Monoethylene Ketal Research Articles

A Straightforward Synthesis of Trideuterated α‐Terpinene for Mechanistic Studies

Regiospecifically trideuterated (2,6,6‐2H3)‐α‐terpinene was prepared in six steps and with a deuterium incorporation of >99 % in 24 % yield from 1,4‐cyclohexanedione monoethylene ketal. The synthetic procedure involved twofold cross‐coupling reactions of alkylcuprates (lithium dimethylcuprate and chloromagnesium cyano(isopropyl)cuprate, respectively) with enol triflates to introduce the alkyl substituents on the 1,3‐cyclohexadiene backbone. By changing the alkylcuprates, the synthetic approach could serve as a prototype for the synthesis of various 1,4‐dialkyl‐substituted 1,3‐cyclohexadiene derivatives, which could be deuterium‐labeled as well, for example for mechanistic studies.

Metal‐Free Synthesis of Thermally Stable Fluorescent p‐Terphenyls by Ring Transformation of 2H‐Pyran‐2‐ones

AbstractA metal‐free approach for the synthesis of p‐terphenyls 7 a–i and cyclic p‐terphenyls 9 a–d and 11 a–d is described via carbanion induced ring transformation reaction of 6‐biphenyl‐2H‐pyran‐2‐ones 5 with malononitrile 6, cyclohexanone 8 and 1,4‐cyclohexanedione monoethylene ketal 10 respectively. Additionally, the base‐mediated ring transformation reactions were working smoothly under mild reaction conditions and ring transformation products 7, 9 and 11 were isolated in good to excellent yields. The synthetic approach provides the flexibility of introducing of both electron‐withdrawing and ‐donating functionalities in p‐terphenyl architecture. Moreover, the photo physical properties of compounds 7, 9 and 11 were analyzed using UV‐visible and Fluorescence Spectroscopy. p‐Terphenyls 7 c showed cyan fluorescence in chloroform (λmax (em): 508 nm) and acetonitrile (λmax (em): 420 nm) while cyclic p‐terphenyl 9 a showed blue fluorescence in chloroform and 1,4‐dioxane (λmax (em): 470 nm). Similarly, compound 11 a showed blue fluorescence in chloroform (λmax (em): 468 nm) and 1,4‐dioxane (λmax (em): 473 nm). Additionally, the thermal stability of synthesized cyclic p‐terphenyls 11 a, 11 c and 11 d were also studied using TG and DTA techniques.

A Metal-Free Approach for the Synthesis of 2-Tetralones via Carbanion-Induced Ring Transformation of 2H-Pyran-2-ones

A metal-free, ultrasound-assisted approach for the synthesis of highly functionalized 2-tetralones in high yields is described. The process involves ring transformation of 2H-pyran-2-ones with the spirocyclic ketone 1,4-cyclohexandione monoethylene ketal to yield spiro­cyclic ketals and subsequent acid-mediated hydrolysis. This protocol is free from any organometallic reagents, is economical and tolerates a wide range of functional groups.

An unexpected acid mediated rearrangement of monoethylene ketal of 2-methyl-2-(3-methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to chromane

We herein report a serendipitously observed acid mediated rearrangement of monoethylene ketal of 2-methyl-2-(3-methylbut-2-en-1-yl)cyclohex-4-ene-1,3-diones to Dihydrobenzopyran and demonstrated the application of this methodology in the construction of core carbon scaffolds of dimethoxyajacareubin, cariphenone-A and crotamadine.

Selective reductive dimerization of homocubane series oximes

The mixture of di- and monoethylene ketals obtained by the reaction of 1,9-dibromopentacyc lo[5.4.0.02,6.03,10.05,9]-undeca-8,11-dione followed by hydrolysis and ring contraction by Faworsky method was converted into a mixture of ethylene ketals of 7-bromopentacyclo[5.3.0.02,5.03,9.04,8]decan-6-one-4- and 5-bromopentacyclo[5.3.0.02,5.03,9.04,8]decan-6-one-8-carboxylic acid where the carboxy group was replaced by bromine along the procedure of Hunsdiecker-Borodine-Cristol. 6-Ethylene ketal of the pentacyclo[5.3.0.02,5.03,9.04,8] decan-6-one obtained by the debromination of ethylene ketals of 4,7- and 5,8-dibromopentacyclo[5.3.0.02,5.03,9.04,8] decan-6-one was hydrolyzed to ketone whose oxime was selectively reduced on a platinum catalyst into the di-6-pentacyclo[5.3.0.02,5.03,9.04,8]decylamine. The reaction of reductive dimerization was also characteristic of pentacyclo[4.3.0.02,5.03,8.04,7]-nonan-9-one and pentacyclo[6.3.0.02,6.03,10.05,9]undecan-4-one oximes, whereas the composition of the reduction products of pentacyclo[5.4.0.02,6.03,10.05,9]undecan-8-one oxime depended on the amount of the catalyst.

13,13-Dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2MD): Total synthesis, docking to the VDR, and biological evaluation

As a continuation of our studies focused on the vitamin D compounds lacking the C,D-hydrindane system, 13,13-dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2, 2MD) were prepared by total synthesis. The known cyclohexanone 30, a precursor of the desired A-ring phosphine oxide 11, was synthesized starting with the keto acetal 13, whereas the aldehyde 12, constituting an acyclic ‘upper’ building block, was obtained from the isomeric esters 34, prepared previously in our laboratory.The commercial 1,4-cyclohexanedione monoethylene ketal (13) was enantioselectively α-hydroxylated utilizing the α-aminoxylation process catalyzed by l-proline, and the introduced hydroxy group was protected as a TBS, TPDPS, and SEM ether. Then the keto group in the obtained compounds 15–17 was methylenated and the allylic hydroxylation was performed with selenium dioxide and pyridine N-oxide. After separation of the isomers, the newly introduced hydroxy group was protected and the ketal group hydrolyzed to yield the corresponding protected (3R,5R)-3,5-dihydroxycyclohexanones 30–32. The esters 34, starting compounds for the C,D-fragment 12, were first α-methylated, then reduced and the resulted primary alcohols 36 were deoxygenated using the Barton-McCombie protocol. Primary hydroxy group in the obtained diether 38 was deprotected and oxidized to furnish the aldehyde 12. The Wittig–Horner coupling of the latter with the anion of the phosphine oxide 11, followed by hydroxyl deprotection furnished two isomeric 13,13-dimethyl-des-C,D analogues of 2MD (compounds 10 and 42) differing in configuration of their 7,8-double bond. Pure vitamin D analogues were isolated by HPLC and their biological activity was examined. The in vitro tests indicated that, compared to the analogue 7, unsubstituted at C-13, the synthesized vitamin D analogue 10 showed markedly improved VDR binding ability, significantly enhanced HL-60 differentiation activity as well as increased transcriptional potency. Docking simulations provided a rational explanation for the observed binding affinity of these ligands to the VDR. Biological in vivo tests proved that des-C,D compound 10 retained some intestinal activity. Its geometrical isomer 42 was devoid of any biological activity.

ChemInform Abstract: Short Enantioselective Approach to Heteroyohimbine Alkaloids from meso- Bicyclo(3.3.0)octane-3,7-dione: Synthesis of Methyl 2-Epielenolate.

meso-Bicyclo[3.3.0]octane-3,7-dione mono ethylene ketal 1 has been converted into chiral enol derivatives with good enantioselectivity. In this paper we report the efficient stereoselective transformation of meso-bicyclo[3.3.0]octane-3,7-dione mono ethylene ketal into methyl 2-epielenolate 15, a direct precursor to the heteroyohimbine alkaloid tetrahydroalstonine. The synthetic work described shows that each ring of the bicyclic ketone can be functionalized independently with good regio- and stereo-control. A new procedure for installing the alkoxyacrylate function of mono-terpenoids is described and it has been shown that the cyclopentanone ring of methyl (1αH,6αH)-2α-methyl-8-oxo-3-oxabicyclo[4.3.0]non-4-ene-5--carboxylate 11 can be regiosalectively converted into enol derivatives which are cleaved to give D/E-ring precursors of Corynanthe alkaloids.

A validated, related substance, GC method for 1,4-cyclohexanedione mono-ethylene Ketal

ABSTRACT A simple, economic, and time-efficient related substance, GC method has been developed for the analysis of 1,4-Cyclohexanedione mono- ethylene ketal(will be specified as ketal) in the presence of a potential impurity 1,4-cyclohexa- nedione bis (ethylene ketal) [will be specified as diketal]. Successful chromatographic separa- tion of the ketal from the impurity was achieved on a DBWAX ETR, 30 m x 0.32 mm x 1.0μ FT column with nitrogen as carrier gas and FID detector. The method was validated for linearity, accuracy, precision, and specificity and can be used for quality control during manufacture of ketal. A validated GC method is reported for the ketal for the first time.

Synthetic approach to preparation of indole derivatives fused with a bicyclo[3.3.1]nonane framework

Synthetic procedures for N-(2-methoxy-6,7,8,9,10,11-hexahydro-5H-6,10-methanocycloocta[b]-indol-9-yl)acetamide were investigated. The desired product was obtained from the mono ethylene ketal of bicyclo[3.3.1]nonane-2,6-dione in a six-stage procedure involving as the key point the formation of an indole fragment on the bicyclo[3.3.1]nonane framework by Fischer reaction.

Enantio‐ and Diastereoselective Total Synthesis of (+)‐Panepophenanthrin, a Ubiquitin‐Activating Enzyme Inhibitor, and Biological Properties of Its New Derivatives

The asymmetric total synthesis of (+)-panepophenanthrin, an inhibitor of ubiquitin-activating enzyme (E1), has been accomplished using catalytic asymmetric alpha aminoxylation of 1,4-cyclohexanedione monoethylene ketal as a key step, followed by several diastereoselective reactions. The biomimetic Diels-Alder reaction of a monomer precursor was found to proceed efficiently in water. The investigation of the biological properties of new derivatives of (+)-panepophenanthrin enabled us to develop new cell-permeable E1 inhibitors, RKTS-80, -81, and -82.

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.

Extension of a One‐Pot Synthesis of Bicyclo[n.4.0]alkanols; Indications of Scope and Limitations for Formation of Substituted Bicyclo[n.4.0]alkanols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric Synthesis of Axially Chiral cis‐Arylmethylenebicyclo[3.3.0]octanes Using α‐Thio‐ and α‐Selenoorganolithium Compounds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Extension of a One-Pot Synthesis of Bicyclo[n.4.0]alkanols; Indications of Scope and Limitations for Formation of Substituted Bicyclo[n.4.0]alkanols

Novel bicyclo[n.2.0]alkan-1-ols with incorporation of methyl substitution at the C6 bridgehead and C2 position on a six-member ring, and incorporation of methyl substitution at the C2 position on a five-member ring were obtained. The presence or absence of a group at these positions had a role in the preference of the major stereochemical isomer observed. Potential limitations of the cyclisation methodology was observed when the ketone was hindered (camphor), and where conjugation was present in the enolate. By contrast, another functional group, as illustrated with 1,4-cyclohexanedione mono-ethylene ketal 24, can be incorporated in the bicyclo[4.2.0]octan-1-ol, and the ketal group converted to a ketone, as in 28, without disrupting the bicyclo[4.2.0]octan-1-ol ring.

Asymmetric Synthesis of Axially Chiral cis-Arylmethylenebicyclo[3.3.0]octanes Using α-Thio- and α-Selenoorganolithium Compounds

Abstract Enantioselective reaction of α-thio carbanion derived from 1-phenyl-1-(phenylthio)-1-(tributylstannyl)methane with cis-bicyclo[3.3.0]octane-3,7-dione monoethylene ketals in the presence of bis(oxazoline)s gave products with high diastereoselectivity and with high enantioselectivity. The reaction of α-seleno carbanions derived from bis(phenylseleno)arylmethanes also showed high diastereoselectivity and enantioselectivity. Deprotection and subsequent stereospecific elimination afforded axially chiral cis-arylmethylenebicyclo[3.3.0]octanes with high enantioselectivity (up to 99% ee).

A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β‐Enones to 1,4‐Enediones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Pi-Facial stereoselectivity in Diels-Alder cycloadditions to 1-oxaspiro[4.5]deca-6,9-dien-8-one. The strong directive effect of ether oxygen in a cross-conjugated ketone setting.

[reaction: see text] The title compound 1, prepared from 1,4-cyclohexanedione monoethylene ketal, was treated with several reactive dienes, including diphenylisobenzofuran and 9,10-dihydro-11,12-dimethylene-9,10-ethanoanthracene. These [4 + 2] cycloadditions proceed with a strong kinetic bias for bonding to the dienophile from the direction syn to the tetrahydrofuranyl oxygen and consequently hold value in stereoselective synthesis.

A mild, catalytic, and highly selective method for the oxidation of alpha,beta-enones to 1,4-enediones.

A new and simple method is described for the one-step oxidation of alpha,beta-enones to 1,4-enediones in good yields (generally 80-90%) using t-butylhydroperoxide as stoichiometric oxidant and 20% Pd(OH)2 on carbon (5 mol %) as catalyst in CH2Cl2 solution. The same reagents have been used to convert ethylene ketals of alpha,beta-enones to the corresponding monoethylene ketals of 1,4-enediones. Seven representative examples are presented in Table 1. All of the available evidence on these oxidations points to a radical-chain mechanism initiated by the tert-butylperoxy radical (see Scheme 1). gamma-tert-Butylperoxy ethers are formed as major products in the oxidation of alpha,beta-enones possessing only a single gamma-hydrogen.

Aromatization of 1,6,7,7a-tetrahydro-2H-indol-2-ones by a novel process. Preparation of key-intermediate methyl 1-benzyl-5-methoxy-1H-indole-3-acetate and the syntheses of serotonin, melatonin, and bufotenin.

Imine 7 of 1,4-cyclohexanedione mono-ethylene ketal 6 was reacted with maleic anhydride, affording the cyclized adduct 8. Methyl esterification of 8, accompanied by transacetalization, led to the dihydrooxindole derivative 10. Aromatization of 10 was then accomplished with POCl(3), leading directly to the key-intermediate title compound 11 in 74% yield from ketone 6. Serotonin, melatonin, and bufotenin were then obtained by standard reactions.

Synthesis of 2-amino-7,8-dihydro-6(5H)-quinazolinone, 2,4-diamino-7,8-dihydro-6(5H)-quinazolinone, 5,6,7,8-tetrahydro-2,6-quinazoline-diamine and 5,6,7,8-tetrahydro-2,4,6-quinazolinetriamine derivatives

N-(2-Amino-5,6,7,8-tetrahydro-6-quinazolinyl)acetamide (9) and N-(2,4-diamino-5,6,7,8-tetrahydro-6-quinazolinyl)acetamide (6) were synthesized from N-(4-oxocyclohexyl)acetamide (5) as novel peptidomimetic building blocks. With similar purpose, N-(6-oxo-5,6,7,8-tetrahydro-2-quinazolinyl)acetamide (18) and N-[2-(acetylamino)-6-oxo-5,6,7,8-tetrahydro-4-quinazolinyl]acetamide (14) were prepared from cyclohexane-1,4-dione monoethylene ketal (11).