methods and design in organic synthesis - UBdiposit.ub.edu/dspace/bitstream/2445/134177/8/6.1....
70
methods and design in organic synthesis 2018-19 Master Course Pere Romea in Organic Chemistry
Transcript of methods and design in organic synthesis - UBdiposit.ub.edu/dspace/bitstream/2445/134177/8/6.1....
methodsanddesigninorganicsynthesis
2018-19Master Course
PereRomea
inOrganicChemistry
6.1.Rings
Gollum/Sméagolin
TheLordoftheRings
Myprecious!
Cyclic Compounds
carbocycle
O NH
heterocycle saturated unsaturated aromatic
spirorings fusedrings bridgedrings
bicyclo[2.2.2]octanedecalinespiro[5.5]undecane
Synthesis of Cyclic Compounds
Ringscanbepreparedbyexpansion/contractionfromotherrings…
Baeyer-Villiger6 7
O
O
O OCl
CO2HFavorskii
6 5
…orbycyclizationofachainoracycliccompounds.
Acycloadditioncorrespondstoaringclosureinwhichtheresultantadductcontainsalltheatomsoftheinitialcomponent(s).
Nolossesofatomsorsmallmolecules
OOH
Br
O+
Paterno-BüchiWilliamson
cyclization cycloaddition
Thermodynamics: Strain Energy
STRAINENERGYreferstotheexcessenergyofagivenarrayofatomsan(asyethypothetical)moleculeovertheminimumarraythatthearraywouldpossess
ifcertainkindsofinteractionswere“turnedoff”
V=Vs+Va+Vt+Vnb+VE–Vsol
bondstretching
bondangle
bondtorsion
nonbonding
electrostatic
solvation
Eliel.E.L.StereochemistryofOrganicCompounds.p33
Pitzerstrain
Baeyerstrain vanderWaals
Thermodynamics: Ring Strain
RINGSTRAIN(ENERGY)foracycloalkanereferstotheexcessenergyrelative
totheparentacyclicalkane
V=Vs+Va+Vt+Vnb+VE–Vsol
bondstretching
bondangle
bondtorsion
nonbonding
electrostatic
solvation
Eliel.E.L.StereochemistryofOrganicCompounds.p33
Thermodynamics: Ring Strain
butane
H
H H
HH
H HH
HH 16kJmol–1
3.8kJmol–1
19kJmol–1
eclipsed
eclipsed
eclipsed
staggered staggered staggeredstaggered
Me
Me
Me
Me
MeMe
MeMe
MeMe Me
Me
Me
Me
antiperiplanar synperiplanar antiperiplanar
gauchegaucheanticlinal anticlinal
α ~ 109°
Me
H HMe
HH
antiperiplanar
Thermodynamics: Ring Strain
butane cyclobutane
H
H H
HH
HHHH
H H
HH
H HH
HH
α ∼ 109°
Me
H HMe
HH
antiperiplanar
α ∼ 88°
H HHH
eclipsed
Thermodynamics: Ring Strain
butane cyclobutane
H
H H
HH
HHHH
H H
HH
H HH
HH
α ∼ 109°
Me
H HMe
HH
antiperiplanar
α ∼ 88°
H HHH
eclipsed
ringstrain
∆∆Gof
∆∆Gocombustion
bendangle
torsion
Thermodynamics: Ring Strain in Cycloalkanes
3 5 7 9 11 13 15 164 6 1412108size
0
20
40
60
80
100
120
strain(kJmol–1)
Thermodynamics: Ring Strain in Cycloalkanes
3 5 7 9 11 13 15 164 6 1412108size
0
20
40
60
80
100
120
strain(kJmol–1)
SMALLRINGS3 4
Highlyreactive
Thermodynamics: Ring Strain in Cycloalkanes
3 5 7 9 11 13 15 164 6 1412108size
0
20
40
60
80
100
120
strain(kJmol–1)
COMMONRINGS
5 6 7
Thermodynamics: Ring Strain in Cycloalkanes
3 5 7 9 11 13 15 164 6 1412108size
0
20
40
60
80
100
120
strain(kJmol–1)
MEDIUMRINGS 8–11
Thermodynamics: Ring Strain in Cycloalkanes
3 5 7 9 11 13 15 164 6 1412108size
0
20
40
60
80
100
120
strain(kJmol–1)
LARGERINGS 12–16
Thermodynamics: Ring Strain in Cycloalkanes
3 5 7 9 11 13 15 164 6 1412108size
0
20
40
60
80
100
120
strain(kJmol–1)
RINGS≥8areusuallycalledMACROCYCLES
Thermodynamics: Ring Strain in Cycloalkenes
6 8 95 7size
0
10
20
30
40
50
60
strain(kJmol–1)
5
6
7
8E
8Z
9Z
9E
ATTENTION!!!ZorEstereoisomers
Thermodynamics: Ring Strain
Bicyclicalkenesrequireaspecialattention
Thesesubstratesaresubjecttostrainresultingfromdistortionofthesp2carboncenters.TheanglestrainisthebasisofBredt’srule,whichdictatesthat
bridgeheadcarbonatomsarenotincorporatedinalkenesbecausethestrainangle
Norbornene Forbiddennorbornenes
but…
Fullerene
CP-Molecules
orTaxol(seeChapter1)
Kinetics
Kinetics
Thermo
Reactioncoordinate
ΔGo Transition State, TS
Reactants
Products
Thekineticsofthecyclizationisassociatedwith[∆G°]‡
[∆G°]‡=[∆H°]‡–T[∆S°]‡
X( )
Yn
Z
( )ncyclization
…(polymerization)
X( )
Zn ( )
Zn ( )Yn
n n
dimerization
X( )
Zn ( )
Yn n
n
Kinetics
Thekineticsofthecyclizationisassociatedwith[∆G°]‡
[∆G°]‡=[∆H°]‡–T[∆S°]‡
cyclization
Br ( ) CO2n
O
( )n
O
[∆H°]‡>0providesameasureofthestrain
[∆S°]‡<0providesameasureoftheprobabilityofend-to-end(intramolecularreaction)
Entropydecreasesasthechainlengthincreases
Illluminati,G.;Mandolini,L.ACR1981,14,95
3 5 7 9 11 13 15 17 19 21 23
–4
–3
–2
–1
0
1
2
ringsize
logkintra
Kinetics
cyclization
Br ( ) CO2n
O
( )n
Okcycle
Kinetics
Br ( ) CO2n
O
( )n
O
Highdilutionisrequired
kcycle
Br ( ) On
O( ) CO2n
kinter
vcycle
vinter
kcycle [S]kinter [S]2
= =kcycle
kinter [S]
vcycle
vinter[S] 0
MediumandLargeRings
Illluminati,G.;Mandolini,L.ACR1981,14,95
3 5 7 9 11 13 15 17 19 21 23
–4
–3
–2
–1
0
1
2
ringsize
logkintra
Synthesis of Medium and Large Rings
Thesynthesisofmedium-andlarge-sizedcycliccompoundsisadauntingchallengemainlyduetounfavorableenthalpiesandentropicfactors
Threemainstrategiescanbedeployedtoattempttheirsynthesis
RingExpansionA
B
A
B
RingContractionA
B
A
B
CyclizationA
B
A
Synthesis of 9-Membered Carbocycles
Arepresentativeexampleinvolvestheconstructionofnine-memberedcarbocycles
Magauer,T.CEJ2018,24,12107
Synthesis of 9-Membered Carbocycles
HO
BnO
HO
O
HHBnO H
H O
H
HO
O
1) MsCl, i-Pr2NEt
2) KOt-Bu
98%
Grobfragmentation
JatrophatrionePaquette,L.JACS2003,125,1567
O
O
PMBOOTBS
O
OH
PMBOOTBS
O
O
O
OH
50 mol% HG
66%
Toluene, Δ
Altman,K.H.ACIE2008,47,10081 Blumiolide C
Metathesis
Synthesis of Medium and Large Rings: Macrolactones
Lactones(cyclicesters)areacommonstructuralmotifinnaturalproducts
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
OOctalactin A
(8)
Erythromycin A (14)
Bafilomycin A (16)
Scytophycin C (20)
O (C)nHO (C)n
O
O
L
?Campagne,J.-M.
CR2006,106,911&2013,113,PR1
Synthesis of Medium and Large Rings: Macrolactones
Acylationwithmixedanhydrides
Mixedanhydridesareusuallypreparedquantitativelyfromacidchloridesorotheranhydrides.Theyarenotisolated.
Yamaguchi Method
R1 O
O O
Nu
Cl
ClCl
R1 O
O O
Nu
Me
O2N
Shiina MethodJOC2004,69,1822
HO( )n OH
O
( )n
O
O
TheCOOHisnotactiveenoughtofacilitatethesynthesisofanester
HO( )n X
O
Itneedstobeactivated…
( )n
O
O
…toprovidethemacrolactone
TheCOOHmustbeactivatedchemoselectivelytocompletethecyclisationunderhighdilutionconditions
Synthesis of Medium and Large Rings: Macrolactones
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%
Synthesis of Medium and Large Rings: Macrolactones
CuTC, DMF60%
Pd(PPh3)4
Stille
Bu3Sn
OTES
OTBDPS
I
O
O
OPiv
OTES
OTBDPSO
O
OPiv
OTES
OTBDPSO
O
CO2H
2) TPAP, NMO
59%
1) DIBAL-H
OH
OTBDPSHO
HO
CO2H
58%
AcOH, HCl
THF
8
10
16
Thiskindofmacrolactonizationcanbeverysiteselective
O
OTBDPSHO
HO
O
71%
Cl
Cl Cl
Cl
O
Et3N, DMAP, THF/PhMe, rt
Syringepumpaddition2.5µM
Maier,M.E.OL2016,18,3146
Synthesis of Medium and Large Rings: Macrolactones
Althoughcompetingmacrolactonizationreactionsusually
favorthelargerring,occasionallytheoutcomemaybedifferentdependingonstructural
features
Fürstner,A.ACIE2018,57,13575
Chagosensine
O OHClHO
HOH
H
O
HO
O HO
OOHH
OBu3SnHO
HOMOM
H
OTBSO
O
Bu3Sn
O
O HO
HO
OSiMe3
I
Pd(PtBu3)2, PhPO2NBu4LiCl, NMP, 60 °C
50%
OBu3SnHO
HOMOM
H
OTBSO
O
O
O CO2CH2CH2SiMe3
OH
CuCl2, 2,6-lutidineTHF
OClHO
HOMOM
H
OTBSO
O
O
O CO2CH2CH2SiMe3
OH
78%
Synthesis of Medium and Large Rings: Macrolactones
Althoughcompetingmacrolactonizationreactionsusually
favorthelargerring,occasionallytheoutcomemaybedifferentdependingonstructural
features
Fürstner,A.ACIE2018,57,13575
Chagosensine
O OHClHO
HOH
H
O
HO
O HO
OOHH
OClRO
HOMOM
H
ORO
O
O
O CO2HO
H
OHOMOM
H
OHO
O
O
Cl
OO
O
O
H
H
N Br
BF4NaHCO3
DCE, 80 °C30%
OClMOMO
HOMOM
H
O
O
O
OO
HO
O
Cl
OCl
Cl Cl
i-Pr2NEtTHF, toluene, Δ
40%
R=R=H
R=MOMR=H
Synthesis of Medium and Large Rings: Macrolactones
Isitpossibletorunadirectmacrolactonizationundercatalyticconditions…?
Currentmacrolactonizationreactionsfromsecoacidsinvolvestoichiometricactivationofthecarboxylicacidand
cyclizationconductedathighdilutionconditions
Twomainproblems:equilibriumopen/cyclic&polimerizationsoefficientcatalyticdirectmacrolactonizationofsecoacidsarerare
HO( )n OH
O
( )n
O
O
5 mol% Hf(OTf)4
Toluene, 110 °C, 24 h
5 mM
O
O
O
O
O
O
O
O
11 13 16 17
< 5% 55% 83% 87%Collins,S.K.
ACSCatalysis2015,5,1462
Synthesis of Medium and Large Rings: Macrolactones
…andenantioselectivemanner?
Breit,B.ACIE2016,55,9738
OH
•
O
O
O O
O
O
O
( )n-1
( )n-1
( )n ( )n
O
O
( )n
+ +
OO
PAr2Ar2P
9 mol %[Rh(cod)acac]
Ar: 3,5-t-Bu-4-MeOPh
0.01 MDCE, rt, 24 h
exoattack
endoattack
O
O
O O
89% ee 73% (90:10:nd) 85% ee 84% (80:14:6) 72% ee 86% (83:14:3)
93% ee 81% (78:15:7) 93% ee 86% (94:3:3)
17
17 17
16 20OO
O
O
OO
O
OO O
OO
( )3 ( )7
Synthesis of Medium and Large Rings: Macrolactones
Breit,B.CEJ2019,25,3532
OO
OO
OO
O
OOO
OO
O
O
OOH
O
•
Vermiculine
OOH
O
•O
O
OO
O
O
PPh2
PPh2O
O
4 mol% Rh(cod)Cl2
8 mol%
DCE, 10 °C, 48 hsyringe pump addition
dr 81:19 ee 99% 73%
OO
OO
O
O
2-butene10 mol% Grubbs II
DCE, 40 °C90%
OO
OO
OO
O
O
TBHP20 mol% Pd(quinox)Cl2
50 mol% AgSbF6
DCE, rt
60%
Synthesis of Medium and Large Rings: Ring Closing Metathesis
RingClosingMetathesis(RCM)isapowerfulreactiontoobtainmacrocycles
Forinstance,itcanbeusedtopreparemacrolactones
( ) O ( )O
mn
( ) ( )O
O
nmCatalyst
MesN NMes
Ru CHPh
PCy3
Cl
Cl
PCy3
Ru CHPh
PCy3
Cl
ClMoN
(F3C)2MeCO(F3C)2MeCO
i-Pr i-PrPhTi
Cp
CpW(CO)5
R
Ph
Grubbs I 1995 Grubbs II 1999Schrock 1990Katz 1976 Tebbe 1978
MesN NMes
Ru
O
Cl
Cl
Hoveyda 2000
MesN NMes
Ru
O
Cl
Cl
Grela 2002
NO2
GrelaK.OlefinMetathesis.TheoryandPractice.
Wiley
Synthesis of Medium and Large Rings: Ring Closing Metathesis
( ) O ( )O
mn
( ) ( )O
O
nmGrubbsII
CH2Cl2,40°C
Synthesis of Medium and Large Rings: Ring Closing Metathesis
( ) O ( )O
mn
( ) ( )O
O
nmGrubbsII
CH2Cl2,40°C
Highdilutionconditionsareoftenrequired
PROBLEM:CONTROLOFTHEZ/ECONFIGURATION
5mM0.5mM
29%70%
5mM0.5mM
41%95%
E/Z41:59
5mM 94%
E/Z89:11
5mM 99%
E/Z72:28
O
OO
OO
O
OO OO
7 8 10 14 16
Fogg,D.E.JACS2007,129,1024
Synthesis of Medium and Large Rings: Ring Closing Metathesis
Hoveyda,A.H.JACS1997,119,10302
O
O
OTBS
O NH
O
O
OMe
O
O
OTBS
O NH
O
O
OMe
PhMe, reflux
70%
20mol%GrubbsII
0.5mM
Danishefsky,S.JACS2003,125,6042
PhH, 20 °C
91%
20mol%Schrock
O
HN
OSugar
O
HN
OSugar
10mM
Synthesis of Medium and Large Rings: Ring Closing Metathesis
Song,Z.OL2015,17,4706
O OMeO2C
O
O
MeO2C
O OMeO2C
O
O
MeO2C
PhH, reflux
78%
10mol%HGII
5mM
O OMeO2C
O
O
MeO2C H2, LindlarEtOAc, rt
70%(–)Exiguolide
Synthesis of Medium and Large Rings: C–C bond formation
PhMe, reflux
54%
2–3mol%Pd(PPh₃)₄
8mMI
O
OMEMO
MEMO O
Bu3Sn
O
OMEMO
MEMO O
Hegedus,L.S.JOC1991,56,2883Nicolaou,K.C.ACIE1998,37,2534
O
OHO
HO O
5% HCl
THF, rt
80%(S)Zearalenone
Forinstance,theSTILLEREACTION
hasbeenusedforthesynthesisofmacrocycles
R1 X + R3Sn R2 R1 R2Pd(0) O ( )
O
I
O ( )
O
Bu3Sn
n nPd(0)
PhMe, reflux
5 mM
100%1212%
1449%1561%
sizeyield
Synthesis of Medium and Large Rings: C=C bond formation
TheHORNER-WADSWORTH-EMMONShasalsobeenusedforthesynthesisofmacrocycles
(AlkO)2P R2
OO
R1 H
O+ R1 R2
Obase
O
O O
MEMO
OP
OHC(OEt)2
O
OMe
NO
O
O O
MEMO
O
OMe
NO
CH3CN, rt87%
i-Pr2NEt,LiCl
Keck,G.E.ACIE2001,40,231
O
O O
HO
O
OMe
NO
78%
Me2BBrTHF/CH2Cl2–78 to 0 °C
Rhizoxin D
Synthesis of Large Rings. A Case Study: Rhizopodin
NH
O
MeO O
OMe
O
HO
OHOMeOMeO
N OO
OMeOMeOHO
OH
O N
MeO
N HO OMe
O
38
(–)-Rhizopodin
Menche,D.ACIE2012,515667Menche,D.JOC2012,77,10782Paterson,I.ACIE2013,52,6517
Yamaguchi(Paterson)
Suzuki,Heck(Menche)
Synthesis of Large Rings. A Case Study: Rhizopodin
Menche,D.ACIE2012,515667
CyclizationthroughaSuzukireaction
TBSO
OMe
O
TBSO
OOMeOMeO
N OO
OMeOMeOO
OTBS
O N
OTBS
MeO
TBS
TBS
DMF, rt
65%
Ba(OH)2·8H2OPd(dppf)Cl2
9 mM
TBSO
OMe
O
TBSO
OOMeOMeO
N OO
OMeOMeOO
OTBS
O N
OTBS
MeO
TBS
I
BO
OTBS
Synthesis of Large Rings. A Case Study: Rhizopodin
Menche,D.JOC2012,77,10782
PMBO
OMe
O
TBSO
OOMeOMeO
N OO
OMeOMeOO
OTBS
O N
OPMB
MeO
TBS
TBS
I
PMBO
OMe
O
TBSO
OOMeOMeO
N OO
OMeOMeOO
OTBS
O N
OPMB
MeO
TBS
TBS
DMF, 50 °C
65%
K2CO3, Bu4NClPd(OAc)2
5 mM
CyclizationthroughaHeckreaction
Synthesis of Large Rings. A Case Study: Rhizopodin
Paterson,I.ACIE2013,52,6517
CyclizationthroughaYamaguchireaction
TBSO
OMe
O
TESO
OOMeOMeO
N OO
OMeOMeOO
OTES
O N
OTBS
MeO
TBS
TBS
THF/PhH, rt
63%
Et3N, DMAP
0.4 mM
TBSO
OMe
O
TESO
OOMeOMeO
N OOH
OMeOMe
OTES
O N
OTBS
MeO
TBS
HO O
OTBS
SyringePump
ClCOCl
ClCl
6.2.BaldwinRules
ThreeRingsfortheElven-kingsunderthesky,SevenfortheDwarf-lordsintheirhallsofstone,NineforMortalMendoomedtodie,OnefortheDarkLordonhisdarkthroneIntheLandofMordorwheretheShadowslie.
OneRingtorulethemall,OneRingtofindthem,OneRingtobringthemallandinthedarknessbindthemIntheLandofMordorwheretheShadowslie.
TheLordoftheRings
1970 1980NOBELPRIZE1981
KenichiFukui
RoaldHoffmann
Fortheirtheoriesconcerningthecourseofchemicalreactions
NOBELPRIZE1969
DerekH.Barton
OddHassel
Fortheircontributiontothedevelopmentofthe
conceptofconformationanditsapplicationinchemistry
TheConservationofOrbitalSymmetryWoodward,R.B.;Hoffmann,R.
ACIEE1969,8,781
NOBELPRIZE1975
JohnW.Cornforth
VladimirPrelog
Fortheirresearchintothestereochemistryof
organicmoleculesandreactions
StereochemistryofReactionPathsatCarbonylCentresBürgi,H.B.;Dunitz,J.D.;Lehn,J.M.;Wipff,GTetrahedron1974,30,1563
OHCO2MeO O O
CO2Me
OHCO2MeO O O
CO2Me
1970 1980NOBELPRIZE1981
KenichiFukui
RoaldHoffmann
Fortheirtheoriesconcerningthecourseofchemicalreactions
NOBELPRIZE1969
DerekH.Barton
OddHassel
Fortheircontributiontothedevelopmentofthe
conceptofconformationanditsapplicationinchemistry
TheConservationofOrbitalSymmetryWoodward,R.B.;Hoffmann,R.
ACIEE1969,8,781
NOBELPRIZE1975
JohnW.Cornforth
VladimirPrelog
Fortheirresearchintothestereochemistryof
organicmoleculesandreactions
StereochemistryofReactionPathsatCarbonylCentresBürgi,H.B.;Dunitz,J.D.;Lehn,J.M.;Wipff,GTetrahedron1974,30,1563
1976BaldwinRules
Baldwin Rules
SirJackE.Baldwin
JCSChem.Commun.1976,734Morethan1300cites
Inowadumbrateasetofsimpleruleswhich
Ihavefoundusefulinpredictingtherelativefacility
ofdifferentringclosures
Ring Forming Processes
Anucleophilicring-formingprocesscanbedescribedwiththeprefixExowhenthebreakingbondisexocyclictothesmallestsoformedringandEndocorrespondingly.
Anumericalprefixisusedtodescribetheringsizeandasuffixindicatethehybridizationoftheelectrophiliccarbonatomundergoingthering-closurereaction
(tetrahedralorsp3:Tet,trigonalorsp2:Trig,anddigonalorsp:Dig)
Baldwin,J.E.JCSChem.Commun.1976,734,736;JOC1977,42,3846.Johnson,C.D.ACR1993,26,476
6-exo-tet 6-endo-tet
Y
Y
X X
Y
X X
6-exo-trig 6-endo-trig
Y
Y
X X
Y
X XY
6-exo-dig 6-endo-dig
Y
Y
X X
Y
X XY
Theserulesalsoapplytohomoliticandcationicprocesses
Baldwin Rules
Baldwin,J.E.JCSChem.Commun.1976,734,736;JOC1977,42,3846.Johnson,C.D.ACR1993,26,476
Exo Endo
Tet Trig Dig Tet Trig Dig
3
7
6
5
4
easy
difficult
Baldwin Rules
However
N
CO2MeMeO2C
HN
MeO2C
H O
MeO2C CO2Me
NH2
Δ Δ
HNPh
HN
O
Ph OMe
O
OMe
O
PhCH2NH2PhCH2NH2
100%0%
5-exo-trig 5-endo-trig
Baldwin Rules
YO
O
Y
O
O
Forcyclizationinvolvingatrigonalcarbon,abitmorecomplicatedanalysishasbeenproposed
6-enolendo-exo-tet
6-enolexo-exo-tet
YO Y
O
O
O
Y Y
6-enolendo-exo-trig
6-enolexo-exo-trig
Suchamodelcanbeapplicabletoenaminesandotherallylicandheteroallylicsystems,aswellaselectrophiliccyclizationwhereacationiccenterisstabilizedbytheoverlapwithanadjacentlonepair,
forexample,oxycarbeniumoriminiumions.
Baldwin Rules
Baldwin,J.E.JCSChem.Commun.1977,323.Tet1982,38,2939
Enolendo-Exo Enolexo-Exo
Tet Trig Tet Trig
3
7
6
5
4
easy
difficult
Baldwin Rules
5-exo-tet 5-enolendo-exo-tet
O
BrBr
OO O
OO BrBr OO
6-exo-tet 6-enolendo-exo-tet
Baldwin Rules
5-enolendo-exo-tet
O
O O
Δ ΔO
O O
6-enolendo-exo-tet
O
OO
OOO
O
OO
OO
O
OO
O
OOO
…but
OO
OO
OO
6-enolendo-exo-tet
5-enolendo-exo-tet
5-enolendo-exo-tet
thesynthesisofthesix-memberedringisfavoredCaution:theringformingisnottheRDS
Baldwin Rules
Thephysicalbasesoftheruleslieinthestereochemicalrequirementsofthetransitionstatesforthevarioustetrahedral,trigonal,anddigonalringclosureprocesses.
Ineachcase,thesubtendedangleismaintainedduringthereactionpathway
Tet
Trig
Y XX
α
YX
Y
X α
Thefavoredring-closingreactionsarethoseinwhichthelengthandthenatureofthelinkingchainenabletheterminalatomstoachievethepropergeometryforthereactions.
Thedisfavoredringclosingprocessesrequiredistortionsofbondanglesrenderingthesereactionspathwayshigherinenergy.
Baldwin Rules
Theseideasarerootedonstereoelectronicgrounds…
Forareactiontotakeplace,moleculesmust:
–overcometheirelectronicrepulsionbychargeattractionand/ororbitaloverlap
–haveorbitalsofappropriateenergytointeract:afilledorbitalonthenucleophileandanemptyorbitalontheelectrophile
–approacheachothersuchthattheseorbitalscanoverlaptoformabondinginteraction
Chapter5
Baldwin Rules
Trig
Burgi-Dunitztrajectory
YX
Y
X
LUMO
π∗
HOMO
Tet Y XXσ∗
LUMOHOMO
Forinstance,theyareassociatedwiththeSN2andtheionicadditionstocarbonyls
…orthealkylationofenolates…
Baldwin Rules
ImagefromDavidA.Evanshandouts
Baldwin Rules
Somecaveatsand“violations”shouldbeconsidered
toavoidwrongpredictions
SimpleFirstlineofanalysisUsefulforthestudyofmechanismsSyntheticlanguage
Don’tforgetthatBaldwinrulesonlypredicttherelativefacilityofdifferentringclosures
Baldwin Rules
2.Pericyclicreactionsarenotaffected
1.Donotapplytoequilibriumprocesses:theRDSshouldbetheringformingstep
3.Atomsinvolvedmustbeinthefirstrow:C,N,O.Sulfurandhydrogen,forinstance,NO
CO2Me
HO
CO2Me
O
CO2Me
HS
CO2Me
Sbut
5-endo-trig 5-endo-trig
Alabugin,I.V.Chem.Commun.2013,49,11246
Caveatstobeconsidered:
Baldwin Rules
4.Anionic,radical,andcationicprocessesarenotruledbythesamestereoelectronicpatterns
Caveatstobeconsidered:
AnionicTrig
HOMO
LUMO
Burgi-Dunitztrajectory
YX
Y
X
LUMO
π∗
HOMO
CationicTrig
Alabugin,I.V.Chem.Commun.2013,49,11246
π
Attacktrajectoriesforelectrophilicreagentsarequitedifferentfromthenucleophilictrajectories
Baldwin Rules
Nucleophilic ElectrophilicTarget:HOMOTarget:LUMO
YnNu
nNu
σ*C–YY
σ*C–Y
Y Y
nNu nNu
π*C–Y π*C–Y
Y Y
nNu nNu
π*C–Y π*C–Y
Y
pElec
Y
πC–Y
pElec
Y
pElec
πC–Y
Alabugin,I.V.
Baldwin Rules
4.Anionic,radical,andcationicprocessesarenotruledbythesamestereoelectronicpatterns
Caveatstobeconsidered:
SometrendsinradicalcyclizationweresummarizedbyBeckwithasfollows:
1.Intramolecularadditionsunderkineticcontrolinloweralkenylandalkynylradicalsoccurpreferentiallyintheexomode
2.Substituentsonanolefinicbonddisfavorradicaladditiontothesubstitutedposition
3.Homolyticcleavageisfavoredwhenthebondconcernedliesclosetotheplaneofanadjacentsemi-occupiedorbital,oranadjacentfillednon-bondingorbital,orπ-orbital
Beckwith,A.L.J.JCSChem.Commun.1980,482.SeealsoAlabugin,I.V.JACS2011,133,12608
Cationicandradical5-endocyclizationareoftenobserved
Forrecentexamples,seeSmith,M.D.NatureChemistry2015,7,171;Bonjoch,J.OL2017,19,878
Baldwin Rules
5.Intramolecularepoxideopeningstendtofollowrulesthatliebetweenthosefortenandtrig
R O
HO
R O
HO5-exo-tet 6-endo-tet
representsthesp3hybridization
adoptsadoublebondnotation:fromastrictpoint–atetcyclization–ofview,bothapproachesshouldbeexo
Normally,exoprocessesarefavoredJamison,T.F.
Mar.Drugs2010,8,763
Caveatstobeconsidered:
Baldwin Rules
R O
HOO
ROH
5-exo-tetR O
OHO
R OH6-endo-tet
Ananti-Baldwinpathwaymaybecomecompetitivewhenitispossibletolowerthe∆∆G≠
R exo/endo
MeO
O
MeO
O
100/0
40/60
0/100
Nicolaou,K.C.JACS1989,111,5330
SeeAlabugin,I.V.Chem.Commun.2013,49,11246
Baldwin Rules
Caveatstobeconsidered:
6.Alkynesrequireanewsetofrules
DigX
Y
X
Y
TheoriginalBaldwin’sproposalisnotsupportedby
theoreticalcalculations
Theproposeddigonaltrajectorydoesnotsatisfythestereoelectronicrequirementsfornucleophilicattacktoaπ-bond,
assupportedbyhighlevelcalculations
H H
X
π∗
H
X H
Actually,thepreferredtrajectorydependsonthetypeofcyclization…Alabugin,I.V.CR2011,111,6513
Baldwin Rules
Exo Endo
Tet Trig Dig Tet Trig Dig
3
7
6
5
4
≈
≈≈
easy difficult≈ borderline
Rulesadaptedfrom:Alabugin,I.V.CR2011,111,6513;JACS2011,133,12608;JACS2012,134,10584
