Experiments on the Total Synthesis of Lysolipin I. Part I. On Configuration and Conformation of 5-Substituted 1,2,3,4,4a,9,10,10a-Ocathydrophenanthrene-4,9-diones

The substituted 1,2,3,4,4a,9,10,10a-octahydrophenanthrene-4,9-dione 2 , synthesized from the cyclohexanone 8 and quinone 11 (Scheme 2), was found by X-ray analysis adn ¹H-NMR studies to be the isomer with cis-junction of the saturated rings. The cis-fusion could also be determined from the ¹H-NMR data of the related compound 17 (Scheme 4), which was previously considered to be trans-fused. In contrary to previous argumentations, the interaction of the C(4)-carbonyl O-atom of trans-fused octahydrophenanthenes is more severe with a 5-methoxy than with a 5-methyl substituent.     

The Reaction of Singlet Oxygen with 1,3-Dimethylindole in the Presence of Aldehydes. Formation of 1,2,4-Trioxanes

The dye-sensitized photo-oxygenation of 1,3-dimethylindole in the presence of aldehydes initially generates a zwitterionic peroxide which condenses with the carbonyl function to give the corresponding cis-fused 1,2,4-trioxanes. Acetaldehyde gives a pair of diastereomers, one of whose structures was determined by X-ray analysis (cis,cisisomer), whereas pivaladehyde gives only the cis,cis diastereomer.     

Stereoselective Syntheses of Benz[f]isoindoline-Derivatives by Intramolecular Cycloadditions of Styrenes to Olefins

The N-allyl-N-cinnamyl amide 10 undergoes thermal cyclization to a 2:1-mixture of the trans- and cis-benz(f)isoindolines 11a and 12a . By comparison, the thermolysis of the corresponding bis-cinnamylamide 14 proceeds in a highly stereoselective manner to give the cis-fused[4+2]-adduct 16a . Similarly, the trans-fused stereoisomeric adducts 30a and 31a were obtained with high stereochemical control on heating the N-allyl-N-diphenylallyl amide 28 . The thermal transformations 4 → 5 + 6a and 17 → 18a + 20a show the competitive formation of [2+2]-adducts. An alternative approach to (substituted) benz[f]isoindolines 16 via the all-cis-isomer 24a has been developed. The described structures have been assigned on the basis of spectral evidence, chemical correlations and by X-ray-diffraction study of the isomer 16b . These results illustrate the utility of substituent interactions in order to direct intramolecular cyclo-additions at will towards either endo- or exo-products.     

The Reaction of Difluorocarbene with Bicyclo[2.2.2]octadiene

The addition of difluorocarbene to bicyclo[2.2.2]octa-2,5-diene gave the exo and endo 1:1 cyclopropane adducts. In contrast to norbornadiene, no homo-1,4 adduct was formed. The adducts were thermally stable under the conditions of their formation and separation (<170°). However, smooth equilibration was achieved on heating at 250° for 36 h. The same mixture resulted from either isomer. At 250° ΔΔG = 1.83 kcal/mol; the endo isomer being the more stable. Heating to higher temperatures caused decomposition, rather than further reaction to the intramolecular [2+2]cyclization products. The kinetic and thermodynamic product compositions were essentially the same on extrapolating to the same temperature, viz. endo/exo = 19–22 at 25°. The mechanisms by which the cyclo-addition and the stereomutation of the cis-fused cyclopropane moiety occur are discussed.     

Low-temperature 15N NMR spectra of reduced 1,3-heterocyclic systems

The ¹⁵N NMR spectra of the O-inside cis-fused conformer of perhydropyrido[1,2-c][1,3]thiazine shows a shielding of the nitrogen of 23.0 ppm relative to the trans-fused conformer. In contrast, ¹⁵N shifts for the cis-and trans-fused conformers of perhydro-oxazolo[3,4-a]pyridine and perhydrothiazolo[3,4-a]pyridine show corresponding shieldings of only 0.6 and 2.5 ppm, respectively.     

SYNTHETIC APPROACH TO TETRAHYDROFURAN UNITS AND FIVE-MEMBERED RING LACTONES FUSED TO HEXOPYRANOSIDES *

A stereoselective synthesis of the miharamycin sugar moiety epimer at C-3′ was accomplished in high yield starting from an appropriate (Z)-Wittig product, synthesized by Wittig reaction of a 4,6-O-benzylidene protected hexopyranosid-3-ulose with [(ethoxycarbonyl)methylene]triphenylphosphorane followed by iodine promoted isomerisation of the (E)-Wittig product formed. Reduction of the (Z)-isomer obtained in quantitative yield, cyclisation and dihydroxylation with osmium tetroxide, gave the target molecule containing a cis-fused tetrahydrofuran ring in its structure. Synthesis of five-membered rings trans-fused to the hexopyranosidic units succeeded via two different synthetic pathways. Stereoselective Reformatsky reaction of a 2,6-di-O-pivaloyl protected hexopyranosid-3-ulose, followed by cyclisation with dimethylzinc gave a 3,4-trans-fused lactone. The approach using the reaction of 2,3-and 3,4-epoxides with the dianion of phenylselenoacetic acid led to low yield but novel phenylseleno derivatives of trans-fused five-membered rings, namely a phenylselenolactone 2,3-trans-fused to a 4,6-O-benzylidenehexopyranoside and a phenylselenolactenol 3,4-trans-fused to a 6-O-pivaloyl-hexopyranoside.     

Proton magnetic resonance studies of compounds with bridgehead nitrogen. 37–a comparison of the positions of conformational equilibria in 1-methylperhydro-oxazolo[3,4-a]pyridines and in 1-methylperhydrothiazolo [3,4-a]pyridines

cis(1-H, 8a-H)-1-Methylperhydro-oxazolo[3,4-a]pyridine and cis(1-H, 8a-H)-1-methylperhydrothiazolo[3,4-a]pyridine both adopt exclusively the trans-fused conformation in carbon tetrachloride solution at room temperature. Both parent unsubstituted systems exist under similar conditions as equilibria containing c. 67% (oxazolo compound) and 64% (thiazolo compound) of the trans-fused conformation. In marked contrast to these similar positions of conformational equilibria in both systems the trans(1-H,8a-H)-1-methylperhydrooxazolo[3,4-a]pyridine exists as c. 73% trans-fused in equilibrium with a cis-fused conformation whereas the trans(1-H, 8a-H)-1-methylperhydrothiazolo[3,4-a]pyridine exists almost exclusively in a cis-fused ring conformation. These differences in conformational equilibria are explained in terms of changes in non-bonded interactions.     

Direct benzyne-C60 addition does not generate a [5,6] open fulleroid

Recent reports describe the different products resulting from the reaction of C₆₀ with benzyne generated from anthranilic acid derivatives and isoamyl nitrate in the presence and absence of triethylamine. Reinvestigation here via ¹H, ¹³C, HMBC NMR and Mass spectroscopy elucidates that these products are the [6,6] closed C₆₀-fused δ lactones, and not the [5,6] open fulleroids which would result from benzyne addition. Furthermore, theoretical calculations show that the open isomer [5,6] benzyne addition is less stable than the [5,6] closed isomer as an isolable product.     

Synthesis of cis-Fused Bicyclic Systems by Radical Cyclization Approach: Formal Synthesis of Ethisolide and iso-Avenaciolide

Formal synthesis of ethisolide and iso-avenaciolide was achieved using furanoid glycal-vinyl radical intermediates. The vinyl radical cyclization by 5-exo-dig mode gave the cis-fused bicyclic systems with an efficient introduction of the exo-methylene group, besides helping in the inversion of the adjacent stereocentre. Further, the study describes the synthesis of cis-fused bicyclic systems from L-arabinose and D-xylose for the creation of diverse natural and synthetic products of this class.     

Compounds with bridgehead nitrogen: 45—the 1H NMR spectra and stereochemistry of some dimethylperhydro-oxazolo[3,4-a]pyridines

The positions of conformational equilibria in 1,5-, 1-6- and 1,8-dimethylperhydro-oxazolo[3,4-a]pyridines were determined by ¹H NMR spectroscopy. The cis-(H-5, H-8a)-1,6-dimethyl-perhydro-oxazolo[3,4-a]pyridine. In contrast, r-1,t-6,t-8a-1,6-dimethylperhydro-oxazolo[3,4- a]pyridine preferred the cis-fused conformation. Three of the 1,8-dimethylperhydro-oxazolo[3,4-a]pyridines adopted the trans-fused conformations (with distortion of the system in the case of the r-1,c-8,c-8a derivative) and the r-1,c-8,t-8a-1,8-dimethyl derivative adopted the cis-fused conformation.     

A New Total Synthesis of dl-Pumiliotoxin-C via an Indanone

dl-Pumiliotoxin-C (4) was synthesized in a practical manner from trans-4-hexenal (9) . The key step 14 → 15 (Scheme 3) involves an intramolecular Diels-Alder reaction giving mainly the cis-fused indanols 15a , which were converted to the cis-fused ketone 16 . After Beckmann-rearrangement of 16 the octahydroquinolinone 7 was transformed to the lactim-ether 23 . (Scheme 7). Reaction of 23 with propylmagnesium bromide followed by hydrogenation furnished dl- 4 in a highly stereoselective fashion.     

Montmorillonite K10-catalyzed synthesis of N-fused imino-1,2,4-thiadiazolo isoquinoline derivatives

A novel synthesis of N-fused imino-1,2,4-thiadiazolo derivatives is described. This approach involves the inexpensive, nontoxic, recoverable, and easy to handle montmorillonite K10 that catalyzes the coupling of 3-aminoisoquinolines and phenylisothiocyanates to afford the N-fused imino-1,2,4-thiadiazolo isoquinoline motifs in exemplary yields. The main attractions of this synthetic strategy were simple procedure and excellent yields.     

Compounds with bridgehead nitrogen. 44—the conformational analysis of perhydropyrido[1,2-c] [1,3]thiazine

The 270 MHz NMR data on trans- and cis-(H-4a, H-7)-7-ethylperhydropyrido[1,2-c][1,3]thiazine show heavy conformational bias to the trans- and S-inside cis-fused conformations, respectively. Comparison of the ¹³C NMR spectra of these anancomeric systems with the ¹³C NMR spectrum of perhydropyrido[1,2-c][1,3]thiazine indicates a trans-?S-inside cis-conformational equilibrium for the latter compound in CDCl₃ at 25°C, containing ca 75% trans-fused conformer. The ¹³C NMR spectrum of perhydropyrido[1,2-c][1,3]-thiazine at ?75°C showed 64% trans-fused conformer and 36% S-inside cis-conformer.     

The stereochemistry of 1,6,7,12b-Tetrahydro-2H,4H-[1,2] oxazino[3′,4′:1,2]-pyrido[3,4-b]indole and of 1,2,3,6,7,12b-Hexahydro-3-methyl-4H-pyrimido[3′,4′:1,2]pyrido[3,4-6] indole

From an analysis of nmr spectral data, 1,6,7,12b-tetrahydro-2H,4H-[1,3 ]oxazino[3′, 4′ :1,2]-pyrido[ 3,4-b ]indole is shown to exist in solution at room temperature almost entirely in the cis-fused ring conformation with the nitrogen lone pair bisecting the C4 methylene group whereas under the same conditions 1,2,3,6,7,12b-hexahydro-3-methyl-4H-pyrimido[3′,4′:1,2] pyrido-[3,4-b ]indole exists as an approximately 50:50 equilibrium mixture of the cis and trans-fused ring conformations.     

Synthesis and amoebicid properties of emetin analogs. Analysis of the new compounds by 13C-NMR. B/C-cis or trans-fused (+/-) 1-alkyl-3-desethyl-emetin (author's transl)]

Synthesis and amoebicid properties of emetin analogs. Analysis of the new compounds by ¹³C-NMR. B/C-cis or trans-fused (±) 1-alkyl-3-desethyl-emetin. New 1-alkyl-3-desethyl-emetines were prepared for pharmacological purposes. The usual emetine synthesis sequence applied to cis-1-alkylbenzo [a]quinolizidin-2-ones afforded new cis-1-alkyl-3-desethyl-emetines. The trans-fused isomers were also prepared. The relative configuration are determined by ¹H- and ¹³C-NMR. spectra.     

Preparation of uracil by cycloreversion. Structure of cycloalkane/ene- and norbornane/ene-fused dihydrouracils

The reactions of the 2-amino-1-cycloalkane-, cycloalkene-, norbornane- and norbornenecarboxylates 1–9 with potassium cyanate gave urea esters, which were cyclized to cycloalkane-, cycloalkene-, norbornane- and norbornene-fused 5,6-dihydrouracils 10–17 . On cyclization, the urea ester formed from trans-4-cyclohexene-1-carboxylate, furnished the cis-fused 5,6-dihydropyrimidine-2,4(1H,3H)-dione. On heating, the norbornene-diexo-fused dihydrouracil 16 yielded 2,4-pyrimidinedione through the splitting-off of cyclopentadiene. The structures of the compounds were proved by ¹H and ¹³C nmr spectroscopy.     

Ring distortion effect on δ13C values of bicyclo[4.n.0] alkanes

The ¹³C NMR spectra of trans- and cis-fused bicyclo[4.n.0]alkanes, where n=4, 3 and 2, were determined. The distortion of the six membered ring, which is due to the strain arising from the 1,2 fusion of cyclohexane with a smaller ring, is apparent mainly for the chemical shifts of the ring junction carbons. Both for the trans-and for the cis-fused hydrocarbons the results support a cyclohexane in a chair conformation, distorted to a different degree according to the size of the other ring. The geometries of the different compounds in the series were calculated.     

Trimethylaluminum-Promoted Cyclization of Cyanoenaminones. A Versatile Synthesis of Substituted Pyrazolopyridines

Trimethylaluminum (TMA) promotes the cyclization of cyanoenaminones to form [b]-fused pyrazolopyridine derivatives.     

Formal Lossen Rearrangement/Alkenylation or Annulation Cascade of Heterole Carboxamides with Alkynes Catalyzed by CpRhIII Complexes with Pendant Amides

It has been established that a cyclopentadienyl (Cp) Rh^III complex with two aryl groups and a pendant amide moiety catalyzes the formal Lossen rearrangement/alkenylation cascade of N-pivaloyl heterole carboxamides with internal alkynes, leading to alkenylheteroles. Interestingly, the use of sterically demanding internal alkynes afforded not the alkenylation but the [3+2] annulation products ([5,5]-fused heteroles). In these reactions, the pendant amide moiety of the CpRh^III complex may accelerate the formal Lossen rearrangement. The use of five-membered heteroles may deter reductive elimination to form strained [5,5]-fused heteroles; instead, protonation proceeds to give the alkenylation products. Bulky alkyne substituents accelerate the reductive elimination to allow the formation of the [5,5]-fused heteroles.     

Reappraisal of the diastereoselectivity of intramolecular Diels-Alder reactions of some o-quinodimethanes generated by benzocyclobutene thermolysis: some complementary results and an improvement

In a synthetic approach to 19-nor steroids and in order to compare the diastereoselectivities observed for the intramolecular Diels-Alder reactions of o-quinodimethanes generated either from 1 or 2, the thermolysis of benzocyclobutenes such as 2 was reexamined. The IMDA diastereoselectivity was highly dependent on the nature of the protective group of the hydroxyl substituent at the unique chiral stereocentre of the o-quinodimethane intermediate, in a position α to the double bond of the dienophile. Consistently with previous results reported for benzocyclobutenes 2, the trans-fused cycloadducts were the major products, the trans syn or trans anti predominant isomer being determined by the hydroxyl protective group. In contrast with these previous reports, the cis-fused cycloadducts were always formed competitively, although as minor products. In the present work, the diastereoselectivity was improved by achieving the thermolysis of a benzocyclobutene 2 having a lithium alkoxide which afforded the trans syn adduct in high yield.