Indolizidines enantioselective synthesis

A novel approach to azabicyclic ring systems, based on an epoxide-initiated electrophilic cyclization of an alkyl azide, has been developed by Baskaran. A new stereo- and enantioselective synthesis of the 5-hydroxymethyl azabicyclic framework 91a, present in (+)- and (-)-indolizidines 167B and 209D, for example, was... 

First Enantioselective Synthesis of Dendrobatid Alkaloids Indolizidine 2091 and 223J 53... 

Randl, S., Blechert, S. Concise Enantioselective Synthesis of 3,5-Dialkyl-Substituted Indolizidine Alkaloids via Sequential Cross-Metathesis-Double-Reductive Cyclization. J. Org. Chem. 2003, 68, 8879-8882. 

Gallc er and co-workers devised a formal enantioselective synthesis of ( — )-3 in wduch the stereogenic center at C-6 was derived fiom Cbz-protected (S)-2-amino-4-pentenoic acid (36) (44). Acylation of 3,3-dimethoxy-pyrrolidine (37) with this acid yielded amide 38, which was converted into aldehyde 39 by cleavage of the terminal alkene vnth osmium tetroxide and sodium periodate (Scheme 5). The indolizidine nucleus was constructed from 39 by a problematic intramolecular aldol condensation, which was eventually optimized by using 2,2,6,6-tetramethylpiperidine as base followed by adsorption onto, and elution from, silica gel (45). Diastereoselective reduction of the ketone group of the aldol product 40 was accomplished in better than 95% enantiomeric excess (ee) with the Corey... 

An attempted enantioselective synthesis of ipalbidine from the protected (S)-prolinol 860 was based on the regioselective 6-exo-trig cyclization of the radical intermediate derived from the reaction of the phenylthio compound 861 with tributyltin hydride (Scheme 111) (577). The reaction gave a 1 1 mixture of two indolizidin-5-one diastereomers 862 in 65% yield. At the end of the synthesis, the target 842 was found to possess virtually no optical activity. The most likely candidate for racemization is the aldehyde 863, which might scramble under the basic conditions required for the subsequent Wittig reaction. 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Scheme 228 Enantioselective synthesis of various 3,5-dialkylated indolizidine alkaloids by Remuson and coworkers. Reagents and conditions (a) ISOO + SnCU (1 M in CH2CI2), CH2CI2, 78 °C, then allylsilane 1801 (1.1 equiv.), -20 °C, 90 min (b) pyridi-nium dichromate, CH2CI2, 25 °C, 24 h (c) H2 (3 atm), 10% Pd/C, MeOH, rt, 5 h.

A previously communicated synthesis of (—)-indohzidine 209B (1876) by Michael and Gravestock, described in the earHer review chapter in this series, was subsequendy pubUshed with lull experimental details. " This work was later extended to include the enantioselective synthesis of the (5J .,8S,8aS)-diastereomer, (—)-8- -indolizidine 209B (2007)... 

SCHEME 17.13. Enantioselective synthesis of (—)-indolizidines 209B 57 and 209D 58 by an aza-[2,3]-Wittig rearrangement ring expansion of aziridine 55. 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

The alio series of the pumiliotoxin A class have an additional hydroxyl group that has been placed at C-7 on the indolizidine ring, without assignment of configuration. Three members of the alio series have been assigned the tentative structures (7), (8), and (9).3 Pumiliotoxins A and B are relatively toxic, and comparable in potency to strychnine. Pumiliotoxin B has a potent cardiotonic and myotonic activity.3 An enantioselective total synthesis of pumiliotoxin A alkaloids from L-proline has already been announced.4... 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

Weymann, M, Pfrengle, W, Schollmeyer, D, Kunz, H, Enantioselective syntheses of 2-alkyl, 2,6-dialkylpiperidines and indolizidine alkaloids through diastereoselective Mannich-Michael reactions, Synthesis, 1151-1160, 1997. 

The concise enantioselective total synthesis of (+)-monomorine I, a 3,5-dialkyl-substituted indolizidine alkaloid, was completed by S. Blechert et al. using a sequential cross-metathesis double reductive cyclization strategy. The enedione substrate was prepared in two steps. The Stetter reaction between the masked equivalent of acrolein and butyl vinyl ketone was followed by a retro Diels-Alder reaction under flash vacuum pyrolysis (FVP) conditions. 

The synthesis of indolizidine 195B (450) has in general been the fortuitous result of indifferent diastereoselectivity in routes to its diastereomer monomorine I (427). The racemic alkaloid accompanied ( )-monomorine I, and sometimes other diastereomers, in several post-1985 syntheses (393,397,399,400,402,403). Enantioselective syntheses of 450 published during the period 1985-1993, most of them also producing 427, were discussed in Volume 44 of this treatise (2), while post-1993 enantioselective syntheses leading to mixtures of 427 and 450 were detailed in Section V.A of this chapter (404,410,413,415,419). A conference paper describing the synthesis of (+ )-450 and the C-5 epimer (+ )-595 was also highlighted in Volume 44 this work has subsequently been published with full experimental details (468). 

Nine routes to racemic indolizidine 223AB (rac-432), occasionally accompanied by diastereomers, were published between 1985 and 1994 (393,469-476), but subsequent syntheses all appear to have been enantioselective (vide infra). The only recent synthesis of indolizidine 239CD yielded the racemic alkaloid ( )-597 (477). 

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