The rising flow of single-isomer, chiral drugs onto U.S. and world markets is an important trend in today's pharmaceutical industry. In part, this trend has been prompted by the FDA's continuing emphasis to have companies clarify the relationship between a new drug's stereochemical features and its biological effects. It has been estimated that the 1993 worldwide market for single-isomer, chiral drugs reached $35.6 billion, a growth of 22% over 1992. In 1997 the chiral drug market could be as high as $60 billion (S. Stinson, Chem. & Engin. News, Sep. 19, 38 (1994)). As a result, practical methods for the production of optically pure synthetic building blocks applicable to the pharmaceutical industry are being heavily researched (R. Noyori, Asymmetric Catalysis In Organic Synthesis, John Wiley & Sons, Inc. (1994); D. Ager, Asymmetric Synthetic Methodology, CRC Press (1996)). A steady stream of monographs, reviews (Chem. & Engin. News, Apr. 24, 37 (1995); Organic Synthesis, 401 (1994)), special conferences (Chiral Synthesis Symposium and Workshop, Spring Innovation, Manchester, UK, Apr. 18 (1989); Smith Kline and French Research Symposium: Chirality in Drug Design and Synthesis. Cambridge, UK Mar. 27 (1990); The International Conference on Chirality, Cancun, Mexico, Jun. 6 (1990); Chiral 90, Spring Innovation, Manchester, UK Sep. 18 (1990); Second International Symposium on Chiral Discrimination, Rome, Italy, May 27 (1991)) and new journals (Chirality, Vol 1); Tetrahedron: Asymmetry, Vol. 1) dedicated to this topic have appeared.
Chiral benzylamine-related systems represent a class of compounds which have considerable potential to be useful as chiral auxiliary reagents. In addition to the common use of the benzyl group as a protecting moiety for oxygen and nitrogen (K. Harada et al. Bull. Chem. Soc. Jpn. 46, 1865 (1973)), the N-benzyl system has been shown to be generally useful as a practical means to deliver nitrogen in a regiospecific manner by decreasing the propensity for over alkylation during various synthetic strategies (P. Erhardt, Synth. Comm., 13 (2), 103 (1983)). In these simple structural settings, the benzyl groups are not .alpha.-substituted and they quite generally possesss the desirable feature of being able to be readily O- or N-debenzylated at any convenient, subsequent step during an overall synthesis (P. Erhardt, ibid.). Now, when these reagents are additionally .alpha.-substituted so as to be made chiral, it follows that any racemic asymmetry present within the reagent's substrate, especially when present in the vicinity near the point of attack by nitrogen, will interact with the auxiliary in a diastereomeric fashion. Thus, this overall approach becomes potentially useful as a general asymmetric method to obtain nitrogen-containing systems which have defined neighboring asymmetry. The latter is a common structural motif within many pharmaceutical drug entities; .alpha.- and .beta.-adrenergic agonists and antagonists, HIV protease inhibitors, and numerous antimicrobial agents representing just a few of the many examples.
Although considerable prior art has demonstrated the general utility of using .alpha.-unsubstituted benzylamines during synthesis, an extensive literature search reveals that .alpha.-substituted, asymmetric benzylamines have been employed in only a very limited number of cases. These cases are now incorporated herein by the following references. In one of these cases, optically pure .alpha.-methylbenzylamine was found to react with a racemic epoxide to provide diastereomeric N-alkylated products which were readily separable by column chromatography (R. Kuhlmeyer, et al. Tetrahedron Lett., 25, 3429 (1984)). In another case, optically pure .alpha.-methylbenzylamine was reacted with a racemic, substituted cyclohexanone to directly afford an asymmetric synthesis of the corresponding cyclohexanamine in high diastereomeric excess (A. Frahm and G. Knupp, Tetrahedron Lett., 28, 2633 (1981)). These key literature reactions are depicted below in Schemes 1 and 2, respectively, and serve as precedent that the asymmetric elements when placed within the family of reagents that are encompassed by the present invention can, indeed, be expected to be deployed advantageously. ##STR1##
However, a major road-block pertaining to the practical and more general use of these types of chiral reagents, of concern especially during process and manufacturing chemistry, has been the purported inability to subsequently remove the benzyl portion of the reagent (i.e. CHR'Ph) in a convenient manner, such as by routine catalytic hydrogenolysis. This is because when the nitrogen becomes sterically hindered, a situation inherent to the asymmetric versions of such reagents, it is commonly accepted within the present state of the art that the general hydrogenolysis reaction can be expected to be significantly impeded by the presence of the additional steric bulk. The basis for this prevailing view has its origins in the very early chemical literature.
N-debenzylation (cleavage of a carbon-nitrogen bond) has been widely used in chemical synthesis, most often after employing the benzyl as a protecting group for a nitrogen atom within a molecule undergoing other synthetic manipulations. The ease of such debenzylations when undertaken at room temperature and atmospheric pressure increases in the series primary&lt;secondary&lt;tertiary&lt;quaternary ammonium salts (H. Dahn, et al. Helv. Chim. Acta, 37, 565 (1954)). However, M. Freifelder was very careful to point out that within any family of amines having the same degree of N-substitution, the steric features of the substituents will also effect the reaction rate and that in particular, difficulty arises when the .alpha.-benzyl portion is substituted or hindered (M. Freifelder, Catalytic Hydrogenation in Organic Synthesis Procedures and Commentary, John Wiley & Sons (1978)). Likewise, R. Baltzly has previously demonstrated that even a methyl group in the .alpha.-position of what would otherwise be a very simple, unhindered system, significantly decreases the rate of hydrogenolysis (R. Baltzly and P. Russell, J. Am. Chem. Soc., 75, 5598 (1953)). Similarly, the effects of a variety of other substituents placed on the aromatic nucleus or in the benzylic position have been studied and, in general, the presence of additional substituents stabilizes these compounds toward hydrogenolysis except for when the groups form more extended aromatic systems (R. Baltzly and J. Buck, J. Am. Chem. Soc., 65, 1984 (1943); R. Baltzly and P. Russell, J. Am. Chem. Soc., 72, 3410 (1950)). For example, the debenzylation of dibenzyl tertiary amine with one of the benzyl rings bearing additional substituents invariably results in the preferential loss of the unsubstituted benzyl group (R. Baltzly and J. Buck, J. Am. Chem. Soc., 65, 1984 (1943)).
Nevertheless, when .alpha.-substituted asymmetric benzylamine hydrogenolyses have been forced to occur as part of small scale laboratory studies, the stereochemical course of these reactions are such that inversion of configuration has been observed with both palladium (C. Murchu, Tetrahedron Lett., 38, 3231 (1969); H. Dahn, et al., Helv. Chim. Acta., 53, 1370 (1970); Y. Sugi and S. Mitsui, Tetrahedron, 29, 2041 (1973); A. Kieboom and F. Van Rantwijk eds. Hydrogenation And Hydrogenolysis In Synthetic Organic Chemistry, Delft University Press, Netherlands, 132 (1977)) and nickel catalysts (Y. Sugi and S. Mitsui, Tetrahedron, 29, 2041 (1973); A. Kieboom and F. Van Rantwijk eds. Hydrogenation And Hydrogenolysis In Synthetic Organic Chemistry, Delft University Press, Netherlands, 132 (1977)). Two of the most relevant reactions from this body of literature are illustrated in the accompanying Scheme 3 which again provides precedent that the asymmetric nature of these kinds of reagents should be able to be advantageously manipulated, provided that the .alpha.-substituted benzyl portions can be conveniently removed in any given specific application. ##STR2##
Reemphasizing, it has been established that .alpha.-substitution lessens the ease of both N-debenzylation and O-debenzylation (R. Baltzly and P. Russell, J. Am. Chem. Soc., 75, 5598 (1953); A. Kieboom, et al., Journal of catalysis, 20, 58 (1971)) and that .alpha.-alkyl substitution, in particular, causes a far greater degree of difficulty than when similar substitutions are effected on the aryl moiety (M. Freifelder, Practical Catalytic Hydrogenation, John Wiley & Sons (1971)). This general assessment for the process of debenzylation is widely acknowledged and is routinely accepted as an overall limitation during consideration of possible synthetic strategies (A. Bellamy, Tetrahedron, 16, 4711 (1995)) which might have otherwise tried to employ the chiral reagent methods as proposed herein.
Therefore, as a prelude to attempting to deploy asymmetric, .alpha.-substituted benzylamine compounds as practical chiral auxiliary synthetic reagents in specific settings, it was decided to experimentally define the general scope and limits for subsequent removal of the .alpha.-substituted benzyl portion as impacted by the presence of the inherent, increase in steric bulk. Toward this end, the specific series of tertiary amine steric probes as shown within Table 1 was first synthesized. These compounds specifically model the steric environment for intermediates which will need to undergo debenzylation smoothly in order to successfully use the proposed reagents in any practical manner. By intention, the probes span a considerable range of the perceived steric impediment.
TABLE 1 ______________________________________ Structures of molecules synthesized to probe the steric impediment toward N-debenzylation that results from employing asymmetric versions of a simple benzyl-group. - 1 STR3## - Name R.sub.1 R.sub.2 R.sub.3 ______________________________________ N,N-dipropyl- benzylamine (1) 2 STR4## 2 H R5## - N-isopropyl-N-propyl- benzylamine (2) 2 STR6## 3 H R7## - N,N-diisopropyl- benzylamine (3) 3 STR8## 3 H R9## - N,N-dipropyl- .alpha.-methylbenzylamine (4) 2 STR10## 2 CH.sub.3 - N-iospropyl-N-propyl- .alpha.-methylbenzylamine (5) 2 STR12## 3 CH.sub.3 - N,N-diisopropyl- .alpha.-methylbenzylamine (6) 3 STR14## 3 CH.sub.3 ______________________________________
It was found upon careful examination of their N-debenzylation rate profiles, that this reaction is not impeded in any predictable manner that is proportional to increasing steric bulk. In fact, the most sterically hindered system, 6 was found to exhibit the fastest rate of N-debenzylation. These results are summarized in Table 2. A detailed description of these studies can be found in a recent M.S. degree thesis submitted to the University of Toledo (Y. Ni, Synthesis And N-Debenzylation Of Steric Probes To Define The Practical Limit For Employing Potential Benzylamine-Related Chiral Auxiliary Reagents) that is hereby incorporated in total by its reference herein.
TABLE 2 ______________________________________ Comparison of the reaction rate data as measured by high pressure liquid chromotographic (HPLC) assay, to the steric features for 1to 6: (a) Reaction time is defined as the time needed for at least 95% completion of the hydrogenolysis reaction. (b) Reaction rate is defined as moles substrate reacted per minute from T = 0 to 80% conversion and is reported as mean .+-. sd. .COPYRGT. The steric energy values were obtained through CS Chem3D Pro. (d) Molar refractivity values were obtained using standard algebraic methods from literature tabulated data. Steric Steric Reaction energy Molar Probe time (min) Reaction rate (kcal/mole) refrac- molecule (a) (mole/min) (b) (c) tivity (d) ______________________________________ 1 80 (3.81 .+-. 0.16) .times. 10.sup.-4 9 0 2 120 (2.20 .+-. 0.13) .times. 10.sup.-4 12 5 3 360 (9.57 .+-. 0.34) .times. 10.sup.-5 15 9 4 180 (1.84 .+-. 0.06) .times. 10.sup.-4 13 5 5 100 (2.80 .+-. 0.11) .times. 10.sup.-4 16 9 6 20 (1.46 .+-. 0.01) .times. 10.sup.-3 25 14 ______________________________________
These completely unexpected results clearly show that the heretofore prevailing dogma about steric features limiting the potential use of such reagents in the proposed manner is actually not applicable. Interestingly, this appears to be the case even within the most extreme of such steric environments envissioned for the reagent's potential ussage, i.e. in compound 6 where all three positions .alpha.- to the nitrogen atom have been additionally substituted. Instead, these results indicate that when the net steric features are relatively small, subtle increments of steric bulk do impede the reaction rate. However, when the overall steric features are relatively large and a significant component is specifically located on the benzyl methylene carbon (i.e. the same .alpha.-position within the reagents which will be utilized to achieve the chirality for delivery by the methods proposed herein), further increments of steric bulk actually result in a faster reaction rate. Apparently, two opposing factors are manifest simultaneously at the level of the reaction mechanism. One is that the presence of steric bulk can interfere with the discrete process whereby hydrogen enters the reactive site of a given substrate such that this factor tends to slow the reaction. The other factor is that steric bulk can increase the net strain energy of the specific nitrogen-carbon bond to be broken and thus render it more susceptible to the reaction. Importantly, since all of the model reactions proceeded smoothly under reasonably mild reaction conditions, the studies clearly demonstrate that .alpha.-substituted benzylamines can indeed be deployed as chiral auxiliary reagents and that .alpha.-substituents even larger than a simple methyl group can be expected to be tolerated during N-debenzylation in any given instance. This completely unexpected finding, then, provides the confidence needed to deploy the method toward eventual use in a practical manner and constitutes the main factor of the inventive aspect of this disclosure.
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