Normant Reagent Research Articles

X-ray Crystallographic and Mass Spectrometric Probing of the Conformational and Ionophoric Properties of Stereoisomeric Hexatetrahydrofuranylhexane Segments

A full account of the synthesis of the 12 hexacyclic tetrahydrofuran isomers represented by the nearby formulas is first provided. The key steps involved in further elaboration of the spiro ethers 12, 15, 28, and 45 include controlled ozonolysis, 1,2-addition of the Normant reagent, and heterocyclization. Eight of the end products proved to be sufficiently crystalline to enable X-ray analysis and determination of their solid-state conformational features. The alkali metal ion selectivities of the 12 hexamers were evaluated by a picrate extraction method and by electrospray ionization mass spectrometry (ESI-MS) which indicated that small, but significant, selectivity differences exist within the groups of diastereomers. These results revealed that each hexamer demonstrated a preference for lithium ion complexation relative to sodium or potassium ion complexation. Stereoisomeric classification of the hexamers was based on the competition between two dissociation routes promoted by collision-induced dissociation. The preference for each of the two dissociation pathways, both of which involved cleavage at the midpoint of the hexamer, correlated with the stereochemical configurations (syn versus anti) of the THF groups near the termini.

Synthesis and conformational properties of several maximally substituted hexa(spirotetrahydrofuranyl)cyclohexanes. Assessment Of the pronounced bias of the all-trans D(3)(d)()-symmetric isomer for total equatorial oxygen occupancy

The poly(spirotetrahydrofuranyl)cyclohexanes 1-4 were prepared in a series of steps that began with oxidative demercuration of pentaspirocyclic chloromercurials. Once the resulting alcohols were transformed into their ketones, it proved possible to cap this center with the Normant reagent and introduce the final heterocyclic ring. The cyclohexanones and the title compounds showed a strong tendency to project their C-O bonds equatorially to the maximum extent possible. The reluctance of these systems to participate in chair-to-chair conformational equilibration was made apparent during measurements to assess their coordination capability toward alkali metal ions. Although 3 was superior to its isomers, this polyether was overshadowed by 15 to an extent in excess of two powers of 10 in their relative capability to coordinate lithium cations. The synthesis, conformation, and low-level dynamic character of 5 are also detailed. To set the stereochemistry of the sixth spirotetrahydrofuranyl ring properly in this case, it was necessary to implement a novel strategy involving late-stage introduction of the oxygen atom. This protocol required intermediate formation of homoallylic alcohol 39, the epoxidation of which proceeded principally in the desired direction. X-ray crystallographic analysis of 5 established that the chair conformation which is adopted has all six C-O bonds projected equatorially. The total inability of 5 to bind to Li(+), Na(+), and K(+) denotes the existence of a substantial barrier to ring inversion. DNMR studies undertaken to assess the magnitude of this barrier demonstrated no change in high-field (1)H and (13)C line shapes up to 573K in 1, 3-([D(3)]methoxy)benzene. Consequently, 5 may qualify as the cyclohexane having the highest chair-chair conformational inversion barrier to the present time.

Vicinal tetrahydrofuranyl substitution of alkyl chains. Tetra-, penta-, and hexafunctionalized arrays.

The tetrakis (tetrahydrofuranyl) dialdehydes 14 and 19 are accessible by oxidative cleavage of extensively substituted cyclohexenes, which have in turn been assembled in a stereocontrolled manner. Reaction of 14 with an excess of the Normant reagent followed by ring closure resulted in conversion to the hexafunctionalized polyether 15. Allylindation of the same dialdehyde gave rise to lactol 16, a reactivity pattern that was essentially duplicated when 19 was treated with the Normant reagent. Attempts to add allylmagnesium bromide to 19 resulted in operation of a Tishchenko reaction with formation of lactone 23. By means of X-ray diffraction analysis, it was possible to ascertain the conformation adopted by 20 and 23 in the solid state. In addition, 15 was shown to populate a conformation in which the oxygen are very predominantly in gauche arrangements, this structural preorganization taking place in the absence of any metal ions.

A head-to-head comparison of α- and β-alkoxy effects on stereoselectivity. Nucleophilic additions to a cyclohexanone substituted with five axial CO bonds

The stereochemical course of the hydride reduction and of the 1,2-addition of allylmagnesium bromide as well as the Normant reagent to 1 has been determined.

Definition of Several Control Elements Relevant to the Stereodefined Serial Elaboration of Belted Poly(spirotetrahydrofurans) Fitted with a Cyclohexane Core.

The stereochemistry of the condensations of 2-cyclohexenones, alpha-arylidenecyclohexanones, and alpha-(tert-butyldimethylsiloxy)cyclohexanones carrying one or two (both syn and anti) spirotetrahydrofuran units adjacent to the carbonyl with allyl organometallics (especially indium) and with the Normant reagent (ClMgO(CH(2))(3)MgCl) is described. Good levels of anti stereoselection are observed in the alpha-arylidene series. Subsequent cyclization generates a second (or third) tetrahydrofuran ring possessing trans vicinal oxygens. Useful levels of matched and mismatched diastereoselection are also attainable by prior alpha-oxygenation. The intrinsic differences in diastereomer production between indium and magnesium organometallics are highlighted. A clear distinction regarding the anticipated direction of stereoselectivity is made on the grounds of chelation capabilities and the intra- or intermolecularity of carbon-carbon bond formation. Finally, the two protocols that are described in detail are shown to be iterative, a feature that augurs well for ultimately accessing the eight possible hexaspirocyclohexanes in an efficient and stereocontrolled manner.

Trans,anti,trans-Tetra(spirotetrahydrofuranyl)cyclohexane-1,2-dione. Stereocontrolled Synthesis and Definition of Its Susceptibility to Photoisomerization.

The title alpha-diketone (18) has been synthesized in stereocontrolled fashion. The ability to introduce the four contiguous spirocyclic ether oxygens in extended trans fashion rests on the ability of the Normant reagent (ClMgCH(2)CH(2)CH(2)OMgCl) to engage in chelation control during 1,2-addition to an alpha-oxy substituted cyclohexanone. The successful pathway is dependent on the ability of osmium tetraoxide to add (slowly) across the double bond of the cyclohexene precursor. The highly substituted 1,2-cyclohexanedione is quite sensitive to light and rearranges by means of an interesting photoisomerization process to a laterally fused pyran system. A likely mechanistic pathway for this intramolecular isomerization is presented.

Solution composition of the Normant reagent. Identification of new THF soluble magnesium methylcuprates CunMgmMe2m+n

Solution composition of the Normant reagent. Identification of new THF soluble magnesium methylcuprates CunMgmMe2m+n

Comparative studies on the addition reactions of the Normant reagent ("CH3MgBr" + CuBr) and the new tetrahydrofuran-soluble magnesium methylcuprates MgmCun(CH3)2m+n with phenylacetylene

Comparative studies on the addition reactions of the Normant reagent ("CH3MgBr" + CuBr) and the new tetrahydrofuran-soluble magnesium methylcuprates MgmCun(CH3)2m+n with phenylacetylene

The addition of the normant reagent (“CH 3MgBr” + CuBr) to terminal alkynes in THF. Concerning the nature of the reactive species in solution

The reactive intermediates in the Normant reagent responsible for reaction with terminal alkynes in THF have been determined.

Concerning the solution composition of the normant reagent. New THF soluble methyl copper(I)ate complexes by reaction of “CH 3MgBr” and (CH 3) 2Mg with cuprous bromide

The composition of the Normant reagent in THF has been studied resulting in the identification of the species in solution as halogen-free copper-magnesium “ate” complexes of type Cu m Mg n Me ( m+2 n ( m = 1, 2, 3, 4, 6; n = 1, 2).

The reaction of l,3-dioxolanes with Normant's reagent

1. Vinylmagnesium bromide is a less reactive reagent with respect to the C-O bonds of 1,3-dioxolanes than Grignard reagents and some Iotsich complexes. 2. Vinylmagnesium bromide cleaves cyclic ketals forming low yields of hydroxyalkyl ethers of tertiary ethylenic alcohols.

Organomagnesium synthesis of 2- and 3-(Trimethylsilyl) acrylic acids and vinyl derivatives of silicon, germanium, and tin

1. (1- and 2-Bromovinyl) trimethyisilanes readily form Grignard reagents in tetrahydrofuran, and by reaction with carbon dioxide these give 2- and 3-(trimethylsilyl) acrylic acids. 2. With the aid of Normant's reagent silanes, germanes, and stannanes containing any of the possible numbers of vinyl groups can be synthesized. 3. In the dehydrobromination of Cl3SiCHBrCH2Br, quinoline eliminates the β-bromine atom and aluminum chloride eliminates the -bromine atom.

Organomagnesium synthesis of vinyl compounds of silicon, germanium and tin

It was shown that condensation of Normant's reagent (CH2=CHMgBr) with alkylchlorosilanes, -germanes, and -stannanes results in the synthesis of vinyl derivatives of silanes, germanes, and stannanes containing one, two, or three, vinyl radicals.