Development of a third-generation total synthesis of (+)-discodermolide: An expedient Still-Gennari-type fragment coupling utilizing an advanced β-ketophosphonate

Article abstract of DOI:10.1021/jo050481a

A novel total synthesis of the complex polyketide discodermolide, a promising anticancer agent of marine sponge origin, has been completed in 11.1% overall yield over 21 linear steps. This third-generation approach features an unprecedented Still-Gennari-

Full text of DOI:10.1021/jo050481a

Development of a Third-Generation Total Synthesis of
(+)-Discodermolide: An Expedient Still-Gennari-Type Fragment
Coupling Utilizing an Advanced â-Ketophosphonate
Ian Paterson* and Isabelle Lyothier
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ip100@cam.ac.uk
Received March 10, 2005
A novel total synthesis of the complex polyketide discodermolide, a promising anticancer agent of
marine sponge origin, has been completed in 11.1% overall yield over 21 linear steps. This third-
generation approach features an unprecedented Still-Gennari-type HWE olefination reaction
between advanced C1-C8 â-ketophosphonate 61 and C9-C24 aldehyde 7, introducing the (8Z)-
alkene with 10:1 selectivity. The stereotetrad found in the C1-C8 subunit 61 was established via
a highly diastereoselective boron-mediated aldol reaction/in situ reduction between ketone (S)-8
and 3-benzyloxypropanal. The (7S)-configuration was installed by the reduction of enone 73 with
K-Selectride.
Introduction
In 1990, Gunasekera and co-workers at the Harbor
Branch Oceanographic Institution in Florida reported the
isolation of discodermolide (1, Figure 1), a polyketide
metabolite obtained in low yields from the Caribbean
deep-water sponge Discodermia dissoluta (0.002% w/w
from the frozen sponge).1 In preliminary biological stud-
ies, discodermolide was found to be an immunosuppres-
sive agent, both in vitro and in vivo.2 Further studies
revealed discodermolide to be a potent microtubule-
stabilizing agent that, like Taxol (paclitaxel), arrests cells
at the G2/M boundary of the cell cycle.3,4 This mechanism
FIGURE 1. Structure of discodermolide
of action is shared by several other antimitotic agents,
including the epothilones,5 eleutherobin,6 laulimalide,7
peloruside A,8 and most recently, dictyostatin.9
* To whom correspondence should be addressed. Fax: +44 (0)1223
336 362.
(1) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G.
K. J. Org. Chem. 1990, 55, 4912. Corrections: J. Org. Chem. 1991,
56, 1346.
(2) (a) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.;
Gunasekera, S. P. Transplantation 1991, 52, 650. (b) Longley, R. E.;
Caddigan, D.; Harmody, D.; Gunasekera, M.; Gunasekera, S. P.
Transplantation 1991, 52, 656.
(5) Bolag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal,
L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C. M. Cancer Res. 1995,
55, 2325.
(6) (a) Long, B. H.; Carboni, J. M.; Wasserman, A. J.; Cornell, L.
A.; Casazza, A. M.; Jensen, P. R.; Lindel, T.; Fenical, W.; Fairchild, C.
R. Cancer Res. 1998, 58, 1111. (b) Hamel, E.; Sackett, D. L.; Vourlou-
mis, D.; Nicolaou, K. C. Biochemistry 1999, 38, 5490.
(7) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarn, A.;
Davidson, B. S. Cancer Res. 1999, 59, 653.
(8) Hood, K. A.; West, L. M.; Rouwe, B.; Northcote, P. T.; Berridge,
M. V.; Wakefield, S. J.; Miller, J. H. Cancer Res. 2002, 62, 653.
(9) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley, R. E.;
Wright, A. E. Biochem. Pharmacol. 2003, 66, 75.
(3) (a) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley,
R. E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry
1996, 35, 243. (b) Schreiber, S. L.; Chen, J.; Hung, D. T. Chem. Biol.
1996, 3, 287.
(4) Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665.
10.1021/jo050481a CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/02/2005
5494
J. Org. Chem. 2005, 70, 5494-5507

Total Synthesis of (+)-Discodermolide
The IC50 values reported for discodermolide in breast,
prostate, colon, lung, and ovarian cancer cell lines are
generally in the low nanomolar range.10 Comparative
studies showed that discodermolide was 1000-fold more
active than Taxol in promoting the same microtubule
polymerization/bundling.3 Of particular interest is the
fact that multidrug-resistant human colon and ovarian
cancer cells retained significant sensitivity to disco-
dermolide.10b Cancers treated with Taxol or other hydro-
phobic antitumor drugs can become resistant to the drugs
by acquiring the multidrug resistance (MDR) pheno-
type.11 The expression of P-glycoprotein (P-gp), a trans-
membrane transporter protein that significantly reduces
the intracellular concentration of these drugs, is associ-
ated with this phenotype. More recently, further studies
regarding the precise mechanism by which discoder-
molide binds to â-tubulin and induces its polymerization
have been performed.12 These findings highlighted that
binding of discodermolide and Taxol to â-tubulin are
mutually exclusive, although it could not be ascertained
whether they share the same or an overlapping binding
site. This remarkable biological profile has been recog-
nized by Novartis Pharmaceutical Corporation, leading
to discodermolide entering clinical trials as a new-
generation anticancer agent.
FIGURE 2. Previous coupling strategies employed for the
total synthesis of discodermolide.
have come from Schreiber and co-workers,14 followed by
the groups of Smith,15 Myles,16 Marshall,17 and Pater-
son.18 The key bond disconnections and coupling reactions
used in each of these syntheses are shown in Figure 2.
All of the strategies coincide in the disassembly of the
target molecule into three fragments of similar size and
stereochemical complexity. Not surprisingly, the two
internal (Z)-alkenes have been pivotal in the choice of
disconnection strategies, either in Wittig-type olefination
(Smith), Pd-catalyzed sp2-sp3 couplings (Smith and
Marshall), enolate alkylations with allylic halides
(Schreiber and Myles), Nozaki--ishi couplings (Schreiber
and Myles), or acetylide addition to aldehydes (Marshall).
In contrast, the fragment coupling strategies developed
in our group are entirely different, with stereocontrolled
aldol reactions performed at C16-C17 and C6-C7 (first-
generation route) or C5-C6 (second-generation route).20
Within the pharmaceutical industry, over 60 g of disco-
dermolide has recently been synthesized by Novartis
chemists for Phase I clinical trials, following a hybrid
Smith-Paterson route, and making use of our late-stage
C6-C7 aldol coupling step.21 Herein, we report full
details of our third-generation total synthesis based on
a novel C8-C9 fragment coupling using the Still-
Gennari modification of the Horner-Wadsworth-Em-
mons olefination reaction.18e This improved synthesis has
the potential to be scaled up to provide significant
quantities of discodermolide and to provide novel struc-
tural analogues for SAR studies.
The supply problem for discodermolide is chronic and
can be solved at present only by total synthesis. Conse-
quently, because of the remarkable biological activity,
there has been considerable synthetic effort directed
toward providing a sustainable supply of discoder-
molide,13 culminating in several total syntheses14-18 and
numerous fragment syntheses.19 Notable contributions
from academic groups achieving completed syntheses
(10) (a) Balachandran, R.; ter Haar, E.; Welsh, M. J.; Grant, S. G.;
Day, B. W. Anti-Cancer Drugs 1998, 9, 67. (b) Kowalski, R. J.;
Giannakakou, P.; Gunasekera, S. P.; Longley, R. E.; Day, B. W.; Hamel,
E. Mol. Pharm. 1997, 52, 613.
(11) Cole, S. P.; Sparks, K. E.; Fraser, K.; Loe, D. W.; Grant, C. E.;
Wilson, G. M. Cancer Res. 1994, 54, 5351.
(12) (a) Martello, L. A.; McDaid, H. M.; Regl, D. L.; Yang, C. 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.
(b) Martello, L. A.; LaMarche, M. J.; He, L.; Beauchamp, T. J.; Smith,
A. B., III; Horwitz, S. B. Chem. Biol. 2001, 8, 843. (c) Stachel, S. J.;
Biswas, K.; Danishefsky, S. J. Curr. Pharm. Des. 2001, 7, 1277.
(13) Reviews: (a) Paterson, I.; Florence, G. J. Eur. J. Org. Chem.
2003, 2193. (b) Mickel, S. J. Curr. Opin. Drug Discuss. 2004, 7, 869.
(14) (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S.
L. J. Am. Chem. Soc. 1993, 115, 12621. (b) Nerenberg, J. B.; Hung, D.
T.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054.
(15) (a) Smith, A. B.; Qiu, Y. P.; Jones, D. R.; Kobayashi, K. J. Am.
Chem. Soc. 1995, 117, 12011. (b) Smith, A. B.; Kaufman, M. D.;
Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1,
1823. (c) Smith, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman,
M. D.; Qiu, Y. P.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 2000, 122, 8564. (d) Smith, A. B.: Freeze, B. S.; Brouard, I.;
Hirose, T. Org. Lett. 2003, 5, 4405.
(16) (a) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 1313. (b)
Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 2503. (c) Harried,
S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62,
6098. (d) Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D.
C. J. Org. Chem. 2003, 68, 6646.
(17) (a) Marshall, J. A.; Lu, Z. H.; Johns, B. A. J. Org. Chem. 1998,
63, 817. (b) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(18) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew.
Chem., Int. Ed. 2000, 39, 377. (b) Paterson, I.; Florence, G. J.
Tetrahedron Lett. 2000, 41, 6935. (c) Paterson, I.; Florence, G. J.;
Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123,
9535. (d) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott,
J. P.; Sereinig, N. Org. Lett. 2003, 5, 35. (e) Paterson, I.; Lyothier, I.
Org. Lett. 2004, 6, 4933. (f) Paterson, I.; Delgado, O.; Florence, G. J.;
Lyothier, I.; O’Brien, M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005,
70, 150.
Results and Discussion
Synthesis Plan. In 2000, we reported an initial
synthesis of discodermolide, based on the application of
complex aldol reactions, that proceeded in 10.3% yield
over 23 steps in the longest linear sequence with 42 steps
in total.18a-c In 2003, we reported a second-generation
(19) See ref 18f for a recent listing of discodermolide fragment
syntheses and other synthetic studies in progress. See also: (a)
Loiseleur, O.; Koch, G.; Wagner, T. Org. Process Res. Dev. 2004, 8,
597. (b) Ramachandran, P. V.; Prabhudas, B.; Chandra, J. S.; Reddy,
M. V. R. J. Org. Chem. 2004, 69, 6294. (c) BouzBouz, S.; Cossy, J.
Synlett 2004, 11, 2034.
(20) For a review of asymmetric boron-mediated aldol reactions,
see: Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
J. Org. Chem, Vol. 70, No. 14, 2005 5495

Paterson and Lyothier
SCHEME 1. Summary of Fragment Coupling Strategies Investigated for Discodermolide
synthesis, relying solely upon substrate-based stereocon-
trol, which proceeded in 7.8% yield over 24 linear steps,
with 35 steps in total.18d,f These two total syntheses were
based on pivotal boron-mediated aldol coupling reactions
performed, at a late stage, either at C6-C7 or at C5-C6
(Scheme 1).20 In the former case using (+)-Ipc2BCl/
Et3N,18a-c the reagent-controlled fragment union of ke-
tone 2 and (Z)-enal 3 sets up the required (7S)-
configuration, while in the second-generation route using
c-Hex2BCl/Et3N,18d,f a reversed C5-C6 aldol coupling
between aldehyde 4 and ketone 5, exploiting 1,6-asym-
metric induction from the remote C10 stereocenter, sets
up the required (5S)-configuration under substrate con-
trol. In light of perceived technical difficulties in perform-
ing such complex aldol couplings on an industrial scale
at a late stage with such valuable highly functionalized
intermediates,21e where the quality of organoboron re-
agents from commercial suppliers is variable and arduous
chromatographic isolation of the product is usually
required, simplification of this key coupling step to
complete the carbon skeleton was sought to further
streamline the synthesis. To this end, we proposed a more
convenient endgame, involving the use of an unprec-
edented Still-Gennari-type HWE olefination22 at C8-
C9 to couple the advanced â-ketophosphonate 6 with the
aldehyde 7, giving direct access to the entire carbon
skeleton of discodermolide (Scheme 1).
Initial Attempts at Preparing the Advanced C1-
C8 â-Ketophosphonate Subunit 6. The stereotetrad
present in the C1-C8 â-ketophosphonate 6 was installed
efficiently in one step, utilizing the highly diastereo-
selective anti-aldol reaction of ethyl ketone23 8 and 2-tert-
butylsilyloxypropanal 9, mediated by c-Hex2BCl/Et3N,
followed by in situ reduction of the intermediate boron
aldolate with LiBH4 (Scheme 2).24 This afforded 1,3-syn
1
diol 10 in 84% yield after oxidative workup, where H
NMR analysis of the crude product indicated >97:3 dr,
as expected from our earlier studies. Removal of the PMB
group in diol 10 was performed by hydrogenolysis in
EtOH using Pearlman’s catalyst. The choice of solvent
in this step was crucial to avoid any competing cleavage
of the primary TBS ether. Oxidation of the resulting triol
11 with catalytic TEMPO and PhI(OAc)2 afforded the
δ-lactone 12 cleanly.25 The C3-hydroxyl group was then
protected as its TBS ether and the primary silyl group
removed selectively by treatment with catalytic amounts
of camphorsulfonic acid (CSA) in DCM and MeOH to
afford alcohol 14. Oxidation of 14, using Dess-Martin
periodinane,26 provided aldehyde 15 in near-quantitative
yield.27
(21) (a) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Daeffler, R.;
Osmani, A.; Schreiner, K.; Seeger-Weibel, M.; Berod, B.; Schaer, K.;
Gamboni, R.; Chen, S.; Chen, W.; Jagoe C. T.; Kinder, F. R., Jr.; Loo,
M.; Prasad, K.; Repicˇ, O.; Shieh, W. C.; Wang, R. M.; Waykole, L.; Xu,
D. D.; Xue, S. Org. Process Res. Dev. 2004, 8, 92. (b) Mickel, S. J.;
Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Grimler, D.; Koch, G.;
Daeffler, R.; Osmani, A.; Hirni, A.; Schaer, K.; Gamboni, R.; Bach, A.;
Chaudhary, A.; Chen, S.; Chen, W.; Hu, B.; Jagoe, C. T.; Kim, H. Y.;
Kinder, F. R., Jr.; Liu, Y.; Lu, Y.; McKenna, J.; Prashad, M.; Ramsey,
T. M.; Repicˇ, O.; Rogers, L.; Shieh, W. C.; Wang, R. M.; Waykole L.
Org. Process Res. Dev. 2004, 8, 101. (c) Mickel, S. J.; Sedelmeier, G.
H.; Niederer, D.; Schuerch, F.; Koch, G.; Kuesters, E.; Daeffler, R.;
Osmani, A.; Seeger-Weibel, M.; Schmid, E.; Hirni, A.; Schaer, K.;
Gamboni, R.; Bach, A.; Chen, S.; Chen, W.; Geng, P.; Jagoe, C. T.;
Kinder, F. R., Jr.; Lee, G. T.; McKenna, J.; Ramsey, T. M.; Repic´, O.;
Rogers, L.; Shieh, W. C.; Wang, R. M.; Waykole L. Org. Process Res.
Dev. 2004, 8, 107. (d) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.;
Schuerch, F.; Seger, M.; Schreiner, K.; Daeffler, R.; Osmani, A.; Bixel,
D.; Loiseleur, O.; Cercus, J.; Stettler, H.; Schaer, K.; Gamboni, R.; Bach,
A.; Chen, G. P.; Chen, W. C.; Geng, P.; Lee, G. T.; Loeser, E.; McKenna,
J.; Kinder, F. R.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Reel,
N.; Repic, O.; Rogers, L.; Shieh, W. C.; Wang, R. M.; Waykole, L.; Xue,
S.; Florence, G.; Paterson, I. Org. Process Res. Dev. 2004, 8, 113. (e)
Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani, A.; Kuesters, E.;
Schmid, E.; Schaer, K.; Gamboni, R.; Chen, W. C.; Loeser, E.; Kinder,
F. R.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Repic, O.; Wang,
R. M.; Florence, G.; Lyothier, I.; Paterson, I. Org. Process Res. Dev.
2004, 8, 122.
To install the required phosphonate moiety, aldehyde
15 was first transformed into the corresponding acid
(22) Still W. C.; Gennari C. Tetrahedron Lett. 1983, 24, 4405.
(23) (a) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287. (b) Paterson, I.; Goodman,
J. M.; Isaka, M. Tetrahedron Lett. 1989, 30, 7121. (c) Paterson, I.;
Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185. See also ref 18.
(24) (a) Paterson, I.; Perkins, M. V. Tetrahedron 1996, 52, 1811. (b)
Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 801.
(25) (a) Hansen T. M.; Florence G. J.; Lugo-Mas P.; Chen J.; Abrams
J. N.; Forsyth C. J. Tetrahedron Lett. 2003, 44, 57. (b) Paterson, I.;
Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343.
(26) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(27) It should be noted that aldehyde 15 could not be purified by
flash chromatography on silica gel, as it undergoes partial decomposi-
tion by â-elimination and ring-opening of the δ-lactone ring.
5496 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of (+)-Discodermolide
SCHEME 2. Synthesis of C1-C7 Aldehyde 15
SCHEME 3. Attempted Synthesis of
â-Ketophosphonate 6
to form acid chloride 18. The latter was added to a
solution of the lithiated methyl phosphonate 19.31 Un-
fortunately, only trace quantities of the desired phos-
phonate 6 could be isolated, after extensive chromato-
graphic purification, and characterized. To ascertain that
acid chloride 18 was indeed formed, it was quenched with
an excess of methanol, and the corresponding methyl
ester 20 was isolated in 97% yield from the alcohol 14,
confirming that 18 was generated in essentially quanti-
tative yield. However, all efforts to improve the synthesis
of phosphonate 6 failed. This setback was attributed to
the substrate undergoing facile decomposition by â-elim-
ination and ring-opening of the δ-lactone ring. We
therefore proposed a new strategy, making use of linear
â-ketophosphonate 21, which should be accessible from
acid chloride 22 (Scheme 4), with the objective of inves-
tigating its HWE olefination reaction with aldehydes to
give enone 23 under Still-Gennari-type conditions.
Synthesis of Linear â-Ketophosphonate 21. The
synthesis of the revised phosphonate 21 started out with
the bis-TBS protection of the 1,3-syn-diol 10 (Scheme 5).
Removal of the PMB protecting group was then best
achieved here by treatment of 24 with DDQ, to afford
alcohol 25 in 80% yield. In contrast to the situation
encountered with 10 (Scheme 3), hydrogenolysis of the
PMB group in 24 failed to provide 25 in satisfactory yield
when using Pearlman’s catalyst with a variety of sol-
vents, due to unavoidable competing cleavage of the
primary TBS ether. The primary hydroxyl in 25 was next
oxidized to the aldehyde 26, using TEMPO and PhI-
(OAc)2, in 83% yield.32 Further oxidation with NaClO2
provided the corresponding carboxylic acid 27,29 which
was esterified with an ethereal solution of TMSCHN2,
affording methyl ester 28 in 84% yield.
chloride (Scheme 3).28 Oxidation of 15 with NaClO2
provided carboxylic acid 16,29 which was treated im-
mediately with the Ghosez chloroenamine reagent 17,30
(28) The initial plan was to react aldehyde 15 with lithiated methyl
phosphonate 19, however this failed to produce the desired adduct 76.
1H NMR analysis of the crude product indicated the presence of a trans
double bond, which was attributed to partial â-elimination and ring-
opening of the lactone. Also a substantial amount of unreacted
aldehyde 15 was present in the crude product mixture.
With the desired stereochemistry and oxidation states
in place for the C1-C7 region, the next objective was to
install the â-ketophosphonate moiety in order to reach
(29) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888. (b) Bal, B. S.; Childers, W. E. J.; Pinnick, H. W. Tetrahedron 1981,
37, 2091. (c) Mann, J.; Thomas, A. Tetrahedron Lett. 1986, 27, 3533.
(30) Devos, A.; Remion, J.; Frisque-Hesbain, A. M.; Colens, A.;
Ghosez, L. J. Chem. Soc., Chem. Commun. 1979, 1180.
(31) Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725.
(32) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
J. Org. Chem, Vol. 70, No. 14, 2005 5497

Paterson and Lyothier
SCHEME 4. Revised Strategy Utilizing
Phosphonate 21
SCHEME 6. Synthesis of â-Ketophosphonate 21
SCHEME 5. Synthesis of C1-C7 Ester 28
Implementing the C8-C9 Still-Gennari-Type
HWE Coupling. With the advanced phosphonate 21 in
hand, its HWE olefination reaction with the C9-C24
aldehyde 7 was then investigated. Aldehyde 7 was readily
prepared in two steps and 85% yield from the known bis-
PMB ether 33, by selective deprotection of the primary
PMB group, with BCl3‚DMS in DCM at 0 °C,33 and
oxidation of the resulting alcohol 34 using either the
TEMPO/PhI(OAc)2 system32 or Swern conditions34 (Scheme
7). Phosphonate 21 was treated with NaH in THF at 0
°C for 30 min prior to the addition of aldehyde 7. Analysis
1
of the crude product by H NMR spectroscopy showed a
mixture of Z and E olefins in a 5:1 ratio. Gratifyingly,
the desired (Z)-isomer 35 could be isolated by flash
chromatography in 73% yield.35 Notably, this coupling
proceeds satisfactorily employing NaH under experimen-
tally undemanding conditions, without resorting to ex-
pensive crown ether additives, which is of prime impor-
tance for minimizing the cost of goods in scaling up. As
such, this represents a major improvement over the
endgames used in our first and second generation routes,
which rely on the availability of good quality boron
reagents for performing the late-stage aldol coupling
steps.21e Moreover, this constitutes one of the first
examples of a (Z)-selective intermolecular Still-Gennari-
type HWE olefination employing such an elaborate
â-ketophosphonate.36
Further Elaboration of (Z)-Enone 35. Following the
successful HWE olefination reaction performed between
phosphonate 21 and aldehyde 7, the full C1-C24 carbon
skeleton of discodermolide was now in place. The comple-
tion of the synthesis now required installation of the
carbamate moiety at C19, selective reduction at C7, and
the desired C1-C8 segment 21 (Scheme 6). Thus, 28 was
treated with a catalytic amount of CSA in DCM and
MeOH to cleave selectively the primary TBS ether. The
resulting primary alcohol 29 was oxidized to the aldehyde
30 with TEMPO and PhI(OAc)2.32 Further oxidation with
NaClO2 provided crude carboxylic acid 31.29 Acid 31 was
then treated with the Ghosez reagent 17,30 providing the
corresponding acid chloride 32, which was reacted im-
mediately with the lithium anion of methyl phosphonate
19 at -100 °C (external bath temperature).31 Pleasingly,
this reaction proceeded smoothly to provide â-ketophos-
phonate 21 in 71% yield over three steps. In contrast to
the instability experienced with δ-lactone 6, the phos-
phonate 21 could be isolated easily by flash chromatog-
raphy on silica gel and was amenable to long-term
storage without any degradation.
(33) Congreve, M. S.; Davison, E. C.; Fuhry, M. A.; Holmes, A. B.;
Payne, A. N.; Robinson, A.; Ward, S. E. Synlett 1993, 663.
(34) (a) Omura, K.; Swern, D. Tetrahedron Lett. 1978, 34, 1651. (b)
Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2231.
5498 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of (+)-Discodermolide
SCHEME 7. Still-Gennari-Type HWE Olefination
of Aldehyde 7 and Phosphonate 21
SCHEME 8. Synthesis of 7-epi-Discodermolide
δ-lactone was already in place, as in 38 (Scheme 9),
reduction of the C7 ketone with K-Selectride proceeded
smoothly at -78 °C to provide the desired (7S)-alcohol
43 (85%, >97:3 dr).18d,f However, with the linear C1-C6
side chain, bearing TBS ethers at C3 and C5, the
reduction facial selectivity is overturned with use of
K-Selectride under more forcing conditions, affording only
the undesired (7R)-alcohol 37. These findings suggest
that the conformational preference of the C1-C6 region
plays a controlling role in determining the facial selectiv-
ity of reduction of the C7 ketone, while the influence of
the C9-C24 region is apparently less important.
Achieving Selective C7 Reduction by Adjustment
of Protecting Groups. As mentioned previously, a
variety of other reducing agents were screened for the
reduction of enone 35. However, there was either no
reaction or poor diastereoselectivity was observed. Efforts
were therefore directed toward converging with the
second-generation endgame, where the aim was to lac-
tonize first and then use K-Selectride to reduce 38 at C7
in the desired stereochemical sense for discodermolide
(Scheme 9).18d,f As the TBS ether at C5 in our most
advanced intermediate 35 could not be cleaved selec-
tively, the protecting group strategy required revision.
Two strategies were consideredsprotecting the C3- and
C5-hydroxyl groups either as their TES ethers, as in 44,
global TBS deprotection with concomitant δ-lactoniza-
tion. Due to problems encountered with performing the
reduction at C7 when the C19 carbamate moiety was
already installed, it was envisaged to conduct the reduc-
tion step first (Scheme 8). This reduction step proved to
be unexpectedly troublesome. A range of reducing agents
were screened, including (R)- and (S)-CBS‚BH3,37 NaBH4/
CeCl3,38 LiBH4, and L-Selectride. However, these experi-
ments all resulted either in poor diastereoselectivities or
no reaction. Hoping to build on the results obtained in
our second-generation route,18d,f the reduction of 35 was
next attempted with K-Selectride. Under suitable reac-
tion conditions (-25 °C, 24 h), a single diastereomeric
alcohol 37 was formed selectively and isolated in 59%
yield (70% based on recovered starting material). By
analogy with the results obtained for a similar substrate
(38, Scheme 9) employed in our second-generation
route,18d,f this alcohol 37 was tentatively assigned as
having the desired (7S)-configuration. However, after
DDQ deprotection of the PMB ether at C19 in 39 to give
alcohol 40, and installation of the carbamate moiety,39
treatment with HF‚py provided 7-epi-discodermolide (42)
rather than discodermolide (Scheme 8)!
This complete reversal in the sense of stereoinduction
obtained by the reduction of enone 35 at C7 with
K-Selectride was totally unexpected. When the C1-C5
J. Org. Chem, Vol. 70, No. 14, 2005 5499

Paterson and Lyothier
SCHEME 9. Endgame for the Second-Generation
Synthesis of Discodermolide
SCHEME 10. Revised Protecting Group Strategies
synthesis of phosphonate 21 needed some modification.
A benzyl ether at C7 was introduced to allow its cleavage
in the presence of the two TES ethers. The anti-aldol
reaction between ethyl ketone 8 and 3-benzyloxypropanal
49, mediated by c-Hex2BCl and Et3N, followed by an in
situ reduction with LiBH4 afforded syn-diol 50, in 84%
yield and >97:3 dr (Scheme 11).23,24 Treatment of diol 50
with TESOTf and 2,6-lutidine afforded bis-TES ether 51
in 80% yield. Oxidative cleavage of the PMB group with
DDQ provided alcohol 52, which was oxidized to the
corresponding aldehyde 53 under Swern conditions.34
Treatment with NaClO2 provided the corresponding
carboxylic acid 54 in 98% yield.29 Esterification was
achieved by treatment of 54 with TMSCHN2 in excellent
yield. The resulting methyl ester 55 was used as a model
for studying the possibility of cleaving the TES group at
C5 and inducing δ-lactonization under mild acidic condi-
tions. Gratifyingly, treatment of 55 with CSA (1 equiv)
in DCM proceeded smoothly to provide δ-lactone 56 in
91% yield. At this point, the prospect of obtaining the
ketolactone 46, after treatment of 44 with CSA, was good,
as too was the opportunity to converge with our second-
generation synthesis of discodermolide (see Scheme
10).18d,f
or as a cyclic cyclopentylidene acetal,40 as in 45 (Scheme
10).
Initial efforts were directed toward the synthesis of the
revised phosphonate 48, bearing TES ethers at C3 and
C5 (Scheme 11). The chemistry already developed for the
(35) To shorten the synthesis by one step, the olefination reaction
with the aldehyde 77, having a free hydroxyl group at C19, was
attempted. Unexpectedly, this led to a diminished selectivity (Z/E )
2:1) and a reduced 35% yield.
Attention was now focused on the installation of the
phosphonate moiety. Hydrogenolysis of the benzyl ether
55 in THF, using Pd(OH)2/C as the catalyst, provided
alcohol 57. The choice of solvent was found to be crucial
to avoid any competing TES deprotection. Swern oxida-
tion of alcohol 57 afforded the corresponding aldehyde
58 in 94% yield over the two steps.34 Oxidation of 58 to
the corresponding carboxylic acid was achieved with
NaClO2 in 69% yield.28 Acid 59 was then treated with
the Ghosez chloroenamine 17,30 affording the acid chlo-
ride 60, which was reacted immediately with a solution
of (CF3CH2O)2P(O)CH2Li at -100 °C.31 Unfortunately,
this reaction failed to produce the desired phosphonate
48, even though no starting acid 59 was recovered after
aqueous workup. The presence of olefinic signals in the
1H NMR spectrum of the crude product was evident, and
loss of the TES group at C5, with partial δ-lactonization,
(37) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 9, 5551.
(38) (a) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101,
5848. (b) Gemal, A. L.; Luche, L. J. Am. Chem. Soc. 1981, 103, 5454.
(39) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
(40) Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899.
(36) For another example of a complex fragment coupling by a Still-
Gennari-type HWE olefination, see: Paterson, I.; Britton, R.; Delgado,
O.; Meyer, A.; Poullennec, K. Angew. Chem., Int. Ed. 2004, 43, 4629.
5500 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of (+)-Discodermolide
SCHEME 11. Attempted Synthesis of Phosphonate 48
was suspected. As it was unlikely that the cleavage of
the TES ether had occurred under the reaction conditions
to install the phosphonate moiety (LiHMDS, -100 °C),
it was therefore reasoned that this had happened either
on the acid 59 or on the acid chloride 60, leading to
partial δ-lactonization and inducing decomposition by
â-elimination. At this stage, the TES protecting group
strategy was abandoned in favor of the cyclopentylidene
acetal alternative.
The synthesis of the revised phosphonate 61 was
performed in a fashion similar to that of its TBS-
protected analogue 21 (Schemes 12 and 13). Diol 50 was
converted in near-quantitative yield into cyclopentylidene
acetal 62 by treatment with cyclopentanone dimethyl
acetal,41 under mild acid catalysis with PPTS. PMB ether
cleavage in 62 with DDQ was followed by Dess-Martin
oxidation of the resulting alcohol 63 to provide the
aldehyde 64.26 Subsequent oxidation to the corresponding
acid 65 (NaClO2),29 and treatment with TMSCHN2,
afforded methyl ester 66 in a high-yielding sequence (four
steps, 93%).
reagent 1730 to generate acid chloride 70, which was
reacted immediately with (CF3CH2O)P(O)CH2Li.31 Pleas-
ingly, this acylation reaction proceeded smoothly, provid-
ing â-ketophosphonate 61 in 70% yield from aldehyde 68.
Starting from ketone (S)-8, this sequence can be per-
formed conveniently on a multigram scale in 45% overall
yield.
Completion of the Total Synthesis of Discoder-
molide. With the new phosphonate 61 in hand, the stage
was now set to again investigate the Still-Gennari HWE
olefination with aldehyde 7.22,31 Utilizing the optimized
conditions developed previously, phosphonate 61 was
treated with NaH in THF at -10 °C for 30 min and then
reacted with aldehyde 7 (Scheme 14). A clean olefination
reaction occurred that was now more selective than
obtained with bis-TBS-protected phosphonate 21 (Z/E )
10:1, compared to 5:1 for 21), with the (Z)-enone 71
isolated by simple flash chromatography on silica gel in
74% yield. With the carbon backbone of discodermolide
now in place, the carbamate moiety at C19 needed to be
installed. First, the PMB ether was cleaved oxidatively
with DDQ in essentially quantitative yield. Subsequent
treatment of the resulting alcohol 72 with trichloroacetyl
isocyanate and methanolysis of the intermediate trichlo-
roacetyl adduct (K2CO3, MeOH) provided 73 in 98%
yield.39 With compound 73 in hand, the original plan was
to treat it with a mild acid to cleave the cyclopentylidene
acetal, and then reduce at C7 with K-Selectride (vide
supra). However, to minimize the total number of steps,
Ester 66 was further elaborated into the desired
phosphonate 61 using chemistry similar to that described
previously (Scheme 13). Hydrogenolysis of the benzyl
ether was followed by stepwise oxidation to the carboxylic
acid 69 (Dess-Martin periodinane, followed by Na-
ClO2).26,29 The crude acid 69 was treated with the Ghosez
(41) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217.
J. Org. Chem, Vol. 70, No. 14, 2005 5501

Paterson and Lyothier
SCHEME 12. Synthesis of Ester 66
at -78 °C, and provided a single diastereomeric alcohol,
74, in 90% yield. The desired (7S)-configuration in 74 was
easily established by carrying out the final global depro-
tection. This proceeded cleanly using HF‚py, with con-
comitant δ-lactonization, providing (+)-discodermolide in
84% yield, which was identical to an authentic sample
in all respects. The similar stereochemical outcome for
the reduction of the δ-lactone containing enone 38 and
the cyclopentylidene acetal-protected enone 73 is at-
tributed to their both having restricted conformational
flexibility in the C1-C6 region, which serves to direct
the bulky hydride reagent to the same face of the C7
ketone.
Conclusions. In summary, a highly convergent, third-
generation synthesis of discodermolide has been com-
pleted. It proceeds in seven steps and 47% yield from the
advanced C9-C24 intermediate 33, which was also used
in the two previous synthetic routes to discodermolide
developed in our group. In the first-generation route,
compound 33 was converted into discodermolide in nine
steps and 42% yield,18a-c whereas eight steps were
required following the second-generation endgame
(Scheme 15).18d,f Overall, this represents a significant
improvement in terms of efficiency, together with the
ease of performing the final fragment coupling step and
purification of the coupled product, which are key criteria
for developing an industrial synthesis.21,13b
This third-generation synthesis exploits a late-stage
Still-Gennari-type HWE coupling using phosphonate 61
under experimentally undemanding conditions, both in
terms of reaction conditions and isolation protocols.
Notably, this coupling proceeds satisfactorily by simply
using NaH as a base, without resorting to expensive
crown ether additives, important for minimizing the cost
of goods in scaling up.42 As such, this new endgame
represents a major advance over our first and second
generation routes. The overall stereocontrol has also been
improved, as the C5 stereocenter is now set up at an early
stage via an expedient in situ aldol reaction/reduction
(>97:3 dr), while the C7 stereocenter is installed by
reduction of enone 73 by K-Selectride (>97:3 dr). This
new synthesis of discodermolide proceeds in 11.3% yield
over 21 steps (longest linear sequence) from the Roche
ester 75, based on our first-generation synthesis of
intermediate 33 followed by the revised endgame re-
ported herein.43 By avoiding some of the experimentally
challenging steps associated with earlier syntheses,21e
this new route should be more applicable to the prepara-
tion of larger quantities of discodermolide as required for
clinical development, as well as being amenable to the
synthesis of novel structural analogues for further SAR
studies.
SCHEME 13. Synthesis of Phosphonate 61
Experimental Section
General experimental methods can be found in the Sup-
porting Information.
(2S,3R,4S,5S)-1-(4-Methoxybenzyloxy)-7-benzyloxy-2,4-
dimethylheptane-3,5-diol (50). To a stirred solution of
c-Hex2BCl (920 µL, 4.20 mmol) in Et2O (10 mL) at 0 °C was
the selective reduction of 73 was attempted first. Enone
73 was therefore treated with K-Selectride in toluene at
-78 °C (Scheme 15). Gratifyingly, the reduction proved
to be clean and efficient, going to completion within 3 h
(42) To drive the olefination reaction to completion, an excess of
either the aldehyde or the phosphonate was used. However, these can
be recovered readily by flash chromatography and recycled.
(43) The overall yield would be 9.5% over 23 steps based on the
second-generation synthesis of 33. See ref 18d,f.
5502 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of (+)-Discodermolide
SCHEME 14. Completion of the Third-Generation Total Synthesis of Discodermolide
was stirred for 3 h at -78 °C. LiBH4 (2 M in THF) was added,
SCHEME 15. Comparison of the Three Different
Synthetic Routes to Discodermolide from
Advanced Intermediate 33
and the mixture was stirred at -78 °C for 3 h and then
transferred to a freezer (-23 °C, 20 h). Aqueous NH4Cl (20
mL) was added to the cold (-20 °C) mixture, which was then
allowed to warm to rt and extracted with Et2O (3 × 20 mL).
The combined organic extracts were concentrated under
vacuum, redissolved in MeOH (10 mL), and cooled to 0 °C.
NaOH (10%, 10 mL) was added, followed by H2O2 (30%, 10
mL). The mixture was stirred at rt for 3 h, diluted with H2O
(20 mL), and extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried (Na2SO4), concentrated under
vacuum, and purified by flash chromatography (20 to 50% Et2O
in hexane) to afford diol 50 as a colorless oil (1.09 g, 84%): Rf
0.45 (50% AcOEt in hexane); [R]20 -3.0 (c 0.85, CHCl3); IR
D
(thin film) 3428 (br, s), 2964 (s), 2861 (s), 1613, 1514, 1248,
1
1092, 699 (s); H NMR (500 MHz, CDCl3) δH 7.36-7.27 (5H,
m), 7.26-7.23 (2H, m), 6.90-6.86 (2H, m), 4.53 (2H, s), 4.45
(2H, s), 3.87-3.83 (1H, m), 3.80 (3H, s), 3.77-3.66 (3H, m),
3.53 (2H, qd, J ) 9.0, 5.4 Hz), 1.93-1.88 (2H, m), 1.78-1.72
(1H, m), 1.70-1.64 (1H, m), 1.43 (1H), 1.21 (1H), 0.95 (3H, d,
J ) 7.0 Hz), 0.75 (3H, d, J ) 6.9 Hz); 13C NMR (125 MHz,
CDCl3) δC 159.2, 138.0, 130.3, 129.2, 128.4, 127.7, 113.8, 77.9,
75.7, 75.1, 73.3, 73.1, 70.0, 55.3, 40.9, 35.2, 33.8, 30.3, 12.7,
9.3; m/z (CI+) 403.3 (40, [M + H]+), 210.1 (50), 182.1 (55), 154.1
(85), 138.2 (70), 121.1 (100); HRMS (+ESI) calcd for C24H35O5
[M + H]+ 403.2479, found 403.2475.
(2S,3R,4S,5S)-1-(4-Methoxybenzyloxy)-7-benzyloxy-3,5-
cyclopentylidene acetal-2,4-dimethylheptane (62). Diol
50 (900 mg, 2.23 mmol) was dissolved in DCM (5 mL) and
cyclopentylidene dimethyl acetal (10 mL, contaminated with
25% of cyclopentanone).41 A catalytic amount of PPTS (10 mg)
was added, and the reaction mixture was stirred for 1.5 h at
50 °C. The mixture was cooled to rt, and the solvents were
removed under reduced pressure. Purification by flash chro-
matography (33% Et2O in hexane) afforded 62 (1.05 g, 100%)
as a colorless oil: Rf 0.75 (33% AcOEt in hexane); [R]20D -6.8
(c 0.50, CHCl3); IR (thin film) 2963 (s), 2856 (s), 1613 (s), 1513
added Et3N (675 µL, 4.84 mmol), followed by a solution of
ketone 818c (763 mg, 3.23 mmol) in Et2O (5 mL). The reaction
mixture was stirred at 0 °C for 2 h and was then cooled to
-78 °C. A solution of 3-benzyloxypropanal (530 mg, 3.23 mmol)
in Et2O (8 mL) was cannulated in the reaction mixture, which
1
(s), 1247 (s), 1095 (s), 698 (s); H NMR (500 MHz, CDCl3) δH
7.39-7.35 (4H, m), 7.33-7.27 (3H, m), 6.92-6.88 (2H, m), 4.56
(1H, d, J ) 12.0 Hz), 4.50 (1H, d, J ) 12.0 Hz), 4.47 (1H, d, J
J. Org. Chem, Vol. 70, No. 14, 2005 5503

Paterson and Lyothier
) 5.1 Hz), 4.43 (1H, d, J ) 5.1 Hz), 3.83 (3H, s), 3.67-3.59
(3H, m), 3.56 (1H, dt, J ) 9.8, 2.2 Hz), 3.48 (1H, dd, J ) 8.6,
8.6 Hz), 3.30 (1H, dd, J ) 8.8, 6.1 Hz), 2.09-2.05 (2H, m),
1.90-1.78 (4H, m), 1.66-1.52 (6H, m), 0.88 (3H, d, J ) 7.0
Hz), 0.78 (3H, d, J ) 6.7 Hz); 13C NMR (125 MHz, CDCl3) δC
159.1, 138.7, 130.8, 129.2, 128.3, 127.6, 127.4, 113.7, 109.7,
74.5, 73.2, 73.0, 72.8, 72.7, 66.7, 55.2, 40.2, 35.6, 33.8, 33.4,
31.1, 24.4, 22.6, 11.5, 9.7; m/z (CI+) 486.4 (100, [M + NH4]+),
469.4 (95, [M + H]+); HRMS (+ESI) calcd for C29H41O5 [M +
H]+ 469.2949, found 469.2925.
(2S,3R,4S,5S)-7-Benzyloxy-3,5-cyclopentylidene acetal-
2,4-dimethylheptan-1-ol (63). Compound 62 (90 mg, 0.192
mmol) was dissolved in DCM (5 mL) and pH 7 buffer (0.5 mL).
The mixture was stirred vigorously, and DDQ (66 mg, 0.288
mmol) was added. After 45 min, the reaction mixture was
diluted with pH 7 buffer (25 mL) and extracted with DCM (3
× 10 mL). The combined organic extracts were dried (Na2SO4),
concentrated under reduced pressure, and purified by flash
chromatography (10% Et2O in hexane), to afford alcohol 63
as a colorless oil (66 mg, 99%): Rf 0.44 (33% AcOEt in hexane);
[R]20D -17.6 (c 0.60, CHCl3); IR (thin film) 3449 (br, m), 2966
(s), 2872 (s), 1099 (s), 1000 (s), 698 (s); 1H NMR (400 MHz,
CDCl3) δH 7.37-7.26 (5H, m), 4.53 (1H, d, J ) 12.0 Hz), 4.47
(1H, d, J ) 12.0 Hz), 3.73 (1H, dd, J ) 10.6, 3.4 Hz), 3.68-
3.47 (5H, m), 2.06-1.99 (1H, m), 1.94-1.70 (5H, m), 1.69-
1.53 (6H, m), 0.98 (3H, d, J ) 7.1 Hz), 0.75 (3H, d, J ) 6.7
Hz); 13C NMR (100 MHz, CDCl3) δC 138.6, 128.3, 127.6, 127.5,
109.8, 78.9, 73.1, 73.0, 67.8, 66.5, 40.2, 35.7, 34.8, 33.3, 31.2,
24.3, 22.4, 11.6, 9.2; m/z (CI+) 349.3 (100, [M + H]+), 265.2
(97); HRMS (+ESI) calcd for C21H33O4 [M + H]+ 349.2373,
found 349.2372.
10.4, 2.2 Hz), 3.65-3.57 (3H, m), 2.74 (1H, dq, J ) 7.1, 2.3
Hz), 2.06-2.01 (1H, m), 1.96-1.74 (4H, m), 1.64-1.53 (6H,
m), 1.16 (3H, d, J ) 7.0 Hz), 0.80 (3H, d, J ) 6.6 Hz); 13C NMR
(100 MHz, CDCl3) δC 180.2, 138.5, 128.3, 127.6, 127.5, 110.1,
76.0, 73.0, 72.9, 66.4, 40.7, 39.9, 35.7, 33.2, 30.8, 24.2, 22.3,
11.5, 8.4; HRMS (+ESI) calcd for C21H31O5 [M + H]+ 363.2166,
found 363.2170.
Methyl (2S,3R,4S,5S)-7-Benzyloxy-3, 5-cyclopentyl-
idene acetal-2,4-dimethylheptanoate (66). Crude acid 65
(max ) 1.72 mmol) was dissolved in hexane (16 mL) and
MeOH (2 mL). TMS-CHN2 (2 M in hexane) was added
dropwise until the yellow color persisted. The reaction mixture
was then stirred for 30 min, quenched with 1 drop of AcOH,
and concentrated under reduced pressure. Purification by flash
chromatography (10-33% Et2O in hexane) afforded ester 66
as a colorless oil (608 mg, 94% over three steps): Rf 0.67 (33%
AcOEt in hexane); [R]20D -37.0 (c 0.60, CHCl3); IR (thin film)
2950 (s), 2873 (s), 1744 (s), 1197 (s), 1111 (s), 699 (s); 1H NMR
(500 MHz, CDCl3) δH 7.35-7.26 (5H, m), 4.53 (1H, d, J ) 12.0
Hz), 4.47 (1H, d, J ) 12.0 Hz), 3.95 (1H, dd, J ) 10.4, 3.1 Hz),
3.68 (3H, s), 3.62-3.53 (3H, m), 2.69 (1H, dq, J ) 7.1, 3.1 Hz),
2.06-1.98 (1H, m), 1.95-1.72 (4H, m), 1.65-1.48 (6H, m), 1.14
(3H, d, J ) 7.1 Hz), 0.78 (3H, d, J ) 6.7 Hz); 13C NMR (125
MHz, CDCl3) δC 174.9, 138.6, 128.3, 127.6, 127.5, 109.9, 76.2,
73.1 (2C), 66.5, 51.6, 40.8, 39.9, 35.9, 33.3, 30.9, 24.2, 22.4,
11.6, 8.7; m/z (CI+) 394.3 (90, [M + NH4]+), 377.3 (80, [M +
H]+), 293.2 (100); HRMS (+ESI) calcd for C22H33O5 [M + H]+
377.2323, found 377.2321.
Methyl (2S,3R,4S,5S)-3,5-Cyclopentylidene acetal-7-
hydroxy-2,4-dimethylheptanoate (67). Compound 66 (200
mg, 0.53 mmol) was dissolved in THF (10 mL). Pd(OH)2 (10%
on C, 20 mg) was added, and the reaction system was purged
three times with H2 and then stirred under an atmosphere of
H2 for 20 min. Filtration through Celite and removal of
solvents in vacuo afforded alcohol 67, which was used without
any further purification. For characterization purposes, a
sample was purified by flash chromatography (20% Et2O in
(2S,3R,4S,5S)-7-Benzyloxy-3, 5-cyclopentylidene ac-
etal-2,4-dimethylheptanal (64). Alcohol 63 (600 mg, 1.72
mmol) was dissolved in DCM (10 mL). NaHCO3 (1.46 g, 17.2
mmol) was added, followed by Dess-Martin periodinane (1.46
g, 3.44 mmol). The reaction mixture was stirred for 3 h and
then diluted with Et2O (20 mL), aq Na2S2O3 (20 mL), and aq
NaHCO3 (20 mL). After 30 min of vigorous stirring, the layers
were separated, the aqueous phase was extracted with Et2O
(3 × 20 mL), and the combined organic extracts were washed
with aq NaHCO3 (2 × 40 mL), dried (MgSO4), and concentrated
under reduced pressure. The crude aldehyde 64 was used
without any further purification. For characterization pur-
poses, a sample was purified by flash chromatography (20%
Et2O in hexane): colorless oil; Rf 0.68 (33% AcOEt in hexane);
hexane): colorless oil; Rf 0.29 (33% AcOEt in hexane); [R]20
D
-13.2 (c 1.40, CHCl3); IR (thin film) 3452 (br m), 2952 (s), 2877
(s), 1733 (s), 1197 (s), 1109 (s), 986 (s); 1H NMR (400 MHz,
CDCl3) δH 3.97 (1H, dd, J ) 10.4, 2.9 Hz), 3.82-3.70 (2H, m),
3.67 (3H, s), 3.64 (1H, dd, J ) 9.5, 2.3 Hz), 2.68 (1H, dq, J )
7.0, 3.0 Hz), 2.60-2.10 (1H, br s), 1.95-1.52 (11H, m), 1.14
(3H, d, J ) 7.1 Hz), 0.76 (3H, d, J ) 6.7 Hz); 13C NMR (100
MHz, CDCl3) δC 174.7, 110.1, 76.9, 76.1, 61.1, 51.7, 40.8, 40.0,
35.6, 34.7, 30.9, 24.2, 22.3, 11.6, 8.6; m/z (CI+) 287.2 (60, [M
+ H]+), 203.1 (100); HRMS (+ESI) calcd for C15H27O5 [M +
H]+ 287.1853, found 287.1854.
[R]20 -54.4 (c 0.50, CHCl3); IR (thin film) 2968 (s), 2871 (s),
D
1734 (s), 1079 (s), 1001 (s); 1H NMR (500 MHz, CDCl3) δH 9.64
(1H, s), 7.36-7.26 (5H, m), 4.53 (1H, d, J ) 12.0 Hz), 4.47
(1H, d, J ) 12.0 Hz), 4.02 (1H, dd, J ) 10.3, 2.6 Hz), 3.65-
3.54 (3H, m), 2.47 (1H, dq, J ) 7.0, 2.6 Hz), 2.06-2.01 (1H,
m), 1.98-1.70 (4H, m), 1.64-1.42 (6H, m), 1.14 (3H, d, J )
7.0 Hz), 0.80 (3H, d, J ) 6.7 Hz); 13C NMR (125 MHz, CDCl3)
δC 204.6, 138.6, 128.3, 127.6, 127.5, 110.0, 75.1, 73.1, 73.0, 66.4,
47.1, 39.9, 35.3, 33.3, 31.2, 24.3, 22.3, 11.7, 6.5; HRMS (+ESI)
calcd for C21H30O4Na [M + Na]+ 369.2054, found 369.2052.
Methyl (2S,3R,4S,5S)-3,5-Cyclopentylidene acetal-2,4-
dimethyl-7-oxoheptanoate (68). Crude alcohol 67 (max )
0.53 mmol) was dissolved in DCM (5 mL). NaHCO3 (451 mg,
5.30 mmol) was added, followed by Dess-Martin periodinane
(452 mg, 1.06 mmol). The reaction mixture was stirred for 30
min, hexane (3 mL) was then added, and the precipitate was
filtered through a pad of silica and concentrated in vacuo.
Purification by flash chromatography (10-33% Et2O in hex-
ane) provided aldehyde 68 as a colorless oil (125 mg, 83% over
2 steps): Rf 0.50 (33% AcOEt in hexane); [R]20D -18.0 (c 0.65,
CHCl3); IR (thin film) 2954 (s), 2877 (s), 1730 (s), 1201 (s), 1110
(s); 1H NMR (400 MHz, CDCl3) δH 9.77 (1H, s), 4.03-3.93 (2H,
m), 3.68 (3H, s), 2.69 (1H, dq, J ) 7.0, 3.1 Hz), 2.61 (1H, dd,
J ) 15.8, 1.5 Hz), 2.52 (1H, ddd, J ) 16.0, 8.5, 2.6 Hz), 1.98-
1.71 (4H, m), 1.68-1.51 (5H, m), 1.14 (3H, d, J ) 7.1 Hz), 0.78
(3H, d, J ) 6.7 Hz); 13C NMR (100 MHz, CDCl3) δC 201.4,
174.6, 110.3, 76.0, 72.3, 51.7, 46.9, 40.8, 39.7, 35.6, 30.9, 24.3,
22.3, 11.5, 8.7; m/z (CI+) 302.2 (100, [M + NH4]+), 285.2 (40,
[M + H]+), 201.1 (37), 90.1 (60); HRMS (+ESI) calcd for
C15H26O5 [M + H]+ 285.1697, found 285.1699.
(2S,3R,4S,5S)-7-Benzyloxy-3,5-cyclopentylidene acetal-
2,4-dimethylheptanoic Acid (65). Crude aldehyde 64 (max
1.72 mmol) was dissolved in t-BuOH (10 mL) and a few drops
of 2-methyl-2-butene. A solution of NaClO2 (390 mg, 3.44
mmol) and NaH2PO4‚2 H2O (1.61 g, 10.32 mmol) in water (10
mL) was added dropwise, and the reaction mixture was stirred
for 1 h before being partitioned between brine (50 mL) and
DCM (20 mL). The aqueous layer was re-extracted with DCM
(2 × 20 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. The crude
acid 65 was used without any further purification. For
characterization purposes, a sample was purified by flash
chromatography (25% Et2O in hexane): colorless oil; Rf 0.38
(33% AcOEt in hexane); [R]20D -27.8 (c 0.90, CHCl3); IR (thin
film) 2958, 2873 (s, CH), 1711 (s), 1336, 1195, 1098, 999 (s);
1H NMR (400 MHz, CDCl3) δH 7.37-7.26 (5H, m), 4.54 (1H,
d, J ) 12.0 Hz), 4.48 (1H, d, J ) 12.0 Hz), 3.99 (1H, dd, J )
(2S,3R,4S,5S)-3,5-Cyclopentylidene acetal-2,4-dimeth-
ylheptanedioic Acid 1-Methyl Ester (69). Aldehyde 68 (120
mg, 0.42 mmol) was dissolved in t-BuOH (5 mL) and 2-methyl-
2-butene (a few drops). A solution of NaClO2 (80%, 104 mg,
5504 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of (+)-Discodermolide
0.91 mmol) and NaH2PO4‚2H2O (428 mg, 2.74 mmol) in water
(5 mL) was added dropwise, and the reaction mixture was
stirred at rt for 45 min. The mixture was diluted with brine
(50 mL) and extracted with DCM (3 × 20 mL). The combined
organic extracts were dried (MgSO4) and concentrated under
reduced pressure. The resulting acid was used without any
further purification. For characterization purposes, 69 was
purified by flash chromatography (20% Et2O in hexane):
3.39 (1H, dd, J ) 6.9, 3.7 Hz), 3.25 (1H, dd, J ) 7.4, 3.6 Hz),
3.03-2.97 (1H, m), 2.54 (1H, m), 2.35 (1H, br s), 2.05 (1H, dd,
J ) 12.5, 12.4 Hz), 1.85-1.77 (3H, m), 1.76-1.61 (1H, m), 1.57
(3H, s), 1.11 (3H, d, J ) 6.8 Hz), 1.01 (3H, d, J ) 6.9 Hz), 0.99
(3H, d, J ) 7.2 Hz), 0.96-0.90 (21H, m), 0.72 (3H, d, J ) 6.7
Hz), 0.11-0.06 (12H, m); 13C NMR (100 MHz, CDCl3) δC 159.1,
134.5, 132.8, 132.3, 131.2, 130.4, 129.2 (2C), 129.0, 117.5, 113.7
(2C), 84.5, 81.7, 77.0, 75.0, 65.3, 55.3, 40.1, 38.4, 36.8, 36.0,
35.3, 35.2, 26.3, 26.2, 23.0, 18.7, 18.6, 18.3, 17.6, 15.8, 14.7,
10.6, -3.2, -3.4, -3.6, -3.9; m/z (+ESI) 734.6 (100, [M +
H2O]+), 717.6 (80, [M + H]+); HRMS (+ESI) calcd for C42H77O5-
Si2 [M + H]+ 717.5304, found 717.5298.
colorless oil; Rf 0.12 (33% AcOEt in hexane); [R]20 -12.5 (c
D
0.90, CHCl3); IR (thin film) 2952 (s), 2880 (s), 1740 (s, CdO),
1717 (s), 1198 (s), 1111 (s), 986 (s); 1H NMR (400 MHz, CDCl3)
δH 3.98 (1H, dd, J ) 10.3, 2.6 Hz), 3.89 (1H, dt, J ) 9.1, 2.5
Hz), 3.66 (3H, s), 2.68-2.64 (2H, m), 2.42 (1H, dd, J ) 15.6,
9.0 Hz), 1.89 - 1.72 (4H, m), 1.60-1.50 (5H, m), 1.11 (3H, d,
J ) 7.1 Hz), 0.77 (3H, d, J ) 6.7 Hz); 13C NMR (100 MHz,
CDCl3) δC 176.5, 174.6, 110.3, 75.9, 73.2, 51.7, 40.7, 39.6, 38.7,
35.4, 30.7, 24.1, 22.2, 11.5, 8.6; HRMS (+ESI) calcd for
C15H25O6 [M + H]+ 301.1646, found 301.1641.
(10S,11S,12S,13Z,16S,17R,18S,19S,20S,21Z)-11,17-Bis-
(tert-butyldimethylsilyloxy)-19-(4-methoxybenzyloxy)-
10,12,14,16,18,20-hexamethylhexadeca-13,21, 23-trienal
(7). Alcohol 34 (300 mg, 0.418 mmol) was dissolved in DCM
(5 mL). PhI(OAc)2 (162 mg, 0.502 mmol) was added, followed
by TEMPO (13.1 mg, 0.084 mmol), and the reaction mixture
was stirred at rt for 8 h. Aqueous Na2S2O3 (10 mL) was added,
and the mixture was vigorously stirred for a further 20 min
before being extracted with DCM (3 × 10 mL). The combined
organic extracts were dried (Na2SO4), concentrated under
reduced pressure, and purified by flash chromatography (10%
Et2O in hexane) to afford the desired aldehyde 7 as a colorless
oil (266 mg, 89%): Rf 0.53 (20% AcOEt in hexane); [R]20D +22.8
(c 1.25, CHCl3); IR (thin film) 2957 (s), 2930 (s), 2857 (s), 1721
(s), 1372, 1248 (s); 1H NMR (500 MHz, CDCl3) δH 9.59 (1H, s),
7.28 (2H, d, J ) 8.5 Hz), 6.88 (2H, d, J ) 8.5 Hz), 6.60 (1H,
ddd, J ) 16.8, 10.6, 10.6 Hz), 6.03 (1H, dd, J ) 11.0, 11.0 Hz),
5.58 (1H, dd, J ) 10.6, 10.6 Hz), 5.22 (1H, d, J ) 16.9 Hz),
5.13 (1H, d, J ) 10.2 Hz), 4.79 (1H, d, J ) 10.6 Hz), 4.57 (1H,
d, J ) 10.6 Hz), 4.48 (1H, d, J ) 10.6 Hz), 3.80 (3H, s), 3.75
(1H, dd, J ) 8.2, 3.5 Hz), 3.43 (1H, dd, J ) 4.7, 3.9 Hz), 3.26
(1H, dd, J ) 7.5, 3.5 Hz), 3.04-2.98 (1H, m), 2.55-2.46 (2H,
m), 2.01 (1H, dd, J ) 12.4, 12.4 Hz), 1.85-1.75 (2H, m), 1.63
(1H, app br d, J ) 10.6 Hz), 1.54 (3H, s), 1.12 (3H, d, J ) 6.8
Hz), 1.06 (3H, d, J ) 6.9 Hz), 1.03 (3H, d, J ) 6.8 Hz), 0.96
(9H, s), 0.94 (3H, d, J ) 6.6 Hz), 0.91 (9H, s), 0.71 (3H, d, J )
6.6 Hz), 0.12 (3H, s), 0.11 (3H, s), 0.09 (3H, s), 0.07 (3H, s);
13C NMR (100 MHz, CDCl3) δC 202.8, 159.0, 135.2, 134.4,
132.1, 131.1, 129.1 (2C), 128.9, 117.5, 113.7 (2C), 84.5, 78.3,
77.1, 75.0, 55.2, 52.1, 40.0, 36.4, 36.3, 35.3, 35.1, 26.2, 25.8,
22.8, 18.6, 18.1, 17.9, 14.7, 10.5, 9.5, -3.1, -3.5, -4.3, -4.4;
m/z (+ESI) 739.5 (100, [M + Na]+); HRMS (+ESI) calcd for
C42H76O5Si2Na [M + Na]+ 739.51184, found 739.512347.
Methyl (2S,3R,4S,5S)-3,5-cyclopentylidene acetal-2,4-
dimethyl-7-oxo-8-[bis(2,2,2-trifluoroethoxy)phosporyl]-
octanoate (61). Acid 69 (max 0.42 mmol) was dissolved in
DCM (5 mL). 1-Chloro-N,N,2-trimethyl-1-propenylamine (121
µL, 0.914 mmol) was added, and the reaction mixture was
stirred at rt for 1 h before being concentrated under reduced
pressure. The crude acid chloride was dried under high
vacuum for 30 min. In the meantime, methylphosphonic acid
bis(2,2,2-trifluoroethyl) ester31 19 (357 mg, 1.37 mmol) was
dissolved in THF (1 mL) and cooled to -98 °C. LiHMDS (1 M
in THF, 1.36 mL, 1.36 mmol) was added, and the reaction
mixture was stirred at -98 °C for 10 min before the addition
of the crude acid chloride in solution in THF (3 mL). The
mixture was stirred for 1 h at -98 °C, quenched with aq NH4-
Cl (5 mL), and allowed to warm to rt. After dilution with more
aq NH4Cl (20 mL), the mixture was extracted with DCM (3 ×
10 mL), and the combined organic extracts were dried (Mg-
SO4), concentrated under reduced pressure, and purified by
flash chromatography (25-50% AcOEt in hexane), affording
â-ketophosphonate 61 as a viscous colorless oil (160 mg, 70%
over three steps): Rf 0.36 (50% AcOEt in hexane); [R]20D -28.8
(c 0.70, CHCl3); IR (thin film) 2968 (m), 2876 (m), 1727 (s),
1263 (s), 1171 (s), 1072 (s); 1H NMR (500 MHz, CDCl3) δH
4.48-4.38 (4H, m), 3.98 (1H, dd, J ) 10.3, 3.1 Hz), 3.89 (1H,
ddd, J ) 12.1, 8.5, 3.6 Hz), 3.68 (3H, s), 3.35 (2H, d, JPH
21.1 Hz), 2.76-2.65 (3H, m), 1.92-1.61 (4H, m), 1.60-1.49
(5H, m), 1.13 (3H, d, J ) 7.1 Hz), 0.77 (3H, d, J ) 6.7 Hz); 13
)
C
NMR (125 MHz, CDCl3) δC 200.1 (d, J ) 7.0 Hz), 174.5, 122.5
(qdd, J ) 276.2, 7.0, 1.6 Hz), 110.4, 75.9, 73.5, 62.3 (qdd, J )
53.2, 15.0, 5.4 Hz), 51.7, 47.7 (d, J ) 5.4 Hz), 43.2, 42.1, 40.8,
39.7, 35.6, 30.8, 24.2, 22.3, 11.5, 8.7; m/z (CI+) 560 ([M +
NH4]+), 543 (20, [M + H]+); HRMS (+ESI) calcd for C20H30O8F6P
[M + H]+ 543.1583, found 543.1582.
Methyl (2R,3S,4S,5S,8Z,10S,11S,12S,13Z,16S,17R,18S,-
19S,20S,21Z)-11,17-Bis(tert-butyldimethylsilyloxy)-3,5-
cyclopentylidene acetal-19-(4-methoxybenzyloxy)-2,4,-
10,12,14,16,18,20-octamethyl-7-oxotetracosa-8,13,21,23-
tetraenoate (71). Phosphonate 61 (10 mg, 18.4 µmol) was
dissolved in THF (1 mL) and cooled to -10 °C. Sodium hydride
(60% in oil, 0.8 mg, 19 µmol) was added, and the reaction
mixture was stirred at -10 °C for 30 min. Aldehyde 7 (40 mg,
55.3 µmol) was added in solution in THF (2 mL), and the
reaction mixture was allowed to warm to rt slowly and stirred
for 2.5 d. Aqueous NH4Cl (10 mL) was added, the mixture was
extracted with DCM (4 × 5 mL), and the combined organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. The Z/E ratio was determined by 1H NMR spectros-
copy as being 10:1. Purification by flash chromatography (10%
AcOEt in hexane) afforded the Z-enone 71 as a colorless oil
(10S,11S,12S,13Z,16S,17R,18S,19S,20S,21Z)-11,17-Bis-
(tert-butyldimethylsilyloxy)-19-(4-methoxybenzyloxy)-
10,12,14,16,18,20-hexamethylhexadeca-13,21, 23-trien-9-
ol (34). PMB ether 33 (100 mg, 0.119 mmol) was dissolved in
DCM (10 mL) and cooled to 0 °C. BCl3‚DMS (2 M in DCM, 60
µL, 0.119 mmol) was added dropwise, and the reaction mixture
was stirred for 20 min at 0 °C before being partitioned between
aq NaHCO3 (20 mL) and DCM (10 mL). The aqueous phase
was re-extracted with DCM (3 × 10 mL), and the combined
organic extracts were dried (Na2SO4) and concentrated under
reduced pressure. Purification by flash chromatography (10%
Et2O in hexane) afforded alcohol 34 as a colorless oil (680 mg,
(13.5 mg, 74%): Rf 0.75 (33% AcOEt in hexane); [R]20 +57.4
D
(c 0.35, CHCl3); IR (thin film) 2958 (s), 2932 (s), 2857 (s), 1747
95%): Rf 0.30 (20% AcOEt in hexane); [R]20 +32.7 (c 0.95,
(s), 1250 (s), 1039 (s), 836 (s); H NMR (500 MHz, CDCl3) δH
1
D
CHCl3); IR (thin film) 3448 (br w), 2958 (s), 2856 (s), 1613 (s),
1514 (s), 1250 (s), 1031 (s); 1H NMR (500 MHz, CDCl3) δH 7.27
(2H, d, J ) 8.6 Hz), 6.87 (2H, d, J ) 8.6 Hz), 6.60 (1H, ddd, J
) 16.9, 10.7, 10.5 Hz), 6.05 (1H, dd, J ) 11.1, 11.0 Hz), 5.58
(1H, dd, J ) 10.6, 10.6 Hz), 5.23 (1H, d, J ) 16.8 Hz), 5.12
(1H, d, J ) 10.2 Hz), 4.97 (1H, d, J ) 10.2 Hz), 4.56 (1H, d, J
) 10.6 Hz), 4.47 (1H, d, J ) 10.6 Hz), 3.80 (3H, s), 3.68-3.64
(1H, m), 3.52-3.48 (1H, m), 3.44 (1H, dd, J ) 4.8, 3.9 Hz),
7.27 (2H, d, J ) 8.6 Hz), 6.86 (2H, d, J ) 8.6 Hz), 6.59 (1H,
ddd, J ) 16.8, 10.6, 10.4 Hz), 6.13-6.00 (3H, m), 5.57 (1H,
dd, J ) 10.6, 10.5 Hz), 5.21 (1H, d, J ) 16.9 Hz), 5.12 (1H, d,
J ) 10.1 Hz), 4.85 (1H, d, J ) 10.3 Hz), 4.55 (1H, d, J ) 10.5
Hz), 4.47 (1H, d, J ) 10.6 Hz), 3.98-3.93 (2H, m), 3.79 (3H,
s), 3.67 (3H, s), 3.60-3.57 (1H, m), 3.44-3.40 (2H, m), 3.24
(1H, dd, J ) 7.5, 3.5 Hz), 3.05-2.95 (1H, m), 2.65 (1H, dq, J
) 7.0, 3.2 Hz), 2.62 (1H, dd, J ) 15.6, 3.3 Hz), 2.62 (1H, dd, J
J. Org. Chem, Vol. 70, No. 14, 2005 5505

Paterson and Lyothier
) 15.5, 8.2 Hz), 2.38 - 2.30 (1H, m), 1.97 (1H, dd, J ) 12.4,
12.4 Hz), 1.90-1-61 (6H, m), 1.60-1.48 (6H, m), 1.51 (3H, s),
1.11 (3H, d, J ) 7.1 Hz), 1.10 (3H, d, J ) 6.8 Hz), 1.05-0.87
(24H, m), 0.86 (3H, d, J ) 6.6 Hz), 0.73 (3H, d, J ) 6.6 Hz),
0.68 (3H, d, J ) 6.6 Hz), 0.10-0.01 (12H, m); 13C NMR (125
MHz, CDCl3) δC 198.4, 174.8, 159.0, 151.2, 134.4, 132.3, 132.2,
131.2, 130.7, 129.1, 129.0, 125.4, 117.6, 113.7, 110.1, 84.7, 80.4,
76.1, 75.0, 73.1, 55.3, 51.7, 48.1, 40.8, 40.1, 39.8, 38.2, 37.1,
35.9, 35.8, 35.3 (2C), 30.8, 26.3, 26.2, 24.3, 22.8, 22.4, 18.7,
18.6, 18.4, 18.0, 17.1, 14.8, 11.6, 10.5, 8.7, -3.1, -3.3, -3.6,
-4.0; HRMS (+ESI) calcd for C58H102O9Si2N [M + NH4]+
1012.7088, found 1012.7081.
133.6, 132.4, 132.1, 130.6, 129.8, 125.5, 118.0, 110.2, 80.4, 78.9,
76.1, 73.2, 51.7, 48.2, 40.9, 39.8, 38.1, 38.0, 37.3, 36.1, 36.0,
35.1, 34.5, 30.8, 26.23, 26.19, 25.9, 24.3, 22.8, 22.4, 18.5, 18.4,
18.0, 17.5, 17.3, 13.7, 11.7, 10.2, 8.7, -3.43, -3.45, -3.5, -4.0;
HRMS (+ESI) calcd for C51H91O9Si2Na [M + Na]+ 940.6125,
found 940.6149.
Methyl (2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,-
18S,19S,20S,21Z)-11,17-Bis(tert-butyldimethylsilyloxy)-
19-carbamoyloxy-3,5-cyclopentylidene acetal-7-hydroxy-
2,4,10,12,14,16,18,20-octamethyltetracosa-8,13,21,23-
tetraenoate (74). Ketone 73 (7 mg, 7.6 µmol) was dissolved
in toluene (1 mL) and cooled to -78 °C. K-Selectride (1 M in
THF, 23 µL, 23 µmol) was added, and the reaction mixture
was stirred for 6 h, allowing the temperature to warm slowly
up to -40 °C. The mixture was quenched with aq NH4Cl (10
mL) and extracted with AcOEt (3 × 10 mL). The organic
extracts were stirred vigorously with a solution of sodium
perborate (120 mg, 0.76 mmol) in water (20 mL). After 2 h,
the layers were separated, and the aqueous phase was reex-
tracted with AcOEt (10 mL). The combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure.
Purification by flash chromatography (15-20% AcOEt in
hexane) afforded alcohol 74 as a colorless oil (6.3 mg, 90%):
Methyl (2R,3S,4S,5S,8Z,10S,11S,12S,13Z,16S,17R,18S,-
19S,20S,21Z)-11,17-Bis(tert-butyldimethylsilyloxy)-3,5-
cyclopentylidene acetal-19-hydoxy-2,4,10,12,14,16,18,20-
octamethyl-7-oxotetracosa-8,13,21,23-tetraenoate (72).
Compound 71 (40 mg, 40.1 µmol) was dissolved in DCM (2
mL) and pH 7 buffer (0.2 mL) and cooled to 0 °C. DDQ (18.3
mg, 80.3 µmol) was added, and the reaction mixture was
stirred at 0 °C for 30 min and then at rt for 45 min. The
mixture was partitioned between pH 7 buffer (20 mL) and
DCM (10 mL). The aqueous phase was re-extracted with DCM
(3 × 10 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Purifica-
tion by flash chromatography (20-50% AcOEt in hexane)
afforded alcohol 72 as a colorless oil (35 mg, 99%): Rf 0.56
(20% AcOEt in hexane); [R]20D +51.6 (c 0.60, CHCl3); IR (thin
film) 2958 (s), 2932 (s), 1735 (s), 1087 (s), 1022 (s), 773 (s); 1H
NMR (500 MHz, CDCl3) δH 6.63 (1H, ddd, J ) 16.8, 10.7, 10.4
Hz), 6.19-6.08 (2H, m), 6.07 (1H, d, J ) 11.6 Hz), 5.34 (1H,
dd, J ) 10.4, 10.4 Hz), 5.24 (1H, d, J ) 16.7 Hz), 5.15 (1H, d,
J ) 10.1 Hz), 4.90 (1H, d, J ) 10.3 Hz), 4.00-3.95 (2H, m),
3.68 (3H, s), 3.63-3.59 (2H, m), 3.42 (1H, dd, J ) 6.8, 3.1 Hz),
3.33 (1H, dd, J ) 7.4, 2.9 Hz), 2.82-2.78 (1H, m), 2.68 (1H,
dq, J ) 7.0, 3.1 Hz), 2.65 (1H, dd, J ) 15.6, 3.5 Hz), 2.60 (1H,
dd, J ) 15.5, 7.9 Hz), 2.40-2.36 (1H, m), 2.16 (1H, dd, J )
12.4, 12.4 Hz), 1.92-1.67 (7H, m), 1.66-1.48 (5H, m), 1.60 (3H,
s), 1.14 (3H, d, J ) 7.1 Hz), 0.98-0.87 (30H, m), 0.75 (3H, d,
Rf 0.30 (33% AcOEt in hexane); [R]20 +43.4 (c 0.35, CHCl3);
D
IR (thin film) 3355 (br, m), 2958 (s), 2930 (s), 2857 (s), 1726
1
(s), 1038 (s), 836 (s), 773 (s); H NMR (400 MHz, CDCl3) δH
6.60 (1H, ddd, J ) 16.8, 10.5, 10.3 Hz), 6.03 (1H, dd, J ) 11.0,
11.0 Hz), 5.48 (1H, dd, J ) 10.7, 9.8 Hz), 5.42-5.34 (2H, m),
5.22 (1H, d, J ) 17.2 Hz), 5.13 (1H, d, J ) 10.2 Hz), 5.00 (1H,
d, J ) 10.0 Hz), 3.97 (1H, dd, J ) 6.1, 6.0 Hz), 4.73 (1H, t, J
) 7.7 Hz), 4.54 (2H, br s), 3.97 (1H, dd, J ) 10.3, 3.2 Hz),
3.81-3.72 (1H, m), 3.68 (3H, s), 3.42 (1H, dd, J ) 4.6, 4.4 Hz),
3.28 (1H, dd, J ) 5.7, 4.6 Hz), 3.03-2.95 (1H, m), 2.79 (1H, br
s), 2.75-2.62 (2H, m), 2.49-2.38 (1H, m), 2.04 (1H, dd, J )
12.8, 12.4 Hz), 1.92-1.70 (8H, m), 1.70-1.49 (6H, m), 1.59 (3H,
s), 1.15 (3H, d, J ) 7.1 Hz), 0.99 (3H, d, J ) 6.8 Hz), 0.94-
0.90 (24H, m), 0.86 (3H, d, J ) 6.6 Hz), 0.76 (3H, d, J ) 6.7
Hz), 0.71 (3H, d, J ) 6.7 Hz), 0.11-0.02 (12H, m); 13C NMR
(100 MHz, CDCl3) δC 174.9, 156.9, 134.7, 133.6, 132.1, 131.9,
131.2, 131.1, 129.8, 118.0, 110.2, 80.6, 78.7, 77.2, 76.9, 76.2,
74.1, 65.0, 51.7, 40.9, 40.1, 39.4, 37.9, 37.3, 36.2, 36.1, 35.5,
35.1, 34.5, 30.9, 26.2 (2C), 24.3, 22.9, 22.4, 18.5, 18.4, 17.5,
17.1, 13.6, 11.6, 10.1, 8.8, -3.2, -3.4, -3.5, -4.0; HRMS
(+ESI) calcd for C51H93O9Si2Na [M + Na]+ 942.6281, found
942.6304.
J ) 6.7 Hz), 0.71 (3H, d, J ) 6.8 Hz), 0.09-0.01 (12H, m); 13
C
NMR (125 MHz, CDCl3) δC 198.5, 174.7, 151.1, 134.7, 132.5,
132.1, 131.0, 130.7, 125.6, 118.4, 110.2, 80.5, 78.8, 76.3, 76.2,
73.1, 51.6, 48.1, 40.9, 39.8, 38.3, 38.0, 37.4, 36.4, 36.3, 35.8,
34.9, 30.8, 26.23, 26.19, 24.3, 23.1, 22.4, 18.5, 18.4, 17.8, 17.5,
17.2, 13.4, 11.7, 9.5, 8.7, -3.4, -3.5 (2C), -4.0; HRMS (+ESI)
calcd for C50H90O8Si2Na [M + H]+ 897.6066, found 897.6087.
Methyl (2R,3S,4S,5S,8Z,10S,11S,12S,13Z,16S,17R,18S,-
19S,20S,21Z)-11,17-Bis-(tert-butyldimethylsilyloxy)-19-
carbamoyloxy-3, 5-cyclopentylidene acetal-2,4,10,12,14,-
16,18,20-octamethyl-7-oxotetracosa-8,13,21,23-
tetraenoate (73). Alcohol 72 (10 mg, 11.4 µmol) was dissolved
in DCM (1 mL). Trichloroacetyl isocyanate (6.8 µL, 57.1 µmol)
was added, and the reaction mixture was stirred for 1.5 h. The
mixture was loaded onto the top of a plug of neutral alumina
and left there for 2 h. Elution with AcOEt, concentration under
reduced pressure, and purification by flash chromatography
(10-20% AcOEt in hexane) afforded carbamate 73 as a
colorless oil (9.9 mg, 95%): Rf 0.47 (33% AcOEt in hexane);
(+)-Discodermolide (1). To a stirred solution of 74 (6 mg,
6.5 µmol) in THF (1 mL) at 0 °C was added HF‚py (0.2 mL).
The reaction mixture was stirred at rt for 3 h and recooled to
0 °C, and a second aliquot of HF‚py (0.2 mL) was added. After
16 h at rt, the mixture was cooled to 0 °C, and a final aliquot
of HF‚py (0.1 mL) was added. After 6 h at rt, the mixture was
carefully quenched at 0 °C with aq NaHCO3 (20 mL). Extrac-
tion with AcOEt (5 × 10 mL), drying (MgSO4), and concentra-
tion under vacuum afforded the crude product, which was
purified by flash chromatography (5-10% MeOH in DCM) to
give (+)-discodermolide 1 as a white solid (3.0 mg, 84%): Rf
0.20 (10% MeOH in DCM); [R]20 +13.2 (c 1.1, MeOH), Lit.17
D
[R]20 +63.3 (c 0.15, CHCl3); IR (thin film) 2958 (s), 2932 (s),
+7.2 (c 0.7, MeOH); IR (thin film) 3429 (br), 2966 (s), 2929
D
2857 (s), 1732 (s), 1037 (s), 836 (s), 773 (s); 1H NMR (500 MHz,
CDCl3) δH 6.60 (1H, ddd, J ) 16.8, 10.7, 10.6 Hz), 6.15 (1H,
dd, J ) 11.6, 9.3 Hz), 6.08-6.01 (2H, m), 5.38 (1H, dd, J )
10.7, 10.5 Hz), 5.22 (1H, d, J ) 16.8 Hz), 5.14 (1H, d, J ) 10.0
Hz), 4.87 (1H, d, J ) 10.4 Hz), 4.73 (1H, dd, J ) 6.1, 6.1 Hz),
4.52 (2H, br s), 4.00-3.96 (2H, m), 3.68 (3H, s), 3.60-3.52 (1H,
m), 3.45-3.40 (2H, m), 3.08-2.96 (1H, m), 2.68 (1H, dq, J )
7.1, 3.1 Hz), 2.62 (1H, dd, J ) 15.5, 3.8 Hz), 2.57 (1H, dd, J )
15.5, 7.7 Hz), 2.40-2.30 (1H, m), 2.07 (1H, dd, J ) 12.5, 12.3
Hz), 1.92-1.67 (7H, m), 1.66-1.48 (5H, m), 1.57 (3H, s), 1.13
(3H, d, J ) 7.1 Hz), 0.99 (3H, d, J ) 6.8 Hz), 0.96 (3H, d, J )
7.0 Hz), 0.95-0.88 (21H, m), 0.87 (3H, d, J ) 6.6 Hz), 0.75
(3H, d, J ) 6.7 Hz), 0.69 (3H, d, J ) 6.7 Hz), 0.11-0.02 (12H,
m); 13C NMR (125 MHz, CDCl3) δC 198.4, 174.8, 156.9, 151.4,
(s), 1729 (s), 1602 (m), 1265 (s); H NMR (400 MHz, CDCl3)
1
δH 6.62 (1H, ddd, J ) 16.8, 10.6, 10.6 Hz), 6.03 (1H, dd, J )
11.0, 11.0 Hz), 5.53 (1H, dd, J ) 11.1, 7.9 Hz), 5.43 (1H, dd, J
) 10.7, 10.3 Hz), 5.36 (1H, dd, J ) 10.5, 10.2 Hz), 5.22 (1H, d,
J ) 16.8 Hz), 5.17 (1H, d, J ) 9.7 Hz), 5.13 (1H, d, J ) 10.1
Hz), 4.75 (1H, ddd, J ) 7.5, 7.5, 2.6 Hz), 4.71 (1H, dd, J ) 7.2,
4.2 Hz), 4.63 (1H, ddd, J ) 10.0, 9.8, 2.1 Hz), 4.61 (2H, br s),
3.75 (1H, dd, J ) 4.0, 4.0 Hz), 3.29 (1H, dd, J ) 4.9, 4.5 Hz),
3.20 (1H, dd, J ) 6.6, 4.9 Hz), 3.00 (1H, ddq, J ) 9.9, 6.9, 6.9
Hz), 2.80 (1H, ddq, J ) 9.7, 6.8, 6.8 Hz), 2.68 (1H, dq, J ) 7.3,
4.5 Hz), 2.65-2.53 (1H, m), 2.10-1.80 (10H, m), 1.74-1.67
(1H, m), 1.65 (3H, s), 1.32 (3H, d, J ) 7.3 Hz), 1.08 (3H, d, J
) 6.9 Hz), 1.02 (3H, d, J ) 6.8 Hz), 1.00 (3H, d, J ) 5.9 Hz),
0.99 (3H, d, J ) 6.3 Hz), 0.95 (3H, d, J ) 6.8 Hz), 0.83 (3H, d,
5506 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of (+)-Discodermolide
J ) 5.7 Hz); 13C NMR (100 MHz, CDCl3) δC 173.7, 157.1, 134.4,
133.7, 133.4, 132.9, 132.1, 129.9, 129.7, 117.9, 79.0, 78.9, 77.2,
75.7, 73.2, 64.4, 43.1, 41.0, 37.4, 36.1, 36.0, 35.7, 35.3, 34.8,
33.1, 23.3, 18.4, 17.5, 15.6, 15.5, 13.7, 12.5, 9.0; HRMS (+ESI)
calcd for C33H55O8NNa [M + Na]+ 616.3825, found 616.3839.
(Novartis, Basel) for helpful discussions and the provi-
sion of various reagents and intermediates.
Supporting Information Available: General experimen-
tal methods, detailed experimental procedures, and spectro-
scopic data for compounds 6, 10-16, 20, 21, 24-32, 35-37,
39-42, and 51-59 and selected NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the EPSRC and No-
vartis Pharma AG for support and Dr. Stuart J. Mickel
JO050481A
J. Org. Chem, Vol. 70, No. 14, 2005 5507