Enantioselective and Diastereodivergent Synthesis of Spiroindolenines via Chiral Phosphoric Acid-Catalyzed Cycloaddition

Article abstract of DOI:10.1021/jacs.1c04648

A diastereodivergent and enantioselective synthesis of chiral spirocyclohexyl-indolenines with four contiguous stereogenic centers is achieved by a chiral phosphoric acid-catalyzed cycloaddition of 2-susbtituted 3-indolylmethanols with 1,3-dienecarbamates. Modular access to two different diastereoisomers with high enantioselectivities was obtained by careful choice of reaction conditions. Their functional group manipulation provides an efficient access to enantioenriched spirocyclohexyl-indolines and -oxindoles. The origins of this stereocontrol have been identified using DFT calculations, which reveal an unexpected mechanism compared to our previous work dealing with enecarbamates.

Full text of DOI:10.1021/jacs.1c04648

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Enantioselective and Diastereodivergent Synthesis of
Spiroindolenines via Chiral Phosphoric Acid-Catalyzed
Cycloaddition
̌
́
Thomas Varlet, Mateja Matisic, Elsa Van Elslande, Luc Neuville, Vincent Gandon,*
and Géraldine Masson*
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ABSTRACT: A diastereodivergent and enantioselective synthesis
of chiral spirocyclohexyl-indolenines with four contiguous stereo-
genic centers is achieved by a chiral phosphoric acid-catalyzed
cycloaddition of 2-susbtituted 3-indolylmethanols with 1,3-
dienecarbamates. Modular access to two different diastereoisomers
with high enantioselectivities was obtained by careful choice of
reaction conditions. Their functional group manipulation provides
an efficient access to enantioenriched spirocyclohexyl-indolines and
-oxindoles. The origins of this stereocontrol have been identified
using DFT calculations, which reveal an unexpected mechanism
compared to our previous work dealing with enecarbamates.
containing a heteroatom in the spirocyclohexyl ring were
produced, catalytic asymmetric syntheses of all-spirocarbocyclic
indoline derivatives have remained extremely scarce. To the best
of our knowledge, only very recently Breit et al. achieved a
stereoselective synthesis of unfused spirocarbocyclic indolenines
though rhodium-catalyzed cyclization of N-allenyltryptamines
and 3-allenylindoles, delivering a moderate to high level of
enantio- and diastereoselectivity (Scheme 1, a).5f Indeed, the
enantioselective construction of highly substituted spirocarbo-
cycles with the control of multiple stereocenters, including the
quaternary spirocenter, in a single assembly step from easily
accessible starting materials remains a significant challenge.
Recently, we disclosed an efficient enantioselective synthesis of
cyclohepta[b]indoles involving a chiral phosphoric acid-
catalyzed formal (4+3)-cycloaddition of 3-indolylmethanols
with 1,3-dienecarbamates (Scheme 1, b).6a,7−9 Mechanistic
investigations provided evidence for a two-step reaction process
involving vinylogous addition of the diene to a vinyliminium
ion10 generated in situ from the 3-indolylmethanol, followed by
an intramolecular C2-indole alkylation of the resulting imine A.
On this basis, we reasoned that incorporation of a substituent at
the C2-position of the indole moiety may promote electrophilic
INTRODUCTION
■
Chiral spiro indole-derived units are important structural motifs
encountered in various naturally occurring alkaloids as well as
biologically active compounds.1 They are key intermediates for
the synthesis of numerous natural products.2 The development
of direct and efficient catalytic methods for their enantioselective
synthesis has therefore attracted the attention of synthetic
organic chemists. A number of enantioselective methodologies
have been successively reported over the years.3 However, in
contrast to spirocyclohexyl-oxindoles,4 asymmetric strategies for
building related indolines and indolenines are limited in
number.5 Pd-catalyzed spiroindolenine synthesis was reported
in 2014 by You et al. and illustrated in a single enantioselective
example leading to modest enantioenrichment (52% ee).5a In
2017, Gandon, Guinchard, et al.5b reported an example of Au(I)-
catalyzed enantioselective cyclizations of N-propargyl trypt-
amines, providing the corresponding spiroindolenines in
moderate yield and enantioselectivity (up to 68% ee). The
same year, Zheng, You, et al.5c developed an efficient method for
synthesizing spirocyclohexyl-indolenines based on Ir-catalyzed
asymmetric dearomatization of bis(indol-3-yl)allylic carbonates.
One year later, the same group disclosed an enantioselective
dearomatization of indolyl dihydropyridines using chiral
phosphoric acid catalysis to afford various spiroindolines with
high yields and enantioselectivities.5d More recently, Wei, Shi, et
al. developed an elegant enantioselective desymmetrization of
bis(indol-3-yl)-allenes catalyzed by a chiral Au complex, which
afforded fused spirocyclohexyl derivatives with high enantiose-
lectivities.5e Despite these achievements and while derivatives
Received: May 5, 2021
Published: July 23, 2021
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© 2021 American Chemical Society
11611

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Scheme 1. Enantioselective Catalytic Synthesis of
Spirocyclohexyl-Indolines and -Indolenines
Table 1. Optimization of Catalytic Enantioselective Synthesis
of Spiroindolenines
4a yield
b
4a ee
cd
5a yield
b
5a ee
cd
,
,
entry
T, °C
(%)
(%)
(%)
(%)
a
1
0
−20
−20
−20
−20
−20
−30
−40
44
69
67
69
63
70
69
64
92
92
92
92
90
92
92
88
20
90
a
2
ae
,
3
4
5
6
7
8
9
10
11
12, ,
af
,
ag
,
h
h
h
h
i
substitution at C3 rather than C2 and may lead to an efficient
synthesis of enantioenriched spirocarbocyclic indolenines.
Herein we report a highly enantioselective synthesis of
polysubstituted spirocyclohexyl-indolenines having up to four
contiguous stereocontrolled chiral centers, including a quater-
nary one, in satisfying yields and with excellent enantio- and
diastereoselectivity (Scheme 1, c). Density functional theory
(DFT) computations and experimental studies provided a clear
mechanistic picture of the transformation and revealed an
unexpected activation mode by the chiral phosphoric acid
catalyst.
rt
54
70
86
93
−20 then 60
−20
0 to 60
hj
d
,
70
94
ik
70
94
a
General conditions: 2a (0.10 mmol), 3a (0.15 mmol), and 1a (5 mol
b
%) in DCM (0.05 M). Yield of isolated pure product after
chromatography. 4a refers to absolute (1S,2S,5R,6R) configuration;
c
5a refers to (1S,2R,5R,6R) configuration, assigned by X-ray crystal-
structure analysis of 4a and 5a (see Supporting Information).
d
e
Determined by HPLC analysis on a chiral stationary phase. C =
f
g
h
0.1 M. C = 0.025 M. Without 4 Å MS. General conditions: 2a
(0.12 mmol), 3a (0.10 mmol), and 1a (5 mol %) in DCM (0.05 M).
RESULT AND DISCUSSION
■
i
General condition: 2a (0.10 mmol), 3a (0.12 mmol), and 1a (5 mol
Reaction Optimization, and Scope. Initially, (2-methyl-
1H-indol-3-yl)(phenyl)methanol (2a) and benzyl (penta-1,3-
dien-1-yl)carbamate (3a) were chosen as model substrates to
evaluate our hypothesis (Table 1, entry 1). Pleasingly,
performing the reaction at 0 °C with (S)-H8-BINOL-phosphoric
acid catalyst 1a delivered the desired spirocyclohexyl-indole-
nines 4a and 5a as a mixture of diastereomers (2.2:1 ratio) with
high enantioselectivity, albeit with a relatively moderate yield.
Lower yields were due to the competitive formation of about
10−25% of bis-indole 6a, presumably formed via the retro-
Friedel−Crafts reaction of 1a followed by C2-alkylation of the
resulting 2-methylindole. This side reaction could be signifi-
cantly reduced at lower temperature (−20 °C), thereby
improving the yield, but interestingly the reaction produced
exclusively the diastereomer 4a with still a good 92% ee. Neither
concentrating nor diluting the reaction mixture affected the yield
and enantioselectivity (entries 3 and 4). Molecular sieves were
not mandatory for the transformation, but were found to slightly
increase the yields and enantioselectivity (entry 5). Since
changing the ratio between both starting materials only
marginally affected the reaction outcome (entry 6 vs entry 2),
for practical reasons, we adopted a 1.2:1 ratio between 2a:3a for
subsequent evaluations. Extensive screening of catalysts and
solvents did not improve the yield and enantioselectivity (see
Supporting Information, Tables S1 and S2). Lowering the
reaction temperaturedid nothave a positive impact onboth yield
and enantioselectivity (entries 7 and 8). However, additional
investigation showed that the diastereoselectivity was com-
pletely switched at room temperature to form exclusively 5a in
%) in DCE (0.05 M) at −20 °C for 24 h, then heated at 60 °C for 3 h.
j
k
With 1 mmol of 2a. With 0.5 mmol of 2a.
high enantioselectivity (entry 9). The retro-Friedel−Crafts side
reaction accounts for the modest yield (54%) obtained under
these last conditions. To our delight, diastereomer 5a could be
produced in a significantly improved 70% yield, along with only
10% of side product 6a when the reaction was initially performed
at −20 °C in dichloroethane (DCE) and subsequently heated to
60 °C for 3 h (entry 10). This clearly established that 4a is a
kinetic adduct, while 5a represents the thermodynamic one.
Furthermore, no erosion of enantioselectivity was observed
during the thermodynamic equilibration. The robustness of this
diastereodivergent enantioselective11 transformation was dem-
onstrated by a larger scale synthesis of compounds 4a (1 mmol,
70% yield, 94% ee, entry 11) and 5a (0.5 mmol, 70% yield, 94%
ee, entry 12).
Having established the optimal reaction conditions for the
formation of the kinetic spiroproduct 4, we next explored the
substrate scope with a diverse set of dienecarbamates 3 (Scheme
2). In all cases, the β-spirocyclohexyl-indolenines 4a−4l were
obtained with excellent diastereo- and enantioselectivity (Table
1). The N-thiobenzyl- and N-thioallyl-carbamate-substituted
dienes were also tolerated, affording the corresponding spiro-
products 4b to 4e in similar yields and enantioselectivity. Use of
dienecarbamates 4c and 4d substituted by linear alkyl groups at
the 4-position altered neither the yield nor stereoselectivity (95%
ee and >95:5 dr). Additional functional groups such as remote
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indolylmethanols bearing diverse alkyl groups, such as ethyl and
isopentyl, reacted smoothly to produce the corresponding
spiroproducts 4x and 4y in decent yields with excellent
enantiomeric excesses. Use of a 2-phenylindolyl precursor was
however not tolerated, and only degradation of the latter was
observed. In contrast, when 2-ethoxyindole derivatives were
used, we were pleased to see that the reaction proceeded
smoothly to give the corresponding products 4z−4ab in higher
yields (71−85% yield) with excellent enantioselectivities (up to
99% ee).
Scheme 2. Scope of the Enantioselective Synthesis of Kinetic
Spirocyclohexyl-Indolenines 4
The reaction scope for the synthesis of thermodynamic
spiroproducts 5 was also examined. As shown in Scheme 3, 4-
Scheme 3. Scope of the Enantioselective Synthesis of
Thermodynamic Spirocyclohexyl-Indolenines 5
a
b
At 0 °C for 24 h, then at 60 °C for 3 h. At −20 °C for 24 h, then at
c
60 °C for 12 h. At −20 °C for 48 h, then at 60 °C for 3 h.
a
b
c
d
On a 0.05 mmol scale. For 48 h. At 0 °C for 48 h. Without 4 Å
MS.
substituted dienecarbamates 3 were converted to the corre-
sponding products 5b−5f in low to good yields with excellent
enantioselectivities. As previously observed, the diene bearing an
iPr group delivered product 5c with a decreased yield,
presumably due to the steric hindrance of its bulky side chain.
Changing the carbamate group from benzyl to allyl (5g and 5h)
and tBu (5i) led to similar yields and enantiomeric excesses. A
variety of thermodynamic spiroproducts (5j to 5m) was
obtained with high enantio- and diastereoselectivities from
selected 2-alkylindole-3-methanols. This demonstrated that
electron-rich and -poor substituents either on the indole core
(5m and 5n) or on the aryl moiety (5i−5k) were well tolerated.
It is also worth noting that our methodology is compatible with
various alkyl substituents at the C2-position of indoles (5o to
5q).
Mechanistic Studies. Control experiments confirmed that
the two diastereomers 4 and 5 were formed under kinetic and
thermodynamic conditions, respectively. Epimerization could be
monitored by heating pure spiroproduct 4a at various temper-
atures in DCE (Table 2). In the absence of catalyst, no
epimerization occurred at room temperature after 15 h, while
total epimerization of 4a to thermodynamic product 5a was
observed in the same amount of time at 60 °C. However, the
phosphoric acid catalyst seems to favor the isomerization.
Indeed, a complete epimerization took place at room temper-
ature and at 60 °C in respectively 15 h (entry 2) and 5 min (entry
unsaturation (4f) and a silyl ether (4g) were also well tolerated.
Notably, the enantioenriched dienecarbamate (prepared from
(S)-citronellal) participated in the reaction with equal efficiency.
The presence of an additional chiral center did not influence the
enantioselective process. Meanwhile, dienes carrying bulkier
alkyl groups (such as iPr and iBu) were found to be compatible
with the reaction. The corresponding enantioenriched spiro-
products 4i−4k could be obtained in moderate to good yields,
albeit requiring longer reaction times. Subsequently, 4-phenyl-
substituted and 4-unsubstituted dienes were studied, and the
respective products 4l and 4h were isolated in relatively lower
yield or enantioselectivity, respectively. Extension of this
enantioselective transformation to other 2-alkylindole-3-meth-
anols 2 was successful. Indolyl methanol containing various aryl
groups on the side chain with either an electron-donating group
or halide group at the ortho-, meta-, and para-positions gave the
desired products 4m−4s in moderate to good yields and high
stereoselectivities. Moreover, the presence of the 2-naphthyl or
benzothiophene group was found to be suitable, and the
corresponding spiroproducts 4t−4u were obtained in lower
yields but still with excellent enantioselectivity. Methoxy or halo
(Br, Cl) substitution at the aromatic core of the indoles was also
tolerated as exemplified with the synthesis of compounds 4m, 4v,
4w, and 4aa, obtained in moderate to good yields but with
excellent enantioselectivities. Notably, various C2-substituted 3-
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ization mechanism is consistent with the isolation of
intermediate 10a (see Supporting Information, Figures S1 to
S6).
Table 2. Control Experiments Confirm Kinetic and
Thermodynamic Product Formation
a
A computational study was undertaken at the M06-2X/6-
311+G(d,p)//M06-2X/6-31G(d) level of theory in order to get
deeper insight into the mechanism and importantly to rationalize
the observed stereochemistry of 5. Initial calculations inves-
tigated according to the above mechanism did however furnish a
conflicting result, as it provided systematically the wrong
enantiomer. The details are provided in the Supporting
Information (Schemes S3 to S6). As such, it questioned the
dual activation of the vinyliminium and the dienecarbamate by
the chiral phosphoric acid 1a (TS-8, Scheme 4). This finding
required the reevaluation of the mechanism of this spirocycliza-
tion. Our novel set of computations clearly indicated that the
process of water abstraction from the indolyl alcohol had to be
taken into account, and that the resulting H-bonded water
molecule could play a major role in the stereoselectivity.13,14
Figure 1 shows what we believe fully rationalizes our
experimental findings. As a reference system, we chose
indolylmethanol 2a, the s-trans diene 3a, and the model catalyst
1b. The s-cis diene 3a′ was found to be 3.0 kcal/mol less stable
than 3a. The formation of a H-bond between the alcohol
functionality of 2a andthe acidic proton of 1b leads to B, with the
release of 4.8 kcal/mol of free energy. Cleavage of the C−O bond
provides intermediate C,15 which is of course axially chiral by the
phosphate side, but this especially induces planar chirality as the
water molecule is located on the lower face of the vinyl-
indoliniminium ion framework when the Me group is oriented to
the right. The corresponding transition state, TSBC, lies at 12.5
kcal/mol on the free energy surface, and this step is endergonic
by 4.3 kcal/mol. The diastereomers of B and C, B′ and C′, are
shown on the lower energy profile. While these intermediates are
virtually as stable as B and C, TSB′C′ is 0.9 kcal/mol less stable
than TSBC. An adduct is then formed between 3a′ and the
vinylindoliniminium species C or C′, which can only occur on
the face opposite water. Of note, in D and D′, the carbamate is
oriented as to give an endo-adduct in the Diels−Alder sense of
the word. The exo-orientation did not allow any subsequent C−
C bond formation. D′ is markedly less stable than D by 4.3 kcal/
mol (from −0.9 to 3.4 kcal/mol). The last step is an
asynchronous [4+2] cycloaddition furnishing the spiro-adduct
E or E′, which are equally stable. However, TSDE is 4.2 kcal/mol
more stable than TSD′E′ (from 12.1 to 16.3 kcal/mol).
Comparison of these two profiles clearly indicates that the
formation of E is kinetically preferred over that of E′. The
absolute configuration of E matches that of the experimentally
observed kinetic product (KP) 4a (R,R configuration), located at
−12.5 kcal/mol on the free energy surface. The corresponding
thermodynamic product (TP) 5a was found at −14.3 kcal/mol.
While the S enantiomer of B shown in the upper part of Figure 1
reacts faster than the R enantiomer depicted in the lower part, we
observed no kinetic resolution in this transformation. Thus, the
two profiles must be connected in some way by transition states
of lower energies than those already discussed to allow a dynamic
kinetic resolution. We found indeed that C and C′ are in fast
equilibrium (see the Supporting Information, Scheme S7). Thus,
based on these computations and all the other options
summarized in the Supporting Information, we can conclude
that the planar chirality of the vinylindoliniminium ion
intermediate controls the enantioselectivity of the formal
cycloaddition reaction.
b
b
entry 1a (x mol %) T, °C
time
15 h
5a conv (%)
5a yield (%)
1
2
3
4
5
6
7
0
5
0
0
0
0
5
rt
rt
0
100
0
100
20
15 h
15 h
100
35
35
35
60
60
c
6 h
80
ND
100
100
cd
,
18 h
15 h
100
100
5 min
a
General conditions: 4a (0.05 mmol) and 1a (5 mol %) in DCE (0.05
M). Conversion and yields determined by H NMR spectroscopy
using Bn2O as standard. Irradiated with EvoluChem, P206-18-1 at
b
1
c
d
405 nm, 28 mW/cm2. In MeOH.
7) in the presence of 5 mol % of 1a. In addition, the isomerization
of 4a was complete at 35 °C in the absence of catalyst 1a applying
a 405 nm irradiation (80% NMR yield of 5a after 6 h, entry 4).
Interestingly, the reaction performed in MeOH under such
conditions resulted in the formation of the hemiaminal 10a; this
trapped iminium intermediate spontaneous cyclizes after its
isolation (15% yield) in the NMR tube (entry 5).
Based on these experiments and our previous mechanistic
studies,6 a catalytic cycle of the enantioselective spirocyclization
was proposed. Even though we were not able to identify any
iminium (or trapped intermediate 10a) under the catalyzed
process(see Supporting Information, Scheme S2)12 we favoreda
stepwise mechanism. The vinylindoliniminium ion is formed
upon initial chiral phosphoric acid 1a-mediated dehydration of
2-alkyl-3-indolylarlymethanols 2, furnishing complex 7 (Scheme
4). Then, dienecarbamate 3 reacts with the vinyliminium
Scheme 4. Plausible Reaction Mechanism
complex 7 to form the iminium intermediate 8. The latter
undergoes an intramolecular C3 aza-alkylation of indolyl-
methane, delivering iminium 9, which produces the desired β
spirocyclohexyl-indolenines 4. Finally, the kinetic product
isomerizes to yield the thermodynamically more stable spiro-
product 5 via iminium intermediate 9′. The stepwise isomer-
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Figure 1. Computed free energy profiles (ΔG253, kcal/mol).
The experimental level of enantioselectivity (close to 95%)
does not match the calculated gap between enantiomers (4.2
kcal/mol). Indeed, calculated data performed with a simplified
phosphoric acid catalyst provide only qualitative insights.
Refinement of transition states performed with real catalyst 1i
(see Supporting Information, Table S1) using the cheaper STO-
3G basis16 to account for the increased number of atoms led to a
lowering of the ΔΔG⧧ to 3.2 kcal/mol. Such a value does again
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not exactly match the experimental ee values (56%), but this
indicates a clear trend to support the new proposed mechanism.
To bring additional support that no specific Lewis base
activation of the dienecarbamate was required for overall
reactivity, we experimentally devised a series of experiments
involving other Brønsted acid catalysts (see the Supporting
Information, Scheme S1 and Table S3). When trifluoroacetic
acid (TFA) (50 mol %) was employed, a 1:1 mixture of 4a and 5a
was formed in 47% yield. In addition, the reaction conducted in
the presence of(+)-camphorsulfonic acid (20 mol %)ledto 4a in
51% yield with 28% ee. These results cannot totally exclude a
bifunctional activation mode of the catalyst, but agree with the
mechanism that is further supported by DFT in which the chiral
phosphate counterion controls the stereochemical outcome of
the reaction. By that, they concur with a monoactivation of 2 by
the catalyst.17
Scheme 6. Stereospecific Derivatizations of Spiroindolenines
into Spiroindolines and Spirooxindoles
In light of these experimental and computational data, the
initially proposed mechanism (Scheme 4) was adjusted as shown
in Scheme 5. As originally proposed, the reaction begins with the
Scheme 5. Revisited Reaction Mechanism
a
The relative configuration was assigned by NOESY experiments (see
the Supporting Information).
produced in good yield with no loss of enantioselectivity. The
resulting product 14ab was protected with Boc and then reduced
with NaBH4 to give the spiro-aminal 15ab with excellent
diastereoselectivity (>95:5). Finally, the thermodynamic spiro-
product 5a could undergo a dihydroxylation to give the highly
substituted enantioenriched spiroproduct 16a in moderate yield
albeit with full diastereocontrol of six contiguous stereogenic
centers
formation of a chiral vinyliminium phosphate ion pair upon
treatment of 2 with catalyst 1a. However, in contrast to our initial
thought, water stays coordinated to 1a, generating a stable
complex, which undergoes the addition of the dienecarbamate 2
in an asynchronous concerted manner through a well-organized
transition state, TS-10. Finally, the catalyst 1a is liberated upon
release of water, which is trapped by molecular sieves.
CONCLUSION
Applications and Derivatizations. The value of kinetic
and thermodynamic spirocyclic compounds 4a, 4ab, and 5a
prepared by the novel catalytic process was further illustrated by
performing various stereospecific transformations (Scheme 6).
For instance, chiral spiroindolenine 4a was reduced with
NaBH3CN and TiCl4 to provide the corresponding indoline
11a in 84% yield as a single diastereomer bearing five fully
defined stereocenters and with no erosion of enantioselectivity.
The absolute configuration of 11a was confirmed by X-ray
diffraction. The reduction was also realized in a sequential one-
potprocess, whichavoids the purificationof the spiroindoline 4a.
Under sequential process, the spiroindoline 11a was isolated in
58% overall yield (corresponding to the sum of the yields of
individual steps) with 90% ee as a single diastereomer (see the
Supporting Information). Addition of allylmagnesium bromide
to 4a proceeded with complete diastereoselectivity, leading to
the formation of two products: the expected allylated spiroindo-
line 12a and the double allylated spiroindoline 13a in a 7:3 ratio,
respectively. Both products were readily separated by column
chromatography and isolated without loss of enantioselectivity.
When an excess of allylmagnesium bromide was used, the double
allylated spiroindoline 13a was formed as the major compound
in better yield. In addition, the acetamidate product 4ab was
submitted to hydrolysis and the spirooxindole 14ab was
■
In summary, we developed a novel enantioselective and
diastereodivergent spirocyclization of 2-susbtituted 3-indolyl-
methanols with 1,3-dienecarbamates by a chiral phosphoric acid.
In this reaction, a variety of valuable chiral polysubstituted
spirocyclohexyl-indolenines bearing four contiguous stereogenic
centers, including one spiro quaternary center, were conven-
iently constructed with excellent enantioselectivities and
diastereoselectivities. The [4+2] cycloaddition can be directed
to different diastereomers of the spiroindolenine simply through
temperature change, moving from kinetic to thermodynamic
control. Besides, chiral spiroindolenines were amenable to
further transformations and converted into enantioenriched
spiroindolenines and spirooxindoles. DFT calculation and
experimental findings corroborate an asynchronous concerted
mechanism with a monoactivation of chiral phosphoric acid.
Finally, this also revealed the fundamental role played by a water
molecule in the transition state accounting for the enantiose-
lectivity.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04648.
■
sı
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I. R. Total Syntheses of Natural Products Containing Spirocarbocycles.
Org. Biomol. Chem. 2015, 13, 9907. (h) Zheng, Y.; Tice, C. M.; Singh, S.
B. The Use of Spirocyclic Scaffolds in Drug Discovery. Bioorg. Med.
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Experimental procedures and additional optimizations
studies, computational details, charts of 1H and 13C NMR
spectra, chiral and racemic HPLC traces (PDF)
Accession Codes
CCDC 2080057 and 2080064−2080065 contain the supple-
mentary 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.
AUTHOR INFORMATION
Corresponding Authors
■
Vincent Gandon − Institut de Chimie Moléculaire et des
Matériaux d’Orsay (ICMMO), 91405 Orsay, France;
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR
́
9168, Ecole Polytechnique, Institut Polytechnique de Paris,
91128 Palaiseau Cedex, France; Email: vincent.gandon@
universite-paris-saclay.fr
Géraldine Masson − Institut de Chimie des Substances
Naturelles, Université Paris-Saclay, ICSN-CNRS UPR, 2301
Gif sur Yvette, France; orcid.org/0000-0003-2333-7047;
Email: geraldine.masson@cnrs.fr
Authors
Thomas Varlet − Institut de Chimie des Substances Naturelles,
Université Paris-Saclay, ICSN-CNRS UPR, 2301 Gif sur
Yvette, France
̌
́
Mateja Matisic − Institut de Chimie des Substances Naturelles,
Université Paris-Saclay, ICSN-CNRS UPR, 2301 Gif sur
Yvette, France
Elsa Van Elslande − Institut de Chimie des Substances
Naturelles, Université Paris-Saclay, ICSN-CNRS UPR, 2301
Gif sur Yvette, France
Luc Neuville − Institut de Chimie des Substances Naturelles,
Université Paris-Saclay, ICSN-CNRS UPR, 2301 Gif sur
Yvette, France; orcid.org/0000-0002-4648-2469
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04648
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.V. thanks Paris-Saclay University for the doctoral fellowship.
M.M. acknowledges the French Embassy for financial support.
We thank the UPSaclay, Ecole Polytechnique, and CNRS for
financial support of this work. This work was granted access to
the HPC resources of CINES under the allocation 2020-
A0070810977 made by GENCI.
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the presence of 5 equiv of H2O (see the Supporting Information,
Scheme S2).
́
́
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