Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-30
2004-06-01
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S257000, C546S268400, C546S268100
Reexamination Certificate
active
06743922
ABSTRACT:
The present invention relates to a class of novel chiral compounds, a process for the preparation thereof, the use thereof as catalysts, and a process for mediating asymmetric organic transformations therewith. More specifically, the invention relates to a novel class of atropisomeric analogues of 4-aminopyridine, the preparation thereof, the use thereof as catalysts, and a method for performing enantioselective acylation (and related transformations) using the catalyst to preferentially mediate reaction of one enantiomer of an enantiomer pair in a racemic mixture by means of simple-(e.g. H. B. Kagan et al.
Top. Stereochem.
1988, 18, 249), parallel-(e.g. E. Vedejs et al.
J. Am. Chem. Soc.
1997, 119, 2584), or dynamic-(e.g. S. Caddick et al.
Chem. Soc. Rev.
1996, 25, 447) kinetic resolution; or preferentially mediate reaction of one of two enantiotopic functional groups in an achiral meso compound by means of enantioselective desymmetrisation (e.g. M. C. Willis,
J. Chem. Soc., Perkin Trans.
1 1999, 1765).
Kinetic resolution relies on the fact that one enantiomer of an enantiomer pair in a racemic mixture will react at a faster rate with an enantiomerically enriched chiral reagent or in the presence of an enantiomerically enriched chiral catalyst than the other. Enantioselective desymmetrisation relies on the fact that one of two enantiotopic functional groups in an achiral meso compound will react at a faster rate with an enantiomerically enriched chiral reagent or in the presence of an enantiomerically enriched chiral catalyst than the other.
Enantiomerically enriched reagents and catalysts have enormous potential for the efficient synthesis of enantiomerically highly enriched products such as pharmaceuticals, agrochemicals, fragrances and flavourings, conducting and light emitting polymers and the like. The use of such products in enantiomerically highly enriched form, and preferably as single enantiomers, is significant both for performance reasons and also in some cases to comply with regulatory constraints. Such constraints apply particularly to compounds intended for human or animal consumption or application wherein the desired enantiomer is active and its antipode may be either inert or harmful.
Enantioselective acylation by means of kinetic resolution or enantioselective desymmetrisation is traditionally performed using enzymes. High selectivities (E: 7-1000, wherein E is enzymatic enantioselectivity) have been obtained for selected substrates with specific enzymes (e.g. S. M. Roberts
J. Chem. Soc., Perkin Trans.
1 1998, 157). However, those enzymes which are compatible with the widest range of substrates (e.g. lipases) are often of low selectivity. Moreover, lipase-mediated acylations can be reversible and undesired equilibria can cause problems. Additionally, enzymes are provided by nature in only one enantiomeric form and are invariably both thermally and mechanically unstable. Furthermore their reactions are usually heterogeneous, only operate efficiently within narrow reaction parameters, are prone to inhibition phenomena, display poor batch-to-batch reproducibility, and consequently are difficult to scale-up.
Recently, chemical methods for mediating enantioselective acylation by means of kinetic resolution or enantioselective desymmetrisation have begun to emerge. Early methods relied on the use of enantiomerically enriched chiral acylating reagents (e.g. D. A. Evans et al.
Tetrahedron Lett.
1993, 34, 5563) but promising chiral chemical catalysts are now being developed. Chiral chemical catalysts offer some attractive features relative to the use of enzymes. Reactions catalysed in this manner can be rendered irreversible such that no undesired equilibria are present. Chemical catalysts can be made in both enantiomeric forms. Chemical catalysts can be thermally and physically robust. Chemical catalysts can be used under homogeneous conditions. Ideally, they can constitute a tiny fraction of the material to be processed, and can be readily recovered.
The stereoselectivity factor s is the counterpart to enzymatic enantioselectivity, E. Kagan's equation for s for the kinetic resolution of a given substrate (e.g. a secondary alcohol) reacting by pseudo-first order kinetics is given by:
p
r
o
d
u
c
t
:
s
=
ln
[
1
-
C
(
1
+
e
e
′
)
]
ln
[
1
-
C
(
1
-
e
e
′
)
]
r
e
c
o
v
e
r
e
d
s
t
a
r
t
in
g
m
a
t
e
r
i
a
l
:
s
=
ln
[
(
1
-
C
)
(
1
-
e
e
)
]
ln
[
(
1
-
C
)
(
1
+
e
e
)
]
where C is the conversion (as a fraction of unity, sum of both reaction enantiomers) while ee and ee′ are the enantiomeric excess values of unreacted alcohol and the product, respectively. The enantiomeric excess ee is also referred to as the optical purity; cc is the proportion of (major enantiomer)—(minor enantiomer). For example, a 90% optical purity is 90% ee, i.e., the enantiomer ratio is 95:5, major:minor. Using as an example acylation of a secondary alcohol via kinetic resolution, if s=50, the ee′ value of the chiral ester product of kinetic resolution remains above 90% until the conversion exceeds 46%. For example, the unreacted (chiral) alcohol reaches 80% ee at 50% conversion (C=0.5) and 99% ee at 55% conversion. Theoretically, the less reactive alcohol enintiomer could therefore be recovered with 90% efficiency and 99% ee (45% yield based on racemic alcohol).
Impressive selectivities (s: 7-400) have been reported for a number of enantioselective acylation processes by means of kinetic resolution or enantioselective desymmetrisation using a variety of chiral chemical catalysts. Such chiral chemical catalysts are chiral Lewis acids (e.g. F. Iwasaki
Org. Letts.
1999, 1, 969), chiral phosphines (e.g. E. Vedejs et al.
J. Am. Chem. Soc.
1999, 121, 5813), chiral diamines (e.g. T. Oriyama et al.
Chem. Lett.
1999, 265), chiral imidazoles (e.g. S. J. Miller et al.
J. Org. Chem.
1998, 63, 6784), and chiral 4-aminopyridines (e.g. E. Vedejs et al.
J. Am. Chem. Soc.
1997, 119, 2584; G. C. Fu et al.
J. Am. Chem. Soc.
1999, 121, 5091; G. C. Fu et al.
J. Org. Chem.
1998, 63, 2794; K. Fuji et al.
J. Am. Chem. Soc.
1997, 119, 3169). All these chiral chemical catalysts except the chiral Lewis acids are believed to operate by nucleophilic catalysis. A possible mechanism of nucleophilic catalysis of acylation of a secondary alcohol mediated by the achiral 4-aminopyridine derivative 4-dimethylaminopyridine (DMAP) is illustrated in Scheme A.
Of the chiral 4-aminopyridine-based catalysts, Fu's planar chiral ferrocenyl chiral 4-aminopyrindine has been shown to be the most versatile (e.g. G. C. Fu et al.
J. Org. Chem.
1998, 63, 2794). It catalyses a variety of useful enantioselective acylation processes by means of kinetic resolution (e.g. of arylalkylcarbinols with acetic anhydride) via nucleophilic catalysis with excellent selectivity (s: 7-100). However, the published synthesis involves 13 linear steps, has an overall yield of 0.6% from adiponitrile (for the racemate), requires glove-box techniques, and involves chiral stationary phase high-performance liquid chromatography (HPLC) for the final enantiomer separation. Additionally, it is a slow catalyst, typically requiring several days at 0° C. in tert-amyl alcohol to give efficient resolution.
Accordingly, there is a need for enantioselective catalysts which are capable of mediating enantioselective acylation with high selectivity, which can be readily synthesised in high yield and used in low quantities, an
Fekner Tomasz Slawomir
Spivey Alan Christopher
Jacobson & Holman PLLC
Seaman D. Margaret
University of Sheffield
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