Upload
roland-strickland
View
218
Download
0
Embed Size (px)
Citation preview
Promising molecules in Drug Discovery : Syntheses and Applications of Oxetanes.
A presentation by Guillaume Pelletier on October 6th 2009
What can wikipedia and Chem3D teach you on oxetanes?“Oxetane, or 1,3-propylene oxide, is an heterocyclic organic compound with themolecular formula C3H6O, having a four-membered ring with three carbon atomsand one oxygen atom.”
“Other possible reactions to form oxetane ring is the Paternò-Büchi reaction.Also, diol cyclization can form oxetane rings.”
Cl O
OKOH, 150 °C O
ca. 40% Yield
Citations taken from Wikipedia : http://en.wikipedia.org/wiki/Oxetane
Ph
O NH
Ph
O
O
OHOH
OO
O
O
PhO
H
OH
O
O
O
Puckering of 4-membered cycles
Moriarty, R. M. Top. Stereochem. 1974, 8, 273-421.
Comparaison with other 4-membered heterocycles
Legon, A. C. Chem. Rev. 1980, 80, 231-262.
O
S
Se
SiH2
NH
CF2
Molecule
Inversion barrier energy
cm-1 kcal/mol
0.040.10
0.75
1.07
1.26
1.26
1.281.48
15.3 ± 0.535 ± 5
274.2 ± 2
373
440
441
448 ± 18518 ± 5
N.B. : 1kcal/mol = 350 cm-1
Dihedral angle (in deg)
241 ± 5 0.68
33-35
27
37
---
~0
28
32.5
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.
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.
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.
Far-infrared and raman spectroscopic analysis of oxetane vs cyclobutane
Moriarty, R. M. Top. Stereochem. 1974, 8, 273-421.
• 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, 7736-7739.
N
Large hydrophobicunit
Polar head group
N
X
O
X = Me (A) F (B) H (C)
ArN
ArN
ArN
ArN
O
O
O
O
D E
F G
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.
S. Jarvis :
Synthesis of compounds A-G
Kozikowski, A. P.; Fauq, A. H. Synlett, 1991, 783.
HO OH
OMeOH, p-TSA
H
OMe
OMe
OMe
HO OHMeO OMe
1) TsCl, Et3N, DCM2) NaH
O
OMe
MeO
37% Overall yield
O
O
62% Yield
K10 Montmorillonite2,2-Dimethoxypropane
ClO
1) AcOH, FeCl3 (cat.)65°C, 24 hrs.
2) p-TSA, CH2Cl2
OEt
OOEt
Cl
AcO
3) NaOH 2N, 105 °C,5 hrs.
4) CSA, MeOH, r.t. O
HO
O
O
Kozikowski :
Carreira :
50% Yield 2 steps
PCC, NaOAc, DCM, 40 hrs.
51% Yield 2 steps
54% Yield
O
H2N
CO2H
NMDA ReceptorAntagonist
(Prep GC Purification)
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.
Synthesis of compounds A-G
O
O
N(Me)2
O
HO
O
CO2Et
N(Me)2
O
H
N(Me)2
O
F
N(Me)2
O
Me
N(Me)2
O
N(Me)2
Li
CO2EtPh3P
DCM, r.t.
THF, -78°C
1) NaH, Et2O, 0°C2) TsCl, 0°C
3) LiAlH4, -78°C
CH2Cl2, -78°C
1) [Rh(cod)Cl]2, KOH, Dioxane, H2O
2) DIBAL-H, -78°C3) [(PPh3)3RhCl], tol., 105°C
N
SF F
F
N(Me)2
(HO)2B
MgBr1)
2) Me2NH, NaBH3CN, MeOH
TMSCl, CuI, THF
71% Yield
89% Yield
58% Yield (3 steps)
40% Yield
27% Yield (3 steps)
28% Yield (2 steps)
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.
Synthesis of compounds A-G
O
CHO
O
NO2
N(Me)2
N(Me)2
N(Me)2
O
O
O
CHOPh3P
DCM, r.t.
1) MeNO2, Et3N, r.t.
2) Et3N, MsCl, DCM, -78°C
O
O
1) 4-(t-Bu)Ph-B(OH)2
[Rh(cod)Cl]2, KOH, Dioxane2) MeNO2, NEt3, r.t. then TsCl
3) Reduction/Amination
B(OH)21)
[Rh(cod)Cl]2, KOH, Dioxane
2) Reduction/Amination
1) HNMe2, DBU, THF2) 4-(t-Bu)PhCH=PPh3
3) H2, Pd/C, MeOH
81% Yield
81% Yield (2 steps)
15% Yield (5 steps)
36% Yield (3 steps)
34% Yield (3 steps)
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 .
N
N
NHN
HN
Me
O
N
N
Gleevec (STI571) Novartis
MW = 493.60Log P = 3.83
# H Donnors = 2# O, N = 8
N
N
N
N
NH
HN
HO
R-Roscovitine (Seliciclib)Cylacel (Short Hills, NJ)
MW = 354.45Log P = 2.75
# H Donnors = 3# O, N = 7
Aherne, R. et al. Breast Cancer Res. 2002, 4,148.
Physico- and Biochemical properties of compounds A-G vs starting target
N(Me)2
O
H
N(Me)2
O
F
N(Me)2
O
Me
N(Me)2
N(Me)2
N(Me)2
N(Me)2
O
O
O
O
Target molecule
"Oxetane-free" amine
pKa (in H2O)
7.2
8.0
9.2
9.6
9.9
9.9
9.9
9.9
log P
4.3
2.4
2.0
3.3
3.9
3.5
4.0
3.6
< 1
4000
Solubility in H2O (g/mL) (pH = 9.9)
Intrinsic clearance (L/min*mg)Human Mouse
16 417
2 27
6 50
0
0
6
42
13 580
383
13
147
43
6100
4400
270
4100
25
57
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.
N
(A) to (G)
Buffers pH 1-1037°C, 2hrs No degradation
N N
O
(G)
hERG IC50 = 35 M hERG IC50 = 7 M
Acid/Base stability:
hERG Activity:
Oxetanes as carbonyl isosters
Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008, 47, 4512-4515.
N N
R R
N
R
N
R
N
R
N
O
R
N
O
R
R =
O
O
• « […] 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, 4512-4515.
N
N
R
R
N
R
N
R
N
R
N
O
R
Structure Function Log P Solubility in H2O (g/mL) (pH = 9.9)
Clearance (L/min*mg)
pKa (in H2O)a
gem-Me2OxetaneCarbonyl
gem-Me2
OxetaneCarbonyl
gem-Me2
OxetaneCarbonyl
gem-Me2OxetaneCarbonyl
gem-Me2
OxetaneCarbonyl
3.11.2n.d.
29024000
n.d.
167
n.d.
9.68.0n.d.
3.71.5-0.1
40730
4100
3927
580
9.78.16.1
4.42.01.6
22014004000
312288
9.58.37.5
4.32.30.5
1320002100
8955
120
9.47.97.6
3.92.41.6
30750
6200
1823039
10.27.0n.d.
Morpholine 1.6 8000 8 7.0
a Amine basicity in H2O measured spectrophotometrically.
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.
Are stereoselective syntheses of oxetanes representative?
O
HOOH
N
N
N
N
NH2
Oxetanocin A
O
H
H
OH
COOH
Thromboxane A2
OMe
HOMe
Me OO
O
(+)-Merrilactone A
Ph
O NH
Ph
O
O
OHOH
OO
O
O
PhO
H
OH
O
O
O
Taxol
Org. Lett. 2002, 4, 1147.Synthesis 2002, 1, 1.
Tetrahedron Lett. 1990, 31, 6931.Tetrahedron Lett. 1990, 31, 5445.Tetrahedron Lett. 1988, 29, 4743.
J. Am. Chem. Soc. 2007, 129, 498.Angew. Chem. Int. Ed. 2006, 45, 953.J. Am. Chem. Soc. 2003, 125, 10772.J. Am. Chem. Soc. 2002, 124, 2080.
Natural : COX protein and blood platelets
K. C. Nicolaou Nature 1994, 367, 630.R. A. Holton J. Am. Chem. Soc. 1994, 116, 1599.
S. J. Danishefsky J. Am. Chem. Soc. 1996, 118, 2843.P. A. Wender J. Am. Chem. Soc. 1997, 119, 2755.I. Kuwajima J. Am. Chem. Soc. 1998, 120, 12980.
T. Mukaiyama Chem. Eur. J. 1999, 5, 121.
Strategies used for the synthesis of oxetanes
Paterno-Büchi Reaction
RS
O
RL
S0
RS
O
RL
S1
h (UV light)
R3
R4R1
R2
stereospecificcycloaddition O
R4
R3
R2
R1
+ Regioisomers
ISCRS
O
RL
T1
non-stereospecificcycloaddition O
R4
R3
R2
R1
O
R4
R3
R2
R1
Secondary Alcohol-Derived Ring Closing (SN2)
O
R1 LG
R1
O
H
R3
R2
Asymmetric Reduction
OH
R1 LG
R3
R2
*Base O
R1
R3R2
Asymmetric Allylation/Crotylation
OH
R1
R2
EpoxidationBase
*
**
OR1
R2
OH
*
Catalytic Enantioselective methods (2000-<)
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 : (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.
Me Me
MeH
Ph
O OMe
Me
Me Ph
Me Me
MeH
n-Pr
O OMe
Me
Me n-Pr
Applications of the Paternò-Büchi reaction in total synthesis
(a) 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.
NH
O
OH
N
(+)-Preussin (T. Bach)
OO
N
OO
O
H
HPh
88 N
H
HOH
H
Ph 8
1) H2/Pd(OH)2/C MeOH
2) LiAlH4, THF
(+)-Preussin
PhCHOh(350nm)
MeCN
(53% Si + 12% Re)
(±)-Avenaciolide (S. L. Schreiber)
O
C8H17
O 450W Hanovia Lamp
Vycor filter, -20°C~100% Yield
OO
H
HC8H17
1) H2, Rh/Al2O3
EtOAc
2) 0.1N HCl/THF (1:4)OH
CHO
C18H17
OH
OO
O
O
H
HC18H17
(±)-Avenaciolide
Ultraviolet = energy = reaction
http://www.thomasnet.com/articles/image/electromagnetic-spectrum.jpg
• 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.
~ 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
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.
Absorption characteristics
Image taken from : Atkins, P.; De Paula, J. Physical Chemistry, 7th editionE, 2001, Oxford d., Chap. 17, pp.1098-1099.
Absorption characteristics
Image taken from : Atkins, P.; De Paula, J. Physical Chemistry, 7th editionE, 2001, Oxford d., Chap. 17, pp.1098-1099.
[Cu(NH3)4]2+ (aq) [Cu(OH2)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 : 10-12 – 10-6 sec (permitted desactivation, intramolecular)Lifetime of triplet state : 10-6 – 10 sec (forbidden desactivation, intermolecular)
Illustration of the triplet and singlet state for diradical carbenes or oxygen
Image taken from : http://www.meta-synthesis.com/webbook/16_diradical/diradical.html
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.
O
R2R1
R4R3
R5 R6
hv
electron transfer R4R3
R5R6
O
R2
R1
O
R5R6
R3
R4R2
R1
Reaction
hv O
R2R1
*1
O
R2R1
*3
Inter-systemcrossing
KISC
R4R3
R5 R6
O
R5R6
R3
R4
R2
R1
Singlet biradical
O
R5R6
R3
R4
R2
R1
Triplet biradical
R4R3
R5 R6
Spin-rotation
Reaction
O
R5R6
R3
R4R2
R1
(a) Bach, T. Synthesis 1998, 683-703. (b) Griesbeck, A. G.; Abe, M.; Bondock, S. Acc. Chem. Res. 2004, 37, 919-928.
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.
Triplet state sensitizers• What do we do if KISC is ~ 0? Answer is photosensitization :
Sens *Sens1h *Sens3KISC
*Sens3
R1
O
R2
Ktransfer
R1
O3
R2
*Sens
Reactiontriplet state
R4R3
R5 R6
O
R2
R1
R3
R4
R6
R5
Triplet state sensitizers• What do we do if KISC is ~ 0? Answer is photosensitization :
Me Me
O
Photosensitizer KISC ET (kcal/mol)
Ph Me
O
Ph Ph
O
0.98
1.00
1.00
0.86
0.68
78.9
73.9
68.6
66.9
60.5
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/Supra Supra/Antara
X
O
O
O
HOMO
LUMO
X = O-Alkyl, S-Alkyl N,N-Dialkylamine
O
O
HOMO
LUMO
How can we illustrate orbitals when a concerted-photochemical [2+2] mechanim is implemented (Fukui)?
Supra/Supra
Supra/Antara
X
O
O
O
SOMO
SOMO
X = O-Alkyl, S-Alkyl N,N-Dialkylamine
O
O
HOMO
LUMO
O
O
Different mechanism means different selectivity for the Paternò-Büchi reaction.
Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112, 1281-1282.
Singlet state :
OPh
O
O
Oh
Ph
H
HO
O
Ph
H
H
d.r = 88 : 12
Endo Exo
OPh
O
OO
hH
HOO
H
H
d.r = >5 : 95
Endo Exo
Ph Ph
O
O
Ph H
O
O
Ph H
Exo transition stateFavored
O
O
H Ph
O
O
H Ph
Endo transition stateNot favored
Regioselectivity for the Paternò-Büchi reaction.
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)
• 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, 1281-1282.
Ph
Oh
O
O
O
O
H
Ph
OOPh
H
ISC
ISC
O
O
OO
Ph
Ph H
H
H
H
Endo
Exo
Endo-selectivity rationale for non-aromatic substrates (cyclic) with triplet state
Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112, 1281-1282.
Prefered ISC Geometry (Rapid spin inversion)
O
Ph H O
h
O
OPh
H
Inward rotation
Fast ISC
O
O
H
HPh
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.
Ph
O
PhMeO
t-Bu
(E/Z) = 5 : 1
h
Benzene, r.t.
OPh
Ph
OMe
t-Bu
H
H
90:10 endo/exo
OPh
Ph
Ht-Bu
OMe
H
OPh
Ph
Ht-Bu
OMe
H
(Z)
O
PhPh
Ht-Bu
OMe
H
OPh
Ph
Ht-Bu
OMe
H
O
PhPh
MeOt-Bu
H
H
Favored
Non-favored
OPh
Ph
OMe
t-Bu
H
H
OPh
Ph
H
t-Bu
H
OMe
Solvent effect on triplet vs singlet states
O
O
(a) Ph
O
Et
O(b)
O
O
O
O
h
h
Et
Ph
H
H
H
H
O
(c) Et
O
Me
O(d)
O
O
O
h
h
Me
Et
H
H
H
H
OO
Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70-76.
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.
O
O
(a) Ph
O
Et
O(b)
O
O
O
O
h
h
Et
Ph
H
H
H
H
O
(c) Et
O
Me
O(d)
O
O
O
h
h
Me
Et
H
H
H
H
OO
Photoinduced Electron-transfer effect on regioselectivity
O
O
Ph
O
Ph
O
O
O
OO
h
Ph
H
H
H
H
O
O
Ph
H
H
d.r = 88 : 12
PET
Ph
OO
H
H
Ph
d.r = 10 : 90
Endo A Exo A
Endo B Exo B
Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70-76.
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.
Diastereoselectivity via retro-cleavage
Ph
O
H TMSO
h
Benzene, r.t.
O
t-Bu
OTMS
90:10 endo/exo>95% regioselectivity
OPh
H
TMSOH
H
OPh
H
TMSOH
H
O
HPh
TMSOH
H
O
PhH
TMSOH
H
Favored
Non-favored
O
Ph
t-Bu
OTMS
t-Bu
O
t-Bu
OTMSPh Ph
OPh
H
TMSOH
H H
O
Ph
t-Bu
OTMS
H
Ph
O
H TMSO t-Bu
Diastereofacial selectivity via allylic strain
Bach, T.; Jödicke, K.; Kather, K.; Frölich, R. J. Am. Chem. Soc. 1997, 119, 2437-2445.
Ph
O
HOTMS H
RRs
RL
A1,3 minimizedOTMS
R
H
H
RsRLO
HPh
OTMS
R
H
H
RsRL
O
H
Ph
Non-favoredMost hindered face
FavoredLess hindered face
OR
OTMS
R
H
H
RsRLO
HPh
R
TMSO
H
H
RsRLO
PhH
Non-favoredFavored
OTMS
R
H
H
RsRLO
PhH
O
Ph OTMS
O
Ph R
R
H
RL Rs
H
H
OTMS
RL Rs
HO
Ph OTMSR
H
RL Rs
H
H
Diastereofacial selectivity via allylic strain (example)
Bach, T.; Jödicke, K.; Kather, K.; Frölich, R. J. Am. Chem. Soc. 1997, 119, 2437-2445.
O
CHO
O Me
Me O
O Me
Me
OHt-Bu
t-BuMgCl, THF
-78°C to r.t.
TPAP, NMO
Mol. sieves, r.t., DCMO
O Me
Me
Ot-Bu
LDA, TMSCl, -78°C to r.t., THF
O
O Me
Me
OTMSt-Bu
PhCHO, h
Benzene, 30°C
O
O Me
Me
OTMSt-Bu
H
O
Ph
70% YieldRegio >95:5, d.r. = 90:10
OR
i) (PhMe2Si)2CuLi,THF, -25°C - 0°C
ii) TMSCl, NEt3, 0°C to r.t.
OTMSR
SiMe2Ph PhCHO, h
Benzene, 30°C
SiMe2Ph
OTMSR
H
O
Ph
If R = t-Bu, 44% Yield, d.r. >95:5, Regio = 70/30
If R = C(OMe)2Me, 51% Yield, d.r. = 83:17, Regio = 80/20
Me
TBAF, r.t., THF
PhMe
OH
HO R
Diastereofacial selectivity via chiral auxiliary (example)
Nehrings, A.; Scharf, H.-D.; Runsink, J. Angew. Chem. Int. Ed. 1985, 24, 877-878.
O
Me
Ph
O
O
O
O Me
Me
h
benzene
O
Ph
*ROOC
H
H
O
O
MeMe
Up to 99% Yield, Exo selectiveWhen (-)-8-Phenyl-Menyl is used, d.r. ~ 96%
MeOH, H2SO4 cat.
HO
Ph
*ROOC
H
H
O
O
MeMe
OMe
LiAlH4, THFHO
PhO
OOMeH
H
Me
Me
Acetone,CSA
O
OO
PhOMe
O
OO
PhOH
50% Yield 20% Yield
78% Yield 90% Yield
O
OMeMe
Ph
O
O
OMe
MeMe
30% Yield
Diastereofacial selectivity via hydroxy-directed reaction
Adam, W.; Peters, K.; Peters, E. M.; Stegmann, V. R. J. Am. Chem. Soc. 2000, 122, 2958-2959.
Me
MeH
Me
MeH
ROH
HOH
H R
A1,3 Minimized[Ph2CHO]*3 [Ph2CHO]*3
Me
Me
O
H R
HO
Ph
Ph 3*
O
Ph
Ph 3*
Me
MeH
RO
H
H
Me
Me
OH
H R
O
Ph
Ph O
Ph
Ph
Me
MeH
ROH
HH
KISC KISCPh
Ph
MeMe
O
OH
H R
MeMe
PhPh
O
H
OH
HR
Favored Not-Favored
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.
Me Me
R
OX
Ph2CO, h = 350 nm
Me
R
OX
O
MePhPh Me
R
OX
O
MePhPh Me
R
OX
O
MePhPh
Hydroxydirectedmajor
Hydroxydirectedminor
Electron-transferproduct
A B C
X R Conversion (%) Stereoselectivity(A : B)
Regioselectivity ((A + B) : C)
H
H
H
H
TBDMS
Me
Et
i-Pr
i-Pr
Me
90
90
89
92
84
90 : 10
93 : 7
95 : 5
>95 : 5
52 : 48
>95 : 5
>95 : 5
>95 : 5
>95 : 5
83 : 17 (d.r. = 78 : 22)
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, 9742-9743.
Me
O
Br H
O
R
Catalyst 10mol%
i-Pr2NEt
OO
R
O
C
H H
N
N
NAl
Bn
Tf TfX
X = Cl (Cat. A)X = Me (Cat. B)
i-Pr i-Pr
+ CHO+ Cat.
Thermally Allowed[2+2]
R3N
R3NH Br Ketene
Nelson, S. G.; Peelen, S. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121, 9742-9743.
Chiral oxetanes from β-lactones formation involving « P-A like » reactions (ketene-derived)
Me
O
Br H
O
R
Catalyst 10mol%
i-Pr2NEt
OO
R
Aldehyde (R) Catalyst Temp. (°C) Yield (%) ee (%)
BnOCH2
PhCH2CH2
PhCH2CH2
CH27
BnO
TBDPSOCH2
C6H11
B
B
B
A
A
A
B
-40
-40
-40
-50
-78
-50
-50
91
93
89
80
86
74
56
92
92
95
91
93
89
54
Chiral oxetanes from β-lactones formation involving « P-A like » reactions (ketene-derived)
Evans, D. A.; Jacobs, J. N. Org. Lett. 2001, 3, 2125-2128.
C
O
R1
Oi)Bisox xxxmol%
DCM, -50°C to -40°C
ii) KF, MeCNO
O
R2O2C
Catalyst 20mol%Yield (%) / ee (%)
OEt
OMe
OMe
OMe
OMe
OEt
>99 / 91
>99 / 95
92 / 99
87 / 83
79 / 87
86 / 85
TMS H O
OR3R1
Keto EsterSilyl ketene
OR2R1 Catalyst 10mol%Yield (%) / ee (%)
BrCH2
Me
Et
i-Bu
Ph
i-Pr
75 / 91
93 / 95
89 / 93
89 / 86
76 / 83
78 / 88
Chiral oxetanes from β-lactones formation involving « P-A like » reactions (ketene-derived)
Evans, D. A.; Jacobs, J. N. Org. Lett. 2001, 3, 2125-2128.
C
O
R1
O
TMS O
R3
Transformation of β-lactones to chiral building blocks
Arnold, L. D.; Drover, J. C. G.; Vederas, J. C. J. Am. Chem. Soc. 1987, 109, 4649-4659.
O
O
O
OR2
R1
or BF3
-CO2
R2
R1
O
OR2
R1
Me2S
S OH
O
R1
R2
OH2N
O
1) Zn(BH4)
2) BF3, HCl
O
CuCN, R'Li (2 equiv.)R'
H2N
O
OH
Ring-closing approach to oxetanes (example)
Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591-4593.
R2
OHR1 O Red-Al
R2
OHR1OH R1 = H, R2 = C6H13 (85% Yield)
R1 = Me, R2 = C16H33 (86% Yield)
OHMe OLiAlH4 OHMe OH
OHMe O
1) Dess-Martin2) MeMgBr
3) Red-Al
OHMe OH
Me
93% Yield
39% Yield (3 steps)
OHMe O MeMgBr OHMe OH
MeH
76% Yield
Ring-closing approach to oxetanes (example)
Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591-4593.
Diols1) KOt-Bu, TsCl, THF
2) KOt-BuOxetanes
O O OMe
C16H33
H
C6H11
Me
Me Me
2
OMe
Me Me
2
OMe
Me Me
2
Me
Me
H
H
87% Yield 40% Yield
75% Yield
40% Yield 65% Yield
Ring-closing approach to oxetanes (example)
Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591-4593.
H2O2 in Et2O
Lewis Acid
OMe
C16H33
C16H33
OHMeHOO
If L.A. = TMSOTf, 48% Yield, >90% inversion Sc(OTf)3, 60% Yield, >90% inversion Yb(OTf)3, 50% Yield, >90% inversion
Catalytic enantioselective reaction to form oxetanes (kinetic resolution)
Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 1677-1680.
Catalyst
R
O
Me R
Me OO
Me
R
AsymmetricCorey-Chaykovsky
AsymmetricCorey-Chaykovsky
ee (%) amplification
Additive/Catalyst (S)-1a(1:1) 5 mol%
Ylide 1.2 equiv.THF, r.t., 5A Mol. Sieves, 12 hrs.
Additive/Catalyst (S)-1a(1:1) 20 mol%
Ylide 1.0 equiv.THF, 45°C, 5A Mol. Sieves, 72 hrs.
Additive YlideO
P
OMe
OMeMeO
3
H2C S
O
Catalytic enantioselective reaction to form oxetanes (kinetic resolution)
Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 1677-1680.
O
O O O
O
OO O
Me
Me Me Me
Me
MeMe Me
Cl F
Me7
8
ee (%) of epoxideee (%) of oxetaneYield (%) of oxetane
ee (%) of epoxideee (%) of oxetaneYield (%) of oxetane
969974
969962
949986
979985
939988
939968
96>99.558
97>99.562
Utility of oxetanes as masked functionalities
O
R X
Nu
Hydrogenolysisor
Metal mediated reduction (Na/Naphtalene)Nucleophilic attack
under basic conditions
Nucleophilic attack under acidic conditions
OO
H
HC8H17
1) H2, Rh/Al2O3
EtOAc
2) 0.1N HCl/THF (1:4)OH
CHO
C18H17
OH
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.
Masked aldol products
Utility of oxetanes as masked functionalities
Bach, T. Synthesis 1998, 683-703.
SiMe2Ph
OTMSR
H
O
Ph
Me
TBAF, r.t., THF
PhMe
OH
HO R
1,2-syn-diols
O
Ph OHR
LiAlH4
PhMe
OH
HO R
H
O
Ph NCOOt-Bu
O
Ph NHCHO
O
Ph OTMS
CH(OMe)2
1) TFA2) TsCl
3) LiAlH4
Me
PhMe
OH
MeHN H
H
1,2-anti-aminoalcohol
LiAlH4
PhMe
OH
MeHN H
H
1,2-syn-aminoalcohol
MeH2, Pd/C
Ph Me
OH
HO CH(OMe)2
Dihydroxylation
In conclusion…
•Don’t be afraid of the dark… and the light!