7 26 2010 raup lit · 2011. 11. 7. · 1 30 ent-l-20 °c none 5 >99%60% 2 30 l-20 °c dmap 3...
TRANSCRIPT
Short Literature7/26/10
Dustin Raup
Tuberculosis: A Global Problem
Prevalence of TB/100 000 people
Scheidt Group
Shibasaki Group
- caused by mycobacteria (especially mycobacterium tuberculosis)
- mycobacteria are becoming resistant to conventional therapies
- No new TB drugs introduced for 10 years.
R207910
N OMe
(R)
Ph
Br (S)
HONMe2
R207910
Developed by Johnson & Johnson
(see Science, 2005, 307, 223-227)
-Specific for mycobacteria
-Targets oligomeric subunit c of ATP synthase
(see Nat. Chem. Bio 2007, 3, 323-324)
0.100 µg/mL is 1.8 µM
J & J Patented Synthesis
0.2 % yield overall.
Cl
O Br
NH2NH
OBr
N Cl
PhBr
N OMe
PhBr
O
Cl
O
Cl
Cl
O
NMe2
N OMe
(R)
Ph
Br (S)
HONMe2
N OMe
(S)
Ph
Br (R)
HONMe2
N OMe
Ph
Br
HONMe2
AlCl3
S,S and R,R16% combined
61% 100%
HNMe2
84%NEt3
POCl3DMF67%
LDA
0.9% yield 1% yield
NaOMe33%
Retrosynthetic Analysis
N OMe
(R)
Ph
Br (S)
OHNMe2 N O
(R)
Ph
Br (S)
OH
N O
(R)
Ph
ON O
Ph
O
H H
MOM
MOMMOM
NH OO
Ph
O I
Catalytic EnantioselectiveProton Migration
Catalytic DiastereoselectiveAllylation
Early Stages of Synthesis
IPh H
Sonagashira CouplingPd(PPh3)2Cl2 (4 mol %)
CuI, i-Pr2NHTHF, r.t.quant.
Ph1-naphthyl
O
O
PhPdCl2DMSOquant.
NH
O
NaHMOMCl
THF91% N O
MOMN O
Ph
O
H H
MOM
1. LDA, THF2. SOCl2, pyridine
75%, 2 steps
Wacker Oxidation?
Wacker Oxidation?
An interesting aside...
Ph
1-naphthyl
O
O
PhPdCl2DMSOquant.
Tetrahedron, 2002, 58, 1607
PhPh
HBr/DMSO
I2/DMSOPdCl2/DMSO
Ph
O
O
Ph
O
Ph
OPh
Back to R207910...
N O
Ph
Br
O
H H
MOM
N O
(R)
Ph
Br
O
MOM
Enantioselective H+
Migration
What is the history behind this type of transformation?
Earliest Example!
Me
HH
O NH
O
Me
H
N
O
Me
N
H
O O
HOO
O
O
OHR
O
R
O
R =Me
MeMe
Me
R = Me
HH
O
Me
HH
O
S: 25 % ee!
R: 25 % ee!
Shibasakiʼs Rare Earth Catalysis:A Crash Course
On Paper:
O
OO
POPh
Ph
OM
LR1
R2
In Real Life:
This is not to indicate that one metal binds to one ligand!
This reaction in particular has been studied in great detail: Org. Biomol. Chem. 2007, 5, 2027-2039
O
RL RS
Gd(Oi-Pr)3 (1-10 mol %)Ligand (1-5 mol %)
RL RS
TMSO CN
TMSCNEtCN, -60 °C79-97% yieldup to 97% ee
Application
Shibasakiʼs First Enantioselective ProtonationOTMS
n
R1R2
Gd(Oi-Pr)3 (1-10 mol %)Ligand (1-5 mol %)DMP (1.5 equiv.)
THF, -30-0 °C
O
n
R1R2
O
Me
O
Et
O
Me
MeO
O
Me
O
Et
O O
Me
MeO95% yield87% ee
92% yield88% ee
89% yield80% ee
>99% yield85% ee
88% yield84% ee
>99% yield86% ee
94% yield82% ee
Me MeOHO
OO
POPh
Ph
OM
LF
F
Ligand: DMP:
A relatively small scope, but good selectivities.
A more interesting process...
OO
OP
OPhPh
OM
LF
F
N
O
R
Gd(Oi-Pr)3 (10 mol %), Ligand (15 mol %)
TMSCN (1.5 equiv.), HCNN
O
R
CNtoluene
N
O
Me
CN
N
O
CN
N
O
Ph
CN
N
O
CN
Me
MeOMe
98% yield80% ee
90% yield89% ee
99% yield85% ee
88% yield83% ee
N
O
Me
CN
OH
Me
CN
N
O
Me
CO2Et
O
Me
CO2Et
EtOK-Selectride HCl/EtOH NaOEt (cat.)
Ligand:
Selected Scope:
Manipulations Achieved Without Epimerization:
Once More Back to R207910...
N O
Ph
Br
O
H H
MOM
N O
(R)
Ph
Br
O
MOM
Y(HMDS)3 (X mol %)ligand (1.5X mol %)
additive (0.5X mol %)
Entry X ligand temp additive time yield ee
1 30 ent-L -20 °C none 5 >99% 60%2 30 L -20 °C DMAP 3 >99% 72%3 10 L -40°C MEPO 8 >99% 86%4 2.5 L -50 °C MEPO, Bu3NCl (0.5 mol %) 8 >99% 88%
MEPO:NMeO O O
HON
POPh
Ph
HO
MeL:
THF
Unfortunately, the Gd system failed to yield good selectivity for this system. (63% ee)
Another Hurdle...Allylation
N O
(R)
Ph
O
MOM
CuF•3PPh3•2EtOH (10 mol %)KOt-Bu (15 mol %)
ZnCl2 (1 equiv.)Bu4PBF4 (1 equiv.)
N O
(R)
Ph(S)
MOM
HOTHF, r.t.>99 % yield, 14:1 d.r.
(95%, 5.6:1 d.r with 1 mol %)
B OOMe Me
MeMe
(2 equiv.)
OB
OBr 83%
NH
O
(R)
Ph
(S)
HO
1. O3, then NaBH4,MeOH/H2O, 74%
2. NBS, NaOAc 83%NH
O
(R)
Ph
(S)
HOOH
Br
Conventional carbon nucleophiles could not be utilized due to steric hindrance and the acidity of that proton installed in the
previous step.
Endgame
NH
O
(R)
Ph
(S)
HOOH
Br Ag2CO3, MeI,EtOH
MeCN, 63%N OMe
(R)
Ph(S)
HOOH
Br
1. TsCl, pyridine, DMAP, 90%2. Me2NH (aq.), DMF, 62%
N OMe
(R)
Ph(S)
HONMe2
Br
Recap:
Previous Work: 4 steps longest linear sequence, 0.2% overall yield
This Work:12 steps longest linear sequence,5% overall yield