Dr. Pere Romea Department of Organic Chemistry
Sky and Water I Maurits Cornelis Escher, 1938
6. Functional Group Interconversion
Organic Synthesis 2014-2015 Autumn Term Carbon Backbone & Functional Groups
The synthesis of an organic compound must pay attention to ...
Carbon backbone Functional groups (Chapters 2–4 ) Functional Group Interconversion (FGI)
I. Nucleophilic Substitutions Electrophilic Additions to C=C Addition-Eliminations on Carboxylic Acids and Derivatives II. Reductions Mechanism!!! III. Oxidations
Pere Romea, 2014 2 Nucleophilic Substitutions
The nucleophilic substitutions involve the interconversion of functional groups bound to sp3 carbonis
+ Nu + X X Nu
Csp3
RX
Electrophile Nucleophile Leaving group
Chap. 15 Pere Romea, 2014 3 Nucleophilic Substitutions
Two model mechanisms, called SN1 i SN2, are used to explain the nucleophilic substitutions
+ Nu + X X Nu
Unimolecular (SN1) or bimolecular (SN2) nucleophilic substitution?
A slightly different model, called SN2’, may be useful in substitutions on allylic substrates
X + Nu Nu + X
4 Pere Romea, 2014 Nucleophilic Substitutions and FGI
There are three main sources to carry out FGI through nucleophilic substitutions: sulfonates, alcohols, and alkyl halides
Nu Sulfonates R–OSO2R’ R–Nu
Nu Alcohols R–OH R–Nu
Alkyl halides Nu R–X R–Nu X: I, Br, Cl
5 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 Y R R R OH
Y R H2O or OH R N R OR ROH CN or RO R X O N3 O R N O R R 3 O R NH H2S 3 RSH or HS or RS
R NH2 R SH
Pere Romea, 2014 R SR 6 Nucleophilic Substitutions and FGI
How easy is to interconvert sulfonates, alcohols, and alkyl halides?
Nu Sulfonates R–OSO2R’ R–Nu
Nu Alcohols R–OH R–Nu
Alkyl halides Nu R–X R–Nu X: I, Br, Cl
7 Pere Romea, 2014 Alcohols and Sulfonic Esters
Conversion of alcohols into sulfonic esters
pyridine + RSO2Cl or (RSO2)2O OH CH2Cl2 or Et2O OSO2R 0 °C – rt
Mesyl chloride MsCl MeSO2Cl Mesylate
Tosyl chloride TsCl p-MePhSO2Cl Tosylate
Triflic Anhidride Tf2O (CF3SO2)2O Triflate
– Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance OH TsCl, pyr Me Me Me H Me
– 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 8 Pere Romea, 2014 Sulfonic Esters and Alkyl Halides
Conversion of sulfonate into alkyl halides
X OH X SN2 X: Cl, Br, I
OH 1) MsCl, Et3N, CH2Cl2 Cl
Pr 2) LiCl, DMF Pr 83%
Ph 1) TsCl, pyr, CH2Cl2 Ph OH Br 2) LiBr, DMF Ph Ph 89%
1) MsCl, Et3N, CH2Cl2 TBDPSO OH TBDPSO I 2) Lil, acetone 94% 9 Pere Romea, 2014 Alcohols and Alkyl Halides
Conversion of alcohols into alkyl halides
Sulfonates R–OSO2R’
R’SO2Cl
Alcohols R–OH X–
?
Alkyl halides R–X X: I, Br, Cl
10 Pere Romea, 2014 Alcohols and Alkyl Halides
Conversion of alcohols into alkyl halides
OH X X: Cl, Br, I
Reagents & Conditions Alcohols Mechanism
HCl conc Tert SN1 (racemization)
HCl/ZnCl2 (Lucas reagent) Prim & Sec SN2 (inversion) PCl3 Prim & Sec SN2 (inversion) SOCl2, 1,4-dioxane Prim & Sec SN2 + SN2 (retention) SOCl2, non nucleophilic solvent Prim & Sec SN2 (inversion)
HBr conc Tert SN1 (racemization)
HBr conc, ∆ Prim SN2 PBr3 Prim & Sec SN2 (inversion)
P/I2 Prim & Sec SN2 (inversion)
11 Pere Romea, 2014 Alcohols and Alkyl Halides
Problem! Too harsh experimental conditions: mixture of mechanisms and transpositions
H Br OH OH2 Br SN2 single
OH OH2 H
Br Br SN1 Br
86% 14% Br
Cl
H Cl OH OH2 single Pere Romea, 2014 12 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
E Ph3P + E–Nu Ph3P Ph3P E + Nu Nu
Ph3P E + HO Ph3P O + HE H H Alkoxyphosphonium salt
Ph3P O + Nu Ph3P=O + Nu H H Alkoxyphosphonium salt 13 Pere Romea, 2014 Alcohols and Alkyl Halides
Ph3P / X2 : Ph3P / I2, Ph 3P / Br2, Ph3P / Cl2
Br – Br Ph3P + Br–Br Ph3P Ph3P Br Br + Br
– HBr – Ph3P=O Ph3P Br + HO Ph3P O Br H H Br H SN2
This transformation is very useful for secondary alcohols and those systems that easily produce transpositions, as neopentylic alcohols The control on the configuration is very good.
Br Br PBr3 Ph3P/Br2 + + Br OH Br
11% 26% 63% 90%
OMe OMe Ph3P, Br2 Ph3P, I2 OH I O O R O O R Imidazole OH Br Et2O, rt 85% 96% 14 OBn OBn Alcohols and Alkyl Halides
Since chlorine (Cl2) is a gas difficult to handle ....
HO
– CCl3 H – Ph3P=O Ph3P + Cl–CCl3 Ph3P Cl Ph3P O Cl – HCl H Cl H carbon tetrachloride
O O Cl Cl Ph3P + CCl3 CCl3 Cl Cl Cl hexachloroacetone
OH Cl Ph3P/Cl2 Ph3P/CCl4 OH Cl 92% 70%
Ph3P/CCl3COCCl3 OH Cl 99%
15 Pere Romea, 2014 Nucleophilic Substitutions and FGI
Nu Sulfonates R–OSO2R’ R–Nu
Nu Alcohols R–OH R–Nu
Alkyl halides Nu R–X R–Nu X: I, Br, Cl
16 Pere Romea, 2014 Carbon Nucleophiles
O O O
R NH2 R OH R H R Me Amine 1 Carboxylic Acid Aldehyde Methyl ketone
Red Hydrolisis Red Hydration + 2+ LiAlH4 H3O DIBALH cat Hg , H 2O
R CN R C CH
+ C + 2 C
Attention! Alkyl halides are very useful for R X R OH the construction of C–C bonds
17 Pere Romea, 2014 Nitrogen Nucleophiles: Primary Amines
The alkylation of ammonia, NH3, is not easy ...
R X – HX NH3 R NH3 X R NH2 Primary Amine + HX
R X – HX R NH2 R2 NH2 X R2 NH Secondary Amine + HX
R X – HX R2 NH R3 NH X R3 N Tertiary Amine + HX
R X R3 N R4 N X 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
CO2Et CO2Et CO2Et 1) Br CO Et 1) RCH2Cl 2 NH N 2) NaHCO 2) NaHCO H2N 3 R N 3 H R: C15H31 18 Pere Romea, 2014 Nitrogen Nucleophiles: Primary Amines
Potassium phthalimide, PhthNK
O O Br Ph NaOH Ph H N N K N 2 Ph 95% O SN2 O Potassium phthalimide, pKa 8.3 Gabriel synthesis of amines
– Azide, N3
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
NaN I 3 N NH Bu Bu 3 Bu 2 DMSO, Δ 90% O O O O 1) MsCl, Et3N OTBDPS OTBDPS 2) NaN3, DMF OH N3 85% 19 Nitrogen Nucleophiles: Primary Amines
Mitsunobu conditions: Ph3P / DEAD / HN3 or DPPA [(PhO)2PON3]
Ph3P, EtO2C N N CO2Et OH N3 H HN3 o (PhO)2PON3, H
Ph3P CO2Et Ph3P CO2Et N N N N EtO2C EtO2C
OH Ph3P CO2Et CO2Et H N N O PPh3 + N N EtO2C H EtO2C H O P (PhO)2PO CO2Et CO2Et H CO2Et (PhO)2 N3 HN3 N3 + N N N N N N + N3 DPPA EtO2C H EtO2C H EtO2C H
N3 O PPh3 N3 + O=PPh3 H H
20 Pere Romea, 2014 Nitrogen Nucleophiles
Reduction Mitsunobu LiAlH4, H 2 cat, Ph3P/H2O Ph3P/DEAD/ HN3 or DPPA O
1 R N R R NH2 R N3 R OH H Amide Amine 1 Azide
SN2 SN2 – Phthalimide N3
R X R OSO2R'
O O O O Ph3P, DEAD, HN3 O N OH O N N3 CH2Cl2, 0 °C Bn 97% Bn
O O O 1) H2, Pd/C, THF/MeOH/TFA, ta O N N Ph H 2) PhCOCl, Et3N, CH2Cl2, 0 °C
Bn 97% 21 Oxygen Nucleophiles: Alcohols
– The most simple nucleophile: H2O / OH
– H2O, OH X 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
No eliminations can occur at this benzylic position Me Cl OH
Cl2 K2CO3
hν H2O NC NC 85% NC Radical chlorination
22 Pere Romea, 2014 Oxygen Nucleophiles: Ethers
Alkoxydes, RO–: Williamson Synthesis
RO– X RO SN2 H H X: Cl, Br, I
Only on 1ary substrates to avoid E2 eliminations ... and the most successful deconnections are applied to activated systems
O 2 O O Ar + XCH2R R1 R2 R1 + MeX o BnX
NO2 NO2 O O OH OBu O O BuBr, K2CO3 1) NaH, THF O O O O H2O H 2) BnCl, Δ H HO O BnO O 80% 95%
23 Pere Romea, 2014 Oxygen Nucleophiles: Esters
– Carboxilates, RCO2
– RCO2 X RCO2 SN2 H H X: Cl, Br, I, OSO2R
They are usually applied to 1ary substrates to avoid E2 eliminations
O O OK Br 18-crown-6 O + O 95% O Br Br why KF? O O CO2H O O CO2Me MeI, KF O O O DMF O O O 84% Attention: interconversion of carboxílic acids and derivatives 24 Oxygen Nucleophiles: Esters
Mitsunobu conditions: Ph3P / DEAD / RCO2H
Ph3P, EtO2C N N CO2Et OH RCO2 SN2 H RCOOH H
Ph3P CO2Et Ph3P CO2Et N N N N EtO2C EtO2C
OH Ph3P CO2Et CO2Et H N N N N + O PPh3 EtO2C EtO2C H H
RCO2H H CO2Et N N RCO2 RCO2 EtO2C H H
OH PhCO2 Ph3P, DEAD CO2Me CO2Me O PhCO2H O 25 Pere Romea, 2014 89% Oxygen Nucleophiles
Configuration inversion
SN2 Hidrolysis – – RCO2 OH
OH OSO2R' RCO2 HO H H H H
Mitsunobu Hidrolysis – Ph3P/DEAD/RCO2H OH
OH RCO2 HO H H H
O
OH O OH Ph Ph Ph Ph3P, DEAD O2N KOH
p-O2NPhCO2H MeOH 99% overall
26 Pere Romea, 2014 Phosphorus Nucleophiles: in Route to Wittig Reactions
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
B 1 1 1 1 R CH2–X + PR3 R CH2–PR3 R CH–PR3 R CH PR3 phosphine X phosphorus ylide phosphonium salt Attention: Wittig reaction
O O O NaOH Ph P + Br Ph3P Ph3P 3 OEt OEt OEt Br
BuLi Ph P + Br Ph3P Ph3P 3 OPh OPh OPh Br
Ph P Attention: no E2 occurs 3 OPh 27 Phosphorus Nucleophiles: in Route to Wittig Reactions
Phosphites are also good nucleophiles and react with alkyl halides: Michaelis-Arbuzov reaction
1 O R R R OCHR2 (R CHO) P + R1–X 2 3 P P 1 H O OCHR2 (R2CHO)2 R X phosphite alkylphosphonate alkyltrialkoxyphosphonium halide Attention: Horner-Wadsworth-Emmons reaction
O O O O O Δ EtO Br (EtO) P (EtO) P (EtO)3P + 2 OEt 2 OEt OEt EtBr
O O (EtO) P 2 OEt
O O
(EtO)2P Pere Romea, 2014 28 OEt Sulfur Nucleophiles: Thiols
The easiest option is troublesome ...
–H R–X R–X + HS R SH R S R S R +H S
NH2 thiourea H2N NH2 NaOH
H S NH2 O X H H SH O S NaOH H S thioacetate or LiAlH4
1) Thiourea AcSCs Br HS C H C H Br H 10 21 2) NaOH 10 21 DMF i-Pr i-Pr H SAc 80% 84%
29 Pere Romea, 2014 Sulfur Nucleophiles: Thioethers
Thiolates are the best option since they are excellent nucleophiles ...
X–R2 R1–SH + OH R1 S R1 S R2
NaOH Br SH S S 95%
O O O MsCl, Et N BnSH, K CO Me 3 Me 2 3 Me N N N CH2Cl2 CH3CN HO OMe MsO OMe BnS OMe 100% 80% Weinreb Amide O EtMgBr
BnS
30 Pere Romea, 2014 Carbon Backbone & Functional Groups
The synthesis of an organic compound must pay attention to ...
Carbon backbone Functional groups (Chapters 2–4 ) Functional Group Interconversion (FGI)
I. Nucleophilic Substitutions Chap. 19 Electrophilic Additions to C=C Addition-Eliminations on Carboxylic Acids and Derivatives II. Reductions Mechanism!!! III. Oxidations
Pere Romea, 2014 31 Hydroboration of C=C
Borane, BH3, as a reacting species
Lewis Base R R H H X R R H X B B 2 H B H H H H H H B H H Lewis Acid H3B· SMe2 H3B· OEt2 H3B· THF LUMO H B H H − + δ δ H H BH H B 2 BH3 H C C C C C C C C + − π δ δ syn Addition HOMO Cyclic transition state 4 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
32 Pere Romea, 2014 Hydroboration of C=C
Additions of BH3 to olefins produce boranes R
H R R R BH2 B B BH3 R R R R R Alkylborane Dialkylborane Trialkylborane
– The appropriate choice permits to obtain a wide array of alkylboranes
3 + BH3 B
2 + BH 3 B Sia2BH H
+ BH3 BH 2 ThxBH2
H B + BH3 9-BBN Pere Romea, 2014 33 Hydroboration of C=C
– Steric effects rule the reactivity
H R H H R R H H H R R R R > R > R > R > R > R H H R H H H
... the regioselectivity,
BH 94 80 99 57 3 % atack B Sia BH 99 98 97 to the less 2 substituted carbon atom 9-BBN 99.9 98.5 99.5 99.8
... and the stereoselectivity R2BH H + BR2 H BR2 BH3 72 28
34 9-BBN 97 3 Hydroboration of C=C
Protonolysis: synthesis of alkanes
BH RCO H R 3 R 2 3 R B H Δ 3 Trialkylborane Alkane
Conversion of trialkylboranes into alcohols: H2O2/NaOAc, ...
R R R OR HO B B B B 3 ROH R R O R RO R RO OR 3 R – HO – BO3 HO HO O Borate – The migration does not Hidrolysis produce the inversion of the configuration
H 1) B H OH It looks like 2 6 an anti-Markovnikov hydration – 2) H2O2, OH with a syn stereochemistry
35 85% Pere Romea, 2014 Hydroboration of C=C
Hidroboration of alkynes
H H RCO2H
Δ R1 R2 Alquè Z
L B H – HO H 2 L2B H 2 H2O2, OH O R R1 R2 R1 R2 R1 R2 R1
(HO) B H H2O 2
1 2 R R Vinilboronic acid
O 1) B H Br O OH B 2) H2O OH Pd(0) cat 75% Suzuki Coupling 36 Pere Romea, 2014 Dr. Pere Romea Department of Organic Chemistry
The moneychanger and his wife Marinus Claesz van Reymerswaele, 1539
6. Functional Group Interconversion
Organic Synthesis 2014-2015 Autumn Term Carboxylic Acids and Derivatives
Carboxylic acids Derivatives of carboxylic acids
O O
R1 OH R1 L
O O O O O O O 2 1 1 2 1 1 2 1 2 1 R R Cl R O R R N3 R SR R OR R N R3 Acid chloride Anhydride Acyl azide Thioester Ester Amide
R1 C N Nitrile
All these FG participate in reactions that can be understood using the addition-elimination mechanism
2 Pere Romea, 2014 Addition-Elimination Mechanism
Addition-elimination mechanism
O Addition Nu O Elimination O + L Trigonal Planar R1 L R1 L R1 Nu
Nu Tetrahedral Trigonal Planar
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 ...
3 Pere Romea, 2014 Addition-Elimination Mechanism
Activation with a Lewis Acid, LA, ...
LA LA LA LA O O HNu O Nu O O O LA –LH –LA R1 L R1 L R1 L R1 LH R1 Nu R1 Nu Activation Addition Elimination NuH Remember: Fischer esterification
Activation with a Lewis Base, B , ...
O O Nu O O –L –B R1 L R1 B R1 B R1 Nu
B Activation NuH Addition Elimination
Remember: synthesis of esters by addition of alcohols to acid chlorides in the presence of DMAP
4 Pere Romea, 2014 Addition-Elimination Processes
O H2O R1 Cl Very easy Chap. 16 Chap. 10 2 – R CO2
O O 2 – R CO2 H2O R1 O R2 Easy O 1 R2OH R OH
2 O R OH H2O R1 OR2 Moderate
R2R3NH
O 2 3 R R NH 2 H2O 1 R R N Difficult R3 5 Pere Romea, 2014 Addition-Elimination Processes
O ? R1 Cl Chap. 16 Chap. 10 2 – R CO2
O O 2 – R CO2 ? R1 O R2 O
1 R2OH R OH
R2OH O ? R1 OR2
R2R3NH
O R2R3NH ? R2 R1 N R3 6 Pere Romea, 2014 Acid Chlorides from Carboxylic Acids
Via SOCl2 o PCl5
O O O O SOCl2 OH PCl5 Cl OH Cl 85% O2N 93% O2N
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.
O Bn O Bn
O (COCl)2 O N N N N
CO2Na 83% COCl HO O HO O
7 Pere Romea, 2014 Anhydrides from Carboxylic Acids
Regioselectivity in the nucleophilic attacks to anhydrides
O O O O Regioselectivity In mixed anhydrides R1 O R1 R1 O R2 is not a problem for the R2 group must prevent the symmetric anhydrides the nucleophilic attack Nu Nu O O Cl O O The mixed anhydrides are usually prepared quantitatively from acid chlorides or other anhydrides. R1 O R1 O They are not isolated. Cl Cl Yamaguchi Method Nu Nu
O O O Cl O O O O O P P P (OMe) Cl (OMe) H OBn (OMe)
Cl Cl HO O BnO PMBO O Et N, DMAP PMBO O O Cl PMBO O H 3 95% THF–PhMe, rt PMBO OH PMBO O PMBO O
Cl Cl Nu Pere Romea, 2014 8 Esters from Carboxylic Acids and Derivatives
The retrosynthetic analysis shows two ways of deconnecting the ester group ...
O b) O a) O + HOR2 R2 + R2–X R1 L R1 O R1 O
Addition-elimination Processes SN2 Processes
– Fischer Esterification X
– H – Using coupling agents as carbodiimides RCO2 RCO2 X: Cl, Br, I, OSO2R H – Acylation with acid chlorides or anhydrides OH H RCOOH RCO2 Ph3P, DEAD H Mitsunobu
HH CH2N2 RCO2H RCO2 H Pere Romea, 2014 9 Esters through SN2 Transformations
Synthesis of methyl esters by reaction with diazomethane
Diazomethane is a highly volatile (it must be handled in etherial solutions), toxic, and explosive compound ...
H H H C N N C N N C N N H H H
The best leaving group
O H O H O HH H – N2 H C N N N N R O R O R O H H H Acid-base SN2
O O CH2N2 HO O MeO O Et2O O O 95%
pKa 10 pKa 16
PhOH + CH2N2 PhOMe PrOH + CH2N2 PrOMe
10 Pere Romea, 2014 Esters through Addition-Elimination Transformations
Fischer esterification O H + HOR2 R1 O A problem
H H H 2 H O O O HO R O O H O R2 HO O –H H H H 2 2 1 1 1 1 1 1 R 1 R R O R O R O R OH R O H R O R O H Activation HO R2
O O H 2 H + HOR2 R + H O R1 O R1 O 2
– Reversible reaction catalyzed by H+ 2 – Excess of R OH or removal of H2O are necessary to obtain esters in high yields
O O O O HCl cat TsOH cat + MeOH + HO Cl OH Δ OMe OH Δ O Cl solvent –H O azeotropic 95% 2 85% 11 Pere Romea, 2014 Esters through Addition-Elimination Transformations
Esterification with carbodiimides
O O O 2 H + + HOR2 R R R R1 O R N C N R R1 O + N N Carbodiimide H H
O O H O NHR O O R1 O R1 O H R2 R R R1 O NR R1 O + N N R N C N R R N C N H H R R OH – Neutral and aprotic apolar medium Good leaving group – DMAP is usually used as catalyst
TBSO OMe TBSO OMe
O DCC: DiCiclohexylCarbodiimide O O
OH O N C N O H H + HO DMAP cat, CH2Cl2 97% H 12 H Pere Romea, 2014 Esters through Addition-Elimination Transformations
Acylation with acid chlorides and anhydrides
O O O O R2OH o R2 R1 Cl R1 O R1 R1 O R3N Good leaving groups
O O O PhCOCl O O O pyr, DMAP cat O O Ac Ac O CH2Cl2 O HO O 85% O Ph
CO2Me CO2Me Ac O OH 2 OAc Et3N, DMAP cat OH OAc CH2Cl2 95% OH OAc
13 Pere Romea, 2014 Esters through Addition-Elimination Transformations
Acylation with mixed anhydrides O O Cl O O Me R1 O R1 O Mixed anhydrides are usually prepared quantitatively Cl Cl O N from acid chlorides or other anhydrides. 2 They are not isolated. Nu Nu Yamaguchi Method Shiina Method J. Org. Chem. 2004, 69, 1822
O O O Cl O O O O O P P P (OMe) Cl (OMe) H OBn (OMe)
Cl Cl HO O BnO
PMBO O Et3N, DMAP PMBO O O Cl PMBO O H 95% THF–PhMe, ta PMBO OH PMBO O PMBO O
Cl Cl Nu Me O O Me
O
X X TBSO O TBSO O X: NO2 Ph OH + HO Ph Ph O Ph Et3N, DMAP cat, CH2Cl2 Pere Romea, 2014 92% 14 Lactones in Natural Products
Lactones (cyclic esters) are a common structural motif in natural products
OMe O HO O O OH Scytophycin C (20) O N O H O MeO MeO OH Octalactin A (8) H O O OMe O
HO OH O OH Bafilomycin A (16) OH NMe2 O O O OMe O OH O O OMe O OH O Erythromycin A (14) O OH HO HO OMe
O HO (C)n L O (C)n ? O Campagne, J. -M. Pere Romea, 2014 15 Chem. Rev. 2006, 106, 911 & 2013, 113, PR1 Lactones in Natural Products
The size of the ring determines the synthetic method ...
Cyclization of γ- and ∂-hydroxy acids is straightforward … O O O O Very easy OH Very easy O OH O
γ δ OH OH 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 O O inter inter k1 k2 L (C)n OH L (C)n O (C)n OH vintra >> vinter O intra intra k1 k2 intra inter 2 O O vintra = k1 [S] vinter = k1 [S]
intra inter vintra 1 O (C)n si k1 k1 = monòmer dímer vinter [S] O O Per a v >> v [S] High dilution conditions are required as well as intra inter 0 activation of the carboxylate group compatible with the OH group 16 Synthesis of Macrolactones
Mixed anhydrides (Yamaguchi and Shiina methods) met these conditions
O Cl O O Cl O O Cl Cl
O 1) Et3N, THF, rt O
OH O 1) PhMe, DMAP, 60 °C O O [S] = 30 mM HOOC O O O 78%
Me O O Me
O
O X X O X: NO O OH 2 O O O O O Et N, DMAP, CH Cl , 40 °C HO 3 2 2 O [S] = 2.7 mM O O 42%
17 Pere Romea, 2014 Amides through Addition-Elimination Transformations
The retrosynthetic analysis of amides also shows two options …
O b) O a) O + HNR2R3 R2 + R2–X R1 L R1 N R1 NR3 R3
Addition-elimination processes SN2 Processes
– Acylation with acid chlorides and anhydrides No very common, but N-substitutions using – Via coupling agents: carbodiimides, HATU sterically unindexed alkyl halides are useful options. Attention with E2
O O H Me N NaH, MeI N Benzè
18 Pere Romea, 2014 Amides through Addition-Elimination Transformations
Acylation with acid chlorides and anhydrides
O O O O R2R3NH o R2 R1 Cl R1 O R1 R1 N R3N Good leaving groups R3
O O 1) SOCl2 OH NH2 2) NH3 excess
70%
O O 2 eq Me NH Me Cl 2 N + Me2NH2 Cl Me 85%
O O Ac O, pyr H NH 2 N HO 2 HO 90% O 19 Pere Romea, 2014 Amides through Addition-Elimination Transformations
Synthesis of amides by using carbodiimides
O O O 2 H + + HNR2R3 R R R R1 O R N C N R R1 N + N N Carbodiimide R3 H H
O O H O NHR O O R1 O R1 O H R2 R R R1 O NR R1 N + N N R N C N R R N C N R3 H H R R2 NH – Neutral and aprotic apolar medium Good leaving group R3 – DMAP is usually used as catalyst
R2 HO Boc O H N O H R2 O H R2 N O H N Boc TFA N H RO H RO N RO N DCC R1 R1 O H R1 O H Coupling Deprotection
Peptide synthesis 20 Pere Romea, 2014 Amides through Addition-Elimination Transformations
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 esters with a beneficial effect on the overall efficiency
O NHR O O HOXt Xt 2 1 1 R R O NR R O R1 N R3 O R2 NH HOXt R R N N R3 H H HOXt O N N N N N OH N N N OH OH O HOBt HOAt HOSu
21 Pere Romea, 2014