Lanosterol Biosynthesis: The Critical Role of the Methyl‐29 Group of 2,3‐Oxidosqualene for the Correct Folding of this Substrate and for the Construction of the Five‐Membered D Ring

Lanosterol synthase catalyzes the polycyclization reaction of (3S)‐2,3‐oxidosqualene ( 1 ) into tetracyclic lanosterol 2 by folding 1 in a chair‐boat‐chair‐chair conformation. 27‐Nor‐ and 29‐noroxidosqaulenes ( 7 and 8 , respectively) were incubated with this enzyme to investigate the role of the methyl groups on 1 for the polycyclization cascade. Compound 7 afforded two enzymatic products, namely, 30‐norlanosterol ( 12 ) and 26‐normalabaricatriene ( 13 ; 12 / 13 9:1), which were produced through the normal chair‐boat‐chair‐chair conformation and an atypical chair‐chair‐boat conformation, respectively. Compound 8 gave two products 14 and 15 ( 14 / 15 4:5), which were generated by the normal and the unusual polycyclization pathways through a chair‐chair‐boat‐chair conformation, respectively. It is remarkable that the twist‐boat structure for the B‐ring formation was changed to an energetically favored chair structure for the generation of 15 . Surprisingly, 14 and 15 consisted of a novel 6,6,6,6‐fused tetracyclic ring system, thus differing from the 6,6,6,5‐fused lanosterol skeleton. Together with previous results, we conclude that the methyl‐29 group is critical to the correct folding of 1 , with lesser contributions from the other branched methyl groups, such as methyl‐26, ‐27, and ‐28. Furthermore, we demonstrate that the methyl‐29 group has a crucial role in the formation of the five‐membered D ring of the lanosterol scaffold.     

2,4‐Bis(o‐tolyl)‐3‐azabicyclo[3.3.1]nonan‐9‐one

The crystal structure of the title compound, C₂₂H₂₅NO, confirms that the bicyclic ring system adopts the chair–chair conformation. The phenyl rings are equatorially disposed with respect to the bicyclic ring. There is a slight deviation from the chair conformation in the case of the cyclo­hexane ring.     

Stereochemistry of heterocycles

The conformations of stereoisomeric 2,5-dialkyl-1,3-dioxanes were studied by means of dipole moments (DM), and it was shown that the low-boiling isomers have a chair conformation or a somewhat distorted symmetrical boat conformation, while the high-boiling isomers have a chair conformation with diequatorial orientation of the substituents. The DM measurements lead to values for the ketals which are closest to those calculated for the chair conformation.See [1] for communication V.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 593–596, May, 1971.The authors sincerely thank Academician D. A. Arbuzov for his unflagging interest and involvement in this investigation.     

Synthesis,crystal and molecular structure of 3,7-ditosyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonane

3,7-Ditosyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonane has been found to adopt a chair–chair conformation in the crystalline state in contrast to 3,7-ditosyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one, which had been previously found to exist in a chair-boat conformation.     

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

Summary The active conformation of several histamine H₁-antagonists is investigated. As a template molecule we used the antagonist cyproheptadine, which consists of a piperidylene ring connected to a tricyclic system. The piperidylene moiety is shown to be flexible. The global minimum is a chair conformation but, additionally, a second chair and various boat conformations have to be considered, as their energies are less than 5 kcal/mol above the energy of the global minimum. Two semi-rigid histamine H₁-antagonists, phenindamine and triprolidine, were fitted onto the various conformations of cyproheptadine in order to derive the pharmacologically active conformation of cyproheptadine. At the same time, the active conformation of both phenindamine and triprolidine was derived. It is demonstrated that, within the receptor-bound conformation of cyproheptadine, the piperidylene ring most probably exists in a boat form.     

Conformational control in activation of an enediyne

In the bicyclo[7.3.1]tridec-4-ene-2,6-diyne framework characteristic of calicheamicin, DFT calculations predict that the chair conformer should be much more reactive toward cycloaromatization compared to the boat form. A functionalized derivative of this framework with an added two-atom bridge to enforce the boat conformation was synthesized and shown to be stable at 23 degrees C. Cleavage of the bridge releases the conformational lock and cycloaromatization proceeds with t1/2 42.5 min/23 degrees C, presumably through the chair conformation. This confirms the prediction based on computation and points to a new principle for triggering the enediyne toxins.     

Synthesis and conformational analysis of isomeric 3-propananilidotropanes

The isomeric 3-anilino and 3-propananilidotropanes have been synthesized and obtained in isomerically pure form. The configurations and solute conformations of these isomers were studied via glc and nrar analysis. The 3β-isomers have been shown to exist in the normal piper-idine chair conformation whereas the 3α-anilino tropane exists in a flattened piperidine chair conformation and the 3α-propananilidotropane isomer preferentially exists in a conformation in which the piperidine ring system is a boat.     

Chair/Twist-Boat Energy Gap in Monocyclic, Conformationally Unconstrained Polyalkylcyclohexanes

A conformational search procedure (HUNTER), in combination with the MM3(92) program, was used for the exploration of the conformational hypersurface of alkyl-substituted cyclohexanes and for the calculation of their chair/twist-boat (TB) energy gap. The systems studied were conformationally unconstrained polyalkylcyclohexanes (alkyl = methyl, ethyl, isopropyl, and tert-butyl) possessing either geminal and/or vicinal arrangements of the alkyl groups, but differing in the number of alkyl substituents and in their relative disposition (i.e., cis or trans). The calculations indicate that in 1,1,3,3,5,5-hexaisopropylcyclohexane the TB is the lowest energy form. Modification of the cis,trans relationship of vicinal alkyl groups changes the chair/TB energy gap, and in the minimum energy conformation of cis,trans,trans-1,2,3,4-tetraisopropylcyclohexane (23c) and cis,syn,cis-1,2,4,5-tetraisopropylcyclohexane (31c) the cyclohexyl ring adopts a TB conformation. The tetrasubstituted systems cis,syn,cis-1,2-diisopropyl-3,4-dimethylcyclohexane (46), cis,syn,cis-1,4-diisopropyl-2,5-dimethyl-cyclohexane (47), and cis,trans,trans-1,2-diisopropyl-3,4-dimethylcyclohexane (41) are the least crowded monocyclic unconstrained cyclohexanes found in which the TB conformation is of lower energy than the chair form. The present study indicates that two methyls and two isopropyl substituents are sufficient for stabilizing the TB form of a cyclohexyl ring relative to the chair form.     

Catalytic and structural studies of Rh complexes of (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane. Asymmetric hydrogenation of acetophenonebenzylimine and acetophenone

Rhodium(I) complexes formed by (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane (BDPP) are efficient catalysts for the hydrogenation of acetophenone and acetophenonebenzylimine. The composition of the solvent mixture and the reaction temperature have a marked influenced on the enantioselectivity. These effects are thought to be related to the enhanced conformational flexibility of six-membered rings when simple substrates without functional groups are coordinated to the rhodium. X-ray crystallographic studies reveal that in [Rh((S,S)-BDPP)NBD]⁺ (1) the ligand is in a chair conformation, and that in [Rh((S,S)-BDPP)COD]⁺ (2) the chelate ring is in a δ-skew conformation. Studies of Rh((S,S)-BDPP)(NBD)Cl (3) in solution indicate a trigonal bipyramidal structure with a chair conformation of the ring in aromatic solvents and a conformationally labile ring in methanol.     

Synthesis and three-dimensional structures of substituted 4-silyl-4-piperidols

1,2 5-Trimethyl-4-(methyldiphenylsilyl)- and 4-(dimethylphenyl)silyl-4-piperidols were obtained. The isomers of these piperidols of the series, which exist in the chair conformation, have all of their substituents, except the hydroxyl group, equatorially oriented. The isomers of the series exist in solution in the form of an equilibrium mixture of chair and boat conformations, and all of the substituents, except the silyl grouping, are equatorially oriented in the chair conformation.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 502–505, April, 1976.     

The endo and exo isomers of 1‐(4‐isopropyl‐3,5‐dioxa‐8‐aza­bicyclo­[5.1.0]octan‐8‐yl)pyrrolidine‐2,5‐dione

The crystal structures of the title compounds, C₁₂H₁₈N₂O₄, have been determined in order to establish the relative configurations. In both structures, the isopropyl substituent strongly prefers the quasi‐equatorial position. Therefore, the exo isomer adopts a dioxepanoaziridine pattern of a chair–chair (CC) conformation and the endo isomer a boat–chair (BC) conformation.     

16‐[3‐Methoxy‐4‐(2‐piperidin‐1‐yl­ethoxy)­benzyl­idene]‐17‐oxoandrost‐5‐en‐3β‐yl acetate monohydrate

The title compound, C₃₆H₄₉NO₅·H₂O, has the outer two six‐membered rings of the steroid nucleus in chair conformations. The central ring B of the steroid nucleus is in an 8β,9α‐half‐chair conformation, while ring D of the steroid adopts a slightly distorted 13β,14α‐half‐chair conformation. The piperidine ring is in a chair conformation. The methoxy­benzyl­idene moiety has an E configuration with respect to the carbonyl group at position 17. Intermolecular O—H?O and O—H?N hydrogen bonds link the steroid and water mol­ecules into chains which run parallel to the b axis.     

Formation of a Novel Cage Compound with a Pentacyclo

Abnormally long C-C single bonds are found in the polycyclic caged diol with a pentacyclo[6.3.0.1(4,11).0(2,6).0(5,10)]dodecane skeleton formed by photolysis (see scheme). This skeleton resembles the structure of diamantane, but instead of having six cyclohexane rings in a chair conformation it contains only two cyclohexane rings in a distorted chair conformation and four cyclopentane rings, which makes it more highly strained than diamantane.     

Conformational studies on pertrimethylsilyl derivatives of some mono- and disaccharides by 220 MHz PMR spectroscopy

The complete interpretation of 220 MHz PMR spectra and the accurate chemical shifts and coupling constants, obtained after computer simulation of the spectra, of a number of TMS-mono and -disaccharides are given. By means of an adapted Karplus equation the conformation of the derivatives has been studied in detail. All pyranose rings are found to occur in the Cl(D) chair conformation. As a consequence of their greater steric requirement, the OTMS groups deform the chair conformation more than the OAc groups. The preferred conformation of the C-5-CH₂OTMS group is determined and found to be dependent on the configuration at C-4.     

Conformation of 1,4-dineopentyl-2,5-cis-diphenylpiperazine and its diammonium salts: remarkable change in conformation depending upon the counter anion

The free base of 1,4-dineopentyl-2,5-diphenylpiperazine takes a chair conformation in CDCl3, while the conformation of its diammonium salts changes depending upon the counter anion.     

Stereochemistry of heterocycles

2-Methyl-and 2,5-dialkyl-5-phenoxy-1,3-dioxanes were synthesized and separated into their geometrical isomers by precision rectification. The configuration and conformations of these isomers were determined by PMR spectroscopy. It is shown that the low-boiling trans isomers exist primarily in the chair conformation with an equatorial phenoxy group, whereas the high-boiling cis isomers exist primarily in the chair conformation with an axial phenoxy group.     

Investigation of the stereochemistry of N-substituted 2,5-dimethyl-4-piperidinones by NMR spectroscopy

The conformations of the cis and trans isomers of N-substituted 2,5-dimethyl-4-piperidinones were studied by means of the¹H and¹³C NMR parameters. It was established that in the case of bulky and electron-acceptor substituents attached to the N atom the cis isomers are virtually completely represented by the chair (2a,5e) conformation, while the trans isomers are characterized by the chair (2e,5e) twistboat (2a,5e) chair (2a,5a) conformational equilibrium. It is demonstrated that 1-tert-butyltrans-2,5-dimethyl-4-piperidinone hydrochloride has the twist (2a,5e) conformation.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1760–1768, August, 1990.     

Triterpenoide. XX. 3β‐Acetoxy‐12‐oxo‐18β‐olean‐ und 3β‐Acetoxy‐12,19‐dioxo‐9(11),13(18)‐oleandien‐28‐säure‐methyl­ester

The structures of methyl 3β‐acetoxy‐12‐oxo‐18β‐olean‐28‐oate [C₃₃H₅₂O₅, (I)] and methyl 3β‐acetoxy‐12,19‐dioxoolean‐9(11),13(18)‐dien‐28‐oate [C₃₃H₄₆O₆, (II)] are described. In (I), all rings are in the chair conformation, rings D and E are cis and the other rings trans‐fused. In compound (II), only rings A and E are in the chair conformation, ring B has a distorted chair conformation, ring C a distorted half‐boat and ring D an insignificantly distorted half‐chair conformation.     

X‐ray investigations of bicyclic α‐methyl­ene‐δ‐valerolactones. III. trans‐(4aR,8aR)‐4a‐Methoxy‐3‐methyleneperhydro­chromen‐2‐one

The title compound, C₁₁H₁₆O₃, adopts a conformation in which the δ‐valerolactone and cyclo­hexane rings are almost coplanar with one another. The β‐methoxy substituent occupies an axial position with respect to the cyclo­hexane ring. The δ‐valerolactone moiety adopts a half‐chair arrangement, while the cyclo­hexane ring exists in a chair conformation.     

Stereochemistry and opioid receptor affinity of 2,4‐dipyridine‐3,7‐diazabicyclo[3.3.1]nonanones ‐ influence of the substituent in position N7

The stereochemistry the 2,4‐di‐arene substituted 3,7‐diazabicyclo[3.3.1]nonan‐9‐one 1,5‐dicarboxylate skeleton was found to be regulated by the kind of substituents attached to the arene rings as well as to the nitrogens N3 and N7. Conformational isomers, i.e., chair/chair, boat/chair and chair/boat, in addition to cis/trans conflgurational isomerism with respect to the arene rings were reported. Since the analgesic potency of the diazabicyclononanones, which is related to their affinity toward the κ‐opioid receptor, is governed by the stereochemistry of the molecules, the influence of the substituents at nitrogen N7 was studied herein. The various differently N7 substituted diazabicyclononanones were found to crystallise in a highly symmetrical chair/chair conformation. However, beside HZ2 none of the compounds exhibits high affinity to the κ receptor. In contrast, some compounds with affinity to the μ receptor could be identified. In addition, the N7‐(4‐carboxybenzyl) substituted compound was found to have affinity to the δ receptor in the submi‐cromolar range of concentration.