Chiral enol ethers

Tab. 3.4 Cyclopropanation of the chiral enol ether 89 under Simmons-Smith conditions...

Tab. 3.5 Cyclopropanation of the chiral enol ethers 92-95 under Furukawa conditions...

Selenski investigated the use of chiral enol ether auxiliaries in order to adapt method F-H for enantioselective syntheses. After surveying a variety of substituted and unsubstituted enol ethers derived from a vast assortment of readily available chiral alcohols, she chose to employ enol ethers derived from trans-1,2-phenylcyclohexanol such as 73 and 74 (Fig. 4.37). These derivatives were found to undergo highly diastereoselective cycloadditions resulting in the formation of 75 and 76 in respective... 

Jason Green has successfully applied the Selenski method to the synthesis of (+ )-bromoheliane (79, Fig. 4.38).34 In this example, two equivalents of the chiral enol ether are added to the benzaldehyde 77 in diethyl ether (0.1 M) and cooled to —78 °C. Methyl Grignard is then added. The cycloaddition occurs while the reaction warms to room temperature. The benzopyran adduct 78 forms in 80% yield with 50 1 diaster-eoselectivity. DFT calculations and experiments suggest that the diastereoselectivity depends on the magnitude of the HOMO-LUMO band gap. In this instance, the LUMO of the supposed o-QM intermediate is computed to be —2.6 eV, whereas the HOMO of the enol ether is —5.9 eV. A 50 1 selectivity is recorded for resulting 3.3 eV gap. For reactions of 2,5-bis-OBoc-4-methyl-benzaldehyde, where the HOMO-LUMO gap is larger (3.6 eV), a 20 1 ratio of diastereomers is observed. 

Isoquinolinium 369 and [2,7]naphthyridin-2-ium 371 salts have also been used for the preparation of 2,3,8,8a-tetrahydro-57/-oxazolo[3,2-tf]pyridine derivatives (Scheme 98) addition of Grignard reagents to 369 is followed by a spontaneous cyclization to 370 <1998JOC1767> while an asymmetric version of the Bradsher cycloaddition between 371 and chiral enol ether 372 gives 373 in good yield and selectivities <1996TL7019>. 

Substituted cyclohexanones, bearing a methyl, isopropyl, tert-butyl or phenyl group, give, on deprotonation with various chiral lithium amides in the presence of chlorotrimethylsilane (internal quench), the corresponding chiral enol ethers with moderate to apparently high enantioselec-tivity and in good yield (see Table 2)13,14,24> 29 36,37,55. Similar enantioselectivities are obtained with the external quench " technique when deprotonation is carried out in the presence of added lithium chloride (see Table 2, entries 5, 10, and 30)593. 

Chiral ketals of 4-alkylcyclohexanones and of m-3,5-dimethylcyclohexanone with (/ ,/ )-2,4-pentanediol are converted, on treatment with triisobutylaluminum in dichloromethane at 0°C and subsequent acetylation of the first formed alcohol with acetic anhydride, to chiral enol ethers with high yield and good diastereoselectivity82. 

A very useful class of chiral auxiliaries has been developed for alkenes substituted with a heteroatom. These auxiliaries, attached to the heteroatom, allow for the preparation of enantiomerically enriched cyclopropanols, cyclopropylamines and cyclopropylboronic acids. Tai and coworkers have developed a method to efficiently generate substituted cyclopropanol derivatives using the cyclopropanation of a chiral enol ether (equation 78) . The reaction proceeds with very high diastereocontrol with five- to eight-membered ring sizes as well as with acyclic enol ethers. The potential problem with the latter is the control of the double bond geometry upon enol ether formation. A detailed mechanistic study involving two zinc centers in the transition structure has been reported. ... 

An ab initio study of the 2 + 2-cycloadditions of allene to isocyanic acid and ketene to vinylimine found the reactions to be concerted and mostly asynchronous.28,29 The diastereoselective 2 + 2-cycloaddition of dichloroketene with a chiral enol ether (26) produced the cyclobutanone (27), which leads to a key intermediate (28) in (g) the total synthesis of the natural alkaloid (-)-Swainsonine (29) (Scheme 8).30 The... 

The absolute configuration and enantiomeric excess of amino ketones 20 were evaluated by gas chromatography (GC) and, 3C NMR studies after conversion into the diastereomeric acetals 21. The reaction proceeds via addition of the nitrene 18 to the double-bond of 19. The yield and diastereoselectivity of this reaction were significantly enhanced when using chiral enol ethers 23, generated from C2 symmetric 22. The best result (36 % yield and 50 % ee) was obtained using a fivefold excess of reagent 6e and equimolar amount of triethylamine [12d] (Scheme 9). 

In order to carry out asymmetric cycloadditions of nitrosoalkenes, Reissig et al. have introduced chiral enol ethers derived from terpenes [378] and from the glucose derivative 4-46 [379]. Using these compounds, considerable asymmetric induction has been obtained thus, the 5,6-dihydro-4H-l,2-oxazine 4-45 was formed by hetero Diels-Alder reaction of 4-34 with chiral 4-44 in good diastereo-selectivity (Fig. 4-10) [379]. 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

A very recent study presented by Dujardin et al. describes the complementary use of chiral enol ethers as dienophiles in oxa Diels-Alder reactions. This approach has yielded promising results with regard to the synthesis of enantio-merically pure carbohydrates [481]. Further noteworthy studies directed to the preparation of biologically active amino sugars from enaminoketones have been carried out in our group [110]. 

Starting from 2-(2-(2-aminophenylthio)-l//-pyrrol-l-yl)acetic acid 60, available through two synthetic steps from o-aminothiophenol, 9//-pyrrolo[2,l -b 1,3,6]bcnzothiadiazocine-10(l l//)-one 61 was obtained in 54% yield (Scheme 11, Section 14.08.5.4 <1995JHC683>). Azidoformate 51 derived from chiral enol ether, when irradiated, gives 3,6-dioxazocan-2-one derivative 52 by a highly diastereoselective intramolecular cycloaddition (Scheme 9, Section 14.08.5.3 <1999EJO2709>). 

The most recent formal asymmetric synthesis of (+)-anatoxin-a was achieved through a highly diastereoselective [2+2] cycloaddition of dichloroketene with a chiral enol ether(63 Scheme 7.15) in order to reach the general stracture of 2,5-disubstituted pyrrolidine (66) for generating the acyliminum ion and getting the required bicycle skeleton (67) (Muniz et al. 2005). 

The [2+2] cycloaddition of this chiral enol ether 63 with in situ generated dichloroketene proceeded with a high level of facial discrimination (95 5) to afford dichlorocyclobutanone 64 (Greene... 

Greene, A.E., and Charbonier, F. 1985. Asymmetric induction in the cyclo-addition reaction of dichloroketene with chiral enol ethers. Aversatile approach to optically-active cyclopentenone derivatives. Tetrahedron Lett 16, 5525-5528. 

Photochemical [2 + 2] Cycloadditions. Photochemical [2 + 2] cycloadditions between alkenes and chiral phenylgly-oxylate derivatives of 3-hydroxyisobomeol show minimal diastereoselectivity (16% de). Better results are obtained in [2 + 2] cycloadditions between chiral enol ethers and Dichloroketene (eq 7). After ring expansion and expulsion of the auxiliary (Diazomethane, Chromium ll) Perchlorate),... 

Alternatively monosaccharides have been prepared via cycloaddition of chiral enol ethers to oxadienes [372,373,374]. 

J ,4i )-Pentane-2,4-diol was used as chiral auxiliary in the diastereo-differentiating Simmons-Smith reaction of the corresponding chiral enol ethers 53 to give a diastereomeric mixture of 54 and 55 in a ratio of ca. 96 4, which was found to be solvent dependent for the diethylzinc reagent. The major isomer was separated by recrystallization from a suitable solvent. 

T. Mukaiyama and M. Murakami, Synthesis, 1987, 1043 and refs, therein T. Mukaiyama, K. Wariishi and Y. Saito, Chem. Lett., 1988, 1101 U. von der BrUggen, R. Lammers and H. Mayr, J. Org. Chem., 1988, S3, 2920 and refs, therein for a promising reaction of a chiral enol ether with an acetal under mild conditions and with high diastereoselectivity, see D. J. Krysan and P. B. Mackenzie, J. Am. Chem. Soc., 1988, 110, 6273. 

Inverse demand cycloaddition of isoquinolinium salt 1 to chiral enol ethers, acetals and ortho esters 2 gives diastereomeric tetralins 3 and 4 with the diastereoselectivity depending on the nature of the dienophile and on the chiral auxiliary1. The primary tricyclic adduct solvolyzes to the tetralinaldehyde acetal in acidified alcohol. 

Among them, cyclopentanone 9 has been obtained from the chiral enol ether 8, even in gram quantities188. 

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