Asymmetric Dehydrative Cyclization of ω‐Hydroxy Allyl Alcohols Catalyzed by Ruthenium Complexes

Abstract

Chiral cyclic ethers constitute one of the most important structural units in biologically active compounds such as polycyclic ethers, polyether antibiotics, acetogenins, as well as coumaran-and chromane-related natural products.[1] Among many key building blocks reported so far, a-alkenyl-substituted cyclic ethers are widely recognized as the most useful because the alkenyl moiety can be transformed into a wide range of functionalities, thereby facilitating further elongation. The development of an efficient strategy for the construction of these cyclic ethers has attracted a great deal of attention over the last two decades. In particular, the focal point is the creation of catalytic enantioselective protocols, which have been categorized into three types: 1) Wacker-type oxidative cyclization of ortho-allyl-or homoallylphenol derivatives, [2] 2) Tsuji-Trost-type intramolecular allylation using w-hydroxy allyl esters, [1c,f, 3] and 3) hydroalkoxylation of alkynes [4] and allenes.[5] Herein, we report a new type of protocol, in which non-activated or non-protected diols 1 dehydratively cyclize into the corresponding cyclic ethers 2 with high regio-and enantioselectivity.We have developed a new chiral ligand-R-naphpyCOOH 4 [naph = naphthyl, py = pyridine, R = substituent (see structures)]-based on the knowledge that a catalytic system combining [CpRu(CH 3 CN) 3 ]PF 6 (3; Cp = cyclopentadienyl) [6] with a pyridine-2-carboxylic acid derivative or the corresponding cationic CpRu IV -p-allyl carboxylato complex can convert a 1:1 mixture of alcohols or allyl alcohols into allyl ethers with the liberation of water.[7] The ligand is characterized by the sterically flexible axial chirality through the C6-C1' bond [8] and the adjustability of electronic and steric properties of the naphthalene ring by changing the R substituent at C2'. The allyl esters R-naph-pyCOOallyl (allyl = CH 2 CH = CH 2 ) 5 were also target ligands because of the convenient formation of the CpRu IV -p-allyl complex directly from 3. A series of compounds 5 a-c were prepared in 44-64 % yield from 2-bromo-3-methylpyridine through a Suzuki-Miyaura coupling between pyridine and naphthalene moieties, modified Reissert-Henze reaction, hydrolysis, and an allyl esterification sequence in combination with MuraiChatani silylation of aromatic C À H bonds and chlorination or phenylation at C2'.[9] The enantiomers were separated by HPLC on a chiral stationary phase, and the absolute configurations were determined by single-crystal X-ray analysis of the ester of (1R,2S,5R)-menthol or the amide of (R)-1-phenylethylamine.[9]The effectiveness of R-naph-pyCOOH 4 and the allyl ester 5 in combination with 3 in the asymmetric dehydrative cyclization was investigated by use of 1 a (C

CpRu/Brønsted Acid-Catalyzed Enantioselective Dehydrative Cyclization of Pyrroles N-Tethered with Allylic Alcohols

“…Cyclization using 2j with a C(3)-methyl substituent afforded 3j with a 9:1 C(2)/C(5) regioselectivity and in a 78% total yield (Table , entry 17). Elongation of the methylene tether from three to four carbons gave a pyrrole-fused vinylazepane 3k with er = 97:3, whereas shortening from three carbons to two carbons led to no production of the desired dihydropyrrolidine 3l (Table , entries 18 and 19), in contrast to the corresponding OH case . Replacement of the pyrrole of 2a with indole resulted in no reaction.…”

“…We have challenged the unachieved issue using our catalyst, ( R )- 1 , shown in Figure a. The CpRu/Brønsted acid hybrid complex, which is in a quick equilibrium between ( R , R Ru )- 1 and ( R , S Ru )- 1 , efficiently catalyzes the dehydrative intramolecular asymmetric allylation of protic nucleophiles (NuH) such as OH, COOH, NHAc, and NHTs, and to selectively furnish various exo-trig cyclic ethers, lactones, and saturated N-heterocycles with up to a >99:1 S / R enantiomeric ratio (er). A detailed study on the mechanism using a substrate with OH as the terminal NuH strongly supported that the major S enantiomer should be produced via a σ-allyl Ru intermediate .…”

“…Replacement of the pyrrole of 2a with indole resulted in no reaction. The general trend of enantioselectivity observed with these E substrates was the same as that observed in the ( R )- 1 -catalyzed dehydrative cyclization of NuH (Figure a). − The same trend of enantioselectivity suggests that a similar mechanism to the OH case is operating.…”

Asymmetric Dehydrative Allylation Using Soft Ruthenium and Hard Brønsted Acid Combined Catalyst

“…As shown in Figure 5, the Intramol RDACat, [Ru(II) Cp(CH 3 CN) 3 ]PF 6 /(R)-3 ((R)-4), quantitatively cyclizes an aliphatic allylic alcohol, (E)-hept-2-ene-1,7-diol (5 a), to obtain 2-vinyltetrahydro-2H-pyran (6 a) with an S/R er of 97 : 3 with 6-exo-trig selectivity ([substrate] = 100-1000 mM; 0.1 mol% of (R)-4; N,N-dimethylacetamide (DMA); 100 °C; 1-3 h). [15] Aprotic solvents such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and cyclopentyl methyl ether were adopted. Protic solvents such as tert-butyl alcohol (t-BuOH) and isopropyl alcohol may also be used although the er is marginally decreased.…”

Supramolecular Halogen Bonds in Asymmetric Catalysis

“…The scope of the reaction revealed that in almost all of the cases the cyclic products 10 were obtained with high yields (up to 99%) and excellent selectivities (up to 98% ee). Interestingly, the catalytic system and its analogs were first developed ten years ago by Kitamura et al and have been used in similar asymmetric intramolecular dehydrative allylations ( Figure 6C; Tanaka et al, 2009;Seki et al, 2012;Suzuki et al, 2015). In the initial publication, the chloro group seemed to play a more crucial role than just a steric control unit and it was speculated that the chloro group helped to stabilize the TS by lowering the LUMO level (Tanaka et al, 2009).…”