A synthetic entry to pladienolide B and FD-895

Article abstract of DOI:10.1016/j.bmcl.2007.06.094

Presented within are syntheses of the pladienolide B and FD-895 side-chains, as well as models of the essential ring-closing metathesis and Stille coupling that will be used to complete their total syntheses. Several analogs of the pladienolide B side-cha

Full text of DOI:10.1016/j.bmcl.2007.06.094

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5159–5164
A synthetic entry to pladienolide B and FD-895
Alexander L. Mandel, Brian D. Jones, James J. La Clair and Michael D. Burkart*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Received 10 June 2007; revised 21 June 2007; accepted 28 June 2007
Available online 7 July 2007
Abstract—Presented within are syntheses of the pladienolide B and FD-895 side-chains, as well as models of the essential ring-clos-
ing metathesis and Stille coupling that will be used to complete their total syntheses. Several analogs of the pladienolide B side-chain
were also prepared in order to evaluate the scope of the methodology and to create a library of structures that could be used for
stereochemical and SAR analyses.
Ó 2007 Elsevier Ltd. All rights reserved.
The pladienolides (1a–g) are a set of highly bioactive
macrocyclic polyketides isolated from an Okinawan
strain of Streptomyces platensis (Fig. 1).1 FD-895 (1h)
was reported in 1994 from an isolate of Streptomyces
hygroscopicus.2
This family of macrolides (1a–h) displays potent anti-
proliferative and tumor suppressive activity when
assayed in both cell culture and xenograft models.1a,c,2
Several members of the family, including pladienolide
B (1b), inhibited tumor cell growth at low nanomolar
concentrations. Subsequent cell cycle studies indicate
that 1b blocks cell growth in both the G1 and the G2/
M phase, suggesting a unique mode of action. In addi-
tion, pladienolide B (1b) has been shown to deliver
potent tumor regression and inhibition of mouse xenografts.
At the beginning of our studies, only the two-dimen-
Figure 1. Structures of the pladienolides (1a–g) and FD-895 (1h). The
stereochemical assignments of pladienolide B (1b) and D (1d)3 were
recently determined by NMR and synthetic methods. Stereochemist-
ries of other members of the family (1a, 1c, 1e–g) and FD-895 (1h) are
expected to follow from 1b and 1d, but have yet to be confirmed.
sional structures of 1a–h were known. This combined
with lack of access to the compounds themselves or their
producer strains meant that we would have to determine
the stereochemistry de novo.4 Given recent advances in
NMR techniques and the use of libraries to elucidate
the three-dimensional configuration of natural prod-
ucts,5 we felt that this study would provide an ideal plat-
form to use chemical synthesis in concert with more
traditional methods to determine the stereochemistry
of these macrolides.6 Moreover, the required general
approaches to the stereochemistry of 1b and 1h are syn-
thetic strategies that allow access to many analogs for
future research on these promising lead compounds. In
parallel, the methods developed in this research serve
as a prelude to the total synthesis of the pladienolides
and FD-895.7
Our general retrosynthetic analysis (Scheme 1) of the
family began by visualizing a convergent union at the
diene by a Stille coupling of side-chain 2 to core 3.
Stannane 2 was ideal because conditions for tin insertion
do not cause side reactions with the C18–C19 epoxide.8
Keywords: Macrolides; Natural products; Antitumor agents; Meta-
thesis; Analogs.
*
Corresponding author. Tel.: +1 858 534 5673; fax: +1 858 822
2182; e-mail: mburkart@ucsd.edu
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.094

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A. L. Mandel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5159–5164
Scheme 1. Retrosynthetic analysis of the pladienolides (1a–g). A convergent strategy was developed to fuse the side-chain to macrolide core 3. As
depicted, the route developed from four fragments: aldehyde 6, sulfone 7, carbinol 9, and carboxylic acid 10.
Stannane 2 could then be derived from alcohol 4 that
would result from epoxidation of olefin 5 using a suit-
able method.9 Olefin 5 would follow naturally from a
Julia–Kociensky reaction of aldehyde 6 and sulfone
7.10 Macrolide 3 would then be derived from a ring-clos-
ing metathesis of 8. In turn, 8 could be prepared by cou-
pling of alcohol 9 and carboxylic acid 10. This two-step
ester formation—RCM has precedent in our laboratory
and elsewhere.11 As this article was being prepared, Ko-
take indeed showed that these disconnections can be
used to assemble pladienolide B (1b) and D (1d).3
Aldehydes 18a and 18b were accessed through the Crim-
mins chiral aldol protocol.16 This methodology is un-
iquely suited to divergent approaches because reagent
control directs the stereochemical outcome with a high
diastereomeric excess. Starting from thiazolidinethione
15, treatment with TiCl4, (À)-sparteine, and N-meth-
ylpyrrolidinone afforded the Evans syn-aldol product
16a, but by using TiCl4 and Hunig’s base without
¨
NMP the ‘non-Evans’ syn-aldol adduct 16b was the
product. Both substances were protected with TBSOTf
to give 17a and 17b.17 The chiral auxiliary was removed
by treatment with DIBAL-H in toluene to offer alde-
hydes 18a and 18b in yields of 85% and 72%,
respectively.18
With a synthetic plan in hand, we turned to evaluate the
complexity of the proposed synthetic endeavor. Without
simplification, the total synthesis of all stereoisomers of
1
1b would be a wasteful enterprise. By examining the H
NMR data for pladienolide B (1b), the C18–C19 epox-
ide was assigned as a trans-epoxide based on presence
A total of four Julia olefinations, 14a + 18a, 14a + 18b,
14b + 18a, and 14b + 18b, were conducted to produce
olefins 19a–d with yields ranging from 37% to 68% rela-
tive to the limiting aldehyde (Scheme 2). Conditions
were refined as the process was repeated. While the addi-
tion of the aldehyde to the sulfone anion was conducted
at low temperature, the reaction mixture required warm-
ing to room temperature immediately after addition was
complete, otherwise aldehydes 18a–b were returned and
the sulfones 14a–b decomposed. In addition, commer-
cially available anhydrous glyme contained sufficient
water (ꢀ10–50 ppm) to hinder the reaction, resulting
in basic decomposition of aldehydes 18a–b. This compli-
cation was in part responsible for the rather unpredict-
able yields of the couplings presented in Scheme 2.
2
of a 2.4 Hz coupling constant in CDCl3 . We also as-
signed a syn-configuration at C20–C21 by the presence
of a 4.1 Hz coupling constant for 1h in CDCl3 using
J-value comparisons to literature examples.12 Addition-
ally, the C10–C11 diad had a 9.8 Hz coupling constant,
which was indicative of anti stereochemistry at that po-
sition. Given these simplifications, we decided that we
should prepare the four possible side-chain isomers of
1b. The fragments were anticipated to be useful for com-
parison with degradation products of 1b. They could
also be used in the preparation of an NMR database.13
The synthesis of the pladienolide B side-chain began
with the preparation of sulfone 14a from commercially
available R-2-methyl-1,4-butanediol (11a) (Scheme 2).
Mono-protection of 11a with TBDPSCl gave 12a in
60% yield.14 After purification, the material was pro-
At this stage, olefins 19a–d could be epoxidized using the
Shi protocol but subsequent conditions required to re-
move the BOM protecting group were incompatible
with the epoxide. Acidic conditions were too harsh,
and catalytic hydrogenation induced 5-exo-tet cycliza-
tion.19 Interestingly, when a mixture of diastereomeric
epoxides (i.e., 20a and its 4S,5S diastereomer; prepared
by oxidation with mCPBA) was hydrogenated, one dia-
stereomer cyclized readily while the other remained
mostly intact over 30 min of treatment with Pd on C un-
der an H2 atmosphere.
tected with BOMCl and Hunig’s base, and the crude
¨
material was treated with TBAF to afford alcohol 13a.
Mitsunobu displacement with 1H-phenyltetrazolethiol,
followed by oxidation with ammonium molybdate and
hydrogen peroxide, produced 14a in 79% yield for the
two steps.15 Sulfone 14b was prepared by repeating the
procedure on the commercially available S-isomer 11b.

A. L. Mandel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5159–5164
5161
Scheme 2. Divergent synthesis of side-chain diastereomers. Reagents and conditions: (a) TBDPSCl, DBU, DMF, À50 °C; (b) i—BOMCl, DIPEA,
CH2Cl2; ii—TBAF, wet THF; (c) i—1H-phenyltetrazolethiol, DIAD, PPh3, CH2Cl2, 0 °C to rt; ii—(NH4)6Mo7O24Æ4H2O, H2O2, EtOH, 0 °C to rt;
(d) TiCl4, DIPEA, CH2Cl2, À78 °C; (e) TiCl4, (À)-sparteine, NMP, CH2Cl2, À78 °C; (f) TBSOTf, DIPEA, CH2Cl2; (g) DIBAL-H, toluene, À78 °C;
(h) KHMDS, DME, À78 °C, then add 18a warm to rt; (i) KHMDS, DME, À78 °C, then add 18b warm to rt; (j) i—Li wire, naphthalene, THF;
ii—22, oxone, K2CO3, Bu4NHSO4, CH3CN, H2O, borax–EDTA buffer, 0 °C; (k) 35% H2SiF6, CH3CN, rt, PT = 1H-phenyltetrazole.
The solution was to cleave the BOM ether prior to epox-
idation. The stereoselectivities and yields of the epoxida-
tions were unaffected by the presence of a free alcohol at
the terminal position. Therefore, lithium naphthelenide
was chosen for this deprotection since it would not re-
duce the olefin. Performing the reaction at room temper-
ature resulted in yields of 54–82%.20 The resulting
alcohols were then epoxidized using the method of
Shi.9 While not air-sensitive, the Shi epoxidation de-
mands precise conditions. When carried out at room
temperature, yields were below 25% as most of the inter-
mediate oxirane from 22 decomposed prior to epoxida-
tion. At 0 °C, yields of product increased to between
40% and 55%. In the end, slow addition of oxone and
pH control were shown to stabilize the oxirane and in-
crease the output of epoxide.
results were poor for 20b and 20d, which were recovered
with 74% and 50% de, respectively. In addition, the yields
of 20a–d were modest at best, though the unreacted olefin
could be recovered and re-reacted after purification.
Cleavage of the TBS ether without side-reactivity
proved difficult. When treated with 1.25 equivalents of
fluoride ion from 35% aqueous fluorosilicic acid21 in
acetonitrile, epoxides 20a–d were deprotected and cyc-
lized to the corresponding furans 21a–d in seconds.
TBAF worked over several days, but also resulted in
the partial formation of cyclized furan. While this obser-
vation was not desired for synthetic progress, the intro-
duction of the furan ring allowed each stereoisomer to
be verified by NOE studies.22 These furans would also
be useful to compare with fragments obtained from an
authentic sample of 1b.
The Shi epoxidation was very sensitive to the stereochem-
istry already installed in the olefin. When installed anti to
the adjacent C20 stereocenter as in 20a and 20c, the Shi
epoxidation delivered a high diastereoselection as indi-
cated by 91% and 81% de, respectively. However, the
1
Unfortunately, direct correlation of H or 13C chemical
shifts of 20a–d also failed to produce a convincing argu-
ment to conclusively assign the stereochemistry of the
pladienolide B (1b) side-chain. No trend existed between

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A. L. Mandel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5159–5164
protons and carbons from C15–C23 in 20a–d when com-
pared to 1a–h.
Next, model studies were conducted to demonstrate the
application of the olefin metathesis—Stille relay. The
approach began by crotylboration of aldehyde 2625
using the procedure of Brown.26 Not knowing the abso-
lute stereochemistry, we synthesized both anti stereoiso-
mers 9a and 9b in modest yields. Subsequent
esterification with 8-nonenoic acid afforded 27a and
27b. Ring-closing metathesis with the second generation
Grubbs catalyst delivered lactone 28a and 28b in 84%
and 74% yield, respectively. NMR confirmed that the
olefin geometry was E and there was no detectable
Z-isomer. This reactivity profile of RCM on 12-mem-
bered rings is nicely in accord with the synthesis of
mycolactone carried out in our laboratory.11 While not
yet optimized, the Stille coupling between stannane 25
and 28a does provide 29a in 21% yield when run at
10 mg scale. Coupling 25 with 28b afforded a better yield
of 29b at 40%. The reaction seems to stall, but additional
catalyst does not move the reaction forward. It is inter-
esting to note that these reactions contain an allylic acyl
group, but no acetyl elimination occurs. In fact, it is pos-
sible to recover all of the iodide (28a or 28b) from the
reaction, although stannane 25 is lost. Subsequent TBS
deprotection with HFÆpyridine afforded pladienolide B
analogs 30a and 30b. Comparing the NMR spectra of
the analogs and authentic 1b showed that neither are
similar to pladienolide B (1b). This would have made
the library approach a dubious method to determine
the stereochemistry.
Without a sample of 1b, we turned to investigate the via-
bility of our overall synthetic scheme (Scheme 1). Our
studies began with a model using 20c, which our
NMR analysis determined was the most likely match
to 1b side-chain stereochemistry. Oxidation of 20c with
Dess–Martin periodinane buffered by solid NaHCO3
afforded aldehyde 23 without cyclization to a tetrahy-
drofuran or lactol. Subsequent homologation using
iodoform and chromium(II) chloride furnished vinyl io-
dide 24 with no detectable Z-isomer.23 Iodide 24 was
then converted to vinyl stannane 25 using a palladium
catalyzed tin/halogen exchange.24 Stannane 25 turned
out to have the correct stereochemistry for the synthon
to pladienolide B (1b) (Scheme 3).
Because of the similarity of the pladienolides and FD-
895, an effort has been launched to adapt the strategy
for 1b to synthesize 1h, its cytotoxic cousin. As outlined
in Scheme 4, all of the stereocenters in the FD-895 side-
chain have been synthesized. The route begins by con-
version of Crimmins aldol product 16a to its corre-
sponding Weinreb amide 31.16 Subsequent methylation
to 32 followed by reduction afforded aldehyde 33 in
80% yield over the two steps. 33 was then homologated
to allylic alcohol 34 in two steps by Horner–Wads-
worth–Emmons olefination and subsequent reduction
with DIBAL-H. After screening a variety of conditions,
we found that the Sharpless epoxidation provided the
most effective reaction, delivering 35 in 82% yield and
82% de. From there oxidation to 36 with IBX27 pro-
ceeded in quantitative yield, and contrasted modest
yields from the Parikh–Doering28 and Dess–Martin29
methods. Finally, crotylboration afforded 37, albeit with
low efficiency.
While not yet optimized, this route now provides the
first access to the FD-895 side-chain. Efforts are now
underway to complete the synthesis of the pladienolides
(1a–g) and FD-895 (1h). We have illustrated through
model studies the use of stannane 25 as it applies to
the total synthesis of pladienolide B (1b). While not opti-
mized, we have also shown how to construct the FD-895
side-chain, and it could be used in a similar manner to
complete the synthesis of 1h. Efforts have been under-
way to install the C3, C6, and C7 stereocenters in 10.
While Kotake has already demonstrated a route to 10,
their use of the Sharpless dihydroxylation to install the
C6–C7 diad failed to provide good diastereoselection.3
Scheme 3. Establishing the synthetic strategy through model studies.
Reagents and conditions: (a) Dess–Martin periodinane, NaHCO3,
CH2Cl2, rt; (b) CHI3, CrCl2, THF, dioxane (1:6), rt; (c) (Bu3Sn)2,
Pd(PPh3)2Cl2, THF, 50 °C; (d) dIpc2BOMe, KOtBu, nBuLi, trans-2-
butene, BF3ÆEt2O, Et2O, THF, À78 °C; (e) 8-octenoic acid, EDC,
DMAP, DIPEA, THF, rt; (f) Grubbs second generation catalyst,
CH2Cl2, reflux; (g) Pd(MeCN)2Cl2, DMF, rt; (h) HFÆpyridine, rt; (i)
lIpc2BOMe, tBuOK, nBuLi, trans-2-butene, BF3ÆEt2O, Et2O, THF,
À78 °C.

A. L. Mandel et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5159–5164
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4. Although repeated requests were made for authentic
samples in 2005, we have yet to obtain samples of 1a–g
or their producer organisms. We were able through
additional efforts to obtain samples of FD-895 (1h).
5. (a) Takayasu, Y.; Tsuchiya, K.; Aoyama, T.; Sukenaga,
Y. J. Antibiot. 2002, 54, 1111; (b) Small, P. L. C.; George,
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Scheme 4. Synthesis of the FD-895 side-chain. (a) MeNHOMÆHCl,
imidazole, CH2Cl2, rt; (b) NaH, MeI, DMF, THF, 0 °C; (c) DIBAL-
H, CH2Cl2, À78 °C; (d) triethylphosphonoacetate, NaH, THF, 0 °C;
(e) DIBAL-H, CH2Cl2; (f) (À)-DET, Ti(OiPr)4, tBuOOH, CH2Cl2,
À10 °C; (g) IBX, EtOAc, reflux; (h) dIpc2BOMe, tBuOK, nBuLi, cis-2-
butene, BF3ÆEt2O, THF.
Comparable observations were also obtained in our pre-
liminary efforts to 10. We are currently pursuing a route
to 10 using the chiral pool to circumvent this problem.
9. Wang, Z.; Tu, Y.; Frohn, M.; Zhang, J.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224.
10. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
Acknowledgments
We thank Xuemei Huang, John Wright, and Anthony
Mrse for assistance with NMR studies and Yongxuan
Su for mass spectral analysis. We also thank Thomas
J. Baiga and Joseph Noel of the Salk Institute for the
generous use of their NMR facilities. We would also like
to thank David Slade and Michael T. Crimmins at the
University of North Carolina for providing us with de-
tailed protocols for preparing 15. We gratefully
acknowledge the Department of Chemistry and Bio-
chemistry, University of California, San Diego, and
the American Cancer Society RSG-06- 011-01-CDD
for funding.
11. (a) Alexander, M. D.; Fontaine, S. D.; La Clair, J. J.;
Dipasquale, A. G.; Rheingold, A. L.; Burkart, M. D.
Chem. Commun. 2006, 4602; (b) Chou, C. Y.; Hou, D. R.
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12. Examples of stereochemical homologs are depicted in: (a)
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Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.06.094.
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