Based on our earlier results employing lithiated methoxyallene 2 as C(3) building block and imines 3 for the synthesis of dihydropyrrole derivatives 5, we have investigated chiral imines 6, 10, and 15 as electrophilic components. Combined with lithiated alkoxyallenes, these imines provide the corresponding primary adducts and finally the dihydropyrrole derivatives 8, 12, 17, 20, and 22 in good yields and with high to excellent syn selectivities. This stereochemical outcome is interpreted as a result of alpha-chelate control. Treatment with hydrochloric acid converted syn-8 and syn-12 into bicyclic compounds 9 and 13, whereas under more mildly acidic conditions adduct syn-17 was transformed into diol syn-18. The total synthesis of the uncommon gamma-amino acid (-)-detoxinine could be achieved by starting from (S)-malic acid, which was converted into imine 15 in four steps. Lithiated benzyloxyallene added to imine 15 and efficiently furnished the crucial dihydropyrrole derivative syn-22. The hydrogenolysis of this compound did not directly provide the protected triol 29 as anticipated, but a stepwise protocol made the triol available in a fairly satisfactory manner. A second crucial step of the synthesis was the selective oxidation of 29, which could be achieved by employing platinum dioxide and oxygen. The resulting bicyclic lactone 30 was smoothly transformed into enantiopure (-)-detoxinine. Thus, a fairly short synthesis of this natural product based on a lithiated alkoxyallene could be performed, demonstrating the potential of these intermediates for syntheses of interesting functionalized heterocyclic compounds.
In a brief exploratory study we investigated the reactions of lithiated methoxyallene with different oxime derivatives. With E‐benzaldehyde oxime a 3,6‐dihydro‐2H‐1,2‐oxazine derivative was isolated in low yield, being the result of an overall [3+3] cyclization. The reaction of lithiated methoxyallene with phenylhydroximoyl chloride provided a moderate yield of an isoxazole derivative that incorporated two benzonitrile oxide‐derived moieties. In situ generated α‐nitrosostyrene and lithiated methoxyallene combine to the expected primary 1,4‐addition product which could be trapped by O‐methylation. On the other hand, the primary adduct cyclized after aqueous work‐up to give a vinyl‐substituted isoxazole derivative in good yield. Mechanisms for the formation of the products are presented. The discovered new routes to 1,2‐oxazine or isoxazole derivatives seem to be restricted to aryl‐substituted electrophiles.
A Stereoselective and Short Total Synthesis of the Polyhydroxylated γ-Amino Acid (-)-Detoxinine (I), Based on Stereoselective Preparation of Dihydropyrrole Derivatives from Lithiated Alkoxyallenes. -(FLOEGEL, O.; AMOMBO, M. G. O.; REISSIG*, H.-U.; ZAHN, G.; BRUEDGAM, I.; HARTL, H.; Chem. Eur.
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