Sparteine, kinetic resolution

Analogously it was proposed an alternative synthetic pathway for the preparation of monteleukast sodium 153 comprising the Pd(II)-(—)-sparteine kinetic resolution of a disubstituted benzyl alcohol 154 that presents also an inert tertiary alcohol moiety (Scheme 34.40). 

An efficient kinetic resolution of racemic secondary allyl carbamates was accomplished by the jw-butyllithium-(-)-sparteine complex76 131. Whereas the R-enantiomer (80% ee) is recovered unchanged, the 5-enantiomer is deprotonated preferentially. 

Configuration of the intermediate lithium compound, formed by kinetic resolution under the influence of (-)-sparteine. b Yield based on (-)-sparteine. 

The complex Pd-(-)-sparteine was also used as catalyst in an important reaction. Two groups have simultaneously and independently reported a closely related aerobic oxidative kinetic resolution of secondary alcohols. The oxidation of secondary alcohols is one of the most common and well-studied reactions in chemistry. Although excellent catalytic enantioselective methods exist for a variety of oxidation processes, such as epoxidation, dihydroxy-lation, and aziridination, there are relatively few catalytic enantioselective examples of alcohol oxidation. The two research teams were interested in the metal-catalyzed aerobic oxidation of alcohols to aldehydes and ketones and became involved in extending the scopes of these oxidations to asymmetric catalysis. 

Sigman et al. have optimized their system too [45]. A study of different solvents showed that the best solvent was f-BuOH instead of 1,2-dichloroethane, which increased the conversion and the ee. To ensure that the best conditions were selected, several other reaction variables were evaluated. Reducing the catalyst loading to 2.5 mol % led to a slower conversion, and varying temperature from 50 °C to 70 °C had little effect on the selectivity factor s. Overall, the optimal conditions for this oxidative kinetic resolution were 5 mol % of Pd[(-)-sparteine]Cl2, 20 mol % of (-)-sparteine, 0.25 M alcohol in f-BuOH, molecular sieves (3 A) at 65 °C under a balloon pressure of O2. 

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

Interestingly, the scope of the reaction using this catalyst can be extended to oxidative kinetic resolution of secondary alcohols by using (-)-sparteine as a base (Table 10.2) [25]. The best enantiomeric excess of the alcohol was obtained when a chiral enantiopure base and an achiral catalyst were used. The use of chiral enantiopure catalyst bearing ligand 17 led to low enantioselectivity. 

Scheme 10.6 Mechanism of aerobic oxidation catalysed by complex 13 [23] Table 10.2 Oxidative kinetic resolution of alcohols using (-)-sparteine [25]...

The empirical observation that (—)-sparteine 55 is necessary for catalysis implicates a base-promoted pathway in the mechanism. In the first step, a palladium alk-oxide is formed after alcohol binding, followed by p-hydride elimination of the alkoxide to yield a ketone product. On the basis of a kinetic study of the enantio-selective oxidation of 1-phenylethanol, it was revealed that (—)-sparteine plays a dual role in the oxidative kinetic resolution of alcohols, as a ligand on palladium and an exogeneous base " ... 

The groups of Sigman and Stoltz have concurrently published the palladium-catalyzed oxidative kinetic resolution of secondary alcohols using molecular oxygen as the stoichiometric oxidant. Both communications also described a single example of a diol desymmetrization using a palladium catalyst in the presence of (—(-sparteine [Eqs. (10.42) ° and (10.43) ] ... 

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). 

Kinetic resolution is also very efficient in the ine50-1,4-dicarbamate 107 (equation 23) . Here the proton H,y in the pro-R branch turned out to be more reactive towards s-BuLi/(—)-sparteine (11), and the hthium compound 108 is formed in large excess besides a trace of 110 leading to 111. Adding electrophiles leads to the major products 109 with high diastereomeric... 

The products 109 are versatile precursors for bicyclic tetrahydro-2-furanones and -furans °. The tributylstannane rac-109d undergoes a kinetic resolution of medium efficiency when it is treated with MeLi/(—)-sparteine (equation 24) °. The substitution products 109b and the less reactive enantiomer ewt-109d are obtained with medium enantioselectivity. 

An efficient kinetic resolution was also observed during the (—)-sparteine-mediated deprotonation of the piperidin-2-yhnethyl carbamate rac-112 (equation 25). By treatment of rac-112 with s-BuLi/(—)-sparteine (11), the pro-S proton in (/ )-112 is removed preferentially to form the lithium compound 113, which undergoes intramolecular cyclo-carbolithiation, and the indolizidinyl-benzyllithium intermediate 114 was trapped with several electrophiles. The mismatched combination in the deprotonation of (5 )-112, leading to cp/-113, does not significantly contribute to product formation. Under optimized conditions [0.75 equivalents of s-BuLi, 0.8 equivalents of (—)-sparteine, 22 h at —78°C in diethyl ether] the indolizidine 115 was isolated with 34% yield (based on rac-112), d.r. = 98 2, e.r. = 97 3 optically active (5 )-112 was recovered (46%, 63% ee). 

Kinetic resolution between diastereomeric (—)-sparteine-lithium complexes may also occur on a later step of a reaction sequence. Almost no stereodifferentiation between the enantiomers (R)- and (5)-116 takes place in the deprotonation of rac-116 (S,S)-117 and (7 ,5 )-117 are formed in essentially equal amounts (equation 26) . Only (R,S)-... 

An interesting stereochemical situation was found for the lithium-)—)-sparteine complex derived from o-ethyl-A,A-diisopropylcarboxamide 267 (equation 65) . Control experiments, involving lithiodestannylation experiments and the Hoffmann test, led to the conclusion that 268/ep/-268 are configurationally unstable at —78 °C and the e.r. in 269 is determined by a dynamic kinetic resolution of the rapidly interconverting intermediates . It is noteworthy that the configuration is inverted by using tosylates . 

Surprisingly, the unsubstituted indenyllithium-(—)-sparteine 289c (R = H) in many cases leads to similarly high enantioselectivities. The stereoselection here is considered to occur by kinetic resolution at constitutionally identical but diastereotopic positions 1 and 3. Unfortunately, the absolute configuration of the addition products could not be determined due to its facile racemization. 

When the racemic carbamate 299b is deprotonated by 0.5 equivalents of w-BuLi/(—)-sparteine (11), an efficient kinetic resolution takes place to produce the lithium compound (5)-300b (80-82% ee) and leaving (R)-299b (80% ee) behind (equation 75)9.219,221-223... 

The asymmetric lithiation/substitution of Af-Boc-Af-(3-chloropropyl)-2-alkenylamines 395 by w-BuLi/(—)-sparteine (11) provides (5 )-Af-Boc-2-(alken-l-yl)pyrrolidines 397 via the allyllithium-sparteine complexes 396 (equation 106) . Similarly, the piperidine corresponding to 397 was obtained from the Af-(4-chlorobutyl)amine. Intramolecular epoxide openings gave rise to enantioenriched pyrrolidinols. Beak and coworkers conclude from further experiments that an asymmetric deprotonation takes place, but it is followed by a rapid epimerization a kinetic resolution in favour of the observed stereoisomer concludes the cyclization step. 

Even more interesting is the oxidative kinetic resolution of alcohols under aerobic conditions. The system Pd(lI)/sparteine/02 was reported to convert a racemic alcohol with high selectivity into the ketone and the alcohol [97-99]. This has also been shown to work with palladium carbene complexes (Scheme 16). 

Racemic 1-phenylethyl methacrylate is resolved efficiently by a cy-clohexylmagnesium chloride-(—)-sparteine complex to give, at 70% conversion, optically active polymer and the unreacted monomer in greater than 90% ee (181). Similarly, reaction of racemic phenyl-2-pyridyl-o-tolylmethyl methacrylate in the presence of 4-fluorenyllithium and (+)- or (—)-2,3-dimethoxy-l,4-bis(dimethylamino)butane proceeds with a high degree of kinetic resolution (182). 

Laqua, H. Frohlich, R. Wibbeling, B. Hoppe, D. Synthesis of enantioenriched indene-de-rived bicyclic alcohols and tricyclic cyclopropanes via (-)-sparteine-mediated lithiation of a racemic precursor and kinetic resolution during the cyclocarbolithiation. J. Organomet. Chem. 2001, 624, 96-104. 

Pd(II) catalysts have been widely used for aerobic oxidation of alcohols. The catalytic systems Pd(OAc)2-(CH3)2SO [14] and Pd(OAc)2-pyridine [15] oxidize allylic and benzylic alcohols to the corresponding aldehydes and ketones. Secondary aliphatic alcohols, with relatively high water solubility, have been oxidized to the corresponding ketones by air at high pressure, at 100 °C in water, by using a water-soluble bathophenanthroline disulfonate palladium complex [PhenS Pd(OAc)2] [5d]. The Pd catalyst has also been successfully used for aerobic oxidative kinetic resolution of secondary alcohols, using (-)-sparteine [16]. 

Aerobic Oxidative Kinetic Resolution of l-(4-Methoxyphenyl)ethanol (10), Catalyzed by Pd(nbd)CI2 and (-)-sparteine [16]... 

Asymmetric synthesis relied upon the use of (-)-sparteine in the final annelation step leading to 40 (Fig. 15.15). Mechanistic studies revealed that (-(-sparteine-mediated stereoinduction was associated with kinetic resolution in the incomplete formation of dilithiated intermediate 30-Li2 and the reaction of diaster-eomeric complexes of 30-Li2 with bis (phenyl sulfonyl) sulfide [85]. The absolute... 

Chiral N-arylated imidazolinylidene ligands have been employed in the palladium(II) catalyzed aerobic oxidation of secondary alcohols to the corresponding ketones [55]. The chiral variant of this reaction, which does not generate a new element of chirality, is again based on the kinetic resolution of racemic mixtures. The active catalyst is formed in situ by a combination of two precursors, a dinuclear NHC-palladium(II) complex and an achiral (acetate) or chiral base ((-)-sparteine) (Scheme 18). 

Generation of Enantioenriched, Configurationally Stable Organolithium Reagents. (1 S,2E)-1 -(N.Af-Diisopropyl-carbamoyloxy)-l-methyl-2-butenyllithium-(—)-sparteine is configurationally stable in solution and is obtained by kinetic resolution of the racemic 2-alkenyl carbamate by n-butyllithium-(—)-sparteine with >80% de (eq 4). The enantioenriched allylstan-nane, obtained on y-stannylation, was used as chiral homoenolate reagent. The methoxycarbonylation (a, inversion) yields enantioenriched 3-alkenoates. ... 

Y. Okamato, K. Suzuki, T. Kitayama, H. Yuki, H. Kageyama, K, Miki, N. Tanaka, and N. Kasai, Kinetic resolution of racemic methylbenzyl methacrylate Asymmetric selective polymerization catalysed by Grignard reagent-(-)-sparteine derivative complexes, /. Am, Chem, Soc., 104 4618 (1982). 

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