Introduction

Eribulin (1) is a truncated derivative of halichondrin B (2), a complex natural product originally isolated from the marine sponge Halichondria okadai (Figure 1) . Already within their isolation study on halichondrin B, in 1986, Hirata and Uemura showed its promising activity against murine cancer cells , which led to a great interest in the pharmaceutical society . Only 6 years later, Kishi and co-workers first described the total synthesis of the marine natural product and shortly thereafter, also its simplified structure, 1, was assembled and showed similar anticancer behavior . Since 2010, the mesylate salt of 1 is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally advanced breast or metastatic cancer and has evolved to a commonly used agent for this type of cancer in nowaday’s medicine (commercial name: Halaven) . Therefore, the discovery of 1 also marked a significant milestone in the field of medicinal chemistry, as it exemplifies the successful translation of marine natural products into effective therapeutic agents.

Figure 1: Eribulin with common synthetic precursor fragments and halichondrin B.

The clinical importance of 1 primarily stems from its efficacy in treating aggressive and refractory cancers, notably metastatic breast cancer and liposarcoma . Historically, treatment options for advanced breast cancer have been limited, especially after patients have progressed on initial therapies such as anthracyclines and taxanes . 1 has demonstrated a significant survival benefit in this setting. Similarly, in liposarcoma, a rare but challenging soft tissue sarcoma, 1 has shown promise in prolonging overall survival and improving quality of life. The key feature that underpins 1's clinical importance is its unique mechanism of action . Unlike other microtubule inhibitors such as taxanes and vinca alkaloids, 1 binds to a specific site on tubulin, inhibiting microtubule growth without affecting its disassembly. This results in the suppression of mitotic spindle formation, leading to cell cycle arrest at the G2/M phase and subsequent induction of apoptosis. Its distinctive mode of action not only enhances its therapeutic efficacy but also helps in overcoming resistance mechanisms that limit the effectiveness of other microtubule-targeting agents.

Research continues to explore additional applications of 1 in various cancer types, including non-small cell lung cancer, ovarian cancer, and other soft tissue sarcomas. Moreover, ongoing studies aim to optimize combination therapies involving 1 with targeted agents, immunotherapies, and other chemotherapeutics to enhance its efficacy and reduce adverse effects .

Given the challenging structure of 1, its rapid development from first total synthesis to large scale production also highlights advances in the realm of synthetic chemistry. This progress was indispensable to ensure today`s broad accessibility, since only smallest quantities would be obtainable through isolation form its natural source (12.5 mg from 600 kg Halichondria okadai) . The commercial manufacture of 1 is carried out by the company Eisai and involves multiple linear and convergent synthesis paths (Scheme 1, 67 steps in total with the longest linear sequence of 32 steps from 8→9→12→1), which aim towards the merger of C1–C13 fragment 11 with C14–C35 fragment 12 . Despite these great advances, still, the research on improving synthetic efficiency, reducing production costs, omitting toxic chemicals, as well as on new pathways towards 1`s 4 heterocyclic precursor fragments is rigorously ongoing . In 2016, Bauer already reported on the current state of research, focusing on contributions from Kishi and co-workers and the Eisai process . However, due to the great demand of 1, this research field continues to grow. In this context, the following review should summarize and explain modern approaches towards the key fragments and total synthetic strategies for 1 in recent years.

Scheme 1: Overview of the industrial process pathway for the large-scale production of the mesylate salt of 1 by Eisai.

Review

In 2016, Konda and co-workers reported two approaches for the assembly of the tetrasubstituted tetrahydrofuran unit of 1 (Scheme 2 and Scheme 3) . For the first path, (S,S)-tartaric acid (13) was used as a starting material and was protected as acetonide within the first step to enable the reduction of both acid moieties towards 14 (Scheme 2). Bn-protection, followed by oxidation and olefination yielded sulfone 15, which was vinylated leading to 16 as a single diastereomer. Further Grubbs metathesis with ethyl acrylate, acidic cleavage of the diol protecting group and addition of NaH induced the oxy-Michael reaction towards 18 in 4:1 dr. Reduction of the ester moiety, subsequent protection with TBDPSCl and methylation of the secondary alcohol furnished 19. After Bn-deprotection, iodination and addition of vinylmagnesium bromide, 21 was received and dihydroxylated towards 22 in 5:1 dr.

Scheme 2: Synthesis of 22. (a) i. 2,2-dimethoxypropane, p-TsOH, MeOH, 65 °C; ii. NaBH4, MeOH, rt; (b) i. NaH, BnBr, THF, rt; ii. iodobenzoic acid, MeCN, 80 °C; iii. PhOOSCH2PO(OEt)2, NaH, THF, 0 °C; (c) vinylmagnesium bromide, CuI, THF, −78 °C; (d) i. ethyl acrylate, Grubbs cat 2nd generation, toluene, 110 °C; ii. p-TsOH, H2O, THF, 60 °C; (e) NaH, THF, 0 °C; (f) i. LiAlH4, THF, 0 °C to rt; ii. TBDPSCl, imidazole, DCM, 0 °C to rt; iii. MeI, Ag2O, DMF, 0 °C to rt; (g) i. Pd/C, H2, EtOAc; ii. I2, PPh3, imidazole, DCM, 0 °C to rt; (h) vinylmagnesium bromide, CuI, HMPA, THF, −30 °C; (i) OsO4, (DHQ)2PYR, 0 °C; (DHQ)2PYR: hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether.

The second path towards 27 commenced with the assembly of 23 from 14 via Bn-protection, following oxidation and Horner–Wadsworth–Emmons (HWE) reaction (Scheme 3). Stereospecific vinylation with a Gilman cuprate and acidic treatment afforded 25 in 13:1 dr. After protection with 2,6-DCBCl, reduction with LiAlH4, TBDPS-protection and methylation, 26 was received in 35% yield. Eventually, the addition of I2 triggered an iodocyclization towards 27. While in the first sequence only mg amounts of 22 were received, 1.45 g of 27 were obtainable during the second one from one batch (Scheme 3, step e) showing the scalability of this path. Moreover, besides 22 and 27, Konda and co-workers also accomplished the stereoselective syntheses of other diastereomers of the target tetrahydrofuran unit starting from 13.

Scheme 3: Synthesis of 27. (a) i. NaH, BnBr, THF, rt; ii. iodobenzoic acid, MeCN, 80 °C; iii. (EtO)2POCH2COOEt, NaH, THF, 0 °C; (b) vinylmagnesium bromide, CuI, THF, TMSCl, HMPA, −78 °C to rt; (c) 2 M HCl, THF, H2O, 65 °C; (d) i. Ag2O, 2,6-DCBCl, DMF, TBAI, rt, darkness; ii. LiAlH4, THF, 0 °C to rt; iii. TBDPSCl, imidazole, DCM, 0 °C to rt; iv. NaH, MeI, DMF, 0 °C; (e) I2, MeCN, −20 °C; 2,6-DCBCl: 2,6-dichlorobenzyl chloride.

The Kishi group has made major contributions in the area of 1 synthesis over the last three decades . Also recently, the group established a versatile protocol for the macrocyclization towards precursor 36 (Scheme 4 and Scheme 5) . Herein, fragments 31 and 33 were fused via Nozaki–Hiyama–Kishi (NHK) coupling and Pd-mediated cyclization. Fragment 31 was synthesized from known precursor 28 in 9 steps via MMTr-protection, replacement of the Bn- with TBDMS-protecting groups, hydroxylation of sulfone 29 to alcohol 30, tosylation, bromide substitution, acidic MMTr-cleavage and DMP-oxidation (Scheme 4, above). For the assembly of 33, only the hydrolysis of previously reported 32 with Me3SnOH and thioesterification using EtSH and DCC were necessary (Scheme 4, below).

Scheme 4: Synthesis of 31 and 33. (a) i. MMTrCl, iPr2NEt, DCM, rt; ii. K2CO3, MeOH, DCM, rt; iii. TBDMSCl, imidazole; (b) i. n-BuLi, THF, −78 °C, Sia2BH, −10 °C to rt; ii. H2O2, 3 M NaOH, 0 °C; (c) i. TsCl, DMAP, NEt3, DCM, rt; ii. NaBr, n-Bu4NBr, acetone, reflux; iii. HFIP, H2O, rt; iv. DMP; (d) i. Me3SnOH, DCE, 80–85 °C, then 0.1 M HCl; ii. EtSH, DCC, DMAP, DCM, rt; MMTrCl: 4-methoxytriphenylmethyl chloride; Sia2BH: disiamylborane; HFIP: 1,1,1,3,3,3-hexafluoroisopropanol.

Both fragments (31 and 33) were fused together via NHK coupling to furnish 34 in 86% yield. The addition of SrCO3 proved to be suitable for the cyclization towards 35 and the eventual macrocyclization was achieved via coupling of the alkyl bromide unit with the thioester. Mechanistically, this reaction is enabled by the formation of an intermediate alkylzinc halide, which is produced by single electron transfer using CrCl3 and NbCpCl4. The last steps towards 1 are known procedures . By comparison to former methods, this technique does not require further desulfonylation after the macrocyclization .

Scheme 5: Synthesis of 1. (a) CrCl2, 37, 38, 39 (proton sponge), LiCl, Mn, ZrCp2Cl2, MeCN, EtOAc; (b) SrCO3, t-BuOH, H2O, open air; (c) Pd2dba3, PCyp3, CrCl3, NbCpCl4, Zn(0), DMI, THF; PCyp3: tricyclopentylphosphine; DMI: 1,3-dimethyl-2-imidazolidinone.

Choi and co-workers used a previously reported protocol on stereo- and regioselective allene-Prins reactions for the assembly of fragment 45 (Scheme 6) . Here, 40 and 42 served as the substrates for the allene-Prins reaction towards 43. Notably, the Bz-derivative of 40, 41, served as a starting point for a corresponding halichondrin B analog. The stereoselective course of this cyclization is described in Scheme 6 below (R1 and R2 in equatorial position). From 43, the methylene unit in 44 was formed by Pd(0)-mediated generation of a π-allyl–palladium intermediate, followed by reductive termination (Tsuji-reduction), alongside the substrate-controlled alignment of the adjacent methyl substituent. Eventual change of the two PNB- with TBDMS-protecting groups yielded 45 in 58%. Notably, by this technique, the central pyran motif was assembled in one step and required only the stereoinformation of 42`s alcohol unit, while in former works two individual steps and the use of expensive metal catalysts were necessary .

Scheme 6: Synthesis of 45. Above: Reaction conditions: (a) methoxyacetic acid, BF3·OEt2, DCM, −30 °C; (b) Pd(PPh3)4, PPh3, HCOOH, NEt3, THF, 60 °C; (c) i. Mg(OMe)2, THF, MeOH, rt; ii. TBDMSCl, imidazole, DMF, rt. Below: Mechanism of the allene-Prins reaction.

In early 2018, Gaddam and co-workers assembled the northern fragment of 1 from ᴅ-mannose (48, Scheme 7) . The synthesis commenced with the protection of 48 as acetonide, vinylation and cyclization to 49 by the treatment with TsCl according to a procedure from Liu and co-workers . Regioselective deprotection, oxidative cleavage, reduction with NaBH4 and Bn-protection afforded 50, which was subsequently transformed to aldehyde 51 via ozonolysis and treatment with SMe2. Next, HWE reaction and acidic treatment triggered the cyclizations towards enone 53. Protection of the free alcohol unit enabled the transformation towards 55, which involved the reduction of lactone to lactole, protection of the alcohol as acetate, BF3·Et2O-mediated C-allylation of the aldehyde (via oxocarbenium intermediate) and cyclization (oxy-Michael reaction). Hydroboration–oxidation, stereoselective dihydroxylation with AD-mix β and diol-protection yielded acetonide 57. Another DMP-oxidation, followed by HWE reaction, and deprotection of the diol motifs enabled the cyclization towards 60. After TBDMS-protection and reduction to the respective aldehyde (62), an alkylation with the α-sulfonyl carbanion of 65 (intermediate from the Eisai process ) via interrupted Julia olefination was performed to furnish 63. Eventually, 64 was received by oxidation and SmI2-induced desulfonylation. Herein, Gaddam and co-workers enable the synthesis of 1 by the merger of northern fragment 64 with a potential southern fragment (ongoing research by the same group) and thereby provide an alternative approach to the current one by Eisai .

Scheme 7: Synthesis of 64. Reaction conditions: (a) i. acetone, I2, rt; ii. vinylmagnesium bromide, THF, −20 °C to rt; iii. TsCl, pyridine, 65 °C; (b) i. AcOH, rt; ii. NaIO4, MeOH, 0 °C to rt; iii. NaBH4, MeOH, 0 °C to rt; iv. NaH, BnBr, 0 °C to rt; (c) i. O3, DCM, −78 °C; ii. SMe2; (d) (PhO)2POCH2COOMe, KHMDS, 18-crown-6, THF, −78 °C; (e) p-TsOH, toluene, H2O, 100 °C; (f) MOMCl, DIPEA, DCM, 0 °C to rt; (g) i. DIBAL-H, DCM, −78 °C; ii. Ac2O, pyridine, DMAP, DCM, rt; iii. allyl-TMS, BF3·Et2O, DCM, −78 °C; (h) 9-BBN, THF, H2O2, 0 °C to rt; (i) i. AD-mix β, MsNH2, t-BuOH, H2O, rt; ii. 2,2-dimethoxypropane, (±)-CSA, DCM, rt; (j) i. DMP, DCM, rt; ii. Ph3PCH2COOEt, toluene, rt; (k) p-TsOH, EtOH, reflux; (l) i. DBU, toluene, reflux; ii. TBAF, THF, rt; (m) TBDMSCl, imidazole, DCM, 50 °C; (n) DIBAL-H, toluene, −78 °C; (o) 36, n-BuLi, −78 to −50 °C; (p) i. DMP, DCM, rt; ii. SmI2, MeOH, THF, −78 to −50 °C; 18-crown-6: 1,4,7,10,13,16-hexaoxacyclooctadecane, 9-BBN: 9-borabicyclo[3.3.1]nonane, (±)-CSA: camphorsulfonic acid.

Shortly thereafter, Kim and co-workers made use of 66, a byproduct formed during the multigram synthesis of Halaven, to assemble 79 (Scheme 8) . 66 was received within a filtrate during this process and isolated as a diastereomeric mixture of 2.6:1. At first, the benzyl moieties of 66 were cleaved off and the diol was reprotected as acetonide to afford 67. The remaining secondary alcohol was PMB-protected and the olefin was oxidatively cleaved, before addition of a lithiated furanyl unit took place. The so-obtained 1:1 diastereomeric mixture of 68 was treated with (PhO)3PMeI in dimethylacetamide and formed an intermediate trans-olefin, which subsequently underwent an asymmetric Sharpless dihydroxylation. The acetonide was cleaved with AcOH and the addition of NBS under basic conditions triggered an Achmatowicz rearrangement (shown in Scheme 8, below) to assemble a hydropyranone ring . Eventual acetylation of the free alcohol units afforded 70 in 3:1 dr. C-Glycolysation with allyl-TMS and oxidative cleavage of the PMB moiety yielded 71. The stereochemistry of the secondary alcohol unit of 71 was changed via oxidation and stereospecific reduction, then 1,4-reduction of the enone and treatment with camphorsulfonic acid led to fully cyclized intermediate 72 as a single isomer. During this process the acetate groups were cleaved off and had to be reinstalled using acetic anhydride. Oxidative cleavage of olefin 73, followed by treatment with ʟ-proline led to an intermediate β-aldehyde with inverted stereochemistry at the β-C (4:1 dr). Subsequent reduction with NaBH4 yielded alcohol 74. Piv-protection of the primary alcohol, reductive deprotection of the Bn-moiety and reprotection with (iPr)2SiHCl afforded 75. The addition of BF3·OEt2 at low temperatures induced the fluorination of the silane protecting group and a follow-up intramolecular hydride transfer (via 76). Afterwards, the introduced fluoride was substituted with Mg(OMe)2 in MeOH and the stereochemistry of the central protected alcohol unit was inverted within a sequence involving deprotection of all acetates, protection of the 1,2-diol as an acetonide, oxidation of the central alcohol with DMP and stereospecific reduction, which yielded alcohol 78. Finally, the silyl protecting group was cleaved with TBAF leading to 79. Although the synthesis of 79 through this method is quite laborious, especially with regard to all necessary adjustments of stereocenters, the idea of recycling byproducts of Halaven production clearly shows the advancements in this process. Therefore, this route should not be valued solely for its total yield, but rather as a starting point for improving atom economy.

Scheme 8: Synthesis of 79. Above: Reaction conditions: (a) i. K2CO3, MeOH, 60 °C; ii. 2,2-dimethoxypropane, H2SO4 (aq), acetone, rt; (b) i. PMBCl, t-BuOK, TBAI, DMF, THF, rt; ii. OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane, H2O, −20 °C; iii. N-BuLi, furan, THF, 0 °C; (c) i. (PhO)3PMeI, dimethylacetamide, rt; ii. AD-mix-α, t-BuOH, H2O, rt; (d) i. AcOH, H2O, rt; ii. NBS, NaHCO3, NaOAc, THF, H2O, 0 °C; iii. acetic anhydride, pyridine, DCM, 0 °C; (e) i. allyl-TMS, BF3·OEt2, MeCN, −10 °C; ii. DDQ, DCM, H2O; (f) i. DMP, NaHCO3, DCM, rt; ii. NaBH4, DCM, MeOH, −78 °C; iii. Stryker’s reagent, toluene, rt; iv. (±)-CSA, MeOH, 60 °C; (g) acetic anhydride, DMAP, DCM, rt; (h) i. OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane, rt; ii. ʟ-proline, MeOH, −10 °C; iii. NaBH4, MeOH, 0 °C; (i) i. PivCl, pyridine, DMAP, DCM, rt; ii. H2, Pd/C, MeOH, EtOAc, rt; iii. (iPr)2SiHCl, imidazole, DMAP, DCM, rt; (j) BF3·OEt2, DCM, −20 to −10 °C; (k) i. Mg(OMe)2, MeOH, rt; ii. 2,2-dimethoxypropane, pyridinium p-toluenesulfonate, acetone, rt; iii. DMP, NaHCO3, DCM, rt; iv. NaBH4, MeOH, 0 °C; (l) TBAF, THF, rt. Below: Mechanism of the Achmatowicz rearrangement during step (d).

The same group also reported on a metal-free synthesis of 92 starting from an intermediate occuring during the current large-scale production of Halaven (Scheme 9) . Initially, the diol motif of 85 was protected with TESCl, then regioselective oxidation of the primary TES ether and addition of vinyl grignard led to 87. Another oxidation afforded α,β-unsaturated carbonyl 88 and acidic treatment with BnOH triggered the oxa-Michael reaction and transketalization towards tetracyclic 90. Following Kishi reduction , epimerization of the secondary alcohol was effected via DMP-oxidation, and stereospecific reduction with Li(t-BuO)3AlH yielded 92. In comparison to the current pathway from 85 to 92, which involves the use of heavy metals adding considerable amounts of cost , this technique stands out for the employment of cheaper and more eco-friendly reagents.

Scheme 9: Synthesis of 92. Reaction conditions: (a) TESCl, imidazole, DCM, 0 °C to rt; (b) i. oxalyl chloride, DMSO, NEt3, DCM, −78 °C; ii. vinylmagnesium bromide, THF, −70 °C; (c) DMP, NaHCO3, DCM, rt; (d) BnOH, p-TsOH·H2O, toluene, 70–75 °C; (e) BF3·OEt2, Et3SiH, DCM, 0 °C to rt; (f) i. DMP, NaHCO3, DCM, 0 °C; ii. Li(t-BuO)3AlH, THF, 0−10 °C.

In 2019, Lee and co-workers developed a technique towards the octahydropyrano[3,2-b]pyran fragment of 1 from ᴅ-gluconolactone (93) (Scheme 10) . After protection of 93, the lactone unit was reduced with DIBAL-H and the emerging aldehyde motif (equilibrium of lactol to aldehyde and alcohol) was trapped by HWE reaction to obtain 95. The secondary alcohol unit of 95 was protected and the ester reduced to the respective alcohol, before Sharpless epoxidation, oxidation of the alcohol and subsequent Wittig reaction yielded allylic epoxide 98. Deprotection of the alcohol motif of 98 enabled the cyclization towards tetrahydropyran 99. Next, 99 underwent an esterification with acrylic acid, was cyclized via Grubbs metathesis and the remaining double bond was hydrogenated leading to bicyclic core structure of 101. Notably, during the cyclization also considerable amounts of dimerized product were observed. Again, reduction with DIBAL-H led to the regioselective deprotection of the alcohols and reduction to an intermediate lactol unit, which is in equilibrium with its acyclic aldehyde and alcohol. The aldehyde was trapped by HWE reaction and the so obtained α,β-unsaturated carbonyl was reattacked by the adjacent hydroxy moiety via oxy-Michael reaction to form 102. This sequence is shown in detail in Scheme 10 below. From here, a sequence involving the oxidation of the unprotected 1,2-diol moiety towards an intermediate aldehyde, Ni(II)/Cr(II)-mediated coupling of 1-bromo-2-trimethylsilylethene, acidic cleavage of the remaining cyclohexylidene ring, TBDMS-protection of the three alcohol units and electrophilic substitution of the silyl moiety to afford vinyl iodide 103 was applied. Eventually, ester 103 was reduced to target aldehyde 104, which contains the necessary functional group pattern to be used as a building block for the assembly of 1. By the design of this novel synthetic pathway, Lee and co-workers showed that the commonly used NHK reaction involving dual chromium/nickel catalysis can be circumvented . Here, intramolecular ring opening of epoxide 98 and metathesis led to target 104 with high regio- and stereoselectivity.

Scheme 10: Synthesis of 104. Above: Reaction conditions: (a) cyclohexanone, p-TsOH, toluene, 110 °C, crystallization. (b) i. DIBAL-H, THF/toluene, −10 °C; ii. Ph3PCHCO2Et, benzoic acid, DCM, 50 °C; (c) i. TESOTf, 2,6-lutidine, DCM, 0 °C; ii. 5 mol % Pn-Bu3 (5 mol %), THF, 50 °C; (d) DIBAL-H, DCM, 20 °C; (e) i. (−)-DET, Ti(OiPr)4, DCM, 0 °C; ii. DMP, DCM, 0 °C; iii. MePPh3Br, NaHMDS, THF, 0 °C; (f) i. TBAF, THF, 0 °C; ii. pyridinium p-toluenesulfonate, DCM, 0 °C; (g) acrylic acid, DIC, DMAP, DCM, rt; (h) i. Grubbs cat 2nd generation, toluene, reflux; ii. Pd/C, H2, EtOAc; (i) i. DIBAL-H, THF/toluene, 10 °C ; ii. triethyl phosphonoacetate, t-BuOK, THF, 60 °C; iii. AcOH, 40 °C; (j) i. NaIO4, EtOAc, 15 °C; ii. CrCl2, NiCl2, 1-bromo-2-trimethylsilylethene, DMSO, MeCN, 30 °C; iii. AcOH, H2O, 95 °C, crystallization; iv. TBDMSOTf, 2,6-lutidine, MTBE, 30 °C, crystallization; v. NIS, MeCN, toluene, TBDMSCl, 35 °C; (k) DIBAL-H, 2,6-di-t-Bu-4-hydroxytoluene, toluene, 65 °C. Below: Reaction sequence towards 102; DIC: N,N′-diisopropylcarbodiimide.

A novel approach towards C1–C10 fragment of 1 was reported by Kathravath and co-workers (Scheme 11) . From ʟ-ascorbic acid (108), protection of the diol motif and treatment with H2O2, then EtI yielded ester 109. The alcohol motif was protected with BnBr, before the ester unit was completely reduced to the respective alcohol and selectively oxidized to aldehyde 110. After HWE reaction, the dihydroxylation of (Z)-111 furnished diol 112 in 7:3 dr. The shown major diastereomer of 112 was cyclized towards 113 upon acidic treatment and TBDMS-protection. Reduction, cleavage of the silyl-protecting groups and acetylation led to tetrahydropyran 114. Lewis acid-catalyzed C-allylation, cross metathesis, basic cleavage of the acetate motifs and transesterification enabled the DBU-induced isomerization of 116’s double bond and following oxy-Michael reaction to the target compound 117. In total, 117 was obtained in a yield below 1% via the 17-step sequence, mainly due to mediocre yields (partially due to unselective reactions) in steps c→g.

Scheme 11: Synthesis of 117. (a) i. acetone, CuSO4, rt; ii. H2O2, K2CO3, H2O, rt; iii. EtI, MeCN, 70 °C; (b) i. Ag2O, BnBr, toluene, rt; ii. LiAlH4, THF, rt; iii. (COCl)2, NEt3, DMSO, DCM, −78 °C; (c) (PhO)2POCH2COOEt, DBU, THF, −78 °C; (d) K3(FeCN)6, OsO4, K2CO3, (DHQ)2PHAL, t-BuOH, H2O, 0 °C; (e) i. TFA, H2O, MeCN, 70 °C; ii. TBDMSCl, imidazole, DMAP, DMF, 55 °C; (f) i. DIBAL-H, toluene, −78 °C; ii. TBAF, THF, rt; iii. Ac2O, NaOAc, 90 °C; (g) BF3·OEt2, MeCN, 80 °C, allyltrimethylsilane; (h) allyl-COOBn, Grubbs cat 2nd generation, DCM, 40 °C; (i) i. K2CO3, MeOH, rt; ii. DBU, toluene, 100 °C; (DHQ)2PHAL: hydroquinine 1,4-phthalazinediyl diether.

In the following year, Krishna and co-workers used an enzymatic transformation for the continuous flow production of acetate 121 (C14–C19‘ fragment), which is a starting material needed in large quantities for the total synthesis of 1 (Scheme 12) . Herein, pent-4-en-1-ol (118) was protected with TBDPSCl, before ozonolysis, followed by reduction with PPh3 yielded aldehyde 119. The addition of propargyl bromide led to racemic 120. By the use of a flow setup involving a column packed with Amano lipase, an enzyme from the bacterium Pseudomonas fluorescens, a kinetic resolution of 120 was performed leading to the continuous production of acetate 121 and free alcohol 122. Here, 121 bears the right configuration needed for Halaven synthesis, but the authors also showed that 122 was easily converted to 121 via Mitsunobu inversion. Although 121 only represents a small building block for the total assembly of 1, this method especially stands out for its cost-efficiency and the continuous production in bigger scales (100 mg/mL (272 mM) at 0.1 mL/min).

Scheme 12: Synthesis of 121. Reaction conditions: (a) i. TBDPSCl, imidazole, DMF, rt; ii. O3, DCM, −78 °C; iii. PPh3, rt; (b) propargyl bromide, Zn, NH4Cl, THF, −15 °C; (c) enzyme, vinyl acetate, MTBE, continuous flow reactor, rt; enzyme: Amano lipase produced by Pseudomonas fluorescens.

In 2021, Mallurwar and co-workers used (R,R)-tartaric acid (123) for the assembly of fragment 131 (Scheme 13) . After diol-protection as acetonide and reduction of the acid motifs to receive diol 124, one alcohol moiety was Bn-protected, while the other one was iodinated. From 125, the addition of vinylmagnesium bromide and acidic deprotection furnished diol 126, which underwent an iodocyclization towards a diastereomeric mixture of 127 (4:1 dr). The shown main diastereomer of 127 could be isolated and underwent TBDPS-protection, which enabled the malonic ester synthesis towards 128. Reduction with subsequent Piv-protection and TBDPS-deprotection was followed by DMP-oxidation. Finally, the olefination of 129 with PPh3MeBr and addition of TiCl4 for the cleavage of the Bn-moiety furnished target structure 131.

Scheme 13: Synthesis of 131. (a) i. 2,2-dimethoxypropane, p-TsOH, MeOH, 60 °C; ii. LiAlH4, THF, 0 °C to rt; (b) i. NaH, BnBr, THF, rt; ii. PPh3, imidazole, I2, THF, 50–60 °C; (c) i. vinylmagnesium bromide, CuI, HMPA, −30 °C; ii. p-TsOH, THF, H2O, 23 °C; (d) I2, NaHCO3, Et2O, H2O, 0 °C; (e) i. TBDPSCl, imidazole, DCM, 0 °C; ii. NaH, diethyl malonate, TBAI, DMF, 120 °C; iii. DMSO, NaCl, 160 °C; (f) i. LiAlH4, THF, 0 °C to rt; ii. PivCl, NEt3, DCM, 0 °C to rt; iii. TBAF, THF, 0 °C to rt; iv. DMP, DCM, 0−20 °C; (g) PPh3MeBr, n-BuLi, THF, 0 °C; (h) TiCl4, DCM, 0 °C.

Within the same work, a similar fragment (143) was synthesized using an oxy-Michael reaction as the key step (Scheme 14). Starting material 132 was obtained from natural ʟ-ascorbic acid (108) by a sequence involving the protection of diol motif, oxidative cleavage, reduction and regioselective Bn-protection. 132 was further iodinated and reacted with vinylmagnesium bromide to afford 133 in 48% yield. Consecutive acidic deprotection, TBDMS-protection of the secondary alcohol, dihydroxylation, oxidative cleavage and olefination with Ph3PCHCOOEt yielded acrylic acid ester 135. The addition of benzyltrimethylammonium hydroxide induced the oxy-Michael reaction towards an unseparable mixture of 137 and 138, and 136. A plausible explanation for the formation of 138 could be a [1,2]-rearrangement of the deprotonated alcohol motif and the OTBDMS-moiety of 137 via an epoxide intermediate (indicated in arrows) and subsequent oxy-Michael reaction. The mixture (137 + 138) was treated with p-TsOH leading to alcohols 139 and 140, which were separated via chromatography. From 140, Bn-deprotection of the primary, followed by Bn-protection of the secondary alcohol unit afforded 141 in 52% yield. Eventually, the ester motif of 141 was reduced to the respective alcohol and Piv-protected, and the secondary alcohol oxidized to an intermediate ketone, then olefinated towards 143. Although both sequences require multiple applications and removals of protecting groups, they represent attractive pathways towards the C14–C21 fragment of 1 due to the use of inexpensive starting materials.

Scheme 14: Synthesis of 143. (a) i. I2, PPh3, imidazole, DCM; ii. HMPA, CuI, vinylmagnesium bromide, THF, −20 °C; (b) i. p-TsOH, MeOH, rt; ii. TBDMSCl, imidazole, DCM; (c) i. OsO4, NMO, THF, H2O, 0 °C; ii. NaIO4, THF, H2O, 0 °C; iii. Ph3PCHCOOEt, DCM, rt; (d) benzyltrimethylammonium hydroxide, EtOH, 0 °C to rt; (e) p-TsOH, MeOH, rt; (f) i. Pd/C, H2, EtOAc; ii. Ag2O, BnBr, toluene, rt; (g) i. LiAlH4, THF, 0 °C; ii. PivCl, NEt3, DMAP, DCM, rt; (h) i. DMP, DCM, 0 °C; ii. PPh3CH2Br, n-BuLi, THF, 0 °C to rt.

Kim and co-workers enhanced the procedure from Lee and co-workers by changing few intermediate steps (Scheme 15) . From 144, the authors performed a HWE reaction towards 145 in 80%. Cleavage of the TES-protecting group and Rh(I)-induced cyclization afforded 147 in good yield, which was hydrogenated subsequently. Thereafter, DIBAL-H reduction led to lactol formation towards 149, which intercepted the former route (Scheme 10, step (i) i.) With these changes, the synthesis was enhanced with regard to scalability of the process. Scaling up the Grubbs metathesis of the first route (Scheme 10, step (h) i.) led to an increasement of dimer yield derived from cross metathesis reactions. Therefore, by the replacement with the Rh(I)-catalyzed cyclization performed herein, this drawback is circumvented and the reactions were performed with kg amounts.

Scheme 15: Modified synthesis of 104. Reaction conditions: (a) (EtO)2POCH2COOEt, KOt-Bu, THF, 15 °C; (b) TBAF, imidazole·HCl, THF, 5 °C to rt; (c) [Rh(CO2)Cl]2 (0.5 mol %), THF, 60 °C; (d) H2, Pd/C, EtOAc, rt; (e) DIBAL-H, toluene, −65 °C.

In 2021, Senapati and co-workers developed a route towards key fragment 161 containing the 3-methylenetetrahydrofuran and the 3-methylenetetrahydro-2H-pyran motifs of 1 (Scheme 16) . As a cheap and commerically available starting material, ᴅ-glyceraldehyde (150) was chosen and allylated with crotyl bromide according to a procedure from Loh and co-workers . The diastereomeric mixture thus obtained was separated via chromatography and (R)-151 was protected using BnBr. After hydroboration–oxidation and DMP-oxidation to the respective aldehyde, Ohira–Bestman reaction was applied to afford 154. Allylation and acidic deprotection led to diol 156 in excellent yields. Next, Au(I)-catalyzed cyclization and reduction led to tetrahydropyran 157, which was TBDMS-protected subsequently. The cross metathesis of 158 and 162 (obtained from ʟ-glutamic acid) yielded 159 in 81%. After mesylation of the free alcohol moiety and dihydroxalation using AD-mix α, a diastereomeric mixture of tetrahydropyrans (R)-160 and (S)-160 was obtained and separated for analytical purposes. The Bn-moiety of (S)-160 was cleaved using DDQ and the intermediate diol was further transformed to the respective dicarbonyl via Swern oxidation, and finally olefinated via Wittig reaction. Hence, by the use of one-pot Au(I)-catalyzed cyclization/Kishi reduction for the assembly of the tetrahydropyran and cross metathesis/Sharpless dihydroxylation/etherification for the tetrahydrofuran motifs, this pathway describes a novel and sustainable, but not fundamentally improved alternative in terms of yield towards the structure of 161 (7.2% yield over 14 steps).

Scheme 16: Synthesis of 161. Reaction conditions: (a) crotyl bromide, Sn, TBAI, NaI, DMF/H2O, rt; (b) NaH, BnBr, DMF, rt; (c) 9-BBN, THF, NaOH·H2O2, EtOH, rt; (d) i. DMP, NaHCO3, DCM, rt; ii. Ohira–Bestmann reagent, MeOH, rt; (e) allyl bromide, K2CO3, CuI, Na2CO3, DBU, DMF, rt; (f) AcOH (60%), rt; (g) i. Au(PPh3)Cl (1 mol %), AgSbF6 (1 mol %), DCM, rt; ii. Et3SiH, BF3·OEt2, 0 °C; (h) TBDMSCl, imidazole, DMF, rt; (i) 162, Grubbs cat 2nd generation, CuI, Et2O, 40 °C; (j) i. MsCl, NEt3, DCM, 0 °C; ii. AD-mix α, MsNH2, t-BuOH, H2O, 0 °C; (k) i. DDQ, DCM, 45 °C; ii. TFAA, DMSO, DIPEA, DCM, −78 °C; iii. Ph3PCH2, toluene, 40 °C.

In the same year, Nicolaou and co-workers achieved the total synthesis of halichondrin B, which included the assembly of C1–C26‘ fragment 186 (Schemes 17–19) . To afford 3-methylene tetrahydrofuran 169, both starting materials, 163 and 164, were prepared within few steps from commercially available sources . The etherification of 163 and 164 (Nicholas reaction) led to a diastereomeric mixture, which was separated (Scheme 17). (S)-165 was converted to 166 via radical cyclization, then the TBDPS-protecting group was cleaved and the obtained alcohol oxidized to aldehyde 167. The Cr(II)/Co(II)-induced asymmetric NHK coupling mediated by 172 with vinyl iodide 171 led to tetrahydrofuran 168. Protection of the secondary alcohol enabled the conversion to ketophosphonate 169 using MePO(OMe)2 and n-BuLi. Notably, building block 171 used herein can be synthesized from 170 within 6 steps including a kinetic resolution with Amano lipase PS-800.

Scheme 17: Synthesis of 169. Reaction conditions: (a) i. Co2(CO)8, BF3·Et2O, DCM, 23 °C; ii. CAN, acetone, 0 °C; (b) AIBN, n-Bu3SnH, toluene, 100 °C; (c) i. TBAF, THF, 0–23 °C; ii. DMP, DCM, 0–23 °C; (d) 171, CrCl2, CoPc, 172, LiCl, Mn, 39 (proton sponge, see Scheme 5), ZrCp2Cl2, DME, 23 °C; (e) i. TBDMSOTf, 2,6-lutidine, DCM, −78–0 °C; ii. N-BuLi, MePO(OMe)2, THF, −78 °C; (f) i. TMSCl, NaI; ii. m-MePhCOOH, NaHCO3; iii. ClPO(OEt)2; iv. AlMe3, CuBr; v. Amano lipase PS-800; vi. I2, PPh3, imidazole; CAN: ceric ammonium nitrate.

Another fragment, 181, was synthesized from alcohols 173 and 174, which were perpared from tri-O-acetyl-ᴅ-glucal and (S)-methyl-2,3-dihydroxypropanoate, respectively (Scheme 18) . Again, Nicholas etherification of both starting materials was conducted to afford 175 in 5:1 dr. The major isomer was further transformed to 176 in a microwave oven via Kornblum oxidation. Radical cyclization and DMP-oxidation yielded intermediate 178, which was reduced with K-selectride, before acidic treatment was applied to remove the TBDPS-protecting group and the tin moiety. From 179, ozonolysis and subsequent reduction afforded 180 stereoselectively, and eventual protection of the 1,2-diol motif followed by oxidation yielded aldehyde 181.

Scheme 18: Synthesis of 181. Reaction conditions: (a) i. Co2(CO)8, BF3·Et2O, DCM, 23 °C; ii. (NH4)2Ce(NO3)6, acetone, 0–23 °C; (b) DMSO, 2,4,6-collidine, microwave, 180 °C; (c) AIBN, n-Bu3SnH, toluene, 100 °C; (d) DMP, NaHCO3, DCM, 23 °C; (e) i. K-selectride, THF, −20–0 °C; ii. HCl (aq.); (f) i. O3, MeOH, −78 °C; ii. NaBH4, 23 °C; (g) i. 2,2-dimethoxypropane, p-TsOH·H2O, acetone, 0–23 °C; ii. DMP, DCM, 0–23 °C.

Both building blocks from Scheme 17 and Scheme 18 were fused together via HWE reaction to construct 182 (Scheme 19). Treatment with HF·pyridine led to cleavage of the acetonide- and TBDMS-protecting groups, which induced the oxy-Michael cyclization towards 183. Notably, during this cyclization also considerable amounts of 183`s epimer were formed (2:1 dr). Oxidation with DDQ removed the Bn-moiety (184) and triggered ketalization towards 185. Eventual mesylation formed key fragment 186 in 95% yield. For the assembly of both heterocyclic subunits of 186, Nicholas etherification and radical cyclization proved to be suitable, but only moderately yielding, procedures. Further, this pathway, with the exception of the coupling reaction between 167 and 171, involves only simple and mild transformations using standard reagents. As mentioned above, 186 served as an intermediate for the total synthesis of halichondrin B, which was assembled in a total of 25 steps.

Scheme 19: Synthesis of 186. Reaction conditions: (a) NEt3, LiCl, MeCN, 0–23 °C; (b) HF·pyridine, MeCN, 23 °C; (c) DDQ, hν, MeCN, 23 °C; (d) MsCl, NEt3, DMAP, DCM, 0 °C.

One year later, Nicolaou and co-workers focused specifically on the total synthesis of 1 and therefore optimized few steps from their previous halichondrin B synthesis (Schemes 20–23) . Hence, for the assembly of fragment 181 the route shown in Scheme 18 was intercepted at 176. Instead of the previous radical cyclization, here, a reductive Ni(II)-induced cyclization afforded 188 (Scheme 20). Oxidation and ozonolysis with subsequent addition of NaBH4 yielded diol 190, whose TBDPS-group was cleaved under acidic conditions, before the 1,2-diol motif was protected as acetonide. Eventually, DMP-oxidation afforded aldehyde 181.

Scheme 20: Modified synthesis of 181. Reaction conditions: (a) i. Ni(cod)2, P(n-Bu)3, Et3SiH, THF, 23 °C; ii. HCl (aq), 23 °C; (b) DMP, DCM, 0–23 °C; (c) i. O3, MeOH, −78 °C; ii. NaBH4, −78–23 °C; (d) HCl (aq), acetone, MeOH, 0–23 °C; (e) DMP, DCM, 0–23 °C.

The synthesis of fragment 200 was accomplished starting from substrates 192 and 193 (Scheme 21). After Nicholas etherification of both substrates, which led to a diastereomeric mixture, (S)-194 was isolated and further treated with Lindlar catalyst and DIBAL-H to afford the alkene and aldehyde motifs of 195, respectively. Oxime formation and oxidation yielded an intermediate nitrile oxide, which underwent an intramolecular [3 + 2]-cycloaddition with the adjacent ethene substituent towards isoxazoline 196. Reductive N–O bond cleavage and stereospecific reduction with Me4NBH(OAc)3 yielded diol 198, whose primary alcohol unit was PMB-protected, while the secondary one was methylated. Dihydroxylation and protection with 2,2-dimethoxypropane yielded 199. Then, desilylation with TBAF and DMP-oxidation led to aldehyde 200.