History of the Ryanoids Synthetic Efforts Toward...
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Transcript of History of the Ryanoids Synthetic Efforts Toward...
Synthetic Efforts Toward Ryanodine and Ryanodol
Raissa Trend, Haiming Zhang, Dave Ebner,Uttam Tambar, Mike Krout
Molecule Features/ Synthetic Challenges
Sterically congested pentacyclic core
Eleven contiguous stereocenters
Five free hydroxyl functional groups, all present on the same face of the molecule
Instability of the hemiketal
!-Pyrrole carboxylic ester at C3
O
HO
OHHO
HOHO
O
OH
O
HN
(+)-Ryanodine
Monday, August 23, 2004
3
History of the Ryanoids
- Extracts from Ryania family members were used by local Central/South American natives as poison for arrowheads. The toxic nature of the shrubs were such that even termites would not feed on them.
- Ryanoid formulations were first patented and marketed by Merck & Co., Inc. (Ryanex) in 1943 as potent insecticides.
- Ryanodine was first isolated by Folkers and coworkers in 1948 from extracts of the tropical shrub Ryania speciosa Vahl. It was found that pure ryanodine had 700x the insecticidal potency of crude extracts.
- Absolute structure was determined in 1967 based on chemical degradation studies and x-ray analysis. - First total synthesis of (+)-Ryanodol achieved by Deslongchamps and coworkers in 1979; ryanodine has not yet been synthesized.
- Ryanodine has allowed the identification and partial characteriation of a family of intracellular calcium release channels, termed Ryanodine Receptors (RyRs).
Isolation/Biology:
Folkers, K., et al J. Am. Chem. Soc. 1948, 70, 3086.Weisner, K. et al Tet. Lett. 1967, 221.Sutko, J. L. et al Pharmacol. Rev. 1997, 49, 53.
Synthetic Efforts:
Deslongchamps, P. et al Can. J. Chem. 1979, 57, 3348.Deslongchamps, P. et al Can. J. Chem. 1990, 68, 115-192.Wood, J. L. et al Tetrahedron 2003, 59, 8855.Graeber, J. K. Yale University Graduate Thesis 2003.
Ryanodine Reactivity
O
HO
OHHOHO
H2O+
HO
O
H3O+
HH2O
Ryanodol
O
HO
OHHOHO
HO
O
Anhydroryanodol
O
HO
OHHO
HOHO
RO
OH
2
34
15
9
21
11
A B
C
E
D
R=H, Ryanodol
R= , RyanodineHN
O
5
12
- Cage-like shape of molecule prevents selective ester formation at C3; esterification occurs at C10.
- Dehydration occurs in the presence of acid to form anhydroryanodine. This major degradation product was key to elucidation of absolute structure.
- Due to the bridgehead nature of the molecule, stereocenters at C1, C5, C11, C12, and C15 are geometrically related. - Deslongchamps uses this rationale to focus on setting the other six stereocenters en route to anhydroryanodol, the targeted precursor to (+)-ryanodol.
1
10
O
HO
OHHOHO
HO
O
OH
O
HN
Related Ryanoids
9,21-didehydroryanodineMajor component of ryania extracts; equipotent
insecticide as ryanodine.
O
HO
OHHOHO
O
OH
O
HN
OH
SpiganthineIsolated from Spigelia anthelmia; found with ryanodine.
O
OHHOHO
HO
OH
HO
O
HO
OHHOHO
HO
OH
O
HO
OHHOHO
HO
OH
HO
3 3
18
20
10
3
Cinnzeylanol Cincassiol B PerseanolIsolated from Persea indica, the tree that
ryanodol was first isolated.Non-alkaloidal ryanoids isolated from the Cinnamonum genus; insecticidal.
O
HO
OHHOHO
HO
RO
OH
Biosynthesis and Biological Activity
OH
3
213
15
5
10
14
2
35
10
13
15 14
OH
Geranyl Geraniol
- Thought to be derived from geranyl geraniol; however, "the mechanism of carbon-carbon bond formation... is not obvious... nor is that of introducing the required hydroxyl functionalities."
- Effects on calcium levels were known for some time, but it wasn't until 9,21-didehydroryanodine was isolated that the receptor could be identified (via [ H]-labeled derivative)
- RyRs are a family of calicum channels that release Ca from intracellular stores; physically the largest ion channel known, RyRs exist as a homotetramer.
- Understanding of the binding site is unclear; at low [ryanodine], the receptor is at partial (50%) to full conductance; however, at high [ryanodine], the channel is in a closed state.
- The !-pyrrole ester is necessary for biological activity; ryanodol has lost all affinity for RyR. The next most important feature is the shape of the ryanoid skeleton. It is believed that ryanodine binds the receptor with the hydrophobic surface, exposing the polar alcohol functionalities.
- Total synthesis efforts could provide analogs not accessible through degradation, facilitating elucidation of binding models, biosynthesis, binding site characteristics, and provide clues about endogenous RyR ligands.
3
2+
OHOH
HO
O
O
HO
HO
H
Retrosynthesis of RyanodineOHOH
HO
O
HO
OH
OH
H
HO
OHOH
HO
O
HO
OH
OH
H
HO
O
HN
CH3
O
O
O
O
O+
(S)
Ryanodine
Ryanodol
Anhydroryanodol
O
O
OHOH
HO
O
HO
OH
O
H
HO
MeO
MeO
1. CH3OCHCl2, TiCl4, CH2Cl22. BBr3, CH2Cl2
HO
HO80%
CHO
1. BrCH2COBr, Pyr, PhH2. Na2CO3, THF
O
O
CHO
O
80%
Wolff-Kishner
80%
O
O
CH3
O
NaOH, H2O, MeCN, NBS
95%
Synthesis of o-Spirolactone Dienone
CH3
O
O
O
O
OHOHHO
O
HO
OH
OH
H
HO
17
Pt/H2, Et2O
80%
1. O3, EtOAc2. (CH2OH)2, p-TsOH, PhH3. MeI, K2CO3, CH3COCH3
70% from (+)-carvone
1. NaOH, MeOH2. LiH, THF, CH2=CHLi
75%
Synthesis of Vinylketone Acetal
O
CH3
(+)-Carvone
O
CH3
MeO2CO
O
O
OO
OHOHHO
O
HO
OH
OH
H
HO
17
Diels-Alder Reaction
O
OR
R'
H
CH3
O
O
O
O
O
OO
+
PhH, reflux
100% (1:1)
A R = O, R' = H2B R = H2, R' = O
A R = O, R' = H2B R = H2, R' = O
O
O
O
O
O
OR
R'
H
O
O
O
O
(S)
(S) (S)
OHOH
HO
O
HO
OH
OH
H
HO
O
OR
R'
H
A R = O, R' = H2B R = H2, R' = O
A R = O, R' = H2B R = H2, R' = O
O
HO H
O
O
O
O
O
O
OR
R'
H
O
O
O
O
HH
OO
HO H
O
OH
OO
H
OHH
O
O
H
OO
H
OHH
O
OH
H
OO
(S) (S)
(R) (R) (R) (R)
aq NaOH, THF
endo exo3 : 1
endo exo3 : 1
Intramolecular Aldol Reaction
HO H
O
OHH
OO
OHH
O
OH
H
OO
(R) (R)
endo endo
1. AcOH/H2O 75°C2. aq NaOH, THF
HO H
OH
CHO
H
HO
OHH
O
H
OHC
H
OH
Second Aldol Reaction OHOH
HO
O
HO
OH
OH
H
HO
HO H
OH
CHO
H
HO
H
OH
CHO
H
O
O
O
27% based on Diels-Alder adduct
1. MeOH, (MeO)3CH, p-TsOH2. CH3CO3H, CH3CO2Na
O
H
H
CH(OMe)2
H
O
O
O
O
85%
O
O
H
H
CH(OMe)2
H
O
O
O
O
COCl2, Pyr, PhH
WCl6, n-BuLi, THF
80%
plus 15% isomeric lactone
Key lactone Intermediate OHOHHO
O
HOOH
OH
H
HO
O
OHO
O
O
O
HH
X
O
OHO
O
O
O
HH
X
O
O
LDA, THF, -78°C;Et3B, -25°C; MeI
70%
1) NaBH4, MeOH THF, 0°C, > 95%
2) MOMCl, NaH THF 80% + 13% SM
O
OOO
O
HH
X
HO
O O
OHOHHO
O
HOOH
OH
H
HO
O
HO
O
O
H
OMe
OMe
OH
Ozonolysis and Aldol Condensation – the C Ring
O3, EtOAc, p-TsOH;
Me2S
> 90%
X = –CH(OCH3)2
611
10
6
10
11
10
116
O
OHO
O
O
O
HH
X
O
OHOH
HO
O
HO
OH
OH
H
HO
O
HO
O
O
H
OMe
OMe
OH
Ozonolysis and Aldol Condensation
O3, EtOAc, p-TsOH;
Me2S
> 90%
O
HO
O
O
H
X
OH
O
O
O
OO
O
O
O
HH
X
O
H
Aldol
O
O
O
O
O
HH
X
O
H
O
O
O
O
O
O
HH
X
O
H
OH
Undesired
1) LAH, THF, 95%
2) CrO3•2Py, CH2Cl2 -45 to -22 °C, 76%
3) MsCl, Py, 0 °C,
89%
O
OOO
O
HH
X
HO
O O
R = Ms
O
OOOH
H
X
RO
O O
OH
OOOH
H
X
O O
O
O
S
OLi
DMSO
OHOHHO
O
HOOH
OH
H
HO
X = –CH(OCH3)2
Grob Fragmentation to a Macrolactone –Strategy for the D Ring
O
OOOH
H
X
RO
O O
O–
11
15
11
15
11
15
HBF4, THF, 0 °C92%
(2 steps)
OHOOH
H
X
O
O
O
17
17
17
OHOOH
H
X
O
OOH
HOO
OHOOH
H
X
O
O
OpNBO
O
1) CF3CO3H, Na2HPO4
DCE, 4 °C
2) NaOH, MeOCH2CH2OMe
77% over 2 steps
1) pNBCl Py, 0 °C
2) CrO3•2Py CH2Cl2, 78%
OHOOH
H
X
O
O
O
OHOHHO
O
HOOH
OH
H
HO
11
15
17
17
1) LiBH4, THF
-30 to -20 °C
73%, + axial alcohol
2) Ac2O, Py
OHOOH
H
O
O
OpNBO
AcO
MeO
MeO
173
3
11
15
17
D Ring Formation and FGI
X = –CH(OCH3)2
OHOOH
H
O
O
OpNBO
AcO
OMe
OHOOH
H
O
O
OpNBO
AcO
O
OHOOH
O
O
OpNBO
AcO
AcO
OHOO
O
O
O
AcO
O
O3, CH2Cl2-78 to -55°C
then Me2S
Ac2ONaOAc
100°C
DBNPhH75°C
50%(4 steps)
OHOHHO
O
HOOH
OH
H
HO
OHOOH
H
O
O
OpNBO
AcO
MeO
MeO pTSAPhH
reflux
Degradation of Ring A
17
17
17
OHOOH
O
O
OpNBO
AcO
AcO
OHOO
O
O
O
AcO
O
DBN, PhH
-pNBOH
OHOHHO
O
HOOH
OH
H
HO
Enone Formation Details
OHOO
O
O
O
AcO
O
O
B:
B:H
OHOO
O
O
O
AcO
OH+
-ketene17
17
17
17
17
OHO
O
O
O
O
AcO
O
OHO
O
O
O
O
AcO
HO
H
OHOH
HO
O
O
HO
HO
H
OHOH
HO
HO
HO
O
H
O
NaBH4, THF
MeOH, 0°C
! 90%
NaOH, THF
Synthesis of Anhydroryanodol OHOH
HO
O
HO
OH
OH
H
HO
3:1
OHOH
HO
O
O
HO
HO
H
OHOH
HO
HO
HO
O
H
O
OHOH
HO
HO
HO
O
H
O
OOHOH
HO
O
O
HO
OH
H
O
CF3CO3HNa2HPO4, DCE
room temp.85%
OHOH
HO
O
HO
OH
OH
H
HO
Li, NH3THF
! 60%
Completion of the Synthesis
(+)-ryanodol
OHOH
HO
O
HO
OH
OH
H
HO
NaOH, THF
3:2
NaOH, THF
3:1
OHOH
HO
O
HO
OH
OR
H
HO
OH OHOH
O
O
O
Wood's Retrosynthetic Analysis of RyanodineRhodium-Mediated Claisen Rearrangement andPhenolic Oxidation / Singlet Oxygen Diels Alder
O
R
O
O
O
OH
OH
HO
OO
O
R
Br
OH
O
HO
CO2R
O
Phenolic OxidationSinglet Oxygen Diels Alder
Br
OBn
N2
ORhodium-Mediated
Claisen RearrangementOH
O
Wood's Phenolic Oxidation/Singlet Oxygen Diels Alder
General Strategy
OH
Model System Substrate Synthesis
OHO
OPhenolic [O]
1O2
OO
O O
O
Cl
OH
+!
(90% yield)
O
O
AlCl3, !
(45% yield)
OHO
OEtBr
O
Zn, !(52% yield)
O
O
OH
EtO
O
H2, Pd(OH)2
EtOH(90% yield)
1. NaOH2. HCl(95% yield)
3. NBS, DMF(70 %yield)
OH
HO
O
Br
OHOHHO
O
HOOH
OH
H
HO
Wood's Phenolic Oxidation/Singlet Oxygen Diels Alder (cont.)
OH
HO
O
Br
Model System Validates the Strategy
PhI(O2CCF3)2
MeCN(80% yield)
O
Br
O
O
1O2
(95% yield)
O
Br
O
O
O O
H2, Pd/C(95% yield)
OO
O
OH
OH
OH OHOH
O
O
O
OHOHHO
O
HOOH
OH
H
HO
Wood's Phenolic Oxidation/Singlet Oxygen Diels Alder (cont.)
OH
HO
O
Br
Strategy for the Real System
OH OHOH
O
O
O
Model Real
Br
OH
O
HO
CO2H
O
OH OHOH
O
O
O
O
O
OHO1. NBS, DMF(70% yield)
2. BnBr, K2CO3(85% yield)
OBnO
Br
OBnO
Br
1. (s-Bu)ONO, HCl (70% yield)
2. NH2Cl, H2O/THF(78% yield)
N2
Real System Substrate Synthesis
OHOHHO
O
HOOH
OH
H
HO
Wood's Phenolic Oxidation/Singlet Oxygen Diels Alder (cont.)
OBnO
Br
N2
Real System Validates the Strategy
HO 2 steps
(80% yield)
BnO O
OEt
LiCuMe2
(85% yield)
O
OEtBnO
DIBAL-H(72% yield)
OHBnO+
Rh2(OAc)4!, PhH
(62% yield)
OBnO
Br
LnRh
OBnO
Br
O
LnRh
OBn HOBnHO
Br
O
OBn
Br
OH
O
HO
OBn
[3,3]
OHOHHO
O
HOOH
OH
H
HO
Concluding Remarks
"...it can be concluded from this analysis that ryanodol is indeed a very complex diterpene..." – Deslongchamps
OHOH
HO
O
HO
OH
O
H
HO
O
NH
– Lack of obvious disconnections
– Synthesis of the C6–C11 trans diol
– Many hydroxyls vs. compact polycyclic structure
– Inclusion/installation of the pyrrole ester moiety