differentiation of nonconventional “carbanions” – the total synthesis...
TRANSCRIPT
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Differentiation of Nonconventional “Carbanions” –The Total Synthesis of Nemorosone and Clusianone
Chihiro Tsukano, Dionicio R. Siegel, and Samuel J. DanishefskyAngew. Chem. Int. Ed. 2007, early view
William PaquetteCurrent Literature – 10/27/07
Wipf Group
Bill Paquette @ Wipf Group 1 10/29/2007
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O
Ph
O
HO O
Nemorosone
O
HO O
O Ph
Clusianone
O
HO
R1 R2O
3-D representation
•Isolated in 2001 from the flowers of Clusia rosea•Telomerase and ERK-1/2 Inhibitor
•Isolated in 1976 from the flowers of Clusia congestiflora•Anti-HIV properties
O O
OOHO H
Garsubellin A
Structurally Related Polyprenylated Natural Products
Bill Paquette @ Wipf Group 2 10/29/2007
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Biosynthesis of Polyprenylated Natural Products
Ciochina, R. and Grossman, R. B. Chem. Rev. 2006, 106, 3963-3986.
R SCoA
OSCoAHO
OO
HO OH
O
R
O
HO OH
O
R
O
R
O O
O SCoA
O
OH
R
O
HO OH
O
R
O
HO O
O
HO O
O R
3 x
Dieckmanncondensation
prenylpyrophosphate
5
1
C(1) attack
Nemorosone, R = PhClusianone, R = Ph
C(5) attack
1
1
5
5
(malonyl-CoA)
"prenyl"
Bill Paquette @ Wipf Group 3 10/29/2007
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M. Shibasaki, et. al. J. Am. Chem. Soc. 2005, 127, 14200-14201.
First Total Synthesis of (+)-Garsubellin AO
MOMO
OTIPS
1. AD-mix-!
2. Triphosgene30% (2 steps)
3. HF-pyr4. PDC, 70% (2 steps)
O
MOMO
O
O
O
O
O
MOMO
O
O
O
O
NaHMDS, ethylene carbonate,allyl iodide, 82%
O
MOMO
O
O
O
O
NaOAc, ", 96% Hoveyda-Grubbs cat.
92%
O
MOMO
O
O
O
O
1. (PhSe)2, PhIO22. CSA
70% (2 steps)
O
HO
O
O
O
O
O
1. LiOH2. Na2PdCl4,
TBHP
71% (2 steps)
O
HO
O
OOHO
1. I2, CAN2. p-TsOH
80% (2 steps)
O O
OOHO
I
PdCl2-dppf,tributyl prenyl tin
20%
O O
OOHO
Garsubellin A
O
OEt
commercially available
9 steps
Bill Paquette @ Wipf Group 4 10/29/2007
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[3.3.1] BicyclesFacile Construction Toward Polyprenylated Compounds
SePh
O
O
O
MeO2C
OAcO
O
H
CO2Me
N-(phenylseleno)phthalimideSnCl4
95%
SePh
O
MeO2C
Ac
SePh
O
MeO2C
OH
CO2Et
OAc
CO2Et
X
O
CO2Et
PhSe
HN-(phenylseleno)phthalimide
SnCl4, 0 oC
88%
Kinetic product
Ac2O,DMAP89%
N-(phenylseleno)phthalimide
SnCl4, -78 oC
94%
NuThermodynamic product
O
HO
O
H
OTBS
Cl Cl
O O
1.
2. KOH, BnEt3NCl36% (87% BRSM)
single diastereomer
O
Me Me
O
O
Me Me
Me
Me
Me
MeO
Me
Me
HO H
Garsubellin A
Nicolaou, J. Am. Chem. Soc. 1999, 121, 4724-4725
Nicolaou, Org. Lett. 1999, 1, 807-810
Stoltz, Org. Lett. 2002, 4, 1943-1946
Bill Paquette @ Wipf Group 5 10/29/2007
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Expedient Synthesis of (+)Clusianone
OH
Ph
O
HO OH
MeO2C
OAc
O
MeO2C
OMe
O
Ph
O
a. Michael addition
b. elimination
OH
Ph
O
HO OH
CHOAcO
O
OHC
OMe
O
Ph
O
MgBr
O OMe
O
Ph
O
AcOO OMe
O
Ph
O
O OH
O
Ph
O
KHMDS, 65oC
2. TMSCHN2
1.
54%2. Ac2O, iPr2EtN
74%
1.
1. Pd(PPh3)4, formic acid90%
2. Grubbs 2nd gen.2-methyl-2-butene
89%
LiOH, 77%
OH
Ph
O
HO OH
Br
aq. KOH45%
(+)-Clusianone
J. Qi and J. A. Porco, Jr. J. Am. Chem. Soc. 2007, 129, 12682-12683
Bill Paquette @ Wipf Group 6 10/29/2007
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Substitutions of Bridged Carbonyl CompoundsReactivity of “anti-Bredt” Carbanions
NPh
OLiCl, THF
E, -105 oC
NPh
O
E
Ph NLi
Ph
O OLi
LiTMP
heptanert
OHO
90%
•Lithiated species could not be trapped in situ with TMSCl
highly reactive
C. Shiner, J. Am. Chem Soc. 1988, 110, 957-958
NPh
OLDA, LiCl, THF
TMSCl, -105 oC
NPh
O
TMS
74%racemicO
TMS
TBAT, THF
electrophile
O
E
N. S. Simpkins, Chem. Commun. 2001, 2668-2669
F-mediated silyl exchange
N. S. Simpkins, Org. Lett. 2003, 5, 1673-1675
Bill Paquette @ Wipf Group 7 10/29/2007
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Racemic Clusianone SynthesisBridgehead Functionalization of the [3.3.1] Ring
O
O
OMe
H
O
O
OMe
H
O
O
OMe
H
Ph
O
O
O
OH
H
Ph
O
O
OMe O
OMe OMe
Cl Cl
O O
O
LiOH, 90%
(+)-Clusianone
1. MeLi2. HCl
MeMgBr, TMSCl,HMPA, CuBr-SMe2
(85:15, syn favored)
t-BuOK, DMSO,then Me2SO4
88%
(75:25)
87%
then KOH,BnEt3NCl
1.
2. HC(OMe)3,p-TsOH, 24% (2 steps)
LDA (2 eq.),prenyl bromide
91%
LTMP,PhCOCl
91%
Rodeschini, V.; Ahmad, N. M.; Simpkins, N. S. Org. Lett. 2006, 8, 5283-5285
Bill Paquette @ Wipf Group 8 10/29/2007
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O
Ph
O
HO O
Nemorosone
O
HO O
O Ph
Clusianone
O
MeO O
Differentiation of Nonconventional “Carbanions” –The Total Synthesis of Nemorosone and Clusianone
Title Paper
Construct from a common intermediate
Chihiro Tsukano, Dionicio R. Siegel, and Samuel J. DanishefskyAngew. Chem. Int. Ed. 2007, early view
Bill Paquette @ Wipf Group 9 10/29/2007
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OMe
OHMeO
OMeO
O
OH
I
OOHO H
I
OH
I
OOHO H
I
OMeO
OMe
O
I
MeO O
I
OMeO
OI
I
OMeO
OMe
OMeO
O
OMeO
I
O
I
Garsubellin A
3,5-dimethoxyphenol
allylOH, Pd(OAc)2,PPh3, Ti(OiPr)4, mol sieves
50 oC, 50%
Grubbs' 2nd gen.,2-methyl-2-butene
CH2Cl2, 40 oC, 79%
LiI, 2,4,6-collidine
140 oC, 82%
I2, KI, KHCO3
THF/H2O
32% 29% 24%
Zn, THF/H2O
vs
A B
Exclusive formation of bicycle (85%) through B in Garsubellin A synthesis
(THF moiety may provide conformational restrictions for C-C bond formation)
Siegel, D. R. and Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048-1049
Construction of the Requisite Bicycle
Bill Paquette @ Wipf Group 10 10/29/2007
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O
I
MeO O
I
O
MeO O
O
MeO O
O
MeO O
R1
R2
O
I
MeO O
O
MeO O
TMS
1
3
iPrMgCl, 93% TMSI, 98%
AllylSnBu3, AIBN
84% 1
3
R1 = D, R2 = H
R1 = H, R2 = D
1
3
LDA
O
MeO O
1
3
LDA (5 eq)
in situ TMSCl
74%
-No TMS incorporation at C1
LDA
I2 quench
O
MeO O
TMS
1
3
I
(low yield)
45% (TMSCl present)
excess LDA, TMSCl,then I2
51%
•Deprotonation studiesshow ~1:1 D incorporation
Selective Quenching of the [3.3.1] System
Bill Paquette @ Wipf Group 11 10/29/2007
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O
MeO O
I
TMS
O
MeO O
Ph
O
O
MeO O
Ph
O
O
HO O
Ph
O
O
MeO O
Ph
O
Nemorosone
Grubbs' 2nd gen.,2-methylpropene
CH2Cl2, 40 oC, 91%
LiI, 2,4,6-collidine
140 oC, 31%
1. iPrMgCl, then PhCHO
2. DMP3. TBAF, 61% (3 steps)
LDA,lithium 2-thienylcyanocuprate,
then allyl bromide
88%
Site-selective Functionalization using Orthogonal GroupsCompletion of Nemorosone
Bill Paquette @ Wipf Group 12 10/29/2007
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O
MeO O
O
MeO O
O Ph
O
MeO O
PhO
O
HO O
O Ph
O
MeO O
PhO
I
Clusianone
1. Grubbs' 2nd gen.,2-methylpropene, 94%
1. LDAthen PhCHO
2. DMP, 57% (2 steps)
LDA, TMSCl,then I2
48%
AllylSnBu3, Et3B, air
71% 2. 10% aq NaOH, 64%
Completion of Clusianone
Bill Paquette @ Wipf Group 13 10/29/2007
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Summary and ConclusionsO
HO
R1 R2O
SePh
O
O
O
MeO2C
OAcO
O
H
CO2Me
N-(phenylseleno)phthalimideSnCl4
95%
O
HO
O
H
OTBS
Cl Cl
O O
1.
2. KOH, BnEt3NCl36% (87% BRSM)
single diastereomer
OMeO
O O
I
MeO O
II2, KI, KHCO3
THF/H2O
32%
•Bicyclo[3.3.1] ring systems can be constructed rapidly from relatively simple structures
OH
MeO O
TMS
I
•Iodine-induced carbocycle formation•Differentiation of reactive
carbanions
∴Concise syntheses of nemorosone, clusianone, and related natural products offer good starting points for potential structure-activity profiling
Bill Paquette @ Wipf Group 14 10/29/2007