The first total synthesis of concanamycin f (concanolide a)

A highly stereoselective total synthesis of the macrolide antibiotic concanamycin F (1), a specific and potent inhibitor of vacuolar H(+)-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 18-membered tetraenic lactone and beta-hydroxyl hemiacetal side chain subunits. The C1-C19 18-membered lactone aldehyde 4 was synthesized through the intermolecular Stille coupling of the C5-C13 vinyl iodide 24 and the C14-C19 vinyl stannane 25, followed by construction of the C1-C4 diene and macrolactonization. Synthesis of 4 via a second convergent route including the esterification of the C1-C13 vinyl iodide 45 and the C14-C19 vinyl stannane 47 followed by the intramolecular Stille coupling was also realized. The highly stereoselective aldol coupling of 4 and the C20-C28 ethyl ketone 5 followed by desilylation provided 1 which was identical with natural concanamycin F.     

Enantioselective synthesis of the C1-C11 fragment of bafilomycin A1 using non-Wittig and desymmetrization strategies

The synthesis of the C1-C11 fragment 33 of bafilomycin A(1) was achieved. Intermediate ketone 16 was prepared in six steps from 4-oxopimelate 13. Desymmetrization of this ketone using Koga's chiral base followed by TMSCl quench furnished silyl enol ether 17 with excellent enantioselectivity. Further elaboration led to C5-C11 aldehyde 24, which was coupled with sulfone 3 to give lactone 25 in very good yield. The subsequent reductive elimination created the E-trisubstituted C4-C5 olefin with a 13:1 selectivity. The E C2-C3 double bond was then installed by methanol elimination, and compound 33 was obtained after a few functional group manipulations and a Negishi methyl zirconation.     

C-F or C-H bond activation and C-C coupling reactions of fluorinated pyridines at rhodium: synthesis, structure and reactivity of a variety of tetrafluoropyridyl complexes

Reactions of [RhH(PEt3)3] (1) or [RhH(PEt3)4] (2) with pentafluoropyridine or 2,3,5,6-tetrafluoropyridine afford the activation product [Rh(4-C5NF4)(PEt3)3] (3). Treatment of 3 with CO, 13CO or CNtBu effects the formation of trans-[Rh(4-C5NF4)(CO)(PEt3)2] (4a), trans-[Rh(4-C5NF4)(13CO)(PEt3)2] (4b) and trans-[Rh(4-C5NF4)(CNtBu)(PEt3)2] (5). The rhodium(III) compounds trans-[RhI(CH3)(4-C5NF4)(PEt3)2] (6a) and trans-[RhI(13CH3)(4-C5NF4)(PEt3)2] (6b) are accessible on reaction of 3 with CH3I or 13CH3I. In the presence of CO or 13CO these complexes convert into trans-[RhI(CH3)(4-C5NF4)(CO)(PEt3)2] (7a), trans-[RhI(13CH3)(4-C5NF4)(CO)(PEt3)2] (7b) and trans-[RhI(13CH3)(4-C5NF4)(13CO)(PEt3)2] (7c). The trans arrangement of the carbonyl and methyl ligand in 7a-7c has been confirmed by the 13C-13C coupling constant in the 13C NMR spectrum of 7c. A reaction of 4a or 4b with CH3I or 13CH3I yields the acyl compounds trans-[RhI(COCH3)(4-C5NF4)(PEt3)2] (8a) and trans-[RhI(13CO13CH3)(4-C5NF4)(PEt3)2] (8b), respectively. Complex 8a slowly reacts with more CH3I to give [PEt3Me][Rh(I)2(COCH3)(4-C5NF4)(PEt3)](9). On heating a solution of 7a, the complex trans-[RhI(CO)(PEt3)2] (10) and the C-C coupled product 4-methyltetrafluoropyridine (11) have been obtained. Complex 8a also forms 10 at elevated temperatures in the presence of CO together with the new ketone 4-acetyltetrafluoropyridine (12). The structures of the complexes 3, 4a, 5, 6a, 8a and 9 have been determined by X-ray crystallography. 19F-1H HMQC NMR solution spectra of 6a and 8a reveal a close contact of the methyl groups in the phosphine to the methyl or acyl ligand bound at rhodium.     

Rare-earth-metal-hydrocarbyl complexes bearing linked cyclopentadienyl or fluorenyl ligands: synthesis, catalyzed styrene polymerization, and structure-reactivity relationship

A series of rare-earth-metal-hydrocarbyl complexes bearing N-type functionalized cyclopentadienyl (Cp) and fluorenyl (Flu) ligands were facilely synthesized. Treatment of [Y(CH(2)SiMe(3))(3)(thf)(2)] with equimolar amount of the electron-donating aminophenyl-Cp ligand C(5)Me(4)H-C(6)H(4)-o-NMe(2) afforded the corresponding binuclear monoalkyl complex [({C(5)Me(4)-C(6)H(4)-o-NMe(μ-CH(2))}Y{CH(2)SiMe(3)})(2)] (1a) via alkyl abstraction and C-H activation of the NMe(2) group. The lutetium bis(allyl) complex [(C(5)Me(4)-C(6)H(4)-o-NMe(2))Lu(η(3)-C(3)H(5))(2)] (2b), which contained an electron-donating aminophenyl-Cp ligand, was isolated from the sequential metathesis reactions of LuCl(3) with (C(5)Me(4)-C(6)H(4)-o-NMe(2))Li (1 equiv) and C(3)H(5)MgCl (2 equiv). Following a similar procedure, the yttrium- and scandium-bis(allyl) complexes, [(C(5)Me(4)-C(5)H(4)N)Ln(η(3)-C(3)H(5))(2)] (Ln=Y (3a), Sc (3b)), which also contained electron-withdrawing pyridyl-Cp ligands, were also obtained selectively. Deprotonation of the bulky pyridyl-Flu ligand (C(13)H(9)-C(5)H(4)N) by [Ln(CH(2)SiMe(3))(3)(thf)(2)] generated the rare-earth-metal-dialkyl complexes, [(η(3)-C(13)H(8)-C(5)H(4)N)Ln(CH(2)SiMe(3))(2)(thf)] (Ln=Y (4a), Sc (4b), Lu (4c)), in which an unusual asymmetric η(3)-allyl bonding mode of Flu moiety was observed. Switching to the bidentate yttrium-trisalkyl complex [Y(CH(2)C(6)H(4)-o-NMe(2))(3)], the same reaction conditions afforded the corresponding yttrium bis(aminobenzyl) complex [(η(3)-C(13)H(8)-C(5)H(4)N)Y(CH(2)C(6)H(4)-o-NMe(2))(2)] (5). Complexes 1-5 were fully characterized by (1)H and (13)C NMR and X-ray spectroscopy, and by elemental analysis. In the presence of both [Ph(3)C][B(C(6)F(5))(4)] and AliBu(3), the electron-donating aminophenyl-Cp-based complexes 1 and 2 did not show any activity towards styrene polymerization. In striking contrast, upon activation with [Ph(3)C][B(C(6)F(5))(4)] only, the electron-withdrawing pyridyl-Cp-based complexes 3, in particular scandium complex 3b, exhibited outstanding activitiy to give perfectly syndiotactic (rrrr >99%) polystyrene, whereas their bulky pyridyl-Flu analogues (4 and 5) in combination with [Ph(3)C][B(C(6)F(5))(4)] and AliBu(3) displayed much-lower activity to afford syndiotactic-enriched polystyrene.     

Total synthesis of epothilone a through stereospecific epoxidation of the p-methoxybenzyl ether of epothilone C

The total synthesis of epothilone A is described by the coupling four segments 4-7 a. Three of the segments, 4, 5 and 7 a, have only one chiral center; all other chiral centers were introduced by simple asymmetric catalytic reactions. The key steps are the ring opening of epoxide 5 with acetylide 8 for the construction of the C12-C13 cis double bond and a practical hydrolytic kinetic resolution (HKR) developed by Jacobsen group for the introduction the chiral center at C3. Especially, the stereospecific epoxidation of 3-O-PMB epothilone C 3 b through long-range effect of 3-O-PMB protecting group gave high yields of the C12-C13 alpha-epoxide for the synthesis of target molecule.     

Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B

The total synthesis of the epidermal growth factor inhibitor reveromycin B (2) in 25 linear steps from chiral methylene pyran 13 is described. The key steps involved an inverse electron demand hetero-Diels-Alder reaction between dienophile 13 and diene 12 to construct the 6,6-spiroketal 11 which upon oxidation with dimethyldioxirane and acid catalyzed rearrangement gave the 5,6-spiroketal aldehyde 9. Lithium acetylide addition followed by oxidation/reduction and protective group manipulation provided the reveromycin B spiroketal core 8 which was converted into the reveromycin A (1) derivative 6 in order to confirm the stereochemistry of the spiroketal segment. Introduction of the C1-C10 side chain began with sequential Wittig reactions to form the C8-C9 and C7-C6 bonds, and a tin mediated asymmetric aldol reaction installed the C4 and C5 stereocenters. The final key steps to the target molecule 2 involved a Stille coupling to introduce the C21-C22 bond, succinoylation, selective deprotection, oxidation, and Wittig condensation to form the final C2-C3 bond. Deprotection was effected by TBAF in DMF to afford reveromycin B (2) in 72% yield.     

Study of the total synthesis of (-)-exiguolide

In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (-)-exiguolide ((-)-1). Two first types of approaches were set, both relying on the Trost's domino ene-yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14-C21 and C1-C13) by creating the C13-C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16-C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1-C5 and C6-C21 subunits through Trost's domino ene-yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (-)-exiguolide.     

Carbenerhodium complexes of the half-sandwich-type: synthesis, substitution, and addition reactions

A series of carbenerhodium(I) complexes of the general composition [(eta5-C5H5)Rh(=CRR')(L)] (2a-2i) with R = R'= aryl and L = SbiPr3 or PR3 has been prepared from the square-planar precursors trans-[RhCl(=CRR')(L)2] and NaC5H5 in excellent yields. Reaction of the triisopropylsibane derivative 2a. which contains a rather labile Rh-Sb bond, with CO, PMe3, and CNR (R = Me, CH2Ph, tBu) leads to the displacement of the SbiPr3 ligand and affords the substitution products [(eta5-C5H5)Rh(=CPh2)(L)] (3-7). In contrast, treatment of the triisopropylphosphane compound 2c with CO and CNtBu leads to the cleavage of the Rh=CPh2 bond and gives besides [(eta5-C5H5)Rh(PiPr3)(L)] (10, 12) by metal-assisted C-C coupling diphenylketene Ph2C=C=O (11) or the corresponding imine Ph2C=C=NtBu (13). While the reaction of 2a, c with C2H4 yields [(eta5-C5H5)Rh(C2H4)(L)] (14, 15) and the trisubstituted olefin Ph2C=CHCH3 (16), treatment of 2a, c with RN3 leads to the cleavage of both the Rh-EiPr3 and Rh=CPh2 bonds and gives the chelate complexes [(eta5-C5H5)Rh(kappa2-RNNNNR)] (19, 20). The substitution products 3 (L=CO) and 4 (L= PMe3) react with an equimolar amount of sulfur or selenium by addition of the chalcogen to the Rh=CPh2 bond to generate the complexes [(eta5-C5H5)Rh(kappa2-ECPh2)(L)] (21-24) with thio- or selenobenzophenone as ligand. Similarly, treatment of 3 with CuCl affords the unusual 1:2 adduct [(eta5-C5H5)(CO)Rh(mu-CPh2)(CuCl)2] (25), which reacts with NaC5H5 to form [(eta5-C5H5)(CO)Rh(muCPh2)Cu(eta5-C5H5)] (26). The molecular structures of 3 and 22 have been determined by X-ray crystallography.     

Total synthesis of amphidinolide J

The marine natural product amphidinolide J has been synthesized according to a convergent strategy. The key steps of this synthesis include a B-alkyl Suzuki-Miyaura coupling and the addition of an alkynyllithium reagent to a Weinreb amide to build the C4-C5 and C12-C13 bonds, respectively, and a Yamaguchi macrolactonization.     

Enantioselective total synthesis of (+)-amphidinolide t1

An enantioselective first total syntheis of amphidinolide T1 (1) is described. Amphidinolide T1 (1), a 19-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C21 segment 3 by an oxocarbenium ion-mediated alkylation and Yamaguchi macrolactonization sequence. The synthesis of fragment 2 involves an efficient cross metathesis and hydrogenation sequence between the terminal olefins of 5 and 6 to form the C4-C5 carbon-carbon bond. Enol ether 4 is designed to be the surrogate of fragment 3 where the sensitive C16-exo-methylene and the C13-hydroxyl group were protected as the bromoether derivative during the Lewis acid-catalyzed alkylation process. Both stereocenters in fragment 5 as well as the C2 and C3 stereocenters in fragment 4 are accessed by a highly diastereoselective ester-derived titanium enolate-mediated syn-aldol reaction. The bromoether derivative 24 was unraveled at the final stage of the synthesis, providing (+)-amphidinolide T1.     

Toward the synthesis of peloruside a: fragment synthesis and coupling studies

[reaction: see text] The asymmetric synthesis of building blocks 3, 4, and 5, corresponding to C(12)-C(19), C(7)-C(11), and C(1)-C(6) segments of peloruside A, is reported, along with boron-mediated aldol coupling studies directed toward the assembly of the complete carbon skeleton of this microtubule-stabilizing macrolide.     

Concerning the synthesis of the tedanolide C(13)-C(23) fragment via anti-aldol reaction

Synthesis of C(13)-C(23) aldehyde 4, an important intermediate in a planned total synthesis of tedanolide, is described. The stereoselectivity of the key anti-aldol reaction of aldehyde 5 and ketone 6 (en route to 4) perfectly tracks the enantiomeric purity of 5. It is demonstrated that aldehyde 24, a precursor of 5, undergoes facile epimerization during a Swern oxidation and stabilized ylide olefination sequence.     

Crotylsilane reagents in the synthesis of complex polyketide natural products: total synthesis of (+)-discodermolide

An efficient, highly convergent stereocontrolled synthesis of (+)-discodermolide has been achieved with 2.1% overall yield (27 steps longest linear sequence). The absolute stereochemistry of the C1-C6 (12), C7-C14 (13), and C15-C24 (11) subunits was introduced using asymmetric crotylation methodology. Key elements of the synthesis include the use of hydrozirconation-cross-coupling methodology for the construction of C13-C14 (Z)-olefin, acetate aldol reaction to construct the C6-C7 bond and install the C7 stereocenter with high levels of 1,5-anti stereoinduction, and the use of palladium-mediated sp(2)-sp(3) cross-coupling reaction to join the advanced fragments, which assembled the carbon framework of discodermolide.     

Toward the synthesis of norzoanthamine: complete fragment assembly

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product.     

Total synthesis of ingenol

Total synthesis of ingenol, a diterpene isolated from the genus Euphorbia, was accomplished on the basis of the novel key reactions. The highly strained ingenane skeleton was constructed through an intramolecular cyclization reaction of an acetylene dicobalt complex followed by a rearrangement reaction of an epoxy alcohol. The C(3),C(4),C(5)-triol moiety was introduced by a stereoselective double dihydroxylation reaction of a diene having C(2)-C(3) and C(4)-C(5) double bonds.     

Studies on the synthesis of apoptolidin: synthesis of a C1-C27 fragment of apoptolidin D

Synthesis of a C(1)-C(27) fragment, a key intermediate in the synthesis of apoptolidin D, is reported. The synthesis involves a combination of Heck coupling and Horner-Wadsworth-Emmons reaction for the C(1)-C(7) trienoate portion and an efficient Suzuki cross-coupling protocol for the C(10)-C(13) diene portion.     

Total synthesis of rutamycin B and oligomycin C

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.     

A cross-metathesis approach for the synthesis of tedanolide and 13-deoxytedanolide: stereoselective synthesis of the C3-C16 segment

A unified synthetic strategy has been devised for the synthesis of both tedanolide and 13-deoxytedanolide, which involves a cross-metathesis reaction as the key step. We report herein the stereoselective synthesis of the C3-C16 segment (+)-5b and subsequent manipulation of the C12-C13 double bond leading to the preparation of both tedanolides.     

Total synthesis of incednam, the aglycon of incednine

The first total synthesis of incednam (1), the aglycon of antibiotic incednine (2), is described. Incednine has been reported to exhibit significant inhibitory activity against the antiapoptotic oncoproteins Bcl-2 and Bcl-xL. The synthesis of 1 commenced with the preparation of the C1-C13 subunit 3 and the C14-C23 subunit 4. The construction of the novel 24-membered macrocycle was achieved by the application of a Stille coupling between 3 and 4, followed by macrolactamization.     

Toward a modular, bidirectional synthesis of (−)-mucocin

A convergent stereoselective synthesis of the C13-C34 fragment of (−)-mucocin is described. The salient features include (a) the bidirectional synthesis of the C-2 symmetric C13-C21 subunit, (b) regio- and stereoselective preparation of a 1,3-diol derivative from a diene activated by NBS via intramolecular nucleophilic sulfinyl group participation, (c) utilizing the self-metathesis reaction to prepare a functionalized C10 alkene, and (d) regio- and stereoselective intermolecular epoxide opening to construct the ether bond between C20 and C24. An organocatalytic α-hydoxylation has been employed to create the C4 stereogenic center of C1-C12 subunit. Attempted union of the two subunits utilizing the B-alkyl Suzuki coupling did not succeed.