Acyloin compounds

The mechanism involved in the formation of maltol (XXXIX) from the streptose residue of streptomycin, a mechanism which also applies to 5-hydroxystreptose, has been outlined by Lemieux and Wolfrom.1 An alternative theory has been suggested63 this is based on the supposed formation of an intermediate acyloin compound, as shown by the following formulas. However, this theory is unacceptable since one of the require-... 

The reason why the acyloin synthesis is especially characteristic of aromatic aldehydes, depends on the circumstance that in the aromatic series the tertiary carbon atom in the ring does not allow of the aldol condensation, a reaction for which conditions are otherwise much more favourable. The simplest example of the acyloin condensation, moreover, was already encountered in the case of formaldehyde (p. 218) glycollic aldehyde is the simplest acyloin. Acyloin compounds are also produced, in the aliphatic series, by the action of sodium or potassium on esters, and hence are also formed as by-products in the acetoacetic ester synthesis (Bouveault, Scheibler). 

Since one secondary alcohol is adjacent to a gem-dimethyl unit, it might be possible to selectively oxidize the less hindered OH to the acyloin (compound 13) without all those steps ... 

Aromatic a-diketones can be prepared from the acyloin compounds however, aliphatic diketones cannot be prepared by this method. The reaction proceeds well in complex systems without epimerization of adjacent stereocenters, as in the yohimbine example (eq 15). This method compares favorably with that of dimethyl sulfoxide-dicyclohexylcarbodiimide. 

The ability of benzoylformate decarboxylase to form an acyloin compound when incubated with benzoylformate and acetaldehyde was demonstrated for the first time with P. putida [89]. Cells of P. putida were transferred a minimum of four times at 24 h intervals in the liquid medium of Hegeman [83,85], containing 3 g/L ammonium mandelate in order to maximize induction of the synthesis of enzymes participating in mandelate catabolism. The cells were then harvested by centrifugation, washed with 50 mM sodium phosphate buffer (pH 6.0), and the pellets were stored frozen until required. Whole cells were used to catalyze acyloin formation or for preparation of cell extracts. 

By further manipulations of substrate concentrations, conditions for quantitative conversion of benzoylformate to 2-hydroxypropiophenone and benzaldehyde were established [90]. In the presence of 100 mM of benzoylformate and 1600 mM acetaldehyde, the biotransformation mixture after a 1-h reaction contained 61.76 mM/L of the acyloin compound and 38.2 mM/L of benzaldehyde. Under the optimized biotransformation conditions, acyloin product formation in 1 h reaction catalyzed by crude extract of 1 g DW of P. putida amounted to 0.617 g. The stereoselectivity of the biotransformation reaction was not improved in these exj riments. 

No studies have been published on the ability of this enzyme to form acyloin compounds. 

The term acjdoin is commonly used as a class name for the symmetrical keto-alcohols RCOCH(OH)R, and the name of the individual compound Is derived by adding the suffix oin to the stem name of the acid to which the acyloin corresponds, e.g., acetoin, propionoin, butyroin, etc. 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

Acyloins are useful starting materials for the preparation of a wide variety of heterocycles (e.g., oxazoles and imidazoles ) and carbocyclic compounds (e.g., phenols ). Acyloins lead to 1,2-diols by reduction, and to 1,2-diketones by mild oxidation. 

Active carbonyl compounds such as benzaldehyde attack the electron-rich double bond in DTDAFs to give a dipolar adduct, which immediately undergoes dissociation with formation of two molecules of 146 (64BSF2857 67LA155).Tlie existence of by-products such as benzoin led to the synthetic application of thiazolium salts in the acyloin condensation. For example, replacement of the classic cyanide ion by 3-benzyl-4-methyl-5(/3-hydroxyethyl) thiazolium salts allowed the benzoin-type condensation to take place in nonaqueous solvents (76AGE639) (Scheme 57). 

A spectacular application of the acyloin ester condensation was the preparation of catenaries like 11. These were prepared by a statistical synthesis which means that an acyloin reaction of the diester 10 has been carried out in the presence of an excess of a large ring compound such as 9, with the hope that some diester molecules would be threaded through a ring, and would then undergo ring closure to give the catena compound ... 

As expected, the yields of catenanes by this approach are low, which is why improved methods for the preparation of such compounds have been developed. The acyloins are often only intermediate products in a multistep synthesis. For example they can be further transformed into olefins by application of the Corey-Winter fragmentation. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

In general, yields of (/ )-acyloins and (2S,3/ )-diols, respectively, are low due to the formation of several byproducts (mainly reduction products of the substrate). Nevertheless, the optically active compounds thus obtained are extremely useful intermediates for the synthesis of many natural products51. 

The present procedure for ring expansion has also been applied to l,2-bis(trimethylsilyloxy)bicyclo[n.l.0]alkanes, which are prepared by cyclopropanation of l,2-bis(silyloxy)cycloalkenes. The latter are readily available from acyloin condensations in the presence of chlorotrimethylsilane. " This reaction provides a new route to cyclic 1,3-diketones and macrocyclic compounds containing two 1,3-diketone units in the ring. 

Spiro compound (18), also containing two fIve-membered rings, can be made by oxidation of the acyloin (19) (Chapter T24). 

This method has an analogy in the well known acyloin condensation, a reaction which takes place between two molecules of an aromatic aldehyde in a solution containing an alkali cyanide. Thus for example, benzaldehyde gives rise to benzoin, a compound in which the enediolic system, —C(OH)=C(OH)—, exists mainly in the ketonic form —CO—CHOH—. If a hydroxy aldehyde like D-glucose (X) is allowed to... 

The so-called acyloin or benzoin condensation is a further interesting aldehyde reaction. In the aromatic series it takes place as a result of the action of potassium cyanide, and it is very probable that the potassium compound of the cyanohydrin is formed as an intermediate pro-... 

The preparative importance of the acyloins depends on the fact that they are intermediate products, from which many 1 2-diketones can be obtained. The simplest aromatic member of this group is benzil (anisil and furil are analogous) like its aliphatic prototype diacetyl CH3.CO.CO.CH3 (and like anhydrous glyoxal) it is yellow in colour. Diacetyl is obtained from methyl-ethyl ketone via the monoxime of the former compound (von Pechmann). It is remarkable that diacetyl condenses to p-xyloquinone. (Formulate). 

Preparation and phytochemical reduction of 2,2 -thenoin and 2,2 -thenil have been studied in the authors laboratory (20a). It has been shown that 2,2 -thenoin gives a color reaction similar to that shown by benzoin and other acyloin condensation products in- the presence of alcoholic alkali. The hydroxy ketone may be oxidized by iodine in the presence of sodium methoxide to give the diketone, 2,2 -thenil, in excellent yields. Phytochemical reduction was shown also to be applicable to both compounds. It is significant that thenoin differs from benzoin, since reduction products were not obtained enzymatically from the latter. 

Probably the most familiar radical reactions leading to 1,2-D systems are the so called acyloin condensation and the different variants of the "pinacol condensation". Both types of condensation involve an electron-transfer from a metal atom to a carbonyl compound (whether an ester or an aldehyde or a ketone) to give a radical anion which either dimerises directly, if the concentration of the species is very high, or more generally it reacts with the starting neutral carbonyl compound and then a second electron is transferred from the metal to the radical dimer species (for an alternative mechanism of the acyloin condensation, see Bloomfield, 1975 [29]). 

Acyloin condensation of diester 30a with sodium in liquid ammonia, followed by direct hydrogenation in the presence of Adam s catalyst, furnished the diol 32 in 49% yield. Diol 32 was transformed into the cyclic thiocarbonyl derivative (80% yield) which after heating with trimethylphosphite [14] afforded twistene 33 in 50% yield. Hydrogenation of 33 gave a compound identical in all respects with twistane 1. From the diester (-)-30a (+)-twistene was obtained, m.p. 35.5-36.5 °C, +... 

Tin was used for reduction of acyloins to ketones [173], of enediones to diketones [174], of quinones [175] and especially of aromatic nitro compounds [176] Procedure 35, p. 214). 

Of trialkyl phosphites the most frequently used is triethyl phosphite (EtO)3P (M.W. 166.16, b.p. 156°, density 0.969) which combines with sulfur in thiiranes [291, 294] and gives alkenes in respectable yields. In addition, it can extrude sulfur from sulfides [295], convert a-diketones to acyloins [296], convert a-keto acids to a-hydroxy acids [297], and reduce nitroso compounds to hydroxylamines [298] Procedure 47, p. 111). 

The study (05ZOR89) showed that thenoines actively react with thiols in acidic media at room temperature to give /1-keto sulfides 250 in good yields. On alkaline hydrolysis, the latter compounds are readily cleaved to ketones 251, which are valuable intermediates for subsequent syntheses. In 06MI2, they were involved in a Fischer reaction and indole- bridged dithienylethenes 252 and 253 were obtained. Hence, a convenient procedure was developed for the transformation of readily available acyloins into photochromic indole-bridged dithienylethenes (Scheme 71). 

---