Divergent Asymmetric Total Synthesis of All Four Pestalotin Diastereomers from (R)-Glycidol

All four chiral pestalotin diastereomers were synthesized in a straightforward and divergent manner from common (R)-glycidol. Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan’s diene) with (S)-2-benzyloxyhexanal derived from (R)-glycidol produced a syn-aldol adduct with high diastereoselectivity and enantioselectivity using a Ti(iOPr)4/(S)-BINOL/LiCl catalyst. Diastereoselective Mukaiyama aldol reactions mediated by catalytic achiral Lewis acids directly produced not only a (1′S,6S)-pyrone precursor via the syn-aldol adduct using TiCl4, but also (1′S,6R)-pyrone precursor via the antialdol adduct using ZrCl4, in a stereocomplementary manner. A Hetero-Diels-Alder reaction of similarly available mono(TMSO)diene (Brassard’s diene) with (S)-2-benzyloxyhexanal produced the (1′S,6S)-pyrone precursor promoted by Eu(fod)3 and the (1′S,6R)-pyrone precursor Et2AlCl. Debenzylation of the (1′S,6S)-precursor and the (1′S,6R)-precursor furnished natural (−)-pestalotin (99% ee, 7 steps) and unnatural (+)-epipestalotin (99% ee, 7 steps), respectively. Mitsunobu inversions of the obtained (−)-pestalotin and (+)-epipestalotin successfully produced the unnatural (+)-pestalotin (99% ee, 9 steps) and (−)-epipestalotin (99% ee, 9 steps), respectively, in a divergent manner. All four of the obtained chiral pestalotin diastereomers possessed high chemical and optical purities (optical rotations, 1H-NMR, 13C-NMR, and HPLC measurements).

On the other hand, there are three natural 3-acyl-4-hydroxy-5,6-dihydroxy-pyran-2-one products relevant to 4-methoxy-5,6-dihydroxy-pyran-2-ones: (R)-podoblastins [19], (R)-lachnelluloic acid [20], and alternaric acid [21] (Figure 2). We previously reported asymmetric total syntheses of all these natural products utilizing a catalytic asymmetric Mukaiyama aldol reaction and an asymmetric Ti-Claisen condensation as the crucial steps [22,23]. Consistent with our expeditious total syntheses of all these compounds, we envisaged a divergent synthetic access to all four chiral pestalotin diastereomers starting from a common and readily-available chiral building block, i.e., (R)-glycidol. Consistent with our expeditious total syntheses of all these compounds, we envisaged a divergent synthetic access to all four chiral pestalotin diastereomers starting from a common and readily-available chiral building block, i.e., (R)-glycidol.

Total Syntheses of All Four Pestalotin Diastereomers
Synthesis of (S)-2-benzyloxyhexanal (1) (S)-2-Benzyloxyhexanal (1) was synthesized from (R)-glycidol as shown in Scheme 2. (R)-Glycidol was converted to trityl ether 6 (or commercially available) as a crude solid, which was purified by recrystallization (83% yield). CuI-catalyzed Grignard reaction of n-PrMgBr with epoxide 6 [25] gave secondary alcohol 7 in 93% yield. After the benzyl group protection of 7, the trityl group was removed using a PTS•H 2 O catalyst to afford primary alcohol 8 in 92% yield (2 steps). Finally, TEMPO (or Swern) oxidation of 8 produced (S)-2-benzyloxyhexanal 1 in 86% (or 97%) yield. Because of its easier recrystallization purification procedure, trityl protection method was selected instead of an alternative p-methoxybenzyl protective method. The present sequence (four steps and 61% overall yield) is superior regarding steps and overall yield compared with the relevant reported route starting from (S)-norleucine (five steps and 27% overall yield) [14].
According to Midland's report, stereocomplementary (1′S,6R)-diastereoselective reaction using Et2AlCl catalyst was examined to obtain pyrone (1′S,6R)-5 in our hands (Scheme 5). Due to the subtle reported conditions, the reaction was hardly reproducible, and our best result was addressed; the obtained crude product contained considerable amounts of aldol-type compound 9 with the desirable product (1′S,6R)-5. Compound 9 was converted to (1′S,6R)-5 by PPTS/toluene under reflux conditions, albeit in poor yield (12%). Finally, debenzylation of (1′S,6S)-5 and (1'S,6R)-5 using the H2/Pd(OH)2-C catalyst produced (−)-pestalotin and (+)-epipestalotin, respectively, in good yield and with excellent optical purities (Scheme 6). Gratifyingly, Mitsunobu inversions of (−)-pestalotin and (+)-epipestalotin smoothly proceeded to furnish (+)-epipestalotin and (−)-pestalotin, respectively (Scheme 6). The present inversion step increases the value of the whole synthesis by a convergent process. Physical and spectral data (mp, optical rotation, 1 H-NMR) of all four pestalotin diastereomers matched completely with Mori's reported data [9]. Additional 13 C-NMR spectral data and HPLC measurements are described in the experimental and in the ESI, respectively. The present divergent methodology is superior compared with Mori's approach to the only reported total synthesis of all four pestalotin Mori's reported data [9]. Additional 13 C-NMR spectral data and HPLC measurements are described in the experimental and in the ESI, respectively. The present divergent methodology is superior compared with Mori's approach to the only reported total synthesis of all four pestalotin families [9] in the following respects: (i) common (R)-glycidol starting compound, (ii) short syntheses (7 and 9 steps), and (iii) higher total yield. families [9] in the following respects: (i) common (R)-glycidol starting compound, (ii) short syntheses (7 and 9 steps), and (iii) higher total yield. Scheme 6. Final stage of the total synthesis all four pestalotin diastereomers.

Materials and Methods
All reactions were carried out in oven-dried glassware under an argon atmosphere. Flash column chromatography was performed with silica gel 60 (230-400 mesh ASTM, Merck, Darmstadt, Germany). TLC analysis was performed on Merck 0.25 mm Silicagel 60 F254 plates. Melting points were determined on a hot stage microscope apparatus (ATM-01, AS ONE, Osaka, Japan) and were uncorrected. NMR spectra were recorded on a JEOLRESONANCE EXC-400 or ECX-500 spectrometer (JEOL, Akishima, Japan) operating at 400 MHz or 500 MHz for 1 H-NMR, and 100 MHz and 125 MHz for 13 C NMR. Chemical shifts (δ ppm) in CDCl3 were reported downfield from TMS (=0) for 1 H-NMR. For 13 C-NMR, chemical shifts were reported in the scale relative to CDCl3 (77.00 ppm) as an internal reference. Mass spectra were measured on a JMS-T100LC spectrometer (JEOL, Akishima, Japan). HPLC data were obtained on a SHIMADZU (Kyoto, Japan) HPLC system (consisting of the following: LC-20AT, CMB20A, CTO-20AC, and detector SPD-20A measured at 254 nm) using Chiracel AD-H or Ad-3 column (Daicel, Himeji, Japan, 25 cm) at 25 °C. Optical rotations were measured on a JASCO DIP-370 (Na lamp, 589 nm).

Materials and Methods
All reactions were carried out in oven-dried glassware under an argon atmosphere. Flash column chromatography was performed with silica gel 60 (230-400 mesh ASTM, Merck, Darmstadt, Germany). TLC analysis was performed on Merck 0.25 mm Silicagel 60 F 254 plates. Melting points were determined on a hot stage microscope apparatus (ATM-01, AS ONE, Osaka, Japan) and were uncorrected. NMR spectra were recorded on a JEOLRESONANCE EXC-400 or ECX-500 spectrometer (JEOL, Akishima, Japan) operating at 400 MHz or 500 MHz for 1 H-NMR, and 100 MHz and 125 MHz for 13 C NMR. Chemical shifts (δ ppm) in CDCl 3 were reported downfield from TMS (=0) for 1 H-NMR. For 13 C-NMR, chemical shifts were reported in the scale relative to CDCl 3 (77.00 ppm) as an internal reference. Mass spectra were measured on a JMS-T100LC spectrometer (JEOL, Akishima, Japan). HPLC data were obtained on a SHIMADZU (Kyoto, Japan) HPLC system (consisting of the following: LC-20AT, CMB20A, CTO-20AC, and detector SPD-20A measured at 254 nm) using Chiracel AD-H or Ad-3 column (Daicel, Himeji, Japan, 25 cm) at 25 • C. Optical rotations were measured on a JASCO DIP-370 (Na lamp, 589 nm).
Pale A mixture of benzyl bromide (4.85 mL, 41 mmol) and (S)-alcohol 7 (12.4 g, 34 mmol) in DMF (25 mL) were added to a stirred suspension of NaH (60%; 2.04 mg, 51 mmol) in DMF (10 mL) at 0-5 °C under an Ar atmosphere. TBAI (126 mg, 0.3 mmol) was added to the mixture and the mixture was allowed to warm up to 20-25 °C, followed by stirring for 1 h. The mixture was quenched with MeOH and K2CO3, which was extracted three times with AcOEt. The combined organic phase was washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude oil (15.6 g) was used for the next step without purification.
TsOH·H2O (647 mg, 3.4 mmol) was added to a solution of the oil (15.6 g) in MeOH (70 mL) at 20 -25 °C under an Ar atmosphere, and the mixture was stirred for 1 h at the same temperature. The mixture was quenched with sat. NaHCO3 aq. and concentrated, which was extracted three times with AcOEt. The combined organic phase was washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by SiO2-column chromatography (hexane/AcOEt = 15:1-3:1) to give 8 (6.52 g, 92% for 2 steps, >98% ee). A mixture of benzyl bromide (4.85 mL, 41 mmol) and (S)-alcohol 7 (12.4 g, 34 mmol) in DMF (25 mL) were added to a stirred suspension of NaH (60%; 2.04 mg, 51 mmol) in DMF (10 mL) at 0-5 • C under an Ar atmosphere. TBAI (126 mg, 0.3 mmol) was added to the mixture and the mixture was allowed to warm up to 20-25 • C, followed by stirring for 1 h. The mixture was quenched with MeOH and K 2 CO 3 , which was extracted three times with AcOEt. The combined organic phase was washed with water, brine, dried (Na 2 SO 4 ), and concentrated. The obtained crude oil (15.6 g) was used for the next step without purification. TsOH·H 2 O (647 mg, 3.4 mmol) was added to a solution of the oil (15.6 g) in MeOH (70 mL) at 20-25 • C under an Ar atmosphere, and the mixture was stirred for 1 h at the same temperature. The mixture was quenched with sat. NaHCO 3 aq. and concentrated, which was extracted three times with AcOEt. The combined organic phase was washed with water, brine, dried (Na 2 SO 4 ), and concentrated. The obtained crude product was purified by SiO 2 -column chromatography (hexane/AcOEt = 15:1-3:1) to give 8 (6.52 g, 92% for 2 steps, >98% ee). used for the next step without purification.
TsOH·H2O (647 mg, 3.4 mmol) was added to a solution of the oil (15.6 g) in MeOH (70 mL) at 20 -25 °C under an Ar atmosphere, and the mixture was stirred for 1 h at the same temperature. The mixture was quenched with sat. NaHCO3 aq. and concentrated, which was extracted three times with AcOEt. The combined organic phase was washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by SiO2-column chromatography (hexane/AcOEt = 15:1-3:1) to give 8 (6.52 g, 92% for 2 steps, >98% ee  TEMPO (106 mg, 0.68 mmol) and KBr (407 mg, 3.4 mmol) was added to a stirred solution of alcohol 8 (7.08 g, 34 mmol) in CH2Cl2 (34 mL) at 0-5 °C under an Ar atmosphere. A mixture of NaOCl aq. (1.5 M, 34 mL, 51 mmol), NaHCO3 (6.7 g, 80 mmol), and Na2CO3 (318 mg, 3 mmol) in water (220 mL), was added to the solution at same temperature. The mixture was allowed to warm to 20-25 °C, followed by stirring at the same temperature for 1 h. The mixture was quenched with water, which was extracted twice with CH2Cl The combined organic phase was washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude oil was purified by Florisil ® column chromatography (hexane/AcOEt = 5:1) to give the desired product 1 (6.04 g, 86%).
(S)-2-(Benzyloxy)hexanal (1) [15] TEMPO (106 mg, 0.68 mmol) and KBr (407 mg, 3.4 mmol) was added to a stirred solution of alcohol 8 (7.08 g, 34 mmol) in CH 2 Cl 2 (34 mL) at 0-5 • C under an Ar atmosphere. A mixture of NaOCl aq. (1.5 M, 34 mL, 51 mmol), NaHCO 3 (6.7 g, 80 mmol), and Na 2 CO 3 (318 mg, 3 mmol) in water (220 mL), was added to the solution at same temperature. The mixture was allowed to warm to 20-25 • C, followed by stirring at the same temperature for 1 h. The mixture was quenched with water, which was extracted twice with CH 2 Cl 2 . The combined organic phase was washed with water, brine, dried (Na 2 SO 4 ), and concentrated. The obtained crude oil was purified by Florisil ® column chromatography (hexane/AcOEt = 5:1) to give the desired product 1 (6.04 g, 86%). An alternative method is following: DMSO (4.26 mL, 60 mmol) in CH 2 Cl 2 (20 mL) was added slowly to a stirred solution of oxalyl dichloride (3.43 mL, 40 mmol) in CH 2 Cl 2 (60 mL) at −78 • C under an Ar atmosphere. After the mixture was stirred for 5 min, 8 (4.22 g, 20 mmol) in CH 2 Cl 2 (20 mL) was added and the mixture was stirred for 0.5 h at the same temperature. Et 3 N (16.6 mL, 120 mmol) was added to the mixture and the mixture was allowed to warm up to 0-5 • C over a period of 1 h, followed by stirring for 1 h at 0-5 • C. The mixture was quenched with water, which was extracted three times with Et 2 O. The combined organic phase was washed with a large amounts of water, brine, dried (Na 2 SO 4 ), and concentrated. The obtained crude product was purified by SiO 2 -column chromatography (hexane/AcOEt = 25/1) to give the desired product 1 (3.99 g, 97%). An alternative method is following: DMSO (4.26 mL, 60 mmol) in CH2Cl2 (20 mL) was added slowly to a stirred solution of oxalyl dichloride (3.43 mL, 40 mmol) in CH2Cl2 (60 mL) at −78 °C under an Ar atmosphere. After the mixture was stirred for 5 min, 8 (4.22 g, 20 mmol) in CH2Cl2 (20 mL) was added and the mixture was stirred for 0.5 h at the same temperature. Et3N (16.6 mL, 120 mmol) was added to the mixture and the mixture was allowed to warm up to 0-5 °C over a period of 1 h, followed by stirring for 1 h at 0-5 °C. The mixture was quenched with water, which was extracted three times with Et2O. The combined organic phase was washed with a large amounts of water, brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by SiO2-column chromatography (hexane/AcOEt = 25/1) to give the desired product 1 (3.99 g, 97%).
Pale Asymmetric Mukaiyama aldol reaction: Ti-BINOL solution was added to a stirred suspension of aldehyde 1 (103 mg, 0.50 mmol) and LiCl (0.85 mg, 20 µmol) in THF (0.5 mL) at 20-25 • C under an Ar atmosphere, followed by stirring at the same temperature for 0.5 h. Chan's diene 2 (260 mg, 1.0 mmol) in THF (0.3 mL) was added slowly to the mixture, which was stirred for 14 h. PPTS (25 mg, 0.10 mmol) in MeOH (1.0 mL) was added to the mixture, followed by stirring at the same temperature for 2 h. The resulting mixture was quenched with sat. NaHCO 3 aq., which was extracted three times with Et 2 O. The combined organic phase was washed with water, brine, dried (Na 2 SO 4 ), and concentrated. The obtained crude oil was purified by SiO 2 -column chromatography (hexane/AcOEt = 8/1) to give the desired product syn-3 (85% ee, dr 93:7, 51 mg, 31%). Ar atmosphere, followed by stirring at the same temperature for 0.5 h. Chan's diene 2 (260 mg, 1.0 mmol) in THF (0.3 mL) was added slowly to the mixture, which was stirred for 14 h. PPTS (25 mg, 0.10 mmol) in MeOH (1.0 mL) was added to the mixture, followed by stirring at the same temperature for 2 h. The resulting mixture was quenched with sat. NaHCO3 aq., which was extracted three times with Et2O. The combined organic phase was washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude oil was purified by SiO2-column chromatography (hexane/AcOEt = 8/1) to give the desired product syn-3 (85% ee, dr 93:7, 51 mg, 31%).