Asymmetric induction

Asymmetric induction (also enantioinduction) in stereochemistry describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment.[1] Asymmetric induction is a key element in asymmetric synthesis.

Asymmetric induction was introduced by Hermann Emil Fischer based on his work on carbohydrates.[2] Several types of induction exist.

Internal asymmetric induction makes use of a chiral center bound to the reactive center through a covalent bond and remains so during the reaction. The starting material is often derived from chiral pool synthesis. In relayed asymmetric induction the chiral information is introduced in a separate step and removed again in a separate chemical reaction. Special synthons are called chiral auxiliaries. In external asymmetric induction chiral information is introduced in the transition state through a catalyst of chiral ligand. This method of asymmetric synthesis is economically most desirable.

Energy diagram for enantioselective synthesis
A Gibbs free energy plot of an enantioselective addition reaction. The effect of asymmetric induction is to lower the transition state energy for the formation of one enantiomer over the other

Carbonyl 1,2 asymmetric induction

Several models exist to describe chiral induction at carbonyl carbons during nucleophilic additions. These models are based on a combination of steric and electronic considerations and are often in conflict with each other. Models have been devised by Cram (1952), Cornforth (1959), Felkin (1969) and others.

Cram's rule

The Cram's rule of asymmetric induction developed by Donald J. Cram in 1952[3] is an early concept relating to the prediction of stereochemistry in certain acyclic systems. In full the rule is:

In certain non-catalytic reactions that diastereomer will predominate, which could be formed by the approach of the entering group from the least hindered side when the rotational conformation of the C-C bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent asymmetric center.

The rule indicates that the presence of an asymmetric center in a molecule induces the formation of an asymmetric center adjacent to it based on steric hindrance.

In his 1952 publication Cram presented a large number of reactions described in the literature for which the conformation of the reaction products could be explained based on this rule and he also described an elaborate experiment (scheme 1) making his case.

Scheme 1. Cram's rule of asymmetric induction
Scheme 1. Cram's rule of asymmetric induction

The experiments involved two reactions. In experiment one 2-phenylpropionaldehyde (1, racemic but (R)-enantiomer shown) was reacted with the Grignard reagent of bromobenzene to 1,2-diphenyl-1-propanol (2) as a mixture of diastereomers, predominantly the threo isomer (see for explanation the Fischer projection).

The preference for the formation of the threo isomer can be explained by the rule stated above by having the active nucleophile in this reaction attacking the carbonyl group from the least hindered side (see Newman projection A) when the carbonyl is positioned in a staggered formation with the methyl group and the hydrogen atom, which are the two smallest substituents creating a minimum of steric hindrance, in a gauche orientation and phenyl as the most bulky group in the anti conformation.

The second reaction is the organic reduction of 1,2-diphenyl-1-propanone 2 with lithium aluminium hydride, which results in the same reaction product as above but now with preference for the erythro isomer (2a). Now a hydride anion (H) is the nucleophile attacking from the least hindered side (imagine hydrogen entering from the paper plane).

In the original 1952 publication, additional evidence was obtained for the structural assignment of the reaction products by applying them to a Chugaev elimination, wherein the threo isomer reacts to the cis isomer of -α-methyl-stilbene and the erythro isomer to the trans version.

Scheme 2. Cram Asymmetric Induction Chugaev Reaction
Scheme 2. Cram Asymmetric Induction Chugaev Reaction

Felkin model

The Felkin model (1968) named after Hugh Felkin also predicts the stereochemistry of nucleophilic addition reactions to carbonyl groups.[4] Felkin argued that the Cram model suffered a major drawback: an eclipsed conformation in the transition state between the carbonyl substituent (the hydrogen atom in aldehydes) and the largest α-carbonyl substituent. He demonstrated that by increasing the steric bulk of the carbonyl substituent from methyl to ethyl to isopropyl to isobutyl, the stereoselectivity also increased, which is not predicted by Cram's rule:

Scheme 3. Felkin model for chiral induction
Scheme 3. Felkin model for chiral induction

The Felkin rules are:

  • The transition states are reactant-like.
  • Torsional strain (Pitzer strain) involving partial bonds (in transition states) represents a substantial fraction of the strain between fully formed bonds, even when the degree of bonding is quite low. The conformation in the TS is staggered and not eclipsed with the substituent R skew with respect to two adjacent groups one of them the smallest in TS A.
Scheme 4. Felkin transition state A and Cram transition state B
For comparison TS B is the Cram transition state.
Scheme 4. Felkin transition state A and Cram transition state B
  • The main steric interactions involve those around R and the nucleophile but not the carbonyl oxygen atom.
  • A polar effect or electronic effect stabilizes a transition state with maximum separation between the nucleophile and an electron-withdrawing group. For instance haloketones do not obey Cram's rule, and, in the example above, replacing the electron-withdrawing phenyl group by a cyclohexyl group reduces stereoselectivity considerably.

Felkin–Anh model

The Felkin–Anh model[5] is an extension of the Felkin model that incorporates improvements suggested by Nguyễn Trọng Anh and Odile Eisenstein to correct for two key weaknesses in Felkin's model. The first weakness addressed was the statement by Felkin of a strong polar effect in nucleophilic addition transition states, which leads to the complete inversion of stereochemistry by SN2 reactions, without offering justifications as to why this phenomenon was observed. Anh's solution was to offer the antiperiplanar effect as a consequence of asymmetric induction being controlled by both substituent and orbital effects.[6][7] In this effect, the best nucleophile acceptor σ* orbital is aligned parallel to both the π and π* orbitals of the carbonyl, which provide stabilization of the incoming anion.

Felkinanhfigure1

Felkinanhfigure1

The second weakness in the Felkin Model was the assumption of substituent minimization around the carbonyl R, which cannot be applied to aldehydes.

Felkinanhfigure2

Felkinanhfigure2

Incorporation of Bürgi–Dunitz angle[8][9] ideas allowed Anh to postulate a non-perpendicular attack by the nucleophile on the carbonyl center, anywhere from 95° to 105° relative to the oxygen-carbon double bond, favoring approach closer to the smaller substituent and thereby solve the problem of predictability for aldehydes.[6][10][11]

Felkinanhfigure3

Felkinanhfigure3

Anti–Felkin selectivity

Though the Cram and Felkin–Anh models differ in the conformers considered and other assumptions, they both attempt to explain the same basic phenomenon: the preferential addition of a nucleophile to the most sterically favored face of a carbonyl moiety. However, many examples exist of reactions that display stereoselectivity opposite of what is predicted by the basic tenets of the Cram and Felkin–Anh models. Although both of the models include attempts to explain these reversals, the products obtained are still referred to as "anti-Felkin" products. One of the most common examples of altered asymmetric induction selectivity requires an α-carbon substituted with a component with Lewis base character (i.e. O, N, S, P substituents). In this situation, if a Lewis acid such as Al-iPr2 or Zn2+ is introduced, a bidentate chelation effect can be observed. This locks the carbonyl and the Lewis base substituent in an eclipsed conformation, and the nucleophile will then attack from the side with the smallest free α-carbon substituent.[12] If the chelating R group is identified as the largest, this will result in an "anti-Felkin" product.

Felkinanhfigure4

Felkinanhfigure4

This stereoselective control was recognized and discussed in the first paper establishing the Cram model, causing Cram to assert that his model requires non-chelating conditions.[13] An example of chelation control of a reaction can be seen here, from a 1987 paper that was the first to directly observe such a "Cram-chelate" intermediate,[14] vindicating the model:

Felkinanhfigure5

Felkinanhfigure5

Here, the methyl titanium chloride forms a Cram-chelate. The methyl group then dissociates from titanium and attacks the carbonyl, leading to the anti-Felkin diastereomer.

A non-chelating electron-withdrawing substituent effect can also result in anti-Felkin selectivity. If a substituent on the α-carbon is sufficiently electron withdrawing, the nucleophile will add anti- relative to the electron withdrawing group, even if the substituent is not the largest of the 3 bonded to the α-carbon. Each model offers a slightly different explanation for this phenomenon. A polar effect was postulated by the Cornforth model[15] and the original Felkin model,[16] which placed the EWG substituent and incoming nucleophile anti- to each other in order to most effectively cancel the dipole moment of the transition structure.

Felkinanhfigure6

Felkinanhfigure6

This Newman projection illustrates the Cornforth and Felkin transition state that places the EWG anti- to the incoming nucleophile, regardless of its steric bulk relative to RS and RL.

The improved Felkin–Anh model, as discussed above, makes a more sophisticated assessment of the polar effect by considering molecular orbital interactions in the stabilization of the preferred transition state. A typical reaction illustrating the potential anti-Felkin selectivity of this effect, along with its proposed transition structure, is pictured below:

Felkinanhfigure7

Felkinanhfigure7

Carbonyl 1,3 asymmetric induction

It has been observed that the stereoelectronic environment at the β-carbon of can also direct asymmetric induction. A number of predictive models have evolved over the years to define the stereoselectivity of such reactions.

Chelation model

According to Reetz, the Cram-chelate model for 1,2-inductions can be extended to predict the chelated complex of a β-alkoxy aldehyde and metal. The nucleophile is seen to attack from the less sterically hindered side and anti- to the substituent Rβ, leading to the anti-adduct as the major product.[17]

Felkinanhfigure8

Felkinanhfigure8

To make such chelates, the metal center must have at least two free coordination sites and the protecting ligands should form a bidentate complex with the Lewis acid.

Cram–Reetz model

Cram and Reetz demonstrated that 1,3-stereocontrol is possible if the reaction proceeds through an acyclic transition state. The reaction of β-alkoxy aldehyde with allyltrimethylsilane showed good selectivity for the anti-1,3-diol, which was explained by the Cram polar model. The polar benzyloxy group is oriented anti to the carbonyl to minimize dipole interactions and the nucleophile attacks anti- to the bulkier (RM) of the remaining two substituents.[18][19]

Felkinanhfigure9

Felkinanhfigure9

Evans model

More recently, Evans presented a different model for nonchelate 1,3-inductions. In the proposed transition state, the β-stereocenter is oriented anti- to the incoming nucleophile, as seen in the Felkin–Anh model. The polar X group at the β-stereocenter is placed anti- to the carbonyl to reduce dipole interactions, and Rβ is placed anti- to the aldehyde group to minimize the steric hindrance. Consequently, the 1,3-anti-diol would be predicted as the major product.[20]

Felkinanhfigure10

Felkinanhfigure10

Carbonyl 1,2 and 1,3 asymmetric induction

If the substrate has both an α- and β-stereocenter, the Felkin–Anh rule (1,2-induction) and the Evans model (1,3-induction) should considered at the same time. If these two stereocenters have an anti- relationship, both models predict the same diastereomer (the stereoreinforcing case).

Felkinanhfigure11

Felkinanhfigure11

However, in the case of the syn-substrate, the Felkin–Anh and the Evans model predict different products (non-stereoreinforcing case). It has been found that the size of the incoming nucleophile determines the type of control exerted over the stereochemistry. In the case of a large nucleophile, the interaction of the α-stereocenter with the incoming nucleophile becomes dominant; therefore, the Felkin product is major one. Smaller nucleophiles, on the other hand, result in 1,3 control determining the asymmetry.[21]

Felkinanhfigure12

Felkinanhfigure12

Acyclic alkenes asymmetric induction

Chiral acyclic alkenes also show diastereoselectivity upon reactions such as epoxidation and enolate alkylation. The substituents around the alkene can favour the approach of the electrophile from one or the other face of the molecule. This is the basis of the Houk's model, based on theoretical work by Kendall Houk, which predicts that the selectivity is stronger for cis than for trans double bonds.[22]

Diastereoselective epoxidation of a cis alkene
Diastereoselective epoxidation of a cis alkene

In the example shown, the cis alkene assumes the shown conformation to minimize steric clash between RS and the methyl group. The approach of the electrophile preferentially occurs from the same side of the medium group (RM) rather than the large group (RL), mainly producing the shown diastereoisomer. Since for a trans alkene the steric hindrance between RS and the H group is not as large as for the cis case, the selectivity is much lower.

Felkin-Ahn model for nucleophilic addition to chiral aldehydes
Felkin–Ahn model for nucleophilic addition to chiral aldehydes
Substrate control. addition of achiral allylmetals to α-chiral aldehydes.
Substrate control. addition of achiral allylmetals to α-chiral aldehydes.
An example of substrate controlled addition of achiral allyl-boron to α-chiral aldehyde.
An example of substrate controlled addition of achiral allyl-boron to α-chiral aldehyde.

Substrate control: asymmetric induction by molecular framework in acyclic systems

Asymmetric induction by the molecular framework of an acyclic substrate is the idea that asymmetric steric and electronic properties of a molecule may determine the chirality of subsequent chemical reactions on that molecule. This principal is used to design chemical syntheses where one stereocentre is in place and additional stereocentres are required.

When considering how two functional groups or species react, the precise 3D configurations of the chemical entities involved will determine how they may approach one another. Any restrictions as to how these species may approach each other will determine the configuration of the product of the reaction. In the case of asymmetric induction, we are considering the effects of one asymmetric centre on a molecule on the reactivity of other functional groups on that molecule. The closer together these two sites are, the larger an influence is expected to be observed. A more holistic approach to evaluating these factors is by computational modelling,[23] however, simple qualitative factors may also be used to explain the predominant trends seen for some synthetic steps. The ease and accuracy of this qualitative approach means it is more commonly applied in synthesis and substrate design. Examples of appropriate molecular frameworks are alpha chiral aldehydes and the use of chiral auxiliaries.

Asymmetric induction at alpha-chiral aldehydes

Possible reactivity at aldehydes include nucleophilic attack and addition of allylmetals. The stereoselectivity of nucleophilic attack at alpha-chiral aldehydes may be described by the Felkin–Anh or polar Felkin Anh models and addition of achiral allylmetals may be described by Cram’s rule.

Felkin–Anh and polar Felkin–Anh model

Selectivity in nucleophilic additions to chiral aldehydes is often explained by the Felkin–Anh model[24] (see figure). The nucleophile approaches the carbon of the carbonyl group at the Burgi-Dunitz angle.[25] At this trajectory, attack from the bottom face is disfavored due to steric bulk of the adjacent, large, functional group.

The polar Felkin–Anh model is applied in the scenario where X is an electronegative group. The polar Felkin–Anh model postulates that the observed stereochemistry arises due to hyperconjugative stabilization arising from the anti-periplanar interaction between the C-X antibonding σ* orbital and the forming bond.

Improving Felkin–Anh selectivity for organometal additions to aldehydes can be achieved by using organo-aluminum nucleophiles instead of the corresponding Grignard or organolithium nucleophiles. Claude Spino and co-workers[26] have demonstrated significant stereoselectivity improvements upon switching from vinylgrignard to vinylalane reagents with a number of chiral aldehydes.

Cram’s rule

Addition of achiral allylmetals to aldehydes forms a chiral alcohol, the stereochemical outcome of this reaction is determined by the chirality of the α-carbon on the aldehyde substrate (Figure "Substrate control: addition of achiral allylmetals to α-chiral aldehydes"). The allylmetal reagents used include boron, tin and titanium.

Cram’s rule explains the stereoselectivity by considering the transition state depicted in figure 3. In the transition state the oxygen lone pair is able to interact with the boron centre whilst the allyl group is able to add to the carbon end of the carbonyl group. The steric demand of this transition state is minimized by the α-carbon configuration holding the largest group away from (trans to) the congested carbonyl group and the allylmetal group approaching past the smallest group on the α-carbon centre. In the example below (Figure "An example of substrate controlled addition of achiral allyl-boron to α-chiral aldehyde"), (R)-2-methylbutanal (1) reacts with the allylboron reagent (2) with two possible diastereomers of which the (R, R)-isomer is the major product. The Cram model of this reaction is shown with the carbonyl group placed trans to the ethyl group (the large group) and the allyl boron approaching past the hydrogen (the small group). The structure is shown in Newman projection. In this case the nucleophilic addition reaction happens at the face where the hydrogen (the small group) is, producing the (R, R)-isomer as the major product.

Chiral auxiliaries

Asymmetric stereoinduction can be achieved with the use of chiral auxiliaries. Chiral auxiliaries may be reversibly attached to the substrate, inducing a diastereoselective reaction prior to cleavage, overall producing an enantioselective process. Examples of chiral auxiliaries include, Evans’ chiral oxazolidinone auxiliaries (for asymmetric aldol reactions)[27] pseudoephedrine amides and tert-butanesulfinamide imines.

Substrate control: asymmetric induction by molecular framework in cyclic systems

Cyclic molecules often exist in much more rigid conformations than their linear counterparts. Even very large macrocycles like erythromycin exist in defined geometries despite having many degrees of freedom. Because of these properties, it is often easier to achieve asymmetric induction with macrocyclic substrates rather than linear ones. Early experiments performed by W. Clark Still[28] and colleagues showed that medium- and large-ring organic molecules can provide striking levels of stereo induction as substrates in reactions such as kinetic enolate alkylation, dimethylcuprate addition, and catalytic hydrogenation. Even a single methyl group is often sufficient to bias the diastereomeric outcome of the reaction. These studies, among others, helped challenge the widely-held scientific belief that large rings are too floppy to provide any kind of stereochemical control.

A number of total syntheses have made use of macrocyclic stereocontrol to achieve desired reaction products. In the synthesis of (−)-cladiella-6,11-dien-3-ol,[29] a strained trisubstituted olefin was dihydroxylated diasetereoselectively with N-methylmorpholine N-oxide (NMO) and osmium tetroxide, in the presence of an unstrained olefin. En route to (±)-periplanone B,[30] chemists achieved a facial selective epoxidation of an enone intermediate using tert-butyl hydroperoxide in the presence of two other alkenes. Sodium borohydride reduction of a 10-membered ring enone intermediate en route to the sesquiterpene eucannabinolide[31] proceeded as predicted by molecular modelling calculations that accounted for the lowest energy macrocycle conformation. Substrate-controlled synthetic schemes have many advantages, since they do not require the use of complex asymmetric reagents to achieve selective transformations.

Reagent control: addition of chiral allylmetals to achiral aldehydes

In organic synthesis, reagent control is an approach to selectively forming one stereoisomer out of many, the stereoselectivity is determined by the structure and chirality of the reagent used. When chiral allylmetals are used for nucleophilic addition reaction to achiral aldehydes, the chirality of the newly generated alcohol carbon is determined by the chirality of the allymetal reagents (Figure 1). The chirality of the allymetals usually comes from the asymmetric ligands used. The metals in the allylmetal reagents include boron, tin, titanium, silicon, etc.

17 fig. 1
Fig. 1: Reagent control: addition of chiral allylmetals to achiral aldehydes

Various chiral ligands have been developed to prepare chiral allylmetals for the reaction with aldehydes. H. C. Brown was the first to report the chiral allylboron reagents for asymmetric allylation reactions with aldehydes.[32] The chiral allylboron reagents were synthesized from the natural product (+)-a-pinene in two steps. The TADDOL ligands developed by Dieter Seebach has been used to prepare chiral allyltitanium compounds for asymmetric allylation with aldehydes.[33] Jim Leighton has developed chiral allysilicon compounds in which the release of ring strain facilitated the stereoselective allylation reaction, 95% to 98% enatiomeric excess could be achieved for a range of achiral aldehydes.[34]

17 fig. 2
Fig. 2: Example of chiral allylmetals used: (a) allylboron, (b) allyltitanium, and (c) allyl silicon

See also

References

  1. ^ IUPAC Gold Book definition Link
  2. ^ Asymmetric Synthesis of Natural Products, Ari Koskinen ISBN 0-471-93848-3
  3. ^ Studies in Stereochemistry. X. The Rule of "Steric Control of Asymmetric Induction" in the Syntheses of Acyclic Systems Donald J. Cram, Fathy Ahmed Abd Elhafez J. Am. Chem. Soc.; 1952; 74(23); 5828–5835. Abstract
  4. ^ Torsional strain involving partial bonds. The stereochemistry of the lithium aluminium hydride reduction of some simple open-chain ketones Marc Chérest, Hugh Felkin and Nicole Prudent Tetrahedron Letters Volume 9, Issue 18, 1968, Pages 2199-2204 doi:10.1016/S0040-4039(00)89719-1
  5. ^ It bears mentioning that in Vietnamese, the surname is given first, and so this would be better called the Felkin–Nguyen Model.
  6. ^ a b Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61.
  7. ^ Anh, N. T.; Eisenstein, O.; Lefour, J-M.; Dau, M-E. J. Am. Chem. Soc. 1973, 95, 6146.
  8. ^ Bürgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95, 5065.
  9. ^ Bürgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563.
  10. ^ Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 155.
  11. ^ Anh, N. T. Top. Curr. Chem. 1980, 88, 146.
  12. ^ Mengel A., Reiser O.Chem. Rev., 1999, 99 (5), 1191–1224.
  13. ^ Cram DJ, Elhafez FA. J. Am. Chem. Soc.; 1952; 74(23); 5828–5835.
  14. ^ Reetz MT, Hullmann M, Seitz T. Angew. Chem. Int. Ed. Engl. 1987. 26, 477–480.
  15. ^ Cornforth JW, Cornforth MRH, Mathew KK. J. Chem.Soc. 1959, 112–127.
  16. ^ Cherest M, Felkin H, Prudent N. Tetrahedron Lett. 1968, 18, 2199–2204.
  17. ^ Reetz, M.T.; Jung, A. J. Am. Chem. Soc., 1983, 105, 4833.
  18. ^ Leitereg, T.J.; Cram, D.J. J. Am. Chem. Soc. 1968, 90, 4011.
  19. ^ Reetz. M.T.; Kesseler, K.; Jung, A. Tetrahedron Lett. 1984, 25, 729.
  20. ^ Evans, D.A.; Duffy, J.L.; Dart, M.J. Tetrahedron Lett. 1994, 35, 8537.
  21. ^ Evans, D.A.; Dart, M.J.; Duffy, J.L.; Yang, M.G. J .Am. Chem. Soc. 1996, 118, 4322.
  22. ^ Clayden; Greeves; Warren; Wothers (2001). Organic Chemistry. Oxford University Press. p. 895. ISBN 978-0-19-850346-0.
  23. ^ Houk, K. N. et al., Science, 1986, 231, 1108-1117.
  24. ^ a) Anh, N. T. Top. Curr. Chem. 1980, 88, 145–162; (b) Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61–70; (c) Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 26, 155–158.
  25. ^ Burgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron. 1974. 12, 1563–1572.
  26. ^ Spino, C.; Granger, M. C.; Boisvert, L.; Beaulieu, C. Tetrahedron Lett. 2002, 43, 4183–4185.
  27. ^ Evans, D. A.; Bartroli, J.; Shih, T. L., Am. Chem. Soc., 1981, 103, 2127-2129.
  28. ^ Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981-3996.
  29. ^ Kim, Hyoungsu; Lee, Hyunjoo; Kim, Jayoung; Kim, Sanghee; Kim, Deukjoon (2006-12-01). "A General Strategy for Synthesis of Both (6Z)- and (6E)-Cladiellin Diterpenes: Total Syntheses of (−)-Cladiella-6,11-dien-3-ol, (+)-Polyanthellin A, (−)-Cladiell-11-ene-3,6,7-triol, and (−)-Deacetoxyalcyonin Acetate". Journal of the American Chemical Society. 128 (49): 15851–15855. doi:10.1021/ja065782w. ISSN 0002-7863. PMID 17147397.
  30. ^ Still, W. Clark (1979-04-01). "(.+-.)-Periplanone-B. Total synthesis and structure of the sex excitant pheromone of the American cockroach". Journal of the American Chemical Society. 101 (9): 2493–2495. doi:10.1021/ja00503a048. ISSN 0002-7863.
  31. ^ Still, W. Clark; Murata, Shizuaki; Revial, Gilbert; Yoshihara, Kazuo (1983-02-01). "Synthesis of the cytotoxic germacranolide eucannabinolide". Journal of the American Chemical Society. 105 (3): 625–627. doi:10.1021/ja00341a055. ISSN 0002-7863.
  32. ^ Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
  33. ^ Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807.
  34. ^ Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920.

External links

1,3-Dipolar cycloaddition

The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. Hence, the reaction is sometimes referred to as the Huisgen cycloaddition (this term is often used to specifically describe the 1,3-dipolar cycloaddition between an organic azide and an alkyne to generate 1,2,3-triazole). 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives.

2,3-Wittig rearrangement

The [2,3]-Wittig rearrangement is the transformation of an allylic ether into a homoallylic alcohol via a concerted, pericyclic process. Because the reaction is concerted, it exhibits a high degree of stereocontrol, and can be employed early in a synthetic route to establish stereochemistry. The Wittig rearrangement requires strongly basic conditions, however, as a carbanion intermediate is essential. [1,2]-Wittig rearrangement is a competitive process.

Alkane stereochemistry

Alkane stereochemistry concerns the stereochemistry of alkanes.

Alkane conformers are one of the subjects of alkane stereochemistry.

Alpha-ketol rearrangement

The α-ketol rearrangement is the acid-, base-, or heat-induced 1,2-migration of an alkyl or aryl group in an α-hydroxy ketone or aldehyde to give an isomeric product.

Asymmetric nucleophilic epoxidation

Nucleophilic epoxidation is the formation of epoxides from electron-deficient double bonds through the action of nucleophilic oxidants. Nucleophilic epoxidation methods represent a viable alternative to electrophilic methods, many of which do not epoxidize electron-poor double bonds efficiently.Although the most commonly used asymmetric epoxidation methods (the Sharpless-Katsuki, and Jacobsen epoxidations) rely on the catalytic reactivity of electrophilic oxidants, nucleophilic oxygen sources substituted with a suitable leaving group can also act as epoxidation reagents. The classic example, the Weitz-Scheffer reaction employs hydrogen peroxide under basic conditions (Z = OH below). Other notable examples have employed hypochlorites (Z = Cl) and chiral peroxides (Z = OR*).

(1)

Asymmetric versions of the above reaction have taken advantage of a number of strategies for achieving asymmetric induction. The highest yielding and most enantioselective methods include:

Use of stoichiometric chiral oxidant

Use of stoichiometric metal peroxides substituted with chiral ligands

Use of stoichiometric chiral base

Use of polypeptidesAlthough the mechanisms of each of these reactions differ somewhat, in each case the chiral catalyst or reagent must be involved in the enantio determining conjugate addition step. Cis-epoxides are difficult to access using nucleophilic epoxidation methods. Nearly all nucleophilic epoxidations of cis olefins afford trans epoxides.

Bürgi–Dunitz angle

The Bürgi–Dunitz angle (BD angle) is one of two angles that fully define the geometry of "attack" (approach via collision) of a nucleophile on a trigonal unsaturated center in a molecule, originally the carbonyl center in an organic ketone, but now extending to aldehyde, ester, and amide carbonyls, and to alkenes (olefins) as well. Precisely, in the case of nucleophilic attack at a carbonyl, it is defined as the Nu-C-O bond angle, where Nu is the atom of the nucleophile forming the bond with the carbon atom. The angle was named after crystallographers Hans-Beat Bürgi and Jack D. Dunitz, its first senior investigators. The second angle defining the geometry describes the "offset" of the nucleophile's approach toward one of the two substituents attached to the carbonyl carbon or other electrophilic center, and was named the Flippin–Lodge angle by Clayton Heathcock after his contributing collaborators Lee A. Flippin and Eric P. Lodge. These angles are generally best construed to mean the angle observed or measured for a given system, and not the historically observed value range for the original Bürgi–Dunitz aminoketones, or an idealized value computed for a particular system (such as hydride addition to formaldehyde, image at left). I.e., the BD and FL angles of the hydride-formadehyde system have one pair of values, while the angles observed for other systems are expected to vary.The BD angle adopted during an approach by a nucleophile to a trigonal unsaturated electrophile depends primarily on the molecular orbital (MO) shapes and occupancies of the unsaturated center (e.g., carbonyl center), and only secondarily on the molecular orbitals of the nucleophile. Original measurements for a series of intramolecular amine-carbonyl ketone interactions observed in crystals of compounds bearing both functionalities—e.g., methadone and protopine, images at left and right, below—gave a narrow range of BD angle values (105 ± 5°). Corresponding computational estimates (SCF-LCAO-MO calculations) on the approach of the s-orbital of the hydride anion (H−) to the pi-system of the simplest aldehyde, formaldehyde (H2C=O), gave a BD angle value of 107°. Both the crystallographic measurement for aminoketones and the computational estimated for this simplest system are quite close to the theoretical ideal of a tetrahedral angle (internal angles of a tetrahedron, 109.5°), consistent with the importance of this geometry in developing transition states in nucleophilic attacks at trigonal centers.

The convergence of observed BD angles can be viewed as arising from the need to maximize overlap between the highest occupied MO (HOMO) of the nucleophile, and the lowest unoccupied MO (LUMO) of the unsaturated, trigonal center of the electrophile. (See, in comparison, the related inorganic chemistry concept of the angular overlap model.) In the case of addition to a carbonyl, the HOMO is often a p-type orbital as shown in the figure (e.g., on an amine nitrogen or halide anion), and the LUMO is generally understood to be the antibonding π* MO perpendicular to the plane containing the ketone C=O bond and its substituents (see figure at right above). The BD angle observed for nucleophilic attack is believed to approach the angle that would produce optimal overlap between HOMO and LUMO (based on the principle of the lowering of resulting new MO energies after such mixing of orbitals of similar energy and symmetry from the participating reactants). At the same time, the nucleophile avoids overlap with other orbitals of the electrophilic group that are unfavorable for bond formation (not apparent in image at right, above, because of the simplicity of the R=R'=H in formaldehyde).

To understand cases of real chemical reactions, this HOMO-LUMO-centered view has to be modified by an understanding of further complex, electrophile-specific repulsive and attractive electrostatic and van der Waals interactions that alter the BD angle, and bias the Flippin-Lodge angle toward one substituent or the other. In addition, any dynamics at play in the system (e.g., easily change torsional angles) have to be taken into account in real cases. (Recall that BD angle theory was developed based on "frozen" interactions in crystals, while most chemistry takes place via collisions of molecules tumbling in solution.) Moreover, it appears likely that in constrained environments (e.g., in enzyme and nanomaterial binding sites) the BD angles for reactivity will be quite distinct, since normal orbital overlap principles assuming reactivity dependent on random collision are not applicable in simple fashion. For instance, the BD value determined for enzymatic cleavage of an amide by the serine protease subtilisin was 88° (quite distinct from the hydride-formaldehyde value of 107°), and a careful compilation of literature crystallographic BD angle values clustered at 89 ± 7° for the same reaction mediated by different catalysts (i.e., only slightly offset from directly above or below the carbonyl carbon). At the same time, the subtilisin FL value was 8°, see the Flippin–Lodge angle article, and FL angle values from the careful compilation clustered at 4 ± 6° (i.e., only slightly offset from directly behind the carbonyl).Finally, it is noteworthy that the Bürgi–Dunitz and Flippin–Lodge angles were central, practically, to the development of understanding of asymmetric induction during nucleophilic attack at hindered carbonyl centers (see the Cram–Felkin–Anh and Nguyen model). As well, the stereoelectronic principles that underlie nucleophiles adopting a proscribed range of Bürgi–Dunitz angles appears to contribute to the conformational stability of proteins and are invoked to explain the stability of particular conformations of molecules in one hypothesis of a chemical origin of life.

C2-Symmetric ligands

In homogeneous catalysis, a C2-symmetric ligands usually describes bidentate ligands that are dissymmetric but not asymmetric by virtue of their C2-symmetry. Such ligands have proven valuable in catalysis. With C2 symmetry, C2-symmetric ligands limit the number of possible reaction pathways and thereby increase enantioselectivity, at least relative to asymmetrical analogues. Chiral ligands combine with metals to form chiral catalyst, which engages in a chemical reaction in which chirality is transfer to the reaction product. C2 symmetric ligands are a subset of chiral ligands.

Chiral Lewis acid

Chiral Lewis acids (CLAs) are a type of Lewis acid catalyst that effects the chirality of the substrate as it reacts with it. In such reactions the synthesis favors the formation of a specific enantiomer or diastereomer. The method then is an enantioselective asymmetric synthesis reaction. Since they affect chirality, they produce optically active products from optically inactive or mixed starting materials. This type of preferential formation of one enantiomer or diastereomer over the other is formally known as an asymmetric induction. In this kind of Lewis acid. the electron-accepting atom is typically a metal, such as indium, zinc, lithium, aluminium, titanium, or boron. The chiral-altering ligands employed for synthesizing these acids most often have multiple Lewis basic sites (often a diol or a dinitrogen structure) that allow the formation of a ring structure involving the metal atom.Achiral Lewis acids have been used for decades to promote the synthesis of racemic mixtures in a myriad different reactions. Starting in the 1960s chemists have use the chiral acids to induce the enantioselective reactions. Common reaction types include Diels-Alder reactions, the ene reaction, [2+2] cycloaddition reactions, hydrocyanation of aldehydes, and most notably, Sharpless expoxidations.

Chiral auxiliary

A chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

Most biological molecules and pharmaceutical targets exist as one of two possible enantiomers; consequently, chemical syntheses of natural products and pharmaceutical agents are frequently designed to obtain the target in enantiomerically pure form. Chiral auxiliaries are one of many strategies available to synthetic chemists to selectively produce the desired stereoisomer of a given compound.Chiral auxiliaries were introduced by E.J. Corey in 1975 with chiral 8-phenylmenthol and by B.M. Trost in 1980 with chiral mandelic acid. The menthol compound is difficult to prepare and as an alternative trans-2-phenyl-1-cyclohexanol was introduced by J. K. Whitesell in 1985.

Donald J. Cram

Donald James Cram (April 22, 1919 – June 17, 2001) was an American chemist who shared the 1987 Nobel Prize in Chemistry with Jean-Marie Lehn and Charles J. Pedersen "for their development and use of molecules with structure-specific interactions of high selectivity." They were the founders of the field of host–guest chemistry.

Enantioselective reduction of ketones

Enantioselective ketone reductions convert prochiral ketones into chiral, non-racemic alcohols and are used heavily for the synthesis of stereodefined alcohols.

Enantioselective synthesis

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as: a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric (enantiomeric or diastereoisomeric) products in unequal amounts.Put more simply: it is the synthesis of a compound by a method that favors the formation of a specific enantiomer or diastereomer.

Enantioselective synthesis is a key process in modern chemistry and is particularly important in the field of pharmaceuticals, as the different enantiomers or diastereomers of a molecule often have different biological activity.

Ene reaction

The ene reaction (also known as the Alder-ene reaction) is a chemical reaction between an alkene with an allylic hydrogen (the ene) and a compound containing a multiple bond (the enophile), in order to form a new σ-bond with migration of the ene double bond and 1,5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the allylic position.

This transformation is a group transfer pericyclic reaction, and therefore, usually requires highly activated substrates and/or high temperatures. Nonetheless, the reaction is compatible with a wide variety of functional groups that can be appended to the ene and enophile moieties. Also,many useful Lewis acid-catalyzed ene reactions have been developed which can afford high yields and selectivities at significantly lower temperatures, making the ene reaction a useful C–C forming tool for the synthesis of complex molecules and natural products.

Galantamine total synthesis

The article concerns the total synthesis of galanthamine, a drug used for the treatment of mild to moderate Alzheimer's disease.The natural source of galantamine are certain species of daffodil and because these species are scarce and because the isolation of galanthamine from daffodil is expensive (a 1996 figure specifies 50,000 US dollar per kilogram, the yield from daffodil is 0.1–0.2% dry weight) alternative synthetic sources are under development by means of total synthesis.

Jonathan Clayden

Jonathan Paul Clayden (born 6 February 1968) is a Professor of organic chemistry at the University of Bristol.

N-Sulfinyl imine

N-Sulfinyl imines (N-sulfinylimines, sulfinimines, thiooxime S-oxides) are a class of imines bearing a sulfinyl group attached to nitrogen. These imines display usefully stereoselectivity reactivity and due to the presence of the chiral electron withdrawing N-sulfinyl group. They allow 1,2-addition of organometallic reagents to imines. The N-sulfinyl group exerts powerful and predictable stereodirecting effects resulting in high levels of asymmetric induction. Racemization of the newly created carbon-nitrogen stereo center is prevented because anions are stabilized at nitrogen (i.e., the sulfinyl group is a versatile amine protection group). The sulfinyl chiral auxiliary is readily removed by simple acid hydrolysis. The addition of organometallic reagents to N-sulfinyl imines is the most reliable and versatile method for the asymmetric synthesis of amine derivatives. These building blocks have been employed in the asymmetric synthesis of numerous biologically active compounds.

Soai reaction

In organic chemistry, the Soai reaction is the alkylation of pyrimidine-5-carbaldehyde with diisopropylzinc. The reaction is autocatalytic and leads to rapidly increasing amounts of the same enantiomer of the product. The product pyrimidyl alcohol is chiral and induces that same chirality in further catalytic cycles. Starting with a low enantiomeric excess produces a product with very high enantiomeric excess. The reaction has been studied for clues about the origin of homochirality among certain classes of biomolecules.

The Japanese chemist Kenso Soai (1950–) discovered the reaction in 1995. For his work in "elucidating the origins of chirality and homochirality", Soai received the Chemical Society of Japan award in 2010.Other chiral additives can be used as the initial source of asymmetric induction, with the major product of that first reaction being rapidly amplified. For example, Soai's group has demonstrated that even chiral quaternary hydrocarbons, which have no clear Lewis basic site for binding the nucleophile, are nonetheless capable of inducing asymmetric catalysis in the reaction.

The chiral induction is believed to occur as a result of interactions between the C–H bonds of the alkane and the pi electrons of the aldehyde.

Torquoselectivity

Torquoselectivity is a special kind of stereoselectivity observed in electrocyclic reactions in organic chemistry, defined as "the preference for inward or outward rotation of substituents in conrotatory

or disrotatory electrocyclic reactions." Torquoselectivity is not to be confused with the normal diastereoselectivity seen in pericyclic reactions, as it represents a further level of selectivity beyond the Woodward-Hoffman rules. The name derives from the idea that the substituents in an electrocyclization appear to rotate over the course of the reaction, and thus selection of a single product is equivalent to selection of one direction of rotation (i.e. the direction of torque on the substituents). The concept was originally developed by Kendall N. Houk.

For ring closing reactions, it is an example of enantioselectivity, wherein a single enantiomer of a cyclization product is formed from the selective ring closure of the starting material. In a typical electrocyclic ring closing, selection for either conrotatory or disrotatory reactions modes still produces two enantiomers. Torquoselectivity is a discrimination between these possible enantiomers that requires asymmetric induction.

Torquoselectivity is also used to describe selective electrocyclic ring openings, in which different directions of rotation produce distinct structural isomers. In these cases, steric strain is often the driving force for the selectivity. Studies have shown that the selectivity can also be changed by the presence of electron donating and electron withdrawing groups.

Other mechanisms by which torquoselectivity can operate include chiral Lewis acid catalysts, induction via neighboring stereocenters (in which case the torquoselectivity is a case of diastereoselectivity), and axial-to-tetrahedral chirality transfer. An example of the latter case is shown below for the torquoselective Nazarov cyclization reaction of a chiral allenyl vinyl ketone.

Chirality types
Chiral molecules
Analysis
Chiral resolution
Reactions

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