Stereochemical studies — 79 synthesis and kinetic study on the retrodiene decomposition of norbornene-condensed 1,3-oxazin-4-ones

The $\text{cis}$-$\text{cxo}$- amino acid $\text{c}$ with norbornene skeleton was converted into 2-aryvl-$\text{cis}$-$\text{cxo}$-1,3-oxazin-4-ones $\text{5a}$-$\text{d}$. These compounds, similarly to the $\text{diendo}$ isomers $\text{1a}$-$\text{d}$ studied by us earlier, undergo retrodiene decomposition under mild conditions to give 2-aryl-6$\text{2}$-l,3-oxazin-6-ones ($\text{2}$$\text{a}$-$\text{d}$) in 50-60% yield. The ratio of the decomposition rate constants of the tricyclic $\text{diendo}$ and $\text{diexo}$-1,3-oxazin-4-ones, measured in toluene solution, is about 2.     

Boat-chair conformational preference of exo, exo-9-oxobicyclo[3.3.1]nonane-2,4-dicarboxylic acid

The ¹H and ¹³C nmr spectra of $\text{exo}$, $\text{exo}$-9-oxobicyclo[3.3.1]nonane-2,4-dicarboxylic acid, 3, in DMSO-d₆ or alkaline D₂O, clearly show that it exists in a $\text{boat}$-$\text{chair}$-conformation with $\text{equatorial}$ carboxyl groups, thus being the first case of $\text{boat}$-$\text{chair}$ preference of a bicyclo[3.3.1] nonan-9-one due to the presence of $\text{exo}$,$\text{exo}$-2,4- substituents.     

Substituted cyclononatetraenes and nonafulvenes

Reaction of $\text{cis}$,$\text{cis}$,$\text{cis}$,$\text{cis}$-[9]annulene anion ($\text{1}$) with electrophiles ($\text{2a}$-$\text{d}$) leads to substituted $\text{cis}$,$\text{cis}$,$\text{cis}$,$\text{cis}$-1,3,5,7-cyclononatetraenes ($\text{3a}$-$\text{d}$) which are precursors for the preparation of 10- and 10,10′-donor-substituted nonafulvenes (e.g. $\text{7b′}$$\text{e′}$). The influence of solvent and temperature on the ¹H-nmr spectra of the nonafulvenes $\text{7b′}$-$\text{h′}$ has been investigated.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.     

High-Performance liquid chromatographic separation of enantiomers of unusual amino acids possessing cycloalkane or cycloalkene skeletons on a chiral crown ether containing stationary phase

Summary Direct reversed-phase high-performance liquid chromatographic methods were developed for the separation and identification of the enantiomers of mono- and bicyclic racemic β-amino acids:cis- andtrans-2-aminocyclopentane-1-carboxylic acids,cis- andtrans-2-aminocyclohexane-1-carboxylic acids,cis- andtrans-2-amino-4-cyclohexene-1-carboxylic acids,diendo- anddiexo-3-aminobicyclo[2.2.1]heptane-2-carboxylic acids anddiendo- anddiexo-3-amino-5-bicyclo[2.2.1]heptene-2-carboxylic acids. Enantioseparation was carried out by the application of a chiral stationary phase, Crownpak CR(+). The conditions of separation were optimized by changing the temperature, the flow rate and the pH of the mobile phase. Presented at: Balaton Symposium on High-Performance Separation Methods, Siófok, Hungary, September 3–5, 1997.     

Saturated heterocycles. 254 . synthesis and stereochemistry of saturated or partially saturated pyridazino-[6,1-b]- and phthalazino[1,2-b]quinazolinones

By the reaction of anthranilic hydrazide 1 with cis-2-(p-methylbenzoyl)-1-cyclohexanecarboxylic acid 2a or diendo-3-(p-methylbenzoyl)bicyclo[2.2.1]heptane-2-carboxylic acid 2b , fused tetra- and pentacyclic ring systems 3a, b were prepared, trans-2-Amino-1-cyclohexanecar-bohydrazide 4b was reacted with 3-(p-chlorobenzoyl)propionic acid 5 to yield the pyridazino[6,1-b]quinazolinone 6 . From the reaction of cis-2-amino-1-cyclohexanecarbohydrazide 4a with 2a , three isomeric partially saturated 8H-phthalazino[1,2-b]quinazolin-8-ones 7a-c were formed. The reaction of diexo-2-aminobicyclo[2.2.1]heptane-3-carbohydrazide 4c and 2a furnished the pentacyclic derivatives 8 and 9 containing a 3-aryl-4,5-dihydropyridazine or 3-arylhexahydropyridazine ring C with cis annelated C/D rings. The formation of 8 and 9 involving different ring systems can be rationalized by two reaction pathways: (i) in the bislactam 9 the carboxyl group acylates the hydrazide, while (ii) in 8 it forms a pyridazine ring with the cyclic amino group by cyclocondensation. The structures of the products were elucidated by ¹H and ¹³C nmr methods, including DEPT, DNOE and 2D-HSC measurements.     

The octant rule. XIV. synthesis and circular dichroism of α-exo and endo-deuteriobicyclo[3.2.1]octan-3-one and 6,6-dimethybicyclo[3.1.1]heptan-3-one

(1R,5S)-2S-Deuteriobicyclo[3.2.1]octan-3-one ($\text{1}$) and (1R,5S)-2R-Deuteriobicyclo[3.2.1]octan-3-one ($\text{2}$), prepared by diazomethane ring enlargement of (1S,4R)-2(exo)-deuteriobicyclo-[2.2.1] heptan-2-one and (1S,4R)-2(endo)-deuteriobicyclo[2.2.1]heptan-2-one respectively, both gave (?) n-π^* circular dichroism (CD) Cotton effects, Δε^max₂₉₄ = ?0.05 and Δε^max₂₉₄=?0.1, respectively, in hydrocarbon solvent. (1S,5R)-2S-Deuterio-6,6-diaethylbicyclo[3.1.1] heptan-3-one ($\text{3}$) and (1S,5R)-2R-deuterio-6,6-dimethylbicyclo[3.1.1] heptan-3-one ($\text{4}$), prepared from (-) myrtenal, both exhibited extraordinary vibrational fine structure for the n-π^* CD transitions observed in hydrocarbon solvent and oppositely?signed CEs, Δε^max₂₈₂=?0.01 and Δε^max₂₇₉=+0.01 respectively in CF₃CH₂OH solvent.     

On the mode of incorporation of leucine samples labelled at positions 5 and 2 with 3H and 14C into the isoprenylated tryptophan derivative echinuline from aspergillusamstelodami

Feeding experiments with (4$\text{S}$) [5-³H;5-¹⁴C]$\text{L}$-leucine ($\text{1a}$) and with the (4$\text{S}$) [5-³H;2-¹⁴C]-isomer ($\text{1b}$) show that incorporation into the isoprenylated tryptophan derivative echinuline ($\text{3}$), produced by $\text{Aspergillus}$$\text{amstelodami}$, involves, to a large extent, loss of the fragment enbodying the carbon atom at position 2 of the fed amino acid.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

The synthesis of a 3-diazobicyclo[2.2.1]Heptan-2-one inhibitor of thromboxane a2 synthetase

The synthesis of a PGH₂ analog 5-$\text{endo}$(2(Z), 6-$\text{exo}$(1E)-3-diazo-5-(7-hydroxy-2-heptenyl)-6-(3-hydroxy-1-octenyl)bicyclo[2.2.1]heptan-2-one 2 is described.     

Synthesis of “9-deazaadenosine”; A new cytotoxic C-nucleoside isostere of adenosine

The synthesis of 7-(β-$\text{D}$-ribofuranosyl)-4-amino-5H-pyrrolo[3,2-$\text{d}$]pyrimidine (9-deazaadenosine) $\text{9}$ is described. It involves base-catalyzed cyclization of N-carboethoxyenamine $\text{4}$ to give β- and α-ribosylated 3-amino-2-cyanopyrroles $\text{6}$ and $\text{7}$, respectively, followed by a one-step conversion to the desired pyrrolo[3,2-$\text{d}$]pyrimidine system.     

Condensed cyclic and bridged-ring systems : part 12: A novel synthetic route to 4-p-methoxyphenyl-bicyclo[ 2.2.2 ]octan-2-ones and some bicyclo [ 3.2.1 ] octane derivatives by acid-catalyzed intramolecula

The efficacy of a new acid-catalyzed intramolecular C-alkylation has been demonstrated by the synthesis of 1-methyl-4-$\text{p}$-methoxyphenylbicyclo [2.2.2] octan-2-one ($\text{5}$) and 4-$\text{p}$-methoxyphenylbicyclo [2.2.2] octan-2-one ($\text{6}$) from easily accessible starting materials. The carbinol $\text{20}$, derived from $\text{5}$, undergoes facile rearrangement leading to 1-$\text{p}$-methoxyphenyl-4-methyl bicyclo [3.2.1] oct-3-ene ($\text{22}$), which has been transformed to $\text{endo}$-1-$\text{p}$-methoxyphenyl-4-methylbicyclo [3.2.1] octan-3-one ($\text{25}$).     

Fluorocarbon derivatives of nitrogen. Part 11. Synthesis of some 2-(trifluoromethyl)imidazo[1,2-a]pyridines from trifluoroacetonitrile

3-(t-Butoxycarbonyl)-2-(trifluoromethyl)imidazo[1,2-$\text{a}$]-pyridine, prepared from trifluoroacetonitrile and pyridinium t-butoxycarbonylmethylide, reacts smoothly with trifluoroacetic acid to provide 2-(trifluoromethyl)imidazo[1,2-$\text{a}$]pyridine-3-carboxylic acid, which gives 2-(trifluoromethyl)imidazo[1,2-$\text{a}$]-pyridine when heated. 3-Cyano-2-(trifluoromethyl)imidazo[1,2-$\text{a}$]pyridine can be obtained $\text{via}$ treatment of trifluoroacetonitrile with pyridinium cyanomethylide, which is sufficiently reactive to effect nucleophilic displacement of fluorine from pentafluoropyridine under mild conditions [→pyridinium cyano(tetrafluoro-4-pyridyl)methylide].     

Oxidative decarboxylation of [n.2.2]propellane carboxylic acids with lead tetraacetate. rearrangement approach to bicyclo [n.2.2.]bridgehead alkenes.

Oxidative decarboxylation of [n.2.2]propellane carboxylic acids ($\text{1a}$-$\text{c}$) with lead tetraacetate gave the bicyclic acetates ($\text{2b}$, $\text{c}$) having a bridgehead double bond and/or the tricyclic acetates ($\text{3a}$, $\text{b}$) in good yields. Vapor phase thermolysis of $\text{3a}$ or $\text{3b}$ afforded the bridgehead olefin $\text{2a}$ or $\text{2b}$ quantatively.     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.     

Action of tert-butyl azidoformate on the conjugate bases of 1,2,3,4-tetrahydro-9H-carbazole and other indole derivatives

tert-Butyl azidoformate ($\text{2}$) reacts with the conjugate bases of $\text{3a}$, $\text{7a}$, $\text{9}$ (R¹ = R² = CH₃), and $\text{9}$ (R¹ = CH₃, R² = H) to give products [$\text{4}$, $\text{8}$, $\text{12}$, and $\text{14}$, respectively] in addition to the expected N-(tert-butoxycarbonyl)indole derivatives.     

Enantioselective microbial hydroxylation of bicyclo(2.2.1)heptane carbon skeleton

Bicyclo(2.2.1)heptane-7-carboxylic acid ($\text{9}$) and methyl bicyclo(2.2.1)hept-2-ene-7-$\text{syn}$-carboxylate ($\text{5}$) were microbiologically hydroxylated to give (1$\text{R}$)-2-hydroxy derivatives.     

Photocyclization of n-[ω-(cycloalken-1-yl)alkyl]-and n-[ω-(inden-3-yl)alkyl]phthalimides : Synthesis of spiro-nitrogen multicyclic systems

Photolysis of the N-[ω-(cycloalken-1-yl)alkyl]phthalimides 6b-$\text{e}$ in each case gave a pair of stereoisomers of spiro-nitrogen multicyclic systems (9b-$\text{e}$) in moderate yields, whose stereochemistry was determined by means of chemical and spectroscopic analyses. Similarly, in N-[ω-(inden-3-yl)alkyl]-phthalimides (8), spiro-nitrogen macrocycles up to 13-membered 13a-$\text{c}$ were obtained in good yields     

Bridgehead nitrogen heterocycles from 2,4,6-triphenyl- pyrylium cation and thiosemicarbazide or thiocarbohydrazide

2,4,6-Triphenylpyrylium with thiosemicarbazide and thiocarbohydrazide, gives 2-pyrazolines $\text{3a}$ and $\text{3b}$ which undergo cyclization yielding pyrazolo(1,5-c]pyrimidine 5 and pyrazolo [2,3-d]-1,2,4-triazepine $\text{7}$ derivatives, respectively. Reaction of $\text{7}$ with phenacyl bromides gave 1,3-thiazolo[3,2-b]pyrazolo [2,3-d]-1,2,4-triazepin-4-iums $\text{10}$. Compound $\text{3a}$ on treatment with phenacyl bromides gave 1-(4'-aryl-thiazol-2'-yl)-2-pyrazoline derivatives $\text{6}$. Compound $\text{3b}$ reacts with acyl chlorides to give pyrazolo[1,5-c]pyrimidine derivatives $\text{14}$, and with aromatic aldehydes giving the 2-(Δ^2'1 pyrazolin-1-yl)-5-aryl-1,3,4-Δ²-thiadiazolines $\text{12}$ which were easily converted to the corresponding 2-(Δ²-pyrazolin-1-yl)-5-aryl-1,3,4-thiadiazoles $\text{13}$.     

Cycloaddition reactions of 1,3-benzothiazines - 6. Reactions of 1,3-benzothiazine derivatives with substituted acetyl chlorides

6, 7-Dimethoxy-2$\text{H}$-l,3-benzothiazine derivatives ($\text{1}$, $\text{8}$) react with substituted acetyl chlorides to give angularly condensed β -lactams ($\text{3a}$-$\text{d}$, $\text{10}$, $\text{11}$). The $\text{cis}$ compound $\text{11}$ was epimerised to the $\text{trans}$ derivative $\text{12}$. From the interaction of 2-phenyl-6,7-dimethoxy-4$\text{H}$-1,3-benzothiazine ($\text{7}$) and α -chloro-phenylacetyl chloride two stereoisomeric β -lactam derivatives ($\text{9a}$, $\text{b}$) were isolated, whereas in the other cases studied the reactions leading to β -lactams proved to be stereospecific. Analogous reactions of $\text{4}$-methyl-6,7-dimethoxy-2$\text{H}$-l,3-benzothiazine ($\text{5}$) furnished the enamides $\text{6a}$,$\text{c}$, $\text{d}$. Structures of the new compounds and configurations of the diastereomers were elucidated by IR and NMR spectroscopy.