Total Synthesis of Brevenal Jon D. Rainier Department of Chemistry, University of Utah. J. Am. Chem. Soc. 2011, 133, 3208–3216
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