Epilupinine syntheses

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

Quinolizidine synthesis via intramolecular immonium ion based Diels-Alder reactions total synthesis of ( )-lupinine, ( )-epilupinine, ( )-criptopleurine and ( )-julandine [97]... 

The key step in the total synthesis of (—)-epilupinine 253 involved the ring expansion of a proline-derived spirocyclic ammonium ylide to give 252 through a [1,2] Stevens rearrangement, as shown in Scheme 51 <1997T16565>. 

Another useful route to alkaloids involves the electrochemical oxidation of lactams (145) bearing functionality on nitrogen that can be used to intramolec-ularly capture an intermediate acyl im-minium ion (146). The concept is portrayed in Scheme 33 and is highlighted by the synthesis of alkaloids lupinine (150) and epilupinine (151) shown in Scheme 34 [60]. Thus, the electrooxidation of lactam (147) provided a 71% yield of ether (148). Subsequent treatment with titanium tetrachloride affected cyclization and afforded the [4.4.0] bicyclic adduct (149). Krapcho decarbomethoxylation followed by hydride reduction of both the... 

This methodology was applied to a concise synthesis of the alkaloid epilupinine (Scheme 18.10) [27]. N-alkylation of proline benzyl ester with bromo diazoketone 25 gave substrate 26. Treatment with either Rh2(OAc)4 or various copper-based catalysts... 

Lupinine (2) is easily epimerized to epilupinine (33), a compound occurring in nature and also formed by synthesis (82-87). The synthesis of optically active natural lupinine and epilupinine was accomplished in 1967 (S5). Optically active... 

Analogous reactions involving the more reactive iminium ions have also been observed. For example, a lupinine synthesis involved (203) as a reactive intermediate (60JA502). The decarboxylation of. the diacid was relatively nonstereospecific giving, after reduction, a mixture of ( )-lupinine and ( )-epilupinine. 

The cyclic ammonium ylide/[l,2]-shift approach has been successfully applied by West and Naidu to a key step in the total synthesis of (—)-epilupinine, one of the biologically active lupin alkaloids. Cu(acac)2-catalyzed diazo decomposition of enantiomeric pure diazoketone 160 in refluxing toluene generates a spiro ammonium ylide 161 and 162, which then undergoes [l,2]-shift to give rise to a quinolizidine skeleton as a mixture of diastereomers (95 5) (Scheme Major diastereomer 164 has enantiomeric purity of 75% ee. The partial retention of stereo-... 

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). 

Pandey, G., Devi Reddy, G., and Chakrabarti, D. (1996) Stereoselectivity in the photoinduced electron transfer (PET) promoted intramolecular cyclisations of l-alkenyl-2-silyl-piperidines and -pyrrolidines rapid construction of 1-azabicyclo [m.n.o] alkanes and stereoselective synthesis of ( )-isoretronecanol and ( )-epilupinine. Journal of the Chemical Society, Perkin Transactions 1, 219-224. 

However, there has been no report on the highly stereoselective chiral synthesis of (- )-trachelanthamidine (100a) and ( + )-epilupinine (enr-lOOd) type alkaloids without the use of a chiral building block, except for Takano s chiral synthesis (33% optical purity) (81H(16)915),... 

The synthesis of alkaloids lupinine (106) and epilupinine (107) (Scheme 10) nicely illustrates the methodology [25]. Thus, electrochemical oxidation of lactam 103 (constant current, 50 mA Pt/Pt, Et4NC104) in methanol at room temperature afforded a 71% yield of ether 104 after the passage of 2.8F/mol. Subsequent treatment with titanium tetrachloride affected cyclization to the [4.4.0] bicyclic adduct 105. Krapcho decarbomethox-ylation followed by hydride reduction of both the amide and ester units of the resulting epimeric esters provided the natural products 106 and 107. 

A synthesis of epilupinine under physiological conditions was accomplished as follows (42). Ethyl A-benzyliminodivalerate (XXII) yields an acyloin (XXIII) which was reduced with lithium aluminum hydride to the diol XXIV, the benzyl group of which was removed by hydro-genolysis. Subsequent oxidation with periodic acid at 25°, pH 5, gave an intermediate dialdehyde which cyclized to lupinaldehyde (XXV). This unstable aldehyde on reduction with lithium aluminum hydride gives only the more stable epilupinine (XIV). 

A mixture of lupinine and epilupinine is obtainable by the following series of reactions. The betaine XXVI on cyclic hydrogenation and subsequent decarboxylation with 20 % hydrochloric acid gives a mixture of epimeric lupininic acids (XXIX). The dicarboxylic ester XXVIII is also obtained by the mercuric acetate dehydrogenation of the piperidine derivative XXX and by the alkylation of monomeric piperideine with a y-bromopropylmalonic ester. The last route is presumably a first Mannich condensation followed by an alkylation. Hydrolysis of the malonic esters, decarboxylation (XXIV), esterification, and reduction with lithium aluminum hydride complete the synthesis of a mixture which consists of 80% dZ-epilupinine and 20% dMupinine. Thermal... 

A simple synthesis of the lupininic acids has been reported as follows 43) ethyl a-pyridylacetate and an acrylic ester or acrylic nitrile undergo a simple Michael addition and hydrogenation of the product generates an epimeric mixture (7 3 or 1 4, respectively) of epilupininic and lupininic acids. 

Another synthesis under physiological conditions has been reported (36). The piperidinoquinolizidine (LIII), obtainable from epilupinine via bromolupinine, cyclizes when dehydrogenated with mercuric acetate to a mixture of LIV and LV which on reduction with sodium borohydride gives a separable mixture of sparteine and allomatrine. The epimeric piperidinoquinolizidine obtainable from lupinine gives a mixture of fl -isosparteine (LVIII) and allomatridine (LVI). The dehydrogenation... 

West and Naidu found that the diazoketone 358, prepared by alkylating the benzyl ester of L-proline with 5-bromo-l-diazopentan-2-one, cyclized to give a transient spirobicyclic ammonium ylide 359 when heated with coppeifll) acetylacetonate in toluene (Scheme 44) (355,356). This unstable ylide underwent a diastereoselective [1,2]-Stevens rearrangement to give the quinolizidinone 360 and its bridgehead epimer in a ratio of 95 5. However, some racemization (possibly through an achiral diradical intermediate) must have occurred, since 360 had an ee of only 75%. Reduction of the ester and defimctionalization of thioketal 361 with the unusual combination of sodium and hydrazine in hot ethylene glycol completed a synthesis of the unnatural (- )-enantiomer of epilupinine (ent-331). 

BCnight and co-workers approached the synthesis of the unnatural ( + )-enantiomer of lupinine (ent-344) by first resolving racemic 2-(piperidin-2-yl)-ethanol with (+ )-camphorsulfonic acid (357,358). The (i -( + )-enantiomer 362 was then converted into the substituted acetic ester 363, the enolate of which was stereoselectively allylated to give 364 and 365 in isolated yields of 71% and 12%, respectively (Scheme 45). The major isomer 364 was readily hydroborated and cyclized to the bicyclic ester 366, reduction of which completed the first reported synthesis of (+ )-lupinine (ent-344). The optical rotation was measured as +19.5° (c 1, EtOH), which compared favorably with the rotation of natural (- )-lupinine (-21°) recorded under similar conditions (359). It was also hoped that epimeriza-tion of 366 would give the thermodynamically more stable compound 377 in which the ester group is equatorial, after which reduction would provide access to (- )-epilupinine (ent-331). However, the product obtained after these transformations was optically inactive, which indicated that epimerization was accompanied by racemization, probably through base-induced retro-Michael reaction followed by Michael recyclization. 

B. Bicyclic Alkaloids.—Full details of the syntheses of lupinine and epilupinine, first reportedin 1960, have now been published this paper also includes the synthesis of sparteine. 

In spite of their recognized Lewis acidity and the propensity to complex with Lewis bases (particularly in an intramolecular chelate) [8], the organoyttrium complexes can be utilized for the synthesis of nitrogen heterocycles. The protocol has been employed in a concise synthesis of ( )-epilupinine (Scheme 3) [43]. 

Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. 

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