A New Method for the Synthesis of Cycloheptenones by RhI-Catalyzed Intramolecular Hydroacylation of 4,6-Dienals

Abstract

The development of methodology for the synthesis of cyclic compounds is important in modern synthetic organic chemistry, not least because there are many biologically active compounds with complicated cyclic structures. The construction of a medium-sized ring is relatively difficult due to unfavorable entropy and nonbonding interactions occurring at the transition state during the cyclization. Transition metal catalyzed cyclization is one of the most promising strategies for the construction of such medium-sized ring compounds. [1] Rh I -mediated cyclization of 4-alkenals to give cyclopentanone derivatives was first reported by Sakai et al. in 1972, [2] and this hydroacylation has subsequently been developed into a catalytic process [3] and asymmetric reaction. [4] On the basis of results of mechanistic studies, [5] it is thought that the reaction proceeds as follows (Scheme 1): a CÀH bond of the aldehyde moiety of 1 is oxidatively added to a Rh I complex followed by insertion of a C C bond of an olefin to give the rhodacycle intermediate I. Reductive elimination from I occurs to produce cyclopentanone 2 along with regeneration of the Rh I complex. We speculated that if a and recycled for 1.5 h. This process was repeated for the addition of the next three amino acids, Fmoc-glycine-Pfp, 5, and Fmoc-glycine-Pfp. After completion of the fifth coupling the resin was washed with CH 2 Cl 2 for 15 minutes, and the beads were removed from the synthesizer and dried overnight. 4-ä Molecular sieves (5 beads) and CH 2 Cl 2 (1 mL) were added to the resin beads, and the suspension was agitated for 1 h. TfOTMS solution (160 mL of a 16 % v/v solution in CH 2 Cl 2 ) was added to a solution of NIS (400 mg, 1.78 mmol in THF (4 mL) and CH 2 Cl 2 (1 mL). A 1.25-mL aliquot of the resulting mixture was added to the resin beads, and the suspension was agitated for 18 h. The solution was then removed by filtration, and the resin was washed with CH 2 Cl 2 (3 Â 2.5 mL). The resin was treated with 20 % piperidine in CH 2 Cl 2 (2 mL), and the mixture was agitated for 15 min. The solvent was drained and the resin was washed with CH 2 Cl 2 (3 Â 2.5 mL). A solution of NaOH (10 mg, 0.25 mmol) in THF (0.5 mL) and methanol (2 mL) was transferred to the resin beads. The mixture was then agitated for 1 h, after which the solution was filtered from the resin and the filtrate concentrated to dryness under reduced pressure. The crude products were dissolved in CH 2 Cl 2 (5 mL), washed with water (2 Â 5 mL), and dried (MgSO 4 ), and the major a isomer was purified by preparative HPLC on an Alltech Econosil Silica normal-phase preparative column (10 mm, 250 Â 22 mm) with a flow rate of 10 mL min À1 and gradient elution (0 min: hexane 95 %, 2-propanol 5 %; 20 min: hexane 65 %, 2-propanol 35 %; then isocratic for 5 min) to give 9a (14 mg).

Synthesis of Five‐ and Six‐Membered Benzocyclic Ketones through Intramolecular Alkene Hydroacylation Catalyzed by Nickel(0)/N‐Heterocyclic Carbenes

“…This method can also be applied to substituted allyl groups (1 i and 1 j) to give the corresponding ketones (2 i and 2 j) in moderate to good yields. Furthermore, we applied the method to the hydroacylation of o-homoallylbenzaldehyde derivatives 1 k-p. For reported transition-metal-catalyzed alkene hydroacylations, the formation of six-membered (or larger) ring systems is difficult, [3,[12][13][14] as the rate of the ringclosing step is much slower than that of the decarbonylation from an acyl metal intermediate. [1a] Thus, the introduction of suitable chelation assistance by heteroatoms has been essential for stabilizing the acyl metal intermediate.…”