Aldehyde intermediate

We said in Section 17.4 that carboxylic acids are reduced by L1AIH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which —H replaces -OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition. The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated. 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

In the presence of a long-chain fatty aldehyde, intermediate A (Fig. 2.1) is converted into intermediate B that contains a perox-yhemiacetal of flavin (Macheroux et al., 1993). The apparent Km value of the intermediate B produced with an aldehyde of 10-13 carbon atoms is approximately 200 pM when P. phosphoreum luciferase is used (Watanabe and Nakamura, 1972), and 1-10 pM when P. fischeri luciferase is used (Spudich and Hastings, 1963 Hastings and Nealson, 1977). The decomposition of intermediate B,... 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

Three of the alkaloids (55-57) were isolated from Corydalis incisa (63-65) and two (57, 58) from Hypecoum procumbens (66), where they coexist with the parent protoberberines. They are formed in plants by an oxidative C-6—N bond cleavage, possibly through an aldehyde intermediate 61. This assumption was supported by in vivo experiments in which ( )-tetrahydrocorysamine-8,/4-/2 (59) and (+ )-tetrahydrocoptisine-8,74-/2 (60) were fed to Corydalis incisa (67) to produce corydalic acid methyl ester-8-/ (55) along with corydamine-8-f (58) and corydalic acid methyl ester-8-/ (55) with corynoline-8-/ (62), a benzophenantridine alkaloid, respectively (Scheme 14). 

Hydrocarbon formation involves the removal of one carbon from an acyl-CoA to produce a one carbon shorter hydrocarbon. The mechanism behind this transformation is controversial. It has been suggested that it is either a decarbonylation or a decarboxylation reaction. The decarbonylation reaction involves reduction to an aldehyde intermediate and then decarbonylation to the hydrocarbon and releasing carbon monoxide without the requirement of oxygen or other cofactors [88,89]. In contrast, other work has shown that acyl-CoA is reduced to an aldehyde intermediate and then decarboxylated to the hydrocarbon, releasing carbon dioxide [90]. This reaction requires oxygen and NADPH and is apparently catalyzed by a cytochrome P450 [91]. Whether or not a decarbonylation reaction or a decarboxylation reaction produces hydrocarbons in insects awaits further research on the specific enzymes involved. 

The reaction was most easily monitored by noting the disappearance of the highly uv absorbing unsaturated aldehyde intermediate at Rf = 0.41 (20% ethyl acetate in hexane eluant). 

In this example, we will consider asymmetric hydroformylation to give an aldehyde intermediate with a high ee. Gas Recycle is out of the question because of the low volatility of the product. Vaporization in a Liquid Recycle process is theoretically possible, but impractical if we wish to maintain the high enantioselectivity of the product. 

The enantioenriched sulfoxide intermediate 72 (R = CH2OH), obtained by asymmetric 5-oxidation with a chiral oxaziridine (89 11 enantiomeric ratio), has provided a highly enantioselective synthesis of the benzothiepin derivative 71 (4R, 5R). The aldehyde intermediate 72 (R = CHO) was cyclized asymmetrically to 71 (4R, 5R) with >98 2 enantiomeric ratio. Base treatment (f-BuOK, -10°C, THF) of the racemic benzothiepin 73... 

Biosynthesis is performed in one step by the enzyme L-histidine decarboxylase (HDC, E.C. 4.1.1.22). Histamine metabolism occurs mainly by two pathways. Oxidation is carried out by diamine oxidase (DAO, E.C. 1.4.3.6), leading to imidazole acetic acid (IAA), whereas methyla-tion is effected by histamine N-methyltransferase (HMT, E.C. 2.1.1.8), producing fe/e-methylhistamine (t-MH). IAA can exist as a riboside or ribotide conjugate. t-MH is further metabolized by monoamine oxidase (MAO)-B, producing fe/e-methylimidazole acetic acid (t-MIAA). Note that histamine is a substrate for DAO but not for MAO. Aldehyde intermediates, formed by the oxidation of both histamine and t-MH, are thought to be quickly oxidized to acids under normal circumstances. In the vertebrate CNS, histamine is almost exclusively methylated... 

FIGURE 14-3 Synthesis and metabolism of histamine. Solid lines indicate the pathways for histamine formation and catabolism in brain. Dashed lines show additional pathways that can occur outside the nervous system. HDC, histidine decarboxylase HMT, histamine methyltransferase DAO, diamine oxidase MAO, monoamine oxidase. Aldehyde intermediates, shown in brackets, have been hypothesized but not isolated. 

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

Scheme 25 C-Pyranosyl compounds by reaction of the sugar-aldehyde intermediates equilibrating with the pyranoses.

The isomeric propargylic stannylated aldehyde intermediate, on the other hand, could be prepared from the alcohol precursor without competing cyclization to an seven-membered enol ether product (Eq. 9.105). Treatment of this stannane with SnCl4 afforded the cis-disubstituted tetrahydrofuran stereoselectively. Presumably, this reaction proceeds through an allenyl trichlorostannane intermediate. 

A series of conjugated polyenes capped with chromophores and containing an androstane spacer were synthesized by Wittig or Wittig-type olefinations from epi-androsterone 5150. For example, vinyl carboxaldehyde 52, prepared from 51 in 60% yield as shown in equation 32, was treated with 9-anthrylmethylphosphonium bromide and n-butyllithium to give diene 53. Exocyclic diene 53 was subsequently oxidized to vinyl carboxaldehyde 54. The androsterone vinyl aldehyde intermediate could either be treated with a tetraphenylporphyrinpolyenyl phosphonium ylide, or, as shown below, the phosphonium salt of the androsterone (55) could be reacted with TPP polyeneal 56. The desired all-(E) isomer, 57, was obtained from the ( )/(Z)-isomeric mixture by chromatographic purification. 

Ethyl hexanol, sometimes called 2-ethyl hexyl alcohol, 2-ethyl hex, or more simply 2-EH, is one of the oldest high molecular weight aliphatic alcohols. What does it have in common with NBA Both are made from propylene via the Oxo process, and both have the same aldehyde intermediate— normal butyraldehyde. 

Reduction of the carboxylic acid group passes through the intermediate aldehyde. For a number of examples in the heterocyclic series, the aldehyde becomes a major product because it is trapped as the hydrated vfc.-diol form. Examples include imidazole-2-caiboxylic acid [139], thiazole-2-carboxylic acid [140] and pyridine-4-carboxylic acid [141] reduced in dilute aqueous acid solution. Reduction of imidazole-4-carboxylic acid proceeds to the primary alcohol stage, the aldehyde intermediate is not isolated. Addition of boric acid and sodium sulphite to the electrolyte may allow the aldehyde intermediate to be trapped as a non-reducible complex, Salicylaldehyde had been obtained on a pilot plant scale in this way by... 

These problems were circumvented by protecting the C(4),C(5) diol prior to Wittig olefination step (Figure 3). Thus, treatment of 10b (a mixture of pyranose and furanose anomers prepared by hydrolysis of 8 with aqueous trifluoroacetic acid) with excess EtSH and concentrated HCI (as solvent) at provided dithioacetal 9 in 50% yield, along with 25% of a mixture of thiopyranosides and thiofuranosides that was recycled to 10b in high yield by treatment with HgCIa and CaCOa in aqueous CH3CN. Finally, the diol unit was protected as a cyclohexylidene ketal, and then the thioacetal was hydrolyzed under oxidative conditions to arrive at the key aldehyde intermediate 3. 

Fused cyclic system 340 can be obtained by type (i) reaction through the reduction of the nitro aldehyde intermediate 339 and its sequential cyclization in acetic acid. Alternate type (iii) process starts from the corresponding formamide 341 that can be cyclized with phosphorus oxychloride by a Bischler-Napieralski reaction (Scheme 72 (1994JHC1033)). 

The hydrogenation step following hydroformylation serves two important purposes. It reduces the aldehyde intermediate product to the desired primary alcohol functional group, which is the primary site of reactivity of the polyol with isocyanates. It also reduces the residual olefins in the FAMEs to saturated hydrocarbons, thus eliminating the pathway to Hock degradation and odor development, which is inherent to other processes that leave fatty acid unsaturation in the polyols. This step eliminates the typical vegetable oil odor from the final namral oil polyols of this process. 

Lastly, Corey has developed B LA species 65, derived from zwitterionic oxazaboro-lidine 64 and tri-n-butyltin trifalte, as a novel catalybc system for the enanboselec-bve synthesis of P-lactones from ketene and aldehydes (Scheme 5.81) [152]. The reaction of B LA 65 with ketene generates intermediate A. The subsequent addition of the ketene acetal unit to the coordinated aldehyde (intermediate B) followed by extrusion of the P-lactone completes the catalybc cycle. 

Fig. 2.3 Formation of an aldehyde intermediate with TPAP in the synthesis of irisquinone [95]...

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