Ketols, isomerization

Figure 10.26 Short enzymatic synthesis of L-fucose and hydrophobic analogs, and of L-rhamnose, by aldolization-ketol isomerization, including kinetic resolution of racemic hydroxyaldehyde precursors.

Fig. 2.2.S.3 Structure of rhamnose isomerase, and proposed hydride-shift mechanism for the ketol isomerization.

Scheme 2.2.5.13 Tandem conversions based on ketol transfer/ketol isomerization.

Being restricted to DHAP as the nucleophile, aldol additions will only generate ketoses and derivatives from which aldose isomers may be obtained by biocatalytic ketol isomerization (cf. Sect. 7.1) [306]. For a more direct entry to aldoses the inversion strategy may be followed (Scheme 19) [290] which utilizes monoprotected dialdehydes. After aldolization and stereoselective chemical or enzymatic ketone reduction, the remaining masked aldehyde function is deprotected to provide the free aldose. Further examples of the directed, stereodivergent synthesis of sugars and related compounds such as aza- or thiosugars are collected in Sect. 7. 

D-Aldoses are thus converted into D-ketoses. The reaction is analogous to the ketol isomerization described on page 1061. 

Short syntheses of L-fucose analogues have been achieved (3 enzymatic steps) by aldol condensation of DHAP with various a-hydroxyaldehyde derivatives (using L-fuculose phosphate aldolase), followed by phosphate hydrolysis (alkaline phosphatase) and subsequent ketol isomerization (L-fucose isomerase). Selective C-labelling of thymidine in all positions of the 2 -deoxyribose ring has been achieved using an aldolase-catalysed reaction with appropriately C-labelled DHAP/acetaldehyde substrates. The labelled sugar was then converted... 

Stereospecific diversification of aldol products by ketol isomerization or carbonyl reduction. 

The scope and synthetic usefulness of reactions catalyzed by DHAP aldolases may be further illustrated by exemplary syntheses of some interesting compounds that comprise functionalities and skeletons of a different nature. Aldol additions of 22 will typically generate ketose derivatives from which aldose isomers may be obtained by biocatalytic ketol isomerization [130]. For an alternative entry to aldoses, the inversion strategy [131] utilizes monoprotected dialdehydes for adolization which, after stereoselective ketone reduction, provide free aldoses from deprotection of the masked aldehyde function. 

Rate and equilibrium constants have been determined for the aldol condensation of a, a ,a -trifluoroacetophenone (34) and acetone, and the subsequent dehydration of the ketol (35) to the cis- and fraw -isomeric enones (36a) and (36b)." Hydration of the acetophenone, and the hydrate acting as an acid, were allowed for. Both steps of the aldol reaction had previously been subjected to Marcus analyses," and a prediction that the rate constant for the aldol addition step would be 10" times faster than that for acetophenone itself is borne out. The isomeric enones are found to equilibrate in base more rapidly than they hydrate back to the ketol, consistent with interconversion via the enolate of the ketol (37), which loses hydroxide faster than it can protonate at carbon. 

Diaryl-2-hydroxypropiophenones (607) are obtained from 4-hydroxychalcone and a reactive phenol on treatment with alkaline hydrogen peroxide in an epoxide-mediated coupling reaction. The ketones undergo a base-catalyzed a-ketol rearrangement to the isomeric l-hydroxypropan-2-ones (608) and acid-catalyzed ring closure provides a route to 4-arylflavan-3-ones (Scheme 231) (80JCS(Pl)1025). 

The first results which indicate that stereoelectronic effects play an important role in the aldol condensation were reported by Hajos and Parrish (6) who found that (a) triketone J8 cyclizes to the bicyclo[3.2.1]octane ketol on treatment with piperidinium acetate in water and (b) ketol 19 undergoes an epimerization at C-4 yielding the more stable isomeric ketol 20 on treatment with piperidine. The authors concluded that the formation of ketol 19 from 18 under kinetically controlled conditions is the result of... 

Indeed in the transition state leading to ketol 19 (cf. 21), the enolate double-bond is oriented anti peri planar to the carbonyl group. This stereochemical approach must therefore be electronically favored over that leading to the isomeric ketol 20. In the last case, the carbonyl group of the side chain is gauche (synclinal) with the enolate double-bond (cf. 22). 

While examples of intermolecular electrophilic additions to 7t-deficient heterocycles are reported less frequently than with -excessive heterocycles, intramolecular electrophilic cyclization strategies can be used to access some heterocycles of interest. In some cases, different reaction conditions can afford isomeric heterocycles as exemplified in the cyclization of 1,2-diaryl ketols with 2-amino-pyrazoles. With hydrogen chloride in the reaction media, pyrrolo[2,3-c]pyrazoles (170) are obtained, whereas imidazo[l,2-6]pyrazoles (171) were obtained in the absence of hydrogen chloride (Scheme 29) <84JHC945>. Cycloacylation of the a-(thiazolylthio)acetic acid (172) was accomplished with phosphorus oxychloride to give thiazole (173) (Equation (50)) <56AC(R)275>. 

Lewis acids readily isomerize both 1,3-dioxolanes and 1,3-oxathiolanes in ether solution. The reaction proceeds by coordination with the oxygen atom in the latter case since 1,3-dithiolanes do not isomerize under the same conditions. With trityl carbonium ion, an oxidative cleavage reaction takes place as shown in Scheme 6. Hydride extraction from the 4-position of 2,2-disubstituted 1,3-dioxolanes leads to an a-ketol in a preparatively useful reaction. 1,3-Oxathiolanes are reported to undergo similar cleavage but no mention of products other than regeneration of the ketone has been made (71CC861). Cationic polymerization of 1,3-dioxolane has been initiated by a wide variety of proton acids, Lewis acids and complex catalytic systems. The exact mechanism of the polymerization is still the subject of controversy, as is the structure of the polymer itself. It is unclear if polymerization... 

The a-ketol rearrangement65 is an isomerization reaction of a-hydroxy ketones (as well as aldehydes) which takes place under acid as well as base catalysis. Compound 11/71, a 17 a-hydroxy-20-ketosteroid, yields, under acid catalysis, the six-membered isomer 11/72, and under base catalysis, the mixture of the isomeric compounds 11/73, as reviewed in [1],... 

The hydrogen atom is always stereospecifically introduced by the enzyme, so that, at a methylene group, only one of the two hydrogen atoms becomes labeled. Thus, D-glucose 6-phosphate ketol isomerase (E.C. 5.3.1.9) incorporates only one deuterium atom from deuterium oxide,33 or one tritium atom34 from water-1, giving D-fructose-1 (R)-t 6-phosphate (11). The isomeric D-fructose-l(S)-f 6-phosphate (12) can be obtained from D-glucose-l-t in water,35 or,... 

Ironically, until 1953, Nazarov incorrectly described the mechanism of the general transformation which now bears his name. In 1952, Braude and Coles were the first to suggest the intermediacy of car-bocations and demonstrated that the formation of 2-cyclopentenones actually proceeds via the a,a -divi-nyl ketones (equation 1). This fact together with further mechanistic clarification, has led to the specific definition of the Nazarov cyclization as the acid-catalyzed closure of divinyl ketones to 2-cyclopentenones. This process was already documented in 1903 by Vorliinder who isolated a ketol of unknown structure by treatment of dibenzylideneacetone with concentrated sulfuric acid and acetic acid followed by mild alkaline hydrolysis (equation 2). The correct structure of Vorliinder s ketol, finally proposed in 1955, ° arises from Nazarov cyclization followed by oxidation and isomerization. Other examples of acid-catalyzed cyclizations of divinyl ketones exist in the early literature. ... 

Active metals readily cleave a-ketols and a-ketol acetates. Reductions can be carried out with the aid of lithium, barium or calcium in ammonia, or with zinc or tin, which are usually used in acidic media. Zinc is a relatively mild reducing agent and is therefore somewhat selective. Axial steroidal ketol acetates are reduced more readily than equatorial (equations 16 and 17). On the other hand, metal-ammonia systems are powerful reductants thus, calcium and barium reduce axial and equatorial isomeric ketol acetates with equal ease. Lithium is a more powerful reductant and frequently overreduces a-ketols... 

The remaining two alkaloids in this group, mersingines A (243a) and B (243b), also from Kopsia teoi (188,189), are regarded as artifacts, the consequence of using ammonia in the extraction process. They are presumably derived from kopsinitarines B (240) and C (241), via ammonolysis of the isomeric a-ketols. 

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