Heliotridine, synthesis

Regioselective reduction of a succinimide intermediate for a (-i-)-heliotridine synthesis [269] must be due to the influence of the acetoxy group. It is conjectured that the a-a array of the intervening carbon atoms activates the carbonyl. Steric effects should he minimal on the choice of the two sites. 

Scheme 11.14 The synthesis of building block 44 in the total synthesis of (+)-heliotridine, a necine base present in a large diversity of pyrrolizidine alkaloids [69], a)78 22 mixture of diastereomers.

Another route to ( )-retronecine, together with its C-7 epimer ( )-heliotridine (21), has been described by Keck and Nickell.9 This synthesis depends upon the transfer of an acylnitroso moiety, generated from the Diels-Alder adduct (15) with dimethylanthracene.10 Addition of the lithium enolate of this adduct to the unstable dienal (14), formed as shown in Scheme 4, gave an alcohol (16). 

Precursors for the enantioselective synthesis of the pyrrolizidine alkaloids hastanecine and heliotridine can be prepared by the reaction sequence 13 to 19964. 

A few examples have recently appeared involving intramolecular cycloadditions of acylnitroso dienophiles in alkaloid total synthesis. Keck has utilized such an intramolecular reaction as the key step in total syntheses of the necine bases heliotridine (21) and retronecine (22) (Scheme 3-XIII). In this work, the dimethylanthracene adduct 19 was used as a precursor for the acylnitroso compound. The Diels-Alder cyclization afforded a 1.3 1 mixture of epimeric adducts 20, which was converted to the individual alkaloids. 

The alkaloid ( + )-retronecine (883, Scheme 129) is structurally similar to ( + )-heliotridine (850), with the exception that the stereocenter at C-7 is of opposite configuration. The basic approach to its synthesis involves a carbenoid displacement similar to that in the previous scheme. The acetyl protecting group of the common intermediate 875 (R=SPh) is changed to a TBS group, and the benzoate is converted to pivalate. Carbenoid displacement with dibenzyl a-diazomalonate in the presence of rhodium acetate gives 879. Reductive desulfurization... 

In the presence of TMSOTf, BFs.OEtz and dimethyl sulfide, the iminium ions 204 (masked as N,0-acetals) have been employed to couple with a very board range of readily available Michael acceptors, including acrolein and acrylates, in both an inter- and intramolecular MBH-type reaction to give densely functionalized heterocycles 207 (Scheme 1.78). The process has been rendered asymmetric and high enantioselectivity is obtained in reactions of iminium ions 210 (masked as N,0-acetals) and cyclic enones (Scheme 1.79). Finally, the usefulness of the methodology has been exemplified in a short synthesis of ( + )-heliotridine 208 and (-)-retronecine 209 (Scheme 1.78). ... 

Recently, a novel methodology has been developed to prepare densely functionalized heterocycles from the coupling of various Michael acceptors with readily available iminium ions (masked as N,0-acetals) via an intermolecular MBH-type reaction. An intramolecular MBH-type reaction was developed to construct a bicyclic pyrrolizidine ring. As shown Scheme 5.32, the total synthesis of ( + )-heliotridine, as this basic structure unit existed in many plants, was achieved. ... 

Selective synthesis of diesters of the pyrrolizidine diols has proved more difficult. A number of semisynthetic pyrrolizidine diesters were prepared by CuLVENOR etal. 81) by acylation of heliotridine (79) with various acyl chlorides. Selective acylation at C-9 of heliotridine and retronecine (18) is possible by conversion of the base into its 1-chloromethyl derivative, followed by nucleophilic substitution with the appropriate carboxylate anion. 

---