Pyrrolidines total synthesis

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

A total synthesis of (+/—)-gephyrotoxin started with the pyrrolidine-2,4-dione 161 which upon treatment with ethoxyacetylene magnesium chloride followed by dilute HCl gave the acrylate derivative 162. Subsequent reduction and treatment with phenoxyformyl chloride afforded 163. 

The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

These stereoselective IHs of internal aminoallenes have been used for the key step of the enanhoselective total synthesis of (-1-)-pyrrolidine 197B and (-i-)-xenove-nine [322]. 

As expected, some sequences also occur where a domino anionic/pericyclic process is followed by another bond-forming reaction. An example of this is an anionic/per-icyclic/anionic sequence such as the domino iminium ion formation/aza-Cope/ imino aldol (Mannich) process, which has often been used in organic synthesis, especially to construct the pyrrolidine framework. The group of Brummond [450] has recently used this approach to synthesize the core structure 2-885 of the immunosuppressant FR 901483 (2-886) [451] (Scheme 2.197). The process is most likely initiated by the acid-catalyzed formation of the iminium ion 2-882. There follows an aza-Cope rearrangement to produce 2-883, which cyclizes under formation of the aldehyde 2-884. As this compound is rather unstable, it was transformed into the stable acetal 2-885. The proposed intermediate 2-880 is quite unusual as it does not obey Bredf s rule. Recently, this approach was used successfully for a formal total synthesis of FR 901483 2-886 [452]. 

Whereas the Annonaceae are characterized primarily by benzylisoquinoline alkaloids, two pyrrolidine alkaloids have recently been found in species belonging to this family. Squamolone (29) was isolated from Annona squamosa L. by Chinese workers in 1962 (68). Despite careful spectroscopic investigation and a total synthesis (Eq. 1), squamolone was assigned the incorrect diazepine formula 30. The correct structural formula (29) was later established by an unambiguous synthesis of 30 (Eq. 2). Compounds 29 and 30 proved to have very similar spectroscopic properties, which could justify the early confusion (69). 

Last but not least, a very intriguing terpenoid pyrrolidine alkaloid, poly-zonimine was milked from the millipede Polyzonium rosalbum (148). The structural formula of polyzonimine (118) is based on an X-ray crystallographic analysis of its perchlorate and by a total synthesis. 

Pyrrolidines are attainable by [3 + 2] cycloaddition of azomethine ylides and olefins one such reaction is exemplified by a total synthesis of a-allokainic acid (Scheme 36) (182). 

Piper methysticum Forst is a bush tree from Polynesia, known under the local name of kawa-kawa its roots are used in the preparation of an inebriating social beverage called kava, the active principles of which are not alkaloids. Two alkaloids were isolated from the root 1-cinnamoylpyrrolidine (138) and 1 -(m-methoxycinnamoyl)pyrrolidine (139) (208). Their structures were determined by spectroscopic means as well as by total synthesis. 

During synthesis of the hormone rf-aldosterone, 20,21-dihydroxy-lip,18-epoxy-5a-pregnan-3-one diacetate was oxidised to the 3-oxo acid by stoich. RuOy CCl [78, 79], Oxidation of a substituted pyrrolidine to a pyroglutamate, part of the total synthesis of the antibiotic biphenomycin B, was effected by RuO /aq. Na(lO )/ EtOAc [102], Oxidation of a number of A-5 steroids to enones was effected by RuClj/TBHP/cyclohexane [391] safety aspects of these large-scale reactions were examined, as in the preparation of the antibacterial squalamine [186],... 

The plethora of piperidine (242) and pyrrolidine alkaloids in Nature have made attractive targets for total synthesis, particularly since many contain a hydroxyl moiety adjacent to the amino group. This functionality is the case with the pseudodisto-mins-piperidines with antitumor activity isolated from the Okinawan tunicate Pseudodistoma kanaka. The limited availability of the natural material has prompted... 

An efficient stereoselective synthesis of the (pyrrolidin-2-ylidene)glycinate intermediate 325 was reported in a total synthesis of carzinophilin (326), employing an intramolecular cycloaddition of an azide with an alkene (63) (Scheme 9.63). The arabinose derivative 319 was converted into the required azide 321 via the triflate 320. Thermolysis of the azide 321 at 50 °C in THF produced the unstable triazoline 322, which on rearrangement gave the (pyrrolidin-2-ylidene)glycinate 325 in 60-72% overall yield from the triflate 320. 

Note that Pearson has extended the classical anionic [3 + 2] cycloadditions to allow the generation of nonstabilized 2-azaallyl anions, and has successfully applied this methodology to the held of alkaloid total synthesis. A key discovery was that (2-azaallyl)stannanes are capable of undergoing tin-lithium exchange to generate the nonstabilized anions (63-76), which can be trapped either intramole-cularly or intermolecularly with unactivated alkenes to produce pyrrolidines, often in a stereoselective fashion. Thus, a variety of 2-azaallyl anions are accessible by his method. A few examples of Pearson s contributions are illustrated in Scheme 11.3 (70,76). 

The power of this cycloaddition method is clearly illustrated in its application to the synthesis of 80 (Scheme 2.22), a known intermediate for the total synthesis of cyanocycline A (81) and bioxalomycin (32 (82) 43 The condensation of aldehyde 78 and 75 in neat methyl acrylate (27) took place to afford the pyrrolidine 79 in 74% yield as a single stereoisomer.44 This compound was then converted into 80 in 12 steps. The method has also been applied to the synthesis of a number of analogs of 81 and 82 with... 

Pearson, W.H. and Stoy, P. (2003) Cydoadditions of nonstabilized 2-azaallyllithiums (2-azaallyl anions) and azomethine ylides with alkenes [3 +2] cydoaddition approaches to pyrrolidines and application to alkaloid total synthesis. Synlett, 903—921. 

Still and Schneider employed Ireland-Claisen rearrangement in the total synthesis of ( )-frullanolide (ll)6 (Scheme 1.3f). The key step of the synthesis is efficient Ireland-Claisen rearrangement of the P-pyrrolidinopropionate ester 12. The triethylsilylketene acetal rearranged in toluene at reflux and the pyrrolidine moiety was eliminated after stirring with a mixture of dimethyl sulfate and potassium carbonate in methanol to afford the a-substituted acrylic ester (13). Saponification followed by iodolactonization gave the iodolactone 14, which upon treatment with DBU led to ( )-frullanolide. 

Deng and Overman employed the aza-Cope-Mannich reaction in the enantios-elective total synthesis of (+)-preussin (21), a potent antifungal agent possessing a pyrrolidine skeleton8 (Scheme 1.6h). Conversion of the amino alcohol 22 to the oxazolidine derivative 23 was readily accomplished by reacting with decanal in hot benzene with removal of water using a Dean-Stark trap. Treatment of... 

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

---