Oxetane Presentation.Pptx

O O O O O Oxetane Drug Development, Synthesis & Applications! John Thompson" Dong Group Literature Seminar" September 24th, 2014" OH O O O Overview! 1.# Drug Discovery & Pharmaceutical Interest" 2.# Chemical Properties & Synthesis of Oxetane Rings" 3.# Applications of Oxetane Rings" i.# Ring Opening for Complex Molecule Synthesis" ii.# Organometallic Chemistry " O R'O OH R O NH O O O OH O OH O O O R = Ph, R' = Ac, Paclitaxel (Taxol) R = OtBu, R' = H, Taxotere (Docetaxel) All marketed drugs containing the oxetane ring come from the Taxane family of natural products Computational studies show the oxetane moiety providing: (1) rigidification of the overall structure (2) H-Bond acceptor for a threonine-OH group in binding pocket The full extent of the oxetane biological role is still unclear Other Oxetanes in Natural Products" NH2 N Me O N O HO O H N N CO2H Me O O C H O 5 11 OH O OH O O O Me O OH Me Me OH OH Thromboxane A 2 Merrilactone A Maoyecrystal I Oxetanocin A promotes vasoconstriction/ stimulates rat neuron growth anti-cancer HIV Inhibitor platelet aggregation Me Me NH Me Me NH 2 H N NH O O 2 2 O CO2H Me O O OH Me O O MeO2C Me O Me Bradyoxetin Oxetin Dictyoxetane gene regulation in soybean Mitrephorone A herbicidal / antibacterial polycyclic diterpenoid high cytotoxicity Angew. Chem. Int. Ed. 2010, 49, 9052.! Medicinal Chemistry" §# Compound property optimization is a major hurdle for drug discovery" " §# Small molecules that can be easily added onto and change compound properties in predictable ways are highly valued" " §# The oxetane ring is a very small molecule whose properties in the past decade have shown far reaching advantages for biological modulation" –# This compound has been neglected due to difficult synthetic access and concerns about chemical and metabolic stability" O Key Figures Erick M. Carreira Klaus Müller " ETH Zürich" " Angew. Chem. Int. Ed. 2010, 49, 9052.! Angewandte Oxetanes Chemie and safety screens to examine, refine, as well as predict chemical space beyond the structures that initiated the druglike attributes of the candidate structures. As predictive research endeavor. The collection of molecules generated tools and assays become available the process is conducted result in a multidimensional network of structure–activity increasingly earlier in the drug discovery process so as to relationships that provide the basis for identifying and Oxetan-3-one: Chemistry and Synthesis 221 minimize attrition at the later (and more expensive) preclin- defining the pharmacophore. ical and clinical phases as a result of toxicity or lack of Our own studies wereaffords initiated regioselectively by the the idea corresponding that oxetanes oxetanes in good yield.51 An important difference efficacy. In medicinal chemistry it is common to identify could be viewed as a gembetween-dimethyl the various equivalent, approaches is wherein that in the theWilliamson approach, stereochemical issues are addressed separately from the ring-closing event. By contrast, in the processes that commence with robust surrogates for typical functional groups. These surro- two methyl groups arecarbonyl bridged substrates, by an control oxygen must be atom. exercised It over was the generation of stereocenters during the ring gates are modules that may share a limited set of key reasoned that the polarclosure oxygen step. Although bridge the would approach beinvolving able intramolecular to Williamson ether synthesis permits access to a range of substituted oxetanes, the latter two methods necessarily lead to oxetanes that properties with the parent functional group, such as acidity/ compensate for the intrinsicincorporate lipophilicity substitution at C-2. of the methylene basicity, size, and conformational biases. For example, com- groups, such that the net change in lipophilicity would be mon replacements for carboxylic acids (RCOOxetanes2H) and gem- small to or Replace even vanish (Figure13.4 Common 1). OXETANES Further IN research DRUG Functionalities DISCOVERY on oxetanes " dimethyl groups are tetrazoles (RCN4H) and cyclopropanes, has undergone additionalThe twists calculated and van turns der Waals that volumes have of revealed trimethylene oxide and propane are essentially the same. respectively. Although on one level these surrogates are a number of other intriguingConsistent structural with this feature, relationships. the measured Thus, partial formolar volumes in water are similar.52,53 This leads perceived as interchangeable in the discovery process, it is to the hypothesis that it may be a fruitful exercise to consider the replacement of gem-dimethyl §# Replacement of gem-dimethyl groupsgroups (t-butyl with oxetanes = methyl (Figure substituted13.5). This would gem-dimethyl lead to geometrically group) similar" structures with well appreciated that the equivalence is merely superficial, markedly different pharmacokinetic properties. In a related fashion, the tert-butyl group can be because each functional group has its own intrinsic structural considered a gem-dimethyl substituted ethyl group. Thus, in a model construct wherein oxetanes would function as gem-dimethyl group equivalents, 3-methyl 3-oxetanyl linked units would serve or electronic characteristics. Nonetheless, the replacement as tert-butyl surrogates. Both gem-dimethyl as well as tert-butyl groups can be found in many groups permit the medicinal chemist to navigate among pharmaceutical compounds. A search of the World Drug Index reveals 714 entries for molecules various structural classes and bridge to diverse regions of incorporating a tert-butyl group, and 69 such compounds are currently in the market. Tert-butyl groups are often used to fill hydrophobic pockets of a certain target; gem-dimethyls are often –# Why are these groups so commonintroduced toin protect drugs? metabolically Steric labile hindrance positions. Inprevents both cases, chemicalhowever, their introduction is or metabolic liabilities of nearbyassociated functional with decreased groups water " solubility and elevated lipophilicity. Higher lipophilicity in general Johannes Burkhard was born in Zurich, makes the molecule as a whole a better substrate for oxidative metabolic enzymes. However, the Switzerland in 1983. In 2006, he received •# More than 10% of all launchedoxetane groupdrugs is considerablycontain at reduced least in one lipophilicity. gem-dimethyl In a series ofgroup studies," we were able to his Masters in chemistry from the ETH demonstrate that introduction of the oxetane into a model compound can lead to increased water solubility in excess of 4000-fold over the parent compound. Moreover, the 3,3-disubstituted oxet- Zurich under the supervision of Franç–ois# However, replacing H for Me increasesanes were shown lipophilicity to be stable in (maya pH range have from adverse 1 to 10 and toeffects) enhance "metabolic stability of the Diederich. For his PhD studies he stayed at parent molecules significantly in standard liver microsomal assays.19 the ETH, where he joined the research In order to make use of these potential beneficial properties of oxetanes as surrogates of gem- group of Erick M. Carreira in 2007.§# Oxetane His & gem-dimethyl groups havedimethyl near and tert equivalent-butyl groups, partialsynthetic methodsmolar hadvolumes to be developed in water that allow" access to a variety of 3,3-disubstituted oxetanes. In principle, there are at least two approaches that could be pursued research is focused on the development–# ofLeads to geometrically similar structures with markedly different pharmacokinetic small heterocyclic building blocks and theirproperties" Figure 1. Oxetane analogies in medicinal research. R1 evaluation in the context of drug discovery. Me R1 Me Me R1 – # World Drug Index (2008)" Me Me OH Me •# 714 molecules with t-butyl groups" H Me •# 69 in market" Georg Wuitschik, born in Bad Tölz, Ger- Klaus Müller, born in 1944 near Lucerne, R1 R1 many in 1980, received his Diploma in Switzerland, studied chemistryR1 at ETHO Zur- O O chemistry in 2004 from the TU Munich for ich (PhD with Albert Eschenmoser). AfterOH Me Angew. Chem. Int. Ed. 2010, 49, 9052.! H work carried out in the group of Barry M. several years in the US (Chicago, Harvard), Trost under the supervision of Wolfgang A. he returned to ETH Zurich, where he R3 R2 R Herrmann. He then joined the group of completed his habilitationxy in Physical and R3 xy2 Me Me Erick M. Carreira, and received his PhD in Theoretical Organic Chemistry in 1977. In O 2008. He is currently working as an 1982 he joined F. Hoffmann–La Roche, FIGURE 13.5 Relevant structural motifs for the replacement of a gem-dimethyl group by an oxetanyl unit. Alexander-von-Humboldt postdoctoral fellow Basel, to set up programs in molecular in the group of Steve V. Ley, where he works modeling, structural biology, and on natural product synthesis. bioinformatics. In 1990 he became extra- ordinary professor at the University of Basel. Since his retirement in Spring 2009, he has continued as a chemistry consultant for Roche and holds a teaching position at ETH Zurich. Mark Rogers-Evans was born in London in Erick M. Carreira was born in Havana, 1963. After his PhD and postdoctoral Cuba, in 1963. He received his BSc from studies in England (Brian Marples and the University of Urbana-Champaign work- Raymond Bonnett) and Canada (Victor ing with Scott Denmark, and his PhD from Snieckus), he joined Hoffmann—La Roche Harvard University working under the direc- in Switzerland (1996) as a Process Research tion of David A. Evans. After postdoctoral

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