Stereoselective Synthesis of 3-C-Branched-Chain Sugars by Aldol Reaction of Furanos-3-Uloses with Acetone

Abstract

Aldol reaction of 1,2-O-isopropylidene-5-O-tertbutyl-dimethylsilyl-α-D-erythro-pentofuranos-3-ulose (1) with acetone in the presence of aqueous K₂CO₃ afforded 3-C-acetonyl-1,2-O-isopropylidene-5-O-tertbutyl-dimethylsilyl-α-D-ribofuranose(2). Similar reaction of 1,2:5, 6-di-o-isopropylidene- α-D-ribo-hexofuranos-3-ulose (3) afforded 3-C-acetonyl-1,2:5, 6-di-o-isopropylidene- α-D-allofuranose (4) and (1R, 3R, 7R, 8S, 10R)-perhydro-8-hydroxy-5,5,10-trimethyl-2,4,6,11,14-pentaoxatetracyclo[8,3,1,0^1,8,0^3,7] tetradecane. The stereochemistry of the new chiral centers were determined by ¹H NOE experiments.     

Synthesis of 2-Carbamoyl-2-Deoxy Glycosides

Abstract

Recently we have reported the addition of trichloracetyl isocuyanate to glycals 1 _1,2,3. The reaction led to the highly stereoselective formation of a mixture of unstable [2+2] and [4+2] cycloadducts 2 and 3. The isocyanate adds to the glycal moiety anti to the substituent at C-3. The addition of benzylamine to the reac6tion mixture led to N-deprotection of 2 and allowed us to isolate stable bicyclic β-lactams 4 _1-3. We have shown also that 2 (a mixture of α-L-gluco and β-L-manno isomers) obtained from L-rhamnal 1 (R¹[dbnd]Ac, R²[dbnd]CH₃ under high pressure, when treated with methanol, underwent a rapid trans opening of the four-membered ring to give respective glycosides 5(β-L-gluco and α-L-manno isomers). On the other hand 3 (R¹[dbnd]Ac, R²[dbnd]CH₃) under the same conditions added a molecule of methanol to the C[dbnd]N double bond affording 6.     

A Facile Synthesis of 2-Hydroxy-6-Methylacetophenone

Recently, we identified 2-hydroxy-6-methylacetophenone (3) and 2-acetoxy-6-methylacetophenone (4) as exocrine compounds in several neotropical species of ants in the dolichoderine genus Hypoclinea. Although 3 has been reported at least four times in the literature as a synthetic intermediate or as the object of a nuclear magnetic resonance study, neither 3 nor 4 had been reported as natural products, and 4 is a novel compound.^2,3,4,5     

Darstellung Der Isomeren 1,6-DI-O-Acetyl-3,4-Didesoxy-α, β-D-Glycero-Hex-3-Enopyrahos-2-Ulosen

Abstract

Prolonged treatment of tetra-O-acetyl-1, 5-anhydro-hex-1-enitols (“tetra-O-acetyl-hydroxy-glycals”) 3 and 5 with BF₃ in CH₂Cl₂ at RT lead to anomeric mixtures of the title compounds 2 and 4a, the α-anomer 4a dominating. Reaction of 5 gave the higher yields of 4a (71%) and 2 (12%), the results being accounted mechanistic grounds. The same reaction performed in an aromatic solvent, like toluene, gave rise to competing C-alkylation., The ortho and para-tolyl derivatives 6 and 7, also with enone structure, were isolated in a combined maximum yield of 40% from 5. β-Enone 2 was also prepared in moderate yield by thermolysis of β-d-glucopyranose pentaacetate (1). In this case no α-anomer 4a was detected.     

Synthesis of 2′,3′-Dideoxy-2′-Fluorokanamycin A

2′,3′-Dideoxy-2′-fluorokanamycin A (23) was prepared by condensation of 6-azido-4-0-benzoyl-2,3,6-trideoxy-2-fluoro-α-D-ribo-hexopyranosyl bromide (13) and a protected disaccharide (19). Methyl 4,6-0-benzylidene-3-deoxy-β-D-arabino-hexopyranoside (5) prepared from methyl 4,6-0-benzylidene-3-chloro-3-deoxy-β-D-allo-hexopyranoside (1) by oxidation with pyridinium chlorochromate followed by reduction with Na₂ S₂O₄ was fluorinated with the DAST reagent to give methyl 4,6-O-benzylidene-2,3-dideoxy-2-fluoro-β-D-ribo-hexopyranoside (7). Successive treatment of 7 with NBS, NaN₃ and SOBr₂ gave 13. The structure of the final product (23) was determined by the ¹H and ¹⁹F and shift-correlated 2D NMR spectra.     

Tetronic Acids and Derivatives Part VIII (1) o-Alkylation of 3-Unsubstituted Tetronic Acids

4-methoxy-(5H)-furan-2-ones 1 are useful starting materials for the synthesis of naturally occuring lactones². In a previous communication we have described an efficient entry to 4-alkoxy-(5H)-furan-2-ones 1–3 (alkyl tetronates) by lactonization of ethyl 4-acetoxy 3-ketoesters 4 using hydrochloric acid in several alcohols¹. The detection of 4-hydroxy-(5H)-furan-2-ones 5 (tetronic acids) during the reaction course³ allowed us to postulate them as intermediates which were subsequently etherified to the products 1–3. In a very recent communication⁴, it was claimed that attempted alkylation of tetronic acids 5 using HC1 in an alcohol or alkyl halides on tetronic acids sodium salts are unsuccessful; moreover, the structure of our compounds 1–3 was questionned by arguing that isomeric 2-alkylated materials     

The Reaction of Diethanolamine with 2-Chloronitrobenzene-A Reinvestigation

In a report on the reaction of 2-chloronitrobenzene (1) with diethanolamine (2), Meltsner et al ¹ claim that the expected S_NAr product, N-(2-nitrophenyl)diethanolamine (3), is not formed; rather that the products are 2,2′-dichloroazobenzene (4), 2-nitrophenol (5), 2-chloroaniline (6) and 4-(2-aminophenyl)morpholine (7). Similar products in which the nitro function is reduced are also reported² for the corresponding reaction with ethanolamine. In this laboratory, in an attempted preparation of 2,2′-dichloroazobenzene (4) for reference purposes in photochemical studies on the antineoplastic agent 5-(3-azido-4-chlorophenyl)-6-ethyl-pyrimidin-2,4-diamine³, the expected S_NAr product (3) was obtained along with other products.     

Sodium Complexes of Isomaltol and Maltol

Sodium bis(3-O-hydroxy-2-furyl methyl ketone) (3) and sodium 3-O-hydroxy-2-methyl-4-pyrone hydrate (4) were isolated and characterized from the interaction of isomaltol and maltol with sodium methoxide in boiling benzene (toluene or acetone). Elemental analyses of 3 furnished the formula C₁₂H₁₁NaO₆, and this composition was confirmed by conversion to isomaltol O-benzoyl ester.     

Total Synthesis of (±) Flavipucine

In 1972 we proposed¹ structure 3 for flavipucine, an antibiotic from an Aspergillus flavipes strain. Later we reported² a novel reaction of 6-methyl-4-hydroxy-2-pyridone with α keto aldehydes which provided 1a from isobutylglyoxal and it was stated that we believed 1a would serve as a key intermediate in the total synthesis of flavipucine 3.     

Asymmetric Synthesis of Phosphinous Tungsten Complexes

Abstract

The asymmetric synthesis of phosphinous compounds from diheterophosphacycloal kane-1,3,2 was investigated in a transition metal complex series. Complexes 1 and 2 were prepared from diaminophosphine, (?)-ephedrine and W (CO)₅ THP (1: δ³¹ P=+147,6 ppm; J_PW=313 Hz M^.+=595;2 δ³ p=+156 ppm J_PW=304 Hz M^.+=533; 90%dp) in two steps. Methyl lithium reacted with 1 to give stereospecific 3 (83%Yield) by P-O linkage (3 δ³¹ P=+64 ppm; J_PW =261 Hz; M^.+ ? 28=583). The aminophosphine complex 3 was stereochemically stable and was used for studies of synthetic applications. HCL gas reacted with 3 in CH₂Cl₂ to give the non optically active chlorophosphine complex 4 (δ³¹ P=+103,6 ppm; J_PW=290 Hz; M^.+ =482). This compound immediately gave salt 6 (δ³¹ P=+66,7 ppm; J_PW =240 Hz) by reaction with (?)-menthol and triethylamine. The acid methanolysis of 3 gave a mixture of 5 and 6 and the unchanged (?)-ephedrine salt [5:30% yield; δ³¹ P=+114 ppm; J_pw=280 Hz; [α]_D=+1,2° (CH₂Cl₂); M^.+=478; 6 : 60% yield; δ³¹p=+102,9 ppm; J_PW=264 Hz; [α]_D =+16,9° (CH₂Cl₂); M^.+=464]. Compound 6 was thus obtained with a 80% yield and a specific rotation of + 20,2° (CH₂Cl₂) in isopropanol/H₂SO₄ 5M medium. The enantiomeric excess of 6 was determined by RMN³¹P. Acid hydrolysis of 3 or the reaction with CH₃SO₃H, gave phosphinous acid complex 6 with an optical rotation of + 4,8° or ?1,8° respectively. These results provide precious informations about the stereochemistry and reactivity of the P-N linkage in this aminophosphine transition metal series, which differs notably from that of the corresponding (PO) N bond.     

The Synthesis of Hydronaphthalenes from m-Toluic Acid via Cyclization of Thioacetal Monosulfoxides

We recently developed a convenient route to hexahydronaphthalenols such as 5 (R=CO₂CH₃ or CH₃) starting from m-toluic acid (1)¹. The key features of the route involved reduction-alkylation of the toluic acid to the dihydro derivative 2 ², subsequent deprotection and oxidation of the side chain primary alcohol, and acid-catalyzed cyclization of the resulting aldehyde 4. In the case of the dimethylnaphthalenols 5 (R=CH₃), conversion of the angular carboxylic function to the methyl group was effected prior to cyclization via reduction of the p-toluenesulfonic ester of the neopentyl alcohol 3 (R=CH₂OH) using lithium triethylborohydride³.     

Reaktionen Mit Trimethylsilylhalogeniden an Derivaten Der Digitoxose

Abstract

Treatment of methyl 3,4-di-O-acyl-2,6-dideoxy-α-D-ribo-hexo-pyranoside 1 or 2 with trimethylsilyl halide leads to the formation of a complex mixture of α-D-ribo-hexopyranosyl halides 3 or 5 together with the educts 1 or 2 as well as their β-anomers 8 or 9. The bromides 3 and 5, suitable for glycosidations, are preferably obtained by reaction of the digitoxose acetate derivatives 6 and 7, respectively, which in turn are prepared from 1 and 2 by mild acetolysis. Further reaction of the halides 3 to 5 with trimethylsilyl halides gives rise to a quantitative formation of the 2,3,6-trideoxy-4-0-acyl-3-halo-α-D -arabino-hexopyranosyl halides 10 to 12. In another reaction sequence starting with the olivose triacetate 20 the formation of 10 via the halide 13 is demonstrated. Structural evidence for the halides 10 to 12 is given by ¹H NMR data as well as by analyses of their glycosides 14 to 19. The results support a mechanistic interpretation for the formation of 10 to 12 via a 3,4-acetoxonium ion as the key intermediate obtained from 3 by an S_Nfi and from 13 and S_N2i step. Final conversion into the terminal halodeoxy compounds 10 to 12 proceeds by and S_N2 reaction with the halide ion.     

A Synthesis of 2-(6′-Carboxy-2′-cis-Hexenyl)-4-Hydroxycyclopent-2-EN-1-ONE,a Prostagiandin Intermediate1

Several recent publications² report the synthesis of prostaglandin E₁ (PGE₁, 2) and some of its derivatives by conjugate addition reactions to ether-ester forms of hydroxycyclopentenone acid 1.³ The simplicity of this approach makes its application to the preparation of prostaglandins of the PG₂- and PG₃ - series (cis-Δ⁵)⁴ an attractive alternative to the existing elegant methods.⁵ We now wish to report a five-step synthesis of the requisite hydroxycyclopentenone precursor 3 from the readily available⁶ lactone 4.     

20-ISO-20-Deethylaspidospermidine

The two-step process of hydrogenation of l-alkyl-3-acylpyridinium salts and cyclization of the resultant 1, 4, 5, 6-tetrahydropyridines has been the foundation of a general scheme of alkaloid synthesis.¹ Its application in the indole alkaloid field has yielded ready access to tetrahydro-β-carboline systems, e.g. 1a → 2 → eburnamonine.² Since acid treatment of N_b -acyl derivatives of substances related to la has been shown to lead to products of indole β-cyclization³, it became of interest to test the cyclization behavior of the vinylogous imide lb, prepared by the dicyclohexylcarbodiimide-induced acylation of 3-acetyl-1, 4, 5, 6-tetrahydropyridine⁴ with indoleacetic acid. Treatment of lb with boron trifluoride gave a 62 yield of ketolactam 3a. Thus a two-step entry into the pentacyclic Aspidosperma alkaloid skeleton is on hand.     

The structure of cis and trans lsomers of 1-(p-Bromobenzylidene)-2-indanone

Abstract

In this communication we wish to report an interesting case of the isolation and characterization of the cis and trans isomers of 1-(p-bromobenzylidene)-2-indanone and their ketals. Prior to this work, Hoogstreen and Trenner² had reported on the cis and trans isomers of 1-(p-chlorobenzylidene)-2-methyl-5-methoxyindenylacetic acid. The condensation of 2-(N-morpholinyl)-indene (1, prepared by the reaction of 2-indanone³ and morpholine) with P-bromobenzaldehyde was conducted by refluxing them in the presence of acetic acid for 4 hours. Acid hydrolysis of the reaction mixture followed by dry column chrcmatography over sillica gel using a fraction collector afforded two iscmeric monobenzylidenes, compounds 2(36.6%, mp 110–111°)and 3(1.3%, mp 115–116°) and a dibenylidene, compound 4 (8.7%, mp 205°). The relative rations of the mono- and dibenzylidenes seemed to depend on the reaction conditions. Higher yields of the monobenzylidenes 2 and 3 were obtained by conducting the reaction in the presence of UV light. The structures of these monobenzylidenes were established as cis and trans isomers of 1-(p-bromobenzylidenes)-2-indanone on the Basis of elemental analyses and ir and nmr spectroscopy. The ir spectra⁴ (CHCl₃)

of compounds 2 [1725 (c=0), 1620 (c=c)cm^?1] and 3[1710 (c=o), 1570, 1600 (c=c) cm^?1] were consistent with the structures. The molecular ion peaks as well as the fragmentation patterns in the mass spectra of both these compounds were consistent with the assigned structures. Before going into the omr discussion it should be pointed out that treatment of compound 2 with athylene glycol in the presence of p-toluene sulfonic acid produced two ketals, 5 (38.3% mp, 118–120°) and 6 (30.6% mp, 125–126°). As depicted; the ketals 5and 6 were also found (by omr) to be related to each other as cis and trans isomers. Furthermore, each of them could be hydrolyzed with acid to the corresponding monobenzylidenes 2 and 3 without any isomerization. However, UV irradiation of compounds 2 and 3 gave equilibrium mixtures containing both the isomers, indicating isomerization had occurred under photolytic conditions.     

Occurrence of the Unusual 2C5 (1C4) Chair Conformation in Two Carbohydrates and the Reverse Anomeric Effect. X-Ray Structures of 3,4,5,7-Tetra-O-Acetyl-2,6-Anhydro-D-Glycero-D-Ido-Heptonamide (1) and 3,4,5,7-Tetra-O-Acetyl-2,6-Anhydro-D-Glycero-L-Gluco-Heptonamide (2)

Abstract

The title compounds 1 and 2 (both C₁₅O₁₅NH₂₁) crystallized in the monoclinic space group P2₁ (Z = 2) with a=8.864(1), b=8.346(1), c =13.569(1)Å, β =114.12(1), V=918.1(2)A3, D(calc) = 1.358 g/cc for compound 1, and a=15–045(1), b=8.106(1), c=7.491(1)Å, β =97.23(1)°, V=906.4(3)Å3 D(calc)= 1.375 g/cc, for compound 2. The structures were solved by direct methods and refined by the full-matrix least squares technique to R indices of 0.010 and 0.046, respectively. Both compounds are in the α ? D configuration and adopt the unusual ²C₅, (¹C₄) chair conformation with the carbamoyl groups on the anomeric carbon atoms equatorially oriented. In this conformation the orientations of the substituents are 2e, 3a, 4a, 5a and 6a in 1 and 2e, 3a, 4a, 5e and 6a in 2 which leads to unfavorable 1,3-diaxial interactions. The “reverse anomeric effect” which induces the ²c₅ chair conformation in these compounds, may have its origin in the unfavorable steric interactions found in the ⁵c₂ (⁴C₁) conformation where the carbamoyl group is axially oriented. Furthermore, the ²C₅ conformation is stabilized by the N-H … O intramolecular hydrogen bond between the carbamoyl nitrogen atom and the pyranosyl ring oxygen atom. Semi-empirical energy calculations reveal that the rotational freedom of the carbamoyl group is greater for the equatorial orientation (²C₅) than for the axial orientation (⁵C₂).     

Methyl-2,6-Anhydro-α-D-Mannofurahosid Eine Verbesserte Darstellungsmethode Sowie Die Bestimmung Der Kristall- Und Molekolstruktur

Abstract

The title compound 3, which is the first member of a new class of anhydroglycosides, was initially isolated from the methanolysis mixture of the pyranoid isomer 1 in about 1% yield. Improved yields of greater than 30 % of 3 are obtained by treating the main product of the aforementioned methanolysis, the dimethylacetal 2, with a catalytic amount of p-toluenesulfonic acid in boiling xylene. 3 (C₇H₁₂O₅) crystallizes from diisopropyl ether in the monoclinic space group P21 (Z=2) with a = 552.4(1), b = 685.2(1), c = 1052.9(3) pm, α = 90.0, β = 98.95(6) and Y = 90.0°. The structure was solved by X-ray crystal structure analysis using direct methods to R indices of 0.036 and 0.045, respectively, for 1180 independent reflections. The furanoid ring in 3 adopts a conformation intermediate between ²T₃(D) and E₃(D) (puckering parameters: Q = 48.9 pm; Φ = 102.4°). The oxane ring adopts an ^a2C_a5(D) conformation, which is heavily distorted by flattening at C-6 (puckering parameters: Q = 64.2 pm; Φ = 58.1° and 0 = 159.5°). Orientation of the glycosidic methyl group is in accord with the exo-anomeric effect. The molecules of 3 are interchained in three dimensions by a system of hydrogen bonds.     

NOUVELLE SYNTHÈSE DE [1,2-A]BENZIMIDAZOLO-1,3,5,2-TRIAZAPHOSPHORINES ET DE [1,2-A]BENZIMIDAZOLO-1,3,5,2- TRIAZAPHOSPHORINE-2-THIONES

The condensation of N₁-benzimidazolyl amidines 1 with tris(dimethy- lamino)phosphine leads to the corresponding [1,2a]Benzimidazolo-1,3,5,2-triazaphosphorines 3 . The N₂-phosphoroamidine intermediates 2′ are isolated and yielded the corresponding cyclic compounds 4 upon heating. The oxidation by sulfur of the compounds 3 gives the thiooxide derivatives 4 .

The structure of these compounds is unambiguously confirmed by IR, ¹H, ³¹P, and ¹³C NMR spectroscopy and by MS for some products.     

Complete Solid State 13C NMR Chemical Shift Assignments for α-D-Glucose, α-D-Glucose-H2O and β-D-Glucose

Abstract

NMR spectra of crystalline α-D-glucose DH₂O (1), α-D-glucose (2), and β-D-glucose (3) were examined by 13C cross polarization magic angle spinning (CPMAS) methods. Each of the three forms of glucose exhibited a distinctly different spectrum. Chemical interconversion of 2 and 3 as well as the in situ dehydration of 1 during the course of the CPMAS NMR experiment was monitored in the ¹³C spectra. Samples of 1, 2, and 3 specifically enriched at C-1 and C-6 with ¹³C yielded ¹³C spectra in which the resonances corresponding to the adjacent C-2 and C-5 carbons were not visible due to strong homonuclear ¹³C dipolar interactions with the high abundance label. Spectra of these analogues as well as the C-2 and C-3 labeled materials provided the complete ¹³C chemical shift assignments of crystalline 1 2, and 3. A comparison of the solid state and solution ¹³C spectra revealed substantial resonance shifts for each of the three structures examined.