Total synthesis of the potent microtubule-stabilizing agent (+)-discodermolide

Article abstract of DOI:10.1021/jo034521r

The total synthesis of the potent microtubule-stabilizing, antimitotic agent (+)-discodermolide is described. The convergent synthetic strategy takes advantage of the diastereoselective alkylation of a ketone enolate to establish the key C15-C16 bond. The synthesis is amenable to preparation of gram-scale quantities of (+)-discodermolide and analogues.

Full text of DOI:10.1021/jo034521r

Tota l Syn th esis of th e P oten t Micr otu bu le-Sta bilizin g Agen t
(+)-Discod er m olid e
Scott S. Harried,† Christopher P. Lee,† Ge Yang,† Tony I. H. Lee,† and David C Myles*,†,‡
Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, and
Kosan Biosciences, Hayward, California 94545
myles@kosan.com
Received April 22, 2003
The total synthesis of the potent microtubule-stabilizing, antimitotic agent (+)-discodermolide is
described. The convergent synthetic strategy takes advantage of the diastereoselective alkylation
of a ketone enolate to establish the key C15-C16 bond. The synthesis is amenable to preparation
of gram-scale quantities of (+)-discodermolide and analogues.
In tr od u ction
to inhibit growth of colon, ovarian,10 and breast carci-
noma cells.11 Of particular interest is the recent report
that discodermolide has been found to function syner-
gistically with taxol.12
This paper describes the total synthesis of the potent
microtubule stabilizing agent (+)-discodermolide (1) and
its C7-epimeric analogue via a highly convergent and
versatile synthetic strategy. Isolated from the Caribbean
sponge Discodermia dissoluta in 0.002% yield,1 1 was
identified by its apparent immunosuppressive activity in
both in vitro (IC50 values in the 9-14 nM range)2 and in
vivo3 studies. A subsequent series of experiments re-
vealed discodermolide to be a microtubule-stabilizing
(MT) agent that, like taxol, arrests cells at the G2/M
boundary of the cell cycle.4,5 MT-stabilizing agents com-
prise a growing class of promising chemotherapeutic
agents that include such natural products as the
epothilones, eleuthrobin, laulimalide, and discoder-
molide.6 Discodermolide was found to bind to microtu-
bules at one molecule per tubulin dimer with an approxi-
mate 100 times greater affinity than taxol.7,8 Interestingly,
synthetic samples of both antipodes of discodermolide
were reported to have antiproliferative activity, in which
(-)-discodermolide was found to block the cell cycle at
the S phase.9 The chemotherapeutic potential of (+)-
discodermolide was recently demonstrated in its ability
Resu lts a n d Discu ssion
Discodermolide’s potent biological activity and limited
natural availability have spurred synthetic efforts13,14
(Figure 1). We adopted a highly convergent strategy for
the total synthesis of discodermolide, disconnecting the
molecule into three subunits of similar size and complex-
ity, to afford fragments of similar complexity (Figure 2).
In the synthetic direction, the C15-C16 bond was
envisioned to be formed via a chelation-controlled alky-
lation of the lithium enolate derived from ethyl ketone 5
(10) Kowalski, R. J .; Giannakakou, P.; Gunasekera, S. P.; Longley,
R. E.; Day, B. W.; Hamel, E. Mol. Pharmacol. 1997, 52, 613.
(11) Balachandran, R.; ter Haar, E.; Welsh, M. J .; Grant, S. G.; Day,
B. W. Anti-Cancer Drugs 1998, 9, 67.
(12) Martello, L. A.; McDaid, H. M.; Regl, D. L.; Yang, C.-P. H.;
Meng, D.; Pettus, T. R. R.; Kaufman, M. D.; Arimoto, H.; Danishefsky,
S. J .; Smith, A. B., III.; Horwitz, S. B. Clin. Cancer Res. 2000, 6, 1978.
(13) (a) Paterson, I.; Wren, S. P. J . Chem. Soc., Chem. Commun.
1993, 1790. (b) Clark, D. L.; Heathcock, C. H. J . Org. Chem. 1993, 58,
5878. (c) Golec, J . M. C.; J ones, S. D. Tetrahedron Lett. 1993, 34, 8159.
(d) Evans, P. L.; Golec, J . M. C.; Gillespie, R. J . Tetrahedron Lett. 1993,
34, 8163. (e) Golec, J . M. C.; Gillespie, R. J . Tetrahedron Lett. 1993,
34, 8167. (f) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 1313.
(g) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 2503. (h)
Paterson, I.; Schlapbach, A. Synlett 1995, 5, 498. (i) Miyazawa, M.;
Oonuma, S.; Maruyama, K.; Miyashita, M. Chem. Lett. 1997, 1191. (j)
Miyazawa, M.; Oonuma, S.; Maruyama, K.; Miyashita, M. Chem. Lett.
1997, 1193. (k) Marshall, J . A.; Lu, Z.-H.; J ohns, B. A. J . Org. Chem.
1998, 63, 817.
(14) (a) Nerenberg, J . B.; Hung, D. T.; Somers, P. K.; Schreiber, S.
L. J . Am. Chem. Soc. 1993, 115, 12621. (b) Smith, A. B., III.; Qiu, Y.;
J ones, D. R.; Kobayashi, K. J . Am. Chem. Soc. 1995, 117, 12011. (c)
Hung, D. T.; Nerenberg, J . B.; Schreiber, S. L. J . Am. Chem. Soc. 1996,
118, 11054. (d) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J .
Org. Chem. 1997, 62, 6098. (e) Marshall, J . A.; J ohns, B. A. J . Org.
Chem. 1998, 63, 7885. (f) Smith, A. B., III.; Kaufman, M. D.;
Beauchamp, T. J .; LaMarche, M. J .; Arimoto, H. Org. Lett. 1999, 1,
1823. (g) Smith, A. B., III.; Beauchamp, T. J .; LaMarche, M. J .;
Kaufman, M. D.; Qiu, Y.; Arimoto, H.; J ones, D. R.; Kobayashi, K. J .
Am. Chem. Soc., 2000, 122, 8654. (h) Paterson, I.; Florence, G. J .;
Gerlach, K.; Scott, J . P.; Sereinig, N. J . Am. Chem. Soc. 2001, 123,
9535. (i) Paterson, I.; Delgado, O.; Florence, G. J .; Lyothier, I.; Scott,
J . P.; Sereinig, N. Org. Lett. 2003, 5, 35.
* Corresponding author. Tel: (510) 732-8400 ext 261. Fax: (510)
732-8401.
† UCLA.
‡ Kosan Biosciences.
(1) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G.
K. J . Org. Chem. 1990, 55, 4912. Correction: J . Org. Chem. 1991, 56,
1346.
(2) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.;
Gunasekera, S. P. Transplantation 1991, 52, 650. Correction: Trans-
plantation 1993, 55, 236.
(3) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.;
Gunasekera, S. P. Transplantation 1991, 52, 656.
(4) Longley, R. E.; Gunasekera, S. P.; Faherty, D.; McLane, J .;
Dumont, F. Ann. N. Y. Acad. Sci. 1993, 696, 94.
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Am. Assoc. Cancer Res. 1994, 35, 337.
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(7) ter Haar, E.; Kowalski, R. J .; Hamel, E.; Lin, C. M.; Longley, R.
E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry
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(8) Hung, D. T.; Chen, J .; Schreiber, S. L. Chem. Biol. 1996, 3, 287.
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1, 67.
10.1021/jo034521r CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/25/2003
6646
J . Org. Chem. 2003, 68, 6646-6660

Total Synthesis of (+)-Discodermolide
F IGURE 1. Synthese of (+)-discodermolide (1).
F IGURE 2. Retrosynthesis of discodermolide.
by allylic iodide 4. We had previously demonstrated that
this reaction could afford diastereoselectivities and yields
suitable for the synthesis of a complex target and were
confident that our methodology could be incorporated
successfully in the synthesis of (+)-discodermolide.13f,g
We considered, and ultimately investigated (vide infra),
two options for coupling in the C7 to C9 region of the
discodermolide backbone. Option A called for a Wittig-
type Z-selective olefination process to establish the C8-
C9 bond. Option B called for the diastereoselective
addition of a Z-vinyl anion equivalent at C8 to a C7
aldehyde to establish simultaneously the desired C7
stereochemistry and the C7-C8 bond. A priori, each of
these approaches has visible and hidden strengths and
weaknesses. It remained for experimentation to distin-
guish between these two options. Although portions of
the work described in this paper were initially carried
out in the (-)-discodermolide series, for clarity all figures
depict precursors of (+)-discodermolide.
F IGURE 3. Chelation-controlled alkylation.
one face of lithium (Z)-enolate 6 while exposing the other
face toward electrophilic attack (Figure 3). Interestingly,
in the context of syntheses of discodermolide based on a
similar alkylation, both Schreiber et al.14a and Heathcock
et al.13b found that the use of a p-methoxybenzyl ether
at C19 afforded alkylation products having stereochem-
istries opposite to that predicted by this chelation model.
We had chosen methoxymethyl (MOM) as the protecting
group at this position with the expectation that this
blocking group would furnish high levels of chelation
control in both the key alkylative coupling reaction and
subsequent C17 ketone reduction (vide infra).
C15-C16 Alk yla tion . We envisioned that 4 and 5
would be joined by a stereoselective alkylative coupling
in which the stereocenters of ethyl ketone 5 would
provide substrate control to establish the stereocenter at
C16. Our hypothesis was that a chelating alkoxy moiety
at C19 would impart rotational rigidity and thereby block
To investigate this alkylation reaction, we required
synthons for coupling partners 4 and 5. We prepared
allylic iodide from optically active alcohol 815,16 via a
Lewis acid-catalyzed cyclocondensation reaction of alde-
J . Org. Chem, Vol. 68, No. 17, 2003 6647

Harried et al.
F IGURE 4. Synthesis of the C9 to C21 portion of (+)-discodermolide.
hyde 9 and diene 10. The stereochemical considerations
at C10, C11, and C12, and the presence of a Z-trisubsti-
tuted alkene pose barriers to the synthesis of the C9-
C15 fragment. The cyclocondensation reaction elegantly
addresses all of these stereochemical issues through
stereochemical communication in the condensation and
the creation of a cyclic framework that enforces complete
control of the alkene geometry.17 Aldehyde 9 was obtained
from 8 via Swern18 oxidation and was used immediately
in the condensation with diene 1019 in a process promoted
by precise (1.10 equiv) stoichiometric titanium(IV). The
aldehyde-TiCl4 complex20 was treated with diene 10 to
give a mixture of condensation products. These materials
were concentrated and then taken up in benzene and
treated with catalytic TsOH to provide pyrone 11 as the
major component of a 7:1 diastereomeric mixture in 60-
80% yield. Following Luche reduction21,22 of pyrone 11,
a TsOH-promoted Ferrier rearrangement23 provided lac-
tols 12 in 80% yield over two steps. Lithium borohydride
reduction opened 12 to afford diol 13. Facile protecting
group manipulations then furnished allylic alcohol 14 in
85% yield. Allylic alcohol 14 was directly converted to
iodide 15 by treatment with triphenyl phosphite methio-
dide.24
With the synthesis of the allylic iodide 15 secure, we
next addressed the preparation of fully functionalized
analogues of ketone 5. We have described a synthesis of
this compound previously,13f,g but we found that a revised
sequence afforded superior access to synthons for 5.25
PMB-protected alcohol 16 was oxidized using oxalyl
chloride and DMSO and subjected to a standard Evans
aldol reaction26,27 to produce 18 in 88% yield with >20:1
diastereoselectivity. Aldol adduct 18 was converted to the
analogous Weinreb amide by treatment with trimethyl
aluminum and N,O-dimethylhydroxylamine.28,29 The C19
(24) Landauer, S. R.; Rydon, H. N. J . Chem. Soc. 1953, 2224.
(25) For the large-scale synthesis of (+)-discodermolide, multigram
production of ketone 19 was required. To avoid using pyrophoric
trimethylaluminum in large quantities, the synthesis of fragment 19
was modified. Aldol 18 was treated sequentially with methoxymethyl
chloride, lithium borohydride reduction, Swern oxidation, and ethyl-
magnesium bromide and resubjected to Swern oxidation to afford
ketone 19 in 62% yield over five steps. Although this synthetic line
requires two more steps than that outlined in Figure 4, the overall
yield is only slightly lower and the large-scale handling of trimethyl-
aluminum is circumvented.
(26) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 83-91.
(27) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 77-82.
(28) (a) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989. (b) Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc.
1988, 110, 2506.
(15) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(16) Walkup, R. D.; Boatman, P. D. J .; Kane, R. R.; Cunningham,
R. T. Tetrahedron Lett. 1991, 32, 3937.
(17) Danishefsky, S. J .; Pearson, W. H.; Harvey, D. F.; Maring, C.
J .; Springer, J . P. J . Am. Chem. Soc. 1985, 107, 1256.
(18) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480. Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(19) Myles, D. C.; Bigham, M. H. Org. Synth. 1986, 70, 231.
(20) Springer, J . B.; Deboard, J .; Corcoran, R. C. Tetrahedron Lett.
1995, 36, 8733.
(29) (a) Bottaro, J . C.; Hanson, R. N.; Seitz, D. E. J . Org. Chem.
1981, 46, 5221. (b) Gilbert, G. C.; Weerasooriya, U. J . Org. Chem. 1982,
47, 1837. (c) Brown, D. G.; Velthuisen, E. J .; Commerford, J . R.;
Brisbois, R. G.; Hoye, T. R. J . Org. Chem. 1996, 61, 2540.
(21) Luche, J .-L.; Gemal, A. L. J . Am. Chem. Soc. 1979, 101, 5848.
(22) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454.
(23) Ferrier, R. J . J . Chem. Soc. 1964, 5443.
6648 J . Org. Chem., Vol. 68, No. 17, 2003

Total Synthesis of (+)-Discodermolide
TABLE 1. Dih yd r oxyla tion of I
ligand
pyridine
(DHQD)2PHAL
(DHQD)2PYR
Corey diamine
conditions
equiv of OsO4
oxidant
none
K3Fe(CN)6
K3Fe(CN)6
none
C7 ratio
% yield
-90 °C, CH2Cl2
1.0
0.01
0.5
1:1
1.1:1
3.5:1
>5:1
80
80
95
tert-BuOH, H2O, 0 °C
tert-BuOH, H2O, 0 °C
-90 °C, CH2Cl2
1.0
75-88
hydroxyl group was then blocked as its MOM ether. The
final C-C bond of the desired ethyl ketone was then
prepared by treatment of the amide with excess ethyl-
magnesium bromide to complete the synthesis of C16-
C21 ketone 19 in 70% yield over three steps.
The lithium (Z)-enolate of ethyl ketone 19 (1.0 equiv)
was generated at -78 °C using lithium hexamethyldisil-
azide (1.25 equiv) and tetramethylethylenediamine (TME-
DA, 1.5 equiv). Although the precise role of the TMEDA
in this reaction is not known, it likely functions by
influencing the aggregation state of the enolate.30 Allylic
iodide 15 (0.5 equiv) was then added to the enolate in a
45:55 hexanes:THF solvent system. After 48-72 h at -78
°C, the reaction yielded a 50-70% mixture of diastere-
omers at C16 in a 5-6:1 ratio favoring what we believed,
based on the chelation model and our earlier model
experiments,13g,h to be the desired product.
After extensive experimentation, we found that many
factors impact the diastereoselectivity of this alkylative
process, including temperature, electrophile, counterion,
additive, solvent system, and concentration. A systematic
study of the percent hexanes in THF of the alkylative
coupling reaction showed a remarkable solvent effect, in
which the diastereoselectivity of the process changed
from 1:1 in 0% hexanes in THF up to 6:1 in 45% hexanes
in THF. In addition, the selectivity of this reaction was
inversely related to ketone concentration, with higher
selectivities found at lower ([ketone] < 0.16 M) concen-
trations.
The stereocenter at C17 was established using chela-
tion control with the C18 MOM group. In this case,
lithium iodide and LAH were added to ketone 20,
affording as the major product the desired diastereomer
21 in an 8:1 ratio of separable epimers at C16 in 90%
yield.31 Protection of the resulting alcohol as its TIPS
ether, followed by chemoselective deprotection of the
benzyl ether using H2 and Raney Ni32,33 (freshly prepared
and then aged for 2-4 days) provided primary alcohol
22 in 71% yield over two steps. At this point, 22 is easily
separated chromatographically from its C16 epimer.
With the C9 to C21 fragment of the discodermolide
framework in hand, we began to consider options for
formation of the C8 to C9 Z-alkene. The most inviting
strategy for fabrication of this bond was the Wittig
olefination. To prepare for this olefination, we studied
the conversion of the C9 alcohol moiety into the phos-
phonium salt. Although the literature contains a plethora
of examples in which a Wittig salt is prepared from a
primary alcohol via the iodide,34 we found that activated
forms of the alcohol at C9 of 22 were prone to undergo
an unexpected carbocyclization reaction to afford 38 as
a mixture of alkene isomers. Smith et al. had observed a
similar tendency for compounds that were activated at
C9 to undergo cyclization; however, this side reaction was
suppressed by formation of the phosphonium salt under
high-pressure conditions.14b This propensity for cycliza-
tion can be rationalized by examining the X-ray crystal
and solution structures of discodermolide, in which
carbons 9 and 13 appear to be in close proximity.35
During the same time, we were also investigating
potential strategies for the synthesis of a C1 to C8
aldehyde. Toward this end, we used unsaturated lactones
I as the substrate for a study of the osmium peroxide
mediated dihydroxylation reaction. Not surprisingly, the
substrate-controlled dihydroxylation reaction gave no
selectivity. Reagent controlled conditions would be re-
quired for successful installation of the C7 stereocenter.
Initially, we focused our efforts on the asymmetric
dihydroxylation chemistry of Sharpless, commercially
available as the AD-mix. Although these conditions did
not afford selectivity, the dihydroxylation reaction cata-
lyzed by the (DHQD)2PYR ligand did provide a 3.5:1 ratio
at C7 of an inseparable mixture of diols in 80% yield
using 0.5 equiv of osmium tetroxide. Stoichiometric
osmylation under the conditions of Corey and co-workers
using a chiral C2-symmetric diamine ligand [N,N′-bis-
(mesitylmethyl)(R,R′)-1,2-diphenyl-1,2-diaminoethane] in-
duced a synthetically useful 5-8:1 ratio at the newly
created C7 stereocenter in a good chemical yield of 75-
88%.
To prepare for oxidation of C8 to the aldehyde required
for the upcoming olefination, we needed to block C7
selectively, preferably as a silyl ether to maintain com-
patibility with our global protecting group stately. We
had anticipated that this goal would be achieved via an
uneventful series of protecting group manipulations.
However a range of blocking group combinations failed
(30) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(31) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron
Lett. 1988, 29, 5419.
(32) Mozingo, R. Org. Synth 1955, 3, 181.
(33) Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu, O. Tetrahedron
Lett. 1984, 25, 5397.
(34) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(35) (a) Monteagudo, E.; Cicero, D. O.; Cornett, B.; Myles, D. C.;
Snyder, J . P. J . Am. Chem. Soc. 2001, 123, 6929. (b) Smith, A. B., III.;
LaMarche, M. J .; Falcone-Hindley, M. Org. Lett. 2001, 3, 695.
J . Org. Chem, Vol. 68, No. 17, 2003 6649

Harried et al.
F IGURE 5. The C8 to C24 fragment.
to give the desired block group pattern, instead affording
the highly unstable C1 to C7 ortho ester. The difficulties
that we encountered both with activation at C9 and
protecting group manipulations at C7 and C8 caused us
to reconsider our strategy for assembling this region of
the carbon skeleton of discodermolide.
treatment with potassium hydride to afford diene 26 in
80% yield over two steps and with >20:1 Z:E selectivity.
The removal of the methoxymethyl ether required
careful optimization. Standard Lewis acid promoters for
this process such as dimethylboron bromide at -78 °C,43
B-chlorocatecholborane,44 and others afforded mixtures
of the desired alcohol and an undesired tetrahydrofuran
formed by cyclization of an oxonium ion intermediate.45
Extensive experimentation revealed that the C19 MOM
ether could be removed with acetyl chloride in 1:1 EtOH:
THF at 60 °C to afford the desired alcohol reliably in 90%
yield. The required carbamate at C19 could then be
installed in 90% yield by treatment of the secondary
alcohol with trichloroacetyl isocyanate followed by
Al2O3.46,47
The strategy we chose as an alternative to the Wittig
coupling called for the diastereoselective addition of a
Z-vinyl anion or equivalent at C8 to an aldehyde at C7.
The method of Nozaki and Kishi for the direct coupling
of vinyl halides to aldehydes under the aegis of Cr(II)
and Ni(II) seemed particularly attractive because the
reaction conditions were known to be chemoselective,36
mild, and likely to be compatible with a wide range of
blocking groups and other functionality. With these
features in mind, we undertook to prepare suitable
precursors of maximum complexity for this coupling
process. Alcohol 22 was converted to a fully elaborated
C8 to C24 vinyl iodide in a short but delicate series of
manipulations. Homologation of 22 began with TPAP/
NMO oxidation of the primary alcohol moiety to the
aldehyde in 88% yield.37 Olefination with iodomethylene-
triphenylphosphorane afforded vinyl iodide 23 in 90%
yield with a 20:1 ratio of Z:E isomers.38 The PMB ether
was removed under oxidative conditions using DDQ, to
afford the expected primary alcohol in 87% yield.39,40 The
primary alcohol was oxidized to aldehyde 24 in 89% yield
as before using TPAP and NMO. To install the terminal
diene,41 24 was treated with (E)-γ-(trimethylsilyl)allyl-
boronate reagent 2542 to provide the hydroxysilane ad-
duct. This adduct was then immediately eliminated by
The C8 to C24 fragment of 1 contains all stereochem-
istry and functionality required for the synthesis of the
target molecule. By simply removing the silyl ethers, one
could unmask this fully elaborated fragment. Thus, to
achieve a synthesis of maximum convergency, we hoped
to implement a synthesis of the C1 to C7 portion of 1
(43) Guindon, Y.; Yoakim, C.; Morton, H. E. J . Org. Chem. 1984,
49, 3912.
(44) Boeckman, R. K., J r.; Potenza, J . C. Tetrahedron Lett. 1985,
26, 1411.
(45) Castaneda, A.; Kucera, D. J .; Overman, L. E. J . Org. Chem.
1989, 54, 5695.
(46) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
(47) An alternative sequence was developed for the conversion of
alcohol 21 (Figure 4) to vinyl iodide 27 (Figure 5). Although somewhat
longer, this sequence proved to be equally reliable on a large scale.
Thus, alcohol 21 was silylated with triisopropyltrifluoromethane-
sulfonyl trifluoromethanesulfonate (TIPS-OTf) and triethylamine.
After oxidative cleavage of the p-methoxybenzl ether, the resulting
primary alcohol was silylated (TIPS-OTf). Hydrogenolysis (Pd/C,
hydrogen) of the C9 benzyl ether afforded the analogous primary
alcohol (99%, two steps). This alcohol was then homologated to the
vinyl iodide via Swern oxidation and Zhao-Stork-Wittig reaction in
80% yield over two steps (see Figure 4). Both the C19 MOM and C21
TIPS ethers were then cleaved solvolytically (acetyl chloride, ethanol,
THF) to afford the C19-C21 diol in 75% yield. Differentiation of the
diol was accomplished by forming the p-methoxybenzylidene acetal (p-
methoxybenzaldehyde dimethyl acetal, CSA) and reducing with
DIBAL-H to give the C21 primary alcohol in 87% yield over two steps.
In analogy to the sequence described in figure 5, the diene was
installed. DDQ removal of the PMB ether at C19 gave the alcohol in
92% yield. This material was converted to carbamate 27 as described.
(36) J in, H.; Uenishi, J .-I.; Christ, W. J .; Kishi, Y. J . Am. Chem.
Soc. 1986, 108, 5644. Takai, K.; Tagashira, M.; Kuroda, T.; Oshima,
K.; Utimoto, K.; Nozaki, H. J . Am. Chem. Soc. 1986, 108, 6048.
(37) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(38) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(39) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(40) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021.
(41) Tsai, D. J . S.; Matteson, D. S. Tetrahedron Lett. 1981, 22, 2751.
(42) Roush, W. R.; Grover, P. T. Tetrahedron Lett. 1992, 48, 1981.
6650 J . Org. Chem., Vol. 68, No. 17, 2003

Total Synthesis of (+)-Discodermolide
F IGURE 6. Synthesis of (+)-discodermolide.
that left the secondary alcohols of this region also blocked
as silyl ethers.
recycled to desired alcohol 31 in a two-step process by
protecting both hydroxyl groups as their TBS ethers and
regioselectively deprotecting the primary TBS ether.54
The remaining two stereocenters were introduced using
Evans diastereoselective aldol chemistry.55 Following
Swern oxidation of alcohol 31, the resulting aldehyde was
immediately reacted under Evans aldol conditions to give
syn-aldol 32 in >20:1 diastereomeric ratio. The crude
material was treated with lithium hydroperoxide to
cleave the chiral auxiliary and provide the carboxylic
acid.56 This material was converted to its methyl ester
33 by treatment with (trimethylsilyl)diazomethane57 in
79% yield over four steps. The decision to store C1 as its
methyl ester rather than converting the material directly
to the lactone present in discodermolide was driven by
the observation that lactones containing the C7 aldehyde
required for the upcoming coupling reaction underwent
a facile epimerization at C5 (presumably via an elimina-
tion-addition mechanism). After the C3 hydroxyl group
was protected as its TIPS ether in 92% yield, ozonolysis
gave aldehyde 34 in 95% yield. This synthetic route to
C1-C7 aldehyde is much improved from the original
route, producing twice the overall yield. This sequence
has been carried out at multigram scale for the synthesis
of (+)-discodermolide.
We have described previously13e a first-generation
synthesis of synthons for aldehyde 2 (Figure 2) based on
the allyl- and crotylborane chemistry of Brown.48,49 The
successful application of this methodology, in our syn-
thesis of (-)-discodermolide and many others, demon-
strates its power as a tool for the preparation of complex
organic structures. However, we elected to develop a
second-generation synthesis of synthons 2 or 3. Like the
first-generation synthesis, our revised strategy for the
synthesis of C1-C7 aldehyde 2 began with alcohol 28
(enantiomer of 8). The single stereogenic center in this
material controlled the diastereoselectivity in a chelation-
controlled allyltributylstannane addition.50 Oxidation of
28, followed by allyltributylstannane addition at -90
°C,51,52 produced homoallylic alcohol 29 in a >20:1 ratio
of diastereomers and in 85% yield over two steps. The
resulting C5 secondary alcohol was blocked as its TBS
ether53 and the benzyl ether was removed under dissolv-
ing metal conditions, affording alcohol 31 and diol 30 in
68% and 17% yields, respectively. Diol 30 was smoothly
(48) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 5919.
(49) Brown, H. C.; Bhat, K. S.; Randad, R. S. J . Org. Chem. 1989,
54, 1570.
(50) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883.
(51) Linderman, R. J .; Cusack, K. P.; J aber, M. R. Tetrahedron Lett.
1996, 37, 6649.
(52) White, J . D.; Nylund, C. S.; Green, N. J . Tetrahedron Lett. 1997,
38, 7329.
(54) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(55) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 77.
(56) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141.
(53) Fisher, M. J .; Myers, C. D.; J oglar, J .; Chen, S. H.; Danishefsky,
S. J . J . Org. Chem. 1991, 56, 5826.
(57) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475.
J . Org. Chem, Vol. 68, No. 17, 2003 6651

Harried et al.
MHz, CDCl3) δ 9.71 (d, J ) 1.7 Hz, 1H), 7.34-7.24 (m, 5H),
4.51 (s, 2H), 3.65 (m, 2H), 2.63 (m, 1H), 1.11 (d, J ) 7.1 Hz,
3H); 13C NMR (90 MHz, CDCl3) δ 203.8, 137.8, 128.7, 127.7,
127.5, 73.2, 70.0, 46.7, 10.7.
The fully elaborated C8-C24 fragment 27 was coupled
to aldehyde 34 using 1% NiCl2/CrCl2 in DMSO to produce
a 3:1 ratio of C7 epimers in 20-40% yield. A more reliable
42% yield was obtained when Kishi’s chiral bispyridinyl
ligand (35) was incorporated into the reaction mixture
and the solvent was changed from DMSO to THF,58 with
the same 3:1 diastereomeric ratio. The chemoselectivity
of this reaction allows for optimal convergency in that
the carbamate, terminal diene, methyl ester, and â-silyl-
oxy aldehyde all can be present during the coupling.
Consequently, the only step remaining to complete the
synthesis of (+)-discodermolide synthesis was removal
of the silyl blocking groups. Alcohols 36 were subjected
to 10% aqueous HF in acetonitrile, resulting in the mono-
TIPS ether of discodermolide. The final TIPS ether was
then removed with a second deprotection step in 30% HF‚
pyr in THF, to afford (+)-discodermolide in 52% yield and
its separable C7 epimer in 13% yield.
This synthetically derived material was compared (1H
NMR, 13C NMR, HRMS, IR, optical rotation, TLC) to
natural (+)-discodermolide and was found to be identical
in all respects. Cell-based cytotoxicity assay of the
synthetic material show it to have potency similar to
natural discodermolide and to arrest the cell cycle at the
G2/M boundary.58 The synthesis proceeds in a highly
convergent manner, the longest linear sequence for this
synthesis of discodermolide is 22 steps from aldehyde 9
in a 1.5% overall yield. The syntheses of the three key
fragments, 34, 19, and 15, can be easily carried out at
tens of grams scale. Both fragment coupling reactions are
readily amenable to large scale. The final coupling
sequence has yielded hundreds of milligrams of the
natural product. The convergent strategy allows for the
facile preparation of analogues of discodermolide.
Hom oa llylic Alcoh ol 29. To a flame-dried 1 L round-
bottom flask equipped with a magnetic stir bar and a rubber
septum was added CH2Cl2 (400 mL). The flask was placed in
a -78 °C bath for 5 min before the addition of SnCl4 (neat 7.6
mL, 65.0 mmol) in one portion. To this SnCl4 solution in CH2-
Cl2 was added allyltributyltin (neat 20.0 mL, 65.0 mmol) via
syringe (10 mL) in a quick steady manner. The reaction was
allowed to stir for 30 min at -78 °C before cooling it in a -90
°C bath (liquid N2/MeOH), where it was allowed to stir for an
additional 10 min. After this additional cooling period, a
prechilled (-78 °C) solution of the above aldehyde (CH2Cl2)
was added to the reaction via a cannula down the side of the
flask. Analysis of the reaction (TLC) showed that all of the
aldehyde was consumed within 2 min of its addition. The
reaction was quenched after 8 min by pouring it into an
aqueous solution of KF (1 M, 700 mL) in a separatory funnel
(4 L) containing hexanes (600 mL). The separated organic layer
was washed with aqueous KF (1 M, 700 mL), aqueous NaCO3
(1 M, 700 mL), and aqueous NaCl (saturated, 700 mL) before
drying with anhydrous Na2SO4. The dried organic layer was
filtered through a short plug of silica gel and concentrated in
vacuo to provide a crude product. The crude residue was
purified by flash column chromatography (28 cm of silica gel
on a 6 cm diameter column, 10% EtOAc in hexanes, 200-300
mL fractions) to give a clean alcohol 29 as a colorless oil (12.4
g, 56 mmol) in 85% yield from alcohol 28 (two steps) as a
greater than 20:1 ratio of diastereomers (1H NMR): Rf ) 0.5,
1
10% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ 7.35-
7.30 (m, 5H), 5.94-5.86 (m, 1H), 5.14-5.09 (m, 2H), 4.52 (s,
2H), 3.61-3.57 (m, 2H), 3.50 (dd, J ) 8.5, 7.0 Hz, 1H), 3.22
(br s, 1H), 2.34-2.31 (m, 1H), 2.23-2.17 (m, 1H), 1.92-1.88
(m, 1H), 0.92 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 137.9, 135.3, 128.5, 127.8, 127.7, 117.2, 74.9, 74.7, 73.4, 39.4,
38.0, 13.9; IR (thin film on NaCl) 3447, 3070, 3031, 2964, 2933,
2905, 2862, 1641, 1497, 1454, 1433, 1364, 1313, 1262, 1208,
1159, 1095, 1075, 1048, 1028, 990, 960, 912, 871, 834, 737,
698 cm-1; HRMS (CI) (m/z) calculated for C14H20O2 (M + H)+
Exp er im en ta l Section
) 221.1541, observed 221.1542; [R]20 ) -8.0 (c ) 2.29, CH2-
D
Ald eh yd e 9. To a flame-dried 1 L round-bottom flask
equipped with a magnetic stir bar and a rubber septum was
added CH2Cl2 (300 mL). The flask was placed in a -78 °C bath
for 10 min before adding oxalyl chloride (12.0 mL, 133.0 mmol)
in one portion. Anhydrous DMSO (19.0 mL, 267 mmol) was
added dropwise over 10 min, resulting in gas evolution. The
resulting solution was allowed to stir for an additional 15 min
before the addition of alcohol 8 (12.0 g, 66.7 mmol, 20 mL of
CH2Cl2, 2 × 4 mL of CH2Cl2 rinses) via cannula. The reaction
mixture was allowed to stir at -78 °C for 60 min before adding
triethylamine (56 mL, 400 mmol) and then stirred for an
additional 5 min at -78 °C before removing from the dry ice/
acetone bath. After allowing the reaction to warm for ap-
proximately 10 min it was quenched by pouring into an
aqueous solution of NH4Cl (1 M, 500 mL) in a separatory
funnel. The organic layer was washed with aqueous NH4Cl (1
M, 5 × 300 mL) until TLC indicated that all the triethylamine
was extracted away from the CH2Cl2. The organic layer was
washed with aqueous NaCl (saturated, 1 × 500 mL), dried
(Na2SO4), filtered, and concentrated in vacuo to a smaller
volume (100 mL) before transferring to a 250 mL pear-shaped
flask and then further concentrated in vacuo until almost neat.
The crude aldehyde was treated with anhydrous benzene (2
× 5 mL) to azeotropically dry it and then placed under high
vacuum (2 mmHg) for 30 min before addition of anhydrous
CH2Cl2 (150 mL). This dry solution of aldehyde was im-
mediately used in the following reaction in order to minimize
racemization: Rf ) 0.50, 20% EtOAc in hexanes; 1H NMR (360
Cl2).
P r im a r y Alcoh ol 31. A flame-dried 500 mL round-bottom
flask containing homoallylic alcohol 29 (11.17 g, 50.77 mmol)
was equipped with a magnetic stir bar and a rubber septum.
The alcohol 29 was then azeotropically dried by the addition
of anhydrous benzene (1 × 5 mL) followed by subjecting it to
a high vacuum (2 mmHg) for 30 min. To the dry alcohol 29
was added CH2Cl2 (300 mL) followed by triethylamine (12.5
mL, 89.0 mmol) in one portion. The solution was allowed to
stir for 5 min before adding TBSOTf (13.0 mL, 56.4 mmol)
dropwise over 5 min. The solution was allowed to stir for 1 h
(TLC shows complete) before pouring it into NaHCO3 (1M, 400
mL) to quench the reaction. The phases were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 150 mL).
The combined organic layers were washed with aqueous NaCl
(saturated, 500 mL) and dried with anhydrous Na2SO4. The
dried organic layer was filtered through a short plug of silica
gel and concentrated in vacuo to provide crude TBS ether. The
resulting product was used in the following procedure without
any further purification: Rf ) 0.95, 20% EtOAc in hexanes;
1H NMR (400 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 5.92-5.83
(m, 1H), 5.08-5.01 (m, 2H), 4.50 (ABq, J ) 12.1 Hz, ∆ν ) 22
Hz, 2H), 3.76 (ddd, J ) 5.4, 5.4, 5.4 Hz, 1H), 3.53 (dd, J ) 9.1,
5.5 Hz, 1H), 3.34 (dd, J ) 9.1, 6.8 Hz, 1H), 2.23 (m, 2H), 2.00
(m, 1H), 0.96 (d, J ) 6.9 Hz, 3H), 0.93 (s, 9H), 0.09 (s, 3H),
0.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.8, 135.5, 128.3,
127.5, 127.4, 116.7, 73.4, 73.0, 72.5, 38.5, 38.3, 25.9, 18.1, 13.4,
-4.2, -4.7.
To a flame-dried 2 L round-bottom flask containing a
magnetic stir bar and the crude TBS ether (approximately 17
(58) Chen, C. P.; Tagami, K.; Kishi, Y. J . Org. Chem. 1995, 60, 5386.
6652 J . Org. Chem., Vol. 68, No. 17, 2003

Total Synthesis of (+)-Discodermolide
g, 50.75 mmol) from the above experimental procedure was
added anhydrous benzene (15 mL). The mixture was then
subjected to high vacuum (2 mmHg) for 30 min. To the dried
starting material was added triethylamine (500 mL, Aldrich
99%, used as purchased) and THF (250 mL) before placing the
reaction flask in a 0 °C bath. After allowing the solution to
stir and cool for 10 min, Li wire (approximately 4 g) was
cleaned (washed successively in hexane, MeOH, and hexane)
and cut (2 mm × 3 mm chunks) before adding it portionwise
to the chilled reaction flask. The reaction mixture was stirred
vigorously to ensure efficient dispersion of the floating chunks
of Li. Ethylenediamine (33 mL, Aldrich 99%, used as pur-
chased) was then added in one portion. After allowing the
reaction mixture to stir for 10 min, an additional portion of
ethylenediamine (5 mL) was added and the reaction changed
color from blue to dark brown. The reaction mixture was
stirred for another 10 min before a third portion of ethylene-
diamine (6 mL) was added. The reaction mixture was stirred
at 0 °C for a total of 2 h, at which time TLC analysis indicated
that all the starting material was consumed. At this time, the
excess Li was quenched by the slow addition of aqueous NH4-
Cl (1 M, 500 mL) to the chilled (0 °C) reaction flask and then
it was allowed to stir for 10 min (CAUTION: heat and H2
evolution). The resulting mixture was poured into a separatory
funnel containing NaHCO3 (1 M, 1 L) producing an emulsion.
The organic and aqueous layers were partitioned after the
addition of CH2Cl2 (700 mL) and aqueous NH4Cl (1M, 500 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 400 mL).
The combined organic layers were washed with aqueous NaCl
(saturated, 1 L), dried with anhydrous Na2SO4, and concen-
trated in vacuo, providing a viscous oil (12.6 g). This crude
material was purified by flash column chromatography (28 cm
of silica gel on a 6 cm diameter column, 10% EtOAc in hexanes,
gradient to 40% EtOAc, 200-300 mL fractions), providing
clean alcohol 31 as a colorless oil (8.41 g, 34.5 mmol) in 68%
yield from alcohol 29 (two steps): Rf ) 0.5, 20% EtOAc in
hexanes. Additionally, clean diol 30 (1.16 g, 8.67 mmol) due
to loss of TBS protecting group was isolated in 17% yield (two
steps): Rf ) 0.05, 20% EtOAc in hexanes; 1H NMR (400 MHz,
CDCl3) δ 5.79-5.69 (m, 1H), 5.05-4.97 (m, 2H), 3.70 (m, 2H),
3.50 (dd, J ) 10.9, 5.2 Hz, 1H), 2.83 (s, 1H), 2.32-2.26 (m,
2H), 1.74 (m, 1H), 0.94 (d, J ) 7.0 Hz, 3H), 0.86 (s, 9H), 0.04
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 134.4, 117.2, 76.5, 65.1,
39.5, 38.1, 25.8, 17.9, 14.4, -4.3, -4.9; IR (thin film on NaCl)
3364, 2957, 2930, 2886, 2857, 1642, 1473, 1464, 1436, 1416,
1389, 1377, 1361, 1257, 1217, 1074, 1033, 1005, 940, 911, 889,
836, 809, 775, 665 cm-1; HRMS (EI) (m/z) calculated for
Into a flame-dried 500 mL round-bottom flask were placed
white, crystalline 17 (20.5 g, 88.0 mmol, 4 equiv relative to
aldehyde) and a magnetic stir bar. To the dry oxazolidinone
17 were added sequentially CH2Cl2 (150 mL) and triethyl-
amine (12.0 mL, 85.4 mmol). The reaction flask was then
placed in a 0 °C bath. After allowing the reaction to cool for
10 min, Bu2BOTf (1.0 M in CH2Cl2, 75 mL, Aldrich, yellow
solution) was added in a quick, dropwise fashion via a syringe.
(Note: Red or black solutions from Aldrich were found to give
no enolization or poor diastereoselectivity. Freshly prepared
reagent gave consistent and reproducible results.40,59) The color
of the reaction remained yellow (a red color indicates moisture
has entered the flask), the reaction was allowed to stir at 0 °C
for 65 min before placing it in a -78 °C bath for an additional
30 min. At this time, a solution of dry aldehyde (ca. 23 mmol,
15 mL CH2Cl2, 3 × 3 mL rinses) from the Swern oxidation
was added dropwise down the side of the reaction flask using
a syringe. The reaction was allowed to stir at -78 °C for 120
min, at which time TLC analysis showed that all the aldehyde
was consumed. The reaction flask was then placed in a 0 °C
bath before addition of a buffer solution (1 M NaOAc in 9
MeOH: 1 H2O, 250 mL) in one portion followed by dropwise
addition of aqueous H2O2 (35%, 25 mL) (CAUTION: exother-
mic; add very slowly), which turned the reaction mixture
cloudy. The resulting mixture was stirred for 12 h and allowed
to warm to room temperature in the process before pouring
into H2O (700 mL). The layers were partioned, and the aqueous
layer was extracted with CH2Cl2 (3 × 400 mL). The combined
organic layers were concentrated in vacuo, and the resulting
material was used in the following procedure: Rf ) 0.35, 20%
EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 7.33-7.18
(m, 5H), 5.96-5.74 (m, 1H), 5.06-5.00 (m, 2H), 4.66 (m, 1H),
4.16 (m, 2H), 4.01 (m, 1H), 3.87 (qd, J ) 7.0, 1.9 Hz, 1H), 3.79
(dd, J ) 9.8, 1.7 Hz, 1H), 3.42 (br s, 1H), 3.26 (dd, J ) 13.4,
3.2 Hz, 1H), 2.77 (dd, J ) 13.4, 9.5 Hz, 1H), 2.30-2.10 (m,
2H), 1.83 (m, 1H), 1.22 (d, J ) 7.0 Hz, 3H), 0.89 (s, 9H), 0.83
(d, J ) 7.0 Hz, 3H), 0.09 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 177.2, 152.8, 135.8 135.0, 129.3, 128.8, 127.2, 116.5, 73.7,
72.9, 66.0, 55.2, 40.7, 39.7, 37.5, 37.3, 25.7, 17.9, 10.9, 8.8, -4.6,
-4.8.
Hyd r oxy Meth yl Ester 33. To the crude material from the
previous experimental in a 2 L round-bottom flask containing
a magnetic stir bar was added THF (500 mL) and H2O (125
mL) before placing the reaction flask in a 0 °C bath. The
solution was allowed to chill for 10 min followed by the addition
of aqueous H2O2 (35%, 50 mL) and solid LiOH‚H2O (7.4 g, 176
mmol). The reaction was allowed to stir and slowly warm to
room temperature over a 3 h time period, at which point TLC
analysis showed that all of the starting material was con-
sumed. The reaction was then quenched by chilling the
reaction back down to 0 °C followed by addition of aqueous
Na2SO3 (1.5 M, 200 mL). The resulting mixture was stirred
for 10 min, at which time aqueous NaHCO3 (1M, 200 mL) was
added to the reaction flask. The remaining THF was removed
by concentration in vacuo down to an approximate volume of
600 mL. The remaining aqueous phase was extracted with
CH2Cl2 (5 × 150 mL). The combined organic extracts were
washed with aqueous NaCl (saturated, 700 mL), dried with
Na2SO4, and purified by passing through a short plug of silica
gel. The resulting filtrate was concentrated in vacuo, producing
a crude mixture of hydroxy acid and crystalline oxazolidinone
that was directly taken on to the following procedure.
C
13H28O2Si (M + H)+ ) 245.1859, observed 245.1944; [R]20
)
D
29.9 (c ) 2.41, CH2Cl2).
Ald ol 32: To a flame-dried 500 mL round-bottom flask
equipped with a magnetic stir bar and a rubber septum was
added CH2Cl2 (150 mL). The flask was placed in a -78 °C bath
for 10 min before adding oxalyl chloride (4.5 mL, 50 mmol) in
one portion. Anhydrous DMSO (7.0 mL, 99 mmol) was added
dropwise over 10 min. The resulting solution was allowed to
stir for an additional 15 min before addition of alcohol 31 (5.25
g, 21.5 mmol, 15 mL CH2Cl2, 2 × 4 mL CH2Cl2 rinses) via
syringe. The reaction mixture was allowed to stir at -78 °C
for 60 min before addition of triethylamine (20 mL, 142 mmol)
and then stirred for an additional 5 min at -78 °C before being
removed from the dry ice/acetone bath. After allowing the
reaction to warm for approximately 10 min, it was quenched
by pouring into an aqueous solution of NH4Cl (1 M, 250 mL)
in a separatory funnel. The layers were allowed to separate
and the organic layer was washed with aqueous NH4Cl (1 M,
5 × 200 mL) until TLC indicated that all the triethylamine
was extracted away from the CH2Cl2 layer. The organic layer
was washed with aqueous NaCl (saturated, 1 × 300 mL), dried
(Na2SO4), filtered, and concentrated in vacuo to provide a
yellow viscous oil. The product was used immediately in the
following experimental: Rf ) 0.75, green with vanillin stain,
20% EtOAc in hexanes.
To a 1 L round-bottom flask containing the dried mixture
of oxazolidinone and hydroxy acid and a magnetic stir bar was
added CH2Cl2 (150 mL). The solution was allowed to stir and
TMS-diazomethane (2.0 M, 5.0 mL) was added dropwise to the
solution, causing instantaneous bubbling, along with a color
change from colorless to yellow. After allowing the reaction to
proceed for 5 min, TLC analysis indicated that not all of the
hydroxy acid was consumed yet. So, an additional portion of
TMS-diazomethane (2.0 M, 3.0 mL) was added to the reaction
flask. The reaction was quenched after a total of 30 min by
J . Org. Chem, Vol. 68, No. 17, 2003 6653

Harried et al.
addition of silica gel (approximately 300 mg), at which time
gas evolved and the reaction mixture became colorless. The
solvent was removed in vacuo, which resulted in the crystal-
lization of the white oxazolidinone along with the oily methyl
ester 33 as a crude mixture. Two different methods, of equal
efficiency and ease, were developed to purify and separate the
methyl ester 33 away from the oxazolidinone. In the first
method, the oxazolidinone was recrystallized from 2:1 EtOAc:
hexanes. The filtrate, containing the methyl ester 33 and
residual oxazolidinone, was further purified by flash column
chromatography (20% EtOAc in hexanes) providing clean,
separated material. The other method of purifying the crude
mixture (the one used for this experiment) involved two stages
of chromatography and no recrystallization of oxazolidinone.
The entire crude mixture was dissolved in CH2Cl2 and
subjected to flash column chromatography (14 cm of silica gel
on a 6 cm diameter column, CH2Cl2). This first flash column
chromatography only provided partial separation. The frac-
tions that contained both the compounds were collected and
concentrated in vacuo (4.8 g) and resubjected to a second flash
column chromatography (28 cm of silica gel on a 6 cm diameter
column, 10% EtOAc in hexanes) to provide cleanly separated
material. Material from both columns was combined. The
methyl ester (5.33 g, 17.0 mmol) was isolated in 79% yield (four
steps from primary alcohol 31 with chromatography at this
step only): Rf ) 0.25, 20% EtOAc in hexanes. Additionally,
pure oxazolidinone was isolated from the columns (7.97 g, 45
mmol) in 51% yield: Rf ) 0.05, 20% EtOAc in hexanes; 1H
NMR (400 MHz, CDCl3) δ 5.85-5.75 (m, 1H), 5.04-4.98 (m,
2H), 3.96 (dt, J ) 7.5, 4.3 Hz, 1H), 3.83 (dd, J ) 9.9, 2.4 Hz,
1H), 3.67 (s, 3H), 3.1 (br s, 1H), 2.58 (qd, J ) 7.1, 2.4 Hz, 1H),
2.25-2.11 (m, 2H), 1.75 (m, 1H), 1.12 (d, J ) 7.2, 3H), 0.86 (s,
9H), 0.77 (d, J ) 7.0, 3H), 0.05 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 176.8, 135.9, 116.6, 73.8, 73.2, 51.8, 41.4, 40.5, 37.5,
25.8, 18.0, 11.2, 8.8, - 4.4, - 4.6; IR (thin film on NaCl) 2955,
2930, 2888, 2857, 1721, 1644, 1472, 1437, 1381, 1314, 1254,
1202, 1181, 1073, 1059, 1005, 989, 939, 912, 885, 837, 810,
775, 685 cm-1; HRMS (FAB, NBA/NaI) (m/z) calculated for
1738, 1464, 1472, 1435, 1385, 1362, 1348, 1254, 1196, 1165,
1122, 1071, 1017, 999, 941, 912, 901, 883, 837, 810, 775, 679
cm-1; HRMS (FAB, NBA/ NaI) (m/z) calculated for C26H54O4-
Si2Na (M + Na)+ ) 509.3458, observed 509.3457; [R]20D ) 25.6
(c ) 2.995, CH2Cl2).
Ald eh yd e 34. Into a flame-dried 250 mL round-bottom flask
was placed a solution of alkene 33a in CH2Cl2 and the solvent
was then removed in vacuo. To the neat alkene was added a
magnetic stir bar and anhydrous benzene (5 mL). The material
was allowed to stir under high vacuum (2 mmHg) for 12 h to
remove any volatile material (this process was found to remove
any residual TipsOH left over from silylation). After this high
vacuum treatment, argon and CH2Cl2 (75 mL) were added to
the reaction flask. The flask was then placed in a -78 °C bath
and allowed to stir and chill for 5 min. At the end of this cooling
period, O3 was bubbled into the solution through a Pasteur
pipet until the persistence of a blue color (approximately 10
min). Once the blue color appeared, argon was bubbled into
the solution for 2 min and then Bu3P (1.2 mL, 4.75 mmol) was
added dropwise to the chilled (-78 °C) reaction. The reaction
was stirred at -78 °C for 5 min and then allowed to warm to
room temperature. After stirring for 20 min at room temper-
ature, TLC analysis showed that approximately 50% of the
material was still at the ozonide oxidation state. So, a second
portion of Bu3P (0.70 mL, 2.78 mmol) was added to the reaction
flask. The reduction of the ozonide was allowed to occur for a
total of 90 min and then the solvent was removed in vacuo to
give a colorless oil. This material was purified by flash column
chromatography (18 cm of silica gel on a 3 cm diameter
column, 5% EtOAc in hexanes, 10 mL fractions), providing
1
aldehyde 34 (1.84 g): Rf ) 0.30, 10% EtOAc in hexanes; H
NMR (400 MHz, CDCl3) δ 9.80 (dd, J ) 2.8, 1.8 Hz, 1H), 4.39
(dd, J ) 5.5, 3.1 Hz, 1H), 4.31 (ddd, J ) 5.7, 5.7, 5.7 Hz, 1H),
3.64 (s, 3H), 2.74 (dq, J ) 3.1, 7.1 Hz; 1H), 2.63-2.51 (m, 2H),
2.01-1.95 (m, 1H), 1.18 (d, J ) 7.1 Hz, 3H), 1.06-1.04 (m,
21H), 0.93 (d, J ) 7.2 Hz, 3H), 0.83 (s, 9H), 0.06 (s, 3H), 0.03
(s, 3H) 13C NMR (100 MHz, CDCl3 δ 201.8, 175.7, 73.2, 68.9,
51.5, 47.8, 45.0, 42.6, 25.7, 18.3-18.2 3 carbons, 13.2, 11.8,
11.0, -4.5, -4.6; IR (thin film on NaCl) 2949, 2894, 2887, 1732,
1464, 1386, 1253, 1086, 837, 777 cm-1; HRMS (FAB, NBA/
NaI) (m/z) calculated for C25H52O5Si2Na (M + Na)+ ) 511.3251,
C17H34O4SiNa (M + Na)+ ) 353.2124, observed 353.2127; [R]20
D
) 6.6 (c ) 1.965, CH2Cl2).
TIP S Eth er 33a . A flame-dried 500 mL round-bottom flask
containing methyl ester 33 (2.83 g, 9.04 mmol) was equipped
with a magnetic stir bar and a rubber septum. The alcohol
was azeotropically dried by addition of anhydrous benzene (2
× 3 mL) followed by subjecting it to a high vacuum (2 mmHg)
for 30 min. To the dry 33 was added CH2Cl2 (20 mL) followed
by triethylamine (2.0 mL, 14.4 mmol) in one portion. The
solution was allowed to stir for 5 min before adding TipsOTf
(3.0 mL, 10.8 mmol) dropwise over 5 min. The solution was
allowed to stir for 24 h when TLC indicated incomplete
protection of starting material. Therefore, more triethylamine
(0.40 mL, 2.85 mmol) and TipsOTf (0.40 mL, 1.50 mmol) were
added at this time. The reaction was allowed to stir for another
12 h before pouring it into NaHCO3 (1 M, 250 mL) in order to
quench the reaction. The phases were separated and the
aqueous layer was extracted with CH2Cl2 (4 × 75 mL). The
combined organic layers were washed with aqueous NaCl
(saturated, 300 mL) and dried with anhydrous Na2SO4. The
dried organic layer was filtered through a short plug of silica
gel and concentrated in vacuo to provide crude product. The
crude product was purified by flash column chromatography
(14 cm of silica gel on a 6 cm diameter column, 3% EtOAc in
hexanes) resulting in a clean, viscous oil (4.08 g, 8.34 mmol)
in 92% yield: Rf ) 0.80, 5% EtOAc in hexanes; 1H NMR (400
MHz, CDCl3) δ 5.87-5.79 (m, 1H), 5.09-5.04 (m, 2H), 4.59
(dd, J ) 5.0, 2.5 Hz, 1H), 3.72 (ddd, J ) 5.3, 5.3, 5.3 Hz, 1H),
3.64 (s, 3H), 2.80 (qd, J ) 7.1, 2.5 Hz, 1H), 2.37 (m, 1H), 2.26
(m, 1H), 1.94 (m, 1H), 1.19 (d, J ) 7.0 Hz, 3H), 1.05 (m, 21H),
0.90 (d, J ) 7.2 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.02 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 134.4, 117.0, 73.3,
71.8, 51.3, 44.1, 42.1, 38.5, 25.9, 18.3, 18.2, 18.1, 13.0, 11.7,
11.1, -4.2, -4.7; IR (thin film on NaCl) 2948, 2892, 2866, 1734,
observed 511.3245; [R]20 ) 0.96 (c ) 3.96, CH2Cl2).
D
Ald ol 18: To a flame-dried 500 mL round-bottom flask was
placed white, crystalline 17 (12.08 g, 51.78 mmol) and a
magnetic stir bar. The oxazolidinone 17 was azeotropically
dried by the addition of anhydrous benzene (15 mL) followed
by subjecting it to high vacuum (2 mmHg) for 30 min. To the
dried oxazolidinone 17 was sequentially added CH2Cl2 (100
mL) and triethylamine (9.5 mL, 67.6 mmol) before placing the
reaction flask in a 0 °C bath. After allowing the reaction to
cool for 10 min, Bu2BOTf (1.0 M in CH2Cl2, 60 mL, Aldrich,
yellow solution) was added in a quick dropwise fashion via an
addition funnel. (Note: red or black solutions from Aldrich were
found to give no enolization or poor diastereoselectivity.
Freshly prepared reagent gave consistent and reproducible
results.40,59) The color of the reaction stayed yellow to slightly
brown (a red color indicates moisture has entered the flask).
The reaction was allowed to stir at 0 °C for 60 min before
placing it in a -78 °C bath for an additional 30 min. At this
time, dry aldehyde (approximately 70 mmol, 75 mL of CH2-
Cl2, 3 × 3 mL rinses) from a Swern oxidation was added
dropwise down the side of the reaction flask using a syringe.
The reaction was allowed to stir at -78 °C and slowly warm
to room temperature overnight (12 h). At this time, the
reaction flask was then placed in a 0 °C bath before the
addition of a buffer solution (1 M NaOAc in 9:1 MeOH:H2O,
150 mL) in one portion followed by dropwise addition of
aqueous H2O2 (30%, 25 mL) (CAUTION: exothermic; add very
slowly), which turned the reaction mixture cloudy. The result-
ing mixture was stirred for 90 min and allowed to warm to
room temperature in the process before pouring the mixture
into H2O (200 mL). The layers were partioned, and the aqueous
6654 J . Org. Chem., Vol. 68, No. 17, 2003

Total Synthesis of (+)-Discodermolide
layer was extracted with CH2Cl2 (4 × 150 mL). The combined
organic layers were washed with aqueous NaHCO3 (1 M, 400
mL) and aqueous NaCl (saturated, 400 mL). The organic layers
were then dried with Na2SO4, filtered, and concentrated in
vacuo to give a crude mixture (31.6 g). This crude mixture was
purified by flash column chromatography (28 cm of silica gel
on a 6 cm diameter column, 20% EtOAc in hexanes, 200 mL
fractions) to give aldol 18 (20.09 g, 45.56 mmol) in 88% yield
aqueous layer was extracted with Et2O (4 × 125 mL) and
EtOAc (1 × 200 mL). The combined organic layers were
washed with aqueous NH4Cl (1 M, 400 mL) and aqueous NaCl
(saturated, 400 mL). The organic layers were dried with
MgSO4, filtered, and concentrated in vacuo to give a viscous,
thick oil. This material was purified by flash column chroma-
tography (14 cm of silica gel on a 6 cm diameter column, 30%
EtOAc in hexanes, 100-200 mL fractions) to give methoxy-
methyl ether (13.0 g, 35.1 mmol): 1H NMR (400 MHz, CDCl3)
δ 7.16 (d, J ) 8.7 Hz, 2H), 6.77 (d, J ) 8.5 Hz, 2H), 4.55 (ABq,
J ) 6.6 Hz, ∆ν ) 15.4 Hz, 2H), 4.33 (s, 2H), 3.72-3.68 (m,
4H), 3.52-3.48 (m, 4H), 3.27 (s, 3H), 3.22 (dd, J ) 9.1, 7.0 Hz,
1H), 3.10-3.06 (m, 4H), 1.86 (m, 1H), 1.08 (d, J ) 7.0 Hz, 3H),
0.96 (d, J ) 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.2,
159.0, 130.7, 129.2, 113.6, 98.3, 82.2, 72.7, 71.8, 61.1, 56.1, 55.1,
38.4, 37.2, 32.2,15.3, 12.9.
1
as a pale, viscous oil: Rf ) 0.20, 25% EtOAc in hexanes; H
NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 7H), 6.85 (d, J ) 8.7
Hz, 2H), 4.65 (m, 1H), 4.43 (s, 2H), 4.15 (m, 2H), 3.92 (m, 1H),
3.86 (m, 1H), 3.78 (s, 3H), 3.77 (m, 1H), 3.58-3.50 (m, 2H),
3.30 (dd, J ) 13.4, 3.2 Hz, 1H), 2.76 (dd, J ) 13.3, 9.6 Hz,
1H), 1.95 (m, 1H), 1.25 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 6.9
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 159.3, 153.2,
135.4, 129.9, 129.5, 129.4, 129.0, 127.3, 113.8, 75.5, 74.7, 73.2,
66.2, 55.6, 55.3, 40.7, 37.7, 36.0, 13.6, 9.7.
A flame-dried 500 mL round-bottom flask containing meth-
oxymethyl ether (13.0 g, 35.1 mmol) was equipped with a
magnetic stir bar and a rubber septum. The methoxymethyl
ether was azeotropically dried by the addition of anhydrous
benzene (5 mL) followed by subjecting it to high vacuum (2
mmHg) for 30 min. The dried methoxymethyl ether was
dissolved in THF (350 mL) and placed in a 0 °C ice bath. After
5 min, a solution of EtMgBr (3.0 M in Et2O, 30 mL) was added
to the reaction flask. The reaction was allowed to stir at 0 °C
for 7 h and then the excess reagent was quenched by the slow
addition of MeOH (15 mL), causing a gas to evolve. The
quenched reaction solution was concentrated in vacuo to a
gelatinous mixture (250 mL) that was dissolved in aqueous
HCl (5%, 400 mL). The aqueous phase was extracted with
EtOAc (2 × 300 mL) and Et2O (2 × 300 mL). The combined
organic layers were washed with aqueous NaHCO3 (1 M, 500
mL) and aqueous NaCl (saturated, 500 mL), dried with MgSO4,
filtered, and concentrated in vacuo to give a crude product.
The crude material was purified by flash column chromatog-
raphy (14 cm on a 6 cm diameter column, 15% EtOAc in
hexane, 150 mL fractions) providing clean ethyl ketone 19
(10.8 g, 32.0 mmol) in 70% yield over three steps from aldol
18 as a thick, viscous oil: Rf ) 0.50, 20% EtOAc in hexanes;
1H NMR (400 MHz, CDCl3) δ 7.18 (d, J ) 8.7 Hz, 2H), 6.80 (d,
J ) 8.7 Hz, 2H), 4.55 (ABq, J ) 6.7 Hz, ∆ν ) 29.9 Hz, 2H),
4.34 (s, 2H), 3.81 (dd, J ) 6.6, 4.8 Hz, 1H), 3.72 (s, 3H), 3.48
(dd, J ) 9.1, 5.1 Hz, 1H), 3.33 (dd, J ) 9.1, 5.5 Hz, 1H), 3.21
(s, 3H), 2.72 (m, 1H), 2.60-2.38 (m, 2H), 1.91 (m, 1H), 1.03
(d, J ) 7.0 Hz, 3H), 0.96-0.93 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 213.2, 159.1, 130.5, 129.2, 113.6, 97.9, 81.3, 72.7, 71.6,
55.9, 55.1, 48.4, 37.1, 34.3, 14.9, 11.0, 7.7; IR (thin film on
NaCl) 2971, 2938, 2901, 1713, 1613, 1514, 1460, 1302, 1248,
1173, 1148, 1098, 1084, 1036, 976, 920, 820 cm-1; HRMS (FAB,
Eth yl Keton e 19. To a cooled (0 °C) suspension of N,O-
dimethylhydoxlamine hydrochloride (1.28 g, 13.12 mmol) in
THF (20 mL) in a vented reaction flask was added dropwise
Me3Al (2.3 M in benzene, 5.0 mL) (CAUTION: Me3Al is
pyrophoric and reactive to moisture). The resulting homoge-
neous solution was stirred for 10 min and then removed from
the 0 °C ice bath. The clear solution was stirred at room
temperature for 30 min and then cooled to 0 °C. The substrate
18 (2.32 g, 5.25 mmol) in THF (10 mL, 3 × 2 mL rinses) was
added dropwise over 10 min, causing more gas to evolve. The
reaction was allowed to stir for 3.5 h and then quenched by
the addition of CH2Cl2 (50 mL) and aqueous tartaric acid (1
M, 25 mL) to the cooled (0 °C) reaction. The quenched mixture
was allowed to stir at 0 °C for 1 h and then diluted with H2O
(50 mL). The layers were allowed to separate, and the aqueous
layer was extracted with CH2Cl2 (4 × 50 mL). The combined
organic layers were washed with aqueous NaCl (saturated, 250
mL) and dried with Na2SO4. The dried organic layer material
was filtered and concentrated in vacuo to give a crude mixture
(2.66 g). The crude material was purified by flash column
chromatography (18 cm of silica gel on a 3 cm diameter
column, 40% EtOAc in hexanes) to give the Weinreb amide
(1.47 g, 4.51 mmol) in 86% yield: Rf ) 0.45, 50% EtOAc in
hexanes. Additionally, oxazolidinone (0.73 g. 4.13 mmol) was
recovered from the column in 78% yield: Rf ) 0.40, 50% EtOAc
in hexanes. Alternatively, the crude mixture was subjected to
a recrystalization step (2:1 EtOAc:hexane) to remove 60-75%
of the side product oxazolidinone. The partially purified mother
liquor containing the Weinreb amide was routinely taken on
1
to the next experiment without any further purification; H
NMR (400 MHz, CDCl3) δ 7.19 (d, J ) 8.4 Hz, 2H), 6.81 (d, J
) 8.5 Hz, 2H), 4.44 (ABq, J ) 11.6 Hz, ∆ν ) 10.3 Hz, 2H),
3.95 (d, J ) 2.8 Hz, 1H), 3.73 (s, 3H), 3.65 (m, 1H), 3.60 (s,
3H), 3.56 (m, 1H), 3.48 (dd, J ) 8.7, 5.9 Hz, 1H), 3.11 (s, 3H),
2.99 (brs, 1H), 1.83-1.79 (m, 1H), 1.12 (d, J ) 7.0 Hz, 3H),
0.93 (d, J ) 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1,
130.6, 129.2, 113.7, 113.6, 73.9, 72.9, 72,7, 61.4, 55.2, 36.5, 36.0,
14.3, 10.5; IR (thin film on NaCl) 3449, 2963, 2936, 1640, 1612,
1585, 1514, 1462, 1421, 1387, 1248, 1175, 1090, 1034, 820
NBA/NaI) (m/z) calculated for C19H30O5Na (M + Na)+
)
361.1991, observed 361.1994; [R]20D ) 32.7 (c ) 2.94, CH2Cl2).
Dih yd r op yr on e 11. To a flame-dried 500 mL round-bottom
flask containing freshly prepared aldehyde 9 (30 mmol) was
added CH2Cl2 (80 mL). The flask was placed in a -78 °C bath.
To a separate 100 mL pear-shaped flask was added freshly
distilled TiCl4 (4.0 mL, 37 mmol) and CH2Cl2 before cooling
the solution to -78 °C. The cooled solution of TiCl4 in CH2Cl2
was added to the cold aldehyde over 2 min via cannula causing
the solution of aldehyde to turn from pale yellow to an orange/
red color. A similarly prechilled (-78 °C) solution of diene 10
(10.0 g, 49.9 mmol) in CH2Cl2 (85 mL) was added via cannula
over 3 min, causing the solution of the aldehyde-TiCl4 complex
to turn from orange/red to black. The reaction was allowed to
stir at -78 °C for 1 h before MeOH (50 mL) was added to
quench the reaction. After warming to room temperature,
aqueous NaHCO3 (1 M, 200 mL) was added to the quenched
reaction, causing the aqueous layer to turn milky white and
the organic layer to become orange/red. The aqueous layer was
extracted with CH2Cl2 (1 × 150 mL) and Et2O (3 × 150 mL).
The combined organic layers were washed with aqueous NaCl
(saturated, 700 mL) and dried with Na2SO4. The dried organic
solution was filtered and concentrated in vacuo to an oil. To
cm-1
.
To the crude Weinreb amide (approximately 42 mmol)
(containing residual oxazolidinone from the previous experi-
ment) in a 500 mL round-bottom flask was added diisopropyl-
ethylamine (75 mL). The flask was placed in a 0 °C bath and
allowed to stir for 5 min. After this cooling period, MOM-Cl
(20.0 mL, 214 mmol) (CAUTION: carcinogen) was added
dropwise. The reaction was allowed to stir for 15 min and then
(nBu)4N+I- (1.5 g, 4.2 mmol) was added to the reaction in one
portion. The reaction mixture was then stirred for another 2.5
h, during which time a white precipitated formed and TLC
analysis indicated that the reaction was complete. At this time,
MeOH (20 mL) was added to the reaction, causing the solid to
dissolve and heat to evolve. To the quenched reaction was
added aqueous NaHCO3 (1 M, 200 mL) and the mixture was
allowed to stir for 45 min. The layers were separated, and the
J . Org. Chem, Vol. 68, No. 17, 2003 6655

Harried et al.
the oil was added benzene (250 mL) and PPTs (87 mg) and
the solution was allowed to stir for 12 h before pouring into
aqueous NaHCO3 (1 M, 300 mL). The layers were allowed to
separate and the aqueous layer was extracted with Et2O (3 ×
200 mL). The organic layers were dried with MgSO4 and then
concentrated in vacuo to a crude residue. The crude residue
was purified by flash column chromatography to give the major
diastereomer 11 (4.72 g, 17.2 mmol) in 56% yield: Rf ) 0.60,
25% EtOAc in hexanes. Additionally, the minor diastereomer
(0.60 g, 2.18 mmol) was isolated in 7% yield: Rf ) 0.65, 25%
EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 7.38-7.33
(m, 5H), 7.18 (br s, 1H), 4.52 (ABq, J ) 12.1 Hz, ∆ν ) 14.8
Hz, 2H), 4.17 (dd, J ) 10.5, 2.7 Hz, 1H), 3.61 (m, 2H), 2.44
(qd, J ) 7.4, 2.8 Hz, 1H), 2.16 (m, 1H), 1.67 (d, J ) 1.1 Hz,
3H), 1.05 (d, J ) 7.4 Hz, 3H), 1.00 (d, J ) 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 198.0, 159.0, 138.5, 128.2, 127.4,
127.4, 112.0, 82.0, 73.1, 71.0, 41.1, 34.3, 12.9, 10.5, 9.3.
Alcoh ol 11a . To a 250 mL round-bottom flask were added
CeCl3‚7H2O (3.10 g, 8.31 mmol) and MeOH (15 mL). The
solution was allowed to stir for 1.5 h at room temperature and
then cooled to 0 °C. A solution of 11 (1.95 g, 7.11 mmol) in
MeOH (15 mL, 3 × 3 mL rinses) was added to the reaction
flask. After 5 min, solid NaBH4 (310 mg, 8.20 mmol) was added
in one portion, causing a gas to evolve. The reaction was
allowed to stir for 15 min and then quenched by the dropwise
addition of aqueous HCl (5%, 10 mL). After 10 min, Et2O (30
mL) and H2O (30 mL) were added. The layers were allowed to
separate, and the aqueous layer was extracted with Et2O (4
× 40 mL). The combined organic layers were washed with
aqueous NaHCO3 (1 M, 200 mL) and aqueous NaCl (saturated,
200 mL) before being dried with MgSO4. The dried organic
layer was filtered and subjected to a short plug of silica gel
and then concentrated in vacuo to provide clean alcohol (1.93
g, 6.98 mmol) in 98% yield as a white solid: Rf ) 0.40, 20%
EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 7.34-7.26
(m, 5H), 6.08 (s, 1H), 4.51 (ABq, J ) 12.1 Hz, ∆ν ) 12.2 Hz,
2H), 4.43 (m, 1H), 3.70 (dd, J ) 10.2, 1.3 Hz, 1H), 3.61 (dd, J
) 8.9, 3.1 Hz, 1H), 3.47, (dd, J ) 8.9, 6.2 Hz, 1H), 2.19-2.13
(m, 1H), 2.04-1.97 (m, 1H), 1.58 (br s, 3H), 1.34 (dd, J ) 7.8,
2.6 Hz, 1H), 1.04 (d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 139.6, 138.8, 128.3, 127.5, 127.5,
109.5, 79.0, 73.2, 72.2, 69.4, 35.1, 33.0, 13.6, 13.4, 4.8.
11.8, 1H), 3.54 (dd, J ) 4.2, 9.2 Hz, 1H), 3.45 (dd, J ) 6.4, 9.2
Hz, 1H), 3.28 (dd, J ) 5.5, 10.6 Hz, 1H), 2.63 (m, 1H), 1.96
(m, 1H), 1.77 (s, 3H), 0.99-0.96 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 137.6, 134.3, 131.4, 128.5, 127.9, 127.9, 80.3, 74.3,
73.6, 61.6, 36.2, 35.5, 21.8, 16.5, 15.3.
Allylic Alcoh ol 14. To a chilled (0 °C) 500 mL round-bottom
flask containing diol 13 (2.73 g, 9.8 mmol) were added CH2Cl2
(100 mL), triethylamine (1.65 mL, 11.76 mmol), and pivaloyl
chloride (1.2 mL, 9.81 mmol). A catalytic amount of DMAP
was added to the reaction before it was allowed to warm to
room temperature and stir for 24 h. After this time, the
reaction was poured into aqueous NH4Cl (1 M, 100 mL). The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 100 mL). The combined organics were
washed with aqueous NaCl (saturated, 300 mL), dried with
Na2SO4, filtered, and concentrated in vacuo to provide crude
pivalate (3.5 g). This crude oil was purified by flash column
chromatography (18 cm of silica gel on a 3 cm diameter
column) to provide pure pivaloate ester (3.14 g) in 88% yield:
Rf ) 0.50, 20% EtOAc in hexanes.
This pivaloate ester (3.14 g, 8.67 mmol) was subjected to
high vacuum (2 mmHg) for 45 min and then dissolved in CH2-
Cl2 (50 mL). To the solution was added a magnetic stir bar
and triethylamine (1.83 mL, 13.00 mmol) in one portion.
TipsOTf (3.0 mL, 11.3 mmol) was added dropwise via a
syringe. The reaction was allowed to stir for 24 h and then
poured into aqueous NH4Cl (1 M, 100 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 75 mL). The combined organic
layers were washed with aqueous NaCl (saturated, 200 mL)
and dried with Na2SO4. The dried solution was filtered and
subjected to a short plug of silica gel and then concentrated
in vacuo to a crude mixture (4.77 g) that was taken directly to
the following experiment.
The crude mixture from above was dissolved in CH2Cl2 (100
mL) and then placed on a -78 °C bath. To the magnetically
stirred solution was added dropwise a solution of DIBAL-H
(1.5 M, 10 mL) in toluene. The reaction was allowed to stir for
20 min before MeOH (10 mL) was added dropwise at -78 °C
to quench any excess hydride. After warming to room tem-
perature, aqueous sodium potassium tartrate (1 M, 150 mL)
was added to the reaction flask and the mixture was allowed
to stir for 1 h and then poured into Et2O (150 mL) in
separatory funnel. The layers were separated, and the aqueous
was extracted with Et2O (2 × 150 mL) and EtOAc (150 mL).
The organic layers were washed with aqueous NaCl (saturated,
500 mL) and dried with MgSO4. The solvent was concentrated
in vacuo to provide a crude oil (4.0 g) that was purified by
flash column chromatography (18 cm of silica gel on a 3 cm
diameter column) to give pale yellow oil (3.76 g) that was a
mixture of product 14 and a silyl impurity (TipsOH or
(Tips)2O). This mixture was subjected to high vacuum (2
mmHg) with magnetic stirring for 4 days to remove the silyl
impurity (1H NMR: δ 1.06 singlet) and give pure, clean
primary alcohol 14 (3.61 g, 8.32 mmol) in 95% yield over two
steps: Rf ) 0.55, 20% EtOAc in hexanes; 1H NMR (400 MHz,
CDCl3) δ 7.35-7.26 (m, 5H), 5.12 (d, J ) 10.2 Hz, 1H), 4.48
(s, 2H), 4.14 (dd, J ) 11.8, 5.0 Hz, 1H), 3.88 (dd, J ) 11.8, 7.5
Hz, 1H), 3.68 (dd, J ) 6.6, 3.2 Hz, 1H), 3.59 (dd, J ) 9.3, 6.6
Hz, 1H), 3.24 (dd, J ) 9.3, 6.5 Hz, 1H), 2.73 (m, 1H), 2.12 (m,
1H), 1.93 (dd, J ) 7.5, 5.0 Hz, 1H), 1.75 (s, 3H), 1.08 (br s,
21H), 0.99 (d, J ) 6.8 Hz, 3H), 0.97 (d, J ) 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 138.3, 133.3, 132.7, 128.3, 127.8,
127.6, 79.0, 73.2, 72.8, 61.6, 38.8, 36.2, 21.7, 18.4, 18.4, 18.1,
14.8, 13.5; IR (thin film on NaCl) 3389, 2963, 2943, 2892, 2866,
1464, 1454, 1383, 1365, 1251, 1090, 1067, 1012, 884, 830, 785,
735, 698, 679 cm-1; HRMS (FAB, NBA/NaI) (m/z) calculated
for C26H46O3SiNa (M + Na)+ ) 457.3114, observed 457.3113;
Diol 13. To a 500 mL round-bottom flask containing alcohol
11a (1.89 g, 6.8 mmol) was added a magnetic stir bar and THF
(150 mL). H2O (15 mL) and TsOH (100 mg) were added to the
reaction mixture. The round-bottom flask was fitted with a
reflux condenser and the reaction was allowed to reflux for 7
h. At this time, the reaction was allowed to cool and then
poured into aqueous NaHCO3 (1 M, 100 mL). The quenched
reaction was extracted with Et2O (4 × 100 mL), washed with
aqueous NaCl (saturated, 400 mL), dried with MgSO4, and
concentrated in vacuo to provide crude lactol 12 (1.93 g) as an
off-yellow solid: Rf ) 0.50, 25% EtOAc in hexanes. This
material was taken directly on to the next reaction without
any further purification.
To the crude lactol 12 in a 500 mL round-bottom flask was
added benzene (5 mL), which was removed in vacuo. The flask
was then charged with THF (200 mL) and argon and chilled
in a 0 °C bath. After cooling for 10 min, LiBH4 (310 mg, 14
mmol, 2 equiv) was added to the reaction in one portion. The
reaction was allowed to stir at 0 °C for 4 h and then quenched
with wet Et2O (10 mL), followed by H2O (150 mL). The
quenched reaction was allowed to stir for 1 h and then
extracted with EtOAc (4 × 150 mL). The combined organics
were washed with aqueous NaCl (saturated, 400 mL), dried
with MgSO4, and concentrated in vacuo to give a crude oil.
This material was purified by flash column chromatography
(15% gradient to 30% EtOAc in hexanes) to provide clean diol
13 (1.58 g, 5.68 mmol) in 84% yield for two steps: Rf ) 0.20,
[R]20 ) 4.80 (c ) 8.0, CH2Cl2).
D
Allylic Iodide 15. To a 250 mL round-bottom flask equipped
with a magnetic stir bar and rubber septum were added
triphenyl phosphite methiodide (3.8 g, 8.4 mmol, 3.5 equiv,
Aldrich) and DMF (5 mL). The flask was wrapped in aluminum
1
25% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ 7.35-
7.26 (m, 5H), 5.20 (d, J ) 9.95 Hz, 1H), 4.48 (ABq, J ) 12.1
Hz, ∆ν ) 14.8 Hz, 2H), 4.07 (d, J ) 11.8 Hz, 1H), 3.91 (d, J )
6656 J . Org. Chem., Vol. 68, No. 17, 2003

Total Synthesis of (+)-Discodermolide
foil and kept in the dark. After stirring for 5 min, the allylic
alcohol 14 (1.0 g, 2.42 mmol) was added as a solution in DMF
(6 mL). The reaction was allowed to stir for 30 min and then
poured into a separatory funnel containing aqueous K2CO3 (1
M, 50 mL) and hexanes (50 mL). The layers were separated,
and the organic layer was washed with aqueous K2CO3 (1 M,
4 × 50 mL) and aqueous NaCl (saturated, 50 mL). The organic
layer was dried with Na2SO4, filtered, and then concentrated
in vacuo to approximately 5 mL of hexanes/DMF. This solution
was quickly purified by flash column chromatography on a
short plug (4 cm of silica gel on a 3 cm diameter column, 1%
EtOAc in hexanes) to provide clean allylic iodide 15 (1270 mg,
2.33 mmol) in 96% yield as a viscous oil: Rf ) 0.80, 10% EtOAc
flash column chromatography (20 cm of silica gel on 3 cm
diameter column, 80% EtOAc in hexanes). Concentration in
vacuo of the appropriate fractions provided chelation-controlled
alcohol 21 (240 mg) in 80% yield as pale yellow oil: Rf ) 0.25,
20% EtOAc in hexanes. Additionally, the nonchelation isomer
at C17 (â-OH) was isolated (30 mg) in 10% yield: Rf ) 0.35,
20% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 7.32 (m,
5H), 7.25 (d, J ) 9.0 Hz, 2H), 6.87 (d, J ) 9.0 Hz, 2H), 5.16 (d,
J ) 9.9 Hz, 0.1H), 5.06 (d, J ) 10.1 Hz, 0.9H), 4.66 (ABq, J )
6.2 Hz, ∆ν ) 19.1 Hz, 2H), 4.46 (m, 4H), 3.80 (s, 3H), 3.70 (m,
1H), 3.56-3.37 (m, 5H), 3.37 (s, 3H), 3.26 (m, 1H), 2.88 (brs,
0.7 H), 2.56 (m, 1H), 2.10-1.70 (m, 6H), 1.62 (s, 0.9H), 1.59
(s, 3H), 1.13-0.81 (m, 36H); 13C NMR (100 MHz, CDCl3) δ
159.2, 138.8, 131.6, 131.6, 130.5, 129.3, 128.3, 127.5, 127.4,
113.8, 98.7, 85.1, 79.2, 78.3, 73.3, 72.8, 72.0, 56.1, 55.3, 39.8,
37.2, 36.5, 35.8, 35.5, 33.7, 23.2, 18.4, 18.4, 17.3, 14.9, 14.3,
13.6, 13.4, 7.7; IR (thin film on NaCl) 3513, 2963, 2942, 2867,
1
in hexanes; H NMR (400 MHz, CDCl3) δ 7.39-7.29 (m, 5H),
5.29 (d, J ) 10.1 Hz, 1H), 4.51 (ABq, J ) 12.0 Hz, ∆ν ) 27.7
Hz, 2H), 3.98 (d, J ) 9.0 Hz, 1H), 3.85 (t, J ) 5.7 Hz, 1H),
3.81 (d, J ) 9.0 Hz, 1H), 3.50 (dd, J ) 6.6, 9.1 Hz, 1H), 3.32
(dd, J ) 7.2, 9.1 Hz, 1H), 2.64 (m, 1H), 2.13 (m, 1H), 1.78 (s,
3H), 1.11 (br s, 21H), 1.08-1.03 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 138.7, 134.7, 130.3, 128.4, 128.3, 127.5, 127.4, 76.7,
73.0, 39.8, 36.2, 22.4, 18.4, 18.3, 15.7, 13.5, 13.5, 7.0.
1514, 1455, 1248, 1090, 1036 cm-1
.
P r im a r y Alcoh ol 22. To a stirred solution of alcohol 21
(2050 mg, 2.71 mmol) in CH2Cl2 (17 mL) were added excess
triethylamine (0.84 mL, 6.0 mmol), TipsOTf (1.0 mL, 4.0
mmol), and catalytic DMAP (20 mg). The stirring was contin-
ued at room temperature for 48 h, at which time NaHCO3 (1
M, 20 mL) was added to the reaction flask. The phases were
separated and the aqueous layer was extracted with CH2Cl2
(5 × 20 mL). The combined organic extracts were then washed
with aqueous NaCl (saturated, 200 mL) and dried with Na2-
SO4. The dried solution was filtered through a plug of silica
gel and concentrated in vacuo to provide a crude residue (2.95
g). This crude material was used in the following reaction
without any further purification: Rf ) 0.8, 20% EtOAc in
Keton e 20. To a flame-dried 250 mL round-bottom flask
equipped with a magnetic stir bar and rubber septum was
placed lithium hexamethyldisilazide (820 mg, 4.68 mmol, solid,
97%, Aldrich) inside a N2 atmosphere drybox. The round-
bottom flask was sealed and removed from the drybox before
adding THF (5 mL) and hexane (5 mL). The reaction flask was
placed in a -78 °C bath before adding dry (2 × 3 mL of benzene
azeotrope) ethyl ketone 19 (1267 mg, 3.75 mmol) in THF (4
mL, 2 × 1 mL rinses) dropwise over 15 min. The reaction
mixture was stirred at -78 °C for 45 min before the addition
of tetramethylethylenediamine (0.850 mL, 5.63 mmol) in THF
(3 mL) dropwise over 5 min. The resulting reaction mixture
was allowed to stir for 30 min at -78 °C before adding dry
(30 mL benzene azeotrope) allyl iodide 15 (1020 mg, 1.875
mmol) in hexane (5 mL, followed by 2 × l mL of hexane rinses
and 1 × 1 mL of THF rinse) dropwise. The reaction mixture
was stirred in the dark at -78 °C for 49 h and then quenched
by addition of aqueous NaHCO3 (1 M, 50 mL). The resulting
mixture was extracted with Et2O (4 × 50 mL). The combined
organic layers were washed with aqueous NaCl (saturated, 250
mL) and dried with MgSO4. The dried organic layers were
filtered through a short plug of silica gel and concentrated in
vacuo, providing a colorless, viscous oil. The crude material
was purified by flash column chromatography (20 cm of silica
gel on a 3 cm diameter column, 7% EtOAc in hexanes),
providing clean ketone 20 (980 mg, 1.30 mmol) in 70% yield
as an approximately 6:1 ratio of inseparable epimers at C16
(1H NMR integration and mass of separated diastereomers at
a latter stage of synthesis): Rf ) 0.5, 20% EtOAc in hexanes;
1H NMR (400 MHz, CDCl3) δ 7.31 (m, 5H), 7.25 (d, J ) 9 Hz,
2H), 6.87 (d J ) 9 Hz, 2H), 5.13 (d, J ) 10 Hz, 1H), 4.60-4.40
(m, 6H), 3.80 (s, 3H), 3.75 (m, 2H), 3.51-3.30 (m, 7H), 3.00-
2.85 (m, 2H), 2.53 (m, 1H), 2.40-1.50 (m, 7H), 1.12-0.87 (m,
36H); 13C NMR (100 MHz, CDCl3) δ 216.2, 159.1, 138.8, 133.0,
130.6, 130.5, 129.1, 128.2, 127.4, 127.3, 113.6, 97.9, 80.9, 78.0,
73.2, 72.9, 72.7, 71.6, 56.0, 55.2, 47.4, 42.1, 39.8, 37.3, 37.3,
35.2, 22.9, 18.3, 18.3, 17.4, 15.4, 14.8, 13.6, 13.4, 11.0.
1
hexanes; H NMR (400 MHz, CDCl3) δ 7.31 (m, 5H), 7.24 (d,
J ) 8.7 Hz, 2H), 6.86 (d, J ) 8.7 Hz, 2H), 4.97 (d, J ) 10.3 Hz,
1H), 4.59 (ABq, J ) 6.6 Hz, ∆ν ) 24.3 Hz, 2H), 4.45 (m, 4H),
3.80 (s, 3H), 3.73 (dd, J ) 7.3, 3.4 Hz, 1H), 3.39 (dd, J ) 8.9,
3.5 Hz, 1H), 3.44 (m, 2H), 3.38 (m, 3H), 3.35 (s, 3H), 3.28 (m,
1H), 2.51 (m, 1H), 2.41 (m, 1H), 2.17-1.93 (m, 3H), 1.88-1.71
(m, 2H), 1.55 (s, 3H), 1.20-0.85 (m, 54H), 0.70 (d, J ) 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 138.9, 131.7, 131.0,
130.7, 129.1, 128.2, 127.5, 127.3, 113.7, 98.7, 83.0, 79.1, 78.0,
73.4, 73.0, 72.8, 72.7, 56.1, 55.2, 40.5, 38.7, 37.1, 36.8, 35.9,
33.7, 22.7, 18.5, 18.4, 18.4, 18.2, 17.7, 15.4, 14.2, 13.4, 12.6,
11.7, 11.0.
To the solution containing the residue from the preceding
reaction in absolute EtOH (20 mL), was added aged (48 h) W-2
Raney Ni (400 mg) (1-2 h old material was too active to
provide selective debenzylation; material over a week old was
inactive). The reaction mixture was stirred at room temper-
ature under 1 atm of H2 for 24 h, at which time TLC analysis
indicated that all of the starting material had been consumed.
At this time, the Raney Ni was removed by filtration through
Celite (4 cm) on top of a plug of silica gel (10 cm). The filtrate
was then concentrated in vacuo, providing a crude residue.
Flash column chromatography (10% EtOAc in hexanes) of the
residue resulted in complete separation of the C16 epimers
and gave 22 as a clear oil (1.59 g, 1.93 mmol). in 71% yield
from 21 (two steps): Rf ) 0.40, 20% EtOAc in hexanes.
Additionally, the C16 minor epimer (0.213 g, 0.26 mmol) was
isolated in 9% yield: Rf ) 0.45, 20% EtOAc in hexanes; 1H
NMR (400 MHz, CDCl3) δ 7.22 (d, J ) 8.6 Hz, 2H), 6.86 (d, J
) 8.6 Hz, 2H), 5.07 (d, J ) 10.1 Hz, 1H), 4.58 (ABq, J ) 6.6
Hz, ∆ν ) 25.4 Hz, 2H), 4.42 (brs, 2H), 3.81 (m, 1H), 3.80 (s,
3H), 3.70 (dd, J ) 7.1, 3.5 Hz, 1H), 3.57 (d, J ) 5.8 Hz, 2H),
3.48 (dd, J ) 8.9, 3.5 Hz, 1H), 3.44 (dd, J ) 7.3, 3.6 Hz, 1H)
3.36 (m, 1H), 3.35 (s, 3H), 2.60 (m, 1H), 2.40 (m, 1H), 2.10 (m,
1H), 2.03-1.94 (m, 3H), 1.83 (m, 2H), 1.63 (s, 3H), 1.14-1.09
(m, 42H), 1.01-0.88 (m, 12H) 0.71 (d, J ) 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.1, 133.0, 130.7, 130.4, 129.1,
113.7, 98.7, 83.0, 80.3, 78.0, 72.8, 72.0, 65.8, 56.0, 55.3, 40.6,
38.6, 37.1, 36.7, 36.6, 33.9, 31.6, 22.9, 22.7, 18.5, 18.5, 18.4,
18.3, 15.4, 14.1, 13.5, 11.9, 11.0; IR (thin film on NaCl) 3463,
Alcoh ol 21. To a stirred solution of 20 (300 mg, 0.398 mmol)
in dry Et2O (5 mL) at 0 °C was added LiI (532 mg, 3.98 mmol)
in diethyl ether (5 mL). The solution was stirred until the LiI
was completely dissolved (10 min). The mixture was then
cooled to -78 °C for 10 min. A fresh solution of LAH in THF
(1.0 M, 4 mL, centrifuged) was added in one portion (dropwise
addition gave poor diastereoselectivity). The stirring was
continued at -78 °C for 30 min, and then sodium potassium
tartrate solution (1 N, 30 mL) was added. The mixture was
stirred at room temperature for 30 min, and the phases were
allowed to separate. The aqueous layer was extracted with
EtOAc (4 × 30 mL). The combined organic extracts were then
washed with aqueous NaCl (saturated, 100 mL), dried (Na2-
SO4), filtered, and concentrated. The material was purified by
J . Org. Chem, Vol. 68, No. 17, 2003 6657

Harried et al.
2944, 2867, 1514, 1464, 1377, 1248, 1090, 1036 cm-1; [R]20
- 3.9 (c ) 1.25, CHCl3).
)
NBA/NaI) (m/z) calculated for C48H8906Si2INa (M + Na)+
)
D
967.5141, observed 967.5140; [R]20 ) -56.7 (c ) 1.06, CH2-
D
Cl2).
Iod oa lk en e 23. To alcohol 22 (540 mg, 0.657 mmol) in a
50 mL round-bottom flask equipped with a magnetic stir bar
was added dry benzene (3 mL). The solution was concentrated
in vacuo in order to azeotropically remove any water. To the
dried alcohol were added CH2Cl2 (4.5 mL), acetonitrile (0.70
mL) and 4 Å molecular sieves (powdered, 330 mg, Aldrich, used
as received). After allowing the solution to stir for 5 min,
anhydrous NMO (115 mg, 0.985 mmol) was added in one
portion followed by TPAP (12 mg, 30 mmol), causing an instant
color change from colorless to green. The oxidation reaction
was allowed to stir for 2 h, during which time the color changed
from green to black, and the reaction was judged to be complete
by TLC analysis. The crude mixture was then concentrated
in vacuo in order to remove the acetonitrile, a polar solvent
that causes the Ru to pass through the silica gel during flash
chromatography. The crude residue was purified by flash
column chromatography (4 cm of silica gel on a 3 cm diameter
column elute CH2Cl2) to give clean aldehyde (475 mg, 0.577
mmol) in 88% yield. The aldehyde was then dried azeotropic-
aIly with benzene (3 mL) in vacuo and then dissolved in THF
(10 mL). This solution was immediately used in the following
Ald eh yd e 24. To a 50 mL round-bottom flask containing
PMB ether 23 (540 mg, 0.571 mmol) and a magnetic stir bar
were added CH2Cl2 (10 mL) and H2O (0.5 mL). The solution
was allowed to stir for 5 min before adding DDQ (190 mg, 0.831
mmol) in one portion, causing an instant color change from
colorless to green. The reaction mixture was allowed to stir at
room temperature for 45 min and then quenched by pouring
the reaction into aqueous NaHCO3 (1 M, 100 mL). Upon
quenching the reaction, the aqueous layer became burgundy
in color. The layers were partitioned and the aqueous layer
was extracted with CH2Cl2 (5 × 30 mL). The combined organic
layers were washed with aqueous NaCl (saturated, 1 × 200
mL) and dried with anhydrous Na2SO4. The organic layer was
filtered and concentrated in vacuo to provide crude product
(495 mg) as a colorless oil. This material was purified by flash
column chromatography (20 cm of silica gel on a 3 cm diameter
column, 5% EtOAc in hexanes, gradient to 10% EtOAc in
hexanes), providing clean primary alcohol (412 mg, 0.500
mmol) in 87% yield: Rf ) 0.2, 10% EtOAc in hexanes; 1H NMR
(400 MHz, CDCl3) δ 6.33 (dd, J ) 8.5, 7.4 Hz, 1H), 6.10 (d, J
) 7.3 Hz, 1H), 4.94 (d, J ) 10.3 Hz, 1H), 4.67 (d, J ) 6.5 Hz,
1H), 4.61 (d, J ) 6.5 Hz, 1H), 3.79 (dd, J ) 11.5, 3.3 Hz, 1H),
3.73 (dd, J ) 7.5, 1.7 Hz, 1H), 3.57 (dd, J ) 8.2, 2.0 Hz, 1H),
3.53 (dd, J ) 11.2, 4.2 Hz, 1H), 3.46 (dd, J ) 7.7, 3.2 Hz, 1H),
3.41 (s, 3H), 2.72-2.66 (m, 2H), 2.36-2.26 (m, 2H), 2.06-1.98
(m, 1H), 1.90-1.81 (m, 2H), 1.64 (s, 3H), 1.16-1.07 (m, 42H),
1.02-0.95 (m, 12H), 0.54 (d, J ) 6.7 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 142.9, 132.7, 130.3, 98.9, 84.3, 81.8, 78.8, 65.0,
56.3, 44.4, 39.4, 38.1, 38.0, 31.6, 25.3, 23.0, 18.8, 18.6, 18.5,
18.5, 18.5, 16.6, 15.1, 14.1, 14.0, 13.7, 12.1, 10.9; IR (thin film
1
procedure: Rf ) 0.65, 20% EtOAc in hexanes; H NMR (400
MHz, CDCl3) δ 9.55 (d, J ) 0.5 Hz, 1H), 7.23 (d, J ) 8.7 Hz,
2H), 6.86 (d, J ) 8.7 Hz, 2H), 4.73 (d, J ) 10.8 Hz, 1H), 4.56
(ABq, J ) 6.6 Hz, ∆ν ) 23.7 Hz, 2H), 4.42 (s, 2H), 4.10 (dd, J
) 8.8, 3.1 Hz, 1H), 3.80 (s, 3H), 3.78 (m, 1H), 3.48-3.35 (m,
3H), 3.33 (s, 3H), 2.56-2.37 (m, 3H), 2.15-1.72 (m, 4H), 1.56
(s, 3H), 1.18-1.05 (m, 45H), 1.02 (d, J ) 6.5 Hz, 3H), 0.99 (m,
6H), 0.68 (d, J ) 6.8 Hz, 3H).
To a flame-dried, single-neck 500 mL round-bottom flask
equipped with a magnetic stir bar and rubber septum were
added solid, white iodomethylenetriphenylphosphonium iodide
(930 mg, 1.75 mmol) and THF (20 mL) to give a white
suspension. The suspension was placed in a -20 °C bath for
10 min before a NaHMDS (solid, 334 mg, 1.85 mmol) solution
in THF (10 mL) was added dropwise, transforming the white
suspension to a bright yellow solution. Upon completion of the
addition of NaHMDS, the reaction mixture was allowed to stir
at -20 °C for an additional 5 min. The reaction mixture was
then placed in a -78 °C bath for 3 min before adding the
freshly prepared THF (10 mL) solution of aldehyde from the
previous experimental via a cannula. Care was taken to cool
the THF solution of aldehyde by passing it down the side of
the reaction flask during the addition. The reaction mixture
was allowed to stir for 10 min and then quenched by pouring
it into aqueous NH4Cl (1 M, 50 mL). The resulting mixture
was extracted with EtOAc (3 × 50 mL) and CH2Cl2 (1 × 20
mL). The combined organic layers were washed with aqueous
NaCl (saturated, 1 × 200 mL) and dried with anhydrous Na2-
SO4. The dried organic layers were filtered through a short
plug of silica gel and concentrated in vacuo to provide the crude
product (1.75 g). This crude residue was purified by flash
column chromatography (20 cm of silica gel on a 3 cm diameter
column, 5% EtOAc in hexane), providing clean iodoalkene 23
as a colorless foamy oil (493 mg, 0.521 mmol) in 90% yield: Rf
on NaCl) 3438, 2944, 2889, 1464, 1385, 1260, 1035, 884 cm-1
;
HRMS (FAB/NaI) (m/z) calculated for C40H81IO5Si2Na (M +
H)+ ) 847.4565, observed 847.4561; [R]20 ) -46.8 (c ) 2.40,
D
CH2Cl2).
To the alcohol from above (190 mg, 0.230 mmol) in a 50 mL,
round-bottom flask equipped with a magnetic stir bar were
added CH2Cl2 (4 mL), acetonitrile (0.4 mL), and 4 Å molecular
sieves (powdered, 120 mg). After allowing the solution to stir
for 5 min, NMO (40 mg, 0.345 mmol) was added in one portion,
followed by TPAP (5 mg, 1.42 µmol), which caused an instant
color change from colorless to green. The oxidation reaction
was allowed to stir for 40 min and then judged to be complete
by TLC analysis. The color of the reaction solution turned from
green to black over the 40 min of reaction time. After 1 h, the
reaction mixture was concentrated in vacuo. The crude residue
was purified by flash column chromatography (5 cm of silica
gel on a 2 cm diameter column, 5% EtOAc in CH2Cl2). The
eluate was concentrated in vacuo to give pure aldehyde 24 (170
mg, 0.206 mmol) in 89% yield. This compound was im-
mediately used in the following procedure.
(Z)-Ter m in a l Dien e 26. To aldehyde 24 in a 100 mL round-
bottom flask were added toluene (3 mL), a stir bar, and 4 Å
molecular sieves (powdered, 100 mg). The reaction mixture
was placed in a 0 °C bath and allowed to stir for 5 min before
adding (E)-γ-(trimethylsilyl)allylboronate (2 mL of a crude 1
M solution in toluene) 25 dropwise over 2 min. The reaction
mixture was allowed to stir for 1 h and then judged to be
complete by TLC. At this time, the reaction mixture was
purified by flash column chromatography (20 cm of silica gel
on a 3 cm diameter column, 5% EtOAc in hexane) by loading
the reaction mixture directly on to a column. The eluate was
concentrated in vacuo to give hydroxytrimethylsilane (176 mg),
which was immediately used in the following procedure.
1
) 0.4, 10% EtOAc in hexanes; H NMR (500 MHz, CDCl3) δ
7.29 (d, J ) 8.7 Hz, 2H), 6.92 (d, J ) 8.7 Hz, 2H), 6.39 (dd, J
) 8.4, 7.3 Hz, 1H), 6.17 (d, J ) 7.3 Hz, 1H), 5.01 (d, J ) 10.3
Hz, 1H), 4.68 (d, J ) 6.6 Hz, 1 H), 4.63 (d, J ) 6.6 Hz, 1H),
4.50 (br s, 2H), 3.86-3.83 (m, 4H), 3.65 (dd, J ) 8.3, 2.1 Hz,
1H), 3.55-3.48 (m, 2H), 3.45-3.41 (m, 4H), 2.79-2.76 (m, 1H),
2.46-2.35 (m, 2H), 2.17-2.09 (m, 1H), 2.05-2.00 (m, 1H),
1.90-1.86 (m, 2H), 1.70 (s, 3H), 1.23-1.10 (m, 38H), 1.08-
1.02 (m, 12H), 0.76 (d, J ) 6.7 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.0, 142.8, 133.0, 130.6, 129.9, 129.0, 113.6, 98.5,
82.7, 81.7, 80.5 79.0, 72.6, 71.9, 55.9, 55.0, 44.3, 38.6, 37.9,
37.0, 31.5, 22.8, 22.5, 18.7, 18.4, 18.4, 16.5, 15.2, 14.0, 14.0,
13.6, 13.3, 11.6, 10.8; IR (thin film on NaCl) 2963, 2944, 2867,
1613, 1514, 1464, 1248, 1086, 884, 677 cm-1; HRMS (FAB,
To the hydroxy trimethylsilane in a 100 mL round-bottom
flask equipped with a magnetic stir bar was added THF (10
mL). The reaction mixture was placed in a 0 °C bath and
stirred for 10 min before adding KH (approximately 100 mg,
from 20 to 25 wt. % dispersion in mineral oil, rinsed and
decanted 3 × 50 mL of hexanes) (CAUTION: cleaned KH is
6658 J . Org. Chem., Vol. 68, No. 17, 2003

Total Synthesis of (+)-Discodermolide
pyrophoric). After 10 min, the reaction was quenched by the
addition of aqueous NaHCO3 (1 M, 20 mL). The resulting
mixture was extracted with Et2O (4 × 20 mL). The combined
organic layers were wash with aqueous NaCl (saturated, 50
mL) and then dried with anhydrous Na2SO4. The dried organic
layers were filtered and concentrated in vacuo, furnishing the
crude product (172 mg) as a colorless, viscous oil. The crude
product was purified by flash column chromatography (20 cm
of silica gel on a 3 cm diameter column, 3% EtOAc in hexanes).
The eluate was concentrated in vacuo, providing clean terminal
diene 26 (141 mg, 0.166 mmol) in 80% yield from aldehyde
24. The Z:E ratio is >20:1 as judged by 1H NMR: Rf ) 0.8,
5% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 6.61 (ddd,
J ) 16.8, 11.1, 11.1 Hz, 1H), 6.32 (dd, J ) 8.6, 7.3 Hz, 1H),
6.10 (d, J ) 7.3 Hz, 1H), 6.00 (dd, J ) 11.2, 11.2 Hz, 1H), 5.43
(dd, J ) 10.2, 10.2 Hz, 1H), 5.19 (dd, J ) 16.8, 1.9 Hz, 1H),
5.10 (d, J ) 10.l Hz, 1H), 4.93 (d, J ) 10.4 Hz, 1H), 4.66 (d, J
) 6.8 Hz, 1H), 4.56 (d, J ) 6.8 Hz, 1H), 3.75 (dd, J ) 6.2, 2.8
Hz, 1H), 3.58 (dd, J ) 8.2, 2.2 Hz, 1H), 3.39-3.30 (m, 4H),
2.98-2.92 (m, 1H), 2.78-2.66 (m, 1H), 2.40-2.32 (m, 1H), 2.22
(t, J ) 12.5 Hz, 1H), 2.04-1.96 (m, 1H), 1.83-1.76 (m, 2H),
1.63 (s, 3H), 1.18-1.09 (m, 42H), 1.03 (d, J ) 7.4 Hz, 3H),
1.02 (d, J ) 6.9 Hz, 3H), 1.02 (d, J ) 6.9 Hz, 3H), 0.98 (d, J )
6.6 Hz, 3H), 0.69 (d, J ) 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.0, 135.0, 133.0, 132.5, 130.1, 129.4, 117.6, 98.5,
84.7, 81.8, 80.6 78.7, 56.1, 44.5, 39.3, 38.0, 36.5, 35.7, 34.1,
31.6, 22.9, 22.7, 18.7, 18.6, 18.5, 18.3, 16.5, 14.1, 13.7, 12.8,
11.0; IR (thin film on NaCl) 2963, 2946, 2892, 2868, 1464, 1377,
1260, 1152, 1121, 1088, 1036, 970, 905, 883, 714, 677, 646
cm-1; HRMS (FAB, NBA/NaI) (m/z) calculated for C43H83O4-
In a flame-dried 50 mL round-bottom flask equipped with
magnetic stir bar and rubber septum was placed the
a
secondary alcohol from above (78 mg, 0.0947 mmol), which was
then azeotropically dried with benzene (2 × 1 mL). To the dried
alcohol was added CH2Cl2 (4 mL), followed by dropwise
addition of trichloroacetyl isocyanate (100 µL, 0.937 mmol) over
1 min. The reaction was allowed to stir at room temperature
for 30 min and then directly placed on a short pad of Al2O3
(neutral, activity II) that was prewetted with a 1:1 benzene to
CH2Cl2 solution. The reaction mixture was allowed to soak on
the column of Al2O3 for 30 min before eluting it with 1:1
benzene:CH2Cl2 solution (60 mL). Concentration of the eluate
provided a crude residue (88 mg) which was purified by flash
column chromatography (18 cm of silica gel on 2 cm diameter
column, 8% EtOAc in hexanes). Concentration of the eluate
in vacuo provided carbamate 27 (62 mg, 0.073 mmol) as a
white foamy solid in 75% yield: Rf ) 0.2, 10% EtOAc in
hexanes.1H NMR (400 MHz, CDCl3) δ 6.61 (ddd, J ) 16.7, 11.2,
11.2 Hz, 1H), 6.34 (dd, J ) 6.1, 6.1 Hz, 1H), 6.16 (d, J ) 7.0
Hz, 1H), 6.02 (dd, J ) 10.9, 10.9 Hz, 1H), 5.36 (dd, J ) 10.3,
10.3 Hz, 1H), 5.21 (d, J ) 9.1 Hz, 1H), 5.11 (d, J ) 10.3 Hz,
1H), 4.92 (d, J ) 10.3 Hz, 1H), 4.72 (dd, J ) 7.6, 4.3 Hz, 1H),
4.45 (brs, 2H), 3.67 (dd, J ) 6.3, 2.2 Hz, 1H), 3.58 (dd, J )
8.2, 2.2 Hz, 1H), 3.05-2.95 (m, 1H), 2.76-2.63 (m, 1H), 2.42-
2.31 (m, 1H), 2.38 (dd, J ) 9.6, 9.6 Hz, 1H), 2.09-1.90 (m,
2H), 1.82-1.75 (m, 1H), 1.63 (s, 3H), 1.17-1.05 (m, 42H),
1.03-0.95 (m, 12H), 0.72 (d, J ) 6.7 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 156.7, 143.2, 134.1, 133.0, 132.3, 130.0, 129.8,
128.3, 117.7, 81.7, 80.4 78.4, 78.2, 44.5, 37.9, 37.8, 36.4, 34.8,
34.5, 29.8, 22.9, 18.7, 18.5, 18.5, 17.4, 16.3, 14.0, 13.7, 12.8,
10.3; IR (thin film on NaCl) 3507, 3360, 2965, 2946, 2869, 1727,
1601, 1464, 1385, 1325, 1259, 1038, 884 cm-1; HRMS (FAB,
Si2INa (M + Na)+ ) 869.4773, observed 869.4787; [R]20 ) -
D
64.7 (c ) 1.7, CH2Cl2).
NBA/NaI) (m/z) calculated for C42H80O4INSi2Na (M + Na)+
)
868.4568, observed 868.4578; [R]20 ) - 51.3 (c ) 0.71, CH2-
Ca r ba m a te 27. To a flame-dried 50 mL round-bottom flask
was added a benzene solution of methoxymethyl ether 26 (32.5
mg, 0.0384 mmol) and then the solution was placed under high
vacuum (2 mmHg) for 30 min to azeotropically dry the starting
material. After this drying procedure, EtOH (absolute, 3 mL)
and THF (3 mL) were added to the reaction flask, and the flask
was equipped with a reflux condenser. The flask was then
placed in a 60 °C oil bath and warmed over 5 min. At this
time, AcCl (0.6 mL) was added to the reaction flask in one
portion. As soon as the AcCl was added to the reaction, a brief
gas evolution occurred. After 30 s, analysis of the reaction by
TLC showed that approximately 50% of the starting material
was cleanly deprotected. The reaction was allowed to stir a
total of 8 min after the addition of the AcCl and then poured
into aqueous NaHCO3 (1 M, 100 mL). The layers were
partioned, and the aqueous layer was extracted with CH2Cl2
(5 × 20 mL). The combined organic extracts were dried with
D
Cl2).
Allylic Alcoh ol 36. To a flame-dried 50 mL pear-shaped
flask equipped with
a magnetic stirring bar and Teflon
stopcock were added aldehyde 34 (139 mg, 0.285 mmol) and
vinyl iodide 27 (241 mg, 0.285 mmol). To a separate flame-
dried 25 mL pear-shaped flasked equipped with a magnetic
stirring bar and Teflon stopcock was added (-)-bispyridinyl
ligand 35 (419 mg, 1.42 mmol). The azeotroped starting
materials (3 × 1 mL of benzene) were placed under vacuum
and transported into a nitrogen atmosphere drybox. To the
(-)-bispyridinyl ligand 35 were added anhydrous and deoxy-
genated THF (10 mL) and 20% NiCl2/CrCl2 (175 mg, 1.42
mmol). The homogeneous brown solution was allowed to stir
for 1 h, at which time it was transferred to the flask containing
aldehyde 34 and vinyl iodide 27 in THF (5 mL, followed by 2
× 5 mL rinses). After stirring for 5 days, the reaction mixture
was removed from the drybox. To the mixture were added ethyl
acetate (10 mL) and 1 M sodium serinate (10 mL). The
resulting purple mixture was allowed to stir for 1 h, at which
time it was extracted with ethyl acetate (2 × 30 mL). The
combined organic extracts were washed with water (2 × 60
mL) and brine (60 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The crude material was purified by
column chromatography (5% EtOAc in hexanes, gradient to
14% EtOAc in hexanes) to provide a white solid (144 mg, 42%)
as a 3:1 mixture of inseparable diastereomers: Rf ) 0.32, 10%
EtOAc in hexanes; IR (thin film on NaCl) 2946, 2867, 1732,
1464, 1385, 1325, 1256, 1044, 884 cm-1. LRMS (FAB, NBA/
NaI) (m/ z) calculated for C67H133NO9Si4Na (M + Na)+ ) 1231,
observed 1231.
Na2SO4, filtered through
a short plug of silica gel, and
concentrated in vacuo to provide a crude residue (37 mg). The
crude residue was purified by flash column chromatography
(18 cm of silica gel on a 2 cm diameter column, 5% EtOAc in
hexanes) resulting in pure secondary alcohol (28 mg, 0.0350
1
mmol) in 90% yield; H NMR (400 MHz, CDCl3) δ 6.64 (dt, J
) 16.8, 10.4 Hz, 1H), 6.33 (dd, J ) 8.6, 7.4 Hz, 1H), 6.15 (dd,
J ) 10.9, 10.9 Hz, 1H), 6.11 (d, J ) 7.3 Hz, 1H), 5.31 (dd, J )
10.5, 10.5 Hz, 1H), 5.24 (dd, J ) 16.8, 1.5 Hz, 1H), 5.15 (d, J
) 10.1 Hz, 1H), 4.94 (d, J ) 10.1 Hz, 1H), 3.83 (dd, J ) 6.4,
2.3 Hz, 1H), 3.59 (dd, J ) 8.0, 2.3 Hz, 1H), 3.36 (dd, J ) 8.4,
2.0 Hz, 1H), 2.87-2.75 (m, 1H), 2.75-2.66 (m, 1H), 2.44-2.33
(m, 1H), 2.28 (dd, J ) 12.4, 12.4 Hz, 1H), 2.07-1.93 (m, 1H),
1.91-1.79 (m, 2H), 1.63 (s, 3H), 1.54 (br s, 1H), 1.20-1.09 (m,
42H), 1.03-0.93 (m, 12H), 0.74 (d, J ) 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.0, 134.9, 133.0, 132.2, 131.3, 130.1,
118.5, 81.8, 80.6, 80.0, 75.9, 44.4, 38.2, 38.0, 36.6, 36.4, 34.2,
31.6, 23.l, 22.7, 18.6, 18.5, 17.1, 16.6, 14.1, 14.0, 13.7, 13.0,
9.5; IR (thin film on NaCl) 3582, 2963, 2943, 2866, 1462, 1379,
1259, 1087, 884, 877 cm-1; HRMS (FAB, NBA/NaI) (m/z)
calculated for C41H79O3ISi2Na (M + Na)+ ) 825.4510, observed
(+)-Discod er m olid e 1. To a 1.5 mL polypropylene vial
equipped with a magnetic stirring bar was added Nozaki-
Kishi adduct 36 (16 mg, 0.013 mmol) in a solution of anhydrous
dichloromethane. After evaporating the dichloromethane over
a stream of air then under high vacuum, 10% HF in acetoni-
trile (0.5 mL) was added. The reaction mixture was allowed
to stir for 24 h, at which time the mixture was poured into a
separatory funnel containing 1 M NaHCO3 (10 mL). After
825.4520; [R]20 ) - 83.0 (c ) 1.40, CH2Cl2).
D
J . Org. Chem, Vol. 68, No. 17, 2003 6659

Harried et al.
adding additional solid NaHCO3 to the separatory funnel until
the solution reached saturation, the mixture was extracted
with ethyl acetate (4 × 15 mL). The combined organic extracts
were dried over Na2SO4, filtered, and concentrated in vacuo.
The crude material was used in the next step without further
purification: Rf ) 0.45, 5% methanol in dichloromethane.
To a 1.5 mL polypropylene vial equipped with a magnetic
stirring bar was added mono-TIPS ether (ca. 0.013 mmol) in
a solution of anhydrous dichloromethane. To a separate 1.5
mL polypropylene vial was added anhydrous THF (0.5 mL)
and 70% HF‚pyr (0.2 mL). The azeotroped mono-TIPS ether
(2 × 5 drops benzene) was treated with the HF‚pyr in THF
solution (0.7 mL). After stirring for 40 h, additional HF‚pyr
in THF solution (0.1 mL) was added. The reaction mixture was
allowed to stir for 63 h before additional HF‚pyr in THF
solution (0.1 mL) was added. After allowing the mixture to
stir for a total of 82 h, the mixture was poured into a
separatory funnel containing 1 M NaHCO3 (10 mL). Additional
solid NaHCO3 was added to the separatory funnel until the
solution reached saturation. The mixture was extracted with
ethyl acetate (10 × 10 mL). The combined organic extracts
were dried over Na2SO4, filtered, and concentrated in vacuo.
The crude material was purified by column chromatography
(5% methanol in dichloromethane) to provide a white solid (4
mg, 52% over two steps). A second white solid, the C7 epimer
of discodermolide, was also isolated (1 mg, 13% over two steps).
(+)-Discod er m olid e 1: Rf ) 0.38, 10% methanol in dichlo-
romethane; 1H NMR (360 MHz, 10% CD3OD in CDCl3) δ 6.54
(ddd, J ) 16.7, 10.6, 10.6 Hz, 1H), 5.95 (dd, J ) 10.9, 10.9 Hz,
1H), 5.37 (m, 2H), 5.29 (dd, J ) 11.2, 11.2 Hz, 1H), 5.14 (d, J
) 16.9 Hz, 1H), 5.04 (m, 2H), 4.65 (t, J ) 5.8 Hz, 1H), 4.59
(m, 1H), 4.50 (t, J ) 10.0 Hz, 1H), 3.57 (t, J ) 3.7 Hz, 1H),
3.16 (m, 1H), 3.10 (t, J ) 5.7 Hz, 1H), 2.96 (m, 1H), 2.61 (m,
2H), 2.43 (m, 1H), 1.81 (m, 6H), 1.54 (m, 1H), 1.54 (s, 3H),
1.22 (d, J ) 7.4 Hz, 3H), 0.97 (d, J ) 6.9 Hz, 3H), 0.94 (d, J )
6.6 Hz, 3H), 0.92 (d, J ) 6.5 Hz, 3H), 0.88 (d, J ) 7.1 Hz, 3H),
0.86 (d, J ) 7.2 Hz, 3H), 0.74 (d, J ) 5.4 Hz, 3H); 13C NMR
(90 MHz, 10% CD3OD in CDCl3) δ 175.3, 157.8, 133.5, 133.1,
132.5, 132.3, 131.8, 129.9, 129.7, 117.8, 78.8, 77.3, 76.6, 75.6,
72.4, 63.2, 42.9, 40.9, 37.1, 35.8, 35.5, 35.3, 35.1, 34.2, 33.0,
22.9, 17.9, 17.3, 15.7, 15.4, 13.9, 12.4, 8.5; IR (thin film on
NaCl) 3366, 2967, 2932, 1713, 1601, 1387, 1325, 1101, 1028,
974 cm-1; HRMS (FAB, NBA/NaI) (m/z) calculated for C33H55
-
)
NO8Na (M + Na)+ ) 616.3826, observed 616.3827. [R]20
D
+14.9 (c ) 0.18, CH3OH) C7-ep i-Discod er m olid e 37: Rf )
1
0.49, 10% methanol in dichloromethane; H NMR (360 MHz,
10% CD3OD in CDCl3) δ 6.52 (ddd, J ) 16.8, 10.6, 10.6 Hz,
1H), 5.92 (dd, J ) 10.8, 10.8 Hz, 1H), 5.30 (m, 3H), 5.13 (m,
2H), 5.02 (d, J ) 10.4 Hz, 1H), 4.61 (m, 2H), 4.26 (dt, J ) 9.8,
2.4 Hz, 1H), 3.57 (t, J ) 3.3 Hz, 1H), 3.16 (m, 1H), 3.04 (dd, J
) 5.9, 3.3 Hz, 1H), 2.93 (m, 1H), 2.53 (m, 2H), 2.37 (m, 1H),
1.81 (m, 6H), 1.56 (m, 1H), 1.56 (s, 3H), 1.20 (d, J ) 7.4 Hz,
3H), 0.95 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 7.0 Hz, 3H), 0.89 (d,
J ) 6.7 Hz, 3H), 0.85 (d, J ) 6.9 Hz, 3H), 0.84 (d, J ) 6.4 Hz,
3H), 0.73 (d, J ) 6.6 Hz, 3H); 13C NMR (90 MHz, 10% CD3OD
in CDCl3) δ 174.8, 157.8, 136.4, 133.4, 133.1, 131.9, 131.6,
129.9, 129.6, 117.6, 80.4, 78.8, 78.5, 75.6, 72.2, 64.0, 43.0, 40.2,
37.0, 35.8, 35.5, 35.4, 34.9, 34.3, 32.9, 23.0, 17.7, 17.2, 15.6,
15.5, 13.2, 12.6, 8.7; IR (thin film on NaCl) 3366, 2969, 2934,
1712, 1603, 1387, 1327, 1097, 1040, 974, 737 cm-1; HRMS
(FAB, NBA/NaI) (m/z) calculated for C33H55NO8Na (M + Na)+
) 616.3826, observed 616.3840. [R]20D ) +29.8 (c ) 3.06, CH3-
OH).
Ack n ow led gm en t . This research was supported
in part by the National Institutes of Health (1R01-
CA074227) and Novartis Pharma. A fellowship to
D.C.M. from the Alfred P. Sloan Foundation is gratefully
acknowledged. The authors would like to acknowledge
Mr. Marcus Strawn for the preparation of a number of
advanced intermediates. We thank Dr. Ross P. Longley
of the Harbor Branch Oceanographic Institution for
providing an authentic sample of (+)-discodermolide.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal methods and selected H and 13C NMR and IR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O034521R
6660 J . Org. Chem., Vol. 68, No. 17, 2003