Thermodynamic control stereochemistry

The silicon- and sulfur-substituted 9-allyl-9-borabicyclo[3.3.1]nonane 2 is similarly prepared via the hydroboration of l-phenylthio-l-trimethylsilyl-l,2-propadiene with 9-borabicy-clo[3.3.1]nonane36. The stereochemistry indicated for the allylborane is most likely the result of thermodynamic control, since this reagent should be unstable with respect to reversible 1,3-borotropic shifts. Products of the reactions of 2 and aldehydes are easily converted inlo 2-phenylthio-l,3-butadienes via acid- or base-catalyzed Peterson eliminations. 

The stereochemistry of the carboxylation of 4-substituted ( + )-(/ S)-fra ,v-1-(4-mcthylphcnyl-sulfinylmethyl)cyclohexane after metalation with methyllithium and quenching with carbon dioxide was reported64. The results listed in Table 1 show that the d.r. of around 75 25 under kinetic control changes to 25 75 under thermodynamic control. This is the result of the equilibration of the two diastereomeric metalated species. As shown by the experiment in hexamethylphosphoric Iriamide (IIMI A) (d.r. = 57 43 under kinetic control) an electrophilic assistance of the lithium cation to the electrophilic approach is probably involved. 

This contrary stereochemistry in the Bucherer - Bergs reaction of camphor has been attributed to steric hindrance of e.w-attack of the cyanide ion on the intermediate imine. Normally, equatorial approach of the cyanide ion is preferred, giving the axial (t>Mr/o)-amino nitrile by kinetic control. This isomer is trapped under Bucherer-Bergs conditions via urea and hydan-toin formation. In the Strecker reaction, thermodynamic control of the amino nitrile formation leads to an excess of the more stable compound with an equatorial (e.w)-amino and an axial (endo)-cyano (or carboxylic) function13-17. 

Therefore, most of the nonoxidative generation methods that have evolved can be viewed as a crossover reaction of sorts whereby one o-QM product is exchanged for another by application of heat. The stereochemistry accruing in the products of these procedures is expectedly subject to thermodynamic control. For example, while exploring a synthetic approach for nomofungin (Fig. 4.2), Funk recently showed that... 

All mechanistic pathways that generate product (H) represent examples of neighboring group participation, but anchimeric assistance is observed only if the rate-limiting step is that of ring closured Since each of the steps may be readily reversible under the conditions of the reaction, it is not always clear whether a given reaction was conducted under conditions of kinetic or thermodynamic control, which step was rate-limiting, or which step controlled the stereochemistry. 

Reactions on SP2 Type Unsaturated Systems Very few studies have been carried out on the stereochemistry of the Michael reaction. However, Abramovitch and Struble (36) have found that compound 101 was the main product when diethyl sodiomalonate (free of ethoxide ion and ethanol) was added to 4- t-butyl-1-cyano cyclohexene (99) in boiling toluene. This result can be rationalized by axial attack on 99 to give first 100 having a chair-like conformation which is then transformed into 101 by internal trapping (see arrow). However, when the addition of diethyl malon-ate anion was carried out in ethanol under thermodynamically controlled conditions, product 103 with an equatorial malonate group was obtained, presumably via the twist-boat intermediate 102. 

We have expanded our collection of stereoselective reactions even more in the making of alkenes by the Wittig reaction (chapter 15), from acetylenes (chapter 16), by thermodynamic control in enone synthesis (chapters 18 and 19) and in sigmatropic rearrangements (chapter 35). We have seen that such E- or Z-alkenes can be transformed into three-dimensional stereochemistry by the Diels-Alder reaction (chapter 17), by electrophilic addition (chapters 23 and 30), by carbene insertion (chapter 30) and by cycloadditions to make four-membered rings (chapters 32 and 33). 

Although analysis in terms of short-lived carbanions fits the stereochemistry discussed up to now, the results should not be taken as indicative of short-lived ions. Thermodynamic control via long-lived carbanions will give the same results, as was actually suggested by Truce and coworkers. 

The palladium-allylation of ambident aromatic heterocycles is covered by Professor Moreno-Mafias and Dr. Pleixats (Barcelona, Spain) in the second chapter of this volume. The preference for carbon versus oxygen, nitrogen, and sulfur allylation is discussed from the diverse viewpoints of regioselectivity, kinetic versus thermodynamic control, mechanisms, stereochemistry, and synthetic targets in the first general survey of this topic. 

Lithiated silyl enol ethers related to 124 have been used in the synthesis of polyunsaturated aldehydes by chain extension, as shown below.109110 The stereospecificity (or otherwise) of the reaction is irrelevant to the stereochemistry of the products 131 and 132, which is under thermodynamic control. 

Tin-lithium exchange of 125 gives an intermediate 126 that retains its stereochemistry, presumably (though this was not proven) under kinetic and not simply thermodynamic control. A variety of electrophiles to give various c/s-substituted aziridines 127.60... 

Consiglio and Morandini and co-workers (67) have investigated the stereochemistry involved in the addition of acetylenes to chiral ruthenium complexes. Reaction of propyne with the separated epimer of the chiral ruthenium phosphine complex 34 at room temperature results in the chemo- and stereospecific formation of the respective propylidene complex 64. An X-ray structure of the product (64) proves that the reaction proceeds with retention of configuration at the ruthenium center. The identical reaction utilizing the epimer with the opposite configuration at ruthenium (35) also proceeded with retention of configuration at the metal center, proving that the stereospecificity of the reaction in not under thermodynamic control [Eq. (62)]. 

Once you know the gross structure of the product, the stereochemistry should be no surprise. This is a typical thermodynamically controlled formation of a six-membered ring with all the substituents equatorial. 

This section has been strong on thermodynamic control but weak on the more common kinetic control. This will be remedied in Chapter 35 where you will meet the most important cydization reaction of all—the Diels-Alder reaction. It is under kinetic control and there is a great deal of stereochemistry associated with it. 

Scheme 5.5. Product stereochemistry is thermodynamically controlled. A = aldolase P = PO32-.

Atropisomers should be suited to enantioselec-tive synthesis using thermodynamic control, and Curran has proposed using anilides as prochiral auxiliaries , responding to stereochemistry within... 

The choice of the solvent and of the electrophile is very important since the reaction can be carried out under kinetic or thermodynamic control. The possibility of equilibrating a cyclic intermediate strongly influences the regio- and stereochemistry of the reaction. The presence of a base in an aqueous medium generally results in kinetic control of the cyclization process18, while reversible conditions are favored by iodine in acetonitrile19. In addition, A -iodosuccin-imide in chloroform, iodine in chloroform and iodine in tetrahydrofuran/pyridine are considered to give cyclizations under kinetic control. On the other hand, the use of AT-bromosuccin-imide or bromine affords lower selectivity. 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

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