Reactivity, enantiomers

EinaHy, kinetic resolution of racemic olefins and aHenes can be achieved by hydroboration. The reaction of an olefin or aHene racemate with a deficient amount of an asymmetric hydroborating agent results in the preferential conversion of the more reactive enantiomer into the organoborane. The remaining unreacted substrate is enriched in the less reactive enantiomer. Optical purities in the range of 1—65% have been reported (471). 

Assuming that the enzymatic reaction is highly enantioselective, then even after only four cycles the enantiomeric excess will have reached 93.4% whereas after seven catalytic cycles the enantiomeric excess is >99% (Figure 5.3). This type of deracemization is really a stereoinversion process in that the reactive enantiomer undergoes stereoinversion during the process. One of the challenges of developing this type of process is to find conditions under which the enzyme catalyst and chemical reactant can coexist, particularly in the case of redox chemistry in which the coexistence of an oxidant and reductant in the same reaction vessel is difficult to achieve. For this... 

Figure 6.40 P-Lactams resolved by lactamase-catalyzed hydrolysis (the reactive enantiomer is shown).

Attention. In pursuing high ee of the digested products (more reactive enantiomers) under kinetically resolving conditions, termination of the reaction at the proper conversion is very important. When the relationship between conversion and ees of the digested product and of the unaffected substrate was calculated using the mathematical model of Chen et al., it was predicted that 80 % conversion should be the critical point, as depicted in Figure 5.3, which corroborated the empirical results mentioned in steps 2 and 3. 

The products 109 are versatile precursors for bicyclic tetrahydro-2-furanones and -furans °. The tributylstannane rac-109d undergoes a kinetic resolution of medium efficiency when it is treated with MeLi/(—)-sparteine (equation 24) °. The substitution products 109b and the less reactive enantiomer ewt-109d are obtained with medium enantioselectivity. 

When enantiomerically pure (/ )- and (S)-ll were reacted with racemic 1-bromo-l-phenylethane (13), d.r. s of 97 3 were obtained. The somewhat lower d.r. obtained on reaction of the resolved complexes was explained as a mass action effect during the course of the reaction the reactive enantiomer of the haloalkane is depleted relative to the less reactive enantiomer. 

Scheme 4.36 CALB-catalyzed acylation of arylalkylamines 8 [117], 119 [113], 120 [121], and 121 [115]. The most reactive enantiomers toward acylation are shown.

A limitation on resolution is that the desired enantiomer is only half of the racemic starting material. Kurt Faber of the University of Graz has reported (Org. Lett. 2004,6,5009) a clever solution to this problem. On exposure of the sulfate 1 of a secondary alcohol to aerobically grown whole cells of Sulfolobus acidocaldarius DSM 639, one enantiomer of the sulfate was smoothly converted into the other enantiomer of the starting alcohol. The enzyme consumed the more reactive enantiomer > 200 times more rapidly than the less reactive enantiomer. For the last bit of conversion, the of the product alcohol will of course fall. One solution to this would be to run the reaction near 50% conversion, then hydrolyze the mixture to give high product alcohol 2. Exposure of the mixture to a lipase that selectively acetylated the minor enantiomer would then polish the of 2. 

Reactivity. Enantiomer recognition in solution results in various intriguing stereochemical outcomes for organic reactions. The molecular interaction may be direct or may occur by way of some other atoms or molecules. 

Rate-determining step, hydroformylation, 163 Reactivity, enantiomers, 286 Recognition, enantiomers, 278 Reduction and oxidation, 5 Reductive coupling, dissolving metal, 288 Reductive elimination, 5, 111 Resolution. See Kinetic resolution Rhenium-carbene complexes, 288 Rhodium-catalyzed hydrogenation, 17, 352 amino acid synthesis, 18, 352 BINAP, 20... 

A disadvantage of resolutions of this type is that the more reactive enantiomer usually is not recoverable from the reaction mixture. 

Within limits, an increase in the steric bulk at the olefin terminus of allylic alcohols of the type R1 CH(OH)CH=CHR2 causes an increase in the rate of epoxidation of the more-reactive enantiomer, and a decrease in the rate for the less-reactive enantiomer, resulting in enhanced kinetic resolution334. However, complexes of diisopropyl tartrate and titanium tetra-terf-butoxide catalyse the kinetic resolution of racemic secondary allylic alcohols with low efficiency335. Double kinetic resolution techniques can show significant advantages over the simple Sharpless epoxidation techniques336. 

Unlike a traditional resolution performed with diastereomeric salts, time is a key factor in a kinetic resolution. The resolution must be stopped at a point that maximizes the desired outcome. Unfortunately, even the desired outcome is more complex in a kinetic resolution. Kinetic resolutions can be performed with one of two different goals isolate the converted, more reactive enantiomer from the product, or recover the less reactive enantiomer from the unreacted starting material. 

The first possibility for a kinetic resolution is isolation of the product derived from the more reactive enantiomer. In both graphs of Figure 13.12, the e.e. of the product starts... 

One way of preventing the concentration effect of this less reactive enantiomer A being dominant near the end of the resolution is to remove it in parallel using a complementary... 

These reports into the use of a PKR strategy have relied on an additional complementary reagent C to remove the less reactive enantiomer (Scheme 6). However, this need not be the... 

Commeyras and co-workers investigated the kinetics of NCA polycondensation in water [150]. Since the aminolysis of the NCA is much faster than its hydrolysis, the formation of peptides is possible provided that sufficient concentration of free amino groups is attained. Practically the formation of peptides is observed at any pH above 4. In the pH 4-7 range, the competition with hydrolysis enhances the effects of chemo- and stereo-selectivity of NCA condensation, through removing unreacted NCA (for example, the less reactive enantiomer in excess) before complete conversion. 

Racemic chiral secondary allylic alcohols can be subjected to a kinetic resolution by means of the Sharpless epoxidation (Figure 3.39). The reagent mixture reacts with both enantiomers of the allylic alcohol—they may be considered as a-substituted crotyl alcohols—with very different rates. The unreactive enantiomer is therefore isolated with enantiomer excesses close to ee = 100% in almost 50% yield at approximately 50% conversion. The other enantiomer is the reactive enantiomer. Its epoxidation proceeds much faster (i.e., almost quantitatively) at 50% conversion. The epoxide obtained can also be isolated and, due to its enantiomeric excess, used synthetically. 

In the kinetic resolution of secondary allylic alcohols hy means of the Sharpless epoxidation (Figure 3.39), the ee value of the epoxy alcohol formed does not quite reach the ee value of the unreacted allyhc alcohol. The reason might be deduced from the epoxidation exemphfied in Figure 3.40. Until 50% conversion is reached it is almost only the reactive enantiomer of the a-substituted crotyl alcohol that undergoes epoxidation. This is not only a very rapid, hut a highly diastereoselective reaction as well, yielding a 98 2 mixture of the anti- and syn-epoxy alcohol. Epoxidation of the unreactive enantiomer of the a-substituted crotyl alcohol is also observed until 50 % conversion is reached, but only to a very minor extent. The result is most... 

The first preparations of roxifiban were limited in scale to about 100 g and on such a scale the question of the recycle of the less-reactive enantiomer (S)-9 was unimportant. Since we expected annual API requests to exceed 100 kg within 1-2 years, a means to recycle this enantiomer would soon be required. First, a good preparation of the isoxazoline substrate (R/S)-9 was necessary. 

Besides eliminating the need to recycle (S)-9 in separate steps, there are other advantages to converting this kinetic resolution into a dynamic resolution. If both enantiomers of 9 are substrates for an enzyme, enantioselectivity will remain constant only with the continuous racemization of 1 [24, 25]. Otherwise under non-ra-cemizing conditions, the eep would remain high only at low conversions once the more-reactive enantiomer supply is exhausted, the eep would typically begin to deteriorate as the now-predominant, less-reactive enantiomer begins to hydrolyze. 

A kinetic resolution of an ester requiring separate steps to recover and recycle the less reactive enantiomer has been transformed into a dynamic resolution of the corresponding thioester. While the thioester route requires an additional synthetic step, the efficiency of this step renders the dynamic resolution route to (R)-l shorter. The development of an alternative route provides our company with additional options for commercial-scale roxifiban preparation. 

It is this complex which can add to epichlorhydrin and, in a reverse reaction that may happen from either side, racemise it 36. Note that under the reaction conditions the azide half of TMSN3 adds quickly but the Me3Si half slowly - the reactive enantiomer of epichlorhydrin is there to be had at the start but must be made by continuous racemisation in the second part of the reaction. A potential by-product from these reactions is the double azide 37 which the authors think looks suspiciously explosive. 

Recently, almond meal was used for the resolution of rac-2-hydroxy-2-phenyl-propanenitrile. Under the optimized conditions, (S)-2-hydroxy-2-phenylpropaneni-trile, as the less reactive enantiomer, was obtained in 98-99% ee at approximately 50 % conversion11181. In a similar way the (S)-cyanohydrin was afforded from racemic 2-methyl-2-hydroxyhexanenitrile with P. amygdalus HNL in more than 90%... 

Asymmetric hydroacylation via kinetic resolution is achieved with racemic 2-methvl-2-phenyl-4-pentenal to give 15-50% (—)-(S )-2-methyl-2-phenyl-l-cyclopentanone with up to 69% ee at lower conversion rates, 5-7s. A complex of the type RhClL2 [L2 = (5,5)-2,3-bis(diphenylphos-phino)butane, Chiraphos]77 is used. The unreacted aldehyde shows an equally high enantiomeric excess of the less reactive -enantiomer. 

Double kinetic resolution. Davies et at.2 have noted that the enantiomeric selectivity of Sharplcss asymmetric epoxidation of an allylic alcohol can be enhanced in some cases by use of two kinetic resolutions. Thus epoxidation of the allylic alcohol 1 with (+)-DiPT as the chiral component (58% conversion) provides the epoxide 2 and the less reactive enantiomer (R) of I, which can be recovered and epoxidized with (—)-DiPT. Using this technique, the epoxide 3 was obtained from I in 86% ec. This strategy is... 

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