Subscribe to RSS
DOI: 10.1055/s-0036-1588150
Towards Waltheriones C and D: Synthesis of the Oxabicyclic Core
Publication History
Received: 22 November 2016
Accepted after revision: 02 February 2017
Publication Date:
24 February 2017 (online)
◊ These authors contributed equally.
Abstract
A route to the oxabicyclic cores of the HIV cytoprotective quinolone alkaloids, waltheriones C and D, is described. The approach relies on a stereospecific transannular bromoetherification followed by reductive debromination. The route can also be rendered enantioselective via enzymatic reduction of a key intermediate (>99:1 er).
#
Key words
alkaloids - natural products - ethers - cyclization - enantioselectivity - reduction - enzymesWaltheriones are a family of bioactive 4-quinolone alkaloids. To date, 18 compounds belonging to this family have been isolated from a variety of oriental plants (see the Supporting Information for a full account).[1a] [b] [c] [d] [e] [f] The family is divided into open-chained and oxabicylic compounds, and representative members of the waltheriones are shown in Figure [1] (a). Waltheriones C (3) and D (4) (Figure [1, a]), isolated in 2014, contain a benzofused oxabicyclo[3.2.1]octene core.[1c] [2] Importantly, waltherione C (3) exhibits significant biological activity: It is cytoprotective (>50% inhibition at 0.95 µM) against HIV-1 infected cells. Its structure is related to the currently used HIV integrase inhibitor Elvitegravir (5), and bears some resemblance to Raltegravir (6).[3a] [b] Waltherione C also does not appear to be cytotoxic.[1c] Hence, waltherione C represents a highly attractive target for total synthesis and chemical biology. Its absolute stereochemistry also remains unknown but could be confirmed by chemical synthesis.
To access waltheriones C and D, we envisioned the quinolone moiety to be built around latent nitrogen functionality on a suitably functionalized oxabicyclic core. To construct the core, a transannular etherification of compounds of type 7 was considered (Scheme [2]). The advantage of the proposed sequence is that the tertiary stereocenter at C9 should form in a stereospecific manner because of the rigidity of the seven-membered ring conferred by the fused aromatic ring.[4] In addition, mechanistic analysis (Scheme [2]) shows that the resulting relative C9–C10 stereochemistry would match that of waltherione D. This reaction could be carried out at various oxidation states of the nitrogen substituent of 7 (e.g., amine or nitro group). For example, Brønsted acid mediated cyclization should give the waltherione C core 8 directly, and ring opening of the corresponding epoxide should generate the core of waltherione D.
With this plan at hand, the cyclization precursor 14 was accessed in five steps from benzosuberone (9, Scheme [1]). Benzosuberone was nitrated according to a literature procedure with potassium nitrate and sulfuric acid to give 3-nitrobenzosuberone (10).[5] Attempts at using nitric acid in place of potassium nitrate led to low yields, presumably due to competing oxidative degradation.
The synthesis of vinyl bromide 12 from 10 required careful optimization of the bromination–dehydrobromination sequence.[6] Thus, dibromination of 10 using NBS and AIBN, followed by elimination of the intermediate dibromide 11 with pH 4.0 buffer under microwave heating provided vinylic bromide 12 in 51% yield over two steps. Interestingly, attempts at promoting the elimination with bases (KOt-Bu, DBU) led instead to the corresponding monobromide, presumably via a single-electron transfer process. Coupling 12 with phenylboronic acid proceeded smoothly to provide 13 in 81% yield,[7] which was then reduced with LiAlH(Ot-Bu)3 to give alcohol 14.[8]
The key cyclization was then addressed. Alcohol 14 failed to cyclize under Brønsted acidic conditions (Table [1], entries 1–6) as well as under Lewis acid catalysis (Table [1], entries 7 and 8). After prolonged heating in dioxane/sulfuric acid, a modest amount (<20%) of cyclization product 15a could be observed in the crude 1H NMR spectrum. However, halogen-promoted cyclization turned out to be more efficient. With NBS, 80% of the desired bromoether 15b was obtained in five hours (Table [1], entry 11). With NIS, etherification proceeded as well, but only very slowly (Table [1], entry 10).
a 0.035 mmol of substrate, 0.2–0.3 mL of solvent run at r.t. for 48 h with no reaction and heated 50 °C for 20 h.
b 1.8 μmol of substrate, 1.0 mL of solvent, r.t., 1 h.
c 0.018 mmol of substrate, 0.3 mL of solvent, 80 °C, 72 h.
d 0.071 mmol (entry 8)/0.035 mmol (entry 9) of substrate, 0.5 mL of solvent, r.t., after 48 h no reaction, heated to 50 °C.
e 0 °C to r.t., 5 h.
f Assessed by TLC.
g Conversion determined from crude 1H NMR spectrum, product not isolated.
h Isolated yield in 0.1 mmol scale.
At this stage, the relative stereochemistry of bromide 15b was confirmed by 1H NMR spectroscopy. The 1H signal of H10 at δ = 4.91 ppm is a doublet of doublets with coupling constants of 5.6 Hz and 11.3 Hz, confirming that the stereochemistry of 15b matches that of waltherione D (4, Figure [2]).[1c] [2] In both 4 and 15b, the H13 proton at the bridgehead C13 is a narrow apparent doublet, with a coupling constant of 2 Hz, as expected for a pseudoequatorially disposed hydrogen atom. The facile cyclization of 14 to 15b via a presumed bromiranium cation (see Scheme [2]) suggests that the biosynthesis of waltherione D might proceed via the corresponding C10–C11 epoxide intermediate and not via hydration of a C10 carbocation, as suggested previously.[2]
The seemingly mundane task of reducing the C–Br bond of the product 15b was unsuccessful with either the standard stannane protocol (cat. AIBN/Bu3SnH) or heterogenous hydrogenation with Pd/C using ammonium formate as the hydride source.[9] An attempt at debromination with Raney nickel led to facile reduction of the nitro group to the corresponding amine 16, but also failed to remove the bromine. Gratifyingly, the aniline 16 was amenable to reductive debromination with AIBN/Bu3SnH, affording oxabicyclic core of waltherione C 17 in 85% yield.
To achieve the asymmetric synthesis of waltheriones C and D following this route, it was necessary to find a suitable method for the enantioselective reduction of the prochiral ketones 12 or 13. To this end, enzymatic reduction conditions were screened with the Codexis panel of 24 ketoreductase (KRED) enzymes.[10] Preliminary screens with ketone 13 and the corresponding N-Boc-protected aniline revealed that the presence of the nitro group was beneficial for the enzymatic reduction.[11] With 12, >99:1 er and >95% conversion to the corresponding alcohol was obtained with KRED-P1-B02, KRED-P2-C11, and KRED-P2-D11. With 13, the reactions were slower, but >99:1 er was also obtained with two enzymes, KRED-P1-B02 and KRED-P2-D03 of the panel (Table [2]).[12]
a A solution of substrate (0.013 mmol) in DMSO (60 μL), i-PrOH (60 μL), and KRED Recycle Mix P solution (190 µL) was added to a solution of KRED (2.5 mg) in KRED Recycle Mix P solution (190 μL).
bAfter 20 h, determined by HPLC (uncorrected, see the Supporting Information).
In conclusion, we have reported a synthetic route to access the oxabicyclic core of waltherione C through a transannular bromoetherification.[13] [14] We have also demonstrated that enantiopure cyclization precursor 14 is accessible using ketoreductase enzymes. Future work towards waltheriones C and D encompasses elaborating a quinolone unit on the oxabicyclic core 17 and accessing synthetic variants of the structure.
#
No conflict of interest has been declared by the author(s).
Acknowledgment
We thank Johanna Lind and Elina Kalenius for their assistance with HRMS analyses, and Esa Haapaniemi for his assistance with the NMR analyses. Support for this work has been obtained from the University of Jyväskylä and the Academy of Finland (project #259532).
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0036-1588150.
- Supporting Information
-
References and Notes
- 1a Hoelzel SC. S. M, Vieira ER, Giacomelli SR, Dalcol II, Zanatta N, Morel AF. Phytochemistry 2005; 66: 1163-1163
- 1b Gressel V, Stüker CZ, Dias Gde O. C, Dalcol II, Burrow RA, Schmidt J, Wassjohann L, Morel AF. Phytochemistry 2008; 69: 994-994
- 1c Jadulco DR. C, Pond CD, Van Wagoner RM, Koch M, Gideon OG, Matainaho TK, Piskaut P, Barrows LR. J. Nat. Prod. 2014; 77: 183-183
- 1d Jang JY, Dang QL, Choi YH, Choi GJ, Jang KS, Cha B, Luu NH, Kim J.-C. J. Agric. Food Chem. 2015; 63: 68-68
- 1e Cretton S, Breant L, Pourrez L, Ambuehl C, Marcourt L, Ebrahimi SN, Hamburger M, Perozzo R, Karimou S, Kaiser M, Cuendet M, Christen P. J. Nat. Prod. 2014; 77: 2304-2304
- 1f Cretton S, Dorsaz S, Azzollini A, Favre-Godal Q, Marcourt L, Ebrahimi SN, Voinesco F, Michellod E, Sanglard D, Gindro K, Wolfender J.-L, Cuendet M, Christen P. J. Nat. Prod. 2016; 79: 300-300
- 2 In the original isolation paper (ref. 1c), the stereochemistry of waltherione D is drawn correctly in Figure 3 (equatorial OH, C10 R*). However, in all other figures of ref. 1c, the C10 configuration is depicted as C10 S*. Unfortunately, this error appears to have been propagated in a later paper on the biosynthesis of waltheriones: Erwin NA, Soekamto NH, van Altena I, Syah YM. Biochem. Syst. Ecol. 2014; 55: 358-358
- 3a Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Paz OG, Hazuda DJ, Jones P, Kinzel O, Laufer R, Monteagudo E, Muraglia E, Nizi E, Orvieto F, Pace P, Pescatore G, Scarpelli R, Stillmock K, Witmer MV, Rowley M. J. Med. Chem. 2008; 51: 5843-5843
- 3b Sorbera LA, Serradell N. Drugs Future 2006; 31: 310-310
- 4 Systems less rigid than 14 have been shown to undergo diastereoselective transannular etherifications: Takahashi A, Aso M, Tanaka M, Suemune H. Tetrahedron 2000; 56: 1999-1999
- 5a Lizos DE, McKerchar C, Murphy J, Siigi Y, Suckling C, Yasumatsu H, Zhou S, Pratt J, Morris B. US 20060199978, 2006
- 5b Lütant I, Schepmann D, Wünsch B. Eur. J. Med. Chem. 2016; 116: 136-136
- 6 Khan AM, Proctor GR, Rees L. J. Chem. Soc. C 1966; 990-990
- 7 For a similar vinylic bromide coupling, see: Piras E, Läng F, Rüegger H, Stein D, Wörle M, Grützmacher H. Chem. Eur. J. 2006; 12: 5849-5849
- 8 Reduction with NaBH4, while chemoselective, afforded lower yields.
- 9a Miwa A, Nii Y, Sakakibara M. Agric. Biol. Chem. 1987; 12: 3459-3459
- 9b Brücher O, Bergsträßer U, Kelm H, Hartung J, Greb M, Svoboda I, Fuess H. Tetrahedron 2012; 68: 6968-6968
- 10a Itoh N, Mizuguchi M, Mizuguchi M. J. Mol. Catal. B: Enzym. 1999; 6: 41-41
- 10b Yang W, Xu JH, Xie Y, Xu Y, Zhao G, Lin GQ. Tetrahedron: Asymmetry 2006; 17: 1769-1769
- 10c Vitale P, D’Introno C, Perna FM, Perrone MG, Scilimati A. Tetrahedron: Asymmetry 2013; 24: 389-389
- 10d Liu Y, Tang TX, Pei XQ, Zhang C, Wu ZL. J. Mol. Catal. B: Enzym. 2014; 102: 1-1
- 10e Tang TX, Liu Y, Wu ZL. J. Mol. Catal. B: Enzym. 2014; 105: 82-82
- 10f Zhu D, Mukherjee C, Hua L. Tetrahedron: Asymmetry 2005; 16: 3275-3275
- 10g Zhu D, Hyatt BA, Hua L. J. Mol. Catal. B: Enzym. 2009; 56: 272-272
- 11 In a preliminary screen, N-Boc aniline derived from 10 gave poor conversion but high enantioselectivity (er 99:1). The nitro compound 10 gave very high conversions (>95% in most cases), with access to both enantiomers with different enzymes: KRED-P3-G09 gave 98:2 er, conversion 98%, and KRED-P2-H07 gave 98:2 er, conversion 98% for the corresponding enantiomeric alcohol.
- 12a Hyde AM, Liu Z, Kosjek B, Tan L, Klapars A, Ashley ER, Zhong Y.-L, Alvizo O, Agard NJ, Liu G, Gu X, Yasuda N, Limanto J, Huffman MA, Tschaen DM. Org. Lett. 2016; 18: 5888-5888
- 12b Liang J, Lalonde J, Borup B, Mitchell V, Mundorff E, Trinh N, Kochrekar DA, Cherat RN, Pai GG. Org. Process Res. Dev. 2010; 14: 193-193
- 13 Synthesis of 15b A solution of alcohol 14 (20 mg, 0.071 mmol, 1.0 equiv) in dioxane (0.5 mL) was cooled to 0 °C. NBS (190 mg, 0.106 mmol, 1.5 equiv) was added, and the reaction mixture was stirred under argon at r.t. for 5 h. Purification of the crude reaction mixture by flash chromatography (EtOAc–hexane, 10:90) afforded the product 15b as a white solid (20 mg, 78%); mp 130.3–132.0 °C; Rf = 0.6 (EtOAc–hexane, 2:8). IR (film): 3094, 3064, 2953, 2922, 2850, 2349, 2325, 1519, 1342, 1031 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.30 (dd, 1 H, J = 8.2, 2.0 Hz), 8.15 (d, 1 H, J = 2.0 Hz), 7.57–7.52 (m, 3 H), 7.45–7.41 (m, 3 H), 5.44 (d, 1 H, J = 2.2 Hz), 4.91 (dd, 1 H, J = 11.3, 5.6 Hz), 2.40–2.27 (m, 2 H); 1.77–1.65 (m, 1 H), 1.46–1.35 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 148.7, 147.6, 146.2, 137.4, 129.3, 128.7, 128.0, 125.8, 123.5, 115.6, 89.3, 78.9, 48.9, 31.3, 30.3. HRMS (ESI+): m/z [M + Na]+ calcd for [C17H14BrNO3Na]+: 382.0049; found: 382.0044, Δ = 0.5 mDa.
- 14 Synthesis of 17 To a solution of bromide 16 (20 mg, 0.06 mmol, 1.0 equiv) in dry toluene (1.2 mL), Bu3SnH (33 μL, 0.12 mmol, 2.0 equiv), and AIBN (3 mg, 0.018 mmol, 0.3 equiv) were added under argon. The reaction mixture was heated at 80 °C. After completion of the reaction (6 h), the reaction mixture was loaded directly to flash column for purification (EtOAc–hexane, 15:90). Product 17 was isolated as a white solid (13 mg, 85%); mp 148.1–150.2 °C; Rf = 0.3 (EtOAc–hexane, 20:80). IR (film): 3351, 3233, 2933, 1619, 1591, 1485, 1447, 1346, 1305, 1264, 1160, 1104, 995, 757 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.53 (distorted d, 2 H, J = 7.5 Hz), 7.37 (app. t, 2 H, J = 7.6 Hz), 7.29 (app. t, 1 H, J = 7.4 Hz), 6.66 (d, 1 H, J = 7.9 Hz), 6.56 (d, 1 H, J = 1.8 Hz), 6.50 (dd, 1 H, J = 7.9, 2.0 Hz), 5.29 (br s, 1 H), 2.13–2.07 (dt, 1 H, J = 12.5, 4.5 Hz), 2.05–2.00 (m, 2 H), 1.63 (dt, 1 H, J = 11.3, 5.0 Hz), 1.50 (dd, 1 H, J = 13.1, 5.0 Hz), 1.25–1.15 (m, 1 H). 13C NMR (125 MHz, CDCl3): δ = 145.7, 144.8, 143.4, 136.5, 128.3, 127.4, 125.8, 121.3, 114.0, 107.3, 86.2, 79.4, 33.2, 28.2, 17.8. HRMS (ESI+): m/z [M + H]+ calcd for [C17H18NO]+: 252.1383; found: 252.1382, Δ = 0.1 mDa.
Waltherione A:
Waltherione B:
Waltheriones C:
Waltherione E:
Waltheriones E, F:
Waltheriones M–Q:
Raltegravir:
Elvitegravir:
An improved nitration procedure has also been described:
Representative cases for benzylic debromination of sensitive substrates with AIBN:
For enzymatic reduction of aryl alkyl ketones, see:
The absolute configuration has been tentatively assigned as S on the basis of analogous results with one of the enzymes in our panel (KRED P1C01) with a cyclic aryl ketone, see:
In another study with Codexis enzymes and aryl alkyl ketones, high selectivity for the S isomer was observed, see:
-
References and Notes
- 1a Hoelzel SC. S. M, Vieira ER, Giacomelli SR, Dalcol II, Zanatta N, Morel AF. Phytochemistry 2005; 66: 1163-1163
- 1b Gressel V, Stüker CZ, Dias Gde O. C, Dalcol II, Burrow RA, Schmidt J, Wassjohann L, Morel AF. Phytochemistry 2008; 69: 994-994
- 1c Jadulco DR. C, Pond CD, Van Wagoner RM, Koch M, Gideon OG, Matainaho TK, Piskaut P, Barrows LR. J. Nat. Prod. 2014; 77: 183-183
- 1d Jang JY, Dang QL, Choi YH, Choi GJ, Jang KS, Cha B, Luu NH, Kim J.-C. J. Agric. Food Chem. 2015; 63: 68-68
- 1e Cretton S, Breant L, Pourrez L, Ambuehl C, Marcourt L, Ebrahimi SN, Hamburger M, Perozzo R, Karimou S, Kaiser M, Cuendet M, Christen P. J. Nat. Prod. 2014; 77: 2304-2304
- 1f Cretton S, Dorsaz S, Azzollini A, Favre-Godal Q, Marcourt L, Ebrahimi SN, Voinesco F, Michellod E, Sanglard D, Gindro K, Wolfender J.-L, Cuendet M, Christen P. J. Nat. Prod. 2016; 79: 300-300
- 2 In the original isolation paper (ref. 1c), the stereochemistry of waltherione D is drawn correctly in Figure 3 (equatorial OH, C10 R*). However, in all other figures of ref. 1c, the C10 configuration is depicted as C10 S*. Unfortunately, this error appears to have been propagated in a later paper on the biosynthesis of waltheriones: Erwin NA, Soekamto NH, van Altena I, Syah YM. Biochem. Syst. Ecol. 2014; 55: 358-358
- 3a Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Paz OG, Hazuda DJ, Jones P, Kinzel O, Laufer R, Monteagudo E, Muraglia E, Nizi E, Orvieto F, Pace P, Pescatore G, Scarpelli R, Stillmock K, Witmer MV, Rowley M. J. Med. Chem. 2008; 51: 5843-5843
- 3b Sorbera LA, Serradell N. Drugs Future 2006; 31: 310-310
- 4 Systems less rigid than 14 have been shown to undergo diastereoselective transannular etherifications: Takahashi A, Aso M, Tanaka M, Suemune H. Tetrahedron 2000; 56: 1999-1999
- 5a Lizos DE, McKerchar C, Murphy J, Siigi Y, Suckling C, Yasumatsu H, Zhou S, Pratt J, Morris B. US 20060199978, 2006
- 5b Lütant I, Schepmann D, Wünsch B. Eur. J. Med. Chem. 2016; 116: 136-136
- 6 Khan AM, Proctor GR, Rees L. J. Chem. Soc. C 1966; 990-990
- 7 For a similar vinylic bromide coupling, see: Piras E, Läng F, Rüegger H, Stein D, Wörle M, Grützmacher H. Chem. Eur. J. 2006; 12: 5849-5849
- 8 Reduction with NaBH4, while chemoselective, afforded lower yields.
- 9a Miwa A, Nii Y, Sakakibara M. Agric. Biol. Chem. 1987; 12: 3459-3459
- 9b Brücher O, Bergsträßer U, Kelm H, Hartung J, Greb M, Svoboda I, Fuess H. Tetrahedron 2012; 68: 6968-6968
- 10a Itoh N, Mizuguchi M, Mizuguchi M. J. Mol. Catal. B: Enzym. 1999; 6: 41-41
- 10b Yang W, Xu JH, Xie Y, Xu Y, Zhao G, Lin GQ. Tetrahedron: Asymmetry 2006; 17: 1769-1769
- 10c Vitale P, D’Introno C, Perna FM, Perrone MG, Scilimati A. Tetrahedron: Asymmetry 2013; 24: 389-389
- 10d Liu Y, Tang TX, Pei XQ, Zhang C, Wu ZL. J. Mol. Catal. B: Enzym. 2014; 102: 1-1
- 10e Tang TX, Liu Y, Wu ZL. J. Mol. Catal. B: Enzym. 2014; 105: 82-82
- 10f Zhu D, Mukherjee C, Hua L. Tetrahedron: Asymmetry 2005; 16: 3275-3275
- 10g Zhu D, Hyatt BA, Hua L. J. Mol. Catal. B: Enzym. 2009; 56: 272-272
- 11 In a preliminary screen, N-Boc aniline derived from 10 gave poor conversion but high enantioselectivity (er 99:1). The nitro compound 10 gave very high conversions (>95% in most cases), with access to both enantiomers with different enzymes: KRED-P3-G09 gave 98:2 er, conversion 98%, and KRED-P2-H07 gave 98:2 er, conversion 98% for the corresponding enantiomeric alcohol.
- 12a Hyde AM, Liu Z, Kosjek B, Tan L, Klapars A, Ashley ER, Zhong Y.-L, Alvizo O, Agard NJ, Liu G, Gu X, Yasuda N, Limanto J, Huffman MA, Tschaen DM. Org. Lett. 2016; 18: 5888-5888
- 12b Liang J, Lalonde J, Borup B, Mitchell V, Mundorff E, Trinh N, Kochrekar DA, Cherat RN, Pai GG. Org. Process Res. Dev. 2010; 14: 193-193
- 13 Synthesis of 15b A solution of alcohol 14 (20 mg, 0.071 mmol, 1.0 equiv) in dioxane (0.5 mL) was cooled to 0 °C. NBS (190 mg, 0.106 mmol, 1.5 equiv) was added, and the reaction mixture was stirred under argon at r.t. for 5 h. Purification of the crude reaction mixture by flash chromatography (EtOAc–hexane, 10:90) afforded the product 15b as a white solid (20 mg, 78%); mp 130.3–132.0 °C; Rf = 0.6 (EtOAc–hexane, 2:8). IR (film): 3094, 3064, 2953, 2922, 2850, 2349, 2325, 1519, 1342, 1031 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.30 (dd, 1 H, J = 8.2, 2.0 Hz), 8.15 (d, 1 H, J = 2.0 Hz), 7.57–7.52 (m, 3 H), 7.45–7.41 (m, 3 H), 5.44 (d, 1 H, J = 2.2 Hz), 4.91 (dd, 1 H, J = 11.3, 5.6 Hz), 2.40–2.27 (m, 2 H); 1.77–1.65 (m, 1 H), 1.46–1.35 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 148.7, 147.6, 146.2, 137.4, 129.3, 128.7, 128.0, 125.8, 123.5, 115.6, 89.3, 78.9, 48.9, 31.3, 30.3. HRMS (ESI+): m/z [M + Na]+ calcd for [C17H14BrNO3Na]+: 382.0049; found: 382.0044, Δ = 0.5 mDa.
- 14 Synthesis of 17 To a solution of bromide 16 (20 mg, 0.06 mmol, 1.0 equiv) in dry toluene (1.2 mL), Bu3SnH (33 μL, 0.12 mmol, 2.0 equiv), and AIBN (3 mg, 0.018 mmol, 0.3 equiv) were added under argon. The reaction mixture was heated at 80 °C. After completion of the reaction (6 h), the reaction mixture was loaded directly to flash column for purification (EtOAc–hexane, 15:90). Product 17 was isolated as a white solid (13 mg, 85%); mp 148.1–150.2 °C; Rf = 0.3 (EtOAc–hexane, 20:80). IR (film): 3351, 3233, 2933, 1619, 1591, 1485, 1447, 1346, 1305, 1264, 1160, 1104, 995, 757 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.53 (distorted d, 2 H, J = 7.5 Hz), 7.37 (app. t, 2 H, J = 7.6 Hz), 7.29 (app. t, 1 H, J = 7.4 Hz), 6.66 (d, 1 H, J = 7.9 Hz), 6.56 (d, 1 H, J = 1.8 Hz), 6.50 (dd, 1 H, J = 7.9, 2.0 Hz), 5.29 (br s, 1 H), 2.13–2.07 (dt, 1 H, J = 12.5, 4.5 Hz), 2.05–2.00 (m, 2 H), 1.63 (dt, 1 H, J = 11.3, 5.0 Hz), 1.50 (dd, 1 H, J = 13.1, 5.0 Hz), 1.25–1.15 (m, 1 H). 13C NMR (125 MHz, CDCl3): δ = 145.7, 144.8, 143.4, 136.5, 128.3, 127.4, 125.8, 121.3, 114.0, 107.3, 86.2, 79.4, 33.2, 28.2, 17.8. HRMS (ESI+): m/z [M + H]+ calcd for [C17H18NO]+: 252.1383; found: 252.1382, Δ = 0.1 mDa.
Waltherione A:
Waltherione B:
Waltheriones C:
Waltherione E:
Waltheriones E, F:
Waltheriones M–Q:
Raltegravir:
Elvitegravir:
An improved nitration procedure has also been described:
Representative cases for benzylic debromination of sensitive substrates with AIBN:
For enzymatic reduction of aryl alkyl ketones, see:
The absolute configuration has been tentatively assigned as S on the basis of analogous results with one of the enzymes in our panel (KRED P1C01) with a cyclic aryl ketone, see:
In another study with Codexis enzymes and aryl alkyl ketones, high selectivity for the S isomer was observed, see:
