Multiple stereoselection

Let us now consider the reactions of an enantiomerically pure reagent with the two pure enantiomers of a substrate. The stereoselectivity of the process depends on how the structure of the reactants co-operate with each other or contrast each other in determining the course of the reaction. Generally, one reaction exhibits a higher stereoselection than the other. 

This approach represents a powerful method to enhance the intrinsic stereoselectivity of a given reactant and is called double or, more generally, multiple stereoselection . The reasons for the increased stereoselectivity of these processes are evident from the examples collected in Fig. 6 [33], 

The Diels-Alder cycloaddition of acrolein with the (ft)-diene reported in reaction A affords a 4.5 1 ratio of the indicated diastereoisomers. When an enantiomerically pure (R)-dienophile is reacted with an achiral equivalent of the previous diene (Fig. 6 reaction B), two diastereoisomers are obtained in a 8 1 ratio. As the two major isomers of reactions A and B have the same configuration at the newly formed stereocenters, it can be anticipated that when the two enantiomerically pure (R)-partners are combined, the intrinsic stereoselection of each reactant is exalted to give a very stereoselective process. 

As can be seen from reaction C in Fig. 6, this is indeed the case and the expected product is obtained virtually as a single isomer (d.r. 40 1).The control experiment (reaction D) carried out with an (S)-dienophile and the (R)-diene confirms that in this case the two reactants contrast each other s intrinsic stereoselectivity, leading to poor stereocontrol. Reactions C and D are defined to occur between matched and mismatched reaction partners, respectively [33], 

Three main features of this multiple stereoselection approach are worth mentioning (i) The configuration of the products of the matched and mismatched pairs are predictable on the basis of the results of the simple stereoselective reactions (ii) the efficiency of the stereocontrol seems also predictable (although not in a very precise manner) by simply multiplying (matched pair) or dividing (mismatched pair) the stereoselectivity of the simple stereoselective reactions and (iii) only the combination of enantiomerically pure reactants is productive, as shown by the result of reaction E, in which a racemic dienophile is exposed to the (R)-diene in a process the diastereoselection of which is calculated on the hypothesis that no kinetic resolution is at work. 

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Kolodiazhnyi OI. Multiple stereoselectivity and its application in organic synthesis. Tetrahedron 2003 59 5953-6018. 

Multiple stereoselectivity and its application in asymmetric epoxidation, 1,3-dipolar cycloaddition, [2 + 2] cycloaddition and Diels-Alder reactions 03T5953. 

The new approach took advantage of the availability in enantiomerically pure form of (S)-2-methoxycyclohexanone, the precursor of enolether 10.This was reacted in the presence of an excess of tin tetrachloride with the iminium ion 11, obtained in situ from 1 by N-silyla-tion and exposure to the LA, to afford directly ketone 4 in high yield (up to 79%) and excellent stereoselectivity (up to 96 4 d.r.). This high level of stereocontrol appears to be the result of a matching combination of enantiomerically pure reactants in a multiple stereoselective process, and this is currently exploited for the large-scale preparation of sanfetrinem. 

Multiple stereoselection can be at work whenever two enantiomerically pure reactants are combined in a reaction that generates at least one new stereocenter. 

An example of multiple stereoselective process is represented by the synthesis of the San-fetrinem precursor 4 (Fig. 11) by the condensation of pure azetidinone 1 and silylenolether 10, in which two contiguous stereocenters (at C-4 of the p-lactam ring and at the adjacent C-4 in the cyclohexanone moiety) are created with virtually complete stereocontrol. 

The preparation of the HIV-protease inhibitor 47 reported by Merck researchers and described in Fig. 18 provides another example of the multiple stereoselective approach [59]. 

Tokoroyama T. Synthesis of Clerodane Diterpenoids and Related Compounds -Stereoselective Construction of the DecaUn Skeleton With Multiple Contiguous Stereogenic Centers Synthesis 2000 611-633... 

Keywords Lewis acids, stereoselectivity, multiple processes... 

Styrene was successfully oxidized to the S-product both by xylene monooxygenase from P. putida mt-2 [113] and styrene monooxygenase from Pseudomonas sp.VLB120 [114] (Scheme 9.13), with the latter enzyme displaying a particularly large substrate tolerance with excellent stereoselectivity (>99% ee). In this context it is interesting to note that both xylene monooxygenase as well as chloroperoxidase are very selective for mono-epoxidation in case of presence of multiple alkene functionalities [115]. 

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

The fourth chapter gives a comprehensive review about catalyzed hydroamina-tions of carbon carbon multiple bond systems from the beginning of this century to the state-of-the-art today. As was mentioned above, the direct - and whenever possible stereoselective - addition of amines to unsaturated hydrocarbons is one of the shortest routes to produce (chiral) amines. Provided that a catalyst of sufficient activity and stabihty can be found, this heterofunctionalization reaction could compete with classical substitution chemistry and is of high industrial interest. As the authors J. J. Bmnet and D. Neibecker show in their contribution, almost any transition metal salt has been subjected to this reaction and numerous reaction conditions were tested. However, although considerable progress has been made and enantios-electivites of 95% could be reached, all catalytic systems known to date suffer from low activity (TOP < 500 h ) or/and low stability. The most effective systems are represented by some iridium phosphine or cyclopentadienyl samarium complexes. 

The stereoselective allylation of carbon-nitrogen multiple bonds have also been studied. The addition of allylzinc bromide to aromatic imines derived from (. S j-valine esters was affected by reversibility, which caused the lowering of the diastereoisomeric ratio with increasing reaction time. The retroallylation reaction could be avoided by performing the reaction in the presence of trace amounts of water or by using CeC - 7H2O as the catalyst with a decreased reaction rate.71... 

This quantity represents the energy of the multiple-site charge-transfer interaction which will later play an important role in the theory of stereoselection. It is to be remarked that, although any MO may involve an arbitrary constant of which the absolute value is unity, the value of the numerator in each term of the right side of this equation is always definite. 

Concept With the discovery of the fullerenes, it has become evident that elemental carbon can exist in almost an infinite number of stable allotropes that are either molecular or polymeric in nature. Whereas achiral and chiral fullerenes can now be prepared in bulk quantities and methods for their regio- and stereoselective multiple functionalization are being developed in increasing numbers, the... 

Following the discovery of a bulk fullerene preparation process in 1990, the covalent chemistry of these carbon allotropes has developed at a phenomenal pace. Frontier orbital (LUMO) and tether-directed functionalization concepts have been successfully applied to the regio- and stereoselective preparation of multiple covalent adducts of C60. These have found increasing applications in the construction of functional supramol-ecules. More recently, the sequence of Bingel reaction - retro-Bingel reaction has provided an elegant access to isomerically pure higher fullerenes and, in particular, to pure carbon enantiomers. 

F. Diederich, R. Kessinger, Regio- and Stereoselective Multiple Functionalization of Fullerenes in Templated Organic Synthesis , Eds. P. J. Stang, F. Diederich, Wiley-VCH, Weinheim, 1999, pp. 189-218. 

In an extensive investigation of the stereochemical memory effect, a series of six diastereomeric pairs of substrates was prepared to probe the effect of single, then multiple substituents on the 5-exo cyclization of amines onto alkene radical cations [144,145]. Overall, these cyclizations were highly dia-stereoselective and were accounted for by a transition-state model employing a chairlike transition state with attack of the nucleophilic amine on the opposite face of the alkene radical to the one shielded by the phosphate anion in the initial contact ion pair (Scheme 34), as exemplified in Schemes 35 and 36. 

In Section 5.03.6.2, a stereoselective synthesis of L-homophenylalanine from the racemic AAacetylated amino acid is described. The authors, however, found that substrate solubility limited the utility of this procedure. Having found an L-N-carbamoylase in Bacillus kaustophilus, they introduced the gene for this enzyme together with that for the N-acyl amino acid racemase from D. radiodurans into E. coli for coexpression. These cells, permeabilized with 0.5% toluene, were able to deliver L-homophenylalanine in 99% yield and were able to be used for multiple reaction cycles. 

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