Chiral auxiliaries drug synthesis

Aldol reactions enjoy great recognition as a useful tool for the synthesis of building blocks in natural product and drug synthesis [42, 182]. The stereochemistry of the stereogenic centers formed can be controlled by various means. Besides chiral auxiliaries, catalytic methods with chiral Lewis acids, organocatalysts, or catalytic antibodies were established for stereochemical control [183-187]. 

A chiral auxiliary is a temporary chiral group on a molecule that directs the stereochemical outcome of a reaction on another part of the molecule. Almost all synthetic routes involving chiral auxiliaries follow three steps (1) covalently attach the auxiliary to the molecule, (2) perform the reaction that forms the new stereocenter, and (3) remove the auxiliary. Under this model, use of a chiral auxiliary adds two steps to a synthesis because the auxiliary must be added and removed. Additional steps in a synthetic scheme require additional time, increase cost, and decrease the overall yield. Despite these disadvantages, chiral auxiliaries are fairly common in drug synthesis. 

All the optically active terpenes mentioned in this chapter are commercially available in bulk (>kg) quantities and are fairly inexpensive. Although many of them are isolated from natural sources, they can also be produced economically by synthetic methods. Actually, two thirds of these monoterpenes sold in the market today are manufactured by synthetic or semi-synthetic routes. These optically active molecules usually possess simple carbocyclic rings with one or two stereo-genic centers and have modest functionality for convenient structural manipulations. These unique features render them attractive as chiral pool materials for synthesis of optically active fine chemicals or pharmaceuticals. Industrial applications of these terpenes as chiral auxiliaries, chiral synthons, and chiral reagents have increased significantly in recent years. The expansion of the chiral pool into terpenes will continue with the increase in complexity and chirality of new drug candidates in the research and development pipeline of pharmaceutical companies. 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

Major interest has been expressed in the synthesis of chiral sulfoxides since the early 1980s, when it was discovered that chiral sulfoxides are efficient chiral auxiliaries that are able to bring about important asymmetric transformations [22]. Sulfoxides are also constituents of important drugs (e.g., omeprazole (Losec , Priso-lec )) [23]. There is a plethora of routes of access to enantioenriched sulfoxides, and many involve metal-catalyzed asymmetric oxidations [24]. Examples of ruthenium metal-based syntheses of sulfoxides are scarce, presumably due to the tendency of sulfur atoms to bind irreversibly to a ruthenium center. Schenk et al. reported a dia-stereoselective oxidation of Lewis acidic Ru-coordinated thioethers with dimethyl-dioxirane (DMD) (Scheme 10.16) [25[. Coordination of the prochiral thioether to the metal is followed by diastereoselective oxygen transfer from DMD in high yield. The... 

Dihydrooxazoles continue to occupy an important place in organic synthesis and medicinal chemistry as they have found use as versatile synthetic intermediates, protecting groups/pro-drugs for carboxylic acids, and chiral auxiliaries in asymmetric synthesis. There are several protocols in the literature for the transformations of functional groups such as acids, esters, nitriles, hydroxyl amides, aldehydes, and alkenes to 2-oxazolines. Newer additions to these methods feature greater ease of synthesis and milder conditions. 

This type of reaction forming unnatural L-amino acids uses enzymes from the metabolism of proteinogenic amino acids which additionally have an unexpectedly versatile substrate specificity by also accepting highly sterically hindered a-keto acids. L-Tle and L-Npg are of growing importance because of their extended use as building blocks in pharmaceutical drugs and as chiral auxiliaries in asymmetric synthesis [114]. 

Perhaps the most famous Jacobsen epoxidation is that of indene 206 used in the synthesis of the amino-indanol45 209. The anti-AIDS drug Crixivan incorporates 209 which is also a cheap chiral auxiliary in its own right. 

Evans s oxazolidinones 1.116 and 1.117 are a class of chiral auxiliaries that has been widely applied [160, 167, 261, 411]. Deprotonation of 7/-acyl-l,3-oxa-zolidin-2-ones 5 30 and 5.31 smoothly gives chelated Z-enolates, which then suffer alkylation between -78 and -30°C on their least hindered face [167, 1036]. After hydrolysis, the corresponding enantiomeric acids are obtained according to the auxiliary that was used (Figure 5.21). Due to the low reactivity of lithium enolates, sodium analogs are preferred in some cases [411, 862, 1036], This methodology has been applied to the synthesis of chiral a-arylpropionic acid anti-inflammatory drugs [1037, 1038], natural products [1039, 1040], and a-substituted optically active 3-lactams en route to nonracemic a,a-disubstituted aminoacids [136,1041]. 

Limitations of this method are the poor selectivity observed with 2-cyclo-hexencne and the lack of reactivity of these enolates toward (3-alkyl-a,p-un-saturated esters [413], Conjugate addition of the sodium enolate of 530 (R = H) to a substituted nitrostyrene 7.96 is the first step of the synthesis of an antidepres-sive drug [1448], The chiral auxiliary is excised by lactam formation induced by hydrogenation of the nitro group. This leads to pyrrolidine 7.97 (Figure 7.62). 

The Zambon synthesis of the non-steroidal anti-inflammatory agent (5)-2-(6-methoxy-2-naphthyl)propanoic acid (naproxen) is a landmark-setting application of the chiral auxiliary approach in the industrial stereoselective synthesis of an enantiomerically pure drug [51]. The chiral auxiliary employed, a (2f ,Jf )-dialkyltartrate, is a paradigmatic representative of this class of stereocontroller, being cheap, readily available, easily introduced on the substrate and removed from the product, and eventually recycled (although as its parent acid). 

Far from being industrially viable, this synthesis showed that a chiral auxiliary-based approach to the drug was possible, and very recently an alternative and much more attractive route has been reported by DSM [53]. This is described in Fig. 14. 

An interesting example of a chirality pool material used as a chiral auxiliary, is the industrial synthesis of -naproxen, reported by Zambon [15]. Naproxen is the generic name of the non-steroidal anti-inflammatory drug, S-2-(6-methoxy-2-naphthyl) propanoic acid, described originally by Syntex in 1967 [16]. It is interesting to compare the Syntex and Zambon strategies for the production of S-naproxen (Schemes 7.2 and 7.3, respectively). 

Enantioselective as well as diastereoselective synthesis of axially chiral biaryls is the subject of a rapidly growing interest, due to its role as a cmcial motif in a great number of drug candidates, chiral polymers, chiral auxiliaries, catalysts, etc. 

The disadvantages of the auxihary approach should not be concealed the attachment and the removal of the chiral residue are two extra steps, each of them requiring not only an individual reaction but also isolation and purification. A further comphcation may arise if the separation of the cleaved stoichiometric auxihary from the product requires chromatography - a drawback that becomes severe if the individual procedure aims at delivering larger amounts of products, for example, in drug synthesis. Therefore, such protocols are particularly valuable, wherein auxiliary and product differ strongly in solubility and acidity [2]. 

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