Diols, DYKAT

DYKAT of 1,4-symmetrical diols Marti n-Matute, B., Edin, M. and Backvall, J.-E. (2006) Chemistry-A European Journal, 12, 6053-6061. 

The Shvo catalyst 1 was successfully used in the transfer hydrogenation of 1,3-diones to the corresponding 1,3-diols with isopropanol as the hydrogen donor (2) [36, 37], This reaction is synthetically useful for the reduction of cyclic diones since reduction of these diketones by LiAlIli preferentially gives the aUyUc alcohol [36]. Also piperidine-3,5-diones were efficiently reduced to the corresptMiding diols by isopropanol using 1 as catalyst [37], and these diols were subsequently used in dynamic kinetic asymmetric transformatimis (DYKATs) to provide stereodefined 3,5-disubstituted piperidines [36, 37],... 

The Shvo catalyst has found many applications as a racemization catalyst in enzymatic resolutions of alcohols and amines leading to a DKR. Also diols and amino-alcohols have been used in these applications in DYKATs. 

Backvall and coworkers also reported a DYKAT of unsymmetrical 1,3-diols with one small and one large group [83]. The method makes use of (0 selective enzymatic acylation of the least sterically hindered alcohol ii) epimerization of a secondary alcohol and in) intramolecular acyl migration in a syn-l,3-diol monoacetate in a one-pot procedure. Shvo s catalyst 1 (4 mol%) was used for the epimerization. CALB was used for the enzymatic resolution along with isopropenyl acetate as the acyl donor. The products were obtained in moderate to high yields (53-73%) and with ee values exceeding 99% in all cases. Also, the diastereomeric ratios for the sy -diacetates were consistently high, typically >90% syn (19). 

Enzymatic resolution of 1,4-diols with CALB in combination with a hydrogen transfer process catalyzed by Shvo s complex 1 led to an efficient DYKAT, providing access to chiral y-acetoxy ketones [84]. A variety of unsymmetrical 1,4-diols were transformed into the products in high to excellent yields (70-96%) and with ee values typically exceeding 85% (20). The chiral y-acetoxy ketones are useful as versatile building blocks for tetrahydrofurans and dihydrofurans. 

An efficient DYKAT of a racemic cisitrans mixture of cyclohexane-1,3-diol using Shvo s complex 1 was reported in 2006 [85]. Pseudomonas cepacia lipase (PS-C) was used for the enzymatic resolution along with para-chlorophenyl acetate as the acyl donor. The cis-diacetate was obtained in 95% yield with high diaster-eoselectivity cisitrans = 97/3). 

The enzyme-catalyzed kinetic asymmetric transformation (KAT) of a diastereomeric 1 1 syn anti mixture is limited to a maximum theoretical yield of 25% of one enantiomer. This important drawback has been overcome by the combination of the actions of a ruthenium complex and a lipase in a dynamic kinetic asymmetric transformation (DYKAT), the desymmetrization of racemic or diastereomeric mixtures involving interconverting diastereomeric intermediates, implying different equilibration rates of the stereoisomers. Thus, this strategy allows the preparation of optically active diols, widely employed in organic and medicinal chemistry, as they are an important source of chiral auxiliaries and ligands and they can be easily employed as precursors of much other functionality. 

In this sense, Persson et al. carried out the first DYKAT process of symmetrical diols via coupled Shvo s catalyst 2 and CALB catalysis. Thus, 1 1 mixtures of meso-and R,S-diols were transformed to enantiomerically pure diacetates in moderate yields and high ee values (Figure 14.12a), although undesired meso-diacetates were formed by an intramolecular acyl-transfer pathway [26]. 

The applicability of this methodology was further demonstrated by Boren et al, who described the DYKAT of a series of aliphatic 1,4-diols, catalyzed by CALB and ruthenium catalyst 8. Through these reaction conditions, the corresponding optically... 

Ruthenium catalyst 8 has been also coupled with CALB in the DYKAT of 1,5-diols 46 and 47 (Figure 14.14a), affording the enantiomerically pure diacetates in high yields, precursors of chiral 2,6-disubstituted piperidine and 3,5-disubstituted morpholine, respectively [51]. A similar procedure has been reported for the preparation of enantiopure antiangiogenic (+)-solenopsin A (Figure 14.14b) [48]. 

DYKAT of 1,4-diols as the key step in the preparation of 2,5-disubstituted pyrrolidines. 

Application of the DYKAT of 1,5-diols. (a) Synthesis of 2,6-dis-ubstituted and 3,5-disubstituted six-membered chiral heterocycles. (b) Preparation of enantiopure (+)-solenopsin A. 

DYKAT is a dynamic system closely related to DKR. Although four types of DYKAT have been reported in the literature, all the examples reviewed here are included in DYKAT type 111. They focus on the asymmetric transformation of a diastereomeric mixture of enantiomeric pairs of acyclic and cyclic diols by means of lipase-catalyzed transesterification and epimerization of the chiral centers mediated by the Ru catalyst 3a. The major differences with respect to DKR reside in the formation of chiral intermediates (hydroxyketones) during the metal-catalyzed epimerization as well as the involvement of two successive enzymatic transformations with different selectivities. An additional complexity originates from possible intramolecular acyl-migrations. Nevertheless, if similar requirements to those described for an efficient DKR are fulfilled, the result of these DYKATs could be the formation of only one stereoisomer of the diacylated product. 

Backvall et al. have recently reported on an interesting application of the DYKAT methodology for producing optically active ra 5-bicyclic diol derivatives. These starting... 

SCHEME 57.18. DYKAT of bicyclic diols and synthesis of sertraline. 

Diols are immediate precursors of stereodefined 2,6-disubstituted and 3,5-disubstituted six-membered heterocycles, some of which are well-known alkaloids occurring in nature. The previous DYKAT methodology also has been applied to both symmetrical 1,5-diols, which are dllmeso mixtures 80b,c,e-h, and unsymmetrical 1,5-diols, which are diastereomeric mixtures of enantiomeric pairs 80a,d,i (Scheme 57.19). Initially, diol 80a was used as a model substrate to optimize the reaction parameters. 

Fig. 8.33 DYKAT of 1,3-diols via lipase-catalyzed acyl-transfer in combination with Ru-catalyzed epimerization of hydroxyl groups. G=chiral carbon, convertible for equilibration and acyl migration, but not for the irreversible step H=chiral carbon, convertible for equilibration, acyl migration and the irreversible step l=chiral carbon, convertible for acyl migration, stable chirality. (From J. Steinreiber, K. Faber, H. Griengl, De-racemization of enantiomers versus de-epimerization of diastereomers-chssification of dynamic kinetic asymmetric transformations (DYKAT), Chemistry 14 (2(X)8), 8060. Copyright 2008 Wiley).

For de-epimerization (eg, transformation of a mixture ofdiastereomers), the reaction enthalpy is not equal to zero, since diastereomers have different physical properties. Thus de-epimerization is more facile than de-racemization. An example of DYKAT is provided in Fig. 8.33, where the substrates are racemic mixtures of diastereomeric 1,3-diols. 

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