massive attack · 2011. 11. 3. · enantioselective synthesis of tertiary thiols by intramolecular...
TRANSCRIPT
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The Beatles - 1964
Massive Attack -
Oasis - 1992
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Biography 2001-present: University of Bristol 1997-2000: Professor, Sheffield 1988-1997: Various Reader Positions 1986-1988: Post-doc with Gilbert Stork 1983-1986: PhD at University of Cambridge 1983: Undergrad at Cambridge University
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Enantioselective Construction of Quaternary Stereogenic Centers fromTertiary Boronic Esters: Methodology and Applications–Ravindra P. Sonawane, Vshal Jheengut, Constantinos Rabalakos, Robin Larouche-Gauthier,Helen K. Scott, and Varinder K. Aggarwal*
Angew. Chem. Int. Ed. 2011, 50, Early View
Ar R1
BpinR2
>99:1 e.r.
M-Alk-LG
Ar R1
Alk-OHR2
>99:1 e.r.
Sounds cool, but how do you make chiral tertiary boronic esters?
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Tertiary Boronic Esters Ar R1
BpinR2
Ar R1
OCbH
>99:1 e.r.
Ar R1
BpinR2
>99:1 e.r.
s-BuLi
R2Bpin
From secondary chiral carbamates of course!
Noyori Asymmetric Transfer Hydrogenation
Ar R1
O
Carbamate Formation
H
OCbArMe
sBuLi Li
OCbArMe
RB(OR')2
retention
B(OR')2
OCbArMe
R
Li
OArMe
O
NiPr2
R
B(OR')2ArMe
Δ
H2O2NaOH R
OHArMe
Aggarwal et al Nature, 2008, 456, 778-782
Ph Me
Et OH
91% (99:1)
Ph Me
OH
95% (1:99)
OHEt
69% (99:1)
Ph Me
OHO
94% (98:2)
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Ph
Bpin
MeEt
a) LiCH2Br THF, –78 oC
b) H2O2, NaOH Ph MeEt
OH
83%
Ph
B
MeEtOO
Br
HH
Application of Matteson Homologation Conditions
D. S. Matteson Tetrahedron, 1998, 54, 10555-10607
MeEt
OH
83%, >99:1 e.r.
MeEt
OH
Cl
88%, >99:1 e.r.
MeEt
OH
MeO
62%, 99:1 e.r.
Me
OH
82%, >99:1 e.r.
Me
OH
37%, >99:1 e.r.
MePh
OH
MeO
41%, 98:2 e.r.
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Extention to Vinylation of Boronic Esters
Ph
Bpin
MeEt
MgBr
(n equiv)
Ph
B
MeEtOO
Ph
B
MeEt
Ph
B
MeEt
I
I2
PhMe Et
BI
PhMe Et
NaOMe
Me Et MeEt
Me Et Me
66%, >99:1 e.r.
Cl
79%, >99:1 e.r.
MeO
62%, >99:1 e.r. 79%, >99:1 e.r.
Ph
Bpin
MeEtLi
OEta)
b) I2, NaOMePh Me
Et
OMe
66%, >99:1 e.r.a) LiCHCl2
b) H2O2, NaOH Ph MeEt
OH
68%, >99:1 e.r.
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Applications
MeO
Me
OCb
a) s-BuLi
b) Bpin
c) MgBr2, MeOH
Ar
Me Bpin
MgBra)b) I2; NaOMe Ar
MeMeMgI, neat
180 oCMe
HO
98:2 e.r.69%
92%, 97:3 e.r.(+)-(S)-sporochnol
91%
Ph Me
OCb Bpin
a) s-BuLi
b) MgBr2 Ph Allyl
pinB Me
>99:1 e.r. 92% >99:1 e.r.
a) LCHCl2b) H2O2, NaOH Ph Allyl
MeOH
a) PhMgBr
b) PCC Ph Allyl
MeOPh
70% from boronic ester>99:1 e.r.
a) O3, Me2S
Ph
MeOPh
O
NN
OMePh
MePh
ON N Ar
NaBH(OAc)3
63% over two steps
serotonin antagonist
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Biography 2001-present: University of Manchester 1992-1994: Post-doc with Prof Marc Julia 1989-1992: PhD at University of Cambridge 1968: Born: Kampala, Uganda
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Enantioselective synthesis of tertiary thiols by intramolecular arylation ofLithiated thiocarbamates–Paul MacLellan and Jonathan Clayden*
Chem. Comm. 2011, 47, 3395-3397
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R1
SH
R2R3 General Conundrum
R1
O
R2
NucleophileCoordinating Chiral Ligand
R1
OH
R2Nu
O
Me Me
O O
OMe
O
ZnEt2ZnMe2 EtMgBr
NH HNO2S SO2
OH HO
N
Me Ot-BuHN
O OTrtMe
NHnBu
OMeO
OH
Enantiofacial selectivity in nucleophilic attack on a
prochiral ketone
R1
S
R2
NucleophileCoordinating Chiral Ligand
R1
SH
R2Nu
"A synthesis of thioacetone in Freiburg in 1889 was abandoned after widespread public protest and the evacuation of whole sectors of the city" – J. Sulfur Chem. 2009, 30, 167
R1
S
R2 R1
SNu
R2H
Tet. Lett. 1976, 17, 4295-4296
NuMgX
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H
OCbArMe
sBuLi Li
OArMe
O
NiPr2
General Strategy
If:
Then: R1 S
R2
N
OMe
Ar
aryl migration
R1
S
R2
N
O
Me
H
Ar
R1
SH
R2
Arbase
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In Practice
S N
OMe
R2
R1 LDA, DMPU–78 oC S N
H
OMeR
1
R2
NaOEtSH
R1
R2
42-96%
works with electron rich as well as
deficient aromatics
S N
OMe
Me
Me
98:2 e.r.
LiTMP, THF–78 oC
S NH
OMe
Me
Me
83%
96:4 e.r.
S NMe
R2R1
OLi
NLi
MeMe
Me
Me
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Substrates and Scope
SH
MeOMe
97%
SH
Me
Cl
97%
SH
Me
51%
SH
Me
89%
Ar1
R
OH
1. ClC=NMe2+Cl–2. MeCOSH3. LiAlH4
4.
N
O
NAr2
MeNMe
I–
Ar1 S N
OMe
Ar2
Me 1. LiTMP2.NaOEt
Ar1 SH
MeAr2
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A general synthetic approach to the amnesic shellfish toxins: totalsynthesis of (–)-isodomoic acid B, (–)-isodomoic acid E and(–)-isodomoic acid F–Gilles Lemiere, Simon Sedehizadeh, Julie Toueg, Nadia Fleary-Roberts and Jonathan Clayden*
Chem. Comm. 2011, Advanced Article
NHt-BuO2C
H
H
CO2t-Bu
NH
Me
HO2CH
H
CO2H
R
R = E Isomers Z Isomers
HO2C
Me
HO2C
Me
HO2C
Me
isodomoicacid B
isodomoicacid A
isodomoicacid E
domoicacid
isodomoicacid F
isodomoicacid D
H kainic acid
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(SiMe3)2CuCNLi2,N
O
O
Ph
H
H Ph
Me3Si
Single Diastereomer
86%
TMSCl NO
O
Boc
H
H
Me3Siacid;Boc2O
NO
O
Boc
H
H CO2t-Bu
Me3Si1. RuCl3 (10 mol%) NaIO4
2. t-BuOH, DCC
Sharpless et al J. Org. Chem. 1981, 46, 3936
NO
Boc
H
H CO2t-Bu
Me3Si
Reduction
Oxidation
N
O
H
CO2t-BuTMS
BocO
OO
Ar
O
mCPBA N
O
O
BocH
H CO2t-Bu
Me3Si
O83%
64%
MeO
N
O
Ph
PhNLi
Ph
Me
NO
O
Ph
H
H Ph67%
99:1 e.r.(after single
recryst.)
Clayden et al. Chem. Comm. 2002, 38-39 Org. Lett. 2000, 2, 4229-4231
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Towards the Core
N
O
BocH
H CO2t-Bu
Me3Si
Ot-BuO2C
N BocH
H CO2t-Bu
1. TBAF
2. Boc2O, t-BuOH
70%
O3
t-BuO2C
N BocH
H CO2t-Bu
O
98%
"the use of NaOMe...allowed us to avoid the epimerisation of the sensitive aldehyde which resulted when potassium carbonate in methanolwas used a base."
t-BuO2C
N BocH
H CO2t-Bu
N2
PO
MeOMeO
O
Me
NaOMe89%
t-BuO2C
N BocH
H CO2t-Bu
MeBu3Sn
1. Bu3SnCu(Bu)CNLi22. MeI
HO2C
NH
H
H CO2H
Me
HO2CNH
H
H CO2H
Me
HO2C
NH
H
H CO2H
Me
HO2C
Me
HO2C
Me
HO2C Me
1. PdCl2(MeCN)2 allylbromide2. TFA
Pd; TFA
Pd; TFA
71%(–)-isodomoic acid B
51%(–)-isodomoic acid E
49%(–)-isodomoic acid F
HO2C
NH
H
H CO2H
MeH
TFA
(–)-kainic acid