Isoretronecanol

Formal syntheses of (-)-isoretronecanol, (+)-laburnine, and a concise enantioselective synthesis of (+)-turneforcidine.[Pubmed:30894676]

J Antibiot (Tokyo). 2019 Mar 20. pii: 10.1038/s41429-019-0169-9.

The synthesis of functionalized pyroglutamates 15 and 16 could be achieved by the application of recently developed diastereodivergent asymmetric Michael addition reaction of iminoglycinate 7 to ethyl gamma-silyloxycrotonate with >98:<2 diastereoselectivity followed by hydrolysis and lactamization. Formal syntheses of (-)-Isoretronecanol and (+)-laburnine as well as a concise enantioselective synthesis of (+)-turneforcidine could be achieved from functionalized pyroglutamates 15 or 16.

Asymmetric [3+2] Annulation Approach to 3-Pyrrolines: Concise Total Syntheses of (-)-Supinidine, (-)-Isoretronecanol, and (+)-Elacomine.[Pubmed:26447827]

Angew Chem Int Ed Engl. 2015 Nov 9;54(46):13706-10.

An asymmetric [3+2] annulation reaction to form 3-pyrroline products is reported. Upon treatment with lithium diisopropylamide, readily available ethyl 4-bromocrotonate is deprotonated and trapped with Ellman imines selectively at the alpha-position to yield enantiopure 3-pyrroline products. This new method is compatible with aryl, alkyl, and vinyl imines. The efficacy of the method is showcased by short asymmetric total syntheses of (-)-supinidine, (-)-Isoretronecanol, and (+)-elacomine. This novel annulation approach also works for an aldehyde, thus providing access to a 2,5-dihydrofuran product in a single step from simple precursors. By modifying the structure of the carbanion nucleophile, an asymmetric vinylogous aza-Darzens reaction can be realized.

The cyano group as a traceless activation group for the intermolecular [3+2] cycloaddition of azomethine ylides: a five-step synthesis of (+/-)-isoretronecanol.[Pubmed:25820905]

Angew Chem Int Ed Engl. 2015 May 18;54(21):6306-10.

The cyano group was used as a traceless activation group for the [3+2] cycloaddition of azomethine ylides in a two-step process, thereby providing a highly effective approach to 5-unsubstituted pyrrolidines. The transformation includes the silver acetate catalyzed intermolecular 1,3-dipolar cycloaddition of alpha-iminonitriles and an unprecedented sodium borohydride induced reductive decyanation reaction. A diverse array of substrates is amenable to this transformation. The methodology was further extended to a five-step total synthesis of the pyrrolizidine natural product Isoretronecanol.

Recognition of pyrrolizidine alkaloid esters in the invasive aquatic plant Gymnocoronis spilanthoides (Asteraceae).[Pubmed:25645745]

Phytochem Anal. 2015 May-Jun;26(3):215-25.

INTRODUCTION: The freshwater aquatic plant Gymnocoronis spilanthoides (Senegal tea plant, jazmin del banado, Falscher Wasserfreund) is an invasive plant in many countries. Behavioural observations of pyrrolizidine alkaloid-pharmacophagous butterflies suggested the presence of pyrrolizidine alkaloids in the plant. OBJECTIVE: To determine whether the attraction of the butterflies to the plant is an accurate indicator of pyrrolizidine alkaloids in G. spilanthoides. METHODS: The alkaloid fraction of a methanolic extract of G. spilanthoides was analysed using HPLC with electrospray ionisation MS and MS/MS. Two HPLC approaches were used, that is, a C18 reversed-phase column with an acidic mobile phase, and a porous graphitic carbon column with a basic mobile phase. RESULTS: Pyrrolizidine alkaloids were confirmed, with the free base forms more prevalent than the N-oxides. The major alkaloids detected were lycopsamine and intermedine. The porous graphitic carbon HPLC column, with basic mobile phase conditions, resulted in better resolution of more pyrrolizidine alkaloids including rinderine, the heliotridine-based epimer of intermedine. Based on the MS/MS and high-resolution MS data, gymnocoronine was tentatively identified as an unusual C9 retronecine ester with 2,3-dihydroxy-2-propenylbutanoic acid. Among several minor-abundance monoester pyrrolizidines recognised, spilanthine was tentatively identified as an ester of Isoretronecanol with the unusual 2-acetoxymethylbutanoic acid. CONCLUSIONS: The butterflies proved to be reliable indicators for the presence of pro-toxic 1,2-dehydropyrrolizidine alkaloids in G. spilanthoides, the first aquatic plant shown to produce these alkaloids. The presence of the anti-herbivory alkaloids may contribute to the plant's invasive capabilities and would certainly be a consideration in any risk assessment of deliberate utilisation of the plant. The prolific growth of the plant and the structural diversity of its pyrrolizidine alkaloids may make it ideal for investigating biosynthetic pathways or for large-scale production of specific alkaloids.

Synthesis of gamma-lactams and gamma-lactones via intramolecular Pd-catalyzed allylic alkylations.[Pubmed:25415844]

Acc Chem Res. 2014 Dec 16;47(12):3439-47.

CONSPECTUS: Lactones and lactams are a well-known class of natural products and can be used as building blocks in organic synthesis. In addition, they can be found in many natural sources and synthetic drugs and have a broad range of biological or odorant properties. Chemists can create these useful compounds through palladium catalysis, which is a highly efficient tool for organic synthesis and is conveniently functional group tolerant. In this Account, we describe our work over the past 15 years in intramolecular Pd-catalyzed allylations where we have tethered the nucleophile and the electrophile by either an amide or an ester moiety, to produce gamma-lactams and gamma-lactones. We discuss in detail how the nature of the heteroatom tether influences the regioselectivity of the reaction. For example, a ketone [-C(O)CH2-] tether leads to mixtures of 5-exo and 7-endo cyclization products, while ester or amide [-C(O)X-] tethers afford sole 5-exo products. However, in the case of X = O, we were required to overcome two issues in the synthesis of gamma-lactones. First of all, the tethering ester function can compete with the allylic leaving group in the oxidative addition to the Pd(0) center. Second, in this case, the proportion of the conformers that have a suitable geometry for cyclization is very low. When we insert a juxtaposed silyl group on the allyl fragment, the molecule can undergo oxidative addition and functionalization of the lactone via Hiyama cross-coupling. We also performed DFT calculations on these systems, which allowed us to better understand the behavior of [-C(O)X-] and [-C(O)CH2-] tethers. Computations also let us rationalize the different reactivities that we observed as a function of the geometry (Z or E) of the starting substrates. In addition, we were able to synthesize natural products or analogs (alpha-kainic acid, Isoretronecanol, and picropodophyllin). We could turn these allylation reactions into asymmetric transformations and incorporate them into domino sequences. Thus, an allylation/Mizoroki-Heck sequence allowed us to straightforwardly access an aza-analog of picropodophyllin, as well as reach the lysergic acid backbone. Finally, we found that through carbopalladation of allenes, we could efficiently synthesize the key eta(3)-allylpalladium intermediates that were then ready for allylation reactions.

The asymmetric syntheses of pyrrolizidines, indolizidines and quinolizidines via two sequential tandem ring-closure/N-debenzylation processes.[Pubmed:25300749]

Org Biomol Chem. 2014 Dec 7;12(45):9223-35.

Concise asymmetric syntheses of (-)-lupinine, (+)-Isoretronecanol, (+)-5-epi-tashiromine and (R,R)-1-(hydroxymethyl)octahydroindolizine (the azabicyclic core within stellettamides A-C) have been achieved in 8 steps or fewer from commercially available starting materials. The key steps in these syntheses involved the preparation of enantiopure beta-amino esters, upon conjugate addition of lithium (R)-N-(p-methoxybenzyl)-N-(alpha-methyl-p-methoxybenzyl)amide to either zeta-chloro or zeta-hydroxy substituted tert-butyl (E)-hept-2-enoate, or epsilon-chloro or epsilon-hydroxy substituted tert-butyl (E)-hex-2-enoate. Activation of the omega-substituent as a leaving group led to SN2-type ring-closure, which occurred with concomitant N-debenzylation via an E1-type deprotection step, to give the corresponding pyrrolidine or piperidine in good yield. Subsequent alkylation of these enantiopure azacycles, followed by a second ring-closure/concomitant N-debenzylation step formed the pyrrolizidine, indolizidine or quinolizidine motif, and reduction with LiAlH4 gave the target compounds in diastereoisomerically and enantiomerically pure form.

Diastereoselective synthesis of gamma- and delta-lactams from imines and sulfone-substituted anhydrides.[Pubmed:24552208]

J Org Chem. 2014 Mar 21;79(6):2601-10.

Sulfone-substituted gamma- and delta-lactams have been prepared in a single step with high diastereoselectivity. Sulfonylglutaric anhydrides produce intermediates that readily decarboxylate to provide delta-lactams with high diastereoselectivity. Substituents at the 3- or 4-position of the glutaric anhydride induce high levels of stereocontrol. Sulfonylsuccinic anhydrides produce intermediate carboxylic acids that can be trapped as methyl esters or allowed to decarboxylate under mild conditions. This method has been applied to a short synthesis of the pyrrolizidine alkaloid (+/-)-Isoretronecanol.

Hydrogenation of pyrrolizin-3-ones; new routes to pyrrolizidines.[Pubmed:19830302]

Org Biomol Chem. 2009 Nov 7;7(21):4502-11.

Pyrrolizin-3-ones (e.g. 1) can be easily hydrogenated to their hexahydro (pyrrolizidin-3-one) derivatives in the presence of heterogeneous catalysts. Good diastereoselectivity (up to >97:3, depending on catalysts and solvent) can be achieved if the pyrrolizin-3-one is substituted at the 1- (or 7-) position(s), but the selectivity is reduced if both positions are substituted. Subsequent deoxygenation of the pyrrolizidin-3-ones provides concise, diastereoselective routes to the necine bases (+/-)-heliotridane 5, (+/-)-Isoretronecanol 6 and (+/-)retronecanol 7.

E/Z-Thesinine-O-4'-alpha-rhamnoside, pyrrolizidine conjugates produced by grasses (Poaceae).[Pubmed:18466931]

Phytochemistry. 2008 Jun;69(9):1927-32.

Based on direct infusion mass spectrometry we identified a novel alkaloid as a major component of perennial ryegrass (Lolium perenne). Initial mass spectral data suggested it to be a pyrrolizidine conjugate. As this class of alkaloids has not been described before from grasses, we isolated it to elucidate its structure. The isolated alkaloid proved to be a mixture of two stereoisomers. The structures of the two compounds as determined by 1D and 2D NMR spectroscopy, were E-thesinine-O-4'-alpha-rhamnoside (1) and Z-thesinine-O-4'-alpha-rhamnoside (2). These identifications were supported by the characterisation by GC-MS and optical rotation of (+)-Isoretronecanol as the necine base released on alkaline hydrolysis of these alkaloids. 1 and 2 together with the aglycone and a hexoside were also detected in tall fescue (Festuca arundinacea). This is the first report of pyrrolizidine alkaloids produced by grasses (Poaceae).

Tissue distribution and biosynthesis of 1,2-saturated pyrrolizidine alkaloids in Phalaenopsis hybrids (Orchidaceae).[Pubmed:16815502]

Phytochemistry. 2006 Jul;67(14):1493-502.

Phalaenopsis hybrids contain two 1,2-saturated pyrrolizidine monoesters, T-phalaenopsine (necine base trachelanthamidine) and its stereoisomer Is-phalaenopsine (necine base Isoretronecanol). T-Phalaenopsine is the major alkaloid accounting for more than 90% of total alkaloid. About equal amounts of alkaloid were genuinely present as free base and its N-oxide. The structures were confirmed by GC-MS. The quantitative distribution of phalaenopsine in various organs and tissues of vegetative rosette plants and flowering plants revealed alkaloid in all tissues. The highest concentrations were found in young and developing tissues (e.g., root tips and young leaves), peripheral tissues (e.g., of flower stalks) and reproductive organs (flower buds and flowers). Within flowers, parts that usually attract insect visitors (e.g., labellum with colorful crests as well as column and pollinia) show the highest alkaloid levels. Tracer feeding experiments with (14)C-labeled putrecine revealed that in rosette plants the aerial roots were the sites of phalaenopsine biosynthesis. However active biosynthesis was only observed in roots still attached to the plant but not in excised roots. There is a slow but substantial translocation of newly synthesized alkaloid from the roots to other plant organs. A long-term tracer experiment revealed that phalaenopsine shows neither turnover nor degradation. The results are discussed in the context of a polyphyletic molecular origin of the biosynthetic pathways of pyrrolizidine alkaloids in various scattered angiosperm taxa. The ecological role of the so called non-toxic 1,2-saturated pyrrolizidine alkaloids is discussed in comparison to the pro-toxic 1,2-unsaturated pyrrolizidine alkaloids. Evidence from the plant-insect interphase is presented indicating a substantial role of the 1,2-saturated alkaloids in plant and insect defense.

Titanium-Mediated Cyclization of omega-Vinyl Imides in Alkaloid Synthesis: Isoretronecanol, Trachelanthamidine, 5-Epitashiromine, and Tashiromine.[Pubmed:11674685]

J Org Chem. 1999 Sep 3;64(18):6771-6775.

A new method for the stereocontrolled synthesis of pyrrolizidine and indolizidine alkaloids by means of titanium-mediated cyclization of omega-vinyl imides is described. The general procedure involves treatment of readily available omega-vinyl imides 9 and 10 with 2.5 equiv of cyclopentylmagnesium chloride in the presence of ClTi(O-i-Pr)(3) (1.1 equiv) and subsequent stereoselective reduction of the N-acylaminal group. The cis and trans ring junction stereoisomers can be stereoselectively prepared by catalytic hydrogenation (H(2), PtO(2), EtOAc) and NaCNBH(3) reduction (TFA, MeOH), respectively. Finally, treatment of the resulting lactams with LAH or diborane afforded the target alkaloids 1-8 in good yields.

Enamino Ester Reduction: A Short Enantioselective Route to Pyrrolizidine and Indolizidine Alkaloids. Synthesis of (+)-Laburnine, (+)-Tashiromine, and (-)-Isoretronecanol.[Pubmed:11674411]

J Org Chem. 1999 Apr 30;64(9):3122-3131.

Various chiral pyrrolidine tetrasubstituted beta-enamino esters were reduced catalytically or chemically with good to moderate diastereoselectivity owing to a chiral induction originated from (S)-alpha-methylbenzylamine. With endocyclic double bond compounds, the best result was obtained using PtO(2) as hydrogenation catalyst and led to a major syn addition product (e.d. 90%). In the case of exocyclic double bond compounds, hydrogenation over Pd/C gave rise to the higher diastereoselectivity and mainly afforded the unexpected anti addition product (e.d. 84%). The scope of these reductions has been extended to the synthesis of three pyrrolizidine or indolizidine alkaloids: (+)-tashiromine, (+)-laburnine, and (-)-Isoretronecanol. Syntheses of these natural products, starting from chiral beta-enamino diesters, were achieved in a short and convenient manner, leading to enantiopure compounds in good overall yields.

Synthesis of [3,5-14C]trachelanthamidine and [5-3H]isoretronecanol and their incorporation into the retronecine moiety of riddelliine in Senecio riddellii.[Pubmed:3546596]

J Nat Prod. 1986 Sep-Oct;49(5):838-44.

(+/-)-[3,5-14C]Trachelanthamidine and (+/-)-[5-3H]Isoretronecanol, which are diastereomers, were prepared from potassium [14C]cyanide and [5-3H]proline, respectively. These compounds and [1,4-14C]putrescine were administered to Senecio riddellii plants resulting in the formation of labeled riddelliine, in which almost all the radioactivity was located in its retronecine moiety. The activity of the beta-alanine obtained by degradation of the retronecine was consistent with specific labeling of this pyrrolizidine base at the expected positions. The extremely high absolute incorporation (15.1, 22.1%) of trachelanthamidine into riddelliine strongly favors this 1-hydroxymethylpyrrolizidine as the one on the main biosynthetic pathway to retronecine. The lower incorporation (0.75%) of Isoretronecanol may represent a minor or aberrant pathway to retronecine.