DOI: 10.1002/chem.201402495
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& Natural Products
A Domino Approach to the Enantioselective Total Syntheses of Blennolide C and Gonytolide C Lutz F. Tietze,* Stefan Jackenkroll, Judith Hierold, Ling Ma, and Bernd Waldecker[a] Dedicated to Professor Max Malacria on the occasion of his 65th birthday
second stereocentre at C-4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both the anti-isomer 14 a and the syn-isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to syn-acid 25 and 2’-epi-gonytolide C 28.
Abstract: The first enantioselective total syntheses of the tetrahydroxanthenone ()-blennolide C (ent-4) and related g-lactonyl chromanone ()-gonytolide C (ent-3) are reported. Key to the syntheses is an enantioselective domino-Wacker/ carbonylation/methoxylation reaction to set up the stereocentre at C-4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The
Introduction
1),[13] 4-dehydroxydiversonol[14] and the proposed structures of paecilin A and B[15] by using an enantioselective dominoWacker/carbonylation/methoxylation reaction. This versatile domino process[16] has also been applied to the synthesis of chromanes, dioxins and oxazins.[17] Herein, we report its application to the first enantioselective total syntheses of ()-blennolide C (ent-4), ()-gonytolide C (ent-3), as well as some related chromanones.
The rapidly growing class of tetrahydroxanthenone natural products has recently attracted increasing interest in the chemical community, fuelled by their intriguing structural features and varied biological profiles.[1] Among the most prominent members are the dimeric rugulotrosins,[2] dicerandrols[3] and secalonic acids,[4, 5] which exhibit antimicrobial, antibiotic, cytotoxic, antifungal, and antialgal activities. The monomeric series includes diversonol (1)[6] and the blennolides (Figure 1). Blennolide C (4), the structure of which was originally assigned as b-diversonolic ester, was isolated from the endophytic fungus Blennoria sp. by Krohn and co-workers.[7] In 2008, both Brse[8] and Nicolaou[9] reported biomimetic approaches to the racemic natural product; in 2011, Porco utilized a “retrobiomimetic” process in the synthesis of racemic blennolides and the related isomeric gonytolide C (3).[10] Gonytolide C (3) was isolated in 2011 from the fungus Gonytrichum sp. by Kikuchi and co-workers.[11] The chromanone with a tethered g-lactone moiety is the monomeric unit of gonytolide A (6), an innate immune promoter. Our group has recently reported the syntheses of enantiopure ()-blennolide A,[12] ()-diversonol (ent- Figure 1. Tetrahydroxanthenones and related natural products. [a] Prof. Dr. L. F. Tietze, S. Jackenkroll, Dr. J. Hierold, Dr. L. Ma, B. Waldecker Institute of Organic and Biomolecular Chemistry Georg-August-University Gçttingen Tammannstrasse 2, 37077 Gçttingen (Germany) Fax: (+ 49) 551-39-9476 E-mail: [email protected]
Results and Discussion Retrosynthetic analysis reveals that both ent-4 and ent-3 can be accessed from advanced intermediate 7 (Scheme 1). Chromanone 7 can be transformed into ent-4 by intramolecular acylation and global deprotection, while a desilylating lactonisation followed by demethylation would enable access to
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402495. Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper The conversion of 9 to chromane 8 was then investigated in the presence of a chiral BOXAX ligand, catalytic amounts of palladium(II)-trifluoroacetate and the reoxidant p-benzoquinone under an atmosphere of carbon monoxide in methanol (Table 1). In line with our syntheses of ()-diversonol (ent-1)[13] and ()-blennolide A,[12] we initially utilized the (S,S)-BnBOXAX ligand (i.e. 13, R = Bn) to induce enantioselectivity. Chromane 8 was isolated in good yield (68 %) and very good enantioselectivity (93 % ee) (Table 1, entry 1). Steric tuning at the C-4 position of the BOXAX-isoxazoline rings (cf. 13, Scheme 2) was reported to affect both the catalytic activity and the enantioselectivity.[18] Novel iBu-BOXAX ligand brought about the domino process in a similar yield (68 %) Scheme 1. Retrosynthetic analysis of ()-blennolide C (ent-4) and ()-gonytolide C (entand with excellent enantioselectivity (99 % ee) 3). (Table 1, entry 2). iPr-BOXAX, the ligand of choice in our synthesis of vitamin E,[19] gave an equally high ent-3. Synthesis of 7 may be achieved from 8 by C-4 hydroxylenantioselectivity (> 99 % ee) but a decreased yield of 62 % ation (numbering as in 4), chain elongation and benzylic oxida(entry 3). It seems that the increased bulk disturbs the coordition. The efficient access of chromane 8 from phenolic precurnation of the palladium–ligand complex to the alkene, thus sor 9, a key transformation in these total syntheses, was prolowering the catalytic activity. Indeed using the bulky tBuposed to proceed by the enantioselective domino-Wacker/carBOXAX ligand, 8 was only isolated in a moderate yield of 7 % bonylation/methoxylation reaction central to our research pro(entry 4). On the other hand, we assume that the improved gramme. enantioselectivity in the transformation of 9 compared to subOur synthesis commenced with the preparation of dominostrates lacking the benzyloxy group is due to a tighter enantioprecursor 9 from readily available orcinol (10). The six-step sefacial coordination of the catalyst to the double bond. quence required methylation, formylation, a Wittig-transformaReduction of 8 with LiAlH4 and subsequent elimination following the Grieco protocol[20] gave vinyl chromane 12 in 90 % tion to install the side chain, hydrogenation, a second Wittigtransformation to incorporate the terminal alkene and chemoyield over three steps. Direct conversion of a derivative of 9 selective cleavage of one of the methyl ethers to afford 9 in containing an ethylidene instead of the methylidene group to 62 % overall yield (Scheme 2). vinyl chromane 12 by an enantioselective Wacker oxidation had been shown to proceed with low enantioselectivity on related substrates and was therefore avoided.[12, 13] For the introduction of the hydroxyl group at C-4 a Sharpless dihydroxylation[21] was used (Table 2). Commercial AD-mix-a gave access to the desired anti-isomer 14 a, though the yield was only moderate and the anti/syn ratio of 2.4:1 unsatisfactory (Table 2, entry 1). Since the diastereoselectivity of this transformation was equally low in previous syntheses (diversonol: 3.8:1, blennolide A: 2.4:1),[12, 13] we decided to survey other commercial dihydroquinine (DHQ) ligands for their ability to carry out the dihydroxylation. Phthalazine-based (DHQ)2-PHAL, the chiral ligand present in the commercial mix, gave the expected low selectivity (1:8:1) albeit a higher yield when compared with the premixed AD-mix-a (entry 2). Use of pyrimidine-based (DHQ)2-Pyr and the monomerScheme 2. Synthesis of vinyl chromane 12: a) Me2SO4, K2CO3, acetone, 60 8C, 24 h, 96 %; ic “first generation” ligand DHQ-MEQ resulted in an inb) 1) nBuLi, TMEDA, Et2O, 0 to 45 8C, 3 h, 2) DMF, RT, 3 h, 92 %; c) 1-(benzyloxy)-3-(triphecreased anti/syn ratio of 4.3:1 and 6.7:1, respectively nylphosphoranylidene)propan-2-one, toluene, 120 8C, 19.5 h, 89 %; d) 1) H2 (1 atm.), (entries 3–4). The best result was obtained by em4 mol % PtO2, EtOAc, RT, 2 h, 2) IBX, CH3CN, 80 8C, 1 h, 91 % (2 steps); e) Ph3PCH3Br, nBuLi, THF, RT, 4 h, 93 %; f) NaSEt, DMF, 120 8C, 21 h, 87 % (92 % based on recovered starting maploying anthraquinone-based (DHQ)2-AQN,[22] which terial (brsm)); g) see Table 1; h) LiAlH4, Et2O, 0 8C to RT, 2 h, 100 %; i) nBu3P, o-NO2gave 14 a in 77 % yield and an excellent selectivity of C6H4SeCN, THF, 0 8C, 4 h, j mCPBA, Na2HPO4·2 H2O, CH2Cl2, 40 8C, 1 h, iPr2NH, 40 8C to 13.7:1 (entry 5). The obtained diastereomers 14 a and RT, 15 h, 90 % (2 steps). IBX = 2-iodoxybenzoic acid; TMEDA = N,N,N’,N’-tetramethylethyle14 b were readily separable by preparative HPLC. nediamine. &
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Full Paper intrinsic diastereofacial preference of the olefin substrate, thus a lower diastereoselectivity seems plausible. Diastereomer 14 a, displaying the anti-configuration present in the targeted natural products, was then silylated at both hydroxyl groups by using (tert-butyldimethylsilyl)trifluoromethanesulphonate (Scheme 3). Selective deprotection of the primary alcohol and subsequent oxidation with DMP provided aldehyde 15 in 78 % yield (89 % based on recovered starting material (brsm)) over three steps. Chain elongation by Wittig– Horner reaction with trimethyl phosphonoacetate gave the corresponding a,b-unsaturated methyl ester as a mixture of E/ Z-isomers (4:1). Reduction of the double bond with concomitant cleavage of the benzyl ether under hydrogenolytic conditions yielded primary alcohol 16, which was converted to methyl ester 17, by using a stepwise oxidation sequence. At this stage, it was necessary to oxidize 16 at the benzylic chromane position (C-9) without affecting the competing benzylic methyl group (C-6, cf. numbering in 4, Figure 1). A related direct oxidation in our total synthesis of ()-diversonol was plagued by low yields;[13] instead we applied a more suitable and higher-yielding three-step procedure. Accordingly, chromane 17 was dehydrogenated to the corresponding chromene with 2,3-dichloro-5,6-dicyanobenzoquinone, which was hydroxylated in the presence of phenylsilane, oxygen and catalytic amounts of [Mn(dmp)3],[23] and further oxidized with perruthenate and NMO[24] to afford chromanone 7 in 80 % yield over the three steps. At this junction, 7 was modified following two different pathways, allowing access to both ()-blennolide C (ent-4) and ()-gonytolide C (ent-3). For the total synthesis of ()-blennolide C, 7 was treated with trichlorotitanium isopropoxide and triethylamine in dichloromethane at 0 8C to give the tetrahydroxanthenone scaffold in 84 % yield (Scheme 4). Though we observed some epimerisation at C-4a (18 a/18 b 9.5:1), the diastereomers were separable by standard column chromatography. Unfortunately the subsequent silyl deprotection of 18 a was again afflicted by epimerisation. Thus, both the conditions we applied in the total synthesis of diversonol (HF·py, 30 8C, 5 d)[13] and blennolide A (HF·3 Et3N, 50 8C, 6 d)[12] led to complete epimerisation, while basic deprotection conditions using tetrabutylammonium fluoride (TBAF) or tris(dimethylamino)sulfur trimethylsilyl difluoride (TASF) resulted in decomposition of 18 a. As the undesired syn-isomer is likely stabilised through intramolecular hydrogen bonding, the presence of water was predicted to suppress epimerisation. Indeed, treatment of 18 a with aqueous fluorosilicic acid gave 19 in 56 % yield and an anti/syn ratio of 10.5:1. While it was possible to separate the epimers at this stage by using reverse-phase HPLC (H2O/MeOH), we decided to conduct the final step of the synthesis with the mixture. Thus, treatment of 19 with BBr3 gave ()-blennolide C (ent-4) in a yield of 60 %, alongside 6 % of a syn-isomer. The ester group of the syn-isomer was hydrolysed to the corresponding acid under the reaction conditions (vide infra), allowing separation from ent-4 by HPLC. Reversing the order of silyl-/methyldeprotection was also investigated. When 18 a was treated with BBr3, phenol 20 was isolated in 86 % with no observable epimerisation. Desilylation with fluorosilicic acid then provided
Table 1. Enantioselective domino-Wacker/carbonylation/methoxylation.
Yield [%][a]
Entry
Ligand 13
1 2 3 4
(S,S)-Bn-BOXAX (S,S)-iBu-BOXAX (S,S)-iPr-BOXAX (S,S)-tBu-BOXAX
ee [%][b]
68 68 62 7
93 99 > 99 –[c]
[a] Isolated yield following flash column chromatography. [b] Determined by HPLC (Chiracel IB, nHex/iPrOH 98:2, 234 nm). [c] Not determined.
Table 2. Diastereoselective dihydroxylation of 12.
Entry 1 2 3 4 5 6 7 8 9 10 11 12
Ligand [c]
– (DHQ)2-PHAL (DHQ)2-Pyr DHQ-MEQ (DHQ)2-AQN –[d] (DHQD)2-PHAL (DHQD)2-Pyr DHQD-CLB DHQD-MEQ (DHQD)2-AQN DHQD-PHN
t [d] 4 2 2 2 3 3 2 2 2 2 3 2
Yield [%][a]
Ratio (14 a/14 b)[b]
64 82 90 84 77 94 80 90 90 89 93 88
2.4:1 1.8:1 4.3:1 6.7:1 13.7:1 1:1.7 1:2.2 1:1.9 1:1.5 1:3.1 1:3.0 1:3.7
[a] Isolated yield following flash column chromatography. [b] Separation of the diastereomers by HPLC (IB column, nHex/iPrOH (96:4)). [c] Commercial ADmix-a used. [d] Commercial AD-mix-b used.
For an entry to the C-4 epimer of blennolide C, the monomeric unit of the rugulotrosins, we also investigated the selective preparation of syn-isomer 14 b. Commercial AD-mix-b afforded the diol in an excellent yield of 94 %; however, the selectivity was poor (14 a/14 b 1:1.7) (Table 2, entry 6). Similar results were obtained by separate addition of the AD-mix components as well as by replacing the (DHQD)2-PHAL ligand with (DHQD)2-Pyr or monomeric ligand DHQD-CLB (entries 7–9). DHQD-MEQ gave an increased diastereoselectivity of 1:3.0, comparable with that observed for (DHQD)2-AQN (1:3.1) (entries 10–11). The best result was obtained with the monocinchona alkaloid DHQD-PHN, which favoured the syn-isomer 14 b with a ratio of 1:3.7 (Table 2, entry 12). It should be noted that for the synthesis of 14 b, the chiral ligand has to override the Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper sponding to the methyl ester moiety. Thus, instead of the 4-epimer of blennolide C, acid 25 had been obtained in a yield of 44 %, presumably formed by blactone intermediate 24. To complete the total synthesis of gonytolide C, chromanone 7 was treated with triethylamine trihydrofluoride in dioxane at 60 8C (Scheme 6). Cleavage of the silyl ether and exclusive in situ formation of the g- over the b-lactone furnished 26 in a very good yield of 87 %, which was then demethylated with BBr3 to give rise to ()-gonytolide C (ent-3). Again, the spectroscopic data matched those reported for Scheme 3. Synthesis of chromanone 7: a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 2.5 h, 96 %; natural 3. The optical rotation was determined to be b) HF·py, THF/py (5:1), RT, 24 h, 85 %, (97 % brsm); c) DMP, CH2Cl2, 0 8C to RT, 2 h, 96 %; 28.5 (c = 0.10 in CHCl3, 24.7 8C) relative to + 25.1 d) NaH, (MeO)2P(O)CH2CO2Me, THF, 0 8C, 30 min, then 15, THF, 0 8C to RT, 2 h; e) 10 mol % (c = 0.184, CHCl3) published by Kikuchi,[11] showing Pd/C, H2 (4 bar), MeOH, 2 d, 90 % (2 steps); f) DMP, CH2Cl2, 0 8C to RT, 2 h, 92 %; g) KOH, I2, that we have synthesized the enantiomer of the natMeOH, 0 8C to RT, 9 h, 100 %; h) DDQ, benzene, reflux, 3 h, 87 %; i) 30 mol % [Mn(dpm)3], PhSiH3, O2 (1 atm.), MeOH, 50 8C, 24 h; j) 20 mol % TPAP, NMO, CH2Cl2/CH3CN (3:1), 4 ural product. It should be noted that natural MS, 24 h, 92 % (2 steps). DMP = Dess-Martin periodinane; NMO = N-methylmorpholine-N(+)-blennolide C (4) and (+)-gonytolide C (3) are oxide; TPAP = tetrapropylammonium perruthenate. readily accessible by completing our synthetic sequence with an (R,R)-BOXAX ligand. Lastly, we converted chromanone 21 to 2’-epi-gonytolide 28, a diastereomer of 3. A desilylating lactonisation of 21 by using triethylamine trihydrofluoride yielded 27 in 84 %, which was then treated with BBr3 to give 28 in 86 % yield.
Conclusion We have achieved the first enantioselective total syntheses of ()-blennolide C (ent-4) and ()-gonytolide C (ent-3). Key to the syntheses was an enantioselective domino-Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre, the hydroxyl group at C-4, was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both anti- 14 a and syn-isomer 14 b in very good selectivities of 13.8:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to synacid 25 and 2’-epi-gonytolide C 28.
Scheme 4. Synthesis of ()-blennolide C (ent-4): a) Ti(OiPr)Cl3, Et3N, CH2Cl2, 0 8C, 1 h, 59 % of pure 18 a plus 25 % of a mixture of 18 a/18 b (2.2:1); b) aq. H2SiF6, DMF, 50 8C, 6 d, 56 % (anti/syn = 10.5:1); c) BBr3, CH2Cl2, RT, 1 h, 60 %; d) BBr3, CH2Cl2, 78 to 0 8C, 4 h, 86 %; e) aq. H2SiF6, DMF, 50 8C, 6 d, 50 %.
()-blennolide C (ent-4) in 50 % yield, alongside 17 % of the syn acid. All spectroscopic data are in complete agreement with the published information of natural (+)-blennolide C (4). We have prepared ent-4 with an optical rotation of 175.3 (c = 0.20 in CHCl3, 22.7 8C), which is slightly lower than the value of + 181.7 (c = 0.06 in CHCl3, 25 8C) reported by Krohn.[7] For an entry to the 4-epimer of blennolide C, syn-diol 14 b was converted to chromanone 21 by using the sequence established for ent-4 (Scheme 5). Both the intramolecular acylation of 21 to 22 and the desilylation to afford 23 proceeded smoothly without any epimerisation at C-4a. To our surprise, the crude 1H NMR spectra of the product isolated after the final methyl ether cleavage with BBr3 lacked the signal corre&
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Experimental Section Experimental procedures and spectroscopic data of key intermediates 7, 8, 12, 14 a, (S,S)-iBu-BOXAX ligand 13, ()blennolide C (ent-4), 25, ()-gonytolide C (ent-3) and 2’-epigonytolide (28): The syntheses of all other new compounds including the analytical data can be found in the Supporting Information. ()-Gonytolide C (ent-3): BBr3 (0.44 mL, 1 m in CH2Cl2, 440 mmol, 10.0 equiv) was added to a stirred solution of chromanyl lactone 26 (14.7 mg, 44.0 mmol, 1.00 equiv) in CH2Cl2 (2.2 mL) at 78 8C and stirring was continued at 78 8C for 2 h. The reaction was quenched by dropwise addition of sat. aq. NaHCO3 (10 mL) at 78 8C, the aq. layer extracted with EtOAc (3 10 mL), and the
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Scheme 5. Attempted synthesis of the 4-epimer of blennolide (4) with observed demethylation: a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 2.5 h, 98 %; b) HF·py, THF/py (5:1), RT, 30 h, 81 % (89 % brsm); c) DMP, CH2Cl2, 0 8C to RT, 2 h, 98 %; d) NaH, (MeO)2P(O)CH2CO2Me, THF, 0 8C, 30 min, then aldehyde, THF, 0 8C to RT, 2 h; e) 10 mol % Pd/C, H2 (4 bar), AcOH, MeOH, 80 h, 91 % (2 steps); f) DMP, CH2Cl2, 0 8C to RT, 1.5 h, 93 %; g) KOH, I2, MeOH, 0 8C to RT, 6.5 h, 96 %; h) DDQ, benzene, reflux, 3 h, 77 %; i) 30 mol % [Mn(dpm)3], PhSiH3, O2 (1 atm.), MeOH, 50 8C, 30 h; j) 20 mol % TPAP, NMO, CH2Cl2/CH3CN (3:1), 4 MS, RT, 24 h, 85 % (2 steps); k) Ti(OiPr)Cl3, Et3N, CH2Cl2, 0 8C, 2 h, 73 %; l) aq. H2SiF6, DMF, 50 8C, 6 d, 96 %; m) BBr3, CH2Cl2, RT, 1 h, 44 %. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
()-Blennolide C (ent-4): A stirred solution of tetrahydroxanthenone 20 (28.4 mg, 65.4 mmol, 1.00 equiv) in DMF (2.3 mL) was treated with H2SiF6 (0.84 mL, 23 wt. % in H2O, 1.63 mmol, 25.0 equiv) at RT and stirring was continued at 50 8C for 3 d. Additional H2SiF6 (0.84 mL, 23 wt. % in H2O, 1.63 mmol, 25.0 equiv) was added at RT and the mixture stirred at 50 8C for a further 3 d. The reaction was quenched by addition of H2O (10.0 mL) at 0 8C, the aq. layer extracted with MTBE (3 5 mL) and the combined organic phases were dried over Na2SO4. After column chromatography on silica gel (CH2Cl2/MeOH 100:1!5:1), ()-blennolide C (ent-4) was obtained alongside ent-25 as a white solid (13.7 mg, 43.3 mmol, 66 %, ent-4/ent-25 = 3:1). Purification by RP-HPLC (Jasco Kromasil 100-C18, 4.6 250 mm, 5 mm, eluent: H2O (A)/ MeOH (B), gradient: 0–30 min: 50A/50B!0A/100B, 30– 40 min: 0A/100B!50A/B50, flow: 0.8 mL min1, tR = 16.4 min) furnished ()-blennolide C (ent-4) as a white solid. [a]D = 175.3 (c = 0.20 in CHCl3, 22.7 8C); 1H NMR (600 MHz, CDCl3): d = 1.93 (mc, 1 H; 3-Ha), 2.12 (mc, 1 H; 3Hb), 2.27 (s, 3 H; 6-CH3), 2.36 (ddd, J = 19.2, 6.9, 1.3 Hz, 1 H; 2-Ha), 2.67 (s, 1 H; 4-OH), 2.80 (ddd, J = 18.8, 11.3, 7.0 Hz, 1 H; 2-Hb), 3.67 (s, 3 H; CO2CH3), 4.29 (s, 1 H; 4-H), 6.32 (s, 1 H; 5-H), 6.36 (s, 1 H; 7-H), 11.25 (s, 1 H; 8-OH), 14.02 ppm (s, 1 H; 1-OH); 13C NMR (125 MHz, CDCl3): d = 22.5 (6-CH3), 23.1 (C-3), 24.3 (C-2), 53.4 (CO2CH3), 67.0 (C4), 83.8 (C-4a), 100.1 (C-9a), 104.9 (C-8a), 108.7 (C-5), 111.7 (C-7), 149.9 (C-6), 157.6 (C-10a), 161.9 (C-8), 171.2 (CO2CH3), 179.1 (C-1), 186.9 ppm (C-9); IR: n˜ = 3484, 2922, 2852, 1740, 1613, 1571, 1456, 1416, 1363, 1298, 1256, 1239, 1206, 1149, 1111, 1078, 1051, 957, 879, 837, 819, 736, 568 cm1; UV (MeOH): lmax (lg e) = 279 (3.4955), 333 nm (4.0719); MS (ESI): m/z (%): 663.2 (44) [2M+Na] + , 343.1 (100) [M+Na] + , 321.1 (36) [M+H] + ; HRMS (ESI): m/ z: calcd for C16H16O7: 321.0969 [M+H] + ; found: 321.0966.
Methyl (2S,1’R)-2-[1-(tert-butyldimethylsilyloxy)-4-methoxy-4-oxobutyl]-5-methoxy-7-methyl-4-oxochroman2-carboxylate (7): A stirred solution of methyl (2S,1’R)-2Scheme 6. Synthesis of ()-gonytolide C (ent-3) and the diastereomeric 2’-epi-gonytoli[1-(tert-butyldimethylsilyloxy)-4-methoxy-4-oxobutyl]-5de C (28): a) 3 HF·Et3N, dioxane, 60 8C, 6 d, 87 %; b) BBr3, CH2Cl2, 78 8C, 2 h, 77 %; methoxy-7-methyl-2H-chromene-2-carboxylate (240 mg, c) 3 HF·Et3N, dioxane, 60 8C, 6 d, 84 %; d) BBr3, CH2Cl2, 78 8C, 2 h, 86 %. 517 mmol, 1.00 equiv) in MeOH (12 mL) was treated with [Mn(dpm)3] (32 mg, 51.7 mmol, 10 mol %) at RT and oxygen was passed through the resulting mixture for 20 min. PhSiH3 (1.30 mL, 10.3 mmol, 20.0 equiv) was added by sycombined organic phases were dried over Na2SO4. After column ringe pump (0.06 mL min1), while the reaction mixture was stirred chromatography on silica gel (n-pentane/EtOAc 2:1!1:2), ()-gounder an atmosphere of O2 (1 atm.) at 50 8C. Additional [Mn(dpm)3] nytolide C (ent-3) was obtained as a white solid (10.9 mg, (32 mg, 51.7 mmol, 10 mol %) was added after 8 and 16 h. After stir34.0 mmol, 77 %). [a]D = 28.5 (c = 0.10 in CHCl3, 24.7 8C); 1H NMR ring at 50 8C for a further 8 h (overall 24 h), the reaction was (600 MHz, CDCl3): d = 2.29 (s, 3 H; 7-CH3), 2.41 (mc, 2 H; 3’-H2), 2.57 quenched by adsorption on silica gel. Evaporation of the solvent (ddd, J = 17.7, 10.2, 6.6 Hz, 1 H; 4’-Ha), 2.69 (ddd, J = 17.2, 9.9, and column chromatography on silica gel (n-hexane/EtOAc 10:1! 7.1 Hz, 1 H; 4’-Hb), 2.93 (d, J = 16.9 Hz, 1 H; 3-Ha), 3.09 (d, J = 1:1) furnished two diastereomeric alcohols (157 mg, 325 mmol, 16.9 Hz, 1 H; 3-Hb), 3.72 (s, 3 H; CO2CH3), 4.84 (dd, J = 8.0, 5.7 Hz, 63 %) and (83 mg, 172 mmol, 33 %) as colourless oils. A solution of 1 H; 2‘-H), 6.36 (s, 1 H; 8-H), 6.38 (s, 1 H; 6-H), 11.36 ppm (s, 1 H; 513 the diastereomeric alcohols (157 mg, 325 mmol, 0.65 equiv) and OH); C NMR (125 MHz, CDCl3): d = 22.0 (C-3’), 22.6 (7-CH3), 27.6 (C(83 mg, 172 mmol, 0.35 equiv) in CH2Cl2 (22.5 mL) and CH3CN 4’), 39.4 (C-3), 53.6 (CO2CH3), 80.9 (C-2’), 84.0 (C-2), 105.6 (C-4a), (7.5 mL) in the presence of 4 molecular sieves (400 mg) was 108.5 (C-8), 111.1 (C-6), 151.6 (C-7), 159.0 (C-8a), 161.8 (C-5), 169.0 treated with NMO (150 mg, 1.24 mmol, 2.50 equiv) at 0 8C and then (CO2CH3), 175.5 (C-5’), 193.0 ppm (C-4); IR: n˜ = 2924, 2853, 1785, stirred at 0 8C for a further 5 min. TPAP (17.5 mg, 47.9 mmol, 1759, 1738, 1644, 1570, 1455, 1366, 1262, 1120, 1131, 1074, 1055, 10 mol %) was added at 0 8C and the resulting reaction mixture 1033, 935, 837, 800, 734, 702, 555 cm1; UV (CH3CN): lmax (lg e) = stirred at RT for 12 h. Additional NMO (150 mg, 1.24 mmol, 277 (3.9702), 344 nm (3.3917); MS (ESI): m/z (%): 663.2 (50) 2.50 equiv) and TPAP (17.5 mg, 47.9 mmol, 10 mol %) were added at + + + [2M+Na] , 658.2 (10) [2M+NH4] , 343.1 (85) [M+Na] , 338.1 (29) 0 8C and the resulting reaction mixture stirred at RT for a further + + [M+NH4] , 321.1 (100) [M+H] ; HRMS (ESI): m/z calcd for C16H16O7: 12 h. After adsorption on silica gel, evaporation of the solvent and + 321.0969 [M+H] ; found: 321.0970. column chromatography on silica gel (n-pentane/EtOAc 4:1!3:1) Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper chromanone 7 (228 mg, 474 mmol, 95 %, 92 % over 2 steps) was obtained as a colourless oil. [a]D = 71.3 (c = 0.20 in CHCl3, 25 8C); 1 H NMR (600 MHz, CDCl3): d = 0.08 (s, 3 H; Si(CH3)a), 0.14 (s, 3 H; Si(CH3)b), 0.85 (s, 9 H; SiC(CH3)3), 1.66 (mc, 2 H; 2’-H2), 2.30 (s, 3 H; 7CH3), 2.36 (dt, J = 16.2, 7.9 Hz, 1 H; 3’-Ha), 2.52 (ddd, J = 16.2, 7.6, 6.4 Hz, 1 H; 3’-Hb), 2.96 (d, J = 16.6 Hz, 1 H; 3-Ha), 3.10 (d, J = 16.6 Hz, 1 H; 3-Hb), 3.65 (s, 6 H; 4’-OCH3, 2-CO2CH3), 3.85 (s, 3 H; 5OCH3), 4.13 (dd, J = 6.8, 5.3 Hz, 1 H; ’-H), 6.30 (s, 1 H; 8-H), 6.42 ppm (s, 1 H; 6-H); 13C NMR (125 MHz, CDCl3): d = 4.7, 3.7 (Si(CH3)a, Si(CH3)b), 18.3 (SiC), 22.4 (7-CH3), 26.0 (SiC(CH3)3), 27.4 (C-2’), 30.3 (C-3’), 39.2 (C-3), 51.6 (4’-OCH3), 53.0 (2-CO2CH3), 56.1 (5-OCH3), 74.3 (C-1’), 87.2 (C-2), 105.8 (C-6), 108.6 (C-4a), 110.5 (C-8), 147.9 (C-7), 160.4, 160.8 (C-5, C-8a), 170.6 (2-CO2CH3), 173.3 (C-4’), 188.7 ppm (C-4); IR: n˜ = 2953, 2928, 2855, 1738, 1686, 1614, 1568, 1463, 1436, 1415, 1389, 1251, 1222, 1124, 1107, 1055, 993, 833, 777, 689 cm1; UV (CH3CN): lmax (lg e) = 219 (4.2702), 268 (3.9879), 324 nm (3.6228); MS (ESI): m/z (%): 983.4 (24) [2M+Na] + , 503.2 (49) [M+Na] + , 481.2 (100) [M+H] + ; HRMS (ESI): m/z calcd for C24H36O8Si: 481.2252 [M+H] + ; found: 481.2247.
treated with Na2HPO4·2 H2O (3.59 g, 20.2 mmol, 5.00 equiv) and meta-chloroperoxybenzoic acid (mCPBA) (2.48 g, 70 %, 10.1 mmol, 2.50 equiv) at 40 8C and stirred at this temperature for 1 h. Diisopropylamine (2.82 mL, 20.2 mmol, 5.00 equiv) was added at 40 8C and the reaction mixture warmed to RT within 15 h. The reaction mixture was adsorbed on silica gel and the solvent removed under reduced pressure. Column chromatography on silica gel (n-pentane/EtOAc 100:0!90:10) furnished vinyl chromane 12 as a yellow oil (1.18 g, 3.62 mmol, 90 %). [a]D = 72.0 (c = 0.50 in CHCl3, 23.7 8C); 1H NMR (600 MHz, CDCl3): d = 1.91 (ddd, J = 13.6, 6.1, 4.0 Hz, 1 H; 3-Ha), 1.99 (ddd, J = 13.6, 11.0, 5.6 Hz, 1 H; 3-Hb), 2.28 (s, 3 H; 7-CH3), 2.39 (ddd, J = 17.1, 10.9, 6.2 Hz, 1 H; 4-Ha), 2.68 (dt, J = 16.8, 4.8 Hz, 1 H; 4-Hb), 3.52 (d, J = 10.0 Hz, 1 H; CHaOBn), 3.57 (d, J = 10.0 Hz, 1 H; CHbOBn), 3.77 (s, 3 H; 5-OCH3), 4.60 (d, J = 12.3 Hz, 1 H; OCHaPh), 4.63 (d, J = 12.3 Hz, 1 H; OCHbPh), 5.16 (dd, J = 10.9, 1.4 Hz, 1 H; 2’-Hcis), 5.25 (dd, J = 17.3, 1.4 Hz, 1 H; 2’-Htrans), 5.84 (dd, J = 17.3, 10.9 Hz, 1 H; 1’-H), 6.22 (s, 1 H; 8-H), 6.41 (s, 1 H; 6-H), 7.27 (mc, 1 H; Ph-Hp), 7.32 ppm (mc, 4 H; Ph-Ho, Ph-Hm); 13C NMR (125 MHz, CDCl3): d = 16.0 (C-4), 21.6 (7-CH3), 26.6 (C-3), 55.3 (5OCH3), 73.6 (OCH2Ph), 75.5 (CH2OBn), 78.7 (C-2), 102.8 (C-8), 107.7 (C-4a), 110.0 (C-6), 116.1 (C-2’), 127.5 (Ph-Cp), 127.6, 128.3 (Ph-Co, Ph-Cm), 136.9 (C-7), 137.9 (C-1’), 138.4 (Ph-Ci), 154.1, 157.4 ppm (C-5, C-8a); IR: n˜ = 2932, 2854, 1616, 1584, 1497, 1453, 1410, 1351, 1320, 1291, 1227, 1196, 1135, 1099, 1026, 991, 927, 812, 734, 696, 580, 550 cm1; UV (CH3CN): lmax (lg e) = 207 (4.6903), 271 nm (2.9781); MS (ESI): m/z (%): 671.3 (86) [2M+Na] + , 666.4 (56) [2M+NH4] + , 347.2 (48) [M+Na] + , 342.2 (13) [M+NH4] + , 325.2 (100) [M+H] + ; HRMS (ESI): m/z calcd for C21H24O3 : 325.1798 [M+H] + ; found: 325.1796.
Methyl (2S)-2-(2-benzyloxymethyl-5-methoxy-7-methylchroman2-yl)acetate (8): A solution of palladium(II)-trifluoroacetate (2.7 mg, 8.1 mmol, 5 mol %) and (S,S)-iBu-BOXAX 13 (16.2 mg, 32.1 mmol, 20 mol %) in MeOH (0.5 mL) was stirred at RT for 15 min before being transferred to alkenylphenol 9 (50 mg, 160 mmol, 1.00 equiv) by syringe (rinsing with 0.5 mL MeOH). p-Benzoquinone (71 mg, 640 mmol, 4.00 equiv) was added and the reaction stirred under an atmosphere of CO (1 atm.) at RT for 24 h. The reaction mixture was poured into 1 n aq. HCl (10 mL) and the aq. layer was extracted with MTBE (methyl tert-butyl ether) (3 5 mL). The combined organic phases were washed with 1 n aq. NaOH (3 5 mL), dried over Na2SO4 and evaporated in vacuo. Column chromatography on silica gel (n-pentane/EtOAc 25:1!10:1) furnished methyl ester 8 as a colourless oil that solidified under vacuum (40.5 mg, 109 mmol, 68 %); analytical HPLC: Daicel Chirapak IB, 4.6 250 mm, eluent: nhexane/2-PrOH 98:2, flow: 0.8 mL min1, wavelength: 234 nm, tR = 11.0 min ()-(R)-8, 0.7 %, tR = 14.2 min (+)-(S)-8, 99.3 %, 99 % ee. [a]D = + 0.9 (c = 0.18 in CHCl3, 22.9 8C); 1H NMR (600 MHz, CDCl3): d = 2.01 (mc, 2 H; 3-H2), 2.26 (s, 3 H; 7-CH3), 2.58 (mc, 2 H; 4-H2), 2.71 (d, J = 15.0 Hz; 2’-Ha), 2.82 (d, J = 14.4 Hz; 2’-Hb), 3.61 (s, 3 H; CO2CH3), 3.65 (d, J = 3.0 Hz, 2 H; CH2OBn), 3.78 (s, 3 H; 5-OCH3), 4.53 (d, J = 12.0 Hz; OCHaPh), 4.61 (d, J = 12.0 Hz; OCHbPh), 6.23 (s, 1 H; 8-H), 6.33 (s, 1 H; 6-H), 7.25–7.34 ppm (m, 5 H; 5 PhH); 13C NMR (125 MHz, CDCl3): d = 15.8 (C-4), 21.6 (7-CH3), 26.2 (C-3), 39.3 (C-2’), 51.5 (CO2CH3), 55.4 (5-OCH3), 72.7 (CH2OBn), 73.6 (OCH2Ph), 76.27 (C-2), 103.1 (C-8), 107.2 (C-4a), 110.4 (C-6), 127.5, 127.6, 128.3 (PhCo, Ph-Cm, PhCp), 137.2 (C-7), 138.2 (PhCi), 153.3, 157.5 (C-5, C8a), 170.8 ppm (C-1’); IR: n˜ = 2923, 2360, 2885, 1728, 1579, 1316, 1223, 1094, 824, 750, 701 cm1; UV (CH3CN): lmax (lg e) = 208 (4.7849), 272 (3.0529), 279 nm (3.0219); MS (ESI): m/z (%): 763.3 (75) [2M+Na] + , 393.2 (100) [M+Na] + ; HRMS (ESI): m/z calcd for C22H26O5 : 393.1672 [M+Na] + ; found: 393.1677.
(S)-2,2’-Bis-[(4S)-iso-butyl)-4,5-dihydrooxazol-2-yl]-1,1’-binaphthalene (13, R = iBu): A solution of (4’S)-2-(1-bromonaphthalen-2yl)-4-isobutyl-4,5-dihydrooxazole (2.00 g, 6.02 mmol, 1.00 equiv) in pyridine (46 mL, distilled over calcium hydride) was treated with activated copper powder (1.15 g, 18.1 mmol, 3.00 equiv) at RT and the reaction mixture heated at reflux for 11 h. After cooling to RT, the solvent was evaporated in vacuo, the residue taken up in CH2Cl2 (100 mL) and filtered over Celite (rinsing with CH2Cl2). The filtrate was washed with conc. NH3 solution (3 100 mL) until the organic layer was colourless. The organic phase was dried over Na2SO4 and evaporated in vacuo. Purification of the residue by column chromatography on silica gel (n-pentane/EtOAc 100:1! 9:1) and HPLC (Jasco LiChrosorb, n-hexane/2-PrOH 99:1) furnished the targeted (S,S)-iBu-BOXAX-ligand (0.73 g, 1.45 mmol, 48 %). Alternatively, the (S,S)-iBu-BOXAX-ligand can be purified by recrystallization from 2-PrOH. Analytical HPLC: Jasco LiChrosorb Si60, 4.6 250 mm, 5 mm, eluent: n-hexane/2-PrOH 99:1, flow: 0.8 mL min1, tR = 7.0 min. Preparative HPLC: Jasco LiChrosorb Si60, 20 250 mm, 7 mm, eluent: n-hexane/2-PrOH 99:1, flow: 10 mL min1, wavelength: 233 nm, tR = 10.4 min. [a]D = 199.5 (c = 0.48 in CHCl3); 1 H NMR (600 MHz, CDCl3): d = 0.70 (d, J = 6.6 Hz, 6 H; 2’’-CH3,a), 0.74 (d, J = 6.6 Hz, 6 H; 2’’-CH3,b), 0.82 (dt, J = 13.3, 7.3 Hz, 2 H; 1’’-Ha), 1.05 (dt, J = 13.6, 6.9 Hz, 2 H; 1’’-Hb), 1.33 (dp, J = 13.4, 6.7 Hz, 2 H; 2’’-H), 3.42 (t, J = 7.7 Hz, 2 H; 5’-Ha), 3.76 (dd, J = 9.2, 8.0 Hz, 2 H; 5’Hb), 3.89 (dq, J = 9.2, 7.2 Hz, 2 H; 4’-H), 7.22 (mc, 4 H, 6-H; 7-H), 7.44 (ddd, J = 8.0, 5.1, 2.8 Hz, 2 H; 5-H), 7.88 (d, J = 8.2 Hz, 2 H; 8-H), 7.92 (d, J = 8.6 Hz, 2 H; 4-H), 8.03 ppm (d, J = 8.7 Hz, 2 H; 3-H); 13C NMR (150 MHz, CDCl3): d = 22.5, 22.6 (2’’-CH3,a, 2’’-CH3,b), 25.0 (C-2“), 45.0 (C-1”), 64.7 (C-4’), 72.8 (C-5’), 126.0 (C-8), 126.1, 126.3, 126.7, 127.0 (C-3, C-5, C-6, C-7), 127.5, 127.8 (C-4, C-8a), 132.9, 134.2 (C-2, C-4a), 137.8 (C-1), 163.7 ppm (C-2’); IR: n˜ = 2953, 2916, 2891, 2866, 2360, 2341, 1656, 1505, 1468, 1379, 1364, 1296, 1243, 1233, 1103, 982, 951, 909, 854, 823, 753, 738, 569 cm1; UV (CH3CN): lmax (lg e) = 228 (4.8388), 288 (4.1057), 336 (3.3266), 370 nm (2.5677); MS (ESI): m/z
(2S)-2-Benzyloxymethyl-5-methoxy-7-methyl-2-vinylchromane (12): A solution of chromanyl alcohol 11 (1.38 g, 4.03 mmol, 1.00 equiv) in THF (50 mL) was treated with 2-nitrophenyl selenocyanate (1.83 g, 8.06 mmol, 2.00 equiv) and nBu3P (2.00 mL, 7.70 mmol, 1.91 equiv) at 0 8C and stirred at 0 8C for 1.5 h. Additional 2-nitrophenyl selenocyanate (458 mg, 2.02 mmol, 0.50 equiv) and PnBu3 (0.50 mL, 1.93 mmol, 0.48 equiv) were added at 0 8C and stirring was continued at 0 8C for 2.5 h. The reaction was quenched by addition of sat. aq. NaHCO3 solution (180 mL) at 0 8C and the aq. layer extracted with MTBE (5 50 mL). The combined organic phases were dried over Na2SO4 and the solvent evaporated in vacuo. A suspension of the crude product in CH2Cl2 (80 mL) was
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Full Paper (%): 505.3 (100) [M+H] + ; HRMS (ESI): m/z calcd for C34H36N2O2 : 505.2850 [M+H] + ; found: 505.2851.
phases were dried over Na2SO4. After column chromatography on silica gel (n-pentane/EtOAc = 2:1!1:3), 2’-epi-gonytolide C (28) was obtained as a white solid (13.2 mg, 41.2 mmol, 86 %). [a]D = 32.4 (c = 0.10 in CHCl3, 22.5 8C); 1H NMR (600 MHz, CDCl3): d = 2.28 (s, 3 H; 7-CH3), 2.28–2.35 (m, 1 H; 3’-Ha), 2.47 (mc, 1 H; 3’-Hb), 2.55 (ddd, J = 17.7, 10.5, 4.9 Hz, 1 H; 4’-Ha), 2.79 (ddd, J = 17.9, 10.2, 4.9 Hz, 1 H; 4’-Hb), 3.04 (d, J = 17.2 Hz, 1 H; 3-Ha), 3.43 (d, J = 17.3 Hz, 1 H; 3-Hb), 3.72 (s, 3 H; CO2CH3), 4.75 (dd, J = 8.5, 4.1 Hz, 1 H; 2’-H), 6.34 (s, 1 H; 8-H), 6.35 (s, 1 H; 6-H), 11.39 ppm (s, 1 H; 5OH); 13C NMR (125 MHz, CDCl3): d = 21.7 (C-3’), 22.6 (7-CH), 27.8 (C4’), 40.3 (C-3), 53.7 (CO2CH3), 79.7 (C-2’), 84.6 (C-2), 105.5 (C-4a), 108.3 (C-8), 111.0 (C-6), 151.2 (C-7), 158.9 (C-8a), 161.7 (C-5), 169.1 (CO2CH3), 176.0 (C-5’), 194.0 ppm (C-4); IR: n˜ = 3358, 2955, 1773, 1741, 1636, 1568, 1455, 1359, 1288, 1263, 1207, 1181, 1120, 1087, 1064, 1030, 837, 807, 743, 704 cm1; UV (MeOH): lmax (lg e) = 224 (3.9672), 276 (3.8614), 343 nm (3.2846); MS (ESI): m/z (%): 663.2 (71) [2M+Na] + , 343.1 (67) [M+Na] + , 338.1 (25) [M+NH4] + , 321.1 (100) [M+H] + ; HRMS (ESI): m/z calcd for C16H16O7: 343.0788 [M+Na] + ; found: 343.0787.
(1’R,2R)-1-(2-Benzyloxymethyl-5-methoxy-7-methylchroman-2yl)ethane-1,2-diol (14 a): A solution of vinyl chromane 12 (376 mg, 1.16 mmol, 1.00 equiv) in tBuOH/H2O (5.8/5.8 mL) was treated with K2OsO4·2 H2O (21.3 mg, 58 mmol, 5 mol %), (DHQ)2-AQN (143 mg, 159 mmol, 10 mol %), K3[Fe(CN)6] (2.29 g, 6.95 mmol, 6.00 equiv) and K2CO3 (961 mg, 6.95 mmol, 6.00 equiv) at RT. After stirring for 3 d, the reaction was quenched by addition of sat. aq. NaHSO3 solution (20 mL) at 0 8C and stirred at RT for an additional 30 min. The aq. layer was extracted with EtOAc (3 10 mL), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. After column chromatography on silica gel (n-pentane/EtOAc 5:1!1:1), a mixture of diastereomers was obtained as a colourless oil (320 mg, 894 mmol, 77 %, d.r. = 13.7:1). The diastereomeric alcohols 14 a (anti) and 14 b (syn) can be separated by HPLC (Daicel Chiracel IB, 20 250 mm, n-hexane/2-PrOH 96:4, 7 mL min1, 210 nm): tR = 14.7 min (14 a), tR = 19.7 min (14 b); for the analytical data of 14 b, see the Supporting Information. Compound 14 a: [a]D = + 2.8 (c = 0.50 in CHCl3, 23.0 8C); 1H NMR (600 MHz, CDCl3): d = 2.00 (mc, 2 H; 3-H2), 2.26 (s, 3 H; 7-CH3), 2.47 (dt, J = 16.8, 7.9 Hz, 1 H; 4-Ha), 2.69 (dt, J = 17.4, 5.7 Hz, 1 H; 4-Hb), 2.74 (sbr, 1 H; 2’-OH), 2.99 (d, J = 6.8 Hz, 1 H; 1’-OH), 3.57 (d, J = 10.0 Hz, 1 H; CHaOBn), 3.64 (d, J = 10.0 Hz, 1 H; CHaOBn), 3.76–3.83 (m, 2 H; 2’-H2), 3.78 (s, 3 H; 5-OCH3), 3.85 (q, J = 5.8 Hz, 1 H; 1’-H), 4.47 (d, J = 11.8 Hz, 1 H; OCHaPh), 4.56 (d, J = 11.8 Hz, 1 H; OCHbPh), 6.24 (s, 1 H; 8-H), 6.30 (s, 1 H; 6-H), 7.27–7.34 ppm (m, 5 H, 5 PhH); 13C NMR (125 MHz, CDCl3): d = 15.4 (C-4), 21.6 (7-CH3), 23.5 (C3), 55.4 (5-OCH3), 61.9 (C-2’), 70.2 (CH2OBn), 74.0 (OCH2Ph), 74.2 (C1’), 77.6 (C-2), 103.3 (C-8), 107.4 (C-4a), 110.0 (C-6), 127.7, 128.5 (PhCo, Ph-Cm), 127.9 (Ph-Cp), 137.2, 137.3 (C-7, Ph-Ci), 153.1, 157.5 ppm (C-5, C-8a); IR: n˜ = 3399, 2924, 2855, 1618, 1584, 1497, 1453, 1413, 1352, 1291, 1223, 1139, 1098, 1073, 1026, 951, 814, 775, 736, 697, 576 cm1; UV (CH3CN): lmax (lg e) = 208 (4.7425), 271 nm (3.0948); MS (ESI): m/z (%): 739.4 (100) [2M+Na] + , 717.4 (6) [2M+H] + , 381.2 (32) [M+Na] + , 359.2 (48) [M+H] + ; HRMS (ESI): m/z calcd for C21H26O5 : 359.1853 [M+H] + ; found: 359.1852.
Acknowledgements This work was supported by Deutsche Forschungsgemeinschaft (DFG), Land Niedersachsen and Volkswagenstiftung. S.J. thanks the CaSuS Program for a PhD scholarship and J.H. thanks the Dorothea-Schlçzer Program for a postdoctoral scholarship. Keywords: dihydroxylation · domino reactions · natural products · tetrahydroxanthones · total synthesis [1] For an excellent recent review on xanthone natural products, see: K.-S. Masters, S. Brse, Chem. Rev. 2012, 112, 3717 – 3776. [2] M. Stewart, R. J. Capon, J. M. White, E. Lacey, S. Tennant, J. H. Gill, M. P. Shaddock, J. Nat. Prod. 2004, 67, 728 – 730. [3] M. M. Wagenaar, J. Clardy, J. Nat. Prod. 2001, 64, 1006 – 1009. [4] a) B. Franck, E. M. Gottschalk, U. Ohnsorge, G. Baumann, Angew. Chem. 1964, 76, 438 – 439; Angew. Chem. Int. Ed. Engl. 1964, 3, 441 – 442; b) B. Franck, G. Baumann, U. Ohnsorge, Tetrahedron Lett. 1965, 6, 2031 – 2037; c) B. Franck, E. M. Gottschalk, U. Ohnsorge, F. Hper, Chem. Ber. 1966, 99, 3842 – 3862; d) P. S. Steyn, Tetrahedron 1970, 26, 51 – 57. [5] For the recent first total syntheses of secalonic acids, see: a) T. Qin, J. A. Porco, Jr., Angew. Chem. 2014, 126, 3171 – 3174: Angew. Chem. Int. Ed. 2014, 53, 3107 – 3110. For a recent report on novel dimeric chromanone natural and semi-synthetic products, see: b) D. Rçnsberg, A. Debbab, A. Mandi, V. Vasylyeva, P. Bohler, B. Stork, L. Engelke, A. Hamacher, R. Sawadogo, M. Diederich, V. Wray, W. Lin, M. U. Kassack, C. Janiak, S. Scheu, S. Wesselborg, T. Kurtan, A. H. Aly, P. Proksch, J. Org. Chem. 2013, 78, 12409 – 12425. [6] a) W. B. Turner, J. Chem. Soc. Perkin Trans. 1 1978, 1621; b) I. N. Siddiqui, A. Zahoor, H. Hussain, I. Ahmed, V. U. Ahmad, D. Padula, S. Draeger, B. Schulz, K. Meier, M. Steinert, T. Kurtn, U. Flçrke, G. Pescitelli, K. Krohn, J. Nat. Prod. 2011, 74, 365 – 373. [7] W. Zhang, K. Krohn, Z. Ullah, U. Flçrke, G. Pescitelli, L. Di Bari, S. Antus, T. Kurtn, J. Rheinheimer, S. Draeger, B. Schulz, Chem. Eur. J. 2008, 14, 4913 – 4923. [8] E. M. C. Grard, S. Brse, Chem. Eur. J. 2008, 14, 8086 – 8089. [9] K. C. Nicolaou, A. Li, Angew. Chem. 2008, 120, 6681 – 6684; Angew. Chem. Int. Ed. 2008, 47, 6579 – 6582. [10] T. Qin, R. P. Johnson, J. A. Porco, Jr., J. Am. Chem. Soc. 2011, 133, 1714 – 1717. [11] H. Kikuchi, M. Isobe, M. Sekiya, Y. Abe, T. Hoshikawa, K. Ueda, S. Kurata, Y. Katou, Y. Oshima, Org. Lett. 2011, 13, 4624 – 4627. [12] L. F. Tietze, L. Ma, J. R. Reiner, S. Jackenkroll, S. Heidemann, Chem. Eur. J. 2013, 19, 8610 – 8614.
(4S,4aS)-1,4,8-Trihydroxy-6-methyl-9-oxo-2,3,4,4a-tetrahydroxanthene-4a-carboxylic acid (25): A solution of methyl ester 23 (18.0 mg, 54.0 mmol, 1.00 equiv) in CH2Cl2 (2.20 mL) was treated with BBr3 (0.54 mL, 1 m in CH2Cl2, 0.54 mmol, 10.0 equiv) at 0 8C and stirred at RT for 1 h. The reaction was quenched by dropwise addition of H2O (10 mL) at 0 8C, the aq. layer extracted with CH2Cl2 (3 10 mL) and the combined organic phases were dried over Na2SO4. After column chromatography on RP silica gel (H2O/MeOH 50:50!0:100), carboxylic acid 25 was obtained as a white powder (7.2 mg, 23.5 mmol, 44 %). [a]D = 166.9 (c = 0.40 in MeOH, 23.6 8C); 1 H NMR (600 MHz, CD3OD): d = 1.98 (ddd, J = 12.2, 8.8, 5.2 Hz, 1 H; 3-Ha), 2.23–2.30 (m, 1 H; 3-Hb), 2.26 (s, 3 H; 6-CH3), 2.53 (dd, J = 19.4, 6.7 Hz, 1 H; 2-Ha), 2.70 (ddd, J = 19.0, 11.3, 7.2 Hz, 1 H; 2-Hb), 4.21 (dd, J = 12.4, 4.6 Hz, 1 H; 4-H), 6.27 (s, 1 H; 5-H), 6.41 ppm (s, 1 H; 7H); 13C NMR (125 MHz, CD3OD): d = 22.5 (6-CH3), 26.2 (C-3), 28.6 (C2), 72.4 (C-4), 85.9 (C-4a), 103.8 (C-9a), 106.2 (C-8a), 110.1 (C-5), 111.1 (C-7), 151.2 (C-6), 161.1 (C-8), 162.9 (C-10a), 173.8 (CO2H), 178.5 (C-1), 188.7 ppm (C-9); MS (ESI): m/z (%): 611.1 (7) [2MH] , 305.1 (100) [MH] ; HRMS (ESI): m/z calcd for C15H14O7: 305.0667 [MH] ; found: 305.0667. 2‘-epi-Gonitolyde C (28): A solution of chromanyl lactone 27 (16.0 mg, 47.9 mmol, 1.00 equiv) in CH2Cl2 (2.4 mL) was treated with BBr3 (0.48 mL, 1 m in CH2Cl2, 479 mmol, 10.0 equiv) at 78 8C and stirred at 78 8C for 2 h. The reaction was quenched by dropwise addition of sat. aq. NaHCO3 solution (10.0 mL) at 78 8C, the aq. layer extracted with EtOAc (3 10 mL) and the combined organic Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper [17] a) L. F. Tietze, A. Heins, M. Soleiman-Beigi, C. Raith, Heterocycles 2009, 77, 1123 – 1146; b) L. F. Tietze, J. Zinngrebe, D. A. Spiegl, F. Stecker, Heterocycles 2007, 74, 473 – 489. [18] a) Y. Uozumi, H. Kyota, E. Kishi, K. Kitayama, T. Hayashi, Tetrahedron: Asymmetry 1996, 7, 1603 – 1606; b) Y. Uozumi, K. Kato, T. Hayashi, J. Am. Chem. Soc. 1997, 119, 5063 – 5064; c) L. F. Tietze, J. K. Lohmann, Synlett 2002, 2083 – 2085. [19] L. F. Tietze, K. M. Sommer, J. Zinngrebe, F. Stecker, Angew. Chem. 2005, 117, 262 – 264; Angew. Chem. Int. Ed. 2005, 44, 257 – 259. [20] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41, 1485 – 1486. [21] a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu, X.-L. Zhang, J. Org. Chem. 1992, 57, 2768 – 2771; b) H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483 – 2547. [22] H. Becker, K. B. Sharpless, Angew. Chem. 1996, 108, 447 – 449; Angew. Chem. Int. Ed. Engl. 1996, 35, 448 – 451. [23] a) S. Inoki, K. Kato, T. Mukaiyama, Chem. Lett. 1990, 1869 – 1872; b) T. Mukaiyama, Aldrichimica Acta 1996, 29, 59 – 76; c) O. F. Jeker, E. M. Carreira, Angew. Chem. 2012, 124, 3531 – 3534; Angew. Chem. Int. Ed. 2012, 51, 3474 – 3477. [24] C. F. Nising, U. K. Ohnemller, S. Brse, Angew. Chem. 2006, 118, 313 – 315; Angew. Chem. Int. Ed. 2006, 45, 307 – 309.
[13] L. F. Tietze, S. Jackenkroll, C. Raith, D. A. Spiegl, J. R. Reiner, M. C. Ochoa Campos, Chem. Eur. J. 2013, 19, 4876 – 4882. [14] L. F. Tietze, D. A. Spiegl, F. Stecker, J. Major, C. Raith, C. Grosse, Chem. Eur. J. 2008, 14, 8956 – 8963. [15] L. F. Tietze, L. Ma, S. Jackenkroll, J. R. Reiner, J. Hierold, B. Gnanaprakasam, S. Heidemann, Heterocycles 2014, 88, 1101 – 1119. [16] For selected recent books and reviews on domino reactions, see: a) Domino Reactions—Concepts for Efficient Organic Synthesis Lutz F. Tietze (Ed), Wiley-VCH, Weinheim, 2014; b) L. F. Tietze, S.-C. Dfert, J. Hierold, in Domino Reactions: Concepts for Efficient Organic Synthesis (Ed: L. F. Tietze), Wiley-VCH, Weinheim, 2014, pp. 523 – 578; c) H. Pellissier, Chem. Rev. 2013, 113, 442 – 524; d) L. F. Tietze, M. A. Dfert, S.-C. Schild, in Comprehensive Chirality, Vol. 2 (Eds: E. M. Carreira, H. Yamamoto), Elsevier, Amsterdam, 2012, pp. 97 – 121; e) L. F. Tietze, S. Stewart, M. A. Dfert, in Modern Tools for the Synthesis of Complex Bioactive Molecules (Eds: J. Cossy, S. Arseniyades), Wiley, Hoboken, 2012, pp. 271 – 334; f) H. Pellissier, Adv. Synth. Catal. 2012, 354, 237 – 294; g) S. Giboulot, F. Liron, G. Prestat, B. Wahl, M. Sauthier, Y. Castanet, A. Montreux, G. Poli, Chem. Commun. 2012, 48, 5889 – 5891; h) M. Platon, R. Amardeil, L. Djakovitch, J.-C. Hierso, Chem. Soc. Rev. 2012, 41, 3929 – 3968; i) L. F. Tietze, A. Dfert, Pure Appl. Chem. 2010, 82, 1375 – 1392; j) L. F. Tietze, A. Dfert, in Catalytic Asymmetric Conjugate Reactions (Ed: A. Cordova), WileyVCH, Weinheim, 2010, pp. 321 – 350; k) C. Grondall, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167 – 178; l) L. F. Tietze, Chem. Rev. 1996, 96, 115 – 136.
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FULL PAPER & Natural Products L. F. Tietze,* S. Jackenkroll, J. Hierold, L. Ma, B. Waldecker && – && Highly efficient domino reactions: An enantioselective PdII-catalyzed dominoWacker/carbonylation/methoxylation reaction combined with a diastereoselective dihydroxylation reaction enables the first total syntheses of both ()-
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blennolide C and ()-gonytolide C with ee values of 99 % (see scheme). The preparation of an epimeric acid derivative of blennolide C and 2’-epi-gonytolide C are also reported.
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A Domino Approach to the Enantioselective Total Syntheses of Blennolide C and Gonytolide C
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A Domino Approach to the Enantioselective Total Syntheses of Blennolide C and Gonytolide C Lutz F. Tietze,* Stefan Jackenkroll, Judith Hierold, Ling Ma, and Bernd Waldecker[a] Dedicated to Professor Max Malacria on the occasion of his 65th birthday
second stereocentre at C-4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both the anti-isomer 14 a and the syn-isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to syn-acid 25 and 2’-epi-gonytolide C 28.
Abstract: The first enantioselective total syntheses of the tetrahydroxanthenone ()-blennolide C (ent-4) and related g-lactonyl chromanone ()-gonytolide C (ent-3) are reported. Key to the syntheses is an enantioselective domino-Wacker/ carbonylation/methoxylation reaction to set up the stereocentre at C-4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The
Introduction
1),[13] 4-dehydroxydiversonol[14] and the proposed structures of paecilin A and B[15] by using an enantioselective dominoWacker/carbonylation/methoxylation reaction. This versatile domino process[16] has also been applied to the synthesis of chromanes, dioxins and oxazins.[17] Herein, we report its application to the first enantioselective total syntheses of ()-blennolide C (ent-4), ()-gonytolide C (ent-3), as well as some related chromanones.
The rapidly growing class of tetrahydroxanthenone natural products has recently attracted increasing interest in the chemical community, fuelled by their intriguing structural features and varied biological profiles.[1] Among the most prominent members are the dimeric rugulotrosins,[2] dicerandrols[3] and secalonic acids,[4, 5] which exhibit antimicrobial, antibiotic, cytotoxic, antifungal, and antialgal activities. The monomeric series includes diversonol (1)[6] and the blennolides (Figure 1). Blennolide C (4), the structure of which was originally assigned as b-diversonolic ester, was isolated from the endophytic fungus Blennoria sp. by Krohn and co-workers.[7] In 2008, both Brse[8] and Nicolaou[9] reported biomimetic approaches to the racemic natural product; in 2011, Porco utilized a “retrobiomimetic” process in the synthesis of racemic blennolides and the related isomeric gonytolide C (3).[10] Gonytolide C (3) was isolated in 2011 from the fungus Gonytrichum sp. by Kikuchi and co-workers.[11] The chromanone with a tethered g-lactone moiety is the monomeric unit of gonytolide A (6), an innate immune promoter. Our group has recently reported the syntheses of enantiopure ()-blennolide A,[12] ()-diversonol (ent- Figure 1. Tetrahydroxanthenones and related natural products. [a] Prof. Dr. L. F. Tietze, S. Jackenkroll, Dr. J. Hierold, Dr. L. Ma, B. Waldecker Institute of Organic and Biomolecular Chemistry Georg-August-University Gçttingen Tammannstrasse 2, 37077 Gçttingen (Germany) Fax: (+ 49) 551-39-9476 E-mail: [email protected]
Results and Discussion Retrosynthetic analysis reveals that both ent-4 and ent-3 can be accessed from advanced intermediate 7 (Scheme 1). Chromanone 7 can be transformed into ent-4 by intramolecular acylation and global deprotection, while a desilylating lactonisation followed by demethylation would enable access to
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402495. Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper The conversion of 9 to chromane 8 was then investigated in the presence of a chiral BOXAX ligand, catalytic amounts of palladium(II)-trifluoroacetate and the reoxidant p-benzoquinone under an atmosphere of carbon monoxide in methanol (Table 1). In line with our syntheses of ()-diversonol (ent-1)[13] and ()-blennolide A,[12] we initially utilized the (S,S)-BnBOXAX ligand (i.e. 13, R = Bn) to induce enantioselectivity. Chromane 8 was isolated in good yield (68 %) and very good enantioselectivity (93 % ee) (Table 1, entry 1). Steric tuning at the C-4 position of the BOXAX-isoxazoline rings (cf. 13, Scheme 2) was reported to affect both the catalytic activity and the enantioselectivity.[18] Novel iBu-BOXAX ligand brought about the domino process in a similar yield (68 %) Scheme 1. Retrosynthetic analysis of ()-blennolide C (ent-4) and ()-gonytolide C (entand with excellent enantioselectivity (99 % ee) 3). (Table 1, entry 2). iPr-BOXAX, the ligand of choice in our synthesis of vitamin E,[19] gave an equally high ent-3. Synthesis of 7 may be achieved from 8 by C-4 hydroxylenantioselectivity (> 99 % ee) but a decreased yield of 62 % ation (numbering as in 4), chain elongation and benzylic oxida(entry 3). It seems that the increased bulk disturbs the coordition. The efficient access of chromane 8 from phenolic precurnation of the palladium–ligand complex to the alkene, thus sor 9, a key transformation in these total syntheses, was prolowering the catalytic activity. Indeed using the bulky tBuposed to proceed by the enantioselective domino-Wacker/carBOXAX ligand, 8 was only isolated in a moderate yield of 7 % bonylation/methoxylation reaction central to our research pro(entry 4). On the other hand, we assume that the improved gramme. enantioselectivity in the transformation of 9 compared to subOur synthesis commenced with the preparation of dominostrates lacking the benzyloxy group is due to a tighter enantioprecursor 9 from readily available orcinol (10). The six-step sefacial coordination of the catalyst to the double bond. quence required methylation, formylation, a Wittig-transformaReduction of 8 with LiAlH4 and subsequent elimination following the Grieco protocol[20] gave vinyl chromane 12 in 90 % tion to install the side chain, hydrogenation, a second Wittigtransformation to incorporate the terminal alkene and chemoyield over three steps. Direct conversion of a derivative of 9 selective cleavage of one of the methyl ethers to afford 9 in containing an ethylidene instead of the methylidene group to 62 % overall yield (Scheme 2). vinyl chromane 12 by an enantioselective Wacker oxidation had been shown to proceed with low enantioselectivity on related substrates and was therefore avoided.[12, 13] For the introduction of the hydroxyl group at C-4 a Sharpless dihydroxylation[21] was used (Table 2). Commercial AD-mix-a gave access to the desired anti-isomer 14 a, though the yield was only moderate and the anti/syn ratio of 2.4:1 unsatisfactory (Table 2, entry 1). Since the diastereoselectivity of this transformation was equally low in previous syntheses (diversonol: 3.8:1, blennolide A: 2.4:1),[12, 13] we decided to survey other commercial dihydroquinine (DHQ) ligands for their ability to carry out the dihydroxylation. Phthalazine-based (DHQ)2-PHAL, the chiral ligand present in the commercial mix, gave the expected low selectivity (1:8:1) albeit a higher yield when compared with the premixed AD-mix-a (entry 2). Use of pyrimidine-based (DHQ)2-Pyr and the monomerScheme 2. Synthesis of vinyl chromane 12: a) Me2SO4, K2CO3, acetone, 60 8C, 24 h, 96 %; ic “first generation” ligand DHQ-MEQ resulted in an inb) 1) nBuLi, TMEDA, Et2O, 0 to 45 8C, 3 h, 2) DMF, RT, 3 h, 92 %; c) 1-(benzyloxy)-3-(triphecreased anti/syn ratio of 4.3:1 and 6.7:1, respectively nylphosphoranylidene)propan-2-one, toluene, 120 8C, 19.5 h, 89 %; d) 1) H2 (1 atm.), (entries 3–4). The best result was obtained by em4 mol % PtO2, EtOAc, RT, 2 h, 2) IBX, CH3CN, 80 8C, 1 h, 91 % (2 steps); e) Ph3PCH3Br, nBuLi, THF, RT, 4 h, 93 %; f) NaSEt, DMF, 120 8C, 21 h, 87 % (92 % based on recovered starting maploying anthraquinone-based (DHQ)2-AQN,[22] which terial (brsm)); g) see Table 1; h) LiAlH4, Et2O, 0 8C to RT, 2 h, 100 %; i) nBu3P, o-NO2gave 14 a in 77 % yield and an excellent selectivity of C6H4SeCN, THF, 0 8C, 4 h, j mCPBA, Na2HPO4·2 H2O, CH2Cl2, 40 8C, 1 h, iPr2NH, 40 8C to 13.7:1 (entry 5). The obtained diastereomers 14 a and RT, 15 h, 90 % (2 steps). IBX = 2-iodoxybenzoic acid; TMEDA = N,N,N’,N’-tetramethylethyle14 b were readily separable by preparative HPLC. nediamine. &
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Full Paper intrinsic diastereofacial preference of the olefin substrate, thus a lower diastereoselectivity seems plausible. Diastereomer 14 a, displaying the anti-configuration present in the targeted natural products, was then silylated at both hydroxyl groups by using (tert-butyldimethylsilyl)trifluoromethanesulphonate (Scheme 3). Selective deprotection of the primary alcohol and subsequent oxidation with DMP provided aldehyde 15 in 78 % yield (89 % based on recovered starting material (brsm)) over three steps. Chain elongation by Wittig– Horner reaction with trimethyl phosphonoacetate gave the corresponding a,b-unsaturated methyl ester as a mixture of E/ Z-isomers (4:1). Reduction of the double bond with concomitant cleavage of the benzyl ether under hydrogenolytic conditions yielded primary alcohol 16, which was converted to methyl ester 17, by using a stepwise oxidation sequence. At this stage, it was necessary to oxidize 16 at the benzylic chromane position (C-9) without affecting the competing benzylic methyl group (C-6, cf. numbering in 4, Figure 1). A related direct oxidation in our total synthesis of ()-diversonol was plagued by low yields;[13] instead we applied a more suitable and higher-yielding three-step procedure. Accordingly, chromane 17 was dehydrogenated to the corresponding chromene with 2,3-dichloro-5,6-dicyanobenzoquinone, which was hydroxylated in the presence of phenylsilane, oxygen and catalytic amounts of [Mn(dmp)3],[23] and further oxidized with perruthenate and NMO[24] to afford chromanone 7 in 80 % yield over the three steps. At this junction, 7 was modified following two different pathways, allowing access to both ()-blennolide C (ent-4) and ()-gonytolide C (ent-3). For the total synthesis of ()-blennolide C, 7 was treated with trichlorotitanium isopropoxide and triethylamine in dichloromethane at 0 8C to give the tetrahydroxanthenone scaffold in 84 % yield (Scheme 4). Though we observed some epimerisation at C-4a (18 a/18 b 9.5:1), the diastereomers were separable by standard column chromatography. Unfortunately the subsequent silyl deprotection of 18 a was again afflicted by epimerisation. Thus, both the conditions we applied in the total synthesis of diversonol (HF·py, 30 8C, 5 d)[13] and blennolide A (HF·3 Et3N, 50 8C, 6 d)[12] led to complete epimerisation, while basic deprotection conditions using tetrabutylammonium fluoride (TBAF) or tris(dimethylamino)sulfur trimethylsilyl difluoride (TASF) resulted in decomposition of 18 a. As the undesired syn-isomer is likely stabilised through intramolecular hydrogen bonding, the presence of water was predicted to suppress epimerisation. Indeed, treatment of 18 a with aqueous fluorosilicic acid gave 19 in 56 % yield and an anti/syn ratio of 10.5:1. While it was possible to separate the epimers at this stage by using reverse-phase HPLC (H2O/MeOH), we decided to conduct the final step of the synthesis with the mixture. Thus, treatment of 19 with BBr3 gave ()-blennolide C (ent-4) in a yield of 60 %, alongside 6 % of a syn-isomer. The ester group of the syn-isomer was hydrolysed to the corresponding acid under the reaction conditions (vide infra), allowing separation from ent-4 by HPLC. Reversing the order of silyl-/methyldeprotection was also investigated. When 18 a was treated with BBr3, phenol 20 was isolated in 86 % with no observable epimerisation. Desilylation with fluorosilicic acid then provided
Table 1. Enantioselective domino-Wacker/carbonylation/methoxylation.
Yield [%][a]
Entry
Ligand 13
1 2 3 4
(S,S)-Bn-BOXAX (S,S)-iBu-BOXAX (S,S)-iPr-BOXAX (S,S)-tBu-BOXAX
ee [%][b]
68 68 62 7
93 99 > 99 –[c]
[a] Isolated yield following flash column chromatography. [b] Determined by HPLC (Chiracel IB, nHex/iPrOH 98:2, 234 nm). [c] Not determined.
Table 2. Diastereoselective dihydroxylation of 12.
Entry 1 2 3 4 5 6 7 8 9 10 11 12
Ligand [c]
– (DHQ)2-PHAL (DHQ)2-Pyr DHQ-MEQ (DHQ)2-AQN –[d] (DHQD)2-PHAL (DHQD)2-Pyr DHQD-CLB DHQD-MEQ (DHQD)2-AQN DHQD-PHN
t [d] 4 2 2 2 3 3 2 2 2 2 3 2
Yield [%][a]
Ratio (14 a/14 b)[b]
64 82 90 84 77 94 80 90 90 89 93 88
2.4:1 1.8:1 4.3:1 6.7:1 13.7:1 1:1.7 1:2.2 1:1.9 1:1.5 1:3.1 1:3.0 1:3.7
[a] Isolated yield following flash column chromatography. [b] Separation of the diastereomers by HPLC (IB column, nHex/iPrOH (96:4)). [c] Commercial ADmix-a used. [d] Commercial AD-mix-b used.
For an entry to the C-4 epimer of blennolide C, the monomeric unit of the rugulotrosins, we also investigated the selective preparation of syn-isomer 14 b. Commercial AD-mix-b afforded the diol in an excellent yield of 94 %; however, the selectivity was poor (14 a/14 b 1:1.7) (Table 2, entry 6). Similar results were obtained by separate addition of the AD-mix components as well as by replacing the (DHQD)2-PHAL ligand with (DHQD)2-Pyr or monomeric ligand DHQD-CLB (entries 7–9). DHQD-MEQ gave an increased diastereoselectivity of 1:3.0, comparable with that observed for (DHQD)2-AQN (1:3.1) (entries 10–11). The best result was obtained with the monocinchona alkaloid DHQD-PHN, which favoured the syn-isomer 14 b with a ratio of 1:3.7 (Table 2, entry 12). It should be noted that for the synthesis of 14 b, the chiral ligand has to override the Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper sponding to the methyl ester moiety. Thus, instead of the 4-epimer of blennolide C, acid 25 had been obtained in a yield of 44 %, presumably formed by blactone intermediate 24. To complete the total synthesis of gonytolide C, chromanone 7 was treated with triethylamine trihydrofluoride in dioxane at 60 8C (Scheme 6). Cleavage of the silyl ether and exclusive in situ formation of the g- over the b-lactone furnished 26 in a very good yield of 87 %, which was then demethylated with BBr3 to give rise to ()-gonytolide C (ent-3). Again, the spectroscopic data matched those reported for Scheme 3. Synthesis of chromanone 7: a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 2.5 h, 96 %; natural 3. The optical rotation was determined to be b) HF·py, THF/py (5:1), RT, 24 h, 85 %, (97 % brsm); c) DMP, CH2Cl2, 0 8C to RT, 2 h, 96 %; 28.5 (c = 0.10 in CHCl3, 24.7 8C) relative to + 25.1 d) NaH, (MeO)2P(O)CH2CO2Me, THF, 0 8C, 30 min, then 15, THF, 0 8C to RT, 2 h; e) 10 mol % (c = 0.184, CHCl3) published by Kikuchi,[11] showing Pd/C, H2 (4 bar), MeOH, 2 d, 90 % (2 steps); f) DMP, CH2Cl2, 0 8C to RT, 2 h, 92 %; g) KOH, I2, that we have synthesized the enantiomer of the natMeOH, 0 8C to RT, 9 h, 100 %; h) DDQ, benzene, reflux, 3 h, 87 %; i) 30 mol % [Mn(dpm)3], PhSiH3, O2 (1 atm.), MeOH, 50 8C, 24 h; j) 20 mol % TPAP, NMO, CH2Cl2/CH3CN (3:1), 4 ural product. It should be noted that natural MS, 24 h, 92 % (2 steps). DMP = Dess-Martin periodinane; NMO = N-methylmorpholine-N(+)-blennolide C (4) and (+)-gonytolide C (3) are oxide; TPAP = tetrapropylammonium perruthenate. readily accessible by completing our synthetic sequence with an (R,R)-BOXAX ligand. Lastly, we converted chromanone 21 to 2’-epi-gonytolide 28, a diastereomer of 3. A desilylating lactonisation of 21 by using triethylamine trihydrofluoride yielded 27 in 84 %, which was then treated with BBr3 to give 28 in 86 % yield.
Conclusion We have achieved the first enantioselective total syntheses of ()-blennolide C (ent-4) and ()-gonytolide C (ent-3). Key to the syntheses was an enantioselective domino-Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre, the hydroxyl group at C-4, was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both anti- 14 a and syn-isomer 14 b in very good selectivities of 13.8:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to synacid 25 and 2’-epi-gonytolide C 28.
Scheme 4. Synthesis of ()-blennolide C (ent-4): a) Ti(OiPr)Cl3, Et3N, CH2Cl2, 0 8C, 1 h, 59 % of pure 18 a plus 25 % of a mixture of 18 a/18 b (2.2:1); b) aq. H2SiF6, DMF, 50 8C, 6 d, 56 % (anti/syn = 10.5:1); c) BBr3, CH2Cl2, RT, 1 h, 60 %; d) BBr3, CH2Cl2, 78 to 0 8C, 4 h, 86 %; e) aq. H2SiF6, DMF, 50 8C, 6 d, 50 %.
()-blennolide C (ent-4) in 50 % yield, alongside 17 % of the syn acid. All spectroscopic data are in complete agreement with the published information of natural (+)-blennolide C (4). We have prepared ent-4 with an optical rotation of 175.3 (c = 0.20 in CHCl3, 22.7 8C), which is slightly lower than the value of + 181.7 (c = 0.06 in CHCl3, 25 8C) reported by Krohn.[7] For an entry to the 4-epimer of blennolide C, syn-diol 14 b was converted to chromanone 21 by using the sequence established for ent-4 (Scheme 5). Both the intramolecular acylation of 21 to 22 and the desilylation to afford 23 proceeded smoothly without any epimerisation at C-4a. To our surprise, the crude 1H NMR spectra of the product isolated after the final methyl ether cleavage with BBr3 lacked the signal corre&
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Experimental Section Experimental procedures and spectroscopic data of key intermediates 7, 8, 12, 14 a, (S,S)-iBu-BOXAX ligand 13, ()blennolide C (ent-4), 25, ()-gonytolide C (ent-3) and 2’-epigonytolide (28): The syntheses of all other new compounds including the analytical data can be found in the Supporting Information. ()-Gonytolide C (ent-3): BBr3 (0.44 mL, 1 m in CH2Cl2, 440 mmol, 10.0 equiv) was added to a stirred solution of chromanyl lactone 26 (14.7 mg, 44.0 mmol, 1.00 equiv) in CH2Cl2 (2.2 mL) at 78 8C and stirring was continued at 78 8C for 2 h. The reaction was quenched by dropwise addition of sat. aq. NaHCO3 (10 mL) at 78 8C, the aq. layer extracted with EtOAc (3 10 mL), and the
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Scheme 5. Attempted synthesis of the 4-epimer of blennolide (4) with observed demethylation: a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 2.5 h, 98 %; b) HF·py, THF/py (5:1), RT, 30 h, 81 % (89 % brsm); c) DMP, CH2Cl2, 0 8C to RT, 2 h, 98 %; d) NaH, (MeO)2P(O)CH2CO2Me, THF, 0 8C, 30 min, then aldehyde, THF, 0 8C to RT, 2 h; e) 10 mol % Pd/C, H2 (4 bar), AcOH, MeOH, 80 h, 91 % (2 steps); f) DMP, CH2Cl2, 0 8C to RT, 1.5 h, 93 %; g) KOH, I2, MeOH, 0 8C to RT, 6.5 h, 96 %; h) DDQ, benzene, reflux, 3 h, 77 %; i) 30 mol % [Mn(dpm)3], PhSiH3, O2 (1 atm.), MeOH, 50 8C, 30 h; j) 20 mol % TPAP, NMO, CH2Cl2/CH3CN (3:1), 4 MS, RT, 24 h, 85 % (2 steps); k) Ti(OiPr)Cl3, Et3N, CH2Cl2, 0 8C, 2 h, 73 %; l) aq. H2SiF6, DMF, 50 8C, 6 d, 96 %; m) BBr3, CH2Cl2, RT, 1 h, 44 %. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
()-Blennolide C (ent-4): A stirred solution of tetrahydroxanthenone 20 (28.4 mg, 65.4 mmol, 1.00 equiv) in DMF (2.3 mL) was treated with H2SiF6 (0.84 mL, 23 wt. % in H2O, 1.63 mmol, 25.0 equiv) at RT and stirring was continued at 50 8C for 3 d. Additional H2SiF6 (0.84 mL, 23 wt. % in H2O, 1.63 mmol, 25.0 equiv) was added at RT and the mixture stirred at 50 8C for a further 3 d. The reaction was quenched by addition of H2O (10.0 mL) at 0 8C, the aq. layer extracted with MTBE (3 5 mL) and the combined organic phases were dried over Na2SO4. After column chromatography on silica gel (CH2Cl2/MeOH 100:1!5:1), ()-blennolide C (ent-4) was obtained alongside ent-25 as a white solid (13.7 mg, 43.3 mmol, 66 %, ent-4/ent-25 = 3:1). Purification by RP-HPLC (Jasco Kromasil 100-C18, 4.6 250 mm, 5 mm, eluent: H2O (A)/ MeOH (B), gradient: 0–30 min: 50A/50B!0A/100B, 30– 40 min: 0A/100B!50A/B50, flow: 0.8 mL min1, tR = 16.4 min) furnished ()-blennolide C (ent-4) as a white solid. [a]D = 175.3 (c = 0.20 in CHCl3, 22.7 8C); 1H NMR (600 MHz, CDCl3): d = 1.93 (mc, 1 H; 3-Ha), 2.12 (mc, 1 H; 3Hb), 2.27 (s, 3 H; 6-CH3), 2.36 (ddd, J = 19.2, 6.9, 1.3 Hz, 1 H; 2-Ha), 2.67 (s, 1 H; 4-OH), 2.80 (ddd, J = 18.8, 11.3, 7.0 Hz, 1 H; 2-Hb), 3.67 (s, 3 H; CO2CH3), 4.29 (s, 1 H; 4-H), 6.32 (s, 1 H; 5-H), 6.36 (s, 1 H; 7-H), 11.25 (s, 1 H; 8-OH), 14.02 ppm (s, 1 H; 1-OH); 13C NMR (125 MHz, CDCl3): d = 22.5 (6-CH3), 23.1 (C-3), 24.3 (C-2), 53.4 (CO2CH3), 67.0 (C4), 83.8 (C-4a), 100.1 (C-9a), 104.9 (C-8a), 108.7 (C-5), 111.7 (C-7), 149.9 (C-6), 157.6 (C-10a), 161.9 (C-8), 171.2 (CO2CH3), 179.1 (C-1), 186.9 ppm (C-9); IR: n˜ = 3484, 2922, 2852, 1740, 1613, 1571, 1456, 1416, 1363, 1298, 1256, 1239, 1206, 1149, 1111, 1078, 1051, 957, 879, 837, 819, 736, 568 cm1; UV (MeOH): lmax (lg e) = 279 (3.4955), 333 nm (4.0719); MS (ESI): m/z (%): 663.2 (44) [2M+Na] + , 343.1 (100) [M+Na] + , 321.1 (36) [M+H] + ; HRMS (ESI): m/ z: calcd for C16H16O7: 321.0969 [M+H] + ; found: 321.0966.
Methyl (2S,1’R)-2-[1-(tert-butyldimethylsilyloxy)-4-methoxy-4-oxobutyl]-5-methoxy-7-methyl-4-oxochroman2-carboxylate (7): A stirred solution of methyl (2S,1’R)-2Scheme 6. Synthesis of ()-gonytolide C (ent-3) and the diastereomeric 2’-epi-gonytoli[1-(tert-butyldimethylsilyloxy)-4-methoxy-4-oxobutyl]-5de C (28): a) 3 HF·Et3N, dioxane, 60 8C, 6 d, 87 %; b) BBr3, CH2Cl2, 78 8C, 2 h, 77 %; methoxy-7-methyl-2H-chromene-2-carboxylate (240 mg, c) 3 HF·Et3N, dioxane, 60 8C, 6 d, 84 %; d) BBr3, CH2Cl2, 78 8C, 2 h, 86 %. 517 mmol, 1.00 equiv) in MeOH (12 mL) was treated with [Mn(dpm)3] (32 mg, 51.7 mmol, 10 mol %) at RT and oxygen was passed through the resulting mixture for 20 min. PhSiH3 (1.30 mL, 10.3 mmol, 20.0 equiv) was added by sycombined organic phases were dried over Na2SO4. After column ringe pump (0.06 mL min1), while the reaction mixture was stirred chromatography on silica gel (n-pentane/EtOAc 2:1!1:2), ()-gounder an atmosphere of O2 (1 atm.) at 50 8C. Additional [Mn(dpm)3] nytolide C (ent-3) was obtained as a white solid (10.9 mg, (32 mg, 51.7 mmol, 10 mol %) was added after 8 and 16 h. After stir34.0 mmol, 77 %). [a]D = 28.5 (c = 0.10 in CHCl3, 24.7 8C); 1H NMR ring at 50 8C for a further 8 h (overall 24 h), the reaction was (600 MHz, CDCl3): d = 2.29 (s, 3 H; 7-CH3), 2.41 (mc, 2 H; 3’-H2), 2.57 quenched by adsorption on silica gel. Evaporation of the solvent (ddd, J = 17.7, 10.2, 6.6 Hz, 1 H; 4’-Ha), 2.69 (ddd, J = 17.2, 9.9, and column chromatography on silica gel (n-hexane/EtOAc 10:1! 7.1 Hz, 1 H; 4’-Hb), 2.93 (d, J = 16.9 Hz, 1 H; 3-Ha), 3.09 (d, J = 1:1) furnished two diastereomeric alcohols (157 mg, 325 mmol, 16.9 Hz, 1 H; 3-Hb), 3.72 (s, 3 H; CO2CH3), 4.84 (dd, J = 8.0, 5.7 Hz, 63 %) and (83 mg, 172 mmol, 33 %) as colourless oils. A solution of 1 H; 2‘-H), 6.36 (s, 1 H; 8-H), 6.38 (s, 1 H; 6-H), 11.36 ppm (s, 1 H; 513 the diastereomeric alcohols (157 mg, 325 mmol, 0.65 equiv) and OH); C NMR (125 MHz, CDCl3): d = 22.0 (C-3’), 22.6 (7-CH3), 27.6 (C(83 mg, 172 mmol, 0.35 equiv) in CH2Cl2 (22.5 mL) and CH3CN 4’), 39.4 (C-3), 53.6 (CO2CH3), 80.9 (C-2’), 84.0 (C-2), 105.6 (C-4a), (7.5 mL) in the presence of 4 molecular sieves (400 mg) was 108.5 (C-8), 111.1 (C-6), 151.6 (C-7), 159.0 (C-8a), 161.8 (C-5), 169.0 treated with NMO (150 mg, 1.24 mmol, 2.50 equiv) at 0 8C and then (CO2CH3), 175.5 (C-5’), 193.0 ppm (C-4); IR: n˜ = 2924, 2853, 1785, stirred at 0 8C for a further 5 min. TPAP (17.5 mg, 47.9 mmol, 1759, 1738, 1644, 1570, 1455, 1366, 1262, 1120, 1131, 1074, 1055, 10 mol %) was added at 0 8C and the resulting reaction mixture 1033, 935, 837, 800, 734, 702, 555 cm1; UV (CH3CN): lmax (lg e) = stirred at RT for 12 h. Additional NMO (150 mg, 1.24 mmol, 277 (3.9702), 344 nm (3.3917); MS (ESI): m/z (%): 663.2 (50) 2.50 equiv) and TPAP (17.5 mg, 47.9 mmol, 10 mol %) were added at + + + [2M+Na] , 658.2 (10) [2M+NH4] , 343.1 (85) [M+Na] , 338.1 (29) 0 8C and the resulting reaction mixture stirred at RT for a further + + [M+NH4] , 321.1 (100) [M+H] ; HRMS (ESI): m/z calcd for C16H16O7: 12 h. After adsorption on silica gel, evaporation of the solvent and + 321.0969 [M+H] ; found: 321.0970. column chromatography on silica gel (n-pentane/EtOAc 4:1!3:1) Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper chromanone 7 (228 mg, 474 mmol, 95 %, 92 % over 2 steps) was obtained as a colourless oil. [a]D = 71.3 (c = 0.20 in CHCl3, 25 8C); 1 H NMR (600 MHz, CDCl3): d = 0.08 (s, 3 H; Si(CH3)a), 0.14 (s, 3 H; Si(CH3)b), 0.85 (s, 9 H; SiC(CH3)3), 1.66 (mc, 2 H; 2’-H2), 2.30 (s, 3 H; 7CH3), 2.36 (dt, J = 16.2, 7.9 Hz, 1 H; 3’-Ha), 2.52 (ddd, J = 16.2, 7.6, 6.4 Hz, 1 H; 3’-Hb), 2.96 (d, J = 16.6 Hz, 1 H; 3-Ha), 3.10 (d, J = 16.6 Hz, 1 H; 3-Hb), 3.65 (s, 6 H; 4’-OCH3, 2-CO2CH3), 3.85 (s, 3 H; 5OCH3), 4.13 (dd, J = 6.8, 5.3 Hz, 1 H; ’-H), 6.30 (s, 1 H; 8-H), 6.42 ppm (s, 1 H; 6-H); 13C NMR (125 MHz, CDCl3): d = 4.7, 3.7 (Si(CH3)a, Si(CH3)b), 18.3 (SiC), 22.4 (7-CH3), 26.0 (SiC(CH3)3), 27.4 (C-2’), 30.3 (C-3’), 39.2 (C-3), 51.6 (4’-OCH3), 53.0 (2-CO2CH3), 56.1 (5-OCH3), 74.3 (C-1’), 87.2 (C-2), 105.8 (C-6), 108.6 (C-4a), 110.5 (C-8), 147.9 (C-7), 160.4, 160.8 (C-5, C-8a), 170.6 (2-CO2CH3), 173.3 (C-4’), 188.7 ppm (C-4); IR: n˜ = 2953, 2928, 2855, 1738, 1686, 1614, 1568, 1463, 1436, 1415, 1389, 1251, 1222, 1124, 1107, 1055, 993, 833, 777, 689 cm1; UV (CH3CN): lmax (lg e) = 219 (4.2702), 268 (3.9879), 324 nm (3.6228); MS (ESI): m/z (%): 983.4 (24) [2M+Na] + , 503.2 (49) [M+Na] + , 481.2 (100) [M+H] + ; HRMS (ESI): m/z calcd for C24H36O8Si: 481.2252 [M+H] + ; found: 481.2247.
treated with Na2HPO4·2 H2O (3.59 g, 20.2 mmol, 5.00 equiv) and meta-chloroperoxybenzoic acid (mCPBA) (2.48 g, 70 %, 10.1 mmol, 2.50 equiv) at 40 8C and stirred at this temperature for 1 h. Diisopropylamine (2.82 mL, 20.2 mmol, 5.00 equiv) was added at 40 8C and the reaction mixture warmed to RT within 15 h. The reaction mixture was adsorbed on silica gel and the solvent removed under reduced pressure. Column chromatography on silica gel (n-pentane/EtOAc 100:0!90:10) furnished vinyl chromane 12 as a yellow oil (1.18 g, 3.62 mmol, 90 %). [a]D = 72.0 (c = 0.50 in CHCl3, 23.7 8C); 1H NMR (600 MHz, CDCl3): d = 1.91 (ddd, J = 13.6, 6.1, 4.0 Hz, 1 H; 3-Ha), 1.99 (ddd, J = 13.6, 11.0, 5.6 Hz, 1 H; 3-Hb), 2.28 (s, 3 H; 7-CH3), 2.39 (ddd, J = 17.1, 10.9, 6.2 Hz, 1 H; 4-Ha), 2.68 (dt, J = 16.8, 4.8 Hz, 1 H; 4-Hb), 3.52 (d, J = 10.0 Hz, 1 H; CHaOBn), 3.57 (d, J = 10.0 Hz, 1 H; CHbOBn), 3.77 (s, 3 H; 5-OCH3), 4.60 (d, J = 12.3 Hz, 1 H; OCHaPh), 4.63 (d, J = 12.3 Hz, 1 H; OCHbPh), 5.16 (dd, J = 10.9, 1.4 Hz, 1 H; 2’-Hcis), 5.25 (dd, J = 17.3, 1.4 Hz, 1 H; 2’-Htrans), 5.84 (dd, J = 17.3, 10.9 Hz, 1 H; 1’-H), 6.22 (s, 1 H; 8-H), 6.41 (s, 1 H; 6-H), 7.27 (mc, 1 H; Ph-Hp), 7.32 ppm (mc, 4 H; Ph-Ho, Ph-Hm); 13C NMR (125 MHz, CDCl3): d = 16.0 (C-4), 21.6 (7-CH3), 26.6 (C-3), 55.3 (5OCH3), 73.6 (OCH2Ph), 75.5 (CH2OBn), 78.7 (C-2), 102.8 (C-8), 107.7 (C-4a), 110.0 (C-6), 116.1 (C-2’), 127.5 (Ph-Cp), 127.6, 128.3 (Ph-Co, Ph-Cm), 136.9 (C-7), 137.9 (C-1’), 138.4 (Ph-Ci), 154.1, 157.4 ppm (C-5, C-8a); IR: n˜ = 2932, 2854, 1616, 1584, 1497, 1453, 1410, 1351, 1320, 1291, 1227, 1196, 1135, 1099, 1026, 991, 927, 812, 734, 696, 580, 550 cm1; UV (CH3CN): lmax (lg e) = 207 (4.6903), 271 nm (2.9781); MS (ESI): m/z (%): 671.3 (86) [2M+Na] + , 666.4 (56) [2M+NH4] + , 347.2 (48) [M+Na] + , 342.2 (13) [M+NH4] + , 325.2 (100) [M+H] + ; HRMS (ESI): m/z calcd for C21H24O3 : 325.1798 [M+H] + ; found: 325.1796.
Methyl (2S)-2-(2-benzyloxymethyl-5-methoxy-7-methylchroman2-yl)acetate (8): A solution of palladium(II)-trifluoroacetate (2.7 mg, 8.1 mmol, 5 mol %) and (S,S)-iBu-BOXAX 13 (16.2 mg, 32.1 mmol, 20 mol %) in MeOH (0.5 mL) was stirred at RT for 15 min before being transferred to alkenylphenol 9 (50 mg, 160 mmol, 1.00 equiv) by syringe (rinsing with 0.5 mL MeOH). p-Benzoquinone (71 mg, 640 mmol, 4.00 equiv) was added and the reaction stirred under an atmosphere of CO (1 atm.) at RT for 24 h. The reaction mixture was poured into 1 n aq. HCl (10 mL) and the aq. layer was extracted with MTBE (methyl tert-butyl ether) (3 5 mL). The combined organic phases were washed with 1 n aq. NaOH (3 5 mL), dried over Na2SO4 and evaporated in vacuo. Column chromatography on silica gel (n-pentane/EtOAc 25:1!10:1) furnished methyl ester 8 as a colourless oil that solidified under vacuum (40.5 mg, 109 mmol, 68 %); analytical HPLC: Daicel Chirapak IB, 4.6 250 mm, eluent: nhexane/2-PrOH 98:2, flow: 0.8 mL min1, wavelength: 234 nm, tR = 11.0 min ()-(R)-8, 0.7 %, tR = 14.2 min (+)-(S)-8, 99.3 %, 99 % ee. [a]D = + 0.9 (c = 0.18 in CHCl3, 22.9 8C); 1H NMR (600 MHz, CDCl3): d = 2.01 (mc, 2 H; 3-H2), 2.26 (s, 3 H; 7-CH3), 2.58 (mc, 2 H; 4-H2), 2.71 (d, J = 15.0 Hz; 2’-Ha), 2.82 (d, J = 14.4 Hz; 2’-Hb), 3.61 (s, 3 H; CO2CH3), 3.65 (d, J = 3.0 Hz, 2 H; CH2OBn), 3.78 (s, 3 H; 5-OCH3), 4.53 (d, J = 12.0 Hz; OCHaPh), 4.61 (d, J = 12.0 Hz; OCHbPh), 6.23 (s, 1 H; 8-H), 6.33 (s, 1 H; 6-H), 7.25–7.34 ppm (m, 5 H; 5 PhH); 13C NMR (125 MHz, CDCl3): d = 15.8 (C-4), 21.6 (7-CH3), 26.2 (C-3), 39.3 (C-2’), 51.5 (CO2CH3), 55.4 (5-OCH3), 72.7 (CH2OBn), 73.6 (OCH2Ph), 76.27 (C-2), 103.1 (C-8), 107.2 (C-4a), 110.4 (C-6), 127.5, 127.6, 128.3 (PhCo, Ph-Cm, PhCp), 137.2 (C-7), 138.2 (PhCi), 153.3, 157.5 (C-5, C8a), 170.8 ppm (C-1’); IR: n˜ = 2923, 2360, 2885, 1728, 1579, 1316, 1223, 1094, 824, 750, 701 cm1; UV (CH3CN): lmax (lg e) = 208 (4.7849), 272 (3.0529), 279 nm (3.0219); MS (ESI): m/z (%): 763.3 (75) [2M+Na] + , 393.2 (100) [M+Na] + ; HRMS (ESI): m/z calcd for C22H26O5 : 393.1672 [M+Na] + ; found: 393.1677.
(S)-2,2’-Bis-[(4S)-iso-butyl)-4,5-dihydrooxazol-2-yl]-1,1’-binaphthalene (13, R = iBu): A solution of (4’S)-2-(1-bromonaphthalen-2yl)-4-isobutyl-4,5-dihydrooxazole (2.00 g, 6.02 mmol, 1.00 equiv) in pyridine (46 mL, distilled over calcium hydride) was treated with activated copper powder (1.15 g, 18.1 mmol, 3.00 equiv) at RT and the reaction mixture heated at reflux for 11 h. After cooling to RT, the solvent was evaporated in vacuo, the residue taken up in CH2Cl2 (100 mL) and filtered over Celite (rinsing with CH2Cl2). The filtrate was washed with conc. NH3 solution (3 100 mL) until the organic layer was colourless. The organic phase was dried over Na2SO4 and evaporated in vacuo. Purification of the residue by column chromatography on silica gel (n-pentane/EtOAc 100:1! 9:1) and HPLC (Jasco LiChrosorb, n-hexane/2-PrOH 99:1) furnished the targeted (S,S)-iBu-BOXAX-ligand (0.73 g, 1.45 mmol, 48 %). Alternatively, the (S,S)-iBu-BOXAX-ligand can be purified by recrystallization from 2-PrOH. Analytical HPLC: Jasco LiChrosorb Si60, 4.6 250 mm, 5 mm, eluent: n-hexane/2-PrOH 99:1, flow: 0.8 mL min1, tR = 7.0 min. Preparative HPLC: Jasco LiChrosorb Si60, 20 250 mm, 7 mm, eluent: n-hexane/2-PrOH 99:1, flow: 10 mL min1, wavelength: 233 nm, tR = 10.4 min. [a]D = 199.5 (c = 0.48 in CHCl3); 1 H NMR (600 MHz, CDCl3): d = 0.70 (d, J = 6.6 Hz, 6 H; 2’’-CH3,a), 0.74 (d, J = 6.6 Hz, 6 H; 2’’-CH3,b), 0.82 (dt, J = 13.3, 7.3 Hz, 2 H; 1’’-Ha), 1.05 (dt, J = 13.6, 6.9 Hz, 2 H; 1’’-Hb), 1.33 (dp, J = 13.4, 6.7 Hz, 2 H; 2’’-H), 3.42 (t, J = 7.7 Hz, 2 H; 5’-Ha), 3.76 (dd, J = 9.2, 8.0 Hz, 2 H; 5’Hb), 3.89 (dq, J = 9.2, 7.2 Hz, 2 H; 4’-H), 7.22 (mc, 4 H, 6-H; 7-H), 7.44 (ddd, J = 8.0, 5.1, 2.8 Hz, 2 H; 5-H), 7.88 (d, J = 8.2 Hz, 2 H; 8-H), 7.92 (d, J = 8.6 Hz, 2 H; 4-H), 8.03 ppm (d, J = 8.7 Hz, 2 H; 3-H); 13C NMR (150 MHz, CDCl3): d = 22.5, 22.6 (2’’-CH3,a, 2’’-CH3,b), 25.0 (C-2“), 45.0 (C-1”), 64.7 (C-4’), 72.8 (C-5’), 126.0 (C-8), 126.1, 126.3, 126.7, 127.0 (C-3, C-5, C-6, C-7), 127.5, 127.8 (C-4, C-8a), 132.9, 134.2 (C-2, C-4a), 137.8 (C-1), 163.7 ppm (C-2’); IR: n˜ = 2953, 2916, 2891, 2866, 2360, 2341, 1656, 1505, 1468, 1379, 1364, 1296, 1243, 1233, 1103, 982, 951, 909, 854, 823, 753, 738, 569 cm1; UV (CH3CN): lmax (lg e) = 228 (4.8388), 288 (4.1057), 336 (3.3266), 370 nm (2.5677); MS (ESI): m/z
(2S)-2-Benzyloxymethyl-5-methoxy-7-methyl-2-vinylchromane (12): A solution of chromanyl alcohol 11 (1.38 g, 4.03 mmol, 1.00 equiv) in THF (50 mL) was treated with 2-nitrophenyl selenocyanate (1.83 g, 8.06 mmol, 2.00 equiv) and nBu3P (2.00 mL, 7.70 mmol, 1.91 equiv) at 0 8C and stirred at 0 8C for 1.5 h. Additional 2-nitrophenyl selenocyanate (458 mg, 2.02 mmol, 0.50 equiv) and PnBu3 (0.50 mL, 1.93 mmol, 0.48 equiv) were added at 0 8C and stirring was continued at 0 8C for 2.5 h. The reaction was quenched by addition of sat. aq. NaHCO3 solution (180 mL) at 0 8C and the aq. layer extracted with MTBE (5 50 mL). The combined organic phases were dried over Na2SO4 and the solvent evaporated in vacuo. A suspension of the crude product in CH2Cl2 (80 mL) was
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Full Paper (%): 505.3 (100) [M+H] + ; HRMS (ESI): m/z calcd for C34H36N2O2 : 505.2850 [M+H] + ; found: 505.2851.
phases were dried over Na2SO4. After column chromatography on silica gel (n-pentane/EtOAc = 2:1!1:3), 2’-epi-gonytolide C (28) was obtained as a white solid (13.2 mg, 41.2 mmol, 86 %). [a]D = 32.4 (c = 0.10 in CHCl3, 22.5 8C); 1H NMR (600 MHz, CDCl3): d = 2.28 (s, 3 H; 7-CH3), 2.28–2.35 (m, 1 H; 3’-Ha), 2.47 (mc, 1 H; 3’-Hb), 2.55 (ddd, J = 17.7, 10.5, 4.9 Hz, 1 H; 4’-Ha), 2.79 (ddd, J = 17.9, 10.2, 4.9 Hz, 1 H; 4’-Hb), 3.04 (d, J = 17.2 Hz, 1 H; 3-Ha), 3.43 (d, J = 17.3 Hz, 1 H; 3-Hb), 3.72 (s, 3 H; CO2CH3), 4.75 (dd, J = 8.5, 4.1 Hz, 1 H; 2’-H), 6.34 (s, 1 H; 8-H), 6.35 (s, 1 H; 6-H), 11.39 ppm (s, 1 H; 5OH); 13C NMR (125 MHz, CDCl3): d = 21.7 (C-3’), 22.6 (7-CH), 27.8 (C4’), 40.3 (C-3), 53.7 (CO2CH3), 79.7 (C-2’), 84.6 (C-2), 105.5 (C-4a), 108.3 (C-8), 111.0 (C-6), 151.2 (C-7), 158.9 (C-8a), 161.7 (C-5), 169.1 (CO2CH3), 176.0 (C-5’), 194.0 ppm (C-4); IR: n˜ = 3358, 2955, 1773, 1741, 1636, 1568, 1455, 1359, 1288, 1263, 1207, 1181, 1120, 1087, 1064, 1030, 837, 807, 743, 704 cm1; UV (MeOH): lmax (lg e) = 224 (3.9672), 276 (3.8614), 343 nm (3.2846); MS (ESI): m/z (%): 663.2 (71) [2M+Na] + , 343.1 (67) [M+Na] + , 338.1 (25) [M+NH4] + , 321.1 (100) [M+H] + ; HRMS (ESI): m/z calcd for C16H16O7: 343.0788 [M+Na] + ; found: 343.0787.
(1’R,2R)-1-(2-Benzyloxymethyl-5-methoxy-7-methylchroman-2yl)ethane-1,2-diol (14 a): A solution of vinyl chromane 12 (376 mg, 1.16 mmol, 1.00 equiv) in tBuOH/H2O (5.8/5.8 mL) was treated with K2OsO4·2 H2O (21.3 mg, 58 mmol, 5 mol %), (DHQ)2-AQN (143 mg, 159 mmol, 10 mol %), K3[Fe(CN)6] (2.29 g, 6.95 mmol, 6.00 equiv) and K2CO3 (961 mg, 6.95 mmol, 6.00 equiv) at RT. After stirring for 3 d, the reaction was quenched by addition of sat. aq. NaHSO3 solution (20 mL) at 0 8C and stirred at RT for an additional 30 min. The aq. layer was extracted with EtOAc (3 10 mL), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. After column chromatography on silica gel (n-pentane/EtOAc 5:1!1:1), a mixture of diastereomers was obtained as a colourless oil (320 mg, 894 mmol, 77 %, d.r. = 13.7:1). The diastereomeric alcohols 14 a (anti) and 14 b (syn) can be separated by HPLC (Daicel Chiracel IB, 20 250 mm, n-hexane/2-PrOH 96:4, 7 mL min1, 210 nm): tR = 14.7 min (14 a), tR = 19.7 min (14 b); for the analytical data of 14 b, see the Supporting Information. Compound 14 a: [a]D = + 2.8 (c = 0.50 in CHCl3, 23.0 8C); 1H NMR (600 MHz, CDCl3): d = 2.00 (mc, 2 H; 3-H2), 2.26 (s, 3 H; 7-CH3), 2.47 (dt, J = 16.8, 7.9 Hz, 1 H; 4-Ha), 2.69 (dt, J = 17.4, 5.7 Hz, 1 H; 4-Hb), 2.74 (sbr, 1 H; 2’-OH), 2.99 (d, J = 6.8 Hz, 1 H; 1’-OH), 3.57 (d, J = 10.0 Hz, 1 H; CHaOBn), 3.64 (d, J = 10.0 Hz, 1 H; CHaOBn), 3.76–3.83 (m, 2 H; 2’-H2), 3.78 (s, 3 H; 5-OCH3), 3.85 (q, J = 5.8 Hz, 1 H; 1’-H), 4.47 (d, J = 11.8 Hz, 1 H; OCHaPh), 4.56 (d, J = 11.8 Hz, 1 H; OCHbPh), 6.24 (s, 1 H; 8-H), 6.30 (s, 1 H; 6-H), 7.27–7.34 ppm (m, 5 H, 5 PhH); 13C NMR (125 MHz, CDCl3): d = 15.4 (C-4), 21.6 (7-CH3), 23.5 (C3), 55.4 (5-OCH3), 61.9 (C-2’), 70.2 (CH2OBn), 74.0 (OCH2Ph), 74.2 (C1’), 77.6 (C-2), 103.3 (C-8), 107.4 (C-4a), 110.0 (C-6), 127.7, 128.5 (PhCo, Ph-Cm), 127.9 (Ph-Cp), 137.2, 137.3 (C-7, Ph-Ci), 153.1, 157.5 ppm (C-5, C-8a); IR: n˜ = 3399, 2924, 2855, 1618, 1584, 1497, 1453, 1413, 1352, 1291, 1223, 1139, 1098, 1073, 1026, 951, 814, 775, 736, 697, 576 cm1; UV (CH3CN): lmax (lg e) = 208 (4.7425), 271 nm (3.0948); MS (ESI): m/z (%): 739.4 (100) [2M+Na] + , 717.4 (6) [2M+H] + , 381.2 (32) [M+Na] + , 359.2 (48) [M+H] + ; HRMS (ESI): m/z calcd for C21H26O5 : 359.1853 [M+H] + ; found: 359.1852.
Acknowledgements This work was supported by Deutsche Forschungsgemeinschaft (DFG), Land Niedersachsen and Volkswagenstiftung. S.J. thanks the CaSuS Program for a PhD scholarship and J.H. thanks the Dorothea-Schlçzer Program for a postdoctoral scholarship. Keywords: dihydroxylation · domino reactions · natural products · tetrahydroxanthones · total synthesis [1] For an excellent recent review on xanthone natural products, see: K.-S. Masters, S. Brse, Chem. Rev. 2012, 112, 3717 – 3776. [2] M. Stewart, R. J. Capon, J. M. White, E. Lacey, S. Tennant, J. H. Gill, M. P. Shaddock, J. Nat. Prod. 2004, 67, 728 – 730. [3] M. M. Wagenaar, J. Clardy, J. Nat. Prod. 2001, 64, 1006 – 1009. [4] a) B. Franck, E. M. Gottschalk, U. Ohnsorge, G. Baumann, Angew. Chem. 1964, 76, 438 – 439; Angew. Chem. Int. Ed. Engl. 1964, 3, 441 – 442; b) B. Franck, G. Baumann, U. Ohnsorge, Tetrahedron Lett. 1965, 6, 2031 – 2037; c) B. Franck, E. M. Gottschalk, U. Ohnsorge, F. Hper, Chem. Ber. 1966, 99, 3842 – 3862; d) P. S. Steyn, Tetrahedron 1970, 26, 51 – 57. [5] For the recent first total syntheses of secalonic acids, see: a) T. Qin, J. A. Porco, Jr., Angew. Chem. 2014, 126, 3171 – 3174: Angew. Chem. Int. Ed. 2014, 53, 3107 – 3110. For a recent report on novel dimeric chromanone natural and semi-synthetic products, see: b) D. Rçnsberg, A. Debbab, A. Mandi, V. Vasylyeva, P. Bohler, B. Stork, L. Engelke, A. Hamacher, R. Sawadogo, M. Diederich, V. Wray, W. Lin, M. U. Kassack, C. Janiak, S. Scheu, S. Wesselborg, T. Kurtan, A. H. Aly, P. Proksch, J. Org. Chem. 2013, 78, 12409 – 12425. [6] a) W. B. Turner, J. Chem. Soc. Perkin Trans. 1 1978, 1621; b) I. N. Siddiqui, A. Zahoor, H. Hussain, I. Ahmed, V. U. Ahmad, D. Padula, S. Draeger, B. Schulz, K. Meier, M. Steinert, T. Kurtn, U. Flçrke, G. Pescitelli, K. Krohn, J. Nat. Prod. 2011, 74, 365 – 373. [7] W. Zhang, K. Krohn, Z. Ullah, U. Flçrke, G. Pescitelli, L. Di Bari, S. Antus, T. Kurtn, J. Rheinheimer, S. Draeger, B. Schulz, Chem. Eur. J. 2008, 14, 4913 – 4923. [8] E. M. C. Grard, S. Brse, Chem. Eur. J. 2008, 14, 8086 – 8089. [9] K. C. Nicolaou, A. Li, Angew. Chem. 2008, 120, 6681 – 6684; Angew. Chem. Int. Ed. 2008, 47, 6579 – 6582. [10] T. Qin, R. P. Johnson, J. A. Porco, Jr., J. Am. Chem. Soc. 2011, 133, 1714 – 1717. [11] H. Kikuchi, M. Isobe, M. Sekiya, Y. Abe, T. Hoshikawa, K. Ueda, S. Kurata, Y. Katou, Y. Oshima, Org. Lett. 2011, 13, 4624 – 4627. [12] L. F. Tietze, L. Ma, J. R. Reiner, S. Jackenkroll, S. Heidemann, Chem. Eur. J. 2013, 19, 8610 – 8614.
(4S,4aS)-1,4,8-Trihydroxy-6-methyl-9-oxo-2,3,4,4a-tetrahydroxanthene-4a-carboxylic acid (25): A solution of methyl ester 23 (18.0 mg, 54.0 mmol, 1.00 equiv) in CH2Cl2 (2.20 mL) was treated with BBr3 (0.54 mL, 1 m in CH2Cl2, 0.54 mmol, 10.0 equiv) at 0 8C and stirred at RT for 1 h. The reaction was quenched by dropwise addition of H2O (10 mL) at 0 8C, the aq. layer extracted with CH2Cl2 (3 10 mL) and the combined organic phases were dried over Na2SO4. After column chromatography on RP silica gel (H2O/MeOH 50:50!0:100), carboxylic acid 25 was obtained as a white powder (7.2 mg, 23.5 mmol, 44 %). [a]D = 166.9 (c = 0.40 in MeOH, 23.6 8C); 1 H NMR (600 MHz, CD3OD): d = 1.98 (ddd, J = 12.2, 8.8, 5.2 Hz, 1 H; 3-Ha), 2.23–2.30 (m, 1 H; 3-Hb), 2.26 (s, 3 H; 6-CH3), 2.53 (dd, J = 19.4, 6.7 Hz, 1 H; 2-Ha), 2.70 (ddd, J = 19.0, 11.3, 7.2 Hz, 1 H; 2-Hb), 4.21 (dd, J = 12.4, 4.6 Hz, 1 H; 4-H), 6.27 (s, 1 H; 5-H), 6.41 ppm (s, 1 H; 7H); 13C NMR (125 MHz, CD3OD): d = 22.5 (6-CH3), 26.2 (C-3), 28.6 (C2), 72.4 (C-4), 85.9 (C-4a), 103.8 (C-9a), 106.2 (C-8a), 110.1 (C-5), 111.1 (C-7), 151.2 (C-6), 161.1 (C-8), 162.9 (C-10a), 173.8 (CO2H), 178.5 (C-1), 188.7 ppm (C-9); MS (ESI): m/z (%): 611.1 (7) [2MH] , 305.1 (100) [MH] ; HRMS (ESI): m/z calcd for C15H14O7: 305.0667 [MH] ; found: 305.0667. 2‘-epi-Gonitolyde C (28): A solution of chromanyl lactone 27 (16.0 mg, 47.9 mmol, 1.00 equiv) in CH2Cl2 (2.4 mL) was treated with BBr3 (0.48 mL, 1 m in CH2Cl2, 479 mmol, 10.0 equiv) at 78 8C and stirred at 78 8C for 2 h. The reaction was quenched by dropwise addition of sat. aq. NaHCO3 solution (10.0 mL) at 78 8C, the aq. layer extracted with EtOAc (3 10 mL) and the combined organic Chem. Eur. J. 2014, 20, 1 – 9
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Full Paper [17] a) L. F. Tietze, A. Heins, M. Soleiman-Beigi, C. Raith, Heterocycles 2009, 77, 1123 – 1146; b) L. F. Tietze, J. Zinngrebe, D. A. Spiegl, F. Stecker, Heterocycles 2007, 74, 473 – 489. [18] a) Y. Uozumi, H. Kyota, E. Kishi, K. Kitayama, T. Hayashi, Tetrahedron: Asymmetry 1996, 7, 1603 – 1606; b) Y. Uozumi, K. Kato, T. Hayashi, J. Am. Chem. Soc. 1997, 119, 5063 – 5064; c) L. F. Tietze, J. K. Lohmann, Synlett 2002, 2083 – 2085. [19] L. F. Tietze, K. M. Sommer, J. Zinngrebe, F. Stecker, Angew. Chem. 2005, 117, 262 – 264; Angew. Chem. Int. Ed. 2005, 44, 257 – 259. [20] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41, 1485 – 1486. [21] a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu, X.-L. Zhang, J. Org. Chem. 1992, 57, 2768 – 2771; b) H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483 – 2547. [22] H. Becker, K. B. Sharpless, Angew. Chem. 1996, 108, 447 – 449; Angew. Chem. Int. Ed. Engl. 1996, 35, 448 – 451. [23] a) S. Inoki, K. Kato, T. Mukaiyama, Chem. Lett. 1990, 1869 – 1872; b) T. Mukaiyama, Aldrichimica Acta 1996, 29, 59 – 76; c) O. F. Jeker, E. M. Carreira, Angew. Chem. 2012, 124, 3531 – 3534; Angew. Chem. Int. Ed. 2012, 51, 3474 – 3477. [24] C. F. Nising, U. K. Ohnemller, S. Brse, Angew. Chem. 2006, 118, 313 – 315; Angew. Chem. Int. Ed. 2006, 45, 307 – 309.
[13] L. F. Tietze, S. Jackenkroll, C. Raith, D. A. Spiegl, J. R. Reiner, M. C. Ochoa Campos, Chem. Eur. J. 2013, 19, 4876 – 4882. [14] L. F. Tietze, D. A. Spiegl, F. Stecker, J. Major, C. Raith, C. Grosse, Chem. Eur. J. 2008, 14, 8956 – 8963. [15] L. F. Tietze, L. Ma, S. Jackenkroll, J. R. Reiner, J. Hierold, B. Gnanaprakasam, S. Heidemann, Heterocycles 2014, 88, 1101 – 1119. [16] For selected recent books and reviews on domino reactions, see: a) Domino Reactions—Concepts for Efficient Organic Synthesis Lutz F. Tietze (Ed), Wiley-VCH, Weinheim, 2014; b) L. F. Tietze, S.-C. Dfert, J. Hierold, in Domino Reactions: Concepts for Efficient Organic Synthesis (Ed: L. F. Tietze), Wiley-VCH, Weinheim, 2014, pp. 523 – 578; c) H. Pellissier, Chem. Rev. 2013, 113, 442 – 524; d) L. F. Tietze, M. A. Dfert, S.-C. Schild, in Comprehensive Chirality, Vol. 2 (Eds: E. M. Carreira, H. Yamamoto), Elsevier, Amsterdam, 2012, pp. 97 – 121; e) L. F. Tietze, S. Stewart, M. A. Dfert, in Modern Tools for the Synthesis of Complex Bioactive Molecules (Eds: J. Cossy, S. Arseniyades), Wiley, Hoboken, 2012, pp. 271 – 334; f) H. Pellissier, Adv. Synth. Catal. 2012, 354, 237 – 294; g) S. Giboulot, F. Liron, G. Prestat, B. Wahl, M. Sauthier, Y. Castanet, A. Montreux, G. Poli, Chem. Commun. 2012, 48, 5889 – 5891; h) M. Platon, R. Amardeil, L. Djakovitch, J.-C. Hierso, Chem. Soc. Rev. 2012, 41, 3929 – 3968; i) L. F. Tietze, A. Dfert, Pure Appl. Chem. 2010, 82, 1375 – 1392; j) L. F. Tietze, A. Dfert, in Catalytic Asymmetric Conjugate Reactions (Ed: A. Cordova), WileyVCH, Weinheim, 2010, pp. 321 – 350; k) C. Grondall, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167 – 178; l) L. F. Tietze, Chem. Rev. 1996, 96, 115 – 136.
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Chem. Eur. J. 2014, 20, 1 – 9
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Received: March 6, 2014 Published online on && &&, 0000
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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Full Paper
FULL PAPER & Natural Products L. F. Tietze,* S. Jackenkroll, J. Hierold, L. Ma, B. Waldecker && – && Highly efficient domino reactions: An enantioselective PdII-catalyzed dominoWacker/carbonylation/methoxylation reaction combined with a diastereoselective dihydroxylation reaction enables the first total syntheses of both ()-
Chem. Eur. J. 2014, 20, 1 – 9
blennolide C and ()-gonytolide C with ee values of 99 % (see scheme). The preparation of an epimeric acid derivative of blennolide C and 2’-epi-gonytolide C are also reported.
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These are not the final page numbers! ÞÞ
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A Domino Approach to the Enantioselective Total Syntheses of Blennolide C and Gonytolide C
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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