An immobilized form of Candida antarctica lipase (Chirazyme L-2) catalyzed enantioselective hydrolysis (E > 1000) of N-Boc-indoline-2-carboxylic acid methyl ester. The reaction proceeded efficiently at 60 °C, a temperature over the melting point of substrate, in the conversion of 49.9% to provide the hydrolyzed product, (S)-carboxylic acid with >99.9% ee and the unreacted (R)-ester with 99.6% ee. A newly developed expeditious route to the racemic substrate (a total of six steps, 60% yield), starting from aniline and ethyl α-methylacetoacetate, established the scalable chemo-enzymatic synthesis of the desired compounds in both enantiomerically pure forms.

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Vilsmeier -Haack-type cyclization of 1H-indole-4-propanoic acid derivatives was examined as model construction for the A -B -C ring system of lysergic acid (1). Smooth cyclization from the 4 position of 1H-indole to the 3 position was achieved by Vilsmeier -Haack reaction in the presence of K 2 CO 3 in MeCN, and the best substrate was found to be the N,N-dimethylcarboxamide 9 ( Table 1). The modified method can be successfully applied to an a-amino acid derivative protected with an N-acetyl function, i.e., to 27 (Table 2); however, loss of optical purity was observed in the cyclization when a chiral substrate (S)-27 was used (Scheme 5). On the other hand, the intramolecular Pummerer reaction of the corresponding sulfoxide 20 afforded an S-containing tricyclic system 22, which was formed by a cyclization to the 5 position (Scheme 3).1. Introduction. -Lysergic acid (1), a tetracyclic indole derivative with two stereogenic centers, is the core unit of ergot alkaloids showing wide spectra of biological activities [1] such as prolactin inhibition, anti-Parkinsonian effect, and depression of hypertension. The total synthesis of racemic 1 has been reported by nine research groups [2], and two groups have successfully achieved the asymmetric synthesis [3].Recently, we have explored a novel aziridination from guanidinium ylides and aromatic (or unsaturated) aldehydes, applicable to asymmetric synthesis [4], and designed the atom-economical synthesis of bioactive N-containing compounds using the formed aziridine as a key synthetic intermediate. Our retro-synthetic strategy of lysergic acid (1) is shown in Scheme 1, in which all the C-and the N-units of the aziridine 2, derived from guanidinium ylide 3 and 1H-indole-4-carboxaldehyde 4, are incorporated in the lysergic acid structure during the synthesis. One of the key reactions is the construction of ring C via cyclization from the 4 position of the 1H-indole skeleton 2 to its 3-position. Such cyclizations had already been examined by four groups [2i] [5], among which Nedelec and Raincy [5a] reported the application of the Vilsmeier -Haack reaction to 1H-indole-4-propanamide in their patent. Thus, we extensively examined the cyclization based on their methodology and, in this paper, describe experimental results obtained by using varieties of 1H-indole-4-propanoic acid derivatives.

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