Synthesis of Protein Farnesyltransferase and Protein Geranylgeranyltransferase Inhibitors: Rapid Access to Chaetomellic Acid A and Its Analogues

A facile two-step stereospecific synthesis of the protein farnesyltransferase inhibitor chaetomellic acid A (1) and its analogues was developed. Addition of organocuprates derived from Grignard reagents (e.g. tetradecylmagnesium chloride and CuBr.Me(2)S) to dimethyl acetylenedicarboxylate (DMAD) in tetrahydrofuran containing hexamethylphosphoramide was followed by capture of the resulting copper enolates with a variety of electrophiles (e.g. methyl iodide) to give dimethyl cis-butenedioate derivatives 4-11. Hydrolysis with lithium hydroxide generated the corresponding lithium carboxylates, which readily closed to 2,3-disubstituted maleic anhydrides 17-20 upon acid treatment. Compound 16, an analogue wherein the tetradecyl group of 1 is replaced by a farnesyl moiety, is 7-fold more potent than 1 as an inhibitor of protein farnesyltransferase from yeast and displays a 100:1 selectivity for this enzyme relative to yeast protein geranylgeranyltransferase. In contrast, analogue 15, which contains a geranylgeranyl side chain, shows ca. 10:1 selectivity for the latter enzyme.     

Preparation of gamma-siloxyallyltributylstannanes and their use in the synthesis of (+/-)-1-deoxy-6,8a-di-epi-castanospermine

gamma-siloxyallyltributylstannanes were selectively obtained as E or Z isomers from beta-tributylstannylacrolein upon reaction with lithium or magnesium alkylcyanocuprates. The ability of the reagents to give a high syn selectivity when added to iminium salts has been used for the efficient synthesis of (+/-)-1-deoxy-6,8a-di-epi-castanospermine from succinimide. The key step of the synthesis was the allylstannation of the N-allyliminium intermediate followed by ring closing metathesis.     

New process for the preparation of 3,5-dihydroxy-1-pentylbenzene

A new process for the preparation of 3,5-dihydroxy-1-pentylbenzene, which is used as medicinal intermediate and raw material for the synthesis of HIV restrainer, is proposed in this paper. Technical 3,5-dimethoxybenzoic acid reacted with lithium hydride to form a salt (I) which acylated n-butyllithium directly to give 1-(3,5-dimethoxyphenyl)-1-pentanone (II) in 85.06% yield. Then (II) was reduced through a Wolff-K-Huangminglong reaction at 210°C to give 3,5-dimethoxy-1-pentylbenzene (III). Finally, (III) refluxed with melt pyridine hydrochloride at 200°C for 2 h to afford the target product 3,5-dihydroxy-1-pentylbenzene (IV). The total yield of (IV) amounted to 61.50% and its mass percentage was 98.22%. The products were characterized by means of IR, ¹H-NMR, GC and HLPC-MS. The results indicated that this synthetic route was feasible, characterized by simple process and higher yield, and superior to the published ones.     

Synthesis of carboxamides by LDA-catalyzed Haller-Bauer and Cannizzaro reactions

[reaction: see text] The first direct synthesis of N-alkylcarboxamides and N,N-dialkylcarboxamides by Haller-Bauer (HB) and Cannizzaro-type reactions has been realized. Lithium N,N-diisopropylamide (LDA) catalyst was successfully used in not only the HB reaction of benzylic ketones with lithium N-alkylamides to give the corresponding carboxamides and hydrocarbons but also in the Cannizzaro-type reaction of aldehydes with lithium N-alkylamides or lithium N,N-dialkylamides to give the corresponding carboxamides and alcohols.     

Polyfluorocycloalkenes. Part XVIII. Aryl adducts of decafluorocyclohexene

Decafluorocyclohexene reacted slowly with aniline to give 1-phenylamino- 3-phenyliminoheptafluorocyclohex-2-ene, which was hydrolysed by hydrochloric acid to 3-phenylaminoheptafluorocyclohex-2-enone. Decafluorocyclohexene reacted stepwise with phenyl lithium, giving 1-phenylnonafluorocyclohexene and thence 1,2-diphenyloctafluorocyclohexene: the former product was attacked slowly by pentafluorophenyl lithium at ?40°C affording 1-pentafluorophenyl- 1-phenyloctafluorocyclohexene. Phenyl lithium reacted sluggishly with bis(pentafluorophenyl)octafluorocyclohexene to give 1-pentafluorophenyl-2-(2′,3′,5′,6′-tetrafluoro-1′-biphenylyl)octafluorocyclohexene and 1,2-bis(2′,3′,5′,6′-tetrafluoro-1′-biphenylyl)octafluorocyclohexene. 1,2-Diphenyloctafluorocyclohexene and 1,2-bis(pentafluorophenyl) octafluorocyclohexene were fluorinated by cobalt(III) fluoride to give the olefin, 1,2-bis(undecafluorocyclohexyl)octafluorocyclohexene.     

Synthesis of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles as potential selective serotonin reuptake inhibitors

Two 2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2a,b have been synthesized by the reaction of isoindoline with 4-chloropyridines. In addition, a number of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2c-h were obtained from 2-(4-pyridinyl)phthalimide (5). The addition of alkyl Grignard reagents to 5 gave 1-alkylhydroxyisoindolones 6a-f which, in two cases 6a,b , were dehydrated and subjected to three separate reductions to give targets 2c,d . In three cases, the intermediate hydroxyisoindolones 6c-e were reduced in one step to the target compounds 2c-g with lithium aluminum hydride-aluminum chloride. When 6f , the product of the addition of phenyl Grignard to 5 , was subjected to these conditions, a hydroxyisoindoline 7 was obtained which was further reduced to 2h with triethylsilane-trifluoroacetic acid. The lithium aluminum hydride-aluminum chloride conditions were successfully applied to the synthesis of a 1-benzyl-4-piperidine derivative 21.     

Reactivity of chiral alpha-amidoalkylphenyl sulfones with stabilized carbanions. stereoselective synthesis of optically active 1-aminopyrrolizidine

Metal enolates and functionalized allylzinc reagents react with optically active alpha-amidoalkylphenyl sulfones to give N-carbamoylamino derivatives with variable levels of anti diastereoselectivity. Zinc enolates provide comparable results with respect to lithium enolates in terms of diastereoselectivity but afford beta-amino ester derivatives in lower yield. The synthetic utility of the obtained chiral N-carbamoylamino esters is demonstrated by the first enantioselective synthesis of (-)-1-aminopyrrolizidine a central intermediate for the preparation of various biologically active substances.     

Electrocyclic ring-opening/pi-allyl cation cyclization reaction sequences involving gem-dihalocyclopropanes as substrates: application to syntheses of (+/-)-, (+)-, and (-)-gamma-lycorane

The readily prepared gem-dibromocyclopropanes (+/-)-13 and (+/-)-19 each engage in a silver(I)-promoted electrocyclic ring-opening/pi-allyl cation cyclization sequence to deliver the hexahydroindole (+/-)-20, which participates in a Suzuki cross-coupling reaction with arylboronic acid 3 to give the tetracyclic compound (+/-)-21. Catalytic hydrogenation of this last compound proceeds in a completely stereoselective manner to give the saturated analogue (+/-)-24, which undergoes Bischler-Napieralski cyclization on reaction with phosphorus oxychloride. The resulting lactam (+/-)-25 is then reduced with lithium aluminum hydride to give (+/-)-gamma-lycorane [(+/-)-1]. By using (-)-menthyl-derived carbamates 27 and 28, this chemistry has been extended to the synthesis of the (+)- and (-)-modifications of the title compound.     

Asymmetric synthesis of (−)-(S,S)-homaline

The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)₃-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date.     

泰地唑胺的合成工艺改进

以4-溴-3-氟苯胺为原料,用氯甲酸苄酯保护氨基后,采用一锅两步法制得关键中间体--N-苄氧羰基-3-氟-4-［2-(2-甲基四唑-5-基)吡啶-5-基］苯胺（6）; 6在二异丙基氨基锂作用下与(R)-丁酸缩水甘油酯经环合反应合成了泰地唑胺,总收率53.2%,含量98.5%,其结构经¹H NMR和LC-MS确证。     

Reactions of methylcopper and chiral organocuprates with 1-nitro-2-phenylethene and of lithium dimethylcuprate with methyl 3(nitrophenyl)propenoates

Organocopper compounds like methylcopper, lithium dimethylcuprate, chiral lithium methyl-(S)-2(1-dimethylaminoethyl)-phenylcuprate and lithium menthoxy(methyl)cuprate react with 1-nitro-2-phenylethene to give the conjugate addition product 1-nitro-2-phenylpropane in moderate yields. In the reaction with lithium methyl-(S)-2(1-dimethylaminoethyl)phenylcuprate 2% asymmetric induction was obtained. The reaction between lithium dimethylcuprate and methyl 3(4-nitrophenyl)propenoate gave the corresponding azoxy compound and no conjugate addition product, while methyl 3(3-nitrophenyl)propenoate gave some conjugate addition.     

The cleavage of meso-epoxides with homochiral thiols: synthesis of (+)- and (−)-trans-1-mercaptocyclohexan-2-ol

The synthesis of (+)- and (−)-trans-1-mercaptocyclohexan-2-ol is described. Ring opening of cyclohexene oxide with (−)-4-methoxybenzylnopan-3(R)-thiol 1a followed by oxidation gives two readily separable diastereomeric sulfoxides. These sulfoxides display very different thermal stability but both undergo regio-specific syn-elimination to give cyclohexan-1-ol-2-sulfenic acid that can be reacted in situ with 3,5-dimethylthiophenol to give a mixed disulfide. Reduction of these disulfides with lithium aluminium hydride gives the title compounds in enantiomerically pure form.     

Asymmetric synthesis of polyhydroxylated pyrrolizidines via transannular iodoamination with concomitant N-debenzylation

The doubly diastereoselective "matched" conjugate addition of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (4S,5R,E)-4,5-O-isopropylidene-2,7-dienoate (derived from d-ribose in 3 steps) and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine was followed by ring-closing metathesis with Grubbs I to give a hexahydroazocine scaffold. Subsequent treatment with I(2) resulted in transannular iodoamination accompanied by loss of the α-methyl-p-methoxybenzyl group to give the corresponding pyrrolizidine scaffold as a single diastereoisomer upon direct crystallization from the crude reaction mixture. Further functional group manipulations enabled the preparation of (-)-7a-epi-hyacinthacine A1.     

Conjugate addition of lithium N-phenyl-N-(α-methylbenzyl)amide: application to the asymmetric synthesis of (R)-(-)-angustureine

The conjugate addition of lithium (R)-N-phenyl-N-(α-methylbenzyl)amide to a range of α,β-unsaturated 4-methoxyphenyl esters proceeds with excellent levels of diastereoselectivity to give the corresponding β-amino esters in good yield and as single diastereoisomers (>99:1 dr). The synthetic utility of this methodology has been demonstrated via the short and concise asymmetric synthesis of the tetrahydroquinoline alkaloid (R)-(-)-angustureine in six steps and 32% overall yield from commercially available oct-2-enoic acid.     

First synthesis of polyoxin M

Chiral enolate derived from (4R)-4-tert-butyldiphenylsilyloxymethyl-4-butanolide 10 with lithium hexamethyldisilyazide (LiHMDS) was treated with trisyl azide, followed by addition of TMSCl to give (2S,4R)-2-azido-4-[(tert-butyldiphenylsilyloxy)methyl]-4-butanolide 8 (53%), from which the first total synthesis of polyoxin M (1) was achieved in overall 3.2% yield (13 steps) from d-glutamic acid. Moreover, the synthesis of the reported synthetic intermediate (2S,4R)-4-hydroxyornithine congener 6 for biphenomycins A and B was also achieved in overall 4.1% yield (12 steps) from d-glutamic acid.     

Lithiation of 3-(Acylamino)-2-unsubstituted-, 3-(Acylamino)-2-ethyl-, and 3-(Acylamino)-2-propyl-4(3H)-quinazolinones: Convenient Syntheses of More Complex Quinazolinones(1)

3-(Pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones react with alkyllithium reagents to give 1,2-addition products in very good yields. Lithiation takes place with LDA and is regioselective at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the corresponding substituted derivatives in very good yields. Reactions of the lithium reagents with iodine give oxidatively dimerized cyclic structures. 3-(Pivaloylamino)- and 3-(acetylamino)-2-ethyl-4(3H)-quinazolinones and 3-(pivaloylamino)- and 3-(acetylamino)-2-propyl-4(3H)-quinazolinones are lithiated at the benzylic position with LDA. The lithium reagents so produced also react with a variety of electrophiles to give the corresponding 2-substituted-4(3H)-quinazolinone derivatives in very good yields. However, lithiation of 3-(acylamino)-2-(1-methylethyl)-4(3H)-quinazolinones was unsuccessful, as were lithiations of compounds having a diacetylamino group at position 3. The amide groups have been cleaved in good yield under basic or acidic conditions from some of the products to provide access to the free amino compounds.     

Hypervalent tetracoordinate organobismuth compounds (10-Bi-4)

A stable hypervalent 10-Bi-4 species, tetraethylammonium bis[α,α-bis(trifluoromethyl)benzenemethanolato(2-)-C²],Obismuthanate(1-), was prepared by the reaction of bismuth trichloride with 2 equiv of lithium 2-(2-lithiophenyl)-2-propoxide derivatives. The ate complex was inert toward MeI, instead, the corresponding nonfluorinated analogue, bis[α,α-bis(dimethyl)benzenemethanolato(2-)-C², O]bismuthanate(1-), was reactive enough toward MeI to give O-methylated product. Regioselective methylation at the nonfluorinated methanolate was observed in the reaction of unsymmetrically substituted ate complex, [α,α-bis(dimethyl)benzenemethanolato(2-)-C², O[]α,α-bis(trifluoromethyl) benzenemethanolato(2-)-C², O]bis-muthanate(1-). Mechanism of isomerization of these ate complexes and related protonated compounds and the synthesis and stability of [α,α-bis(trifluoromethyl)-benzenemethanolato (2-) -C², O]diarylbismuthanate-(1-) were also described.     

Asymmetric lithiation of 2-alkynyl aryl sulfides—Enantio- and diastereoselective formation of allenyl aryl sulfides and their application in nickel-catalyzed cross-coupling reactions

The enantio- and diastereoselective synthesis of allenyl aryl sulfides by asymmetric lithiation of 2-alkynyl (2-hetero)aryl sulfides is described. A dynamic thermodynamic resolution by selective crystallization of the intermediate lithium complexes derived from deprotonation, applying a bis(oxazoline) ligand, was achieved to give enantioselectivities up to 85% ee. Subsequent stereospecific nickel-catalyzed cross-coupling reactions with arylzinc reagents established a versatile access to threefold carbon-substituted allenes.     

A new chiral lithium amide based on (S)-2-[1-(3,3-dimethyl)pyrrolidinylmethyl]pyrrolidine—synthesis,NMR studies and use in the enantioselective deprotonation of cyclohexene oxide

A new chiral lithium amide has been designed starting from (S)-proline. This new chiral lithium amide has been used for asymmetric deprotonation/ring opening of cyclohexene oxide to give (S)-2-cyclohexen-1-ol in 88% yield and 78% enantiomeric excess. NMR studies of the lithium amide and the ligand–substrate complex are also presented.     

Chemistry of α-halometalcompounds : A general method for obtaining epoxides from aldehydes and ketones

A general oxirane synthesis from a geminal dibromide and a carbonyl compound was studied. The reaction proceeds through an α-bromolithium species, most conveniently generated by reacting a geminal dihalogenide (e.g. ethylidene, isopropylidene, benzylidene bromide and ethyl dibromoacetate) and butyllitium or lithium suspended in THF. Aliphatic, alicyclic and aromatic aldehydes and ketones give rise to the corresponding epoxides, in good yields.