Cu-mediated Stille reactions of sterically congested fragments: towards the total synthesis of zoanthamine

A study on the Stille reaction of alkenyl iodides and stannanes with structural resemblance to retrosynthetic fragments of a projected total synthesis of the marine alkaloid zoanthamine was carried out. A range of reaction conditions was examined, and a protocol developed by Corey utilizing excess copper(I) chloride and lithium chloride was found to be most efficient. The methodology was successfully applied to join two major fragments of the zoanthamine skeleton.     

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.     

On Ni catalysts for catalytic, asymmetric Ni/Cr-mediated coupling reactions

The importance of the Ni catalyst in achieving catalytic asymmetric Ni/Cr-mediated coupling reactions effectively is demonstrated. Six phenanthroline-NiCl(2) complexes 1a-c and 2a-c and five types of alkenyl iodides A-E were chosen for the study, thereby demonstrating that these Ni catalysts display a wide range of overall reactivity profiles in terms of the degree of asymmetric induction, geometrical isomerization, and coupling rate. For three types of alkenyl iodides A-C, a satisfactory Ni catalyst(s) was found within 1a-c and 2a-c. For disubstituted (Z)-alkenyl iodide D, 2c was identified as an acceptable Ni catalyst in terms of the absence of Z → E isomerization and the degree of asymmetric induction but not in terms of the coupling rate. Two phosphine-based Ni catalysts, [(Me)(3)P](2)·NiCl(2) and [(cy)(3)P](2)·NiCl(2), were found to meet all three criteria for D. The bond-forming reaction at the C16-C17 position of palytoxin was used to demonstrate the usefulness of the Ni catalysts thus identified.     

Studies on the synthesis of (-)-gymnodimine. Subunit synthesis and coupling

Two principal subunits of the marine algal toxin (-)-gymnodimine were synthesized. A trisubstituted tetrahydrofuran representing C10-C18 of the toxin was prepared via a highly stereoselective iodine-mediated cyclization of an acyclic alkene bearing a bis-2,6-dichlorobenzyl (DCB) ether. The formation of a cis-2,5-disubstituted tetrahydrofuran in this process conforms to a stereodirecting effect by the DCB group proposed by Bartlett and Rychnovsky. A cyclohexene subunit corresponding to the C1-C8, C19-C24 portion of gymnodimine was synthesized via Diels-Alder cycloaddition of a 1,2,3-trisubstituted diene to a symmetrical dienophile obtained from Meldrum's acid. Differentiation of carbonyl groups in the cycloadduct was made by an intramolecular reaction with a neighboring alcohol to form a gamma-lactone. Linkage of the two subunits at C18-C19 was accomplished by using a B-alkyl Suzuki coupling in which a borane prepared from the pendent alkenyl chain of the cyclohexene domain was reacted with the (E)-iodoalkene attached at C16 of the tetrahydrofuran sector. Subsequent transformations positioned functional groups in the coupled product for a future macrocyclization event that would close the 15-membered ring of gymnodimine.     

Synthesis of vinylic iodides for incorporation into the C17-C27 fragment of bryostatins

Vinylic iodides were identified as useful intermediates for the synthesis of the C17-C27 fragment of the bryostatins with control of the geometry of the exocyclic methoxycarbonylmethylene group. Following literature precedent, the Piers (E)-stereoselective addition of tributyltin hydride to an alkynoate followed by ester reduction and tin-iodine exchange gave vinylic iodides that could be used to form the C20-C21 bond of the bryostatins. Chelation controlled addition of lithiated 3-silyloxypropynes to 2-alkoxyaldehydes followed by reductive iodination was used to prepare vinylic iodides that could be used in the complementary assembly of the C21-C22 bond of the bryostatins. Initial studies of the synthesis of intermediates for metathesis studies using metal catalysed reactions of a vinylic iodide for C21-C22 bond formation were complicated by cyclisation reactions.     

Stereocontrolled total syntheses of isodomoic acids G and H via a unified strategy

Marine neuroexcitatory compounds isodomoic acids G and H were efficiently synthesized from a common intermediate using a silicon-based cross-coupling reaction. Dividing each target compound into the core fragment and the side-chain fragment enabled the synthesis to be convergent. The trans-2,3-disubstituted pyrrolidine core fragment was accessed through a diastereoselective rhodium-catalyzed carbonylative silylcarbocyclization reaction of a vinylglycine-derived 1,6-enyne. A stereochemically divergent desilylative iodination reaction was developed to convert the cyclization product to both E- and Z-alkenyl iodides, which would eventually lead to isodomoic acid G and isodomoic acid H, respectively. The late-stage alkenyl-alkenyl silicon-based cross-coupling reaction uniting the core alkenyl iodides and the side-chain alkenylsilanol was achieved under mild conditions. Finally, two mild deprotections afforded the target molecules.     

Total synthesis of 8-deshydroxyajudazol B

The total synthesis of a stereoisomer of 8-deshydroxyajudazol B (4), the putative biosynthetic intermediate of the ajudazols A (1) and B (2), is described. The key steps in the synthesis included an intramolecular Diels-Alder (IMDA) reaction to secure the isochromanone fragment, a novel selective acylation/O,N-shift to give a hydroxyamide which was cyclized to the oxazole and a high yielding Sonogashira coupling to form the C18-C19 bond. Partial alkyne reduction then afforded the target 4.     

Total synthesis of (+)-superstolide A

A convergent and highly stereocontrolled total synthesis of the cytotoxic macrolide (+)-superstolide A is described. Key features of this synthesis include the use of bimetallic linchpin 36b for uniting the C(1)-C(15) (43) and the C(20)-C(27) (38) fragments of the natural product, a late-stage Suzuki macrocyclization of 49, and a highly diastereoselective transannular Diels-Alder reaction of macrocyclic octaene 4. In contrast, the intramolecular Diels-Alder reaction of pentaenal 5 provided the desired cycloadduct with lower stereoselectivity (6:1:1).     

Rhodium-Catalyzed Anti-Markovnikov Transfer Hydroiodination of Terminal Alkynes**

A rhodium-catalyzed anti-Markovnikov hydroiodination of aromatic and aliphatic terminal alkynes is reported. Depending on the choice of ligand and substrate, either (E)- or (Z)-configured alkenyl iodides are obtained in high to exclusive isomeric purity. The reaction exhibits a broad substrate scope and high functional group tolerance, employing easily accessible or commercially available aliphatic iodides as HI surrogates through a shuttle process. The synthesized vinyl iodides were applied in several C−C and C−heteroatom bond-forming reactions with full retention of the stereoselectivity. The developed method could be used to significantly shorten the total synthesis of a marine cis-fatty acid. Additionally, initial deuterium-labeling experiments and stoichiometric reactions shed some light on the potential reaction mechanism.     

Total synthesis of cruentaren B

A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C1-C11 benzolactone fragment of the molecule, the key steps used were O-methylation, using a Mitsunobu reaction, a Stille coupling method to construct the C7-C8 bond, and a Brown's asymmetric crotylboration reaction for the direct enantioselective installation of the two chiral centers present in this fragment. For diastereoselective installation of the chiral centers in the C12-C20 polyketide fragment, an Evans syn aldol reaction on a chiral aldehyde, derived from methyl (R)-3-hydroxyl-2-methylpropionate, and subsequently a Mukaiyama aldol reaction were employed. For the construction of the C21-C28 tail, a "non-Evans" syn aldol reaction was used. The three fragments were coupled by an SN2 reaction and a Wittig olefination reaction followed by standard functional group manipulations to furnish the target molecule.     

Stereoselective preparation of functionalized acyclic alkenylmagnesium reagents using i-PrMgCl.LiCl

Acyclic functionalized alkenyl iodides are converted with high stereoselectivity to the corresponding functionalized alkenylmagnesium derivatives by the reaction with i-PrMgCl.LiCl between -40 and -20 degrees C. Functional groups such as a nitrile, chloride, iodide, and ester are readily tolerated. The conversion of an alkenyl iodide bearing a keto group to the corresponding silylated cyanohydrin allows preparation of the corresponding Grignard reagent affording, after acylation and deprotection, unsaturated 1,4-diketones.     

半稳定磷叶立德和亚胺高选择性合成卤代烯烃

半稳定磷叶立德分别和合适的磺酰基活化的亚胺在温和的反应条件下得到高选择性的卤代烯烃产物,对于芳香族、杂芳环、α,β-不饱和以及脂肪族亚胺产物都可以得到良好的收率.除此之外,我们还以良好的收率选择性合成了单一构型的一系列的氯代和碘代烯烃产物.该反应机理和Wittig反应类似,反应通过[2+2]环加成生成中间体然后消除得到...     

Relay-Heck Cross-Coupling Between Alkenyl Halides and Unsaturated Alcohols in the Synthesis of Open-Chain Analogues of Musk Odorant Vulcanolide

Unactivated alkenyl iodides and bromides underwent an unprecedented palladium-catalyzed relay-Heck cross-coupling with a whole range of alkenols of different chain lengths linking the alkene and the alcohol, affording unsaturated aldehydes and ketones in moderate to good yields. In contrast, alkenyl triflates were not suitable partners for this reaction. This method allowed the preparation of open-chain analogues of the musk odorant Vulcanolide, several of which retained key olfactory properties of the parent molecule.     

Synthesis of amphidinolide E C10-C26 fragment

The key C10-C26 fragment in a total synthesis of (-)-amphidinolide E has been prepared from an oxolane-containing C10-C17 segment (9, derived from L-glutamic acid) via a Julia-Kocienski reaction with aldehyde 3, followed by a Sharpless AD to obtain the desired diol. The C22-C26 fragment was installed by means of an efficient Suzuki-Molander coupling, with an organotrifluoroborate reagent (4, arising from a cross-metathesis reaction between a vinylboronate and 2-methyl-1,4-pentadiene).     

Pd-catalyzed cross-coupling of α-(acyloxy)-tri-n-butylstannanes with alkenyl, aryl, and heteroaryl electrophiles

Racemic and scalemic α-(acyloxy)-tri-n-butylstannanes undergo Pd-catalyzed cross-couplings with alkenyl/aryl/heteroaryl iodides, bromides, and triflates in moderate to good yields in THF at 45 °C. Simple aryl iodides and unprotected aza-arenes, two classes of electrophiles that typically react sluggishly, are also good substrates. Cross-couplings proceed with retention of configuration at the alkenyl and stannyl-substituted stereocenters.     

Synthetic studies toward phorboxazole A. stereoselective synthesis of the C(28)-C(46) side chain fragment

A stereoselective synthesis of the C(28)-C(46) fragment (3) of phorboxazole A is described. Key advances include an enantioselective allylation to establish the stereochemistry of the tetrahydropyran unit and a useful SmI(2)-mediated modification of the Barbier reaction of iodomethyloxazole 15 with aldehyde 14.     

Coupling reactions of alpha-bromoalkenyl phosphonates with aryl boronic acids and alkenyl borates

[reaction: see text] Transition metal-catalyzed arylation and alkenylation of the alpha-bromoalkenyl phosphonates were investigated with organoboranes and -borates. Arylation was successful with the aryl boronic acids and a palladium catalyst, while alkenylation was found to proceed with alkenyl borates and a nickel catalyst. In addition, an intramolecular Diels-Alder reaction of the diene prepared by the alkenylation afforded the corresponding adduct.     

Michael-type reaction of ethyl bromodifluoroacetate with alpha,beta- unsaturated carbonyl compounds in the presence of copper powder

We have reported that the reaction of ethyl bromodifluoroacetate (1) with alkenyl iodides in the presence of copper powder gives ethyl alkenyldifluoroacetates. As an extension of this reaction, reaction of 1 with Michael acceptors in the presence of copper powder was examined and found to give 1,4-addition products selectively, unless the acceptor has a group stabilizing a radical intermediate, such as a phenyl group.     

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.     

Synthesis and cross-coupling reaction of alkenyl[(2-hydroxymethyl)phenyl]dimethylsilanes

Highly stable alkenyl[2-(hydroxymethyl)phenyl]dimethylsilanes are prepared by stereo- and regioselective hydrosilylation of alkynes catalyzed either by a platinum or ruthenium catalyst using protected [2-(hydroxymethyl)phenyl]dimethylsilanes. Cyclic silyl ether, 1,1-dimethyl-2-oxa-1-silaindan, also serves as a starting material for the alkenylsilanes by the ring-opening reaction with alkenyl Grignard reagents. The resulting alkenylsilanes undergo cross-coupling reaction with various aryl and alkenyl iodides under reaction conditions employing K₂CO₃ as a base at 35–50 °C in highly regio- and stereospecific manners. The reaction tolerates a diverse range of functional groups including silyl protections. The silicon residue is readily recovered and reused on a gram-scale synthesis. Intramolecular coordination of a proximal hydroxyl group is considered to efficiently form pentacoordinate silicates having a transferable group possibly at an axial position and, thus, responsible for the cross-coupling reaction under conditions significantly milder than those reported for the silicon-based reactions.