Total synthesis of natural and unnatural lamellarins with saturated and unsaturated D-rings

Twenty-eight natural and unnatural lamellarins with either a saturated or an unsaturated D-ring were synthesized according to our developed synthetic route. The key step involved the Michael addition/ring closure (Mi-RC) of the benzyldihydroisoquinoline and alpha-nitrocinnamate derivatives, which provided the 2-carboethoxypyrrole intermediates in moderate to good yields (up to 78% yield). Subsequent hydrogenolysis/lactonization furnished lamellarins with a saturated D-ring in excellent yields (up to 93% yield). DDQ oxidation of the saturated lamellarin acetates led directly to the corresponding unsaturated analogues in 54-95% yield. In addition, only two steps in our developed strategy require column chromatography.     

Further developments in the synthesis of lamellarin alkaloids via direct metal-halogen exchange

Direct metal-halogen exchange of 2-bromopyrrole carbonate derivatives with tert-butyllithium followed by the intramolecular lactonization of the resulting 2-pyrrole anion onto the carbonate provided the corresponding lamellarins in moderate to good yield. The lamellarin framework could be obtained from the direct metal-halogen exchange strategy in a 26-33% overall yield over 5-6 steps.     

Titanocene(III) chloride mediated radical-induced addition to Baylis-Hillman adducts: synthesis of (E)- and (Z)-trisubstituted alkenes and alpha-methylene/arylidene delta-lactones

Baylis-Hillman adduct underwent smooth radical-induced condensation with activated bromo compounds and epoxides using titanocene(III) chloride (Cp2TiCl) as the radical generator. The reactions of activated bromo compounds with 3-acetoxy-2-methylene alkanoates provided (E)-alkenes exclusively, whereas similar reactions with 3-acetoxy-2-methylenealkanenitriles led to (Z)-alkenes as the major product. The reactions of epoxides with Baylis-Hillman adduct furnished alpha-methylene/arylidene-delta-lactones in good yield via addition followed by in situ lactonization.     

Palladium-catalyzed coupling reaction of terminal alkynes with aryl iodides in the presence of indium tribromide and its application to a one-pot synthesis of 2-phenylindole

The use of a novel PdCl(2)(PPh(3))(2)-InBr(3) reagent system to catalyze cross-coupling reactions of a variety of aryl iodides with several terminal alkynes is described. The corresponding functional alkyne derivatives were produced in good to excellent yields. Moreover, a catalytic amount of InBr(3) effectively catalyzes the intramolecular cycloaddition of 2-phenylethynylaniline to form an indole skeleton in high yield.     

Synthesis of fused uracils: pyrano[2,3-d]pyrimidines and 1,4-bis(pyrano[2,3-d]pyrimidinyl)benzenes by domino Knoevenagel/Diels-Alder reactions

Abstract  

Knoevenagel condensation of barbituric acids with aromatic aldehydes containing one or two formyl groups was carried out. 5-Arylidenebarbituric acids underwent smooth hetero-Diels-Alder (HDA) reactions with enol ethers to afford cis and trans diastereoisomers of pyrano[2,3-d]pyrimidine-2,4-diones and 5,5′-(1,4-phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives in excellent yields (75–88 %). Syntheses were realized by Knoevenagel condensation and HDA reaction in four different reaction conditions: Knoevenagel condensation in water and Diels-Alder reaction in methylene chloride solution, Knoevenagel condensation in water and Diels-Alder reaction without solvent, three-component one-pot reaction in methylene chloride solution, or three-component one-pot reaction in water. All reactions were carried out without catalyst at room temperature. The reactions of malononitrile with Knoevenagel condensation products of barbituric acids and heteroaromatic aldehydes or terephthalaldehyde were examined and did not provide corresponding pyranopyrimidines.     

Lewis Acid-Catalyzed Intramolecular [2 + 2] Cycloaddition of alpha-Ester-Substituted Conjugated Dienyl- and Trienylphosphonates. New Synthesis of Functionalized Cyclic Terpenoids

alpha-Ester-substituted 1,3-dienylphosphonates 7 and 8, prepared by the Knoevenagel condensation, underwent intramolecular [2 + 2] cycloaddition in the presence of Lewis acid to form bicyclo[4.2.0] (26-57% yield) and bicyclo[3.2.0]skeleton (14-38% yield), respectively. Similar treatment of homologous 1,3-dienylphosphonate 11 and 1,3,5-trienylphosphonate 12 resulted in the formation of ionone derivatives (30-94% yield). The intramolecular cycloaddition reaction was applicable to several conjugated dienes bearing an ester group.     

Nickel nanoparticles catalyzed chemoselective Knoevenagel condensation of Meldrum’s acid and tandem enol lactonizations via cascade cyclization sequence

A novel protocol has been reported wherein, polyethylene glycol (PEG) stabilized nickel nanoparticles have been used as catalyst for chemoselective Knoevenagel condensation of aromatic aldehydes and Meldrum’s acid to give 5-arylidene Meldrum’s acid which underwent tandem enol lactonization by Michael addition/cyclization sequence with active methylene compounds in the presence of Ni nanoparticles to give corresponding enol lactone derivatives.     

Synthesis and Reactions of Enediynes and Enyne-Allenes

The thermal cycloaromatization reactions of (Z)-3-hexene-1,5-diynes (enediynes) and (Z)-1,2,4-heptatrien-6-ynes (enyne-allenes) provide easy entries to a variety of carbon biradicals. Several new synthetic routes to these highly unsaturated compounds were developed by using multifunctional reagents properly substituted with combinations of boron, silicon, and tin appendages. Condensation of γ-(trialkylsilyl)allenylboranes 1 and 2 with conjugated acetylenic and allenic aldehydes followed by the elimination step of the Peterson olefination reaction furnished enediynes and enyne-allenes with high geometric purity. Convenient procedures for the synthesis of enediynes and enyne-allenes were also developed by using alkenylboronic ester 28 and the trimethyltin-substituted alkenylboranes 34 for cross-coupling reactions. On heating, acyclic enyne-allene 22 underwent a sequence of intramolecular transformations through biradical intermediates to form 26 , providing a new example of a one-step 0 → ABCD ring construction of the tetracyclic-steroidal skeleton.     

1,5-Electrocyclisation of azomethine ylides leading to pyrrolo[2,1-a]isoquinolines—concise construction of the lamellarin skeleton

A new, general route to the 1,2-diaryl-substituted pyrrolo[2,1-a]isoquinolines has been developed via the 1,5-dipolar electrocyclisation reactions of azomethine ylides derived from readily available stilbenic acid derivatives. This method was applied to the concise construction of a lamellarin skeleton.     

The chemistry of homophthalic acid: a new synthetic strategy for construction of substituted isocoumarin and indole skeletons

Homophthalic acid was reacted with thionylchloride/DMF and chloroethylformate/NEt₃ in the presence and absence of NaN₃. In all cases completely different isocoumarin derivatives were obtained. These unusual isocoumarin derivatives were isolated and characterized and their formation mechanisms are discussed. The homophthalic acid monomethyl ester was converted into the corresponding isocyanate. Reaction of the isocyanate with different amines produced the urea derivatives. Base-supported condensation reactions of these products gave first an indolinone derivative, which underwent further intermolecular condensation to give substituted indole derivatives. However, when the condensation reaction was carried out in the presence of acetic anhydride, the intermolecular reactions were suppressed. This methodology opens up a new way of synthesizing of various five-membered ring substituted indole derivatives.     

Polymer Supported Synthesis of 2,3,4,6-Tetra-O-Acetyl-β-D-Glucopyranosyl Esters of Aromatic Carboxylic Acids

Aromatic carboxylic acids bound to Amberlyst A-26 react with α-acetobromoglucose to form 2,3,4,6-tetra-O-acetyl-1-0-aroyl-β-D-glucopy ranose derivatives in good yield. Glucosylation occurs satisfactorily with carboxylic acids and nitrophenols (pKa 7–4), but not with phenols whose pKa values are higher (pka ～ 10). Selective glucosylation at the carboxylic group is easily achieved in the case of phenolic acids.     

The application of ANS modified Amberlyst A-26 anion-exchange resin for the preseparation of silver before its determination by atomic absorption spectrometry

Summary A new chelate-forming resin was prepared from Amberlyst A-26 and 8-amino-naphthalene-2-sulphonic acid (ANS). ANS-loaded resin is stable and resistant to mineral acid. The application of the resin to the determination of silver in copper ore is described.

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Anwendung von ANS-modifiziertem Anionenaustauscher Amberlyst A-26 zur Abtrennung von Silber vor dessen bestimmung mit AAS

Zusammenfassung Ein neues komplexbildendes Harz wurde aus Amberlyst A-26 und 8-Aminonaphthalin-2-sulfonsäure (ANS) hergestellt. Dieses mit ANS beladene Harz ist stabil und widerstandsfähig gegen Mineralsäuren. Die Anwendung zur Silberbestimmung mit AAS in Kupfererzen wird beschrieben.

     

Cyclization of functionalized ketene-N,S-acetals to substituted pyrroles: applications in the synthesis of marine pyrrole alkaloids

α-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinates with β-oxodithiocarboxylates followed by alkylation, underwent cyclization in the presence of the Vilsmeier reagent to afford alkyl 3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates in excellent yields. When the reaction was extended to β-oxodithiocarboxylates derived from deoxyanisoin, 3,4-diarylpyrrole-2-carboxylates, the key intermediates in the synthesis of lukianol A and lamellarin Q were formed.     

Transformation of β-Nitrostyrenes to Carboxylic Acids Using Amberlyst A-26 Supported Hydroperoxide

Summary.  Nitrostyrenes are conveniently converted to the corresponding carboxylic acids in high yields at room temperature with Amberlyst A-26 supported hydroperoxide which is prepared in situ from 35% hydrogen peroxide and amberlyst A-26 (OH⁻). Corresponding authors. E-mail: mlakouraj@yahoo.com Received October 5, 2001. Accepted November 28, 2001     

Formal total synthesis of the potent renin inhibitor aliskiren: application of a SmI2-promoted acyl-like radical coupling

A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based class of protease inhibitors. The thioester derivative of the amino acid representing the C5-C9 fragment of the aliskiren carbon skeleton underwent a carbon chain extension via a SmI2-promoted radical addition to n-butyl acrylate. Introduction of the C3-isopropyl group with the correct relative configuration was accomplished via stereoselective reduction of the obtained ketone with concomitant lactonization, followed by an aldol reaction with acetone. Further functional group and protecting group manipulation culminated in a formal total synthesis of aliskiren in 10 steps from the corresponding fully protected non-natural amino acid.     

天然产物Combretastatin A-1和Combretastatin B-1的合成

基于Perkin反应策略合成了具有强效抗肿瘤、抗血管活性的天然产物Combretastatin A-1(CA1)和Combretastatin B-1(CB1).以2,3,4-三羟基苯甲醛(1)为起始物, 经单甲基化反应得到2,3-二羟基-4-甲氧基苯甲醛(2), 再经酚羟基保护得到2,3-二异丙基-4-甲氧基苯甲醛(3), 该化合物与3,4,5-三甲氧基苯乙酸(4)发生Perkin反应分离得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5), 经脱羧反应得到Z-3,4,4',5-四甲氧基-2',3'-二异丙氧基二苯乙烯(6), 最后经脱保护反应得到CA1.另外, 将E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5)脱去保护基得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二羟基-4'-甲氧基)丙烯酸(7), 该化合物经脱羧-异构化反应得到E-3,4,4',5-四甲氧基-2',3'-二羟基二苯乙烯(E-CA1), 最后经催化氢化得到CB1.     

Conformationally constrained beta-amino acid derivatives by intramolecular [2 + 2]-photocycloaddition of a tetronic acid amide and subsequent lactone ring opening

[reaction: see text] The N-Boc-protected N-3-alkenyltetronic acid amides 9 and 12 were prepared from tetronic acid bromide (7) and the corresponding amines 6 and 10 by nucleophilic substitution and subsequent acylation in 71% and 39% overall yield. They underwent an intramolecular [2 + 2]-photocycloaddition upon direct irradiation (lambda = 254 nm) to yield diastereoselectively the strained lactones 15 (76%) and 16 (91%) with a 2-azabicyclo[3.2.0]heptane core. In attempts to defunctionalize the 1-hydroxymethyl substituent of the 2-azabicyclo[3.2.0]heptane skeleton, lactone 15 was converted into mesylate 18 (74% overall yield). Intermolecular substitution reactions on this mesylate, however, proceeded sluggishly or failed completely. Lactone 15 could be opened reductively (Dibal-H) or by substitution with benzylamine to the N-Boc-protected 2-azabicyclo[3.2.0]heptanes 21 (71%) and 22 (81%). Conformationally constrained beta-amino acid derivatives were obtained by quantitative N-Boc deprotection of photocycloaddition product 15, followed by N-functionalization and subsequent lactone ring opening. The N-functionalization was conducted by acylation (to 24-26), alkylation (to 27), tosylation (to 28), and isocyanate addition (to 30). The reactions proceeded in yields of 70-84%. Lactone ring opening reactions were conducted with amines to establish the suitability of this process for library synthesis. As an example, the tripeptide 38 was obtained from photocycloaddition product 15 in an overall yield of 51%.     

An oxazaphospholidine approach for the stereocontrolled synthesis of oligonucleoside phosphorothioates

The stereocontrolled synthesis of oligodeoxyribonucleoside phosphorothioates (PS-ODNs) using nucleoside 3'-O-oxazaphospholidine derivatives as monomer units is described. 2-Chloro-1,3,2-oxazaphospholidine derivatives were prepared from six kinds of enantiopure 1,2-amino alcohols and used for the phosphitylation reactions of 5'-O-protected nucleosides. A detailed study of these reactions revealed that the diastereoselectivity of the reaction depended on the structure of the enantiopure 1,2-amino alcohol, the reaction temperature, and the amine used as a scavenger of HCl. In addition, ab initio molecular orbital calculations for the 2-chlorooxazaphospholidine derivatives were carried out to elucidate the mechanism of these diastereoselective phosphitylation reactions. The LUMO of the 2-chloro-5-phenyloxazaphospholidine derivatives on the phosphorus atom was found to be almost orthogonal to the P-Cl bond. This LUMO may be involved in the phosphitylation reactions with predominant retention of the P-configuration. A series of dialkyl(cyanomethyl)ammonium salts were developed and used as activators for the condensation reactions of the diastereopure nucleoside 3'-O-oxazaphospholidines with 3'-O-protected nucleosides. In the presence of the new activators, the reactions proceeded rapidly to give the corresponding dinucleoside phosphite triesters. The diastereoselectivity of the condensation reaction did not depend on the counteranion but on the structure of the dialkyl(cyanomethyl)amine. In the presence of the activator, which consists of a relatively small dialkyl(cyanomethyl)amine, the condensation proceeded with excellent diastereoselectivity. After sulfurization and deprotection, diastereopure (R(p))- and (S(p))-dinucleoside phosphorothioates were obtained in excellent yields. The present methodology was also applied to the solid-phase synthesis of stereoregulated PS-ODNs. all-(R(p))-[T(PS)](3)T, all-(S(p))-[T(PS)](3)T, all-(R(p))-d[G(PS)A(PS)C(PS)]T, and all-(R(p))-[T(PS)](9)T were synthesized on a highly cross-linked polystyrene resin.     

Preparation of new nitrogen-bridged heterocycles 72. A new approach to 1-acyl-3-(substituted methylthio)thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives. [corrected

The alkaline treatment of the pyridinium salts, readily available from the S-alkylations of 3-amino-4-(1-pyridinio)thiophene-5-thiolates with various alkyl halides, in chloroform at room temperature afforded the corresponding thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives in low to moderate yields via the intramolecular cyclization of the resulting 1,5-dipoles followed by the aromatization of the primary cycloadducts. Interestingly, the reactions using unsymmetrical 3-amino-4-[1-(3-methylpyridinio)]thiophene-5-thiolates afforded only 8-methylthieno[3',4':4,5]imidazo[1,2-a]pyridines and the other 6-methyl derivatives were not formed at all. In addition the isolation of a byproduct in the condensation reaction of pyridinium salt with the solvent (CHCl?) is also discussed.     

Stereoselective synthesis of constrained oxacyclic hydroxyethylene isosteres of aspartyl protease inhibitors. Nitroaldol methodology toward 2,3-substituted tetrahydrofurans

The Shibasaki heterobimetallic Binol lanthanide, and Trost dinuclear zinc catalysts were studied in a nitroaldol reaction of 3-methyl-1-nitrobutane with a chiral non-racemic tetrahydrofuran aldehyde. Other methods utilized KF, Amberlyst A-21, and t-BuOK as bases for the same nitroaldol reaction. The major isomer in the Binol lanthanide and dinuclear zinc catalyzed reactions was the syn/syn-nitroaldol product. Structures were confirmed by single-crystal X-ray crystallography. The major nitroaldol isomer was converted to a 2,3-substituted tetrahydrofuran 2-carboxylic acid containing a γ,δ-amino alcohol branch, corresponding to a constrained oxacyclic analogue of a hydroxyethylene isostere of aspartyl protease inhibitors.