Asymmetric synthetic methods based on phase transfer catalysis

Details Asymmetric synthetic methods based on phase transfer catalysis Asymmetric synthetic methods based on phase transfer catalysis

2001-07-10

2003-07-22

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S134000, C546S135000, C546S126000

Reexamination Certificate

active

06596870

ABSTRACT:

BACKGROUND OF THE INVENTION
Phase Transfer Catalysis
Phase Transfer Catalysis (PTC) technology is used in the commercial manufacture of more than $10 billion of chemicals per year. PTC technology is also used in pollution prevention, pollution treatment and the removal or destruction of impurities in waste and product streams. PTC technology is used in these applications, because it provides many compelling benefits, primarily related to reducing the cost of manufacture of organic chemicals and pollution prevention. Many significant and advantageous process performance achievements are routinely realized by using PTC. Cost reduction and pollution prevention are the two most powerful driving forces in the chemical industry today, and they match precisely the strengths and benefits provided by PTC.
PTC is useful primarily for performing reaction between anions (and certain neutral molecules such as H
2
O
2
and transition metal complexes such as RhCl
3
) and organic substrates. PTC is needed because many anions (in the form of their salts, such as NaCN) and neutral compounds are soluble in water and not in organic solvents, whereas the organic reactants are not usually soluble in water. A phase transfer catalyst acts as a shuttling agent by extracting the anion or neutral compound from the aqueous (or solid) phase into the organic reaction phase (or interfacial region) where the anion or neutral compound can freely react with the organic reactant already located in the organic phase. Reactivity is further enhanced, sometimes by orders of magnitude, because once the anion or neutral compound is in the organic phase, it has very little (if any) hydration or solvation associated with it, thereby greatly reducing the energy of activation. Since the catalyst is often a quaternary ammonium salt (e.g., tetrabutyl ammonium, [C
4
H
9
]
4
N
+
), the ion pair with the counter ion is much looser than say Na
+
X
−
. This looseness of the ion pair is a third key reason for enhanced reactivity, which will ultimately lead to increased productivity (reduced cycle time) in commercial processes. At the end of the reaction, an anionic leaving group is usually generated. This anionic leaving group is conveniently brought to the aqueous (or solid) phase by the shuttling catalyst, thus facilitating the separation of the waste material from the product. This mechanism is often called the “extraction mechanism” of phase-transfer catalysis.
The extraction mechanism accounts for many of the benefits of PTC, including: achieving high reactivity (reactants are in the same phase with less hydration in an ion pair); flexibility in choosing or eliminating solvent (a properly chosen quaternary ammonium catalyst can extract almost any anion into almost any organic medium, including into the product or into one of the organic reactants resulting in a solvent-free process); reducing the excess of water-sensitive reactants (such as phosgene, benzoyl chloride, esters and dimethyl sulfate since they are protected in the bulk organic phase from the aqueous phase by interfacial tension); higher selectivity (lower energy of activation allows reduction of reaction temperature and time); the use of inexpensive and less hazardous bases (hydroxide is easily transferred and activated in nearly all organic solvents) and many other benefits.
PTC delivers high productivity, enhanced environmental performance, improved safety, better quality and increased plant operability in hundreds of commercial manufacturing processes for organic chemicals in dozens of reaction categories. PTC provides high performance in real world applications, primarily in reducing cost of manufacture and pollution prevention. Enormous opportunity exists right now to increase corporate profits and process performance by retrofitting existing non-PTC processes with PTC and by developing new processes using PTC. Companies can achieve higher performance using PTC by developing these processes.
Asymmetric Synthesis Using Phase Transfer Catalysis
The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. The advantages associated with enantiomerically pure compounds often include fewer side effects and greater potency. See, e.g., Stinson, S. C.,
Chem Eng News,
Sep. 28, 1992, pp. 46-79.
Traditional methods of organic synthesis were often optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: (a) the use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); and (b) the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thus decreasing efficiency and wasting half of the material.
Taken together, the many advantages of PTC and the increasing importance of ready access to enantiomerically-enriched and/or enantiomerically-pure compounds and intermediates make desirable methods of phase transfer catalysis which induce asymmetry into product molecules.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to methods of asymmetric synthesis, e.g., asymmetric hydride reductions of carbonyl groups, using a chiral, non-racemic phase transfer catalyst, a helper nucleophile, and a sterically bulky reagent nucleophile, e.g., an alkoxyhydride derived from a sacrificial ketone and a hydride reagent. Moreover, the sterically bulky reagent nucleophile may be generated in situ or prepared in a prior step. Another aspect of the present invention relates to chiral non-racemic phase transfer catalysts, and their use in the subject methods.


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International Search Report Completed on Jan. 22, 2002 and Mailed on Feb. 1st, 2002.
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