Sébastien Goudreau
38
1 Sébastien Goudreau Literature meeting : 24-01-2006 Total synthesis of Total synthesis of crambescidin 800, crambescidin 800, crambescidin 359, crambescidin 359, 13,14,15-isocrambescidin 13,14,15-isocrambescidin 800 and crambidine. 800 and crambidine. N N H H N H H O O Cl - cram bescidin 359 N N H H O N H O H Cl - O O N O 14 NH 3 + Cl - NH 3 + Cl - OH 13,14,15-isocram bescidin 800 N N H H O N O O O Cl - N OH NH 3 + Cl - NH 3 + Cl - cram bidin 14 OH N N H H O N H O H O O O Cl - N OH NH 3 + Cl - NH 3 + Cl - cram bescidin 800 14
description
Total synthesis of crambescidin 800, crambescidin 359, 13,14,15-isocrambescidin 800 and crambidine. Sébastien Goudreau. Literature meeting : 24-01-2006. Natural compound. Members of the crambescidin family. - PowerPoint PPT Presentation
Transcript of Sébastien Goudreau
1
Sébastien Goudreau
Literature meeting : 24-01-2006
Total synthesis of Total synthesis of crambescidin 800, crambescidin 800, crambescidin 359, crambescidin 359,
13,14,15-isocrambescidin 13,14,15-isocrambescidin 800 and crambidine.800 and crambidine.
N
NH
H
NH
H
O OCl-
crambescidin 359
N
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
N
NH
HO
N
O
O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambidin
14
OH
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
2
Natural compoundNatural compound
N
NH
H
NH
H
O OCl-
crambescidin 359
N
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
N
NH
HO
N
O
O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambidin
14
OH
• Members of the crambescidin family.
• Contain structurally unique pentacyclic guanidinium moieties having two distinctive spiroaminal units.
• Cytotoxicity toward several cancer cell lines, antifungal activity, antiviral activities toward herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus (HIV), inhibition of HIV-1 envelope-mediated cell fusion, induction of differentiation of chronic mylogenous leukemia cells and inhibition of the binding of various proteins to HIV-1 Nef.
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
3
OverviewOverview
N
NH
H
NH
H
O OCl-
crambescidin 359
N
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
N
NH
HO
NH
OH
O O
O
Cl-
N NH3+Cl-
NH3+Cl-
ptilomycalin A
14
Isolation : 1989
Isolation : 1991
Isolation : 1993
Isolation : 2000
Total synthesis : Overman, JACS 1995
Total synthesis : Overman JACS 1999Overman JACS 2000
Total synthesis : Overman JACS 2000
Total synthesis : Nagasawa Org. Lett. 2002
Murphy Tet. Lett. 2003
Model studies : Snider JOC 1992, Overman JOC 1993, Snider JACS 1994, Murphy JCS Chem. Comm. 1994, Weinreb JOC 1996
N
NH
HO
N
O
O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambidin
14
OH
Isolation : 1993Total synthesis : Overman JACS 2005
4
Crambescidin 800 SynthesisCrambescidin 800 Synthesis
Coffey, D. S.; McDonald, A. I.; Overman, L.E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc. 2000, 122, 4893-4903.
• Isolated from Crambe crambe, a bright red conspicuous species of sponge found at the shallow depths along the rocky coast of the Mediterranean.
• First and only total synthesis : Overman’s group.
• 3% overall yield, 16 isolated and purified intermediates.
• Synthesis of the guanidinium unit : Snider, Murphy, Nagasawa.
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.; Hashimoto, Y. Org. Lett. 2002, 4, 177-180.
Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett. 2003, 44, 251-254.
Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 549-557.
5
Crambescidin 359 SynthesisCrambescidin 359 Synthesis
Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.; Hashimoto, Y. Org. Lett. 2002, 4, 177-180.
Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett. 2003, 44, 251-254.
N
NH
H
NH
H
O OCl-
crambescidin 359
• Isolated from the marine sponge of the genus Monanchora.
• First total synthesis : Nagasawa’s group.
• Other synthesis : Murphy’s group.
Braekman, J. C.; Daloze, D.; Tavares, R.; Hajdu, E.; Van Soest, R. W. M. J. Nat. Prod. 2000, 63, 193.
6
Nagasawa’s retrosynthesisNagasawa’s retrosynthesis
7
Nagasawa’s synthesisNagasawa’s synthesis N
NH
H
NH
H
O OCl-
crambescidin 359
8
Nagasawa’s synthesisNagasawa’s synthesis N
NH
H
NH
H
O OCl-
crambescidin 359
(7:1 ds)
9
Nagasawa’s synthesisNagasawa’s synthesis N
NH
H
NH
H
O OCl-
crambescidin 359
10
Biomimetic approachBiomimetic approach
Moore, C. G. M.; Murphy, P. J.; Williams, H. L.; McGown, A. T.; Smith, N. K. Tetrahedron Lett. 2003, 44, 251-254.Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 549-557.
11
Snider’s SynthesisSnider’s Synthesis
Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 549-557.
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
TBDMSOH
TBDMSO
OH
TBDMSO
O
TBDMSO
OH
TBDMSOOH
TBDMSOOTBDS HO
OTBDS OOTBDS
OTBDS
TBDMSOH
OH
OTBDMS
OTBDSOH
OH
OTBDSO
O
O
BuLi
94%
Swern [ox]
91%
9-BBN
-pinene
95%, 93% ee
H2
Lindlar cat.TBDPSCl
DMAP, Et3N
98%
93%
TsOH
EtOH90%
Swern [ox]
BuLi
LAH
92% (2steps)
Swern [ox]
85% 96%
12
Snider’s SynthesisSnider’s Synthesis
Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 549-557.
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
Knoevanagel Condensation
OH
OEt
O TBDPSO
OEt
O TBDPSO
OH
TBDPSO
I
TBDPSOO
OMe
OO
OMe
OOTBDS
O
O
OO
OR
Me Me
MeO2C
1:1
TBDPSCl
imidazole95%
DIBAL-H
66%
i) TsCl, pyridine
ii) NaI, acetone
LDA (2 equiv)
91%
66%
NH
64%
Jones, G. Org. React. 1967, 15, 204.
13
Snider’s SynthesisSnider’s Synthesis
Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 549-557.
4:1
1:1
1.3:1
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
1:1
14
Overman’s RetrosynthesisOverman’s Retrosynthesis
Biginelli Condensation
15
Synthesis of the IodideSynthesis of the Iodide
OTIPS
I
95%
H
OH
TfOH H
O
O
O
Oi) n-BuLi, THF, -40°C
ii) DMF, -40°C to rt
OPMBO
OPMB
OH
OPMB
OTIPS
TIPS-OTf
2,6-lutidineCH2Cl2
90% (2 steps)
OTIPS
OPMB
H2, Pd/CaCO3/PdO
quinoline, hexane
OTIPS
OH
DDQ
CH2Cl2, H2O
95% (3 steps)
PPh3, I2, imidazole
Et2O, MeCN
Cl3C
NH
Et2O, 0°C
Et2Zn, Ti(Oi-Pr)4
(-)-TADDOL (20 mol%)
Et2O, -30°C
94%, >98% ee
Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473-7484.
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
16
Synthesis of the Weinreb AmideSynthesis of the Weinreb Amide
Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227-4230.
Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350.
OTES
NMe
OMeO
OH
NMe
OMeO
OHO
MeO
OO
MeO
O
O
MeO OMe
NaH H2, MeOH
NH2+Cl-
MeO
Me
Me3Al
TES-Cl
BINAP RuCl2
i-PrNEt2
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
17
Synthesis of the UreaSynthesis of the Urea
OTIPS
I
95%
OTES
NMe
OMeO
OTESOOTIPS
i) t-BuLi, Et2O
OHOTIPS
OO NOTIPS
OO
NN
NH2
OTIPS
OO HNOTIPS
OONH2
O
ii)
60-70%
O OOMeH HO(CH2)3OH
MeCN, Amberlyst-15
80%
HN3, Ph3P
DEAD, THF88%
LiAlH4, Et2O
88% 89%
TMSNCO
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
18
Synthesis of the Synthesis of the -Ketoester-Ketoester
Taber, D. F.; Amedio, J. C., Jr.; Patel, Y. K. J. Org. Chem. 1985, 50, 3618.
O
O
OTBDMS
O
O
14
O
O
O
OTBDMS
O
O
14OHO
O
O O
I
OTBDMS
NaH, BuLi
DMAP
73%88%
Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc. 1995, 117, 2657-2658.
I
OTBDMS
MeO
OHO
Kitumura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth., Coll. Vol. 9 1998, 589-595.
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
19
Synthesis of the pyrolidine unitSynthesis of the pyrolidine unit
Note : Knoevenagel conditions : MeOH, piperidine and acetic acid.
Jones, G. Org. React. 1967, 15, 204.
OTIPS
OON
OH
NO
NH2
OTIPS
OON
OH
O
NH
OH
HNOTIPS
OONH2
O
OH
OHHNOTIPS
OONH2
O OsO4 (2mol%)NMO
THF, H2O
Pd(OAc)4
NH2
+
O
AcO-
Toluene
(a complex mixture)
CF3CH2OH, 60°C
61% (3 steps)
ds = 7:1
OTBDMS
O
O
14
O
O
OTBDMS
O
O
14
O
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
20
Biginelli CondensationBiginelli Condensation
O H
Ph
EtO2C
OMe H2N O
NH2
NH
NH
O
EtO2CPh
H+
Pietro Biginelli, 1893
Kappe, C. O. Tetrahedron 1993, 49, 6937-6963.
dihydropyrimidinone
Kappe, C. O. J. Org. Chem. 1997, 62, 7201-7204.
N-acyliminium
21
Biginelli CondensationBiginelli Condensation
McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999, 64, 1520-1528
trans cis
late transition state
Weakly electron-withdrawingamidine group
16 = Ethyl acetoacetate
EtO2C
OMe
22
SynthesisSynthesis
Spiroaminal center : stereoelectronic effect.
Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon: London, 1983; Chapter 1.
Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1993, 58, 3235-3237.
(1 product)
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
TBAF, DMF
TsOH, CHCl3
71% (2 steps)
N
O
O
NH
OH
O
O
O
14
60°C, 15 minH
OOH
OTIPS
OON
OH
O
NH
OH
OTBDMS
O
O
14
OH
OON
OH
O
NH
OH
OH
O
O
14
23
Kinetic protonationKinetic protonation
Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1993, 58, 3235-3237.
Coffey, D. S.; McDonald, A. I.; Overman, L.E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc. 2000, 122, 4893-4903.
Coffey, D. S.; Overman, L. E.; Stappenbeck, F. J. Am. Chem. Soc. 2000, 122, 4904-4914.
Kinetic protonation
TsOH, CHCl3 N
O
O
NH
OH
O
O
O
14
60°C, 15 minH
OOHOH
OON
OH
O
NH
OH
OH
O
O
14
24
SynthesisSynthesis
N
O
O
NH
OH
O
O
O
14H
OO
ClH2C O
Cl
O
CH2Cl
pyridine
86%
N
MeO
OR
N
OH
O
H
O
Nt-Bu t-Bu
MeOTf, rt
N
NH
HO
NH
OH
Cl-O O
O
O
14 N
NH
HO
NH
OH
O O
O
O
+
Cl-(dr = 1.5:1)
NH3, NH4Cl
AllOH, 60°C81% (2 steps)
NH3, NH4Cl, AllOH, 60°C52% after 2 recycles
N
O
O
NH
OH
O
O
O
14H
OOH
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
25
Synthesis of Spermidin unitSynthesis of Spermidin unit
HN
OH
NHBocNHBoc
BnN
OH
NHBocNHBoc
H2, Pd/C
MeOH
99%
BnN
OH
NHBocNH2
LAH Boc2O
91% (2 steps)
BnN
OHC
NHBoc
N
BocHN NHBn
ClO
(97% ee)
(neat)
n-Bu4NCNtoluene, 70°C
80%, >95% ee
Coffey, D. S.; McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999, 64, 8741-8742.
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
26
Synthesis of Crambescidin 800Synthesis of Crambescidin 800
N
NH
HO
NH
OH
O O
OH
O
Cl-
(Ph3P)4Pd
NH
O
MeCN
94%
HN
OH
NHBocNHBoc
BOP reagentEt3N, CH2Cl2
N
NH
HO
NH
OH
O O
O
Cl-
94%
N
OH
NHBocNHBoc
N
NH
HO
NH
OH
O O
O
Cl-
75%
N
OH
NH3+Cl-
NH3+Cl-
3 M HCl, EtOAc
crambescidin 800
N
NH
HO
NH
OH
O O
O
O
Cl-
27
13,14,15-isocrambescidin 800 Synthesis13,14,15-isocrambescidin 800 Synthesis
Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Stappenbeck, F. J. Am. Chem. Soc. 1999, 121, 6944-6945.
Coffey, D. S.; Overman, L. E.; Stappenbeck, F. J. Am. Chem. Soc. 2000, 122, 4904-4914.
N
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
• Isolated from Crambe crambe, a bright red marine sponge that is the most widespread species of littoral sponge found in the Northwestern Mediterranean.
• First and only total synthesis : Overman’s group.
• 3% overall yield, 14 isolated and purified intermediates.
28
RetrosynthesisRetrosynthesis
Biginelli Condensation
29
SynthesisSynthesisN
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
NH2
OTIPS
OO HNOTIPS
OONH2
NH2+Cl-
88%
NN
NH2+Cl-H2N
(i-Pr)2EtN, DMF99%
OTIPS
OON
-Cl+H2NH
NO
NH2
OTIPS
OON
-Cl+H2NH
O
NH
OH
HNOTIPS
OONH2
NH2+Cl-
OH
OH
OsO4 (2mol%)NMO
THF, H2O
Pd(OAc)4
NH2
+
O
AcO-
Toluene
(a complex mixture)
CF3CH2OH, 60°C
49% (3 steps)
ds = 7:1
TBAF, DMF
80%
OTBDMS
O
O
14
O
O
OTBDMS
O
O
14
O
OH
OON
-Cl+H2NH
O
NH
OH
OH
O
O
14
30
Biginelli CondensationBiginelli Condensation
McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999, 64, 1520-1528
trans cis
late transition state
Weakly electron-withdrawingamidine group
16 = Ethyl acetoacetate
EtO2C
OMe
31
Formation of the pentacycleFormation of the pentacycleN
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
• Spiroaminal center : stereoelectronic effect.
• Steric interactions between the ester and the tetrahydropyran ring in the major compound.
HCl, EtOAc
78%
N
NH
HO
NH
OH
Cl-O O
O
O
14
80%
OH
OON
-Cl+H2NH
O
NH
OH
OH
O
O
14
N
NH
HO
NH
OH
Cl-O O
O
O
14
+HCl ( 3 equiv)
EtOAc, rt
8-9:1
major
minor
32
SynthesisSynthesisN
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
N
NH
HO
NH
OH
Cl-O O
OH
O
14
(Ph3P)4Pd
NH
O
MeCNEt3N, MeOH
60°C
N
NH
HO
NH
OH
Cl-O O
O
O
14
N
NH
HO
NH
OH
Cl-O O
OH
O
14
60% (2 steps)
N
NH
HO
NH
OH
Cl-O O
OH
O
14 N
NH
HO
NH
OH
Cl-O
OH
O
14
HO
10-14:1:1
33
SynthesisSynthesis
13,14,15-isocrambescidin 800
N
NH
HO
NH
OH
Cl-O O
OH
O
14
HN
OH
NHBocNHBoc
BOP reagentEt3N, CH2Cl2
N
NH
HO
NH
OH
Cl-O O
N
O
14
71%
NHBocNHBoc
OH
N
NH
HO
NH
OH
Cl-O O
N
O
14
70%
NH2+Cl-
NH2+Cl-
OH
2M HCl
34
Crambidin SynthesisCrambidin Synthesis
Overman, L.E.; Rhee, Y. H. J. Am. Chem. Soc. 2005, 127, 15652-15658.
• Isolated from Crambe crambe, a bright red marine sponge.
• First and only total synthesis : Overman’s group.
35
Crambidine RetrosynthesisCrambidine Retrosynthesis
36
Crambidine SynthesisCrambidine Synthesis
37
Crambidine SynthesisCrambidine Synthesis
38
ConclusionConclusion
N
NH
H
NH
H
O OCl-
crambescidin 359
N
NH
HO
NH
OH
Cl-O O
N
O
14NH3
+Cl-
NH3+Cl-
OH
13,14,15-isocrambescidin 800
N
NH
HO
N
O
O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambidin
14
OH
N
NH
HO
NH
OH
O O
O
Cl-
N
OH
NH3+Cl-
NH3+Cl-
crambescidin 800
14
