Trans-debenzylation

Amino- and 2-acetamino-4-ferf-butyltoluene, in turn, are unreactive. In the case of 2,2,6,6,-tetramethyl-4,4 -di-fcrt-butyldiphenylmethane, trans-debenzylation competes with trans-terf-butylation. It was also observed in the ring closure of 2,2 -dihydroxybiphenyls276 (see Section 5.14.1.1). 

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. 

On the basis of fundamental experiments (see Section IV,A,2) some indenobenzazepine alkaloids have been efficiently synthesized from the corresponding protoberberines via 8,14-cycloberbines. For example, the cycloberbine 428 derived from the protoberberine 427 was heated with methanesulfonic acid in aqueous tetrahydrofuran to afford a 2 1 mixture of cis- and trans-indenobenzazepines 429 in 92% yield (Scheme 85). The mixture was methylated with methyl iodide to give the cts-N-methyl derivative 430 and the unchanged trans secondary amine (21%), which was very difficult to methylate and which gave the /V-methyl derivative only in 6% yield even on treatment with dimethyl sulfate for 43 hr. Contrary to the ordinary cases (Section IV,A,2), the trans derivative did not isomerize to the cis isomer 430 under various acidic conditions. Debenzylation of 430 by hydrogenolysis afforded fumarofine (417), which was converted to O-methylfumarofine (316) by methylation with diazomethane (215). 

The enantioselective preparation of trans-2,4-disubstituted azetidines 4 by treatment of 3 with methanesulfonyl chloride and triethylamine followed by benzylamine at 45 °C has been reported. A-Arylation of the debenzylated 4 has given 5 in yields of 32-96% by use of rac-Binap and moderate reaction temperatures to suppress racemization of the amines . Azetidines can also be formed from certain oxetanes (see 4.2.3) and from P-Iactams (see 4.3 and 4.6) <99JOC9596>. 

Conversion of the resulting separate D-seco D-E trans i-vincadiffor-mine diols 198-201 to their primary tosylates and tertiary trimethylsilyl-oxy derivatives 202-205 and coupling to vindoline by the chlorination-silver tetrafluoroborate-potassium borohydride sequence provided amino tosylates 206-209, which could be directly subjected to cyclization or, alternatively, converted to the C-20 -C-21 epoxides 178, 181, 210, and 211 by reaction with tetrabutylammonium fluoride (Scheme 53). While cyclization of the tosylates 206-209 led essentially only to quaternary salts which could be debenzylated to provide the lower energy atropi-somer of vinblastine (1), leurosidine (56), vincovaline (184), and its C-20 epimer (212) respectively, cyclization of the epoxides 178, 181, 210, and... 

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive de-cyanation (596) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH4 in MeOH led to predominant (8 2) formation of the trans isomer (232) which was then debenzylated to ( )-solenopsin A (Id). The cis product (Ic) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by de-benzylation (Scheme 10). 

The structures of the ds-hydroindole 130 (Ar = Ph) and the trans-hydroindole 131 (Ar = Ph) were established by their conversion to ( )-a- and ( )-(3-lycorane (57 and 58), respectively. In the event, catalytic hydrogenation of the double bond in the hydroindoles 130 and 131 (Ar = Ph) over 5% Pd/C in AcOH proceeded with concomitant N-debenzylation to provide the corresponding secondary amines, which were then allowed to react with methyl chloroformate to furnish the corresponding carbamates 132 and 133. On heating in POCl3, 132 and 133 underwent Bischler-Napieralski cyclization to provide the 7-oxo-a- and -(3-lycoranes 134 and 135, which were then converted to 57 and 58, respectively, by reduction with LiAlH4. 

A mixture of l-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinone (140 mg), benzylamine (61 mg), Pd 10% on charcoal (100 mg) and a 0.02% solution of thiophene in THF was reacted under hydrogen gas for 3 hours at 50°C. The catalyst was filtered off and fresh palladium 10% on charcoal (100 mg) was added. Debenzylation of the formed intermediate took place under hydrogen atmosphere for 18 hours at 50°C. The reaction mixture was filtered and evaporated under a stream of nitrogen to yield l-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine having a cis/trans ratio of about 93/7. 

This intermediate was alkylated with tert. -butyI-cj-iodohexanoate to the ester 30. Conversion to the acid 31 was achieved by cleavage of the fed.-butylester with trifluoroacetic acid at low temperature. The triple bond was reduced to a trans-double bond and simultanously the benzylether groups had been removed with lithium in ethylamine, under formation of the desired 15-deoxy-7-oxaprostaglandin Fla 32 in crystalline form. The ds-isomer was prepared by first reducing the triple bond of compound 30 with palladium on barium sulfate to 33, removal of the ted. -butylgroup with formic acid to 34 and debenzylation of the acid with lithium in ethylamine to 35. 

Gratifyingly, when imine 55 was reduced with NaCNBH3, a 12 1 ratio of the cis/trans esters 56 57 was obtained. The authentic reference products had been synthesized by debenzylation of known cis ester 2 and... 

Some specific compounds might be mentioned. A method has been devised for the preparation of optically active (2-aminopropyl)phosphonic acid by a procedure involving initial addition of optically active 1-phenylethylamine to a dialkyl (l,2-propadiene)phosphonate. This produces a mixture of cis and trans (aminoalkene)phosphonates which is reduced and the product hydrolysed and debenzylated. ... 

Benzyloxy derivative 764a can be transformed to the carbapenem antibiotic ( + )-PS-5 (758) as shown in Scheme 101. The first required manipulation is removal of the benzyloxy group in the 3-position, which is accomplished by reductive debenzylation, conversion of the resultant hydroxy group to a xanthate, and Barton deoxygenation. Next, enolate formation with LDA followed by alkylation with four equivalents of ethyl iodode gives the trans-3,4-disubstituted j5-lactam 766. Removal of the PMP group with CAN furnishes intermediate 753, which is required for completion of the synthesis of ( + )-PS-5. 

Chromatographic separation of this mixture provides the two diastereomers 401 and 402 in 46% yield and in gram quantities. The highly selective catalytic hydrogenation of 401 in the presence of platinum on charcoal followed by reductive debenzylation in the presence of palladium on charcoal provides a mixture of L-nZ o-403 (3,5-trans) and L-xy/o-404 (3,5-cw) in a diastereomeric ratio of 93 7. Similarly, 402 in two steps affords L-lyxo-405 (3,5-trans) and L-arabino-406 (3,5-cis) in a diastereomeric ratio of 80 20. With the ready availability of (R)-390, the corresponding D-series compounds can be prepared with similar diastereochemical results [136] (Scheme 90). 

Cyclic Disulphides and Cyclic Diselenides.—Formation. No fundamentally new methods of synthesis of this class of compounds have been reported in the past two years. For l,2>dithiolan the oxidation of l,3>dithiols remains a favoured method, the use of iodine in the presence of triethylamine leading smoothly to 1,2-dithiolans without attendant polymerization. cis- and tra/ -l,2-Dithiolan-3,5-dicarboxylic acids were prepared from a diastereo-isomeric mixture of dimethyl 2,4-dibromoglutarates by sequential treatment with potassium thioacetate and potassium hydroxide in the presence of iodine,and jyn-2,3-dithiabicyclo[3,2,l]octan-8-ol was formed from 2,6-dibromocyclohexanone by successive treatment with potassium thiocyanate, lithium aluminium hydride, and iodine. The stereoselective formation of the less thermodynamically stable alcohol in this case was attributed partly to the formation of chelates with sulphur-aluminium bonds. 2,2-Dimethyl-l,3-dibromopropane was converted into 4,4-dimethyl-l,2-diselenolan on treatment with potassium selenocyanate at 175 °C, but at 140 °C the product was 3,3-dimethylselenetan. Reductive debenzylation of 2-alkylamino-l,3-bis(benzylthio)propanes with lithium in liquid ammonia and oxidation of the resultant dithiols with air afforded 4-dialkylamino-l,2-dithiolans, whilst treatment of a-bromomethyl-chalcone with sodium hydrosulphide gave, as minor product, trans-3 phenyl-4-benzoyl-l,2-dithiolan. Among the many products of thermal decomposition of /ra/ -2,4-diphenylthietan was l,4,5,7-tetraphenyl-2,3-dithiabicyclo [2,2,2]octane. ... 

Alkylation via enamine 18 and successive alkaline hydrolysis furnished 2-oxo-cyclohexylacelic acid derivative 19. Refluxing keto acid with benzylamine in orf/io-xylene and then in 87 % formic acid yielded unsaturated lactame 20. Catalytic hydrogenation of the C=C bond afforded trans,cis 21 as the sole stereoisomeric product. In the last steps, reduction of lactame by a complex hydride, hydrogenolytic debenzylation and the Pictet-Spengler reaction gave ( )-a-lycorane TM 9.4 in a moderate overall yield. 

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