An Improved Total Synthesis of (±) - Podocarpic Acid by a Cyclialkylation Route

A number of total syntheses of (±) - podocarpic acid (i) have been described¹ King, King and Topliss² first identified one of the products from nonstereo-selective cyclization of (4) with polyphosphoric acid as (±)- ethyl-O-methylpodocarpate (2) and correlated that with the corresponding acid (3), prepared in an extremly poor yield (ca 0.4%)³ by Bhattacharyya³, and Haworth and Moore⁴ by cyclization of (5) with a mixture of sulfuric acid and acetic acid. More recently Mancini, Fringuelli and Taticchi⁵ prepared (3) (in 4.8% yield) by repeating Howorth¹ s cyclization of (4). In continuation of our studies on cyclialky-     

An Efficient Synthesis of 3,4-Dihydro-4-Imino-2(1H)-Quinazolinones

A new one-pot convenient preparation of 3,4-dihydro-4-imino-2(1H)-quinazolinones (4) is described by the reaction of 2-aminobenzonitriles (1) with chlorosulfonyl isocyanate (2), while the reaction of 1 with chlorocarbonyl isocyanate (6) affords ureidobenzonitriles (7), which on thermal cyclization gives 4.     

Synthesis of C-Glycosyl α-Glycines

Abstract

A scheme of asymmetric synthesis of C-glycosyl α-glycines is described. Reductive hydrolysis of 2-deoxy-3,5-di-O-p-toluoyl-β D-erythropentofuranose 1-cyanide (4) in the presence of N,N-diphenylethylenediamine gave the imidazolidine 5, which was converted to 2,5-anhydro-3-deoxy-4,6-di-O-p-toluoyl-β-D-allose (3)by acid hydrolysis. The aldehyde (3), chiralamine, benzoic acid and t-butyl isocyanide four component condensation afforded in good yield two diastereomeric adducts (6a and 6b), which were separated by column chromatography and deblocked to furnish 2-deoxy-β-D-erythropentofuranosyl R and S-glycines (1a) and (1b).     

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.     

Nonreducing-Sugar Subunit Analogs of Bacterial Lipid a Carrying the Ester-Bound (3R)-3-(Acyloxy)Tetradecanoyl Group

Abstract

In order to elucidate further the relationship between the composition of the fatty acyl groups in the nonreducing-sugar subunit of bacterial lipid A and its biological activity, 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-2-[(3R)-3-hydroxytetradecanamido]-4-O-phosphono-D-glucose [GLA-63(R, R) and GLA-64(R, R)], and 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-4-O-phosphono-2-tetradecanamido-D-glucose [GLA-67(R), GLA-68(R) and GLA-69(R)] have been synthesized. Benzyl 2-[(3R)-3-(benzyloxymethoxy)tetradecanamido]-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside (5) and benzyl 2-deoxy-4,6-O-isopropylidene-2-tetradecanamido-β-D-glucopyranoside (6) were each esterified with (3R)-3-dodecanoyloxytetradecanoic acid (1), (3R)-3-tetradecanoyloxytetradecanoic acid (2) or (3R)-3-hexadecanoyloxy-tetradecanoic acid (3), to give 7-11, which were then transformed, by the sequence of deisopropylidenation, 6-O-tritylation and 4-O-phosphorylation, into a series of desired compounds.     

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.     

Synthesis of the Four Configurational Isomers of N-Benzoyl-2, 3, 6-Trtdeoxy-3-C-Methyl-3-Amino-L-Hexose from the (2S, 3R)-Diol Obtained from α-Methylcinnamaldehyde by Fermentation with Baker'S Yeast

Abstract

The erythro and threo chiral C₅ methyl ketones (4) and (5), prepared from the (2S, 3R)-methyl diel (1b), were converted into the phenylsulfenimines (6) and (7), which, in turn, on reaction with allyl-magnesiutn bromide, yielded after acid hydrolysis and benzoylation, the diastereoisomeric C₈-N-aminodiol derivatives (9) and (11), with threo stereochemistry relative to positions 4 and 5. Ozonolysis of (9) and (11) yielded the l-arabino and l-xylo 3-O-methyl branched aminodeoxysugar derivatives (13) and (15), respectively. Using diallylzinc as the reagent, the diastereoisomeric erythro products (8) and (10) were obtained. The latter materials gave the l-ribo-and l-lyxo-(lL-vancosamine) derivatives (12) and (14) upon oxonolysis. The ¹H and ¹³C NMR spectra of the four isomeric aminodeoxysugar derivatives (12)—(15) were discussed.     

A Convenient Synthesis of (Z)-7-Nonadecen-Ll-One and (Z)-7-Eicosen-Ll-Cne -the Pheromones of Peach Fruit Moth

In 1977 Tamaki¹ et al have isolated and synthesized² (Z)-7-nonadecen-ll-one (la) and (Z)-7-eicosen-l1-one (1b) which are active components of the female sex pheromones of the peach fruit moth Carposina niponensis Walsingham, a major economic pest of apple, peach and other fruits of Japan. We report in this communication a practical, convenient and stereospecific route to 1a and 1b.     

N-(Chlorosulfinyl)-Imidazole as a New Imidazole Transfer Reagent1

The usefulness of diimidazoles² such as N, N′-carbonyldi-imidazole (1), and N, N′-thionyldiimidazole (2) in organic synthesis has been accumulated recently. In connection with the continuing our studies on the reaction using 1 or 2 ³ (carbonyl, thionyl, and imidazole transfer reactions), our particular interest was focused on the synthesis of N-(chlorosulfinyl)-imidazole (3) in which one imidazole group in 2 was replaced by the other leaving group (Cl). Also, 3 was interesting for preparative purposes as a chlorine atom could be introduced via the addition reaction of 3 to carbonyl compounds as known in the reaction of 1 or 2 with ketones.     

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.     

New Preparation of Cyclic Acyloxyphosphorane by Reaction of Glyoxylic Acid with Phosphorus(III) Compounds

We have recently found that the reaction of α-keto acids (1) with phosphorus (III) compounds (3) yielded cyclic acyloxyphosphoranes(C-AOPs, 4), a new class of pentacovalent phosphorus species having a P-OC(O) group.^{1, 2)} The present paper deals with a new reaction of glyoxylic acid (2) with 3 to give C-AOPs (5) having no substituent at the C-3 position. 1 is an α-keto acid whereas 2 can be taken as an α-formyl acid. Although it is well known in the field of organic chemistry that the formyl group often behaves differently from a keto group, the reaction of 2 with 3 provides an example in which both groups behave in a similar manner.     

A Facile Synthesis of Tetracycles of the γ-Lycorane Type

When an attempted application of the general scheme of alkaloid synthesis, based on the partial hydrogenation of 1 -alkyl-3-acylpyridinium salts and acid-induced cyclization of the resultant 2-piperideines,² to the construction of an Amaryllidaceae alkaloid system failed in the cyclization step, i.e. the transformation of dihydroisoquinoline 4a (prepared by the treatment of ester 2a ³ with 5-bromo-2 -pentanone ethylene ketal, followed by hydrogenation of the salt over palladium-charcoal) into a tricyclic ketal ester,⁴ an alternate, route of synthesis still utilizing a previously prepared isoquinoline precursor (3b) was investigated. The initial observation of the easy conversion of 3b into N-methyl (1a) and O-ethyl products (2b) was helpful in this connection.     

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.     

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.     

Synthesis of Retro-γ-Ionols and the Corresponding-Ionones1

Both the direct² and the sensitized^3,4 photolyses of (E)-β-ionol (2) have been studied in some detail. In a preliminary publication⁵ we have indicated that direct photolyses of (E)-β-ionol (2) with λ = 254 nm yields (Z)-retro-γ-ionol (3) as the primary product; upon further irradiation 3 is converted into the corresponding (E)-isomer (4) which rapidly yields the bicyclic alcohol 5. A quantitative study revealed that the photoconversion of (E)-β-ionol with λ = 254 nm to 3 is about 10 times faster than the conversion of 3 into (E)-retro-γ-ionol.⁶ This rate difference thus allows the photosynthesis of 3.     

Synthesis of Methyl (-)-Shikimate From D-Lyxose

Abstract

Methyl (-)-shikimate (1), the methyl ester of naturally occurring (-)-shikimic acid, has been synthesized from D-lyxose. The key reaction in the synthesis was a one-step construction of the cyclohexane ring by simultaneous C-C bond formation of both terminal carbons of a D-lyxose derived synthon (7) with the methylene carbon of dimethyl malonate. The cyclization products (9) and (9′) were transformed to some derivatives of shikimic acid.     

Monomeric and Dimeric (Aminomethylidene)phosphines and -Arsines

Abstract

In (dimethylaminomethylidene)phosphines (1) [1] and -arsines (2) the internal rotation of the dimethylamino group is hindered by a barrier of 50 to 55 kJmol^?1? analogous to the corresponding amidines. In order to evaluate the influence of this conjugative effect upon the P=C and (P)-C-N bond lengths, single crystal x-ray structure determinations of 1a and 2a have been carried out. For comparison, the cyclic (aminomethylidene)phosphine 1H-1,3-benzazaphosphole 5 [2] as well as the dimeric compounds 3a, 3b, and 3c [3] have been analyzed, too, while the arsenic derivative 6 was studied by others [4]. The diarsetanes 4 could not yet be isolated. The structural results indicate the E=C bonds in 1a, 2a, 5, and 6 to be scarcely elongated, the (E)-C-N bonds, however, to be shortened considerably with respect to the dimers.     

Synthesis of N-[2-S -(2-Acetamido-2,3-dideoxy-D-glucopyranose-3-y1)-2-Thio-D-Lactoyl]-L-alanyl-D-isoglutamine

Abstract

N-[2-S-(2-Acetamido-2,3-dideoxy-D-glucopyranose-3-y1)-2-thio-D-lactoyl]-L-alanyl-D-isoglutamine, in which the oxygen atom at C-3 of N-acetylmuramoic acid moiety in N-acetylmuramoyl-L-alanyl-D-isoglutamine (MDP) has been replaced by sulfur, was synthesized from allyl 2-acetamido-2-deoxy-β-D-glucopyranoside (1).

Treatment with sodium acetate of the 3-O-mesylate, derived from 1 by 4,6-O-isopropylidenation and subsequent mesylation, gave allyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-β-D-allopyranoside (4). When treated with potassium thioacetate, the 3-O-mesylate, derived from 4, afforded allyl 2-acetamido-3-S-acetyl-2-deoxy-4,6-0-isopropylidence-β-D-glucopyranoside (6). S-Deacetylation of 6, condensation with 2-L-chloropropanoic acid, and subsequent esterification, gave the 3-s[D-1(methoxycarbonyl)ethyl]-3-thio-glucopyranoside derivative (7). Coupling of the acid, derived from 7, with the methyl ester of L-alanyl-D-isoglutamine, and subsequent hydrolysis, yielded the title compound.     

Selective Hydrolysis of Thioacetals with Thallium(III) Nitrate

In connection with research at present being pursued in these laboratories we required quantities of thioacetal (1) for study. Reaction of Wieland-Miescher ketone (2) with one equivalent of 1,2-ethanedithiol gave only (3) resulting from reaction at the α,β-unsaturated carbonyl group. The structure for (3) was deduced primarily from C n. m. r. which showed a saturated carbonyl absorption (δ212.6)¹. The preferential reaction of 1,2-ethanedithiol with α,β-unsaturated ketone     

Aminohaloborane in Organic Synthesis. V.1 An Aldol-Type Condensation of Acetonitrile and Phenylacetonitrile with Benzaldehydes Using Secondary Aminodichloroborane

3-Phenyl-3-sec-aminopropionitriles (1) are not found in literature. We describe here a simple synthesis of 1 from acetonitriles (2) and benzaldehydes (3) using sec-aminodichloroboranes (4)² and triethylamine (5).