Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5), http://www.mdpi.org/ecsoc-5.htm, 1-30 September 2001

[C0020]

Combinatorial Modification of Natural Product Derived Steroids

Christoph M. Huwe,* Hermann Künzer and Cornelia Schlicht

Schering AG, Medicinal Chemistry Department, Research Center Europe, 13342 Berlin, Germany,
Phone: (+4930) 468-17226, Fax: (+4930) 468-97226, E-Mail: [email protected]

Received: 15 August 2001 / Uploaded 22 August 2001

Abstract: Starting from b-sitosterol, a regrowing steroid source, a model library of steroidal ureas was synthesized by means of microbiological as well as solution-phase and solid-phase chemical transformations utilizing a thioketal linker derived from (±)-a-lipoic acid.

Steroids are important pharmacologically active scaffolds. Herein we describe the application of our lipoic acid derived thioketal linker¹ (Scheme 1) to the solid-phase synthesis of D⁴-3-keto steroidal ureas from b-sitosterol, a regrowing steroid source.
 
 

The phytosterol b-sitosterol (6) is easily available from soy beans. This compound was subjected to microbiological oxidation (mycobacterium sp.) yielding D^1,4-3-keto intermediate 7, followed by selective hydrogenation (Wilkinson's catalyst) to give D⁴-3-keto compound 8, which was chosen as the scaffold for the model library described herein. Introduction of our thioketal linker (dithiol 3, BF₃^.Et₂O, CH₂Cl₂, r.t., 5d, 90%; see Scheme 1), protection of the hydroxyl group of 9 as a TBS ether (TBSCl, imidazole, THF, r.t., 2h, ~quant.) and selective hydrolysis of the methyl ester of 10 (NaOH, H₂O, THF, r.t., 16h, 76%) gave carboxylic acid intermediate 11, ready to be attached to the solid support. Immobilization of 11 utilizing commercially available aminomethylated polystyrene resin² (DIC, HOBT, DMF, r.t., o/n) could easily be tracked by means of solid-phase IR spectroscopy (KBr, ~1660 cm^-1) and yielded material with a resin loading of ~0.75 mmol/g.³ Removal of the silyl protecting group of 12 (Bu₄N⁺F^-, DMF, r.t., o/n, IR ~3410 cm^-1), and activation of the resulting hydroxyl group of 13 as a mesylate (MsCl, pyridine, CH₂Cl₂, r.t., o/n, IR ~1175 cm^-1) gave intermediate 14, ready for diversification (see Scheme 3).
 
 

This material (14) was then distributed into 40 reactors of an automated synthesizer⁴ and, in the sense of a matrix synthesis, sequentially treated with a set of 5 primary amines (R¹NH₂, NaI, DMF, 80°C, 10h) to give immobilized secondary amines 15, and a set of 8 isocyanates (R²NCO, DMF, r.t., 4h) to generate a 5x8 matrix of 40 immobilized steroidal ureas 16 (see Scheme 3). Cleavage of the products from the solid support (PhI(Tfa)₂, CH₂Cl₂, EtOH, H₂O, r.t., 30 min.),⁵ followed by aqueous work-up finally gave the desired compounds 17 in ~10% average isolated overall yield.⁶

In summary, we have utilized microbiological as well as solution-phase and solid-phase chemical transformations to generate a model library of steroidal ureas starting from the regrowing steroid source b-sitosterol using our (±)-a-lipoic acid based thioketal linker system.
   

References and Notes

1. Huwe, C.M.; Künzer, H. Tetrahedron Lett. 1999, 40, 683.
2. Aminomethylated polystyrene resin was obtained from Rapp Polymere GmbH, Germany.
3. The polymer loading was determined gravimetrically, i.e., calculated from the observed change of resin mass.
4. A Chemspeed ASW2000 synthesizer by Chemspeed Ltd., Switzerland, was used.
5. For details about linker synthesis and cleavage see ref. 1.
6. Yields were determined gravimetrically, products were characterized by HPLC-MS.