Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-09-11
2003-07-15
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C562S504000, C548S221000
Reexamination Certificate
active
06593489
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel substituted cyclopentenes and their use, e.g. via directed hydrogenation, in the synthesis of chiral scaffolds for the preparation of information-rich single enantiomer compound libraries.
BACKGROUND OF THE INVENTION
The use of combinational chemistry to synthesize libraries of compounds for screening of biological activity is now a central part of the drug discovery process. Compound diversity is widely perceived to be crucial in order to maximize the information gathered and the probability of finding a lead, and to this end there is an increasing requirements for novel and structurally diverse libraries. One element of diversity can be a variation of the stereochemistry in a scaffold from which the library is formed.
Whilst library diversity is a major consideration, it has to be considered together with other factors such as ease of synthesis, molecular size, lipophilicity, rigidity, solubility and pharmacophore focus. Pharmacophore scaffolds for library generation to data are of limited availability, and tend to be flat and thus two-dimensional. There is a need for more three-dimensional chiral building blocks, which are small and contain multiple points of functional attachment, and which have some resemblance to a known pharmacophore.
In a typical drug discovery process, the first stage of lead identification is to screen a library widely, including mixtures of isomers. Having done this, any hits are defined and deconvoluted into their component-contributing features and further optimised. It is at this relatively late stage that isomer formation is considered, and the medicinal chemist is challenged with synthesizing the separate isomers and testing individually for activity and selectivity. Screening isomer mixtures can also lead to false positives, since an isomer mixture in which any component is active will give an active mixture. However, and importantly, if any component is unselective the mixture will be unselective. This means that an active but unselective mixture may contain a valuable selective component.
A more efficient strategy for drug discovery is to begin screening using a library whose individual compounds are single isomers, thus incorporating a lead characterisation stage into the initial lead identification. This generates more 3-dimensional information that can be enhanced further by applying computational methods for lead optimisation. In order to prepare single isomer libraries, there is a requirement for the appropriate chiral scaffolds in isometrically pure form, in which relative and absolute configurations are defined across all stereogenic centres. It is equally important that, for a scaffold having a particular bond connectivity, all possible stereoisomers can be prepared. Thus a series of scaffolds of this type can be elaborated chemically into different but defined directions of 3-D space, to give isomeric compounds which may have very different properties in a chiral biological environment. In summary, differing stereochemistry at the points of attachment to a scaffold molecule provides a compound library having enhanced information. For an overview of this strategy, see McCague,
Modern Drug Discovery,
Jul./Aug. 29, 2000, (published after the priority dates claimed herein).
In the preparation of organic compounds that contain two or more stereogenic centres, a common synthetic strategy is to utilise a functional group, attached to a pre-existing stereogenic centre in the substrate, as a stereochemical control element for the creation of new stereogenic centres. Processes of this type are frequently referred to as substrate-directable chemical reactions (for a review, see Hoveyda et al,
Chem. Rev.,
1993, 93, 1307). Although primarily a means of controlling relative configuration of products, this approach has particular value in applications where the substrate is readily accessible in enantiomerically pure form.
Successful implementation of a substrate-directable reaction requires a transient bonding interaction between the direction functional group and either the reagent or a catalyst. This contrast with, and is frequently complementary to, reactions where stereoselectivity is achieved through steric efforts alone, in which no such interaction occurs. In addition, conformational effects in the substrate can influence the relative orientation of the directing group and the reaction site, and different effects may prevail in small- and medium-ring cyclic substrates compared with acyclic and large-ring cyclic substrates.
One category of substrate-directable reactions is directed homogenous hydrogenation. It is well established that, in the presence of a catalyst comprising a transition metal-phosphine complex, hydrogen may be efficiently transferred from the metallic centre to unsaturated organic molecules under homogenous conditions. The reactivity of the intermediate transition metal hydrides depends on both the metal and the electronic and steric properties of the ligands. Metals have proven useful in achieving such transformations include rhodium, iridium and ruthenium, and a variety of phosphines, both chiral and achiral, have received attention as suitable ligands. Such hydrogenations can be made stereoselective by utilizing functional groups present in the substrate to chelate to the catalyst, although a practice, only a limited number of functional groups are well characterized as being capable of directing the hydrogenation efficiently.
For example, studies by Stork and Kahne (
J. Am. Chem. Soc.,
1983, 105, 1072) and independently by Crabtree and Davis (
J. Org. Chem.,
1986, 51, 2655) have shown that the hydroxyl group, in conjunction with [Ir(COD)py(PCy
3
)]PF
6
as catalyst, is highly effective as directing group in the hydrogenation of cyclic alkenes. Stereocontrol was highest in cases where the hydroxyl group is attached directly to the cycloalkene ring, although an acceptable level of stereocontrol was also achieved in cases where an intervening methylene unit is present. Comparative experiments on O-acetyl derivatives (Stork and Kahne), in which no stereocontrol was observed, underline the effectiveness of hydroxyl as a directing group.
Amides and esters, in which the carbonyl group is either attached directly or linked via a methylene unit to a cycloalkene ring, and also ethers, act as efficient directing groups in hydrogenations catalysed by [Ir(COD)py(PCy
3
)]PF
6
. For these substrates and hydroxyl-containing substrates, comparable selectivity can also be achieved using certain rhodium complexes as catalysts, for example the cationic complex {Rh[nbd][Ph
2
P—(CH
2
)
4
—PPh
2
]}BF
4
(for lead references, see pp. 1331-1336 in Hoveyda et al, supra).
Amines, or simple protected derivatives thereof, have been reported as useful directing groups only in isolated examples, for acyclic allylic substrates (Brown et al.,
Tetrahedron Lett.,
1987, 28, 2179; Takagi and Yamamoto,
Terrahedron,
1991, 47, 8869).
Carbocyclic nucleoside drugs having potent antiviral properties can be synthesised using enantiometrically pure (−)-2-azabicyclo[2.2.1]hept-5en-3-one as a chiral building block. An economical bioresolution of 2-azabicyclo[2.2.1]hept-5-en-3-one, providing the chiral building block as a single enantiomer, is disclosed in WO-A-98/10075. This bioresolution uses a cloned lactamase at high volume efficiency, and can be operated on a multi-tone scale.
The residual (−)-lactam and the (+)-amino acid product can be converted, using standard chemical methods, into the following single enantiomer N-Boc cis-amino esters
Vince et al, Nucleic Acid Chem., 1991, 4, 46, discloses (3&agr;,4&bgr;)-4-amino-3-hydroxy-1-cyclopentene-2-carboxylate.
as an intermediate for the synthesis of carbocyclic nucleosides. This compound is in trans configuration, and is a racemate.
An object behind the present invention is the generation of a series of scaffolds comprising the eight trifunctionalised cyclopen
Derrien Nadine
Smith Mark Edward Brennan
ChirotechTechnology Limited
Killos Paul J.
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