Axial Alcohol Research Articles

An examination of hyperconjugative and electrostatic effects in the hydride reductions of 2-substituted-4-tert-butylcyclohexanones.

To better understand electronic effects on the diastereoselectivity of nucleophilic additions to the carbonyl group, a series of 2-X-4-tert-butylcyclohexanones (X = H, CH(3), OCH(3), F, Cl, Br) were reacted with LiAlH(4). Reduction of ketones with equatorial substituents yields increasing amounts of axial alcohol in the series for X [H < CH(3) < Br < Cl < F << OCH(3)]. These data cannot be explained by steric or chelation effects or by the theories of Felkin-Anh or Cieplak. Instead, an electrostatic argument is introduced: due to repulsion between the nucleophile and the X group, axial approach becomes energetically less favorable with an increase in the component of the dipole moment anti to the hydride approach trajectory. The ab initio calculated diastereoselectivities were close to the experimental values but did not reproduce the relative selectivity ordering among substituents. For reduction of ketones with axial substituents, increasing amounts of axial alcohol are seen in the series for X [Cl < Br < CH(3) < OCH(3) < H < F]. After some minor adjustments are made, this ordering is consistent with both the electrostatic model and Felkin-Anh theory. Cieplak theory cannot account for these data regardless of adjustments. Ab initio calculated diastereoselectivities were reasonably accurate for the nonpolar substituents but were poor for the polar substituents.

Synthesis and characterization of stereospecific 1-propargyl-2-(dimethoxymethyl)-1-cyclohexanols.

Stereochemical isomers with hydroxy groups were synthesized by reacting 2-(dimethoxymethyl)cyclohexanone with propargylmagnesium bromide. The stereo chemical structures were identified by NMR spectral interpretation and the geometry optimization. To assist the NMR interpretation, geometry optimization based on semi-empirical AM1 and PM3 methods was applied. Throughout this study, the structures of the two isomers were all determined and 1H and 13C NMR spectra were fully assigned. It was proven that the less polar isomer is an axial alcohol and the more polar one is an equatorial alcohol.

Observations on the stereochemistry of reduction of 2,6-dimethylcyclohexanones

The reduction of cis-2,6-dimethylcyclohexanone with NaBH4 in methanol is shown to produce predominantly the axial alcohol, an unexpected result based upon prior reports and current paradigms for similar cyclohexanone reductions. This finding prompted a careful and systematic investigation of the NaBH4 and LiAlH4 reductions of cis- and trans-2,6-dimethylcyclohexanones in various solvents, with additional results contrary to literature reports. Possible explanations for these discrepancies are given, an unusual solvent effect is noted, the rate of epimerization versus reduction is examined, molecular modeling results are reported, and an important caveat is offered for future stereochemical studies of this nature.Key words: cyclic ketone reduction, stereochemistry, molecular modeling.

Ligand effects in selective addition reactions of organoindium reagents with carbonyl compounds

The reaction of the allyl indium sesquibromide (CH 2=CHCH 2) 3In 2Br 3 with four equivalents of a bulky lithium alkoxide ((CH 3) 3COLi or (CH 3) 3CCH 2OLi) results in modified reagents which show unusual degrees of chemo- and stereoselectivity in reactions with carbonyl compounds. For example, in reactions with cyclohexanone derivatives, 84–93% equatorial attack with preferential formation of the axial alcohols is observed. Chiral aldehydes react in a highly diastereoselective manner.

Regioselective dehydration of axial and equatorial tertiary alcohols with α-methyl group in the cyclohexane ring by Swern’s reagent

Swern’s reagent (a complex of oxalyl chloride with DMSO) was shown to dehydrate tertiary alcohols containing an α-methyl group in the cyclohexane ring. Dehydration of equatorial alcohols affords mixtures of isomeric compounds where isomers with an exocyclic double bond dominate, whereas isomers with an endocyclic double bond prevail in the products of dehydration of axial tertiary alcohols. Thus, Swern’s reagent can serve as a chemical test to determine the configuration of tertiary alcohols containing an α-methyl group in cyclohexane ring. The composition of the products of dehydration of these alcohols with Swern’s reagent is similar to that obtained by their dehydration with POCl3 in pyridine.

Stereo- and chemoselective transfer hydrogenation of carbonyl groups with RuCl 2(PPh 3) 3 and BINAP-Ru as catalysts and Et 3NH +H 2PO 2−·1,5H 2O as a hydrogen donor

Using Et 3NH +H 2PO 2 −.1.5 H 2O as a hydrogen donor, the RuCl 2(Ph 3P) 3, RuCl 2(PPh 3) 3 C and BINAP-Ru proved highly active catalysts for transfer hydrogenation of ketones under milder conditions than other hydrogen donors. 2-Methyl-, 2-chloro-, 2-(ethoxy-carbonyl)cyclohexanones and -cyclopentanones were reduced to the less stable axial alcohols in excellent diastereoisomeric excess (de: 90–100%), and the carbonyl group of α,β-unsaturated ketones was selectively reduced, in contrast with other hydrogen donors the CC bond was reduced.

Samarium(II) Triflate as a New Reagent for the Grignard-Type Carbonyl Addition Reaction

On treatment of a THF solution of Sm(OTf)3 with 1 equiv of an organolithium or organomagnesium reagent at ambient temperature, the purple or deep green solution of the divalent samarium triflate [Sm(OTf)2] was readily obtained. For this preparation, s-BuLi was the most effective as was evidenced by the reduction of 2-phenylethyl iodide in the presence of HMPA. The Sm(OTf)2 reagent mediated the Grignard-type reaction effectively in THF/HMPA; alkylation and allylation of ketones or aldehydes with alkyl, allyl, or benzyl halides proceeded via organosamarium intermediates. Diastereoselectivity of the samarium−Grignard reaction was examined using 2-methylcyclohexanone, 4-tert-butylcyclohexanone, and 2-phenylpropanal and was found to be higher in each case than that with SmI2. With 2-methylcyclohexanone, for example, Sm(OTf)2 gave the greatest ratio of axial alcohol:equatorial alcohol = 99:1, and SmI2 gave a ratio of 91:9. Halides containing an ester or a silyl group were reactive in the Reformatsky- or Peterson-type reaction, respectively, using the Sm(OTf)2 reagent.

Aminoborohydrides. 5. Reduction of alkylcyclohexanones to the corresponding alcohols with unique steric selectivity

Lithium aminoborohydrides (LAB), obtained by the reaction of n-butyllithium with amineboranes, are powerful reducing agents for a wide range of functional groups including the carbonyl group of alkylcyclohexanones. Reduction of 2-methylcyclohexanone with LAB reagents shows superior formation of the axial alcohol as compared to sodium borohydride (NaBH4). Reduction of 3- and 4-methylcyclohexanones shows formation of the equatorial alcohol in proportions similar to that obtained with NaBH4. Reduction of 4-tert-butylcyclohexanone leads predominantly to the corresponding cyclohexanol containing an equatorial alcohol group. Unlike NaBH4, LAB reagents are soluble in ether solvents allowing for homogeneous reductions.

Ligand effects in selective carbonyl addition reactions of organomanganese and cerium reagents

Transmetalation of organolithium reagents RLi (R = CH 3, n-Bu) with manganese pivalate produces reagents of the type RMnOC(O) tBu which react stereoselectively with substituted cyclohexanones to afford the axial alcohols preferentially. These reagents as well as cerium ate complexes RCe(O iPr) 3MgX react aldehyde-selectively in the presence of ketone functionality.

Allylic functionalization of the 1,7-dioxaspiro[5.5]-undec-4-ene and d1,6,8-trioxadispiro[4.1.5.3]-pentadec-13-ene ring systems.

Allylic bromination of the bicyclic spiroacetals 5, 6 and 7 gave predominantly the axial bromides 15, 21 and 23 which underwent S N2 displacement to the equatorial alcohols 17, 22 and 25 respectively, using potassium superoxide and 18-crown-6 in THF/DMSO (10:1). Allylic bromination of the cis-bis-spiroacetal 26 gave predominantly the rearranged allylic bromide 29 which afforded alcohols 30 and 31 resulting from both S N2′ and S N2 displacement upon treatment with potassium superoxide. Bromination of the trans-bis-spiroacetal 27 afforded a complex mixture from which only the non-rearranged bromide 34 could be isolated. This bromide 34 afforded the axial alcohol 37 upon treatment with potassium superoxide.

Stereochemistry of nitrogenous heterocycles. 71. Isomerization ? Equilibration of stereoisomeric ethinylcarbinols epimeric at the carbinol center

Equilibration of stereoisomeric cyclic ethinylcarbinols, epimeric at the carbinol center, was conducted for the first time and it was shown that the equilibrium is shifted toward the equatorial alcohol (at 50‡C for 2e-methyl-4-hydroxy-4-phenylethinyl-trans-decahydroquinoline, 2e-methyl-4-hydroxy-4-ethinyl-trans-decahydroquinoline, 4-hydroxy-4-ethinyl-trans-decahydroquinoline —(78±1)% equatorial and (22±1)% axial alcohol, for 1,2e,5e-trimethyl-4-ethinylpiperidol-4 (74±1)% equatorial and (26±1)% axial alcohol). The epimerization of stereoisomeric ethinylcarbinols can be used as a method for determination of the configuration of the quaternary carbinol center.

Carbohydrate-derived partners display remarkably high stereoselectivity in aldol coupling reactions

Aldol condensation between 3-keto and aldehyde sugars have been studied. The enolate 3 reacts with aldehydes preferentially from the β-face to give axial C2 condensation products. However, if the reaction conditions are not controlled properly some C2 epimerization may be observed. With respect to the aldehyde partner, facial selectivity can be predicted on the basis of the preferred, permissible chelation pattern. Thus α/β chelation (which occurs whenever possible) produces Cram products, while α-chelation produces anti-Cram products. For the major (C2-axial) products, the stereochemistry around the newly forged C2C7 bond can be determined by the magnitude of J 2,7= 8–10 Hz for the C7-(S) condensation product, and ~5 Hz for the C7-(R) analogue. The C3-carbonyl group of the aldol products can be reduced with DIBAL and LiALH 4 to give products bearing equatorial and axial C3-OH groups, respectively. On the other hand, LiBHEt 3 gives axial alcohols only. The ease of formation of an isopropylidene ring between the equatorial C3-OH and C7-OH can be used to deduce the C7 orientation. For example, with the C7-(R) isomer 25 (eq), an isopropylidene ring was readily formed whereas for the C7-(S) analogue 28, ring formation was not observed.

Selective hydrogen transfer reactions from alcohols to ketones promoted by rhodium complexes with 1,10-phenanthroline and related ligands

Substituted cyclohexanones are effectively reduced to the corresponding alcohols using propan-2-ol as hydrogen source and Rh(I) complexes with 1,10-phenanthroline (phen) and substituted derivatives as catalyst precursors. Rh(I) derivatives with phen, 4,7-Ph 2phen and 4,7-Mc 2phen (chel/Rh ⩾ 2) promote the preferential formation of the axial alcohol (substrate = 4-t-butylcyclohexanone), while the 4,7-(MeO) 2phen derivative gives in higher yield the equatorial isomer. Hindered substrates such as 2-methylcyclohexanone and 3,3,5-Me 3cyclohexanone are reduced to the corresponding axial alcohol with a selectivity ⩾ 98% (chel = 4,7-Me 2phen).

ChemInform Abstract: An Approach to the Total Synthesis of Aplysiatoxin.

AbstractCoupling of the synthons (IV) and (VI) gives the spiroketal enol ether (VII) which is elaborated to the axial alcohols (Xa) and (Xb).

Synthesis of branched-chain sugars: A stereoselective route to sibirosamine, kansosamine, and vinelose from a common precursor

Methyl 4,6-dideoxy-3- C-methyl-4-( N-methyl- N-phenylsulfonylamino)-α- l-mannopyranoside and methyl 4-amino-4,6-dideoxy-3- C-methyl-α- l-mannopyranoside, derivatives of the branched-chain amino sugars sibirosamine and kansosamine, respectively, were synthesized by nucleophilic ring-opening of methyl 3,4-anhydro-6-deoxy-3- C-methyl-α- l-talopyranoside. Catalytic reduction of methyl 6-deoxy-2,3- O-isopropylidene-3- C-methyl-α- l- lyxo-hexopyranosid-4-ulose gave the axial alcohol methyl 6-deoxy-2,3- O-isopropylidene-3- C-methyl-α- l-talopyranoside, a known precursor to vinelose.

A mild method for the conversion of 1,3-glycols into unsaturated alcohols

Some transformations of 1,3-glycols utilizing dimethylformamide dimethyl acetal have been examined with the diterpenoids aphidicolin and foliol and some steroids as substrates. Axial alcohols with a suitably disposed trans hydrogen atom undergo an elimination reaction to give the formate of an unsaturated alcohol via the quaternary salt of the cyclic formamido acetal.

Stereoselective reduction of C-2 substituted steroid C-3 ketones with lithium tris-(R,S-1,2-dimethylpropyl)-borohydride and sodium borohydride

The effect of C-2 substitution on the stereoselective reduction of steroid C-3 ketones with lithium tris-(R,S-1,2-dimethylpropyl)-borohydride and sodium borohydride was investigated. The C-2 mono- and di-substituted chloro and methyl derivatives were predominantly reduced to one of the epimeric alcohols. The 2α-chloro and 2α-methyl derivatives of 17β-acetoxy-5α-androstan-3-one undergo stereoselective reduction with lithium tris-(R,S-1,2-dimethylpropyl)-borohydride to the axial (3α) alcohol as observed in the unsubstituted compound, whereas sodium borohydride gives predominantly the equatorial (3β) alcohol. The 2β-chloro, 2β-methyl, 2,2-dichloro, and 2,2-dimethyl derivatives are reduced predominantly to the equatorial (3β) alcohol by both reagents.

Three-dimensional structures of stereoisomers of 2-phenyl-4-ethynyldecahydro-4-quinolinol

The three-dimensional structures of four stereoisomers of 2-phenyl-4-ethynyldecahydro-4-quinolinol were determined by PMR and IR spectroscopy. The IR spectra of axial alcohols with an axial γ substituent provide evidence for the existence of two equilibrium forms in solution.

Microbial Transformation of Tetracyclic Diterpenes: Conversion of Ent-Beyerenes by Rhizopus nigricans Cultures

Microbial transformation of ent-7a, 18-diacetoxy- 14P-hydroxybeyer- 15- ene (2) was carried out with Rhizopus nigricans. The fungus produced an mt- 15a, lba-epoxida- tion and/or mt-3P-hydroxylation. The structures of resulting products were established by chemical and spectroscopic methods. Occasionally, microbial transformations constitute an alternative for introducing chemical functions into inaccessible sites of molecules. Thus, a great number of micro- bial transformations of steroids have been performed for this purpose (1). Microbial transformations have been also applied to nonsteroid compounds (2, 3). On certain occasions, the products formed by this procedure can be easily obtained by chemical reactions. When transformations are made on natural substrates, the intro- duction of functions into biogenetically favorable sites is a frequent phenomenon (4). As far as we know, only one paper on the microbial transformation of ent-beyerenes by hydroxylating fungi has been published (5): Aspergilh ochraceous catalyzes a reduc- tion at C-3 on ent-3-ketobeyer-15-en-17-oic acid to give an axial alcohol at this posi- tion, and Calonectria decora catalyzes hydroxylation at C-6, giving an equatorial hydro- xyl group. No transformation were observed using Rhizopus nigricans cultures. Incuba- tion of a 19-norderivative of this substrate with C. decora cultures produced an equato- rial hydroxylation at C-6 of this substrate. Incubation of this latter substrate with A. ochraceous and R. nigricans yielded no metabolites. As indicated above, reports on microbial transformations of ent-beyerenic systems are scarce, and no information is available on the transformation of 14-hydroxy- beyerenes. As a continuation of our studies on microbial transformations of tetracyclic diter- penes (6, 7), we now report the action of hydroxylating fungi (R. nigricans and A. oc- hraceous) on ent-beyer- 15-enic substrates with an ent- 14p hydroxylation.

Conformation and reactivity of some substituted oxan-4-ols in the oxidation with cerium(IV)

The kinetics of the oxidation of some substituted oxan-4-ols by cerium(IV) in an aqueous acetic acid medium at 60 °C in the presence of sulphuric acid have been investigated. The reaction is first-order each in oxidant and substrate at constant acid concentration. t-2,t-6-Diphenyl-c-3,c-5-dimethyloxan-r-4-ol, an axial alcohol, reacts slower than the corresponding equatorial epimer, c-2,c-6-diphenyl-t-3,t-5-dimethyloxan-r-4-ol. This anomalous observation and the reactivity of other oxanols towards oxidation have been discussed on the basis of conformational differences.