Intramolecular thermodynamic control

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

The diastereoselective intramolecular Michael addition of /(-substituted cyclohexcnoncs results in an attractive route to ra-octahydro-6//-indcn-6-ones. The stereogenic center in the -/-position of the enone dictates the face selectivity, whereas the trans selectivity at Cl, C7a is the result of an 6-exo-trig cyclization. c7.v-Octahydro-5//-inden-5-ones are formed as the sole product regardless of which base is used, e.g., potassium carbonate in ethanol or sodium hydride in THF, under thermodynamically controlled conditions139 14°. An application is found in the synthesis of gibberellic acid141. 

An interesting approach to zr n.v-2,3-disubstituted cyeloalkanones is offered by auxiliary controlled intramolecular Michael additions. The diastereoselectivity depends on the chiral alcohol used193> l94. When the borneol derivative 7 was used as substrate, a single diastereomer of 8 resulted when the reaction was performed at 25 "C under thermodynamic control with a catalytic amount of sodium hydride in benzene. 

In summary, then, the orientation of electrophilic thallation can be controlled by an appropriate manipulation of reaction conditions. Under conditions of kinetic control, ortho substitution results when chelation of the electrophilic reagent (TTFA in the studies described above) with the directing substituent permits intramolecular delivery of the electrophile, and para substitution results when such capabilities are absent this latter result is an expression of the very large steric requirements of the bulky thallium electrophile. Under conditions of thermodynamic control, however, meta substitution is observed. 

Attempted intermolecular cross-benzoin reactions typically generate a thermodynamically controlled mixture of products [50], although several groups including Enders [51], Suzuki [52] and You [53] have utilised catalysts 116-118 for the intramolecular crossed benzoin of keto-aldehydes (Scheme 12.22). 

The intramolecular version of ester condensation is called the Dieckmann condensation.217 It is an important method for the formation of five- and six-membered rings and has occasionally been used for formation of larger rings. As ester condensation is reversible, product structure is governed by thermodynamic control, and in situations where more than one product can be formed, the product is derived from the most stable enolate. An example of this effect is the cyclization of the diester 25.218 Only 27 is formed, because 26 cannot be converted to a stable enolate. If 26, synthesized by another method, is subjected to the conditions of the cyclization, it is isomerized to 27 by the reversible condensation mechanism. 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

Intramolecular nitroaldol reactions are a useful choice for the conversion of sugars into polyhydroxylated nitro cyclopentanes, nitro cyclohexanes and their derivatives.46 Baer et al. in the course of their studies on the cyclization of 6-deoxy-6-nitrohexoses under kinetic and thermodynamic control,47 established the reaction pathway involved in the formation of nitroinositols mediated by intramolecular Henry reactions. Firstly, a nitronate is formed and then, under thermodynamic control conditions, an epimerization occurs before cyclization. But, under kinetic controlled conditions, the cyclization occurs first.48... 

Imidazo[2,l-fl]isoindolone 187 is the product of an intramolecular a-aza-amidoalkylation of N-acyliminium species 186. Nevertheless, when the jS-substituent is an aromatic moiety, a competing a-amidoalkylation takes place and isoindolo[l,4]benzodiazepine 188 is obtained under thermodynamic control (Scheme 37 (2004T11029)). 

The above observations are consistent with a thermodynamically controlled process shown in Figure 9.17. Thus, when two strands, A and B, with complementary H bonding sequences and termini that can be reversible cross-linked, are present in the same solution under redox conditions, products A-A (or self-cyclized A ), B-B (or self-cyclized B ), and A-B, may be generated. Among these products, A-B gains the most stabilization from the newly generated, complementary intramolecular H bonds because of the formation of the two disulfide bonds. Thus,... 

Intramolecular coupling reactions bear some important advantages namely, the opportunity of directed cross coupling and, in most cases, a reliable regioselectivity by kinetic or thermodynamic control of the atropisomer ratio. 

While the regiochemistry of simple electrophilic additions to double bonds is controlled by a combination of electronic (Maikovnikov rule), stereoelectronic (trans diaxial addition to cyclohexenes) and steric factors,9 the intramolecular nature of electrophilic heteroatom cyclizations introduces additional conformational, stereoelectronic and entropic factors. The combination of these factors in cyclofunctionalization reactions results in a general preference for exo cyclization over endo cyclization (Scheme 4).310 However, endo closure may predominate in cases where electronic or ring strain factors strongly favor that mode of cyclization. The observed regiochemistry may differ under conditions of kinetic control from that observed under conditions of thermodynamic control. 

Intramolecular amidomercuration of carbamate derivatives to generate 2,6-disubstituted piperidine systems (equation 113 and Table 31) proceeds with low selectivity under conditions of kinetic control (cis.trans = 40 60),246 248 but cyclization under conditions of thermodynamic control highly favors the cis isomer (cis. trans > 98 2).246 Interestingly, only the cis isomer was isolated from cyclization with phe-nylselenenyl chloride in the presence of silica gel.216 ... 

In the course of the total synthesis of enmein, Fujita and co-workers (7) have discovered that the intramolecular cyclization of the enolate 23 of the corresponding tetracyclic keto-aldehyde at room temperature gave only ketol 24. However, when the same reaction is conducted at 60°C, thermodynamically controlled conditions prevail, and the epimeric product 25 is obtained. Inspection of molecular models indicates that the kinetically controlled product 24 is again the result of an anti peri planar arrangement of the enolate and the aldehyde double-bonds. Also, as in the previous examples, the isomer 25 comes from a synclinal arrangement of the reacting functional groups. 

In this dissociative pathway (which is assumed to be the major one today) first a phosphine is displaced from the metal center to form an active 14-electron-intermediate 42. After alkene coordination cis to the alkylidene fragment the 16-electron-olefine-complex 43 undergoes [2 + 2]-cycloaddition to give a metallacylobutane 44. Compound 44 breaks down in a symmetric fashion to form carbene complex 45. The ethylene is replaced in the conversion to complex 46. In the next steps (they are not further discribed above), another intramolecular [2 + 2]-cycloaddition joins up the eight-membered ring 11 regenerating the catalyst 42. Each step of the reaction is thermodynamically controlled making the whole RCM reversible. With additional excess of phosphine added to the reaction mixture an associative mechanism is achieved, in which both phosphines remain bound. 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

The relative power of DMG (Table 1), established by experiments at low temperature and short reaction times and thus crudely representative of kinetic control conditions, may vary with inter- and intramolecular competition, conditions, and sometimes results are conflicting. Nevertheless, for synthetic practice this hierarchy follows a qualitative order consistent with CIPE and serves as a useful predictive chart. For thermodynamic control conditions, the pchart of Fraser of 12 DMG [27], determined by equilibrium deprotonation using LiTMP (pka=37.8), is a guide for lithium dialkylamide DoM reactions. 

The theoretical treatment for the self-assembly of a molecular entity into rings or cages occurring under thermodynamic control is based on two fundamental physicochemical quantities the effective molarity (EM) of the intramolecular interaction of the cyclic n-mer and the value of the stability constant of the intermolecular interaction (fCinter) [5]. The following formula has been derived by Ercolani and allows calculation of the minimum value of the product fCinterEM to obtain a virtually complete self-assembled macrocycle at certain monomer concentration ... 

Two dialkyl boranes arc in common use. The bicyclic 9-borabicyclo[3.3.1] nonane (9-BBN), introduced in Chapter 34 as a reagent for diastereoselcctive aldol reactions, is a stable crystalline solid. This is very unusual for an alkyl borane and makes it a popular reagent. It is made by hydroboration of cyclo-octa-1,5-diene. The second hydroboration is fast because it is intramolecular but the third would be very slow. The regioselectivity of the second hydroboration is under thermodynamic control. 

Intramolecular mercury-induced cyclization of A -allvlcarbamate with mercury(II) nitrate in dichloromethane proceeded under thermodynamic control and gave after reductive cleavage the more stable diethyl m-2.5-dimethyl-1,4-piperazinedicarboxylate (3), exclusively, in 98 % yield124... 

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