Enantioselective Syntheses of 2-Alkyl-, 2,6-Dialkylpiperidines and Indolizidine Alkaloids Through Diastereoselective Mannich-Michael Reactions

Weymann, Markus; Pfrengle, Waldemar; Schollmeyer, Dieter; Kunz, Horst

doi:10.1055/s-1997-3185

Cited by 105 publications

(43 citation statements)

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“…However, the isolated yield was modest (37%), almost certainly because the product is very volatile, as several authors have pointed out; Holmes and co-workers, for example, chose to isolate the alkaloid as its hydrochloride salt [7] . More to the point, the NMR spectra recorded on our product were in perfect agreement with those reported in the literature for indolizidine 167B [9] [11] [12] [15] [17] , and the 13 C-NMR spectrum in particular was quite different from that reported for the alternative diastereoisomer [11] . In summary, we have achieved a short (eight-step) synthesis of (±)-rel-(5R,9R)-indolizidine 167B (1) in an overall yield of 7.2% based on pyrrolidine-2-thione (5).…”

Section: Resultssupporting

confidence: 83%

“…The structure and relative stereochemistry shown in 1 (which also shows the conventional numbering of the indolizidine system) are now accepted as correct, although the absolute configuration of the natural product remains uncertain. The alkaloid is a popular synthetic target, and syntheses of the racemic compound [7] [8] [9] [10] , the (5R,9R)-(Ϫ) enantiomer 1 [11] [12] [13] [14] [15] [16] [17] and the (5S,9S)-(ϩ) enantiomer ent-1 [18] have been published. The diastereoisomer 2 has also been synthesised as the racemate [8] and as clude a ring closure that takes advantage of the nucleophilicity of a vinylogous urethane 8, and stereoselective reduction of the C=C double bond of a bicyclic vinylogous amide 12.…”

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confidence: 99%

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An Expeditious Synthesis of the Dendrobatid Indolizidine Alkaloid 167B

Michael

Gravestock

1998

Eur. J. Org. Chem.

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Section: Resultssupporting

confidence: 83%

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confidence: 99%

An Expeditious Synthesis of the Dendrobatid Indolizidine Alkaloid 167B

Michael

Gravestock

1998

Eur. J. Org. Chem.

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“…The X-ray analysis of 53 proved (R) configuration of the major diastereomer ( Figure 22). Despite their low reactivity, these enaminones can be converted into chiral 2,6-disubstituted piperidinones with high stereoselectivity by reaction with organo-cuprates in combination with hard electrophiles [42].Condensations of the N,N-dibenzyl-α-amino esters with the anion of acetonitrile, yielded compound 54, which was followed by the addition of a Grignard reagents and a fforded rapid access to the peptidomimetic α-a m i n o enaminones 55 in one pot from the esters. The use of methyl and phenyl Grignard reagents gave enaminones 55 (Figure 23) with an asymmetric center adjacent to the carbonyl.…”

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confidence: 99%

Recent development in preparation reactivity and biological activity of enaminoketones and enaminothiones and their utilization to prepare heterocyclic compounds

Negri

Kascheres

2004

Journal of Heterocyclic Chem

177

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Enaminoketones and esters are gaining increased interest, particularly cyclic-β-enaminoesters, which are known as important intermediates for the synthesis of heterocycles and natural products, because the enantioselective preparation of highly functionalized compounds is of central importance in synthetic chemistry. Enaminones are versatile synthetic intermediates that combine the ambident nucleophilicity of enamines with the ambident eletrophilicity of enones. Enaminoketones and enaminonitriles have proven to be versatile building blocks for the synthesis of various heterocycles such as pyridine, pyrimidine and pyrrole derivatives. Enaminones systems have "enone" character, and may act as acceptors in both 1,2 and 1,4-additions. In this way the enaminone serves as a scaffold for annulation, and can gain access to systems such as pyrroles indolizidines, quinolizidines and perhydroindoles, all of which are common motifs in alkaloid structures. Enaminones are frequently employed as building blocks for the preparation of a variety of bicyclic compounds of biological interest and have been recently recognized as potential anticonvulsant compounds. Since a large number of developments in the use of enaminones in heterocyclic synthesis have occurred, a review of the recent developments in the synthetic approaches, covering the literature since 1995 until 2004, to these interesting molecules and their useful chemical transformations and biological activity can be considered of considerable value.J. Heterocyclic Chem., 41, 461 (2004).Enaminoketones. Introduction.The term enaminone was introduced by Greenhill to define the enamine of a 1,3-diketone, β-ketoester or similar 1,3-difunctional reagents, and is used to indicate any compound containing the conjugated system N-C=C-C=O [1]. Enaminones are versatile synthetic intermediates that combine the ambident nucleophilicity of enamines with the ambident eletrophilicity of enones. The chemistry of the enaminocarbonyl group 1 is potentially an area of considerable scope when one considers that there are present in this moiety, three nucleophilic sites (a, c and e) and two electrophilic sites (b and d) [2][3][4] (Figure 1).Theorically, primary and secondary acyclic enaminones can exist in three tautomeric forms: ketamino form, iminoenol form and oxoimino form [1][2][3]. There is also evidence that cyclic enaminones exist primarily in the enaminoketo form. A study of cyclic enaminoketones shows that these compounds have a significant steric fator in the six-membered ring. The six-membered ring enaminoketones are only slightly stronger bases than the saturated amines, whereas five-and-seven membered rings are much stronger bases than saturated amines. This has been attributed to a large steric strain present in six-membered enaminoketones [5].β-Aminoenones or enaminoketones can exist in four conformations owing to restricted rotations around the C=C double and C-C=O single bonds [3]. Enaminones with primary or secondary amino groups can exist in both Z-and E-forms. If there is a...

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“…On one hand, the time-consuming procedures of particle syn- The potential of this stereodifferentiating synthesis on solid phase becomes evident, if one keeps in mind that the corresponding l-amino acid derivatives are available by analogous use of the d-arabinopyranosylamine, [15] that combinatorial reactions with phosphites give a-aminophosphonic acid derivatives, [16] those with silyl ketene acetals yield bamino acid derivatives [17] or with silyl dienol ethers furnish mono-and bicyclic chiral nitrogen heterocycles. [18,19] Thus, the stereodifferentiating effect of solid-phase-linked glycosylamines of type 11 provides a versatile combinatorial access to chiral products of diverse structure.…”

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confidence: 99%