A formyl group has been introduced onto the cyclopentadienyl ring of 17R-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 17R-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 R 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.

Starting from (2S,4S)-2-ferrocenyl-4-(methoxymethyl)-1,3-dioxane (4), use of the stereogenic ortho-directing menthyl para-tolyl sulfoxide group, which occupies the 2' position in the ferrocenyl ring and redirects subsequent lithiation to the 3' position, allowed the synthesis of optically pure (S(p))-1-formyl-3-iodoferrocene (8), that was characterized by single-crystal X-ray diffraction. Combination of this method with a protection-deprotection strategy, using trimethylsilyl as a temporary blocking group, yielded (R(p))-1-formyl-3-iodoferrocene (13). Separate Sonogashira coupling of each of the enantiomeric iodoformylferrocenes 8 and 13 with 17alpha-ethynyl-estradiol produced (R(p))-17alpha-[(3'-formylferrocenyl)ethynyl]estradiol (14) and (S(p))-17alpha-[(3'-formylferrocenyl)ethynyl]estradiol (15), respectively.

The preparation of metallocene sulfoxides and their ortho-diastereoselective functionalization are described. The applications of enantiopure 1,2-and 1,3-disubstituted metallocenes are reviewed, with special emphasis on the preparation of ligands for asymmetric catalysis. The sulfoxide functionality is a useful, traceless, chiral diastereoselective orthodirecting group, as explained in the article. It allows one to synthesize a wide range of enantiopure metallocenes with planar chirality and predictible configuration. Most of the examples are related to the ferrocene area.