Total Synthesis of (-)-Mitrephorone A Enabled by Stereoselective Nitrile Oxide Cycloaddition and Tetrasubstituted Olefin Synthesis

Article abstract of DOI:10.1021/jacs.0c09520

A highly enantioselective and diastereoselective total synthesis of the diterpenoid (-)-mitrephorone A is presented. Key to the synthesis are stereocontrolled 1,4-semihydrogenation of a 1,3-diene to a tetrasubstituted double bond, enzyme-catalyzed malonat

Full text of DOI:10.1021/jacs.0c09520

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Total Synthesis of (−)-Mitrephorone A Enabled by Stereoselective
Nitrile Oxide Cycloaddition and Tetrasubstituted Olefin Synthesis
Michael Schneider, Matthieu J. R. Richter, and Erick M. Carreira*
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ABSTRACT: A highly enantioselective and diastereoselective
total synthesis of the diterpenoid (−)-mitrephorone A is
presented. Key to the synthesis are stereocontrolled 1,4-semi-
hydrogenation of a 1,3-diene to a tetrasubstituted double bond,
enzyme-catalyzed malonate desymmetrization, and highly
diastereoselective nitrile oxide cycloaddition. The streamlined
strategy is a considerable improvement to those reported earlier in
terms of diastereo- and enantioselectivity. For the first time, the
combination of modern Pd-cross-coupling with Cr-catalyzed reduction allows for rapid access to tetrasubstituted olefins with full
stereocontrol.
stereodefined strategies to the caged structure of (−)-mitre-
phorone A (1) and other trachylobanes.
INTRODUCTION
■
(−)-Mitrephorone A (1) is a trachylobane natural product
characterized by a pentacyclic carbon skeleton, which includes
a tricyclo[3.2.1.02,7]octane (Scheme 1).1,2 The carbon frame-
work of 1 encompasses at the core a unique fully substituted
oxetane. Its five contiguous stereocenters along with its
complex caged structure render 1 a formidable target for
stereoselective synthesis.3,4 In addition to synthetic challenges,
(−)-mitrephorone A (1) exhibits cytostatic activity against a
number of bacterial and fungal pathogens as well as
cytotoxicity against selected cancer cell lines (MCF-7, H460,
SF-268).1,2,5
The successful use of olefin 4 in our synthesis requires
control over both facial selectivity and olefin geometry. To
address the former, we conceived of an approach involving an
intramolecular annulation reaction. The strategic design of
precursors such as 9 includes a resident stereogenic center (*)
along the connecting backbone as a stereochemical controlling
feature (Scheme 2). In addressing the latter, it is important to
note that addition reactions to tetrasubstituted olefin 9 set two
stereocenters, and olefin geometry dictates their relative
configuration ((E)-9 → 10 vs (Z)-9 → 11).
We have previously reported the first and enantioselective
total synthesis of (−)-mitrephorone A (1), which lacked
diastereocontrol.3 Herein, we report a new route for a highly
enantio- and diastereoselective synthesis of 1. Our retro-
synthetic analysis involved disconnection of (−)-mitrephorone
A (1) to 2 (Scheme 1). The 1,3-relationship of ketone and
tertiary alcohol in 2 is a partial retron for a nitrile oxide
cycloaddition strategy via isoxazoline 3.6 We wondered
whether the stereogenic center α to the nitrile oxide in 4
would lead to control over facial selectivity in an intra-
molecular dipolar cycloaddition reaction (4 → 3). A key
requirement of this approach is the stereoselective synthesis of
the tetrasubstituted olefin embedded in 4. Although traditional
approaches to such an olefin might feature condensation
reactions of the corresponding tricyclic ketone, we envisioned
a different strategy involving diene 5. At the outset, it was not
clear how we would control the configuration of a
tetrasubstituted olefin. The approach we describe reveals an
effective solution to the synthesis of tetrasubstituted olefins,
enabling diastereoselective functionalization of chiral tricyclo-
[3.2.1.02,7]octanes and related structures. More broadly, the
new retrosynthetic plan outlined in Scheme 1 leads to novel
RESULTS AND DISCUSSION
■
Olefin Synthesis. There are numerous methods available
for ketone olefination en route to 4 (Scheme 1). In our initial
studies, we tested several approaches for olefin synthesis from
tricyclo[3.2.1.02,7]octanone 12 (Scheme 3).7 The tetrasub-
stituted alkenes we envisioned synthesizing feature two
structural elements that render their stereoselective synthesis
challenging: (1) They include an allylic quaternary center,
which can reduce reactivity of olefin precursors, and (2)
methyl and methylenes at one end of the olefin can be
sterically challenging to differentiate when controlling olefin
geometry. Initial attempts employing Wittig and Horner−
Wadsworth−Emmons olefinations8 as well as McMurry
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A

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Scheme 1. (−)-Mitrephorone A (1) and Retrosynthetic Analysis
couplings9 did not afford any tetrasubstituted olefins. Claisen
rearrangements have been previously employed in the
stereoselective synthesis of tetrasubstituted alkenes.10 To this
end, we transformed hydroxyketone 12 (95% ee) into allylic
acetate 15 in three steps and 40% yield as 1.2:1 mixture of
diastereomers (Scheme 3). Ireland−Claisen rearrangement
was induced by treatment of 15 with LiHMDS, TBSCl, and
HMPA,11 and after treatment with methyl iodide and
potassium carbonate, ester 16 was obtained in 87% yield as
a 2.3:1 mixture of diastereomers. After reduction using
DIBAL-H, the two double bond isomers were separated and
assigned via 2D NOESY NMR experiments (see the
Supporting Information (SI) for details). Further attempts to
optimize the diastereoselectivity in the Ireland−Claisen
reaction by employing different silyl groups did not lead to
improvement. As we opted for a highly stereoselective
synthesis, we subsequently envisioned different routes to the
tetrasubstituted olefin not involving nucleophilic addition to
tricyclic ketones.
Scheme 3. Synthesis of Tetrasubstituted Olefin via Ireland−
a
Claisen Rearrangement
Stereocontrolled preparation of tetrasubstituted olefins has
been a longstanding challenge in organic synthesis.8,12
A
conceptually new route to tetrasubstituted olefin 4 would
require stereoselective reduction of the diene in 5 in a catalyst-
controlled process (Scheme 1). 1,3-Dienes may be conven-
iently accessed via palladium-catalyzed sp2−sp2 cross-coupling.
a
Reagents and conditions: (a) TBSCl, imidazole, DMAP, CH2Cl2, r.t.,
73%; (b) isopropenylmagnesium bromide (14), LaCl3·2LiCl, THF,
then 13, 0 °C to r.t., 86%, dr = 6:5; (c) PhNMe2, AcCl, 50 °C, 64%;
(d) LiHMDS, TBSCl, HMPA, THF, −78 °C to r.t., then 1 M HCl;
(e) MeI, K2CO3, DMF, r.t., 87% over two steps, dr = 2.3:1; (f)
DIBAL-H, PhMe, −78 °C to r.t., 59% trans-17, 27% cis-17.
Scheme 2. Stereochemical Considerations Associated with
Olefin Functionalization
Transition-metal-catalyzed semireductions of dienes by Cr and
Ru catalysts have been reported to proceed via the s-cis η4
complex/metallacyclopentene, delivering single olefin isomers
(Scheme 4).13 The configuration of the tetrasubstituted olefin
would be controlled by the structure of the coupling partners
and the reduction mechanism. While the first reports on diene
semihydrogenation date back to the 1960s, there is only one
report, by Shibasaki, for the synthesis of a tetrasubstituted
olefin (trialkyl-substituted acrylonitrile) in a complex structure
via semihydrogenation of a 1,3-diene.13b This report predates
coupling chemistry, and numerous steps were required to
access the 1,3-diene. The combination of modern sp2−sp2
cross-coupling reactions and 1,4-semihydrogenation would
allow for rapid access to a tetrasubstituted olefin in a
stereodefined manner (Scheme 4).
B
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varying the coupling partners allows for the selective
preparation of both olefin isomers. Accordingly, both olefin
isomers 21a and 21b as well as 21c and 21d could be prepared
in high stereoselectivities and yields from the corresponding
vinyl triflates and boronates. For 21c and 21d, the olefin
geometries were confirmed by 2D NOESY NMR experiments
(see SI for details). The ketone in 21e was well tolerated under
cross-coupling and hydrogenation conditions (97% and 95%
yield, respectively). Also, styrenes 21f and 21g could be
prepared selectively. Next, we turned our attention to the
synthesis of tetrasubstituted olefins on the tricyclo[3.2.1.02,7]-
octane scaffold. In a first attempt, a symmetric isopropylidene
substituent could be installed successfully (21h). During the
cross-coupling reaction, most of the silyl ether was cleaved and
the alcohol was reprotected prior to hydrogenation. Employing
more complex vinyl boronates, 21i and 21j were synthesized
stereoselectively. Changing the protecting group to pivalate
was well tolerated under both cross-coupling and hydro-
genation conditions, and 21k was obtained in 96% over two
steps. All hydrogenation reactions were initially performed
using 20 mol% catalyst. This led to incomplete conversion for
21e, 21g, 21j, and 21k. Increasing the catalyst loading to 50
mol% ensured full conversion for these substrates. All
tetrasubstituted olefins 21 were obtained in >20:1 dr. In
most cases, only traces of regioisomeric olefins (<5%) were
observed. For 21c, decreasing the catalyst loading to 5 mol%
led to 54% conversion after 18 h. After the reaction time was
increased to 42 h, full conversion and 89% yield was observed
showing that the catalyst is still active after the standard
Scheme 4. Conceptual Approach to Tetrasubstituted Olefin
Synthesis via Cross-Coupling and 1,4-Semihydrogenation
To study this approach, we prepared a series of dienes 20 via
Suzuki cross-coupling14 of vinyl boronates 18 with vinyl
triflates 19 and subjected them to semihydrogenation
conditions (Table 1).15 We selected [Cr(CO)3(η6-MeOBz)]
as the catalyst for the 1,4-semihydrogenation over Cp*Ru-
based catalysts as very high yields and stereoselectivities have
been reported for the application of this catalyst and it is
readily accessible in one step from commercially available
Cr(CO)6 and MeOBz.13d We focused on tetrasubstituted
olefins featuring the same stereochemical challenges as
encountered in the natural product. As the design of the
cross-coupling partners determines the olefin geometry,
Table 1. Synthesis of Tetrasubstituted Olefins via Cross-Coupling and Semihydrogenation
a
b
c
d
20 mol% catalyst was used. 50 mol% catalyst was used. 5 mol% catalyst was used for 42 h. During the cross-coupling, most of the silyl ether was
cleaved and was reformed using TBSCl, imidazole and DMAP (10−20 mol%) in CH2Cl2 at r.t. The yields refer to combined yields over two steps.
C
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a
Scheme 5. Synthesis of Isoxazoline 26 via Nitrile Oxide Cycloaddition
a
Reagents and conditions: (a) Pd(PPh3)4 (3 mol%), NaHCO3, DME−H2O (9:1), 80 °C, then HCl, MeOH, r.t., 66%; (b) TBSCl, imidazole,
DMAP (20 mol%), CH2Cl2, r.t., 94%; (c) H2 (70 bar), [Cr(CO)3(η6-MeOBz)] (50 mol%), acetone, 120 °C, 97%; (d) TBAF, THF, r.t., 91%; (e)
pig liver esterase (PLE), aq NaOH, 0.1 M pH 7 sodium phosphate buffer−DMSO (10:1), r.t., dr = 20:1; (f) TBSCl, imidazole, DMAP, CH2Cl2,
r.t.; K2CO3, MeOH−THF−H2O (20:10:3), r.t.; (g) ClCO2Me, Et3N, THF, 0 °C to r.t.; NaBH4, MeOH, 0 °C, 68% over three steps; (h) DMP,
t-BuOH, CH2Cl2, r.t., 71%; (i) H2NOH·HCl, EtOH−pyr (8:1), r.t., 82%; (j) PhI(OAc)2, MeOH, 0 °C; PhMe, Δ, 64%; (k) TBAF, THF, 60 °C,
99%; (l) DMP, t-BuOH, CH2Cl2, r.t., 86%; (m) MeLi, THF−Et2O (3:1), −78 °C; (n) DMP, t-BuOH, CH2Cl2, r.t., 94% over two steps.
reaction time. Decreasing the H2 pressure to 55 bar completely
shut down the reaction. Notably, variation of the concentration
between 7 and 50 mM and scaling-up the reaction to 2.3 mmol
for 21j had no effect on yield or stereoselectivity.
We continued our efforts toward the synthesis of (−)-mitre-
phorone A (1) using 21j, which was prepared from vinyl
boronate 18e and vinyl triflate 19d (Scheme 5). For malonate
desymmetrization, we turned to the application of biocatalysis
for the stereoselective monohydrolysis of α,α-disubstituted
malonate 21j. Subjecting malonate 21j to pig liver esterase
Figure 1. Putative transition states for nitrile oxide cycloaddition.
(PLE) in a mixture of aqueous phosphate buffer and DMSO
(10:1) did not lead to any conversion of starting material.16 In
contrast, after silyl ether cleavage with TBAF, the correspond-
ing malonic acid monoester was obtained in 20:1 dr under the
same reaction conditions. Reprotection of the hydroxy group
with TBSCl and chemoselective reduction of the carboxylic
acid to the corresponding alcohol (ClCO2Me followed by
NaBH4) afforded alcohol 23 in 68% from malonate 22.17
Oxime 24 was obtained via oxidation with DMP and treatment
with hydroxylamine hydrochloride in 58% yield over two steps.
Subjecting 24 to PhI(OAc)2 led to its oxidation to the
corresponding nitrile oxide,18 which underwent cycloaddition
to give isoxazoline 25 in 64% yield as a single diastereomer as
determined by analysis of the 1H NMR spectrum. The relative
configuration was established by 1D NOE NMR experiments
(see SI for details). It is worth noting that the cycloaddition
sets two challenging stereocenters, namely the vicinal tertiary
ether and quaternary center concomitant with 6-membered
ring formation. Notably, when a 1:1 mixture of diastereomers
of oxime 24 (epimeric at C4) was subjected to the reaction
conditions, two diastereomers were obtained that have the
same relative configuration at C4, C9, and C10 as determined by
X-ray crystallography (see SI for details). This clearly shows
that the facial selectivity in the dipolar cycloaddition is fully
controlled by the α stereocenter of the nitrile oxide.
incorporating a 1,3-diaxial interaction between an ester and a
methyl group, is energetically favored over transition state II,
in which a 1,3-dimethyl axial interaction is present (∼2.8 vs
∼3.7 kcal/mol).19 This is consistent with the formation of a
1
single diastereomer as observed by H NMR spectroscopy.
A common problem in nitrile oxide cycloaddition is
dimerization of the nirile oxide, and it has been shown that
cycloreversion can be induced by heating.20 However, we did
not observe any dimer, and all byproducts were highly polar
baseline compounds, which could not be characterized.
Despite being scalable and relatively high yielding (7.6%
over 16 steps from 12), we aimed to further optimize the route
toward isoxazoline 26 with respect to the following points: (1)
Achiral vinyl boronate 18e could be replaced by a chiral,
enantioenriched analogue 27, which would render the
synthesis more convergent (Scheme 6). It is important to
note that the dr of coupling product 28 will depend on the ee
of vinyl boronate 27. (2) The protecting group strategy is
suboptimal: The TBS ether in vinyl triflate 19d is cleaved
during cross-coupling and was reprotected for hydrogenation
but enzymatic desymmetrization only proceeded with the free
alcohol. So again a sequence of deprotection, desymmetriza-
tion, and reprotection had to be carried out. Transformation of
the alcohol to the corresponding methyl ketone prior to cross-
coupling may improve the synthesis.
Examination of putative transition states as shown for I and
II in Figure 1 proves instructive. Transition state I,
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was in full agreement with Keese’s result (95% ee). When we
subjected vinyl boronate 29b to the enzymatic step, low yield
(9%) and modest enantioselectivity (75% ee) were observed.
Consequently, we examined the enzymatic reaction with 29c
and 29d, which furnished products in 74% and 97% yield,
respectively, albeit in low enantiomeric excess, 20% and 23%
ee, respectively. Examination of silyl ethers 29e and 29f
revealed that the former afforded 30e in 67% yield and the
highest enantiomeric excess, namely >95% ee. Interestingly, no
reaction was observed for the analogous TBDPS-protected
substrate 29f.26 As a consequence of its high yield and
enantiomeric excess, 30e was selected for further studies.
Based on previous investigations, the absolute configuration of
carboxylic acid 30e was tentatively assigned as (R).16,21
Scheme 6. Envisioned Optimization of the Route
Synthesis of Vinyl Boronate 33. Enantiopure27,28
malonic acid monoester 30e was transformed into silyl ether
31 via chemoselective reduction of the carboxylic acid to the
corresponding alcohol (ClCO2Me followed by NaBH4),17 and
TBDPS protection in 61% yield from 29e (Scheme 7).
Malonate Desymmetrization Studies. For the asym-
metric synthesis of enantioenriched vinyl boronate 27, we
wanted to further explore the stereoselective monohydrolysis
of α,α-disubstituted malonates. Previous studies on desymmet-
rization of 2-methyl-2-alkylmalonates 29 have shown that the
length of R has a strong effect on the enantioselectivity in the
hydrolysis to give 30.21 Accordingly, we prepared a series of
malonates 29a−f, which vary in length and nature of side chain
and, after enzymatic transformation, could all be elaborated to
7 (Table 2).22,23 Dimethyl malonates 29 may be conveniently
a
Scheme 7. Synthesis of Vinyl Boronate 33
a
Table 2. Enzymatic Desymmetrization of Malonates 29
a
Reagents and conditions: (a) pig liver esterase (PLE), aq NaOH, 0.1
M pH 7 sodium phosphate buffer−DMSO (10:1), r.t.; (b) ClCO2Me,
Et3N, THF, 0 °C to r.t.; NaBH4, MeOH, 0 °C, 64% from 29e; (c)
TBDPSCl, imidazole, DMAP (20 mol%), CH2Cl2, r.t., 95%; (d)
PPTS (20 mol%), EtOH, r.t.; (e) DMP, t-BuOH, CH2Cl2, r.t., 87%
over two steps; (f) MePPh3Br, KOt-Bu, THF, r.t., 86%; (g)
isopropenylboronic acid pinacol ester (18d), Grubbs second-
generation catalyst (10 mol%), CH2Cl2, 50 °C, 49%.
Selective cleavage of the TBS-ether in 31 with PPTS in
ethanol,29 subsequent oxidation with DMP, and Wittig
methylenation of the resulting aldehyde afforded olefin 32 in
75% yield over three steps. Vinyl boronate 33 was prepared via
cross-metathesis of 32 with isopropenylboronic acid pinacol
ester (18d) in 49% yield.23
Synthesis of Tetrasubstituted Olefin 37. We sub-
sequently transformed hydroxyketone 127 into a suitable
building block for cross coupling. Following a short sequence
(Comins reagent (34); DMP; MeLi; DMP), 35 was prepared
(Scheme 8).30 Cross-coupling of 35 with vinyl boronate 33
afforded 1,3-diene 36 in 65% yield.14 Intermediate 36 was
subjected to hydrogenation conditions in the presence of 50
mol% of catalyst [Cr(CO)3(η6-MeOBz)]. Desired tetrasub-
stituted olefin 37 was obtained in 93% yield as a single olefin
isomer.
a
1
Enantiomeric excesses (ee) were determined by analysis of the H
NMR spectra after amide coupling with enantiopure (S)-phenyl-
ethanamine, see SI for details.25
prepared by alkylation reactions.24 For rapid determination of
enantioselectivities in our study, we developed a quick assay
involving coupling of acids 30 with (S)-phenylethanamine to
the corresponding diastereomeric amides.25 To benchmark the
method, we repeated the pig liver esterase-mediated hydrolysis
of TBS-protected 2-methyl-2-hydroxymethylmalonate 29a,
which has been previously reported by Keese.16 The
enantiomeric excess we observed for the formation of 30a
Completion of the Carbon Skeleton via Nitrile Oxide
Cycloaddition. Silyl ether 37 was converted into oxime 38 via
deprotection with TBAF, oxidation with DMP and oxime
E
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a
and either trapping the resulting enolate as the corresponding
enol ether (e.g., TBSOTf, 2,6-lutidine or proton sponge) or
oxidizing it (IPh2BF4, I2/NaHCO3, NBS/NaHCO3,
PhI(OAc)2/KOt-Bu, O2/KOt-Bu, MoOPH/KHMDS) were
unsuccessful. Also, oxidative transformation of the enone to the
diosphenol proved unfruitful (epoxidation followed by
rearrangement or dihydroxylation followed by elimination).
At this point, 41 was reduced to the corresponding saturated
ketone 42 with H2 and Pd/C in 77% yield.32 Isoxazolidine 40
could also be directly reduced to 42 using H2 and Pd/C in the
presence of AcOH at 80 °C in 72% yield.
Scheme 8. Synthesis of Tetrasubstituted Olefin 37
α-Oxidation of 42 (O2, KOt-Bu, then PPh3) gave
α-hydroxyketone 43 in 72% yield (Scheme 10).33 Treatment
a
Scheme 10. Completion of the Synthesis
a
Reagents and conditions: (a) TMSCl, imidazole, THF, r.t., then
KHMDS, −78 °C, then Comins reagent (34), −78 °C, then aq HCl,
r.t., 79%; (b) DMP, t-BuOH, CH2Cl2, r.t., 85%; (c) MeLi, THF,
−78 °C; (d) DMP, t-BuOH, CH2Cl2, r.t., 52% over two steps; (e) 33,
Pd(PPh3)4 (2.5 mol%), NaHCO3, DME−H2O (9:1), 85 °C, 65%; (f)
H2 (70 bar), [Cr(CO)3(η6-MeOBz)] (50 mol%), acetone, 120 °C,
93%.
formation with hydroxylamine hydrochloride in 62% yield over
three steps (Scheme 9).6c Subjecting 38 to the same nitrile
oxide cycloaddition conditions as described above afforded
isooxazoline 26 in 52% yield as a single diastereomer along
with 10% recovered starting material. No side products were
observed in significant quantities (>5% yield). Enolization of
26 with LDA or synthesis of the corresponding trimethylsilyl
enol ether followed by treatment with BF3·OEt2 did not induce
intramolecular addition to the isoxazoline. In contrast, after
N-methylation of 26 using Meerwein’s salt (Me3OBF4),31 the
intermediate isoxazolinium salt 39 was subjected in situ to
TMSOTf and Et3N to induce cyclization. The Mannich-type
reaction afforded isoxazolidine 40 in 69% yield and completed
the carbon skeleton of the natural product. Treatment of 40
with Zn in AcOH at 50 °C led to N−O bond cleavage with
concomitant methylamine elimination to give enone 41 in 65%
yield. Various attempts to induce oxa-Michael addition of 41
a
Reagents and conditions: (a) KOt-Bu, O2, THF, −78 °C, then PPh3,
−78 °C to r.t., 72%; (b) DMP, t-BuOH, CH2Cl2; SiO2, hexane−
EtOAc (3:1), 74%; (c) PhI(OH)OTs, NaHCO3, CH2Cl2, 72%.
with DMP furnished hydroxydiosphenol 44 in 74% yield. It is
worth noting that oxidation of 42 to diosphenol 44 was carried
out in an efficient sequence with the tertiary alcohol being
unprotected. This was not possible in our first route employing
an isomeric ketone, which necessitated protection of the
tertiary alcohol as its silyl ether.3 Finally, (−)-mitrephorone A
(1) was obtained via oxidative cyclization of 44 mediated by
a
Scheme 9. Synthesis of 42 via Nitrile Oxide Cycloaddition
a
Reagents and conditions: (a) TBAF, THF, r.t.; (b) DMP, t-BuOH, CH2Cl2, r.t., 73% over two steps; (c) H2NOH·HCl, pyr−EtOH (8:1), r.t.,
85%; (d) PhI(OAc)2, MeOH, 0 °C; PhMe, Δ, 52%; (e) Me3OBF4, CH2Cl2, r.t., then TMSOTf, Et3N, r.t., 69%; (f) Zn, AcOH, 50 °C, 65%; (g) H2
(1 atm), Pd/C (30 mol%), EtOAc, r.t., 77%; (h) H2 (1 atm), Pd/C, EtOAc−AcOH (5:1), 80 °C, 72%.
F
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Diterpenoid Possessing an Oxetane Ring from Mitrephora glabra.
Org. Lett. 2005, 7, 5709−5712.
Koser’s reagent (PhI(OH)OTs) in the presence of NaHCO3
in 72% yield and >99% ee, which compares favorably with
previous total syntheses (88 and 85% ee).3,4a,34,35 Spectro-
scopic data of the material we obtained is identical with that
reported for the natural isolate.2
̈
(3) Richter, M. J. R.; Schneider, M.; Brandstatter, M.; Krautwald, S.;
Carreira, E. M. Total Synthesis of (−)-Mitrephorone A. J. Am. Chem.
Soc. 2018, 140, 16704−16710.
(4) (a) Wein, L. A.; Wurst, K.; Angyal, P.; Weisheit, L.; Magauer, T.
Synthesis of (−)-Mitrephorone A via a Bioinspired Late Stage C-H
Oxidation of (−)-Mitrephorone B. J. Am. Chem. Soc. 2019, 141,
19589−19593. Very recently, Renata and co-workers reported a
semisynthetic approach to (−)-mitrephorone A: (b) Zhang, X.; King-
Smith, E.; Dong, L.-B.; Yang, L.-C.; Rudolf, J. D.; Shen, B.; Renata, H.
Divergent synthesis of complex diterpenes through a hybrid oxidative
approach. Science 2020, 369, 799−806.
CONCLUSION
■
We have reported a highly enantioselective and diastereo-
selective total synthesis of (−)-mitrephorone A (1, >99% ee).
The synthesis relies on intramolecular nitrile oxide cyclo-
addition, which sets two stereocenters, forms one all-carbon
ring and introduces an isoxazoline, which serves as a handle for
elaboration of the cycloadduct to the natural product.
Additional salient features of the synthesis include highly
enantioselective pig liver esterase-catalyzed malonate desym-
metrization, 1,4-semihydrogenation of a 1,3-diene, and hyper-
valent iodine-mediated oxidative cyclization to furnish the
oxetane. Stereo- and regioselective synthesis of tetrasubstituted
double bonds via sp2−sp2 cross-coupling and 1,4-semi-
hydrogenation has no precedence and represents a powerful
method for olefin synthesis.
(5) Zgoda-Pols, J. R.; Freyer, A. J.; Killmer, L. B.; Porter, J. R.
Antimicrobial diterpenes from the stem bark of Mitrephora celebica.
Fitoterapia 2002, 73, 434−438.
(6) For a discussion on nitrile oxide cycloaddition followed by
reductive cleavage for the synthesis of β-hydroxyketones, see:
(a) Bode, J. W.; Carreira, E. M. Stereoselective Syntheses of
Epothilones A and B via Directed Nitrile Oxide Cycloaddition. J.
Am. Chem. Soc. 2001, 123, 3611−3612. (b) Muri, D.; Carreira, E. M.
Stereoselective Synthesis of Erythronolide A via Nitrile Oxide
Cycloadditions and Related Studies. J. Org. Chem. 2009, 74, 8695−
8712. (c) Becker, N.; Carreira, E. M. Hydroxyl-Directed Nitrile Oxide
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9, 3857−3858.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09520.
■
sı
(7) Schneider, M.; Richter, M. J. R.; Krautwald, S.; Carreira, E. M.
Asymmetric Synthesis of the Tricyclooctane Core of Trachylobane
Natural Products and Related Terpenoids. Org. Lett. 2019, 21, 8705−
8707.
Experimental procedures and characterization data for
all new compounds (PDF)
Crystallographic data for a mixture of 25 and its
diastereomer S6 (CIF)
(8) Wittig and Horner−Wadsworth−Emmons olefinations have
previously been shown to suffer from low reactivity and stereo-
selectivity in the formation of tetrasubstituted double bonds. In our
studies, we were able to react the tricyclooctanone with methyl-
triphenylphosphonium bromide or diethyl cyanomethylphosphonate,
but the obtained di- or trisubstituted olefins could not be transformed
into tetrasubstituted olefins. For a review on the synthesis of
tetrasubstituted olefins, including Wittig and Horner−Wadsworth−
Emmons olefinations of carbonyls, see: Flynn, A. B.; Ogilvie, W. W.
Stereocontrolled Synthesis of Tetrasubstituted Olefins. Chem. Rev.
2007, 107, 4698−4745.
AUTHOR INFORMATION
Corresponding Author
■
Erick M. Carreira − ETH Zurich, 8093 Zurich, Switzerland;
̈ ̈
orcid.org/0000-0003-1472-490X;
Email: erickm.carreira@org.chem.ethz.ch
(9) Casimiro-Garcia, A.; Micklatcher, M.; Turpin, J. A.; Stup, T. L.;
Watson, K.; Buckheit, R. W.; Cushman, M. Novel Modifications in
the Alkenyldiarylmethane (ADAM) Series of Non-Nucleoside
Reverse Transcriptase Inhibitors. J. Med. Chem. 1999, 42, 4861−4874.
(10) (a) Wipf, P. Claisen Rearrangements. Comprehensive Organic
Synthesis; Pergamon Press: Oxford, 1991; Vol. 5, pp 827−873.
(b) Ziegler, F. E. The Thermal, Aliphatic Claisen Rearrangement.
Chem. Rev. 1988, 88, 1423−1452.
(11) Clark, D. A.; Kulkarni, A. A.; Kalbarczyk, K.; Schertzer, B.;
Diver, S. T. Tandem Enyne Metathesis and Claisen Rearrangement: A
Versatile Approach to Conjugated Dienes of Variable Substitution
Patterns. J. Am. Chem. Soc. 2006, 128, 15632−15636.
Authors
Michael Schneider − ETH Zu
orcid.org/0000-0001-8519-6505
rich, 8093 Zurich,
̈
̈
rich, 8093 Zurich, Switzerland;
̈
Matthieu J. R. Richter − ETH Zu
Switzerland; orcid.org/0000-0001-7957-3474
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09520
Funding
This work was funded by the European Research Council
(OLECAT, Grant-ID 833540).
Notes
(12) Wang, J.; Dong, Z.; Yang, C.; Dong, G. Modular and
regioselective synthesis of all-carbon tetrasubstituted olefins enabled
by an alkenyl Catellani reaction. Nat. Chem. 2019, 11, 1106−1112.
(13) (a) Frankel, E. N.; Selke, E.; Glass, C. A. Homogeneous 1,4-
addition of Hydrogen Catalyzed by Tricarbonyl(arene)chromium
Complexes. J. Am. Chem. Soc. 1968, 90, 2446−2448. (b) Sodeoka, M.;
Ogawa, Y.; Kirio, Y.; Shibasaki, M. Stereocontrolled Synthesis of
Exocyclic Olefins Using Arene Tricarbonyl Chromium Complex-
Catalyzed Hydrogenation. I. Efficient Synthesis of Carbacyclin and Its
Analogs. Chem. Pharm. Bull. 1991, 39, 309−322. (c) Steines, S.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
We thank Jan Kovacovic for assistance with high-pressure
reactions.
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1
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H
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