Lithium lactam reduction with

Preparation of nefopam starts with the acylation of aminobenzhydrol 1 (obtainable by reduction of the corresponding benzoylbenzamide) with chloroacetyl chloride treatment of the chloroamide (2) with potassium tertiary butoxide results in internal alkylation to give the eight-membered ring (3). Reduction of the lactam function with lithium aluminum hydride gives the amine and, thus, nefopam (4). ... 

Ozonolysis of alkene 446 in the presence of acetaldehyde afforded diketone 448 through the intermediacy of 447. Ring expansion through Beckmann rearrangement took place when bis-oxime 449 was mesylated and warmed in aqueous tetrahydrofuran (THF). The bis-lactam so formed gave piperidinediol 450 on reduction with lithium aluminium hydride, and this compound was transformed into ( )-sparteine by treatment with triphenylphosphine, CCI4, and triethylamine (Scheme 105) <20050BC1557>. 

Reduction of o /i-unsatin-ated lactams, S,6-dihydro-2-pyridones, with lithium aluminum hydride, lithium alkoxyaluminum hydrides and alane gave the corresponding piperidines. 5-Methyl-5,6-dihydro-2-pyridone (with no substituent on nitrogen) gave on reduction with lithium aluminum hydride in tetrahydrofuran only 9% yield of 2-methylpiperidine, but l,6-dimethyl-5,6-dihydro-2-pyridone and 6-methyl-l-phenyl-5,6-dihydro-2-pyridone afforded 1,2-dimethylpiperidine and 2-methyl-1-phenylpiperidine in respective yields of 47% and 65% with an excess of lithium aluminum hydride, and 91% and 92% with alane generated from lithium aluminum hydride and aluminum chloride in ether. Lithium mono-, di- and triethoxyaluminum hydrides also gave satisfactory yields (45-84%) [7752]. 

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

Reduction of hydroxy lactams (154) with a complex of DIBAL and butyl-lithium gave an inseparable mixture of perhydropyrido[2,l-b][l,3]oxazines (155) (92TL507). When Red-Al was used as a reducing agent, side products... 

Although more rare, the ring opening of A-acyl (3-lactams has also been realized by using hydrides, giving rise to the corresponding reduction products. In this context, Scheme 40, Lee and Pak [107] have described the treatment of A-Boc (3-lactam 119 with lithium aluminium hydride to give A-protected amino alcohol 120. Compound 120 could serve as potential intermediate for the synthesis of various hydroxylated indolizidine alkaloids. 

Protopine has been isolated from Bocconia frutescens,110 Fumaria judaica,111 F. schleicheri,112 and Papaver bracteatum,146 cryptopine from F. schleicheri,112 and allocryptopine from B. frutescens110 and Zanthoxylum nitidum.141 The protopine ring-system has been prepared from tetrahydrobenzindenoazepines (75) by photo-oxidation to the amides (76) followed by reduction with lithium aluminium hydride and re-oxidation with manganese dioxide.148-150 The tetrahydrobenzindenoazepines have been prepared from A-chloroacetyl-/ -phenylethylamines (73) by cyclization to the lactam (74) followed by reaction with a benzyl bromide and phosphorus oxychloride. -Protopine (77 R R2 — CH2)148 and fagarine II (77 R1 = R2 = Me)149 have been synthesized in this way. 

Following preliminary work,528 ( )-chelidonine (118) has been synthesized from the acid (115) (obtained from methylenedioxyhomophthalic anhydride and TV-methyldimethoxybenzalimine) by its conversion into the diazo-ketone (116), cyclization of this (using trifluoroacetic acid) to the keto-lactam (117), and reduction with lithium aluminium hydride.529,530... 

Alternatively, yohimban and alloyohimban were also synthesized via the route of reduction with lithium aluminum hydride of the conjugated lactam (193), followed by catalytic hydrogenation. 

The use of 1,1-diiodomethane as an electrophile in the Birch reduction (with lithium in liquid ammonia) of electron-deficient pyrroles 915 furnished pyrrolines 916 (in high to excellent yields), which provided access to the synthetically important functionalized 5,6-dihydro-2(l//)-pyridinones 917 (via radical ring expansion), substructures commonly found in biologically active natural products (Scheme 177) <2004CC1422>. 2-(Chloroalkyl)-substituted pyrrolines 919 were duly prepared by the reductive alkylation (with l-chloro-3-iodopropane or 1-chloro -iodobu-tane) of electron-deficient pyrrole 918. Allylic oxidation then furnished lactams 920 (Scheme 178). 

Treatment of lactam 258 with /-BuLi followed by reaction with trans 2-phenylsulfonyl-3-(/i-nitrophenyl)oxazir-idine 259 and lithium aluminium hydride (LAH) reduction gave the hydropiperidine 260 in 61% yield <2002JA11689>. Interestingly, the nitro group apparently does not interfere with the hydroxylation. 

Disubstituted pyrrolidinones are formed when the bicyclic lactam is tieaiedvjith AllyltrimethylsilanelJitaniumilV) Chloride. The remaining phenylglycinol moiety is cleaved with Li/NHs (see Lithium Amide) (eq 12). Further reduction with lAthium Aluminum Hydride affords 2,2-disubstituted pyrrolidines. 

Angustifoline, C14H22ON2 (mp 81° [ ]i —8.0°), has been isolated from Lupinus angustifolius L., L. polyphyllus L., and L. albus L. Its structure was elucidated almost simultaneously by three different groups (31-33). It forms an A-acetyl derivative, has a terminal double bond as indicated by IR-spectra and proved by oxidation to formaldehyde, and reduction of the lactam grouping with lithium aluminum hydride generates a tmws-quinolizidine system (trans bands in the IR-spectrum), and these facts lead to structure XXXVII for angustifoline. 

All these results are consistent with the 8-lactam structures CCCXCVI and CCCXCVII which received confirmation by conversion of the amino alcohol CCCC to CCCCIII and unambiguous synthesis of the latter from CCCXCVIII. The monotosylate of the methylated diol CCCCI was subjected to reduction with lithium aluminum hydride to give the base CCCCIII. Reaction of the amino alcohol CCCXCVIII with methyl... 

This assignment was confirmed by the work of Kaneko (9). Tuberostemonine was converted to the lactam XX which was transformed by reduction with lithium aluminum hydride followed by cleavage with cyanogen bromide into XXI. Debromination by hydrogen over palladium followed by reductive removal of the cyano group gave XXII. The... 

On the other hand, reductive cleavage of the dienone lactam 91 with chromium(II) chloride gave the dibenz[with lithium aluminum hydride. Deprotection of 76biosynthetic precursor of the Schelhammera alkaloids. Oxidation of the diphenol 76a by potassium ferricyanide in the two-phase system gave the expected 5,7-fused dienone 77 in 61% yield (50). 

A transannular route to 1-substituted pyrrolizidines has recently been reported by Wilson and Sawicki. The lactam (79) was prepared by Beckmann rearrangement of the oxime p-toluenesulfonate of cyclohept-4-enone. Reduction with lithium aluminum hydride gave the amine (80), which on treatment with bromine yielded the 1-bromopyrrolizidine (81) in one stereospecific step (95%). The stereochemistry of the product corresponds to a disfavored exo-mode of cyclization by attack of the nitrogen on the bromonium ion. Further modification of this route to produce naturally occurring alkaloids would appear feasible, but has not yet been reported. 

The only asymmetric synthesis of the Nuphar indolizidine to date is due to Barluenga and co-workers (615). Their route to the (5S,8 ,8aS)-( -) enantiomer of 944 commenced with cycloaddition between the proline-derived 2-amino-butadiene 957 and imine 958 (Scheme 125). Hydrolysis of the adduct 959 gave piperidinone 960 in 51% yield and an ee of better than 99%. Once the alcohol and amine groups had been mutually protected as the cyclic carbamate 961, defimctionalization of the ketone was accomplished via an enol triflate. Chain-extension of the deprotected piperidine 962 at the hydroxymethyl substituent afforded 963, which was cyclized to the bicyclic lactam 964 simply by heating in toluene. Reduction with lithium aluminum hydride completed the synthesis of ( - )-944 ([a]n -99°, c 1.3, CH2CI2). 

Fuchs also prepared ( )-ll hydroxycephalotaxine (26), Scheme 8, starting from tetracyclic lactam 84-cji which was treated with lithium diisopro-pylamide followed by 5-phenyl benzenethiosulfonate to give monosulfenyl-ated lactam 85 (37). Treatment of 85 with lithiated hexamethyldisilazane (LiHMDS), followed by molecular oxygen, afforded a-keto lactam 86. Reduction with BH3/THF, acylation, and deprotection of the diol yielded 87, which was oxidized under Swem conditions. Treatment with 2,2-dhmethoxy-... 

Synthesis from L-threitol The L-threitol derivative 24, obtained from D-(-)-diethyl tartarate in three steps and 90% overall yield, was used as a starting material for the synthesis of nectrisine (1) (Scheme 5). " Swern oxidation of 24 produced the L-threose derivative 25, which was transformed into the aminonitrile 26 in 96% overall yield from 24, as an inseparable diastereomeric mixture. Removal of the silyl protecting group from 26 followed by oxidation of the resulting primary hydroxyl group with TPAP afforded the lactam 27, which was treated with sodium methoxide to produce the methyl ester 28 in 62% yield from 26. Lithium borohydride reduction of 28 afforded a chromatographically separable mixture of the lactams 29 and 30 in a ratio of 56 44 and 87% total yield. Silylation... 

In a somewhat similar synthesis (16) the lactam 46 which was prepared by two distinct routes was shown to undergo reductive cycliza-tion to give elaeocarpidine and dihydroelaeocarpidine. When this reduction step was carried out with lithium aluminum hydride in tetrahydrofuran a 1 2 mixtime of elaeocarpidine and dihydroelaeocarpidine was obtained but reduction with lithium aluminum hydride in pyrrolidine-tetrahydrofuran (1 1) at 0° gave a 52% yield of elaeocarpidine along with unchanged lactam (46). 

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