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Stereoselective synthesis of the right-hand cores of 16-methylated oxazolomycins
Tetrahedron 74 (2018) 711e719
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Stereoselective synthesis of the right-hand cores of 16-methylated oxazolomycins Kohei Eto a, Jun Ishihara a, Susumi Hatakeyama b, * a b
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan Medical Innovation Center, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 November 2017 Received in revised form 13 December 2017 Accepted 16 December 2017 Available online 18 December 2017
The right-hand heterocyclic cores of oxazolomycins having either 16R or 16S-methyl group configurations on the b-lactones were stereoselectively synthesized from the common intermediate utilized for our previous syntheses of neooxazolomycin and oxazolomycin A. In addition, the right-hand segment required for the synthesis of KSM-2690 and lajollamycin members was also synthesized in a stereoselective manner. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Oxazolomycins Antibiotics Stereoselective synthesis
1. Introduction The oxazolomycin family of antibiotics identified to date includes neooxazolomycin,1 oxazolomycins A-C,1,2 16methyloxazolomycin,3 curromycins A and B,4 KSM-2690 B and C,5 lajollamycin,6 and lajollamycin B-D7 (Fig. 1). These oxazolomycins are of great interest8 due to the synthetically challenging structures and wide-ranging biological activities such as antibacterial, antiviral, and antitumor activities.9 The characteristic b-lactone-g-lactam motif draws much attention due to the structural similarity with the pharmacophores of omuralide and salinosporamide A, representative 20 S proteasome inhibitors.10 Therefore, a number of efforts have been dedicated towards the synthesis of oxazolomycins.8,11,12 However, among these twelve members, only neooxazolomycin13,14 and oxazolomycin A15 have been successfully synthesized so far. In this context, the development of a comprehensive synthetic methodology applicable to most members of the oxazolomycin family is in high demand. We utilized neooxazolomycin core 1 as a common intermediate for the constructions of the key right-hand segments 2 and 3 in our convergent syntheses of neooxazolomycin and oxazolomycin A13b,15 (Scheme 1). To further extend this methodology to the synthesis of other oxazolomycins, we studied the stereoselective
* Corresponding author. E-mail address: [email protected] (S. Hatakeyama). https://doi.org/10.1016/j.tet.2017.12.036 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
constructions of the right-hand spiro-b-lactone-g-lactam cores 4 and 5 having either 16S or 16R-methyl group configurations from 1, which are found in 16-methylated members of the oxazolomycin family. Donohoe and co-workers reported the synthesis of the right-hand core having a 16R-methyl group, and this has been the only approach for 16-methylated oxazolomycins.16 In addition, we studied the synthesis of the right-hand segment 6 which are required for the syntheses of KSM-2690 and lajollamycin members. 2. Results and discussion We first examined the stereoselective introduction of a methyl group at the C16 position of the neooxazolomycin core 1 (Scheme 2). Upon Dess-Martin oxidation followed by Grignard reaction using methylmagnesium bromide at 78 C in THF, 1 was found to afford 16S-isomer 7 and 16R-isomer 8 in a ratio of 3:1 in 65% total yield. The reaction using methyllithium in Et2O at 40 C produced a 4:1 mixture of 7 and 8 in low yield (25%). In this case, the lactone carbonyl also partially reacted with methyllithium. The C16 configurations of both isomers were unambiguously determined by the modified Mosher's method.17 The preferential production of 7 over 8 in the Grignard reaction can be explained by assuming chelated intermediate 918 where the si face attack of MeMgBr is favored because the re face is more shielded by the sterically demanding Nmethylpyrrolidinone moiety. The major isomer 7 was then converted to MOM ether 10 which, upon NaBH4 reduction followed by
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Fig. 1. Oxazolomycin family of antibiotics.
Scheme 2. Synthesis of the right-hand core 4 with a 16 S-methyl group.
Scheme 1. Right-hand cores and segment.
silylation, gave diol 11 in 64% yield. The subsequent methyl etherification of 11 was achieved using Meerwein's reagent and a proton sponge19 to give methyl ether 12, desilylation of which afforded 13 in 67% yield. Upon Jones oxidation followed by Pinnick oxidation and ZrCl4-mediated cleavage of the MOM protecting group,20 13 afforded hydroxy acid 14. Treatment of 14 with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU)21 and N,N-diisopropylethylamine (Hünig's base) in THF at room temperature allowed us to obtain the right-hand core 4 with a methyl group of 16S configuration in 45% yield in 4 steps. On the other hand, the right-hand core 5 with a methyl group of 16R configuration was also prepared from the neooxazolomycin core 1 stereoselectively (Scheme 3).
Thus, compound 1 was protected as its MOM ether to give 15 quantitatively. The lactone ring of 15 was reduced with NaBH4 to give the corresponding triol, the primary alcohol of which was protected as its TIPS ether to afford 16 in 94% yield. Methyl etherification of 16 was undertaken in the same manner as described for that of 11 to give 17 in 70% yield. ZrCl4-mediated cleavage of the MOM protecting group of 17 occurred cleanly to afford 18 in 86% yield. After Swern oxidation of 18, the aldehyde was subjected to Grignard reaction using methylmagnesium bromide at 78 C in THF to give 19 as a 1:11 mixture of 16S and 16R-isomers in 69% yield. In this case, the observed high diastereoselectivity can be understood by assuming chelated intermediate 20 where the highly bulky (TIPSoxy)methyl group hinders the si face attack of MeMgBr. Without separation of the stereoisomers, 19 was desilylated with TBAF to give triol 21 quantitatively, the primary alcohol of which was selectively converted into a carboxylic acid by TEMPO oxidation followed by Pinnick oxidation to afford hydroxy acid 22. In the same manner described for the condensation of 14, 20 was treated with HATU and Hünig's base in THF at room temperature to give 4 and 5 in 6% and 61% yields in 3 steps, respectively, after chromatographic separation. It is important to note that compound 4 showed an NOE between 16-Me and N-Me as observed for 16methyloxazolomycin3a but compound 5 did not; instead, it exhibited an NOE between 16-H and N-Me as observed for lajollamycin6 (Fig. 2). With intention of synthesizing both KSM-2690 and lajollamycin members, we then investigated the preparation of the right-hand
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Scheme 3. Synthesis of the right-hand core 5 with a 16R-methyl group.
Scheme 4. Synthesis of the right-hand segment 6 for KSM-2690 and lajollamycin members.
3. Conclusion Fig. 2. Definitive NOEs.
segment 6 following the methodology we have developed in the synthesis of oxazolomycin A15 (Scheme 4). Thus, crude hydroxy acid 22 obtained from triol 21 was selectively esterified with triisopropylsilyloxymethyl (dodecyl)sulfane22 in the presence of CuBr2, tetra-n-butylammonium bromide, and triethylamine to give 23 as an epimeric mixture in 68% yield from 21. After protection of 23 as the dioxasilinane and hydrogenolytic debenzylation of 24, the 16S/R-epimers became separable to afford 25 and 26 in 8% and 91% yields, respectively. Dess-Martin oxidation of 26 gave aldehyde 27 in 90% yield, which was then subjected to Nozaki-Hiyama-TakaiKishi reaction23,24 with dienyl iodide 28 to produce a 1:1 mixture of 6 and its 7S-epimer. The epimeric mixture was then successively subjected to Dess-Martin oxidation to give ketone 29, which, upon L-selectride reduction, afforded a 16:1 mixture of 6 and the 7 Sepimer. Chromatographic separation of the epimeric mixture allowed us to obtain the desired right-hand segment 6 in 31% overall yield from 27.
The stereoselective routes to right-hand heterocyclic cores of oxazolomycins having either 16S- or 16R-methyl group configurations have been developed starting from the neooxazolomycin core 1, which relied on a chelation-controlled Grignard reaction in a pyrrolidinone aldol system. Furthermore, the right-hand segment 6 required for the syntheses of KSM-2690 and lajollamycin members has been synthesized in highly stereoselective manner for the first time. The synthesis of lajollamycin employing 6 is currently under investigation.
4. Experimental section 4.1. General Where appropriate, reactions were performed in flame-dried glassware under argon atmosphere. All extracts were dried over MgSO4 and concentrated by rotary evaporation below 30 C at 25 Torr. Commercial reagents and solvents were used as supplied with following exceptions. Acetonitrile (MeCN), dichloromethane (CH2Cl2), 1,2-dichloroethane (ClCH2CH2Cl), and dimethyl sulfoxide
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(DMSO) were distilled from CaH2. Thin layer chromatography (TLC) was performed using precoated silica gel plates (0.2 or 0.5 mm thickness). Column chromatography was performed using silica gel (particle size 100e210 mm (regular) or 40e50 mm (flash)). Optical rotations were recorded on a digital polarimeter at ambient temperature. Infrared spectra (FTIR) were measured on a Fourier transform infrared spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured using CDCl3 as solvent, and chemical shifts are reported as d values in ppm based on internal (CH3)4Si (0.00 ppm, 1H) or solvent peak CHCl3 (1H: 7.26 ppm; 13C: 77.0 ppm). Mass (MS) and high resolution mass (HRMS) spectra were taken in EI (dual focusing sector field) or FAB (dual focusing sector field) mode.
4.2. (3R,3aS,4S,6aR)-4-((R)-3-(Benzyloxy)-2-methylpropyl)dihydro-3a-hydroxy-6a-((S)-1-hydroxyethyl)-1,3-dimethyl-1H-furo [3,4-b]pyrrole-2,6(3H,6aH)-dione (7) and (3R,3aS,4S,6aR)-4-((R)-3(benzyloxy)-2-methylpropyl)-dihydro-3a-hydroxy-6a-((R)-1hydroxyethyl)-1,3-dimethyl-1H-furo[3,4-b]pyrrole-2,6(3H,6aH)dione (8) To a solution of 1 (133 mg, 0.35 mmol) in CH2Cl2 (3.5 mL) were added Dess-Martin periodinane (373 mg, 0.88 mmol) and NaHCO3 (74 mg, 0.88 mmol) at room temperature. After being stirred at room temperature for 2.5 h, the reaction was quenched with 10% Na2S2O3 (5.0 mL) at 0 C. The mixture was extracted with AcOEt and the extract was washed with saturated NaHCO3, dried, and concentrated to give the corresponding aldehyde (138 mg) as a yellow oil. The crude aldehyde (138 mg) was dissolved in THF (2.5 mL) and the mixture was cooled to 78 C. MeMgBr (3.0 M in Et20; 0.93 mL, 2.81 mmol) was then added and the mixture was stirred at 78 C for 16 h. The reaction was quenched by the addition of saturated NH4Cl (3 mL) at 78 C. The mixture was extracted with AcOEt, washed with saturated NaHCO3, dried, and concentrated to give a yellow oil (112 mg), the 1H NMR of which showed the ratio of 16Sand 16R-epimers to be 1:3. Purification of the crude product by flash column chromatography (SiO2 6.0 g, hexane:AcOEt ¼ 2:1 to 1:2) gave 7 (64.7 mg, 47%) and 8 (25.4 mg, 18%) each as a yellow oil. 1 Compound 7: [a]22 D þ34.5 (c 0.89, CHCl3); H NMR (400 MHz, CDCl3) d 7.38e7.29 (m, 5H), 4.53 (s, 2H), 4.34 (brs, 1H), 4.28e4.22 (m, 2H), 3.43 (dd, J ¼ 4.6, 8.8 Hz, 1H), 3.27 (t, J ¼ 8.4 Hz, 1H), 2.94 (s, 3H), 2.81 (brs, 1H), 2.49 (q, J ¼ 7.6 Hz, 1H), 2.03 (dt, J ¼ 14.0, 5.2 Hz, 1H), 1.85e1.80 (m, 1H), 1.74 (dt, J ¼ 14.0, 6.4 Hz, 1H), 1.50 (d, J ¼ 6.8 Hz, 3H), 1.21 (d, J ¼ 7.6 Hz, 3H), 1.01 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.5, 171.3, 137.3, 128.5, 128.0, 127.9, 86.7, 81.7, 75.2, 73.4, 67.1, 46.0, 32.3, 30.1, 27.0, 18.6, 18.3, 11.7; FTIR (neat) 3383, 2932, 1769, 1679, 1454, 1394, 1233, 1104, 1013, 916 cm1; MS (EI) m/z 91 (100), 157, 289, 307, 392 [(Mþ1)þ]; HRMS (EI) calcd for C21H29NO6 [(Mþ1)þ] 392.2073, found 392.2076. 1 Compound 8: [a]23 D þ43.6 (c 0.68, CHCl3); H NMR (400 MHz, CDCl3) d 7.38e7.29 (m, 5H), 4.78 (s, 1H), 4.53 (s, 2H), 4.49 (q, J ¼ 7.2 Hz, 1H), 4.25 (t, J ¼ 7.0 Hz, 1H), 3.44 (dd, J ¼ 4.6, 9.0 Hz, 1H), 3.29 (dd, J ¼ 8.4, 9.0 Hz, 1H), 3.04 (d, J ¼ 7.2 Hz, 1H), 2.83 (s, 3H), 2.52 (q, J ¼ 7.6 Hz, 1H), 2.00 (ddd, J ¼ 14.4, 7.2, 5.2 Hz, 1H), 1.86e1.79 (m, 1H), 1.72 (dt, J ¼ 14.4, 6.8 Hz, 1H), 1.32 (d, J ¼ 7.2 Hz, 3H), 1.22 (d, J ¼ 7.6 Hz, 3H), 1.01 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.2, 172.3, 137.3, 128.5, 128.0, 127.9, 87.4, 81.4, 75.2, 73.4, 72.4, 67.0, 46.2, 32.5, 30.0, 26.1, 18.3, 17.6, 11.3; FTIR (neat) 3355, 2940, 2873, 1770, 1673, 1454, 1376, 1231, 1104, 1006 cm1; MS (EI) m/z 91, 136, 154 (100), 307, 392 [(Mþ1)þ]; HRMS (EI) calcd for C21H29NO6 [(Mþ1)þ] 392.2073, found 392.2085.
4.3. (3R,3aS,4S,6aS)-4-((R)-3-(Benzyloxy)-2-methylpropyl)dihydro-3a-hydroxy-6a-((S)-1-(methoxymethoxy)ethyl)-1,3dimethyl-1H-furo[3,4-b]pyrrole-2,6(3H,6aH)-dione (10) To an ice-cooled solution of 7 (60.6 mg, 0.15 mmol) in ClCH2CH2Cl (1.5 mL) were added N,N-diisopropylethylamine (0.22 mL, 1.84 mmol) and methoxymethyl chloride (0.10 mL, 0.92 mmol). The mixture was heated under reflux for 9 h, and saturated NaHCO3 (5.0 mL) was added with cooling in an ice bath. The mixture was extracted with AcOEt, washed with brine, dried, and concentrated. The residue was purified by column chromatography (SiO2 5.0 g, hexane:AcOEt ¼ 2:1 to 3:2) to give 10 1 (58.2 mg, 87%) as a yellow oil. [a]22 D þ48.9 (c 1.08, CHCl3); H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 4.76 (d, J ¼ 7.1 Hz, 1H), 4.53 (d, J ¼ 7.1 Hz, 1H), 4.50 (s, 2H), 4.35e4.30 (m, 2H), 3.38 (dd, J ¼ 5.2, 9.3 Hz, 1H), 3.32e3.28 (m, 1H), 3.31 (s, 3H), 2.96 (s, 1H), 2.90 (s, 3H), 2.44 (q, J ¼ 7.6 Hz, 1H), 1.96 (m, 1H), 1.92 (dd, J ¼ 14.4, 4.1 Hz, 1H), 1.74 (dd, J ¼ 14.4, 5.6 Hz, 1H), 1.43 (d, J ¼ 6.8 Hz, 3H), 1.27 (d, J ¼ 7.6 Hz, 3H), 1.02 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 174.7, 170.9, 138.2, 128.4, 127.6, 94.6, 87.3, 81.9, 74.8, 74.5, 73.1, 69.3, 56.3, 45.7, 31.7, 30.3, 25.3, 18.0, 15.4, 11.0; FTIR (neat) 3418, 2945, 1770, 1698, 1454, 1386, 1151, 1106, 1033, 918 cm1; MS (EI) m/z 136, 154 (100), 307, 404, 436 [(Mþ1)þ]; HRMS (EI) calcd for C23H33NO7 [(Mþ1)þ] 436.2336, found 436.2371.
4.4. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-hydroxy-3methylbutyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy5-((S)-1-(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one (11) To an ice-cooled solution of 10 (52.9 mg, 0.12 mmol) in THFEtOH (1:1) (1.2 mL) was added NaBH4 (23 mg, 0.61 mmol), and the mixture was stirred at room temperature for 3 h NaBH4 (14 mg, 0.36 mmol) was added again and the mixture was stirred at room temperature for 21 h. The mixture was cooled in an ice bath, and saturated NH4Cl (5.0 mL) was added. The mixture was extracted with AcOEt, washed with brine, dried, and concentrated. The residue was dissolved in MeOH (20 mL) and evaporated to dryness to remove the moisture content. As a result, the corrsponding triol (48.1 mg) was obtained as a yellow oil. The crude triol (48.1 mg) was dissolved in CH2Cl2 (1.2 mL) and cooled to 78 C. Then, 2,6-lutidine (57 mL, 0.49 mmol) and tertbutyldimethylsilyl trifluoromrthanesulfonate (56 mL, 0.24 mmol) were added, and the mixture was stirred at e78 C for 22 h. The reaction was quenched with saturated NaHCO3 (3.0 mL) and the mixture was allowed to warm to room temperature. The mixture was extracted with AcOEt, washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 4.0 g, hexane:AcOEt ¼ 1:1) to give 11 (49 mg, 74%, 2 steps) as a colorless oil. [a]24 D þ6.8 (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.36e7.29 (m, 5H), 4.64 (d, J ¼ 6.8 Hz, 1H), 4.53 (d, J ¼ 12.0 Hz, 1H), 4.52 (d, J ¼ 6.8 Hz, 1H), 4.49 (d, J ¼ 12.0 Hz, 1H), 4.23 (q, J ¼ 6.3 Hz, 1H), 4.17e4.13 (m, 1H), 3.95 (d, J ¼ 11.0 Hz, 1H), 3.82 (d, J ¼ 11.0 Hz, 1H), 3.60 (d, J ¼ 5.4 Hz, 1H), 3.40 (m, 2H), 3.37 (s, 1H), 3.30 (s, 3H), 2.82 (s, 3H), 2.28 (q, J ¼ 7.3 Hz, 1H), 2.13e2.07 (m, 1H), 1.71 (dt, J ¼ 3.7, 11.0 Hz, 1H), 1.48e1.42 (m, 1H), 1.35 (d, J ¼ 6.3 Hz, 3H), 1.17 (d, J ¼ 7.3 Hz, 3H), 1.00 (d, J ¼ 7.0 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) d 176.9, 137.7, 128.4, 127.7, 127.5, 95.8, 80.8, 75.5, 75.2, 73.3, 71.2, 61.2, 55.8, 43.6, 36.8, 30.5, 27.2, 25.7, 18.0, 17.8, 10.6, 5.6, 5.7; FTIR (neat) 3452, 2944, 1654, 1462, 1396, 1255, 1095, 1032, 842, 777 cm1; MS (EI) m/z 91 (100), 154, 272, 360, 554 [(Mþ1)þ]; HRMS (EI) calcd for C29H51NO7Si [(Mþ1)þ] 554.3513, found 554.3525.
K. Eto et al. / Tetrahedron 74 (2018) 711e719
4.5. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy5-((S)-1-(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one (12) To a mixture of 11 (49 mg, 0.09 mmol) and molecular sieves 4 Å (200 mg, preactivated at 200 C for 3 h in vacuo) in CH2Cl2 (1.5 mL) were added trimethyloxonium tetrafluoroborate (106 mg, 0.72 mmol) and proton sponge (163 mg, 0.76 mmol) at 0 C, and the mixture was stirred at 0 C. After 8 h and 20 h, trimethyloxonium tetrafluoroborate (106 mg, 0.72 mmol) and proton sponge (163 mg, 0.76 mmol) were added each time, and stirring was continued at 0 C for additional 8 h. The mixture was filtered through Celite and the filter pad was washed with AcOEt. The filtrate and washings were washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 1:1) to give 12 (36.2 mg, 71%) as a colorless oil. 1 [a]22 D þ17.2 (c 0.95, CHCl3); H NMR (400 MHz, CDCl3) d 7.35e7.26 (m, 5H), 4.66 (d, J ¼ 6.8 Hz, 1H), 4.50 (d, J ¼ 6.8 Hz, 1H), 4.48 (s, 2H), 4.31 (q, J ¼ 6.4 Hz, 1H), 4.08 (d, J ¼ 11.5 Hz, 1H), 3.81 (dd, J ¼ 3.9.5.9 Hz, 1H), 3.64 (d, J ¼ 11.5 Hz, 1H), 3.41e3.36 (m, 1H), 3.39 (s, 3H), 3.37 (s, 3H), 3.26 (dd, J ¼ 6.8.8.9 Hz, 1H), 2.83 (s, 3H), 2.74 (s, 1H), 2.37 (q, J ¼ 7.4 Hz, 1H), 2.02 (dt, J ¼ 15.0, 5.9 Hz, 1H), 1.85e1.80 (m, 1H), 1.32 (d, J ¼ 6.4 Hz, 3H), 1.29e1.22 (m, 1H), 1.19 (d, J ¼ 7.4 Hz, 3H), 1.04 (d, J ¼ 6.6 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) d 176.9, 138.4, 128.3, 127.4, 95.6, 81.6, 75.6, 75.5, 75.3, 73.0, 61.3, 55.9, 55.8, 43.2, 33.1, 31.8, 27.8, 25.8, 18.1, 17.9, 10.2, 5.4, 5.6; FTIR (neat) 3450, 2951, 2892, 1690, 1466, 1255, 1091, 1029, 838, 420 cm1; MS (EI) m/z 85, 91 (100), 154, 298, 538, 568 [(Mþ1)þ]; HRMS (EI) calcd for C30H53NO7Si [(Mþ1)þ] 568.3669, found 568.3699. 4.6. (3R,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-(hydroxymethyl)-5-((S)-1(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one (13) To a solution of 12 (36 mg, 0.064 mmol) in THF (1.0 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.19 mL, 0.19 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated NH4Cl (3.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (AcOEt) to give 13 (25 mg, 94%) as a colorless oil. [a]23 D þ20.8 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.35e7.27 (m, 5H), 4.67 (d, J ¼ 7.0 Hz, 1H), 4.53 (d, J ¼ 7.0 Hz, 1H), 4.48 (s, 2H), 4.20 (q, J ¼ 6.3 Hz, 1H), 3.80 (d, J ¼ 5.6 Hz, 1H), 3.74 (t, J ¼ 5.0 Hz, 1H), 3.44 (s, 3H), 3.41e3.34 (m, 2H), 3.36 (s, 3H), 3.16 (s, 1H), 2.88 (s, 3H), 2.55 (q, J ¼ 7.6 Hz, 1H), 2.10e2.03 (m, 1H), 1.98e1.89 (m, 1H), 1.45e1.39 (m, 1H), 1.32 (d, J ¼ 6.3 Hz, 3H), 1.12 (d, J ¼ 7.6 Hz, 3H), 1.03 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 176.6, 138.3, 128.3, 127.6, 127.5, 95.4, 82.5, 81.5, 75.9, 75.2, 75.0, 73.2, 60.7, 57.8, 56.0, 43.2, 35.0, 32.2, 27.3, 18.2, 17.6, 9.6; FTIR (neat) 3353, 2940, 1667, 1454, 1399, 1214, 1149, 1084, 1027, 976 cm1; MS (EI) m/z 91, 136, 154 (100), 307, 454 [(Mþ1)þ]; HRMS (EI) calcd for C24H39NO7 [(Mþ1)þ] 454.2805, found 454.2797. 4.7. (3S,4S,7R,8S)-8-((1S,3R)-4-(benzyloxy)-1-methoxy-3methylbutyl)-8-hydroxy-3,5,7-trimethyl-2-oxa-5-azaspiro[3.4] octane-1,6-dione (4) To a solution of 13 (26 mg, 0.057 mmol) in acetone (1.0 mL) was added Jones' reagent (2.67 M, 67 mL, 0.18 mmol) at 0 C. After stirring at 0 C for 30 min, the reaction was quenched with i-PrOH (1.0 mL), and the mixture was filtered through Celite, and extracted with AcOEt. The extract was washed with water and brine, dried,
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and concentrated to give the corresponding aldehyde (26 mg). The crude aldehyde (26 mg) was dissolved in t-BuOH-H2O (5:1) (1.2 mL) and then NaH2PO4$2H2O (28 mg, 0.18 mmol), 2-methyl-2butene (0.20 mL, 1.80 mmol), and NaClO2 (22 mg, 0.24 mmol) were added at 0 C. After being stirred at room temperature for 12 h, the mixture was diluted with brine (2.0 mL), and extracted with AcOEt. The extract was washed with brine, dried, concentrated to give the corresponding carboxylic acid (34 mg). The crude carboxylic acid (34 mg) was dissolved in i-PrOH (1.0 mL) and ZrCl4 (14 mg, 0.06 mmol) was added at room temperature. The mixture was heated under reflux for 4 h, diluted with water (2.0 mL), extracted with AcOEt. The extract was dried, concentrated, and purified by reverse phase column chromatography (Cosmosil 1.5 g, H2O:MeCN ¼ 2:1) to give 14 (14.5 mg) as a colorless oil. To a solution of 14 (14.5 mg) in THF (1.0 mL) were added HATU (26.1 mg, 0.069 mmol) and N,N-diisopropylethylamine (17 mL, 0.14 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. The mixture was diluted with brine (1.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 2:3) to give 4 (10.3 mg, 45%; 4 steps) 1 as a colorless oil. [a]23 D þ9.1 (c 0.51, CHCl3); H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 5.15 (q, J ¼ 6.6 Hz, 1H), 4.49 (d, J ¼ 11.9 Hz, 1H), 4.47 (d, J ¼ 11.9 Hz, 1H), 3.78 (s, 1H), 3.46 (t, J ¼ 4.3 Hz, 1H), 3.40 (dd, J ¼ 4.2, 9.0 Hz, 1H), 3.34 (s, 3H), 3.29 (dd, J ¼ 6.6, 9.0 Hz, 1H), 3.00 (s, 3H), 2.48 (q, J ¼ 7.3 Hz, 1H), 1.96e1.89 (m, 2H), 1.49 (d, J ¼ 6.6 Hz, 3H), 1.36e1.27 (m, 1H), 1.12 (d, J ¼ 7.3 Hz, 3H), 0.98 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 176.3, 169.2, 138.1, 128.3, 127.6, 85.2, 81.2, 80.2, 77.2, 75.6, 73.2, 56.9, 41.6, 33.5, 31.7, 30.0, 18.4, 15.0, 11.7; FTIR (neat) 3396, 2927, 2860, 1817, 1695, 1454, 1378, 1287, 1089, 1024 cm1; MS (FAB) m/z 91, 137 (100), 289, 307, 406 [(Mþ1)þ]; HRMS (FAB) calcd for C22H32NO6 [(Mþ1)þ] 406.2229, found 406.2245.
4.8. (3R,3aS,4S,6aS)-4-((R)-3-(Benzyloxy)-2-methylpropyl)dihydro-3a-hydroxy-6a-((methoxymethoxy)methyl)-1,3-dimethyl1H-furo[3,4-b]pyrrole-2,6(3H,6aH)-dione (15) To a solution of 1 (0.92 g, 2.44 mmol) in CH2Cl2 (24 mL) were added methoxymethyl chloride (0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL, 7.31 mmol) at 0 C. After stirring at room temperature for 9 h, methoxymethyl chloride (0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL, 7.31 mmol) were added again, and the mixture was stirred at room temperature for 17 h. Additional methoxymethyl chloride (0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL, 7.31 mmol) were added, and stirring was continued at room temperature for 19 h. The mixture was diluted with saturated NaHCO3 (20 mL) at 0 C, extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by column chromatography (SiO2 30 g, hexane:AcOEt ¼ 1:2) to afford 15 1 (1.12 g, 100%) as a yellow oil. [a]20 D þ44.3 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) d 7.37e7.26 (m, 5H), 4.66 (d, J ¼ 6.4 Hz, 1H), 4.59 (d, J ¼ 6.4 Hz, 1H), 4.51 (s, 2H), 4.34 (m, 1H), 3.92 (d, J ¼ 11.0 Hz, 1H), 3.87 (d, J ¼ 11.0 Hz, 1H), 3.58 (s, 1H), 3.41 (m, 1H), 3.34 (s, 3H), 3.29 (m. 1H), 2.87 (s, 3H), 2.47 (q, J ¼ 7.6 Hz, 1H), 1.97e1.93 (m, 2H), 1.72 (m, 1H), 1.25 (d, J ¼ 7.6 Hz, 3H), 1.02 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.1, 170.7, 137.9, 128.4, 127.7, 96.7, 86.7, 80.3, 75.0, 73.2, 71.5, 62.2, 55.9, 44.9, 32.0, 30.2, 25.8, 18.1, 11.1. FTIR (neat) 3380, 2933, 2884, 1770, 1675, 1455, 1386, 1234, 1112, 1043, 953 cm1; MS (EI) m/z 91, 149, 189, 238, 376, 421 (100) (Mþ); HRMS (EI) calcd for C22H31NO7 (Mþ) 421.2100, found 421.2094.
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4.9. (3R,4S,5R)-4-((1S,3R)-4-(benzyloxy)-1-hydroxy-3methylbutyl)-4-hydroxy-5-((methoxymethoxy)methyl)-1,3dimethyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (16)
4.11. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-(hydroxymethyl)-1,3-dimethyl-5(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (18)
To a solution of 15 (307 mg, 0.73 mmol) in THF-EtOH (1:1, 7.4 mL) was added NaBH4 (136 mg, 3.64 mmol) at 0 C, and the mixture was stirred at room temperature for 24 h. The mixture was diluted with saturated NH4Cl (10 mL) at 0 C, extracted with AcOEt, washed with brine, dried, and concentrated to give the corresponding triol (315 mg). To a solution of the crude triol (315 mg) in CH2Cl2 (5.0 mL) were added 2,6-lutidine (0.51 mL, 4.37 mmol) and triisopropylsilyl trifluoromethanesulfonate (0.59 mL, 2.19 mmol) at 78 C, and the mixture was stirred at 78 C for 21 h. The mixture was diluted with AcOEt, washed with 1 M HCl and saturated NaHCO3, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 12 g, hexane:AcOEt ¼ 1:2 to AcOEt then AcOEt:MeOH ¼ 20:1) to give 16 (398 mg, 94%, 2 steps) as a colorless oil. 1 [a]23 H NMR (400 MHz, CDCl3) D 11.0 (c 0.55, CHCl2o:13); d 7.36e7.28 (m, 5H), 4.64 (d, J ¼ 6.7 Hz, 1H), 4.60 (d, J ¼ 6.7 Hz, 1H), 4.50 (d, J ¼ 12.1 Hz, 1H), 4.48 (d, J ¼ 12.1 Hz, 1H), 4.13e4.08 (m, 1H), 3.98 (d, J ¼ 12.8 Hz, 1H), 3.96 (d, J ¼ 12.8 Hz, 1H), 3.87 (d, J ¼ 10.5 Hz, 1H), 3.81 (d, J ¼ 10.5 Hz, 1H), 3.60 (d, J ¼ 5.6 Hz, 1H), 3.47 (s, 1H), 3.44 (dd, J ¼ 6.1, 9.0 Hz, 1H), 3.38 (s, 3H), 3.36 (m, 1H), 2.86 (s, 3H), 2.43 (q, J ¼ 7.3 Hz, 1H), 2.19e2.08 (m, 1H), 1.69 (dt, J ¼ 4.1, 11.0 Hz, 1H), 1.52 (dt, J ¼ 2.7, 11.0 Hz, 1H), 1.53e1.48 (m, 1H), 1.21 (d, J ¼ 7.3 Hz, 3H), 1.12e1.01 (m, 24H); 13C NMR (100 MHz, CDCl3) d 175.9, 138.1, 128.3, 127.6, 127.4, 96.9, 81.4, 77.2, 75.2, 73.1, 71.2, 70.8, 67.5, 62.4, 56.0, 43.1, 36.5, 30.3, 26.2, 18.4, 17.9, 11.8, 10.0; FTIR (neat) 3454, 2944, 2866, 1652, 1462, 1404, 1099, 1041, 882, 697 cm1; MS (FAB) m/z 91 (100), 202, 307, 538, 582 [(Mþ1)þ]; HRMS (FAB) calcd for C31H56NO7Si [(Mþ1)þ] 582.3818, found 582.3828.
To a solution of 17 (1.20 g, 2.01 mmol) in i-PrOH (20 mL) was added ZrCl4 (141 mg, 0.60 mmol) at room temperature, and the mixture was heated under reflux for 3.5 h. The mixture was diluted with water (10 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by flush column chromatography (SiO2 40 g, hexane:AcOEt ¼ 2:1 to 1:2) to give 18 (0.96 g, 86%) as a colorless oil. 1 [a]23 D þ11.2 (c 1.06, CHCl3); H NMR (400 MHz, CDCl3) d 7.36e7.29 (m, 5H), 4.49 (s, 2H), 4.03 (d, J ¼ 12.0 Hz, 1H), 3.77 (t, J ¼ 4.7 Hz, 1H), 3.72 (s, 1H), 3.69e3.65 (m, 1H), 3.54e3.48 (m, 1H), 3.36 (s, 3H), 3.45 (m, 1H), 3.38 (d, J ¼ 11.0 Hz, 1H), 3.32 (d, J ¼ 11.0 Hz, 1H), 2.89 (s, 3H), 2.53 (q, J ¼ 7.3 Hz, 1H), 2.06e1.90 (m, 2H), 1.39e1.33 (m, 1H), 1.16 (d, J ¼ 7.3 Hz, 3H), 1.09e0.99 (m, 24H); 13C NMR (100 MHz, CDCl3) d 175.4, 137.9, 128.4, 127.7, 127.6, 83.1, 81.0, 77.2, 75.8, 73.2, 71.9, 63.0, 61.7, 56.7, 42.6, 33.9, 31.7, 26.4, 18.3, 18.0, 17.9, 11.8, 8.9; FTIR (neat) 3326, 2942, 2866, 1667, 1463, 1400, 1096, 1013, 883, 696 cm1; MS (FAB) m/z 85, 91, 154, 344, 552 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C30H54NO6Si [(Mþ1)þ] 552.3721, found 552.3730.
4.10. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-((methoxymethoxy)methyl)-1,3dimethyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (17) To a mixture of 16 (1.65 g, 2.83 mmol) and molecular sieves 4 Å (5 g, preactivated at 200 C for 3 h in vacuo) in CH2Cl2 (6.0 mL) were added trimethyloxonium tetrafluoroborate (3.13 g, 21.2 mmol) and proton sponge (4.87 g, 22.7 mmol) at 0 C, and the mixture was stirred at 0 C. After 6 h, trimethyloxonium tetrafluoroborate (3.13 g, 21.2 mmol) and proton sponge (4.87 g, 22.7 mmol) were added again, and stirring was continued at 0 C for additional 2 h. The mixture was filtered through Celite and the filter pad was washed with AcOEt. The filtrate and washings were washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 50 g, hexane:AcOEt ¼ 3:1 to 1:1) to give 17 (1.18 g, 70%) as a colorless oil. 1 [a]23 D 0.85 (c 0.97, CHCl3); H NMR (400 MHz, CDCl3) d 7.35e7.27 (m, 5H), 4.64 (d, J ¼ 6.6 Hz, 1H), 4.58 (d, J ¼ 6.6 Hz, 1H), 4.49 (s, 2H), 4.01 (d, J ¼ 10.7 Hz, 1H), 3.98 (d, J ¼ 10.7 Hz, 1H), 3.94 (d, J ¼ 11.2 Hz, 1H), 3.79 (d, J ¼ 11.2 Hz, 1H), 3.69 (t, J ¼ 5.2 Hz, 1H), 3.57 (s, 1H), 3.40 (s, 3H), 3.37 (s, 3H), 3.42e3.36 (m 1H), 3.31e3.25 (m, 1H), 2.91 (s, 3H), 2.57 (q, J ¼ 7.1 Hz, 1H), 2.02e1.85 (m, 2H), 1.37 (dt, J ¼ 14.4, 6.6 Hz, 1H), 1.19 (d, J ¼ 7.1 Hz, 3H), 1.11e1.01 (m, 24H); 13C NMR (100 MHz, CDCl3) d 175.6, 138.5, 128.3, 127.4, 96.8, 82.1, 81.1, 77.2, 75.5, 73.0, 70.6, 67.8, 63.1, 56.9, 55.8, 43.0, 33.6, 31.5, 26.6, 18.3, 18.0, 17.9, 11.8, 9.0; FTIR (neat) 3453, 2943, 2866, 1693, 1462, 1382, 1097, 1041, 882 cm1; MS (FAB) m/z 91 (100), 145, 207, 388, 596 [(Mþ1)þ]; HRMS (FAB) calcd for C32H58NO7Si [(Mþ1)þ] 596.3981, found 596.3973.
4.12. (3S,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-((R)-1-hydroxyethyl)-1,3-dimethyl-5(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (19) To a stirred solution of oxalyl chloride (34 mL, 0.39 mmol) in CH2Cl2 (0.5 mL) at 78 C was added DMSO (41 mL, 0.58 mmol). After stirring at 78 C for 1 h, a solution of 18 (71 mg, 0.13 mmol) in CH2Cl2 (0.8 mL) was added. After stirring at 78 C for 1 h, triethylamine (0.11 mL, 0.77 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was neutralized with 1 M HCl and extracted with AcOEt. The extract was washed with brine and saturated NaHCO3, dried, and concentrated to give the corresponding aldehyde (77 mg) as a yellow oil. The crude aldehyde (77 mg) was dissolved in THF (1.5 mL) and cooled to 78 C. MeMgBr (0.99 M in Et2O; 0.65 mL, 0.64 mmol) was then added and the mixture was stirred at 78 C for 15 h. The reaction was quenched by the addition of saturated NH4Cl (3.0 mL) at 78 C. The mixture was extracted with AcOEt, washed with brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 1:1) to give 19 (50 mg, 69%, 2 steps), a colorless oil, as an epimeric mixture (16S:16R ¼ 1:11). 1H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 4.55e4.45 (m, 0.1H), 4.49 (s, 2H), 4.36 (q, J ¼ 6.8 Hz, 0.9H), 3.96e3.88 (m, 2H), 3.75e3.62 (m, 3H), 3.55 (s, 0.25H), 3.41 (s, 2.75H), 3.38e3.30 (m, 2H), 2.98 (s, 0.25H), 2.94 (s, 2.75H), 2.52 (q, J ¼ 7.3 Hz, 1H), 2.00e1.90 (m, 2H), 1.38e1.29 (m, 1H), 1.26e0.96 (m, 30H); 13C NMR (100 MHz, CDCl3) d 175.9, (175.1), 138.1, 128.3, 127.6, 127.5, (84.0), 83.1, 81.2, (80.5), (77.2), (76.2), 75.7, 73.8, 73.2, (68.1), 66.8, (64.3), 61.6, (60.0), 56.5, 42.9, (37.8), 33.7, 31.3, (31.0), (27.6), (27.4), (20.1), (19.0), 18.5, 18.4, 18.0, (11.9), 11.8, 9.8, (8.6); FTIR (neat) 3337, 2943, 2866, 1669, 1461, 1391, 1090, 996, 882, 695 cm1; MS (FAB) m/z 91, 340, 358, 566 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C31H56NO6Si [(Mþ1)þ] 566.3877, found 566.3909. Note that 13C NMR peaks in the parentheses belong to the minor epimer. 4.13. (3R,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-((R)-1-hydroxyethyl)-5(hydroxymethyl)-1,3-dimethylpyrrolidin-2-one (21) To a solution of 19 (50 mg, 0.089 mmol) in THF (1.0 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.18 mL,
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0.18 mmol), and the mixture was stirred at room temperature for 2.5 h. The mixture was diluted with saturated NH4Cl (3.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (AcOEt) to give 21 (37 mg, 100%), a colorless oil, as an epimeric mixture (16S:16R ¼ 1:11). 1H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 4.50 (d, J ¼ 11.5 Hz, 1H), 4.46 (d, J ¼ 11.5 Hz, 1H), 4.39 (q, J ¼ 7.0 Hz, 1H), 3.98e3.89 (m, 1H), 3.80e3.78 (m, 1H), 3.67 (d, J ¼ 12.7 Hz, 1H), 3.54e3.43 (m, 6H), 3.32 (dd, J ¼ 9.0, 7.5 Hz, 1H), 2.94 (s, 2.75H), 2.85 (s, 0.25H), 2.65e2.58 (m, 1H), 2.14e1.99 (m, 2H), 1.50e1.43 (m, 1H), 1.33 (d, J ¼ 7.1 Hz, 3H), 1.02e0.98 (m, 6H); 13 C NMR (100 MHz, CDCl3) d (176.1), 175.8, 137.4, 128.5, 128.4, 128.0, (127.8), (83.3), 83.1, (82.0), 81.7, (77.2), 76.3, 73.6, (72.7), 72.6, (69.5), 67.2, (60.5), (60.4), (59.7), 59.3, 59.1, (59.0), (42.8), 42.0, (37.4), 36.2, 32.4, (31.9), (29.6), 27.4, (26.1), (19.9), (18.9), 18.5, 18.4, (8.7), 8.3, 7.8; FTIR (neat) 3360, 2940, 2877, 1665, 1458, 1387, 1090, 737 cm1; MS (FAB) m/z 91, 154, 202, 410 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C22H36NO6 [(Mþ1)þ] 410.2543, found 410.2580. Note that 13C NMR peaks in the parentheses belong to the minor epimer. 4.14. (3R,4S,7R,8S)-8-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-8-hydroxy-3,5,7-trimethyl-2-oxa-5-azaspiro[3.4] octane-1,6-dione (5) To a solution of 21 (52 mg, 0.13 mmol) in CH2Cl2 (1.3 mL) were added (diacetoxyiodo)benzene (82 mg, 0.25 mmol) and 2,2,6,6tetramethylpiperidine 1-oxyl (TEPMPO) (6.0 mg, 0.038 mmol) at 0 C. After stirring at 0 C for 24 h, the reaction was quenched with saturated Na2S2O3 (5.0 mL), and the mixture was extracted with AcOEt. The extract was washed with water and brine, dried, and concentrated to give the corresponding aldehyde (54 mg). The crude aldehyde (54 mg) was dissolved in t-BuOH-H2O (5:1) (1.5 mL) and NaH2PO4$2H2O (59 mg, 0.38 mmol), 2-methyl-2butene (0.44 mL, 3.80 mmol), and NaClO2 (46 mg, 0.51 mmol) were added at 0 C. After being stirred at room temperature for 24 h, the mixture was diluted with brine (2.0 mL), and extracted with AcOEt. The extract was washed with brine, dried, concentrated to give hydroxy acid 22 (87 mg). Crude 22 (87 mg) was dissolved in THF (1.5 mL) were added HATU (96.2 mg, 0.25 mmol) and diisopropylethylamine (62 mL, 0.51 mmol) at room temperature, and the mixture was stirred at room temperature for 6 h. The mixture was diluted with brine (3.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 4:5) to give 4 (3.2 mg, 6%, 3 steps) and 5 (31 mg, 61%, 3 steps) each as a colorless oil. [a]23 D þ44.7 (c 1.41, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.36e7.27 (m, 5H), 4.83 (q, J ¼ 6.4 Hz, 1H), 4.51 (d, J ¼ 12.2 Hz, 1H), 4.48 (d, J ¼ 12.2 Hz, 1H), 3.70 (t, J ¼ 4.6 Hz, 1H), 3.40e3.37 (m, 1H), 3.39 (s, 3H), 3.29 (dd, J ¼ 7.0, 9.0 Hz, 1H), 3.18 (s, 1H), 2.91 (s, 3H), 2.44 (q, J ¼ 7.6 Hz, 1H), 2.07e1.90 (m, 2H), 1.73 (d, J ¼ 6.4 Hz, 3H), 1.36e1.27 (m, 1H), 1.20 (d, J ¼ 7.6 Hz, 3H), 0.99 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 174.9, 169.5, 138.0, 128.3, 127.6, 84.2, 81.2, 77.2, 75.8, 73.2, 57.3, 42.9, 34.2, 31.6, 26.5, 18.7, 16.6, 9.8; FTIR (neat) 3404, 2932, 1820, 1695, 1456, 1389, 1299, 1267, 1183, 1088, 1036 cm1; MS (FAB) m/z 136, 154 (100), 289, 307, 406 [(Mþ1)þ]; HRMS (FAB) calcd for C22H32NO6 [(Mþ1)þ] 406.2229, found 406.2246. 4.15. (2S,3S,4R)-((Triisopropylsilyl)oxy)methyl 3-((1S,3R)-4(benzyloxy)-1-methoxy-3-methylbutyl)-3-hydroxy-2-((R)-1hydroxyethyl)-1,4-dimethyl-5-oxopyrrolidine-2-carboxylate (23) To a mixture of crude 22 (366 mg), obtained from 21 (258 mg, 0.63 mmol) as described above, and molecular sieves 4 Å (2.0 g, preactivated at 180 C for 3 h in vacuo) in CH2Cl2 (8.3 mL) were
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added C12H25SCH2OTIPS (245 mg, 0.63 mmol), tetra-n-butylammonium bromide (203 mg, 0.63 mmol), CuBr2 (140 mg, 0.63 mmol), and tiethylamine (0.18 mL, 1.26 mmol) in that order at 0 C. The mixture was stirred in the dark at room temperature for 1 h, and C12H25SCH2OTIPS (490 mg, 1.26 mmol), tetra-n-butylammonium bromide (406 mg, 1.26 mmol), and CuBr2 (280 mg, 1.26 mmol) were again added at 0 C. After being stirred in the dark at room temperature for 1 h, the mixture was filtered through Celite and the filter pad was washed with AcOEt. The filtrate and washings were washed with saturated NaHCO3 and brine, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 25 g, hexane:AcOEt ¼ 3:1 to 1:3) to give 23 (263 mg, 68% from 21), a yellow oil, as an epimeric mixture. 1H NMR (400 MHz, CDCl3) d 7.36e7.28 (m, 5H), 5.51 (d, J ¼ 3.9 Hz, 1H), 5.47 (d, J ¼ 3.9 Hz, 1H), 4.64 (q, J ¼ 6.8 Hz, 1H), 4.49 (s, 2H), 3.98 (s, 1H), 3.60 (dd, J ¼ 3.0, 6.4 Hz, 1H), 3.40e3.30 (m, 2H), 3.35 (s, 3H), 2.87 (s, 3H), 2.49 (q, J ¼ 7.2 Hz, 1H), 1.99e1.93 (m, 1H), 1.83e1.77 (m, 1H), 1.46e1.42 (m, 1H), 1.15e0.90 (m, 24H), 0.97 (d, J ¼ 6.6 Hz, 3H). 4.16. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a-((1S,3R)-4benzyloxy-1-methoxy-3-methylbutyl)-2,2-diisopropyl-4,5,7trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4acarboxylate (24) To a solution of 23 (263 mg, 0.43 mmol) in ClCH2CH2Cl (4.3 mL) were added 2,6-lutidine (0.50 mL, 4.32 mmol) and diisopropyl bis(trifluoromethanesulfonate) (0.42 mL, 1.42 mmol) at room temperature, and the mixture was refluxed for 1 h. The mixture was diluted with AcOEt, washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by column chromatography (SiO2 13 g, hexane:AcOEt ¼ 7:1) to give 24 (273 mg, 88%), a yellow oil, as an epimeric mixture. 1H NMR (400 MHz, CDCl3) d 7.35e7.26 (m, 5H), 5.45 (brs, 2H), 4.95 (q, J ¼ 6.6 Hz, 0.9H), 4.90 (q, J ¼ 6.6 Hz, 0.1H), 4.51 (d, J ¼ 12.1 Hz, 1H), 4.47 (d, J ¼ 12.1 Hz, 1H), 3.45e3.25 (m, 3H), 3.31 (s, 3H), 2.94 (s, 3H), 2.68 (q, J ¼ 7.1 Hz, 1H), 2.00e1.80 (m, 3H), 1.51 (d, J ¼ 6.6 Hz, 3H), 1.16e0.83 (m, 41H); 13C NMR (100 MHz, CDCl3) d 176.6, 168.7, 138.5, 128.2, 127.5, 127.4, 86.0, 85.3, 77.2, 75.9, 75.6, 73.1, 68.2, 60.1, 41.9, 34.2, 31.5, 29.2, 20.7, 19.1, 17.6, 17.0, 16.8, 13.9, 13.2, 11.8, 7.7; FTIR (neat) 2943, 2866, 1738, 1710, 1463, 1381, 1164, 1109, 991, 883 cm1; MS (FAB) m/z 91 (100), 157, 284, 648, 722 [(Mþ1)þ]; HRMS (FAB) calcd for C38H68NO8Si2 [(Mþ1)þ] 722.4483, found 722.4494. 4.17. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a-((1S,3R)-4hydroxy-1-methoxy-3-methylbutyl)-2,2-diisopropyl-4,5,7trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4acarboxylate (26) A mixture of 24 (260 mg, 0.36 mmol) and 20% Pd(OH)2 (150 mg) in AcOEt (3.6 mL) was stirred at room temperature under hydrogen atmosphere. After being stirred at room temperature for 1 h, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash column chromatography (SiO2 12 g, hexane:AcOEt ¼ 4:1 to 1:1) to give 25 (18 mg, 8%) and 26 (208 mg, 91%) each as a yellow oil. 1 Compound 25. [a]22 D 21.7 (c 0.81, CHCl3); H NMR (400 MHz, CDCl3) d 5.48 (d, J ¼ 3.0 Hz, 1H), 5.43 (d, J ¼ 3.0 Hz, 1H), 4.88 (q, J ¼ 6.7 Hz, 1H), 3.58e3.49 (m, 2H), 3.38 (s, 3H), 3.33 (dd, J ¼ 10.7, 2.0 Hz, 1H), 2.94 (s, 3H), 2.75 (q, J ¼ 7.1 Hz, 1H), 2.17 (dt, J ¼ 4.0, 10.7 Hz, 1H), 1.84e1.75 (m, 1H), 1.70e1.60 (m, 1H), 1.51 (d, J ¼ 6.7 Hz, 3H), 1.17 (d, J ¼ 7.1 Hz, 3H), 1.11e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.4, 168.6, 86.0, 85.5, 77.1, 75.3, 68.7, 68.3, 61.0, 41.8, 36.6, 32.9, 29.2, 20.6, 17.6, 17.0, 16.7, 16.6, 14.0, 13.2, 11.8, 7.6; FTIR (neat) 3450, 2945, 2870, 1743, 1698, 1462, 1171, 1118, 999, 690 cm1; MS (FAB) m/z 85, 145 (100), 284, 558, 632 [(Mþ1)þ]; HRMS (FAB) calcd
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for C31H62NO8Si2 [(Mþ1)þ] 632.4014, found 632.4059. 1 Compound 26. [a]23 D þ30.0 (c 0.61, CHCl3); H NMR (400 MHz, CDCl3) d 5.46 (s, 2H), 4.98 (q, J ¼ 6.6 Hz, 1H), 3.59 (dd, J ¼ 5.4, 10.5 Hz, 1H), 3.49 (dd, J ¼ 6.3, 10.5 Hz, 1H), 3.40e3.32 (m, 1H), 3.35 (s, 3H), 2.94 (s, 3H), 2.69 (q, J ¼ 7.1 Hz, 1H), 1.99e1.80 (m, 3H), 1.51 (d, J ¼ 6.6 Hz, 3H), 1.17 (d, J ¼ 7.1 Hz, 3H), 1.11e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.5, 168.8, 86.0, 85.3, 82.3, 77.2, 75.6, 68.2, 67.6, 60.0, 41.9, 33.6, 32.8, 29.6, 29.3, 20.6, 18.0, 17.6, 17.0, 16.8, 14.0, 13.3, 11.8, 11.5, 7.7; FTIR (neat) 3450, 2944, 2869, 1742, 1698, 1462, 1170, 1125, 998, 886 cm1; MS (FAB) m/z 87, 115, 145 (100), 284, 558, 632 [(Mþ1)þ]; HRMS (FAB) calcd for C31H62NO8Si2 [(Mþ1)þ] 632.4014, found 632.4031. 4.18. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 2,2diisopropyl-7a-((1S,3R)-1-methoxy-3-methyl-4-oxobutyl)-4,5,7trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4acarboxylate (27) To a solution of 26 (190 mg, 0.30 mmol) in CH2Cl2 (3.0 mL) were added Dess-Martin periodinane (255 mg, 0.60 mmol) and NaHCO3 (51 mg, 0.60 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated Na2S2O3 (5.0 mL) at 0 C and extracted with AcOEt. The extract was washed with saturated NaHCO3 and brine, dried, concentrated. The residue was purified by flush column chromatography (SiO2 10 g, hexane:AcOEt ¼ 5:1) to give 27 (171 mg, 90%) as a colorless oil. 1 [a]22 D þ44.3 (c 1.68, CHCl3); H NMR (400 MHz, CDCl3) d 9.62 (d, J ¼ 2.0 Hz, 1H), 5.48 (d, J ¼ 3.8 Hz, 1H), 5.40 (d, J ¼ 3.8 Hz, 1H), 4.93 (q, J ¼ 6.4 Hz, 1H), 3.30e3.20 (m, 1H), 3.24 (s, 3H), 2.95 (s, 3H), 2.69 (q, J ¼ 7.2 Hz, 1H), 2.62 (brs, 1H), 2.40 (ddd, J ¼ 14.0, 10.4, 3.6 Hz, 1H), 2.26 (dd, J ¼ 14.0, 8.4, 2.4 Hz, 1H), 1.53 (d, J ¼ 6.4 Hz, 3H), 1.16e0.95 (m, 41H); 13C NMR (100 MHz, CDCl3) d 204.0, 176.2, 168.6, 85.9, 85.6, 81.0, 77.2, 75.3, 60.3, 43.6, 41.8, 30.9, 29.2, 20.6, 17.6, 17.1, 17.0, 16.9, 16.7, 13.9, 13.2, 11.7, 7.6; FTIR (neat) 2943, 2867, 1729, 1713, 1463, 1384, 1123, 1005, 883, 684 cm1; MS (FAB) m/z 55, 145, 284, 440, 600, 630 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C31H60NO8Si2 [(Mþ1)þ] 630.3857, found: 630.3870. 4.19. Nozaki-Hiyama-Takai-Kishi (NHTK) reaction of 27 and 28 To a solution of NiCl2 (2.70 mg, 0.021 mmol) in degassed THFDMSO (3:1) (1.0 mL) was added CrCl2 (105 mg, 0.86 mmol) at 0 C, and the mixture was stirred at room temperature for 10 min. Then a solution of 27 (135 mg, 0.21 mmol) and 28 (184 mg, 0.43 mmol) in degassed THF-DMSO (3:1) (2.0 mL) was added. After stirring at room temperature for 67 h in the dark, the reaction was quenched with water (3.0 mL) at 0 C, and the mixture was filtered through Celite. The filtrate was extracted with AcOEt, dried, concentrated, and purified by flash column chromatography (SiO2 20 g, hexane:AcOEt ¼ 4:1) to give a 1:1 mixture of 6 and its 7S-epimer (121 mg, 61%) as a colorless oil. Compound 6 and its 7 S-epimer were obtained in pure forms by preparative TLC (toluene:AcOEt ¼ 4:1). 1 Compound 6. [a]28 D þ12.8 (c 0.45, CHCl3); H NMR (400 MHz, CDCl3) d 7.76 (d, J ¼ 7.6 Hz, 2H), 7.59 (d, J ¼ 7.6 Hz, 2H), 7.40 (t, J ¼ 7.6 Hz, 2H), 7.31 (t, J ¼ 7.6 Hz, 2H), 6.25e6.13 (m, 2H), 5.72e5.67 (m, 2H), 5.46 (d, J ¼ 3.0 Hz, 1H), 5.45 (d, J ¼ 3.0 Hz, 1H), 4.96 (q, J ¼ 6.8 Hz, 1H), 4.89 (brs, 1H), 4.42 (d, J ¼ 7.0 Hz, 2H), 4.22 (t, J ¼ 7.0 Hz, 1H), 3.97 (t, J ¼ 6.8 Hz, 1H), 3.86 (brs, 2H), 3.41 (dd, J ¼ 2.4, 9.6 Hz, 1H), 3.37 (s, 3H), 2.94 (s, 3H), 2.69 (q, J ¼ 7.2 Hz, 1H), 2.13e2.06 (m, 1H), 1.97e1.88 (m, 2H), 1.82e1.75 (m, 1H), 1.51 (d, J ¼ 6.8 Hz, 3H), 1.17 (d, J ¼ 7.2 Hz, 3H), 1.14e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.5, 168.8, 156.1, 143.9, 141.3, 134.3, 131.2, 130.7, 129.6, 127.6, 127.0, 124.9, 119.9, 86.1, 85.3, 82.9, 77.1, 75.6, 68.3, 66.7, 60.1, 47.2, 42.6, 41.8, 37.4, 32.4, 29.6, 29.3, 20.6, 17.7, 17.1, 17.0,
16.8, 16.5, 14.1, 14.0, 13.3, 11.8, 7.7; FTIR (neat) 3414, 3333, 2943, 2866, 1729, 1710, 1694, 1463, 1245, 991 cm1; MS (FAB) m/z 69 (100), 145, 284, 549, 905, 935 [(Mþ1)þ]; HRMS (FAB) calcd for C51H79N2O10Si2 [(Mþ1)þ] 935.5273, found 935.5250. 1 7S-Epimer of 6. [a]25 D þ23.0 (c 1.70, CHCl3); H NMR (400 MHz, CDCl3) d 7.77 (d, J ¼ 7.2 Hz, 2H), 7.59 (d, J ¼ 7.2 Hz, 2H), 7.40 (t, J ¼ 7.2 Hz, 2H), 7.31 (t, J ¼ 7.2 Hz, 2H), 6.27e6.15 (m, 2H), 5.75e5.66 (m, 2H), 5.46 (brs, 2H), 4.98 (q, J ¼ 6.4 Hz, 1H), 4.84 (brs, 1H), 4.42 (d, J ¼ 6.8 Hz, 2H), 4.22 (brs, 2H), 3.87 (brs, 2H), 3.40e3.30 (m, 1H), 3.86 (s, 3H), 2.95 (s, 3H), 2.67 (q, J ¼ 7.2 Hz, 1H), 2.19e2.11 (m, 1H), 1.85e1.74 (m, 2H), 1.51 (d, J ¼ 6.4 Hz, 3H), 1.17 (d, J ¼ 7.2 Hz, 3H), 1.15e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.5, 168.7, 156.1, 143.8, 141.3, 134.8, 131.2, 129.9, 129.4, 127.6, 127.0, 124.9, 119.9, 86.0, 85.3, 82.8, 77.2, 75.7, 68.2, 66.7, 60.0, 47.2, 42.6, 41.9, 36.0, 32.3, 29.3, 20.6, 17.6, 17.1, 16.8, 15.4, 13.9, 13.3, 11.8, 7.9; FT-IR (neat) 3419, 3335, 2944, 2866, 1725, 1707, 1692, 1246, 1163, 991 cm1; MS (FAB) m/z 145, 179 (100), 284, 666, 739, 935 (Mþþ1); HRMS (FAB) calcd for C51H79N2O10Si2 (Mþþ1) 935.5273, found: 935.5267. 4.20. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a((1S,3R,5E,7E)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1methoxy-3-methyl-4-oxonona-5,7-dien-1-yl)-2,2-diisopropyl4,5,7-trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole4a-carboxylate (29) To a solution of the NHTK coupling product (21 mg, 0.023 mmol) in CH2Cl2 (1.0 mL) were added Dess-Martin periodinane (19 mg, 0.045 mmol) and NaHCO3 (3.8 mg, 0.045 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated Na2S2O3 (3.0 mL) at 0 C, and the mixture was extracted with AcOEt. The extract was washed with saturated NaHCO3 and brine, dried, and concentrated. The residue was purified by preparative TLC (hexane-AcOEt ¼ 2:1) to give 29 (18 mg, 1 84%) as a colorless oil. [a]28 D þ25.1 (c 0.83, CHCl3); H NMR (400 MHz, CDCl3) d 7.76 (d, J ¼ 7.2 Hz, 2H), 7.58 (d, J ¼ 7.6 Hz, 2H), 7.40 (t, J ¼ 7.2 Hz, 2H), 7.31 (t, J ¼ 7.6 Hz, 2H), 7.22e7.19 (m, 1H), 6.31e6.23 (m, 2H), 6.14e6.10 (m, 1H), 5.49 (d, J ¼ 3.8 Hz, 1H), 5.39 (d, J ¼ 3.8 Hz, 1H), 4.95e4.87 (m, 2H), 4.45 (d, J ¼ 6.8, 2H), 4.22 (t, J ¼ 6.8 Hz, 1H), 3.94 (brs, 2H), 3.23 (s, 3H), 3.13 (dd, J ¼ 1.8, 10.6 Hz, 1H), 3.02e2.96 (m, 1H), 2.94 (s, 3H), 2.67 (q, J ¼ 6.8 Hz, 1H), 2.41e2.32 (m, 1H), 2.12e2.04 (m, 1H), 1.51 (d, J ¼ 6.4 Hz, 3H), 1.19 (d, J ¼ 6.8 Hz, 3H),1.17e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 202.8, 176.5, 168.5, 156.1, 143.7, 141.4, 139.4, 129.3, 128.1, 127.7, 124.9, 120.0, 86.0, 85.5, 77.2, 75.4, 68.3, 66.7, 60.9, 47.2, 42.5, 41.9, 41.7, 32.4, 29.2, 20.6, 18.8, 17.6, 17.1, 17.0, 16.8, 14.0, 13.3, 11.8, 7.7; FTIR (neat) 3325, 2943, 2867, 1725, 1705, 1692, 1463, 1245, 1123, 1001 cm1; MS (FAB) m/z 136, 154 (100), 307, 903, 933 [(Mþ1)þ]; HRMS (FAB) calcd for C51H77N2O10Si2 [(Mþ1)þ] 933.5117, found 933.5137. 4.21. L-selectride reduction of 29 giving 6 To a solution of 29 (16.6 mg, 0.0178 mmol) in THF (1.0 mL) was added L-selectride (1.0 M in THF, 36 mL, 0.036 mmol) at 78 C, and the mixture was stirred at 78 C for 30 min. The reaction was quenched with saturated NH4Cl (3.0 mL), and the mixture was extracted with AcOEt. The extract was dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 2:1) to give a 16:1 mixture of 6 and its 7S-epimer (12.1 mg, 73%). Pure 6 (10.0 mg, 60%) was obtained as a colorless oil by further preparative TLC (toluene:AcOEt ¼ 4:1). Acknowledgments This work was supported by JSPS KAKENHI Grant Numbers
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JP25253002 and JP16H05074. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.tet.2017.12.036. References 1. (a) Mori T, Takahashi K, Kashiwabara M, et al. Tetrahedron Lett. 1985;26:1073; (b) Takahashi K, Kawabata M, Uemura D, et al. Tetrahedron Lett. 1985;26:1077. 2. Kanzaki H, Wada K, Nitoda T, Kawazu K. Biosci Biotechnol Biochem. 1998;62: 438. 3. (a) Ryu G, Hwang S, Kim S-K. J Antibiot. 1997;50:1064; (b) Ryu G, Kim S-K. J Antibiot. 1999;52:193. 4. Ogura M, Nakayama H, Furihata K, Shimazu A, Seto H, Otake N. J Antibiot. 1985;38:669. 5. Otani T, Yoshida K, Kubota H, et al. J Antibiot. 2000;53:1397. 6. Manam RR, Teisan S, White DJ, et al. J Nat Prod. 2005;68:240. 7. Ko K, Lee S-H, Kim S-H, Kim E-H, Oh K-B, Shin J, Oh D-C. J Nat Prod. 2014;77: 2099. 8. For a review, see: Moloney MG, Trippier PC, Yaqoob M, Wang Z Curr Drug Discovery Technol. 2004;1:181. 9. (a) Kawai S, Kawabata G, Kobayashi A, Kawazu K. Agric Biol Chem. 1989;53: 1127; (b) Kawazu K, Kanzaki H, Kawabata G, Kawai S, Kobayashi A. Biosci Biotechnol Biochem. 1992;56:1382.
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10. For reviews, see: (a) Masse CE, Morgan AJ, Adams J, Panek JS. Eur J Org Chem. 2000:2513; (b) Shibasaki M, Kanai M, Fukuda N. Chem Asian J. 2007;2:20; (c) Potts BC, Lam KS. Mar Drugs. 2010;8:835. 11. Ishihara J, Hatakeyama S. Chem Rec. 2014;14:663. and references therein. 12. (a) Hale KJ, Hatakeyama S, Urabe F, et al. Org Lett. 2014;16:3536; (b) Athawale PR, Kashinath K, Reddy DS. ChemistrySelect. 2016;1:495. 13. (a) Kende AS, Kawamura K, DeVita RJ. J Am Chem Soc. 1990;112:4070; (b) Onyango EO, Tsurumoto J, Imai N, Takahashi K, Ishihara J, Hatakeyama S. Angew Chem Int Ed. 2007;46:6703. 14. Bastin R, Dale JW, Edwards MG, Papillon JPN, Webb MR, Taylor RJK. Tetrahedron. 2011;67:10026. 15. Eto K, Yoshino M, Takahashi K, Ishihara J, Hatakeyama S. Org Lett. 2011;13: 5398. 16. Donohoe TJ, Chiu JYK, Thomas RE. Org Lett. 2007;9:421. 17. Ohtani I, Kusumi T, Kashman Y, Kakisawa H. J Am Chem Soc. 1991;113:4092. 18. For chelation-controlled Grignard reactions of aldols, see: (a) Reetz MT. Angew Chem Int Ed. 1984;23:556; (b) Iwasaki J, Ito H, Nakamura M, Iguchi K. Tetrahedron Lett. 2006;47:1483; (c) Moon NG, Harned AM. Org Lett. 2015;17:2218. 19. Garcia-Fortanet J, Debergh JR, De Brabander JK. Org Lett. 2005;7:685. 20. Sharma GVM, Reddy KL, Lakshmi PS, Krishna PR. Tetrahedron Lett. 2004;45: 9229. 21. Carpino LA. J Am Chem Soc. 1993;115:4397. 22. Yoshimura H, Eto K, Takahashi K, Ishihara J, Hatakeyama S. Chem Pharmaceut Bull. 2012;60:1334. 23. Panek JS, Liu P. J Am Chem Soc. 2000;122:11090. 24. Gil A, Albericio F, Alvarez M. Chem Rev. 2017;117:8420.
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Stereoselective synthesis of the right-hand cores of 16-methylated oxazolomycins Kohei Eto a, Jun Ishihara a, Susumi Hatakeyama b, * a b
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan Medical Innovation Center, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 November 2017 Received in revised form 13 December 2017 Accepted 16 December 2017 Available online 18 December 2017
The right-hand heterocyclic cores of oxazolomycins having either 16R or 16S-methyl group configurations on the b-lactones were stereoselectively synthesized from the common intermediate utilized for our previous syntheses of neooxazolomycin and oxazolomycin A. In addition, the right-hand segment required for the synthesis of KSM-2690 and lajollamycin members was also synthesized in a stereoselective manner. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Oxazolomycins Antibiotics Stereoselective synthesis
1. Introduction The oxazolomycin family of antibiotics identified to date includes neooxazolomycin,1 oxazolomycins A-C,1,2 16methyloxazolomycin,3 curromycins A and B,4 KSM-2690 B and C,5 lajollamycin,6 and lajollamycin B-D7 (Fig. 1). These oxazolomycins are of great interest8 due to the synthetically challenging structures and wide-ranging biological activities such as antibacterial, antiviral, and antitumor activities.9 The characteristic b-lactone-g-lactam motif draws much attention due to the structural similarity with the pharmacophores of omuralide and salinosporamide A, representative 20 S proteasome inhibitors.10 Therefore, a number of efforts have been dedicated towards the synthesis of oxazolomycins.8,11,12 However, among these twelve members, only neooxazolomycin13,14 and oxazolomycin A15 have been successfully synthesized so far. In this context, the development of a comprehensive synthetic methodology applicable to most members of the oxazolomycin family is in high demand. We utilized neooxazolomycin core 1 as a common intermediate for the constructions of the key right-hand segments 2 and 3 in our convergent syntheses of neooxazolomycin and oxazolomycin A13b,15 (Scheme 1). To further extend this methodology to the synthesis of other oxazolomycins, we studied the stereoselective
* Corresponding author. E-mail address: [email protected] (S. Hatakeyama). https://doi.org/10.1016/j.tet.2017.12.036 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
constructions of the right-hand spiro-b-lactone-g-lactam cores 4 and 5 having either 16S or 16R-methyl group configurations from 1, which are found in 16-methylated members of the oxazolomycin family. Donohoe and co-workers reported the synthesis of the right-hand core having a 16R-methyl group, and this has been the only approach for 16-methylated oxazolomycins.16 In addition, we studied the synthesis of the right-hand segment 6 which are required for the syntheses of KSM-2690 and lajollamycin members. 2. Results and discussion We first examined the stereoselective introduction of a methyl group at the C16 position of the neooxazolomycin core 1 (Scheme 2). Upon Dess-Martin oxidation followed by Grignard reaction using methylmagnesium bromide at 78 C in THF, 1 was found to afford 16S-isomer 7 and 16R-isomer 8 in a ratio of 3:1 in 65% total yield. The reaction using methyllithium in Et2O at 40 C produced a 4:1 mixture of 7 and 8 in low yield (25%). In this case, the lactone carbonyl also partially reacted with methyllithium. The C16 configurations of both isomers were unambiguously determined by the modified Mosher's method.17 The preferential production of 7 over 8 in the Grignard reaction can be explained by assuming chelated intermediate 918 where the si face attack of MeMgBr is favored because the re face is more shielded by the sterically demanding Nmethylpyrrolidinone moiety. The major isomer 7 was then converted to MOM ether 10 which, upon NaBH4 reduction followed by
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Fig. 1. Oxazolomycin family of antibiotics.
Scheme 2. Synthesis of the right-hand core 4 with a 16 S-methyl group.
Scheme 1. Right-hand cores and segment.
silylation, gave diol 11 in 64% yield. The subsequent methyl etherification of 11 was achieved using Meerwein's reagent and a proton sponge19 to give methyl ether 12, desilylation of which afforded 13 in 67% yield. Upon Jones oxidation followed by Pinnick oxidation and ZrCl4-mediated cleavage of the MOM protecting group,20 13 afforded hydroxy acid 14. Treatment of 14 with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU)21 and N,N-diisopropylethylamine (Hünig's base) in THF at room temperature allowed us to obtain the right-hand core 4 with a methyl group of 16S configuration in 45% yield in 4 steps. On the other hand, the right-hand core 5 with a methyl group of 16R configuration was also prepared from the neooxazolomycin core 1 stereoselectively (Scheme 3).
Thus, compound 1 was protected as its MOM ether to give 15 quantitatively. The lactone ring of 15 was reduced with NaBH4 to give the corresponding triol, the primary alcohol of which was protected as its TIPS ether to afford 16 in 94% yield. Methyl etherification of 16 was undertaken in the same manner as described for that of 11 to give 17 in 70% yield. ZrCl4-mediated cleavage of the MOM protecting group of 17 occurred cleanly to afford 18 in 86% yield. After Swern oxidation of 18, the aldehyde was subjected to Grignard reaction using methylmagnesium bromide at 78 C in THF to give 19 as a 1:11 mixture of 16S and 16R-isomers in 69% yield. In this case, the observed high diastereoselectivity can be understood by assuming chelated intermediate 20 where the highly bulky (TIPSoxy)methyl group hinders the si face attack of MeMgBr. Without separation of the stereoisomers, 19 was desilylated with TBAF to give triol 21 quantitatively, the primary alcohol of which was selectively converted into a carboxylic acid by TEMPO oxidation followed by Pinnick oxidation to afford hydroxy acid 22. In the same manner described for the condensation of 14, 20 was treated with HATU and Hünig's base in THF at room temperature to give 4 and 5 in 6% and 61% yields in 3 steps, respectively, after chromatographic separation. It is important to note that compound 4 showed an NOE between 16-Me and N-Me as observed for 16methyloxazolomycin3a but compound 5 did not; instead, it exhibited an NOE between 16-H and N-Me as observed for lajollamycin6 (Fig. 2). With intention of synthesizing both KSM-2690 and lajollamycin members, we then investigated the preparation of the right-hand
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Scheme 3. Synthesis of the right-hand core 5 with a 16R-methyl group.
Scheme 4. Synthesis of the right-hand segment 6 for KSM-2690 and lajollamycin members.
3. Conclusion Fig. 2. Definitive NOEs.
segment 6 following the methodology we have developed in the synthesis of oxazolomycin A15 (Scheme 4). Thus, crude hydroxy acid 22 obtained from triol 21 was selectively esterified with triisopropylsilyloxymethyl (dodecyl)sulfane22 in the presence of CuBr2, tetra-n-butylammonium bromide, and triethylamine to give 23 as an epimeric mixture in 68% yield from 21. After protection of 23 as the dioxasilinane and hydrogenolytic debenzylation of 24, the 16S/R-epimers became separable to afford 25 and 26 in 8% and 91% yields, respectively. Dess-Martin oxidation of 26 gave aldehyde 27 in 90% yield, which was then subjected to Nozaki-Hiyama-TakaiKishi reaction23,24 with dienyl iodide 28 to produce a 1:1 mixture of 6 and its 7S-epimer. The epimeric mixture was then successively subjected to Dess-Martin oxidation to give ketone 29, which, upon L-selectride reduction, afforded a 16:1 mixture of 6 and the 7 Sepimer. Chromatographic separation of the epimeric mixture allowed us to obtain the desired right-hand segment 6 in 31% overall yield from 27.
The stereoselective routes to right-hand heterocyclic cores of oxazolomycins having either 16S- or 16R-methyl group configurations have been developed starting from the neooxazolomycin core 1, which relied on a chelation-controlled Grignard reaction in a pyrrolidinone aldol system. Furthermore, the right-hand segment 6 required for the syntheses of KSM-2690 and lajollamycin members has been synthesized in highly stereoselective manner for the first time. The synthesis of lajollamycin employing 6 is currently under investigation.
4. Experimental section 4.1. General Where appropriate, reactions were performed in flame-dried glassware under argon atmosphere. All extracts were dried over MgSO4 and concentrated by rotary evaporation below 30 C at 25 Torr. Commercial reagents and solvents were used as supplied with following exceptions. Acetonitrile (MeCN), dichloromethane (CH2Cl2), 1,2-dichloroethane (ClCH2CH2Cl), and dimethyl sulfoxide
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(DMSO) were distilled from CaH2. Thin layer chromatography (TLC) was performed using precoated silica gel plates (0.2 or 0.5 mm thickness). Column chromatography was performed using silica gel (particle size 100e210 mm (regular) or 40e50 mm (flash)). Optical rotations were recorded on a digital polarimeter at ambient temperature. Infrared spectra (FTIR) were measured on a Fourier transform infrared spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured using CDCl3 as solvent, and chemical shifts are reported as d values in ppm based on internal (CH3)4Si (0.00 ppm, 1H) or solvent peak CHCl3 (1H: 7.26 ppm; 13C: 77.0 ppm). Mass (MS) and high resolution mass (HRMS) spectra were taken in EI (dual focusing sector field) or FAB (dual focusing sector field) mode.
4.2. (3R,3aS,4S,6aR)-4-((R)-3-(Benzyloxy)-2-methylpropyl)dihydro-3a-hydroxy-6a-((S)-1-hydroxyethyl)-1,3-dimethyl-1H-furo [3,4-b]pyrrole-2,6(3H,6aH)-dione (7) and (3R,3aS,4S,6aR)-4-((R)-3(benzyloxy)-2-methylpropyl)-dihydro-3a-hydroxy-6a-((R)-1hydroxyethyl)-1,3-dimethyl-1H-furo[3,4-b]pyrrole-2,6(3H,6aH)dione (8) To a solution of 1 (133 mg, 0.35 mmol) in CH2Cl2 (3.5 mL) were added Dess-Martin periodinane (373 mg, 0.88 mmol) and NaHCO3 (74 mg, 0.88 mmol) at room temperature. After being stirred at room temperature for 2.5 h, the reaction was quenched with 10% Na2S2O3 (5.0 mL) at 0 C. The mixture was extracted with AcOEt and the extract was washed with saturated NaHCO3, dried, and concentrated to give the corresponding aldehyde (138 mg) as a yellow oil. The crude aldehyde (138 mg) was dissolved in THF (2.5 mL) and the mixture was cooled to 78 C. MeMgBr (3.0 M in Et20; 0.93 mL, 2.81 mmol) was then added and the mixture was stirred at 78 C for 16 h. The reaction was quenched by the addition of saturated NH4Cl (3 mL) at 78 C. The mixture was extracted with AcOEt, washed with saturated NaHCO3, dried, and concentrated to give a yellow oil (112 mg), the 1H NMR of which showed the ratio of 16Sand 16R-epimers to be 1:3. Purification of the crude product by flash column chromatography (SiO2 6.0 g, hexane:AcOEt ¼ 2:1 to 1:2) gave 7 (64.7 mg, 47%) and 8 (25.4 mg, 18%) each as a yellow oil. 1 Compound 7: [a]22 D þ34.5 (c 0.89, CHCl3); H NMR (400 MHz, CDCl3) d 7.38e7.29 (m, 5H), 4.53 (s, 2H), 4.34 (brs, 1H), 4.28e4.22 (m, 2H), 3.43 (dd, J ¼ 4.6, 8.8 Hz, 1H), 3.27 (t, J ¼ 8.4 Hz, 1H), 2.94 (s, 3H), 2.81 (brs, 1H), 2.49 (q, J ¼ 7.6 Hz, 1H), 2.03 (dt, J ¼ 14.0, 5.2 Hz, 1H), 1.85e1.80 (m, 1H), 1.74 (dt, J ¼ 14.0, 6.4 Hz, 1H), 1.50 (d, J ¼ 6.8 Hz, 3H), 1.21 (d, J ¼ 7.6 Hz, 3H), 1.01 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.5, 171.3, 137.3, 128.5, 128.0, 127.9, 86.7, 81.7, 75.2, 73.4, 67.1, 46.0, 32.3, 30.1, 27.0, 18.6, 18.3, 11.7; FTIR (neat) 3383, 2932, 1769, 1679, 1454, 1394, 1233, 1104, 1013, 916 cm1; MS (EI) m/z 91 (100), 157, 289, 307, 392 [(Mþ1)þ]; HRMS (EI) calcd for C21H29NO6 [(Mþ1)þ] 392.2073, found 392.2076. 1 Compound 8: [a]23 D þ43.6 (c 0.68, CHCl3); H NMR (400 MHz, CDCl3) d 7.38e7.29 (m, 5H), 4.78 (s, 1H), 4.53 (s, 2H), 4.49 (q, J ¼ 7.2 Hz, 1H), 4.25 (t, J ¼ 7.0 Hz, 1H), 3.44 (dd, J ¼ 4.6, 9.0 Hz, 1H), 3.29 (dd, J ¼ 8.4, 9.0 Hz, 1H), 3.04 (d, J ¼ 7.2 Hz, 1H), 2.83 (s, 3H), 2.52 (q, J ¼ 7.6 Hz, 1H), 2.00 (ddd, J ¼ 14.4, 7.2, 5.2 Hz, 1H), 1.86e1.79 (m, 1H), 1.72 (dt, J ¼ 14.4, 6.8 Hz, 1H), 1.32 (d, J ¼ 7.2 Hz, 3H), 1.22 (d, J ¼ 7.6 Hz, 3H), 1.01 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.2, 172.3, 137.3, 128.5, 128.0, 127.9, 87.4, 81.4, 75.2, 73.4, 72.4, 67.0, 46.2, 32.5, 30.0, 26.1, 18.3, 17.6, 11.3; FTIR (neat) 3355, 2940, 2873, 1770, 1673, 1454, 1376, 1231, 1104, 1006 cm1; MS (EI) m/z 91, 136, 154 (100), 307, 392 [(Mþ1)þ]; HRMS (EI) calcd for C21H29NO6 [(Mþ1)þ] 392.2073, found 392.2085.
4.3. (3R,3aS,4S,6aS)-4-((R)-3-(Benzyloxy)-2-methylpropyl)dihydro-3a-hydroxy-6a-((S)-1-(methoxymethoxy)ethyl)-1,3dimethyl-1H-furo[3,4-b]pyrrole-2,6(3H,6aH)-dione (10) To an ice-cooled solution of 7 (60.6 mg, 0.15 mmol) in ClCH2CH2Cl (1.5 mL) were added N,N-diisopropylethylamine (0.22 mL, 1.84 mmol) and methoxymethyl chloride (0.10 mL, 0.92 mmol). The mixture was heated under reflux for 9 h, and saturated NaHCO3 (5.0 mL) was added with cooling in an ice bath. The mixture was extracted with AcOEt, washed with brine, dried, and concentrated. The residue was purified by column chromatography (SiO2 5.0 g, hexane:AcOEt ¼ 2:1 to 3:2) to give 10 1 (58.2 mg, 87%) as a yellow oil. [a]22 D þ48.9 (c 1.08, CHCl3); H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 4.76 (d, J ¼ 7.1 Hz, 1H), 4.53 (d, J ¼ 7.1 Hz, 1H), 4.50 (s, 2H), 4.35e4.30 (m, 2H), 3.38 (dd, J ¼ 5.2, 9.3 Hz, 1H), 3.32e3.28 (m, 1H), 3.31 (s, 3H), 2.96 (s, 1H), 2.90 (s, 3H), 2.44 (q, J ¼ 7.6 Hz, 1H), 1.96 (m, 1H), 1.92 (dd, J ¼ 14.4, 4.1 Hz, 1H), 1.74 (dd, J ¼ 14.4, 5.6 Hz, 1H), 1.43 (d, J ¼ 6.8 Hz, 3H), 1.27 (d, J ¼ 7.6 Hz, 3H), 1.02 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 174.7, 170.9, 138.2, 128.4, 127.6, 94.6, 87.3, 81.9, 74.8, 74.5, 73.1, 69.3, 56.3, 45.7, 31.7, 30.3, 25.3, 18.0, 15.4, 11.0; FTIR (neat) 3418, 2945, 1770, 1698, 1454, 1386, 1151, 1106, 1033, 918 cm1; MS (EI) m/z 136, 154 (100), 307, 404, 436 [(Mþ1)þ]; HRMS (EI) calcd for C23H33NO7 [(Mþ1)þ] 436.2336, found 436.2371.
4.4. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-hydroxy-3methylbutyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy5-((S)-1-(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one (11) To an ice-cooled solution of 10 (52.9 mg, 0.12 mmol) in THFEtOH (1:1) (1.2 mL) was added NaBH4 (23 mg, 0.61 mmol), and the mixture was stirred at room temperature for 3 h NaBH4 (14 mg, 0.36 mmol) was added again and the mixture was stirred at room temperature for 21 h. The mixture was cooled in an ice bath, and saturated NH4Cl (5.0 mL) was added. The mixture was extracted with AcOEt, washed with brine, dried, and concentrated. The residue was dissolved in MeOH (20 mL) and evaporated to dryness to remove the moisture content. As a result, the corrsponding triol (48.1 mg) was obtained as a yellow oil. The crude triol (48.1 mg) was dissolved in CH2Cl2 (1.2 mL) and cooled to 78 C. Then, 2,6-lutidine (57 mL, 0.49 mmol) and tertbutyldimethylsilyl trifluoromrthanesulfonate (56 mL, 0.24 mmol) were added, and the mixture was stirred at e78 C for 22 h. The reaction was quenched with saturated NaHCO3 (3.0 mL) and the mixture was allowed to warm to room temperature. The mixture was extracted with AcOEt, washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 4.0 g, hexane:AcOEt ¼ 1:1) to give 11 (49 mg, 74%, 2 steps) as a colorless oil. [a]24 D þ6.8 (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.36e7.29 (m, 5H), 4.64 (d, J ¼ 6.8 Hz, 1H), 4.53 (d, J ¼ 12.0 Hz, 1H), 4.52 (d, J ¼ 6.8 Hz, 1H), 4.49 (d, J ¼ 12.0 Hz, 1H), 4.23 (q, J ¼ 6.3 Hz, 1H), 4.17e4.13 (m, 1H), 3.95 (d, J ¼ 11.0 Hz, 1H), 3.82 (d, J ¼ 11.0 Hz, 1H), 3.60 (d, J ¼ 5.4 Hz, 1H), 3.40 (m, 2H), 3.37 (s, 1H), 3.30 (s, 3H), 2.82 (s, 3H), 2.28 (q, J ¼ 7.3 Hz, 1H), 2.13e2.07 (m, 1H), 1.71 (dt, J ¼ 3.7, 11.0 Hz, 1H), 1.48e1.42 (m, 1H), 1.35 (d, J ¼ 6.3 Hz, 3H), 1.17 (d, J ¼ 7.3 Hz, 3H), 1.00 (d, J ¼ 7.0 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) d 176.9, 137.7, 128.4, 127.7, 127.5, 95.8, 80.8, 75.5, 75.2, 73.3, 71.2, 61.2, 55.8, 43.6, 36.8, 30.5, 27.2, 25.7, 18.0, 17.8, 10.6, 5.6, 5.7; FTIR (neat) 3452, 2944, 1654, 1462, 1396, 1255, 1095, 1032, 842, 777 cm1; MS (EI) m/z 91 (100), 154, 272, 360, 554 [(Mþ1)þ]; HRMS (EI) calcd for C29H51NO7Si [(Mþ1)þ] 554.3513, found 554.3525.
K. Eto et al. / Tetrahedron 74 (2018) 711e719
4.5. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy5-((S)-1-(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one (12) To a mixture of 11 (49 mg, 0.09 mmol) and molecular sieves 4 Å (200 mg, preactivated at 200 C for 3 h in vacuo) in CH2Cl2 (1.5 mL) were added trimethyloxonium tetrafluoroborate (106 mg, 0.72 mmol) and proton sponge (163 mg, 0.76 mmol) at 0 C, and the mixture was stirred at 0 C. After 8 h and 20 h, trimethyloxonium tetrafluoroborate (106 mg, 0.72 mmol) and proton sponge (163 mg, 0.76 mmol) were added each time, and stirring was continued at 0 C for additional 8 h. The mixture was filtered through Celite and the filter pad was washed with AcOEt. The filtrate and washings were washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 1:1) to give 12 (36.2 mg, 71%) as a colorless oil. 1 [a]22 D þ17.2 (c 0.95, CHCl3); H NMR (400 MHz, CDCl3) d 7.35e7.26 (m, 5H), 4.66 (d, J ¼ 6.8 Hz, 1H), 4.50 (d, J ¼ 6.8 Hz, 1H), 4.48 (s, 2H), 4.31 (q, J ¼ 6.4 Hz, 1H), 4.08 (d, J ¼ 11.5 Hz, 1H), 3.81 (dd, J ¼ 3.9.5.9 Hz, 1H), 3.64 (d, J ¼ 11.5 Hz, 1H), 3.41e3.36 (m, 1H), 3.39 (s, 3H), 3.37 (s, 3H), 3.26 (dd, J ¼ 6.8.8.9 Hz, 1H), 2.83 (s, 3H), 2.74 (s, 1H), 2.37 (q, J ¼ 7.4 Hz, 1H), 2.02 (dt, J ¼ 15.0, 5.9 Hz, 1H), 1.85e1.80 (m, 1H), 1.32 (d, J ¼ 6.4 Hz, 3H), 1.29e1.22 (m, 1H), 1.19 (d, J ¼ 7.4 Hz, 3H), 1.04 (d, J ¼ 6.6 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) d 176.9, 138.4, 128.3, 127.4, 95.6, 81.6, 75.6, 75.5, 75.3, 73.0, 61.3, 55.9, 55.8, 43.2, 33.1, 31.8, 27.8, 25.8, 18.1, 17.9, 10.2, 5.4, 5.6; FTIR (neat) 3450, 2951, 2892, 1690, 1466, 1255, 1091, 1029, 838, 420 cm1; MS (EI) m/z 85, 91 (100), 154, 298, 538, 568 [(Mþ1)þ]; HRMS (EI) calcd for C30H53NO7Si [(Mþ1)þ] 568.3669, found 568.3699. 4.6. (3R,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-(hydroxymethyl)-5-((S)-1(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one (13) To a solution of 12 (36 mg, 0.064 mmol) in THF (1.0 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.19 mL, 0.19 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated NH4Cl (3.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (AcOEt) to give 13 (25 mg, 94%) as a colorless oil. [a]23 D þ20.8 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.35e7.27 (m, 5H), 4.67 (d, J ¼ 7.0 Hz, 1H), 4.53 (d, J ¼ 7.0 Hz, 1H), 4.48 (s, 2H), 4.20 (q, J ¼ 6.3 Hz, 1H), 3.80 (d, J ¼ 5.6 Hz, 1H), 3.74 (t, J ¼ 5.0 Hz, 1H), 3.44 (s, 3H), 3.41e3.34 (m, 2H), 3.36 (s, 3H), 3.16 (s, 1H), 2.88 (s, 3H), 2.55 (q, J ¼ 7.6 Hz, 1H), 2.10e2.03 (m, 1H), 1.98e1.89 (m, 1H), 1.45e1.39 (m, 1H), 1.32 (d, J ¼ 6.3 Hz, 3H), 1.12 (d, J ¼ 7.6 Hz, 3H), 1.03 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 176.6, 138.3, 128.3, 127.6, 127.5, 95.4, 82.5, 81.5, 75.9, 75.2, 75.0, 73.2, 60.7, 57.8, 56.0, 43.2, 35.0, 32.2, 27.3, 18.2, 17.6, 9.6; FTIR (neat) 3353, 2940, 1667, 1454, 1399, 1214, 1149, 1084, 1027, 976 cm1; MS (EI) m/z 91, 136, 154 (100), 307, 454 [(Mþ1)þ]; HRMS (EI) calcd for C24H39NO7 [(Mþ1)þ] 454.2805, found 454.2797. 4.7. (3S,4S,7R,8S)-8-((1S,3R)-4-(benzyloxy)-1-methoxy-3methylbutyl)-8-hydroxy-3,5,7-trimethyl-2-oxa-5-azaspiro[3.4] octane-1,6-dione (4) To a solution of 13 (26 mg, 0.057 mmol) in acetone (1.0 mL) was added Jones' reagent (2.67 M, 67 mL, 0.18 mmol) at 0 C. After stirring at 0 C for 30 min, the reaction was quenched with i-PrOH (1.0 mL), and the mixture was filtered through Celite, and extracted with AcOEt. The extract was washed with water and brine, dried,
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and concentrated to give the corresponding aldehyde (26 mg). The crude aldehyde (26 mg) was dissolved in t-BuOH-H2O (5:1) (1.2 mL) and then NaH2PO4$2H2O (28 mg, 0.18 mmol), 2-methyl-2butene (0.20 mL, 1.80 mmol), and NaClO2 (22 mg, 0.24 mmol) were added at 0 C. After being stirred at room temperature for 12 h, the mixture was diluted with brine (2.0 mL), and extracted with AcOEt. The extract was washed with brine, dried, concentrated to give the corresponding carboxylic acid (34 mg). The crude carboxylic acid (34 mg) was dissolved in i-PrOH (1.0 mL) and ZrCl4 (14 mg, 0.06 mmol) was added at room temperature. The mixture was heated under reflux for 4 h, diluted with water (2.0 mL), extracted with AcOEt. The extract was dried, concentrated, and purified by reverse phase column chromatography (Cosmosil 1.5 g, H2O:MeCN ¼ 2:1) to give 14 (14.5 mg) as a colorless oil. To a solution of 14 (14.5 mg) in THF (1.0 mL) were added HATU (26.1 mg, 0.069 mmol) and N,N-diisopropylethylamine (17 mL, 0.14 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. The mixture was diluted with brine (1.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 2:3) to give 4 (10.3 mg, 45%; 4 steps) 1 as a colorless oil. [a]23 D þ9.1 (c 0.51, CHCl3); H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 5.15 (q, J ¼ 6.6 Hz, 1H), 4.49 (d, J ¼ 11.9 Hz, 1H), 4.47 (d, J ¼ 11.9 Hz, 1H), 3.78 (s, 1H), 3.46 (t, J ¼ 4.3 Hz, 1H), 3.40 (dd, J ¼ 4.2, 9.0 Hz, 1H), 3.34 (s, 3H), 3.29 (dd, J ¼ 6.6, 9.0 Hz, 1H), 3.00 (s, 3H), 2.48 (q, J ¼ 7.3 Hz, 1H), 1.96e1.89 (m, 2H), 1.49 (d, J ¼ 6.6 Hz, 3H), 1.36e1.27 (m, 1H), 1.12 (d, J ¼ 7.3 Hz, 3H), 0.98 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 176.3, 169.2, 138.1, 128.3, 127.6, 85.2, 81.2, 80.2, 77.2, 75.6, 73.2, 56.9, 41.6, 33.5, 31.7, 30.0, 18.4, 15.0, 11.7; FTIR (neat) 3396, 2927, 2860, 1817, 1695, 1454, 1378, 1287, 1089, 1024 cm1; MS (FAB) m/z 91, 137 (100), 289, 307, 406 [(Mþ1)þ]; HRMS (FAB) calcd for C22H32NO6 [(Mþ1)þ] 406.2229, found 406.2245.
4.8. (3R,3aS,4S,6aS)-4-((R)-3-(Benzyloxy)-2-methylpropyl)dihydro-3a-hydroxy-6a-((methoxymethoxy)methyl)-1,3-dimethyl1H-furo[3,4-b]pyrrole-2,6(3H,6aH)-dione (15) To a solution of 1 (0.92 g, 2.44 mmol) in CH2Cl2 (24 mL) were added methoxymethyl chloride (0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL, 7.31 mmol) at 0 C. After stirring at room temperature for 9 h, methoxymethyl chloride (0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL, 7.31 mmol) were added again, and the mixture was stirred at room temperature for 17 h. Additional methoxymethyl chloride (0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL, 7.31 mmol) were added, and stirring was continued at room temperature for 19 h. The mixture was diluted with saturated NaHCO3 (20 mL) at 0 C, extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by column chromatography (SiO2 30 g, hexane:AcOEt ¼ 1:2) to afford 15 1 (1.12 g, 100%) as a yellow oil. [a]20 D þ44.3 (c 1.50, CHCl3); H NMR (400 MHz, CDCl3) d 7.37e7.26 (m, 5H), 4.66 (d, J ¼ 6.4 Hz, 1H), 4.59 (d, J ¼ 6.4 Hz, 1H), 4.51 (s, 2H), 4.34 (m, 1H), 3.92 (d, J ¼ 11.0 Hz, 1H), 3.87 (d, J ¼ 11.0 Hz, 1H), 3.58 (s, 1H), 3.41 (m, 1H), 3.34 (s, 3H), 3.29 (m. 1H), 2.87 (s, 3H), 2.47 (q, J ¼ 7.6 Hz, 1H), 1.97e1.93 (m, 2H), 1.72 (m, 1H), 1.25 (d, J ¼ 7.6 Hz, 3H), 1.02 (d, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 175.1, 170.7, 137.9, 128.4, 127.7, 96.7, 86.7, 80.3, 75.0, 73.2, 71.5, 62.2, 55.9, 44.9, 32.0, 30.2, 25.8, 18.1, 11.1. FTIR (neat) 3380, 2933, 2884, 1770, 1675, 1455, 1386, 1234, 1112, 1043, 953 cm1; MS (EI) m/z 91, 149, 189, 238, 376, 421 (100) (Mþ); HRMS (EI) calcd for C22H31NO7 (Mþ) 421.2100, found 421.2094.
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4.9. (3R,4S,5R)-4-((1S,3R)-4-(benzyloxy)-1-hydroxy-3methylbutyl)-4-hydroxy-5-((methoxymethoxy)methyl)-1,3dimethyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (16)
4.11. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-(hydroxymethyl)-1,3-dimethyl-5(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (18)
To a solution of 15 (307 mg, 0.73 mmol) in THF-EtOH (1:1, 7.4 mL) was added NaBH4 (136 mg, 3.64 mmol) at 0 C, and the mixture was stirred at room temperature for 24 h. The mixture was diluted with saturated NH4Cl (10 mL) at 0 C, extracted with AcOEt, washed with brine, dried, and concentrated to give the corresponding triol (315 mg). To a solution of the crude triol (315 mg) in CH2Cl2 (5.0 mL) were added 2,6-lutidine (0.51 mL, 4.37 mmol) and triisopropylsilyl trifluoromethanesulfonate (0.59 mL, 2.19 mmol) at 78 C, and the mixture was stirred at 78 C for 21 h. The mixture was diluted with AcOEt, washed with 1 M HCl and saturated NaHCO3, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 12 g, hexane:AcOEt ¼ 1:2 to AcOEt then AcOEt:MeOH ¼ 20:1) to give 16 (398 mg, 94%, 2 steps) as a colorless oil. 1 [a]23 H NMR (400 MHz, CDCl3) D 11.0 (c 0.55, CHCl2o:13); d 7.36e7.28 (m, 5H), 4.64 (d, J ¼ 6.7 Hz, 1H), 4.60 (d, J ¼ 6.7 Hz, 1H), 4.50 (d, J ¼ 12.1 Hz, 1H), 4.48 (d, J ¼ 12.1 Hz, 1H), 4.13e4.08 (m, 1H), 3.98 (d, J ¼ 12.8 Hz, 1H), 3.96 (d, J ¼ 12.8 Hz, 1H), 3.87 (d, J ¼ 10.5 Hz, 1H), 3.81 (d, J ¼ 10.5 Hz, 1H), 3.60 (d, J ¼ 5.6 Hz, 1H), 3.47 (s, 1H), 3.44 (dd, J ¼ 6.1, 9.0 Hz, 1H), 3.38 (s, 3H), 3.36 (m, 1H), 2.86 (s, 3H), 2.43 (q, J ¼ 7.3 Hz, 1H), 2.19e2.08 (m, 1H), 1.69 (dt, J ¼ 4.1, 11.0 Hz, 1H), 1.52 (dt, J ¼ 2.7, 11.0 Hz, 1H), 1.53e1.48 (m, 1H), 1.21 (d, J ¼ 7.3 Hz, 3H), 1.12e1.01 (m, 24H); 13C NMR (100 MHz, CDCl3) d 175.9, 138.1, 128.3, 127.6, 127.4, 96.9, 81.4, 77.2, 75.2, 73.1, 71.2, 70.8, 67.5, 62.4, 56.0, 43.1, 36.5, 30.3, 26.2, 18.4, 17.9, 11.8, 10.0; FTIR (neat) 3454, 2944, 2866, 1652, 1462, 1404, 1099, 1041, 882, 697 cm1; MS (FAB) m/z 91 (100), 202, 307, 538, 582 [(Mþ1)þ]; HRMS (FAB) calcd for C31H56NO7Si [(Mþ1)þ] 582.3818, found 582.3828.
To a solution of 17 (1.20 g, 2.01 mmol) in i-PrOH (20 mL) was added ZrCl4 (141 mg, 0.60 mmol) at room temperature, and the mixture was heated under reflux for 3.5 h. The mixture was diluted with water (10 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by flush column chromatography (SiO2 40 g, hexane:AcOEt ¼ 2:1 to 1:2) to give 18 (0.96 g, 86%) as a colorless oil. 1 [a]23 D þ11.2 (c 1.06, CHCl3); H NMR (400 MHz, CDCl3) d 7.36e7.29 (m, 5H), 4.49 (s, 2H), 4.03 (d, J ¼ 12.0 Hz, 1H), 3.77 (t, J ¼ 4.7 Hz, 1H), 3.72 (s, 1H), 3.69e3.65 (m, 1H), 3.54e3.48 (m, 1H), 3.36 (s, 3H), 3.45 (m, 1H), 3.38 (d, J ¼ 11.0 Hz, 1H), 3.32 (d, J ¼ 11.0 Hz, 1H), 2.89 (s, 3H), 2.53 (q, J ¼ 7.3 Hz, 1H), 2.06e1.90 (m, 2H), 1.39e1.33 (m, 1H), 1.16 (d, J ¼ 7.3 Hz, 3H), 1.09e0.99 (m, 24H); 13C NMR (100 MHz, CDCl3) d 175.4, 137.9, 128.4, 127.7, 127.6, 83.1, 81.0, 77.2, 75.8, 73.2, 71.9, 63.0, 61.7, 56.7, 42.6, 33.9, 31.7, 26.4, 18.3, 18.0, 17.9, 11.8, 8.9; FTIR (neat) 3326, 2942, 2866, 1667, 1463, 1400, 1096, 1013, 883, 696 cm1; MS (FAB) m/z 85, 91, 154, 344, 552 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C30H54NO6Si [(Mþ1)þ] 552.3721, found 552.3730.
4.10. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-((methoxymethoxy)methyl)-1,3dimethyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (17) To a mixture of 16 (1.65 g, 2.83 mmol) and molecular sieves 4 Å (5 g, preactivated at 200 C for 3 h in vacuo) in CH2Cl2 (6.0 mL) were added trimethyloxonium tetrafluoroborate (3.13 g, 21.2 mmol) and proton sponge (4.87 g, 22.7 mmol) at 0 C, and the mixture was stirred at 0 C. After 6 h, trimethyloxonium tetrafluoroborate (3.13 g, 21.2 mmol) and proton sponge (4.87 g, 22.7 mmol) were added again, and stirring was continued at 0 C for additional 2 h. The mixture was filtered through Celite and the filter pad was washed with AcOEt. The filtrate and washings were washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 50 g, hexane:AcOEt ¼ 3:1 to 1:1) to give 17 (1.18 g, 70%) as a colorless oil. 1 [a]23 D 0.85 (c 0.97, CHCl3); H NMR (400 MHz, CDCl3) d 7.35e7.27 (m, 5H), 4.64 (d, J ¼ 6.6 Hz, 1H), 4.58 (d, J ¼ 6.6 Hz, 1H), 4.49 (s, 2H), 4.01 (d, J ¼ 10.7 Hz, 1H), 3.98 (d, J ¼ 10.7 Hz, 1H), 3.94 (d, J ¼ 11.2 Hz, 1H), 3.79 (d, J ¼ 11.2 Hz, 1H), 3.69 (t, J ¼ 5.2 Hz, 1H), 3.57 (s, 1H), 3.40 (s, 3H), 3.37 (s, 3H), 3.42e3.36 (m 1H), 3.31e3.25 (m, 1H), 2.91 (s, 3H), 2.57 (q, J ¼ 7.1 Hz, 1H), 2.02e1.85 (m, 2H), 1.37 (dt, J ¼ 14.4, 6.6 Hz, 1H), 1.19 (d, J ¼ 7.1 Hz, 3H), 1.11e1.01 (m, 24H); 13C NMR (100 MHz, CDCl3) d 175.6, 138.5, 128.3, 127.4, 96.8, 82.1, 81.1, 77.2, 75.5, 73.0, 70.6, 67.8, 63.1, 56.9, 55.8, 43.0, 33.6, 31.5, 26.6, 18.3, 18.0, 17.9, 11.8, 9.0; FTIR (neat) 3453, 2943, 2866, 1693, 1462, 1382, 1097, 1041, 882 cm1; MS (FAB) m/z 91 (100), 145, 207, 388, 596 [(Mþ1)þ]; HRMS (FAB) calcd for C32H58NO7Si [(Mþ1)þ] 596.3981, found 596.3973.
4.12. (3S,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-((R)-1-hydroxyethyl)-1,3-dimethyl-5(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (19) To a stirred solution of oxalyl chloride (34 mL, 0.39 mmol) in CH2Cl2 (0.5 mL) at 78 C was added DMSO (41 mL, 0.58 mmol). After stirring at 78 C for 1 h, a solution of 18 (71 mg, 0.13 mmol) in CH2Cl2 (0.8 mL) was added. After stirring at 78 C for 1 h, triethylamine (0.11 mL, 0.77 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was neutralized with 1 M HCl and extracted with AcOEt. The extract was washed with brine and saturated NaHCO3, dried, and concentrated to give the corresponding aldehyde (77 mg) as a yellow oil. The crude aldehyde (77 mg) was dissolved in THF (1.5 mL) and cooled to 78 C. MeMgBr (0.99 M in Et2O; 0.65 mL, 0.64 mmol) was then added and the mixture was stirred at 78 C for 15 h. The reaction was quenched by the addition of saturated NH4Cl (3.0 mL) at 78 C. The mixture was extracted with AcOEt, washed with brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 1:1) to give 19 (50 mg, 69%, 2 steps), a colorless oil, as an epimeric mixture (16S:16R ¼ 1:11). 1H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 4.55e4.45 (m, 0.1H), 4.49 (s, 2H), 4.36 (q, J ¼ 6.8 Hz, 0.9H), 3.96e3.88 (m, 2H), 3.75e3.62 (m, 3H), 3.55 (s, 0.25H), 3.41 (s, 2.75H), 3.38e3.30 (m, 2H), 2.98 (s, 0.25H), 2.94 (s, 2.75H), 2.52 (q, J ¼ 7.3 Hz, 1H), 2.00e1.90 (m, 2H), 1.38e1.29 (m, 1H), 1.26e0.96 (m, 30H); 13C NMR (100 MHz, CDCl3) d 175.9, (175.1), 138.1, 128.3, 127.6, 127.5, (84.0), 83.1, 81.2, (80.5), (77.2), (76.2), 75.7, 73.8, 73.2, (68.1), 66.8, (64.3), 61.6, (60.0), 56.5, 42.9, (37.8), 33.7, 31.3, (31.0), (27.6), (27.4), (20.1), (19.0), 18.5, 18.4, 18.0, (11.9), 11.8, 9.8, (8.6); FTIR (neat) 3337, 2943, 2866, 1669, 1461, 1391, 1090, 996, 882, 695 cm1; MS (FAB) m/z 91, 340, 358, 566 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C31H56NO6Si [(Mþ1)þ] 566.3877, found 566.3909. Note that 13C NMR peaks in the parentheses belong to the minor epimer. 4.13. (3R,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-4-hydroxy-5-((R)-1-hydroxyethyl)-5(hydroxymethyl)-1,3-dimethylpyrrolidin-2-one (21) To a solution of 19 (50 mg, 0.089 mmol) in THF (1.0 mL) was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.18 mL,
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0.18 mmol), and the mixture was stirred at room temperature for 2.5 h. The mixture was diluted with saturated NH4Cl (3.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (AcOEt) to give 21 (37 mg, 100%), a colorless oil, as an epimeric mixture (16S:16R ¼ 1:11). 1H NMR (400 MHz, CDCl3) d 7.37e7.28 (m, 5H), 4.50 (d, J ¼ 11.5 Hz, 1H), 4.46 (d, J ¼ 11.5 Hz, 1H), 4.39 (q, J ¼ 7.0 Hz, 1H), 3.98e3.89 (m, 1H), 3.80e3.78 (m, 1H), 3.67 (d, J ¼ 12.7 Hz, 1H), 3.54e3.43 (m, 6H), 3.32 (dd, J ¼ 9.0, 7.5 Hz, 1H), 2.94 (s, 2.75H), 2.85 (s, 0.25H), 2.65e2.58 (m, 1H), 2.14e1.99 (m, 2H), 1.50e1.43 (m, 1H), 1.33 (d, J ¼ 7.1 Hz, 3H), 1.02e0.98 (m, 6H); 13 C NMR (100 MHz, CDCl3) d (176.1), 175.8, 137.4, 128.5, 128.4, 128.0, (127.8), (83.3), 83.1, (82.0), 81.7, (77.2), 76.3, 73.6, (72.7), 72.6, (69.5), 67.2, (60.5), (60.4), (59.7), 59.3, 59.1, (59.0), (42.8), 42.0, (37.4), 36.2, 32.4, (31.9), (29.6), 27.4, (26.1), (19.9), (18.9), 18.5, 18.4, (8.7), 8.3, 7.8; FTIR (neat) 3360, 2940, 2877, 1665, 1458, 1387, 1090, 737 cm1; MS (FAB) m/z 91, 154, 202, 410 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C22H36NO6 [(Mþ1)þ] 410.2543, found 410.2580. Note that 13C NMR peaks in the parentheses belong to the minor epimer. 4.14. (3R,4S,7R,8S)-8-((1S,3R)-4-(Benzyloxy)-1-methoxy-3methylbutyl)-8-hydroxy-3,5,7-trimethyl-2-oxa-5-azaspiro[3.4] octane-1,6-dione (5) To a solution of 21 (52 mg, 0.13 mmol) in CH2Cl2 (1.3 mL) were added (diacetoxyiodo)benzene (82 mg, 0.25 mmol) and 2,2,6,6tetramethylpiperidine 1-oxyl (TEPMPO) (6.0 mg, 0.038 mmol) at 0 C. After stirring at 0 C for 24 h, the reaction was quenched with saturated Na2S2O3 (5.0 mL), and the mixture was extracted with AcOEt. The extract was washed with water and brine, dried, and concentrated to give the corresponding aldehyde (54 mg). The crude aldehyde (54 mg) was dissolved in t-BuOH-H2O (5:1) (1.5 mL) and NaH2PO4$2H2O (59 mg, 0.38 mmol), 2-methyl-2butene (0.44 mL, 3.80 mmol), and NaClO2 (46 mg, 0.51 mmol) were added at 0 C. After being stirred at room temperature for 24 h, the mixture was diluted with brine (2.0 mL), and extracted with AcOEt. The extract was washed with brine, dried, concentrated to give hydroxy acid 22 (87 mg). Crude 22 (87 mg) was dissolved in THF (1.5 mL) were added HATU (96.2 mg, 0.25 mmol) and diisopropylethylamine (62 mL, 0.51 mmol) at room temperature, and the mixture was stirred at room temperature for 6 h. The mixture was diluted with brine (3.0 mL) and extracted with AcOEt. The extract was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 4:5) to give 4 (3.2 mg, 6%, 3 steps) and 5 (31 mg, 61%, 3 steps) each as a colorless oil. [a]23 D þ44.7 (c 1.41, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.36e7.27 (m, 5H), 4.83 (q, J ¼ 6.4 Hz, 1H), 4.51 (d, J ¼ 12.2 Hz, 1H), 4.48 (d, J ¼ 12.2 Hz, 1H), 3.70 (t, J ¼ 4.6 Hz, 1H), 3.40e3.37 (m, 1H), 3.39 (s, 3H), 3.29 (dd, J ¼ 7.0, 9.0 Hz, 1H), 3.18 (s, 1H), 2.91 (s, 3H), 2.44 (q, J ¼ 7.6 Hz, 1H), 2.07e1.90 (m, 2H), 1.73 (d, J ¼ 6.4 Hz, 3H), 1.36e1.27 (m, 1H), 1.20 (d, J ¼ 7.6 Hz, 3H), 0.99 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 174.9, 169.5, 138.0, 128.3, 127.6, 84.2, 81.2, 77.2, 75.8, 73.2, 57.3, 42.9, 34.2, 31.6, 26.5, 18.7, 16.6, 9.8; FTIR (neat) 3404, 2932, 1820, 1695, 1456, 1389, 1299, 1267, 1183, 1088, 1036 cm1; MS (FAB) m/z 136, 154 (100), 289, 307, 406 [(Mþ1)þ]; HRMS (FAB) calcd for C22H32NO6 [(Mþ1)þ] 406.2229, found 406.2246. 4.15. (2S,3S,4R)-((Triisopropylsilyl)oxy)methyl 3-((1S,3R)-4(benzyloxy)-1-methoxy-3-methylbutyl)-3-hydroxy-2-((R)-1hydroxyethyl)-1,4-dimethyl-5-oxopyrrolidine-2-carboxylate (23) To a mixture of crude 22 (366 mg), obtained from 21 (258 mg, 0.63 mmol) as described above, and molecular sieves 4 Å (2.0 g, preactivated at 180 C for 3 h in vacuo) in CH2Cl2 (8.3 mL) were
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added C12H25SCH2OTIPS (245 mg, 0.63 mmol), tetra-n-butylammonium bromide (203 mg, 0.63 mmol), CuBr2 (140 mg, 0.63 mmol), and tiethylamine (0.18 mL, 1.26 mmol) in that order at 0 C. The mixture was stirred in the dark at room temperature for 1 h, and C12H25SCH2OTIPS (490 mg, 1.26 mmol), tetra-n-butylammonium bromide (406 mg, 1.26 mmol), and CuBr2 (280 mg, 1.26 mmol) were again added at 0 C. After being stirred in the dark at room temperature for 1 h, the mixture was filtered through Celite and the filter pad was washed with AcOEt. The filtrate and washings were washed with saturated NaHCO3 and brine, dried, and concentrated. The residue was purified by flash column chromatography (SiO2 25 g, hexane:AcOEt ¼ 3:1 to 1:3) to give 23 (263 mg, 68% from 21), a yellow oil, as an epimeric mixture. 1H NMR (400 MHz, CDCl3) d 7.36e7.28 (m, 5H), 5.51 (d, J ¼ 3.9 Hz, 1H), 5.47 (d, J ¼ 3.9 Hz, 1H), 4.64 (q, J ¼ 6.8 Hz, 1H), 4.49 (s, 2H), 3.98 (s, 1H), 3.60 (dd, J ¼ 3.0, 6.4 Hz, 1H), 3.40e3.30 (m, 2H), 3.35 (s, 3H), 2.87 (s, 3H), 2.49 (q, J ¼ 7.2 Hz, 1H), 1.99e1.93 (m, 1H), 1.83e1.77 (m, 1H), 1.46e1.42 (m, 1H), 1.15e0.90 (m, 24H), 0.97 (d, J ¼ 6.6 Hz, 3H). 4.16. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a-((1S,3R)-4benzyloxy-1-methoxy-3-methylbutyl)-2,2-diisopropyl-4,5,7trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4acarboxylate (24) To a solution of 23 (263 mg, 0.43 mmol) in ClCH2CH2Cl (4.3 mL) were added 2,6-lutidine (0.50 mL, 4.32 mmol) and diisopropyl bis(trifluoromethanesulfonate) (0.42 mL, 1.42 mmol) at room temperature, and the mixture was refluxed for 1 h. The mixture was diluted with AcOEt, washed with 1 M HCl, saturated NaHCO3, and brine, dried, and concentrated. The residue was purified by column chromatography (SiO2 13 g, hexane:AcOEt ¼ 7:1) to give 24 (273 mg, 88%), a yellow oil, as an epimeric mixture. 1H NMR (400 MHz, CDCl3) d 7.35e7.26 (m, 5H), 5.45 (brs, 2H), 4.95 (q, J ¼ 6.6 Hz, 0.9H), 4.90 (q, J ¼ 6.6 Hz, 0.1H), 4.51 (d, J ¼ 12.1 Hz, 1H), 4.47 (d, J ¼ 12.1 Hz, 1H), 3.45e3.25 (m, 3H), 3.31 (s, 3H), 2.94 (s, 3H), 2.68 (q, J ¼ 7.1 Hz, 1H), 2.00e1.80 (m, 3H), 1.51 (d, J ¼ 6.6 Hz, 3H), 1.16e0.83 (m, 41H); 13C NMR (100 MHz, CDCl3) d 176.6, 168.7, 138.5, 128.2, 127.5, 127.4, 86.0, 85.3, 77.2, 75.9, 75.6, 73.1, 68.2, 60.1, 41.9, 34.2, 31.5, 29.2, 20.7, 19.1, 17.6, 17.0, 16.8, 13.9, 13.2, 11.8, 7.7; FTIR (neat) 2943, 2866, 1738, 1710, 1463, 1381, 1164, 1109, 991, 883 cm1; MS (FAB) m/z 91 (100), 157, 284, 648, 722 [(Mþ1)þ]; HRMS (FAB) calcd for C38H68NO8Si2 [(Mþ1)þ] 722.4483, found 722.4494. 4.17. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a-((1S,3R)-4hydroxy-1-methoxy-3-methylbutyl)-2,2-diisopropyl-4,5,7trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4acarboxylate (26) A mixture of 24 (260 mg, 0.36 mmol) and 20% Pd(OH)2 (150 mg) in AcOEt (3.6 mL) was stirred at room temperature under hydrogen atmosphere. After being stirred at room temperature for 1 h, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash column chromatography (SiO2 12 g, hexane:AcOEt ¼ 4:1 to 1:1) to give 25 (18 mg, 8%) and 26 (208 mg, 91%) each as a yellow oil. 1 Compound 25. [a]22 D 21.7 (c 0.81, CHCl3); H NMR (400 MHz, CDCl3) d 5.48 (d, J ¼ 3.0 Hz, 1H), 5.43 (d, J ¼ 3.0 Hz, 1H), 4.88 (q, J ¼ 6.7 Hz, 1H), 3.58e3.49 (m, 2H), 3.38 (s, 3H), 3.33 (dd, J ¼ 10.7, 2.0 Hz, 1H), 2.94 (s, 3H), 2.75 (q, J ¼ 7.1 Hz, 1H), 2.17 (dt, J ¼ 4.0, 10.7 Hz, 1H), 1.84e1.75 (m, 1H), 1.70e1.60 (m, 1H), 1.51 (d, J ¼ 6.7 Hz, 3H), 1.17 (d, J ¼ 7.1 Hz, 3H), 1.11e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.4, 168.6, 86.0, 85.5, 77.1, 75.3, 68.7, 68.3, 61.0, 41.8, 36.6, 32.9, 29.2, 20.6, 17.6, 17.0, 16.7, 16.6, 14.0, 13.2, 11.8, 7.6; FTIR (neat) 3450, 2945, 2870, 1743, 1698, 1462, 1171, 1118, 999, 690 cm1; MS (FAB) m/z 85, 145 (100), 284, 558, 632 [(Mþ1)þ]; HRMS (FAB) calcd
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for C31H62NO8Si2 [(Mþ1)þ] 632.4014, found 632.4059. 1 Compound 26. [a]23 D þ30.0 (c 0.61, CHCl3); H NMR (400 MHz, CDCl3) d 5.46 (s, 2H), 4.98 (q, J ¼ 6.6 Hz, 1H), 3.59 (dd, J ¼ 5.4, 10.5 Hz, 1H), 3.49 (dd, J ¼ 6.3, 10.5 Hz, 1H), 3.40e3.32 (m, 1H), 3.35 (s, 3H), 2.94 (s, 3H), 2.69 (q, J ¼ 7.1 Hz, 1H), 1.99e1.80 (m, 3H), 1.51 (d, J ¼ 6.6 Hz, 3H), 1.17 (d, J ¼ 7.1 Hz, 3H), 1.11e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.5, 168.8, 86.0, 85.3, 82.3, 77.2, 75.6, 68.2, 67.6, 60.0, 41.9, 33.6, 32.8, 29.6, 29.3, 20.6, 18.0, 17.6, 17.0, 16.8, 14.0, 13.3, 11.8, 11.5, 7.7; FTIR (neat) 3450, 2944, 2869, 1742, 1698, 1462, 1170, 1125, 998, 886 cm1; MS (FAB) m/z 87, 115, 145 (100), 284, 558, 632 [(Mþ1)þ]; HRMS (FAB) calcd for C31H62NO8Si2 [(Mþ1)þ] 632.4014, found 632.4031. 4.18. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 2,2diisopropyl-7a-((1S,3R)-1-methoxy-3-methyl-4-oxobutyl)-4,5,7trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4acarboxylate (27) To a solution of 26 (190 mg, 0.30 mmol) in CH2Cl2 (3.0 mL) were added Dess-Martin periodinane (255 mg, 0.60 mmol) and NaHCO3 (51 mg, 0.60 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated Na2S2O3 (5.0 mL) at 0 C and extracted with AcOEt. The extract was washed with saturated NaHCO3 and brine, dried, concentrated. The residue was purified by flush column chromatography (SiO2 10 g, hexane:AcOEt ¼ 5:1) to give 27 (171 mg, 90%) as a colorless oil. 1 [a]22 D þ44.3 (c 1.68, CHCl3); H NMR (400 MHz, CDCl3) d 9.62 (d, J ¼ 2.0 Hz, 1H), 5.48 (d, J ¼ 3.8 Hz, 1H), 5.40 (d, J ¼ 3.8 Hz, 1H), 4.93 (q, J ¼ 6.4 Hz, 1H), 3.30e3.20 (m, 1H), 3.24 (s, 3H), 2.95 (s, 3H), 2.69 (q, J ¼ 7.2 Hz, 1H), 2.62 (brs, 1H), 2.40 (ddd, J ¼ 14.0, 10.4, 3.6 Hz, 1H), 2.26 (dd, J ¼ 14.0, 8.4, 2.4 Hz, 1H), 1.53 (d, J ¼ 6.4 Hz, 3H), 1.16e0.95 (m, 41H); 13C NMR (100 MHz, CDCl3) d 204.0, 176.2, 168.6, 85.9, 85.6, 81.0, 77.2, 75.3, 60.3, 43.6, 41.8, 30.9, 29.2, 20.6, 17.6, 17.1, 17.0, 16.9, 16.7, 13.9, 13.2, 11.7, 7.6; FTIR (neat) 2943, 2867, 1729, 1713, 1463, 1384, 1123, 1005, 883, 684 cm1; MS (FAB) m/z 55, 145, 284, 440, 600, 630 (100) [(Mþ1)þ]; HRMS (FAB) calcd for C31H60NO8Si2 [(Mþ1)þ] 630.3857, found: 630.3870. 4.19. Nozaki-Hiyama-Takai-Kishi (NHTK) reaction of 27 and 28 To a solution of NiCl2 (2.70 mg, 0.021 mmol) in degassed THFDMSO (3:1) (1.0 mL) was added CrCl2 (105 mg, 0.86 mmol) at 0 C, and the mixture was stirred at room temperature for 10 min. Then a solution of 27 (135 mg, 0.21 mmol) and 28 (184 mg, 0.43 mmol) in degassed THF-DMSO (3:1) (2.0 mL) was added. After stirring at room temperature for 67 h in the dark, the reaction was quenched with water (3.0 mL) at 0 C, and the mixture was filtered through Celite. The filtrate was extracted with AcOEt, dried, concentrated, and purified by flash column chromatography (SiO2 20 g, hexane:AcOEt ¼ 4:1) to give a 1:1 mixture of 6 and its 7S-epimer (121 mg, 61%) as a colorless oil. Compound 6 and its 7 S-epimer were obtained in pure forms by preparative TLC (toluene:AcOEt ¼ 4:1). 1 Compound 6. [a]28 D þ12.8 (c 0.45, CHCl3); H NMR (400 MHz, CDCl3) d 7.76 (d, J ¼ 7.6 Hz, 2H), 7.59 (d, J ¼ 7.6 Hz, 2H), 7.40 (t, J ¼ 7.6 Hz, 2H), 7.31 (t, J ¼ 7.6 Hz, 2H), 6.25e6.13 (m, 2H), 5.72e5.67 (m, 2H), 5.46 (d, J ¼ 3.0 Hz, 1H), 5.45 (d, J ¼ 3.0 Hz, 1H), 4.96 (q, J ¼ 6.8 Hz, 1H), 4.89 (brs, 1H), 4.42 (d, J ¼ 7.0 Hz, 2H), 4.22 (t, J ¼ 7.0 Hz, 1H), 3.97 (t, J ¼ 6.8 Hz, 1H), 3.86 (brs, 2H), 3.41 (dd, J ¼ 2.4, 9.6 Hz, 1H), 3.37 (s, 3H), 2.94 (s, 3H), 2.69 (q, J ¼ 7.2 Hz, 1H), 2.13e2.06 (m, 1H), 1.97e1.88 (m, 2H), 1.82e1.75 (m, 1H), 1.51 (d, J ¼ 6.8 Hz, 3H), 1.17 (d, J ¼ 7.2 Hz, 3H), 1.14e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.5, 168.8, 156.1, 143.9, 141.3, 134.3, 131.2, 130.7, 129.6, 127.6, 127.0, 124.9, 119.9, 86.1, 85.3, 82.9, 77.1, 75.6, 68.3, 66.7, 60.1, 47.2, 42.6, 41.8, 37.4, 32.4, 29.6, 29.3, 20.6, 17.7, 17.1, 17.0,
16.8, 16.5, 14.1, 14.0, 13.3, 11.8, 7.7; FTIR (neat) 3414, 3333, 2943, 2866, 1729, 1710, 1694, 1463, 1245, 991 cm1; MS (FAB) m/z 69 (100), 145, 284, 549, 905, 935 [(Mþ1)þ]; HRMS (FAB) calcd for C51H79N2O10Si2 [(Mþ1)þ] 935.5273, found 935.5250. 1 7S-Epimer of 6. [a]25 D þ23.0 (c 1.70, CHCl3); H NMR (400 MHz, CDCl3) d 7.77 (d, J ¼ 7.2 Hz, 2H), 7.59 (d, J ¼ 7.2 Hz, 2H), 7.40 (t, J ¼ 7.2 Hz, 2H), 7.31 (t, J ¼ 7.2 Hz, 2H), 6.27e6.15 (m, 2H), 5.75e5.66 (m, 2H), 5.46 (brs, 2H), 4.98 (q, J ¼ 6.4 Hz, 1H), 4.84 (brs, 1H), 4.42 (d, J ¼ 6.8 Hz, 2H), 4.22 (brs, 2H), 3.87 (brs, 2H), 3.40e3.30 (m, 1H), 3.86 (s, 3H), 2.95 (s, 3H), 2.67 (q, J ¼ 7.2 Hz, 1H), 2.19e2.11 (m, 1H), 1.85e1.74 (m, 2H), 1.51 (d, J ¼ 6.4 Hz, 3H), 1.17 (d, J ¼ 7.2 Hz, 3H), 1.15e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 176.5, 168.7, 156.1, 143.8, 141.3, 134.8, 131.2, 129.9, 129.4, 127.6, 127.0, 124.9, 119.9, 86.0, 85.3, 82.8, 77.2, 75.7, 68.2, 66.7, 60.0, 47.2, 42.6, 41.9, 36.0, 32.3, 29.3, 20.6, 17.6, 17.1, 16.8, 15.4, 13.9, 13.3, 11.8, 7.9; FT-IR (neat) 3419, 3335, 2944, 2866, 1725, 1707, 1692, 1246, 1163, 991 cm1; MS (FAB) m/z 145, 179 (100), 284, 666, 739, 935 (Mþþ1); HRMS (FAB) calcd for C51H79N2O10Si2 (Mþþ1) 935.5273, found: 935.5267. 4.20. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a((1S,3R,5E,7E)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1methoxy-3-methyl-4-oxonona-5,7-dien-1-yl)-2,2-diisopropyl4,5,7-trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole4a-carboxylate (29) To a solution of the NHTK coupling product (21 mg, 0.023 mmol) in CH2Cl2 (1.0 mL) were added Dess-Martin periodinane (19 mg, 0.045 mmol) and NaHCO3 (3.8 mg, 0.045 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated Na2S2O3 (3.0 mL) at 0 C, and the mixture was extracted with AcOEt. The extract was washed with saturated NaHCO3 and brine, dried, and concentrated. The residue was purified by preparative TLC (hexane-AcOEt ¼ 2:1) to give 29 (18 mg, 1 84%) as a colorless oil. [a]28 D þ25.1 (c 0.83, CHCl3); H NMR (400 MHz, CDCl3) d 7.76 (d, J ¼ 7.2 Hz, 2H), 7.58 (d, J ¼ 7.6 Hz, 2H), 7.40 (t, J ¼ 7.2 Hz, 2H), 7.31 (t, J ¼ 7.6 Hz, 2H), 7.22e7.19 (m, 1H), 6.31e6.23 (m, 2H), 6.14e6.10 (m, 1H), 5.49 (d, J ¼ 3.8 Hz, 1H), 5.39 (d, J ¼ 3.8 Hz, 1H), 4.95e4.87 (m, 2H), 4.45 (d, J ¼ 6.8, 2H), 4.22 (t, J ¼ 6.8 Hz, 1H), 3.94 (brs, 2H), 3.23 (s, 3H), 3.13 (dd, J ¼ 1.8, 10.6 Hz, 1H), 3.02e2.96 (m, 1H), 2.94 (s, 3H), 2.67 (q, J ¼ 6.8 Hz, 1H), 2.41e2.32 (m, 1H), 2.12e2.04 (m, 1H), 1.51 (d, J ¼ 6.4 Hz, 3H), 1.19 (d, J ¼ 6.8 Hz, 3H),1.17e0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) d 202.8, 176.5, 168.5, 156.1, 143.7, 141.4, 139.4, 129.3, 128.1, 127.7, 124.9, 120.0, 86.0, 85.5, 77.2, 75.4, 68.3, 66.7, 60.9, 47.2, 42.5, 41.9, 41.7, 32.4, 29.2, 20.6, 18.8, 17.6, 17.1, 17.0, 16.8, 14.0, 13.3, 11.8, 7.7; FTIR (neat) 3325, 2943, 2867, 1725, 1705, 1692, 1463, 1245, 1123, 1001 cm1; MS (FAB) m/z 136, 154 (100), 307, 903, 933 [(Mþ1)þ]; HRMS (FAB) calcd for C51H77N2O10Si2 [(Mþ1)þ] 933.5117, found 933.5137. 4.21. L-selectride reduction of 29 giving 6 To a solution of 29 (16.6 mg, 0.0178 mmol) in THF (1.0 mL) was added L-selectride (1.0 M in THF, 36 mL, 0.036 mmol) at 78 C, and the mixture was stirred at 78 C for 30 min. The reaction was quenched with saturated NH4Cl (3.0 mL), and the mixture was extracted with AcOEt. The extract was dried, and concentrated. The residue was purified by preparative TLC (hexane:AcOEt ¼ 2:1) to give a 16:1 mixture of 6 and its 7S-epimer (12.1 mg, 73%). Pure 6 (10.0 mg, 60%) was obtained as a colorless oil by further preparative TLC (toluene:AcOEt ¼ 4:1). Acknowledgments This work was supported by JSPS KAKENHI Grant Numbers
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