Optically active 1,2-amino alcohols

Evans has recently reported the use of structurally well-defined Sn(II) Lewis acids 119 and 120 (Fig. 9)for the enantioselective aldol addition reactions of a-heterosubstituted substrates [83]. These complexes are easily assembled from Sn(OTf)2 and C2-symmetric bisoxazoline Hgands 124 and 126 (Fig. 10). The facile synthesis of these ligands commences with optically active 1,2-amino alcohols 122, which are themselves readily available from the corresponding a-amino acids 121 [84, 85]. The Sn(II) bis(oxazoHne) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, using 10 mol % of 119, thioacetate and thiopropionate derived silyl ketene acetals add at -78 °C in CH2CI2 to glyoxaldehyde to give hydroxy diesters 130 in superb yields and enantioselectivities as well as diastereo-selectivities (Eq. 12). The process represents an unusual example wherein 2,3-anti-aldol adducts are obtained in a stereoselective manner. 

The isopropyl esters of optically active 1,2-amino alcohols 695a,b were converted to the corresponding cyclic carbamates 696a,b with GDI [461, 462]. 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

As with the reduction of aldehydes and ketones (16-23), the addition of organometallic compounds to these substrates can be carried out enantioselectively and diastereoselectively. Chiral secondary alcohols have been obtained with high ee values by addition to aromatic aldehydes of Grignard and organolithium compounds in the presence of optically active amino alcohols as ligands. ... 

Considerable improvement was achieved with binuclear copper(II) chelates of type 195 whose ligands are derived from salicylaldehyde and an optically active amino alcohol 91>92>. 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

Essentially all of the early studies were directed towards enantioselective cyclopropanation and Maas has reviewed the literature up to 198 54. The most successful of these early studies were those of Aratani and coworkers"2 174 who developed chiral copper(II) chelates of type 153 from salicylaldehyde and optically active amino alcohols with which to catalyse intermolecular cyclopropanation with diazoesters. Enantioselectivities exceeding 90% ee could be achieved in selected cases (equations 133 and 134) including the synthesis of permethrinic acid 154 and /ram-chrysanthemic acid 155. 

The most important development of this useful procedure has been the incorporation of an optically active amino alcohol, to provide a chiral adjuvant (or auxilliary), in the resulting oxazoline. The amino alcohol employed was (1S.2S)-... 

Barbas and colleagues have applied the organocatalytic direct amination of aldehydes in a series of reports [7]. By combining acetone, various aldehydes, dibenzyl azodicarboxylate and i-proline as the catalyst, a one-pot synthesis of functionalized /Tamino alcohols was achieved [7a]. The scope of the reaction was found to be quite general for various aldehydes, and the optically active / -amino alcohols were obtained in high yields with low diastereoselective control. However, excellent enantioselectivity of especially the anti-adduct was obtained. 

The yield of amino alcohols has been shown to improve by addition of tertiary alkyl bulkhead amines, and catalytic cycles using chloramine-T (364, 366, 367) or IV-chloro-lV-argentocarbamates (368) have been devised. By the use of asymmetric inductants such as (-)-10,11-dihydro-quinine with the imide, optically active amino alcohols have been produced (369). 

Metallation-alkylation of chiral formamidine derivatives of 1,2,3,4-tetrahydroisoquin-oline provides optically active 1-alkyl-1.2,3,4-tetrahydroisoquinolines. The formam-idines of 10 optically active amino alcohols have been examined as the chiral auxiliaries and of these, the bistrimethylsilyl ether 2 (S.S-BISPAD) of 1 proved to be the mc>st efficient as well as consistent (equation II). The configuration (S) was established by synthesis of the benzoquinolizine (S)-5, a degradation product of an alkaloid. 

Diastereoselective allylation of optically pure sulfinyl dienal complexes using tributyl allyltin can be obtained (Scheme 138). 2,4-Hexadien-1,6-dial iron tricarbonyl complex (88) undergoes nucleophilic addition reactions with diaUcylzincs in the presence of a catalytic amount of an optically active amino alcohol (Scheme 139). Very high enantio-and diastereoselectivity is observed. Related reactions of (88) with chiral allyl boronic esters give allylated alcohols in very high enantiomeric excess. 

When chiral amines are used in the oxyamination reaction, stereogenicity is induced in the amination step and in this way optically active amino alcohols are obtained after oxidation69. An optically active secondary or tertiary amine can be used as a ligand for palladium in the intermediate 7t-complex, to which an excess of an achiral amine can be added (reagent-induced diastereoselectivity). Here, a pair of diastereomeric tt-complexes are formed which may be in equilibrium with each other, the degree of asymmetric induction is dependent on the ratio between the diastereomeric complexes and/or on their different reactivity. 

Preparation of Chiral Sulfinates. Optically active sulfinates can be prepared by reaction of a symmetrical sulfite with t-Butylmagnesium Chloride in the presence of an optically active amino alcohol. The best enantioselectivity has been observed using quinine as the optically active amine (eq 2)3 An alternative approach to this new enantioselective asymmetric synthesis of alkyl t-butylsulfinates would be reaction of a racemic sulfinate with r-butylmagnesium chloride complexed by optically active alkaloids (eq 3). In this case, kinetic resolution of the racemic sulfinate leads to an optically active sulfinate and an optically active sulfoxide. 

A new perspective was opened up recently when Denmark demonstrated diat with chirally modified phosphoryl-activated allenes an asymmetric induction could be effected. From easily generated allenyl phosphoramidates containing an optically active amino alcohol, the diastereomeric adducts (37) and (39) could be obtained by addition of dlyl alcohol. When the separated adducts were employed in the carb-anionic Claisen rearrangement, a remarkable asymmetric induction (90 10) could be achieved with preferential formation of the diastereomers (38) or (40) respectively, whereas in a thermal reaction no stereoselection was observed (Scheme 63). Another example of an asymmetric induction in Claisen rearrangements is reported by Welch. ... 

Enantioselective Michael addition of thiols to enones is a useful reaction for the synthesis of sex pheromones [26] and terpenes [27]. For example, enantioselective Michael additions of thiols to 2-cyclohexenone (64) and maleic acid esters in the presence of chiral bases such as cinchona alkaloids [28, 29] and optically active amino alcohols [30, 31] have been reported. It has also been found that the enantioselective Michael addition reaction proceeds efficiently in an inclusion crystal... 

With optically active amino alcohols and aldehydes, a mixture of diastereomers generally results. For N—H oxazolidines, the ratio of isomers is about 2 1, and for N—Me or N—Pr analogues the ratio is about 9 1. For A-tosyl derivatives, however, diastereomerically pure 2,4-cw-oxazolidines are isolated <92H(33)28i>. Trans isomers (189) are obtained in ratios >10 1 from the zinc chloride or trimethylsilyl triflate-catalyzed reaction of 2-methoxy-oxazolidines with allyltrimethylsilane or... 

Pybox L8 (Fig. 4) was synthesized from pyridine-2,6-dicarboxylic acid and optically active amino alcohols via an amido chloride intermediate [ 16,23 ] or via BFj-catalyzed cychzation of intermediate amino alcohols [24]. The combination of Pybox-i-Pr (L8a) and [Rh(COD)Cl]2 (Rl) exhibited catalytic activity as an in-situ catalyst for the reduction of acetophenone (Kl) to give 76% ee (S) [16].However, the complex RhCl3(Pybox-z-Pr) R4a under assistance with AgBF4 accelerated the reduction in THF to give 94-95% ees [23]. Diphenylsilane (SI) was also the best silane in this system. Most aromatic methyl ketones were reduced in 90-99% ees, and reactions of levurinate KIO and 2-octanone Kl 1 resulted in 95% ee and in 63% ee, respectively. The Pybox-Rh catalyst R4a reduced selectively 2-phenylcyclohexanone K12 to give the S-alcohols for both trans- and cis-isomers PI and P2 in 96-99% ees [25]. The catalyst R4a can differentiate only the enan-... 

Our research group independently found a catalytic enantioselective proto-nation of preformed enolate 47 with (S,S)-imide 30 founded on a similar concept (Scheme 5) [51]. The chiral imide 30, which has an asymmetric 2-oxazoline ring and is easily prepared from Kemp s triacid and optically active amino alcohol, is an efficient chiral proton source for asymmetric transformation of simple metal enolates into the corresponding optically active ketones [50]. When the lithium enolate 47 was treated with a stoichiometric amount of the imide 30, (K)-en-riched ketone 48 was produced with 87% ee. By a H-NMR experiment of a mixture of (S,S)-imide 30 and lithium bromide, the chiral imide 30 was found to form a complex rapidly with the lithium salt. We envisaged that a catalytic asym-... 

Muzart and coworkers have succeeded in a catalytic asymmetric protonation of enol compounds generated by palladium-induced cleavage of 3-ketoesters or enol carbonates under nearly neutral conditions [47,48]. Among the various optically active amino alcohols tested, (-i-)-e do-2-hydroxy-endo-3-aminoborn-ane (25) was effective as a chiral catalyst for the enantioselective reaction. Treatment of the P-ketoester of 2-methyl-1-indanone 58 with a catalytic amount of the amino alcohol 25 (0.3 equiv) and 5% Pd on charcoal (0.025 equiv) under bubbling of hydrogen at 21 °C gave the (P)-enriched product 59 with 60% ee... 

Reaction of optically active a-amino esters with an excess of Grignard reagent gives optically active amino alcohols with complete retention of configuration... 

Chiral aminophosphane-phosphinites (AMPP), prepared by the reaction of chloro(diphenyl)-phosphane with optically active amino alcohols, such as ephedrines, prolinol and A -methyl-phenylglycinol, are used as ligands in transition metal catalyzed cyclodimerization of butadiene to 4-vinylcyclohexene62,10 . With a nickel(0)LJ catalyst (L = Proliphos), (—)-4-vinylcyclo-hexene with 15% ee was obtained in 50% yield6. ... 

Asymmetric synthesis of dialkylacetic acids can be done using a chiral oxazoline intermediate 4 derived from a readily available optically active amino alcohol. The... 

These transformations serve to illustrate the principles involved in asymmetric synthesis. The requirements for efficient synthetic utilization are (a) an easily available optically active reagent that can carry out the desired transformation, and (b) reaction conditions that lead to a high percentage of enantiomeric preference. In general, it is also desirable to be able to recover the optically active reagent. The Diels-Alder example is a case where this can be accomplished. Hydrolysis or lithium aluminum hydride reduction gives the product and also returns the original alcohol, which can be reused. Similarly, in the synthesis of dialkylacetic acids, the optically active amino alcohol can be recovered by hydrolysis. 

The adducts from these reactions can be transformed in a variety of compounds. As mentioned earlier, the unstable a-hydrazinoaldehydes are often not isolated but rather subjected to further reactions to yield a more stable compound, such as amino alcohols or oxazolidinones. Other transformations are illustrated in Scheme 11.5. For example, the so-formed a-hydrazinoaldehyde can further react with acetone under catalysis by 1 in a one-pot fashion to give optically active amino alcohols containing two stereogenic centers [19]. A subsequent Passerini reaction of the a-hydrazinoal-dehyde can be performed by reacting the aldehyde with an isocyanide. Schmidt and co-workers [20] have shown that this sequential reaction can provide rapid access to... 

Phosphinophenyl)-oxazolines [51] such as 19 can be easily prepared in two steps from 2-bromobenzonitrile (Scheme 23). An alternative route involves oxazoline formation from benzonitrile and an amino alcohol, followed by or-tho-metallation with BuLi [52] and subsequent reaction with Ph2PCl (Scheme 24). Starting from commercially available optically active amino alcohols, a variety of differently substituted enantiomerically pure ligands is readily accessible. 

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