Equatorial Alcohol Research Articles

Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first t...

Chemoselective Oxidation of Equatorial Alcohols with N-Ligated λ3-Iodanes.

The site-selective and chemoselective functionalization of alcohols in complex polyols remains a formidable synthetic challenge. Whereas significant advancements have been made in selective derivatization at the oxygen center, chemoselective oxidation to the corresponding carbonyls is less developed. In cyclic systems, whereas the selective oxidation of axial alcohols is well known, a complementary equatorial selective process has not yet been reported. Herein we report the utility of nitrogen-ligated (bis)cationic λ3-iodanes (N-HVIs) for alcohol oxidation and their unprecedented levels of selectivity for the oxidation of equatorial over axial alcohols. The conditions are mild, and the simple pyridine-ligated reagent (Py-HVI) is readily synthesized from commercial PhI(OAc)2 and can be either isolated or generated in situ. Conformational selectivity is demonstrated in both flexible 1,2-substituted cyclohexanols and rigid polyol scaffolds, providing chemists with a novel tool for chemoselective oxidation.

Surface Modified Nano Fly Ash as an Activator in the Reduction of Ketones

Surface modified nano fly ash has been used as an activator, in the reduction of a few cyclic and acyclic ketones with NaBH4 as reducing agent. Exclusive formation of trans-4--butyl cyclohexanol was observed in such case. Reduction of 3-methylcyclohexanone yielded only cis-3-methylcyclohexanol (equatorial -OH). In case of reduction of other substituted cyclohexanones, propensity to form more of equatorial alcohol was observed. The chemical yields of various alcohols were high (∼95-99%). The rates of reductions of the ketones were also appreciably high. It appears that the silanol groups present in the surface modified fly ash cause nucleophilic activation of the carbonyl groups leading to faster reaction rate. Exclusive formation of the epimer with equatorially disposed -OH group is most likely due to the same reason. Finally, the advantage of the activator lies in its low cost.

Diterpenoids from Scutellaria galericulata

Neo-clerodane diterpenoids have attracted interest for their varied biological activities. In continuation of our systematic studies on Scutellaria plants [1–3], we have now investigated S. galericulata L. The acetone extract of the aerial parts of S. galericulata was subjected to column chromatography to yield five compounds: 1–5. The IR spectrum of 3 showed signals for the hydroxyl group (3444 cm–1), oxirane (3050 cm–1), and ester groups (1733, 1712, 1651, 1276, 1256 cm–1), one of which is for a tigloyloxy moiety (1651 cm–1). The 1H NMR spectrum showed signals for an acetate  1.79 (3H, s) and tigloyloxy group H 7.10 (qq, H-3; 1.81 m, Me-4; 1.89 m, Me-5), as well as characteristic signals for the neo-clerodane structure (Me-17 at  0.84 d, J17,8 = 6.1 Hz, and Me-20 at  0.93 s) with a 4,18-oxirane ring (HA-18 2.44 d and HB-18 3.00 d, Jgem = 4.4 Hz) and a 19,2-hemiacetal function (H-19 6.78 s, H-2 4.23 m). The 1H NMR spectrum also showed signals for a 16,15--lactone (HA-15 3.94 ddd, HB-15 4.09 td, Jgem = 8.4 Hz, J15A,14A = 7.8 Hz, J15A,14BA = 4.7 Hz, J15B,14A = 7.8 Hz, J15B,14B =2.3 Hz). In addition to these groups, 3 possesses two esterified equatorial alcohols at C-6 (H-6 4.64 d, J6,7 = 10.9 Hz) and C-7 (H-7 5.19 dd, J7,6 = 10.9 Hz). On the basis of all the physical and spectroscopic data, compared with those described in the literature, compound 3 was established to be scutegalin D (16R and 16S epimers), because the 1H NMR spectrum also showed a series of double signals for the H-19 ( 6.78 s and 6.79 s) and CH3-17 group ( 0.84 d and 0.85 d). Moreover, the signals at  5.32 (0.5H, dd, J1 = 6.4, J2 = 2.7 Hz) and 5.15 (0.5H, t, J = 2.7 Hz) were assigned to the two C-16 epimeric forms of the 16,15-hemiacetal group [4]. Compounds 1, 2, 4, and 5 were neo-clerodanes with very similar structures. Their spectroscopic data showed the presence of a decalin ring system bearing one spiroepoxide substituent at C-4 (of C-1–C-10 fragment) and a furofuran system in the C-11–C-16 fragment ( 4.08 dd, H-11; 2.83 m, H-13; 5.63 d, H-16). The furofuran substructure was hexahydro in 1, 2, and 5 and tetradydro in 4 (3090, 1615 cm–1; and at  4.79 t, H-14; 6.43 t, H-15, J14,15 = 2.5 Hz, vinyl ether). DITERPENOIDS FROM Scutellaria galericulata

Reduction of 1-methyl-2-phenyldecahydroquinolin-4-one

Stereochemistry of the reduction of 1-methyl-2е-phenyl-trans-decahydroquinoline-4-one has been studied under different conditions: the reduction by sodium in ethanol in accordance with the mechanism of this reaction gives mainly an equatorial alcohol; with sodium boron hydride – there forms a mixture of aminoalcohols with the predominance of an equatorial epimer; the reduction of aminoketone by aluminum isopropylate proceeds with the direction, usual for this method, and results in the predominant formation of axial alcohol.

Stereoselectivity of sodium borohydride reduction of saturated steroidal ketones utilizing conditions of Luche reduction

A series of keto steroids were reduced with sodium borohydride in the presence of cerium(III) chloride or samarium(III) iodide (Luche reduction). The ratios of axial and equatorial alcohols were determined by HPLC and the results were compared with those obtained by a standard sodium borohydride reduction. The best results were obtained with the 2-keto derivative 1, 7-keto derivatives 5 and 6, and 12-keto derivative 8 where the cerium(III) ion addition resulted in the inversion of the axial/equatorial ratios. The Luche reduction of the 20-keto derivative 11 improved the proportion of the (20 S)-alcohol in a mixture of (20 S)/(20 R) alcohols up to 35% from 5% in a standard sodium borohydride reduction.

Studies on a Total Synthesis of the Microbial Immunosuppresive Agent FR901483

A strategy is outlined for construction of the fungal immunosuppressant FR901483 (1). It was possible to convert 1,4-cyclohexanedione monoethylene ketal in five simple steps to iodoacetamide ketone 10, which was cyclized in good yield to the key bridged keto lactam 11 containing the A/B 2-azabicyclo[3.3.1]nonane ring system of the natural product. This intermediate could be transformed to N-Boc lactam 16, whose derived enolate underwent stereoselective hydroxylation with the Davis oxaziridine to produce alcohol 17 having the desired C-2 configuration. Compound 17 was then converted in three steps to alkoxy carbamate 20. The N-acyliminium ion derived from intermediate 20 could be alkylated in good overall yield with p-methoxybenzylmagnesium chloride to afford a 5:4 mixture of the desired PMB product 21 and the epimer 23. In an attempt to improve the stereoselectivity in this alkylation, the inverted C-4 protected alcohol N-Boc lactam 33 was prepared and its enolate was hydroxylated. Inexplicably, the product of this reaction was the undesired equatorial alcohol 34. Some model systems were investigated toward annulation of the C-ring of the natural product. It was found that homoallylic amine 40 could be cyclized with PhSCl in the presence of silica gel to generate the desired 5-endo tetracyclic product 42 in moderate yield. This cyclization protocol was also successfully applied to the actual FR901483 system 22, leading to the requisite tricycle 43.

Use of the intramolecular Heck reaction for forming congested quaternary carbon stereocenters. Stereocontrolled total synthesis of (+/-)-gelsemine.

Intramolecular Heck reactions of alpha,beta-unsaturated 2-haloanilides derived from azatricyclo[4.4.0.0(2,8)]decanone 5 efficiently install the congested spirooxindole functionality of gelsemine. Depending upon the Heck reaction conditions and the nature of the beta-substituent, either products having the natural or unnatural configuration of the spirooxindole group are formed predominantly. Efforts to elaborate the hydropyran ring of gelsemine from the endo-oriented nitrile substituent of pentacyclic Heck product 18 were unsuccessful. Important steps in the ultimately successful route to (+/-)-gelsemine (1) are as follows: (a) intramolecular Heck reaction of tricyclic beta-methoxy alpha,beta-unsaturated 2-iodoanilide 68 in the presence of silver phosphate to form pentacyclic product 69 having the unnatural configuration of the spirooxindole fragment, (b) formation of hexacyclic aziridine 80 from the reaction of cyanide with intermediate 79 containing an N-methoxycarbonyl-beta-bromoethylamine fragment, (c) introduction of C17 by ring-opening of the aziridinium ion derived from aziridine 80, and (d) base-promoted skeletal rearrangement of pentacyclic equatorial alcohol 82 to form the oxacyclic ring and invert the spirooxindole functional group to provide hexacyclic gelsemine precursor 83.

Synthesis of the C3−C19 Segment of Phorboxazole B

[reaction: see text]. Three segment-coupling Prins approaches to the C3-C19 segment of phorboxazole B have been developed. One successful strategy utilized a novel TMSBr-mediated cyclization that proceeded with complete axial selectivity. Displacement of bromide with cesium acetate provided the C13 hydroxyl stereocenter of 22. Additionally, treatment of alpha-acetoxy ether 20 with TFA enabled a more concise synthesis of the C3-C19 target 13 by allowing direct access to the equatorial alcohol.

Spinosyn G: Proof of Structure by Semisynthesis

[reaction: see text] Spinosyn G was isolated in the late 1980s as a minor component from the broth of our potent, fermentation-derived insecticide spinosad. Its structure was then tentatively identified as 5' '-epispinosyn A (3) on the basis of (1)H and (13)C NMR data, but the 4' '-epi compound 4 could not be conclusively ruled out with the data available. Described herein are unambiguous syntheses of both 3 and 4, whereby 3 was proved identical to the natural product. Compound 4 was prepared from intact spinosyn A by a novel F-TEDA-promoted oxidative deamination to the 4' '-ketone 5, stereoselective reduction to the equatorial alcohol 6, and nitrogen incorporation via the axial azide 7. Compound 3 was obtained by coupling spinosyn A 17-pseudoaglycone (9) with the N-protected dihydropyran 16 derived from methyl l-ossaminide (14). This gave an approximately 2:1 mixture of anomeric products 17 with the desired equatorial glycoside predominating, which was then converted to 3 by N-deprotection and methylation.

A Free Radical Method for Reduction of Cyclohexanones — Preferential Formation of Equatorial Alcohols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Free Radical Method for Reduction of Cyclohexanones—Preferential Formation of Equatorial Alcohols

Cyclohexanones react with 2-hydroselenobenzoic acid to afford spiro- [4H–3,1-benzoxaselenin-2,1′-cyclohexan]-4-ones. Stannane reduction and basic hydrolysis gives epimeric cyclohexanols, with the equatorial isomer predominating.

Low-temperature X-ray structural studies of the ester and ether derivatives of cis- and trans-4-tert-butyl cyclohexanol and 2-adamantanol: application of the variable oxygen probe to determine the relative sigma-donor ability of C-H and C-C bonds.

Results of low-temperature X-ray structural studies for five cis-, and three trans-4-tert-butyl cyclohexanol, and six 2-adamantanol ester and ether derivatives are reported. Plots of C-OR bond distance against pKa(ROH) for derivatives of axial alcohol (5), equatorial alcohol (6) and 2-adamantanol derivatives (7) give slopes of -2.77 x 10(-3), -2.86 x 10(-3) and -3.05 x 10(-3), respectively. Given that the relative differences in the slopes are modest, no clear distinction can be made about the relative sigma-donor ability of a C-H bond and a C-C bond.

1,2-Bis(2-benzimidazolyl)-1,2-ethanediol, a chiral, tridentate, facially coordinating ligand

The ligand 1,2-bis(1H-benzimidazol-2-yl)-1,2-ethanediol, 1, and its methylated derivative 2 are readily synthesized from tartaric acid, and act as chiral, facially coordinating tridentate ligands, forming complexes of composition ML2 with octahedral transition metals. The copper(II) complexes show distorted 4 + 2 coordination with benzimidazoles occupying the equatorial sites and alcohol functions weakly binding in the axial sites. Nickel(II) complexes in three different states of protonation show regular octahedral geometry with the alcohols mutually cis. Deprotonation of the coordinated alcohol produces little structural change but the monodeprotonated complex forms a hydrogen bonded dimer. Magnetic measurements show the hydrogen bonded bridge to offer a pathway for weak antiferromagnetic coupling. UV-Visible spectroscopy shows the ligand to have a field intermediate between water and pyridine. The diastereoselectivity of complexation depends on the geometry: nickel(II) shows a weak preference for the homochiral complex, whereas copper(II) forms almost exclusively homochiral complexes.

The Stereochemistry of the Reduction of Cyclic Enaminones

The stereo- and regiochemistry of di-, tri-, and tetracyclic enaminones upon catalytic hydrogenation on Pd and Pt catalysts seems to be mainly a function of the catalyst and the medium. The highest stereoselectivity was observed for multiflorine on Pd/C in which 99% of equatorial alcohol were formed in this case, the formation of alcohols proceeds via a ketonic intermediate. On platinum, irrespective of the solvent used (EtOH, H2O, AcOH, HCl), the hydrogenation reaction proceeds through ketonic (piperidone system) and dehydro (pyridone system) intermediates. In EtOH or H2O solution, the dehydro product remains unchanged, whereas the ketonic intermediate is reduced to a mixture of epimeric alcohols. In HCl and acetic acid, both intermediates are hydrogenolyzed to a product with a methylene group, but the ketonic one is additionally reduced to a mixture of epimeric alcohols. Reductions with complex metal hydrides provide mixtures of epimeric alcohols with a predominance of equatorial orientation. The structures of products were determined by NMR spectroscopy and/or by GC-MS analysis.

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.

ChemInform Abstract: Formal Synthesis of D‐myo‐Inositol 1,4,5‐Tris(dihydrogen phosphate): Cyclization by an Unusual Ene Reaction and Use of the Bu2SnCl2/Bu2SnH2 Reagent for Generating an Equatorial Alcohol.

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Formal Synthesis of d-myo-Inositol 1,4,5-Tris(dihydrogen phosphate): Cyclization by an Unusual Ene Reaction and Use of the Bu2SnCl2/Bu2SnH2 Reagent for Generating an Equatorial Alcohol

d-Glucose was converted into the propargyl silane aldehyde 5, which, on treatment with camphorsulfonic acid, cyclized with retention of silicon. The allenic product (7) was elaborated via ketone 24 into 4, which had previously been converted into d-myo-inositol 1,4,5-tris(dihydrogen phosphate). Selective reduction of the advanced intermediate 24 was accomplished with Bu2SnCl2/Bu2SnH2, a reagent mixture that shows a very strong preference for generating equatorial alcohols. The cyclization step leading to allene 7 was studied by examining a number of model compounds; the unusual retention of silicon appears to be limited to highly oxygenated substrates, such as 5 and its all-benzyl analogue (27).

A synthetic route from D-glucose to D- myo-inositol-1, 4, 5-tris(dihydrogenphosphate): use of an unusual ene reaction and the Bu 2SnCl 2/Bu 2SnH 2 reagent

d-Glucose was converted into the propargylsilane aldehyde 3, which underwent ring closure with retention of silicon, in the presence of camphorsulfonic acid, to give 5, and this was elaborated, via ketone 22, into 2, which had previously been transformed into d-myo-inositol-1, 4, 5-tris(dihydrogenphosphate). A crucial step in the synthesis is the stereoselective reduction of 22 with Bu 2SnCl 2/Bu 2SnH 2, a reagent system that shows a strong preference for generating equatorial alcohols.

Chelation-Controlled Reduction of α-Methylated 8-Oxabicyclo[3.2.1]oct-6-en-3-ones with Samarium Diiodide. Diastereoselective Preparation of Secondary Alcohols

The title reduction has been effected with high stereocontrol using samarium diiodide in the presence of a proton source. It is concluded that chelation of samarium by the ether oxygen of the substrate directs and facilitates the reduction to equatorial alcohol.