Phenylalanine, Hajos-Wiechert reaction

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. 

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). 

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... 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

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