Acetals thermodynamic control

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

A cursory inspection of key intermediate 8 (see Scheme 1) reveals that it possesses both vicinal and remote stereochemical relationships. To cope with the stereochemical challenge posed by this intermediate and to enhance overall efficiency, a convergent approach featuring the union of optically active intermediates 18 and 19 was adopted. Scheme 5a illustrates the synthesis of intermediate 18. Thus, oxidative cleavage of the trisubstituted olefin of (/ )-citronellic acid benzyl ester (28) with ozone, followed by oxidative workup with Jones reagent, affords a carboxylic acid which can be oxidatively decarboxylated to 29 with lead tetraacetate and copper(n) acetate. Saponification of the benzyl ester in 29 with potassium hydroxide provides an unsaturated carboxylic acid which undergoes smooth conversion to trans iodolactone 30 on treatment with iodine in acetonitrile at -15 °C (89% yield from 29).24 The diastereoselectivity of the thermodynamically controlled iodolacto-nization reaction is approximately 20 1 in favor of the more stable trans iodolactone 30. 

The Pummerer reaction346 of conformationally rigid 4-aryl-substituted thiane oxides with acetic anhydride was either stereoselective or stereospecific, and the rearrangement is mainly intermolecular, while the rate-determining step appears to be the E2 1,2-elimination of acetic acid from the acetoxysulfonium intermediates formed in the initial acetylation of the sulfoxide. The thermodynamically controlled product is the axial acetoxy isomer, while the kinetically controlled product is the equatorial isomer that is preferentially formed due to the facile access of the acetate to the equatorial position347. The overall mechanism is illustrated in equation 129. 

The use of the enolsilyl ether of 1-menthone [16, 19, 21-23] and of some free triflic acid favors the formation of the thermodynamically controlled products as with free 2,2 -dihydroxydiphenyl [22] and only subsequently added HMDS 2 [22]. On reacting silylated alcohols and carbonyl compounds with pure trimethylsilyl triflate 20 under strictly anhydrous conditions no conversion to acetals is observed [24]. Apparently, only addition of minor amounts of humidity to hydrolyze TMSOTf 20 to the much stronger free triflic acid and hexamethyldisiloxane 7 or addition of traces of free triflic acid [18-21, 24, 26] or HCIO4 [25] leads to formation of acetals. 

It has therefore been established170 from the product distributions that, while the oxymercuration is reversible, unless a base (e.g. sodium acetate) is added to the reaction medium, and gives almost exclusively the more stable compound 199, the aminomercu-ration takes place to give the kinetically controlled adduct 200, or under thermodynamic control the aminomercurial 201. Reactions are kinetically controlled when the mercurating species is a mercury(II) salt deriving from a weak acid such as mercury(II) acetate. Conversely, they are thermodynamically controlled with the covalent mercury(II) chloride. In the latter case, the presence of a strong acid in the medium allows the thermodynamically controlled product to be obtained. 

It has been demonstrated that organotin-mediated multiple carbohydrate esterifications can be controlled by the acytaring reagent and the solvent polarity. When acetyl chloride is used, the reactions are under thermodynamic control, whereas when acetic anhydride is employed, kinetic control takes place. Very good selectivity can furthermore be obtained in more polar solvents. These results can be used in the efficient preparation of prototype carbohydrate structures. 

Treatment of em/ -2-methylbicyclo[3.2.0]heptan-<3.x n-2-ol with 0.25 M sulfuric acid in acetic acid, followed by reduction of the resulting acetate with lithium aluminum hydride, gave l-methylbicyclo[2.2.1]heptan-7-ol (10) in almost quantitative yield and with greater than 95% purity.10 The virtually exclusive formation of the norbornane derivative under thermodynamic control is commensurate with the lower strain energy of the bicyclo[2.2.1]heptane skeleton (62.8 kJ mol ), as compared to that of bicyclo[3.2.0]heptane (138.2 kJ mol- l.10... 

Important in this quite general strategy is that, for practically all instances, die reaction is under thermodynamic control, and the control of the stoichiometry is extremely difficult It follows that only the more stable acetals are produced (see Sec. H.B) and usually multiacetals are obtained if several hydroxyl groups are available within die same molecule. This has been a major concern in acetalation reactions in neutral conditions. For instance, use of copper(II)sulfate either in acetone alone or in N, N-dunethylformamide without any additional catalyst leads to acetals with structures that differ from those resulting from reactions in the presence of an acid The reaction depends on the temperature [31] however, the strict neutrality of a medium in which copper(II)sulfate and polyols are interacting can be questioned. 

The major mechanistic and structural aspect of the acetalation process is its orientation toward derivatives obtained either under thermodynamically controlled conditions or under kinetically controlled conditions. We will not discuss here all structural factors concerning the relative stabilities of acyclic and cyclic acetals of polyols and monosaccharides, because such a discussion has been extensively reviewed and adequately commented on [8,10,12 -14]. However, it is important to focus here on the main consequences of these relative stabilities in relation to the various experimental conditions to orientate the choice of specific conditions, particularly for the most important monosaccharides (D-glucose, D-mannose, and D-galactose). 

Electron-withdrawing fluorine atoms are introduced on the methylenic a-carbon by the Reformatsky reaction of Boc-leucinal with ethyl bromodifluoroacetate in the presence of activated zinc dust with no diastereoselection. Under thermodynamic control, the y -isomer is obtained almost exclusively (Scheme 16)J15 The use of additives such as diethylaluminium chloride-silver(II) acetate enhances the chemical yield of the reaction, but also presents the disadvantage of being nonstereoselectiveJ78 ... 

Benzoylation of benzoylmethylene triphenylarsorane (20) with benzoyl bromide gave a kinetically controlled acylated product, which on treatment with sodium acetate in chloroform afforded thermodynamically controlled dibenzoylmethylene triphenylarsorane (21) (56). Acylation with carbonic acid anhydride (32, 56), phenylisocyanate (32), or chloroformic ester (32) gave in no case O-acylated product. Similarly, reaction with acetic anhydride afforded l,3-dioxo-l-phenyl-butylidene-(2)-triphenylar-sorane (56). 

In one of the first papers on the subject, Billups et al. (80SC147) reported that the Pd(0)-catalyzed allylation of indole 96 with allyl acetate gave N-allyl- (97) and 3-allylindole (98) plus the diallylation product 99 (Scheme 21). They also showed that the yV-allyl isomer 97 rearranged under Pd(0) catalysis to the C-3 isomer 98, thus indicating that the formation of 98 was thermodynamically controlled (C > N). The work of Billups also includes the use of allyl alcohol instead of allyl acetate in the Tsuji-Trost reaction. 

Bronsted acid (Scheme 2.42) [26-28]. (For experimental details see Chapter 14.9.4). These catalysts mediate the addition of ketones to nitroalkenes at room temperature in the presence of a weak acid co-catalyst, such as benzoic acid or n-butyric acid or acetic acid. The acid additive allows double alkylation to be avoided, and also increases the reaction kinetic. The Jacobsen catalyst 24 showed better enantio- and diastereoselectivity with higher n-alkyl-ethyl ketones or with branched substrates (66 = 86-99% dr = 6/1 to 15/1), and forms preferentially the anti isomer (Scheme 2.42). The selectivity is the consequence of the preferred Z-enamine formation in the transition state the catalyst also activates the acceptor, and orientates in the space. The regioselectively of the alkylation of non-symmetric ketones is the consequence of this orientation. Whilst with small substrates the regioselectivity of the alkylation follows similar patterns (as described in the preceding section), leading to products of thermodynamic control, this selectivity can also be biased by steric factors. 

Figure 9.19 shows a biacetalization of a pentaol. There, the existence of thermodynamic control leads to the preferential production of one, namely A, of three possible bis(six-mem-bered ring acetals)—A, B, and C. In the presence of catalytic amounts of />-toluenesulfonic acid, the pentaol from Figure 9.19 is converted into the bisacetal in acetone as the solvent but by a reaction with the dimethylacetal of acetone. From the point of view of the dimethyl-acetal, this reaction is therefore a transacetalization. Each of the two transacetalizations involved—remember that a bisacetal is produced—takes place as a succession of two SN1 reactions at the acetal carbon of the dimethylacetal. Each time the nucleophile is an OH group of the pentaol. 

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