Pyrrolizidine alkaloids synthesis

Matsumoto, T., K. Fukui, and J. D. Edwards Pyrrolizidine Alkaloids. Synthesis and Configuration of Fulvinic and Crispatic Acids. Chem. Lett. 1973, 283. 

Hudlicky and coworkers also reported a related 2-pyrroline formation from viny-laziridines [81], which are extremely useful for the synthesis of pyrrolizidine alkaloids such as the protected (+)-trihydroxyheliotridane 210 (Scheme 2.51). Since the pyrolysis of either diastereomer of 208 furnished the cyclized product 209 as a... 

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (-)-hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties. The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that... 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

The synthesis of pyrrolizidine alkaloid (-)-rosmarinecine illustrates the power of the fused mode tandem cycloaddition, as shown in Scheme 8.40.180 The all-cA relationship at the three contiguous centers C(l), C(7), and C(7a) can be constructed in a single-pot reaction with correct stereochemistry but C(6) cannot. 

Nitroalkenes are shown to be effective Michael acceptor B units in three sequential reactions (A + B + C coupling) in one reaction vessel. The sequence is initiated by enolate nucleophiles (A) and is terminated by aldehydes or acrylate electrophiles (C). The utility of this protocol is for rapid assembly of complex structures from simple and readily available components. A short total synthesis of a pyrrolizidine alkaloid is presented in Scheme 10.16.114... 

Another Michael addition route for synthesis of the pyrrolizidine alkaloide trachelan-thamidin is shown in Scheme 10.18.118... 

The aza-tricyclic lactone 320 is an intermediate in the synthesis of the indolizidine 321, which is the indolizine analogue of the pyrrolizidine alkaloid platynecine <1995TL5109> (Scheme 84). 

An intermediate 5-hydroxy-5,6-dihydro-2/7-pyrrolo[l,2- ][l,2]oxazin-7(4a//)-one 142 has been described in the total synthesis of (—)-loline, a pyrrolizidine alkaloid extracted from rye grass Lolium cuneatum. The key step of the synthesis was an intramolecular cycloaddition of acylnitrosodienes (obtained by in situ oxidation of the corresponding hydroxamic acids 143). This reaction generated predominantly the rro/o-stereoisomer that was further cleaved at the N-O bond with Na(Hg) and further elaborated in several steps to reach the target compound (Scheme 19) <2001J(P 1)1831 >. 

This method of cyclization has been used successfully for synthesis of four 11-membered dilactone pyrrolizidine alkaloids,2 but it does not appear to be useful for cyclization to simple macrolides. 

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.

This methodology has been applied to the diastereoselective synthesis of the pyrrolizidine alkaloid 196 from 194 via 195 (Scheme 15.62) [123], Furthermore, the diastereoselectivity of these reactions for different dipolarophiles has been investigated in detail [124] and could be extended to a ring closure to seven-membered nitrogen heterocycles [125,126]. 

We have extended our work on a new synthesis of the antiprotozoal antibiotic anisomycin to the necine bases of the pyrrolizidine alkaloids, in particular retronecine and crotanecine. The key intermediate, (2R,3S,4R)-2-(alkoxy-carbonylmethyl)-3,4—isopropylidenedioxypyrrolidine, has been prepared by three distinct routes from D-ribose and g-erythrose, using reactions of high stereoselectivity. 

Lactam systems have been synthesized by rehance on configurational matching, as exemplified in the synthesis of the pyrrolizidine alkaloid (-)-heliotridane (Scheme 15.9)... 

A related oxime 304 was prepared for the total synthesis of 305, an unusual pyrrolizidine alkaloid isolated from the venom of a variety of thief ant... 

Hudlicky et al. (65) reported a formal stereoselective total synthesis of the oxygenated pyrrolizidine alkaloids platynecine (336), dihydroxyheliotridane (337), hastanecine (341), and tumeforcidine (342), involving an intramolecular azide-diene cycloadditions (Scheme 9.65). Intramolecular 1,3-dipolar cycloaddition of... 

LDA was used in the cyclization of tosylate 9, an intermediate in the synthesis of the pyrrolizidine alkaloid (+)-retronecine, which was prepared from (+ )-(7 )-malic acid in nine steps. The tricyclic lactone 10 was isolated in 53% yield70. 

More recently, Naidu and West have utilized a ring expansion reaction of spiro azetidinium ylide 167 in the synthesis of pyrrolizidine alkaloids. Spiro azetidinium ylide 167 is generated through a Cu(acac)2-catalyzed intramolecular reaction of a copper carbene complex with a pendant amino moiety. Subsequent [l,2]-shift gives fused bicyclic products 168 and 169 as a diastereomeric mixture. Each diastereomer was further converted to naturally occurring pyrrolizidines ( )-turneforcidine and ( )-platynecine, respectively (Scheme 18). ... 

Silver ion catalysis has also been used with allenic oximes to generate cyclic nitrones, which are trapped by 1,2-dipolarophiles (equation 142).270 This reaction was used in a synthesis of pyrrolizidine alkaloids.270 5... 

Imidate-derived dipoles have played a prominent role in the synthesis of the pyrrolizidine alkaloid retronecine (121).119 The imidate salt derived from lactam (118) was found to undergo a smooth desilylation reaction to produce azomethine ylide (119). Trapping of this dipole with methyl acrylate affords... 

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