Asymmetric Total Syntheses of (-)-Fennebricin A, (-)-Renieramycin J, (-)-Renieramycin G, (-)-Renieramycin M, and (-)- Jorunnamycin A via C-H Activation

Article abstract of DOI:10.1021/acs.orglett.0c01493

Collective total synthesis of five tetrahydroisoquinoline alkaloids including the first total synthesis of (-)-fennebricin A and (-)-renieramycin J has been accomplished. The synthesis features employing a single common amino acid to symmetrically construct the pentacycle of title alkaloids. The palladium-catalyzed arylation of alanine-derived amide developed by Yu was tactically utilized to afford unnatural amino acid building block rapidly and practically. The structure of synthetic (-)-renieramycin M has been confirmed by single crystal X-ray analysis for the first time.

Full text of DOI:10.1021/acs.orglett.0c01493

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Letter
Asymmetric Total Syntheses of (−)-Fennebricin A, (−)-Renieramycin
J, (−)-Renieramycin G, (−)-Renieramycin M, and (−)- Jorunnamycin A
via C−H Activation
Yu Zheng, Xue-Dan Li, Peng-Zhen Sheng, Hong-Dou Yang, Kun Wei, and Yu-Rong Yang*
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ABSTRACT: Collective total synthesis of five tetrahydroisoquino-
line alkaloids including the first total synthesis of (−)-fennebricin A
and (−)-renieramycin J has been accomplished. The synthesis
features employing a single common amino acid to symmetrically
construct the pentacycle of title alkaloids. The palladium-catalyzed
arylation of alanine-derived amide developed by Yu was tactically
utilized to afford unnatural amino acid building block rapidly and
practically. The structure of synthetic (−)-renieramycin M has
been confirmed by single crystal X-ray analysis for the first time.
he tetrahydroisoquinoline antibiotics that cover more
Tthan 50 natural products such as renieramycins, Et-743,
jorumycin, saframycins, quinocarcin, and bioxalomycins have
commanded considerable attention from the synthetic
community over the past 40 years because of their intriguing
chemical structures, potent antitumor and antimicrobial
activities, and unique mechanisms of action.1 Among them,
Et-743 is a representative that is used clinically as a drug for the
treatment of advanced soft tissue sarcoma.2
Fennebricin A (1), a new renieramycin-type tetrahydro-
isoquinoline, was first isolated by Guo and co-workers from the
skin of the South China Sea nudibranch Jorunna Funebris and
its sponge-prey Xestospongia sp. in 2014 (Figure 1).3 Although
the absolute configuration and bioactivities could not be
determined then due to the scarcity and instability of 1,
fortuitously, Guo reisolated 1 (3.1 mg) from a different sample
collected in Ximao Island, Hainan Province, China. Based on
the second isolation, the absolute configuration of 1 was
established by ECD computation. Primary bioassay results
revealed that fennebricin A (1) exhibits significant cytotoxicity
against A549 and HL-60 tumor cell lines with IC50 values of
6.2 and 2.5 μm, respectively. Given the less potent biological
activity of renieramycin J (2), the C-1 hydroxyl group may be
the key function for the bioactivities of 1.3 Intrigued by the
chemical structure of 1, in particular the presence of an acetone
side chain at C-21 instead of a carbinolamine or cyano
function,4 we started its total synthesis, hoping to develop a
unified and collective approach that would be applicable to
other pentacyclic tetrahydroisoquinolines. Herein we wish to
Figure 1. Tetrahydroisoquinoline alkaloids.
report the first total syntheses of 1 and 2 along with the
syntheses of three tetrahydroisoquinoline alkaloids.
As shown in Scheme 1, the acetone side chain at C-21 was
envisioned to be generated by utilizing a Mannich reaction
Received: April 30, 2020
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decagram quantities of 11 in hand, we turned our attention to
Yu’s C−H arylation. Despite the wide substrate scope
recorded, it is uncertain whether Yu’s method can be workable
in our substrate because there were few cases in which aryl ring
were substituted with more than two groups. To this end,
alanine derivative 12, which contains a CONHArF amide
auxiliary as a directing group, was used as an amino acid
building block. The proposed reaction between 11 and 12
proceeded smoothly under Yu’s optimal conditions, where 10
mol % Pd(TFA)2 and 20 mol % 2-picoline ligand were used to
give coupled products 15 and 16 in 76% combined yield, with
92% yield based on the recovered starting material. Elongating
the reaction is not recommended due to the decomposition.
Although cleavage of the phenolic O-TBS group was observed,
this was inconsequential because both 15 and 16 could be
converted into the same methyl ester 17 after removal of the
CONHArF amide directing group under BF3·Et2O conditions.
Further removal of the phthalimide protecting group with
ethylenediamine generated amino ester 10. It is noteworthy
that key amino ester 10 could be prepared in approximately
60% yield over three steps from readily available aryl iodide 11
and alanine 12 at gram scale, highlighting the potentialities of
C−H activation in total synthesis.10
Scheme 1. Retrosynthetic Analysis of (−)-Fennebricin A
with an iminium intermediate derivative of 5. The CDE ring
system could be forged through a Pictet−Spengler cyclization
of hemiaminal 6, which was in turn derived from primary
alcohol 7. Peptide 7 was obviously coupled between a
functionalized amine 8 bearing an AB ring system and
carboxylic acid partner 9 containing an E ring. The above
two partners would be eventually prepared from a single
common amino acid derivative 10. Because 10 is an unnatural
amino acid derivative, whose preparation usually would require
a lengthy process, and inspired by Yu’s5 recent methodology of
palladium-catalyzed C−H activation and others,6 we proposed
that 10 could be prepared from arylation of alanine-derived
amide 12 with aryl iodide 11. To our knowledge, this
methodology has not been applied in total synthesis yet. It is
noteworthy that two reports utilizing C−H activation to
synthesize tetrahydroisoquinoline alkaloids appeared in the
literature after we had started the synthesis. In 2019, Stoltz and
co-workers reported concise syntheses of (−)-jorunnamycin A
and (−)-jorumycin enabled by asymmetric catalysis.7 Shi and
co-workers published a scalable formal synthesis of (−)-qui-
nocarcin employing an 8-aminoquinoline directing group
shortly thereafter.8
As shown in Scheme 3, with versatile amino ester 10 in
hand, the stage was set to access the key peptide coupling
Scheme 3. Synthesis of the Common Pentacyclic Ring
System of Tetrahydroisoquinoline
Our synthesis commenced with the preparation of aryl
iodide 11 (Scheme 2), whose precursor 14 was readily
prepared in 80% yield according to a three-step, well-known
procedure9 from commercially available 2, 6-dimethoxy-
toluene (13). Regiospecific iodination of aryl 14 with NIS/
TFA gave rise to aryl iodide 11 in 81% yield at 30 g scale. With
Scheme 2. Preparation of Amino Ester 10 through the Yu’s
C−H Activation
components, amino alcohol 8 and carboxylic acid 9. To this
end, in one pathway, protection of amino ester 10 with a Boc
group at the nitrogen atom followed by hydrolysis of ester 18
with LiOH yielded carboxylic acid 19, which was converted to
phenolic O-TBS protected compound 9; in another pathway,
intermolecular Pictet−Spengler reaction of 10 with benzoxy-
acetaldehyde (20) under Zhu’s conditions11 provided
tetrahydroisoquinoline 21 with 6:1 dr. Silylation of phenol
21 followed by LAH reduction of the ester provided amino
B
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alcohol 8. Notably, all of the above-mentioned reactions
resulted in excellent yields and could be carried out at gram
scale. Although acylation of 1,3-cis-disubstituted tetrahydro-
isoquinoline proved difficult,12 after extensive efforts, peptide 7
was finally synthesized in 90% yield from coupling of 8 and 9
in the presence of BOPCl and Et3N.13 The undesired coupling
reaction of primary alcohol of 8 with carboxylic acid 9 was not
observed under the conditions. Oxidation of the primary
alcohol 7 with DMP provided hemiaminal 22, whose NMR
signals are too complicated to be assigned. In spite of this, after
removal of the phenolic TBS protecting group and treatment
of phenol intermediate with trifluoromethanesulfonic aicd
(TFSA), clean product 23 was obtained, in which the Boc
group was concomitantly removed during the intramolecular
Pictet−Spengler reaction.14 Subsequent reductive amination of
23 gave N-methylamine 5 in 92% yield.
hemiaminal intermediate, which was immediately subjected to
the conditions of TMSCN and BF3·OEt2 and was then
converted to more stable aminonitrile 26.16 Aminonitrile 26 is
a crystalline compound whose chemical structure including
absolute configuration was secured by a single crystal X-ray
analysis (CCDC 1972948). Furthermore, DDQ oxidation of
aminonitrile 26 provided jorunnamycin A (3) in high yield.
Similarly, acylation of alcohol 26 gave rise to angelic acid ester
27 using the same procedure as that for 24. Subsequent DDQ
oxidation of 27 furnished renieramycin M (28). Our synthetic
renieramycin M is also a crystalline compound, and its
chemical structure was confirmed by X-ray crystallographic
analysis (CCDC 1972949). To our best knowledge, it is the
first time acquiring X-ray data for pentacyclic tetrahydroiso-
quinoline that contains two quinone rings. Moreover, we
surprisingly found that there were a few of the previous
syntheses in which similar X-ray crystallographic analysis of the
synthetic tetrahydroisoquinoline had been performed. Un-
doubtedly, the crystallographic information would be in-
structive in the structural elucidation, understanding of the
SAR, and drug design for these natural products. Eventually,
reieramycin M (28), upon treatment with AgNO3 in acetone,
underwent an intermolecular Mannich reaction and yielded
renieramycin J (2).17,4 As renieramycin J (2) is the angelated
analogue of (−)-fennebricin A (1), logically, direct hydrolysis
of 2 would give (−)-fennebricin A (1). However, our attempts
(Na2CO3, K2CO3, LiOH, and Bu2SnO) to accomplish the
requisite hydrolysis failed.
With the key pentacyclic tetrahydroisoquinoline 5 in hand,
we continued the collective total synthesis. As shown in
Scheme 4, acylation of primary alcohol 5 with angelic acid
under modified Yamaguchi conditions15 afforded 24. DDQ
oxidation of 24 gave renieramycin G (25) smoothly.
Meanwhile, LAH reduction of peptide 5 provided a labile
Scheme 4. Total Syntheses of (−)-Renieramycin G,
(−)-Jorunnamycin A, (−)-Renieramycin M, and
(−)-Renieramycin J
To accomplish the first total synthesis of (−)-fennebricin A
(1) (Scheme 5), we were redirected to start with jorunnamycin
Scheme 5. Total Synthesis of (−)-Fennebricin A
A (3). Protection of jorunnamycin A (3) gave its TBS ether
29. Intermolecular Mannich reaction of aminonitrile 29
installed the acetone side chain of compound 30. Removal
of the TBS protecting group with HF·pyridine furnished
synthetic fennebricin A (1). The synthetic material exhibited
physical, spectroscopic, and spectrometric characteristics
(NMR, IR, HRMS, and [α]D) identical to those reported for
the natural product. As discussed previously, Guo and co-
workers assigned the absolute configuration of 1 with the ECD
method. In this work, the absolute configuration of 1 could be
confirmed unequivocally with the single crystal X-ray analysis
of 26 and reieramycin M (28), and optical rotation
comparison for 1.
In summary, we successfully completed the first asymmetric
total synthesis of (−)-fennebricin A (1) and (−)-renieramycin
C
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J (2) in a longest linear sequence of 20 steps from 2,6-
dimethoxy-toluene with an overall yield of 4% and 3%,
respectively. (−)-Renieramycin G, (−)-jorunnamycin A, and
(−)-renieramycin M have also been synthesized using the
same strategies. Our synthesis features symmetrically con-
structing the pentacycle of title alkaloids from a single common
amino acid that was readily prepared with the palladium-
catalyzed arylation of alanine-derived amide developed by Yu.
Further applications of Yu’s C−H logic in other natural
product syntheses are ongoing, and the results will be disclosed
in due course.
ACKNOWLEDGMENTS
■
Financial support was provided by the Key Research Program
of the Frontier Sciences of the CAS (Grant No. QYZDB-SSW-
SMC026) and the National Natural Science Foundation of
China (21672224 and 21971249).
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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.0c01493.
Experimental procedures and analytical data for all new
compounds (PDF)
Accession Codes
CCDC 1972948−1972949 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 Author
■
Yu-Rong Yang − State Key Laboratory of Phytochemistry and
Plant Resources in West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming 650201, China;
orcid.org/0000-0001-6874-109X; Email: yangyurong@
mail.kib.ac.cn
Authors
Yu Zheng − State Key Laboratory of Phytochemistry and Plant
Resources in West China, Kunming Institute of Botany, Chinese
Academy of Sciences, Kunming 650201, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Xue-Dan Li − State Key Laboratory of Phytochemistry and
Plant Resources in West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming 650201, China;
University of Chinese Academy of Sciences, Beijing 100049,
China
Peng-Zhen Sheng − State Key Laboratory of Phytochemistry
and Plant Resources in West China, Kunming Institute of
Botany, Chinese Academy of Sciences, Kunming 650201, China
Hong-Dou Yang − State Key Laboratory of Phytochemistry and
Plant Resources in West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming 650201, China;
University of Chinese Academy of Sciences, Beijing 100049,
China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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