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 - 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 (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 via oxidative dimerization 2 of monomeric precursors. CH 3 oxaelectrocyclization/Diels-Alder cascade already demonstrated in an earlier racemic synthesis by the same authors.

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 - a powerful combination indeed.