Vinylogous lactams

Unsaturated y-lactams. Vinylogous iron complexes are transformed into the lactams by incorporating a primary amine. 

Ultraviolet absorptions ofvinylogous lactams were found by MOLCAO calculations and compared with experimental values (663). Infrared spectroscopic studies of vinylogous amides (664) and some fifty vinylogous urethanes (665) allowed configurational and structural assignments. The effect of enamine-imine equilibrium in a series of benzophenone derivatives was established (666) and the effect of structure on enamine basicity studied (667). 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

The formation of five- (362) and six- (581) membered vinylogous lactams and pyrroles by intramolecular enamine acylations has been accomplished in some examples by formation of the cyclization precursor through an initial enamine exchange (362). 

Scheme 6.79 Conversion of one vinylogous Mannich adduct obtained from the 63-catalyzed Mannich addition of a,a-dicyanoalkenes to N-Boc-protected aldimines to the corresponding chiral 5-lactam.

One method for the synthesis of hydroxyalkyl-substituted P-lactams is by the Staudinger reaction, the most frequently used method for the synthesis of P-lactams.86 This method for the preparation of 4-acetoxy- and 4-formyl-substituted P-lactams involves the use of diazoketones prepared from amino acids. These diazoketones are precursors for ketenes, in a diastereoselective, photochemically induced reaction to produce exclusively tram-substituted P-lactams. The use of cinnamaldimines 96, considered as vinylogous benzaldimines, resulted in the formation of styryl-substituted P-lactams. Ozonolysis, followed by reductive workup with dimethyl sulfide, led to the formation of the aldehyde 97, whereas addition of trimethyl orthoformate permitted the production of the dimethyl acetal 98 (Scheme 11.26). 

The latter example (reaction 36) already indicates that the Yang cydization can also be used to synthesize four-membered heterocycles. After light absorption, the a,(3-unsaturated carbonyl compound 84 undergoes intramolecular hydrogen abstraction at the a-position of the carbonyl moiety (reaction 37), leading to the 1,4-biradical intermediate XXX [87]. A radical combination then efficiently yields the spirocyclic P-lactam derivative 85, and only one stereoisomer is formed in this case. In this transformation, the a,P-unsaturated carbonyl function can be considered as being vinylogous to a simple ketone. 

As depicted in Scheme 13, the SnCU-promoted vinylogous aldol reaction between silyloxy pyrrole 76 and D-glyceraldehyde 11 afforded the unsaturated lactam 77 in a good yield and excellent diastereoselectivity. Saturation of the carbon-carbon double bond within 77 using the NiC /NaBfLt mixture, followed by protection of the free secondary carbinol group as a TBS-ether and TV-Bn for TV-Boc protecting... 

As summarized in Scheme 37, gulo- and allo-configured l-amino-5a-carba-P-D-hexopyranoses 228 and 231, as well as the related amino acid counterparts, 229 and 232, sprang from the common lactam intermediate 224. The preparation of aldehyde 224 from silyloxypyrrole 76 and D-glyceraldehyde 11 entailed a Lewis acid promoted vinylogous cross aldolization followed by functional group manipulation, including olefin... 

During the same study, the Italian researchers aiming at the synthesis of carbaoctanose compounds (vide infra), synthesized a nine-carbon long intermediate 308 which served both to access the octanose and the septanose targets. As shown in Scheme 50, the route to 308 entailed vinylogous aldol coupling between pyrrole 76 and D-arabinose derived aldehyde 306 producing lactam 307, the immediate precursor of 308. To... 

In contrast to hydroxy-N-heterocycles, which usually occur in the lactam or vinylogous lactam form (Section IV,A), the alkoxy- or aryloxy-... 

Reduction of the double bond of vinylogous lactams 42 and 43 with sodium cyanoborohydride and subsequent hydrogenolysis of the resulting thioethers gave rise to the pwntacyclic ketones 44 and 45 as prepared by Biichi (71JA3299 75JA6880). The conversions of the pentacyclic ketones to vindrosine (46) and vindoline (47) involved a five-step sequence (Scheme 5). 

In a related fashion, certain types of vinylogous amides can be prepared by a modification of this same method, as reported by Suzuki (equations 45 and 46). The triphenylsilyl moiety is essential for this transformation. The corresponding t-butyldimethylsilylacetylene gave the simple acylation product without subsequent Michael addition of the amine. In Ae ring expansion process the use of unmodified lithium acetylide (LiC uCH) lead to the formation of by-products. A similar ring expansion process was reported for a-lactams with formation of five-membered ring vinylogous amides. ... 

The action of oxonium salts on vinylogous amides affords iminium salts (71 equation 44), which are useful for synthetic purposes in heterocyclic chemistry. ° " - Alkyldiphenylsulfonium tetrafluoro-borates (72 equation 45) were recommended as reagents which alkylate amides and lactams under smooth conditions.2 2 With the aid of fluorosulfonic acid esters as well as with trifluorometh-anesulfonic acid esters, - - which have alkylation power comparable to oxonium salts, iminium salts, e.g. (73) and (74 Scheme 5), could be synthesized from amides, - vinylogous amides and lactams. Trimethylsilyloxymethyleneiminium salts (75 equation 46) are accessible by reacting tri-methylsilyltrifluoromethanesulfonate with amides. - ... 

Many TP derivatives are subject to tautomerism. Thus substance 92 (Scheme 24) can be drawn in the form of one (vinylogous) lactim structure (92a) and three different (vinylogous) lactams (921>-d). Several tools have been used to establish the exact tautomeric structures, especially NMR, IR, and mass spectrometry. X-ray diffraction, alkylation reactions, and quantum-chemical calculations cf 01AHC(81)l). 

Despite the fact that two syntheses of lycopodine have been reported, synthetic activity in this area has not diminished. A total synthesis of optically active annotinine (4) has been achieved. The readily available vinylogous lactam... 

Orthoesters and carbonic acid derivatives can be employed in lieu of carbonyl compounds. For example, 2,2-diethoxy-2//-chromene (178) and mediyl cyanoacetate give the 2//-chromene derivative (179 Scheme 31). (Methylthio)alkylideniminium salts (180) react with active methylene compounds under basic conditions (K2CO3 or EtsN) to give the corresponding condensation products (181 Scheme 32) 240 jjjis method is an alternative to the Eschenmoser procedure for synthesizing vinylogous lactams and urethanes. A(-Alkyl and A(-acylpyridinium salts can also serve as electrophiles in the Knoevena-gel condensation with activated methylenes. " Suitably activated nitriles (R CN) such as trichloroacetonitrile or ethyl cyanoformate react with various 1,3-dicarbonyl compounds to afford (182) in the presence of catalytic amounts of metal acetylacetonates [M(acac)n]. In the presence of TiCU non-... 

Warming the above a-thioiminium salt in the presence of the thiophile and base was critical in order to accomplish the sulfide-contraction process. At ambient temperature, work-up of the same reaction mixture produced the oxolactam analog of (102) as the major product (74%) along with a small amount (12%) of vinylogous carbamate (103). In order to better understand the underlying mechanism that prevailed under ambient versus elevated temperatures, NMR studies were conducted on the a-thioiminium salt (107). This intermediate, when dissolved in deuterated chloroform at ambient temperature in the presence of DBU, was converted immediately to a proposed S,N-ketene acetal (108 Scheme 23). Triphenylphosphine had no effect on the iminium salt. Aqueous work-up yielded the lactam (109), which is consistent with formation of the S,N-ketene acetal. However, wanning the intermediate (107) in the presence of the base and thiophile allowed the reaction to eventually proceed via the sulfur-extrusion pathway, due to the reversibility of the S,N-ketene acetal formation. 

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