Synthesis of quinolizidines

An interesting synthesis of quinolizidines was achieved using a vinylogous variation of the Bischler-Napieralski reaction. Angelastro and coworkers reported that treatment of amide 26 with PPSE (polyphosphoric acid trimethylsilyl ester) followed by reductive... 

The intramolecular cyclization of l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5, 6-tetrahydropyridine (140) and l-(3-bromopropyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (143) (89T5269) resulted in the synthesis of quinolizidine ring system 141 and indolizidine ring system 144 in 43% and 72% yields along with the reduced tetrahydropyridines 142 and 145 in 21% and 8% yields, respectively. All the cyclized products appeared to be (ran.s-fused indolizidines or quinolizidines. The (ran.s -fused simple indolizidines are known to be some 2.4 kcal mol more stable than the d.s-fused isomers (68TL6191). In the and-isomer the methoxycarbonyl substituent occupies an equatorial position. 

The Hg(ll) cation was used to activate the double bond in lactam 178, which was obtained by detosylation of 177 using the Parsons method. This strategy allowed the synthesis of quinolizidine derivative 179, which was obtained as a single /raar-diastereoisomer (Scheme 31). Besides its higher thermodynamic stability with respect to that of the m-isomer, formation of the trans-isomer must involve a lower activation energy since its intermediate precursor, in which the lone pair of electrons of nitrogen must attack from the back side of the mercuronium ion, is sterically less hindered than the precursor of the m-isomer <2003TL4653>. 

In a formal synthesis of quinolizidine 233A 296, the 2,6-m-disubstituted piperidine 292, as a mixture of dia-stereomers, was transformed into 293 by N-acylation with but-3-enoyl chloride. An RCM afforded 294, which was transformed into 295 by hydrogenation of the double bonds and hydride reduction of the lactam, thereby completing a formal synthesis <2000JOC8908> of quinolizidine 233A 296 (Scheme 65) <2004JA4100>. 

Tribromo acids of this type (41) can also be used for the synthesis of quinolizidine and other 1-azabicyclic alkanes with functional substituents. 

The synthesis of quinolizidine (3-spiro-2 )-tetrahydrothiophene (67a, 67b), a model compound for the synthesis of dimeric sulfur alkaloids, was reported (65, 66). The compound was prepared from 2-cyanotetrahydrothiophene (66) by two independent routes, both utilizing phase-transfer catalysis (Scheme 10). 

As mentioned previously, acyliminium ions are electrophilic enough to react intramolecularly even with nonactivated alkenic ir-systems. These cyclization reactions have been recognized and elaborated as valuable tools in the stereoselective total synthesis of quinolizidine, indolizidine and pyrrolizidine alkaloids. A typical example from Speckamp s laboratory is the highly stereospecific acid-catalyzed cyclization of (81) to (83 Scheme 40), presumably via the corresponding acyliminium ion (82). Analogously, other more complex natural products, such as the antiulcerogenically active alkaloid ma-trine (85), can be built up with high stereocontrol (Scheme 41), with an enol ether function as a more electron-rich nucleophile for the intermediate iminium ion (84). ... 

Sulfinimines (A-sulfinyl imines) in asymmetric synthesis of quinolizidines and indolizidines 04T8003. 

Intramolecular iminoacetonitrile [4-1-2] cycloaddition has been exploited in the synthesis of quinolizidine alkaloids (Scheme 54). The intermediate 187 was generated by elimination of trifluoromethanesulfinate from 188 and underwent the desired aza Diels-Alder reaction to give 189. A series of steps which included reduetive decyanation, alkylation with (Z)-3-bromo-l-chloropropene, classical resolution, and Sonogashira coupling provided the alkaloid (-)-217A 190<050L3115>. 

Synthesis of (—)-Lasubine II. A reductive desulfonylation with lithium in ammonia is employed in the total synthesis of quinolizidine alkaloid (—)-lasubine II.264 A conjugate addition of methyl (.S )-(2-pipcridyl)acetate to an acetylenic sulfone, followed by lithium diisopropylamide (LDA)-promoted intramolecular acylation is the key step in the preparation of the quinolizine structure of (—)-lasubine II (Eq. 154). 

Scheme 18 Completion of the total synthesis of quinolizidine-type alkaloids...

Another synthesis of quinolizidine is due to the work of Clemo, Ramage, and Raper (133). Ethyl 7-2-pyridylbutyrate (XL) was... 

Heteroatom nucleophiles were described less often. Ye and coworkers published a phospha-Michael addition catalysed by prolinol silyl ether catalyst. Another method for constructing a new C-N bond is the aza-Michael addition, that is the addition of nitrogen-based nucleophiles to a,(3-unsaturated aldehydes. Several groups published these type of reactions using diatylprolinol silyl ether as catalyst. " Fustero and coworkers used this reaction as a key step in the synthesis of biologically active chiral heterocycles. Recently, the authors showed the synthesis of quinolizidine alkaloids, such as (-l-)-myrtine, (-)-lupine and (-l-)-epiquinamide. Vicario applied 5-mercaptotetrazoles as nucleophiles towards a range of unsaturated aldehydes. The reaction proceeded via the iminium activation. The... 

Wink M, Hartmaim T (1982) Enzymatic synthesis of quinolizidine alkaloid esters a tigloyl-CoA 13-hydroxyhipanine O-tigloyltransferase from Lupinus albus L. Planta 156 560-565... 

Wink M, Hartmaim T (1981) Sites of enzyme synthesis of quinolizidine alkaloids and their accumulation in Lupinus polyphyllus. J Plant Physiol 102 337-344... 

The focalpoint of the synthesis of (—)-quinolizidine 217A (2246) by Maloney and Danheiser was the assembly of the quinolizidine nucleus by an... 

Michel and coworkers adapted their synthesis of ( )-quinolizidine 2071 (rac-1728) described at the beginning of this section (cf Scheme 282) in order to... 

Liebeskind s synthesis of (lil,4il,9aS)-quinolizidine 251AA (2297), referred to above, was an extension of the route his team had previously used in the synthesis of 5,8-disubstituted indolizidine alkaloids (cf. Scheme 241 Section 6.2.5). In brief, the chiral molybdenum complex (—)-1909 was converted in six steps into the 2,3-iraHS-2,6-n 5-tetrahydropyr-idine (2S,3il,6il)-(—)-2298 (Scheme 293). Tandem hydrogenation of the alkene and hydrogenolysis of the protecting groups followed by ring closure of the amino alcohol (—)-2299 under Mitsunobu conditions then completed the synthesis of (—)-quinolizidine 251AA (2297) (Scheme 293). 

A completely different approach to the synthesis of quinolizidine alkaloids is described by Tufariello. The synthesis makes use of the ready addition of conjugated dienes to nitrones to yield bicyclic isoxazolidines (Scheme 72),... 

The synthesis of quinolizidine alkaloids and of pyrrolidines as precursors of retronecine are mentioned in Chapter 24... 

SCHEME 40.63. Aza-Diels Alder reaction as the key step for the synthesis of quinolizidine (-)-217A. 

In the last decade, aza-Diels Alder reactions were used effectively to synthesize chiral six-member cyclic systems. Maloney and Danheiser reported on a strategy for the total synthesis of quinolizidine alkaloid (—)-217A 285 where aza-Diels-Alder reaction was used as the key step to induce the chirality in the molecule. The sulfonamide 282 prepared from 5-hexenol 281 by multistep procedures was converted into the aza-Diels Alder precursor 283. It underwent an intramolecular hetero Diels-Alder reaction at 130°C to afford cyclic a-amino nitrile 284 with 56-59% yield. From 284 quinolizidine (—)-217A 285 was prepared following simple steps (Scheme 40.63). This alkaloid is present in the skin of small dendrobatid frog, Dendrobates pumilio ... 

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