Double Conjugate Additions to Quinone Monoketals

Double Conjugate Additions to
Double Conjugate
Additions
to Quinone Monoketals
Quinone
Monoketals
O
O
O
R
R
R
RO
RO
OR
O
R
OR
Regioselective Single and Double Conjugate Additions to Substituted
Cyclohexa-2,5-dienone Monoactals
Grecian, S.; Wrobleski, A. D.; Aubé, J. Org. Lett. 2005, 7, 3167-3170.
Double Conjugate Addition of a Nitropropionate Ester to a Quinone Monoketal:
Synthesis of an Advanced Intermediate to (±)-Gelsemine
Grecian, S.; Aubé, J. Org. Lett. 2007, 9, 3153-3156.
Gelsemine
Me
O
N
Previous syntheses by
Johnson, Speckamp, Hart,
Fukuyama, Overman, and
Danishefsky
N
H
Gelsemine Retrosynthesis
O
[3.2.1] bicyclooctane core
quinone
monoketal
OAc
EtO2C
O
NO2
O2N
CO2Et
+
Alloc
O
N
Me
MeO
MeO
OMe
OMe
O
CO2t-Bu
N
MOM
This intermediate previously converted to
(±)-gelsemine by Fukuyama and Liu.
(J. Am. Chem. Soc. 1996, 118, 7426-7427)
Quinone Monoketals
"The use of a quinone monoacetal instead of its parent quinone is very useful in complex
synthesis because it permits an additional level of regiochemical control and allows
differentiation of the two carbonyl groups in subsequent steps."
Quinone Monoketals
OH
1,2 addition
O
[O]
Annulations
ROH
OR
O
R
SN2'
• Cycloadditions
RO
OR
• Hypervalent iodine reagents are popular oxidants
• Tl(NO3)3 and DDQ/Fe(III) are also capable oxidants
1,4 addition
• Michael-Dieckmann
R
RO
OR
Annulations via double conjugate addition are known with
1,3-dinucleophiles.
• Other methods of preparation include:
O
• Monoprotection of quinones
1)
MeO2C
• Monodeprotection of bis-ketals
CO2Me
NaOEt, EtOH
• Oxidation of phenols
O
Review:
Pettus, T. R. R; et al. Chem. Rev. 2004, 104, 1383-1430.
O
O
O
2) LiOH, DMF
77%
OH
O
O
CO2Me
Mulzer, J. et al. Tetrahedron Lett. 2000, 41, 9229-9232.
Single and Double Conjugate Additions
OH
Conjugate Additions
CO2Me
EtO2C
CO2Et
CO2Et
15 mol % KOt-Bu
THF, 25 oC, 10 h
OEt
74% yield,
aromatization achieved
by treatment w/ p-TsOH
CO2Et
O
O
OH
O2N
O
CO2Me
CO22Me
CO2Et
15 mol % KOt-Bu
THF, 25 oC, 10 h
H
CO2Me
MeI
H
quantitative (10:1 d.r.)
CO2Et
CO22Et
EtO
EtO OEt NO2
2
OEt NO2
45%, (10:1 d.r.)
Me
EtO
Me
O
OEt
O
CO2Et
Me
15 mol % KOt-Bu
THF, 25 oC, 10 h
CO2Et
OH
EtO
OEt
84% yield
CO2Me
Me
O
Me
NO2
15 mol % KOt-Bu
THF, 25 oC, 10 h
O
NO2
OH
EtO
OEt
52% yield
CO2Me
Grecian, S.; Wrobleski, A. D.; Aubé, J. Org. Lett. 2005, 7, 3167-3170.
Other Electron Withdrawing Substituents
15 mol % KOt-Bu
THF, 25 oC, 10 h
O
More Substrates
O
O2N
CO2Et
Me
Me
O
O
NHPh
CO2Et
OH
CONHPh
CO2Et
OH
CO2Et
EtO
EtO
OEt
OEt
CONHPh
OEt
57% yield
42% yield
OH
O
EtO2C
O
NO2
EtO
NO2
EtO
OEt
Ar
No Reaction
76% yield
OEt
OH
O
EtO2C
O
NHPh
EtO
OEt O
No Reaction
69% yield
EtO
OEt CONHPh
Grecian, S.; Wrobleski, A. D.; Aubé, J. Org. Lett. 2005, 7, 3167-3170.
Carbon Versus Oxygen Nucleophiles
C-Alkylation vs. O-Alkylation
O
R1
EtO
O
Y
EtO
OEt
EtO
Nuc
OEt
Nuc
OEt
R2
EtO
OH
Y
R1
R2
O
Nuc
EtO
R1
Nuc
OEt
O
O
BH
R2
Nuc
OEt
O
R1
Nuc
R2
EtO
OH
O
O
BH
OEt
O
O
Y
Y
Nuc
EtO
Nuc
OEt
EtO
OEt
stabilized enolate
The nature of the conjugate acceptor is different enough that the
reactivity preference is changed from O-alkylation to C-alkylation.
OH
With diethyl malonate as the nucleophile,
treatment with p-TsOH gives one aromatized
product and one stable adduct.
O
O
R1
Y
CO2Et
OEt
CO2Et
EtO2C
EtO2C EtO
R2
OEt
Double Conjugate Addition of a 1,2-Dinucleophile
Seebach’s 1,2-Dianion
Remember this?
New Target:
OH
O
CO2Me
O2N
O
CO2Me
CO2Et
H
EtO
15 mol % KOt-Bu
THF, 25 oC, 10 h
quantitative (10:1 d.r.)
OEt
CO2Et
EtO
NO2
OEt NO2
RO
Most acidic proton, so further
conjugate addition is not possible.
O2N
CO2Me
1) LDA (2 equiv.), DMPU,
RCHO
Still the most acidic proton,
but now that's a good thing.
OH
R
2) DBU, THF
CO2Me
O
O
O
Me
N
OR CO2Et
N
OMe
O
N
Me
N,N'-Dimethylpropyleneurea (DMPU)
Seebach, D.; et al. Chem. Ber. 1982, 115, 1705-1720.
functionalizes exclusively
at !"position of the ester
Double Conjugate Addition of a 1,2-Dinucleophile
Double Conjugate Addition of
1,2-Dinucleophile
Additive (equiv)
O2N
CO2Et
EtO2C
i. LDA (2.1 equiv), additive
ii. quinone monoketal
NO2
O
MeO
OMe
O
O
MeO
N
O
OEt
1.2 equiv
N
MeO
MeO
OMe
H2O
excess
(>15 equiv)
O
OMe CO2Et O
CO2Et
O2N
EtO2C
O
<5
8
51-59
50
64-69
O
O
MeO
O
no additive
DMPU (12)
HMPA (12)
TMEDA (12)
HMPA (12), TMEDA (2.4)
yield (%)
+
NO2
N
MeO
OMe CO2Et O
O
1.4:1 mixture
MeO
OMe
Grecian, S.; Aubé, J. Org. Lett. 2007, 9, 3153-3156.
O
Formal Synthesis of Gelsemine
Formal Synthesis of
Gelsemine
EtO2C
NO2
EtO2C
O
2) i. LiHMDS, HMPA, THF
ii. 2-BrPhNCO
OMe
Br
OH
N
1) DBU, THF
MeO
MeO
1) NEt3, Tf2O
2) Pd(Ph3)4, n-Bu3SnH,
LiCl, THF
3) NaH, MOMCl
O
OMe
56%, 3 steps
62%, 2 steps
EtO2C
EtO2C
1) BF3•OEt2, CH2Cl2
Pd(PPh3)4
MeO
MeO
OMe
O
N
MOM
Br
MeCN, microwave
61%
(35% undesired diastereomer)
2) n-BuLi, THF
OMe
O
N
(EtO)2(O)P
MOM
54% over two steps (20% E isomer)
EtO2C
OAc
1) NH2Me, MeOH
2) AllocCl, pyr., 4-DMAP
O
CO2t-Bu
CO2t-Bu
N
MOM
3) LiBH4, THF
4) Ac2O, Et3N, 4-DMAP
52% over 4 steps
Alloc
N
Me
O
CO2t-Bu
Grecian, S.; Aubé, J. Org. Lett. 2007, 9, 3153-3156.
N
MOM
How To Write Consistently Boring Scientific Literature
"Science ought to be fun and attractive, particularly when many months of hard
work with grant applications, data collections and calculations are over and
everything is ready for publishing the wonderful results, it is most unfortunate
that the final reading and writing phases are so tiresome."
Sand-Jensen, K. Oikos 2007, 116, 723-727.
AVOID FOCUS, ORIGINALITY, AND PERSONALITY,
AND FOR THE LOVE OF GOD, DON’T SPECULATE
ON THE IMPLICATIONS OF THE DATA
My own research gives the following data.
TIME
COMPREHENSION
1 min.
0.84
15 min.
0.64
45 min.
0.37
3 hrs.
0.12
Some other research has been carried out that shows that
comprehension may be inversely proportional to the amount of time
required to extract the information.
The point is, don’t bury the lead.
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EVERY EFFORT MUST BE MADE TO LOSE THE AUDIENCE
Use nano-jargon at every nano-opportunity
If A implies B1, and B implies C2, then it goes without saying that D3 is true.4
Seriously, it goes without saying.
Stop saying it, someone5 might figure out what you mean.
1Trust
me.
Ref. 1
3 You can also use references to make simple text almost unreadable
4 I have nothing to say.
5 Someone who might cite your work, horror of horrors!
2 See
1,000 WORDS IS A VERY OPTIMISTIC ESTIMATE
The two kids were very surprised.