A R T I C L E S
Fu¨rstner et al.
Scheme 2 a
As has been reported recently, however, this somewhat
conservative and seemingly secure blueprint could not be
reduced to practice.7a Although the chosen strategy brought seco-
acid 5 into reach, we were unable to effect its cyclization by
any of the standard lactonization protocols. Most notably, the
Yamaguchi method converted 5 into the phenol derivative 8
by an unprecedented aromatization process which is believed
to involve ketene intermediates as shown in Scheme 1.7a,14 This
failure prompted a major revision of the original synthesis plan
because the closure of the iejimalide’s 24-membered ring needed
to be relocated from the ester C-O bond to a distal C-C bond
within the backbone.
Among the various conceivable scenarios, we opted for ring-
closing metathesis (RCM).15 Despite our excellent and long-
lasting experiences with this transformation,16,17 this strategic
decision bore considerable risk and might even seem somewhat
counterintuitive. Application of RCM to the iejimalide case
demands for no less than the selective activation of 2 out of 10
double bonds in a suitable cyclization precursor. Furthermore,
conjugated dienes in general are somewhat capricious substrates
for metathetic transformations, not least because Grubbs-type
carbene complexes can react either with the terminal or the
internal double bond; in the latter case, cyclization affords
undesired ring-contracted homologues, whereas insufficient
regiocontrol over the site of attack leads to mixtures of limited
synthetic utility.18 Moreover, the still missing control over the
stereochemical outcome of RCM-based macrocylizations may
increase the number of possible isomers even further.19,20
Finally, one has to keep in mind that polar substituents in the
substrate, when located at positions where they can chelate the
incipient metal carbene intermediates, strongly impact the
effectiveness of RCM-based macrocyclizations.16,21 In consid-
eration of these daunting issues, it appeared to us that the C.11-
C.12 double bond in 2 might be the only promising site, if any,
for an RCM-based approach toward this particular target.
Preparation of the Building Blocks. The synthetic route to
iejimalide B commenced with the acylation of commercial bis-
(trimethylsilyl)ethyne with 4-pentenoic acid chloride 9, which
a Reagents and conditions: (a) bis(trimethylsilyl)acetylene, AlCl3,
CH2Cl2, 0 °C, 83%; (b) complex 11 (0.6 mol %), i-PrOH, 98% (ee )
98.8%); (c) (i) n-BuLi, MeI, THF, -78 °C; (ii) DMSO, -25 °C f room
temperature; (d) OsO4 cat., NaIO4, 2,6-lutidine, aqueous 1,4-dioxane, 74%
(over both steps); (e) (CF3CH2O)2P(O)CH(Me)COOMe, KHMDS, 18-
crown-6 (0.7 equiv), toluene, -20 °C, 87%; (f) (i) DIBAl-H, CH2Cl2, -78
°C; (ii) MnO2, CH2Cl2, 96% (over both steps); (g) [Ph3PCH3]+Br-, n-BuLi,
THF, -78 °C f room temperature, quantitative; (h) K2CO3, MeOH, 83%;
(i) pinacolborane, 9-BBN (10 mol %), THF, 45 °C, 56%.
gave the monosubstitution product 10 in 83% yield on a >16
g scale after convenient purification by Kugelrohr distillation
(Scheme 2).22 Asymmetric reduction of the ketone by transfer
hydrogenation following Noyori’s conditions worked admirably
well, furnishing propargyl alcohol 12 in 98% yield in almost
optically pure form (ee ) 98.8%) without affecting the olefinic
(18) For leading references on the synthesis of cyclic 1,3-dienes by RCM and
illustrations of the associated selectivity issues, see: (a) Sedrani, R.; Kallen,
J.; Martin Cabrejas, L. M.; Papageorgiou, C. D.; Senia, F.; Rohrbach, S.;
Wagner, D.; Thai, B.; Eme, A.-M. J.; France, J.; Oberer, L.; Rihs, G.; Zenke,
G.; Wagner, J. J. Am. Chem. Soc. 2003, 125, 3849. (b) Paquette, L. A.;
Basu, K.; Eppich, J. C.; Hofferberth, J. E. HelV. Chim. Acta 2002, 85, 3033.
(c) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J.
Am. Chem. Soc. 2001, 123, 10903. (d) Yang, Z.-Q.; Geng, X.; Solit, D.;
Pratislas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004,
126, 7881. (e) Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell, M. D.;
Chou, T.-C.; Guan, Y.; Tong, W. P.; He, L.; Horwitz, S. B.; Danishefsky,
S. J. J. Am. Chem. Soc. 2002, 124, 9825. (f) Dvorak, C. A.; Schmitz, W.
D.; Poon, D. J.; Pryde, D. C.; Lawson, J. P.; Amos, R. A.; Meyers, A. I.
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Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem., Int.
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(14) For another instructive example implying the formation of ketenes during
Yamaguchi lactonization see: (a) Va, P.; Roush, W. R. Org. Lett. 2007, 9,
307. (b) Va, P.; Roush, W. R. Tetrahedron 2007, 63, 5768.
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