Other Classes of Substrates

Benzvlic Grignard reagents and halides have been discussed previously (Sections 2.4.1.1 and 2.4.21. For eilher. low yields and homo-coupling are frequently (hut not always) encountered, and an SHT mechanism (or possibly unintentionally catalyzed side reactions) may be involved. 

---

In summary, the research effort aimed towards active, chemoselective hydrogenations of certain C=0 and C=N bonds have delivered several catalysts that approach the level of activity required for use in the synthesis of alcohols and amines. However, other classes of substrate require considerable additional investigations to be conducted before homogeneous catalysts may be considered for this purpose. 

H-bond interactions between the catalyst and substrate were suggested by Campbell to explain why his N-(4/-pyridinyl)-a-methylproline-derived catalysts 16 and 17 (Fig. 8.4) are more enantioselective for N-acylated 1,2-amino alcohols (s = 9-18.8) than for other classes of substrate [95-98]. Recently, Ishihara has designed the histidine derivative 34 as a minimal artificial acylase for the KR of mono-protected cis- 1,2-diols and N-acylated 1,2-amino alcohols [135]. This catalyst incorporates a sulfonamide linkage specifically to allow the NH group to engage as a H-bond donor with the substrates, and gives impressive levels of selectivity with a range of appropriate substrates (Scheme 8.16). 

The MTO/H202 system has been used to oxidize several other classes of substrates. Internal alkynes may be oxidized to a-diketones and/or carboxylic acids, whereas terminal alkynes are oxidized to mixtures of carboxylic acids, -ketoacids, and (in alcoholic solvents) esters.49 These conversions are proposed to proceed through an oxirene intermediate by analogy to the alkene epoxidations discussed earlier. 

As a result of the many advantages of the allyl p-ketoesters, we were able to quickly prepare a large number of substrates and demonstrate that the reaction gave yields and enantioselectivities equivalent to the other classes of substrates (Table 9). Additionally, we were able to access a number of products that we had not been able to access previously, such as enantioenriched tertiary fluorides, vinylogous esters and thioesters, nitrogen heterocycles, and compounds containing multiple quaternary stereocenters. These advances comprised the bulk of our secmid paper in the field [25]. 

The influence of the 0-alkyl chain of ester substrates needs to be evaluated carefully, since in some cases longer chains are tolerated (such as in the case of n-butyl and n-hexyl citraconates) but with other classes of substrates only methylesters are accepted (such as the a-haloesters). 

The kinetically deduced existence of two classes of substrate sites may also account for the molar ratio between ATP analogs and inhibitors on the one hand and phosphoenzyme on the other hand. This ratio has been reported to be 2 1 for the ATP analogs adenylyl imido diphosphate (AMP-PNP) [135] and 2, 3 -0-(2,4,6-trinitrophenylcyclohexadienylidine)-ATP (TNP-ATP) [97], and also 2 1 for the ATP-site directed fluorescent inhibitors eosin [99] and FITC [49,50] and the transition-state inhibitor vanadate [126]. 

In Other classes of organic halides, for example perfluoroalkyl and vinyl halides, the distinction between stepwise and concerted electron-transfer-bond-breaking upon reduction by outer sphere heterogeneous and/or homogeneous electron donors is less unambiguous than in the case of aryl and alkyl halides. As discussed in Section 3, they also present the interest of being active substrates in Sg l reactions. 

Electronic effects seem to have very little influence on the overall enantioselectivity with both electron-donating and- withdrawing groups giving very small changes to the enantioselectivity when all other variables were the same. Substrate geometry seems to play a much more influential role with this particular class of substrates. 

As one of the most reactive groups of carboxylic acid derivatives, acyl halides are very useful substrates for the preparation of the other classes of derivatives. For example, anhydrides may be synthesized by the reaction of carboxylic acid salts with an acyl halide. In this reaction, the carboxylate anion acts as the nucleophile, eventually displacing the halide leaving group. 

The enantioselective lithiation of anisolechromium tricarbonyl was used by Schmalz and Schellhaas in a route towards the natural product (+)-ptilocaulin . In situ hthi-ation and silylation of 410 with ent-h M gave ewf-411 in an optimized 91% ee (reaction carried ont at — 100°C over 10 min, see Scheme 169). A second, substrate-directed lithiation with BuLi alone, formation of the copper derivative and a quench with crotyl bromide gave 420. The planar chirality and reactivity of the chromium complex was then exploited in a nucleophilic addition of dithiane, which generated ptilocaulin precnrsor 421 (Scheme 172). The stereochemistry of componnd 421 has also been used to direct dearomatizing additions, yielding other classes of enones. ... 

The values of the standard rate constants vary considerably along the series of disulfides, the logk°i,et going from —0.80 for the nitro to —4.36 for the methoxy derivatives. Again, as observed for the other class of disulfides, most of them are unusually low for substrates undergoing a stepwise mechanism. By using the Eyring equation (4), the values of the intrinsic barriers AG, reported in Table 12 were obtained. 

The other classes of flavoproteins in table 10.2 interact with molecular oxygen either as the electron-acceptor substrates in redox reactions catalyzed by oxidases or as the substrate sources of oxygen atoms for oxygenases. Molecular oxygen also serves as an electron acceptor and source of oxygen for metalloflavoproteins and dioxygenases, which are not listed in the table. These enzymes catalyze more complex reactions, involving catalytic redox components, such as metal ions and metal-sulfur clusters in addition to flavin coenzymes. 

---