Structure and Tautomerism of the Esters of Several β-Substituted Pyruvic Acids<sup>1</sup>

Stock, Albert M.; Donahue, W. E.; Amstutz, E. D.

doi:10.1021/jo01106a006

Cited by 20 publications

(8 citation statements)

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“…Methyl phenylpyruvate exists as the enol in CDCl 3 and as mixture of enol and keto forms in CD 3 CN 13. Other methyl arylpyruvates exist mainly in the enol form in MeOH 14. Simpkins reported that amide formation from an indol-3-ylpyruvic acid was presumably thwarted by the intervention of the enol form of the α-ketoacid 15.…”

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confidence: 99%

Synthesis of (±)-Eusynstyelamide A

Barykina

Snider

2010

Org. Lett.

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The synthesis of (±)-eusynstyelamide A has been accomplished in six steps in 13% overall yield from 6-bromoindole, methyl glycidate, and Boc-protected agmatine. If oxygen is carefully excluded from the reaction, the key NaOH-catalyzed aldol dimerization of the α-ketoamide proceeded efficiently to give Boc-protected eusynstyelamide A.Tapiolas and co-workers recently reported the isolation of eusynstyelamides A (1), B (2), and C (3) from the Great Barrier Reef ascidian Eusynstyela latericius and assigned their structures from analysis of the spectral data (see Figure 1). 1 The spectral data for 1 are virtually identical to those reported for eusynstyelamide (4), isolated from E. misakiensis ,2 indicating that the structure of 4 should be reassigned as 1, rather than the acyclic ketone dihydrate. Eusynstyelamides A-C (1-3) inhibit neuronal nitric oxide synthase (nNOS), with IC 50 values * snider@brandeis.edu . Supporting Information Available: Complete experimental procedures, comparison of the NMR spectral data of natural and synthetic eusynstyelamide A, and copies of 1 H and 13 C NMR spectral data. This material is available free of charge via the Internet at http://pubs.acs.org. We were intrigued by these structures because the dihydroxybutyrolactam core is identical to that of anchinopeptolide D (7b), which we synthesized several years ago (see Scheme 1). 3 α-Ketoamide 5 underwent an aldol dimerization on treatment with KOH in THF/MeOH. The amide nitrogen of the initially formed aldol adduct cyclized to the remaining ketone to form a dihydroxybutyrolactam. The phenol acetate was also hydrolyzed under these reaction conditions. We isolated three of the four possible diastereomeric products. The major product was anchinopeptolide D precursor 7a, which was formed in 58% yield. Lactam 6a, which was isolated in 19% yield, has the opposite stereochemistry at the hemiaminal center, but was formed from the same aldol adduct 10 (see Scheme 2) as 7a. The third product 8a, which was isolated in <5% yield, was formed from the diastereomeric aldol product. Cleavage of the four Boc groups of 6a and 7a in 1:1 TFA/CH 2 Cl 2 for 1 h at 25 °C afforded 6b (94%) and anchinopeptolide D (7b, 91%), respectively. NIH Public AccessThe stereochemistry of the major aldol adduct 10 can be rationalized by consideration of a chelated transition state for the aldol reaction. Enolization should give the Z-enolate to avoid steric interactions between the amide and the R 1 substituent. Transition state 9, which leads to aldol product 10, might be favored for the aldol reaction since the metal can bind to all four oxygens. The amide nitrogen of adduct 10 can then add to either face of the ketone carbonyl group to give products 6 or 7.As expected, equilibration occurred readily at the hemiaminal center. Heating either 6a or 7a at reflux in CD 3 OD for 1 h afforded an equilibrium 2:1 mixture of 6a and 7a, presumably by ring opening to give the aldol adduct 10. Equilibration of either 6a or 7a with KOH in THF/ MeOH for 17 h at 25 °C afforde...

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confidence: 99%

Synthesis of (±)-Eusynstyelamide A

Barykina

Snider

2010

Org. Lett.

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“…We chose to investigate the tautomerism by using NMR rather than the classical Kurt Meyer bromine titrations (12) because of convenience. For this, we established the enol-keto tautomerism of methyl phenylpyruvate by NMR and found it to approximate the results obtained by Stock et al (9) using bromine titrations.…”

Section: And Discussionmentioning

confidence: 59%

“…In this work, we noticed that some ofthe ketophosphonates we prepared produced pronounced color changes with ferric chloride, suggesting that these compounds exist as enols. Inasmuch as we found no literature reports on the enol-keto tautomerism of a-ketophosphonates, it was of interest to investigate this phenomenon by comparing it to the situation with substituted pyruvic acids (8) and esters (9). RESULTS …”

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Enol-keto tautomerism of α-ketophosphonates

Tam

Mattocks

Tishler

1981

Proc. Natl. Acad. Sci. U.S.A.

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A number ofa-ketophosphonates have been prepared and their enol-keto tautomerism has been studied by means ofproton and phosphorus NMR and infrared spectroscopy and the ferric chloride test. Aliphatic ketophosphonates exist largely in the keto tautomeric forms, with only a small amount of enol forms present. All the aromatic acylphosphonates studied, however, enolize extensively. An x-ray analysis confirmed enolization and E configuration as the only stereochemical isomer. Reaction of diazomethane with diethyl p-methoxyphenylacetyl phosphonate gave a mixture of 0-methylation and carbene insertion products, whereas the same reaction with diethyl isobutyryl phosphonate gave only carbene insertion products.Recent publications have indicated that a number of amino phosphonic acids, as such or in small peptides, possess biological activities (1-4) and therefore can be considered as bioisosteres of the amino carboxylic acids. In a program designed to synthesize some specific peptides containing a phosphonic acid residue, we have had occasion to prepare some a-amino phosphonic acids by the reported procedures involving the conversion of the appropriate alkyl a-ketophosphonate into its oxime followed by reduction of the latter (5-7). In this work, we noticed that some ofthe ketophosphonates we prepared produced pronounced color changes with ferric chloride, suggesting that these compounds exist as enols. Inasmuch as we found no literature reports on the enol-keto tautomerism of a-ketophosphonates, it was of interest to investigate this phenomenon by comparing it to the situation with substituted pyruvic acids (8) and esters (9). RESULTS AND DISCUSSIONThe diethyl ketophosphonates la-li (Scheme 1) were prepared Qualitative and quantitative studies of the keto-enol tautomerism ofthese a-ketophosphonates were based on results offerric chloride color test, proton and phosphorus NMR, and infrared spectroscopy. We chose to investigate the tautomerism by using NMR rather than the classical Kurt Meyer bromine titrations (12) because of convenience. For this, we established the enol-keto tautomerism of methyl phenylpyruvate by NMR and found it to approximate the results obtained by Stock et al. (9) using bromine titrations.The proton NMR characteristics of the a-ketophosphonates shown in Scheme 1 were examined in chloroform-dl (Table 1).Each of the aliphatic diethyl ketophosphonates la-ic exhibited a signal around 3 ppm with appropriate splitting, indicating the presence of the methylene protons (in la and ic) or methine proton (in lb) attached to a carbon atom adjacent to a carbonyl function. No vinylic proton was observed in the downfield region. This strongly suggested that these aliphatic diethyl ketophosphonates exist predominantly in the keto tautomeric form, although the presence ofa small singlet at 1.14 ppm (about 5%) in addition to the large singlet at 1.04 ppm (95%) for the t-butyl group in Ic suggested the presence of about 5% enol form in this case (this was supported by evidence of 31P NMR, see below). One ...

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“…For the synthesis, see: Kolehmainen et al (2000); Ośmiałowski et al (2002Ośmiałowski et al ( , 2003. For its melting point, see: Stock et al (1958); Leonard & Boyer (1950). For hydrogen-bond motifs, see: Bernstein et al (1995).…”

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confidence: 99%

(Z)-Ethyl 2-oxo-3-(1,2-dihydroquinolin-2-ylidene)propanoate

et al. 2010

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Both independent molecules in the asymmetric unit of the tautomeric title compound, C14H13NO3, a synthetic product obtained from 2-lithiomethylquinoline and diethyl oxalate, crystallize in the enaminone form with a Z configuration around the double bond. Intramolecular N—H⋯O hydrogen bonds occur, generating an S(6) graph-set motif. In the crystal, weak intermolecular C—H⋯O and π–π stacking interactions [centroid–centroid distances = 3.7020 (14)–3.7429 (13)Å] define a three-dimensional supramolecular network.

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Structure and Tautomerism of the Esters of Several β-Substituted Pyruvic Acids¹

Cited by 20 publications

References 4 publications

Synthesis of (±)-Eusynstyelamide A

Synthesis of (±)-Eusynstyelamide A

Enol-keto tautomerism of α-ketophosphonates

(Z)-Ethyl 2-oxo-3-(1,2-dihydroquinolin-2-ylidene)propanoate

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Structure and Tautomerism of the Esters of Several β-Substituted Pyruvic Acids1

Cited by 20 publications

References 4 publications

Synthesis of (±)-Eusynstyelamide A

Synthesis of (±)-Eusynstyelamide A

Enol-keto tautomerism of α-ketophosphonates

(Z)-Ethyl 2-oxo-3-(1,2-dihydroquinolin-2-ylidene)propanoate

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Structure and Tautomerism of the Esters of Several β-Substituted Pyruvic Acids¹