Jan H. Noordik

Racemate resolution via crystallization of diastereomeric salts: thermodynamic considerations and molecular mechanics calculations

Abstract It is of crucial importance in many areas of (bio)chemistry to use enantiomerically pure substances. On an industrial scale, enantiopure compounds are often produced by resolution of racemic mixtures via crystallization of diastereomeric salts. The technique is still applied on a trial and error basis. In this paper, we present a thermodynamic approach which shows that resolution efficiency is related to the lattice energy difference in a pair of diastereomeric salts. Application of this line of reasoning to an extensive series of closely related resolutions allows for a qualitative rationalization of these resolutions. Reliable quantitative calculations by means of computer assisted crystal modeling are not (yet) possible due to inaccuracies of present computational techniques, but such calculations may be successful in the near future, and a truly predictive model for racemate resolutions becomes feasible.

Nucleophilic eliminative ring fission of bridgehead substituted 1,3-bishomocubyl acetates

The base induced cage fission of three different types of functionalized bridgehead substituted 1,3-bishomocubyl acetates, viz A,B and C is described. The synthesis of two 6-functionalized 1,3-bishomocubyl 4-acetates (type A ), viz 4 -acetoxypentacyclo[5.3.0.0 2,5 .0 3,9 .0 4,8 ]decan-6-one 5 and its ethylene acetal 6 has been accomplished starting from the readily available Diels-Alder adduct 4 . The synthesis of three 1,3-bishomocubyl 8-acetates (type B ), viz 8-acetoxypentacyclo[5.3.0 2,5 .0 3,9 .0 4,8 ]decan-6-one 15 , its ethylene acetal 16 and the parent acetate 20 has been carried out starting from the cyclopentadiene-benzoquinone adduct 7 . Base induced homoketonization of 6, 16 and 20 leads regio- and stereospecifically to the thermodynamically favored half cage ketones 22,28 and 31 , respectively. In contrast, the cage opening of the β-ketoacetates 5 and 15 is essentially directed by the β-ketone function. In the case of 5 , regiospecific cleavage of the central C 4 -C 5 bond is observed producing in a stereospecific manner diketone 25 in quantitative yield. Under similar conditions, acetate 15 gives a complex mixture of cage opened products arising from further fragmentation of the initially formed diketone 34 . Deuterium labeling experiments reveal an anti -Bredt behavior of half cage ketones 28 and 31 . The synthesis of a bridgehead acetate of type C has been accomplished by stereoselective reduction of ketone acetate 5 with LiAlH(t-OBu) 3 followed by mesylation. A mixture of epimers 36a and 36b (ratio 1:4) is obtained from which the predominant anti -epimer 36b could be isolated. An X-ray analysis established its structure. Base induced cage fission of 36b leads regiospecifically to tetracyclo[5.3.0.0 2,5 .0 4,8 ]decenone 37 . In contrast the syn -epimer 36a , under similar conditions, only affords the bridgehead alcohol 38 .

Long-Range Strategies in the LHASA Program: The Quinone Diels-Alder Transform

The quinone Diels−Alder (QDA) reaction has considerable synthetic power in terms of introducing structural complexity. As a consequence, the corresponding transform is a worthwhile goal in retrosynthetic analysis and therefore has been implemented as a transform-goal, or long-range, strategy in the LHASA program. The implemented strategy allows LHASA to convert any suitable target containing the decalin ring system into a tetrahydronaphthoquinone to which the QDA transform can be directly applied. Illustrative examples of retrosynthetic sequences produced by the long-range transform are given.

Automated Overlap Analysis of Reaction Databases

presents the automated procedure w e developed to determine the number o f shared references between two or more databases without any manual interference. In order to relate the number of shared references to the number o f shared reaction entries, w e performed a series o f sample analyses. The sample analyses allowed us to derive a rule o f thumb which can be used to interpret future comparisons performed with our automated procedure. METHODS

CAOS/CAMM Services: An Integrated System of Computer Assisted Chemistry Tools

The CAOS/CAMM Center, the Dutch National Center for Computer Assisted Chemistry, was founded in 1985 to make molecular modelling and synthesis planning available to organic chemists. Since then the Center has expanded its scope to related fields in structural chemistry and microbiology.

CAOS/CAMM Services: Synthesis Planning and Molecular Modelling Tools

The advanced and sophisticated computer tools for molecular design which have become available over the last few years, require considerable resources in terms of hardware and expertise when they are to be used as an integrated system. However, the bench chemist, and in particular the academic bench chemist, generally lacks both. To provide easy access to the new tools, The Dutch National Facility for Computer Assisted Organic Synthesis and Computer Assisted Molecular Modelling has been established in 1985. The CAOS/CAMM Centre provides all the software tools, databases and computing facilities needed for molecular design, by making them accessible online at all Dutch Universities. A user-friendly, graphics menu interface allows even the novice user direct access to the module(s) of his choice. Training sessions and workshops given at the Centre are another means to introduce the new techniques in the chemical laboratory.