D-Threo-isomer

Brenner et al.333 studied the isomerization of ascorbic acids. Epimerization at C-4 occurs in boiling 50% aqueous methanol containing potassium hydroxide, and an approximately equal mixture of epimers was obtained after 16-24 h. The rare l-erythro- and d-threo isomers of ascorbic acid were isolated as solids by fractional recrystallization of epimerized mixtures... 

A more-direct method of preparation is oxidation of aldoses, and optimal yields are afforded by the action of cupric acetate in methanol or ethanol.417 This method is suitable for large-scale preparation of intermediates however, a pure product is obtained only by chromatographic separation from the unreacted sugar byproducts. The synthesis of D-eryt/wo-pentos-2-ulose and its D-threo isomer by oxidation of D-arabinose and D-xylose, respectively, with cupric acetate followed by anion-exchange chromatography has been reported.418 The only product obtained by oxidation of D-glucose with sodium 2-anthraquinonesulfonate in alkaline... 

Out of four possible isomers (1-4) only the D-threo isomer (1) is active. The activity of the remaining isomers is about 1 %. 

In the case of the D-threo isomer 110, nitronate 111 was isolated under the same conditions, while 3-nitroglycal 112 was isolated under conditions that included treatment with KF in the presence of 18-crown-6-ether (O Scheme 37). 

It has been observed that the biological activity resides almost exclusively in the D-Threo-isomer whereas the j-Threo, and D- and Y,-Erythro isomers are virtually inactive. 

Nucleosides. Nucleotides, and Derivatives.- 2, 3 ,5 -Trl-0 -acetyl-adenosine and -guanosine, 4- -ethyl-thymidlne, N -methyl-2 -deoxyadenoslne, 5-raethoxymethyl-2 -deoxy-urldlne and its 0-D-threo-isomer, 5-fluoroarablnosylcytoslne, the 2 -deoxynucleo-side (17), cls-thymldine 3 ,5 -cyclic methyl phosphonate and the corresponding 3, 5 -cycllc N,N-dlmethylphosphoramldate,a cobalt(II) complex with 2 -deoxyinosine 5 -monophosphate,... 

Although decomposition of (134) does give cyclopropane, the major product of reaction is believed to be the a-D-threo-isomer of (135), which results from radical... 

Scheme 4). The L-erythro-. D-erythro-. L-threo- and D-threo-isomers (6), present as a complex mixture of hemiacetals, were formed in a combined yield of 40-60% in the ratio 33 30 21 16. This was determined after reduction to the corresponding tetritols as mentioned in Chapter 18. ... 

Dihydroxy-D-eo i o-norvaIine (as its lactone 34) and its D-threo-isomer 37 were synthesized by stereospecific hydrogenation of butenolides 33 and 36, available from D-ribono-1,4-lactone via the known deiivates 32 and 35 (Schemes 7 and 8), respectively. ... 

This indicated that retention had taken place. Note that both products are optically inactive and so caimot be told apart by differences in rotation. The meso and d/ dibromides have different boiling points and indexes of refraction and were identified by these properties. Even more convincing evidence was that either of the two threo isomers alone gave not just one of the enantiomeric dibromides, but the dl pair. The reason for this is that the intermediate present after the attack by the neighboring group (17) is symmetrical, so the external nucleophile Br can attack... 

Jackman, Hamilton, and Lawlor have studied the stereochemistry of the addition of [Co(CN)5D] to a,/3-unsaturated acids and identified the product of the addition of fumarate as the threo isomer, i.e., adduct formation has occurred by a stereospecific cis addition of Co—D across the double bond 94). 

Dideoxy-2-fluoro- 3-D-co r/zrc>-pentofuranosyl)adenine (877) was prepared from the 5 -(9-protected precursors (876) by treatment with DAST (CH2CI2 82% yield) or with BU4NF for the corresponding 2 -triflate. The corresponding threo isomer (879) was obtained by deoxygenation at... 

Methyl oxetane-2-carboxylate derivatives (e.g., 284), obtained by ring contraction of aldonolactones, have been employed for the synthesis (279) of the nucleoside / -noroxetanocin [9-(/ -D-eryt/iro-oxetanosyl)adenine, 304] and its a-anomer via an a-chloride obtained by a modified Hunsdiecker reaction. Displacement of chloride by adenine and debenzylation gave 304. The threo isomer of304, /J-epinoroxetanocin (305), was likewise synthesized from D-lyxono-1,4-lactone. The oxetane nucleosides display potent antiviral activity against the human immunodeficiency virus (HIV). 

A very elegant synthetic approach was reported a year later by Davies et al., leveraging asymmetric C-H activation chemistry to accomplish a one-pot synthesis of d-threo methyiphenidate (Scheme 17.10) (Davies et al., 1999). A-Boc piperidine (33) was selectively alkylated by the carbene formed by decomposition of diazoester 34 in a reaction mediated by 25 mol% of chiral Rh (II) catalyst 35, giving the A-Boc protected (2R,2 R) isomer in a single step. TFA was added to accomplish removal of the Boc group after the C-H insertion reaction was complete, affording (R,R)-methylphenidate (2) with an ee of 86% in 52% overall yield. 

Methylphenidate possesses two asymmetric carbon moieties, giving rise to four optical isomers d-threo, /-threo, d-erythro, and /-erythro (Patrick et ah, 1987). There is stereoselectivity in receptor site binding and its relationship to response. The standard preparation is comprised of the threo racemate as it appears to be the central nervous system (CNS) active form (Patrick et ah, 1987 Hubbard et ah, 1989). In addition, in rats, the d-methylphenidate isomer shows greater reuptake inhibition of DA and NE than the /-isomer (Patrick et ah, 1987). D-Methylphenidate is now available under the brand name Focalin. 

Ester enolates replace bromide from a-bromo boronic esters with remarkable diastereoselcctiv-ity. (Dibromomethyl)lithium is generated by addition of lithium diisopropylamide to dibro-momethane in the presence of a boronic ester at — 78 "C to produce an a-bromo boronic ester. Reaction of the a-bromo boronic ester with lithium 1-tert-butoxy-Tpropen-l-olate yields a product that is almost exclusively the threo-isomer (d.r. = 15 1 to 60 1), as shown by conversion to the / -hydroxy carboxylic ester24. It is worth noting the facility with which a-bromo boronic esters racemize in the presence of halide ions72. 

The (S)-leucine derivative (215) was allowed to react with diene (216) to afford the threo isomer (217) as the major product (d.s. = 80%) 213). Mukaiyama et al. 215) have reported the total synthesis of the sesquiterpene (-l-)-farnesiferol, starting from (R)-phenylglycinol, a derivative of the amino acid (R)-phenylglcine. They key step of this synthesis was an asymmetric Diels-Alder reaction. 

Because the positions of the H and D on C-3 in the threo isomer are opposite that in the erythro, the deuterium content of cis- and /ra .v-2-butcnc would be reversed. //m.v-2-Butene obtained from the threo isomer would contain deuterium, and d.v-2-butcnc would not. 1-Butene obtained from the threo isomer would also contain deuterium. 

FDP A was employed in a study of pancratistatin analogs to catalyze the formation of the D-threo stereochemistry (Scheme 5.24). When rhamnulose 1-phosphate aldolase (Rha 1-PA) was used the L-threo stereoisomer was obtained with excellent selectivity. Thus these two enzymes allow the stereoselective synthesis of the two threo-stereoisomers [44]. They were also utilised successfully for the synthesis of different diastereoisomers of sialyl Lewis X mimetics as se-lectin inhibitors. Not only the two threo-selective aldolases RAMA and Rha 1-PA, but also the D-erythro-selective Fuc 1-PA was employed. In this way it was possible to synthesise three of the four diastereoisomers enantioselectively (Scheme 5.25). The L-erythro stereochemistry as the only remaining diastereo-isomer was not prepared [45]. This is because the aldolase that might catalyze its formation, TDP A, is not very stereoselective and therefore often yields mixtures of diastereoisomers. 

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