Alcohols as substrate

An interesting way to control the stereoselectivity of metathesis-reactions is by intramolecular H-bonding between the chlorine ligands at the Ru-centre and an OH-moiety in the substrate [167]. With this concept and enantiomerically enriched allylic alcohols as substrates, the use of an achiral Ru-NHC complex can result in high diastereoselectivities like in the ROCM of 111-112 (Scheme 3.18). If non-H-bonding substrates are used, the selectivity not only decreases but proceeds in the opposite sense (product 113 and 114). 

Various methylenetetrahydrofurans were accessible by a combination of a Zn-promoted Michael addition and a cyclization using alkylidenemalonates and pro-pargyl alcohol as substrates, as reported by Nakamura and coworkers [108]. Tetrasubstituted pyridines of type 2-189 have been obtained through a solvent-free InCl3-promoted domino process of 2-187 and 2-188 (Scheme 2.44) [109]. 

Diastereoselective hydrogenations of this type have been reported by Burgess and coworkers [54—59] using chiral-protected and -unprotected allylic and homo allylic alcohols as substrates with their carbene catalyst lr(9). Catalyst control was found to be dominant, but depending on the position and nature of the oxygen substituents, moderate to strong match/ mismatch effects were observed. 

In an earlier report, Maitlis et al. showed that 1 could be easily converted into a hydrido complex [Cp lrHCl]2 (2) under ambient conditions by treatment with alcohol and a weak base (Scheme 5.1) [19], probably accompanied by the formation of carbonyl compounds. This fact means that the hydrogen atom in an alcohol can be rapidly transferred to the iridium center in the form of a hydride but then, if the hydride on the iridium could be re-transferred to another hydrogen acceptor, a new catalytic system using alcohols as substrates might be realized. In fact, a wide variety of Cp Ir complex-catalyzed hydrogen transfer systems using alcohols as substrates, and based on the above hypothesis, have been reported to date [20]. 

Ir-catalyzed allylic substitutions employing allylic alcohols as substrates and diethyl malonate as pronucleophile were first reported by Takeuchi and coworkers [11]. Here, the substitution step was found to be preceded by OH activation via transesterification to a malonic ester derivative. The asymmetric alkylation of cinnamic alcohol was similarly accomplished by Helmchen and colleagues, using a PHOX ligand and the procedure described in Section 9.2.3 [19]. 

An entirely different approach has been developed by Carreira and coworkers [57], who used sulfamic acid as the ammonia source. In conjunction with dimethyl formamide (DMF), amination occurred via an imidate, which was formed in situ. Although only those examples with branched allyUc alcohols as substrates were reported, a promising enantiomeric excess was achieved with the novel phosphora-midite L9 (Scheme 9.24). 

Bovine aldose reductase Inhibited by ahphatic, cychc and aromatic oximes, using benzyl alcohol as substrate 123... 

Enzyme Properties. The two isolated veratryl alcohol oxidases had very similar properties (Table I). The difference in isoelectric points might be accounted for by aspartate content all other amino acid contents except glycine were the same within experimental error (5%). The specific activities (veratryl alcohol as substrate) were significantly different, but both enzymes contained a flavin prosthetic group (25) and converted one molecule of oxygen to one molecule of hydrogen peroxide during alcohol oxidation. 

Several crystal structures of the enzyme in the presence of the coenzyme and substrate or substrate analogues have served as important indicators of the role of the coenzyme in the enzymic reaction. A crystal structure of the enzyme in the presence of NAD+ and p-bromobenzyl alcohol as substrate revealed that the oxygen of the alcohol is directly bound to the catalytic zinc, thus putting the carbon 1 of the alcohol 3.5 A from carbon 4 of the nicotinamide ring the substrate is thus positioned ideally for direct transfer of hydrogen. The position of the alcohol is close to where the water molecule is bound in the free enzyme, but it was not possible to establish whether this had been displaced on binding of the substrate.1364... 

AO Activity in Strain YR-1 with Various Alcohols as Substrates in Experiments of Mycelium Transfer"... 

The reason for the increased regioselectivity is that with tertiary alcohols as substrates there is no longer exclusively kinetic control. This is because the regioisomeric olefins are no longer formed irreversibly. Instead they can be reprotonated, deprotonated again, and thereby finally equilibrated. In this way, the greatest part of the initially formed Hofmann product is converted to the more stable Saytzeff isomer. Product formation is thus... 

A Pd-catalyzed oxidative cyclization of phenols with oxygen as stoichiometric oxidant in the noncoordinating solvent toluene has been developed for the synthesis of dihydrobenzo[ ]furans (Equation 136). Asymmetric variants of this Wacker-type cyclization have been reported by Hayashi and co-workers employing cationic palladium/2,2 -bis(oxazolin-2-yl)-l,l -binaphthyl (boxax) complexes <1998JOC5071>. Stoltz and co-workers have reported ee s of up to 90% when (—)-sparteine is used as a chiral base instead of pyridine <2003AGE2892, 2005JA17778>. Attempts to effect such a heteroatom cyclization with primary alcohols as substrates, on the other hand, led to product mixtures contaminated with aldehydes and alkene isomers, which is in contrast to the reactions with the Pd(ii)/02 system in DMSO <1995TL7749>. 

Two transformations require special note because of their very high potential in organic synthesis. First, the use of allylic alcohols as substrates has been shown to result in /3-hydride elimination toward the OH group, and the resulting enol tautomerizes to the aldehyde. This overall conversion, illustrated for 2-methaUyl alcohol and 1-bromobutene, opens a new strategy for the synthesis of carbonyl-containing compounds, and is equivalent (with very different selectivities)... 

Looking at the mechanism we have written, we recognize the reaction for what it is nucleophilic substitution, with the protonated alcohol as substrate and... 

Ether formation by dehydration is an example of nucleophilic substitution with the protonated alcohol as substrate and a second molecule of alcohol as nucleophile. 

Likewise, once the initial screening of ADHs was performed, we took a closer look at the catalytic properties of the new ADH. We selected two secondary alcohols as substrates for the enzymatic oxidation and measured the rate of NADH formation for both enantiomers individually, so the enantiodiscrimination of the enzyme could be estimated. While this is not a true enantioselectivity value since the competition factor between enantiomers has been eliminated by making separate reactions for each isomer instead of the racemic mixture, it gives an estimate and allows a quick identification of highly selective enzymes. Table 5 shows the results of this screening. Most of the enzymes found were selective for the S-alcohol isomer, except AD99, which shows reversed selectivity towards the 7 -alcohol. 

It should be emphasized that one major advantage of diastereoseleclive methods using allylic alcohols as substrates is their availability in cnantiomerically pure or enriched form (c.g., kinetic resolution by Sharpless oxidation, see Section D.4.5.). 

Experimental thermodynamic information on these ions was obtained by DPA using chlorides and alcohols as substrates. Treatment of the experimental data by... 

This mechanism in which reactant coenzyme may leak from the ternary complex was first suggested for liver alcohol dehydrogenase to reconcile the results of initial rate studies with primary and secondary alcohols as substrates and isotope exchange experiments (39), and it has also been proposed for yeast alcohol dehydrogenase (40) and a-glycero-phosphate dehydrogenase from rabbit muscle ( l). 

The kinetics with all the substrates and isotope exchange studies are consistent with the preferred pathway mechanism described in Section II,B,4. With secondary alcohols, hydride transfer is slow, the steady-state concentration of the reactant ternary complex is large, and leak of NAD from this complex occurs thus, < a = Ak- /kki (Table I) and is different for different alcohols. With primary alcohols as substrates, hydride transfer and aldehyde dissociation are much faster than NADH dissociation. Under initial rate conditions, therefore, the ternary complex is not present in significant steady-state concentration, and dissociation of NAD from it does not occur to an appreciable extent thus, 4> = 1/ki, and like < o is the same for all primary alcohols. 

---