Aldol reactions Norephedrine

A highly diastereofacial /7-selective aldol reaction by using ester derivatives of norephedrine as a chiral auxiliary has been recently reported by Kurosu and Lorca (Scheme 38).138 This practical and general method proceeds via initial ( )-selective substrate enolization and provides access to a broad range of optically active 2-alkyl-3-hydroxycarboxylic acid esters of type 91. 

By the use of chiral oxazolidines derived from a chiral norephedrine and methyl ketones, an asymmetric aldol reaction proceeds in a highly enantioselective manner. In the case of ethyl or a-methoxy ketones, the corresponding anti aldol products were obtained with high diastereo- and enantioselectivities. A chiral titanium reagent, generated from... 

Aldol reactions.1 The chiral oxazolidine (1), formed from 3-pentanone and (-)-norephedrine, after conversion to the tin azaenolate reacts with aldehydes to give predominantly anti-aldols (2) in >90% ee. Reduction of the carbonyl group of the anti-aldol 2 provides (3S,4R)-4-methyl-3-heptanol (3) in 95% ee. 

Allyltributyltin, 10 Boron trifluoride etherate, 43 Di-jjL-carbonylhexacarbonyldicobalt, 99 Grignard reagents, 138 Ketenylidenetriphenvlphosphorane, 154 Methoxyamine, 177 Reformatsky reagent, 346 Tin(IV) chloride, 300 Tributylcrotyltin, 10 Aldol reactions General considerations, 202 Directed aldols using imines Norephedrine, 200... 

The stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with <7-Hex2BOTf and triethylamine produced anti-aldol products, and that of with Bu2BOTf and diisopropylethylamine selectively gave syn-aldol products after reaction with aldehydes (Equation (180)).684 685 Complementary anti- and yy/z-selective asymmetric aldol reactions were also demonstrated in structurally related chiral norephedrine-derived propionate esters (Equation (181)).686... 

The norephedrine-derived Masamune asymmetric aldol reaction was utilized in the total synthesis of (+)-testudinariol A (12), a triterpene marine natural product that possesses a highly functionalized cyclopentanol framework with four contiguous stereocenters appended to a central 3-alkylidene tetrahydropyran6 (Scheme 2.2f). The norephedrine-derived ester 13 was enolized with dicyclo-hexylboron triflate and triethylamine in dichloromethane and then treated with 3-benzyloxypropanal to afford the aldol adduct (14) as a 97 3 mixture of anti/syn diastereomers in 72% yield. Diastereoselectivity within the anti -manifold was 90 10. Protection of alcohol as the methoxyethoxymethyl (MEM) ether followed by conversion of the ester to an aldehyde by LiAlELt reduction and subsequent Swem oxidation gave the aldehyde 16 in 64% yield over three steps. 

Aldol reactions of methyl ketones. The optically active 1,3-oxazolidine (1) formed from a methyl ketone and ( — (-norephedrine aftir conversion to the tin(ll) enolate undergoes enantioselective aldol condensation with aldehydes. The enantioselectivity is partic-... 

Evans and coworkers have developed chiral oxazolidinone auxiliaries such as 10 and 11 that are easily obtainable from (5)-vanilol or from (liS, 2R)-norephedrine. As well as the excellent selectivities obtained in aldol reactions, ease of attachment and removal of these auxiliaries has made this method widely popular. The auxiliary may be recovered and reused after cleavage from the aldol product. 

The f.Z-diene of the seco acid 2 would result from Horner-Emmons and Wittig reactions from aldehyde 3 (Scheme 2). The trimethoxyaniline functionality is carried along as a stable nitrobenzene that would be unmasked at a late stage prior to macrolactam formation. The syn methoxy-hydroxy functionality at C6-7 in 3 is installed using the newly developed glycolate aldol reaction with enal 4 and norephedrine glycolate ester auxiliary 5. This new method is an application of Masamune s recent work with propionate norephedrine aldol reactions.The CIO methyl is installed using the aforementioned hydroboration reaction,... 

Asymmetric aldol reactions mediated by zirconium enolates with chiral auxiliary were reported (Equations 1 and 2). The zirconium enolate derived firom pseudoephedrine-based amide (1) and Cp2ZrCl2 was treated with a series of aldehydes to afford the corresponding aldol adducts (2) in high yields with excellent diastereoselectivity [2]. The high syn selectivity was explained by dinu-dear cyclic intermediates. In contrast, the aldol reactions with norephedrine-based ester (3) proceed with highly anti-selective manner (Equation 2) [3]. In both cases, 2 equivalent of Cp2ZrCl2 were necessary to achieve such high stereoselectivity. 

The Evans oxazolidinone methodology is quite versatile and quite apart from its use in aldol reactions (section 5.3.3) lends itself well to the asymmetric synthesis of carboxylic acids substituted in the a-position with oxygen, nitrogen, and carbon.ti l The auxiliary shown is derived from (+)-norephedrine and the opposite enantiomers of the products are available from the valine-derived auxiliary. 

The diastereofacial selectivity of an asymmetric aldol reaction can also be controlled on the enolate side, and this is the basis of the second-generation methods of Evanst l and Masamune.l24] The complementary Evans auxiliaries (66) and (67) are synthesised from (5)-valine and (15,2/ )-norephedrine respectively. TheZ-enolate (68) is formed exclusively on reaction with dibutylboron triflate, and this reacts with aldehydes to give essentially only one aldol product (69). The diastereofacial selectivity derives from the bulky groups on the auxiliaries which force attack from the opposite face. 

An anti-selective diastereoselective aldol reaction [14] has been performed by using enantiomerically pure carboxylic esters derived from (-) or (+) norephedrine 30 [15], This method is applicable to a wide range of aldehydes with high selectivity (both syn/anti and diastereoselectivity of anti isomer). It is proposed that ( ) boron enolates 31 are formed by this procedure and aldol reaction proceeds via the six-membered transition state (Eq. (14)). The aldol products 32 are converted to the corresponding alcohols (LiAlH4 THF) or carboxylic acids (LiOH, THF-H2O) without loss of stereochemical integrity. 

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. 

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

The Masamune aldol condensation, in common with the Evans aldol condensation, involves a boron enolate of an ester containing a norephedrine derived chiral auxiliary however, unlike the latter, the Masamune aldol delivers a 3-hydroxy-2-methyl carbonyl moiety with the an/z-stereochemistry. Crucial to the success of this reaction is the use of dicyclohexylboron triflate to generate the boron enolate. Note in the Evans aldol condensation, dibutylboron triflate is utilized. 

This new aldol method was then applied to cnal 4 en route to geldanamycin (Scheme 13). Reaction with norephedrine 5 (2 equiv.) gave adduct 43 with >20 1 selectivity in 90% isolated yield. The ester was hydrolyzed with lithium hydroxide and the methyl ester was formed using TMS diazomethane. The alcohol was protected as the TES ether and the aldehyde intermediate 3 was generated with DIBAL. Treatment with the hexafluorophosphonate reagent under Still-Gennari conditions gave Z-unsaturated ester 45 with 13 1 selectivity. 

The chiral auxiliary is the oxazolidinone (24) derived from IS,2R) norephedrine. Acylation with propionyl chloride gives (25) and this is deprotonated to afford exclusively the internally chelated Z-enolate, which reacts with methallyl iodide from the face opposite the methyl and phenyl groups of the auxiliary. The product (26), a 97 3 mixture of diastereomers, is purified to a ratio of better than 500 1. Reductive removal of the auxiliary and careful oxidation of the primary alcohol under non-racemising conditions affords the chiral (5)-aldehyde (27). This in turn is reacted with the boron enolate of (25), which furnishes with remarkable selectivity the u aldol product (28). The reason for the choice of boron rather than lithium is to invert the facial selectivity of the reaction— the enolate is no longer constrained to be planar by internal chelation and rotates in order to place the bulky dibutyl borinyl group on the opposite side to the methyl and phenyl ... 

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