Showing papers by "Tomas Hudlicky published in 2012"

Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine via Palladium-Catalyzed N-Demethylation/Acylation and/or Concomitant O-Demethylation

Abstract: An improved preparation of buprenorphine via palladium-catalyzed N-demethylation/acylation is reported. Three routes were investigated and compared in overall yield. The first involved N-demethylation/acylation of an advanced intermediate obtained from thebaine followed by hydrolysis of the N-acetamide and alkylation with cyclopropylmethyl bromide and/or reduction of the N-acetyl group with the Schwartz reagent followed by N-alkylation. The second route employed cyclopropylcarboxylic acid anhydride in the N-demethylation/acylation protocol and subsequent reduction of the cyclopropylcarboxamide by either lithium aluminum hydride or under hydrosilylation conditions. Both of these routes originated in thebaine and therefore required O-demethylation as a final step. The third route employed an N-demethylation/acylation sequence starting from oripavine rather than thebaine, thus avoiding the O-demethylation. The routes are compared for overall efficiency and experimental and spectral data are provided for all new compounds.

Direct Synthesis of Naltrexone by Palladium-Catalyzed N-Demethylation/Acylation of Oxymorphone: The Benefit of CH Activation and the Intramolecular Acyl Transfer from C-14 Hydroxy

Abstract: Oxymorphone was converted to naltrexone in three steps by palladium-catalyzed oxidative N-demethylation and intramolecular acyl transfer from C-14 hydroxy to N-17. Vitride™ reduction of N-acylamide to N-alkylamine proceeded with concomitant reductive deprotection of C-6 and O-3 functionalities.

Unnatural C-1 homologues of pancratistatin — Synthesis and promising biological activities

Abstract: Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene–phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxyl...

Unexpected N‐Demethylation of Oxymorphone and Oxycodone N‐Oxides Mediated by the Burgess Reagent: Direct Synthesis of Naltrexone, Naloxone, and Other Antagonists from Oxymorphone

Abstract: N-Oxides derived from oxycodone and O-acyloxymorphone were treated with the Burgess reagent to provide the corresponding oxazolidines in excellent yields. Oxazolidines derived from O-acyloxymorphone were further hydrolyzed to noroxymorphone, whose alkylation furnished naltrexone, naloxone, and nalbuphone, which can be converted to nalbuphine, the mixed agonist-antagonist analgesic. The entire sequence from oxymorphone to the various antagonists was reduced to three one-pot operations, proceeding in excellent overall yields. In addition, quaternary salts of the oxazolidines with allyl or cyclopropylmethyl groups in fixed equatorial configurations were synthesized. Complete spectral and experimental data are provided for all compounds.

A novel synthetic C-1 analogue of 7-deoxypancratistatin induces apoptosis in p53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement of activity by tamoxifen

Abstract: The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies.

Toluene dioxygenase mediated oxidation of halogen-substituted benzoate esters

Abstract: A series of ortho-, meta-, and para- halogen-substituted methyl benzoate esters was subjected to enzymatic dihydroxylation via the whole-cell fermentation with E coli JM109 (pDTG601A) Only ortho-substituted benzoates were metabolized Methyl 2-fluorobenzoate yielded one diol regioselectively whereas methyl 2-chloro-, methyl 2-bromo- and methyl 2-iodobenzoates each yielded a mixture of regioisomers Absolute stereochemistry was determined for all new metabolites Computational analysis of these results and a possible rationale for the regioselectivity of the enzymatic dihydroxylation is advanced

Enhancement of apoptotic and autophagic induction by a novel synthetic C-1 analogue of 7-deoxypancratistatin in human breast adenocarcinoma and neuroblastoma cells with tamoxifen.

Abstract: Breast cancer is one of the most common cancers amongst women in North America. Many current anti-cancer treatments, including ionizing radiation, induce apoptosis via DNA damage. Unfortunately, such treatments are non-selective to cancer cells and produce similar toxicity in normal cells. We have reported selective induction of apoptosis in cancer cells by the natural compound pancratistatin (PST). Recently, a novel PST analogue, a C-1 acetoxymethyl derivative of 7-deoxypancratistatin (JCTH-4), was produced by de novo synthesis and it exhibits comparable selective apoptosis inducing activity in several cancer cell lines. Recently, autophagy has been implicated in malignancies as both pro-survival and pro-death mechanisms in response to chemotherapy. Tamoxifen (TAM) has invariably demonstrated induction of pro-survival autophagy in numerous cancers. In this study, the efficacy of JCTH-4 alone and in combination with TAM to induce cell death in human breast cancer (MCF7) and neuroblastoma (SH-SY5Y) cells was evaluated. TAM alone induced autophagy, but insignificant cell death whereas JCTH-4 alone caused significant induction of apoptosis with some induction of autophagy. Interestingly, the combinatory treatment yielded a drastic increase in apoptotic and autophagic induction. We monitored time-dependent morphological changes in MCF7 cells undergoing TAM-induced autophagy, JCTH-4-induced apoptosis and autophagy, and accelerated cell death with combinatorial treatment using time-lapse microscopy. We have demonstrated these compounds to induce apoptosis/autophagy by mitochondrial targeting in these cancer cells. Importantly, these treatments did not affect the survival of noncancerous human fibroblasts. Thus, these results indicate that JCTH-4 in combination with TAM could be used as a safe and very potent anti-cancer therapy against breast cancer and neuroblastoma cells.

Processes and intermediates in the preparation of morphine analogs via n-demethylation of n-oxides using cyclodehydration reagents

Abstract: A high-yielding method for the N-demethylation of oxycodone- and oxymorphone-N-oxides by the reaction of these compounds with cyclodehydration reagents has been performed. This method has been utilized to improve the synthesis of various morphine analogs, such as naltrexone, nalbuphone and naloxone.

Process for the preparation of morphine analogs via metal catalyzed n-demethylation/functionalization and intramolecular group transfer

Abstract: The present application is directed to an efficient conversion of C-14 hydroxylated morphine alkaloids to various morphine analogs, such as naltrexone, naloxone and nalbuphone. One feature of this process is an intramolecular functional group transfer from the C-14 hydroxyl to the N-17 nitrogen atom following a palladium-catalyzed N-demethylation.

Application of D-chiro-Inositol as a Chiral Template for the DielsAlder Reaction

Abstract: by John F. Trant, Lee Belding, Travis Dudding, and Tomas Hudlicky*Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue,St Catharines ON, L2S 3A1, Canada(phone: þ1905688-5550 (ext. 3406); fax: þ1905682-9020; e-mail: thudlicky@brocku.ca)DedicatedtoProfessorDieterSeebachontheoccasionofhis75thbirthdayandinrecognitionofhismanycontributions to our disciplineThe Diels Alder reaction can reliably provide the expected endo-product in the presence ofsecondary orbital overlap. It can be considerably more difficult to access a single enantiomer of the exo-product. In this paper, a d-chiro-inositol derivative is used as a chiral tether to facilitate the regio-,diastereo-, and enatioselective cycloaddition between cinnamic acid and hexa-3,5-dienoic acid. TheDiels Alder reaction between these two substrates, or their respective esters, does not occur underthermal conditions. Because of the ease of removal of the chiral tether from the resulting cyclohexene,this approach could provide a viable technique to access otherwise unavailable systems.

Synthesis of Nalbuphine from Oripavine via N-Demethylation of N-Cyclobutylmethyl Oripavine.

Abstract: The synthesis of nalbuphine (VI) from oripavine (I) requires only five chemical transformations and is conducted with an overall yield of 45%, in contrast to current methods requiring seven to ten steps.

Intermediates in the preparation of morphine analogs

Abstract: A compound of Formula V wherein ---- represents a single or double bond, provided that two double bonds are not adjacent to each other; R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present; PG is a protecting group; R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl; X is a counteranion, and one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label, or a salt or solvate thereof.