The Hydrolytic Kinetic Resolution – Jacobsen’s Catalyst

An Introduction

Enantiomerically pure epoxides are extremely valuable
chemical compounds due to controllable but high reactivity of
epoxides coupled with the vast array of reactions they can
undergo with retention of stereochemical integrity. One can
envision a number of direct routes to asymmetric epoxides
(Figure 1). Asymmetric carbene addition has never achieved
broad applicability due to both the instability of the carbenes,
low yields and low enantioselectivities. The most common
methods for epoxide formation is controlled addition of
activated oxygen to an alkene. For some olefins, this process
can be made enantioselective, an achievement for which K.
Barry Sharpless was awarded 1/2 of the Nobel prize in 2001.
The Sharpless asymmetric epoxidation is restricted to internal
olefins with pendent functionality such as an alcohol which
helps direct the reaction. In 1990, Jacobsen, fresh of a postdoc with Sharpless and at the beginning of his
independent career at UIUC, introduced a system which obviated the use of a directing group, but the
enantioselctivies were not phenomenal and yields were not spectacular. Furthermore, terminal olefins were still
difficult. Simultaneously and independently, Katsuki (a Sharpless postdoc from ten years prior) revealed a
closely related system which suffered the same drawbacks.
In the mid 1990’s, having moved to Harvard, Jacobsen
was exploring the use of a variety of metal catalysts all based
around a chiral “salen” ligand scaffold (Figure 2). The first
breakthrough came with the desymmetrization of meso
epoxides with Me3SiN3 catalyzed by a complex where M =
CrCl (Figure 3). While it is generally easily controlled on the
laboratory scale, the potentially explosive nature of Me3SiN3
makes it a poor choice for industrial processes. Furthermore, the resolution of terminal epoxides remained
elusive. Thus the search of a better both a better catalyst and a better nucleophile continued. The hydrolytic
kinetic resolution (Figure 3) was discovered due to a fortunate accident. Jacobsen had been working with a
reduced for of a chromium-salen complex. Surprisingly, 1,2-epoxyhexane (Figure 3, R = n-Bu) proved to be an
extraordinarily good substrate. Furthermore, the
solid residue isolated from the end of reactions
with that substrate worked extraordinarily well to
resolve others! Careful investigation led to the
discovery that acetic acid, left from the industrial
synthesis of epoxyhexane, had served to catalyze
the air-oxidation of the metal, increasing the activity of the catalyst. At long last, enantiomerically pure terminal
epoxides were readily available through a simple two step process – epoxidation of a terminal olefin and
selective hydrolysis of one enantiomer of the resulting epoxide. This was an event dramatic enough to warrant
publication in Science, an extreme rarity for a synthetic methodology.
Jacobsen has proceeded to exploit this ligand framework, and some variations on it, to enantioselectively
catalyze a broad range of reactions including an array of nucleophilic epoxide opening reactions,
hydrocyanation of aldehydes and imines, conjugate addition of HCN, aldol variations and Diels-Alder
variations, to name a few. In fact, the ligand shown in Figure 2 has become known simply as “Jacobsen’s
ligand”. The technologies developed in Jacobsen’s lab have been commercialized by Rhodia ChiRex, a joint
venture between Jacobsen and global chemical giant Rhodia. The catalysts have been used in many
pharmaceutical syntheses and, it sometimes seems, by nearly every synthetic organic chemist alive. Other
researchers too numerous to name have also used these ligands and catalysts in developing other reactions too
numerous to count. Truly it is a phenomenal impact for an accidental discovery barely a decade old.

From: http://www.chem.colostate.edu/rovis/

Stains for TLC

Although the recipes can be found on internet, here are some I used in the lab.

Ceric Ammonium Molybdate (CAM): This stain is prepared by dissolving 2.5 g of (NH4) 6-Mo7O24 and 1.0 g Ce(SO4)2 in 90 mL of water and 10 mL of conc. H2SO4. The plate is developed by heating on a hot plate. This stain chars blue and is good for polyhydroxylated compounds.


Potassium Permanganate: This stain is prepared by dissolving 3 g of KMnO4 and 20 g of K2CO3 in 5 mL of 5% NaOH and 300 mL of water.

p-Anisaldehyde: This clear tan stain is prepared by dissolving 0.7 mL of p-anisaldehyde in 250 mL of EtOH containing 9.5 mL of conc. H2SO4 and 2.7 mL of acetic acid. The plate is developed by heating on a hot plate. This stain chars lavender and is good for oxygenated compounds.

Sometimes, I found PMA is the only one that can show me the spot.

Phosphomolybdic acid (PMA): This green-yellow stain is prepared by dissolving ~3-4 g of PMA in 100 mL of EtOH. The plate is developed by heating on a hot plate. PMA is the most commonly used stain for organic materials, since it reacts with a wide variety of functional moieties. The spots are usually black against a yellow-green background. PMA is also effective with extremely dilute reaction samples and in this regard can be used semi-quantitatively.

Sulfur containing quaternary carbon center

How to build a S-containing quaternary carbon center
like this:



ways I can find out:
1. enolate attack a S-nucleophile. ex. MeSSMe.
2. 3,3-sigmatropic rearrangement.
3. thioketone attacked by a Nu-.
4. thiol 1,4-addition.
5. thionium ions (ex. from thiolketal) attacked by a Nucleophile.
6. methoxyphenylthiomethyllithium addition to ketone, then rearrange using SOCl2 in py or MeSO2Cl /TEA.

Some pdf from group of Professor Scott Denmark

very good presentations, very broad topics.

http://www.scs.uiuc.edu/denmark/presentations/

List of 2008:

Transition Metal‐Catalyzed Carbon‐Carbon Bond Cleavage (C‐C Activation)

The Petasis-Ferrier Union/Rearrangement

Interrupted Nazarov Cyclizations

Nickel Catalyzed sp3-sp3 Couplings

Rhodium Catalyzed [5+2] Cycloaddition

The 5 W's of Chiral Dienes as Ligands for Asymmetric Catalysis

Theory and Design of Mobius Molecules

Alois Fürstner: Applying Organometallic Chemistry in Total Synthesis

Pyrrole-Imidazole Alkaloids

Go With the Flow. . . Microfluidics and Microreactors: An Organic Chemist's New Round Bottomed Flask

Catalytic Carbonylative Ring Expansion of Epoxides and Aziridines


Conbinatorial Approaches in Homogeneous Catalysis Development: Case Studies

Biology as a Tool for Synthetic Chemistry

Enantioselective Protonation

The Mechanism of Rhenium Catalyzed Olefination of Aldehydes

Gold Activation of pi-Systems [Propargylic Esters] What Makes Gold Special Relativity Speaking

Frustrated Lewis Pairs: Novel Reactivity and Mechanism

benzylidene acetal of glucopyranoside

formation:
1. bnezaldehyde -ZnCl2
2. benzaldehyde dimethyl acetal 3 eq.- TsOH 0.1 eq. in MeCN, refluxing. 2hr.
works great. >60% yield.
workup procedure:
remove mecn to about half invacuo, then NaHCO3 aq. solution added to quench TsOH. Further remove meCN completely invacuo.
EtOAc used to dissolve the product. wash with naHCO3,brine. then concentrated.
Add acetone to dissolve the solid. Add hexanes to precipitate the product. product collected by filtration.
(EtOAc is not a good solvent for the product, so have to use acetone, benzaldehyde dimethyl acetal can dissolve in hexanes).

the rxn is reversible, so base should be used to destroy the catalyst after done.

3. phCHBr2 -base

4. benzaldehyde dimethylacetal , I2 in MeCN ,rt. 1-2 hr.
although the author claimed more than 90% yield, I can only get about 30-40% yield after workup( Na2S2O3 quenching). the author also claimed a simple workup by vacuum away MeCN and I2, but removal of I2 by vacuum is really not practical.


removal:
1. MeOH, I2, reflux, 2 hr
works great, >80%
2. MeOH, TsOH, rt

Titrating n-buLi,s-buli, t-buli

method 1:

Take a briquette of menthol (usually about 80-100 mg), dissolve that in dry THF (~2 mL) and then add 1-2 mg (you don't need to really weight it) of triphenylmethane. You can roughly calculate how much of your lithium reagent you will need, and then add it dropwise to the solution of menthol/Ph₃CH/THF. When all the menthol is deprotonated the triphenylmethane will be deprotonated abnd the solution will turn pink (eventually dark red if you add to much), then you can back calculate the concentration based on the volume of alkyl lithium you added. I usally carry this procedure out in triplicate ad average the results. It really only takes about 30 mins start to finish and it doesn't take much material either.

note:
1,1'-dipyridyl can also be used instead of triphenylmethane.




a link:
http://www.chemistry.mcmaster.ca/emslie/Titrating%20Alkyllithium%20Reagents%202.pdf

preparation of Methyl triphenyl Phosphonium Acetate

the correspongind phosphonium bromide 1 eq.
dissolve in DCM. (0.5 M)
NaOH 2 eq. dissolve in water. 1 M.
then put the two solutions together in a separatory funnel, shake vigorously for 10 min at rt.
then organic layer separated. washed with nahco3, brine.
concentrated to 50 ml or until solid started to showup.
then hexanes 100 ml added. further remove dcm in vacuo.
this will percipitate the product.
after all dcm removed, solid can be easily collected by filtration. washing with hexanes.

use:
ex: mecn, 3 eq. phosphonium, 60C.

petasis reagent cp2TiMe2

titanocene dichloride 1 eq.
meli 2 eq. (can use excess)
-5 C, meli in Et2O was added dropwise into titanocene dichloride in toluene (0.1-0.2 M) during 10 min.
upon addition, red insoluable TiCP2Cl2 disappeared slowly.
an intermediate TiCp2ClMe is soluable and red colored.
the product ticp2me2 is also soluable but orange colored.

although standard prodcedure require 2 eq. of meli. I found out excee meli won't affect anything.

quench the rxn by nh4Cl solution;, then extract with Et2O. dried over mgso4 and concentrated to 0.5M (toluene). stored in freezer.