Ring Closing Alkyne Metathesis. Comparative Investigation of Two Different Catalyst Systems and Application to the Stereoselective Synthesis of Olfactory Lactones, Azamacrolides, and the Macrocyclic Perimeter of the Marine Alkaloid Nakadomarin A

Abstract

Previously unknown ring closing metathesis reactions of diynes are described which open an efficient and stereoselective entry into macrocyclic (Z)-alkenes if the resulting cycloalkyne products are subjected to Lindlar reduction. This new two-step strategy offers significant advantages in stereochemical terms over conventional RCM of dienes which usually leads to (E,Z)-mixtures when applied to the formation of large rings. The tungsten alkylidyne complex (tBuO)₃W⋮CCMe₃(1a) and analogues thereof as well as a structurally unknown species formed in situ from Mo(CO)₆ and p-chlorophenol effect the crucial alkyne metathesis reactions in a highly efficient manner, with the former catalyst being more tolerant toward structural variations of the substrates and polar functional groups. Applications to the stereoselective synthesis of the olfactory compounds ambrettolide 23 and yuzu lactone 24, the insect repellent azamacrolides epilachnene 31 and homoepilachnene 33, as well as to the fully functional building block 64 required for a total synthesis of the cytotoxic alkaloid nakadomarin A 51 highlight the relevance of this new concept for natural product chemistry. In the latter case, the diyne substrate 62 necessary for ring closing alkyne metathesis was obtained via a novel furan synthesis relying on a palladium-catalyzed opening of a vinyl epoxide followed by an oxidative cyclization of the heterocyclic ring

A frustrated-Lewis-pair approach to catalytic reduction of alkynes to cis-alkenes

“…Stereoselective hydrogenation of alkynes is an important protocol in synthesis of natural and industrially relevant compounds. 19,20,21,22,23 . Heterogeneous as well as homogeneous metal catalysts for this purpose are known 24,25,26,27,28 , however, metal-free catalytic hydrogenation of unactivated alkynes into alkenes has not been reported previously.…”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…Thus, in target synthesis of biologically active macroheterocycles, after the stage of the formation of unsaturated cycles, the reaction of reduction of multiple bonds follows: exhaustive hydrogenation of C≡C, C=C and C=N bonds over Wilkinson's catalyst, Raney nickel and Pd/C, [6][7][8][9][10][11] reduction of C=N bonds using NaBH 4 or LiAlH 4 [6][7][8][9][10][11][12] and partial hydrogenation of the C-C triple bond to Z-double over Lindlar catalyst [13][14][15][16][17][18] that allow obtaining both isolated bonds, and conjugated systems.…”

“…Good solubility of the resulting complex in water significantly worsens its transfer to the organic phase. To increase hydrophobicity compound (14) was transformed into mono-(15), di-(16) and tri-(17) N-dodecyl derivatives. [32] Alkylation of triamine (14) with excess n-dodecyl iodide in DMF in the presence of NaHCO 3 proceeds with the formation of disubstituted compound (16).…”

“…[32] Alkylation of triamine (14) with excess n-dodecyl iodide in DMF in the presence of NaHCO 3 proceeds with the formation of disubstituted compound (16). Selective alkylation of two out of three equivalent nitrogen atoms of compound (14) may be explained by high proton affinity of the ring. Reductive amination of compound (14) with n-dodecanal yielded trisubstituted product (17).…”

Total Synthesis of (±)‐Haliclonacyclamine C

“…138 We were aware that this was an ambitious endeavor as few examples of this approach applied in the context of total synthesis have been reported. 139,148,[159][160][161][162][163][164][165][166][167][168][169][170] One major issue that has likely contributed to little published work in the area of alkyne metathesis is preparation and use of catalysts and precatalysts, which typically requires rigorous exclusion of moisture and air in order to preserve activity. Furthermore, basic amines were known to be incompatible with the most common and readily accessible alkyne metathesis catalyst, Schrock's tungsten neopentylidyne (4.75), due to the Lewis acidic tungsten center ( Figure 34).…”