Total synthesis of macrosphelides A, B, and E: first application of ring-closing metathesis for macrosphelide synthesis

A new synthetic route for macrosphelides A, B, and E based on ring-closing metathesis (RCM) was established. The substrates for RCM could be synthesized starting from commercially available chiral materials, methyl (S)-lactate and methyl (S)- or (R)-3-hydroxybutyrate, in good overall yields. In the investigation of the key RCM step, it was found that the steric factor around the reaction site significantly affected the reaction rate of macrocyclization. A detailed account regarding this synthetic study is described herein.     

Synthesis of the C1-C23 fragment of Spirastrellolide A

Synthesis of the C1-C23 fragment in spirastrellolide A is described, featuring a cyclic acetal-tethered RCM for stereoselective constructions of spiroketal, and a 1,3- anti aldol involving methyl ketone enolate and Mukaiyama conditions.     

Synthesis of the C12-C19 fragment of (+)-peloruside A through a diastereomer-discriminating RCM reaction

[reaction: see text]. A short and efficient asymmetric synthesis of the C12-C19 fragment of the cytotoxic macrolide (+)-peloruside A has been achieved via a highly diastereomer-discriminating RCM of alpha-branched but-3-enoate ester of a methallylic alcohol derived from hydrolytically resolved (S)-(-)-propylene oxide.     

Highly concise routes to epothilones: the total synthesis and evaluation of epothilone 490

A concise modular laboratory construction of the epothilone class of promising antitumor agents has been accomplished. For the first time in the epothilone area, the new synthesis exploits the power of ring-closing olefin metathesis (RCM) in a stereospecific way. Previous attempts at applying RCM to epothilone syntheses have been repeatedly plagued by complete lack of stereocontrol in the generation of the desired 12,13-olefin geometry in the products. The isolation of epothilone 490 (3) prompted us to reevaluate the utility of the RCM procedure for fashioning the 10,11-olefin, with the Z-12,13-olefin geometry already in place. Olefin metathesis of the triene substrate 12 afforded the product diene macrolide in stereoselective fashion. For purposes of greater synthetic convergency, the C3-(S)-alcohol was fashioned late in the synthesis, using chiral titanium-mediated aldol conditions with the entire O-alkyl fragment as a C15 acetate as the enolate component. Examination of the effects of protecting groups on the RCM process showed that deprotection of the C7 alcohol has a beneficial effect on the reaction yield. Performing the RCM as the last synthetic step in the sequence afforded a 64% yield of only the desired E-olefin. Selective diimide reduction of the new 10,11-olefin yielded 12,13-desoxyepothilone B, our current clinical candidate, demonstrating the utility of this new RCM-reduction protocol in efficiently generating the epothilone framework. Furthermore, the new olefin was selectively funtionalized to demonstrate the advantage conferred by this route for the construction of new analogues for SAR studies, in cytoxicity and microtubule affinity screens. Also described is the surprisingly poor in vivo performance of epothilone 490 in xenografts in the light of very promising in vitro data. This disappointing outcome was traced to unfavorable pharmacokinetic features of the drug in murine plasma. By the pharmacokinetic criteria, the prognosis for the effectiveness of 3 in humans is, in principle, much more promising.     

Convenient strategy for the synthesis of highly functionalizable hydroxylated unsaturated azepanes

A convenient approach to the construction of dihydroxylated unsaturated azepanes featuring a functional group (ethoxycarbonyl)methyl or (cyano)methyl at C-2 was achieved from a pent-4-enal synthon obtained in four steps from d-xylose. The key step of the sequence relied on the conjugate addition of allylamine to α,β-unsaturated ester or nitrile, prepared by Wadsworth-Emmons olefination. Subsequent RCM afforded the target unsaturated azepanes.     

Gamma-lactone-tethered ring-closing metathesis. A route to enantiomerically enriched gamma-lactones alpha,beta-fused to medium-sized rings

[reaction: see text] The stereoselective alkylation of alpha-(phenylsulfonyl)-beta-[(methoxycarbonyl)methyl]-gamma-lactones obtained by the base-induced cyclization of enantiomerically enriched alpha-[(phenylthio)acyl]-alpha,beta-unsaturated esters and ring-closing olefin metathesis (RCM) are the basis of a new approach for gaining access to gamma-lactones that are alpha,beta-fused to medium-sized carbocycles and cyclic ethers.     

Asymmetric synthesis of new beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives

The synthesis of new beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives 1 in which a ring-closing metathesis reaction (RCM) constitutes the key step is described. The approach employs imidoyl chlorides 3 as fluorinated building blocks, and the overall process involves the stereoselective creation of a quaternary stereocenter. Complete selectivity was achieved when (R)-phenylglycinol methyl ether was used as chiral auxiliary, allowing for the preparation of new six-membered cyclic fluorinated alpha-amino acids as single enantiomers.     

Selective domino ring-closing metathesis-cross-metathesis reactions between enynes and electron-deficient alkenes

[reaction: see text] A selective domino ring-closing metathesis (RCM)-cross-metathesis (CM) process between enynes and electron-deficient alkenes is reported. The conditions have been optimized for enynes 3 and methyl acrylate with catalyst IV. The scope and limitations of this reaction are described, and a possible mechanism is discussed.     

Cascade and RCM syntheses of chiral tricyclic alkaloids from (S)-1,2,3,4-tetrahydro isoquinoline carboxylic acid

Concise syntheses of novel chiral pyrroloazacyclo and chiral tricyclic isoquinoline alkaloids, starting from the readily available (S)-1,2,3,4-tetrahydroisoquinoline carboxylic acid methyl ester, by utilizing cascade spiro-to fused and RCM protocols, are reported.     

Application of ring-closing metathesis for the synthesis of macrocyclic peptidomimetics as inhibitors of HCV NS3 protease

An efficient synthetic approach for the preparation of macrocyclic peptidomimetics for inhibition of HCV NS3 is presented. The macrocyclic core is built using ring-closing metathesis (RCM) of a tripeptidic diene. The presented approach allows the introduction of heteroatoms in strategic places along the macrocyclic ring. The methyl ester moiety in the RCM products was synthetically manipulated to install a keto-amide moiety via a Passerini reaction.     

Total synthesis of nor-1,6-germacradien-5-ols

The first total synthesis of (+/-)-nor-1,6-germacradien-5-ols is described. The synthetic route involves the RCM methodology for the ring formation and a selective 1,2 addition of MeLi to cyclodecenone. By altering the order of the last synthetic steps, TBSO-protected (+/-)-(1Z,6E)-nor-1,6-germacradien-5-ols (+/-)-(5S*,8R*)-16 and -(+/-)-(5S*,8S*)-16 were obtained. The synthetic strategy via cyclodecenone offers the possibility of preparing different analogues of the title compounds through addition of other nucleophiles. Moreover, nor-germacrene D could be accessed from the target molecule by methylenation of its carbonyl moiety. (+/-)-nor-1,6-Germacradien-5-ol [(+/-)-(1E,5S*,6E,8S*)-2] was synthesized in eight steps from isovaleric acid. The 10-membered ring was formed by RCM, and the tertiary alcohol moiety was introduced in the last step via a highly diastereoselective addition of MeLi to (+/-)-(1E,6E)-1,6-cyclodecen-5-one (+/-)-E,E-5. Addition of MeLi to cyclodecenone (+/-)-Z,E-5 also occurred with complete selectivity to provide (+/-)-(1Z,5S*,6E,8S*)-2. A slightly different synthetic pathway was also explored, in which the order of the final synthetic steps was switched: the enone formation and the addition of MeLi were conducted prior to the cyclization. When the hydroxy group was protected as a TBS ether, the newly formed olefin had exclusively Z configuration. Thus, TBSO-protected (+/-)-(1Z,6E)-nor-1,6-germacradien-5-ols (+/-)-16 were obtained as a 1:1 (5S*,8S*)/(5R*,8S*) mixture. The NMR spectra of these two diastereomers confirmed the relative stereochemistry of natural (-)-1,6-germacradien-5-ol (1) at C5 and C8.     

A formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid

[reaction: see text] A stereocontrolled approach for the preparation of the Danishefsky intermediates has been developed starting with the azaspirobicyclic ketone as a common precursor, representing a formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid. This approach involves the construction of the 1,7-disubstituted 6-azaspiro[4.5]decane with the proper stereochemistry established by olefin hydrogenation followed by C-methylation of the spirotricyclic lactam and the subsequent processes involving lactam ring-opening using methyl triflate and RCM to form the azaspirotricyclic quinolizidine skeleton.     

The reaction of (4R,5R)- and (4S,5S)-4,5-epoxy-2(E)-hexenoates and secondary amines.

A reaction of methyl (4R,5R)-4,5-epoxy-2(E)-hexenoate 1 with N-benzylmethylamine gave a diastereomerically pure methyl (4R,5R)-4,5-epoxy-(3S)-N-benzylmethylamino hexanoate 6 and methyl (4S,5R)-4-N-benzyl-methylamino-5-hydroxy-2(E)-hexenoate 7. The former was chemoenzymatically converted to (-)-osmundalactone 11, which is an aglycone of osmundalin. On the other hand, the directly conjugated addition of dimethylamine to methyl (4S,5S)-4,5-epoxy-2(E)-hexenoate 1 followed by treatment with MeOH at 40 degrees C exclusively provided methyl (4R,5S)-4-dimethylamino-5-hydroxy-2(E)-hexenoate 16, which was converted into L-(-)-forosamine 18.     

Cross-linking dendrimers with allyl ether end-groups using the ring-closing metathesis reaction

A third generation Frechet-type dendrimer containing 24 allyl ether end-groups was synthesized, cross-linked using the ring-closing metathesis (RCM) reaction, and the core was removed hydrolytically without significant fragmentation. The results are analogous to those previously reported for homoallyl ether dendrimers (Wendland, M. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1999, 121, 1389-1390) suggesting that the less readily available homoallyl ether dendrimers can be replaced by their allyl ethers analogues in a range of applications.     

Ring-closing metathesis of chiral allylamines. Enantioselective synthesis of (2S,3R,4S)-3,4-dihydroxyproline

The ring-closing metathesis (RCM) of two types of unsaturated chiral allylamines III, easily available from enantiomerically enriched epoxy alcohols, has been studied. Fully protected allylamines IIIa [(1)R = CH(2)-(CH(2))(n)()-CH=CH(2); (2)R = Boc; (3)R = PMB] have been prepared from unsaturated epoxy alcohols, whereas bis-allylamines IIIb ((1)R = Ph, (2)R = allyl,(3)R = Boc or PMB) have been prepared from 2,3-epoxy-3-phenylpropanol. Both types have been subjected to RCM to provide either cyclic allylamine I or II. The synthetic potential of these intermediates has been demonstrated by the enantioselective synthesis of (2S,3R,4S)-3,4-dihydroxyproline.     

Total synthesis of (+)-phomopsolide C by ring-size selective ring-closing metathesis/cross-metathesis

[reaction: see text]A new strategy for the synthesis of chiral 6-substituted 5,6-dihydro-5-hydroxypyran-2-ones by ring-size selective ring-closing metathesis (RCM) and its application to a short total synthesis of (+)-phomopsolide C are described. The key bond-forming reactions in this approach are a chemoselective cross-metathesis (CM) and RCM.     

Development of environmentally benign organometallic catalysis for drug discovery and its application

We have developed a novel organometallic catalysis and applied it to drug discovery. Two new catalysts were found, ruthenium hydride with a nitrogen-containing heterocyclic carbene (A) and an organopalladium catalyst supported on a sulfur-terminated semiconductor, gallium arsenide (001) (B). Both catalysts are environmentally benign, because A can yield indole derivatives with good atom economy, and B can catalyze the Mizoroki-Heck reaction more than 10 times with only trace amounts of leached palladium (ppb level). We also describe our synthetic study of nitrogen-containing heterocycles using ring-closing metathesis (RCM), such as chiral bicyclic lactams, azacycloundecenes, axially chiral macrolactams, 1,2-dihydroquinolines and indoles, including the development of silyl-enol ether ene metathesis, selective isomerization of terminal olefin, enamide metathesis and cycloisomerization and its application to the syntheis of 4 natural products, (-)-coniceine, (S)-pyrrolam A, angustureine, and fistulosin.     

Synthesis,Crystal Structure and Anti-breast Cancer Activity of ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-Methylbenzenesulfonate

The new heterocycle compound ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (1), designed using((3R,5S)-5-(2,4-difluorophenyl)-5-iodotetrahydrofuran-3-yl)methyl isobutyrate(2) as the start material, was successfully obtained via multiple synthesis route and finally characterized by IR, ~1H NMR, and single-crystal X-ray crystallography. In addition, the in vitro anticancer activities of the newly synthesized complex 1 have been emulated against three human breast cancer cell lines BT474, MCF7 and MB.     

Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids

Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3'N-benzoyl group (C3'BzN), which are ca. 7.5 A apart, with a short linker (4-6 atoms). 7-TES-14beta-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-beta-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.     

Total synthesis of (-)-nakadomarin A

A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A.