Total Synthesis of Meayamycin and O-Acyl Analogues

Article abstract of DOI:10.1021/acs.orglett.0c03308

A short, scalable total synthesis of meayamycin is described by an approach that entails a longest linear sequence of 12 steps (22 steps overall) from commercially available chiral pool materials (ethyl l-lactate, BocNH-Thr-OH, and d-ribose) and introduces the most straightforward preparation of the right-hand subunit detailed to date. The use of the approach in the divergent synthesis of a representative series of O-acyl analogues is exemplified.

Full text of DOI:10.1021/acs.orglett.0c03308

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Letter
Total Synthesis of Meayamycin and O‑Acyl Analogues
Christopher Gartshore, Shinji Tadano, Prem B. Chanda, Anindya Sarkar, Naidu S. Chowdari,
Sanjeev Gangwar, Qian Zhang, Gregory D. Vite, Jelena Momirov, and Dale L. Boger*
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ABSTRACT: A short, scalable total synthesis of meayamycin is described by an
approach that entails a longest linear sequence of 12 steps (22 steps overall) from
commercially available chiral pool materials (ethyl L-lactate, BocNH-Thr-OH,
and D-ribose) and introduces the most straightforward preparation of the right-
hand subunit detailed to date. The use of the approach in the divergent synthesis
of a representative series of O-acyl analogues is exemplified.
R901464, isolated by Fujisawa Pharmaceutical Company
1
Ffrom Pseudomonas sp. no. 2663, is the first member of a
growing class of potent antitumor antibiotics that includes the
spliceostatins2 and thailanstatins.3 Initial total syntheses of
FR901464 confirmed the assigned structure and relative
stereochemistry within each noncontiguous subunit and
permitted assignment of the absolute stereochemistry. These
were disclosed first by Jacobsen and co-workers (40 steps),4
utilizing a powerful asymmetric hetero Diels−Alder reaction to
form the two tetrahydropyrans, and shortly thereafter by
Kitahara (41 steps),5 enlisting the chiral pool to access the two
tetrahydropyrans. Subsequent total syntheses by Koide6 (28
steps) and later by Ghosh7 (22 steps) provided more expedient
assembly of the two highly substituted and functionalized
tetrahydropyran rings.8 In addition to demonstrating the
critical role of the epoxide,4 Jacobsen defined the instability of
FR901464 and further showed that removal of the right-hand
Figure 1. Target structures, key intermediates, and chiral pool starting
subunit tertiary alcohol not only abrogated this instability, but
also enhanced biological potency.4 In an extension of these
observations, Koide later found that replacement of the tertiary
alcohol with a methyl group (vs H)4 not only avoided the
rapid compound degradation but also improved potency as
much as 100-fold.6 Such synthetic analogues, named the
meayamycins (Figure 1), represented an early contribution to
the growing number of natural products and analogues in the
class accessed by total synthesis.4−13 In 2007, Yoshida
disclosed that FR901464 binds a subunit of the spliceosome
disrupting conversion of pre-mRNA to mRNA.14 Shortly
thereafter, Koide established that the meayamycins act in an
analogous manner.15 The mechanism by which spliceosome
inhibition is achieved has been shown to be effective in
selectively controlling both cancer cell proliferation and
metastasis with selected members exhibiting efficacious in
vivo antitumor activity.16
materials.
In a program that explores natural product analogues as
therapeutics17 or components of antibody−drug conjugates,
we targeted the potent meayamycins with the objective of
developing a short, scalable total synthesis. After several
iterations on the approach, each subunit used to assemble 1
herein is derived from chiral pool starting materials with all 8
chiral centers introduced or controlled by chirality found in
Received: October 3, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03308
© XXXX American Chemical Society
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inexpensive commercial starting materials (Figure 1). The
approach provided 1 in a longest linear sequence of 12 steps
(22 steps overall),18 complementary to an improved approach
recently disclosed by Koide (11 longest linear sequence, 24
steps overall).19
Scheme 2
The most challenging subunit is the right-hand tetrahy-
dropyran 7, bearing three of the stereocenters and the essential
epoxide. Intermediate 7 was accessed in four steps from known
aldehyde 2,20 itself prepared from D-ribose in three steps
(Scheme 1). Grignard addition of 2-methylallylmagnesium
Scheme 1
three steps from BocNH-L-Thr (1 equiv of MeONHMe, 1.2
equiv of EDCI, 1.2 equiv of HOBt, 2 equiv of (iPr2)NEt,
CH2Cl2, 23 °C, 22 h; 0.2 equiv of PPTS, 10 equiv of
MeC(OMe)2Me, THF, reflux, 18 h, 85−88% for two steps),
including the reported DIBAL-H reduction of the Weinreb
amide (2 equiv DIBAL-H, CH2Cl2, −78 °C, 3 h).22 A Z-
selective modified Wadsworth−Horner−Emmons reaction of
1023 with aldehyde 9 provided the α,β-unsaturated ester 11
(86% for two steps, 4.6:1 Z/E) where preferential generation
of the Z-isomer facilitates but may not be required for an
ensuing lactonization. Acid-catalyzed N,O-ketal cleavage
effected with 10-camphorsulfonic acid (CSA) and in situ
lactonization (0.04 equiv of CSA, MeOH, 23 °C, 74%)
provided 12 in a single step. The subsequent alkene reduction
of 12 proceeded with lower diastereoselectivity (6:1 vs 10:1)
than reported and provided 13 contaminated with lactone
ethanolysis product in our hands under conditions reported (2
mol % of PtO2, H2, EtOH, 23 °C, 2 h, 98%).6 For our
purposes, this was reoptimized to provide 13 in high yield
(quantitative) and excellent diastereoselectivity (10:1, THF >
EtOH, iPrOH, EtOAc) through use of THF as solvent (23 °C,
15 h) without competitive solvent lactone ring opening.
More substantial optimizations were required for imple-
mentation of the Koide6 two-step conversion of 13 to 15.
Significant amounts of double addition product were observed
when the reaction of allylmagnesium chloride (1.9 equiv) with
13 was conducted as detailed, likely accounting for the lower
overall conversion of 13 to 15 than reported herein. Although
a reduction in the amount of allylmagnesium chloride (1.3−1.6
equiv) attenuated the overaddition, increasing amounts of
recovered starting 13 offset any improvement in this selectivity.
However, by lowering the reaction temperature (−98 vs −78
°C) and adjusting the reaction solvent (2-MeTHF vs THF),
14 was obtained in excellent yield (85−87%) with minimal
over addition (6%) or recovered starting lactone (7%). Final
diastereoselective reduction of the lactol provided 15 in
improved conversions (49%) provided triethylsilane (10
equiv) and trifluoroethanol (TFE, 8 equiv) were also added
at −78 °C and stirred for 10 min prior to addition of BF3−
OEt2 (4 equiv). The entire sequence and latter reaction were
conducted on gram scales, completing the synthesis of the
central subunit (24% overall, eight steps from BocNH-L-Thr).
The left-hand subunit was assembled by several approaches,
two of which are illustrated in Scheme 3 that were employed
depending on the target structure (e.g., 1 vs O-acyl analogues).
For meayamycin (1) itself, we first implemented a straightfor-
chloride (2 equiv) to aldehyde 2 (THF, 0−25 °C, 5 h, 61−
65%) provided 3 as an inconsequential diastereomeric mixture.
Dess−Martin periodinane (DMP) oxidation (1.5 equiv DMP,
CH2Cl2, 0 °C, 3 h, 78−88%) and subsequent acid-catalyzed
acetonide deprotection, alkene isomerization, and 6-endo-trig
cyclization of the distal alcohol provided cyclic ketone 6. Initial
optimization of this reaction found that treatment of 3 with
pyridinium p-toluenesulfonate (PPTS) in MeOH (0.2 equiv
PPTS, 60 °C, 4 h) afforded principally the corresponding diol
and subsequent addition of aqueous 1 M HCl (MeOH/H2O
9:1, 60 °C, 2−4 h) completed the isomerization of the double
bond into conjugation with the ketone to provide 5. Without
purification, treatment of crude 5, already containing
substantial amounts of 6, with Amberlyst-15 (CHCl3, 80 °C,
12 h) completed the distal alkoxy conjugate addition to
provide 6 (76% overall). Conversion of 6 to 7 was achieved by
diastereoselective epoxide introduction (73%) following
Koide’s protocol.21 In addition to the concise nature of the
synthesis of 7 (four to five steps, 32% from 2; seven to eight
steps, 20% from D-ribose), the approach avoids the generation
of diastereomers and provides full control of the absolute
stereochemistry.
The central tetrahydropyran, bearing four chiral centers, was
accessed by an approach that relied on the chiral pool to set
the absolute stereochemistry (Scheme 2). Although inspired by
Koide’s original synthesis,6 it is substantially shorter (5 vs 8
steps) and enlists further optimized protocols for overlapping
steps. Analogous improvements were independently reported
by Koide earlier this year for synthesis of intermediate lactone
12.19 Additional subtle improvements are also highlighted
herein for the original conversion6 of 12 to 15.18 Central to the
synthesis of 15 was use of the known starting material 9,22 the
BocNH-L-Thr derived variant of Garner’s aldehyde, available in
B
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Scheme 3
Scheme 4
ward approach starting with the commercially available
optically active alcohol 16. Its acetal protection with ethyl
vinyl ether (96%), alkyne carboxylation with Boc2O, and acetal
deprotection without intermediate purification of 18 (80−
89%, 2 steps) provided 19. Alcohol acetylation (82%) followed
by stereoselective reduction of the alkyne to the cis alkene with
Lindlar’s catalyst and subsequent tert-butyl ester deprotection
(96%, two steps) provided 22. The conversion of 16 to 20
could be accomplished without purification of intermediates to
provide 20 in yields as high as 81% (>7 g scale) and 22 in 78%
overall yield (six steps). A more versatile subunit 27,
permitting late-stage divergent24 functionalization and avoiding
a coupling isomerization, was also employed. Compound 27
was prepared with small variations on the approach described
by Kitahara5 and itself adopted from earlier unrelated studies.25
Commercial ethyl L-lactate protected as its TBDPS ether25d
(98%) was reduced with DIBAL-H (Et2O, −78 °C, 3 h) to the
aldehyde 2425d and subjected to Z-selective Wadsworth−
Horner−Emmons olefination with 2523 (THF, −78 to −55
°C, 10 h), affording 26 in high yield (95%, two steps) and
stereoselectivity (>99:1 Z/E). Methyl ester hydrolysis (LiOH,
90%) completed the synthesis of 27, which was conducted on
gram scales and required four steps (84% overall) from ethyl L-
lactate.
meayamycin O-acetyl group may be accomplished at any
stage in this alternative sequence and is exemplified with the
conversion of 31 to 28 by silyl ether deprotection and
acetylation. It uses the left-hand subunit 27 available in four
steps, proceeds in higher overall yields because of the more
robust stability of the alcohol substituent, avoids a problematic
Z to E isomerization of the left-hand subunit that we observed
during the coupling introduction of 22 to provide 28, proceeds
with a more reproducible cross-metathesis reaction in the
conversion of 33 to 34 (0.3 equiv Grela cat., 0.4 equiv p-BQ,
ClCH2CH2Cl, 40 °C, 12 h, 44−52%), and permits a late-stage
diversification of the O-acyl substituent. Without optimization,
this latter feature was exemplified by the preparation of
carbamate 37b from 34 (Bu4NF, THF, 0 °C, quant; 3 equiv of
carbonyldimidazole (CDI), 0.2 equiv of 4-dimethylaminopyr-
idine (DMAP), CH2Cl2, 23 °C then thiomorpholine), eq 1.
The initial assemblage of the subunits for meayamycin
paralleled earlier approaches and is summarized in Scheme 4.6
Deprotection of 15 (10% TFA−CH2Cl2, 23 °C) followed by
acylation of the liberated amine with 22 (1.2 equiv of HATU, 4
equiv of iPr2NEt, MeCN, 23 °C, 3−6 h, 69%) provided 28.
Cross metathesis of 28 with methacrolein (20 equiv) provided
the α,β-unsaturated aldehyde 29 (0.2 equiv Grubbs II26 cat.,
CH2Cl2, 23 °C, 36−48 h, 60−80%) or 0.01 equiv of Grela
cat.,27 CH2Cl2, 23 °C, 12 h, 60%) followed by Wittig
olefination afforded 30 (1.5 equiv Ph3P+MeBr−, 1.4 equiv
tBuOK, THF, 0−23 °C, 12 h, 57−65%). Final cross-metathesis
of 30 with the right-hand subunit 7 (0.2 equiv Grela cat., 0.3
equiv of benzoquinone (p-BQ), ClCH2CH2Cl, 45 °C, 12 h)
notably without the protection of the secondary alcohol
provided meayamycin (1) in yields as high as 54% and on
scales up to 130 mg. This completed a synthesis of 1 by an
approach that required a longest linear sequence of 12 steps
(22 steps overall) from commercial materials and introduced
what we suggest is the most straightforward preparation of the
right-hand subunit detailed to date.
As this latter approach was in development, an initial series
of meayamycin O-acyl analogues, including meayamycin B,12
was prepared from the alcohol derived from acetate hydrolysis
of 30 (K2CO3, MeOH, 95%) or later by TBDPS deprotection
of 33 (Bu4NF, THF, 23 °C, 4 h, quant), its acylation to access
alternative and representative more stable carbamates,12 and
final cross-metathesis of the resulting 36a−c with 7, Figure 2.
The results of their initial evaluation, along with that of 1
and intermediate alcohol 35, are summarized in Figure 2.
Whereas the removal of the O-acyl substituent reduced
potency (35) as previously disclosed,12 the more stable
carbamate replacements for the acetate (37a−c) matched the
activity of 1. These observations, and those not reported
A further improved approach is also summarized in Scheme
4 and enlisted 27 in place of 22. Introduction of the
C
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Scheme 5
Herein, a short scalable total synthesis of meayamycin is
described by an approach that entails a longest linear sequence
of 12 steps (22 steps overall) from inexpensive commercially
available chiral pool materials (ethyl L-lactate, BocNH-Thr-
OH, and D-ribose). It introduces the most straightforward
preparation of the ornate right-hand subunit that contains the
essential epoxide by an approach amenable to structural
modifications. Its use in the divergent synthesis of O-acyl
analogues is exemplified that helps define a site for productive
modification on the stand-alone drugs or for linkage as
antibody−drug conjugates.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03308.
1
Full experimental details and H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 2. O-Acyl analogues, synthesis, and activity.
Dale L. Boger − Department of Chemistry and Skaggs Institute
for Chemical Biology, The Scripps Research Institute, La Jolla,
California 92037, United States; orcid.org/0000-0002-
3966-3317; Email: dale.boger@outlook.com
herein,18 complement those disclosed initially by Koide12 and
Webb11 and more recently by Nicolaou10 on the thailanstatins
and help define a site and functionality available for productive
modification on the stand-alone drugs themselves or for
linkage as antibody−drug conjugates.
Authors
Christopher Gartshore − Department of Chemistry and Skaggs
Institute for Chemical Biology, The Scripps Research Institute,
La Jolla, California 92037, United States; orcid.org/0000-
0002-1332-7147
Shinji Tadano − Department of Chemistry and Skaggs Institute
for Chemical Biology, The Scripps Research Institute, La Jolla,
California 92037, United States
Prem B. Chanda − Department of Chemistry and Skaggs
Institute for Chemical Biology, The Scripps Research Institute,
La Jolla, California 92037, United States
Anindya Sarkar − Department of Chemistry and Skaggs
Institute for Chemical Biology, The Scripps Research Institute,
La Jolla, California 92037, United States
Finally, and as these studies were concluding, we reexamined
an alternative sequence for assembling 33 from the same three
subunits (Scheme 5). This entailed first elaborating 15 to 39
through cross metathesis with acrolein and subsequent Wittig
olefination prior to introduction of the left-hand amide. In the
absence of the labile acetate and Z-alkene found in the left-
hand subunit, the transformations proved easier to implement
and proceeded in higher conversions. In prior studies, acid-
catalyzed Boc deprotection (10% TFA, CH2Cl2, 23 °C)
conducted on 39 was reported to result in diene isomerization6
and we confirmed these observations. However, we found that
Boc deprotection under alternative conditions (1 N HCl,
EtOAc, 23 °C, 15 min) did not suffer competitive isomer-
ization and the liberated free amine could be coupled with 27
(1.2 equiv HATU, iPr2NEt, MeCN, 23 °C, 15 h) to provide 33
in excellent yields, providing a viable alternative in future
studies.
Naidu S. Chowdari − Bristol Myers Squibb Research &
Development, Redwood City, California 94063, United States;
orcid.org/0000-0001-8795-2570
Sanjeev Gangwar − Bristol Myers Squibb Research &
Development, Redwood City, California 94063, United States
D
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FR901464 and spliceostatin A and evaluation of splicing activity of
key derivatives. J. Org. Chem. 2014, 79, 5697−5709.
Qian Zhang − Bristol Myers Squibb Research & Development,
Redwood City, California 94063, United States
Gregory D. Vite − Bristol Myers Squibb Research &
Development, Redwood City, California 94063, United States
Jelena Momirov − Department of Chemistry and Skaggs
Institute for Chemical Biology, The Scripps Research Institute,
La Jolla, California 92037, United States
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03308
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the NIH
(CA042056, D.L.B.) and Bristol Myers Squibb.
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