Synthesis of Optically Pure <i>o</i>-Formylcyclopentadienyl Metal Complexes of 17α-Ethynylestradiol. Recognition of the Planar Chirality by the Estrogen Receptor

A formyl group has been introduced onto the cyclopentadienyl ring of 17α-ethynylestradiol derivatives bearing a ferrocenyl, a cymantrenyl, or a cyrhetrenyl group at the ortho position with respect to the ethynyl group. The presence of this group on the cyclopentadienyl ring induces a planar chirality that provokes the formation of two diastereomers, the Sp and Rp derivatives. These compounds were prepared from Sp and Rp 1-formyl-2-iodoferrocenes, -cymantrenes, and -cyrhetrenes, which were separately prepared by using a combination of suitable ortho directing substituents, such as methoxymethyldioxane and p-tolylsulfoxide, as well as trimethylsilyl as a temporary blocking group. A cross-coupling reaction between these precursors and 17α-ethynylestradiol led to the formation of the hormone complexes. The ferrocenyl hormone compounds were only obtained from a Sonogashira reaction, the cyrhetrenyl compounds were only formed by using a Stille reaction, and the cymantrenyl compounds were obtained from both reactions. A tentative explanation for this interesting behavior is proposed. The affinity of the R diastereomers for the α receptor of estradiol is almost twice that of the S diastereomers. This is the first example of estradiol receptor discrimination between organometallic diastereomers possessing planar chirality. However, in contrast to 1,2-disubstituted derivatives, when the formyl group is at the 1,3-position, the receptor does not differentiate between the two planar chiral diastereomers.