Commercial Manufacture of Halaven^®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones

Abstract

The evolution of the synthesis of Halaven^® (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven^® from C1–C13 ester and C14–C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven^®.

Amongst the synthetic issues to be addressed in order to provide the necessary quantities of Halaven^® (1)[1] [2] [3] for full clinical evaluation are: (i) procurement of the fragments 3 (C14–C35)[ ⁴ ] and 4 (C1–C13),[ ⁵ ] (ii) stereo- and chemoselective coupling of these fragments, (iii) carbon–carbon bond formation to generate the macrocycle, and (iv) controlled establishment of the polycyclic ketal and amino ­alcohol functionalities. This paper describes the current status of synthetic studies at Eisai which address these issues and have enabled commercial supply of 1 in a totally synthetic manner (Scheme [1]).

The synthesis of 1 from C14–C35 sulfone 3 and C1–C13 ester 4 is depicted in Scheme [2]. The synthesis begins with DIBAL reduction of 4 in toluene solution at –78 °C. Aldehyde 5 is isolated in 93% yield following quench with methanol, workup, and chromatographic purification for removal of the overreduction byproduct. The aldehyde is prone to oxidation to the carboxylic acid during isolation and storage, which had previously been managed by careful handling of the neat preparation or solutions under inert atmospheres, usually argon. However, after several sampling cycles, the carboxylic acid impurity had increased and repurification of the aldehyde was required. Addition of 0.5–1 wt% 3,5-di-tert-butyl-4-hydroxy­toluene (BHT) to the reaction mixture and to chromatographic fractions prior to concentration inhibits the oxidation of the aldehyde. The aldehyde is then readily stored and delivered as a solution for the coupling with 3.

The sulfone–aldehyde coupling between 3 and 5 presented two opportunities for improvement: (i) use of excess n-BuLi and (ii) incomplete and irreproducible conversion. The original medicinal chemistry procedure employed 2.7 equivalents of n-BuLi (1.6 M in hexanes) with 1,2-di­methoxyethane (DME) as solvent.[ ³ ] The first-pass reaction resulted in a modest yield of 6 (ca. 60%), and recovered sulfone 3 (ca. 30%).[ ⁶ ] Multiple recycles of 3 were required to achieve the reported yield of ca. 87%.

Several factors were postulated and subsequently investigated to determine their effects on the overall efficiency of the coupling of 3 and 5. These factors include: (i) stoichiometry, (ii) reaction temperature, and (iii) solvent composition. In theory, only two equivalents of base are required for this transformation, one for the unprotected alcohol moiety and one for the sulfone. It has been hypo­thesized that superstoichiometric n-BuLi may be required for sulfone–aldehyde couplings, thus suggesting that a dianionic species is the reactive intermediate, although these references also report the observation of significant overalkylation.[ ⁷ ] A series of deuterium-labeling studies were conducted in order to assess the required stoichiometry of base in the coupling reaction. To confirm the extent of deprotonation of the sulfone in the original procedure, 3 was exposed to the reaction conditions (2.7 equiv n-BuLi, –40 °C, in DME solution), and the resulting anion was quenched with deuterium oxide (D₂O). This experiment revealed that 2.7 equivalents of n-BuLi is insufficient to fully α-monodeprotonate the sulfone at –40 °C. Moreover, other bases tried with varying stoichiometry, including KHMDS, NaHMDS, s-BuLi, and t-BuLi, provided similar results. Sulfone 3 is not fully deprotonated at or below –40 °C. However, increasing the temperature of deprotonation to 0 °C resulted in complete deprotonation even with use of a stoichiometric amount (2 equiv) of n-BuLi.

These modifications resulted in the improvement of the overall quality of the sulfone–diol product 6; however, unreacted sulfone 3 still persists upon completion of the reaction. Competitive enolization of the aldehyde partner vs. nucleophilic addition of the sulfone anion is a known phenomenon[ ⁷ ] and potentially a contributing factor in the observation of unreacted sulfone starting material in this case. If the recovered sulfone is the base in a competitive enolization of the aldehyde partner, in the presence of deuterated aldehyde, the reaction should result in the production of α-deuterated sulfone byproduct. In order to gain further insight into this reaction, aldehyde 5 was α-perdeuterated by treatment with D₂O and potassium carbonate to give C2-deuterated analogue 5-d₂ . The aldehyde was subjected to the reaction conditions; however, the isolated unreacted sulfone partner did not contain deuterium, as analyzed by the ¹H NMR incorporation experiment described above. This suggests that the sulfone is not competitively enolizing the aldehyde partner.[ ⁸ ]

Based on the crystal structure of 3,[ ⁹ ] hypothesizing that coordinating solvents might disfavor an organized sulfone–alcohol dianion structure, which might be more favorably disposed towards nucleophilic addition, alternative solvent and co-solvent combinations were investigated. Minimal amounts of THF (i.e., sufficient to dissolve the dianion) along with increased portions of heptane or toluene as a co-solvent were determined to be suitable. The final procedure was to dissolve the sulfone in THF (5 volumes), cool to 0 °C, treat with exactly 2.0 equivalents of n-BuLi (note: a color change from faint yellow to bright yellow occurs at 2.0 equiv), cool the resulting sulfone dianion to –78 °C, and add the hexane solution of aldehyde to the dianion while maintaining internal temperature < –65 °C. The mixture is quenched with aqueous ammonium chloride solution and chromatographically purified to yield 86% of sulfone alcohol 6 in a 1:2:2:1 mixture of diastereomers along with 8% of recovered 3 (Scheme [3]).

Oxidation of 6 with Dess–Martin periodinane[ ¹⁰ ] provides ketone 7 as a 1:1 ratio of diastereomers. The addition of catalytic water (0.004 wt%)[ ¹¹ ] is essential to ensure reproducible and smooth oxidation of 6. Under anhydrous conditions, the reaction proceeds slowly (4–5 h), requiring a large excess of reagent (4–4.5 equiv), and results in a modest and variable yield (54–65%). The addition of water results in an increased reaction rate (20–30 min), minimizes the required reagent (2.1–2.5 equiv), and results in a 92% yield of 7.

Selective removal of the sulfone moiety of 7 is accomplished via samarium(II) iodide mediated reduction in THF and methanol solution at –78 °C to provide 8 in 95% yield. Investigation of different alcohols revealed that methanol was optimal for this process. For example, use of EtOH, 2-PrOH, or t-BuOH resulted in increasingly higher levels of aldehyde reduction. The apparent reason for higher chemoselectivity with more nucleophilic (less sterically demanding) alcohols was hypothesized to involve a samarium-mediated temporary protection of the aldehyde as a hemiacetal. LC–MS analysis of the reaction mixture is consistent with this hypothesis.

The macrocyclic carbon–carbon bond formation relies on the application of the Ni(II)/Cr(II)-mediated coupling (Nozaki–Hiyama–Kishi reaction; NHK). Examination of the original process revealed several opportunities for improvement. Namely, the reaction was conducted at high volume (350 volumes), required 4–5 days for completion, and was not demonstrated in quantities in excess of 6–7 grams. With the need to deliver significantly greater quantities of macrocycle, alternate methods were investigated. At the time of our investigation, the asymmetric variant of the intermolecular NHK process had been reported.[ ¹² ] However, no examples had yet described the application of this process to a macrocyclization.[ ¹³ ] We rationalized that, in principle, addition of the aldehyde 8 to a highly reactive species could simulate the high dilution conditions if the cyclization process proceeded efficiently. Based upon the literature precedent established by Kishi for ligand-accelerated Ni/Cr coupling, we reasoned that this reaction offered a particularly attractive opportunity to apply the ligand-accelerated strategy. Even though stereoselective construction of the macrocyclization adduct 10 was of no consequence given the need for downstream oxidation to the enone, we thought to apply the recently disclosed asymmetric variant of the Ni/Cr coupling. Gratifyingly, in an initial experiment conducted on less than 100 mg, the reaction proceeded more efficiently, both in time and in yield, than the ligand-free process. Interestingly, either antipode of the asymmetric ligand provides an increased reaction rate than the ligand-free process. We ultimately chose the less selective ligand because the reaction rate was faster. Proof of concept to execution on 200 g scale was accomplished within weeks, thereby allowing for delivery of the first clinical batch of 1. Subsequently this process has been conducted on kg scale in fixed equipment.

Further refinements to the procedure were achieved upon examination of the workup. Standard workup of Ni/Cr coupling incorporates the use of an aqueous solution of ammonium chloride or other complexing agent[ ¹⁴ ] to wash the organic reaction mixture to remove chromium residuals. In this case, we rationalized an alternative method based upon the physical properties of the reagents and reactants. First, the asymmetric ligand was soluble in the acetonitrile reaction solvent. Second, the macrocyclic product was soluble in heptane but only sparingly so in acetonitrile, likely due to the presence of the highly lipophilic TBS protecting groups adorning the molecule. Following heptane dilution of the reaction mixture upon completion of the reaction and Celite filtration to remove particulate nickel, an organic liquid–liquid extraction of the chromium ligand complex into acetonitrile leaves the product cleanly in heptane solution. Overall, the process involves the addition of a THF and acetonitrile solution of 8 to a mixture of nickel(II) chloride and the preformed complex of chromium(II) chloride and S ligand (Figure [1])[ ¹² ] in acetonitrile and provides, after purification, an 78% yield of 9 as a mixture of diastereomers.

Oxidation of allylic alcohol 9 generates enone 10 in 93% yield following chromatographic purification. The resulting enone 10 is then globally deprotected using TBAF buffered with imidazole hydrochloride at 0–5 °C yielding 11 as a 9:1 ratio of diastereomers at C12. Additionally, the bridged bicyclic isomer 13 is obtained as a minor impurity, which presumably forms from oxy-Michael addition of the C8 hydroxy group to the presumed intermediate enone–pentaol 14. The TBAF-mediated global deprotection of 10 requires extended reaction time at 0–5 °C to maintain the 9:1 ratio of 11/12 (Scheme [4]). Early in the development process, this reaction was run at room temperature. Under those conditions, the reaction proceeded rapidly (within 24 h); however, the 11/12 ratio was significantly lower (4:1).

Ketalization of the desired C12 diastereomer is achieved with PPTS to provide 2 in 82% yield following chromatographic purification and crystallization from acetonitrile and water.[ ¹⁵ ]

Introduction of the amine functionality is accomplished via activation of the final intermediate 2 as the C35 primary tosylate 15, which cyclizes in situ to epoxide 16 upon treatment with alcoholic ammonium hydroxide (Scheme [5]). It should be noted that the epoxide intermediate 16 forms, and reacts, in situ but is isolable and crystalline.[ ¹⁶ ] The epoxide 16 reacts further with ammonia to provide the eribulin free base. The free base is dissolved in acetonitrile and treated with aqueous ammonium mesylate. The solvent is exchanged with dichloromethane, and 1 is precipitated from a mixture of dichloromethane and pentane. The powder is dried in vacuo resulting in 1 as an amorphous form suitable for intravenous formulation and administration.

In summary, completion of the synthesis of Halaven^® (1) reproducibly in multigram quantities was enabled by: (i) effective supply chain management providing high quality and sufficient quantities of 3 (C14–C35) and 4 (C1–C13), (ii) efficient sulfone–aldehyde coupling aided by controlled dianion formation and optimized nucleophilic addition over proton transfer in a nonpolar solvent, (iii) chemoselective samarium iodide mediated sulfone removal in the presence of aldehyde and vinyl iodide moieties, (iv) efficient Ni(II)/Cr(II)-mediated macro-cyclization under non-high-dilution conditions facilitated by inverse addition of substrate to a soluble organometallic species using the asymmetric version of the NHK reaction, (v) controlled formation and crystallization of the polycyclic caged penultimate diol 2, and (vi) selective amino alcohol formation and generation of eribulin mesylate. The overall commercial process to Halaven^® underscores the power of the Nozaki–Hiyama–Kishi reaction to realize the construction of structurally complex molecules with human health care impact.

Acknowledgment

We thank Dr. Richard J. Staples (Crystallographic Resources, Inc.) for X-ray structural analysis of 2 and 16.

• References and Notes


Halaven^® (1) is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B. See:
• 1a Uemura D, Takahashi K, Yamamoto T, Katayama C, Tanaka J, Okumura Y, Hirata Y. J. Am. Chem. Soc. 1985; 107: 4796
  CrossrefSearch in Google Scholar
• 1b Hirata Y, Uemura D. Pure Appl. Chem. 1986; 58: 701
  CrossrefSearch in Google Scholar

First total synthesis of halichondrin B:
• 2a Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK. J. Am. Chem. Soc. 1992; 114: 3162
  CrossrefSearch in Google Scholar

Total synthesis of norhalichondrin B by Phillips:
• 2b Jackson KL, Henderson JA, Motoyoshi H, Phillips AJ. Angew. Chem. Int. Ed. 2009; 48: 2346
  CrossrefSearch in Google Scholar

Total synthesis of halichondrin C:
• 2c Yamamoto A, Ueda A, Brémond P, Tiseni PS, Kishi Y. J. Am. Chem. Soc. 2012; 134: 893
  CrossrefSearch in Google Scholar

Review of synthetic work on halichondrins:
• 2d Jackson KL, Henderson JA, Phillips AJ. Chem. Rev. 2009; 109: 3044 ; and references cited therein
  CrossrefSearch in Google Scholar

For discovery and development of Halaven^® (1), see:
• 3a Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, DiPietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA. Cancer Res. 2001; 61: 1013
  Search in Google Scholar
• 3b Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ. Bioorg. Med. Chem. Lett. 2004; 14: 5551
  CrossrefSearch in Google Scholar
• 3c Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. US 6214865, 2001
• 3d Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. US 6365759, 2002
• 3e Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. WO 9965894, 1999
• 3f Yu MJ, Kishi Y, Littlefield BA In Anticancer Agents from Natural Products . Cragg GM, Kingston DG. I, Newman DJ. CRC Press; Boca Raton: 2005: 241-265
  Search in Google Scholar
• 3g Austad B, Chase CE, Fang FG. WO 2005118565, 2005
• 3h Newman S. Curr. Opin. Invest. Drugs 2007; 8: 1057
  Search in Google Scholar
• 3i Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, Wright J, Tan AR, DaCosta NA, Chuang E, Smith J, O’Shaughnessy J, Shuster DE, Meneses NL, Chandrawansa K, Fang F, Cole PE, Ashworth S, Blum JL. J. Clin. Oncol. 2009; 27: 2954
  CrossrefSearch in Google Scholar
• 3j Chiba H, Tagami K. J. Synth. Org. Chem. Jpn. 2011; 69: 600
  CrossrefSearch in Google Scholar
• 4 See accompanying article: Austad BC, Benayouda F, Calkins TL, Campagna S, Chase CE, Choi H.-w, Christ W, Costanzo R, Cutter J, Endo A, Fang FG, Hu Y, Lewis BM, Lewis MD, McKenna S, Noland TA, Orr JD, Pesant M, Schnaderbeck MJ, Wilkie GD, Abe T, Asai N, Asai Y, Kayano A, Kimoto Y, Komatsu Y, Kubota M, Kuroda H, Mizuno M, Nakamura T, Omae T, Ozeki N, Suzuki T, Takigawa T, Watanabe T, Yoshizawa K. Synlett 2013; 24: 327
  Thieme ConnectSearch in Google Scholar
• 5 See accompanying article: Chase CE, Fang FG, Lewis BM, Wilkie GD, Schnaderbeck MJ, Zhu X. Synlett 2013; 24: 323
  Thieme ConnectSearch in Google Scholar
• 6 Unpublished information.
• 7a Langer P, Wuckelt J, Döring M, Görls H. J. Org. Chem. 2000; 65: 3603
  CrossrefSearch in Google Scholar
• 7b Magnus PD. Tetrahedron 1977; 33: 2019
  CrossrefSearch in Google Scholar
• 8 The experiment was carried out with 3 (170 mg), deprotonated with n-BuLi (2.05 equiv), and coupled with 1 equiv of the doubly deuterated aldehyde D/D-5. After workup and reverse-phase column separation, the recovered aldehyde was found to contain 25% deuterium incorporation on the basis of ¹H NMR analysis and H integration. However, ¹H NMR analysis of the recovered sulfone indicated that deuterium had not been incorporated. LC–MS analysis of the isolated products revealed that the main products were sulfone–diol coupled adduct D/D-6 doubly deuterated at C2, monodeuterated aldehyde D/H-5, and 3.
• 9 See Ref. 4
• 10a Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
  CrossrefSearch in Google Scholar
• 10b Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
  CrossrefSearch in Google Scholar
• 11 Acceleration effect of water on Dess–Martin periodinane mediated oxidations: Meyer SD, Schreiber SL. J. Org. Chem. 1994; 59: 7549
  CrossrefSearch in Google Scholar
• 12 Wan Z.-K, Choi H.-W, Kang F.-A, Nakajima K, Demeke D, Kishi Y. Org. Lett. 2002; 4: 4431
  CrossrefSearch in Google Scholar
• 13 Catalytic NHK macrocyclization process that does not require high-dilution conditions: Namba K, Kishi Y. J. Am. Chem. Soc. 2005; 127: 15382
  CrossrefSearch in Google Scholar
• 14 Stamos DP, Sheng C, Chen SS, Kishi Y. Tetrahedron Lett. 1997; 38: 6355
  CrossrefSearch in Google Scholar

Ion-exchange-resin-based protocol is reported for effective construction of Halaven^®/halichondrin C8–C14 polycyclic ring system:
• 15a Namba K, Jun H.-S, Kishi Y. J. Am. Chem. Soc. 2004; 126: 7770
  CrossrefSearch in Google Scholar
• 15b Kaburagi Y, Kishi Y. Tetrahedron Lett. 2007; 48: 8967
  CrossrefSearch in Google Scholar
• 15c Dong C.-G, Henderson JA, Kaburagi Y, Sasaki T, Kim D.-S, Kim JT, Urabe D, Guo H, Kishi Y. J. Am. Chem. Soc. 2009; 131: 15642
  CrossrefSearch in Google Scholar
• 16 Hu Y. WO 2009124237, 2009

• References and Notes


Halaven^® (1) is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B. See:
• 1a Uemura D, Takahashi K, Yamamoto T, Katayama C, Tanaka J, Okumura Y, Hirata Y. J. Am. Chem. Soc. 1985; 107: 4796
  CrossrefSearch in Google Scholar
• 1b Hirata Y, Uemura D. Pure Appl. Chem. 1986; 58: 701
  CrossrefSearch in Google Scholar

First total synthesis of halichondrin B:
• 2a Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK. J. Am. Chem. Soc. 1992; 114: 3162
  CrossrefSearch in Google Scholar

Total synthesis of norhalichondrin B by Phillips:
• 2b Jackson KL, Henderson JA, Motoyoshi H, Phillips AJ. Angew. Chem. Int. Ed. 2009; 48: 2346
  CrossrefSearch in Google Scholar

Total synthesis of halichondrin C:
• 2c Yamamoto A, Ueda A, Brémond P, Tiseni PS, Kishi Y. J. Am. Chem. Soc. 2012; 134: 893
  CrossrefSearch in Google Scholar

Review of synthetic work on halichondrins:
• 2d Jackson KL, Henderson JA, Phillips AJ. Chem. Rev. 2009; 109: 3044 ; and references cited therein
  CrossrefSearch in Google Scholar

For discovery and development of Halaven^® (1), see:
• 3a Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, DiPietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA. Cancer Res. 2001; 61: 1013
  Search in Google Scholar
• 3b Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ. Bioorg. Med. Chem. Lett. 2004; 14: 5551
  CrossrefSearch in Google Scholar
• 3c Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. US 6214865, 2001
• 3d Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. US 6365759, 2002
• 3e Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. WO 9965894, 1999
• 3f Yu MJ, Kishi Y, Littlefield BA In Anticancer Agents from Natural Products . Cragg GM, Kingston DG. I, Newman DJ. CRC Press; Boca Raton: 2005: 241-265
  Search in Google Scholar
• 3g Austad B, Chase CE, Fang FG. WO 2005118565, 2005
• 3h Newman S. Curr. Opin. Invest. Drugs 2007; 8: 1057
  Search in Google Scholar
• 3i Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, Wright J, Tan AR, DaCosta NA, Chuang E, Smith J, O’Shaughnessy J, Shuster DE, Meneses NL, Chandrawansa K, Fang F, Cole PE, Ashworth S, Blum JL. J. Clin. Oncol. 2009; 27: 2954
  CrossrefSearch in Google Scholar
• 3j Chiba H, Tagami K. J. Synth. Org. Chem. Jpn. 2011; 69: 600
  CrossrefSearch in Google Scholar
• 4 See accompanying article: Austad BC, Benayouda F, Calkins TL, Campagna S, Chase CE, Choi H.-w, Christ W, Costanzo R, Cutter J, Endo A, Fang FG, Hu Y, Lewis BM, Lewis MD, McKenna S, Noland TA, Orr JD, Pesant M, Schnaderbeck MJ, Wilkie GD, Abe T, Asai N, Asai Y, Kayano A, Kimoto Y, Komatsu Y, Kubota M, Kuroda H, Mizuno M, Nakamura T, Omae T, Ozeki N, Suzuki T, Takigawa T, Watanabe T, Yoshizawa K. Synlett 2013; 24: 327
  Thieme ConnectSearch in Google Scholar
• 5 See accompanying article: Chase CE, Fang FG, Lewis BM, Wilkie GD, Schnaderbeck MJ, Zhu X. Synlett 2013; 24: 323
  Thieme ConnectSearch in Google Scholar
• 6 Unpublished information.
• 7a Langer P, Wuckelt J, Döring M, Görls H. J. Org. Chem. 2000; 65: 3603
  CrossrefSearch in Google Scholar
• 7b Magnus PD. Tetrahedron 1977; 33: 2019
  CrossrefSearch in Google Scholar
• 8 The experiment was carried out with 3 (170 mg), deprotonated with n-BuLi (2.05 equiv), and coupled with 1 equiv of the doubly deuterated aldehyde D/D-5. After workup and reverse-phase column separation, the recovered aldehyde was found to contain 25% deuterium incorporation on the basis of ¹H NMR analysis and H integration. However, ¹H NMR analysis of the recovered sulfone indicated that deuterium had not been incorporated. LC–MS analysis of the isolated products revealed that the main products were sulfone–diol coupled adduct D/D-6 doubly deuterated at C2, monodeuterated aldehyde D/H-5, and 3.
• 9 See Ref. 4
• 10a Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
  CrossrefSearch in Google Scholar
• 10b Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
  CrossrefSearch in Google Scholar
• 11 Acceleration effect of water on Dess–Martin periodinane mediated oxidations: Meyer SD, Schreiber SL. J. Org. Chem. 1994; 59: 7549
  CrossrefSearch in Google Scholar
• 12 Wan Z.-K, Choi H.-W, Kang F.-A, Nakajima K, Demeke D, Kishi Y. Org. Lett. 2002; 4: 4431
  CrossrefSearch in Google Scholar
• 13 Catalytic NHK macrocyclization process that does not require high-dilution conditions: Namba K, Kishi Y. J. Am. Chem. Soc. 2005; 127: 15382
  CrossrefSearch in Google Scholar
• 14 Stamos DP, Sheng C, Chen SS, Kishi Y. Tetrahedron Lett. 1997; 38: 6355
  CrossrefSearch in Google Scholar

Ion-exchange-resin-based protocol is reported for effective construction of Halaven^®/halichondrin C8–C14 polycyclic ring system:
• 15a Namba K, Jun H.-S, Kishi Y. J. Am. Chem. Soc. 2004; 126: 7770
  CrossrefSearch in Google Scholar
• 15b Kaburagi Y, Kishi Y. Tetrahedron Lett. 2007; 48: 8967
  CrossrefSearch in Google Scholar
• 15c Dong C.-G, Henderson JA, Kaburagi Y, Sasaki T, Kim D.-S, Kim JT, Urabe D, Guo H, Kishi Y. J. Am. Chem. Soc. 2009; 131: 15642
  CrossrefSearch in Google Scholar
• 16 Hu Y. WO 2009124237, 2009

• Supplementary Material
• Primary Data