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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)
H
H
HO2C H
H
98%
OAcO
EtO2C
O
N2
H
H
O
O
CO2Et
H
H
OAcDauben/McMills Approach:
major
Rh2(OAc)2
86%
Dauben JOC 1993, 58, 7635McMills TL 1994, 35, 8311
OH
H
O
O1. KH, 18C62. m-CPBA
HO
LDA
1:1 dr
H
H
O
H
H
H
H
H
H
Paquette: Oxy-Cope Ring Expansion/Contraction
Ovaska: Chiral Pool to Tandem Cyclization Paquette T 1994, 50, 4071
Br 1. t–BuLi, CeCl32. B
OB =
OH
cat. MeLi
OH
H
185 ºC76%
Ovaska Org. Lett. 2001, 3, 115Wender: Why not a [4 + 2] ... or 3
MeO
O
CO2Et
8 steps O
O
OBn
heat
O
O
MeOMeO
MeO OMe 1. Wittig
2. H+
OO
OBn
OBnO
OBnO
TBSO
EtO
OEt
OTBS
ZnI2
18 stepsHO
OHHOHO
J. Am. Chem. Soc. 1987, 109, 4390
OH
Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting
3/17/2007
Tiglianes: Total Synthesis (Wender's Game)
O
OTBS
HOAcO
O
AcO
OAc
OTBS
O
1. m-CPBA2. Ac2O DMAP
O
O
OTBS
AcO
DBU, 92%2:1
O
OTBS
AcO
O
O
OTBS
HO
OHC
1. TMSCN, ZnI22. DIBAL
O
OTBS
HO
OTMSON
1. NH2OH2. NaOCl
OTMS
52%8 steps
5 steps78%
46%4 steps 15:1
O
OTBS
O
OO
OAc1. m–CPBA2. P(OEt)33. Ph2SC(Me)24. DIBAL
O
OTBS
HO
OO
O
OTBS
OH
O OTMS
1. H2, RaNi, H2O2. Bz2O, DMAP3. DBU
9 steps37% ov.
Wender: The First Total Synthesis of a Tigliane
SPh
72%
OH
OH
HO
OO
OPiv
5 Steps45%
1. PCC2. NaBH(OAc)3
OH
HO
OO
OPiv
OH
BzO
OO
OBz
DIBAL; Bz2OSeO2, tBuO2H
OH
OH
BzO
OO
OBz
1. SOCl2, propylene oxide2. AgOBz, KOBz
OBz
OH
BzO
O OTMS
OBz
OBz
1. HClO42. SO3•pyr3. CF3CON(Me)TMS4. KN(TMS)2; TMSCl, NBS5. LiBr, Li2CO3
34% ov.58%
1. TsOH2. KCN 86%
OH
HO
O OH
OH
OH
(±)-phorbol52 steps
0.16% yield
JACS 1989, 111, 8954JACS 1989, 111, 8957
Wender's Formal Asymmetric
O
TBSOCHO
O N
O O
Ph
13 stepsMe
OAc
O
OTBS
H12% ov.
Me
O
O
OTBS
H
OTMSPh
O
Me
OAc
O
OTBS
HTMSO
Ph
PhCCLiLiBr, TMSCl
Cp2ZrCl2n–BuLi, HOAc;PCC, NaOAc
Me
O
O
OTBS
H
OTMSPh
1. LDA; TMSCl, PhSCl2. Pb(OAc)23. m–CPBA4. P(OEt)35. Ph2S(C(Me)2
1. HF2. O3; DMS3. Tf2O, pyr4. n–Bu4NI5. Zn, EtOH
OAc
Steps
phorbol36 steps
1.2% yield
16 steps9% ov.
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.
JACS, 1988, 110, 6192
Paquette: out-out Analogue
(+)-3-carene
10 steps
O
Me
O
MeO2C H
O
1. LiHMDS TBSCl2. PhMe, 95 ºC
O
Me
MeO2C H
HO2C3. HF
88%
Funk Delivers the In-Out
Rigby: Another in-out TechniqueJOC 1993, 58, 5873
O
O
OR
ROROR = MOM
1. Pd(OAc)2 (20%) TEA, PPh32. KH, 18C6
55%
O
O
OR
ROROOrg. Lett. 2002, 4, 799
O
O
OR
RORO
1. OsO42. m–CPBA3. thiocarbonyl- diimidazole4. P(OMe)3
H
Ingenanes: Total Syntheses of IngenolWinkler: First Total Synthesis
O11 steps
23%O
O
O
H
Cl
1. hv, MeCN2. K2CO3, MeOH
O
H
Cl
CO2Me
1. LAH2. DBU3. TBSCl
O
HOTBS
O
HOTBS
1. CHBr3, NaOH Et3N(Bn)Cl2. MeLi, CuSCN MeI
72%
35%
27 steps
rac–ingenol43 steps0.0068%
JACS, 2002, 124, 9726
O
OMe
Br
OTES
11 steps
OMeOTIPS
Co(CO)3
Co
OAc
OMeOTIPS
MeOH
Co(CO)3
Co
MeAl(OAr)2
OMeOTIPS
Me
OHO
1. Li, NH32. CHBr3, -OH BnEt3NCl3. Me3CuLi2, MeI4. Ti(Oi-Pr)4, TBHP
AlMe3
MeO
Me
Me
H
MeO
HO
OTIPS
34%5 steps
18 stepsrac–ingenol45 steps
0.03%
Tanino and Kuwajima: Improvement (?)
JACS 2003, 125, 1498
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
3/17/2007
Ingenanes: Total Syntheses of Ingenol
Kigoshi: Formal Asymmetric Approach via RCM
MeO2C
O
HH
MeO2C
O
HH
THPO
INaH +
OTHPO
HH
Cl
75%
1. LiI2. PPTS3. CCl4, PPh3
O
HH
H
Et3CONa53%
O
HH
H
LDA
I
1. Grubbs 22. SeO2
O
HO
H
74%
H
formally36 Steps
0.01%
Me
Me
O
Wood: ROMRCM to VictoryMe
Me
O
Me
Me
O
Me
Me
OOPMB
O
O
Grubbs
59% 98%
3 steps
Grubbs II
76%
HS O
Me
Me
H
H
OPMB
O
O17 steps
37 steps0.002%
Org. Lett. 2001, 3, 1563JACS, 2004, 126, 16300
JOC 2004, 69, 7802
Lathyranes Continued
CHCl2
MeOOMe O
1. n–BuLi; MeI2. HClO4
+
I
O
O
CrCl2 (4.0 eq)NiCl2 (5%)
H
H
H
HO
O
HO
CCMe
from (+)-3-carene 1. LiEt3BH2. CP2Zr(H)Cl3. I2
O
O
HO
I
1. HCl2. CrCl2, NiCl2
HO
OH
O
O
IBX
Yamamura: Cr-Ni Coupling to the Core
TL 2000, 41, 2189