Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly

Article abstract of DOI:10.1021/acs.orglett.0c01718

A concise and modular total synthesis of the highly potent N14-desacetoxytubulysin H (1) has been accomplished in 18 steps in an overall yield of up to 30percent. Our work highlights the complexity-augmenting and route-shortening power of diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple and step economy but will also stimulate major advances in the development of new tubulysin analogues.

Full text of DOI:10.1021/acs.orglett.0c01718

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pubs.acs.org/OrgLett
Letter
Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly
Convergent Multicomponent Assembly
̈
Thimmalapura M. Vishwanatha, Ben Giepmans, Sayed K. Goda, and Alexander Domling*
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sı Supporting Information
1
4
ABSTRACT: A concise and modular total synthesis of the highly potent N -desacetoxytubulysin H (1) has been accomplished in
1
8 steps in an overall yield of up to 30%. Our work highlights the complexity−augmenting and route-shortening power of
diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective
and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple
and step economy but will also stimulate major advances in the development of new tubulysin analogues.
1
13
he Ugi four-component (U-4CR) and the Passerini
clinical promises (Figure 1). However, the large-scale
2
T
three-component (P-3CR) are the lynchpin in modern
fermentation of tubulysins is still a poorly solved challenge.
multicomponent reaction organic chemistry. As “mix and go”
reactions, multiple bonds are formed in one-pot reactions with
3
minimal waste, ecce a blueprint of green chemistry. These truly
versatile reactions have found extensive applications in drug
discovery, natural products, pharmaceuticals, polymers, and
4
complex macrocycles. Despite the massive benefits of U-4CR
and P-3CR, they normally gave racemic products via the newly
formed stereo center which results in tedious separations of the
active enantiopure product for medicinal chemistry applica-
5
tions. To overcome the stereochemical limitation of multi-
6
7
component reactions, control is necessary. Lewis acids and
8
chiral phosphoric acid catalysts recently emerged as promising
catalysts to control the new chiral center formed in these
multicomponent reactions. Thus, enantioselective multicom-
ponent reactions open an exciting opportunity for the synthetic
and medicinal chemists to easily access molecular complexity
Figure 1. Importance and evolution of tubulysins for medicine and
total synthesis (TS) to date.
9
and diversity.
The natural product family of tubulysins, since their
Thus, they are exciting targets for total synthesis in several
discovery by Ho
broth, has experienced impressive progress, with respect to
̈
fle in 2000 from a myxobaterial fermentation
14
15
laboratories around the world. Our laboratory and the
16
Zanda group disclosed the first total synthesis of tubulysin U
10
understanding biology and drug development. Tubulysins
exhibit extraordinary potent cytotoxicities against cancer cells
exerted through tubulin binding. Strikingly, tubulysins are
0-fold to 1000-fold more potent than the epothilones,
and V; Ellman described the first total synthesis of Tubulysin
17a
17b,c
D
and N-methyl tubulysins.
Since those reports, several
11
2
Received: May 20, 2020
vinblastine, and taxol as cell growth inhibitors and thus they
were promising lead compounds for the development of new
12
anticancer drugs. However, it rapidly turned out that the
therapeutic window for single agent use is too small for any
human application. Recently, tubulysins as payloads, folic acid
conjugates, or antibody drug conjugates (ADCs) showed high
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01718
A
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
modifications on tubulysins and their total synthesis have been
well-documented.
All the classical total synthesis of the nonribosomal peptidic
structure of tubulysins A (Figure 2) involves a multistep
retrosynthetic analysis, we envisioned that the intermediates
2, 3, and 4 bearing orthogonal protecting groups could serve as
advanced intermediates for our divergent multicomponent
reaction synthesis of 1. We thus initially designed efficient
routes to synthesize the building blocks on a multigram scale
18
(
see the Supporting Information (SI) for the preparation of the
24
building blocks 2−4).
RESULTS AND DISCUSSION
■
With the desired three components in our hand, we initiated
studies to probe various P-3CR parameters, such as solvent,
temperature, and concentration, to obtain the desired
diastereomer 5a (see the SI) at the best yield and selectivity.
The first optimization revealed that excellent yield (90%) of
the P-3CR product was obtained as a 1:1 mixture of
diastereomers 5a and 5b at 1 M concentration at room
temperature for 48 h. At 0.1 M concentration, we observed a
slight improvement in the diastereoselectivity, but with a
reduced yield of 50%. These studies showed that temperature,
solvent, and concentration have great impact on the P-3CR.
However, complete stereocontrol of the newly formed
asymmetric carbon is challenging to tune, based on only
those reaction parameters. Taking advantage of the chiral and
bulky nature of our designed components, we hypothesized
that the judicious choice of a catalyst or additive might help to
improve the diastereoselectivity. Inspired by the work of Tan
on chiral phosphoric acid (CPA)-catalyzed enantioselective
MCRs, we initially examined various promising chiral
phosphoric acid catalysts. After screening readily available
catalysts, CPA 5 (see the SI) provided excellent 95:5 dr, albeit
in very low yields (38%). This might be due to the fact that
highly acidic phosphoric acids considerably cleave the side-
chain trityl group, resulting in a series of side reactions (see the
SI). We then speculated that basic ligands could protect the
cleavage of the trityl group. Thus, P-3CR was conducted in the
presence of 20 mol % pyridine and 10 mol % CPA 2. However,
in this case, we obtained mostly hydroxylated product (P-
Figure 2. Retro synthesis of tubulysins A and most representative
synthetic methods developed for Tuv and Tup synthesis.
approach and proceeds through sequential coupling of four
amino acid fragments such as D-N-methyl pipecolic acid
(
Mep), isoleucine (Ile), tubuvaline (Tuv), and the tubuphe-
19
nylalanine (Tup) as logical precursors. Most of the current
synthetic routes suffer from severe drawbacks. First, the
syntheses of Tuv and Tup were only accomplished through
extensive functional group manipulations and chiral separa-
tions. Next, the sequential difficult coupling of sterically
hindered Mep, Ile and Tuv amino acids was challenging. These
costly and labor-intensive routes have hampered large-scale
synthesis. We have previously shown the use of the
multicomponent reaction tactic in our first total synthesis of
8
a
15
tubulysin U and V, and also the Wessjohann and Kazmaier
groups used multicomponent reactions for their synthesis of,
however, unnatural tubulysin derivatives (“Tubugis”) through
2
CR) with a 95:5 diastereomeric ratio (70%; see the SI). The
7d,e 7a
20
Banfi group
and our group showed that chiral
the combination of P-3CR and U-4CR.
1
4
components yielded enantioselective and diastereoselective
However, from a biological activity point of view, N -
desacetoxytubulysin H showed high potency, with increased
25
P-3CR, in the presence of achiral Lewis acids. Thus, we
extensively screened various Lewis acids in P-3CR (see the SI)
21
hydrolytical stability. Based on these findings, the Ellman
1
7c
21a
21b
and we were delighted to find that 10 mol % ZnBr gave
group, the Nicolaou group, and the Wipf group have
developed synthetic routes to access 1 and its analogues. While
total synthesis landmark achievements, most reported
approaches generally suffer from a high synthetic step count
and low overall yields. For example, the tubulysin-linker part of
the ADC MEDI4276 was reportedly synthesized by a more-
2
moderate diastereoselectivity (80:20) without diminishing the
yield (70%). Our previous studies on the screening of Lewis
acids along with ligands in enantioselective P-3CR revealed
that Lewis acids, along with supporting bulky chiral ligands,
may completely lock the other plane of the isocyanide attack,
22
7a,26
than-40-step synthesis. To attenuate the current demand for
thereby leading to high diastereoselectivity.
Based on this
23
tubulysins in ADC therapies, we targeted a general and
stereoselective synthetic method to access tubulysins in just
few steps and overall high yield. There are two important
obstacles in the chemistry and biology of tubulysins natural
products. The unnatural amino acids (Tup and Tuv) and the
hypothesis, we examined serval chiral ligands in association
with ZnBr , and the results are summarized in Scheme 1.
Interestingly, when ligand L1 was used as the chiral ligand
together with ZnBr , the P-3CR pathway afforded 5a as the
2
2
major product formation with high diastereoselectivity (92:8)
in acceptable yield (71%). Other tested ligands gave moderate
yields and diastereoselectivities (see Scheme 1).
The stereo chemical outcome of the P-3CR could be
rationalized by the probable transition state (TS), as shown in
1
4
two contiguous stereocenters are ubiquitous; the N
substituent on the Tuv has a great influence on the biological
activities. Therefore, our synthetic plan was designed to rapidly
and controllably assemble the core structure while, at the same
time, maximizing the possibilities of peripheral modifications.
This communication documents our high yielding short and
convergent synthesis of 1 in just 18 steps from commercially
available very simple building blocks. Based on our
Scheme 2. Coordination of the ZnBr by the aldehyde carbonyl
2
and the urethane protecting group carbonyl results in a Cram-
chelated complex. The isocyanide attack from the less-
hindered si face of the carbonyl group in a Cram chelate
B
https://dx.doi.org/10.1021/acs.orglett.0c01718
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pubs.acs.org/OrgLett
Letter
Scheme 1. Diastereoselective Passerini Three-Component
Reaction for the Synthesis of 5a
Scheme 3. Diastereoselective Synthesis of Tup 9*
*
Reaction conditions: (a) AcCl (3 equiv), 100 °C, 2 h; (b) CuI (10
t
mol %), BuXPhos (20 mol %), 2 M PhCH MgBr in THF (0.9 equiv),
2
−
78 °C, 6 h; (c) H (55 bar), NH Cl (3.0 equiv), Ru(OAc) , R-dm-
2 4 2
SEGPHOS, trifluoroethanol (TFE), 12 h; and (d) conditions of
reactions (b) and (c) in one pot.
a modified ruthenium-catalyzed reductive amination protocol
to afford 9 in good yield (81%) and excellent diastereose-
28
lectivity (>99:1). A one-pot synthesis of 7 to 9 was also
conducted; in this case, the yield obtained was quite low
(
43%).
With the key building blocks in our hand, we focused on the
final assembly of 1. We first installed the thiazole via post-
translational modification of 5a through one-pot two step
a
Screening of solvents, concentration and other catalysts is described
b
strategy using TiCl -mediated cyclodehydration of Cys(Trt)
4
in detail in the Supporting Information (SI). Equimolar amounts of
all three components were added to a solution containing ZnBr and
corresponding ligand in CH Cl at 0 °C; after 5 min, the reaction
mixture was stirred at room temperature. Yield of 5a was determined
amide, followed by MnO oxidation to afford 10 in excellent
2
2
29
yield without racemization (see the SI). The resulting
2
2
c
thiazole 10 was then subjected to Fmoc deprotection and then
acyl migration under mild conditions to give hydroxy
tetrapeptide analogue 11 in excellent yield (93%). This type
of Passerini reaction−amine deprotection−acyl migration
d
after chromatographic purification. Diastereomeric ratio was
determined by HPLC analysis of the crude reaction mixture.
e
Confirmation of the stereochemistry is determined by applying 5a
3
0
to the total synthesis of 1.
(
PADAM) was first described by Banfi and independently
31 32
by Semple and others. However, its practical utility and
superiority over other methods has never been disclosed in the
sterically hindered amide formation. The resulting tetrapeptide
Scheme 2. Predicted Model for Diastereoselective Synthesis
of 5a
1
1 was then hydrolyzed to afford 12 in a yield of 98%.
Synthesis of 13 was accomplished by activation of 12 as the
pentafluorophenyl ester-mediated coupling of 9 and 12 gave
1
3 in 87% overall yield. Furthermore, acetylation of hydroxyl
group was produced 14 in 88% yield. Finally, the late stage N-
methylation of the N-terminus was accomplished by the
catalytic hydrogenation with paraformaldehyde, affording 1 in
33
good yield (90%; see Scheme 4). The synthesized analogue 1
complex favors the formation of 5a as the major product (see
Scheme 2).
is equivalent to reported in the literature in all spectroscopic
35
aspects (see the SI).
We evaluated the biological activity in HCT-116 cancer cells
Next, we turned our attention to the development of an
innovative synthesis of Tup (Scheme 3). We figured that
commercially available and affordable S-(−)-methyl succinic
acid 6 would provide a versatile component via its anhydride 7.
We set out to investigate the regioselective ring opening of 7
1
4
(Figure 3). Notably, the inhibition by N -desacetoxytubulysin
H 1 was most prominent in HCT-116 cells, but was less
effective at sub-μM concentrations in HeLa cells.
1
4
In conclusion, the total synthesis of N -desacetoxytubulysin
H was accomplished in 18 steps with an overall yield of 30%.
To the best of our knowledge, this is the shortest and most
convergent total synthesis of 1. Key features of our strategy
included (a) a one-pot unprecedented highly diastereoselective
P-3CR, and (b) a two-step diastereoselective synthesis of Tup
and (c) productive construction of the tripeptide unit Mep-Ile-
Tuv, which is common and essential unit in all tubulysins. We
anticipate that the practicality, scalability, and conciseness of
our strategy should have implications to access a variety of
other analogues of tubulysins, which are the focus of our future
27
by a Grignard reagent. However, the direct addition of
Grignard reagent to the anhydride 7 gave a mixture of
regioisomers 8a and 8b in equal amounts (see the SI). To
improve the selective formation of 8a, various copper catalysts
were examined (see the SI) in THF at −78 °C. To our delight,
bulky t-BuXPhos along with CuI resulted in exclusive
formation of 8a in >99:1 regioselectivity in 70% yield. The
regioselective outcome can be rationalized by the steric
encumbrance imparted by the bulky copper complex,
effectively shielding the carbonyl group next to the methyl
group of 7. The enantiopure keto acid 8a was then subjected to
34
work.
C
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Letter
Scheme 4. End Game of the Total Synthesis of 1*
Sayed K. Goda − Faculty of Science, Chemistry Department,
Cairo University, Giza, Egypt
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01718
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding has been provided by the Qatar National Research
Foundation (No. NPRP6-065-3-012), ITN “Accelerated Early
stage drug dIScovery” (AEGIS, Grant Agreement No.
675555). Moreover, funding was received by the National
Institute of Health (NIH) (No. 2R01GM097082-05), the
European Lead Factory (IMI) (Grant Agreement No.
115489), and COFUNDs ALERT (Grant Agreement No.
665250) and Prominent (Grant Agreement No. 754425) and
KWF Kankerbestrijding grant (Grant Agreement No. 10504).
We thank Klaas Sjollema (University Medical Center
Groningen (UMCG) Microscopy and Imaging Center;
UMIC) for microscopical analysis of tubulysin cell effects.
*
Reagents and conditions: (a) step 1:1 M TiCl in CH Cl (3.0
4
2
2
equiv), 0 °C, 48 h; step 2: activated MnO , (10 equiv) 70 °C, 3 h. (b)
2
step 1: diethylamine (30 equiv), CH CN, 0 °C, 2 h; step 2: CH Cl ,
3
2
2
DIPEA, 50 °C, 24 h. (c) 2 M LiOH, THF: H O: MeOH, 6 h, room
2
temperature (rt). (d) step 1: DIC, pentafluorophenol, 0 °C, CH Cl ,
2
2
step 2:9 (3.0 equiv), DMF, DIPEA, rt, 12 h. (e) Ac O, pyridine,
2
CH Cl , 0 °C to rt, 24 h. (f) H , Pd/C, 37% aqueous formaldehyde,
MeOH, rt, 24 h.
2
2
2
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AUTHOR INFORMATION
Corresponding Author
■
Alexander Domling − Department of Drug Design, University
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