Synthesis of Some Members of the Hydroxylated Phenanthridone Subclass of the <i>Amaryllidaceae</i> Alkaloid Family

Padwa, Albert; Zhang, Hongjun

doi:10.1021/jo0626111

Cited by 95 publications

(49 citation statements)

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“…This synthesis was designed to produce the C-1 aldehyde that could eventually serve as as ource of unnatural derivatives (see Section 3.16). Thea mide nitrogen was then reprotected as its corresponding PMB ether,a nd the TBDMS ether was cleaved with TBAF.I nt he following step,C hugaev elimination [62] of an alcohol at C-2 provided olefin 63 in 22 %yield over three steps.C ompound 63 is ak nown intermediate in Padwas synthesis of 7-deoxypancratistatin [50] and its attainment formalized the synthesis of 7-deoxypancratistatin (Padwa prepared 2 in 7steps from 63). [60] Theo riginal aim of this particular strategy was the synthesis of aldehyde 61 and its conversion to 7-deoxypancratistatin (2)was of secondary importance.Itdid not proceed without problems,a se videnced by the number of quite arduous transformations required to convert 61 to 7-deoxypancratistatin (2)( Scheme 13).…”

Section: Hudlicky (2010) -( + +)-7-deoxypancratistatin (2)mentioning

confidence: 99%

“…[41] Compound 294 was found to be inactive while tosylamide 292 exhibited > 10 mgmL À1 as GI 50 [41] Compound 294 was found to be inactive while tosylamide 292 exhibited > 10 mgmL À1 as GI 50 …”

Section: Reviewsmentioning

confidence: 99%

“…[159] TheC -1 acetoxymethylene derivative 385 exhibited the highest levels of potencyagainst pancreatic (0.07 mm), lung (0.07 mm)a nd prostate (0.06 mm)c ancer cell lines,w ith activity levels approaching that of (+ +)-narciclasine (3)[ IC 50 values,p ancreatic (0.05 mm), lung (0.04 mm), prostate (0.05 mm), and breast (0.04 mm)cancer cell lines].This finding is in accordance with Pettits observation that ahydrophobic substituent at the C-1 position does not decrease the potency of the compound, and may in fact increase activity. As expected, the C-1 analogues of pancratistatin demonstrated higher levels of potencyt han their 7-deoxy counterparts [for 384,p ancreatic (0.22 mm), prostate (0.09 mm), lung (0.09 mm)a nd breast (0.24 mm)c ancer cell lines;f or 385, pancreatic (0.07 mm), prostate (0.06 mm), lung (0.07 mm)a nd breast (0.52 mm)cancer cell lines (values are denoted for half maximal inhibitory concentration, IC 50 )],c onfirming again the importance of the C-7 hydroxy moiety for anti-cancer activity.…”

Section: Kornienko( 2009) -C-ring Analogues Of (+ +)-Pancratistatinmentioning

confidence: 99%

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Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

et al. 2016

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This update covers the syntheses of Amaryllidaceae alkaloids since the publication of the last major review in 2008. A short summary of past syntheses and their step count is provided for the major constituents; pancratistatin, 7-deoxypancratistatin, narciclasine, lycoricidine, lycorine, and for other natural constituents, as well as for unnatural derivatives. Discussion of biological activities is provided for unnatural derivatives. Future prospects and further developments in this area are covered at the end of the review. The literature is covered to the end of August 2015.

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Section: Hudlicky (2010) -( + +)-7-deoxypancratistatin (2)mentioning

confidence: 99%

Section: Reviewsmentioning

confidence: 99%

Section: Kornienko( 2009) -C-ring Analogues Of (+ +)-Pancratistatinmentioning

confidence: 99%

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Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

et al. 2016

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“…1,2,3 However, little attention has been given to approaches to these systems which utilise metal-catalysed aryl-allene couplings, despite the obvious 20 potential of this route to produce such systems with high degrees of chemo-and regioselectivity. Nonetheless, the potential of this approach has been underlined previously.…”

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confidence: 99%

A facile palladium catalysed 3-component cascade route to functionalised isoquinolinones and isoquinolines

et al. 2016

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Palladium catalysed three component cascade process, involving coupling of 2-iodobenzoates, -benzaldehydes, or acetophenones with substituted allenes and ammonium 10 tartrate as an ammonium surrogate, provides a novel and facile route to substituted functionalised isoquinolinones and isoquinolines in good yields.Isoquinolinone and isoquinoline derivatives are important 15 constituents of a diverse range of molecules of biological and pharmaceutical relevance as well as a common structural component within many alkaloids. 1,2,3 However, little attention has been given to approaches to these systems which utilise metal-catalysed aryl-allene couplings, despite the obvious 20 potential of this route to produce such systems with high degrees of chemo-and regioselectivity. Nonetheless, the potential of this approach has been underlined previously. Thus, Larock reported that annulation of a substituted allene with N-tosyl-2-iodobenzylamine under Pd(II) catalysis afforded isoquinolines as 25 a mixture of three regio-and stereo-isomers. 4 Additionally, 2-iodobenzaldehyde imines have also been used with Pd(0) catalysis to annulate substituted allenes giving isoquinoline derivatives. 5 Ni(0)/chiral phosphine ligand mediated regio-and enantioselective synthesis of isoquinoline-1(2H)-one derivatives 30 has been reported via denitrogenation or decarbonylation of Naryl-1,2,3-benzotriazin-4(3H)-ones or N-substituted phthalimide, respectively, followed by intermolecular annulation with substituted allenes. 6 Recently, Glorius et al., employed Rh(III) to catalyse C-H activation of N-(pivaloyloxy)benzamide involving 35 intermolecular annulation with substituted allenes to furnish isoquinoline-1(2H)-ones. 7 As part of our program of research into the development and application of palladium catalysed allene insertion cascades, we have previously reported a number of examples of three-40 component cascades for the synthesis of N-substituted 4-methylene-3,4-dihydro-1(2H)-isoquinolinones. A feature of these reactions is that, following an initial Pd-mediated intramolecular allene insertion, both intra-and intermolecular nucleophilic addition then occurs to give tetra-fused ring systems containing 45 an isoquinolinone ring. 8, 9a These include, following the initial Pd catalysed intramolecular allene insertion, intermolecular nucleophilic addition involving N-allenyl-2-iodobenzamide, 9b,c and nitrogen-tethered 1,6-enynes 9d respectively. Additionally, we have also reported two types of cascade reactions that can furnish 50 isoquinolines; (i) intermolecular allene insertion into the C-I bond of an aryl iodide linked N-nucleophile followed by intramolecular N-addition to the generated -allyl, 10 and (ii) intermolecular allene insertion to an aryl iodide carrying a dipolarophile/Michael acceptor followed by intermolecular N-addition of an azide/amine 55 and finally intramolecular 1,3-dipolar cycloaddition/Michael addition. 11 In the present study, we report a new approach utilising our "ammonium surrogate" technology 12 as a nove...

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“…Thus, treatment of isomer 26 (in which the OH group resides anti to H-10) with POCl 3 (py, 60 8C) led directly to 28 (81 % yield), whereas isomer 27 (in which the OH group is syn to H-10) required conversion into its xanthate first (NaH, CS 2 , MeI, 0!25 8C), and then syn elimination, a process that proceeded smoothly upon microwave irradiation at 185 8C (92 % overall yield). [12] The next hurdle to be overcome was the regio-and stereoselective hydration of the C-10-C-28 olefinic bond in the presence of the other two within intermediate 28. An expedient tactic to solve this seemingly thorny problem was devised based on the unique steric environment of each olefinic bond within this substrate.…”

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confidence: 99%

Total Synthesis of the Originally Assigned Structure of Vannusal B

et al. 2008

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Vannusals A (1 a, Figure 1) and B (1 b) are two marine natural products notable for their unusual molecular architectures. Isolated from the tropical interstitial ciliate Euplotes vannus strains Si121 and BUN3, these intriguing molecules include in their C 30 molecular framework seven rings and thirteen stereogenic centers, three of which are quaternary. Their structures have been assigned on the basis of mass spectrometric and NMR spectroscopic data and chemical transformations. [1,2] Herein we report the total synthesis of structure 1 b that proved that it does not represent the true structure of vannusal B.Our retrosynthetic analysis of the vannusal molecule dissected it as shown in Figure 2, revealing vinyl iodide 2 and aldehyde 3 as the key building blocks required for the projected total synthesis. The devised strategy anticipated their fusion through two carbon-carbon bond-forming reactions, namely lithiation of 2 followed by addition of 3 to join them, and a samarium-induced ring closure of a subsequent intermediate to forge the final ring of the target molecule.Scheme 1 summarizes the construction of vinyl iodide 2 from the commercially available meso diol 4. Thus, dehydration of 4 through the action of POCl 3 (py, 90 8C) furnished conjugated diene 5 (97 % yield), [3] which was regio-and stereoselectively converted into the new meso diol 6 by a hydroboration-oxidation process (CyBH 2 ; H 2 O 2 , NaOH, 51 % yield). The latter compound was then desymmetrized through the enantioselective hydrolytic action of Lipase Amano PS [4] on its bis-acetate (prepared in quantitative yield by reaction of 6 with Ac 2 O in the presence of 4-DMAP), leading to the monoacetate 7 in 100 % yield and 99 % ee (determined by Mosher ester analysis). Silylation of 7 (TBDPSCl, imid, 93 % yield) followed by acetate cleavage (DIBAL-H, 98 % yield) and treatment of the resulting alcohol with Martins sulfurane (Et 3 N, CH 2 Cl 2 , 91 % yield) afforded enantiomerically pure cyclopentene derivative 8. The planned stereoselective epoxidation of 8 was achieved through a two-step procedure that involved first iodohydrin formation (NIS, H 2 O), and then ring closure (K 2 CO 3 , MeOH) to give b-epoxide 9 in 91 % overall yield. This epoxide was then regio-and stereoselectively opened with 2-lithiopropene (generated from the corresponding bromide and tBuLi) in the presence of BF 3 ·Et 2 O to afford hydroxy compound 10 (83 % yield), whose stereochemistry was inverted through application of a Mitsunobu (pNO 2 C 6 H 4 CO 2 H, Ph 3 P, DEAD) [5] /ester cleavage (DIBAL-H) protocol, leading to the desired hydroxy compound 11 in 90 % overall yield. With the proper stereochemistry now installed on 11, a BOM group was placed on the free hydroxy group (BOMCl, iPr 2 NEt) and the TBDPS group was removed (TBAF, 97 % overall yield) to furnish compound 12. The newly generated hydroxy group within 12 was then oxidized [NMO, TPAP (cat.), 96 % yield], and the resulting ketone was converted into its tris-hydrazone 13 (TrisNHNH 2 , 80 % yield). Finally, the targeted...

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Synthesis of Some Members of the Hydroxylated Phenanthridone Subclass of the Amaryllidaceae Alkaloid Family

Cited by 95 publications

References 87 publications

Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

A facile palladium catalysed 3-component cascade route to functionalised isoquinolinones and isoquinolines

Total Synthesis of the Originally Assigned Structure of Vannusal B

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