Ephedrine-derived chiral auxiliaries

An ephedrine derived chiral auxiliary 32 on a solid support has been applied in the asymmetric synthesis of y-butyrolactones [13, 21], The auxiliary was attached to the resin through the nitrogen. Treatment with a,(i-unsaturated acid chlorides afforded the corresponding esters 33. SmI mediated conversion with aldehydes or ketones gave y-butyrolactones 34 in the so-called asymmetric catch-release reaction (Scheme 12.15). The resin catches the reactive intermediate and undergoes stereocontrolled addition. The product is released spontaneously from the resin-bound auxiliary 32. The resulting y-butyrolactones (34) were obtained in 37-73% yield and 70-96% ee. 

Only few allyltitanium reagents bearing a removable chiral auxiliary at the allylic residue are known. The outstanding example is a metalated 1-alkyl-2-imidazolinone14, derived from (—)-ephedrine, representing a valuable homoenolate reagent. After deprotonation by butyllithium, metal exchange with chlorotris(diethylamino)titanium, and aldehyde or ketone addition, the homoaldol adducts are formed with 94 to 98% diastereoselectivity. 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Ramamurthy et al. have examined enantioselective and diastereoselective ODPM rearrangements of cyclohexadienone and naphthalenone derivatives within MY zeolites, where M is an alkali ion [38, 39]. For example, in Scheme 4.27, in NaY in the presence of several chiral inductors such as ephedrine, pseudoephedrine, and camphorquinone-3-oxime, an enantioselective ODPM rearrangement of 65 and 66 took place to afford 68 in 30% ee yield. In the frame of the chiral auxiliary approach, the compound 67 linked to (S)-ephedrine was irradiated within NaY to give 68 in moderate diastereoselective excess (de) (59%). Interestingly, the reaction media of KY, RbY, and CsY reverse the diastereoselectivities. The cation-dependent diastereo-meric switch has been discussed with respect to the N- or O-functional group in 67 [39]. Recently, Arumugan reported that the irradiation of naphthalenones 65 linked chiral auxiliaries (R3 = COO(—)-Ment or (S)-NHCH(Me)Ph) in Li+ or Na + Nafion resulted in chiral products ( 14% de) [40],... 

Phosphorus-Containing Ring Systems. - The chiral a-diazophosphonic acid derivatives (289), (290) and (291) have been prepared from (-) ephedrine and (S,S)-N,N -dimethyl-l,2-diaminocyclohexane. Preliminary experiments suggest that the new chiral auxiliaries investigated exert little influence over the subsequent reactions of the derived rhodium (II) acetate-catalysed O-H and N-H insertion reactions. ... 

To explore the viability of chiral auxiliaries in the vinyl phosphate-p-ketophosphonate rearrangement, a series of vinyl phosphates derived from ephedrine, pseudoephedrine, (lR,2S,5R)-(-)-menthol, (15,25,35,57 )-(-i-)-isopinocampheol, (5)-(-)-2-methylbutanol, binaphtol, and (2R,4R)- or (25,45)-pentane-2,4-diol have been examined. (5)-(-)-2-methylbutanol and 2,4-pentane-2,4-diol derivatives appear as the most attractive chiral auxiliaries. 

Enantiopure P-alkoxyalcohols have also been used as chiral auxiliaries. Among the most useful auxiliaries in this class are the acyclic methylether 1.11 [148] or silylether 1.12 [149, 150], and the cyclic monobenzyl- or neopentylethers 1.13 (R = PhCH2 or tert-BuCH2) derived from exo-bomane-2,3-diols [147], From inexpensive, commercially available ephedrine, (li , 2S)-Af-methylephedrine 1.14 is easily obtained, its (15,2R)-enantiomer is easily available too. The esters of these alcohols [151-154] have frequently been used. Among the cyclic alcohols, sulfonamide derivatives 1.8 and 1.9 (R = NHS02Ar or N(Ar)S02Ph) are especially useful [147,155],... 

Chiral aminonitriles such as 1.70 and 1.71 have been prepared either from the corresponding amino-1,3-diol [300] or from (LR, 2S)-ephedrine 1.61 (R = Me) [301], Carbanion derivatives of these reagents undergo stereoselective alkylations, carbonyl additions [301] and Michael reactions [300], Since the reaction products are aminonitriles, the chiral auxiliary is easily cleaved by mild hydrolysis. 

The enolates of //-acylimidazolidinones derived from 1.131 generated from ephedrine 1.61 (R = H) are useful in asymmetric alkylations [447, 448] and aldol reactions [449, 450] and cuprate additions to the a,p-unsaturated acyl analogs have recently been described [451], These chiral auxiliaries are cleaved by MeONa/MeOH or LiEtBHj. Recently, Davies and coworkers have suggested the use of symmetrical AyV-diacyl-1,3-imidazolidin-2-ones 1.132, formed from diamines having a C2 axis of symmetry [452], for asymmetric aldol reactions [449]. Juaristi [453] has used peihydropyrimidin-4-ones for related purposes. 

These results are interpreted by the attack of the aldehyde on the least hindered side of the enolate 6.104, through a chair or twist-boat-like transition state [408] (see above). Both (S)- and (R)-chromium tricarbonyl complexes of 2-me-thoxyacetophenone have been prepared, and their boron enolates react selectively with MeCH=CHCHO, although further decomplexation was not carried out [1280]. Chiral aminonitrile 1.71 bearing the ephedrine skeleton [301] or men-thone-derived ketals [374] have been used as chiral auxiliaries in aldol reactions, but modest selectivities were obtained. 

In an application of the chiral auxiliary technique, succindialdehyde has been transformed into mono-N-tosyloxazolidine 1.83 (n = 0, Y = CH=CHCOOH) derived from ephedrine. Treatment of 1.83 with KOC1 leads to an epoxyacid with high diastereoselectivity [1385], After nucleophilic ring opening of epoxide, the chiral auxiliary is recovered by treatment with ethanedithiol (Figure 7.35). Epoxidation of the (2, 47 )-pentane-2,4-diol monoketal of a prochiral quinone with tri-tylhydroperojdde has been performed with a moderate selectivity by Corey and Wu en route to a natural product (70%) [1386],... 

Palladium catalyzed [3+2j-cycloadditions of 2-(trimethylsilylmethyl)-3-ace-toxy-l-propene to electron-deficient double bonds bearing chiral auxiliaries is usually poorly stereoselective. However, face selectivity is interesting when using ephedrine-derived system 1.93 [352]. 

All four chiral auxiliaries are available derivatives of ephedrine. Structurally, they are vicinal amino-alcohols, which are able to act as l,4-N,0-bidentate ligands for many metal cations. The stability of such complexes generally enhances with the hardness of the central metal ion [17]. 

Optically active allylboronates bearing chiral auxiliary located at the boron atom found widespread applications in asymmetric synthesis. Enantiomerically enriched a-alkylidene-y-lactones and lactams can also be synthesized following such a synthetic approach. VUlieras et al. (41, 45] demonstrated the potential of chiral allylboronates derived from 2-phenyl-2,3-bomanediol, ephedrine, or norephedrine for this purpose. Chiral allylboronates 46a,b were obtained in a sequence of reactions involving transformation of achiral precursors 32 into the corresponding boronic acids 44 followed by their esterification with enantiomerically pure diol or 1,2-aminoalcohol 45 (Scheme 4.10). In the case of methyl-substituted derivatives 32b (R = Me), initial composition of E- and Z-isomers was transferred to the target allylboronates 46b. Importantly, the isomeric mixture was separated by means of the column chromatography. 

Hitchcock and covrorkers developed ephedrine-derived 3,4,5,6-tetrahydro-21-f-l,3,4-oxadiazin-2-one-based chiral auxiliary 141 and demonstrated its utility in aldol reactions [50]. It vas discovered that the aldehyde had to be present during enolization for reaction to occur, because of difficulties in enolization. Use of aromatic aldehydes resulted in good yield and good to excellent selectivity, as did aliphatic aldehydes vithout a-hydrogen atoms. This method is not useful for aldehydes bearing a-hydrogen atoms, because of self-condensation. 

Chiral benzophospholanes are an interesting class of compounds with potential appUca-tions as chiral ligands in enantioselective reactions. These reactions can be promoted by palladium complexes however, the selectivity is moderate [1]. An alternate approach used an ephedrine-derived auxiliary (Scheme 4.192) [330], One of the keys to the synthesis was the use of ether as the solvent. Other solvents such as THF were not as effective. The final step in the synthesis involved loss of the chiral auxiliary and formation of the borane-protected l-phenyl-2-ox-a-l-phosphindane. The yield and selectivity of the process were outstanding (96%, 97.5% ee). 

Accordingly, the Evans protocol, when applied to A-propionyl oxazolidinone 51 derived from ephedrine, leads to the predominant formation of the diastere-omeric syw-aldols, again with outstanding stereoselectivity. In this case, the enolate attacks the Re-hce of aldehydes with high preference. The procedure is illustrated in Scheme 4.48 for an aldol addition to a-benzyloxyacetaldehyde yielding the crude product 213 in a diastereomeric ratio of higher than 99 1. After recrystallization, the stereochemically homogeneous aldol adduct 213 was transformed into the Weinreb amide 214 in the course of a total synthesis of the macrolide antibiotic cytovaricin. In the transamination step, the chiral auxiliary 46 was recovered [111]. 

The chiral amide coupling technology can be extended to pre-formed a-functionalised chiral boronates derived from ephedrine" (Table 16.3). Other chiral auxiliaries, such as the Evans oxazolidinones, were not stable to the basic conditions necessary for Suzuki coupling however, the ephedrine-based amides do not suffer a loss in diastereomeric ratio (dr) due to epimerisation at the a-centre. 

The ketones 56,57, and 58 are some of the monocychc P,y-enones whose photochemical reactions upon sensitized irradiation have been examined. Irradiation of the dienone 56 in ether is reported to give the bicyclic ketone 59 via oxa-di-Ji-methane reaction. Recently, the photoreaction of cyclohexadienone 56 and its derivatives having chiral auxiliaries was examined in alkali ion exchanged Y zeolites. Thus, irradiation of 56 in dry (-)-ephedrine-modified zeoHte gave the ODPM product in 30% ee. Significant... 

Reports on general chiral auxiliaries for the diastereoselective hetero-Diels-Alder reaction have been more sporadic than those of chiral auxiliaries developed for the parent Diels-Alder reaction (Section 17.4). Tietze demonstrated that an (-)-ephedrine-derived auxiliary functioned as an excellent controller group in the Et2AlCl-catalyzed inverse-electron-demand cydoaddition reaction of enone 216 (Scheme 17.30) [112]. After the formation of 217 (dr >98 2), the auxiliary could be readily excised by hydrolysis to give chiral lactone 218. 

Both enantiomers of 2-methylamino-l-phenylpropanol (ephedrine, 1), which are commercially available and relatively inexpensive, have been used as auxiliaries in many syntheses of chiral compounds. Ephedrine can be used for amide alkylations both directly1-3, or as derived heterocyclic compounds (see Sections 1.1.1.3.3.4.2.1. and 1.1.1.3.3.4.2.2.). Acyclic derivatives of ephedrine are discussed in this section. For example, either enantiomer of ephedrine gives A-acylephedrines 2 in good yield without epimerization if treated with an anhydride at 65 °C for 10 minutes2. 

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