Studies Toward the Total Synthesis of Natalamycin A: Stereoselective Synthesis of the C9

Abstract

Toward the total synthesis of natalamycin A, we have synthesized the C9-C21 segment corresponding to the northwestern part of the natural product. Key features of this synthesis were an asymmetric α-chlorination of an aldehyde using MacMillan's catalyst and stereoselective assembly of three contiguous stereocenters via a butenolide intermediate.

Keywords

natalamycin A ansamycin stereoselective synthesis asymmetric chlorination butenolide

Introduction

Natalamycin A (1) was isolated from Streptomyces sp. M56 along with other ansamycins including geldanamycin (2) and reblastatin (3) by Clardy et al. in 2014 (Figure 1).¹ Structurally, natalamycin A (1) is closely related to geldanamycin (2) but has an additional eight-membered 1,4-oxazocine moiety fused to a benzene ring.

Figure 1.

Structures of natalamycin A (1), geldanamycin (2), and reblastatin (3).

Geldanamycin (2), a representative ansamycin antibiotic, exhibits potent antitumor activity due to its strong inhibition of Hsp90,^2–5 making it an enticing target compound for synthetic organic chemists. Indeed, five total syntheses of 2 have been reported to date.^6–10 Natalamycin A (1) has been reported to show moderate antifungal and antimicrobial activities, but further detailed biological evaluations are eagerly awaited. Thus, we began synthetic studies on natalamycin A (1). This article reports a stereoselective synthesis of the C9-C21 segment containing three contiguous stereocenters corresponding to the northwestern part of natalamycin A (1) by a sequence involving an asymmetric chlorination and appropriate stereoselective functionalization of a butenolide intermediate.

Results and Discussion

Our retrosynthetic analysis of natalamycin A (1) is shown in Scheme 1. Toward the key intermediate 4 in the hypothetical biosynthetic pathway of natalamycin A (1) proposed by Clardy,¹ the C9–C21 segment 5 was set as our initial synthetic target. Segment 5 would be obtained from butenolide 6, which would be derived from aldehyde 7 via an asymmetric α-functionalization. Aldehyde 7 was retrosynthetically disconnected into protected hydroquinone 8¹¹ and optically active aldehyde 9.¹²

Scheme 1.

Retrosynthetic analysis of natalamycin A (1).

The two known compounds 8¹¹ and 9¹² were initially coupled to give an inseparable diastereomeric mixture of benzyl alcohol 10 in 98% yield,¹³ in which the hydroxy group was then efficiently reduced with Et₃SiH and CF₃CO₂H to afford 11 in 98% yield (Scheme 2).¹⁴ Removal of the benzyl group (12, 96%), bromination of the benzene ring (13, quant.), and subsequent oxidation of primary alcohol 13 with Dess–Martin periodinane furnished aldehyde 7 in 95% yield.

Scheme 2.

Synthesis of aldehyde 7.

Our attempt to apply the well-known proline-catalyzed α-aminooxylation^15,16 to aldehyde 7 gave a mixture of compounds containing the desired product (data not shown). Thus, α-chlorination was next employed as an alternative for asymmetric α-functionalization. Combinations of a chlorinating reagent and a catalyst were screened, and the results are summarized in Table 1. Hexachloroquinone 15 or N-chlorosuccinimide (NCS) with L-proline catalyst resulted in poor stereoselectivity, despite full consumption of the starting aldehyde 7 (entries 1 and 2).¹⁷ The Hayashi–Jørgensen catalyst with NCS showed slightly improved diastereoselectivity (entry 3).¹⁸ With MacMillan's catalyst and 15 in CHCl₃, diastereoselectivity was greatly improved (dr 10:1), affording 14 quantitatively (entry 4).¹⁹ Acetone was not effective as the solvent in this reagent/catalyst system (entry 5).¹⁹

Table 1.

Asymmetric α-chlorination of Aldehyde 7.

Entry	Reagent	Catalyst	Solvent	Temp.	Time (h)	Conv. (%)^a	dr^a
1		L-proline	CHCl₃	−30 °C to rt	30	>95	1:1
2	NCS	L-proline	CHCl₃	4 °C to 10 °C	29	>95	2:1
3	NCS		CHCl₃	0 °C	17	>95	3:1
4	15		CHCl₃	−30 °C	17	>95	10:1
5	15		Acetone	−30 °C	6	66	3.5:1

^aDetermined by ¹H NMR analysis of the crude product.

With good α-chlorinating conditions, our next task was to form butenolide 6 from α-chloroaldehyde 14 (Scheme 3). Reduction of 14 with NaBH₄ provided alcohol 16 (quant. from 7), which could be smoothly converted into epoxide 17 (85%) by treatment with t-BuOK.²⁰ Mioskowski's methylenation²¹ of 17 quantitatively gave allylic alcohol 18,²² and acylation of 18 by methacryloyl chloride²³ was followed by ring-closing metathesis using the second-generation Grubbs catalyst to obtain the desired butenolide 6 in 73% yield.²⁴ Butenolide 6 was stable against oxidation conditions such as epoxidation, dihydroxylation, or 1,4-addition of oxygen functionality. To our delight, oxidation of 6 with OsO₄ and pyridine formed a cyclic osmate ester/pyridine complex, which was immediately reduced by NaHSO₃ to give diol 19 in high yield and stereoselectivity.^25–27 Finally, stereoselective removal of the tertiary hydroxy group in 19 was achieved by SmI₂-mediated reduction,^28,29 and TBS protection of the remaining secondary alcohol led to the C9-C21 segment 5 in 79% yield.

Scheme 3.

Completion of the synthesis of the C9–C21 segment 5.

Conclusion

We have successfully synthesized the C9-C21 segment with three contiguous stereocenters of natalamycin A (1), via asymmetric α-chlorination of an aldehyde followed by formation and stereoselective functionalization of a butenolide. Further investigation toward the hypothetical biosynthetic precursor 4 of 1 is in progress, and the total synthesis of 1 in our laboratory will be reported in due course.

Materials and Methods

General

¹H NMR spectra were measured at 400 MHz (JNM-ECZL400S, JEOL). Chemical shifts are expressed in ppm relative to tetramethylsilane (δ = 0) as an internal standard (CDCl₃). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. ¹³C NMR spectra were measured at 100 MHz (JNM-ECZL400S, JEOL). The chemical shifts are reported in ppm, relative to the central line of the triplet at 77.0 ppm for CDCl₃. Infrared spectra were measured on an infrared spectrometer (IRAffinity-1, Shimadzu) and are reported in wavenumbers (cm⁻¹). High-resolution mass spectra were obtained using a mass spectrometer (JMS-T100LP, JEOL). Optical rotations were measured on a polarimeter (P-2200, JASCO) using a 100-mm-path-length cell. Column chromatography was carried out on silica gel (40-100 mesh). Analytical thin-layer chromatography was performed using 0.25 mm silica gel 60-F plates.

Experimental Procedures and Characterization Data

(S)-5-(Benzyloxy)-2-methylpentanal (9)

To a stirred solution of (S)-5-(benzyloxy)-2-methylpentan-1-ol (50 mg, 0.24 mmol) in THF (3.0 mL) was added Dess–Martin periodinane (123 mg, 0.290 mmol) at 0 °C, and the mixture was stirred for 18 h at the room temperature. The reaction was quenched by adding saturated aqueous NaHCO₃ (1.5 mL), 5% aqueous Na₂S₂O₃ (1.5 mL), and H₂O (3.0 mL), and the mixture was extracted with Et₂O twice. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The crude product was used for the next reaction without further purification.

(1S,2S)-5-(Benzyloxy)-1-(3,6-diisopropoxy-2-methoxyphenyl)-2-methylpentan-1-ol and (1R,2S)-5-(benzyloxy)-1-(3,6-diisopropoxy-2-methoxyphenyl)-2-methylpentan-1-ol (10)

A solution of 2-methoxy-1,4-diisopropoxy-2-methoxybenzene 8 (135 mg, 0.602 mmol) and freshly distilled N,N,N’,N’-tetramethylethylenediamine (TMEDA; 26 μL, 0.17 mmol) in Et₂O (5.0 mL) was degassed by freeze-thawing. After cooling to 0 °C, n-BuLi (1.52 M in hexanes, 0.40 mL, 0.61 mmol) was slowly added, and the mixture was stirred for 30 min. The mixture was allowed to warm to room temperature and stirred for 3 h. Then, a solution of 9 in Et₂O (1.5 mL) was added, and the mixture was stirred for 14 h. The reaction was quenched by adding saturated aqueous NH₄Cl (10 mL) and extracted with Et₂O twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 19:1) to afford 10 (101 mg, 98%, 1:1 diastereomeric mixture) as a colorless oil. ${[α]}_{D}^{24}$ −9.1 (c 0.20, CHCl₃); IR (KBr) 3567, 2976, 2365, 1698, 1653, 1636, 1542, 1508, 1497, 1226, 1054, 884, 757, 737 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.70 and 1.06 (3H, d, J = 6.4 Hz), 1.22-1.38 (14H, m), 1.42-2.02 (3H, m), 3.37 and 3.51 (2H, t, J = 6.4 Hz), 3.69 and 3.91 (1H, d, J = 12.0 Hz), 3.86 (3H, s), 4.39 and 4.51 (2H, m), 4.42 and 4.51 (2H, s), 4.69 and 4.76 (1H, dd, J = 8.0, 12.0 Hz), 6.52 (1H, d, J = 8.8 Hz), 6.74 (1H, d, J = 8.8 Hz), 7.20-7.40 (5H, m); ¹³C NMR (100 MHz, CDCl₃) δ 16.1 and 16.3, 22.2 and 22.3 (2C), 22.4 and 22.5 (2C), 27.6 and 27.7, 29.8 and 29.9, 39.8, 60.8, 70.1, 70.9 and 71.2, 71.9, 72.9 and 73.0, 73.3 and 73.4, 107.6 and 107.7, 115.95 and 116.03, 127.6, 127.7, 127.78 and 127.82 (2C), 128.5 (2C), 138.9, 144.5, 149.4 and 149.5, 150.0 and 150.1; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₆H₃₈O₅Na: 453.2611, found 453.2614.

(S)-2-(5-(Benzyloxy)-2-methylpentyl)-1,4-diisopropoxy-3-methoxybenzene (11)

To a stirred mixture of 10 (2.51 g, 5.84 mmol) and Et₃SiH (2.8 mL, 18 mmol) was added CF₃CO₂H (18 mL) at room temperature, and the mixture was stirred for 1 h. After adding 1 M aqueous NaOH (265 mL), the mixture was extracted with Et₂O twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 19:1) to afford 11 (2.36 g, 98%) as a colorless oil. ${[α]}_{D}^{24}$ −7.8 (c 0.10, CHCl₃); IR (KBr) 2974, 2931, 1588, 1478, 1420, 1371, 1251, 1119, 979, 790, 756 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.83 (3H, d, J = 6.8 Hz), 1.22-1.44 (2H, m), 1.29 (6H, d, J = 6.0 Hz), 1.32 (3H, d, J = 6.4 Hz), 1.32 (3H, d, J = 6.0 Hz), 1.62-1.89 (3H, m), 2.43 (1H, dd, J = 8.4, 12.4 Hz), 2.61 (1H, dd, J = 6.0, 12.4 Hz), 3.46 (2H, t, J = 6.8 Hz), 3.80 (3H, s), 4.37-4.43 (2H, m), 4.49 (2H, s), 6.48 (1H, d, J = 8.8 Hz), 6.69 (1H, d, J = 8.8 Hz), 7.22-7.40 (5H, m); ¹³C NMR (100 MHz, CDCl₃) δ 19.9, 22.35, 22.40, 22.43, 22.44, 27.7, 31.4, 33.5, 33.8, 60.4, 70.0, 71.2, 71.7, 73.0, 107.6, 114.6, 125.8, 127.5, 127.8 (2C), 128.4 (2C), 138.9, 144.5, 150.3, 151.1; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₆H₃₈O₄Na: 437.2662, found 437.2664.

(S)-5-(3,6-Diisopropoxy-2-methoxyphenyl)-4-methylpentan-1-ol (12)

To a stirred solution of 11 (2.31 g, 5.58 mmol) in EtOH (50 mL) was added 10% Pd/C (463 mg), and the reaction mixture was stirred under a hydrogen atmosphere at 35 °C for 12 h. The mixture was filtered through a pad of Celite, and the residue was washed with EtOAc. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 17:3) to afford 12 (1.68 g, 96%) as a pale-yellow oil. ${[α]}_{D}^{24}$ −2.4 (c 0.10, CHCl₃); IR (KBr) 3447, 2088, 1637, 1477, 1252, 1117, 1061 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.85 (3H, d, J = 6.8 Hz), 1.17-1.41 (2H, m), 1.28 (3H, d, J = 6.0 Hz), 1.29 (3H, d, J = 6.1 Hz), 1.31 (6H, d, J = 6.0 Hz), 1.50-1.86 (3H, m), 1.75 (1H, br s), 2.45 (1H, dd, J = 8.0, 12.4 Hz), 2.60 (1H, dd, J = 6.0, 12.4 Hz), 3.56-3.65 (2H, m), 3.81 (3H, s), 4.32-4.45 (2H, m), 6.49 (1H, d, J = 8.8 Hz), 6.69 (1H, d, J = 8.8 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 20.0, 22.3, 22.4 (3C), 30.5, 31.3, 33.1, 33.4, 60.4, 63.5, 70.1, 71.8, 107.9, 114.6, 125.7, 144.5, 150.2, 151.0; HRMS (ESI) m/z: [M + Na⁺] calcd for C₁₉H₃₂O₄Na: 347.2193, found 347.2191.

(S)-5-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-4-methylpentan-1-ol (13)

To a stirred solution of 12 (1.65 g, 5.09 mmol) in DMF (50 mL) was added N-bromosuccinimide (NBS; 1.09 g, 6.11 mmol) at 0 °C. After being stirred for 17 h at the same temperature, the mixture was diluted with H₂O (50 mL) and extracted with Et₂O twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 17:1) to afford 13 (2.05 g, quant.) as a pale-yellow oil. ${[α]}_{D}^{24}$ −5.3 (c 0.10, CHCl₃); IR (KBr) 3314, 2926, 2854, 1464, 1378, 1268, 1230, 1172, 1139, 1106, 1029, 966, 913 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.83 (3H, d, J = 6.8 Hz), 1.17-1.27 (2H, m), 1.30 (3H, d, J = 6.0 Hz), 1.31 (3H, d, J = 6.4 Hz), 1.36 (6H, d, J = 6.0 Hz), 1.48-1.91 (3H, m), 1.75 (1H, br s), 2.51 (1H, dd, J = 8.0, 12.4 Hz), 2.66 (1H, dd, J = 6.4, 12.4 Hz), 3.61 (1H, dt, J = 10.4, 6.4 Hz), 3.65 (1H, dt, J = 10.4, 6.4 Hz), 3.81 (3H, s), 4.40-4.51 (2H, m), 6.96 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 19.8, 22.3 (2C), 22.5 (2C), 30.2, 32.8, 33.0, 33.4, 60.6, 63.4, 71.5, 76.0, 111.2, 117.7, 131.7, 147.4, 147.6, 148.6; HRMS (ESI) m/z: [M + Na⁺] calcd for C₁₉H₃₁BrO₄Na: 425.1298, found 425.1294.

(S)-5-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-4-methylpentanal (7)

To a stirred solution of 13 (200 mg, 0.498 mmol) in CH₂Cl₂ (10 mL) was added Dess–Martin periodinane (254 mg, 0.599 mmol) at 0 °C, and the mixture was stirred for 1 h at the same temperature. The reaction was quenched by adding saturated aqueous NaHCO₃ (5.0 mL) and 5% aqueous Na₂S₂O₃ (5.0 mL), and the mixture was extracted with EtOAc twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 17:1) to afford 7 (191 mg, 95%) as a colorless oil. ${[α]}_{D}^{24}$ −3.5 (c 0.10, CHCl₃); IR (KBr) 2975, 2931, 2717, 1465, 1436, 1382, 1230, 1139, 1105, 844, 783 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.83 (3H, d, J = 6.4 Hz), 1.30 (6H, d, J = 6.4 Hz), 1.34 (6H, d, J = 6.4 Hz), 1.42-1.57 (1H, m), 1.59-1.70 (1H, m), 1.77-1.89 (1H, app octet, J = 6.4 Hz), 2.34-2.57 (2H, m), 2.53 (1H, dd, J = 8.0, 12.8 Hz), 2.64 (1H, dd, J = 6.4, 12.8 Hz), 3.81 (3H, s), 4.40-4.50 (2H, m), 6.96 (1H, s), 9.74 (1H, t, J = 2.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 19.6, 22.3 (2C), 22.6 (2C), 29.0, 32.8, 33.4, 41.9, 60.6, 71.6, 76.0, 111.1, 117.8, 131.1, 147.3, 147.6, 148.6, 203.4; HRMS (ESI) m/z: [M + Na⁺] calcd for C₁₉H₂₉BrO₄Na: 423.1141, found 423.1141.

(2R,4R)-5-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-2-chloro-4-methylpentanal (14)

To a stirred solution of 7 (1.81 g, 4.50 mmol) in CHCl₃ (25 mL) was added (R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one trifluoroacetic salt (74.8 mg, 0.225 mmol) at room temperature, and the mixture was cooled to −30 °C. After stirring for 15 min, 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one (15, 1.62 g, 5.40 mmol) was added, and the mixture was stirred for 17 h at the same temperature, and then it was carefully concentrated in vacuo at 0 °C. Crude chlorinated aldehyde 14 was used for the next reaction without further purification.

(2R,4R)-5-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-2-chloro-4-methylpentan-1-ol (16)

To a stirred solution of aldehyde 14 in EtOH (45 mL) was added NaBH₄ (204 mg, 5.40 mmol) at 0 °C, and the mixture was stirred for 1.5 h at the same temperature. After the addition of more NaBH₄ (204 mg, 5.40 mmol), stirring was continued for 1 h. To the reaction mixture, saturated aqueous NH₄Cl (50 mL) was carefully added, and the mixture was extracted with Et₂O twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 9:1) to afford 16 (1.97 g, quant. from 7) as a pale orange oil. ${[α]}_{D}^{24}$ +18.8 (c 0.10, CHCl₃); IR (KBr) 3440, 2925, 2854, 2089, 1464, 1437, 1230, 1105, 1027, 965, 909, 843, 783 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.83 (3H, d, J = 6.8 Hz), 1.29 (3H, d, J = 6.2 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.35 (6H, d, J = 6.0 Hz), 1.67 (1H, ddd, J = 6.4, 8.8, 14.4 Hz), 1.73 (1H, ddd, J = 5.6, 7.2, 14.4 Hz), 2.05-2.17 (1H, m), 2.21 (1H, br s), 2.50 (1H, dd, J = 8.8, 12.4 Hz), 2.71 (1H, dd, J = 5.6, 12.4 Hz), 3.63 (1H, dd, J = 7.2, 12.4 Hz), 3.77 (1H, dd, J = 3.6, 12.4 Hz), 3.83 (3H, s), 4.11 (1H, dddd, J = 3.6, 5.6, 7.2, 8.8 Hz), 4.41-4.51 (2H, m), 6.97 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 20.3, 22.5 (2C), 22.6 (2C), 30.8, 32.2, 42.3, 60.6, 63.6, 67.2, 71.6, 76.0, 111.1, 118.1, 130.5, 147.3, 147.6, 148.6; HRMS (ESI) m/z: [M + Na⁺] calcd for C₁₉H₃₀BrClO₄Na: 459.0908, found 459.0912.

(S)-2-((R)-3-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-2-methylpropyl)oxirane (17)

To a stirred solution of 16 (31 mg, 0.071 mmol) in THF (2.0 mL) was added t-BuOK (12 mg, 0.11 mmol) at 0 °C. After being stirred for 30 min at the same temperature, the mixture was warmed to room temperature and stirred for 12 h. The reaction was quenched by adding H₂O, and the mixture was extracted with Et₂O twice. The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 19:1) to afford 17 (24.2 mg, 85%) as a colorless oil. ${[α]}_{D}^{24}$ −3.8 (c 0.20, CHCl₃); IR (KBr) 2974, 2926, 1582, 1465, 1435, 1381, 1105, 1051, 1025, 984 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.88 (3H, d, J = 6.8 Hz), 1.28 (6H, d, J = 6.4 Hz), 1.33 (6H, d, J = 6.4 Hz), 1.34-1.39 (1H, m), 1.51 (1H, dt, J = 6.4, 13.6 Hz), 1.98-2.10 (1H, m), 2.43 (1H, dd, J = 2.8, 4.8 Hz), 2.55 (1H, dd, J = 8.4, 12.8 Hz), 2.65-2.78 (2H, m), 2.91-2.98 (1H, m), 3.79 (3H, s), 4.39-4.48 (2H, m), 6.94 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 20.1, 22.5 (3C), 22.6, 32.1, 33.1, 39.9, 47.4, 51.5, 60.6, 71.5, 75.9, 111.1, 117.8, 131.2, 147.3, 147.6, 148.6; HRMS (ESI) m/z: [M + Na⁺] calcd for C₁₉H₂₉BrO₄Na: 423.1141, found 423.1137.

(3S,5R)-6-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-5-methylhex-1-en-3-ol (18)

To a stirred suspension of freshly recrystallized trimethylsulfonium iodide (2.78 g, 13.6 mmol) in THF (45 mL) was added n-BuLi (1.52 M in hexanes, 9.0 mL, 14 mmol) over 5 min at −15 °C, and the mixture was vigorously stirred for 30 min. To the mixture was added 17 (1.37 g, 3.40 mmol) in THF (30 mL) over 10 min, and stirring was continued for 20 h. The reaction was quenched by adding saturated aqueous NH₄Cl (75 mL), and the mixture was extracted with Et₂O twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 9:1) to afford 18 (1.42 g, quant.) as a yellow oil. ${[α]}_{D}^{24}$ −1.2 (c 0.10, CHCl₃); IR (KBr) 3419, 2975, 2931, 1465, 1435, 1379, 1229, 914, 847, 767, 715 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.84 (3H, d, J = 6.4 Hz), 1.25 (3H, d, J = 8.4 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.33 (6H, d, J = 6.0 Hz), 1.31-1.38 (1H, m), 1.51 (1H, ddd, J = 5.2, 8.4, 14.0 Hz), 1.93-2.05 (1H, m), 2.54 (1H, dd, J = 8.4, 12.4 Hz), 2.67 (1H, dd, J = 6.4, 12.4 Hz), 3.79 (3H, s), 4.14-4.23 (1H, m), 4.38-4.47 (2H, m), 5.05 (1H, dt, J = 10.0, 1.2 Hz), 5.21 (1H, dt, J = 17.2, 1.2 Hz), 5.87 (1H, ddd, J = 6.0, 10.0, 17.2 Hz), 6.93 (1H, s), a signal due to one proton (OH) was not observed; ¹³C NMR (100 MHz, CDCl₃) δ 19.9, 22.5 (2C), 22.6 (2C), 30.4, 33.5, 44.9, 60.6, 71.4, 71.6, 76.0, 111.1, 114.1, 117.8, 131.2, 141.8, 147.3, 147.7, 148.6; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₀H₃₁BrO₄Na: 437.1298, found 437.1301.

(3S,5R)-6-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-5-methylhex-1-en-3-yl methacrylate (S1)

To a stirred solution of 18 (8.5 mg, 0.021 mmol) and Et₃N (30 μL, 0.22 mmol) in CH₂Cl₂ (0.90 mL) were added methacryloyl chloride (16 μL, 0.16 mmol) and DMAP (0.3 mg, 0.002 mmol) at 0 °C, and the mixture was stirred for 30 min. The reaction was quenched by adding saturated aqueous NaHCO₃ and H₂O, and the mixture was extracted with Et₂O twice. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 19:1) to afford S1 (9.2 mg, 93%) as a colorless oil. ${[α]}_{D}^{24}$ −1.7 (c 0.10, CHCl₃); IR (KBr) 2977, 2371, 2322, 1749, 1716, 1699, 1541, 1508, 1467, 1339, 1230, 1105, 892, 705 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.84 (3H, d, J = 6.8 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.29 (3H, d, J = 6.6 Hz), 1.35 (3H, d, J = 6.0 Hz), 1.36 (3H, d, J = 6.0 Hz), 1.45 (1H, ddd, J = 4.8, 8.8, 14.0 Hz), 1.73 (1H, ddd, J = 4.8, 8.8, 14.0 Hz), 1.93 (3H, t, J = 1.6 Hz), 1.93-2.01 (1H, m), 2.54 (1H, dd, J = 8.0, 12.8 Hz), 2.68 (1H, dd, J = 6.4, 12.8 Hz), 3.79 (3H, s), 4.37-4.49 (2H, m), 5.13 (1H, dt, J = 10.2, 1.2 Hz), 5.24 (1H, dt, J = 17.2, 1.2 Hz), 5.40-5.45 (1H, m), 5.54 (1H, t, J = 1.6 Hz), 5.83 (1H, ddd, J = 6.0, 10.2, 17.2 Hz), 6.09 (1H, t, J = 1.6 Hz), 6.95 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 18.5, 19.7, 22.3 (2C), 22.6 (2C), 30.1, 33.2, 41.9, 60.5, 71.6, 73.2, 75.9, 111.1, 116.0, 118.0, 125.4, 131.1, 136.7, 137.2, 147.3, 147.8, 148.7, 166.9; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₄H₃₅BrO₅Na: 505.1560, found 505.1562.

(S)-5-((R)-3-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-2-methylpropyl)-3-methylfuran-2(5H)-one (6)

A solution of S1 (618 mg, 1.28 mmol) in CH₂Cl₂ (25 mL) was degassed by freeze-thawing. To the solution was added Grubbs second generation catalyst (163 mg, 0.192 mmol) at room temperature. After being stirred for 10 min, the mixture was warmed to 40 °C, refluxed for 11 h, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 9:1→17:3) to afford 6 (425 mg, 73%) as a pale-yellow oil, and unreacted 18 (103 mg, 17%) was recovered as a brown oil. ${[α]}_{D}^{24}$ +43.2 (c 0.10, CHCl₃); IR (KBr) 2975, 2372, 2326, 1758, 1718, 1558, 1459, 1230, 1104, 1053, 838, 795 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.87 (3H, d, J = 6.4 Hz), 1.21 (3H, d, J = 6.0 Hz), 1.22 (3H, d, J = 6.0 Hz), 1.29 (6H, d, J = 6.0 Hz), 1.41 (1H, ddd, J = 5.2, 7.2, 14.0 Hz), 1.48 (1H, ddd, J = 6.0, 8.4, 14.0 Hz), 1.82 (3H, t, J = 1.6 Hz), 1.92-2.04 (1H, m), 2.51 (1H, dd, J = 7.2, 12.4 Hz), 2.63 (1H, dd, J = 6.8, 12.4 Hz), 3.74 (3H, s), 4.33-4.44 (2H, m), 4.91 (1H, ddt, J = 6.0, 7.2, 1.6 Hz), 6.89 (1H, s), 6.94 (1H, t, J = 1.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 10.8, 22.3, 22.5 (2C), 22.6 (2C), 31.2, 32.9, 40.2, 60.6, 71.5, 76.0, 79.9, 111.0, 117.9, 128.5, 130.7, 147.4, 147.5, 148.5, 149.8, 174.6; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₂H₃₁BrO₅Na: 477.1247, found 477.1251.

(3S,4S,5S)-5-((R)-3-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-2-methylpropyl)-3,4-dihydroxy-3-methyldihydrofuran-2(3H)-one (19)

To a stirred solution of 6 (87.4 mg, 0.198 mmol) in acetone/H₂O (9:1, 2.0 mL) and pyridine (0.020 mL) was added OsO₄ (4% in H₂O, 1.9 mL) over 5 min at room temperature, and the mixture was stirred for 2 h at the same temperature. The reaction was quenched by adding saturated aqueous Na₂SO₃ (4.0 mL) and H₂O (2.0 mL), and the mixture was extracted with CHCl₃ twice. The combined organic layers were washed with H₂O, dried (Na₂SO₄), and concentrated in vacuo.

To a stirred solution of the crude product in THF/H₂O (1:1, 3.5 mL) was added NaHSO₃ (108 mg, 1.04 mmol) at room temperature, and the mixture was stirred for 30 min. After the addition of more NaHSO₃ (108 mg, 1.04 mmol), the mixture was stirred for another 1 h, and then warmed to 40 °C and stirred for 1 h. NaHSO₃ (108 mg, 1.04 mmol) was added, and the stirring was continued for 2 h. The reaction mixture was diluted with H₂O (10 mL), extracted with CHCl₃ twice, dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 4:1→3:1) to afford 19 (70 mg, 72%) as a colorless oil. ${[α]}_{D}^{24}$ −79.4 (c 0.10, CHCl₃); IR (KBr) 3410, 2925, 2855, 1771, 1647, 1558, 1542, 1508, 1458, 1357, 1230, 1105, 720, 540 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.00 (3H, d, J = 6.4 Hz), 1.23-1.38 (12H, m), 1.44 (3H, s), 1.48-1.67 (2H, m), 2.03-2.12 (1H, m), 2.60-2.70 (2H, m), 2.87 (1H, br s), 3.37 (1H, d, J = 6.0 Hz), 3.49 (1H, t, J = 6.0 Hz), 3.83 (3H, s), 4.40-4.50 (3H, m), 6.98 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 20.1, 22.0, 22.2 (2C), 22.3, 22,6, 31.2, 32.5, 38.5, 60.8, 71.6, 72.4, 76.6, 77.9, 81.2, 111.3, 117.9, 130.8, 147.0, 147.6, 148.3, 176.0; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₂H₃₃BrO₇Na: 511.1302, found 511.1303.

(3R,4R,5S)-5-((R)-3-(3-Bromo-2-isopropoxy-6-methoxy-5-methylphenyl)-2-methylpropyl)-4-hydroxy-3-methyldihydrofuran-2(3H)-one (S2)

To a stirred solution of 19 (69.7 mg, 0.142 mmol) in THF (2.0 mL) were added HMPA (75 μL, 0.43 mmol) and ethylene glycol (65 μL, 1.1 mmol), and the mixture was degassed by freeze-thawing. To a stirred solution was added samarium (II) iodide (0.070 M in THF, 10 mL, 0.70 mmol) over 5 min at room temperature, and the mixture was stirred for 2 h. The reaction was quenched by adding saturated aqueous NaHCO₃ (10 mL), and the mixture was extracted with CHCl₃ twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 4:1) to afford S2 (57.6 mg, 86%) as a colorless oil. ${[α]}_{D}^{24}$ −24.2 (c 0.40, CHCl₃); IR (KBr) 3437, 2975, 2937, 1636, 1625, 1508, 1458, 1374, 1339, 1306, 1273, 1231, 1173, 1105, 773, 758, 686 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.98 (3H, d, J = 6.8 Hz), 1.20-1.40 (15H, m), 1.50-1.69 (2H, m), 1.97-2.12 (1H, m), 2.50-2.71 (3H, m), 3.27 (1H, br s), 3.66 (1H, t, J = 8.2 Hz), 3.83 (3H, s), 4.26 (1H, dt, J = 4.4, 8.2 Hz), 4.41-4.51 (2H, m), 6.98 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 12.7, 20.3, 22.2, 22.3, 22.4, 22.5, 31.1, 32.3, 38.9, 43.7, 60.8, 71.6, 76.7, 79.5, 81.3, 111.3, 117.8, 130.7, 147.0, 147.5, 148.1, 177.0; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₂H₃₃BrO₆Na: 495.1353, found 495.1357.

(3R,4R,5S)-5-((R)-3-(3-Bromo-2,5-diisopropoxy-6-methoxyphenyl)-2-methylpropyl)-4-((tert-butyldimethylsilyl)oxy)-3-methyldihydrofuran-2(3H)-one (5)

To a stirred solution of S2 (423 mg, 0.893 mmol) in CH₂Cl₂ (18 mL) were added 2,6-lutidine (0.60 mL, 5.4 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.70 mL, 3.0 mmol) at 0 °C, and the mixture was stirred for 30 min. The reaction was quenched by adding saturated aqueous NaHCO₃ (10 mL), and the mixture was extracted with Et₂O twice. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane-EtOAc 19:1) to afford C9-C21 segment 5 (413 mg, 79%) as a colorless oil. ${[α]}_{D}^{24}$ −35.3 (c 0.40, CHCl₃); IR (KBr) 2976, 2883, 1636, 1558, 1521, 1473, 1374, 1339, 1231, 1104, 834, 775, 720 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.11 (3H, s), 0.12 (3H, s), 0.87-0.95 (12H, m), 1.26 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 6.4 Hz), 1.31 (3H, d, J = 6.4 Hz), 1.36 (3H, d, J = 6.0 Hz), 1.37 (3H, d, J = 6.0 Hz), 1.49 (1H, ddd, J = 4.8, 10.4, 14.8 Hz), 1.59 (1H, ddd, J = 2.0, 9.6, 14.8 Hz), 2.07 (1H, m), 2.53 (1H, dq, J = 8.8, 7.2 Hz), 2.62 (1H, dd, J = 7.2, 12.8 Hz), 2.68 (1H, dd, J = 7.2, 12.8 Hz), 3.63 (1H, dd, J = 7.2, 8.8 Hz), 3.83 (3H, s), 4.11 (1H, ddd, J = 2.0, 7.2, 10.4 Hz), 4.40-4.51 (2H, m), 6.97 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ −4.2, −4.0, 12.9, 18.0, 19.5, 22.3, 22.5, 22.7, 25.7 (2C), 25.8 (2C), 31.2, 33.5, 39.8, 44.1, 60.7, 71.6, 75.9, 80.4, 82.4, 110.9, 118.0, 130.7, 147.3, 147.7, 148.7, 177.0; HRMS (ESI) m/z: [M + Na⁺] calcd for C₂₈H₄₇BrO₆SiNa: 609.2217, found 609.2219.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X241250236 - Supplemental material for Studies Toward the Total Synthesis of Natalamycin A: Stereoselective Synthesis of the C9–C21 Segment

Supplemental material, sj-docx-1-npx-10.1177_1934578X241250236 for Studies Toward the Total Synthesis of Natalamycin A: Stereoselective Synthesis of the C9–C21 Segment by Momoko Suzuki, Kazuhiko Takatori and Kenichi Kobayashi in Natural Product Communications

Footnotes

Acknowledgments

We thank Dr Kazuma Matsunaga of Meiji Pharmaceutical University for helpful discussions and suggestions on the use of SmI₂.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Ethical approval is not applicable for this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

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There are no human subjects in this article and informed consent is not applicable.

Supplemental Material

Supplemental material for this article is available online.

ORCID iD

Kenichi Kobayashi

References

Kim

Ramadhar

Beemelmanns

, et al. Natalamycin A, an ansamycin from a termite-associated Streptomyces sp. Chem Sci. 2014;5(11):4333-4338.

Whitesell

Mimnaugh

Costa

, et al. Inhibition of heat shock protein Hsp90-pp60^v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A. 1994;91(18):8324-8328.

Grenert

Sullivan

Fadden

, et al. The amino-terminal domain of heat shock protein 90 (Hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates Hsp90 conformation. J Biol Chem. 1997;272(38):23843-23850.

Pratt

. The Hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors. Proc Soc Exp Biol Med. 1998;217(4):420-434.

Brazidec

JYL

Kamal

Busch

, et al. Synthesis and biological evaluation of a new class of geldanamycin derivatives as potent inhibitors of Hsp90. J Med Chem. 2004;47(15):3865-3873.

Andrus

Meredith

Simmons

, et al. Total synthesis of (+)-geldanamycin and (–)-o-quinogeldanamycin with use of asymmetric anti- and syn-glycolate aldol reactions. Org Lett. 2002;4(20):3549-3552.

Andrus

Meredith

Hicken

, et al. Total synthesis of (+)-geldanamycin and (–)-o-quinogeldanamycin: asymmetric glycolate aldol reactions and biological evaluation. J Org Chem. 2003;68(21):8162-8169.

Qin

Panek

. Total synthesis of the Hsp90 inhibitor geldanamycin. Org Lett. 2008;10(12):2477-2479.

Hampel

Neubauer

Leeuwen

, et al. Stereoselective preparation of (E)-configured 1,2-disubstituted propenes from two aldehydes by a two-carbon stitching strategy: convergent synthesis of 18,21-diisopropyl-geldanamycin hydroquinone and its C7 epimer. Chem Eur J. 2012;18(33):10382-10392.

10.

Zhang

, et al. Total synthesis of geldanamycin. J Org Chem. 2021;86(21):15063-15075.

11.

Jürjens

Kirschning

. Synthesis of a cytotoxic ansamycin hybrid. Org Lett. 2014;16(11):3000-3003.

12.

Altmann

Bold

Caravatti

, et al. The total synthesis and biological assessment of trans-epothilone A. Helv Chim Acta. 2002;85(11):4086-4110.

13.

Lemarchand

Bach

. Synthesis of chiral ansa-bridged macrocyclic lactams ([16]metacyclophanes) related to geldanamycin. Synthesis (Mass). 2005;2005(12):1977-1990.

14.

Anderson

Denton

Wilson

. A biomimetic strategy for the synthesis of the tricyclic dibenzofuran-1,4-dione core of popolohuanone E. Org Lett. 2005;7(1):123-125.

15.

Hayashi

Yamaguchi

Hibino

, et al. Direct proline catalyzed asymmetric α-aminooxylation of aldehydes. Tetrahedron Lett. 2003;44(45):8293-8296.

16.

Devalankar

Chouthaiwale

Sudalai

. Organocatalytic sequential α-aminoxylation and cis-Wittig olefination of aldehydes: synthesis of enantiopure γ-butenolides. Tetrahedron Asymmetry. 2012;23(3-4):240-244.

17.

Because chlorinated product 14 was prone to epimerization, the diastereomeric ratio was determined by ¹H NMR analysis of the crude product without purification.

18.

Jensen

Dickmeiss

Jiang

, et al. The diarylprolinol silyl ether system: a general organocatalyst. Acc Chem Res. 2012;45(2):248-264.

19.

Brochu

Brown

MacMillan

DWC

. Direct and enantioselective organocatalytic α-chlorination of aldehydes. J Am Chem Soc. 2004;126(13):4108-4109.

20.

Steward

Corbett

Goodman

, et al. Asymmetric synthesis of diverse glycolic acid scaffolds via dynamic kinetic resolution of α-keto esters. J Am Chem Soc. 2012;134(49):20197-20206.

21.

Alcaraz

Harnett

Mioskowski

, et al. Novel conversion of epoxides to one carbon homologated allylic alcohols by dimethylsulfonium methylide. Tetrahedron Lett. 1994;35(30):5449-5452.

22.

The absolute configuration of the newly formed hydroxy group in 18 was confirmed by the modified Mosher’s method (see Supporting Information).

23.

Shi

Tan

Wan

, et al. Induced salt-responsive circularly polarized luminescence of hybrid assemblies based on achiral Eu-containing polyoxometalates. Chem Commun. 2017;53(31):4390-4393.

24.

Riclea

Gleitzmann

Bruns

, et al. Algicidal lactones from the marine Roseobacter clade bacterium Ruegeria pomeroyi. Beilstein J Org Chem. 2012;8:941-950.

25.

Gao

Rao

, et al. Total synthesis of (–)-rhodomollanol A. J Am Chem Soc. 2020;142(10):4592-4597.

26.

Araki

Nakazaki

Nishikawa

. Biomimetic synthesis of the CDE ring moiety of physalins, complex 13,14-secosteroids. Org Lett. 2021;23(3):989-994.

27.

The relative stereochemistry of the lactone ring in 19 and 5 was determined by NOESY experiments (see Supporting Information).

28.

Matsuo

Sakaguchi

. Enantioselective synthesis of (–)-vertinolide. Chem Pharm Bull. 1997;45(10):1620-1625.

29.

Takatori

Ota

Tendo

, et al. Synthesis of methylenebicyclo[3.2.1]octanol by a Sm(II)-induced 1,2-rearrangement reaction with ring expansion of methylenebicyclo[4.2.0]octanone. Org Lett. 2017;19(14):3763-3766.

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