Molecular Design

The study of the molecular interactions between biologically active natural products (cf. antitumor compounds, immunomodulators, enzyme inhibitors) and the corresponding cellular receptors is of great importance from a biological as well as medicinal point of view. A prerequisite for such studies are, besides the natural products themselves, appropriate analogs which however, have to be prepared by chemical synthesis. Therefore, an important research topic of our group is the rational design and the synthesis of modified analogs of natural products. In the case of synthetic projects that are derived from natural products, aspects such as topology, stereochemistry and reactivity have to be considered.

Current Projects:

Parallel Synthesis of Hapalosin Analogs: Hapalosin is a cyclic depsipeptide which is able to reverse multidrug resistance (MDR) in tumor cells.1,2 Common MDR is caused by overexpression of the MDR1 gene that encodes for a 170 kDa P-glycoprotein. It has been shown that hapalosin inhibits this transmembrane protein (P-gp). Structurally, hapalosin consists of three subunits, a b-hydroxy acid, an a-hydroxy acid and a g-amino-b-hydroxy acid. Because of this modular structure, it seems obvious to prepare hapalosin analogs by variation of the subunits. The aim of the project is to prepare libraries of hapalosin analogs and to study their conformation and biological activity. The conformations will be elucidated by multidimensional NMR methods. Similar to the technique of positional scanning, the g-amino-b-hydroxy acid will be kept constant, while the two other subunits will be varied. These studies will help to identify the pharmacophore and important conformational features.

From a synthetic point of view the synthesis of the b-hydroxy-g-amino acid represents the biggest challenge. Usually this amino acid is fashioned from phenylalanine by a stereoselective chain elongation. However, protecting group and functional group manipulations make these routes rather lengthy. We recently developed an alternative strategy that is based on an Evans aldol reaction and a subsequent Curtius rearrangement.3

With a view towards changing the aryl group, an alternative synthesis was devised. This is based upon the asymmetric dihydroxylation of the allylic chloride 6. The asymmetric dihydroxylation was performed under standard conditions using (DHQD)2PHAL as chiral ligand which furnished the diol and by base treatment the epoxide 7. Protection of the free hydroxyl group gave the key building block 8. Through a cuprate opening compound 9 was generated. From there introduction of the azide under Mitsunobu conditions led to 10. A few straightforward steps concluded the synthesis of the acid 5.

Using acid 5, the synthesis of hapalosin could be achieved. We are now studying the synthesis of analogs by solid phase chemistry. A small library of analogs was recently prepared in our group.

(1) Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patterson, G. M. L.; Smith, C. D.; Hapalosin, a Cyanobacterial Cyclic Depsipeptide with Multidrug-Resistance Reversing Activity; J. Org. Chem. 1994, 59, 7219-7226.

(2) Dinh, T. Q.; Du, X.; Smith, C. D.; Armstrong, R. W.; Synthesis, Conformational Analysis, and Evaluation of the Multidrug Resistance-Reversing Activity of the Triamide and Proline Analogs of Hapalosin; J. Org. Chem. 1997, 62, 6773-6783.

(3) Pais, G. C. G.; Maier, M. E.; Efficient Synthesis of the g-Amino-b-hydroxy Acid Subunit of Hapalosin; J. Org. Chem. 1999, 64, 4551-4554.

(4) Maier, M. E.; Hermann, C.; Synthesis of the g-Amino-b-hydroxy Acid of Hapalosin via an Asymmetric Dihydroxylation Route; Tetrahedron 2000, 56, 557-561.

(5) Hermann, C.; Pais, G. C. G.; Geyer, A.; Kühnert, S. M.; Maier, M. E.: Total Synthesis of Hapalosin and Two Ringexpanded Analogs. Tetrahedron 2000, 56, 8461-8471.


Analogs of the Antitumor Compound Salicylihalamide: The salicylihalamides are cytotoxic macrolides which have been isolated from a marine sponge.1 They display a potent and unique cytotoxicity profile in the NCI cell based antitumor assays. Therefore, these macrolides represent a new class of interesting antitumor compounds. Related molecules are the lobatamides, CJ-12,950 and the oximides.2

The aim of the project is to develop a flexible synthesis strategy to the 12-membered ring system and to prepare analogs. One strategy we developed utilizes an ortho-allylation reaction and an Evans aldol reaction for establishing the stereochemistry.

(1) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R.; Salicylihalamides A and B, Novel Cytotoxic Macrolides from the Marine Sponge Haliclona sp; J. Org. Chem. 1997, 62, 8188-8192.

(2) Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.; Oximidines I and II: Novel Antitumor Macrolides from Pseudomonas sp.; J. Org. Chem. 1999, 64, 153-155.


Intramolecular Diels-Alder Reactions with Cyclic Dienophiles: The intramolecular Diels-Alder reaction is one of the most useful reactions for the synthesis of polycyclic structures since the number of rings increases by two.1-4 With a view to extending the scope of this reaction we are utilizing cyclic dienophiles. For example, the a-methylene lactone system reacts to tricyclic cycloadducts. These dienophiles are easily available by Reformatsky-like reactions from suitable aldehydes and allow the preparation of polycyclic ring systems such as 5, 6 and 7.5

Moreover, it could be shown that the oxidative rearrangement of the furfuryl alcohol 8 leads via the hydroxypyranone 9 to the decaline system 11.

(1) Craig, D.; Stereochemical Aspects of the Intramolecular Diels-Alder Reaction; Chem. Soc. Rev. 1987, 16, 187-238.

(2) Ciganek, E.; The Intramolecular Diels-Alder Reaction; Org. React. 1984, 32, 1-374.

(3) Swindell, C. S.; Taxane Diterpene Synthesis Strategies. A Review; Org. Prep. Proc. Intl. 1992, 23, 465-543.

(4) Nemoto, H.; Fukumoto, K.; Second Generation of Steroid Synthesis via o-Quinodimethane; Tetrahedron 1998, 54, 5425-5464.

(5) Maier, M. E.; Perez, C.; Intramolecular Diels-Alder Reaction with an a-Methylene Lactone as Dienophile; Synlett 1998, 159-160.


Approach to the Synthesis of Epothilone: The epothilones are macrolides with a relatively simple structure. Nevertheless the biological activity of these compounds is interesting since they are microtubule-stabilizing agents.1,2 In this regard they are similar to taxol. However, epothilones are about 2000-5000 times more active than taxol in these assays. The purpose of this project is the development of a synthetic strategy that also allows rapid access to analogs. A key feature is the creation of stereo centers by aldol reactions.3 We recently could in fact realize the aldol reaction of the chiral oxazolidinone 4 with an aldehyde. While the reaction did not work with the boron enolate, the corresponding titanium enolate added cleanly to the aldehyde.

The cis double bond of the oxazolidinone 4, in turn would be fashioned by a Wittig reaction between a 6-carbon building block and an aldehyde that was prepared from D-arabinose.

(1) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D.; Chemical Biology of Epothilones; Angew. Chem. 1998, 110, 2120-2153; Angew. Chem. Int. Ed. Engl., 1998, 37, 2014-2045.

(2) Service, R. F.; Race for Moleular Summits; Science 1999, 285, 184-187.

(3) Gage, J. R.; Evans, D. A.; Diastereoselective Aldol Condensation Using a Chiral Oxazolidinone Auxiliary: (2S*,3S*)-3-Hydroxy-3-Phenyl-2-Methylpropanoic Acid; Org. Synth. 1989, 68, 83-91.


Approach to the Synthesis of Dysidiolide: Dysidiolide (1) is a recently isolated C25 isoprenoid compound with a novel structure and biological mechanism of action.1 It was found that this natural product is an inhibitor of the protein phosphatase cdc25. This causes arrest of the cell cycle at the G2/M transition (mitose inhibitor). It is thus interesting as a potential antitumor drug. Moreover, it could prove useful for studying signal transduction. The challenge in this molecule is not only the construction of the decalin ring system but rather the construction of the quaternary centers in relation to the bridgehead stereocenter.

In the current approach we constructed one ring by a Diels-Alder reaction combining the Rawal diene 2 and the enoate 3. After hydrolytic workup, the highly functionalized cyclohexenone was obtained. A Michael addition with dimethyl cuprate led to the 3,5-trans-cyclohexanone 5. The second ring was established after a Wacker oxidation of the terminal double bond to the ketone 6 followed by an intramolecular aldol condensation.2 The remaining steps (vinyl cuprate addition to the enone and trapping of the enolate) are currently under investigation.

(1) Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M.; Lobkovsky, E.; Clardy, J.; Dysidiolide: A Novel Protein Phophatase Inhibitor from the Caribbean Sponge Dysidea etheria de Laubenfels; J. Am. Chem. Soc. 1996, 118, 8759-8760.

(2) Paczkowski, R.; Maichle-Mössmer, C.; Maier, M. E.: A Formal Total Synthesis of Dysidiolide. Org. Lett. 2000, 2, 3967-3969.


This work was funded by the Deutschen Forschungsgemeinschaft, the Alexander von Humboldt foundation, and the Fonds der Chemischen Industrie.

 

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