Total synthesis of (+)-discodermolide: An improved endgame exploiting a Still-Gennari-type olefination with a C1-C8 β-ketophosphonate fragment

Article abstract of DOI:10.1021/ol0478842

(Chemical Equation Presented) An improved, third-generation, total synthesis of (+)-discodermolide, a potent microtubule-stabilizing anticancer agent of marine sponge origin, is achieved in 11.1% yield over 21 steps. Key steps include a Still-Gennari HWE

Full text of DOI:10.1021/ol0478842

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4933-4936
Total Synthesis of (
An Improved Endgame Exploiting a
Still Gennari-Type Olefination with a
C1 C8
-Ketophosphonate Fragment†
+)-Discodermolide:
−
−
â
Ian Paterson* and Isabelle Lyothier
UniVersity Chemical Laboratory, UniVersity of Cambridge, Lensfield Road,
Cambridge, CB2 1EW, UK
ip100@cam.ac.uk
Received October 13, 2004
ABSTRACT
An improved, third-generation, total synthesis of (
origin, is achieved in 11.1% yield over 21 steps. Key steps include a Still
C1 C8 -ketophosphonate 7 and C9 C24 aldehyde 8, introducing the (8Z)-alkene with 10:1 selectivity, and K-Selectride reduction of the
+
)-discodermolide, a potent microtubule-stabilizing anticancer agent of marine sponge
−Gennari HWE olefination, performed using NaH as the base, between
−
â
−
derived enone 16, installing the (7S)-configuration.
As a structurally unique antimitotic agent that is a potent
inhibitor of cell proliferation, discodermolide (1) represents
a promising candidate for development in cancer chemo-
therapy.1-3 While sharing the same microtubule-stabilizing
mechanism of action as paclitaxel (Taxol), discodermolide
is a comparatively poor substrate for the P-glycoprotein drug
efflux pump and thus circumvents the problem of multidrug
resistance. Moreover, discodermolide induces significant
growth inhibition of paclitaxel-refractory tumors in hollow
fiber and xenograft mouse models, such that it has recently
moved into human clinical trials. Despite considerable
progress over the past decade in refining synthetic routes to
discodermolide,4-7 there remains a supply problem, ham-
pering its development as a new-generation anticancer drug.8
(4) Review: Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193.
(5) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew.
Chem., Int. Ed. 2000, 39, 377. (b) Paterson, I.; Florence, G. J.; Gerlach,
K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535. (c) Paterson,
I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org.
Lett. 2003, 5, 35. (d) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier,
I.; O’Brien, M.; Scott, J. P.; Sereinig, N. J. Org. Chem., published online
Dec. 4, 2004 http://dx.doi.org/10.1021/jo048534w.
(6) For previous total syntheses of discodermolide, see: (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. (c) Smith, A. B., III; Qiu, Y. P.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011. (d) Smith, A. B., III;
Kaufman, M. D.; Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H. Org.
Lett. 1999, 1, 1823. (e) Smith, A. B., III; 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. (f) Smith, A. B., III; Freeze, B. S.;
Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405. (g) Marshall, J. A.; Lu, Z.
H.; Johns, B. A. J. Org. Chem. 1998, 63, 817. (h) Marshall, J. A.; Johns,
B. A. J. Org. Chem. 1998, 63, 7885. (i) Harried, S. S.; Yang, G.; Strawn,
M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098. (j) Harried, S. S.; Lee,
C. P.; Yang, G.; Lee, T. I. H.; Myles, D. C. J. Org. Chem. 2003, 68, 6646.
† Dedicated to Professor Amos B. Smith on the occasion of his 60th
birthday.
(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) 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. (c) Kowalski, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R.
E.; Day, B. W.; Hamel, E. Mol. Pharm. 1997, 52, 613.
(3) For recent reviews of microtubule-stabilizing anticancer agents, see:
(a) Altmann, K.-H. Curr. Opin. Chem. Biol. 2001, 5, 424. (b) Myles, D. C.
Ann. Rep. Med. Chem. 2002, 37, 125. (c) He, L.; Orr, G. A.; Horwitz, S.
B. Drug DiscoV. Today 2001, 6, 1111. (d) Wood, K. W.; Cornwell, W. D.;
Jackson, J. R. Curr. Opin. Pharmacol. 2001, 1, 370.
10.1021/ol0478842 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/23/2004

Scheme 1
At present, due to the low isolation yield from the deep-
in performing such complex aldol couplings on an industrial
scale, where the quality of organoboron reagents from
commercial suppliers is variable and arduous chromato-
graphic isolation of the product is required,8 we sought to
simplify the key coupling step and further streamline our
synthesis. This led us to propose a more convenient endgame,
involving a challenging Still-Gennari-type HWE olefination
at C8-C9 to connect an advanced â-ketophosphonate such
as 6 or 7 with the aldehyde 8, leading directly to the carbon
skeleton of discodermolide.
sea sponge source,1 total synthesis offers the only viable
means of supply to support its clinical development. Within
the pharmaceutical industry, Novartis chemists have recently
reported the large-scale synthesis of over 60 g of discoder-
molide (for Phase I) based on a Smith-Paterson hybrid
route,8 where the need for developing a more practical and
robust synthesis to potentially become a manufacturing
process was highlighted. Following on from our previous
work,5 we now disclose a highly convergent, third-generation,
total synthesis of (+)-discodermolide based on a novel
endgame strategy. By exploiting an experimentally straight-
forward Still-Gennari-type fragment union using an ad-
vanced C1-C8 â-ketophosphonate, a more practical process
is realized relative to existing synthetic routes.
The synthesis of the linear C1-C8 â-keto phosphonate 7
(Scheme 2) commenced from the ethyl ketone (S)-9, readily
obtained from the Roche ester in three steps as described
In considering the options for devising an improved
synthetic plan, we sought a simple and convenient fragment
union to assemble the carbon skeleton in a convergent
manner, followed by a small number of straightforward steps
to arrive at discodermolide (Scheme 1). Previously, we have
reported completed total syntheses of discodermolide based
on pivotal boron-mediated aldol coupling reactions per-
formed, at a late stage, either at C5-C6 or at C6-C7. In
the latter case,5a,b the reagent-controlled fragment union of
ketone 2 and (Z)-enal 3 sets up the required (7S)-configu-
ration, overturning the intrinsic facial bias of the aldehyde
partner. In our second-generation synthesis,5c,d a reversed
C5-C6 aldol coupling between aldehyde 4 and ketone 5,
exploiting 1,6-asymmetric induction from the remote C10
stereocenter, sets up the required (5S)-configuration under
substrate control. In light of perceived technical difficulties
Scheme 2
(7) See ref 5d for a recent comprehensive listing of discodermolide
fragment syntheses and other synthetic studies in progress.
(8) 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
and preceding papers.
4934
Org. Lett., Vol. 6, No. 26, 2004

periodinane or Swern; NaClO2) was realized. Without
purification, acid 12 was treated with the Ghosez reagent
(Me2CdC(Cl)NMe2)11 to generate acyl chloride 13, which
was immediately reacted with a solution of (CF3CH2O)2P-
(O)CH2Li at -98 °C.12 Pleasingly, this acylation reaction
proceeded smoothly, providing â-ketophosphonate 7 in 70%
yield from 12. Starting from ketone (S)-9, this sequence can
be performed conveniently on a multigram scale in 45.4%
overall yield.
Scheme 3
With the C1-C8 â-ketophosphonate 7 in hand, we now
required the C9-C24 aldehyde 8 (Scheme 4), which should
be accessible from the common intermediate 14 employed
in our two preceding discodermolide syntheses.5 Thus,
selective cleavage of the primary PMB ether proceeded on
treatment of 14 with Cl3B‚SMe2 complex at 0 °C, followed
by Swern oxidation of the resulting alcohol to give aldehyde
8 in readiness for exploring the viability of the pivotal
fragment assembly. Gratifyingly, when phosphonate 7 was
treated with NaH in THF at 0 °C for 30 min, followed by
the addition of aldehyde 8, a clean HWE olefination occurred.
1
Analysis of the crude product by H NMR spectroscopy
previously.5 To install the stereotetrad sequence correctly,
we exploited the highly diastereoselective anti-aldol chem-
istry of the derived (E)-enol dicyclohexylborinate, which is
applied here to addition to 2-benzyloxypropanal followed
by in situ reduction of the intermediate aldolate with LiBH4,9
giving 1,3-syn-diol 10 in 84% yield (97:3 dr). Conversion
of diol 10 into a cyclopentylidene acetal was then followed
by PMB ether cleavage (DDQ), where subsequent transfor-
mation of the resulting alcohol into methyl ester 11 proved
to be straightforward (four steps, 93%).
With the correct stereochemistry and oxidation states now
in place for the C1-C6 segment, we now focused on
installing the CF3CH2O-substituted phosphonate moiety
(Scheme 3), required for the Still-Gennari modified HWE
olefination.10 Following hydrogenolysis of benzyl ether 11,
oxidation to the corresponding acid 12 (Dess-Martin
indicated that the desired (Z)-enone 15 was formed selec-
tively (Z:E ) 10:1), which was then isolated in 74% yield
after a simple chromatographic separation. Notably, this
constitutes one of the first examples of a (Z)-selective
intermolecular Still-Gennari olefination employing such an
elaborate â-ketophosphonate.13 Furthermore, this coupling
also proceeds satisfactorily by simply using NaH as a base
under experimentally undemanding conditions, without
resorting to expensive crown ether additives (important for
minimizing the cost of goods in scaling up).10 This mild
coupling method for highly functionalized and sterically
encumbered fragments, as in 7 + 8 f 15, may well prove
to be useful in other complex natural product synthesis.
However, in contrast to the success achieved using the linear
â-ketophosphonate 7, the preparation of the alternative
Scheme 4
Org. Lett., Vol. 6, No. 26, 2004
4935

fragment 6 (see Scheme 1), already containing the δ-lactone
ring of discodermolide, proved to be problematic.14
With the carbon backbone of discodermolide now in place,
all that remained was to install the carbamate moiety at the
C19 hydroxyl, followed by stereocontrolled reduction of the
C7 ketone and deprotection. First, PMB ether 15 was cleaved
oxidatively with DDQ (99%), subsequent treatment of the
resulting alcohol with trichloroacetyl isocyanate15 and metha-
nolysis of the intermediate trichloroacetyl adduct (K2CO3,
MeOH) then gave 16 in 98% yield. Following our second-
generation route,5c,d we treated (Z)-enone 16 with K-
Selectride in PhMe/THF at -78 °C. Gratifyingly, this led
to a highly selective 1,2-reduction, providing the required
(7S)-alcohol 17 (97:3 dr) in 90% yield. Finally, global
deprotection and concomitant δ-lactonization proceeded
cleanly on treatment with HF‚py to provide (+)-discoder-
molide (1), which was identical to an authentic sample in
all respects.
Scheme 5
fragment coupling step. This third-generation synthesis
exploits a late-stage Still-Gennari-type HWE coupling using
phosphonate 7 under experimentally undemanding conditions
and proceeds in 11.1% yield over 21 steps (longest linear
sequence) from the Roche ester.16 By avoiding some of the
problematic steps associated with earlier syntheses,8 this new
endgame should be more applicable to the preparation of
larger quantities of discodermolide, enabling further biologi-
cal and clinical studies.
In summary, we have completed a highly convergent
synthesis of discodermolide from the advanced intermediate
14, which represents a significant improvement over our
previous synthetic routes both in terms of efficiency (see
comparison in Scheme 5) and ease of performing the key
Acknowledgment. We thank the EPSRC and Novartis
Pharma AG for support and Dr. Stuart J. Mickel (Novartis,
Basel) for helpful discussions and the provision of various
reagents and intermediates.
(9) (a) Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 801. (b)
Paterson, I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
(10) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. (b)
Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725.
(11) Devos, A.; Remion, J.; Frisque-Hesbain, A. M.; Colens, A.; Ghosez,
L. J. Chem. Soc., Chem. Commun. 1979, 1180.
Supporting Information Available: Spectroscopic data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Patois, C.; Savignac, P.; About-Jadet, E.; Collignon, N. Synth.
Commun. 1991, 21, 2391.
(13) For another example of a complex fragment coupling by a Still-
Gennari HWE olefination, see: Paterson, I.; Britton, R.; Delgado, O.; Meyer,
A.; Poullennec, K. Angew. Chem., Int. Ed. 2004, 43, 4629.
(14) Our initial plan was to use phosphonate 6 (Scheme 1); however, its
synthesis proved to be troublesome due to the propensity for â-elimination
across C5-C6 with opening of the lactone ring under mild acidic or basic
conditions.
OL0478842
(16) This is based on our first-generation synthesis of intermediate 14
(ref 5b); the overall yield is 9.5% over 23 steps following our second-
generation synthesis (ref 5c,d).
(15) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
4936
Org. Lett., Vol. 6, No. 26, 2004