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Feb 14, 2018 - Therefore, we have set out to develop a next-generation taxoid radiotracer by labeling 1 with the positron-emitting 11C isotope for ana...
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Cite This: J. Org. Chem. 2018, 83, 2847−2857

Synthesis of a Next-Generation Taxoid by Rapid Methylation Amenable for 11C‑Labeling Joshua D. Seitz,† Tao Wang,† Jacob G. Vineberg,† Tadashi Honda,†,‡ and Iwao Ojima*,†,‡ †

Department of Chemistry and ‡Institute of Chemical Biology and Drug Discovery, Stony Brook University − State University of New York, Stony Brook, New York 11794-3400, United States S Supporting Information *

ABSTRACT: Next-generation taxoids, such as SB-T-1214, are highly potent cytotoxic agents that exhibit remarkable efficacy against drug-resistant tumors in vivo, including those that overexpress the P-glycoprotein (Pgp) efflux pump. As SB-T-1214 is not a substrate for Pgp-mediated efflux, it may exhibit a markedly different biodistribution and tumor-accumulation profile than paclitaxel or docetaxel, which are both Pgp substrates. To investigate the biodistribution and tumor-accumulation levels of SB-T1214 using positron emission tomography (PET), a new synthetic route has been developed to allow the incorporation of 11C, a commonly employed positron-emitting radionucleide, via methyl iodide at the last step of chemical synthesis. This synthetic route features a highly stereoselective chiral ester enolate−imine cyclocondensation, regioselective hydrostannation of the resulting β-lactam, and the Stille coupling of the novel vinylstannyl taxoid intermediate with methyl iodide. Conditions have been established to allow the rapid methylation and HPLC purification of the target compound in a time frame amenable to 11Clabeling for applications to PET studies.

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labeling 1 with the positron-emitting 11C isotope for analysis using positron emission tomography (PET). PET is a noninvasive method that can be used to map the biodistibution of small molecules in vivo.12,13 In the PET study, an organic molecule is labeled with a positron-emitting radionucleide, and it is used as a molecular probe to monitor the localization of the molecule within a living system. Of the taxanes currently in clinical use or study, paclitaxel, docetaxel, and ortataxel have all been successfully labeled with the shortlived positron emitter 11C for applications in PET.14−17 These syntheses make use of commonly employed nucleophilic substitution or acylation reactions for the introduction of the 11 C-radionucleide. However, the development of transitionmetal-catalyzed cross-coupling reactions has expanded the synthetic scope of 11C-labeling using methyl iodide, facilitating the synthesis of radio-labeled compounds not available by other conventional methods.18 It should be noted that the half-life of 11 C is only 20.3 min. Thus, a rapid and final-step or late-stage methylation and quick purification are required for 11C-labeled tracer synthesis. Biologically active compounds that have been successfully labeled using cross-coupling reactions include Celecoxib, dehydropravastatin, and structurally modified

INTRODUCTION Taxane anticancer agents, including paclitaxel and docetaxel (Figure 1), have long been a mainstay for conventional chemotherapy.1,2 Next-generation taxoids, such as SB-T-1214 (1) (Figure 1), possess a potency 2−3 orders of magnitude higher than that of paclitaxel and docetaxel against drugresistant cancer cell lines and exhibit remarkable efficacy against tumors derived from these cancer cells.3,4 In contrast to paclitaxel, next-generation taxoid 1 remains highly potent against cell lines that overexpress the P-glycoprotein (Pgp).5 Pgp is an efflux pump that removes hydrophobic molecules, such as paclitaxel and doxorubicin, from cancer cells, and it is overexpressed in many multi-drug-resistant (MDR) cancers, greatly reducing the efficacy of these drugs.6 Pgp is active in many healthy tissues, including the colon, liver, pancreas, and the blood−brain barrier. As a result, Pgp-mediated efflux can greatly influence the pharmacokinetics of biologically active molecules.7−9 Thus, 1 may exhibit an interesting biodistribution profile that is markedly different than either paclitaxel or docetaxel, which are both Pgp substrates. Furthermore, 1 has been used as a cytotoxic payload in multiple tumor-targeting drug conjugates,10,11 and a detailed understanding of its biodistribution will aid in examining the tumor-targeting efficiency of these drug-delivery systems. Therefore, we have set out to develop a next-generation taxoid radiotracer by © 2018 American Chemical Society

Received: December 28, 2017 Published: February 14, 2018 2847

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Figure 1. Structures of paclitaxel, docetaxel, and SB-T-1214 (1).

prostacyclins.19−22 Therefore, in spite of the structural complexity of 1, it was envisioned that a Pd-mediated crosscoupling reaction could be used to develop a viable route to 11 C-labeled 1 without the need for altering the chemical structure.

Synthesis of 3′-Stannylpropenyl Taxoid 2, a Precursor for 11C-Labeled Taxoid 1. We planned to synthesize literature-unknown enantiopure β-lactam 5 through chiral ester enolate−imine cyclocondensation, but the hydrostannation of 4-propynyl-β-lactam, such as 5, had not been reported, either. Accordingly, we set out to prepare racemic β-lactam (±)-9 to examine the hydrostannation and stannylcupration approaches to 4-stannylpropenyl-β-lactam 4. β-Lactam cis-(±)-9 was prepared through Staudiner [2 + 2] cycloaddition of N-PMP-2-butynylideneamine (6) and acetoxyketene generated in situ from acetoxyacetyl chloride and triethylamine, as shown in Scheme 2. The resulting cis-(±)-3acetoxyl-β-lactam 7 was deacetylated and protected with TIPS to give cis-(±)-9 in good overall yield. Hydrostannation and stannylcupration were examined for the regio- and stereoselective introduction of a stannylpropenyl group at the C-4 position of β-lactam, as shown in Scheme 3. First, the hydrostannation of (±)-9 with Bu3SnH catalyzed by (Ph3P)2PdCl2 was carried out, which gave the desired product (±)-10 and its regioisomer (±)-11 in 42 and 27% yield, respectively. Next, the stannylcupration23 of (±)-9 with (Bu3Sn)2, CuCN, and BuLi was performed, which led to the exclusive formation of (±)-10 in 66% yield. However, unfortunately, an attempted removal of the PMP group with ceric ammonium nitrate resulted in a complex mixture of degradation products; that is, the stannylpropenyl group did not tolerate this standard protocol. Accordingly, we decided to introduce a stannylpropenyl group to β-lactam 5. With two viable options for stannylation of 4-propynyl-βlactam in hand, we moved to the enantioselective synthesis of (3R,4S)-β-lactam (+)-9. Although it would be possible to obtain (+)-9 using enzymatic optical resolution of 3-acetoxyl-βlactam (±)-7,24 we decided to use the asymmetric chiral ester enolate−imine cyclocondensation developed in our laboratory.25−27 While we have demonstrated the robustness of this method for the asymmetric synthesis of β-lactams,25,27,28 N-2-

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RESULTS AND DISCUSSION Retrosynthetic Analysis for 11C-Labeled Taxoid 1. As Scheme 1 shows, the retrosynthetic analysis of radio-labeled Scheme 1. Retrosynthetic Analysis for 11C-Labeled Taxoid 1

taxoid [11C]-1 suggests that methylation can be performed at the last step of chemical synthesis using the Stille coupling of methyl iodide with stannanylpropenyl taxoid 2. Taxoid 2 can be assembled by the Ojima−Holton coupling of baccatin 3 and 4stannylpropenyl-β-lactam 4. Then, β-lactam 4 can be synthesized through hydrostannation of 4-propynyl-β-lactam 5. Thus, enantiopure (3R,4S)-3-TIPSO-4-propynyl-β-lactam 5 is identified as the first key intermediate in this retrosynthetic analysis. Scheme 2. Preparation of cis-(±)-β-Lactam 9

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The Journal of Organic Chemistry Scheme 3. Synthesis of 4-Stannylpropenyl-β-lactam (±)-10

has been shown that the reaction of N-PMP-butanaldimine with 14 gave the corresponding β-lactam with only 44% ee.28 Because the 1-propynyl group is less bulkier than the n-propyl group, there was a concern about the enantioselectivity of this reaction. However, rather surprisingly, an excellent result was obtained, as mentioned above. As aromatic and alk-1enylaldimines give excellent enantioselectivity in this reaction, the acetylenic moiety may have a favorable π−π interaction to form the transition state A. β-Lactam (+)-9 (99% ee), thus obtained, was converted to (+)-5 through deprotection of PMP, followed by t-Boc protection in good yield (Scheme 6). Pd-catalyzed hydrostannation of (+)-5 with Bu3SnH proceeded in the same manner as its racemic counterpart (see Scheme 3) to give the desired stannylpropenyl-β-lactam (+)-4 and its regioisomer (+)-17 in 43 and 27% yield, respectively (Scheme 6). Attempted synthesis of (+)-4 through stannylcupration of (+)-5 resulted in the exclusive formation of ring-opened side products; that is, an activated β-lactam with N-acylation did not tolerate this reaction condition. Although we could have tried the stannylcupration of 1-NH-4-propynyl-β-lactam 16, we

butynylideneamines have never been used as substrates. Thus, it was rather difficult to predict what level of enantioselectivity could be attained. To our happy surprise, the reaction of imine 6 with (1S,2R)-2-phenylcyclohexyl TIPSO-acetate, (−)-13,27 gave desired (+)-9 with 99% ee in 57% yield (Scheme 4). Scheme 4. Synthesis of (+)-9 through Chiral Ester Enolate− Imine Cyclocondensation of (−)-13 with 6

According to the generally accepted mechanism,27 the (E)enolate of (−)-13 is generated from (−)-13, which reacts with (E)-aldimine 6 to give β-amino ester intermediate 15 through chairlike transition state A, as illustrated in Scheme 5. Then, the subsequent cyclization affords β-lactam (+)-9 and regenerates chiral auxiliary (1S,2R)-2-phenylcyclohexanol (Scheme 5). It

Scheme 5. Plausible Mechanism for the Highly Efficient Chiral Ester Enolate−Imine Cylocondensation of 14 with 6

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The Journal of Organic Chemistry Scheme 6. Transformation of (+)-9 to N-t-Boc-β-lactam (+)-4

the same combination in THF, instead of DMF, resulted in the formation of a complex mixture. Finally, we have explored more practical conditions for the Stille coupling of stannylpropenyl taxoid 2 with 11CH3I for PET imaging studies. For the synthesis of 11C-radio-labeled compounds with high radioactivity, a short reaction time and a limited amount of radioactive reagent or substrate are required. Thus, we employed 0.1 equiv of cold CH3I for 2, as a model reaction for 11C-methylation of 2, wherein not only excess 2 (1.0 equiv) but also excess Pd(PPh3)4 (1.0 equiv) and CuTC (1.0 equiv) were used. The model reaction promoted by the Pd/CuTC system in DMF at 60 °C completed in 5 min to give the desired taxoid 1 along with two side products 20 and 21 and unconsumed 2 based on LC-UV-MS (HRMS) analyses (see Scheme 8, as well as Figure S39 in the Supporting Information). This rapid Stille coupling reaction is very different from usual catalytic processes because excess amounts of the Pd complex and the Cu salt are used beside the substrate in large excess. However, in our case, this rapid Stille coupling gave results similar to those under usual Stille coupling conditions, although the ratios of side products and unconsumed 2 versus the desired compound 1 increased. As 10-fold excess of 2 was used in this reaction, cold CH3I became the limiting reactant. The yield of 1 based on cold CH3I (100% conversion) estimated by HPLC analysis was virtually quantitative (see Figure S39), while the consumption of 2 was ca. 30% (i.e., 10% for 1 and ca. 20% for 20 and 21). The good separation of the hot compound on HPLC for PET imaging studies is technically the most important issue. At least, under our HPLC conditions, 1 was cleanly separated from side products and unconsumed 2 (see Figure S39). Overall, it has been demonstrated that the rapid Stille coupling method described above is certainly amenable to the radiosynthesis of [11C]-1 for PET imaging studies from 2 and 11CH3I. Structure Elucidation of Side Products. The structures of three side products, 19−21 (Figure 2), were hypothesized on the basis of their HRMS values obtained with the use of the LC-UV-TOF instrument (Table 1) and 1H NMR spectra. In order to unambiguously elucidate the structures of these three compounds, we decided to synthesize each compound using solid alternative procedures for use as authentic samples, as well as for full characterization with sufficient amounts. In fact, compounds 19−21 were successfully synthesized and fully characterized. These authetic samples were identical (HPLC retention times, HRMS, 1H and 13C NMR) to the side products 19−21. Iodo taxoid 19 was prepared in 92% yield via electrophillic iodination of 2, as shown in Scheme 9. Phenyl taxoid 20 was

moved to the next step with a sufficient amount of (+)-4 obtained via the hydrostannation route. The Ojima−Holton coupling of β-lactam (+)-4 with 7-TES10-cyclopropanecarbonyl baccatin III5 proceeded smoothly to afford the ring-opening coupling product 18, which was deprotected with HF/pyridine to give 3′-(E)-(2-stannylprop2-enyl) taxoid 2 in good overall yield (Scheme 7). This novel taxoid 2 serves as the precursor to [11C]-1. Stille Coupling of the Precursor 2 with CH3I for Hot Synthesis of [11C]-Taxiod 1. To convert precursor 2 to [11C]-1, we have initially screened suitable conditions of the Stille coupling of 2 with cold CH3I (1.0 equiv). As Pd catalysts, we have examined Pd[P(o-tol)3]4,29 which was generated in situ from Pd2(dba)3 and P(o-tol)3 and commercially available Pd(PPh3)4. Attempted Stille coupling using these Pd catalysts (1.0 equiv) alone, however, did not proceed at all. Subsequently, combinations of these Pd catalysts (1.0 equiv) with cuprous salts (1.2 equiv), such as CuF, CuCl, CuBr, CuI, and Cu(I) 2-thiophenecarboxylate (CuTC), were examined. Combinations of Pd[P(o-tol)3]4 with cuprous salts in DMF or THF at 60 °C did not yield the desired Stille coupling product 1 in spite of the substantial consumption of 2. Combinations of Pd(PPh3)4 and cuprous halides also gave similar results. Eventually, combination of Pd(PPh3)4 (1 equiv) and CuTC (1.2 equiv) in DMF proceeded at 60 °C to give the desired product 1 (38−40% yield based on consumed 2 by HPLC analysis; conversion of 2 was 40%) along with a considerable amount of three side products 19−21 (see Figure 2 for structures) and unconsumed 2 on the basis of HPLC and LCMS analyses using a LC-UV-TOF (HRMS) instrument (Figure S38 in the Supporting Information). Attempted reaction using Scheme 7. Synthesis of 3′-Stannylpropenyl Taxoid 2

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Figure 2. Structures of Side Products 19−21 and a Possible Side Product 22 and Its Isomer 22′.

Scheme 8. Rapid Stille Coupling of 2 with CH3I (0.1 equiv) Amenable to Hot Synthesis

Table 1. HRMS (TOF) Data of Side Products 19−21 compound

molecular formula

m/z calcd for [M − H ]

19 20 21

C44H56INO15 C50H61NO15 C49H59NO17S

964.2616 914.3963 964.3425

−

Scheme 10. Synthesis of 20

m/z found 964.2625 914.3964 964.3427

Scheme 9. Synthesis of 19

obtained, was found to be 12.00 min, which was clearly different from that of the side product in Scheme 11. Consequently, the side product in Scheme 11 was unambiguously assigned to allenyl taxoid 22. Because the retention time of allenyl taxoid 22 is virtually the same as that of taxoid 1, there is a possibility that a small amount of 22 might be eluted together with 1 after the rapid Stille coupling. However, 22 was formed in the absence of any Pd species, which undergoes facile transmetalation with vinylcopper complexes to form the corresponding vinyl Pd species 26 (see Figure 3). Therefore, it is very likely that this βhydride elimination of a vinylcopper species, forming allenyl taxoid, is limited to the reaction of 2 with CuTC (Scheme 11) and negligible under the Stille coupling conditions. In fact, the LC-UV-TOF analysis of the peak at 17.73 min (see Figure S39) did not show any molecular ion peak corresponding to 22 (Mw = 837.35), whereas that of 1 (Mw = 853.39) was apparent. Proposed Mechanisms for the Formation of 1 and 19−22 under the Stille Coupling Conditions Using CuTC. Although full mechanistic studies on the formation of 1 and the side products 19−21 through this Stille coupling are beyond the scope of this report, plausible mechanisms are

synthesized in 44% yield by the Stille coupling of 2 with iodobenzene (1.2 equiv) in the presence of Pd(Ph3P)4 (10 mol %) and CuTC (1 equiv) in DMF at 60 °C for 10 h (Scheme 10). Thiophenecarboxy taxoid 21 was obtained in 50% yield along with allenyl taxoid 22 or its isomer, prop-1-ynyl-taxoid 22′ (19% yield), by the treatment of 2 with CuTC (1.1 equiv) in DMF at 60 °C for 6 h (Scheme 11). It was found that the retention time of this side product was 17.10 min, which could overlap with taxoid 1 (tR = 17.09 min, Scheme S38). In order to determine the structure of this side product, we decided to synthesize prop-1-ynyl-taxoid 22′ in an unambiguous pathway and compare its retention time with that of this product. Prop-1-ynyl taxoid 22′ was synthesized in 72% yield by Ojima−Holton coupling of β-lactam (+)-5 with 3, followed by removal of the protective groups with HF-pyridine (Scheme 12). The retention time of prop-1-ynyl taxoid 22′, thus 2851

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The Journal of Organic Chemistry Scheme 11. Synthesis of 21

Scheme 12. Synthesis of 22′

Figure 3. Proposed mechanisms for the formations of 1 and 19−22.

proposed based on the structures of the side products and the literature precedents for similar transformations (Figure 3). In addition to scavenging excess phosphine ligands, Cu(I) salts have been shown to promote the Stille couplings through the formation of a vinylcopper species and its facile transmetalation with a Pd catalyst.30 Based on the drastic rate-enhancing effect observed, it is highly likely that vinylcopper species 24 is formed in this system. Following the transmetalation of 24 with

Pd(II) complex 25, generating vinyl Pd species 26, the isomerization of 26 (trans) to 27 (cis) takes place, and the subsequent reductive elimination affords taxoid 1. After the transmetalation of 24 with 25, forming 26, CuI should be generated. It is well-known that CuI is readily oxidized by air to CuO and I2.31 Thus, CuI may be oxidized by residual oxygen in the system. Also, CuI may disproportionate to Cu(0) and I2 in an organic medium. Electrophilic iodination 2852

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Stille coupling with methyl iodide, a methyl group can be efficiently introduced at the last stage of the synthesis of nextgeneration taxoid 1 in a time frame (5 min) and preparative HPLC purity amenable for 11C-labeling for PET. These results demonstrated the versatility of the Stille coupling for the labeling of complex molecules with CH3I as a cold surrogate of hot 11CH3I. Furthermore, this study has disclosed other interesting pathways that are operative in this reaction. These mechanistic insights may guide further optimization of the Stille coupling process for the isotope labeling of a variety of compounds. The synthesis of 11C-labeled taxoid 1 and its applications to PET studies are currently underway in our laboratory.

of 2, which exists in a large excess in this reaction with I2, gives the side product 19 and Bu3SnI. Because the amount of I2 generated by this process is dependent on the amount of Pd(II) complex 25, there should be a recognizable difference when 1.0 and 0.1 equiv of methyl iodide is used in this process. Indeed, the formation of 19 was not detected in the reaction using 0.1 equiv of methyl iodide, whereas a trace amount of 19 was observed in the reaction using 1.0 equiv of methyl iodide (see Figures S38 and S39 in the Supporting Information). The formation of 19 is, however, apparently a very minor process. The migration of a phenyl group from a phosphine ligand to a Pd(II) species has been well documented in the literature and occurs through the exchange of a phenyl group of a triphosphine ligand with an alkyl group on the palladium.32 The kinetics of such alkyl/phenyl exchange has been reported for a methyl group on palladium, which proceeds at a rate that competes with transmetalation in the Stille couplings.33 In the present rapid Stille coupling process, a phenyl group migration from triphenylphosphine to palladium takes place in 25, leading to the formation of phenyl−Pd(II) complex 28, followed by transmetalation with 24 to afford 29. Then, the subsequent reductive elimination gives the side product 20. However, the yield of 1 was virtually quantitative in the rapid Stile coupling reaction, using 0.1 equiv of methyl iodide to vinyltin taxoid 2 (vide supra). This indicates that only a tiny portion of methyl iodide was consumed to produce 20. Accordingly, this result may suggest that once a tiny amount of PhPdIII species 28 is formed, Ph migration from Ph3P to Pd keeps taking place without requiring methyl iodide. There are two possible pathways for the formation of TCvinyl taxoid 21 from vinylstannyl taxoid 2. The first pathway involves the transmetalation of 2 with CuTC to form 24 and Bu3SnTC. In competition with transmetalation with Pd(II) complex 25, 24 undergoes another transmetalation with Bu3SnTC to give 21 and Bu3SnCu, which might disproportionate to 1/2 (Bu3Sn)2 and Cu(0). The second pathway involves a reverse transmetalation of vinylstannyl taxoid 2 with CuTC to directly form 21 and Bu3SnCu. Again, Bu3SnCu might disproportionate to 1/2 (Bu3Sn)2 and Cu(0), as mentioned above. Since there is a competition between transmetalation of 24 with Pd(II) complex 25 and Bu3SnCu, the amount of 25 should have significant influence on the relative amounts of 1 and 21 formed, especially when 21 is formed only through the first pathway. Indeed, the relative amount of 21 formed in the reaction using 0.1 equiv of methyl iodide (see Figure S39) is larger than that in the reaction using 1.0 equiv of methyl iodide (see Figure S38). However, the difference is much less than 10fold. Accordingly, it is very likely that two pathways mentioned above are operative in parallel, and the second pathway is the major process for the formation of 21. The allenyl taxoid side product 22 in the reaction of 2 with CuTC (Scheme 12) is formed through β-hydride elimination of vinylstannyl taxoid 24, generating Cu−H, which may disproportionate to 1/2 H2 and Cu(0). This process, however, appears to be operative in the absence of Pd(II) complex 25, as shown in the reaction of 2 with CuTC (Scheme 11).

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EXPERIMENTAL SECTION

General Methods. Melting points were measured on a ThomasHoover capillary melting point apparatus and are uncorrected. 1H and 13 C NMR spectra were measured on a Varian 300 MHz spectrometer or a Bruker 400 or 500 MHz NMR spectrometer. TLC was performed on Sorbent Technologies aluminum-backed silica G TLC plates (Sorbent Technologies, 200 μm, 20 × 20 cm), and column chromatography was carried out on silica gel 60 (Merck, 230−400 mesh ASTM). LC-MS analysis was performed on an Agilent LC-UVTOF system with a G6224A TOF mass spectrometer operating in the m/z range of 100−3200 Da with a resolution of 20000 at m/z = 1522 Da. Reverse-phase chromatographs were obtained using a Phenomenex PFP column (Kinetex, 2.6 μ, 100 × 4.6 mm), employing aqueous ammonium acetate and methanol as the mobile phase. Normal phase chromatographs were obtained using a Shimadzu L-2010A HPLC system, employing hexanes and isopropyl alcohol as the mobile phase. Low-resolution mass spectra were obtained using flow injection analysis on an Agilent LC-MSD with a single quadrupole mass analyzer, operating in the m/z range of 100−1500 Da. High-resolution mass spectrometry (HRMS) was performed at the Institute of Chemical Biology & Drug Discovery Mass Spectrometry Laboratory, Stony Brook, NY, or the Mass Spectrometry Laboratory, University of Illinois at UrbanaChampaign, Urbana, IL. Materials. The chemicals were purchased from Sigma-Aldrich, Fisher Scientific, and VWR International and used as received or purified before use by standard methods. Tetrahydrofuran was freshly distilled under nitrogen from sodium metal and benzophenone. Dichloromethane was also distilled under nitrogen from calcium hydride. Methyl iodide was distilled at reduced pressure immediately prior to use. 10-Deacetylbaccatin III was generously provided by Indena, SpA, Italy. Experimental Procedures. (±)-1-(4-Methoxyphenyl)-3-acetoxy4-(prop-1-ynyl)azetidin-2-one [(±)-7]. p-Anisidine (2.00 g, 16 mmol), recrystallized from hexanes, was dissolved in CH2Cl2 (25 mL) with anhydrous Na2SO4 (1.0 g) and cooled to −20 °C in an acetone bath with dry ice. To this mixture was added but-2-ynal (1.40 g, 21 mmol) dropwise under inert conditions. The mixture was stirred at −20 °C and monitored by TLC (2:1 hexanes/EtOAc). After 1 h, the reaction mixture was filtered, and the filtrate was washed with CH2Cl2 (20 mL) and then concentrated in vacuo to afford 6 (2.81 g, 100% yield) as red oil, which was used immediately in the subsequent step: 1H NMR (300 MHz, CDCl3) δ 2.08 (d, J = 1.5 Hz, 3H), 3.81 (s, 3H), 6.89 (m, J = 8.7 Hz, 2H), 7.16 (m, J = 8.7 Hz, 2H), 7.67 (m, J = 1.5 Hz, 1H); MS (ESI) m/z calcd for C11H12NO (M + H)+ 174.08, found, 174.1. Crude 6 (2.81 g, 16 mmol) was dissolved in CH2Cl2 (25 mL), cooled to −78 °C, and triethylamine (TEA) (3.5 mL, 26 mmol) was added dropwise under inert conditions. Acetoxyacetyl chloride (2.2 mL, 21 mmol) was added to the solution dropwise via syringe. The temperature of the solution was maintained at −78 °C under N2 atmosphere overnight. The mixture was then allowed to warm slowly to room temperature. The reaction was quenched with saturated aqueous NH4Cl solution (2 mL). The reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic layer was washed with brine (3 × 20 mL), dried over MgSO4, and filtered. The filtrate

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CONCLUSIONS A viable synthetic route to novel C3′-vinylstannyl taxoids has been developed via enantiopure 4-vinylstannyl-β-lactams formed by a highly stereoselective chiral ester enolate−imine cyclocondensation and subequent hydrostannation. Using the 2853

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The Journal of Organic Chemistry

(Sn−1H), 1H), 6.84 (d, J = 9.2 Hz, 2H), 7.35 (d, J = 9.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 9.1 (Sn−13C), 11.9, 13.7, 17.77, 17.80, 19.8, 27.4 (Sn−13C), 29.1, 55.5, 55.6, 77.3, 114.2, 118.3, 131.6, 134.5, 148.2, 156.0, 165.8; HRMS (ESI) m/z calcd for C34H62NO3SiSn (M + H)+ 680.3521, found 680.3532 (Δ 1.6 ppm). (See Figures S8 and S9 for the 1H and 13C NMR spectra.) Method 2: Alternatively, (±)-9 (100 mg, 0.25 mmol) was weighed into a round-bottom flask with (PPh3)2PdCl2 (4.0 mg, 5 μmol), purged with N2, and dissolved in THF (3 mL). To this solution was added Bu3SnH (155 mg, 0.53 mmol) dropwise, and the mixture was stirred for 1 h. The progress of the reaction was monitored by TLC (9:1 hexanes/EtOAc). The crude reaction mixture was loaded directly onto a silica gel column and purified by column chromatography (hexanes/EtOAc 1:0 to 49:1) to give (±)-10 (76 mg, 42% yield) as a white solid: mp 67−68 °C. Spectroscopic data were identical to those of the product obtained by the Method 1. (±)-1-(4-Methoxy)phenyl-3-triisopropylsiloxy-4-(2-methyl-1-tributylstannylvinyl)-azetidin-2-one [(±)-11]. Using Method 2, (±)-11 was eluted just before (±)-10 to afford a white solid (466 mg, 27% yield): mp 61−63 °C; 1H NMR (300 MHz, CDCl3) δ 0.58−0.97 (m, 15H), 1.10−1.23 (m, 21H), 1.25−1.46 (m, 12H), 1.97 (d, J = 6.3 Hz, 3H), 3.83 (s, 3H), 5.12 (d, J = 5.1 Hz, 1H), 5.28 (m, J = 1.2, 5.1, 67.5 Hz (Sn−1H), 1H), 6.08 (m, J = 1.2, 6.3 63.0 Hz [Sn−1H], 1H), 7.34 (d, J = 9.6 Hz, 2H), 7.89, (d, J = 9.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 10.5 (Sn−13C), 12.0, 13.7, 15.9, 17.7, 17.8, 27.5 (Sn−13C), 29.0, 55.5, 60.7, 77.9, 114.2, 118.1, 131.6, 140.1, 142.6, 156.1, 165.7; HRMS (ESI) m/z calcd for C34H62NO3SiSn (M + H)+ 680.3521, found 680.3546 (Δ 3.7 ppm). (+)-1-(4-Methoxy)phenyl-3-triisopropylsiloxy-4-(prop-1-ynyl)azetidin-2-one [(+)-9]. Diisopropylamine (1.86 g, 18.46 mmol) was dissolved in anhydrous THF (20 mL) under inert atmosphere and cooled to −30 °C in an acetone bath with dry ice. To this solution was added n-BuLi (1.6 M in hexanes, 10.5 mL) dropwise. The mixture was allowed to warm to room temperature for 1 h and then cooled to −78 °C. To this solution was added a precooled solution of (−)-1326 (6.00 g, 15.38 mmol) in THF (30 mL) via cannula over 30 min at −78 °C, wherein the color of the solution turned pale yellow. To this reaction mixture was added a precooled solution of 6 (3.20 g, 18.46 mmol) in THF (40 mL) at −78 °C over the period of 2 h via cannula. During the addition, the reaction mixture turned into a deep orange color. The reaction mixture was stirred for 2 h at −78 °C, and LiHMDS (1.0 M in t-butyl methyl ether, 12.3 mL) was added dropwise. The reaction mixture was allowed to warm to −40 °C over 1 h and quenched with aqueous NH4Cl solution (5 mL). The reaction mixture was warmed to room temperature, and water was added (50 mL), and then the aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layers were washed with brine (3 × 60 mL), dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford an orange oil. Purification of the crude product by column chromatography on silica gel (hexanes/EtOAc 1:0 to 25:1) afforded a yellow solid, which was recrystallized from hexanes at −40 °C to afford (+)-9 (3.42 g, 57%) as white crystals: mp 106−107 °C; [α]D +135 (22 °C, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 1.09−1.21 (m, 21H), 1.85 (d, J = 2.1 Hz, 3H), 3.79 (s, 3H), 4.69 (m, 1H), 5.05 (d, J = 4.5 Hz, 1H), 6.88 (m, J = 8.7 Hz, 2H), 7.46 (m, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 3.8, 12.0, 17.7, 51.5, 55.5, 72.3, 85.1, 114.3, 118.5, 130.9, 156.3, 164.5; HRMS (ESI) m/z calcd for C22H34NO3Si (M + H)+ 388.2308, found 388.2313 (Δ 1.3 ppm). Enantiomeric purity of (+)-9 (99% ee) was assessed by comparison to an authentic sample of (±)-9 using normal phase HPLC on a Shimadzu LC-2010A with a Chiracel OD-H column. The mobile phase was hexanes/isopropyl alcohol with an isocratic ratio of 98:2. The analysis was performed at a flow rate of 0.6 mL/min with the UV detector set at 210 nm. (3R,4S)-3-Triisopropylsilyloxy-4-(propargyl)-azetidin-2-one [(+)-16]. An aliquot of (+)-9 (2.80 g, 7.23 mmol) was dissolved in acetonitrile (250 mL) and cooled to −10 °C. To this solution was added a solution of cerium ammonium nitrate (15.08 g, 25.3 mmol) in water (250 mL), dropwise via an addition funnel. The reaction temperature of −10 °C was maintained throughout the reaction. The

was concentrated in vacuo to afford a dark brown solid. Purification of the crude product by column chromatography on silica gel (hexanes/ EtOAc 1:0 to 1:1) to afford (±)-7 as a pale yellow solid, which was recrystallized from hot hexanes, giving (±)-7 (2.74 g, 63% yield) as a white solid: mp 137−138 °C; 1H NMR (300 MHz, CDCl3) δ 1.84 (d, J = 2.4 Hz, 3H), 2.30 (s, 3H), 4.93 (m, 1H), 5.82 (d, J = 4.5 Hz, 1H), 6.97 (m, J = 8.7 Hz, 2H), 7.53 (m, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 3.7, 20.5, 49.7, 55.5, 70.6, 75.4, 85.8, 114.4, 118.7, 130.1, 156.8, 160.3, 169.7; HRMS (ESI) m/z calcd for C15H16NO4 (M + H)+ 274.1075, found 274.1079 (Δ −1.5 ppm). (±)-1-(4-Methoxyphenyl)-3-hydroxy-4-(prop-1-ynyl)azetidin-2one [(±)-8]. Racemic (±)-7 (1.20 g, 4.42 mmol) was dissolved in THF (12 mL) and cooled to 0 °C. To this mixture was added 2 M aqueous KOH solution (12 mL). The reaction mixture was stirred for 3 h and monitored by TLC (2:1 hexanes/EtOAc). Upon completion, the reaction was quenched with saturated aqueous NH4Cl solution (5 mL), and the reaction mixture was extracted with CH2Cl2 (2 × 30 mL). The organic layers were collected, washed with brine (3 × 15 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo to afford (±)-8 (876 mg, 85% yield) as a white solid: mp 150−151 °C; 1H NMR (300 MHz, CDCl3) δ 1.83 (d, J = 1.2 Hz, 3H), 3.48 (s, br, 1H), 3.63 (s, 3H), 4.63 (m, 1H), 4.83 (dd, 1H), 6.71 (m, J = 8.7 Hz, 2H), 7.28 (m, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 3.9, 51.1, 55.5, 71.3, 76.0, 87.0, 114.4, 118.7, 130.3, 156.7, 164.6; HRMS (ESI) m/z calcd for C13H14NO3 (M + H)+ 232.0974, found 232.0972 (Δ −0.9 ppm). (±)-1-(4-Methoxy)phenyl-3-triisopropylsiloxy-4-(prop-1-ynyl)azetidin-2-one [(±)-9]. To a solution of (±)-8 (860 mg, 3.74 mmol) and DMAP (163 mg, 1.34 mmol) in CH2Cl2 (15 mL) was added TEA (0.8 mL, 6.7 mmol), followed by the dropwise addition of TIPSCl (1.08 g, 5.61 mmol) at 0 °C under inert conditions. The reaction mixture was stirred at room temperature for 3 h and monitored by TLC (9:1 hexanes/EtOAc). Upon completion, the reaction was quenched with saturated aqueous NH4Cl solution (3 mL). The reaction mixture was diluted with water (15 mL) and extracted with CH2Cl2 (1 × 40 mL). The organic layer was washed with brine (3 × 20 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo to afford a crude product. Purification of the crude product by column chromatography on silica gel (hexanes/ EtOAc = 19:1) gave (±)-9 (1.39 g, 92% yield) as a white solid: mp 105−106 °C; 1H NMR (300 MHz, CDCl3) δ 1.09−1.21 (m, 21H), 1.85 (d, J = 2.1 Hz, 3H), 3.79 (s, 3H), 4.69 m, 1H), 5.05 (d, J = 4.5 Hz, 1H), 6.88 (m, J = 8.7 Hz, 2H), 7.46 (m, J = 8.7 Hz, 2H); HRMS (ESI) m/z calcd for C22H34NO3Si (M + H)+ 388.2308, found 388.2314 (Δ 1.6 ppm). (±)-1-(4-Methoxy)phenyl-3-triisopropylsiloxy-4-(2-methyl-2-tributylstannylvinyl)-azetidin-2-one [(±)-10]. Method 1: To a solution of (Bu3Sn)2 (1.10 g, 1.9 mmol) in THF (1.5 mL) cooled at −78 °C was added n-BuLi (1.6 M in hexanes, 1.2 mL) dropwise. The reaction mixture was allowed to warm to −40 °C for 20 min and then cooled back to −78 °C. This reaction mixture was added to a suspension of CuCN (85 mg, 0.95 mmol) in THF (1.5 mL) at −78 °C via cannula, and the solution color changed to a deep orange. The reaction mixture was allowed to stir at −40 °C for 20 min and then cooled to −78 °C. To this reaction mixture was added MeOH (0.5 mL) dropwise to form a red gel, which turned into a solution upon warming to −10 °C for 20 min. The reaction mixture was cooled to −78 °C, and a solution of (±)-9 (100 mg, 0.25 mmol) in THF (1.5 mL) was added dropwise. The reaction mixture was then warmed to −10 °C and stirred at this temperature for 16 h. The reaction was quenched by adding MeOH (0.5 mL). The reaction mixture was diluted with water (10 mL) and extracted with Et2O (3 × 15 mL). The organic layers were washed with brine (3 × 15 mL), dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford a brown oil. Purification of the crude product by column chromatography on silica gel (hexanes/ EtOAc 1:0 to 49:1) afforded (±)-10 (114 mg, 66% yield) as a white solid: mp 67−68 °C; 1H NMR (300 MHz, CDCl3) δ 0.79−1.01 (m, 15H), 1.04−1.20 (m, 21H), 1.22−1.33 (m, 6H), 1.34−1.55 (m, 6H), 2.12 (s, J = 1.8, 43.8 Hz [Sn−1H], 3H), 3.79 (s, 3H), 5.02 (dd, J = 9.2, 5.2 Hz, 1H), 5.09 (d, J = 5.2 Hz, 1H), 5.70 (m, J = 1.8, 9.2, 67.2 Hz 2854

DOI: 10.1021/acs.joc.7b03284 J. Org. Chem. 2018, 83, 2847−2857

Article

The Journal of Organic Chemistry

Purification of the crude product by column chromatography on silica gel (hexanes/EtOAc 1:0 to 4:1) afforded silyl-protected vinylstannyl taxoid 18 (1.152 g, 85% yield) as a white solid: 1H NMR (300 MHz, CDCl3) δ 0.52−0.61 (m, 6H), 0.81−1.07 (m, 32H), 1.09 (m, 21H), 1.19 (s, 3H), 1.23 (s, 3H), 1.25−1.34 (m, 6H), 1.36 (s, 9H), 1.45− 1.64 (m, 9H), 1.74 (s, 3H), 1.84 (m, 1H), 1.90−1.96 (m, 1H), 2.04 (s, 3H), 2.20−2.13 (m, 2H), 2.30 (s, 3H), 2.38−2.53 (m, 3H), 3.83 (d, J = 6.6 Hz, 1H), 4.20 (d, J = 8.4 Hz, 1H), 4.30 (d, J = 8.4 Hz, 1H), 4.42−4.47 (m, 2H), 4.90−4.98 (m, 3H), 5.63−5.75 (m, 2H), 6.04 (t, J = 8.7 Hz, 1H), 6.49 (s, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 8.10 (d, J = 7.5 Hz, 2H); HRMS (ESI) m/z calcd for C71H118NO15Si2Sn (M + H)+ 1400.7062, found 1400.7045 (Δ −1.2 ppm). Protected taxoid 18 (1.14 g, 0.83 mmol) was dissolved in a 1:1 mixture of acetonitrile/pyridine (50 mL total) and cooled to 0 °C under nitrogen. To the solution was added HF/pyridine (70% in pyridine, 11.4 mL) dropwise. The mixture was stirred at room temperature for 5 h, and the progress of the reaction was monitored by TLC (1:1 hexanes/EtOAc). Upon completion, the reaction was quenched with 10% aqueous citric acid solution (5 mL), and the reaction mixture was neutralized with saturated aqueous NaHCO3 solution (30 mL) and extracted with EtOAc (3 × 40 mL). The organic layers were collected and washed with saturated CuSO4 aqueous solution (3 × 30 mL), water (2 × 30 mL), and brine (3 × 30 mL). The combined organic extract was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to give a crude product. Purification of the crude product by column chromatography on silica gel (hexanes/EtOAc = 1:0−1:1) afforded 2 (725 mg, 77% yield) as a white solid: mp 137−139 °C; 1H NMR (300 MHz, CDCl3) δ 0.80− 0.95 (m, 15H), 0.96−1.10 (m, 4H), 1.15 (s, 3H), 1.26 (s, 3H), 1.27− 1.39 (m, 6H), 1.35 (s, 9H), 1.40−1.54 (m, 6H), 1.56−1.64 (m, 1H), 1.70−1.78 (m, 1H), 1.90 (s, 3H), 1.98 (m, 1.5, 62.5 Hz [Sn−1H]), 3H), 2.34 (s, 3H), 2.36−2.42 (m, 1H), 2.44−2.60 (m, 2H), 3.31 (s, br, 1H), 3.84 (d, J = 6.6 Hz, 1H), 4.20 (d, J = 8.7 Hz, 1H), 4.30 (d, J = 8.7 Hz, 1H), 4.46 (m, 2H), 4.84−5.06 (m, 4H), 5.70 (m, 2H), 6.04 (t, 1H), 6.49 (s, 1H), 7.45 (t, J = 7.2 Hz, 2H), 7.60 (t, J = 7.2 Hz, 8.10 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 9.3, 9.5 (Sn−13C), 13.1, 13.8, 15.1, 20.0, 22.0, 22.4, 26.7, 27.4 (Sn−13C), 28.3, 29.1 (Sn−13C), 43.2, 45.7, 50.3, 58.6, 72.3, 72.6, 73.5, 75.1, 75.5, 76.5, 79.2, 80.0, 81.1, 84.5, 128.7, 129.2, 130.2, 132.9, 132.7, 135.0, 142.8, 145.6, 155.4, 167.0, 170.1, 173.4, 175.2, 204.0; HRMS (ESI) m/z calcd for C56H84NO15Sn (M + H)+ 1130.4863, found 1130.4874 (Δ 1.0 ppm). 3′-Dephenyl-3′-(2-methylprop-2-enyl)-10-(cyclopropanecarbonyl)docetaxel (1). Methyl iodide (0.06 mg, 0.4 μmol) in DMF (100 μL) was added to a vial containing Pd(PPh3)4 (2.2 mg, 2 μmol in DMF (100 μL). This solution was added to a suspension of cuprous thiophenecarboxylate (CuTC) (0.2 mg, 5 μmol) and 2 (5 mg, 4 μmol) in DMF (100 μL) in a vial, and the reaction mixture was heated to 60 °C for 5 min. The reaction was quenched by the addition of MeOH (300 μL). The reaction mixture was passed through a SPE filter, and the filtrate was analyzed by LC-UV-TOF (HRMS) using a Kinetex PFP column (100 Å, 2.6 μm, 100 × 2 mm/mm) and background subtraction of pure MeOH. The mobile phase was 10 mM aqueous ammonium acetate and MeOH. Analysis was performed at a flow rate of 0.4 mL/min using the following gradient: t = 0−5 min, 60% MeOH; t = 5−15 min, 60−65% MeOH; t = 15−20 min, 65−70% MeOH; t = 20−30 min, 70−75% MeOH; t = 30−40 min, 75−95% MeOH; t = 40−50 min, 95% MeOH. The UV detector was set for 215.4 and 254.4 nm. The product, 1, eluted at 17.73 min (see Figure S39). HRMS (ESI) m/z calcd for C45H60NO15 [M + H]+ 854.3958, found 854.3966 (Δ 0.9 ppm). The LC-UV-TOF (HRMS) analysis indicated that the yield of 1 was virtually quantitative based on methyl iodide used (100% conversion). The consumption of 2 was 30 ± 2%. The HPLC trace of the reaction mixture (recorded on a LC-UV-TOF instrument) is shown in Figure S39. 10-Cyclopropanecarbonyl-3′-dephenyl-3′-(prop-1-ynyl)-7-triethylsilyl-2′-triisopropylsilyldocetaxel (23). An aliquot of 3 (41 mg, 0.056 mmol) and β-lactam (+)-5 (27 mg, 0.067 mmol, 1.2 equiv) were dissolved in THF (6 mL) and cooled to −40 °C under inert conditions for 30 min. To the mixture was added LiHMDS (0.08

reaction was monitored by TLC (3:1 hexanes/EtOAc), and upon completion after 3 h, the reaction mixture was extracted with EtOAc (150 mL). The organic layer was washed with aqueous Na2SO3 solution (4 × 60 mL) and brine (3 × 50 mL), dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford a crude product. Purification of the crude product by column chromatography on silica gel (hexanes/EtOAc 1:0 to 2:1) afforded (+)-16 (1.48 g, 73% yield) as a pale yellow solid: mp 58−62 °C; 1H NMR (300 MHz, CDCl3) δ 1.02−1.23 (m, 21H), 1.85 (d, J = 2.1 Hz, 3H), 4.36 (m, J = 2.1 Hz, 1H), 5.00 (dd, J = 2.1, 4.5 Hz, 1H), 6.01 (s, br, 1H); 13C NMR (125 MHz CDCl3) δ 3.7, 12.0, 17.7, 47.8, 74.3, 79.3, 83.8, 169.2; HRMS (ESI) m/z calcd for C15H27NO2Si (M + H)+ 282.1889, found 282.1881 (Δ −2.8 ppm). (3R,4S)-1-(t-Butoxycarbonyl)-3-triisopropylsiloxy-4-(prop-1-ynyl)azetidin-2-one [(+)-5]. To a solution of (+)-16 (1.48 g, 5.27 mmol), 4-(N,N-dimethylamino)pyridine (DMAP) (160 mg, 1.4 mmol), and di-tert-butyl dicarbonate (1.38 g, 6.4 mmol) in CH2Cl2 (20 mL) was added TEA (1.2 mL, 80 mmol) dropwise at 0 °C under inert conditions. The reaction mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC (9:1 hexanes/EtOAc). Upon completion, the reaction was quenched with saturated aqueous NH4Cl solution (5 mL), and the reaction mixture was extracted with CH2Cl2 (40 mL). The organic layer was washed with brine (3 × 60 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo to give a crude product. Purification of the crude product by column chromatography on silica gel (hexanes/ EtOAc = 9:1) afforded (+)-5 (1.74 g, 87% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.03−1.22 (m, 21 H), 1.52 (s, 9H), 1.86 (d, J = 1.6 Hz, 3 H), 4.65 (m, 1H), 4.95 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz CDCl3) δ 3.8, 11.9, 17.55, 17.61, 28.1, 50.8, 71.8, 76.7, 83.7, 84.5, 147.8, 165.0; HRMS (ESI) m/z calcd for C20H39N2O4Si (M + NH4)+ 399.2674, found 399.2679 (Δ 1.2 ppm). (3R,4S)-1-(t-Butoxycarbonyl)-3-triisopropylsiloxy-4-(2-methyl-2tributylstannylvinyl)-azetidin-2-one [(+)-4]. To a solution of (+)-5 (1.00 g, 2.62 mmol) and (PPh3)2PdCl2 (40 mg, 50 μmol) in THF (20 mL) was added Bu3SnH (1.52 g, 5.3 mmol) dropwise, and the reaction mixture was stirred for 2 h. The progress of the reaction was monitored by TLC (9:1 hexanes/EtOAc). Upon completion of the reaction, the crude reaction mixture was loaded directly onto a silica gel column and purified by column chromatography (hexanes/EtOAc 1:0 to 50:1) to afford (+)-4 (746 mg, 43% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.76−0.94 (m, 15H) 0.98−1.16 (m, 21H), 1.29 (m, J = 7.6 Hz, 6H), 1.40−1.58 (m, 6H), 1.47 (s, 9H), 2.00 (m, J = 2.4, 59.2 Hz [Sn−1H], 3H), 4.90−5.00 (m, 2H), 5.61 (m, J = 2.4, 8.8, 89.2 Hz [Sn−1H], 1H); 13C NMR (100 MHz, CDCl3) δ 9.1 (Sn−13C), 11.9, 13.6, 17.6, 19.6, 27.4 (Sn−13C), 28.0, 29.1, 54.8, 82.8, 132.4, 147.8, 148.3, 166.8; HRMS (ESI) m/z calcd for C32H64NO4SiSn (M + H)+ 674.3627, found 674.3624 (Δ −0.4 ppm). (3R,4S)-1-(t-Butoxycarbonyl)-3-triisopropylsiloxy-4-(2-methyl-1tributylstannylvinyl)azetidin-2-one [(+)-17)]. Compound (+)-17 was eluted directly before (+)-4 to afford a colorless oil (466 mg, 27%): 1H NMR (300 MHz, CDCl3) δ 0.82−0.96 (m, 15H), 1.03−1.22 (m, 21H), 1.30−1.39 (m, 6H), 1.40−1.51 (m, 6H), 1.52 (s, 9H), 1.82 (d, J = 6.8 Hz, 3H), 5.00 (d, J = 6.0 Hz, 1H), 5.19 (m, J = 1.2, 6.0, 51.2 Hz [Sn−1H], 1H), 5.94 (m, J = 1.2, 6.8, 50.8 Hz [Sn−1H], 1H); 13C NMR (125 MHz CDCl3) δ 10.4 (Sn−13C), 11.8, 12.3, 13.7, 15.9, 17.7, 27.5 (Sn−13C), 29.0, 29.1, 60.6, 77.6, 83.2, 139.5, 141.0, 148.6, 166.2; HRMS (ESI) m/z calcd for C32H64NO4SiSn (M + H)+ 674.3621, found 674.3632 (Δ 1.6 ppm). 3′-Dephenyl-3′-(2-methyl-2-tributylstannylvinyl)-10-(cyclopropanecarbonyl)-docetaxel (2). To a solution of 3 (700 mg, 0.96 mmol) and (+)-4 (775 mg, 1.15 mmol) in THF (30 mL) was added LiHMDS (1.0 M in t-butyl methyl ether, 1.3 mL) dropwise at −40 °C under inert conditions. The reaction was monitored by TLC (4:1 hexanes/ EtOAc), and upon completion after 1.5 h, the mixture was quenched with saturated aqueous NH4Cl solution (5 mL). The reaction mixture was then allowed to warm to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 × 30 mL). The organic layers were washed with brine (3 × 30 mL), dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give a crude product. 2855

DOI: 10.1021/acs.joc.7b03284 J. Org. Chem. 2018, 83, 2847−2857

Article

The Journal of Organic Chemistry

Figure S38), and thus this minor product was unambiguously assigned to 22. 20: 1H NMR (500 MHz, CDCl3) δ 1.01 (m, 1H), 1.16 (m, 1H), 1.19 (s, 2H), 1.40 (s, 6H), 1.61 (s, 9H), 1.71 (s, 2H), 1.80 (m, 1H), 1.88 (m, 1H), 1.94 (s, 2H), 2.16 (s, 2H), 2.43 (s, 3H), 2.55 (m, 1H), 3.50 (s, 1H), 3.85 (d, J = 7 Hz, 1H), 4.20 (d, J = 8.45 Hz, 1H), 4.33 (m, 2H), 4.44 (m, 1H), 4.86 (t, 1H), 4.99 (d, J = 11.1 Hz, 2H), 5.54 (d, J = 8.75 Hz, 1H), 5.69 (d, J = 6.9 Hz, 1H), 6.21 (t, J = 8.55 Hz, 1H), 6.34 (s, 1H), 7.15 (t, J = 4.65 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.62 (m, 1H), 7.88 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 9.2, 9.4, 9.5, 13.0, 15.1, 16.3, 21.8, 22.4, 26.7, 28.2, 35.5, 43.2, 45.7, 50.8, 58.6, 72.2, 72.4, 73.2, 75.0, 75.4, 7.1, 80.3, 81.1, 84.4, 114.8, 128.0, 128.6, 129.2, 130.1, 132.7, 133.1, 133.4, 133.7, 134.5, 142.4, 150.2, 155.2, 160.4, 167.0, 170.2, 172.5, 175.1, 203.9; HRMS (TOF) m/z calcd for C49H58NO17S [M − H]− 964.3431, found 964.3427 (Δ −0.4 ppm); tR = 21.6 min (HPLC conditions for Figure S38), 23.17 min (HPLC conditions for Figure S39). 22: HRMS (TOF) m/z calcd for C44H55NO15 [M − H]− 836.3493, found 836.3494 (Δ −0.1 ppm); tR = 17.10 min (HPLC conditions for Figure S38). 10-Cyclopropanecarbonyl-3′-dephenyl-3′-(2-methyl-2-phenyl)docetaxel (21). To a solution of 10 mol % of Pd(Ph3)4 (0.82 mg, 0.71 μmol) in DMF (1 mL) was added a solution of iodobenzene (8.5 μg, 1.73 μmol, 1.2 equiv) in DMF (1 mL), and the solution was added to a solution of 2 (8.0 mg, 7.1 μmol) in DMF (400 μL). The reaction mixture was heated to 60 °C and allowed to react for 6 h with stirring. The reaction was quenched with MeOH (400 μL). The reaction mixture was lyophilized to remove DMF, and the crude product was purified by column chromatography on silica gel (hexanes/EtOAc 1:0 to 4:1) to give crude 21. Further purification was carried out by preparative HPLC using a Jupiter C18 preparative HPLC column (5 μm, 300 A, 250 × 21.2 mm) on a Shimadzu LC-6AD assembly, employing aqueous MeOH as the gradient solvent system, a flow rate of 10 mL/min under room temperature and with the UV detector set at 275 and 230 nm. The gradient was run from 20 to 95% aqueous MeOH over 30 min. The fractions containing 21 were combined and lyophilized to give 21 (3 mg, 3.1 μmol, 44%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.19 (s, 2H), 1.26 (m, 3H), 1.40 (s, 9H), 1.70 (s, 2H), 1.93 (s, 2H), 2.20 (s, 3H), 2.41 (s, 3H), 3.46 (s, 3H), 3.84 (d, J = 6.95 Hz, 2H), 4.21 (d, J = 8.4 Hz, 2H), 4.33 (m, 2H), 4.44 (m, 2H), 4.91 (d, J = 8.9 Hz, 2H), 4.99 (m, 2H), 5.70 (d, J = 7.05 Hz, 2H), 5.95 (d, J = 8.1 Hz, 2H), 6.21 (t, J = 8.85 Hz, 2H), 6.33 (s, 1H), 7.31 (t, J = 7.25 Hz, 2H), 7.35 (t, J = 7.75 Hz, 2H), 7.43 (d, J = 7.25 Hz, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 8.14 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 9.2, 9.5, 13.0, 15.0, 16.7, 21.9, 22.4, 26.7, 28.2, 29.7, 35.6, 43.2, 45.6, 51.8, 58.6, 72.2, 72.6, 73.6, 75.0, 75.4, 79.1, 80.2, 81.1, 84.4, 123.1, 125.9, 127.8, 128.4, 128.6, 129.2, 130.1, 133.7, 142.2, 166.9, 170.1, 175.1, 203.9; HRMS (TOF) m/z calcd for C49H58NO17S− [M − H]− 964.3425, found 964.3427 (Δ 0.2 ppm); tR = 23.72 min (HPLC conditions for Figure S38), 25.57 min (HPLC conditions for Figure S39). 10-Cyclopropanecarbonyl-3′-dephenyl-3′-(prop-1-ynyl)docetaxel (22′). An aliquot of 23 (56 mg, 0.051 mmol) was dissolved in a 1:1 mixture of acetonitrile−pyridine (3 mL) and cooled to 0 °C under inert conditions. To the mixture was added 0.56 mL HF/pyridine dropwise. The reaction mixture was stirred at room temperature for 24 h. Upon completion, the reaction was quenched with 0.2 M citric acid in water (3.8%, 10 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were collected, washed with CuSO4, washed with diluted water until the organic layer became clear, then washed with brine (10 mL × 3), dried over anhydrous MgSO4, and concentrated in vacuo to give a crude product. Purification of the crude product by column chromatography on silica gel (hexanes/EtOAc 1:0 to 4:1) gave 22′ (34 mg, 0.041 mmol, 80% yield), which was recrystallized from ethyl acetate to afford pure 22′ as a white solid (HPLC purity >99%): 1 H NMR (500 MHz, CD3OD) δ 1.00 (m, 2H), 1.06 (m, 1H), 1.13 (m, 1H), 1.21 (m, 6H), 1.44 (s, 9H), 1.70 (s, 3H), 1.78 (m, 2H), 1.84 (m, 1H), 1.86 (d, J = 2.35 Hz, 2H), 2.00 (d, J = 1 Hz, 3H), 2.28 (m, 1H), 2.43 (m, 1H), 2.47 (s, 3H), 2.51 (m, 1H), 3.90 (d, J = 7.05 Hz,

mmol, 1.5 equiv) in THF (0.07 mL) dropwise. The mixture was stirred and allowed to slightly warm to −20 °C for 4 h. Upon completion, the reaction was quenched with saturated aqueous NH4Cl (20 mL) solution and extracted with EtOAc (20 mL × 3). The organic layers were collected, washed with brine (20 mL x 3), dried over anhydrous MgSO4, and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (hexanes/ EtOAc 1:0 to 4:1) gave 23 (56 mg, 0.051 mmol, 90% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 0.57 (m, 6 H), 0.92 (m, 12H), 1.15 (m, 21H), 1.21 (m, 4H), 1.25 (m, 4H), 1.35 (s, 6H), 1.46 (s, 2H), 1.71 (s, 3H), 1.83 (m, 2H), 2.00 (s, 3H), 2.20 (m, 1H), 2.34 (m, 1H), 2.45 (s, 2H), 3.85 (d, J = 7 Hz, 1H), 4.19 (d, J = 8.25 Hz, 1H), 4.31 (d, J = 8.35 Hz, 1H), 4.46 (t, J = 6.65 Hz, 1H), 4.61 (d, J = 2.45 Hz, 1H), 5.04 (d, J = 9.3 Hz, 1H), 5.70 (d, J = 7 Hz, 1H), 6.17 (t, J = 8.75 Hz, 1H), 6.49 (s, 1H), 7.50 (t, J = 7.55 Hz, 2H), 7.61 (t, J = 7.45 Hz, 1H), 8.13 (d, J = 7.2 Hz, 2H); HRMS (TOF) m/z calcd for C59H90NO15Si2+ [M + H]+ 1108.5844, found 1108.5839 (Δ −0.4 ppm). 3′-Dephenyl-3′-(2-methyl-2-iodovinyl)-10-(cyclopropanecarbonyl)docetaxel (19). To a solution of 2 (250 mg, 0.22 mmol) in CH2Cl2 (3 mL) was added a solution of I2 (62 mg, 0.24 mmol) in CH2Cl2 dropwise, and the reaction was monitored by TLC. Upon completion of the addition after 3 h, the reaction mixture was diluted with CH2Cl2, washed with aqueous sodium thiosulfate solution (3 × 10 mL) and brine (3 × 10 mL), dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give a crude product. Purification of the crude product by column chromatography on silica gel (hexanes/EtOH = 1:1) afforded 19 (197 mg, 92% yield) as a white solid: mp 136−138 °C; 1H NMR (400 MHz, CDCl3) δ 0.83−0.92 (m, 2H), 0.96−1.07 (m, 2H), 1.16 (s, 3H), 1.25 (s, 3H), 1.35 (s, 9H), 1.67 (s, 3H), 1.73−1.81 (m, 1H), 1.81−1.92 (m, 1H), 1.90 (s, 3H), 2.28− 2.40 (m, 2H), 2.35 (s, 3H), 2.48−2.60 (m, 2H), 2.58 (s, 3H), 3.45 (s, br, 1H), 3.80 (d, J = 6.8 Hz), 4.17 (d, J = 8.4 Hz, 1H), 4.26 (m, 1H), 4.29 (d, J = 8.4 Hz, 1H), 4.40 (m, 1H), 4.76 (m, 1H), 4.92−4.99 (m, 2H), 5.65 (d, J = 7.2 Hz, 1H), 6.20 (t, J = 8.4 Hz, 1H), 6.30 (s, 1H), 6.35 (d, J = 8.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 8.09 (d, J = 8.10 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 9.2, 9.47, 9.52, 13.0, 15.1, 21.8, 22.5, 26.8, 28.2, 28.7, 35.6, 43.2, 45.7, 52.4, 58.6, 72.3, 72.7, 75.0, 75.4, 76.5, 79.1, 80.4, 81.3, 84.4, 100.7, 128.7, 129.2, 130.2, 133.3, 133.7, 136.4, 142.2, 155.0, 167.0, 170.1, 175.1, 203.8; HRMS (ESI−) m/z calcd for C44H55INO15 [M − H]− 964.2616, found 964.2625; tR = 19.31 min (HPLC conditions for Figure S38). 10-Cyclopropanecarbonyl-3′-dephenyl-3′-[2-methyl-2-(thiophene-2-carbonyloxy)]-docetaxel (20) and 10-Cyclopropanecarbonyl-3′-dephenyl-3′-allenyldocetaxel (22). To a reaction vial were added CuTC (1.62 mg, 8.5 μmol) and 2 (8 mg, 7.1 μmol) suspended in DMF (400 μL). The reaction mixture was heated to 60 °C and allowed to react for 6 h with stirring. The reaction was quenched with MeOH (400 μL). The reaction mixture was lyophilized to remove DMF, and the crude product was purified by column chromatography on silica gel (hexanes/EtOAc 1:0 to 4:1) to give crude 20. A portion of starting material 2 (1 mg, 0.9 μmol) was recovered. Further purification was carried out by preparative HPLC using a Jupiter C18 preparative HPLC column (5 μm, 300 A, 250 × 21.2 mm) on a Shimadzu LC-6AD assembly, employing aqueous MeOH as the gradient solvent system at a flow rate of 10 mL/min at room temperature with the UV detector set at 275 and 230 nm. The gradient was run from 20 to 95% aqueous MeOH over 30 min. The fractions containing 20 were combined and lyophilized to give 20 (3.0 mg, 50% yield) as a white solid. In addition to 20, another product was isolated, which showed the HRMS-exact mass of 836.3494 (M − H−, TOF, negative mode), corresponding to either 3′-allenyl taxoid 22 or 3′-(prop-1-ynyl) taxoid 22′ (1.0 mg, 19% yield). Because it was difficult to fully characterize this product based on 1H and 13C NMR, we decided to synthesize 3′-(prop-1-ynyl) taxoid 22′ as the authentic sample. The synthesis of 22′ is described below. Based on the retention time in the HPLC analysis, we were able to distinguish 22′ (tR = 12.00 min) from 22 (tR= 17.10 min) (HPLC conditions for 2856

DOI: 10.1021/acs.joc.7b03284 J. Org. Chem. 2018, 83, 2847−2857

Article

The Journal of Organic Chemistry 1H), 4.21 (q, J = 8.45 Hz, 2H), 4.35 (m, 2H), 4.76 (s, 1H), 5.03 (d, J = 9.6 Hz, 1H), 5.70 (d, J = 7.1 Hz, 1H), 6.21 (t, J = 8.8 Hz, 1H), 6.51 (s, 1H), 7.53 (t, J = 7.55 Hz, 2H), 7.65 (t, J = 7.45 Hz, 1H), 8.14 (d, J = 7.2 Hz, 2H); 13C NMR (125 MHz, CD3OD) δ 1.9, 7.7, 7.8, 9.0, 12.3, 13.5, 20.8, 21.6, 25.5, 27.3, 35.4, 36.1, 43.2, 46.7, 57.9, 70.8, 70.9, 73.5, 74.8, 75.0, 75.3, 76.1, 77.6, 79.4, 80.1, 80.9, 84.5, 128.3, 129.7, 129.9, 133.2, 133.5, 140.8, 156.0, 166.2, 170.6, 171.8, 173.7, 203.7; HRMS (TOF) m/z calcd for C44H54NO15− [M − H]− 836.3493, found 836.3494 (Δ 0.1 ppm); tR = 12.00 min (HPLC conditions for Figure S38).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03284. 1 H and 13C NMR spectra of all new compounds synthesized in this work; chiral HPLC analysis of (+)-9 and (±)-9; NMR analysis for determination of regiochemistry for (±)-10, (±)-11, (+)-4, and (+)-17; chiral HPLC traces of (±)-9 and (+)-9; LC-UV-TOF analysis of the products of the rapid methylation of 2 using the Stille coupling (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Iwao Ojima: 0000-0002-3628-1161 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a grant from the National Cancer Institute (CA 103314 to I.O.). The authors would like to thank Dr. Bela Ruzsiczka for his advice and technical help for LC/ HRMS analysis, and Indena SpA, Italy, for the generous gift of 10-deacetylbaccatin III used in this work.

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REFERENCES

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DOI: 10.1021/acs.joc.7b03284 J. Org. Chem. 2018, 83, 2847−2857