Diastereomeric Adducts Research Articles

Construction of an Advanced Tetracyclic Intermediate for Total Synthesis of the Marine Alkaloid Sarain A

In work directed toward a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 54, containing all the key elements and the seven stereogenic centers of sarain A, has been successfully synthesized from bicyclic lactam 4, previously prepared via an intramolecular stereospecific [3 + 2]-azomethine ylide dipolar cycloaddition. Intermediate lactam 4 could be efficiently converted to N-Boc derivative 12. Introduction of a two-carbon fragment into lactam 12 which eventually becomes the C-7',8' syn diol of the "eastern" ring was then achieved by C-acylation of the corresponding enolate with methoxyacetyl chloride followed by a highly stereoselective ketone reduction with Zn(BH4)2 to afford alcohol 16. Intermediate 16 has the incorrect C-7' relative stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7' center via an intramolecular Ohfune-type cyclization of the silyl carbamate derived from Boc mesylate 27 to produce the key cyclic carbamate 28. It was then possible to convert acetal 28 to allylsilane 32 followed by cyclization to the alkaloid tricyclic core 33 via an allylsilane/N-sulfonyliminium ion cyclization. Formation of the "western" macrocyclic ring has been successfully addressed using functional group handles at C-3' and N-1' on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs ruthenium catalyst to produce intermediate macrolactam 47. A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 51 afforded a single diastereomeric adduct 53 which is tentatively assigned to have the correct C-7',8' syn-diol stereochemistry. This adduct could be rearranged to the conveniently protected amino carbonate 54 which is set up for construction of the remainder of the eastern ring of sarain A.

3He NMR as a Sensitive Probe of Fullerene Reactivity: [2 + 2] Photocycloaddition of 3-Methyl-2-cyclohexenone to C70

The [2 + 2] photoadditions of 3-methyl-2-cyclohexenone to C70 and 3He@C70 have been studied by a combination of HPLC chromatography and FAB-MS, as well as IR and 1H and 3He NMR spectroscopies. The total yield of the mixture of monoadducts was 55% (67% on the basis of the recovered C70). The use of 3He NMR was especially powerful in determining the regioselectivity of the photoaddition reaction of enone to C70. Results of the 3He NMR experiments conducted on the product mixture implicate the two [6,6] bonds closest to the poles of the fullerene (C1-C2 and C5-C6) in the photoaddition process. This reaction mode is analogous to that of most thermal addition reactions to C70. Separation and characterization of the product mixture shows that eight distinct monoadducts are formed in the photoaddition, namely, the four diastereomeric adducts to the C1-C2 and C5-C6 bonds of the C70 cage, each consisting of cis- and trans-fused isomers in a ratio of 2:3. The major mode of photoaddition, accounting for 65% of the product mixture, involves addition to the C1-C2 bond of the ovoid fullerene. Mechanistic implications of these findings are discussed.

Photochromic Behavior and Diastereomeric Isomerism in [(η6-spirobenzopyran)RuCp*]PF6

Complexation of photochromic spirobenzopyran 1 (SP-X) with the labile cationic ruthenium complex [Cp*Ru(NCMe)3]PF6 (2) furnishes two isomers of the η6-arene adducts, [Cp*Ru(η6-SP-X)]PF6 (3 and 4), i.e., one of the two diastereomeric adducts of the indoline part in the closed form of 1 (3) and the adduct of the dihydrobenzopyran part in the open trans-merocyanine form of 1 (4). UV irradiation of the pale yellow adduct 3 does not cause an apparent color change, but 1H NMR monitoring reveals formation of the diastereomer 3‘ with the inverted configuration of the chiral spiro carbon atom, which gradually reverts to 3 when left at ambient temperature in the dark over the course of a few days. The two diastereomers 3/3‘ are interconverted with each other through the open, merocyanine form III, which should result from photochemical C−O bond heterolysis of 3/3‘. In the case of the SP-H complex 3b, photochromic behavior (3b ↔ III‘b (trans isomer of IIIb)) is noted but the amount of the colored species III‘b formed is limited. On the other hand, irradiation of the deep red isomer 4 with visible light brings about trans to cis isomerization of the olefinic part to result in complete conversion to an equilibrated mixture of the two diastereomeric closed species 5 and 5‘, which are interconverted with each other at ambient temperature via the transient cis-open intermediate II. UV irradiation of the equilibrated mixture 5/5‘ reverses the ring-opening process to give a photoequilibrated mixture containing 4 in addition to 5/5‘. Thus, 3 and 4 undergo interconversion of the diastereomers via photochemical C−O bond heterolysis and photochromic behavior is noted for 4.

Chirality Recognition of Selenium Compounds by NMR Spectroscopy in the Presence of a Chiral Dirhodium Complex

Diastereomeric adducts of chiral soft-base selenium ligands with the enantiopure dirhodium complex Rh* allows stereodifferentiation by NMR spectroscopy of various nuclei (dirhodium method). The individual adduct species can be identified by low-temperature NMR spectroscopy.

Resolution of β-aminophosphines with chiral cyclopalladated complexes

Resolution of the racemic chiral β-aminophosphines Ph 2PCH 2CH(Ph)NH(Ar) ( L 1 for Ar = C 6H 5 and L 2 for Ar = 2,6-C 6H 3 i Pr 2) has been investigated by use of different cyclopalladated complexes as chiral agents. The resulting complexes afford diastereomeric adducts in a 1:1 ratio. After successive crystallizations from ethanol, a d.e. of 98% was achieved for one aminophosphine palladium complex, while no significant d.e. was obtained after crystallizations from chlorinated solvents. The X-ray structure analysis has pointed out intermolecular hydrogen interactions N–H⋯Cl between the P,N ligand and the chloride ion, which are responsible for the formation and stabilization of the diastereomeric adducts. Thus, the use of oxygenated solvents cancels such hydrogen interactions by their stronger donor character and makes the diastereomers separation possible, allowing to isolate the optically pure ( R)-Ph 2PCH 2CH(Ph)NH(Ph) L 1 of which the absolute configuration has been determined from the X-ray structure analysis of the related palladium dichloride complex.

Bridgehead nitrogen heterocycles which contain the quinazoline moiety – synthesis and cycloaddition of 1,2-dihydroquinazoline 3-oxides

A novel synthesis of 1,2-disubstituted 1,2-dihydroquinazoline 3-oxides 8 and the first ever examples of 1,3-dipolar trapping of these nitrones to homonuclear dipolarophiles is described. The new dipoles 8 reacted with N-methyl maleimide, generating diastereomeric adducts 14-16. In the reaction between 8 and dimethyl acetylenedicarboxylate, primary cycloadducts 17 and/or stable rearrangement products, azomethine ylides 18, are formed depending on the substitution pattern of the dipole. The structure of 18c is unambiguously assigned by X-ray crystallographic analysis. An X-ray crystal structure determination is also presented for the cyclopropylisoxazoloquinazoline 22 formed by a [3 + 2] addition of 8a to 21, the dimethyl acetylenedicarboxylate tetramer.

The Formation of Substituted 1,N6-Etheno-2‘-deoxyadenosine and 1,N2-Etheno-2‘-deoxyguanosine Adducts by cis-2-Butene-1,4-dial, a Reactive Metabolite of Furan

Furan is an environmental chemical that induces liver toxicity and tumor formation in rodents, leading to its classification as a probable human carcinogen. cis-2-Butene-1,4-dial, the metabolite considered responsible for furan's toxicological effects, is mutagenic in the Ames assay and reacts with 2'-deoxycytidine (dCyd), 2'-deoxyadenosine (dAdo), and 2'-deoxyguanosine (dGuo) to form previously characterized diastereomeric adducts. The initially formed dCyd adducts are stable to rearrangement, while the dAdo and dGuo adducts are unstable and rearrange to form secondary products. On the basis of UV absorbance, fluorescence, 1H NMR, and mass spectral data, the rearrangement product of the dAdo adduct was identified as the substituted etheno-dAdo adduct, 1''-[3-(2'-deoxy-beta-D-erythropentafuranosyl)-3H-imidazo[2,1-i]purin-8-yl]ethane-2''-al. The NMR characterization of the O-methyloxime derivative of the secondary dGuo adduct, along with mass spectral and UV data on the underivatized adduct, allowed for its structural assignment as the substituted etheno-dGuo compound, 3-(2'-deoxy-beta-D-erythropentafuranosyl)imidazo-7-(ethane-2''-al)[1,2-alpha]purine-9-one. The characterization of the primary and secondary products formed in the reaction of cis-2-butene-1,4-dial with nucleosides is important for understanding the mechanism of furan-induced carcinogenesis. These secondary adducts retain a reactive aldehyde with the potential to form cross-links and are likely to contribute significantly to furan's toxic and carcinogenic effects.

Steric course of some cyclopropanation reactions of L- threo-hex-4-enopyranosides

Completely protected 4-deoxy-α- L- threo-hex-4-enopyranosides 1c, d undergo the dichlorocarbene addition affording exclusively diastereomeric adducts 5c, d with the cyclopropane ring anti to the C-3 alkyloxy substituent, while the reaction with 3-unprotected derivatives 1a, b affords a mixture of syn and anti derivatives. Under the Simmons–Smith cyclopropanation adducts 2a- d with a syn stereochemistry are obtained. Starting from 5b , the cyclopropanated sugar 3b is obtained by reduction with LiAlH 4, thus the two diastereomers 2b and 3b can be stereoselectively obtained through the two different pathways. For a useful comparison, 4-deoxy-β- L- threo-hex-4-enopyranoside 1e was also subjected to the above two cyclopropanation methods affording the expected cycloadduct 2e and a diastereomeric mixture of dichlorocycloadducts 4e and 5e ( 4e / 5e =2.8:1).

Identification and characterization of a series of nucleoside adducts formed by the reaction of 2'-deoxyguanosine and 1,2,3,4-diepoxybutane under physiological conditions.

The carcinogenicity of 1,3-butadiene (BD) has been attributed to its in vivo metabolites, 3,4-epoxy-1-butene (EB) and 1,2,3,4-diepoxybutane (DEB). In this study, DEB was demonstrated to react with 2'-deoxyguanosine (dG) under in vitro physiological conditions (pH 7.4, 37 degrees C) to yield several pairs of diastereomeric adducts, including N-(2-hydroxy-1-oxiranylethyl)-2'-deoxyguanosine (P4-1 and P4-2), 7,8-dihydroxy-3-(2-deoxy-beta-d-erythro-pentofuranosyl)-3,5,6,7,8,9-hexahydro-1,3-diazepino[1,2-a]purin-11(11H)one (P6), 1-(2-hydroxy-2-oxiranylethyl)-2'-deoxyguanosine (P8 and P9), 1-[3-chloro-2-hydroxy-1-(hydroxymethyl)propyl]-2'-deoxyguanosine (1AP9 and 2AP9), and 4,8-dihydroxy-1-(2-deoxy-beta-d-erythro-pentofuranosyl)-9-hydroxymethyl-6,7,8,9-tetrahydro-1H-pyrimido[2,1-b]purinium ion (1BP4 and 2BP4). The 7-alkylation dG adducts (P5 and P5') were not characterized directly by NMR spectrometry because of their instability. However, their formula weights were determined to be 354, and their acid hydrolysis products were characterized as 2-amino-7-(3-chloro-2,4-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H3), consistent with the structures of P5 and P5' being diastereomers of 6-oxo-2-amino-9-(2-deoxy-beta-d-erythro-pentofuranosyl)-7-(2-hydroxy-2-oxiranylethyl)-6,9-dihydro-1H-purinium ion. Time-course experiments indicated that alkaline pH and/or high DEB:dG molar ratios made the reactions faster without changing the adduct profile. The adducts were detected in the following chronological order: 7- (P5 and P5'), 1- (P8 and P9), N(2)- (P4-1 and P4-2), and P6. Whereas P4-1, P4-2, and P6 appeared stable during the courses of the reactions, P5, P5', P8, and P9 were labile and completely decomposed by the time dG was fully consumed. These results may contribute to a better understanding of the chemical reactivity and strong mutagenicity and carcinogenicity of DEB.

Atroposelectivity of Reactions of Benzylic Metalated Thiobenzamides and Thionaphthamides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Atroposelectivity of Reactions of Benzylic Metalated Thiobenzamides and Thionaphthamides

AbstractN,N‐Dialkyl‐2‐methylbenzenecarbothioamides and naphthalenecarbothioamides were prepared by thionation of amides with Lawesson’s reagent under unusual conditions. Their axial chirality was evidenced. Benzylic deprotonation of thioamides bearing N,N‐diisopropyl groups with sec‐butyllithium was selective. The resulting anions were reacted with prochiral electrophiles (aromatic aldehydes, an unsaturated aldehyde or ketone, and an imine) to afford diastereomeric adducts (up to 88:12 dr). This is the first report on atroposelective C−C bond formation in the benzylic position of thioamides. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

New Benzo[b]xanthones from Diels—Alder Reactions of Chromone‐3‐carboxaldehydes with ortho‐Benzoquinodimethanes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chiral 1,8-bis( tert-butylphenylphosphino)naphthalene oxides and sulfides: resolution and structures

Chiral racemic 1,8-bis( tert-butylphenylphosphino)naphthalene oxide ( 2a) was resolved into enantiomers by fractional crystallization of its diastereomeric adducts 3a with (+)-(2 S,3 S)-di- O-benzoyl tartaric acid (DBTA), followed by neutralization. Racemic 1,8-bis( tert-butylphenylphosphino)naphthalene ( 1a) was oxidized with sulfur to two isomers of 1,8-bis( tert-butylphenyl-phosphino)naphthalene monosulfide, rac- 4a and rac- 4a′, or 1,8-bis( tert-butylphenylphosphino)naphthalene disulfide, rac- 5a. The compounds were characterized by NMR spectroscopy ( 1H, 31P, 13C). Crystal structures were determined by the X-ray method for (−)- 3a, rac- 4a, rac- 4a′ and rac- 5a; this allowed the determination of the absolute configuration ( S, S) for the more soluble adduct (−)- 3a. It was found that rac- 1a undergoes partial epimerization in boiling xylene to give the meso form.

New Benzo[ b ]xanthones from Diels-Alder Reactions of Chromone-3-carboxaldehydes with ortho -Benzoquinodimethanes

New benzo[b]xanthone derivatives, having substituents in the A and D rings, were prepared from cycloaddition reactions of chromone-3-carboxaldehydes with ortho-benzoquinodimethanes, generated in situ from 1,3-dihydrobenzo[c]thiophene 2,2-dioxide, followed by oxidation of the obtained diastereomeric adducts. The structure of all compounds was fully established by 1D and 2D NMR, MS, and elemental analysis. The stereochemistry of the obtained diastereomeric cycloadducts was established by NOESY experiments.

Study of chiral β-enaminones prepared from pyrrolidine, cytisine, salsoline and 2-amino-1-(4-nitrophenyl)propane-1,3-diol: resolution of salsoline via diastereomeric modified carane-type β-enaminones

A series of novel optically active β-enaminones have been prepared regio- and stereoselectively from primary and secondary amines (pyrrolidine, cytisine salsoline and 2-amino-1-(4-nitrophenyl)propane-1,3-diol) and (+)-3-carene-derived β-chlorovinylketone. Resolution of the isoquinoline alkaloid salsoline has been demonstrated as well as isolation of a single diastereomeric adduct from racemic 2-amino-1-(4-nitrophenyl)propane-1,3-diol.

Chiral discrimination in platinum anticancer drugs.

In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

Phenylselenenylmenthane derivatives and their enantiomeric discrimination by 1H and 13C NMR spectroscopy in the presence of a chiral dirhodium complex

AbstractThe phenylselenenylmenthane and ‐menthene derivatives 1–4 were studied in terms of 1H and 13C signal assignments, conformational analysis and also complexation shifts (Δδ) and dispersion effects (Δν) observed when non‐racemic (ca 2 : 1) mixtures of the chiral selenides were exposed to an equimolar amount of the chiral dirhodium complex Rh*. The complexation site is the selenium atom exclusively. Whereas Δδ values are moderate or small, dispersed signals (split into two owing to the existence of diastereomeric adducts) can be observed, many of which are large enough for a facile determination of enantiomeric ratios of the selenides irregardless of the conformational behaviour of the selenides and the adduct composition. Thus, the ‘dirhodium method’ is simple and reliable for chiral recognition in the class of organoselenium compounds which is gaining increasing importance in developing new techniques of asymmetric synthesis. Copyright © 2002 John Wiley & Sons, Ltd.

Characterization of nucleoside adducts of cis-2-butene-1,4-dial, a reactive metabolite of furan.

Furan is a hepatic toxicant and carcinogen in rodents. Its microsomal metabolite, cis-2-butene-1,4-dial, is mutagenic in the Ames assay. Consistent with this observation, cis-2-butene-1,4-dial reacts with 2'-deoxycytidine, 2'-deoxyguanosine, and 2'-deoxyadenosine to form diastereomeric adducts. HPLC analysis indicated that the rate of reaction with deoxyribonucleosides was dependent on pH. At pH 6.5, the relative reactivity was 2'-deoxycytidine > 2'-deoxyguanosine > 2'-deoxyadenosine whereas it was 2'-deoxyguanosine > 2'-deoxycytidine > 2'-deoxyadenosine at pH 8.0. Thymidine did not react with cis-2-butene-1,4-dial. The primary 2'-deoxyguanosine and 2'-deoxyadenosine reaction products were unstable and decomposed to secondary products. NMR and mass spectral analysis indicated that the initial 2'-deoxyadenosine and 2'-deoxyguanosine reaction products were hemiacetal forms of 3-(2'-deoxy-beta-D-erthyropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2''-al)-9H-imidazo[1,2-alpha]purine-9-one (structure 2) and 3-(2'-deoxy-beta-D-erythropentafuranosyl)-3,6,7,8-tetrahydro-7-(ethane-2''-al)-8-hydroxy-3H-imidazo[2,1-i]purine (structure 4), respectively. These adducts resulted from the addition of cis-2-butene-1,4-dial to the exo- and endocyclic nitrogens of 2'-deoxyadenosine and 2'-deoxyguanosine. The data provide support for the hypothesis that cis-2-butene-1,4-dial is an important genotoxic intermediate in furan-induced carcinogenesis.

Reactions between Triazolinediones and Equilibrating Forms of Cycloheptatriene Derivatives Featuring 7,7-Spiro and 1,7-Fused Heterocyclic Rings

Nitrile oxide−azaheptafulvene adducts consist of rapidly equilibrating mixtures of fused (1) and spiro (2) isomers, the relative stabilities of which are nicely reproduced by B3LYP/6-31G* calculations. The reaction between these compounds and MTAD affords only two diastereomeric adducts [9 (dominant) and 10], both deriving from the reaction of MTAD with 1 even in cases in which that isomer could not be detected by NMR spectroscopy. These adducts are formal Diels−Alder adducts deriving from attacks on the two diastereotopic faces of the triene moiety of 1 and involving only the diene system adjacent to the amino substituent (N4−C4a=C5−C6=C7). The structures of the adducts are firmly supported by spectroscopic data and X-ray analysis, and so previous incorrect assignments are revised. The mechanism of the reaction between MTAD and 1 is briefly discussed.

Chiral discrimination of monofunctional alcohols and amines in the gas phase

A methodology has been developed for enantiodiscriminating chiral monoalcohols and monoamines by mass spectrometry. The approach is based on the generation of supersonically expanded complexes of these molecules with suitable chromophores, i.e. R-(+)-1-phenyl-ethanol (ER) or R-(+)-1-phenyl-1-propanol (PR). The jet-cooled diastereomeric complexes, otherwise elusive at room temperature, have been ionized by one-color resonant two-photon absorption (R2PI) and their fragmentation pattern analyzed by time-of-flight (TOF) spectrometry. Enantiodifferentiation of the chiral monoalcohols and monoamines is based on: (1) the different spectral shifts of the band origin of their molecular complexes relative to that of the bare chromophore (Δ) and (2) the different mass spectral fragmentation patterns of the jet-cooled diastereomeric adducts. Detection of stable aggregates of methane, n-butane, and other simple molecules with the selected chromophores suggests that the R2PI/TOF method can be a potential tool for enantiodifferentiating chiral hydrocarbons in the gas phase.