Application of Relay C?H Oxidation Logic to Polyhydroxylated Oleanane Triterpenoids

Article abstract of DOI:10.1016/j.chempr.2020.04.007

Although clinical applications of abundant feedstock triterpenoids such as oleanolic acid are limited because of poor solubility and bioavailability, synthetic access to higher hydroxylated oleanane terpenoids is challenging. We now report the use of relay C?H oxidation logic to mimic the processes carried out in nature by P450 monooxygenase enzymes. To this end, we used the C-23-OH as natural handle for a hydrogen-atom transfer to access C-6, enabling the first syntheses of highly oxidized natural products uncargenin C and protobassic acid as well as uncovering the anti-leukemic activity of a synthetic intermediate. Chemical modification of readily available, scarcely oxidized natural products not only enables access to higher and more valuable congeners but can also pave the way to pharmaceutically relevant derivatives with enhanced properties. Achieving site-selective oxidation of such natural products is an endeavor often controlled by the presence of directing elements. Because of this fact, the oxidation of C?H bonds remote from such elements is either unfeasible or requires more elaborate synthetic strategies. We report the use of relay C?H oxidation as a concept to achieve the oxidation of previously inaccessible ring B in the abundant feedstock oleanolic acid. This resulted not only in the first total synthesis of a number of polyhydroxylated natural triterpenoids but also revealed an anti-leukemic intermediate. The strategy presented here could become a very general approach in the synthesis of valuable triterpenoids. Although biological applications of abundant feedstock triterpenoids such as oleanolic acid are limited because of poor solubility, synthetic access to higher hydroxylated metabolites is challenging. We use relay C?H oxidation logic to mimic the processes carried out in Nature by P450 monooxygenase enzymes. To this end, we use the C-23-OH as natural handle for a hydrogen-atom-transfer access to C-6, enabling the first syntheses of highly oxidized natural products as well as uncovering the anti-leukemic activity of a synthetic intermediate.

Full text of DOI:10.1016/j.chempr.2020.04.007

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Article
Application of Relay CÀH Oxidation Logic to
Polyhydroxylated Oleanane Triterpenoids
Martin Berger, Christian
Knittl-Frank, Sophie Bauer,
Georg Winter, Nuno Maulide
nuno.maulide@univie.ac.at
HIGHLIGHTS
Functionalization of a cheap and
abundant feedstock triterpenoid
Relay CÀH oxidation logic
Synthesis of highly oxygenated
natural products
C−H oxidation
sequence
Anti-leukemic activity of a
synthetic intermediate
Although biological applications of abundant feedstock triterpenoids such as
oleanolic acid are limited because of poor solubility, synthetic access to higher
hydroxylated metabolites is challenging. We use relay CÀH oxidation logic to
mimic the processes carried out in Nature by P450 monooxygenase enzymes. To
this end, we use the C-23-OH as natural handle for a hydrogen-atom-transfer
access to C-6, enabling the first syntheses of highly oxidized natural products as
well as uncovering the anti-leukemic activity of a synthetic intermediate.
Berger et al., Chem 6, 1183–1189
May 14, 2020 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.04.007

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Article
Application of Relay CÀH Oxidation Logic
to Polyhydroxylated Oleanane Triterpenoids
Martin Berger,1 Christian Knittl-Frank,1 Sophie Bauer,2 Georg Winter,2 and Nuno Maulide1,2,3,
*
SUMMARY
The Bigger Picture
Chemical modification of readily
available, scarcely oxidized
Although clinical applications of abundant feedstock triterpenoids
such as oleanolic acid are limited because of poor solubility and
bioavailability, synthetic access to higher hydroxylated oleanane
terpenoids is challenging. We now report the use of relay CÀH
oxidation logic to mimic the processes carried out in nature by
P450 monooxygenase enzymes. To this end, we used the C-23-OH
as natural handle for a hydrogen-atom transfer to access C-6,
enabling the first syntheses of highly oxidized natural products un-
cargenin C and protobassic acid as well as uncovering the anti-
leukemic activity of a synthetic intermediate.
natural products not only enables
access to higher and more
valuable congeners but can also
pave the way to pharmaceutically
relevant derivatives with
enhanced properties. Achieving
site-selective oxidation of such
natural products is an endeavor
often controlled by the presence
of directing elements. Because of
this fact, the oxidation of CÀH
bonds remote from such elements
is either unfeasible or requires
more elaborate synthetic
INTRODUCTION
A large part of modern medicine owes its success to the development of synthetic
organic chemistry of steroids.1 Spectacular advances since the past century have
relied on the ability to manipulate readily available steroidal feedstock using syn-
thetic organic chemistry.2,3 Pentacyclic triterpenes, epitomized by abundantly
available, olive-extracted oleanolic acid (1), cover a wide range of biological activ-
ities (Figure 1).4 Although compounds such as 1 are available in bulk quantities
(costing less than 1 USD per gram5), their intrinsic low aqueous solubility hinders
their application as drugs.6,7 Efforts to overcome this limitation via the synthesis
of derivatives have been made in order to exploit their full pharmacological poten-
tial.8–10 However, a prerequisite for derivatization of such compounds is the pres-
ence of functional handles for the appendage of suitable residues to their carbon
skeleton. Most families of pentacyclic triterpenes such as the oleananes, lupanes,
or ursanes share a uniform western hemisphere, and enzymatic hydroxylation oc-
curs by P-450 monooxygenases with high regioselectivity, meaning that highly
oxidized family members have been isolated from natural sources.11,12 However,
and in contrast to 1, such highly functionalized derivatives either occur naturally
typically in trace amounts or mandate laborious separation procedures for
isolation.13
strategies. We report the use of
relay CÀH oxidation as a concept
to achieve the oxidation of
previously inaccessible ring B in
the abundant feedstock oleanolic
acid. This resulted not only in the
first total synthesis of a number of
polyhydroxylated natural
triterpenoids but also revealed an
anti-leukemic intermediate. The
strategy presented here could
become a very general approach
in the synthesis of valuable
triterpenoids.
RESULTS AND DISCUSSION
Oxidation of the Skeleton of Oleanane Triterpenoids
In natural product synthesis, the site-specific oxidation of non-activated CÀH bonds
in terpenes has recently gained considerable attention.14–16 In the case of pentacy-
clic triterpenoids such as 1, only a restricted number of positions within the lipophilic
skeleton are accessible by synthetic C–H oxidation17–19 and modifications have
mainly been realized in the proximity of existing functional groups.20 Ring A has
been the primary target for functionalization, and an often utilized entry is the
remote oxidation of C-23 by using Baldwin’s stoichiometric cyclopalladation
method (Figure 1B).21–23 More recently, an indirect catalytic C-23-hydroxylation of
1 via CÀH silylation was reported by Hartwig.24
Chem 6, 1183–1189, May 14, 2020 ª 2020 Elsevier Inc. 1183

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Figure 1. Regioselective Hydroxylation of the Western Hemisphere of Oleanolic Acid (1)
(A) Natural oxidation of pentacyclic triterpenoids by P-450 monooxygenases, (B) previous approaches for oxidation of the western hemisphere by
cyclopalladation or CÀH silylation, and (C) extension of the chemical space by oxidation of ring B via a CÀH oxidation sequence as presented herein.
In contrast, oxidation of ring B in pentacyclic triterpenoids is more challenging
because of its isolation from directing functionalities. The group of Baran reported
an extensive survey of CÀH oxidation methods on the closely related lupane scaf-
fold.20 Therein, C-6 has been identified as the most electron-rich of the numerous
methylene groups; it was postulated that it should most likely be oxidized in a
non-directed fashion. Such an oxidation, however, could not be achieved. Indeed,
significant steric hindrance at C-6 caused by the gem-dimethyl at C-4 likely
thwarted all attempts. Furthermore, highly hydroxylated metabolites, such as pro-
tobassic acid (2b), possessing extreme diaxial strain are formidable challenges in
their own right; longstanding structural misassignments resulted from easy
(strain-relieving) dehydration of its axial C-6-OH under acidic conditions25 and
skeletal reorganization.26 Here, we present the application of relay CÀH oxidation
logic to conquer the synthesis of such highly hydroxylated oleananes from their
simplest precursor, oleanolic acid 1. We envisaged the installation of the C-23-
OH through directed catalytic oxidation of 1 and foresaw its role as ‘‘naturally
occurring’’ directing element that would enable the elusive C-6 oxidation to take
place (Figure 1C).
CÀH Oxidation Sequence for Functionalization of Ring B
Although Sanford’s catalytic CÀH acetoxylation protocol proved scalable for
oxidation of C-23,27–29 the alkene in 1 does not tolerate strong oxidants. We there-
fore developed a one-pot sequence to 330 consisting of protection via halolacto-
nization with N-bromosuccinimide (NBS), oxidation of C-3-OH with trichloroisocya-
nuric acid (TCCA), and oxime formation with hydroxylamine in quantitative yield
1Institute of Organic Chemistry, University of
Vienna, Wahringer Straße 38, 1090 Vienna,
¨
without the need for any further purification (Scheme 1). CÀH acetoxylation of 3
was found to take place even at room temperature and, at 45ꢀC, 4 was obtained
in 56% yield with a diastereomeric ratio (d.r.) of 75:25 in favor of the desired iso-
mer. The minor diastereomer was found to be the C-4 epimer of 4, and activation
of the axial methyl group might be attributed to a distorted chair conformation of
the cyclohexanone oxime moiety in 3. In spite of the moderate diastereoselectivity,
this catalytic direct oxidation is scalable and presents considerable advantages
when compared with the oleanane oxidations mentioned earlier.
Austria
2CeMM Research Center for Molecular Medicine
of the Austrian Academy of Sciences,
Lazarettgasse 14, 1090 Vienna, Austria
3Lead Contact
*Correspondence: nuno.maulide@univie.ac.at
https://doi.org/10.1016/j.chempr.2020.04.007
1184 Chem 6, 1183–1189, May 14, 2020

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O
O
HO
O
O
O
B) Pd(OAc)2
PIDA, 45 °C
A) NBS, py,
then TCCA
then H2NOH
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
3
3
C–H
acetoxylation
Br
Me
Br
Me
HO
Me
*
Me
23
23
N
N
Me Me
Me Me
Me Me
OAc
OAc
OH
C) K2CO3, MeOH
then CuSO4
oleanolic acid (1)
3 (>95%)
4 (56%)
*d.r. = 3:1
O
O
O
O
O
O
D) PPTS, (CH2OH)2
E) PIDA, I2, RT
Me
O
Me
Me
Me
Me
O
Me
Br
F) PTSA
Me
Me
Me
1,5-HAT
Br
Me
Br
Me
O
4
H
6
O
O
Me
H
23
Me Me
Me Me
Me Me
O
OH
H
7 (>95%)
6 (53% over 2 steps)
5 (65%)
"AcOI"
O
O
O
O
Me
O
Me
Me
Me
-fragmentation
at C-4
G) RuCl3, NaIO4
Me
O
C-23 oxidation
Br
Me
Br
Me
4
O
O
Me
Me Me
Me Me
7 (x-ray)
8a (69%)
Scheme 1. Oxidation Sequence from Oleanolic Acid (1) to Dilactone 8a
Reagents and conditions: (A) NBS, pyridine, RT, 1 h, then TCCA, 1.5 h, then i-PrOH, then NH2OH$HCl, 16 h, >95%; (B) Pd(OAc)2 (15 mol %), PIDA, AcOH,
Ac2O, 45 ꢀC, 15 h, 56%, 3:1 d.r.; (C) K2CO3, MeOH, 60 ꢀC, 1.5 h, then CuSO4$5H2O, THF, H2O, 50ꢀC, 15 h, 65%; (D) PPTS, ethylene glycol, benzene, Dean-
Stark, reflux, 16 h; (E) PIDA, I2, CaCO3, RT, 2 h, 53% over 2 steps; (F) PTSA, acetone, 50 ꢀC, 18 h, >95%; (G) RuCl3$3 H2O, NaIO4, CH3CN, CCl4, water,
phosphate buffer, RT, 65 h, 69%.
Global deprotection to generate ketol 5 was performed again in a one-pot fashion
by treatment with K2CO3 in MeOH and subsequent addition of CuSO4 pentahy-
drate in a ternary solvent mixture.31 This optimized and scalable sequence might
serve for a gram-scale preparation of hederagonic acid (deprotected 5) if desired.
Next, we attempted CÀH oxidation of C-6 via in situ generation of a hypoiodite
intermediate at C-23, which should then undergo homolytic cleavage to give an
O-centered radical and subsequent HAT (hydrogen atom transfer) from C-6. How-
ever, first experiments on 5 resulted only in b-fragmentation at C-4.32,33 The facile
nature of this fragmentation can once more be attributed to release of the consid-
erable 1,3-diaxial strain in 5 (cf. Scheme 1). After screening several derivatives of 5,
simple ketalization of the C-3 carbonyl was found to prevent this undesired b-frag-
mentation. Ether 6 was thus obtained in 53% yield over 2 steps by treatment with
iodobenzene diacetate (PIDA) and iodine at an ambient temperature.34 Remark-
ably, this cyclization proceeds readily, even without heating or irradiation.19 Unam-
biguous assignment was accomplished by X-ray analysis of ketone 7 (obtained af-
ter deprotection with p-toluenesulfonic acid [PTSA]). Subsequent ruthenium-
mediated oxidation at C-23 in 7 yielded the versatile dilactone 8a in 69% yield
over 2 steps.35
Access to Polyhydroxylated Natural Triterpenoids
With 8a in hand, we targeted the natural products uncargenin C (2a)36 and proto-
bassic acid (2b).37 The high anti-inflammatory activity of these secondary metabo-
lites is also ascribed to the additional OH group at C-6.38 As shown in Scheme 2,
the synthesis of 2b was conducted in analogy to 2a but with prior diversification at
C-2 by a-acetoxylation of the ketone, affording 8b as a single isomer. For conver-
sion to the natural products, redox differentiation of the two neopentylic lactones
Chem 6, 1183–1189, May 14, 2020 1185

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O
OH
O
28
28
O
O
then
Zn/AcOH
Me
Me
B) LiAlH4
(excess)
Me
Me
Me
Me
Me
OH
2 Me
O
Me
OH
R
R
R
HO
HO
Br
Me
Br
Me
6
Me
HO
O
O
HO
Me Me
Me Me
Me Me
R
H
R
R
8a
9a
9b
10a
10b
H
OH
H (60%)
OH
A) Pb(OAc)4
8b
OAc (51%)
C) PPTS, acetone
D) TPAP, NMO·H2O
28
HO
O
28
HO
O
28
HO
O
Me
Me
E) PPTS,
MeOH
Me
Me
Me
OH
Me
R
R
R
F) LiBH4
Me
Me
Me
2
2
2
O
HO
HO
HO
HO
O
Me
Me
6
6
Me
Me
6
Me Me
O
R
Me Me
Me Me
O
Me
R
R
Uncargenin C (2a)
Protobassic acid (2b)
H (96%)
OH (58%)
12a H,H (83%)
12b
O (77%)
11a H,H (50% over 2 steps)
11b O (16% over 3 steps)
Scheme 2. Diversification of Intermediate 8a Leading to Natural Products Uncargenin C (2a) and Protobassic Acid (2b)
Reagents and conditions: (A) Pb(OAc)4, AcOH, 75 ꢀC, 16 h, 51%; (B) 10a: LiAlH4, THF, 0/20 ꢀC, 20 min, then Zn, AcOH, 50 ꢀC, 1 h, then RT, 16 h, 60%;
10b: LiAlH4, THF, 0/20 ꢀC, 20 min, then Zn, AcOH, 40 ꢀC, 1.5 h; (C) PPTS, acetone, RT, 16 h; (D) 11a: TPAP (40 mol %), NMO$H2O, NMO, CH3CN, RT, 48
h, 50% over 2 steps; 11b: TPAP (90 mol %), NMO$H2O, NMO, CH3CN, RT, 72 h, 16% over 3 steps from 8b; (E) 12a: PPTS, MeOH, RT, 8 h, 83%; 12b: PPTS,
MeOH, RT, 12 h, 77%; (F) 2a: LiBH4, THF, RT, 2 h, 96%; 2b: LiBH4, THF, 0 ꢀC/RT, 4 h, 58%;
was required. This was achieved by treatment with LiAlH4. Instead of an expected
global reduction of the numerous carbonyl groups in 8a,b, the northern lactone
resisted full reduction and remained in the lactol form. Given that 9a,b were found
prone to elimination of HBr and undesired epoxyaldehyde formation upon at-
tempted isolation, direct reduction with zinc powder in one-pot led to aldehydes
10a,b. Simultaneous inversion of the alcohols at C-6 (and C-2 in case of 10b) was
expected to be challenging because of generation of high 1,3-diaxial strain. How-
ever, protection of the polyols 10a,b via acetonide formation allowed a selective
oxidation of C-2- and C-6-OH and concomitant regeneration of the acid function-
ality at C-28. Use of the Ley oxidation39 with NMO-monohydrate as co-oxidant40
was decisive for smooth generation of 11a,b in 2 steps from 10a,b. Deprotection
with pyridinium p-toluenesulfonate (PPTS) and reduction of the ketone functional-
ities in 12a,b at C-6 (and C-2 in case of 12b) with excess LiBH4 coerced both OH-
groups into axial orientation, affording uncargenin C (2a) and protobassic acid
(2b), respectively.
Furthermore, diol 13 (Figure 2A)41 was prepared from 10a by using a procedure by
the group of Li,42 albeit in low yield (see Supplemental Information).
To assay putative antineoplastic activities of the compounds prepared in this work,
their effect on the proliferative capacity of the MV4-11 myelomonocytic leukemia
cell line was assessed, including commercially available b-amyrin (14) as reference
(structures summarized in Figure 2A). MV4-11 cells feature a genomic rearrange-
ment of the Mixed Lineage Leukemia (MLL-AF4) gene known to be associated
with an aggressive and treatment-refractory disease progression.43 Compared
with vehicle (DMSO) control, most synthetic derivatives (12a, uncargenin C (2a), pro-
tobassic acid (2b), 13, and 14) had no measurable effect on the proliferation of MV4-
11 leukemia cells. In contrast, cellular treatment with 10a prompted a pronounced
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A
C
D
R28
R2
Me
Me
R6
Me
HO
R23
R6
Me
Me Me
Compound
uncargenin C (2a)
R2
R23
R6
R6
R28
CO2H
H
OH
H
OH
OH
OH
OH
H
H
H
OH
protobassic acid (2b)
triol 10a
OH CO2H
OH
H
CHO
CO2H
ketone 12a
diol 13
H
O
H
OH
H
H
H
CH3
CH3
-amyrin (14)
H
H
B
E
Figure 2. Anti-leukemic Properties of Natural Products and Synthetic Intermediates
(A) Summary of tested compounds.
(B) Effect of the compounds on the myelomonocytic leukemia cell line MV4-11 showing a pronounced effect of triol 10a (triplicate analysis).
(C) Activity of triol 10a (compared with DMSO and b-amyrin [14]) on MV4-11, K052 and HL-60 acute myeloid leukemia cell line models (triplicate
analysis).
(D) Dose-ranging cellular viability assays after 72 h drug incubation. (Triplicate analysis, nd, not determined).
(E) Cell cycle profile in MV4-11 cell line after treatment with triol 10a compared with that of DMSO and b-amyrin (14) (triplicate analysis). Treatments in
(B), (C), and (E) were performed with 20 mM compound concentrations. Data are represented as mean G SEM.
growth defect (Figures 2B and 2C). Importantly, the anti-proliferative effect of 10a
extended from MV4-11 cells to non-MLL-rearranged acute myeloid leukemia cell
line models (HL-60 and K052) (Figures 2C and 2D). Mechanistically, its anti-leukemic
properties were linked to an S/G2 cell-cycle arrest (Figure 2E).
Conclusion
In summary, we report a versatile approach for functionalization of ring B in ole-
anane triterpenoids and demonstrate its utility with the first synthesis of polyhy-
droxylated natural products uncargenin C (2a) and protobassic acid (2b). Among
the tested aglycons and synthetic intermediates, triol 10a featured a unique anti-
leukemic activity by inducing an S/G2 arrest in the cell cycle. As the potency of
10a limits in vivo efficacy studies, future research will aim to further increase its
cellular potency. Because hydroxylation not only improves solubility and bioavail-
ability of abundant pentacyclic triterpenoids, we are certain this approach
will find application in the synthesis of further derivatives of pentacyclic
triterpenoids.
Chem 6, 1183–1189, May 14, 2020 1187

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EXPERIMENTAL PROCEDURES
Resource Availability
Lead Contact
Further information and requests for resources and reagents should be directed
to and will be fulfilled by the Lead Contact, Nuno Maulide (nuno.maulide@univie.
ac.at).
Materials Availability
Supplemental Information containing Figures S1–S33 and Tables S1–S5 can be
found online.
Data and Code Availability
Parameters for the structure of 7 (see Supplemental Information) is available free of
charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.
ac.uk/) under reference number CCDC: 1896161.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.04.007.
ACKNOWLEDGMENTS
Generous support by the University of Vienna is acknowledged. M.B. and C.K.-F. are
fellows of the Austrian Science Fund (FWF)-funded doctoral program MolTag
(W1232). We thank Dr. A. Oppedisano and Ing. A. Roller (both from U. Vienna) for
early experiments, discussions and X-ray measurements, respectively. S. Felsinger
and H. Kahlig (U. Vienna) are acknowledged for 2D-NMR measurements. CeMM
¨
and the Winter lab are supported by the Austrian Academy of Sciences and FWF.
AUTHOR CONTRIBUTIONS
M.B. and C.K.-F. performed and analyzed the chemical experiments. M.B., C.K.-F.,
G.W., and N.M. co-wrote the manuscript. S.B. performed the biological testing.
N.M. directed the project.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: January 24, 2020
Revised: March 21, 2020
Accepted: April 9, 2020
Published: May 5, 2020
REFERENCES
1. Lednicer, D. (2011). Steroid Chemistry at a
Glance (Wiley).
Pharmacological activities of natural
triterpenoids and their therapeutic
implications. Nat. Prod. Rep. 23, 394–411.
oleanolic acid after intravenous and oral
administration in rats. Biopharm. Drug Dispos.
28, 51–57.
2. Djerassi, C. (1992). Steroid research at syntex:
8. Xu, K., Chu, F., Li, G., Xu, X., Wang, P., Song, J.,
Zhou, S., and Lei, H. (2014). Oleanolic acid
synthetic oligoglycosides: a review on recent
progress in biological activities. Pharmazie 69,
483–495.
‘‘the pill’’ and cortisone. Steroids 57, 631–641.
5. 100 g available for 99 USD at AK scientific in
October. (2019).
3. Renata, H., Zhou, Q., and Baran, P.S. (2013).
Strategic redox relay enables a scalable
synthesis of ouabagenin, a bioactive
cardenolide. Science 339, 59–63.
6. Liu, J. (2005). Oleanolic acid and ursolic acid:
Research Perspectives. J. Ethnopharmacol.
100, 92–94.
9. Zhou, M., Zhang, R.H., Wang, M., Xu, G.B., and
Liao, S.G. (2017). Prodrugs of triterpenoids and
their derivatives. Eur. J. Med. Chem. 131,
222–236.
4. Dzubak, P., Hajduch, M., Vydra, D., Hustova, A.,
Kvasnica, M., Biedermann, D., Markova, L.,
Urban, M., and Sarek, J. (2006).
7. Jeong, D.W., Kim, Y.H., Kim, H.H., Ji, H.Y., Yoo,
S.D., Choi, W.R., Lee, S.M., Han, C.K., and Lee,
H.S. (2007). Dose-linear pharmacokinetics of
1188 Chem 6, 1183–1189, May 14, 2020

ll
Article
10. Salvador, J.A.R., Leal, A.S., Valdeira, A.S.,
Gonc¸alves, B.M.F., Alho, D.P.S., Figueiredo,
S.A.C., Silvestre, S.M., and Mendes, V.I.S.
(2017). Oleanane-, ursane-, and quinone
methide friedelane-type triterpenoid
22. Zhu, C., Tang, P., and Yu, B. (2008). Total
synthesis of lobatoside E, a potent antitumor
cyclic triterpene saponin. J. Am. Chem. Soc.
130, 5872–5873.
reaction of alkoxy radicals in steroidal systems.
J. Org. Chem. 62, 2975–2981.
33. Deng, Y., and Snyder, J.K. (2002). Preparation
of a 24-Nor-1,4-dien-3-one triterpene
derivative from betulin: a new route to 24-
Nortriterpene analogues. J. Org. Chem. 67,
2864–2873.
23. Honda, T., Janosik, T., Honda, Y., Han, J., Liby,
K.T., Williams, C.R., Couch, R.D., Anderson,
A.C., Sporn, M.B., and Gribble, G.W. (2004).
Design, synthesis, and biological evaluation of
biotin conjugates of 2-cyano-3,12-
derivatives: recent advances in cancer
treatment. Eur. J. Med. Chem. 142, 95–130.
11. Ghosh, S. (2017). Triterpene structural
diversification by plant cytochrome P450
enzymes. Front. Plant Sci. 8, 1886.
34. Concepcio´ n, J.I., Francisco, C.G., Hernande´ z,
R., Salazar, J.A., and Sua´rez, E. (1984).
Intramolecular hydrogen abstraction.
dioxooleana-1,9(11) dien-28-oic acid for the
isolation of the protein targets. J. Med. Chem.
47, 4923–4932.
Iodosobenzene diacetate, an efficient and
convenient reagent for alkoxy radical
generation. Tetrahedron Lett 25, 1953–1956.
12. Miettinen, K., Pollier, J., Buyst, D., Arendt, P.,
Csuk, R., Sommerwerk, S., Moses, T., Mertens,
J., Sonawane, P.D., Pauwels, L., et al. (2017).
The ancient CYP716 family is a major
contributor to the diversification of eudicot
triterpenoid biosynthesis. Nat. Commun. 8,
14153.
24. Simmons, E.M., and Hartwig, J.F. (2012).
Catalytic functionalization of unactivated
primary CÀH bonds directed by an alcohol.
Nature 483, 70–73.
35. Carlsen, P.H.J., Katsuki, T., Martin, V.S., and
Sharpless, K.B. (1981). A greatly improved
procedure for ruthenium tetroxide catalyzed
oxidations of organic compounds. J. Org.
Chem. 46, 3936–3938.
25. Yosioka, I., Inada, A., and Kitagawa, I. (1974).
Soil bacterial hydrolysis leading to genuine
aglycone—VIII: structures of a genuine
sapogenol protobassic acid and a
13. Bucar, F., Wube, A., and Schmid, M. (2013).
Natural product isolation – how to get from
biological material to pure compounds. Nat.
Prod. Rep. 30, 525–545.
36. Khan, I.A., Sticher, O., and Rali, T. (1993). New
triterpenes from the leaves of Timonius Timon.
J. Nat. Prod. 56, 2163–2165.
prosapogenol of seed kernels of Madhuca
longifolia L. Tetrahedron 30, 707–714.
14. Hung, K., Condakes, M.L., Morikawa, T., and
Maimone, T.J. (2016). Oxidative entry into the
Illicium sesquiterpenes: enantiospecific
synthesis of (+)-Pseudoanisatin. J. Am. Chem.
Soc. 138, 16616–16619.
37. Kitagawa, I., Inada, A., Yosioka, I., Somanathan,
R., and Sultanbawa, M.U.S. (1972). Protobassic
acid, a genuine Sapogenol of seed kernels of
Madhuca longifolia. L. Chem. Pharm. Bull. 20,
630–632.
26. Sen, S., Sahu, N.P., and Mahato, S.B. (1993).
Novel migrated oleanane triterpenoid
sapogenins from Mimusops elengi.
Tetrahedron 49, 9031–9038.
27. Desai, L.V., Hull, K.L., and Sanford, M.S. (2004).
Palladium-catalyzed oxygenation of
unactivated sp3 C-H Bonds. J. Am. Chem. Soc.
126, 9542–9543.
15. See, Y.Y., Herrmann, A.T., Aihara, Y., and
Baran, P.S. (2015). Scalable C-H oxidation with
copper: synthesis of polyoxypregnanes. J. Am.
Chem. Soc. 137, 13776–13779.
38. Quang, T.H., Ngan, N.T.T., Minh, C.V., Kiem,
P.V., Nhiem, N.X., Tai, B.H., Thao, N.P., Tung,
N.H., Song, S.B., and Kim, Y.H. (2011). Anti-
inflammatory triterpenoid saponins from the
stem bark of Kalopanax pictus. J. Nat. Prod. 74,
1908–1915.
28. Neufeldt, S.R., and Sanford, M.S. (2010). O-
acetyl oximes as transformable directing
groups for Pd-catalyzed C-H Bond
16. Chen, K., and Baran, P.S. (2009). Total synthesis
of eudesmane terpenes by site-selective CÀH
oxidations. Nature 459, 824–828.
39. Griffith, W.P., Ley, S.V., Whitcombe, G.P., and
White, A.D. (1987). Preparation and use of
tetra-n-butylammonium per-ruthenate (TBAP
reagent) and tetra-n-propylammonium per-
ruthenate (TPAP reagent) as new catalytic
oxidants for alcohols. J. Chem. Soc., Chem.
Commun. https://doi.org/10.1039/
functionalization. Org. Lett. 12, 532–535.
17. Newhouse, T., and Baran, P.S. (2011). If C-H
Bonds Could Talk: selective C-H Bond
oxidation. Angew. Chem. Int. Ed. Engl. 50,
3362–3374.
29. Siler, D.A., Mighion, J.D., and Sorensen, E.J.
(2014). An enantiospecific synthesis of
Jiadifenolide. Angew. Chem. Int. Ed. Engl. 53,
5332–5335.
18. White, M.C., and Zhao, J. (2018). Aliphatic C-H
Oxidations for late-stage functionalization.
J. Am. Chem. Soc. 140, 13988–14009.
C39870001625.
30. Kaminskyy, D., Bednarczyk-Cwynar, B.,
Vasylenko, O., Kazakova, O., Zimenkovsky, B.,
Zaprutko, L., and Lesyk, R. (2012). Synthesis of
new potential anticancer agents based on 4-
thiazolidinone and oleanane scaffolds. Med.
Chem. Res. 21, 3568–3580.
40. Schmidt, A.K., and Stark, C.B.W. (2011). TPAP-
catalyzed direct oxidation of primary alcohols
to carboxylic acids through stabilized aldehyde
hydrates. Org. Lett. 13, 4164–4167.
19. Qiu, Y., and Gao, S. (2016). Trends in applying
CÀH oxidation to the total synthesis of natural
products. Nat. Prod. Rep. 33, 562–581.
41. Wang, K.W., Mao, J.S., Tai, Y.P., and Pan, Y.J.
(2006). Novel skeleton terpenes from Celastrus
hypoleucus with anti-tumor activities. Bioorg.
Med. Chem. Lett. 16, 2274–2277.
20. Michaudel, Q., Journot, G., Regueiro-Ren, A.,
Goswami, A., Guo, Z., Tully, T.P., Zou, L.,
Ramabhadran, R.O., Houk, K.N., and Baran,
P.S. (2014). Improving physical properties via C-
H oxidation: chemical and enzymatic
approaches. Angew. Chem. Int. Ed. Engl. 53,
12091–12096.
31. Attanasi, O., Gasperoni, S., and Carletti, C.
(1980). Effect of copper(II) ions in organic
synthesis. V. regeneration of carbonyl
compounds from tosylhydrazones,
phenylhydrazones, hydrazones, oximes and
semicarbazones by hydrolysis in the presence
of copper(II) sulphate pentahydrate. J. Prakt.
Chem. 322, 1063–1066.
42. Dai, X.J., and Li, C.J. (2016). En route to a
practical primary alcohol deoxygenation.
J. Am. Chem. Soc. 138, 5433–5440.
21. Baldwin, J.E., Jones, R.H., Najera, C., and Yus,
M. (1985). Functionalisation of unactivated
methyl groups through cyclopalladation
reactions. Tetrahedron 41, 699–711.
43. Grimwade, D., Ivey, A., and Huntly, B.J.P.
(2016). Molecular landscape of acute myeloid
leukemia in younger adults and its clinical
relevance. Blood 127, 29–41.
32. Boto, A., Freire, R., Herna´ndez, R., Sua´rez, E.,
and Rodrı´guez, M.S. (1997). Tandem
b-fragmentationÀhydrogen abstraction
Chem 6, 1183–1189, May 14, 2020 1189