Aldol-type reactions chiral

Aldol-type reactions. Chiral dioxinone derivatives and a-amino y-keto esters are readily obtained. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

Nagao, Y., Hagiwara, Y., Kumagai, T., Ochiai, M., Inoue, T., Hashimoto, K., and Fujita, E. (1986). New C4-chiral l,2-thiazolidine-2-thiones Excellent chiral auxiliaries for highly diastereocontrolled aldol-type reactions of acetic acid and a,b-unsaturated aldehydes. J. Org. Chem. 51, 2391-2393. 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

Chiral bis-phosphine acylplatinum complex 210 with a strong acid such as TfOH serves as an effective enantio-selective catalyst for aldol-type reactions of aldehydes with ketene silyl acetals (Equation (127)).486 The presence of water and oxygen in the catalyst preparation step is required to obtain the highly enantioselective catalyst. The intermediacy of a C-bound platinum enolate was suggested by IR and 31P NMR spectroscopies. 

Oxazolidones as Chiral Auxiliaries Chiral Auxiliary-Mediated Aldol-Type Reactions... 

A study of the kinetics and products of the thermolysis of a series of diaryl-phosphinic azides has been reported.119 Diethyl 1-diazomethylphosphonates undergo an aldol-type reaction with aldehydes to give l-diazo-2-hydroxyalkylphosphonates (152).120 Acidification of the diazophosphonates (153) possessing a chiral phosphorus centre yields mixtures of diastereoisomers (154) and epimers at C. For given R1 and R2, the reaction becomes increasingly stereoselective for X= OAc < Cl < OTs. It may be argued that protonation of (153) will yield a mixture of diastereoisomeric di-... 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

These compounds derived from 3-acetylthiazolidine-2-thione are very versatile chiral materials, capable of being transformed into various synthetic intermediates as previously demonstrated (30). Furthermore, in the stannous enolate mediated aldol-type reactions of 3-(2-benzyloxyacetyl)thiazolidine-2-thione, the stereochemical course of the reaction is dramatically altered by the addition of TMEDA as a ligand. High asymmetric induction is also achieved by the addition of a chiral diamine derived from (S)-proline (31). 

Other chiral magnesium enolates derived from amides are known to react with aldehydes. For example, the aldol-type reaction of magnesium enolate of —)-trans-2-N,N-diethylacetamide-l,3-dithiolanes-5 -oxide with isobutyraldehyde affords a single diastere-omer in 82%. The relative stereochemistry of the adduct originates from a rigid transition state 87 where the oxygen atoms of the enolate and the aldehyde are coordinated to the magnesium atom. ... 

The scope of the present article comprises syntheses of sugar-type compounds containing four or more carbon atoms, an aldehyde or a ketone group, and a minimum of two hydroxyl groups (or their equivalents, such as amino or thiol groups) at least one of them being bound to a center of chirality. The subject of aldol-type reactions of formaldehyde and two- or three-carbon atom hydroxy aldehydes and hydroxy ketones has been omitted a comprehensive discussion of this topic, including a historical survey, has appeared in this Series.5... 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Scheme 120 illustrates aldol-type reaction of aldehydes and silyl ene-thiolates catalyzed by 20 mol % of Sn(II) triflate-chiral diamine combined system in propionitrile or dichloromethane (291). A variety of aldehydes such as aliphatic, ,/3-unsaturated, and aromatic aldehydes are usable. The reaction is facilitated by high affinity of the Sn atom to sulfur atoms and the weak Si—S bond. A binaphthol-containing Ti oxo... 

Scheme 8C.29. Asymmetric aldol-type reaction catalyzed by chiral Schiff base-Ti...

The formation of diastereomers is also possible when two new chiral centers are produced from achiral starting materials. A pertinent example is found in aldol-type reactions between enolates and carbonyl compounds. The achiral enolate and the achiral aldehyde or ketone gives a product with two new... 

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

Asymmetric aldol-type reactions.1 This chiral diamine (1) in combination with tin(II) triflate and tributyltin fluoride (15, 314-315) effects a highly enantioselective aldol-type reaction between ketene silyl acetals and aldehydes. A tentative structure (2) has been suggested for the promotor. 

Aldol-type reactions are among the most important methods for the formation of carbon-carbon bonds. A number of examples of aldol-reactions in ionic liquids have been reported,121 241 of which those involving chiral organic catalysts are particularly promising.125"271 While, for example,... 

Asymmetric Aldol-Type Reaction. CAB complex (2) is an excellent catalyst for the Mukaiyama condensation of simple achiral enol silyl ethers of ketones with various aldehydes. The CAB-catalyzed aldol process allows the formation of adducts in a highly diastereo- and enantioselective manner (up to 96% ee) under mild reaction conditions (eqs 4 and 5). The reactions are catalytic 20 mol % of catalyst is sufficient for efficient conversion, and the chiral auxiliary can be recovered and reused. 

Optically active ferrocenylbisphosphines, (/J)-N,iV-dimethyl-l-[(5)-1, 2-bis(diphenylphosphino)ferrocenyIJethylamine [(/J)-(5)-BPPFA] and its derivatives, are efficient chiral bisphos-phine ligands for rhodium-catalyzed asymmetric hydrogenation, palladium-catalyzed asymmetric allylic substitution reactions, and gold-catalyzed asymmetric aldol-type reactions of a-isocyano carboxylates. ... 

CAB 2, R = H, derived from monoacyloxytartaric acid and diborane is also an excellent catalyst (20 mol %) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. The reactivity of aldol-type reactions can, furthermore, be improved, without reducing the enantioselectivity, by use of 10-20 mol % of 2, R = 3,5-(CF3)2C6H3, prepared from 3,5-bis(trifluoromethyl)phenyl-boronic acid and a chiral tartaric acid derivative. The enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol % 2, R = o-PhOCgH4, prepared from o-phenoxyphenylboronic acid and chiral tartaric acid derivative. The CAB 2-catalyzed aldol process enables the formation of adducts in a highly diastereo- and enantioselective manner (up to 99 % ee) under mild reaction conditions [47a,c]. These reactions are catalytic, and the chiral source is recoverable and re-usable (Eq. 62). 

Yamamoto and co-workers found that 27 is an excellent chiral promoter not only for the aza Diels-Alder reaction of aldimines [40] but also for the stereoselective aldol-type reaction of aldimines with ketene silyl acetals [55]. The reaction of (5)-benzyli-dene a-methylbenzylamine with trimethylsilyl ketene acetal derived from terf-butyl acetate in the presence of (R)-27 produces the (R) adduct in > 92 % diastereomeric excess (de), whereas reaction with (5)-27 gives the adduct in 74 % de. In a similar way, (5)-butylidene a-methylbenzylamine, an aliphatic imine, can be converted to the (R)-)3-amino ester in 94 % de by use of (R)-27 (Eq. 73). 

BLA 28 is very useful in the double stereodifferentiation of aldol-type reactions of chiral imines [41], Reaction of (5)-benzylidene-a-methylbenzylamine with trimethyl-silyl ketene acetal derived from tert-butyl acetate in the presence of (R)-28 at -78 °C for 12 h provides the corresponding aldol-type adduct in 94 % de (Eq. 78). Including phenol in the reaction mixture does not influence the reactivity or the diastereoselec-tivity. The aldol-type reaction using yellow crystals of (R)-28.(5)-benzylidene-a-methylbenzylamine PhOH proceeds with unprecedented (> 99.5 0.5) diastereoselec-tivity (Eq. 79). In general, 28 is a more efficient chiral Lewis acid promoter than 27. 

On the basis of these results, we have developed the first method for the enantiose-lective synthesis of chiral /3-amino acid esters from achiral imines and ketene silyl acetals using BLA 28. The enantioselectivity of the aldol-type reaction is dramatically increased by using sterically bulky A-substituents. Condensation of the imine derived from benzhydrylamine occurs with high enantioselectivity (90 % ee) (Eq. 80). Furthermore, the best result (96 % ee) is achieved by use of a 1 1 (v/v) mixture of toluene and dichloromethane as solvents. Thus, excellent enantioselectivity (95 % ee or better) has been achieved in reactions of aromatic aldehyde-derived imines... 

Enantioselective aldol-type reactions were achieved by addition of chiral diamines, readily prepared from (5)-proline, to the reaction mixture [29]. Sn(II) has three vacant orbitals, and after coordination of two nitrogen atoms one vacant orbital still... 

Soloshonok and Hayashi applied chiral ferrocenylphosphine-gold(I) complexes to asymmetric aldol-type reactions of fluorinated benzaldehydes with methyl isocyano-acetate (27) and A, A/-dimethyl-a-isocyanoacetamide (95). It is noteworthy that successive substitution of hydrogen atoms by fluorine in the phenyl ring of benzaldehyde causes gradual increase of both the cis selectivity and the ee of cw-oxazolines [53]. 

Enzymes turned out to be very helpful in the de novo synthesis of certain monosaccharides. Generally, two chiral carbonyl compounds are combined in an aldol-type reaction. In carbohydrate metabolism, aldolases catalyze the condensation of dihydroxyacetone phosphate (DHAP) and aldehydes to higher sugar components. To date, about thirty aldolases have been classified, but only... 

Similar chiral aldol-type reactions using compound 30, 3-acetyl-(4S)-EOT (31), 3-propanoyl-(4/ ,5S)-MPOT (34), and 3-propanoyl-(4S)-EOT (35) gave fairly high diastereoselectivity (Schemes 5 and 6). 

The aldol-type reaction described in Section V,A.l was applied to the synthesis of chiral azetidinones SO and SI (Schemes 8 and 9). 

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