Photochemistry of 4-(2‘-Aminoethyl)quinolones:  Enantioselective Synthesis of Tetracyclic Tetrahydro-1aH-pyrido[4‘,3‘:2,3]- cyclobuta[1,2-c] Quinoline-2,11(3H,8H)-diones by Intra- and Intermolecular [2 + 2]-Photocycloaddition Reactions in Solution

Abstract

Enantioselective [2 + 2]-photocycloaddition reactions on 4-(2'-aminoethyl)quinolones in solution were studied using the enantiomerically pure complexing agent 1 as source of chirality. The intermolecular reactions of fully N-protected substrates 5a-5c with different 2-alkyl-substituted acrylates 12-15 represent the first systematic study on the diastereoselectivity of their intermolecular [2 + 2]-photocycloadditions to unsymmetrically 1,1-disubstituted olefins (75-91% yield, d.r. = 58/42-95/5). N-Benzylic-protected photoproducts exo-16a/b-19a/b could easily be converted into lactams 20a/b-23a/b by a sequence of Boc deprotection and thermal lactamization (74-98% yield). Identical products 20a-22a were directly accessible by the intramolecular [2 + 2]-photocycloaddition of acrylic acid amides 2-4 (41-61% yield). The suitability of both pathways for an enantioselective reaction variant was proven (70-92% ee). Thus, tetracyclic lactams possessing the carbon framework C were obtained with good yields and enantioselectivities of up to 92% ee in intramolecular reactions. Comparative investigation of both routes showed that quinolone dimerization was the single most decisive factor preventing a complete chirality transfer. Functional group manipulations were successfully conducted with the primary photoproduct exo-17a. Finally, a new and unexpected type of benzylic hydrogen abstraction-radical cyclization reaction was discovered for substrate 5a, which explains the photochemical instability of substrates 2-5 under short wavelength irradiation (lambda = 300 nm).

Total Synthesis of Meloscine by a [2+2]‐Photocycloaddition/Ring‐Expansion Route

“…[19] Results and Discussion Studies towards iminium ion rearrangement: The photochemistry of protected aminoethylquinolone 8 and the synthesis of 1-alkyl substituted cyclobutanes by [2 + 2]-photocycloaddition reactions have already been investigated extensively. [20] Indeed, the envisioned cyclobutane 7 was readily accessible in both racemic as well as enantiomerically enriched form by the [2 + 2]-photocycloaddition of quinolone 8 and methyl a-ethylacrylate, although the diastereomeric ratio with respect to C1 [d.r.A C H T U N G T R E N N U N G (exo/endo) % 60:40] and the difficulties encountered in the separation of diastereoisomers somehow limited the yield of the required 1-exo isomer. Thus, more easily accessible 1-methyl substituted cyclobutanes were chosen as initial test substrates for the construction of rearrangement precursors, while they still retained the pivotal quaternary center at C1.…”

“…[21] Lithium aluminum hydride (LAH) reduction of lactam 9, [20] however, only resulted in moderate yields of the two fully reduced amines 10 and 11, and no hint of the formation of an intermediate lactol could be found (Scheme 2).…”

“…To our surprise, the up-to-now straightforward N-Boc deprotection of cyclobutane photocycloaddition products [10 vol % trifluoroacetic acid (TFA) in CH 2 Cl 2 ] failed in the case of aldehyde 12, [20] and resulted exclusively in the fragmentation of the cyclobutane unit. [25] Less acidic conditions or milder deprotection agents, for example, ZnBr 2 [27] or TMS-I [28] did not give any conversion.…”

“…Obviously, the a-silyloxy substituent of acrylate 15 and the resulting captodative electronic situation at C-a exhibit a favorable effect on the course of the [2 + 2]-photocycloaddition, as both yield and stereoselectivity surpassed the values obtained with any a-alkyl substituted acrylate investigated earlier. [20] Using established conditions, cyclobutane 16 was readily converted into the a-hydroxy lactam 17 by N-Boc deprotection and thermal cyclization of the free aminoester in refluxing toluene. Thermal conditions simultaneously affected the cleavage of the O-TMS (trimethylsilyl) protective group (Scheme 4).…”

Enantioselective Total Synthesis of the Melodinus Alkaloid (+)‐Meloscine

“…[10] The plan to construct the stereogentic center at C19 by reductive amination and to introduce the exocyclic double bond by a carbonyl olefination resulted in the hypothetical 1,2-diketone 4 as a formal intermediate, which was to be derived from a [2+2] photocycloaddition product of the known quinolone 5. [11] In fact, an enantioselective [2+2] photocycloaddition in the presence of the chiral complexing agent 6 [12] was considered as the pivotal step for the generation of the stereogenic centers at positions C3 and C12.…”