groups of Curran6 and Paterson.7 In addition, the synthesis
of the C9-C19 subunit was described by Philipps.8 Biologi-
cal studies are consistent with the hypothesis that the
macrocyclic structure of dictyostatin resembles the bioactive
conformation of the more flexible discodermolide.9 Most
recently, an analogue, 16-normethyldictyostatin, turned out
to have an activity profile toward several cell lines different
from that of dictyostatin.10
The macrolactone of dictyostatin features a dienoate, a
dienyl side chain, and several clusters of stereocenters that
are commonly found in polyketides.11,12 Proven strategies
to reach the stereotriads of discodermolide are based on aldol
reactions with the Roche aldehyde13-16 or with methacrolein
followed by hydroboration.17 To combine the various sub-
units, the Paterson group employed Wittig-Horner reactions.
The Curran synthesis features an acetylide addition to a
Weinreb amide and a Wittig-Horner coupling as key steps
for connecting the subunits.
Figure 2. Retrosynthetic cuts for dictyostatin (1).
We devised a strategy to dictyostatin on the basis of an
intramolecular Nozaki-Hiyama-Kishi reaction (Figure 2,
structure A).18-20 Building block B containing a Z-vinyl
iodide can be traced back to the 2,4-pentane diol C which is
available from the corresponding diol by enzymatic sym-
metry breaking.21 As an alternative, building block D could
also be considered. Finally, we wanted to circumvent the
use of the Roche ester because of its prohibitive costs. In
this paper, we illustrate the realization of these goals.
The meso-diol 4 is available by reduction of the anhydride
meso-3 (Scheme 1). Unfortunately, the synthesis produces
a mixture of diastereomeric anhydrides that has to be
separated by repeated recrystallization leading to a low yield
for meso-3.22 However, we found that the diastereomeric
mixture of meso-3/dl-3 could be converted more or less
completely to meso-3 by stirring the mixture with Hu¨nig’s
base in ethyl acetate. One crystallization provided the meso-
anhydride in excellent yield. The derived diol 4 was then
converted to the acetate 5 using lipase Amano AK in the
presence of vinyl acetate.23 This reaction could be run on a
multigram scale in high ee (98%). Silylation and basic
cleavage of the acetate gave alcohol 7.24 This operation could
be performed without chromatography. Oxidation25 of alco-
hol 7 with bis(acetoxy)iodobenzene in the presence of
catalytic amounts of tetramethyl-1-piperidinyloxyl (TEMPO)
(4) Paterson, I.; Britton, R.; Delgado, O.; Wright, A. E. Chem. Commun.
2004, 632-633.
(5) Shin, Y.; Choy, N.; Balachandran, R.; Madiraju, C.; Day, B. W.;
Curran, D. P. Org. Lett. 2002, 4, 4443-4446.
(6) Shin, Y.; Fournier, J.-H.; Fukui, Y.; Bru¨ckner, A. M.; Curran, D. P.
Angew. Chem. 2004, 116, 4734-4737; Angew. Chem., Int. Ed. 2004, 43,
4634-4637.
(7) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K. G.
Angew. Chem. 2004, 116, 4729-4733; Angew. Chem., Int. Ed. 2004, 43,
4629-4633.
(8) O’Neil, G. W.; Phillips, A. J. Tetrahedron Lett. 2004, 45, 4253-
4256.
(9) Madiraju, C.; Edler, M. C.; Hamel, E.; Raccor, B. S.; Van Balachan-
dran, R.; Zhu, G.; Giuliano, K. A.; Vogt, A.; Shin, Y.; Fournier, J.-H.;
Fukui, Y.; Brueckner, A. M.; Curran, D. P.; Day, B. W. Biochemistry 2005,
44, 15053-15063.
(10) Shin, Y.; Fournier, J.-H.; Balachandran, R.; Madiraju, C.; Raccor,
B. S.; Zhu, G.; Edler, M. C.; Hamel, E.; Day, B. W.; Curran, D. P. Org.
Lett. 2005, 7, 2873-2876.
(11) Lergier, J. G.; Broadbelt, L. J.; Hatzimanikatis, V. J. Am. Chem.
Soc. 2005, 127, 9930-9938.
(12) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677-
690.
(18) For recent examples of intramolecular Nozaki-Hiyama-Kishi
reactions, see: (a) Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge,
C. E.; Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,
6563-6579. (b) Banfi, L.; Guanti, G. Tetrahedron Lett. 2000, 41, 6523-
6526. (c) Trost, B. M.; Pinkerton, A. B. J. Org. Chem. 2001, 66, 7714-
7722. (d) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2003, 125, 6650-6652. (e) Venkatraman, L.; Aldrich, C. C.; Sherman,
D. H.; Fecik, R. A. J. Org. Chem. 2005, 70, 7267-7272. (f) Namba, K.;
Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382-15383.
(13) (a) Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman,
M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 2000, 122, 8654-8664. (b) Smith, A. B., III; Freeze, B. S.; Xian, M.;
Hirose, T. Org. Lett. 2005, 7, 1825-1828.
(14) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Daeffler, R.; Osmani,
A.; Schreiner, K.; Seeger-Weibel, M.; Berod, B.; Schaer, K.; Gamboni, R.;
Chen, S.; Chen, W.; Jagoe, C. T.; Kinder, F. R., Jr.; Loo, M.; Prasad, K.;
Repic, O.; Shieh, W.-C.; Wang, R.-M.; Waykole, L.; Xu, D. D.; Xue, S.
Org. Process Res. DeV. 2004, 8, 92-100 and the following four papers in
the same issue.
(15) For reviews, see: (a) Kalesse, M. ChemBioChem 2000, 1, 171-
175. (b) Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193-2208.
(16) This short route to stereotriads allowed for the synthesis of various
discodermolide analogues: (a) Johns, S. J.; Sundermann, K. F.; Burlingame,
M. A.; Myles, D. C.; Freeze, B. S.; Xian, M.; Brouard, I.; Smith, A. B., III.
J. Am. Chem. Soc. 2005, 127, 6532-6533. (b) Smith, A. B., III; Xian, M.
Org. Lett. 2005, 7, 5229-5232. (c) Smith, A. B., III; Rucker, P. V.; Brouard,
I.; Freeze, B. S.; Xia, S.; Horwitz, S. B. Org. Lett. 2005, 7, 5199-5202.
(d) Smith, A. B., III; Xian, M.; Liu, F. Org. Lett. 2005, 7, 4613-4616. (e)
Smith, A. B., III; Freeze, B. S.; LaMarche, M. J.; Hirose, T.; Brouard, I.;
Xian, M.; Sundermann, K. F.; Shaw, S. J.; Burlingame, M. A.; Horwitz, S.
B.; Myles, D. C. Org. Lett. 2005, 7, 315-318. (f) Smith, A. B., III; Freeze,
B. S.; Xian, M.; Hirose, T. Org. Lett. 2005, 7, 1825-1828.
(17) Loiseleur, O.; Koch, G.; Wagner, T. Org. Process Res. DeV. 2004,
8, 597-602.
(19) For a review, see: Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1046.
(20) For an intermolecular Nozaki-Hiyama-Kishi reaction of a Z-vinyl
iodide, see: Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D.
C. J. Org. Chem. 2003, 68, 6646-6660.
(21) For a review, see: Garc´ıa-Urdiales, E.; Alfonso, I.; Gotor, V. Chem.
ReV. 2005, 105, 313-354.
(22) (a) Boulet, S. L.; Paquette, L. A. Synthesis 2002, 895-900. (b)
Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain, G. Org.
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(23) (a) Lin, G.-Q.; Xu, W.-C. Tetrahedron 1996, 52, 5907-5912. (b)
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(24) For the enantiomer of 7, see: Nagamitsu, T.; Takano, D.; Fukuda,
T.; Otoguro, K.; Kuwajima, I.; Harigaya, Y.; Oˆ mura, S. Org. Lett. 2004, 6,
1865-1867.
(25) (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974-6977. (b) Rychnovsky, S. D.; Vaidy-
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Org. Lett., Vol. 8, No. 6, 2006