FIELD OF THE INVENTION This invention relates to triene-substituted compounds, to pharmaceutical compositions containing them, and to methods and intermediates useful in their preparation.

BACKGROUND OF THE INVENTION The spongipyrans, a new family of sponge metabolites available only in minute quantities, appear to be the most potent inhibitors of cancer cell growth discovered to date.

Pettit, et al., described the first examples, spongistatins,<BR> in 1993 (Pettit, et al., J. Org. Chem. 1993,58,1302) and<BR> subsequently isolated congeners thereof (Pettit, Pure & Appl.

Chem. Spongistatin 1 (1, Figure 1), the most abundant compound, proved to be active against several chemoresistant tumor types, including human melanoma and lung, colon, and brain cancers, with GI50's of 2.5-3.5 x 10-11 M (see, e. g., Bai, et al., Biochemistry 1995,34,9714). Further

investigations revealed that 1 inhibits mitosis by binding to tubulin and blocking microtubule assembly. Other sponges produce cinachyrolide A and the altohyrtins A-C, isolated by the Fusetani (see, Fusetani, et al., J. Am. Chem. Soc. 1993, 115,3977), and Kitagawa groups (see, Kobayashi, et al., Tetrahedron Lett. 1993,34,2795; Kobayashi, et al., Tetrahedron Lett. 1994,35,1243; Kobayashi, et al., Chem.

Pharm. Bull. 1996,44,2142). These substances likewise display cytotoxicity against cancer cell lines but, likewise, are difficult to obtain from natural sources yet are structurally complex and, thus, difficult to synthesize.

There is, therefore, a need for improved synthetic methods and/or less complex compounds having similar levels of cytotoxicity.

OBJECTS OF THE INVENTION It is one object of the present invention to provide compounds which mimic the chemical and/or biological activity of the spongistatins.

It is a further object to provide compositions having antitumor activity comprising such compounds.

It is another object to provide processes for the preparation of such compounds.

It is yet another object of this invention to provide intermediates useful in such processes.

SUMMARY OF THE INVENTION These and other objects are satisfied by the present invention, which provides triene-containing compounds which mimic the chemical and/or biological activity of the spongistatins. In preferred embodiments, such compounds have formula I:

wherein: Z is O, S or NR'where R'is H or Cl-C6 alkyl; Ri is H, Cl-Cl0 alkyl, =O, or ORA wherein RA is H, Cl- Clo alkyl, C6-Cl4 aryl, C7-C15 arylalkyl, or an acid labile hydroxyl protecting group; R2, R3, and R4 are, independently, H, Cl-Cl0 alkyl, or ORB wherein each RB is, independently, H, Cl-Cl0 alkyl, C6-C14 aryl, C7-C15 arylalkyl, or an acid labile hydroxyl protecting group; R5is H, Cl-Cl0 alkyl, =O, or ORC wherein RC is H, Cl- Cl0 alkyl, C6-Cl4 aryl, C7-C15 arylalkyl, or an acid labile hydroxyl protecting group; R6, R7, R9, and Rlo are, independently, H, F, Cl, Br, I, or where: RD is H, Cl-Cl0 alkyl, ORF, or =O; RE is ORF or-CH2-RF; RF is C6-C14 aryl, tetrahydropyranyl, furanosyl, pyranosyl, C3-C10 lactonyl or 2-pyranonyl; and R8 is H, F, Cl, Br, or I.

The present invention also provides methods for inhibiting mammalian cell proliferation by contacting mammalian cells with a compound according to the invention or by administering a compound according to the invention (or a

pharmaceutical composition comprising such a compound) to a mammal suffering from undesired cell proliferation.

BRIEF DESCRIPTION OF THE DRAWINGS The numerous objects and advantages of the present invention may be better understood by those skilled in the art by reference to the accompanying figures, in which: Figure 1 shows spongistatins 1 and 2 and a retrosynthetic analysis for compounds 3a and 3b.

Figure 2 shows a synthetic scheme for compound 6. Figure 3 shows a synthetic scheme for compounds 3a and 3b.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides compounds which mimic the chemical and/or biological activity of the spongistatins.

In preferred embodiments, such compounds have formula I: wherein: Z is O, S or NR'where R'is H or C1-C6 alkyl; Ri is H, C1-C10 alkyl, =O, or ORA wherein RA is H, Ci- Clo alkyl, C6-C14 aryl, C7-C1s arylalkyl, or an acid labile hydroxyl protecting group; R2, R3, and R4 are, independently, H, C1-C10 alkyl, or <BR> <BR> OR, wherein each RB is, independently, H, Cl-Cl0 alkyl, C6-C14

aryl, C7-C15 arylalkyl, or an acid labile hydroxyl protecting group; R5 is H, C1-Cl0 alkyl, =O, or ORC wherein RC is H, C1- C10 alkyl, C6-C14 aryl, Cl-C15 arylalkyl, or an acid labile hydroxyl protecting group; R6, R7, R9, and Rio are, independently, H, F, Cl, Br, I, or CH (RD) (RE) where: RD is H, Cl-Cl alkyl, ORF, or =O ; ORFor-CH2-RF;REis RF is C6-C14 aryl, tetrahydropyranyl, furanosyl, pyranosyl, C3-C10 lactonyl or 2-pyranonyl; and R8 is H, F, Cl, Br, or I.

In particularly preferred embodiments: Z is O; R1 is <BR> <BR> ORA wherein RA is H or C1-Clo alkyl; R2, R3, and R4 are,<BR> <BR> <BR> independently, C1-Clo alkyl or ORB wherein each RB is,<BR> <BR> <BR> independently, H or C7-C15 arylalkyl; R5 is ORC wherein RC is H or an acid labile hydroxyl protecting group; R6, R7, R9, and Rio are, independently, H; and/or Ra is H or Cl.

Alkyl groups according to the invention include but are not limited to straight chain and branched chain hydrocarbons such as methyl, ethyl, propyl, pentyl, isopropyl, 2-butyl, isobutyl, 2-methylbutyl, and isopentyl moieties having 1 to about 10 carbon atoms, preferably 1 to about 6 carbon atoms. Alkyl groups according to the invention optionally can be unsubstituted or can bear one or more substituents such as, for example, halogen hydroxyl, amine, and epoxy groups.

Aryl groups according to the invention are aromatic and heteroaromatic groups having 6 to about 14 carbon atoms, preferably from 6 to about 10 carbon atoms, including, for example, naphthyl, phenyl, indolyl, and xylyl groups and substituted derivatives thereof, particularly those substituted with amino, nitro, hydroxy, methyl, methoxy, thiomethyl, trifluoromethyl, mercaptyl, and carboxy groups. Alkaryl groups are groups that contain alkyl and aryl portions and are covalently bound to other groups through the alkyl portion, as in a benzyl group.

Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionality, such as hydroxyl and amine groups, present in a chemical compound to render such functionality inert to certain chemical reaction conditions to which the compound is exposed. See, e. g., Greene and Wuts, Protective Groups in Organic Synthesis, 2d edition, John Wiley & Sons, New York, 1991. Numerous hydroxyl protecting groups are known in the art, including the acid-labile t-butyldimethylsilyl, diethylisopropylsilyl, and triethylsilyl groups and the acid- stable aralkyl (e. g., benzyl), triisopropylsilyl, and t- butyldiphenylsilyl groups.

Certain compounds of the invention contain amino groups and, therefore, are capable of forming salts with various inorganic and organic acids. Such salts are also within the scope of this invention. Representative salts include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, sulfate, tartrate, tosylate, and undecanoate. The salts can be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is later removed in vacuo or by freeze drying. The salts also can be formed by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

In our unified approach to the spongistatins, the labile C (48-51) conjugated diene moiety of the side-chain will be introduced at the end of the synthesis. As shown in Figure 1, our initial targets were trienes 3a and 3b, in which a D-glucosyl moiety is believed to mimic the C (39-43) F-ring pyran. Triene 3a, which contains the unsubstituted diene of

spongistatin 2, can be generated by Horner-Emmons olefination of the C (48) aldehyde derived from 4 with diisopropyl allylphosphonate 7. The chlorinated diene in 3b, the model for spongistatin 1, can be produced from the same aldehyde upon treatment with propargyltrimethylsilane 8 and TiCl4, generally according to the method of Pornet (see, e. g., Pornet, Tetrahedron Lett. 1981,22,453). Precursor 4 in turn can be prepared via coupling of iodide 5 (see, e. g., Hosokawa, et al., Synlett 1996,351) with sulfone 6 (see, e. g., Akiyama, et al., Synlett 1996,100) followed by Julia methylenation (see, e. g., De Lima, et al., Synlett 1992,133).

As shown in Figure 2, sulfone (-)-6 was obtained in three steps from commercially available (R)- (+)-glycidol [ (+)-9]. Protection as the p-methoxybenzyl (PMB) ether (NaH, Bu4NI, PMBCl; 72% yield) and quantitative epoxide opening with the lithio derivative of methyl phenyl sulfone furnished (-)-11; the absolute configuration was confirmed by Mosher <BR> <BR> <BR> analysis (see, e. g., Dale, et al., J. Am. Chem. Soc. 1973,95, 512). Silylation (TBSOTf, 2,6-lutidine, CH2Cl2; 100%) then completed the synthesis of (-)-6.

Coupling of model iodide (+)-5 (see, e. g., Hosokawa, <BR> <BR> <BR> et al., Synlett 1996,351) available in five steps from methyl a-D-glucopyranoside, with sulfone (-)-6 provided 12a, b (as characterized using its infrared, 500-MHZ 1H NMR, and 125-MHZ 13C NMR spectra, as well as appropriate parent ion identification by high resolution mass spectrometry) in 95% yield as an inconsequential mixture of C (45) epimers, as shown in Figure 3. Introduction of the methylene moiety via the Julia protocol (see, e. g., De Lima, et al., Synlett 1992,133) then furnished (+)-13. The requisite aldehyde (+)-4 was generated by removal of the PMB ether with DDQ and Dess-Martin <BR> <BR> <BR> oxidation (see, e. g., Dess, et al., J. Org. Chem. 1983,48,<BR> <BR> <BR> 4155; Ireland, et al., J. Org. Chem. 1993,58,2899) of the resultant alcohol (95% yield). Olefination of (+)-4 with 7 gave exclusively the desired E diene (+)-15 in 87% yield.

Desilylation of (+)-15 furnished triene (+)-3a in 95% yield.

Reaction of (+)-4 with 8 and TiCl4 likewise afforded the E

chloro analog (+)-16 as a single isomer in 52% yield.

Desilylation of (+)-16 furnished triene (+)-3b in 59% yield.

Although preferred methods are those directed to (+)- trienes 3 and compounds having like stereochemistry, those skilled in the art will recognize that the methods disclosed herein can be readily adapted to the synthesis of antipodal compounds such as, for example, (-)-trienes, and vice versa.

All such synthetic methods are within the scope of the present invention.

The compounds of the invention can be admixed with carriers, excipients, and/or diluents to form novel compositions. Such compositions can be used in prophylactic, diagnostic, and/or therapeutic techniques. By administering an effective amount of such a composition, prophylactic or therapeutic responses can be produced in a human or some other type mammal. It will be appreciated that the production of prophylactic or therapeutic responses includes the initiation or enhancement of desirable responses, as well as the mitigation, cessation, or suppression of undesirable responses.

The compositions of the invention are expected to find use, for example, in the inhibition of undesired cell proliferation (e. g., cancer). (See, e. g., Bai, et al., Biochemistry 1995,34, 9714).

Compositions of the invention can be prepared by any of the methods well known in the pharmaceutical art, for <BR> <BR> example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980). The compositions can include a compound of the invention as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable, for example, for oral administration. Other suitable modes of administration will be apparent to those skilled in the art. The compound of the invention can be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, solutions, suppositories, suspensions, and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium

trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The compound of the invention is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in appropriately soluble (e. g., gelatin) capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.

When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, glycerin and various like combinations thereof.

For parenteral administration, suspensions containing a compound of the invention in, for example, aqueous propylene glycol can be employed. The suspensions should be suitably buffered (preferably pH>8) if necessary and the liquid diluent first rendered isotonic. The aqueous suspensions are suitable for intravenous injection purposes. The preparation of such suspensions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is possible to administer

the compounds of the invention topically and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

The compounds of the invention can be employed as the sole active agent in a pharmaceutical composition or can be used in combination with other active ingredients, e. g., other agents useful in diseases or disorders.

The amount of active ingredient that is to be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are first divided into several small doses for administration throughout the day. The concentrations of the active ingredient in therapeutic compositions will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e. g., hydrophobicity) of the active ingredient, and the route of administration. Typical dose ranges are from about 285 yg/kg of body weight per day in three divided doses; a preferred dose range is from about 42 Ug/kg to about 171 yg/kg of body weight per day. The preferred dosage to be administered is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration, as well as other factors,

including bioavailability, which is in turn influenced by several factors well known to those skilled in the art.

Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are not intended to be limiting.

All reactions were carried out in oven-dried or flame-dried glassware under an argon atmosphere, unless otherwise noted. All solvents were reagent grade. Tetrahydrofuran (THF) was freshly distilled from sodium/benzophenone under argon before use. Dichloromethane, hexamethylphosphoramide (HMPA) was freshly distilled from calcium hydride. Anhydrous pyridine and dimethylformamide were purchased from Aldrich and used without purification. n-Butyllithium and t-butyllithium were purchased from Aldrich.

Unless stated otherwise all reactions were magnetically stirred and monitored by thin layer chromatography using 0.25 mm E. Merck pre-coated silica gel plates. Flash column chromatography was performed with the indicated solvents using E. Merck silica gel-60 (230-400 mesh). Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise stated.

EXAMPLE 1 Epoxide (-)-10 To a stirred suspension of NaH (60% dispersion in<BR> mineral oil, 3.24 g, 81.0 mmol) in 270 ml of anhydrous DMF at 0°C was added R- (+)-glycidol (5.00 g, 67.5 mmol). After stirring at 0°C for 30 minutes, PMBC1 (10.57 g, 9.15 ml, 67.5 mmol) and catalytic tetrabutylammonium iodide was added. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (gradient elution: 1: 9 to 2: 8 ethyl acetate/hexane) gave 10 (9.40 g, 72%) as colorless<BR> oil. [a] D =-3.45° (c 3.80, CHCl3)

EXAMPLE 2 Alcohol (-)-11 To a stirred solution of methyl phenyl sulfone (15.12 g, 96.8 mmol) in 450 ml dry THF and 25 ml of dry HMPA at-50°C was added n-BuLi (2.5 M in hexane, 38.7 ml, 96.8 mmol). After stirring at-50°C for 20 minutes, epoxide 10 (9.40 g, 48.4 mmol) in 50 ml of dry THF was added via cannula. The reaction mixture was stirred at-50°C for 1 hour, then slowly warmed to room temperature over 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (gradient elution: 4: 6 to 6: 4 ethyl acetate/hexane) gave 11 (17.0 g, 100%) as colorless oil. [a] D =-10.9° (c 3.80, CHC13).

EXAMPLE 3 Sulfone (-)-6 To a stirred solution of alcohol 11 (615 mg, 1.75 mmol) and 2,6-lutidine in (375 mg, 408 ml, 3.50 mmol) in 15 ml of dry methylene chloride at 0°C was added TBSOTf (695 mg, 604 ml, 2.63 mmol) via syringe. The reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched with water, extracted with ether. Ether layer was washed with brine, dried over MgSO4. Filtered and concentrated. Flash chromatography (2: 8 ethyl acetate/hexane) gave 6 (816 mg, 100%) of product as colorless oil. [a] D =-13.0° (c 3.00, CHC13).

EXAMPLE 4 Sulfone 12a, b To a stirred solution of sulfone 6 (4.604 g, 9.907 mmol) in 60 ml of dry THF under argon at-78°C was added n-BuLi (2.5 M in hexane, 3.96 ml, 9.907 mmol) dropwise via a syringe.

The resulting yellow solution was stirred at-78°C for 30 minutes, 8 ml of HMPA was added via a syringe and stirred at -78°C for 10 minutes. The iodide 5 (2.846 g, 4.954 mmol) in 20 ml of dry THF was added via cannula. The reaction mixture was slowly warmed to room temperature over 4 hours 20 minutes.

The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (gradient elution 1: 9 to 2: 8 ethyl acetate/hexane) gave 12a, b (4.308 g, 95%) as colorless oil.

EXAMPLE 5 Compound (+)-13 To a stirred solution of sulfone 12a, b (862 mg, 0.946 mmol) in 6 ml of dry THF and 1.2 ml of dry HMPA at-78°C was added n-BuLi (1.6 M in hexane, 650 ml, 1.04 mmol) dropwise.

The resulting orange solution was stirred at-78°C for 45 minutes. The carbenoid was prepared independently at the same time by the following procedure: to a stirred solution of diiodomethane (760 mg, 229 ml, 2.838 mmol) in 6 ml of dry THF at-78°C was added i-PrMgCl dropwise. The reaction mixture was stirred at-78°C for 30 minutes. To this carbenoid mixture was added the above lithiated sulfone via cannula. The resultant yellow solution was stirred at-75°C for 1 h, then slowly warmed to 10°C over 4 hours. The reaction was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (gradient elution: 1: 9 to 2: 8 ethyl acetate/hexane) gave 13 (556 mg, 75%) colorless oil as well as 109 mg (13%) recovery of starting material 12a, b.

For 13, [a] D = +7.8° (c 3.20, CHC13).

EXAMPLE 6 Alcohol (+)-14 To a stirred solution of 13 (73 mg, 0.093 mmol) in 2 ml of methylene chloride and 111 ml of water was added DDQ (43 mg, 0.186 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHC03, extracted with methylene chloride. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash

chromatography (2: 8 ethyl acetate/hexane) gave 14 (50 mg, 81%) as colorless oil. [a] D = +17.5° (c 5.25, CHCl3).

EXAMPLE 7 Aldehyde (+)-4 To a stirred solution of alcohol 14 (125 mg, 0.189 mmol) in 2 ml of dry methylene chloride at room temperature was added pyridine followed by Dess-Martin periodinate (120 mg, 0.284 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with 10 ml of 1: 1 saturated NaHCO3/Na2S203, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (2: 8 ethyl acetate/hexane) gave 4 (118 mg, 95%) as colorless oil.

[a] D = +6.0° (c 3.95, CHCl3).

EXAMPLE 8 Diene (+)-15 To a stirred solution of diisopropyl ally phosphonate 7 (188 mg 0.91 mmol) in 2 ml of dry THF at-78°C was added n-BuLi (1.6 M in hexane, 569 ml, 0.91 mmol) dropwise via a syringe. The resulting pale yellow solution was stirred at -78°C for 30 minutes, the aldehyde 4 (60 mg, 0.091 mmol) was then added via cannula. The reaction mixture was slowly warmed to room temperature over 5 hours 40 minutes. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ether. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (gradient elution: 2% to 5% ethyl acetate/hexane) gave 15 (54 mg, 87%) as colorless oil. [a] D = +9.2° (c 0.60, CHC13).

EXAMPLE 9 Diene (+)-16 To a stirred mixture of aldehyde 4 (23 mg, 0.035 mmol) and LiCl (15 mg, 0.35 mmol) in 0.5 ml of dry methylene chloride at-78°C was added TiCl4 (1.0 M in methylene chloride, 18 ml, 0.018 mmol). The resulting yellow mixture was warmed

to-60°C over 10 minutes. Propargyl trimethylsilane 8 (79 mg, 105 ml, 0.70 mmol) was then added. The reaction mixture was warmed to 4°C over 2 hours 10 minutes. The reaction was quenched with saturated NaHCO3, extracted with ethyl acetate.

The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (gradient elution: 1: 9 to 2/8 ether/hexane) gave 16 (13 mg, 52%) as colorless oil as well as 3 mg (13%) of recovery of aldehyde 4.

For 16, [a] D = +11.6° (c 0.85, CHCl3).

EXAMPLE 10 Triene (+)-3a To a stirred solution of 15 (24 mg, 0.035 mmol) in 0.5 ml of dry THF was added TBAF (1.0 M in THF, 175 ml, 0.175 mmol). The reaction mixture was stirred at room temperature for 4 hours 50 minutes, diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (gradient elution: 1: 9 to 2: 8 ethyl acetate/hexane) gave 3a (19 mg, 95%) as colorless oil. [a] D = +26.60° (c 0.85, CHC1,).

EXAMPLE 11 Triene (+)-3b To a stirred solution of 16 (18 mg, 0.025 mmol) in 0.25 ml of dry THF was added TBAF (1.0 M in THF, 175 ml, 0.175 mmol) and acetic acid (14 ml, 0.25 mmol) (TBAF and AcOH were pre-mixed). The reaction mixture was stirred at room temperature for 44 hours, diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated.

Flash chromatography (gradient elution: 1: 9 to 2: 8 ethyl acetate/hexane) gave 3b (9 mg, 59%) as colorless oil. [a] D = +22.8° (c 0.40, CHC1,).

EXAMPLE 12 Trienes (+)-3a and (+)-3b were tested for antitumor activity generally in accordance with the procedure described by Bai, et al., Biochemistry 1995,34,9714. As shown in Table

I, both 3a and 3b are active against a series of human cancer cell lines.

Table I: Antitumor Activity (in vitro) of 3a and 3b GIso values in ym Pancreas-a Neuroblast Thyroid Lung-NSC Pharynx-Prostate BXPC-3 SK-N-SH ca NCI-H460 sq DU-145 SW 1736 FADU 3a 0.44 0.54 1.2 0.46 0.47 0.56 3b 5.3 3.6 9.6 11 8.3 > 16 Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all equivalent variations as fall within the true spirit and scope of the invention.