Highly Diastereoselective Synthesis of 2-(1-N-Boc-aminoalkyl)thiazole-5-carboxylates by Reduction of tert-Butylsulfinyl Ketimines

Abstract

Positional isomers of naturally occurring peptide subunits were synthesized via highly diastereoselective reduction of tert-butylsulfinyl ketimines as a key reaction. While NaBH₄ reduction of ketimines derived from 2-thiazolyl ketones afforded the (R_S,R)-isomer with moderate diastereoselectivity, L-Selectride^® reduction afforded the (R_S,S)-isomer as the sole product. In contrast, ketimines derived from tert-butyl 2-thiazolyl ketone afforded the (R_S,R)-isomer with low diastereoselectivity by both NaBH₄ and L-Selectride^® reduction. Stereochemistry of the reaction was discussed based on calculation of the conformational energies for ketimines.

A variety of macrocyclic peptides containing thiazole rings have been isolated from nature.^1–7) Thiazole-containing peptides exhibit interesting biological activity, such as cytotoxicity, antimalarial activity, and antiviral activity. The thiazole moiety is produced by intramolecular condensation of the thiol group in cysteine and the neighboring carbonyl group. Therefore, the substituents on naturally occurring thiazoles exist at the C2 and C4 positions.

As a result, all nitrogen atoms in 2,4-substituted azole rings orient inside the macrocyclic peptides. We are interested in incorporating 2,5-positional isomers of thiazole amino acid units into bioactive thiazole-containing macrocyclic peptides with respect to their effect on the biological activity and pharmacokinetic properties, since the role of heteroatoms in azole rings in recognizing target biomolecules is not clear (Fig. 1). Although replacement of the thiazole in other heterocycles^8–11) and positional isomers of the oxazole unit^12–15) have been reported, there are few reports on the synthesis of positional isomers of the thiazole unit. The preceding method for synthesizing 2-(1-aminoalkyl)thiazole-5-carboxylates was restricted to (1) condensation of 2-chloro-3-oxopropanoate and thioamide derived from natural amino acids (Hantzsch thiazole synthesis)^16,17) and (2) alkylation of N-tert-butanesulfinyl aldimines with Grignard reagents.¹⁸⁾ The former chiral pool strategy depends on the structure of amino acids, and the latter method was restricted to tert-butyl ester, which are relatively stable to Grignard reagents. Therefore, the development of alternative methods with high stereoselectivity is still required to create a variety of amino acid units.

Fig. 1. Representatives of Thiazole-Containing Peptides and Amino Acid Units

Herein, we report a highly diastereoselective synthesis of 2,5-positional isomers of the thiazole unit based on reduction of N-tert-butanesulfinyl ketimines.

Results and Discussion

N-tert-Ketimines 8a–e were synthesized starting from commercially available 2-bromothiazole (1). A halogen−lithium exchange reaction of 1 followed by reaction with aldehydes afforded alcohols 2a–e (Chart 1).

Chart 1

After protection of 2a–e as triisopropylsilyl (TIPS) ethers, the C5 proton of thiazole was selectively deprotonated with t-BuLi in ether at −78°C, and the resulting lithium salt was quenched with N,N-dimethylformamide (DMF) to give aldehydes 4a–e in good yields. Then, the aldehydes were oxidized under Pinnick oxidation conditions (NaClO₂, NaH₂PO₄, 2-methyl-2-butene in t-BuOH/H₂O) to carboxylic acids, which were immediately converted to ethyl esters 5a–e. Ketones 7a–e were synthesized by deprotection of TIPS ether with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran (THF) followed by 2-hydroxy-2-azaadamantane (AZADOL^®) oxidation (AZADOL^®, NaOCl·5H₂O, n-Bu₄NHSO₄, CH₂Cl₂).¹⁹⁾ The homobenzylic alcohol 6c did not afford ketone 7c by AZADOL^® oxidation, but the desired 7c was obtained by Dess-Martin oxidation. Finally, condensation of ketones 7a–e with (R)-tert-butanesulfinamide was carried out using Ti(OEt)₄ in an appropriate solvent to afford (R)-N-tert-butanesulfinyl ketimines 8a–e.^20,21) It was shown by ¹H-NMR spectroscopy that all the ketimines exist as a single geometric isomer. We noted that only the t-Bu proton in ketimine 8e shifted by about 0.1 ppm upfield from those in ketimines 8a–d, which ranged from 1.33 to 1.35 ppm. Ellman reported that the steric effects of the two substituents on sulfinyl ketimines control the ratio of geometric isomers.²¹⁾ We speculated that ketimines 8a–d exist as (E)-isomers. On the other hand, ketimine 8e would form as a (Z)-isomer. The upfield shift observed in 8e would be caused by the shielding effect of the thiazole ring.²²⁾ This speculation was supported by molecular orbital calculations described later. Suna and colleagues reported a similar change in geometry in aryl tert-butyl N-tert-butylsulfinyl ketimines.^23,24)

The reduction of (R)-N-tert-butanesulfinyl ketimines was investigated. On treatment with NaBH₄ at −78°C, ketimine 8a was reduced to give tert-butanesulfinamide (R_S,R)-9a with 4 : 1 diastereomeric ratio (dr) in 46% yield (Table 1, entry 1). The addition of Lewis acid did not improve the dr (entries 2–4). These results are in sharp contrast with that for the sulfinyl ketimine prepared from acetophenone, which showed higher diastereoselectivity as a result of NaBH₄ reduction. Since reduction of sulfinyl ketimines with NaBH₄ was reported to proceed diastereoselectively via coordination of the sulfinyl oxygen to the reducing agent, the existence of heteroatoms in the thiazole moiety presumably disturbs the coordination of the reducing agent, causing a decrease in diastereoselectivity.

Table 1. Effect of Lewis Acid on Diastereoselective Reduction of N-tert-Butanesulfinyl Ketimine 8a with NaBH₄^a)

Entry	Additive	Yield (%)b)	drc)
1	None	46	4 : 1
2	ZnBr2	93	3 : 1
3	Ti(OEt)4	95	4 : 1
4	MgBr2	21	4 : 1

a) Reaction was carried out with sulfinyl ketimine (1 equiv.) and NaBH₄ (4 equiv.) in THF at −78°C for 1 h. b) Isolated yield. c) Determined from ¹H-NMR spectroscopic data.

Next, we examined the reduction of sulfinyl ketimine 8a with L-Selectride^®, which shows reversal of diastereofacial selectivity via a non-chelated open transition state.²⁵⁾ The results are shown in Table 2. To our delight, the diastereoselectivity was remarkably improved to give (R_S,S)-tert-butanesulfinamide (R_S,S)-9a in 94% yield as the sole product (entry 1). To examine the scope and limitations of L-Selectride^®, the reduction of ketimines bearing a thiazole substituent, compounds 8b−e with different substituents, was performed (entries 2–5). Except for 8e, the reaction proceeded with excellent diastereoselectivity, giving exclusively (R_S,S)-9b−d in good yields (67–89%).²⁶⁾ Chelucci et al. reported the reaction of N-tert-butanesulfinyl ketimines bearing a 2-pyridyl substituent instead of thiazole with L-Selectride^®.²⁷⁾ In the 2-pyridyl substrates, the diastereoselectivity decreased as the steric bulkiness of the other substituent increased. For instance, the diastereomeric ratio decreased to 88 : 12 with an i-Pr substituent. In sharp contrast, the diastereoselectivity of the 2-thiazole derivatives was not affected by the bulkiness of the other substituent except with t-Bu. It is noteworthy that ketimine 8d afforded a single isomer by L-Selectride^® reduction, although the cyclohexyl substituent has similar steric demand to the thiazole ring.

Table 2. Diastereoselective Reduction of N-tert-Butanesulfinyl Imines 8a–e with L-Selectride^®a)

Entry	Compound	R	Product	Yield (%)b)	De (%)c)
1	8a	Me	(RS,S)-9a	94	>98
2	8b	i-Pr	(RS,S)-9b	97	>98
3	8c	Bzl	(RS,S)-9c	67	>98
4	8d	c-Hex	(RS,S)-9d	87	>98
5	8ed)	t-Bu	(RS,S)-9e	0	—

a) Reaction was carried out with sulfinyl ketimine (1 equiv.) and L-Selectride^® (2 equiv.) in THF at −78°C for 0.5 h. b) Isolated yield. c) Determined from ¹H-NMR spectroscopic data. d) Geometry of C=N bond is assumed to be Z.

However, the reaction of compound 8e bearing a t-Bu substituent was sluggish due to reduction of the ester group. Therefore, we examined the reaction of sulfinyl imine 8f without an ester group to confirm the effect of the t-Bu group on diastereoselectivity with L-Selectride^® reduction (Chart 2). We found that the (R_S,R)-isomer of sulfinamide was obtained mainly with a low diastereomeric ratio. The result for 8f was significantly different from those for other sulfinyl ketimines 8a–d.

Chart 2

Removal of the N-tert-butanesulfinyl group was readily achieved on treatment with HCl (Chart 3).^28,29) The resulting amine was immediately protected with a tert-butoxycarbonyl (Boc) group to give amino acid units 10a–d with high enantiomeric excess.³⁰⁾

Chart 3

The stability of geometric isomers of tert-butylsulfinyl ketimines was evaluated by molecular orbital calculations (Chart 4).³¹⁾ The (E)-isomer of sulfinyl ketimines 8a–d was 4.5–7.4 kcal/mol more stable than the corresponding (Z)-isomer. On the other hand, the (Z)-isomers of 8e–f were more stable by 2.4–2.7 kcal/mol than the corresponding (E)-isomer. These results are consistent with the speculation arising from the above-mentioned chemical shift in the ¹H-NMR spectral data.

Chart 4. The Minimum Energy Conformations for 8b (Left) and 8e (Right) Based on Calculations Using Spartan’10 Software

Dihedral angles between two C=N bonds in (E)-8b and (Z)-8e were −169.10° and −72.37°, respectively.

In Suna’s substrates, the preference for the (E)-isomer was caused by intramolecular hydrogen bonding between imino (C=N) and ortho-amino (N–H) groups on the aromatic ring.^23,24) In our substrates, there are no intramolecular hydrogen bonds to stabilize (E)-conformers. The calculation results predict that conjugation between the thiazole and imino groups would be lost in the (Z)-isomers, presumably to avoid steric interaction between the tert-butyl sulfinyl group and the thiazole ring. Considering that ketimine 8d bears a cyclohexyl substituent with high steric demand, conjugation of the thiazole and the imine as well as the steric effects of the two substituents on the sulfinyl ketimines would be major factors in the preference for (E)-conformers in sulfinyl ketimines 8a–d. For substrates 8e–f, steric repulsion between the two t-Bu groups overwhelms the stabilization due to the conjugation.

In the (E)-conformers, the si-faces of ketimines 8a–d are shielded by a t-Bu group on the sulfinyl group. Reduction with L-Selectride^® occurs at the re-face to avoid steric repulsion. On the other hand, the t-Bu group on the chiral auxiliary in the (Z)-isomers of 8e–f shields the re-face of the C=N bond, causing reversal of diastereoselectivity. The observed low reactivity and moderate selectivity in 8e–f would be caused by both sides of the C=N plane being shielded by the two t-Bu substituents and the thiazole ring being twisted out of the C=N plane.

Conclusion

In conclusion, we have developed a novel synthesis of 2,5-substituted thiazole amino acid units using highly diastereoselective reduction of tert-butylsulfinyl ketimines. We found that reduction using L-Selectride^® is more effective with respect to high diastereoselectivity. The resulting peptide mimetics would be useful tools for synthesizing bioactive cyclic peptide analogues.

Experimental

General Information

Optical rotations were measured with a JASCO P-1020 digital polarimeter. The ¹H- and ¹³C-NMR spectra were recorded in CDCl₃ solution at 400 and 100 MHz, respectively, with a JEOL JNM-AL-400 or a JNM-ECZ-400S spectrometer. Chemical shifts of ¹H-NMR are expressed in ppm downfield from tetramethylsilane as an internal standard (δ=0). Chemical shifts of ¹³C-NMR are expressed as ppm using CDCl₃ as an internal standard (δ=77). The following abbreviations are used: broad=br, singlet=s, doublet=d, triplet=t, quartet=q, and multiplet=m. IR absorption spectra (FT: diffuse reflectance spectroscopy) were recorded with KBr powder with a JASCO FT-6300 IR spectrophotometer, and only noteworthy absorptions (cm⁻¹) are listed. Mass spectra were obtained with a JEOL GC-Mate II mass spectrometer. Purification of the crude products was carried out by flash column chromatography. Fuji Silysia Silica Gel BW-300 was used as an adsorbent for column chromatography. For preparative TLC (PTLC), Silica gel 60F₂₅₄ (Merck) was used. All air- or moisture-sensitive reactions were carried out in flame-dried glassware in an atmosphere of Ar or N₂. All organic extracts were dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure with a rotary evaporator, unless otherwise stated.

General procedures and characterization data for representative compounds are described. The data for other compounds are provided in the supplementary materials, which can be found as an attachment.

General Procedure for Addition of 2-Lithiothiazole to Aldehyde

Synthesis of 2-Methyl-1-(thiazol-2-yl)propan-1-ol (2b)

n-BuLi (19.8 mL, 1.65 M in n-hexane, 32.7 mmol) was added dropwise to a solution of 2-bromothiazole (1) (2.70 mL, 30.5 mmol) in dry diethyl ether (50 mL) with stirring at −78°C in Ar. The mixture was stirred at the same temperature for 0.5 h and then a solution of isobutyraldehyde (2.79 mL, 30.5 mmol) in dry diethyl ether (50 mL) was added. After 1 h, the reaction mixture was poured into saturated aq NH₄Cl (5 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (50 mL), then with brine (50 mL), and dried over MgSO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 3 : 1) to give 2b (4.60 g, 96%) as a pale yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 2.19 (m, 1H), 3.19 (d, J=5.1 Hz, 1H), 4.81 (t, J=5.1 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.72 (d, J=3.4 Hz, 1H); ¹³C-NMR δ: 16.70, 18.61, 34.90, 75.92, 118.51, 141.45, 176.27; IR (KBr) cm⁻¹: 3244, 1503; MS (FAB) m/z: 158 [M+H]⁺; high resolution (HR)-MS (FAB) m/z: Calcd for C₇H₁₂NOS: 158.0640. Found: 158.0641 [M+H]⁺.

General Procedure for TIPS Protection of Alcohol

Synthesis of 2-[2-Methyl-1-[(triisopropylsilyl)oxy]propyl]thiazole (3b)

TIPSOTf (7.25 mL, 27.0 mmol) was added to a solution of alcohol 2b (4.04 g, 25.7 mmol) and 2,6-lutidine (3.29 g, 28.3 mmol) in dry CH₂Cl₂ (64 mL) with stirring at 0°C in Ar. The mixture was stirred at room temperature (r.t.) for 2 h. The reaction mixture was diluted with CHCl₃ (50 mL), washed with 1 M aq HCl (2×30 mL), H₂O (30 mL), and brine (30 mL), and dried over MgSO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 20 : 1) to give 3b (7.86 g, 98%) as a colorless oil. ¹H-NMR δ: 0.86 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.94–1.15 (m, 24H), 2.06–2.17 (m, 1H), 5.04 (d, J=4.9 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H); ¹³C-NMR δ: 12.47 (3C), 16.93, 17.95 (3C), 17.96 (3C), 18.14, 36.23, 77.97, 118.40, 141.51, 175.12; IR (KBr) cm⁻¹: 3082, 1501; MS (FAB) m/z: 314 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₆H₃₂NOSSi: 314.1974. Found: 314.1965 [M+H]⁺.

General Procedure for C5-Selective Formylation of Thiazole

Synthesis of 2-[2-Methyl-1-[(triisopropylsilyl)oxy]propyl]thiazole-5-carbaldehyde (4b)

t-BuLi (7.27 mL, 1.65 M in n-pentane, 12.0 mmol) was added dropwise to a stirred solution of 3b (2.50 g, 8.00 mmol) in dry diethyl ether (40 mL) at −78°C in Ar. The mixture was stirred at the same temperature for 2 h and then dry DMF (3.10 mL, 40.0 mmol) was added to the mixture. After 0.5 h, the reaction mixture was poured into saturated aq NH₄Cl (10 mL) and water (100 mL). The ether layer was separated and the aqueous layer was extracted with ether (2×100 mL). The combined organic layer was washed with brine (100 mL) and dried over MgSO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 10 : 1) to give 4b (2.63 g, 97%) as a pale yellow oil. ¹H-NMR δ: 0.88 (d, J=6.8 Hz, 3H), 1.00–1.17 (m, 24H), 2.17 (m, 1H), 5.06 (d, J=4.4 Hz, 1H), 8.30 (s, 1H), 10.01 (s, 1H); ¹³C-NMR δ: 12.46 (3C), 16.61, 17.81, 17.94 (3C), 17.98 (3C), 36.07, 78.00, 138.80, 150.88, 182.41, 184.58; IR (KBr) cm⁻¹: 3079, 1682, 1513; MS (FAB) m/z: 342 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₇H₃₂NO₂SSi: 342.1923. Found: 342.1928 [M+H]⁺.

General Procedure for Pinnick Oxidation and Esterification

Synthesis of Ethyl 2-[2-Methyl-1-[(triisopropylsilyl)oxy]propyl]thiazole-5-carboxylate (5b)

To a solution of aldehyde 4b (9.24 g, 27.1 mmol) and 2-methyl-2-butene (22.9 mL, 216.4 mmol) in THF/t-BuOH (1 : 1, 400 mL) was added a solution of NaH₂PO₄ (16.9 g, 108.2 mmol) and NaClO₂ (4.89 g, 54.1 mmol) dissolved in water (67 mL). After 2 h at r.t., the reaction mixture was poured into saturated aq NH₄Cl (200 mL). The organic phase was separated and the water phase was extracted with EtOAc (2×200 mL). The combined organic phase was washed with brine (200 mL), and dried over Na₂SO₄. After removal of the solvent in vacuo, the residue was dissolved in dry CH₃CN (200 mL). Ethyl iodide (6.49 mL, 81.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (12.1 mL, 81.2 mmol) were then added, and the mixture was stirred at r.t. for 16 h and then diluted with EtOAc (30 mL). After evaporation of the reaction solvent, EtOAc (400 mL) and 1 M aq HCl (100 mL) were added to the residue. The organic phase was separated and the water phase was extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated aq NaHCO₃ (100 mL), then brine (100 mL), and dried over MgSO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 20 : 1) to give 5b (8.33 g, 80%) as a pale yellow oil. ¹H-NMR δ: 0.87 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.95–1.20 (m, 21H), 1.39 (t, J=7.0 Hz, 3H), 2.14 (m, 1H), 4.36 (q, J=7.1 Hz, 1H), 4.37 (q, J=7.2 Hz, 1H), 5.02 (d, J=4.6 Hz, 1H), 8.28 (s, 1H); ¹³C-NMR δ: 12.45 (3C), 14.28, 16.61, 17.90, 17.96 (3C), 17.99 (3C), 36.07, 61.46, 77.96, 129.03, 147.44, 161.71, 181.47; IR (KBr) cm⁻¹: 3094, 1719, 1521; MS (FAB) m/z: 386 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₉H₃₆NO₃SSi: 386.2185. Found: 386.2168 [M+H]⁺.

General Procedure for Deprotection of TIPS Ether

Synthesis of Ethyl 2-(1-Hydroxy-2-methylpropyl)thiazole-5-carboxylate (6b)

TBAF (9.00 mL, 1 M in THF) was added dropwise to a solution of 5b (3.04 g, 7.88 mmol) in dry THF (118 mL). The mixture was stirred at r.t. for 0.5 h. The reaction mixture was poured into saturated aq NH₄Cl (30 mL) and water (30 mL). The organic phase was separated and the water phase was extracted with EtOAc (3×55 mL). The combined organic phase was washed with brine (170 mL), and dried over MgSO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 3 : 1 to 1 : 2) to give 6b (1.76 g, 97%) as colorless needles. mp 49°C−50°C; ¹H-NMR δ: 0.92 (d, J=6.6 Hz, 3H), 1.02 (d, J=7.1 Hz, 3H), 1.38 (t, J=7.1 Hz, 3H), 2.22 (m, 1H), 3.65 (m, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.80 (t, J=4.4 Hz, 1H), 8.28 (s, 1H); ¹³C-NMR δ: 14.21, 16.16, 18.73, 34.94, 61.60, 76.56, 129.26, 147.69, 161.45, 181.09; IR (KBr) cm⁻¹: 3292, 1717, 1523; MS (FAB) m/z: 230 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₀H₁₆NO₃S: 230.0851. Found: 230.0869 [M+H]⁺.

General Procedure for AZADOL^® Oxidation

Synthesis of Ethyl 2-Isobutyrylthiazole-5-carboxylate (7b)

NaOCl·5H₂O (921 mg, 5.6 mmol) was added to a solution of 6b (917 mg, 4.0 mmol), AZADOL^® (6.1 mg, 0.04 mmol), and n-Bu₄NHSO₄ (68 mg, 0.2 mmol) in CH₂Cl₂ (40 mL) with stirring at r.t. After stirring at r.t. for 0.5 h, the mixture was poured into saturated aq Na₂SO₃ (25 mL). The organic layer was separated and the aqueous layer was extracted with CHCl₃ (3×25 mL). The combined organic layer was washed with brine (50 mL) and dried over Na₂SO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 20 : 1) to give 7b (878 mg, 97%) as a colorless oil. ¹H-NMR δ: 1.28 (d, J=6.8 Hz, 6H), 1.40 (t, J=7.0 Hz, 3H), 3.81 (m, 1H), 4.41 (q, J=7.0 Hz, 2H), 8.50 (s, 1H); ¹³C-NMR δ: 14.16, 18.41 (2C), 36.22, 62.13, 135.11, 149.03, 160.78, 170.18, 197.78; IR (KBr) cm⁻¹: 1723, 1688, 1505; MS (FAB) m/z: 244 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₀H₁₄NO₃S: 228.0694. Found: 228.0696 [M+H]⁺.

Dess–Martin Oxidation of 6c

Synthesis of Ethyl 2-(2-Phenylacetyl)thiazole-5-carboxylate (7c)

Dess−Martin periodinane (891 mg, 2.1 mmol) was added to a solution of 6c (416 mg, 1.5 mmol) in CH₂Cl₂ (7.5 mL) with stirring at r.t. in Ar. After stirring at r.t. for 0.5 h, the reaction mixture was poured into 10% aq Na₂S₂O₃ (20 mL) and 10% aq NaHCO₃ (20 mL). The organic layer was separated and the aqueous layer was extracted with CHCl₃ (2×40 mL). The combined organic layer was washed with brine (40 mL) and dried over MgSO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 10 : 1) to give 7c (403 mg, 98%) as a colorless oil. ¹H-NMR δ: 1.39 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz, 2H), 4.44 (s, 2H), 7.20–7.40 (m, 5H), 8.53 (s, 1H); ¹³C-NMR δ: 14.16, 44.66, 62.21, 127.20, 128.63 (2C), 129.83 (2C), 132.97, 135.65, 149.07, 160.68, 170.00, 191.16; IR (KBr) cm⁻¹: 1720, 1692, 1502; MS (FAB) m/z: 276 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₄H₁₄NO₃S: 276.0694. Found: 276.0693 [M+H]⁺.

General Procedure for Condensation of (R)-tert-Butanesulfinamide

Synthesis of Ethyl (R_S,E)-2-[1-[(tert-Butylsulfinyl)imino]-2-methylpropyl]thiazole-5-carboxylate (8b)

Ti(OEt)₄ (0.31 mL, 1.5 mmol) was added to a solution of 7b (114 mg, 0.50 mmol) and (R)-tert-butanesulfinamide (91 mg, 0.75 mmol) in dry diethyl ether (3.6 mL) with stirring at r.t. in Ar. The mixture was heated at reflux for 22 h and then diluted with ether (10 mL). Saturated aq NaHCO₃ (2 mL) was added to the mixture dropwise with vigorous stirring at 0°C. The resulting slurry was filtered through a plug of Celite^® and the filter cake was washed with ether (100 mL). The filtrate was dried over Na₂SO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 10 : 1) to give 8b (161 mg, 98%) as a yellow oil. [α]_D²⁵ +268.2 (c 0.75, CHCl₃); ¹H-NMR δ: 1.34 (s, 9H), 1.40 (t, J=7.1 Hz, 3H), 1.47 (d, J=7.1 Hz, 3H), 1.51 (d, J=7.1 Hz, 3H), 4.12 (br s, 1H), 4.39 (q, J=7.1 Hz, 2H), 8.43 (s, 1H); ¹³C-NMR δ: 14.19, 19.97, 20.06, 22.65 (3C), 33.53, 58.67, 61.88, 132.70, 148.67, 161.00, 172.27, 177.77; IR (KBr) cm⁻¹: 1720, 1586, 1510; MS (FAB) m/z: 331 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₄H₂₃N₂O₃S₂: 331.1150. Found: 331.1149 [M+H]⁺.

General Procedure for Reduction of Sulfinyl Ketimine with L-Selectride^®

Synthesis of Ethyl 2-[(R_S,S)-1-(1,1-Dimethylethylsulfinamido)-2-methylpropyl]thiazole-5-carboxylate [(R_S,S)-9b]

L-Selectride^® (0.60 mL, 1 M in THF, 0.60 mmol) was added to a solution of 8b (99 mg, 0.30 mmol) in THF (6 mL) at −78°C in Ar. After 0.5 h, EtOH (0.6 mL) was added at −78°C to the mixture. Then, the whole was partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layer was washed with brine (20 mL), and dried over Na₂SO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 2 : 1 to 1 : 1) to give 9b (97 mg, 97%) as colorless needles. mp 48°C−49°C; [α]_D²⁵–57.78 (c 0.89, CHCl₃); ¹H-NMR δ: 0.97 (d, J=6.9 Hz, 3H), 1.05 (d, J=6.9 Hz, 3H), 1.29 (s, 9H), 1.38 (t, J=7.1 Hz, 3H), 2.40 (m, 1H), 3.77 (d, J=5.0 Hz, 1H), 4.37 (qd, J=7.1, 1.3 Hz, 2H), 4.63 (t, J=5.0 Hz, 1H), 8.33 (s, 1H); ¹³C-NMR δ: 14.24, 17.61, 18.77, 22.56 (3C), 34.39, 56.51, 61.57, 63.25, 129.52, 148.38, 161.35, 179.21; IR (KBr) cm⁻¹: 3212, 1715, 1520; MS (FAB) m/z: 333 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₄H₂₅N₂O₃S₂: 333.1307. Found: 333.1307 [M+H]⁺.

General Procedure for N-Boc Protection

Synthesis of Ethyl (S)-2-[1-[(tert-Butoxycarbonyl)amino]-2-methylpropyl]thiazole-5-carboxylate (10b)

HCl (4 M) in AcOEt (2 mL) was added to a solution of 9b (133 mg, 0.40 mmol) in MeOH (2 mL) with stirring at 0°C. The mixture was stirred at r.t. for 0.5 h. After evaporation of the solvent, MeOH (2 mL) was added to the residue. After removal of the solvent in vacuo, the residue was dissolved in dry 1,4-dioxane (4 mL). Et₃N (0.067 mL, 0.48 mmol) and Boc₂O (105 mg, 0.48 mmol) were then added to the mixture and stirring was continued at r.t. for 2 h. The solvent was evaporated and then partitioned between EtOAc (15 mL) and saturated aq NaHCO₃ (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layer was washed with brine (10 mL) and dried over Na₂SO₄. After removal of the solvent in vacuo, the crude product was purified by column chromatography on SiO₂ (hexane/EtOAc, 10 : 1) to give 10b (106 mg, 81%) as colorless needles. mp 60–61°C. [α]_D²⁷–28.84 (c 0.51, CHCl₃); ¹H-NMR δ: 0.92 (d, J=6.9 Hz, 3H), 0.99 (d, J=6.9 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 1.46 (s, 9H), 2.38 (m, 1H), 4.36 (q, J=7.2 Hz, 2H), 4.90 (dd, J=8.6, 5.3 Hz, 1H), 5.36 (d, J=8.6 Hz, 1H), 8.31 (s, 1H); ¹³C-NMR δ: 14.18, 17.20, 19.14, 28.20 (3C), 33.17, 58.10, 61.46, 80.05, 128.87, 148.23, 155.32, 161.22, 178.33; IR (KBr) cm⁻¹: 3308, 1717, 1522; MS (FAB) m/z: 329 [M+H]⁺; HR-MS (FAB) m/z: Calcd for C₁₅H₂₅N₂O₄S: 329.1535. Found: 329.1534 [M+H]⁺.

Acknowledgment

This study was supported by the Osaka Ohtani University Research Fund (Pharmaceutical Sciences).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials (details of computations).

References and Notes

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