Diels Alder: endo and exo
to give analogous etrdo-endo 7 and endo-exo 9 diadducts; further addition of furan to the latter at ' affords four triadducts . and as expected an increasing 4:s product ratio. Inde- . perimental and simulated spectra were super- posable . assume a correlation between behaviour early in the reaction path and behaviour at perturbational treat- ments of interaction energies agree well with good super- . namely the competition between an endo and exo orientation of the substituent . mental results verify that exo product formation is rare for these reactions. The endo:exo ratio of for the reaction of cyclopentadiene with methyl methacrylate observed in organic Antiradical activity of novel phenolic products .
Exo vs Endo Products In The Diels Alder: How To Tell Them Apart
Enantioselective synthesis of chiral organic compounds is an important task for synthetic chemists, and the design of catalytic, asymmetric reactions that proceed with high enantioselectivity is an important goal in chemical synthesis. The strategy is to employ a reagent that under normal circumstances does not react with the substrate, but undergoes a selective reaction under the influence of catalytic amounts of a chiral compound. Much effort has been devoted to the development of catalytic asymmetric reactions in which a large quantity of a chiral product can be prepared with only a small amount of a readily available and recov erable chiral auxiliary3,4.
Asymmetric catalysis using chiral Lewis acids, provides a general, powerful tool in this context5,6. Since the early s, a large number of research groups have become interested in discovering new and practical techniques for the control of absolute stereochemistry and there has been remarkable progress in the field of catalytic asymmetric synthesis employing chiral Lewis acids7,8.
This review covers recent progress in chiral Lewis acids catalyzed Diels-Alder reactions9, Catalysis of the Diels-Alder Reaction Introduction The Diels-Alder reaction is one of the most powerful methods of C-C bond construction in synthetic organic chemistry11, It enables, in a one-step inter- or intra-molecular reaction, the rapid preparation of cyclic compounds having a six-membered ring.
The Diels-Alder reaction has several attractive features that have resulted in its use in innumerable syntheses of natural products: If a concerted reaction is assumed, both a cis addition suprafacial mode and a preferred endo orientation Alder rule can be expected. However, significant exceptions to the Alder rule have been observed and several examples appear in this review. For example, unsaturated aldehydes with an a-substituent are used extensively in asymmetric Diels-Alder reactions and consistently favor the exo adduct, with a few exceptions66,71, There are three basic strategies for the control of absolute configuration of the desired product in Diels-Alder reactions: In the past few years, a number of chiral auxiliaries and catalysts for asymmetric Diels-Alder reactions have been developed10, This coordination of Lewis acids to the dienophile serves as the activation process and pro vides a chiral environment that affects facial selectivity.
The understanding of enantioselectivity requires a knowledge of the detailed structure and concentration of each dienophile-Lewis acid complex present in equilibrium and the relative rates for the reaction of each with the diene.
Even if the catalyst has a single fixed geometry in the complex with the a,b-unsaturated carbonyl compound, the proportion of s-cis and s-trans a,b-unsaturated complexes must be controlled, since these will lead to enantiomeric products.
This complexation leads to the lowering of the activation energy and to the enhancement of the endo selectivity and regioselectivity commonly observed upon catalysis. Clearly the conformational preferences of the Lewis acid carbonyl complex are ultimately responsible for determining the stereochemical course of Lewis acid mediated reactions18, Three factors influence the reactivity and conformation of Lewis acid carbonyl complexes: Some representative h1 s-type and h2 p-type complexes and their X-ray structres were published by Schreiber in a.
Examples of h2 p-type complexes involve electron-rich transition metals and electron deficient carbonyl compounds Fig. For the most part, main group, early transition metal, and lanthanide-based Lewis acids are believed to coordinate in a s-fashion. It is interesting that cationic Re complexes exhibit h1 complexation with ketones and h2 complexation with aldehydes Fig 3.
The geometry of h1 complexes anti or syn coordination should be well-defined Fig. In aldehydes, complexation with BF3 occurs anti to the alkyl substituent and the B-O-C-C fragment lies essentially in a common plane, as shown by X-ray crystallography of the complex between benzaldehyde and boron trifluoride It is also noteworthy that NOE measurements are consistent with anti complexation based on a NOE interaction between Fluorine and the aldehyde proton even in solution Fig.
Irradiation of the fluorine signal at Very recently, Fu and coworkers provided structural data that suggests that p interaction of the type illustrated in Fig. The authors provided crystallographic evidence for s and p donation simultaneously by a lone pair and by the p system of a carbonyl group to a divalent boron Lewis acid.
This donation of electron density can organize the resulting complex without the need for a two-point binding between the carbonyl compound and the Lewis acid Fig. Very recently, Corey pubbshed three very interesting papers describing experimental X-ray crystallographic evidences for formyl CH--O and formyl CH--F hydrogen bonds Fig.
In these papers, Corey desclibes the use of formyl CH--O hydrogen bond as an additional factor which contributes to the high degree of enantioselectivity that is observed in several enantioselective Lewis acid catalyzed Diels-Alder cycloadditions Fig. In the last paper of this series, Corey describes applications of this new kind of hydrogen bond in determining transition-state geometry in chiral Lewis-acid catalyzed aldol.
It has been suggested that this formyl CH--O hydrogen bond is an important factor that controls the crystal structures of simple bis-formamides21b. Calculations of the energies and geometries of complexes of some aldehydes and ketones with Lewis acids have been performed and the effect of BH3 and BF3 coordination upon the rotational barriers about the C-C bond adjacent to the carbonyl group in these aldehydes was minimal, while the effect upon the conformational preferences of acetone was pronounced It is important to note that theory predicts a small rotational barrier about B-O bond.
In esters, complexation of the Lewis acid occurs anti to the R'O- moiety, as demonstrated by X-ray diffraction Fig. Such stabilization of the Z -ester conformation should be expected to increase in Lewis acid-substrate complex Fig 9. In amides, Lewis acid complexation is oriented anti to R2N moiety, because allylic strain strongly disfavors Lewis acid complexation syn to the R2N moiety Fig. InWiberg, Marquez and Castejon published an interesting paper on the availability of lone pairs on oxygen The authors studied properties related to the lone pairs such as: This study, based on ab initio wave functions, showed considerable variation in the angle between the lone pair on oxygen and the axis of the carbon-oxygen double bond in aldebydes, ketones and carboxylic acid derivatives.
The "size" of the lone pair also varies, and unsymmetrical ketones offer up an unsymmetrical pair of orbitals for interactions with reagents. This suggests that the geometries for hydrogen bonding found in X-ray crystallographic studies may be a result of crystal forces As was mentioned earlier, the conformation of the dienophile is also an important issue. The observed enantioselectivity is a consequence of the effective steric shielding of one face of the coordinated a,b-enal in the more reactive complex Fig 12 18,19, It is worthy of mention that the relative proportion of each one of these conformations in the equilibrium depends on the nature of X, R1, R2 and R3 Fig.
It is generally accepted that Lewis acid complexation of a,b-unsaturated carbonyl compounds dramatically stabilizes the s-trans conformation relative to the s-cis by either electronic or steric effects A recent conformational study by Houk showed that acrolein adopts the s-cis conformation upon Diels-Alder reaction with a diene, thus overriding the ground-state preference for the s-trans conformation27, If the s-cis form is available in the equilibrium for reaction, it may be the more reactive conformation.
A similar trend has been suggested by Corey for catalyzed Diels-Alder reactions of 2-bromoacrolein15b, The Diels-Alder reaction between butadiene and methyl acrylate has been studied at several ab initio levels considering both the non-catalyzed and the BF3-catalyzed process28b.
In the non-catalyzed reaction, the s-cis transition states are more stable than the corresponding s-trans transition states, and the exo approaches are preferred over the endo. This situation is reversed in the case of the BF3-catalyzed reaction, in which the endo-s-trans is the most stable transition state28b. The comparison of these calculations with those carried outforthereaction between methyl acrylate and cyclopentadiene show that both the Lewis acid and the steric interactions of the methylene group of the cyclopentadiene influence these selectivities.
Corey isolated a 1: For the uncomplexed 2-methylacrolein the s-trans form is about 2. There is no experimental evidence to support a preference ior s-cis or s-trans forms of the Lewis acid-complexed a-haloacroleins. It appears that electronic or steric interactions in the transition state might favor the s-cis or s-trans complexed form, depending on the catalytic system used.
The same trend was observed for uncomplexed 2-heptenal Fig. Gung and Yanik, using a variable temperature NMR technique, showed that the a,b-unsaturated aldehydes 1, the a,b-unsaturated esters 2 and their SnCl4 complexes prefer the s-trans form and the eclipsed conformation C illustrated in Fig. The predominant conformation for the SnCl4 complexed a,b-unsaturated ester 3, is the s-trans form E, with a rotational barrier around the Csp2-Csp2 single bond of about Although the s-trans form C is preferred in solution for a,b-unsaturated aldebydes, experimental observation led to the conclusion that the s-cis form F must be the more reactive conformation, as proposed by Corey and by Marshall32, Ab initio calculations have been performed on the conformations of acrylate derivatives and their complexes with Lewis acids.
These calculations confirm thatthe acrylate-Lewis acid complexes prefer the s-trans conformation with coordination of the Lewis acid anti to the methoxy group favored by steric and electronic effects. For non-complexed acrylates, the s-cis conformation is preferred These authors studied the reactions of these enoates to elucidate the preference in the transition state.
They also used supersonic jet spectroscopy, NOE experiments, and X-ray analysis to clarify the preference in the ground state. They observed that for uncomplexed methyl cmnamate m solution the s-cis conformation has a slight preference over the s-trans confonnation and that the populations of s-cis and s-trans conformers of methyl cinnamate in the gas phase at 4 K are nearly 1: In an earlier work by Lewis et al.
The crystal structure shows that the ligand lies anti to the ethoxy group and adopts an s-trans conformation with tin coordinated syn to the double bond Fig. In a very interesting example, there is experimental evidence that supports an s-cis conformation for a complex between an acrylate with a lactate moiety and TiCl4 Fig.
The authors were able to obtain crystals of this complex and determine its structure. The enoate group adopts an s-cis conformation in a chelated seven-membered cyclic structure, in which titanium is coordinated to two ester carbonyls. The Lewis acid is anti to the acrylate double bond and the enoate adopts an s-cis geometry Fig. In conclusion, a,b-unsaturated ester-Lewis acid complexes prefer the s-trans conformation not only in the ground state but also in the transition state except for the complexes of certain chiral acrylates in which a bidentate Lewis acid coordinates to a carbonyl oxygen of the enoate and an oxygen atom of a chiral auxiliary38, Regarding the use of acyl-l ,3-oxazolidinones, it has been assumed that the uncomplexed carbonyl moiety would exist in the s-cis conformation avoiding nonbonding interactions present between the c,lefin and the ring atoms in its s-trans conformation Support for this assumption follows from conformational studies on a,b-unsaturated amides in which it was concluded that the s-cis conformer is strongly favored However, the s-cis form becomes unfavored in the a-methyl substituted amides.
Although the complexed s-cis form should be more stable for imide dienophiles, some authors sometimes use the s-trans form of the complexed carbonyl moiety to explain the observed selectivity18,48,94, The situation becomes more complex because a bidentate ligand like acyl-1,3-oxazolidinones can occupy 1-free coordination site 1-point substrate binding or 2-free coordination sites 2-point substrate binding in the metal Depending on the metal used, several complexes G-J might be present in ecluilibrium Fig.
The participation of each one of these c. Although there is more experhnental evidence favoring the participation of the complexed s-cis form G, conformations H and I have also been used to explain the observed enantioselectivities in some Diels-Alder reactions Fig. Although in almost every case the s-trans geometry is preferred, many examples of proposed s-cis geometry are presented in this review.
It appears that the dienophile geometry is very case-dependent in present literature. At this point we should emphasize that a critical element in the rational design of chiral Lewis acids for effecting stereoselective cycloaddition reactions to achiral a,b-unsaturated carbonyl compounds is an understanding of the geometry of the reactive intermediates.
It is of great importance to evaluate how the equilibrium structures may change in going from the ground state to the transition state and designing models to test the kinetic competence of various alternative structures. It is also hnportant to point out the need for caution in basing predictions of reactive geometries on X-ray and spectroscopic data, because the thermodinamically favored geometry of a molecule or complex is not necessarilly the same as the reactive geometry cf.
Chiral aluminum Lewis acids One of the earliest examples of an asymmetric Diels-Alder reaction was published in by Koga and coworkers and involved a chiral aluminum catalyst44,18c,d.
They proposed an interpretation of the stereo chemical relationship between the chiral auxiliary and the Diels-Alder adduct, based on the observed absolute configuration Fig. Corey developed an asymmetric Diels-Alder approach to prostaglandin synthesis based on a chiral aluminum catalyst The reaction of 5- benzyloxymethyl -1,3-cyclopentadiene and 3-acryloyl This protocol was used as the initial step in a catalytic enantioselective synthesis of a key intermediate for the synthesis of prostanoids Fig.
The structure of the chiral Diels-Alder catalyst in the crystalline state was determined by an X-ray diffraction study and revealed a dimeric structure with diazaaluminolide subunits The authors suggested that the dienophile is mono-coordinated to aluminum and adopts the s-trans conformation in the 1: These data are consistent with the assigned geometry shown in Fig.
This also suggests that the transition state assembly for the formation of Diels-Alder adduct 9 is that shown in Fig. One of the phenyl groups blocks the access to the front face of the dienophile, and cyclopentadiene approaches from the back side in an endo transition state, consistent with the absolute configuration of the reaction product. Catalyst 10 proved to be the best of a series of examples in terms of ease of preparation, yields, and enantioselectivity.
Treatment of methyl acrylate 1. The optical yields appeared to be increased by lowering the reaction temperature and by the use of nonpolar solvents such as toluene, but with a concomitant decrease in chemical yields Fig. Recently Wulff et al. The authors examined catalysts generated from the vaulted biaryls 16,17 and 18 and diethylaluminum chloride for reactions of methacrolein and cyclopentadiene Fig.
The vaulted 2 2'-binaphthol 17 provides a catalyst that is unselective relative to that derived from the vaulted 3 3'-biphenantrol Using catalyst 16, high inductions were observed with slow addition of dienophile to give exo-Diels-Alder adducts 11 in up to This is one of the highest inductions ever reported for the Diels-Alder reaction with a chiral catalyst and one of the lowest catalyst loadings ever reported for any asymmetric Diels-Alder reaction with any catalyst.
The use of aromatic rings to construct the walls of the"chiral pocket" not only gives a deeper pocket when the walls are extended but at the same time gives a high definition to the asymmetry of possible approaches to the active site. This system allows for the creation of a "chiral pockett" that wraps around the reaction center.
InCativiela and coworkers reported an asymmetric Diels-Alder reaction catalyzed by menthoxy-aluminum derivatives supported on silica-gel and alumina Fig. The solids obtained by treatment of alumina or silica gel with Et2AlCl are efficient catalysts for Diels-Alder reactions. A similar methodology has been used to support menthoxyaluminum derivatives. The introduction of - -menthol reduces the catalytic activity but these solids are able to promote reaction between methacrolein and cyclopentadiene leading to a moderate asymmetric induction.
Both reaction rate and enantioselectivity are greatly influenced by the amount of - -menthol used to prepare the catalyst. So solids obtained from equimolecular amounts of - -menthol and diethyl aluminum chloride lead to higher percentages of enantiomeric excess but they have lower catalytic activity.
Exo vs Endo Products In The Diels Alder: How To Tell Them Apart — Master Organic Chemistry
Silica-supported catalysts are more active than alumma-supported ones The endo product that results has a kind of C-shape. Let's look at these two modes of addition with real molecules.
Here we are adding furan, the diene, to maleic anhydride, the dienophile. The two reactants can approach each other such that one appears to be trailing behind the other, and in this case they appear to be facing the same direction, as far as the orientation of the oxygen atoms goes. This approach leads to the zig-zag exo product.
In the other case, the two molecules can be directly on top of each other; one molecule appears to be folded underneath the other. This approach leads to the curled-up endo product. In fact, as the diagram shows, the endo product is usually the favoured one. A number of researchers attribute the prefernece to a "secondary molecular orbital interaction" between the diene and the dienophile, whereas others describe the interaction as a London dispersion interaction, in which the weak intermolecular attractions stabilise the transition state in one geometry.
The endo and exo products are really two different diastereomers. If you think about it, you can see that when two rings fuse together to make a third, four new stereocenters can be created. Since each chiral centre could have two possible configurations, there are sixteen possible stereoisomers that could result in the reaction shown above. That's a lot of structures. Just eight of them are shown below.
Note that they occur in pairs of enantiomers. However, most of those diastereomers don't really occur. Draw the other stereisomers of the product formed from the reaction between furan and maleic anhydride.
If we look at the molecule in this way, with the hydrogens highlighted on the ends of the diene and the dienophile, it may be easier to see the stereochmical relationships in the exo and endo products. In the exo product, the pair of hydrogens on the diene ends up cis to the pair of hydrogens on the dienophile when the rings become fused.
In the endo product, the opposite is true: Note that the hydrogens on the ends of the diene come out cis to each other, as well. They would be cis to each other in the ring, and that relationship does not change over the course of the reaction.
The same thing is true with the hydrogens on the dienophile. It would be very difficult for the two cis hydrogens on one ring to become trans in the product, because it would require that one ring react via two different faces at the same time. It would be difficult to get one ring twisted around to do that.