Stereospecific reactions reaction, intramolecular

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

Rhodium carbonyl complexes also catalyze the cascade cyclization/hydrosilylation of 6-dodecene-l,l 1-diynes to form silylated tethered 2,2 -dimethylenebicyclopentanes. For example, reaction of ( )-85 with dimethylphenylsilane catalyzed by Rh(acac)(CO)2 in toluene at 50 °G under GO (1 atm) gave 86a in 55% yield as a single diastereomer (Equation (56)). Rhodium-catalyzed caseade cyclization/hydrosilylation of enediynes was stereospecific, and reaction of (Z)-85 under the conditions noted above gave 86b in 50% yield as a single diastereomer (Equation (57)). Rhodium(i)-catalyzed cascade cyclization/hydrosilylation of 6-dodecene-1,11-diynes was proposed to occur via silyl-metallation of one of the terminal G=G bonds of the enediyne with a silyl-Rh(iii) hydride complex, followed by two sequential intramolecular carbometallations and G-H reductive elimination. ... 

B. Fraser-Reid, Z. Benko, R. Guiliano, K. M. Sun, and N. Taylor, Complete stereospecificity in the intramolecular Diels-Alder reaction of an ester derived from diacetone glucose, J. Chem. Soc. Chem. Commun. p. 1029 (1984). 

Once the strategy was selected, the validation of the relevant cyclization in solution and the determination of its stereochemical outcome and yield were carried out. The synthetic scheme is reported in Fig. 3.6. The commercially available allyl (3.3) and propargylglycines (3.7) were sequentially tosylated and alkylated with propargyl and allyl bromide, respectively, to give 3.5 and 3.9. The intramolecular Pauson-Khand cyclization produced the two isomers 3.6 and 3.10, with different stereochemistries, in a stereospecific reaction (the chiral allylglycine produced 3.6 as a single enantiomer. 

One particularly effective way nature uses to reduce activation energies and other molecular requirements is by the intensive use of intramolecular reactions. In this case the interacting species are held together on the same molecular template at a very short distance, thus paving the way to regio- and stereospecific reactions. 

Until recently, the intramolecular cyclization procedure had been used only to synthesize fused heterocyclic structures. The first report of a bridged product, in 1978, involved only a minor amount (9%) of an azabicyclo[3.3.1]nonane derivative obtained from the reaction of ds-carveol with acetonitrile and BFj-EtiO. However, several effective examples are now known. These all involve reaction of the nitri-lium intermediate with an internal alkenic nucleophile to yield a 1-azacyclohexene ring and a new carbe-nium ion which undergoes conventional, but stereospecific, Ritter reaction fiom the least hindered face. Such reactions are typified by formation of the multicyclic structures (64 equation 38) 5<) and (65 equation 39), 5i considerable potential in the synthesis of complex nitrogen heterocyclic systems... 

Unlike intermolecular cyclopropanation reactions, the intramolecular version is stereo-specific with respect to the configuration of both, the C-C double bond and (due to steric constraints) the carbenoid center. This fact can be used for the directed synthesis of cis-1,2-disubstituted, all-ci. -l,2,3-trisubstituted or d. , ra . -l,2,3-trisubstituted cyclopropanes. For example, a-diazo esters (a-diazocarboxamides) with an unsaturated ester (amide) residue yield bicyclic lactones (lactams) stereospecifically which can be ring opened to give the monocyclic cyclopropanes mentioned with defined stereochemistry. Some possibilities are illustrated by the examples, 20 -+ 22 -> 23, and 24 25. ... 

An intramolecular counterpart of the photochemical step used in the formation of (6) has been successfully applied to the synthesis of 12-epi-lycopodine (14). Photolysis of (10) yielded the intermediate (11) which was converted into the diketone (12). The latter compound gave the aldol product (13) which, in four steps, produced 12-epi-lycopodine (14). An amazing simplification of the overall route resulted when it was found that the diketolactam corresponding to the ketal (15) underwent a stereospecific Michael reaction to give (13) directly in 30% yield. 

An intramolecular photocycloaddition of a vinylogous amide tethered at C-3 of a 1-acylindole has also been achieved in a stereospecific reaction, in which the cyclobutane adduct (332) undergoes a retro-Mannich reaction to give the imino ketone (333), a synthetic precursor of vindorosine (Scheme 104) <90JA8971>. 

The most common application of carbenes in synthesis is in the formation of three-membered rings by addition to multiple bonds. This is a typical reaction of all carbenes that do not undergo intramolecular insertion. Generation of the carbene in the presence of an alkene gives a cyclopropane product. Addition of halocarbenes to alkenes is a stereospecific cis reaction, but this is not necessarily the case with all carbenes. Hence Z-2-butene 109 gives the cyclopropane 110, in which the two methyl groups remain cis to one another (4.86). The stereospecificity... 

A new synthesis of chiral cyclopentanoid intermediates involves the stereospecific reaction of the carbanion (30) with the tartaric acid derived epoxide (31). An intramolecular enolate anion alkylation, induced by a Michael reaction, has been utilized in the preparation of cyclopentanes (Scheme 6). Additionally, variation... 

Aryl-A-tosyl aziridines react quantitatively, with the carbon nucleophile generated from 2-(bromoaryl)acetonitriles and t-BuOK, at the benzyl carbon in a highly regio-and stereo-selective 5 2 reaction. Subsequent treatment of the ring-opened product gives an excellent yield of a tetrahydroquinoline in a stereospecific, Pd-catalysed, intramolecular displacement reaction. 

Allylic or propargylic metal compounds are often intermediates in isomerization reactions of unsaturated systems (see Section 4.5.5) the product distribution on protonation depends very much on the substitution and the conditions of hydrolysis and most often mixtures of isomers are obtained. In contrast double bond shift generally occurs on protodesilylation of allylic silanes by acids, a reaction which takes place stereospecifically Only when intramolecular delivery of the proton in a chair-like transition state is possible may a different kind of stereoselectivity be effective and good 1,3- or 1,4-induction in hydrogen transfer be observed (Scheme 83). ... 

Some electrophiles require a separate activation step, as in the stereospecific reaction of alkenes with benzenesulfenyl chloride (eq 15). The intermediate that actually reacts with the aUylsilane is presumably the episulfonium ion. There is a corresponding reaction of epioxonium ions derived from 2-bromoethyl ethers. Intramolecular hydrosilylation of an ester generates an acetal, which reacts with allyltrimethylsilane in the usual way and with high stereocontrol to make an anti 1,3-diol derivative (eq 16). ... 

In conclusion, the tautomerization is intramolecular and the suprafacial 1,3 proton shift occurs across a azaallylic anion. The model differs slightly, however, from the biological system by providing competing stereochemical and isotope-labeling reactions pathways. Therefore, coenzymes carry out stereospecific reactions due to their apoenzymes, while nonenzymatic model reactions are not as stereospecific (310). 

Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exemplified by the iodolactonization reaction. Reaction of iodine with carboxylic acids having carbon-carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones." The reaction shows a preference for formation of five-membered rings over six-membered" and is a strictly anti stereospecific addition when carried out under basic conditions. 

Overall the stereospecificity of this method is the same as that observed m per oxy acid oxidation of alkenes Substituents that are cis to each other m the alkene remain CIS m the epoxide This is because formation of the bromohydrm involves anti addition and the ensuing intramolecular nucleophilic substitution reaction takes place with mver Sion of configuration at the carbon that bears the halide leaving group... 

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

Although these reactions are thus closely related to the acyl-alkyl diradical disproportionation to ketenes, the stereospecificity of (55) -> (56) and (57) -> (58) shows that these hydroxyketones cannot proceed through free radicals capable of rotating about single bonds prior to the intramolecular hydrogen... 

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