Intramolecular double

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

Finally, by a diastereoselective intramolecular double Michael reaction of a lithium dieno-late to an a,j6-unsaturated ester moiety, a spiro-fused bicyclo[2.2.2]octane may be prepared. These MIMIRC form the key step in the synthesis of ( )-atisine361 and (-t-)-alisirene362-365. 

Scheme 6/1.17. Influence of the substitution pattern on the enantioselectivity in intramolecular double Heck reaction.

Various nmr techniques have been used to investigate the intramolecular double proton transfer which occurs in the tautomerisation of meso-tetra-phenylporphyrin (40) (Limbach et al., 1982). The reaction has been studied (Storm and Teklu, 1972) by observation of the nmr signals due to the protons... 

If there are suitable inter- or intramolecular double-bond contacts, (2 + 2) photocycloaddition is the favored process. 

The results are explained as indicating that the addition of triplet arylcarbenes to intramolecular double bonds is accelerated by factor of 300-800 relative to inter-molecular addition. The intramolecular addition reactions of singlet arylcarbenes exhibit much smaller rate enhancements. The most stable planar conformer of singlet (102) cannot interact with the n bond of an allyl group attached to the ortho position. Rotation about the bond connecting the divalent carbon to the ring must occur in order for an electrophilic approach to take place. This rotation will result in the loss of benzylic stabilization. In marked contrast, the first step of the triplet addition can take place with no rotation of the divalent carbon. 

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

The intermolecular carbopalladation of a triple bond can be faster than that of an intramolecular double bond as, for example, in the (9-iodo(l-methylallyl)benzene 152. The arylpalladium iodide initially formed from 152 and a palladium(O) species intermolecularly carbopalladates diphenylacetylene 71, and only the thus formed alkenylpalla-dium intermediate 153 undergoes insertion into the internal double bond to furnish the neopentylpalladium species 154 which, by <9r/ (9-attack on the adjacent phenyl group, finally forms the tetracyclic system 155. ... 

In conclusion, a typical time of 300 fs has been found for the excited-state intramolecular double proton transfer in TAB and DAC. The proton transfer dynamics is not influenced by aggregation. In addition, a vibronic cooling time of 20 ps has been measured for the probe molecules in the molecular and stacked configurations. Finally, aggregation is found to almost completely hamper the rotational diffusion motions of the molecules during the fluorescence state lifetime of 4 ns. 

Ribosomal RNA (rRNA) As discussed on p. 414, prokaryotic ribosomes contain three molecules of rRNA, whereas eukaryotic ribosomes contain four molecules of rRNA (see Figure 31.8). The rRNAs have extensive regions of secondary structure arising from the base-pairing of complementary sequences of nucleotides in different portions of the molecule. The formation of intramolecular, double-stranded regions is comparable to that found in tRNA. 

A wide variety of disilanyl-substituted terminal alkenes undergo regio-and stereoselective intramolecular double silylation to yield cyclic bis(silyl) ring closure products [Eq. (16)].59abe... 

Similar results are observed in the intramolecular double silylation of alkynes.59cd Both terminal and internal alkynes lead to exocyclic olefin formation. Interestingly, the reaction is not successful for internal alkynes tethered to a disilanyl functionality by a four atom chain, but is accomplished when four atoms link a disilanyl to a terminal alkyne. Internal alkynes with ester or olefin in conjugation with the C-C triple bond undergo chemoselective double silylation, and alkynes with substituents in the tether are also good substrates for the reaction. 

R. H. Martin, M. J. Marchant, Thermal Racemisation of Hepta-, Octa- and Nonahelicene Kinetic Results, Reaction Path and Experimental Proofs that the Racemisation of Hexa- and Heptaheli-cene Does Not Involve an Intramolecular Double Diels—Alder Reaction, Tetrahedron 1974, 30, 347-349. 

M. Ihara, K. Fukumoto, Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction, Angew. Chem. Int. Ed. Engl. 1993, 32, 1010-1022. 

Musso has reported the synthesis of diasterane (tricyclo-[3.1.1.I2 4]octane) 15. For this first member of the series of asteranes, the decarboxylation of 16b -> 16c was best achieved via the photolysis of the Barton ester of 16a in the presence of BuSH, as shown in Scheme 5.14 Fukumoto has accomplished asymmetric total synthesis of atisine 17, where the bridged pentacyclic intermediate 18, a precursor for atisine, was synthesized via an intramolecular double Michael reaction starting with 19, Scheme 6.15 Barton protocol was favored during the late stages of the synthesis and the presence of various functionalities was easily accommodated. 

Asymmetric intramolecular double Michael reaction.3 Treatment of the 8-phenylmenthyl ot,(3-unsaturated amide ester (2) with r-butyldimethylsilyl triflate and triethylamine effects this Michael reaction with almost complete diastereose-lectivity to give the indolizidine 3, which was used for synthesis of (- )tylophorine (4). 

Synthesis of polycyclic alkaloids using an intramolecular double Michael reaction 93AG(E)1010. 

An intramolecular double nitrile oxide cycloaddition with alkyne and olefin moieties was exploited in the synthesis of novel unsymmetrical hybrid spiro (isoxazole-isoxazoline) ligands 14 which were effective in promoting a Pd-catalyzed tandem cyclization <07TA919>. 

An intramolecular double Horner-Wittig reaction of dialdehyde 861 using NaOMe as base provides the naphtho-dithiophene 862 <2002BCJ1795>. 

The rate constants of the intramolecular double-proton transfer of N-labelled porphine crystal have been determined by CP/MAS nmr spectroscopy, and the HH/HD/DD kinetic isotope effects have also been obtained. TTie observed kinetic isotope effects for porphine at 273 K are knu/kHD = 17, and kHn/ oo = 1-9 (Braun et al, 1994). Judging from the large difference of the isotope effect, the double-proton transfer is considered to proceed by the stepwise mechanism. The observed tendency is different from that of the tautomerization of carboxylic acids. The stepwise mechanism is also observed in solution. 

The key step in a short synthesis of ( )-tylophorine77 is an intramolecular double conjugate addition reaction. Reaction of the ( , )-unsaturatcd ester 1 (R2 = 8-phcnylmcnthyl) with ferf-butyldimethylsilyl triflate in the presence of excess of triethylamine in dichloromethane produces an 80 20 inseparable mixture of the indolizidines 2A and 2B78. Treatment of a mixture of 2A and 2B (R2 = 8-phenylmethyl) with sodium hydride in refluxing tetrahydro-furan for 2.5 hours gives the single indolizidine 2 A. Dioxanyl ester 1 furnishes, on reaction with... 

Synthesis of Cyclopropanes. Chiral imide enolates which contain y-halide substituents undergo intramolecular displacement to form cyclopropanes. Halogenation of y,5-unsamrated acyl imides occurs at the y-position in 85% yield with modest stereoinduction. The (Z) sodium enolates of these compounds then cyclize through an intramolecular double stereodifferentiating reaction (eq 61). 

M. ihara and co-workers utilized an intramolecular double Michael addition for the efficient and completely stereoselective construction of the tricyclo[6.3.0.0 ]undecan-10-one framework during the total synthesis of (+)-longiborneol. The substituted cyciopentenone precursor was exposed to several different reaction conditions, and the highest yield was obtained when LHMDS was used as the base. The first deprotonation took place at C11 the resulting enolate added to C9, and the ester enolate (negative charge located at CIO) in turn added to the cyciopentenone at C3. 

The Larock modified Saegusa oxidation conditions were utilized in the total synthesis of ( )-8,14-cedranoxide by M. lhara et al. The main strategy was to apply an intramolecular double Michael addition reaction to assemble the tricyclic cedranoid skeleton. The precursor five-membered enone was prepared in high yield from the corresponding substituted cyclopentanone in two steps. 

Takasu, K., Mizutani, S., Noguchi, M., Makita, K., lhara, M. Total Synthesis of ( )-Culmorin and ( )-Longiborneol An Efficient Construction of Tricyclo[6.3.0.03,9]undecan-10-one by Intramolecular Double Michael Addition. J. Org. Chem. 2000, 65, 4112-4119. 

Dilactones can be synthesized by a palladium-catalyzed stereospecific intramolecular double cycliza-tion of 3-hydroxy-4-pentenoic acids (Scheme 21). The cis stereochemistry of the reaction is rationalized by assuming that attack of Pd" on the alkene is directed by the allylic OH group, forming the intermediate (12). 

From 1988 to 1990, Ihara and co-workers modified the above synthesis approach to develop an asymmetric total synthesis of (-)-tylophorine [(-)- ] via an intramolecular double Michael reaction of a,p-imsaturated esters. Their work proved that the absolute configuration of naturally occurring (-)-tylophorine is (R). Two different chiral auxiliaries, (-)-phenylmenthol [52, 53] or (2R,4S,5R)-(-)-4-(tert-butyldimethylsiloxymethyl)-5-hydroxy-2-phenyl-1,3-dioxane(BDH), were employed [53, 54]. The reactions are summarized in Scheme (2). The resulting (E, E)-esters (26) and (27) underwent a double Michael reaction through proposed transition states (A) (B), respectively, to give a highly enantioselective product (28 and 29, respectively). (-)-... 

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