Stereoselective synthesis steroids

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

Bruttomesso AC, Eiras J, Ramirez JA, Galagovsky LR (2009) Highly stereoselective synthesis of steroidal 2, 5-diketopiperazmes based on isocyanide chemistry. Tetrahedron Lett 50 4022 024... 

A stereoselective synthesis of aminoalkyl-substituted P-lactams (41) has been developed, the key step of which is [2+2] cycloaddition of imines to ketenes generated photochemically from diazoketones (42), which are derived from protected a-amino acids. A number of steroidal diazoketones related to progesterone have been synthesized as potential photoaffinity labelling reagents for the mineralocorticoid receptor. ... 

These transformations can be applied to the stereoselective synthesis of several other carbo- and heteropolycyclic dienes, and are therefore regarded as a model system for the diastereoselective synthesis of steroid and alkaloid compounds47 53,68 70. Thus, estradiol is obtained via intramolecular cocyclotrimerization of a linear enediyne, with silyl- and acetal-protecting groups, which again preferentially leads to one stereoisomer of the primary diene complex 646. 

STEREOSELECTIVE SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL STEROIDS... 

The Zambon synthesis of the non-steroidal anti-inflammatory agent (5)-2-(6-methoxy-2-naphthyl)propanoic acid (naproxen) is a landmark-setting application of the chiral auxiliary approach in the industrial stereoselective synthesis of an enantiomerically pure drug [51]. The chiral auxiliary employed, a (2f ,Jf )-dialkyltartrate, is a paradigmatic representative of this class of stereocontroller, being cheap, readily available, easily introduced on the substrate and removed from the product, and eventually recycled (although as its parent acid). 

Isopropylidene glyceraldehyde 305 submitted to orthoester rearrangement was used by Suzuki in the initial steps of the synthesis of intermediate 333 leading to vitamin Dj [74] (Scheme 6.54). Still in the field of vitamin D, a stereoselective synthesis of steroid side chain and CD rings has been described by Takahashi and Tsuji [75]. Triethylorthohexenoate 335 was used as an orthoester. The stereochemical control of carbon fi to ester was good but as in other cases the a center was obtained as a mixture of diastereomers in ester 336 (Scheme 6.54). 

Developed in the early 1970s, this reaction, also called the Hajos-Parrish reaction or Hajos-Parrish-Ender-Sauer-Wiechert reaction, is one of the earliest processes for the stereoselective synthesis of Wieland-Miescher ketone, an important building block for steroids and terpenoid synthesis. This reaction is a proline mediated asymmetric variation to the Robinson annulation. Hajos and Parrish of Hoffmann-La Roche Inc. in 1971 and 1974 published an asymmetric aldol cyclization of triketones such as that of structure 39, which affords optically active annulation products in the presence of catalytic amounts of (S)-proline (Z-proline). One of the early examples is the synthesis of 41 from the triketone 39 (a product of the Michael addition of MVK to the corresponding 2-methylcyclopentane-l,3-dione), the reaction is performed in two steps first by ring formation in the presence of 3 mol % of (iS)-proline in DMF to afford the ketol 40 in 100% yield after crystallization with 93% ee and then by reaction with toluenesulfonic acid to give the dehydrated adduct 41. The formation of the Wieland-Miescher Ketone 44 follows the same synthetic route, starting from the tri-ketone 42 to give the end product in 75% optical purity and 99.8% of optical yield. 

During the first synthesis of a parent [lOJannulene, the important last step entailed a bis-decarbonylation reaction. This was achieved in 88% yield using two equivalents of tris(triphenylphosphine)rhodium(i) chloride in benzene at 80 °C (Scheme 38). A similar decarbonylation process proved to be a key reaction in a short stereoselective synthesis of a steroidal c-d ring fragment. ... 

A phospha-Michael addition has also been applied to a stereoselective synthesis of steroid derivatives of type 130 (Scheme 47.32). ° Addition of catalytic amounts of Pd(OAc)2 was not necessary, but it improved the reactivity... 

Skoda-Foldes R, Kollar L. Stereoselective synthesis of androstane-based steroidal phosphine oxides possessing the 16a-diphenylphosphinyl moiety. Synth. Commun. 2006 36 2825-2832. 

Gong, J.-X., Miao, Z.-H., Yao, L-G., Ding, (., Kurtan, T and Guo, Y.-W. (2010) Stereoselective synthesis of methyl spongoate, a new steroid with potent antitumor activity. Synktt, 480-482. 

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