Quinolizidine alkaloids, chiral synthesis

The 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines are the more common structural patterns found in amphibian skin[21]. None of these alkaloids has so far been reported from any other source. In addition, the biological activity of only a few 5,8-disubstituted indolizidines has been investigated due to the isolation in minute quantities from the skin. Among them, the relative stereochemistry of quinolizidine 2071 was anticipated to be 75 by our chiral synthesis of 76[35] followed by stereocontrolled synthesis of 75[36]. A sample of synthetic racemate of 75 had produced the best separations on GC analysis with (3-dextrin chiral column[36]. 

A new convenient procedure for the chiral alkylation of 5-acetoxy-2-pyrrolidinone (91) and 6-acetoxy-2-piperidinone (92) has been developed. This procedure should be useful for an extremely short chiral synthesis of the bicyclic alkaloids involving pyrrolizidine, indolizidine, and quinolizidine skeletons (88JA289). 

In a similar manner, the 2-cyano-6-oxazolopiperidine synthon is useful for the chiral synthesis of in-dolizidine (monomerine piperidine [(+)- and (-)-coniine and dihydropinidine] and quinolizidine alkaloids.2-Hydroxymethyl-1-amino-1-cyclopropanecarboxylic acid (-)-(2I )-hydroxy-(3S)-nonylamine and a-substituted phenylethylamines are obtained in optically active form from (-)-N-cyanomethyl-4-phenyloxazolidine. 

Progress in total synthesis of marine alkaloids, aaptamines 99H(50)549. Racemic and chiral syntheses of some indolo[2,3-a]quinolizidine alkaloids through a lactim ether route 98H(47)525. 

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... 

On the other hand, a direct asymmetric Mannich reaction was reported, in 2009, by Rutjes et al. in the course of developing a synthesis of the bioactive quinolizidine alkaloid lasubine II. Therefore, the key step of this synthesis was the L-proline-catalysed Mannich reaction between acetone, para-mtm-benzaldehyde and veratryl aldehyde, providing the expected Mannich adduct in moderate yield and almost complete enantioselectivity (Scheme 3.5). This chiral p-amino ketone was further converted into the desired (-F )-lasubine II. 

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 ... 

Bicyclic alkaloids. Nagao et al. have developed a general synthesis of chiral bicyclic alkaloids with a nitrogen atom at the ring juncture, such as pyrrolizidines [5.5], quinolizidines [6.6], and indolizidines [6.5], based on a highly diastereose-lective alkylation of 3-a>-chloroacyl-(4S)-isopropyl-l,3-thiazolidine-2-thiones (1, m = 1,2) with 5-acetoxy-2-pyrrolidinone (2, n = 1) or 6-acetoxy-2-piperidinone (2, n = 2). Thus the tin enolate of 1 (m = 1), prepared with Sn(OTf) and N-... 

Consistently high levels of asymmetric induction have been achieved in the alkylation of tetrahydroisoquinolines using this methodology, as is demonstrated in the synthesis of chiral isoquinolinium alkaloids, e.g., (-)-salsolidine (61% yield, 95% ee)13, ( + )-homolaudanosine (48% yield, 96% op)14, ( —)-norcoralydine (37% yield, 98.5% op)15, some ben-zo[ ]quinolizidines (>99%ee), precursors of natural emetine16, corynantheine alkaloids17 and some azasteroids (93% ee)18. 

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). 

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