Literature Seminar

Tomohiro Yamamoto

2011/10/11
Total Synthesis of Ingenol

DC1HOO

10AD8H101

BC8AHOHOBOHIngenolcontents
1. Introduction
2. What's In/Out chemistry?
3. Synthesis of Ingenane core
4. Tanino & Kuwajima's total synthesis
5. Summary
1. Introduction
Structual Features and Synthetic Challenges
1) Trans-fused bicyclo[4,4,1]undecane ring2) Highly strained inside-outside intrabridgehead stereochemistry of the BC ring3) cis-triol segment located on upper face
Comparison of Ingenol and Isoingenol(in-H)(out-H)Ingenol

Isoingenol

OO

Structure

HHHOHOHOHOOHHOHOOH

Erel (kcal/mol)

5.90First total synthesis(yeah)

2002

1988(Paquete, L. A.)

Biological activity

tumor promoting etc.

no activity

1/17

Natural source
Euphorbia Ingens (Hecker, E. et al., Cancer Res. 1968, 28, 2338)
Bioactivity
Tumor promoting, antileukemic, and anti-HIV properties (activation of PKC)
Biosynthesis

Although no details are known,
a 1,2-alkyl shift (ex. WagnerMeerwein rearrangement)
connects tiglanes to ingenanes.

History1) Ingenol was isolated by Hecker, E. and co-workers in 1968
2) Zeckmeister, K. and co-workers determined its structure by X-ray
crystallography in 1970
3) Synthetic approach to Ingenol
Funk, R.
Rigby, J. H.

1993(J. Org. Chem.)
1998(T etrahedron, Lett.)4) Total synthesis of Ingenol
Winkler, J. D.
Tanino, K. and Kuwajima, I.
Kigoshi, H. (formal synthesis)
Wood, J. L.

2002(J. am. Chem. Soc.)
2002(J. am. Chem. Soc.)
2004(J. Org. Chem.)
2004(J. am. Chem. Soc.)
5) Synthetic Studies toward 13-Oxyingenol
Kigoshi, H.
2011(Org. Lett.)
now (2011)

2/17

2. What's In/Out chemistry?

Alder, R. W. et al., Chem. Rev. 1996, 96, 2097

Angle Definition
C-H in : 0º < < 90º
C-H out : 90º < < 180º
Homeomorphic isomerisation

Half-twist

out,out-isomers are strongly preferred forsmaller bicyclic system

Ingenolin,out-isomers become the moststablein,in-isomers is most stable
Due to nonbinding interactions between
methylene groups in the bridges, out,out-isomer
is itself usually severely strained.
3/17

AminesNN

41
lone pairout/out

flat nitrogenatom

lone pairin/in1,4-diazabicyclo-[2,2,2]-octane (DABCO, 41)
1,5-diazabicyclo-[3,3,3]-undecane (43)
1,6-diazabicyclo-[4,4,4]-tetradecane (10)Transannular interactions involving inside functionally
311

By Barton-McCombie deoxygenation of in/outsubstrate,unusual rearrangement was discovered.
insidein/outout/out

outside4/17

Application of in/out chemistry

Alder, R. W. J . Am. Chem. Soc. 2005, 127, 7924
Proton is strongly caught, and not detached.

MeH
MeNN
MeMe

proton sponge

HMe H
11 N 1
8 N 4HMe H

new designed
proton sponge

syn-RRRR

Inside-monoprotonatedMe N

H N Me ion could not be

deprotonated easily.
syn-RRRRH+

anti-RRRR

anti-RRRRH+

5/17

Enatioselective epoxidaton by threitol-strapped Manganese porphyrin
Collman, J. P. et al., Bull. Chem. Soc. Jpn., 1988, 61, 47

Background

1,5-dicyclohexylimidazole binds to the unhinderedface of the manganese porpjirin

Collman, J. P. et al., J . Am. Chem. Soc. 1993, 115, 3834
Collman, J. P. et al., J . Am. Chem. Soc. 1995, 117, 692

12+

K2CO3, DMF
100 ºC
10R=OOut/Out

Out/In

4: X = H,H

5: X = H,H

7: X = MnCl

8: X = MnCl

+
O
In/In
6: X = H,H
9: X = MnCl

6/17

OI O+Cl(1 mmol)(100 mol)cat. 7~9 (1 mol)ligand (250 mol)
CH2Cl2Cl

In three catalist, in/in - isomer 9 is
the most effective assymmetric catalist.

Out/Out
Out/InIn/In

The fuction of the bridge is to pull the threitol
rings closer to the center of the macrocycle.

In/In

O
substrate(1 mmol)+I O(100 mol)Ncat. 9 (1 mol)
1,5-dicyclohexylimidazole (250 mol)
CH2Cl29NCl(Yields are based upon iodosylbenzene.)

7/17

Dibridehead diphosphines

Gladysz, J. A. et al., Angew. Chem. Int. Ed., 2011, 50, 6647

only in,in-2 was produced

31

P NMR and 31P EXCY experiment established thatthe species responcible for the two signals are in
equilibium.

Lonepair inversion in simple trialkylphosphinesrequire 29-36 kcal/mol, which corresponds tovery slow process at room temperature.

(strong peak: in,in-weak peak: out,out-)

homeomorphic
isomerization

8/17

in,out-2 exhibited a single signal in the 31P NMR
spectrum at -50 ºC. But at -90 ºC, two signals wereobserved. This implies that a degeneratein,out/out,in homeomorphic isomerization israpid on the NMR time scale.

9/17

3. Synthesis of Ingenane core
Funk's approach
Ireland-Claisen rearrangement

Winkller's route[2+2] photocycloaddition

OH

OhO
O
H

O

H
O
O

H

LHMDS;

MeO2C
HO2C
H

H

TBSCl;
HF

MeO2C
O

HOOO
H
HOHOHOOH

HO

HOKH
ORO
MOMOO

HOO

OMOMHKigoshi, Wood's routering-closing olefin metathesis

Rigby's approach[1,5]-hydrogen shift

R=SEM

Hoveyda cat.
HO

O
MOMO

OMOM

OO

H

OR

Winkller's routeClO

Clh ,MeCN

11 stepsO1H

2[2+2] photocycloaddition

HK2CO3O

O

O

ClHO

O MeOH

OOMe

O

H

H

3Retro-aldol
f ragmentation( )-IngenolO

27 steps

ClClO

6 steps

H

H

H

O

H

H
OTBS

54

CO2Me

CO2MeHFunk's approach
1) LDA (2 eq), HMPA

5 stepsBrMeMeO
OMeOTIPS

MeO2C2) NaH, Br
CO2Me59% (2 steps)O

MeO2C2) KOH

MeO2C

7(+)-3-carene
6Me1) HF, CH3CN
O

8HO2C
OTIPS

9 OH
DCC, DMAP
78% (3 steps)

Ireland-Claisen
rearrangement
O
H

O H
12O

6 steps
MeO2C
HO2C
HHF
H

1188%

H H
H
Me
MeO2C

O

O

OTBS

O

LHMDS;TBSCl

Metoluene

MeO2C
O

O
O

1010/17

Rigby's approachO
O

PhH,MgBr

H

ClO

69% (2 steps)

14[ 6+4]
cycloadditionO
138 steps

ORO
MOMO

H
15

H

OMOM
16Pd(OAc)2 (0.2 eq)
PPh3, Et3N
toluene, reflux
80%HO
ORO
MOMOKH, THF
18-crown-6

HHOOR

0ºC, 69%

OMOM[ 1,5]-hydrogen
shif t

18O
MOMO

OMOM
17

Wood's RouteO

H2C CH2(PCy3)2Cl2RuCHPh

BF3 OEt2OO

19

20

4 steps

PhH,
Ring-opening
metathesis

OO

O

Prepared in 10 steps
from a chiral terpene

Ring-closing
metathesis

OH
HO
25

HO
HO
IngenolRu cat.

Ru cat.

Ring-opening
metathesis

Ring-closing
metathesis

OPMB

2221

O

O

17 steps

25
PhH,H

O
H

OH

OPMB
23

11/17

4. Tanino & Kuwajima's total synthesis of Ingenol
Synthetic strategyOBr

OMe

OTES

OAc

OH

11 steps

Co(CO)3Co(CO)3Co(CO)3 MeAl(OAr)

Co(CO)35 steps
H

CH2Cl2OMe

6Prepared in
4 steps

OTIPS

OMe

Nicholasreaction

14OHO

18 steps

HOHOOTIPS

15O

Me3Al

H
HOOH

2H

O

OH

CH2Cl2MeO
OH
17OTIPS

OTIPS

OMe
16

Pinacolrearrangement

Br

OH

NaH

O

CHCl2CO2H

OMe
OMe

PhH, 70 ºC

OMe
OMe

DMF, reflux
79% (2steps)

12OH
O

NBS
H2O-DMSO

OH
O

Br

OH
O+Br

Zn dust
NH4Cl
Et2O(52% of 3 was recovered)

OMe
5OHTESClimidazole

O

DMF
99%

OMe

OMe

OMe
3OMe
4(32%)BrO4Br

LHMDS, ZnBr2
CH3CHO
THF, 71%

OTES

6OBr

OMe

OTES

7OLi

TFAA, pyridine
DBUbenzene
95%

O

OMe
8Br

t-BuOAc, LDA
LiBr

OTES

Et2O
91%

OtBu

CO2t-Bu
OH
Br

OO
R

Li
Me

OMe

OTES

912/17

Preparation of key intermidiate 14CO2tBu
OH
Br

OMe
H

Me3Al, LDA
THF

TESO
BrtOMe9OTES

CO2tBu
OH

HCl

BuO O

66%

O
Al
Me2OH

OMe
10Cl1) TIPSCl, DMAP
DMF, 100%2) LiAlH4, THF, 84%3) SO3 pyridine
DMSO, Et3N, 97%

CHO
OH

OMe
11(EtO)2P(O)CCl3
BuLi
OTIPS

THF
85%

OMe

OTIPS

12OAc

1) BuLi, THF;
(CH2O)n, 91%2) Ac2O, Et3N, DMAP
CH2Cl2, 99%

ClOH

OAc

Co2(CO)8OH

OH

Co(CO)3Co(CO)3CH2Cl295%

OMe
13OTIPSOMe
14OTIPS

Dicobalt hexacarbonyl complex(i) Introduction

Saito (M1) Literature seminar(2010)
Omae et al., Appl. Organometal.. Chem, 2007, 21, 318

Organocobalt compounds in organic synthesis have three characteristic reacitons.
A) A high affinity to C-C -bonds or C-N -bonds.
B) A high affinity to carbonyl groups.
C) Easily tending to form square-planar bipyramidal six-coordination structures at thesquare-planar position, and to bond with one or two carbon atoms at axial position.

Nicholas reaction , Pauson-Khand reaction and [2+2+2] cyclizaiton are based on character A.
(Pauson-Khand reaction is also based on character B)(ii) Nicholas reaction (character A)

The cation at the -position of the cobalt is stabilized by dicobalt hexacarbonyl acetylenemoiety.
Ref : Mayr et al., JACS, 1998, 120, 900

13/17

Model study of Nicholas reaction

OAc

MeAl O

Co(CO)3OH

Co(CO)3Co(CO)3NO2215

Co(CO)3OH

CH2Cl2OMeOTIPSOMe

14OTIPS

16Br

1) Li, liq NH367% (2 steps)2) CHBr3, aq. NaOH
BnEt3NCl
CH2Cl2, H2O, 71%Br
OHOMe
171) Me3CuLi2, Et2O;
MeI, 95%O

OTIPS

OH2) TBHP, Ti(OiPr)4MS4A, CH2Cl2OMe
18OTIPS
14/17

Construction of ABCD ring by pinacol rearrangement
DCHOO

OAlMe3OHHO

CH2Cl2, 76% (2 steps)
OMe18

HA

HOB

HOHOOH

MeO

OTIPS

OTIPS
19

Introduction of hydroxyls for tetraol 28

HOO

O

DMSO, (COCl)2H

1) tBuO(Me2N)2CH, DMF
100 ºCO
H

Et3N, CH2Cl2, 93%

MeO2) DIBAL, CH2Cl2, MeI
THF, 98% (2 steps)3) NaBH4, EtOH, 95%

MeO
OTIPSOOH

MeO

OTIPS

19OTIPS

20O

1) DIBAL, CH2Cl2O

1) TBAF, THF, 100%
H2) TFAA, 2,6-lutidine
DBU, CH2Cl2,83% (2 steps)

21H2) PDC, CH2Cl2, 97%

MeO

MeOOTIPSO

2223NNN1) OsO4, pyridine
Et2OOHH

2) NaHSO3, H2O

DMF, 120 ºC, 86%24O

HOHOOO251) NaBH4, CeCl3
MeOH, H2O2) TESCl, imidazole
DMF, 99% (2 steps)

1) OsO4, pyridine
Et2O

O
HOHO

H
HO
HO

Retro-AldolOO

HH2) NaHSO3, H2O
59% (2 steps)

O

OTES

OTES

HOO

26 Dead End
282715/17

HOHO

CDIH

23HHO

toluene

43O

HOHOO

OO

OTES+4OOO HOHOOOH OTESO

29a18%28H23OTES

29b78%DMAPtoluene
100 ºC, 2 h

By repeating 9 times of this sequence

29a (25%) + 29b (75%)

O

AnCH(OMe)2CSA

H

HOO
O

DMF, 93%OOH OTESOO
1) SOCl2, pyridine

HHOO
O2) AcOH, H2O
96% (2 steps)

O
O

O
AnO
HOOH
3130

29a: 86%
29b: 8%O

O
Me2S, NCS

HO
O

6O
HO

H

TESOTf, 2,6-lutidine

7

CH2Cl2OOO
OTES O

O

3233O

O
TMSCl, Et3N
LDA, THF

O
O

29atoluene, 75%

HHOO2) HF, CH3CNO
OTES OTMS
34H1) NBS, CH2Cl2OOBrOHOO
3516/17

OO
HOOO
HOCH2I2, MeLi

HBr THF, 39% (5 steps) OOOO
HOBrOO

1) Zn, NH4Cl
THF-H2O, 91%2) KOH, MeOH
89%HHOHOHOOH

Ingenol

5. Summary
Total synthesis of Ingenol
Winkler, J. D.
[2+2]-photocycloaddition
racemic total synthesis - 43 steps, 0.007% yield
Tanino, K. and Kuwajima, I.
Nicholas reaction and pinacol rearrangement
racemic total synthesis - 45 steps, 0.03% yield
Wood, J. L.
ring-closing metathesis
assymmetric synthesis - 35 steps, 0.002% yield