A quarter of a century of explorations in organozirconium chemistry

Systematic explorations of organozirconium chemistry over the past quarter of a century have led to the discoveries and development as well as structural and mechanistic clarifications of novel Zr-catalyzed and -promoted carbon-carbon bond-forming reactions including (i) Ni- or Pd-catalyzed cross-coupling reaction of organozirconiums, (ii) Zr-catalyzed carboalumination of alkynes, (iii) Zr-catalyzed asymmetric carboalumination of alkenes, (iv) generation and carbometallative ring expansion of zirconacyclopropanes and zirconacyclopropenes and a myriad of their transformations and (v) various organozirconium migratory insertion reactions.     

Zirconium-catalyzed carboalumination of α-olefins and chain growth of aluminum alkyls: kinetics and mechanism

A mechanism based on Michaelis-Menten kinetics with competitive inhibition is proposed for both the Zr-catalyzed carboalumination of α-olefins and the Zr-catalyzed chain growth of aluminum alkyls from ethylene. AlMe(3) binds to the active catalyst in a rapidly maintained equilibrium to form a Zr/Al heterobimetallic, which inhibits polymerization and transfers chains from Zr to Al. The kinetics of both carboalumination and chain growth have been studied when catalyzed by [(EBI)Zr(μ-Me)(2)AlMe(2)][B(C(6)F(5))(4)]. In accord with the proposed mechanism, both reactions are first-order in [olefin] and [catalyst] and inverse first-order in [AlR(3)]. The position of the equilibria between various Zr/Al heterobimetallics and the corresponding zirconium methyl cations has been quantified by use of a Dixon plot, yielding K = 1.1(3) × 10(-4) M, 4.7(5) × 10(-4) M, and 7.6(7) × 10(-4) M at 40 °C in benzene for the catalyst species [rac-(EBI)Zr(μ-Me)(2)AlMe(2)][B(C(6)F(5))(4)], [Cp(2)Zr(μ-Me)(2)AlMe(2)][B(C(6)F(5))(4)], and [Me(2)C(Cp)(2)Zr(μ-Me)(2)AlMe(2)][B(C(6)F(5))(4)] respectively. These equilibrium constants are consistent with the solution behavior observed for the [Cp(2)Zr(μ-Me)(2)AlMe(2)][B(C(6)F(5))(4)] system, where all relevant species are observable by (1)H NMR. Alternative mechanisms for the Zr-catalyzed carboalumination of olefins involving singly bridged Zr/Al adducts have been discounted on the basis of kinetics and/or (1)H NMR EXSY experiments.     

Asymmetric Synthesis of Chiral Cyclopentanes Bearing an All‐Carbon Quaternary Stereocenter by Zirconium‐Catalyzed Double Carboalumination

Herein, we report a zirconium‐catalyzed enantio‐ and diastereoselective inter/intramolecular double carboalumination of unactivated 2‐substituted 1,5‐dienes, which provides efficient and direct access to chiral cyclopentanes through the generation of two stereocenters, including one all‐carbon quaternary stereocenter, generally with excellent diastereo‐ and high enantioselectivity. This tandem carboalumination process creates two new C−C bonds as well as one C−Al bond, which can be oxidized in situ with O₂ or hydrolyzed. Furthermore, the obtained chiral cyclopentanes can be readily functionalized to provide various chiral compounds.     

1,4-Pentenyne as a five-carbon synthon for efficient and selective syntheses of natural products containing 2,4-dimethyl-1-penten-1,5-ylidene and related moieties by means of Zr-catalyzed carboalumination of alkynes and alkenes

Two highly efficient protocols for enantioselective synthesis of 2,4-dimethyl-1-penten-1,5-ylidene derivatives involve the combined use of the Zr-catalyzed methylalumination of alkynes (ZMA) and the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA). The ZMA/ZACA protocol has been applied to the synthesis of a nafuredin intermediate 14 and a potential intermediate 18 for milbemycin beta 3, while the ZACA/ZMA protocol has been applied to the synthesis of a (-)-bafilomycin A(1) intermediate 25.     

Dihexylmagnesium promoted carboalumination of silylacetylenes

The bimetallic species, ⁿBu₂Mg·2Et₃A1 has been found to be effective for the carboalumination of silylacetylenes.     

Synthesis and transformation of metallacycles. 25. On a mechanism of the Ni(acac)2-catalyzed conversion of 3-alkyl-1-ethylalumacyclopentanes into 1,1-disubstituted cyclopropanes

The reactions of 3-alkyl-1-ethylalumacyclopentanes with allyl halides in the presence of Ni(acac)₂ as a catalyst were studied by dynamic NMR spectroscopy. Under the action of Ni complexes, alumacyclopentanes initially undergo intramolecular hydride transfer to give but-3-enyl(ethyl)aluminum hydrides and then react with the starting allyl halide, yielding but-3-enyl(ethyl)aluminum halides. Subsequent intramolecular carboalumination affords the corresponding 1,1-disubstituted cyclopropanes.     

Efficient and selective synthesis of 6,7-Dehydrostipiamide via Zr-catalyzed asymmetric carboalumination and Pd-catalyzed cross-coupling of organozincs

[structure: see text] 6,7-Dehydrostipiamide has been synthesized in 23% yield in 15 steps in the longest linear sequence through the application of the Zr-catalyzed asymmetric carboalumination and the Pd-catalyzed organozinc cross-coupling in addition to the Brown crotylboration, the Corey-Peterson olefination, and the Corey-Fuchs reaction for carbon-carbon bond formation.     

All-catalytic, efficient, and asymmetric synthesis of alpha,omega-diheterofunctional reduced polypropionates via "one-pot" Zr-catalyzed asymmetric carboalumination-Pd-catalyzed cross-coupling tandem process

A highly efficient method for the synthesis of stereochemically pure (>/=99% ee and >50/1 dr) alpha,omega-diheterofunctional reduced polypropionates has been developed. The essential features of the method are represented by the conversion of inexpensive styrene into 2-methyl-4-phenyl-1-pentanol (1) in 50% yield over two steps from styrene via Zr-catalyzed asymmetric carboalumination (ZACA) reaction in the presence of (NMI)2ZrCl2 and Pd-catalyzed vinylation of the in situ generated isoalkylalanes in the presence of Zn(OTf)2 and a catalytic amount of Pd(DPEphos)Cl2. This ZACA-Pd-catalyzed vinylation may be repeated as needed without purification. After the final ZACA reaction, oxidation with O2 provides alpha-hydroxy-omega-phenyl reduced polypropionates, which can be fully or partially purified by chromatography. After acetylation, Ru-catalyzed oxidative cleavage of the Ph ring, and reduction with BH3.THF, the second chromatographic purification provides stereoisomerically pure alpha,omega-diheterofunctional reduced polypropionates (e.g., 9 and 11) that can be further converted to key intermediates 6 and 7 for the synthesis of ionomycin (4) and borrelidin (5), respectively, by known reactions.     

Synthesis of (+)-manoalide via a copper(I)-mediated 1,2-metalate rearrangement

An enantiospecific synthesis of the phospholipase A(2) inhibitor (+)-(4R)-manoalide is reported in which all 25 carbons of the sesterterpenoid skeleton are constructed from 3-furaldehyde, trimethylalane, oxirane, CO, beta-ionone, and propargyl bromide. The overall yield for the longest linear sequence (12 steps) is 12%. Key steps include (a) a zirconium-catalyzed carboalumination reaction to construct the C10-C11 trisubstituted alkene, (b) a Cu(I)-mediated 1,2-metalate rearrangement to construct the C6-C7 trisubstituted alkene, (c) a Sharpless kinetic resolution to secure the (4R)-stereochemistry, (d) generation of a 5-stannyl-2,3-dihydrofuran by Mo-catalyzed cycloisomerization of a homopropargylic alcohol, and (e) construction of the hydroxyfuranone ring by photooxidation of a silylfuran.     

On study of chemoselectivity of reaction of trialkylalanes with alkenes, catalyzed with Zr π-complexes

The influence of the organoaluminium compound nature, Zr π-ligand environment, solvent type and reagent ratio on the chemoselectivity of reactions of trialkylalanes (AlMe₃, AlEt₃) with alkenes, catalyzed with L₂ZrCl₂ [L = Cp, Cp′ (Cp′-η⁵-C₅H₄CH₃), Cp^∗ (Cp^∗-η⁵-C₅(CH₃)₅), Ind (indenyl), Flu (fluorenyl)] has been studied. It is shown that in the case of AlMe₃, the hydro- and carboalumination products, and alkene dimers are formed. The catalytic reaction of AlEt₃ with the olefins yields aluminacyclopentanes altogether with the hydro- and carboalumination products, and the dimers. A probable reaction mechanism has been proposed.     

有机铝杂环化合物的合成与应用

有机铝杂环化合物作为金属杂环化合物中的重要一员,在有机合成中表现出一些独特的性质。有机铝杂环化合物主要包括铝杂环戊二烯、铝杂环戊烯,以及铝杂环戊烷。本文介绍近年来有机铝杂环化合物的合成方法学、反应化学及其在有机合成中的应用研究进展。     

Synthesis of the N-acetylcysteamine thioester of seco-proansamitocin

[structure: see text] The enantioselective total synthesis of the N-acetylcysteamine thioester of seco-proansamitocin, a key biosynthetic intermediate of the highly potent antitumor agent ansamitocin, is described, which twice utilizes the Nagao acetate aldol reaction, as well as an indium-mediated alkynylation of a benzyl bromide followed by carboalumination. The key step is a Heck reaction between two terminal alkenes for merging the two major fragments.     

Insect pheromones and their analogs

A four-stage asymmetric synthesis of (+)-disparlure [(7R,8S)-(+)-cis-methyl-7,8-epoxyoctadecane (V)] has been effected from 8-methylnon-2Z-en-l-ol (I), obtained by the carboalumination of acetylene with tris(5-methylhexyl)aluminum using the Sharpless reaction. The asymmetric epoxidation of (I), (Ar, mol. sieve A, (+)-DET, (iOPr)₄Ti, t-BuOOH, ?15°C, 20 h; H₂O, 1 h, NaOH, ?7°C, 30 min) gave 8-methyl-2S,3R-epoxynonan-l-ol (II), which was oxidized (kieselguhr-CrO₃-Py, 0°C, 2 h; 25°C, 2 h) to 8-methyl-2S,3R-epoxynonan-l-al (III). The coupling of (III) with n-C₈H₁₇CH=PPh₃ (?78°C, 1 h; 25°C, 15 h) gave 2-methyl-7R,8S-epoxyoctadec-9Z-ene (IV), the hydrogenation (H₂/5% Pd-C, 25°C, 5 days) of which led to (V) in admixture with an isomerization product. Compound (V) was isolated by HPLC. Substance, yield, [α] _D ²⁵ : (II), 73, ?2.75°; (III), 80, [80.8°; (IV), 50, +37.25°; (V), 50, +0.8°. The IR and PMR spectra of (II–IV), the¹³C NMR spectra of (II) and (III), and the mass spectrum of (IV) are given.     

Dialkylaluminum hydride-promoted cyclodimerization of silylated 1,3-enynes via skeletal rearrangement

The dialkylaluminum hydride-promoted reaction of 1-silylalk-3-en-1-ynes gave symmetrical 1,2,3,5-tetrasubstituted benzenes as single regioisomers. The novel cyclodimerization via skeletal rearrangement can be rationalized by an unprecedented mechanism involving sequential hydroalumination, alkene isomerization, carboalumination, carbon-carbon bond cleavage, and retro-hydroalumination.     

A novel, selective, and efficient route to carotenoids and related natural products via Zr-catalyzed carboalumination and Pd- and Zn-catalyzed cross coupling

[structure: see text]. A highly efficient and stereoselective protocol for the syntheses of symmetrical and unsymmetrical carotenoids involving Zr-catalyzed carboalumination of conjugated oligoenynes and Pd- and Zn-catalyzed alkenyl-alkenyl coupling has been developed and applied to the syntheses of beta- and gamma-carotene and vitamin A. gamma-Carotene of > or =99% isomeric purity was prepared in three linear steps (five steps overall) from beta-ionone, enyne 8, (E)-ICH=CHBr, and (E)-Me3SiC triple bond CCH=CHBr in 32% overall yield.     

Stereo- and regioselective routes to allylic silanes

The Ni- or Pd-catalyzed reaction of alkenyl iodides with Me₃SiCH₂Mgcl provides various types of allytrimethylsilanes in excellent yields in a highly stereo- and regioselective manner, while the Zr-catalyzed carboalumination of Me₃SiCH₂CCH followed by replacement of Al with carbon groups by known reactions produces allylsilanes represented by $\text{2}$.     

Rare-Earth Catalyzed C−H Bond Alumination of Terminal Alkynes

Organoaluminum reagents’ application in catalytic C−H bond functionalization is limited by competitive side reactions, such as carboalumination and hydroalumination. Herein, rare-earth tetramethylaluminate complexes are shown to catalyze the exclusive C−H bond metalation of terminal alkynes with the commodity reagents trimethyl-, triethyl-, and triisobutylaluminum. Kinetic experiments probing alkyl-group exchange between rare-earth aluminates and trialkylaluminum, C−H bond metalation of alkynes, and catalytic conversions reveal distinct pathways of catalytic aluminations with triethylaluminum versus trimethylaluminum. Most significantly, kinetic data point to reversible formation of a unique [Ln](AlR₄)₂⋅AlR₃ adduct, followed by turnover-limiting alkyne metalation. That is, C−H bond activation occurs from a more associated organometallic species, rather than the expected coordinatively unsaturated species. These mechanistic conclusions allude to a new general strategy for catalytic C−H bond alumination that make use of highly electrophilic metal catalysts.     

Water-accelerated tandem Claisen rearrangement-catalytic asymmetric carboalumination

[reaction: see text] The addition of stoichiometric quantities of water accelerates both the trimethylaluminum-mediated aromatic Claisen reaction and the chiral zirconocene-catalyzed asymmetric carboalumination of terminal alkenes. The two reactions occur in a tandem sequence resulting in the selective formation of two new C-C and one C-O bond after oxidative quench of the intermediate trialkylalane.     

Transition-metal-mediated cascade reactions: the water-accelerated carboalumination-Claisen rearrangement-carbonyl addition reaction

[Chemical reaction: See text] A three-step cascade reaction involving a water-accelerated catalytic carboalumination, a Claisen rearrangement, and a nucleophilic carbonyl addition converts terminal alkynes and allyl vinyl ethers into allylic alcohols containing up to three contiguous asymmetric carbon centers. Stoichiometric quantities of water as an additive increase the rate of the [3,3] sigmatropic rearrangement as well as the diastereoselectivity of the carbonyl addition process. Reaction products contain 1,6-diene functionalities that are readily cyclized to substituted cyclopentenes. An extension of this methodology to a sequence involving a [1,3] sigmatropic shift was feasible with a cyclopropylmethyl vinyl ether substrate.     

Catalytic, efficient, and syn-selective construction of deoxypolypropionates and other chiral compounds via Zr-catalyzed asymmetric carboalumination of allyl alcohol

An efficient, syn-selective, all catalytic asymmetric protocol for the synthesis of alpha,omega-diheterofunctional deoxypolypropionates via Zr-catalyzed asymmetric carboalumination (ZACA reaction) was developed. The success of the method critically hinges on the one-pot conversion of unprotected allyl alcohol into TBS-protected (R)- or (S)-3-iodo-2-methyl-1-propanol (1) of 91% enantiomeric purity in 82% yield via (i) Zr-catalyzed asymmetric methylalumination, (ii) iodination, and (iii) protection with TBSCl. After zincation of 1, its Pd-catalyzed cross-coupling with various organic halides can give various organic derivatives, including 3 and 4, which can serve as key intermediates for efficient and selective syntheses of deoxypolypropionates, such as doliculide and 2,4,6,8-tetramethyldecanoic acid, and other chiral compounds, such as callystatin A. Selective monocarboalumination of 1,4-pentadiene (5 equiv) gave, after oxidation, the expected product 5, but it was 0% ee. A plausible mechanism for racemization has been proposed and experimentally supported.