DOI: 10.1002/chem.201404679
Full Paper
& Total Synthesis
Enantioselective Total Synthesis of the Lignan (+)-Linoxepin Lutz F. Tietze,*[a] Jrme Clerc,[a] Simon Biller,[a] Svenia-C. Duefert,[a] and Matthias Bischoff[a, b] Dedicated to Professor Alan Battersby on the occasion of his 90th birthday
Abstract: An enantioselective total synthesis of the natural (+)-linoxepin (1) was accomplished in eleven steps from bromovanin (24). Key steps are a domino carbopalladation/
Mizoroki–Heck reaction with the formation of a pentacyclic system, an asymmetric hydroboration as well as an oxidative lactonization.
Introduction The development of highly efficient synthetic transformations is an important goal in modern synthesis, whereas natural products are widely used as synthetic platform in the development of active pharmaceutical ingredients.[1] The access to natural metabolites from plant sources on an industrial scale is often prevented due to the scarcity of available sources. Hence, an entry to those compounds by semi- or total synthesis is necessary for their study or use. An efficient, ecologically and economically favorable access can be accomplished by using the concept of domino reactions, implemented by our group.[2, 3] Linoxepin (1) is a natural product which was first isolated from Linum perenne L. (Linaceae) by Schmidt et al. in 2007.[4] It belongs to the aryldihydronaphthalene lignans and contains a novel benzonaphtho[1,8-bc]oxepine moiety. The biological profile of linoxepin is yet unknown. However, it bears close structural resemblance to other biologically active lignans, such as podophyllotoxin (2) and etoposide (3); the latter is used clinically to treat small-cell lung carcinoma and testicular cancer as well as lymphoma and glioblastoma (Figure 1).[5] Recently, we reported the first total synthesis of (+)- and ()-linoxepin (1) and (ent-1), the key step of which featured a Pd-catalyzed domino transformation consisting of a carbopalladation and a silyl-terminated Heck reaction that allowed access to the pentacyclic core of the natural product in a single process.[6] Shortly thereafter, the group of Lautens disclosed an asymmetric approach to the natural product that
Figure 1. Structures of the lignans (+)-linoxepin (1), podophyllotoxin (2) and etoposide (3).
employed a Catellani reaction and relied on the chiral pool as the source of the target molecule’s stereocenter.[7] We hereby report an enantioselective total synthesis of (+)-linoxepin (1) using a new, even more efficient approach, whereby the stereogenic center is introduced by an asymmetric hydroboration (Scheme 1).
Scheme 1. Retrosynthetic approach to (+)-linoxepin (1) with an asymmetric hydroboration and a domino carbopalladation/Heck reaction as key step (R1 = H or SiMe2Ph; R2 = H or TIPS).
[a] Prof. L. F. Tietze, Dr. J. Clerc, S. Biller, Dr. S.-C. Duefert, Dr. M. Bischoff Institut fr Organische und Biomolekulare Chemie Georg-August-Universitt Gçttingen Tammannstrasse 2, 37077 Gçttingen (Germany) E-mail: [email protected]
Results and Discussion First synthetic approach
[b] Dr. M. Bischoff Present address: Max-Planck-Institute fr Psychiatry, Kraepelinstrasse 2, 80804 Mnchen (Germany)
Our initial strategy relied on a threefold domino reaction which comprised a Sonogashira reaction, a carbopalladation and a concluding Mizoroki–Heck reaction. However, the reac-
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404679. Chem. Eur. J. 2014, 20, 1 – 7
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Full Paper On the one hand, CuI seems to prevent the ensuing carbopalladation and, on the other hand, the reaction temperature is too low for the subsequent reactions. As expected transformation of 7 in the presence of Pd(OAc)2 and [Pd(PPh3)4] again did not lead to the desired compound 9 in an acceptable yield. It is reasonable to assume that the use of bulkier ligands should slow down the readdition of the catalyst and thus helps suppress the formation of the unwanted aromatic side product.[8] Indeed, using XantPhos (14)[9] as ligand 20 % of 9 and less than 5 % of isomer 10 were formed, whereas 40 % of the starting material could be recovered (Table 1). It should be noted that the choice of base is also important, only with 4-DMAP or pyridine the isomerization of the double bond could be avoided; bases as Cs2CO3, TEA, DIEA, TMEDA, NMP, DAPCO and N,Ndimethylaniline were not suitable. In addition to XantPhos (14) we also tested the sterically encumbered and electron-rich biarylphosphine DavePhos, (15)[10] which gave slightly better yields. Other ligands as XPhos, SPhos, BrettPhos, JohnPhos and tBuXPhos as well as N-heterocyclic carbenes were less suitable. In addition to the use of electron-rich and sterically demanding ligands, we explored the possibility of pursuing a cationic catalytic pathway by adding AgI salts.[11] It has been previously shown that the addition of silver salts can help suppress alkene isomerization in the case of aryl iodides as substrates.[12] Thus, in the reaction of 7 with DavePhos (15) in the presence of 10 mol % of Ag2CO3 we were able to isolate the diene 9 in 43 % yield with only 27 % of 10 present. To further increase the bulkiness of the system we used the alkyne 11 as substrate containing a TIPS ether moiety instead of a hydroxyl group, which was easily accessible by Sonogashira reaction of iodide 5 a with the TIPS-protected propargylic alcohol 6 b in 92 % yield.
Scheme 2. Threefold domino process for the formation of 10. a) [Pd(PPh3)4], TBAF·3 H2O, DME, 80 8C, 24 h, 50 %.
tion of alkene 5 a and propargyl alcohol (6 a) in the presence of [Pd(PPh3)4] did not lead to the desired compound 9 but instead formed the aromatic congener 10 in 50 % yield (Scheme 2).[6] Mechanistically, one can assume that initially the Sonogashira product 7 is formed, followed by a carbopalladation and a Mizoroki–Heck reaction. However, the desired product 9 seems not to be stable under the reaction conditions and gives 10 by an isomerization of the double bond, probably by readdition of a [PdH] species followed by a b-hydride elimination. To avoid the incompatibility of reagents and allow for a suppression of the undesired alkene isomerization, we opted for a twofold domino process consisting of a carbopalladation and a Mizoroki–Heck reaction (Scheme 3). The precursor 7 can easily be obtained from 5 a and 6 a in 90 % yield by a Sonogashira reaction using [Pd(PPh3)4], CuI and TBAF as base at 60 8C. Under these reaction conditions, the subsequent Pd-catalyzed transformations do not take place.
Table 1. Conditions for the domino carbopalladation/Mizoroki–Heck reaction. Substrate Pd source Ligand
Base
Additive
Yield
7[a]
4-DMAP 1.0 equiv 4-DMAP 1.0 equiv 4-DMAP 1.0 equiv 4-DMAP 1.0 equiv
–
9: 20 % 10: < 5 % 9: 43 % 10: 27 % 12/13: (3:1) 91 %
7[b] 11[c] 11[c]
Pd(OAc)2 15 mol % Pd(OAc)2 10 mol % Pd(OAc)2 5.0 mol % Pd(OAc)2 5.0 mol %
XantPhos 30 mol % DavePhos 50 mol % DavePhos 25 mol % DavePhos 25 mol %
Ag2CO3 10 mol % Ag2CO3 10 mol % Ag2CO3 12: 97 % 1.25 equiv
[a] Toluene, 90 8C, 1 h, 42 % of 7 was recovered. [b] Toluene, 110 8C, 40 min, 13 % of 7 was recovered. [c] Toluene, 110 8C, 30 min.
The domino reaction of 11 using the catalytic system Pd(OAc)2/DavePhos and 0.10 equivalents of Ag2CO3 was much cleaner as well as faster and gave an almost quantitative yield of an inseparable 3:1 mixture of 12 and 13. Optimal reaction conditions were finally found by employing 1.25 equivalents of silver carbonate leading exclusively to 12 in 97 % isolated yield (Scheme 3 and Table 1). It should be noted that treatment of 12 with p-toluene sulfonic acid leads to the aromatic system 13 through isomerization of the exo-methylene double bond.
Scheme 3. Synthesis of alkenes 9 and 12. a) [Pd(PPh3)4], CuI, TBAF·3 H2O, 1,4dioxane, 60 8C, 1 h, 90 %; b) [Pd(PPh3)4], CuI, Bu4NOAc, 1,4-dioxane, 60 8C, 30 min, 92 %. For reaction conditions and results of the domino reaction see Table 1.
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Full Paper In the final steps of the total synthesis of racemic linoxepin (rac-1), diene 12 was transformed into alcohol 16 in 72 % yield by hydroboration with BH3·Me2S and oxidative work-up. Removal of the TIPS group with TBAF gave the corresponding diol 17 in quantitative yield. The selective oxidation of the allylic alcohol in presence of the aliphatic hydroxyl group could be achieved by manganese dioxide. For the oxidation of the aldehyde to the corresponding carboxylic acid the use of iodine in the presence of K2CO3 led to the formation of the lactone during work-up and gave rac-1 in 54 % yield based on 12 (Scheme 4).
Scheme 5. CuI-catalyzed hydroboration of 9: a) i) CuI, (+)-(S,S)-Me-DuPhos, B2pin2, tBuOK, tBuOH, toluene, RT, 17 h; ii) aq. H2O2, aq. NaOH, 0 8C to RT, 30 min, 81 %.
Scheme 4. a) i) BH3·Me2S, THF, 0 8C to RT, 3 h; ii) aq. H2O2, aq. NaOH, 0 8C to RT, 15 h, 72 %; b) TBAF·3 H2O, THF, 0 8C, 15 min, 99 %; c) MnO2, DCM, RT, 2.5 h; d) I2, K2CO3, tBuOH, 50 8C, 4.5 h, 75 % (2 steps).
Enantioselective synthesis of 1 For the enantioselective synthesis of (+)-linoxepin (1), we evaluated the hydroboration of 12 using Brown’s chiral boranes (ipc)2BH and (ipc)BH2. Diene 12 could be transformed into 16 in 70 % yield but with only 11 % ee using ()-(ipc)2BH. The low enantiomeric excess is in accordance with the literature, which describes the asymmetric hydroboration of 1,1-disubstituted alkenes as highly challenging.[13] However, recent developments of copper(I)-catalyzed hydroborations by several groups have opened new perspectives for the asymmetric functionalization of alkenes.[14] We attempted the enantioselective hydroboration of alkene 9 using conditions similar to those recently reported by Ito for the borylation of 1,3-dienes.[14a] However, in the presence of CuI and (+)-MeDuPhos, not the expected alcohol but its isomer 18 was obtained in 81 % yield (Scheme 5). The formation of the bisallylic alcohol 18 can be explained by the following reaction mechanism. In the borylation of 1,3dienes, a SE2’ mode of protonation of the initially formed sallylcopper intermediate 19 to give 20 can be assumed, which is then oxidized to the bisallylic alcohol 18.[14a] In order to enhance the formation of the desired product 17, various modifications were attempted (e.g., solvent, ligand or proton source), but did not lead to an increased formation of the desired product. Similar results were observed for the TIPSprotected diene 12. In a revised approach, we therefore chose to use the Me2PhSi-substituted substrate 21 to circumvent the problems associated with the asymmetric hydroboration of 1,1-disubstituted alkenes. The desired stereogenic center in 17 could thus be obtained either by an asymmetric hydroboration or an enantioselective hydrogenation (Scheme 6). For the synthesis of vinyl silane 21, bromovanin (24) was first acetylated. Subsequent treatment of acetate 25 with the Chem. Eur. J. 2014, 20, 1 – 7
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Scheme 6. Revised synthetic strategy for the enantioselective formation of 17.
lithiated alkyne 29 led to the formation of 26 in 80 % yield over 2 steps. The observed in situ transesterification of the acetyl moiety from the phenolic to the propargylic hydroxyl group can most likely be attributed to the relative alcoholate stabilities. Reductive removal of the acetate group was achieved by dimethylphenylsilane as hydrogen source under acidic conditions to give 27 in 84 % yield. The conversion of alkyne 27 to afford the corresponding Z configured vinyl silane 28 was accomplished by treatment with DIBAL-H (Scheme 7). Silane 28 was then alkylated with 4-(bromomethyl)-5iodobenzo[d][1,3]dioxole (30) under basic conditions and the resulting benzyl ether 5 b was subsequently coupled with the TIPS-protected propargylic alcohol 6 b in a Sonogashira reaction to give alkyne 31. The Pd-catalyzed domino reaction of 31 in the presence of Pd(OAc)2, DavePhos, 4-DMAP and stoichiometric amounts of Ag2CO3 gave almost exclusively the desired vinyl silane 21 in 96 % yield, most likely via intermediate 32 (Scheme 8). 3
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Full Paper The asymmetric hydroboration of the trisubstituted alkene 21 was however successful. The best results were obtained with Brown’s borane ()-(ipc)BH2 and (+)-(ipc)BH2with 77 % yield of the hydroboration product 22; ()-(ipc)2BH and (+)-(ipc)2BH led to more side products with only 30 % yield of 22. Under all conditions the formation of the corresponding aromatic isomer cannot be suppressed completely. At this stage the enantiomeric excess of the products could not be determined, so the crude product was taken on to the subsequent desilylation. Thus, hydroxysilane 22 was transformed into the diol 17 using TBAF with 89 % yield. Determination of the ee values by analytical HPLC revealed a moderate enantioselectivity when using ()-(ipc)BH2 and (+)-(ipc)BH2 as well as ()-(ipc)2BH and (+)-(ipc)2BH of 52 % ee and 47 % ee, respectively. However, 17 was obtained in enantiopure form by preparative HPLC on chiral support. In the process the use of ()-(ipc)BH2 and ()(ipc)2BH led to the diol 17 with the natural configuration whereas (+)-(ipc)BH2 and (+)-(ipc)2BH gave the unnatural enantiomer ent-17. Attempts to use the Masamune borane[17] for the hydroboration to improve the enantioselectivity were not successful, since the borane did not add to the vinyl silane 21. The final steps towards (+)-linoxepin (1) were performed with enantiopure 17 as described for the racemic synthesis: oxidation of the allylic alcohol moiety in 17 with MnO2 followed by oxidation of the formed aldehyde with I2 in the presence of K2CO3 with an overall yield of 75 % (Scheme 10). The spectroscopic data of the isolated 1 matched those previously reported in literature.[18] In addition, the unnatural ent-1 was synthesized based on ent-17 in 71 % yield.
Scheme 7. Synthesis of 28. a) Ac2O, K2CO3, MeCN, 80 8C, 2 h, 99 %; b) 29, nBuLi, THF, 78 8C to RT, 17 h, 81 %; c) PhMe2SiH, TFA, toluene, 0 8C, 30 min, 84 %; d) DIBAL-H, hexane, 0 8C, 1 h, 85 %.
Scheme 8. Synthesis of 21. a) K2CO3, MeCN, 80 8C, 3.5 h, 99 %; b) 6 b, [Pd(PPh3)4], CuI, nBu4NOAc, 1,4-dioxane, 60 8C, 30 min, 94 %; c) 7.5 mol % Pd(OAc)2, 38 mol % DavePhos, 1.40 equiv Ag2CO3, 1.00 equiv 4-DMAP, toluene, 110 8C, 30 min, 96 %.
For the asymmetric hydrogenation of vinyl silane 21 we tested the Pfaltz catalyst [COD]Ir[Cy2PThrePHOX] under a hydrogen atmosphere (30 bar pressure).[15] However, instead of obtaining the desired alkyl silane 23, the hexacyclic silane 33 was formed exclusively (Scheme 9). Compound 33 is the result of an acid-mediated Friedel– Crafts cyclization/isomerization sequence. According to work by Burgess, the hydrogenation of acid-sensitive substrates can prove challenging due to the acidity of the catalytic intermediates, which could be overcome by the use of Nheterocyclic carbene iridium(I) complexes or basic additives.[16] Unfortunately, modification of the reaction conditions (catalyst, basic additives) did not facilitate hydrogenation to afford the desired homoallylic silane 23.
Scheme 10. Synthesis of (+)-linoxepin (1). a) i) ()-(ipc)BH2, THF, 0 8C to RT, 16 h; ii) aq. H2O2, aq. NaOH, 0 8C to RT, 1 h, 77 % of 22; b) 2.5 equiv TBAF (1 m in THF), THF, 0 8C 30 min, 89 %, 52 % ee; c) MnO2, DCM, RT, 2.5 h; d) I2, K2CO3, tBuOH, 50 8C, 4.5 h, 75 % (2 steps).
Conclusions In conclusion, we have accomplished an enantioselective total synthesis of (+)-linoxepin. The key features are a Pd-catalyzed domino reaction consisting of a carbopalladation and a Mizoroki–Heck reaction using DavePhos as a bulky electron-rich ligand and an AgI salt as additive to suppress the alkene isomerization. The instalment of the stereogenic center was realized by using an asymmetric regioselective hydroboration. The enantiopure natural product was synthesized over eleven steps from commercially available starting materials with an overall yield of 27 %.
Scheme 9. Hydrogenation of 21. a) H2 (30 bar), (S,S)-[COD]Ir[Cy2PThrePHOX], DCM, RT, 90 min, 99 % of 33.
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20 mL). The combined organic layers were washed with brine (40 mL) and dried over sodium sulfate. After concentration in vacuo the crude product was purified by flash column chromatography (petroleum ether/EtOAc = 10:1 to 4:1) to yield 22 (108 mg, 164 mmol, 77 %) with a small amount of impurities as a colorless foam. Rf = 0.17 (petroleum ether/EtOAc = 5:1); UV (CH3CN): lmax (log e) = 290 nm (3.756); IR (ATR): ~ n = 2941, 2864, 1459, 1250, 1098, 1032, 881, 796, 681 cm1; 1H NMR (600 MHz, CDCl3): d = 0.33 (s, 3 H), 0.35 (s, 3 H), 0.85–1.10 (m, 21 H), 2.86–2.99 (m, 3 H), 3.75 (s, 1 H), 3.77 (s, 3 H), 4.05 (d, J = 10.7 Hz, 1 H), 4.12 (d, J = 10.7 Hz, 1 H), 5.11 (d, J = 12.4 Hz, 1 H), 5.28 (d, J = 12.4 Hz, 1 H), 5.95 (d, J = 1.5 Hz, 1 H), 6.00 (d, J = 1.5 Hz, 1 H), 6.37 (d, J = 7.9 Hz, 1 H), 6.54 (d, J = 8.2 Hz, 1 H), 6.65 (d, J = 7.9 Hz, 1 H), 6.99 (d, J = 7.9 Hz, 1 H), 7.28– 7.39 (m, 3 H), 7.55 ppm (dd, J = 7.9, 1.4 Hz, 2 H); 13C NMR (125 MHz, CDCl3): d = 4.4, 3.8, 12.0, 18.1, 32.8, 38.7, 55.9, 62.7, 64.1, 67.2, 101.4, 107.6, 109.6, 117.3, 119.5, 122.6, 123.1, 127.9, 128.9, 129.3, 134.1, 137.2, 137.2, 139.5, 141.9, 144.6, 145.8, 147.3, 148.8 ppm; HRMS (ESI): m/z calcd for C38H50O6Si2Na + [M+Na] + 681.3038, found 681.3025.
Synthesis of 12 In a flame-dried Schlenk flask were mixed 11 (300 mg, 0.51 mmol, 1.00 equiv), silver carbonate (176 mg, 0.64 mmol, 1.25 equiv) and 4-dimethylaminopyridine (63.0 mg, 0.51 mmol, 1.00 equiv) in toluene (24 mL) under argon. At 110 8C, a solution of palladium(II) acetate (5.70 mg, 26.0 mmol, 5.00 mol %) with DavePhos (51.0 mg, 0.13 mmol, 25.0 mol %) in toluene (6 mL) was added. After 30 min at 110 8C, the mixture was cooled and concentrated. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 12:1) to yield 12 (256 mg, 0.50 mmol, 97 %) as a colorless foam. Rf = 0.27 (petroleum ether/EtOAc = 9:1). UV n= (CH3CN): lmax (log e) = 216 nm (4.622), 315 (4.204); IR (ATR): ~ 2863, 1458, 1244, 1080, 1033, 881, 794, 677 cm1; 1H NMR (300 MHz, CDCl3): d = 0.82–1.13 (m, 2 H), 3.37 (d, J = 16.3 Hz, 1 H), 3.55–3.66 (m, 1 H), 3.79 (s, 3 H), 4.24 (d, J = 10.6 Hz, 1 H), 4.61 (d, J = 10.6 Hz, 1 H), 5.08 (d, J = 12.2 Hz, 1 H), 5.17 (d, J = 3.2 Hz, 1 H), 5.30 (d, J = 12.2 Hz, 1 H), 5.32 (d, J = 4.0 Hz, 1 H), 5.98 (d, J = 11.1 Hz, 1 H), 5.99 (d, J = 11.1 Hz, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 6.70 (d, J = 7.9 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 7.05 ppm (d, J = 8.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3): d = 12.1, 18.0, 39.7, 56.1, 61.4, 64.2, 101.5, 107.7, 109.6, 111.5, 117.7, 118.5, 122.1, 123.8, 129.0, 133.9, 135.4, 137.4, 142.3, 144.6, 146.2, 147.6, 148.8 ppm; HRMS (ESI): m/z calcd for C30H38O5SiH + [M+H] + 507.2561, found 507.2564.
Synthesis of 17 In a flame-dried Schlenk flask were mixed 22 (93.0 mg, 141 mmol, 1.00 equiv) with TBAF (1 m in THF, 353 mL, 353 mmol, 2.50 equiv) in THF (3 mL) at 0 8C under argon. After 1 h the reaction was quenched with a sat. aq. ammonium chloride solution (5 mL) and the crude product was extracted with dichloromethane (3 5 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. After concentration in vacuo the crude product was purified by flash column chromatography (dichloromethane/methanol = 100:1 to 25:1) to yield 17 (45.9 mg, 125 mmol, 89 %, 52 % ee) as a colorless foam. The enantiopurity of 17 was analyzed by analytic HPLC on an IA-column (Chiralpak IA column, 250 4.6 mm, particle size 5 mm). Under the elution conditions (12 % isopropanol in n-hexane, 0.8 mL min1, l = 226 nm), two peaks were detected at tR = 23.8 min for (+)-(R)-17 (76 %) and tR = 29.7 min for ()-(S)-17 (24 %). The diol 17 was resolved by preparative HPLC on an IA-column (Chiralpak IA column, 250 20 mm, particle size 5 mm) to give (+)-(R)-17 and ()-(S)-17 in > 99 % ee and 98 % ee purity, respectively (10 % isopropanol in n-hexane, 18 mL min1, l = 226 nm, tR = 30 min for (+)-(R)-17 and tR = 41 min for ()-(S)-17. (+)-(R)-17: ½a22 D = + 1.2 (c = 0.5, CHCl3); ()-(S)-17: ½a22 D = 1.0 (c = 0.5, CHCl3); Rf = 0.36 (dichloromethane/methanol = 15:1); UV (CH3CN): lmax (log e) = 287 nm (4.047); IR (ATR): ~n = 3313, 2930, 1573, 1461, 1255, 1098, 1031 cm1; 1H NMR (600 MHz, CDCl3): d = 2.66 (d, J = 15.4 Hz, 1 H), 2.72–2.78 (m, 1 H), 2.89 (dd, J = 15.4, 5.5 Hz, 1 H), 3.45 (dd, J = 9.8, 5.9 Hz, 1 H), 3.55 (dd, J = 9.5, 9.5 Hz, 1 H), 3.77 (s, 3 H), 4.17 (d, J = 12.5 Hz, 1 H), 4.34 (d, J = 12.5 Hz, 1 H), 5.11 (d, J = 12.3 Hz, 1 H), 5.25 (d, J = 12.3 Hz, 1 H), 5.95 (d, J = 13.8 Hz, 1 H), 5.96 (d, J = 13.8 Hz, 1 H), 6.52 (d, J = 7.9 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 6.68 ppm (d, J = 6.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3): d = 32.4, 38.2, 55.9, 62.1, 63.1, 63.9, 101.5, 107.4, 109.6, 117.5, 119.7, 121.5, 123.0, 127.5, 132.8, 132.9, 139.2, 144.7, 145.9, 147.4, 148.7 ppm; HRMS (ESI): m/z calcd for C21H20O6Na + [M+Na] + 391.1152, found 391.1151.
Synthesis of 21 In a flame-dried Schlenk flask were mixed 31 (295 mg, 409 mmol, 1.00 equiv), silver carbonate (158 mg, 573 mmol, 1.40 equiv) and 4dimethylaminopyridine (50.0 mg, 409 mmol, 1.00 equiv) in toluene (24 mL) under argon. At 110 8C, a solution of palladium(II) acetate (9.20 mg, 41.0 mmol, 10.0 mol %) with DavePhos (81.0 mg, 205 mmol, 50.0 mol %) in toluene (6 mL) was added. After 45 min at 110 8C, the mixture was cooled and concentrated. The crude product was purified by flash column chromatography (petroleum ether/EtOAc = 12:1) to yield 21 (236 mg, 368 mmol, 96 %) as a colorless foam. Rf = 0.22 (petroleum ether/EtOAc = 9:1); UV (CH3CN): lmax (log e) = 314 nm (4.196); IR (ATR): ~ n = 2938, 1608, 1458, 1231, 1084, 1034, 841, 733, 687cm1; 1H NMR (300 MHz, CDCl3): d = 0.27 (d, J = 11.4 Hz, 6 H), 0.94 (dd, J = 8.7, 6.8 Hz, 21 H), 3.25 (d, J = 14.3 Hz, 1 H), 3.68 (dt, J = 14.2, 1.8 Hz, 1 H), 3.81 (s, 3 H), 3.88 (d, J = 9.4 Hz, 1 H), 4.12 (d, J = 9.4 Hz, 1 H), 5.04 (d, J = 12.1 Hz, 1 H), 5.31 (d, J = 12.1 Hz, 1 H), 5.71 (d, J = 1.9 Hz, 1 H), 5.98 (dd, J = 13.7, 1.5 Hz, 2 H), 6.62 (d, J = 2.8 Hz, 1 H), 6.65 (d, J = 2.8 Hz, 1 H), 6.75 (dd, J = 8.1, 1.2 Hz, 1 H), 7.21–7.28 (m, 3 H), 7.40–7.47 ppm (m, 3 H); 13C NMR (125 MHz, CDCl3): d = 1.7, 0.9, 12.0, 18.0, 46.2, 56.0, 63.8, 64.2, 101.4, 107.5, 109.2, 117.0, 117.9, 122.3, 123.0, 123.4, 127.5, 127.6, 128.8, 131.0, 133.0, 133.7, 135.3, 138.8, 139.0, 144.4, 146.3, 147.4, 148.4, 156.5 ppm; HRMS (ESI): m/z calcd for C38H48O5Si2H + [M+H] + 641.3113, found 641.3103.
Synthesis of 22 In a flame-dried Schlenk flask were mixed 21 (137 mg, 214 mmol, 1.00 equiv) with ()-(ipc)BH2 (128 mg, 855 mmol, 4.00 equiv) in THF (15 mL) at 0 8C under argon. After 2 h at 0 8C, the mixture was allowed to warm to RT, overnight. At 0 8C, 2 m aq. sodium hydroxide solution (2 mL) and 30 % aq. hydrogen peroxide solution (2 mL) were added slowly and the reaction mixture was stirred at 0 8C for 30 min, then warmed to RT and stirred for 30 min. The reaction was quenched with a sat. aq. ammonium chloride solution (20 mL) and the crude product was extracted with ethyl acetate (3 Chem. Eur. J. 2014, 20, 1 – 7
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Synthesis of 1 In a flame-dried round bottom flask was dissolved (+)-(R)-17 (15.0 mg, 41.0 mmol, 1.00 equiv) in dichloromethane (1.5 mL). Manganese dioxide (35.4 mg, 407 mmol, 10.0 equiv) was added in three portions over 2.5 h. The mixture was then filtered through a pad of Celite. After being washed with dichloromethane, the filtrate was concentrated to give the crude aldehyde that was directly used in
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Full Paper the next step without further purification. In a flame-dried round bottom flask the aldehyde was dissolved in tert-butanol (1.5 mL) under argon. Potassium carbonate (19.7 mg, 143 mmol, 3.50 equiv) and iodine (15.5 mg, 61.0 mmol, 1.50 equiv) were successively added and the mixture was heated to 50 8C for 4.5 h. After cooling and addition of ethyl acetate (15 mL) the mixture was washed with a half-saturated aqueous sodium thiosulfate solution (2 15 mL) and a half-saturated aqueous sodium chloride solution (15 mL). The aqueous layers were combined and further extracted with ethyl acetate (2 15 mL). The combined organic layers were dried over sodium sulfate. After concentration in vacuo the crude product was purified by flash column chromatography (dichloromethane/methanol = 99:1) to yield (+)-(R)-linoxepin (1; 11.1 mg, 31.0 mmol, 75 %) as a yellow solid. Based on the enantioenriched (R)-17, obtained through the enantioselective hydroboration followed by chromatography on chiral support, the yield of the enantiopure (+)-(R)-linoxepin (1) would be 57 %.
[3]
The same procedure was applied to ()-(S)-17 (15.0 mg, 41.0 mmol, 1.00 equiv) and afforded ()-(S)-linoxepin (ent-1) (10.5 mg, 29.0 mmol, 71 %) as a colorless solid. 22 (+)-(R)-1: ½a22 D = + 96.1 (c = 0.61, CHCl3). ()-(S)-1: ½aD = 99.7 (c = 0.87, CHCl3). Rf = 0.21 (silica gel, 33 % ethyl acetate in petroleum ether); 1H NMR (600 MHz, CDCl3): d = 2.66 (d, J = 15.4 Hz, 1 H), 2.72– 2.78 (m, 1 H), 2.89 (dd, J = 15.4, 5.5 Hz, 1 H), 3.45 (dd, J = 9.8, 5.9 Hz, 1 H), 3.55 (dd, J = 9.5, 9.5 Hz, 1 H), 3.77 (s, 3 H), 4.17 (d, J = 12.5 Hz, 1 H), 4.34 (d, J = 12.5 Hz, 1 H), 5.11 (d, J = 12.3 Hz, 1 H), 5.25 (d, J = 12.3 Hz, 1 H), 5.95 (d, J = 13.8 Hz, 1 H), 5.96 (d, J = 13.8 Hz, 1 H), 6.52 (d, J = 7.9 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 6.68 ppm (d, J = 6.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3): d = 32.4, 38.2, 55.9, 62.1, 63.1, 63.9, 101.5, 107.4, 109.6, 117.5, 119.7, 121.5, 123.0, 127.5, 132.8, 132.9, 139.2, 144.7, 145.9, 147.4, 148.7 ppm; HRMS (ESI): m/z calcd for C21H20O6Na + [M+Na] + 391.1152, found 391.1151.
[4] [5] [6]
[7]
Acknowledgements
[8] [9]
The work was funded by the Deutsche Forschungsgemeinschaft (DFG), The State of Lower Saxony and the VolkswagenFoundation. J.C. thanks the Alexander von HumboldtFoundation for a postdoctoral fellowship. S.-C.D. thanks the Konrad-Adenauer-Foundation for a Ph.D. scholarship. We are indebted to Prof. Dr. A Pfaltz, Dr. F. Menges and Dr. A. Dfert for helpful discussions.
[10] [11] [12] [13]
Keywords: asymmetric hydroboration · carbopalladation · lignans · natural products · total synthesis
[14]
[1] D. J. Newman, G. M. Cragg, J. Nat. Prod. 2012, 75, 311 – 315. [2] a) L. F. Tietze, U. Beifuss, Angew. Chem. Int. Ed. Engl. 1993, 32, 131 – 163; Angew. Chem. 1993, 105, 137 – 170; b) L. F. Tietze, Chem. Rev. 1996, 96, 115 – 136; c) L. F. Tietze, Nachr. Chem. Tech. Lab. 1997, 45, 1181 – 1187; d) L. F. Tietze, M. Lieb, Curr. Opin. Chem. Biol. 1998, 2, 363 – 337; e) L. F. Tietze, F. Haunert, in Stimulating Concepts in Chemistry (Eds.: M. Shibasaki, J. F.Stoddart, F. Vçgtle), Wiley-VCH, Weinheim, 2000, pp. 39 – 64; f) L. F. Tietze, A. Modi, Medicinal Research Reviews 2000, 20, 304 – 322; g) L. F. Tietze, N. Rackelmann, Pure Appl. Chem. 2004, 76, 1967 – 1983; h) L. F. Tietze, N. Rackelmann, in Multicomponent Reactions (Eds.: J. Zhu, H. Bienaym), Wiley-VCH, Weinheim, 2005, p. 121 – 168; i) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, WileyVCH, Weinheim, 2006; j) L. F. Tietze, L. Levy, in The Mizoroki – Heck Reac-
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Received: August 1, 2014 Published online on && &&, 0000
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FULL PAPER & Total Synthesis L. F. Tietze,* J. Clerc, S. Biller, S.-C. Duefert, M. Bischoff && – &&
Smooth operation: The key feature in the enantioselective total synthesis of the lignan, (+)-linoxepin, is a Pd-catalyzed domino reaction consisting of a carbopalladation and a Mizoroki–Heck reaction using DavePhos as a bulky
Chem. Eur. J. 2014, 20, 1 – 7
electron-rich ligand and an AgI salt as additive to suppress aromatization. The stereogenic center was introduced by an asymmetric regioselective hydroboration to give the natural product.
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Enantioselective Total Synthesis of the Lignan (+)-Linoxepin
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Enantioselective Total Synthesis of the Lignan (+)-Linoxepin Lutz F. Tietze,*[a] Jrme Clerc,[a] Simon Biller,[a] Svenia-C. Duefert,[a] and Matthias Bischoff[a, b] Dedicated to Professor Alan Battersby on the occasion of his 90th birthday
Abstract: An enantioselective total synthesis of the natural (+)-linoxepin (1) was accomplished in eleven steps from bromovanin (24). Key steps are a domino carbopalladation/
Mizoroki–Heck reaction with the formation of a pentacyclic system, an asymmetric hydroboration as well as an oxidative lactonization.
Introduction The development of highly efficient synthetic transformations is an important goal in modern synthesis, whereas natural products are widely used as synthetic platform in the development of active pharmaceutical ingredients.[1] The access to natural metabolites from plant sources on an industrial scale is often prevented due to the scarcity of available sources. Hence, an entry to those compounds by semi- or total synthesis is necessary for their study or use. An efficient, ecologically and economically favorable access can be accomplished by using the concept of domino reactions, implemented by our group.[2, 3] Linoxepin (1) is a natural product which was first isolated from Linum perenne L. (Linaceae) by Schmidt et al. in 2007.[4] It belongs to the aryldihydronaphthalene lignans and contains a novel benzonaphtho[1,8-bc]oxepine moiety. The biological profile of linoxepin is yet unknown. However, it bears close structural resemblance to other biologically active lignans, such as podophyllotoxin (2) and etoposide (3); the latter is used clinically to treat small-cell lung carcinoma and testicular cancer as well as lymphoma and glioblastoma (Figure 1).[5] Recently, we reported the first total synthesis of (+)- and ()-linoxepin (1) and (ent-1), the key step of which featured a Pd-catalyzed domino transformation consisting of a carbopalladation and a silyl-terminated Heck reaction that allowed access to the pentacyclic core of the natural product in a single process.[6] Shortly thereafter, the group of Lautens disclosed an asymmetric approach to the natural product that
Figure 1. Structures of the lignans (+)-linoxepin (1), podophyllotoxin (2) and etoposide (3).
employed a Catellani reaction and relied on the chiral pool as the source of the target molecule’s stereocenter.[7] We hereby report an enantioselective total synthesis of (+)-linoxepin (1) using a new, even more efficient approach, whereby the stereogenic center is introduced by an asymmetric hydroboration (Scheme 1).
Scheme 1. Retrosynthetic approach to (+)-linoxepin (1) with an asymmetric hydroboration and a domino carbopalladation/Heck reaction as key step (R1 = H or SiMe2Ph; R2 = H or TIPS).
[a] Prof. L. F. Tietze, Dr. J. Clerc, S. Biller, Dr. S.-C. Duefert, Dr. M. Bischoff Institut fr Organische und Biomolekulare Chemie Georg-August-Universitt Gçttingen Tammannstrasse 2, 37077 Gçttingen (Germany) E-mail: [email protected]
Results and Discussion First synthetic approach
[b] Dr. M. Bischoff Present address: Max-Planck-Institute fr Psychiatry, Kraepelinstrasse 2, 80804 Mnchen (Germany)
Our initial strategy relied on a threefold domino reaction which comprised a Sonogashira reaction, a carbopalladation and a concluding Mizoroki–Heck reaction. However, the reac-
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404679. Chem. Eur. J. 2014, 20, 1 – 7
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Full Paper On the one hand, CuI seems to prevent the ensuing carbopalladation and, on the other hand, the reaction temperature is too low for the subsequent reactions. As expected transformation of 7 in the presence of Pd(OAc)2 and [Pd(PPh3)4] again did not lead to the desired compound 9 in an acceptable yield. It is reasonable to assume that the use of bulkier ligands should slow down the readdition of the catalyst and thus helps suppress the formation of the unwanted aromatic side product.[8] Indeed, using XantPhos (14)[9] as ligand 20 % of 9 and less than 5 % of isomer 10 were formed, whereas 40 % of the starting material could be recovered (Table 1). It should be noted that the choice of base is also important, only with 4-DMAP or pyridine the isomerization of the double bond could be avoided; bases as Cs2CO3, TEA, DIEA, TMEDA, NMP, DAPCO and N,Ndimethylaniline were not suitable. In addition to XantPhos (14) we also tested the sterically encumbered and electron-rich biarylphosphine DavePhos, (15)[10] which gave slightly better yields. Other ligands as XPhos, SPhos, BrettPhos, JohnPhos and tBuXPhos as well as N-heterocyclic carbenes were less suitable. In addition to the use of electron-rich and sterically demanding ligands, we explored the possibility of pursuing a cationic catalytic pathway by adding AgI salts.[11] It has been previously shown that the addition of silver salts can help suppress alkene isomerization in the case of aryl iodides as substrates.[12] Thus, in the reaction of 7 with DavePhos (15) in the presence of 10 mol % of Ag2CO3 we were able to isolate the diene 9 in 43 % yield with only 27 % of 10 present. To further increase the bulkiness of the system we used the alkyne 11 as substrate containing a TIPS ether moiety instead of a hydroxyl group, which was easily accessible by Sonogashira reaction of iodide 5 a with the TIPS-protected propargylic alcohol 6 b in 92 % yield.
Scheme 2. Threefold domino process for the formation of 10. a) [Pd(PPh3)4], TBAF·3 H2O, DME, 80 8C, 24 h, 50 %.
tion of alkene 5 a and propargyl alcohol (6 a) in the presence of [Pd(PPh3)4] did not lead to the desired compound 9 but instead formed the aromatic congener 10 in 50 % yield (Scheme 2).[6] Mechanistically, one can assume that initially the Sonogashira product 7 is formed, followed by a carbopalladation and a Mizoroki–Heck reaction. However, the desired product 9 seems not to be stable under the reaction conditions and gives 10 by an isomerization of the double bond, probably by readdition of a [PdH] species followed by a b-hydride elimination. To avoid the incompatibility of reagents and allow for a suppression of the undesired alkene isomerization, we opted for a twofold domino process consisting of a carbopalladation and a Mizoroki–Heck reaction (Scheme 3). The precursor 7 can easily be obtained from 5 a and 6 a in 90 % yield by a Sonogashira reaction using [Pd(PPh3)4], CuI and TBAF as base at 60 8C. Under these reaction conditions, the subsequent Pd-catalyzed transformations do not take place.
Table 1. Conditions for the domino carbopalladation/Mizoroki–Heck reaction. Substrate Pd source Ligand
Base
Additive
Yield
7[a]
4-DMAP 1.0 equiv 4-DMAP 1.0 equiv 4-DMAP 1.0 equiv 4-DMAP 1.0 equiv
–
9: 20 % 10: < 5 % 9: 43 % 10: 27 % 12/13: (3:1) 91 %
7[b] 11[c] 11[c]
Pd(OAc)2 15 mol % Pd(OAc)2 10 mol % Pd(OAc)2 5.0 mol % Pd(OAc)2 5.0 mol %
XantPhos 30 mol % DavePhos 50 mol % DavePhos 25 mol % DavePhos 25 mol %
Ag2CO3 10 mol % Ag2CO3 10 mol % Ag2CO3 12: 97 % 1.25 equiv
[a] Toluene, 90 8C, 1 h, 42 % of 7 was recovered. [b] Toluene, 110 8C, 40 min, 13 % of 7 was recovered. [c] Toluene, 110 8C, 30 min.
The domino reaction of 11 using the catalytic system Pd(OAc)2/DavePhos and 0.10 equivalents of Ag2CO3 was much cleaner as well as faster and gave an almost quantitative yield of an inseparable 3:1 mixture of 12 and 13. Optimal reaction conditions were finally found by employing 1.25 equivalents of silver carbonate leading exclusively to 12 in 97 % isolated yield (Scheme 3 and Table 1). It should be noted that treatment of 12 with p-toluene sulfonic acid leads to the aromatic system 13 through isomerization of the exo-methylene double bond.
Scheme 3. Synthesis of alkenes 9 and 12. a) [Pd(PPh3)4], CuI, TBAF·3 H2O, 1,4dioxane, 60 8C, 1 h, 90 %; b) [Pd(PPh3)4], CuI, Bu4NOAc, 1,4-dioxane, 60 8C, 30 min, 92 %. For reaction conditions and results of the domino reaction see Table 1.
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Full Paper In the final steps of the total synthesis of racemic linoxepin (rac-1), diene 12 was transformed into alcohol 16 in 72 % yield by hydroboration with BH3·Me2S and oxidative work-up. Removal of the TIPS group with TBAF gave the corresponding diol 17 in quantitative yield. The selective oxidation of the allylic alcohol in presence of the aliphatic hydroxyl group could be achieved by manganese dioxide. For the oxidation of the aldehyde to the corresponding carboxylic acid the use of iodine in the presence of K2CO3 led to the formation of the lactone during work-up and gave rac-1 in 54 % yield based on 12 (Scheme 4).
Scheme 5. CuI-catalyzed hydroboration of 9: a) i) CuI, (+)-(S,S)-Me-DuPhos, B2pin2, tBuOK, tBuOH, toluene, RT, 17 h; ii) aq. H2O2, aq. NaOH, 0 8C to RT, 30 min, 81 %.
Scheme 4. a) i) BH3·Me2S, THF, 0 8C to RT, 3 h; ii) aq. H2O2, aq. NaOH, 0 8C to RT, 15 h, 72 %; b) TBAF·3 H2O, THF, 0 8C, 15 min, 99 %; c) MnO2, DCM, RT, 2.5 h; d) I2, K2CO3, tBuOH, 50 8C, 4.5 h, 75 % (2 steps).
Enantioselective synthesis of 1 For the enantioselective synthesis of (+)-linoxepin (1), we evaluated the hydroboration of 12 using Brown’s chiral boranes (ipc)2BH and (ipc)BH2. Diene 12 could be transformed into 16 in 70 % yield but with only 11 % ee using ()-(ipc)2BH. The low enantiomeric excess is in accordance with the literature, which describes the asymmetric hydroboration of 1,1-disubstituted alkenes as highly challenging.[13] However, recent developments of copper(I)-catalyzed hydroborations by several groups have opened new perspectives for the asymmetric functionalization of alkenes.[14] We attempted the enantioselective hydroboration of alkene 9 using conditions similar to those recently reported by Ito for the borylation of 1,3-dienes.[14a] However, in the presence of CuI and (+)-MeDuPhos, not the expected alcohol but its isomer 18 was obtained in 81 % yield (Scheme 5). The formation of the bisallylic alcohol 18 can be explained by the following reaction mechanism. In the borylation of 1,3dienes, a SE2’ mode of protonation of the initially formed sallylcopper intermediate 19 to give 20 can be assumed, which is then oxidized to the bisallylic alcohol 18.[14a] In order to enhance the formation of the desired product 17, various modifications were attempted (e.g., solvent, ligand or proton source), but did not lead to an increased formation of the desired product. Similar results were observed for the TIPSprotected diene 12. In a revised approach, we therefore chose to use the Me2PhSi-substituted substrate 21 to circumvent the problems associated with the asymmetric hydroboration of 1,1-disubstituted alkenes. The desired stereogenic center in 17 could thus be obtained either by an asymmetric hydroboration or an enantioselective hydrogenation (Scheme 6). For the synthesis of vinyl silane 21, bromovanin (24) was first acetylated. Subsequent treatment of acetate 25 with the Chem. Eur. J. 2014, 20, 1 – 7
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Scheme 6. Revised synthetic strategy for the enantioselective formation of 17.
lithiated alkyne 29 led to the formation of 26 in 80 % yield over 2 steps. The observed in situ transesterification of the acetyl moiety from the phenolic to the propargylic hydroxyl group can most likely be attributed to the relative alcoholate stabilities. Reductive removal of the acetate group was achieved by dimethylphenylsilane as hydrogen source under acidic conditions to give 27 in 84 % yield. The conversion of alkyne 27 to afford the corresponding Z configured vinyl silane 28 was accomplished by treatment with DIBAL-H (Scheme 7). Silane 28 was then alkylated with 4-(bromomethyl)-5iodobenzo[d][1,3]dioxole (30) under basic conditions and the resulting benzyl ether 5 b was subsequently coupled with the TIPS-protected propargylic alcohol 6 b in a Sonogashira reaction to give alkyne 31. The Pd-catalyzed domino reaction of 31 in the presence of Pd(OAc)2, DavePhos, 4-DMAP and stoichiometric amounts of Ag2CO3 gave almost exclusively the desired vinyl silane 21 in 96 % yield, most likely via intermediate 32 (Scheme 8). 3
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Full Paper The asymmetric hydroboration of the trisubstituted alkene 21 was however successful. The best results were obtained with Brown’s borane ()-(ipc)BH2 and (+)-(ipc)BH2with 77 % yield of the hydroboration product 22; ()-(ipc)2BH and (+)-(ipc)2BH led to more side products with only 30 % yield of 22. Under all conditions the formation of the corresponding aromatic isomer cannot be suppressed completely. At this stage the enantiomeric excess of the products could not be determined, so the crude product was taken on to the subsequent desilylation. Thus, hydroxysilane 22 was transformed into the diol 17 using TBAF with 89 % yield. Determination of the ee values by analytical HPLC revealed a moderate enantioselectivity when using ()-(ipc)BH2 and (+)-(ipc)BH2 as well as ()-(ipc)2BH and (+)-(ipc)2BH of 52 % ee and 47 % ee, respectively. However, 17 was obtained in enantiopure form by preparative HPLC on chiral support. In the process the use of ()-(ipc)BH2 and ()(ipc)2BH led to the diol 17 with the natural configuration whereas (+)-(ipc)BH2 and (+)-(ipc)2BH gave the unnatural enantiomer ent-17. Attempts to use the Masamune borane[17] for the hydroboration to improve the enantioselectivity were not successful, since the borane did not add to the vinyl silane 21. The final steps towards (+)-linoxepin (1) were performed with enantiopure 17 as described for the racemic synthesis: oxidation of the allylic alcohol moiety in 17 with MnO2 followed by oxidation of the formed aldehyde with I2 in the presence of K2CO3 with an overall yield of 75 % (Scheme 10). The spectroscopic data of the isolated 1 matched those previously reported in literature.[18] In addition, the unnatural ent-1 was synthesized based on ent-17 in 71 % yield.
Scheme 7. Synthesis of 28. a) Ac2O, K2CO3, MeCN, 80 8C, 2 h, 99 %; b) 29, nBuLi, THF, 78 8C to RT, 17 h, 81 %; c) PhMe2SiH, TFA, toluene, 0 8C, 30 min, 84 %; d) DIBAL-H, hexane, 0 8C, 1 h, 85 %.
Scheme 8. Synthesis of 21. a) K2CO3, MeCN, 80 8C, 3.5 h, 99 %; b) 6 b, [Pd(PPh3)4], CuI, nBu4NOAc, 1,4-dioxane, 60 8C, 30 min, 94 %; c) 7.5 mol % Pd(OAc)2, 38 mol % DavePhos, 1.40 equiv Ag2CO3, 1.00 equiv 4-DMAP, toluene, 110 8C, 30 min, 96 %.
For the asymmetric hydrogenation of vinyl silane 21 we tested the Pfaltz catalyst [COD]Ir[Cy2PThrePHOX] under a hydrogen atmosphere (30 bar pressure).[15] However, instead of obtaining the desired alkyl silane 23, the hexacyclic silane 33 was formed exclusively (Scheme 9). Compound 33 is the result of an acid-mediated Friedel– Crafts cyclization/isomerization sequence. According to work by Burgess, the hydrogenation of acid-sensitive substrates can prove challenging due to the acidity of the catalytic intermediates, which could be overcome by the use of Nheterocyclic carbene iridium(I) complexes or basic additives.[16] Unfortunately, modification of the reaction conditions (catalyst, basic additives) did not facilitate hydrogenation to afford the desired homoallylic silane 23.
Scheme 10. Synthesis of (+)-linoxepin (1). a) i) ()-(ipc)BH2, THF, 0 8C to RT, 16 h; ii) aq. H2O2, aq. NaOH, 0 8C to RT, 1 h, 77 % of 22; b) 2.5 equiv TBAF (1 m in THF), THF, 0 8C 30 min, 89 %, 52 % ee; c) MnO2, DCM, RT, 2.5 h; d) I2, K2CO3, tBuOH, 50 8C, 4.5 h, 75 % (2 steps).
Conclusions In conclusion, we have accomplished an enantioselective total synthesis of (+)-linoxepin. The key features are a Pd-catalyzed domino reaction consisting of a carbopalladation and a Mizoroki–Heck reaction using DavePhos as a bulky electron-rich ligand and an AgI salt as additive to suppress the alkene isomerization. The instalment of the stereogenic center was realized by using an asymmetric regioselective hydroboration. The enantiopure natural product was synthesized over eleven steps from commercially available starting materials with an overall yield of 27 %.
Scheme 9. Hydrogenation of 21. a) H2 (30 bar), (S,S)-[COD]Ir[Cy2PThrePHOX], DCM, RT, 90 min, 99 % of 33.
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20 mL). The combined organic layers were washed with brine (40 mL) and dried over sodium sulfate. After concentration in vacuo the crude product was purified by flash column chromatography (petroleum ether/EtOAc = 10:1 to 4:1) to yield 22 (108 mg, 164 mmol, 77 %) with a small amount of impurities as a colorless foam. Rf = 0.17 (petroleum ether/EtOAc = 5:1); UV (CH3CN): lmax (log e) = 290 nm (3.756); IR (ATR): ~ n = 2941, 2864, 1459, 1250, 1098, 1032, 881, 796, 681 cm1; 1H NMR (600 MHz, CDCl3): d = 0.33 (s, 3 H), 0.35 (s, 3 H), 0.85–1.10 (m, 21 H), 2.86–2.99 (m, 3 H), 3.75 (s, 1 H), 3.77 (s, 3 H), 4.05 (d, J = 10.7 Hz, 1 H), 4.12 (d, J = 10.7 Hz, 1 H), 5.11 (d, J = 12.4 Hz, 1 H), 5.28 (d, J = 12.4 Hz, 1 H), 5.95 (d, J = 1.5 Hz, 1 H), 6.00 (d, J = 1.5 Hz, 1 H), 6.37 (d, J = 7.9 Hz, 1 H), 6.54 (d, J = 8.2 Hz, 1 H), 6.65 (d, J = 7.9 Hz, 1 H), 6.99 (d, J = 7.9 Hz, 1 H), 7.28– 7.39 (m, 3 H), 7.55 ppm (dd, J = 7.9, 1.4 Hz, 2 H); 13C NMR (125 MHz, CDCl3): d = 4.4, 3.8, 12.0, 18.1, 32.8, 38.7, 55.9, 62.7, 64.1, 67.2, 101.4, 107.6, 109.6, 117.3, 119.5, 122.6, 123.1, 127.9, 128.9, 129.3, 134.1, 137.2, 137.2, 139.5, 141.9, 144.6, 145.8, 147.3, 148.8 ppm; HRMS (ESI): m/z calcd for C38H50O6Si2Na + [M+Na] + 681.3038, found 681.3025.
Synthesis of 12 In a flame-dried Schlenk flask were mixed 11 (300 mg, 0.51 mmol, 1.00 equiv), silver carbonate (176 mg, 0.64 mmol, 1.25 equiv) and 4-dimethylaminopyridine (63.0 mg, 0.51 mmol, 1.00 equiv) in toluene (24 mL) under argon. At 110 8C, a solution of palladium(II) acetate (5.70 mg, 26.0 mmol, 5.00 mol %) with DavePhos (51.0 mg, 0.13 mmol, 25.0 mol %) in toluene (6 mL) was added. After 30 min at 110 8C, the mixture was cooled and concentrated. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 12:1) to yield 12 (256 mg, 0.50 mmol, 97 %) as a colorless foam. Rf = 0.27 (petroleum ether/EtOAc = 9:1). UV n= (CH3CN): lmax (log e) = 216 nm (4.622), 315 (4.204); IR (ATR): ~ 2863, 1458, 1244, 1080, 1033, 881, 794, 677 cm1; 1H NMR (300 MHz, CDCl3): d = 0.82–1.13 (m, 2 H), 3.37 (d, J = 16.3 Hz, 1 H), 3.55–3.66 (m, 1 H), 3.79 (s, 3 H), 4.24 (d, J = 10.6 Hz, 1 H), 4.61 (d, J = 10.6 Hz, 1 H), 5.08 (d, J = 12.2 Hz, 1 H), 5.17 (d, J = 3.2 Hz, 1 H), 5.30 (d, J = 12.2 Hz, 1 H), 5.32 (d, J = 4.0 Hz, 1 H), 5.98 (d, J = 11.1 Hz, 1 H), 5.99 (d, J = 11.1 Hz, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 6.70 (d, J = 7.9 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 7.05 ppm (d, J = 8.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3): d = 12.1, 18.0, 39.7, 56.1, 61.4, 64.2, 101.5, 107.7, 109.6, 111.5, 117.7, 118.5, 122.1, 123.8, 129.0, 133.9, 135.4, 137.4, 142.3, 144.6, 146.2, 147.6, 148.8 ppm; HRMS (ESI): m/z calcd for C30H38O5SiH + [M+H] + 507.2561, found 507.2564.
Synthesis of 17 In a flame-dried Schlenk flask were mixed 22 (93.0 mg, 141 mmol, 1.00 equiv) with TBAF (1 m in THF, 353 mL, 353 mmol, 2.50 equiv) in THF (3 mL) at 0 8C under argon. After 1 h the reaction was quenched with a sat. aq. ammonium chloride solution (5 mL) and the crude product was extracted with dichloromethane (3 5 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. After concentration in vacuo the crude product was purified by flash column chromatography (dichloromethane/methanol = 100:1 to 25:1) to yield 17 (45.9 mg, 125 mmol, 89 %, 52 % ee) as a colorless foam. The enantiopurity of 17 was analyzed by analytic HPLC on an IA-column (Chiralpak IA column, 250 4.6 mm, particle size 5 mm). Under the elution conditions (12 % isopropanol in n-hexane, 0.8 mL min1, l = 226 nm), two peaks were detected at tR = 23.8 min for (+)-(R)-17 (76 %) and tR = 29.7 min for ()-(S)-17 (24 %). The diol 17 was resolved by preparative HPLC on an IA-column (Chiralpak IA column, 250 20 mm, particle size 5 mm) to give (+)-(R)-17 and ()-(S)-17 in > 99 % ee and 98 % ee purity, respectively (10 % isopropanol in n-hexane, 18 mL min1, l = 226 nm, tR = 30 min for (+)-(R)-17 and tR = 41 min for ()-(S)-17. (+)-(R)-17: ½a22 D = + 1.2 (c = 0.5, CHCl3); ()-(S)-17: ½a22 D = 1.0 (c = 0.5, CHCl3); Rf = 0.36 (dichloromethane/methanol = 15:1); UV (CH3CN): lmax (log e) = 287 nm (4.047); IR (ATR): ~n = 3313, 2930, 1573, 1461, 1255, 1098, 1031 cm1; 1H NMR (600 MHz, CDCl3): d = 2.66 (d, J = 15.4 Hz, 1 H), 2.72–2.78 (m, 1 H), 2.89 (dd, J = 15.4, 5.5 Hz, 1 H), 3.45 (dd, J = 9.8, 5.9 Hz, 1 H), 3.55 (dd, J = 9.5, 9.5 Hz, 1 H), 3.77 (s, 3 H), 4.17 (d, J = 12.5 Hz, 1 H), 4.34 (d, J = 12.5 Hz, 1 H), 5.11 (d, J = 12.3 Hz, 1 H), 5.25 (d, J = 12.3 Hz, 1 H), 5.95 (d, J = 13.8 Hz, 1 H), 5.96 (d, J = 13.8 Hz, 1 H), 6.52 (d, J = 7.9 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 6.68 ppm (d, J = 6.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3): d = 32.4, 38.2, 55.9, 62.1, 63.1, 63.9, 101.5, 107.4, 109.6, 117.5, 119.7, 121.5, 123.0, 127.5, 132.8, 132.9, 139.2, 144.7, 145.9, 147.4, 148.7 ppm; HRMS (ESI): m/z calcd for C21H20O6Na + [M+Na] + 391.1152, found 391.1151.
Synthesis of 21 In a flame-dried Schlenk flask were mixed 31 (295 mg, 409 mmol, 1.00 equiv), silver carbonate (158 mg, 573 mmol, 1.40 equiv) and 4dimethylaminopyridine (50.0 mg, 409 mmol, 1.00 equiv) in toluene (24 mL) under argon. At 110 8C, a solution of palladium(II) acetate (9.20 mg, 41.0 mmol, 10.0 mol %) with DavePhos (81.0 mg, 205 mmol, 50.0 mol %) in toluene (6 mL) was added. After 45 min at 110 8C, the mixture was cooled and concentrated. The crude product was purified by flash column chromatography (petroleum ether/EtOAc = 12:1) to yield 21 (236 mg, 368 mmol, 96 %) as a colorless foam. Rf = 0.22 (petroleum ether/EtOAc = 9:1); UV (CH3CN): lmax (log e) = 314 nm (4.196); IR (ATR): ~ n = 2938, 1608, 1458, 1231, 1084, 1034, 841, 733, 687cm1; 1H NMR (300 MHz, CDCl3): d = 0.27 (d, J = 11.4 Hz, 6 H), 0.94 (dd, J = 8.7, 6.8 Hz, 21 H), 3.25 (d, J = 14.3 Hz, 1 H), 3.68 (dt, J = 14.2, 1.8 Hz, 1 H), 3.81 (s, 3 H), 3.88 (d, J = 9.4 Hz, 1 H), 4.12 (d, J = 9.4 Hz, 1 H), 5.04 (d, J = 12.1 Hz, 1 H), 5.31 (d, J = 12.1 Hz, 1 H), 5.71 (d, J = 1.9 Hz, 1 H), 5.98 (dd, J = 13.7, 1.5 Hz, 2 H), 6.62 (d, J = 2.8 Hz, 1 H), 6.65 (d, J = 2.8 Hz, 1 H), 6.75 (dd, J = 8.1, 1.2 Hz, 1 H), 7.21–7.28 (m, 3 H), 7.40–7.47 ppm (m, 3 H); 13C NMR (125 MHz, CDCl3): d = 1.7, 0.9, 12.0, 18.0, 46.2, 56.0, 63.8, 64.2, 101.4, 107.5, 109.2, 117.0, 117.9, 122.3, 123.0, 123.4, 127.5, 127.6, 128.8, 131.0, 133.0, 133.7, 135.3, 138.8, 139.0, 144.4, 146.3, 147.4, 148.4, 156.5 ppm; HRMS (ESI): m/z calcd for C38H48O5Si2H + [M+H] + 641.3113, found 641.3103.
Synthesis of 22 In a flame-dried Schlenk flask were mixed 21 (137 mg, 214 mmol, 1.00 equiv) with ()-(ipc)BH2 (128 mg, 855 mmol, 4.00 equiv) in THF (15 mL) at 0 8C under argon. After 2 h at 0 8C, the mixture was allowed to warm to RT, overnight. At 0 8C, 2 m aq. sodium hydroxide solution (2 mL) and 30 % aq. hydrogen peroxide solution (2 mL) were added slowly and the reaction mixture was stirred at 0 8C for 30 min, then warmed to RT and stirred for 30 min. The reaction was quenched with a sat. aq. ammonium chloride solution (20 mL) and the crude product was extracted with ethyl acetate (3 Chem. Eur. J. 2014, 20, 1 – 7
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Synthesis of 1 In a flame-dried round bottom flask was dissolved (+)-(R)-17 (15.0 mg, 41.0 mmol, 1.00 equiv) in dichloromethane (1.5 mL). Manganese dioxide (35.4 mg, 407 mmol, 10.0 equiv) was added in three portions over 2.5 h. The mixture was then filtered through a pad of Celite. After being washed with dichloromethane, the filtrate was concentrated to give the crude aldehyde that was directly used in
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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Full Paper the next step without further purification. In a flame-dried round bottom flask the aldehyde was dissolved in tert-butanol (1.5 mL) under argon. Potassium carbonate (19.7 mg, 143 mmol, 3.50 equiv) and iodine (15.5 mg, 61.0 mmol, 1.50 equiv) were successively added and the mixture was heated to 50 8C for 4.5 h. After cooling and addition of ethyl acetate (15 mL) the mixture was washed with a half-saturated aqueous sodium thiosulfate solution (2 15 mL) and a half-saturated aqueous sodium chloride solution (15 mL). The aqueous layers were combined and further extracted with ethyl acetate (2 15 mL). The combined organic layers were dried over sodium sulfate. After concentration in vacuo the crude product was purified by flash column chromatography (dichloromethane/methanol = 99:1) to yield (+)-(R)-linoxepin (1; 11.1 mg, 31.0 mmol, 75 %) as a yellow solid. Based on the enantioenriched (R)-17, obtained through the enantioselective hydroboration followed by chromatography on chiral support, the yield of the enantiopure (+)-(R)-linoxepin (1) would be 57 %.
[3]
The same procedure was applied to ()-(S)-17 (15.0 mg, 41.0 mmol, 1.00 equiv) and afforded ()-(S)-linoxepin (ent-1) (10.5 mg, 29.0 mmol, 71 %) as a colorless solid. 22 (+)-(R)-1: ½a22 D = + 96.1 (c = 0.61, CHCl3). ()-(S)-1: ½aD = 99.7 (c = 0.87, CHCl3). Rf = 0.21 (silica gel, 33 % ethyl acetate in petroleum ether); 1H NMR (600 MHz, CDCl3): d = 2.66 (d, J = 15.4 Hz, 1 H), 2.72– 2.78 (m, 1 H), 2.89 (dd, J = 15.4, 5.5 Hz, 1 H), 3.45 (dd, J = 9.8, 5.9 Hz, 1 H), 3.55 (dd, J = 9.5, 9.5 Hz, 1 H), 3.77 (s, 3 H), 4.17 (d, J = 12.5 Hz, 1 H), 4.34 (d, J = 12.5 Hz, 1 H), 5.11 (d, J = 12.3 Hz, 1 H), 5.25 (d, J = 12.3 Hz, 1 H), 5.95 (d, J = 13.8 Hz, 1 H), 5.96 (d, J = 13.8 Hz, 1 H), 6.52 (d, J = 7.9 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 6.68 ppm (d, J = 6.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3): d = 32.4, 38.2, 55.9, 62.1, 63.1, 63.9, 101.5, 107.4, 109.6, 117.5, 119.7, 121.5, 123.0, 127.5, 132.8, 132.9, 139.2, 144.7, 145.9, 147.4, 148.7 ppm; HRMS (ESI): m/z calcd for C21H20O6Na + [M+Na] + 391.1152, found 391.1151.
[4] [5] [6]
[7]
Acknowledgements
[8] [9]
The work was funded by the Deutsche Forschungsgemeinschaft (DFG), The State of Lower Saxony and the VolkswagenFoundation. J.C. thanks the Alexander von HumboldtFoundation for a postdoctoral fellowship. S.-C.D. thanks the Konrad-Adenauer-Foundation for a Ph.D. scholarship. We are indebted to Prof. Dr. A Pfaltz, Dr. F. Menges and Dr. A. Dfert for helpful discussions.
[10] [11] [12] [13]
Keywords: asymmetric hydroboration · carbopalladation · lignans · natural products · total synthesis
[14]
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FULL PAPER & Total Synthesis L. F. Tietze,* J. Clerc, S. Biller, S.-C. Duefert, M. Bischoff && – &&
Smooth operation: The key feature in the enantioselective total synthesis of the lignan, (+)-linoxepin, is a Pd-catalyzed domino reaction consisting of a carbopalladation and a Mizoroki–Heck reaction using DavePhos as a bulky
Chem. Eur. J. 2014, 20, 1 – 7
electron-rich ligand and an AgI salt as additive to suppress aromatization. The stereogenic center was introduced by an asymmetric regioselective hydroboration to give the natural product.
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Enantioselective Total Synthesis of the Lignan (+)-Linoxepin
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