Lactam trans

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

The indolyldithiane dianion 83 reacted with piperidein-2-ones 84a and 84b to give, in 64—80% yield, a mixture of diastereoisomeric lactams trans-85/ds-86 and trans-871 as-88 in ratio 1 1.5 and 1 1.4, respectively. Partial reduction of lactams 85-88 afforded the corresponding iminium salts that spontaneously cyclized either on the indole nitrogen or indole 3-position. Thus, treatment of lactam 86 with an excess of Red-Al in THF yielded a 3 1 mixture of diazocinoindole 89a and 90a in excellent total yield. Under identical conditions, lactam 88 yielded diazocinoindole 89b as major product and small amounts of 90b and 91b (61%, ratio = 10 1 1). Treatment of lactam 85 with Red-Al gave no reaction, whereas with LiAlPU it gave only 91a. 

Figure 2-16. Blocked cyclization of the y-lactams trans-form of enyne-amide.

Scheme 4.5 Diastereoselective synthesis of a-methylene-y-lactams trans-2 b.

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

Azetidin-2-one formation by N—C(4) ring closure has also been observed in the irradiation of cfs-a-phenylcinnamides (143) in degassed benzene. Both cis and trans lactams are formed (68JA2333). 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

In 1991, Ohfune and coworkers reported palladium(O)-catalyzed carbonylation of vinylaziridines 262 with carbon monoxide (1 atm.) in benzene (Scheme 2.65) [31]. Interestingly, 3,4-trans-azetidinone 264 was exclusively obtained from a dia-stereomeric mixture of trans- and cis-vinylaziridines 262 (3 1). Tanner and Somfai synthesized (+)-PS-5 (267) by use of palladium(O)-catalyzed trons-selective (3-lactam formation in the presence of Pd(dba)3 CHC13 (15mol%) and excess PPh3 in toluene. 

Addition of lithium dibutylcuprate (3 equiv) to 8 provides the corresponding trans-fi-lactam 9 exclusively15. 

Reaction of p-nitrophenyl 2-(p-tolylsulfinyl)acetate 161 with aryl aldimines in the presence of imidazole was found to give /j-lactams 162 and amides 163206. In the cyclization, only the two 3,4-trans derivatives were formed out of a possible four diastereomeric pairs and, interestingly, the ratio of two diastereomeric pairs went up to 6.7 1. This means not only that internal asymmetric induction207 affords the trans derivative, but that also a relatively high asymmetric induction took place during the reaction. 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

Development of new synthetic routes to optically active (3-lactam derivatives is still an attractive problem in organic chemistry. As a synthetic approach to penicillin derivatives, photocyclization of oe-oxoamides 76 to (3-lactams has long been studied 41, 42). This reaction (Scheme 6), however, results in a complex mixture of racemic cis-and trans-isomers of (3-lactams 72 and of oxazolidin-4-ones 73, since the reaction proceeds via a zwitterionic intermediate 7143>. Of these isomers, only the optically... 

The Hg(ll) cation was used to activate the double bond in lactam 178, which was obtained by detosylation of 177 using the Parsons method. This strategy allowed the synthesis of quinolizidine derivative 179, which was obtained as a single /raar-diastereoisomer (Scheme 31). Besides its higher thermodynamic stability with respect to that of the m-isomer, formation of the trans-isomer must involve a lower activation energy since its intermediate precursor, in which the lone pair of electrons of nitrogen must attack from the back side of the mercuronium ion, is sterically less hindered than the precursor of the m-isomer <2003TL4653>. 

The photocyclization of enamides has been the subject of detailed study and provides a valuable approach to the synthesis of alkaloids. A comprehensive review has been published.31 A variety of reaction types has been reported. The N-benzoylenamine 33, for example, is converted on irradiation to the trans-lactam 34 by a process involving conrotatory photocyclization followed by a thermally allowed [l,5]-suprafacial hydrogen migration.32 The influence of substituents on this transformation has been studied.33 The enacylamine 35 undergoes an analogous cyclization to give a mixture of cis- and trans-lactams 36, the ratio of which is solvent... 

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