Enantioselective synthesis chiral agents

The cataracts that can appear even in those diabetics whose disease is under control have been attributed to accumulation in the eye of sorbitol that results from the reduction of glucose by elevated levels of the enzyme aldose reductase that accompanies the disease. Inhibitors of that enzyme have been investigated as a means for controlling such cataracts. Known agents, as would be expected with enzyme inhibitors, tend to show marked differences in potency between optical isomers. The enantioselective synthesis of one of these compounds starts with the formation of an imine (12-3) of dihydrochromone (12-1) with the S form of the chiral... 

In summary, the C-H insertion chemistry of rhodium carbenoids is a very powerful method for transformation of C-H bonds. Highly regioselective and stereoselective reactions are possible and several classes of chiral catalyst are capable of very high asymmetric induction. The chemoselectivity in this chemistry is exceptional, as illustrated by the numerous intermolecular and intramolecular reactions described in this overview. Most notably, this chemistry offers new and practical strategies for enantioselective synthesis of a variety of natural products and pharmaceutical agents. 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

The Sharpless asymmetric epoxidation (sec. 3.4.D.i) exploits this chelation effect because its selectivity arises from coordination of the allylic alcohol to a titanium complex in the presence of a chiral agent. The most effective additive was a tartaric acid ester (tartrate), and its presence led to high enantioselectivity in the epoxidation.23 An example is the conversion of allylic alcohol 40 to epoxy-alcohol 41, in Miyashita s synthesis of the Cg-Ci5 segment of (-t-)-discodermolide.24 in this reaction, the tartrate, the alkenyl alcohol, and the peroxide bind to titanium and provide facial selectivity for the transfer of oxygen from the peroxide to the alkene. Binding of the allylic alcohol to the metal is important for delivery of the electrophilic oxygen and... 

Example 9.7 One enantioselective synthesis of -)-sertraline TM 9.3 starts firom the easily available oxabenzonorbomadiene 2. This mew-compound is desym-metrized by the catalytic action of chiral complex Ni(ll)-(5)-BlNAP and diisobutylaluminium hydride as the reducing agent (Scheme 9.11) [18, 19]. 

Among substituents, electron-withdrawing o-Cl and o-Br substituents appear to induce better enantioselectivities. Besides, they represent a convenient handle for further synthetic modification, e.g. through coupling reactions [25]. Chiral benz-hydryl fragment can be found in a variety of pharmaceutically relevant molecules. Synthetic application of the reduction of prochiral diaryl ketones was illustrated by enantioselective synthesis of antihistamine agents (I )-orphenadrine (37) and (5)-neobenodine (38) [26]. The former was synthesized in two easy steps from alcohol 35, whereas synthesis of 38 from 36 also included debromination step. 

CILs are a subclass of ILs in which the cation or the anion (or both) may be chiral. The chirality can be either central, axial, or planar. It is well established that chirality plays an important role in chemistry. Over the last few years, research for new chiral selectors, solvents, and materials based on CILs has become a topic of increasing interest. A growing number of CILs have been designed, synthesized, and utilized for potential applications in chiral discrimination and separation [24], asymmetric catalysis and synthesis [25], as well as optical resolution of racemates [26]. Because of their high-resolution abilities and liquidus properties, CILs can be used as either chiral agents in regular solvent, or chiral solvents, or both simultaneously. With the rapid development of CILs, these new chiral solvents have the potential to play an important role in enantioselective organic chemistry, chiral separation chemistry, and chiral materials chemistry. Thus, their role in these fields is expected to expand tremendously. 

Han ZS, Meyer AM, Xu Y, Zhang Y, Busch R, Shen S, Grinherg N, Lu BZ, Krishnamurthy D, Senanayake CH. Enantioselective synthesis of diverse suliinamides and sulfi-nylferrocenes from phenylglycine-derived chiral sulfinyl. transfer agent. J. Org. Chem. 2011 76 5480-5484. 

The alternative strategy involving chiral proton source C led to the enantioselective synthesis of (/ )-chlorophenir-amine R)-7, an important antihistaminic agent, which was obtained in good yield with moderate enantioselectivity (75% ee). 

Another approach in the search for useful chiral reducing agents has been the derivatization of borane and boron hydrides [110, 111, 114]. Some of the most successful chiral reagents based on boron are those derived from the hydroboration of a-pinene, which is conveniently available in both enantiomeric forms (Scheme 2.22). Midland reported that the hydroboration product of a-pinene with 9-BBN, a reagent that subsequently came to be known as Alpine-Borane (179), is superb in the enantioselective reduction of aiyl alkynyl ketones [124]. He showcased the use of Alpine-Borane in the context of an enantioselective synthesis of Prelog-Djerassi lactone 181... 

In addition to the enantioselective synthesis of oxiranes through the use of electrophilic oxidants as described above, there have also been significant advances in the development of nucleophilic oxidation catalysts for the epoxi-dation of electron-deficient substrates. Shibasaki has reported an effective chiral catalyst system readily prepared from equimolar amounts of BINOL (102), Ph3As = 0, and La(Oi-Pr)3 (Scheme 9.12) [101]. Use of 1-5 mol % of the chiral lanthanide catalyst permits the epoxidation of a,/3-unsaturated ketones. The method has also been extended to include a,/funsaturated imi-dazolides as substrates to provide convenient access to chiral carboxylic acids [102]. As an example, asymmetric epoxidation of enone 101 proceeded in excellent selectivity and yield (96% ee, 94%) [103], The resulting epoxide 103 was subsequently converted into (-i-)-decursin (104), a potent cytotoxic agent associated with protein kinase C activation. 

Among chiral dialkylboranes, diisopinocampheylborane (8) is the most important and best-studied asymmetric hydroborating agent. It is obtained in both enantiomeric forms from naturally occurring a-pinene. Several procedures for its synthesis have been developed (151—153). The most convenient one, providing product of essentially 100% ee, involves the hydroboration of a-pinene with borane—dimethyl sulfide in tetrahydrofuran (154). Other chiral dialkylboranes derived from terpenes, eg, 2- and 3-carene (155), limonene (156), and longifolene (157,158), can also be prepared by controlled hydroboration. A more tedious approach to chiral dialkylboranes is based on the resolution of racemates. /n j -2,5-Dimethylborolane, which shows excellent enantioselectivity in the hydroboration of all principal classes of prochiral alkenes except 1,1-disubstituted terminal double bonds, has been... 

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