Expedient Total Syntheses of Pladienolide-Derived Spliceosome Modulators

Article abstract of DOI:10.1021/jacs.1c01135

Atom and step economical total syntheses of spliceosome modulating natural products pladienolides A and B are described. The strategic functionalization of an unsaturated macrolide precursor enabled the most concise syntheses of these natural products to date and provides convenient, flexible access to stereodefined macrolides to streamline medicinal chemistry explorations. Notably, this synthetic route does not depend on protecting group manipulations that traditionally define synthesis planning for polyhydroxylated natural products of polyketide origin. Its utility is further demonstrated by the enantioselective total synthesis of H3B-8800, a hitherto semisynthetic pladienolide-derived spliceosome modulator undergoing clinical trials for hematological malignancies.

Full text of DOI:10.1021/jacs.1c01135

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Expedient Total Syntheses of Pladienolide-Derived Spliceosome
Modulators
Derek Rhoades,* Arnold L. Rheingold, Bert W. O’Malley,* and Jin Wang*
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ABSTRACT: Atom and step economical total syntheses of spliceosome modulating natural products pladienolides A and B are
described. The strategic functionalization of an unsaturated macrolide precursor enabled the most concise syntheses of these natural
products to date and provides convenient, flexible access to stereodefined macrolides to streamline medicinal chemistry explorations.
Notably, this synthetic route does not depend on protecting group manipulations that traditionally define synthesis planning for
polyhydroxylated natural products of polyketide origin. Its utility is further demonstrated by the enantioselective total synthesis of
H3B-8800, a hitherto semisynthetic pladienolide-derived spliceosome modulator undergoing clinical trials for hematological
malignancies.
ladienolides A and B (1 and 2, Figure 1), isolated by Eisai
P
Co. in 2004 from Streptomyces platensis Mer-11107,1 are
among the most potent and structurally complex natural
products known to target the spliceosome, an intricate protein
assembly that catalyzes pre-messenger ribonucleic acid (pre-
mRNA) splicing.2 A breakthrough discovery showed that 2
potently modulates spliceosomal activity by targeting the
RNA-binding protein SF3B1.3 Intriguingly, 2 was recently
identified as a potent inhibitor of viral replication for SARS-
CoV-2 at concentrations nontoxic to human cells.4 Further-
more, semisynthetic pladienolide derivative H3B-8800 (3,
Figure 1)5 has progressed to clinical trials as a first-in-class
therapy for hematological malignancies.6 Clearly, the pladie-
nolide scaffold represents a privileged pharmacophore for
cancer, infection, and other diseases tractable via splicing
deregulation.
Despite their validated clinical promise and immense
therapeutic potential, synthetic access to the pladienolides
remains a laborious endeavor, and the reported semisynthesis
of clinical candidate 3 requires 16 chemical steps.5 In 2007,
Eisai Co. reported the first total syntheses of 1 and 2.7 Since
then, total syntheses of 2 were disclosed by three other
groups,8 in addition to efforts toward its fragments.9 However,
the tactics employed rely on a multitude of concession steps
(e.g., chiral auxiliaries, protecting groups)10 generally consid-
ered unavoidable in the synthesis of polyhydroxylated
polyketide natural products, resulting in lengthy overall routes
[longest linear sequence (LLS) of 18−22 steps (0.63%−2.9%
overall yields), 33−51 total steps] that impose considerable
barriers for analogue development.11
Figure 1. Molecular structures of pladienolide A (1), pladienolide B
(2), and H3B-8800 (3). The total syntheses of 1−3 were achieved
through unsaturated macrolide A via elaboration of fragments 4−10.
transformations of an unsaturated macrolide precursor (i.e., A,
Figure 1), our unusually simple strategy permits access to 1−3
in only seven or eight steps (LLS) from readily available
starting materials 4−10 and is expected to guide future
medicinal chemistry exploits.
The total syntheses of 1 and 2 are depicted in Scheme 1 and
began with the pursuit of macrocyclic vinyl iodides 25 and 26
Although complex polyketides such as 2 serve as valuable
templates for drug design, limited examples of protecting
group-free approaches have been disclosed to date, and new
strategies that limit their use represent a growing area of
interest in natural product synthesis.12 In this Communication,
we report concise total syntheses of 1−3 from building blocks
4−10 (Figure 1). By leveraging site- and stereoselective
Received: January 31, 2021
Published: March 23, 2021
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© 2021 American Chemical Society
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a
Scheme 1. Stereodivergent Syntheses of Macrolides 16−22 and Total Syntheses of Pladienolides A (1) and B (2)
a
Reagents and conditions: (a) 6 (1.0 equiv), 7 (2.0 equiv), 11 (0.05 equiv), K3PO4 (0.5 equiv), i-PrOH (2.0 equiv), H2O (5.0 equiv), THF, 22 →
60 °C, 24 h, 72%; (b) 9 (1.1 equiv), NaH (1.1 equiv); then n-BuLi (1.1 equiv); then 8 (1.0 equiv), THF, 0 → −78 → 0 °C, 2 h, 84%; (c) 12 (1.0
equiv), 13 (1.2 equiv), Pd(OAc)2 (0.15 equiv), AgOAc (1.5 equiv), DMF, 22 → 60 °C, 4 h, 88% (98% brsm); (d) 4 Å MS, PhMe, 125 °C, 15 min,
70% for 16, 65% for 17; (e) KEt3BH (1.0 equiv), THF, −78 °C, 30 min, 91% for 18, 88% for 19; (f) AD-mix-α or AD-mix-β, methanesulfonamide
(1.0 equiv), 1:1 t-BuOH/H2O, 0 °C, 48 h, 77% (85% brsm) for 20, 68% for 21, 81% for 22; (g) 23 (1.5 equiv), Et3N (3.0 equiv), DMAP (0.3
equiv), CH2Cl2, 0 → 22 °C, 1 h, 73%; (h) NIS (3.0 equiv), HFIP, 0 °C, 30 s, 98%; (i) Ac2O (1.2 equiv), Et3N (3.0 equiv), DMAP (0.2 equiv),
CH2Cl2, 0 °C, 30 min, 90%; (j) 4 (1.0 equiv), 5 (2.0 equiv), 27 (0.07 equiv), CH2Cl2, 50 °C, 6 h, 64% [(E):(Z) = 7:1, 56% overall for 28]; (k) 29
(3.5 equiv), Oxone (4.1 equiv), K2CO3 (12 equiv), MeCN/pH 9.3 buffer, 0 °C, 2 h, 76%; (l) PIDA (1.1 equiv), TEMPO (0.1 equiv), CH2Cl2, 22
°C, 1 h, 80%; (m) 32 (5.0 equiv), NaOMe (5.0 equiv), THF, −78 → −50 °C, 2 h, 85%; (n) CuCl (0.15 equiv), 34 (0.15 equiv), NaOt-Bu (0.6
equiv), B2pin2 (1.2 equiv), MeOH (2.1 equiv), THF, 22 °C, 12 h, 66%; (o) 25 or 26 (1.0 equiv), 35 (1.2 equiv), Pd(dppf)Cl2·CH2Cl2 (0.1 equiv),
K3PO4 (3.0 equiv), THF/H2O (3:1), 22 °C, 3 h; then 36 (0.5 equiv), 22 °C, 1 h, 76% for 1, 87% for 2. AD = asymmetric dihydroxylation; Ad =
adamantyl; brsm = based on recovered starting material; Cy = cyclohexyl; DIBAL = diisobutylaluminum hydride; DMAP = 4-
dimethylaminopyridine; DMF = dimethylformamide; dppf = 1,1′-bis(diphenylphosphino)ferrocene; HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol;
MS = molecular sieves; NIS = N-iodosuccinimide; Oxone = 2KHSO5·KHSO4·K2SO4; PIDA = phenyliodine(III) diacetate; pin = pinacolato;
TEMPO = (2,2,6,6-tetramethylpiperidin-1-yl)oxyl; TFA = trifluoroacetate; THF = tetrahydrofuran.
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(Scheme 1A). Thus, aldehyde 613 was subjected to Krische’s
crotylation14 with 3-buten-2-yl acetate (7) and Ir catalyst 1115
to furnish alcohol 12 on a multigram scale in good yield with
excellent levels of diastereo- and enantiocontrol (72% yield,
20:1 dr, 98% ee).16 To access its coupling partner, allylic
bromide 817 was reacted with the bis-enolate of tert-butyl
acetoacetate (9) (NaH; then n-BuLi; then 8) to provide (Z)-
iodoolefin 13 in 84% yield. Construction of the intended (E,Z)
diene was achieved via Mizoroki−Heck coupling between
alcohol 12 and vinyl iodide 13 under conditions similar to
those reported by Jeffery18 [Pd(OAc)2, AgOAc] to afford β-
ketoesters 14 and 15 in excellent yield as a mixture of olefinic
isomers (88% yield, 98% brsm, 14:15 = 7:3, 62% overall for
14).19 This reaction was unproductive in the absence of
silver(I) salts (inset Table 1, Scheme 1A), indicating that a
cationic palladium center is critical for its success.20 To induce
macrolactonization, β-ketoesters 14 and 15 were heated to
reflux (PhMe, 4 Å MS, 125 °C, 15 min) to afford rigid β-
ketolactones 16 (70% yield) and 17 (65% yield) via the
intramolecular trapping of an in situ derived acylketene.21
While this transformation is commonly performed on small
scale with 1,3-dioxinones,22 our carefully tuned reaction
conditions (inset Table 2, Scheme 1A) have proven effective
on the gram scale. Next, stereoselective ketone reduction of 16
to form the desired secondary alcohol at C3 was investigated.
After screening a number of reducing agents (inset Table 3,
Scheme 1A), potassium triethylborohydride was identified (1.0
equiv, THF, −78 °C) as the optimal reagent,23 providing
alcohol 18 in 91% yield on gram scale as a single
diastereomer.24 Similarly, macrocyclic ketone 17 was cleanly
reduced to alcohol 19 in 88% yield as a single diastereomer.24
With macrocyclic dienes 18 and 19 in hand, we examined the
key transformation: a regio- and diastereoselective dihydrox-
ylation of the C6−C7 (Z)-trisubstituted olefin. Gratifyingly,
treatment of 18 with AD-mix-β under standard Sharpless
conditions afforded the desired triol 20 in 77% yield (85%
brsm) with complete regioselectivity and good diastereose-
lectivity (10:1 dr). The absolute configuration of 20 was
determined via X-ray crystallographic analysis (Scheme 1A).25
Conversely, the use of AD-mix-α gave C6−C7 diastereomer 21
in 68% yield with complete regioselectivity, albeit modest
diastereoselectivity (3:1 dr). In contrast to the catalyst-
controlled reaction outcomes observed with (E,Z) diene 18,
(Z,Z) diene 19 provided only triol 22 in either instance (i.e.,
AD-mix-α or AD-mix-β) in 81% yield. The absolute
configuration of 22 was confirmed by X-ray crystallographic
analysis of its C7-derived p-bromobenzoyl ester 24.26 The C10
angular methyl group likely induces a more sterically hindered
α face of the ring system, resulting in this striking example of
macrocyclic stereocontrol.27 To our knowledge, these are the
first examples of site- and stereoselective dihydroxylations of
macrocyclic conjugated dienes. Its displayed stereodivergence
permits entry to the natural product core and unexplored
chemical space (i.e., 20 and 21), obviates protecting groups,
and may find general use in the synthesis of complex
macrolides. Subsequent silicon-for-iodine exchange28 (NIS,
HFIP, 98% yield) provided vinyl iodide 25, a key intermediate
for accessing targets 1−3. Regioselective acetylation of the
allylic alcohol (Ac2O, 90% yield) afforded macrolide 26 in
seven steps (LLS) from building blocks 6−9. This sequence
proceeds reliably and offers unique opportunities for medicinal
chemistry efforts via stereodefined macrolides 16−22.
a
Scheme 2. Total Synthesis of H3B-8800 (3)
a
Reagents and conditions: (a) Cu(OAc)2 (0.02 equiv), 37 (0.02
equiv), PMHS (4.0 equiv), t-BuOH (4.0 equiv), PhMe, 0 → 22 °C, 4
h, 95% (94% ee); (b) 3.0 M HCl in MeOH, 60 °C, 4 h, 92%; (c)
LiAlH4 (1.0 equiv), THF, 0 °C, 30 min, 90%; (d) 41 (2.0 equiv), n-
Bu3P (2.0 equiv), THF, 0 °C, 2 h, 51%; (e) 43 (1.0 equiv), py (5.0
equiv), CH2Cl2, 0 → 22 °C, 6 h, 82%; (f) n-Bu2SnO (1.1 equiv), 4 Å
MS, PhMe, 100 °C, 12 h; then 45 (2.5 equiv), Et3N (3.4 equiv), 80
°C, 36 h, 81%; (g) 44 (3.0 equiv), 46 (1.0 equiv), Pd(PPh3)4 (0.1
equiv), Et3N (3.0 equiv), PhH, 80 °C, 4 h; then 36 (0.5 equiv), H2O
(12 equiv), 22 °C, 1 h, 96% [(E,E):(Z,E) = 5:1, 80% overall for 3].
PMHS = polymethylhydrosiloxane; py = pyridine; tol = tolyl.
The synthesis of vinyl boronate 35 is depicted in Scheme 1B.
Cross metathesis of terminal olefins 429 and 530 under the
influence of Grubbs second generation catalyst (27) provided
dihydroxy olefin 28 [64% yield, (E):(Z) = 7:1, 56% overall for
28]. Exposure of diol 28 to Shi’s epoxidation conditions31 (29,
Oxone, K2CO3) produced epoxy diol 30 stereoselectively in
76% yield. Chemoselective oxidation of the primary alcohol
(PIDA, TEMPO, 80% yield) generated the corresponding
aldehyde 31.32 It was envisioned that vinyl boronate 35 could
be obtained from 31 through alkyne 33 via application of the
Ohira−Bestmann modification of the Seyferth−Gilbert homo-
logation.33 To avoid epimerization at C16, we adapted
successful reports from Nicolaou and Fu
̈
rstner,34 utilizing
preactivated Ohira−Bestmann reagent 3235 at low temperature
(NaOMe, THF, −78 → −50 °C), which pleasingly provided
alkyne 33 in 85% yield without hydroxy group protection.
Alkyne borylcupration catalyzed by an N-heterocyclic carbene
(NHC)-ligated Cu(I) complex (34, CuCl, B2pin2, 66%
yield)36 afforded vinyl boronate 35 in five steps (LLS) from
building blocks 4 and 5.
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Accession Codes
Suzuki coupling of vinyl iodides 25 and 26 with vinyl
boronate 35 was selected due to its mild conditions and
demonstrated success in related systems (Scheme 1C).37
Accordingly, treatment of 25 or 26 with 35, K3PO4, and
catalytic Pd(dppf)Cl2·CH2Cl2 in aqueous THF, followed by
workup with the metal-chelating ammonium pyrrolidinedithio-
carbamate (36),38 cleanly afforded pladienolides A (1) and B
(2) in 76% and 87% yield, respectively (seven and eight steps
LLS, 14.0% overall for 1, 14.4% overall for 2).
CCDC 2046514−2046515 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Finally, we applied our strategy to the enantioselective total
synthesis of clinical candidate H3B-8800 (3, Scheme 2). Thus,
(E)-α,β-unsaturated nitrile 1039 was subjected to Yun’s
asymmetric conjugate reduction protocol [Cu(OAc)2, 37,
PMHS], a robust method that produced nitrile 38 in excellent
yield and enantiomeric excess (95% yield, 94% ee) on a
multigram scale.40 Nitrile solvolysis with methanolic HCl
provided ester 39 in 92% yield, and subsequent reduction with
LiAlH4 produced the corresponding alcohol 40 (90% yield).
The synthesis of allylic pyridine 44 was not straightforward,
and eventually a modified two-step Grieco−Sharpless elimi-
nation was adopted.41 Thus, alcohol 40 was treated with 2-
nitrophenyl selenocyanate (41) and n-Bu3P to provide selenide
42 (51% yield). Exposure of 42 to oxaziridine 43, a mild
oxidant that tolerates aromatic amines and, in contrast to
H2O2, does not catalyze selenide decomposition,42 afforded
volatile allylic pyridine 44 (82% yield). Meanwhile, versatile
triol 25 was regioselectively acylated with n-Bu2SnO, and the in
situ formed stannylene acetal was treated with carbamoyl
chloride salt 45 and Et3N to afford carbamate 46 (81%
yield).43 Attempts to synthesize 3 via Suzuki coupling similar
to our strategy shown in Scheme 1C were thwarted by the
recalcitrance of 44 to form a stable vinyl boronate through
cross metathesis. Therefore, a direct Mizoroki−Heck coupling
of fragments 44 and 46 was pursued (inset Table 4, Scheme
2). Treatment of these fragments with Pd(PPh3)4 (Et3N, PhH,
80 °C) formed H3B-8800 (3) in excellent yield [96% yield,
(E,E):(Z,E) = 5:1, 80% overall for 3]. Remarkably, the strategy
depicted in Scheme 2 for the total synthesis of 3 (eight steps
LLS from building blocks 6−10, 12.0% overall yield) is
fundamentally distinct, yet compares favorably to the semi-
synthetic approach reported by Eisai Co. (12 steps LLS, 4.2%
overall yield).5
Derek Rhoades − Department of Pharmacology and Chemical
Biology and Center for Drug Discovery, Baylor College of
Medicine, Houston, Texas 77030, United States;
orcid.org/0000-0002-9536-424X; Email: drhoades@
bcm.edu
Bert W. O’Malley − Department of Molecular and Cellular
Biology and Center for Drug Discovery, Baylor College of
Medicine, Houston, Texas 77030, United States;
Email: berto@bcm.edu
Jin Wang − Department of Pharmacology and Chemical
Biology, Department of Molecular and Cellular Biology, and
Center for Drug Discovery, Baylor College of Medicine,
Houston, Texas 77030, United States; orcid.org/0000-
0003-3625-7919; Email: wangj@bcm.edu
Author
Arnold L. Rheingold − Department of Chemistry and
Biochemistry, University of California San Diego, La Jolla,
California 92093, United States; orcid.org/0000-0003-
4472-8127
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01135
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare the following competing financial
interest(s): B.W.O and J.W. are the co-founders of CoActigon,
Inc., and J.W. is the founder of Chemical Biology Probes, LLC.
ACKNOWLEDGMENTS
This manuscript is dedicated to Professor K. C. Nicolaou for
his commitment to excellence in organic synthesis. We thank
■
In summary, a simple approach for synthesizing natural and
designed pladienolides resulted in the most concise total
syntheses of 1 and 2 to date, in addition to the first total
synthesis of 3. This also represents a rare case of protecting
group-free total syntheses of polyhydroxylated polyketide
natural products. The implementation of stereoselective
transformations utilizing catalyst and substrate control,
including a site-selective dihydroxylation of macrocyclic dienes,
enabled a direct, flexible strategy for realizing this fascinating
class of spliceosome modulating natural products with
unprecedented efficiency.
Professor László Kurti (Rice University), Professor Brian J.
̈
Myers (Ohio Northern University), and Drs. Ruocheng Yu,
Ruofan Li, and Pengxi Chen (Rice University) for helpful
discussions. We thank Drs. Lawrence B. Alemany and Quinn
Kleerekoper (Rice University) for NMR spectroscopic
assistance and Dr. Ian Riddington (University of Texas at
Austin) for mass spectrometric assistance. This work was
supported by the American Cancer Society (133266-PF-19-
007-01-CDD, postdoctoral fellowship to D.R.) and Baylor
College of Medicine (seed support to J.W.).
ASSOCIATED CONTENT
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■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01135.
Experimental procedures and characterization data for
all compounds (PDF)
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