Deprotonation stereospecificity

The carbamate 366 can be made from enantiomerically pure alcohol 365 and deprotonated stereospecifically to give organolithium 367, as shown by formation of esters 368 with retention of stereochemistry.53... 

Potassium Amides. The strong, extremely soluble, stable, and nonnucleophilic potassium amide base (42), potassium hexamethyldisilazane [40949-94-8] (KHMDS), KN [Si(CH2]2, pX = 28, has been developed and commercialized. KHMDS, ideal for regio/stereospecific deprotonation and enolization reactions for less acidic compounds, is available in both THF and toluene solutions. It has demonstrated benefits for reactions involving kinetic enolates (43), alkylation and acylation (44), Wittig reaction (45), epoxidation (46), Ireland-Claison rearrangement (47,48), isomerization (49,50), Darzen reaction (51), Dieckmann condensation (52), cyclization (53), chain and ring expansion (54,55), and elimination (56). 

Direct deprotonation/electrophile trapping of simple aziridines is also possible. Treatment of a range of N-Bus-protected terminal aziridines 265 with LTMP in the presence ofMe3SiCl in THF at-78 °C stereospecifically gave trans-a, 3-aziridinylsi-lanes 266 (Scheme 5.67) [96]. By increasing the reaction temperature (to 0 °C) it was also possible to a-silylate a (3-disubstituted aziridine one should note that attempted silylation of the analogous epoxide did not provide any of the desired product [81],... 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

Clear evidence in favor of 6.75 being an intermediate came, however, from stereochemistry. If the indazole cyclization takes place at a chiral carbon atom in the exposition of the alkyl group in 6.78, the stereochemistry of the 3-i/-indazole 6.79 can indicate whether the 5-diazo-6-methylene-l,3-cyclohexadiene 6.75 is an intermediate or whether, on the other hand, deprotonation and cyclization are synchronous. In the first case a racemic indazole 6.79 is expected. In the case of a synchronous reaction, however, a stereospecific product, probably with retention of the chirality at Ca, should be observed. 

Addition of such a-lithiosulfinyl carbanions to aldehydes could proceed with asymmetric induction at the newly formed carbinol functionality. One study of this process, including variation of solvent, reaction temperature, base used for deprotonation, structure of aldehyde, and various metal salts additives (e.g., MgBrj, AlMej, ZnClj, Cul), has shown only about 20-25% asymmetric induction (equation 22) . Another study, however, has been much more successful Solladie and Moine obtain the highly diastereocontrolled aldol-type condensation as shown in equation 23, in which dias-tereomer 24 is the only observed product, isolated in 75% yield This intermediate is then transformed stereospecifically via a sulfoxide-assisted intramolecular 8, 2 process into formylchromene 25, which is a valuable chiron precursor to enantiomerically pure a-Tocopherol (Vitamin E, 26). 

Preparation of all four diastereomers of /3-hydroxydiphenylethyl spirophosphoranes 72 via deprotonation of hydrospirophosphoranes 70 (R = H) with BuLi facilitated a subsequent mechanistic study on stereospecific alkene formation <1997TL7753, 2002CL170>. Three of the diasteromers could be formed by reacting 70 (R = H) with BuLi, followed by treatment with cis or /ra/w-stilbene oxide at room temperature (Scheme 12). 

A second route to nonracemic /-oxygenated allylic stannanes utilizes an enantioselective deprotonation of allylic carbamates by BuLi in the presence of (—)-sparteine. The configurationally stable a-lithio carbamate intermediate undergoes enantioselective S/,-2 reaction with Bu3SnCl and Mc SnCI (Scheme 28)65. Once formed, the /-carbamoyloxy stannanes can be inverted by successive lithiation with. s-BuLi and stannation with R3SnCl (Scheme 29)65. The former reaction proceeds with S/.-2 retention and the latter by Sf2 inversion. Nonracemic allylic carbamates can also be used to prepare chiral stannanes. Deprotonation with. s-BuLi TMEDA proceeds stereospecifically with retention (Scheme 29)65. 

Providing the deprotonation reaction is kinetically controlled, meaning the intermediates 6 and epi-6 do not interconvert (path A), the enantiomeric ratio Hepi-1 (e.r.) of the trapping products reflects the ratio ks/kg. This is exactly true, if the deprotonation is irreversible and if the reactions of both epimers are complete and stereospecific and proceed with identical yields. (—)-Sparteine 11 proved to be a powerful ligand for the... 

Compound 211 and several related compounds are readily accessible by stereospecific deprotonation of the appropriate optically active carbamic esters with 5-BuLi/TMEDA ° . Much of the knowledge about the stereochemical course of substitution in benzyUithium derivatives was obtained from experiments with these compounds. Only the reaction with proton acids, aliphatic aldehydes, ketones or esters as electrophiles proceed with retention for alkyl, silyl and stannyl halides, acid chlorides. 

The bislactim ether method has also been applied to an intramolecular alkylation (84JOC2286) to generate stereospecifically the /3-tum-inducing element, (LL) 3-amino-2 piperidone-6-carboxylic acid as shown in Scheme 62. The efficiency of chiral induction was in the range 99.5%. It is noteworthy that there is no racemization of the intermediate bromo compound, thus proving the regiospecificity of the deprotonation. 

Aldolases have been classified into mechanistically distinct classes according to their mode of donor activation. Class 1 aldolases achieve stereospecific deprotonation via covalent imine/enamine formation at an active-site lysine residue, while Class II aldolases utilize a divalent transition metal cation for substrate coordination as an essential Lewis acid cofactor (usually Zn ) to facilitate deprotonation... 

Mechanistically, the activation of the aldol donor substrates by stereospecific deprotonation is achieved in two different ways (Fig. 1) [43], Class I... 

Typically, because of mechanistic requirements the lyases are highly specific for the nucleophilic donor component. This includes the necessity for a reasonably high substrate affinity as well as the general difficulty of binding and anchoring a rather small molecule in a fashion that restricts solvent access to the carb-anionic site after deprotonation and shields one enantiotopical face of the nucleophile in order to secure correct diastereofacial discrimination (Figs. 2 and 3) [51]. Usually, approach of the aldol acceptor to the enzyme-bound nucleophile occurs stereospecifically following an overall retention mechanism,... 

Hydroxyaldehydes are relatively good acceptors, and the D-isomers are superior to the L-isomers [370]. It is noteworthy that from the reaction with 111 as the donor only a single diastereomeric product (e.g. 126) of absolute (2R,3S) configuration results [370], indicative not only of the high level of asymmetric induction at the newly formed stereogenic center at C-3, but also of a stereospecific deprotonation at C-2 of the donor. 

The degradation of nicotinic acid by Clostridium barkeri involves the cleavage of the intermediate 2,3-dimethylmalate 132 from which propionic and pyruvic acids are formed by a specific lyase (EC 4.1.3.32). In the reverse direction, the enzyme must have the unusual capacity to deprotonate propionic acid at the a-carbon instead of the carboxylic acid function, or next to an anionic car-boxylate. Purified dimethylmalic acid aldolase has been used to catalyze the stereospecific addition of 133 to the oxoacid acceptor, yielding the (2R,3S) configurated dimethylmalic acid 132 at the multi-gram scale [381]. The substrate tolerance of this enzyme has not yet been determined. 

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