Brevetoxin B
K. C. Nicolaou, 1995
O
O
O
O
O
O
O
O O
O O H
O
O
Me
H H H
H H H Me
H
H
H
HO
H Me HH
Me Me H
H
H
Me
Me
A B C D
E F G H
I
J
K
Introduction
Brevetoxin B is a marine neurotoxin most commonly
associated with Red Tides
– Annually responsible for the deaths of thousands of marine
organisms
The structure of this poison was identified in 1981 by Lin,
Nakanishi, and Clardy.
The framework consists of a single carbon chain folded into
eleven fused rings.
Twenty three stereocenters are present in the molecule
O
O
O
O
O
O
O
O O
O O H
O
O
Me
H H H
H H H Me
H
H
H
HO
H Me HH
Me Me H
H
H
Me
Me
A B C D
E F G H
I
J
K
Third Generation Retrosynthetic Approach
O
O
O
O
O
O
O
O O
O O
O
O
Me
H H H
H H H Me
H
H
H
HO
H Me HH
Me Me H
H
H
Me
Me
A B C D
E F G H
I
J
K
1: brevetoxin B
O
O
O
O
O
O
O
O
O O OTPS
Me
H H H
H H H Me
H
H
H
TBSO
H Me HH
Me Me
EtS
H
Me
Me
A B C D
E F G
I
J
K
EtS
HO
85
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A
OTMS
PPh3
O
O
OH H
OTBS
EtS H Me
I
EtS
H
H
O
J K OTPS+
8687
B C D
E F G
Retrosynthetic Approach Cont.
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A
OTMS
PPh3
87
B C D
E F G
OH
OH OH
OH
OH
OH
CHOTBSO Me
PivO
+
99: D-mannitol 97
O
O
OH H
OTBS
EtS H Me
I
EtS
H
H
O
J K OTPS
86
HO
O
OH
OHHO
OH
79: D-mannose
Total Synthesis
Construction of Key Intermediates 86 and 87
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A
OTMS
PPh3
87
B C D
E F G
O
O
OH H
OTBS
EtS H Me
I
EtS
H
H
O
J K OTPS
86
Construction of Intermediate 86
HO
O
OH
OHHO
OH
79: D-mannose
O
OHO
O
H OTPS
1. Ac2O (excess), pyr., 25 oC
2. allyltrimethylsilane, BF3 OEt2,
TMSOTf, CH3CN, 0 oC
3. NaOMe, MeOH, 25 oC
(75% overall)
4. t-BuPh2SiCl, imid., DMF, 0 oC;
then 2-methoxypropene,
CSA (cat.), 0 oC
(82%)
112
1. Im2C=S, PhCH3, 110 oC
2. n-Bu3SnH, AIBN (cat),
PhCH3, 110 oC
(66% overall)
O
O O
H OTPS
113
1. amberlyst-15 (H+),
MeOH, 60 oC (72%)
2. n-Bu2SnO, MeOH,
60 oC; then BnBr,
DMF, 100 oC (74%)
O
HOBnO
H OTPS
114
(COCl)2, DMSO,
CH2Cl2, -78 oC;
then Et3N, 0 oC
(100% Yield)
O
H
O
O
H
OTPS M
L
L
Ph
Nu
O
OBnO
H OTPS
115
AlMe3, MgBr2 OEt2,
CH2Cl2, -50 oC
(61% Yield of 91)
O
HO
H OTPS
91
MeOBn
K
(ca. 3:1 mixture of
diastereomers)
1. O3, CH2Cl2, -78 oC;
then Me2S, Ph3P
2. CH2=CHMgBr, TFH, 0 oC
(44% Yield) O
HO
OTPS
117
MeOBn
K
HO H
H
(ca. 1:1 mixture of
diastereomers)
O
HO
OTPS
90
MeOBn
K
TPSO H
H
CO2Me1. t-BuPh
2SiCl, imid.,
DMF, 25 oC
2. O3, CH2Cl2, -78 oC;
then Me2S, Ph3P
3. Ph3P=CHCO2Me,
PhH, 25 oC
(78% overall)
Construction of Intermediate 86 Continued
O
HO
OTPS
90
MeOBn
K
TPSO H
H
CO2Me
NaH, THF, 25 oC
(92%)
O
OTPS
89
MeOBn
K
TPSO H
H
MeO2C O
H Dibal-H (1.5 eq),CH2Cl2,
-78 oC; then
Ph3P=CHCO2Me
(75% overall)
J O
OTPS118
MeOBn
K
HH
OH
J
O
TPS
MeO2C
1. Dibal-H (2.2 eq),
CH2Cl2, -78 oC
2. mCPBA, CH2Cl2, 0 oC
(77% overall)
O
OTPS119
MeOBn
K
HH
OH
J
O
TPS
OHO
(ca. 10:1 mixture of epoxide
stereoisomers in favor
of 119)
1. (COCl)2, DMSO, CH2Cl2,
-78 oC, then Et3N
2. Ph3P=CHCO2Me, PhH, 25 oC
3. TBAF (1.2 equiv.), THF, 25 oC
(75% overall)
O
OTPS88
MeOBn
K
HH
OH
J
HO
O
MeO2C
O
OTPS120
MeOBn
K
HH
OH
J
O
MeO2C
HO H
I
H
CSA (cat.), CH2Cl2, 25 oC
(71%)
1. O3, CH2Cl2, -78 oC;
then Ph3P; then
NaBH4, MeOH, 25 oC
2. 2-methoxypropene,
CSA (cat.), CH2Cl2, 25 oC
(85% overall)
O
OTPS121
MeOBn
K
HH
OH
J
O
H
I
H
O
O
O
122
MeOBn
K
HH
OH
J
O
H
I
H
O
O CO
2Me
1. TBAF, THF, 25 oC
2. (COCl)2, DMSO,
CH2Cl2, -78 oC;
then Et3N
3. Ph3P=CHCO2Me,
CH2Cl2, 25 oC
(93% overall) (E:Z ca. 4:1)
O
122
MeOBn
K
HH
OH
J
O
H
I
H
O
O CO
2Me
1. H2, Pd(OH)2, EtOAc, 25 oC
2. LAlH4, THF, 0 oC
(92% for steps 1 and 2)
3. t-BuPh2SiCl, Et3N,
4-DMAP, CH2Cl2, 25 oC
4. t-BuMe2SiOTf, 2,6-lutidine,
CH2Cl2, 0 oC
(95% for steps 3 and 4)
O
124
MeOTBS
K
HH
OH
J
O
H
I
H
O
O OTPS
1. CSA, CH2Cl2:MeOH (1:1), 0 oC
2. TBSCl, imid., DMF, 0 oC
3. NMO, TPAP (cat.), CH3CN, 25 oC
O
125
MeOTBS
K
HH
OH
J
O
I
H
O
OTPS
OTBS
1. EtSH, Zn(OTf)2, CH2Cl2, 25 oC
2. CSA, MeOH, 25 oC
3. SO3 pyr., Et3N, DMSO, CH2Cl2, 0 oC
(68% overall)O
O
OH H
OTBS
EtS H Me
I
EtS
H
H
O
J K OTPS
Key Intermediate 86
Construction of Intermediate 86 Continued
Construction of Intermediate 87
O
OH
HO
HO H
H 1. Ph3P=CMeCO2Et
THF, 80 oC
2. PhCH(OMe)2,
CSA, CH2Cl2,
25 oC
(96% overall)
O
O
Me
Ph
OH
H
CO2Et
1. (COCl)2, DMSO,
CH2Cl2, -78 oC;
then Et3N
110: 2-deoxy-D-ribose
109
O
OPh
H
CO2Et
127
Me
2. AlMe3, CH2Cl2, -20 oC
(75% from 109)
Me
OH
1. TMS-imidazole,
CH2Cl2, 25 oC
2. Dibal-H, CH2Cl2,
-78 oC
(96% overall)
O
OPh
H
128
MeOTMS Me OH
1. (-)-DET, Ti(Oi-Pr)4,
t-BuOOH, CH2Cl2, -25 oC
2. SO3 pyr., DMSO,
CH2Cl2, -78 oC
3. Ph3P=CH2, THF, 0 oC
(73% overall)O
OPh
H
130
MeOTMS Me
O
1. TBAF, THF, 25 oC
2. PPTS, CH2Cl2, 0 to 25 oC
(89% overall)
O
OPh
H
131
Me O Me
H OH
F
1. t-BuMe2SiCl, imid.,
DMF, 50 oC
2. 9-BBN, THF, 25 oC;
then NaOH, H2O2, 0 oC
(88% overall)
O
OPh
H
132
Me O Me
H OTBS
F
OH
Construction of Intermediate 87
1. (COCl)2, DMSO, CH2Cl2,
-78 oC; then Et3N O
OPh H
133
MeO Me
H OTBS
F
Me
CO2Et
O
OPh H
132
MeO Me
H OTBS
F
OH 1. Dibal-H, CH2Cl2, -78
oC
2. mCPBA, CH2Cl2, 0 oC
(94% overall)
O
OPh H
134
MeO Me
H O
F
TBS
OHO
Me
1. SO3 pyr., Et3N, DMSO,
CH2Cl2, 0 oCO
OPh H
135
MeO Me
H O
F
TBS
O
Me
1. TBAF, THF, 25 oC
2. PPTS, CH2Cl2, 0 to 25 oC
(86% overall)
O
OPh H
136
MeO Me
H O
F
OHH
Me
1. KH, BnBr, THF, 45 oC
2. 9-BBN, THF, 25 oC;
then NaOH, H2O2, 0 oC
G O
OPh H
137
MeO Me
H O
F
OBnH
Me
G
OBn
2. Ph3P=CMeCO2Et,
PhCO2H (cat.), PhH, 50 oC
(86% overall)
2. Ph3P=CH2, THF, 0 oC
(81% overall)
3. KH, BnBr, THF, 45 oC
(75% overall)
1. CSA (cat.), MeOH, 0 oC
(95%)
2. t-BuMe2SiCl (2.5 equiv.),
imid., DMF, 50 oC
3. CSA (cat.), MeOH, 0oC
4. (COCl)2, DMSO, CH2Cl2,
-78 oC; then Et3N
(81% for steps 2-4)
O
TBSO H
105
MeO Me
H O
F
OBnH
Me
G
OBn
TBSO PPh3
THF, 0 oC (99%)TBSO H
139
MeO Me
H O
F
OBnH
Me
G
OBn
TBSO
Only diasteromer observed
TBSO H
139
Me O Me
H O
F
OBnH
Me
G
OBn
TBSO
1. H2, 10% Pd/C (cat.),
Na2CO3, EtOAc
2. CSA (1 equiv.), CH2Cl2,
MeOH, 0 oC
(95% overall)
TBSO H
140
MeO Me
H O
F
OBnH
Me
G
OBn
HO
1. (COCl)2, DMSO, CH2Cl2,
-78 oC, then Et3N
2. NaClO2, NaH2PO4
3. TBAF, THF, 65 oC
(88% overall)
HO H
141
MeO Me
H O
F
OBnH
Me
G
OBn
HO
O
2,4,6-Cl3C6H2COCl,
Et3N, THF, 0 oC;
then 4-DMAP, PhH, 80 oC
(90%)
H
104
MeO Me
H O
F
OBnH
Me
G
OBnO
O
E
LiN(SiMe3)2, HMPA,
THF, -78 oC; then PhNTf2,
-78 to 25 oC (93%)
H
102
Me O Me
H O
F
OBnH
Me
G
OBnO
TfO
E
Construction of Intermediate 87
Important Murai Coupling
103
I
O
O
Me
Me
O
H
102
MeO Me
H O
F
OBnH
Me
G
OBnO
TfO
E
O
O
O
O
O
OBn
OBn
HMeMe
MeHH
Me
Me
O E
F G
146
Murai Coupling
+
O
Me
O
SOBr2
ZnBr2, 55 oC
Br
O
Me
Br
O
Me
OH
Et3N, 4-DMAP (cat.),
CH2Cl2, 25 oC
O
O
Me
BrMe
O
142 143 144
NaI (excess), 18-crown-6,
(CH3)2CO, 25 oC
O
O
Me
IMe
O
145
BF3 OEt2, CH2Cl2, -30 oC
O
OO
Me
I
Me103
Construction of Intermediate 87 Continued
(Construction of Intermediate 103)
Construction of Intermediate 87 Continued
H
102
MeO Me
H O
F
OBnH
Me
G
OBnO
TfO
E
103
t-BuLi, Et2O, -120 to -78 oC;
then (2-thienyl)(CN)CuLi
Et2O:THF:HMPA (1:1:1);
then 102, -78 oC (85%) O
O
O
O
O
OBn
OBn
HMeMe
MeHH
Me
Me
O E
F GI
O
O
Me
Me
O
146
(2.4:1 mixture of stereoisomers in favor of 146)
O
O
O
O
O
OBn
OBn
HMeMe
MeHH
Me
Me
E F G
147
OHHO
1. BH3-THF, THF, 0 oC;
then NaOH, H2O2, 0 oC
2. LiOH, MeOH, H2O
(73% overall)
PPTS, DME, H2O,
25 oC, (ca. 100%)
O
O
O
OBn
OBn
HMeMe
MeHH
Me
E F G
101CO2H
2,4,6-Cl3C6H2COCl,
Et3N, THF, 0 oC;
then 4-DMAP, PhH, 80 oC
(85%)
O
O
O
OBn
OBn
HMeMe
MeHH
E F GO
H
H
O
Me
100-B
O
O
O
OBn
OBn
HMeMe
MeHH
E F GO
H
H
O
100Me
+
D
H
HO
O
O
O
OBn
OBn
HMeMe
MeHH
E F GO
H
H
O
100Me
1. LiN(SiMe3)2, HMPA, THF
-78 oC; then Tf2NPh, 25 oC
D
CHOTBSO
Me
PivO
O
O
O
OBn
OBn
HMeMe
E F GO
H
H 150
Me
D
TBSO
PivO
Me
HO
CrCl2, NiCl2 (cat.), DMF,
25 oC, ultrasound
(64% overall)
2.
1. KH, CS2, Et2O, 25 oC;
then MeI
2. n-Bu3SnH, AIBN,
PhH, 80 oC
(60% overall)
TBSO O
O
O
O
H H H Me
Me H
Me Me
Me
D
E F G
OBn
OBn
H
PivO
H H Me
96
TBSO
O
O
O
O
O
H
H H H Me
Me HH
Me Me
Me
D
E F G
OBn
OBn
H
PivO
TES
151
1. BH3-THF, THF, -30 oC;
then NaOH, H2O2, 0 oC
2. Et3SiOTf, 2,6-lutidine,
CH2Cl2, 0 oC
(79% overall)
TBSO
O
O
O
O
O
H
H H H Me
Me HH
Me Me
Me
D
E F G
OBn
OBn
H
TESMeO2C 152
1. Dibal-H, CH2Cl2, -78 oC
2. DMP, CH2Cl2, 25 oC
3. (MeO)2P(O)CH2CO2Me,
KN(SiMe3)2, 18-crown-6, THF, 0 oC
(82% overall)
TBSO
O
O
O
O
O
H H
H H H Me
Me HH
Me Me
Me
C D
E F G
OBn
OBn
H
MeO2C
1. CSA, MeOH, 25 oC
2. KH, Et2O, 25 oC
(90% overall)
153
Construction of Intermediate 87 Continued
Nozaki
Hiyama
Kishi
TBSO
O
O
O
O
O
H H
H H H Me
Me HH
Me Me
Me
C D
E F G
OBn
OBn
H
MeO2C
153
1. Dibal-H, CH2Cl2, -78 oC
2. Ph3P=CHCO2Et,
CH2Cl2, 25 oC
3. Dibal-H, CH2Cl2, -78 oC
(91% overall)
O
O
O
O
O
O
H H
H H H Me
Me HH
Me Me
Me
C D
E F G
OBn
OBn
HTBS
HO
154
O
O
O
O
O
O
H H
H H H Me
Me HH
Me Me
Me
C D
E F G
OBn
OBn
HTBS
O
155
1. (+)-DET, Ti(Oi-Pr)4,
t-BuOOH, CH2Cl2, -20 oC
2. SO3-pyr., DMSO,
Et3N, CH2Cl2, 0 oC
3. Ph3P=CH2, THF, 0oC
(79% overall)
TBSO
O
O
O
O
O
O
H H H
H H H Me
H Me HH
Me Me
Me
B C D
E F G
OBn
OBn
H
156
1. TBAF, THF, 25 oC
2. PPTS, CH2Cl2, 0 oC
3. t-BuMe2SiOTf, 2,6-lutidine
CH2Cl2, 0 oC
(76% overall)
O
TBSO
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
B C D
E F G
OBn
OBn
H
157
1. O3, CH2Cl2, -78 oC; then Ph3P, 25 oC
2. MeMgCl, THF, 0 oC
3. DMP, CH2Cl2, 25 oC
(91% overall)
Construction of Intermediate 87 Continued
O
TBSO
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
B C D
E F G
OBn
OBn
H
157
O
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
B C D
E F G
OBn
OBn
H
O
(MeO)2P O
92
1. TBAF, THF, 25 oC
2. BrCH2COCl, pyr., CH2Cl2, 0 oC
3. (MeO)3P, 90 oC
(73% overall
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A B C D
E F G
OBn
OBn
H
O 158
i-Pr2EtN, LiCl, CH3CN, 25 oC
(89% Yield)
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A B C D
E F G
OBn
OBn
H
159
1. Dibal-H, CH2Cl2, -78 oC
2. BF3-OEt2, Et3SiH, CH2Cl2, -10 oC
(93% overall)
Construction of Intermediate 87 Continued
Arbuzov Rxn
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A B C D
E F G
OBn
OBn
H
159
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A B C D
E F G
OH
OTs
H
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A B C D
E F G
OTMS
PPh3
I
160
1. Li, NH3(l), -78 oC
2. p-TsCl, pyr., CH2Cl2, 25 oC
(73% overall)
1. NaI, (CH3)2CO, 60 oC
2. TMS-imidazole, CH2Cl2, 25 oC
3. Ph3P, CH3CN, 80 oC
(92% overall)
Key Intermediate 87
Construction of Intermediate 87 Continued
Putting the Key Pieces Together
O
O
O
O
O
O
O
Me
H H H
H H H Me
H Me HH
Me Me
Me
A B C D
E F G
OTMS
PPh3
I O
O
OH H
OTBS
EtS H Me
I
EtS
H
H
O
J K OTPS
1. n-BuLi, HMPA, THF, -78 oC
2. PPTS, MeOH, 25 oC
(75% overall)
O
O
O
O
O
O
O
O
O O OTPS
Me
H H H
H H H Me
H
H
H
TBSO
H Me HH
Me Me
EtS
H
Me
Me
A B C D
E F G
I
J
K
EtS
HO
O
O
O
O
O
O
O
O O
O O OTPS
Me
H H H
H H H Me
H
H
H
TBSO
H Me HH
Me Me H
H
H
Me
Me
A B C D
E F G H
I
J
K
85
8687
1. AgClO4, NaHCO3, SiO2,
4 A mol. sieves, CH3NO2, 25 oC
2. Ph3SnH, AIBN, PhCH3, 110 oC
(85% overall)
161
The Final Stage
O
O
O
O
O
O
O
O O
O O OTPS
Me
H H H
H H H Me
H
H
H
TBSO
H Me HH
Me Me H
H
H
Me
Me
A B C D
E F G H
I
J
K
161
O
O
O
O
O
O
O
O O
O O H
O
O
Me
H H H
H H H Me
H
H
H
TBSO
H Me HH
Me Me H
H
H
Me
Me
A B C D
E F G H
I
J
K
O
O
O
O
O
O
O
O O
O O H
O
O
Me
H H H
H H H Me
H
H
H
HO
H Me HH
Me Me H
H
H
Me
Me
A B C D
E F G H
I
J
K
162
(+)-brevetoxin B
1. PCC, PhH, 80 oC
2. TBAF, THF, 25 oC
3. DMP, CH2Cl2, 25 oC
(49% overall)
1.CH2=NMe2 I
Et3N, CH2Cl2
2. HF-pyr., CH2Cl2, 0 oC
(76% overall)
Conclusion
Total synthesis of Brevetoxin B was first
completed by Nicolaou in 1995
First synthesis of a highly complex
molecule of the brevetoxin class
124 steps employed in the total synthesis
