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Lars Jørgensen, Steven J. McKerrall, Christian A. Kuttruff, Felix Ungeheuer, Jakob Felding, Phil S. Baran,
Science, Published online 1 August 2013, DOI: 10.1126/science.1241606
14-Step Synthesis of (+)-Ingenol from (+)-3-Carene
“…I think that most organic chemists had considered ingenol beyond the reach of scalable chemical synthesis…” P. S. Baran
Raffaele Colombo – 8/24/2013
Me
Me
Me
(+)-3-Carene
Me
Me
Me
OTBS
Me
HO
TMSO
Me
Me
HOHO
Me
Me
O
HO
OH
(+)-Ingenole
H
Raffaele Colombo @ Wipf Group Page 1 of 28 8/24/2013
Ingenol
Ingenol is a diterpenoid first isolated by Hecker in 1968 from Euphorbia ingens
Ingenol esters showed: -‐ an.cancer ac.vity in vivo
-‐ an. HIV ac.vity in vitro
Ingenol mebutate (Picato®, Leo Pharma) is FDA
approved (2012) for the treatment of ac=nic keratosi
and has completed phase II clinical trials for the
topical treatment of basal cell carcinomas
Me
Me
HO
HO
Me
Me
O
O
OH
H
O
Picato®
The structure was elucidated through X-‐ray crystallography by Hecker in 1970 and contains a
unique bicyclo[4.4.1]undecan-‐11-‐one core (rings BC)
whit a in,out intrabridgehead rela=onship
Me
Me
HOHO
Me
Me
O
HO
OH
(+)-Ingenole
HA B
CD
O
H
in-out-[4.4.1]-undecane
HB
C
Raffaele Colombo @ Wipf Group Page 2 of 28 8/24/2013
Ingenol mebutate
The current sources of ingenol mebutate are: -‐ direct isola=on from E. peplus (commercial source)
-‐ semisinthesis from ingenol
Isola=on of ingenol mebutate and ingenol are:
1.1 mg of ingenol mebutate per Kg of E. peplus
275 mg of ingenol per Kg of E. lathryis
Me
Me
HO
HO
Me
Me
O
HO
OH
H
protection
Me
Me
HOO
Me
Me
O
HO
O
H
Acetone, PTSA
angeloylation
Me
Me
HOO
Me
Me
O
O
O
H
O
O O
LiHMDS O
deprotection
Me
Me
HOHO
Me
Me
O
OOH
H
OH3PO4
on 6 g scale:
31% over 3 steps3 crystallyzation
ingenol ingenol mebutate
SynleK 2012, 23, 2647-‐2652 (Leo Pharma procedure)
Raffaele Colombo @ Wipf Group Page 3 of 28 8/24/2013
Ingenol -‐ previous approaches
3 total synthesis: -‐ Winkler (2002): [2+2] photocycloaddi=on – 43 steps, 0.007% -‐ racemic
-‐ Tanino/Kuwajima (2003): pinacol rearrangement – 45 steps, 0.03% -‐ racemic
-‐ Wood (2004): ring close metathesis -‐ 37 steps, 0.002% -‐ asymmetric
1 formal synthesis: -‐ Kigoshi (2004): ring close metathesis – 36 steps, 0.01% based on Winkler’s route,
asymmetric
Synthethic challenges: -‐ in-‐out intrabridgehead stereochemistry
-‐ 4 hydroxyl groups int the south part
-‐ Sterochemistry at C-‐11
Me
Me
HO
HO
Me
Me
O
HO
OH
(+)-Ingenol
HA
B
C
D11
Raffaele Colombo @ Wipf Group Page 4 of 28 8/24/2013
Winkler’s strategy
Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc.. 2002, 124, 9726-‐9728.
O 1) Li/NH3methyl crotonate
2) TBSOTf
OTBS
CO2Me
H
14:1 d.r.
O
H
O
H
O
O
O
H
LiO
O
vs
O
H
O
O
Li
H
1) SeO2, TBHP2) (Cl3C)2CO
O
H
O
O
hv
CH3CN
Cl
60%O
Cl
OO
[2 + 2]
O
Cl
OO
H
60%O-
Cl
O
OMe
H K2CO3
retro-aldol
O
Cl
OOMe
H
H CO2Me
Me O
H
Cl
HHH
H
H
6 steps
Me O
H
HOTBS
Me
Me
HOHO
Me
Me
O
HO
OH
H27 steps
4 steps 3 steps
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Tanino/Kuwajima’s strategy
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc.. 2003, 125, 1498-‐1500.
O
OTES
Br
OMe
3 steps
OTIPS
OH
AcO
OMe
Co(CO)3
Co(CO)3
MeAl(OAr)2
CH2Cl2
OTIPS
OH
OMe
Co(CO)3
Co(CO)31) Li/NH3
2) CHBr3, NaOH3) Me3CuLi2, MeI
OTIPS
HO
OMe
HO
Me3AlCH2Cl2
OTIPS
O
OMe
HHO
OTIPS
O
H
MeO
pinacol rearrangement
Ar = NO2
HO
OTIPS
OHCOOtBu
OMe
OH
OMe
OMe
6 steps 6 steps
OTIPS
HO
OMe
HTBHP
Ti(OiPr)4
7 steps
O
O
H
MeOO
O
H
2) NaBH43) TES-Cl
1) N N
N Me
Me
HOHO
Me
Me
O
HO
OH
H
13 steps
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Wood’s strategy
Total Synthesis of Ingenol. Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.;. Greene, B.; Yusuff, N.; Wood, J. L.. J. Am. Chem. Soc. 2004, 126, 16300-‐16301
O
BF3.Et2O
O
CH2=CH2(PCy3)2Cl2RuCHPh
PhH, !
ring-opening metathesis O
4 steps
O
O
O
OPMB
ring-closingmetathesis
O
H
HOPMB
O
O
N N
Cl
Cl
O
Mes Mes
HOHO
O
HO
OH
H
O
H
HOPMB
SeO2
tBuOOH
O
H
HOPMB
O
H
HOPMB
O HO
tBuOK, O2, P(OMe)3
O
H
HOOPMB
O
O
H
OOPMB
OO
O
H
OSO2Me
OO
O
H
OSO2Me
OHO
DBU
86%
10 steps
4 steps1) DMP
2) RhCl3
4 steps
98%
76%
4 steps1) Na(Hg)2) HCl
3) SeO2
28%
(+)-Ingenol
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MeO2CO
Funk's keto ester
THPOI
NaH
75%
MeO2C
O
THPO
1) LiI2) PPTS
O
THPO
1) Ph3P, CCl42) Et3CONa
76% 50%O
1) LDA
2) Br59%
O
N N
Cl
Cl
O
Mes Mes
87%
O
H
H
SeO2
85%
O
H
HCHO
Winkler's aldehyde
Kigoshi’s strategy (formal synthesis)
Watanabe K, Suzuki Y, Aoki K, Sakakura A, Suenaga K, Kigoshi H. J. Org. Chem. 2004, 69, 7802-‐7808
Raffaele Colombo @ Wipf Group Page 8 of 28 8/24/2013
This work
Highly stereocontrolled synthesis of (+)-‐ingenole star.ng from (+)-‐carene ($10.2/mol) 14 steps 1.2% overall yield 2 phases strategies: cyclase and oxidase
Me
Me
Me
(+)-3-Carene
Me
Me
Me
OTBS
Me
H
MeTMSO
Me
Me
HOHO
Me
Me
O
HO
OH
(+)-Ingenole
H
(1.08 g)
HO
cyclase phase
7 steps
rearrangement/oxydase phase
7 steps
7 C-C bonds
5 stereocenters
4 C-O bonds
4 stereocenters
Raffaele Colombo @ Wipf Group Page 9 of 28 8/24/2013
This work
Highly stereocontrolled synthesis of (+)-‐ingenole star.ng from (+)-‐carene ($10.2/mol) 14 steps -‐ 1.2% overall yield 2 phase strategy: cyclase and oxidase
Me
Me
Me
(+)-3-Carene
Me
Me
Me
OTBS
Me
H
MeTMSO
Me
Me
HOHO
Me
Me
O
HO
OH
(+)-Ingenole
H
(1.08 g)
HO
cyclase phase
7 steps
rearrangement/oxydase phase
7 steps
7 C-C bonds
5 stereocenters
4 C-O bonds
4 stereocenters
AcO O OH
OH
OAcO
Ph
O
OHO
O
Ph
NH
OH
Bz
Me Br
O
O
Me3Al
ZnMe2
HH O
8 steps, 18-20% overall yield
cyclasephase
oxidase phase
(+)-"taxadienone"
Taxol
A. Mendoza, Y. Ishihara, P. S. Baran. Nature Chemistry 2012, 4, 21–25
Raffaele Colombo @ Wipf Group Page 10 of 28 8/24/2013
Biosynthe.c inspira.on
OPP
OPP
OPP
geranylgeranylpyorophosphate
O2
PO
P
O
O-
O
O-
O-
casbene(31 mg/L engineered
in S. cerevisiae)
lathyrane type
H
H
tigliane type
H
H
HH
H
OHH
[putative byosinthetyc intermedie]
H
O
H
HO
O
H
HOHO OH
Ingenol
HO
OHH
OHOH
O
OH
H
phorbol[tigliane type]
1 total synthesis (36 steps)
ingenane type
HO
O
H
OHO OH
Ingenol mebutate(31 mg/Kg in E. peplus)
O
Cyclase phase
Rearrangement/ oxidase phase
Raffaele Colombo @ Wipf Group Page 11 of 28 8/24/2013
Cyclase phase
Me
Me
Me
NCS, DMAP
DCM, rt
Me
MeO3, DCM/MeOH, -78 °C
then thiourea, -78 °C to rt
Cl
48% over 2 steps
O
Me
Me
ClLiNap, THF, -78 °C,
then HMPA, MeI, -78 °C to rtthen LiHMDS, 17
1 2 3
O
Me
17
OH
Me
16
IBX (2 eq), THF,
65 °C (or 80 °C)
O
Me
Me
Me
44%
OH
Me
4
HO
Me
Me
Me
OH
Me
5
Br-Mg , THF
-78 °C to -15 °C
81%
TBSOTf, Et3N, DCM, 0 °C,
then TMSOTf, Et3N
71%
HH TMSO
Me
Me
Me
OTBS
Me
6
H
[RhCl(CO)2]2, CO
p-xylene, 140 °C
72%
Me
Me
Me
OTBS
Me
7 8
MeMgBr, THF
-78 °C to 0 °C
80%
HO
Me
Me
Me
OTBS
Me
HHO
MeTMSO TMSO
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Rearrangement/oxidase phase
8
OsO4, Py, rt
then Na2SO3, THF
CDI, DMAP
DCM, rt
64% over 2 steps
Me
Me
Me
OTBS
Me
HHO
Me
9
Me
Me
Me
OTBS
Me
HHO
Me
HO
HO
TMSO TMSO
10
Me
Me
Me
OTBS
Me
HHO
Me
O
O
TMSO
O
Martinʼs sulfurane#
BF3.Et2O, DCM
-78 °C to -40°C
then MeOH/Et3N
-40 °C to rt
80%11
Me
Me
OO Me
OTBS
Me
O
Me
O
SeO2, dioxane, 80°C
then Ac2O, Py, DMAP
59%12
Me
Me
OO Me
OTBS
Me
O
Me
O
AcO
HF, CH3CN,
50°C
90%
13
Me
Me
OO Me
OH
Me
O
Me
O
AcO
Martin's sulfuraneCHCl3, reflux
then NaOH, THF
81%14
Me
Me
HOHO Me
Me
Me
O
HO
Me
Me
HOHO
Me
Me
O
HO
SeO2, HCOOH, dioxane, 80°C
then NaOH
OH
Ingenole
H H
H H H
Pinacol rearrangement
76%
Raffaele Colombo @ Wipf Group Page 13 of 28 8/24/2013
Key step 1
Me
Me
Me
OTBS
Me
7
H
O
TMSOTMSOMe
Me
Me
OTBS
Me
HLnRh
TMSOMe
Me
Me
OTBS
Me
HLnRh
Me
Me
Me
OTBS
Me
H
TMSO
LnRh
Me
Me
Me
OTBS
Me
H
TMSO
LnRh
O
O
or
CO
-LnRh
6
Pauson - Khand [2 + 2 + 1]
K. M. Brummond, H. Chen, K. D. Fisher, A. D. Kerekes, B. Rickards, P. C. Sill, S. J. Geib. Organic LeKers, 2002, 4, 1931-‐1934
R2
R4
R3
R1
n
n = 1, 2
5 mol%[Rh(CO)2Cl2]
CO(1 atm), toluene
R1
R2R3
R4
On
COOEt
COOEt
60%
COOEt
COOEt
C6H13C6H13
O
76%
iPr
iPrO
COOEt
COOEt
COOEt
COOEt
77%
Ph
PhO
COOEt
COOEt
COOEt
COOEt
Raffaele Colombo @ Wipf Group Page 14 of 28 8/24/2013
10
Me
Me
Me
OTBS
Me
HHO
Me
O
O
BF3.Et2O, DCM
-78 °C to -40°C
then MeOH/Et3N
-40 °C to rt
80%
O
11
O
Me
Me
O
O Me
OTBS
Me
O
Me
O
H
Pinacol-type rearrangement
TMS
Key step 2
Raffaele Colombo @ Wipf Group Page 15 of 28 8/24/2013
G. Appendino, G. C. Tron, G. Cravolo, G. Palmisano, R. Annunziata, G. Baj, N. Surico, European Journal of Organic Chemistry, 1999, 12, 3413–3420
Me
Me
HOHO
Me
Me
O
HO
OH
HMeOH
H+MeOH
Me
Me
Me
HHO
Me
HOHO
HO
HO
OH
H+
Ingenoltigliane - type
49%
10
Me
Me
Me
OTBS
Me
HHO
Me
O
O
BF3.Et2O, DCM
-78 °C to -40°C
then MeOH/Et3N
-40 °C to rt
80%
O
11
O
Me
Me
O
O Me
OTBS
Me
O
Me
O
H
Pinacol-type rearrangement
TMS
Key step 2
H
OHH
[putative biosinthetyc intermedie]
“Bio” vs “chem” inspira.on
HO
OHH
OHOH
O
OH
H
phorbol
Raffaele Colombo @ Wipf Group Page 16 of 28 8/24/2013
SeO2 oxida.ons
Wood
Baran
O
H
HOPMB
SeO2
tBuOOH
O
H
HOPMB
HO HOHO Me
O
HO
H
SeO2
HOHO
O
HO
OH
H
40%
HOHO
O
HO HOHO
O
HO
SeO2, HCOOH, dioxane, 80°C
then NaOH
OH
Ingenol
H H
76%
OO Me
OTBS
O
O
SeO2, dioxane, 80°C
then Ac2O, Py, DMAP
59%
OO
OTBS
O
O
AcO
H H
49%
Ingenol
(Shibuya’s condi=on) Shibuya, K., Synth. Commun., 1994, 24, 2923-‐2941
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“Hidden” steps
OH
Me
OH O
O
O
O
OO
OEt-EtOH
OEt
OEt
OEt
OH
enzymatic resolution
OH
Me
26% 98.7% e.e.
!
!
racemic
Pseudomona cepacia
65%(over 2 steps)
LiAlH4
vinyl acetate
3 more steps, 17% overall yield
Raffaele Colombo @ Wipf Group Page 18 of 28 8/24/2013
Wipf Group Raffaele Colombo @ Wipf Group Page 19 of 28 8/24/2013
Key step procedures
Pinacol rearrangement To a soluUon of 10 (191 mg, 0.338 mmol, 1.0 equiv) in DCM (7 mL) was added BF3.Et2O (420 μL, 3.38 mmol, 10 equiv) dropwise at -‐78 °C. The reacUon mixture was sUrred at this temperature for 2 min before being warmed to -‐50 °C. Acer 30 min, a 1:1 mixture of Et3N/MeOH (3 mL) was added at -‐40 °C, the soluUon was sUrred for 2 min and saturated aqueous NaHCO3 (5 mL) was added…
Pauson Khand A 1L three-‐neck flask was charged with a soluUon of 6 (1.5 g, 3.25 mmol, 1.0 equiv) in anhydrous p-‐xylene (650 mL) and the soluUon was degassed using carbon monoxide under sonicaUon. [RhCl(CO)2]2 (126.3 mg, 0.325 mmol, 0.1 equiv) was added and the reacUon mixture was transferred into a preheated oil bath and sUrred at 140 °C under 1 atm of CO for 12 h.
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Winkler: first steps
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Winkler: last steps
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Winkler: final steps
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Tanino: first steps
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Tanino: final steps
[1] Trost, B. M.; Preckel, M. J. Am. Chem. Soc. 1973, 95, 7862-‐7864
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Tanino: final steps
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Wood: first steps
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Wood: final steps
Raffaele Colombo @ Wipf Group Page 28 of 28 8/24/2013
