Stereoselective synthesis of perillaldehyde-based chiral β-amino acid derivatives through conjugate addition of lithium amides

Abstract

The Michael addition of dibenzylamine to (+)-tert-butyl perillate (3) and to (+)-tert-butyl phellandrate (6), derived from (S)-(−)-perillaldehyde (1), resulted in diastereomeric β-amino esters 7A–D in a moderately stereospecific reaction in a ratio of 76:17:6:1. After separation of the diastereoisomers, the major product, cis isomer 7A, was quantitatively isomerized to the minor component, trans-amino ester 7D. All four isomers were transformed to the corresponding β-amino acids 10A–D, which are promising building blocks for the synthesis of β-peptides and 1,3-heterocycles in three steps. The steric effects of the isopropyl group at position 4 and of the α-methyl substituent of (R)-N-benzyl-N-α-methylbenzylamine on the reactivity were also studied and, upon application of a chiral amine, excellent stereoselectivity of the conjugate addition was observed. Amino ester 11 was obtained as a single product and transformed to the corresponding amino acids 10A and 10D in good yields on the gram scale.

Introduction

In the past decade, cyclic β-amino acids proved to be versatile building blocks both in pharmacological developments and asymmetric syntheses [1–8]. Alicyclic and bicyclic chiral β-amino acids have played a key role in the synthesis of β-peptide-type foldamers, where through the selection of an appropriate alicyclic or bicyclic ring system, the backbone stereochemistry, stereochemical patterning or additional functional groups, well-defined β-helical (e.g., β-H12, β-H14, β-H16 or β-H18) or β-sheet structures can be prepared [9–13]. While it is primarily the backbone stereochemistry that determines the secondary structure of foldamers, the introduction of well-designed hydrophilic or hydrophobic substituents on the alicyclic ring of β-amino acids can modify the fine structure of β-peptides.

There are several powerful synthetic methods through which alicyclic or bicyclic β-amino acid enantiomers can be obtained. These include the selective reduction of β-enamino ester enantiomers [14], enzyme-catalyzed kinetic resolution [15], and a variety of asymmetric syntheses, for example, the enantioselective syntheses of β-lactams followed by ring opening [16–17], or the enantioselective desymmetrization of achiral anhydrides followed by Curtius degradation [18–20].

The highly stereoselective Michael addition of lithium amide-type nucleophiles to α,β-unsaturated esters also proved to be a very efficient and useful method for the preparation of alicyclic β-amino acids in homochiral form [21–22]. Generally, in these transformations, the source of chirality is served by chiral lithium amides, and there are only few examples where chiral α,β-unsaturated esters are applied [23–27].

Easily obtainable chiral monoterpenes, such as (+)-3-carene as well as all the enantiomers of pulegone, α-pinene and verbenone, have frequently been used as starting materials for the preparation of chiral reagents and as unique synthons in asymmetric syntheses of β-amino acids and 1,3-amino alcohols, which in turn can be applied as chiral additives, catalysts or building blocks [17,28–34]. From this aspect, chiral, monoterpene-based α,β-unsaturated esters might be excellent starting materials, in which the natural monoterpene skeleton may serve as the chiral origin for the stereoselective construction of the β-amino acid moiety.

Our present aim was the synthesis of new, limonene-based chiral β-amino acid derivatives derived from commercially available (−)-perillaldehyde (1). These 4-isopropyl-substituted analogues of ACHC (2-aminocyclohexanecarboxylic acid) might serve as promising building blocks for the synthesis of chiral 1,3-heterocycles and foldamers [7,11,23,35].

Results and Discussion

The key intermediate Michael acceptor, tert-butyl perillate (3), was prepared by a combination of literature protocols, starting from commercially available (−)-(4S)-perillaldehyde (1) in a two-step reaction. First, oxidation of 1 led to perillic acid (2) [36], which was subsequently converted to the tert-butyl ester (3) [37]. In order to study the steric effect of the more bulky isopropyl group on the Michael addition, (4S)-tert-butyl phellandrate (6) was prepared via (4S)-phellandral (4) and (4S)-phellandric acid (5) (Scheme 1) [38–40].

Scheme 1.

Reagents and conditions: (i) 2-methyl-2-butene, t-BuOH, NaClO₂ (aq), NaH₂PO₄ (aq), yield: 60%; (ii) (CF₃CO)₂O, dry toluene, t-BuOH, rt, yield: 53%; (iii) 5% Pt/C, 1 atm H₂, n-hexane/EtOAc 1:1, 12 h, rt, yield: 77%; (iv) 2-methyl-2-butene, t-BuOH, NaClO₂ (aq), NaH₂PO₄ (aq), yield: 58%; (v) (CF₃CO)₂O, dry toluene, t-BuOH, rt, yield: 48%.

The asymmetric Michael addition was accomplished by the reaction of in situ generated achiral lithium dibenzylamide with compound 3 following a published protocol [23], to exploit the effect of the isopropenyl group on the cyclohexene ring. An NMR study of the crude product demonstrated the good stereoselectivity of the addition. The ¹H NMR measurements of the crude product indicated that all four possible diastereosomers are formed in a ratio 7A:7B:7C:7D = 76:17:6:1 (Scheme 2). The diastereoisomers 7A–D could be successfully separated through a two-step chromatographic process, and their relative configurations were determined by 2D NMR techniques. Remarkable nOe correlations were observed between C2-H and C9-Me (10A and 10D), between C1-H and C8-H (10A), and a weak effect was found between C1-H and C8-H (10B) (see Figure 1 for numbering).

Scheme 2.

Reagents and conditions: (i) 2.4 equiv LiNBn₂, dry THF, −78 °C, 6 h, then NH₄Cl (aq), overall yield: 87% (isomeric mixture), ratio 7A:7B:7C:7D = 76:17:6:1; (ii) 5% Pt/C, n-hexane/EtOAc 1:1, 1 atm. H₂, rt, 16 h, yield: 90–92%; (iii) 5% Pd/C, n-hexane/EtOAc 1:1, 1 atm H₂, rt, 24 h, yield: 92–95%; (iv) 10% HCl (aq), rt, 24 h, yield: 90–94%.

Figure 1.

Structure of 10D and an ORTEP plot of its configuration.

Amino esters 7A–D were transformed to the appropriate amino acids 10A–D in three steps. The selective reduction of the isopropenyl double bond over a Pt/C catalyst resulted in 8A–D. The subsequent removal of the benzyl groups by hydrogenolysis over palladium on carbon (Pd/C) in a 1:1 mixture of n-hexane/EtOAc for 24 h gave primary amino esters 9A–D in excellent yields. The final hydrolysis of the ester groups under acidic conditions successfully led to amino acids 10A–D.

In addition to the NOESY experiments, the relative configuration of 10D was determined by means of X-ray crystallography (Figure 1).

The Michael addition was also carried out on 6, the 7,8-dihydro analogue of tert-butyl perillate (3), however the saturation of the isopropenyl function at position 4 proved to have no effect on the stereoselectivity of the reaction (Scheme 3).

Scheme 3.

Reagents and conditions: (i) 2.4 equiv LiNBn₂, dry THF, −78 °C, 6 h, then NH₄Cl (aq), overall yield: 85% (isomeric mixture).

When N-benzyl-N-α-methylbenzylamine was applied as a chiral nucleophile in the conjugate addition, the steric effect of the α-methyl substituent could be investigated. The addition was proven highly stereoselective (de > 99%), based on the ¹H NMR data of the crude product and cis-amino ester 11 as a single product was obtained in gram-scale quantities and high yield (Scheme 4). In addition to the NOESY examinations, the relative stereochemistry of 11 was also proven through its conversion to 9A in two steps.

Scheme 4.

Reagents and conditions: (i) 2.4 equiv lithium (R)-N-benzyl-N-α-methylbenzylamide, dry THF, −78 °C, 6 h, then NH₄Cl (aq), yield: 88%; (ii) 5% Pt/C, n-hexane/EtOAc 1:1, 1 atm H₂, rt, 16 h, yield: 91%; (iii) 5% Pd/C, n-hexane/EtOAc 1:1, 1 atm H₂, rt, 16 h, yield: 90%.

Applying (S)-N-benzyl-N-α-methylbenzylamide as a chiral lithium amide, only formation of the mixture of diastereoisomers with very low yield (ca. 10%) was observed.

Under alkaline conditions, cis-amino esters 7A and 11 underwent isomerization at the carboxylic function, resulting in trans-amino esters 7D and 13 in excellent yields (Scheme 5). The relative stereochemistry of 13 was proven through its conversion to 9D in two steps. This rapid and quantitative isomerization allows the gram-scale synthesis of the minor component amino acid 10D (see Scheme 2).

Scheme 5.

Reagents and conditions: (i) 0.2 equiv KOt-Bu/t-BuOH, 40 °C, 24 h, yield: 93% (7D), 91% (13); (ii) 5% Pt/C, n-hexane/EtOAc 1:1, 1 atm H₂, rt, 16 h, yield: 90% (8D), 91% (14); (iii) 5% Pd/C, n-hexane/EtOAc 1:1, 1 atm H₂, rt, 16 h, yield: 92%.

Conclusion

In conclusion, the highly stereoselective Michael addition of lithium dibenzylamide and (R)-N-benzyl-N-α-methylbenzylamide to tert-butyl perillate (3) proved to be an efficient method for the preparation of limonene-based β-amino acids through the three-step transformation of the resulting N,N-dialkyl β-amino esters 7A–D and 11. The minor component, trans-amino acid 10D, was successfully prepared on gram-scale quantities through the facile isomerization of the cis-amino esters under alkaline conditions. It appears likely that the resulting new monomers 10A–D incorporated in a β-peptide sequence will be able to force the formation of unique β-helix or β-sheet structures, thereby affording a novel route to promising β-peptides.

Supporting Information

File 1

General information, experimental details, characterization data and copies of ¹H and ¹³C NMR spectra.