Convergent Total Synthesis of Yaku'amide A

Article abstract of DOI:10.1002/anie.202014238

Total synthesis of the anticancer peptide natural product yaku'amide A is reported. Its β-tert-hydroxy amino acids were prepared by regioselective aminohydroxylation involving a chiral mesyloxycarbamate reagent. Stereospecific construction of the E- and Z-ΔIle residues was accomplished through a one-pot reaction featuring anti dehydration, azide reduction, and O→N acyl transfer. Alkene isomerization was negligible during this process. These methods enabled a highly convergent and efficient synthetic route to the natural product.

Full text of DOI:10.1002/anie.202014238

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Accepted Article
Title: Convergent Total Synthesis of Yaku’amide A
Authors: Yu Cai, Zhiwei Ma, Jintao Jiang, Concordia Lo, Shi Luo,
Ankur Jalan, Joseph Cardon, Alexander Ramos, Diego Moya,
Daniel Joaquin, and Steven L. Castle
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014238
Link to VoR: https://doi.org/10.1002/anie.202014238

10.1002/anie.202014238
Angewandte Chemie International Edition
COMMUNICATION
Convergent Total Synthesis of Yaku’amide A
Yu Cai, Zhiwei Ma, Jintao Jiang, Concordia C. L. Lo, Shi Luo, Ankur Jalan, Joseph M. Cardon,
Alexander Ramos, Diego A. Moyá, Daniel Joaquin, and Steven L. Castle*
Abstract: Total synthesis of the anticancer peptide natural product
yaku’amide A is reported. Its -tert hydroxy amino acids were
prepared via regioselective aminohydroxylation involving a chiral
mesyloxycarbamate reagent. Stereospecific construction of the E-
and Z-Ile residues was accomplished via a one-pot reaction
featuring anti dehydration, azide reduction, and O→N acyl transfer.
Alkene isomerization was negligible during this process. These
methods enabled a highly convergent and efficient synthetic route to
the natural product.
workers constructed both epimers of the initially proposed
structure of 1 and assigned the S-configuration to the NTA
stereocenter.[4] Their subsequent attempts to prepare 2 cast
doubt on the originally assigned structures of both yaku’amides.
In a painstaking effort involving total synthesis combined with
degradation studies conducted on ca. 0.1 mg each of 1 and 2,
Inoue and co-workers confirmed the S-stereochemistry of the
NTA moiety and determined that the configurational
assignments of two pairs of adjacent residues (D- and L--
OHVal, D- and L-Val) had been transposed (Figure 1).[5a] Their
further studies employing fluorescent and biotinylated
derivatives of 2 established that this peptide inhibits ATP
synthesis and also promotes ATP hydrolysis. This divergent
effect on these processes, which are both mediated by the
mitochondrial enzyme F0F1-ATP synthase, is unprecedented.[5b]
Yaku’amides A and B (1 and 2, Figure 1) are linear peptides that
were isolated in minute quantities by Matsunaga and co-workers
from Ceratopsion sp., a deep-sea sponge found in the East
China Sea.[1] They are comprised of thirteen amino acids
including four dehydroamino acids (AAs) and three -hydroxy
amino acids (-OHAAs), an N-terminal acyl group (NTA), and a
C-terminal amine (CTA). The NTA stereochemistry was
undefined at the time of isolation. The presence of both E- and
Z-Ile is noteworthy; whereas the former is found in a select
group of natural products,[2] 1 and 2 are the first known
metabolites to contain the latter. Screening of 1 against the
JFCR39 cancer cell line panel[3] revealed a unique pattern of
activity, which is suggestive of a novel mode of action.
In addition to establishing the structures of 1 and 2 and
revealing key aspects of their mode of action, Inoue’s pioneering
work highlights the difficulties involved in constructing -tert-
hydroxy amino acids and unsymmetrical tetrasubstituted AAs.
For example, peptide couplings of fragments with C-terminal Ile
residues were plagued by alkene isomerization via an azlactone
intermediate unless the neighboring amide was protected.[4]
Similar observations were made by Wandless[6] and Joullié[7]
while synthesizing the phomopsins, which contain E-Ile.
Moreover, preparation of (2S,3R)--OHIle required a lengthy
seven-step sequence from D-Ser.[8] Inoue and co-workers
recently disclosed another total synthesis of
2 that was
conducted mostly on solid support.[5c] While their new route is
higher yielding and contains fewer purification steps than their
previous route, it requires solution-phase preparation of three
Ile-containing subunits that are used in excess to ensure high-
yielding couplings to the resin-bound peptide. Prompted by our
interest in constructing unusual peptides[9] and devising efficient
routes to tetrasubstituted AAs and -tert-hydroxy amino acids,
we targeted the yaku’amides for synthesis. Herein, we report a
concise and convergent total synthesis of 1 that introduces novel
strategies for generating these challenging residues and does
not require large excesses of precious intermediates.
Figure 1. Yaku’amides A (1) and B (2). AAs are shown in red, -OHAAs are
shown in blue, and configurations assigned by Inoue are shown in green.
Our retrosynthetic analysis of 1 is shown in Scheme 1.
Disconnection of the indicated amide bonds revealed three key
intermediates: the NTA (3), left-hand pentapeptide 4, and
nonapeptide 5. Following Inoue’s precedent,[4,5] we planned to
attach the NTA in the final step of the synthesis. Recognizing
that E- and Z-Ile would be the most challenging components of
1 to prepare, we divided the rest of the structure into a smaller
subunit containing two of these residues (4) and a larger subunit
possessing only one such residue (5). This approach would
maximize convergency, as the number of linear steps required
to access each intermediate should be comparable. Inspection
of 5 indicated that it could be derived from dipeptide 6, tripeptide
7, and tetrapeptide 8. We decided to employ base-free OsO4-
catalyzed aminohydroxylation[10] to construct the -OHAAs and a
The yaku’amides are attractive synthetic targets due to their
striking molecular architecture, potent bioactivity, distinctive
mode of action, and natural scarcity. In 2013, Inoue and co-
[*]
Y. Cai, Z. Ma, J. Jiang, C. C. L. Lo, S. Luo, A. Jalan, J. M. Cardon,
A. Ramos, D. A. Moyá, D. Joaquin, Prof. S. L. Castle
Department of Chemistry and Biochemistry
Brigham Young University
Provo, UT 84602 (USA)
E-mail: scastle@chem.byu.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202014238
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Scheme 1. Retrosynthesis of 1. Boc = tert-butoxycarbonyl, TES = triethylsilyl.
sequence combining aminohydroxylation with stereospecific anti
dehydration and O→N acyl transfer[11] to install the Ile residues
without recourse to backbone amide protection.
Attempts
to
develop
an
enantioselective
base-free
aminohydroxylation leading to -OHVal and -OHIle derivatives
were fruitless,[10d] in line with the observations of McLeod and
co-workers.[10c] Accordingly, we evaluated chiral nitrogen source
reagents. Base-free aminohydroxylation of ethyl 3,3-
dimethylacrylate (9) with Lebel’s mesyloxycarbamate 10[12]
afforded 11 in 97% yield and 1:1 dr (Scheme 2a). Fortunately,
the fact that both enantiomers of -OHVal are present in 1
allowed us to capitalize on this result. Thus, TES protection
afforded a separable mixture of D--OHVal derivative 12 and L-
-OHVal derivative epi-12 in 87% yield.[13] The generation of
these residues simultaneously in just two steps from 9 illustrates
the efficiency of the chiral-reagent-based aminohydroxylation
strategy. Application of this chemistry to enoate 13 furnished the
required -OHIle derivative (2S,3R)-15 along with its separable
diastereomer (Scheme 2b).[13] The latter compound was
funnelled into the synthesis of 1 via transformation into Z-Ile
precursor 22,[14] enabling the productive use of both isomers
obtained from the aminohydroxylation reaction. The lower yield
of 14 compared to 11 presumably reflects the impact of the
steric hindrance of the alkene substrate (i.e., 13 vs 9) on the
aminohydroxylation reaction.
Scheme 2. Aminohydroxylation-based synthesis of -OHAAs present in 1. Tf
= trifluoromethanesulfonyl, Ms = methanesulfonyl.
We anticipated that right-hand tetrapeptide 8 would be the
simplest of the key subunits of 1 to prepare since it contains
Val and not E- or Z-Ile. Indeed, the absence of alkene
stereochemistry allowed us to construct 8 rapidly as shown in
Scheme 3 by capitalizing on the propensity of peptides with C-
terminal AAs to form azlactones upon treatment with peptide
coupling agents.[4,6,7] First, coupling of Boc-D-Val with L-Val-OMe
and subsequent hydrolysis delivered dipeptide 17. This acid was
coupled with racemic -OHVal derivative 18[15] to furnish
tripeptide 19 as an inconsequential mixture of diastereomers.
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Saponification of 19 was followed by treatment of the
intermediate acid with EDC•HCl, which served to both activate
the carboxylate and dehydrate the tertiary alcohol. This triggered
spontaneous formation of an azlactone, which was opened[16]
upon addition of amine 20,[17] generating tetrapeptide 8 in 71%
yield from 19.
original procedure that employed PMe3 to reduce the azide.[11]
Finally, one-pot Dess–Martin/Pinnick oxidation[20] of 27 with
complete removal of the acetic acid byproduct during workup
delivered a quantitative yield of acid 7.
Scheme 3. Synthesis of right-hand tetrapeptide 8. EDC•HCl = 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide
hydrochloride,
HOBt
=
1-
hydroxybenzotriazole, THF = tetrahydrofuran, DMF = N,N-dimethylformamide.
Dipeptide 6 and tripeptide 7 were then constructed as
outlined in Scheme 4. The chiral carbamate and the TES group
were simultaneously removed from 12 via hydrogenolysis in an
EtOH–EtOAc solvent mixture, and the resulting amine was
coupled with Boc-D-allo-Ile to afford dipeptide 21 (Scheme 4a).
Saponification furnished acid 6. Selective cleavage of the ester
moiety of epi-12 was challenging due to the base labile nature of
the chiral carbamate. We eventually found that Me3SnOH[18] was
suitable for this purpose (Scheme 4b). Coupling of the acid
obtained from epi-12 with racemic -OHIle derivative 22[11]
produced dipeptide 23 as an inconsequential 1:1 mixture of
diastereomers. The subsequent hydrolysis and alkylation steps
were complicated by the presence of the base-sensitive chiral
carbamate. Accordingly, it was exchanged for a more robust Boc
group to afford 24 in a single step. The use of NaHCO3 in this
reaction was key to preventing TES ether cleavage. Hydrolysis
of the ethyl ester of 24 was followed by alkylation with
enantiopure iodide 25,[19] producing -azidoethyl ester 26 in 66%
yield over two steps. A survey of bases in the alkylation revealed
that Cs2CO3 was most effective at suppressing retroaldol
fragmentation of the -OHIle residue. After some
Scheme 4. Syntheses of dipeptide 6 and tripeptide 7. Stereocenters marked
with asterisks show relative, not absolute, stereochemistry. DMP = Dess–
Martin periodinane.
Intermediates 6–8 were elaborated into nonapeptide 5 as
shown in Scheme 5. First, exposure of right-hand tetrapeptide 8
to HCl removed the Boc moiety, and coupling with tripeptide 7
furnished heptapeptide 28 in excellent yield. Then, treatment of
28 with HCl cleaved the Boc and TES groups simultaneously.
Coupling of the crude heptapeptide amine with dipeptide 6
delivered nonapeptide 5 in high yield. Attempted couplings with
either or both tertiary alcohols protected were unsuccessful,
presumably due to the steric hindrance introduced by the silyl
ethers. HPLC analysis of the heptapeptide and the nonapeptide
indicated that little if any epimerization occurred during the two
fragment couplings.
experimentation, we developed
a one-pot version of our
dehydration/azide reduction/O→N acyl transfer sequence.[11]
Thus, treatment of 26 with the Martin sulfurane induced
stereoconvergent anti dehydration, and a solvent switch set the
stage for azide reduction via Lindlar hydrogenation. Addition of
piperidine upon completion of the reduction triggered O→N acyl
transfer, delivering Z-Ile-containing tripeptide 27 in 77% yield
and 12:1 dr. The trace amounts of E-isomer are likely generated
during the reduction or the acyl transfer, as no minor isomers
were visible in 1H NMR spectra of the crude dehydration product.
This one-pot protocol gives slightly better results than our
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10.1002/anie.202014238
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transformation of 29 into -azidoethyl ester 32 proceeded
similarly to the conversion of 23 into 26 (see Scheme 4b), with
the exception that the carboxylate alkylation proceeded best with
Et3N instead of Cs2CO3. Gratifyingly, 32 underwent facile
stereoconvergent anti dehydration followed by azide reduction
and O→N acyl transfer, furnishing tripeptide 33 in 83% yield and
18:1 dr. One-pot Dess–Martin/Pinnick oxidation produced acid
34, which was coupled with racemic -OHIle derivative 35[11] (the
diastereomer of 22) to afford tetrapeptide 36. The familiar three-
step sequence of reactions used to convert 36 into alcohol 39
proceeded smoothly in spite of the bulkiness of iodide 37.[11]
Assessment of the diastereomeric ratio of 39 by 1H NMR
spectroscopy was complicated by the presence of both E- and
Z-Ile in this compound. Nonetheless, it was clear that any
alkene isomerization during the azide reduction–O→N acyl
transfer process was at most minimal. Sequential oxidation of 39
using the Dess–Martin and Pinnick protocols delivered the key
left-hand pentapeptide 4.
Scheme 5. Synthesis of nonapeptide 5.
The synthesis of left-hand pentapeptide 4 began with
Me3SnOH-mediated hydrolysis of -OHIle derivative (2S,3R)-15
and coupling of the resulting acid to racemic amine 22.
Dipeptide 29 was obtained in good yield as an inconsequential
mixture of diastereomers (Scheme 6). The three-step
Scheme 6. Synthesis of pentapeptide 4. Stereocenters marked with asterisks show relative, not absolute, stereochemistry.
The N-terminal acyl subunit (NTA) 3 was constructed via the
streamlined route depicted in Scheme 7. Acidic hydrolysis[21] of
known pseudoephedrine amide 40[22] furnished enantiopure
carboxylic acid 41. Claisen condensation of 41 and silyl ketene
acetal 42 was accomplished using Baba’s protocol employing
trimethoxysilane and catalytic InBr3.[23] In situ reduction of the
resulting -keto ester by addition of LiAlH4 yielded diol 43 as an
inconsequential mixture of diastereomers. Oxidation of 43 to -
keto acid 3 was achieved by slightly modifying the procedure
described by Inoue[4] that enlists AZADO and PhI(OAc)2.[24] Our
route to 3 (three steps from 40 and five steps from commercially
available compounds)[25] is significantly shorter than the
previously published ten-step synthesis of this compound.[4]
Scheme 7. Synthesis of NTA carboxylic acid 3. AZADO = 2-azaadamantane
N-oxyl, TMS = trimethylsilyl.
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The three building blocks 3–5 were assembled and
elaborated into 1 as outlined in Scheme 8. HCl-mediated Boc-
deprotection of nonapeptide 5 set the stage for the critical
coupling with pentapeptide 4. Extensive experimentation
revealed that the combination of EDC•HCl and HOBt with
CH2Cl2 as solvent was uniquely effective for joining these
complex building blocks. Other conditions delivered inferior
results. One-step deprotection of the Boc and TES groups from
tetradecapeptide 44 was facile in the presence of HCl, and
attachment of carboxylic acid 3 to the resulting amine was
achieved by following the precedent developed by Inoue and co-
workers.[4] HPLC has been established as the most reliable
technique for distinguishing yaku’amide A from its isomers.[5]
Accordingly, we were pleased to find that our synthetic sample
of 1 was identical by HPLC to a synthetic sample from the Inoue
laboratory that was previously demonstrated to be identical to
naturally occurring 1.
Scheme 8. Completion of the total synthesis of 1. COMU
=
1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium
hexafluorophosphate.
In summary, we have synthesized the unusual peptide
natural product yaku’amide A. Its -tert hydroxy amino acids
were rapidly constructed via regioselective aminohydroxylation
of enoates enlisting a chiral mesyloxycarbamate. Stereospecific
preparation of the E- and Z-Ile residues was accomplished by
means of an anti dehydration utilizing the Martin sulfurane. The
dehydration was merged with an azide reduction and an O→N
acyl transfer into a one-pot process. This streamlined procedure
enabled the generation of E- and Z-Ile and couplings at their C-
termini to proceed in a single step with only negligible amounts
of alkene isomerization. These methods facilitated a convergent
synthetic route to 1 (19-step longest linear sequence with 13
chromatographic purifications, 3.5% overall yield) that compares
favorably to Inoue’s pioneering synthesis of this compound (25-
step longest linear sequence, 1.9% overall yield).[4,5a] The use of
straightforward protocols combined with the lack of reagents that
are difficult to handle bodes well for the scalability of our route.
Although Inoue’s solid-phase synthesis of 2 possesses some
advantages such as a higher yield (9.1%) and fewer required
purifications,[5c] it also has some intrinsic limitations. For example,
the requirement for large excesses of precious intermediates
that are challenging to construct attenuates the benefit offered
by the high overall yield.[26] Perhaps more significant is the fact
that solid-phase peptide synthesis requires a linear rather than
convergent synthetic strategy. Our route complements Inoue’s
work by avoiding excess amounts of valuable subunits and by
proceeding in a convergent fashion. The latter feature should
prove highly advantageous in the construction of yaku’amide A
analogs. Specifically, the preparation of a few variants of each
key subunit in our route followed by their convergent assembly
would afford numerous analogs, thereby constituting a notable
application of the “Multiplication of Diversity” strategy.[27]
Accordingly, the synthesis and biological evaluation of analogs
of 1 will be the subject of future reports from our laboratory.
Acknowledgements
We thank the National Institutes of Health (R15GM114789) and
Brigham Young University (Graduate Studies, Bradshaw, Robins,
and Simmons Center for Cancer Research Fellowships to Z.M.,
Y.C., J.J., C.C.L.L., A.J., D.A.M., and D.J.; Undergraduate
Research Awards to S.L. and J.M.C.; MEG and CHIRP Awards
to S.L.C.) for support. We also thank Profs. Masayuki Inoue and
Hiroaki Itoh for helpful discussions and an analytical sample of
yaku’amide A, and Blake L. Christensen and Stephen M. White
for assistance with the preparation of reagents and starting
materials.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: peptides • natural products • total synthesis •
aminohydroxylation • O→N acyl transfer
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Angewandte Chemie International Edition
COMMUNICATION
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[14] Please see the Supporting Information for details.
[15] Amine 18 was prepared by a modification of the procedure used in ref.
10b to prepare this compound (see Supporting Information for details).
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quality of AZADO, which is expensive and often out of stock in the USA.
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radical nature. Accordingly, we developed an alternate route to 3 that
does not rely on AZADO. Details are found in the Supporting
Information.
[7]
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amounts of alkenyl azides and air-sensitive phosphinophenol esters,
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[13] Details of the assignments of the absolute configurations of 12, epi-12,
(2S,3R)-15, and (2R,3S)-15 are found in the Supporting Information.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Yaku’amide A, an anticancer peptide,
was synthesized via a route featuring
a one-pot anti dehydration–azide
reduction–O→N acyl transfer process
for stereospecific construction of E-
and Z-Ile. OsO4-catalyzed
Yu Cai, Zhiwei Ma, Jintao Jiang,
Concordia C. L. Lo, Shi Luo, Ankur
Jalan, Joseph M. Cardon, Alexander
Ramos, Diego A. Moyá, Daniel Joaquin,
Prof. Steven L. Castle*
Page No. – Page No.
aminohydroxylation was employed to
produce the -hydroxy amino acids.
Convergent Total Synthesis of
Yaku’amide A
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