Diastereomeric cyclohexenes

Cinnamyl bromide 24 and the iodocarbohydrate 23 are combined in a zinc-mediated fragmentation/allylation reaction to afford a highly functionalized 1,7-diene, which is then treated with Hoveyda-Grubbs second-generation catalyst to produce a mixture of diastereomeric cyclohexenes 25 (35% yield) and 26 (32% yield). From the major isomer 25, subsequent Overman rearrangement, dihydroxylation, and deprotection afford the natural product pancrastistatin (28) (Scheme 3.10). 

The regioselectivity of this reaction is excellent (92 8), and the diastereomeric purity of 2 is estimated to be 93% de on the basis of the oxidation of 2 to (5)-2-cyclohexen-1-ol (93% ee). Similarly, the reaction of 2 with acetaldehyde provides (S.iS H- -cyclohexeny ethanol with an enantiomeric purity of 92% cc. Reactions of 2 with other aldehydes, however, have not yet been reported. 

The analogous reaction with 1,1,3-trimethyl-2-(trimethylsilyloxy)cyclohexene employing titani-um(IV) as the Lewis acid also proceeded in the same stereochemical sense and gave 1,2-benzox-azin-2-ium 2-oxide 6 as the only diastereomeric product in 75% yield16. 

In considering the retrosynthetic analysis of juvabione, two factors draw special attention to the bond between C(4) and C(7). First, this bond establishes the stereochemistry of the molecule. The C(4) and C(7) carbons are stereogenic centers and their relative configuration determines the diastereomeric structure. In a stereocontrolled synthesis, it is necessary to establish the desired stereochemistry at C(4) and C(7). The C(4)-C(7) bond also connects the side chain to the cyclohexene ring. As a cyclohexane derivative is a logical candidate for one key intermediate, the C(4)-C(7) bond is a potential bond disconnection. 

Reaction of 299 with benzaldehyde was found to give an equimolar mixture of diastereomeric j3-hydroxysulfoxides (314). Addition of 299 to a-tetralone 300 was more satisfactory, since the corresponding diastereomeric/3-hydroxysulfoxides 301 were formed in a 1.8 1 ratio. Their subsequent desulfuration with Raney nickel yielded levorota-tory 1-hydroxy-1-methyl-1,2,3,4-tetrahydronaphthalene 302 of unknown absolute configuration and optical purity. Similarly, addition of 299 to cyclohexene oxide leads to the formation of diastereomeric /3-hydroxysulfoxides 303 in a 2 1 ratio which, after separation, may be desulfurized to give (R,R)- and (S,S)- trans-2-methylcyclo-hexanols 304, respectively. Analysis of NMR spectra of the... 

Unusual amino acids include a class of unnatural a-amino acids such as phenylalanine, tyrosine, alanine, tryptophan, and glycine analogs, and f)-amino acid analogs containing 1,2,3,4-tetrahydroisoquinoline, tetraline, l,2,3,4-tetrahydro-2-carboline, cyclopentane, cyclohexane, cyclohexene, bicyclo[2.2.1]heptane or heptene skeletons. Different selectors were exploited for the separation of unusual amino acids, most of the production being made by Peter and coworkers teicoplanin [41, 56, 84, 90, 93, 124, 141-144], ristocetin A [33, 94, 145, 146], and TAG [56, 147]. Enantiomeric and diastereomeric separations of cyclic -substituted a-amino acids were reported by other authors on a teicoplanin CSP [88, 89], Ester and amide derivatives of tryptophan and phenylalanine were recently analyzed on a Me-TAG CSP [58],... 

The vinyloxirane reaction was later extended to methylidene cyclohexene oxide and to related meso derivatives [53]. The effects of the diastereomeric ligands 42 and 43 (Fig. 8.5), derived from (S)-binaphthol and (S, S)- or (R, R)-feis-phenylethyl-amine respectively, were investigated. In the case of kinetic resolution of racemic methylidene cyclohexane epoxide 45 with Et2Zn, ligand 42 produced better yields, regioselectivity, and enantioselectivity than 43 (Scheme 8.27). 

SchOllkopf et al. reacted lithiated isocyanides with epoxides to obtain 3-hydroxyalkyl isocyanides. The reaction was also performed with cyclohexene oxide, and the hydroxyisocyanate formed was cyclized to oxazines with copper(I) oxide, resulting in a diastereomeric mixture of 174 and 175 (76LA2105 86AG755). Irradiation of aliphatic dieneamides yielded a variety of dihydrooxazines of type 167 (88T1959). 

However, treatment of (2/ ,3/ )-8-rer/-butyl-2,3-dimethyl-l,4-dioxaspiro[5.4]decane with trimethyliodosilane and hexamethyldisilazane in dichloromethane, followed by deprotection of the silyl ethers with tetrabutylammonium fluoride gives, in a combined yield of 78%, diastereomeric (S)-l-[(l) ,2/i)-2-hydroxy-l-methyl-propoxy]-4-tm-butyl-l-cyclohexene and () )-methylpropoxyl]-4- CT7-butyl-l-cyclohexene in a ratio of 20 1 (by GC)83a. 

The combined Birch reduction alkylation of chiral, enantiomerically pure aroyl amides of 2-pyrrolidinemethanol (prolinol) or 2-pyrrolidinecarboxylic acid (proline) gives chiral, non-racemic, 1,1-disubstituted 2,5-cyclohexadienes 1 or 2-cyclohexenes 2, respectively, in high diastereomeric ratios. These reactions are useful for the preparation of valuable chiral synthetic intermediates 3 25 29-31-36. 

When (2S)-1-(1-cyclohexene-l-yl)-2-(methoxymethyl)pyrrolidine (206), enamine from cyclohexanone, and (S)-proline-derived (2S)-(methoxymethyl)pyrrolidine is added to the Knoevenagel condensation products (207), mainly one of the possible four diastereomers is formed. The diastereomeric purity was found to be excellent (d.s. > 90%) 203). The stereochemical course of this highly effective asymmetric synthesis allowed the synthesis of the optically active target molecules (208). A possible mechanism discussed by Blarer and Seebach 203). 

Asymmetric cyclopropanation.3 The anion of ( + )-l reacts with 2-cyclohexene-1 -ones to form two diastereomeric adducts (2), which are separated by chromatography on silica gel. Cyclopropanation of optically pure 2a or 2b with the Simmons-Smith... 

Elwesine. The starting material for a synthesis [83] of elwesine (320) [84] (Scheme 48), the 0-protected cyclohexene derivative 321, itself obtained from 4-benzyloxycyclo-hexanone, was converted into a 1 4 diastereomeric mixture of bromohydrins 322 and 323 with N-bromosuccinimide and thence by dehydration to a mixture of a-allyl bromide 324 and the p isomer325. 

Azido-phenylselenenylations of olefinic compounds can be effected with BAIB/PhSeSePh/NaN3 in CH2C12 (Scheme 14) [37]. Such additions proceed in anti-Markovnikov fashion and appear to be initiated by addition of the azido radical to the C,C-double bond. While cyclohexene and ds-4-octene gave 3 1 and 2 1 mixtures of diastereomeric adducts under these conditions, dihydropy-ran was converted cleanly to the trans-addition product. Regioselective azido-phenylselenenylations of dihydropyran derivatives and O-protected glycals with this reagent have also been documented [21,38,39]. 

Another strategy for the synthesis of lycorine commenced with the Diels-Alder reaction of l-methylenedioxyphenyl-2-nitroethylene with butadiene to provide the cyclohexene derivative 85, which on reaction with MCPBA gave 86 together with the diastereomeric epoxide (1 1) (Scheme 6) (112). Hydrogena-... 

Because the C=C double bond of the cyclohexene used in Figure 3.22 is labeled with deuterium, it is possible to follow the stereochemistry of the whole reaction sequence. First there is a c -selective hydroboration. Two diastereomeric, racemic trialkylboranes are produced. Without isolation, these are oxidized/hydrolyzed with sodium hydroxide solution/ H202. The reaction product is the sterically homogeneous but, of course, racemic di-deuteriocyclohexanol. The stereochemistry of the product proves the cw-selectivity of this hydration. 

Computational chemistry has been employed to calculate energy differences between diastereomeric activated complexes in the stereoselective deprotonations of cyclohexene oxide by monomeric, homo- and heterodimeric lithium amides (see Section II.A.2). Computational chemistry has also been used as a tool for design of highly stereoselective amides. Such a design approach has resulted in the homochiral base 20 and its enantiomer. These are readily available from both enantiomers of norephedrine, by inexpensive routes... 

Bromo-2-pyrone is not only a valuable precursor for the synthesis of various 3-substituted 2-pyrones,7 but it is also a reactive unsymmetrical diene.8 3-Bromo-2-pyrone undergoes Diels-Alder cycloadditions with a regioselectivity and stereoselectivity that is superior to that of 2-pyrone. Furthermore, 3-bromo-2-pyrone is a chameleon (i.e., ambiphilic) dienophile, undergoing cycloaddition to both electron deficient and electron rich dienophiles. The cycloadducts of bromopyrone with dienophiles are isolable and are useful in the synthesis of diastereomerically pure cyclohexene carboxylates (Scheme 2).8... 

When this free radical azidoselenenylation procedure is applied to cyclohexene and ( )-4-octene, the corresponding azidoselenides 64 and 65 are formed as 3 1 and 2 1 diastereomeric mixtures, respectively101. 

Alternatively, ethyl A-(/J-chloroalkyl)carbamates can be obtained by the addition of ethyl N.N-dichlorocarbamate to alkenes, followed by a reduction step with sodium bisulfite or sodium metabisulfite (Na,S205). The same mixture of diastereomeric adducts (antijsyn 62 38) was obtained from (E)- and (Z)-2-butene under UV irradiation74, and the thermal addition by a radical mechanism to cyclohexene, cycloheptene, and cyclooctene was unsatisfactory because of the low yield and/or the low diastereoselectivity72,142. However, the addition to cyclopentene, indene, and acenaphthene in benzene as solvent was stereoselective in all cases the <7.s-adducts were formed initially at 0 C, but on heating the m-ad ducts or performing the reaction at 25 °C the tram-adducts were exclusively obtained142. 

The stereochemistry of the cyclohexene adduct was established as cis by comparison of the product with the authentic tnms-isomcr prepared by ring opening of cyclohexene oxide with tert-butylamine. Similarly, the products obtained from (Z)- and ( )-l-deuterio-l-decene were converted to diastereomeric oxazolidinones which were compared with the authentic diastereo-mers. Furthermore, different diastereomers were obtained from ( )- and (Z)-l-phenylpropene, It is therefore reasonable to assume complete syn addition for all alkenes. 

The reaction of cyclohexene with AT-(phenylseleno)phthalimide in the presence of (S,S)-hydrobenzoin in methylene chloride afforded two diastereomeric oxyselenides (38 and the (li , 2R) diastereomer) in a 1 1 ratio. Compound 38 was separated and converted into the olefin 39 via selenoxide elimination. The second PhSeOTf promoted oxyselenenylation reaction gave only the cis fused bicyclic dioxane 40. Oxidation and subsequent elimination provided the olefin 41. This is the key intermediate for the syntheses of the cyclitols 42 and 43, that were obtained from a series of classical reactions as indicated in the Scheme. Oxyselenenylation reactions have also been employed to promote glycosylation reactions [43]. 

Quite recently, a new asymmetric addition reaction has been described by Tiecco. The oxidation of the diselenide 26 with ammonium persulfate produces the camphorselenyl sulfate, which reacts with alkenes in acetonitrile in the presence of water, to afford the hydroxyselenenylation products in good yields and with moderate to good diasteroselectivities [46b]. The results of these experiments are collected in Table 3. Moderate diastereomeric ratios were observed in the hydroxyselenenylation of cyclohexene, styrene and -methylstyrene. Good facial selectivity was observed in all the other cases. The two diastereomeric addition products thus obtained could be separated in most cases. Enantiomerically pure saturated or allylic alcohols... 

Asymmetric azo-ene reactions of di-(-)-(li ,25)-2-phenyl-l-cyclohexyl diazenedi-carboxylate with alkenes are promoted by SnCU. Use of cyclohexene affords the ene adduct in 80 % yield with a diastereomeric excess of > 97 3 (Eq. 58) [92]. 

We also felt that the relative solubilities of the diastereomeric amides (or their crystal lattice energies) might be related to the sense of steric bulk disymmetry about that central backbone. If one could perform a chemical reaction, such as addition to the double bond, that could alter the distribution of steric bulk, one could hope to invert diastereomer solubility. Addition of a symmetrical reagent, such as bromine, avoids positional isomerism and the stability of the bromonium ion ensures stereoselectivity. Thus each diastereomeric amide gave only one bromine adduct. The solubilities were indeed dramatically altered and, since bromine is easily removed (Zn, acetic acid) it became possible to use the amide mixture that had been recovered from purification to claim the more soluble diastereomer as its bromine adduct. A process was established to obtain both enantiomeric cyclohexene acids using only one chiral amine. 

Singlet photosensitized polar addition of methanol to (A )-(>)-limonene (102) in nonpolar solvents afforded a mixture of the diastereomeric ethers 103 and 104 and the rearrangement product 105 (Scheme 6.42).677 The diastereomeric excess (de) of the photoadduct was optimized by varying the solvent polarity, reaction temperature and nature of the sensitizer. The first step of the reaction is the Z E photoisomerization (Section 6.1.1) of 102 to a highly strained /i-isomer, followed by protonation and methanol addition. The initial formation of a carbocation via the protonation step has been excluded under those reaction conditions. The Markovnikov-oriented methanol attack on the less-hindered (Rp)-(E)-102 compared with that of (Sp)-(E)-U)2 explains why 103 can be obtained in up to 96% de upon sensitization with methyl benzoate in a methanol solution. The hypothesis that Z E isomerization of the cyclohexene moiety affords a strained (reactive) alkene, whereas isomerization of the exocyclic double bond does not, was supported by the observation of an exclusive nucleophilic addition to the cyclohexene double bond. 

Further work with the molecular sieve-free Ti(IV)-binaphthol catalyst 56 showed that 1 -alkoxydienes react with methacrolein to afford cyclohexene products possessing a quaternary center adjacent to a stereo chemically defined secondary urethane in near diastereomeric purity and high enantiomeric excess (Scheme 44). 

Scheme 8. Antibodies elicited to the JV-oxide hapten 36 catalyze the cationic cyclization of the arenesulfonate 35 to cyclohexene 38 and the diastereomeric alcohol 39. The background reaction generates a much broader product spectrum 38 to 42...

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