species, Cp2TidCH2), we examined the effect of possible
scavengers or additives with sacrificial CO groups17 such
as tert-butyl acetate, N-butyryl-4-benzyl-1,3-oxazolidin-2-
one, or DMF. DMF (20 mol %) turned out to be the
scavenger of choice: although the conversion was incomplete
(76%, with 1.2 equiv of Cp2TiMe2),18 only the methylenated
compound, 4, was formed and the remaining starting material
was fully recovered (100% yield brsm). It is worth noting
that the chiral auxiliary survived (was amenable to) the cross
metathesis conditions and methylenation reaction. Finally,
standard removal of the chiral auxiliary gave carboxylic acid
5 in practically quantitative yield. Therefore, we had achieved
carboxylic acid 5 in g95% overall yield from 1.
°C, then Et3N),20 afforded the desired azido-aldehyde 7 in
high overall yield from 1 (g75%). Among several alterna-
tives for the allylation21 of 7, we chose the allylsilane
derivative reported by Leighton et al.,22 shown in Scheme
3, mainly because it had given us excellent results in another
total synthesis. Reaction of 7 with freshly prepared (S,S)-
siladiazolidine (Leighton reagent, LR) afforded the syn
adduct 8a in 86% yield as a single product by 1H NMR (dr
>98:2).23 The hydroxyl group of 8a was protected as its TBS
ether 8b.
The direct coupling of the azide group of 8b with
carboxylic acid 5 gave amide 9 quantitatively (Scheme 4)
The C7-C13 fragment was synthesized from azide 6,
according to Scheme 3. We prepared this azide by the one-
Scheme 4. RCM and Hydrogenation
Scheme 3. Synthesis of Azides 8
pot hydroboration (with cyclohexene and PhNEtiPr-BH3) and
iodination of 1 (86% overall),12d followed by the quantitative
replacement of the iodine atom by azide anion in DMSO at
rt.19 The standard reductive removal of the auxiliary of 6,
followed by the Swern reaction (DMSO/ClCOCOCl, -78
by using a catalytic variant of the Staudinger-Vilarrasa
reaction.24 However, as this particular reaction was too slow
at rt, with catalytic amounts of 2,2′-dipyridyl diselenide
(PySeSePy), we effected it stoichiometrically.
We were ready to subject amide 9 to a RCM. To generate
a macrocycle-embedded trisubstituted double bond with the
desired configuration by RCM is a difficult task.25 In light
of our previous studies with other macrocyclic substrates,25e
we used 20 mol % of H-G II initiator in toluene at 80 °C.
(13) Representative review: Hoveyda, A. H.; Zhugralin, A. R. Nature
2007, 450, 243.
(14) In this case, the Grubbs II initiator gave only 50% of conversion
after 5 h in refluxing CH2Cl2 (18% after 5 h at rt).
(15) For CM studies with propenal (acrolein), alkyl acrylates, vinyl
ketones, and related derivatives, see: (a) O’Leary, D. J.; Blackwell, H. E.;
Washenfelder, R. A.; Miura, K.; Grubbs, R. H. Tetrahedron Lett. 1999,
40, 1091. (b) Blanco, O. M.; Castedo, L. Synlett 1999, 557. (c) Blackwell,
H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann,
D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58. (d) Chatterjee,
A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783. (e) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet.
Chem. 2001, 634, 216. (f) Dreher, S. D.; Leighton, J. L. J. Am. Chem. Soc.
2001, 123, 341. (g) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451. (h)
Cossy, J.; Bargiggia, F.; BouzBouz, S. Org. Lett. 2003, 5, 459. (i) Chatterjee,
A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360. (j) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900. (k) Lee, C.-H. A.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 809. (l)
Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K. Org. Lett.
2008, 10, 1325. (m) Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2008,
10, 4489.
(20) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(21) For illustrative reviews, see: (a) Kargbo, R. B.; Cook, G. R. Curr.
Org. Chem. 2007, 11, 1287. (b) Zanoni, G.; Pontiroli, A.; Marchetti, A.;
Vidari, G. Eur. J. Org. Chem. 2007, 3599. (c) Hall, D. G. Synlett 2007,
1644. (d) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (e) Kennedy,
J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732.
(22) (a) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42,
946. (b) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc.
2003, 125, 9596. (c) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L.
Org. Lett. 2004, 6, 4375. (d) Zhang, X.; Houk, K. N.; Leighton, J. L. Angew.
Chem., Int. Ed. 2005, 44, 938. For a recent application, see: (e) Guo, H.;
Mortensen, M. S.; O’Doherty, G. A. Org. Lett. 2008, 10, 3149.
(23) The allylsilane reagent derived from (R,R)-pseudoephedrine gave,
under identical conditions, yields around 60% and a 88:12 dr (syn/anti).
(24) Bure´s, J.; Mart´ın, M.; Urp´ı, F.; Vilarrasa, J. J. Org. Chem. 2009,
74, 2203.
(16) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392. For a review of Ti-based alkylidenations, see: (b) Hartley, R. C.; Li,
J.; Main, C. A.; McKiernan, G. J. Tetrahedron 2007, 63, 4825.
(17) (a) 1,1-Dimethyl-2-phenylethyl acetate has been used as a sacrificial
additive: Payack, J. F.; , M. A.; Cai, D.; Hughes, D. L.; Collins, P. C.;
Johnson, B. K.; Cottrel, I. F.; Tuma, L. D. Org. Process Res. DeV. 2004,
8, 256. For the use of ethyl pivalate, cf. : (b) Smith, A. B.; Razler, T. M.;
Ciavarri, J. P.; Hirose, T.; Ishikawa, T.; Meis, R. M. J. Org. Chem. 2008,
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(18) This is the optimum conversion yield (and the maximum recovery
of 3) we found, after various experiments with higher ratios of DMF and/
or Cp2TiMe2.
(25) Very recent reviews on RCM: (a) Coquerel, Y.; Rodriguez, J. Eur.
J. Org. Chem. 2008, 1125. (b) Kotha, S.; Lahiri, K. Synlett 2007, 2767. (c)
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