“Trimethyl lock” facilitated spirocyclizations: A structural analysis

A trimethyl lock was shown earlier to significantly facilitate certain cyclization reactions. Our renewed interests in such facile cyclization systems stemmed from their potential applications in the preparation of redox-, esterase-, and phosphatase-sensitive prodrugs. Furthermore, such systems have also been used for the development of redox-sensitive protecting groups for amines and alcohols. However, there is an undesirable spirocyclization reaction associated with certain trimethyl lock facilitated cyclization systems. In an effort to probe factors important for the controlling of the undesirable spirocyclization reaction, we undertook the X-ray crystallographic studies of the such trimethyl lock facilitated spirocyclization systems. The spirocyclization product was crystallized from ethyl acetate/hexane mixture (space group: P2₁/c,a=13.467(1),b=13.297(2),c=13.626(8) Å, =92.120(6)°. It was found that spirocyclization results in release of steric congestion caused by the trimethyl lock to a larger degree than the desired lactonization. However, this release of steric congestion itself is not enough to bring about the cyclization. A kinetically reactive nucleophile is also essential for the initiation of the spirocyclization reaction. This is consistent with the fact that such spirocyclization reactions require specific base catalysis.     

Synthesis of Z and E-(2',5'-dimethoxyphenyl)-methylene-butyrolactones

Pseudotaxlactone was isolated by Zhang1 from Taxaceae plant pseudotaxus chienii(Cheng) Cheng. It's structure was tentatively assigned as 5-(4-hydroxy-3,5- 20%(Z,9), 4%(E,8).The intermediate 7 was synthesized using 2,5-dimethoxy-phenyl acetic acid as astarting material. However, cyclization reaction gave Z-(2,5-dimethoxy-phenyl)methylene-butyrolactone 9 (20%) and E-(2,5-dimethoxy-phenyl)-methylelactone 8 (4%), instead of the desired counterpart with endocyclic unsaturation. Thereaction of t…     

Accidental discovery of a ‘longer-range’ vinylogous Pummerer-type lactonization: formation of sulindac sulfide lactone from sulindac

Unexpected formation of sulindac sulfide lactone occurred when sulindac was treated with oxalyl chloride and triethylamine. Structurally analogous sulindac sulfide and indomethacin did not undergo such lactonization under similar reaction conditions. We believe that the sulfoxide function in sulindac plays a pivotal role possibly via a ‘longer-range’ vinylogous Pummerer-type reaction as a driving force for the observed lactonization. The structure of the lactone was confirmed by single crystal X-ray analysis.     

Formal synthesis of Cladospolide C & epi-Cladospolide C using R-(+)-γ-valerolactone as a chiral synthon

The formal synthesis of Cladospolide-C and its analog is achieved by using enantiopure (R)-γ–valerolactone 10. The significant points of this synthesis are the stereoselective dihydroxylation of α, β-unsaturated ester 16 using Sharpless protocol, Wittig olefination of γ –valerolactol 6 with triphenylphosphonium iodide salt 7, one pot selective oxidation of 22 and subsequent C2-homologation with good E/Z ratio.     

Total synthesis of the aromatase inhibitor dihydroisocoumarin via protective opening of lactones

Asymmetric total synthesis of a dihydroisocoumarin, (3R,4R)-(−)-6-methoxy-1-oxo-3-pentyl-3,4-dihydro-1H-isochromen-4-yl acetate (1) starting from commercially available m-anisic acid is described. Herein, we depict the use of protective opening of lactones and construction of δ lactone. The synthesis involves Wittig, Grubbs cross metathesis, and Sharpless dihydroxylation reactions.     

An improved synthesis of (−)-brevisamide, a marine monocyclic ether amide of dinoflagellate origin

An improved synthesis of (−)-brevisamide a marine cyclic ether isolated from the red-tide dinoflagellate Karenia brevis was achieved. The ether ring portion was constructed from an unsaturated lactone, which was prepared enantioselectively via an Evans aldol reaction and one-pot lactonization in the presence of excessive base after an Ando reaction. The ether ring and a dienol side chain fragment were connected via Suzuki-Miyaura coupling.     

Stereoselective synthesis of C1-C9 and C9-C17 fragments of (+)-13-deoxytedanolide

An efficient and highly stereoselective asymmetric synthesis of C1-C9 and C9-C17 fragments of (+)-13-deoxytedanolide have been achieved. Utilization of desymmetrization technique to prepare the triol with five stereogenic centers, regioselective Sharpless asymmetric dihydroxylation, Evans' aldol reaction, chiral methylation, and Wittig olefination are highlights of the synthesis.     

Stereoselective total synthesis of stagonolide E

The first total synthesis of a 10-membered macrolide, stagonolide E is described from readily available 4-penten-1-ol. The synthetic strategy involves Jacobsen’s kinetic resolution, Sharpless epoxidation, Stille-Gennari, and Yamaguchi lactonization as key reactions.     

Stereoselective synthesis (+)-cephalosporolide D

A simple and efficient stereoselective synthesis of macrolactone, (+)-cephalosporolide D has been accomplished in 13 steps from inexpensive and commercially available starting materials in an overall yield of 17%, respectively. This convergent synthesis utilizes Maruoka asymmetric allylation reaction, Grubb’s cross metathesis for the formation of a fully functionalized acid, and Yamaguchi lactonization as key steps.