Synthesis of (-)-mitrephorone A via a bioinspired late stage C-H oxidation of (-)-mitrephorone B

Article abstract of DOI:10.1021/jacs.9b11646

We present a bioinspired late-stage C-H oxidation of the ent-trachylobane natural product mitrephorone B to mitrephorone A. The realization of this unprecedented transformation was accomplished by either an iron-catalyzed or electrochemical oxidation and enabled access to the densely substituted oxetane in one step. Formation of mitrephorone C, which is lacking the central oxetane unit but features a keto-function at C2, was not formed under these conditions.

Full text of DOI:10.1021/jacs.9b11646

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Communication
Synthesis of (–)-Mitrephorone A via a Bio-inspired
Late Stage C–H Oxidation of (–)-Mitrephorone B
Lukas Anton Wein, Klaus Wurst, Péter Angyal, Lara Weisheit, and Thomas Magauer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11646 • Publication Date (Web): 26 Nov 2019
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Synthesis of (–)-Mitrephorone A via a Bio-inspired Late Stage C–H
Oxidation of (–)-Mitrephorone B
Lukas Anton Wein,† Klaus Wurst,‡ Peter Angyal,§ Lara Weisheit,† and Thomas Magauer*,†
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†Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80–
82, 6020 Innsbruck, Austria
‡Institute of General, Inorganic and Theoretical Chemistry, Leopold-Franzens-University Innsbruck, Innrain 80−82, 6020 Inns-
bruck, Austria
§Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, 1117 Budapest, Hungary
Supporting Information Placeholder
Retrosynthetic bond disconnections of our initial target, mi-
trephorone B (2), revealed tricyclo-[3.2.1.02,7]oct-3-ene 7 as the
ABSTRACT: We present a bio-inspired late stage C–H oxidation
of the ent-trachylobane natural product mitrephorone B to mi-
precursor. For the installation of this motif, 7 was traced back to
5-vinyl-1,3-cyclohexadiene 8 by employing an intramolecular
retro-Diels–Alder (IMDA) reaction.
trephorone A. The realization of this unprecedented transformation
was accomplished by either an iron-catalyzed or electrochemical
oxidation and enabled access to the densely substituted oxetane in
one step. Formation of mitrephorone C, which is lacking the central
oxetane unit but features a keto-function at C2, was not formed un-
der these conditions.
Scheme 1. Schematic Biosynthesis of Mitrephorone A (1), B
(2), and C (3) and Retrosynthetic Analysis.
GGPP (C20
)
The ent-trachylobane natural products mitrephorone A (1), B (2)
and C (3) are structurally related to the diterpenoids ent-atise-
rene, ent-beyerene, and ent-kaurene, but they display a rare and
synthetically challenging oxidation pattern (Scheme 1).1,2 An ini-
tial bioactivity screen revealed moderate anti-microbial and anti-
cancer activities for 1–3.2 The proposed biosynthesis begins with
the cyclization of geranylgeranyl pyrophosphate (GGPP, C20) to
the ent-pimarenyl carbocation 4. The mechanism for the conver-
sion of 4 into the ent-trachylobane skeleton 5 was clarified by
Tantillo and excludes the intermediacy of a previously postulated
secondary carbocation.3 After the initial cyclization phase, 5 is
enzymatically postmodified. As shown for the formation of mi-
trephorone B (2), it is reasonable that either the trans-decalin
framework is oxidized first (Path A) or that functionalization of
C19 to give ent-trachyloban-19-oic acid (6) precedes this event
(Path B). At the outset of this project, we hypothesized that 2
represents the pivotal intermediate from which 1 and 3 are gen-
erated via selective oxidation. Based on this consideration and
our continued interest to constructing synthetically challenging
oxetanes,4 we envisioned investigation of this oxidation process
in the chemical laboratory. Notably, mimicking the putative oxi-
dation of mitrephorone B (2) to mitrephorone A (1) would allow
us to circumvent the limited substrate scope generally associ-
ated with conventional oxetane formation methods such as ring-
expansion, [2+2]-cycloaddition, and nucleophilic displacement
reactions.5,6 Carreira recently disclosed the synthesis of 1 em-
ploying an elegant Umpolung strategy.5 Here we present the first
total synthesis of mitrephorone B (2) and show its conversion to
mitrephorone A (1) via a bio-inspired late-stage C–H oxidation.7,8
Me
Me
Me
[O]
Path B
Me
Me
Me
H
H
H
H
H
H
– H
HO2C Me
Me Me
Me Me
19
19
19
ent-pimarenyl cation (4)
5
6
[O], then [O]
Path A
Me
[O]
Me
Me
[O]
Me
Me
Me
9
2
O
[O]
O
H
H
5
O
O
O
MeO2C
MeO2C
Me OH
MeO2C
Me O
mitrephorone A (1)
Me OH
mitrephorone B (2)
mitrephorone C (3)
Aldol/Elimination
Alkylation
Me
Diels–Alder
Me
Me
Me
16
8
9
2
O
O
O
5
B Me
B
Me
MeO2C
Me O
MeO C Me
2
7
8
O
Robinson
16
O
Me
Me
H
5
8
OH
6
MeO2C Me
10 (ref 11)
MeO C Me
OH
2
Dihydroxylation
9
(85% ee, 8 steps)
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Page 2 of 6
This powerful type of IMDA was previously emulated in related
provide 15 in 72% overall yield after three cycles. Having gained
access to 15 also enabled investigation of the limitation of ox-
etane formation based on nucleophilic substitution.21 Attempts to
initiate ring-closure of diol 15 or its C6-keto derivative by proto-
nation, halogenation or epoxidation of the C9–C11 alkene were
met with failure. In most cases, unreacted starting material was
recovered and decomposition prevailed under more forcing con-
ditions.
For the selective alkene reduction of 15, Shenvi’s direct hydro-
gen atom transfer (HAT) protocol22 was identified to be method
of choice. Under these conditions (Mn(dpm)3, PhSiH3, t-BuOOH,
23 °C) hydrogenolysis of the cyclopropane was not observed
and 16 was isolated in 75% yield as a single diastereomer at C9
together with only minor amounts of diastereomerically pure triol
17 (22%, vide infra).
Completion of the synthesis of mitrephorone B (2) involved oxi-
dation (tetrapropylammonium perruthenate (TPAP), NMO, 4 Å
molecular sieves) of 16 to 18 (77%), removal of the tertiary alco-
hol using samarium(II) iodide (74%)4,23 and installation of the 1,2-
diketone (SeO2, 100 °C, 1,4-dioxane).24 The analytical data ob-
tained for synthetic mitrephorone B (2) were in full agreement
with those reported for the natural material.
Having secured ample amounts of 2, we set out to test the fea-
sibility of the bio-inspired C–H oxidation to 1. Gratifyingly, expo-
sure of mitrephorone B (2) to the White–Chen catalyst system
(25 mol% Fe(R,R)-PDP, H2O2, AcOH, MeCN, 23 °C, 1 h) af-
forded mitrephorone A (1) in 60% yield.25 To the best of our
knowledge, this represents the first example of oxetane for-
mation via C–H oxidation. The use of the enantiomeric Fe(S,S)-
PDP catalyst appears to represent the mismatched case for this
C–H oxidation and only 30% of mitrephorone A (1) were ob-
tained. In the absence of the iron catalyst, no oxidation was ob-
served. In addition, we were also able to access 1 by electro-
chemical oxidation of 2 (49%) using the protocol described by
Baran (quinuclidine, Me4NBF4, RVC foam anode, Ni cathode,
0.2 mA, 1.4–1.7 V, 2 F/mol, HFIP, MeCN, 23 °C, 4 h).26 Alterna-
tively, applying photocatalysis (TBADT, aq. HCl; 365 nm)27 we
observed significantly lower yields of 1 (14%).
We found that the presence of the enol is crucial to furnish the
oxetane. All attempts to effect oxetane formation employing the
a-hydroxyketone 18 failed, and only decomposition was ob-
served or starting material was recovered. Further insight was
obtained by investigating the iron-mediated C–H oxidation of
known diosphenol 20.5 For this purpose, triol 17 was first con-
verted to 19 in four steps. Exposure of 19 to tris(dimethyla-
mino)sulfonium difluorotrimethylsilicate (TASF) liberated the ter-
tiary alcohol and induced tautomerization to give 20. This inter-
mediate was subjected to the White–Chen system as before to
promote cyclization to mitrephorone A (1) in 13%.28
The selectivity towards oxetane formation of 2 might be a result
of the short distance between C5 of the enol and H9 (2.64 Å). In
agreement with the literature, we believe that the sequence is
initiated by oxidation of the enone to a tertiary radical.26,29 The
subsequent incorporation of oxygen might occur directly at C5
or, after radical translocation,30 at C9. Final ring-closure to the
oxetane can occur for both pathways (see Supporting Infor-
mation for details).
systems by Trauner9 and has proven its efficiency in the synthe-
sis of 1.5 Removal of the C16 quaternary stereocenter revealed
enone 9, which contains the retron for a simplifying Robinson
annulation.10 Further disconnection of 9 generated known ketone
1011 as the ideal starting point for our investigations.
1
2
3
4
5
6
7
8
As shown in Scheme 2, asymmetric synthesis of 10 was carried
out on multigram scale (4.4 g) in good overall yield. The Upjohn
dihydroxylation of the neopentylic alkene was exceptionally chal-
lenging and no conversion of the starting material took place at
ambient temperature. Fortunately, it was found that 1,2-diol 11
was obtained in good yield and as a single diastereomer by con-
ducting the dihydroxylation at elevated temperature (90 °C) us-
ing 1,4-diazabicyclo[2.2.2]octane (DABCO) as a crucial additive
in this transformation.12 The early dihydroxylation of the C5–C6
alkene enabled investigation of the limitation of oxetane for-
mation via nucleophilic substitution and revealed valuable infor-
mation about the structural requirements for the realization of the
C–H oxidation (vide infra). Conversion of 11 to tricyclic enone 9
was accomplished by employing a two-step Robinson annulation
protocol.10 First, 11 was activated by installation of a b-keto al-
dehyde (NaH, methyl formate). Subsequent exposure of this in-
termediate to methyl vinyl ketone (MVK), followed by addition of
sodium methoxide gave 9 in reproducibly good yield (57% over
two steps) and excellent diastereoselectivity (20:1).13
Further functionalization and installation of the quaternary car-
bon center at C16 required protection of the 1,2-diol motif. From
a survey of protecting groups (e.g. dialkylsilylenes, acetonides,
benzylidene acetal, cyclic carbonates), installation of a rarely
used cyclic boronic ester14 emerged as the sole solution
(MeB(OH)2, benzene, 30 °C). The boronic ester was stable
enough to undergo the following alkylation/aldol sequence and
was amenable to selective cleavage at a later stage. While the
α-methylation (LiHMDS, MeI, 82%) proceeded efficiently, all at-
tempts to realize a subsequent direct a-vinylation15 resulted in
complex reaction mixtures and low isolated yields. Therefore, a
two-step protocol was employed. First, aldol reaction with acet-
aldehyde as an inexpensive C2 synthon (LDA, TMEDA, acetal-
dehyde, –78 °C)16 gave 12, whose single crystal structure vali-
dated the depicted stereochemistry. Sequential exposure of 12
to Martin sulfurane17 and Luche conditions18 provided the corre-
sponding allylic alcohol 13. Treatment of 11 with p-toluenesul-
fonic acid (40 mol%) at 23 °C effected clean elimination to fur-
nish the desired 5-vinyl-1,3-cyclohexadiene 8 (96%). Subse-
quent heating at 170 °C induced smooth Diels–Alder reaction to
afford 7 in excellent yield (98%). Crystallization from n-pentane–
ethyl acetate enabled single-crystal structure analysis to validate
the depicted structure. For the formation of 7 it was crucial to
separate the elimination from the cycloaddition step, as cyclo-
propane ring-opening followed by extrusion of ethylene and aro-
matization to 14 was observed at elevated temperatures in the
presence of acid.3,19 In this context it is interesting to note that
the formed carbocyclic framework was recently also found in nat-
ural products isolated from Burmese amber, raising questions
about their (biosynthetic) origin.20 For the cleavage of the cyclic
boronic ester, 7 was treated with potassium bifluoride (20.0
equiv) to give diol 15 (47%). Unreacted starting material was re-
covered (39%) and resubmitted to the reaction conditions to
9
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Scheme 2. Total Synthesis of Mitrephorone B (2) and Mitrephorone A (1)a
1
O
H
2
3
4
5
6
7
8
b) NaH, MeOCHO
c) MVK, NEt3,
then NaOMe
16
O
O
Me
a) OsO4, NMO,
DABCO
Me
Me
d) MeB(OH)2 (90%)
OH 8
OH
OH
(57%, two steps)
e) LiHMDS, MeI (82%)
f) LDA, MeCHO (59%)
(83%)
MeO C Me
MeO C Me
MeO2C Me
OH
9 (dr = 20:1)
2
2
10
11
[X-ray]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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O
OH
Me
g) Martin
sulfurane
(89%)
Me
OH
Me
Me
Me
k) p-TsOH
Me
H
Me
Me
H
O
O
– ethene
(20%)
O
O
170 °C
O
h) CeCl3ꢀ7H2O
NaBH4, (93%)
B
Me
B Me
B
B
Me
Me
MeO C Me
O
2
MeO C Me
2
MeO C Me
MeO C Me
O
2
O
2
7
14
13
12
i) p-TsOH (96%)
Me
Me
16
11
Me
Me
j) 170 °C
(98%)
l) KHF2
(72%)
8
9
6
O
HO
B
Me
MeO C Me
O
2
MeO C Me
OH
2
8
15
[X-ray]
[X-ray]
Me
Me
Me
m) Mn(dpm)3,
PhSiH3,
o) SmI2
(74%)
Me
Me
Me
9
9
n) TPAP
(77%)
t-BuOOH
R
HO
H
HO
MeO C Me
H
p) SeO2
(70%)
5
O
MeO C Me
MeO2C
OH
O
2
2
OH
Me
mitrephorone B (2)
16: R = H (75%)
17: R = OH (22%)
18
[X-ray] C5–H9: 2.64 Å
x
Conditions for C–H Oxidation
u) TPAP (99%)
v) SmI2 (69%)
w) TMSCl (68%)
x) SeO2 (83%)
Entry
Conditions
Yield
Me
Me
Me
y) TASF
(73%)
q) Fe(R,R)-PDP, H2O2 60%
r) Fe(S,S)-PDP, H2O2 30%
s) quinuclidine, 0.2 mA, 49%
1.4–1.7 V, (+)C/(–)Ni
t) TBADT, air, MeCN,
365 nm
Me
z) Fe(R,R)-PDP,
Me
OH
Me
9
H2O2
O
H
OR
(13%)
5
5
O
O
O
14%
MeO C Me
MeO2C
OH
2
MeO C Me
O
Me
O
2
mitrephorone A (1)
19: R = TMS
20
aReagents and conditions: (a) OsO4, NMO, DABCO, acetone–H2O, 90 °C, 72 h, 83%; (b) NaH, then MeOCHO, THF–PhMe, 0 °C to
23 °C, 4 h; (c) MVK, NEt3, CH2Cl2, 23 °C, 96 h, then NaOMe, MeOH, 44 °C, 4 h, 57% over two steps; (d) MeB(OH)2, C6H6, 30 °C,
2 h, 90%; (e) LiHMDS, then MeI, THF, –50 °C to 23 °C, 13 h, 82%; (f) LDA, TMEDA, then MeCHO, THF, –20 °C to –78 °C, 3 h,
59%; (g) Martin sulfurane, C6H6, 23 °C, 2 h, 89%; (h) NaBH4, CeCl3•7H2O, MeOH, 0 °C, 3 h, 93%; (i) p-TsOH, 4 Å MS, PhMe,
23 °C, 40 h, 96%; (j) PhMe, 170 °C, 3 h, 98%; (k) p-TsOH, 4 Å MS, PhMe, 23 °C to 170 °C, 72 h, 20%; (l) KHF2, MeOH–H2O,
40 °C, 24 h, 72% over three cycles; (m) Mn(dpm)3, PhSiH3, t-BuOOH, i-PrOH, 23 °C, 17 h, 97%; (n) TPAP, NMO, 4 Å MS, CH2Cl2,
23 °C, 3 h, 77%; (o) SmI2, THF–MeOH, 23 °C, 20 min, 74%; (p) SeO2, 1,4-dioxane, 100 °C, 7 h, 70%; (q) Fe(R,R)-PDP, H2O2 (aq.),
AcOH, MeCN, 23 °C, 1 h, 60%; (r) Fe(S,S)-PDP, H2O2 (aq.), AcOH, MeCN, 23 °C, 1 h, 30%; (s) (+)RVC foam/(–)Ni, Me4NBF4,
quinuclidine, air, HFIP, MeCN, 0.2 mA, 23 °C, 4 h, 49%; (t) TBADT, HCl (aq.), 365 nm, 23 °C, 9 h, 14%; (u) TPAP, NMO, CH2Cl2,
23 °C, 3 h, 99%; (v) SmI2, THF–MeOH, 23 °C, 12 min, 69%; (w) TMSCl, DMAP, imidazole, DMF, 90 °C, 6 d, 68%; (x) SeO2, 1,4-
dioxane, 100 °C, 2 h, 83%; (y) TASF, H2O, DMF, 0 °C; 30 min, 73%; (z) Fe(R,R)-PDP, H2O2 (aq.), AcOH, MeCN, 23 °C, 1 h, 13%.
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In summary, we were able to mimic a bio-inspired C–H oxidation
of mitrephorone B (2) to mitrephorone A (1) using either iron-
catalysis or electrochemical oxidation. Despite a careful screen
of oxidants as well as literature precedence for structurally re-
lated substrates,25,26 oxidation of the C2-position to give mi-
trephorone C (3) was never observed.31 Our inability to realize
this transformation might reveal current limitations of modern C–
H oxidation methods or indicate an alternative biosynthetic path-
way. For the latter scenario, oxidation of C2 would precede for-
mation of the delicate diosphenol motif thus ruling out mitrepho-
rone B (2) as the parent compound.32
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental details and spectroscopic data (PDF)
X-ray crystallographic data for 2, 7, 11, and 12 (ZIP)
AUTHOR INFORMATION
Corresponding Author
*thomas.magauer@uibk.ac.at
ORCID
Thomas Magauer: 0000-0003-1290-9556
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Austrian Science Fund FWF
(P31023-NBL to T.M.) and the Center for Molecular Biosciences
CMBI. Furthermore, we thank Dr. Kevin Mellem (Maze Therapeu-
tics) and Dr. Cedric Hugelshofer (Merck) for assistance during the
preparation of this paper, Juri Skotnitzki (LMU Munich) for chiral
GC analysis and Dr. Matthias Schmid (University of Innsbruck) for
helpful discussions.
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