Syn/anti selectivity

Hayakawa and Shimizu developed a novel C-C bond-forming reaction by epoxi-dation of methoxyallene 145 with m-chloroperbenzoic acid, which provides a meth-oxyallene oxide intermediate capable of adding to aldehydes. This reaction sequence provides 3-hydroxy-2-methoxy ketones 234 (Scheme 8.59) [133]. The best anti/syn selectivity was obtained by application of a 1 1 mixture of Til4 and Ti(OiPr)4. They also observed the formation of a,/3-unsaturated ketones 236 under comparable reaction conditions when 1-silylated methoxyallene 235 was employed as starting material (Scheme 8.60) [134]. 

Use of the preformed Z-silyl enol ether 18 results in quite substantial anti/syn selectivity (19 20 up to 20 1), with enantiomeric purity of the anti adducts reaching 99%. The chiral PT-catalyst 12 (Schemes 4.6 and 4.7) proved just as efficient in the conjugate addition of the N-benzhydrylidene glycine tert-butyl ester (22, Scheme 4.8) to acrylonitrile, affording the Michael adduct 23 in 85% yield and 91% ee [10]. This primary product was converted in three steps to L-ornithine [10]. The O-allylated cinchonidine derivative 21 was used in the conjugate addition of 22 to methyl acrylate, ethyl vinyl ketone, and cydohexenone (Scheme 4.8) [12]. The Michael-adducts 24-26 were obtained with high enantiomeric excess and, for cydohexenone as acceptor, with a remarkable (25 1) ratio of diastereomers (26, Scheme 4.8). In the last examples solid (base)-liquid (reactants) phase-transfer was applied. 

Under thermodynamic control, the homoallylic alcohol is obtained with an anti/syn selectivity up to 95 531-33. In order to prevent competition between the transmetallation and the complexation of the aldehyde, it is important that the allyltin reagent is added first to the Lewis acid. This is termed a reverse addition . 

Aldol condensation (8, 467). Complete details have been published concerning the fluoride-ion-catalyzed aldol reaction of enol silyl ethers with aldehydes. I hc primary product is the silyl ether of the aldol, and yields can be markedly improved by addition of FSi(CHj), to the reaction. The reaction exhibits only slight anti-syn selectivity, but does show high axial selectivity when the substituent is added to the a-position of a cyclohexanone (equation I). 

The Nicholas reaction was used to synthesize the p-lactam precursor of thienamycin in the laboratory of P.A. Jacobi and thereby accomplish its formal total synthesis. The necessary p-amino acid was prepared by the condensation of a boron enolate (derived from an acylated oxazolidinone) with the cobalt complex of an enantiopure propargylic ether. The resulting adduct was oxidized with ceric ammonium nitrate (CAN) to remove the cobalt protecting group from the triple bond, and the product was obtained with a 17 1 anti.syn selectivity and in good yield. 

Epoxidation of prochiral dialkenyl carbinols 28 provides the anti-epoxide 29 of extremely high optical purity [68, 69, 70]. The first epoxidation occurs in an enantiotopic selective manner while the second one proceeds in an enantiomer-differentiating manner (kinetic resolution). In the second step, the minor (R)-monoepoxides 30 are consumed faster than the major (S)-enantiomers 29 and therefore the enantiomeric excess of the major anfi-monoepoxide 29 increases as the reaction proceeds. If a reaction proceeds with a kfas(/ksio, =104, anti-syn selectivity for the fast reaction=98 2 and for the slow reaction=38 62, as observed in the epoxidation of racemic ( )-l-cyclohexyl-2-buten-l-ol,the enantiomeric excess of anti-29 on calculation is 99.4,99.96, and 99.994% ee at 50,99, and 99.9% conversion, respectively. Yields of anti-29 are 48,93 (maximum), and 91% at the respective conversions. Actually, in the epoxidation of 1,4-pentadien-... 

Both 2,3-e iio,eM(io-dimethylnorboman-7-one 23 and 2,3-enc o,e iio-diethylnor boman-7-one 24 are anti-selective. However, the anti-selectivity of the diethyl derivative is significantly superior to that of the dimethyl derivative. For instance, on reduction with LiAlH4, the anti syn selectivity is 79 21 for 24 and only 55 45 for 23. If cjvicinai —> a interaction, as advocated by Cieplak, is indeed the control element, both molecules will be predicted to exhibit syn selectivity because (a) crc H is more electron-donating than cjc c and (b) the anti side has two endo Cc-h bonds in lieu of the two endo cjc c bonds on the syn side. Consequently, the Cci ce and CJC4-C5 bonds, both on the anti side, must be more electron-rich than the tfci-C2... 

Table 5 Anti/Syn Selectivity of the Aldol Reaction using (2S,5S)-(90)...

In a related process, reaction of the metallated derivatives of the 2-ethyloxazolines (61a-c) with iso-butyraldehyde produces the diastereomeric adducts (62a-c) and (63a-c) (Scheme 23)47 Although reaction of the anion derived from (61a) with isobutyraldehyde proceeds with low (56 44) anti syn selectivity, the reaction of racemic (61b) with isobutyraldehyde proceeds with an acceptable level of anti syn selectivity to give a mixture (9 1) of the adducts (62b) and (63b). When the enantiomerically pure oxazoline (61c) is lithiated and treated with isobutyraldehyde, four diastereomers are produced in a ratio of 18.3 1 2.4 2.2 the anti syn ratio observed in this reaction is thus 82 18. 

Quenching the alkoxyenolate derived from 3 with iodine gives an intermediate iodide 229 with 2 1 anti syn selectivity. Upon warming, iodine is displaced intramolecularly by the hydroxy group, thus forming epoxide 230 in satisfactory yield [79]. 

Enol silyl ethers react with aldehydes with a catalytic amount of TBAF to give the aldol silyl ethers in good yields. These reactions generally proceed under very mild conditions and within shorter periods of time than conventional strong acidic or basic conditions. The products from4-f-butyl-l-methyl-2-(trimethylsilyloxy) cyclohexene and benzaldehyde show very good axial selectivity and a little anti-syn selectivity (eq 20). The aldol condensation of ketones and aldehydes can be achieved in one pot when ethyl (trimethylsilyl)acetate is used as a silylation agent with TBAF (eq 21). 

Similar studies on the cobalt-catalyzed HDA reaction between various 7-substituted norbomadienes and an unactivated terminal acetylene, 1-hexyne, were also investigated (Scheme 16, Table 11). Although the yields remain high, the anti/syn selectivities are poor compared with the corresponding Ni-catalyzed cycloadditions. 

Building on their work reported since 1996 describing investigations on the use of some sugars, notably fructosides, in reduction, epoxida-tion, and indium-promoted allylations, Plusquellec and coworkers recently reported the use of IM sucrose or ethyl fructofuranoside as additives in the aqueous aldolisation reaction of methyl 4-methylcyclo-hexanone with m-nitrophenylbenzaldehyde (and diversely functionalized analogues) performed in the presence of organocatalysts such as L-pro-line (Scheme 8, Table 6). Significant variations in the anti-syn selectivity were observed. 

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