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Pentafulvene for the Synthesis of Complex Natural Products: Total Syntheses of (±)-
Pallambins A and B
Christian Ebner, Erick M. CarreiraAngew. Chem. Int. Ed. 2015, 54, pp–pp
Laboratorium für Organische ChemieETH Zürich, HCl H335
DOI: 10.1002/anie.201505126
Samuel Rieder, 13th Aug 2015
HH4π+2π
O Me
OH
Me
OO
HH
Me
Me
pallambin AO Me
OH
Me
OO
HH
Me
pallambin B
Me
Erick M. CarreiraBiography
2
- 1963: Born in Havana, Cuba- 1984: B.S. degree, University of Illinois, Scott Denmark- 1990: PhD degree, Harvard University, David A. Evans- 1992: Post-Doc, California Institute of Technology, Peter
Dervan- 1993: Assistant Professor, California Institute of
Technology- 1996: Associate Professor, California Institute of
Technology- 1997: Full Professor, California Institute of Technology- 1998: ETH Zurich
Research Interest- Asymmetric synthesis of biologically active, stereochemically complex,
natural products- Unique challenges in asymmetric bond construction- Developing catalytic and stoichiometric reagents for asymmetric
stereocontrolhttp://www.carreira.ethz.ch/people/emc
(±)-Pallambin A and BGeneral Information
3
- Isolated from liverwort Pallavicinia ambigua- Cyclopropane containing diterpenoid (C19)- Unprecedented and highly congested
tetracyclo[4.4.03,5.02,8]decane core- Ten contiguous stereocenters, two quaternary
O Me
OH
Me
OO
HH
Me
Me
pallambin A
O Me
OH
Me
OO
HH
Me
pallambin B
Me
FulveneRule of Fulvene; Synthetic Strategy
4
HH
1956first preparation
"trapped with maleic anhydride"no yield reported
no structural characterization
this work pallambin A+
pallambin Bfirst use of pentafulvene
in complex synthesis
X
R1
R2prior work
X
R1R2sp3 hybridized
strategicallyrestricted
H
Hthis work
X
sp2 hybridizedstrategically flexibleelaboration:oxidationreductioncarbometallation
J. Thiec, J. Wiemann, Bull. Soc. Chim. Fr. 1956, 177–180
Total Synthesis from FulveneRetrosynthesis
5
O Me
OH
Me
OO
HH
Me
Me
O Me
HOH
Me
Me
OHAlkoxy-
carbonylation
O Me
MeO C–H insertion
O Me
MeO
N2
CO2Me
HH4π+2π
- Pentafulvene not susceptible to isomerisation (≠ cyclopentadiene)- sp2 bridge carbon atom à wide variety of transformations
Synthesis IDiels-Alder; Early Installation of Cyclopropane
6
- Starting from fulvene- Known to undergo facile light- or heat-induced polymerization- Acid- and base-sensitive- Stable in neat form only below –70 °C
B. M. Trost, R. M. Cory, J. Org. Chem. 1972, 37 (8), 1106–1110S. E. Denmark, J. P. Edwards, J. Org. Chem. 1991, 56, 6974–6981
NMe2 1. LiAlH4 (1 equiv.) Et2O, –17°C, 88%
2. MeI (1 equiv.) methyl acrylate, 0 °C then Et2AlCl (0.3 equiv.) –20 - 5 °C, 62% (d.r. 10:1)
CO2Me
CO2Me
1. ZnEt2 (2 equiv.) ClCH2I (4 equiv.) CH2Cl2, 0 °C, 85% (d.r. > 20:1)
2. [RhCl(PPh3)3] (4 mol%) H2 (1 atm) CH2Cl2, rt, 96% (d.r. > 20:1) CO2Me
MeH
- Established cyclopropanation-protocols à low conversion, poor chemoselectivity
Synthesis IICarbene Precursor
7D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156
CO2Me
MeH LDA (2 equiv.)THF, –78 °C
then: P(OEt)3 (1 equiv.)DMPU (1 equiv.)O2 (bubbling), –90 °C 85% (d.r. 10:1)
CO2Me
MeH
HO
MeH
O Me
LDA (2.5 equiv.)THF, –78 - 0 °C
then: MeI (18 equiv.)then: NEt3 (18 equiv.)89% (d.r. 5:1)
1. TBSOTf (1.03 equiv.) NEt3 (1.5 equiv.) CH2Cl2, 0 °C
2. MeCHO (10 equiv.) BF3•Et2O (2 equiv.) CH2Cl2, –90 °C, 3x recycl.3. DMP (2 equiv.) tBuOH (2 equiv.) CH2Cl2, 0 °C, 70% (3 steps)
Me
O Me
O
Me
- Intermediate β-hydroxy ketone unstable à Retro aldol (DM oxidation, LA nature)
- DMP/tBuOH à increase rate of oxidation
1. LiAlH4 (0.7 equiv.) Et2O, 0 °C
2. NaIO4 (1.5 equiv.) THF/phosphate buffer (1:1) 0 °C, 97% (2 steps)
MeH
O
Synthesis IIIC-H Insertion
8R. L. Danheiser, R. F. Miller, R. G. Brisbois, S. Z. Park, J. Org. Chem. 1990, 55, 1959–1964T. J. Maimone, J. Shi, S. Ashida, Phil S. Baran J. Am. Chem. Soc., 2009, 131 (47), 17066–17067
[Rh2(OAc)4] (1 mol%)
CH2Cl2, reflux, 76%
Me
O Me
O
Me
O Me
O
Me LiHMDS (1.15 equiv.)THF, –78 °C
then: F3CCH2O2CCF3 (1.3 equiv.)NEt3 (1.5 equiv.)MsN3 (1.5 equiv.)MeCN, rt
Me
O Me
O
N2
Me
O Me
O
LDA (1.5 equiv.)then: PhNTf2 (2 equiv.)
THF, –78 - 5 °C, 64%
Me
O Me
TfO
[Pd(PPh3)4] (5 mol%)ZnMe2 (5 equiv.)
THF, 0 °C - rt, quant.
Me
O Me
Me
Me
O Me
Me
Br2CNOH (2.5 equiv.)KHCO3 (5 equiv.)
EtOAc, rt, 91%
Me
O Me
NOMe
HBr
LiOMe (20 equiv.)
MeOH, reflux, 94%
Me
O Me
NOMe
HOMe
Synthesis IV
9S. Kim, K. H. Ahn, J. Org. Chem. 1984, 49, 1717–1724
Me
O Me
NOMe
HOMe B(OH)3 (6 equiv.)
Ra-Ni (1 equiv.)H2 (1 atm)
MeOH (aq.) (5:1), rt, 91%
Me
O Me
OHO
Me
HOMe
Me
O Me
OHO
Me
HOMe
1. DIBAl-H (3 equiv.) nBuLi (3 equiv.) THF, 0 °C then: ester THF, –60 - 0 °C, 89%
2. (COCl)2 (1.6 equiv.) DMSO (2.7 equiv.) NEt3 (5 equiv.) CH2Cl2, –78 - 0 °C, quant.
Me
O Me
OHO
Me
HH
- DIBAl-H and nBuLi à non-Lewis-acidic Li(iBu)2(nBu)AlH
Synthesis VIntroduction of the Tetrahydrofuran and the γ-Lactone
10M. F. Semmelhack, C. Bodurow, M. Baum, Tetrahedron Lett. 1984, 25, 3171–3174Z. Li, Y. Gao, Z. Jiao, N. Wu, D. Z. Wang, Z. Yang, Org. Lett. 2008, 10, 5163–5166
- Separation of diastereoisomers unsuccessful à mixture used
Me
O Me
OHO
Me
HH vinylmagnesium bromide (3 equiv.)
CeCl3 (3 equiv.)THF, –78 °C
then: aldehyde–78 °C - rt, 90% (d.r. 6:4)
Me
O Me
HOMe
HOH
Me
O Me
HOMe
HOH
Pd(OAc)2 (10 mol%)TMTU (10 mol%)NH4OAc (10 mol%)CuCl2 (2.5 equiv.)propylene oxide (5 equiv.)CO (1 atm)
THF, 50 °C, 26%, 55%
O Me
OH
Me
OO
HH
Me
O Me
OH
Me
OO
HH
Me+
Synthesis VISynthesis of Pallambin A and B
11
O Me
OH
Me
OO
HH
Me
1. LDA (1.4 equiv.) THF, –78 °C then: MeCHO (5.7 equiv.) THF, –78 - –40 °C
2. NEt3 (15 equiv.) DMAP (cat.) MsCl (5 equiv.) CH2Cl2, rt, 11%, 87%
O Me
OH
Me
OO
HH
Me
Me
pallambin AO Me
OH
Me
OO
HH
Me
pallambin B
Me+
- Generation of the β-phosphonate (for HWE) failed- Two-step aldol condensation
Conclusion
12
- First total syntheses of pallambins A and B (3.3% overall yield, 20 steps) - Synthetic strategy centered around use of fulvene in a DA reaction- Highly chemo- and diastereoselective cyclopropanation
- Efforts to expand use of the fulvene DA reaction are ongoing
Thank you for your attention
[1,5]-shift of Substituted Cyclopentadienes
13
R H [1,5] R
HH
[1,5]R
H H
[1,5]etc.
Preparation of Pentafulvene
14
NMe2LiAlH4
NMe2HAl
4
LiH2O NMe2H
NMe2HMeI
NMe3.IH Hofmannelimination
HH
Wilkinson’s Catalyst [RhCl(PPh3)3]
15
Hydroxylation with O2, P(OEt)3
16
R1
OR3
R2
Base
R1
OR3
R2
O2R1
OR3
R2O O
R1
OR3
R2
R1
OR3
R2
R1
OR3
R2O OH
P(OEt)3
R1
OR3
R2OH
DMPU, P(OEt)3, O2
Carbene, C–H insertionMechanism not well Understood, Source of Dispute
17H. M. L. Davies, T. Hansen, M. R. Churchill, J. Am. Chem. Soc. 2000, 122, 3063D. F. Taber, K. K. You, A. L. Rheingold, J. Am. Chem. Soc. 1996, 118, 547
Carbene, C–H insertionMechanism not well Understood, Source of Dispute
18Z. Li, Y. Gao, Z. Jiao, N. Wu, D. Z. Wang, Z. Yang, Org. Lett. 2008, 10, 5163–5166
OH
R
OHH
OH
R
OHH PdX2Ln
PdX2O
O PdLnH
R
O
O PdLn
O
H
RO
OO
R
H
H
CO
co-oxidant
reducedco-oxidant
base
–HX
Biosynthesis
19L.-N. Wang, J.-Z. Zhang, X. Li, X.-N. Wang, C.-F. Xie, J.-C. Zhou, H.-X. Lou, Org. Lett. 2012, 14, 1102–1105
OO
O
O
OHMe
HMe
HH
OR
R
OHMeMe
OHMeMe
OHMeMe