Chiral auxiliaries phenylethyl

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

Fig. 1 a Crystal structure of the carboxylate anion portion of the (R)-(+)-l-phenylethyl-amine salt of keto-acid 37a before irradiation, and b after 70% conversion to the corresponding cyclobutanol (ionic chiral auxiliary not shown)... 

The use of optically active enamines in [2 + 2] cycloadditions with thiocarbonyl 5.5-dioxides gives asymmetric induction in the product thiirane 1,1-dioxides. Thus, when thioformaldehyde S,S-dioxide, generated from methanesulfonyl chloride and triethylamine, is treated with optically active AM-phenylethyl-Af-methylpropanal enamine, a mixture of diastereomeric thietane 1.1-dioxides 6 is formed quantitatively. Removal of the chiral 1-phenylethyl auxiliary followed by Hoffmann elimination gives (-+ )-(5)-2-methyl-2//-thiete 1,1-dioxide (7) with 6% ee1,8. 

The same chiral auxiliary has been used in the cycloaddition of an optically active azomethine ylide to benzaldehyde and to l-nitro-2-(3,4-methylenedioxyphenyl)ethylene Ae ylide was generated in situ by treating (R)-(+)-/V-(l-phenylethyl)-A -cyanomethyl-A -trimethylsilylmethylamine (33) with silver fluoride. Unfortunately, no selectivity was observed in the first case and only a 3 2 preference was expressed in the second. Use of the azomethine ylide derived in the same manner from (/ )-(-)-N-(l-phenyl-2-methoxyethyl)-/V-cyanomethyl-N-trimethylsilylmethylamine (34) displayed a modest, but potentially useful, 4 1 diastereofacial selectivity in its reaction with l-nitro-2-(3,4-methylenedioxyphenyl)ethylene. The precise structure of the major and minor product was not determined (Scheme 25). 

The matched double stereoselective reaction between the chiral C-phenyl A -( 1-phenylethyl) nitrone and the chiral silyl ketene acetals 558 in acetonitrile/dichloromethane at 20 °C under zinc iodide-catalyzed conditions resulted in only the single diastereomer 559 in 98% yield. Exposure of 559 to acid afforded the isoxazolidinone 560 in 74% yield, together with the chiral auxiliary (li ,2 S )-2-phenylcyclohexanol (Scheme 135) <1997JOC6672>. 

The 209D diastereomer (+ )-590 has also been made by Comins and Zhang (Scheme 78) 466,467). After 77-acylation of the 4-methoxypyridine 591 with (1 S,2R,4S)-4-isopropyl-2-( 1 -methyl-1 -phenylethyl)cyclohexyl chloroformate, the resulting pyridinium salt was intercepted with hexylmagnesium chloride to give the optically active enaminone 592. Removal of the chiral auxiliary and A -alkylation with (Z)-l,3-diiodopropene yielded 593, thereby setting the scene for a novel anionic... 

In one approach (Fig. 2, route C) the resolution of the racemic anhydride 6 was attempted via the regioselective opening with various chiral auxiliaries, however, even with sterically hindered alcohols the diastereoisomeric esters could not be separated on a technical scale by crystallization. In contrast, good selectivity was obtained with (S)-phenylethyl hydroxylamine. This pathway, however, failed due to problems at a later stage. 

More recently, the use of the oxoacetate of /ra v-2-phenylcyclohexanol as a chiral auxiliary in ene reactions has been described86. The level of control with this auxiliary is comparable to that obtained with 5-methyl-2-(l-methyl-l-phenylethyl)cyclohcxanol, as exemplified by the reaction with 1-hexene (see Table 4. entry 7), but with the opposite absolute sense of control (R). 

Enantioselective cychzations have also been achieved using chiral auxiliaries. Al -Benzyl groups have been used. The a-phenylethyl [337] and a-naphthylethyl [338] groups achieved diastereoselectivity in the 60-80% range in acid-catalyzed reactions with aromatic aldehydes. The diastereomer with syn orientation of the phenyl and aryl substituents is preferred and this appears to be the result of thermodynamic control. 

An asymmetric intramolecular Michael-aldol reaction which leads to nonracemic tricyclic cyclobutanes is performed by using TMSOTf andbis[(/ )-l-phenylethyl]amine as chiral amine, but only moderate enantioselectivities are reached (eq 68). A similar reaction sequence can also be carried out with TMSOTf and HMDS as base, with (—)-8-phenylmenthol as the chiral auxiliary however, the iodotrimethylsilane-HMDS system is more efficient in terms of yield and diastereoselectivity. The combination EtsN/TMSOTf (or some other trialkylsilyl triflates) has been used to accomplish an intramolecular Michael reaction, which was the key step for the synthesis of sesquiterpene (=E)-ricciocarpin A. ... 

The substrate-induced diastereoselectivity was investigated using an (R)- or (S)-1-phenylethyl group as a chiral auxiliary on the amide nitrogen. The reactions with the unprotected compounds went smoothly and diastereomeric mixtures were obtained in excellent yield and syn diastereoselectivity (> 99% syn) (entries 6-8). The results were better than those obtained with the butylamides. The facial selectivity was in the range of about 8 1. The protection of the hydroxyl group lowered both the facial selectivity and the yield (entry 8). 

Diastereoselective Cyclization Important intermediate for preparation of carbapenam antibiotics was synthesized by electrochemical intramolecular carbon-carbon bond forming reaction (Scheme 8) [9]. In this cyclization, (l )-phenylethyl group works as a good chiral auxiliary. 

An important advantage of enol ether dienophiles is their use in asymmetric synthesis through attachment to a chiral auxiliary. Vinyl ethers derived from (+)-camphor, (l/ ,25)-2-phenylcyclohexanol, (7 )-2,2-diphenylcyclopenta-nol, and (l/ ,25)-2-(l-methyl-l-phenylethyl)cyclohexanol... 

The ionic aza-Diels-Alder cycloaddition reactions of cyclopentadiene and pro-tonated glyoxylate imines possessing two chiral auxiliaries, N-(R) or N-(S)-l-phenylethyl and 8-phenylmenthyl or 8-phenyln omenthyl, yielded optically pure... 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

Hydrosilylation of acetophenone to give silyl ether (M R = Me) can also be achieved using copper(I) complexes with the chiral phosphine ligands (-)-DIOP (87) or (+)-NORPHOS (88). The enantioselectiv-ity is rather low, but a nonphosphine auxiliary, PYTHIA (89) with a Rh(COD)Ch catalyst using neat diphenylsilane reduces aryl ketones to (R)-l-phenylethyl alcohol silyl ethers in high yield and with high enantiomeric excess (Scheme 18). " ... 

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