Steroids Hajos-Wiechert reaction

The total synthesis of enantiopure natural products has been one of the key developments of the modem era of asymmetric synthesis. Since the Hajos-Wiechert reaction allows ready access to useful chiral bicyclic building blocks, the reaction has been widely employed to constmct a variety of precursors for the synthesis of steroids, vitamin D derivatives, and other natural products. The remainder of the review will look at select examples from the total synthesis literature to illustrate this point. 

The cephalostatins are a group of cytotoxic dimeric steroid derivatives from the marine worm Cephalodiscus gilchristi. Tietze and Krahnert prepared a group of natural product analogs using multiple Heck reactions using derivative 106 obtained from the Hajos-Wiechert reaction their approach is outlined below. ... 

Further breakthroughs in enantioselectivity were achieved in the 1970s and 1980s. For example, 1971 saw the discovery of the Hajos-Parrish-Eder-Sauer-Wiechert reaction, i.e. the proline (l)-catalyzed intramolecular asymmetric aldol cyclodehydration of the achiral trione 11 to the unsaturated Wieland-Miescher ketone 12 (Scheme 1.3) [12, 13]. Ketone 12 is an important intermediate in steroid synthesis. 

In a route towards new estrogens which bind to the /1-unit of the K+-channel located on the surface of the endothelium, L.F. Tietze et al. described the synthesis of a novel enantiopure B-Nor-steroid, applying multiple Pd-catalyzed transformations [141] (Scheme 38). A combination of a Suzuki-Miyaura and a Heck reaction using a 2-bromobenzylchloride derivative and a boronic ester, derived from the enantiopure Hajos-Wiechert ketone [142-... 

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. 

Tietze and his co-workers prepared estradiol and a number of other steroid derivatives using a compact sequential Heck reaction approach. Compound 51 was obtained from the known Hajos-Wiechert ketone derivative 50 in 3 steps. Heck reaction with palladium(II) acetate in the presence of triphenylphosphine gave intermediate 52, the precursor of the second Heck reaction. Additional steps converted steroid analog 53 into estradiol (54). 

Proline-catalyzed enolendo aldolizations have been applied to a number of substrates, most often in steroid synthesis. Selected products from such Hajos-Parrish-Eder-Sauer-Wiechert reactions are sho vn in Scheme 4.18 [98-104]. 

The initial spark for proline catalysis was provided independently and simultaneously by two groups in 1971. Hajos and Parrish on the one hand (Scheme 5.1), and Eder, Sauer and Wiechert (Scheme 5.2) on the other developed an asymmetric aldol cyclisation of triketones such as 1 to bicyclic allq l ketones 2. In the former report, (S)-proline was applied at 3 mol%, a low organocatalyst loading, even to date. The quantitative cyclisation reaction was completed in the reasonable time of 20 h, and provided the product in 93.4% ee. Dehydration to enone 3 completed the synthesis of a valuable building block in steroid chemistry. 

As stated above, the studies of Wieland and Miescher, as well as Woodward, on the intramolecular aldol reaction of diketones and dialdehydes were encouraged by this previous work. Wieland, Miescher, and Woodward studied the application of the intramolecular aldol reaction, catalyzed by secondary amine salts, to the synthesis of steroids and believed that their aldolizations proceed via enamine intermediates [ 10]. This was corroborated by the mechanistic studies carried out by Spencer in 1965 [11]. Based on these works, Hajos and Parrish (1974) andEder, Sauer, and Wiechert... 

In 1971, Eder, Sauer, and Wiechert at Schering (72) and Hajos and Parrish at Hoffmann-La Roche 13,14) independently reported a proUne-catalyzed intramolecular aldol reaction of the triketone 16 as the key step in the synthesis of the diketone 17, a highly important intermediate in steroid synthesis. Remarkably, Hajos and Parrish obtained the diketone 18 in excellent yield and enantioselectivity with only 3 mol% of catalyst (Scheme 5). Acid-mediated dehydratiOTi then furnished the targeted 17. The accepted transition state for this reaction is believed to include one proline molecule as elucidated by List and Houk 21, 34). 

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