methods and design in organic synthesisdiposit.ub.edu/dspace/bitstream/2445/134177/9/6.2. cyclic...
TRANSCRIPT
methodsanddesigninorganicsynthesis
2018-19Master Course
PereRomea
inOrganicChemistry
byJohnR.R.Tolkien
6.3.Makingrings(I)
6-Membered Rings
memberedringsareexcellentbenchmarkstotestanykindofreactivity
promotedbynucleophiles,radicals,electrophiles
pericyclicprocesses,
cascadesequences
&others(BIRCHREACTION)
6-Membered Rings
AlkylationReactions
6-enolendo-exotet
O O
Br
O O
Br
6-enolexo-exotet
O
Br
O
LDA
60%O
CN CN
OH
HLDA
73%
6-Membered Rings
6-enolendo-exotrig
OHR
RCOR
O O O
or6-enolexo-exotrig
O
OHR
O
RCOR
O
orAldolReactions
O
OCO2R
O
6-enolendo-exotrig
OCO2R
OR
O O
OR6-enolexo-exotrig
DieckmannReactions
6-Membered Rings
6-enolendo-exotrig
6-enolexo-exotrig
SirRobertRobinson(1886-1975)
NOBELPRIZEINCHEMISTRY1947forhisinvestigationsonplantproductsof
biologicalimportance,especiallythealkaloids
Robinsonannulation
Michaeladditionofacarbonyltoanenonefollowedbyanintramolecularaldolcondensation
O
BaseO
O
O
O
O
O
COR
O
COR
O
MichaelReactions
6-Membered Rings
ArthurJohnBirch(1915-1995)
SirRobertRobinsonwashisPhDsupervisor
EWG:CO2H,COR,CN EDG:OR,NR2,alkyl
NH3, ROH
OMe OMe O O
Li or Na H3O+ H3O+
CO2H CO2
NH3, ROH
Li or Na
H3O+
CO2H
1) MeI
2) H3O+
CO2HMe
EWG EWG EDG EDGBirchReduction
6-Membered Rings
ArthurJohnBirch(1915-1995)
SirRobertRobinsonwashisPhDsupervisor
H
HMeO
H
OO
H
HMeO
H
OO
NH3, EtOH
Li
H
HO
H
O
Progesterone
EWG:CO2H,COR,CN EDG:OR,NR2,alkyl
Birch,A.J.JCS1964,3309
EWG EWG EDG EDGBirchReduction
6-Membered Rings
Initiation
Cyclization
Termination
generationofthecationiccenter
interactionofthecationiccenterwithaπ-bond
fateoftheresultantcation
OH
Nuinitiation cyclization termination
ROH
RO
RO R
RO
6-endo-trig
Cationiccyclizations
6-Membered Rings
TFA, Cl(CH2)2Cl
OH
OO
O
H
H H
O
O
O
O
OO
H
H H
O
H2O, MeOH
K2CO3
72%
O
OH
H H
O
H
1) O3, CH2Cl2/MeOH2) Zn, AcOH
88%
Johnson,W.S.JACS1971,93,4332;1978,100,4274
H
H H
O
H
O
H2O, rt
KOH
51% Progesterone
6-Membered Rings
ThePrinsreactionreferstotheacidmediatedattackofanalkenetoacarbonyl
Foramicroreview,see:Floreancig,P.E.EJOC2013,1193
R2
OH
R1 H
O
OR1
Nu
R2Nu, LA or H+
6-endo-trig
R1 H
O
R1 H
OH
H
R2
OH
R1 O R2
OH
HR1 O R2 R1 O R2
R1 O R2
Nu
Nu
R2
OH
Nu
, H
Prinscyclization
6-Membered Rings
Maier,M.E.CEJ2008,14,11132
O
O O
MeO
O
H H
ON
ON
H OMe
O
O
OTBDPS
MeO
O
H H
O
CF3
OBn
O
H
OTBDPS
MeO
HO OBn
CF3CO2H, CH2Cl2 –5 °C
72%
Neopeltolide
OMe
OMe
OMeO
HO
TBSO
SiMe3
H O
TBSO
HH
OMeO
BF3·OEt2, CH3CN –30 °C
50%
O
HO
H
OMeO
OH OH
Markó,I.E.CEJ2006,8,6111
Methyl Monate C
6-Membered Rings
RingClosingMetathesis(RCM)
+ DielsAlderCycloaddition
ElectrocyclicRearrangement
Diels-Alder Reaction
ThevenerableDiels-Alderreaction:astraightforwardroutetosix-memberedrings
TheNobelPrizeinChemistry1950...
...fortheirdiscoveryanddevelopmentofthedienesynthesis
Otto Diels Kurt Alder
ForareviewontheDiels-Alderreactionintotalsynthesis:Nicolaou,K.C.ACIE2002,41,1668
ForarecentviewonindustrialapplicationsoftheDiels-Alderreaction:Funel,J.-A.ACIE2013,52,3822
Diels-Alder Reaction: Key Concepts
diene
dienophile
ThevenerableDiels-Alderreactionisa[4πs+2πs]cycloaddition
Rememberthatanalkynecanalsoparticipateintheprocess
+
+
Diels-Alder Reaction: Kinetics
Thekineticsofthereactiondependsonconformational…
O
O
O
O
O
O
+
1
2.25
~ 0
3
1350
kDioxane, 20 °C
Foraconformationalanalysison1,3-butadienes:Squillacote,M.E.JOC2005,70,6564
0 90 180 270 360
cis
trans trans
skew
Diels-Alder Reaction: Kinetics
Occasionally,thelackofconformationalfreedomcanbeuseful…
Medrogestone
O
H
O
HH
HOO
H
O
HHBF3·OEt2 +
O
H
O
HH
trans conformation unreactive cis conformation reactive
O
H
O
HH
OO
O
OO
OO
O
O
Winkley,M.W.;Mitchell,R.D.(AmericanHomeProducts)US5428151A,1995
Diels-Alder Reaction: Kinetics
…andelectronicissues.
+ k
CN
CNNC
CNNC
NC
CNNC
NC CN
~ 0
1
5 · 104
5 · 105
5 · 107
Dioxane, 30 °C
ForreviewsonmechanisticaspectsoftheDiels-Alderreaction:Sauer,J.ACIEE1967,6,16;Sustmann,R.ACIEE1980,19,779
Essential:
electronically rich diene & electronically poor dienophileComplementary character.
O
O
O
O
O
O
+
1
2.25
~ 0
3
kDioxane, 30 °C
12.3
OMe
0.1Cl
1350
ClCl
ClCl
ClCl
Diels-Alder Reaction: Kinetics
InDiels-AlderreactionsunderNormalelectronicdemand
diene must be able to achieve the s-cis conformation
s-ciss-trans
diene should contain electrondonating groups (EDG); dienophile, electronwithdrawing groups (EWG)
COR CO2R NO2 CO2RCNO
O
O
OR NR2Me
Lewis acids catalyze such cycloadditions
OO
O
O OOCH2Cl2, 25 °C
+
Without AlCl3
With 1 equiv AlCl3
t1/2 ∼ 2400 h
t1/2 < 1 min
Diels-Alder Reaction: FMO
diene dienophile
ThemechanisticpathwayoftheDiels-AlderreactioncanberationalizedthroughFMOanalysis
HOMO
LUMO
Thermodynamics: broken bonds, 3 πnew bonds, 2 σ + 1 π
2 σ – 2 π
Neutralelectronic demand
Normal electronic demand
Kinetics: As ∆E decreases for the relevant ground state FMOs,
reaction rate increases
The critical energy difference:E (LUMO) - E (HOMO)
The closer the two orbitals are in energy,the better they interact
E
EDGEWG
Diels-Alder Reaction: Siteselectivity
TheHOMO-LUMOinteractionandthecyclictransitionstate
provideoutstandinglevelsofselectivity...
Chemoselectivity(Siteselectivity):richdiene/poordienophile
CHO
+CHO CHO
O
+
O
CN
CN
O
O
CN
CN
O
O CN
CN
16% 62%
Diels-Alder Reaction: Regioselectivity
Regioselectivity:ortho-pararule
EDG
EWG
EDGEWG
EDG
EWG
EWG
EWG
EWGEDGEWGEDG
EWG
EDG
ortho
para
meta
meta
EtONEt2 NEt2
CO2Me EtO
CO2Me
CO2MeCO2Me
Single product Single product
meta
Lewis acids improve the regioselectivityCO2Me
CO2MeCO2Me +
para
Without Lewis acid, 120 °C, 6 h 70 : 30
1 eq AlCl3, 20 °C, 3 h 95 : 5
Diels-Alder Reaction: Regioselectivity
Theortho-pararulecanbeunderstoodthroughanalysisofFMOorbitals
OMeCHO
OMeCHO
HOMO LUMO
OMe
CHO
HOMO LUMO
large
small large
small
OMe
CHO
large
small
large
small
Large/Large & Small/Small interactions are better than Large/Small & Small/Large interactions
Diels-Alder Reaction: Stereoselectivity
Stereoselectivity:endorule
H
O
O
O
OO
O
OO
OH
HH
HOMOLUMO
O
O
O
HOMOLUMO
O
O
O
endo
exo
Diels-Alder Reaction: Stereoselectivity
KineticvsThermodynamicControl
Instead,the exo isomer predominates
at equilibrium
Thermodynamic Control
endoexo
O
H
H
O
O
O
H
H
O
O
O
O
O
E
If equilibrium cannot be reached under the experimental conditions,
the endo isomer predominates
Kinetic Control
ΔΔG
ΔΔG°
Diels-Alder Reaction: Stereoselectivity
Lewisacidsimprove
endostereoselectivity CO2Me CO2Me
H
H
CO2Me+
endo exo
+
CH2Cl2, 0 °C
C6H6, SnCl4, 25 °C
80 : 20
95 : 5
endo : exo
Endostereoselectivityisexcellentwith
planardienophilesO
O
O
O
O
Exodiastereomersarepreferred
withαsubstituteddienophiles
R X endo : exo
HHH
MeMeMe
CNCOOMe
CHOCN
COOMeCHO
55 : 4571 : 2971 : 2916 : 8432 : 6824 : 76
X
R
R
X+ +XR
endo exo
100 °C
Diels-Alder Reaction in Synthesis
ClassicalsynthesesbyWoodwardtookadvantageofDiels-Alderreaction...
+86%
Δ
O
O
Me
HMeO
O
O
MeMeO
O
OMe
MeO
HOH H
H
H
Cholesterol
Woodward,R.B.JACS1952,74,4223endo TS
...evenwithdienescontainingEWGgroups...
O
O
CO2Me
+ MeO2C
O
O
O
O H
H
CO2Me
90%
Δ NH
HH CO2MeOMe
OCOAr
N
MeOH
Reserpineendo TS
Woodward,R.B.JACS1956,78,2023,2657ForareviewonquinonesasdienophilesinDiels-Alderreaction:
Moody,C.J.ACIE2014,53,2056
Diels-Alder Reaction in Synthesis
TMSO
EWG
TMSO
EWG
O
EWG
Infact,electronrichdienescontainingR3SiOsubstituentsareveryuseful...
TMSO
OMe
O
EWG
TMSO
EWGOMeEWG
Danishefsky’s diene
Matsuo,J.-i.OL2010,10,4049
Platensimycin
+Δ TFA
dr 11:1 83%
O
O
HBzOOTBS
O
HBzO
R OMeO
BzOOTBS
OMe O
O
N
O
H
OH
OHHO2C
Diels-Alder Reaction in Synthesis
IntramolecularDiels-Alder(IMDA)reactionsareveryefficient...
Conrotatory ring opening
73%
Δ NO
O
O
O
O
BnONO
O
O
O
O
BnOOO
O
O
NBnO
O
Antibiotic X-14547A
Nicolaou,K.C.JOC1985,50,1440
OH H
O
HOH
O NH
EtH
70%
Δ
H Et
MeO2C HTBDPSOTBDPSO
MeO2C
Et
Carbo Diels-Alder Reaction
Retron:molecularsubstructurethatenablescertaintransformations
+
SupraRetron:molecularsubstructurethatcanbeassociatedwithavariantofageneraltransform
+
O
O+
α-pyrone
O Cl CN+
O R3SiO
OMe
+
Danishefsky’sdiene
Hetero Diels-Alder
ThesubstitutionofaCatomofoneofthereagentsinvolvedintheformercarboDiels-Aldergivesrisetoanew[4πs+2πs]cycloadditionnamedheteroDiels-Alder
Thermodynamics: broken bonds, 3 πnew bonds, 2 σ + 1 π
2 σ – 2 π
KEEP ALSO IN MIND THE ENTROPIC FACTOR
diene dienophile
YX AB
+Y
XBA
X, Y, A, or B: N or O
Hetero Diels-Alder
TheheteroDiels-AlderreactionsaremechanisticallymuchmorecomplexthantherelatedcarboDiels-Alderreactions,
butonecanalsodifferentiatenormalandinverseHDA
OC
+ O
diene dienophile
Normal HDA
HOMOdiene – LUMOdienophile
O+
O
diene dienophile
Inverse HDA
HOMOdienophile – LUMOdiene
ForreviewsonHDAreactionssee,Jorgensen,K.A.ACIE2000,39,3558;EJOC2004,2093Feng,X.Synlett2007,2147;Pellissier,H.Tet2009,65,2839
Miller,M.J.ACIE2011,50,5630;Kumar,K.;Waldmann,H.ACIE2014,53,11146
Oxa Hetero Diels-Alder
electron-richdiene
electron-poordienophile
OMe
R3SiO
OSiR3
AlkO
OAlkyl
Danishefskydienes Brassarddienes
H R
OAlk
OOR
O
Aldehydes a-Oxoesters
OMe
TMSO+
O
RH
O
O R
Lewis acid
50–95%
O
TMSO R
OMe
NormalHDA +OO
C
Stereoselective Synthesis of (+) Ambruticin
Jacobsen,E.N.JACS2001,123,10772
O O
OH
HH
OH
O
HOH
H
H H
C=C#bond#formation
Julia1Kocienski
OO
OH
HH
OH
HO OH H
OOH
HHHO O
H HHO
AsymmetricHDAprovidesaquickaccesstobothpyranheterocycles
(+) Ambruticin
Stereoselective Synthesis of (+) Ambruticin
Jacobsen,E.N.JACS2001,123,10772
10 mol %
rt
OTBS
OBn
OTBDPSO
H
ON
OCr
Cl
97%$ee$$$$$64%
O
OTBS
OBnH
TBDPSOH
then 30% H2O2, 3 M NaOH, rt
BH3·THF, THF, 0 °C94%
O
OTBS
OBnH
TBDPSOH
OH
O
OTBS
OH
TBDPSOH
OTBS
H
2) H2, Pd/C
3) cat TPAP, NMO, CH2Cl2, rt
1) TBSOTf, 2,6-lutidine, CH2Cl2, –30 °C
88%
Oxa Hetero Diels-Alder
electron-poordiene
electron-richdienophile
Deactivatedenones Vinylethers
+O O
OEtO
OOEt
+Lewis acid O OEtEtO
O
95%
ORORO
O
InverseHDA
Aza & Nitroso Hetero Diels-Alder
ForreviewsonasHDAreactionssee,Oh,T.Tet2001,57,6099Masson,G.CSR2013,42,902
N+ N
N+
N
N + N
NO
+ON
Aza Diels Alder
Nitroso Diels Alder
Stereoselective Syntheses of (+) Lasubines
Carretero,J.C.JOC2007,72,10294
N
MeOMeO
OH
H HN
MeOMeO
OH
H H(+) Lasubine I (+) Lasubine II
N
MeOMeO
O
H HN
MeOMeO
O
H H
NH
MeOMeO
O
H HX
heterolytic*C–C*formation
N
MeOMeO
O
HX
radical'C–C'formation
NTs
MeOMeO
O
H
Stereoselective Syntheses of (+) Lasubines
MeOMeO
NTos
H
OTMS
OMe
CH2Cl2, –20 °C; then TFA
97%$ee$$$$$71%
Fe
SP
Cu
t-Bu
RR
Br
25 mol %
10 mol % AgClO4 NTs
O
MeOMeO
H
NTs
O
ArH
THF, rt
Zn, NH4Cl
NH
O
ArH
(Boc)2O, Et3N, DMAP
CH2Cl2, rt NBoc
O
ArH97% 99%
(+) Lasubine I (+) Lasubine II
Carretero,J.C.JOC2007,72,10294
Stereoselective Syntheses of (+) Lasubines
NH
O
ArH
NaH, THF, rt
75%
ClI
N
O
ArH
ClN
O
ArH
Iacetone, Δ
99%
NaI
N
O
ArH H benzene, Δ
69%
Bu3SnH, AIBN(+) Lasubine I N
OH
ArH H THF, –78 °C
79%
L-Selectride
NH
O
ArH
THF, –40 °C
cis/trans)90:1077%)cis
ClMgI
SnCl4
5 eq CuBr·Me2S
NBoc
O
ArH H
Cl
EtOAc NH
O
ArH H
Cl
(+) Lasubine II N
O
ArH H CH2Cl2, rt
70%
K2CO3
N
OH
ArH H THF, –78 °C
65%
L-Selectride
WhatdoIwearinbed?
MarilynMonroe
5-Membered Rings
Fivememberedringsarehighlyvaluablesubstratesandahugevarietyofapproacheshavebeendevised
RadicalcascadesNazarov1,3-DipolarcycloadditionsPauson-Khand
Thesyntheticmethodsforthe5-membered-ringsaresimilarbutnotidenticaltothosefor6-membered-rings
5-Membered Rings
Exo Endo
Tet Trig Dig Tet Trig Dig
3
7
6
5
4
≈
≈≈
5-Membered Rings
Enolendo-Exo Enolexo-Exo
Tet Trig Tet Trig
3
6
5
4
7
5-Membered Rings
6-enolendo-exotet
6-enolexo-exotet
O O
Br
O O
Br
5-enolendo-exotet
5-enolexo-exotet
O
Br
O
Br
OO
Alkylationreactions
5-Membered Rings
Initiation
Cyclization
Termination
generationoftheradicalcenter
interactionoftheradicalcenterwithaπ-bond
fateoftheresultantradical
R O
SR
RadicalcyclizationstoleratealargevarietyofFG
cyclization
termination
5-exo-trig
initiation
IBu3Sn
Bu3SnH
H
Radicalcyclizations
5-Membered Rings
Bu3Sn
H
H
H
H H
Bu3SnH
I H
H H
Bu3SnH, AIBN
PhH, reflux
64%Hirsutene
Curran,D.P.JACS1985,107,1445
Radicalcyclizations
5-Membered Rings
RingClosingMetathesis(RCM)
5-Membered Rings
RingClosingMetathesis(RCM)
+ DielsAlderCycloaddition
ElectrocyclicRearrangement
5-Membered Rings
RingClosingMetathesis(RCM)
ElectrocyclicRearrangement?
Cycloaddition?
+
5-Membered Rings
Nazarov:anelectrocyclicreaction4e–π
HOMO
conrotatoryunderthermicalconditions
O
H H
O
OH
OH
H+
OH
H H
Synthesisofcyclopentenones
5-Membered Rings
Diels-Aldercycloaddition +
diene dienophile
4e–π4atoms
2e–π2atoms
Isitpossibletofindadienewith4e–πandjust3atoms?
O
OO
O
OO
Ozoneanexampleof1,3-dipole
OOO
1,3-dipolarcycloaddition
1,3-dipole
O
OO
O
OO
retrocycloaddition
O
OO
1,3-dipolarcycloaddition
Anyotherdipoles?Other1,3-dipolarcycloadditions?
5-Membered Rings
1,3-Dipolarcycloadditions NO
RNO
R
Nitrones
NO
RR
LUMO HOMO
electron-richalkene
RONR
1,3-dipolarcycloaddition
N RH
ROH
reductionN–Obond
NO
RR
O
R
ONR
O
LUMOelectron-pooralkene
HOMO
1,3-dipolarcycloaddition
R OH
O
NHR
reductionN–Obond
5-Membered Rings
N OR N OR
Nitrileoxides Azides
N N NR
N N NR
LUMO
1,3-dipolarcycloaddition
reductionN–Obond
electron-richalkeneHOMO
R
N OR
NO
R
R
R
O
R
OH
N N NR
R
NN
N
R
R
Cu(I) catalyst
ClickChemistry
Sharpless,B.K.ACIE2001,40,2004
5-Membered Rings
cat Et3NΔ
R NO2 + N C O 2 R N OR + CO2 +RHN NHR
O
TBDPSO H
O
+KHMDS
DME, 0 °C
E/Z 10:1 93%
BnO
BnO
NO2
O
O
SOO
NN
N N
Ph
TBDPSO
BnO
BnO
O
O
NO
Et3N, benzene
4-ClPhNCO
Δ
BnO
BnO
O
O
ON80%
BnO
BnO
O
O
O
i) Mo(CO)6·9H2OCH3CN/H2O, Δ
ii) MsCl, Et3N
67%
BnO
BnO
O
O
O
Lee,J.OL2017,19,6004 (+)-Sieboldine A
5-Membered Rings
Pauson-Khandreaction(PKR)
Aformal[2+2+1]cycloadditionofanalkyne,analkeneandCO
RRCo2(CO)8
R R
(CO)3Co Co(CO)3
R R
COO
RR
RR
( )n ( )n
Co(CO)3(CO)3CoCo2(CO)8
CO( )n O
leadingtotheinterorintramolecularsynthesisofcyclopentenones
OC O
Pérez-Castells,J.CSR2004,33,32;Afonso,C.A.M.CR2016,116,5744
5-Membered Rings
PKRcanbehighlyregioselective…
LargeandEDGgroups
SmallandEWGgroups
R1
R2
CO,
Δ
R2
O
R1Co2(CO)6
Et
Me Me
O
EtCO,
Δ
Et
O
Me+
8 : 1
Co2(CO)6
Laschat,S.Synlett2005,2547;Riera,A.JOC2014,79,10999
CO, Δ
CO2EtMeCo2(CO)6 O
Me
CO2Et
H
H
5-Membered Rings
canbecarriedoutundercatalyticconditions…
Mukai,C.SOL2017,19,320 (+)-Sieboldine A
…andbecomehighenantioselective
OMeO2CMeO2C
MeO2CMeO2C
5 mol % Co2(CO)8
30 mol % NMe Me
N
SMeMe
1 atm CO, PhH, 70 °C
96%
OTBS
OPMB
O
O
H
O
N
H
Me
O
H
OTBS
OPMB
20 mol % Co2(CO)820 mol % TMTU
1 atm CO, PhCH3, 70 °C
dr 98:2 96%
Chen,J.SOL2005,7,593
5-Membered Rings
Verdaguer,X.Science2016,353,866.Synthesisof(+)-ryanodolbyChuang,K.V.;Xu,C.Science2016,353,912
Therefore,thePKreactionisanintraorintermolecularcycloadditionbetweenanalkyne,analkene,andCOpromotedorcatalysedbyCo,butalsoRh,Ir,…
COCo2(CO)8
Toluene, ΔO
O
H
O HO
TMS
TES
O
O
H
O
OTMS
HOTES
O
H O
HO
H
O
O
H
OH
OO
(+)-Propindilactone G
IntramolecularCo-mediated
N
N
N
NHO NH2H
H
NH2H
ClHO
NH
ArO
NH
O
Ar
TMSO
TMSO
O
NHBocNHBoc
OTMS
TMSO
COCo2(CO)8
NMO, CH2Cl2
Axinellamines
IntermolecularCo-mediated
HO
OHO
HO
OH
OHOH
OH
ORO
RO
O
OORO
RO
OCO
1 mol% [RhCl(CO)2]2Δ
(+)-Ryanodol
IntramolecularRh-catalyzed
5-Membered Rings
NTs
NTs
O
HCO, Co2(CO)8, R-BINAP
NMO, PhCH3, 65 °C
72%
NTs
O
HAllylMgCl, CuI, LiCl, TMSCl
THF, –10 °C
91%
HG II, CH2Cl2, Δ
1)
2) HCl
85%
NTs
O
H
OH
OTBS
N CF3
Br
NTs
O
H
O
N CF3
R NaHMDS, THF, –30 °C
NTs
O
H
NH
DMAP, THF, rt
NHBr, Br2
90%
NTs
O
H
HN
1) G-II, CH2Cl2, Δ2) K2CO3
71%
N
H
NH
O
Nakadomarin A
Clark,J.S.ACIE2016,55,4332
NTs
O
H
NCOCF3 PhCH3, Δ
73%
5-Membered Rings
heteroPauson-Khandreaction(h-PKR)
Occasionally,thealkene(C=Cbond)maybereplacedbyacarbonyl(C=Obond)toproduceaconjugatedbutyrolactonethroughaformal[2+2+1]cycloaddition
OO
OC O
(±) Aplykurodione Zhai,H.OL2017,19,1056
2.5 equiv Mo(CO)61 atm CO
PhCH3/DMF, 140 °C
60%O
O
H
TMS OO
O
OO
O
H
HOO
O
H
H
H