Synthesis of propionate motifs: diastereoselective tandem reactions involving anionic and free radical based processes

Reported herein is a strategy employing a Mukaiyama reaction in tandem with a hydrogen transfer reaction for the elaboration of propionate motifs. The nature of the protecting groups on the chiral beta-alkoxy aldehyde and the type of Lewis acid used are varied to modulate the stereochemical outcome of the tandem reactions. The mode of complexation is thus controlled (monodentate or chelate) for the Mukaiyama reaction to give access to either syn or anti aldol products, precursors of the free radical reduction reaction. The endocyclic effect is subsequently capitalized upon to control the hydrogen transfer step so that the syn-reduced product may be achieved. Proceeding with excellent yield and diastereoselectivity, the synthetic sequence proposed gives access to syn-syn and syn-anti propionate motifs. Also considered is a complementary approach using a chelation-controlled Mukaiyama reaction in tandem with a free radical allylation reaction under the control of the endocyclic effect that leads to the anti-anti product.     

Synthesis of tertiary and quaternary stereogenic centers: a diastereoselective tandem reaction sequence combining Mukaiyama and free radical-based allylation

Reported herein is a strategy employing a Mukaiyama reaction in tandem with a free radical-based allyl transfer reaction for the elaboration of functionalized tertiary and quaternary centers. The appropriate choice of alcohol-protecting group on the starting alpha-methyl-beta-hydroxyaldehyde and the nature of the Lewis acid used in the Mukaiyama reaction provided access to 3,4-anti and 3,4-syn aldolization products, precursors of the free-radical allylation reaction. After migration or exchange of the Lewis acid, the allyl transfer reaction with allyltributylstannane is then performed by taking advantage of the endocyclic effect, leading to the 2,3-anti relative stereochemistry. Importantly, (13)C NMR studies of the chelated intermediates are also reported and provide additional support for the endocyclic effect. In some cases, the remarkable reactivity of the aluminum-based Lewis acids allowed the use of allyltrimethylsilane, an interesting reagent from an ecological standpoint. The isolation of a key intermediate is also indicative of an atom transfer mechanism when the silicon-based reagent is employed.     

Diastereodivergent aldol reactions of beta-alkoxy ethyl ketones: modular access to (1,4)-syn and -anti polypropionates

Asymmetric substrate-controlled aldol reactions of ethyl ketones of type 4 with aldehyde 3 are reported. Modular access to all possible syn- and anti-aldol products was obtained by careful choice of reaction conditions. To achieve good selectivities in this diastereodivergent approach, selection of the protective group on the beta-oxygen of the enolate (R (2)) was of critical importance.     

Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols using a highly diastereoselective one-pot double allylboration reaction sequence

Highly diastereo- and enantioselective syntheses of 1,5-disubstituted (E)-1,5-anti-pent-2-endiols 1 and (Z)-1,5-syn-pent-2-endiols 2 have been achieved via the one-pot coupling of two different aldehydes with either (E)-gamma-(1,3,2-dioxaborinanyl)-allyl]diisopinocampheylborane (4) or (E)-gamma-(4,4,5,5-tetraphenyl-1,3,2-dioxaborolanyl)allyl]diisopinocampheylborane (11), respectively. The indicated diols 1 and 2 are obtained in 63-95% yield with 89-96% ee and >/=20:1 diastereoselectivity in all cases. The bifunctional gamma-boryl-substituted allylborane reagents 4 and 11 were generated in situ by the hydroboration of allenes 3 and 10 with diisopinocampheylborane. The keys to the success of this method are the excellent stereocontrol in the allylboration step leading to 5 and the corresponding substituted methallylboronate derived from 11, the stereospecificity of the subsequent allylboration reaction of the substituted methallylboronate intermediates, and the ability of the diol auxiliary to induce equatorial or axial placement of the substituent alpha to boron in transition states 7 and 8.     

A Bidirectional S(E)' Strategy for 1,5-syn and 1,5-anti Stereocontrol toward the Synthesis of Complex Polyols

Studies report a bidirectional S(E)' strategy applicable for the stereocontrolled synthesis of nonracemic 1,5-syn and 1,5-anti diols and their derivatives. Nonracemic 1,3,2-diazaborolidine auxiliaries are incorporated by chemoselective tin-boron exchange to provide reactive allylic boranes. The convergent pathway utilizes sequential reactions with two aldehydes producing stereochemical outcomes from cyclic, closed, and open transition state preferences, respectively. Synthesis of fragment 16 of peloruside A is accomplished in four steps from readily available aldehydes 9 and 13.     

Synthesis and reactions of 3,4-di-t-butylthiophene

3,4-Di-t-butylthiophene (1) was surprisingly easily synthesized from readily accessible bis(2-t-butyl-2-oxoethyl) sulfide (2). Reactions of 1 with a variety of electrophiles were examined.     

Synthesis of postulated molecular probes: stereoselective free-radical-mediated C-glycosylation in tandem with hydrogen transfer

Reported herein is a strategy employing an addition reaction in tandem with a hydrogen-transfer reaction for the elaboration of C-glycoside-based sialyl Lewis X (sLe(X)) analogues. Significant stereocontrol was noted when alkyl radicals were reacted with a series of alkoxytaconates. Transition states were proposed to explain the obtained selectivity. Further reaction between an anomeric-centered fucosyl-derived radical and a galactosylated hydroxytaconate provided easy access to C,O-diglycosides as mimics of sLe(X). In this case, two 1,3-distant stereocenters were created with high diastereoselectivity using free radical intermediates in a tandem process.     

Stereochemistry of the allylation and crotylation reactions of alpha-methyl-beta-hydroxy aldehydes with allyl- and crotyltrifluorosilanes. Synthesis of anti,anti-dipropionate stereotriads and stereodivergent pathways for the reactions with 2,3-anti- and 2,3-syn-alpha-methyl-beta-hydroxy aldehydes

A new method for the stereoselective synthesis of the anti,anti-dipropionate stereotriad via the reaction of alpha-methyl-beta-hydroxy aldehydes with (Z)-crotyltrifluorosilane (24) is described. These reactions were designed to occur through bicyclic transition states (e.g., 31) in which the silane reagent is covalently bound to the beta-hydroxyl group of the aldehyde and the crotyl group is transferred intramolecularly. This methodology was used to synthesize the C(7)-C(16) segment (58) of zincophorin, which contains a synthetically challenging all-anti stereopentad unit. Surprisingly, 2,3-anti- and 2,3-syn-alpha-methyl-beta-hydroxy aldehydes react in a stereodivergent manner with 24: 2,3-anti-beta-hydroxy aldehydes give the targeted anti,anti-dipropionate adducts with high selectivity, but the reactions of 2,3-syn-beta-hydroxy aldehydes are poorly selective. The stereodivergent behavior of 2,3-syn- vs 2,3-anti-alpha-methyl-beta-hydroxy aldehydes is also exhibited in their reactions with the allyl- (68) and (E)-crotyltrifluorosilanes (27). Competition experiments performed with beta-hydroxy aldehydes 37a (anti) and the corresponding p-methoxybenzyl (PMB) ether 48, and between aldehyde 39 (syn) and the PMB ether 90, established that the 2,3-anti-beta-hydroxy aldehydes react predominantly through bicyclic transition states while the 2,3-syn aldehydes react predominantly through conventional Zimmerman-Traxler transition states. NMR studies established that both the 2,3-syn and the 2,3-anti aldehydes form stable, pentavalent silicate intermediates (98 and 100) with PhSiF(3), but chelated structures 99 and 101 could not be detected. The activation energies for the competing bicyclic and conventional Zimmerman-Traxler transition states were calculated by using semiemperical methods (MNDO/d). These calculations indicate that the stereodivergent behavior of the 2,3-syn-beta-hydroxy aldehydes and the 2,3-anti-beta-hydroxy aldehydes is due to differences in nonbonded interactions in the bicyclic transition states. Specifically, nonbonded interactions in the bicyclic transition states for the allylation/crotylation reactions of the 2,3-syn-beta-hydroxy aldehydes permits the traditional Zimmerman-Traxler transition states to be preferentially utilized.     

Synthesis and reactions of a novel 3,4-didehydropyroglutamate derivative

Some reactions such as catalytic hydrogenation, Diels-Alder reaction, cyclopropanation, dihydroxylation, and Michael addition of a novel 3,4-didehydropyroglutamate derivative, in which the carboxylic group is protected as an ABO ester, are examined and found to take place in a stereospecific manner giving 3- and/or 4-substituted pyroglutamate derivatives without loss of enantiomeric purity at the alpha-position.     

Highly diastereoselective boron and titanium mediated aldol reactions of a mannitol derived 2,3-butanediacetal ethyl ketone

A mannitol derived 2,3-butanediacetal ethyl ketone displays high levels of diastereoselectivity in boron and titanium mediated aldol reactions with a range of aliphatic and aromatic aldehydes to afford syn aldol products in high yield. The stereochemical outcome of the reaction was determined using J-value analysis, NMR analysis of O-acetylmandelate derivatives and X-ray crystallography.     

Synthesis and reactions of 3-carbethoxy and 3-aroyl-3,4-dihydro-1h-2,3-benzoxazin-1-ones

A series of 3-substituted 3,4-dihydro-1H-2,3-benzoxazin-1-ones (IV) (Scheme I) was prepared by reaction of 2-bromomethylbenzoyl chlorides (II) with N-hydroxyethylcarbamate (III) or with benzohydroxamic acids. Acid hydrolysis of 3-carbethoxy (IVa) and 3-benzoyl derivatives (IVb) afforded a mixture of 2-(hydroxyaminomethyl)benzoic acid (V) and 2,3-dihydro-2-hydroxy-1H-1-isoindolinone (VII). Compound IVa reacted with ethanol, amines or hydrazine to yield the ethyl ester X, amides XIV (Scheme II) and the hydrazide XII of 2-(N-carbethoxy-N-hydroxy-aminomethyl)benzoic acid. Diazotization of the hydrazide XII afforded the unstable azide XIII which did not undergo the Curtius reaction but gave the benzoxazinone IVa by loss of hydrazoic acid.     

Synthesis of 1-arylidene-2,3-dihydro-1H-inden-2-ols through a tandem carbopalladation/Suzuki-Miyaura sequence

A regio- and stereoselective synthesis of arylidene indenols has been developed. The key step involves a palladium-catalyzed tandem carbocyclization/Suzuki-Miyaura sequence.     

Pyrrolidine-2,3-diones: Synthesis,reactions and biological activity

Pyrrolidine-2,3-diones are of continuing interest as intermediates in the synthesis of heterocycles related to pyrrolidine alkaloids, medicinally relevant compounds, and in the development of antibiotics and drugs. The present review deals with the most important literature on the synthesis and reactions of pyrrolidine-2,3-diones and the related biologically important compounds.     

Synthesis of aromatic ketones by a transition metal-catalyzed tandem sequence

Both simple Ag(I) and Au(I) are effective catalysts for a tandem [3,3]-sigmatropic rearrangement/formal Myers-Saito cyclization of propargyl esters to form aromatic ketones. A mechanism in which the metal catalyzes both of these processes through alkyne activation is proposed. By using this method a wide range of aromatic structures including naphthyl, anthracenyl and indole ketones are available from readily available propargyl esters.     

1,5-anti stereocontrol in the boron-mediated aldol reactions of beta-alkoxy methyl ketones: the role of the formyl hydrogen bond

The boron-mediated aldol reactions of certain types of beta-alkoxy methyl ketone show remarkably high levels of stereoinduction with achiral aldehydes, leading preferentially to 1,5-anti related stereocenters. Given the low levels of asymmetric induction usually observed in acetate aldol reactions, this is of great synthetic utility and has been used successfully in the total synthesis of a number of polyketide natural products. We have investigated the effects of the alkoxy protecting group (OMe, OPMB, PMP acetal, tetrahydropyran, and OTBS) present in the boron enolate on the level and sense of remote 1,5-stereoinduction, using density functional theory calculations (B3LYP/6-31G**). Our predictions of diastereoselectivity from comparison of the competing aldol transition structures are in excellent qualitative and quantitative agreement with experimentally reported values. We conclude that the boron aldol reactions of unsubstituted boron enolates proceed via boat-shaped transition structures in which a stabilizing formyl hydrogen bond exists between the alkoxy oxygen and the aldehyde proton. It is this interaction that leads to preferential formation of the 1,5-anti adduct, by minimizing steric interactions between the beta-alkyl group and one of the ligands on boron. In the case of silyl ethers, the preference for this internal hydrogen bond is not observed due to the size of the protecting group and the electron-poor oxygen atom that donates electron density into the adjacent silicon atom. We show that this stereochemical model is also applicable in rationalizing the 1,4-syn stereoselectivity of boron aldol reactions involving certain alpha-chiral methyl ketones. These detailed results may be summarized as a conformational diagram that can be used to predict the sense of stereoinduction.     

Highly diastereoselective ionic/radical domino reactions: single electron transfer induced cyclization of bis-sulfoxides

SET oxidation of bis-sulfinyl anions has enabled the uses of bis-sulfinyl radical as a synthetic equivalent of chiral acyl and methylene radicals involved in tandem reactions leading to the enantioselective construction of various carbo- and heterocyclic derivatives.     

Synthesis and reactions of heterocyclic 2,3-epoxypropionitriles with pyrrolidine

The Darzen's reaction of 2-(3-)pyridinecarboxaldehydes 5 with chloroacetonitrile yielded a mixture of stereoisomers cis- 6 and trans-3-(pyridinyl)-2,3-epoxypropionitriles 7 in a ratio of approximately 1:1. Oxidation of cis- 6 and trans- 7 afforded the corresponding cis- 8 and trans-3-(1-oxidopyridinyl)-2,3-epoxypropionitriles 9 in good yield. The reaction of 8a and 9a with pyrrolidine at 25° gave the respective threo- 10 and erthyro-2-(1-pyrrolidino)-3-hydroxy-3-(1-oxido-2-pyridinyl)propionitrile ( 11 ). A number of selected compounds ( 7-9a-b ) were found to be inactive in the P388 Lymphocyctic screen.     

Synthesis and reactions of 2-chloro-3,4-dihydrothienopyrimidines and -quinazolines

Reaction of 2,4-dichlorothienopyrimidines and -quinazolines 1 with sodium borohydride gave the corresponding 2-chloro-3,4-dihydro derivatives 2. Some nucleophilic substitutions of 2b afforded 2-substituted derivatives 3b-7b and reaction of 2g,h with ethyl bromoacetate yielded selectively the corresponding 3-substituted compounds 8g,h which were derived to imidazo[2,1-b]quinazolin-2-ones 9g,h .     

Synthesis and structure of 6-bromo-4-hydroxy-2,3-tetramethylene-3,4-dihydroquinazoline and its mixed crystal with 4-hydroxy-2,3-tetramethylene-3,4-dihydroquinazoline

Bromination of the alkaloid 2,3-tetramethylene-3,4-dihydroquinazoline by N-bromosuccinimide was studied. It was shown that either 4-hydroxy-2,3-tetramethylene-3,4-dihydroquinazoline or 6-bromo-4-hydroxy-2,3tetramethylene-3,4-dihydroquinazoline was formed depending on the ratio of reagents. Oxidation of 2,3tetramethylene-3,4-dihydroquinazoline by KMnO₄ produced 4-hydroxy-2,3-tetramethylene-3,4dihydroquinazoline. The crystal structures of 6-bromo-4-hydroxy-2,3-tetramethylene-3,4-dihydroquinazoline and its mixed crystal with 4-hydroxy-2,3-tetramethylene-3,4-dihydroquinazoline were studied by x-ray structure analysis. The enantiomeric molecules in all crystal structures formed associates owing to two opposing OH...N1 H-bonds.