Chiral auxiliaries preparation

Substantially higher enantioselectivities were achieved by reduction of the O-alkyl derivatives of prochiral ketoximes with borane (BH3) and chiral auxiliaries prepared... 

R. B. McAlister, K. Reitz, G. Kang, R. Nakatsu, T. Green, C. Library-Based Lead Compound Discovery Antioxidants by an Analogous Synthe-sis Deconvolutive Assay Strategy, J. Org. Chem. 1994, 59, 5862. (e) Moon, H.-S. Schore, N. E. Kurth, M. J. A Polymer-Supported C2-Symmetric Chiral Auxiliary Preparation of Non-Racemic 3,5-Disubstituted-y-Butyro-... 

Based on the study of the thermal 3-aza-Cope rearrangement of iV-allylketene Af,0-acetals, Kurth and coworkers have developed a similar methodology to the asymmetric synthesis of C(a)- and C( )-substituted-4-pentenoic acids by using a chiral auxiliary. Prepared from the alkylation of oxazolines 179 with tosylate esters 180, followed by neutralization with n-butyllithium in THF, iV-allylketene. /V,0-acetals of 182 rearrange without isolation at 180 °C to 2-butenylisoxazolines (183) with 79-92% diastereoselectivity (d.e,). Enantiomeric excess (e.e.%) reaches as high as 98%. In... 

A -sulfinyl chiral auxiliaries have been used to prepare enantiopure tetrahydro-P-carbolines and tetrahydroisoquinolines in good yields under mild reaction conditions. Both enantiomers of V-p-toluenesulfinyltryptamine 46 could be readily prepared from the commercially available Andersen reagents.Compound 46 reacted with various aliphatic aldehydes in the presence of camphorsulfonic acid at -78 °C to give the A-sulfinyl tetrahydro-P-carbolines 47 in good yields. The major diastereomers were obtained after a single crystallization. Removal of the sulfinyl auxiliaries under mildly acidic conditions produced the tetrahydro-P-carbolines 48 as single enantiomers. 

Another chiral auxiliary used in diastereoselective addition reactions is the 1,3-oxazine derivative 4a which shows a close structural resemblance to the 1,3-oxathiane 16 (vide supra). However, in contrast to the oxathiane, 4a cannot be readily acylatcd in the 2-position. Therefore, the benzoyl derivative 4b was prepared by condensing amino alcohol 3 with phenylglyoxal. 

Further reactions of allyl organometallics with a-alkoxyaldimines 1, prepared from (S)-2-(methoxymcthoxy)propionaldehyde and (R)- and (S)-l-phenylethylamine, illuminate the difference in the influence of the nitrogen chiral auxiliary and the x-alkoxy center7. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Within the biooxidation of disulfides, chiral thiosulfinates become available. Tert-Butyl tert-butanethiosulfinate represents a particularly valuable chiral auxiliary for the preparation of several chiral sulfoxides and sulfinimines, which can be subsequently transformed into branched amine compounds, P-aminoacids, and chiral aziridines. This product is accessible readily by mediated biooxidation of tert-butyl... 

Cyclic dithioketals and acetals represent another important class of sulfur containing chiral auxiliaries, which are available in chiral form by biooxidation. Biotransformations were performed on a preparative scale using whole-cells (wild type and recombinant) and isolated enzyme. Again, enantiocomplementary oxidation of unsubstituted dithianes (linear and cyclic, R = H) was observed when using and CPMOcomo (Scheme 9.28) [211,212]. Oxygenation of functionalized substrates (R = substituted alkyl) with gave preferably trans... 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Crimmins and co-workers have developed (V-acyloxazolidinethiones as chiral auxiliaries. These reagents show excellent 2,3-syn diastereoselectivity and enantio-selectivity in additions to aldehydes. The titanium enolates are prepared using TiCl4, with (-)-sparteine being a particularly effective base.141... 

The possibility of using chiral auxiliaries or chiral catalysts to achieve enantio-selective Claisen rearrangements has been explored.253 One approach is to use chiral boron enolates. For example, enolates prepared with the chiral diazaborolidine bromide O lead to rearranged products of more than 95% enantiomeric excess.254... 

The C(9)-C(14) segment VI was prepared by Steps D-l to D-3. The formation of the vinyl iodide in Step D-3 was difficult and proceeded in only 25-30% yield. The C(15)-C(21) segment VII was synthesized from the common intermediate 17 by Steps E-l to E-6. A DDQ oxidation led to formation of a 1,3-dioxane ring in Step E-l. The A-methoxy amide was converted to an aldehyde by LiAlH4 reduction and the chain was extended to include C(14) and C(15) using a boron enolate of an oxazo-lidinone chiral auxiliary. After reductive removal of the chiral auxiliary, the primary alcohol group was converted to a primary iodide. The overall yield for these steps was about 25%. 

The chiral auxiliary method was not commercially ideal for large scale preparation because of the required introduction of two additional steps (protection and deprotection) and because of its poor atom economy. 

The classical method, which was followed to prepare the first example of an optically pure chiral organotin compound, is characterized by the use of a auxiliary chiral group necessary to convert the racemic mixture of enantiomers into a mixture of diastereomers which are then separated by a suitable physical method and converted back into the separated enantiomers by splitting off the chiral auxiliary group. This last step is sometimes difficult to achieve 34 ). 

Nitroalkenes with Chiral Auxiliaries The use of carbohydrates as chiral auxiliary in Diels-Alder reactions for the stereoselective preparation of carbocyclic and heterocyclic chiral rings is well documented.48 For example, D-manno-nitroalkene reacts with 2,3-dimethyl-1,3-butadiene to give a 65 35 mixture of adducts, as shown in Eq. 8.29. The configurations at C-4 and C-5 have been determined to be (4R,5R) and (45,55), respectively. Hydrolysis of the product followed by degradative oxidation of the sugar side chains leads to enantiomerically... 

Dienes with Chiral Auxiliaries The use of dienes with the chiral auxiliary attached to the C-l position of the dienes is the most popular in asymmetric Diels-Alder reactions.59 In 1980, Trost reported high asymmetric induction in the Diels-Alder reaction using l-(S)-0-methylmandeloxy-l,4-butadiene59a However, the result obtained by Trost et al. has remained unique for more than a decade, at least in terms of enantioselectivity. The asymmetric Diels-Alder reaction of chiral diene-amines with nitroalkenes gives aminocyclohexenes with good diastereoselectivity (Eq. 8.37).60 The development in the area of chiral dienes is slow it may be due to the difficulty of preparing these compounds. 

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