Hajos-Wiechert reaction

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 117, Springer-Verlag Berlin Heidelberg 2009 

Christen, D. P. Hajos-Wiechert Reaction. In Name Reactions for Homologations-Part IT, Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 554-582. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 125, Springer International Publishing Switzerland 2014 

Parrish, D. R. J. Org. Chem. 1974, 39, 1615. Hajos and Parrish were chemists at Hoffmann-La Roche. 

The study of steroids has had a profound impact on the evolution of biological and chemical research during the last sixty years. Steroids function primarily as sex hormones, but participate in many other significant biological pathways as well. 

Reactions 1 and 2 show the initial work by Hajos and Parrish. After an initial Michael reaction, usually with methyl vinyl ketone, starting material 1 was obtained in quantitative yield. Compound 1 was treated with 3 mol% proline in DMF at room temperature to give intermediate 2 upon further reaction with toluenesulfonic acid, the dehydrated product 3 is obtained. In an analogous manner, enantioenriched Wieland-Miescher ketone 4 was obtained in a lesser optical yield. Reactions 3 and 4 show the one-pot reaction discovered by Eder, Sauer and Wiechert. The yields and optical purity of the compounds obtained were similar to those of Hajos and 

Parrish. Crystallisation is commonly used to further purify the final products in order to increase their optical purity. 

Overall, this annulation method delivers a quick entry into 6-5 and 6-6 bicyclic chiral building blocks that can be readily modified as needed. The predictable absolute stereochemistry of the reaction is further expanded in utility by using the readily available enantiomers of the amino acid catalysts to prepare either of the two enantiomeric products. The reaction can be run on kilo scale if needed. 

This reaction was one of the first asymmetric produce concise, elegant solutions for the direct aldol and Mannich reactions. The most closely related work reported in the literature at the time is a single report by 

Eschenmoser, A. Hobi, R. Kratky, C. Chim. Acta 197S, 67,3108. 

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Hajos-Wiechert reaction 368 halichondrin B 716 f. halogen-lithium exchange 516, 616, 773... 

A more efficient approach to control the stereochemical outcome for the Robinson annulation can be through the use of chiral catalysts such as in the case of the enantioselective Hajos-Wiechert variation introduced earlier. There are other chiral agents other than the popular (S)-proline-mediated annulation reaction that are used for these transformations—for example the use of (Bronsted acid such as trifluoroacetic (TFA). This new catalyst for the Robinson annulation was reported in 2007 by Endo et. al., where the Bronsted acid, contrary to Hajos-Wiechert reaction, gives the (i )-isomer of the Wieland-Miescher ketone 44 in a moderate yield of 47% and 75% ee. 

Evans aldol reaction Hajos-Wiechert reaction Keck stereoselective allylation Roush allylboronation... 

The mechanism of the Hajos-Wiechert reaction has not been without controversy. The original paper by Hajos and Parrish proposed two possible mechanisms. The first, via the carbinolamine 7, proposed addition of proline to a ketone, followed by a nucleophilic attack of the pendant, remote enol [transition state 8]. Calculations by Houk and Clemente show that this is one of the higher energy pathways. The second proposed mechanistic pathway proceeded via an enamine intermediate, followed by carbon-carbon bond formation via transition state 9 and a hydrogen transfer between nitrogen and... 

The preparation of Wieland-Miescher ketone has sparked additional interest since the Hajos-Wiechert reaction provides it in lesser purity than the corresponding hydrindane derivative. The groups of Furst and Harada have reported two crystallization protocols for Wieland-Miescher ketone based on recrystallization fi om ether or a 10 1 ether/ethyl acetate blend these protocols, although time consuming, appear to be scaleable. ... 

The most useful variation of the standard Hajos-Wiechert reaction protocol was developed by Hagiwara and Uda. In this approach, a stoichiometric amount of L- or f>phenylalanine and 0.5 equiv of D-CSA were stirred together with precursor 26 at room temperature for 24 h the temperature was then increased by 10 degrees every 24 h for 4 days. Compound 27 was obtained in 79% yield with an ee of 91% after column chromatography. 

Paquette and co-workers were interested in using the Hajos-Wiechert reaction to prepare 6-7 fused ring system analogs such as 28. ° After screening several amino acids, the best yield was obtained with L-phenylalanine (86% yield, 48% ee). The methyl group stereochemistry at the ring junction was inverted from that typically observed in the preparation of the fused 5,5- or 5,6-bicyclic analogs. 

More recently, Gryko reported an isolated example of a proline mediated cyclization of non-cyclic triketones.The reaction followed a domino Michael-Aldol pathway in the preparation of compound 29. The yields and % ee of these reactions are very solvent dependent and much lower than those reported for the Hajos-Wiechert reaction. Typically, the best results were obtained in NMP. 

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. 

Danishefsky and his co-workers have used the Hajos-Wiechert reaction several times during total synthesis projects one of the first such applications was in a nice synthesis of estrone that employed a substituted 6-... 

Tsuji and co-workers completed a total synthesis of (+)-19-nortestosterone by using a key intermediate prepared using the Hajos-Wiechert reaction of 40 with stoichiometric (S)-phenylalanine following the Wiechert protocol. This approach was the best among approximately twenty conditions that were tried the resulting product 41 was oxidized to the known crystalline compound 42 to determine that the Hajos-Wiechert reaction occurred in 76% ee. A series of alkylation and annulation reactions was used to convert 42 into (+)-19-nortestosterone (43). 

One of the first applications of the Hajos-Wiechert reaction in the vitamin D area was undertaken by Uskokovic s group at Hoffman LaRoche. The starting point of a synthesis of la,25S,26-trihydroxy-cholecalciferol was the known acid derivative 72. After five steps, intermediate 73 was converted into the acetate 74 via the Bayer-Villiger oxidation. Following a deprotection, oxidation and acetate removal step, the... 

As already mentioned, the Hajos-Wiechert reaction allows entry into both enantiomers of the CD ring system. Wicha and co-workers employed the Hagiwara-Uda procedure using (J )-phenylalanine to produce the thiophenyl substituted CD ring system precursor 94 in 71% yield with 89% After oxidation of the thiophenyl substituent into the corresponding... 

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. ... 

Lastly, the figure below lists a number of other natural products for which Hajos-Parrish ketone and other derivatives from the Hajos-Wiechert reaction were employed as chiral building blocks to achieve partial or complete total synAeses. 

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