promising molecules in drug discovery : syntheses and applications of oxetanes. a presentation by...

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)


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)



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)



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)


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.


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.


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


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


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


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


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


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



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



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!

promising molecules in drug discovery : syntheses and applications of oxetanes. a presentation by...

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