Stereochemical purity

The guideline on chiral active substances states that particular attention should be paid to identity and stereochemical purity. It states that specifications for a racemate should include a test to show that the substance is indeed a racemate and this is a position supported by the requirements of the European Pharmacopoeia for drug substance monographs [16]. 

Finished product The applicant should show that the manufacturing process produces no unacceptable changes in the stereochemical purity of the active ingredient and that such changes do not occur on storage for the proposed shelf-life. 

R)-Cyanohydrins react with toluenesulfonyl chloride, methanesulfonyl chloride or 4-nitrobenzenesulfonyl chloride without loss of stereochemical purity, and the 2-sulfonyloxy-nitrile reacts with a variety of Sn2 reactions to give a variety of products, such as 2-fluoro nitrile [64], 2-azidonitrile [65] and /V- p h t h a I o yl - p rot e c te d 2-aminonitrile [66], 2-acetoxy nitrile [66], and 2-mercapto nitrile [67]. Hydrogenation of 2-sulfonyloxynitriles with LiAIH4 in good chemical yields and high ee afforded 2-monosubstituted (S)-aziridines [68]. 

Extrusion of sulphur dioxide from cyclic systems leading to dienes has proved to be a synthetically useful reaction112. Thermolysis of cis- and fraw,s-2,5-disubstituted sulp-holenes, which can be readily obtained through regio- and stereoselective alkylation, proceeds in a stereospecific manner affording 1,3-dienes of high stereochemical purity, as predicted by symmetry rules (equations 68 and 69)113. On the other hand, a photochemical process is not completely stereospecific (equation 68)114. 2,5-Dialkylative cyclization... 

Furthermore, the first catalytic synthesis of allenes with high enantiomeric purity [15c, 25] was applied recently to the pheromone 12 by Ogasawara and Hayashi [26] (Scheme 18.7). Their palladium-catalyzed SN2 -substitution process of the bromo-diene 16 with dimethyl malonate in the presence of cesium tert-butanolate and catalytic amounts of the chiral ligand (R)-Segphos furnished allene 17 with 77% ee. Subsequent transformation into the desired target molecule 12 via decarboxylation and selenoxide elimination proceeded without appreciable loss of stereochemical purity and again (cf. Scheme 18.5) led to the formation of the allenic pheromone in practically the same enantiomeric ratio as in the natural sample. 

To the organic chemist, the most striking feature of solid-state reactions is the stereochemical purity of die product obtained in most cases. This feature allows conversion by conventional methods of the solid-state product to other materials of desired stereochemistries. We illustrate this by some examples of reactions starting from the cyclobutanes obtained by solid-state (2 + 2) photodimerization. 

In conclusion, the most important result is that the use of permethylated cyclodextrin as chiral solvating agent for NMR spectroscopy not only affords a simple and practical way for the determination of the stereochemical purities of trisubstituted allenes, but also allows one to simultaneously determine their absolute configuration. Indeed, TRIMEB induced only positive complexation shifts of all the allene protons, which are greater for the (S )-enantiomer than for the (R)-enantiomer, independent of the structure of the allene. This empirical correlation seems to be reliable since it has been satisfied by a large number of trisubstituted allenes. 

A fascinating observation within these transformations was that with certain substrates, regardless of the stereochemical purity of the starting a,P-unsaturated aldehyde, identical levels of asymmetric reduction were observed within the reaction. For example, starting with either (ii)-80, (Z)-80 or a 1 1 mixture of the two... 

Further process optimization by Thiruvengadam and co-workers (Thimvengadam et al., 1999), led to a novel, stereoselective, scalable two-step process devoid of chromatography for chiral 2-azetidinone construction (Scheme 13.4). As above, the titanium-enolate of chiral oxazolidinone 11a was preformed, but now when reacted with well behaved imines of type 16, affords the unexpected anti-addition product. This surprising result was further supported by careful comparison to minor antiproducts obtained in the earlier aldol-addition methodology and determination that the major product was indeed 17a (undesired RSR series). Adjustment of the oxazolidinone absolute stereochemistry to the fortuitously less expensive 2S-series afforded the desired diastereo-mer 17b in 95% de and in 50-70% yield. Recrystallization improved the stereochemical purity to >99% de. 

Allylic a-bromo boronic l,l,2,2-tctramethyl-l,2-ethanediyl esters are too labile to permit preparation in high stereochemical purity. Finacol l-bromo-2-propenylboronate with sodium methoxideyields 1-methoxy-2-propenyl boronic l,l,2,2-tetramethyl-l,2-ethanediyl ester54. Attempted conversion of the corresponding chloro boronic ester to alkoxy derivatives failed54. 

A gas chromatographic analysis of the product by the submitters using a 1.8-m. column packed with 20% Carbowax 20 M suspended on Chromosorb P and operated at 150° with a flow rate of 30 ml. per minute showed a peak for the major component having a retention time of 16 minutes and two minor peaks having retention times of 4 and 7 minutes, with relative areas amounting to 6% and 2% of the major peak, respectively. The stereochemical purity of the product was shown to be >95% cis by the submitters by gas chromatographic analysis using a 50-ft. capillary column... 

Erick Caireira of ETH Honggerbcrg has reported Organic Lett. 2004,6,4575) a catalytic procedure for the reduction of nitroalkenes such as 4 to the nitroalkane 5 with high enantiomeric excess. He has also reported (Angew. Chem. Int. Ed. 2005,44,612) that the enantiomerically-enriched nitroalkane can be converted to the corresponding nitrile 6 without loss of stereochemical purity. 

More recently, we turned to HATU/HOAt/2,4,6-collidine in DMF as coupling conditions to avoid racemization on the sugar ring. It turned out that this coupling proceeds with high yields (up to 90%) with stereochemical purity. Protected Saa can also be cyclized with DIC/HOAt/NMM however, for unprotected Saa very low yields were achieved with this method. 

A similar but conceptually distinct approach to difunctionalization of terminal alkynes consists of sequential carboboration-palladium-catalyzed cross-coupling 137 equation (33) illustrates that this method also provides alkenes of high stereochemical purity by net syn Markovnikov addition. Benzyne-contain-ing molecules can act as highly activated substrates for vicinal difunctionalizations initiated by nucleophiles 138-140 thus, nucleophilic addition-electrophilic trapping can serve as an alternative to sequential directed metallation for the production of 1,2-disubstituted and 1,2,3-trisubstituted aromatic systems (equation 34).141... 

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