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The halichondrin family of marine polyethers, first defined by the isolation and structure elucidation of norhalichondrin A by Uemura and co-workers in 1985, now numbers ~ 15 compounds. The structures of the halichondrins, as exemplified by norhalichondrin B (Figure 1) are characterized by a 53–55 carbon backbone that is defined by two domains: the spiroketal containing C31-C53/55 region and a C1-C30 macrolactone that also contains a 2,6,9-trioxatricyclo[3.3.2.03,7]decane. The structures, in conjunction with impressive levels of cytotoxicity, have attracted significant scientific attention[2,3] highlighted by the total syntheses of halichondrin B and norhalichondrin B by Kishi in 1992,[3,5] and the current efforts of Eisai Pharmaceuticals to establish E7389, a truncated analog of the macrolactone, as an anti-cancer therapeutic. In this communication we describe our studies that have culminated in the total synthesis of norhalichondrin B.
Our overall plans are defined in Figure 1, and involve a late stage Horner-Wadsworth-Emmons coupling of C40-C53 domain, 2 with phosphonate 3. Phosphonate 3 can be traced back to C1-C13 domain 5 and C12-C38 domain 4. In the forward sense, we envisioned that these two domains would be connected by a combination of cross-metathesis and macrolactonization as the key reactions. The C12-C38 domain 4 could be further dissected to arrive at pyranopyran 6 and the C14-C26 THF-ring containing domain 7. Pyran 2 and pyranopyran 6 would ultimately be prepared by the application of our recently reported furan→pyranone conversion, and pyranopyran 5 would arise from a tandem ring-opening-ring-closing metathesis of an oxabicyclo[3.2.1]octene.
The synthesis of the C1-C13 domain 5 commenced with the Davies Rh-catalyzed addition of diazo ester 8 to furan to give oxabicyclo[3.2.1]octene 9 in 59% yield (Scheme 1).[10,11] This ester was advanced to 10 in 16% overall yield by a sequence consisting of: (i) methanolysis and then hydrolysis to the acid; (ii) Curtius rearrangement/enamine hydrolysis; (iii) L-Selectride reduction of the ketone; and (iv) acetal formation with acrolein dimethylacetal. Gratifyingly, when 10 was exposed to 3 mol% of Grubbs’ 2nd generation catalyst conversion of the bridged bicyclic structure to pyranopyran 11 smoothly occurred in 71% yield. Hydroboration of the terminal olefin with Sia2BH gave 12 in 73% yield. Exposure of 12 to Jones reagent resulted in simultaneous oxidation to the lactone and the acid, which was methylated with TMSCHN2, to give 13 in 66% yield. Advancement of 13 to 5 followed our earlier reported 6 step sequence.
Tetrahydrofuran-containing domain 7 was prepared by a sequence that began with Noyori hydrogenation of β-keto ester 14 (62%, Scheme 2), and subsequent Pd-mediated allylation to give O-allyl ester 15 in 80% yield. Hydrolysis of the ester and conversion to the diazoketone 17 ((COCl)2, DMF then CH2N2, Et3N, 60% after chromatography) set the stage for a [2,3]-sigmatropic rearrangement to form the tetrahydrofuran. To this end, when diazoketone 17 was exposed to Cu(acac)2 in THF under reflux, the expected rearrangement occurred to yield 2,5-anti-tetrahydrofuran 18 in 91% yield. Wittig olefination led to diene 19 (99%), which was selectively hydroborated with Sia2BH, and subsequent oxidation of the primary alcohol with Dess-Martin periodinane gave aldehyde 20 (83% yield, 2 steps). Introduction of the remaining two stereocenters was achieved by application of the Kishi protocol.[14a] Aldehyde 20 was reacted with 23 in the presence of oxazoline-sulfonamide ligand 22, to give diol 21 in 52% yield (after desilylation with TBAF). Selective acylation of the primary alcohol with pivaloyl chloride (DMAP, pyridine, 87%) produced 24 and the secondary alcohol was mesylated (Ms2O, Et3N, DMAP, 99%) to give 7.
The syntheses of both the C27-C38 domain and the C40-C53 domain were patterned on our previously reported Achmatowicz oxidation and subsequent ionic hydrogenation process for the conversion of furans to pyranones (Scheme 3). In the case of the C40-C53 domain 2, furfural 25 was subjected to Brown crotylation using (−)-Ipc2-(E)-crotylborane to give 26 in 71% yield. Achmatowicz oxidation with t-BuOOH and VO(acac)2 produced an intermediate pyranone hemiacetal which was immediately subjected to trifluoroacteic acid-mediated ionic hydrogenation using Et3SiH to yield the desired pyranone 27 in 86% yield and as a single diastereomer (d.r. >20:1 by 1H NMR analysis). This material could be converted to aldehyde 28 in 7 steps following the sequence described in Ref 8. Addition of the lithium anion derived from iodide 29 (t-BuLi, Et2O), followed by Dess-Martin oxidation (62% over 2 steps), and quantitative ozonolysis of the olefin (O3, MeOH, pyridine) gave the fully functionalized C40-C53 domain, 2.
Furfural 25 also served as the departure point for the C27-C38 domain 6 (see also Scheme 3). Brown crotylation of 25 with (−)-(Ipc)2-(Z)-crotylborane gave 30 in 75% yield. The two step protocol of Achmatowicz oxidation and ionic hydogenation (t-BuOOH, VO(acac)2 then TFA and Et3SiH), produced 90% of pyranone 31 as a single diastereomer (d.r. >20:1). Conversion of 31 to lactone 32 was achieved by a three step sequence consisting of: (i) removal of the TBS ether with aqueous TFA, (ii) tandem Jones oxidation of the alcohol to the acid and hetero-conjugate addition of the acid to the enone, and (iii) NaBH4 reduction of the pyranone (80%, d.r. = 5:1). Reduction of the lactone in 32 to the diol with LiBH4 in THF, followed by selective formation of the 7-membered ketal, and protection of the secondary alcohol as the TES ether gave 33 in 75% overall yield. Ozonolysis of the olefin gave aldehyde 34 (95%), which was subjected to an asymmetric Nozaki-Hiyama-Kishi reaction with methyl-trans-3-iodoacrylate in the presence of oxazoline-sulfonamide ligand 35[14b] to give 36 in 75% yield (d.r. = 12:1). Protection of the alcohol as the PMB ether using p-methoxybenzyl trichloroacetimidate and BF3·OEt2 was followed by removal of TES group with TBAF. This desilylation was accompanied by hetero-Michael addition and produced the desired pyranopyran 37 in 50% yield for the two steps. Removal of the acetonide (PPTS, MeOH) and reprotection of the diol with TBSOTf gave 38 in 87% yield. Reduction of the ester with LiAlH4 and oxidation of the alcohol to the aldehyde provided the fully functionalized C27-C38 domain, 6 in 90% yield for the two steps.
In advance of the key cross-metathesis for the introduction of the C1-C13 domain, pyranopyran 2 and tetrahydrofuran 3 were unified by the well-established combination of Nozaki-Hiyama-Kishi reaction and pyran ring formation by SN2 reaction to give 39 in 59% yield (Scheme 4). A straightforward sequence of (i) LiAlH4-mediated pivalate removal, (ii) Dess-Martin periodinane oxidation (iii) addition of vinylmagnesium bromide, and (iv) Dess-Martin periodinane oxidation provided enone 4 in 70% overall yield. Gratifyingly, it was possible to engage 4 and allylic alcohol 5 in productive cross metathesis in the presence of 20 mol% of the recently reported catalyst 41 to give 40 in 62% yield.
The final fragment union and completion of the synthesis is shown in Scheme 5 and commences with the formation of the polycyclic acetal-containing C8-C14 domain. Treatment of cross metathesis product 40 with TBAF buffered by acetic acid resulted in removal of the silyl protecting groups and concomitant hetero-Michael addition to provide tetrahydrofuran 41 as a mixture of diastereoisomers. This transformation could be readily followed by TLC, and subjecting the reaction to non-aqueous workup conditions (CaCO3, DOWEX 50WX8-400, MeOH) resulted in formation of the desired 2,6,9-trioxatricyclo[3.3.2.03,7]decane ring system to give 42 in 64% yield, along with 26% of the intermediate tetrahydrofuran 41 in which the C12 stereocenter is epimeric to the desired stereochemistry. This transformation could also be achieved by subjecting crude 41 to mild acid (PPTS, CH2Cl2). Protection of the alcohols as TBS ethers (TBSOTf, Et3N, 0 °C) provided 43 in 78% yield, and subsequent removal of the PMB ether with buffered aqueous DDQ led to 44 (65%). At this juncture it was possible to remove the minor C27 diastereoisomer by column chromatography (16%). Hydrolysis of the methyl ester (LiOH, THF, quantitative) produced seco-acid 45, which readily lactonized under standard Yamaguchi conditions to give the macrolactone 46 in 92% yield. Although complete removal of the primary TBS group to give 47 could not be achieved without partial loss of the secondary TBS group at C35, it was possible to cleanly obtain the desired primary alcohol 47 in 97% yield based on recovered starting material when 46 was exposed to PPTS in MeOH and the reaction was run to ~45% conversion. Oxidation of alcohol 47 with Dess-Martin periodinane yielded aldehyde 48 (89%) and set the stage for a daring two step sequence consisting of (i) Roskamp reaction for the introduction of the desired β-ketophosphonate, and (ii) coupling to the final fragment by Horner-Wadsworth-Emmons reaction. Despite some concerns about the viability of these reactions on highly complex substrates that could prove sensitive to Lewis acids or basic conditions, both reactions proceeded without event: reaction of 48 with dimethyl(diazomethyl) phosphonate and SnCl2 gave 3 in 74% yield, then reaction with aldehyde 2 in the presence of K2CO3 and 18-crown-6 in warm toluene produced enone 49 in 83% yield. Treatment of enone 49 with TBAF resulted in removal of the silyl protecting groups over the course of 12 hours to give an intermediate that contained the C44 spiroketal. Removal of the PMB ether proved to be slightly problematic, however recourse to the use of DDQ in CH2Cl2-MeOH (10:1) was successful and resulted in clean removal of the PMB group to yield norhalichondrin B methyl ester, 50 in 65% yield over the two steps. Subsequent hydrolysis of the methyl ester with LiOH yielded norhalichondrin B, 1 in 60% yield and completed the synthesis. Gratifyingly, 1H NMR data for both of the final two compounds matched data provided by Professor Yoshito Kishi and Professors John Blunt and Murray Munro.
In conclusion, we have described a total synthesis of norhalichondrin B that proceeds in 37 steps from β-furylethanol. Key features of the synthesis are the use of the Achmatowicz oxidation-ionic hydrogenation for the synthesis of pyrans and pyranopyrans, and the application of tandem metathesis for the synthesis of pyranopyrans. The synthesis also provides an example of a cross metathesis reaction on highly functionalized intermediates and establishes the utility of the Roskamp reaction in a complex setting.
Dedicated to Professors Uemura, Blunt, Munro, Pettit, and Kishi in recognition of their research on the halichondrins.
**This research was supported by the National Cancer Institute (NCI CA110246), Eli Lilly & Co under the auspices of the Lilly Awardee Program (to AJP), and in part by The American Chemical Society Petroleum Research Fund (ACS PRF# 38856-G1). We thank Professor R. H. Grubbs and Dr I. C. Stewart (Caltech) and Materia Inc. for catalyst 41, and Professor Yoshito Kishi (Harvard), and Professors John Blunt and Murray Munro (Canterbury) for copies of spectra
Dr. Katrina L. Jackson, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA.
Dr. James A. Henderson, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA.
Dr. Hajime Motoyoshi, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA.
Prof. Dr. Andrew J. Phillips, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA, Fax: (+)1 303 4920439.