Rhodium catalyzed racemization

Scheme 19.4 Dynamic kinetic resolution of a secondary alcohol based on rhodium-catalyzed racemization and enzymatic acylation.

Tab. 10.8 summarizes the application of rhodium-catalyzed allylic etherification to a variety of racemic secondary allylic carbonates, using the copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol vide intro). Although the allyhc etherification is tolerant of linear alkyl substituents (entries 1-4), branched derivatives proved more challenging in terms of selectivity and turnover, the y-position being the first point at which branching does not appear to interfere with the substitution (entry 5). The allylic etherification also proved feasible for hydroxymethyl, alkene, and aryl substituents, albeit with lower selectivity (entries 6-9). This transformation is remarkably tolerant, given that the classical alkylation of a hindered metal alkoxide with a secondary alkyl halide would undoubtedly lead to elimination. Hence, regioselective rhodium-catalyzed allylic etherification with a secondary copper(l) alkoxide provides an important method for the synthesis of allylic ethers. 

Padwa and Prein (105,106) applied chiral, but racemic, isomiinchnone dipoles in diastereoselective 1,3-dipolar cycloadditions. The carbonyl ylide related isomiinch-none derivative rac-70 was obtained from the rhodium-catalyzed cyclization of diazo-derivative rac-69 (Scheme 12.24) (105). The reactions of the in situ formed dipole with a series of alkenes was described and in particular the reaction with maleic acid derivatives 71a-c gave rise to reaction with high selectivities. The tetracyclic products 72a-c were all obtained in good yield with high endo/ exo and diastereofacial selectivities. In another paper by the same authors, the reactions of racemic isomilnchnones having an exo-cyclic chirality was described (106). 

Preparative Methods substituted 2,3-methanoamino acids are difficult to prepare. Unfortunately, most of the reported syntheses give racemic materials whereas stereochemically pure compounds are required for studies of cyclopropane-based peptidomimetics. The only 2,3-methanologs of protein amino acids prepared in optically active form are ( )- and (Z)-cyclo-Phe and -Tyr, all four stereoisomers of cyc/o-Met, (Z)-cyclo-Arg and (25,35)-(Z)-cyc/o-Trp, although several routes to enantio-enriched 2,3-methanologs of simple nonproteogenic amino acids have been reported. " The most practical synthesis of the title compound is that based on a diastereoselective, rhodium-catalyzed cyclopropanation reaction. ... 

The stereochemistry of the homogeneous rhodium-catalyzed alcoholysis reaction has also been studied (77) (eq. [52]). The predominant stereochemistry was established through a Walden cycle, reduction of the alkoxysilane 142 occurring with almost complete retention at silicon. As shown in Table 31, the rhodium-catalyzed alcoholysis occurs with retention of configuration but low stereoselectivity. Moreover, when the alcohol was used as solvent, predominant inversion or racemization was observed. Predominant inversion was also found in alcoholysis of a substituted silacyclopentane (171), but concomitant epimerization yielding the equilibrium mixture of isomers was observed. 

In the hydroformylation of chiral terminal alkenes only the branched products, not the linear products, give information about the discrimination of the diastereotopic alkene planes. The branched product, however, is normally the minor product, thus incomplete information is gained from experiments of this type. In the rhodium-catalyzed deuterioformylation of racemic 3-methyl-1 -pentene the complete extent of attack on each diastereoface of the olefin can be evaluated from the diastereomeric composition of both regioisomers obtained as products148. An overall preference for attack on the Si-face of the S-enantiomer, and on the Re-face of the S-enantiomer is found. Quantitative evaluations show that the relative abundances of anti- and y M-2,3-dimcthylpentanals alone (obtained from simple hydroformylation) do not even qualitatively reflect the extent of the overall discrimination of the tw o diastereotopic planes of either enantiomer148. 

A bimetallic Rh-Re catalyst (9) is effective for related hydrogenations shown in equation (16) that works best if R = R = H (ee 82-98%). The X-ray structure of the racemic complex was determined. Chiral derivatives of the more familiar ferrocenyl phosphines are effective in the rhodium-catalyzed hydrogenation of... 

To this end Baldwin and SwaUow studied the oxidation of (+)-carvomenthene both photolytically and using [RhCl(Hi3P)3] as the catalyst, equations (276) and (277) [462]. The photochemical reaction gave the isomeric carvotanacetols by way of the corresponding hydroperoxide. The rhodium catalyzed oxidation gave a mixture of racemic carvotanacetone, piperitone, and alcohols. Since the intermediate hydroperoxide was found to be optically stable under reaction conditions, these authors conclude that the bulk of the rhodium-catalyzed reaction proceeds via a symmetrized free radical intermediate. 

Mitsui Toatsu investigated the rhodium-catalyzed version of this reaction, which can be conducted at a much lower syngas pressure (Scheme 4.22) [10]. To avoid deterioration of the catalyst by HCl, a buffer or an amine was added. 2-Chloropropionaldehyde, which is preferentially obtained, might be converted into racemic lactic acid by oxidation of the aldehyde group and replacement of the chloro substituent by a hydroxy group in a basic medium [11]. Alternatively, treatment of 2-chloropropionic acid with aqueous ammonia produces racemic alanine. 

After screening a range of metal complexes based on iridium, aluminum, rhodium, or ruthenium toward their suitability to racemize (S)-l-phenylethanol, Williams and Harris et al. [12] demonstrated a proofof concept for the combination of such a metal-catalyzed racemization of 1-phenylethanol with an in situ enzymatic acylation of preferentially one enantiomer, although some Hmitations appeared such as limited conversion and the need for a range of additives. A representative example for this type of DKR is shown in Scheme 19.4 with the successful synthesis of the ester (R)-IO with enantioselectivity of 98% ee at 60% conversion. 

Scheme 17 Rhodium-catalyzed kinetic resolution of racemic tertiary homoallylic alcohols...

The enantioselective synthesis of axially chiral P—N ligands was also accomplished by rhodium-catalyzed [2 + 2+-2] cycloaddition. The reactions of 1,6-diynes 75 with diphenylphosphinoyl-substituted isoquinolinyl acetylenes 76 furnished diphenylphosphinoyl-substituted axially chiral 1-arylisoquinolines 77 with high yields and ee values (Scheme 9.28) [23], The new diphenylphosphinoyl-substituted axially chiral 1-arylisoquinoline 77 (Z = NTs, R = Me) was derivatized to the corresponding axially chiral P—N ligand 78 and isoquinoline A-oxide 79 without racemization, which could be used in the rhodium-catalyzed hydroboration and Lewis base-catalyzed allylation, respectively [23],... 

After extensive studies, rhodium-catalyzed methylenation of xmactivated ketones was achieved by Lebel and coworkers [31] with the development of new reaction conditions. Use of excess isopropanol, 1,4-dioxane as solvent and higher temperatures were the key factors that led to the high yield of the corresponding olefins (Scheme 17). Substrates containing a-chiral centers were shown to proceed without racemization under the new reaction conditions (38e-g). 

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