Design and synthesis of spirocyclic ligands of glucocorticoid receptors

Article abstract of DOI:10.1016/j.tet.2018.02.030

Spirocyclic indazoles were designed as potential ligands for the glucocorticoid receptors (GRs). A short and efficient synthetic sequence was developed allowing the preparation of pure diastereomeric spirocyclic analogs of fluorocortivazol. Our studies also revealed a new application of Burgess reagent leading to a ring expansion. The structures and conformations of several key intermediates and products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. As a proof of concept we tested the affinity of diastereomeric compounds 13b and 14b for the GRs. Rewardingly, it was found that 14b showed a promising IC₅₀ of 27 nM.

Full text of DOI:10.1016/j.tet.2018.02.030

Accepted Manuscript
Design and synthesis of spirocyclic ligands of glucorticoid receptors
Eduard Badarau, Frédéric Robert, Stéphane Massip, Florian Jakob, Simon Lucas,
Sven Frormann, Léon Ghosez
PII:
S0040-4020(18)30164-9
10.1016/j.tet.2018.02.030
TET 29301
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 December 2017
Revised Date: 9 February 2018
Accepted Date: 13 February 2018
Please cite this article as: Badarau E, Robert Fréé, Massip Sté, Jakob F, Lucas S, Frormann S, Ghosez
Lé, Design and synthesis of spirocyclic ligands of glucorticoid receptors, Tetrahedron (2018), doi:
10.1016/j.tet.2018.02.030.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Design and synthesis of spirocyclic ligands of
glucorticoid receptors
Leave this area blank for abstract info.
Eduard Badaraua,b, Frédéric Robertc, Stéphane Massipa, Florian Jakobd, Simon Lucasd, Sven Frormannd and Léon
Ghoseza

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Design and synthesis of spirocyclic ligands of glucorticoid receptors
Eduard Badaraua,b, Frédéric Robertc, Stéphane Massipa Florian Jakobd, Simon Lucasd, Sven Frormannd and
,
Léon Ghoseza
a Univ. Bordeaux, European Institute of Chemistry and Biology (IECB), 2 Rue Robert Escarpit, 33607 Pessac, France
bPresent address: Univ. Bordeaux, Institute of Chemistry & Biology of Membranes & Nano-objects (CBMN), Allée Geoffroy Saint Hilaire, Bât B14, 33600
Pessac, France
c Univ. Bordeaux, Institute of Molecular Sciences (ISM), CNRS UMR 5255, F-33400 Talence, France.
dGrunenthal GmbH, Zieglerstr. 6, 52078 Aachen, Germany
To the late sir Derek, with respect, admiration and friendship
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Spirocyclic indazoles were designed as potential ligands for the glucocorticoid receptors (GRs).
A short and efficient synthetic sequence was developed allowing the preparation of pure
diastereomeric spirocyclic analogs of fluorocortivazol. Our studies also revealed a new
application of Burgess reagent leading to a ring expansion. The structures and conformations of
several key intermediates and products were confirmed by single crystal X-ray diffraction
analysis. Conformational assignments were also supported by DFT calculations. As a proof of
concept we tested the affinity of diastereomeric compounds 13b and 14b for the GRs.
Rewardingly, it was found that 14b showed a promising IC50 of 27 nM.
Available online
Keywords:
Spirocycles
Benzopyrazole
Glucocorticoids
Burgess reagent
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +33 (5) 40 00 30 38; e-mail: l.ghosez@iecb.u-bordeaux.fr

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Glucocorticoids (GCs) belong to the most efficient agents
currently used for the treatment of allergic and inflammatory
diseases. Prednisolone, dexamethasone and fluorocortivazol are
notable examples of this class of drugs. Unfortunately their
immunosuppressive effects are often accompanied by side effects
such as muscle atrophy,1 steroid-induced osteoporosis,2 diabetes
mellitus3 and hypertension.4
We have recently initiated a research program aiming at
developing new potential ligands for the glucocorticoid receptors
(GRs). We started from the simplified analogues of
fluorocortivazol (MK, Scheme 1) uncovered by Ali and coll.5
which were developed as promising selective glucocorticoid
receptor modulators (SEGRMs).6 As originally demonstrated, the
steroidal rings C and D of fluorocortivazol could be successfully
replaced by lipophilic substituents at C11. The introduction of
various side-chains R carrying aryl substituents led to the
discovery of fluorocortivazol analogs with an IC50 in the low nM
range for hGRs.
Scheme 2. Retrosynthetic analysis
2.1. Synthesis of the spirodiketone intermediates
The preparation of the known spirodiketones 5a-b was
inspired by literature precedents (Scheme 3). As already pointed
out by Eaton and Jobe7 the formylation of cyclopentanone was
best effected with ethylformate in the presence of potassium
hydride. For the higher homologs (n = 2) we found that the
reaction proceeded smoothly in the presence of the cheaper but
weaker base, sodium hydride. Compounds 1a-b were used
without purification in the Michael addition to methyl vinyl
ketone in the presence of catalytic amounts of DBU and
triethylamine.8 This classical sequence of reactions allowed the
preparation of multigram quantities of 2a-b in good overall
yields.
Starting from the MK ligand, we decided to explore a
spirocyclic pattern resulting from disconnecting C7 from C7a and
reconnecting C7 with the methyl group at C4a (Scheme 1, target
structures). The replacement of steroidal fused-rings by a spiranic
structure should increase the conformational freedom of the B-D
rings with less entropy loss than with a simple alkyl tether.
Several low-energy conformations could be available in solution
thus offering more possibilities for a better interaction with the
receptor.
Surprisingly the spiroannulation step turned out to be more
difficult than anticipated (Scheme 3). The methanesulfonic acid-
catalyzed spiroannulation described by Eaton and Job7 for the
preparation of 5a-b did not work well in our hands giving low
yields of the desired spirodiketones. Variations of some reaction
parameters (concentration, temperature, use of PTSA or triflic
acid) were not successful: these reactions gave complex mixtures
or starting material was recovered. Eventually, an annulation
product 3 was isolated in 60% yield from the treatment of 2b (n =
2) with 0.5 eq. of MsOH in benzene followed by azeotropic
distillation of water. An X-ray diffraction analysis of a crystal of
the corresponding 2,4-dinitrophenylhydrazone 4 confirmed the
structure of 3. Compound 3 was the result of an acid-catalyzed
deformylation of the non-enolizable ketone 2b (n = 2) followed
by an intramolecular aldol reaction. Both acidic and basic
conditions have indeed been used for the decarbonylation of non-
enolizable α-formylated ketones.9
Scheme 1. Design of new potential spiro-corticoids
2. Synthesis
This initial study was intended to validate the synthetic access
to this type of compounds and not to fully explore the structure-
activity relationships generated by variation of substituents (R),
or the size (n) of the spirocyclic ring (Scheme 1). From this
perspective, it did not require an access to enantiopure
compounds. The stereochemical challenge was thus limited to the
generation of pure diastereomers. Since the conformational
flexibility should increase with the size of the spirocyclic ring,
we decided to prepare representative alcohols of the homologous
5- and 6-membered B-rings. These should be easily obtained by
addition of an organometallic reagent to the corresponding 5- and
6-membered ring ketone (Scheme 2).
This competitive reaction could be avoided by applying a
variation of the conditions described earlier by de Groot et al. for
related spiroannulation reactions.10 The spiroannulation of 2a-b
was thus performed in the presence of a 1:1 mixture of
morpholine and acetic acid in DMSO at room temperature, and
conducted to the

3
ACCEPTED MANUSCRIPT
Scheme 5. DFT calculations at the M06-2X/6-31+G(d,p) level.
The protected ketones 6a-b were first formylated then reacted
with p-fluorophenyl hydrazine to yield the tricyclic pyrazoles 9a-
b in 61% and 73% respectively (Scheme 6). Hydrolysis of 9a-b
yielded ketones 10a-b (66% and 71%, respectively).
O
O
O
Scheme 3. Synthesis of the spirodiketones 5. (a) for n = 1: KH, HCOOEt in
Et2O, 1 h, 0°C to rt; for n = 2: NaH, HCOOEt in Et2O, 48 h, rt ; (b) for n = 1:
methyl vinyl ketone, KOH / 2 h, rt, 55%; for n = 2: methyl vinyl ketone,
DBU, TEA / THF, 12 h, rt, 49%; (c) MsOH (0.5 eq.) / PhCH3, 12 h, reflux,
60%; (d) dinitrophenylhydrazine, H2SO4 / EtOH, 30 min, rt; (e) morpholine :
AcOH (1:1) / DMSO, 24 h, rt, (n = 1: 34%, n = 2: 73%).
O
(a)
(b)
HO
( )n
( )n
O
O
6a-b
O
O
2.2. Construction of the pyrazole ring
O
(c)
( )n
N
( )n
N
The construction of the pyrazole ring first required the
protection of the saturated ketone. Inspection of molecular
models had revealed that the saturated ketone was fairly
congested which raised the problem of chemoselectivity of the
ketalization reaction. The desired selective ketalization of the
saturated ketone was observed upon treatment of 5b (n = 2) with
1 eq. PTSA in the presence of molecular sieves at room
temperature. The lower homolog 5a (n = 1) behaved differently:
treatment of 5a with 1 equivalent PTSA at room temperature
yielded compound 7. The structure of 7 was confirmed by X-ray
diffraction analysis of monocrystals of diphenylhydrazone 8. The
formation of 7 could be explained by an acid-catalyzed cleavage
of the tetrahedral intermediate generated by addition of ethylene
glycol to the carbonyl group of 5a (Scheme 4).
N
N
F
10b
(n = 2)
F
9a-b
10a-b
Scheme 6: Construction of the pyrazole ring. (a) : NaH, HCOOEt, MeOH /
toluene / 48 h, rt; (b) 4-F-Ph-NHNH2, AcONa / AcOH / 24 h, rt, (over two
steps, 9a: 61%, 9b: 73%); (c) HCl / THF / 1.5 h, 65°C, (10a: 66%, 10b:
71%).
The structure and conformation of the six-membered ketone
10b (n=2) was established by X-ray diffraction analysis. A DFT
conformational analysis (M06-2X/6-311+G(2d,p) level in
chloroform) was also performed on this derivative (Scheme 7).
They revealed that the conformer observed in the crystal was also
preferred in chloroform (A, Scheme 7) although another chair
conformation, quite similar in energy, of the cyclohexanone ring
exists (B, Scheme 7). The full details of the conformational
analyses can be found in the supplementary material.
Scheme 4. Selective ketalization of spiranediones 5. (a) ethylene glycol, CSA
(0.1 eq.), m.s. 4 Å / 40 min, rt, 69%; (b) ethylene glycol, PTSA (1 eq.), m.s. 4
Å / 1 h, rt, 72%; (c) ethylene glycol, PTSA (1 eq.), m.s. 4 Å / 40 min, rt, 63%;
(d) NaH, HCOOEt, PhCH3 / 1 h, 0°C to rt; (e) 2,4-dinitrophenyl-hydrazine,
H2SO4 in EtOH / H2O.
Scheme 7 : DFT conformational analysis of the 6-membered ketone 10b
2.3. Synthesis of the target alcohols
A DFT study of the fragmentation reactions in the 5- and 6-
membered spirocycles showed that, despite similar energy
barriers for the fragmentation in both series, the reaction was
exothermic only in the case of the 5-membered ring (Scheme 5).
Eventually we were able to obtain the desired ketal 6a in 69%
yields after treatment of 5a with 0.1 eq. of CSA for 40 min.
The final step of the synthesis was the generation of the target
alcohols from ketones 10a-b. Our studies were first conducted on
the 6-membered ring ketone 10b. The stereochemical course of
addition of metal hydrides, organolithium or Grignard reagents to
cyclohexanones is known to be a complex process depending on
many experimental parameters. In addition, the conformational

4
Tetrahedron
ACCEPTED MANUSCRIPT
analysis of each ketone had revealed the presence of several
conformers of similar energy. However, as different
diastereomeric alcohols could provide more informative
biological data, mixtures of diastereoisomers were therefore
acceptable as long as these could be separated and purified.
OH
OH
R
R
N
N
N
N
Reduction of the ketone 10b with DIBAL-H yielded a 1:3
mixture of secondary alcohols 11 and 12 in 90% yield (Scheme
8). The evidence for the presence of the two isomers was
1
provided by the splitting of H-NMR signals (especially those of
F
F
13a
14a
the vinylic protons) in the crude reaction mixture. Axial and
equatorial alcohols 11 and 12 were separated by preparative
HPLC. Their structures, relative configurations and their
conformations were confirmed by X-ray diffraction analyses
(Figure 1).
Figure 2. Structures of tertiary alcohols 13a and 14a (R = 1-propynyl)
2.4. An unprecedented behaviour of Burgess reagent
We were also interested in the dehydrated derivatives starting
from a mixture of 11 and 12. Unfortunately classical dehydration
conditions (Tf2O/toluene or pyridine, or Ac2O/pyridine) yielded a
complex mixture of products containing only traces of
elimination product 15. As an alternative, we tested the Burgess
reagent which has been successfully used for the syn-dehydration
of alcohols.11 However, refluxing a mixture of alcohols 11 and 12
with 1.1 equiv. of methyl-N-(triethylammoniumsulfonyl)-
carbamate (Burgess reagent) in dry THF did not yield the
expected elimination product 15 (Scheme 9, pathway A), but
partially converted the starting material into a new product 16. A
complete transformation of the starting material into 16 was
observed in the presence of 2.2 equiv. of Burgess reagent
(Scheme 9). The structure of this unexpected product 16 was
unequivocally confirmed by X-rays diffraction analysis.
Compound 16 thus resulted from a ring expansion of the
cyclohexadiene B-ring. We first envisaged (Pathway B)
involving an intramolecular abstraction of a hydrogen atom of
the B-ring concerted with a nucleophilic attack of the activated
alkene on the carbon carrying the leaving group (noted a). This
would give a strained norcaradiene that would isomerize readily
to the more stable cycloheptatriene 16.12 An alternative
mechanism preferred by the referees would be a direct attack of
the fairly nucleophilic and properly oriented double bond
(pathway C) to give a stabilized tetracyclic cation that would
undergo a base-catalyzed rearrangement to 16.
O
OH
H
HO
H
(a)
N
N
N
N
N
N
11
12
10b
F
F
F
Scheme 8. (a) DIBAL-H, Toluene, -78°C, 1h, 11 (22%) and 12 (68%).
Figure 1. Crystal structures of secondary alcohols 11 and 12
As expected, addition of organolithium or Grignard reagent to
ketone 10b generated a mixture of tertiary alcohols (Table 1).
The structure of the major diastereoisomer 13 was revealed in the
case of 13a, by X-rays diffraction analysis of crystals obtained in
acetonitrile (Figure 2, 13a). Molecular modeling showed that the
minor distereoisomer 14 would have another orientation of the
spirocyclic ring, carrying the bulky substituent on the alcohol in
the equatorial position (Figure 2, 13b). As the orientation of the
alcohol moiety is different from one diasteroisomer to another,
this should strongly influence the interaction the glucocorticoid
receptors.
COOMe
O
N
S
H
O
HO
O
N
O
a
O
MeOOC
S
NEt3
N
N
pathway A
Burgess reagent
N
N
N
N
(a)
15
11/12
F
F
F
Table 1. Reaction of organometallics with ketone 10b
pathway C
pathway B
H
O
R
Conditionsa,b
DIBAL-H
Diastereoisomersc
12 (68%)
N
Concerted
mechanism
Stepwise
mechanism
O
MeOOC
S
MeOOC
O
O
S
N
H
O
H
11 (22%)
a
O
a
N
N
1-propynyl 1-propynylMgBr 13a (61%)
14a (NI)
N
N
benzyl
benzylMgBr
2-naphtyl-Li
p-MeOPhMgBr
13b (81%)
13c (49%)
13d (48%)d
14b (13%)
14c (NI)
2-Naphtyl
p-MeOPh
F
X-Rays
F
B
14d (NI)
H
reactions performed in THF; b not optimized; yields of pure compounds
a
c
a
a
a
N
N
N
after chromatography or/and recrystallization unless otherwise mentioned;
N
N
6 e-
π
dconversion (40% starting material was recovered); NI = Not isolated.
N
Norcaradiene
16
F
F
F
Scheme 9. (a). Burgess reagent / THF, reflux, 1 h (87%).

5
We applied the same experimental conditions to the saturated
analogue 17 (Scheme 10). The reaction did not yield a ring
expansion product nor an elimination product: the sulfonylated
was recovered unchanged after 3 h at 80°C.
In the course of our synthetic studies, we also discovered an
ACCEPTED MANUSCRIPT
unprecedented application of Burgess reagent. Instead of
generating an olefin by an intramolecular syn-elimination, the
product resulting from the treatment of spirocyclic alcohols 11
and 12 with Burgess reagent led to the expansion of the
cyclohexadiene ring. Our future plan is to examine whether this
observation could be generalized to other systems containing an
allylic hydrogen atom.
We believe that these preliminary synthetic studies open a
new window for the discovery of new potent and selective
glucocorticoid ligands.
4. Experimental
Scheme 10. (a) H2, Pd/C, HCl (1N) / EtOH; (b) Burgess reagent (2.2 eq.) /
4.1. General experimental
THF, reflux, 3 h (16% over two steps).
The infrared (IR) spectra were recorded on a Bruker IRFT IFS
55 spectrometer on zinc selenide plates, unless stated otherwise.
1H-NMR and 13C-NMR were recorded with Bruker Avance II
300 (at 300.18 MHz and 75.48 MHz, respectively) in CDCl3-d1
and DMSO-d6, using tetramethylsilane (TMS) as an internal
standard. Chemical shifts are reported in parts per million (ppm)
and the coupling constants are reported in units of Hertz [Hz].
Multiplicities were abbreviated as follows: singlet (s), doublet
(d), triplet (t), quartet (q).
As far as
we can tell this ring expansion reaction
represents an unprecedented application of Burgess reagent.
Eventually we managed to obtain the elimination product 15
using the Shapiro reaction. The hydrazone 19 was obtained in
good yield (77%) by treatment of the ketone 10b with
tosylhydrazine in ethanol. Subsequent addition of n-BuLi (2 eq.)
at low temperature delivered a rather low yield of the olefin 15
along with unidentified degradation products (Scheme 11).
Low resolution mass spectra (MS) / High resolution mass
spectra (HRMS) were recorded with a ThermoElectron LCQ
O
S
O
HN
Advantage and
respectively.
Melting points were recorded using a Buchi B-540 apparatus
and are uncorrected.
a ThermoElectron Exactive spectrometer,
O
N
N
N
N
(a)
(b)
N
N
N
Flash chromatography was performed on Merck 40–70 nM
(230–400 mesh) silica gel under air pressure. Thin-layer
chromatography (TLC) was carried out on Merck silica gel 60
F254 precoated plates. Visualization was made with ultraviolet
light (λ = 254/365 nm) or using an aqueous potassium
permanganate staining solution.
F
F
F
19
10b
15
Scheme 11. (a) p-Toluenesulfonyl hydrazide, HCl / EtOH, 12 h, r.t. (77%);
(b) n-BuLi / THF, 3 h, 0°C to r.t. (34%).
3. Conclusions
4.2. Experimental details and characterization data
Spirocyclic indazoles were designed as potential ligands for
the glucocorticoid receptors. Although the synthetic route to
these compounds originally appeared as straightforward, in
practice the construction of the homologous in 5- and 6-
membered spiranic ring systems required specific sequences for
each member of the homologous series as a consequence of very
different reactivity patterns. Eventually, we were able to establish
practical synthetic routes for each member of the homologous
series. The last step leading to the alcohols yielded two
diastereomers. As examples, we separated both diastereoisomers
11 and 12 and also 13b and 14b. The conformations of
representative final products and key intermediates were also
studied by DFT calculations and confirmed by X-rays diffraction
analyses. These synthetic studies offer chemists an easy access to
a wide variety of structural analogs of this new class of
spirocycles. They can be easily modulated to conduct to new
glucocorticoids. In order to test the validity of our design we
tested both diastereoisomers 13b and 14b. If the isomer 13b is
devoid of affinity for the GRs, having an IC50 of 5.7 µM, the
corresponding diastereoisomer 14b has a promising IC50 of 27
nM. The completely different binding pattern of these isomers
could result from the different position of the hydroxyl moiety,
expected to mimic the initial C11 alcohol of fluorocortivazol.
More examples in this series are necessary in order to define the
SAR for this class of derivatives. This will be discussed in a
forthcoming publication in a medicinal chemistry journal.
4.1.1. 2-Oxo-1-(3-oxobutyl)cyclopentanecarb-
aldehyde (2a).
To a stirred suspension of KH (2.58 g, 30% w/w in oil, 19.39
mmol) in anhydrous Et2O (10 ml) was added dropwise a solution
of cyclopentanone (1 g, 11.89 mmol) and ethyl formate (1.07 ml,
13.32 mmol) in anhydrous Et2O (5 ml) at -5°C for 15 min under
argon atmosphere. The reaction mixture was stirred for additional
30 min and poured in ice/water (25 ml). The aqueous layer was
separated and washed with Et2O (10 ml × 2). The organic phase
was discarded and aqueous phase was acidified with NaH2PO4 (1
g) and concentrated HCl (3 ml, pH = 1-2). The aqueous phase
was extracted with Et2O (50 ml × 8). The combined organic
phase was washed with saturated aqueous NH4Cl solution (25
ml), dried over Na2SO4 and evaporated under vacuum to give a
pale brown residue. The resulting residue was triturated with n-
pentane (25 ml × 6) to give (E/Z)-2-(hydroxymethylene)-
cyclopentanone 1a as a white solid. The crude product 1a (8 g,
71.30 mmol) was dissolved in methyl vinyl ketone (14.5 ml) and
powdered KOH (181 mg, 3.23 mmol) was added and the reaction
mixture was stirred at room temperature for 2 h. After the
reaction was complete methyl vinyl ketone was evaporated under
vacuum. The residue was dissolved in DCM (100 ml) and
washed with 1 M aqueous solution of NaH2PO4 (30 ml × 2)
followed by brine wash (20 ml). The organic phase was dried
over Na2SO4 and evaporated under vacuum to give the adduct 2a
(12.2 g, 55% over 2 steps, brown oil). This compound was used

6
Tetrahedron
ACCEPTED MANUSCRIPT
as such without purification for the next step. C10H1 O3; brown
Na2CO3 solution and extracted with EtOAc (50 ml × 4). The
4
oil; yield: 55%; M = 182.22 g / mol; IR (KBr, cm-1): 2959, 1713.
1H NMR (400 MHz; CDCl3): 1.64-1.66 (m, 1H), 1.74-1.89 (m,
3H), 1.99-2.10 (m, 5H), 2.14-2.19 (m, 2H), 2.26-2.37 (m, 2H),
9.25 (s, 1H).
combined organic phase was washed with saturated aqueous
NH4Cl solution (50 ml). The organic phase was dried over
Na2SO4, filtered and concentrated under reduced pressure to give
a residue. The resulting residue was purified by column
chromatography (neutral alumina; eluent: EtOAc/PE 1/9) to
afford the derivative 5a (2.5 g). C10H12O2; M = 164.08 g/mol;
4.1.2. 2-oxo-1-(3-oxobutyl)cyclohexanecarb-
aldehyde (2b)
yield: 34%; IR (KBr, cm-1): 2958, 1736, 1680; H NMR (400
1
Sodium hydride (60% dispersion in mineral oil, 11.4 g) was
added under nitrogen to dry diethyl ether (250 ml). Subsequently,
ethyl formate (12.7 g, 13.8 ml, 1.2 eq.) and then cyclohexanone
(12 g, 12.6 ml, 1 eq.) were added and the mixture was stirred for
48 h at room temperature. The orange mixture was slowly poured
on ice-cold water (200 ml), the aqueous layer separated and
washed with diethyl ether (2 x 200 ml) before being acidified
with hydrogen chloride (aq. soln., 6 N). The organic materials
were extracted with diethyl ether (3 x 150 ml), the combined
organic layers were dried over magnesium sulfate and the solvent
was evaporated to conduct to the desired α-formylated
cyclohexanone 1b as a light-yellow liquid subsequently used
without further purification. The crude compound 1b (6.42 g, 1
eq.) was dissolved in THF (50 ml), then DBU (0.06 ml, 0.05 eq.),
TEA (0.06 ml, 0.05 eq.) and methyl acrylate (1 ml, 1.5 eq.) were
consecutively added to the mixture and stirred for 24 h at room
temperature under inert atmosphere. After the complete
consumption of the starting material, the solvent was evaporated,
the residue diluted with DCM (200 ml) and washed with
ammonium chloride (sat. soln., 2 x 100 ml) and sodium chloride
(sat. soln., 1 x 100 ml). The organic solvent was dried over
magnesium sulfate and evaporated under vacuum. The crude
product was purified by flash-chromatography (eluent: PE /
EtOAc 7/3) to give the desired addition derivative 2b as a
colorless oil (10 g). C11H16O3; colorless oil; yield: 49%; M =
196.24 g / mol; IR (ZnSe) ν = 2940, 1715, 1450, 1367, 1169 cm–
MHz; CDCl3): 1.86-2.13 (m, 6H), 2.28-2.35 (m, 2H), 2.39-2.47
(m, 1H), 2.58-2.66 (m, 1H), 6.02 (d, J = 10.0 Hz, 1H), 6.48 (d, J
= 10.0 Hz, 1H); 13C NMR (100 MHz; CDCl3): 19.09, 30.04,
33.47, 36.38, 37.24, 51.29, 130.48, 149.89, 198.60, 217.06. MS
(APCI): m/z = 165 [M+H]+.
4.1.5. Spiro[5.5]undec-10-ene-5,9-dione (5b)
Under inert atmosphere, morpholine (6.66 ml, 1 eq.) and
acetic acid (4.4 ml, 1 eq.) were added to a solution of the
previously obtained Michel adduct 2b (15 g, 1 eq.) in DMSO
(130 ml). The mixture was vigorously stirred for 48 h at room
temperature, then, after the complete consumption of the starting
material, slowly added to sodium carbonate (satd. soln., 100 ml).
The organics were extracted with ethyl acetate (4 x 50 ml), then
washed with ammonium chloride (100 ml) before drying over
magnesium sulfate. The solvent was evaporated under reduced
pressure and the crude product was purified by flash
chromatography (PE / EtOAc 7/3) to give the desired annulated
compound 5b as a colourless oil (10 g). C11H14O2; colourless oil;
yield: 73%; M = 178.23 g / mol; IR (ZnSe) ν = 2939, 1703, 1680,
1
1125 cm–1; H NMR (300 MHz, CDCl3) δ 1.88-2.05 (m, 5H),
2.30-2.61 (m, 5H), 6.02 (dd, J = 10.2 Hz, J = 7.8 Hz, 1H), 6.95
(dd, J = 10.2 Hz, J = 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
20.9 (CH2), 27.6 (CH2), 30.5 (CH2), 34.0 (CH2), 38.3 (CH2), 39.2
(CH2), 51.2 (Cq), 129.7 (CH), 150.8 (CH), 198.7 (Cq), 210.9 (Cq);
HRMS: calcd. for C11H14O2Na 201.0886, found 201.0887
(0.3737 ppm).
1
1; H NMR (300 MHz, CDCl3) δ 1.55-2.46 (m, 15 H); 13C NMR
(75 MHz, CDCl3) δ 21.4 (CH2), 25.1 (CH2), 26.7 (CH2), 30.0
(CH3), 32.9 (CH2), 38.2 (CH2), 40.7 (CH2), 64.0 (Cq), 201.2
(CHO), 207.6 (Cq), 210.2 (Cq).
4.1.6. 1,4-Dioxadispiro[4.0.5.3]tetradec-7-en-9-one
(6a)
4.1.3. 4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-
To a suspension of compound 5a (4 g, 24.38 mmol) in
ethylene glycol (40 ml) was added (+)-camphor sulfonic acid
(1.69 g, 7.3 mmol) and 4Å molecular sieves (12 g) at 0°C under
Ar atmosphere. The reaction mixture was allowed to stir for 40
min at room temperature. The reaction mixture was filtered and
the filtrates was poured into saturated aqueous NaHCO3 solution
(50 ml) and extracted with EtOAc (100 ml × 3). The combined
organic phase was washed with brine solution, dried over
Na2SO4, filtered and concentrated under reduced pressure to give
a residue. The residue was purified by column chromatography
(neutral alumina; eluent: EtOAc/PE 1/4)) to give the ketal 6a (1
g, 69%). C12H16O3; yellow liquid; yield: 69%; M = 208.11 g/mol;
one (3)
A solution of the previously obtained Michael adduct 2b (1.3
g, 6.62 mmol, 1 eq.) in benzene (60 ml) was refluxed overnight
with water removal (using a Dean-Stark trap) in the presence of
methane sulfonic acid (0.22 ml, 3.31 mmol, 0.5 eq.). After the
solvent evaporation, the residue was diluted with water (50 ml)
and neutralized by sodium bicarbonate (NaHCO3 satd. soln.). The
organic materials were subsequently extracted with DCM (3 x 50
ml), the combined organic layers were dried over magnesium
sulfate and the solvent evaporated under reduced pressure. The
crude product was purified by flash-chromatography (PE /
EtOAc 8/2) to give the pure annulation product 3. C10H14O; light
brown oil; yield: 60%; M = 150.22 g / mol; IR (ZnSe) ν = 2933,
1
IR (KBr): 2953, 1680 cm-1; H NMR (400 MHz; CDCl3): 1.76-
1
2.00 (m, 7H), 2.19-2.26 (m, 1H), 2.35-2.43 (m, 1H), 2.56-2.62
(m, 1H), 3.85-3.94 (m, 4H), 5.97 (d, J = 10.4 Hz, 1H), 6.92 (d, J
= 10.0 Hz, 1H); 13C NMR (100 MHz; CDCl3): 18.53, 28.51,
33.86, 34.52, 34.58, 48.42, 64.83, 65.25, 119.54, 128.86, 153.80,
199.91; MS (APCI): m/z = 209.0 (M+1);
1714, 1671, 1452 cm–1; H NMR (300 MHz, CDCl3) δ 1.12-
1.66 (m, 4H), 1.79-1.95 (m, 3H), 2.01-2.43 (m, 6H), 5.78 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 25.6 (CH2), 27.0 (CH2), 29.3
(CH2), 34.5 (CH2), 35.6 (CH2), 36.6 (CH2), 38.0 (CH), 124.4
(CH); HRMS: calcd. for C10H15O 151.11174, found 151.11137 (-
2.46 ppm).
4.1.7. 1,4-dioxadispiro[4.0.5-6.4-5]pentadec-7-en-
9-one (6b)
4.1.4. Spiro[4.5]dec-6-ene-1,8-dion (5a)
Under nitrogen atmosphere, to a solution of the spiro-
derivative 5b (5 g, 1 eq.) in ethylene glycol (50 ml), were
successively added PTSA (5.35 g, 1 eq.) and activated molecular
sieves (5 g). After 1 h of reaction, the mixture was poured in a
water / sodium bicarbonate (satd. soln.) mixture (2/1, 100 ml),
then extracted with ethyl acetate (3 x 150 ml). The combined
To a solution of compound 2a (8 g, 43.90 mmol) in DMSO
(100 ml) was added morpholine (3.90 g, 45.27 mmol) and AcOH
(2.7 ml, 45.27 mmol) at room temperature under Ar atmosphere.
The reaction mixture was stirred at room temperature for 20 h.
TLC analysis showed the complete consumption of starting
material. The reaction was quenched with saturated aqueous

7
organic layers were washed with brine (100 ml), dried over
magnesium sulfate and the solvent evaporated under vacuum.
The desired ketal was purified by flash-chromatography
(PE/EtOAc 9/1) and isolated as a light-yellow oil. C13H18O3;
light-yellow visc. oil; yield: 72%; M = 222.28 g / mol; IR (ZnSe)
ν = 2936, 1679, 1448, 1088 cm–1; 1H NMR (300 MHz, CDCl3) δ
1.41-1.55 (m, 2H), 1.58-1.64 (m, 5H), 1.75-1.95 (m, 2H), 2.21-
2.44 (m, 2H), 2.50-2.59 (m, 1H), 3.84-3.97 (m, 4H), 5.96 (dd, J =
10.4 Hz, J = 1.3 Hz, 1H), 6.95 (d, J = 10.5 Hz); 13C NMR (75
MHz, CDCl3) δ 20.8 (CH2), 23.4 (CH2), 27.6 (CH2), 30.8 (CH2),
33.9 (CH2), 33.9 (CH2), 44.1 (Cq), 65.1 (CH2), 65.2 (CH2), 111.7
(Cq), 129.4 (CH), 154.6 (CH), 200.0 (Cq); HRMS: calcd. for
C13H18O3Na 245.1154, found 245.1147 (-0.5494 ppm).
10 min at -40°C, then MeOH (97 µl, 2.4 mmol) was added.
ACCEPTED MANUSCRIPT
Reaction mixture was left to come back to room temperature and
stirred for 10 additional minutes. TLC analysis showed the
complete consumption of starting material. The reaction mixture
was poured into ice-cold water (20 ml) and extracted with EtOAc
(50 ml × 4). The combined organic phase was washed with brine
solution (25 ml), dried over Na2SO4 and evaporated under
vacuum to give the crude α-formylation product (1.09 g, 96%,
pale yellow liquid). IR (KBr, cm-1): 2925, 1644. H NMR (400
1
MHz; CDCl3): 1.72-1.82 (m, 4H), 1.90-2.04 (m, 2H), 2.22 (d, J =
14.4 Hz, 1H), 2.73 (d, J = 14.8 Hz, 1H), 3.90-3.95 (m, 4H), 6.06
(d, J = 10.0 Hz, 1H), 6.83 (d, J = 10.0 Hz, 1H), 7.47 (bs, 1H),
13.65 (bs, 1H).
4.1.8. 2-hydroxyethyl 4-(1,4-dioxaspiro[4.5]dec-8-
en-8-yl)butanoate (7)
To a solution of the previously obtained crude product (1.05 g,
4.44 mmol) in acetic acid (20 ml) was added NaOAc (730 mg,
8.89 mmol) and 4-fluorophenyl hydrazine chlorhydrate (795 mg,
4.89 mmol) at room temperature. The reaction mixture was
stirred at room temperature for 30 min. TLC analysis showed the
complete consumption of starting material. Then, the reaction
mixture was poured into ice-cold saturated aqueous Na2CO3
solution (20ml) and extracted with EtOAc (50ml × 4). The
combined organic phase was washed with brine (25 ml), dried
over Na2SO4 and purified over neutral alumina (PE/EtOAc 9/1).
The collected fraction was evaporated under vacuum to give the
title compound 9a (930 mg). C19H19FN2O2; pale yellow oil; yield:
Under nitrogen atmosphere, to a solution of the spiro
derivative 5b (5 g, 30.47 mmol, 1 eq.) in ethylene glycol (50 ml),
were successively added PTSA (5.8 g, 30.47 mmol, 1 eq.) and
activated molecular sieves (8 g). After 1 h of reaction, the
mixture was poured in a water / sodium bicarbonate (satd. soln.)
mixture (2/1, 100 ml), then extracted with ethyl acetate (3 x 150
ml). The combined organic layers were washed with brine (100
ml), dried over magnesium sulfate and the solvent evaporated
under vacuum. The ketal was isolated by flash-chromatography
(PE/EtOAc 8/2) as a colorless oil (5.14 g). C14H22O5; colorless
oil; yield: 63%; M = 270.32 g / mol; IR (ZnSe) ν = 3492, 2952,
1733, 1452, 1382, 1254, 1116 cm–1; 1H NMR (300 MHz, CDCl3)
δ 1.66-1.76 (m, 3H), 1.97 (t, J = 7.6 Hz, 2H), 2.09-2.13 (m, 2H),
2.19 (as, 2H), 2.28 (t, J = 7.5 Hz, 2H), 2.53 (t, J = 5.8 Hz, 1H),
3.73-3.78 (m, 2H), 3.92 (s, 4H), 4.13-4.16 (m, 2H), 5.27 (as, 1H);
13C NMR (75 MHz, CDCl3) δ 22.8 (CH2), 27.3 (CH2), 31.1
(CH2), 33.6 (CH2), 35.6 (CH2), 36.3 (CH2), 61.0 (CH2), 64.4
(2CH2), 65.9 (CH2), 108.1 (Cq), 118.9 (CH), 136.4 (Cq), 174.0
(Cq); MS m/z = 271.1 [M+H]+; HRMS: calcd. for C14H23O5
271.15540, found 271.15509 (4.019 ppm).
1
64%; M = 326.14 g/ mol; IR (KBr): 2922, 2322, 1514 cm-1; H
NMR (400 MHz; CDCl3): 1.72-1.85 (m, 4H), 1.93-1.98 (m, 2H),
2.62 (d, J = 17.6 Hz, 1H), 3.00 (d, J = 16 Hz, 1H), 3.90-3.94 (m,
4H), 6.04 (d, J = 10.4 Hz, 1H), 6.44 (d, J = 10.0 Hz, 1H), 7.12-
7.17 (m, 2H), 7.43-7.47 (m, 3H). 13C NMR (400 MHz; CDCl3):
17.85, 25.64, 33.82, 35.07, 49.82, 65.19, 65.20, 115.25, 115.49,
115.94, 116.17, 119.25, 125.10, 125.19, 134.78, 138.01, 160.25,
162.71; MS: m/z = 327 [M+1]+.
4.1.11. 1-(4-fluorophenyl)spiro[4H-indazole-5,2'-
cyclohexane] -1'-one-ethylene-acetal (9b)
4.1.9. Ethyl 4-(1,4-dioxaspiro[4.5]dec-8-en-8-
yl)butanoate
Under inert atmosphere, the previously obtained ketal 6b
(4.90 g, 1 eq.) was dissolved in dry toluene (150 ml) and the
mixture cooled to -40°C. Ethyl formate (7.1 ml, 4 eq.) and then
sodium hydride (60% dispersion in oil, 3.5 g, 4 eq.) were
subsequently added before slowly add methanol (0.44 ml, 0.5
eq.) at low temperature over 15 minutes. The mixture was stirred
for 30 min at low temperature, then left to slowly come back to
room temperature and stirred for two additional hours. After the
complete consumption of the starting material, the mixture was
slowly poured onto ice-cold water (100 ml), the organic layer
was separated and washed two additional times with water (2 x
75 ml). The combined aqueous layers were subsequently
acidified to with hydrogen chloride (aq. soln., 6 N) before
extracting the organic materials with diethyl ether (3 x 100 ml).
The combined organic layers were dried over magnesium sulfate
and the solvent evaporated to give a light yellow oil turning
brown on standing (4.47 g) which was subsequently used without
further purification.C14H18O4; light-yellow oil; yield: 84%; M =
Sodium hydride (60% dispersion in mineral oil, 6.4 g) was
added under nitrogen to a dry solution of compound 7 (8.3 g,
39.9 mmol) in toluene (80 ml). The mixture was cooled to -40°C,
stirred for 10 min at low temperature before addition of 0.1 ml of
dry methanol. The mixture was left to come back to room
temperature, an, after complete consumption of starting material,
the mixture was slowly poured onto ice-cold water. The organics
were extracted with ethyl acetate (100 ml x 3). The combined
organic layers were dried over magnesium sulfate, then the
solvent was evaporated under vacuum. The crude product was
further purified by flash chromatography (eluent PE / EtOAc 7/3)
to conduct to the ring-opening product. C14H22O4; colorless oil;
yield: 77%; M = 254.32 g / mol; IR (ZnSe) ν = 2952, 1736, 1375,
1
1116 cm–1; H NMR (300 MHz, CDCl3) δ 1.19 (t, J = 7.1 Hz,
3H), 1.65-1.75 (m, 4H), 1.96 (t, J= 7.4 Hz, 2H), 2.09-2.13 (m,
2H), 2.20-2.25 (m, 4H), 3.92 (s, 4H), 4.06 (q, J = 7.1 Hz, 2H),
5.27 (as, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2 (CH3), 22.9
(CH2), 27.3 (CH2), 31.1 (CH2), 33.8 (CH2), 35.6 (CH2), 36.3
(CH2), 60.1 (CH2), 64.2 (2CH2), 108.0 (Cq), 118.8 (CH), 136.5
(Cq), 173.6 (Cq); MS m/z = 255.1 [M+H]+; HRMS: calcd. for
C14H23O4 255.16048, found 255.15995 (3.387 ppm).
1
250.29 g / mol; IR (SeO2) ν = 2937, 1645, 1186, 1086 cm–1; H
NMR (300 MHz, CDCl3) δ 1.41-1.47 (m, 2H), 1.51-1.75 (m,
6H), 2.33 (dd, J = 14.7 Hz, J = 1.2 Hz, 1H), 2.76 (dd, J = 14.6
Hz, J = 1.3 Hz, 1H), 3.90-4.01 (m, 4H), 6.06 (d, J = 10.3 Hz, 1H),
6.91 (dd, J = 10.3 Hz, J = 1.5 Hz, 1H), 7.43 (s, 1H), 13.66 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 21.0 (CH2), 23.4 (CH2), 28.8
(CH2), 30.7 (CH2), 33.8 (CH2), 45.3 (Cq), 65.1 (CH2), 65.3 (CH2),
106.6 (Cq), 111.2 (Cq), 128.2 (CH), 152.5 (CH), 166.4 (CH),
189.2 (Cq); MS: m/z = 249.2 [M-H]+; HRMS: calcd. for C14H17O4
249.1121, found 249.1126 (1.8817 ppm).
4.1.10. 1-(4-fluorophenyl)spiro[4H-indazole-5-2’-
cyclopentane]-1’-one-ethylelene-acetal (9a)
To a cooled solution (-40°C) of ketal 6a (1 g, 4.80 mmol) in
anhydrous toluene (30 ml) was added ethyl formate (1.55 ml,
19.22 mmol) and NaH (768 mg, 60% on mineral oil, 19.22
mmol) under Ar atmosphere. The reaction mixture was stirred for

8
Tetrahedron
At room temperature, sodium acetate (0.31 g, 1.1 eq.) and 4-
(Cq); MS: m/z = 297.2 [M + H]+; HRMS: calcd. for C18H18FN2O
ACCEPTED MANUSCRIPT
F-phenylhydrazine (0.61 g, 1.1 eq.) were added to a solution of
the previously-obtained α-formylation product (0.85 g, 1 eq.) in
acetic acid (15 ml). The mixture was stirred until the complete
consumption of the starting material (approx. 1.5 h), then the
reaction was quenched by addition of sodium carbonate (sat.
soln. 100 ml). The aqueous mixture was washed with ethyl
acetate (3 x 100 ml), the combined organic layers were dried over
magnesium sulfate and the solvent evaporated under reduced
pressure. The crude product was subsequently purified by flash-
chromatography (eluent: PE / EtOAc 8/2) to conduct to the
desired indazole derivative 9b, isolated as a light yellow visc. oil.
C20H21FN2O2; light-yellow visc. oil; yield: 87%; M = 340.39 g /
297.1398, found 297.1394 (-1.2857 ppm).
4.1.14. Reduction of the ketone moieties
Under inert atmosphere and at -78°C, DIBAL-H (1M soln. in
THF, 1.02 ml, 1.02 mmol, 3 eq.) was slowly added to a solution
of the ketone 10b (0.1 g, 0.34 mmol, 1 eq.) in dry THF (10 ml).
The reaction mixture was stirred at low temperature for 1 h. The
reaction was quenched by addition of water (20 ml) at low
temperature then, the organics extracted with ethyl acetate (3 x
30 ml). The combined organic layers were dried over magnesium
sulfate and concentrated under vacuum. The crude product was
purified by flash-chromatography (P.E. / EtOAc 7/3) to conduct
to the desired product as a 3/1 mixture of diastereoisomers.
mol; IR (ZnSe) ν = 2936, 1515, 1222, 840 cm–1; H NMR (300
1
MHz, CDCl3) δ 1.78-1.36 (m, 8H), 2.74 (d, J = 16.0 Hz, 1H),
2.97 (d, J = 16.0 Hz, 1H), 3.97-3.98 (m, 4H), 6.09 (d, J = 10.3
Hz, 1H), 6.43 (d, J = 10.3 Hz, 1H), 7.10-7.15 (m, 2H), 7.41-7.46
(m, 3H); 13C NMR (75 MHz, CDCl3) δ 20.5 (CH2), 23.4 (CH2),
25.1 (CH2), 30.8 (CH2), 33.6 (CH2), 45.7 (Cq), 65.3 (CH2), 65.3
(CH2), 111.8 (Cq), 115.1 (CH), 115.4 (Cq), 116.0 (CH), 116.3
(CH), 125.1 (CH), 125.2 (CH), 135.7 (CH), 136.5 (Cq), 138.4
(CH), 159.9 (Cq), 163.1 (Cq); MS: m/z = 341.2 [M+H]+; HRMS:
calcd. for C20H21FN2O2 341.1660, found 341.1654 (-1.7188
ppm).
1-(4-fluorophenyl)-1'-phenyl-spiro[4H-indazole-5,2'-
cyclohexane]-1'-ol (11). (5S, 8R)-diastereoisomer: C18H19FN2O;
White solid; Mp = 164-166°C; Yield: 22% (based on the H-
1
NMR); M = 298.35 g/mol; IR (ZnSe) ν = 3302, 2941, 1514,
1
1222, 988, 842; H NMR (300 MHz, CDCl3) δ 1.34-1.98 (m,
8H), 2.49 (d, J = 15.9 Hz, 1H), 3.11 (d, J = 15.9 Hz, 1H), 3.54
(dd, J1 = 9.7 Hz, J2 = 4.1 Hz, 1H), 6.13 (d, J = 10.3 Hz, 1H), 6.54
(d, J = 10.2 Hz, 1H), 7.15-7.18 (m, 2H), 7.43-7.48 (3H); 13C
NMR (75 MHz, CDCl3) δ 21.6 (CH2), 23.8 (CH2), 30.5 (CH2),
30.8 (CH2), 36.0 (CH2), 42.4 (Cq), 75.8 (CH), 115.8 (Cq), 116.1
(CH), 116.4 (CH), 116.6 (CH), 125.2 (CH), 125.3 (CH),134.4
(CH), 136.9 (Cq), 138.2 (CH); 160.0 (Cq), 163.3 (Cq).
4.1.12. 1-(4-fluorophenyl)spiro[4H-indazole-5-2’-
cyclopentane]-1’-one (10a)
To a solution of ketal 9a (930 mg, 2.85 mmol) in THF (27
ml) was added 6M aqueous HCl (14 ml) and the reaction mixture
was stirred at room temperature for 10 min. TLC analysis
showed the complete consumption of starting material. Then, the
reaction mixture was poured into saturated aqueous NaHCO3
solution (30ml) and extracted with EtOAc (50 ml × 4). The
combined organic phase was washed with brine solution (25 ml),
dried over Na2SO4 and evaporated under vacuum to give residual
thick oil. The residue was purified by column chromatography
(neutral alumina, eluent: PE/EtOAc 9/1) to afford the desired
ketone 10a (530 mg). C17H15FN2O; pale yellow liquid; yield:
1-(4-fluorophenyl)-1'-phenyl-spiro[4H-indazole-5,2'-
cyclohexane]-1'-ol (12). (5S, 8S)-diastereoisomer: C18H19FN2O;
White solid; Mp = 144-146°C; Yield: 68%; M = 298.35 g/mol;
1
IR (ZnSe) ν = 3320, 2926, 1517, 842 cm–1; H NMR (300 MHz,
CDCl3) δ 1.18-1.60 (m, 5H), 1.72-1.81 (m, 3H), 2.71 (d, J = 16.2
Hz, 1H), 3.00 (d, J = 16.2 1H), 3.63 (dd, J1 = 9.7 Hz, J2 = 3.4 Hz,
1H), 5.75 (d, J = 10.0 Hz, 1H), 6.48 (d, J = 10.0 Hz, 1H), 7.12-
7.18 (m, 2H), 7.43-7.47 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
20.1 (CH2), 22.1 (CH2), 23.5 (CH2), 29.5 (CH2), 32.7 (CH2), 42.8
(Cq), 75.4 (CH), 115.4 (Cq), 116.1 (CH), 116.1 (CH), 116.4 (CH),
125.3 (CH), 125.4 (CH), 136.6 (Cq), 138.4 (CH), 139.2 (CH),
160.1 (Cq), 163.3 (Cq); HRMS: calcd. for C18H20FN2O
299.15542, found 299.15534 (-0.26 ppm).
1
66%; M = 282.32 g/mol; IR (KBr): 1737, 1514 cm-1; H NMR
(400 MHz; CDCl3): 1.90-2.11 (m, 4H), 2.37-2.41 (m, 2H), 2.70
(d, J = 16.0 Hz, 1H), 2.95 (d, J = 16.0 Hz, 1H), 5.69 (d, J = 9.6
Hz, 1H), 6.54 (d, J = 10.0 Hz, 1H), 7.12-7.16 (m, 2H), 7.41-7.46
(m, 3H); 13C NMR (400 MHz; CDCl3): 18.57, 27.16, 35.93,
36.83, 52.08, 116.00, 116.23, 116.97, 125.18, 125.26, 131.71,
137.94, 160.33, 162.80, 220.09; MS: m/z = 282.9 [M+1]+;
4.1.15. 1-(4-fluorophenyl)-1'-prop-1-ynyl-spiro[4H-
indazole-5,2'-cyclohexane]-1'-ol (13a)
Under inert atmosphere and at 0°C, the previously obtained
ketone 10b (0.3 g, 1 eq.) was dissolved in dry THF (10 ml). A
solution of 1-propynylmagnesium bromide bromide (0.5 M soln.
in THF, 2.04 ml, 3 eq.) was slowly added at low temperature and
the mixture was stirred 2 additional hours at 0°C until the
complete conversion of the starting material. The reaction was
quenched by addition of ammonium chloride (satd. soln. 30 ml)
and the organic-soluble materials extracted with ethyl acetate (3 x
50 ml). The organic phase was dried over magnesium sulfate and
concentrated under vacuum to give to a crude product. The crude
alcohol was subsequently purified by flash chromatography
(PE/EtOAc 9/1) to conduct to a white solid which was
subsequently crystallized in acetonitrile to give colorless needles.
C21H21FN2O; colorless crystals; Mp = 188-190°C; Yield: 61%; M
4.1.13. 1-(4-fluorophenyl)spiro[4H-indazole-5,2'-
cyclohexane] -1'-one (10b)
The ketal moiety of compound 9b was deprotected by adding
hydrogen chloride (aq. soln. 6N, 15 ml) to a solution of indazole
9b (1 g, 1 eq.) in THF (30 ml). The reaction was conducted at
65°C for 1.5 h, and then quenched by pouring onto a solution of
sodium bicarbonate (10% aq. soln. 100 ml). The aqueous solution
was washed with ethyl acetate (3 x 100 ml), then the combined
organic layers were dried over magnesium sulfate and the solvent
evaporated under vacuum. The desired ketone 10b was isolated
as a white solid after purification on flash chromatography
(eluent PE/EtOAc 8/2). C18H17FN2O; white solid; Mp = 91-93°C;
yield: 71%; M = 296.34 g / mol; IR (ZnSe) ν = 2936, 1706,
= 336.40 g / mol; IR (ZnSe) ν = 2936, 1516, 1223, 839 cm–1; H
1
NMR (300 MHz, DMSO) δ 1.24-1.63 (m, 6H), 1.79-1.90 (m,
5H), 2.67 (d, J = 16.2 Hz, 1H), 3.00 (d, J = 16.2 Hz, 1H), 5.21 (s,
1H), 6.20 (d, J = 10.2 Hz, 1H), 6.48 (d, J = 10.2 Hz, 1H), 7.32-
7.38 (m, 2H), 7.47-7.54 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
3.8 (CH3), 20.4 (CH2), 22.5 (CH2), 32.1 (CH2), 35.6 (CH2), 45.5
(CH2), 92.1 (Cq), 83.5 (Cq), 115.7 (CH), 115.8 (Cq), 116.1 (CH),
116.7 (CH), 125.1 (CH), 125.2 (CH), 136.5 (Cq), 137.2 (CH),
1
1515, 1222, 840 cm–1; H NMR (300 MHz, CDCl3) δ 1.74-1.93
(m, 6H), 2.40-2.49 (m, 1H), 2.52-2.61 (m, 1H), 2.77 (d, J = 16.0
Hz, 1H), 3.13 (d, J = 16.0 Hz, 1H), 6.10 (d, J = 10.1 Hz, 1H),
6.48 (dd, J = 10.1 Hz, J = 0.5 Hz, 1H), 7.10-7.16 (m, 2H), 7.40-
7.45 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 20.9 (CH2), 27.3
(CH2), 27.8 (CH2), 37.7 (CH2), 38.8 (CH2), 52.0 (Cq), 114.7 (Cq),
116.0 (CH), 116.2 (CH), 116.3 (CH), 125.1 (CH), 125.3 (CH),
132.6 (CH), 136.1 (Cq), 138.2 (CH), 160.0 (Cq), 163.3 (Cq), 211.5

9
138.5 (CH), 160.0 (Cq), 163.2 (Cq); HRMS: calcd. for
C21H22FN2O 337.1711, found 337.1710 (-0.2661 ppm).
IR (ZnSe) ν = 3325, 2936, 1516, 1225, 839 cm–1; 1H NMR (300
ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 1.65-1.99 (m, 8H), 2.55 (d, J = 16.4 Hz, 1H),
2.66 (td, J = 13.5 Hz, J = 4.2 Hz, 1H), 3.21 (d, J = 16.4 Hz, 1H),
6.23 (d, J = 10.3 Hz, 1H), 6.32 (d, J = 10.3 Hz, 1H), 6.91-7.00
(m, 3H), 7.18 (s, 1H), 7.35-7.44 (m, 2H), 7.59 – 7.77 (m, 4H),
7.88 (as, 1H); 13C NMR (75 MHz, CDCl3) δ 21.4 (CH2), 21.8
(CH2), 27.8 (CH2), 35.0 (CH2), 35.8 (CH2), 45.0 (Cq), 77.0 (Cq),
115.7 (CH), 116.0 (CH), 116.0 (CH), 116.5 (Cq), 125.1 (CH),
125.3 (2CH), 125.6 (CH), 125.9 (CH), 125.9 (CH), 126.4 (CH),
127.4 (CH), 128.2 (CH), 132.3 (Cq), 132.4 (Cq), 134.5 (CH),
135.6 (Cq), 135.6 (Cq), 137.8 (CH), 143.1 (Cq), 159.8 (Cq), 163.1
(Cq); MS: m/z = 425.2 [M + H]+;
4.1.16. 1'-benzyl-1-(4-fluorophenyl)spiro[4H-
indazole-5,2'-cyclohexane]-1'-ol
Under inert atmosphere and at 0°C, the previously obtained
ketone 10b (0.3 g, 1 eq.) was dissolved in dry THF (10 ml).
Benzylmagnesium bromide (1M soln. in THF, 1.02 ml, 3 eq.)
was slowly added at low temperature and the mixture was stirred
2 additional hours at 0°C until the complete conversion of the
starting material. The reaction was quenched by addition of
ammonium chloride (satd. soln. 30 ml) and the organic-soluble
materials extracted with ethyl acetate (3 x 50 ml). The organic
phase was dried over magnesium sulfate and concentrated under
vacuum to give to a crude product. This was further purified by
flash-chromatography (eluent: PE / EtOAc 9/1) to conduct to the
desired diastereoisomers in a 5/1 ratio.
4.1.18. 1-(4-fluorophenyl)-1'-(4-methoxyphenyl)
spiro[4H-indazole-5,2'-cyclohexane] -1'-ol
Under inert atmosphere, iPrMgCl (2M in THF, 0.84 ml, 3.55
mmol, 2.1 eq.) was added at -20°C to a solution of 4-iodo-anisole
(0.4 g, 1.69 mmol, 1 eq.) in dry THF (10 ml). After 1 h of stirring
at -20°C, a solution of ketone precursor 10b (0.5 g, 1.69 mmol)
in dry THF (3 ml) was slowly added. The temperature was
allowed to come back to room temperature and the mixture
stirred overnight. The reaction was quenched by addition of
sodium bicarbonate (20% aq. soln., 50 ml), then extracted with
ethyl acetate (3 x 50 ml). The combined organic layers were
dried over magnesium sulfate, the solvent evaporated under
reduced pressure and the crude purified by flash chromatography
(cyclohexane / EtOAc 8/2) to deliver the addition product 13d.
(5S,8R)-1'-benzyl-1-(4-fluorophenyl)spiro[4H-indazole-5,2'-
cyclohexane]-1'-ol (13b): C25H25FN2O; White solid; Mp = 56-
58°C; Yield: 81%; M = 388.48 g / mol; IR (ZnSe) ν = 2931,
1515, 1224, 840 cm–1; 1H NMR (300 MHz, CDCl3) δ 1.41-1.86
(m, 8H), 2.57 (d, J = 13.5 Hz, 1H), 2.67 (d, J = 16.6 Hz, 1H),
3.07 (d, J = 13.5 Hz, 1H), 3.36 (d, J = 16.6 Hz, 1H), 6.13 (d, J =
10.4 Hz, 1H), 6.51 (d, J = 10.3 Hz, 1H), 7.14-7.34 (m, 7H), 7.46-
7.51 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 21.3 (CH2), 21.5
(CH2), 27.2 (CH2), 32.7 (CH2), 34.9 (CH2), 44.1 (CH2), 44.3 (Cq),
74.7 (Cq), 115.2 (CH), 116.0 (CH), 116.3 (CH), 125.2 (CH),
125.2 (CH), 126.6 (CH), 128.3 (2CH), 131.1 (2CH), 135.5 (CH),
136.2 (Cq), 137.1 (Cq), 138.5 (CH), 159.9 (Cq), 163.2 (Cq);
HRMS: calcd. for C25H26FN2O 389.2014, found 389.2022 (-
0.4729 ppm).
1-(4-fluorophenyl)-1'-(4-methoxyphenyl)spiro[4H-indazole-
5,2'-cyclohexane]-1'-ol (13d): C25H25FN2O2; White solid; Mp =
186-188°C; Yield: 48%; M = 404.48 g / mol; IR (ZnSe) ν =
3368, 2941, 1517, 1247, 842 cm–1; 1H NMR (300 MHz, CDCl3)
δ 1.60-1.91 (m, 7H), 2.45-2.54 (m, 1H), 2.53 (d, J = 16.4 Hz,
1H), 3.10 (d, J = 16.3 Hz, 1H), 3.70 (s, 3H), 6.25 (q, J = 10.1 Hz,
2H), 6.71 (d, J = 9.0 Hz, 2H), 7.07-7.13 (m, 2H), 7.24-7.30 (m,
3H), 7.38 (d, J = 9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.5
(CH2), 21.8 (CH2), 27.7 (CH2), 34.9 (CH2), 35.9 (CH2), 44.9
(CH2), 55.3 (CH3), 76.6 (Cq), 112.5 (2CH), 115.8 (CH), 115.9
(CH), 116.2 (CH), 116.6 (Cq), 125.1 (CH), 125.2 (CH), 127.9
(2CH), 135.1 (CH), 135.9 (Cq), 138.0 (Cq), 138.1 (CH), 158.4
(Cq), 159.9 (Cq), 163.2 (Cq); HRMS: calcd. for C25H26O2N2F
405.19728, found 405.19811 (2.042 ppm).
(5S,8S)-1'-benzyl-1-(4-fluorophenyl)spiro[4H-indazole-5,2'-
cyclohexane]-1'-ol (14b): C25H25FN2O; White solid; Mp = 73-
75°C; Yield: 13%; M = 388.48 g / mol; IR (ZnSe) ν = 3415,
2935, 1515, 1223, 839 cm–1; 1H NMR (300 MHz, CDCl3) δ 1.46-
1.93 (m, 9H), 2.85 (dd, J = 35.4 Hz, J = 13.2 Hz, 2H), 3.00 (q, J =
16.0 Hz, 2H), 6.35 (d, J = 10.3 Hz, 1H), 6.54 (dd, J = 10.3 Hz, J
= 0.6 Hz, 1H), 7.17-7.37 (m, 7H), 7.49-7.53 (m, 3H); 13C NMR
(75 MHz, CDCl3) δ 20.3 (CH2), 21.3 (CH2), 25.2 (CH2), 31.3
(CH2), 31.7 (CH2), 43.7 (CH2), 45.0 (Cq), 74.6 (Cq), 114.8 (CH),
115.2 (Cq), 116.0 (CH), 116.3 (CH), 125.2 (CH), 125.3 (CH),
126.7 (CH), 128.4 (2CH), 131.2 (2CH), 136.8 (Cq), 136.9 (Cq),
137.9 (CH), 138.3 (CH), 160.0 (Cq), 163.2 (Cq); MS: m/z = 389.2
[M + H]+; HRMS: calcd. for C25H26FN2O 389.20237, found
389.20155 (-2.102 ppm).
4.1.19. 1-(4-fluorophenyl)-1,6-dihydrocyclohepta-
5,6-cyclohexyl[c]pyrazole (16)
A mixture of alcohols 11 and 12 (0.1 g, 0.335 mmol, 1 eq.)
obtained by addition of DIBAL-H to the ketone 10b (vide supra)
was treated with the Burgess reagent (0.176 g, 0.74 mmol, 2.2
eq.) in dry THF (20 ml). The mixture was refluxed under
nitrogen atmosphere for 1 h, then, after complete consumption of
the starting material, the solvent was evaporated. The crude
product was purified by flash chromatography (PE / EtOAc 95/5)
to conduct to the rearrangement product 16. C18H17FN2; White
solid; m.p. 77-79°C; Yield: 87%; M = 280.34 g / mol; IR (ZnSe)
ν = 2933, 1514, 1397, 1229, 981, 842 cm–1; 1H NMR (300 MHz,
CDCl3) δ 1.61-2.00 (m, 6H), 2.30-2.44 (m, 3H), 5.43 (dd, J1 =
9.8 Hz, J2 = 6.0 Hz, 1H), 6.37-6.41 (m, 2H), 7.12-7.18 (m, 2H),
7.53-7.57 (m, 2H), 7.69 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
21.5 (CH2), 24.2 (CH2), 28.6 (CH2), 30.6 (CH2), 38.8 (CH), 113.9
(CH), 115.8 (CH), 115.9 (CH), 116.2 (CH), 122.4 (Cq), 125.3
(CH), 125.4 (CH), 129.7 (CH), 135.4 (Cq), 138.3 (Cq), 139.2
(CH), 159.9 (Cq), 163.2 (Cq); MS m/z = 281.1 [M+H]+; HRMS:
calcd. for C18H18FN2 281.14573, found 281.14619 (4.754 ppm).
4.1.17. 1'-(4-fluorophenyl)-2-(naphthalen-2-yl)-
1',4'-dihydrospiro[cyclohexane-1,5'-indazol] -2-ol
2-bromo-naphtyl (0.69 g, 1 eq.) was dissolved in a dry
THF/toluene mixture (1.7 ml / 5 ml) before cooling to -78°C. n-
butyl lithium (soln. 1.6 M in hexane, 2.5 ml, 2.4 eq.) was added
at low temperature and the mixture was stirred for 1 h.
Subsequently, a solution of the ketone 10b (0.5 g, 1.69 mmol, 1
eq.) in dry THF (9 ml) was added at low temperature, and the
mixture was allowed to come back to -30°C over 1 h, under
vigorously stirring. After complete consumption of the starting
material, the reaction was quenched by addition of ammonium
chloride (satd. soln., 50 ml), then the organics extracted with
ethyl acetate (3 x 50 ml). By analogy with the previously
conducted organometallic additions on the ketone precursor 10b,
the main diastereoisomer isolated by flash-chromatography
(PE/EtOAc 8/2) was assigned the (5S, 8S) stereochemistry.
4.1.20. 1'-(4-fluorophenyl)-1',4',6',7'-
tetrahydrospiro[cyclohexane-1,5'-indazol] -2-ol (17)
(5S,
8S)-
1’-4-fluorophenyl)-2-(naphthalen-2-yl)-1',4'-
dihydrospiro[cyclohexane-1,5'-indazol]-2-ol (13c): C28H25FN2O;
White solid; Mp = 159-161°C; Yield: 49%; M = 424.51 g / mol;

10
Tetrahedron
4.1.23. 1-(4-fluorophenyl)spiro[4H-indazole-5,3'-
A crude mixture of alcohols 11 and 12 (0.15 g, 0.5 mmol,
ACCEPTED MANUSCRIPT
cyclohexene] (15)
1 eq.) was dissolved in ethanol (5 ml). Pd/C (0.015 g) was added
and hydrogen gas was bubbled for 10 min in the reaction
mixture. Aqueous hydrogen chloride (1 M soln, 0.5 ml, 0.5
mmol, 1 eq.) was added to the solution, and the reaction was
stirred under hydrogen atmosphere overnight. The mixture was
filtered on a celite pad and the solvent was evaporated.
Subsequently the residue was dissolved in DCM (20 ml) and
washed with sodium bicarbonate (20 ml). The organic materials
were further extracted from the aqueous layer with DCM (2 x 20
ml), and the combined organic layers were dried over magnesium
sulfate and evaporated to conduct to a crude product which was
subsequently used without further purification. C18H21FN2O;
White solid; m.p. 179-180°C; Yield: 60%; M = 300.16 g / mol;
IR (ZnSe) ν = 3324, 2933, 1514, 1222, 1057, 838 cm–1; 1H NMR
(300 MHz, CDCl3) δ 1.39-2.10 (m, 9H), 2.29 (d, J = 15.6 Hz,
1H), 2.51-2.84 (m, 4H), 3.50-3.62 (m, 1H), 7.13 (t, J = 8.6 Hz,
2H), 7.45-7.51 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 19.6,19.7
(CH2), 21.1, 21.1 (CH2), 22.7, 23.5 (CH2), 30.2, 30.2 (CH2), 30.4,
30.5 (CH2), 31.5, 32.4 (CH2), 37.5, 37.5 (CH2), 74.1, 76.2 (CH),
116.0, 116.3 (2CH), 117.0, 117.2 (2Cq), 124.8, 124.8 (CH),
124.9, 124.9 (CH), 137.5, 137.8 (2Cq), 139.0, 139.3 (CH), 159.8,
163.1 (2Cq); MS m/z = 301.3 [M+H]+.
Under inert atmosphere, n-BuLi (0.55 ml, 0.81 mmol, 2.5 eq.)
was slowly added over 15 min to a solution of the tosylhydrazone
25 (0.15 g, 0.32 mmol, 1 eq.) in dry THF (3 ml). The mixture
was allowed to come back to room temperature over 3 h, and
then quenched with water (20 ml) before extracting the organic
materials with EtOAc (3 x 20 ml). Flash chromatography
(PE/EtOAc 95/5) of the obtained crude material conducted to the
desired elimination product 15. C18H17FN2; Light yellow solid;
Mp = 118-120°C; Yield: 34%; M = 280.34 g / mol; IR (ZnSe) ν
1
= 2930, 1667, 1609, 1514 cm–1; H NMR (300 MHz, CDCl3) δ
1.63-1.70 (m, 4H), 2.02 (ls, 2H), 2.70 (d, J = 2.0 Hz, 2H), 5.63-
5.69 (m, 2H), 5.81 (d, J = 9.9 Hz, 1H), 6.36 (d, J = 9.9 Hz, 1H),
7.15 (t, J = 8.6 Hz, 2H), 7.41-7.48 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 18.7 (CH2), 25.2 (CH2), 32.5 (CH2), 33.9 (CH2), 37.5
(Cq), 113.8 (CH), 115.4 (Cq), 116.0 (CH), 116.3 (CH), 125.2
(CH), 125.3 (CH), 127.3 (CH), 132.2 (CH), 138.4 (CH), 139.3
(CH), 160.0 (Cq), 163.3 (Cq); MS m/z = 281.2 [M+H]+; HRMS:
calcd. for C18H18FN2 281.14485, found 281.14570 (3.011 ppm).
Acknowledgments
This project was generously supported by Grünenthal GmbH
and IECB. We also thank the staff members of the technical
platform of IECB and Grünenthal GmbH for their availability
and their skills.
4.1.21. methyl{[(1'-(4-fluorophenyl)-1',4',6',7'-
tetrahydrospiro[cyclohexane-1,5'-indazol] -2-
yl)oxy] sulfonyl}- carbamate (18)
Burgess reagent (0.04 g, 0.159 mmol, 2.2 eq.) was added to a
solution of alcohol 17 (0.04 g, 0.133 mmol, 1 eq.) in dry THF (8
ml). The mixture was refluxed under nitrogen atmosphere for 1 h,
then, after complete consumption of the starting material, the
solvent was evaporated. The crude product was purified by flash
chromatography (DCM / MeOH 9/1) to conduct to the
sulfonamide 18. C20H24FN3O5S; White solid; m.p. 105°C; Yield:
26%; M = 437.5 g / mol; IR (ZnSe) ν = 2937, 1758, 1517, 1236,
References
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1
1174, 900 cm–1; H NMR (300 MHz, CDCl3) δ 1.47-1.99 (m,
10H), 2.39-2.86 (m, 5H), 3.73-3.75 (m, 3H), 4.70 (ls, 1H); 7.12
(t, J = 8.6 Hz, 1H), 7.42-7.47 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 19.1, 19.3 (CH2), 20.5 (CH2), 27.0, 27.4 (CH2), 29.5,
30.2 (CH2), 31.0, 31.2 (CH2), 37.4, 37.6 (CH2), 54.0 (CH3),
115.7, 115.9 (Cq), 116.1, 116.3 (2CH), 124.9, 125.0 (2CH),
136.2, 136.2 (Cq), 136.7, 137.3 (Cq), 139.1, 139.4 (CH), 159.8,
163.1 (Cq); MS m/z = 438.1 [M+H]+.
4.1.22. N-[(E)-[1-(4-fluorophenyl)spiro[4H-
indazole-5,2'-cyclohexane]-1'-ylidene]amino] -4-
methyl-benzenesulfonamide (19)
7. P. E. Eaton, P. G. Jobe, Synthesis 1983, 796-797.
8. J. Siewert, A. Textor, S. Grond, P. von Zezschwitz, Chem. Eur. J. 2007,
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9. a) J. A. Elings, H. E. B. Lempers, R. A. Sheldon, Eur. J. Org. Chem.
2000, 1905-1911; b) A. Cook, I. Gunawardana, M. Huestis, K. W. Hunt, N.
C. Kallan, A. T. Metcalf, B. Newhouse, M. Siu, T. P. Tang, A. Thomas, M.
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b) B. J. M. Jansen, C. C. J. Hendrikx, N. Masalov, G. A. Stork, T. M.
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11. D. D. Holsworth, Burgess dehydrating reagent, Name Reactions for
Functional Group Transformations 2007, 189-206.
A solution of the ketone 10b (0.5 g, 1.69 mmol, 1 eq.) in
ethanol (3 ml) was added to a solution of p-tosylhydrazide (0.38
g, 0.02 mmol, 1.2 mmol) in ethanol (10 ml). Subsequently, a few
drops of concentrated hydrochloric acid were added, and the
mixture was vigorously stirred overnight at room temperature.
The white precipitate was filtered and further washed with n-
pentane to conduct to a white powder subsequently used without
further purification. C25H25FN4O2S; White solid; Mp = 183-
185°C; Yield: 77%; M = 464.56 g / mol; IR (ZnSe) ν = 3214,
1
2941, 1514, 1335, 1167 cm–1; H NMR (300 MHz, CDCl3) δ
12. O.A. McNamara, A.R. Maguire, Tetrahedron 2011, 67, 9-40
1.70-1.73 (m, 6H), 2.28 (s, 3H), 2.23 (as, 2H), 2.75 (d, J = 16.0
Hz, 1H), 3.10 (d, J = 16.0 Hz, 1H), 6.10 (d, J = 10.1 Hz, 1H),
6.42 (d, J = 10.1 Hz, 1H), 7.15-7.20 (m, 4H), 7.39-7.48 (m, 3H),
7.70 (d, J = 8.3 Hz, 2H), 13C NMR (75 MHz, CDCl3) δ 21.0
(CH2), 21.6 (CH3), 23.5 (CH2), 25.9 (CH2), 29.2 (CH2), 37.1
(CH2), 45.1 (CH2), 115.1 (CH), 115.8 (Cq), 116.1 (CH), 116.4
(CH), 125.0 (CH), 125.1 (CH), 127.9 (2CH), 129.5 (2CH), 134.7
(CH), 135.3 (Cq), 136.2 (Cq), 138.1 (CH), 143.9 (Cq), 160.0 (Cq),
163.2 (Cq), 163.2 (Cq); HRMS: calcd. for C25H26FN4O2S
465.175501, found 465.17683 (2.86 ppm).