Ru-catalyzed racemization

A significant improvement was achieved when Shvo s Ru-catalyst 2 (Fig. 12b) was employed in combination with the addition of DMP to suppress dehydrogenation reactions [106]. Poly-(R)-6-MeCL, with a promising ee of 86% and Mp of 8.2 kDa, was obtained after workup starting from optically pure (5 )-6-MeCL. The low rate of reaction compared to DKR (typically complete after 48 h with the Shvo catalyst) is attributed to the low concentration of the terminal alcohol as well as to the iterative nature of the system. Racemic 6-MeCL showed comparable rates of reaction for both enantiomers, which polymerized within 220 h with complete conversion of both enantiomers, yielding polymers of high ee (92%) and Mp (9.4 kDa). Successful polymerizations with more than 100 consecutive and iterative enzymatic additions and Ru-catalyzed racemizations on one polymer chain were realized. 

A simplified mechanism for the Ru-catalyzed racemization of secondary alcohol is described in Scheme 5.4. The racemization takes place via ketone. Ru catalysts 5-10 normally catalyze the racemization without releasing free ketone and thus provide the higher 3delds in DKR. 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

SCHEME 61. Kinetic resolution of a racemic hydroxy ketone by BINAP-Ru-catalyzed hydrogenation. 

Wilson RM, Jen WS, MacMillan DWC (2005) Enantioselective organocatalytic intramolecular Diels-Alder reactions. The asymmetric synthesis of solana-pyrone D. J Am Chem Soc 127 11616-11617 Xie JH, Zhou ZT, Kong WL, Zhou QL (2007) Ru-catalyzed asymmetric hydrogenation of racemic aldehydes via dynamic kinetic resolution efficient synthesis of optically active primary alcohols. J Am Chem Soc 129 1868-1869... 

Chiral bis(oxazolines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of tran5-stilbene yielding franx-l,2-diphenyloxirane in up to 69% ee [24]. The asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93% ec. The imide 53 derived from Kemp s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. 

Geraniol or nerol can be converted to citronellol in 96-99% ee in quantitative yield without saturation of the C(6)-C(7) double bond (eq 6). The S C ratio approaches 50000. The use of alcoholic solvents such as methanol or ethanol and initial H2 pressure greater than 30 atm is required to obtain high enantioselectivity. Diastereoselective hydrogenation of the enantiomerically pure al-lylic alcohol with an azetidinone skeleton proceeds at atmospheric pressure in the presence of an (i )-BINAP-Ru complex to afford the (3-methyl product, a precursor of ip-methylcarbapenem antibiotics (eq 7). Racemic allylic alcohols such as 3-methyl-2-cyclohexenol and 4-hydroxy-2-cyclopentenone can be effectively resolved by the BINAP-Ru-catalyzed hydrogenation (eq 8). ... 

Hydrogenation of certain racemic 2-substituted 3-oxocarboxylates occurs with high diastereo- and enantioselectivity via dynamic kinetic resolution involving in situ racemization of the substrates. The (R)-BINAP-Ru-catalyzed reaction of 2-acylamino-3-oxocarboxylates in dichloromethane allows preparation of threonine and DOPS (anti-Parkinsonian agent)... 

Ru-catalyzed hydrogenation of racemic 2-substituted aldehydes via dynamic kinetic resolution... 

Liu et al. [79] further developed a Ru-catalyzed hydrogenation of racemic a,a -disubstituted cycloketones through DKR for the one-step synthesis of chiral diols with three contiguous stereocenters with high diastereoselectivity and enantioselectivity (Scheme 23). This new strategy facilitates the enantioselective total synthesis of alkaloid (-H)-y-lycorane. 

The Ru-catalyzed asymmetric hydrogenation of racemic a-substituted cyclic ketones was applied to the synthesis of various chiral natural products and analogs, such as (-)-galanthamine [80], (-)-ALTHC [81], CP 55,940 [82], and (-)-a-lycorane [83]. 

Zr-catalyzed ethylmagnesation product through three subsequent catalytic procedures (Ti-catalyzed hydromagnesation, Ni-catalyzed cross-coupling, and Ru-catalyzed oxidation) delivers the requisite carboxylic acid synthon in >99% ee. This synthesis route underlines the utility of the Zr-catalyzed carbomagnesation protocol the reaction product carries an alkene and an alcohol function and can thus be readily functionalized to a variety of other non-racemic intermediates. 

S. Hashiguchi, A. Fujii, K.-J. Haack, K. Matsumura, T. Ikariya, R. Noyori, Kinetic resolution of racemic secondary alcohols by Ru-catalyzed hydrogen transfer, Angew. Chem. Int. Ed. Engl., 1997, 36, 288-290. 

Scheme 3.17 Dynamic resolution of iec-alcohols via Ru-catalyzed in-situ racemization...

In contrast to the facile in-situ racemization of sec-alcohols via Ru-catalysts (Schemes 3.14 and 3.17), which allows dynamic resolution, the isomerization of ot-chiral amines requires more drastic conditions. Hydrogen transfer catalyzed by Pd [283, 284], Ru [285, 286] Ni, or Co [287] is slow and requires elevated temperatures close to 100°C, which still requires the spatial separation of (metal-catalyzed) racemization from the lipase aminolysis [288]. 

In 2001, Takahashi et al. [204] described the first Ru-catalyzed asymmetric allylic substitutions. The planar-chiral cydopentadienyl-mthenium complexes led to branched aUylation products with enantiosdectivities of up to 97% ee. Some years later, they showed that such complexes serve as effective catalysts for the kinetic resolution of racemic allyhc carbonates such as 200 in AAAs. The absolute configurations of the recovered carbonates and the alkylation products such as 201 were shown to depend on the substituent on the cyclopentadienyl group at the 4-position of the ruthenium catalyst (Scheme 12.98) [205]. 

The same group has recently reported the use of Ru-catalyzed cross-metathesis reactions to obtain PNA monomers labeled with a Fischer-type carbene complex (Scheme 5.32) [141]. A suitable PNA monomer 63 was prepared from racemic aUylglycine and then subjected to the metal catalyzed metathesis reaction with... 

Oldenhuis NJ, Dong VM, Guan Z (2014) From racemic alcohols to enantiopure amines Ru-catalyzed diastereoselective amination. J Am Chem Soc 136(36) 12548-12551... 

On the other hand, the racemization of amines is more difficult compared to that of alcohols. Several metal systems based on palladium (Pd), Ru, nickel (Ni), cobalt (Co), and Ir have been employed as the racemization catalysts. Pd-based catalysts include Pd/C, Pd/BaSO, and Pd/A10(0H). They are readily available but require higher temperatures for satisfactory racemization. So they should be coupled with thermostable enzymes such as Novozym 435 for the successful DKR. A possible mechanism for the Pd-catalyzed racemization of amine is described in Scheme 5.5. The racemization occurs via reversible dehydrogenation/hydrogena-tion steps including an imine intermediate. The imine intermediate can react with starting material to afford a secondary amine as the byproduct. The deamination of substrate and byproduct are also possible at elevated temperature. In case the... 

The Backvall group reported the DKR of p-amino acids using CAL-A and Ru or Pd catalyst (Scheme 5.38) [61]. CAL-A was immobilized in the functionalized meso-cellular form (MCF) to improve its stability and enantioselectivity. The DKR with Pd catalyst and the MCF-immobilized CAL-A provided (S)-products, with better yields and higher enantiopurities (Chart 5.34). Our group explored the DKR of p-amino acids for preparing Ihe products of opposite configuration with PSL and Pd/ AIO(OH) (Scheme 5.39) [62]. As PSL was not thermally stable, the PSL-catalyzed resolution and Pd-catalyzed racemization were performed alternatively at two different temperatures (RT and 70 °C) to give (R)-product with 90% yield and >99% ee (Scheme 5.39). 

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).

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