Reduction, acid chlorides lactams

Alternatively, the imide-acid chloride is reacted with methanol to give the imide ester which, after borohydride reduction and triethylsilane/trifluoroacetic acid treatment, furnishes the bicyclic lactam 6 as a racemate. The latter is acylated with either propanoyl chloride or 3-phcnylpropanoyl chloride and the resulting amides 7 deprotonated and alkylated with (bro-momethyljbenzene or iodomethane, respectively, to give the major alkylation products 8 with d.r. >98 2 and in 65% yield3. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

R)-3-(4-fluorophenyl)-2-hydroxy propionic acid 1 is a building block for the synthesis of Rupintrivir, a rhinovirus protease inhibitor currently in human clinical trials to treat the common cold (Fig. 1) [1, 2], Retrosynthetically, Rupintrivir was prepared from four fragments the lactam derivative Pi, the chiral 2-hydroxy acid P2 (compound 1), the valine derivative P3, and an isoxazole acid chloride P4 (Fig. 1). In this chapter the preparation of 1 using a biocatalytic reduction performed in a membrane reactor will be discussed in detail. 

The ethylene ketal of 168 was reduced with lithium aluminum hydride in dioxane and then hydrolysed to the amino ketone 169. Treatment of 169 with acrylyl chloride and triethylamine gave the acrylamide 170 containing all the carbons of the lycopodine system. Oyclization to the tetracyclic system shown in 171 occurred when 170 was refluxed in toluene containing p-toluenesulfonic acid. Reduction of the lactam with lithium aluminum hydride in THE followed by Jones oxidation of the product gave racemic 12-epilycopodine (4) identical in spectroscopic properties with the enantiomer derived by reduction of anhydrolycodoline. 

As the first example of the application of our methodology, we picked yohimbine and alloyohimbine. The enamide was prepared from harmalane by acylation with p-methoxybenzoyl chloride and irradiated according to the established reductive photocyclization condition to afford the lactam with a methoxy-substituted dihydrobenzene moiety, which then underwent a facile hydrolytic cleavage to give the corresponding ketone. After reduction of the lactam carbonyl, acid treatment converted the enol ether into the 6,y -unsaturated ketone in good yield. 

One could envision reduction of the lactam carbonyl of 1 to an aldehyde equivalent, that would then, imder acidic conditions, condense to form the desired aminal 2. This approach was, however, not successful. As an alternative, conditions were developed to convert 1 to the amidine 16. Reduction then proceeded with the expected high diastereocontrol, to give the cis 1,3-fused aminal 2. This was not isolated, hut was directly acylated with acryloyl chloride, to 17. 

An early application of enamide photocyclizations to yohimbine alkaloid synthesis is illustrated by Ninomiya and coworkers synthesis of yohimbane (120), epiyohimbane (347) and alloyohimbane (82) (Scheme 3.57) (61, 63, 69). These compounds were prepared by a short sequence starting with har-malane (336) which was condensed with acid chloride 341 to provide enamide 342. Irradiation of 342 in benzene followed by reduction afforded a mixture of the stereoisomeric pentacyclic lactams 344, 345, and 346 which were reduced to provide yohimbane (120), epiyohimbane (347), and alloyohimbane (82), respectively. While the yield of the photocyclization process was modest, this route demonstrated how enamide photocyclizations can be used to rapidly construct pentacyclic yohimbane targets. 

A new total synthesis of flavopereirine perchlorate (148) has been reported by Ninomiya et al. (109) via enamide photocyclization. Harmalane (150) was acy-lated with 3-methoxyethacryloyl chloride to enamide 151 which was irradiated in benzene solution without purification to yield the unstable lactam 152. The latter was treated with hydrochloric acid, resulting in dehydrolactam 153 in a yield of 35% from harmalane (150). Lithium aluminum hydride reduction of 153, followed by dehydrogenation, afforded flavopereirine (148), isolated as its perchlorate (109). 

In a similar manner to that described for bicyclic lactams (Section 1.1.1.3.3.4.1.5.I.). alkylation reactions of tricyclic lactams, which contain a fused benzene ring adjacent to the carbon undergoing alkylation, have been exploited14. The first alkylation of the benzo-annulated bicyclic lactam 1 gives a mixture of diastereomers, which is then further alkylated. In the second alkylation step, the counterion on the alkoxide, which is formed prior to enolate formation, proved to be crucial for the diastereoselectivity of the subsequent alkylation reaction. The best diastcrcoselectivity was obtained when either dichlorobis(ij5-cyclopentadienyl)zirconium or triisopropoxytitanium chloride was added to the preformed alkoxide, followed by enolization and alkylation. Using this method the second alkylation step gives a satisfactory diastereoselectivity. Hydride reduction of the purified major diastereomer 2, followed by acid treatment of the product, furnishes chiral naphthalenones 414. 

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

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