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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Org Lett. Author manuscript; available in PMC 2010 October 15.
Published in final edited form as:
PMCID: PMC2759418
NIHMSID: NIHMS146300

Second Generation Synthesis of C27-C35 Building Block of E7389, A Synthetic Halichondrin Analog

Abstract

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A practical method is reported to synthesize E7389 C27-C35 building block (13) from 1,2-O-isopropylidene-α-D-5-deoxyglucurono-6,3-lactone (3). This synthesis relies on two key processes: (1) C34/C35-diol is introduced via asymmetric dihydroxylation with dr = 3:1, with the undesired C34-diastereomer effectively removed by crystallization of 11 and (2) C30 PhSO2CH2-group is introduced stereoselectively (>100:1) via hydrogenation of 12 in the presence of the Crabtree catalyst. The reported synthesis is practically free from chromatographic separation.

Halichondrins are polyether macrolides, originally isolated from the marine sponge Halichondria okadai by Hirata and Uemura, which have received much attention due to their intriguing structure and extraordinary in vitro and in vivo antitumor activity.1 On completion of the total synthesis of halichondrin B, norhalichondrin B, and homohalichondrin B,2,3 we asked the late Dr. Suffness at the National Cancer Institute (NCI) and Dr. Littlefield at Eisai Research Institute (ERI) to test the in vitro and in vivo antitumor activities of the totally synthetic halichondrins as well as several synthetic intermediates. The results were sensational; their experiments clearly demonstrated that the antitumor activity of halichondrin B resides in the right portion of the molecule. With this crucial information,4 a massive drug discovery effort was undertaken by ERI, resulting in two exceptional drug candidates, one (E7389) of which is currently at the late stage of Phase III clinical trial.5 This is exciting news for us, partly because we have been involved in the chemistry of halichondrins from its infancy, but largely because we believe in the potential that the halichondrins offer to cancer chemotherapy. However, we should point out that, to our best knowledge, the structural complexity of the right half of halichondrin B, or E7389, exceeds by far the structural complexity of synthetic drugs on the market and/or synthetic drug candidates under development. Thus, an economically feasible synthesis of the right half of halichondrin B and/or Eisai’s drug candidate will play the key role for ultimate success of this program. With this analysis in mind, we have continued the synthetic studies on the halichondrins.6 In this letter we report a second-generation synthesis of the E7389 C27-C35 building block, which has several appealing features, including overall efficiency, operational simplicity, and scalability.

In the first generation synthesis of E7389 C27-C35 building block, we chose 1,2-O-isopropylidene-α-D-5-deoxyglucurono-6,3-lactone (3) as the starting material.2c This synthesis relies on two key processes (Scheme 1). First, the C34/C35-diol was incorporated via catalytic asymmetric dihydroxylation. Asymmetric dihydroxylation of terminal olefins is known to often proceed with relatively low asymmetric induction; for the case of 5, asymmetric dihydroxylation was best achieved with Sharpless (DHQ)2PYR, to yield a 3:1 mixture of the C34 diastereomers. 7, 8 Fortunately, the undesired C34-diastereomer was effectively removed by crystallization of 6. Second, the C30 stereocenter was stereospecifically introduced via NaBH(OAc)3-reduction under the influence of the C31 hydroxyl group, cf., 7 → 8.9 For this reason, the synthesis was carried out with the C31 hydroxyl group protected as a benzyl ether.

Scheme 1
Two key processes used in the first generation synthesis of C27-C35 building block 4 from 1,2-O-isopropylidene-α-D-5-deoxyglucurono-6,3-lactone.2c

Although lengthy, the first generation synthesis has attractive features, including the high overall yield and only one required chromatographic purification. In this letter, we report two major modifications that make this synthesis even more practical.

As outlined in Scheme 1, we utilized the C31-hydroxyl group to stereoselectively reduce the α,β-unsaturated phenylsulfone. In principle, either the C27- or C34-hydroxyl group could serve the same purpose, but a molecular model analysis suggested that the C27-hydroxyl group might give a better chance of success. If successful, we could eliminate two steps required for the temporary protection/deprotection of the C31-hydroxyl group (Scheme 1). Then, our concern was how effectively the desired C34-diastereomer could be isolated after the asymmetric dihydroxylation. We made a primitive, and wishful, assumption that, because of their structure similarity, C and D (Scheme 2) might exhibit the chemical property parallel to that of 6 and its C34-diastereomer (Scheme 1), respectively, thereby allowing us to isolate the desired C34 diastereomer C effectively by simple crystallization.

Scheme 2
Two key questions in the new synthesis.

The synthesis began with 1,2-O-isopropylidene-α-D-5-deoxyglucurono-6,3-lactone (3). Following the previous route, except the O-methylation step, 3 was uneventfully converted to 9 in 3 steps. As with the benzyl series, catalytic asymmetric dihydroxylation of 9 was best achieved with Sharpless (DHQ)2PYR, 10 to give a 3:1 mixture of the C34 diastereomers, which was directly subjected to benzoylation and then C-allylation. It should be noted that this C-allylation is closely related to an example reported in the literature11 and that, under the specified condition, the α- and β-selectivity was estimated to be at least 60:1 (1H NMR).

Once again, we were delighted to observe that the α-C-allylated product 11 derived from the desired, major product formed in the dihydroxylation exhibited an excellent crystallinity, whereas the α-C-allylated product derived from the undesired, minor product remained as oil. This remarkable difference in chemical property allowed us to isolate stereochemically homogeneous 11 (mp 112–113 °C; colorless needles) by simple crystallization in >55% overall yield from 3. The 1H NMR spectra included in Supporting Information illustrate the exceptional effectiveness to isolate 11.12 Although the major part of new synthesis is very similar to the first generation of synthesis, we should note that it has several appealing features, including the overall yield and operational simplicity.13,14 We routinely carried out the synthesis of 11 from 3 in a 20 g scale without chromatographic purification, except for filtration through a silica gel pad (1~2 times of the substrate weight).

In order to test the assumption mentioned above, single crystals of 6 and 11 were grown and subjected to X-ray analysis, thereby revealing that their crystal packing is very different from each other (Figure 2). After all, the wishful notion was simply premature and incorrect.

Figure 2
X-ray structure of 6 and 11. For their crystal-packing mode, see Supporting Information.

Dess-Martin oxidation 15 of 11, followed by Horner-Emmons reaction with PhSO2CH2P(O)(OEt)2/LiHMDS in toluene,2c furnished the corresponding α,β-unsaturated phenylsulfone as a 30:1 mixture of the Z/E-isomers (Scheme 4). There are two potentially enolizable sites in the ketone and α,β-unsaturated phenylsulfone, but no epimerized product was detected in this transformation. The terminal olefin was selectively cleaved, followed by reduction, to furnish the primary alcohol 12 as a 30:1 Z/E-mixture.

Scheme 4
Second generation synthesis of the E7389 C27-C35 building block. Conditions: (a) 1. Dess-Martin periodinane/rt. 2. PhSO2CH2P(O)(OEt)2/LiHMDS/ toluene/0 °C → rt (93% yield for 2 steps). 3. OsO4/NMO/ CH2Cl2/rt, followed by NaIO4 treatment. ...

We planned to use the C27-hydroxyl group to reduce the α,β-unsaturated phenylsulfone from the concave face, based on literature precedent reported by Stork and Kahne.16 Indeed, hydrogenation of 12 in the presence of Crabtree catalyst E17 (Scheme 5) in methylene chloride at 0 °C smoothly proceeded, to furnish the C27-C35 building block 13 in 95% yield with a >100:1 stereoselectivity (1H NMR). The C30 stereochemistry of 13 was assigned first by nOe studies and later confirmed by X-ray analysis of its 3,5-dinitrobenzoate. We should note that, if needed, the protecting group of 13 can be easily adjusted in 2 steps, cf., 13 → 14.18

Scheme 5
Three substrates studied for the C27-hydroxyl group directed hydrogenation in the presence of Crabtree catalyst E.

It is noteworthy that Crabtree catalyst E exhibited a high tolerance against the functional groups present in the current system. For example, both Z- and E-geometric isomers of 12 were smoothly reduced, to furnish 13 with a >100:1 stereoselectivity (Scheme 5).14 α,β-Unsaturated phenylsulfones with C34/C35 bis-TBS were reduced well, to give the desired, expected product in a high stereoselectivity, cf., 15 → 16. Similarly, the reduction of α,β-unsaturated esters gave the expected product in a high yield, cf., 17 → 18.

In summary, a practical route has been developed to synthesize E7389 C27-C35 building block 13 from 1,2-O-isopropylidene-α-D-5-deoxyglucurono-6,3-lactone (3). This synthesis relies on two key processes: (1) the C34/C35-diol is introduced via asymmetric dihydroxylation with dr = 3:1, with the undesired C34-diastereomer effectively removed by crystallization of 11 and (2) the C30 PhSO2CH2-group is introduced with a high stereoselectivity (>100:1) via the Stork-Kahne hydrogenation of 12 in the presence of Crabtree catalyst E. Except filtration through a silica gel pad (1~2 times of the substrate weight), this synthesis is practically free from chromatographic separation.

Figure 1
Structure of Halichondrin B and E7389, an analog of the right half of halichondrin B.
Scheme 3
Second generation synthesis of E7389 C27-C35 building block. Conditions: (a) 1. DIBAL/CH2Cl2 (~100%) 2. Ph3PCH3Br/n-BuLi/THF (91% with ~85% purity). 3. NaH/MeI/(n-Bu)4NI/DMF (~100%). (b). 1. Sharpless asymmetric dihydroxylation, (DHQ)2PYR/0 °C. ...

Supplementary Material

1_si_001

2_si_002

Acknowledgment

Financial support from the National Institutes of Health (CA 22215) and Eisai Research Institute is gratefully acknowledged. We thank Drs. T. Sasaki and C.-G. Dong in this laboratory for collecting the spectroscopic data for some of the synthetic intermediates.

Footnotes

Supporting Information Available. Experimental details and analytical data (38 pages). This material is available free of charge via the Internet at http://pubs.acs.org

References

1. For the isolation of the halichondrins from a marine sponge Halichondria okadai Kadota, see: (a) Uemura D, Takahashi 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. For isolation of the halichondrins from different species of sponges, see: (c) Pettit GR, Herald CL, Boyd MR, Leet JE, Dufresne C, Doubek DL, Schmidt JM, Cerny RJ, Hooper JNA, Rützler KC. J. Med. Chem. 1991;34:3339. [PubMed] (d) Pettit GR, Tan R, Gao F, Williams MD, Doubek DL, Boyd MR, Schmidt JM, Chapuis J-C, Hamel E, Bai R, Hooper JNA, Tackett LP. J. Org. Chem. 1993;58:2538. (e) Litaudon M, Hart JB, Blunt JW, Lake RJ, Munro MHG. Tetrahedron Lett. 1994;35:9435. (f) Litaudon M, Hickford SJH, Lill RE, Lake RJ, Blunt JW, Munro MHG. J. Org. Chem. 1997;62:1868. (g) Hickford SJH, Blunt JW, Munro MHG. Bioorg. Med. Chem. 2009;17:2199. [PubMed]
2. For the synthetic work on the marine natural product halichondrins from this laboratory, see: (a) 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. (b) Stamos DP, Chen SS, Kishi Y. J. Org. Chem. 1997;62:7552. (c) Choi H-W, Demeke D, Kang FA, Kishi Y, Nakajima K, Nowak P, Wan Z-K, Xie C. Pure Appl. Chem. 2003;75:1. (d) Namba K, Jun H-S, Kishi Y. J. Am. Chem. Soc. 2004;126:7770. [PubMed] (e) Namba K, Kishi Y. J. Am. Chem. Soc. 2005;127:15382. [PubMed] (f) Kaburagi Y, Kishi Y. Org. Lett. 2007;9:723. [PubMed] (g) Zhang Z, Huang J, Ma B, Kishi Y. Org. Lett. 2008;10:3073. [PubMed] (h) Chen C-L, Namba K, Kishi Y. Org. Lett. 2009;11:409. [PubMed] and references cited therein.
3. For synthetic work by Salomon, Burke, Yonemitsu, and Phillips, see: (a) Kim S, Salomon RG. Tetrahedron Lett. 1989;30:6279. Cooper AJ, Pan W, Salomon RG. Tetrahedron Lett. 1993;34:8193. and the references cited therein. (b) Burke SD, Buckanan JL, Rovin JD. Tetrahedron Lett. 1991;32:3961. Lambert WR, Hanson GH, Benayoud F, Burke SD. J. Org. Chem. 2005;70:9382. [PubMed] and the references cited therein. (c) Horita K, Hachiya S, Nagasawa M, Hikota M, Yonemitsu O. Synlett. 1994:38. Horita K, Nishibe S, Yonemitsu O. Phytochem. Phytopharm. 2000:386. and the references cited therein. (d) Henderson JA, Jackson KL, Phillips AJ. Org. Lett. 2007;9:5299. [PubMed] Jackson KL, Henderson JA, Motoyoshi H, Phillips AJ. Angew. Chem. Int. Ed. 2009;48:2346. [PMC free article] [PubMed] and the references cited therein.
4. Kishi Y, Fang FG, Forsyth CJ, Scola PM, Yoon SK. U.S. Patent. 5338866. and International Patent WO93/17650.
5. (a) 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. [PubMed] (b) Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. U.S. Patent. 6214865, 6365759. and International Patent WO99/65894. (c) Yu MJ, Kishi Y, Littlefield BA. In: Anticancer Agents from Natural Products. Cragg GM, Kingston DGI, Newman DJ, editors. Boca Raton, FL: CRC Press; 2005. pp. 241–265. (d) E7389 website: http://www.drugs.com/nda/e7389_080201.html.
6. One of the research focuses has been the development and application of catalytic asymmetric Cr-mediated coupling reactions. Recent results on this subject will be reported in separate papers.
7. For a review on this subject, see: Kolb HC, VanNieuwenhze MS, Sharpless KB. Chem. Rev. 1994;94:2483.
8. Asymmetric dihydroxylation of terminal olefins often suffers from a low degree of asymmetric induction. Replacement of the terminal olefin in 5 for the E-TMS-CH=CH- resulted in the much improved asymmetric induction (dr = 16:1) in the presence of (DHQ)2PYR.
9. For a review on substrate-directable chemical reactions, see: Hoveyda AH, Evans DA, Fu GC. Chem. Rev. 1993;93:1307.
10. (a) Jacobsen EN, Marko I, Mungall WS, Schroder G, Sharpless KB. J. Am. Chem. Soc. 1988;110:1968. (b) Sharpless KB, Amberg W, Bennani YL, Crispino GA, Hartung J, Jeong K-S, Kwong H-L, Morikawa K, Wang Z-M, Xu D, Zhang X-L. J. Org. Chem. 1992;57:2768. (c) Crispino GA, Jeong K-S, Kolb HC, Wang Z-M, Xu D, Sharpless KB. J. Org. Chem. 1992;58:3785. (d) Becker H, Sharpless KB. Angew. Chem. Int. Ed. 1996;35:448.
11. Garcia-Tellado F, Armas P, Marrero-Tellado JJ. Angew. Chem. Int. Ed. 2000;39:2727. [PubMed]
12. This crystallization was also effective to isolate the stereochemically homogeneous 11 from a 1:1 mixture of the C34 diastereomers obtained via osmylation with OsO4/NMO (22% overall yield from 3).
13. In the new synthesis, the overall yield of 3 → 13 was 45%, whereas that of 3 → the intermediate synthetically equivalent to 13 was 13% in the previous synthesis. The over 3-time improvement in overall yield was primarily attributed to: (1) higher overall yield from 3 to 11, (2) elimination of the benzylation (90%)/debenzylation (75%) steps, (3) higher efficiency of the hydroxyl-directed reduction (vide infra).
14. The C31 BnO-deprotection required FeCl3 or TMS-I under the carefully monitored conditions. In addition, only Z-α,β-unsaturated phenylsulfonthe was efficiently reduced under the hydroxyl-directed NaBH(OAc)3 in the previous synthesis, whereas both Z- and E-α,β-unsaturated phenylsulfonthes were smoothly reduced in the new synthesis (vide infra).
15. Dess DB, Martin JC. J. Org. Chem. 1983;48:4155.
16. Stork G, Kahne DE. J. Am. Chem. Soc. 1983;105:1072.
17. Crabtree RH, Felkin H, Fellebeen-Khan T, Morris GE. J. Organomet. Chem. 1979;168:183.
18. In the previous syntheses, we used 14 and 16 as the C27-C35 building block. However, our recent studies demonstrate that 13 is an ideal C27-C35 building block (reference 6).