P-branched aldehydes

The observed selectivities in these additions are interpreted by the formation of a chelate 7.72, which reacts on its least hindered face (Figure 7.49). A milder method to remove the chiral auxiliary from the products is a sequential treatment with MeOTf and NaBIfy. By using these conditions, p-branched aldehydes are obtained from 1.87 (R = RCHNCH, R = Me) with an excellent enantioselectivity [339, 342] (Figure 7.49). 

Cp Ir °(NHC) complexes are known to be efficient catalysts in the transfer hydrogenation of carbonyl compounds. One of these catalysts has been used by Corberan and Peris in the one-pot en matic DKR of a p-branched aldehyde. Therefore, the treatment of this aldehyde by Amano lipase PS D I and this catalyst at 80 °C in the presence ofp-chlorophenyl acetate as the acyl... 

Reaction conditions aUcenerCOrEL = 1 1 1, T = 100 °C, 0.2 wt% Rh metal loading, silica 100 p = 10 bar for guanidinium and norbos-Cs, p = 5 bar for sulfoxantphos ionic liquid used for impregnation [BMIM][PF6] a) molar ligand to metal ratio b) ratio of ionic liquid volume to support pore volume c) mol aldehyde per mol rhodium per hour d) ratio between linear and branched aldehyde e) support loaded with ionic liquid only. 

Unstabilized enolates react with allylic carbonates in the presence of metalacyclic iridium-phosphoramidite catalysts. Although ketones and aldehydes have not yet been used directly as pronucleophiles with this catalyst system, silyl enol ethers [80] and enamines [81] react with linear allylic carbonates to form, after workup, p-branched, y-8 unsaturated ketones (Scheme 13). Both methods form products in high yield, branched selectivity, and enantioselectivity for a range of cinnamyl and alkyl-substituted allylic carbonates. However, the silyl enol ethers derived from aliphatic ketones reacted in lower yields than enamines derived from the same ketones. 

Veiy recently it was disclosed, that the water-soluble dinuclear complex obtained in the reaction of [ RhCl(COD) 2] and 11-mercaptoundecanoic acid catalyzed the aqueous/organic biphasic hydroformylation of styrene and various arene-substituted styrenes with good activity and useful selectivity to the branched aldehydes (Scheme 4.6) [82], Below pH 4 the acid form of the complex [ Rh(p-S(CH2)ioC02H)(COD) 2] precipitated virtually quantitatively but could be redissolved in water on addition of base. Importantly, higher olefins could also be hydroformylated by this catalyst (for 1-octene TOP = 17.5 h at 55 °C, 35 bar syngas, n/i = 1.0). 

In 2005, Rovis and Reynolds reported the synthesis of a-chloroesters from a,a-dichloroaldehydes using chiral, enantioenriched not chirald pre-catalyst 75c [115], As shown in Table 14, the reaction scope includes a variety of dichloroaldehydes 201 that afford desired esters 202 in good yields and enantioselectivities. The reaction is compatible with various phenols, including electron-rich and electron-poor nucleophiles. Standard reaction conditions accommodate a variety of aldehydes, although substrates containing P-branching inhibit reactivity. 

Scheme 19 Reductive amination of a-branched aldehydes for the preparation of P-branched amines...

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

The selectivity to the linear product nonanal vas strongly dependent on the CO pressure (see Table 6.4). The linear to branched ratio drops from 29 at Pco = 5 bar to 4 at Pco = 40 bar. Part of this selectivity change can be ascribed to enhanced isomerization at lower CO pressure, but faster P-hydride elimination cannot account completely for the increased formation of the branched aldehyde. The reduced selectivity was attributed to partial ligand dissociation resulting in less selective rhodium monophosphites and/or ligand-free complexes. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

V)-2-(4-Isobutylphenyl)propanal (17b) with 92% ee is obtained from p-isobutylstyrene (16b) by using the Rh-BINAPHOS catalyst, which is the precursor of antiinflammatory drug (S)-ibuprofen (entry 15) [19,64,65]. In a similar manner, the precursor of (S)-naproxen is obtained with 85% ee and excellent regioselectivity in the reaction of 16c catalyzed by Rh-(diphosphite 9) complex (entry 16) [25], Pentafluorostyrene (16e) is converted to the corresponding branched aldehyde 17e by the catalysis of the Rh-BINASPHOS complex with... 

Barbas et al. [113] have published the asymmetric synthesis of spiro-p-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with... 

Reaction conditions 5 imol [Rh(CO)2(acac)], P/Rh = 6, 30 bar CO/H2 (1 1), 100 °C for 1-decene and 1-hexadecane, 80 °C for styrene and n-butyl acrylate, hexane/toluene/perfluoromethylcyclohexane = 4/2/4 (mL), 15 h reaction time. The products were analysed by H NMR and the conversion and selectivity confirmed by GC. To aldehyde, olefin isomerisation accounts for the product balance. c Linear to branched aldehyde ratio, determined by HNMR. The branched product was a 1 1 mixture of enol and aldehyde, the linear aldehyde was < 1%. 

Indeed, when we studied various phosphoric acid catalysts for the reductive amination of hydratopicaldehyde (16) with p-anisidine (PMPNH2) in the presence of Hantzsch ester 11 to give amine 17, the observed enantioselectivities and conversions are consistent with a facile in situ racemization of the substrate and a resulting dynamic kinetic resolution (Scheme 16). TRIP (9) once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine products with different a-branched aldehydes and amines in high enantioselectivities (Hoffmann et al. 2006). 

Under lower CO partial pressures a 16e RCo(CO)3 species will have a long enough lifetime to allow reverse P-Hydride Elimination (see Mechanisms of Reaction of Organometallic Complexes) and increase the possibility for alkene reinsertion to the branched alkyl species, which is slightly more favored thermodynamically. At this point, CO addition and insertion will yield a branched aldehyde, or another /3-hydride elimination can give alkene isomerization. This second mechanistic explanation is in line with more recent results from Rh/PPh3-catalyzed hydroformylation studies (see Section 2.4). 

The segment linkage step in a synthesis of Rhizoxin D [129] consists of the coupling of 6-branched saturated sulfone 291 (Scheme 94) with a,P-unsaturated aldehyde 290. The reaction was carried out with LHMDS in THE... 

Both developments opened up a new era of asymmetric hydroformylation. The results are promising and research is now focused on the synthesis of structurally related ligands. Other ligands, such as the P-N ligand 10, are also showing very high selectivities. Faraone and co-workers, in the hydroformylation of vinyl-naphthalene, reported the exclusive formation of the branched aldehyde while a rhodium/10 catalyst was used (conversion 100%) [84], The enantiomeric excess obtained was 78 % for the / -enantiomer. With methylacrylates an ee of 92 % was observed. For further informations see Sections 2.9 and 3.3.1. 

---