Atom Economical Multi-Substituted Pyrrole Synthesis from Aziridine

Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the γ-position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products.


Introduction
Pyrroles are molecules of great interest as key structural elements of various compounds, including pharmaceuticals and natural products [1,2]. For example, inonotus obliquus [3][4][5]. The white rot fungus that belongs to the family Hymenochaetaceae (Basidiomycetes) and is mainly distributed in Europe, Asia, and North America has been used for the treatment of gastrointestinal cancer, cardiovascular disease, and diabetes since the sixteenth century in Russia, Poland, and the Baltic countries. Moreover, the fungus has been reported to have anti-inflammatory [6], antioxidant [7][8][9][10], immunomodulatory [11], and hepatoprotective effects [12]. Some representative examples of 5-hydroxymethyl pyrrole-2carbaldehydes found in the inonotus obliquus, sometimes referred to as 2-formylpyrroles or pyrralines, are displayed in Figure 1.

Introduction
Pyrroles are molecules of great interest as key structural elements of various compounds, including pharmaceuticals and natural products [1,2]. For example, inonotus obliquus [3][4][5]. The white rot fungus that belongs to the family Hymenochaetaceae (Basidiomycetes) and is mainly distributed in Europe, Asia, and North America has been used for the treatment of gastrointestinal cancer, cardiovascular disease, and diabetes since the sixteenth century in Russia, Poland, and the Baltic countries. Moreover, the fungus has been reported to have anti-inflammatory [6], antioxidant [7][8][9][10], immunomodulatory [11], and hepatoprotective effects [12]. Some representative examples of 5-hydroxymethyl pyrrole-2-carbaldehydes found in the inonotus obliquus, sometimes referred to as 2-formylpyrroles or pyrralines, are displayed in Figure 1. The synthesis of highly functionalized pyrroles has drawn considerable attention from organic and medicinal chemists. In general, the classical synthesis routes for multi- The synthesis of highly functionalized pyrroles has drawn considerable attention from organic and medicinal chemists. In general, the classical synthesis routes for multisubstituted pyrroles, including the Knorr condensation [13], the Paal-Knorr reaction [14], the Hantzsch reaction [15], transition metal-catalyzed reactions [16,17], and multicomponent coupling reactions [18][19][20], have been in existence for many years. However, most of them are limited by the inefficient synthesis of highly functionalized pyrroles; it is challenging to introduce various substituents to the pyrrole ring due to its harsh reaction conditions and the instability of widely used keto functionality. The construction of the pyrrole ring allows regioselective functionalization and subsequent diversification of the pyrrole ring with various substituents.
Many synthetic methods have commenced from aziridine and its derivatives by expanding the ring whose nitrogen ends at the pyrrole ring. Specifically, pyrroles are synthesized from propargyl aziridines through intramolecular cyclization and breaking of the aziridine ring with the assistance of various metal catalysts ("M") including "Au(I)" followed by rearrangement for aromatization (Scheme 1, (1)) [16,17]. Our group developed a similar pyrrole synthesis method with 3-(aziridine-2-yl)-3-hydroxypropyne taking an advantage of nucleophilic aziridine ring-opening prior to cyclization [18][19][20]. Vinyl aziridines also served as starting materials for pyrrole after 1,3-sigmatropic shift and oxidation or 2+3 cycloaddition reaction with olefin via the cleavage of the C-N bond (Scheme 1, (2)). Similar [3+2]-cycloadditions were used to generate five-membered rings from 2-methyleneaziridine as a 1,3-dipole with an olefin (Scheme 1, (3)). However, most of these reported methods have two critical drawbacks. First, most of the methods require a metal ("M") catalyst. Second, only a single substituted pyrrole is generated from one set of aziridine substituents properly decorated as a starting material with the necessary counterparts, including olefins and alkynes [21,22]. substituted pyrroles, including the Knorr condensation [13], the Paal-Knorr reaction [14], the Hantzsch reaction [15], transition metal-catalyzed reactions [16,17], and multicomponent coupling reactions [18][19][20], have been in existence for many years. However, most of them are limited by the inefficient synthesis of highly functionalized pyrroles; it is challenging to introduce various substituents to the pyrrole ring due to its harsh reaction conditions and the instability of widely used keto functionality. The construction of the pyrrole ring allows regioselective functionalization and subsequent diversification of the pyrrole ring with various substituents. Many synthetic methods have commenced from aziridine and its derivatives by expanding the ring whose nitrogen ends at the pyrrole ring. Specifically, pyrroles are synthesized from propargyl aziridines through intramolecular cyclization and breaking of the aziridine ring with the assistance of various metal catalysts ("M") including "Au(I)" followed by rearrangement for aromatization (Scheme 1, (1)) [16,17]. Our group developed a similar pyrrole synthesis method with 3-(aziridine-2-yl)-3-hydroxypropyne taking an advantage of nucleophilic aziridine ring-opening prior to cyclization [18][19][20]. Vinyl aziridines also served as starting materials for pyrrole after 1,3-sigmatropic shift and oxidation or 2+3 cycloaddition reaction with olefin via the cleavage of the C-N bond (Scheme 1, (2)). Similar [3+2]-cycloadditions were used to generate five-membered rings from 2methyleneaziridine as a 1,3-dipole with an olefin (Scheme 1, (3)). However, most of these reported methods have two critical drawbacks. First, most of the methods require a metal ("M") catalyst. Second, only a single substituted pyrrole is generated from one set of aziridine substituents properly decorated as a starting material with the necessary counterparts, including olefins and alkynes [21,22]. In this report, we describe an atom economical synthesis of multi-substituted pyrroles from regiospecific aziridine ring-opening by various nucleophiles [23][24][25][26] and the following cyclization in Knorr-type reactions.

Results and Discussion
Treatment of hydroxy keto aziridine 1a [25,26] with TMSN3 in THF or dioxane under reflux did not yield the desired pyrrole product 2a (entries 1 and 2, Table 1). In dichloromethane, under reflux conditions, we obtained the expected pyrrole with a 70% yield (entry 3), whereas in CH3CN the yield increased to 85% (entry 4). In the presence of various Scheme 1. Previous works for construction of pyrroles from activated-aziridines.
In this report, we describe an atom economical synthesis of multi-substituted pyrroles from regiospecific aziridine ring-opening by various nucleophiles [23][24][25][26] and the following cyclization in Knorr-type reactions.

Results and Discussion
Treatment of hydroxy keto aziridine 1a [25,26] with TMSN 3 in THF or dioxane under reflux did not yield the desired pyrrole product 2a (entries 1 and 2, Table 1). In dichloromethane, under reflux conditions, we obtained the expected pyrrole with a 70% yield (entry 3), whereas in CH 3 CN the yield increased to 85% (entry 4). In the presence of various Lewis acids such as BF 3. OEt 2 and FeCl 3 with NaN 3 nucleophile, we did not obtain the desired pyrrole product 2a (entries 5 and 6, Table 1) with all the starting materials remaining. Lewis acids such as BF3.OEt2 and FeCl3 with NaN3 nucleophile, we did not obtain the desired pyrrole product 2a (entries 5 and 6, Table 1) with all the starting materials remaining. Next, the generality of the method was evaluated under optimized conditions that had been cyclization. This protocol provided a versatile entry for a variety of pyrroles (2) is well determined in Table 1. Then, we examined the scope and limitations of several β-(aziridin-2-yl)-β-hydroxy ketones (1) through the one-step regioselective ring-opening of aziridine followed by intramolecular to moderate yields (Scheme 2). In the successive reactions of regioselective ring opening in CH3CN under reflux and Knorr cyclization, the pyrrole compound 2b was obtained in an 80% yield from the Next, the generality of the method was evaluated under optimized conditions that had been cyclization. This protocol provided a versatile entry for a variety of pyrroles (2) is well determined in Table 1. Then, we examined the scope and limitations of several β-(aziridin-2-yl)-β-hydroxy ketones (1) through the one-step regioselective ring-opening of aziridine followed by intramolecular to moderate yields (Scheme 2). Lewis acids such as BF3.OEt2 and FeCl3 with NaN3 nucleophile, we did not obtain the desired pyrrole product 2a (entries 5 and 6, Table 1) with all the starting materials remaining. Next, the generality of the method was evaluated under optimized conditions that had been cyclization. This protocol provided a versatile entry for a variety of pyrroles (2) is well determined in Table 1. Then, we examined the scope and limitations of several β-(aziridin-2-yl)-β-hydroxy ketones (1) through the one-step regioselective ring-opening of aziridine followed by intramolecular to moderate yields (Scheme 2). In the successive reactions of regioselective ring opening in CH3CN under reflux and Knorr cyclization, the pyrrole compound 2b was obtained in an 80% yield from the In the successive reactions of regioselective ring opening in CH 3 CN under reflux and Knorr cyclization, the pyrrole compound 2b was obtained in an 80% yield from the aziridine starting compounds bearing a substituent at R 2 such as phenyl (1b) using TMSN 3 , whereas no pyrrole product 2c or 2d was obtained using TMSCl or TMSCN (see Scheme 2). After TMSN 3 screening (as mentioned in Table 1), we next screened a substrate variant using aziridines bearing a substituent at R 2 , such as o-methoxyphenyl (1e), p-methoxyphenyl (1f), and n-nonanyl (1g), as starting materials, which gave a pyrrole variant (2e-2g) in moderate to good yield under TMSN 3 conditions. The starting substrates with an additional substituent (R 2 as phenyl and t-butyldimethylsilyloxymethyl) and R 1 as methyl and p-methoxyphenyl) gave pyrroles (2h, 2i, and 2j) in 75%, 72%, and 70% yields, respectively. We also applied various thiol nucleophiles under the ZnCl 2 catalyst in MeOH to compounds (1k-1m) with substituents at C2 and C4, resulting in high yields of pyrroles (2k-2m) (Scheme 2).
Next, oxidation of the secondary alcohol of compound 3 at the γ-position of aziridine with Dess-Martin periodinane in CH 2 Cl 2 yielded a complex mixture of compounds, which were directly reacted for the ring-opening with various nucleophiles such as OMe, OAc, Cl, and CN to afford 2,3-disubstituted pyrrole 5-aldehydes (4a-4d) in the one-pot procedure as shown in Scheme 3 with examples in the Scheme 4. Whereas Swern oxidation of secondary alcohol of compound 3, followed by regio and stereoselective aziridine ring-opening with incoming nucleophile, yielded OTBS-protected pyrrole 2 as shown in Scheme 3 (see compounds 2k-2l in Scheme 2). aziridine starting compounds bearing a substituent at R 2 such as phenyl (1b) using TMSN3, whereas no pyrrole product 2c or 2d was obtained using TMSCl or TMSCN (see Scheme 2). After TMSN3 screening (as mentioned in Table 1), we next screened a substrate variant using aziridines bearing a substituent at R 2 , such as o-methoxyphenyl (1e), p-methoxyphenyl (1f), and n-nonanyl (1g), as starting materials, which gave a pyrrole variant (2e-2g) in moderate to good yield under TMSN3 conditions. The starting substrates with an additional substituent (R 2 as phenyl and t-butyldimethylsilyloxymethyl) and R 1 as methyl and p-methoxyphenyl) gave pyrroles (2h, 2i, and 2j) in 75, 72, and 70% yields, respectively. We also applied various thiol nucleophiles under the ZnCl2 catalyst in MeOH to compounds (1k-1m) with substituents at C2 and C4, resulting in high yields of pyrroles (2k-2m) (Scheme 2). Next, oxidation of the secondary alcohol of compound 3 at the γ-position of aziridine with Dess-Martin periodinane in CH2Cl2 yielded a complex mixture of compounds, which were directly reacted for the ring-opening with various nucleophiles such as OMe, OAc, Cl, and CN to afford 2,3-disubstituted pyrrole 5-aldehydes (4a-4d) in the one-pot procedure as shown in Scheme 3 with examples in the Scheme 4. Whereas Swern oxidation of secondary alcohol of compound 3, followed by regio and stereoselective aziridine ringopening with incoming nucleophile, yielded OTBS-protected pyrrole 2 as shown in Scheme 3 (see compounds 2k-2l in Scheme 2).  The difference in cyclization is raised by the substituent of R 2 , whether the substituent R 2 is a simple alkyl or aryl, or hydroxymethyl in Scheme 2. The initial Paal-Knorr cyclization step gives either 6 or 7, regardless of the characteristics of R 2 , with the removal of water molecules. After the generation of the hydroxy pyrrolidine intermediate 6, generated from most substrates with alkyl or aryl substituent on R 2 , the reaction proceeds to aromatization to yield 2 as shown in Scheme 2. From the substrate-bearing hydroxymethyl group, the ammonium ion intermediate 8 was generated, from which the deprotonation occurs to give 9 and its resonance form as 10. One more deprotonation from 10 gives rise to the final 2-formyl pyrroles 4, as shown in Scheme 4 (Scheme 5). aziridine starting compounds bearing a substituent at R 2 such as phenyl (1b) using TMSN3, whereas no pyrrole product 2c or 2d was obtained using TMSCl or TMSCN (see Scheme 2). After TMSN3 screening (as mentioned in Table 1), we next screened a substrate variant using aziridines bearing a substituent at R 2 , such as o-methoxyphenyl (1e), p-methoxyphenyl (1f), and n-nonanyl (1g), as starting materials, which gave a pyrrole variant (2e-2g) in moderate to good yield under TMSN3 conditions. The starting substrates with an additional substituent (R 2 as phenyl and t-butyldimethylsilyloxymethyl) and R 1 as methyl and p-methoxyphenyl) gave pyrroles (2h, 2i, and 2j) in 75, 72, and 70% yields, respectively. We also applied various thiol nucleophiles under the ZnCl2 catalyst in MeOH to compounds (1k-1m) with substituents at C2 and C4, resulting in high yields of pyrroles (2k-2m) (Scheme 2). Next, oxidation of the secondary alcohol of compound 3 at the γ-position of aziridine with Dess-Martin periodinane in CH2Cl2 yielded a complex mixture of compounds, which were directly reacted for the ring-opening with various nucleophiles such as OMe, OAc, Cl, and CN to afford 2,3-disubstituted pyrrole 5-aldehydes (4a-4d) in the one-pot procedure as shown in Scheme 3 with examples in the Scheme 4. Whereas Swern oxidation of secondary alcohol of compound 3, followed by regio and stereoselective aziridine ringopening with incoming nucleophile, yielded OTBS-protected pyrrole 2 as shown in Scheme 3 (see compounds 2k-2l in Scheme 2).  The difference in cyclization is raised by the substituent of R 2 , whether the substituent R 2 is a simple alkyl or aryl, or hydroxymethyl in Scheme 2. The initial Paal-Knorr cyclization step gives either 6 or 7, regardless of the characteristics of R 2 , with the removal of water molecules. After the generation of the hydroxy pyrrolidine intermediate 6, generated from most substrates with alkyl or aryl substituent on R 2 , the reaction proceeds to aromatization to yield 2 as shown in Scheme 2. From the substrate-bearing hydroxymethyl group, the ammonium ion intermediate 8 was generated, from which the deprotonation occurs to give 9 and its resonance form as 10. One more deprotonation from 10 gives rise to the final 2-formyl pyrroles 4, as shown in Scheme 4 (Scheme 5). The difference in cyclization is raised by the substituent of R 2 , whether the substituent R 2 is a simple alkyl or aryl, or hydroxymethyl in Scheme 2. The initial Paal-Knorr cyclization step gives either 6 or 7, regardless of the characteristics of R 2 , with the removal of water molecules. After the generation of the hydroxy pyrrolidine intermediate 6, generated from most substrates with alkyl or aryl substituent on R 2 , the reaction proceeds to aromatization to yield 2 as shown in Scheme 2. From the substrate-bearing hydroxymethyl group, the ammonium ion intermediate 8 was generated, from which the deprotonation occurs to give 9 and its resonance form as 10. One more deprotonation from 10 gives rise to the final 2-formyl pyrroles 4, as shown in Scheme 4 (Scheme 5).

Scheme 5.
Proposed reaction mechanism for the formation of 2 and 4 from 1 and 3 in two different pathways.
This method was extended to the synthesis of the natural product inotopyrrole 19 (Scheme 5). Treatment of compound 11 with Weinreb salt and i-PrMgCl to give compound 12, followed by allyl magnesium bromide and a subsequent reduction of aziridine ketone by NaBH4 yielded the alcohol compound 13 in 68% yield for two steps. Protection of the secondary alcohol with TBSOTf and 2,6-lutidine to furnish olefin 14 at a 73% yield. Olefin 14 was subjected to simple dihydroxylation using OsO4 and NMO to give a diol compound, followed by selective protection of the primary alcohol with TBSCl to afford secondary alcohol, and subsequently, Swern oxidation of alcohol afforded key intermediate keto compound 15 in a 62% yield. Then, we applied our optimized method on compound 15 for the synthesis of pyrrole derivative 16 from a one-step regioselective ring-opening followed by cyclization of keto compound by using AcOH and CH2Cl2 at 0 °C in 82% yield. Then, deacetylation of 16 with K2CO3 to give alcohol 17, followed by Dess-martin oxidation of primary alcohol, afforded aldehyde 18 with a 74% yield. Removal of the TBS group with TBAF gave rise to the desired natural product, inotopyrrole (19), in an 84% yield. Spectral data ( 1 H, 13 C NMR) and HRMS data of our synthetic ionotopyrrole (19) were in full agreement with those reported for the natural product (Scheme 6) [3][4][5]. This method was extended to the synthesis of the natural product inotopyrrole 19 (Scheme 5). Treatment of compound 11 with Weinreb salt and i-PrMgCl to give compound 12, followed by allyl magnesium bromide and a subsequent reduction of aziridine ketone by NaBH 4 yielded the alcohol compound 13 in 68% yield for two steps. Protection of the secondary alcohol with TBSOTf and 2,6-lutidine to furnish olefin 14 at a 73% yield. Olefin 14 was subjected to simple dihydroxylation using OsO 4 and NMO to give a diol compound, followed by selective protection of the primary alcohol with TBSCl to afford secondary alcohol, and subsequently, Swern oxidation of alcohol afforded key intermediate keto compound 15 in a 62% yield. Then, we applied our optimized method on compound 15 for the synthesis of pyrrole derivative 16 from a one-step regioselective ring-opening followed by cyclization of keto compound by using AcOH and CH 2 Cl 2 at 0 • C in 82% yield. Then, deacetylation of 16 with K 2 CO 3 to give alcohol 17, followed by Dess-martin oxidation of primary alcohol, afforded aldehyde 18 with a 74% yield. Removal of the TBS group with TBAF gave rise to the desired natural product, inotopyrrole (19), in an 84% yield. Spectral data ( 1 H, 13 C NMR) and HRMS data of our synthetic ionotopyrrole (19) were in full agreement with those reported for the natural product (Scheme 6) [3][4][5]. This method was extended to the synthesis of the natural product inotopyrrole 19 (Scheme 5). Treatment of compound 11 with Weinreb salt and i-PrMgCl to give compound 12, followed by allyl magnesium bromide and a subsequent reduction of aziridine ketone by NaBH4 yielded the alcohol compound 13 in 68% yield for two steps. Protection of the secondary alcohol with TBSOTf and 2,6-lutidine to furnish olefin 14 at a 73% yield. Olefin 14 was subjected to simple dihydroxylation using OsO4 and NMO to give a diol compound, followed by selective protection of the primary alcohol with TBSCl to afford secondary alcohol, and subsequently, Swern oxidation of alcohol afforded key intermediate keto compound 15 in a 62% yield. Then, we applied our optimized method on compound 15 for the synthesis of pyrrole derivative 16 from a one-step regioselective ring-opening followed by cyclization of keto compound by using AcOH and CH2Cl2 at 0 °C in 82% yield. Then, deacetylation of 16 with K2CO3 to give alcohol 17, followed by Dess-martin oxidation of primary alcohol, afforded aldehyde 18 with a 74% yield. Removal of the TBS group with TBAF gave rise to the desired natural product, inotopyrrole (19), in an 84% yield. Spectral data ( 1 H, 13 C NMR) and HRMS data of our synthetic ionotopyrrole (19) were in full agreement with those reported for the natural product (Scheme 6) [3][4][5].

General Information
Chiral aziridines are available from Sigma-Aldrich as reagents. They are also available from Imagene Co., Ltd. (http://www.imagene.co.kr/) in bulk quantities. All commercially available compounds were used as received unless stated otherwise. All reactions were carried out under an atmosphere of nitrogen in oven-dried glassware with magnetic stirrer. Dichloromethane was distilled from calcium hydride. Reactions were monitored by thin layer chromatography (TLC) with 0.25 mm E. Merck pre-coated silica gel plates (60 F254). Visualization was accomplished with either UV light, or by immersion in solutions of ninhydrin, p-anisaldehyde, or phosphomolybdic acid (PMA) followed by heating on a hot plate for about 10 sec. Purification of reaction products was carried out by flash chromatography using Kieselgel 60 Art 9385 (230-400 mesh). The 1 H-NMR and 13 C-NMR spectra were obtained using Varian unity lNOVA 400WB (400 MHz) or Bruker AVANCE III HD (400 MHz) spectrometer. Chemical shifts are reported relative to chloroform (δ = 7.26) for 1 H NMR, chloroform (δ = 77.2) for 13 C NMR, acetonitrile (δ = 1.94) for 1 H NMR, and acetonitrile (δ = 1.32) for 13 C NMR (see Supplementary Materials). Data are reported as br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet. Coupling constants are given in Hz. Ambiguous assignments were resolved using standard one-dimensional proton decoupling experiments. Optical rotations were obtained using a Rudolph Autopol III digital polarimeter and JASCO P-2000. Optical rotation data are reported as follows: [α] 20 (concentration c = g/100 mL, solvent). High-resolution mass spectra were recorded on a 4.7 Tesla IonSpec ESI-TOFMS, JEOL (JMS-700), and an AB Sciex 4800 Plus MALDI TOF TM , (2,5-dihydroxybenzoic acid (DHB) matrix was used to prepare samples for MS. Data were obtained in the reflector positive mode with internal standards for calibration).
To a stirred solution of above crude ketone compound was dissolved in MeOH (3 mL) under N 2 at 0 • C and ZnCl 2 (86 mg, 0.632 mmol) was added to the reaction mixture and allowed to stir for 2 h. After 2 h, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), quenched with water, and extracted with CH 2 Cl 2 (2 × 10 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (EtOAc/hexane, 1:9) to obtain pyrrole compound 4a (102 mg, 75% yield) as a yellow liquid.   (11) To a stirred solution of ethyl 2,3-dibromopropanoate (5.0 g, 19.30 mmol, 1.0 equiv) dissolved in acetonitrile (60 mL), were added potassium carbonate (8.0 g, 57.9 mmol, 3.0 equiv) followed by 2-phenylethanamine (2.9 mL, 23.16 mmol, 1.2 equiv) in dropwise manner at room temperature and reaction mixture were allowed to stir for 12 h. After completion, quenched with water (25 mL) and filtered out over filter paper (pore size 8-10 µm). The organic mixture was extracted with Et 2 O (2 × 30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude mixture of Ethyl 1-phenethylaziridine-2-carboxylate 11 as a yellow liquid (3.8 g, 89%). To a stirred solution of ester 11 (3.8 g, 17.35 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.53 g, 26.0 mmol) in dry THF (50 mL) at 0 • C was slowly added i-PrMgCl (26.0 mL, 2.0 M in THF, 52.05 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (EtOAc/hexanes, 1:1) to afford Weinreb amide 12 as a yellow color oil ( 1-(1-Phenethylaziridin-2-yl)but-3-en-1-ol (13) To a stirred solution of Weinreb amide 12 (3.2 g, 13.67 mmol) was slowly added allylMgBr (8.2 mL, 2.0 M in THF, 16.4 mmol) in dry THF (40 mL) at 0 • C, and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated NH 4 Cl solution and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo to obtain the crude allyl product, which was used for the next reaction without further purification.
To a stirred solution of dihydroxy alcohol (2.5 g, 6.8 mmol) in dry CH 2 Cl 2 (30 mL) was added imidazole (0.93 g, 13.67 mmol) and TBSCl (1.13 g, 7.5 mmol), sequentially, at 0 • C under an N 2 atmosphere. After 2 h of being stirred at rt, the reaction mixture was quenched with saturated aqueous NH 4 Cl (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (2 × 20 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to obtain the crude product, which was used for the next reaction without further purification.
To a solution of oxalyl chloride (0.67 mL, 7.81 mmol) in CH 2 Cl 2 (20 mL) at −78 • C was added dimethyl sulfoxide (1.1 mL, 15.63 mmol) over 15 min. The resulting mixture was stirred for another 45 min and then a solution of alcohol (2.5 g, 5.21 mmol) in CH 2 Cl 2 (20 mL) was added dropwise. The resulting white suspension was stirred for 2h before adding triethylamine (2.18 mL, 15.63 mmol). The reaction mixture was stirred for 30