Total Synthesis of the Spliceosome Modulator Pladienolide B via Asymmetric Alcohol-Mediated syn- and anti-Diastereoselective Carbonyl Crotylation

Article abstract of DOI:10.1002/anie.202103845

The potent spliceosome modulator pladienolide B, which bears 10 stereogenic centers, is prepared in 10 steps (LLS). Asymmetric alcohol-mediated carbonyl crotylations catalyzed by ruthenium and iridium that occur with syn- and anti-diastereoselectivity, re

Full text of DOI:10.1002/anie.202103845

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Total Synthesis Hot Paper
Total Synthesis of the Spliceosome Modulator Pladienolide B via
Asymmetric Alcohol-Mediated syn- and anti-Diastereoselective
Carbonyl Crotylation
Minjin Yoo and Michael J. Krische*
Abstract: The potent spliceosome modulator pladienolide B,
which bears 10 stereogenic centers, is prepared in 10 steps
(
LLS). Asymmetric alcohol-mediated carbonyl crotylations
catalyzed by ruthenium and iridium that occur with syn- and
anti-diastereoselectivity, respectively, were used to form the
C20-C21 and C10-C11 CÀC bonds.
T
he pladienolides are a family of 12-membered macrolides
isolated in 2004 by researchers at Eisai from the culture broth
of Mer-11107, an engineered strain of Streptomyces platensis
[
1]
(
Figure 1). Earlier in 1994, a related polyketide, FD-895,
was isolated from the Okinawan soil bacteria Streptomyces
[
2]
hygroscopicus A-9561. The pladienolides were identified in
a cell-based reporter assay for hypoxia-induced gene expres-
[
1a]
sion controlled by human VEGF promoter and were shown
to inhibit proliferation of multiple drug resistant human
[3]
cancer cells at low nanomolar IC50 values. In 2007,
researchers at Eisai determined that the pladienolides bind
[
4,5]
splicing factor 3b (SF3b),
inducing cell cycle arrest at both
G1 and G2/M phase. In 2018, researchers at the Max Planck
Institute for Biophysical Chemistry and H3 Biomedicine,
Inc., obtained a crystal structure of SF3b bound by pladie-
[6]
nolide B, providing precise insight into its mode of action.
Eisai launched two phase I clinical trials of pladienolide
[7]
analogue E7107, which were discontinued due to side-
effects involving vision loss. Interest in anti-cancer drugs that
target the spliceosome persisted, and in 2017 the pladienolide
derivative H3B-8800 developed by Eisai and H3 Biomed-
icine, Inc. was granted orphan drug status by the FDA for
treatment of myelogenous and chronic myelomonocytic
[
8]
leukemia.
Although pladienolide and its derivatives show great
promise vis-ꢀ-vis cancer treatment, concise routes to com-
pounds of this class remain elusive. To date, four total
syntheses of pladienolide B (and its C7 epimer) and have
Figure 1. Pladienolides A–G, FD-895 and related clinical candidates
E7107 and H3B-8800. LLS=Longest Linear Sequence. TS=Total
Steps.
[
9]
been reported, along with the total synthesis of FD-895 (and
[
2b,10]
its C17 epimer).
6–22 steps (LLS; Figure 1). The manufacturing routes to the
clinical candidate E7107 involves a 6 step (LLS) semi-
These routes range in length between
1
from synthetic pladienolide D prepared using Kotakeꢀs
[
11a]
[9a]
[11b]
synthesis from Pladienolide D
and, according to the
route,
giving a total of 28 steps (LLS).
Finally, the
patent literature, H3B-8800 is prepared in 8 steps (LLS)
syntheses of pladienolide and FD-895 substructures also have
been disclosed. As documented in the review literature,
[
12]
[13]
catalytic methods for the direct enantioselective conversion
of lower alcohols to higher alcohols developed in our
laboratory have the potential to streamline type 1 polyketide
total synthesis by circumventing discrete alcohol-to-carbonyl
redox reactions and operations associated with the installa-
[
*] M. Yoo, Prof. M. J. Krische
University of Texas at Austin, Department of Chemistry
105 E 24th St. (A5300), Austin, TX 78712-1167 (USA)
E-mail: mkrische@mail.utexas.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202103845.
[14]
tion and removal of chiral auxiliaries and protecting groups.
To enable more concise entry to the pladienolides and related
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clinical candidates, the total synthesis of pladienolide B, the
most potent member of this class, was undertaken. Here,
using asymmetric alcohol-mediated carbonyl crotylations
Thus, a total of three CÀC bonds are formed via asymmetric
alcohol-mediated carbonyl allylation (C16-C17) and crotyla-
tion (C20-C21 and C10-C11), the latter with both syn- and
anti-diastereoselectivity.
[
15]
[16]
catalyzed by ruthenium
and iridium
that occur with
syn- and anti-diastereoselectivity, we report the total synthesis
of pladienolide B in 10 steps (LLS).
The synthesis of Fragment A begins with the kinetic
resolution of the doubly allylic alcohol 1, which is prepared
[
21]
Our retrosynthesis of pladienolide B maximizes conver-
gency for optimal step-economy (Scheme 1). Specifically, it
was anticipated pladienolide B could be formed via Suzuki
cross-coupling of Fragments A and B, as similar Stille cross-
couplings were used to in the total syntheses of pladienolide B
from methacrolein and the vinyl Grignard reagent, using
[
22]
the Sharpless asymmetric epoxidation (Scheme 2). Exclu-
sive epoxidation of the more substituted alkene was observed,
providing glycidol 2 in highly enantiomerically enriched form.
The unprotected epoxide was exposed to the dienolate
derived from tert-butyl acetoacetate followed by acetic
anhydride to form the product of epoxide ring opening 3 in
[
9c]
[9d]
reported by Chandrasekhar and Maier,
and Burkartꢀs
[2b]
synthesis of FD-895. Also, a related Suzuki coupling was
used in the total synthesis of 6-deoxypladienolide D reported
[
23]
86% yield.
Compound exists as a dynamic mixture of
[
9e]
by Keaney.
Fragment A was envisioned to arise from
hydroxy ketone 3 and, predominantly, the 5-membered lactol.
If the free hydroxyl is present at C7 (rather than the acetate),
a six-membered lactol is formed that does not participate in
the subsequent ketone reduction (not shown). Ruthenium-
catalyzed transfer hydrogenation of 3 mediated by formic acid
enables access to the b-hydroxy ester 4 as a 4:1 mixture of
[
17]
Fragments C and D via Yamaguchi esterification followed
by Grubbsꢀ ring-closing metathesis, as practiced in all prior
total syntheses of the pladienolides and FD-895 with the
exception of Maierꢀs synthesis. Fragment C is accessible via
dienolate-mediated epoxide ring opening. A related ring-
opening of an epoxide lacking the C6 methyl group was used
by Ghosh in the total syntheses of pladienolide B. Frag-
ment D is accessible via asymmetric iridium-catalyzed anti-
crotylation of alcohol 10 using a-methyl allyl acetate 11 as the
crotyl donor. Fragment B could be obtained from Frag-
ments E and F through a sequence involving Grubbsꢀ cross-
[9d]
[
24]
diastereomers. Acidic cleavage of the tert-butyl ester gave
the carboxylic acid, which was isolated as a single stereoiso-
mer. Treatment of the hydroxy acid with tert-butyldimethyl-
silyl chloride results in silylation of both the C1 carboxylic
acid and C3 hydroxyl groups. Addition of methanolic K CO
[
9b]
[
16]
2
3
to the reaction mixture results in concomitant cleavage of the
[19]
[25]
metathesis, Shi epoxidation
and Cu-catalyzed alkyne
silyl ester and the C7 acetate to furnish the C6-C7 diol,
hydroboration. Fragment E is accessible via asymmetric
ruthenium-catalyzed syn-crotylation of n-propanol using
Fragment C. Under Yamaguchi conditions, Fragment C and
Fragment D undergo esterification to form compound 5
[
15]
[17,26]
butadiene as the crotyl donor. Finally, fragment F can be
prepared via asymmetric iridium-catalyzed reductive allyla-
tion of the acetylenic aldehyde 12 mediated by 2-propanol
despite the presence of the unprotected C7 hydroxyl.
The
formation of Fragment D is accomplished via asymmetric
iridium-catalyzed alcohol-mediated carbonyl anti-crotyla-
[
18]
[16]
using allyl acetate as pronucleophile, followed by propargyl
tion
of the allylic alcohol 10, which is prepared via
[20]
substitution with inversion using the Normant reagent.
zirconium-catalyzed carboalumination of propargyl alcohol
Scheme 1. Retrosynthetic analysis of pladienolide b: maximizing convergency for step-economy.
2
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[
a]
Scheme 2. Synthesis of Fragment A. [a] Yields are of material isolated by silica gel chromatography. Enantioselectivities were determined by
chiral stationary phase HPLC analysis. See Supporting Information for further experimental details.
[
27]
(
Scheme 3). Finally, ring-closing metathesis of 5 followed
excess of Fragment E was required to suppress homo-
coupling of Fragment F. Excess Fragment E could be
recovered in 46% yield and recycled. The 1,5-acetylenic
olefin 14 readily underwent highly chemo- and diastereose-
by acetylation of the C7 hydroxyl with acidic workup provides
Fragment A. It is worth noting that although allyl acetates are
well-established participants in diverse metathetic processes,
attempted metathesis of the C7 allyl acetates 6 and 7 resulted
in low conversion accompanied by formation of the unantici-
pated CÀC bond cleavage side-products, methyl ketones 8
[
19]
[29]
lective Shi epoxidation
and alkyne hydroboration
to
deliver Fragment B. Finally, Suzuki cross-coupling under
[
9e]
conditions reported by Keaney provided pladienolide B in
a total of 10 steps (LLS), the shortest route to any
[
28]
and 9.
[
30]
With Fragment A in hand, the preparation of Fragment B,
and therefrom, the total synthesis of pladienolide B could be
achieved (Scheme 4). The formation of Fragment B begins
with conversion of propargyl alcohol 13 to Fragment F via
acylation with methyl chloroformate followed by methyl-
substitution of the mixed carbonate using the Normant
reagent. Propargyl alcohol 13 is prepared via asymmetric
iridium-catalyzed reductive coupling of acetylenic aldehyde
2 and allyl acetate mediated by 2-propanol (Scheme 3).
Although a slight erosion in enantiomeric enrichment was
observed in each step of the conversion of propargyl alcohol
pladienolide family member reported to date.
In conclusion, by maximizing convergency and exploiting
diverse metal-mediated methods for CÀC coupling, a concise
total synthesis of the spliceosome modulator pladienolide B
was achieved. Among the 10 stereogenic centers found in
pladienolide B, half are formed using catalytic asymmetric
alcohol-mediated carbonyl additions. Specifically, enantio-
selective alcohol-mediated carbonyl crotylations catalyzed by
ruthenium and iridium that occur with syn- and anti-
diastereoselectivity, respectively, were used to forge the
C20-C21 and C10-C11 CÀC bonds. Additionally, an enantio-
[
20]
[18]
1
1
3 to Fragment F, the latter could be formed in 91%
selective asymmetric iridium-catalyzed reductive coupling of
acetylenic aldehyde 12 with allyl acetate mediated by
2-propanol was used to form forge the C16ÀC17 bond. It is
enantiomeric excess. Cross-metathesis of Fragments E and
F catalyzed by the second-generation Grubbs catalyst was
followed by concomitant fluoride-mediated removal of the
silyl protecting groups to provide compound 15, which was
isolated as a single stereoisomer. In the cross-metathesis, an
our hope that the present synthetic route will broaden access
to pladienolide and related clinical candidates for cancer
chemotherapy that target the spliceosome.
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Scheme 3. Catalytic enantioselective anti- and syn-crotylations of allylic alcohol 10 and propanol to form Fragments D and E, respectively, and the
catalytic enantioselective allylation of acetylenic aldehyde 12 mediated by 2-propanol to form propargyl alcohol 13. [a] Yields are of material
isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information
for further experimental details.
[
a]
Scheme 4. Synthesis of Fragment B and total synthesis of pladienolide B. Yields are of material isolated by silica gel chromatography.
Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information for further experimental details.
4
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Acknowledgements
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Conflict of interest
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[
[
[
26] Related esterifications en route to pladienolide B have involved
compounds in which the C7 hydroxyl is protected (see refer-
ences [9b] and [9c]).
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method for enantioselective iridium-catalyzed anti-crotylation
(https://doi.org/10.1021/jacs.1c01135). As their aldehyde starting
material is not commercially available and requires a 2-step
synthesis, their routes to pladienolide B and H3B-8800 are each
10 steps (10 LLS; 25 TS and 10 LLS; 21 TS, respectively), making
their longest linear sequence to pladienolide B equivalent in
length to our own.
1
999, 1, 1123 – 1125.
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total syntheses of pladienolide B and H3B-8800 using our
[
[
2
Manuscript received: March 17, 2021
Accepted manuscript online: April 1, 2021
Version of record online: && &&, &&&&
6
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Communications
Total Synthesis
The potent spliceosome modulator pla-
dienolide B, which bears 10 stereogenic
centers, is prepared in 10 steps (LLS).
Asymmetric alcohol-mediated carbonyl
crotylations catalyzed by ruthenium and
iridium that occur with syn- and anti-dia-
stereoselectivity, respectively, were used
to form the C20-C21 and C10-C11 CÀC
M. Yoo, M. J. Krische*
&&&& — &&&&
Total Synthesis of the Spliceosome
Modulator Pladienolide B via Asymmetric
Alcohol-Mediated syn- and anti-
Diastereoselective Carbonyl Crotylation
bonds.
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