Aldehydes ester reduction

McFADYEN - STEVENS Ester Reduction Reduction of esters to aldehyde via hydrazides. 

Alcohols are among the most versatile of all organic compounds. They occur widely in nature, are important industrial 7, and have an unusually rich chemistry. The most widely used methods of alcohol synthesis start with carbonyl compounds. Aldehydes, ketones, esters, and carboxylic acids are reduced by reaction with LiAlH4. Aldehydes, esters, and carboxylic acids yield primary alcohols (RCH2OH) on reduction ketones yield secondary alcohols (R2CHOH). 

The mechanism of ester (and lactone) reduction is similar to that of acid chloride reduction in that a hydride ion first adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde. Further reduction of the aldehyde gives the primary alcohol. 

Because the olefin geometry in compound 9 will most certainly have a bearing on the stereochemical outcome of the hydroboration step, a reliable process for the construction of the trans trisubsti-tuted olefin in 9 must be identified. A priori, the powerful and predictable Wittig reaction28 could be used to construct E u, [3-unsaturated ester 10 from aldehyde 11. Reduction of the ethoxycarbonyl grouping in 10, followed by benzylation of the resulting primary alcohol, would then complete the synthesis of 9. Aldehyde 11 is a known substance that can be prepared from 2-furylacetonitrile (12). 

The strategy for the construction of 13 from aldehyde 16 with two units of phosphonate 15 is summarized in Scheme 12. As expected, aldehyde 16 condenses smoothly with the anion derived from 15 to give, as the major product, the corresponding E,E,E-tri-ene ester. Reduction of the latter substance to the corresponding primary alcohol with Dibal-H, followed by oxidation with MnC>2, then furnishes aldehyde 60 in 86 % overall yield. Reiteration of this tactic and a simple deprotection step completes the synthesis of the desired intermediate 13 in good overall yield and with excellent stereoselectivity. 

Aldehydes and ketones can be converted to ethers by treatment with an alcohol and triethylsilane in the presence of a strong acid or by hydrogenation in alcoholic acid in the presence of platinum oxide. The process can formally be regarded as addition of ROH to give a hemiacetal RR C(OH)OR", followed by reduction of the OH. In this respect, it is similar to 16-14. In a similar reaction, ketones can be converted to carboxylic esters (reductive acylation of ketones) by treatment with an acyl chloride and triphenyltin hydride. " ... 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Hydrolysis of 20 with the aid of butanol followed by syn-selective reduction of jS-keto ester 21 and protection as the isopropylidene acetal was accomplished in 87% yield. L1A1H4 reduction and TBS protection of the primary alcohol gave 22 in very good yields. In this strategy, the furan residue serves as an aldehyde synthon and ozonolysis followed by esterification gave the corresponding methyl ester. Reduction and consecutive oxidation established aldehyde 23 in 71% yield. 

Usually alcohols accompany aldehydes in reductions with lithium aluminum hydride [1104] or sodium bis 2-methoxyethoxy)aluminum hydride [544], or in hydrogenolytic cleavage of trifluoroacetylated amines [7772]. Thus terr-butyl ester of. -(. -trifluoroacetylprolyl)leucine was cleaved on treatment with sodium borohydride in ethanol to rerr-butyl ester of A7-prolylleucine (92% yield) and trifluoroethanol [7772]. During catalytic hydrogenations over copper chromite, alcohols sometimes accompany amines that are the main products [7775]. 

Aldol products do not have to come from an aldol condensation. In another example of catalysis by a small organic molecule, Jeffrey Bode of UC Santa Barbara reports (J- Am. Chem. Soc. 2004,126, 8126) that the thioazolium salt 7 effects the rearrangement of an epoxy aldehyde such as 6 to the aldol product 8. This is a net oxidation of the aldehyde, and reduction of the epoxide. As epoxy aldehydes such as 6 are readily available by Sharpless asymmetric epoxidation, this should be a general route to enantiomerically-aldol products. The rearrangement also works with an aziridine aldehyde such as 9, to give the ff-amino ester 10. 

Preparation of the Aldehyde 2 The absolute configuration of the iriene aldehyde 2 was set by Noyori hydrogenation of ethyl butyrylacetate S. Silylation and Dibal reduction then gave the aldehyde 6. Reduction of the homologated ester gave the alcohol, which was oxidized to the desired aldehyde 7 by the Swem procedure. Condensation of 7 with the Wollenberg stannyl diene followed by deprotection then gave the unstable aldehyde 2. 

Mercedes Amat and Joan Bosch of the University of Barcelona have been exploring (Cltem. Commun. 2005, 1327) a kinetic resolution route to piperidines. Condensation of a ketone or aldehyde ester such as 7 with an enantiomerically-pure amino alcohol such as 8 with proceeds with high (15 1) diastereoselectivity, to give 9. Reduction of 9 then delivers the piperidine 10 in high enantiomeric excess. 

Selective reduction. NaHTe reduces a./J-unsaturated ketones, aldehydes, esters, and lactones at room temperature to the corresponding saturated carbonyl compounds in high yield. It is not satisfactory for reduction of enediones. 

Table 3 Preparation of N -Protected Amino Aldehydes by Reduction of Ester and Amide Derivatives n o...

Preparation of a Boc-Protected a-Amino Aldehyde via Reduction of the Corresponding Phenyl Ester General Procedure 12 1... 

N-Methylated y-amino-p-hydroxy acids are accessible by the usual synthetic sequences, i.e. aldol condensation or y-amino-P-oxo ester reduction, starting from the corresponding N-methylated a-amino acids, but are obtained with low diastereoselectivity. 61-63 Alternatively, Brown allylboration of the ALBoc-ALMe amino aldehyde 16 (R1 = Bzl, X=Boc, Y = Me) gives the allyhc N-methylated intermediate 27 in 64% yield and 90% de (Scheme 12). 64 Oxidative cleavage of the alkenol is performed using the two-step ozonolysis and sodium chlorite oxidation sequence. 

Alternative methods for the synthesis of peptide aldehydes include reduction of acid halides, phenyl esters, thioesters, and anhydrides prepared from corresponding acids, isoxazolidides, and the hydrolysis of thiazolidine peptides 17,54-56 Enzymes such as thermolysin, subtilisin, and pronase E have proven valuable as effective semisynthetic alternatives 40,57 5 62 ... 

Overall yield, including reduction of the intermediate g-substituted aldehyde esters and lactonization. 

In dissolving-metal ester reduction, the ester carbonyl is believed to accept an electron to form a radical oxyanion 37 (Scheme 12.12). Chelation with a lithium counterion then ensues to produce a tertiary radical 38 which then captures a second electron to become a carbanion. Protonation of 39 next yields 40, whose fate is to collapse to aldehyde 41. Another multiple electron transfer/protonation sequence subsequently yields the product alcohol 46. 

Functional Group Transformation Alcohols can be prepared by nucleophilic substitution of alkyl halides, hydrolysis of esters, reduction of carboxylic acids or esters, reduction of aldehydes or ketones, electrophilic addition of alkenes, hydroboration of alkenes, or substitution of ethers. 

Acid chlorides are more reactive than other acid derivatives, and they are reduced to aldehydes by mild reducing agents such as lithium tri-ferf-butoxyaluminum hydride. Diisobutylaluminum hydride (DIBAL-H) reduces esters to aldehydes at low temperatures, and it also reduces nitriles to aldehydes. These reductions were covered in Sections 18-9,18-10, and 20-13. 

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