Quinolizidine derivatives Quinolizidines

Bohlmann et al. (118-121) observed that an infrared absorption band between 2700-2800 cm is characteristic of a piperidine derivative possessing at least two axial carbon-hydrogen bonds in antiperiplanar position to the free-electron pair on the nitrogen atom. The possibility of forming an enamine by dehydrogenation can be determined by this test. Compounds which do not fulfill this condition cannot usually be dehydrogenated (50, 122,123). Thus, for example, yohimbine can be dehydrogenated by mercuric acetate,whereas reserpine or pseudoyohimbine do not react (124). The quinolizidine (125) enamines (Scheme 4), l-azabicyclo(4,3,0)-nonane, l-azabicyclo(5,3,0)decane, l-azabicyclo(5,4,0)undecane, and l-azabicyclo(5,5,0)dodecane have been prepared in this manner (112,126). 

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>. 

Many polyhydroxylated quinolizidines <1995CRV1677>, frequently designed as azasugars, are powerful glycosidase inhibitors and therefore have potential therapeutic application. The 7-oxa-l-azabicyclo[2.2.1]heptane derivative 191, obtained from 3-0-benzyl-l,2-0-isopropylidene-l,5-pentadialdo-a-D-xylofuranose with... 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

Alternatively, the enamine portion may be located in the Aralkyl chain. For instance, piperidines bearing a 7-chloro substituent yielded quinolizidines 263 through a conjugate addition of the nitrogen atom to acetylenic sulfones followed by an intramolecular alkylation (Scheme 55) <2000JOC4543>. Other cyclizations that are summarized below used as starting materials piperidine derivatives obtained by similar conjugate additions to vinyl sulfones (see Section 12.01.9.3.6). 

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>. 

An intramolecular Mannich reaction of carboline derivative 352 afforded a complex bridged system containing an indolo[2,3-tf]quinolizidine moiety, as a mixture of two diastereomers. One of them, 353, was transformed into the alkaloid tacamonine 15 (Scheme 79) <2002T4969>. 

A double RCM reaction of 367 permitted the efficient construction of the fused bicyclic quinolizidine skeleton 368 as the major product, together with a small amount of the other possible double-metathesis product 369 (Scheme 84) <20020L639, 2004CEJ3286>. Similarly, an RCEYM process from substrate 370, carried out in an atmosphere of ethylene, afforded the quinolizine derivative 371 <2004JOC6305>. 

Nitrones derived from 2-azabicyclo[5.3.0]decane give quinolizidine compounds by photochemical Beckmann rearrangement which implies simultaneous ring expansion and ring contraction reactions. Intramolecular Schmidt reactions in 2(4-azidobutyl)-cyclopentanones also give quinolizidinone derivatives by ring expansion. Examples of both types of reactions are given in Sections 12.01.11.1 and 12.01.11.3, respectively. 

Intramolecular 1,3-dipolar cycloaddition reactions of N -(3-alkenyl)nitrones, as presented in Scheme 2.21 le, led to the synthesis of polyhydroxy derivatives of quinolizidine (474) and indolizidine (475) (Scheme 2.234) (732). 

Two protected 3-amino acids, containing indolizidine and quinolizidine skeletons (607a,b), have been synthesized by using 1,3-dipolar cycloaddition of nitrones (551) and (552) to methyl ( )-5-mesyloxy-2-pentenoate. The key steps of this approach is demonstrated by novel syntheses of indolizidinone and quino-lizidinone derivatives (606a,b) and by the ring opening of the tricyclic 1,3-dipolar cycloaddition products (605a,b) (Scheme 2.268) (779). 

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. 

When pyridinium salt 187 was transformed to an indolo[2,3-a]quinolizidine compound in a similar way and the unsaturated lactone 188 was hydrogenated over platina catalyst, a mixture of vallesiachotamine-type compounds (189 di-astereomers) epimeric at C-20 was formed (134). These compounds have also been prepared in optically active form from vallesiachotamine (9), thus producing the first chemical correlation between synthetic and natural vallesiachotamine derivatives (134). 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

Results and data gathered on mass spectroscopy of various indole alkaloids have been summarized by Hesse (320). The derivation of the characteristic fragments of indolo[2,3-a]quinolizidines has been interpreted by Gribble and Nelson (321), who investigated C-3, C-5, C-6, C-20, and C-21 deuterated derivatives of octahydroindolo[2,3-a]quinolizine (1). Kametani et al. have observed and proved, with labeled compounds, a methyl transfer from the ester function of reserpine derivatives to the basic nitrogen atom during mass-spectroscopic measurement (322). 

Pyridinium salts tethered to ketones also undergo cathodic cyclization [1]. The reaction provides a convenient diastereoselective route to quinolizidine and indolizidine derivatives such as 203, 204 and 206, 208, and 209, and appears to hold significant promise as a route to alkaloids. Examples are portrayed and the optimal conditions are listed below the equations. A mercury cathode is preferred, as passivation occurs when lead is used, and the reaction does not occur... 

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. ... 

L-methionine L-phenylalanine Phenylalanine-derived alkaloids Piperidine alkaloids Quinolizidine alkaloids Indolizidine alkaloids True alkaloids... 

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