The structure and function of oestrogens. VIII. Synthesis of 5,5, 10b-Trimethyl-cis-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol from 6-Methoxy-3,4-dihydronaphthalen-1(2H)-one

1984 ◽  
Vol 37 (11) ◽  
pp. 2279 ◽  
Author(s):  
DJ Collins ◽  
JD Cullen ◽  
GD Fallon ◽  
BM Gatehouse
Keyword(s):  
Methanesulfonic Acid ◽  
Enol Ether ◽  
X Ray ◽  
X Ray Crystallography ◽  
Hydride Reduction ◽  
Lithium Aluminium ◽  
Ring Junction ◽  
Clemmensen Reduction ◽  
And Function ◽  
Zinc Iodide

Treatment of 2-hydroxymethylene-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (13a) with p-meth-oxyphenyllead triacetate afforded 93% of 2-formyl-6-methoxy-2-(p-methoxyphenyl)-3,4-dihydro- naphthalen-1(2H)-one (14a) which upon deformylation and methylation gave 60% of 6-methoxy- 2-(p-methoxyphenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-one (17). An alternative route to the α α'-disubstituted ketone (17) by way of 6-methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one (15) and 2-chloro-6-methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one (16) was less efficient. Lithium aluminium hydride reduction of the ketone (17) followed by acetylation yielded 80% of 1 ξ acetoxy- 6-methoxy-2-(p-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydronaphthalene (23), treatment of which with the trimethylsilyl enol ether of ethyl 2-methylpropanoate in the presence of zinc iodide afforded 71% of ethyl (1SR,2RS)-2-methyl-2-[6'-methoxy-2'-(p-methoxyphenyl)-2'-methyl-1',2 ',3',4'-tetrahydronaphthalen-yl'ξ-yl]propanoate (26a). Treatment of the ester (26a) or the corresponding acid (26b) with methanesulfonic acid yielded 68 or 82% respectively, of 2*-dimethoxy-5,5,10b-trimethyl- cis-4b,10b,11,12-tetrahydrochrysen-6(5H)-one (27a); Clemmensen reduction of this followed by demethylation with hydrobromicacidin aceticacid gave 49% of cis-5,5,10b-trimethyl-4b,5,6,10b,11,12- hexahydrochrysene-2,8-diol (7a). The sterochemistry of the ring junction in compound (7a) was established by X-ray crystallography of the corresponding dimethyl ether (27b).

Synthesis of 3-(4′-Methoxyphenyl)-2,2,4,4-Tetramethylpentane and Some Cyclic Analogs

1986 ◽  
Vol 39 (12) ◽  
pp. 2095 ◽  
Author(s):  
DJ Collins ◽  
HA Jacobs
Keyword(s):  
Methanesulfonic Acid ◽  
Similar Reaction ◽  
Reaction Sequence ◽  
Quinone Methides ◽  
Hydride Reduction ◽  
Lithium Aluminium ◽  
Clemmensen Reduction ◽  
Analogous Manner ◽  
Hydrolysis Of ◽  
Zinc Iodide

Reaction of 1-methoxy-2-methyl-1-trimethylsilyloxyprop-1-ene (8) with 1-acetoxy-1-(4′-methoxyphenyl)-2,2-dimethylpropane (7b) in the presence of zinc iodide gave 84% of methyl 3-(4′methoxyphenyl)-2,2,4,4- tetramethylpentanoate (9a), which was reduced with lithium aluminium hydride to 3-(4′-methoxyphenyl)-2,2,4,4-tetramethylpentan-1-ol(12a). Hydride reduction of the derived tosylate (12b) afforded 3-(4′-methoxyphenyl )-2,2,4,4-tetramethylpentane (5b) which upon demethylation yielded the corresponding phenol (10a). In an analogous manner, 1-acetoxy-1-(4′-methoxyphenyl)-2-methylpropane (7d) was converted into 3- (4′-hydroxyphenyl)-2,2,4-trimethylpentane (10b). By a similar reaction sequence, 6-methoxy-2,2-dimethyl-3,4- dihydronaphthalen-1(2H)-one (14) was transformed into 6-hydroxy-2,2- dimethyl-1-(1′,1′-dimethylethyl)-1,2,3,4-tetrahydronaphthalene (16b). Hydrolysis of the ester (9a) and cyclization of the resulting carboxylic acid (19) by treatment with methanesulfonic acid at 20° for 18 h afforded 3-(1′, 1′-dimethylethyl)-6-methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (20). Clemmensen reduction of this followed by demethylation yielded 1-(1′,1′-dimethylethyl)-2,2-dimethyl-2,3-dihydro-1H-inden-5-ol (21b). Attempts to oxidize the phenols (10a), (10b), (16b) and (21b) to the corresponding quinone methides by conventional methods failed.

The Structure and Function of Estrogens. IX. Synthesis of the trans Isomer of 5,5,10b-Trimethyl-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol

1988 ◽  
Vol 41 (5) ◽  
pp. 735 ◽  
Author(s):  
DJ Collins ◽  
JD Cullen
Keyword(s):  
Trans Isomer ◽  
Methanesulfonic Acid ◽  
Structure And Function ◽  
Clemmensen Reduction ◽  
And Function ◽  
Zinc Iodide ◽  
Cis Isomer

Alkylation of ketene methyl trimethylsilyl acetal (10) with 1ξ-acetoxy- 6-methoxy-2-(p- methoxyphenyl )-2-methyl-1,2,3,4-tetrahydronaphthalene (9) in the presence of zinc iodide gave 84% of methyl (1′RS,2′RS)-2- [6′-methoxy-2′-(p-methoxyphenyl )-2?-methyl-1′,2′,3′,4′- tetrahydronaphthalen-1′-yl] ethanoate (11a). Cyclization of the derived acid (11b) with methanesulfonic acid gave 89% of 2,8-dimethoxy-10b-methyl-cis-4b,10b,11,12-tetrahydrochrysen-6(5H)-one (12a), Clemmensen reduction of which afforded 52% of 2,8-dimethoxy-4b-methyl-cis- 4b,5,6,10b,11,12-hexahydrochrysene (12b). Oxidation of (12b) with dichlorodicyanobenzoquinone gave 70% of the conjugated enone (4), which upon hydrogenation over 10% palladium/charcoal gave a 5:1 ratio of 2,8-dimethoxy-10b-methyl-trans-4b,10b,11,12-tetrahydrochrysen-6(5H)-one (14) and the cis isomer (12a). Exhaustive methylation of the trans ketone (14) yielded 49% of 2,8-dimethoxy-5,5,10b-trimethyl-trans-4b,10b,11,12-tetrahydrochrysen-6(5H)-one (16), which upon Clemmensen reduction followed by O- demethylation afforded 5,5,10b-trimethyl-trans-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol(2).

Selective O-Methyloxime Formation From 6-Methoxy-2-[(1'-methyl-2',5'-dioxocyclopentyl)-methyl]-3,4-dihydronaphthalen-1(2H)-one

1994 ◽  
Vol 47 (4) ◽  
pp. 649 ◽  
Author(s):  
DJ Collins ◽  
GD Fallon ◽  
CE Skene
Keyword(s):  
Lithium Aluminium Hydride ◽  
X Ray ◽  
X Ray Crystallography ◽  
Lithium Aluminium ◽  
Major Isomer ◽  
Toluenesulfonic Acid ◽  
Ester Formation ◽  
Diastereomeric Mixture ◽  
A Minor

Reaction of 6-methoxy-2-[(1′-methyl-2′,5′-dioxocyclopentyl)methyl]-3,4-dihydronaphthalen-1(2H)-one (4a) with 1 or 2 moles of O- methylhydroxylamine hydrochloride in pyridine gave (1′SR,2RS)-6-methoxy-2-[(1′-methyl-2′,5′-dioxocyclopentyl)methyl]-3,4-dihydronaphthalen-1(2H)-one (E)-2′-O-methyloxime (5a), or the corresponding 2′,5′-bis(O-methyloxime ) (6), respectively. A minor product from the formation of the bis (O- methyloxime ) (6) was the (Z) isomer (5b) of the mono(O- methyloxime ) (5a); the structure and stereochemistry of (5a) and (5b) were established by X-ray crystallography. Reduction of the keto bis (O-methyloxime ) (6) with 0.25 mole of lithium aluminium hydride gave a diastereomeric mixture of the corresponding alcohols (7a), of which the major isomer was characterized by ester formation. The bis (O-methyloxime ) (6) could be hydrolysed to the parent triketone (4a), but it resisted deprotection with cetyltrimethylammonium permanganate. Reaction of the triketone (4a) with 1 mole of 4-anisidine in the presence of 4-toluenesulfonic acid resulted in retro Michael cleavage with formation of 3-(4′-methoxyphenyl)amino-2-methylcyclopent-2-en-1-one (1).

scholarly journals General discussion summary

2002 ◽  
Vol 357 (1426) ◽  
pp. 1419-1420 ◽  
Keyword(s):  
Water Splitting ◽  
Molecular Mechanisms ◽  
Structure And Function ◽  
X Ray ◽  
X Ray Crystallography ◽  
And Function ◽  
Splitting Process

This general discussion was chaired by A. W. Rutherford ( Service de Bioénergétique, Saclay, France ) and revolved around two major topics: (i) the implications of X–ray crystallography on the relationships between structure and function; (ii) the molecular mechanisms of the water–splitting process.

scholarly journals Structure and function of cement proteins in human adenovirus

2014 ◽  
Vol 70 (a1) ◽  
pp. C1603-C1603
Author(s):  
Vijay Reddy ◽  
Glen Nemerow
Keyword(s):  
Protein Structures ◽  
Human Adenovirus ◽  
Icosahedral Symmetry ◽  
Virion Assembly ◽  
X Ray ◽  
X Ray Crystallography ◽  
Capsid Shell ◽  
Multiple Copies ◽  
And Function ◽  
Cement Protein

Human adenoviruses (HAdVs) are large (~150nm in diameter, 150MDa) nonenveloped double-stranded DNA (dsDNA) viruses that cause respiratory, ocular, and enteric diseases. The capsid shell of adenovirus (Ad) comprises multiple copies of three major capsid proteins (MCP: hexon, penton base and fiber) and four minor/cement proteins (IIIa, VI, VIII and IX) that are organized with pseudo T=25 icosahedral symmetry. In addition, six other proteins (V, VII, μ, IVa2, terminal protein and protease) are encapsidated along with the 36Kb dsDNA genome inside the capsid. The crystal structures of all three MCPs are known and so is their organization in the capsid from prior X-ray crystallography and cryoEM analyses. However structures and locations of various cement proteins are of considerable debate. We have determined and refined the structure of an entire human adenovirus employing X-ray crystallpgraphic methods at 3.8Å resolution. Adenovirus cement proteins play crucial roles in virion assembly, disassembly, cell entry and infection. Based on the refined crystal structure of adenovirus, we have determined the structure of the cement protein VI, a key membrane-lytic molecule and its associations with proteins V and VIII, which together glue peripentonal hexons beneath vertex region and connect them to rest of the capsid. Following virion maturation, the cleaved N-terminal pro-peptide of VI is observed deep in the peripentonal hexon cavity, detached from the membrane-lytic domain. Furthermore, we have significantly revised the recent cryoEM models for proteins IIIa and IX and both are located on the capsid exterior. Together, the cement proteins exclusively stabilize the hexon shell, thus rendering penton vertices the weakest links of the adenovirus capsid. Adenovirus cement protein structures reveal the molecular basis of the maturation cleavage of VI that is needed for endosome rupture and delivery of the virion into cytoplasm.

Interactions between the Aldehyde and Anhydride Groups in the Diterpenoid Fujenal

2002 ◽  
Vol 2002 (12) ◽  
pp. 647-648 ◽  
Author(s):  
James R. Hanson ◽  
Peter B. Hitchcock ◽  
Ivana Pibiri ◽  
Cavit Uyanik
Keyword(s):  
Magnesium Bromide ◽  
X Ray ◽  
X Ray Crystallography ◽  
Ring Junction

Methanolysis of the diterpenoid aldehyde:anhydride, fujenal, catalysed by tetracyanoethylene afforded C-6:C-7 methoxylactones whilst the addition of methyl magnesium bromide to fujenal afforded a 6,7-lactone but with an cis A/B ring junction; the structures of these products were established by X-ray crystallography.

scholarly journals Solving a new R2lox protein structure by microcrystal electron diffraction

2019 ◽  
Vol 5 (8) ◽  
pp. eaax4621 ◽  
Author(s):  
Hongyi Xu ◽  
Hugo Lebrette ◽  
Max T. B. Clabbers ◽  
Jingjing Zhao ◽  
Julia J. Griese ◽  
...  
Keyword(s):  
Protein Structure ◽  
Electron Diffraction ◽  
Model Building ◽  
Protein Structures ◽  
X Ray Diffraction ◽  
X Ray ◽  
X Ray Crystallography ◽  
Potential Map ◽  
Metal Cofactor ◽  
And Function

Microcrystal electron diffraction (MicroED) has recently shown potential for structural biology. It enables the study of biomolecules from micrometer-sized 3D crystals that are too small to be studied by conventional x-ray crystallography. However, to date, MicroED has only been applied to redetermine protein structures that had already been solved previously by x-ray diffraction. Here, we present the first new protein structure—an R2lox enzyme—solved using MicroED. The structure was phased by molecular replacement using a search model of 35% sequence identity. The resulting electrostatic scattering potential map at 3.0-Å resolution was of sufficient quality to allow accurate model building and refinement. The dinuclear metal cofactor could be located in the map and was modeled as a heterodinuclear Mn/Fe center based on previous studies. Our results demonstrate that MicroED has the potential to become a widely applicable tool for revealing novel insights into protein structure and function.

scholarly journals Room-temperature X-ray crystallography reveals the oxidation and reactivity of cysteine residues in SARS-CoV-2 3CL Mpro: insights into enzyme mechanism and drug design

IUCrJ ◽  
2020 ◽  
Vol 7 (6) ◽  
pp. 1028-1035 ◽  
Author(s):  
Daniel W. Kneller ◽  
Gwyndalyn Phillips ◽  
Hugh M. O'Neill ◽  
Kemin Tan ◽  
Andrzej Joachimiak ◽  
...  
Keyword(s):  
Drug Design ◽  
Room Temperature ◽  
Enzyme Mechanism ◽  
Cysteine Residues ◽  
Acid Oxidation ◽  
Detailed Knowledge ◽  
X Ray ◽  
X Ray Crystallography ◽  
Novel Coronavirus ◽  
And Function

The emergence of the novel coronavirus SARS-CoV-2 has resulted in a worldwide pandemic not seen in generations. Creating treatments and vaccines to battle COVID-19, the disease caused by the virus, is of paramount importance in order to stop its spread and save lives. The viral main protease, 3CL Mpro, is indispensable for the replication of SARS-CoV-2 and is therefore an important target for the design of specific protease inhibitors. Detailed knowledge of the structure and function of 3CL Mpro is crucial to guide structure-aided and computational drug-design efforts. Here, the oxidation and reactivity of the cysteine residues of the protease are reported using room-temperature X-ray crystallography, revealing that the catalytic Cys145 can be trapped in the peroxysulfenic acid oxidation state at physiological pH, while the other surface cysteines remain reduced. Only Cys145 and Cys156 react with the alkylating agent N-ethylmaleimide. It is suggested that the zwitterionic Cys145–His45 catalytic dyad is the reactive species that initiates catalysis, rather than Cys145-to-His41 proton transfer via the general acid–base mechanism upon substrate binding. The structures also provide insight into the design of improved 3CL Mpro inhibitors.

Synthesis of 1,8,8-Trimethyl-6,10-dioxaspiro[4.5]dec-2-ene-1-ethanol; X-Ray Crystallography of (1RS,2SR)-1,8,8-Trimethyl-1-(prop-2'-enyl)-6,10-dioxaspiro[4.5]dec-2-yl Benzoate

1994 ◽  
Vol 47 (4) ◽  
pp. 739 ◽  
Author(s):  
DJ Collins ◽  
GD Fallon ◽  
RP Mcgeary
Keyword(s):  
Oxidative Cleavage ◽  
Quantitative Yield ◽  
Borohydride Reduction ◽  
X Ray ◽  
X Ray Crystallography ◽  
Flash Vacuum Pyrolysis ◽  
Hydride Reduction ◽  
Tetrabutylammonium Fluoride ◽  
Vacuum Pyrolysis ◽  
Relative Stereochemistry

Reaction of 2-methyl-2-(prop-2′-enyl)cyclopentane-1,3-dione (2) with 2,2-dimethylpropane-1,3-diol gave 1,8,8-trimethyl-1-(prop-2′-enyl)-6,10-dioxaspiro[4.5]decan-2-one (3), hydride reduction of which afforded a 1:1 epimeric mixture of the corresponding alcohols (4a) and (4b). They were separated, and the derived benzoates (5a) and (5b) were each subjected to a three-step sequence of oxidative cleavage, borohydride reduction and silylation to give the pure epimers (8a) and (8b) of 1,8,8-trimethyl-1-(2′-t-butyldimethylsilyloxyethyl)-6,10-dioxaspiro[4.5]dec-2-yl benzoate. Flash vacuum pyrolysis of a mixture of these epimeric benzoates (8a,b) gave an almost quantitative yield of 1,8,8-trimethyl-1-(2′-t-butyldimethylsilyloxyethyl)-6,10-dioxaspiro[4.5]dec-2-ene (9a), treatment of which with tetrabutylammonium fluoride afforded the corresponding alcohol (9b). The relative stereochemistry of (1RS,2SR)-1,8,8-trimethyl-1-(prop-2′-enyl)-6,10-dioxaspiro [4.5]dec-2-yl benzoate (5b) was established by X-ray crystallography.

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