Highlights in the Progress of Biomimetic Strategies for the Construction of Complex Natural Products
Chris Galliford 26th August 2003 The Biomimetic Approach
Inspiration for biomimetic synthesis of a target compound generally comes from the biosynthetic pathway for that compound.
Rapid generation of molecular complexity and challenging stereochemical environments are often created in a single stereogenic event.
The symmetry or pseudo-symmetry of readily accessible starting materials is often exploited.
An early example of this approach is Robinson’s 1917 biomimetic synthesis of tropinone. Tropinone - Setting the Stage
H3C O O N H H HO2C CO2H O CH NH 3 2 O
tropinone
HCl -2CO2
H3C H3C CO2H N N CO H 2 CO H OH 2 N CH3 OH CO2H OH HO2C CO2H O
Robinson, R. J. Chem. Soc., 1917, 762 Carpanone
CH 3 A lignan obtained from the bark of the carpano tree. H3C
H Possesses no element of symmetry and has five O O contiguous stereogenic centers. H
O O O O
(±)-carpanone
Chapman and co-workers had developed the reaction of o-quinone methide with electron-rich olefins:
OCH3 H3CO OCH3 O O OCH3
Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C., J. Am. Chem. Soc., 1971, 93, 24, 6696 Carpanone - Retrosynthesis
CH3 CH3
H3C H3C H O O O O H O O O O O O O O
C-C bond rotation
O O CH3 CH3 H3C
O O O
O OH O O C2 symmetric Carpanone - Generation of the o-Quinone Methide Precursors
CH3 CH3 H3C O O O O O O OH O Pd O
o-quinone methide generated by Pd- mediated oxidative phenolic coupling
CH 3 Carpanone formed only from H C H 3 conformation shown H H O H3C CH3 O O O
O O O O O O O O Carpanone - Synthesis
CH3 CH3
H3C O O tBuOK PdCl2 O O NaOAc O OH DMSO O OH MeOH/H2O O O O O
[4+2]
CH3
H3C
H O O H
O O O O
(±)-carpanone
48% Panepophenanthrin
OH Recently discovered inhibitor of the ubiquitin-proteosome H3C pathway (UPP). CH3
H3C Panepophenanthrin is the first example of a Ubiquitin- H C activating enzyme (E1) inhibitor. 3 O OH
H O o H OH OH O
Panepophenanthrin
Racemic synthesis: Baldwin, J.; Moses, J. E.; Commeiras, L.; Adlington, R. M. Org. Lett., 2003, 5, 17, 2987
Asymmetric synthesis: Porco, J. A.; Lei, X.; Johnson, R. P. Angew. Chem., Intl. Ed. Eng., 2003, 42, 3913 Panepophenanthrin - Retrosynthesis
OH OH H3C H3C CH3 CH3
H3C H3C H C H3C 3 O O OH OH [4+2] H O O o o H OH OH OH OH O O
O CH3 O OH Pd-mediated coupling reaction Br CH3 O O
OH OH Panepophenanthrin - Racemic
Synthesis by Baldwin andH C OH Co-workers 3 CH3 O O O CH3 OH Br Br Bu3Sn TESCl, CH3 O imidazole rt O Pd (dba) , AsPh O 94% 2 3 3 toluene, reflux 75% OH OTES OTES
one pot
OH OH H3C H3C CH3 CH3
H3C H3C H C H C 3 O 3 O OH OH TBAF, MeOH 85% H O H O O O H H OH OTES OH OTES O O Panepophenanthrin - Asymmetric Synthesis by Porco
PPh3, DIAD, O O 4-nitrobenzoic acid, O O O O Br Br -50 to 0 oC, 1 h Br TBSCl, imidazole, O O O DMF, rt NaOMe (1M), MeOH rt, 0.5 h OH OH 80% OTBS
85% H3C OH CH3
Bu3Sn
Pd(OAc)2, DMF 90 oC OH 75% H3C CH3
H3C H3C CH3 O O HO OH 10 % HF, CH3CN/ CH2Cl2, rt H3C O H O O 40% H OTBS OH OH O Torreyanic Acid
Isolated as part of a program to explore the biosynthetic CO2H H3C potential of endophytic fungi. O O H3C O O Fungi residing in Florida torreya, (Torreya taxilofica), an endangered species of tree, closely related to the taxol- CH3 producing Pacific yew. O O O H O CO2H The endophyte Pestalotiopsis microspora was identified H and cultured. Several phytotoxic and antifungal secondary metabolites were isolated from this fungus, including Torreyanic acid 1.
CH Dimeric quinone structure with selective cytotoxicity 3 agaist human cancer cell lines.
Lee, J. C.; Strobel, G.A.; Lobhovsky, E.; Clardy, J. J. Org. Chem., 1996, 61, 3232 Li, C.; Johnson, R. P.; Porco Jr, J. A. J. Am. Chem. Soc., 2003, 125, 5095 Proposed Biosynthetic Pathway
O O CO2H H3C R O O H3C O O O O O CH3 O O O O O CO H O H 2 H R O H3C
H3C
CH3
R= CO H Proposed biosynthesis via oxidative dimerization 2 of monomeric precursors. CH 3 oxaelectrocyclization/Diels-Alder cascade already demonstrated in an earlier racemic synthesis by the same authors. Retrosynthetic Analysis
CO2R H3C O O O O H3C O R O
CH3 O O O O O O O H O CO2R H O R
R= H3C O CO2H H3C CH3 CH3
O H O
O O O O R R O O
H3C H3C Retrosynthetic Analysis
H O O O
O HO TBDPSO O O O
C5H11 R C5H11 R C5H11 R O O O
OCH 3 RO OR RO OR
TBDPSO TBDPSO TBDPSO
Br Br Br O O O Model Studies
O H O O
HO O O O DMP O O C H C5H11 C5H11 5 11 CH2Cl2 rt O O O
26% 46%
H3C H C O O O 3 O O O O O
O O O H O O O O O H H H
CH3 CH3 Stereochemical Rationale
O O O O R pentyl side R chains O O O O O O O O O O R R H3C O H3C O H3C H3C
restrict diene faceselectivity
O O O O R R restrict epoxide chirality O O O O O O O O O O R R O H3C H3C O H3C H3C Synthesis
H3C CH3 H3CO OCH3 H3C CH3 OH OH TBDPSO O O PPTs PhH Br TBDPSO O O Ph3CO3H, KHMDS, THF 73% Br O
1. NMO, OsO4, acetone/H2O, 30 h 2. Pb(OAc)4, THF, 5 min 3. Ph3P=C(CH3)CO2tBu 60% over three steps
H3C CH3
O O TBDPSO O CO2tBu Br
O CH3 H3C CH3 Synthesis O O O TBDPSO HO O 1. Pd(PPh3)4, toluene, O CO2tBu CO2tBu Br reflux C5H11 2. TBAF/AcOH O CH3 O CH3 o 3. 48% HF, CH3CN, 0 C
CO2H CO2tBu H3C H3C O O O O H3C O H3C O O O DMP CH Cl , rt, 1 h 2 2 CH CH3 followed by TFA/ 3 O CH2Cl2 O O O O O O H O CO2H 80% H CO2tBu H H
CH3 CH3 Summary
Biomimetic approaches to complex natural products can be spectacularly successful, both in nature and at the lab bench.
Advances in asymmetric processes have extended the scope of biomimetic strategies from being limited to mainly racemic syntheses, to enantioselective total synthesis - a powerful combination indeed.