Design, total synthesis, and evaluation of C(13)-C(14) cyclopropane analogues of (+)-discodermolide

Article abstract of DOI:10.1021/ol051691c

(Chemical Equation Presented) The design, total synthesis, and biological evaluation of two C(13)-C(14)-cyclopropyl analogues [(+)-1 and (+)-2] of (+)-discodermolide have been achieved. Key features of the syntheses include highly stereoselective, hydroxy

Full text of DOI:10.1021/ol051691c

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4613-4616
Design, Total Synthesis, and Evaluation
of C(13) C(14) Cyclopropane Analogues
−
of (+)-Discodermolide
Amos B. Smith, III,*,† Ming Xian,† and Fenghua Liu‡
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104, and Kosan Bioscience, Inc., 3832 Bay Center Place,
Hayward, California 94545
smithab@sas.upenn.edu
Received July 18, 2005
ABSTRACT
The design, total synthesis, and biological evaluation of two C(13)−C(14)-cyclopropyl analogues [(+)-1 and (+)-2] of (+)-discodermolide have
been achieved. Key features of the syntheses include highly stereoselective, hydroxyl-directed cyclopropanations of vinyl iodides and higher
order cuprate-mediated cross-coupling reactions between cyclopropyl iodides and alkyl iodides. Biological evaluation revealed that neither
orientation of the cyclopropyl methylene completely substitutes for the C(14) methyl found in (+)-discodermolide (3).
(+)-Discodermolide (3, Figure 1), a potent antitumor
polyketide natural product first isolated in 1990 by Gunasek-
era et al. at the Harbor Branch Oceanographic Institute from
extracts of the rare Caribbean marine sponge Discodermia
dissoluta,1 comprises a linear 24-membered polyketide
backbone punctuated by 13 stereogenic centers. The pioneer-
ing syntheses of both the (+)- and (-)-antipodes by Schreiber
and co-workers permitted assignment of the absolute stere-
ochemistry of 3.2
discodermolide displays not only significant tumor cell
growth inhibitory activity against a wide panel of human
cancel cell lines including paclitaxel-resistant cells5 but also
cytotoxic synergy with paclitaxel in a variety of cell lines6
as well as the induction of accelerated cell senescence.7 The
remarkable, wide-ranging biological activity, in conjunction
with both the challenging architecture and the growing
interest in providing useful quantities of (+)-discodermolide
for clinical development, has stimulated considerable chemi-
Discodermolide was initially reported to be a potent
immunosuppressive agent, both in vivo and in vitro;3 this
activity was subsequently recognized to be due to the potent
microtubule-stabilizing antimitotic activity.4 Importantly,
(2) (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J.
Am. Chem. Soc. 1993, 115, 12621-12622. (b) Hung, D. T.; Nerenberg, J.
B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080.
(3) (a) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.;
Gunasekera, S. P. Transplantation 1991, 52, 650-655. (b) Longley, R. E.;
Caddigan, D.; Harmody, D.; Gunasekera, M.; Gunasekera, S. P. Trans-
plantation 1991, 52, 656-661.
† University of Pennsylvania.
‡ Kosan Bioscience, Inc.
(1) (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G.
K. J. Org. Chem. 1990, 55, 4912-4915. Additions and corrections: J. Org.
Chem. 1991, 56, 1346. (b) Gunasekera, S. P.; Pomponi, S. A.; Longley, R.
E. U.S. Patent No. US5840750, Nov 24, 1998. (c) Gunasekera, S. P.; Paul,
G. K.; Longley, R. E.; Isbrucker, R. A.; Pomponi, S. A. J. Nat. Prod. 2002,
65, 1643-1648.
(4) (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, 243-250. (b) Hung, D. T.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996,
3, 287-293.
(5) Kowalski, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R.
E.; Day, B. W.; Hamel, E. Mol. Pharm. 1997, 52, 613-622.
10.1021/ol051691c CCC: $30.25
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syn-pentane nonbonded interactions along the carbon back-
bone appears to play a major role in defining the observed
turn conformation.12,13 From the SAR perspective, our initial
results indicate that congeners of discodermolide lacking the
C(14) methyl substituent, as in the (+)-14-normethyl con-
gener (4), demonstrate a general trend of relative inactivity
against the NCI/ADR multidrug-resistant cell line,11b despite
retaining nanomolar cytotoxicity against a wide variety of
drug-sensitive cell lines.11b The underlying nature of these
results involving the subtle interplay between structure and
function in the C(13)-C(14) region of discodermolide
continues to be the subject of active investigation in our
laboratory. In this paper, we disclose the design, total
synthesis, and biological evaluation of two cyclopropyl
congeners of discodermolide: (+)-13S,14S-cyclopropyldis-
codermolide (1) and (+)-13R,14R-cyclopropyldiscodermolide
(2).
Figure 1.
congener (4).
(+)-Discodermolide (3) and the (+)-14-normethyl
cal efforts resulting in seven total syntheses.2,8 Additional
endeavors have focused on the design and synthesis of
structurally simplified analogues of this potentially important
chemotherapeutic agent.9
Initial efforts focused on the direct cyclopropanation of
the known advanced olefin (+)-511a to install the cyclopro-
pane functionality at C(13)-C(14) as required for an
advanced recursor such as 8 (Scheme 1).
In parallel with our efforts to develop an ever more
practical total synthesis of discodermolide to provide material
for clinical development,10 we broadened our program in
collaboration with Kosan Bioscience, Inc., to include the
production of analogues designed to probe the structure-
activity relationship (SAR), as well as to define the critical
minimum structural element necessary for tumor cell growth
inhibition.11 In conjunction with this effort, we assigned the
solution conformation, similar to the solid-state structure, on
the basis of a combination of 1- and 2-D NMR techniques
and computational studies.12,13 A combination of A1,3 and
Scheme 1
(6) Martello, L. A.; McDiad, 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, 1978-1987.
(7) Klein, L. E.; Freeze, B. S.; Smith, A. B., III; Horwitz, S. B. Cell
Cycle 2005, 4, e124-e130.
(8) (a) 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, 8654-8664. (b) Paterson, I.; Florence, G. J.; Gerlach, K.;
Scott, J. P.; Sereing, N. J. Am. Chem. Soc. 2001, 123, 9535-9544. (c)
Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997,
62, 6098-6099. (d) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
7885-7892. (e) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Daeffler,
R.; Osmani, A.; Schreiner, K.; Seeger-Weibel, M.; Be´rod, B.; Schaer, K.;
Gamboni, R.; Chen, S.; Chen, W.; Jagoe, C. T.; Kinder, F. R.; Loo, M.;
Prasad, K.; Shieh, W.-C.; Wang, R.-M.; Waykole, L.; Xu, D. D.; Xue, S.
Org. Process Res. DeV. 2004, 8, 92-130. (f) Arefolov, A.; Panek, J. J.
Am. Chem. Soc. 2005, 127, 5596-5603.
(9) (a) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. Chem. Biol. 1994,
1, 67-71. (b) Choy, N.; Shin, Y.; Nguyen, P. Q.; Curran, D. P.;
Balachandran, R.; Madiraju, C.; Day, B. W. J. Med. Chem. 2003, 46, 2846-
2864.
(10) Recently, we reported a fourth-generation synthesis comprised of a
longest linear sequence of 17 steps and proceeded in 9% overall yield; see:
Smith, A. B., III; Freeze, B. S.; Xian, M.; Hirose, T. Org. Lett. 2005, 7,
1825-1828. Also see: Paterson, I.; Lyothier, I. Org. Lett. 2004, 6, 4933-
4936.
All attempts, however, employing a variety of cyclopro-
panation conditions provided only trace amounts of the
desired cyclopropanes, and then only as mixtures of diaster-
eomers. The related secondary alcohols (+)-6 and (+)-7 were
likewise unreactive.
Attention therefore quickly shifted to an alternative
strategy to construct 8. We reasoned that introduction of the
cyclopropane moiety prior to elaboration of the C(14)-C(15)
bond, employing intermediates such as (+)-9 and (+)-11
readily available in our laboratory, might be feasible. This
synthetic plan called for construction of cyclopropyl iodide
10 (Scheme 1).
Not entirely unexpectedly, direct cyclopropanation of
known vinyl iodide (+)-1111a again proved unsuccessful,
given the electron-deficient nature of the olefin. Literature14
precedent, however, suggested that an allylic hydroxyl group
might significantly augment the chance for successful
cyclopropanation. With this scenario in mind, removal of
the TBS group in (+)-11 and cyclopropanation employing
the conditions of Denmark and co-workers (Scheme 2)
(11) (a) Martello, L. A.; LaMarche, M. J.; He, L.; Beauchamp, T. J.;
Smith, A. B., III; Horwitz, S. B. Chem. Biol. 2001, 8, 843-855. (b) Smith,
A. B., III; Freeze, B. S.; LaMarche, M.; Hirose, T.; Brouard, I.; Xian, M.;
Sundermann, K. F.; Shaw, S. J.; Burlingame, M. A.; Horwitz, S. B.; Myles,
D. C. Org. Lett. 2005, 7, 315-318. (c) Smith, A. B., III; Freeze, B. S.;
LaMarche, M.; Hirose, T.; Brouard, I.; Xian, M.; Sundermann, K. F.; Shaw,
S. J.; Burlingame, M. A.; Horwitz, S. B.; Myles, D. C. Org. Lett. 2005, 7,
311-314. (d) Shaw, S. J.; Sundermann, K. F.; Burlingame, M. A.; Myles,
D. C.; Freeze, B. S.; Xian, M.; Brouard, I.; Smith, A. B., III. J. Am. Chem.
Soc. 2005, 127, 6532-6533.
(13) A similar, albeit not identical solution conformation of (+)-
discodermolide has been proposed by Synder et al.; see: Synder, J. P.;
Nevins, N.; Cicero, D. O. J. Am. Chem. Soc. 2000, 122, 724-725.
(12) Smith, A. B., III; LaMarche, M.; Falcone-Hindley, M. Org. Lett.
2001, 3, 695-698.
4614
Org. Lett., Vol. 7, No. 21, 2005

Scheme 2
Scheme 4
ence with (+)-16, we reasoned that (+)-17 should be
available from (+)-9 and the C(13,S)-C(14,S) cyclopropyl
iodide (+)-18. To introduce the requisite cyclopropane
configuration, vinyl iodide 19, bearing a hydroxymethyl
group at C(12), was selected as the precursor.
Toward this end, known aldehyde (+)-208a (Scheme 5)
Scheme 5
gratifyingly furnished a single cyclopropyl iodide (+)-12 in
71% yield.15,16 The stereochemical outcome was tentatively
assigned as 13R,14R, based on a likely reactive conformation
imposed by A1,3 interactions, in conjunction with the ste-
reogenicity at C(12). Protection of the secondary hydroxyl
as the MOM ether, followed by DDQ removal of the PMB
moiety and reprotection of the primary hydroxyl as the TBS
ether, furnished cyclopropyl iodide (-)-14 in excellent
overall yield. To verify the stereochemistry, camphanic ester
(-)-15 was prepared, crystallized, and analyzed by X-ray
diffraction (see ORTEP in Scheme 2).
With (+)-910 and (-)-14 in hand, we explored their union
initially by palladium(0)-catalyzed cross-coupling. To this
end, alkyl iodide (+)-9 was converted to the trialkyl boronate
by lithiation, followed by addition of B-methoxy-9-BBN.10
Treatment with the cyclopropyl iodide (-)-14, under the
modified Suzuki conditions developed by Charette,17 how-
ever, resulted in none of the desired product. Traditional
alkylation methods likewise proved unsuccessful; only
complex product mixtures were obtained. Ultimately, we
discovered that the 2-thienyl cyanocuprate derived from (-)-
1418 underwent clean alkylation to provide (+)-16 in 61%
yield (Scheme 3). Success with this transformation was
Scheme 3
was converted to epoxy alcohol (-)-21 according to a known
three-step sequence.19 Conversion to vinyl iodide (-)-22 then
entailed treatment with vinylmagnesium bromide in the
presence of CuI, followed by bis-TBS protection, oxidative-
(16) Other conditions (cf. Simmons-Smith reaction employing the
Furukawa or Shi variants) led either to no reaction or to low yields; see:
(a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53-
58. (b) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621-
8624.
(17) (a) Charette, A. B.; Giroux, A. J. Org. Chem. 1996, 61, 8718-
8719. (b) Charette, A. B.; De Freitas-Gil, R. P. Tetrahedron Lett. 1997, 38,
2809-2812.
(18) (a) Lipshutz, B. H. Synlett 1990, 119-128. (b) Lipshutz, B. H.;
Koerner, M.; Parker, D. V. Tetrahedron Lett. 1987, 28, 945-948. (c) Martin,
S. F.; Dwyer, M. P. Tetrahedron Lett. 1998, 39, 1521-1524.
critically dependent upon rigorous removal of oxygen to
avoid oxidative coupling products.
Having successfully constructed the C(13,S)-C(14,S) cy-
clopropyl fragment (+)-16, we turned to the synthesis of
the diastereomer (+)-17 (Scheme 4). Based on our experi-
(14) Piers, E.; Coish, P. D. Synthesis 1995, 47-55.
(15) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974-
6981.
Org. Lett., Vol. 7, No. 21, 2005
4615

cleavage of the terminal olefin, and Wittig reaction using
the Zhao protocol;20 (-)-22 was obtained in 38% yield (four
steps) with a Z/E selectivity of 10:1. Selective removal of
the primary TBS group next furnished (+)-23, which was
subjected to cyclopropanation to afford the desired product
(+)-24, albeit in low yield (∼15%).
step, one-pot protocol.23 The desired TBS ether (+)-28 was
then further elaborated to the corresponding Wittig salt (+)-
29 employing conditions similar to that reported in our
fourth-generation total synthesis of (+)-discodermolide.10
Wittig union with aldehyde (-)-30, removal of the secondary
PMB group, and installation of the carbamate at C(19),
followed by global deprotection completed construction of
(+)-13S,14S-cyclopropyldiscodermolide (1). In a similar
fashion, (+)-17 was advanced through the same synthetic
sequence to furnish (+)-13R,14R-cyclopropyldiscodermolide
(2) with a similar overall yield (see the Supporting Informa-
tion for experimental details).
Reasoning that the low efficiency was due to the PMB
group, vinyl iodide (-)-22 was converted to the correspond-
ing TBDPS ether (+)-25 via an efficient (90%) three-step
sequence (DDQ, TBDPSCl/imidazole, 1% HCl/EtOH). Hy-
droxyl-directed cyclopropanation, again employing the con-
ditions of Denmark et al.,15 provided (+)-26 as a single
diastereomer in 70% yield. To complete construction of
cyclopropyl iodide (+)-18, removal of the primary hydroxyl
group was now required. We immediately ruled out the
Barton-McCombie or related radical-based protocols given
the likely effect on the cyclopropyl iodide functionality. After
some effort, we were pleased to uncover a high-yielding,
two-step deoxygenation protocol entailing iodination (I2/Ph3P,
95% yield) followed by selective deiodination using a com-
bination of NaBH3CN and DMPU21 (95% yield). Attempts
to couple (+)-27 with (+)-9, however, employing the same
higher order cuprate as for (+)-16, proved unsuccessful.
Reasoning that the difference in the two systems was the
pattern of protecting groups, (+)-27 was converted to (+)-
18 and then subjected to the same cuprate-coupling protocol.
Cyclopropane (+)-17 was obtained in 63% yield.
Biological evaluation of (+)-1 and (+)-2 revealed the
general trend, as observed for 14-normethyldiscodermolide
analogues, of relative inactivity against the NCI/ADR
multidrug-resistant cell line (Table 1). However, the cyto-
Table 1. Cytotoxicity Observed for Analogues (+)-1 and
(+)-2
cytotoxicity IC50, nM
MCF-7
NCI/ADR
A549
SKOV-3
(+)-1
(+)-2
(+)-3
(+)-4
46
38
14
34
4000
4000
320
210
29
110
70
180
54
>1000
94
84
toxicities in the MCF-7 and SKOV-3 lines proved compa-
rable to that of (+)-14-normethyldiscodermolide (4), while
activity in the A549 cell line was somewhat reduced. Taken
together, these results suggest that the relative geometry of
the cyclopropane ring appears to have little impact on
bioactivity vis-a`-vis (+)-14-normethyldiscodermolide (4).
In summary, we have achieved the total synthesis of two
C(13)-C(14) cyclopropane analogues of discodermolide.
Highlights of the syntheses include highly stereoselective,
hydroxyl-directed cyclopropanations of vinyl iodide sub-
strates and efficient higher order cuprate-mediated cross-
coupling reactions between cyclopropyl iodides and alkyl
iodides. The cell growth inhibitory activities of (+)-1 and
(+)-2 imply that neither orientation of the cyclopropane ring
completely substitutes for the C(14) methyl found in (+)-
discodermolide, suggesting further that the bioactive con-
formation is governed, at least in part, by A1,3-strain.
Having assembled both diastereomeric cyclopropanes (+)-
16 and (+)-17, we were poised to complete the synthesis of
1 and 2 (Scheme 6). Reduction of the acetal in (+)-16 with
DIBAL furnished the corresponding primary alcohol, which
in turn was subjected to Dess-Martin periodinane oxidation22
and installation of the terminal diene via the Paterson two-
Scheme 6
Acknowledgment. Financial support was provided by the
National Institutes of Health (Institute of General Medical
Sciences) through Grant No. GM-29028.
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.
OL051691C
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4616
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