Dynamic-thermodynamic resolution

Dynamic thermodynamic resolution in a lithiation substitution reaction sequence was used to provide access to the amino ester 48 which could then be converted, via 49 and 50, into the chiral substituted 1-benzazepine derivative 51 <06OL2667>. 

If kepi, k-epi are much larger than the rates k, ki of substitution, the enantiomeric ratio Hepi-1 is similar to kxjk (path C, dynamic kinetic resolution . Both mechanisms are performing when the rates of the two steps are similar. Since rates and equilibrium are temperature-dependent, enhancement of stereoselectivities can be achieved by sophisticated protocols (see Section m.E). The equilibrium 6/epi-6 is determined by the difference of free energy A AG. This effective energy difference is enlarged if it can be coupled with a second order transformation such as the selective crystallization of one diastere-omer dynamic thermodynamic resolution ). In fact, this applies to the first successful (—)-sparteine-mediated deprotonation (Section FV.C.l). 

The closely related a-(pyrid-2-ylthio)benzyllithium (257) has a higher configurational stability, and equilibration with the chiral ligand prior to the substitution step is required , indicating that a dynamic thermodynamic resolution is important (equation 61). Depending on the method of calculation, (7 )-257 255b was found to be by 1.42 to 1.92 kcalmoD ... 

Dilithiation of Af-methyl-3-phenylpropaneamide (261) and subsequent addition of a slight excess of (—)-sparteine (11) form a mixture of epimeric ion pairs 262/epi-262, which is substituted by electrophiles to give the -substitution products 263 with good ee values (equation 63) . The intermediates are not configurationally stable, but at low temperature one epimer 262 or epi-262 dominates due to the higher thermodynamic stability. Consequently, Beak and coworkers propose on the basis of a detailed mechanistic investigation the pathway of dynamic thermodynamic resolution . 

Repeated deprotonation of 278 removed due to a high H/D kinetic isotope effect the 1-proton, forming the dideuterio compound 279 with low diastereoselectivity . It is quite likely that a dynamic thermodynamic resolution is the origin. Intermediate 277 is configurationally labile, enabling an equilibration of the diastereomeric ion pairs 277 and epi-211. Similar studies were undertaken with 1-phenyl-l-pyrid-2-ylethane (280) and l-(4-chlorophenyl)-l-(pyrid-2-yl)-3-(dimethylamino)propane (281) (50% eef. An improvement of the achieved enantiomeric excesses resulted when external chiral proton sources, such as 282 or 283, were applied (84% ee for 280 with 283 and 75% ee for 281). 

The lithium-(—)-sparteine complexes, derived from primary 2-alkenyl carbamates, are usually configurationally labile even at —78 °C. During the investigation of the (ii)-crotyl carbamate 301, the (—)-sparteine complex (5 )-302 crystallized in a dynamic thermodynamic resolution process (equation 76) and stereospecific substitutions could be performed with the slurry An incorrect assignment of the configuration of the lithium inter-... 

An asymmetric synthesis of 3,4,5-trisubstituted-tetrahydro-l-benzazepines has been reported based on a type a ring construction process mediated by triethylaluminium with a chiral amino ester followed by lactam reduction with borane <2006OL2667>. Dynamic thermodynamic resolution in a lithiation-substitution sequence was integral to the preparation of the amino ester. An acid-catalyzed ring construction approach to the asymmetric synthesis of 4,5,6-trisubstituted- and 3,4,5,6-tetrasubstituted azepanes based on chiral acyclic precursors has also been described <2006JA2178>. 

Scheme 6.2.2 Asymmetric substitution by dynamic thermodynamic resolution.

In some cases, crystallisation of the intermediate organolithium-(-)-sparteine complexes is necessary to force their equilibration to the major diastereoisomer.54 This type of dynamic thermodynamic resolution was involved in one of the very first effective uses of (-)-sparteine in organolithium chemistry. Hoppe showed in 1988 that the carbamate 82 could be deprotonated in the presence of (-)-sparteine, and that when the product 83 was transmetallated with titanium and then added to an aldehyde, a homoaldol product 85 was formed in 83% ee. It became apparent that acceptable enantiomeric excesses were obtained only when the intermediate organolithium-(-)-sparteine complex was allowed to crystallise the complexes 83a and 83b interconvert in solution, but one diastereoisomer crystallises preferentially, leading to a dynamic resolution of the organolithium. 

In Fig. 11, at high concentrations of ethylene carbonate, the rate constants ks[EC] and kR[EC] for insertion into the EBTHI zirconaaziridine 17q are much greater than kSSR and ksss and insertion occurs more rapidly than the equilibrium can be maintained. The product ratio reflects the equilibrium of 17q, where Keq is 17.2 (Eq. 32) [21]. Beak has called this limit a dynamic thermodynamic resolution pathway [66]. In contrast, at the lowest concentration of ethylene carbonate in Fig. 10, the first-order rate constants kSSR and ksss for diastereomer interconversion are comparable to the effective first-order rate constants for insertion. As Keq is known to be 17.2, ks/kR can be calculated the 53% ee of (S)-amino acid ester 19q (Scheme 9) implies that kslkR<0.19 (Eq. 33) and that the rate constant for insertion kR[EC] into the minor diastereomer is at least five times faster than ks[EC] into the major diastereomer. 

In Chapter 22 we saw resolution with racemisation applied to the synthesis of L-364,718. That could have been described as a dynamic resolution or possibly even a dynamic thermodynamic resolution but not a dynamic kinetic resolution as it did not depend on one enantiomer reacting faster than the other. Rather it depended on the thermodynamic stability of one crystalline form over the other. 

The deprotonation of 247 in hexane by t-BuLi/excess 248 at -78°C for 1 h gave the best results (E)-O-methylmandelic acid (250) with greater than 95% ee and the hydroxy ethers (several examples) with high anfi-selectivity, and as well, very good ee. On the basis of control experiments, the authors assume a dynamic thermodynamic resolution as the origin. This mechanism impHes an essentially complete conversion to one epimer 249 of unknown configuration at -78 °C and its stereospecific carbonyl addition. 

Keywords. Amine elaboration, Asymmetric deprotonation. Dynamic thermodynamic resolution, Conjugate addition... 

A reaction profile which provides an understanding of these observations is a dynamic thermodynamic resolution as described in Fig. 1 [7,9-11]. The initial reaction of 9 with (-)-sparteine carried out at -78°C produces effectively a one-to-one mixture of epimers at the carbanionic carbon as non-equilibrating dias-tereomeric complexes. The reaction with one equivalent of the electrophile then captures all of the carbanionic species to give an essentially racemic product. When the reaction is warmed to -25 °C prior to the addition of the electrophile, equilibration occurs and the diastereomeric complexes achieve their thermodynamic equilibrium. Rapid cooling to -78°C maintains this ratio and subsequent... 

Interestingly, the stereochemical outcome in the reaction of a-Hthiated benzyl phenyl sulfide is different from that in the reaction of a-hthiated benzyl methyl ether which proceeds through a dynamic thermodynamic resolution pathway [Eq. (7)] [15,43]. Taking account of Wiberg s results, namely, that the a-oxy carbanion of dimethyl ether places the lone pair of carbanion syn to the methyl group by the electron repulsive effect [25], the difference in the stereochemical outcome between a-thio and a-oxy carbanions would be ascribed to their different preferred conformations. A similar change in the stereochemical outcome has been observed in reactions of dipole-stabilized a-thio and a-oxy organoUth-ium compound, as shown in Eqs. (4) and (5). 

The reaction of a-lithiated benzyl 2-pyridyl sulfide was proved to proceed through a dynamic thermodynamic resolution pathway by the experiments us-... 

The Sg2 reaction on the 5p -like hybridized carbanion tends to proceed with inversion of the stereochemistry [45]. It is reasonable that a-thio carbanions, having higher s character than a-oxy carbanions, more frequently invert the stereochemistry on the anionic carbon in the reaction with electrophiles. As in the case of a-lithiated benzyl 2-pyridyl sulfide, the reaction of a-lithiated benzyl 2-quinolyl sulfide also proceeds through a dynamic thermodynamic resolution pathway. The quinolyl group is an excellent protecting group of thiols [46] and can be removed to yield the corresponding chiral thiols without racemization (Tables) [47]. 

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