Keto lactam

Hydroxyoxaziridines like (117) undergo double ring cleavage to form, for example, a nine-membered keto lactam (81AG(E)670). 

An interesting method for preparing 2,6-dioxo-l,3-oxazine derivatives was described by Wasserman and Koch who stated that the five-membered ring of an a-keto-lactam could be transformed into the 1,3-oxazine (22) by ozone followed by reduction with zinc. 

The reaction of oxyberberine (58) and berberine (15) with dichlorocarbene has been previously reviewed (11). An interesting product was the keto lactam 189, which was obtained from 58 via the adduct 188 (Scheme 34) (105). This product was later isolated from Berberis darwinii and named magallanesine (106) however, this alkaloid has since been shown to be an artifact (107). 

This method for preparing 2-phenyl-1-pyrroline, and assorted 2-substituted 1-pyrrolines, is one of the best currently available, particularly because it reproducibly affords clean materials. Generally, the procedure is amenable to various aromatic esters 2 it has also been applied successfully to aliphatic esters (Table I).3 An advantage of this method is the use of readily available, inexpensive N-vinyl-pyrrolidin-2-one as a key starting material. This compound serves effectively as a 3-aminopropyl carbanion equivalent. The method illustrated in this procedure has been extended to include the synthesis of 2,3-disubstituted pyrrolines. Thus, alkylation of the enolate of the intermediate keto lactam, followed by hydrolysis, leads to various disubstituted pyrrolines in good yields (see Table II).3... 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

As an extension of this methodology, Gribble et al. reported a formal total synthesis of olivacine (238a). This synthesis starts from the same keto lactam 1181, used for the synthesis of ellipticine (228), and exploits the lower reactivity of the lactam carbonyl as compared to the carbonyl of the keto lactam. Reaction of the keto lactam 1181 sequentially with methyllithium and superhydiide (LiBHEts) led to 11-demethylellipticine (1191) in 57% yield, along with 30% of ellipticine (228). Finally, using Kutney s procedure (220), ll-demethylellipticine (1191) could be transformed to olivacine (238a) (701) (Scheme 5.195). 

The hydroperoxide (50) rearranges in the presence of acid to give keto lactam (51) (51JA2196, 51JA2641). 

In the event, iodolactonization of the carboxylate salt derived from the ester 458 afforded 459, and subsequent warming of the iodo lactone 459 with aqueous alkali generated an intermediate epoxy acid salt, which suffered sequential nucleophilic opening of the epoxide moiety followed by relactonization on treatment with methanol and boron trifluoride to deliver the methoxy lactone 460. Saponification of the lactone function in 460 followed by esterification of the resulting carboxylate salt with p-bromophenacylbromide in DMF and subsequent mesylation with methanesulfonyl chloride in pyridine provided 461. The diazoketone 462 was prepared from 461 by careful saponification of the ester moiety using powdered potassium hydroxide in THF followed by reaction with thionyl chloride and then excess diazomethane. Completion of the D ring by cyclization of 462 to the keto lactam 463 occurred spontaneously on treatment of 462 with dry hydrogen chloride. 

In the alternate and unsuccessful approach to haemanthidine (382), which entailed the construction of the D ring prior to the functionalization of the C ring, the ester 458 was converted to the unsaturated keto lactam 468 by a straightforward route analogous with the one discussed above for the transformation of 461 to 463. The carbonyl group at C-6 was then reduced with sodium borohydride to alleviate concern over its reactivity, but epoxidation of the double bond at C-2 and C-3 of 469 afforded a mixture of diastereomeric a- and (3-epoxides. Owing to the lack of stereoselectivity in this crucial step, this route was abandoned (202). 

Novel indole derivatives continue to be found in marine organisms those reported recently include dendrodoine (3), a cytotoxic thiadiazole derivative, which occurs in the tunicate Dendrodoa grossularia, from Brittany,4 and the keto-lactam (4), one of two lactams isolated from the Caribbean sponge Hali-chondria melanodocia.5... 

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... 

The oxidation of vincamine by means of trifluoroperacetic acid simply gives the keto-lactam that results from oxidative fission of the indole 2,7 bond.71... 

New synthetic work in this area includes syntheses of desethyldihydro-cleavamine (desethylquebrachamine),119" 20crH- and 20/IH-dihydrocleavamine,1196 and cleavamine.119" Takano s route to the dihydrocleavamines119ft is essentially an adaptation of his earlier synthesis of quebrachamine,119d while the synthesis of (-t-)-cleavamine (254) by Imanishi et al. consists in essence of a brief route to the unsaturated keto-lactam (255), which affords ( )-cleavamine and a hydroxy-cleavamine (256) (major product) on reduction (Scheme 35).119c... 

X-Ray crystallographic structure determinations of several degradation products of lycoctonine, including the keto-lactam acid (3), have been reported.5 Chemical... 

Representative procedure. To a solution of Sml2 (0.1 M in THF, 2.80 mmol) at 0 °C was added MeOH (21.0 mmol) and the mixture was left to stir for 30 min. A solution of keto-lactam 163 (X = 7V-PMP) (0.70 mmol) in THF was then added by cannula and the reaction mixture was left to stir for 5h. The reaction was quenched by opening to air and the subsequent addition of aqueous saturated NaCl. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were then dried (NaS04) and concentrated in vacuo. The crude product was purified by column chromatography (60% ethyl acetate-petroleum ether as eluent) to give 164 (X — /V-PM P) (0.55mmol, 79%) as a colourless oil. 

Two diastereoisomers of this cyclic keto-lactam have been prepared. The NMR spectra have many overlapping signals but the proton marked in green can clearly be seen. In isomer A it is 5h 4.12 (1H, q, j 3.5), and isomer B has Sh 3.30 (1H, dt, 74,11,11). Which isomer has which stereochemistry ... 

A new method of hydroxylating the C-2 position in dendrobine (127) has recently been achieved.60 Bromination of the keto-lactam (129) derived from dendrobine (127) followed by hydrolysis provides the 2-hydroxy-derivative (130) which can be... 

Closure of the nine-membered ring for the trans-isomer of the indole derivative 205 was carried out by heating with PPA for 30 min at 90°C to give the desired tetracyclic keto lactam 206 in good yield (Equation 16) <2006JOC3804>. 

In unpublished work, Gribble and Obaza-Nutaitis (60) have adapted the Saul-nier-Gribble ellipticine synthesis (61) to the synthesis of olivacine (Scheme 14). Keto lactam 85, available from indole in four steps (71% yield) (61), was treated sequentially with methyllithium and lithium triethylborohydride to give diol 86, which, without isolation, was reduced with sodium borohydride to give 1-de-methylolivacine (87). This had been previously converted to olivacine (4) by Kutney and co-workers (62). The success of this synthesis of 87 was due to the fact that Saulnier and Gribble (63) had previously established that the ketone carbonyl of keto lactam 85 is more reactive than the lactam carbonyl group. 

Gribble and Saulnier (79) have extended their ellipticine synthesis 43) to the synthesis of 9-methoxyellipticine (2) (Scheme 24). One of the key features of this approach is the regioselective nucleophilic addition to the C-4 carbonyl group of pyridine anhydride 28. The other noteworthy transformation is the conversion of keto lactam 142 to the diol 143 with methyllithium, a process that presumably involves cleavage of the initial adduct to a methyl ketone which undergoes cyclization at the C-3 position of the indolyl anion. Reduction of 143 with sodium borohydride completes the synthesis of 2, in 47% overall yield from 5-methoxyindole (139). Gribble and students 80) have also used this method to synthesize 8-methoxyellipticine (134), 9-fluoroellipticine (144), and the previously unknown 7,8,9,10-tetrafluorellipticine (145), each from the appropriate indole. 

In an improvement of the earlier use of keto lactam 85 to synthesize the alkaloid 17-oxoellipticine (148) 63) [alkaloid numbering (57)], Obaza-Nutaitis and Gribble (52) have found that vinyllithium is an excellent alternative to the more conventional acyl anion equivalents (Scheme 25). Thus, the addition to... 

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