Total synthesis 3+2 reactions

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

We conclude this section with another description of a total synthesis, in which many reactions developed within the last decade have been applied. 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

In the total synthesis of the naturally occurring big molecule of palytoxin, which has numerous labile functional groups, this coupling is the most useful for the creation of E, Z-conjugated diene part 653. In this case, thallium hydroxide as a base accelerates the reaction 1000 times more than KOH[523]. Even TECOj can be used instead of a strong base in other cases[524]. 

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

The reaction can be applied to the synthesis of q, /3-unsaturated esters and lactones by treatment of the ketene silyl acetal 551 with an allyl carbonate in boiling MeCN[356]. The preparation of the q,, 3-unsaturated lactone 552 by this method has been used in the total synthesis of lauthisan[357]. 

The key step in the total synthesis of rhizobitoxine is the Pd-catalyzed exchange reaction of the methyl alkenyl ether moiety in 4 with the functionalized alcohol, although the yield is low[3]. The enol pyruvate 6 (a-ethoxyacrylic acid) is prepared by the reaction of methyl a-methoxyacrylate or a-methoxy-acrylic acid (5) with ethanol catalyzed by PdCl2(PhCN)2 at room temperature in the presence of CuCli and NaH2P04[4],... 

Covalent synthesis of complex molecules involves the reactive assembly of many atoms into subunits with aid of reagents and estabUshed as well as innovative reaction pathways. These subunits are then subjected to various reactions that will assemble the target molecule. These reaction schemes involve the protection of certain sensitive parts of the molecule while other parts are being reacted. Very complex molecules can be synthesized in this manner. A prime example of the success of this approach is the total synthesis of palytoxin, a poisonous substance found in marine soft corals (35). Other complex molecules synthesized by sequential addition of atoms and blocks of atoms include vitamin potentially anticancer KH-1 adenocarcinoma antigen,... 

Total Synthesis. Poor yields encountered duriag the manufacture of vitamin D stimulated early attempts to synthesize vitamin D. In 1959 Inhoffen synthesized vitamin from 3-methyl-2-(2-carboxyethyl)-2-cyclohexenone (40), uskig the Wittig reaction extensively (103). 

The total synthesis of caryophyllene and its Z-isomer involved a photochemical [2 + 2] cycloaddition reaction to generate the 4-membered ring and a fragmentation process Helv. Chim. Acta, 1951, 34, 2338) to establish the 9-membered ring. Caryophyllene and various oxygenated derivatives protect plants against insects. 

The initial observation that menthone reacts with amyl nitrite in the presence of base to give a good yield of an open-chain oximino ester was not expanded for synthetic purposes until Woodward almost forty years later utilized this reaction for the cleavage of a 7-keto-decahydroisoquinoline in the course of his total synthesis of quinine. 

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

The first application of the Jacobsen-Katsuki epoxidation reaction to kinetic resolution of prochiral olefins was nicely displayed in the total synthesis of (+)-teretifolione B by Jacobsen in 1995. 

Jacobsen-Katsuki epoxidation reaction in total synthesis Scheme 1.4.11... 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

A facile way of promoting the cyclization is to increase the nucleophilicity of the aryl system when possible. In the total synthesis of diazadiquinomycins A and B, for example, the authors were able to effect a double Knorr cyclization with concomitant in situ oxidation to the internal diquinone 23 by deprotecting the hydroquinone thereby lowering the activation barrier for the desired transformation. If the hydroquinone is left protected as the di-MOM ether, the reaction does not take place. ... 

The discovery of junipal focused the attention of Sorensen, who had been investigating the occurrence of polyacetylenes in Com-positae, on the possibility that these acetylenes were accompanied by thiophenes. From Coreopsis grandiflora Hogg ex sweet, 2-phenyl 5-(1-propynyl) thiophene (240) was isolated and its structure confirmed by synthesis of the tetrahydro compound, 2-phenyl-5-n-propyl-thiophene. From the root of tansy, the cis and trans isomers of methyl 5-(l-propynyl)-2-thienylacrylate (241) have been isolated. The total synthesis of trans (241) was achieved by reacting junipal with methylcarbethoxy triphenylphosphonium bromide (Wittig reaction) Several monosubstituted thiophenes, (242), (243), and... 

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

Heterocyclic and acyclic azadiene Diels-Alder reaction in total synthesis of nothapodyine B, alkaloid with antiviral activity 98JHC1003. 

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