Resin-Supported Aldehydes

Yan, B Li, W. Rapid Fluorescence Determination of the Absolute Amount of Aldehyde and Ketone Groups on Resin Supports, J. Org. Chem. 1997,62, 9354. 

Resin-supported benzocyclobutenol 597 provides a solid phase source of of/fo-quinoncdimethidc 598, which undergoes hDA reactions with aldehydes to afford 1,3-disubstituted isochromans 599, treatment of which with a Lewis acid liberates isochromans 600 with excellent 1,3-anti selectivity (Scheme 128, Table 28) <1998SL1381>. 

Another aminomethyl PS resin supported o-nitrobenzyl photolabile hnker 1.23 (80) has been employed for the synthesis of heterocycles such as thiazohdinones. Attachment to the resin is through an acid or aldehyde group and photolytic cleavage is performed in 5% dimethyl sulfoxide (DMSO)-aqueous buffer to facilitate the biological testing of the final compound. A photolabile hydroxyl linker 1.24 (81), again supported on aminomethyl PS resin, has been used to synthesize carbohydrate and peptide derivatives in SP. The easily prepared diol linker 1.25 (82) allowed the attachment of aldehydes as acetals and their photo induced release using standard conditions. 

The one-pot three-component reaction of polyethylene glycol-supported acrylate 623 with aldehydes 621 and hydrazines 622 in the presence of chloramine-T followed by methanolysis afforded pyrazolines 624 in good yields and high purities (Scheme 77) <2003SL1467>. 1,3-Dipolar cycloaddition of resin-supported acrylic acid 625 with the nitrilimines generated in situ by oxidation of the aldehyde phenylhydrazones with (diacetoxy)iodobenzene under microwave irradiation gave 626, which was converted into l-phenyl-3-substituted-2-pyrazolinyl-5-carboxylates 627 (Scheme 78) <2004SC3521>. 

The most common C-X fragments are imines, which can be readily obtained from a polymeric support aldehyde by many high-yielding methods [281, 282, 283]. Dor-wald et al. reported Wang resin-supported 3-enaminoamides [284]. Yamazaki generated enamines from support-bound phosphonoesters [148]. Imines serve as starting materials for [2 -r 2]-cycloadditions, [2 -i- 3]-dipolar cycloadditions, and het-ero Diels-Alder reactions (HD). 

A novel route for the synthesis of piperazin-2-ones on a solid support relies on an intramolecular Mitsunobu reaction [111]. First, commercially available amino alcohols are attached to an aldehyde resin by reductive ami-nation. The alcohol function is protected and the secondary amine obtained is acylated with an amino add. Sulfonamide activation of the free amino group allows intramolecular alkylation through a Mitsunobu reaction, and thereby the formation of a derivatized ring. 

Reductive alkylation of RAM resin 7c using aldehydes or ketones provides a route to resin-bound secondary amines that is an alternative to the reductive amination of aldehyde resins discussed in Section III. After acylation, secondary amides can be cleaved from the support using TFA-CH2CI2 (1 19) [284]. Ileductive alkylation of the Knorr resin by aldehydes has also been reported. The products were further alkylated and the resulting tertiary amines could be cleaved directly from the support using TFA-CH2CI2 (1 1) [285]. 

In 2009, Kudo and coworkers investigated the asymmetric Michael-type addition of N-methylated and unsubstituted indoles to a,(3-unsaturated aldehydes by resin-supported polypeptides. In an initial survey of several amphiphilic polyethyleneglycol-grafted crosslinked polystyrene-supported catalysts, organocatalyst 22, which adopts a p-turn conformation aided by the polyleucine moiety under aqueous conditions, was revealed as the ideal catalyst for the preparation of a series of Michael adducts that were, in a final... 

Scheme 13.15 1,4-conjugate addition of indoles to a,p-unsaturated aldehydes catalysed by resin-supported pol) eptide 22. 

The application of resin-supported peptides for the asymmetric Michael addition was further investigated by the group of Kudo for the preparation of p-substituted y-lactones via addition of boronic acids to y-hydroxy-a,p-un-saturated aldehydes followed by an additional oxidation step. Intense screening of resin-supported peptide catalysts gave the desired intermediate lactols in moderate to excellent yield and enantioselectivity. ROESY and CD spectra of related peptides indicated that both the p-turn as well as a partial helicily of the peptide are important for the high enantioselectivity of the catalyst. 

In 2012, Kudo and coworkers examined the construction of all-carbon quaternary stereocentres via an asymmetric Michael addition, catalysed by resin-supported polypeptide 23. Using a,p-unsaturated aldehydes, comprising a short-chained allq l group in the p-position, and nitromethane as the Michael donor, a series of quaternaiy-carbon containing Michael adducts were synthesised with moderate to good yield (Scheme 13.16) The substitution pattern of the substrates has a vanishingly low impact on the enantioselectivity which was, in all cases, excellent. A further application of... 

The application of resin-supported polypeptide 23 was, in succeeding reports, further expanded to consecutive 1,6- and 1,4-addition of thiols to a,p,y,5-unsaturated aldehydes towards dithioadducts. When benzoic acid is used as additive at low temperatures the desired dithio-adducts are obtained with excellent conversion and diastereoselectivity and moderate to good enantiomeric excesses. ... 

The oxidation of alcohols to the corresponding aldehydes or ketones is an important reaaion in organic synthesis. " This reaction can be catalyzed under aerobic conditions and the alcohol conversion can be monitored by gas chromatography (GC). It is important to note that water is almost the only solvent currently deemed suitable for the industrial application of this catalytic process, because it avoids the hazards associated with the use of oxidizable organic solvents under oxygen pressure. Recently, Uozumi et have reported the aerobic oxidation in water of various alcohols by using amphiphilic PS-PEG resin-supported Pt NPs as catalyst. Biffs et have studied the catalytic activity of microgel-stabilized Au nanoclusters in the aerobic oxidation of benzylic and aliphatic alcohols in water under mild conditions (50-70 °C, 1-3 atm O2). 

P-Melhyl substituted cinnamaldehydes have been reduced under aqueous media employing a resin-supported N-terminal prolyl peptide having a P-tum motif and a hydrophobic polyleucine chain [22]. The reaction, which is performed in a mixture of THF and water (1/2) at rt, allows the preparation of chiral aldehydes with high enantioselectivities (93-96%) employing a 20 mol% of catalyst 10 and 1.2 equivalents of ester 4 in aqueous media at rt (Scheme 2.4). 

FIGURE 14.7. Resin-supported Jprgensen-Hayashi s and MacMillan s catalysts in the a-selenylation of aldehydes. 

The synthesis of a novel Merrifield resin-supported dipeptide Pro-Ala-O-P, derived from proline and alanine, was reported by Wang and Yan with the aim of being used as an organocatalyst in asymmetric aldol reactions of ketones with aldehydes. " Indeed, this supported dipeptide was found to be an efficient catalyst to promote the asymmetric aldol reaction under neat conditions between aromatic aldehydes and cyclic ketones, generating the corresponding aldol products with moderate to high yields and diastereoselectivities of up to 80% de combined with good enantioselectivities of up to 95% ee, as shown in Scheme 2.18. Moreover, this catalyst could be used for seven times with only a minor decrease in product yields, but maintained stereoselectivities. 

Scheme 2.18 Aldolisations of ketones with aldehydes catalysed by Merrifield resin-supported dipeptide.

Knoevenagel condensation reaction between a Wang resin-supported ethylmalonate and hydroxyaiyl aldehydes (Figure 14.4). ... 

Yan, B., Sun, Q., Wareing, J.R. and Jewell, C.R, Real-time monitoring of the catalytic oxidation of alcohols to aldehydes and ketones on resin support by single-bead Fourier Transform Infrared Microspectroscopy, J. Org. Chem., 61 (1996) 8765-8770. 

The enantio- and diastereoselective epoxidation of a,P-unsaturated aldehydes in aqueous media was also performed by using the poly-leucine resin supported peptide catalyst developed by Kudo [45]. It was that the novel terminal sequence D-Pro-Ach-[Ala(l-Pyn)]3 possessing a highly hydrophobic and bulky aromatic ring was particularly effective (Scheme 5.13). 

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