A Practical Improvement, Enhancing the Large-Scale Synthesis of (+)-Discodermolide: A Third-Generation Approach

Article abstract of DOI:10.1021/ol035697i

(Equation presented) A significant improvement to the Penn one-gram synthesis of (+)-discodermolide (1) has been achieved. Specifically, reduction of the steric bulk of the C(11) hydroxyl protecting group permits formation of the requisite AB Wittig salt at the expense of the undesired intramolecular cyclization upon treatment with PPh₃ at ambient pressure.

Full text of DOI:10.1021/ol035697i

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4405-4408
A Practical Improvement, Enhancing the
Large-Scale Synthesis of
(+)-Discodermolide: A Third-Generation
Approach
Amos B. Smith III,* B. Scott Freeze, Ignacio Brouard, and Tomoyasu Hirose
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received September 4, 2003
ABSTRACT
A significant improvement to the Penn one-gram synthesis of (+)-discodermolide (1) has been achieved. Specifically, reduction of the steric
bulk of the C(11) hydroxyl protecting group permits formation of the requisite AB Wittig salt at the expense of the undesired intramolecular
cyclization upon treatment with PPh3 at ambient pressure.
(+)-Discodermolide (1, Figure 1), an architecturally intrigu-
ing marine sponge natural product1 possessing significant
antitumor activity,2 is currently undergoing clinical trials.3
The mechanism of action, similar to that of the epothilones
(2), the eleutherobins, and the clinically proven anticancer
drug Taxol (3), entails stabilization of mitotic spindle
microtubules.2 Importantly, (+)-discodermolide (1) is effec-
tive against Taxol-resistant cell lines.4 In addition, (+)-
discodermolide (1) displays the unusual property of synergy
with Taxol.5 Not surprisingly, the promise of therapeutic use,
in conjunction with the interesting architecture of (+)-1, has
led to a number of total syntheses,6 including our develop-
ment of a preparative-scale approach, which in 1999
culminated in the synthesis of over 1 g of the natural
product.6d The latter was sufficient to permit extensive
preclinical pharmacological studies leading to Phase 1 clinical
trials by the Novartis Pharmaceutical Corp.
The continued need for an even more efficient, practical
synthesis of (+)-discodermolide, however, has prompted us
to reinvestigate what we saw as a significant limiting step
in the ultimate scalability of our gram-scale approach, namely
the requirement to employ ultrahigh-pressure conditions (ca.
(6) (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J.
Am. Chem. Soc. 1993, 115, 12621. (b) Hung, D. T.; Nerenberg, J. B.;
Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054. (c) Smith, A. B., III;
Qiu, Y.; 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.; Arimoto, H.; Jones, D. A.;
Kobayashi, K. J. Am. Chem. Soc., 2000, 122, 8654. (f) Harried, S. S.; Yang,
G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098. (g) Marshall,
J. A.; Lu, Z.-H.; Johns, B. A. J. Org. Chem. 1998, 63, 7885. (h) Paterson,
I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem., Int. Ed. 2000,
39, 377. (i) Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D.
C. J. Org. Chem. 2003, 68, 6646. (j) Halstead, D. P. Ph.D. Thesis, Harvard
University, Cambridge, 1998.
(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) (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) Hung, D. T.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996, 3,
287.
(3) Novartis Pharmaceuticals.
(4) Kowalski, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R.
E.; Day, B. W.; Hamel, E. Mol. Pharm. 1997, 52, 613.
(5) Martello, L. A.; McDaid, H. M.; Regl, D. L.; Yang, C. H.; Meng,
D.; Pettus, T. R.; Kaufman, M. D.; Arimoto, H.; Danishefsky, S. J.; Smith,
A. B., III; Horwitz, S. B. Clin. Cancer Res. 2000, 6, 1978.
10.1021/ol035697i CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/16/2003

readily to furnish (+)-7, with essentially no cyclopentane
formation (Scheme 2). This reaction permitted construction
Scheme 2
Figure 1. Representative microtubulin-stabilizing natural products.
of (+)-14-normethyldiscodermolide 8, a congener of (+)-
discodermolide (1) displaying similarly potent in vivo
cytotoxicity.8
12.8 kbar) to generate the Wittig salt (+)-AB (Scheme 1).
Standard conditions, involving heating a mixture of PPh3 and
iodide (+)-4 in solvents of varying polarity, at best furnished
only modest amounts of the requisite Wittig salt. Detailed
1H NMR studies revealed that the bulk of the material was
instead a mixture of 5a and 5b, the result of five-membered
ring formation6e involving the electron-rich C(13,14) olefin.
Olefin-assisted cyclizations are of course well precedented.7
In addition, some decomposition occurred, presumably due
to the HI generated via the requirement to heat the PPh3-
iodide mixture.
To circumvent the impass in the construction of Wittig
salt (+)-AB, we exploited high pressure conditions, known
to accelerate dramatically the alkylation of phosphines at
room temperature.9 To this end, pressurizing a benzene/
toluene solution of iodide (+)-4 and PPh3 at 12.8 kBar for
10-14 days at ambient temperature furnished the desired
(+)-AB Wittig salt in 75% yield. Although reaction scales
of up to 2 g were readily accommodated by the Leco High-
Pressure Cell,10 these conditions were by no means optimal,
especially in the context of an industrial-scale synthesis.
In an attempt to understand the formation of cyclic
products upon treatment with PPh3 at ambient pressure, we
examined the chairlike transition state (Scheme 3). This
Scheme 1
Scheme 3
In contrast to this observation, heating a mixture of the
corresponding primary iodide (+)-6, possessing a disubsti-
tuted instead of the more electron-rich trisubstituted olefin
at C(13,14), with PPh3 and diisopropylethylamine proceeded
(7) (a) Johnson, W. S.; Bailey, D. M.; Owyang, R.; Bell, R. A.; Jaques,
B.; Crandall, J. K. J. Am. Chem. Soc. 1964, 86, 1959. (b) Johnson, W. S.;
Owyang, R. J. Am. Chem. Soc. 1964, 86, 5593.
analysis suggested that the bulky TBS ether might promote
a turn-structural bias to the ground-state conformation of the
4406
Org. Lett., Vol. 5, No. 23, 2003

primary iodide (+)-4, thereby inducing a predisposition
toward intramolecular cyclization. We reasoned that this
“reactive rotamer effect”11 might be suppressed by replace-
ment of the large protecting group with a sterically less
demanding one. Indeed, reaction of several readily prepared
model iodides (9a-f) incorporating less encumbered protect-
ing groups (Scheme 3) demonstrated the anticipated trend;
less encumbered protecting groups increased the ratio of
Wittig salt formation at ambient pressure versus cyclization.12
Best results were obtained with the MOM protecting group.
With these observations in hand, we returned to our triply
convergent approach to (+)-discodermolide (1),13 now with
a MOM protecting group incorporated at C(11) in fragment
(+)-B (Scheme 4).
Scheme 5
Union of fragments (+)-A and (+)-B via a modified
Negishi coupling,14 followed by elaboration to the corre-
sponding dienyl alcohol (+)-13, then proceeded efficiently
under conditions similar to our earlier gram-scale synthesis
(Scheme 6).6e
Scheme 4
Scheme 6
Gratifyingly, heating a mixture of the primary iodide
derived from (+)-13 with PPh3 in the presence of i-Pr2NEt
at 100 °C furnished the requisite Wittig salt (+)-14 in 70%
yeild, with only modest cyclopentane formation. Subsequent
Wittig union with aldehyde (-)-C, removal of the secondary
PMB group, and installation of the carbamate at C(19),
followed by global deprotection (Scheme 7) led to synthetic
(+)-discodermolide (1), identical in all respects to the natural
Toward this end, fragment (+)-B possessing the MOM
group was prepared in three steps from the common
precursor (-)- CP (Scheme 5).
1
material (500-MHz H NMR and 125-MHz 13C NMR in
(8) Smith, A. B., III; Beauchamp, T. J.; Lamarche, M. J. Chem. Biol.
1996, 3, 287.
CD3CN, HRMS, optical rotation).
(9) Dauben, W. G.; Gerdes, J. M.; Bunce, R. A. J. Org. Chem. 1984,
49, 4293. For reviews on the use of high pressure in organic synthesis, see:
(a) Organic Synthesis at High Pressure; Matsumoto, K., Morrin Acheson,
R., Eds.; John Wiley: New York, 1991. (b) Matsumoto, K.; Sera, A.;
Uchida, T. Synthesis 1985, 1. (c) Matsumoto, K.; Sera, A. Synthesis 1985,
999.
In conclusion, we have developed a third-generation
synthesis for (+)-discodermolide which does not require
ultrahigh pressure to access the Wittig salt required for
construction of the C(8,9) disubstituted olefin. This approach,
(10) Model PG-200-HPC, Leco Corp., Bellefonte, PA.
(11) Jung, M. E.; Dervay, J. J. Am. Chem. Soc. 1991, 113, 224.
(12) An alternative explanation, kindly suggested by one reviewer, is
that smaller protecting groups selectively increase the rate of SN2 displace-
ment by PPh3 by increasing the population of the SN2 reactive conformer.
(13) For reference, our original retrosynthetic scheme can be found in
ref 6d.
(14) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
102, 3298. For our modified conditions, see ref 6d.
Org. Lett., Vol. 5, No. 23, 2003
4407

Scheme 7
we believe, now holds the promise of an efficient, scalable,
and practical synthetic route to this potentially important
antitumor agent.
thank Mark Burlingame, Kurt Sundermann, Simon Shaw,
and David Myles for helpful comments and suggestions
regarding this work.
Acknowledgment. Financial support at the University of
Pennsylvania was provided by the Department of the Army
through Grant No. DAMD 17-00-1-0404 and by a Sponsored
Research Agreement between the University of Pennsylvania
and Kosan Biosciences, Inc. A.B.S. is a member of the SAB
of Kosan Biosciences and holds equity in the company. We
Supporting Information Available: Representative pro-
cedures, spectral data, and analytical data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL035697I
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Org. Lett., Vol. 5, No. 23, 2003