Palladium debenzylation with

Two isomers of chirally deuterated glycerol have been synthesized from a common boronic ester intermediate 1 (synthesis Section I.I.2.1.3.I.)71. (15,25)-Glycerol-l-fi results if the carbon to which the label is attached is derived from dibromomethane and incorporated into an a-bromo boronic ester intermediate 2, which is then reduced with potassium triisopropoxyborodeuteride to the (1 / ,2/ )-l-deutero boronic ester 3. The synthesis of (lS,25)-glycerol-l- / is completed efficiently by dcboronation with hydrogen peroxide and debenzylation with hydrogen over palladium. 

For synthesis decumbenine B, compound 2-14 was condensed with 2-7 in THF with LDA (lithium diisopropylamide) at -70°C followed by deprotonation with dilute hydrochloric acid. The desired intermediate 2-15 was obtained successfully in 49% yield. Lithium aluminum hydride reduction of 2-15 afforded the amine 2-16, which was converted to 2-17 by debenzylation with palladium on charcoal in acetic acid. The final step was dehydrogenation, after comparison with several reagents including palladium on charcoal in acetic acid and DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone)/l,4-dioxane, the best results were obtained by using DDQ/benzene. The yield of decumbenine B was 41% (Scheme 3). 

The piperidine was prepared from 2-(2-cyanoethyl)-butryraldehyde (470) via ketal 471, which was reduced with lithium aluminum hydride and reductively alkylated with benzaldehyde over 10% palladium on charcoal to 472. Acid hydrolysis led to spontaneous cyclization and formation of enamine 473. Treatment of this enamine with methyl bromoacetate and reduction of the iminium species with sodium borohydride gave the 1-benzyl-3,3-disubstituted piperidine 474 which was debenzylated with palladium charcoal under acidic conditions to give the desired piperidine, 466 (216). 

A second route to the 6H-pyrido[4,3-ft]carbazole nucleus of ellipticine involves as a key step the internal condensation of a 2-alkylskatolyl-piperidone. Le Goffic et al. (259) developed this synthesis in the 5,11-bisdemethyl series. When enamine 630 was condensed with 2-methyl-gramine (635), hydrolysis afforded the skatolylpiperidone (636). Cycliza-tion was carried out with glacial acetic acid under reflux, debenzylation with sodium/liquid ammonia, and dehydrogenation with palladium-charcoal to give 637. 

The synthesis pathway started with the lithiation of ethylbenzene 121 at the benzylic position, followed by acylation of the toluate anirni intermediate at low temperature. It is noteworthy that a potentially competing orf/io-lithiati(Mi of the type championed by Snieckus 85) i.e. between the two stabilizing methoxyl radicals) was not reported under these conditions. Subsequent reduction of benzyUcetone 122 provided smooth access to the t/irco-dimethyl-substituted bicy-clic intermediate 123 via lactonization. DIBAL reduction (—> 124) and reductive debenzylation with palladium on charcoal gave the ring-opened alcohol 125, which was further demethylated to provide a 1,3-diphenol, and then carboxylated under buffered conditions to yield acid 117, also known as phenol B . This compound was formylated with trimethyl orthoformate and acid, then cyclized to give the quinone structure and natural product, 116 (Scheme 3.1). 

A cold soln. of 2-oxobutyric acid in ethanol treated with L-(—)-a-methylhenzyl-amine in the same solvent, 10%-Pd-on-charcoal added, hydrogenated 10 hrs. at 30 /50 p.s.i. until 1 mole of has been absorbed, the catalyst removed by filtration, the filtrate coned., aq. 30%-alcohol and palladium hydroxide-on-charcoal added, then hydrogenated at 25 /50 p.s.i. until Hg-uptake ceases L-butyrine. Y 75.9-84.9% excess of enantiomorph 81.4%.— Debenzylation with other catalysts was not successful. Asym. induction occurs during reduction of the azomethine and debenzylation can be performed with little or no loss of configurational integrity. The configuration of the amino acids is the same as that of the a-methylbenzylamine from which it is derived. The magnitude of the induced asymmetry depends on the substrate and the catalyst. F. e. s. R. G. Hiskey and R. G. Northrop, Am. Soc. 83 4798 (1961) asym. synthesis of amino acids s. a. J. G. Sheehan and R. E. Chandler, Am. Soc. 83, 4795 (1961). 

In the synthesis of (lS,8aS)-(- -)-indolizidin-l-ol (88) by Chandrasekhar and coworkeis, the aldehyde 104 derived from D-glucose was converted in situ into the N-benzyHmine, to which was added but-3-enylmagnesium bromide to give the adduct (—)-105 as the sole diastereomer in 72% yield after chromatographic purification (Scheme 10). Protection of the amine as the Cbz carbamate and hydroboration—oxidation of the terminal alkene afforded alcohol (—)-106 which, after debenzylation with ammonium formate and palladium on carbon, needed to be re-protected with Cbz. 

Reaction of 10a and 11a with the aluminum amide prepared from MejAl and the (R)-phenethylamine and subsequent reduction step occurred with the same excellent anti/syn diastereoselection as precedently, leading respectively to anti amino alcohols 8a and 9a. These amino alcohols were obtained in an excellent purity from 10a (8a/9a = 93/7) and from 11a (9a/8a = 90/10). The stereoisomeric excess is the same as the enantiomeric excess of starting epoxy ethers. No racemization occurred in the reaction ring opening does not involve a carbenium ion, and no enolization occurs from intermediate A or B. Both enantiommc amino alcohols 12a and 13a were obtained by debenzylation with palladium hydroxide imfortunately, we have not been able to assign the absolute configuration of the asymmetric carbons of 8a and 9a (Scheme 7). 

Choice of catalyst and solvent allowed considerable flexibility in hydrogenation of 8. With calcium carbonate in ethanol-pyridine, the sole product was the trans isomer 9, but with barium sulfate in pure pyridine the reaction came to a virtual halt after absorption of 2 equiv of hydrogen and traws-2-[6-cyanohex-2(Z)-enyl]-3-(methoxycarbonyl)cyclopentanone (7) was obtained in 90% yield together with 10% of the dihydro compound. When palladium-on-carbon was used in ethyl acetate, a 1 1 mixture of cis and trans 9 was obtained on exhaustive hydrogenation (S6). It is noteworthy that in preparation of 7 debenzylation took precedence over double-bond saturation. 

Hydrogenation of 2-butoxy-3//-azepine (3) with palladium on charcoal and hydrogen affords 2-butoxy-4,5,6,7-tetrahydro-3f/-azepine (4),79 whereas reduction of the 2-benzyloxy derivative, under the same conditions, is accompanied by debenzylation and formation of hexahydroazepin-2-one (77% mp 67-69 C).79,241... 

Buchwald-Hartwig amination of iodobenzene 92 with 2-benzyloxy-4-methyl-aniline 93 affords the diarylamine 94 in high yield (Scheme 32). In this case the Goldberg coupling gives poor yields. Oxidative cyclization of compound 94 using stoichiometric amounts of palladium(II) acetate in acetic acid under reflux leads to the carbazole 95, which by reductive debenzylation provides... 

AcOH (step f) and N-acylation with a suitable fatty acid in the presence of 1,3-dicyclohexylcarbodiimide (DCC) (step g) provided the intermediate which after global debenzylation by hydrogenolysis in the presence of palladium on charcoal provided the desired lipid A mimetic (step h). 

Loperamide Loperamide, l-(4-chlorophenyl)-4-hydroxy-iV,iV-dimethyl-a,a-diphenyl-l-piperidinebutyramide (3.1.55), proposed here as an analgesic, is synthesized by the alkylation of 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) using iV,A-dimethyl(3,3-diphenyltetrahydro-2-furylidene)ammonium bromide (3.1.54) in the presence of a base. The 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) is synthesized by reacting l-benzylpiperidine-4-one (3.1.48) with 4-chlorophenylmagnesiumbromide, followed by debenzylation of the product (3.1.49) by hydrogenation using a palladium on carbon catalyst. 

A second way is by alkylation of 10,ll-dihydro-5H-dibenz[b,f]azepine with 3-(A-benzyl-A-methylamino)propyl chloride in the presence of sodium amide and the subsequent debenzylation of the resulting product (7.1.14) by hydrogenation using a palladium catalyst [21,22]. 

It is synthesized from 4-benzyloxypropiophenone, which undergoes bromination into 4-benzyloxy-a-bromopropiophenone (11.1.17). This is reacted with 2-(4-benzy-loxyphenyl)ethylamine, forming an intermediate product (11.1.18), which undergoes fnrther debenzylation by hydrogen nsing a palladium catalyst, giving ritodrine (11.1.19) [24,25]. 

A structurally unusual 3-blocker that uses a second molecule of itself as the substituent on nitrogen is included here in spite of the ubiquity of this class of compounds. Exhaustive hydrogenation of the chromone (13-1) leads to a reduction of both the double bond and the carbonyl group, as in the case of (11-2). The car-boxyhc acid is then reduced to an aldehyde (13-2) by means of diisobutylaluminum hydride. Reaction of that intermediate with the ylide from trimethylsulfonium iodide gives the oxirane (13-3) via the addition-displacement process discussed earlier (see Chapters 3 and 8). Treatment of an excess of that epoxide with benzylamine leads to the addition of two equivalents of that compound with each basic nitrogen (13-4). The product is then debenzylated by catalytic reduction over palladium to afford nebivolol (13-5) [16]. The presence of four chiral centers in the product predicts the existence of 16 chiral pairs. 

Epoxy sugars are frequently used as starting compounds in the synthesis of sugar derivatives (compare Section IV) such as halo, amino, azido, thio, deoxy, and branched-chain derivatives. The oxirane ring is in general more reactive than the oxetane or oxolane ring. It is opened with nucleophiles under base or acid catalysis. On the other hand, the oxirane ring remains unattacked under the conditions of catalytic debenzylation on palladium,... 

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