7-Hydroxy-7-lactam

Huonnations with DAST proceed with high chemoselectivity In general, under very mild reaction conditions usually required for the replacement of hydroxyl groups, other functional groups, including phenolic hydroxyl groups [112], remain intact This provides a method for selective conversion of hydroxy esters [95 97] (Table 6), hydroxy ketones [120, 121], hydroxy lactones [722, 123], hydroxy lactams [124] and hydroxy nitriles [725] into fluoro esters, fluoro ketones, fluoro lactones, fluoro lactams, and fluoro nitnles, respectively (equations 60-63)... 

Ebumamonine was assembled utilizing a Pictet-Spengler cyclization of hydroxy-lactam 52 in the presence of trifluoroacetic acid at low temperature to give a mixture of diastereomers 53 in 95% yield. These compounds were readily separated by chromatography and the a-epimer was further elaborated to give the natural product. 

The reactions that accomplished the conversion of intermediate 16 into intermediate 23 have taken place very smoothly. It is worth acknowledging that the //-hydroxy lactam moiety did not, at any stage, participate in any undesirable side reaction processes. The stability of the //-hydroxy lactam substructure in the presence of basic reagents is particularly noteworthy since a destructive retro-aldol cleavage reaction could have conceivably occurred on several occasions. The stability of this potentially labile moiety permits all of the desired transformations leading from 16 to 23 to be conducted without prior protection of the C-8 hydroxyl group. 

The hydroxy lactams 1 are converted into the 2//-2,4-benzodiazepin-l(3//)-ones 3 in refluxing benzene in the presence of p-toluenesulfonic acid. The reaction proceeds by ring opening to the oxo amides 2, followed by dehydration.16,166... 

Dicarbonsaure-imide ergeben als cyclische sekundare Carbonsaure-amide mit Hydri-den die verschiedensten Reduktionsprodukte, z. B. Hydroxy-lactame, Lactame, cyclische Amine, a>-Hydroxy-carbonsaureamide und a>-Amino-alkohole4. 

A series of N-substituted narceine amides (Section III,D,1) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the ( )-narceine imide (117) type (100). Similar transformations were performed in the hydrastine series (101). JV-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (Z)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5). 

It has been postulated that secophthalideisoquinoline ene lactams and hydroxy lactams are most probably artifacts of isolation resulting from the reaction of enol lactones or keto acids with ammonia during the extraction process. The hydroxy lactams are probably formed initially and then undergo dehydration to give ene lactams (5,8). For this reason, this section covers the hydroxy lactams in addition to the ene lactams. The hydroxy lactams are... 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

Pyrrolo[l,2]thiazepines. Hydroxy lactam 280a (n — m — 1), upon treatment with neat TFA at room temperature gives a 20 1 mixture of benzothiazepines 283 and 284 in overall 94% yield. In contrast, 280b (n — 2,m — 0) produces... 

Intramolecular addition of hydroxylamines and hydroxamic acids to the non-activated double bonds is possible through oxidative cyclization. Reaction of O-Acyl fi,y-unsaturated hydroxamates (e.g. 56, equation 38) with bromine provides 3,4-substituted iV-hydroxy -lactams such as 57 with high diastereoselectivity. Analogous reaction of O-benzyl hydroxylamine 58 (equation 39) with iodine results in five-membered cyclization with 2 1 ratio of diastereomers. ... 

Kano and co-workers.Once the 2,4-oxazolidinedione moiety has been incorporated, amide reduction then affords an a-hydroxy lactam, the key N-acyliminium ion precursor. Representative examples of 2,4-oxazolidinediones and the products derived from A -acyliminium ion cyclization are shown in Schemes 6.61-6.63, pp. 110-112. 

Reaction of hydroxy lactam 97 with acetic formic anhydride gives the formyl derivative 98 in high yield <20000L99>. 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

Base/h v oder Se02 0 II R-C-NH-OH N-Acyl-hydroxylamine, N-Hydroxy-lactame E 5, 1142-1143 1985... 

Reduction of imides.1 The N-imidotryptamine (1) is reduced selectively by NaBH4 CoCl2 (5 1 equivalents) to the hydroxy lactam 2 in 95% yield. The product is converted in quantitative yield to the /l-curbolinc 3 by treatment with cone. I IC I ill. 31). ... 

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... 

A major method for the preparation of y-amino-()-hydroxy adds of syn configuration is the stereocontrolled reduction of enantiomerically pure tetramic acids 32, followed by alkaline or acid hydrolysis of the resulting N-protected 4-hydroxy lactams 33 (Scheme 9))53-571... 

Banik, B.K., Manhas, M.S., Kaluza, Z., Barakat, K.J. and Bose, A.K., Microwave-induced organic reaction enhancement chemistry, 4 convenient synthesis of enantiopure (v hydroxy lactams, Tetrahedron Lett., 1992, 33, 3603. 

Schoemaker and Speckamp (8) have reported the quantitative conversion of hydroxy-lactam 26 (n=l) (HCOOH, 18 h, r.t.) into the spirocyclic lactam ester 27 (n=l). The other possible spiroisomer 28 (n=l) was not formed. 

Hydroxy-lactam 26 (n=2) gave spiroisomer 27 (n=2), albeit in lower yield, under similar conditions. The same authors 191 have also reported the successful cyclization of hydroxy-lactam 29 into spirolactam 30. Analogous results were obtained by Evans and Thomas (10) who found that the cyclization of a 9 1 mixture of enamides 31 and 32 in anhydrous formic acid gave the spirocompound 30. This compound is a key intermediate in Kishi s total synthesis of perhydrohistrionicotoxin (11, 12). 

Allylation of organic halides. T wo laboratories2 have reported briefly that in the presence of a radical initiator organic halides undergo allylic substitution reactions with allyltrialkyltin compounds in moderate yield. This reaction was used in a recent Synthesis of the neurotoxin (+ )-perhydrohistrionicotoxin (7) to introduce the n-butyl tide chain.3 AI BN-catalyzed reaction of the bromide 2 with 1 proceeds in unexpectedly igh yield and with complete stereocontrol to give a single product 3. It is the tndesired isomer, but the desired stereochemistry is obtained by epimerization of the Intermediate ketone 5. The hydroxy lactam (6) had previously been used for the Synthesis of 7. 

Ahn, K. H. Lee, S. J. Synthesis of 1-oxaquino-lizidines via reductive cydization of hydroxy-lactams. Tetrahedron Lett. 1992, 33, 507—510. 

Mechanistic studies41"43 by Dixon and Jones excluded the possibility of dimeric catalytic species because a linear dependence was observed between the catalyst s enantiopurity and the reaction s enantioselectivity.43 The test reaction was the desymmetrization of meso-imide 22 using chiral oxazaborolidine catalysts. The sense of the enantioselectivity of the reduction was established by conversion of hydroxy lactam 23 to the known ethoxy lactam 24 (Scheme 17.6). 

Indium-promoted reaction of l,4-dibromo-2-butyne with carbonyl compounds gives 1,3-butadiene derivatives via the allenic indium intermediates (Scheme 56).220 Similar indium-mediated l,3-butadien-2-ylation reactions of optically pure azetidine-2,3-diones have been investigated in aqueous media, offering a convenient asymmetric entry to the 3-substituted 3-hydroxy-/ -lactam moiety (Equation (40)). The diastereoselectivity of the addition reaction is controlled by the bulky chiral auxiliary at Q4 221 222... 

Another synthetic route to ( )-retronecine (27) has been developed by Vedejs and Martinez.11 The protected hydroxy-lactam (22) was prepared from 2-methoxy-1-pyrroline by known methods. The key ylide intermediate (24) was then generated from the salt (23) by desilylation with caesium fluoride (Scheme 6). This ylide (24) reacted with methyl acrylate in a 1,3-dipolar cycloaddition to afford the unsaturated pyrrolizidine (25) in 57% yield from the lactam (22). Catalytic hydrogenation of the ester (25) gave an unstable endo-product, which epimerized to the exo-form (26). Introduction of the 1,2-double-bond into (26) was carried out by insertion and thermal elimination of a phenylseleno-group.12 Reduction then yielded ( )-retronecine (27). 

Methyl- -carboxylater E21b, 2002 (Cyclis. of cu-Hydroxy-lactames) Oxo- E2lb, 2000 (Cycl. of cu-Alkoxy-lactames)... 

The choice of Lewis acid promoter for these reactions can change the sense of asymmetric induction. " For example, tandem [4 + 2]/ [3 + 2] cycloadditions (eq 4) mediated by Ti(0-i-Pr)2Cl2, followed by hydrogenolysis afforded tricyclic (-)-a-hydroxy lactam [(-)-8] in 98% ee. When mediated by methyl-aluminum-bis(2,6-diphenylphenoxide) (MAPh), the same reaction gave (+ )-8 in 93% ee. Importantly, the observed selectivity is not chiral auxiliary dependent. Rather, it is attributed to a highly endo selective cycloaddition in the case of Ti compared to high exo selectivity in the case of MAPh. 

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