Daphnane, Tigliane, Ingenane and Lathyrane Diterpenes I.B. Seiple Baran Group Meeting 3/17/2007 tigliane daphnane ingenane Daphnanes: - Triciclic diterpenes with a tricyclo[9.3.0.0]tetradecane ring system - Obtained from the extracts of seeds and sap of Euphorbiaceae species (shrub) - Several members shown to exhibit cytotoxic, irritant, analgesic activity - Resiniferatoxin is the most potent irritant known in the literature at over a thousand times more potent than capsaicin - Only total synthesis reported of any daphnane was by Wender in 1997 Tiglianes: - Identical triciclo[9.3.0.0]tetradecane ring system as daphnanes, with additional gem-dimethyl cyclopropane appended to the 6-membered ring - Isolated as a mix of many esters from Euphorbia and Thymelaeaceae - Most famous: Phorbol (named in 25 BC by King Juba II of Mauritania) - Used for 2000 years in traditional medicine for tumors, migraines, parasites, venereal diseases, and as purgatives - Tetradodecanoyl phorbol acetate is the most potent tumor promoter (co-carcinogen) known - Acts on Protein Kinase C (PKC), which plays a role in regulating cellular growth and differentiation - Paradoxically, C 12 deoxy derivatives inhibit tumor formation - Two total syntheses completed by Wender (one formal), and one by Cha (formal) 12 Ingenanes: - Bicyclo[4.4.1]undecane ring system with in – out stereochemistry - Ingenol esters found in Euphorbiaceae, and used traditionally to treat tumors, migraines, parasites, gingivitis, and also as purgatives. - Derivatives have shown HIV-1 inhibition - Derivatives have also shown tumor-promoting and anti-tumor-promoting activities. - Racemic total syntheses reported by Winkler and Tanino/Kuwajima, asymmetric by Wood and Kigoshi (formal) lathyrane Lathyranes: - Triciclic diterpenes with an 11-membered macrocycle and a cyclopropane - Obtained from Euphorbiaceae species (shrub) (W. Australia) - Various proinflammatory and tumor-promoting activities - Only one total synthesis reported of bertyadionol in 1986 (Smith III) - Stable to mild acid, base and UV-light
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Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. Seiple Baran Group Meeting3/17/2007
tiglianedaphnane ingenane
Daphnanes: - Triciclic diterpenes with a tricyclo[9.3.0.0]tetradecane ring system - Obtained from the extracts of seeds and sap of Euphorbiaceae species (shrub) - Several members shown to exhibit cytotoxic, irritant, analgesic activity - Resiniferatoxin is the most potent irritant known in the literature at over a thousand times more potent than capsaicin - Only total synthesis reported of any daphnane was by Wender in 1997
Tiglianes: - Identical triciclo[9.3.0.0]tetradecane ring system as daphnanes, with additional gem-dimethyl cyclopropane appended to the 6-membered ring - Isolated as a mix of many esters from Euphorbia and Thymelaeaceae - Most famous: Phorbol (named in 25 BC by King Juba II of Mauritania) - Used for 2000 years in traditional medicine for tumors, migraines, parasites, venereal diseases, and as purgatives - Tetradodecanoyl phorbol acetate is the most potent tumor promoter (co-carcinogen) known - Acts on Protein Kinase C (PKC), which plays a role in regulating cellular growth and differentiation - Paradoxically, C12 deoxy derivatives inhibit tumor formation - Two total syntheses completed by Wender (one formal), and one by Cha (formal)
12Ingenanes: - Bicyclo[4.4.1]undecane ring system with in – out stereochemistry - Ingenol esters found in Euphorbiaceae, and used traditionally to treat tumors, migraines, parasites, gingivitis, and also as purgatives. - Derivatives have shown HIV-1 inhibition - Derivatives have also shown tumor-promoting and anti-tumor-promoting activities. - Racemic total syntheses reported by Winkler and Tanino/Kuwajima, asymmetric by Wood and Kigoshi (formal)lathyrane
Lathyranes: - Triciclic diterpenes with an 11-membered macrocycle and a cyclopropane - Obtained from Euphorbiaceae species (shrub) (W. Australia) - Various proinflammatory and tumor-promoting activities - Only one total synthesis reported of bertyadionol in 1986 (Smith III) - Stable to mild acid, base and UV-light
Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting
3/17/2007
Tiglianes: Approaches to the Core12
Rigby Approaches: Hydroazulene Precursors
O TBSO
O
OOMeO
MeO MeO2C
OOMeO
MeO CO2Me
2:1 desired, 60%
8 kbar
O
O
1. TBAF2. Swern
O
O
1. LDA, F-, A
2. KOt-Bu
56% A =
O
TMS
Rigby, TL, 1989, 30, 5073
Shibasaki Asymmetric Approach: Tapping the Chiral Pool
H
H(+)-3-carene
20 stepsH
H
HO
O2N
p-ClC6H4NCOEt3N
65%
H
H
HO
O
N
Heterocycles, 1992, 33, 161TL 1992, 33, 4937
H
H
TBSO
HO
O
Steps
Me CeCl2H
H
TBSO
HO
HO
H
H
TBSO4 steps
O
Similar approaches with C12 oxygenationand C20 installation (but not both)
For another formal asymmetric synthesis see Cha, JACS 2001, 123, 559043 steps, 0.4% overall
JACS 1997, 119, 7897
Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting
3/17/2007
Ingenanes: Approaches to the Core
Me
Me
HOHO
HO
O
OH
Me
Me
H
Me
Me
HOHO
HO
O
OH
Me
Me
H
ingenol isoingenol
- ingenol is 5.9 kcal/mol higher in energy than isoingenol- the "in-out" stereochemistry of ingenol is essential to bioactivity- see Funk JACS 1988, 110, 2097
MeO
O 1. KNH2, NH32.
Cl Cl
MeO
O
3. KH32%
O
ORsteps
O
hv
RO
OHO
steps
O
ROHO
HOOH
R = palmitate
Derivative completely devoid of biological activity.
Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting
3/17/2007
Daphnane Diterpenes
OEt
TIPSO
OMe
Li
OTBS
OEt
TIPSO
OMe
OHOTBSHO
O
1. Co2(CO)82. TBAF
Carreira: Tricyclic Rearrangement
TIPSO
OEt1. H2/Pd2. MsCl3. TBAF
MsO
HO
OEt
O
OEt
OH
OH
1. KOtamyl2. OsO4
O
EtO MeO
1. hv, TFA pentane
OOH
MeO
MeO MeO
HO
MeO
OH O
OH
OMeMeO
H
HH
Wender: Sugar to BC Rings + C12 Oxygenation
O
OH
OHHO
OH13 steps
9% ov.O
TBSO
OH
Me
OAc
OBn
OBn
1. VO(acac)2 t-BuOOH2. Ac2O, py.3. DBU
OAc
OBn
OBnO
OTBS
O
H
Angew. Chem. Int. Ed. 2001, 40, 2694
Wender: Total Synthesis of Resiniferatoxin
O
OBn
via kinetic resolution
1. Li-ethoxyacetylide2. p–TsOH
OO
OBnMe
OO
OTBS
H
OAc
OBn10 steps
See Classics II for more info
Org. Lett. 2006, 8, 5373
OMe
OOR
MeMe
H
HO
O
O
H
Ph
Resiniferatoxin
Lathyrane Diterpenes
Lathyrane IngenaneTigliane
Daphnane
HOOCcis-chrysanthemic acid
H
H
1. (COCl)22. CH2N23. hv, MeOH
H
HMeO2C
1. SeO22. HS(CH2)3SH BF3•OEt23. (EtO)2(O)PCLiHMe
H
H
S
S
O
(EtO)2(O)P
1. NaH, BuLi2. A; HCl
O
O
O
= A
H
H
O
(EtO)2(O)P
SS
O
6 steps
HOS
S
O
H
H
OCOPhO
H
H
OH
9 steps
O
(–)-bertyadionolJACS 1986, 108, 3110
Lathyrane diterpenes have been proposed as biosynthetic precursors for tigliane, ingenane, daphnane, jatrophane, and jatrapholane skeletons by Adolf et. al. (Isr. J. Chem. 1977, 16, 75). Groups have attempted to convert Lathyrane-type skeletons into the more complex cyclized products, but thusfar there has been no success.
Smith III: The First and Only Synthesis of a Lathyrane
Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting