Camphor aldol reaction

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

In Holton s and Wender s work, the total synthesis was achieved by sequentially forming the AB ring through the fragmentation of epoxy alcohols derived from (—)-camphor and a-pinene. Nicolau s, Danishefsky s, and Kuwa-jima s total syntheses involved B ring closure connecting the A and C rings, whereas in Mukaiyama s synthesis, the aldol reaction was extensively applied to construct the polycyclic system. 

Acyliron complexes with central chirality at the metal are obtained by substitution of a carbon monoxide with a phosphine ligand. Kinetic resolution of the racemic acyliron complex can be achieved by aldol reaction with (1 R)-( I (-camphor (Scheme 1.14) [41], Along with the enantiopure (R, c)-acyliron complex, the (Spe)-acyliron-camphor adduct is formed, which on treatment with base (NaH or NaOMe) is converted to the initial (SFe)-acyliron complex. Enantiopure acyliron complexes represent excellent chiral auxiliaries, which by reaction of the acyliron enolates with electrophiles provide high asymmetric inductions due to the proximity of the chiral metal center. Finally, demetallation releases the enantiopure organic products. 

As with most camphor-based chiral auxiliaries, the size and steric congestion at the C-8 position of the camphor moiety can determine its efficiency. Through the formation of a connection between C-8 and C-2, a novel camphor-based oxazinone auxiliary 29, which can be prepared from camphor in 3 steps,52 becomes highly effective in directing stereoselective aldol reactions (Scheme 5.11).53... 

Aldol reactions using chiral auxiliaries are popular as the stereochemical outcome is usually highly predictable and, as such, they provide a reliable method for the incorporation of adjacent stereocenters. The oxazolidinone-based imides 36 and (ent)-36 are the most commonly employed, and these lead to syn aldol products with high levels of stereocontrol [20]. The reaction can be extended to include a variety of a-heteroatom functionality as in 37 (Scheme 9-13) [21]. Numerous examples of the use of these auxiliaries in the synthesis of polypropionate natural products have been reported. Many related auxiliaries are also available and the camphor-based sultam 38 is notable [22]. 

In the middle of the 198O s some silyl enolates derived from homochiral esters were reported to enable highly enantioselective synthesis of aldols [106]. Later, Oppolzer et al. disclosed the utility of camphor sultam as a chiral auxiliary for asymmetric aldol reactions [107]. Braun et al. have recently achieved high levels of asymmetric induction in the aldol reaction of ketones with homochiral silyl enolate 43 (Scheme 10.38) [108]. 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

Building on the work reported by Mosbach and NichoUs in 1996, in which an artificial class II aldolase was prepared to effect an aldol condensation between acetophenone and benzaldehyde, in 2006, the Nicholls group has reported the first example of an enantioselective C-C bond-forming reaction using an MIP, a TM-mediated aldol reaction between camphor and benzaldehyde to prepare 3-benzylidenecamphor (Scheme 10). A 4-vinylpyridine-DVB-styrene copolymer was imprinted with a complex of Co + and one of two enantiomeric bicycloheptanones. Correspondingly, enantioselective recognition of the template... 

Scheme 10 The enantioselective aldol reaction between (5)-camphor and benzaldehyde and the proposed metal-ion-coordinated transition state of this reaction. ...

An unusual face selectivity in an aldol condensation has been explained by invoking an interaction between the formyl group and a 4,5-positioned unsaturation. Lithium enolates of a-hydroxy ketones, derived from camphor, undergo aldol reactions with typically 90% def onward reaction to a variety of carbonyl products can be achieved with recycling of the camphor auxiliary. 

Highly diastereoselective aldol reactions with camphor-based acetate enolate equivalents have been reported. ... 

Kinetic resolution of iron acyl complex (Structure 1) via aldol reaction with (+)-camphor 5 (Scheme 4.2) ... 

Yan and covrorkers developed titanium enolate acetate aldol reactions as an extension of their boron acetate enolate methodology [13, 14]. Good yields and diastereoselectivity vere reported vhen using camphor-derived N-acyloxazolidinethione 19 (Scheme 2.3, Table 2.4, entries 1-7, and Figure 2.1). The high selectivities vere attributed to additional chelation afforded by the thiocarbonyl of the chiral auxiliary in transition state assembly 20, sho vn in Scheme 2.3. The corresponding camphor-derived oxazolidinone acetate imide provided no stereocontrol, supporting the chelation control hypothesis. 

Shortly thereafter, acetate aldol reactions using camphor-derived imidazo-lidinone 27 vere reported by Palomo and co vorkers [15]. They reported moderate yields and enantioselectivity for a variety of unsaturated and aliphatic aldehydes (Table 2.4, entries 8-12). Interestingly, enantioselectivity for unsaturated aldehydes vas opposite that for aliphatic aldehydes. Also, enantioselectivity reported for titanium vas completely opposite that of the corresponding lithium enolate reactions. 

Camphor-derived asymmetric acetate aldol reactions. 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

Of special interest are chiral-at-iron complexes bearing a carbonyl, a phosphane, a Cp, and an acetyl ligand. The racemic complexes can be kinetically resolved by aldol reaction of their enolates with (l/ )-(+)-camphor (Scheme 4-43). " ... 

Helmchen [67] and Oppolzer [68] investigated and documented the use of camphor-derived auxiliaries in Mukaiyama aldol reactions. Silyl ketene acetals 106 and 108 participate in diastereoselective additions to aldehydes in the presence of TiCl4, affording adducts with up to 99 1 diastereoselectivity (Equations 7 and 8). 

An oxazoline AT-oxide is a versatile dipole and can react with a variety of dipolarophiles (Scheme 8.134). Langlois group has been very active in this area and has made extensive use of the Ai-oxides of camphor-derived oxazolines for these reactions. The initial adduct can be converted to the anti aldol product after hydrolysis and hydrogenolysis. This subject has been thoroughly reviewed by Langlois, " most recently in 2000. " ... 

Boryl enolates prepared from A-propionylsultam reacted with aliphatic, aromatic and a,/Tunsaturated aldehydes to provide diastereomerically pure. qw-aldols (Equation (174), whereas the presence of TiCl4 caused complete reversal of the diastereoface selectivity giving anti-aldols (Equation (175)).676-678 Camphor-derived chiral boryl enolates 423 were highly reactive and highly anti-selective enolate synthon system in aldol addition reactions promoted by TiCl4 or SnCl4 co-catalyst (Equation (176)).679... 

The potassium enolate of camphor (130) is oxidized with oxaziridine (63a) at — 78 °C to afford a-hydroxyketone (131) in 85% yield (Equation (29)) <84JOC324i>. As mentioned earlier lower yields were observed for the lithium enolate because of the imino-aldol side-reaction. The exclusive formation of the endo product is consistent with attack of the oxaziridine from the sterically least-hindered face of the enolate and is a general phenomena for these reagents. 

The 3-hydroxy-K end group is characteristic of capsorubin (28), and other carotenoids isolated from paprika (Capsicum annuum). All syntheses are based on the Cio + C2o + Cio = C4o strategy, and use crocetindialdehyde (27) as central building block and the aldol condensation as the coupling reaction Scheme 6). The synthesis of optically active capsorubin (28), reported in 1973, was the first synthesis of an enantiomerically pure xanthophyll [11]. For the optically active form of the key building block, the frans-Cio-hydroxyketone 26, two approaches have been reported. In the first reaction sequence, (+)-camphor (143) was converted into camphoric acid (144) by treatment with nitric acid. Camphoric acid (144) was then esterified with dimethyl sulphate... 

P-Hydroxy amides. Cerium(III) enolates of amides show better reactivities than the Li enolates toward ketones and aldehydes. Reaction with camphor gives >94% yield of the aldol. 

---