Efficient syntheses of 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi- dictyostatin, two potent new microtubule-stabilizing agents

Article abstract of DOI:10.3762/bjoc.7.161

The dictyostatins are powerful microtubule-stabilizing agents that have shown antiproliferative activity against a variety of human cancer cell lines. Two highly active analogs of dictyostatin, 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, were prepared by a new streamlined total synthesis route. Three complete carbon fragments were prepared to achieve maximum convergency. These were coupled by a Horner-Wadsworth-Emmons reaction sequence and an esterification. A late stage Nozaki-Hiyama-Kishi reaction was then used to form the 22-membered macrolide. The stereoselectivity of this reaction depended on the configurations of the nearby stereocenter at C6.

Full text of DOI:10.3762/bjoc.7.161

Efficient syntheses of 25,26-dihydrodictyostatin and
25,26-dihydro-6-epi-dictyostatin, two potent new
microtubule-stabilizing agents
María Jiménez1, Wei Zhu1, Andreas Vogt2, Billy W. Day1,2,3
and Dennis P. Curran*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1372–1378.
1Department of Chemistry, University of Pittsburgh, 219 Parkman
Avenue, Pittsburgh, PA 15260 USA, 2Department of Computational
and Systems Biology, and Drug Discovery Institute, University of
Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA and
3Department of Pharmaceutical Sciences, School of Pharmacy, 3501
Terrace Street, University of Pittsburgh, Pittsburgh, PA 15261 USA
doi:10.3762/bjoc.7.161
Received: 30 June 2011
Accepted: 12 September 2011
Published: 05 October 2011
Associate Editor: M. S. Sherburn
Email:
María Jiménez - m_delsol@yahoo.com; Wei Zhu -
zhuweisioc@hotmail.com; Andreas Vogt - avogt@pitt.edu;
Billy W. Day - bday@pitt.edu; Dennis P. Curran* - curran@pitt.edu
© 2011 Jiménez et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
anticancer agents; dictyostatin; microtubules; NHK
Abstract
The dictyostatins are powerful microtubule-stabilizing agents that have shown antiproliferative activity against a variety of human
cancer cell lines. Two highly active analogs of dictyostatin, 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, were
prepared by a new streamlined total synthesis route. Three complete carbon fragments were prepared to achieve maximum conver-
gency. These were coupled by a Horner–Wadsworth–Emmons reaction sequence and an esterification. A late stage
Nozaki–Hiyama–Kishi reaction was then used to form the 22-membered macrolide. The stereoselectivity of this reaction depended
on the configurations of the nearby stereocenter at C6.
Introduction
The discovery of compounds that function as anticancer agents taxanes, epothilones, and discodermolides, among others [3,4].
by altering the dynamics of microtubules continues to be an Dictyostatin (1a) is an exceptionally potent microtubule-stabi-
important goal in medicinal chemistry. Such agents can force lizing agent that has shown antiproliferative activity in a variety
the cell to exit mitosis aberrantly, leading to apoptosis [1,2]. of human cancer cell lines in the low nanomolar range. Isolated
Important classes of microtubule-stabilizing agents include first in 1994 by Pettit and coworkers [5,6], its complete stereo-
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structure was proposed by Paterson and Wright in 2004 [7]. The routes. We recently reported a streamlined synthesis of dictyo-
structure assignment phase was finalized in 2004 when total statin (1a) and used it to prepare two new analogs: 16-des-
syntheses by Paterson and our group confirmed the assignment methyl-25,26-dihydrodictyostatin (2a) and its C6 epimer 2b
[8,9].
(Figure 1) [29]. The terminal C25–C26 alkene of the C23–C26
diene is a synthetic liability, so it was welcome news when the
The two synthetic samples of dictyostatin provided exciting bio- biological data revealed that the analogs lacking this alkene
logical results [10], which in turn spurred structure–activity retained significant activity. Prior results suggested that most if
studies in both Paterson’s group [11-17] and ours [18-23]. not all of the lost activity could be regained by reinstating the
These studies, founded on total synthesis, were largely comple- missing C16-methyl group [11,19].
mentary and together provide a solid if still evolving [24]
picture of dictyostatin SAR. Phillips [25], Ramachandran [26] We thus set out to synthesize and test two new analogs of
and Gennari [27] have also developed efficient synthetic routes dictyostatin: 25,26-dihydrodictyostatin (3a) and 25,26-dihydro-
to the natural product or fully functionalized analogs.
6-epi-dictyostatin (3b) (Figure 1). The later parts of this syn-
thesis have been briefly communicated in a recent paper whose
Based on the biological profile of over 30 analogs of dictyo- primary focus was biological evaluation [30]. Indeed, 3a and 3b
statin synthesized in Pittsburgh, we selected 6-epi-dictyostatin prove to be promising anticancer agents with in vitro and
(1b) for scale-up and in vivo testing [28]. Indeed, 1b proved to cellular testing data superior to those of the 16-desmethyl
be more effective than paclitaxel in treating mice bearing analogs 2a and 2b, and roughly comparable to those of dictyo-
human breast cancer xenografts. Encouraged by these results, statin (1a) and 6-epi-dictyostatin (1b). Here we report the full
we have pursued both new analogs and improved synthetic details of the synthesis of 3a and 3b.
Figure 1: Structures of dictyostatin and selected analogs varying at C6, C16, and C25–C26.
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Figure 2: Retrosynthetic analysis for 3a and 3b.
Results and Discussion
Figure 2 shows key aspects of the retrosynthetic analysis to
make analogs 3a and 3b, which follows after the successful
streamlined route to make 1a [29]. For high convergence, the
analogs were dissected strategically into three complete frag-
ments called top (8, C18–C26), middle (7, C10–C17), and
bottom (6a,b, C1–C9), respectively. The top 8 and middle 7
fragments were first combined through an established
Horner–Wadsworth–Emmons (HWE) reaction sequence to give
5 [8,9]. The bottom fragment 6a or 6b was then attached to the
top/middle fragment 5 through an esterification reaction.
Finally, an intramolecular Nozaki–Hiyama–Kishi (NHK) reac-
tion [31,32] of compounds 4a and 4b was used to form the
macrolactone at C9–C10.
Scheme 1: Synthesis of top fragment 8 (C18–C26).
The shared middle fragment 7 was conveniently made by the
pathway shown in Scheme 2, which is a streamlined version of
prior routes in the 16-desmethyl series [14]. (However, some
material 7 was also made by an extension of a prior middle
fragment route, as described in Supporting Information File 1,
Scheme S1). Myers alkylation [17] of commercially available
pseudoephedrine amide 10 and alkyl iodide 11 afforded amide
12 in 95% yield. The chiral auxiliary was then removed with
BH3·NH3 (92%) [34], then the resulting primary alcohol was
oxidized under Swern conditions to provide aldehyde 13 (86%).
A Marshall palladium-catalyzed addition reaction [35] between
We have previously described in detail the synthesis of the top
fragment 8, which is shared by both analogs 3a,b [29,33]. As
summarized in Scheme 1, this fragment was made on multi-
gram scale in seven steps starting from the well-known inter-
mediate 9.
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aldehyde 13 and mesylate 14 [36] gave alcohol 15 in 77% yield. zene sulfonylhydrazide (NBSH) [38] to the cis-vinyl iodide 19
Interestingly, the Marshall reaction works well even with mesy- in 94% yield. The primary TBS group of 19 was selectively
lates containing a terminal alkyne; reaction of 13 with 16 removed with HF·pyridine in pyridine/THF to afford a primary
provided 17 in 72% yield.
alcohol (97%), which was then oxidized to aldehyde 7 with the
aid of the Dess–Martin reagent (85%). Overall, the synthesis of
the middle fragment was accomplished in 10 steps in over 40%
yield starting from commercially available pseudoephedrine
amide 10.
The syntheses of the bottom fragments 6a and 6b were achieved
by applying the previously reported cross-metathesis reactions
of readily available 20a,b with (2Z,4E)-methyl hexa-2,4-
dienoate followed by silylation to provide 21a,b [39]. These
dienoates were converted to the carboxylic acids by using
TMSOK [40], followed by transformation into the acid chlo-
ride 6a and 6b with the Ghosez reagent [41] (Scheme 3). This
acid chloride was then used directly in the subsequent esterifi-
cation reaction.
Scheme 3: Synthesis of bottom fragments 6a,b (C1–C9).
With the top, middle and bottom fragments in hand, we turned
to the initial fragment couplings as summarized in Scheme 4.
Fragments 7 and 8 were first combined by a proven sequence
starting with an HWE reaction mediated by Ba(OH)2 [42] to
provide enone 22 in good yield (80%). This enone was then
treated with Stryker’s reagent [43] to selectively reduce the
conjugated alkene, followed directly by removal of the PMB
group with DDQ. This sequence afforded alcohol 23 in 76%
yield over two steps. A stereoselective 1,3-syn reduction was
Scheme 2: Synthesis of middle fragment 7 (C10–C17).
The TIPS and primary TBS groups of 15 were simultaneously then performed under Prasad conditions [44] to give the target
cleaved under basic conditions with TBAF [37] (88%), fol- diol (90%) as a single isomer. The stereochemistry at C19 was
lowed by protection of both primary and secondary hydroxy confirmed by NMR analysis of the corresponding acetonide
groups with TBSOTf to afford 18 in 96% yield. The terminal [45] (Supporting Information File 1). This diol was then selec-
alkyne of 18 was then converted to the iodoalkyne with BuLi tively protected at the less hindered hydroxy group (C19), with
and I2 (92%), followed by diimide reduction with o-nitroben- TBSOTf at −78 °C [46], to provide 5 in 86% yield.
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Beilstein J. Org. Chem. 2011, 7, 1372–1378.
Scheme 4: Coupling of the top and middle fragments.
The synthetic route to 3a and 3b continues in Scheme 5 with the 71% yield (90% BRSM) after careful flash chromatography.
coupling of alcohol 5 with the bottom fragments 6a and 6b. The Selective deprotection of purified 24b with HF·pyridine
hydroxy group in 5 was deprotonated with NaHMDS followed afforded the respective primary alcohol 25b in 84% yield.
by addition of the crude reaction mixture containing acid chlo-
ride 6a or 6b. The coupled products 24a and 24b proved diffi- Next, treatment of each primary alcohol 25a,b with
cult to purify by flash chromatography. In the C6 (S)-series, 24b Dess–Martin reagent provided aldehydes 4a and 4b in compa-
was successfully isolated in 57% yield (82% BRSM). In the C6 rable yields (95% and 94%). Initial NHK reactions were
(R)-series, the crude coupled product 24a could not be sep- performed in THF with 15 equiv of CrCl2, 0.2 equiv of
arated from 5, and was immediately subjected to HF·pyridine NiCl2(dppf) and 15 equiv of 4,4'-di-tert-butyl-2,2'-dipyridine
deprotection. The resulting primary alcohol 25a was isolated in [47]. The target product 26b for the C6 (S)-series was obtained
Scheme 5: Coupling with the bottom fragment and end game.
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Beilstein J. Org. Chem. 2011, 7, 1372–1378.
in respectable yield (42%). Only the target C9-β epimer was
detected in the 1H NMR spectrum of the crude product, though
we cannot rule out the presence of small amounts of the
α-epimer. However, in the C6 (R)-series, the C9 β/α ratio was
only about 75/25 and the isolated yield of pure β-epimer 26a
was only 22%. After surveying several other conditions and
solvents, we found that treatment of 4a with 15 equiv of CrCl2
and 0.2 equiv of NiCl2 in DMF/THF [48] improved the β/α
ratio to about 85/15 and improved the isolated yield of pure 26a
to 48%. Again, formation of acetonides confirmed the stereo-
chemical assignment (Supporting Information File 1) [45].
Finally, treatment of 26a and 26b with HF·pyridine afforded the
desired analogs 3a and 3b in good yields (86% and 82%, res-
pectively). These compounds were fully characterized by the
usual spectroscopic means.
Supporting Information
Supporting Information File 1
Experimental details, characterization data and copies of
NMR spectra of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-161-S1.pdf]
Acknowledgements
We thank the National Institutes of Health, grants CA78039 and
HD053287, for funding this work.
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