Unified synthesis of enantiopure β²h, β³h and β^2,3-amino acids

Abstract

One for all, all for one! A single chiral auxiliary and synthetic route can be used for a three-step (cycloaddition, auxiliary removal and fragmentation) preparation of enantiopure β³h, β²h and β^2,3-amino acids (>99% ee). This approach works for a wide variety of both natural and unnatural side chains, provides access to either enantiomeric form, and can be executed on a preparative scale without recourse to column chromatography.

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Introduction

The discovery that oligomers of homologated amino acids form discrete, stable, and predictable secondary and tertiary structures has played a starring role in the emerging field of foldamers and the synthetic preparation of non-natural oligomers with defined structure and properties.¹ Intense research into the preparation and properties of β-oligopeptides have led to remarkable achievements including the preparation of biologically active oligomers,² artificial enzymes,³ and β-oligopeptides with tunable secondary, tertiary and quarternary structures.⁴ The enhanced structural and metabolic stability of these oligomers, relative to those composed from natural α-amino acids, make them one of the most promising approaches for the preparation of molecules with programmed properties and biological activities.

Oligomers of various β-amino acids stand out as the most studied and sought after class of unnatural foldamers. The three general classes of the constituent β-amino acid monomers, as defined by Seebach,^1b are the β³h-amino acids, the β²h-amino acids, and various diastereomers of β^2,3-amino acids (Scheme 1). Unlike peptides consisting of natural α-amino acids, which are widely available in enantiomercially pure form at a nominal cost, each enantiopure β-amino acid monomer must be synthesized from a suitable chiral starting material or by asymmetric synthesis.⁵

Scheme 1 Three-step synthesis of enantiopure βh³, βh², and β^2,3-amino acids by isoxazolidine fragmentation.

For enantiopure β³h-amino acids, Seebach and co-workers have refined the Arndt–Eistert homologation of α-amino acids with diazomethane. This method is widely employed and is the basis for the commercially available β³h-amino acids,⁶ but it is not well suited to the preparation of monomers with unnatural side chains or configurations due to the requirement of the enantiopure, Fmoc-protected α-amino acids as the starting material. The plethora of catalytic, enantioselective approaches to β-amino acids are rarely employed in practice due to issues of protecting groups and sub-optimal levels of enantioinduction,⁵ although several chiral auxiliary based routes are useful.⁷ To be amenable for the preparation of oligopeptides the monomers must be obtained in >99% ee as their Fmoc-protected β-amino acids.

Other important and desirable classes include β^2,3-substituted variants and, especially, β²-amino acids, which are even more challenging to prepare and specialized methods are often needed for each different side chain. The contemporary challenge of reliable routes to diverse enantiopure β²-amino acid derivates has been beautifully outlined by Seebach in a recent review.⁸ The leading methods utilize several different types of chiral auxiliaries.⁹ Asymmetric hydrogenation of aminoacrylic acid derivatives¹⁰ or enantioselective Mannich-type reactions¹¹ have proven useful in certain cases but with limited versatility. Some β^2,3-amino acids are accessible by alkylation of β³h-derivatives¹² or by enantioselective Michael addition of nitrogen nucleophiles to acrylate esters.^13,14

In this communication we describe a general, unified approach to the preparation of β³h, β²h and both like- and unlike-β^2,3-amino acids in enantiomerically pure form (>99% ee). This approach works for a wide variety of side chains from the corresponding aldehydes, provides access to either enantiomeric form, and can be executed on a preparative scale without recourse to column chromatography (Scheme 1). The key starting materials are readily available on scale at a reasonable cost, rendering this protocol an attractive alternative to β³h-amino acids and a viable approach to β²h and some β^2,3-amino acids.

Results and discussion

In the course of our studies on the synthesis of β³h-oligopeptides via chemoselective ligation of α-ketoacids and cyclic hydroxylamines,¹⁵ we recognized the potential for a variant of Vasella's asymmetric nitrone cycloaddition¹⁶ to provide general access to β-amino acid monomers via an unexpectedly facile N–O cleaving fragmentation reaction (Scheme 2). We investigated a number of different acrylates for the key nitrone cycloaddition and fragmentation and selected cyclohexanone-derived acrylate 2a for further studies.¹⁷ Refinement of this protocol identified advantages of D-gulose, rather than the original D-mannose, derived auxiliaries in terms of diastereoselection in the nitrone cycloaddition and increased crystallinity of the cycloadducts.¹⁸ Most importantly, the D-gulose-derived auxiliary afforded products that correspond with the “natural” configuration usually desired for β-oligopeptides. The D-mannose-derived auxiliary afforded the “unnatural” configuration; L-mannose is prohibitively expensive.

Scheme 2 Fragmentation of isoxazolidine lactones to form β-amino acids.

The cycloadducts were isolated with good to excellent levels of diastereoselectivity as solids that could be readily crystallized to high levels of diastereo- and enantiopurity (Table 1). Single crystal X-ray analysis confirmed the expected relative stereochemistry (see ESI‡), which follows the stereochemical model previously proposed by Vasella.¹⁹ The auxiliary could be removed with a variety of mild conditions, such as treatment with perchloric acid in acetonitrile, which allowed acid-sensitive protecting groups to survive. This two-step protocol was applied to several different aldehydes and the results are summarized in Table 1. Alternatively, the initial cycloadducts could be transformed prior to auxiliary removal, making possible the synthesis of precursors to a number of β³h-amino acids containing unnatural side chains (see Table 2 and ESI‡ for examples and procedures).

Table 1 Cycloadditions and auxiliary removal for β³h-amino acids

Entry	Isoxazolidine	dr^a	Yield (%)^b	Yield (%)^c
a dr of cycloadducts as determined by ^1H NMR. b Isolated overall yield of cycloadducts; Number in parentheses refers to yield of enantiopure major diastereomer after recrystallization. c Isolated yield of isoxazolidines after auxiliary removal. d Overall yield for deprotection of N-Cbz and auxiliary removal. e Prepared from (−)−1.
1		87 : 8 : 5 : 0	93(56)	73
2^e		75 : 18 : 7 : 0	93(47)	83
3		86 : 9 : 5 : 0	96(59)	58
4		84 : 8 : 8 : 0	69(43)	68
5		83 : 11 : 6 : 0	95(50)	47^d
6		86 : 8 : 6 : 0	88(55)	47
7		not determined	(71)	71

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Table 2 Synthesis of β³h-amino acids from isoxazolidines.^a

Entry	Isoxazolidines	Amino acids	Solvent	Yield (%)^b
a All reactions performed with isoxazolidines or their HCl salts (0.1 M) in the indicated solvent (1 mL) at 60 °C 12–36 h. b Isolated yield of amino acids or their HCl salts. c Prepared from (+)−1. d Prepared from (−)−1. e Overall yield for fragmentation and Fmoc-protection.
1^c			H2O	100
2^d			H2O	100
3^c			H2O/tBuOH	92
4^c			H2O/tBuOH	93
5^c			H2O/tBuOH	96
6^c			H2O/tBuOH	42^e
7^c			H2O/tBuOH	70
8^c			H2O/tBuOH	84
9^d			H2O/tBuOH	97
10^d			H2O/tBuOH	99
11^d			H2O/tBuOH	87

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Simply warming isoxazolidines 5 in water leads to spontaneous fragmentation to β-amino acids (Scheme 2). The only byproduct of this reaction is cyclohexanone, which does not interfere with the product isolation and excellent yields are usually obtained following precipitation or removal of solvent from the reaction mixture. Every isoxazolidine we have tested to date provides the corresponding enantiopure β³-amino acid in good to quantitative yield (Table 2). It was also possible to prepare Fmoc-protected amino acids by treatment of the crude reaction mixture with FmocCl (entry 6 and ESI‡).

Table 3 Three-step synthesis of β²h and β^2,3-amino acids

Entry	Amino acids	Acrylate	dr^a	Yield (%)^b	Yield (%)^c	Yield (%)^d
a dr of cycloadducts as determined by ^1H NMR. b Isolated yield of cycloadducts; number in parentheses refers to yield of enantiopure major diastereomer after recrystallization. c Isolated yield of isoxazolidines. d Isolated yield of amino acids. e The fragmentation of isoxazolidines performed in H2O/tBuOH. f The fragmentation of isoxazolidines performed in H2O. g The cycloaddition was carried out in toluene.
1^e		R^1 = iPr	77 : 23	85(50)	92	100
		R^2 = H
		E-2d
2^e		R^1 = H	84 : 16	91(62)	94	100
		R^2 = iPr
		Z-2d
3^e		R^1 = iBu	85 : 15	88(61)	91	99
		R^2 = H
		E-2f
4^e		R^1 = H	84 : 16	90(57)	92	100
		R^2 = iBu
		Z-2f
5^e		R^1 = Bn	75 : 25	88(47)	90	99
		R^2 = H
		E-2e
6^e		R^1 = H	82 : 18	91(63)	79	98
		R^2 = Bn
		Z-2e
7^f		R^1 = Me	70 : 26 : 4 : 0	42(27)	98	100
		R^2 = H
		E-2b
8^f		R^1 = Et	71 : 26 : 3 : 0	75(43)	99	100
		R^2 = H
		E-2c
9^e^,^g		R^1 = H	not determined	59(39)	93	100
		R^2 = Et
		Z-2c

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Encouraged by these results for the synthesis of β³h-amino acids, we sought to extend this procedure to the preparation of more challenging β²h and β^2,3-amino acids. The synthesis of the β²h-amino acid required the cycloaddition of a formaldehyde-derived nitrone with β-substituted acrylate 2, which can be prepared from the identical aldehydes used for the preparation of the β³-amino acids. Importantly, either the pure E or Z form of the acrylate can be accessed by known procedures from a phosphonate prepared in two steps from glyoxylic acid, cyclohexanone, and diethylphosphite.²⁰ The cycloadditions were conducted by simply combining the aldehyde, acrylate, and chiral auxiliary in benzene or toluene and refluxing overnight (Table 3). Although the diastereoselectivities were slightly lower than those observed for the synthesis of the β³h-amino acids, we could isolate diastereomerically pure products in moderate to good yields. The E and Z acrylates provided diastereomeric cycloadducts that result in the opposite absolute configuration at the side chain position; thus, the D-gulose chiral auxiliary can be used to prepare both enantiomers of the β²h-amino acids (entries 1–6). When higher aldehydes were employed for the cycloaddition, either like or unlike 2,3-disubstituted isoxazolidines were obtained in good yield and diastereoselectivity (entries 7–9). In either series, removal of the chiral auxiliary was accomplished without difficulty by treatment with perchloric acid. The hydrolysis and fragmentation of these isoxazolidines to the β²h-amino acids proceeded cleanly and in high yield, although care must be taken to avoid epimerization (entries 1–6). Determination of the enantiopurity of the resulting β²h-amino acids derived from the free base isoxazolidines, analyzed as their Fmoc-protected derivatives, revealed that the products were isolated in only 80% ee for β²h-phenylalanine 6u and 90% ee for β²h-valine 6q. We eventually traced the epimerization to the fragmentation step, implicating the discrete intermediacy of II in the reaction (Scheme 2). After careful investigation, we found that epimerization could be almost completely suppressed by performing the reaction under acidic conditions. Addition of 2 equiv. HCl (aq.) or using HCl salts of isoxazolidines as precursors to β²-amino acids is sufficient to prevent epimerization. In our preliminary studies on the synthesis of β^2,3-amino acids with this chemistry (entries 7–9), we were pleased that fragmentation of both the like and unlike-isoxazolidines proceeded smoothly to give the expected β^2,3-amino acids in excellent yield.

For the purpose of developing and optimizing this chemistry, we have isolated and characterized the two intermediates between the aldehyde starting material and the β-amino acids. The crystallinity of the gulose-derived isoxazolidines makes it possible to prepare enantipure β-amino acids without chromatography or isolation of the intermediates. For example, 1.7 g enantiopure (S)-β³h-phenylalanine 6c (>99% ee) was prepared from acrylate 2a and phenylacetaldehyde. Likewise, 2.2 g (R)-β²h-phenylalanine HCl salt 6u·HCl (99% ee) was prepared from acrylate Z-2e and paraformaldehyde (Scheme 3).

Scheme 3 Preparative scale synthesis of enantiopure (S)-β³h-phenylalanine and (R)-β²h-phenylalanine without chromatography.

Conclusions

In summary, we have documented a general, unified synthesis of enantiopure βh² and βh³-amino acids from a single, readily available chiral auxiliary (Fig. 1). The same aldehyde starting material is the precursor to the amino acid side chain in either case, making possible the preparation of the valuable β-amino acid monomers by synthesis of the appropriate acrylate. The power of this route lies in its generality and reliability to afford enantiopure products. While other routes may be more direct for specific derivatives, this process may be widely applied to natural and unnatural derivatives of either configuration and without the need for dangerous or toxic reagents. We have also demonstrated that for both β² and β³-amino acids it can be executed on a preparative scale without the need for column chromatography.

Fig. 1 Overview of the synthesis of β-amino acids and their configuration from gulose-derived auxiliaries. The opposite enantiomers of those shown may be prepared from the L-gulose-derived auxiliary.

Experimental section

Synthesis of (S)-β³h-phenylalanine (6c)

A mixture of phenyl acetaldehyde (4.0 mL, 34.3 mmol, 1.2 equiv.), acrylate 2a (5.73 g, 34.1 mmol, 1.2 equiv.) and D-gulose-derived hydroxylamine (+)−1 (7.82 g, 28.4 mmol, 1.0 equiv.) in PhH (140 mL) was heated to reflux with a Dean–Stark trap for 24 h. The solvent was removed under reduced pressure and the residue was crystallized from EtOAc (10 mL) and hexanes (30 mL) to give the diastereomerically pure cycloadduct (8.84 g, 57%) as white crystals.

To a solution of this cycloadduct (7.78 g, 14.3 mmol, 1.0 equiv.) in CH₃CN (140 mL) was added HClO₄ (60%, 3.6 mL, 35.7 mmol, 2.5 equiv.) at RT and stirred 15 h. The reaction was quenched by the addition of aq. NaHCO₃, extracted with EtOAc (3×), and the combined organic extracts were washed with brine and dried over Na₂SO₄. After concentration under reduced pressure, the residue was dissolved in 2 : 1 (v/v) H₂O/tBuOH (150 mL) and stirred 24 h at 60 °C. The resulting mixture was cooled to RT, the solvent was removed and the remaining solid was collected and washed with EtOAc to give (S)-β³h-Phe (6c) (1.72 g, 69% for 2 steps, > 99% ee) as a light pale solid.

Synthesis of (R)-β²h-phenylalanine (6u•HCl)

A mixture of paraformaldehyde (1.29 g, 1.2 equiv.), acrylate Z-2e (10.29 g, 39.8 mmol, 1.2 equiv.) and D-gulose-derived hydroxylamine (+)−1 (9.20 g, 33.4 mmol, 1.0 equiv.) in PhH (150 mL) was heated to reflux with a Dean–Stark trap for 24 h. The solvent was removed under reduced pressure and the residue was crystallized from iPrOH (8 mL) and hexanes (24 mL) to give the diastereomerically pure cycloadduct (10.14 g, 56%) as white crystals.

To a solution of this cycloadduct (10.14 g, 18.6 mmol, 1.0 equiv.) in CH₃CN (140 mL) was added HClO₄ (60%, 4.7 mL, 46.6 mmol, 2.5 equiv.) at RT and stirred 15 h. The reaction was quenched by the addition of aq. NaHCO₃, extracted with EtOAc (3×), and the combined organic extracts were washed with brine and dried over Na₂SO₄. After concentration under reduced pressure, the residue was dissolved in 2 : 1 (v/v) H₂O/tBuOH (150 mL) and concentrated aq. HCl (3.1 mL, 37.2 mmol, 2.0 equiv.) was added, then stirred 24 h at 60 °C. The resulting mixture was cooled to RT, the solvent was removed and the remaining solid was collected and washed with EtOAc to give (R)-β²h-Phe hydrochloride (6u·HCl) (2.23 g, 56% for 2 steps, 99% ee) as a light pale solid.

Acknowledgements

This work was supported by the Arnold and Mabel Beckman Foundation, the David and Lucille Packard Foundation, and Research Corporation (Cottrell Scholar Award to J. W. B.). H. I. was generously supported by Kyowa Kirin. We appreciate protocols from Nancy Carrillo, Justin Russak and Ying-Ling Chiang. We are grateful to BioBlocks, Inc. for a generous gift (+)-1.

Notes and references

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18. Both of the D- and L-gulose-derived auxiliaries are commercially available from BioBlocks, Inc. Alternatively, they can be prepared in three steps without chromatography from the corresponding gulonic-acid lactones, which are both available from a variety of suppliers for ∼1 euro/gram in lots of 100 grams.
19. R. Huber and A. Vasella, Tetrahedron, 1990, 46, 33–58.
20. (a) U. Schmidt, J. Langner, B. Kirschbaum and C. Braun, Synthesis, 1994, 1138; (b) See the ESI for an improved procedure.

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Footnotes

† Dedicated to Professor Andrea Vasella.

‡ Electronic supplementary information (ESI) available: Experimental procedures and characterization for all compounds and preparation of key reagents and auxiliaries. CCDC 763138–763140. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0sc00317d

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