Promising molecules in Drug Discovery : Syntheses and Applications of Oxetanes. A presentation by Guillaume Pelletier on October 6 th 2009

What can wikipedia and Chem3D teach you on oxetanes? “Oxetane, or 1,3-propylene oxide, is an heterocyclic organic compound with the molecular formula C 3 H 6 O, having a four-membered ring with three carbon atoms and one oxygen atom.” “Other possible reactions to form oxetane ring is the Paternò-Büchi reaction. Also, diol cyclization can form oxetane rings.” Citations taken from Wikipedia :

Puckering of 4-membered cycles Moriarty, R. M. Top. Stereochem. 1974, 8,

Comparaison with other 4-membered heterocycles Legon, A. C. Chem. Rev. 1980, 80,

Theorical reasons why oxetane prefers a planar conformation. The variations of the potential energy with ring-puckering coordinate (V(x)) as been assumed to arise solely (majorly) from deformation of the ring angle strain (V d ) and torsional motion about the ring bonds (V t ) : We can integrate/derivatize these formula under this more general equation (as a power series) : Where A is a positive coefficient and B is variable in term of ring size and substituents on the ring. In general, the more B is positive, the more the molecule is planar.

Theorical reasons why oxetane prefers a planar conformation. Torsional strain (motion): arises when bonds are not ideally staggered Angle strain : arises when the C-C-C bonds of the ring depart (because of geometric necessity) from the ideal tetrahedral angle preferred for sp 3 carbon.

Theorical reasons why oxetane prefers a planar conformation. The variations of the potential energy with ring-puckering coordinate (V(x)) as been assumed to arise solely (majorly) from deformation of the ring angle (V d ) and torsional motion about the ring bonds (V t ) : We can integrate/derivatize these formula under this more general equation (as a power series) : Where A is a positive coefficient and B is variable in term of ring size and substituents on the ring. In general, the more B is positive, the more the molecule is planar.

Far-infrared and raman spectroscopic analysis of oxetane vs cyclobutane Moriarty, R. M. Top. Stereochem. 1974, 8, The most widely used route to vibrational spacing in the puckering mode in four-membered rings is through far-infrared spectra. Once the vibrational spacing have been mesured, a one dimentional plotting of the potential is usualy fitted to the data.

Current topics in medicinal chemistry on oxetanes (E. M. Carreira) Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fisher, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem. Int. Ed. 2006, 45,

Current topics in medicinal chemistry on oxetanes (E. M. Carreira) Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fisher, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem. Int. Ed. 2006, 45, S. Jarvis :

Synthesis of compounds A-G Kozikowski, A. P.; Fauq, A. H. Synlett, 1991, 783.

Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fisher, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem. Int. Ed. 2006, 45, Synthesis of compounds A-G

Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fisher, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem. Int. Ed. 2006, 45, Synthesis of compounds A-G

Reminder of the Lipinski’s rule of thumb (Oral Bio-Availability) The rule is important for drug development where a pharmacologically active lead structure is optimized step-wise for increased activity and selectivity, as well as drug-like properties : Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms) Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms) A molecular weight under 500 daltons An octanol-water partition coefficient log P of less than 5 (in -0.4 to +5.6 range).

Reminder of the Lipinski’s rule of thumb (Oral Bio-Availability) The rule is important for drug development where a pharmacologically active lead structure is optimized step-wise for increased activity and selectivity, as well as drug-like properties : Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms) Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms) A molecular weight under 500 daltons An octanol-water partition coefficient log P of less than 5. Aherne, R. et al. Breast Cancer Res. 2002, 4,148.

Physico- and Biochemical properties of compounds A-G vs starting target

Herg Activity : hERG (human Ether-a-go-go Related Gene) is a gene that codes a protein known as Kv 11.1 or potassium ion channel. When inhibited or compromised, it can induce the fatal disorder called the « long QT syndrome » and causes a concomittant sudden death.

Oxetanes as carbonyl isosters Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008, 47, « […] the oxetane and aliphatic carbonyl groups have a similarly high H-bonding affinity. » « Consequently, the nominal analogy of an oxetane to C=O may be of interest in molecular design, particularly when a larger volume occupancy and deeper oxygen placement may be adventegeous to a receptor pocket. »

Oxetanes as carbonyl isosters (properties) Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008, 47,

What can we conclude with both of these studies? Oxetane can be employed to access novel analogues and expand chemical space around morpholine and piperidine rings. It can be grafted (in a racemic fashion) easily onto molecules. Oxetane ring is positionned between a gem-dimethyl and carbonyl groups in term of lipophilicity, solubility and influence of basicity. Oxetane ring is more stable than a carbonyl group towards metabolisation. Oxetane is very stable under acidic-basic conditions. Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008, 47,

Are stereoselective syntheses of oxetanes representative?

Strategies used for the synthesis of oxetanes

Stereospecific mechanism : In chemistry, a reaction is stereospecific if the result is dependant on the stereochemistry of the reagent. This is true because the arrangement of the atoms in the transition state is pre-defined, giving a product with a particular stereochemistry or the reaction won’t work in a different fashion. Stereoselective mechanism : A reaction is stereoselective if the issue of the reaction gives stereoselectively one product over another (or others), that can be drawn from a single mechanism. Usually, it’s a reaction that gives a stereocenter under a kinetic or thermodynamic control.

- reaction Emanuele Paternò di Sessa : ( ) In 1892 he became a professor at the University of Rome. He did photochemistry research, and discovered the Paternò-Büchi reaction in He was politically active. He was the mayor of Palermo ( ) and a member of the regional parliament ( ). George Hermann Büchi : ( ) He received the D.Sc. in organic chemistry from the ETH, while working in the laboratory of Professor Leopold Ruzicka in He accepted an offer from the late Arthur C. Cope to join the faculty of the Chemistry Department at the MIT in Established molecular toxicology as an important scientific discipline.

Applications of the Paternò-Büchi reaction in total synthesis (a)Bach, T.; Brummerhop, H. Angew. Chem. Int. Ed. 1998, 37, (b) Bach, T.; Brummerhop, H.; Harms, K. Chem. Eur. J. 2000, 6, (c) Schreiber, S. L.; Hoveyda, A. H.; Wu, H. J. A. J. Am. Chem. Soc. 1983, 105, (d) Schreiber, S. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1984, 106,

Ultraviolet = energy = reaction E = h = c/ E = hc/

What does energy means in terms of molecules’ view? Skoog, D. A.; Holler, J. F.; Nieman, T. A. Principle of Instrumental Analysis, 5th edition, 1997, Thompson Learning Ed., Chap. 4.  ~ Å (Gamma rays) = Nuclear interactions ~ 0.1 – 100 Å (X-Rays) = Inner electrons ~ nm (UV -Visible) = Bonding electrons ~ 780 nm – 300 μm (Infrared) = Rotation and vibration ~ 0.73 – 3.75 mm (Microwaves) = Rotation of molecules ~ 0.6 – 10 m (Radiowaves) = Spin of nuclei

Photochemical processes and absorbance (wavelenght) Ionization Electron-Transfer Dissociation Addition Abstraction Isomerisation or rearrangement Image taken from : Atkins, P.; De Paula, J. Physical Chemistry, 7th edition, 2001, Oxford Ed., Chap. 26, pp

Absorption characteristics Image taken from : Atkins, P.; De Paula, J. Physical Chemistry, 7th editionE, 2001, Oxford d., Chap. 17, pp

Absorption characteristics Image taken from : Atkins, P.; De Paula, J. Physical Chemistry, 7th editionE, 2001, Oxford d., Chap. 17, pp [Cu(NH 3 ) 4 ] 2+ (aq) [Cu(OH 2 ) 6 ] 2+ (aq)

Illustration of the singlet and triplet excited state (Jablonski-Morse). Image taken from : Atkins, P.; De Paula, J. Physical Chemistry, 7th edition, 2001, Oxford Ed., Chap. 6. Lifetime of singlet state : – sec (permitted desactivation, intramolecular) Lifetime of triplet state : – 10 sec (forbidden desactivation, intermolecular)

Illustration of the triplet and singlet state for diradical carbenes or oxygen Image taken from :

How can we put physical chemistry in the P-B mechanism? Singlet and triplet biradical are observable by spectroscopy. (Half-lives ~ ns). Singlet biradical can also decompose back to the alkene and the carbonyl. (a) Bach, T. Synthesis 1998, (b) Griesbeck, A. G.; Abe, M.; Bondock, S. Acc. Chem. Res. 2004, 37,

How can we put physical chemistry in the P-B mechanism? Singlet and triplet biradical are observable by spectroscopy (Half-lives ~ ns). Singlet biradical can also decompose back to the alkene and the carbonyl. Nemirowski, A.; Schreiner, P. R. J. Org. Chem. 2007, 72,

Triplet state sensitizers What do we do if K ISC is ~ 0? Answer is photosensitization :

Triplet state sensitizers What do we do if K ISC is ~ 0? Answer is photosensitization :

General features of the P-B reaction The carbonyl singlet state reacts with the alkene when aliphatic aldehyde and ketone is used and when the concentration of the alkene is high. The reaction with the singlet state is stereospecific and the alkene stereochemical information is transferred. In the triplet state, the biradical is observed and the most stable conformer collapse to the oxetane. When pure (E) or (Z) alkene is used, during the reaction with the triplet state, the stereochemical information is lost and the trans oxetane is favoured. Facial selectivity can be induced by either allylic strain, allylic alcohols, chiral auxiliaries or chiral alkenes.

Concerted vs stepwise cycloaddition (FMO analysis) The cyclic transition state must correspond to an arrangement of the participating orbitals which has to maintain a bonding interaction between the reaction components throughout the course of the reaction. We can predict if a transformation involving n-  electron is thermally or photochemically allowed using either : The Fukui Frontier-Molecular Orbital Theory Dewar-Zimmerman Hückel-Möbius Aromatic Transition States (Woodward-Hoffmann Correlation Diagrams)

How can we illustrate orbitals when a concerted- thermal [2+2] mechanim is implemented (Fukui)? Supra/SupraSupra/Antara

How can we illustrate orbitals when a concerted- photochemical [2+2] mechanim is implemented (Fukui)? Supra/Supra Supra/Antara

Different mechanism means different selectivity for the Paternò-Büchi reaction. Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112, Singlet state :

Regioselectivity for the Paternò-Büchi reaction. Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112, (b) Carless, J. H. A.; Halfhide, A. F. J. Chem. Soc.; Perkin Trans , (c) Dramatic differences in regioselectivity in photochemical [2+2] can be explain by confirming : - The character of the n  * excited carbonyl state - The stability of the intermediate biradical triplet 2-oxabutane-1,4- diyl The excited state of carbonyl compounds has an electrophilic radical character on the oxygen atom. Thus, in the HOMO orbital of the alkene, the position corresponding to the highest electron density should react with the excited carbonyl.

Different mechanism means different regioselectivity for the Paternò-Büchi reaction. Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112,

Endo-selectivity rationale for non-aromatic substrates (cyclic) with triplet state Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112,

Endo-selectivity rationale for non-aromatic substrates (acyclic) with triplet state Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, (b) Griesbeck, A. G.; Bondock, S. J. Am. Chem. Soc. 2001, 123,

Solvent effect on triplet vs singlet states Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27,

Effect of the concentration of alkene quencher on triplet vs singlet states Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27,

Photoinduced Electron-transfer effect on regioselectivity Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27,

Exo-selectivity rationale for aromatic substrates (acyclic) with triplet state (a) Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, (b) Abe, M.; Kawakami, T.; Ohata, S.; Nozaki, K.; Nojima, M. J. Am. Chem. Soc. 2004, 126,

Diastereoselectivity via retro-cleavage

Diastereofacial selectivity via allylic strain Bach, T.; Jödicke, K.; Kather, K.; Frölich, R. J. Am. Chem. Soc. 1997, 119,

Diastereofacial selectivity via allylic strain (example) Bach, T.; Jödicke, K.; Kather, K.; Frölich, R. J. Am. Chem. Soc. 1997, 119,

Diastereofacial selectivity via chiral auxiliary (example) Nehrings, A.; Scharf, H.-D.; Runsink, J. Angew. Chem. Int. Ed. 1985, 24,

Diastereofacial selectivity via hydroxy-directed reaction Adam, W.; Peters, K.; Peters, E. M.; Stegmann, V. R. J. Am. Chem. Soc. 2000, 122,

Diastereofacial selectivity via hydroxy-directed reaction (example) Adam, W.; Peters, K.; Peters, E. M.; Stegmann, V. R. J. Am. Chem. Soc. 2000, 122,

Chiral oxetanes from β-lactones formation involving « P-A like » reactions (ketene derived) Nelson, S. G.; Peelen, S. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121,

Chiral oxetanes from β-lactones formation involving « P-A like » reactions (ketene-derived)

Evans, D. A.; Jacobs, J. N. Org. Lett. 2001, 3,

Chiral oxetanes from β-lactones formation involving « P-A like » reactions (ketene-derived) Evans, D. A.; Jacobs, J. N. Org. Lett. 2001, 3,

Transformation of β-lactones to chiral building blocks Arnold, L. D.; Drover, J. C. G.; Vederas, J. C. J. Am. Chem. Soc. 1987, 109,

Ring-closing approach to oxetanes (example) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4,

Ring-closing approach to oxetanes (example) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4,

Ring-closing approach to oxetanes (example) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4,

Catalytic enantioselective reaction to form oxetanes (kinetic resolution) Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, Catalyst

Catalytic enantioselective reaction to form oxetanes (kinetic resolution) Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48,

Utility of oxetanes as masked functionalities Schreiber, S. L.; Hoveyda, A. H.; Wu, H. J. A. J. Am. Chem. Soc. 1983, 105, (d) Schreiber, S. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1984, 106, Masked aldol products

Utility of oxetanes as masked functionalities Bach, T. Synthesis 1998,

In conclusion… Don’t be afraid of the dark… and the light!