Diastereoselective Alkylations of Chiral Tetrazolo[1,5a]azepines via Heterobenzylic Anion Intermediates

Abstract

The alkylations of chiral seven-membered rings fused to tetrazoles are highly diastereoselective. The diastereoselectivity depended on the placement and the size of the substituent on the ring and on the electrophile. Subsequent alkylations occurred with high stereoselectivity, allowing for the construction of quaternary stereocenters. Computational studies revealed that torsional effects are responsible for the observed diastereoselectivity. Substituted products can be reduced to the corresponding secondary amines, thus providing an approach to synthesize diastereomerically enriched azepanes.

Graphical Abstract

The synthesis of 1,5-disubstituted tetrazoles has been developed because this heterocyclic core structure is present in biologically active synthetic compounds,^1-4 including cis-amide bond isosteres.^5-6 Introduction of a tetrazole moiety can enhance the potency and specificity of biologically active compounds.^7-9 When fused to seven-membered rings, tertrazole-containing compounds display analeptic and nervous-system stimulant properties^10-11 that can be tuned by making modifications to the seven-membered ring.¹²

In this Letter, we report that seven-membered-ring-fused 1,5 substituted tetrazoles can be functionalized through anionic intermediates with high diastereoselectivity. The transformations outlined herein allow for the synthesis of these heterocyclic compounds with well-defined three-dimensional structures.¹³ Additionally, the substituted tetrazole products can be reduced to the corresponding secondary amines, thus providing a new approach for the synthesis of highly substituted and diastereomerically enriched azepanes.^14-16 These reactions build upon the growing number of stereoselective transformations of seven-membered-ring reactive intermediates.^17-18 Investigations of the diastereoselective reactions of seven-membered-ring-fused tetrazoles commenced with the alkylations of C4-methyl-substituted tetrazole 1. Lithiation with lithium diisopropylamide followed by treatment with various electrophiles¹⁹ afforded α-substituted tetrazoles with high diastereoselectivity (Scheme 1). When iodomethane was used, methylated product trans-2a was formed as a single diastereomer. Bulkier alkyl halides, including allyl bromide, ethyl iodide, and benzyl bromide, underwent alkylation with lower stereoselectivity. Lithiation of tetrazole 1 with tert-butyllithium²⁰ followed by quenching with D₂O effected a modestly stereoselective deuteration at C2. In all cases, the electrophile approached the carbanion preferentially from the face opposite that of the remote C4 substituent,²¹ which contrasts what was observed in the alkylations of seven-membered-ring ε-lactam enolates.¹⁷

Scheme 1. Alkylations of C4-methyl tetrazole 1.^a,b.

^aDiastereomeric ratios were determined by ¹³C{H} analysis of the crude reaction mixture.^{22 b}Isolated yields of purified products.

The diastereoselectivity for the alkylations of C4-substituted seven-membered-ring-fused tetrazoles was general (Scheme 2). C4-Phenyl tetrazole 3 was alkylated with similarly high stereoselectivities as with methyl-substituted tetrazole 1. The α-alkylations of tetrazole 5, which bears a bulkier tert-butyl substituent, proceeded with lower diastereoselectivity. The observation of lower diastereoselectivity with a larger remote substituent is opposite of what is observed in the alkylations of the analogous seven-membered-ring enolates.¹⁷ The alkylations of tetrazole 7 with a benzyl-protected hydroxyl group were moderately diastereoselective, but protection with a sterically larger silyl group led to higher diastereoselectivities.

Scheme 2. Scope of C4-substituted seven-membered-ring-fused tetrazoles.^a,b.

^aDiastereomeric ratios were determined by ¹³C{H} analysis of the crude reaction mixture.^{22 b}Isolated yields of purified products. ^cReaction was performed on a 1.1 mmol scale.

The products of mono-alkylation could be alkylated a second time to afford compounds with quaternary stereocenters (Scheme 3). For example, the alkylation of α-methylated product trans-2a with allyl bromide afforded trans-2f as a single diastereomer. The other diastereomer, cis-2f, was synthesized by reversing the order of introduction of electrophiles. High diastereofacial selectivity was achieved with a remote phenyl substituent to afford diastereomerically pure products trans-4c and cis-4c. Remote substituents that were less effective at controlling the stereoselectivity of the first alkylation, such as a benzyloxy group, gave lower stereoselectivities for the second alkylation (trans-8c and cis-8c). As with the first alkylation, the allylation of a compound bearing a remote tert-butyldiphenylsilyloxy substituent (trans-10a) was completely diastereoselective, forming substituted tetrazole trans-12c.²³ The alkylation of a cholesterol derivative with benzyl bromide afforded quaternary substituted tetrazole trans-13 with the same sense of high diastereoselectivity, which showcases the generality of stereoselectivity for the alkylations of substrates that bear C4 substituents.

Scheme 3. Diastereoselective syntheses of compounds with quaternary stereocenters.^a,b.

^aDiastereomeric ratios were determined by ¹³C{H} analysis of the crude reaction mixture.^{22 b}Isolated yields of purified products.

The stereoselectivities of alkylation depended upon the position of a substituent on the seven-membered ring. When a methyl group occupied the C3 position (eq 1), alkylation with iodomethane proceeded with high diastereoselectivity. The fact that the electrophile approached from the same face as the methyl group at C3 contrasts with the generally trans-selective reactions of similar cyclic enolates.¹⁷ This cis-selectivity suggests that torsional effects, not just steric effects, may be important in controlling diastereoselectivity. Alkylation with a larger electrophile, allyl bromide, led to complete erosion of diastereoselectivity, suggesting that steric factors might also play a role. Similar selectivity was observed with menthone derivative 16, which was alkylated with iodomethane to afford cis-17a (eq 2). Alkylations of substrates with a substituent at C5 (eq 3) were also cis-selective, regardless of the size of the electrophile. Diastereoselectivity was not observed when the methyl group was situated at the C6 position (eq 4). With a larger C6 substituent, modest stereoselectivity was achieved with a more hindered electrophile (eq 5).

(1)

(2)

(3)

(4)

(5)

Computational methods were employed to probe the origin of diastereoselectivity in the α-alkylations of tetrazole-fused seven-membered-rings.²⁴ Calculations on a reaction of a simplified model of the carbanion of C4-methyl substrate 1 revealed that delocalization of the carbanion in 24 forces C2, C1, and N7 into coplanarity, which causes the seven-membered ring to adopt a twist-chair conformation (Figure 1a). The twist-chair conformation observed for these intermediates differs from the geometries of the analogous seven-membered-ring enolates, which adopt chair conformations. The difference between chair and twist-chair conformations has a significant impact on the dihedral angles about the C2 and C3 substituents, which leads to the contrasting diastereoselectivities observed for the metalated tetrazoles and the corresponding enolates. A Newman projection looking down the C2─C3 bond of 24 reveals that electrophilic attack with methyl chloride from the β-face of the carbanion would lead to a compression of the torsional angles^25-30 between the substituents on C2 and C3, whereas attack from the α-face should be accompanied by expansion of those same dihedral angles. Transition state calculations confirm this notion: in TS-24β, the dihedral angles between substituents at C2 and C3 become increasingly eclipsed, whereas in TS-24α, the same key dihedral angles are either expanded or unchanged (Figure 1b). These torsional strain differences in the transition states account for the relatively high ΔΔG^‡, which was calculated to be 2.2 kcal/mol in favor of formation of the experimentally observed trans product.

Figure 1.

a) Geometry of resonance-stabilized carbanion 24. b) Newman projections looking down the C2─C3 bond of carbanion 24 and of transition states TS-24α and TS-24β.

The placement of the remote substituent on the seven-membered ring was also assessed with computational methods. Constrasteric alkylations of C3 substituted substrates can be rationalized by similar torsional strain arguments as the C4 case. The carbanion of the C3-methyl substrate, 25, adopts a similar twist-chair geometry as the C4-substituted carbanion 24, except in the case of 25 the torsionally favored approach, TS-25α, occurs from the same face of the remote methyl substituent (Figure 2). The disfavored transition state, TS-25β, is destabilized by accumulation of torsional strain, as evidenced by the small dihedral angles between the C2 and C3 substituents. The preference for the electrophile to approach the carbanion such that torsional strain is relieved, as in TS-25α, outweighs the destabilizing gauche interaction that develops between the incoming methyl group and the C3 methyl group. The sum of the torsional and steric factors account for the calculated ΔΔG^‡ of 1.6 kcal/mol, which is in good agreement with the experimental results. Similarly, the C5 substituted carbanion adopts a conformation such that the methyl substituent occupies the face that is torsionally favored (Figure 3). Due to the remoteness of the C5 methyl group, and therefore the absence of a developing gauche interaction in the torsionally favored transition state, the calculated ΔΔG^‡ was greater than in the C3 case (2.2 kcal/mol in favor of TS-26α over TS-26β).

Figure 2.

Twist-chair geometry of C3-substituted carbanion 25 and the C2─C3 Newman projections of TS-25α and TS-25β.

Figure 3.

Twist-chair geometry of C5-substituted carbanion 26 and the C2─C3 Newman projections of TS-26α and TS-26β.

In the case of the C6-substituted anion, two twist-chair carbanion conformers, 27 and 28, were found to be close in energy (ΔΔG⁰=0.2 kcal/mol), so the products are likely to be formed by multiple transition states. The torsionally favored transition states from each conformer, TS-27β and TS-28α, which lead to the cis and trans products, respectively, were found to be close in energy (ΔΔG^‡ =0.6 kcal/mol, Figure 4). In TS-27β, the electrophile approaches from the same face as the pseudoaxial C6 methyl group, which leads to an increase in transannular steric repulsion in the transition state. TS-28α is destabilized by the A^1,2 repulsion³¹ between the equatorial C6 methyl group and the tetrazole ring, although the approach of the electrophile is relatively unchanged compared to attack on TS-27β. When the C6 substituent is a methyl group, the magnitude of these destabilizing factors is similar, but with a tert-butyl substituent, the preference for alkylation to occur from the opposite face of the remote substituent is greater due to the larger size of the substituent.

Figure 4.

Geometries of C6-methyl carbanions 27 and 28 and their respective torsionally favored transition states of TS-27β and TS-28α.

Compounds bearing C2 quaternary stereocenters were sufficiently acidic at the C6-position to permit further functionalization (Scheme 4). The anions were formed at −78 °C with tert-butyllithium.³² Subsequent alkylations occurred with excellent stereoselectivity from the opposite face with respect to the remote C4 substituent.

Scheme 4. Diastereoselective C6 alkylations of C2 quaternary substitution products.^a,b.

^aDiastereomeric ratios were determined by ¹³C{H} analysis of the crude reaction mixture.^{22 b}Isolated yields of purified products. ^cProduct was isolated with a rearranged byproduct. ^dReaction was performed on a 90:10 mixture of trans-8c and cis-8c. The reported diastereomeric ratio reflects the conversion of trans-8c to product.

The access to highly substituted tetrazoles provides a route to synthesize the corresponding diastereomerically enriched azepanes. Sequential treatment of phenyl tetrazole 3 with iodomethane and allyl bromide furnished α-quaternary tetrazole trans-4c as a single diastereomer. Subsequent reduction of the tetrazole ring with lithium triethylborohydride³³ and methylation³⁴ provided diastereomerically pure N-methyl azepane trans-32, albeit in low yield (eq 6). This strategy for the synthesis of 3,5-disubstituted azepanes provides a complementary approach to the synthesis that involves alkylating the corresponding seven-membered-ring lactam, which undergoes stereoselective α-alkylations from the opposite face (eq 7).¹⁷ In conclusion, the alkylations of anions derived from chiral seven-membered rings fused to tetrazoles are highly diastereoselective. Computational methods revealed that differences in torsional strain in the diastereomeric transition states account for the high diastereoselectivity. The diastereofacial preference was not altered in subsequent alkylations, which allowed for the controlled construction of quaternary stereocenters and for the introduction of an additional

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(7)

stereocenter at the C6 position. The products of anionic functionalization, while potentially relevant medicinally, can also be reduced to the corresponding azepanes.^{14, 35}