listed below are definitions of various terms used to describe this invention . these definitions apply to the terms as they are used throughout this specification , unless otherwise limited in specific instances , either individually or as part of a larger group . the term “ alkyl ” refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms , preferably 1 to 7 carbon atoms . the expression “ lower alkyl ” refers to unsubstituted alkyl groups of 1 to 4 carbon atoms . the term “ substituted alkyl ” refers to an alkyl group substituted by , for example , one to four substituents , such as , halo , phenyl , substituted phenyl , heterocyclo , trifluoromethyl , trifluoromethoxy , hydroxy , alkoxy , cycloalkyoxy , heterocylooxy , oxo , alkanoyl , aryloxy , alkanoyloxy , amino , alkylamino , arylamino , aralkylamino , cycloalkylamino , heterocycloamino , disubstituted amines in which the 2 amino substituents are selected from alkyl , aryl or aralkyl , alkanoylamino , aroylamino , aralkanoylamino , substituted alkanoylamino , substituted arylamino , substituted aralkanoylamino , thiol , alkylthio , arylthio , aralkylthio , cycloalkylthio , heterocyclothio , alkylthiono , arylthiono , aralkylthiono , alkylsulfonyl , arylsulfonyl , aralkylsulfonyl , sulfonamido ( e . g . so 2 nh 2 ), substituted sulfonamido , nitro , cyano , carboxy , carbamyl ( e . g . conh 2 ), substituted carbamyl ( e . g . conh alkyl , conh aryl , conh aralkyl or cases where there are two substituents on the nitrogen selected from alkyl , aryl or aralkyl ), alkoxycarbonyl , aryl , substituted aryl , guanidino and heterocyclos , such as , indolyl , imidazolyl , furyl , thienyl , thiazolyl , pyrrolidyl , pyridyl , pyrimidyl and the like . where noted above where the substituent is further substituted it will be with halogen , alkyl , alkoxy , aryl or aralkyl . the term “ halogen ” or “ halo ” refers to fluorine , chlorine , bromine and iodine . the term “ aryl ” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion , such as phenyl , naphthyl , biphenyl and diphenyl groups , each of which may be substituted . the term “ aralkyl ” refers to an aryl group bonded directly through an alkyl group , such as benzyl . the term “ substituted aryl ” refers to an aryl group substituted by , for example , one to four substituents such as alkyl ; substituted alkyl , halo , trifluoromethoxy , trifluoromethyl , hydroxy , alkoxy , cycloalkyloxy , heterocyclooxy , alkanoyl , alkanoyloxy , amino , alkylamino , aralkylamino , cycloalkylamino , heterocycloamino , dialkylamino , alkanoylamino , thiol , alkylthio , cycloalkylthio ; heterocyclothio , ureido , nitro , cyano , carboxy , carboxyalkyl , carbamyl , alkoxycarbonyl , alkylthiono , arylthiono , alkysulfonyl , sulfonamido , aryloxy and the like . the substituent may be further substituted by halo , hydroxy , alkyl , alkoxy , aryl , substituted aryl , substituted alkyl or aralkyl . the term “ cycloalkyl ” refers to optionally substituted , saturated cyclic hydrocarbon ring systems , preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated c 3 - c 7 carbocyclic ring . exemplary groups include cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , cycloheptyl , cyclooctyl , cyclodecyl , cyclododecyl , and adamantyl . exemplary substituents include one or more alkyl groups as described above , or one or more groups described above as alkyl substituents . the terms “ heterocycle ”, “ heterocyclic ” and “ heterocyclo ” refer to an optionally substituted , fully saturated or unsaturated , aromatic or nonaromatic cyclic group , for example , which is a 4 to 7 membered monocyclic , 7 to 11 membered bicyclic , or 10 to 15 membered tricyclic ring system , which has at least one heteroatom in at least one carbon atom - containing ring . each ring of the heterocyclic group containing a heteroatom may have 1 , 2 or 3 heteroatoms selected from nitrogen atoms , oxygen atoms and sulfur atoms , where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized . the heterocyclic group may be attached at any heteroatom or carbon atom . exemplary monocyclic heterocyclic groups include pyrrolidinyl , pyrrolyl , indolyl , pyrazolyl , oxetanyl , pyrazolinyl , imidazolyl , imidazolinyl , imidazolidinyl , oxazolyl , oxazolidinyl , isoxazolinyl , isoxazolyl , thiazolyl , thiadiazolyl , thiazolidinyl , isothiazolyl , isothiazolidinyl , furyl , tetrahydrofuryl , thienyl , oxadiazolyl , piperidinyl , piperazinyl , 2 - oxopiperazinyl , 2 - oxopiperidinyl , 2 - oxopyrrolidinyl , 2 - oxazepinyl , azepinyl , 4 - piperidonyl , pyridyl , n - oxo - pyridyl , pyrazinyl , pyrimidinyl , pyridazinyl , tetrahydropyranyl , tetrahydrothiopyranyl , tetrahydrothiopyranyl sulfone , morpholinyl , thiomorpholinyl , thiomorpholinyl sulfoxide , thiomorpholinyl sulfone , 1 , 3 - dioxolane and tetrahydro - 1 , 1 - dioxothienyl , dioxanyl , isothiazolidinyl , thietanyl , thiiranyl , triazinyl , and triazolyl , and the like . exemplary bicyclic heterocyclic groups include benzothiazolyl , benzoxazolyl , benzothienyl , quinuclidinyl , quinolinyl , quinolinyl - n - oxide , tetrahydroisoquinolinyl , isoquinolinyl , benzimidazolyl , benzopyranyl , indolizinyl , benzofuryl , chromonyl , coumarinyl , cinnolinyl , quinoxalinyl , indazolyl , pyrrolopyridyl , furopyridinyl ( such as furo [ 2 , 3 - c ] pyridinyl , furo [ 3 , 1 - b ] pyridinyl ] or furo [ 2 , 3 - b ] pyridinyl ), dihydroisoindolyl , dihydroquinazolinyl ( such as 3 , 4 - dihydro - 4 - oxo - quinazolinyl ), benzisothiazolyl , benzisoxazolyl , benzodiazinyl , benzofurazanyl , benzothiopyranyl , benzotriazolyl , benzpyrazolyl , dihydrobenzofuryl , dihydrobenzothienyl , dihydrobenzothiopyranyl , dihydrobenzothiopyranyl sulfone , dihydrobenzopyranyl , indolinyl , isochromanyl , isoindolinyl , naphthyridinyl , phthalazinyl , piperonyl , purinyl , pyridopyridyl , quinazolinyl , tetrahydroquinolinyl , thienofuryl , thienopyridyl , thienothienyl , and the like . exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents . also included are smaller heterocyclos , such as , epoxides and aziridines . the compounds of formula i and ii may form salts with alkali metals such as sodium , potassium and lithium , with alkaline earth metals such as calcium and magnesium , with organic bases such as dicyclohexylamine , tributylamine , pyridine and amino acids such as arginine , lysine and the like . such salts can be obtained , for example , by exchanging the carboxylic acid protons , if they contain a carboxylic acid , in compounds of formula i and ii with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation . other salts can be formed as known to those skilled in the art . the compounds for formula i and ii form salts with a variety of organic and inorganic acids . such salts include those formed with hydrogen chloride , hydrogen bromide , methanesulfonic acid , hydroxyethanesulfonic acid , sulfuric acid , acetic acid , trifluoroacetic acid , maleic acid , benzenesulfonic acid , toluenesulfonic acid and various others ( e . g ., nitrates , phosphates , borates , tartrates , citrates , succinates , benzoates , ascorbates , salicylates and the like ). such salts are formed by reacting a compound of formula i and ii in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation . compounds of the formula i and ii may also have prodrug forms . any compound that will be converted in vivo to provide the bioactive agent ( i . e ., the compound for formula i and ii ) is a prodrug within the scope and spirit of the invention . for example compounds of the formula i and ii may form a carboxylate ester moiety . the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure ( s ). various forms of prodrugs are well known in the art . for examples of such prodrug derivatives , see : a ) design of prodrugs , edited by h . bundgaard , ( elsevier , 1985 ) and methods in enzymology , vol . 42 , p . 309 - 396 , edited by k . widder , et al . ( acamedic press , 1985 ); b ) a textbook of drug design and development , edited by krosgaard - larsen and h . bundgaard , chapter 5 , “ design and application of prodrugs ,” by h . bundgaard , p . 113 - 191 ( 1991 ); c ) h . bundgaard , advanced drug delivery reviews , 8 , 1 - 38 ( 1992 ); d ) h . bundgaard , et al ., journal of pharmaceutical sciences , 77 , 285 ( 1988 ); and e ) n . kakeya , et al ., chem phar bull , 32 , 692 ( 1984 ). it should further be understood that solvates ( e . g ., hydrates ) of the compounds of formula i and ii are also within the scope of the present invention . methods of solvation are generally known in the art . the compounds of formula i and ii are microtubule - stabilizing agents . they are thus useful in the treatment of a variety of cancers , including ( but not limited to ) the following ; carcinoma , including that of the bladder , breast , colon , kidney , liver , lung , ovary , pancreas , stomach , cervix , thyroid and skin ; including squamous cell carcinoma ; hematopoietic tumors of lymphoid lineage , including leukemia , acute lymphocytic leukemia , acute lymphoblastic leukemia , b - cell lymphoma , t - cell lymphoma , hodgkins lymphoma , non - hodgkins lymphoma , hairy cell lymphoma and burketts lymphoma ; hematopoietic tumors of myeloid lineage , including acute and chronic myelogenous leukemias and promyelocytic leukemia ; tumors of the central and peripheral nervous system , including astrocytoma , neuroblastoma , glioma , and schwannomas ; other tumors , including melanoma , xenoderma pigmentosum , keratoactanthoma , seminoma , thyroid follicular cancer and teratocarcinoma . compounds of formula i and ii may also inhibit tumor angiogenesis , thereby affecting the growth of tumors . such anti - angiogenesis properties of the compounds of formula i and ii may also be useful in the treatment of certain forms of blindness related to retinal vascularization , arthritis , especially inflammatory arthritis , multiple sclerosis , restinosis and psoriasis . compounds of formula i and ii may induce or inhibit apoptosis , a physiological cell death process critical for normal development and homeostasis . alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases . compounds of formula i and ii , as modulators of apoptosis , will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer ( particularly , but not limited to follicular lymphomas , carcinomas with p53 mutations , hormone dependent tumors of the breast , prostrate and ovary , and precancerous lesions such as familial adenomatous polyposis ), viral infections ( including but not limited to herpesvirus , poxvirus , epstein - barr virus , sindbis virus and adenovirus ), autoimmune diseases ( including but not limited to systemic lupus erythematosus , immune mediated glomerulonephritis , rheumatoid arthritis , psoriasis , inflammatory bowel diseases and autoimmune diabetes mellitus ), neurodegenerative disorders ( including but not limited to alzheimer &# 39 ; s disease , aids - related dementia , parkinson &# 39 ; s disease , amyotrophic lateral sclerosis , retinitis pigmentosa , spinal muscular atrophy and cerebellar degeneration ), aids , myelodysplastic syndromes , aplastic anemia , ischemic injury associated myocardial infarctions , stroke and reperfusion injury , arrhythmia , atherosclerosis , toxin - induced or alcohol induced liver diseases , hematological diseases ( including but not limited to chronic anemia and aplastic anemia ), degenerative diseases of the musculoskeletal system ( including but not limited to osteoporosis and arthritis ), aspirin - sensitive rhinosinusitis , cystic fibrosis , multiple sclerosis , kidney diseases , and cancer pain . the compounds of this invention are also useful in combination with known anti - cancer and cytotoxic agents and treatments , including radiation . if formulated as a fixed dose , such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range . compounds of formula i and ii can be used sequentially with known anticancer or cytotoxic agents and treatment , including radiation when a combination formulation is inappropriate . especially useful are cytotoxic drug combinations wherein the second drug chosen acts in a different phase of the cell cycle , e . g . s phase , than the present compounds of formula i and ii which exert their effects at the g 2 - m phase . the present compounds may exist as multiple optical , geometric , and stereoisomers . included within the present invention are all such isomers and mixtures thereof in the racemic form . the compounds of this invention can be formulated with a pharmaceutical vehicle or diluent for oral , intravenous or subcutaneous administration . the pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles , diluents and additives appropriate to the desired mode of administration . orally , the compounds can be administered in the form of tablets , capsules , granules , powders and the like . the compounds are administered in a dosage range of about 0 . 05 to 200 mg / kg / day , preferably less than 100 mg / kg / day , in a single dose or in 2 to 4 divided doses . compounds of formula i and ii are prepared by the following schemes . compounds of formula i can be prepared as outlined in scheme 1 . a compound of formula 1b can be prepared fromi an epothilone of formula 1a by reduction with a reducing agent such as “ reactive titanocene ” ( cp 2 ticl 2 / mg ) or tungsten metal ( wcl 6 / n - buli ). optionally , a compound of formula 1c , where p 1 is an oxygen protecting group such as triethylsilyl , can be prepared from a compound of formula 1b by methods known in the art . a compound of formula 1d , where r 10 and r 11 are h , can be prepared from a compound of formula 1c by addition of a carbene group according to the method of denmark ( denmark , s . e ., et al ., j . org . chem ., ( 1991 ) 56 , 6974 ). when p 1 is an oxygen protecting group , a deprotection step using , for example when p 1 is a triethylsilyl group , hydrogen fluoride in acetonitrile or tetra - n - butylammonium fluoride in thf or trifluoroacetic acid in dichloromethane provides a compound of formula i ( 1e ) where r 1 , r 2 , r 3 , r 4 and r 5 are defined as described above . alternatively , a compound of formula 1b can be converted directly to a compound of formula i ( 1e ) without using oxygen protecting groups ( i . e ., p 1 is h ) using the method described above for the conversion of 1c to 1d . alternatively , a compound of formula 1b , or its optionally protected form 1c , can be converted to a compound of formula 1d where where rio and r 11 are halogen , such as bromine , by treatment with a dihalocarbene which can be generated , for example , by reaction of sodium hydroxide and bromoform . dehalogenation of a compound of formula 1d can be achieved with a reducing agent such as tri - n - butyltin hydride to give a compound of formula i ( 1e ). if p 1 is an oxygen protecting group , a deprotection step using , for example when p 1 is a triethylsilyl group , hydrogen fluoride in acetonitrile or tetra - n - butylammonium fluoride in thf or trifluoroacetic acid in dichloromethane provides a compound of formula i ( 1e ) where r 1 , r 2 , r 3 , r 4 and r 5 are defined as described above . other compounds of formula i ( i . e ., 1e where r 10 and r 11 are not h or halo ) can be prepared from a compound of formula 1c by reaction of a diazo compound and a transition metal catalyst ( see for example : davies , h . m . l ., et al ., j . org chem ., ( 1991 ) 56 , 3817 , and the methods described in “ the chemistry of the cyclopropyl group ” parts 1 and 2 , z . rappoport , ed ., john wiley and sons : new york ( 1987 )). compounds of formula ii can be prepared from a compound of formula ie , where b 1 and b2 are hydroxyl groups , as shown in scheme 2 . a compound of formula 2a can be prepared from compounds of formula i by addition of formyl groups using standard conditions such as formic acid , triethylamine , acetic anhydride in dichioromethane . elimination of a compound of formula 2a using 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] undec - 7 - ene in dichloromethane provides a compound of formula 2b . deprotection of a compound of formula 2b using ammonia in methanol provides a compound of formula ii ( 2c ). the in vitro assessment of biological activity of the compounds of formula i and ii was performed as follows : twice cycled ( 2x ) calf brain tubulin was prepared following the procedure of williams and lee ( see williams , r . c ., jr ., and lee , j . c . preparation of tubulin from brain . methods in enzymology 85 , pt . d : 376 - 385 , 1982 ) and stored in liquid nitrogen before use . quantification of tubulin polymerization potency is accomplished following a modified procedure of swindell , et al ., ( see swindell , c . s ., krauss , n . e ., horwitz , s . b ., and ringel , i . biologically active taxol analogues with deleted a - ring side chain substituents and variable c - 2 ′ configurations . j . med . chem . 34 : 1176 - 1184 , 1991 ). these modifications , in part , result in the expression of tubulin polymerization potency as an effective concentration for any given compound . for this method , different concentrations of compound in polymerization buffer ( 0 . 1m mes , 1mm egta , 0 . 5 mm mgcl2 , ph 6 . 6 ) are added to tubulin in polymerization buffer at 37 ° in microcuvette wells of a beckman ( beckman instruments ) model du 7400 uv spectrophotometer . a final microtubule protein concentration of 1 . 0 mg / ml and compound concentration of generally 2 . 5 , 5 . 0 , and 10 μm are used . initial slopes of od change measured every 10 seconds were calculated by the program accompanying the instrument after initial and final times of the linear region encompassing at least 3 time points were manually defined . under these conditions linear variances were generally & lt ; 10 − 6 , slopes ranged from 0 . 03 to 0 . 002 absorbance unit / minute , and maximum absorbance was 0 . 15 absorbance units . effective concentration ( ec 0 . 01 ) is defined as the interpolated concentration capable of inducing an initial slope of 0 . 01 od / minute rate and is calculated using the formula : ec 0 . 01 = concentration / slope . ec 0 . 01 values are expressed as the mean with standard deviation obtained from 3 different concentrations . ec 0 . 01 values for the compounds in this invention fall in the range 0 . 01 - 1000 μm . cytoxicity was assessed in hct - 116 human colon carcinoma cells by mts ( 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 5 -( 3 - carboxymethoxyphenyl )- 2 -( 4 - sulphenyl )- 2h - tetrazolium , inner salt ) assay as reported in t . l . riss , et . al ., “ comparison of mtt , xtt , and a novel tetrazolium compound mts for in vitro proliferation and chemosensitivity assays .,” mol . biol . cell 3 ( suppl . ): 184a , 1992 . cells were plated at 4 , 000 cell / well in 96 well microtiter plates and 24 hours later drugs were added and serial diluted . the cells were incubated at 37 ° form 72 hours at which time the tetrazolium dye , mts at 333 μg / ml ( final concentration ), in combination with the electron coupling agent phenazine methosulfate at 25 μm ( final concentration ) was added . a dehydrogenase enzyme in live cells reduces the mts to a form that absorbs light at 492 nm which can be quantitated spectrophotometrically . the greater the absorbance the greater the number of live cells . the results are expressed as an ic 50 , which is the drug concentration required to inhibit cell proliferation ( i . e . absorbance at 450 nm ) to 50 % of that of untreated control cells . the ic 50 values for compounds of this invention fall in the range 0 . 01 - 1000 nm . to anhydrous thf ( 5 ml ) at − 78 ° c . under argon was added wcl 6 ( 198 mg , 0 . 5 mmol ) followed by nbuli ( 0 . 625 ml of 1 . 6 m solution in hexanes , 1 . 0 mmol ). the reaction was allowed to warm to room temperature over a 20 min period . an aliquot ( 0 . 50 ml , 0 . 05 mmol ) of the tungsten reagent was removed and added to epothilone b ( 9 . 0 mg , 0 . 018 mmol ) under argon and the reaction stirred for 15 min then quenched by the addition of saturated nahco 3 ( 1 ml ). the reaction was extracted with etoac ( 3 × 1 ml ). the combined extracts dried ( na 2 so 4 ), and filtered . the volatiles removed under vacuum . the residue was chromatographed with 35 % etoac / hexanes to give compound a ( 7 . 0 mg , 0 . 014 mmol ) in 80 % yield . m / z : 492 . 3 ( m + h ) + . to a solution of compound a ( 30 mg , 0 . 061 mmol ) in anhydrous ch 2 cl 2 ( 1 . 25 ml ) under argon were added n , n - diisopropylethylamine ( 0 . 16 ml , 0 . 92 mmol , 15 eq ) followed by triethysilytcheoride ( 0 . 10 ml , 0 . 61 ml , 10 eq ). the reaction mixture was stirred for 18 hrs . the reaction mixture was cooled to 0 ° c . then 2 , 6 - lutidine ( 0 . 021 ml , 0 . 18 mmol , 3 eq ) was added followed by triethylsilyltrifluoromethanesulphonate ( 0 . 056 ml , 0 . 2 4 mmol , 4 eq ). the reaction was stirred for 0 . 5 hr then poured into a 1 : 1 mixture of h 2 o / saturated nahco 3 ( 1 ml ) and extracted with ch 2 cl 2 ( 3 × 1 ml ). the combined organics were dried ( na 2 so 4 ), filtered , and the volatiles were removed . the residue was chromatographed with 1 % et 2 o / ch 2 cl 2 to give 35 mg of compound b ( 80 % yield ) as a clear glass . m / z : 720 . 5 ( m + h ) + . to a solution of diethylzinc ( 0 . 24 ml of 1 . 0 m in heptane , 0 . 24 mmol , 5 eq ) in 1 , 2 - dichloroethane ( 1 . 5 ml ) at − 15 ° c . under argon was added chloroiodomethane ( 0 . 035 ml , by 0 . 48 mmol , 10 eq ), and the mixture was stirred for 10 mn . a solution of compound b ( 35 mg , 0 . 048 mmol ) in 1 , 2 - dichloroethane ( 0 . 40 ml ) was slowly added , and the reaction mixture 25 was stirred for 1 . 5 hrs . the reaction was quench ed by addition of saturated nh 4 cl ( 1 . 5 ml ) and extracted with ch 2 cl 2 ( 3 × 2 ml ). the combined organics were dried ( na 2 so 4 ), filtered , and the volatiles removed in vacuo . to the residue was added 15 % trifluoroacetic acid / ch 2 cl 2 ( 0 . 50 ml ) and the reaction stirred for 15 min . the volatiles were removed under a stream of air and the residue was chromatographed with 70 % etoac / hexanes to give 2 . 2 mg of title compound ( 10 % yield - two steps ) as a white film ; m / z : 506 . 3 ( m + h ) + . alternatively , sodium hydroxide ( 0 . 3 ml of 50 % solution in h 2 o ) was added to compound 1b ( 109 mg , 0 . 15 mmol ), phch 2 ( ch 3 ch 2 ) 3 ncl ( 0 . 7 mg , 0 . 002 mmol ), and etoh ( 0 . 03ml ) in chbr 3 ( 1 . 0 ml ). the resulting mixture was heated at 40 ° c . for 2 hr . the brown reaction mixture was diluted with h 2 o ( 30 ml ), extracted with ch 2 cl 2 ( 3 × 30 ml ), dried over na 2 so 4 , concentrated and purified by flash chromatography ( stepwise gradient : 5 to 25 % et2o / hexanes ) to afford a dibromocyclopropane intermediate as a light brown oil ( 40mg , 30 % yield ). ( m + h ) + 892 . 3 bu 3 snh ( 3 . 4 mmol , 0 . 91 ml ) was added to the dibromocyclopropane intermediate ( 0 . 34 mmol , 305 mg ) and 2 , 2 - azobisisobutyronitrile ( 0 . 034 mmol , 6 mg ) in hexanes ( 7 . 0 ml ). the reaction mixture was heated at 70 ° c . for 5 hr . the reaction was concentrated and purified by flash chromatography ( stepwise gradient : hexanes to 20 % et 2 o / hexanes ) to afford a reduced cyclopropane intermediate as a clear film ( 228 mg , 91 %). ( m + h ) + 734 . 7 . the preceding cyclopropane intermediate ( 0 . 31 mmol , 228 mg ) was dissolved in cf 3 co 2 h / ch 2 cl 2 ( 20 % solution by volume , 10 ml ) and stirred at − 15 ° c . for 1 . 5 hr . the reaction mixture was concentrated and purified by flash chromatography ( 70 % etoac / hexanes ) to afford the title compound as a clear oil ( 111 mg , 71 %). ( m + h ) + 506 . 3 . 1 h nmr ( cdcl 3 , 400 mhz ) d 7 . 04 ( s , 1h ), 6 . 64 ( s , 1h ), 5 . 16 ( dd , j = 8 . 0 , 3 . 4 hz , 1h ), 4 . 17 ( dd , j = 9 . 5 , 2 . 8 hz , 1h ), 3 . 79 - 3 . 83 ( m , 1h ), 3 . 23 ( dq , j = 6 . 7 , 4 . 5 hz , 1h ), 2 . 79 ( s , 3h ), 2 . 52 ( dd , j = 15 . 1 , 9 . 7 hz , 1h ), 2 . 41 ( dd , j = 15 . 2 , 2 . 9 hz , 1h ), 1 . 98 - 2 . 02 ( m , 1h ), 2 . 00 ( s , 3h ), 1 . 63 - 1 . 73 ( m , 1h ), 1 . 40 - 1 . 58 ( m , 5h ), 1 . 36 ( s , 3h ), 1 . 20 - 1 . 3 ( m , 1h ), 1 . 11 - 1 . 17 ( m , 1h ), 1 . 15 ( d , j = 6 . 8 hz , 3h ), 1 . 08 ( s , 3h ), 0 . 96 ( d , j = 7 . 0 hz , 3h ), 0 . 94 ( s , 3h ), 0 . 40 - 0 . 54 ( m , 1h ), 0 . 37 ( dd , j = 8 . 8 , 4 . 1 hz , 1h ), − 0 . 14 -(− 0 . 10 ) ( m , 1h ). sodium hydroxide ( 1 . 7 ml of 50 % solution in h 2 o ) was added to compound 1b ( 1 . 04 g , 1 . 44 mmol ), benzyltriethylammonium chloride ( 7 mg , 0 . 03 mmol ), and etoh ( 0 . 06ml ) in chcl 3 ( 11 ml ). the reaction mixture was stirred at room temperature for 2 hr . the brown reaction mixture was diluted with h 2 o ( 60 ml ), extracted with ch 2 cl 2 ( 3 × 50 ml ), dried over na 2 so 4 , concentrated and purified by flash chromatography ( stepwise gradient : hexanes to 8 % etoac / hexanes ) to afford compound a as light brown oil ( 361 mg , 31 % yield ). ( m + h ) + 804 . 5 compound a ( 0 . 27 mmol , 220 mg ) in cf 3 co 2 h / ch 2 cl 2 ( 20 % solution by volume , 10 ml ) was stirred at − 15 ° c . for 1 . 5 hr . the reaction was concentrated and purified by flash chromatography ( 70 % etoac / hexanes ) to afford the title compound as a light brown oil ( 126 mg , 81 %). ( m + h ) + 574 . 4 sodium hydroxide ( 0 . 3 ml of 50 % solution in h 2 o ) was added to compound 1b ( 109 mg , 0 . 15 mmol ), benzyltriethylammonium chloride ( 0 . 7 mg , 0 . 002 mmol ), and etoh ( 0 . 03ml ) in chbr 3 ( 1 . 0 ml ). the resulting mixture was heated at 40 ° c . for 2 hr . the brown reaction mixture was diluted with h 2 o ( 30 ml ), extracted with ch 2 cl 2 ( 3 × 30 ml ), dried over na 2 so 4 . the organic extracts were concentrated and the residue was purified by flash chromatography ( stepwise gradient : 5 to 25 % et2o / hexanes ) to afford compound a as light brown oil ( 40mg , 30 % yield ). ( m + h ) + 892 . 3 compound a ( 0 . 0045 mmol , 4 mg ) in cf 3 co 2 h / ch 2 cl 2 ( 15 % solution by volume , 10 ml ) was stirred at − 15 ° c . for 1 . 5 hr . the reaction mixture was concentrated and purified by flash chromatography ( 70 % etoac / hexanes ) to afford the title compound as a clear oil ( 2 mg , 66 %). ( m = h ) + 664 . 2 to a two - necked flask was added chopped pieces of magnesium turnings ( 24 mg , 1 . 0 mmol ). the flask was flame - dried under vacuum and cooled under argon . bis ( cyclopentadienyl ) titanium dichloride ( 250 mg , 1 . 0 mmol ) was added followed by anhydrous thf ( 5 ml ). the stirring suspension was evacuated with low vacuum , and the reaction flask was refilled with argon . the red suspension became dark , turning a homogeneous deep green after 1 . 5 hr with nearly all the magnesium metal being consumed . an aliquot ( 3 . 5 ml , 0 . 70 mmol , 3 . 5 eq ) was removed and cooled to − 78 ° c . under argon . to this solution was added epothilone a ( 99 mg , 0 . 20 mmol , 1 . 0 eq ). the reaction mixture was warmed to room temperature and stirred for 15 min . the volatiles were removed in vacuo and the residue was chromatographed two times on silica ( 25 g ), eluting with 35 % etoac / hexanes to give 76 mg ( 80 %) of compound a as a pale yellow viscous oil . tert - butyldimethylsilyl trifluoromethanesulfonate ( 0 . 1 ml , 0 . 43 mmol ) was added to compound a ( 76 mg , 0 . 16 mmol ) and 2 , 6 - lutidine ( 0 . 074 ml , 0 . 64 mmol ) in ch 2 cl 2 ( 2 . 5 ml ). the reaction mixture was stirred at − 20 ° c . for 30 min , and quenched with h 2 o ( 10 ml ). the reaction mixture was extracted with ch 2 cl 2 ( 2 × 10 ml ), dried over na 2 so 4 , concentrated and puriified by flash chromatography ( 10 % etoac / hexanes ) to afford compound b as a white solid ( 89mg , 79 %). ( m + h ) + 706 . 2 to a solution of compound b ( 85 mg , 0 . 12 mmol ) in chbr 3 ( 1 . 0 ml ) was added benzyltriethylammonium chloride ( 3 . 0 mg , 0 . 013 mmol ), etoh ( 0 . 010 ml ), and then 50 % naoh ( aq ) ( 0 . 17 ml , 3 . 2 mmol ). the reaction mixture was vigorously stirred at 50 ° c . for 48 hr , cooled to room temperature , and then chromatographed directly ( 7 % etoac / hexanes ) to give compound c ( 15 mg , 14 %) as a pale yellow solid . ( m + h ) + 878 to a solution of compound c ( 11 . 5 mg , 0 . 013 mmol ) in hexanes ( 0 . 20 ml ) was added tributyltin hydride ( 0 . 021 ml , 0 . 080 mmol ) followed by 2 , 2 -* azobisisobutyronitrile ( 0 . 0013 mmol , & lt ; 1 mg ). the reaction mixture was heated at reflux for 2 hr . the reaction mixture was cooled to room temperature . the volatiles removed under a stream of air , and the residue was chromatographed ( 0 to 8 % etoac / hexanes ) to give compound d ( 7 . 2 mg , 77 %) as a clear oil . ( m + h ) + 720 to compound d ( 7 . 1 mg , 0 . 0099 mmol ) at − 15 ° c . was added 20 % trifluoroacetic acid / ch 2 cl 2 ( 0 . 30 ml ). the reaction was warmed to 0 ° c . and stirred for 2 hr . the volatiles were removed under a stream of air , and the residue was chromatographed with 40 % etoac / hexanes to give the title compound ( 4 . 3 mg , 89 %) as a clear , viscous oil . ( m + h ) + 492 . 1 h nmr ( cdcl 3 , 400 mhz ) 6 . 93 ( s , 1h ), 6 . 54 ( s , 1h ), 5 . 25 ( dd , j = 9 . 2 , 3 . 6 hz , 1h ), 4 . 07 - 4 . 11 ( m , 1h ), 3 . 83 - 3 . 87 ( m , 1h ), 3 . 15 - 3 . 20 ( m , 1h ), 2 . 68 ( s , 3h ), 2 . 51 ( dd , j = 15 . 0 , 9 . 2 hz , 1h ), 2 . 44 ( dd , j = 15 . 0 , 3 . 4 hz , 1h ), 2 . 01 - 2 . 07 ( m , 1h ), 2 . 03 ( s , 3h ), 1 . 67 - 1 . 71 ( m , 1h ), 1 . 44 - 1 . 53 ( m , 3h ), 1 . 37 - 1 . 45 ( m , 1h ), 1 . 3 ( s , 3h ), 1 . 16 - 1 . 30 ( m , 2h ), 1 . 14 ( d , j = 7 . 0 hz , 3h ), 1 . 13 ( s , 3h ), 1 . 05 - 1 . 13 ( m , 1h ), 0 . 97 ( d , j = 7 . 0 hz , 3h ), 0 . 57 - 0 . 72 ( m , 3h ), − 0 . 33 ( dd , j = 9 . 7 , 5 . 3 hz , 1h ). m - chloroperoxybenzoic acid ( 1 . 5 mmol , 260 mg ) was added to compound 2b ( 303 mg , 0 . 53 mmol ) in ch 2 cl 2 ( 12 ml ). the reaction mixture was stirred at room temperature for 5 hr . the reaction mixture was washed with nahcoa ( 2 × 50 ml ), na 2 so 3 ( 2 × 50 ml of 50mg / ml solution ), h 2 o ( 2 × 50 ml ), and then dried over na 2 so 4 . the organic extracts were concentrated and the residue was purified using hplc ( 500 × 30 mm ymc ods column , 15 to 100 % solvent b over 50 min ; solvent a : 10 : 90 , h 2 o : ch 3 cn ; solvent b : 90 : 10 , h 2 o : ch 3 cn ; flow rate : 20 ml / min ) to afford title compound , as a white solid ( 91 mg , 27 %). ( m + h ) + 590 . 2 m - chloroperoxybenzoic acid ( 0 . 013 mmol , 2 . 2 mg ) was added to compound 1c ( 3 mg , 0 . 006 mmol ) in ch 2 cl 2 ( 0 . 15 ml ). the reaction mixture was stirred at room temperature for 2 . 5 hr . the reaction mixture was concentrated and purified by flash chromatography ( 2 % meoh / chcl 3 ) to afford the title compound ( 1 . 0 mg , 32 %) as a white solid . ( m + h ) + 522 . 3 .