Efficient and selective formation of macrocyclic disubstituted Z alkenes by ring-closing metathesis (RCM) reactions catalyzed by Mo- or W-based monoaryloxide pyrrolide (MAP) complexes: applications to total syntheses of epilachnene, yuzu lactone, ambrettolide, epothilone C, and nakadomarin A.
The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.2-7.5 mol% of a Mo- or W-based monoaryloxide pyrrolide (MAP) complex at 22 °C and proceed to complete conversion typically within two hours. Utility is demonstrated by synthesis of representative macrocyclic alkenes, such as natural products yuzu lactone (13-membered ring: 73% Z) epilachnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanced precursor to epothilones C and A (16-membered ring: up to 97% Z), and nakadomarin A (15-membered ring: up to 97% Z). We show that catalytic Z-selective cyclizations can be performed efficiently on gram-scale with complex molecule starting materials and catalysts that can be handled in air. We elucidate several critical principles of the catalytic protocol: 1) The complementary nature of the Mo catalysts, which deliver high activity but can be more prone towards engendering post-RCM stereoisomerization, versus W variants, which furnish lower activity but are less inclined to cause loss of kinetic Z selectivity. 2) Reaction time is critical to retaining kinetic Z selectivity not only with MAP species but with the widely used Mo bis(hexafluoro-tert-butoxide) complex as well. 3) Polycyclic structures can be accessed without significant isomerization at the existing Z alkenes within the molecule.
Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
Chenbo
C
Wang
Miao
M
Yu
Andrew F
AF
Kyle
Pavol
P
Jakubec
Darren J
DJ
Dixon
Richard R
RR
Schrock
Amir H
AH
Hoveyda
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D003516:Cycloparaffins / Q000138:chemical synthesis* / Q000737:chemistry; D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D008982:Molybdenum / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism
D000470:Alkaloids; D001688:Biological Products; D001952:Bridged-Ring Compounds; D002243:Carbolines; D003516:Cycloparaffins; D034261:Epothilones; D007783:Lactones; D047028:Macrocyclic Compounds; C583632:ambrettolide; C476640:nakadomarin A; C081529:epilachnene; C426624:epothilone C; D012428:Ruthenium; D008982:Molybdenum