see: Kiyoshi Tomioka, Hisashi Kawasaki, Kosuke Yasuda, and Kenji Koga. "A Model for the Diastereofacial Differentiation in the Alkylation of Endocyclic Enolate." J. Am. Chem. Soc. 1988, 110, 3597-3601.

Introduction:

Control of stereoselectivity in a reaction can involve the recognition of the structural features within the substrate. One of these is the conformational strain intrinsic to a molecule. Therefore, information on the height of rotational barriers between possible conformers becomes significant when predicting the major conformers of a molecule.¹ If one conformer is highly populated, stereoselectivity can be achieved.

One case of interest is that of the vinylic bonds of highly substituted allylic systems. Consider the following conformations of 1 (Figure 1). Ab initio calculations for the energy of several different conformations of simple allylic systems such as 1 (3-methyl-1-butene) reveal that the lowest energy conformations are 1a and 1b, i.e. the conformers where there is a substituent eclipsing the double bond.² The bisected conformation 1c does not correspond to an energy minimum and so it is significantly less populated.

Furthermore, while 1a will be the most populated state, 1b will also have a significant population, as there are no severe steric interactions between the eclipsed substituents at the 1 and 3 positions of the allylic system to disfavor this conformation.

However, introduction of a substituent on the double bond cis to the allylic position (Figure 2) severely destabilizes the conformer 2b (which is analogous to 1b). Therefore, 2a is the major conformer in this equilibrium due to the allylic strain present in 2b.²

Allylic strain, the unfavorable steric interaction of Z substituents in an allylic system was first recognized in 1965 by Johnson and Malhotra in their investigation of the different conformations of cyclohexane systems containing an endocyclic or an exocyclic double bond.^3,4 It was observed that in certain conformations, the geometry of the double bonds can place ring substituents in close proximity to one another, disfavoring those conformations if the steric interactions are severe enough. This can be seen in the analysis of the conformations of compound 3 (Scheme 1).

In the conformation represented by 3a the dihedral angle between C_g-R₃ and the double bond is approximately zero.³ Thus, the spatial arrangement of the sequence R₃-C_g-C_b-C_a-R₂ is essentially coplanar. Because of this geometry there will be disfavorable steric interactions between R₂ and R₃, even if R₃ is only of moderate size, such as a methyl group. In the case of 3b the steric hinderance between R₂ and R₃ is absent, but 1,3-diaxial interactions of R₃ with ring hydrogens are now present. However, if R₂ and R₃ are methyl groups, conformation 3b has been estimated to be favored by roughly 1 kcal/mol and therefore present in an 85:15 ratio with 3a.³ This is a case of 1,3 allylic strain, or A_1,3 strain where the numbers 1 and 3 refer to the substituents at the 1 and 3 positions of the allylic system.

Johnson and Malhotra also described another type of allylic strain, 1,2 allylic strain, or A_1,2 strain which is illustrated in the different conformations of the 2,3-disubstituted cyclohexene 4 (Scheme 2).³ A_1,2 strain is due to steric interactions between substituents at the 1 and 2 positions of an allylic system.

The dihedral angle between R₁-C_b and R₂-C_g is approximately 35∞ in 4a, so steric hindrance between R₁ and R₂is present. However, in 4b this angle is increased to approximately 85∞, essentially eliminating the steric interactions between R₁ and R₂ and thereby favoring 4b over 4a.³

Allylic strain can be used to control facial selectivity of reactions on olefins. Consider, for example, the two possible 3,3 sigmatropic rearrangements of 5 (Scheme 3).

The conformation of 5b is of a much higher energy than 5a due to the A_1,3 strain between the two methyl groups.⁵ Therefore, 6 forms exclusively over 7.

Facial selectivity of an olefin can also be accessed by utilizing A_1,2 strain present in a substrate. It has been shown previously that chiral allylic alcohols, such as 8, can be hydrogenated with a high degree of diastereoselectivity.⁶ Using an achiral rhodium catalyst and H₂, 8 was hydrogenated to form 9 and 10 in a 99:1 ratio. The rhodium catalyst must form a complex with 8 for the reaction to occur (Scheme 4). However, the A_1,2 strain present in 8b, where the methyl is in the plane of the carbonyl oxygen, causes it to be much less populated compared to 8a, where the methyl is above the plane of the carbonyl oxygen. Therefore, formation of 9 is highly favored, resulting in the observed ratio.
 
 

In the previous examples methyl groups were used as agents to control the strain present in a system, and therefore the stereoselectivity of subsequent reactions. How can we affect the selectivity of a reaction by incorporating different substituents in the allylic system? Will these changes predictably alter the stereochemical outcome of the reaction? The study of alkylations of various endocyclic enolates by Koga et. al.⁷provide insight into these questions.

Results:

Koga et. al.⁷ found that allylic strain can effect diastereofacial differentiation of endocyclic enolates upon alkylation.A series of enolates 12 with varying R¹ and R² substituents were generated from lactones 11 using lithium diisopropylamide (LDA) in the presence of hexamethylphosphoric triamide (HMPA).

The enolates were alkylated with varying alkylating agents (E-X). The products (13,14) were isolated and diastereomeric ratios were determined by GC and ¹H NMR. Table 1 shows the results from the experimental work.

Discussion:

The experimental results are best understood by using conformational analysis. Formation of an enolate from a lactone results in a cyclohexene like structure. The enolate can exist in several possible conformations, as shown in Scheme 6. (Note that in Scheme 6 the R² substituent is represented as -CH₂R³). A and B represent a conformational pair and differ only by a ring flip. The conformations C and D, and E and F represent the other two conformational pairs.

Diastereofacial differentiation will depend upon alkylation of the most populated cyclohexene conformation. By considering conformations E and F one sees that R³ is eclipsed with the enolate oxygen. When R³ is a substituent other than hydrogen, A_1,3 strain is present due to steric interactions between R³ and the enolate oxygen. Therefore, it is expected that the conformations E and F will be highly unfavorable. Conformations A, B, C, and D have a hydrogen eclipsed with the enolate oxygen, which relieves the A_1,3 strain existing in E and F. The stability among conformations A, B, C and D will be dictated by the steric interactions of R¹ and R³ and thus, the relative size of R¹ and R³. A_1,2 strain results from steric interaction between R¹ and R³.⁴

From the experimental results in Table 1 it appears that the relative size of R¹ and R³ can influence facial selectivity. It is assumed that when R³ is a larger group than H or methyl the A and B conformations are preferred due to the A_1,3 strain present in E and F and A_1,2 strain present in C and D.⁶ In conformations A and B the allylic hydrogen is eclipsed with the enolate oxygen, relieving A_1,3 strain. Also, R¹ and R³ are on different faces of the ring so as to minimize steric interactions between them, thus relieving A_1,2 strain. Now diastereoselectivity is dictated by the relative size of R¹ and R².

As a reference the authors used a vinyl substituent as R² (12a, 12e,). The preferred conformation of enolate 1a is for the vinyl hydrogen to be eclipsed with the enolate oxygen (Figure 3)⁷. Alkylation proceeds from the bottom face with 99.5 : 0.5 selectivity as diastereofacial selectivity is dictated solely by the substituent R¹.

When R¹=Ph and R²=Et (12c) selectivity is 98.0 : 2.0 in favor of 13. Alkylation is favored from the bottom face because the phenyl group (R¹) is bulkier than the ethyl group (R² ) and the bottom face is less sterically hindered. As the size of R² is increased, attack from the bottom face becomes less favorable and more of 14 is formed. When R² is much larger than R¹, 14 is formed in great excess. For example, when R¹=Ph and R²=CH₂C(SMe)₂SiMe₃ (12d) the selectivity is 3.0:97.0 in favor of 14. Now attack from top face is more favorable because R² is bulkier than R¹. All of the other results (12g - 12i) can be explained using the rationale discussed above.

It is important to keep in mind the role allylic strain plays in the above results. If A_1,3 strain was not present, then conceivably E and F would be favorable conformations in which alkylation could take place. Consequently, R² would not have any influence on facial selectivity and one would expect to get alkylation from the bottom face leading to 13 as the major product in all cases. Since the influence of A_1,3 strain favors conformations A and B or C and D, diastereoselectivity is dependent upon the relative size of R¹ and R². So it is A_1,3 strain that makes the relative size of R¹ and R² a factor. Furthermore, the relative size of R¹ and R² is responsible for the degree of A_1,2 strain. It is the presence of A_1,2 strain that favors conformations A and B over C and D. Thus, allylic strain is directly responsible for effecting diastereofacial selectivity upon alkylation.

To further support the conformational analysis presented above the authors performed MM2 modeling studies. They found that enolate 12 (R¹=Me and R² -tBu) is roughly equal in energy in conformations A and B, but that conformations C and D were higher in energy by a factor of 3.5 kcal/mol. This supports the argument that steric interactions between R¹ and R² make A and B preferred conformations when R² is large.

The influence of A_1,3 on product distribution is not limited to endocyclic enolates. In the formation of 17 and 18 (Scheme 7), Kim et. al. found that allylic strain determines the degree of selectivity in the intramolecular alkylation of 16.⁸

Two products are formed in the intramolecular alkylation, one in which the b -hydrogen and a -methyl group are trans (17) and the other in which they are cis (18). The trans diastereomer is formed in high selectivity due to A_1,3 strain. The alkylation proceeds primarily through conformation 16a in which the b -hydrogen and either OEt or O^- are eclipsed. The butene group could potentially be eclipsed with OEt or O^-, as in 16b, but this conformation is highly disfavored due to increased steric interactions caused by A_1,3 strain. Consequently, the conformation in which the b -hydrogen is eclipsed with either OEt or O^- is the most highly favored conformation. This conformation places the b -hydrogen and a -methyl group trans, thus producing the trans diastereomer in high selectivity.

Conclusion:

Koga et. al. have shown that product distribution can be influenced by A_1,3 and A_1,2 strain. Depending upon the relative size of R¹ and R² and the resulting allylic strain, alkylation took place at either the top or bottom face of the endocyclic enolate.

It is important to remember that allylic strain can be present not only in allylic systems, but in pseudo-allylic systems, such as the enolates described in the case study. The degree of strain present in a molecule will be determined by the size of the substituents of the allylic or pseudo-allylic system. However, the exact degree of strain is difficult to predict from first principles, so individual systems must be thoroughly analyzed on a case by case basis.

Allylic strain is an important aspect of organic chemistry. In an equilibrium between two conformations in which allylic strain is present, the more highly favored conformation will be the one which has the least strain. If these are reactive conformations, product distribution may be influenced. While allylic strain can influence the population of one conformation over another it is important to keep in mind that allylic strain may not be solely responsible for product distribution.

References:

1. Karabatsos, G.J.; Fenoglio, D. J. "Rotational Isomerism about sp2-sp3 Carbon-Carbon Single Bonds." Top. Stereochem. 1970, 5, 167-203.

2. Hoffmann, R. W. "Allylic 1,3-Strain as a Controlling Factor in Stereoselective Transformations." Chem. Rev. 1989, 89, 1841-1860.

3. Johnson, F. and Malhotra, S. K. "Steric Interference in Allylic and Pseudo-Allylic Systems. I. Two Stereochemical Theorems." J. Am. Chem. Soc.1965, 87, 5492-5493.

4. Johnson, F. "Allylic Strain in Six-Membered Rings." Chem. Rev. 1968, 68, 375-411.

5. Takahashi, T.; Yamada, H.; Tsuji, J. "Highly Stereoselective Claisen Rearrangement of Vinyl Ether of 1-(1-Hydroxyethyl)-2-Methyl-3-Alkylcyclopentene. A Route to cis- and trans- (1E)-Ethylidene-8-Methylhydrindan-5-one." Tetrahedron Lett. 1982, 23, 233-234.

6. Brown, J. "Directed Homogenous Hydrogenation." Angew. Chem. Int. Ed. Engl. 1987, 26, 190-203.

7. Tomioka, K.; Kawasaki, H.; Yasuda, K.; Koga, K. "A Model for the Diastereofacial Differentiation in the Alkylation of Endocyclic Enolate." J. Am. Chem. Soc. 1988, 110, 3597-3601.

8. Ahn, S. H.; Kim, D.; Chun, M. W.; Chung,W-K. "Highly Stereoselective Intramolecular Alkylation of Ester Enolate: An Approach to Trans-Hydrindane System.." Tetrahedron Lett. 1986, 27, 943-945.

Question #1: Evans and coworkers have investigated the reactivity of b-keto imides.^1,2 The reaction of the enolate of 1 with an acid chloride has been shown to proceed with remarkable stereoselectivity to form product 2 in great excess over 3.

Products 2 and 3 are stable in acidic conditions. With weak bases, such as pyridine in CD3OD, no epimerization or deuterium exchange is seen, even after 3 days. When a stronger base was used, such as Et3N, 2 and 3 equilibrated after 18 hours at room temperature. Propose an explanation for the low kinetic acidity of 2 and 3.

Answer: The most stable conformation of 2 is shown in Scheme 1. In this conformation the methine hydrogen shown is oriented towards the carbamate carbonyl in order to avoid the A_1,3 strain that would be present if the methyl group or the ketone were placed in that position. In fact, the crystal structure of 2 shows that the hydrogen lies nearly in the plane of the pi-system, as shown in Scheme 1 (remember that the nitrogen is sp2 hybridized). This hydrogen is no longer highly acidic, as might be expected, as its orientation to the pi-system is far from optimal (recall the Beta group's PDP #2). Thus, epimerization of the newly created stereocenter is kinetically unfavorable in this conformer.

Question #2

Monensin is a naturally occurring polyether antibiotic with 17 asymmetric centers.

Kishi et. al. presented the first total synthesis of Monensin.³ As part of the synthetic strategy Kishi et. al. used the concept of allylic strain to gain diastereoselectivity. Compound 1 was hydroborated using B₂H₆ in THF followed by an alkaline hydrogen peroxide workup to yield an alcohol. The alcohol was isolated as an 8:1 mixture of diastereomers. Draw the major diastereomer and give an explanation for the diastereoselectivity.

Furthermore, Kishi et. al. exploited this same reaction a second time during the synthesis.⁴ Using compound 2 hydroboration gave a 12:1 diastereomeric ratio. Draw the major diastereomer and offer an explanation for the selectivity. (Note: Incidentally,

Kishi used the concept of allylic strain to selectively form an epoxide from an olefin in a later part of the Monensin synthesis.)

Answer: Selectivity in both reactions is due to A_1,3 strain. The preferred conformation of compound 1 is shown in Figure 1.

This conformation minimizes A_1,3 strain by placing the hydrogen in the plane of the olefin. Hydroboration will selectively take place at the sterically less hindered bottom face. This affords compound 3 as the major diastereomer. Hydroboration selectivity of compound 2 can be determined using similar conformational analysis as above. The preferred conformation is shown in Figure 2.

In this conformation hydroboration will occur selectively from the top face affording compound 4.

References for Test Questions:

1. Evans, D. A.; Ennis, M. D.; Le, T. "Asymmetric Reactions of Chiral Imide Enolates. The First Direct Approach to the Construction of Chiral b -Dicarbonyl Synthons." J. Am. Chem. Soc. 1984, 106, 1154-1156.

2. Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. "Diastereoselective Aldol Reactions Using b -Keto Imide Derived Enolates. A Versatile Approach to the Assemblage of Polypropionate Systems." J. Am. Chem. Soc. 1990, 112, 866-868.

3. Kishi, Y.; Akasaka, K.; Schmid, G. "Total Synthesis of Monensin. 1. Stereocontrolled Synthesis of the Left Half of Monensin." J. Am. Chem. Soc. 1979, 101, 259-260.

4. Kishi, Y.; Fukuyama, T.; Wang, C.-L. J. "Total Synthesis of Monensin. 2. Stereocontrolled Synthesis of the Right Half of Monensin" J. Am. Chem. Soc. 1979, 101, 260-262.