Asymmetric MBH-reaction

Scheme 6.107 Product range of the 106-catalyzed asymmetric MBH reaction between aldehydes and 2-cyclohexen-l-one.

Scheme 6.163 Product range of the asymmetric MBH reaction catalyzed by bisthiourea 176 in the presence of DABCO.

DMAP) [27], imidazoles [28], guanidine [29], azole [30], and N-methylpiperidine [31] were also used successfully in non-asymmetric MBH reactions. 

The influence of solvents was extensively studied [38, 40b, 42], with reactions shown capable of being performed in neat, or, virtually in any polar medium. Whilst high dielectric constant oxygenated solvents such as tetrahydrofuran (THF), 1,4-dioxane, acetone (Et20), dimethyl sulfoxide (DMSO), and dimethyl-formamide (DMF) are used in non-asymmetric MBH reactions, dichloroethane (CH2C12) or acetonitrile are preferred for asymmetric transformations. MBH re-... 

The first chiral catalysts were developed from achiral molecules such as DABCO, quinuclidine, indolizine or pyrrolizine-derived catalysts by introducing asymmetric functions. Hirama and co-workers examined chiral C2-symmetric 2,3-disubstituted l,4-diazabicyclo[2.2.2]octanes such as 2,3-(dibenzoxymethyl)-DABCO (29) as catalysts for asymmetric MBH reaction between 4-nitro-benzaldehyde 27 and methyl vinyl ketone (MVK, 28) (Scheme 5.6) [57]. The additive function of the catalyst compared to the achiral DABCO resulted, however, in diminished reactivity, and the reaction required high pressure in order to... 

Scheme 5.6 Asymmetric MBH reaction using chiral DABCO 29.

Natural products having chiral tertiary amine functions were tested among the first catalysts in asymmetric MBH reactions [24, 60]. The importance of the proton donor capacity of the catalyst in the rate and selectivity of the MBH reaction was recognized very quickly, and attention was turned to genuine a-amino alcohol structures, such as the compounds listed in Scheme 5.8 [61]. Results were modest, however. Apart from the earlier discussed (R)-3-HDQ, which catalyzed the MBH reaction at atmospheric pressure (though with no enantioselectivity),... 

Scheme 5.8 Some natural product-derived catalysts in asymmetric MBH reactions.

An important step in the development of asymmetric MBH reactions was the introduction of the quinidine-derived /Msocupreidine catalyst (/MCD) 44, by the Hatalceyama group [64, 65]. /MCD mediated the addition of acrylate 43 to a variety of aromatic and aliphatic aldehydes even at —55 °C in DMF, and afforded (R)-adducts in good yields (40-58%) and excellent enantioselectivity (ee up to 99%) (Table 5.3). The contribution of the 1,1,1,3,3,3-hexafluoroisopropyl acryl ester (HFIPA) to the reactivity of the system deserves comment. This ester displayed... 

Table 5.3 Asymmetric MBH reaction of aldehydes and HFIPA (43) catalyzed by /MCD (44).

Although dimeric Sharpless ligands as catalysts showed impressive results in related organocatalytic transformations, they provided only limited success in asymmetric MBH reactions (Scheme 5.12) [70]. These compounds are bifunctional catalysts in the presence of acid additives one of the two amine function of the dimers forms a salt and serves as an effective Bronsted acid, while another tertiary amine of the catalyst acts as a nucleophile. Whereas salts derived from (DHQD)2PYR, or (DHQD)2PHAL afforded trace amounts of products in the addition of methyl acrylate 8a and electron-deficient aromatic aldehydes such as 27, (DHQD)2AQN, 56, mediated the same transformation in ee up to 77%, albeit in low yield. It should be noted that, without acid, the reaction afforded the opposite enantiomer in a slow conversion. 

Several D-mannitol-derived phosphines have also been examined in the asymmetric MBH reaction (Scheme 5.18) [86, 87]. Phospholane 89a catalyzed this reaction with low conversion and low ee (19%). In the presence of the hydroxyl phospholane 89b as catalyst, the reaction was accelerated significantly (83% in 9 h versus 29% in 70 h), while the enantioselectivity could not be ameliorated (Scheme 5.18). 

Nagasawa and co-workers reported the use of a chiral bis-thiourea catalyst (108) for the asymmetric MBH reactions of cyclohexenone with aldehydes [95]. Since others had already shown that thioureas form hydrogen bonds with both aldehydes and enones, it was hypothesized that the inclusion of two thiourea moieties in close proximity on a chiral scaffold would organize the two partners of the MBH reaction and lead to enantiofacial selectivity. Initial studies showed that the achiral 3,5-bis-(trifluoromethyl)phenyl-substituted urea increased the rate of MBH reaction between benzaldehyde and cyclohexenone. These authors then showed that chiral 1,2-cyclohexyldiamine-linked bis-thiourea catalyst 108, used at 40 mol% loading in the presence of 40 mol% DMAP, promoted the MBH reactions of cyclohexenone with various aliphatic and aromatic aldehydes (40) to produce allylic alcohols in moderate to high yields (33-99%) and variable enantio-selectivities (19-90% ee Table 6.33). 

Typical Procedure for the Triethyl Phosphine and Chiral Binaphthol-Derived Bronsted Acid Co-Catalyzed Asymmetric MBH Reaction [43] (pp. 173 and 232)... 

One of the first practical catalytic asymmetric MBH reactions was reported by Hatakeyama and coworkers, who utilized (i-isocupreidine (69, P-ICD), derived from quinidine, as a catalyst (10mol%) [45a]. Enantioselectivities as high as 99% were achieved in the reaction of a variety of aliphatic and aromatic aldehydes with the very... 

In an important achievement Vo-Thanh and co-workers realized that chiral ionic liquids such as 35 can act as chiral inducers for the asymmetric MBH reaction.The V-octyl-V-methylephedrinium trifluoromethanesulfonate salt 35, used as solvent in the DABCO-mediated reaction of methyl acrylate and benzaldehyde, produced the corresponding allylic alcohol in 60% yield and 44% ee after 7 days at 30 °C. 

In addition to tertiary amines, triphenylphosphine is also an effective promoter and the use of enantiomerically pure amines or phosphines to catalyse the reaction is an interesting prospect, since the products would be synthetically useful. In addition there is also the potential for Lewis acid/Bronsted acid-catalysed asymmetric MBH reactions. While early attempts at the development of a catalytic asymmetric variant were only moderately successful, providing products with up to 50% ee, some recent progress has been made in this area and high ees have been obtained in both the MBH and aza-Baylis-Hillman reaction of a,p-carbonyls with imines. 

A number of BINOL-based bifunctional organocatalysts, for example (7.171-7.173), containing both Bronsted acidic and Lewis basic sites have been used to good effect in the asymmetric MBH reaction. The amine-thiourea (7.171) promotes the MBH reaction of aliphatic aldehydes with 2-cyclohexenone with ees ranging from 80 to 94% while both the (pyridinylaminomethyl)BINOL (7.172) and phosphine (7.173) catalyse the aza-Bayhs-Hilhnan reaction of simple a,p-carbonyls such as MVK and phenyl acrylate with N-tosyl arylaldmines with similar levels of enantioselectivity. 

Subsequently, the novel bi-stereogenic chiral ionic liquids 310 and 311, containing two chiral centers in the side chain bonded to the 2-position of the imidazolium cation and different anions, have been synthesized and applied to asymmetric MBH reactions of aldehydes with acrylates or cyclohexenone as reaction media. The corresponding adducts were obtained with fair enantioselectivities (up to 25% ee), albeit in moderate to high yields (up to 97%), by using chiral ionic liquid 311 as solvent (Scheme 1.123). ... 

However, the most important progress in the development of cinchona derivative catalyzed asymmetric MBH reactions was the introduction of the... 

Subsequently, Hatakeyama et successfully employed this methodology for the synthesis of the important biologically active molecules epopromycin B (125), 2 -cpi-epopromycin B (126) and (-)-mycestericin E (127), which involved a p-ICD-catalyzed asymmetric MBH reaction as the key step (Scheme 2.62). 

Br0nsted or Lewis acid additives increases the reaction rate, yield and selectivity in some cases. The highest ee achieved is 49% with R) configuration at the newly formed stereogenic centre. For ot-naphthyl acrylate as substrate, the p-ICD catalyzed asymmetric MBH reaction can be achieved with 92% ee. 

Although dimeric Sharpless ligands, as another kind of cinchona catalyst, showed impressive results in related organocatalytic transformations, they provided only limited success in asymmetric MBH reactions (Scheme 2.78). These compounds can act as bifunctional catalysts in the presence of acid... 

During their studies on kinetic resolution (KR) of secondary alcohols, Connon et al. found that chiral pyridine catalyst 177 and its optimized analogue 178 promoted the synthetically useful KR of MBH adducts 179 derived from deactivated precursors (which were difficult to synthesize using catalytic asymmetric MBH reactions), allowing the convenient preparation of 179 in 62-90% ee and 82-97% ee, respectively (Scheme 2.87). This study also represents the first examples of effective non-enzymatic acylative KR of sec-sp -sp ... 

Several D-mannitol-derived phosphines (CP7-CP10) catalyzed asymmetric MBH reactions have been investigated by Zhang and co-workers. These phosphine catalysts did not offer any satisfactory enantioselectivities (2-19% ee) however, some rate acceleration was observed in the case of hydroxyl phospholane CP9 (Scheme 2.117). 

At almost the same time, Nagasawa s group developed the C2-symmetric chiral bis-thiourea-catalyzed asymmetric MBH reaction of cychc enones with aldehydes (Scheme 2.196). They found that the bis-thiourea catalyst 363 promoted the reaction of cyclohexenone with benzaldehyde in the presence of an additive (0.4 equiv) such as DMAP or imidazole to afford the allyhc alcohol (DMAP — 5 °C, 88%, 33% ee imidazole room temperature, 40%, 57% ee). Higher enantioselectivities were obtained in the reaction with aliphatic aldehydes (up to 90% ee). A transition state 364, in which both the aldehyde and the enone coordinate to the thiourea groups of 363 through hydrogen bonding interactions, was proposed to explain the stereochemistry of the product. 

In addition, mono-thioureas 366, which straightforwardly derived from commercially available enantiopure amino alcohols, have been found to promote the asymmetric MBH reaction of 2-cyclohexen-l-one with different aldehydes in the presence of triethylamine under solvent-free conditions. The corresponding allylic alcohols were obtained in good to high yields with up to 88% ee (Scheme 2.198). ... 

Recently, Aggarwal et al. have found that MBH adducts 179 are excellent dienophiles in Diels-Alder reactions, providing essentially complete diaster-eocontrol with all dienes. Although exojendo stereoisomers 180 were formed with cyclopentadiene and no regioisomers were obtained with isoprene, the emerging asymmetric MBH reaction coupled with these new Diels-Alder reactions rapidly builds up complex architectures in a stereocontrolled process from very simple and inexpensive starting materials, and this will no doubt find applications in synthesis (Scheme 3.72). ... 

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