Total Synthesis of Palytoxin
O
NH
2
OH
O
O
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
HO
OH
O
Me
OH
OH
OH
O
OH
HO
OH
OH
H
O
OH
OH
OH
HO
O
O
Me
O
N
H
N
H
HO
OH
OH
Me OH
H
OHHO
OH
Me
OH
HO
Me
OH
OH
OH
HO
OH
OH
OHOH MeOO
Me
OH
Armstrong, R.W.; Beau, J.M.; Cheon, S.H.; Christ,
W.J.; Fujioka, H.; Ham, W.H.; Hawkins, L.D.; Jin,
H.; Kang, S.H.; Kishi, Y.; Martinelli, M.J.;
McWhorter, W.W., Jr.; Mizuno, M.; Nakata, M.;
Stutz, A.E.; Talamas, F.X.; Taniguchi, M.; Tino,
J.A.; Ueda, K.; Uenishi, J.; White, J.B.; Yonaga,
M. J.Am.Chem.Soc., 1989, 111, 7525; Armstrong,
R.W.; Beau, J.M.; Cheon, S.H.; Christ, W.J.;
Fujioka, H.; Ham, W.H.; Hawkins, L.D.; Jin, H.;
Kang, S.H.; Kishi, Y.; Martinelli, M.J.;
McWhorter, W.W., Jr.; Mizuno, M.; Nakata, M.;
Stutz, A.E.; Talamas, F.X.; Taniguchi, M.; Tino,
J.A.; Ueda, K.; Uenishi, J.; White, J.B.; Yonaga,
M. ibid, 1989, 111, 7530; Suh, E.M.; Kishi, Y. ibid,
1994, 116, 11205; Kishi, Y. Chem,Scr. 1987, 27,
573; Kishi, Y. Pure & Appl. Chem, 1989, 61, 313.
Y.Kishi
Chris Hupp CEM 852
What is Palytoxin?
? One of the most toxic non-peptidic natural products known to man!
? Vasoconstrictor
? Hemolysis agent
? Lethal dose for a human = <5μg
Vasoconstriction and Hemolysis
http://www.nlm.nih.gov/medlineplus/ency/imagepages/8983.htm
http://www.physiology.rwth-aachen.de/user/martin/DuUndDeinBlut/Bl-
Terminologie-d.html
What is Palytoxin?
? One of the most toxic non-peptidic natural products known to man!
? Vasoconstrictor
? Hemolysis agent
? Lethal dose for a human = <5μg
http://www.rockefeller.edu/pubinfo/012103.php
? Comes from the soft coral species Palythoa Toxica found in a small tidal
pool in Maui
From the Tidal Pool to the Lab
? The gross structure was first reported by two groups:
? Hirata—Japan
1
? Moore—Hawaii
2
? 64 stereogenic centers
? 115 carbon backbone ? One of the longest
contiguous carbon chains in a natural product
? There are about 2
71
different stereoisomers
? Y. Kishi succeeded in elucidating the complete
structure of palytoxin in 1982 and then completed the
synthesis in 1994
3
1
Uremura, D.; Ueda, K.; Hirata, Y.; Naoki, H.; Iwashita, T. Tetrahedron Lett. 1981, 22, 2781
2
Moore, R.E.; Bartolini, G. J. J. Am. Chem. Soc. 1981, 103, 2491
3
Kishi et al.
Notable Reactions
? NiCl
2
/CrCl
2
-catalyzed coupling reaction between
vinyl iodides and aldehydes (NHK Coupling).
? Pd(0) catalyzed and thallium hydroxide assisted
synthesis of cis-trans conjugated dienes from vinyl
iodides and vinyl boronic acids.
? New Methods for the construction of N-acyl
vinylogous ureas
NiCl
2
/CrCl
2
Coupling
1
R
X
+
H R'
O
CrCl
2
, DMF
25°C R R'
OH
X=I, Br
i.e.
1
I
Me
+
H
O
O
CrCl
2
, DMF
25°C
Me
OH
O
?This carbon-carbon bond forming reaction is highly chemoselective
? Aldehyde carbonyls are selectively attacked even in the presence
of other electrophilic groups
e.g. Ketones, esters, and nitriles
?Gives benzylic or allylic alcohols
1
Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281.
NiCl
2
/CrCl
2
Coupling Cont.
? Problem: Reaction didn’t always work. The success
of the Cr(II) coupling depended on the batch of the
CrCl
2
.
?Possible Reasons:
? Quality of CrCl
2
?
NO! Homemade CrCl
2
reagent didn’t help
?Possible contaminant in the CrCl
2
?
Yes!! Kishi examined the effect of transition metals
on the reaction and found that NiCl
2
had an effect.
NiCl
2
/CrCl
2
Coupling Cont.
? The stereochemistry of the trans or cis iodo
olefin is retained.
? Reaction produces diastereomers although a
preference for one is usually observed.
? Has an advantage over conventional carbonyl
additions.
NiCl
2
= Catalytic amount
CrCl
2
= Excess
Kishi et al. J. Am. Chem. Soc. 1986, 108, 5644
NiCl
2
/CrCl
2
Coupling Cont.
Transmetalation
X Ni-X
Cr(III)
RCHO
R
OH
Cr(III)
Ni(II)Ni(0)
2Cr(II)2Cr(III)
X= I, Br, OTf
Oxidative Addition
Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
NiCl
2
/CrCl
2
Coupling Cont.
O
t-BuPh
2
SiO
I
H
Me
OC(O)t-Bu
Me
H
H
CrCl
2
(excess)
NiCl
2
(0.5%)
DMSO/Me
2
S
(73%)
OHC
O
t-BuPh
2
SiO
H
HO
Me
H
OC(O)t-Bu
Me
H
H
H
Me
H
Me
H
H
Me
Me
O
Me
HO
OHC
H
(+)- ophiobolin C
Rowley, M.; Tsukamoto, M.; Kishi, Y.; J. Am. Chem. Soc. 1989, 111, 2735
Notable Reactions
? NiCl
2
/CrCl
2
-catalyzed coupling reaction
between vinyl iodides and aldehydes
? Pd(0) catalyzed and thallium hydroxide assisted
synthesis of cis-trans conjugated dienes from
vinyl iodides and vinyl boronic acids.
? New methods for the construction of N-acyl
vinylogous ureas
Retrosynthesis
O
NH
2
OH
O
O
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
HO
OH
O
Me
OH
OH
OH
O
OH
HO
OH
OH
H
O
OH
OH
OH
HO
O
O
Me
O
N
H
N
H
HO
OH
OH
Me OH
H
OHHO
OH
Me
OH
HO
Me
OH
OH
OH
HO
OH
OH
OHOH MeOO
Me
OH
1
Retrosynthesis II
O
N-TEOC
OTBS
O
O
O
O
OH
H
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
Ph
3
P
CH(SEt)
2
I
OTBS
OTBS
OTBSI
OCPh
2
(C
6
H
4
-p-OMe)
Wittig Rxn.
NiCl
2
/CrCl
2
Coupling
8
9
10
Matteson Rxn.;
Suzuki Coupling
OAc
O
OTBS
OTBS
OTBS
O
OTBS
TBSO
OTBS
OTBS
H
OTBS
TBSO
I
MeO
O
O
OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
OTHP
HO
NH
2
N
H
HO
O
SePh
O
OMe
OBz
OBz
BzO
Me
O
OBz
HO
O
O
O
Me
Me
Me
OTBS
PPh
3
I
Me
OAc
O MeO
TBS
MeO
NiCl
2
/CrCl
2
Coupling
Amide Bond Formation
Wittig Rxn.; Hydrog.
12
13
14
15
16
HWE
11
Wittig Rxn.; Hydrog.
Synthesis I
O
OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
OTHP
HO
O
O
Me
Me
Me
OTBS
PPh
3
I
1.(COCl)
2
, DMSO; then Et
3
N
2.n-BuLi, THF, -78°C; then aldehyde from 14
3.H
2
, 10% Pd/C
4.TBAF, THF, 25°C
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
OH
THPO
17
14
13
88%
Synthesis II
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
OH
THPO
17
1.MsCl, Et
3
N, 0°C
2.NaI, 2-butanone, 60°C
3.Ph
3
P, DMF, 110°C
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
PPh
3
THPO
18
I
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
THPO
O
OO
BzO
Me
OBz
OBz
OMe
BzO
20
O
OMe
OBz
OBz
BzO
Me
O
OBz
HO
O
O
OMe
OBz
OBz
BzO
Me
O
OBz
O
O
12 19
(COCl)
2
DMSO;
then Et
3
N
100%
1.18, n-BuLi, THF, -78°C;
then add 19
2.H
2
, 10% Pd/C
62% from 12
Synthesis III
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
THPO
O
OO
BzO
Me
OBz
OBz
OMe
BzO
20
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
O
OO
BzO
Me
OBz
OBz
OMe
BzO
21
1.PPTS, MeOH/Et
2
O
42°C
2.(COCl
2
), DMSO; then
Et
3
N
Synthesis IV
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
O
OO
BzO
Me
OBz
OBz
OMe
BzO
21
Me
OAc
O MeO
I
TBS
MeO
15
CrCl
2
, NiCl
2
(0.11%)
DMSO/THF (1:3), 32°C
(68-82%)
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OO
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OH
22
Synthesis V
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OO
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OH
22
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OH OH
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OAc
23
1.Ac
2
O, 4-DMAP, pyr.
2.PPTS, MeOH/Et
2
O 40°C
97%
Synthesis VI
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OH OH
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OAc
23
RuCl
2
(PPh
3
)
3
25°C (72-81%)
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OH O
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OAc
24
What we have so far
O
NH
2
OH
O
O
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
HO
OH
O
Me
OH
OH
OH
O
OH
HO
OH
OH
H
O
OH
OH
OH
HO
O
O
Me
O
N
H
N
H
HO
OH
OH
Me OH
H
OHHO
OH
Me
OH
HO
Me
OH
OH
OH
HO
OH
OH
OHOH MeOO
Me
OH
Synthesis VII
TEOC = C(O)CH
2
CH
2
SiMe
3
O
N-TEOC
OTBS
O
O
O
O
OH
H
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
Ph
3
P
CH(SEt)
2
I
89
(COCl)
2
, DMSO; then Et
3
N
LDA (0.4M THF)
THF/HMPA (5:1)
25°C (ylide formation)
(60-80%)
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
CH(SEt)
2
25
≥8:1 cis:trans
Synthesis VIII
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
CH(SEt)
2
25
I
2
, NaHCO
3
, (CH
3
)
2
CO/H
2
O (19:1)
0°C (98%)
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
O
26
OTBS
OTBS
OTBSI
OCPh
2
(C
6
H
4
-p-OMe)
10
CrCl
2
, NiCl
2
(0.11%)
DMSO/THF (3:1)
(90%)
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
OCPh
2
(4-MeOPh)
HO
OTBS
OTBS
OTBS
27
Synthesis IX
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
O
HO
OTBS
OTBS
OTBS
27
1.PDC, DMF, 0°C
2.Ph
3
P=CH
2
, hexanes/THF (2:1), 0°C
3.PPTS, MeOH/CH
2
Cl
2
4.(COCl)
2
, DMSO; then Et
3
N
(80% overall)
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
O
OTBS
OTBS
OTBS
28
C
OMe
Synthesis X
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
O
OTBS
OTBS
OTBS
28
LiCH[B(OCH
2
CH
2
CH
2
O)]
2
-TMEDA
THF, 0°C; then EtOAc, brine/1N HCl
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
OTBS
OTBS
OTBS
B
OH
HO
29
8-10:1 trans:cis
Synthesis XI
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
OTBS
OTBS
OTBS
B
OH
HO
29
OAc
O
OTBS
OTBS
OTBS
OTBS
TBSO
OTBS
OTBS
H
OTBS
TBSO
I
MeO
O
11
1.Pd(PPh
3
)
4
(cat.), TlOH;
then add 11
2.LiCH
2
P(O)(OMe)
2
THF, -78°C
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
OTBS
OTBS
OTBS
O
O
P
OTBS
OTBS
OTBS
H
OTBS
OAc
OTBS
OTBS
TBSO
OTBS
TBSO
O
O
MeO
OMe
30
Taking Inventory
O
NH
2
OH
O
O
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
HO
OH
O
Me
OH
OH
OH
O
OH
HO
OH
OH
H
O
OH
OH
OH
HO
O
O
Me
O
N
H
N
H
HO
OH
OH
Me OH
H
OHHO
OH
Me
OH
HO
Me
OH
OH
OH
HO
OH
OH
OHOH MeOO
Me
OH
Haven’t made this connection yet
Synthesis XII
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OH O
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OAc
24
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O OTBS
OTBS
OTBS
O
O
P
OTBS
OTBS
OTBS
H
OTBS
OAc
OTBS
OTBS
TBSO
OTBS
TBSO
O
O
MeO
OMe
30
NaH, THF; then
add 24
1.LiBH
4
, EuCl
3
, MeOH/Et
2
O (1:1)
2.Ac
2
O, 4-DMAP, pyr., 0°C
(75-80%)
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O OTBS
OTBS
OTBS
O
O
OTBS
OTBS
OTBS
H
OTBS
OAc
OTBS
OTBS
TBSO
OTBS
TBSO
OAc
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OAc
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OAc
31
Synthesis XIII
O
NH-TEOC
OTBS
O
O
O
TBSO OTBS
OTBS
OTBS
OTBS
TBSO
Me
O
O
OTBS
OTBS
OTBS
O
O
OTBS
OTBS
OTBS
H
OTBS
OAc
OTBS
OTBS
TBSO
OTBS
TBSO
OAc
O
O
Me
O
Me OPMB
H
OPMBPMBO
OPMB
OPMB
PMBO
OPMB
OPMB
OPMB
Me
O
OAc
BzO
Me
OBz
OBz
OMe
BzO
MeO
O OTBSMe
OAc OAc
31
O
NH
2
OH
O
O
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
HO
OH
O
Me
OH
OH
OH
O
OH
HO
OH
OH
H
O
OH
OH
OH
HO
O
O
Me
O
HO
OH
OH
Me OH
H
OHHO
OH
Me
OH
HO
Me
OH
OH
OH
HO
OH
OH
OHOH MeO
Me
OH
32
1.DDQ, t-BuOH/CH
2
Cl
2
/pH7, 25°C then Ac
2
O,
4-DMAP, pyr., 25°C
2.HClO
4
(1.18N)/THF, 25°C
3.LiOH(0.08N), H
2
O/MeOH/THF, 25°C
4.TBAF, THF, 22°C; then in DMF/THF, 22°C
5.AcOH/H
2
O, 22°C
Synthesis XIV
O
NH
2
OH
O
O
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
HO
OH
O
Me
OH
OH
OH
O
OH
HO
OH
OH
H
O
OH
OH
OH
HO
O
O
Me
O
OH
OH
Me OH
H
OHHO
OH
HO
Me
OH
OH
OH
HO
OH
OH
OHMe
Me
OH
33
32
AcOH
O
Me
HO
O
Synthesis XV…the end
NH
2
N
H
HO
O
SePh
16 33
1.pyr. (62%)
2.oxaziridine A (43%)
3.hν (cis→trans ? isomerization)
O
NH
2
OH
O
O
OH
OH
O
HO OH
OH
OH
OH
OH
OH
OH
HO
OH
O
Me
OH
OH
OH
O
OH
HO
OH
OH
H
O
OH
OH
OH
HO
O
O
Me
O
N
H
N
H
HO
OH
OH
Me OH
H
OHHO
OH
Me
OH
HO
Me
OH
OH
OH
HO
OH
OH
OHOH MeOO
Me
OH
Me
Me
N
S
O
O
O
A: Camphor Sulfonyl
Oxaziridine
1
O
Me
HO
O
R
Summary
? NHK coupling was utilized to bring together key
connections in the molecule.
? Strategically picked protecting groups allowed the
manipulation of the molecule.
? The total synthesis as well as structure elucidation of
palytoxin was a great achievement.
The End