A Stereoselective and Short Total Synthesis of the Polyhydroxylated γ‐Amino Acid (−)‐Detoxinine, Based on Stereoselective Preparation of Dihydropyrrole Derivatives from Lithiated Alkoxyallenes

Abstract

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.

Stereodivergent Syntheses of Highly Substituted Enantiopure 4‐Alkoxy‐3,6‐dihydro‐2H‐1,2‐oxazines by Addition of Lithiated Alkoxyallenes to Carbohydrate‐Derived Aldonitrones

“…These reaction sequences would nicely supplement earlier investigations with carbonyl compounds [5] and imines [6] as electrophiles, which had provided the expected primary adducts and, under base or transition metal catalysis conditions, had given dihydrofuran or dihydropyrrole derivatives. The formal [3+2] cyclizations of methoxyallene with these two-centre electrophiles were synthetically very productive and allowed us several natural product syntheses [7] and-possibly more importantly-led to completely unexpected reaction pathways providing interestingly functionalized compounds [8] not (easily) available by alternative methods. We therefore hoped that similarly versatile and surprising chemistry would be possible with three-centre electrophiles such as nitrones A.…”

Preparation of α,β‐Unsaturated γ‐Keto Aldehydes and New Tetronic Acid and Pyridazine Derivatives by Oxidative Transformations of Alkoxyallene‐Based Dihydrofurans

“…[3,4] The new [3ϩ2] cyclization method for the construction of functionalized dihydropyrrole derivatives 2 has been applied to a rather efficient and entirely stereoselective preparation of the uncommon γ-amino acid (Ϫ)-detoxinine. [5] The use of nitrones as electrophiles allows an entry into the class of 3,6-dihydro-2H-1,2-oxazines 3 by a related [3ϩ3] cyclization process. These heterocycles have turned out to be particularly synthetically valuable.…”

Toward the Total Synthesis of Amphidinolide O: An Enantioselective Synthesis of C3-C8 Fragment

“…Two carboxylic acid moieties of L-malic acid was reduced easily by borane-dimethyl sulfide complex to produce 1,2,4-butanetriol 6, and selective protection of 1,3-diol moiety over the 1,2-diol moiety was performed successfully by reaction with benzaldehyde dimethyl acetal and PPTS in 82% two-step yield. 4 After the primary alcohol 7 was oxidized using Swern protocol, 5 the resulting aldehyde 8 was subjected to Horner-Wadsworth-Emmons olefination reaction to provide the conjugated ester 9 in 67% two-step yield.…”