Direct Synthesis of 6‐Azabicyclo[3.2.1]oct‐6‐en‐2‐ones and Pyrrolizidines from Divinyl Ketones and Observation of Remarkable Substituent Effects

Abstract

Substituents create access to molecular diversity. Under basic conditions, 6-azabicyclo-

Facile [7C+1C] Annulation as an Efficient Route to Tricyclic Indolizidine Alkaloids

“…On the basis of the above results (Table 2) together with our previous observations, [6,13] a possible mechanism for the formation of 2 from the symmetrical dialkenoyl ketene dithioacetals 1 is proposed in Scheme 2. The overall process would involve the diastereoselective double Michael addition ([7+1] annulation) of the active methylene of ethyl isocyanoacetate to the 1,7-dielectrophilic 1 under basic conditions to provide the enolate intermediate A. Intramolecular cyclization of A through CÀC bond formation at the isocyanide carbon atom (B) and subsequent protonation would give 2 (Scheme 2).…”

“…Unlike the synthesis of pyrrolizidines and C 2 -tethered pyrrole/oxazole pairs (Scheme 1) in which [5C+1C] annulation intermediates can be obtained, [6,13] the synthesis of 2 does not result in an intermediate corresponding to the [7C+1C] annulation of 1 a with ethyl isocyanoacetate under optimal reaction conditions ( Table 1, entry 6), even at a temperature of 0 8C. To the best of our knowledge, no report has been published on the [7C+1C] annulation using a seven-carbon acyclic precursor.…”

“…With the optimal reaction conditions ( Table 1, entry 6) in hand, the scope of the tandem [7C+1C] annulation/intramolecular cyclization reaction with dialkenoyl ketene dithioacetals (1) as C 7 1,7-dielectrophiles was investigated and the results are summarized in Table 2. It was observed that the reactions of ethyl isocyanoacetate with symmetrical C 7 1,7dielectrophiles (1) having electron-deficient aryl groups (entries 1, 2, 4 and 5), phenyl (entry 6), electron-rich aryl groups (entries 7-11), and heteroaryl groups (entries [12][13][14] at the 1,7-positions (b positions of the enone moiety) can afford the corresponding 8-azabicyclo [5.2.1]dec-8-enes 2 in high to excellent yields. It is important to note that all the above reactions (except for 1 c; entry 3) proceed in a highly diastereoselective manner.…”

“…In contrast, the reaction of the substrate 1 o bearing two ferrocenyl groups at the electrophilic 1,7-positions gave the desired product 2 o in good yield (entry 15). [12] To further examine the steric effect, nonsymmetrical substrates 1 p and 1 q were subjected to the reactions. As a result, 2 p and 2 p' were obtained as a mixture of diastereomers in high combined yield in a ratio of about 15:1 when the nonsymmetrical substrate 1 p, bearing two chlorine atoms at the para-and ortho-positions of the 1,7-phenyl groups, respectively, was used (entry 16).…”

Catalytic Asymmetric Synthesis of Spirocyclic Azlactones by a Double Michael‐Addition Approach

“…[3,4] Although these catalytic asymmetric methodologies have only very recently been available, nonenantioselective versions for these stepwise formal [5+1] cycloadditions have been known for a long time, the first example apparently dating back to 1924 for the formation of functionalized cyclohexanones (although in that case, lacking a spirocyclic motif). [5,6] In this paper, we give a detailed account on the development of the catalytic asymmetric tandem reaction [7] to prepare highly enantioenriched azlactone/cyclohexanone spiro-cycles (3-oxa-1-azaspiroA C H T U N G T R E N N U N G [4.5]dec-1-ene-4,8-diones), which proceeds through a double Michael addition of an achiral glycine-derived azlactone to symmetric and unsymmetric divinylketones. In this approach, which generates up to three contiguous stereocenters (one of which is quaternary), [8] the azlactone pronucleophile can be formed in situ from N-benzoyl glycine.…”