Highly stereoselective synthesis of C2-chiral and meso nitroxides from an optically active pyrrolidine

Starting from (2R,5R)-2,5-bis(methoxymethyl)pyrrolidine 1, hydroxylamine cis-3 was synthesized with high stereoselectivity by successive oxidation and addition of PhMgBr. By using PhLi, trans (C₂-chiral) pyrrolidine nitroxide trans-7 was obtained from nitrone 5 derived from hydroxylamine 3. The cis (meso) counterpart cis-7 was produced along with trans-7 when PhMgBr was employed in place of PhLi. Moreover, cis-7 was also obtained selectively by using PhLi and Et₂AlCl with nitrone 5. The change of stereochemical bias observed when EtMgBr and/or nitrone 10 bearing an ethyl group were employed is also discussed.     

Chemoenzymatic synthesis of A C5-chiral building block: A substrate modification approach.

The enantioselectivity of α-chymotrypsin hydrolysis of prochiral dimethyl-3-hydroxyglutarates was controlled by the proper choice of the hydroxyl protecting groups. This strategy allows the synthesis of a versatile C₅-chiral building block.     

Systematic synthesis of Bis-THF ring cores in annonaceous acetogenins

Systematic synthesis of bis-THF ring cores, synthetic intermediates of adjacent bis-THF annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yields of erythro- and threo-adducts with very high diastereoselectivity. These adducts were converted into four types of bis-THF cores via two kinds of one-pot THF ring formation. [reaction: see text]     

Concise and highly stereoselective synthesis of the C20-C26 building block of halichondrins and Eribulin

A concise, stereoselective, and scalable synthesis of the C20-C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective S(N)2' substitution, and selective conversion of a C-Si to C-I bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration through a silica-gel plug, to give the C20-C26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1.     

Stereodivergent and reiterative synthesis of bistetrahydrofuran ring cores of annonaceous acetogenins

Eight diastereoisomers of the bistetrahydrofuran ring cores of annonaceous acetogenins have been synthesized by asymmetric alkynylation of alpha-tetrahydrofuranic aldehydes and stereodivergent one-pot tetrahydrofuran (THF) ring formation. In all cases, the asymmetric alkynylation proceeded with very high diastereoselectivity to give eight kinds of optically pure THF cores. We also describe a comparison of the (1)H and (13)C NMR spectral data of the eight isomers and give full details of the THF ring construction.     

The first alpha-fluoroallenylphosphonate, the synthesis of conjugated fluoroenynes, and the stereoselective synthesis of vinylfluorophosphonates using a new multifunctional fluorine-containing building block

Limitations on current methodologies for the introduction of CF(2) and CFH in complex alpha-fluorophosphonates led to the synthesis of a fluorine-containing building block TIPS-C&tbd1;CCFXP(O)(OEt)(2), where X = H or F. This multifunctional fluorine synthon reacts with carbonyl compounds under WHE conditions to give high yields of fluorinated conjugated enynes and enediyne. When X = F, trapping of the desilylated anion with an electrophile after TIPS removal provided exclusive access to gamma-substituted derivatives of alpha-fluorophosphonates. When X = H, TBAF deprotection of the silyl group yields H(2)C=C=CFP(O)(OEt)(2) through an allenyl-propargyl resonance stabilized anion. The allene moiety has been used as template in the stereoselective synthesis of alpha-fluoro-beta, gamma-diiodopropenyl phosphonate, via electrophilic iodination, and alpha-fluoro-gamma-amino-alpha,beta-unsaturated phosphonates, including unsaturated phosphononucleosides, by nucleophilic displacement of an allylic iodide. Hydroamination of H(2)C=C=CFP(O)(OEt)(2) using secondary amines produced (Z)-alpha-fluoroenaminophosphonates, whereas Diels-Alder cycloaddition with cyclopentadiene provides the corresponding exocyclic vinylfluorophosphonate.     

Highly regio- and stereoselective synthesis of tricyclic frameworks using Baylis-Hillman derivatives

A simple and convenient synthetic route for the synthesis of tricyclic chromeno[4,3-b]pyrrolidine frameworks using Baylis-Hillman bromides involving in situ formation of an imine, decarboxylation and a [3+2] cycloaddition sequence is described.     

Highly efficient and stereoselective synthesis of beta-glycolipids

beta-Galactosylceramide and glycolipid analogues were prepared in high yield and with complete chemo and stereoselectivity by reaction of alpha-iodo glycosides with stannyl ceramides, formed in situ. TBAI was used to activate both the iodogalactose and the stannyl ether.     

N-tritylprolinal: an efficient building block for the stereoselective synthesis of proline-derived amino alcohols

N-Tritylprolinal (prepared in four steps from l-proline) shows a very high Felkin diastereoselectivity in its reaction with various nucleophiles, leading to a straightforward and highly stereoselective access to syn-proline-derived amino alcohols.     

Highly chemoselective and stereoselective synthesis of z-enol silanes

Three-component nickel-catalyzed couplings of enals, alkynes, and silanes have been developed as a new entry to enol silanes. The enol silane and a trisubstituted alkene are both formed with >98:2 stereoselectivity, and the reaction tolerates a broad range of functionality including aldehydes, ketones, esters, free hydroxyls, and basic secondary amines. A mechanistic pathway involving the formation of a metallacycle that possesses an eta1 nickel O-enolate motif explains the high level of stereoselection.     

Systematic construction of a monotetrahydrofuran-ring library in annonaceous acetogenins by asymmetric alkynylation and stereodivergent tetrahydrofuran-ring formation

All eight diastereoisomers of the monotetrahydrofuran-ring cores of annonaceous acetogenins have been synthesized through utilization of asymmetric alkynylation and stereodivergent one-pot tetrahydrofuran-ring formation. In all cases, the asymmetric alkynylation proceeded with very high diastereoselectivity to give eight kinds of optically pure tetrahydrofuran core from a common alpha-oxyaldehyde. We also describe a comparison of the (1)H NMR, (13)C NMR, and CD spectral data of the eight isomers and give full details of the tetrahydrofuran-ring construction including a model study of asymmetric alkynylation.     

Highly stereoselective and easy synthesis of enantiopure phosphoranyl oxiranes

The highly stereoselective synthesis of enantiopure phosphoranyl alkyl oxiranes has been accomplished by the addition of a nucleophilic stable phosphino(silyl)carbene to chiral aldehydes prepared from (−)-verbenone and d-mannitol, respectively. In the process, two new stereogenic centers are created one of them being on an oxirane quaternary carbon. The excellent π-facial diastereoselection of the aldehydes combined with the diastereoselectivity of the carbene addition allowed us to synthesize the title compounds as single stereoisomers with well defined absolute configuration.     

Highly stereoselective and efficient total synthesis of (+)-laurencin

A highly stereoselective and efficient asymmetric total synthesis of (+)-laurencin (1) has been accomplished from the known oxazolidinone 5 in 15 steps. The route features an efficient internal alkylation to form oxocene 3 from 4 and a novel use of acetonitrile anion as a two-carbon acetaldehyde equivalent for direct synthesis of ketone 2 from alpha-alkoxy amide 3.     

Highly stereoselective approach to chiral building block possessing three contiguous asymmetric centers. Preparation of four possible diastereomers of β,β′-dimethyl-bis-homoallylic alcohol derivative

All four diastereomere of chiral alcohol $\text{2}$ with three contiguous chiral centers were stereoselectively prepared via diastereoselective addition of nucleophiles (crotyl metal or H^-) to α-methyl-β,γ-unsaturated carbonyl compounds $\text{1}$.     

Highly regio- and stereoselective one-pot synthesis of carbohydrate-based butyrolactones

The use of manganese(III) acetate allows the direct synthesis of diverse arrays of [4.3.0] bicyclic carbohydrate-based γ-lactone building blocks from glycals. A mechanism to explain the high regio- and stereoselectivity is proposed. The new reaction has the potential to generate libraries for biological screening.     

Synthesis of vinyl-substituted alcohols using acetylene as a C2 building block

Vinyl-substituted alcohols represent a highly useful class of molecular skeletons. The current method typically requires either stoichiometric metallic reagents or preformed precursors. Herein, we report a nickel catalysis-enabled synthesis of vinyl-substituted alcohols via a 5-membered oxa-metallacycle. In this protocol, acetylene, the simplest alkyne and abundant feedstock, is employed as an ideal C2 synthon. The reaction features mild conditions, good functional group tolerance and broad substrate scope. Mechanistic exploration implies that the oxa-metallacycle originated from the cyclometallation of aldehyde and acetylene is the key intermediate for this transformation, which is then terminated by a silane-mediated σ-bond metathesis and subsequent reductive elimination.

Acetylene and aldehydes are coupled through cyclometallation and silane-mediated σ-bond metathesis to synthesize various vinyl-substituted alcohols. This reaction features good functional group tolerance using acetylene as a C2 synthon.

As a class of versatile motifs in organic synthesis, vinyl-substituted alcohols (abbreviated as vinyl alcohols) permit a myriad of opportunities for the manipulation and introduction of functional groups as well as construction of complex molecular architectures.¹ Therefore, numerous methods have been established to prepare such significant synthetic building blocks (Scheme 1A).² Among these approaches, alkenylation of aldehydes with vinyl metal is one of the most common strategies to deliver vinyl alcohols (Scheme 1A, path a).³ Despite widespread utilization of this method in organic synthesis, sensitive and stoichiometric organometallic reagents are often required under harsh conditions with poor functional group tolerance. In addition to the alkenylation of aldehydes, direct 1,2-addition of acrolein with organometallic compounds could give the desired vinyl alcohols as well (path b).⁴ However, the competition between 1,2- and 1,4-addition⁵ makes this method useless from a practical point of view. Apart from nucleophilic addition of metallic reagents, transition metal-catalyzed allylic substitution with O-nucleophiles represents another important route to obtain vinyl alcohols (path c),⁶ while it is often plagued with the control of regioselectivities and requirement of pre-synthesized allylic substrates. Taken together, syntheses of vinyl-substituted alcohols via these strategies are limited to either sensitive metallic reagents or allylic precursors. Therefore, developing alternative efficient approaches with easily available reagents to acquire vinyl-substituted alcohols and their derivatives under mild conditions is highly desirable.Open in a separate windowScheme 1Synthetic strategies of vinyl alcohols.As the simplest alkyne, acetylene is an inexpensive and abundant feedstock, which has been used as a raw material for bulk vinyl-containing monomer production in the chemical industry.⁷ While in the fine chemical field, catalytic transformation of this unique C2 unit into high value-added chemicals is underdeveloped.^7e,8,9 Despite great efforts being devoted to the development of reductive coupling of substituted alkynes with aldehydes,¹⁰ incorporation of acetylene with aldehydes still remains unknown (path d). This may be attributed to the unique properties of acetylene.¹¹ Moreover, the gaseous nature and flammable properties of acetylene make chemists stay away from it.¹²Inspired by the fact that substituted allylic alcohols could be provided by reductive coupling of aldehydes with substituted alkynes via an oxa-metallacycle intermediate,^10a,h,j we investigated whether it is feasible to employ acetylene and aldehyde through cyclometallation and subsequent silane-mediated σ-bond metathesis to construct silyl-protected vinyl alcohols (Scheme 1B). However, the cyclometallation of aldehyde with acetylene in the presence of silane to obtain key intermediate oxa-metallacycle is a really big challenge due to the following potential competitions: (1) self-polymerization of acetylene,^11b,13 (2) direct hydrosilation of aldehyde^10c or acetylene and (3) condensation or dimerization of aldehyde (Tischenko reaction and¹⁴ Aldol reaction¹⁵). More importantly, safety issues concerning explosive and flammable acetylene should not be ignored as well.^12b,16Herein, we report the synthesis of vinyl-substituted alcohols enabled by a nickel-catalyzed reductive coupling of aldehyde with acetylene by utilizing hydrosilane as an efficient terminating reductant. Compared with the previously reported reductive coupling method requiring addition of an alkyne utilizing syringe pump, this protocol only needs slow addition of premixed solution of acetylene and aldehyde dropwise. Both aryl and aliphatic aldehydes with diverse functional groups react smoothly under mild conditions. The robustness of this strategy has also been exhibited by gram-scale reactions and further transformations of the resulting vinyl alcohols into diversely functionalized molecules. The mechanistic studies demonstrate that hydrogen comes from silane, which supports the postulation that the oxa-nickelacycle originated from cyclometallation is terminated by silane-mediated σ-bond metathesis.     

A concise synthesis of (+)-pancratistatin using pinitol as a chiral building block

A concise approach toward (+)-Pancratistatin has been achieved via 12 steps from pinitol. An ultrasound assisted arylcerium induced ring opening of cyclic sulfate was employed as a key step.     

Highly stereoselective synthesis of aristeromycin through dihydroxylation of 4-aryl-1-azido-2-cyclopentenes

Dihydroxylation of 4-aryl-1-azido-2-cyclopentenes 6, in which an aryl group is used as a synthetic equivalent of CH(2)OH, was studied to improve the low to moderate stereoselectivity previously reported for cyclopentenes 3 possessing CH(2)X and nitrogen atom-containing groups. 2-Furyl, Ph, and p-MeOC(6)H(4) groups were chosen as the aryl groups. Compounds 6a-c possessing such aryl groups were prepared by CuCN-catalyzed reaction between 2-cyclopentene-1,4-diol monoacetate 9 and the corresponding Grignard reagents followed by substitution of the hydroxyl group with (PhO)(2)P(=O)N(3). The desired diols 7a-c were obtained with higher selectivities of >7:1 when dihydroxylation of 6a-c was carried out at 0 degrees C with OsO(4) (catalyst) and NMO in a mixed solvent of MeCN, THF, t-BuOH, and H(2)O. Among them, the furyl compound recorded the highest selectivity of 14:1. The furyl and azido groups on diol 7a were converted into hydroymethyl and adeninyl groups, respectively, to produce acetonide 2, which upon hydrolysis affords aristeromycin 1.     

Highly stereoselective synthesis of (-)-monatin, a high-intensity sweetener, using chelation-controlled nitrone cycloaddition

Synthesis of (-)-monatin was achieved by chelation-controlled cycloaddition of nitrone 2 with allyl alcohol 3a in the presence of MgBr2-OEt2.     

Highly stereoselective and modular syntheses of 10-hydroxytrilobacin and three diastereomers via stereodivergent [3 + 2]-annulation reactions

A convergent synthesis of the annonaceous acetogenin, 10-hydroxytrilobacin ( 4a), was accomplished by using the [3 + 2]-annulation reaction of tetrahydrofuranyl carboxaldehyde 2a and allylsilane 3. The stereodivergency of the [3 + 2]-annulation reaction made it possible to achieve modular, highly stereoselective syntheses of three 10-hydroxytrilobacin diastereomers from the same precursors by using simple modifications of reaction conditions.