Samarium diiodide-catalyzed diastereoselective pinacol couplings

A complex of samarium diiodide (SmI(2)) with tetraglyme catalyzes the intermolecular pinacol coupling of aromatic or aliphatic aldehydes at loadings of 10 mol % in the presence of Me(2)SiCl(2) and Mg. Diastereoselectivity of up to 95/5 (+/-/meso) has been achieved for aliphatic aldehydes and up to 19/81 (+/-/meso) for aromatic aldehydes. De values of up to 99% have been achieved in intramolecular pinacol coupling reactions using the SmI(2)/tetraglyme/Mg/Me(2)SiCl(2) catalytic system.     

Samarium-promoted coupling of pyridine-based heteroaryl analogues of benzylic acetates with carbonyl compounds

2-Substituted pyridine, quinoline, isoquinoline, bipyridine, and 1,10-phenanthroline analogues of benzylic acetates undergo SmI(2)-promoted coupling with aldehydes and ketones to afford (2-hydroxyalkyl)heteroaromatics. [reaction: see text]     

An easy, efficient, and completely stereoselective synthesis of (E)-alpha,beta-unsaturated esters via sequential aldol-type/elimination reactions promoted by samarium diiodide or chromium dichloride

(E)-Alpha,beta-unsaturated esters can be obtained with complete stereoselectivity by reaction of different aldehydes and ethyl dibromoacetate promoted by SmI(2) or CrCl(2). The transformation takes place as two sequential reactions: an aldol-type reaction and a beta-elimination reaction.     

Total synthesis of (+)-acutiphycin

Synthetic studies toward the total synthesis of (+)-acutiphycin (1) resulted in the discovery of additive-free, highly regioselective nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes and the construction of an advanced intermediate in studies directed toward the synthesis of 1. Ultimately, although not employing the nickel-catalyzed reaction, a highly convergent total synthesis of (+)-acutiphycin featuring an intermolecular SmI2-mediated Reformatsky coupling reaction and macrolactonization initiated by a retro-ene reaction of an alkoxyalkyne was achieved. The resulting synthesis was 18 steps in the longest linear sequence from either methyl acetoacetate or isobutyraldehyde.     

1-(2,4,6-triisopropylphenyl)ethylamine: a new chiral auxiliary for the asymmetric synthesis of gamma-amino acid derivatives

The title compound has proven to be an excellent chiral auxiliary for nitrones in SmI2-mediated reductive coupling with alpha,beta-unsaturated esters. A variety of such nitrones, prepared from aldehydes and enantiopure N-hydroxy-1-(2,4,6-triisopropylphenyl)ethylamine, afforded gamma-N-hydroxyamino esters in high yields and diastereomeric purity. These adducts, readily available as either enantiomer, could be transformed into gamma-N-acetoxyamino esters, N-Boc-gamma-amino esters, and gamma-lactams.     

Application of samarium diiodide (SmI2)-induced reduction of gamma-acetoxy-alpha,beta-enoates with alpha-specific kinetic electrophilic trapping for the synthesis of amino acid derivatives

Gamma-acetoxy-alpha,beta-enoates were easily reduced by samarium diiodide (SmI2) in THF to generate samarium dienolates which were kinetically trapped with ease at their alpha-positions by electrophiles (proton, aldehydes or ketones) to yield (E)-alkene dipeptide isosteres or gamma-amino acid derivatives in high chemical yields.     

Acetoxyl group directed cyclization promoted by SmI2: directing group determined stereocomplementarity

Complete reversal of diastereoselectivity was observed in the SmI(2)-promoted ketyl-olefin coupling cyclizations of the hydroxy ketone or aldehyde and its acetate. For example, the stereodivergent synthesis of the epimeric five-membered-ring alcohols 2 and 4 has been accomplished through the SmI(2)-induced ketyl-olefin coupling cyclizations of the delta-hydroxy ketone 1 and delta-acetoxy ketone 3.     

SmI2-promoted Reformatsky-type reaction and acylation of alkyl 1-chlorocyclopropanecarboxylates

In the presence of HMPA in THF, highly stereoselective SmI(2)-promoted substitutions of alkyl 1-chlorocyclopropanecarboxylates 1 using various ketones, aldehydes (Reformatsky-type reaction), and acyl chlorides (acylation) proceeded to give trans-adducts (2 or 5) in good to high yield with excellent trans-stereoselectivity (trans-add/cis-add = > 99/1). The Reformatsky-type reaction of 1 with aldehydes and unsymmetrical ketones proceeded with moderate diastereoselectivity (re-face-adduct/si-face-adduct = 60/40-75/25).     

Hydroxy-Directed, SmI(2)-Induced Conversion of Carbohydrates into Carbocycles

Polyoxygenated six-membered carbocycles were derived from carbohydrates with complete stereocontrol through hydroxy-directed coupling cyclization induced by SmI(2). For example, the cis-1,3-cyclohexanediol 3 is obtained from the D-glucopyranoside derivative 1 in excellent yield. The coupling cyclization is initiated by single-electron transfer from SmI(2) to the formyl group of the delta-hydroxy aldehyde 2 generated in an equilibrium process.     

Direct reaction of dibromoacetic acid with aldehydes promoted by samarium diiodide: an easy, efficient, and rapid synthesis of (E)-alpha,beta-unsaturated carboxylic acids with total stereoselectivity

A promoted SmI2 direct reaction of dibromoacetic acid with different aldehydes, followed by an elimination reaction also promoted by samarium diiodide, affords (E)-alpha,beta-unsaturated carboxylic acids 2 with total stereoselectivity. A mechanism to explain this transformation is proposed.     

三碘化钐促进的α, α'-二(取代亚苄基)环戊酮的简便合成

在SmI3作用下和中性室温的条件下, 环戊酮能与醛缩合, 得到几乎定量产率的α, α'-二亚苄基环戊酮; 但对环己酮, 产率仅在20%左右。     

One—Pot Reaction of Aldehydes,α—Haloketones and （Phenylsulfonyl） acetonitrile Promoted by SmI3

One-pot reaction of aldehydes,α-haloketones and (phenylsulfonyl) acetonitrible promotes by SmI3 proceeded smoothyl to give 1-cyano-1-phenylsulfonyl-2-aryl-3-aroyl-propane derivatives in moderate good yields.     

Reformatsky-type reaction of chiral nonracemic alpha-bromo-alpha'-sulfinyl ketones with aldehydes. Synthesis of enantiomerically pure 2-methyl-1,3-diol moieties

Chiral nonracemic alpha-bromo-alpha'-sulfinyl ketones were shown to react with aldehydes in the presence of SmI(2) in a Reformatsky-type reaction to give the corresponding adduct with excellent syn diastereoselectivity. Further reduction of the Reformatsky adducts furnished anti- and syn-2-methyl-1,3-diol moieties in excellent yields and diastereoselectivities.     

Divergent synthetic strategy leading to structurally diverse pyrrolidines and piperidines from common gamma-aminoalkyl butenolide and aldehyde precursors

Condensation between aldehydes and the secondary amino function of 5-(aminoalkyl)furan-2(5H)-ones, obtained by the silyloxyfuran dienolate addition to imine-type derivatives, produces either aminoalkylbenzotriazoles or 1,2,3,4-tetrahydropyridines. The former can be reduced with SmI2 to generate alpha-aminoalkyl radicals that are trapped by the alpha,beta-unsaturated lactone moiety yielding substituted pyrrolidines diastereoselectively, while catalytic hydrogenation of the latter affords isomeric piperidine analogues. Alternatively, SmI2-promoted reduction of tetrahydropyridines in the presence of acid also leads to intermediate alpha-aminoalkyl radicals that participate in inter- or intramolecular olefin addition reactions. Further manipulation of the lactone functionality in various ways gives access to a number of interesting derivatives based upon either a pyrrolidine or a piperidine structural motif. As a result, a high degree of structural diversity is obtained in a few steps starting from a common set of simple materials.     

A New Asymmetric α-Amido-hydroxyalkylation Mediated by SmI_2

Polyhydroxylated indolizidine alkaloids, such as castanospermine (I) and swainsonine (II) are of longstanding interest due to their powerful glycosidase inhibitory activity. Asymmetric hydroxyalkylation via α-amido carbanions to form C-C bands would provide a convenient approach to these compounds. HO HO H OH H OH HO OH N N HO I II In continuation of our efforts in developing asymmetric α-amido-hydroxyalkylation method,1 we report a new SmI2 mediated flexible…     

Synthesis, structure, and metal complexation behavior of a new type of functionalized chiral phenanthroline derivative

SmI(2) serves as an effective promoter for the coupling of 1,10-phenanthroline with an epoxide to generate a new class of chiral, functionalized ligands that readily form complexes with metals. Structural studies of the resulting phenanthroline derivative and two of its metal complexes are reported.     

三碘化钐促进的α,α′-二(取代亚苄基)环戊酮的简便合成

在SmI_3作用下和中性室温的条件下,环戊酮能与醛缩合,得到几乎定量产率的α,α＇-二亚苄基环戊酮;但对环已酮,产率仅在20％左右。     

Stereoselective preparation of (e)-configured 1,2-disubstituted propenes from two aldehydes by a two-carbon stitching strategy: convergent synthesis of 18,21-diisopropyl-geldanamycin hydroquinone and its c7 epimer

The title compounds were synthesized in a longest sequence of 27 linear steps and with an overall yield of 2.9 and 3.9?%. In the course of the synthesis, two aldehydes representing carbon fragments C1?C7 (Eastern fragment) and C9?C21 (Western fragment) were prepared from D-mannitol, each of which incorporated a key stereogenic center at the respective secondary methyl ether group (C6, C12) from the chiral pool material. The assembly of the two aldehydes was achieved employing α-chloroethyl magnesium chloride as a two-carbon building block. The carbenoid reagent was generated from α-chloroethyl para-tolylsulfoxide by sulfoxide-magnesium exchange and it added smoothly to the highly sensitive aldehyde of the Eastern fragment (C1?C7). Upon oxidation, an α-chloroethyl ketone was generated, which underwent a clean and high-yielding reductive SmI(2) -promoted addition to the other aldehyde fragment. Dehydration delivered the key double bond between C8 and C9 in an overall yield of 72?% over four steps. The method was shown to be generally applicable to the racemization-free conversion of several aldehydes into the respective α-chloroethyl ketone (11 examples, 64-95?%) and to the coupling protocol (5 examples, 66-90?%). The further course of the geldanamycin hydroquinone synthesis included a diastereoselective reduction at C7 and the implementation of the amino group at C20. Since deprotection of the two isopropyl protecting groups could not be achieved in significant yields, the structure of 18,21-diisopropyl-geldanamycin hydroquinone was proven by its independent synthesis from the natural product.     

Efficient nitro-aldol reaction using SmI2: a new route to nitro alcohols under very mild conditions

A novel method to obtain racemic 1-nitroalkan-2-ols by reaction of bromonitromethane with a variety of aldehydes and promoted by SmI2 is reported. On the basis of these results, the chiral version has also been performed with chiral N,N-dibenzyl amino aldehydes, affording the corresponding enantiopure 3-amino-1-nitroalkan-2-ols with good stereoselectivity.     

SmI2-mediated reduction of gamma,gamma-difluoro-alpha,beta-enoates with application to the synthesis of functionalized (Z)-fluoroalkene-type dipeptide isosteres

A samarium diiodide (SmI(2))-mediated reduction of gamma,gamma-difluoro-alpha,beta-enoates (15, 29, and 34) was successfully applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres (23, 30, and 35), which have served as potential dipeptide mimetics. Reduction of the gamma,gamma-difluoro-alpha,beta-enoates by SmI(2) proceeded via successive two-electron transfers to form dienolate species which upon kinetically controlled trapping with t-BuOH yielded Xaa-Gly-type fluoroalkene isosteres exemplified by 23, 30, and 35. Replacement of the t-BuOH kinetic trapping agent with aldehydes or ketones provided access to alpha-substituted fluoroalkene isosteres (43 and 45) through aldol reactions of Sm-dienolates with the carbonyl compounds. Of particular note, the use of the SmI(2)-HCHO reagent system with chiral enoate 34 provided D-Phe-psi[(Z)-CF[double bond]CH]-D/L-Ser isosteres (45), which could be converted to enantiomerically pure isosteres (49-52) that bore a variety of side chain functionalities at the alpha-position. This was achieved by a sequence of manipulations consisting of beta-lactone formation followed by chromatographic separation and ring-opening with soft nucleophiles. Included in the present work is the first utilization of a Rh-catalyzed Reformatsky reaction of chiral imines for the stereoselective preparation of alpha,alpha-difluoro-beta-amino acid derivatives (28 and 33). The appropriate choice of reagents (carbonyl compounds for kinetic trapping or ring-opening nucleophiles and imines for Reformatsky reactions) allows the presented methodology to yield various fluoroalkene isosteres possessing a wide range of side chain functionalities.