Stereoselectivity chiral alkenes

The origin of stereoselection in 1,3-dipolar cycloadditions to chiral alkenes 97G167. 

Although significant progress in the field of asymmetric hydroformylation has been made, it is limited to a rather narrow substrate scope. An alternative approach to a stereoselective hydroformylation might employ substrate control of a chiral alkenic starting material. Of particular use... 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

The chiral sites which are able to rationalize the isospecific polymerization of 1-alkenes are also able, in the framework of the mechanism of the chiral orientation of the growing polymer chain, to account for the stereoselective behavior observed for chiral alkenes in the presence of isospecific heterogeneous catalysts.104 In particular, the model proved able to explain the experimental results relative to the first insertion of a chiral alkene into an initial Ti-methyl bond,105 that is, the absence of discrimination between si and re monomer enantiofaces and the presence of diastereoselectivity [preference for S(R) enantiomer upon si (re) insertion]. Upon si (re) coordination of the two enantiomers of 3-methyl-l-pentene to the octahedral model site, it was calculated that low-energy minima only occur when the conformation relative to the single C-C bond adjacent to the double bond, referred to the hydrogen atom bonded to the tertiary carbon atom, is nearly anticlinal minus, A- (anticlinal plus, A+). Thus one can postulate the reactivity only of the A- conformations upon si coordination and of the A+ conformations upon re coordination (Figure 1.16). In other words, upon si coordination, only the synperiplanar methyl conformation would be accessible to the S enantiomer and only the (less populated) synperiplanar ethyl conformation to the R enantiomer this would favor the si attack of the S enantiomer with respect to the same attack of the R enantiomer, independent of the chirality of the catalytic site. This result is in agreement with a previous hypothesis of Zambelli and co-workers based only on the experimental reactivity ratios of the different faces of C-3-branched 1-alkenes.105... 

Methylsulfenylation of acyclic chiral alkenes such as 5 can also be regio- and stereoselective as a result of steric and electronic factors. 

Addition of (TMS)3SiH to a-chiral ( )-alkene 7 was found to take place with a complete Michael-type regioselectivity (Reaction 5.8) [26]. A complete syn stereoselectivity was observed for R = Me, and it was rationalized in terms of Felkin-Ahn transition state 8, which favours the syn product similar to nucleophilic addition. 

As already mentioned, the dioxirane epoxidation of an alkene is a stereoselective process, which proceeds with complete retention of the original substrate configuration. The dioxirane epoxidation of chiral alkenes leads to diastereomeric epoxides, for which the diastereoselectivity depends on the alkene and on the dioxirane structure. A comparative study on the diastereoselectivity for the electrophihc epoxidants DMD versus mCPBA has revealed that DMD exhibits consistently a higher diastereoselectivity than mCPBA however, the difference is usually small. An exception is 3-hydroxycyclohexene, which displays a high cis selectivity for mCPBA, but is unselective for DMD . ... 

The alkoxy-inside model was further adapted in order to rationahze the stereoselectivities of nitrile oxide cycloadditions to alkenes that possess other allylic substituents. In the reaction of a-chiral alkenes (124) or allylic diphe-nylphosphane oxides (161) (Table 6.7), it was suggested that the largest group (L, diphenylphosphinoyl substituent) was anti, the medium sized group (M, alkyl or alkoxy substituent) was on the inside and the smallest group (S, hydrogen) was... 

The 1,3-dipolar cycloadditions of 1,3-dipoles with chiral alkenes has been extensively reviewed and thus only selected examples will be highlighted here. We have chosen to divide this section on the basis of the different types of alkenes rather than on the basis of the type of 1,3-dipole. For 1,3-dipolar cycloadditions, as well as for other reactions, it is important that the chiral center intended to control the stereoselectivity of the reaction is located as close as possible to the functional group of the molecule at which the reaction takes place. Hence, alkenes bearing the chiral center vicinal to the double bond are most frequently apphed in asymmetric 1,3-dipolar cycloadditions. Examples of the application of alkenes with the chiral center localized two or more bonds apart from the alkene will also be mentioned. Application of chiral auxiliaries for alkenes is very common and will be described separately in Section 12.3. 

The stereoselective cyclopropanation of chiral alkenes can be divided into two classes cyclic and acyclic alkenes. Furthermore, within each class, a subdivision exists involving those that contain a proximal basic group that can direct the cyclopropanation reaction of zinc carbenoids and the others that do not. The discrimination of reactivity between alkenes that possess a proximal basic group and those that do not was first highhghted early on when Simmons and Smith noticed that the cyclopropanation of l-(o-methoxyphenyl)-l-propene was more efficient than that of the related meta and para isomers (equation 46). ... 

The intermolecular photocycloaddition of alkenes to cyclic enones was found to afford cis- and trans-fused bicyclic systems. This stereoselectivity and the diastereofacial selectivity of chiral alkenes and/or enones is discussed below. 

However, a computational study124 shows that the Kishi model controls the stereoselectivity for (Z)-alkenes. Note also that in the Diels-Alder reactions of hexachloropentadiene with chiral alkenes, the inside alkoxy effect is attributed to electrostatic repulsion of the oxy group in the125 outside position with the chlorine atom of hexachloropentadiene in the 1-position. 

The stereochemical result is no longer characterized solely by the fact that the newly formed stereocenters have a uniform configuration relative to each other. This was the only type of stereocontrol possible in the reference reaction 9-BBN + 1-methylcyclohexene (Figure 3.25). In the hydroborations of the cited chiral alkenes with 9-BBN, an additional question arises. What is the relationship between the new stereocenters and the stereocenter(s) already present in the alkene When a uniform relationship between the old and the new stereocenters arises, a type of diastereoselectivity not mentioned previously is present. It is called induced or relative diastereoselectivity. It is based on the fact that the substituents on the stereocenter(s) of the chiral alkene hinder one face of the chiral alkene more than the other. This is an example of what is called substrate control of stereoselectivity. Accordingly, in the hydroborations/oxidations of Figures 3.26 and 3.27, 9-BBN does not add to the top and the bottom sides of the alkenes with the same reaction rate. The transition states of the two modes of addition are not equivalent with respect to energy. The reason for this inequality is that the associated transition states are diastereotopic. They thus have different energies—just diastereomers. 

Fig. 3.31. Thought experiment I products from the addition of a racemic chiral dialkylborane to a racemic chiral alkene. Rectangular boxes previously discussed reference reactions for the effect of substrate control (top box reaction from Figure 3.26) or reagent control of stereoselectivity [leftmost box reaction from Figure 3.30 (rewritten for racemic instead of enantiomer-ically pure reagent)]. Solid reaction arrows, reagent control of stereoselectivity dashed reaction arrows, substrate control of stereoselectivity red reaction arrows (kinetically favored reactions), reactions proceeding with substrate control (solid lines) or reagent control (dashed lines) of stereoselectivity black reaction arrows (kinetically disfavored reactions), reactions proceeding opposite to substrate control (solid lines) or reagent control (dashed lines) of stereoselectivity.

Conversely, the addition of enantiomerically pure chiral dialkylboranes to enantiomerically pure chiral alkenes can also take place in such a way that substrate control and reagent control of diastereoselectivity act in the same direction. Then we have a matched pair. It reacts faster than the corresponding mismatched pair and with especially high diastereoselectivity. This approach to stereoselective synthesis is also referred to as double stereodifferentiation. 

Whereas the studies described above involve reactions of chiral alkenes with achiral nitrile oxides, the stereoselectivity of reactions of chiral nitrile oxides has also been studied. The nitrile oxide (75) reacted with c/s-but-... 

Tandem intramolecular 1,3-dipolar cycloadditions and cycloreversion, phosphinimine alkyhdenemalonate cyclization, and retro-malonate additions have been reviewed. The origins of the stereoselection in the 1,3-dipolar cycloadditions to chiral alkenes and the 3 - - 2-cycloadditions of fiiUerene, Ceo, have been reviewed. " The selectivity of the double 3 -I- 2-cycloaddition of tethered double vinyl carbene species in the presence of Cso varies with the nature of the tether. 

In addition to the 1,3-ally lie strain concept, Houk has employed a model for 7t-facial stereoselection of electrophilic additions to chiral alkenes, such as hydroboration, epoxidation, and dihydroxylation, with similar predictive success. ... 

Simpler, open-chain, chiral alkenes have also been employed in [3 + 2]-cycloaddition reactions in order to obtain face selectivity of the addition. The introduction of chiral alcohols such as ( —)-(l/ ,27 ,5S)-menthol into acrylic esters provides a simple entry into this field however, the conformational variability of such molecules allows for only relatively low stereoselectivities.The same is true for the (— )-(l /J,2i ,4i )-bornyl and (— )-(l 7 ,27 ,55)-8-phenylmenthyl derivatives. ... 

Few examples of nitrone cycloadditions to acyclic chiral alkenes have been reported84-89. (More recent literature can be found ill references 322 -336.) A-Benzylnitrones add in a poorly stereoselective fashion to benzyl (,S )-1 -metho.xycarbonyl-2-propenylcarbarnate to give (5RIS)-2-benzyl-5-[(benzyloxycarbonyl)methoxycarbonylmethyl]isoxazolidine as precursors of /1-hydroxy ornithinesss. 

The stereoselectivity of addition of ketenes to acyclic chiral alkenes has been examined in only a few cases. Addition of dichloroketene to a chiral Z-propenyl ether gives a mixture of cyclobutanoncs whose ratio varies as a function of the chiral auxiliary as shown in Table 116. Addition of dichloroketene to the T-2-phenylcydohexyl enol ether occurs with >95 5 selectively from the unhindered C -Re face to give a dichlorocyclobulanone which was converted to ( )-a-cuparenone and (+)-/i-cuparenonc1 v. 

In the analysis of multiple stereochemical influences, if is useful fo classify the stereoselectivity as substrate (reactant) controlled or reagent controlled. For example, in the dihydroxylation of the chiral alkene 5, the product is determined primarily by the choice of hydroxylation catalyst, although there is some improvement in the diastereoselectivity with one pair. This is a case of reagent-controlled sfereoselecfion. 

R,2S)-Ephedrine has found most application, e.g., as a catalyst in photochemical proton transfer reactions (Section D.2.1.). and as its lithium salt in enantioselective deprotonations (Section D.2.1.). The amino function readily forms chiral amides with carboxylic acids and enamines with carbonyl compounds these reagents perform stereoselective carbanionic reactions, such as Michael additions (Sections D.1.5.2.1. and D. 1.5.2.4.), and alkylations (Section D.1.1.1.3.1.). They have also been used to obtain chiral alkenes for [1 +2] cycloadditions (Section D. 1.6.1.5.). 

In Fig. 4, reaction A is a highly stereoselective reduction of 1-aryl alkanones with (-)-chlo-ro diisopinocampheylborane [21]. Upon co-ordination of the ketone oxygen with the Lewis acidic chirotopic and non-stereogenic [22] boron atom of the chiral reagent, two diastereo-isomeric complexes arise. The sterically less hindered one is preferentially formed and leads the major (,S)-enantiomer, which is isolated after a work-up that allows recovery of a-pinene, the chiral alkene from which the borane is prepared. 

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