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. Author manuscript; available in PMC: 2014 Aug 21.
Published in final edited form as: J Am Chem Soc. 2013 Aug 9;135(33):12434–12438. doi: 10.1021/ja406255j

Stereoselective Total Synthesis of Hainanolidol and Harringtonolide via Oxidopyrylium-Based [5+2] Cycloaddition

Min Zhang †, Na Liu †, Weiping Tang †,‡,*
PMCID: PMC3798225  NIHMSID: NIHMS514823  PMID: 23930656

Abstract

The tetracyclic carbon skeleton of hainanolidol and harringtonolide was efficiently constructed by an intramolecular oxidopyrylium-based [5+2] cycloaddition. An anionic ring opening strategy was developed for the cleavage of the ether bridge in 8-oxabicyclo[3.2.1]octenes derived from the [5+2] cycloaddition. Conversion of cycloheptadiene to tropone was realized by a sequential [4+2] cycloaddition, Kornblum-DeLaMare rearrangement, and double elimination. The biomimetic synthesis of harringtonolide from hainanolidol was also confirmed.

graphic file with name nihms514823u1.jpg

1. INTRODUCTION

Harringtonolide, hainanolidol, fortunolide A, and fortunolide B are representative members of Cephalotaxus norditerpenes (1–4, Figure 1). They have complex architectures featuring a fused tetracyclic carbon framework 5, a cyclohexane ring A bearing five or six contiguous stereogenic centers, an unusual tropone ring D, and a bridged lactone. The cage-like harringtonolide 1 and fortunolide B 4 have an additional tetrahydrofuran (THF) ring.

Figure 1.

Figure 1

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Representative Cephalotaxus Norditerpenes

Harringtonolide 1 was first isolated in 1978 from C. harringtonia and its structure was assigned unambiguously by X-ray crystallography.1 In 1979, both 1 (named as hainanolide) and 2 were isolated from C. hainanensis.2 Interestingly, the former was found to possess antineoplastic and antiviral activities while the latter was inactive.2–3 This suggests that the THF ring in 1 is important for its bioactivity. Hainanolidol 2 was proposed to be the precursor of harringtonolide 1 as the former could be converted to the latter by transannular oxidation mediated by lead tetraacetate.4 This biomimetic transformation was validated by identical IR and MS of the semi-synthetic and natural 1. Although the structure of 2 was assigned mainly based on this critical reaction,4 its yield has never been reported.

Fortunolides 3 and 4 together with hainanolidol 2 were also isolated from C. fortunei by Chiu’s group in 1999.5 The first synthesis of hainanolidol 2, and thus a formal synthesis of harringtonolide 1, was realized by Mander’s group in 1998, featuring an elegant arene cyclopropanation followed by ring expansion strategy for the construction of the tropone moiety.6 Their attempts towards the preparation of harringtonolide 1 by forming the THF ring at earlier stages have not been fruitful.7 Recently, significantly more synthetic efforts were devoted to harringtonolide 1,8 after the discovery of its remarkably potent and selective anticancer activity by Nay’s group in 2008 (IC50 = 43 nM for KB tumor cells).9

2. RESULTS AND DISCUSSION

To evaluate the therapeutic potential of harringtonolide 1 and related natural products as anticancer agents, we embarked on a synthetic program towards their synthesis. We envisioned that the tropone and lactone in natural products 1 and 2 could be derived from intermediate 6 (Scheme 1). We proposed to construct the tetracyclic carbon skeleton of 6 by an intramolecular [5+2] cycloaddition of intermediate 7, where the oxidopyrylium ion could be prepared from oxidative ring expansion of the furan ring in decalin 8.10 The six contiguous stereogenic centers and their associated functional groups in decalin 8 would be derived from known compound 9, available in two steps diastereoselectively.11

Scheme 1.

Scheme 1

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Retrosynthetic Analysis of 1 and 2

Our synthesis began with oxidation of enone 9 (Scheme 2).12 A mixture of diastereomeric allylic alcohols in a 4:1 (α/β) ratio was obtained and both of them were converted to ketone 15 eventually. The hydroxyl group in 11 could be installed highly diastereoselectively by dihydroxylation of the corresponding silyl enol ether. Initially, we tried to reduce the ketone in enone 11 to a trans-diol by delivering the hydride intramolecularly using NaBH(OAc)3.13 The fact that the resulting diol could be protected as an acetonide in compounds 12 and 13 suggested that a cis-diol was formed.

Scheme 2. Preparation of a Decalin Derivative with Six Contiguous Stereogenic Centers for [5+2] Cycloaddition.

Scheme 2

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a) TMSCl, NaI, Ac2O, 0°C-rt, 85%; b) oxone, NaHCO3, 70%; c) LDA, TESCl; then OsO4, NMO, THF/H2O (10:1), 72% over 2 steps, dr > 20:1; d) NaBH(OAc)3, AcOH, MeOH, 72%, dr > 20:1; e) acetone, TsOH, 74%; f) Dess-Martin periodinane, 76%; g) NaBH4; then TBSOTf, 2, 6-lutidine, 84% over 2 steps, dr > 20:1; h) TFA, 76%; i) Dess-Martin periodinane, 84%; j) NaBH4, 93%, dr > 20:1; k) Hg(TFA)2, vinylbutyl ether, Et3N, 86%; l) toluene, reflux, 85%, dr > 20:1; m) NaClO2, NaH2PO4, 2-methyl-2-butene; then MeONH2, BOP, Et3N, 76% over 2 steps; n) Mn(OAc)3, TBHP, 76%; o) TsNHNH2; then catecholborane and NaOAc, 75% over 2 steps, dr > 20:1; p) furan, BuLi, MgBr2, 92%; q) NaBH4; then VO(acac)2, TBHP, DCM, 87% over 2 steps; r) Ac2O, DMAP, pyridine, 91%; (P = TBS)

Reduction of ketone 11 by NaBH4, on the other hand, afforded a diol that could not be protected as an acetonide. This diol was assigned as a trans-1,2-diol.14 Protection of the resulting diol with TBSOTf followed by selective removal of the TES group by TFA afforded allylic alcohol 14. The desired β-stereochemistry in alcohol 14 could be realized by a sequence of oxidation and diastereoselective reduction,14 through enone 15.

A highly stereoselective Claisen rearrangement of vinylether 16 yielded bicyclic compound 17 with five contiguous stereogenic centers. An olefin isomerization was required for the conversion of this intermediate to desired compound 8 in addition to the appendage of a furan. We envisaged that a stereoselective [3,3]-sigmatropic rearrangement of intermediate 20 might afford a cis-fused decalin derivative with an olefin in the desired position.15 To this end, aldehyde 17 was converted to enone 19 through allylic oxidation of amide 18.16 Treatment of this enone with tosylhydrazine followed by diastereoselective reduction15c of the corresponding hydrazone gave us intermediate 20 (R = Weinreb amide), which underwent stereoselective rearrangement to form cis-decalin 21.15a,15b Ketone 22 was then obtained after the addition of furanyl Grignard reagent to amide 21. In the absence of MgBr2 salt, the furanyl lithium reagent also reacted with the angular ester group. Reduction of ketone 22 by NaBH4 then afforded a mixture of diastereomeric alcohols 8. The synthesis of alcohol 8 from aldehyde 17 would be much more efficient if the olefin isomerization could be performed on intermediate 20 where R is a furanyl alcohol. The furan moiety, however, could not be tolerated under the allylic oxidation conditions.

Substrate 23 was then obtained as a mixture of four diastereomers after VO(acac)2-catalyzed oxidative ring expansion17 of furanyl alcohol 8 followed by esterification. The stereochemistry on the dihydropyran ring of 23 is inconsequential as an achiral oxidopyrylium moiety is formed in the subsequent [5+2] cycloaddition. After screening different solvents and bases, we found that the intramolecular Hendrickson [5+2] cycloaddition18 occurred smoothly in refluxing chloroform in the presence of DBU (Scheme 3).10 Only one stereoisomer was observed for the cycloaddition product 24. Its structure and relative stereochemistry are confirmed by X-ray analysis as shown in the Supporting Information. It is worth to mention that the synthesis of product 24 via the key [5+2] cycloaddition could be carried out on gram scale.

Scheme 3.

Scheme 3

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[5+2] Cycloaddition and Attempts for the Synthesis of Tropone by Dehydration

Addition of methyl Grignard reagent, selective removal of one of the two silyl protecting groups under acidic conditions, and lactonization in the presence of potassium carbonate afforded hexacyclic compound 25. Although the steric environments of the two silyl ethers in 24 are quite different, strong acids or fluoride salts removed both of them non-selectively. High chemoselectivity was achieved by using trichloroacetic acid. The tertiary allylic alcohol in 25 could undergo a PCC-mediated tandem 1,3-transposition/oxidation sequence to afford enone 26. The yield of this reaction, however, varied from 10% to 40%.

A dehydration process involving the removal of two Hs and one O highlighted in red in 26 would furnish product 27, which is just one step away from hainanolidol 2. We were not able to prepare the tropone moiety directly, however, under various dehydration conditions, regardless the thermodynamic preference for the formation of a non-benzenoid aromatic tropone ring. We then turned our attention to the reductive cleavage of the ether bridge in 26 using SmI2. This reductive process would produce an enone, which may be converted to tropone by elimination of water and dehydrogenation. However, treatment of enone 26 with SmI2 or other reducing agents led to either no reaction or a complex mixture.19

After many trials, we developed a two-step protocol to open the ether bridge (Scheme 4). A phenylthio group was first introduced to 28 through a Lewis acid-mediated SN1′ substitution of 25.20 Only one diastereomer was observed for thio ether 28. The thiophenol likely approached intermediate 25 from the less sterically hindered β-face based on the X-ray structure of compound 24. The α-proton of the phenyl sulfide was then removed by LDA in the presence of HMPA and the oxygen bridge was cleaved under this condition. Two potential isomeric dienes can be generated in this anionic ring opening reaction by cleaving either C(β′)-O or C(δ)-O bonds. HSQC spectra indicated that diene 29 was formed by the cleavage of the C(δ)-O bond.

Scheme 4. Opening of Ether Bridge.

Scheme 4

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a) PhSH, BF3 OEt2; b) LDA, HMPA, THF; c) MeMgBr; (P=TBS)

The introduction of the phenylthio group not only solved the reproducibility issue of the 1,3-transposition but also provided a handle for the opening of the oxygen bridge. To test the generality of this strategy, we prepared allylic thio ether 31 from known compound 3021 using the same sequence of addition of methyl Grignard reagent and SN1′ displacement by thiophenol. The anionic opening worked smoothly to yield bicyclic product 32. In related anionic ring opening reactions reported by Lautens and his coworkers,22 oxabicyclo[3.2.1]octenes was opened by a SN2′ process22a,22b or a base-mediated β-elimination.22c

Diene 32 was then used as a model system for the synthesis of tropone. We envisioned that a sequence of hetero-Diels-Alder cycloaddition of a cycloheptadiene with a nitrosoarene,23 reductive cleavage of the N–O bond to an amino alcohol, and double elimination of amine and water might provide the tropone moiety. After protecting the free alcohol in 32, the resulting diene was treated with 2-nitrosopyridine (eq 1). The hetero-Diels-Alder cycloaddition occurred and afforded adduct 33, which was directly converted to tropone 34 by the treatment of SnCl2. Elimination of both 2-aminopyridine and water indeed occurred after the reductive cleavage of the N–O bond. The structure of intermediate 33 was assigned based on the regioselectivity observed in a similar hetero-Diels-Alder reaction involving nitroso compounds.24 With this method in hand, we then treated diene 29 or its derivatives with 2-nitrosopyridine in the absence or presence of different Lewis acids.25 Unfortunately, no desired cycloaddition product was observed.

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Several conditions have been reported for the hydrolysis of vinyl phenylthio ethers to ketones.26 Under these conditions, however, the thio ethers in 29, 32 or their derivatives could not be hydrolyzed to the corresponding enone. We then decided to remove the phenylthio group in 29 and examine conditions for the conversion of the resulting diene 35 (Scheme 5) to a tropone. We could not obtain diene 35 by treating 29 with Raney-Ni directly. Although reductive cleavage of a carbon-sulfone bond by SmI2 has been reported,27 we were not able to prepare the corresponding sulfone from 29 in a good yield. Interestingly, the corresponding sulfoxide can be synthesized efficiently and the reductive cleavage of a carbon-sulfoxide bond worked well. After silyl protection, the phenylthio group in 29 was removed by a two-step sequence: oxidation by magnesium monoperoxyphthalate (MMPP) to its sulfoxide28 and reduction with SmI2.

Scheme 5. Formation of Tropone and Completion of the Synthesis of 1 and 2.

Scheme 5

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a) TESCl, DMAP, TEA, DCM; b) MMPP on silica gel, DCM; c) SmI2, DMPU, MeOH, THF, 70% over 3 steps; d) O2, TPP, light, CH3CN, 40%; e) DBU, DCM; f) TsOH, CDCl3, 85% over 2 steps; g) Pb(OAc)4, benzene, 90 °C, 52%. (P=TBS).

Inspired by the strategy of [4+2] cycloaddition, N–O bond cleavage, and double elimination to access tropone 34 in eq 1, we envisioned a sequence of [4+2] cycloaddition of diene 35 with singlet oxygen to afford peroxide 36, Kornblum-DeLaMare rearrangement of 36 to ketone 37,29 and double elimination to prepare tropones in natural products 1 and 2. Indeed, peroxide 36 was formed by the cycloaddition between diene 35 and singlet oxygen together with a byproduct derived from an ene reaction, using tetraphenylporphyrin (TPP) as the photo sensitizer. DBU-promoted Kornblum-DeLaMare rearrangement provided ketone 37. In the presence of acid, removal of silyl groups and elimination of two water molecules occurred to yield hainanolidol 2. The 1H and 13C NMR spectra of our synthetic hainanolidol are in accordance with natural product as shown in the Supporting Information. 2D NMR data (COSY, HMBC, HSQC, and nOe) further confirmed the structure and stereochemistry of hainanolidol.

Treatment of hainanolidol 2 with lead tetraacetate in refluxing benzene finally provided harringtonolide 1 in a 52% isolated yield.4 The 1H and 13C NMR spectra of our synthetic harringtonolide are in agreement with those reported for natural harringtonolide.1–2,9 The key biomimetic transformation of biologically inactive hainanolidol 2 to bioactive harringtonolide 1 is thus confirmed for the first time by total synthesis.

3. CONCLUSION

In summary, the total synthesis of natural products hainanolidol and harringtonolide was realized featuring two stereoselective [3,3]-sigmatropic rearrangements, an oxidopyrylium-based [5+2] cycloaddition to construct the tetracyclic carbon skeleton, an anionic ring opening of the ether bridge derived from [5+2] cycloaddition, and the formation of a tropone through a sequence of [4+2] cycloaddition, Kornblum-DeLaMare rearrangement, and double elimination. This new synthetic route for hainanolidol and harringtonolide offers the flexibility to access other members of Cephalotaxus norditerpenes and various simplified analogues. Evaluation of the anticancer activity of harringtonolide and its analogues will be reported in due course.

Supplementary Material

1_si_001

Acknowledgments

We are grateful for financial support from NIH (R01GM088285) and the University of Wisconsin. We thank Prof. Mander (Australian National University, Australia), Prof. Chiu (Kunming Institute of Botany, China), and Prof. Nay (CNRS, France) for generously sharing their NMR spectra with us.

Footnotes

The authors declare no competing financial interests.

Supporting Information. Detailed experimental procedures, characterization data, and spectra (IR, 1H, 13C NMR and HRMS). This material is available free of charge via the Internet at http://pubs.acs.org.

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Associated Data

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Supplementary Materials

1_si_001
NIHMS514823-supplement-1_si_001.pdf (6.6MB, pdf)

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