Asymmetric Hetero-Diels-Alder Addition of 1-Methoxybuta-1,3-diene to (2R)-N-Pyruvoyl- and (2R)-N-(Phenylglyoxyloyl)bornane-10,2-sultam

Cycloadditions of 1-methoxybuta-1,3-diene to (2R)-N-pyruvoyl and (2R)-N-(phenylglyoxyloyl)bornane-10,2-sultam ((−)- 1b and (−)- 1c , resp.) under high-pressure conditions are presented. The absolute configurations of the cycloadducts 2b,c and of their resulting reduced alcohols 3b,c are based on their X-ray analyses. The stereochemical course of these reactions is discussed and compared to the inverse diastereoselectivity observed for the analogous cycloaddition to (2R)-N-glyoxyloylbornane-10,2-sultam ( 1a )     

Diastereoselective Synthesis of Polysubstituted Piperidines through Visible-Light-Driven Silylative Cyclization of Aza-1,6-Dienes: Experimental and DFT Studies

A visible-light-driven radical silylative cyclization of aza-1,6-dienes featuring an acrylonitrile or acrylate moiety and an electron-neutral olefin was developed, which allows for stereoselective synthesis of densely functionalized piperidines in a highly atom-economical manner. Depending on the substitution pattern of the electron-neutral olefin, poor-to-excellent diastereoselectivity was observed. It was suggested that the 6-exo-trig cyclization was initiated by a chemoselective addition of silyl radical toward electron-deficient olefin and the geometry of the remaining olefin is closely associated with the cis-stereoselectivity. DFT calculations supported that a transition state with a cyano group locating at the axial position of the forming piperidine ring might be involved, in which either the increase of 1,3-diaxial repulsion or the lack of hydrogen bonding interaction will diminish diastereoselectivity.     

HIGHLY DIASTEREOSELECTIVE DIELS-ALDER REACTIONS OF ACRYLIC ESTERS INCORPORATED INTO A VARIETY OF HEXOPYRANOSIDES

The Diels-Alder reactions of a variety of hexopyranosides carrying an acrylic ester with cyclopentadiene were examined. Some acrylic esters provided the cycloaddition products carrying a norbornene carboxylate with a high level of diastereoselectivity. Plausible mechanisms are presented for the cases of a 4-O-acryloyl-6-deoxy-α-D-glucopyranosidic and 2-O-acryloyl-α-D-glucopyranosidic substrates. By reductive removal of the carbohydrate templates from the adducts, either 2S or 2R-enriched 5-norbornene-2-methanol were obtained.     

Synthesis of chromeno[4,3-b]pyrrolidines from azomethine ylides and vinyl para-quinone methides via (3 + 2) cycloaddition/oxa-1,6-addition

An efficient synthesis of chromeno[4,3-b]pyrrolidines has been successfully developed. This strategy involves a base-catalyzed reaction of p-VQMs and o-hydroxy azomethine ylides via (3 + 2) cycloaddition/oxa-1,6-addition reaction sequence. The reaction condition is mild, and a series of chromeno[4,3-b]pyrrolidines were obtained in 49-95% yields with excellent diastereoselectivity (dr > 20:1).     

Aqueous ethanol: a suitable medium for the diastereoselective Diels–Alder reaction mediated by chiral bases

Abstract

The effect of aqueous ethanol medium on the outcome of a Diels–Alder (DA) reaction with regard to yields, reaction time, and the stereoselectivity observed has been studied. When the reaction between anthrone and (R)-(+)-N-α-methylbenzylmaleimide was carried out in aqueous ethanol in presence of achiral base no diastereoselectivity could be obtained. Moderate diastereoselectivity could be achieved in presence of chiral bases. Use of biodegradable aqueous ethanol solvent for the reaction and stereoselective nature of the reactions studied provide a greener approach.     

DETERMINANTS OF DIASTEREOSELECTIVITY IN -BENZYLATION REACTIONS OF CARBOXYLIC ESTERS OF BORNANOL DERIVATIVES

The influence of the steric bulk and chelation potential of the “blocking group” on the unexpectedly low diastereoselectivity observed during the α-benzylation of carboxylic ester enolates of 3,3-(2,3-butanedioxy)-2-exo-bornanol is examined.     

A New Total Synthesis of D-threo-L-talo-Octose

A new approach to the total, asymmetric synthesis of D -threo-L -talo-octose ((?)- 1 ) and its derivatives is presented. It is based on the chemoselective Wittig-Horner monoolefination of a 5-deoxy-D -ribo-hexodialdose derivative 4 obtained by selective reduction of (?)-5-deoxy-2.3-O-isopropylidene-/β-D -ribo-hexofuranurono-6,1-lactone ((?)- 3 ). Allylic bromination of the resulting methyl (E)-oct-6-enofuranuronate (+)- 5 followed by intramolecular nucleophilic displacement of the so-obtained bromides gave a 13.3:1 mixture of (?)-methyl (E)-l,4-anhydro-6,7-dideoxy-2,3-O-isopropylidene-β-L -talo-oct-6-enopyranuronate ((?)- 8 ) and methyl (E)-l,4-anhydro-6,7-dideoxy-2,3-O-isopropylidene-α-D -allo-oct-6-enopyranuronate ( 9 ). The double hydroxylation of the enoate (?)- 8 followed Kishi's rule and gave the corresponding D -threo-β-L -talo-octopyranuronate derivative (?)- 11 with a good diastereoselectivity. Reduction of ester (?)- 11 and deprotection led to pure (?)- 1 .     

A New Synthesis of Benzylidene Acetals

Aryl-halo-diazirines react under basic conditions with 1,3-cis-, 1,2-cisand 1,2-trans-diols to give acetals. Yields are high. Diastereoselectivities depend upon the diol and upon the reaction conditions. Thus, reaction of the 1,3-cis-diol 1 (Scheme 1) with 2 gave 3 as a single diastereoisomer. The 1,2-cis-diols 4 and 7 led to the endo- and exo-acetals 5 / 6 (93:7) and 8 / 9 (ca.10:1), respectively, The 1,2-trans-diols 10 , 16 , and 19 reacted with 2 to afford 11 / 12 (90:10), 17 / 18 (1:1), and 20 / 21 (6:1), respectively. Reaction of the (4-nitrophenyl)diazirine 13 with 10 at higher temperatures yielded 14 / 15 (6:4). The uracil moiety, the acetamido group, and the enol-ether moiety are compatible with the reaction conditions. The diastereoselectivity is rationalized on the basis of a reaction sequence involving alkoxy-halogen exchange, which is regioselective or not, thermolysis of the ensuing alkoxydiazirine(s), protonation of the alkoxycarbene to form an (E)-configurated oxycarbenium ion, and attack of the neighboring oxy or hydroxy group, which is only possible for a limited range of conformers.     

Carbocyclen aus Monosacchariden. III. Zur Diastereoselektivität der Bildung von Cyclopentanderivaten. Umsetzungen in der Galactosereihe

Carbocycles from monosaccharides. III. Concerning the diastereoselective formation of cyclopentane derivatives. Transformations in the galactose series. The diastereoselectivity of the intramolecular nitrone-olefine cycloaddition of 1 , 3 and 4 (Scheme 1), yielding only 2 , 5 and 6 but none of the isomers 8 , 9 and 10 is explained by assuming a kinetic control and postulating that the relative activation energies of the two relevant transition states in the cyclization of e.g. 1 can be estimated from the conformers A and B , the latter being destabilized by a synperiplanar arrangement of the nitrone function and the 2-alkoxy-group (Scheme 2). It is further postulated, that this destabilization is responsible for the formation of (2,3)-trans configurated products. Since 2 , 5 and 6 are presumably thermodynamically more stable than 8 , 9 and 10 , a case was investigated, where the cycloaddition can either give thermodynamically less stable (2,3)-trans-product such as 12 or a thermodynamically more stable (2,3)-cis-product such as 13. 12 and 13 could both be formed from the aldehyde 25 via the nitrone 11 (Schemes 3 and 5). Treatment of the galactoside 16 first with Zn in aqueous butanol (forming among other products 25 and its 2-debenzyl-oxy-derivative) and then with N-Methyldroxylamine yielded the isoxazolidines 12 (72%), 13 (2%) and 27 (7%) (Schemes 4 and 6). Similarily, the anomeric silylated galactosides 17 and 23 gave 29 (78% from 17 , 77% from 23 ) and 27 (5% and 3%). Upon desilylation, 29 gave 32 , which was converted into 12 . The structure of the isoxazolidines was unambiguously deduced from their NMR. spectra and those of their derivatives 33 and 34 . Compound 32 was further transformed into its deoxyderivative 36 . The high diastereoselectivity of the cycloaddition restricts the number of diastereomeric, pentasubstituted cyclopentanes available by this method. However, cyclization of the 2-Hydroxy-aldehyde 37 (Scheme 8) gave the kinetically less favoured isomer 40 in a higher proportion, showing the differential influence of hydrogen-bonds on the relevant activation energies. Thermolysis of 32 gave 40 (79%) and 41 (11%). The structure of 41 was deduced from its NMR. spectra and those of its derivatives 42 and 43 . Thermolysis of 29 gave, after desilylation, 41 (42%), 40 (22%) and 32 (13%) and thermolysis of 6 lead to a 25 : 75 equilibrium with 44 (combined yield 90%). These transformations illustrate means leading to additional isomers and are in agreement with the proposed explanation of the diastereoselectivity in question.     

Synthese von Pyrano[3,2-b][1]benzopyranen aus 1-Nitroglycalen

Synthesis of Pyranol [3,2-b][1]benzopyrans from 1-Nitroglycals A synthesis of pyrano[3,2-b][l]benzopyrans β-addition of salicylic aldehyde to 1-nitroglycals, followed by a Henry reaction, is described. This sequence gave the cis-annelated pyranobenzopyranes 9 and 11 from 5 in 54 and 9% yield, respectively, demonstrating the pronounced diastereoselectivity of the β-addition. Reductive denitration of the crude product mixture yielded 14 (75%), 15 (15%), and 16 (7%), which were oxidized to the aryl ketones 20 and 21 , respectively. Reduction of 20 (NaBH₄) gave exclusively 15 . The ketone 20 was deprotected to 22 and 23 .     

Diastereoselective rhodium(II)-catalyzed sulfonium ylide formation-[2,3]-sigmatropic rearrangement reaction of chiral non-racemic allylic sulfides

The tandem sulfonium ylide formation-[2,3]-sigmatropic rearrangement reaction of chiral non-racemic secondary allylic sulfides, (E)-9 and (Z)-10, is found to proceed with high diastereocontrol. The C-5 stereocenter bearing the sulfide group is essential for high diastereoselectivity in the reaction. Transition state conformers are proposed to explain the high diastereoselectivity in the formation of the diastereomeric products, 18a and 18b. The method is applied to the synthesis of (R)-4-(4-chlorophenyl)-2-butyrolactone. Modest enantioselectivity (63% ee) was achieved and this is attributed to partial racemization during the formation of the secondary allylic sulfide 22.     

Prearranged Glycosides,Part 10. Intramolecular Glycosylation with Cellobiosyl,Lactosyl, and Maltosyl Donors

ABSTRACT

Acetyl protected 1,2-O-(1-methoxyethylidene)-disaccharides 1 of maltose, cellobiose, and lactose, respectively were converted via the corresponding benzyl protected couterparts 2, the benzyl protected phenyl 2-O-acetyl- 3 and 2-O-unprotected 1-thio-glycoside disaccharides 4 into 2-O-succinoylated disaccharides 5. The latter were esterified with benzyl 2-O-benzoyl-4,6-di-O-benzylidene-α-D-glucopyranoside (6) to afford succinyl linked derivatives 7 the benzylidene groups of which were regioselectively opened to give prearranged glycoside trisaccharides 8. Intramolecular glycosylation of the latter with N-iodosuccinimide resulted in exclusive formation of the corresponding α-(1→4)-linked trisaccharides 9. No influence of the donor moiety on the diastereoselectivity of the intramolecular glycosylation was observed.     

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N–O bond reductive cleavage followed by deprotection of –OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino-l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N–O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.     

Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium-Catalyzed Enantio-, Chemo- and Diastereoselective Methylene C(sp3)−H arylation

The enantioselective desymmetrizing C−H activation of α-gem-dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp³)−H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo- and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,β-contiguous stereogenic centers via Pd^II-catalyzed asymmetric arylation of unbiased methylene C(sp³)−H, in good yields and with high levels of enantio-, chemo- and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem-dialkyl groups with two different aryl iodides, giving a range of β-Ar¹-β′-Ar²-aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.     

L-丙氨酰Betti碱催化环己酮对硝基烯不对称Michael加成反应

合成了3个手性Betti碱的L-丙氨酰衍生物, 并用它们来催化环己酮与硝基烯的Michael加成反应. 发现1a是其中最有效的催化剂, ee值最高大于99%, dr值最高大于99∶1. 考察了催化剂结构与用量、添加剂用量、底物结构等因素对反应的化学产率和光学收率的影响.     

Silicon-induced diastereoselectivity of the catalyzed phosphorylation of 1-(perfluoroalkyl)-ω (trialkylsilyl)alkan-1-ols

The stereochemistry of catalytic phosphorylation of 1-(perfluoroalkyl)--(trialkylsilyl)alkan-1-ols with pentavalent phosphorus acid monochlorides (phosphonochloridates, methyl(phenyl)phosphinic chloride, and phosphorochloridates) was studied. The effects of the structures of alcohols and phosphorylating agents on the degree of the reaction diastereoselectivity were investigated. Methylphosphonochloridates were found to react most stereoselectively; the diastereoselectivity of the phosphorylation is independent of the donor or acceptor character of substituents at the phosphorus atom, being determined by their volumes. In the series of silylalkanols, the diastereoselectivity of the reaction the higher the closer the Si atom to the reactive site of the molecule, the larger the volume of the perfluoroalkyl substituent, and the more pronounced the electron-withdrawing properties of the substituents at the Si atom. A reaction mechanism is proposed that rationalizes the stereoselectivity of the reaction.Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1930–1936, September, 2004.     

Efficient 1,6-addition reactions of 3-substituted oxindoles: Access to isoxazole-fused 3,3′-disubstituted oxindole scaffolds and hexahydro-1h-pyrido[2,3-b]indol-2-one scaffolds

Developed herein is a new methodology for a hybrid of two pharmacophoric oxindole and isoxazole motifs to construct isoxazole-fused 3,3′-disubstituted oxindole scaffolds via an efficient 1,6-addition reaction of 3-substituted oxindoles to 3-methyl-4-nitro-5-alkenylisoxazoles, which might generate novel drug-like molecules for biological screenings. The method gives an easy access to a series of isoxazole-fused 3,3′-disubstituted oxindoles with 26 examples in high yields (up to 92% yield) and good diastereoselectivity (up to >20:1), which makes possible the synthesis of libraries under similar circumstances. Subsequently, a sequential Michael addition/amidation/reductive cyclization process was designed for accessing this hexahydro-1H-pyrido[2,3-b]indol-2-one scaffold, which is a key structural skeleton found in a large number of biologically active natural products and pharmaceutical compounds. Hexahydro-1H-pyrido[2,3-b]indol-2-one scaffold 7cg could be obtained in 42.5% overall yield after 4 steps.     

Base-promoted diastereoselective addition of nitromethane and nitroethane to N-tert-butylsulfinyl imines: synthesis of N-protected α-amino acids and amino ketones

The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO₃ under solvent-free reaction conditions gave β-nitro amine derivatives with reasonable levels of diastereoselectivity. Enantioenriched N-tert-butylsulfinyl protected α-amino acids or α-amino ketones are accessible upon oxidation of the adducts derived from nitromethane or nitroethane, respectively.     

Dearomative [4 + 2] cycloaddition of 3-nitroindoles with ortho-amino Morita−Baylis−Hillman carbonates to forge indole-fused quinolines

A dearomative [4 + 2] cycloaddition of 3-nitroindoles ortho-amino Morita−Baylis−Hillman carbonates was established under mild conditions. This method provides an efficient and practical approach for delivering tetrahydro-5H-indolo[2,3-b]quinolines containing three contiguous stereocenters, two tertiary and one quaternary, in high yield (up to 95%) with excellent diastereoselectivity (all cases >25:1 dr). The potential synthetic applications of this strategy were also highlighted by the scale-up experiment and further synthetic transformation. Moreover, the structure and relative configuration of the cycloadduct was unequivocally confirmed by single-crystal X-ray diffraction.     

Stereoselective allylation and reduction of N-tert-butanesulfinyl-α-keto aldimines

A simple methodology for the synthesis of N-tert-butanesulfinyl-α-keto aldimines from both α-keto aldehydes and carboxylic esters has been developed. The addition of an in situ formed allyl indium reagent to these chiral imines was also studied. The addition took place in a sequential manner, first to the imine group with excellent diastereoselectivity and then to the carbonyl group with lower diastereoselectivity. Ruthenium-catalyzed ring closing metathesis of the resulting 5-aminoocta-1,7-dien-4-ol derivatives provided access to 6-aminocyclohex-3-enols. Reduction of the α-keto aldimines led to N-tert-butanesulfinyl-1,2-aminoalcohols as a 1:1 diastereomeric mixture.