Studies towards the Total Synthesis of Nogalamycin: Construction of

Publication Date (Web): December 25, 2018. Copyright © 2018 American Chemical Society. Cite this:J. Org. Chem. XXXX, XXX, XXX-XXX ...
0 downloads 0 Views 2MB Size
Download PDF
Article Cite This: J. Org. Chem. 2019, 84, 760−768

pubs.acs.org/joc

Studies toward the Total Synthesis of Nogalamycin: Construction of the Complete ABCDEF-Ring System via a Convergent Hauser Annulation Ruogu Peng and Michael S. VanNieuwenhze* Department of Chemistry, Indiana UniversityBloomington, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States

Downloaded via IOWA STATE UNIV on January 18, 2019 at 12:12:28 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: The convergent synthesis of the complete ABCDEF-ring system within nogalamycin, an anthracycline natural product, was studied. The pivotal Hauser annulation for the anthraquinone core construction was achieved by the fusion of two highly functionalized segments: a cyanophthalide (the AB-ring segment) and a tricyclic quinone monoketal (the DEF-ring segment). Key transformations toward the AB-ring segment include an enantioselective enolate α-hydroxylation, a diastereoselective hydroborationoxidation, and a directed aromatic lithiation-formylation. To prepare the DEF-ring segment for annulation, a mild dearomatization of the F-ring phenol group by (diacetoxyiodo)benzene (PIDA) was employed.

■

bond with α-configuration, forming the synthetically interesting DEF-benzoxocin ring system. On the opposite end of the molecule, the methoxycarbonyl substituent at C10 in the Aring further introduces structural complexity, comparable to that resident in daunorubicin. Many synthetic efforts have been devoted toward the total synthesis of nogalamycin,6−21 most of which were focused on the construction of the DEF-ring system. So far, the total synthesis of nogalamycin still remains to be an unaccomplished task, while the total synthesis of menogaril has been reported by both Terashima14 and Hauser.10 Terashima reported the first total synthesis of menogaril (Scheme 1),14 in which a convergent annulation between naphthoquinone 3 and racemic diene 4 delivered the anthraquinone core structure 5, albeit in low yield. Unfavorable steric interactions within the proposed endo transition state resulted in a low yield of the desired product. Nevertheless, this inefficiency was partly compensated for by the three-step conversion to menogaril from 5. A few years later, Hauser’s group reported a racemic total synthesis of menogaril (Scheme 1).10 An efficient Hauser annulation between cyanophthalide 6 and α,β-unsaturated ketone 7 afforded the anthraquinone core structure 8. Multistep derivatization of the A-ring was then implemented to introduce the C-9 tertiary hydroxyl group, via a diastereoselective epoxidation/reduction sequence, with moderate selectivity. Despite their successes in achieving a total synthesis of menogaril, both annulation methods used to construct the anthraquinone core structure lacked overall

INTRODUCTION Nogalamycin 1a (Figure 1), isolated from Streptomyces nogalator,1 is a unique member of the anthracycline natural

Figure 1. Structures of the antitumor compounds nogalamycin, menogaril, and daunorubicin.

product family. Besides being a potent antibiotic, nogalamycin also shows prominent cytotoxicity against tumor cells in vitro.2 However, its weak activity against solid tumors in vivo and unacceptable toxicity profile in large animals prevented its further application in therapy against cancer.3 Subsequent exploration of its semisynthetic derivatives resulted in the discovery of menogaril 1b,3 which possessed better antitumor activity and was finally chosen for evaluation in a clinical trial.4 Structurally, the unique carbohydrate appendages on both sides of the anthracycline core distinguish nogalamycin from the more common daunorubicin-type anthracyclines 2 (Figure 1) that lack a bridging carbohydrate subunit.5 The bridging carbohydrate (nogalamine) subunit is linked to the anthracycline core via an aryl C-glycosidic bond and an O-glycosidic © 2018 American Chemical Society

Received: October 8, 2018 Published: December 25, 2018 760

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

Article

The Journal of Organic Chemistry Scheme 1. Previous Efforts Directed at Construction of the Anthraquinone Core of Menogaril

suited for preparing the 1,4-disubstitued anthraquinone moiety in nogalamycin and menogaril.28,29 Compared to situations where either an α,β-unsaturated ketone10,26,27 or an in situ generated benzyne30,31 are used as dipolarophiles, annulation reactions employing quinone monoketals are conducted under milder conditions, are highly regioselective, and afford higher yields.24,25,28 Given this precedent, we targeted the bridged tricyclic quinone monoketal (11) for use in a convergent Hauser annulation for construction of the anthracycline core. Furthermore, successful construction of the suitably functionalized AB-ring unit precursor 10 would no longer demand installation of the C9 and C10 stereocenters (A-ring) after the anthraquinone core formation, which would be very challenging for the structurally more complex AB-ring in nogalamycin. Our initial target was the AB-ring segment 10. While a racemic synthesis of the ABCD-ring system of nogalamycin has been reported,19 enantioselective construction of the AB-ring unit has not yet been achieved. Our enantioselective synthesis employed a modified route to the reported AB-ring intermediate 20 of aklavinone,32 an anthracycline natural product (Scheme 3). Given the similarities between the AB-

efficiency and/or were not convergent. As part of our ongoing studies directed at the total synthesis of nogalamycin and menogaril,22 we report herein a convergent, diastereoselective, and efficient synthesis of the carbohydrate-bridged core structure of the nogalamycin aglycone.

Scheme 3. Preparation of a Nogalamycin AB-Ring Precursor (17)

■

RESULTS AND DISCUSSION Our retrosynthetic analysis unveiled a novel annulation approach for construction of the anthraquinone core (Scheme 2) via a convergent Hauser annulation23 between two highly Scheme 2. Retrosynthetic Analysis for Synthesis of the Nogalamycin Anthraquinone Core

ring segment 10 and intermediate 20, two key modifications were made in our route: (1) use of the enantiomeric oxaziridine 19 to reverse the facial selectivity during the enolate hydroxylation33 and (2) introduction of a protecting group on the C9 tertiary alcohol to reverse the diastereoselectivity in the hydroboration step. Thus, the enantioselective enolate hydroxylation of 12 by oxaziridine 1934 gave 15 in 58% yield with a 90:10 enantiomeric ratio (Scheme 3).33 The tertiary alcohol group in 15 was protected with a benzyl group, and then, the Wittig olefination afforded alkene 16. Hydroboration followed by oxidative workup gave a separable mixture of 17 and 18 in a combined 76% yield, with a 4:1 diastereoselectivity. The major diastereomeric product was confirmed to be the desired isomer 17 by NOESY experiment.35 This result proved our initial hypothesis that a properly protected alcohol group would be sterically more hindered than the methyl group during the hydroboration step. Besides the benzyl group, silyl protecting groups as TBS and TIPS were also tested. However, much lower diastereoselectivity was observed (for TBS 52:48, TIPS 60:40). Finally, the undesired diastereomeric product 18 could be recycled back to alkene 16 in two steps with 69% yield.

functionalized segments: cyanophthalide 10 (AB-ring segment) and tricyclic quinone monoketal 11 (DEF-ring segment). The Hauser annulation has been successfully employed in the construction of naphthoquinone and anthraquinone natural products.24−27 Moreover, a Hauser annulation employing a quinone monoketal would be well 761

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

Article

The Journal of Organic Chemistry With the core structure of the AB-ring finished, the next step was to functionalize the B-ring in preparation for the Hauser annulation (Scheme 4). Removal of the benzyl protecting

Scheme 5. Synthesis of a DEF-Ring Precursor (30) from DArabinose

Scheme 4. Functionalization of an AB-Ring Precursor for Use in a Hauser Annulation

protected the primary alcohol within the open-chain form of the hemiketal intermediate, affording methyl ketone 29.16 The addition of aryl lithium or aryl Grignard reagent, derived from aryl bromide 14, to methyl ketone 29 was investigated (Scheme 5). It was anticipated that a chelatecontrolled addition would be achieved with the α-benzyloxy group to give the desired tertiary alcohol diastereomer 30.39 However, the product diastereomer ratio from the aryl lithium reagent was found to be only slightly in favor of the desired diastereomer 30. Reaction employing Grignard reagent even favored the undesired diastereomer 31. Stereochemistry of the newly formed tertiary alcohol could not be determined at this stage, but the later conversion of 30 to the DEF-ring segment made the structure assignment possible. The observed selectivity may have been the result of the electron-withdrawing β-azido substituent also participating via Evan’s nonchelation model, which favors the undesired diastereomer 31.40 Despite the moderate yield, the aryl lithium reagent addition could yield multigrams of 30 in one batch to provide enough materials for the subsequent steps. After removal of the primary alcohol protecting group in 30 (Scheme 6), attempts to selectively oxidize the diol to lactol 34 failed with overoxidation to the corresponding lactone. We next opted to pursue a strategy involving protection of both alcohol groups as their TES ethers, followed by oxidation of the primary TES ether under the Swern oxidation conditions to give the aldehyde 33 in good yield.41 The tertiary alcohol was deprotected under acidic conditions, and in situ cyclization of the tertiary alcohol onto the aldehyde gave the lactol 34. 34 was transformed to methyl glycoside 35 in order to be protected against the subsequent CAN oxidation conditions. The p-dimethoxy benzene derivative 35 was converted to the hydroquinone through an oxidation−reduction sequence by CAN and then sodium dithionite (Scheme 6).15 Under mild conditions, 36 was reduced by sodium dithionite. Cyclization of the hydroquinone intermediate under acidic conditions provided the DEF-ring fragment precursor 37. Dearomatization by (diacetoxyiodo)benzene (PIDA) in the presence of MeOH completed our synthesis of the DEF-ring fragment precursor 11 and set the stage for the Hauser annulation.24 The Hauser annulation between 10 and 11 (Scheme 7) was first tested with LiHMDS as base and provided the complete anthracycline core 9 in 31% yield, with a 20% yield of recovered 11. Another base, LiOtBu, was reported to give higher yields in some Hauser annulations.23 Upon using

group and protection of both alcohol groups as TBS ethers afforded 21. The TBS group was used for its stability to the ortho-lithiation conditions and enhanced solubility of 21 in hexane.36 Control experiments involving lithiation followed by D2O quenching revealed that the desired site could be lithiated with high efficiency. Direct formation of diethyl amide by quenching with Et2NCOCl after lithiation failed, even with freshly distilled Et2NCOCl. To circumvent this problem, lithiation was followed by DMF quenching to give aldehyde 22. Aldehyde 22 was then oxidized to carboxylic acid 23, which was coupled with Et2NH to afford the corresponding diethyl amide with good yield in three steps. The second lithiation proceeded smoothly with the amide as the directing group, followed by capturing the lithiated intermediate with DMF to give 24. O-Aldehyde-benzamide 24 was identified to be a mixture of two separable conformational isomers, which quickly re-equilibrated back to the initial mixture upon separation by silica gel chromatography. Due to the presence of two ortho groups, restricted rotation of the amide group may give rise to the conformational isomer formation. Spectroscopic characterization of 24 was indirectly realized by its conversion to 25. A single diastereomer product was observed (by NMR) and isolated, which has confirmed that 24 exists as a mixture of conformational isomers. Finally, 24 was converted to the cyanophthalide 10 as a mixture of diastereomers in good yield.37 Synthesis of the DEF-ring segment began with the commercially available D-arabinose 13 to take advantage of the chirality within its structure (Scheme 5), similar to Terashima’s work on menogaril.16 Instead of a protected amine in the F-ring as utilized in Terashima’s work,16 an azide substituent was employed. With multiple methods available for azide reduction, more flexibility is anticipated for functional group conversion after the anthraquinone core formation. Following the literature precedents, compound 26 was synthesized in five steps from D-arabinose 13 in overall good yields.16,38 Hydrolysis of 27 and subsequent oxidation led to lactone 28, which was reacted with MeLi to give a hemiketal intermediate whereupon treatment by TBS−Cl selectively 762

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

The Journal of Organic Chemistry

■

Scheme 6. Preparation of a Protected DEF-Fragment Precursor (11) from Azidoalcohol 30

Article

EXPERIMENTAL SECTION

General Methods. Unless otherwise noted, all reactions were carried out in oven-dried glassware under an atmosphere of argon. Anhydrous solvents were bought from Aldrich in Sure/Seal bottles. All commercially available reagents were used as received. 1 H NMR spectra were measured at 400 or 500 MHz, and 13C NMR spectra were measured at 100 or 125 MHz. Chemical shifts are reported relative to the internal TMS standard or the solvent residue peak. Analytical thin layer chromatography (TLC) was performed using Whatman glass plates coated with a 0.25 mm thickness of silica gel containing PF 254 indicator, and compounds were visualized with UV light and cerium molybdate stain. Flash chromatography purifications were performed using Silicycle 60 Å, 35−75 μm silica gel. ESI-HRMS were recorded with a Waters/Micromass LCT Classic time-of-flight mass spectrometer. Compounds 12,42 19,34 and 2616,38 were prepared by following the reported procedures. (S)-2-Hydroxy-5-methoxy-2-methyl-3,4-dihydronaphthalen1(2H)-one (15). Following the procedure reported by Davis,33 methyl tetralone 12 (0.57 g, 3 mmol) was dissolved in anhydrous THF (6 mL) and the solution was cooled to −78 °C. NaHMDS (6 mL, 0.6 M in toluene, 3.6 mmol) was added, and the stirring was continued for 30 min. Then, a cooled solution of the oxaziridine 19 (1.07 g, 3.6 mmol) at −78 °C was cannulated into the reaction dropwise and the stirring was continued at −78 °C for 1 h. The reaction was quenched with saturated aqueous NH4Cl (4 mL) and warmed up to room temperature. The mixture was diluted with ether and filtered through silica. The filtrate was concentrated, and the residue was purified by flash chromatography (hexane:EtOAc = 10:1, then 7:1) to give 15 as a white wax (0.362 g, 58%). [α]26D −8.5 (c 1.8, CHCl3); lit.33 enantiomer of 15, [α]20D +7.0 (c 1.8, CHCl3); the er was determined by chiral HPLC to be 90:10 (CHIRALPAK IA, 250 × 2.0 mm2, hexane:EtOAc = 80:20, retention time t1 = 7.20 min, t2 = 8.68 min). The 1H NMR and 13C{1H} NMR spectra were in accordance with those reported in the literature.43 (S)-2-(Benzyloxy)-5-methoxy-2-methyl-1-methylene-1,2,3,4-tetrahydronaphthalene (16). Tertiary alcohol 15 (1.98 g, 9.6 mmol) was dissolved in DMF (25 mL), and then, NaH (1.15 g, 60% in oil, 28.8 mmol) was added portionwise in an ice bath. Twenty minutes later, BnBr (3.4 mL, 28.8 mmol) was added dropwise and the reaction was stirred at room temperature for 1 h before being quenched by ice. The mixture was diluted with hexane and washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 100:0, then 30:1 and 20:1) to give the benzyl protected alcohol as a colorless oil (2.31 g, 81%). A suspension of Ph3PCH3Br (10.05 g, 28.1 mmol) in THF (40 mL) was cooled to −78 °C, and KHMDS in PhMe (0.5 M, 48 mL, 24 mmol) was added. The reaction was then stirred at room temperature for 40 min before being cooled back to −78 °C. A solution of the above benzyl protected alcohol (2.31 g, 8 mmol) in THF (26 mL) was added. The reaction was removed to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with ether. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 100:0, then 25:1) to give 16 as a colorless oil (2.22 g, 77% from 15). [α]26D +29 (c 3.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.26−7.16 (m, 5H), 7.11 (d, J = 6.8 Hz, 2H), 6.80 (d, J = 7.9 Hz, 1H), 5.71 (s, 1H), 5.39 (s, 1H), 4.39 (ABq, J = 11.4 Hz, 2H), 3.86 (s, 3H), 3.02 (ddd, J = 17.5, 9.0, 6.5 Hz, 1H), 2.87−2.69 (m, 1H), 2.26 (ddd, J = 13.2, 6.3, 4.8 Hz, 1H), 1.92 (ddd, J = 13.4, 9.1, 6.4 Hz, 1H), 1.56 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 156.9, 146.8, 139.6, 135.4, 128.0, 127.2, 126.9, 126.2, 125.6, 117.6, 109.8, 108.7, 75.0, 64.6, 55.3, 34.9, 23.6, 20.4; IR (film, cm−1) υmax3053, 2916, 1451, 1250, 1047, 785; HRMS-ESI m/z Calcd for C20H23O2 ([M + H]+): 295.1693. Found: 295.1688. ((1S,2S)-2-(Benzyloxy)-5-methoxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl) Methanol (17) and ((1R,2S)-2-(Benzyloxy)-5methoxy-2-methyl-1,2,3,4-tetrahydro naphthalen-1-yl)methanol (18). A solution of alkene 16 (0.561 g, 1.91 mmol) in THF (10

Scheme 7. Hauser Annulation of 10 and 11 to Provide the Protected Anthraquinone Core Structure of Nogalamycin

LiOtBu as base, the yield of 9 was increased to 43% along with a 17% yield of recovered 11. Increasing the amount of LiOtBu (4.5 equiv) resulted in complete consumption of 11, and the yield of the desired product 9 was increased to 74%. Under these optimized conditions, this Hauser annulation reaction proved to be very efficient, providing nearly 500 mg of 9 in a single batch.

■

CONCLUSION Construction of the fully functionalized ABCDEF-ring system in noglamycin has been achieved via a key Hauser annulation. A tricyclic quinone monoketal has been employed, for the first time, as the Michael acceptor for the Hauser annulation, while a bicyclic cyano phthalide acted as the nucleophile. The high efficiency and convergence of the Hauser annulation have paved the way for the anthraquinone core structure of nogalamycin and provided the foundation for the first total synthesis of nogalamycin. Further studies are ongoing in our laboratory and will be reported in due course. 763

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

Article

The Journal of Organic Chemistry

2962, 2870, 1581, 1459, 1243, 827, 767; HRMS-ESI m/z Calcd for C25H46O3Si2Na ([M + Na]+): 473.2883. Found: 473.2864. (5S,6S)-6-(tert-Butyldimethylsilyloxy)-5-((tertbutyldimethylsilyloxy)methyl)-1-methoxy-6-methyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (22). The bis-TBS ether 21 (0.5 g, 1.1 mmol) and TMEDA (0.88 mL, 6.27 mmol) were dissolved in hexane (11 mL) and cooled to 0 °C. To the solution was added tBuLi (3.7 mL, 1.7 M in pentane, 6.27 mmol), and the reaction was stirred for 80 min at 0 °C. The reaction was cooled to −78 °C, and DMF (1.1 mL, 14.85 mmol) was added. The mixture was slowly warmed up to −30 °C before being quenched with saturated aqueous NH4Cl (2 mL). The mixture was diluted with DCM and washed with saturated aqueous NH4Cl. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1) to give 22 as a colorless oil (0.413 g, 84%). [α]26D −34.3 (c 0.5, DCM); 1H NMR (CDCl3, 500 MHz) δ 10.31 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 4.03 (dd, J = 9.8, 3.6 Hz, 1H), 3.92 (dd, J = 9.8, 5.7 Hz, 1H), 3.86 (s, 3H), 3.01 (ddd, J = 18.0, 6.9, 2.7 Hz, 1H), 2.72− 2.64 (m, 2H), 2.31−2.17 (m, 1H), 1.84−1.69 (m, 1H), 1.24 (s, 3H), 0.89 (s, 9H), 0.76 (s, 9H), 0.15 (s, 6H), −0.11 (s, 3H), −0.21 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 190.1, 161.2, 148.5, 130.0, 126.8, 126.7, 125.4, 73.5, 64.7, 63.1, 53.8, 33.0, 28.2, 25.9, 25.8, 25.7, 21.7, 18.3, 18.1, −1.8, −1.9, −5.6, −5.9; IR (film, cm−1) υmax 3076, 2962, 2867, 1700, 1592, 1240, 850, 782; HRMS-ESI m/z Calcd for C26H47O4Si2 ([M + H]+): 479.3013. Found: 479.3002. (5S,6S)-6-(tert-Butyldimethylsilyloxy)-5-((tertbutyldimethylsilyloxy)methyl)-1-methoxy-6-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic Acid (23). The aldehyde 22 (0.809 g, 1.69 mmol) was dissolved in a mixture of tBuOH (13 mL) and THF (13 mL), and the solution was cooled in an ice bath. Then, a solution of NaClO2 (0.77 g, 8.45 mmol) and NaH2PO4 (0.70 g, 5.07 mmol) in water (13 mL) was added. After 40 min, the reaction was diluted with EtOAc and washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give 23 as a white wax (0.83 g, 99%). [α]26D −31 (c 0.18, DCM); 1H NMR (CDCl3, 500 MHz) δ 11.30 (bs, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 4.03 (dd, J = 9.8, 3.6 Hz, 1H), 3.93−3.87 (m, 4H), 3.00 (ddd, J = 17.8, 6.7, 3.4 Hz, 1H), 2.72−2.66 (m, 2H), 2.23 (ddd, J = 12.4, 10.3, 6.9 Hz, 1H), 1.81−1.69 (m, 1H), 1.26 (s, 3H), 0.89 (s, 9H), 0.77 (s, 9H), 0.15 (s, 3H), 0.15 (s, 3H), −0.09 (s, 3H), −0.19 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 166.9, 157.3, 147.6, 129.7, 129.3, 127.1, 119.3, 73.3, 64.7, 61.9, 53.5, 33.3, 28.2, 25.9, 25.7, 21.9, 18.3, 18.1, −1.9, −5.6, −5.8; IR (film, cm−1) υmax 3089, 2963, 2867, 1708, 1594, 1249, 829, 766; HRMS-ESI m/z Calcd for C26H46O5Si2Na ([M + Na]+): 517.2781. Found: 517.2773. (5S,6S)-6-(tert-Butyldimethylsilyloxy)-5-((tertbutyldimethylsilyloxy)methyl)-N,N-diethyl-3-formyl-1-methoxy-6methyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (24). The carboxylic acid 23 (0.83 g) was dissolved in THF (20 mL), and the solution was cooled in an ice bath. Et3N (0.31 mL, 2.2 mmol) was added, followed by addition of pivaloyl chloride (0.25 mL, 2.0 mmol). The reaction was stirred in an ice bath for 50 min before the addition of Et3N (0.31 mL, 2.2 mmol) and Et2NH (0.47 mL, 3.38 mmol). The reaction was stirred at room temperature for 17 h and diluted with DCM. The mixture was washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 4:1) to give the diethyl amide product as a white wax (0.83 g, 89%). HRMS-ESI m/z Calcd for C30H56NO4Si2 ([M + H]+): 550.3748. Found: 550.3760. Diethyl amide (0.306 g, 0.56 mmol) was dissolved in THF (8 mL), and TMEDA (0.25 mL, 1.68 mmol) was added. The solution was cooled to −78 °C. To the solution was added tBuLi (3.7 mL, 1.7 M in pentane, 6.27 mmol) ,and the reaction was stirred for 1 h at −78 °C. DMF (1.1 mL, 14.85 mmol) was added, and the reaction was slowly warmed up to −40 °C before being quenched with saturated aqueous NH4Cl (1 mL). The mixture was diluted with DCM and washed with saturated aqueous NH4Cl. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product

mL) was cooled by ice bath, and BH3 in THF (11.4 mL, 1 M, 11.46 mmol) was added dropwise. The reaction was stirred at room temperature for 4 h and then cooled back down in an ice bath. EtOH (15 mL), 3 M NaOH (15 mL), and 30% H2O2 (15 mL) were added to the reaction carefully. The mixture was then stirred at room temperature overnight before being diluted with EtOAc and washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 6:1, then 5:1) to give first the major diastereomer 17 (0.36 g, 61%) and then the minor diastereomer 18 (0.09 g, 15%). 17, colorless oil; [α]26D −18.5 (c 3.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.43−7.35 (m, 4H), 7.35−7.27 (m, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.64 (ABq, J = 10.9 Hz, 2H), 4.11 (dd, J = 11.8, 9.0 Hz, 1H), 3.84 (s, 3H), 3.75 (dd, J = 11.8, 3.0 Hz, 1H), 3.55 (s, 1H), 3.14 (m, 1H), 3.01 (ddd, J = 18.3, 6.3, 2.8 Hz, 1H), 2.56 (ddd, J = 18.3, 11.0, 7.3 Hz, 1H), 2.25−1.98 (m, 2H), 1.40 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 156.8, 138.6, 137.4, 128.4, 127.5, 127.3, 126.6, 124.0, 122.2, 107.2, 78.9, 67.3, 63.4, 55.1, 51.8, 26.9, 22.4, 21.5; IR (film, cm−1) υmax 3464, 3018, 2922, 1595, 1264, 1127, 728; HRMS-ESI m/z Calcd for C20H24O3Na ([M + Na]+): 335.1623. Found: 335.1617. 18, colorless oil: [α]26D −9.5 (c 3.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.36−7.13 (m, 5H), 7.15 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.52 (ABq, J = 11.3 Hz, 2H), 3.99 (ABx, J = 11.2, 5.9 Hz, 2H), 3.82 (s, 3H), 3.20 (t, J = 5.8 Hz, 1H), 2.85 (dt, J = 18.0, 7.0 Hz, 1H), 2.67 (dt, J = 18.0, 6.7 Hz, 1H), 2.41 (s, 1H), 2.15−1.93 (m, 2H), 1.41 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 157.1, 139.1, 137.0, 128.2, 127.2, 127.1, 126.5, 125.2, 120.2, 107.5, 76.6, 64.7, 63.0, 55.2, 48.6, 31.0, 21.0, 20.5; IR (film, cm−1) υmax 3375, 3018, 1576, 1475, 1262, 728; HRMS-ESI m/z Calcd for C20H24O3Na ([M + Na]+): 335.1623. Found: 335.1625. Conversion of the Undesired Diastereomer 18 to Alkene 16. The minor diastereomer 18 (0.40 g, 1.3 mmol) was dissolved in DCM (12 mL), and the solution was cooled in an ice bath. Et3N (0.71 mL, 5.2 mmol) was added followed by addition of MsCl (0.2 mL, 2.6 mmol). After 30 min, the reaction was removed to room temperature and stirred for 10 min before being diluted with DCM. The mixture was washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give the crude mesylate (0.63 g). The crude mesylate (0.63 g) was dissolved in MeCN (35 mL), and DBU (1.5 mL, 10.4 mmol) was added. The reaction was stirred at room temperature for 15.5 h, while TLC showed only little conversion. Then, the reaction was stirred at 70 °C for 7 h and concentrated. The residue was purified by flash chromatography (hexane:EtOAc = 25:1) to give 16 (0.26 g, 67% for two steps). tert-Butyl(((1S,2S)-2-(tert-butyldimethylsilyloxy)-5-methoxy-2methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)dimethylsilane (21). The alcohol 17 (0.191 g, 0.61 mmol) was dissolved in EtOH (7 mL), and Pd/C (61 mg, 10 wt %) was added. The reaction was stirred under a balloon of H2 for 80 min before being filtered through Celite. The filtrate was concentrated to give the crude diol. The crude diol was then dissolved in DCM (6 mL), and the solution was cooled in an ice bath. Et3N (0.43 mL, 3.05 mmol) was added, followed by addition of TBSOTf (0.42 mL, 1.83 mmol). The reaction was stirred at room temperature for 1.5 h before being diluted with DCM. The mixture was washed with brine, and the organic phase was dried by MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (hexane:EtOAc = 30:1) to give the product 21 as a colorless oil (0.272 g, 99% for two steps). [α]26D −53 (c 0.25, DCM); 1H NMR (CD2Cl2, 400 MHz) δ 7.09 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.13 (dd, J = 9.6, 3.5 Hz, 1H), 3.85 (dd, J = 9.6, 6.6 Hz, 1H), 3.81 (s, 3H), 2.93 (dd, J = 18.4, 6.0 Hz, 1H), 2.68 (s, 1H), 2.54 (ddd, J = 18.5, 11.0, 7.7 Hz, 1H), 2.20 (td, J = 11.8, 7.5 Hz, 1H), 1.82−1.71 (m, 1H), 1.25 (s, 3H), 0.96 (s, 9H), 0.83 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H), −0.07 (s, 3H), −0.15 (s, 3H); 13C{1H} NMR (CD2Cl2, 100 MHz) δ 157.0, 140.0, 125.4, 123.8, 123.0, 107.0, 74.0, 65.2, 55.1, 53.4, 32.9, 27.8, 25.8, 25.6, 25.5, 22.2, 18.2, 18.0, −2.01, −2.07, −5.9, −6.0; IR (film, cm−1) υmax 3058, 764

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

Article

The Journal of Organic Chemistry was purified by flash chromatography (hexane:EtOAc = 5:1, then 3:1) to give 24 as a white wax, which was shown by 1H NMR as a mixture of conformational isomers (0.29 g, 91%). 1H NMR (400 MHz, CDCl3, mixture of two conformational isomers) δ 9.92 (s), 9.91 (s), 7.78 (s), 7.59 (s), 3.98−3.94 (m), 3.81 (s), 3.80 (s), 3.77−3.69 (m), 3.55−3.50 (m), 3.40−3.38 (m), 3.16−3.08 (m), 2.90−2.89 (m), 2.82−2.75 (m), 2.67−2.57 (m), 2.33−2.21 (m), 2.19−2.12 (m), 1.80−1.70 (m), 1.31 (t, J = 7.1 Hz), 1.28−1.25 (m), 1.23 (s), 1.14 (t, J = 7.0 Hz), 0.98 (q, J = 6.8 Hz), 0.90 (s), 0.86 (s), 0.84 (s), 0.72 (s), 0.15 (s), 0.14 (s), −0.02 (s), −0.08 (s), −0.14 (s), −0.25 (s); HRMSESI m/z Calcd for C31H56NO5Si2 ([M + H]+): 578.3697. Found: 578.3671. (5S,6S)-6-(tert-Butyldimethylsilyloxy)-5-((tertbutyldimethylsilyloxy)methyl)-9-methoxy-6-methyl-5,6,7,8tetrahydronaphtho[2,3-c]furan-1(3H)-one (25). Aldehyde 24 (13 mg, 0.023 mmol) was dissolved in a mixture of THF (1 mL) and EtOH (1 mL). To the mixture was added NaBH4 (1.3 mg, 0.03 mmol), and the reaction was stirred at room temperature for 10 min before being quenched by saturated aqueous NH4Cl. The mixture was extracted with DCM. The organic phase was dried by MgSO4, filtered, and concentrated to give the crude alcohol (12.4 mg). The crude alcohol was dissolved in a mixture of AcOH (1.5 mL) and EtOAc (0.5 mL), and the reaction was stirred at room temperature for 112 h. The reaction was quenched with saturated aqueous NaHCO3, and the mixture was extracted with DCM. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was subjected to the same reaction conditions for 72 h. After workup, the crude product was purified by flash chromatography (hexane:EtOAc = 5:1) to give 25 as a white wax (6.8 mg, 60% for two steps). [α]26D −31 (c 0.17, DCM); 1 H NMR (CDCl3, 500 MHz) δ 7.05 (s, 1H), 5.18 (ABq, J = 15 Hz, 2H), 4.14−4.04 (m, 4H), 3.78 (dd, J = 9.7, 6.8 Hz, 1H), 3.03 (dd, J = 18.5, 5.2 Hz, 1H), 2.76−2.71 (m, 1H), 2.65 (ddd, J = 18.4, 10.7, 7.5 Hz, 1H), 2.19−2.09 (m, 1H), 1.81−1.71 (m, 1H), 1.23 (s, 3H), 0.90 (s, 9H), 0.77 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H), −0.12 (s, 3H), −0.18 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 169.1, 156.9, 148.5, 145.1, 128.9, 118.5, 113.9, 73.4, 68.8, 64.8, 62.0, 54.2, 32.8, 28.1, 25.9, 25.7, 22.1, 18.3, 18.1, −1.8, −1.9, −5.6, −5.8; IR (film, cm−1) υmax 2966, 2860, 1745, 1458, 1251, 1138, 846; HRMS-ESI m/z Calcd for C27H47O5Si2 ([M + H]+): 507.2962. Found: 507.2976. (7S,8S)-7-(tert-Butyldimethylsilyloxy)-8-((tertbutyldimethylsilyloxy)methyl)-4-methoxy-7-methyl-3-oxo1,3,5,6,7,8-hexahydronaphtho[2,3-c]furan-1-carbonitrile (10). To a stirred solution of the aldehyde 24 (0.504 g, 0.87 mmol) in DCM (5 mL) were added KCN (0.006 g, 0.087 mmol) and 18-crown-6 (0.023 g, 0.087 mmol) in an ice bath. TMSCN (0.16 mL, 1.31 mmol) was then added. The stirring was continued at 0 °C for 1.5 h and another 1 h at room temperature. The mixture was concentrated on a rotovap in a fume hood. AcOH (5.5 mL) was added to the residue (CAUTION! HCN formation), and the reaction was stirred at room temperature for 5 days before being quenched by excess saturated aqueous NaHCO3. The mixture was extracted by DCM. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 5:1) to give the cyanophthalide 10 (0.318 g, 78%) as a white solid, which was shown by 1H NMR to be a mixture of diastereomers. 1H NMR (400 MHz, CDCl3, mixture of two diastereomers) δ 7.27 (s), 5.94 (s), 5.90 (s), 4.17−4.07 (m), 3.87 (dd, J = 9.8, 6.3 Hz), 3.78 (dd, J = 9.9, 7.0 Hz), 3.11−2.95 (m), 2.84− 2.57 (m), 2.26−2.07 (m), 1.85−1.70 (m), 1.26 (s), 1.22 (s), 0.90 (s), 0.89 (s), 0.79 (s), 0.78 (s), 0.15 (s), 0.15 (s), −0.04 (s), −0.09 (s), −0.13 (s), −0.14 (s); HRMS-ESI m/z Calcd for C28H45NO5Si2Na ([M + Na]+): 554.2734. Found: 554.2747. (2R,3R,4S,5S)-4-Azido-3,5-bis(benzyloxy)-2-methoxytetrahydro2H-pyran (27). Epoxide 26 (6.68 g, 46 mmol) was dissolved in DMF (90 mL). To the solution was added NH4Cl (8.73 g, 160 mmol) and NaN3 (5.95 g, 92 mmol). The mixture was heated at 95 °C for 23 h and then cooled to room temperature. The reaction was diluted with EtOAc (150 mL) and filtered through a pad of Celite (top) and silica (bottom). The filter cake was washed with EtOAc (250 mL × 3). The

filtrate was dried by MgSO4, concentrated, and azeotroped with toluene to give the crude diol product. The crude diol was dissolved in DMF (60 mL), and the mixture was cooled to 0 °C. NaH (5.86 g, 60% suspension in oil, 147 mmol) was added, and the stirring was continued for 20 min at 0 °C. To the mixture was added BnBr (16.3 mL, 137 mmoL), and the reaction was warmed up to room temperature. After 1 h, the reaction was quenched with MeOH (20 mL) and diluted with icy water. The mixture was extracted with DCM. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 30:1, then 20:1, 15:1, and 10:1) to give 27 as a colorless oil (14.73 g, 87% for two steps). [α]26D −20.2 (c 0.8, acetone); lit.38 [α]15D −21.2 (c 0.82, acetone); 1H NMR (CDCl3, 400 MHz) δ 7.43−7.25 (m, 10H), 4.73 (ABq, J = 11.0 Hz, 2H), 4.71 (ABq, J = 10.8 Hz, 2H), 4.23 (d, J = 7.5 Hz, 1H), 3.92 (dd, J = 11.6, 5.1 Hz, 1H), 3.52 (s, 3H), 3.50 (t, J = 9.6 Hz, 1H), 3.38 (td, J = 9.8, 5.2 Hz, 1H), 3.24−3.10 (m, 2H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 137.9, 137.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8, 105.1, 79.8, 76.1, 74.6, 73.3, 67.5, 64.5, 57.0; IR (film, cm−1) υmax 3032, 2868, 2105, 1455, 1267, 1079, 738, 698; HRMS-ESI m/z Calcd for C20H23N3O4Na ([M + Na]+): 392.1586. Found: 392.1581. (3R,4S,5S)-4-Azido-3,5-bis(benzyloxy)tetrahydro-2H-pyran-2one (28). Methyl acetal 27 (7.32 g, 0.02 mol) was heated in a mixture of AcOH (73 mL) and 4 M HCl (16 mL) at 80 °C for 5 h. The reaction was cooled to room temperature and neutralized with saturated aqueous NaHCO3. The mixture was extracted by DCM, and the organic phase was dried by MgSO4. After evaporation, the residue was purified by flash chromatography (hexane:EtOAc = 4:1) to give the anomeric hemiacetal as a colorless oil (4.73 g, 67%). The hemiacetal (4.73 g, 0.013 mol) was dissolved in DCM (100 mL) and cooled to 0 °C. To the solution was added DMSO (9.46 mL, 0.13 mol), iPr2NEt (9.27 mL, 0.052 mol), and Py·SO3 (6.36 g, 0.039 mol). The reaction was stirred at 0 °C for 40 min before being diluted with DCM. The mixture was washed with brine, and the organic phase was dried by MgSO4. After evaporation, the residue was purified by flash chromatography (hexane:EtOAc = 8:1, then 4:1) to give 28 as a white wax (3.55 g, 76%). [α]27D +7.9 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.50−7.26 (m,10H), 4.89 (ABq, J = 11.2 Hz, 2H), 4.61 (ABq, J = 12 Hz, 2H), 4.27 (dd, J = 12.5, 3.8 Hz, 1H), 4.17 (dd, J = 12.5, 3.1 Hz, 1H), 3.96 (d, J = 9.3 Hz, 1H), 3.90 (dd, J = 9.2, 3.9 Hz, 1H), 3.62 (dd, J = 7.2, 3.7 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.7, 136.5, 136.3, 128.6, 128.6, 128.5, 128.3, 128.3, 127.9, 76.0, 75.1, 73.7, 71.5, 66.4, 65.1; IR (film, cm−1) υmax 3028, 2901, 2874, 2106, 1751, 1454, 1256, 1147, 869, 734; HRMSESI m/z Calcd for C19H19N3O4Na ([M + Na]+): 376.1273. Found: 376.1260. (3R,4S,5S)-4-Azido-3,5-bis(benzyloxy)-6-(tertbutyldimethylsilyloxy)hexan-2-one (29). Lactone 28 (3.55 g, 10 mmol) was dissolved in THF (65 mL). At −78 °C, MeLi (6.9 mL, 11 mmol, 1.6 M in ether) was added dropwise. After 2.5 h, the reaction was quenched with water (4 mL) and diluted with EtOAc. The mixture was washed with brine, and the organic phase was dried by MgSO4. After evaporation, the crude hemiketal (3.89 g) was dissolved in DMF (80 mL) and imidazole (7.49 g, 105.6 mmol) was added. To the solution was added TBSCl (6.33 g, 40.3 mmol) portionwise. The reaction was stirred at room temperature for 24 h and then diluted with ether. The mixture was washed with brine, and the organic phase was dried by MgSO4. After evaporation, the residue was purified by flash chromatography (hexane:EtOAc = 25:1, then 20:1 and 10:1) to give 29 as a colorless oil (4.59 g, 94% for two steps). [α]26D +27.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.42−7.27 (m, 10H), 4.61 (ABq, J = 11.5 Hz, 2H), 4.60 (ABq, J = 12 Hz, 2H), 4.06 (d, J = 6.0 Hz, 1H), 3.91 (t, J = 5.4 Hz, 1H), 3.70 (dd, J = 10.6, 5.5 Hz, 1H), 3.58 (dd, J = 9.8, 4.9 Hz, 1H), 3.49 (dd, J = 10.6, 4.3 Hz, 1H), 2.20 (s, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 208.4, 137.8, 136.6, 128.6, 128.3, 128.3, 128.2, 128.0, 127.8, 83.9, 78.5, 73.4, 73.0, 63.1, 61.3, 26.5, 25.8, 18.1, −5.5, −5.6; IR (film, cm−1) υmax 3032, 2929, 2857, 2107, 1716, 1455, 1257, 1095, 765

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

Article

The Journal of Organic Chemistry 837; HRMS-ESI m/z Calcd for C26H37N3O4SiNa ([M + Na]+): 506.2451. Found: 506.2444. (2R,3R,4S,5S)-4-Azido-3,5-bis(benzyloxy)-6-(tert-butyldimethylsilyloxy)-2-(2,5-dimethoxyphenyl)hexan-2-ol (30) and (2S,3R,4S,5S)4-Azido-3,5-bis(benzyloxy)-6-(tert-butyldimethylsilyloxy)-2-(2,5dimethoxyphenyl)hexan-2-ol (31). To a stirred solution of aryl bromide 14 (2.27 g, 10.5 mmol) in THF (60 mL) at −78 °C was added nBuLi (6.1 mL, 1.6 M in hexane, 9.76 mmol). The reaction was stirred at −78 °C for 20 min before a solution of ketone 29 (1.18 g, 2.4 mmol) in THF (10 mL) was added. The stirring was continued at −78 °C for another 1 h before being quenched by saturated aqueous NH4Cl (5 mL). The mixture was diluted with DCM and washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 15:1, then 10:1 and 5:1) to give first the minor diastereomer 31 (0.57 g, 38%) and then the major diastereomer 30 (0.7 g, 46%). 31, colorless oil; [α]26D −35.4 (c 0.62, DCM); 1H NMR (CDCl3, 400 MHz) δ 7.40−7.18 (m, 8H), 7.15−7.03 (m, 3H), 6.82−6.73 (m, 2H), 4.61 (ABq, J = 11.3 Hz, 2H), 4.31 (ABq, J = 10.4 Hz, 2H), 4.30 (d, J = 5.8 Hz, 1H), 4.05 (s, 1H), 3.79 (dd, J = 6.2, 1.9 Hz, 1H), 3.74−3.67 (m, 5H), 3.65 (s, 3H), 1.62 (s, 3H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 154.0, 150.3, 138.5, 137.9, 133.8, 128.4, 128.3, 128.1, 127.6, 127.6, 114.4, 113.1, 111.8, 81.1, 80.3, 76.6, 75.0, 73.0, 63.5, 62.6, 55.58, 55.55, 25.8, 23.2, 18.1, −5.5, −5.6; IR (film, cm−1) υmax 3472, 3044, 2959, 2869, 2093, 1503, 1214, 855; HRMS-ESI m/z Calcd for C34H47N3O6SiNa ([M + Na]+): 644.3132. Found: 644.3110. 30, colorless oil; [α]26D −61.5 (c 0.54, DCM); 1H NMR (CDCl3, 400 MHz) δ 7.39−7.27 (m, 5H), 7.24−7.21 (m, 3H), 7.17 (s, 1H), 7.05 (dd, J = 6.4, 2.8 Hz, 2H), 6.80 (d, J = 1.6 Hz, 2H), 4.65 (ABq, J = 11.3 Hz, 2H), 4.44 (ABq, J = 11.1 Hz, 2H), 4.38 (d, J = 3.7 Hz, 1H), 4.15 (s, 1H), 3.81−3.69 (m, 8H), 3.64−3.56 (m, 2H), 1.65 (s, 3H), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 154.0, 150.2, 138.1, 137.9, 134.8, 128.3, 128.1, 127.8, 127.7, 127.5, 113.5, 113.1, 112.3, 81.0, 80.7, 77.4, 74.6, 73.4, 62.5, 62.3, 55.74, 55.70, 25.9, 23.6, 18.3, −5.5; IR (film, cm−1) υmax 3541, 3040, 2959, 2851, 2117, 1467, 1227, 1042, 850; HRMS-ESI m/z Calcd for C34H47N3O6SiNa ([M + Na]+): 644.3132. Found: 644.3147. (5R,6R,7S,8S)-7-Azido-6,8-bis(benzyloxy)-5-(2,5-dimethoxyphenyl)-3,3,11,11-tetraethyl-5-methyl-4,10-dioxa-3,11-disilatridecane (32). 30 (0.7 g, 1.1 mmol) was dissolved in THF (40 mL), and TBAF (3.4 mL, 1 M in THF, 3.3 mmol) was added. The reaction was stirred at room temperature for 2.5 h and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc = 2:1) to give the diol (0.52 g, 91%). The diol (0.49 g, 0.97 mmol) was dissolved in THF (21 mL), and the solution was cooled to −50 °C. NaHMDS (0.6 M in toluene, 6.4 mL, 3.88 mmol) was added, and the reaction was warmed up to −30 °C in 30 min. To the reaction mixture was added a solution of TES-Cl (0.44 mL, 2.62 mmol) in THF (2 mL). The reaction was then warmed up to 0 °C in 50 min and kept at this temperature for another 40 min. Saturated aqueous NH4Cl (20 mL) was added to quench the reaction. The mixture was diluted with EtOAc and washed with water. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 15:1) to give 32 as a colorless oil (0.637 g, 82% for two steps). [α]26D −15.5 (c 1.0, DCM); 1H NMR (CDCl3, 400 MHz) δ 7.40−7.23 (m, 10H), 7.11 (d, J = 2.6 Hz, 1H), 6.80 (dd, J = 8.9, 2.8 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 4.87 (ABq, J = 11.6 Hz, 2H), 4.60 (ABq, J = 11.2 Hz, 2H), 4.46 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.60 (td, J = 7.1, 3.6 Hz, 1H), 3.54−3.42 (m, 2H), 3.20 (d, J = 3.6, 1H), 1.95 (s, 3H), 0.94−0.88 (m, J = 8.0 Hz, 18 H), 0.57−0.44 (m, 12H); 13C{1H} NMR (CDCl3, 100 MHz) δ 153.3, 151.7, 139.1, 138.2, 133.7, 128.2, 128.1, 128.0, 127.9, 127.6, 127.2, 115.4, 113.1, 112.1, 82.9, 81.7, 81.6, 74.9, 73.6, 62.9, 62.6, 55.7, 55.2, 23.6, 7.1, 6.8, 6.6, 4.3; IR (film, cm−1) υmax 3056, 2935, 2883, 2093, 1489, 1224, 1104, 749; HRMS-ESI m/z Calcd for C40H61N3O6Si2Na ([M + Na]+): 758.3997. Found: 758.4014.

(2S,3R,4R,5R)-3-Azido-2,4-bis(benzyloxy)-5-(2,5-dimethoxyphenyl)-5-(triethylsilyloxy)hexanal (33). To a stirred solution of oxallyl chloride (0.41 mL, 4.76 mmol) in DCM (2.1 mL) was added a solution of DMSO (0.69 mL, 9.53 mmol) in DCM (2.1 mL) at −78 °C. After 15 min, 32 (0.416 g, 0.53 mmol) in DCM (6 mL) was added and the reaction was warmed up and kept at a temperature between −40 and −30 °C for 2 h. Then, the reaction was cooled back to −78 °C and iPr2NEt (2.38 mL, 12.7 mmol) was added. The reaction was removed to an ice bath and kept there for 30 min before being quenched with saturated aqueous NH4Cl. The mixture was extracted with DCM. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 15:1) to give 33 as a colorless oil (0.278 g, 79%). [α]26D −35 (c 0.25, DCM); 1H NMR (CDCl3, 400 MHz) δ 9.28 (d, J = 2.0 Hz, 1H), 7.42−7.21 (m,10H), 7.05 (d, J = 2.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.9 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 4.85 (ABq, J = 11.4 Hz, 2H), 4.60−4.44 (m, 3H), 3.83−3.74 (m, 4H), 3.68 (s, 3H), 3.26 (d, J = 7.6 Hz, 1H), 1.92 (s, 3H), 0.84 (t, J = 7.9 Hz, 9H), 0.51−0.30 (m, 6H); 13C{1H} NMR (CDCl3, 100 MHz) δ 199.7, 153.3, 151.7, 138.5, 136.6, 133.0, 128.5, 128.2, 128.2, 127.5, 115.2, 113.3, 111.9, 83.4, 81.4, 81.4, 74.7, 73.3, 62.2, 55.8, 55.0, 23.6, 7.0, 6.3; IR (film, cm−1) υmax 3071, 2964, 2869, 2092, 1723, 1502, 1219, 1032, 725; HRMS-ESI m/z Calcd for C34H45N3O6SiNa ([M + Na]+): 642.2975. Found: 642.2992. (2R,3R,4R,5S,6S)-4-Azido-3,5-bis(benzyloxy)-2-(2,5-dimethoxyphenyl)-6-methoxy-2-methyltetrahydro-2H-pyran (35). To a stirred solution of the aldehyde 33 (0.275 g, 0.44 mmol) in THF−AcOH− H2O (1:2:1, 6 mL) was added TsOH·H2O (50 mg, 0.26 mmol). The reaction was stirred at room temperature for 21 h before being diluted with DCM. The mixture was washed with excess saturated aqueous NaHCO3. The organic phase separated was dried by MgSO4, filtered, and concentrated to give the crude 34 (0.262 g) which was used for the next step without further purification. To a stirred solution of the crude 34 (0.262 g) in HC(OMe)3 (5 mL) was added TsOH·H2O (169 mg, 0.88 mmol). The reaction was stirred at room temperature for 1 h before being diluted with DCM. The mixture was washed with excess saturated aqueous NaHCO3. The organic phase separated was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 6:1) to give 35 as a white wax (0.176 g, 76% for two steps). [α]26D +67.5 (c 0.5, DCM); 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J = 2.9 Hz, 1H), 7.45−7.27 (m, 10H), 6.83 (d, J = 8.9 Hz, 1H), 6.78 (dd, J = 8.9, 2.9 Hz, 1H), 4.92 (ABq, J = 11.1 Hz, 2H), 4.78 (ABq, J = 10.8 Hz, 2H), 4.16 (d, J = 7.8 Hz, 1H), 4.14 (m, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 3.54 (s, 3H), 3.47 (d, J = 10.5 Hz, 1H), 3.35 (dd, J = 9.0, 8.1 Hz, 1H), 1.72 (s, 3H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 152.9, 152.0, 138.1, 138.0, 128.5, 128.42, 128.41, 128.2, 127.9, 127.8, 127.7, 115.9, 113.3, 111.9, 101.0, 86.9, 82.2, 79.0, 76.8, 74.7, 65.9, 57.1, 55.6, 55.1, 26.1.; IR (film, cm−1) υmax 3058, 2937, 2103, 1493, 1237, 1067, 753, 705; HRMS-ESI m/z Calcd for C29H33N3O6Na ([M + Na]+): 542.2267. Found: 542.2272. 2-((2R,3R,4R,5S,6S)-4-Azido-3,5-bis(benzyloxy)-6-methoxy-2methyltetrahydro-2H-pyran-2-yl)cyclohexa-2,5-diene-1,4-dione (36). To a stirred solution of 35 (0.74 g, 1.43 mmol) in MeCN (87 mL) was added water (18 mL) in an ice bath. Then, a solution of CAN (2.03 g, 3.71 mmol) in water (10 mL) was added dropwise. After 5 min, the reaction was diluted with EtOAc and washed with water. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 5:1) to give 36 as a yellow oil (0.59 g, 83%). [α]26D +89 (c 0.5, DCM); 1H NMR (CDCl3, 400 MHz) δ 7.41−7.26 (m, 7H), 7.22−7.20 (m, 3H), 6.67 (dd, J = 10.1, 2.4 Hz, 1H), 6.62 (d, J = 10.1 Hz, 1H), 4.81 (dd, J = 11.0, 5.1 Hz, 2H), 4.76 (ABq, J = 11.2 Hz, 2H), 4.61 (ABq, J = 10.9 Hz, 2H), 4.49 (d, J = 7.0 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.71 (d, J = 7.3 Hz, 1H), 3.56 (t, J = 7.3 Hz, 1H), 3.50 (s, 3H), 1.64 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 187.3, 185.9, 148.8, 137.8, 137.6, 137.1, 135.4, 133.0, 128.4, 128.4, 128.1, 127.9, 127.9, 101.6, 83.2, 80.6, 78.2, 74.8, 73.9, 64.4, 56.6, 26.5; IR (film, cm−1) υmax 3040, 2945, 2120, 1652, 766

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

Article

The Journal of Organic Chemistry 1486, 1063, 733; HRMS-ESI m/z Calcd for C27H27N3O6Na ([M + Na]+): 512.1798. Found: 512.1823. (2S,3S,4R,5R,6S)-4-Azido-3,5-dibenzyloxy-6-methyl-8-hydroxy3,4,5,6-tetrahydro-2,6-epoxy-2H-1-benzoxocin (37). To a stirred solution of 36 (0.59 g, 1.21 mmol) in THF (55 mL) was added a solution of Na2S2O4 (2.1 g, 12.1 mmol) in water (10 mL). The reaction was stirred at room temperature for 20 min before being diluted with DCM and washed with brine. The organic phase was dried by MgSO4, filtered, and concentrated to give the crude hydroquinone as a colorless oil. The oil was heated in a mixture of AcOH (30 mL) and 3 M HCl (6 mL) at 70 °C for 100 min. After cooling, the reaction mixture was diluted with DCM and washed with excess saturated aqueous NaHCO3. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 5:1, then 3:1) to give 37 as a colorless oil (0.47 g, 85%). [α]26D −14.6 (c 0.6, DCM); 1H NMR (CDCl3, 400 MHz) δ 7.49−7.27 (m, 10H), 6.81 (d, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.7, 2.9 Hz, 1H), 6.55 (d, J = 2.9 Hz, 1H), 5.42 (d, J = 3.7 Hz, 1H), 4.83 (ABq, J = 11.2 Hz, 2H), 4.79 (s, 2H), 4.41 (s, 1H), 3.56 (dd, J = 9.9, 3.7 Hz, 1H), 3.44 (t, J = 9.8 Hz, 1H), 3.29 (d, J = 9.6 Hz, 1H), 1.49 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 149.2, 144.1, 137.6, 137.4, 128.7, 128.6, 128.4, 128.3, 128.2, 123.3, 116.7, 116.6, 113.7, 92.1, 83.8, 80.3, 75.9, 74.4, 72.9, 65.0, 23.6; IR (film, cm−1) υmax 3380, 2934, 2104, 1491, 1210, 1069, 737, 697; HRMS-ESI m/z Calcd for C26H25N3O5Na ([M + Na]+): 482.1692. Found: 482.1672. (1R,7R,10S,11R,12R)-11-Azido-10,12-bis(benzyloxy)-7-methoxy1-methyl-8,13- dioxatricyclo[7,3,1,02,7]trideca-2,5-dien-4-one (11). 37 (0.47 g, 0.96 mmol) was dissolved in MeOH (30 mL) and DCM (7 mL). At 0 °C, PIDA (0.4 g, 1.15 mmol) was added and the reaction was stirred at 0 °C for 20 min. Then, the reaction was stirred at room temperature for another 10 min before being diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 5:1, then 2:1) to give 11 as a pale yellow oil (0.39 g, 78%). [α]26D −7.0 (c 0.45, DCM); 1H NMR (CDCl3, 400 MHz) δ 7.45−7.29 (m, 10H), 6.82 (d, J = 10.2 Hz, 1H), 6.30 (d, J = 1.9 Hz, 1H), 6.21 (dd, J = 10.2, 1.9 Hz, 1H), 5.34 (d, J = 2.8 Hz, 1H), 4.92 (d, J = 11.1 Hz, 1H), 4.76 (q, J = 12.1 Hz, 2H), 4.68 (d, J = 11.1 Hz, 1H), 3.62 (t, J = 9.9 Hz, 1H), 3.35 (dd, J = 9.7, 2.8 Hz, 1H), 3.28 (s, 3H), 3.18 (d, J = 10.1 Hz, 1H), 1.43 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 184.9, 151.9, 142.1, 137.2, 137.0, 128.6, 128.6, 128.6, 128.3, 128.3, 128.2, 128.2, 125.8, 92.5, 90.6, 83.1, 79.0, 76.3, 75.4, 73.1, 63.9, 50.8, 25.4; IR (film, cm−1) υmax 3040, 2920, 2100, 1685, 1646, 1158, 957, 755; HRMS-ESI m/z Calcd for C27H27N3O6Na ([M + Na]+): 512.1798. Found: 512.1775. (2R,3S,4R,5R,6R,13S,14S)-(+)-4-Azido-3,5-bis(benzyloxy)-13(tert-butyldimethyl siloxy)-14-(tert-butyldimethylsiloxymethyl)6,13-dimethyl-2,6-epoxy-8-hydroxy-10-methoxy3,4,5,6,11,12,13,14-octahydro-2H-naphthaceno[1,2-b]oxocine9,16-dione (9). Cyanophthalide 10 (0.357 g, 0.67 mmol) was dissolved in THF (7.5 mL), and the solution was added to a cooled solution of LiOtBu (3 mL, 1 M in THF, 3.03 mmol) at −78 °C. The reaction was stirred at −78 °C for 0.5 h. To the reaction was added a solution of quinone monoketal 11 (0.340 g, 0.69 mmol) in THF (7 mL), and the reaction was kept at −78 °C for another 80 min. Then, the reaction was removed to room temperature and stirred for 23 h. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was extracted with DCM. The organic phase was dried by MgSO4, filtered, and concentrated to give a crude product. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1, then 6:1) to give 9 as an orange solid (0.480 g, 74%). [α]26D +404 (c 0.09, DCM); 1H NMR (CDCl3, 400 MHz) δ 13.22 (s, 1H), 8.02 (s, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.45−7.29 (m, 8H), 7.10 (s, 1H), 5.73 (d, J = 3.8 Hz, 1H), 4.84 (ABq, J = 11.8 Hz, 2H), 4.83 (ABq, J = 11.3 Hz, 2H), 4.14 (dd, J = 9.9, 4.5 Hz, 1H), 4.01 (dd, J = 9.8, 3.7 Hz, 1H), 3.89 (s, 3H), 3.65 (dd, J = 9.6, 3.8 Hz, 1H), 3.40 (t, J = 9.7 Hz, 1H), 3.32 (d, J = 9.9 Hz, 1H), 3.11 (ddd, J = 18.8, 6.7, 1.8 Hz, 1H), 2.81 (m, 1H), 2.74 (ddd, J = 18.4, 10.6, 7.7 Hz, 1H), 2.40−2.33 (m,

1H), 1.82−1.77 (m, 1H), 1.52 (s, 3H), 1.23 (s, 3H), 0.91 (s, 9H), 0.74 (s, 9H), 0.16 (s, 6H), −0.08 (s, 3H), −0.25 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 188.5, 180.9, 158.5, 156.0, 148.7, 144.6, 138.0, 137.2, 134.0, 133.7, 128.6, 128.6, 128.4, 128.2, 128.2, 128.1, 125.4, 124.0, 121.8, 117.7, 116.7, 92.3, 82.6, 79.7, 75.7, 74.5, 73.3, 72.3, 64.8, 64.4, 60.9, 54.0, 32.9, 28.3, 25.9, 25.7, 23.7, 22.8, 18.3, 18.0, −1.81, −1.84, −5.6, −5.9; HRMS-ESI m/z Calcd for C53H68N3O10Si2 ([M + H]+): 962.4443. Found: 962.4447.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02602. Copies of 1H NMR and 13C{1H} NMR of all new compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Michael S. VanNieuwenhze: 0000-0001-6093-5949 Notes

The authors declare no competing financial interest.

■

REFERENCES

(1) Wiley, P. F.; Mackellar, F. A.; Caron, E. L.; Kelly, R. B. Isolation Characterization and Degradation of Nogalamycin. Tetrahedron Lett. 1968, 9, 663−668. (2) Li, L. H.; Bhuyan, B. K.; Krueger, W. C. Comparative Biological and Biochemical Effects of Nogalamycin and Its Analogs on L1210 Mouse Leukemia. Proc. Am. Assoc. Cancer Res. 1977, 18, 250−250. (3) Wiley, P. F.; Elrod, D. W.; Houser, D. J.; Richard, F. A. Structure-Activity-Relationships of Nogalamycin Analogs. J. Med. Chem. 1982, 25, 560−567. (4) Taylor, S. A.; Blumenstein, B. A.; Stephens, R. L.; Crawford, E. D.; Pistone, B.; Hill, J. B. Phase-II Trial of Menogaril in Metastatic Adenocarcinoma of the Prostate. Invest. New Drugs 1994, 12, 67−70. (5) Egli, M.; Williams, L. D.; Frederick, C. A.; Rich, A. DNA Nogalamycin Interactions. Biochemistry 1991, 30, 1364−1372. (6) Hauser, F. M.; Ganguly, D. Synthetic studies on nogarol anthracyclines. Enantioselective total synthesis of an aminohydroxy epoxybenzoxocin. J. Org. Chem. 2000, 65, 1842−1849. (7) Su, J.; Wulff, W. D.; Ball, R. G. Synthesis of the tetracyclic carbon core of menogaril utilizing the benzannulation reaction of a Fischer carbene complex and an alkyne. J. Org. Chem. 1998, 63, 8440−8447. (8) Krohn, K.; Terstiege, I.; Florke, U. Studies on the synthesis of the C-glycosidic part of nogalamycin, part 3. J. Carbohydr. Chem. 1998, 17, 197−215. (9) Yin, H.; Franck, R. W.; Chen, S. L.; Quigley, G. J.; Todaro, L. A Convergent Synthetic Approach to a Chiral, Nonracemic CDEF Analog of Nogalamycin. J. Org. Chem. 1992, 57, 644−651. (10) Hauser, F. M.; Chakrapani, S.; Ellenberger, W. P. Total Synthesis of (±)-7-Con-O-Methylnogarol. J. Org. Chem. 1991, 56, 5248−5250. (11) Deshong, P.; Li, W.; Kennington, J. W.; Ammon, H. L.; Leginus, J. M. A Nitrone-Based Cycloaddition Approach to the Synthesis of the Glycosyl System of Nogalomycin, Menogaril, and Their Congeners. J. Org. Chem. 1991, 56, 1364−1373. (12) Meschwitz, S. M. Studies directed toward the synthesis of nogalamycin. Thesis (Ph.D.), s.n., Brown University, 1989. (13) Matsuda, F.; Kawasaki, M.; Ohsaki, M.; Yamada, K.; Terashima, S. Synthetic Studies on Nogalamycin Congeners [4] Syntheses and Antitumor-Activity of Various Nogalamycin Congeners. Tetrahedron 1988, 44, 5745−5759. (14) Kawasaki, M.; Matsuda, F.; Terashima, S. Synthetic Studies on Nogalamycin Congeners [3] Total Syntheses of (+)-Nogarene, (+)-7-

767

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768

Article

The Journal of Organic Chemistry Deoxynogarol, and (+)-7-Con-O-Methylnogarol. Tetrahedron 1988, 44, 5727−5743. (15) Kawasaki, M.; Matsuda, F.; Terashima, S. Synthetic Studies on Nogalamycin Congeners [2] Chiral Synthesis of the CDEF-Ring System of Nogalamycin. Tetrahedron 1988, 44, 5713−5725. (16) Kawasaki, M.; Matsuda, F.; Terashima, S. Synthetic Studies on Nogalamycin Congeners [1] Chiral Synthesis of the DEF-Ring System of Nogalamycin. Tetrahedron 1988, 44, 5695−5711. (17) Bates, M. A.; Sammes, P. G.; Thomson, G. A. Synthesis of the C-Glycoside Fragment of Nogalamycin and Some Nogalamycin Precursors. J. Chem. Soc., Perkin Trans. 1 1988, 3037−3045. (18) Smith, T. H.; Wu, H. Y. Synthetic Approaches to NogalamycinRelated Anthracyclines - an Approach to a Western Synthon. J. Org. Chem. 1987, 52, 3566−3573. (19) Krohn, K.; Köhle, H.-J. Synthetische Anthracyclinone, 35. Synthese des Nogalamycin-Aglycons. Liebigs Ann. Chem. 1987, 1987, 1037−1043. (20) Vatele, J. M. Synthetic Studies on Nogalamycin - Stereospecific C-5 Alkylations of a Sugar Derivative Via Claisen Rearrangement and a New Route to 1,1,4-Trialkoxybuta-1,3-Dienes. Tetrahedron 1986, 42, 4443−4450. (21) Joyce, R. P.; Parvez, M.; Weinreb, S. M. An Approach to the Aryl-C-Glycoside DEF-Ring System of Nogalamycin. Tetrahedron Lett. 1986, 27, 4885−4888. (22) Peng, R.; VanNieuwenhze, M. S. A Model Study for Constructing the DEF-Benzoxocin Ring System of Menogaril and Nogalamycin via a Reductive Heck Cyclization. Org. Lett. 2012, 14, 1962−1965. (23) Mal, D.; Pahari, P. Recent advances in the Hauser annulation. Chem. Rev. 2007, 107, 1892−1918. (24) Mitra, P.; Behera, B.; Maiti, T. K.; Mal, D. Angucycline C5 Glycosides: Regio- and Stereocontrolled Synthesis and Cytotoxicity. J. Org. Chem. 2013, 78, 9748−9757. (25) Karmakar, R.; Mal, D. Total Synthesis of Chlorocyclinone A, a PPAR-γ Antagonist. J. Org. Chem. 2012, 77, 10235−10248. (26) Š venda, J.; Hill, N.; Myers, A. G. A multiply convergent platform for the synthesis of trioxacarcins. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 6709−6714. (27) Nicolaou, K. C.; Becker, J.; Lim, Y. H.; Lemire, A.; Neubauer, T.; Montero, A. Total Synthesis and Biological Evaluation of (+)- and (−)-Bisanthraquinone Antibiotic BE-43472B and Related Compounds. J. Am. Chem. Soc. 2009, 131, 14812−14826. (28) Russell, R.; Pilley, B.; Irvine, R.; Warrener, R. Anthracyclines. XVI. Further Comments Concerning the Phthalide Anion Annelation of Quinone Monoacetals. Aust. J. Chem. 1987, 40, 311−323. (29) Chenard, B. L.; Dolson, M. G.; Sercel, A. D.; Swenton, J. S. Annelation reactions of quinone monoketals. Studies directed at an efficient synthesis of anthracyclinones. J. Org. Chem. 1984, 49, 318− 325. (30) Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H.-G. Studies toward the Total Synthesis of Mumbaistatin, a Highly Potent Glucose-6-phosphate Translocase Inhibitor. Synthesis of a Mumbaistatin Analogue. J. Org. Chem. 2002, 67, 9248−9256. (31) Khanapure, S. P.; Reddy, R. T.; Biehl, E. R. The Preparation of Anthraquinones and Anthracyclinones Via the Reaction of Haloarenes and Cyanophthalides under Aryne-Forming Conditions. J. Org. Chem. 1987, 52, 5685−5690. (32) Davis, F. A.; Kumar, A. Asymmetric-Synthesis of the AB-Ring of Aklavinone. Tetrahedron Lett. 1991, 32, 7671−7674. (33) Davis, F. A.; Weismiller, M. C. Enantioselective synthesis of tertiary.alpha.-hydroxy carbonyl compounds using [(8,8dichlorocamphoryl)sulfonyl]oxaziridine. J. Org. Chem. 1990, 55, 3715−3717. (34) Mergelsberg, I.; Gala, D.; Scherer, D.; DiBenedetto, D.; Tanner, M. A convenient, improved synthesis of (camphoryl)sulfonyl oxaziridines. Tetrahedron Lett. 1992, 33, 161−164. (35) See the Supporting Information. (36) Kende, A. S.; Rizzi, J. P. A stereospecific total synthesis of aklavinone. J. Am. Chem. Soc. 1981, 103, 4247−4248.

(37) Okazaki, K.; Nomura, K.; Yoshii, E. An Efficient Synthesis of 3Cyano-1(3H)-Isobehzofuranones. Synth. Commun. 1987, 17, 1021− 1027. (38) Hasegawa, A.; Kiso, M. Synthesis of 2,4-Di-O-Benzyl-3-Deoxy3-[N-(2,4-Dinitrophenyl)-N-Methylamino]-Alpha-D-Xylopyranosyl Chloride (a 1-Halogeno Gentosamine Derivative). Carbohydr. Res. 1975, 44, 121−125. (39) Clark Still, W.; McDonald, J. H. Chelation-Controlled Nucleophilic Additions.1. Highly Effective System for Asymmetric Induction in the Reaction of Organometallics with AlphaAlkoxyketones. Tetrahedron Lett. 1980, 21, 1031−1034. (40) Huh, C. W.; Schroeder, C.; Singh, G.; Aubé, J. Stereoselectivity in Nucleophilic Additions to 3-Azidoalkanals. J. Org. Chem. 2011, 76, 3160−3165. (41) Omura, K.; Swern, D. Oxidation of alcohols by “activated” dimethyl sulfoxide. a preparative, steric and mechanistic study. Tetrahedron 1978, 34, 1651−1660. (42) Fujita, T.; Obata, K.; Kuwahara, S.; Nakahashi, A.; Monde, K.; Decatur, J.; Harada, N. (R)-(+)-[VCD(−)984]-4-Ethyl-4-methyloctane: A Cryptochiral Hydrocarbon with a Quaternary Chiral Center. (1) Synthesis of the Enantiopure Compound and Unambiguous Determination of Absolute Configuration. Eur. J. Org. Chem. 2010, 2010, 6372−6384. (43) Arai, T.; Sato, T.; Kanoh, H.; Kaneko, K.; Oguma, K.; Yanagisawa, A. Organic−Inorganic Hybrid Polymer-Encapsulated Magnetic Nanobead Catalysts. Chem. - Eur. J. 2008, 14, 882−885.

768

DOI: 10.1021/acs.joc.8b02602 J. Org. Chem. 2019, 84, 760−768