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 the
molecular formula C3H6O, having a four-membered ring with three carbon atoms
and one oxygen atom.”
O
KOH, 150 °C
Cl
O
O
ca. 40% Yield
“Other possible reactions to form oxetane ring is the Paternò-Büchi reaction.
O
Also, diol cyclization can form oxetane rings.”
O
O
OH
Ph
O
NH
O
Ph
O
OH
OH O
O
Ph
Citations taken from Wikipedia : http://en.wikipedia.org/wiki/Oxetane
O
H
O
O
Puckering of 4-membered cycles
Moriarty, R. M. Top. Stereochem. 1974, 8, 273-421.
Comparaison with other 4-membered
heterocycles
Inversion barrier energy
Molecule
O
S
Se
SiH2
NH
CF2
cm-1
kcal/mol
15.3 ± 0.5
35 ± 5
0.04
0.10
~0
274.2 ± 2
0.75
28
373
1.07
32.5
440
1.26
37
441
1.26
---
448 ± 18
518 ± 5
1.28
1.48
33-35
241 ± 5
0.68
27
Dihedral angle (in deg)

N.B. : 1kcal/mol = 350 cm-1
Legon, A. C. Chem. Rev. 1980, 80, 231-262.
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
• 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.
Current topics in medicinal chemistry on oxetanes
(E. M. Carreira)
Polar head group
N
Large hydrophobic
unit
O
N
N
Ar
O
N
Ar
O
E
D
O
X
X = Me (A)
F (B)
H (C)
N
Ar
N
Ar
O
F
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.
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.
Synthesis of compounds A-G
Kozikowski :
O
Cl
1) AcOH, FeCl3 (cat.)
65°C, 24 hrs.
O
AcO
2) p-TSA, CH2Cl2
3) NaOH 2N, 105 °C,
5 hrs.
OEt
O
4) CSA, MeOH, r.t.
Cl
50% Yield
2 steps
OEt
HO
51% Yield
2 steps
CO2H
O
H2N
O
O
NMDA Receptor
Antagonist
Carreira :
O
HO
MeOH, p-TSA
OH
MeO
HO
54% Yield
(Prep GC Purification)
1) TsCl, Et3N, DCM
2) NaH
OMe
OH
OMe
OMe
H
PCC, NaOAc,
DCM, 40 hrs.
OMe
MeO
O
OMe
37% Overall yield
O
O
62% Yield
Kozikowski, A. P.; Fauq, A. H. Synlett, 1991, 783.
K10 Montmorillonite
2,2-Dimethoxypropane
Synthesis of compounds A-G
1) NaH, Et2O, 0°C
2) TsCl, 0°C
3) LiAlH4, -78°C
N(Me)2
N(Me)2
H
O
58% Yield (3 steps)
N(Me)2
Li
HO
THF, -78°C
CH2Cl2, -78°C
N(Me)2
O
F
71% Yield
F
F
F
S
O
N
40% Yield
O
1) [Rh(cod)Cl]2, KOH,
Dioxane, H2O
O
N(Me)2
Me
(HO)2B
2) DIBAL-H, -78°C
3) [(PPh3)3RhCl], tol., 105°C
Ph3P
27% Yield (3 steps)
MgBr
O
89% Yield
O
CO2Et
CO2Et
DCM, r.t.
N(Me)2
N(Me)2
1)
TMSCl, CuI, THF
2) Me2NH, NaBH3CN, MeOH
O
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
1) 4-(t-Bu)Ph-B(OH)2
[Rh(cod)Cl]2, KOH, Dioxane
2) MeNO2, NEt3, r.t. then TsCl
O
N(Me)2
3) Reduction/Amination
15% Yield (5 steps)
Ph3P
CHO
DCM, r.t.
CHO
O
1) HNMe2, DBU, THF
2) 4-(t-Bu)PhCH=PPh3
81% Yield
O
N(Me)2
O
3) H2, Pd/C, MeOH
36% Yield (3 steps)
O
O
N(Me)2
NO2 1)
1) MeNO2, Et3N, r.t.
2) Et3N, MsCl, DCM, -78°C
81% Yield (2 steps)
O
B(OH)2
[Rh(cod)Cl]2, KOH, Dioxane
34% Yield (3 steps)
2) Reduction/Amination
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.
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)
N
important
H
development
N
N
The rule isMe
for drug
where
a
N
H
pharmacologically
active lead structure is optimized step-wise
N
N
N
N
for increased activity Nand selectivity, HOas well as drug-like
N
properties
:
NH
HN
• Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms
N
with one
or moreO hydrogen atoms)
• Not moreGleevec
than 10
hydrogen bond acceptorsR-Roscovitine
(nitrogen or(Seliciclib)
oxygen
(STI571)
Cylacel (Short Hills, NJ)
atoms)
Novartis
MW = 354.45
= 493.60under 500 daltons
• A molecularMW
weight
Log P = 2.75
Log P = 3.83
# H than
Donnors
# H Donnors
=2
• An octanol-water
partition
coefficient log P of less
5 =. 3
# O, N = 8
Aherne, R. et al. Breast Cancer Res. 2002, 4,148.
# O, N = 7
Physico- and Biochemical properties of compounds A-G vs
starting target Solubility in H O Intrinsic clearance (L/min*mg)
Target molecule
"Oxetane-free" amine
2
log P
pKa (in H2O)
(g/mL) (pH = 9.9)
Human
Mouse
<1
16
417
4.3
9.9
4000
2
27
2.4
9.9
6100
6
50
2.0
9.9
4400
0
43
3.3
9.9
270
0
147
3.9
9.6
4100
6
13
3.5
9.2
25
42
383
4.0
8.0
57
13
580
3.6
7.2
N(Me)2
H
O
N(Me)2
F
O
N(Me)2
Me
O
O
N(Me)2
N(Me)2
O
O
N(Me)2
N(Me)2
O
Physico- and Biochemical properties of compounds A-G vs
starting target
N
Buffers pH 1-10
37°C, 2hrs
Acid/Base stability:
No degradation
(A) to (G)
• 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
N
O
hERG Activity:
(G)
hERG IC50 = 35 M
hERG IC50 = 7 M
Oxetanes as carbonyl isosters
N
N
N
R
R
R
O
N
N
N
R
R
R
R=
O
O
O
N
R
• « […] 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. »
Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008, 47, 4512-4515.
Oxetanes as carbonyl isosters (properties)
Structure
N
R
N
R
N
R
N
R
N
R
Solubility in H2O Clearance
(g/mL) (pH = 9.9) (L/min*mg)
pKa (in H2O)a
Function
Log P
gem-Me2
Oxetane
Carbonyl
3.1
1.2
n.d.
290
24000
n.d.
16
7
n.d.
9.6
8.0
n.d.
gem-Me2
Oxetane
Carbonyl
3.7
1.5
-0.1
40
730
4100
39
27
580
9.7
8.1
6.1
gem-Me2
Oxetane
Carbonyl
4.4
2.0
1.6
220
1400
4000
31
22
88
9.5
8.3
7.5
gem-Me2
Oxetane
Carbonyl
4.3
2.3
0.5
13
2000
2100
89
55
120
9.4
7.9
7.6
gem-Me2
Oxetane
Carbonyl
3.9
2.4
1.6
30
750
6200
18
230
39
10.2
7.0
n.d.
Morpholine
1.6
8000
8
7.0
O
N
R
a
Amine basicity in H2O measured spectrophotometrically.
Wuitschik, G. et al. Angew. Chem. Int. Ed. 2008, 47, 4512-4515.
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?
NH2
H
N
N
N
N
O
COOH
O
H
OH
OH
HO
Thromboxane A2
Oxetanocin A
Org. Lett. 2002, 4, 1147.
Synthesis 2002, 1, 1.
Tetrahedron Lett. 1990, 31, 6931.
Tetrahedron Lett. 1990, 31, 5445.
Tetrahedron Lett. 1988, 29, 4743.
Natural : COX protein and blood platelets
O
O
O
OH
Ph
O
O
Me
O Me O
O
NH
O
Ph
OH O
OH
O
HO
Ph
Me
(+)-Merrilactone A
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.
O
H
O
O
O
Taxol
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
O
RS
h (UV light)
RL
R1
non-stereospecific
cycloaddition
O
R2
O
O
ISC
RS
S0
RS
RL
RL
T1
S1
R4
R1
stereospecific
cycloaddition
O
R2
R1
R2
+ Regioisomers O
R2
R3
R3
R3
R4
R1
R3
R4
R4
Secondary Alcohol-Derived Ring Closing (SN2)
O
R3
R1
Asymmetric
Reduction
LG
OH
R1
R3
O
R1
H
Catalytic Enantioselective methods (2000-<)
Epoxidation
Base
OH
R1
*
*
R2
O
R2
R2
Asymmetric
Allylation/Crotylation
R1
LG
*
R2
Base
R3
R1
*
R2
O
*
OH
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).
H
Me
Me
Me
O
Me
O
Me
Ph
Me
Ph
• 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.
H
Me
Me
Me
O
n-Pr
Me
O
Me
Me
n-Pr
Applications of the Paternò-Büchi reaction in total
synthesis
(+)-Preussin (T. Bach)
H
OH
O
8
N
N
H
PhCHO
h(350nm)
MeCN
O
O
1) H2/Pd(OH)2/C
MeOH
O
Ph
8
N
H
O
HO
Ph
H
8
N
H H
2) LiAlH4, THF
O
(+)-Preussin
(53% Si + 12% Re)
(±)-Avenaciolide (S. L. Schreiber)
H
O
O
C8H17
450W Hanovia
Lamp
Vycor filter, -20°C
~100% Yield
O
O
1) H2, Rh/Al2O3
EtOAc
C18H17
OH
C8H17
H
2) 0.1N HCl/THF (1:4) OH
CHO
O
H
C18H17
O
O
H
O
(±)-Avenaciolide
(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.
Ultraviolet = energy = reaction
• E = h
•  = c/l
• E = hc/l
http://www.thomasnet.com/articles/image/electromagnetic-spectrum.jpg
What does energy means in terms of molecules’
view?
l ~ 0.005-1.4 Å (Gamma rays) = Nuclear interactions
l ~ 0.1 – 100 Å (X-Rays) = Inner electrons
l ~ 10-780 nm (UV -Visible) = Bonding electrons
l ~ 780 nm – 300 μm (Infrared) = Rotation and vibration
l ~ 0.73 – 3.75 mm (Microwaves) = Rotation of molecules
l ~ 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.
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
[Cu(NH3)4]2+ (aq)
[Cu(OH2)6]2+ (aq)
Image taken from : Atkins, P.; De Paula, J. Physical Chemistry, 7th editionE, 2001, Oxford d., Chap. 17, pp.1098-1099.
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.
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?
R
R
5
6
R5
R1
1O *
hv
O
R1
R2
R3
O
R4
R5
R6
R1
R2
O
R4
R2
R1
Reaction
R3
R2 R3
Singlet biradical
Spin-rotation
R5
3O *
KISC
R5
R6
hv
R3
R1
Inter-system
crossing
O
R4
electron transfer
R1
R2
R6
R5
O
R3
R6
R1
R4
R4
R2
R2
R3
Triplet biradical
R5
R5
R6
O
R3
R4
R6
Reaction
R1
R2 R3
R6
R4
• 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.
R4
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
O
*Sens3
R1
R2
h
*Sens1
Ktransfer
* O3
KISC
Sens
R1
R2
*Sens3
R6
Reaction
triplet state
R5
R6
O
R1
R4
R2 R3
R3
R4
R5
Triplet state sensitizers
• What do we do if KISC is ~ 0? Answer is photosensitization :
Photosensitizer
KISC
ET (kcal/mol)
O
0.98
78.9
1.00
73.9
1.00
68.6
0.86
66.9
0.68
60.5
Me
Me
O
Me
Ph
O
Ph
Ph
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-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)
How can we illustrate orbitals when a concertedthermal [2+2] mechanim is implemented (Fukui)?
LUMO
O
LUMO
O
O
X
X = O-Alkyl, S-Alkyl
N,N-Dialkylamine
O
Supra/Supra
HOMO
HOMO
O
Supra/Antara
How can we illustrate orbitals when a concertedphotochemical [2+2] mechanim is implemented (Fukui)?
Supra/Supra
O
O
O
LUMO
SOMO
X
O
X = O-Alkyl, S-Alkyl
N,N-Dialkylamine
O
O
HOMO
SOMO
Supra/Antara
O
Different mechanism means different selectivity
for the Paternò-Büchi reaction.
H
O
h
O
Ph
H
O
O
O
Ph
O
Ph
H
H
Exo
Endo
H
Ph
O
d.r = 88 : 12
H
Ph
h
O
O
Ph
O
Endo
Exo
H
O
Exo transition state
O
O
H
Favored
H
Ph
O
Singlet state :
O
H
H
Ph
d.r = >5 : 95
O
O
O
Endo transition state
Ph
O
Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112, 1281-1282.
H
Not favored
Ph
O
Regioselectivity for the Paternò-Büchi reaction.
• Dramatic differences in regioselectivity in photochemical [2+2]
can be explain by confirming :
- The character of the np* excited carbonyl state
- The stability of the intermediate biradical triplet 2-oxabutane-1,4diyl
• 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)
Different mechanism means different
regioselectivity for the Paternò-Büchi reaction.
Ph
H
ISC
O
O
O
H
O
O
Ph
H
Endo
O
h
Ph
ISC
H
Ph
O
O
Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112, 1281-1282.
O
H
Ph
O
O
H
Exo
Endo-selectivity rationale for non-aromatic
substrates (cyclic) with triplet state
Prefered ISC Geometry (Rapid spin inversion)
H
O
Ph
h
H
O
Fast ISC
O
Ph
Ph
H
O
Inward rotation
Griesbeck, A. G.; Stadtmüller, S. J. Am. Chem. Soc. 1990, 112, 1281-1282.
O
O
H
Endo-selectivity rationale for non-aromatic
substrates (acyclic) with triplet state
O
Ph
H
t-Bu
Ph
h
O
Benzene, r.t.
MeO
t-Bu
Ph
OMe
Ph H
(E/Z) = 5 : 1
Ph
90:10 endo/exo
H
O
O
H
Ph
Ph H
O
Ph
H
t-Bu
t-Bu
OMe
t-Bu
Ph
Non-favored
H
Ph OMe
H
OMe
Ph
O
Ph H
t-Bu
H
OMe
(Z)
Ph
O
H
O
H
Ph H
t-Bu
Ph
MeO
O
Ph
H
H
t-Bu
Ph
Favored
t-Bu
OMe
Ph H
OMe
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.
Solvent effect on triplet vs singlet states
H
H
h
O
(a)
Ph
O
O
O
Ph
h
O
(c)
Et
O
O
Et
H
H
H
H
h
O
Et
O
(d)
O
Et
h
O
O
(b)
O
O
Me
H
Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70-76.
O
Me
O
H
Effect of the concentration of alkene quencher on
triplet vs singlet states
H
H
h
O
(a)
Ph
O
O
Ph
h
O
O
(c)
Et
O
O
Et
H
H
H
H
h
O
Et
O
(d)
O
Et
h
O
O
(b)
O
O
Me
H
Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70-76.
O
Me
O
H
Photoinduced Electron-transfer effect on
regioselectivity
H
O
h
O
Ph
H
O
O
O
Ph
H
O
Ph
H
Exo A
Endo A
PET
H
Ph
d.r = 88 : 12
H
Ph
O
Ph
O
O
O
d.r = 10 : 90
O
O
H
H
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
O
Ph
O
h
H
TMSO
t-Bu
Ph
Benzene, r.t.
t-Bu
O
OTMS
t-Bu
Ph
OTMS
90:10 endo/exo
>95% regioselectivity
O
O
Ph
H
TMSO
H
H
O
H
Ph
H
H
Non-favored
H
t-Bu
Ph OTMS
TMSO
O
Ph
H
O
H
H
Ph
TMSO
TMSO
H
O
Ph
t-Bu
O
H
H
H
H
TMSO
Ph
TMSO
O
H
H
H
Favored
t-Bu
Ph OTMS
Diastereofacial selectivity via allylic strain
Ph
Rs
R
O
OTMS H
H
RL
Less hindered face
Favored
O H RL Rs
O H RL Rs
Ph
R
H
H
OR
Ph
R
H
H
OTMS
OTMS
A1,3 minimized
Most hindered face
Non-favored
H RL Rs
H
R
Non-favored
Favored
O H RL Rs
H
O
OTMS
R
H
Ph
O H RL Rs
H
TMSO
H
Ph
OTMS
R
Ph
H
RL
H
O
Ph
H
RL
Rs
H
H
R
OTMS
O
Ph
H
RL
Rs
Rs
O
H
H
R
OTMS
Bach, T.; Jödicke, K.; Kather, K.; Frölich, R. J. Am. Chem. Soc. 1997, 119, 2437-2445.
Ph
R
OTMS
Diastereofacial selectivity via allylic strain
(example)
O
Me
O
Me
O
Me
t-BuMgCl, THF
O
Me
t-Bu
O
O
Ph
O
Me
OTMS
t-Bu
Mol. sieves, r.t., DCM
t-Bu
OH
Me
H
Me
O
Me
TPAP, NMO
-78°C to r.t.
CHO
O
O
Me
O
Me
O
LDA, TMSCl,
-78°C to r.t., THF
PhCHO, h
Benzene, 30°C
t-Bu
OTMS
70% Yield
Regio >95:5, d.r. = 90:10
H
i) (PhMe2Si)2CuLi,
THF, -25°C - 0°C
R
O
ii) TMSCl, NEt3,
0°C to r.t.
SiMe2Ph
R
PhCHO, h
Benzene, 30°C
OTMS
O
Ph
Me
SiMe2Ph
OTMS
R
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
OH
Me
Ph
HO
TBAF, r.t., THF
R
Bach, T.; Jödicke, K.; Kather, K.; Frölich, R. J. Am. Chem. Soc. 1997, 119, 2437-2445.
Diastereofacial selectivity via chiral auxiliary
(example)
Me
H
O
O
O
O
O
*ROOC
Ph
O
h
Me
O
benzene
Me
Ph
O
Me
Me
H
Up to 99% Yield, Exo selective
When (-)-8-Phenyl-Menyl is used, d.r. ~ 96%
MeOH, H2SO4 cat.
H OMe
O
LiAlH4, THF
HO
Ph
O
HO
*ROOC
Me
Ph
H
78% Yield
O
O
O
O
O
Ph
O
OMe
Ph
O
OMe
O
OH
O
O
Me
Me
50% Yield
20% Yield
H
90% Yield
Me
Me
Acetone,
CSA
Ph
OMe
O
Me
Me
O
H
Me
30% Yield
Nehrings, A.; Scharf, H.-D.; Runsink, J. Angew. Chem. Int. Ed. 1985, 24, 877-878.
Diastereofacial selectivity via hydroxy-directed
reaction
Me
Me
H
H
Me
OH
H
[Ph2CHO]*3
Me
H
R
R
[Ph2CHO]*3
OH
A1,3 Minimized
Ph
Ph
Me
Me
H
3*
O
H
Me
Me
H
O
H
PhR
Ph
R
Ph
Ph
Me
H
3*
O H
Ph
Me Ph
H O
Ph
O
H
OH
Me
Not-Favored
Favored
O
R
KISC
O
Ph
Me
Me
OH
H
Me
Me
Ph
Ph
Me
R
O
H
H
OH
R
Adam, W.; Peters, K.; Peters, E. M.; Stegmann, V. R. J. Am. Chem. Soc. 2000, 122, 2958-2959.
KISC
H
R
OH
Diastereofacial selectivity via hydroxy-directed
reaction (example)
OX
OX
R
Me
O
Ph2CO, h = 350 nm
Ph
Me
R
Ph Me
OX
OX
O
Me
Ph
O
R
Ph Me
Ph
Me
R
Ph Me
Me
A
B
C
Hydroxydirected
major
Hydroxydirected
minor
Electron-transfer
product
X
R
Conversion (%)
Stereoselectivity
(A : B)
Regioselectivity
((A + B) : C)
H
Me
90
90 : 10
>95 : 5
H
Et
90
93 : 7
>95 : 5
H
i-Pr
89
95 : 5
>95 : 5
H
i-Pr
92
>95 : 5
>95 : 5
TBDMS
Me
84
52 : 48
83 : 17
(d.r. = 78 : 22)
Adam, W.; Peters, K.; Peters, E. M.; Stegmann, V. R. J. Am. Chem. Soc. 2000, 122, 2958-2959.
Chiral oxetanes from β-lactones formation
involving « P-A like » reactions (ketene derived)
O
O
Me
O
Br
Catalyst 10mol%
H
i-Pr2NEt
R
R3N
C
H
Ketene
R3NH Br
Bn
i-Pr
i-Pr
N
N
Tf
R
+ CHO
+ Cat.
O
H
O
Al
X
X = Cl (Cat. A)
X = Me (Cat. B)
N
Tf
Nelson, S. G.; Peelen, S. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121, 9742-9743.
Thermally Allowed
[2+2]
Chiral oxetanes from β-lactones formation
involving « P-A like » reactions (ketene-derived)
O
O
Me
O
Br
H
Catalyst 10mol%
R
i-Pr2NEt
O
R
Aldehyde (R)
Catalyst
Temp. (°C)
Yield (%)
ee (%)
BnOCH2
B
-40
91
92
PhCH2CH2
A
-50
93
92
PhCH2CH2
A
-78
89
95
7CH2
B
-50
80
91
A
-50
86
93
TBDPSOCH2
B
-40
74
89
C6H11
B
-40
56
54
BnO
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)
Silyl ketene
Keto Ester
O
i)Bisox xxxmol%
DCM, -50°C to -40°C
O
C
OR3
R1
TMS
H
ii) KF, MeCN
O
R1
O
R2O2C
O
R1
OR2
Catalyst 20mol%
Yield (%) / ee (%)
Catalyst 10mol%
Yield (%) / ee (%)
Me
OMe
>99 / 95
93 / 95
Et
OMe
92 / 99
89 / 93
i-Bu
OMe
87 / 83
89 / 86
i-Pr
OEt
86 / 85
78 / 88
Ph
OMe
79 / 87
76 / 83
BrCH2
OEt
>99 / 91
75 / 91
Evans, D. A.; Jacobs, J. N. Org. Lett. 2001, 3, 2125-2128.
Chiral oxetanes from β-lactones formation
involving « P-A like » reactions (ketene-derived)
O
O
C
R3
R1
TMS
Evans, D. A.; Jacobs, J. N. Org. Lett. 2001, 3, 2125-2128.
O
Transformation of β-lactones to chiral building
blocks
R2
O
O
-CO2
R1
R2
 or BF3
O
R2
R1
R2
Me2S
O
S
O
OH
R1
R1
O
H2N
R'
CuCN, R'Li (2 equiv.)
O
OH
H2N
O
1) Zn(BH4)
O
2) BF3, HCl
O
Arnold, L. D.; Drover, J. C. G.; Vederas, J. C. J. Am. Chem. Soc. 1987, 109, 4649-4659.
O
Ring-closing approach to oxetanes (example)
R1
O
OH
Red-Al
R2
Me
Me
R1
OH
OH
R1 = H, R2 = C6H13 (85% Yield)
R1 = Me, R2 = C16H33 (86% Yield)
R2
O
O
OH
OH
LiAlH4
1) Dess-Martin
2) MeMgBr
Me
Me
OH
OH
93% Yield
OH
OH
39% Yield (3 steps)
3) Red-Al
Me
O
OH
MeMgBr
Me
Me
OH
OH
H
Me
Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591-4593.
76% Yield
Ring-closing approach to oxetanes (example)
1) KOt-Bu, TsCl, THF
Oxetanes
Diols
Me
2) KOt-Bu
O
H
C16H33
O
O
Me
C6H11
2
87% Yield
40% Yield
Me
Me
75% Yield
H
O
Me
Me
O
Me
H
Me
2
2
Me
Me
40% Yield
Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591-4593.
Me
Me
65% Yield
Ring-closing approach to oxetanes (example)
Me
H2O2 in Et2O
O
C16H33
Lewis Acid
HOO
Me
OH
C16H33
If L.A. = TMSOTf, 48% Yield, >90% inversion
Sc(OTf)3, 60% Yield, >90% inversion
Yb(OTf)3, 50% Yield, >90% inversion
Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591-4593.
Catalytic enantioselective reaction to form
oxetanes (kinetic resolution)
Additive/Catalyst (S)-1a
(1:1) 5 mol%
O
R
Me
Me
O
Additive/Catalyst (S)-1a
(1:1) 20 mol%
Me
R
Ylide 1.2 equiv.
THF, r.t., 5A Mol. Sieves, 12 hrs.
Ylide 1.0 equiv.
THF, 45°C, 5A Mol. Sieves, 72 hrs.
Asymmetric
Corey-Chaykovsky
Asymmetric
Corey-Chaykovsky
ee (%) amplification
MeO
OMe
Additive
OMe
O
P
3
O
O
Ylide
H2C
S
Catalyst
Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 1677-1680.
R
Catalytic enantioselective reaction to form
oxetanes (kinetic resolution)
O
O
Me
O
Me
O
Me
Me
ee (%) of epoxide
ee (%) of oxetane
Yield (%) of oxetane
96
99
62
96
99
74
Cl
F
94
99
86
97
99
85
O
O
O
Me
O
Me
Me
8
7
ee (%) of epoxide
ee (%) of oxetane
Yield (%) of oxetane
Me
93
99
88
Me
93
99
68
96
>99.5
58
Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 1677-1680.
97
>99.5
62
Utility of oxetanes as masked functionalities
Hydrogenolysis
or
Nucleophilic attack
under basic conditions
Metal mediated reduction (Na/Naphtalene)
O
R
X
Nu
Nucleophilic attack
under acidic conditions
H
Masked aldol
products
O
O
1) H2, Rh/Al2O3
EtOAc
C18H17
OH
C8H17
H
2) 0.1N HCl/THF (1:4) OH
CHO
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.
Utility of oxetanes as masked functionalities
H
Me
O
SiMe2Ph
Me
Ph
OTMS
Ph
OH
TBAF, r.t., THF
HO
R
R
1,2-syn-diols
O
Ph
LiAlH4
R
H
HO
1) TFA
2) TsCl
Ph
NCOOt-Bu
H
3) LiAlH4
Ph
Me
MeHN
H
LiAlH4
Ph
Me
OTMS
CH(OMe)2
Bach, T. Synthesis 1998, 683-703.
H
Me
MeHN
O
1,2-anti-aminoalcohol
OH
Ph
NHCHO
R
OH
Ph
Me
O
Me
Ph
OH
O
OH
1,2-syn-aminoalcohol
H
OH
H2, Pd/C
Ph
HO
Me
CH(OMe)2
Dihydroxylation
In conclusion…
• Don’t be afraid of the dark… and the light!