Stereoselective synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol

A highly stereoselective total synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol is described. Key steps involved in this synthesis are diastereoselective zinc allylation, azido-olefin cyclization and reductive amination followed by cyclization which effectively constructed the indolizidine ring. This contributes a unique approach to the synthesis of indolizidine alkaloids that offers the advantages of brevity and relatively high overall yields.     

Total synthesis of the Securinega alkaloid (-)-secu'amamine A

The first enantioselective total synthesis of the rearranged Securinega alkaloid (-)-secu'amamine A is reported starting from D-proline as the source of absolute chirality. The synthesis requires 15 steps starting from D-proline-derived N-trityl aldehyde 11 and proceeds in approximately 9% overall yield. Key steps include a stereoselective conjugate addition of pyrrolidino enedione 19 to afford indolizidine 24 as the major product and cyclization/lactonization of diketoester 25 to produce tetracycle 26. In addition, 1H NMR NOE studies and X-ray analysis on the synthetic alkaloid have established that the indolizidine moiety is trans-fused.     

Total synthesis of (±)-γ-lycorane via the electrocyclic ring closure of a divinylpyrroline

A concise total synthesis of (±)-γ-lycorane is described. The key step in the synthesis is the 6π-electrocyclic ring closure of a divinylpyrroline to give a tetrahydroindole, which is subsequently hydrogenated to give the all-cis indolizidine core.     

Concise synthesis of pyrrolidine and indolizidine alkaloids by a highly convergent three-component reaction

The synthesis of pyrrolidine and indolizidine derivatives through radical carboazidation of alkenes with α-iodoketones, followed by reductive amination, is described. When properly substituted, further lactamization afforded pyrrolizidinones in good yield. This carboazidation/reductive amination sequence was efficiently applied to the total synthesis of three different simple alkaloids, including (±)-monomorine I.     

Enantiospecific synthesis of an indolizidine alkaloid, (+)-ipalbidine

Enantiospecific total synthesis of an indolizidine alkaloid, ipalbidine, was achieved starting from (−)-pyroglutamic acid by employing an intramolecular McMurry coupling reaction with a low-valent titanium, as a key step.     

Epoxide-initiated cationic cyclization of azides: a novel method for the stereoselective construction of 5-hydroxymethyl azabicyclic compounds and application in the stereo- and enantioselective total synthesis of (+)- and (-)-indolizidine 167B and 209D

A novel and general method has been developed for the stereoselective construction of 5-hydroxymethyl azabicyclic ring skeletons based on epoxide-initiated cationic cyclization of azides. The key cyclization reaction was systematically studied with the model compound, 3-(1-oxa-spiro[2.4]hept-4-yl)propyl azide 3a, and EtAlCl(2) was found to be an ideal choice as the catalyst. The generality of this transformation was further tested with different ring sizes, where six- and seven-membered epoxyazides 3b,c underwent smooth cyclization to give 5-hydroxymethyl azepine 4b and 5-hydroxymethyl azocine 4c, respectively, as a single detectable diastereomer. This novel methodology was elegantly applied in the stereoselective total synthesis of indolizidine alkaloids 167B and 209D. Further, the enantioselective total synthesis of natural and unnatural indolizidine alkaloids 167B and 209D was accomplished by using Sharpless asymmetric dihydroxylation as a key step.     

A concise synthetic pathway towards 5-substituted indolizidines

The total synthesis of 5-(2′-hydroxyethyl)indolizidine via 5-thioindolizidinone is described. The key step is the transformation of 5-thioindolizidinone via Eschenmoser’s sulfide contraction. The racemic mixture of 5R,9R- and 5S,9S-5-(2′-hydroxyethyl)indolizidine was obtained in seven steps in 17% overall yield from 2-allyl cyclopentanone.     

A general approach to 3-n-butyl-5-alkylindolizidines: total synthesis of (-)-indolizidine 195B

Indolizidine type alkaloids have been attractive synthetic targets due to their biological activity. The total synthesis of (-)-indolizidine 195B via a general route, which could potentially be used to prepare other indolizidine alkaloids such as (-)-gephyrotoxin 223AB and (-)-myrmicarin 237A, is described.     

Convergent approach to pumiliotoxin alkaloids. Asymmetric total synthesis of (+)-pumiliotoxins A,B, and 225F

A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation[bond]cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh(3))(4) catalyst to give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.     

A concise and convergent route to 5,8-disubstituted indolizidine and 1,4-disubstituted quinolizidine ring cores by diastereoselective aza-Diels-Alder reaction

[reaction: see text] A short and convergent synthesis of 5,8-disubstituted indolizidine and 1,4-quinolizidine scaffolds is described. The key steps of the synthetic pathway are the aza-Diels-Alder reaction of a 2-aminodiene with an N-allyl or N-homoallylaldimine and a ring-closing metathesis. The bicyclic alkaloid analogues are obtained with total diastereoselectivity and through a common pathway.     

Total synthesis of the neotropical poison-frog alkaloid (-)-205B

[reaction: see text]. A stereocontrolled total synthesis of the neotropical poison-frog alkaloid (-)-205B (1) has been achieved, employing a dithiane three-component linchpin coupling, a one-pot sequential construction of the embedded indolizidine ring, and ring-closing metathesis (RCM) to arrive at the novel 8b-azaacenaphthylene ring system comprising the alkaloid. The synthesis proceeded with a longest linear sequence of 19 steps, affording (-)-1 in 5.6% overall yield.     

Studies towards the enantioselective synthesis of 5,6,8-trisubstituted amphibian indolizidine alkaloids via enaminone intermediates

Investigations aimed at the enantioselective total synthesis of indolizidine 223A, a recently described 5,6,8-trisubstituted indolizidine alkaloid from a dendrobatid frog, are described. tert-Butyl (2R,3R)-3-amino-2-ethylhexanoate and its (2S,3R)-diastereomer, prepared in several steps from lithium N-benzyl-N-[(1R)-1-phenylethyl]amide and tert-butyl (2E)-hex-2-enoate by the Davies protocol, served as chiral building blocks from which two complementary suites of diastereomeric intermediates were made en route to pivotal tert-butyl 3-[2-(alkoxycarbonylmethylene)pyrrolidin-1-yl]-2-ethylhexanoate intermediates 20 and 21. Cyclisation of these enaminones, achieved by acid hydrolysis of the tert-butyl esters and activation of the liberated carboxylic acids as mixed anhydrides, afforded 6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate esters 28 and 29. Several further transformations of these potential scaffolds for the synthesis of the target alkaloidal systems are also reported.     

Total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and formal synthesis of pumiliotoxin-251D

A concise and efficient synthesis of (6R,7S,8R,8aS)-6,7,8-trihydroxyindolizidine (1-deoxy-7,8a-di-epi-castanospermine) 2 is described. The synthesis employs cross metathesis in building the key intermediate 9 and is used effectively in constructing indolizidine skeleton for the total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and also for the bicyclic framework of pumiliotoxin 251D 12, 13. The indolizidine skeleton is achieved in one pot sequence of transformations such as deprotection of Cbz group, reduction of double bond, and cyclization. The configurational and conformational structures of compound 10 are unambiguously confirmed by X-ray analysis.     

Tuning the acceptors in catalyzed cyclizations initiated by allenes. Silylstannylation/cyclization of allene-aldehydes for synthesis of polyalkylated indolizidines including 223A congeners

Starting from succinamide and 1,2-heptadiene-4-ol, a racemic allene-aldehyde substrate, 20, suitable for R(3)SiSnR'(3)-mediated cyclization was synthesized in six steps and in 21% yield. Stereoselective cyclization (relative cis configuration at the new stereogenic centers of the homoallyl alcohol generated) proceeded smoothly, giving a mixture of indolizidinols bearing five contiguous stereocenters in a combined yield of 80%. Relative configurations of each of the products were unequivocally established by a combination of 2D NMR experiments and single-crystal X-ray analysis. The major indolizidinol obtained in 32% yield was elaborated into indolizidine 5,8-epi-indolizidine 223A via a five-step reaction sequence in 32% overall yield. The second major component (24%) of the key cyclization yielded, in four steps, indolizidine 6,8-epi-223 in 14% yield. Even though revision of the initially postulated structure foiled our original synthetic plans for the natural product, indolizidine 223A, the new stereoselective cyclization strategy and several selective transformations of the indolizidine derivatives reported here may find further applications for the synthesis of highly alkylated indolizidine and other related alkaloids.     

Indolizidine and quinolizidine alkaloids

This review covers the isolation, structure determination, synthesis, chemical transformations and biological activity of indolizidine and quinolizidine alkaloids. Included in the review are the hydroxylated indolizidines lentiginosine, swainsonine, castanospermine and their analogues; alkaloids from animal sources, including ants, amphibians and beetles; indolizidine alkaloids from the genera Polygonatum, Prosopis and Elaeocarpus; indolizidine and phenanthroindolizidine alkaloids; alkylquinolizidine alkaloids, including myrtine, epimyrtine, plumerinine and Lycopodium metabolites; Lythraceae and Nuphar alkaloids; lupine alkaloids; and alkaloids from marine sources. 150 references are cited.     

A concise formal stereoselective total synthesis of （-）-swainsonine

A short formal stereoselective synthesis of （-）-swainsonine （1） is described. Our synthesis started with the versatile building block （R）-3-benzyloxyglutarimide 5. Through controlled regioselective reduction, Ley＇s-sulfone chemistry （N-α-sulfonylation and ZnCl2-catalyzed N-α-amidovinylation）, an RCM reaction, and an amide reduction, the synthesis of unsaturated indolizidine （8R,8aS）-3 has been achieved in five steps. The indolizidine （8R,8aS）-3 is an advanced intermediate toward the synthesis of （-）-swainsonine （1）.     

A versatile enantioselective synthesis of azabicyclic ring systems: a concise total synthesis of (+)-grandisine D and unnatural analogues

Closing in on azacines: We have developed a new six step approach for the rapid and enantioselective synthesis of indolizidine, pyrrolo[1,2-a]azepine, and pyrrolo[1,2-a]azocine azabicyclic systems and their respective lactam congeners, which are found in a host of natural products as well as pharmaceutical preparations. This protocol enables a concise enantioselective total synthesis of (+)-grandisine?D in 16.4?% overall yield from commercial materials (see scheme).     

Enantioselective approach to indolizidine and quinolizidine scaffolds. Application to the synthesis of peptide mimics

An enantioselective approach to substituted indolizidine and quinolizidine frameworks has been developed. Key steps of the synthesis are the enantioselective, palladium-catalyzed N-allylation of an imide, the nucleophilic allylation of an acyliminium ion and a ring closing metathesis. This general strategy has been applied to the synthesis of indolizidine peptide mimics, starting from a chiral imide derived from l-aspartic acid. It was observed that the preexisting stereogenic center of this substrate has a moderate influence on the stereoselectivity of the electrophilic allylation, which is mainly determined by the sense of chirality of the catalyst.     

A concise sequential photochemical-metathesis approach for the synthesis of (+)-castanospermine and possible uniflorine-A stereoisomers

A recently developed strategy for polyhydroxylated indolizidine ring construction has been applied to the synthesis of (+)-castanospermine and possible isomers of uniflorine-A. The routes to these targets rely on the use of the earlier discovered photocyclization reaction of pyridinium perchlorate in a concise route for preparation of a key N-allylacetamidocyclopentendiol intermediate. Ring rearrangement metathesis of this substance gives an allyl-tetrahydropyridine, which is then transformed to the targets by execution of regio- and stereo-controlled hydroxylation processes followed by indolizidine ring construction.     

Nitrenium ion-mediated alkene bis-cyclofunctionalization: total synthesis of (-)-swainsonine

The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-D-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an γ,δ-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.