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The Intramolecular Diels–Alder Reaction as Part of Multi-step Reactions in Total Syntheses of Complex Natural Products Christoph Zapf Supergroup Meeting Princeton University 6/1/2005
Transcript of The Intramolecular Diels–Alder Reaction as Part of …orggroup/supergroup_pdf/supergroup... ·...
The Intramolecular Diels–Alder Reaction as Part of Multi-step Reactions in
Total Syntheses of Complex Natural Products
Christoph ZapfSupergroup Meeting
Princeton University 6/1/2005
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Kurt Alder
The Diels-Alder Reaction
Otto Diels
CHR
CHR+
[4+2] Cycloaddition R
R
"Syntheses in the Hydroaromatic Series"O. Diels, K. Alder, Annalen 1928, 460, 98.
1950 Nobel Prize in Chemistry: "For their discovery and development of the diene synthesis"
NNH H
H
H
MeO2C OH H
OMe
O
OMe
OMe
MeO
MeO
Reserpine
H
HO
OHO
OH
H
O
Cortisone
O
O
O
O
Cantharidin
R. B. Woodward and coworkers,J. Am. Chem. Soc. 1951, 73, 2403.
G. Stork and coworkers,J. Am. Chem. Soc. 1951, 73, 4501.
R. B. Woodward and coworkers,J. Am. Chem. Soc. 1956, 78, 2023, 2657.
Intramolecular Diels–Alder – Fundamentals
H
H
H
H
and/or
E-diene trans-product cis-product
E-diene
too strained for short tethers
bridged product
H
H
Z-diene cis-product
H
H
trans-product
too strained for short tethers
not
Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 513-550.
Type I Dienes
Intramolecular Diels–Alder – Fundamentals
syn-product anti-product
notR
RH
RH
Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 513-550.
Type II Dienes
Intramolecular Diels–Alder – Fundamentals
160 °C45%
24 : 76
Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 513-550.
Predicting relative Stereochemistry
COOMe
COOMeCOOMe
MeOOC COOMe
COOMe
H
H
COOMeH
COOMeCOOMe
toluene
100 °C
Outline
• Introduction
• Definition
• Examples of Heteroatom Dienes/Dienophiles
• Examples of all Carbon Dienes/Dienophiles
• Conclusion
Outline
Examples of IMDA Triggered by:
• Heat
• Activating Reagents (Acetylation, Sulfonylation)
• Fragment Couplings
• Elimination
• Oxidation
Examples of Heteroatom Dienes/Dienophiles
Total Synthesis of VM55599. Utilization of an Intramolecular Diels–Alder Cycloaddition of Potential Biogenetic Relevance
HN
N
O
O
HN
MeMe
H Me
N
N
OAc
O
HN
MeMe
H Me
N
N
OAc
O
HN
MeMe
Me
AcCl
HN
N
O
O
N
MeMe
H
H
Me
HN
NO
N
MeMe
H
H
Me
(–)-VM55599
14 d
35% syn-addition
+ 15% 'syn-exo'+ 10% 'anti-endo'
DIBAL-H
23 °C, 68%
(a) Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 1675-1683. (b) Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 2002, 124, 2556-2559.
Stereoselective Total Syntheses and Reassignment ofStereochemistry of Cylindrospermopsin
N NH N NH
NHHMe
O3SOH H
OH
OH
O
(±)-Cylindrospermopsin
N N
HMe
BnOH H
O
OBnO
HN
HN
OO
MeMe
N NH
HMe
BnOH H
OBnO
OPMB
OH
N N
HMe
BnOH H
OBnO
S
OPMBO
N N
HMe
BnOH
OBnO
S
OPMBO
N NH2
HMe
BnOH
OBnO
OPMB
SOCl2, CH2Cl2
–78 to 23 °C
81%
1. PhMgBr2. P(OMe)3, MeOH 84%
N-sulfinyl urea
Heintzelman, G. R.; Fang, W.-K.; Keen, S. P.; Wallace, G. A.; Weinreb, S. M. J. Am. Chem. Soc. 2002, 124, 3939-3945.
An enantioselective synthesis of (–)-FR182877 provides a chemical rationalization of its structure
Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393-5407.
MeO
O
Ot-Bu
MeTMSO TESO
Me
Me
OTESMe
MeO
Ot-Bu
O
O OMe
O
TMSO
Me
TESO OTESMe
MeO
O
Ot-Bu
MeTMSO TESO
Me
Me
OTES
TESO
Me
O
TMSO H
Me
MeH
H
OTESH
H
H
H
Me
HCOOt-BuHO
Me
O
OO
H
Me
MeH
H
OH
H
H
H
H
Me
H
(-)-FR182877
Pd2(dba)3
THF, 40 °C, 80%
1. NaHMDSPhSeBr
2. mCPBA
Total Synthesis of (±)-Fasicularin Based on StereocontrolledIntramolecular Acylnitroso-Diels–Alder Reaction
NHOH
O
OMOM
Bu4NIO4
H2O-MeOH, 0 °CO
N
OOMOM
ON
OOMOM
+
NNCS
C6H13
(±)-Fasicularin
O
N OOMOM
MOMO
ON O
ON
O
MOMO
preferred over
or
via
N
O
O
MOMO
84%
4.5 : 1
Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583-4592.
Examples of all Carbon Dienes/Dienophiles
Total Synthesis of (–)-Ircinianinand (+)-Wistarin
I
CH3 CH3O
O
O
H3C
MeO
CH3
CHO
O
O
H3C
MeO
CH3
OTBDPS
O
O
H3C
MeO
OHC
CH3
OTBDPS+
1. LDA2. MsCl
3. DBU
1. TBAF
2. PCC
OHC
O 12 steps
Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem. 1997, 62, 1691-1701.
Total Synthesis of (–)-Ircinianinand (+)-Wistarin
OH3C
CH3O
CH3
CH3O
H
H
I
CH3 CH3OO
O
H3C
MeO
CH3
CHO +0.1% NiCl2
CrCl2
O
O
H3C
MeO
CH3 CH3 CH3OOH
(–)-Ircinianin
OMe
HO
OH3C
CH3O
CH3
CH3O
H
H
OH
1. I2, K2CO32. Bu3SnH
OH3C
CH3O
CH3
H
H
O
CH3 O
(+)-Wistarin
23 °C, 60%
Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem. 1997, 62, 1691-1701.
Enantioselective Total Syntheses of Manzamine A and Related Alkaloids
Pd(PPh3)4
toluene, reflux
NTBDPSO(H2C)5
COOMe
Br
ONBoc
TBDPSO
NTBDPSO(H2C)5
COOMe
ONBoc
TBDPSO
SnBu3
NTBDPSO(H2C)5
O
COOMe
NBoc
TBDPSO
68% H
N
O
CH(OMe)2
N
H
O
O
N
CHO
N
H
H
HH
OH
N
N
H
H
OH
N NH
(+)-Ircinal A
(+)-Manzamine A
Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584-8592.
IMDA Reaction of an in Situ-Generated, Heteroatom-Stabilized Allyl Cation: Total Synthesis of (±)-Lycopodine
OMe
Me
PhS
O
OTBDPSO
Me
Me
O
OHO
Me
Me
O
OTBDPS
CHOS
B
TMS
OMe
Me
PhS
HO
TBSO
OTBDPS
TBSO Li
Ph
O
BH
RPhS
TMSR
OBBN
PhS TMS
SPh
R RSPh
H2SO4anti-elim.
NaOHsyn-elim.
then 4 N NaOH
Grieco, P. A.; Dai, Y. J. Am. Chem. Soc. 1998, 120, 5128-5129.
Pearson, W. H.; Lin, K.-C.; Poon, Y.-F. J. Org. Chem. 1989, 54, 5814-5819.
IMDA Reaction of an in Situ-Generated, Heteroatom-Stabilized Allyl Cation: Total Synthesis of (±)-Lycopodine
OMe
Me
PhS
HO
TBSO
OTBDPS
LiClO4·Et2O
10 mol% TFA
OMe
Me
PhS
TBSO
OTBDPS OMe
Me
OTBDPS
SPhH
OTBS
N
O
H
Me
H
H
H
(±)-Lycopodine
– H
OI
SPhH
HO
H
Me
H
H
H
HN H
H
Grieco, P. A.; Dai, Y. J. Am. Chem. Soc. 1998, 120, 5128-5129.
Total Synthesis of Colombiasin A
OMe
Me
O
OMe
TBSO
(S)-Binol / (iPrO)2TiCl2
toluene, –60 to –10 °C94% e.e.
OMe
Me
O
OMe
TBSOH
H
+OMe
Me
OMe
OMeMe
O
OMe
Me
OMe
OMeMe
O
OMe
Me
OMe
OMeMe
MeO
O
O
OMe
Me
OMe
OMeMe
O
Me
H
LHMDS
Me OCOCl
Pd(PPh3)4, cat.
OMe
Me
OMe
OMeMe
O
Me
H
Me
OMe
Me
O
O
SO2
Me
Me
H
MeH
HO
OMe
Me
OMe
OMe
SO2
Me
Me
H
MeH
HO liq. SO2HNO3, AgNO3
Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Angew. Chem. Int. Ed. Engl. 2001, 40, 2482-2486.Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Chem. Eur. J. 2001, 7, 5359-5371.
Total Synthesis of Colombiasin A
OMe
Me
O
O
SO2
Me
Me
H
MeH
HO
OMe
Me
O
OMe
H
Me
HO
Me
toluene
180 °C
OMe
MeO
OMe
HO
MeH
H
Me
OMe
MeO
OMe
MeH
H
Me
(–)-columbiasin A
Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Angew. Chem. Int. Ed. Engl. 2001, 40, 2482-2486.Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Chem. Eur. J. 2001, 7, 5359-5371.
Total Synthesis of Natural Dysidiolide
O
OMOM
CH3
OTBS
OH
CH3
OTBS
PhS
O
CH3
OTBS
Ph(O)S
O
CH3
OTBS
OO
H
MgBr1.
2. SiO2
3. PhSH4. DIBAL-H
1. mCPBA
2. DCC
COOH
pyridine, toluenereflux
O
CH3
OTBS
O
CH3
OBn
HOH
H3C
OTBSTHPO
1:1, separation
Miyaoka, H.; Kajiwara, Y.; Hara, Y.; Yamada, Y. J. Org. Chem. 2001, 66, 1429-1435.
Total Synthesis of Natural Dysidiolide
CH3
OBn
HOH
H3C
OTBSTHPO
CH3
OH
HH3C
OTBSTHPO
O
PMe2N NMe2Cl1.
93%
2. Li, MeNH2, t-BuOH
92%
CH3
HH3C
CH3
OOH
CH3
HH3C
CH3
OOH
O
HO
O2, hν, Rose BengalDIEA, CH2Cl2, –78 °C, 88%
Miyaoka, H.; Kajiwara, Y.; Hara, Y.; Yamada, Y. J. Org. Chem. 2001, 66, 1429-1435.
Total Synthesis of Anhydrolycorinone Utilizing Sequential Intramolecular Diels-Alder Reactions of a 1,3,4-Oxadiazole
O
O
N
O
MeO
N
NO
COOMe
O
O
HN
MeO
N
NO
COOMe
COOH
+EDC, DMAP
72%
NH
NH
HNMeOOC
O
OHN
N
NO
COOMe
NH
NH2
HNMeOOC
OO
NN 64%
TsCl, Et3N
86%
(a) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292-11294. (b) Wolkenberg, S. E.; Boger, D. L. J. Org. Chem. 2002, 67, 7361-7364.
Total Synthesis of Anhydrolycorinone Utilizing Sequential Intramolecular Diels-Alder Reactions of a 1,3,4-Oxadiazole
triisopropylbenzene
230 °C
O
O
N
O
MeO
N
NO
COOMe
O
O
MeO
N
O
N
N
COOMe
O
O
O
MeO
N
O
COOMe
O
O
O
N
O
COOMe
O
O
O
N
O
O
COOMe
O
O
N
O
COOMe
O
O
N
O
72 %
anhydrolycorin-7-one
– MeOH
– H2O
(a) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292-11294. (b) Wolkenberg, S. E.; Boger, D. L. J. Org. Chem. 2002, 67, 7361-7364.
Total Synthesis of (±)-Stenine Using the IMDA Cycloaddition of a 2-Methylthio-5-amido-substituted Furan
N
OAc
MeS
SMe
O
O
COOMe
N
O
MeS
O
COOMe
N
HO
O
MeOOC
MeS
Me
SMeS Me
BF4
MeCN, –40 °C
N
H
O
O
HH
H
H
Me
Me
O
(±)-Stenine
NTMS
O
80% N
H
O
MeOOC
H H
Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515.
Padwa, A.; Ginn, J. D. J. Org. Chem. 2005, asap.
Total Synthesis of (±)-Batrachotoxinin A
Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627-6628.
O
S
S
OH
H3C
HTBSO
OTBS
H3C
O
O H3C
HTBSO
OTBS
O OH3C
HTBSO
OTBS(±)-Wieland-Miescher
Ketone
1. HCOOEt, NaH2. n-BuSH, TsOH
3. Me3SI, NaHMDS4. HgCl2, Et2O
OH3C
HTBSO
OTBS
Total Synthesis of (±)-Batrachotoxinin A
O
S
S
OH
H3C
HTBSO
OTBS
O
S
S
CHO
H3C
HTBSO
OTBS
MnO2
CH2Cl2
H3C
HTBSO
OTBS
S
SCHO
O
H3C
HTBSO
OTBS
S
SO
NTBSO
Ac
H3C
HHO
N
O
HO
O
OHH3C
H3C
(±)-Batrachotoxinin A
H3C
HMeO
O
NO
O
MOMO
O
Ac
�
70-75%
Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627-6628.
Enantiospecific Synthesis of the ProposedStructure of Diterpenoid Pseudopteroxazole
Pb(OAc)4
EtOAcNH
OH
Me
O
Me
MeN
O
Me
O
Me
MeNH
OH
Me
O
Me
Me
HNH2
OBn
Me
OH
Me
Me
H
OBn
Me
CHO
Me
Me
H
OBn
Me
Me
Me
H
OBn
Me
Me
Me
HMe
Me
Me
H
NO
1. NaNO2, HCl NaCNBH32. DMP
PPh
PhMsOH
69%
separation
Johnson, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 4475-4479.
Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486-13489.
Me
Me
Me
H
NO
Biomimetic Synthesis of (±)-Pinnatal and (±)-Sterekunthal A
Malerich, J. P.; Trauner, D. J. Am. Chem. Soc. 2003, 125, 9554-9555.
Me
O Me
OTHP
OOH
O
HOO
O
O
HO Me
OTHP
O
O
O
HO Me
OTHP
MeO
O
O
HO Me
CHO
Me
O
O
HOO
Me
Me CHOH
H
O
O
HO
O
Me
Me CHO
23 °C
neat91%
160 °C
benzene92%
(±)-Pinnatal (±)-Sterekunthal A
β-alanine, AcOHbenzene, 90°C, 54%
Total Synthesis of (+)-Elisabethin A
OTBS
OMe
Me
TBSO
Me
Me Me
Me
CHO
OMe
Me
MeO
OTBS
OMe
Me
TBSO
BrOTBS
OMe
Me
TBSO
COOEt
OTBS
OMe
Me
TBSO
N O
OO
BnOTBS
OMe
Me
TBSO
OHC
Me
Me
SnBu3EtOOC
ZnBr2, PdCl2(o-tol3P)2DMF, 80 °C, 71%
Me
Me
PPh3
95% !!!
Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003, 125, 4680-4681.
Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003, 125, 9538 (addition correction).
Total Synthesis of (+)-Elisabethin A
OTBS
OMe
Me
TBSO
Me
Me Me O
OMe
Me
O
Me
Me
Me
Me1. TBAF
2. FeCl3
O
OMe
Me
O
H
Me
Me H
Me Me
91%
O
OH
Me
O
H
Me
Me H
Me Me
(+)-Elisabethin A
exo transition state
Me
Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003, 125, 4680-4681.
Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003, 125, 9538 (addition correction).
Biomimetic Synthesis of (–)-Longithorone A
Me
MeO OTBS
O
H
Me
MeO OTBS
TBSO
TBSOH
OMe
TBSO
Me
OTBS
OTBS
OTBSI
1. tBuLi, then ZnBr2
2. nBuLi,
91%, 95% ee
3. TBS-Cl
+
0.5 eqiv. Grubbs I
CH2CH2, DCM, 31%
OMe
TBSO
Me
OHC
TIPSMe
NMe2
Ph
HO
1. TFA, Et3SiH2. PPTS, 46%
3. DMP, 99%
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 125, 773-775.
Biomimetic Synthesis of (–)-Longithorone A
Me
MeO OTBS
O
H
OMeTBSO
Me
MeOMeTBSO
Me
Me
Me
MeO OTBS
OHC
H
+Me2AlCl, DCM, –20 °C
70%, 1:1.4
OO
Me
Me
Me
O O
OHC
H
OO
Me
Me
O OMe
H
H
OHC
1. TBAF2. PhIO, 90%
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 125, 773-774.
Conclusions
• Many intramolecular Diels–Alder reactions can be initiated by simple activation
• Seek the intramolecular Diels–Alder reaction in your natural product synthesis even though it might not be obvious!
• It is difficult to imagine that Nature would not take advantage of IMDA.
