Isocyanides chiral

The mechanistic analogy to the Streckcr synthesis becomes obvious in the addition of the isocyanide to the imine to produce the a-amino nitrilium intermediate. Since all four components are involved in this step, it might be expected that every chiral component (chiral groups R1, R2, R3, R4) contributes to diastereofacial differentiation in the nucleophilic attack on the imine. However, in peptide syntheses by four-component condensation5, the chiral isocyanide or a chiral carboxylic acid component has only limited influence on the diastereoselectivity of the a-amino amide formation5. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

Of the four components reacting in the Ugi reaction, the isocyanide and the carboxylic acid have only limited influence on the overall stereoselection. For instance, in the synthesis of 13-demethyldysidenin (R)-l and 13-demethylisodysidenin (S)-l from a chiral aldehyde, chiral carboxylic acid, isonitrile and methylamine79. 

Even in Ugi reactions of chiral 4,5-dihydro-3//-pyrrole derivatives with aryloxy substituents vicinal to the cWo-cyclic imino group, a low stereoselectivity was found with either chiral or achiral isocyanides and benzoic acid leading to substituted 2-aminoearbonyl-3-aryl-oxy-1 -benzoylpyrrolid ine derivatives82. 

In contrast to the low stereoselections realized in the above syntheses utilizing imines of various chiral aldehydes79-8 1, an almost complete stereoselectivity is reported for the Ugi reaction of 2,3 4,5-bis-O-isopropylidenearabinose with ammonia, acetic acid and cyclohexyl isocyanide giving the 2-acetamino-2-deoxyglueono amides as the exclusive products84. 

As indicated above in chiral mesophases, the introduction of a functional group in mesogenic stmctures offers the opportunity to achieve functional LCs. With this aim, mesomorphic crown-ether-isocyanide-gold(I) complexes (26) have been prepared recently [38]. The derivatives with one alkoxy chain show monotropic SmC mesophases at or close to room temperature. In contrast, the complexes with three alkoxy chains behave as monotropic (n = 4) or enantiotropic (n > 4) LCs. The structure of the mesophases could not be fully eluddated because X-ray diffraction studies in the mesophase were unsuccessful and mesophase characterization was made only on the basis of polarized optical microscopy. These complexes are luminescent not only in the solid state and in solution, but also in the mesophase and in the isotropic liquid state at moderate temperatures. The emission spectra of 26a with n=12 were... 

Omenat, A., Serrano, J.L., Sierra, T., Amabilino, D.B., Minguet, M., Ramos, E. and Veciana, J. (1999) Chiral linear isocyanide palladium(II) and gold(I) complexes as ferroelectric liquid crystals. Journal of Materials Chemistry, 9, 2301-2305. 

For the dehydration of TV-formylamino compounds to give isocyanides the CDI is activated by protonation into its bisimidazolium form (CH3CN, room temperature, 4h). Thus, chiral a-isocyano esters and other base-sensitive isocyanides are obtained in high yield. CDI itself did not produce this dehydration. 

Aldol reactions of isocyanides with aldehydes are catalyzed by cationic platinum complexes having P-C-P or N-C-N ligands in the presence of a catalytic amount of an amine base to give 2-oxazolines (Equation (126)) 48S>485a>485b Platinum-coordinated a-isocyano carbanions presumably serve as nucleophiles toward aldehydes. Low to moderate enantioselectivities were obtained by using chiral platinum complexes.485 4853... 

Asymmetric intramolecular bis-silylation has been achieved by using optically active isocyanide as chiral ligands on palladium (Equation (36)).107... 

Linear-difference effects in SHG have been observed from Lang-muir-Blodgett films of chiral poly(isocyanide)s.6... 

The material system is a Langmuir-Blodgett film of the S enantiomer of a chiral polymer deposited on a glass substrate. The polymer is a poly(isocyanide)30 functionalized with a nonlinear optical chromophore (see Figure 9.14). In this particular system the optical nonlinearity and chirality are present on two different levels of the molecular structure. The chirality of the polymer is located in the helical backbone whereas the nonlinearity is present in the attached chromophores. Hence, this opens the possibility to optimize both properties independently. 

Unlike CO, it is possible to polymerize isocyanides (R—N=C), isoelectronic analogs to CO. When R is a bulky group, such as tert-Bu, the polymer forms a stable helical structure. Asymmetric catalytic polymerization has been reported for t-Bu-NC using [Ni(T 3-allyl)(iV-trifluoroacetyl-proline)]2 providing (M)-helical polymer with 69% ee. The more stable helical polymer was prepared from 1,2-diisocya-nobenzene derivative initiated by a chiral Pd complex. (See Scheme 4.19.)... 

Not only cyanide but also an isocyanide behaves as a nucleophile to attack a carbonyl compound or an imine that is prepared in situ from an carbonyl compound. " In these reactions, an isocyanide is a synthetic equivalent to an aminocarbonyl anion. Asymmetric version of this reaction appeared in 2003. Using a combination of Lewis acid SiCU and a Lewis base chiral bisphosphora-mide, the corresponding a-hydroxyamide is obtained in 96% yield with >98% ee (Scheme 4.23). 

A method for obtaining optically active polyiminomethylenes from achiral monomers was recently devised by Nolte, Drenth and co-workers (420). It consists in the copolymerization of an achiral monomer (e.g., phenyl isocyanide) with an optically active isocyanide endowed with a low tendency to polymerize. The chiral monomer is incorporated in one of the two helices and, due to its low reactivity, stops or slows down its growth. The other helix is unaffected by this phenomenon and continues to grow, permitting the almost complete conversion of the achiral monomer into an optically active polymer. 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

Ugi I, Horl W, Hanusch-Kompa C, Schmid T, Herdtweck E (1998) MCR 6 chiral 2, 6-piperazinediones via Ugi reactions with alpha-amino acids, carbonyl compounds, isocyanides and alcohols. Heterocycles 47(2) 965-975... 

Polymerization of tert-butyl isocyanide using an optically active initiator gives an optically active product comprising helical polymer molecules with units of predominantly one chirality sense. 

Hie first helical SmC mesophase for a gold(I) mesogen has been prepared by means of complexation to an enantiomerically pure chiral isocyanide (Figure 7.32) [30]. This... 

The complexes bearing one chiral substituent display a smectic A mesophase when the non-chiral chain is long, or an enantiotropic cholesteric and a monotropic SmA phase for shorter alkoxy chains. A TGBA phase is observed for the derivative which contains the chiral isocyanide combined with the diethyloxy, when the SmA to cholesteric transition is studied. The compound with two chiral ligands shows a monotropic chiral nematic transition. When this compound is cooled very slowly from the isotropic liquid it exhibits blue phases BP-III, BP-II, and BP-I. 

A chiral TTF-substituted poly(isocyanide) 11 was prepared by Amabilino et al. 

Though alkylation of metal cyanides is one of the oldest routes to metal-isocyanide complexes, at the present time the usefulness of this method is confined to (i) partially characterizing new metal-cyanide complexes, (ii) providing access to complexes containing unstable or unusual isocyanide ligands which cannot be prepared by direct interactions of complex with isocyanide, and (iii) providing a route to chiral metal-isocyanide complexes. The following examples exemplify this. 

Isocyanide Polymers Bulky isocyanides give polymers having a 4 1 helical conformation (115) [154]. An optically active polyisocyanide was first obtained by chromatographic resolution of poly(f-butyl isocyanide) (poly-116) using optically active poly((S)-sec-butyl isocyanide) as a stationary phase and the polymer showing positive rotation was found to possess an M-helical conformation on the basis of CD spectral analysis [155,156]. Polymerization of bulky isocyanides with chiral catalysts also leads to optically active polymers. 

Dehydration of formamides. This reagent converts formamides to isocyanides in 75-90% yield. It was developed particularly for use with chiral substrates that racemize readily in the presence of basic reagents. Thus it converts 2 into the isocyanide 3 with no significant racemization. 

The synthesis of optically active polymers is an important area in macromolecular science, as they have a wide variety of potential applications, including the preparation of CSPs [31-37]. Many of the optically active polymers with or without binding to silica gel were used as CSPs and commercialized [38]. These synthetic polymers are classified into three groups according to the methods of polymerization (1) addition polymers, including vinyl, aldehyde, isocyanide, and acetylene polymers, (2) condensation polymers consisting of polyamides and polyurethanes, and (3) cross-linked gels (template polymerization). The art of the chiral resolution on these polymer-based CSPs is described herein. 

Since asymmetric induction in P-3CRs or U-4CRs is achieved in most cases by using one or more chiral components in enantiomerically pure form, it is important to assess the possibility of racemization under the reaction conditions. While this does not seem to be a problem for carboxylic acid and amine components, there are some reports of racemization of chiral aldehydes or isocyanides. 

While chiral isocyanides such as a-substituted isocyanoacetates also usually react with low stereoselectivity, the specially designed, camphor-derived, isonitrile 11... 

A recent screening of various chiral carboxylic acids has allowed the selection of galacturonic derivative 12 as a very efficient control in the stereochemical course of some Passerini reactions (Scheme 1.5). Although the de seems to be strongly dependent on the isocyanide employed, this result suggests the possibility of employing carboxylic acids as easily removable chiral auxiliaries in the asymmetric synthesis of biologically important mandelamides [16]. 

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