Synthesis from hydroxyaldehyde

Weber [61,62] has developed in the context of prebiotic chemistry an original pathway for a-aminothioester synthesis [180], which can start from hydroxyaldehydes 30 intermediates in the formose reaction (a likely prebiotic pathway to carbohydrates). Obviously, thioesters themselves are not observed as products because of their fast hydrolysis in the medium, but they could be converted into peptide bonds in the presence of amino acids or peptide free amino groups, and into mixed anhydride with phosphoric acid in the presence of inorganic phosphate. The reaction involves two key-steps the condensation of ammonia and of the mercaptan on a-keto aldehyde 31... 

This is a simple example for a macrolide synthesis from an to-hydroxyaldehyde andylideH. 

In these oxidations the use of hydrated CUSO4 is mandatory. In fact, it was found that addition of catalytic amounts of water to the solid oxidant creates a more reactive oxidant for the synthesis of lactones from hydroxyaldehydes (eq lO). Small quantities of aqueous t-butanol added to the solid oxidant permit the direct conversion of alkenes to a-hydroxy ketones anda-cUketones (eq 11). Normally, alkenes are inert to the solid oxidant. These differences are attributed to the formation of a thin aqueous... 

C=N, C=S, C=C, and N N containing substrates. Thus oxa2oles, imidazoles, thiazoles, p rrroles, and 1,2,4-triazoles have been prepared, respectively. Furthermore, p-tolylsulfonylmethyl isocyanide has found use in a one-step conversion of ketones into cyan-idea and in a two-step synthesis of a-hydroxyaldehydes from ketones. ... 

In preparation for scale-up of the strigol synthesis described by Sih (8), efforts were made to improve the yield of some of the seven steps involved in the scheme. Of these steps, nine are satisfactory from the standpoint of yield and experimental conditions. For three of the steps, we have improved the yield and/or experimental conditions such that the yield of (+ )-strigol would be raised to 2.85% overall from citral rather than 1.53% based on Sih s procedure and reported yields. Improvements were developed preparation of a-cyclocitral (III), the oxidation of the hydroxyaldehyde (V) to the ketoacid (VII), and for the preparation of the hydroxybutenolide (XVII). For the remaining five steps, our attempts to change experimental conditions have failed to improve, and in most cases to even obtain, the yields reported in the literature (8). We have considered the preparation of strigol analogs and determined the conditions and limitations for the preparation of a series of alkoxybutenolides (XVI) and a butenolide dimer (XVIII). Modification of the literature procedure (11) to eliminate the use of the mesylate (XX) and the use of polar aprotic solvents gave better yields of the 2-RAS (XXI). 

Several enzymatic procedures have been developed for the synthesis of carbohydrates from acyclic precursors. Aldolases appear to be useful catalysts for the construction of sugars through asymmeteric C-C bond formation. 2-deoxy-KDO, 2-deoxy-2-fluoro-KDO, 9-0-acetyl sialic acid and several unusual sugars were prepared by a combined chemical and enzymatic approach. Alcohol dehydrogenases and lipases have been used in the preparation of chiral furans, hydroxyaldehydes, and glycerol acetonide which are useful as building blocks in carbohydrate synthesis. 

It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R = Me) is allowed to react with the enantiopure )-hydroxyaldehyde 341 or alternatively the corresponding y-lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14 1. Surprisingly, approximately 9% of the iyw,iyw-diastereomer 344 resulted when the starting (ii)-crotyl carbamate was contaminated by the (Z)-isomer. The reasons which apply here are unknown. Extra base has to be used in order to neutrafize the free hydroxy group. The pure awft, awfi-product 345 was obtained with 85% yield from the reaction of the (W-oxy-substituted titanate rac-334b and lactol 340. 345 is an intermediate in the asymmetric synthesis of tylosine . ... 

The diamine (99) was applied 117) to the synthesis of chiral a-hydroxyaldehydes. Thus, treatment of the aminal (100), prepared from the chiral diamine (99) and phenylglyoxal, with the Grignard reagent affords the hydroxyaminal, which in turn was hydrolyzed to yield a-alkyl-a-hydroxyphenylacetaldehyde (101). The chiral auxiliary was recovered ll7). 

The ready availability of the transketolase (TK E.C. 2.2.1.1) from E. coli within the research collaboration in G. A. Sprenger s group suggested the joint development of an improved synthesis of D-xylulose 5-phosphate 19, which was expensive but required routinely for activity measurements [27]. In vivo, transketolase catalyzes the stereospecific transfer of a hydroxyacetyl nucleophile between various sugar phosphates in the presence of a thiamine diphosphate cofactor and divalent cations, and the C2 donor component 19 offers superior kinetic constants. For synthetic purposes, the enzyme is generally attractive for its high asymmetric induction at the newly formed chiral center and high kinetic enantioselectivity for 2-hydroxyaldehydes, as well as its broad substrate tolerance for aldehyde acceptors [28]. 

A convenient asymmetric synthesis of a-hydroxyaldehydes begins with the addition of a Grignard reagent to the methoxycarbonyl aminal (238) prepared from methyl hydroxy-methoxyacetate and diamine (236) (79CL705). Treatment of the derived keto aminal (239) with a second Grignard reagent and hydrolysis of the resulting hydroxy aminal (240) yields the optically active a-hydroxyaldehyde (241). Enantiomeric excesses vary between 78 and... 

As mentioned in the introduction, the synthesis of low molecular N202-chelates as Co(sa-len) (6) is rather easy when starting from salicylaldehyde, diamines and a metal salt. For the polymer synthesis only bifunctional o-hydroxyaldehydes must be used. The limiting factor for practical use of polymers may be the price of the bifunctional monomer. The difficulty in preparation is to get a structurally pure polymer and to reach quantitative metallization. 

The transketolase (TK EC 2.2.1.1) catalyzes the reversible transfer of a hydroxy-acetyl fragment from a ketose to an aldehyde [42]. A notable feature for applications in asymmetric synthesis is that it only accepts the o-enantiomer of 2-hydroxyaldehydes with effective kinetic resolution [117, 118] and adds the nucleophile stereospecifically to the re-face of the acceptor. In effect, this allows to control the stereochemistry of two adjacent stereogenic centers in the generation of (3S,4R)-configurated ketoses by starting from racemic aldehydes thus this provides products stereochemically equivalent to those obtained by FruA catalysis. The natural donor component can be replaced by hydroxy-pyruvate from which the reactive intermediate is formed by a spontaneous decarboxylation, which for preparative purposes renders the overall addition to aldehydic substrates essentially irreversible [42]. 

The first synthesis of arabino-configured cyclic phosphonomethylphosphin-ates (397) has been accomplished. The crucial step of this synthesis consisted in the condensation of H-phosphinylphosphonate (398) with hydroxyaldehyde (399) derived from D-arabinol derivative followed by cyclization of (398) induced under acylation conditions (Scheme 98). 

Fessner et al.[256] developed an efficient method for the synthesis of L-fucose analogs modified at the nonpolar terminus by means of L-fucose isomerase and l-fuculose 1-phosphate aldolase from E. coli. Various L-fucose analogs bearing linear or branched aliphatic side chains were prepared in about 30% overall yield with hydroxyaldehyde precursors and dihydroxyacetone phosphate as the starting materials (Fig. 17-32). 

The diamine (R=Ph) was also applied to the synthesis of optically active a-hydroxyaldehydes. Treatment of the aminal, prepared from the chiral diamine and phenylglyoxal, with Grignard... 

Fitzsimmons and Fraser-Reid (1979) described an enantiospecific synthesis of ( + )- and (-)-chrysanthemdicarbonic acid from the same starting material. The pyranosid 19, used as a a chiralic synthon, yielded on treatment with the propionate 20 the cyclopropane 21. This was converted to the hydroxyaldehyde 22a which could be epimerised to 22b with sodium methoxide. As a result of several further steps, (+ )-chrysanthemdicarbonic acid (23a) has been obtained from 22a and (- )-chrysanthemdicarbonic acid (23b) from 22b, as shown in Scheme 1.2. 

The hydroxyaldehyde (13) hs-as used by Biichi as an intermediate in his synthesis of the natural product nuciferal (14), The tertiary alcohol is the obvious place to disconnect and disconnection (a) seve s the ring from the chain (guideline 2), Fragment (15) will be easy to make but fragment (16) is outside our experience. The alternative disconnection (b) gives two recognisable fragments—a Friedel-Crafts product (17) and a compound (18) of type (12). 

Recently, improved procedures have been developed [17] for the synthesis of the phosphonium bromide 30. Addition of the hydroxyaldehyde 29 to NBS/dimethylsulphide in CH2CI2 at -20°C provided (all- )-8-bromo-2,7-dimethylocta-2,4,6-trienal (31) in 86% yield. Reaction of 31 with triphenylphosphine in ethyl acetate furnished the phosphonium bromide 30 in 88% yield. In most applications carried out so far, the phosphonium salts 30 and 32 (prepared from 33 and 31) have been transformed to the corresponding dimethylacetals 27 and 28, prior to their use in Wittig condensations. However, protection of the aldehyde function of 30 is not always necessary [17]. Direct Wittig reaction between 30 and 34 afforded the Ci6-ketoaldehyde 35 in 43% yield. 

---