Languages
Pages
Legal
Total Synthesis of Brevenal
Jon D. Rainier
Department of Chemistry, University of Utah.
J. Am. Chem. Soc. 2011, 133, 3208–3216
O
O O
OO
H
HH H
OHMe
HHHMe
MeH
HOHMe
H
Me
Me
OHC
AB C D
E
Brevenal
Dinoflagellate-derived marine ladder toxin
Interesting pentacyclic structure
Fused ether architectures
O
O PO
OO
H
HH H
OHMe
HHHMe
MeH
HOH
OP
PO
O
3
PO
OH H
OHMe
H
OPO
OH
O
O
H
H
HHMe
MeH
HOH
PO
HO
4 5
O
O O
OO
H
HH H
OHMe
HHHMe
MeH
HOH
OP
PO
1
Me
H
O
O PO
OO
H
HH H
OHMe
HHHMe
MeH
HOH
OP
PO
2
O
O O
OO
H
HH H
OHMe
HHHMe
MeH
HOHMe
H
Me
Me
OHC
AB C D
E
Brevenal
Olefinic Ester and Diene Ring-Closing Metathesis Using a Reduced Titanium Alkylidene:
O
H
H
On TiCl4, Zn
PbCl2, RCHBr2TMEDA, THF O
H
H
n
J. AM. CHEM. SOC. 2007, 129, 12604-12605
TBDPSOH
O
*Me B
Me
2
6
7
THF
NaOH,H2O2
(90%, 95:5 er)
TBDPSOOH
MeH
H
8
1. PMBBr, KH (90%)
2. BH3-DMS; H2O2, NaOH
3. Dess-Martin periodinane
TBDPSOOPMB
MeH
H
9
CHO 1.Ph3PCH3Br,KOt-Bu(73%,3 steps)2.DDQ,CH2Cl2,H2O(92%)
3.HO2CCH2CH2CH2CH(OMe)2 10 DCC,DMAP,CH2Cl2(95%)
TBDPSOO
MeH
H
11
O
OMe
OMe
3
conditions TBDPSOO
MeH
H12
OMe
OMe
3
N NMes Mes
RuPh
ClCl
PCy3
13
12
O O ,CH2Cl2
-78oC to 0oC
AlMe3-78oC to 0oC
O
Me
R
H
R'
H
H
O
14
AlMe3
O
Me
R
H
R'
H
H
OAl
Me
Me
Me
15
R=CH2CH2CH2OTBDPSR'=CH2CH2CH2(OMe)2
O
MeHH
H
OH
OMe
OMe
TBDPSO
Me16 66%
O
MeHH
H
OH
OMe
Me
TBDPSO
Me17 20%
161. PPTS, PhH, 70oC(91%)
2. TMSOTf, i-Pr2NEt,CH2Cl2 -78oC to 0oC(90%)
O
MeHH
H
TBDPSO
O
Me18
O O ,CH2Cl2
-78oC to 0oC
,CH2Cl2, 0oC(87%, 10:1)
MgCl
O
MeHH
H
TBDPSO
O
Me19
OHH
1.TPAP, NMO,CH2Cl2(93%)
2. LiHMDS, TESCl, THF; m-CPBA, CH2Cl2,NaHCO3, 0oC to rt;Na2S2O3,H2O
O
MeHH
H
TBDPSO
O
Me20
OH
O
1.i-Bu2AlH,CH2Cl2,-78oC (70%,2 steps)
2.Bu2SnO,MeOH,70oC; BnBr,DMF,CsF,rt (77%, 6:1regioselectivity)
O
MeHH
H
TBDPSO
O
Me21
OBn
OH
Synthesis of Brevenal’s E-Ring Precursor:
O
OPhH H
HO
O
OBn
TiCl4,Zn,PbCl2,CH3CHBr2
THF,TMEDA,CH2Cl2,65oC (66%)
O
OPhH H
O
OBnH
22 23
O O ,CH2Cl2
-78oC to 0oC
i-Bu2AlH,CH2Cl2 -78oC
“Rubottom oxidation”
O
OPhH H
O
OBnH
24H
OH1.TPAP,NMO,CH2Cl2 (62%, 2 steps)
2. MeMgBr,PhCH3,-78oC (84%,dr = 7:1)
O
OPhH H
O
OBnH
25H
OHMe 1. TBSOTf,NEt3,CH2Cl2
(92%)
2.PPTS,MeOH,65oC (93%)
HO
HOH
O
OBnH
26H
OTBSMe 1.Tf2O,2,6-lutidine,CH2Cl2;
TESOTf, 2,6-lutidine,CH2Cl2
2. ClMg CuI,THF
(74%, 2 steps)
TESOH
O
OBnH
27
H
OTBSMe
1.CSA, MeOH
2.PMBBr,KH (87%,2 steps)
PMBOH
O
OBnH
28
H
OTBSMe 1.OsO4, NMO,t-BuOH,H2O
2.Pb(OAc)4,PhH
3.NaClO2,NaH2PO4,t-BuOH,H2O
(54%,3 steps)
PMBOH
O
OBnH
29
H
OTBSMe
HO2C
A Novel Carbon-Carbon Bond-Forming Reaction of Triflates withCopper(1)-Catalyzed Grignard Reagents:
One-pot double alkylation strategy.
J. Org. Chem. 1990, 55,4417–422.
21 + 292,4,6-trichlorobenzoyl chloride
NEt3,THF,40oC;PhCH3,DMAP (81%) O
O PMBO
OO
H
HH H
OTBSMe
HHMe
MeH
HOBn
OBn
TBDPSO
O
30
TiCl4,Zn,PbCl2,CH3CHBr2
THF,CH2Cl2,TMEDA,65oC (83%) O
O
OO
H
HH H
OTBSMe
HHMe
MeH
HOBn
OBn
TBDPSO
31
H PMBO
31O O ,CH2Cl2,-78oC;
AlMe3,CH2Cl2,-78oC to 0oC O
H
H
O
OBn
H
OAlH2R3
32
O
H
H
O
OBn 33
O
31O O ,CH2Cl2,-78oC;
AlMe3,PhCH3,-78oC to 0oC
(75%,1.7:1)
O
H
H
O
OBn 34
OH
Me
34 was isolated as an inseparable mixture of diastereomers as a result of the poor selectivity in theepoxidation reaction made this approach untenable and forced us to modify our strategy.
O
OH
OBn
H H
BnO
BnOO O
CH2Cl2
O
O
O
H
H35 36
TESOTf
-78oC to 0oC
O
O
H
H37
OTES
ZnMe2
(82%) O
OH
OBn
H H
BnO
BnO
38
OTES
Me
31O O ,CH2Cl2,-78oC;
TESOTf, ZnMe2 O
H
H
O
OBn
OTES
OMe
trace 39
O
H
H
O
OBn
OTES
Me
trace 40
+ decomposition
model bicyclic enol ether
39 comes from the oxidation of ZnMe2 by the epoxide from 31 and the subsequent transfer of methoxide to the epoxide
O
O
OO
H
HH H
OTBSMe
HHMe
MeH
HOBn
OBn
TBDPSO
41
H PMBO31
O O ,CH2Cl2,-78oC;
EtSH,Zn(OTf)2(89%,1.5:1 dr)
OH
SEt
1. TESOTf,NEt3
2. Me2Zn,Zn(OTf)2 (89%,2 steps)
O
O
OO
H
HH H
OTBSMe
HHMe
MeH
HOBn
OBn
TBDPSO
42
H PMBO
OR
Me R = TES
1.CSA, MeOH
2.TPAP,NMO
3.DDQ,CH2Cl2,H2O
91%,3 steps
O
O
OO
H
HH H
OTBSMe
HMe
MeH
HOBn
OBn
TBDPSO
43
H
Me
OHO
Tetrahedron Letters 51 (2010) 3960–3961
O
O
OO
H
HH H
OTBSMe
HMe
MeH
HOBn
OBn
TBDPSO
44
H
Me
431.Zn(OTf)2, EtSH
2.AgClO4,4A MS,NaHCO3
OEtS H
O
O
OO
H
HH H
OTBSMe
HMe
MeH
HOBn
OBn
TBDPSO
45
H
Me
OHH
Condition
Zn(OTf)2, EtSHO
O
OO
H
HH H
OTBSMe
HMe
MeH
HOBn
OBn
TBDPSO
46
H
Me
OO
TES
(43%)
O
O
OO
H
HH H
OTBSMe
HMe
MeH
HOBn
OBn
TBDPSO
47
H
Me
OH EtS
Ph3SnH,AIBN,PhCH3
110oC,4 days (90%)
O
O
OO
H
HH H
OTBSMe
HMe
MeH
HOBn
OBn
TBDPSO
48
H
Me
OHH
1.LiDBB
2.TBSOTf,NEt3 (85%, 2 steps)
O
O
OO
H
HH H
OTBSMe
HMe
MeH
OTBS
OTBS
TBDPSO
49
H
Me
OHH 23
our spectroscopic data for 49 did not match that previously reported. While not definitivelyestablished, we presume that pentacycle 49 differs from the brevenal core at C(23).
lithium di-t-butyl biphenylide (LiDBB)
O
O O
OO
H
HH H
OPMe
HHHMe
MeH
OP
OP
PO
50
Me
H
OP
O O
OO
H
HH H
OPMe
HHHMe
MeH
OP
OP
PO
51
OPO
O O
OO
H
HH H
OPMe
HHHMe
MeH
OP
OP
PO
52
OP
O
O
H
H
HHMe
MeH
OP
PO
CO2H
HO
OH H
OPMe
H
OP
53
54
+
Brevenal Retrosynthesis-2:
RO
OH
H
OTBSMe
HOBn
OTES
O
O
H
H
HHMe
MeH
OTES
TBDPSO
CO2H
555 steps from 20
+
27:R = TES
56:R = H
CSAMeOH
NO2
Me
O
O O
Me
NO2
57
DMAP,CH2Cl2,rt (87%)
OTES
O O
OO
H
HH H
OTBSMe
HHHMe
MeH
OTES
OBn
TBDPSO
59
30%
OTES
O O
OH H
OTBSMe
HH
HOTES 60
70%
13, CH2=CH2, PhH, 80oC (60%(5:1oxepene:dihydropyran),65% overall yield)
OTESO
O O
OO
H
HH H
OTBSMe
HHHMe
MeH
OTES
OBn
TBDPSO
58
TiCl4,Zn,PbCl2,TMEDA
CH3CHBr2,THF,65oC
O
MeHH
H
TBDPSO
O
Me20
OH
Oi-Bu2AlH,CH2Cl2
O
MeHH
H
TBDPSO
O
Me OH
OH TESOTf,Et3N
CH2Cl2
O
MeHH
H
TBDPSO
O
Me OTES
OTESOsO4, NMO
O
MeHH
H
TBDPSO
O
Me OTES
OTES
HO
HO
Pb(OAc)4
O
MeHH
H
TBDPSO
O
Me
OHC
OTES
OTES
NaClO2
O
MeHH
H
TBDPSO
O
Me
HO2C
OTES
OTES
55
From 20 to 55:
591, O O; i-Bu2AlH (75%)
2.TPAP,NMO(87%) 4A MS
O O
OO
H
HH H
OTBSMe
HHHMe
Me
OTES
OBn
TBDPSO
61
OOTES
1. EtSH,Zn(OTf)2(59%)
2. TBSOTf,2,6-lutidine(82%)
O O
OO
H
HH H
OTBSMe
HHHMe
Me
OTBS
OBn
TBDPSO
62
O
H
SEtH
Me2Zn,Zn(OTf)2
CH2Cl2 (94%)
O O
OO
H
HH H
OTBSMe
HHHMe
Me
OTBS
OBn
TBDPSO
63
O
H
MeH
O O
OO
H
HH H
OTBSMe
HHHMe
Me
OTBS
TBDPSO
63
O
H
MeH
1.LiDBB,-78oC(95%)
2.SO3-pyridine,Et3N,DMSO
3.64,NaHMDS,-78oC
4.H2O2,NaHCO3,30oC (87%,3 steps)
Ph3P SePhBr
64
1.TBAF,HOAc(91%)
2.SO3-pyridine,Et3N,DMSO
3.66,BuLi (85%, 2 steps)
O O
OO
H
HH H
OTBSMe
HHHMe
Me
OTBS 63
O
H
MeH
MeO2C
P(O)(OEt)2
MeO2C
66
1.HF-pyridine
2.i-Bu2AlH,-78oC
3.MnO2(80%,3 steps)
O O
OO
H
HH H
OHMe
HHHMe
Me
OH
O
H
MeH
OHC
(-)-Brevenal
Top Related