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Article Cite This: J. Org. Chem. 2018, 83, 921−929

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Study of the Construction of the Tiacumicin B Aglycone Louis Jeanne-Julien,† Guillaume Masson,† Eloi Astier,† Grégory Genta-Jouve,† Vincent Servajean,‡ Jean-Marie Beau,‡,§ Stéphanie Norsikian,‡ and Emmanuel Roulland*,† †

UMR 8638, CNRS/Université Paris Descartes, Faculté de Pharmacie, 4, Avenue de l’Observatoire, 75006 Paris, France ICSN-CNRS Centre de Recherche de Gif, Univ. Paris-Sud, Université Paris-Saclay, Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France § Laboratoire de Synthèse de Biomolécules, ICMMO, Univ. Paris-Sud and CNRS, Université Paris-Saclay, F-91405 Orsay, France ‡

S Supporting Information *

ABSTRACT: Our study of the synthesis of the aglycone of tiacumicin B is discussed here. We imagined two possible strategies featuring a main retrosynthetic disconnection between C13 and C14. The first strategy was based on Suzuki−Miyaura cross-coupling of 1,1-dichloro-1-alkenes, but the failure of this pathway led us to use a Pd/Cu-dual-catalyzed cross-coupling of alkynes with allenes that had never been implemented before in a total synthesis context. We used density functional theory calculations to guide our strategic choices concerning a [2.3]-Wittig rearrangement step and the final ring-size selective Yamaguchi macrolactonization. This led to two syntheses of the aglycone of tiacumicin B, with one of last generation delivering ultimately an adequately protected and glycosylation-ready aglycone.

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INTRODUCTION It has become vital to identify new molecules interacting with new biological targets to fight against the spread of antibiotic resistance. Tiacumicin B (1) (Figure 1), also known as clostomicin B1, fidaxomicin, or lipiarmycin A3,1 belongs to this category of interesting molecules. The target of tiacumicin B (1) is the β′-subunit of the switch region of the RNA polymerase β′-sr-RNAP. The interaction of 1 with β′-sr-RNAP blocks the separation of the two DNA strands, thus inhibiting RNA synthesis and eventually leading to the death of the bacteria.2 The structure of the bacterial β′-sr-RNAP is conserved across all bacterial species, but the structure is different from that of eukariotes; therefore, a broad spectrum of bacteria could be covered selectively with only limited toxicity to humans. This naturally occurring antibiotic is produced by Dactylosporangium aurantiacum through fermentation, and it was approved by the U. S. FDA in 2011 for the treatment of a deadly nosocomial intestinal infection associated with Clostridium dif f icile.3 Furthermore, β′-sr-RNAP is a drug target exploited since only 2011, so cross-resistance with other antibacterial agents has not yet spread. Tuberculosis is another infection that can potentially be treated by blocking RNAP,4 which is very appreciable considering the worrisome emergence of multiresistant Mycobacterium.5 Within this context, it has appeared to be important to provide analogues of tiacumicin B in order to exploit this new drug target while expecting an improved pharmacokinetic profile, lower toxicity, and a modified antibacterial spectrum. At the present time, chemical synthesis is likely the most efficient way to reach this goal, and performing the total synthesis of this molecule is a classical manner in which to pave © 2017 American Chemical Society

the way toward analogues. For all of these reasons, and also because this complex polyketide/sugar mixed structure represents an excellent synthetic challenge, the macrolactonic core of tiacumicin B has been synthesized by the Gademann6 and Altmann groups,7 and the putative aglycone of lipiarmycin, a diastereomer of 1, has been synthesized by Zhu’s group.8 Ultimately, Gademann and co-workers achieved the total synthesis of tiacumicin B (1) in 2015.9 For our part, we reported the synthesis of the aglycone of tiacumicin B in 2017.10 Our approach enabled us to obtain a glycosylationready aglycone (2). This was largely made possible thanks to the use of DFT calculations that helped us make two crucial strategic choices, thus implementing the concept of a DFTguided strategy. Achieving the total synthesis of natural products is a delicate, time-consuming, and complex task. In fact, we have had to explore many pathways and strategies before finally finding the one that allowed us to reach the goal in a satisfying manner. Our recently published10 synthesis of the aglycone of tiacumicin is actually the result of the design of several other synthetic strategies based on various disconnections and methods of synthesis that focused mainly on catalytic transformations.

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RESULTS AND DISCUSSION The synthesis of the C4−C19 fragment was built around an idea aimed at finding an efficient and innovative way of synthesizing the C12−C15 tetrasubstituted alkene in a Received: November 16, 2017 Published: December 20, 2017 921

DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

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Figure 1. Tiacumicin B, a new potential lead antibiotic, and its targeted aglycone.

Scheme 1. Two Main Types of Strategy Originally Envisioned for the C4−C19 Fragment

would result from the Pd-catalyzed cross-coupling of boronic ester 5,10 with 1,1-dichloro-1-alkene 6 leading to the creation of a C sp2−C sp2 bond. A very similar type of cross-coupling has been previously described by Barluenga and co-workers.13 However, 1,1-dichloroethylene was the only substrate used in this study (eq 1).

stereoselective manner. This led us to imagine two types of strategies that both implemented a retrosynthetic disconnection between C13 and C14 (Scheme 1). In the first type, we imagined the possibility of using a Suzuki cross-coupling of 1,1-dichloro-1-alkenes and, for the second type, a Pd/Cucatalyzed allene/alkyne cross-coupling. The choice of the approach strongly influences the beginning of the synthesis and particularly the nature of the C14−C19 fragment that has to be either a 1,1-dichloro-1-alkene in the first strategy or an allene in the second. However, in both strategies the cross-coupling would deliver products in which the methyl C25 or C24 would be missing and would have to be introduced later in the synthesis by substitution of the Cl atom in the first strategy or by a stereo- and regioselective alkyne functionalization in the second strategy. First Approach of the Synthesis of the C12−C15 Dienic Motif Using the Cross-Coupling of 1,1-Dichloro1-alkenes. In this first strategy, we wanted to extend our cross-coupling method of 1,1-dichloro-1-alkenes that leads to (Z)-vinyl chloride selectively through the creation of a C sp3− C sp2 bond.11 Note that we successfully used this coupling for the total synthesis of oocydin A.12 This reaction presents the advantage of being very selective of the trans-chlorine atom, guaranteeing a high level of control of the configuration of the resulting trisubstituted alkene. Therefore, we imagined that the C12−C15 dienic motif of the targeted aglycone 2 could be built by passing it through the chlorinated intermediate 4 as a precursor of 3 (Scheme 2). The chlorinated intermediate 4

This strategy appeared promising to us since analogous 1,1dibromo-1-alkenes were previously reported to be suitable intermediates for the synthesis of a similar dienic motif. For example, this was successfully implemented in the synthesis of apoptolidin.14 In addition, we have demonstrated previously that to get the desired diene 3, the introduction of the missing methyl group 25 could be performed by substituting the chlorine atom of 4 using trimethylboroxine under Pd-catalyzed cross-coupling conditions.15 Another reason to select this strategy was the very short and direct way the required 1,1dichloro-1-alkene 6 could be obtained. It has been reported that organolithium species 7 can result from a halogen-lithium exchange using tert-BuLi at −100 °C on 1,1,1-trichloropropene 8 (Scheme 3).16 Alternatively, 7 has been more efficiently and cleanly synthesized by transmetalation with n-BuLi of organolead 916 or even by deprotonation of 3,3-dichloroprop-1-ene 10 by LDA in THF at −95 °C.17 Because a selective γ-attack on aldehyde 11 under a FelkinAnh mode is likely, fragment 6 could be obtained in a very direct manner from aldehyde 11 deriving from lactic acid.18 Thus, we synthesized compound 1019 and used LDA to generate labile lithium derivative 7 and condensed it at −100 °C with aldehyde 11. Interestingly, the γ-attack occurred selectively as the exclusive formation of the pair of diastereomers 6-anti and 6-syn was observed. Unfortunately, we never managed to reach a yield higher than 34% and an anti/syn ratio better than 2:1. In comparison, hexanal gave a mixture of γ- and α-attack products 12 and 13.20

Scheme 2. 1,1-Dichloro-1-alkene Strategy

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DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

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The Journal of Organic Chemistry Scheme 3. 1,1-Dichloro-1-alkene Strategy

Scheme 4. Exploration of the Cross-Coupling of 1,1-Dichloro-1-alkenes with C sp2 Nucleophiles

Scheme 5. Allene−Alkyne Cross-Coupling/Hydrosulfuration/Kumada−Corriu Sequence

The Pd-catalyzed cross-coupling of 1,1-dichloro-1-alkenes 6anti and 12 was then explored (Scheme 4). Although the cross-coupling of the model substrate 12 with phenylboronic acid gave compound 14, which was an encouraging result, the transposition of these reaction conditions to the coupling of the fragment 6-anti with vinyl borane 1521 never gave any result. Within this context, and considering the poor yields encountered for these two consecutive steps, we started exploring other pathways. Second Approach for the Synthesis of the C12−C15 Dienic Motif Using the Pd/Cu Dual-Catalyzed CrossCoupling of Allenes with Alkynes. The second strategy we explored was based on the cross-coupling of an alkyne with an allene through Pd/Cu dual catalysis,22 a reaction that has never been used in total synthesis in spite of its great potential. This reaction has many advantages. First, it is atom-economical, and second, its implementation requires no preliminary activation of both cross-coupling partners under the form of a halide/ organometallic couple as in the cases of the Suzuki, Negishi, or Stille reactions. These activations often require the use of protective groups and generate significant amounts of metal and halogen waste, just like the coupling step itself. This allene/alkyne cross-coupling is therefore a greener alternative

to methods traditionally used to assemble complex fragments in a convergent total synthesis. This reaction allowed us to assemble fragments 1710 and 19 (obtained from known 18),10 giving enyne 20 in a remarkable yield of 86% (Scheme 5). Considering the high efficiency of this cross-coupling, it appeared essential to find a way of converting the enyne function thus formed into the desired tetrasubstituted diene. Originally, we wished to introduce the missing methyl-24 directly using the Duboudin reaction.23 Although this reaction has been broadly documented and known to work with related enynes, this approach failed likely because the OH directing group is secondary in our case. We then tried with no success OH-directed cationic rutheniumcatalyzed hydrosilylation,24 hydrostannylation,25 and hydrochlorination,26 as well as the radical hydrostannylation.27 Finally, we explored the possibility of performing a two-step approach consisting of a sequence (hydrochalcogenation−Nicatalyzed cross-coupling). First, we found that a regio- and stereoselective hydrosulfuration28 of 20 could furnish vinylsulfide 21 in a very efficient manner. However, the various Nicatalyzed reaction conditions we tried29,30 failed to give the desired diene 22 from vinylsulfide 21. Ultimately this led to the use of Pd-catalyzed conditions,31 which allowed us to install 923

DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

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The Journal of Organic Chemistry Scheme 6. Our First Cross-Metathesis Strategy

Scheme 7. Our Second Cross-Metathesis Strategy and the Ring-Size Selective Macrolactonization

could be partially corrected to 2:1 by heating the reaction medium to 100 °C. Such a treatment eventually induced the thermal degradation of the Grubbs catalyst into a hydridoruthenium species33 that is known to have the ability to catalyze this interesting E/Z isomerization. However, high loadings of the expensive Grubbs catalyst of the second generation were needed to accomplish this (from 15 to 25 mol %). Strategies using the cross-metathesis of dienic substrates conjugated to an ester function34 were also explored by Altmann7 and Zhu,8 with both groups succeeding in introducing the C1−C4 fragment this way. We also tried this approach; however, with the Grubbs catalyst being known for tolerating the presence of carboxylic acid functions35 and also to give more convergence

the missing methyl-24 with efficiency. Thus, the substitution of the sulfur atom of 21 occurred in the presence of 1 mol % Pd2(dba)3, with MeMgBr as a nucleophile, giving diene 22 in a 77% yield with full stereoretention.32 In the final macrolactonization step, the OH at position 11 was masked by an MOM group to give compound 23, and the OH at position 17 was then deprotected giving alcohol 24. First Generation Synthesis of the Macrolactone. The previously reported syntheses of the aglycone of tiacumicin B by Gademann,6 Altmann,7 and Zhu8 showed that controlling the configuration of the C4−C5 alkene function was one of a the key tasks of this total synthesis. Ring closure metathesis gave in particular an unfavorable 2:3 E/Z ratio that fortunately 924

DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

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were happy to see that under classical Yamaguchi conditions38 the expected macrolactone 41 was formed exclusively and in 64% yield. Note that this macrolactone 41 is actually glycosylation-ready since it could be directly engaged in the next step of glycosylation to introduce the D-noviose moiety because the OH at C11 remained free of protective groups all along this synthesis. To ascertain the viability of this strategy of synthesis, the relevance of the choice of MPM protections for the OH at C7 and C18 had to be tested. The oxidative conditions traditionally used to remove MPM groups could have been incompatible with the oxidizable dienic motive of the macrolactonic core of 1. However, the removal of these protections was planned for the very end of the total synthesis of tiacumicin B (1), where, in particular, the oxidizable OH at C11 is engaged in a glycosidic bond. Therefore, we tested this potentially risky MPM removal on compound 31 that bears a MOM group on the OH at C11 which mimics a glycosidic linkage.42 We then confirmed that under classical oxidative conditions43 the two MPM groups could be cleanly removed, as diol 42 was obtained in 78% yield (88% per MPM). Our protective-group strategy appeared to be totally relevant to achieving the total synthesis of tiacumicin B.

to our synthesis, we decided to use a nonprotected dienic carboxylic acid substrate. Starting from known vinylic bromide 2536 (Scheme 6), we obtained alcohol 26 by transesterification under acidic conditions. Then, a fast Suzuki−Miyaura crosscoupling with potassium (E)-trifluoro(styryl)-borate using a RuPhos ligand37 led to diene 27 in a good yield. Note that this Pd-catalyzed step is more efficient than the Cu-catalyzed crosscoupling of tributylvinylstannane previously performed on an analogue of 26.8 The alcohol function of 27 was then protected as the silyl ether 28, and saponification finally led to the desired carboxylic acid 29. We were happy to see that polyfunctionnalized 24 and carboxylic acid 29 were assembled using only 5 mol % Grubbs catalyst of the second generation, giving seco-acid 30 in a rather good E/Z selectivity of 84:16 and with a yield that was modest yet similar to that which was previously reported.7,8 This secoacid 30 was then cyclized into macrolactone 3110 under classical Yamaguchi macrolactonization conditions38 in a 63% yield, providing us with a first generation synthesis of the aglycone of tiacumicin B. Second Approach for the C2−C5 Dienic Motif Synthesis and Second Generation Synthesis of the Macrolactone. Suppressing or even diminishing the use of protective groups in total synthesis of natural products remains challenging.39 Interestingly, several cases of macrolactonizations occurring with ring-size selectivity have been previously reported.40 In our case, such selectivity should take place, so differentiating the two OH groups at positions 11 and 17 by using protective groups would become useless and would allow economies of few steps. In other words, installing a MOM group to mask the OH at C11 like in 30 (Scheme 6) would no longer be necessary, just as the TBS protection on the OH at C17 would no longer be necessary. For further insight into this hypothesis and to help us choose a strategy, we performed DFT calculations. The latter of these showed a difference of more than 20 kcal mol−1 between the 12-membered lactone and the 18-membered lactone.10 Therefore, with the 12-membered macrolactone cycle being clearly more strained, ring-size selectivity in favor of the larger 18-membered macrolactone should occur. We transposed the first generation strategy to this new pathway using the same main transformations. We were happy to see that the cross-coupling of alkyne 17 and allene 18 led to enyne 32 in a good 78% yield (Scheme 7). Regioselective and trans selective nucleophilic alkyne hydrosulfuration of enyne 32 yielded vinylsulfide 33 efficiently. The Kumada−Corriu cross-coupling of the vinylsulfide function enabled us to efficiently introduce the methyl-24 on the C4−C19 fragment, giving key compound 34, which bore no protective groups on the OH at positions 11 and 17. Taking advantage of the development of this new pathway, we decided to try another cross-metathesis partner, such as vinylic boron ester 35 instead of the diene 29, due to better E/Z selectivity and expectations of higher yields in consideration of the literature.41 Actually, the cross-metathesis of alkene 34 with boron derivative 35 occurred very efficiently, giving 36 with a 90:10 E/Z ratio and an 80% yield with only 4 mol % Grubbs catalyst. Then, transposing the Suzuki−Miyaura cross-coupling conditions used to synthesize diene 27, we assembled boron derivative 36 with bromoacrylate 37. This led to diene 38 in a good yield after reinstallation of the lost TBS group on 39. Saponification gave key seco-acid 40, so ultimately, the ring-size selectivity hypothesis that triggered this second approach was tested. We

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CONCLUSION Our synthesis of the aglycone of tiacumicin B (1) has led to the exploration of three synthetic pathways that finally resulted in two syntheses of the target. After the failure of the 1,1dichloro-1-alkene cross-coupling strategy, we shifted to the allene−alkyne cross-coupling strategy that resulted in a preliminary and first synthesis of a fully protected aglycone. This approach paved the way toward a more accurate synthesis that finally delivered the glycosylation-ready aglycone 41, a molecule decorated with an adequate set of orthogonal and removable protective groups. DFT predictions have helped us make some of the strategic choices for these syntheses featuring the concept of DFT-guided strategy. This led us to use the long-known [2,3]-Wittig rearrangement on propargylic ether of tertiary allylic alcohols and also to design a pathway ending with a ring-size selective Yamaguchi macrolactonization. Also innovative is the sequence (allene−akyne crosscoupling/hydrosulfuration/Kumada−Corriu cross-coupling) that can be seen as a greener surrogate to the traditional Suzuki/Negishi/Stille-type approaches.

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EXPERIMENTAL SECTION

(2R,3S)-2-((tert-Butyldimethylsilyl)oxy)-6,6-dichlorohex-5en-3-ol (6-anti) and (2R,3R)-2-((tert-Butyldimethylsilyl)oxy)6,6-dichlorohex-5-en-3-ol (6-syn). To a solution of LDA (0.806 mmol) in THF (3 mL) at −100 °C under an argon atmosphere was added 3,3-dichloro-1-propene (0.806 mmol, 89 mg), and the red mixture was stirred at this temperature for 5 min. Aldehyde 11 (0.537 mmol, 101 mg) in THF (1 mL) was added at −100 °C, and the mixture was stirred at room temperature for 15 min before the reaction was quenched by addition of an aqueous saturated solution of NH4Cl. Extraction with CH2Cl2 and purification by HPLC (Hept/ AcOEt 15:1) afforded expected dichloroalkenes 6-anti (colorless oil, 37 mg, 23%) and 6-syn (18 mg, 11%). (2R,3S)-2-((tert-Butyldimethylsilyl)oxy)-6,6-dichlorohex-5-en-3-ol (6-anti). Rf = 0.21, eluent (heptane/ethyl acetate 10:1). [α]D20 = −33.3 (c 0.93, CHCl3). IR (νmax/cm−1): 3450, 2955, 2886, 2856, 2889, 1622, 1472, 1463, 1387, 1375, 1362, 1256, 1188, 1145. 1H NMR (400 MHz, CDCl3): δH 6.02 (dd, J = 6.7, 7.8 Hz, 1H), 3.81 (qd, J = 3.7, 6.3 Hz, 1H), 3.58 (dq, J = 3.7, 8.9 Hz, 1H), 2.35 (ddd, J = 4.3, 7.9, 15.2 Hz, 1H), 2.26 (ddd, J = 6.6, 8.9, 15.3 Hz, 1H), 2.17 (d, 925

DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

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The Journal of Organic Chemistry

TOF): calcd for C21H34O3NaSi [M + Na]+ 385.2175, found 385.2167. (4S,5E,7S,8R,11E,14S,15R)-14-((tert-Butyldimethylsilyl)oxy)7-ethyl-4,15-bis((4-methoxybenzyl)oxy)-5,11-dimethylhexadeca-1,5,11-trien-9-yn-8-ol (20). In a flame-dried Shlenck flask under an argon atmosphere, a solution of allene 19 (0.662 mmol, 240 mg) in THF (1.3 mL) was added over a solution of alkyne 17 (0.662 mmol, 217 mg), Pd(OAc)2 (0.033 mmol, 7 mg), (MeOPh)3P (0.067 mmol, 23 mg), and CuCl (0.033 mmol, 3 mg), and the mixture was stirred at 40 °C for 23 h. Filtration over a short silica pad prior to purification by HPLC (Hept/AcOEt 4:1) yielded expected enyne 20 as a colorless oil (391 mg, 86%). Rf = 0.23, eluent (heptane/ethyl acetate 4:1). [α]20D = −4.5 (c 0.97, CHCl3). IR (νmax/cm−1): 3434, 2956, 2930, 2857, 1642, 1612, 1587, 1513, 1463, 1378, 1324, 1302, 1245, 1173, 1147. 1H NMR (400 MHz, CDCl3): δH 7.22−7.26 (m, 4H), 6.83−6.87 (m, 4H), 5.90 (ddd, J = 2.0, 6.5, 7.8 Hz, 1H), 5.72 (tdd, J = 7.0, 10.1, 17.2 Hz, 1H), 5.27 (dd, J = 1.8, 10.1 Hz, 1H), 4.98−5.06 (m, 2H), 4.46 (dd, J = 4.5, 11.1 Hz, 2H), 4.38−4.43 (m, 2H), 4.22 (d, J = 11.7 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.74−3.80 (m, 1H), 3.64−3.69 (m, 1H), 3.38 (dq, J = 4.8, 6.3 Hz, 1H), 2.62 (dddd, J = 4.4, 5.5, 9.7, 10.5 Hz, 1H), 2.16−2.48 (m, 4H), 1.74 (s, 3H), 1.66 (d, J = 1.6 Hz, 3H), 1.63 (bs, 1H), 1.25−1.36 (m, 2H), 1.14 (d, J = 6.3 Hz, 3H), 0.84−0.90 (m, 12H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 159.1, 159.0, 138.2, 135.1, 131.0, 130.8, 129.5, 129.2, 128.7, 118.5, 116.4, 113.8, 88.7, 85.6, 84.1, 77.5, 77.2, 76.8, 74.7, 70.8, 69.3, 66.1, 55.3, 55.2, 46.4, 38.5, 32.8, 26.0, 24.5, 18.1, 17.6, 15.6, 11.8, −4.3, −4.4. HRMS (ESI+-TOF): calcd for C42H62O6NaSi [M + Na]+ 713.4213, found 713.4233. (4S,5E,7S,8R,9Z,11E,14S,15R)-14-((tert-Butyldimethylsilyl)oxy)-9-(butylthio)-7-ethyl-4,15-bis((4-methoxybenzyl)oxy)5,11-dimethylhexadeca-1,5,9,11-tetraen-8-ol (21). In a Schlenk flask under an argon atmosphere, powdered KOH (2.785 mmol, 156 mg) and BuSH (2.785 mmol, 298 μL) were added to enyne 20 (0.557 mmol, 385 mg) in DMF (700 μL), and the mixture was stirred for 70 h at 50 °C. After extraction with Et2O and purification by HPLC (Hept/AcOEt 5:1), the expected thioether 21 was obtained as a pale yellow oil (342 mg, 79%). Rf = 0.26, eluent (heptane/ethyl acetate 5:1). [α]20D = −10.1 (c 2.4, CHCl3). IR (νmax/cm−1): 3477, 2956, 2931, 2857, 1709, 1680, 1612, 1587, 1513, 1463, 1383, 1301, 1246, 1172, 1084. 1H NMR (400 MHz, CDCl3): δH 7.17−7.24 (m, 4H), 6.81−6.87 (m, 4H), 6.38 (s, 1H), 5.64−5.76 (m, 2H), 4.94−5.10 (m, 3H), 4.43 (d, J = 11.3 Hz, 1H), 4.35 (d, J = 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.08 (d, J = 11.4 Hz, 1H), 3.99 (d, J = 7.4 Hz, 1H), 3.78−3.80 (m, 4H), 3.77 (s, 3H), 3.66−3.72 (m, 2H), 3.34−3.42 (m, 1H), 2.52−2.70 (m, 3H), 2.31−2.43 (m, 2H), 2.13−2.29 (m, 2H), 1.92 (s, 3H), 1.75−1.84 (m, 1H), 1.63 (d, J = 0.9 Hz, 3H), 1.48−1.58 (m, 2H), 1.30−1.43 (m, 2H), 1.14−1.22 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.80−0.92 (m, 15H), 0.03 (s, 3H), 0.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 159.1, 137.7, 136.2, 135.3, 134.6, 133.3, 131.9, 131.1, 131.1, 130.3, 129.5, 129.4, 129.2, 116.3, 113.8, 84.8, 80.3, 77.5, 74.9, 70.8, 69.5, 55.3, 55.3, 45.2, 38.7, 35.2, 32.9, 32.1, 32.0, 26.0, 24.1, 22.2, 18.2, 16.0, 15.4, 13.8, 11.7, 11.6, −4.3, −4.4. HRMS (ESI+TOF): calcd for C46H72O6NaSSi [M + Na]+ 803.4717, found 803.4717. (4S,5E,7S,8R,9E,11E,14S,15R)-14-((tert-Butyldimethylsilyl)oxy)-7-ethyl-4,15-bis((4-methoxybenzyl)oxy)-5,9,11-trimethylhexadeca-1,5,9,11-tetraen-8-ol (22). In a Schlenk flask under an argon atmosphere, Pd2(dba)3 (0.013 mmol, 1.2 mg) in THF (1.1 mL) and MeMgBr (1.28 mmol, 426 μL of a 3 M solution in diethyl ether) were added over thioether 21 (0.128 mmol, 100 mg), and the yellow mixture was stirred at 80 °C for 390 min. The reaction was quenched by addition of an aqueous saturated solution of NH4Cl (150 μL/mmolMg), and after filtration and purification by HPLC (Hept/AcOEt 5:1), the expected diene 22 was obtained as a pale yellow oil (70 mg, 77%). Rf = 0.14 (Hept/AcOEt 5:1). [α]20D = −23.3 (c 1.2, CHCl3). IR (νmax/cm−1): 3470, 2955, 2930, 2856, 1740, 1613, 1513, 1463, 1373, 1301, 1245, 1172, 1083, 1035. 1H NMR (400 MHz, CDCl3): δH 7.16−7.26 (m, 4H), 6.81−6.85 (m, 4H), 5.83 (s, 1H), 5.71 (dddd, J = 6.6, 7.3, 10.2, 17.1 Hz, 1H), 5.39 (dd, J = 6.5, 7.5 Hz, 1H), 4.96−5.10 (m, 3H), 4.41 (d, J = 11.3 Hz, 1H), 4.33 (d, J

J = 4.6 Hz, 1H), 1.12 (d, J = 6.3 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 126.9, 121.3, 74.1, 71.1, 32.5, 25.9, 18.2, 17.8, −4.2, −4.8. HRMS (ESI+-TOF): calcd for C12H24Cl2ONaSi [M + Na]+ 321.0820, found 321.0806. (2R,3R)-2-((tert-Butyldimethylsilyl)oxy)-6,6-dichlorohex-5-en-3ol (6-syn). Rf = 0.27, eluent (heptane/ethyl acetate 10:1). [α]20D = +0.5 (c 0.92, CHCl3). IR (νmax/cm−1): 3473, 2930, 2955, 2886, 2857, 1622, 1472, 1463, 1390, 1376, 1362, 1255, 1141, 1068, 1005, 952, 938, 922, 884. 1H NMR (400 MHz, CDCl3): δH 6.05 (t, J = 7.2 Hz, 1H), 3.81 (qd, J = 4.6, 6.2 Hz, 1H), 3.39−3.46 (m, 1H), 2.27−2.46 (m, 3H), 1.18 (d, J = 6.2 Hz, 3H), 0.90 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 126.7, 121.2, 74.6, 71.2, 34.3, 26.0, 20.3, 18.2, −3.9, −4.7. HRMS (ESI+-TOF): calcd for C12H24Cl2O2NaSi [M + Na]+ 321.0820, found 321.0806. 1,1-Dichloroundec-1-en-4-ol (12) and 3,3-Dichloroundec-1en-4-ol (13).20 To a solution of LDA (4.51 mmol) in THF (20 mL) at −95 °C were added a solution of 3,3-dichloro-1-propene (4.51 mmol, 500 mg) in THF (1 mL) and a solution of octanal (4.51 mmol, 700 μL) in THF (1 mL), and the mixture was stirred at room temperature for 30 min. The reaction was quenched by addition of an aqueous saturated solution of NH4Cl, and extraction with CH2Cl2 and purification by HPLC (Hept/AcOEt 8:1) afforded dicholoroalkenes 12 (291 mg, 27%) and 13 (318 mg, 30%). 1,1-Dichloroundec-1-en-4-ol (12). 1H NMR (300 MHz, CDCl3): δH 5.99 (t, J = 7.4 Hz, 1H), 3.66−3.78 (m, 1H), 2.25−2.45 (m, 2H), 1.20−1.55 (m, 12H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δC 126.6, 121.5, 70.7, 37.6, 37.2, 31.9, 29.6, 29.4, 25.7, 22.8, 14.2. 3,3-Dichloroundec-1-en-4-ol (13). IR (νmax/cm−1): 3429, 2956, 2925, 2856, 1466, 1407, 1379, 1297, 1271, 1130, 1076, 976, 936, 889, 792, 760, 724, 667. 1H NMR (300 MHz, CDCl3): δH 6.16 (dd, J = 16.5, 10.4 Hz, 1H), 5.78 (d, J = 16.4 Hz, 1H), 5.42 (d, J = 10.3 Hz, 1H), 3.83 (ddd, J = 9.4, 5.4, 1.8 Hz, 1H), 2.39 (dd, J = 5.5, 1.5 Hz, 1H), 1.20−1.90 (m, 12H), 0.88 (t, J = 6.4 Hz, 3H). (Z)-1-Chloro-1-phenylundec-1-en-4-ol (14). A Schlenk tube was charged with phenylboronic acid (48 mg, 0.391 mmol), Xantphos (9.4 mg, 16 mmol), Pd2(dba)3 (7.5 mg, 8 mmol), and K3PO4 (208 mg, 0.978 mmol) and was placed under argon. Then, a solution of 1,1-dichloro-1-alkene 12 (78.0 mg, 0.326 mmol) in THF (2.5 mL) was introduced, and the tube was put in an oil bath heated to 80 °C. After the medium was stirred for 24 h, the reaction medium was diluted in 20 mL of EtOAc and filtered through a silica gel pad. HPLC purification (Hept/AcOEt 8:1) furnished vinyl chloride 14 as a colorless oil (32.5 mg, 36%). IR (νmax/cm−1): 3350, 2955, 2925, 2854, 1446. 1H NMR (400 MHz, CDCl3): δH 7.58 (m, 2H), 7.32 (m, 3H), 6.26 (t, J = 7.0 Hz, 1H), 3.82 (dq, J = 4.5, 6.3 Hz, 1H), 2.62 (m, 1H), 2.54 (dd, J = 15.4, 7.4 Hz, 1H), 1.61 (bs, 1H), 1.28−1.56 (m, 12H), 0.88 (t, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δC 138.3, 134.7, 128.6, 128.4, 126.6, 124.1, 71.4, 37.8, 37.5, 32.0, 29.7, 29.4, 25.8, 22.8, 14.2. HRMS (ESI+-TOF): calcd for C17H25ClONa [M + Na]+ 303.1492, found 303.1499. tert-Butyl(((2R,3S)-2-((4-methoxybenzyl)oxy)hepta-5,6dien-3-yl)oxy)dimethylsilane (19). To a solution of known allene 18-anti10 (0.805 mmol, 200 mg) and imidazole (2.415 mmol, 243 mg) in DMF (8 mL) under an argon atmosphere was added TBSCl (1.610 mmol, 145 mg), and the mixture was stirred at room temperature for 20 h. The reaction was quenched with water, and extraction with Et2O and purification by HPLC (Hept/AcOEt 20:1) yielded the expected silyl ether 19 as a colorless oil (244 mg, 84%). [α]20D = −6.2 (c 0.34, CHCl3). IR (νmax/cm−1): 2954, 2929, 2885, 2856, 1957, 1614, 1587, 1513, 1463, 1387, 1361, 1302, 1246, 1172, 1148, 1090, 1036, 1006. 1H NMR (400 MHz, CDCl3): δH 7.26 (m, 2H), 6.86 (m, 2H), 5.16 (dq, J = 6.8, 8.3 Hz, 1H), 4.64 (dd, J = 2.8, 6.6 Hz, 1H), 4.63 (dd, J = 2.8, 6.8 Hz, 1H), 4.50 (d, J = 11.1 Hz, 1H), 4.43 (d, J = 11.1 Hz, 1H), 3.80 (s, 3H), 3.70 (q, J = 5.1 Hz, 1H), 3.48 (quint, J = 6.0 Hz, 1H), 2.33−2.42 (m, 1H), 2.17−2.26 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 209.6, 159.2, 131.2, 129.4, 113.9, 86.5, 74.9, 74.2, 71.0, 55.4, 33.3, 26.0, 18.3, 15.8, −4.3, −4.3. HRMS (ESI+926

DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

Article

The Journal of Organic Chemistry

55.2, 42.5, 38.6, 31.3, 25.1, 17.4, 13.7, 13.0, 11.4, 11.2. HRMS (ESI+TOF): calcd for C39H56O7Na [M + Na]+ 659.3924, found 659.3931. Ethyl (E)-3-Bromo-2-(hydroxymethyl)acrylate (26). To a solution of ethyl (E)-2-(acetoxymethyl)-3-bromoacrylate 2536 (1.406 g, 5.599 mmol) was added an H2SO4 solution in EtOH (0.1 M, 10 mL), and the mixture was heated at 55 °C for 18 h. Then, the reaction medium was poured into water, and the medium was extracted with EtOAc. After the medium was dried over Na2SO4, filtration, evaporation, and purification by HPLC (Hept/AcOEt 3:1) yielded the expected alcohol 26 as a colorless oil (1.015 mg, 93%). Rf = 0.17, eluent (heptane/ethyl acetate 3:1). IR (νmax/cm−1) 3419, 3088, 2981, 2938, 1700, 1609, 1309, 1221, 1093. 1H NMR (400 MHz, CDCl3): δH 7.64 (s, 1H), 4.51 (d, J = 6.9 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.69 (t, J = 7.1 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δC 164.7, 136.5, 124.9, 61.8, 60.1, 14.3. HRMS (ESI+-TOF): calcd for C6H9O3NaBr [M + Na]+ 230.9633, found 230.9630. Ethyl (2E,4E)-2-(Hydroxymethyl)-5-phenylpenta-2,4-dienoate (27). Potassium (E)-trifluoro(styryl)borate (306 mg, 1.461 mmol), Ruphos (27.3 mg, 0.058 mmol), Pd(OAc)2 (6.6 mg, 0.029 mmol), and Cs2CO3 (952 mg, 2.92 mmol) were introduced in a Schlenk tube and put under an argon atmosphere. Then, a solution of 26 (190.0 mg, 0.974 mmol) in THF/H2O (10/1, 5 mL) was introduced, and the tube was sealed and placed in an oil bath at 80 °C. After 50 min TLC indicated that the reaction was finished. Then, at room temperature, 5 mL of EtOAc was added to the reaction medium before filtration over a short silica pad. Purification by HPLC (Hept/AcOEt 2:1) yielded expected diene 27 as a pale yellow oil (176.7 mg, 78%). Rf = 0.08, eluent (Hept/AcOEt 4:1). IR (νmax/ cm−1): 3418, 2979, 1683, 1620, 1284, 1223. 1H NMR (400 MHz, CDCl3): δH 7.49 (dd, J = 1.4, 7.9 Hz, 2H), 7.43 (d, J = 11.6 Hz, 1H), 7.35 (m, 3H), 7.17 (dd, J = 11.59, 15.4 Hz, 1H), 6.97 (d, J = 15.3 Hz, 1H), 4.54 (d, J = 6.8 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.58 (t, J = 6.9 Hz, 1H), 1.36 (t, J = 7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δC 168.0, 141.8, 141.1, 136.2, 129.6, 129.4, 129.0, 127.5, 122.8, 61.1, 57.7, 14.5. HRMS (ESI+-TOF): calcd for C14H16O3Na [M + Na]+ 255.0997, found 255.0987. Ethyl (2E,4E)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-5phenylpenta-2,4-dienoate (28). To a solution of alcohol 27 (176.0 mg, 0.7577) and imidazole (103.0 mg, 1.51 mmol) in CH2Cl2 (5 mL) under an argon atmosphere was added TBSCl (137 mg, 0.91 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water, and extraction with CH2Cl2 and purification by HPLC (Hept/AcOEt 10:1) yielded the expected silyl ether 28 as a colorless oil (237.4 mg, 90.5%). Rf = 0.50, eluent (heptane/ethyl acetate 10:1). IR (νmax/cm−1): 2954, 2928, 2856, 1698, 1622, 1224, 1064. 1H NMR (400 MHz, CDCl3): δH 7.48 (dd, J = 1.7, 7.9 Hz, 2H), 7.44 (d, J = 11.9 Hz, 1H), 7.28−7.38 (m, 4H), 6.9 (d, J = 15.2 Hz, 1H), 4.60 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H). 13C NMR (100 MHz, CDCl3): δC 167.6, 141.7, 140.7, 136.6, 130.4, 129.0, 128.9, 127.4, 124.2, 60.8, 58.0, 26.1, 18.5, 14.5, −5.0. HRMS (ESI+-TOF): calcd for C20H30O3SiNa [M + Na]+ 369.1854, found 369.1862. (2E,4E)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-phenylpenta-2,4-dienoic acid (29). To a solution of ester 28 (237.0 mg, 0.684 mmol) in MeOH/H2O (6.8 mL of a 4:1 mixture) under an argon atmosphere was added NaOH (82.0 mg, 2.05 mmol), and the mixture was stirred at 40 °C for 19 h. The reaction medium was poured into 1 M HCl and extracted with EtOAc. After drying over MgSO4 and filtration, the crude was evaporated and taken via CH2Cl2, leading to the formation of a white precipitate. After filtration, the organic solution was evaporated, which delivered the desired carboxylic acid 29 as a white crystalline solid (121.5 mg, 56%). Rf = 0.5, eluent (heptane/ethyl acetate 1:1). Mp 115 °C. IR (νmax/ cm−1): 2929, 2855, 2614, 2565, 1663, 1620, 1425, 1243, 1048. 1H NMR (400 MHz, CDCl3): δH 7.56 (d, J = 11.6 Hz, 1H), 7.5 (dd, J = 1.5, 7.6 Hz, 2H), 7.28−7.40 (m, 4H), 6.95 (d, J = 15.4 Hz, 1H), 4.64 (s, 2H), 0.93 (s, 9H), 0.05 (s, 6H). 13C NMR (100 MHz, CDCl3): δC 172.1, 143.7, 142.1, 136.4, 129.4, 129.0, 128.8, 127.6, 123.6, 58.1,

= 11.3 Hz, 1H), 4.28 (d, J = 11.3 Hz, 1H), 4.04 (d, J = 11.3 Hz, 1H), 3.86 (d, J = 8.2 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.64−3.70 (m, 2H), 3.35 (dq, J = 4.7, 6.3 Hz, 1H), 2.52 (tdd, J = 3.0, 8.4, 10.3 Hz, 1H), 2.30−2.44 (m, 2H), 2.24 (dt, J = 14.1, 7.2 Hz, 1H), 2.14 (dt, J = 14.6, 6.7 Hz, 1H), 1.76 (m, 1H), 1.67 (s, 3H), 1.62 (d, J = 1.1 Hz, 3H), 1.66 (s, 3H), 1.17 (m, 1H), 1.10 (d, J = 6.3 Hz, 3H), 0.86−0.95 (m, 12H), 0.03 (s, 3H), 0.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 159.1, 159.0, 136.2, 135.2, 133.4, 131.6, 131.2, 131.0, 130.5, 129.4, 129.2, 127.5, 116.4, 113.8, 84.7, 82.4, 77.2, 74.9, 70.6, 69.2, 55.4, 55.3, 43.6, 38.6, 32.8, 26.0, 25.9, 24.6, 18.2, 17.5, 15.2, 13.6, 11.7, 11.4, −4.3, −4.4. HRMS (ESI+-TOF): calcd for C43H66O6NaSi [M + Na]+ 729.4526, found 729.4539. (5R,6E,8E,11S)-5-((3S,6S,E)-6-((4-Methoxybenzyl)oxy)-5methylnona-4,8-dien-3-yl)-11-((R)-1-((4-methoxybenzyl)oxy)ethyl)-6,8,13,13,14,14-hexamethyl-2,4,12-trioxa-13-silapentadeca-6,8-diene (23). To a solution of alcohol 22 (0.460 mmol, 325 mg) and DIPEA (2.76 mmol, 481 μL) in CH2Cl2 (550 μL) under an argon atmosphere and hidden from light was added MOMCl (1.84 mmol, 979 μL of a 1.88 M solution in CH2Cl2), and the mixture was stirred at room temperature for 26 h. The reaction was quenched by addition of an aqueous saturated solution of NH4Cl, and extraction with CH2Cl2 and purification by HPLC (Hept/AcOEt 5:1) yielded the expected ether 23 as a colorless oil (296 mg, 86%). Rf = 0.37, eluent (Hept/AcOEt 5:1). [α]20D = +28.6 (c 1.1, CHCl3). IR (νmax/ cm−1): 2953, 2930, 2883, 2856, 1642, 1613, 1587, 1513, 1463, 1442, 1383, 1362, 1323, 1301, 1246, 1172, 1148, 1087, 1033. 1H NMR (400 MHz, CDCl3): δH 7.18 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 5.82 (s, 1H), 5.70 (tdd, J = 7.0, 10.2, 17.1 Hz, 1H), 5.41 (t, J = 7.1 Hz, 1H), 4.94− 5.06 (m, 3H), 4.67 (d, J = 6.6 Hz, 1H), 4.47 (d, J = 6.6 Hz, 1H), 4.41 (d, J = 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.25 (d, J = 11.3 Hz, 1H), 4.01 (d, J = 11.2 Hz, 1H), 3.78 (s, 3H), 3.73−3.78 (m, 4H), 3.65 (m, 2H), 3.40 (s, 3H), 3.35 (dq, J = 4.3, 6.7 Hz, 1H), 2.59 (dq, J = 3.0, 9.9 Hz, 1H), 2.41 (ddd, J = 6.4, 7.2, 14.0 Hz, 1H), 2.18−2.34 (m, 2H), 2.11 (td, J = 6.1, 14.9 Hz, 1H), 1.96 (dqd, J = 3.3, 7.7, 13.1 Hz, 1H), 1.70 (s, 3H), 1.66 (s, 3H), 1.62 (d, J = 1.6 Hz, 3H), 1.13− 1.23 (m, 1H), 1.09 (d, J = 6.3 Hz, 3H), 0.83−0.89 (m, 12H), 0.02 (s, 3H), 0.00 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 159.1, 159.1, 135.3, 135.2, 134.3, 133.3, 132.6, 131.2, 131.0, 130.3, 129.5, 129.2, 127.9, 116.4, 113.8, 113.8, 93.3, 85.9, 84.9, 75.0, 70.7, 69.3, 55.9, 55.4, 55.4, 42.6, 38.7, 32.8, 26.1, 25.2, 18.3, 17.5, 15.2, 13.3, 11.5, 11.4, −4.2, −4.4. HRMS (ESI+-TOF): calcd for C45H70O7NaSi [M + Na]+ 773.4789, found 773.4808. (2R,3S,5E,7E,9R,10S,11E,13S)-10-Ethyl-2,13-bis((4-methoxybenzyl)oxy)-9-(methoxymethoxy)-6,8,12-trimethylhexadeca5,7,11,15-tetraen-3-ol (24). To a solution of silyl ether 23 (0.386 mmol, 290 mg) in THF (400 μL) under an argon atmosphere was added TBAF (1.158 mmol, 1.16 mL of a 1 M solution in THF), and the mixture was stirred at room temperature for 24 h. Further TBAF solution (500 μL) was added to the mixture, and the mixture was stirred for 7 h at room temperature. The reaction was then quenched with water, and extraction with AcOEt and purification by HPLC (Hept/AcOEt 2:1) afforded the expected alcohol 24 as a pale yellow oil (240 mg, 98%). Rf = 0.26, eluent (heptane/ethyl acetate 2:1). [α]20D = +20.8 (c 0.94, CHCl3). IR (νmax/cm−1) 3475, 2934, 1873, 1642, 1612, 1586, 1513, 1464, 1442, 1382, 1323, 1301.41, 1245, 1172, 1148, 1073. 1H NMR (400 MHz, CDCl3): δH 7.14−7.24 (m, 4H), 6.85 (dd, J = 8.7, 16.1 Hz, 4H), 5.82 (s, 1H), 5.70 (tdd, J = 7.1, 10.2, 17.1 Hz, 1H), 5.34 (t, J = 6.5 Hz, 1H), 4.94−5.06 (m, 3H), 4.67 (d, J = 6.7 Hz, 1H), 4.45−4.49 (m, 2H), 4.36 (d, J = 11.4 Hz, 1H), 4.26 (d, J = 11.3 Hz, 1H), 4.01 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 3.73−3.77 (m, 4H), 3.65 (t, J = 7.2 Hz, 1H), 3.58 (ddd, J = 3.4, 5.0, 8.3 Hz, 1H), 3.36−3.44 (m, 4H), 2.59 (dq, J = 3.0, 9.9 Hz, 1H), 2.40 (td, J = 7.3, 14.2 Hz, 1H), 2.05−2.18 (m, 2H), 1.97 (dqd, J = 3.1, 7.8, 12.8 Hz, 1H), 1.74 (s, 1H), 1.70 (s, 3H), 1067 (s, 3H), 1.63 (d, J = 1.5 Hz, 3H), 1.10−1.25 (m, 1H), 1.08 (d, J = 6.3 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δC 159.2, 159.1, 135.2, 135.1, 134.0, 133.9, 133.0, 130.9, 130.6, 130.2, 129.5, 129.2, 127.2, 116.3, 113.8, 113.7, 93.2, 85.6, 84.8, 76.9, 73.0, 70.4, 69.2, 55.8, 55.3, 927

DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

Article

The Journal of Organic Chemistry 26.0, 18.5, −5.0. HRMS (ESI+-TOF): calcd for C18H26O3SiNa [M + Na]+ 341.1549, found 341.1547. (2E,4E,7S,8E,10S,11R,12E,14E,17S,18R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-10-ethyl-17-hydroxy-7,18-bis((4methoxybenzyl)oxy)-11-(methoxymethoxy)-8,12,14-trimethylnonadeca-2,4,8,12,14-pentaenoic Acid (30). In a Schlenk flask under an argon atmosphere, a solution of Grubbs catalyst (second generation) (1 μmol, 1 mg) in CH2Cl2 (150 μL) was added over alkene 24 (0.022 mmol, 14 mg) and diene 29 (0.066 mmol, 22 mg), and the mixture was stirred at 40 °C for 17 h. Filtration over a short silica pad prior to purification by HPLC (Hept/AcOEt 3:2) afforded the expected diene 30 as a colorless oil (7 mg, 39% of an 80:20 E/Z mixture). Rf = 0.18, eluent (heptane/ethyl acetate 3:2). [α]20D = −20.9 (c 1.26, CH2Cl2). IR (νmax/cm−1): 3003, 2970, 2948, 1737, 1729, 1365. 1H NMR (400 MHz, CDCl3): δH 7.27 (d, J = 10.6 Hz, 1H), 7.13−7.24 (m, 4H), 6.81−6.89 (m, 4H), 6.52 (dd, J = 11.5, 15.3 Hz, 1H), 6.06 (td, J = 7.4, 15.0 Hz, 1H), 5.83 (s, 1H), 5.34 (t, J = 7.1 Hz, 1H), 5.01 (dd, J = 1.7, 10.6 Hz, 1H), 4.66 (d, J = 6.6 Hz, 1H), 4.44−4.51 (m, 4H), 4.36 (d, J = 11.3 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.00 (d, J = 11.1 Hz, 1H), 3.80 (s, 3H), 3.73−3.78 (m, 4H), 3.70 (t, J = 7.1 Hz, 1H), 3.54−3.60 (m, 1H), 3.36−3.44 (m, 4H), 2.51−2.64 (m, 2H), 2.32−2.42 (m, 1H), 2.03−2.18 (m, 2H), 1.91− 2.02 (m, 1H), 1.70 (s, 3H), 1.68 (s, 3H), 1.64 (d, J = 1.6 Hz, 3H), 1.10−1.24 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H), 0.82 (t, J = 7.7 Hz, 3H), 0.10 (s, 6H). 13C NMR (100 MHz, CDCl3): δC 170.9, 159.3, 159.3, 143.0, 142.5, 135.0, 134.1, 134.1, 133.1, 130.8, 130.7, 129.7, 129.6, 129.3, 127.3, 127.0, 126.7, 114.0, 113.9, 93.3, 85.6, 84.4, 77.0, 73.1, 70.5, 69.4, 58.1, 56.0, 55.4, 55.4, 42.6, 38.3, 31.3, 26.0, 25.1, 18.4, 17.5, 13.8, 13.1, 11.5, 11.3, −5.2. HRMS (ESI+-TOF): calcd for C49H74O10NaSi [M + Na]+ 873.4949, found 873.4987. (3E,5E,8S,9E,11S,12R,13E,15E,18S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-11-ethyl-8-((4-methoxybenzyl)oxy)-18-((R)1-((4-methoxybenzyl)oxy)ethyl)-12-(methoxymethoxy)9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaen-2one (31). To a solution of acid 30 (0.0148 mmol, 12.6 mg) in THF (500 μL) under an argon atmosphere were added NEt3 (0.066 mmol, 9.31 μL) and 2,4,6-trichlorobenzoyl chloride (0.059 mmol, 9.25 μL), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with toluene (1.5 mL) and stirred at room temperature for an additional 15 min. The mixture was then added over 4 h to a solution of DMAP (0.150 mmol, 18.1 mg) in toluene (1.0 mL) under an inert atmosphere and stirred at room temperature for an additional 1 h. Filtration over a short silica pad prior to purification by HPLC (Hept/AcOEt 3:1) yielded the expected lactone 31 as a colorless oil (7.7 mg, 63%). Rf = 0.29, eluent (heptane/ethyl acetate 3:1). [α]20D = +68.9 (c 0.62, CH2Cl2). IR (νmax/cm−1): 2930, 1705, 1613, 1514, 1464, 1374, 1248, 1173, 1146, 1071, 1037. 1H NMR (300 MHz, CDCl3): δH 7.18−7.28 (m, 4H), 6.97 (d, J = 11.5 Hz, 1H), 6.80−6.90 (m, 4H), 6.57 (dd, J = 11.5, 14.9 Hz, 1H), 5.74−5.88 (m, 2H), 5.36 (t, J = 8.1 Hz, 1H), 5.19 (d, J = 10.5 Hz, 1H), 4.75 (ddd, J = 4.2, 5.4, 6.7 Hz, 1H), 4.67 (d, J = 6.8 Hz, 1H), 4.29−4.56 (m, 7H), 3.74−3.94 (m, 9H), 3.40 (s, 3H), 2.73−2.84 (m, 1H), 2.66 (dddd, J = 10.2, 9.7, 9.2, 3.3 Hz, 1H), 2.52 (ddd, J = 1.6, 3.8, 7.2 Hz, 2H), 2.28−2.40 (m, 1H), 1.93−2.06 (m, 1H), 1.78 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H), 1.27−1.36 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H), 0.82−0.94 (m, 12H), 0.07 (s, 3H), 0.06 (s, 3H). 13C NMR (100 MHz, CDCl3): δC 167.9, 159.3, 159.1, 142.4, 140.3, 135.7, 135.6, 132.4, 131.9, 131.1, 130.9, 129.5, 128.8, 128.3, 127.8, 126.9, 125.1, 113.9, 113.8, 92.9, 85.8, 79.3, 76.4, 74.5, 71.4, 69.9, 58.0, 56.0, 55.4, 41.7, 34.9, 29.9, 27.4, 26.1, 26.0, 18.5, 17.2, 17.1, 15.6, 12.7, 11.1, 0.1, −5.0, −5.1. HRMS (ESI+TOF): calcd for C49H72O9NaSi [M + Na]+ 855.4849, found 855.4843.

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H and 13C NMR spectra for new compounds 6-anti, 6syn, 12−15, 19−24, and 26−31 and COSY of compound 22 (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Emmanuel Roulland: 0000-0002-8012-7946 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the Agence Nationale pour la Recherche (ANR-14-CE16-0019-02, SYNTIA project), the CNRS, and the Université ParisDescartes. We thank Dr. Pascal Leproux for measurement of HRMS spectra.

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REFERENCES

(1) First isolated: (a) Parenti, F.; Pagani, H.; Beretta, G. J. Antibiot. 1975, 28, 247. (b) Coronelli, C.; White, R. J.; Lancini, G. C.; Parenti, F. J. Antibiot. 1975, 28, 253. Some ambiguity existed concerning the structure of tiacumicin B and its relatives. For clarifications, see: (c) Erb, W.; Zhu, J. Nat. Prod. Rep. 2013, 30, 161. (d) Bedeschi, A.; Fonte, P.; Fronza, G.; Fuganti, C.; Serra, S. The co-identity of lipiarmycin A3 and tiacumicin B. Nat. Prod. Commun. 2014, 9, 237− 240. (2) Srivastava, A.; Talaue, M.; Liu, S.; Degen, D.; Ebright, R. Y.; Sineva, E.; Chakraborty, A.; Druzhinin, S. Y.; Chatterjee, S.; Mukhopadhyay, J.; Ebright, Y. W.; Zozula, A.; Shen, J.; Sengupta, S.; Niedfeldt, R. R.; Xin, C.; Kaneko, T.; Irschik, H.; Jansen, R.; Donadio, S.; Connell, N.; Ebright, R. H. Curr. Opin. Microbiol. 2011, 14, 532. (3) Traynor, K. Am. J. Health-Syst. Pharm. 2011, 68, 2320. (4) (a) Kurabachew, M.; Lu, S. H.; Krastel, P.; Schmitt, E. K.; Suresh, B. L.; Goh, A.; Knox, J. E.; Ma, N. L.; Jiricek, J.; Beer, D.; Cynamon, M.; Petersen, F.; Dartois, V.; Keller, T.; Dick, T.; Sambandamurthy, V. K. J. Antimicrob. Chemother. 2008, 62, 713. (b) Banda, S.; Cao, N.; Tse-Dinh, Y.-C. J. Mol. Biol. 2017, 429, 2931. (5) Rifampicin interacts with the β- subunit of sr-RNAP, so crossresistance with tiacumicin B is unlikely since it binds to the β′subunit. See: (a) Gualtieri, M.; Villain-Guillot, P.; Latouche, J.; Leonetti, J.-P.; Bastide, L. Antimicrob. Agents Chemother. 2006, 50, 401. (b) Campbell, E. A.; Korzheva, N.; Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S. A. Cell 2001, 104, 901. (6) Miyatake-Ondozabal, H.; Kaufmann, E.; Gademann, K. Angew. Chem., Int. Ed. 2015, 54, 1933. (7) Glaus, F.; Altmann, K.-H. Angew. Chem., Int. Ed. 2015, 54, 1937. (8) Erb, W.; Grassot, J.-M.; Linder, D.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 1929. (9) Kaufmann, E.; Hattori, H.; Miyatake-Ondozabal, H.; Gademann, K. Org. Lett. 2015, 17, 3514. (10) Jeanne-Julien, L.; Masson, G.; Astier, E.; Genta-Jouve, G.; Servajean, V.; Beau, J.-M.; Norsikian, S.; Roulland, E. Org. Lett. 2017, 19, 4006. (11) (a) Liron, F.; Fosse, C.; Pernolet, A.; Roulland, E. J. Org. Chem. 2007, 72, 2220. (b) Guinchard, X.; Roulland, E. Synlett 2011, 19, 2779. (12) Roulland, E. Angew. Chem., Int. Ed. 2008, 47, 3762. (13) Barluenga, J.; Moriel, P.; Aznar, F.; Valdés, C. Adv. Synth. Catal. 2006, 348, 347. (14) Jin, B.; Liu, Q.; Sulikowski, G. A. Tetrahedron 2005, 61, 401. (15) Guinchard, X.; Bugaut, X.; Cook, C.; Roulland, E. Chem. - Eur. J. 2009, 15, 5793.

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* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02909. 928

DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929

Article

The Journal of Organic Chemistry (16) Seyferth, D.; Murphy, G. J.; Woodruff, R. A. J. Organomet. Chem. 1974, 66, C29. (17) Canepa, C.; Cobianco, S.; Degani, I.; Gatti, A.; Venturello, P. Tetrahedron 1991, 47, 1485. (18) Marshall, J. A.; Yanik, M. M.; Adams, N. D.; Ellis, K. C.; Chobanian, H. R. Org. Synth 2005, 81, 157. (19) King, W. H.; Smith, H. A. J. Am. Chem. Soc. 1950, 72, 3459. (20) We have failed to obtain mass spectra of compounds 12 and 13. The latter compounds were obtained from hexanal; closely related analogues deriving from propanal were previously synthesized using the same reaction, and they share the same main 1H and 13C NMR characteristics: Seyferth, D.; Murphy, G. J.; Mauzé, B. J. Am. Chem. Soc. 1977, 99, 5317. (21) Alfaro, R.; Parra, A.; Alemán, J.; García Ruano, J. L.; Tortosa, M. J. Am. Chem. Soc. 2012, 134, 15165. (22) Bruyere, D.; Grigg, R.; Hinsley, J.; Hussain, R. K.; Korn, S.; Orgaz De La Cierva, C.; Sridharan, V.; Wang, J. Tetrahedron Lett. 2003, 44, 8669. (23) (a) Duboudin, J. G.; Jousseaume, B.; Saux, A. J. Organomet. Chem. 1979, 168, 1. (b) Zhang, X.; Lu, Z.; Fu, C.; Ma, S. Org. Biomol. Chem. 2009, 7, 3258. (24) Rummelt, S.; Radkowski, K.; Roşca, D.-A.; Fürstner, A. J. Am. Chem. Soc. 2015, 137, 5506. (25) Rummelt, S. M.; Fürstner, A. Angew. Chem., Int. Ed. 2014, 53, 3626. (26) Klein, H.; Roisnel, T.; Bruneau, C.; Dérien, S. Chem. Commun. 2012, 48, 11032. (27) Dimopoulos, P.; Athlan, A.; Manaviazar, S.; George, J.; Walters, M.; Lazarides, L.; Aliev, A.; Hale, K. Org. Lett. 2005, 7, 5369. (28) See Waters, M.; Cowen, J. A.; McWilliams, J. C.; Maligres, P. E.; Askin, D. Tetrahedron Lett. 2000, 41, 141. (29) For a review on transition-metal-catalyzed cross-coupling involving organosulfur compounds, see: Dubbaka, S. R.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674−7684. (30) (a) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958. (b) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 20, 43−46. (c) Gerard, J.; Hevesi, L. Tetrahedron 2001, 57, 9109−9121. (31) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J.-i. J. Am. Chem. Soc. 2004, 126, 11778. (32) Yields are slightly lower on larger scales (67% on a 300 mg scale). (33) (a) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 7414−7415. (b) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481−5484. (c) Clark, J. R.; Griffiths, J. R.; Diver, S. T. J. Am. Chem. Soc. 2013, 135, 3327−3330. (34) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5−8. (35) Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40, 1277. (36) Ayedn, T. B.; Amri, H.; El Gaied, M. M. Tetrahedron 1991, 47, 9621. (37) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (38) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. (39) Roulland, E. Angew. Chem., Int. Ed. 2011, 50, 1226−1227. (40) Concerning ring-size selective macrolactonizations, see pages 912−915: Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106, 911. (41) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031. (42) Compound 31 resulted from our first generation synthesis (Scheme 7) but was also synthesized from 41 directly. (43) Nakajima, N.; Abe, R.; Yonemitsu, O. Chem. Pharm. Bull. 1988, 36, 4244.

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DOI: 10.1021/acs.joc.7b02909 J. Org. Chem. 2018, 83, 921−929