alcoholsThe control on the configuration is very good.
OO ROH
Ph3P, Br2
85%
OO RBr
OH
OMe
OBn
Ph3P, I2
ImidazoleEt2O, rt
I
OMe
OBn96%14
Alcohols and Alkyl Halides
Since chlorine (Cl2) is a gas difficult to handle ....
Ph3P + Cl–CCl3 Ph3P ClH
HO– CCl3 Ph3P
HO
Cl
– Ph3P=O
HCl
– HClcarbon tetrachloride
Ph3P + ClCCl3
O
Cl Cl
ClCCl3
Cl
O
hexachloroacetone
OHPh3P/Cl2
Cl
92%
OH ClPh3P/CCl4
70%
OH ClPh3P/CCl3COCCl3
99%
15 Pere Romea, 2014
Nucleophilic Substitutions and FGI
R–OH R–Nu
R–OSO2R’ R–Nu
R–NuR–XNu
Nu
NuSulfonates
Alcohols
Alkyl halidesX: I, Br, Cl
16 Pere Romea, 2014
Carbon Nucleophiles
R C CHR CN
R X R OH
+ C + 2 C
R NH2 R OH R H R Me
O O O
Amine 1 Carboxylic Acid Aldehyde Methyl ketone
Red LiAlH4
Red DIBALH
Hydrolisis H3O+
Hydration cat Hg2+, H2O
Attention! Alkyl halides are very useful forthe construction of C–C bonds
17 Pere Romea, 2014
Nitrogen Nucleophiles: Primary Amines
The alkylation of ammonia, NH3, is not easy ...
NH3R X
R NH3 X R NH2
– HX
+ HX
R XR2 NH2 X R2 NH
– HX
+ HXR NH2
R XR3 NH X R3 N
– HX
+ HXR2 NH
R XR4 N XR3 N
Primary Amine
Secondary Amine
Tertiary Amine
Ammonium Salt
Such an alkylation only becomes efficient when the resulting amine is much less nucleophile than the initial one,
for steric or electronic reasons
NH NCO2Et
CO2EtBr1)
2) NaHCO3
CO2Et
H2N
CO2Et
NH
R
1) RCH2Cl
2) NaHCO3
R: C15H3118 Pere Romea, 2014
Nitrogen Nucleophiles: Primary Amines
Potassium phthalimide, PhthNK
N
O
O
KBr
Ph N
O
O
Ph NaOH
95%H2N Ph
Potassium phthalimide, pKa 8.3
SN2Gabriel synthesis of amines
The azide anion is an excellent nucleophile that participates in a large number of SN2 processes
The reduction of the azide group affords a primary amine
Azide, N3–
BuI NaN3
DMSO, Δ BuN3
90%
BuNH2
OTBDPSOH
O O1) MsCl, Et3N
2) NaN3, DMF
85%
OTBDPS
O O
N319
Nitrogen Nucleophiles: Primary Amines
Mitsunobu conditions: Ph3P / DEAD / HN3 or DPPA [(PhO)2PON3]
HOH
HN3
Ph3P, N N CO2EtEtO2C
HN3 o (PhO)2PON3,
HO PPh3N3
HN3 + O=PPh3
N NCO2Et
EtO2C
Ph3P
N NCO2Et
EtO2C
Ph3P
HOH
N NCO2Et
EtO2C
Ph3PN
EtO2CN
H
CO2Et
HO PPh3 +
NEtO2C
NH
CO2Et HN3(PhO)2P
N3
O
N(PhO)2PO
EtO2CN
H
CO2EtN
H
EtO2CN
H
CO2Et+ N3N3 +
DPPA
20 Pere Romea, 2014
Nitrogen Nucleophiles
R NH2R N R1
O
H
R N3
Amine 1Amide Azide
R OH
R X R OSO2R'
Reduction LiAlH4, H2 cat, Ph3P/H2O
Mitsunobu Ph3P/DEAD/ HN3 or DPPA
SN2 N3
–SN2
Phthalimide
N OHO
Bn
O O
N N3O
Bn
O O
N NH
O
Bn
O O
Ph3P, DEAD, HN3
97%
CH2Cl2, 0 °C
1) H2, Pd/C, THF/MeOH/TFA, ta
97%
2) PhCOCl, Et3N, CH2Cl2, 0 °CPh
O
21
Oxygen Nucleophiles: Alcohols
The most simple nucleophile: H2O / OH–
X OHH2O, OH–
X: Cl, Br, I
This is a rare transformation in which...
... tertiary halides, R3C–X, react with H2O (solvolysis) through SN1 and
... the secondary and primary ones, R2CH–X i RCH2–X, with OH–/H2O through SN2
In both situations E1 and E2 eliminations are competing reactions
Me
NC
Cl2
hν
NC
Cl
NC
OHK2CO3
H2O
85%Radical chlorination
No eliminations can occur at this benzylic position
22 Pere Romea, 2014
Oxygen Nucleophiles: Ethers
Alkoxydes, RO–: Williamson Synthesis
Only on 1ary substrates to avoid E2 eliminations
SN2
... and the most successful deconnections are applied to activated systems
1) NaH, THF
2) BnCl, Δ
95%
O
O
O
BnO
O
OH
O
O
O
HO
O
OH
NO2
OHNO2
OBuBuBr, K2CO3
H2O
80%
HX
HRO
RO–
X: Cl, Br, I
R1 OR2 R1 O
ArO + MeX o BnX+ XCH2R
2
23 Pere Romea, 2014
Oxygen Nucleophiles: Esters
Carboxilates, RCO2–
SN2
They are usually applied to 1ary substrates to avoid E2 eliminations
OO
OBr
O
OBr
BrOK 18-crown-6+
95%
O
O
O
O
OCO2H O
O
O
O
OCO2Me
MeI, KF
84%
DMF
Attention: interconversion of carboxílic acids and derivatives
why KF?
HX
HRCO2
RCO2–
X: Cl, Br, I, OSO2R
24
Mitsunobu conditions: Ph3P / DEAD / RCO2H
Oxygen Nucleophiles: Esters
SN2H
OHH
RCO2Ph3P, N N CO2EtEtO2C
RCOOH
N NCO2Et
EtO2C
Ph3P
N NCO2Et
EtO2C
Ph3P
HOH
N NCO2Et
EtO2C
Ph3PN
EtO2CNH
CO2Et
HO PPh3+
RCO2H
NH
EtO2CNH
CO2EtRCO2
HRCO2
CO2MeOH
OCO2Me
PhCO2
O
Ph3P, DEAD
89%
PhCO2H25Pere Romea, 2014
Configuration inversion
Oxygen Nucleophiles
HOH
HRCO2
HOSO2R'
HHO
HOH
HRCO2
HHO
Hidrolysis OH–
Mitsunobu Ph3P/DEAD/RCO2H
Hidrolysis OH–
SN2 RCO2
–
MeOH
PhOH
PhO
O
O2NPh
OH
KOH
99% overall
p-O2NPhCO2H
Ph3P, DEAD
26 Pere Romea, 2014
Phosphorus Nucleophiles: in Route to Wittig Reactions
R1CH2–X + PR3
X
R1CH2–PR3 R1CH–PR3 R1CH PR3
B
Phosphines are excellent nucleophiles because
they are less basic than amines and the phosphorus atom is very polarizable.
Moreover, E2 reactions do not compete with SN2 because they are weak bases
phosphinephosphonium salt
phosphorus ylide
Attention: Wittig reaction
BrOEt
O
Ph3P + Ph3POEt
O
Br
NaOH Ph3POEt
O
BrOPhPh3P + Ph3P
OPhBr
BuLi Ph3POPh
Ph3P OPhAttention: no E2 occurs27
Phosphorus Nucleophiles: in Route to Wittig Reactions
Phosphites are also good nucleophiles and react with alkyl halides:
Michaelis-Arbuzov reaction
alkylphosphonatephosphitealkyltrialkoxyphosphonium halide
Attention:Horner-Wadsworth-Emmons reaction
(R2CHO)3P + R1–XH O
RR
POCHR2
OCHR2R1
X(R2CHO)2
PR1
O
BrOEt
O
(EtO)3P + (EtO)2POEt
OEtO
O
EtBr
Δ(EtO)2P
OEt
OO
(EtO)2POEt
OO
(EtO)2POEt
OO
28Pere Romea, 2014
Sulfur Nucleophiles: Thiols
The easiest option is troublesome ...
R–X + HS R SH R S S RRR–X–H
+H
Bri-Pr
Hi-Pr SAcH
AcSCs
DMF
84%
1) Thiourea
2) NaOH
80%
C10H21HS
C10H21Br
thioacetate
thiourea
H S
H S
X H H SH
H2N NH2
S
S
O
O
NH2
NH2 NaOH
NaOH
or LiAlH4
29 Pere Romea, 2014
Sulfur Nucleophiles: Thioethers
Thiolates are the best option since they are excellent nucleophiles ...
R1–SH + OH R1 S S R2R1X–R2
NaOHSH S S
Br
95%
N
O
HO
Me
OMeN
O
MsO
Me
OMeN
O
BnS
Me
OMe
MsCl, Et3N
CH2Cl2100%
BnSH, K2CO3
CH3CN
80%
Weinreb AmideO
BnS
EtMgBr
30 Pere Romea, 2014
Carbon Backbone & Functional Groups
The synthesis of an organic compound must pay attention to ...
Functional groups
Functional Group Interconversion (FGI)
Mechanism!!!
Carbon backbone
(Chapters 2–4 )
Chap. 19I. Nucleophilic Substitutions
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
III. Oxidations
31Pere Romea, 2014
Hydroboration of C=C
Borane, BH3, as a reacting species
HBH
HH
HBH
H BHH2
RXR
HB
X
HH
RR
Lewis Acid
Lewis Base
H3B· SMe2
H3B· OEt2 H3B· THF
HOMO Cyclic transition state4 centers, 4 electrons
The regiochemistry for the addition of BH3 to an olefin is controlled by steric as well as electronic factors:the boron atom binds to the less substituted carbon atom
LUMO
syn Addition
CC
π
H BHH
CCCC
B HH
HCC
BH2HBH3
δ+
δ+δ−
δ−
32 Pere Romea, 2014
Hydroboration of C=C
Additions of BH3 to olefins produce boranes
R
RBH2 R
B
H
R RB
R
R
BH3R R
Alkylborane Dialkylborane Trialkylborane
BH2+ BH3
B+ BH32
H
B+ BH33
B+ BH3
H
– The appropriate choice permits to obtain a wide array of alkylboranes
9-BBN
ThxBH2
Sia2BH
33Pere Romea, 2014
Hydroboration of C=C
– Steric effects rule the reactivity
H
H
R
H
H
H
R
R
H
R
R
H
R
H
R
H
> >> R
H
R
R
> R
H
R
R
>
... the regioselectivity,
BH3
Sia2BH
9-BBN
94
99
99.9
80
98
98.5
99
99.5
57
97
99.8
... and the stereoselectivity
% atack Bto the less substituted
carbon atom
BR2
HBR2
HR2BH
BH3
9-BBN
+
72
97
28
334
Hydroboration of C=C
Protonolysis: synthesis of alkanes
Trialkylborane Alkane
BH3R RB3
RCO2H RH
3Δ
Conversion of trialkylboranes into alcohols: H2O2/NaOAc, ...
R
BRR
HO O
R
BO R
R
HO
R
BRROHO–
OR
BORRO
HO3 ROH
– BO33
Borate
– The migration does not produce the inversion of the configuration
Hidrolysis
OHH
1) B2H6
2) H2O2, OH–
85%
It looks likean anti-Markovnikov hydration
with a syn stereochemistry
35 Pere Romea, 2014
Hydroboration of C=C
Hidroboration of alkynes
Alquè Z
R2R1L2B H L2B
R1 R2
H
RCO2H
Δ
H
R1 R2
H
H2O2, OH– HO
R1 R2
H
R1
O R2
H2O (HO)2B
R1 R2
H
Vinilboronic acid
OB
OH1)
2) H2OB
OH
OH
Br
Pd(0) cat
75%
Suzuki Coupling36 Pere Romea, 2014
The moneychanger and his wifeMarinus Claesz van Reymerswaele, 1539
2014-2015 Autumn Term
6. Functional Group Interconversion
Dr. Pere Romea Department of Organic Chemistry
Organic Synthesis
Carboxylic Acids and Derivatives
Carboxylic acids
R1 L
O
R1 OH
O
Derivatives of carboxylic acids
R1 Cl
O
R1 O
O
R1 OR2
O
R1 N
O
R2
O
R2
R3R1 N3
O
R1 SR2
O
Acid chloride Anhydride Acyl azide Thioester Ester Amide
All these FG participate in reactions that can be understood using
the addition-elimination mechanism
R1 C N Nitrile
2 Pere Romea, 2014
Addition-Elimination Mechanism
Addition-elimination mechanism
R1 L
O
Nu
R1 L
ONu
R1 Nu
O
+ L
EliminationAddition
The requirements for a smooth process are …
a) RCOL must be a good electrophile,b) Nu must be a good nucleophile,c) L must be a better leaving group than Nu
Remember: “The lower the pKa (HL), the better the leaving group”
If the system is not reactive enough, it must be activated ...
Trigonal Planar
Tetrahedral Trigonal Planar
3 Pere Romea, 2014
Addition-Elimination Mechanism
Activation with a Lewis Acid, LA, ...
R1 L
O
R1 L
OLA
LA
NuH
R1 L
OHNuLA
R1 LH
ONuLA
R1 Nu
OLA
R1 Nu
O–LA–LH
EliminationAdditionActivation
Remember: Fischer esterification
Activation with a Lewis Base, B, ...
R1 L
O
R1 B
O
NuH
R1 B
ONu
R1 Nu
O–B–L
B EliminationAdditionActivation
Remember: synthesis of esters by addition of alcohols to acid chlorides in the presence of DMAP
4 Pere Romea, 2014
Addition-Elimination Processes
R1 Cl
O
R1 O
O
R1 OR2
O
R1 N
O
R2
O
R2
R3
R2CO2–
R2OH
R2R3NH
R2OH
R2R3NH
R2CO2–
Chap. 16
R1 OH
O
H2O
H2O
H2O
H2O
Very easy
Easy
Moderate
Difficult
Chap. 10
5 Pere Romea, 2014
Addition-Elimination Processes
R1 Cl
O
R1 O
O
R1 OR2
O
R1 N
O
R2
O
R2
R3
R2CO2–
R2OH
R2R3NH
R2OH
R2R3NH
R2CO2–
R1 OH
O
?
Chap. 16
?
?
?
Chap. 10
6 Pere Romea, 2014
Acid Chlorides from Carboxylic Acids
Via SOCl2 o PCl5
Via (COCl)2
Useful for systems sensitive to acid media.
It is usually used with the sodium salt (neutral media) or with catalytic amounts of DMF.
NN
O
O Bn
O
HOCO2Na
NN
O
O Bn
O
HOCOCl
(COCl)2
83%
OH
O
Cl
OSOCl2
85%
PCl5
93%O2N
OH
O
O2N
Cl
O
7 Pere Romea, 2014
Anhydrides from Carboxylic Acids
Regioselectivity in the nucleophilic attacks to anhydrides
R1 O R1
O O
Nu
Regioselectivity is not a problem for
the symmetric anhydrides
In mixed anhydrides the R2 group must prevent
the nucleophilic attack
R1 O R2
O O
Nu
Yamaguchi Method
The mixed anhydrides are usually prepared quantitatively from acid chlorides or other anhydrides.They are not isolated.
R1 O
O O
Nu
Cl
ClCl
R1 O
O O
Nu
O
O
PMBO
PMBO
OPO
(OMe)
O
HBnO
HO
O
OBnH
95%
8
O
OH
PMBO
PMBO
OPO
(OMe)
O
O
PMBO
PMBO
OPO
(OMe)
O Cl
Cl Cl
Et3N, DMAPTHF–PhMe, rt
Cl
O Cl
Cl Cl
NuPere Romea, 2014
Esters from Carboxylic Acids and Derivatives
The retrosynthetic analysis shows two ways of deconnecting the ester group ...
R1 OR2
O
R1 L
O
+ HOR2
R1 O
O
+ R2–Xb) a)
Addition-elimination Processes
– Fischer Esterification
– Using coupling agents as carbodiimides
– Acylation with acid chlorides or anhydrides
SN2 Processes
HRCO2
HHCH2N2RCO2H
HX
HRCO2RCO2
–
X: Cl, Br, I, OSO2R
Mitsunobu
HOH
HRCO2
Ph3P, DEADRCOOH
9Pere Romea, 2014
Esters through SN2 Transformations
Synthesis of methyl esters by reaction with diazomethane
HCH
N NHCH
N NHCH
N N
Diazomethane is a highly volatile (it must be handled in etherial solutions), toxic, and explosive compound ...
– N2
H
HH
R O
O
SN2
The best leaving group
OHOO
O
OMeOO
OCH2N2
Et2O
95%
PhOH + CH2N2 PhOMe PrOH + CH2N2 PrOMepKa 10 pKa 16
Acid-base H
HH
R O
O
H
HCH
N N R O
O
N N
10 Pere Romea, 2014
Esters through Addition-Elimination Transformations
Fischer esterification
A problem
R1 O
O
H + HOR2
R1 O
O
HH
R1 OH
OH
R1 OH
OH
HO R2
R1 OH
OHOH
R2
R1 O
OHO R2
HH R1 O
R2OH
–H
R1 OR2
O
Activation
– Reversible reaction catalyzed by H+
– Excess of R2OH or removal of H2O are necessary to obtain esters in high yields
R1 O
O
H + HOR2R1 O
O
R2+ H2O
H
11
solventOH
O
+ MeOH OMe
OHCl cat
Δ
95%
OH
O
+ HO Cl O
O
ClTsOH cat
Δ
85%–H2O azeotropic
Pere Romea, 2014
Esters through Addition-Elimination Transformations
Esterification with carbodiimides
R1 O
O
H + HOR2R1 O
O
R2R N C N R+ + R
N NR
O
H HCarbodiimide
C NR
HNR
R1 O
O
H
R N C N R
R1 O
O
R1 O NR
O NHR
R OH
R1 O
O
R2 + R N NR
O
H HGood leaving group– Neutral and aprotic apolar medium
– DMAP is usually used as catalyst
OH
H
H
O
TBSO OMe
O
H
H
O
TBSO OMe
O
HO
O
+
N C N
DMAP cat, CH2Cl297%
DCC: DiCiclohexylCarbodiimide
12 Pere Romea, 2014
Esters through Addition-Elimination Transformations
Acylation with acid chlorides and anhydrides
R1 Cl
O
R1 O
O
R1
O
oR1 O
O
R2R2OH
R3NGood leaving groups
O
O
O
O
O
AcHO
O
O
O
O
O
AcO
OPh
PhCOClpyr, DMAP cat
CH2Cl285%
OH
CO2Me
OH
OH
OAc
CO2Me
OAc
OAc
Ac2OEt3N, DMAP cat
CH2Cl295%
13 Pere Romea, 2014
Esters through Addition-Elimination Transformations
Acylation with mixed anhydrides
O
OH
PMBO
PMBO
OPO
(OMe)
O
O
PMBO
PMBO
OPO
(OMe)
O Cl
Cl Cl
Et3N, DMAPTHF–PhMe, ta
Cl
O Cl
Cl Cl
Nu
O
O
PMBO
PMBO
OPO
(OMe)
O
HBnO
HO
O
OBnH
95%
Mixed anhydrides are usually prepared quantitatively from acid chlorides or other anhydrides. They are not isolated.
Yamaguchi Method
R1 O
O O
Nu
Cl
ClCl
R1 O
O O
Nu
Me
O2N
Shiina MethodJ. Org. Chem. 2004, 69, 1822
Ph OH
OTBSO
+ HO Ph Ph O
OTBSO
Ph
O
O
Me
X
O Me
XX: NO2
Et3N, DMAP cat, CH2Cl2
92% 14Pere Romea, 2014
Lactones in Natural Products
Lactones (cyclic esters) are a common structural motif in natural products
OOMe
OOH
HO
O
HOOMe
OH
OHO
H
O
O
O
OH
O
O O
O
OH
O
OHHO
O
O
OH
OMe
NMe2
O
MeO MeO
OMe
O OH
O
OH
O
OMe
N
H
O
Octalactin A (8)
Erythromycin A (14)
Bafilomycin A (16)
Scytophycin C (20)
O (C)nHO (C)n
O
O
L
?Campagne, J. -M.
Chem. Rev. 2006, 106, 911 & 2013, 113, PR115Pere Romea, 2014
Lactones in Natural Products
The size of the ring determines the synthetic method ...
Cyclization of γ- and ∂-hydroxy acids is straightforward …
OH
O
OH
O
O O
OH
OH
O
O
γ δ
Very easy Very easy
For 5- and 6-membered rings, both enthalpy and entropy OK !!!
... but as the size of the ring increases, the cyclization mets the selectivity problem
O (C)n
OH(C)n
O
O
Lk1inter
(C)nO(C)nL
O O
OH
O
O
O
O
k2inter
k2intrak1
intra
monòmer dímer
vintra >> vinter
vintra = k1intra [S] vinter = k1
inter [S]2
si k1intra � k1
inter vintra
vinter
1
[S]=
Per a vintra >> vinter [S] 0High dilution conditions are required as well as activation of the carboxylate group compatible with the OH group
16
Synthesis of Macrolactones
Mixed anhydrides (Yamaguchi and Shiina methods) met these conditions
O
OH
OO
HOOCO
O
O
O
OO
O
OO
Cl
O Cl
Cl
1) PhMe, DMAP, 60 °C[S] = 30 mM
78%
Cl
1) Et3N, THF, rt
O OHO
O
OHO
O
O
OOMe Me
X XX: NO2
Et3N, DMAP, CH2Cl2, 40 °C[S] = 2.7 mM
O OO
O
O
O
42%
17 Pere Romea, 2014
Amides through Addition-Elimination Transformations
The retrosynthetic analysis of amides also shows two options …
b) a)
R1 NR2
O
R1 L
O
+ HNR2R3
R1 NR3
O
+ R2–X
R3
Addition-elimination processes
– Acylation with acid chlorides and anhydrides
– Via coupling agents: carbodiimides, HATU
SN2 Processes
No very common, but N-substitutions using
sterically unindexed alkyl halides are useful options.
Attention with E2
N
O
H N
O
MeNaH, MeI
Benzè
18 Pere Romea, 2014
Amides through Addition-Elimination Transformations
Acylation with acid chlorides and anhydrides
Good leaving groupsR1 Cl
O
R1 O
O
R1
O
oR1 N
O
R2
R3N
R2R3NH
R3
Cl
O
N
OMe
Me+ Me2NH2
2 eq Me2NH
85%
Cl
NH2
O
HOHN
O
HOO
Ac2O, pyr
90%19
OH
O
NH2
O1) SOCl2
2) NH3 excess
70%
Pere Romea, 2014
Amides through Addition-Elimination Transformations
Synthesis of amides by using carbodiimides
Good leaving group– Neutral and aprotic apolar medium
– DMAP is usually used as catalyst
CarbodiimideR1 O
O
H + HNR2R3R1 N
O
R2R N C N R+ + R
N NR
O
H HR3
R1 O NR
O NHR
R2 NH
R1 N
O
R2 + RN N
R
O
H H
R3
R3C N
R
HNR
R1 O
O
H
R N C N R
R1 O
O
NHO
R2
O H
Boc
NRO
R1
O H
H NN
R2
O H
BocDCC
HO
ROR1
TFAN
NR2
O H
HHO
ROR1
Coupling Deprotection
Peptide synthesis20 Pere Romea, 2014
Amides through Addition-Elimination Transformations
21
Occasionally, O-acylisourea intermediates are not stable enough or produce the epimerization of the Cα center.
Then, the addition of N-hydroxy derivatives transforms such intermediates into less reactive active esterswith a beneficial effect on the overall efficiency
R1 O NR
O NHRHOXt
R1 OXt
O
R2 NH
R3
R1 NR2
O
R3
RN N
R
O
H H
HOXt
NNN
OHN N
NN
OH
N
O
O
OH
HOBt HOAt HOSu
HOXt
Pere Romea, 2014