Chemical synthons and intermediates

The invention provides novel six and seven-carbon termini-differentiated polypropionate stereotetrads and stereopentads useful in syntheses of natural products. The invention also provides a novel alkylative sulfenylation-desulfonylation process that efficiently transforms enantiopure epoxyvinyl sulfones to syn and anti dienylsulfides in two operations.

FIELD OF THE INVENTION

The invention provides novel six and seven-carbon termini-differentiated polypropionate stereotetrads and stereopentads useful in syntheses of natural products, including bioactive agents, or for use in the synthesis of bioactive agents or other compounds. The invention also provides a novel alkylative sulfenylation-desulfonylation process that efficiently transforms enantiopure epoxyvinyl sulfones to syn and anti dienylsulfides in two operations.

BACKGROUND OF THE INVENTION

The trimethyldiol stereopentad is a polypropionate sequence found in many medicinally active natural products. It is possible that the pair of hydrogen bond donors/acceptors in conjunction with the conformation-influencing characteristics of the methyl groups is responsible for recognition and binding of these materials at the active site of various biological targets. While the five-center stereopentad can exist in 32 stereoisomeric forms, it appears, based upon examination of the structure-searchable databases, that only 5 of these possibilities appear in natural products reported thus far. This number can be expanded to 10 by adding those compounds which bear a keto or an ethyl group at one of the alcohol or methyl positions, respectively.

The synthesis of biologically significant structures that incorporate polypropionate sequences has been the focal point of recent research efforts. The ever-increasing need for the preparation of chiral drugs as single enantiomers has fostered the evolution of methods of polypropionate segment synthesis including asymmetric aldol and asymmetric allyl metal additions to aldehydes.

All syntheses that target a single enantiomer ultimately must be related to one or more substances obtained from the chiral pool. It is recognized that syntheses that generate their asymmetry via a chiral catalyst are desirable because one molecule of catalyst is responsible for the creation of a multitude of new chiral progeny. For maximum effect, the chiral catalyst must be commercially available, deliver product in high yield, high ee, and exhibit high turnover numbers.

Multiply-convergent syntheses that combine stereochemically defined, functionality rich segments are often inefficient. Adoption of an easily scaled segment synthesis primarily impacts the probability of success of a synthetic project. Enantiopure segments prepared via catalytic processes have intrinsic advantages over stoichiometric use of enantiopure auxiliaries or reagents as these strategies are ‘high overhead,’ in that they generate added time and expense. Even successful syntheses that adopt the latter approach may be limited with respect to potential scale-up.

Cross-conjugated 6 and 7-membered dienyl sulfones have been developed and now comprise a collection of termini-differentiated acyclic arrays bearing 2-5 stereocenters. As illustrated inFIG. 1, scheme 1, Jacobsen asymmetric epoxidation of dienylsulfone of 2 with about 1% catalyst loading can give greater than 80% yields of epoxides RR-3 or SS-3 with greater than 97% ee. Reapplication of the catalytic Jacobsen epoxidation protocol to 5 effects greater than 12:1 double stereoselection, providing greater than 75% isolated crystalline yields of the individual members of the 6 and 7 family with 97% de (Scheme 1). Trimethylaluminum or dimethylcuprate undergoes complementary addition to silyl ether syn-7, giving alcohols 8 and 10, respectively. Alternatively, reaction of alcohol syn-6 with methyl lithium provided the α-methylated product 9α. While cleavage of the vinyl sulfones 8 and 10β gave the pseudoenantiomers (enantiomers with protecting group reversal) 11 and 12β, respectively, further evolution of these compounds in order to access polypropionates having C4,5(arrows, scheme 1) functionalized would not be easily accomplished.

Accordingly, the need exists for improved stereospecific, efficient syntheses of sulfides and sulfones, including dienyl sulfides and sulfones. Novel enantiopure diastereomers made by such syntheses would also prove useful in a number of applications. For example, they could serve as bioactive agents, including pharmaceutical compositions which have stereochemical requirements. Such compounds could also be used as standards for determining the stereochemistry of segments of natural products and other compounds which are suspected of having set stereochemistries within their chemical structuces.

SUMMARY OF THE INVENTION

The invention provides novel six and seven-carbon termini-differentiated polypropionate stereotetrads and stereopentads useful in syntheses of natural products or other chemical compounds or as bioactive agents. The invention also provides a novel alkylative sulfenylation-desulfonylation process that efficiently transforms enantiopure epoxyvinyl sulfones to syn and anti dienylsulfides in two operations. This process permits the stereospecific functionalization of all six or seven carbons of a cyclohexyl or cycloheptyl system, ultimately providing six or seven-carbon termini-differentiated polypropionate stereotetrads and stereopentads appropriate for natural product synthesis.

More specifically, the invention in one embodiment employs epoxy vinylsulfone chemistry to provide improved processes for the general synthesis of both chiral 4-alkylcycloalkenones and enantiopure 2,5-cyclohexadienone synthons. Epoxyvinyl sulfones are employed as a synthon for both unpoled enones as well as chiral 2,5-cyclohexadienone equivalents in which one masked enone is charge-inverted, and the latent enone is normally polarized.

Referring to schemes 1-4,FIGS. 1-2, and the detailed description provided hereinafter, the invention in one embodiment provides enantiopure stereodiads27and29in five operations from cycloheptanone1, with overall yields in excess of around 40% on the 100 g scale. These key substrates serve as progenitors to materials bearing up to five stereocenters on the 7-membered ring, thereby enabling synthesis of an entire collection of enantiopure diastereomers from catalytically-generated epoxide3(or ent-3). Enantiopure anti and syn stereodiads27and29can be used to prepare a group of termini-differentiated seven-carbon segments useful in syntheses of bioactive polypropionate derived natural products.

Further, in accordance with the invention and schemes 4a, 6a, 7a, 8a, and 9a described hereinafter in the detailed description, epoxy vinylsulfone chemistry provides improved methodology for the general synthesis of chiral 4-alkylcycloalkenones and for enantiopure 2,5-cyclohexadienone synthons.

Accordingly, the invention includes, but is not limited to, compounds of the following formulae:

Where R1is a C1-C5alkyl group;R2and R3are independently selected from H, a C1-C4alkyl group or a blocking group, preferably a silyl-containing blocking group such as a trimethyl silyl group or a t-butyl dimethyl silyl group; andR is a phenyl or substituted phenyl group wherein the substituted phenyl group is substituted in one instance at the ortho, meta or para position of the phenyl group with a C1-C4alkyl group, a halogen (F, Cl, Br, I) a nitro group, an amine, hydroxyl, alkyl ester (wherein the alkyl group on the ester is a C1-C4alkyl group), alkylether (wherein the alkyl group on the ester is a C1-C4alkyl group) or acyl group.

More preferred compounds according to the present invention are selected from the following chemical compounds:

Wherein R1is as described above.

Methods of making and using these compounds in the synthesis of bioactive agents, pharmaceutical compounds and other chemical compounds which contain chiral centers and specific stereochemistry are provided by the present invention.

The syntheses of the claimed compounds may be carried out readily using the methods which are identified hereinafter. Alternatives to the disclosed methods are contemplated by relying on analogous applications of the disclosed methods which are presented in significant detail hereinafter.

The present invention also relates to compounds according to the present invention wherein the compound is made by a process in which reaction of allyl sulfones with TMS triflate and an amine, preferably an organic amine such as triethylamine in a solvent such as methylene chloride at reflux effects regiospecific elimination to yield dienylsulfides; the dienylsulfides are oxidized through addition of an oxidizing agent, preferably a peroxide oxidizing agent such as mCPBA; and wherein the process can be done one pot or in steps.

The present invention also relates to methods of making a compound according to the present invention by:(a) reacting allyl sulfones of the formula

with TMS triflate and an amine, such as an organic amine including triethylamine in a solvent, such as methylene chloride, at reflux to yield a dienylsulfide of the formula

and oxidizing the dienylsulfide with an oxidizing agent, preferably a peroxide oxidizing agent such as mCPBA,
where R is C1-C5alkyl, phenyl, substituted phenyl, vinyl, alkynyl, trimethylsilyl or t-butyldimethylsilyl and wherein the reaction can be done one pot or in steps.

The present invention also relates to compounds according to the present invention as otherwise described herein and methods of making such compounds, wherein the compound is made by alkylating an epoxyvinylsulfone of the formula

in a reaction medium comprising (R)2CuLi, a solvent, such as an ether solvent, such as THF, ET2O or a mixture of THF and Et2O, where R is a C1to C5alkyl and wherein the reaction can be done one pot or in steps.

In other aspects of the present invention a compound according to the present invention is made by oxidizing an allylic alcohol of the formula

where R is a C1to C5alkyl, phenyl, substituted phenyl, vinyl, alkynyl, trimethylsilyl or t-butyldimethylsilyl to yield a β-sulfonyl enone of the formula

wherein the β-sulfonyl enone is subjected to Michael addition of heterocuprates and subsequent β-elimination of sulfinate, and
wherein the reactions are done one pot or in steps.

In still other aspects, a compound according to the present invention is made by reacting a sulfone of the formula

where R is a C1to C5alkyl, phenyl, substituted phenyl, vinyl, alkynyl, trimethylsilyl or t-butyldimethylsilyl with one or more alkyl halides.

In still other aspects, the present invention relates to a cleavage process comprising using a tetraacetate cleavage such as lead tetraacetate to promote oxidative cleaveage cleavage of a compound of the formula

to yield an enantiopure aldehyde-ester of the formula

where R is a C1to C5alkyl, phenyl, substituted phenyl, vinyl, alkynyl, trimethylsilyl or t-butyldimethylsilyl, the process is done one pot or in steps, and wherein the enantiopure aldehyde-ester is used in the synthesis of the C12-C18fragment of rhizoxin D.

In still other aspects, the present inventon relates to a synthetic method comprising:(a) reacting allyl sulfones of the formula

with TMS triflate and an amine, preferably, triethylamine in a solvent, preferably, methylene chloride, at reflux to yield a dienylsulfide of the formula

and oxidizing the dienylsulfide with an oxidizing agent, preferably a peroxide oxidizing agent such as mCPBA, where Rais C1-C5alkyl, phenyl, substituted phenyl, vinyl, alkynyl, trimethylsilyl or t-butyldimethylsilyl to yield a compound of the formula

wherein:R1is a C1-C4alkyl group;R2and R3are independently selected from H, a C1-C4alkyl group or a blocking group, preferably a silyl-containing blocking group such as a trimethyl silyl group or a t-butyl dimethyl silyl group; andR is a phenyl or substituted phenyl group wherein the substituted phenyl group is substituted in one instance at the ortho, meta or para position of the phenyl group with a C1-C4alkyl group, a halogen (F, Cl, Br, I) a nitro group, an amine, hydroxyl, alkyl ester (wherein the alkyl group on the ester is a C1-C4alkyl group), alkylether (wherein the alkyl group on the ester is a C1-C4alkyl group) or acyl group,and wherein the reaction can be done one pot or in steps.

These and other aspects of the instant invention are described further in the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms have the following respective meanings. Other terms that are used to describe the present invention have the same definitions as those generally used by those skilled in the art. Specific examples recited in any definition are not intended to be limiting in any way.

“Hydrocarbon” refers to a substituted or unsubstituted organic compound.

“Acetal” refers to a compound in which two ether oxygens are bound to the same carbon. A “ketal” is an acetal derived from a ketone.

“Acyl” means a compound of the formula RCO, where R is aliphatic (characterized by a straight chain of carbon atoms), alicyclic (a saturated hydrocarbon containing at least one ring), or aromatic.

“Alkyl” refers to a fully saturated monovalent hydrocarbon radical containing carbon and hydrogen which may be a straight chain, branched, or cyclic. Examples of alkyl groups are methyl, ethyl, n-butyl, n-heptyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl and cyclohexyl. “Cycloalkyl” groups refer to cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. C1-C7alkyl groups are preferably used in the present invention.

“Substituted alkyl” refers to alkyls as just described which include one or more functional groups such an alkyl containing from 1 to 6 carbon atoms, preferably a lower alkyl containing 1-3 carbon atoms, aryl, substituted aryl, acyl, halogen (i.e., alkyl halos, e.g., CF3), hydroxy, alkoxy, alkoxyalkyl, amino, alkyl and dialkyl amino, acylamino, acyloxy, aryloxy, aryloxyalkyl, carboxyalkyl, carboxamido, thio, thioethers, both saturated and unsaturated cyclic hydrocarbons, heterocycles and the like. The term “substituted cycloalkyl” has essentially the same definition as and is subsumed under the term “substituted alkyl” for purposes of describing the present invention.

“Amine” refers to aliphatic amines, aromatic amines (e.g., aniline), saturated heterocyclic amines (e.g., piperidine), and substituted derivatives such as an alkly morpoline. “Amine” as used herein includes nitrogen-containing aromatic heterocyclic compounds such as pyridine or purine.

“Aralkyl” refers to an alkyl group with an aryl substituent, and the term “aralkylene” refers to an alkenyl group with an aryl substituent. The term “alkaryl” refers to an aryl group that has an alkyl substituent, and the term “alkarylene” refers to an arylene group with an alkyl substituent. The term “arylene” refers to the diradical derived from aryl (including substituted aryl) as exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.

“Alkenyl” refers to a branched or unbranched hydrocarbon group typically although not necessarily containing 2 to about 24 carbon atoms and at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, and the like. Generally, although again not necessarily, alkenyl groups herein contain 2 to about 12 carbon atoms. The term “lower alkenyl” intends an alkenyl group of two to six carbon atoms, preferably two to four carbon atoms.

“Substituted alkenyl” refers to alkenyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom.

“Aryl” refers to a substituted or unsubstituted monovalent aromatic radical having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Other examples include heterocyclic aromatic ring groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazolyl, furyl, pyrrolyl, pyridyl, thienyl and indolyl, among others. Therefore, “aryl” as used herein includes “heteroaryls” having a mono- or polycyclic ring system which contains 1 to 15 carbon atoms and 1 to 4 heteroatoms, and in which at least one ring of the ring system is aromatic. Heteroatoms are sulfur, nitrogen or oxygen.

“Alkynyl” as used herein refers to a branched or unbranched hydrocarbon group typically although not necessarily containing 2 to about 24 carbon atoms and at least one triple bond, such as ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, octynyl, decynyl, and the like. Generally, although again not necessarily, alkynyl groups herein contain 2 to about 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of two to six carbon atoms, preferably three or four carbon atoms. “Substituted alkynyl” refers to alkynyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkynyl” and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.

“Alkoxy” as used herein refers to an alkyl group bound through an ether linkage; that is, an “alkoxy” group may be represented as —O-alkyl where alkyl is as defined above. A “lower alkoxy” group intends an alkoxy group containing one to six, more preferably one to four, carbon atoms.

“Allenyl” is used herein in the conventional sense to refer to a molecular segment having the structure —CH═C═CH2. An “allenyl” group may be unsubstituted or substituted with one or more non-hydrogen substituents.

“Anomer” as used herein means one of a pair of isomers of a cyclic carbohydrate resulting from creation of a new point of symmetry when a rearrangement of atoms occurs at an aldehyde or ketone position.

“Halo” and “halogen” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent. The terms “haloalkyl,” “haloalkenyl” or “haloalkynyl” (or “halogenated alkyl,” “halogenated alkenyl,” or “halogenated alkynyl”) refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.

“Heterocycle” or “heterocyclic” refers to a carbocylic ring wherein one or more carbon atoms have been replaced with one or more heteroatoms such as nitrogen, oxygen or sulfur. A substitutable nitrogen on an aromatic or non-aromatic heterocyclic ring may be optionally substituted. The heteroatoms N or S may also exist in oxidized form such as NO, SO and SO2. Examples of heterocycles include, but are not limited to, piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, tetrahydrofuran, tetrahydropyran, 2-pyrrolidinone, δ-velerolactam, δ-velerolactone and 2-ketopiperazine, among numerous others.

“Heteroatom-containing” refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with an atom other carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon. “Substituted heterocycle” refers to a heterocycle as just described that contains one or more functional groups such as lower alkyl, acyl, aryl, cyano, halogen, hydroxy, alkoxy, alkoxyalkyl, amino, alkyl and dialkyl amino, acylamino, acyloxy, aryloxy, aryloxyalkyl, carboxyalkyl, carboxamido, thio, thioethers, both saturated and unsaturated cyclic hydrocarbons, heterocycles and the like. In other instances where the term “substituted” is used, the substituents which fall under this definition may be readily gleaned from the other definitions of substituents which are presented in the specification as well the circumstances under which such substituents occur in a given chemical compound. One having ordinary skill in the art will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, degree of unsaturation, and valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heterocyclic ring is chemically feasible and stable.

“Isostere” refers to compounds that have substantially similar physical properties as a result of having substantially similar electron arrangements.

“Substituted”, as in “substituted alkyl” or “substituted alkenyl”, means that in the hydrocarbyl, hydrocarbylene, alkyl, alkenyl or other moiety, at least one hydrogen atom bound to a carbon atom is replaced with one or more substituents that are functional groups such as hydroxyl, alkoxy, thio, amino, halo, silyl, and the like. When the term “substituted” appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group.

“Effective amount” refers to the amount of a selected compound, intermediate or reactant which is used to produce an intended result. The precise amount of a compound, intermediate or reactant used will vary depending upon the particular compound selected and its intended use, the age and weight of the subject, route of administration, and so forth, but may be easily determined by routine experimentation. In the case of the treatment of a condition or disease state, an effective amount is that amount which is used to effectively treat the particular condition or disease state. Therefore, “effective amount” includes amounts of compounds of the instant invention that are effective in treating: anxiolytic disorders; a condition requiring treatment of injured mamnmalian nerve tissue; a condition amenable to treatment through administration of a neurotrophic factor; a neurological disorder; obesity; an obesity-related disorder; or a condition related to an endocrine function including inovulation and infertility.

The term “subjects” is used throughout the specification to describe an animal, preferably a human, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal.

Reference to one or more of the following references in relevant part provides background and other information which may prove useful in synthesizing the present compounds and employing the invention of the present application. See, for example:Hentenmann and Fuchs,Tetrahedron Lett.,40, 2699-2701 (1999);Evarts and Fuchs,Tetrahedron Lett.,40, 2703-2706 (1999);Hentenmann and Fuchs,Organic Lett.,1, 355-357 (1999);Jiang, et al.,Organic Lett.,2, 2181-2184 (2000);Tong, et al.,Tetrahedron Lett.,41, 7795-7799 (2000);Evarts and Fuchs,Tetrahedron Lett.,42, 3673-3675 (2001);Myers and Fuchs,J. Org. Chem.,60, 200-204, (2002);Evarts, et al.,J. Am. Chem. Soc.,124, 11093-11101 (2002); andTorres, et al.,Angew. Chem. Int. Ed.,27,3124-3131 (2003), relevant portions of which are incorporated by reference herein.
Chemistry

Referring toFIG. 1, schemes 1 and 2, compounds4and5were treated with methyl lithium to generate allyl sulfonyl anions4Li2and5Li, respectively. Quenching of these anions at low temperature delivered14α and15β, (as mixtures of sulfone diastereomers, E=H) in excess of 85% yield. HPLC analysis revealed that methylation of both intermediates occurred with complementary greater than 10:1 diastereoselectivity. Sulfenylation with dimethyldisulfide or methylthiolsulfonate gave a complicated mixture of products, which appeared to involve both α and γ-sulfenylation of the intermediate allylic anions. Attempted hydrolysis of these mixtures to enones16or17was unrewarding (FIG. 1, Scheme 2).

Reaction of the allylic anions4Li2and5Li with the more sterically-demanding diphenyldisulfide suffered regiospecific quenching at the γ-position, initially affording syn-18and anti-19, as a mixture of sulfide diastereomers. Monitoring of the reaction revealed that isomerization of intermediate vinylsulfones syn-18and anti-19to allyl sulfones syn-21and anti-22occurs under the basic reaction conditions (FIG. 2, Scheme 3). While ionization of the γ-phenylsulfonyl moiety of acyclic vinyl ethers and vinyl sulfides is known to generate enones and enals, the corresponding reaction for cyclic substrates is far less common.

Reaction of allyl sulfones syn-21and anti-22with TMS triflate and triethylamine in methylene chloride at reflux effected regiospecific elimination to dienylsulfides syn-29and anti-27. This transformation relies upon the unique amphoteric nature of the sulfone moiety. While sulfones are used as withdrawing groups to polarize olefins and inductively stabilize anions, it is the leaving group ability of phenyl sulfinic acid (pKa 7.1), which enables the lone pair of phenylvinyl sulfide group to expel sulfinate.[i]Presumably the silyl triflate serves to activate the sulfone moiety by reversible oxygen silylation (to24,25), thereby also preventing readdition of silyl sulfinate26once the vinyl thionium ion loses proximal proton Ha. Oxidation of27and29to key dienyl sulfones27oxand29oxcan be achieved by addition of mCPBA to the crude reaction mixture. This two-operation sequence enables stereoselective methylation with simultaneous establishment of a new, transposed diene (FIG. 1, Scheme 3). This transformation provides enantiopure stereodiads27and29in five operations from cycloheptanone1(overall yields are in excess of 40% on the 100 g scale).

The dienyl sulfone strategy proves useful in those cases where 4-5 stereocenters are required. As described, these key substrates serve as progenitors to materials bearing up to five stereocenters on the 7-membered ring, thereby enabling synthesis of an entire collection of enantiopure diastereomers from catalytically-generated epoxide3(or ent-3). Employing the TMS ether13afforded the unexpected syn-28after elimination of the sulfone moiety. Syn-addition via direction by OLi groups has been demonstrated on many occasions, but since silyloxy groups are generally held not to promote oxygen-coordinated direction, it appeared possible that more subtle conformational effects were involved. Conformational modeling show the TMS ether19preferred an equatorial oxygen, which placed the TMS group away from the α-face of the vinyl sulfone, providing unencumbered access for conjugate addition.

To demonstrate the value of enantiopure anti and syn stereodiads27and29, applicants prepared a group of termini-differentiated seven-carbon segments projected to be of use in synthesis of bioactive polypropionate derived natural products. Targets initially investigated used syn-intermediates21,23,29as enantiopure starting materials; anti-intermediates19,22,27could also be used.

Further functionalization of these substrates gives cycloheptenyl sulfones, which afford termini-differentiated aldehyde segments after oxidative cleavage. For example, referring toFIG. 3, scheme 4, direct methylation of the dianion of alcohol29produced dienylsulfide31(confirmed by X-ray). Oxidation of31affords dienyl sulfone32in 70% overall yield from29. The necessity of ‘protection’ of the alcohol moiety as an oxido anion is apparent from attempted alkylation of TBS ether29, which suffers β-elimination to trienylsulfide30. Treatment of the dianion of29with Eschenmoser's reagent gives amine34, which undergoes smooth tris-oxidation to trienylsulfone35upon exposure to excess mCPBA. Oxidation of dienylsulfones32and33using mCPBA was unselective, but high diastereoselectivity could be obtained using Molybdenum, Manganese, and Osmium catalyzed oxidations to prepare36-39(Scheme 4).

Approach to Rhizoxin

The plan for the synthesis of rhizoxin D40in accordance with the invention involves a 1-2 pot method of sequentially joining a pair of carbonyl compounds with a two-carbon bis-olefination splicer (FIG. 4, Scheme 5). Acylation of ent-21followed by hydrolysis gives β-sulfonyl ketone41, which was then transformed to silyl dienylether42. Singlet oxygen addition to42effected stereospecific (OTIPS necessary for greater than 95% β-face addition) formation of stable bicyclic peroxide43. Dimethyl dioxirane (DMDO) epoxidation of silyl enolether43provided the isolable α-epoxysilyl ether44. Hydrogenation of44proceeded, as desired, with silicon migration to give diol46in 83% yield. Methylation of the keto-diol46required dimethyltin chloride catalysis to effect regiospecific O-methylation at the more electron-rich distal alcohol, rapidly providing ketone47in high yield (first example for a 1-keto-2,3-diol). Methylation or silylation without the tin catalyst was very slow and strongly favored functionalization of the opposite alcohol. Lead tetraacetate cleavage of47in methanol completed the synthesis of enantiopure aldehyde-ester48(Scheme 5).

Referring toFIG. 5, scheme 6, analysis of concanamycin F49envisages the construction of a pair of stereopentads to be derived from vinyl sulfones50and53. Diol39is used to generate stereopentad51. Silylation of39provided vinylsulfone52in quantitative yield which was directly methylated in DMSO to give vinylsulfone53in 94% overall yield. Ozonolysis of53afforded ester-aldehyde51in 92% yield. Compound51is the enantiomer of the C15-C21 stereopentad of concanamycin F49(Scheme 6).

Apoptolidin54is a 20-membered macrocyclic lactone isolated fromNorcardiopsissp (FIG. 6, Scheme 7). Apoptolidin induced apoptotic cell death in rat gila cells transformed with the E1A oncogene at 11 ng/mL but did not cause cell death in normal gila cells or fibroblasts at greater than 100 g/mL.

Discodermolide55, like paclitaxel (taxol), has been shown to stabilize microtubules, but is more potent and inhibits the grown of paclitaxel-resistant cells. The material is in high demand for clinical trials, and synthesis is the only option. Five total syntheses and related synthetic approaches all using aldol-based acyclic stereoselection strategies beginning with enantiopure 3-hydroxy 2-methylpropionate have been reported. The second generation Smith synthesis utilized 34 total operations and enabled delivery of the first gram of (+)-discodermolide55with a linear supply line of only 24 operations. The overall yield was 6%.

Referring toFIG. 6, synthesis of apoptolidin54and discodermolide55in accordance with the invention makes use of the central stereotriads32and33as precursors to key epoxides α36and β36, respectively. Preparation of the C21-C27 segment of apoptolidin54is accomplished from epoxide β36beginning with selective 1,2-reduction with DIBAL-H to provide alcohol56. The complementary 1,4-reduction process to produce alcohol59can be selectively achieved using borane-THF. Completion of the apoptolidin segment synthesis simply involves ozonolysis of56to a δ-hydroxy aldehyde intermediate, which suffers cyclization to hemiacetal57. Protection of57as acetal58gave a 4:1 mixture of anomers, which can be easily separated by silica column chromatography (Scheme 7). Acetal58is also the C20-26 segment of phorboxazole (not shown).

In parallel fashion to the synthesis of58, it was possible to prepare the C1-C7 segment of discodermolide55by employing epoxide α36for 1,2-reduction with DIBAL-H. This afforded alcohol60in 65% yield. Subsequent ozonolysis afforded hemiacetal61, which smoothly underwent PDC oxidation to give lactone-ester62in 75% yield (Scheme 7).

Evaluation of the Cycloheptadienyl Sulfone2as a Stereopentad Precursor

Referring toFIGS. 1 and 7, synthesis of segment51, in accordance with the invention begins with cycloheptanone1. The sulfur atoms used in this strategy are essential for the synthesis (FIG. 1). The initial vinyl sulfide activates the olefin for bromination in operation 1b, after being oxidized to sulfone in 1c, the resultant sulfone regiospecifically activates the allylic position for base promoted 1,4 elimination in operation 1d to dienyl sulfone2. The electrophilic olefin of cross-conjugated dienyl sulfone2is flanked by a sterically demanding sp3-hybridized sulfone moiety, which has been shown to be crucial for obtaining the high enantiomeric excess obtained in the Jacobsen epoxidation. Once again, in operation 3a the epoxy vinyl sulfone3undergoes 1,4 elimination to provide intermediate4which suffers conjugate-addition with methyl lithium in operation 3b to provide an allyl sulfonyl anion66, which is directly sulfenylated to67in stage 3c. Vinyl sulfone67equilibrates to68at stage 3d and is finally protonated to21at stage 3e. Vinylogous dioxythioacetal21undergoes vinyl sulfide promoted loss of sulfinic acid at operation 4 to afford cross-conjugated dienyl sulfide29after workup. Methylation of the dianion of29, followed by oxidation of sulfide, and alcohol protection gives33. Catatytic substrate-based dihydroxylation followed by regiospecific silylation of the more available alcohol generates alcohol52, which undergoes O-methylation to53, then cleavage of the final vinyl sulfone to deliver the target stereopentad51.

In the course of this synthesis, applicants have introduced and ultimately removed two phenyl sulfone moieties; and while these factors are negative from the viewpoint of atom-economy, they are absolutely essential to achieve the chemistry. The dienyl sulfone synthesis of51exploits a chiral catalyst and then relates all further stereochemistry to the newly created stereocenter(s). This creates less costly ‘overhead’ than a synthesis employing an enantiopure starting material and then twice using either a chiral reagent or a chiral auxiliary. This difference will be especially significant in situations where reactions need to be conducted on a significant scale; since auxiliary or reagent cost, recycle, and/or disposal all strongly impact production cost.

General Synthesis of Chiral 4-alkylcycloalkenones and for Enantiopure 2,5-cyclohexadienone Synthons

Methylation of epoxyvinylsulfone SS-9a(Scheme 4a below) proceeds with about 96/4 trans/cis specificity for trans adduct14a. Duplication of this reaction with enantiopure SS-9ausing chiral HPLC analysis reveals that the reaction is essentially stereospecific (Table 1a, entry 1). Repetition of the process for the additional alkyl groups shown in Table 1a can be conveniently conducted with cuprates derived from both lithium and Grignard reagents without the need for addition of any alkyl aluminum reagent (Scheme 4a). The reactions are all high yielding and the product can be directly O-methylated as crude material. Methylation using MeI in basic DMSO is high yielding, fast, and does not require chromatography either before or after the process (Table 1a). Substantial empirical efforts failed to increase the selectivity of phenyl addition beyond 3:1.

Addition of t-BuLi at −78° C. to 13at generates a bright orange solution which, after 15 minutes, is quenched with saturated NaHCO3providing a mixture of sulfone diastereomers15ain high yield accompanied by less than 3% of the desired enone14aMe by NMR (Scheme 5a). An attempt to hydrolyze diastereomeric vinyl ethers15ato ketone14aMe using 5% oxalic acid in 1:1 methanol/water was interrupted after 1 h at 25° C. TLC analysis incorrectly suggested that the reaction contained only the mixture of starting vinyl ethers15a.It was later revealed that15a,14aMe, and16ahave the same Rf value on TLC in the assay system employed. During workup, 10% NaOH was added to the diluted reaction mixture, which was then extracted with CH2Cl2. NMR analysis showed that15ahad been completely hydrolyzed to16awith about 40% conversion to enone14aMe. Et3N was added to a mixture of β-ketosulfones16aand enone14aMe in CH2Cl2. The ratio did not change. Heating the mixture to reflux in CH2Cl2, then in dichloroethane, and finally adding DBU did not positively affect the ratio and side products began to dominate the crude NMR. Since acidic conditions seemed to facilitate elimination, the process was repeated and the oxalic acid hydrolysis step was allowed to stir overnight. The ratio, as analyzed by NMR, was worse, 75%16aand 25%14aMe.

Adding the crude16a/14aMe mixture to THF/water containing 3% Et3N and allowing the reaction to stir at 25° C. for 9 h was highly effective. The ratio of THF to water is critical. The substrate is dissolved in THF (approx. 0.09M), water is added until the reaction becomes slightly cloudy, then the minimum amount of THF is added to establish homogeneity. This process is ineffective without an aqueous wash of the initial reaction, because the lithium salt content does not allow the THF and water to be completely miscible.

Presumably, the basic aqueous conditions are more effective than in CH2Cl2because of the greater polarity of the media. Furthermore, the literature reveals that elimination of sulfinate from γ ketosulfones is a reversible process, and that the equilibria lies far towards the side of the β-ketosulfone under acidic conditions.

With a convenient method for conversion of the isomerized allyl sulfone to the desired enone finally in hand, 4-methylcyclohex-2-en-1-one14aMe was produced in 93% yield. It is significant that the sp3cuprate additions to SS-9aare about 100% anti throughout the series of methyl, ethyl, isopropyl, and t-butyl substituents as assayed by chiral HPLC of the resulting enones (14a) shown in Table 2a.

Epoxy vinylsulfone SS-9acan be obtained in excess of 99% ee, but in this experiment the ee of epoxide SS-9awas fixed at 93% by doping with racemic material, providing an unambiguous HPLC control. Except for14Mea(chiral HPLC inseparable; 93% by rotation), all the ee values in Table 2a were determined by HPLC analysis. With the possible exception of the t-butyl experiment, the reactions in Table 2a are held to be 100% enantiospecific within the limits of experimental detection.

γ-methoxyallyl sulfone anions can be quenched with electrophiles. Extension of this method to the more highly functionalized materials prepared in this study reveals that alkylations of proximally substituted γ-methoxyallyl sulfone anions are strongly influenced by the steric demands of the electrophile (Scheme 6a). As can be seen in Table 3a, synthesis of 3-substituted-4-alkyl cyclohex-2-en-1-ones bearing a secondary substituent in the 4-position are reluctant to alkylate under ‘standard’ conditions, but can be successfully alkylated provided that HMPA is added to the γ-methoxyallyl sulfone anion during the alkylation phase. Still, these conditions cannot overcome the steric demands of the electrophile, with the 3,4-bisisopropyl adduct only being formed in 5-10% yield even using the HMPA protocol.

A complementary method for synthesis of 3-substituted-4-alkyl cyclohex-2-en-1-ones14ainvolves reversing the role of nucleophile and electrophile. Oxidation of allylic alcohols t-12aa,bato β-sulfonyl enones17aa,bausing activated MnO2is high yielding. Michael addition of heterocuprates with subsequent β-elimination of sulfinate gives the desired 3,4-disubstituted enones14ain fair yield (Table 4a, Scheme 7a). While cuprate reactions are well known for vinylogous thiolesters, this is apparently the first report with vinylogous acyl sulfones17a(β-sulfonyl enones).

2-substituted 4-alkylcyclohexenones are also available by the addition of 2 equiv. of alkyl or aryl lithium followed by oxidation and elimination to the desired enone. Application of this process to t-12bagives enone19ain 90% yield (Scheme 8a). Extension of the strategy for synthesis of 2,3,4-trisubstituted enones was also examined beginning with alcohol t-12ba.In this instance, addition of the methyl lithium and subsequent capture of the anion with the methyl iodide produces20aas a mixture of isomers. Oxidation of20afollowed by elimination furnishes trisubstituted enone21ain excellent yield.

Enantiopure epoxyvinyl sulfone SS-9aalso can serve as a synthon for differentiated cyclohexa-2,5-dienones. Treatment of SS-9awith one equivalent of LiHMDS followed by addition of methyl- or isopropyl-lithium proceeds via sequential γ-metalation/epoxide fragmentation followed by OM-directed conjugate-addition with quenching α to the sulfone moiety to generate22aas shown in Table 5a and Scheme 9a. Mo(CO)3catalyzed directed epoxidation with tBu-OOH gives23a;DBU treatment of23afor the absolute minimal time (<1 h) cleanly effects β-elimination of the epoxide moiety. Methylation of the resulting γ-sulfonyl allyl alcohol may be done in the same operation to provide24ain the yields indicated in Table 5a. Treatment of24awith t-butyllithium affords an allylic anion which reacts with methyl iodide (HMPA essential) to give enantiopure enones25ain greater than 92% yield.

Certain compounds of the invention were characterized and determined to have the structures or values presented in Tables 1-3.

EXAMPLES

Experimental Procedures and Spectral Assignment

General Procedures

All purchased reagents were used as received. Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled from sodium benzophenone ketyl. Benzene, toluene, dichloromethane (CH2Cl2), anhydrous methanol, dimethyl sulfoxide (DMSO), were distilled from calcium hydride. Acetonitrile (CH3CN), chloroform (CHCl3), and methanol were spectra-grade. n-BuLi and t-BuLi were titrated prior to use by dropwise addition to a solution of N-benzylbenzamide in THF at −78° C. to 0° C. Sodium sulfate (Na2SO4) and magnesium sulfate (MgSO4) were used as received. Powdered 4 Å molecular sieves (Aldrich) were oven and/or flame activated under vacuum prior to use.

Glassware was oven dried and/or flame dried. All reactions were carried out under a positive pressure of argon in anhydrous solvents (unless otherwise indicated), and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Unless otherwise noted all reaction were worked up using standard conditions. Standard workup conditions are the addition of an equal volume of the stated organic solvent followed by two equal volumes of water or aqueous solution. All subsequent washes were preformed with volumes equal to the organic solution being washed. The progress of reactions was monitored by thin layer chromatography (TLC) in comparison with the starting material(s). TLC was performed on glass-backed silica gel 60 F 254 plates (EM reagents, 0.25 mm) and eluted with (v/v) Ethyl Acetate (EA) in hexanes (Hex) or the specified solvent solutions. The TLC plates were visualized with a UV lamp (254 nm) and/or with TLC visualizing solutions activated with heat. The two commonly employed TLC visualizing solutions were: (i) p-anisaldehyde solution (1350 mL absolute ethanol, 50 mL concentrated H2SO4, 15 mL glacial acetic acid, 37 mL p-anisaldehyde), and (ii) permanganate solution (weight percents of 1% KMnO4and 2% Na2CO3in H2O). All organic extracts were dried with MgSO4unless otherwise noted. Analytical samples were obtained from flash silica gel chromatography (SGC), using silica gel of 230-400 mesh, or from recrystalization of the crude products. Silica gel was washed with Et3N and acetone to render it deactivated. Melting points were obtained on a MEL-TEMP capillary melting point apparatus and uncorrected. Optical rotations were taken on a Rudolph Research Autopol III instrument at 25° C.1H-NMR spectra were recorded on Varian IONVA-300 (300 MHz) and Varian VXR (500 MHz) spectrometers.13C-NMR spectra were recorded on Varian INOVA-300 (75 MHz) and Varian VXR (125 MHz) spectrometers. NMR spectra were determined in chloroform-d1 (CDCl3) solution and are reported in parts per million (ppm) from the residual chloroform (7.26 ppm and 77.00 ppm). Peak multiplicities in1H-NMR spectra, when reported, are abbreviated as s (singlet), d (doublet), t (triplet), m (multiplet), and b (broad). Mass spectra were run by the Purdue University campus wide mass spectrometry facility. The low resolution EI and CI (isobutane) spectra were obtained on a Finnigan 4000 mass spectrometer with a Nova 4 data system with the molecular ion designated as “M+.” The high resolution mass spectra were obtained on a Kratos MS-50 instrument.

General Procedure for the Addition of Mixed Alkyl Cuprates to Epoxyvinyl Sulfone

To 530 mg (5.9 mmol) dry CuCN in 25 mL THF cooled to −78° C. was added 1.15 eq (4.86 mmol) of the desired alkyl lithium or Grignard reagent. The stirred mixture was allowed to warm to −20° C. for 15 min. The reaction temperature was returned to −78° C. and 1.0 g (4.23 mmol) epoxyvinyl sulfone in 10 mL THF was added via cannula. The reaction was then allowed to stir for 4-6 h without further cooling. When complete by TLC, the reaction was quenched with sat'd NH4Cl and extracted with ether. The organic layer was then washed again with 5% HCl. After drying and removing the solvent in vacuo the resulting material can typically be used without purification and was 95% pure by NMR.

General Procedure for the Etherification of γ-Hydroxy Vinyl Sulfones

Crude γ-hydroxy vinyl sulfone (4.0 mmol), was dissolved and rapidly stirred in 30 mL anhydrous DMSO and cooled in a 25° C. water bath. 20-30 equiv. of MeI were added. Powdered KOH was added slowly, approximately 1 pellet every 3 min for a total of 5 pellets. When complete by TLC, the dark mixture was poured into ice water. The mixture was extracted with ether 3 times and the solvent removed in vacuo. SGC, 6:4 Hex/EA, provided the desired methyl ethers in nearly quant. yield.
General Procedure for the Conversion of γ-Methoxy Vinyl Sulfones to Enones
1.2 equiv. of t-BuLi (0.61 mmol) were added to the γ-methoxy vinyl sulfone (0.51 mmol) in 20 mL THF at −78° C. over 2 min. The resulting bright orange reaction was stirred at this temperature for 25 min. 10 mL sat'd solution of NaHCO3was added and the reaction allowed to warm to room temperature. The mixture was extracted into 40 mL ether and concentrated. 15 mL THF was added followed by water until the two solvents begin to separate. More THF was added just until the solution becomes homogeneous. 0.5 mL Et3N was then added and the reaction was stirred for 15 h. Monitoring the reaction was best accomplished by NMR. When complete, ether and water was added and the organic layer separated and the solvent was removed in vacuo. SGC, 8:2 Hex/EA, provided the desired enones in good yield.

(1R, 2R, 3R)-3-Benzenesulfonyl-2-methyl-5-phenylsulfanylcyclohept-4-enol (21): To a solution of dienyl sulfone4(822 mg, 3.29 mmol) in THF (30 mL) at −78° C. was slowly added MeLi in Et2O (1.4M, 5.9 mL, 8.22 mmol) over a period of 30 minutes using a syringe pump. The resulting orange solution was left stirring for 30 minutes to ensure complete reaction. After 30 minutes phenyl disulfide (1.8 g, 8.22 mmol) dissolved in THF (4 mL) was rapidly added via cannula. The temperature was allowed to rise to 25° C. and the reaction mixture was left stirring for 6 h. Saturated NH4Cl (50 mL) was added to the mixture followed by Et2O (100 mL). The aqueous phase was extracted with Et2O (2×100 mL) and the combined organic extracts dried over MgSO4and concentrated. The product was purified via column chromatography using silica gel to give 835 mg of pure21in a 68% yield. Further product may be obtained by heating the higher Rf mixture, diastereomers at the sulfone carbon, at reflux (˜435 mg) in CH2Cl2(10 mL) with a catalytic amount of DBU (0.05 mL) for 24 h. The mixture was washed with 5% HCl (1×5 mL) and the organic layer is dried over Na2SO4and concentrated. The product was purified via column chromatography using silica gel to give an additional 165 mg of21, giving a combined yield of 81%. When the reaction was run on 12.1 g (48.4 mmol) the syringe pump was replaced by a pressure equalizing addition funnel, the final yield was 79% (14.2 g) after isomerization.1HNMR (300 MHz, CDCl3) δ 7.62-7.72 (m, 2H), 7.49-7.52 (m, 2H), 7.30-7.40 (m, 6H), 5.37 (d, J=6.0 Hz, 1H), 3.65-3.75 (m, 2H), 2.82-2.91 (m, 1H), 2.14-2.18 (m, 2H), 1.65-1.72 (m, 1H), 1.45-1.60 (m, 1H), 1.00 (d, J=6.85 Hz, 3H).13CNMR (75 MHz, CDCl3) δ 141.7, 138.5, 134.0, 133.7, 131.5, 129.4, 129.2, 128.7, 128.5, 115.8, 76.4, 65.8, 35.2, 29.8, 27.8, 7.8. LRMS (EI) m/z: 374 (M+); HRMS (CI) calculated for, C20H22O3S2, 375.1089; found 375.1088.

(1R, 2R)-(3-Benzenesulfonyl-2-methyl-5-phenylsulfanylcyclohept-4-enyloxy)-trimethylsilane (23): A solution of dienyl sulfone13(1.70 g, 5.27 mmol) in THF (60 mL) was cooled to −78° C., and 4.2 mL (5.88 mmol) of MeLi (1.4M in diethyl ether) was added dropwise over 30 min via syringe pump. The resulting orange solution was stirred at −78° C. for 15 min followed by addition of a solution of PhSSPh (1.80 g, 8.24 mmol) and THF (10 mL). The resulting mixture was slowly warmed up to room temperature over 6 h, and quenched with H2O and diluted with EtOAc (30 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, then dried (Na2SO4) and concentrated via rotary evaporation. Column chromatography (EtOAc-hexane; 1:7) of the crude residue afforded 2.15 g (91%) of23as a 1:1 diastereomeric mixture. The two diastereomers can be separated by flash column chromatography (EtOAc-hexane; 1:10) for characterization, but were used as a mixture for the next reaction. Characterization data of two isomers:

(1R, 2S)-2-Methyl-5-phenylsulfanylcyclohepta-3,5-dienol (29):22or23(2.15 g, 4.81 mmol) was dissolved in dry methylene chloride (20 mL), and 4.0 mL of Et3N (28.7 mmol) was added at room temperature, followed by addition of 3.0 mL (16.6 mmol) of TMSOTf. This mixture was brought to reflux under N2, and stirred for 8 h until the starting material was consumed (monitored by TLC using 30% ethyl acetate in hexanes). The reaction mixture was cooled to 0° C., and the excess TMSOTf was quenched by adding MeOH (1.0 mL, 24.7 mmol), diluted with EtOAc (20 mL), separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were concentrated via rotary evaporation, dissolved in a mixture of THF (30 mL) and H2O (10 mL). 10 mL of AcOH were added to the mixture and left stirring at room temperature for 3 h. It was then transferred to a 1 L beaker and saturated aqueous NaHCO3was carefully added until the solution became slightly basic, copious CO2evolved during this process. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed by saturated NaHCO3, followed by brine, and dried over Na2SO4. Flash column chromatography (EtOAc-hexane; 1:4) afforded 0.97 g (86%) of29as an oil. Care must be taken during purification that the mixture not be exposed to silica for extended time since this will cause some decomposition. The product slowly decomposes at 25° C., but stores well at −10° C. [α]20D=+200.5 (c=0.55, CH2Cl2);1H NMR (CDCl3, 300 MHz) δ 7.20-7.33 (m, 5H), 6.27 (t, J=5.4 Hz, 1H), 5.92 (d, J=11.4 Hz, 1H), 5.69 (dd, J=4.8, 11.4 Hz, 1H), 4.17 (br s, 1H), 2.59-2.68 (m, 2H), 2.42-2.52 (m, 1H), 1.97 (br s, 1H), 1.22 (d, J=7.2 Hz, 3H);3C NMR (CDCl3, 75 MHz) δ 137.2, 136.1, 133.9, 131.5, 129.9, 129.5, 129.2, 126.7, 76.4, 40.8, 38.3, 16.7; LRMS (CI): m/z 233 [M+H]+; HRMS (CI) calculated for C14H17OS, 233.1000; found, 233.0991.

4-(tert-Butyldimethylsilanyloxy)-6-methoxy-3,5-dimethyltetrahydropyran-2-yl]-acetic acid methyl ester (58): To a solution of compound56(108 mg, 0.263 mmol), NaHCO3(40 mg, 0.47 mmol) in methyl alcohol (3.0 mL) and methylene chloride (1.5 mL) at −78° C. was bubbled O3for 15 minutes, followed by O2for 5 minutes untill the blue solution became colorless. Me2S (0.5 mL) was added, the mixture warmed up to 25° C. for 5 h. Solvent was removed via rotary evaporation, and the residue purified via flash column chromatography (ethyl acetate/hexane, 1:5) to afford 64 mg (73%) of57as an inseparable anomeric mixture (α/β; 1:1). To the lactol mixture57(160 mg, 0.481 mmol) was added Ag2O (236 mg, 1.02 mmol), MeI (0.5 mL), and CH3CN (5 mL). This mixture was brought to reflux and left stirring for 1 h. The solvent was removed via rotary evaporation, the residue was purified by flash column chromatography (ethyl acetate/hexanes; 1:10) to afford 28 mg (17% yield) of58β followed by 108 mg (65% yield) of58α.

General Procedure for Generation of β-Substituted Enones Via Electrophile Capture.

Following the general procedure for the conversion of β-methoxy vinyl sulfones to enones the orange anionic solution was quenched with 1.1 equivalents of the desired electrophile. The reaction decolorizes at −78° C. after 15 min. A sat'd solution of NaHCO3was added followed by ether. The organic layer was dried over MgSO4and concentrated in vacuo. The residue was dissolved in CHCl3mL/mmol and SiO2250 mg/mmol added. After 2 h the solution was filtered and the solvent removed in vacuo. The enones are typically 90-95% pure. Silica gel chromatography can be used if necessary.

HMPA Modified Procedure for Generation of β-Substituted Enones Via Electrophile Capture.

1.2 equiv. of t-BuLi (0.61 mmol) were added to the mixture of β-methoxy vinyl sulfone (0.51 mmol) and HMPA (2.5 mmol) in 20 mL THF at −78° C. over 2 min. The resulting dark orange reaction was stirred at this temperature for 10 min. The solution was quenched with 3.1 equivalents of the desired electrophile. The reaction decolorizes at −78° C. after 15 min. A sat'd solution of NaHCO3was added followed by ether. The organic layer was dried over MgSO4and concentrated in vacuo. The residue was dissolved in CHCl3mL/mmol and SiO2250 mg/mmol added. After 3 h the solution was filtered and the solvent removed in vacuo. The enones are typically 90-95% pure. Silica gel chromatography can be used if necessary

General Procedure for the Oxidation of γ-Hydroxy Vinyl Sulfones.

2 mmol of γ-hydroxy vinyl sulfone was dissolved in 100 mL ether. Activated MnO2was added portionwise with rapid stirring until the reaction was complete as determined by TLC. The reaction was filtered through a 1:1 mixture of celite and SiO2. The resulting enones did not require purification and were routinely used crude.

General Procedure for Generation of β-Substituted Enones Via Addition/Elimination.

Alkyl cuprates, prepared as above, were added to δ-sulfonyl-enones at −78° C. in THF. The reactions were allowed to warm slowly to room temperature overnight. Ether and water were added to the reactions. The organic layer was dried and concentrated in vacuo. SGC, 8:2, Hex:EA, provided the desired enones in the yields indicated with the remaining mass recovered as unreacted starting material.

Procedure for Nucleophilic Addition to γ-Hydroxy Dienyl Sulfones:

(1S, 55, 65)-5-Benzenesulfonyl-6-methylcyclohex-3-enol (22aMe). To a solution of epoxy-dienyl sulfone SS-9a(0.377 g, 1.6 mmol) in THF (10 mL) at −78° C. was slowly added LiHMDS (1.8 mL, 1.8 mmol). The solution was stirred for 30 min, followed by addition of sat'd solution of NH4Cl (5 mL). Et2O (5 mL) was added to the mixture and separated. The aqueous layer was extracted with Et2O (2×5 mL) and the organic layers are combined, dried over MgSO4and concentrated. The resulting solid was dissolved in THF (10 mL) at −78° C. was added MeLi (3.4 mL, 4.8 mmol) in Et2O over a period of 15 min, addition must be done slowly to minimize aromatization. The orange solution was stirred for 20 min and then quenched by slowly adding a solution of sat'd NH4Cl (5 mL). The temperature was allowed to rise to 25° C. and diethyl ether was added (10 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×10 mL). The organic layers were combined, dried over MgSO4, and concentrated. The resultant mixture was filtered through a one inch silica gel plug eluting with a 3:1 mixture of ethyl acetate/hexanes to give 0.370 g of the desired sulfone as an oil in 92% yield and a 9:1 ratio of diastereomers.1H NMR (CDCl3): δ 7.88 (m, 2H), 7.61 (m, 3H), 5.97 (m, 1H), 5.54 (m, 1H), 4.17 (m, 1H), 3.62 (m, 1H), 2.47 (m, 1H), 2.28 (m, 1H), 2.05 (m,1H), 1.77 (m, 1H), 1.07 (d, J=6.9 Hz, 3H).13C NMR (CDCl3): δ137.9 133.7, 132.3, 129.1, 128.9, 117.5, 68.6, 66.2, 32.7, 30.3, 15.5. LRMS: (CI) highest mass 253 (M+H), base peak 143. HRMS: (CI) calculated for C13H16O3S 253.0898, found 253.0905
(1S, 55, 65)-5-Benzenesulfonyl-6-isopropylcyclohex-3-enol (22aPr). To a solution of epoxy-dienyl sulfone SS-9a(0.350 g, 1.5 mmol) in THF (10 mL) at −78° C. was slowly added LiHMDS (1.6 mL, 1.6 mmol). The solution was stirred for 30 min, followed by addition of a sat'd solution of NH4Cl (5 mL). Et2O (5 mL) was added to the mixture and separated. The aqueous layer was extracted with Et2O (2×5 mL) and the organic layers are combined, dried over MgSO4and concentrated. To the resulting solid in THF (10 mL) at −78° C. was slowly added iPrMgCl (3.7 mL, 7.4 mmol) over a period of 15 min, addition must be done slowly to minimize aromatization. The orange solution was stirred for 20 min and the temperature allowed to slowly rise to −10° C. over a period of 1 h. The solution was quenched by slowly adding a solution of sat'd NH4Cl (10 mL). The temperature was allowed to rise to 25° C. and diethyl ether was added (10 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×10 mL). The organic layers were combined, dried over MgSO4, and concentrated. The resultant mixture was filtered through a one inch silica gel plug eluting with a 3:1 mixture of ethyl acetate:hexanes to give 0.375 g of the desired sulfone as an oil in 89% yield and a 30:1 ratio of diastereomers.1H NMR (CDCl3): δ 7.88 (m, 2H), 7.59 (m, 3H), 5.99 (m, 1H), 5.66 (m, 1H), 4.31 (m, 1H), 3.77 (m, 1H), 2.17 (m, 4H), 0.81 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.9 Hz, 3H).13C NMR (CDCl3): δ 137.6, 133.7, 133.2, 129.1, 129.0, 118.5, 65.6, 63.9, 42.6, 31.5, 24.8, 22.1, 19.7. LRMS: (CI) highest mass 281 (M+H), base peak 143. HRMS: (CI) calculated for C15H20O3S 281.1211, found 281.1199.
(2R, 3S, 4S)-(3-Benzenesulfonyl-2-methylcyclohept-4-enyloxy)-tert-butyldimethylsilane (30). To a solution of dienyl sulfone2(FIG. 1) (0.322 g, 0.89 mmol) in THF (9 mL) at −78° C. was slowly added MeLi (1.8 mL, 1.95 mmol) in Et2O over a period of 10 min. The orange solution was stirred for 20 min and was then quenched by slowly adding a solution of sat'd NH4Cl (10 mL). The temperature was allowed to rise to 25° C. and diethyl ether was added (10 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×10 mL). The organic layers were combined, dried over MgSO4, and concentrated. The resultant mixture was filtered through a one inch silica gel plug eluting with a 3:1 mixture of ethyl acetate:hexanes to give 0.317 g of the desired sulfone as an oil in 94% yield and a 20:1 ratio of diastereomers.1H NMR (CDCl3): δ7.87 (m, 2H), 7.58 (m, 3H), 6.03 (m, 1H), 5.87 (m, 1H), 4.60 (m, 1H), 3.83 (m, 1H), 2.42 (m, 4H), 1.77 (m, 1H), 1.63 (m, 1H), 1.41 (m, 1H), 1.09 (d, J=7.0 Hz, 3H), 0.85 (s, 9H), −0.02 (s, 3H), −0.08 (s, 3H).13C NMR (CDCl3): δ 139.0, 134.9, 133.4, 129.1, 128.5, 123.2, 73.6, 62.3, 35.9, 27.1, 25.7, 20.0, 17.9, 12.3, −5.1. LRMS: (CI) highest mass 381 (M+H), base peak 249. HRMS: (CI) calculated for C20H32O3SSi 381.1920, found 381.1917.

General Procedure for Molybdenum Catalyzed Epoxidations:

To a solution of hydroxy allyl sulfone (0.98 mmol) in benzene (10 mL) was added solid molybdenum hexacarbonyl (0.005 g, 0.021 mmol, 5 mol %). The solution was heated to reflux and tert-butyl hydrogen peroxide (0.312 mL, 1.56 mmol) in decanes was slowly added over a period of 5 min. The solution was heated at reflux for 1.5 h. The reaction was allowed to cool to 25° C. and diethyl ether (10 mL) was added to the reaction mixture. The mixture was washed with a saturated solution of sodium bisulfite (5 mL), and the organic layer was concentrated. The resultant mixture was filtered through a one inch silica gel plug eluting with a 1:1 mixture of ethyl acetate/hexanes; which upon concentration affords epoxy sulfone as a crystalline solid in a high yields and the same ratio as that of the corresponding starting material. The crystalline product can be further recrystalized from chloroform and hexanes to separate the diastereomers.

General Procedure for Silyl Protection of the Epoxy Alcohols:

To a stirring solution of the epoxy sulfone (0.42 mmol) and triethylamine (0.63 mmol) in CH2Cl2(4.0 mL) at room temperature was added tert-butyldimethylsilyl triflouromethylsulfonate (0.50 mmol). The solution was stirred for 30 min. Diethyl ether (10 mL) was added and the crude mixture concentrated. The mixture was then filtered through a one inch silica plug eluting with a 1:3 solution of ethyl acetate/hexanes to give, after concentration, the desired protected alcohol in quantitative yield.

General Procedure for Base Induced Epoxide Opening Followed by Etherification of β-Hydroxy Vinyl Sulfones:

To a solution of the silylated epoxy sulfone (0.25 mmol) in THF (2.5 mL) was added DBU (0.30 mmol). The stirring solution was heated to reflux for 1 h. The temperature was lowered to room temperature and diethyl ether (5 mL) was added to the mixture followed by water (5 mL). The organic phase was separated and concentrated. The resulting mixture was filtered through a one inch silica gel plug eluting with a 1:1 solution of ethyl acetate/hexanes, which upon concentration gives the vinyl sulfone in high yield. Etherification is performed as explained previously.

Further Examples

Synthesis of Termini-Differentiated 6-Carbon Stereotetrads: An Alkylative Oxidation Strategy for Preparation of the C21-C26 Segment of Apoptolidin

General Synthetic Procedures

All common reagents and solvents were purchased from commercial suppliers and used as received. Solvents were dried by standard methods: tetrahydrofuran (THF) and diethyl ether were distilled from sodium benzophenone ketyl. Benzene, toluene, dichloromethane (CH2Cl2), and acetonitrile (CH3CN) were distilled from calcium hydride. Powdered 4 Å molecular sieves (Aldrich) were oven and/or flame activated under vacuum prior to use.

All glassware was oven dried and/or flame dried, evacuated, and purged with nitrogen. All reactions involving air and moisture-sensitive compounds were carried out under a nitrogen atmosphere, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. The progress of reactions was monitored by thin layer chromatography (TLC) in comparison with the starting material(s). TLC was performed on glass-backed silica gel 60 F 254 plates (EM reagents, 0.25 mm) and eluted with a mixture of ethyl acetate (EA) and hexanes (Hex) or the specified solvent solutions. Analytically pure samples were obtained from flash silica gel chromatography (SGC), using silica gel 60, 230-400 mesh, or from recrystalization of the crude products. Melting points were obtained on a MEL-TEMP capillary melting point apparatus and uncorrected.1H-NMR spectra were recorded on Varian IONVA-300 (300 MHz) and Varian VXR (500 MHz) spectrometers. C-NMR spectra were recorded on Varian INOVA-300 (75 MHz) and Varian VXR (125 MHz) spectrometers. NMR spectra were determined in chloroform-d1(CDCl3) solution and are reported in parts per million (ppm) from the residual chloroform (7.26 ppm and 77.00 ppm). Peak multiplicities in1H-NMR spectra, when reported, are abbreviated as s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Mass spectra were run by the Purdue University campus wide mass spectrometry facility. Low resolution EI and CI (isobutane) spectra were obtained on a Finnigan 4000 mass spectrometer with a Nova 4 data system with the molecular ion designated as “M+”. High resolution mass spectra were obtained on a Kratos MS-50 instrument.

Experimental Section

(1R, 5R)-2-Benzenesulfonyl-5-methyl-cyclohex-2-enol (24z). A solution of ketone28z (45 g, 206 mmol) and CeCl3.7H2O (106 g, 284 mmol) in MeOH (500 ml) was cooled to 0° C. Under mechanical stirring, 10.6 g (279 mmol) of NaBH4was added in small portions. When the reaction was complete by TLC, H2O was slowly added until no further bubbling was observed, then a total of 500 ml of H2O was added. The solution was then extracted with CH2Cl2(3×300 mL). If the solution forms an emulsion, 10-20 mL of aqueous 5% HCl can be added which will clear the solution and break any emulsion. The combined organic layers were dried over Na2SO4, and concentrated via rotary evaporation to afford 43 g analytically pure compound, which was used directly for next oxidation step. It was dissolved in MeOH (800 mL) and THF (200 mL), and cooled to 0° C., under mechanical stirring, a solution of 380 g (600 mmol) of Oxone in H2O (800 mL) was added in portions. The cooling bath was removed after half of the Oxone solution was added, and the reaction was stirred for further 24 h at room temperature, then 300 mL of CH2Cl2was added, the layers were separated, and the aqueous layer was further extracted with CH2Cl2(4×300 mL). The combined organic layers were dried over Na2SO4, and concentrated via rotary evaporation to give 46.9 g (95%) of an analytically pure white solid. Mp 79.0-81.0° C.;1H NMR (CDCl3, 300 MHz): 67.91-7.95 (m, 2H), 7.53-7.68 (m, 3H), 7.14 (dd, J=5.7, 2.7 Hz, 1H), 4.54 (m, 1H), 3.38 (br s, 1H), 2.38 (dm, J=18.9 Hz, 1H), 2.11 (m, 1H), 1.94 (ddt, J=18.9, 9.8, 2.7 Hz, 1H), 1.76 (m, 1H), 1.41 (td, J=12.4, 8.9 Hz, 1H), 1.00 (d, J=6.6 Hz, 3H).13C NMR (CDCl3, 75 MHz): δ142.9, 142.3, 140.9, 133.6, 129.4, 127.9, 65.6, 40.1, 34.6, 27.5, 21.3. Anal. Calcd for C13H16O3S: C, 61.88; H, 6.39. Found: C, 61.73; H, 6.25.

It is to be understood by those skilled in the art that the foregoing description and examples are illustrative of practicing the present invention, but are in no way limiting. Variations of the detail presented herein may be made without departing from the spirit and scope of the present invention as defined by the following claims.