Total Synthesis of Originally Proposed and Revised Structure of Hetiamacin A

Article abstract of DOI:10.1021/acs.orglett.8b01350

The first total synthesis of the originally proposed and correct structures of hetiamacin A has been accomplished via Wittig olefination and Sharpless asymmetric dihydroxylation reaction. These total syntheses culminated in the stereostructural confirmati

Full text of DOI:10.1021/acs.orglett.8b01350

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Originally Proposed and Revised Structure of
Hetiamacin A
Gang Wu, Shaowei Liu, Ting Wang, Zhongke Jiang, Kai Lv, Yucheng Wang,* and Chenghang Sun*
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian Tan Xi Li No. 1,
Beijing 100050, PR China
S
* Supporting Information
ABSTRACT: The first total synthesis of the originally
proposed and correct structures of hetiamacin A has been
accomplished via Wittig olefination and Sharpless asymmetric
dihydroxylation reaction. These total syntheses culminated in
the stereostructural confirmation of the reassignment of
hetiamacin A.
etiamacins A−D are new members of the amicoumacin
Hgroup antibiotics isolated from the cultured broth of
Bacillus subtilis PJS by our group recently.1 Its homologue (AI-
77-A, 2a) is a new translation inhibitor that is distinct from the
other known antibiotic targeting protein synthesis in chemical
scaffold, and it binds to the ribosome in a unique way and
inhibits translation by an unusual mechanism.2 Preliminary
bioassays of hetiamacin A have displayed in vitro antibacterial
activity (MIC, 2 μg/mL, oxacillin-resistant Staphylococcus
aureus). The structure of hetiamacin A (Figure 1) was
elucidated by spectroscopic methods; however, the stereo-
chemistry of all five chiral centers on hetiamacin A was not
determined. As part of our continued interest in these natural
products, we herein report the first total synthesis, the revised
structure and absolute configuration of hetiamacin A.
The structure of hetiamacin A is similar to that of AI-77-B
(2b), which is a potent gastroprotective agent.3 Hetiamacin A
could arise from a biogenetic process related to that for AI-77-B
(Figure 1). Thus, we hypothesized that all five chiral centers on
Figure 2. Retrosynthetic analysis of compound 1.
hetiamacin A preserved the (S)-configurations as AI-77-B. Our
retrosynthetic analysis of the proposed structure of hetiamacin
A is outlined in Figure 2. We planned to introduce
hexahydropyrimidine in a late stage from compound 3 by
reaction with formaldehyde. Compound 3 would be available
by coupling the known isocoumarin 4 and acid 5. The key
intermediate acid 5 could be derived from the commercially
available, protected aspartic acid derivative 6 by a route
featuring DIBAL-H reduction, Wittig reaction, and Sharpless
asymmetric dihydroxylation.
The synthesis of acid 5 is shown in Scheme 1. Aspartic acid
derivative 6 was converted to Weinreb amide 7 in the presence
of EDCI and NMM at room temperature in 94% yield.
Reduction of 7 with DIBAL-H in toluene at −78 °C, followed
Received: April 28, 2018
Figure 1. Structures of hetiamacins A, AI-77-A, and AI-77-B.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01350
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Letter
Scheme 1. Synthesis of Amino Acid Fragment
Scheme 3. Synthesis of Original Proposed Hetiamacin A
Scheme 2. Synthesis and Crystal Structure of Compound 12
Figure 3. 1H and 13C NMR data of the synthetic and natural
hetiamacin A and the revised structure 15.
derived from 9 was carried out.8 It was revealed that compound
9 conserves the 2S,3S,4S stereochemistry, as shown in Scheme
2.
With the acid segment 5 in hand, we proceeded to the final
stage of the synthesis of compound 1. Coupling of segment 5
with the known compound 4 in the presence of HATU and
DIEA yielded compound 13 in 92% yield.9 Reduction of the
azide moiety and deprotection of the Cbz group simultaneously
over palladium on activated carbon (10%) under hydrogen
yielded the corresponding diamine compound, which was
cyclized by formaldehyde to provide hexahydropyridine 14 in
87% yield over two steps.10 Removal of the TBS group with HF
in pyridine afforded the corresponding alcohol, which upon
hydrolysis using HCl in dioxane (1 N) gave the originally
proposed hetiamacin A (Scheme 3).11
by Wittig olefination of the resulting aldehyde with
commercially available ethyl (triphenylphosphoranylidene)
acetate, gave 8 in 67% yield for two steps.4 Sharpless
asymmetric dihydroxylation of acrylate 8 using AD-mix-α
1
gave diol 9 in 87% yield as a single diastereomer by H NMR
analysis.5 Selective protection of diol 9 with O-p-nitro-
benzenesulfonate (NsCl) in DCM at 0 °C provided the
corresponding sulfonate, which was subjected to SN2 displace-
ment with sodium azide in DMF at 50 °C yielded azide 10 in
70% yield for two steps.6 TBS protection of 10 using the
standard procedure followed by LiOH-mediated hydrolysis
provided the acid 5.7
1
The structure of compound 1 was confirmed by HRMS, H
NMR, 13C NMR, COSY, HMQC, and HMBC (available in the
1
Supporting Information). Unexpectedly, the H and 13C NMR
In order to ascertain the absolute stereochemistry of tert-
butyl ester 9, single-crystal X-ray crystallization of lactone 12
data of the synthetic compound 1 did not match the literature
values of naturally occurring hetiamacin A (Figure 3). In
B
DOI: 10.1021/acs.orglett.8b01350
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Letter
identical with those of the naturally isolated hetiamacin A.
Furthermore, the measured specific rotation of the synthesized
15 [α]2D5 = −140.0 (c 0.01, MeOH) was agreement with the
data of the natural product, [α]2D5 = −140.0 (c 0.01, MeOH).
Therefore, the structure of hetiamacin A was revised to
compound 15, and the absolute configuration of hetiamacin A
was confirmed to be 3S,5′S,8′S,9′S,10′S.
Scheme 4. Synthesis of the Predicted Structure 15 of
Hetiamacin A
In conclusion, we have achieved the first total synthesis of the
originally proposed and corrected structures of hetiamacin A.
The stereochemistry of all five chiral centers on hetiamacin A
was also assigned to be 3S,5′S,8′S,9′S,10′S on the basis of our
synthetic work. The synthesis features of the originally
proposed hetiamacin A include a Sharpless asymmetric
dihydroxylation reaction and a Wittig olefination. The synthesis
features of revised hetiamacin A include a new way of total
synthesis of AI-77-B.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01350.
Experimental procedures and characterization data of all
new compounds; NMR spectra of all new compounds
(PDF)
particular, the chemical shifts of H-8′ and H-14′ were reported
to be δ 3.75 and δ 4.15, 4.50, respectively. However, these
protons for synthetic 1 were observed at δ 3.50 and δ 3.90,
4.29, respectively. Likewise, significant chemical shift differ-
ences for the corresponding C-8′ and C-14′ in the 13C NMR
spectra were also observed. For the natural product 1, the
chemical shifts for C-8′ and C-14′ were reported to be δ 81.3
and δ 79.4, whereas in our synthetic compound 1, these carbon
signals were found at δ 68.9 and δ 60.0.
Accession Codes
CCDC 1533092 contains the supplementary crystallographic
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.
Comparison of the 1H and 13C NMR data originally reported
for the natural product 1 with the synthetic compound 1
established that the original structure assignment for
hetaiamacin A was incorrect; this significant difference can
not arise from the stereochemistry. It seemed more plausible
that the actual structure of hetiamacin A should be revised to
structure 15. The revised structure 15 could be easily acquired
from AI-77-B by cyclization the 8′-hydroxyl group and 10′-
amine group. The total synthesis of AI-77-B was accomplished
from diol 9 in 7 steps. Cyclic sulfite formation from 9 and
subsequent oxidation with catalytic RuO4 and stoichiometric
NaIO4 provided the cyclic sulfate 16 in 52.3% yield over two
steps. The benzoate resulted from the regioselective nucleo-
philic ring opening of the cyclic sulfate 16 at the less hindered
C-2 position giving rise to inversion of stereochemistry at C-2,
formed under the acidic hydrolysis conditions. The benzoate
group was removed by methanolysis, and subsequent treatment
with HCl gave lactone 17 in 33.2% yield over three steps.
Coupling of segment 5 with the known compound 4 in the
presence of HATU and DIEA yielded compound 18 in 92%
yield. Deprotection of the Cbz group simultaneously over
palladium on activated carbon (10%) under hydrogen followed
by with NaOH aqueous solution gave AI-77-B ([α]2D5 = −77.8
(c 0.08, MeOH); lit.8,9b [α]2D2 = −78.2 (c 0.08, MeOH); mp
138.5−140 °C; lit.6 mp 139.5 °C). The absolute stereo-
chemistry of AI-77-B was also ascertained by single-crystal X-
ray crystallography. Treatment of AI-77-B with paraformalde-
hyde in toluene followed by amidation afforded the final
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wangyucheng@imb.pumc.edu.cn.
*E-mail: chenghangsun@hotmail.com.
ORCID
Gang Wu: 0000-0002-1798-4849
Chenghang Sun: 0000-0001-6813-8274
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the CAMS
Innovation Fund for Medical Sciences (Grant Nos. CAMS
2017-12M-B&R-08 and 2017-I2M-1-012) and the National
Natural Sciences Foundation of China (NSFC, Grant Nos.
81373308, 81611530716, and 81621064)
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