Using stereoretention for the stereoselective formation of e-macrocycles with Ru-based olefin metathesis catalysts

A method for producing at least one E-macrocyclic product represented by Formula (III),

• wherein:
• Rr2 is H or linear C1-3 alkyl;
• n is 1, 2, 3, 4, 5 or 6;
• m is 4, 5, 6, or 7;
• and the E-macrocyclic product of Formula (III) is a twelve, thirteen, fourteen, fifteen, sixteen or eighteen-membered ring with an E-selectivity of 95, or 98, or 99, or >99%;
• comprising:
• subjecting a diene substrate bearing two E-olefins or bearing one E-olefin and one terminal olefin, represented by Formula (II)
• wherein:
• n is 1, 2, 3, 4, 5 or 6;
• m is 4, 5, 6 or 7;
• R is H, linear or branched C1-12 alkyl;
• Rr1 is H, linear or branched C1-12 alkyl;
• Rr2 is H or linear C1-3 alkyl;
• and with the proviso that only one of R and Rr1 can be H;
• to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive ruthenium olefin metathesis catalyst represented by Formula (I),
• wherein
• X is O or S;
• Y is O or S;
• Z is N or CR32;
• W is O, halogen, NR33 or S;
• R1 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R2 can form a spiro compound or together with R3 or together with R4 can form a polycyclic ring;
• R2 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl or together with R1 can form a spiro compound or together with R3 or together with R4 can form a polycyclic ring;
• R3 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl or together with R2 or together with R1 can form a polycyclic ring or together with R4 can form a spiro compound;
• R4 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R3 can form a spiro compound or together with R2 or together with R1 can form a polycyclic ring;
• R5 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R6 can form an optionally substituted polycyclic ring;
• R6 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R5 or together with R7 can form an optionally substituted polycyclic ring;
• R7 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl optionally substituted C3-8 cycloalkenyl, or together with R6 or together with R8 can form an optionally substituted polycyclic ring;
• R8 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R7 or together with R9 can form an optionally substituted polycyclic ring;
• R9 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R8 can form an optionally substituted polycyclic ring;
• R10 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R11 can form an optionally substituted polycyclic ring;
• R11 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl or together with R10 or together with R12 can form an optionally substituted polycyclic ring;
• R12 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R11 or together with R13 can form an optionally substituted polycyclic ring;
• R13 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R14 or together with R12 can form an optionally substituted polycyclic ring;
• R14 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R13 can form a polycyclic ring;
• R15 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl, or together with R16 can form an optionally substituted polycyclic ring;
• R16 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl, or together with R15 or together with R17 can form an optionally substituted polycyclic ring;
• R17 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl, or together with R18 or together with R16 can form an optionally substituted polycyclic ring;
• R18 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl, or together with R18 can form an optionally substituted polycyclic ring;
• R19 is H, optionally substituted C1-24 alkyl, —C(R34)(R35)COOR36, —C(R34)(R35)C(O)H, —C(R34)(R35)C(O)R37, —C(R34)(R35)CR38(OR39)(OR40), —C(R34)(R35)C(O)NR41R42, —C(R34)(R35)C(O)NR41OR40, —C(O)R25, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R33 can form an optionally substituted heterocyclic ring or is nil when W is halogen;
• R20 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl or together with R21 can form a polycyclic ring;
• R21 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl or together with R20 or together with R22 can form a polycyclic ring;
• R22 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl or together with R21 or together with R23 can form a polycyclic ring;
• R23 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl or together with R22 can form a polycyclic ring;
• R24 is H, optionally substituted C1-24 alkyl, halogen, —C(O)R25, —OR26, CN, —NR27R28, NO2, —CF3, —S(O)xR29, —P(O)(OH)2, —OP(O)(OH)2, —SR31, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R25 is OH, OR30, NR27R28, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl,
• R26 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R27 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R28 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R29 is H, optionally substituted C1-24 alkyl, OR26, —NR27R28, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R30 is optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R31 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R32 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R33 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl, optionally substituted C3-8 cycloalkenyl, or together with R19 can form an optionally substituted heterocyclic ring;
• R34 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R35 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R36 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R37 is optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R38 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R39 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R40 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R41 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• R42 is H, optionally substituted C1-24 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C5-24 aryl or optionally substituted C3-8 cycloalkenyl;
• and
• x is 1 or 2.