Aldehydes precursors

The general approach has been followed for the de novo synthesis of a multitude of differently substituted, unsaturated [112,113] or regiospedfically labeled sugars [102,114]. Unusual branched-chain (42), (43)) and spiro-annulated sugars (45), (46)) have been synthesized from the corresponding aldehyde precursors... 

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

A biochemically related benzaldehyde lyase (BAL) (EC 4.1.2.38) catalyzes the same carboligation reactions, but with opposite (J )-selectivity (mf-110) [178]. All these enzymes seem to display a rather useful substrate tolerance for variously substituted aldehyde precursors. 

The hydrazine-aldehyde reaction has been used intracellularly to deliver non-toxic drug components, which when linked to form a hydrazone bond in situ, become cytotoxic (Rideout, 1986, 1994 Rideout et al., 1990). This same approach has been used to generate enzyme inhibitors in vivo, wherein the hydrazine and aldehyde precursors are not active, but when coupled together within cells to form a hydrazone linkage, become active site binders (Rotenberg etal, 1991). 

Attempted preparation of the aldehyde precursor of the five-membered ether product through oxidation of the corresponding alcohol led not to the aldehyde, but instead the cyclic ether itself (Eq. 9.104). Evidently the cyclization reaction is facile in this case. 

Honomer Selection. In practice the amide/blocked aldehyde precursor 1 (ADDA) proved more readily accessible than 2. The two forms were completely Interconvertible and equally useful as self-and substrate reactive crosslinkers (6). In our addition polymer systems, the acrylamide derivative 1 (R=CH3) provided a good blend of accessibility, physical properties, and ready copolymerizablllty with most commercially Important monomers. Structure/property relationships for other related monomers will be reported elsewhere. 

An alternative approach consisted of the use of an alcohol as aldehyde precursor since aldehydes are less stable (prone to overoxidation, polymerization or formation... 

It is worthy to note that four of the eight possible diastereomeric pyrrolidine-polyols are accessible by this method. The configuration at C(l) (nitrile oxide part) depends on the enantiomeric aldehyde precursor chosen. The 5-epimers were obtained as a separable 1 1 mixture and were derived from the nonselective cycloaddition (see Section 6.2.3.4). 

Scheme 2.2.5.12 Short enzymatic synthesis of L-fucose and hydrophobic analogues by aldolization-ketol isomerization, including kinetic resolution of racemic aldehyde precursors.

The reaction of a 1,3-dithiolane (336) with n-butyllithium has been shown to result in fragmentation to the corresponding thiocarbonyl compound via the mechanism detailed in Scheme 73 (80JA3S77). The thiocarbonyl compound can react further with excess lithium reagent to provide the product of carbon addition (aldehyde precursors) or reduction (saturated ketones). 

The aldehyde precursor, with the co-alkene derived from lyxose (42.0 mg, 0.12 mmol) was drawn into a syringe with a solution of 1 mL of THF-methanol (3 1 v/v) and added dropwise to a cooled solution ( 78°C) of Sml2 (3.6 mL, 0.1 M in THF), over 5 min. The solution was kept at —78°C for 1 h. When the reaction was complete, as indicated by TLC analysis, it was quenched with aqueous saturated sodium bicarbonate solution (1 mL) and extracted with ether. Chromatography using 50 50 ether-hexane gave 31.0 mg (73%) of pure syn-cyclic alcohol. 

Solid-phase schemes have also been used for the synthesis of the K2K and di-K2K dendrons.1 L2X These dendrons can be further modified with electrophiles and nucleophiles. N-Terminal Ser, which can be readily converted into an aldehyde at neutral pH in an aqueous condition, has been used by Spetzler and Tam[89l as a convenient masked aldehyde precursor. The solid-phase synthesis of aldehyde K2K dendrons by Fmoc chemistry is illustrated in Scheme 7. 

Azomethine imine cycloadditions provide access to pyrazolidines, pyrazolines and pyrazoles. Intramolecular cyclizations were first reported in 1970.78 The main method for generation of azomethine im-ines involves reaction of a 1,2-disubstituted hydrazine with an aldehyde or an aldehyde precursor. 

Mechanistic work has been done on reduction of all three aldehyde oximes 45 the products of macroscale reduction are the picolylamines (Scheme 16).66 These amines are more conveniently made from the nitrile at present because the aldehyde precursor is difficult to make. 

Depending upon the pH compound 166 exhibits a ring-chain tautom-erism, and ring-closed form could be used as a masked aldehyde precursor (07PNA10780,08JOC734, 08USA2008/0138292). 

The required aldehyde precursor 186 was obtained by a Sn(II)-catalyzed asymmetric aldol reaction [90]. It was then mixed in one pot with o-methoxy aniline 187 and enol ether 188 to afford the key /7-amino ketone 189 in a 2 1 diastereomeric ratio through a Mannich-type three-component reaction. This reaction was performed in an aqueous medium and the use of a surfactant such as dodecyl sulfate (DS) was essential. The diastereomeric mixture 189 was treated with HF and the... 

A primary alcohol and amines can be used as an aldehyde precursor, because it can be oxidized by transfer hydrogenation. For example, the reaction of benzyl alcohol with excess olefin afforded the corresponding ketone in good yield in the presence of Rh complex and 2-amino-4-picoline [18]. Similarly, primary amines, which were transformed into imines by dehydrogenation, were also employed as a substrate instead of aldehydes [19]. Although various terminal olefins, alkynes [20], and even dienes [21] have been commonly used as a reaction partner in hydroiminoacylation reactions, internal olefins were ineffective. Recently, methyl sulfide-substituted aldehydes were successfully applied to the intermolecu-lar hydroacylation reaction [22], Also in the intramolecular hydroacylation, extension of substrates such as cyclopropane-substituted 4-enal [23], 4-alkynal [24], and 4,6-dienal [25] has been developed (Table 1). 

Tin-free photolytic conditions for addition of formyl radical equivalents to 3a have been reported by Alonso [53]. Photolysis of 1,3-dioxolane solutions of 3a in the presence of 1 equiv of benzophenone led to formation of the l,3-dioxalan-2-yl radical from solvent, followed by intermolecular radical addition in 87% yield (entry 6). A one-pot variant without isolation of 3a increased the yield and selectivity (entry 7). These conditions gave good yields across a range of chiral /V-acylhydrazones (not shown), but synthetically useful levels were restricted to aliphatic aldehyde precursors. 

These compounds have been obtained130 by nucleophilic substitution (equation 60) with [18F]F" on the corresponding activated aromatic nitro aldehyde precursors, followed by decarbonylation (equation 60a) proceeding usually in 84 5% yields131-134. 

Preparation of enantiometrically pure aldehyde substrates for DHAP-dependent aldolase reactions has been accomplished by a combination of enzymatic and chemical methods. The lipase-catalyzed resolution of racemic aldehyde precursors has been accomplished by enantioselective acetate hydrolysis, as exhibited in the preparation of enantiomerically pure R- and S -glycidaldehyde acetals (Scheme 5.10).31 Regioselective ring opening of the epoxides, followed by acetal hydrolysis, generated the aldehydes in enantiomerically pure form. 

Starting from the chiral pool (/f-(+)-hmonene), the total synthesis of natural (-f)-3,4-epoxycembrene A (56) has been achieved by Liu et al. with the low-valent titanium-mediated intramolecular pinacol couphng of the corresponding sec-keto aldehyde precursor 171 (Scheme 6-25). A more general and efficient enantioselective synthesis of (+)-3,4-epoxy-cembrene A (56) with a chiral pool protocol and Sharpless asymmetric epoxidation for the introduction of three chiral centers has also been reported by the same authors in 2001 (Scheme 6-26). ... 

General Discussion. Aldol-type condensation of the magnesium enolate of (R)-(+)-phenyl (p-toluenesulfinyl)acetate, prepared with f-butylmagnesium bromide, with the aldehyde precursor of maytansine afforded, after desulfurization with Aluminum Amalgam, the desired 4,5-unsaturated 3-(5)-hydroxy ester in high yield and high diastereoselectivity (eq 3). ... 

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