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A short convergent synthesis of the [3.2.1]dioxabicyclooctane subunit of sorangicin A via regioselective epoxide opening
Tetrahedron 74 (2018) 1071e1077
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A short convergent synthesis of the [3.2.1]dioxabicyclooctane subunit of sorangicin A via regioselective epoxide opening Sadagopan Raghavan*, Satyanarayana Nyalata Natural Product Chemistry Division, Indian Institute of Chemical Technology, Hyderabad, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 November 2017 Received in revised form 17 January 2018 Accepted 20 January 2018 Available online 31 January 2018
In this paper, we disclose the synthesis of the dioxabicyclo[3.2.1]octane subunit of the potent antibiotic sorangicin A. The synthesis was achieved in a convergent manner in 8 steps. Regio- and stereoselective intermolecular epoxide opening, ring-closing metathesis and iodo-etherification are key steps. cis-2Butene diol has been employed as a common staring material. © 2018 Elsevier Ltd. All rights reserved.
Keywords: Sorangicin A Mioskowski's protocol 5-endo Trig cyclization Ring-closing metathesis
1. Introduction
2. Results and discussion
Sorangicin A (1) Fig. 1, is an architecturally complex macrolide antibiotic isolated by Hofle and co-workers1 from the myxobacteria Sorangium cellulosum. It exhibits potent activity against Grampositive (MIC 0.01e0.3 mg/mL) and Gram-negative bacteria (MIC 3-25 mg/mL) including methicillin resistant bacteria without affecting eukaryotic cells. Sorangicin A possesses a remarkable ability to adapt to rapidly mutating targets2 and its antibiotic activity has been related to inhibition of RNA polymerase.1a Sorangicin A is a 31-membered macrolactone containing a tetrasubstituted tetrahydropyran, a tri-substituted dihydropyran, a dioxabicyclo[3.2.1]octane moiety and a rare (Z,Z,E)-trienoate linkage. The unique structural features in conjunction with its biological activity has attracted considerable interest from the synthetic community with the first total synthesis being reported by Smith and co-workers.3 Crimmins and co-workers synthesized a known precursor thus completing a formal synthesis.4 The groups of Schinzer,5 H. W. Lee,6 K. Lee,7 Mohapatra and Yadav,8 Srihari9 and Raghavan10 have reported the synthesis of the subunits of sorangicin A. Herein, we disclose our efforts toward sorangicin A by synthesizing the C30-C37 bicyclic ether subunit.
The groups of Smith3a,3c and Schinzer5 have each disclosed a first- and second generation approach to the bicyclic ether moiety in addition to the reports from the groups of Crimmins11 and Mohapatra and Yadav,8 all employing a linear sequence of reactions, Scheme 1. The first generation synthesis of Smith and coworkers by a 15 step sequence (Scheme 1c) involved the construction of the tetrahydrofuran (THF) ring by epoxide opening taking advantage of the Nicolas reaction and the tetrahydropyran (THP) ring by an acid catalyzed epoxide ring opening. The second generation synthesis (Scheme 1d) by a 8 step sequence starting from L-gulonic acid took advantage of a hetero Diels-Alder reaction to construct the pyranose ring and the THF ring by epoxide opening. In the first generation route disclosed by Schinzer (Scheme 1a), the THP ring was elaborated by an acid-catalyzed reaction of an epoxy acetonide, obtained by a lengthy sequence of reactions and the THF ring by a Williamson ether synthesis. In the second approach (Scheme 1b), the dihydropyranone, synthesized from a keto lactone, was subjected to Mukaiyama-Michael reaction to introduce all the stereocenters and the THF ring was created by epoxide opening. Crimmins and co-workers (Scheme 1e) utilized an epoxy tosylate and constructed the THP ring by an epoxide opening followed by formation of another epoxide and its opening to construct the THF ring of the bicyclic ether by a 10 step sequence. Mohapatra and Yadav by a 9 step sequence, taking advantage of iodine catalyzed
* Corresponding author. E-mail address: [email protected] (S. Raghavan). https://doi.org/10.1016/j.tet.2018.01.036 0040-4020/© 2018 Elsevier Ltd. All rights reserved.
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Fig. 1. Sorangicin A
cyclization of d-hydroxy a, b-unsaturated aldehyde to synthesize the trans-2,6-disubstituted dihydropyran moiety and a 5-endo iodo-etherification to introduce the THF ring, synthesized the bicyclic moiety Scheme 1f). We envisioned construction of the C30-C37 bicyclic subunit 2 by a iodo-etherification of dihydropyran 3 followed by radical deiodination. The dihydropyran 3 can be obtained by a ring-closing metathesis reaction of diene 4. The diene 4 was envisaged to be obtained in a convergent fashion by a regio- and stereoselective intermolecular opening of epoxide 6 by alcohol 5. Both the alcohol 5 and epoxide 6 can be traced to a common precursor, butenediol 7, Scheme 2. The synthesis of the homoallyl alcohol 5 began from the known aldehyde 912 which on asymmetric Brown crotylation13 afforded alcohol 5 in good yield and high stereoselectivity (76%, dr: >20:1), Scheme 3.14,15 The synthesis of epoxide 6 began from diol 7 which on selective monoprotection afforded alcohol 10. Subjecting alcohol 10 to Sharpless' asymmetric epoxidation conditions provided epoxide 11.16 Oxidation of alcohol using Dess-Martin periodinane17 yielded aldehyde 12 which on homologation yielded epoxide 6, Scheme 3. The diene 4 was obtained cleanly by reaction of an excess of alcohol 5 with epoxide 6 following Mioskowski's protocol.18 Ringclosing metathesis19 of diene 4 catalyzed by Grubbs's second generation catalyst 13 in refluxing toluene afforded dihydropyran 3 in 85% yield. The 5-endo iodo-etherification of dihydropyran 3 following Knight's protocol20 afforded the iodo ether 14 in moderate yield (50%). After experimentation, satisfactory yield was obtained employing N-iodosuccinimide and catalytic amounts of scandium triflate.21 Radical deiodination of 14 proceeded cleanly using tributyltin hydride and catalytic AIBN to furnish bicyclic subunit 2, Scheme 4. 3. Conclusions In conclusion, we have disclosed a short, convergent synthesis of the bicyclo[3.2.1] subunit of sorangicin A. The THP ring was constructed by a ring-closing metathesis reaction and the THF ring by iodo-etherification. The subunit was constructed by a 8 step sequence in 21.3% overall yield. 4. Experimental section 4.1. (Z)-1,4-bis((4-Methoxybenzyl)oxy)but-2-ene 8 To a suspension of NaH (60% in Nujol, 3.46 g, 86.4 mmol) in anhydrous THF (112 mL) cooled at 0 C was added the solution of cis-2-butene-1,4-diol 7 (2.96 mL, 36 mmol) in anhydrous THF
(16 mL) and stirred for 15 min. Then a solution of 4-methoxybenzyl bromide (15.92 g, 79.2 mmol) in THF (12 mL) and catalytic amount TBAI were added at 0 OC and the reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was quenched by slow addition of aq sat NH4Cl solution (50 mL) and extracted with EtOAc (2 100 mL). The organic layer was separated and washed with water (2 50 mL) and brine (50 mL). The organic extract was dried (Na2SO4) and concentrated. The crude product was purified by silica gel column chromatography using 10-20% EtOAc/hexane (v/v) as the eluent to afford the PMB-ether 8 (11.34 g, 34.57 mmol) in 96% yield, as a colourless liquid. TLC: Rf 0.2 (10% EtOAc/hexane). IR (neat): 3002, 2839, 1611, 1513, 1248, 1079, 820 cm1; 1H NMR (400 MHz, CDCl3): d 7.25 (d, J ¼ 8.7 Hz, 4H), 6.87 (d, J ¼ 8.7 Hz, 4H), 5.77 (t, J ¼ 4.8 Hz, 2H), 4.42 (s, 4H), 4.03 (d, J ¼ 4.8 Hz, 4H), 3.80 (s, 6H); 13C NMR (100 MHz, CDCl3): d 159.1, 130.1, 129.4, 129.3, 113.7, 71.8, 65.3, 55.1; MS (ESI): m/z 351 [MþNa]þ. HRMS (ESI): calcd for C20H24O4Na: 351.1567, found: 351.1580. 4.2. 2-((4-Methoxybenzyl)oxy)acetaldehyde 9 Ozone was bubbled through a solution of the alkene 8 (11.2 g, 34.14 mmol) in a mixture of CH2Cl2 (380 mL) and MeOH (14 mL) at 78 C. After the solution turned blue (about 40 min), Me2S (10.60 g, 170.17 mmol) was added. The reaction mixture was stirred for 10 min at the same temperature, before being warmed to room temperature and stirred for another 4 h. Water (60 mL) was added, and most of the organic solvent was removed under reduced pressure. The residue was extracted with ether (4 65 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 40-50% EtOAc/hexane (v/v) as the eluent to afford the aldehyde 9 (10.33 g, 57.38 mmol) in 84% yield, as a colourless oil. TLC: Rf 0.4 (40% EtOAc/hexane). IR (neat): 3001, 2933, 2838, 1735, 1612, 1513, 1248, 1100, 820 cm1; 1H NMR (400 MHz, CDCl3): d 9.70 (t, J ¼ 0.8 Hz, 1H), 7.29 (d, J ¼ 8.8 Hz, 2H), 6.90 (d, J ¼ 8.8 Hz, 2H), 4.56 (s, 2H), 4.07 (d, J ¼ 0.8 Hz, 2H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3): d 200.2, 159.2, 129.4, 128.7, 113.6, 74.7, 72.9, 54.9; MS (ESI): m/z 235 [MþNaþMeOH]þ. HRMS (ESI): calcd for C10H12O3Na: 203.0684, found: 203.0684. 4.3. (2R,3R)-1-((4-Methoxybenzyl)oxy)-3-methylpent-4-en-2-ol 5 To a stirred suspension of potassium tert-butoxide (5.55 g, 49.54 mmol) in anhydrous THF (8.6 mL) and cooled to 78 OC, trans-2-butene (8.8 mL 98.55 mmol) was added followed by nBuLi (20.9 mL, 2.5 M in hexane. 52.17 mmol). The mixture was warmed to 45 OC and stirred at this temperature for 15 min and then cooled again to 78 OC. A solution of (þ)-lpc2BOMe (19.98 g, 63.24 mmol) in THF (63 mL) was added and the mixture stirred for 30 min. BF3.OEt2 (6.44 mL, 52.17 mmol) was added, followed by aldehyde 9 (9.5 g, 52.7 mmol). The mixture was stirred for 4 h at 78 OC and then quenched with aq NaOH (37.8 mL, 3M), followed by cautious addition of 30% aqueous H2O2 (15.5 mL). The solution was stirred at rt for 16 h and then extracted with ether (3 100 mL). The combined ether layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 10-15% Ether/DCM (v/v) as the eluent to afford compound 5 (9.45 g, 40.04 mmol) in 76% yield, as a colourless oil. TLC: Rf 0.4 (DCM). [a]20 D ¼ þ5.00 (c 1.2, CHCl3); IR (neat): 3455, 3072, 2865, 1612, 1513, 1247, 1095, 1034, 820 cm1; 1H NMR (500 MHz, CDCl3): d 7.26 (d, J ¼ 8.7 Hz, 2H), 6.88 (d, J ¼ 8.7 Hz, 2H), 5.86e5.78 (m, 1H), 5.1e5.08 (m, 1H), 5.07e5.05 (m, 1H), 4.5 (d, J ¼ 11.6 Hz, 1H), 4.47 (d, J ¼ 11.6 Hz, 1H), 3.81 (s, 3H), 3.68e3.60 (m, 1H), 3.52 (dd, J ¼ 9.6, 3.1 Hz, 1H), 3.39 (dd, J ¼ 9.6, 7.6 Hz, 1H), 2.38e2.30 (m, 1H), 2.26 (d, J ¼ 3.2 Hz, 1H), 1.03 (d,
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Scheme 1. Earlier approaches to the bicyclooctane moiety.
J ¼ 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 140.0, 130.0, 129.2, 115.2, 113.6, 73.3, 72.8, 72.1, 55.0, 40.6, 16.0; MS (ESI): m/z 259 [MþNa]þ. HRMS (ESI): calcd for C14H20O3Na: 259.1305, found: 259.1323. 4.4. (2R,3R)-1-((4-Methoxybenzyl)oxy)-3-methylpent-4-en-2yl(S)-2-methoxy-2-phenylacetate I To a solution of the alcohol 5 (11.8 mg, 0.05 mmol) in anhydrous
CH2Cl2 (2 mL) were added (S)-O-methyl mandelic acid (8.3 mg, 0.05 mmol), DCC (12 mg, 0.06 mmol) and a few crystals of DMAP and the mixture was stirred for 45 min. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel using 10-15% EtOAc/hexane (v/v) as the eluent to afford ester I (16.2 mg, 0.042 mmol) in 84% yield as a colourless oil. 1H NMR (400 MHz, CDCl3): d 7.46e7.41 (m, 2H), 7.36e7.28 (m, 3H), 7.22 (d, J ¼ 8.7 Hz, 2H), 6.87 (d, J ¼ 8.7 Hz, 2H), 5.44 (ddd, J ¼ 18.5, 10.4, 8.2 Hz, 1H), 5.06e5.01 (m, 1H), 4.86e4.79
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Scheme 2. Retrosynthetic analysis of subunit 2.
Scheme 3. Synthesis of alcohol 5 and epoxide 6 from cis-2-butene diol.
Scheme 4. Synthesis of the dioxabicyclic subunit of sorangicin A.
(m, 2H), 4.75 (s, 1H), 4.46 (d, J ¼ 11.5 Hz, 1H), 4.38 (d, J ¼ 11.5 Hz, 1H), 3.81 (s, 3H), 3.51 (dd, J ¼ 10.8, 6.2 Hz, 1H), 3.47 (dd, J ¼ 10.8, 4.5 Hz, 1H), 3.40 (s, 3H), 2.47e2.36 (m, 1H), 0.71 (d, J ¼ 7.0 Hz, 3H);
4.5. (2R,3R)-1-((4-Methoxybenzyl)oxy)-3-methylpent-4-en-2-yl (R)-2-methoxy-2-phenylacetate II To a solution of the alcohol 5 (11.8 mg, 0.05 mmol) in anhydrous
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CH2Cl2 (2 mL) were added (R)-O-methyl mandelic acid (8.3 mg, 0.05 mmol), DCC (12 mg, 0.06 mmol) and a few crystals of DMAP and the mixture was stirred for 45 min. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel using 10-15% EtOAc/hexane (v/v) as the eluent to afford ester II (15.8 mg, 0.041 mmol) in 83% yield as a colourless oil. 1H NMR (400 MHz, CDCl3): d 7.47e7.44 (m, 2H), 7.35e7.29 (m, 3H), 7.07 (d, J ¼ 8.7 Hz, 2H), 6.82 (d, J ¼ 8.7 Hz, 2H), 5.68 (ddd J ¼ 17.1, 10.3, 8.2 Hz, 1H), 5.09e4.96 (m, 3H), 4.77 (s, 1H), 4.24 (d, J ¼ 11.6 Hz, 1H), 4.18 (d, J ¼ 11.6 Hz, 1H), 3.80 (s, 3H), 3.42 (s, 3H), 3.40 (dd, J ¼ 10.9, 5.9 Hz, 1H), 3.36 (dd, J ¼ 10.9, 4.2 Hz, 1H), 2.60e2.48 (m, 1H), 0.96 (d, J ¼ 7.0 Hz, 3H); As would be expected the olefinic signals appear upfield in ester I in comparison to ester II while ether signals appear downfield in ester I in comparison to ester II. 4.6. (Z)-4-((tert-butyldiphenylsilyl)oxy)but-2-en-1-ol 10 To a suspension of NaH (60% in Nujol, 1.2 g, 30 mmol) in anhydrous THF (40 mL) cooled at 0 C was added the solution of cis-2butene-1,4-diol 7 (2.64 g, 30 mmol) in anhydrous THF (20 mL). After the mixture was stirred at rt for 16 h, TBDPS-Cl (7.7 mL, 30 mmol) was added and the reaction mixture was stirred at rt for 2 h. After dilution with Et2O (50 mL), the reaction mixture was cooled to 0 C and treated with aq satd NH4Cl solution (40 mL). The aq phase was extracted with Et2O (2 50 mL) and the combined organic extracts were washed with brine (2 50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography using 15-20% EtOAc/ hexane (v/v) as the eluent to afford compound 10 (9.3 g, 28.52 mmol) in 95% yield as a colourless liquid; TLC: Rf 0.25 (20% EtOAc/hexane); IR (neat): 3384, 2933, 2858, 1697, 1426, 1110, 702 cm1; 1H NMR (500 MHz, CDCl3): d 7.70e7.67 (m, 4H), 7.46e7.37 (m, 6H), 5.75e5.68 (m, 1H), 5.67e5.61 (m, 1H), 4.26 (d, J ¼ 6.0 Hz, 2H), 4.02 (d, J ¼ 6.1 Hz, 2H), 1.53e1.47 (br, 1H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3): d 135.5, 133.3, 130.7, 129.9, 129.7, 127.6, 60.1, 58.5, 26.7, 19.0; MS (ESI): m/z 327 [MþH]þ. HRMS (ESI): calcd for C20H27O2Si: 327.1780, found: 327.1778. 4.7. ((2S,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl) methanol 11 To a solution of freshly distilled Ti(O-iPr)4 (8.3 mL, 28 mmol) in dichloromethane (280 mL) was added fresh distilled (þ)-diethyl-Ltartrate (5.3 mL, 30.8 mmol) at 23 C. After stirring for 10 min at 23 C, a solution of compound 10 (9.13 g, 28 mmol) in dichloromethane (16 mL) was added via dropping funnel, and the resulting solution was stirred for 1 h at 23 C. To the above mixture was added a TBHP (dried using molecular sieves, 5 g of 4 Å) solution in dichloromethane (~4.0 M, 14 mL, ~56 mmol) while maintaining the reaction temperature at about 23 C. The mixture was stirred for 4 h at this temperature and was put in a freezer with occasionally stirring for 10 days until the starting material was consumed. To the light yellow reaction mixture was added aqueous D-tartaric acid solution (70 mL, 10%) at 23 C, then stirred for 1 h at this temperature and then at room temperature until the aqueous layer became clear. After separation of the organic layer from the aqueous layer, the organic layer was washed with water (120 mL) and dried. The organic layer was concentrated, the residue was dissolved in ether (220 mL), an aqueous NaOH solution (87 mL, 1 M) was slowly added at 0 C and the solution stirred for 30 min at this temperature. The ether layer was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 20-30% EtOAc/hexane (v/v) as the eluent to afford the epoxide 11 (8.71 g, 25.46 mmol) in 91% yield
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as a colourless oil; TLC: Rf 0.2 (20% EtOAc/hexane); [a]20 D ¼ e 6.40 (c 1.0, CHCl3); IR (neat): 3421, 3067, 2933, 2859, 1746, 1590, 1467, 1427, 1106, 821 cm1; 1H NMR (500 MHz, CDCl3): d 7.70e7.66 (m, 4H), 7.48e7.38 (m, 6H), 3.91 (dd, J ¼ 11.8, 5.5 Hz, 1H), 3.75 (dd, J ¼ 11.8, 5.3 Hz, 1H), 3.73e3.61 (m, 2H), 3.26e3.19 (m, 2H), 1.91 (t, J ¼ 6.1 Hz, 1H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3): d 135.5, 135.4, 132.9, 132.8, 129.9, 127.8, 62.1, 60.7, 56.4, 56.2, 26.7, 19.1; MS (ESI): m/z 365 [MþNa]þ. HRMS (ESI): calcd for C20H26O3NaSi: 365.1549, found: 365.1546. 4.8. (2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxirane-2carbaldehyde 12 The solution of epoxy-alcohol 11 (8.5 g, 24.85 mmol) in CH2Cl2 (46 mL) was added dropwise to Dess-Martin periodinane (17.9 g, 42.24 mmol) in CH2Cl2 (92 mL) at 0OC over 5 min. The reaction mixture was stirred at rt for 2.5 h. A mixture of aqueous saturated NaHCO3 (68 mL) and aqueous Na2S2O3 (136 mL, 10 wt %) was added over 5 min to the reaction mixture. The resulting mixture was stirred for an additional 5 min, then was partitioned between ether (450 mL) and, sequentially, aqueous saturated NaHCO3 (182 mL) and brine (150 mL). The organic extract was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography using 10-15% EtOAc/hexane (v/v) as the eluent to afford the epoxy aldehyde 12 (7.43 g, 21.85 mmol) in 88% yield as a colourless oil. TLC: Rf 0.3 (10% EtOAc/hexane); [a]20 D ¼ þ 52.72 (c 1.1, CHCl3); IR (neat): 3071, 2858, 1723, 1427, 1110, 820 704 cm1; 1H NMR (400 MHz, CDCl3): d 9.48 (d, J ¼ 4.8 Hz, 1H), 7.69e7.63 (m, 4H), 7.48e7.37 (m, 6H), 3.97 (dd, J ¼ 12.5, 3.30 Hz, 1H), 3.93 (dd, J ¼ 12.5, 4.0 Hz, 1H), 3.47e3.39 (m, 2H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3): d 198.0, 135.5, 132.4, 132.3, 130.0, 127.8, 60.7, 59.7, 57.6, 26.6, 19.0; MS (ESI): m/z 395 [MþNaþMeOH]þ. HRMS (ESI): calcd for C20H24O3NaSi: 363.1392, found: 363.1388. 4.9. tert-Butyldiphenyl(((2R,3S)-3-vinyloxiran-2-yl)methoxy)silane 6 To a suspension of Ph3PCH3Br (16.12 g, 45.15 mmol) in anhydrous THF (347 mL) was added KOtBu (4.81 g, 43.0 mmol) at 0 C. After 30 min, a solution of the crude epoxy aldehyde 12 (7.31 g, 21.5 mmol) in anhydrous THF (63 mL) was added over 10 min at 0 C. Stirring was continued for 2 h at rt. The reaction mixture was then partitioned between ether (100 mL), aqueous saturated NaHCO3 (50 mL) and brine (50 mL). The organic extract was dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography using 3-5% EtOAc/hexane (v/v) as the eluent to afford vinylepoxide 6 (6.9 g, 20.41 mmol) in 95% yield, as a colourless oil. Rf 0.4 (3% EtOAc/hexane); [a]20 D ¼ þ19.77 (c 2.2, CHCl3); IR (neat): 3071 2934, 2859, 1590, 1467, 1428, 1107, 820, 702 cm1; 1H NMR (400 MHz, CDCl3): d 7.72e7.66 (m, 4H), 7.47e7.36 (m, 6H), 5.54 (ddd, J ¼ 17.1, 10.4, 6.7 Hz, 1H), 5.39 (dd, J ¼ 17.1, 1.1 Hz, 1H), 5.24 (dd, J ¼ 10.4, 1.1 Hz, 1H), 3.79 (dd, J ¼ 11.7, 5.6 Hz, 1H) 3.76 (dd, J ¼ 11.7, 5.0 Hz, 1H), 3.45 (dd, J ¼ 6.7, 4.4 Hz, 1H) 3.33 (dt, J ¼ 9.7, 5.3 Hz, 1H), 1.07 (s, 9H); 13C NMR (125 MHz, CDCl3): d 135.6, 135.5, 133.3, 133.1, 131.9, 129.7, 127.7, 120.3, 62.0, 58.4, 56.6, 26.7, 19.2; MS (ESI): m/z 361 [MþNa]þ. HRMS (ESI): calcd for C21H26O2NaSi: 361.1600, found: 361.1603. 4.10. (4R,6R,7R)-4-((R)-But-3-en-2-yl)-1-(4-methoxyphenyl)11,11-dimethyl-10,10-diphenyl-6-vinyl-2,5,9-trioxa-10-siladodecan7-ol 4 Redistilled BF3.OEt2 (0.150 mL, 1.25 mmol) was added to a mixture of alcohol 5 (9.2 g, 39 mmol) and epoxide 6 (5.27 g, 15.6 mmol) in anhydrous dichloromethane (32 mL) cooled at 40
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O C under nitrogen. The reaction mixture was stirred at 40 OC for 16 h, the reaction was quenched with water (15 mL) and then extracted with dichloromethane (3 50 mL). The combined dichloromethane layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 7-10% EtOAc/hexane (v/v) as the eluent to afford diene 4 (5.55 g, 9.67 mmol) in 62% yield, as a colourless oil. TLC: Rf 0.25 (10% EtOAc/hexane). [a]20 D ¼ þ1.31 (c 1.3, CHCl3); IR (neat): 3452, 3071, 2931, 1612, 1512, 1465, 1247, 1110, 1037, 704 cm1; 1H NMR (400 MHz, CDCl3): d 7.72e7.62 (m, 4H), 7.46e7.33 (m, 6H), 7.23 (d, J ¼ 8.6 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 5.85e5.71 (m, 2H), 5.30 (d, J ¼ 17.3 Hz, 1H), 5.19 (d, J ¼ 10.2 Hz, 1H), 5.07e5.00 (m, 2H), 4.42 (d, J ¼ 11.6 Hz, 1H), 4.38 (d, J ¼ 11.6 Hz,1H), 4.07 (dd, J ¼ 7.6, 5.6 Hz, 1H), 3.80 (s, 3H), 3.75 (dd, J ¼ 10.3, 4.6 Hz, 1H), 3.67 (dd, J ¼ 10.3, 5.0 Hz, 1H), 3.64e3.59 (m, 1H), 3.52e3.47 (m, 1H), 3.42 (d, J ¼ 5.0 Hz, 2H), 2.76 (d, J ¼ 4.6 Hz, 1H), 2.62e2.52 (m, 1H), 1.05 (s, 9H), 1.01 (d, J ¼ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 140.4, 136.5, 135.6, 135.5, 133.4, 133.3, 130.4, 129.6, 129.2, 127.6, 118.4, 115.2, 113.7, 81.1, 80.4, 74.3, 72.8, 70.1, 64.0, 55.2, 39.6, 26.8, 19.2, 15.8; MS (ESI): m/z 597 [MþNa]þ. HRMS (ESI): calcd for C35H46O5NaSi: 597.3012, found: 597.3019.
4.11. (R)-2-((tert-Butyldiphenylsilyl)oxy)-1-((2R,5R,6R)-6-(((4methoxybenzyl)oxy)methyl)-5-methyl-5,6-dihydro-2H-pyran-2-yl) ethan-1-ol 3 A solution of diene 4 (5.45 g, 9.5 mmol) in toluene (95 mL) was deoxygenated by bubbling N2(g) for 15 min. Then, the mixture was warmed to 80 C and Grubbs' second generation catalyst was added (297 mg, 0.475 mmol). The resulting mixture was stirred at 80 OC for 12 h. Removal of solvent under reduced pressure purification of the crude product by silica gel column chromatography using 1520% EtOAc/hexane (v/v) as the eluent to afforded compound 3 (4.46 g, 8.17 mmol) in 86% as a viscous liquid. TLC: Rf 0.3 (20% EtOAc/hexane). [a]20 D ¼ þ 3.00 (c 1.0, CHCl3); IR (neat): 3451, 2931, 2860, 1611, 1512, 1463, 1248, 1110, 821 cm1; 1H NMR (400 MHz, CDCl3): d 7.72e7.65 (m, 4H), 7.45e7.35 (m, 6H), 7.26 (d, J ¼ 8.8 Hz, 2H), 6.87 (d, J ¼ 8.8 Hz, 2H), 5.73e5.63 (m, 2H), 4.54 (d, J ¼ 11.9 Hz, 1H), 4.48 (d, J ¼ 11.9 Hz, 1H), 4.31e4.26 (m, 1H), 3.88e3.72 (m, 6H), 3.62e3.49 (m, 3H), 2.87e2.81 (bs, 1H), 2.32e2.22 (m, 1H), 1.06 (s, 9H), 0.92 (d, J ¼ 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 135.6, 135.55, 133.3, 133.2, 132.4, 130.3, 129.67, 129.65, 129.2, 127.67, 127.65, 124.6, 113.7, 74.8, 73.0, 72.9, 72.7, 70.3, 64.7, 55.2, 30.2, 26.8, 19.3, 17.6; MS (ESI): m/z 569 [MþNa]þ. HRMS (ESI): calcd for C33H42O5NaSi: 569.2699, found: 569.2701.
4.51 (d, J ¼ 11.9 Hz, 1H), 4.48 (d, J ¼ 11.9 Hz, 1H), 4.29e4.26 (m, 2H), 4.21 (td, J ¼ 6.6, 1.8 Hz, 1H), 4.12 (d, J ¼ 5.3 Hz, 1H), 4.04 (dd, J ¼ 10.5, 6.6 Hz, 1H), 3.93 (dd, J ¼ 10.5, 5.6 Hz, 1H), 3.80 (s, 3H), 3.60 (dd, J ¼ 11.3, 6.7 Hz, 1H), 3.53e3.48 (m, 2H), 2.37e2.29 (m, 1H), 1.04 (s, 9H), 0.81 (d, J ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.0, 135.6, 135.5, 133.2, 133.1, 130.4, 129.7, 129.2, 127.72, 127.70, 113.6, 80.9, 80.3, 77.1, 76.0, 72.9, 71.5, 61.5, 55.2, 33.4, 26.7, 26.1, 19.1, 15.8; MS (ESI): m/z 695 [MþNa]þ. HRMS (ESI): calcd for C33 H41 O5 I Si Na: 695.1666, found: 695.1652. 4.13. tert-Butyl(((1R,3R,4R,5R,7R)-3-(((4-methoxybenzyl)oxy) methyl)-4-methyl-2,6-dioxabicyclo[3.2.1]octan-7-yl)methoxy) diphenylsilane 2 AIBN (385 mg 2.35 mmol) was added to a stirred solution of 14 (3.16 g, 4.7 mmol) in anhydrous toluene (235 mL) followed by Bu3SnH (2.6 mL, 9.4 mmol) and the resulting reaction mixture was heated under reflux under a nitrogen atmosphere for 2 h. After completion of the reaction (monitored by TLC), toluene was removed under reduced pressure and the crude product was purified by silica gel column chromatography using 10-15% EtOAc/ hexane (v/v) as the eluent to afford compound 2 (2.37 g, 4.34 mmol) in 92% yield as a colorless liquid. TLC: Rf 0.2 (10% EtOAc/hexane). [a]20 D ¼ e 45.45 (c 1.1, CHCl3); IR (neat): 3066, 2931, 2859, 1611, 1512, 1462, 1248, 1107, 703 cm1; 1H NMR (500 MHz, CDCl3): d 7.75e7.69 (m, 4H), 7.43e7.32 (m, 6H), 7.21 (d, J ¼ 8.7 Hz, 2H), 6.85 (d, J ¼ 8.7 Hz, 2H), 4.52 (d, J ¼ 11.9 Hz, 1H), 4.47e4.45 (m, 1H), 4.40 (d, J ¼ 11.9 Hz, 1H), 4.22 (d, J ¼ 6.6 Hz, 1H), 4.09 (td, J ¼ 6.3, 2.1 Hz, 1H), 4.0 (dd, J ¼ 10.4, 6.4 Hz, 1H), 3.93 (dd, J ¼ 10.4, 6.0 Hz, 1H), 3.80 (s, 3H), 3.49 (ddd, J ¼ 9.5, 4.6, 2.4 Hz, 1H), 3.43 (dd, J ¼ 10.8, 2.4 Hz, 1H), 3.37 (dd, J ¼ 10.8, 4.7 Hz, 1H) 2.01 (ddd, J ¼ 11.6, 6.7, 2.7 Hz, 1H) 1.85 (dd, J ¼ 11.6, 1.4 Hz, 1H), 1.67e1.60 (m, 1H), 1.04 (s, 9H), 0.80 (d, J ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 135.6, 133.5, 130.4, 129.5, 129.2, 127.6, 113.6, 83.4, 79.2, 77.4, 74.2, 72.9, 70.9, 61.7, 55.2, 38.2, 37.2, 26.7, 19.1, 15.7; MS (ESI): m/z 569 [MþNa]þ. HRMS (ESI): calcd for C33H42O5Si Na: 569.2699, found: 569.2695. Acknowledgements N. Sathyanarayana is thankful to Council of Scientific and Industrial Research (CSIR)-New Delhi for fellowship. S. R is grateful to the Department of Science and Technology, New Delhi for funding the project (EMR/2014/000753) and CSIR, New Delhi for funding under the XII five year plan programme entitled ORIGIN (CSC-108). Appendix A. Supplementary data
4.12. tert-Butyl(((1S,3R,4S,5S,7R,8R)-8-iodo-3-(((4-methoxybenzyl) oxy)methyl)-4-methyl-2,6-dioxabicyclo[3.2.1]octan-7-yl)methoxy) diphenylsilane 14 NIS (5.38 g, 23.94 mmol) and Sc(OTf)3 (590 mg, 1.2 mmol) were added to a stirred solution of the alcohol 3 (4.36 g, 7.98 mmol) in anhydrous dichloromethane (36 mL) and THF (4 mL) under a nitrogen atmosphere at 0 OC. The resulting reaction mixture was stirred in the dark at 0 OC for 12 h. The reaction mixture was quenched with aq saturated NaHSO3 (20 mL) and then extracted with dichloromethane (3 50 mL). The combined dichloromethane layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 7-10% EtOAc/hexane (v/v) as the eluent to afford compound 14 (3.22 g, 4.79 mmol) in 60% yield, as viscous liquid. TLC: Rf 0.4 (10% EtOAc/hexane). [a]20 D ¼ þ2.40 (c 1.0, CHCl3); IR (neat): 3063, 2934, 2859, 1612, 1512, 1462, 1246, 1109, 702, 501 cm1; 1H NMR (500 MHz, CDCl3): d 7.72e7.67 (m, 4H), 7.44e7.32 (m, 6H), 7.24 (d, J ¼ 8.5 Hz, 2H), 6.85 (d, J ¼ 8.5 Hz, 2H),
Supplementary data related to this article can be found at https://doi.org/10.1016/j.tet.2018.01.036. References € fle G. Tetrahedron Lett. 1. (a) Jansen R, Wray V, Irschik H, Reichenbach H, Ho 1985;26:6031; € fle G. Liebigs (b) Jansen R, Irschik H, Reichenbach H, Schomburg D, Wray V, Ho Ann Chem. 1989:111. 2. Campbell EA, Pavlova O, Zenkin N, et al. EMBO J. 2005;24:674. 3. (a) Smith III AB, Fox RJ. Org Lett. 2004;6:1477; (b) Smith III AB, Fox RJ, Vanecko JA. Org Lett. 2005;7:3099; (c) Smith III AB, Dong S. Org Lett. 2009;11:1099; (d) Smith III AB, Dong S, Brenneman JB, Fox RJ. J Am Chem Soc. 2009;131:12109; (e) Smith III AB, Dong S, Fox RJ, Brenneman JB, Vanecko JA, Maegawa T. Tetrahedron. 2011;67:9809. 4. Crimmins MT, Haley MW, O'Bryan EA. Org Lett. 2011;13:4712. 5. (a) Schinzer D, Schulz C, Krug O. Synlett. 2004:2689; (b) Michaelis L, Schinzer D. Synlett. 2014:951. 6. Park HS, Lee HW. Bull Kor Chem Soc. 2008;29:1661. 7. Lee K, Kim H, Hong J. Eur J Org Chem. 2012:1025. 8. (a) Srihari P, Kumaraswamy B, Yadav JS. Tetrahedron. 2009;65:6304;
S. Raghavan, S. Nyalata / Tetrahedron 74 (2018) 1071e1077 (b) Mohapatra DK, Das PP, Pattanayak MR, Yadav JS. Chem Eur J. 2010;16:2072. Sridhar Y, Srihari P. Org Biomol Chem. 2013;11:4640. Raghavan S, Nyalata S. J Org Chem. 2016;81:10698. Crimmins MT, Haley MW. Org Lett. 2006;8:4223. Yang F, Newsome JJ, Curran DP. J Am Chem Soc. 2006;128:14200. Brown HC, Bhat KS. J Am Chem Soc. 1986;108:5919. The absolute stereochemistry and enantiomer ratio of alcohol 5 was determined by analysis of the 1H NMR spectra of the derived methoxymandelate esters. For the assignment of absolute configuration see: Trost BM, Belletire JL, Godleski S, et al J Org Chem. 1986;51:2370. 15. The alcohol 5 was also prepared by employing Krische’ protocol using monoprotected ethylene glycol as the starting material. The yields were
9. 10. 11. 12. 13. 14.
16.
17. 18. 19. 20. 21.
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however, moderate (66%), selectivity poor (dr ¼ 5:1) and the reaction proceeded very slowly. Kim IS, Han SB, Krische MJ J Am Chem Soc. 2009;131:2514 (a) Li X, Lantrip D, Fuchs PL. J Am Chem Soc. 2003;125:14262; (b) Reddy BC, Bangade VM, Ramesh P, Meshram HM. Helv Chim Acta. 2013;96: 266. Dess DB, Martin JC. J Org Chem. 1983;48:4156. Heck M, Baylon C, Nolan SP, Mioskowski C. Org Lett. 2001;3:1989. Blackwell HE, O'Leary DJ, Chatterjee AK, Washenfelder RA, Bussmann DA, Grubbs RH. J Am Chem Soc. 2000;122:58. Knight DW, Shaw DE, Staples ER. Eur J Org Chem. 2004:1973. Hajra S, Bhowmick M, Sinha D. J Org Chem. 2006;71:9237.
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A short convergent synthesis of the [3.2.1]dioxabicyclooctane subunit of sorangicin A via regioselective epoxide opening Sadagopan Raghavan*, Satyanarayana Nyalata Natural Product Chemistry Division, Indian Institute of Chemical Technology, Hyderabad, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 November 2017 Received in revised form 17 January 2018 Accepted 20 January 2018 Available online 31 January 2018
In this paper, we disclose the synthesis of the dioxabicyclo[3.2.1]octane subunit of the potent antibiotic sorangicin A. The synthesis was achieved in a convergent manner in 8 steps. Regio- and stereoselective intermolecular epoxide opening, ring-closing metathesis and iodo-etherification are key steps. cis-2Butene diol has been employed as a common staring material. © 2018 Elsevier Ltd. All rights reserved.
Keywords: Sorangicin A Mioskowski's protocol 5-endo Trig cyclization Ring-closing metathesis
1. Introduction
2. Results and discussion
Sorangicin A (1) Fig. 1, is an architecturally complex macrolide antibiotic isolated by Hofle and co-workers1 from the myxobacteria Sorangium cellulosum. It exhibits potent activity against Grampositive (MIC 0.01e0.3 mg/mL) and Gram-negative bacteria (MIC 3-25 mg/mL) including methicillin resistant bacteria without affecting eukaryotic cells. Sorangicin A possesses a remarkable ability to adapt to rapidly mutating targets2 and its antibiotic activity has been related to inhibition of RNA polymerase.1a Sorangicin A is a 31-membered macrolactone containing a tetrasubstituted tetrahydropyran, a tri-substituted dihydropyran, a dioxabicyclo[3.2.1]octane moiety and a rare (Z,Z,E)-trienoate linkage. The unique structural features in conjunction with its biological activity has attracted considerable interest from the synthetic community with the first total synthesis being reported by Smith and co-workers.3 Crimmins and co-workers synthesized a known precursor thus completing a formal synthesis.4 The groups of Schinzer,5 H. W. Lee,6 K. Lee,7 Mohapatra and Yadav,8 Srihari9 and Raghavan10 have reported the synthesis of the subunits of sorangicin A. Herein, we disclose our efforts toward sorangicin A by synthesizing the C30-C37 bicyclic ether subunit.
The groups of Smith3a,3c and Schinzer5 have each disclosed a first- and second generation approach to the bicyclic ether moiety in addition to the reports from the groups of Crimmins11 and Mohapatra and Yadav,8 all employing a linear sequence of reactions, Scheme 1. The first generation synthesis of Smith and coworkers by a 15 step sequence (Scheme 1c) involved the construction of the tetrahydrofuran (THF) ring by epoxide opening taking advantage of the Nicolas reaction and the tetrahydropyran (THP) ring by an acid catalyzed epoxide ring opening. The second generation synthesis (Scheme 1d) by a 8 step sequence starting from L-gulonic acid took advantage of a hetero Diels-Alder reaction to construct the pyranose ring and the THF ring by epoxide opening. In the first generation route disclosed by Schinzer (Scheme 1a), the THP ring was elaborated by an acid-catalyzed reaction of an epoxy acetonide, obtained by a lengthy sequence of reactions and the THF ring by a Williamson ether synthesis. In the second approach (Scheme 1b), the dihydropyranone, synthesized from a keto lactone, was subjected to Mukaiyama-Michael reaction to introduce all the stereocenters and the THF ring was created by epoxide opening. Crimmins and co-workers (Scheme 1e) utilized an epoxy tosylate and constructed the THP ring by an epoxide opening followed by formation of another epoxide and its opening to construct the THF ring of the bicyclic ether by a 10 step sequence. Mohapatra and Yadav by a 9 step sequence, taking advantage of iodine catalyzed
* Corresponding author. E-mail address: [email protected] (S. Raghavan). https://doi.org/10.1016/j.tet.2018.01.036 0040-4020/© 2018 Elsevier Ltd. All rights reserved.
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Fig. 1. Sorangicin A
cyclization of d-hydroxy a, b-unsaturated aldehyde to synthesize the trans-2,6-disubstituted dihydropyran moiety and a 5-endo iodo-etherification to introduce the THF ring, synthesized the bicyclic moiety Scheme 1f). We envisioned construction of the C30-C37 bicyclic subunit 2 by a iodo-etherification of dihydropyran 3 followed by radical deiodination. The dihydropyran 3 can be obtained by a ring-closing metathesis reaction of diene 4. The diene 4 was envisaged to be obtained in a convergent fashion by a regio- and stereoselective intermolecular opening of epoxide 6 by alcohol 5. Both the alcohol 5 and epoxide 6 can be traced to a common precursor, butenediol 7, Scheme 2. The synthesis of the homoallyl alcohol 5 began from the known aldehyde 912 which on asymmetric Brown crotylation13 afforded alcohol 5 in good yield and high stereoselectivity (76%, dr: >20:1), Scheme 3.14,15 The synthesis of epoxide 6 began from diol 7 which on selective monoprotection afforded alcohol 10. Subjecting alcohol 10 to Sharpless' asymmetric epoxidation conditions provided epoxide 11.16 Oxidation of alcohol using Dess-Martin periodinane17 yielded aldehyde 12 which on homologation yielded epoxide 6, Scheme 3. The diene 4 was obtained cleanly by reaction of an excess of alcohol 5 with epoxide 6 following Mioskowski's protocol.18 Ringclosing metathesis19 of diene 4 catalyzed by Grubbs's second generation catalyst 13 in refluxing toluene afforded dihydropyran 3 in 85% yield. The 5-endo iodo-etherification of dihydropyran 3 following Knight's protocol20 afforded the iodo ether 14 in moderate yield (50%). After experimentation, satisfactory yield was obtained employing N-iodosuccinimide and catalytic amounts of scandium triflate.21 Radical deiodination of 14 proceeded cleanly using tributyltin hydride and catalytic AIBN to furnish bicyclic subunit 2, Scheme 4. 3. Conclusions In conclusion, we have disclosed a short, convergent synthesis of the bicyclo[3.2.1] subunit of sorangicin A. The THP ring was constructed by a ring-closing metathesis reaction and the THF ring by iodo-etherification. The subunit was constructed by a 8 step sequence in 21.3% overall yield. 4. Experimental section 4.1. (Z)-1,4-bis((4-Methoxybenzyl)oxy)but-2-ene 8 To a suspension of NaH (60% in Nujol, 3.46 g, 86.4 mmol) in anhydrous THF (112 mL) cooled at 0 C was added the solution of cis-2-butene-1,4-diol 7 (2.96 mL, 36 mmol) in anhydrous THF
(16 mL) and stirred for 15 min. Then a solution of 4-methoxybenzyl bromide (15.92 g, 79.2 mmol) in THF (12 mL) and catalytic amount TBAI were added at 0 OC and the reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was quenched by slow addition of aq sat NH4Cl solution (50 mL) and extracted with EtOAc (2 100 mL). The organic layer was separated and washed with water (2 50 mL) and brine (50 mL). The organic extract was dried (Na2SO4) and concentrated. The crude product was purified by silica gel column chromatography using 10-20% EtOAc/hexane (v/v) as the eluent to afford the PMB-ether 8 (11.34 g, 34.57 mmol) in 96% yield, as a colourless liquid. TLC: Rf 0.2 (10% EtOAc/hexane). IR (neat): 3002, 2839, 1611, 1513, 1248, 1079, 820 cm1; 1H NMR (400 MHz, CDCl3): d 7.25 (d, J ¼ 8.7 Hz, 4H), 6.87 (d, J ¼ 8.7 Hz, 4H), 5.77 (t, J ¼ 4.8 Hz, 2H), 4.42 (s, 4H), 4.03 (d, J ¼ 4.8 Hz, 4H), 3.80 (s, 6H); 13C NMR (100 MHz, CDCl3): d 159.1, 130.1, 129.4, 129.3, 113.7, 71.8, 65.3, 55.1; MS (ESI): m/z 351 [MþNa]þ. HRMS (ESI): calcd for C20H24O4Na: 351.1567, found: 351.1580. 4.2. 2-((4-Methoxybenzyl)oxy)acetaldehyde 9 Ozone was bubbled through a solution of the alkene 8 (11.2 g, 34.14 mmol) in a mixture of CH2Cl2 (380 mL) and MeOH (14 mL) at 78 C. After the solution turned blue (about 40 min), Me2S (10.60 g, 170.17 mmol) was added. The reaction mixture was stirred for 10 min at the same temperature, before being warmed to room temperature and stirred for another 4 h. Water (60 mL) was added, and most of the organic solvent was removed under reduced pressure. The residue was extracted with ether (4 65 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 40-50% EtOAc/hexane (v/v) as the eluent to afford the aldehyde 9 (10.33 g, 57.38 mmol) in 84% yield, as a colourless oil. TLC: Rf 0.4 (40% EtOAc/hexane). IR (neat): 3001, 2933, 2838, 1735, 1612, 1513, 1248, 1100, 820 cm1; 1H NMR (400 MHz, CDCl3): d 9.70 (t, J ¼ 0.8 Hz, 1H), 7.29 (d, J ¼ 8.8 Hz, 2H), 6.90 (d, J ¼ 8.8 Hz, 2H), 4.56 (s, 2H), 4.07 (d, J ¼ 0.8 Hz, 2H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3): d 200.2, 159.2, 129.4, 128.7, 113.6, 74.7, 72.9, 54.9; MS (ESI): m/z 235 [MþNaþMeOH]þ. HRMS (ESI): calcd for C10H12O3Na: 203.0684, found: 203.0684. 4.3. (2R,3R)-1-((4-Methoxybenzyl)oxy)-3-methylpent-4-en-2-ol 5 To a stirred suspension of potassium tert-butoxide (5.55 g, 49.54 mmol) in anhydrous THF (8.6 mL) and cooled to 78 OC, trans-2-butene (8.8 mL 98.55 mmol) was added followed by nBuLi (20.9 mL, 2.5 M in hexane. 52.17 mmol). The mixture was warmed to 45 OC and stirred at this temperature for 15 min and then cooled again to 78 OC. A solution of (þ)-lpc2BOMe (19.98 g, 63.24 mmol) in THF (63 mL) was added and the mixture stirred for 30 min. BF3.OEt2 (6.44 mL, 52.17 mmol) was added, followed by aldehyde 9 (9.5 g, 52.7 mmol). The mixture was stirred for 4 h at 78 OC and then quenched with aq NaOH (37.8 mL, 3M), followed by cautious addition of 30% aqueous H2O2 (15.5 mL). The solution was stirred at rt for 16 h and then extracted with ether (3 100 mL). The combined ether layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 10-15% Ether/DCM (v/v) as the eluent to afford compound 5 (9.45 g, 40.04 mmol) in 76% yield, as a colourless oil. TLC: Rf 0.4 (DCM). [a]20 D ¼ þ5.00 (c 1.2, CHCl3); IR (neat): 3455, 3072, 2865, 1612, 1513, 1247, 1095, 1034, 820 cm1; 1H NMR (500 MHz, CDCl3): d 7.26 (d, J ¼ 8.7 Hz, 2H), 6.88 (d, J ¼ 8.7 Hz, 2H), 5.86e5.78 (m, 1H), 5.1e5.08 (m, 1H), 5.07e5.05 (m, 1H), 4.5 (d, J ¼ 11.6 Hz, 1H), 4.47 (d, J ¼ 11.6 Hz, 1H), 3.81 (s, 3H), 3.68e3.60 (m, 1H), 3.52 (dd, J ¼ 9.6, 3.1 Hz, 1H), 3.39 (dd, J ¼ 9.6, 7.6 Hz, 1H), 2.38e2.30 (m, 1H), 2.26 (d, J ¼ 3.2 Hz, 1H), 1.03 (d,
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Scheme 1. Earlier approaches to the bicyclooctane moiety.
J ¼ 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 140.0, 130.0, 129.2, 115.2, 113.6, 73.3, 72.8, 72.1, 55.0, 40.6, 16.0; MS (ESI): m/z 259 [MþNa]þ. HRMS (ESI): calcd for C14H20O3Na: 259.1305, found: 259.1323. 4.4. (2R,3R)-1-((4-Methoxybenzyl)oxy)-3-methylpent-4-en-2yl(S)-2-methoxy-2-phenylacetate I To a solution of the alcohol 5 (11.8 mg, 0.05 mmol) in anhydrous
CH2Cl2 (2 mL) were added (S)-O-methyl mandelic acid (8.3 mg, 0.05 mmol), DCC (12 mg, 0.06 mmol) and a few crystals of DMAP and the mixture was stirred for 45 min. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel using 10-15% EtOAc/hexane (v/v) as the eluent to afford ester I (16.2 mg, 0.042 mmol) in 84% yield as a colourless oil. 1H NMR (400 MHz, CDCl3): d 7.46e7.41 (m, 2H), 7.36e7.28 (m, 3H), 7.22 (d, J ¼ 8.7 Hz, 2H), 6.87 (d, J ¼ 8.7 Hz, 2H), 5.44 (ddd, J ¼ 18.5, 10.4, 8.2 Hz, 1H), 5.06e5.01 (m, 1H), 4.86e4.79
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Scheme 2. Retrosynthetic analysis of subunit 2.
Scheme 3. Synthesis of alcohol 5 and epoxide 6 from cis-2-butene diol.
Scheme 4. Synthesis of the dioxabicyclic subunit of sorangicin A.
(m, 2H), 4.75 (s, 1H), 4.46 (d, J ¼ 11.5 Hz, 1H), 4.38 (d, J ¼ 11.5 Hz, 1H), 3.81 (s, 3H), 3.51 (dd, J ¼ 10.8, 6.2 Hz, 1H), 3.47 (dd, J ¼ 10.8, 4.5 Hz, 1H), 3.40 (s, 3H), 2.47e2.36 (m, 1H), 0.71 (d, J ¼ 7.0 Hz, 3H);
4.5. (2R,3R)-1-((4-Methoxybenzyl)oxy)-3-methylpent-4-en-2-yl (R)-2-methoxy-2-phenylacetate II To a solution of the alcohol 5 (11.8 mg, 0.05 mmol) in anhydrous
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CH2Cl2 (2 mL) were added (R)-O-methyl mandelic acid (8.3 mg, 0.05 mmol), DCC (12 mg, 0.06 mmol) and a few crystals of DMAP and the mixture was stirred for 45 min. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel using 10-15% EtOAc/hexane (v/v) as the eluent to afford ester II (15.8 mg, 0.041 mmol) in 83% yield as a colourless oil. 1H NMR (400 MHz, CDCl3): d 7.47e7.44 (m, 2H), 7.35e7.29 (m, 3H), 7.07 (d, J ¼ 8.7 Hz, 2H), 6.82 (d, J ¼ 8.7 Hz, 2H), 5.68 (ddd J ¼ 17.1, 10.3, 8.2 Hz, 1H), 5.09e4.96 (m, 3H), 4.77 (s, 1H), 4.24 (d, J ¼ 11.6 Hz, 1H), 4.18 (d, J ¼ 11.6 Hz, 1H), 3.80 (s, 3H), 3.42 (s, 3H), 3.40 (dd, J ¼ 10.9, 5.9 Hz, 1H), 3.36 (dd, J ¼ 10.9, 4.2 Hz, 1H), 2.60e2.48 (m, 1H), 0.96 (d, J ¼ 7.0 Hz, 3H); As would be expected the olefinic signals appear upfield in ester I in comparison to ester II while ether signals appear downfield in ester I in comparison to ester II. 4.6. (Z)-4-((tert-butyldiphenylsilyl)oxy)but-2-en-1-ol 10 To a suspension of NaH (60% in Nujol, 1.2 g, 30 mmol) in anhydrous THF (40 mL) cooled at 0 C was added the solution of cis-2butene-1,4-diol 7 (2.64 g, 30 mmol) in anhydrous THF (20 mL). After the mixture was stirred at rt for 16 h, TBDPS-Cl (7.7 mL, 30 mmol) was added and the reaction mixture was stirred at rt for 2 h. After dilution with Et2O (50 mL), the reaction mixture was cooled to 0 C and treated with aq satd NH4Cl solution (40 mL). The aq phase was extracted with Et2O (2 50 mL) and the combined organic extracts were washed with brine (2 50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography using 15-20% EtOAc/ hexane (v/v) as the eluent to afford compound 10 (9.3 g, 28.52 mmol) in 95% yield as a colourless liquid; TLC: Rf 0.25 (20% EtOAc/hexane); IR (neat): 3384, 2933, 2858, 1697, 1426, 1110, 702 cm1; 1H NMR (500 MHz, CDCl3): d 7.70e7.67 (m, 4H), 7.46e7.37 (m, 6H), 5.75e5.68 (m, 1H), 5.67e5.61 (m, 1H), 4.26 (d, J ¼ 6.0 Hz, 2H), 4.02 (d, J ¼ 6.1 Hz, 2H), 1.53e1.47 (br, 1H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3): d 135.5, 133.3, 130.7, 129.9, 129.7, 127.6, 60.1, 58.5, 26.7, 19.0; MS (ESI): m/z 327 [MþH]þ. HRMS (ESI): calcd for C20H27O2Si: 327.1780, found: 327.1778. 4.7. ((2S,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxiran-2-yl) methanol 11 To a solution of freshly distilled Ti(O-iPr)4 (8.3 mL, 28 mmol) in dichloromethane (280 mL) was added fresh distilled (þ)-diethyl-Ltartrate (5.3 mL, 30.8 mmol) at 23 C. After stirring for 10 min at 23 C, a solution of compound 10 (9.13 g, 28 mmol) in dichloromethane (16 mL) was added via dropping funnel, and the resulting solution was stirred for 1 h at 23 C. To the above mixture was added a TBHP (dried using molecular sieves, 5 g of 4 Å) solution in dichloromethane (~4.0 M, 14 mL, ~56 mmol) while maintaining the reaction temperature at about 23 C. The mixture was stirred for 4 h at this temperature and was put in a freezer with occasionally stirring for 10 days until the starting material was consumed. To the light yellow reaction mixture was added aqueous D-tartaric acid solution (70 mL, 10%) at 23 C, then stirred for 1 h at this temperature and then at room temperature until the aqueous layer became clear. After separation of the organic layer from the aqueous layer, the organic layer was washed with water (120 mL) and dried. The organic layer was concentrated, the residue was dissolved in ether (220 mL), an aqueous NaOH solution (87 mL, 1 M) was slowly added at 0 C and the solution stirred for 30 min at this temperature. The ether layer was washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 20-30% EtOAc/hexane (v/v) as the eluent to afford the epoxide 11 (8.71 g, 25.46 mmol) in 91% yield
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as a colourless oil; TLC: Rf 0.2 (20% EtOAc/hexane); [a]20 D ¼ e 6.40 (c 1.0, CHCl3); IR (neat): 3421, 3067, 2933, 2859, 1746, 1590, 1467, 1427, 1106, 821 cm1; 1H NMR (500 MHz, CDCl3): d 7.70e7.66 (m, 4H), 7.48e7.38 (m, 6H), 3.91 (dd, J ¼ 11.8, 5.5 Hz, 1H), 3.75 (dd, J ¼ 11.8, 5.3 Hz, 1H), 3.73e3.61 (m, 2H), 3.26e3.19 (m, 2H), 1.91 (t, J ¼ 6.1 Hz, 1H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3): d 135.5, 135.4, 132.9, 132.8, 129.9, 127.8, 62.1, 60.7, 56.4, 56.2, 26.7, 19.1; MS (ESI): m/z 365 [MþNa]þ. HRMS (ESI): calcd for C20H26O3NaSi: 365.1549, found: 365.1546. 4.8. (2R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)oxirane-2carbaldehyde 12 The solution of epoxy-alcohol 11 (8.5 g, 24.85 mmol) in CH2Cl2 (46 mL) was added dropwise to Dess-Martin periodinane (17.9 g, 42.24 mmol) in CH2Cl2 (92 mL) at 0OC over 5 min. The reaction mixture was stirred at rt for 2.5 h. A mixture of aqueous saturated NaHCO3 (68 mL) and aqueous Na2S2O3 (136 mL, 10 wt %) was added over 5 min to the reaction mixture. The resulting mixture was stirred for an additional 5 min, then was partitioned between ether (450 mL) and, sequentially, aqueous saturated NaHCO3 (182 mL) and brine (150 mL). The organic extract was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography using 10-15% EtOAc/hexane (v/v) as the eluent to afford the epoxy aldehyde 12 (7.43 g, 21.85 mmol) in 88% yield as a colourless oil. TLC: Rf 0.3 (10% EtOAc/hexane); [a]20 D ¼ þ 52.72 (c 1.1, CHCl3); IR (neat): 3071, 2858, 1723, 1427, 1110, 820 704 cm1; 1H NMR (400 MHz, CDCl3): d 9.48 (d, J ¼ 4.8 Hz, 1H), 7.69e7.63 (m, 4H), 7.48e7.37 (m, 6H), 3.97 (dd, J ¼ 12.5, 3.30 Hz, 1H), 3.93 (dd, J ¼ 12.5, 4.0 Hz, 1H), 3.47e3.39 (m, 2H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3): d 198.0, 135.5, 132.4, 132.3, 130.0, 127.8, 60.7, 59.7, 57.6, 26.6, 19.0; MS (ESI): m/z 395 [MþNaþMeOH]þ. HRMS (ESI): calcd for C20H24O3NaSi: 363.1392, found: 363.1388. 4.9. tert-Butyldiphenyl(((2R,3S)-3-vinyloxiran-2-yl)methoxy)silane 6 To a suspension of Ph3PCH3Br (16.12 g, 45.15 mmol) in anhydrous THF (347 mL) was added KOtBu (4.81 g, 43.0 mmol) at 0 C. After 30 min, a solution of the crude epoxy aldehyde 12 (7.31 g, 21.5 mmol) in anhydrous THF (63 mL) was added over 10 min at 0 C. Stirring was continued for 2 h at rt. The reaction mixture was then partitioned between ether (100 mL), aqueous saturated NaHCO3 (50 mL) and brine (50 mL). The organic extract was dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography using 3-5% EtOAc/hexane (v/v) as the eluent to afford vinylepoxide 6 (6.9 g, 20.41 mmol) in 95% yield, as a colourless oil. Rf 0.4 (3% EtOAc/hexane); [a]20 D ¼ þ19.77 (c 2.2, CHCl3); IR (neat): 3071 2934, 2859, 1590, 1467, 1428, 1107, 820, 702 cm1; 1H NMR (400 MHz, CDCl3): d 7.72e7.66 (m, 4H), 7.47e7.36 (m, 6H), 5.54 (ddd, J ¼ 17.1, 10.4, 6.7 Hz, 1H), 5.39 (dd, J ¼ 17.1, 1.1 Hz, 1H), 5.24 (dd, J ¼ 10.4, 1.1 Hz, 1H), 3.79 (dd, J ¼ 11.7, 5.6 Hz, 1H) 3.76 (dd, J ¼ 11.7, 5.0 Hz, 1H), 3.45 (dd, J ¼ 6.7, 4.4 Hz, 1H) 3.33 (dt, J ¼ 9.7, 5.3 Hz, 1H), 1.07 (s, 9H); 13C NMR (125 MHz, CDCl3): d 135.6, 135.5, 133.3, 133.1, 131.9, 129.7, 127.7, 120.3, 62.0, 58.4, 56.6, 26.7, 19.2; MS (ESI): m/z 361 [MþNa]þ. HRMS (ESI): calcd for C21H26O2NaSi: 361.1600, found: 361.1603. 4.10. (4R,6R,7R)-4-((R)-But-3-en-2-yl)-1-(4-methoxyphenyl)11,11-dimethyl-10,10-diphenyl-6-vinyl-2,5,9-trioxa-10-siladodecan7-ol 4 Redistilled BF3.OEt2 (0.150 mL, 1.25 mmol) was added to a mixture of alcohol 5 (9.2 g, 39 mmol) and epoxide 6 (5.27 g, 15.6 mmol) in anhydrous dichloromethane (32 mL) cooled at 40
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O C under nitrogen. The reaction mixture was stirred at 40 OC for 16 h, the reaction was quenched with water (15 mL) and then extracted with dichloromethane (3 50 mL). The combined dichloromethane layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 7-10% EtOAc/hexane (v/v) as the eluent to afford diene 4 (5.55 g, 9.67 mmol) in 62% yield, as a colourless oil. TLC: Rf 0.25 (10% EtOAc/hexane). [a]20 D ¼ þ1.31 (c 1.3, CHCl3); IR (neat): 3452, 3071, 2931, 1612, 1512, 1465, 1247, 1110, 1037, 704 cm1; 1H NMR (400 MHz, CDCl3): d 7.72e7.62 (m, 4H), 7.46e7.33 (m, 6H), 7.23 (d, J ¼ 8.6 Hz, 2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 5.85e5.71 (m, 2H), 5.30 (d, J ¼ 17.3 Hz, 1H), 5.19 (d, J ¼ 10.2 Hz, 1H), 5.07e5.00 (m, 2H), 4.42 (d, J ¼ 11.6 Hz, 1H), 4.38 (d, J ¼ 11.6 Hz,1H), 4.07 (dd, J ¼ 7.6, 5.6 Hz, 1H), 3.80 (s, 3H), 3.75 (dd, J ¼ 10.3, 4.6 Hz, 1H), 3.67 (dd, J ¼ 10.3, 5.0 Hz, 1H), 3.64e3.59 (m, 1H), 3.52e3.47 (m, 1H), 3.42 (d, J ¼ 5.0 Hz, 2H), 2.76 (d, J ¼ 4.6 Hz, 1H), 2.62e2.52 (m, 1H), 1.05 (s, 9H), 1.01 (d, J ¼ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 140.4, 136.5, 135.6, 135.5, 133.4, 133.3, 130.4, 129.6, 129.2, 127.6, 118.4, 115.2, 113.7, 81.1, 80.4, 74.3, 72.8, 70.1, 64.0, 55.2, 39.6, 26.8, 19.2, 15.8; MS (ESI): m/z 597 [MþNa]þ. HRMS (ESI): calcd for C35H46O5NaSi: 597.3012, found: 597.3019.
4.11. (R)-2-((tert-Butyldiphenylsilyl)oxy)-1-((2R,5R,6R)-6-(((4methoxybenzyl)oxy)methyl)-5-methyl-5,6-dihydro-2H-pyran-2-yl) ethan-1-ol 3 A solution of diene 4 (5.45 g, 9.5 mmol) in toluene (95 mL) was deoxygenated by bubbling N2(g) for 15 min. Then, the mixture was warmed to 80 C and Grubbs' second generation catalyst was added (297 mg, 0.475 mmol). The resulting mixture was stirred at 80 OC for 12 h. Removal of solvent under reduced pressure purification of the crude product by silica gel column chromatography using 1520% EtOAc/hexane (v/v) as the eluent to afforded compound 3 (4.46 g, 8.17 mmol) in 86% as a viscous liquid. TLC: Rf 0.3 (20% EtOAc/hexane). [a]20 D ¼ þ 3.00 (c 1.0, CHCl3); IR (neat): 3451, 2931, 2860, 1611, 1512, 1463, 1248, 1110, 821 cm1; 1H NMR (400 MHz, CDCl3): d 7.72e7.65 (m, 4H), 7.45e7.35 (m, 6H), 7.26 (d, J ¼ 8.8 Hz, 2H), 6.87 (d, J ¼ 8.8 Hz, 2H), 5.73e5.63 (m, 2H), 4.54 (d, J ¼ 11.9 Hz, 1H), 4.48 (d, J ¼ 11.9 Hz, 1H), 4.31e4.26 (m, 1H), 3.88e3.72 (m, 6H), 3.62e3.49 (m, 3H), 2.87e2.81 (bs, 1H), 2.32e2.22 (m, 1H), 1.06 (s, 9H), 0.92 (d, J ¼ 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 135.6, 135.55, 133.3, 133.2, 132.4, 130.3, 129.67, 129.65, 129.2, 127.67, 127.65, 124.6, 113.7, 74.8, 73.0, 72.9, 72.7, 70.3, 64.7, 55.2, 30.2, 26.8, 19.3, 17.6; MS (ESI): m/z 569 [MþNa]þ. HRMS (ESI): calcd for C33H42O5NaSi: 569.2699, found: 569.2701.
4.51 (d, J ¼ 11.9 Hz, 1H), 4.48 (d, J ¼ 11.9 Hz, 1H), 4.29e4.26 (m, 2H), 4.21 (td, J ¼ 6.6, 1.8 Hz, 1H), 4.12 (d, J ¼ 5.3 Hz, 1H), 4.04 (dd, J ¼ 10.5, 6.6 Hz, 1H), 3.93 (dd, J ¼ 10.5, 5.6 Hz, 1H), 3.80 (s, 3H), 3.60 (dd, J ¼ 11.3, 6.7 Hz, 1H), 3.53e3.48 (m, 2H), 2.37e2.29 (m, 1H), 1.04 (s, 9H), 0.81 (d, J ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.0, 135.6, 135.5, 133.2, 133.1, 130.4, 129.7, 129.2, 127.72, 127.70, 113.6, 80.9, 80.3, 77.1, 76.0, 72.9, 71.5, 61.5, 55.2, 33.4, 26.7, 26.1, 19.1, 15.8; MS (ESI): m/z 695 [MþNa]þ. HRMS (ESI): calcd for C33 H41 O5 I Si Na: 695.1666, found: 695.1652. 4.13. tert-Butyl(((1R,3R,4R,5R,7R)-3-(((4-methoxybenzyl)oxy) methyl)-4-methyl-2,6-dioxabicyclo[3.2.1]octan-7-yl)methoxy) diphenylsilane 2 AIBN (385 mg 2.35 mmol) was added to a stirred solution of 14 (3.16 g, 4.7 mmol) in anhydrous toluene (235 mL) followed by Bu3SnH (2.6 mL, 9.4 mmol) and the resulting reaction mixture was heated under reflux under a nitrogen atmosphere for 2 h. After completion of the reaction (monitored by TLC), toluene was removed under reduced pressure and the crude product was purified by silica gel column chromatography using 10-15% EtOAc/ hexane (v/v) as the eluent to afford compound 2 (2.37 g, 4.34 mmol) in 92% yield as a colorless liquid. TLC: Rf 0.2 (10% EtOAc/hexane). [a]20 D ¼ e 45.45 (c 1.1, CHCl3); IR (neat): 3066, 2931, 2859, 1611, 1512, 1462, 1248, 1107, 703 cm1; 1H NMR (500 MHz, CDCl3): d 7.75e7.69 (m, 4H), 7.43e7.32 (m, 6H), 7.21 (d, J ¼ 8.7 Hz, 2H), 6.85 (d, J ¼ 8.7 Hz, 2H), 4.52 (d, J ¼ 11.9 Hz, 1H), 4.47e4.45 (m, 1H), 4.40 (d, J ¼ 11.9 Hz, 1H), 4.22 (d, J ¼ 6.6 Hz, 1H), 4.09 (td, J ¼ 6.3, 2.1 Hz, 1H), 4.0 (dd, J ¼ 10.4, 6.4 Hz, 1H), 3.93 (dd, J ¼ 10.4, 6.0 Hz, 1H), 3.80 (s, 3H), 3.49 (ddd, J ¼ 9.5, 4.6, 2.4 Hz, 1H), 3.43 (dd, J ¼ 10.8, 2.4 Hz, 1H), 3.37 (dd, J ¼ 10.8, 4.7 Hz, 1H) 2.01 (ddd, J ¼ 11.6, 6.7, 2.7 Hz, 1H) 1.85 (dd, J ¼ 11.6, 1.4 Hz, 1H), 1.67e1.60 (m, 1H), 1.04 (s, 9H), 0.80 (d, J ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 159.1, 135.6, 133.5, 130.4, 129.5, 129.2, 127.6, 113.6, 83.4, 79.2, 77.4, 74.2, 72.9, 70.9, 61.7, 55.2, 38.2, 37.2, 26.7, 19.1, 15.7; MS (ESI): m/z 569 [MþNa]þ. HRMS (ESI): calcd for C33H42O5Si Na: 569.2699, found: 569.2695. Acknowledgements N. Sathyanarayana is thankful to Council of Scientific and Industrial Research (CSIR)-New Delhi for fellowship. S. R is grateful to the Department of Science and Technology, New Delhi for funding the project (EMR/2014/000753) and CSIR, New Delhi for funding under the XII five year plan programme entitled ORIGIN (CSC-108). Appendix A. Supplementary data
4.12. tert-Butyl(((1S,3R,4S,5S,7R,8R)-8-iodo-3-(((4-methoxybenzyl) oxy)methyl)-4-methyl-2,6-dioxabicyclo[3.2.1]octan-7-yl)methoxy) diphenylsilane 14 NIS (5.38 g, 23.94 mmol) and Sc(OTf)3 (590 mg, 1.2 mmol) were added to a stirred solution of the alcohol 3 (4.36 g, 7.98 mmol) in anhydrous dichloromethane (36 mL) and THF (4 mL) under a nitrogen atmosphere at 0 OC. The resulting reaction mixture was stirred in the dark at 0 OC for 12 h. The reaction mixture was quenched with aq saturated NaHSO3 (20 mL) and then extracted with dichloromethane (3 50 mL). The combined dichloromethane layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 7-10% EtOAc/hexane (v/v) as the eluent to afford compound 14 (3.22 g, 4.79 mmol) in 60% yield, as viscous liquid. TLC: Rf 0.4 (10% EtOAc/hexane). [a]20 D ¼ þ2.40 (c 1.0, CHCl3); IR (neat): 3063, 2934, 2859, 1612, 1512, 1462, 1246, 1109, 702, 501 cm1; 1H NMR (500 MHz, CDCl3): d 7.72e7.67 (m, 4H), 7.44e7.32 (m, 6H), 7.24 (d, J ¼ 8.5 Hz, 2H), 6.85 (d, J ¼ 8.5 Hz, 2H),
Supplementary data related to this article can be found at https://doi.org/10.1016/j.tet.2018.01.036. References € fle G. Tetrahedron Lett. 1. (a) Jansen R, Wray V, Irschik H, Reichenbach H, Ho 1985;26:6031; € fle G. Liebigs (b) Jansen R, Irschik H, Reichenbach H, Schomburg D, Wray V, Ho Ann Chem. 1989:111. 2. Campbell EA, Pavlova O, Zenkin N, et al. EMBO J. 2005;24:674. 3. (a) Smith III AB, Fox RJ. Org Lett. 2004;6:1477; (b) Smith III AB, Fox RJ, Vanecko JA. Org Lett. 2005;7:3099; (c) Smith III AB, Dong S. Org Lett. 2009;11:1099; (d) Smith III AB, Dong S, Brenneman JB, Fox RJ. J Am Chem Soc. 2009;131:12109; (e) Smith III AB, Dong S, Fox RJ, Brenneman JB, Vanecko JA, Maegawa T. Tetrahedron. 2011;67:9809. 4. Crimmins MT, Haley MW, O'Bryan EA. Org Lett. 2011;13:4712. 5. (a) Schinzer D, Schulz C, Krug O. Synlett. 2004:2689; (b) Michaelis L, Schinzer D. Synlett. 2014:951. 6. Park HS, Lee HW. Bull Kor Chem Soc. 2008;29:1661. 7. Lee K, Kim H, Hong J. Eur J Org Chem. 2012:1025. 8. (a) Srihari P, Kumaraswamy B, Yadav JS. Tetrahedron. 2009;65:6304;
S. Raghavan, S. Nyalata / Tetrahedron 74 (2018) 1071e1077 (b) Mohapatra DK, Das PP, Pattanayak MR, Yadav JS. Chem Eur J. 2010;16:2072. Sridhar Y, Srihari P. Org Biomol Chem. 2013;11:4640. Raghavan S, Nyalata S. J Org Chem. 2016;81:10698. Crimmins MT, Haley MW. Org Lett. 2006;8:4223. Yang F, Newsome JJ, Curran DP. J Am Chem Soc. 2006;128:14200. Brown HC, Bhat KS. J Am Chem Soc. 1986;108:5919. The absolute stereochemistry and enantiomer ratio of alcohol 5 was determined by analysis of the 1H NMR spectra of the derived methoxymandelate esters. For the assignment of absolute configuration see: Trost BM, Belletire JL, Godleski S, et al J Org Chem. 1986;51:2370. 15. The alcohol 5 was also prepared by employing Krische’ protocol using monoprotected ethylene glycol as the starting material. The yields were
9. 10. 11. 12. 13. 14.
16.
17. 18. 19. 20. 21.
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however, moderate (66%), selectivity poor (dr ¼ 5:1) and the reaction proceeded very slowly. Kim IS, Han SB, Krische MJ J Am Chem Soc. 2009;131:2514 (a) Li X, Lantrip D, Fuchs PL. J Am Chem Soc. 2003;125:14262; (b) Reddy BC, Bangade VM, Ramesh P, Meshram HM. Helv Chim Acta. 2013;96: 266. Dess DB, Martin JC. J Org Chem. 1983;48:4156. Heck M, Baylon C, Nolan SP, Mioskowski C. Org Lett. 2001;3:1989. Blackwell HE, O'Leary DJ, Chatterjee AK, Washenfelder RA, Bussmann DA, Grubbs RH. J Am Chem Soc. 2000;122:58. Knight DW, Shaw DE, Staples ER. Eur J Org Chem. 2004:1973. Hajra S, Bhowmick M, Sinha D. J Org Chem. 2006;71:9237.