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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 June 13.
Published in final edited form as:
Tetrahedron Lett. 2008 April 1; 49(18): 2939–2941.
doi:  10.1016/j.tetlet.2008.03.018
PMCID: PMC2884163

A synthesis of the C1-C15 domain of the halichondrins


A concise route to the C1–C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a pyranone. The stereocenter of this pyranone serves as the starting point for the other 8 stereocenters.

In the context of the development of new reactions and strategies, the halichondrin class of marine macrolides1 has provided a substantial amount of inspiration to the synthesis community.2,3 The gross structures of these molecules, as exemplified by halichondrin B (1, Figure 1) are characterized by a 2,6,9-trioxatricyclo[,7]decane ring system embedded within a 31-membered lactone, and the presence of a number of polyoxyegnated pyranopyrans and furopyrans.

Figure 1
Halichondrin B.

We recently initiated studies directed toward the development of a total synthesis of the halichondrins,4 and in this paper we describe a concise synthesis of the C1–C15 domain of the halichondrins. An overview of the retrosynthesis of the C1–C15 subunit, 2 is presented in Figure 2. As can be seen, these plans are predicated on the use of the Achmatowicz oxidation for the conversion of a furfuryl alcohol to a pyranone (eg 8→7) which would serve as template for the synthesis of the fully functionalized C1–C11 pyranopyran, 4.

Figure 2
Overall synthesis plan for C1–C14.

The departure point for our venture was known alcohol 85,6 (Scheme 1) which was subjected to Achmatowicz oxidation7,8 with tert-butylhydroperoxide as oxidant and VO(acac)2 as catalyst to produce an intermediate pyranone hemiacetal in 83% yield. This pyranone hemiacetal was immediately subjected to O’Doherty’s benzoylation conditions9 to yield 9 (50%). Reduction of ketone 9 with NaBH4 gave alcohol 10 in 92% yield. Cross metathesis with methyl acrylate using 5 mol% of the Grubbs-Hoveyda catalyst in CH2Cl2 produced enoate 11 (82%), which was readily cyclized to pyranopyran 12 in 70% yield upon exposure to TBAF in THF. Subsequent Grieco oxidation10 of 12 with m-CPBA in the presence of BF3•OEt2 produced lactone 13 (85%). Dihydroxylation with catalytic OsO4 and NMO produced a very water soluble diol that was immediately subjected to TBSOTf in the presence of 2,6-lutidine to give bis-TBS ether 14 in 58% yield over the two steps. At this juncture we were able to exercise a selective olefination of the lactone carbonyl group using the Petasis reagent11 in 71% yield, and the enol ether was subjected to hydroboration with BH3•THF and subsequent oxidation with basic H2O2 to give the desired alcohol 15 in 48% yield. Assignment of the stereochemistry of this compound proved problematic, primarily due to the compression of 3JH,H coupling constants. Ultimately, in order to unequivocally determine the stereochemistry we resorted to the preparation of an authentic sample of this compound using Kishi’s reported route.12 Comparison of the material obtained by that route, and the material prepared by the route described in Scheme 1 showed that they were identical.

Scheme 1
Reagents and conditions

With a route to alcohol 15 secured, we were able to evaluate the utility of cross metathesis for the introduction of the enone required for formation of the 2,6,9-trioxatricyclo[,7]decane ring system (Scheme 2). To this end, alcohol 15 was oxidized to aldehyde 17 (Dess-Martin periodinane, 99%). Introduction of a vinyl group was best achieved using vinyl iodide under Nozaki-Hiyama-Kishi reaction conditions to give a 7:1 ratio of the desired product 18 to the undesired diastereoisomer in 85% combined yield. All other methods for the introduction of this group favored the chelation-controlled addition to produce the undesired diastereoisomer. Cross metathesis of 18 and 21 (10 equiv) to produce enone 19 was possible in 81% yield using 5 mol% of the Hoveyda-Blechert catalyst 1613 in toluene at 80 °C. Gratifylingly, when this enone was subjected to the aqueous HF conditions reported by Burke and coworkers,14 global desilylation, followed by hetero-Michael addition and acetalization gave the desired structure X in 36% yield.15 This yield could be dramatically improved by application of Kishi’s recently reported non-aqueous desilylation workup protocol16 followed by ketal formation using Kishi’s ion-exchange column system.17 Under these conditions, the desired compound was obtained in 90% yield.

Scheme 2
Reagents and conditions

In summary, we have described a concise route to the C1–C15 domain of the halichondrins that is based on an Achmatowicz reaction of a furfuryl alcohol. This oxidation produces a pyranone that serves as the template for the remaining stereocenters. Further applications of this strategy and progress toward the synthesis of the halichondrins will be reported in due course.


We thank Eli Lilly and Company (via Lilly Grantee Program), the AP Sloan Foundation and the National Cancer Institute (CA 110246) for support of this research. We thank Melissa Highfill for preliminary studies.


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1. (a) Uemura D, Takahashi K, Yamamoto K, Yamamoto T, Katayama C, Tanaka J, Okumura Y, Hirata Y. J. Am. Chem. Soc. 1985;107:4796. (b) Hirata Y, Uemura D. Pure Appl. Chem. 1986;58:701. (c) Pettit GR, Tan R, Gao F, Williams MD, Doubek DL, Boyd MR, Schmidt JM, Chapuis JC, Hamel E, Bai R, Hooper JNA, Tackett LP. J. Org. Chem. 1993;58:2538. (d) Litaudon M, Hickford SJH, Lill RE, Lake RJ, Blunt JW, Munro MHG. J. Org. Chem. 1997;62:1868.
2. 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.
3. For representative examples see the following papers and references cited therein: (a) Namba K, Jun H-S, Kishi Y. J. Am. Chem. Soc. 2004;126:7770. [PubMed] (b) Keller VA, Kim I, Burke SD. Org. Lett. 2005;7:737. [PubMed] (c) Horita K, Nishibe S, Yonemitsu O. Phytochem. Phytopharm. 2000:386. (d) Cooper AJ, Pan W, Salomon RG. Tetrahedron Lett. 1993;34:8193.
4. Henderson JA, Jackson KL, Phillips A. J. Org. Lett. 2007;9:5299. [PubMed]
5. Fürstner A, Nagano T. J. Am. Chem. Soc. 2007;129:1906. [PubMed]
6. All new compounds were fully characterized by 1H and 13C NMR, HRMS and IR.
7. The oxidation of furans to butenolides has been known since the mid-1960s. See for example: Ferland JM, Lefebvre Y, Deghenghi R, Wiesner K. Tetrahedron Lett. 1966:3617. and references cited therein.
8. For early examples of the Achmatowicz oxidation see: (a) Achmatowicz O, Jr, Bukowski P, Szechner B, Zwierzchowska Z, Zamojski A. Tetrahedron. 1971:1973. (b) Cavill GW, Laing DG, Williams PJ. Aust. J. Chem. 1969:2145. (c) Lefebvre Y. Tetrahedron Lett. 1972:133.
9. Harris JM, Keranen MD, Nguyen H, Young VG, O'Doherty GA. Carbohydr. Res. 2000;328:17. [PubMed]
10. Grieco PA, Oguri T, Yokoyama Y. Tetrahedron Lett. 1978:419.
11. Petasis NA, Bzowej EI. J. Am. Chem. Soc. 1990;112:6392.
12. Aicher TD, Kishi Y. Tetrahedron Lett. 1987;28:3463.
13. (a) Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000;122:8168. (b) Gessler S, Randl S, Blechert S. Tetrahedron Lett. 2000;41:9973.
14. Burke SD, Jung KW, Phillips JR, Perri RE. Tetrahedron Lett. 1994;35:703.
15. The NMR data for the final compounds matched those reported by Burke and co-workers (coupling constants in Hz):
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PositionBurke 1H δ (CDCl3)Phillips 1H δ (CDCl3)
CO2Me3.61–3.66 (m)3.64 (s, 3H)
2a2.41 (dd, J=15.8, 5.0)2.41 (dd, J =15.8 5.1)
2b2.49 (dd, J=15.8, 8.1)2.48 (dd, J=15.8, 7.9)
33.81 (m)3.80 (m)
4a1.33 (m)1.26–1.45 (m)
4b1.73 (m)1.73 (m)
5a1.41 (m)1.26–1.45 (m)
5b2.04 (m)2.02 (m)
64.25 (ddd, J=10.0, 9.6, 4.4)4.25 (m)
72.97 (dd, J=9.6, 1.8)2.97 (dd, J=9.6, 1.8)
84.39 (dd, J=3.9, 1.8)4.39 (dd, J=3.6, 1.7)
94.14 (dd, J=6.5, 3.9)4.13 (dd, J=6.6, 3.8)
104.20 (dd, J=6.5, 4.5)4.20 (dd, J=6.6, 4.5)
114.65 (dd, J=4.5, 4.4)4.64 (dd, J=4.5, 4.4)
124.71 (dd, J=5.0, 4.4)4.71 (dd, J=4.8, 4.6)
131.98 (d, J=13.4)1.97 (d, J=13.4)
15a3.61–3.66 (m)3.60–3.67 (m)
15b3.61–3.66 (m)3.60–3.67 (m)
PhCHH4.69 (d, J=12.2)4.69 (d, J=12.1)
PhCHH4.71 (dd, J=5.0, 4.4)4.71 (dd, J=4.8, 4.6)
Ph7.26–7.36 (m)7.23–7.36 (m)

16. Kaburagi Y, Kishi Y. Org. Lett. 2007;9:723. [PMC free article] [PubMed]
17. See ref 3(a)