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Total Synthesis of Gracilioether F: Development and Application of Lewis Acid Promoted Ketene-Alkene [2+2] Cycloadditions and Late Stage C-H Oxidation
Christopher M. Rasik and M. Kevin Brown Angew. Chem. Intd. Ed. 2014, 53, 1-6
Et
Et
H
HO
O
EtO
OGracilioether F
Mike Frasso @ Wipf Group Page 1 of 18 12/6/2014
Introduction
• Isolated from marine sponge Plakinastrella mamillaris in 2012
• No known biological activity • Other members show antimalarial activity • No prior syntheses of any members
Et
Et
H
HO
O
EtO
O
Gracilioether F
Et
Et
H
HO
O
EtO
Gracilioether E Gracilioether G
MeO2C
Et
Et
H
HOEt
O
MeO2C
OHH
Et
Et
H
HO
Et
EtO
O
Gracilioether I
Et HOH
Gracilioether J
Et
Et HOO
OO
H
Et
Et
Gracilioether H
OEt
MeO2C
HOHEt
Tetrahedron 2012, 68,10157-10163
Mike Frasso @ Wipf Group Page 2 of 18 12/6/2014
Retrosynthesis
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
Et
Et
H
HO
O
EtO
OGracilioether F
C-H oxidationEt
Et
H
H
O
O
OEt
HO
[O]Et
Et
H
H
Et
EtEt
CO
+[2+2]
O
Et
Mike Frasso @ Wipf Group Page 3 of 18 12/6/2014
Previous Generation of Ketenes in Presence of Lewis Acids
J. Am. Chem. Soc. 1999, 121, 9726-9727 Org. Lett. 2000, 2, 1883-1886
R3
N
R1O
O
ClR2
TiCl4.THF2 (cat.)
DIPEA, CH2Cl2
O
NR1
R2
O+
N
OLA
R2
R3
R1
R1 = Me, Cl, PhR2 = Me, Ph, protected heteroatom
O
R
O
BrMe DIPEA, CH2Cl2 -50 0C
78 to 90% yield>90% ee, >7:1 d.r.
+O
O
Me R
N AlN
NiPr iPr
Bn
TfTf
R = Alkyl, Aryl Alkynyl
Mike Frasso @ Wipf Group Page 4 of 18 12/6/2014
Pd-Mediated Ketene-Alkene [2+2]
Pd(II)
MeCN, up to 93%, >10:1 d.r.
R = Alkyl
R Br
CO H
HR
O
Br
• Significant improvement in yield over thermal reaction • Opposite diastereomer of thermal reaction • Very limited scope
Tetrahedron. 2001, 57, 2237-2246
Mike Frasso @ Wipf Group Page 5 of 18 12/6/2014
Previous [2+2] Ketene-Alkene Cycloadditions
R1
R2
Cl
O
R1 R2
COEt3N
CH2Cl2
EtAlCl2
CH2Cl2, -78 to 22 oC
OH
HR2
R1
n
n
R1 = Alkyl, ArylR2 = Aryl
59-91% yield5:1-19:1 d.r.
Et Ph
CO
Et Ph
CO
Et
PhO
Ph Et
CO
LA
Ph Et
CO
LA
Ph
EtO
ThermalPathway
Lewis acidPathway
• Sc(OTf)3, Zn(OTf)2, FeCl3, SnCl4, SiCl4, BCl3, AgOTf, Sn(OTf)2, Mg(ClO4)2, CuOTf, AgClO4, In(OTf)3, AlMe3 all gave no product
• Opposite diastereomer from thermal [2+2]
J. Am. Chem. Soc. 2013, 135, 1673-1676
Mike Frasso @ Wipf Group Page 6 of 18 12/6/2014
Previous [2+2] Ketene-Alkene Cycloadditions
J. Am. Chem. Soc. 2013, 135, 1673-1676 Org. Lett. 2014, 16, 5168-5171
R1
R2
Cl
O
R1 R2
COEt3N
CH2Cl2
EtAlCl2
CH2Cl2, -78 to 22 oC
OH
HR2
R1
n
n
R1 = Alkyl, ArylR2 = Aryl
59-91% yield5:1-19:1 d.r.
Et Ph
CO
Et Ph
CO
Et
PhO
Ph Et
CO
LA
Ph Et
CO
LA
Ph
EtO
ThermalPathway
Lewis acidPathway
Mike Frasso @ Wipf Group Page 7 of 18 12/6/2014
Previous [2+2] Ketene-Alkene Cycloadditions
R1
R2
Cl
O
R1 R2
COEt3N
CH2Cl2
EtAlCl2
CH2Cl2, -78 to 22 oC
OH
HR1
R2
n
n
R1 = Alkyl, ArylR2 = Aryl
59-91% yield5:1-19:1 d.r.
Et Ph
CO
Et Ph
CO
Et
PhO
Ph Et
CO
LA
Ph Et
CO
LA
Ph
EtO
ThermalPathway
Lewis acidPathway
J. Am. Chem. Soc. 2013, 135, 1673-1676 Org. Lett. 2014, 16, 5168-5171
• Alkene from less hindered side in thermal reaction • Lewis acid has steric clash with Ph; leads to selectivity • Rotational barrier for Ph-ketene bond reduced from 3.6
to 1.7 kcal/mol
Mike Frasso @ Wipf Group Page 8 of 18 12/6/2014
Previous [2+2] Ketene-Alkene Cycloadditions
J. Am. Chem. Soc. 2013, 135, 1673-1676 Org. Lett. 2014, 16, 5168-5171
• Alkene from less hindered side in thermal reaction • Lewis acid has steric clash with Ph; leads to selectivity • Rotational barrier for Ph-ketene bond reduced from 3.6
to 1.7 kcal/mol
CO
EtAlCl2
CH2Cl2, -78 to 22 oC
H
H
O69% yield10:1 d.r.opposite diastereomer
H
Mike Frasso @ Wipf Group Page 9 of 18 12/6/2014
Retrosynthesis
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
Et
Et
H
HO
O
EtO
OGracilioether F
C-H oxidationEt
Et
H
H
O
O
OEt
HO
[O]Et
Et
H
H
Et
EtEt
CO
+[2+2]
O
Et
Mike Frasso @ Wipf Group Page 10 of 18 12/6/2014
Development of [2+2] for Gracilioether F
R1
R2 EtCl
O
R2
R1
Et
COEt3N
CH2Cl2
AlMe3
CH2Cl2, -78 to 22 oC
OH
HR1
R2
Et
EtEt
Cl
OPh
EtCl
OPh
EtCl
O
1<2% yield
242% yield
7:1 d.r.
361% yield
3:1 d.r.
4Incorrect
Diastereomer1-3
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
Mike Frasso @ Wipf Group Page 11 of 18 12/6/2014
New Strategy for [2+2]
Et
Et 5
Ph H
CO Lewis Acid
promoted
[2+2]
Et
Et
OH
H Ph7
Alkylation+
Et
Et
OH
H Ph
Et
8
Ph Cl
O AlMe3, DIPEA
CH2Cl2, -78 to -45 oC69%, 8:1 d.r.
OH
H Ph10
KHMDS, then EtI
THF, -78 to 22 oC91%, >20:1 d.r.
OH
H Ph
Et
11
6
9
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
Mike Frasso @ Wipf Group Page 12 of 18 12/6/2014
New Strategy for [2+2]
Et
Et 5
Ph H
CO Lewis Acid
promoted
[2+2]
Et
Et
OH
H Ph7
Alkylation+
Et
Et
OH
H Ph
Et
8
Ph Cl
O AlMe3, DIPEA
CH2Cl2, -78 to -45 oC69%, 8:1 d.r.
OH
H Ph10
KHMDS, then EtI
THF, -78 to 22 oC91%, >20:1 d.r.
OH
H Ph
Et
11
6
9
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
Mike Frasso @ Wipf Group Page 13 of 18 12/6/2014
Synthesis
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
OH
OH
O3, MeOH/CH2Cl2, -78 oC
then NaBH4, 0 oC, 18%
1. TsCl, pyridine 0 to 22 oC
2. Me2CuLi.LiI, Et2O -45 to 22 oC 59%
Et
Et
9, AlMe3, DIPEA
CH2Cl2, -78 to -45 oC65%, >20:1 d.r.
Et
Et
OH
H Ph
KHMDS, then EtI
THF, -78 to 22 oC
Et
Et
OH
H Ph
Et
H
CO
Ph
AlMe3
EtEt
12 13 5
7
8
Ph Cl
OPh
HOOC COOH
2 steps
9
O
Mike Frasso @ Wipf Group Page 14 of 18 12/6/2014
Synthesis (cont’d.)
H2O2, NaOH
MeOH61%, >20:1 d.r.
Et
Et
H
H
O
O
Ph
Et
Et
Et
H
H
O
O
OEt
HO
O3, CH2Cl2,-78 oC
then NaClO2, NaH2PO4t-BuOH, isobutylene
83%
Et
Et
H
HO
O
EtO
O
Et
Et
OH
H Ph
Et
C-H oxidation
Gracilioether F
8 10 11
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
Mike Frasso @ Wipf Group Page 15 of 18 12/6/2014
C-H Oxidation Development
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
O O
F3CTFDO
N
Fe
N
N NCCH3
NNCCH3
Fe(PDP)
Et
Et
H
H
O
O
OEt
HO11
Et
Et
H
HO
O
EtO
O
Conditions
Gracilioether F
Entry Conditions Yield (%) RSM (%)
1
2345678*
RuCl3, KBrO3, pyridineMeCN/H2O <2 ---
TFDO, CH2Cl2, -45 to 22 oC <2 >90Fe(PDP) (20 mol%), H2O2,MeCN 9 48Fe(OAc)2, H2O2,MeCN <2 ~80Mn(OAc)2, H2O2,MeCN <2 ~80Cu(OAc)2, H2O2,MeCN 15 51Cu(OAc)2, H2O2,MeCN, 0 oC 10 88Cu(OAc)2, H2O2,MeCN, 0 oC <2 >90
*using Me ester of 11
Mike Frasso @ Wipf Group Page 16 of 18 12/6/2014
C-H Oxidation Development
Angew. Chem. Intd. Ed. 2012, 68, 10157-10163
O O
F3CTFDO
N
Fe
N
N NCCH3
NNCCH3
Fe(PDP)
Et
Et
H
H
O
O
OEt
HO11
Et
Et
H
HO
O
EtO
O
Conditions
Gracilioether F
Entry Conditions Yield (%) RSM (%)
1
2345678*
RuCl3, KBrO3, pyridineMeCN/H2O <2 ---
TFDO, CH2Cl2, -45 to 22 oC <2 >90Fe(PDP) (20 mol%), H2O2,MeCN 9 48Fe(OAc)2, H2O2,MeCN <2 ~80Mn(OAc)2, H2O2,MeCN <2 ~80Cu(OAc)2, H2O2,MeCN 15 51Cu(OAc)2, H2O2,MeCN, 0 oC 10 88Cu(OAc)2, H2O2,MeCN, 0 oC <2 >90
*using Me ester of 11
Mike Frasso @ Wipf Group Page 17 of 18 12/6/2014
Conclusions
• Gracilioether F was synthesized in 8 steps in 0.35% yield • Features a unique Lewis acid promoted ketene-alkene
[2+2] cycloaddition and a late stage C-H oxidation • Yield is disappointing • C-H oxidation is very impractical
Mike Frasso @ Wipf Group Page 18 of 18 12/6/2014