syntheses using the oxiranyl anion methodology - iasoc · syntheses using the oxiranyl anion...
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Syntheses Using the Syntheses Using the Oxiranyl Oxiranyl Anion MethodologyAnion Methodology
Saverio FlorioSaverio Florio
Dipartimento FarmacoDipartimento Farmaco--Chimico, UniversitChimico, Universitàà degli Studi di Bari degli Studi di Bari -- ItalyItaly
[email protected]@farmchim.uniba.itwww.farmchim.uniba.it/chimica_organicawww.farmchim.uniba.it/chimica_organica
IASOCIASOC--20062006
C I
PI
NM
S
The The HistoryHistory::CopeCope and and CrandallCrandall((late fiftieslate fifties))
Eisch and Galle Eisch and Galle ((middle seventiesmiddle seventies))
Eisch, Molander, Eisch, Molander, PfaltzPfaltz, , YamakawaYamakawa, , SatohSatoh, , Mori, Mori, JacksonJackson, Doris and , Doris and DechouxDechoux, , HodgsonHodgson, , MalacriaMalacria, , UneyamaUneyama, Florio , Florio ((ninetiesnineties))
α-Lithiated Oxiranesαα--LithiatedLithiated OxiranesOxiranes
ReviewsReviews and and AccountsAccounts: : SatohSatoh, , ChemChem. . Rev.Rev. 1996, 96, 33031996, 96, 3303MoriMori, Rev. Heter. , Rev. Heter. ChemChem. 1997, 17, 183. 1997, 17, 183HodgsonHodgson, , SynthesisSynthesis, 2002, 12, 1625 , 2002, 12, 1625 HodgsonHodgson, , SynlettSynlett 2006, 12006, 1--2222FlorioFlorio, Tet. Symposia in , Tet. Symposia in PrintPrint, 2003, 9713, 2003, 9713FlorioFlorio, , SynlettSynlett 2005, 9, 13592005, 9, 1359--13691369ChemlChemlàà, The Chemistry of , The Chemistry of OrganolithiumOrganolithiumCompoundsCompounds, , PataiPatai, 2004, , 2004, Vol.Vol. 2, 2, chapchap. 18. 18
O
Ph
LiO
Ph
Li
OLiOLi
O R1
R2
R
Li
Under investigation:-generation-nature (carbanion or carbenoid)-chemical and configurational stability-stereochemistry
OH OH
RLi
O
Ph
H O
Ph
E1) RLi2) E+
SnR3
O
R2
RR1
TransmetallationTransmetallationTransmetallation
SiMe3
O
R2
RR1
DesilylationDesilylationDesilylation
SOAr
O
R2
RR1
DesulfinylationDesulfinylationDesulfinylation
H
O
R2
RR1
DeprotonationDeprotonationDeprotonation
OxiranyllithiumsOxiranyllithiums in in SyntheticSynthetic OrganicOrganic ChemistryChemistry
Li
O
R2
RR1
R = EWGR = H, Alkyl
Li
OLi
R2
RR1
β-Oxido Carbenoidββ--OxidoOxido CarbenoidCarbenoid
Cl
A. A. PfaltzPfaltz, , TetTet. . Lett.Lett.19911991, , 3232, 615, 615
Shimizu, M. Tet. 2003, 59, 9811
K. K. YamakawaYamakawa, , J. J. OrgOrg. . ChemChem..19891989, , 5454, 3130, 3130
KobayashiKobayashi. . TetTet. . Lett.Lett. 19991999, , 4040, 7371, 7371
MultifacetedMultifaceted ReactivityReactivity of of OxiranyllithiumsOxiranyllithiums::CarbanionsCarbanions and and CarbenoidsCarbenoids
O
Li R2
R1R
RR1
OLi
R2O
E R2
R1R
ROLi
R1
R2
RR1
Nu
R2
R
LiOR2R1
R
OLiR2 R1
OR R1
R2
R
LiO
R1
R2Li
NuOLi
R
R1R
Li C
R3
OLi
R1R2
R4
H
CH
R4 R3
β-elimination
electrophilic
trapping
1,2-R1 shift
eliminativedimerization
NuLi (reductive alkylation)
(E1-like or elettrocyclic
ring-opening)
"C–H" insertion
R =
-Li2O
OLi
n
OH
n
Intramolecular cyclopropanation
R1 = Alkenyl
O
R
Li
Homochiraldimerization
Heterochiraldimerization
RR
O
Li
OLi
RR
OH
OH
R
RO
Li
OLi
R
RHOHO
Syn eliminationO
R
LTMP
OTrOH2C
TrOH2CCH2OTr
OH
OH
LiN(t-Am)2
1) OsO4Me3NO
2) Amberlist 15
1) OsO4TMEDA
2) HClMeOH
CH2OH
HOH2COH
HOOH
HO
CH2OH
HOH2COH
HOOH
HO
D-Mannitol84 %
D-Iditol95 %
D. M, Hodgson Org. Lett. 2005, 2305
22--EneEne--1,41,4--diols diols byby DimerizationDimerization of Terminal of Terminal EpoxidesEpoxides
D. M, Hodgson Synthesis 2005, 1
OxiranylOxiranyl anionanion methodologymethodology: : synthesissynthesis of the of the naturalnaturalproductproduct XialenonXialenon AA
[Si]O
[Si]OO
i-PrLiα-isosparteine
1) -90 °C to 25 °C2) H+
[Si]O
OHH
O[Si]
1) TPAP-NMO2) LDA, TMSCl3) Pd(OAc)2
80 %
[Si]O
OH
O[Si]
AllylMgBrCuI, LiBr, TMSCl
60 %
[Si]O
OH
O[Si]
DBU, MeCN
94 %
[Si]O
O
PhI(OAc)2KOH
HO
O
OH
88 %
[Si]O
[Si]OOLi
XialenonXialenon AA
TPAP: Tetrapropyl ammonium perruthenateNMO: 4-methylmorpholine N-oxide
1) t-BuOK, BuLiTHF, -78 °C, MgBr2
53 %
2) OCl
OHCl
NaOHMeOH93 %
O
LTMPt-BuOMe0 °C to 15 °C
60 %
0 °C to 15 °C
OLi
OH
> 99 % ee
> 99 % ee
TPAP-NMO
95 %
O
OxiranylOxiranyl anionanion mediatedmediated cyclopropanationcyclopropanation: : synthesissynthesisof (of (−−))--Sabina Sabina ketoneketone
Precursor of important flavor chemical foundin a variety of essential oils. D. M, Hodgson Synthesis 2005, 1
TPAP: Tetrapropyl ammonium perruthenateNMO: 4-methylmorpholine N-oxide
((--))--Sabina Sabina KetoneKetone
O
NR1
O
R2
OR1 EWG
R
R2
Li
R
O Ar
Li
O R2
R1
Li
O R2
R1
LiArSO2
R3Si
O R2
R1
Li
O R2
R1
Li
F3C
O R2
R1
Li
O R2
R1
Li
O
RO
Li
O R2
R1
Li
NC
R1
StabilizedStabilized OxiranyllithiumsOxiranyllithiums
SiliconSilicon--StabilizedStabilized OxiranylOxiranyl AnionsAnions::Total Total SynthesisSynthesis of of CeruleninCerulenin
Mani, N. S. et al., J. Org. Chem. 1997, 62, 636
OH
TMS 1) Sharpless Ox
2) Ethylvinylether3) H+
OTMS
O
OEts-BuLi, Et2O
TMEDA, –116°C
OTMS
O
OEt
Li
4E,7E-nonadienal O
OOEt
TMS 1) Bu4NF
2) PPTS MeOH
O
OH
H H TPAP
NMO
OH
OH H
O O
1) NH4OH
2) TPAP NMO
O
O
H
H
H
NH2
O
CERULENIN(Fungal inactivator of fatty acid synthetases)
PPTS: Pyridinium p-toluensulfonateTPAP: Tetrapropyl ammonium perruthenateNMO: 4-Methyl morpholine N-oxide
OH
H
SynthesisSynthesis of of SpatolSpatol AnaloguesAnalogues
Si
H
OTMS
Lindlar
55% OSi
MCPBA
OSi
O
s-BuLi
OSi
O Li
OH
Et2O, –95 °C OSi
O OH
OSi
O OH
+
31% 69%
Bu4NF
83% H
O OH
OH
Me
Me
H
OH
OO
SPATOL
Si
H
OTMS
Lindlar
55% OSi
MCPBA
OSi
O
s-BuLi
OSi
O Li
OH
Et2O, –95 °C OSi
O OH
OSi
O OH
+
31% 69%
Bu4NF
83% H
O OH
OH
Me
Me
H
OH
OO
SPATOL
Salomon, R. G. Terahedron Lett. 1994, 35, 517
OBnO
BnO
OTf
OTESH H
H3C H
AO
SitBu2
OH
HTfO
TESOO
CH3BnO
PhO2S LiO
OTBDPS
SO2PhLi
OBnO
BnO OTESH H
H3C H
A OOTBDPS
SO2Ph TsOH
OBnO
BnOH H
H3C H
AO
HOTBDPS
OB
OBnO
BnOH H
H3C H
AO
HOTf
OTESB
H OOTBDPS
SO2PhLi
OBnO
BnOH H
H3C H
AO
H
OTES
B
H
OOTBDPS
SO2PhO
O
O
O
OH3C H H H H H
BnO
BnOH H H H H
A B C D E OCH3
CH3
H OH OHF
Mory, Y.; Noyori, R.; Takase, T.Tetrahedron Lett. 2003, 2319
O
OO
OO
O
OO
OO
O
CH3
HH
HH
H H HH
HH
H3C OHH
NaO3SO
NaO3SOH
HH
HH
H3C H3C CH3
HH
CH3
H
OH
AB
CD
EF G
HI
JK
YessotoxinYessotoxin
OxiranylOxiranyl anionanion methodologymethodology: Iterative : Iterative synthesissynthesis of of the the ABCDEFABCDEF--ringring system of system of yessotoxinyessotoxin
O
O
XR
O
O
XRLi O
OLi
XR
O
OX R
O
HOX R
RLi
O
O
XR
2) H+
1)O
O
XRE E+
O
OX
R
Li
O
LiO
RO
O
XR
X O
O RX
HO X
RO
RLi
O
O
XR
E
E+H+
O
O
XR
CarbonylCarbonyl--stabilizedstabilized oxiranyloxiranyl anionsanions
“Oxazolinyloxiranyllithiums particularly promising”
G. Molander, Pure & Appl. Chem. 1990, 62, 707-712
αα--LITHIATEDLITHIATEDOXAZOLINYLOXIRANESOXAZOLINYLOXIRANES
O
N
R1
O
*
R
Li R2
-very easy generation (THF, s-BuLi/TMEDA), -high chemical stability, -amenable to synthetic elaboration
O
NR1
O R
Li R2N N
ComputationalComputational DFT DFT studystudy ((bondbondlengthslengths) and IR ) and IR spectroscopyspectroscopy((C=NC=N stretchingstretching frequencefrequence) ) suggestsuggest a a chelatedchelated tetrahedraltetrahedralmonomericmonomeric aggregate.aggregate.
N
O
O
R
R1 H+
RR1
O
N
O Li
O
R
R1N
O
HO
R
R1N
O
Li-100 °C
r.t.
sec-(or n-)BuLiTMEDA
Et2O, -100 °C15 min
HOMO:filled σorbital
LUMO:empty porbital
O
R1RLi
N
O
RR RR11 YieldYield, %, %pp--MeMe--CC66HH44 H H 6767HH pp--MeMe--CC66HH44 6767pp--FF--CC66HH44 pp--FF--CC66HH44 6060PhPh PhPh 6363ii--PrPr H H 3030MeMe MeMe 8080EtEt EtEt 6262
--(CH(CH22))44-- 6262--(CH(CH22))55-- 7575
22--Adamantylidene Adamantylidene 6060
O
NR1
R
OTetrahedronTetrahedron LettLett.,., 20002000, , 4141, 8835, 8835
LithiationLithiation of of OxazolinyloxiranesOxazolinyloxiranes: : SynthesisSynthesis of of OxazolinylOxazolinyl KetonesKetones
PeptidylPeptidyl derivativesderivatives are HNEare HNE(Human Neutrophyl Elastase) (Human Neutrophyl Elastase)
InhibithorsInhibithors
1h-100°C -> r.t.
E+
OxazolineOxazoline--StabilizedStabilized OxiranyllithiumsOxiranyllithiums
TetrahedronTetrahedron LettLett., ., 19981998, 39, 5639, 39, 5639
EurEur. J. . J. OrgOrg. . ChemChem., ., 19991999, 409, 409--417417
s-BuLi/TMEDAEt2O, -100°C, 2h
TetrahedronTetrahedron LettLett., ., 19961996, 37, 4781, 37, 4781
% % YieldYield
959576766262676779798383707065656868
ElectrophileElectrophile
(CH(CH33))33SiClSiClCHCH22=CHCH=CHCH22--BrBr
CHCH33II(CH(CH33))22COCO
CyclohexanoneCyclohexanonePhCHOPhCHO
pp--CHCH33--CC66HH44--CHOCHO(CH(CH33))22CHCHOCHCHO
CHCH33CHOCHO
+ Ph2CON
O
Cl
Li
O Ph
PhEH
O
SynSyn//AntiAnti
50/50/505064/3664/3655/4555/4556/4456/44
O Ph
PhH
N
OOO PhPh
PhPhLiLi
NN
OO
O Ph
PhE
N
O
s-BuLi/TMEDAEt2O, -100°C
OX
N
OO p-Tolyl
HH
Et2O OX O p -Tolyl
HEOX O p-Tolyl
HLi
Li O p-Tolyl
HOX
E +
J. J. OrgOrg. . ChemChem., ., 2001, 2001, 6666, 3049 , 3049 -- 30583058
Regio and Regio and StereospecificStereospecific DeprotonationDeprotonation--TrappingTrapping of of ciscis--OxazolinylOxazolinyl EpoxidesEpoxides
R*R*,S*+R*,,S*+R*,R*R*
E+ = D2O, MeI, PhCHO, MeCHO, Et2CO 60-95% YieldsR*,S*/R*,R* ratio: 80/20 - 95/5
EE++ = D= D22O, O, MeIMeI, , PhCHOPhCHO, , MeCHOMeCHO, Et, Et22CO CO 6060--95% 95% YieldsYieldsR*R*,,S*S*//R*R*,,R*R* ratio: 80/20 ratio: 80/20 -- 95/5 95/5
Li
1.944Å
2.044Å
2.280Å
C
C
N1.286Å
C
C
1.473Å
C
CC
CC
O 3.206Å
O
C
C
CisCis--LiLi1.51 kcal/1.51 kcal/molmol
TransTrans--LiLi0 kcal/0 kcal/molmol
B3LYP/6B3LYP/6--311+G*//RHF/6311+G*//RHF/6--31+G*31+G*
O
C
4.303Å
C
CC
1.485Å
2.038Å
C
C
O
C
2.309Å
1.281Å
Li
1.965Å
C
C
C
N
C
Regio and Regio and StereospecificStereospecific DeprotonationDeprotonation--TrappingTrapping of of transtrans--OxazolinylOxazolinyl EpoxidesEpoxides
s-BuLi/TMEDAEt2O, -100°C
dr > 95:5dr > 95:5dr > 95:5
StableStableE +65 65 -- 80%80%
J. Org. Chem., 2001, 66, 3049 - 3058J. J. OrgOrg. . ChemChem., ., 2001, 2001, 6666, 3049 , 3049 -- 30583058
N
OO H
p-TolylHN
OO H
p -TolylLi
N
OO H
p -TolylE
O H
p -TolylEH
O
E, E’: Me, D, SiMe3, SnBu3, CH2CH=CH2, CH2CH=CMe2, Carbonyl compounds
EE, , EE’’: Me, D, SiMe: Me, D, SiMe33, SnBu, SnBu33, CH, CH22CH=CHCH=CH22, , CHCH22CH=CMeCH=CMe22, , CarbonylCarbonyl compoundscompounds N
OO E’
p -TolylE
E’ +
N
OO Li
p -TolylE
RR
Li(R)
O
N(S) O
RR
Li (S)
O
N(S)O
s-BuLi/TMEDATHF, -98 °C, 1h
E
(S)
O
NO R
RE
(S)
O
NCl
LDA/Ti(i-PrO)4THF, -98°C
(S)
O
NCl
Ti
i-PrO Oi-PrOi-Pr
(S)
O
N
(S)
O R
RH
R2C=O
50 50 -- 75% 75% dr >97:3dr >97:3
LithiationLithiation of of ChiralChiral OxazolinyloxiranesOxazolinyloxiranes
EE++ = D= D22O, CHO, CH33I, AcetoneI, Acetonedr >50:dr >50:5050
•• αα--LithiatedLithiated OxazolinyloxiranesOxazolinyloxiranes are are configurationallyconfigurationally unstableunstable
Tetrahedron. 2003, 9707TetrahedronTetrahedron. . 20032003, 9707, 9707
HOOCNH2
RR1
--presentpresent in in naturalnatural productsproducts--exhibitexhibit importantimportant biologicalbiological propertiesproperties--valuable chiral building blocks for the valuable chiral building blocks for the asymmetricasymmetricconstructionconstruction of of ββ--lactamlactam antibioticsantibiotics--incorporatedincorporated intointo biologicallybiologically activeactive moleculesmolecules enhanceenhancebioactivitybioactivity and can probe and can probe mechanismsmechanisms of action of action
ββ--Amino Amino AcidsAcids
ON
ON
O
R
R4 H R1
R2
R3
O
ON
O
R
R1
R2
R3HOOC
HN
O
R
R1 R2
R3
O
N
LiON
O
R
R4
R1
R2R3
NO
Li
O
R2
R1
R4
NR3
R
O+
RetrosyntheticRetrosynthetic ApproachApproach toto αα--EpoxyEpoxy--ββ--AminoAmino AcidsAcids: : CombiningCombining the the OxiranyllithiumOxiranyllithium MethodologyMethodology withwith the the
ChemistryChemistry of of NitronesNitrones and and OxazolinesOxazolines
NO
Li O R
Rs-BuLi/TMEDA-98 °C; THF
NR1
t-Bu
ON
R1
t-Bu
O
Single Diastereoisomer
Single Single DiastereoisomerDiastereoisomer
O
HN NO
OR R
R1
t-Bu
* **O
HN NO
OR R
R1
t-Bu
* **
NO
H O R
RO
NCl
R2C=O+
LDA
THF, -98°C
ReactionReaction of of LithiatedLithiated OxazolinyloxiranesOxazolinyloxiranes withwith NitronesNitrones
Org. Lett. 2003, 2723Org. Org. LettLett.. 20032003, , 27232723
Yields 68 – 82 % YieldsYields 68 68 –– 82 % 82 %
R = R1 = PhR = RR = R11 = = PhPh
RR RR11 OOxxaazzoolliiddiinnoonneeYYiieelldd %%
AAmmiinnoo AAcciidd YYiieelldd %%
MMee PPhh 6688 9988 ““ pp--MMeeOOCC66HH44 8855 9988 ““ pp--CCFF33CC66HH44 9900 9988 EEtt PPhh 7722 9988
--((CCHH22))55-- PPhh 6611 9988
RR RR11 OOxxaazzoolliiddiinnoonneeYYiieelldd %%
AAmmiinnoo AAcciidd YYiieelldd %%
MMee PPhh 6688 9988 ““ pp--MMeeOOCC66HH44 8855 9988 ““ pp--CCFF33CC66HH44 9900 9988 EEtt PPhh 7722 9988
--((CCHH22))55-- PPhh 6611 9988
O
NH
ON
O R
R
R1
t-Bu
(COOH)2
THF
O
ONt-Bu
O R
R
R1O
HO
HNt-Bu
O
R R
R1 H2
Pd/CO
NH
ON
O R
R
R1
t-Bu
(COOH)2
THF
O
ONt-Bu
O R
R
R1O
HO
HNt-Bu
O
R R
R1 H2
Pd/C
SynthesisSynthesis of of αα--EpoxyEpoxy--ββ--AminoAmino AcidsAcids
NO
Li O R
R
NR1
t-Bu
O+
Org. Lett. 2003, 2723Org. Org. LettLett.. 20032003, , 27232723
ee >99%[α]D = +9eeee >99%>99%[[αα]]DD = +9= +9
ee >99%[α]D = -82eeee >99%>99%[[αα]]DD = = --8282
O
HO
HN(R)
(S)O
H3C CH3
Ph H2/Pd/C
t-Bu
98%O
HO
HN(R)
(S)O
H3C CH3
Ph H2/Pd/C
t-Bu
98%
Org. Lett. 2003, 2723
EnantioselectiveEnantioselective SynthesisSynthesis of of αα--EpoxyEpoxy--ββ--AminoAmino AcidsAcids
Org. Org. LettLett.. 20032003, , 27232723
s-BuLi/TMEDA THF, -98 °C, 1h
(R)
O (S)
N
ON (R)
(S)
O
t-Bu
H CH3
CH3
Ph
O
ON (R)
(S)
O
t-Bu
CH3
CH3
Ph
H+
H2O
(R)
O
N
(R)
O CH3
CH3H
(R)
OH
NH2+
H3CCH3
Li(R)
O
N(R) O
CH3
H3C
Li (S)
O
N(R)O
N
Ph
O
H+
ββ--LITHIATEDLITHIATEDOXAZOLINYLOXIRANESOXAZOLINYLOXIRANES
ON
R1
O
Li
R Ar
N
NO
N
R1
O
*
Li
R ArO
N
R1
O H
R Ar
s-BuLiTMEDA-98 °CTHF
--veryvery easy generationeasy generation--Chemically and Chemically and configurationallyconfigurationally stablestable !!--syntheticallysynthetically usefuluseful
γγ--Amino Amino AcidsAcids
HOOCH2N
OR R1
R2HOOCH2N
OR R1
R2
HOOCH2N
R R1R2
R3
HOOCH2N
R R1R2
R3
α,β-epoxy-γ-amino acids
α,β-cyclopropyl-γ-amino acids
StereoselectiveStereoselective SynthesisSynthesis of of αα,,ββ--EpoxyEpoxy--γγ--Amino Acids and Amino Acids and αα,,ββ--EpoxyEpoxy--γγ--ButyrolactamsButyrolactams
O N
O Ph
Ph
Me
R
O
LiON
Me Ph
NO
Ph
R
O PhMe
HO R
O
NH4Cl
O N
O PhHN
OPh
Me
R
O N
O PhMe
H
R
TFA
Dioxane/H2O
MeOH
O PhMe
NH
OR
51-78 %
R = Ph, p-ClC6H4, p-MeOC6H4, C6H11
40-71 %
CH2Cl2/TFA
R = Ph, p-ClC6H490 %
HCOONH4, Pd/C
R = Ph, 55 %
H2, Pd/C
R = Ph, 70 %
dr > 98/2
dr > 98/2
NH2
O O
Org. Org. LettLett. . 20062006, 0000, 0000
NH
(S)(R)
O
O N(S)
(S)(S)
OH3C Ph
R1
R
(S)
O
N
(S) (R)H
3 O PhH C
NO
R1
R H+(S)
O
N
(S) (R)O
Li
PhH3C
OO N
(S)
(S)(S)
OH3C Ph
R1
R
H+
s-BuLi/TMEDATHF, -78 °C, 30 min
2b
dr > 99:1er >99:1
EnantioselectiveEnantioselective SynthesisSynthesis of 4,5of 4,5--EpoxyEpoxy--1,21,2--OxazinOxazin--55--onesones
Org. Lett. 2006, 0000Org. Org. LettLett. . 20062006, 0000, 0000
51 51 –– 65 %65 %dr > 98:2dr > 98:2
R1 = t-Bu, PhC(CH3)2R = Ph, CH3(CH2)5CH2
RR11 = = tt--BuBu, , PhCPhC(CH(CH33))22R = R = PhPh,, CHCH33(CH(CH22))55CHCH22
50 50 –– 71 %71 %
70 %70 %HOOCNH2
(S)(S)(S)
OH3C PhR
R = Ph
R1 = PhC(CH3)2
(+) Ambruticin SNovel Antifungal
Martin, S. F. et al.Tetrahedron 2003, 59, 6819.
Martin, S. F. et al.Tetrahedron Lett. 2003, 59, 1571.
Brana, M. F. et al.Bioorg. Med. Chem. Lett. 2002, 12, 3561.
Brown, R. C. D. et al.J. Org. Chem. 2004, 69, 122.
Shuto, S. et al.Bioorg. Med. Chem. 2002, 10, 3829.
OO
R3 R2
R4
R1
O
O
R1
Ar
R2R3
HO
O N
HN
R3
ArO2S OTIPS
HN
HN
CONH2
CONH2O
AcHN Ar
R4NH2
NEt2O
R5
CyclopropaneCyclopropane--γγ--lactoneslactones: : UsefulUseful PrecursorsPrecursors of of BiologicallyBiologically ImportantImportant Target Target MoleculesMolecules
H3 Histamine Receptor LigandsFurofuran Lignans
NMDA Receptor Antagonist
Mammalian Grb2-SH2 Antagonist
s-BuLi/TMEDA Et2O, -98 ºC
1.
O
R
RN
O
H
(CO)5W Ar
OMe
O
Ar
N
O
W(CO)5R
RH
2. SiO2
Et2O, -98 to 20 ºCO
R
RN
O
Li
O
Ar
N
O
W(CO)5
RRLi
OMe
OMe
Ar
N
O
W(CO)5RR
H
OLiO
Ar
N
O
ORR
HPyNO H+
Ar = 4-ClC6H4; 80%ArAr = 4= 4--ClCClC66HH44; 80%; 80%
J. Org. Chem. 2004, 69, 9204
Synthesis of Synthesis of CyclopropaneCyclopropane--γγ--lactoneslactones,,precursorsprecursors of of cyclopropanecyclopropane--γγ--aminoamino acidsacids
J. Org. Chem.J. Org. Chem. 20042004, , 6969, 9204, 9204
RR ArAr YieldYield (%)(%)PhPh PhPh 8080““ 22--FurylFuryl 7575““ 44--MeOCMeOC66HH44 8181““ 44--ClCClC66HH44 8383MeMe 44--ClCClC66HH44 6161
Yield of Yield of Pentacarbonyl(3Pentacarbonyl(3--oxaoxa--22--bicyclo[3.1.0]bicyclo[3.1.0]hexylidenehexylidene))--Tungsten ComplexesTungsten Complexes
COOHNH2
Ar
HN
RR
HOR1
HO
(OC)5W OMe
O
ArR
R
H
N
O
LiO
RR
Ar
H
HN
O
Li
H
Ar
OCH3
W(CO)5
Li
O
R
RO
N
Li
O
R
RO
N
ArOH3C
(OC)5W
O
O N
R
R
Ar
H
LiOMe
W(CO)5[M]
O
HR
R
Ar
N
O
Li
H
[M]
(OC)5W
RR
Ar
H
HN
O
O
O
ON
R
R
Ar
H
Li
MeO
(OC)5W
CyclopropanationCyclopropanation of of LithiatedLithiated OxazolinyloxiranesOxazolinyloxiranes withwith FischerFischer CarbeneCarbeneComplexesComplexes: : SynthesisSynthesis of of CyclopropaneCyclopropane--γγ--lactoneslactones
rere faceface sisi faceface
J. Org. Chem. 2004, 69, 9204J. Org. Chem.J. Org. Chem. 20042004, , 6969, 9204, 9204
O Ar'N
O
H3C Li
(CO)5W Ar
OCH3
Ar'
ArW(CO)5
OCH3
OH
H3C
N
O
Ar=4-MeOC6H4 (64%)Ar=4-ClC6H4 (63%)
1.
2. SiO2
Et2O, -98 to 20 ºC
Ar'=4-MeOC6H4
O Ar'N
O
H3C
W(CO)5Ar OCH3
Li
Ar'
ArO
OCH3
OH
H3C
N
O
PyNO
Ar=4-ClC6H4 (81%)
CyclopropanationCyclopropanation of of LithiatedLithiated OxazolinyloxiranesOxazolinyloxiranes withwith FischerFischerCarbenesCarbenes: : SynthesisSynthesis of of cyclopropanecyclopropane--γγ--hydroxyhydroxy estersesters
Ar'
Ar
COOH
H2N R
O
NH
HOR1
J. Org. Chem. 2004, 69, 9204J. Org. Chem.J. Org. Chem. 20042004, , 6969, 9204, 9204
Synthetic Use of Epoxy LactonesSyntheticSynthetic UseUse of of EpoxyEpoxy LactonesLactones
CerulenineCerulenine
EpolactaeneEpolactaene
BriarenicditerpenesBriarenicditerpenesXilobovideXilobovide
O O
O
H
HO
HO
OH
O
O
O
R
HO
O
COOCH3
O
O
O
O
HR H
H
O
O
O
R3 R
R2
R1
COOMeOO
HHR
O
O
OH H
O
NH2
ON
H3C O Ar
Li
s-BuLi/TMEDATHF, -98 °C
RR1C=O
ON
H3C O Ar
OLi
RO
NH3C O Ar
RO
H R1 R1
60 – 95 %60 60 –– 95 %95 %
H+/H2O
H3C O Ar
RO
R1
O
H+/H2O
H3C O Ar
RO
R1
O
StereoselectiveStereoselective SynthesisSynthesis of of αα,,ββ--EpoxyEpoxy--γγ--ButyrolactonesButyrolactones
RR1C=O: (CH3)2C=O, (C2H5)2C=O, Ph2C=O,
CH3CHO, PhCHO,O
( )1,2
ON
CH3
ClO
N
H3C O H
Ar
1) LDA; THF; -98 °C2) ArCHO
+O
N
H3C O Ar
H
dr = 1:1; 71 %dr = 1:1; 71 %dr = 1:1; 71 %
Org. Lett. 2002, 1551OrgOrg. . Lett.Lett. 20022002, 1551, 1551
50%; 50%; erer >99:1>99:1 25%; 25%; erer >99:1>99:1dr 2:1
70%: 70%: erer 98:298:2
(S) ON
H O Ph
H(S)(R)
(S)(R)
ON
H3C O Ph
Li(S)
s-BuLi/TMEDATHF, -98 °C
Ph2CONH
O
H3C O Ph
PhO
Ph(S)(S)
(COOH)2 H2O
O
H3C O Ph
PhO
Ph(S)(S)
(S) NH
O
H3C O Ph
PhO
Ph(S)(S)
(COOH)2 H2O
O
H3C O Ph
PhO
Ph(S)(S)
(S)
NH
O
H3C O Ph
PhO
H(S)NH
O
H3C O Ph
PhO
H(S)(S)(S)(S) (R)(S) (S)
+(S) (S)
(S) ON
H3C O Ph
H(S)(R)
1) s-BuLi/TMEDA THF, -98 °C
2) CH3I
50% 50% dr >99:1dr >99:1
PhCHO
(COOH)2 H2O (S)
(S)O
H3C O Ph
PhO
H(S)(COOH)2 H2O (S)
(S)O
H3C O Ph
PhO
H(S)(S)(R)O
H3C O Ph
PhO
H(S)(COOH)2 H2O(S)
(R)O
H3C O Ph
PhO
H(S)(COOH)2 H2O
EnantioselectiveEnantioselective SynthesisSynthesis of of αα,,ββ--EpoxyEpoxy--γγ--ButyrolactonesButyrolactones
(S)O
N Cl1) LDA; Ti(i-PrO)4; -98 °C; THF2) PhCHO
65% dr >99:1
65% 65% dr >99:1dr >99:1
Org. Lett. 2002, 1551OrgOrg. . Lett.Lett. 20022002, 1551, 1551
O
Ph
N
O i-PrLi/TMEDA E+
THF -110 °C, 20'
O
Ph
N
O E
H
O
Ph
NO Li
(±) (±)
RegioselectiveRegioselective lithiationlithiation of terminal of terminal OxazolinyloxiranesOxazolinyloxiranes
EE YieldYield (%)(%)DD 5353MeMe 7575BnBn 7171AllylAllyl 8585MeMe33SiSi 9090BuBu33SnSn 5050
In In situsituquenchquench
O
Ph
Li
O
Ph PhLiO
LiN
O O
N
N
O
OH
Ph PhHO
N
O O
N H+
MixtureMixture of of DiastereomersDiastereomersEliminativeEliminative dimerizationdimerization
Unpublished ResultsUnpublishedUnpublished ResultsResults
(S)
N H
H
C(Ph)3H
NO
s-BuLiTMEDATHF, -78 °C 4h(S)
N H
H
C(Ph)3
H
O
EtO
E
HO NH2
2) DAST N
CH
Li
H
ON
(S)(R)
N H
E
C(Ph)3H
NO
80 %
1)
(S)
N H
H
C(Ph)3H
NO
s-BuLiTMEDATHF, -78 °C 4h(S)
N H
H
C(Ph)3
H
O
EtO
E
HO NH2
2) DAST N
CH
Li
H
ON
(S)(R)
N H
E
C(Ph)3H
NO
80 %
1)
StericallySterically HinderedHindered
DAST = N SF3
Unpublished resultsUnpublishedUnpublished resultsresults
dr > 99:1dr > 99:1erer > 98:2> 98:2
RegioselectiveRegioselective lithiationlithiation of terminal of terminal OxazolinylaziridinesOxazolinylaziridines
erer > 98 : 2> 98 : 2 erer > 98 : 2> 98 : 2 ConfigurationallyConfigurationallystablestable
EE++ YieldYield %%DD22OO 7575MeIMeI 7575EtIEtI 6060BnBrBnBr 4545AllylBrAllylBr 6666MeMe22AllylSiClAllylSiCl 7070BuBu33SnClSnCl 7575EtEt22COCO 4444
LithiatedLithiated AryloxiranesAryloxiranes::
--ChemicallyChemically and and configurationallyconfigurationally stablestable
--SyntheticallySynthetically usefuluseful
O
R
R
Li
X
LithiatedLithiated AryloxiranesAryloxiranes
R1, R2 = H, Me, Ph, 2-oxazolin-2-yl
ChemicallyChemically and and configurationallyconfigurationally stablestable
LifetimeLifetime : 30 min: 30 min--2h2h
O
R2H
Ph R1RLi/(TMEDA)
–60/–98 °C
O
R2E
Ph R1E
O
R2Li
Ph R1
N H
Ph
Mes-BuLi/(TMEDA),THF, -78 °C, 2h
NMe
H
Li
(±)
Ph +Me2S
+Br2
RNH2
N H
Me
E
(±)
E
ElectrophileElectrophile
DD22OO
MeIMeI
II22
CC22ClCl66
CC22HH22BrBr22
DMFDMF
PhCONHPhCONH((OMeOMe))
YieldYield %%
98 98
85 85
80 80
81 81
63 63
98 98
50 50
EE
DD
MeMe
II
ClCl
BrBr
CHOCHO
PhCOPhCOOrg. Lett. 2005, 7, 3749-3752
TrappingTrapping of of orthoortho--lithiatedlithiated NN--methylphenylaziridinemethylphenylaziridine
Ph (R)OLi
Ph (R)O
Ph (S)OLi
Ph (S)O
RLi / TMEDA
THF, -98 °C, tR1
R1
R1
RLi / TMEDA
THF, -98 °C, tR1
E+
E+
Ph (R)OE
Ph (S)OE
R1
R1
EE++ == DD22O; CHO; CH33I; I; CHCH33CHCH22II;; CHCH22=CHCH=CHCH22Br; Br; PhCHPhCH22Br; Br; MetallylClMetallylCl(CH(CH33))22CO; CO; PhCONPhCON(CH(CH33))22; ; PhCHOPhCHO;; CyclopentanoneCyclopentanone; ; YieldsYields:: 51 51 –– 98 %; 98 %; dr: > 98:2dr: > 98:2; ; er = 97:3 er = 97:3 –– 99:199:1
RR11 = H, CH= H, CH33, , PhPhRRLiLi = = ss--BuLiBuLi, , nn--BuLiBuLi; ; t = 0.5 t = 0.5 –– 2h2h
ChemicallyChemically and and ConfigurationallyConfigurationally
StableStable
Org. Lett. 2002, 2445OrgOrg. . Lett.Lett. 20022002, 2445, 2445
J. Org. Chem. 2004, 3330J. J. OrgOrg. . ChemChem. . 20042004, 3330, 3330
StereospecificStereospecific SynthesisSynthesis of of SubstitutedSubstituted AryloxiranesAryloxiranes
LithiatedLithiated AryloxiranesAryloxiranes::
--Are Are theythey carbanionscarbanions or or carbenoidscarbenoids??
--DoesDoes the the arylaryl groupgroup provideprovide stabilitystability toto the the lithiatedlithiated oxiraneoxirane??
--ChemicalChemical ExperimentsExperiments--AbAb initioinitio CalculationsCalculations
CarbenoidCarbenoid CharacterCharacter of of
αα--Lithiated Styrene Lithiated Styrene OxideOxide
"Eliminative dimerization" "Reductive alkylation"
O
Ph
LiHO
Ph
O
Ph
LiLiLiO
PhO
PhOLiLi
Ph
-Li2O
H
O
Ph
Li
PhPhPh
OHHO
sec-BuLi / (TMEDA)
+
sec-BuLi / TMEDATHF, –98 °C
reaction time > 30 min
pentane, –98 °C
sec-BuLi
1,2-elimination
T > –98 °C
EO
Ph
E
OLi
in in NonNon--DonorDonor SolventsSolvents and in the and in the AbsenceAbsence of of LigandsLigands
The The bridgingbridging Li could help Li could help toto cleavecleave the Cthe C––O bondO bond““MetalMetal--AssistedAssisted IonizationIonization””
160.4 160.4 pmpm
R
Li
°
TransitionTransition State Model of the State Model of the ReactionReaction of of
αα--LithiatedLithiated StyreneStyrene OxideOxide withwith RLiRLi
≠
Metal Assisted Ionization(“MAI”) Effect
Donor Donor solventssolvents (e.g. THF) and (e.g. THF) and ligandsligands (e.g. TMEDA)(e.g. TMEDA)could compete successfully with Licould compete successfully with Li––CC––O bridges favouringO bridges favouring
tetrahedral isomers with tetrahedral isomers with ““less carbenoidless carbenoid”” charactercharacter..
LithiatedLithiated StyreneStyrene OxideOxide mightmight bebe ““TerminallyTerminally BondedBonded””in in GoodGood Donor Donor SolventsSolvents and in the and in the PresencePresence of of LigandsLigands
OLi
O
N N
B3LYP/6B3LYP/6--311+G*// B3LYP/6311+G*// B3LYP/6--31+G*31+G*
ChargeCharge MappingMapping bybyNaturalNatural PopulationPopulation AnalysisAnalysis
--00.733.733
––0.3010.301
+0+0.264.264
––0.1430.143
+0+0.912.912ππ--chargecharge: : ––0.046 0.046
(5 %)(5 %)
LiLi
OO
(26 %)(26 %)
(62 %)(62 %)
148.0148.0
147.8147.8
160.4160.4
143.8143.8
The The σσCC––OO bond is weakened bond is weakened and thus more and thus more easilyeasily attackedattacked
byby a a nucleophilenucleophile !!
B3LYP/6B3LYP/6--311+G*// B3LYP/6311+G*// B3LYP/6--31+G*31+G*
C
C
C
C
C
C
CC
O
LiO
CCC
C
C
C
C
C
NeutralNeutral StyreneStyrene OxideOxide **
αα--LithiatedLithiated StyreneStyrene OxideOxide ** * * BondBond--lengthslengths in in pmpm
148.5148.5
149.3149.3
Lithiated Styrene Oxide: Lithiated Styrene Oxide: a Multinuclear NMR Investigationa Multinuclear NMR Investigation
O Hs-Bu6Li (1 equiv)TMEDA (1 equiv)
THF-d8, –98 °C60.2
13.7
139.5
126.3
129.3 128.8
O 6Li59.4
162.3
122.0
127.7 119.7
122.4
bs, 57.2(Δδ = -3)
0.4 M
Me Me18.5
45.6
O Hs-Bu6Li (1 equiv)TMEDA (1 equiv)
THF-d8, –98 °C52.352.1
129.3
126.2
129.2 128.9
O 6Li55.0
162.4
122.1
127.7 119.8
122.8
bs, 76.0(Δδ = 23.7)
0.4 M
StereospecificStereospecific DeprotonationDeprotonation of of StyreneStyrene OxidesOxides
80 % Yieldsyn/anti = 1/2ee syn > 95 %ee anti > 95 %
80 % 80 % YieldYieldsynsyn//antianti == 1/21/2eeee synsyn > 95 %> 95 %eeee antianti > 95 %> 95 %
O H
Ph
O H
Ph
(S)
(R)
(S)
(R)
O
Ph
OH
Ph
O
Ph
OH
Ph(S)
(R)
(R)
(S)
O
Ph
OH
Ph
O
Ph
OH
Ph
(S)
(R)1) s-BuLi / TMEDA -98 °C; THF
2) PhCHO
1) s-BuLi / TMEDA -98 °C; THF
2) PhCHO
+
+
Org. Lett. 2002, 2445OrgOrg. . Lett.Lett. 20022002, 2445, 2445
OpticallyOptically activeactive StyreneStyrene OxideOxide isis notnot anan AsymmetryAsymmetry InductorInductor
R1 R2 3Yield %
4Yield % dr
Me PhCMe2 42 70 >98/2
Cl PhCMe2 50 70 >98/2
2-Furyl PhCMe2 82 62 >98/2
H PhCMe2 60 50a >98/2
MeO PhCMe2 54 40a >98/2 CF3
O
PhCMe2 82 65 >98/2
CF3 t-Bu 60 50 90/10
H t-Bu 63 58a >98/2
Cl t-Bu 78 >95 >98/2
H PhCH2 no reaction - -
OLi
Ph
ON
OHR2
R1R1
N+
O-
R2
1)2) H+
NaOH
i-PrOH
ON
Ph
R1
R2
HOH
Ph
ON
OHR2
R1
StereoselectiveStereoselective SynthesisSynthesis of 4of 4--HydroxymethylHydroxymethyl--1,21,2--oxazetidinesoxazetidines
((±±))--11--LiLi((±±))--33
((±±))--44
Org. Lett. 2006, 8, 3923-3926 Org. Org. LettLett. . 20062006, 8, 3923, 8, 3923--3926 3926
N
OLi
R
O
H
TS-A
trans-stilbene oxide
MechanisticMechanistic HypothesisHypothesis
Org. Lett. 2006, 8, 3923-3926 Org. Org. LettLett. . 20062006, 8, 3923, 8, 3923--3926 3926
H
O
Li
sire
NR
O
O
NLi
R
O
HN
OLi
R
O
H
TS-BTS-A
H
PhN
OH
O
Ph
R
HON
Ph
O
Ph
R
H
O NH
HO
R
Ph Ph
SN2
4-exo-tet
s-BuLi TMEDA
THF; -98°C
NR4
R3
O
1)
2) H+
5
OH
OLi R4O Ph
NOHR3
(R)- or (S)-1configurationally
stable
NaOHiPrOH
60 °C
N O
R4 PhH
R3
OH
6
AsymmetricAsymmetric SynthesisSynthesis of 1,2of 1,2--OxazetidinesOxazetidines
R4 R3 5 Yield %
6 Yield % er dr
4-ClC6H4 Cumyl 78 78 98/2 >98/22-Furyl Cumyl 60 62 98/2 >98/2
Ph t-Butyl 63 80a) 98/2 >98/2Ph t-Butyl 60 75a) 98/2 >98/2
erer = 98/2= 98/2erer = 98/2= 98/2 erer = 98/2= 98/2
a) a) ReactionReaction performedperformed at room temperatureat room temperature
Org. Lett. 2006, 8, 3923-3926 Org. Org. LettLett. . 20062006, 8, 3923, 8, 3923--3926 3926
NNNN
NNHH OO
CC ll
CC ll
(( SS ))
OO
TriazoleTriazole AntifungalAntifungal AgentsAgents
(±)
H2O2, CF3COCH3pH = 11
O
ClCl
quant.
HydroliticHydrolitic KineticKinetic ResolutionResolutionof 4of 4--Chlorostyrene Chlorostyrene OxideOxide
HKR HKR monitoredmonitoredbyby chiralchiral GCGC 14 15 16 17
min
(R) (S)
(R)
(S)
(S)
3 h3 h
20 h20 h
(S)
O
Cl
(S,S)-(salen)CoIIIOAc
er > 99%
H2O, 24 h38 %
Org. Lett. 2002, 2445OrgOrg. . Lett.Lett. 20022002, 2445, 2445
SynthesisSynthesis of of anan OpticallyOptically ActiveActiveTriazoleTriazole AntifungalAntifungal AgentAgent
(S)
O
Cl
er > 99%
sec-BuLi/TMEDA
THF, –98 °C
80 %, dr anti/syn 2/1
(S)
O
Cl
HOCl
1) p-ClC6H4CHO
2) H
NN
NHO
Cl
Cl
OH
NaH/1,2,4-Triazole
DMF, 70 °C
78 %
(S)
[α]D = +113.5lit. [α]D = +117.3
NN
NHO
Cl
Cl
quant.
Swern ox.(S)
er > 99%
O
Org. Lett. 2002, 2445OrgOrg. . Lett.Lett. 20022002, 2445, 2445
SynthesisSynthesis of of OpticallyOpticallyEnrichedEnriched CyclopropanesCyclopropanes
(S)
OPh
THF, -98°C
(R)
(S)(R)
Ph
Ph
W(CO)5
OCH3
OH
1.5 eq. 3.eq.s-BuLi/TMEDA
OPh
Ph(OC)5W OCH3
OPhW(CO)5
Ph
H3CO
Li
(R)
(S)(R)
Ph
Ph
O
OCH3
OH
PNO(R)
(S)(R)
Ph
Ph
O
OHH2N
Configurationally Stable
er = 98:2
81 %81 %erer: >98:2: >98:2
87 %87 %erer: >98:2: >98:2
(R)O
Ph
(S)
(R)(S)
Ph
Ph
W(CO)5
OCH3
OHW(CO)5H3CO
Ph
THF, -98°C
1) 1.5 eq. 3.eq. s-BuLi/TMEDA
2)
(S)
(R)(S)
Ph
Ph
O
OCH3
OH
PNO (S)
(R)
(S)COOHPh
Ph
H2N
79 %, 79 %, erer: >98:2: >98:2erer: >98:2: >98:2
87 %, 87 %, erer: >98:2: >98:2
PNO = PNO = PyridinePyridine NN--oxideoxide
CyclopropanationCyclopropanation ReactionReaction of of OpticallyOptically ActiveActive LithiatedLithiatedStyreneStyrene OxideOxide withwith FischerFischer CarbenesCarbenes
Single Single DiastereomerDiastereomerLiLi--StyreneStyrene oxideoxide InducesInduces asymmetryasymmetry
J. J. OrgOrg. . ChemChem. . 20052005, 70,5852, 70,5852--58585858
(R)(R)
O
Ph
CH3(S)
(R)(S)
Ph
Ph(R)
W(CO)5
OCH3
OH
H3CTHF, -98°C, 1ora
W(CO)5
H3CO
Ph1.5 eq. 3.eq.s-BuLi/TMEDA
(R) (R)
O
Ph
CH3Li
(S)(S)
O (R)
(S)(R)
Ph
Ph(S)
W(CO)5
OCH3
CH3
HO
THF, -98°C, 1ora
W(CO)5H3CO
Ph1.5 eq. 3.eq.s-BuLi/TMEDAPh
CH3(S)(S)
OPh
CH3Li
68 %68 %erer: >98:2: >98:2erer: >98:2: >98:2
70 %70 %erer: >98:2: >98:2erer: >98:2: >98:2
ConfigurationallyConfigurationallyStableStable
CyclopropanationCyclopropanation ReactionReaction of of OpticallyOptically ActiveActive LithiatedLithiatedtranstrans--PhenylpropylenePhenylpropylene OxideOxide withwith FischerFischer CarbenesCarbenes
Single Single DiastereomerDiastereomer
Single Single DiastereomerDiastereomer
JOC JOC 20052005, 70, 5852, 70, 5852
1h
1h
OPh Phs-BuLi/TMEDA
THF, -60°C(R)
(S)(R)
Ph
Ph(R)
W(CO)5
OCH3
OH
PhW(CO)5
H3CO
PhOPh Ph
Li
ConfigurationallyConfigurationallyStableStable
62 %62 %
CyclopropanationCyclopropanation ReactionReaction of of LithiatedLithiated ciscis-- StylbeneStylbene OxideOxidewithwith FischerFischer CarbenesCarbenes
Single Single DiastereomerDiastereomer
J. J. OrgOrg. . ChemChem. . 20052005, 70, 5852, 70, 5852--58585858
1.5 eq. 3.eq.s-BuLi/TMEDAO
Ph
Ph
THF, -78°C
O Ph
Li
(OC)5WOCH3
Ph
(±)
O PhLi+
Ph
Ph
W(CO)5
OCH3
OH
Ph
W(CO)5H3CO
Ph
O Ph
Ph W(CO)5
OCH3Li
H+
PyNO, THFO
OMe
OHPh
PhW(CO)5
OMe
OHPh
Ph
6-endo tet
DeprotonationDeprotonation of of transtrans--StilbeneStilbene OxideOxide::orthoortho--LithiationLithiation vs. vs. αα--LithiationLithiation
Single Single DiastereomerDiastereomer
73 %73 %
16 %16 %87 %87 %
MajorMajor MinorMinor
Org. Lett. 2005, 7, 4895Org. Org. LettLett. . 20052005, 7, , 7, 48954895
10
90
37
63
5050
74
26
95
50
10
20
30
40
50
60
70
80
90
100
-98°C -98°C -78°C -60°C -60°C
Org. Lett. 2004, 6, 4191.
Ph
O
H
PhH CH3I
Ph
O
H
PhH3CO
H
PhH
CH3
RLi / TMEDA+THF
LithiationLithiation of of transtrans--StilbeneStilbene OOxidexide : : AAlphalpha vsvs OOrthortho
T (T (°°C)C)
alphaalpha
alphaalpha
alphaalpha
orthoortho
orthoortho
orthoortho
(%)(%)
orthoorthoalphaalpha
DeprotonaDeprotonattionion ofoftranstrans--StilbenStilbene e ooxxididee--dd22
O
Ph
PhD
D
O
D
ss--BuLiBuLiTMEDA TMEDA
ss--BuLiBuLiTMEDA TMEDA
ss--BuLiBuLiTMEDA TMEDA
ss--BuLiBuLiTMEDATMEDA
nn--BuLiBuLi
orthoortho
alphaalpha
O
Li
PhPh
W(CO)5
MeO
(S)(R)
(S)(S)
OH
Ph
Ph
W(CO)5
OMeTHF, -78°C, 30 min 2) H+
R.T.1) -78°C
((R,RR,R))--1a1a--LiLi
3g3g
(+)(+)--4a4a
EnantiospecificEnantiospecific SynthesisSynthesis of of TetrahydronaphtholsTetrahydronaphthols
eeee >95%>95%
[[αα]]DD== +245+245°°
eeee >95%>95%
(S)(R)
(S)(S)
OH
Ph
Ph
O
OMe
PyNOTHF
(+)(+)--5a5aChiralChiral SolvatingSolvating AgentAgent
[[αα]]DD== +104+104°°
(R)HO CF3
EeEe determinationdetermination via via 11HH--NMR NMR
Org. Lett. 2005, 7, 4895Org. Org. LettLett. . 20052005, 7, , 7, 48954895
EnantiospecificEnantiospecific SynthesisSynthesis of of DihydrobenzoDihydrobenzo[c][c]furansfurans ((PhthalansPhthalans))
O
(R) (S)PhHO
Me2) H
(60%)ee>95%
Me
1) Me2CO
LiO
PhLi, THF
−78°C
(S)(S)
BrO
(S)(S)
BrO
1) PhLi2) H+
(R)(R)
BrO+
Chiral HPLC
(S)(S)
HO
CHO
Br
DCM, NaOH 50%PTC, 91 %
SMe2Cl
J. Org. Chem. J. Org. Chem. 20062006, 71, 3984, 71, 3984--39873987
αα--LithiationLithiation of transof trans--NN--AlkylAlkyl--2,32,3--diphenylaziridines:diphenylaziridines:StereospecificStereospecific Synthesis of functionalized Synthesis of functionalized AziridinesAziridines
1) s-BuLi (TMEDA) -78 °C, 4h N E
Ph
R
Ph
HTHF
E2)
N E
Ph
Pr
Ph
H
ciscis
N H
Ph
Pr
H
Ph
BnBn > 98/2> 98/2 7070
AllylAllyl > 98/2> 98/2 9292
> 98/2> 98/2 4848
EE dr dr CisCis//TransTrans YieldYield %%
MeMe > 98/2> 98/2 9898
EtEt > 98/2> 98/2 9292
> 98/2> 98/2 3838SnBuSnBu33 50/50/5050 8989
3
NH
HHR
H H
H
Selected NOE interaction
Unpublished resultsUnpublished results
N H
Ph
Pr
H
Ph
αα--LithiationLithiation of transof trans--NN--AlkylAlkyl--2,32,3--diphenylaziridines:diphenylaziridines:StereospecificStereospecific Synthesis of functionalized Synthesis of functionalized AziridinesAziridines
Unpublished resultsUnpublished results
N E
Ph
R
H
Ph
1) s-BuLi (TMEDA) -78 °C, 4h
Hexane or Toluene
E2)
N E
Ph
Pr
H
Ph
transtrans
EE++ dr dr TransTrans//CisCis YieldYield %%
MeIMeI > 98/2> 98/2 6464
EtIEtI > 98/2> 98/2 9595SnBuSnBu33ClCl > 98/2> 98/2 8080
BnBrBnBr 50/50/5050 9898
AllylBrAllylBr 50/50/5050 8484
NH
HH
H
Selected NOE interaction
R
H H
H
O
R
N
O R
O
N
O
LDA, Et2O
–98 °C r.t.
R1 R1
R1 R1
O
R
N
O R
O
N
O
LDA, Et2O
–98 °C r.t.
R1 R1
R1 R1
N
O
Ph
OHPh
R R1 YieldEt H 85Me H 10Et Cl 95Et F 79Et Me 85Et OMe 88n-Pr H 85
IsomerizationIsomerization of of OxazolinylOxazolinyl ArylAryl OxiranesOxiranes: : SynthesisSynthesis of of OxazolinylarylalkanonesOxazolinylarylalkanones
Tetrahedron Lett., 2002, 43, 7739TetrahedronTetrahedron LettLett.,., 20022002, , 4343, 7739, 7739
NO
Li
O
Ar
Ar
RX
85%
O
N
O
O
PhNOLDA, Et2O
-98° -> rt
N
O
O
Li
OLi
PhNO
IsomerizationIsomerization of of OxazolinylOxazolinyl ArylAryl OxiranesOxiranes: : SynthesisSynthesis of of OxazolinylarylalkanonesOxazolinylarylalkanones
Tetrahedron Lett., 2002, 43, 7739TetrahedronTetrahedron LettLett.,., 20022002, , 4343, 7739, 7739
ON
O
Li
O
R1 R2
NO
Br
N
O
R1
R2
R31) R3Li THF, -78°C2)H
O
R1 R2
NO
Li
R3LiTHF, -78°C
N
O
(76 %)
N
O
(69 %)
N
O
(69 %)
N
O
N
O
(70 %) (74 %)
N
O
(67 %)
SynthesisSynthesis of of SubstitutedSubstituted IsoquinolineIsoquinoline DerivativesDerivatives
Unpublished results
N
O
SynthesisSynthesis of of SubstitutedSubstituted IsoquinolineIsoquinoline DerivativesDerivatives
Unpublished results
MechanisticMechanistic HypothesisHypothesis
O
Me
PhLi, THF
–78 °C
NO O
Me
NO
Li
OMe
PhLi
OMe
PhNLiO
Li
ONPhLi
Me
LiOOMeLi
N
Ph
LiO
OHN
Ph
O
Me-H2O N
Me
O Ph
Br
H
NO
LiOMe
NO
H
H+
Unpublished results
Prof. V. CapriatiProf. R. LuisiDr. L. DegennaroDr. F. M. PernaDr. A. Salomone
Prof.Prof. V. V. CapriatiCapriatiProf.Prof. R. LuisiR. LuisiDr. L. Dr. L. DegennaroDegennaroDr. Dr. F.F. M. M. PernaPernaDr. A. SalomoneDr. A. Salomone
PhD Students:Dr. I. NuzzoDr. B. MusioDr. R. MansuetoDr. C. Carlucci
Dr. P. Di Cunto
PhDPhD StudentsStudents::Dr. I. NuzzoDr. I. NuzzoDr. B. Dr. B. MusioMusioDr. R. MansuetoDr. R. MansuetoDr. C. Dr. C. CarlucciCarlucci
Dr. P. Di Dr. P. Di CuntoCunto
AcknowledgementsAcknowledgementsAcknowledgements
MIUR, FIRB C.I.N.M.P.I.S
DOMPE’ (L’Aquila)ANGELINI (Pomezia)
MIUR, FIRB MIUR, FIRB C.I.N.M.P.I.SC.I.N.M.P.I.S
DOMPEDOMPE’’ (L(L’’Aquila)Aquila)ANGELINI (ANGELINI (PomeziaPomezia))
Lithiated Styrene Oxide: Lithiated Styrene Oxide: a Computational Investigation at DFT Levela Computational Investigation at DFT Level
B3LYP/6B3LYP/6--311+G*// B3LYP/6311+G*// B3LYP/6--31+G*31+G*
1.60 1.60 ÅÅ
ππ--chargecharge5 %5 %
1.48 1.48 ÅÅ1.49 1.49 ÅÅ
1.44 1.44 ÅÅ
3 kcal/mol0 kcal/mol“Tetrahedral structure”
in donor solvents, inthe presence of TMEDA
“Bridged structure”in nondonor solvents,in absence of ligands
1.52 Å 1.56 Å
OO O LiO Li
Li
Li O
L
L
O
PhPh
Li
Li O
L
L
O
PhPhO
Ph
Li
L
L
LO
Ph
Li
L
L
LL = THF, TMEDA
OxazolinyloxiranyllithiumOxazolinyloxiranyllithium: : CarbanionCarbanion or or AzaenolateAzaenolate??--An IRAn IR--Spectroscopic StudySpectroscopic Study--
O
H
Me
Me
N
O
O
Li
Me
Me
N
OO Me
Me
N
O
Li
sec-BuLi/TMEDATHF, - 98 °C
?
αα--Lithiated Oxazolinyloxiranes: Lithiated Oxazolinyloxiranes: an an in situin situ ReactReact--IR InvestigationIR Investigation
Bands at 1660 and 1678 cmBands at 1660 and 1678 cm--11
Unpublished resultsUnpublished resultsUnpublished results
O
Me
MeH
NO
Band at 1600 cmBand at 1600 cm--11
O
Me
MeLi
NO
s-BuLi/TMEDA
THF, –98 °C
1.27 Å1.271.27 ÅÅ
1.48 Å1.481.48 ÅÅ
Neutral νC=N = 1727 cm-1NeutralNeutral ννC=NC=N = 1727 cm= 1727 cm--11
1.97 Å1.971.97 ÅÅ1.40 Å1.401.40 ÅÅ
1.35 Å1.351.35 ÅÅ
Planar AzaenolateνC=C = 1844 cm-1
Planar AzaenolatePlanar AzaenolateννC=CC=C = 1844 cm= 1844 cm--11
1.32 Å1.321.32 ÅÅ2.04 Å2.042.04 ÅÅ
1.45 Å1.451.45 ÅÅ
1.92 Å1.921.92 ÅÅ
OxiranyllithiumνC=N = 1550 cm-1OxiranyllithiumOxiranyllithiumννC=NC=N = 1550 cm= 1550 cm--11
A DFT study: B3LYP/6A DFT study: B3LYP/6--31+G*//PM331+G*//PM3
Org. Lett. 2004, 403Org. Lett.Org. Lett. 20042004, 403, 403
J. Am. Chem. Soc. 1983, 105, 2082J. Am. Chem. Soc.J. Am. Chem. Soc. 19831983, 105, 2082, 105, 2082
O
νC=C = 1830 cm-1 Nt-But
Li
νC=N = 1608 cm-1
THFTHF
R1CHNR2
NR1
H
LiH
R2
NR1
H
LiH
R2
R1 = MeR2 = HR1 = MeR2 = H
R3R4CO
NMe H
H
HHO
R4 O
R4
NHMe
H+R3
R3
NMe H
H
HO
R4R3H
H(±)
RR33RR44COCO: (CH: (CH33))22CO (CO (89 %89 %), ), PhCHOPhCHO ((47 %, dr = 1:147 %, dr = 1:1), ), PhPh22CO (CO (52 %52 %), ), nn--PrCOPhPrCOPh ((55 %, dr55 %, dr = 1:1= 1:1))
Org. Org. LettLett. . 20052005,, 7, 37497, 3749--37523752
TrappingTrapping of of orthoortho--lithiatedlithiated NN--methylphenylaziridinemethylphenylaziridine