Synthesis of chiral N^β-protected amino diselenides from the corresponding amino alkyl iodides using NaBH₂Se₃ as a selenating reagent and their conversion to seleninic acids

Abstract

A convenient approach has been presented for the synthesis of N^β-protected amino diselenides from the corresponding amino alkyl iodides using in situ generated NaBH₂Se₃ as an efficient selenating reagent. All the diselenides are obtained in good yields under very mild conditions, short duration times and the protocol is free from racemization. The methodology has been effectively extended to the synthesis of N-protected L-selenocystine methyl ester. Clean oxidation of N^β-protected amino diselenides to N^β-protected amino seleninic acids using 35% aqueous H₂O₂ has also been accomplished. The present protocol is compatible with all the common urethane protecting groups.

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Introduction

Selenium is an essential trace element present in many different compounds with unequivocal functions.¹ Organoselenium compounds find applications in organic synthesis,² ligand chemistry³ and in biological processes.⁴ Selenium supplementation plays an important role in disease prevention like cancer, cardiovascular, neurodegenerative and Alzheimer's.^5–8 The common dietary selenium compounds are selenite, selenomethionine, methylselenocysteine and selenocysteine (SeCys). In contrast to oxygen and sulphur, the selenium based methodologies offer several unique features in organic chemistry.⁹ Remarkably, diselenides have attracted much attention as intermediates in organic synthesis due to their higher stability and easier handling relative to parent selenols. Most importantly chiral diselenides have been employed as useful ligands and catalysts in various asymmetric transformations such as diethyl zinc addition to aldehydes,¹⁰ asymmetric hydrosilylation,¹¹ 1,4-addition of Grignard reagents to enones,¹² stereo selective ring opening of epoxides,¹³ palladium-catalyzed asymmetric allylic substitution¹⁴ and electrophilic selenenylation of alkenes.¹⁵ SeCys, recognized as the 21^st proteinogenic amino acid, often found in enzymatic active sites, where its known function is either acting as a nucleophile, a metal ligand or a redox element. In mammals, selenium is an integral part of selenoproteins as selenocysteine.¹⁶ The derivatives of SeCys are the convenient precursors for the synthesis of dehydroamino acids which are useful in the preparation of peptide conjugates.¹⁷

There are few methods reported for the synthesis of β-amino acid derived diselenides, which are employed in the synthetic organic chemistry. Braga et al., reported the synthesis of β-amino diselenides from N-Boc-aziridines¹⁸ as well as N-Boc-2-oxazolidinones¹⁹ employing Li₂Se₂ as a selenating reagent. But these protocols are limited to the synthesis of N^β-Boc amino diselenides, take more time and give moderate yields. Chandrasekaran et al., reported the synthesis of N-Ts-β-amino diselenides from aziridines using tetraethylammonium tetraselenotungstate [(Et₄N)₂WSe₄] as a selenating reagent.²⁰ Later a variety of N^β-protected amino diselenides and selenocystine derivatives from sulfamidates using potassium selenocyanate (KSeCN) and benzyltriethylammonium tetrathiomolybdate [(BnEt₃N)₂MoS₄] have also been reported.²¹ However, longer reaction duration and use of expensive reagents which decompose on prolonged exposure to air are some of the disadvantages of these protocols. Cu(II) catalyzed synthesis of dialkyl, aryl or heteroaryl diselenides has also been known but the alkaline conditions employed in these protocols are not compatible with Fmoc chemistry.^22,23 A few other approaches have also been reported for the synthesis of dialkyl, aryl or heteroaryl diselenides from the corresponding halides.^24–27 Thus a method circumventing the use of aqueous alkali, compatible with common urethane protecting groups (Boc/Cbz/Fmoc), using easily prepared starting material is desirable for the synthesis of N^β-protected amino diselenides.

Seleninic acids are of synthetic importance due to their utility in the construction of seleninates, selenonates²⁸ and other reaction intermediates.^29,30 They have also found widespread application as catalysts in oxidation reactions.^31,32 Seleninic acid group is the most stable, among the four organic acids of selenium (selenol, selenenic, seleninic, and selenonic acids).³³ Kehler et al., reported the synthesis of 3-aminopropaneseleninic acid dihydrotosylate and piperidine-4-seleninic acid dihydrotosylate from the corresponding diselenides using p-toluene sulfonic acid monohydrate and 35% aqueous H₂O₂.³⁴ Knapp et al., reported the clean oxidation of selenoesters to the seleninic acids using dimethyldioxirane (DMDO) in stoichiometric amounts.²⁸ Oxidative cleavage of organodiselenides by aqueous Br₂,³⁵ aqueous H₂O₂ ³⁶ or ozone³⁷ has also been reported for the synthesis of seleninic acids. In continuation of our efforts in organoselenium chemistry^38,39 and in order to overcome the drawbacks associated with the existing protocols, we envisaged to devise a simple, mild and efficient protocol for the synthesis of N^β-protected amino diselenides from the corresponding alkyl iodides using in situ generated NaBH₂Se₃ as a selenating reagent. Further, the oxidation of N^β-protected amino diselenides to the seleninic acids using 35% aqueous H₂O₂ is delineated.

Results and discussion

The selenating reagent for the present study was prepared by the method of Lalancette et al., which involved the treatment of one mole of NaBH₄ with three moles of selenium in THF at 0 °C under nitrogen atmosphere (Scheme 1).⁴⁰ Hydrogen gas gets evolved immediately and within 10 minutes the conversion of black selenium powder into reddish suspension indicates the formation of sodium selenoborate (NaBH₂Se₃).^41,42 So far NaBH₂Se₃ has been employed as a reducing agent however its selenating ability has not been explored.⁴³

Scheme 1 Preparation of sodium selenoborate (NaBH₂Se₃).

Our initial efforts were focused on the synthesis of Boc–Phe–CH₂–Se–)₂ (2c). In a typical reaction, to the freshly prepared NaBH₂Se₃ suspension in THF at 0 °C in a two-necked round-bottom flask under nitrogen atmosphere, a solution of Boc–Phe–CH₂–I (1c) in THF was added drop wise using dropping funnel at 0 °C. As monitored by TLC, the desired Boc–Phe–CH₂–Se–)₂ (2c) was formed within 20 min. After completion of the reaction, the reaction mixture was filtered through celite and washed with THF. After simple workup, Boc–Phe–CH₂–Se–)₂ (2c) was isolated by column chromatography in 95% yield (Scheme 1). The structure of Boc–Phe–CH₂–Se–)₂ (2c) was confirmed by mass spectral and NMR spectroscopic analysis [¹H NMR δ: 3.16–3.26 (m, 2H, –CH₂–Se–); ¹³C NMR δ: 34.92 ppm for –CH₂–Se– carbon; ⁷⁷Se NMR δ 280.00 ppm]. Other selenating reagents such as Li₂Se₂,¹⁴ (Et₄N)₂WSe₄ ²¹ and Na₂Se₂ ⁴⁴ were found to be inefficient in affording the Boc–Phe–CH₂–Se–)₂ (2c) in good yield (Table 1). Moreover Na₂Se₂ is not compatible with Fmoc chemistry and large scale preparation of Li₂Se₂ using super hydride (Liet₃BH) is inconvenient due to the formation of pyrophoric byproducts. Preparation of some of these selenating reagents (Table 1, entry 2, 3) also take longer reaction duration.

Table 1 Screening of other selenating reagents for the synthesis of 2c

Entry	Selenating reagent	Time	Yield (%)
1	Li2Se2	2.5 h	62
2	(Et4N)2WSe4	70 min	68
3	Na2Se2	3 h	55

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The milder condition, shorter reaction duration (20 min) and the excellent yield obtained in case of 2c prompted us to examine the scope and generality of the present protocol for the conversion of a series of N-protected amino alkyl iodides 1 to the corresponding diselenides 2 (Table 2). The present methodology is an efficient one due to the following attributes: compatibility with the common urethane protecting groups like Boc/Cbz/Fmoc, starting material can be prepared easily, monoselenides and triselenides are not formed as byproducts, simple workup and purification procedure (Scheme 2).

Table 2 List of N^β-protected amino diselenides 2

Entry	Amino alkyl iodide 1	β-Amino diselenide 2	Yield (%)
a			94
b			91
c			95
d			93
e			91
f			92
g			94
h			92
i			94
j			93

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Scheme 2 Synthesis of N^β-protected amino diselenides 2.

Using chiral HPLC, the racemization study of the prepared compounds Fmoc–L–Phe–CH₂–Se)₂– 2h and Fmoc–D–Phe–CH₂–Se)₂– 2h* was analyzed. The retention times were found to be at R_t = 15.45 min for 2h and R_t = 17.54 min for 2h* respectively. Intentionally prepared equimolar mixture of 2h and 2h* showed distinct peaks at R_t = 15.80 min and R_t = 17.38 min. This confirms that the present protocol is free from racemization.

L-Serine is the most widely used starting material for the synthesis of L-selenocysteine among the amino acids (serine, asparatic acid, glycine, cysteine) employed. The conversion of L-serine to the L-selenocysteine can be achieved directly using Woollin's reagent but the protocol is restricted to N-acetyl protection⁴⁵ and the activation through tosylates,⁴⁶ halides,^44,47,48 β-lactones,⁴⁹ or sulfamidates²¹ using conventional selenating reagents is also known. But these protocols often suffer from several limitations, which include harsh reaction conditions, longer reaction duration, use of expensive reagents, inseparable byproducts formation, difficulty in workup, incompatibility with base sensitive groups, etc. A protocol which circumvents some of the drawbacks associated with reported protocols is desirable for the synthesis of L-selenocysteine from L-serine.

In order to demonstrate the wider scope of this reagent, we investigated NaBH₂Se₃ for the synthesis of N-protected L-selenocystine methyl ester 5 from N-protected L-serine methyl ester 3 through the activation to iodide 4 (Scheme 3). In brief, commercially available N-protected L-serine methyl ester 3 was converted to the N-protected L-serine iodide methyl ester 4 in excellent yield using imidazole, PPh₃ and I₂.⁵⁰ The solution of 4 in THF was then treated with in situ generated NaBH₂Se₃ to afford the N-protected L-selenocystine methyl ester 5 in good yield. Due to the instability and high reactivity of selenol (SeH) functional group, Secys is usually prepared as diselenide, which is reduced^51,52 in situ to the selenol when needed. The present methodology is more convenient than existing procedures for the synthesis of N-protected L-selenocystine methyl ester 5 from N-protected L-serine methyl ester 3.

Scheme 3 Synthesis of N-protected L-selenocystine methyl ester 5 from N-protected L-serine methyl ester 3.

Since there are no reports on the synthesis of N^β-protected amino seleninic acids, in the next part of the work, we concentrated on the synthesis of amino acid derived seleninic acids 6 through the oxidation of the diselenides 2 using mild H₂O₂ (35% aqueous). In a typical study, to a solution of Boc–Phe–CH₂–Se–)₂ (2c) in DCM at 0° C, 35% aqueous H₂O₂ was added drop wise under vigorous stirring till the completion of reaction (monitored by TLC, reaction mixture became yellow to colorless). After 30 min, Boc–Phe–CH₂–SeO₂H (6c) was formed as white precipitate, which was filtered off. A simple recrystallization from ethanol yielded Boc–Phe–CH₂–SeO₂H (6c) as white stable solid in 91% (Scheme 4). Other solvents such as MeCN, THF, and 1,4-dioxane were found to be inefficient in affording the desired product 6c in good yield. The standardized reaction conditions provided all N^β-protected amino seleninic acids 6 in good yields (Table 3). The present protocol is more convenient for the synthesis of seleninic acids than reported synthesis from selenoesters and moreover handling of 35% aqueous H₂O₂ is easier than DMDO.²⁸

Scheme 4 Synthesis of N^β-protected amino seleninic acid 6.

Table 3 List of N^β-protected amino seleninic acids 6

Entry	Pg	R	Yield (%)
a	Boc	CH(CH3)2	90
b	Boc	CH2CH(CH3)2	90
c	Boc	CH2C6H5	91
d	Boc	C6H5	89
e	Cbz	CH3	92
f	Cbz	CH(CH3)2	90
g	Cbz	CH2C6H5	92
h	Fmoc	CH2C6H5	90
i	Fmoc	CHCH3CH2CH3	91

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Conclusion

In conclusion, an efficient protocol for the synthesis of N-protected L-selenocystine methyl ester, N^β-protected amino diselenides employing in situ generated NaBH₂Se₃ as a selenating reagent from the corresponding amino alkyl iodides is developed. The preparation of NaBH₂Se₃ is simple and fast, acts as a good selenating reagent under mild conditions without any undesirable side reaction. The N^β-protected amino seleninic acids were also prepared by the oxidation of diselenides with 35% aqueous H₂O₂ at 0 °C. All the diselenides and seleninic acids prepared during the course of these investigations were found to be stable and were characterized by mass spectrometry, and NMR analyses.

Experimental section

General procedure for the synthesis of N^β-protected amino diselenides 2, 5

To a solution of sodium borohydride (NaBH₄, 10 mmol) in dry THF, black selenium powder (30 mmol) was added at 0 °C under N₂ atmosphere. The consumption of selenium powder in less than 10 min lead to heterogeneous reddish suspension which indicated the formation of NaBH₂Se₃. To the resulting NaBH₂Se₃ suspension, a THF solution containing N^α-protected amino alkyl iodide 1 or 4 (10 mmol) was added drop wise at 0 °C and the stirring was continued for another 20 min. After completion of the reaction (as monitored by TLC), the reaction mixture was filtered through celite, washed with THF and the solvent was removed under reduced pressure. The crude mass was diluted with EtOAc, washed with water (2 × 20 mL), brine (2 × 20 mL), dried over Na₂SO₄ and the solvent was removed under reduced pressure. The crude residue 2 or 5 was purified by column chromatography on silica gel with EtOAc/hexane (2 : 8).

General procedure for the synthesis of N^β-protected amino seleninic acids 6

To a solution of N^β-protected amino diselenide 2 (10 mmol) in DCM at 0 °C, 35% aqueous H₂O₂ (64 mmol) was added drop wise under vigorous stirring till the completion of reaction (monitored by TLC). The change in color from yellow to colorless indicated the complete consumption of diselenide. After 30 min, the desired product seleninic acid 6 was formed as white precipitate, which was filtered off and recrystallized using ethanol as a solvent. All seleninic acids were isolated as stable solids.

Acknowledgements

We thank the Council of Scientific and Industrial Research (CSIR), Government of India (no. 02(0149)/13/EMR-II) for the financial assistance. Nageswara Rao Panguluri and Veladi Panduranga are thankful to CSIR for the SRF fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Details of mass spectrometry, ¹H, ¹³C and ⁷⁷Se NMR spectra of synthesized compounds and chiral HPLC chromatograms. See DOI: 10.1039/c5ra06147d

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