Site-selective and metal-free aliphatic C-H oxidation enabled synthesis of [5,24,25-d3]-(25s)-δ7-dafachronic acid

Article abstract of DOI:10.1002/chem.201500324

Steroid hormones play significant roles in both worms and mammalians. (25S)-Δ⁷-Dafachronic acid (Δ⁷-DA, 1) is a member of the dafachronic acid hormonal series that regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated Δ⁷-DA, [5,24,25-D3]-(25S)-Δ⁷-dafachronic acid ([D₃]-Δ⁷-DA, 2), as a useful chemical tool for subsequent biological studies. Key steps for this bioinspired synthesis approach include site-selective aliphatic C-H oxidation mediated by methyl(trifluoromethyl)dioxirane (TFDO), and the iridium/phosphine-oxazoline-catalyzed late-stage asymmetric deuterium reduction. Bio is best! [5,24,25-D3]-(25S)-Δ⁷-Dafachronic acid, an isotope-labeled steroid hormone has been synthesized in 14 steps from cholesterol inspired by biosynthesis. Key steps include a site-selective and metal-free aliphatic C-H oxidation and a late-stage catalytic asymmetric deuteration (see scheme). [5,24,25-D3]-(25S)-Δ⁷-Dafachronic acid will be severed as an effective chemical tool for the illumination of novel molecular mechanisms of longevity.

Full text of DOI:10.1002/chem.201500324

DOI: 10.1002/chem.201500324
Communication
&
Bioinspired Synthesis
Site-Selective and Metal-Free Aliphatic CÀH Oxidation Enabled
Synthesis of [5,24,25-D3]-(25S)-D7-Dafachronic acid
Weilong Liu,[a, b] Xiangke Li,[b] Jie Chen,[b] Tiemei Li,[b] Mengqiu Dong,[b] and
Xiaoguang Lei*[a, b, c]
Abstract: Steroid hormones play significant roles in both
worms and mammalians. (25S)-D7-Dafachronic acid (D7-
DA, 1) is a member of the dafachronic acid hormonal
series that regulates both development and lifespan of C.
elegans. Despite its importance, effective tools for the illu-
mination of its mode of action are lacking. Herein, we
report an efficient synthesis of trideuterated D7-DA,
[5,24,25-D3]-(25S)-D7-dafachronic acid ([D3]-D7-DA, 2), as
Figure 1. Structures of the steroid hormone dafachronic acids: (25S)-D7-Da-
a useful chemical tool for subsequent biological studies.
fachronic acid (D7-DA), [5,24,25-D3]-(25S)-D7-dafachronic acid ([D3]-D7-DA) and
Key steps for this bioinspired synthesis approach include
site-selective aliphatic CÀH oxidation mediated by meth-
yl(trifluoromethyl)dioxirane (TFDO), and the iridium/phos-
phine-oxazoline-catalyzed late-stage asymmetric deuteri-
um reduction.
(25S)-D4-dafachronic acid.
morphology, behavior, and metabolism to help them survive.
Consequently, the worms can live up to several months before
recovering and developing into normal L4 larvae.[3b]. In view of
the conservation of steroidal regulation of reproduction from
worms to humans and the short lifecycle of the worms,[2] C. el-
egans provide us a useful model organism to identify novel
molecular pathways for longevity.
Hormones play significant roles in the life process of organisms
as chemical messengers. Steroid hormones, which are derived
from cholesterol, exist in various species, from worms to mam-
mals. Dafachronic acid (DA, Figure 1) was the first steroid hor-
mone identified in nematodes, which regulates the develop-
ment and lifespan of Caenorhabditis elegans.[1] When environ-
mental conditions are favorable, the DAs bind to the nuclear
receptor DAF-12 and promote reproductive development. As
a result, C. elegans grow into adults in only three days after
four larval stages (L1–L4).[2] Harsh environments including food
shortage arrest development and larvae enter a long-lived
dauer stage.[3] Dauer larvae exhibit many adaptive changes in
As the endogenous ligands of DAF-12, DAs exist in C. ele-
gans in very small quantities, and their expression is regulated
throughout the worms’ lifecycle for performing various func-
tions.[1,4] D7-DA (1), also named as dafachronic acid A, was first
synthesized by Corey et al.[5] After Corey’s pioneering work,
a number of remarkable synthetic studies have also been re-
ported.[6] Enabled by chemical synthesis, several natural-prod-
uct-derived chemical probes have been utilized for biological
studies. To facilitate the studies of the biological function of
D7-DA as well as the related regulatory mechanisms for lon-
gevity, a robust and sensitive quantification method for moni-
toring D7-DA in vivo is urgently needed. In this regard, we de-
signed and developed the [5,24,25-D3]-(25S)-D7-dafachronic acid
([D3]-D7-DA, 2). In a previous publication,[4c] we demonstrated
that chemical probe 2 was effective for absolute quantification
of endogenous D7-DA during the reproductive development of
C. Elegans using mass spectrometry, which provided a new
avenue for further dissecting the related biological pathways.
Herein, we report an efficient synthesis of [D3]-D7-DA applying
a biogenetically inspired sequential CÀH oxidation strategy.
Biosynthetically, D7-DA is synthesized from cholesterol
through sequential oxidations (Scheme 1). D7-DA contains
a D7-double bond as compared to the D5-double bond in cho-
lesterol. Previous biosynthetic studies showed that the Rieske-
like oxidase DAF-36 initiated the first step and converted cho-
lesterol into 7-dehydrocholesterol.[7] The short-chain dehydro-
[a] W. Liu, Prof.Dr. X. Lei
Graduate School of Peking Union Medical College
and Chinese Academy of Medical Sciences, Beijing 100730 (China)
Fax: (+86)10-80704785
E-mail: xglei@pku.edu.cn
Homepage: http://www.chem.pku.edu.cn/leigroup/
[b] W. Liu, X. Li, J. Chen, T. Li, Prof.Dr. M. Dong, Prof.Dr. X. Lei
National Institute of Biological Sciences (NIBS)
Changping District, Beijing 102206 (China)
[c] Prof.Dr. X. Lei
Beijing National Laboratory for Molecular Sciences
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, Department of Chemical Biology
College of Chemistry and Molecular Engineering
Synthetic and Functional Biomolecules Center and Peking-Tsinghua
Center for Life Sciences, Peking University
Beijing 100871 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500324.
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dation and dehydration followed by sequential allylic oxidation
and reduction of the a,b-unsaturated double bond. Overall,
the hypothesis contains three reduction reactions (Scheme 2,
reduction 1, 2, 3) which will provide opportunities for deutera-
tion. The C-5 and C-6 deuteriums may be introduced in reduc-
tion step 1 by reduction of the D5-double bond with deuteri-
um instead of hydrogen gas. Furthermore, the stereoselective
reduction 3 under a deuterium atmosphere could lead to the
C-24 and C-25 isotopic substitution. In this way, we envisioned
that a tetradeuterated [D3]-D7-DA might be prepared.
In nature, enzyme-catalyzed oxidations are performed with
high substrate specificity as well as regioselectivity and/or ste-
reoselectivity. However, selective oxidation reactions of unacti-
vated sp3 CÀH bonds on complex substrates in the laboratory
remain an unfulfilled goal. Encouraged by the advances that
have been witnessed in CÀH activation over the past several
decades,[10] we initially tested methods for the selective CÀH
oxidation of C-25. Guided by a bioinspired strategy, the readily
available ketone 8 was selected as a synthetic precursor, which
was synthesized from cholesterol by acetyl protection, allylic
oxidation, followed by hydrogenation.[11] We thoroughly inves-
tigated various metal catalysts and oxidizing reagents such as
FeII,[12] RuIII,[13] ReVII,[14] and dioxiranes[15] (Scheme 3).
Scheme 1. Proposed biosynthesis of D7-DA.
genase/reductase (SDR), DHS-16, further oxidized 3-hydroxy
sterols into the corresponding 3-keto derivatives,[8] and finally
the terminal carboxylic acid moiety was introduced by the
P450 enzyme DAF-9 (Scheme 1).[1,9]
The combination of RuCl3·xH2O and KBrO3 afforded 25% de-
sired product while nonheme iron catalysts and rhenium cata-
lyst led to no reaction (see Scheme 3, entries 1–4, 7, and 8).
When DMDO was introduced as the oxidant, the reaction pro-
vided alcohol 9 in 30% yield (90% based on recovered starting
material, entry 9). Fortunately, further studies showed that
when the more reactive oxidant TFDO was used, we could
obtain the desired oxidation product 9 in 52% yield (70%
Inspired by the biosynthetic pathway and to make our syn-
thesis flexible for the installation of deuteriums, we designed
a bioinspired pathway (Scheme 2). We envisioned that the C-3
ketone moiety on ring A could be easily generated by oxida-
tion of the secondary alcohol. The D7-double bond on ring B
could be introduced through a sequence of allylic oxidation,
two reduction steps, and dehydration. We planned to install
the terminal C-26 carboxylic acid through a selective CÀH oxi-
Scheme 3. Optimization of the CÀH activation of the side chain. NR=no re-
action; ND=no desired product; mCPBA=3-chloroperoxybenzoic acid;
DMDO=dimethyldioxirane; TFDO=methyl(trifluoromethyl)dioxirane.
Scheme 2. Our bioinspired strategies for the synthesis of D7-DA and [D3]-D7-
DA.
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based on recovered starting material, entry 10), which showed
high site-selectivity as confirmed by Curci.[15b]
Encouraged by this result, our bioinspired approach to the
synthesis of the deuterated D7-DA was initiated by deuterium
reduction of enone 10, which was derived from cholesterol by
acetyl protection and allylic oxidation (Scheme 4).[11a] Previously
we found that enone 10 could be effectively hydrogenated
using stoichiometric Pd/C under a hydrogen atmosphere in
methanol. However, when the hydrogen gas was replaced by
the deuterium gas under normal pressure, the desired deuter-
ated ketone 11 was obtained with low isotopic. Thus we
screened different solvents as well as the pressure. We found
that a 0.5 MPa of deuterium pressure was necessary to achieve
the deuterated product 11 in 84% yield in ethyl acetate.[16]
Then the previously developed protocol for site-selective CÀH
oxidation was performed on 11. As expected, the deuterated
ketone 11 underwent CÀH oxidation reaction with TFDO to
generate alcohol 12 smoothly. Alcohol 12 was treated with
Burgess’ reagent followed by acid-catalyzed isomerization to
afford alkene 13. Unfortunately, the isotopic ratio of two deu-
teriums to one deuterium was significantly reduced from 89:11
to 40:60 based on HRMS analysis. Given the basicity of Bur-
gess’ reagent and the acidity of p-toluenesulfonic acid, both
could lead to hydrogen/deuterium exchange. We tried to find
out the reason for the deuterium loss. When dideu-
terated ketone 11 was treated with different organic
or inorganic bases, only de-acetyl product was ob-
served with little or no hydrogen/deuterium ex-
change even at high temperature. Acids, such as hy-
drochloric acid led to no deuterium loss at room
temperature. However, the C-6 deuterium was totally
exchanged with hydrogen when ketone 11 was re-
fluxed in benzene and water in the presence of cata-
lytic amount of p-toluenesulfonic acid.[17] At the same
time, the acetyl group was partly deprotected. Mono-
deuterated ketone 14 was obtained in 74% yield
after Burgess elimination followed by acid-catalyzed
isomerization, hydrogen/deuterium exchange with
excess amount of water and acetyl protection. The C-
26 oxygen atom was further installed by selenium di-
oxide mediated allylic oxidation to afford a mixture
of alcohol 15 and aldehyde 16.
Scheme 4. a) D2 (0.5 MPa), 5% Pd/C, EA, 84%; b) TFDO, CF3COCH3/CH2Cl2,
52%; c) Burgess’ reagent, PhMe, reflux; d) 1) 0.2 equiv TsOH·H2O, H2O/PhH
(1:99), 2), Ac2O, pyridine, DMAP, CH2Cl2, 74%; e) SeO2, 95% EtOH, reflux. Bur-
gess’ reagent=Et3N+SO2NÀCO2Me; DMAP=p-dimethylaminopyridine.
The mixture of allylic oxidation products 15 and 16
was used directly for the next step (Scheme 5).
Super-hydride reduction, followed by acetyl protec-
tion and Burgess dehydration proceeded smoothly to
afford alkene 19 in 31% yield over four steps. After
removal of the two acetyl groups in 19 with K2CO3,
the two hydroxyl groups were simultaneously oxi-
dized to ketone and aldehyde with PCC in 89% yield.
The aldehyde moiety was further converted to the
corresponding carboxylic acid by Pinnick oxidation to
generate compound 21 quantitatively.
The final catalytic asymmetric deuteration proved
Scheme 5. a) LiBH(Et)3, THF, À788C, a-OH/b-OH=4: 1; g) Ac2O, Py, 08C to RT; h) Burgess’
reagent, PhMe, reflux, 31% for 4 steps; i) K2CO3, MeOH/THF, reflux, 90%; j) PCC, CH2Cl2,
89%; k) NaClO2, NaH2PO4, tBuOH/H2O, quant.; l) Ir–SIPHOX-c, D2, Cs2CO3, CD3OD, 84%.
to be challenging. To the best of our knowledge,
very few examples of the late-stage installation of
the deuterium on complex bioactive molecules using Burgess’ reagent=Et3N+SO2NÀCO2Me; PCC=pyridinium chlorochromate.
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catalytic asymmetric process have been reported.[18] We
screened a number of conditions including the previously re-
ported method using chiral Ru-species catalyzed asymmetric
deuteration;[5,6d,f] however, the attempted reactions either
showed poor reaction kinetics or low deuteration ratio. Inter-
estingly we found that the chiral spiro iridium/phosphine-oxa-
zoline complexes (Ir–SIPHOX) developed by Zhou’s group in
recent years[19] were proven to be the optimal catalysts for this
transformation (Scheme 5). The Ir–SIPHOX-catalyzed asymmet-
ric deuteration showed exceptionally high reactivity with excel-
lent diastereoselectivity. As a result using 2.5% of Ir–SIPHOX-
c catalyst and 0.5 equivalents of Cs2CO3 under 1 atm. of D2, the
unsaturated carboxylic acid 21 was effectively converted to
[D3]-D7-DA (2) as a single diastereomer within only 30 min in
84% yield. The NMR spectra of synthetic [D3]-D7-DA appeared
the same as for the unlabeled D7-DA with the following excep-
tions: the disappearance of C25-H, singlet peak of C25-Me in
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1
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oxidation strategy to achieve the desired oxidation state. Of
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steroid skeleton. We also reported an efficient late-stage cata-
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Acknowledgement
We thank Profs. Qi-Lin Zhou, Jian-Hua Xie, and Shou-Fei Zhu
(Nankai University) for their generous donation of the Ir–
SIPHOX catalysts, and Prof. H.-J. Knçlker (Technische Universitꢁt
Dresden) for providing us the synthetic sample of dafachronic
acid A for comparison. We are also grateful for financial sup-
port from the National High Technology Project 973
(2012CB837400 and 2015CB856200), and the NNSFC
(21222209, 21472010 and 91313303).
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Keywords: asymmetric hydrogenation · bioinspired synthesis ·
CÀH oxidation · deuterium labeling · steroid hormone
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Received: January 26, 2015
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COMMUNICATION
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Bioinspired Synthesis
W. Liu, X. Li, J. Chen, T. Li, M. Dong,
X. Lei*
&& – &&
Bio is best! [5,24,25-D3]-(25S)-D7-Dafachron-
ic acid, an isotope-labeled steroid hor-
mone has been synthesized in 14 steps
from cholesterol inspired by biosynthe-
sis. Key steps include a site-selective
and metal-free aliphatic CÀH oxidation
and a late-stage catalytic asymmetric
deuteration (see scheme). [5,24,25-D3]-(25S)-
D7-Dafachronic acid will be severed as
an effective chemical tool for the illumi-
nation of novel molecular mechanisms
of longevity.
Site-Selective and Metal-Free Aliphatic
CÀH Oxidation Enabled Synthesis of
[5,24,25-D3]-(25S)-D7-Dafachronic acid
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!