Thermodynamic control of stereochemistry

Because of conflicting reports or inadequate controls, the question of kinetic or thermodynamic control of stereochemistry for reported Reformatsky reactions often has no satisfactory answer. Jacques and co-workers have concluded that Reformatsky reactions of benzaldehyde in refluxing benzene can be completed with kinetic stereoselection. The relatively high syn.anti ratios they observed, at least with small R groups (equation 36 and Table 4), are not those expected for equilibrated zinc chelates. 

Hoye, T.R. and North, J.T. (1990) Thermodynamic control of stereochemistry in the synthesis of 1-oxaquinolizidine skeletal portions of xestospongin A. Tetrahedron Lett., 31,4281-4284. 

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. 

A large number of studies have addressed the condensation of cyclic ketones with both aliphatic and aromatic aldehydes under conditions that reflect both thermodynamic (cf. Table 2) and kinetic control of stereochemistry. The data for cyclohexanone enolates are summarized in Table 8. Except for the boryl enolates cited (6), the outcome of the kinetic aldol process for these enolates... 

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. 

Nevertheless, the product data have been exceptionally interpreted only in these terms. (1) An allylic carbocation can afford significant amounts of 1,2-products. For instance, in the above-mentioned DCl addition, 1,2-adducts were the major products whatever the solvent, (ii) In addition to the electrophile and substituent dependence of the charge distribution in the intermediate, solvent and steric effects probably play an important role in the product-forming step of these reactions, as they do in the reactions of monoenes . (iii) 1,2-Adducts isomerize frequently to the more stable 1,4-adducts. Therefore, the kinetic or thermodynamic control of the product distribution 2.i4 should be questioned. As a consequence, a number of early results were later revised when this problem was recognized, (iv) Finally, it has also been suggested " that 1,4-addition products do not necessarily arise from allylic intermediates but could also result from bridged intermediates via an Sn2 process implying a syn stereochemistry. 

Some observations indicate that the stereochemical outcome of the reaction seems to be under thermodynamic control, and stereochemistry at C-4 can be reversed. For example, in the Neu5Ac aldolase catalyzed synthesis of KDO, a mixture of (5)-C-4 and (7 )-C-4 were isolated when D-arabinose was the substrate (Scheme 5) [47,48]. 

One of the low points of the first calcimycin synthesis is introduction of the pyrrole unit via an aldol condensation. The yields are bw and the stereocontrol at Ci9 Is probably marginal. The Grieco synthesis disconnects calcimycin between C213 and the 2-position of the pyrrole. Therefore a significant difference between this approach and the Evans approach Is an attempt to achbve better control of stereochemistry at C g. A secondary difference is that C was to be Introduced with complete control of stereochemistry rather than relying on thermodynamics for stereocontrol. It will be seen that a consequence of this plan is... 

Most dienones that have been reduced have structures such that they cannot give epimeric products. However, reduction of 17 -hydroxy-7,17a-dimethyl-androsta-4,6-dien-3-one (63) affords 17 -hydroxy-7j9,17a-dimethylandrost-4-en-3-one (64), the thermodynamically most stable product, albeit in only 16% yield. The remainder of the reduction product was not identified. Presumably the same stereoelectronic factors that control protonation of the / -carbon of the allyl carbanion formed from an enone control the stereochemistry of the protonation of the (5-carbon of the dienyl carbanion formed from a linear dienone. The formation of the 7 -methyl compound from compound (63) would be expected on this basis. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

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. 

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... 

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