Quinolizidine derivatives

Conformational study of geissoschizine isomers and their model compounds (geissoschizine is the indolo[2,3-fl]quinolizidine derivative considered to be an important participant of indole alkaloids biogenesis) 99H(51)649. 

Structural characterization of many quinolizidine derivatives has been established by X-ray diffraction. For example, this technique, in combination with spectroscopic methods, showed that (+)-2-thionosparteine 21 and (+)-2,17-dithionospartine 22 are conformationally rigid and have their lactam and thiolactam groups close to planarity, with the exception of the lactam group in 21, and that rings A and C adopt distorted sofa conformations <2005JST75>. 

Nuclear Overhauser enhancement spectroscopy (NOESY) experiments play a very important role in structural studies in quinolizidine derivatives. For instance, the endo-type structure of compound 28 was proven by the steric proximity of the H-3a and H-12a protons according to the NOESY cross peak, while the spatial proximity of the H-6f3 and H-8/3 protons reveals that tha A/B ring junction has a /ra t-stereochemistry. Similarly, compound 28 could be distinguished from its regioisomer 29 on the basis of the NOESY behavior of its H-13 atom <1999JST153>. 

The nitrogen atom in quinolizidine derivatives behaves as a tertiary amine and hence it can undergo quaternization by reaction with alkyl halides. For instance, berberine derivative 101 was transformed into 102 by treatment with 3-iodopropanol followed by anion exchange. Compound 102 was then transformed into intermediate 103, which was employed as a precursor for the the preparation of bis-ammonium salt 104 (Scheme 10). This compound showed ultrashort curare-like activity in rhesus monkeys <2001JOC3495>. 

Examples of the more frequent nucleophilic attack of a piperidine nitrogen atom onto an alkyl halide to yield quinolizidine derivatives are described below. Piperidinediol 142, after debenzylation and treatment with PBr5... 

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>. 

The strategy employed in studies aiming at the synthesis of the spiro segment of halichlorine (see also Section 12.01.11.4) involved a ring expansion in indolizidine 264. The double bond of this compound was cleaved by ozonolysis yielding compound 265, which was cyclized to quinolizidine derivative 266 in the presence of base (Scheme 56) <2004TL2879>. 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

The application of the RCM reaction to the construction of nitrogen-containing ring systems, including quinolizidine derivatives, has been reviewed <1999EJ0959>. From that date, this strategy has become more and more common in quinolizidine synthesis, especially in cases where the cyclization takes place by formation of a bond 7 to the heteroatom. Some examples are given below. 

Hetero-Diels-Alder reactions have been succesfully employed for the synthesis of arenoquinolizine systems. For example, as shown in Equation 10, treatment of tetrahydroquinoline 319 with Danishefsky s diene 320 in the presence of a Lewis acid gave the benzo[c]quinolizidine derivative 321 <2000JME3718>. 

Another method that yields quinolizidine derivatives by creation of two ct-bonds from acyclic precursors is based on a domino process involving a sequence of a double N-deprotection and a double intramolecular Michael addition sequence of reactions, as summarized in Scheme 75 <2002TL6505>. 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

Results of a study of acid-catalysed epimerization of indolo [2,3-a]quinolizidine derivatives support a mechanism involving nitrogen lone pairs in an eliminative ring opening-ring closure. ... 

As suggested by the title the principal emphasis in this chapter will be on the quinolizinium ion and its benzo analogs, with quinolizine and quinolizidine derivatives being mentioned only if they are obtained from, or transformed to, the aromatic species. For a more comprehensive treatment of these non-cationic species, the earlier reviews by Thyagarajan <65AHC(5)291> and by Mosby <61HC(15-2)1001> should be consulted. 

Yttrium-catalyzed diene cyclization/hydrosilylation was applied to the synthesis of aliphatic nitrogen heterocycles such as the indolizidine alkaloid ( )-epilupinine. l-Allyl-2-vinylpiperidine 30 was synthesized in four steps in 59% overall yield from commercially available ( )-2-piperidinemethanol (Scheme 10). Treatment of 30 with phenylsilane and a catalytic amount of Gp 2YGH3(THF) gave silylated quinolizidine derivative 31 in 84% yield, resulting from selective hydrometallation of the A-allyl G=G bond in preference to the exocyclic vinylic G=G bond. Oxidation of the crude reaction mixture with tert-huVf hydrogen peroxide and potassium hydride gave (i)-epilupinine in 51-62% yield from 30 (Scheme 10). 

The nature of the ring fusion in quinolizidine derivatives may be determined from the 15N chemical shifts, which are to lower field in the transfused derivatives. This is shown for the indolo[a]quinolizidines 73 and 74 (chemical shifts to low field of external anhydrous liquid ammonia)115 and by the perhydropyrido[l,2-c][l,3]thiazines 8 66.9 trans conformer 312, 8 43.9 S-inside cis conformer 313.ll5a... 

All the monomethyl- and monohydroxyquinolizidines exist predominantly in the trans-fused conformation and the early IR and H-NMR studies on which these assignments were based (cf. especially Ref. 134) have been reviewed.14 The predominance of the trans-fused conformation for many quinolizidine derivatives has also been demonstrated by 13C-NMR spectroscopy.79,86 The trans-fused conformation for 182, the only transfused monomethylquinolizidine to show anomalous Bohlmann IR absorption (Section II,E,1), has been confirmed by 13C-NMR spectroscopy.214... 

C NMR spectra of nine Nuphar alkaloids and of model compounds have been reported. (157) Reference to the spectra of deoxynupharidine [233], 7-epideoxynupharidine [234], and the thiomethylquinolizidines [235] and [236] illustrates the low frequency absorption of axial 13CH3 and axial 13CH2SMe nuclei in trans fused quinolizidine derivatives... 

The common intermediate in two published biomimetic routes to Lythraceae alkaloids was substituted 4-phenylquinolizid-2-one. In one approach based on a biogenetic hypothesis of Ferris et al. (62), Wrobel and Gol biewski condensed pelletierine (126) with isovanillin (128) and obtained a transfused quinolizidine derivative (130, jS H-5) (64) in 75% yield. A model condensation of pelletierine (126) with benzaldehyde which resulted in a mixture of quinolizidones was reported earlier by Matsunaga et al. (65). In another approach Rosazza et al. (52) condensed A -pjperideine (132) with /J-ketoester 133 to get 134. The next stage in both approaches was reduction of the ketone and esterification or transesterification with derivatives of p-hydroxycinna-mic acid (135 or 136). Investigations into the oxidative coupling of 137 were unsuccessful. 

Scheme 10. Routes for, he synthesis of spirotetrahydrothiophene-quinolizidine derivatives.

Intramolecular conjugate additions with nitriles 244 have been performed by deprotonation with n-BuLi in the presence of 12-crown-4 at room temperature, giving mainly indolizidine and quinolizidine derivatives 245 with the cyano group in an axial orientation (Scheme 67)395. The deprotection of the final dithioacetal has been achieved with bis(trifluoroacetoxy)iodobenzene396. 

A related reductive cyclisation has been developed by Schafer et al. in which the cathodic cyclisation of A-(oxoalkyl)pyridinium salts led to indolizidine and quinolizidine derivatives <95AG(E)2007, 03EJO2919>. Electrolyses of the pyridinium salts were carried out in a divided beaker-t5q)e cell at a mercury pool cathode under constant current, using 1 M aqueous sulfuric acid as the electrolyte. In this way, cyclisation of cyclopentanone 129 to the isomeric quinolizidines 130 and 131 was achieved in high yield and with excellent diastereoselectivity (Scheme 38). The stereochemical course of the reaction with cyclohexanone 133 was not as well defined, with three of the four possible diastereoisomers being given in a ratio of 10 21 26 (for 134,135 and 136 respectively). 

Quinolizidine derivatives with a more or less extended and planar aromatic moiety displayed antimicrobial activity [256]. Similar compounds were prepared for testing against Mycobacterium tuberculosis, due to the growing concern for the upsurge of new cases of tuberculosis and of non-tuberculous mycobacterioses in the western world since 1986. Several quinolizidines (Q) bearing different aryl nuclei substituents (which changed both the electronic distribution and the lipophilic-hydrophilic balance of the molecule) were synthesised. Six of these synthesised compounds (Q1-Q6), Fig. (42), were highly active and it is reasonable to state that... 

Fig. (42). Structures of synthetic quinolizidine derivatives that possess an aromatic moiety Ql-Q6 [256]...

Liljefors, T. Bogeso, K.P. Hyttel, J. Wikstrom, H. Svensson, K Carlsson, A. (1990) Pre- and postsynaptic dopaminergic activities of indolizidine and quinolizidine derivatives of 3-(3-hydroxyphenyl)-N-( -propyl)piperidine (3-PPP). Further development of a dopamine receptor model. J. Med. Chem. 33, 1015-1022. 

Intramolecular amine-oxirane cyclizations give mainly quinolizidine derivatives by a 6-exo-tet ring closure <88JOC4452>. 

Many other synthetic benzo a]quinolizidine derivatives, structurally more or less related to the alkaloids of types 72-75, have been available a number of indole alkaloids carrying the indolo[2, 3 3,4]pyrido[l,2-b][2,7]-naphthyridine ring system, structurally analogous to the A. lamarckii alkaloids 56-64, have been isolated from other plants and/or synthesized. However, this section is not intended to cover them because of the limited space. 

EtOH). Nuttalline is a hydroxylactam of the sparteine series, and exhibits i.r. absorption bands characteristic of a trans-quinolizidine derivative its properties indicate that it is (-b )-4a-hydroxy-2-oxosparteine (4), and it is the first example of a naturally-occurring 2,4-dioxygenated sparteine. Nuttalline gives a complicated mixture of products when reduced by lithium aluminium hydride, but with sodium borohydride affords deoxonuttalline [(— )-4a-hydroxy-sparteine], which can be converted by dehydration and hydrogenation into (—)-sparteine. 

Quinolizidine derivatives formed by hydrogenation of the dicyano ketone 4 to catalyst loading affects the stereochemistry of cyclization, probably by isomerization. 

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