Desymmetrizing reactions

The high chemoselectivity for the Baeyer-Villiger process was utilized in the synthetic elaboration of another hetero-bicyclic substrate. The biooxidation only provides the expected unsaturated lactone in a desymmetrization reaction without compromising the olefin functionality. The biotransformation product was then converted to pivotal intermediates for C-nucleosides like showdomycin, tetrahydro-furan natural products like kumausyne, and goniofufurone analogs in subsequent chemical operations (Scheme 9.17) [161]. 

Among recently described new Pd-catalysed enantioselective reactions, the ring opening of meso oxabicyclic alkenes with dialkyl zinc reagents in the presence of chiral P/P and P/N ligands reported by Tautens el al. constitutes a synthetically outstanding C-C bond-forming desymmetrization reaction. 

Formal hydration of the double bond appeared by the hydroboration-oxidation sequence. Desymmetrization reactions with catalytic asymmetric hydroboration are not restricted to norbornene or nonfunctionalized substrates and can be successfully applied to meso bicyclic hydrazines. In the case of 157, hydroxy derivative 158 is formed with only moderate enantioselectivity both using Rh or Ir precatalysts. Interestingly, a reversal of enantioselectivity is observed for the catalytic desymmetrization reaction by exchanging these two transition metals. Rh-catalyzed hydroboration involves a metal-H insertion, and a boryl migration is involved when using an Ir precatalyst (Equation 17) <2002JA12098, 2002JOC3522>. 

RECENT ADVANCES IN CATALYTIC ASYMMETRIC DESYMMETRIZATION REACTIONS... 

Catalytic asymmetric desymmetrization as a field is still growing, with new applications appearing weekly. It is evident that advances in this subfield have kept in step with advances in catalysis as a whole. Some spectacular successes have been reported in recent years, and this strategy has been applied to many new reactions. Willis mentions in conclusion to his 1999 review of this field that desymmetrization reactions involving catalytic enantioselective construction of C—C bonds are... 

Me o-epoxides, nucleophilic ring-opening reactions by aryllithium/(—)-sparteine (11) have been realized by Alexakis and coworkers with very good differentiation between the enantiotopic positions . Eliminative desymmetrization reactions of me o-oxacycles such as 144 or 147, which are triggered by an enantiotopos-differentiating deprotonation... 

In 2000, Tanaka, Sakai, and Suemune expanded the scope of these desymmetrization reactions to more highly substituted substrates (Eq. 16) [19], The high selectivity of Rh(I)/BINAP for addition to one of the enantiotopic olefins leads to the generation of adjacent quaternary and tertiary stereocenters with excellent stereoselection. Unfortunately, for these more sterically demanding substrates, neutral Rh(l)/BINAP complexes furnish a poor yield of the desired cyclopentanone. 

If the 3-position is a quaternary stereocenter, then Rh(I)/Tol-BINAP is the catalyst of choice for the hydroacylation process. With this catalyst, both kinetic resolutions (Eq. 20) and desymmetrization reactions (Eq. 21) may be accomplished. 

A few interesting variants of the Pd-catalyzed acylation of organozincs have been developed. In one such variant, thiol esters are employed in place of acyl chlorides214. Another is the Ni-catalyzed reaction of organozincs with cyclic anhydrides215 shown in Scheme 82. this desymmetrization reaction can be made highly enantioselective, it would become a significant tool for asymmetric synthesis. 

Biocatalysis plays a central role in the manufacturing of statin side chains (Figure 6.2). A first set of approaches exploits enzymatic desymmetrization reactions, for example, of the methoxyacetyl ester of glutaric acid diethyl ester with commercially available a-chymotrypsin as explored by Ciba SC with a yield of 94% and enantiomeric excess of up to 98% [1]. In the optimized procedure, the substrate was available in a concentration of 1 M at an enzyme/substrate ratio of 7% (wt/wt), and the reaction took approximately a day. The subsequent steps to the final acetonide also involved a pig-liver esterase (PLE) catalyzed selective hydrolysis of the methoxyacetyl group (Figure 6.2a). 

Following lipase-catalyzed desymmetrization reactions of the substrate (e. g., 1) on the microtiter plates, an extraction step is necessary prior to MS analysis. This process is controlled by the Facts software (Figure 9.4. Four modules are controlled simultaneously the robot arm (RoMa), the carousel for storing the microtiter plates, the 96-pipette system (TeMo), and the 8-fold pipette head (Gemini). Iteration occurs within 12 min. 

Brase reported an intramolecular asymmetric Heck-intermolecular Heck cascade reaction of l,3-bis(enolnonaflates) 131 to the highly congested bicyclic compound 132 [122] (Scheme 5). Although the level of asymmetric induction is low (up to 52% ee), this result shows that the concept of two leaving groups in the desymmetrization reaction can be applied. 

Use of a chiral catalyst for allylic substitution reactions allows for desymmetrization reactions... 

Major advances were also made in the field of ARCM. Notable examples of this process are shown in Scheme 2 and include AROM <02JA10779>, and the desymmetrization reactions of acetals <00TL9553> and ethers <02JA2868>. Especially noteworthy are the ARCM to yield medium-sized, cyclic amines that occur in high yield and enantiomeric excess in the absence of solvent <01JA6991> [—m indicates the site of RCM]. 

Biotransformation of hetero-bicyclic ketone 8 enabled access to unsaturated lactone 9 in a desymmetrization reaction without compromising the olefin func-... 

Grubbs examined the effect that a C2 symmetric imidazolin-iiim hgand would have on dichloro-, dibromo-, and diiodo-rutheninm alkylidene catalysts (112a- (Scheme 18). The new complexes had activities and stabihties similar to the parent complex (4a) and were thus tested for asymmetric induction in enantioselective desymmetrization reactions. The /trei using these new complexes were low, leading to very low... 

The most powerful approaches, which can be used with several different enzyme systems, lead to a single enantiomer as the product in high yield and do not rely on a classic resolution approach in which the unwanted enantiomer is discarded. These approaches include dynamic kinetic resolutions, der-acemizations, and asymmetric and desymmetrization reactions (49, 50). In some cases, a chemical catalyst may be available to recycle the unwanted isomer in the same reactor vide infra). It is sometimes possible to racemize the unwanted isomer of the substrate and then to perform the reaction again (51). 

The binuclear /x-oxo compound (Scheme 330) has been prepared and is readily isolated by chromatography. Subsequent treatment with SiXMe3 (X = C1, I, OTf) followed by transmetallation and desymmetrization reaction with the lithium salt of cyclohexadiene affords an excellent reagent for the transfer of cyclohexadienyl groups to various aldehydes.503... 

Related to a resolution, a desymmetrization reaction was used in an approach to Uvaricin. Use of AD-mix [1 gave only moderate diastereoselection with 21, but the use of (DHQD)2AQN gave 22 after two cycles the first reaction was run to 50% completion and the recycled diene 21 was then subjected to the reaction conditions for a second time (Scheme 3.17) [320]. 

However, highly interestingly, unusual concentration and temperature effects on the enantioselectivity were observed by Song and coworkers [11a]. As shown in Figure 11.2, the enantioselectivity in the methanolytic desymmetrization reaction of the meso-cyclic anhydride IS increases with increasing dilution of the reaction mixture and on raising the reaction temperature from —20 to 20 °C. 

Significantly improved results were obtained in 2003 by employing the phosphi-nite derivative 22 of cinchonine as a catalyst, which can be obtained as a mixture with the undesired corresponding phosphinate from the reaction of cinchonine (1) and chlorodiphenylphosphane [30a]. The desymmetrization reaction of a range of 1,2-meso-diols with benzoyl chloride in the presence of 30 mol% of the phosphinite 22 as a mixture containing about 15% phosphinate afforded the corresponding monobenzoylated diol in excellent yields and ee values (up to 94% ee) (Scheme 11.15). It was postulated by the authors that the reaction is initiated by the activation of the... 

Desymmetrization reactions. Cinchona alkaloids are relative abundant, morevover, the fact that the two series of quinine/cinchonidine and quinidine/cinchonine often can catalyze reactions in the opposite chirahty sense makes the use of them and their derivatives very valuable in creating new stereogenic centers from prochiral substances, in one or both optical series. 

Another creative synthetic application of the Prins reaction was reported by Rychnovsky and co-workers.17 20 Treatment of acetal 22 with BF3 OEt2 and HOAc effected a Prins desymmetrization reaction, affording pyran 23 in 42-51% yield after acylation. This intermediate was then used to complete a total synthesis of 17-deoxyroflamycoin 24.17... 

Chenevert synthesized both enantiomers of a dibenzylbutyrolactone lignan using as key step an enzymatic desymmetrization reaction of meso alcohols, Scheme (43) [110]. 

Finally, reaction E in Fig. 4 illustrates a stereoselective synthesis that proceeds by differentiation of two enantiotopically related groups of a meso compound. Here, one hydroxyl group of d.s-1,2-cyclohexanediol is preferentially benzoylated in the presence of one molar equivalent of an enantiomerically pure diamine [26]. These desymmetrization reactions (that have many biological versions) are also called meso-tricks , and are currently receiving a great deal of attention for the preparation of new chiral building blocks [27]. 

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