total synthesis of ingenol a literature review
TRANSCRIPT
Christoph ZapfSupergroup Meeting
Princeton University 2/26/2004
Total Synthesis of IngenolA Literature Review
Ingenol – A highly oxygenated diterpene
• Isolation from roots of Euphorbia ingensreported in 1968 by Hecker.
• X-ray structure analysis was reported in 1970.• Ingenol and its derivatives show interesting
biological properties such as tumor-promoting, anti-HIV and anti-leukemia activities.
• Much research is directed toward synthesis and biological evaluation of Ingenol analogs and derivatives.
• Two racemic total syntheses are reported to date by Winkler (2002) and Tanino, Kuwajima(2003).
O
OH
H3C
HOHOHO
Ingenol
H3C
CH3
CH3
HAB
CD
• Trans Intrabridgehead Stereochemistry
• Installation of Hydroxyl Groups
• Stereochemistry at C-11
Synthetic ChallengesO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
O
H
HO
H3CH
O
H3C
OHOHHO
H
H
H
H
HOHO
H3C
H3CHO HO
CH3
CH3
H3C CH3
In/Out Isomerism
C C C C C CH HH H H H
out-out in-in out-in
Hout
Hout Hout
Hin
∆E = 6.3 kcal mol-1
Alder, R. W.; East, S. P. Chem. Rev. 1996, 96, 2097-2111.
Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc. 1988, 110, 3298-3300.
Examples for In/Out Isomerism
C CH
HC C
HH2, PtO2
70%
O
CHO5
TiCl3(DME)1.5
Zn-Cu, DME, 30%
McMurry, J. E.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 10167-10173.Alder, R. W.; East, S. P. Chem. Rev. 1996, 96, 2097-2111.
CH3H3C
H
OHH3C
H3C
AcO
CH3H3C
HH3C
HO OH
3α-Acetoxy-15β-hydroxy-7,16-secotrinervita-7,11-diene
Secotrinerviten-2β‚3α-diol
Key Players in the Ingenol Field
• Rigby (1,5-H Sigmatropic Rearrangement)• Funk (Ireland-Claisen Rearrangement) • Wood and Kigoshi (Ring Closing Metathesis)
• Winkler (De Mayo Photocycloaddition)• Tanino, Kuwajima (Pinacol Rearrangement)
Rigby’s ApproachO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
OO
ClMgBr +
80oC84%
86%
H
H
O
Ti(OiPr)2Cl2 (30 mol%)(S)-Binol (30 mol%)
DCM, 4A MS, RT
80%, 40% ee
[6+4]
H
H
O
Rigby’s ApproachO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
MOMO OMOM
O
HOSEM
Pd(OAc)2 (0.2 eq.)PPh3, Et3N
toluene, reflux, 78%O
MOMO OMOM
OSEM
O
HOH
MOMO OMOM
OSEM
O
O
HKH, 18-crown-6
THF, 0oC69%
MOMO OMOM
O
HOSEM
OMOMO OMOM
HOSEM
O
The 1,5-H Sigmatropic Rearrangement
MOMO OMOM
OSEM
O
HOH
MOMO OMOM
OSEM
O
O
HKH, 18-crown-6
THF, 0oC69%
Fleming, I. Frontier Orbitals and Chemical Reactions; VCH: Weinheim, 1990.
Funk’s ApproachO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
H3C
CH3
CH3
OMeOOC
H3C
CH3
CH3
OOTIPS
OTIPS
Br1. LDA,
2. NaH, 63%
MeOOC Br MeOOC
MeOOC
H3C
CH3
CH3
O
MeOOC
OO
1. HF2. KOH
3. DCC, DMAP 49%
H3C
CH3
CH3
OMeOOC
CH3
CH3
OMeOOC
MeOOMe
1. O3, Me2S2. CeCl3, HCO(Me)3
3. KH, CO(COMe)2 35%
1. TiCl4
2. LiMeCuCN 72%
(+)-Carene
Funk’s ApproachO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
H3C
CH3
CH3
O
MeOOC
OO
OH3C
CH3
CH3
HMeOOCHOOC
O
HO
MeOOC
OTBS
OMeOOC O
HOTBS
H H
1. LHMDS, TBDMS-Cl HMPA, 95oC 2. HF, 88%, 95:5
Funk’s ApproachO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
OH3C
CH3
CH3
HMeOOCHOOC
OH3C
CH3
CH3
HMeOOC
O
1. (COCl)2, DMF2. EtMgBr, CuI
3. NaOMe, 37%
O
CH3
CH3
HO
OH3C
H
O
H3C
HO
H3C
CH3
CH3
H
1. DIBAL-H2. NaOH, 56%
3. TMSCl, Li2S, Et3N4. mCPBA, 37%
LHMDS
90%
OH3C
CH3
CH3
HMeOOC
OO
Wood’s Approach
H3C
CH3
CH3
H
OMeOOC
RCM polymersH3C
CH3
CH3
OMeOOC
allyl bromide
KH, THF, 85%
OH3C
CH3
CH3
H
PCy3
Ru
PCy3PhCl
Cl
10 mol%85% yield MeOOC
H3C
CH3
CH3
H
OMeOOC
H3C
CH3
CH3
OMeOOC
1. allyl bromide KH, DMF, 90%
2. 200oC, 95%
O
OH
H3C
HOHOHO
H3C
CH3
CH3
H
Wood’s Approach
O
H
H3C
CH3
CH3
H
O
O
H
H3C
CH3
CH3
H
O
OO
PCy3
Ru
PCy3PhCl
Cl
80 mol%45% yield
H3C
CH3
CH3
H
O
OO
H3C
CH3
CH3O
OO
H3C
CH3
CH3
O
allyl bromide
KH, THF, 92%
O
OH
H3C
HOHOHO
H3C
CH3
CH3
H
Winkler’s Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
O OTBS
H
H3C
COOMe
O
H
H3C1. Li, NH3, methylcrotonate
2. TBSOTf, 69%
1. LAH2. TsCl, CuI
3. allyl-MgBr4. HF, 64%
O
H
H3C
H
H3C
OO
O
1. LDA, MeO2CCN2. pMBOH
3. TFAA, TFA Ac2O, Me2CO, 80%
H
H3C
OO
O
Cl
1. SeO2, TBHP
2. (Cl3C)2CO, PPh3, 66%
De Mayo Reaction
De Mayo, P. Acc. Chem. Res. 1971, 4, 41-47.
R1
O
R3HO
R2 R5
R4
+hν R5
R4
R2
R3
O
R1
HO
R5
R4
R2
R3
O R1
O
Winkler’s Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
OO
O
OH
H3C
Cl
H
H3C HCl
O
O
hν, CH3CNMe2CO, 0oC
60%
O
COOMeH
H3C
H
Cl
K2CO3, MeOH
Winkler’s Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
O
COOMeH
H3C
H
Cl O
H
H3C
H
OTBS
O
H
H3C
H
OTBS
CH3
CH3
1. LAH2. DBU
3. TBS-Cl 35%
1. CHBr3, NaOH
2. MeLi, CuSCN MeI, 72%
Winkler’s Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
O
H
H3C
H
OTBS
CH3
CH3
O
CHOH
H3C
H
CH3
CH3
1. TBAF2. DMP
3. tBuBr, DMSO4. LiCl, DMF, 64%
O
CHOBr
H3C
H
CH3
CH3
1. Ac2O, AcCl
2. NBS
O
CHOBr
H3C
H
CH3
CH3
OH3C
H
CH3
CH3
HO OHCH2OH
1. LiCl, DMF2. LAH
3. OsO4, 28%
OH3C
H
CH3
CH3
TESO OHCH2OTBDPSHOHO
1. TBDPSCl2. TESOTf
3. OsO4, 71%
Winkler’s Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
OH3C
H
CH3
CH3
TESO OHCH2OTBDPSHOHO
OH3C
H
CH3
CH3
TESO OCH2OTBDPSOBzO
1. Bz-Cl2. SOCl2
3. RuCl3, NaIO4 65%
O2S
OH3C
H
CH3
CH3
HOHOBzO
CH2OTBDPS
1. DBU2. H2SO4
3. TBAF 53%
OH3C
H
CH3
CH3
OOO
CH2OTBDPSPMP
OH3C
H
CH3
CH3
OOO
CH2OTBDPSPMP
H3C
OH3C
H
CH3
CH3
HOHOHO
H3C
OH
1. PMB-DMA2. K2CO3
3. DMP, 67%
1. LDA allylOCOCN
2. MeI, K2CO33. Pd(OAc)2, 23%
1. NaBH4, CeCl32. HCl/MeOH
3. TBAF, 28%
43 STEPS, average 80% yield per step
Ingenol
Tanino-Kuwajima Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
OH
OMeOMe
O
OMe
OOH
OMe
Br1. NaH, allyl-Br
2. Cl2CHCOOH79%
NBS
H2O32%
1. TES-Cl, im2. LHMDS, ZnBr2 CH3CHO
3. TFAA, py, DBU 67%
O
OMe
H3C
OTES
Br
H3C
OTIPS
COOtBuOH
OMe
H3C
OTIPS
OH
OMe
Cl
ClOH
OMeOTIPS
H3C
AcO Co(CO)3Co(CO)31. LDA, tBuOAc, LiBr
2. Me3Al, LDA
3. TIPS-Cl, DMAP, 60%
1. LAH2. SO3-py, DMSO
3. (EtO)2P(=O)CCl3 BuLi, 69%
1. BuLi, CH2O2. Ac2O, Et3N
3. Co2(CO)8, 86%
Tanino-Kuwajima Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
OH
OMe
H3C
OTIPS
CH3
CH3
HOH
OMeOTIPS
H3C
AcO Co(CO)3Co(CO)3 AlMe
OAr
OAr
OH
OMeOTIPS
H3CCo(CO)3
Co(CO)3
=OAr O
H3C
H3C
NO2
1. Li, NH3, 67%2. CHBr3, NaOH
3. Me3CuLi2, MeI 67%
OH
OMe
H3C
OTIPS
CH3
CH3OH
OMe
H3C
OTIPS
CH3
CH3O
O
OTIPSMeO
CH3
CH3
HH H
H3CHOTBHP, Ti(OiPr)4 Me3Al, 76%
Tanino-Kuwajima Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
OH
OMe
H3C
OTIPS
CH3
CH3O
O
OTIPSMeO
CH3
CH3
HH
H3CHO
O
OMe
H3C
OTIPS
CH3
CH3
HMe3AlO
AlMe3Me3Al
R2
R1
OH
R3
R4
OH
R2
R1
O R4
R3H+ R2
R3
R4O
R1
Pinacol Rearrangement
H
Tanino-Kuwajima Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
O
OTIPSMeO
CH3
CH3
H
H3CHO O
OTIPSMeO
CH3
CH3
H
H3CO1. Swern
2. tBuO(NMe2)2CH
3. DIBAL-H, 91%
O
OMeO
CH3
CH3
H
H3C
H3C
1. NaBH42. DIBAL-H
3. Tf2O, DBU4. TBAF5. PDC, 76%
N
NNO
OMeO
CH3
CH3
H
H3C
H3C
O
OTES
CH3
CH3
H
H3C
H3C
1.
2. NaBH4, CeCl33. TES-Cl im, 85%
O
OTES
CH3
CH3
H
H3C
H3CHO
O OHO
O
1. OsO4, py
2. (im)2CO 11%
[1]
[1] Trost, B. M.; Preckel, M. J. Am. Chem. Soc. 1973, 95, 7862-7864.
Tanino-Kuwajima Total SynthesisO
OH
H3C
HOHOHO
H3C
CH3
CH3
H
O
OTES
CH3
CH3
H
H3C
H3CHO
O OHO
O
O
O
CH3
CH3
H
H3C
H3C
O OHO
O
1. PMB-DMA, CSA2. SOCl2
3. AcOH, H2O4. Me2S, NCS 67%
1. TESOTf2. LDA, TMSCl
3. NBS4. HF
O
O
CH3
CH3
H
H3C
H3C
O OHO
O
Br
O
O
CH3
CH3
H
H3C
H3C
O OHO
O
Br
CH2I2, MeLi
39%
O
CH3
CH3
H
H3C
H3C
O OHO
O
Br
O
1. Zn, NH4Cl
2. KOH, 81%
O
OH
H3C
HOHOHO
H3C
CH3
CH3
H
45 STEPS, ca. 0.1% yield overallIngenol
Literature• Ingenol – Isolation and Characterization
Hecker, E. Cancer Res. 1968, 28, 2338. Zechmeister, K.; Brandl, F.; Hoppe, W.; Hecker, E.; Opferkuch, H. J.; Adolf, W. Tetrahedron Lett. 1970, 47, 4075-4078.
• Biological PropertiesHecker, E. Pure Appl. Chem. 1977, 49, 1423-1431. Kupchan, S. M.; Uchida, I.; Branfman, A. R.; Dailey, R. G.; Fei, B. Y. Science 1976, 191, 571. Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta, S.; Konno, K. Antimicrob. Agents Chemother. 1996, 40, 271-273.
• In/Out Isomerism Alder, R. W.; East, S. P. Chem. Rev. 1996, 96, 2097-2111.
• Ingenol SynthesesRigby, J. H.; Rege, S. D.; Sandanayaka, V. P.; Kirova, M. J. Org. Chem. 1996, 61, 842-850.Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-801.Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc. 1988, 110, 3298-3300.Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Org. Chem. 1993, 58, 5873-5875.Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566.Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927-3930.Winkler, J. D.; Henegar, K. E. J. Am. Chem. Soc. 1987, 109, 2850-2851.Winkler, J. D.; Hong, B.-C.; Bahador, A.; Kazanietz, M. G.; Blumberg, P. M. J. Org. Chem. 1995, 60, 1381-1390.Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387-399.Winkler, J. D.; Kim, S.; Harrison, S. J.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296-300.Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728.Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032-3033.Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500.
Problem 1Kuwajima et al. employed a procedure reported by Corey to oxidize the sterically less hindered secondary alcohol to the corresponding ketone as shown below utilizing N-chlorosuccinimideand DMSO. Suggest a mechanism.
Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586-7587.
O
O
CH3
CH3
H
H3C
H3C
O OHO
O
Me2S, NCS 75%
O
OH
CH3
CH3
H
H3C
H3C
O OHO
O
Problem 1
O
O
CH3
CH3
H
H3C
H3C
O OHO
O
Me2S, NCS 75%
O
OH
CH3
CH3
H
H3C
H3C
O OHO
O
DMS + NCS NSH3C
H3CO
OCl O
O
CH3
CH3
H
H3C
H3C
O OHO
O S
CH3
CH3H
- HCl, DMS
Cl
Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586-7587.
Kuwajima et al. employed a procedure reported by Corey to oxidize the sterically less hindered secondary alcohol to the corresponding ketone as shown below utilizing N-chlorosuccinimideand DMSO. Suggest a mechanism.
Problem 2
Toward the end of Winkler’s total synthesis of Ingenol, the final carbon atom was introduced by alkylating a β-keto ester with MeI. Treatment of the methylated compound with Pd(II) acetate removed the allyl ester side chain and installed the α,β-unsaturated ketone. Draw the catalytic cycle.
OH3C
H
CH3
CH3
OOO
CH2OTBDPSPMP
H3C
OH3C
H
CH3
CH3
OOO
CH2OTBDPSPMP
O
O
H3C
Pd(OAc)2
Shimizu, I.; Tsuji, J. J. Am. Chem. Soc. 1982, 104, 5844-5846.
Problem 2
Toward the end of Winkler’s total synthesis of Ingenol, the final carbon atom was introduced by alkylating a β-keto ester with MeI. Treatment of the methylated compound with Pd(II) acetate removed the allyl ester side chain and installed the α,β-unsaturated ketone. Draw the catalytic cycle.
OH3C
H
CH3
CH3
OOO
CH2OTBDPSPMP
H3C
OH3C
H
CH3
CH3
OOO
CH2OTBDPSPMP
O
O
H3C
Pd(OAc)2
O
O
O H3C
Ln(allyl)Pd
OLn(allyl)Pd
O
H3C
Ln(allyl)Pd
H
(allyl)PdHLn
propene
Pd(0)Ln
H3C
Shimizu, I.; Tsuji, J. J. Am. Chem. Soc. 1982, 104, 5844-5846.
Problem 3
OO
O
OH
H3C
OH
H
H3C HOH
O
O
hν, CH3CN
MeCOPh, 0oCO
H
H3CO
O
O
+
B, 16% C, 15%A
H
Winkler, J. D.; Harrison, S. J.; Greaney, M. F.; Rouse, M. B. Synthesis 2002, 14, 2150-2154.
After irradiation of a diastereomeric mixture of compound A, epimeric at the secondary alcohol, Winkler et al. obtained compound B and C in a nearly 1:1 ratio. Speculate on the structural nature of the intermediates leading to the products.
Problem 3
OO
O
OH
H3C
OH
H
H3C HOH
O
O
hν, CH3CN
MeCOPh, 0oCO
H
H3CO
O
O
+
B, 16% C, 15%A
H
Winkler, J. D.; Harrison, S. J.; Greaney, M. F.; Rouse, M. B. Synthesis 2002, 14, 2150-2154.
After irradiation of a diastereomeric mixture of compound A, epimeric at the secondary alcohol, Winkler et al. obtained compound B and C in a nearly 1:1 ratio. Speculate on the structural nature of the intermediates leading to the products.
O
H
H3C HOH
O
O
O
H
H3C
O
O
and
OH
recombination hydrogen transfertautomerization
Problem 4On the way to their key building block for the pinakol rearrangement, Kuwajima and co-workers obtained the indicated trans-decaline compound with the required stereochemistry of the tert-butyl ester by treatment of the substituted cyclohexane system with Me3Al and LDA. Propose a model for the transition state of the ring closure which explains the resulting equatorial orientation of the ester functionality.
H3C
OH
COOtBuOH
OMe
Me3Al, LDA
H3C
OTES
COOtBuOH
OMe
Br
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500.
Problem 4On the way to their key building block for the pinakol rearrangement, Kuwajima and co-workers obtained the indicated trans-decaline compound with the required stereochemistry of the tert-butyl ester by treatment of the substituted cyclohexane system with Me3Al and LDA. Propose a model for the transition state of the ring closure which explains the resulting equatorial orientation of the ester functionality.
H3C
OH
COOtBuOH
OMe
Me3Al, LDA
H3C
OTES
COOtBuOH
OMe
Br
OMe
TESOBr
OO AlMe2
tBuO
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500.
Problem 5
The synthesis of the 1,3-dioxin-4-one moiety required for the de Mayo reaction in Winkler’s synthesis of Ingenol can be accomplished by exposing the β-keto p-methoxybenzyl ester shown below to rather harsh reaction conditions (trifluoracetic anhydride, trifluoroacetic acid, acetic anhydride and acetone). Provide a mechanistic reasoning for this transformation.
O
H
H3C
H
H3C
OO
O
TFAA, TFA
Ac2O, Me2CO, rtO
O
OCH3
Sato, M.; Ogasawara, H.; Oi, K.; Kato, T. Chem. Pharm. Bull. 1983, 31, 1896-1901.
Problem 5
The synthesis of the 1,3-dioxin-4-one moiety required for the de Mayo reaction in Winkler’s synthesis of Ingenol can be accomplished by exposing the β-keto p-methoxybenzyl ester shown below to rather harsh reaction conditions (trifluoracetic anhydride, trifluoroacetic acid, acetic anhydride and acetone). Provide a mechanistic reasoning for this transformation.
O
H
H3C
H
H3C
OO
O
TFAA, TFA
Ac2O, Me2CO, rtO
O
OCH3
O
H
H3C
O
O
H
O
H
H3C
O
O
H+
CR3
OH
HO
H
H3C
O
OO
H
H3C
O
Ac2O or
TFAA
- HOOCCR3
- H+
Me2CO
Sato, M.; Ogasawara, H.; Oi, K.; Kato, T. Chem. Pharm. Bull. 1983, 31, 1896-1901.