Promising molecules in Drug Discovery : Syntheses and Applications of Oxetanes.

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Promising molecules in Drug Discovery Syntheses
and Applications of Oxetanes.

• A presentation by Guillaume Pelletier on October
  6th 2009

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(No Transcript)
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What can wikipedia and Chem3D teach you on
oxetanes?
Oxetane, or 1,3-propylene oxide, is an
heterocyclic organic compound with the molecular
formula C3H6O, 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
http//en.wikipedia.org/wiki/Oxetane
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Puckering of 4-membered cycles
Moriarty, R. M. Top. Stereochem. 1974, 8,
273-421.
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Comparaison with other 4-membered heterocycles
Legon, A. C. Chem. Rev. 1980, 80, 231-262.
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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 (Vd) and torsional motion about
  the ring bonds (Vt)
• 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.

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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 sp3
  carbon.

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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 (Vd) and torsional motion about the
  ring bonds (Vt)
• 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.

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Far-infrared and raman spectroscopic analysis of
oxetane vs cyclobutane

• 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.

Moriarty, R. M. Top. Stereochem. 1974, 8,
273-421.
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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, 7736-7739.
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Current topics in medicinal chemistry on oxetanes
(E. M. Carreira)
S. Jarvis
Wuitschik, G. Rogers-Evans, M. Müller, K.
Fisher, H. Wagner, B. Schuler, F. Polonchuk,
L. Carreira, E. M. Angew. Chem. Int. Ed. 2006,
45, 7736-7739.
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Synthesis of compounds A-G
Kozikowski, A. P. Fauq, A. H. Synlett, 1991,
783.
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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, 7736-7739.
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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, 7736-7739.
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Reminder of the Lipinskis 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) .

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Reminder of the Lipinskis 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.
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Physico- and Biochemical properties of compounds
A-G vs starting target
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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.

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Oxetanes as carbonyl isosters

•   the oxetane and aliphatic carbonyl groups
  have a similarly high H-bonding affinity. 
•  Consequently, the nominal analogy of an oxetane
  to CO may be of interest in molecular design,
  particularly when a larger volume occupancy and
  deeper oxygen placement may be adventegeous to a
  receptor pocket. 

Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008,
47, 4512-4515.
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Oxetanes as carbonyl isosters (properties)
Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008,
47, 4512-4515.
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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, 4512-4515.
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Are stereoselective syntheses of oxetanes
representative?
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Strategies used for the synthesis of oxetanes
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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 wont 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, its a reaction that gives a
stereocenter under a kinetic or thermodynamic
control.
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- reaction

• Emanuele Paternò di Sessa (1847-1935) In 1892
  he became a professor at the University of Rome.
  He did photochemistry research, and discovered
  the Paternò-Büchi reaction in 1909. He was
  politically active. He was the mayor of Palermo
  (1890-1892) and a member of the regional
  parliament (1898-1914).
• George Hermann Büchi (1921-1998) He received
  the D.Sc. in organic chemistry from the ETH,
  while working in the laboratory of Professor
  Leopold Ruzicka in 1947. He accepted an offer
  from the late Arthur C. Cope to join the faculty
  of the Chemistry Department at the MIT in 1951.
  Established molecular toxicology as an important
  scientific discipline.

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Applications of the Paternò-Büchi reaction in
total synthesis

• Bach, T. Brummerhop, H. Angew. Chem. Int. Ed.
  1998, 37, 3400-3402. (b) Bach, T. Brummerhop,
  H. Harms, K. Chem. Eur. J. 2000, 6, 3838-3848.
• (c) Schreiber, S. L. Hoveyda, A. H. Wu, H. J.
  A. J. Am. Chem. Soc. 1983, 105, 660-661. (d)
  Schreiber, S. L. Hoveyda, A. H. J. Am. Chem.
  Soc. 1984, 106, 7200-7202.

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Ultraviolet energy reaction

• E hn
• n c/l
• E hc/l

http//www.thomasnet.com/articles/image/electromag
netic-spectrum.jpg
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What does energy means in terms of molecules
view?

• 0.005-1.4 Å (Gamma rays) Nuclear
  interactions
• 0.1 100 Å (X-Rays) Inner electrons
• 10-780 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
• 
  

Skoog, D. A. Holler, J. F. Nieman, T. A.
Principle of Instrumental Analysis, 5th edition,
1997, Thompson Learning Ed., Chap. 4.
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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.921-924.
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Absorption characteristics
Image taken from Atkins, P. De Paula, J.
Physical Chemistry, 7th editionE, 2001, Oxford
d., Chap. 17, pp.1098-1099.
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Absorption characteristics
Cu(NH3)42 (aq)
Cu(OH2)62 (aq)
Image taken from Atkins, P. De Paula, J.
Physical Chemistry, 7th editionE, 2001, Oxford
d., Chap. 17, pp.1098-1099.
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Illustration of the singlet and triplet excited
state (Jablonski-Morse).
Lifetime of singlet state 10-12 10-6 sec
(permitted desactivation, intramolecular) Lifetime
of triplet state 10-6 10 sec (forbidden
desactivation, intermolecular)
Image taken from Atkins, P. De Paula, J.
Physical Chemistry, 7th edition, 2001, Oxford
Ed., Chap. 6.
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Illustration of the triplet and singlet state for
diradical carbenes or oxygen
Image taken from http//www.meta-synthesis.com/w
ebbook/16_diradical/diradical.html
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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, 683-703. (b)
Griesbeck, A. G. Abe, M. Bondock, S. Acc. Chem.
Res. 2004, 37, 919-928.
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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, 9533-9540.
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Triplet state sensitizers

• What do we do if KISC is 0? Answer is
  photosensitization

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Triplet state sensitizers

• What do we do if KISC is 0? Answer is
  photosensitization

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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.

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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-p
  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)

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How can we illustrate orbitals when a
concerted-thermal 22 mechanim is implemented
(Fukui)?
Supra/Supra
Supra/Antara
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How can we illustrate orbitals when a
concerted-photochemical 22 mechanim is
implemented (Fukui)?
Supra/Supra
Supra/Antara
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Different mechanism means different selectivity
for the Paternò-Büchi reaction.
Singlet state
Griesbeck, A. G. Stadtmüller, S. J. Am. Chem.
Soc. 1990, 112, 1281-1282.
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Regioselectivity for the Paternò-Büchi reaction.

• Dramatic differences in regioselectivity in
  photochemical 22 can be explain by confirming
  
• - The character of the np 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.

Griesbeck, A. G. Stadtmüller, S. J. Am. Chem.
Soc. 1990, 112, 1281-1282. (b) Carless, J. H. A.
Halfhide, A. F. J. Chem. Soc. Perkin Trans. 1
1992, 1081-1082. (c)
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Different mechanism means different
regioselectivity for the Paternò-Büchi reaction.
Griesbeck, A. G. Stadtmüller, S. J. Am. Chem.
Soc. 1990, 112, 1281-1282.
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Endo-selectivity rationale for non-aromatic
substrates (cyclic) with triplet state
Griesbeck, A. G. Stadtmüller, S. J. Am. Chem.
Soc. 1990, 112, 1281-1282.
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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, 964-965. (b) Griesbeck,
A. G. Bondock, S. J. Am. Chem. Soc. 2001, 123,
6191-6192.
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Solvent effect on triplet vs singlet states
Griesbeck, A. G. Mauder, H. Stadtmüller, S.
Acc. Chem. Res. 1994, 27, 70-76.
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Effect of the concentration of alkene quencher on
triplet vs singlet states
Griesbeck, A. G. Mauder, H. Stadtmüller, S.
Acc. Chem. Res. 1994, 27, 70-76.
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Photoinduced Electron-transfer effect on
regioselectivity
Griesbeck, A. G. Mauder, H. Stadtmüller, S.
Acc. Chem. Res. 1994, 27, 70-76.
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Exo-selectivity rationale for aromatic substrates
(acyclic) with triplet state
(a) Griesbeck, A. G. Mauder, H. Stadtmüller, S.
Acc. Chem. Res. 1994, 27, 70-76. (b) Abe, M.
Kawakami, T. Ohata, S. Nozaki, K. Nojima, M.
J. Am. Chem. Soc. 2004, 126, 2838-2846.
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Diastereoselectivity via retro-cleavage
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Diastereofacial selectivity via allylic strain
Bach, T. Jödicke, K. Kather, K. Frölich, R. J.
Am. Chem. Soc. 1997, 119, 2437-2445.
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Diastereofacial selectivity via allylic strain
(example)
Bach, T. Jödicke, K. Kather, K. Frölich, R. J.
Am. Chem. Soc. 1997, 119, 2437-2445.
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Diastereofacial selectivity via chiral auxiliary
(example)
Nehrings, A. Scharf, H.-D. Runsink, J. Angew.
Chem. Int. Ed. 1985, 24, 877-878.
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Diastereofacial selectivity via hydroxy-directed
reaction
Adam, W. Peters, K. Peters, E. M. Stegmann, V.
R. J. Am. Chem. Soc. 2000, 122, 2958-2959.
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Diastereofacial selectivity via hydroxy-directed
reaction (example)
Adam, W. Peters, K. Peters, E. M. Stegmann, V.
R. J. Am. Chem. Soc. 2000, 122, 2958-2959.
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Chiral oxetanes from ß-lactones formation
involving  P-A like  reactions (ketene derived)
Nelson, S. G. Peelen, S. J. Wan, Z. J. Am.
Chem. Soc. 1999, 121, 9742-9743.
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Chiral oxetanes from ß-lactones formation
involving  P-A like  reactions (ketene-derived)
Nelson, S. G. Peelen, S. J. Wan, Z. J. Am.
Chem. Soc. 1999, 121, 9742-9743.
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Chiral oxetanes from ß-lactones formation
involving  P-A like  reactions (ketene-derived)
Evans, D. A. Jacobs, J. N. Org. Lett. 2001, 3,
2125-2128.
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Chiral oxetanes from ß-lactones formation
involving  P-A like  reactions (ketene-derived)
Evans, D. A. Jacobs, J. N. Org. Lett. 2001, 3,
2125-2128.
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Transformation of ß-lactones to chiral building
blocks
Arnold, L. D. Drover, J. C. G. Vederas, J. C.
J. Am. Chem. Soc. 1987, 109, 4649-4659.
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Ring-closing approach to oxetanes (example)
Dussault, P. H. Trullinger, T. K. Noor-e-Ain,
F. Org. Lett. 2002, 4, 4591-4593.
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Ring-closing approach to oxetanes (example)
Dussault, P. H. Trullinger, T. K. Noor-e-Ain,
F. Org. Lett. 2002, 4, 4591-4593.
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Ring-closing approach to oxetanes (example)
Dussault, P. H. Trullinger, T. K. Noor-e-Ain,
F. Org. Lett. 2002, 4, 4591-4593.
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Catalytic enantioselective reaction to form
oxetanes (kinetic resolution)
Catalyst
Sone, T. Lu, G. Matsunaga, S. Shibasaki, M.
Angew. Chem., Int. Ed. 2009, 48, 1677-1680.
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Catalytic enantioselective reaction to form
oxetanes (kinetic resolution)
Sone, T. Lu, G. Matsunaga, S. Shibasaki, M.
Angew. Chem., Int. Ed. 2009, 48, 1677-1680.
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Utility of oxetanes as masked functionalities
Masked aldol products
Schreiber, S. L. Hoveyda, A. H. Wu, H. J. A. J.
Am. Chem. Soc. 1983, 105, 660-661. (d) Schreiber,
S. L. Hoveyda, A. H. J. Am. Chem. Soc. 1984,
106, 7200-7202.
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Utility of oxetanes as masked functionalities
Bach, T. Synthesis 1998, 683-703.
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In conclusion

• Dont be afraid of the dark and the light!