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O
O
O
O
O
O
N
N
N
OMe
OMe
OMe
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
90
88
92
O
O
O
N
N
N
O
O
O
OMe
OMe
OMe
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
91
Styryl-Homoallyl
87
Allyl-Allyl
93
Homoallyl-Vinyl
Scheme 15.20 Three possible strategies for macrocyclization via RCM en route to
vaniprevir (57).
Mes
N
N
Mes
Cl
Ru
Cl
O
94
Figure 15.5
Structure of second-generation Grubbs-Hoveyda catalyst.
When the reaction was first attempted with 1 or 5 mol% of the second-
generation Grubbs-Hoveyda catalyst 94 (Figure 15.5) in toluene at 60 1C,
modest yields were obtained (57 and 67%, respectively) after the subsequent
hydrogenation step. A closer look at the reaction kinetics revealed that the
catalyst was very active at the initial stages of the reaction but its activity
decreased as the reaction proceeded. In addition, during the final stages of
the reaction, the formation of oligomers and other impurities increased.
However, this problem was easily solved via slow addition of the catalyst
(1 mol%) to the reaction mixture (50 mL of toluene per gram of diene 87)at
60 1C over 1 h, which afforded cyclized product 89 in 82% yield for the RCM
and hydrogenation steps combined.
The high dilution employed during the process development described
above was then addressed with the goal of increasing the throughput of the
process. Thus, when the reaction was carried out in 30 vol. of solvent
(0.058 M), the yield decreased to 61% and 19-membered by-product 95 was
obtained, presumably via double-bond isomerization caused by the Ru-H
complex which is formed after Ru catalyst decomposition.
124
Double-bond
isomerization can be limited through the use of quinone additives, which
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