Short and Atom-Economic Enantioselective Synthesis of the σ1-Receptor Ligands (S)- And (R)-Fluspidine - Important Tools for Positron Emission Tomography Studies

Article abstract of DOI:10.1021/acs.joc.9b01882

Aryl bromides 2a and 2b bearing an alkynyl substituent in the o-position reacted with n-butyllithium and 1-benzylpiperidin-4-one in a one-pot Domino reaction to form ester 3 and aldehyde 5, respectively. Enantiomeric alcohols (R)-8 and (S)-8 were obtained by conjugate NaBH₄ reduction of α,β-unsaturated ester 3 in the presence of chiral cocomplexes (R,R)-10 and (S,S)-10. Starting from orthoester 2a, the precursors (R)-8 and (S)-8 for the synthesis of fluspidine enantiomers (R)-1/[¹⁸F](R)-1 and (S)-1/[¹⁸F](S)-1 were obtained in only two reaction steps without additional steps for N-protection in an atom-economic manner in 95.6% ee and 97.2% ee, respectively.

Full text of DOI:10.1021/acs.joc.9b01882

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Article
Short and atom economic enantioselective synthesis of the #1 receptor
ligands (S)- and (R)-fluspidine – important tools for PET studies
Paul Bunse, Christoph Schlepphorst, Frank Glorius, Masato Kitamura, and Bernhard Wünsch
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01882 • Publication Date (Web): 16 Sep 2019
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Short and atom economic enantioselective synthesis of the σ1 receptor ligands
(S)- and (R)-fluspidine – important tools for PET studies
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Paul Bunsea, Christoph Schlepphorstb, Frank Glorius,b Masato Kitamura,c Bernhard
Wünscha,d*
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a
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-
Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Tel.: +49-251-8333311; Fax: +49-251-8332144; Email: wuensch@uni-muenster.de
b
Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster,
Corrensstraße 40, D-48149 Münster, Germany.
c
Graduate School of Pharmaceutical Sciences and Research Center for Materials
Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
d
Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-
Universität Münster, Germany.
Abstract
Aryl bromides 2a and 2b bearing an alkynyl substituent in o-position reacted with n-
butyllithium and 1-benzylpiperidin-4-one in a one-pot Domino reaction to form ester 3
and aldehyde 5, respectively. Enantiomeric alcohols (R)-8 and (S)-8 were obtained by
conjugate NaBH4 reduction of -unsaturated ester 3 in the presence of chiral Co-
complexes (R,R)-10 and (S,S)-10. Starting from orthoester 2a, the precursors (R)-8
and (S)-8 for the synthesis of fluspidine enantiomers (R)-1/[18F](R)-1 and (S)-1/[18F](S)-
1 were obtained in only two reaction steps without additional steps for N-protection in
an atom-economic manner in 95.6 % ee and 97.2 % ee, respectively.
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Key words
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fluspidine; enantioselective synthesis; Domino reaction; enantioselective
hydrogenation; enantioselective conjugate reduction; chiral Co-catalyst;
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Introduction
For a long period of time, the sigma () receptor was termed enigmatic due to its unique
structural features and biological properties.1,2 Very recently however, the crystal
structure of the 1 receptor together with various agonists and antagonists has been
reported.3,4 In contrast to previous reports,5,6 the 1 receptor in the crystal structure
shows only one transmembrane domain and a highly structured carboxy terminal
domain on the cytosolic side of the membrane containing the binding site for the
ligands.
Although the signal transduction of the 1 receptor is not fully understood so far,
regulation of ion channels, modulation of neurotransmitter release and uptake as well
as influence on intracellular Ca2+ signaling by 1 receptor have been reported.7-10 The
1 receptor plays a crucial role in cancer,11-13 (neuropathic) pain,14,15 various
neurological and neurodegenerative disorders such as Alzheimer’s, Parkinson’s,
Huntington’s disease, alcohol and drug abuse and depression.16-20
It has been shown that activation of 1 receptors leads to antidepressive activity.17 1
receptor knock-out mice are viable and fertile, but display a depressive-like
phenotype.21,22 Moreover, several antidepressants, which are used clinically, interact
with moderate to high affinity with 1 receptors.23-26 Therefore, it is of great interest to
learn more about the 1 receptor expression in the central nervous system (CNS) of
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patients suffering from various neurological disorders, e.g. depression. For this
purpose, an imaging modality such as positron emission tomography (PET) can be
used for non-invasively imaging of 1 receptors in the brain of living organisms.
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Recently, we have developed the fluorinated 1 receptor ligand fluspidine (1).27,28
(Figure 1) The fluspidine enantiomers were separated29 and an automated
radiosynthesis of 18-F-labeled enantiomers was established.30 The (R)-configured
enantiomer (R)-1 shows higher 1 affinity (Ki = 0.57 nM),29 but an irreversible binding
behavior at 1 receptors.31 Therefore, the metabolically more stable (S)-configured
enantiomer [18F](S)-fluspidine [18F](S)-1 (Ki = 2.3 nM)29,32 was selected for the first in
men clinical trial. This study included 12 patients with major depressive disorder and
displayed an upregulation of 1 receptors in the CNS of these patients.33
F/[18F]F
F[18F]/F
O
O
N
N
Bn
Bn
18
18
1
1
1
1
(R)- /[ F](R)-
(S)- /[ F](S)-
(R)-fluspidine
(S)-fluspidine
Figure 1: Potent 1 receptor ligands (S)- and (R)-fluspidine: 18-F-labeled [18F](S)-1 was
used for the first in men clinical trial.
For the PET studies the fluspidine enantiomers were prepared by preparative HPLC
on a chiral stationary phase of appropriate precursors. In order to avoid the production
of 50 % waste, an enantioselective synthesis of (S)-fluspidine should be developed.
Very recently, two enantioselective syntheses of fluspidine enantiomers (R)-1 and (S)-
1 have been reported. In the first synthesis, methyl 3-(2-bromohenyl)-3-
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(TBSO)acrylate was reduced enantioselectively by NaBH4 in the presence of a chiral
Co-catalyst.34 Starting from this methyl acrylate, (S)- and (R)-configured fluspidine
enantiomers (S)-1 and (R)- 1 were prepared in a nine-step synthesis, which involved
Suzuki coupling, bromoetherification and radical debromination.35 The key step of the
second synthesis was a Cu-catalyzed enantioselective cyclization / carboetherification
of 2-vinylbenzylacohols. Cu(OTf)2 in the presence of (S,S)-tBu-Box initiated a radical
cyclization, which was trapped by diphenylethene affording the corresponding
phthalane with an enantiomeric excess of 86 %. The overall synthesis starting from 1-
bromo-2-vinylbenzene comprises only four reaction steps up to the important alcohol
(R)-8. However, the atom economy is very low, since benzophenone has to be cleaved
off by ozonolyis.36
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In order to obtain both fluspidine enantiomers with high enantiomeric purity in a short
and atom-economic manner without changing the protective group at the piperidine
moiety, a novel enantioselective synthesis was designed. For this purpose, the double
bond of 1-alkylidenephthalanes 3-7 should be hydrogenated enantioselectively using
chiral catalysts.
Results and Discussion
Very recently, we have reported the one-pot multi-step synthesis of
alkylidenephthalanes comprising bromine-lithium exchange at aryl bromides 2,
nucleophilic addition of the aryllithium intermediate at aldehydes and ketones,
cyclization of the resulting alcoholates by addition at the triple bond and finally
protonation of the vinyllithium intermediate and hydrolysis of the orthoester or acetal.37
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O
OH
OR
EtO OEt
R
R
7a
: R = SiEt3
(d) - (f)
(a)
(c)
7b
: R = Si(iPr)3
O
O
O
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7c
: R = SiMe2Ph
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7d
7e
7f
: R = SitBuMe2
: R = SitBuPh2
: R = SiPh3
Br
N
N
N
Bn
Bn
Bn
7g
7h
: R = Ac
: R = CPh3
6
7a g
-
2a
: R = OEt
2b
: R = H
3
4
5
: R = OEt
: R = OPh
: R = H
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(b)
Scheme 1: synthesis of spirocyclic alkylidenephthalanes 3-7 by Li-promoted 5-exo-dig-
cyclization. Reagents and reaction conditions: (a) n-BuLi, THF, -78 or -90 °C, then 1-
benzylpiperidin-4-one, 62 % (3), 87 % (5). (b) 1. NaOH, dioxane, 16 h, reflux, 78 %. 2.
phenol, EDC.HCl, CH2Cl2, DMAP, 17 h, rt, 60 %. (c) 5, NaBH4, MeOH, 25 min, 0 °C,
78 %. (d) R3SiOTf or R3SiCl, DMF, Et3N, 14 - 19 h (10 d for 7f), rt, 68 - 84 % (7a-f). (e)
isopropenyl acetate, Amano-PS-IM-lipase, TBME, Et2O, 21 h, rt, 89 % (7g). (f) TrCl,
DMF, Et3N, 5 d, rt, 78 % (7h).
Compounds 3, 7c, 7f, and 7g were isolated as pure (Z)-isomers; compounds 4, 5, 6,
7a, 7b, 7d, 7e, 7h were isolated as 95:5 mixtures of (Z)- and (E)-isomers.
The same Domino reaction of the aryl bromides 2a and 2b with n-BuLi and 1-
benzylpiperidin-4-one at -78 °C or -90 °C led to the spirocyclic ester 3 and aldehyde 5
in 62 % and 87 % yield, respectively. In order to obtain phenyl ester 4 with a larger
substituent able to form /-interactions, ethyl ester 3 was hydrolyzed and the resulting
acid was coupled with phenol. Further modifications of size and electronic properties
of the terminal functional group were achieved by NaBH4 reduction of aldehyde 5 and
subsequent silylation, acetylation and tritylation of the formed alcohol 6 to provide
various silyl ethers 7a-7f, acetate 7g and trityl ether 7h. Whereas most of the prepared
alkylidenephthalanes exist as 95:5 mixtures of (Z)- and (E)-isomers, ester 3, silyl ethers
7c and 7f and acetate 7g were isolated as pure (Z)-configured isomers. (Scheme 1)
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OR
RO
R
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(a)
(b)
O
N
O
O
+
N
N
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Bn
Bn
Bn
3 7
-
8
8
R = H: (S)-
R = H: (R)-
(c)
(c)
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9
R = Ts: (S)-
R = Ts: (R)-
Table 1: Enantioselective hydrogenation of alkylidenephthalanes 3 - 7.
ratio
(R)-8 : (S)-8
entry
Educt
R
Ligand
conversion (%)
Phos-1
(Josiphos)
Phos-1
(Josiphos)
Phos-3
1
2
3
3
6
6
CO2Et
CH2OH
CH2OH
0
-
23
56 : 44
46 : 54
100
((R)-BINAP)
4
5
3
3
CO2Et
CO2Et
NHC-5
NHC-7
NHC-7
NHC-5
NHC-7
NHC-5
(R,R)-10
(S,S)-10
29
0
36 : 64
-
6
6
CH2OH
81
6
77 : 23
74 : 26
81 : 19
18 : 82
97.8 : 2.2
1.4 : 98.6
7
7a
7d
7e
3
CH2OSiEt3
CH2OSitBuMe2
CH2OSitBuPh2
CO2Et
8
100
93
100
100
9
10
11
3
CO2Et
Entries 1-3: (a) (Rh(COD)Cl)2, 10 mol%, H2, 100 bar, diphosphane ligand (see Table
SI1), MeOH, 40 °C, 18 h. (b) only for ester 3: LiAlH4, Et2O, -15 °C  rt, 1 h.
Entries 4-9: (a) [Ru(COD)(2-methylallyl)2], 10 mol%, H2, 100 - 120 bar, KOtBu, hexane,
25 °C, 18 – 40 h, NHC ligand (see Table SI2). (b) for ester 3: LiAlH4, Et2O, -15 °C 
rt, 1 h. (b) for silyl ethers 7a-f: TBAF.3H2O, THF, rt.
Entries 10-11: (a) NaBH4, 0.01 equiv. chiral Co-complex 10, CH3OH/CH2Cl2 = 1:1, 0
°C  rt, 30 min. (b) LiAlH4, Et2O, -15 °C  rt, 1 h.
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N
N
N
N
N
N
N
N
6
7
8
Co
Cl2
Co
Cl2
O
(R)
(R)
O
O
(S)
(S)
O
O
O
O
O
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
9
10
10
(S,S)-
(R,R)-
10
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(c) TsCl, NEt3, DMAP, CH2Cl2, 0 °C  rt, 17 h.
Structures of the used diphosphane and NHC ligands Phos-1-5 and NHC-6-9 are
shown in Figures SI1 and SI2 in the Supporting Information. Further experiments are
shown in Tales SI1 and SI2.
The alkylidenephthalanes 3-7 were employed for the enantioselective hydrogenation
of the exocyclic double bond. At first, hydrogenation using Rh(I) in the presence of
chiral diphosphane ligands was tried. Hydrogenation of similar alkylidenindanes with
Rh(I) in the presence of a Josiphos ligand (Phos-1, Figure SI1) led to a ratio of
enantiomers of 96:4.38 However, hydrogenation of various alkylidenephthalanes 3-7
with Rh(I) in the presence of Josiphos (Phos-1) or similar diphosphane ligands led to
very low conversion or almost no enantioselectivity. (Table 1, entries 1-3, Table SI1)
Next, Ru(II) in the presence of chiral N-heterocyclic carbene (NHC) ligands was
employed for the enantioselective hydrogenation. High enantiomeric excess was
achieved for the hydrogenation of flavones and 1-benzofurans with Ru(II) in the
presence of the chiral ligand NHC-5 (Figure SI2)39,40 However, hydrogenation of the
,-unsaturated ester 3 with Ru(II)/NHC-5 led to only 29 % conversion and a ratio of
enantiomers of 36:64. The highest ratio of enantiomers was obtained by hydrogenation
of silyl ethers 7d (NHC-7, 81:19) and 7e (NHC-5, 18:82), but this enantioselectivity
could not be increased although more than 30 experiments using various
alkylidenephthalanes and NHC ligands were performed. (Table SI2)
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In a third approach, NaBH4 reduction of ,-unsaturated esters in the presence of chiral
5
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7
8
Co-catalysts (R,R)-10 and (S,S)-10 was investigated.34,35 NaBH4 reduction of the ,-
unsaturated ester 3 with (R,R)-10 and subsequent LiAlH4 reduction provided the
enantiomeric alcohols (R)-8 and (S)-8 in the ratio 97.8:2.2. A similar but opposite ratio
of 1.4:98.6 was obtained using the enantiomeric Co-catalyst (S,S)-10. The
enantiomeric alcohols (R)-8 and (S)-8 were isolated in 63 % (95.6 % ee) and 82 %
yield (97.2 % ee), respectively. Tosylation of both enantiomeric alcohols (R)-8 and (S)-
8 afforded enantiomeric tosylates (R)-9 (96.2 %ee) and (S)-9 (96.4 %ee) with almost
unchanged enantiomeric excess.
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Conclusion
Recently, we reported on a Domino reaction of aryl bromides 2a and 2b with n-BuLi
and various aldehydes and ketones to produce alkylidenephthalanes in a one-pot
reaction. Herein, this Domino reaction was successfully used to obtain spirocyclic
compounds 3 and 5 upon successive reaction of 2a and 2b with n-BuLi and 1-
benzylpiperidin-4-one. Since the envisaged 1 ligand fluspidine (1) contains the N-
benzyl moiety, tedious N-protective group introduction and removal at the piperidine
ring are not necessary.
Hydrogenation of alkylidenephthalanes 3-7 with Rh(I)/chiral diphosphane ligands and
Ru(II)/chiral NHC ligands afforded only low conversion and/or low enantioselectivity.
However, NaBH4 reduction of the -unsaturated ester 3 in the presence of the chiral
Co-complexes (R,R)-10 and (S,S)-10 resulted in high enantioselectivity and high yields
of the enantiomeric alcohols (R)-8 and (S)-8.
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Fluspidine enantiomers (R)-1 and (S)-1 can be obtained by treatment of enantiomeric
alcohols (R)-8 and (S)-8 with DAST.35,36 Tosylation of the alcohols R)-8 and (S)-8 led
to the tosylates (R)-9 and (S)-9 representing the precursors for the radiosynthesis of
[18F](R)1 and [18F](S)-1.
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Taking the synthesis of the orthoester 2a by Sonogashira reaction of 1-bromo-2-
iodobenzene with triethyl orthopropynoate into account, both fluspidine enantiomers
(R)-1 and (S)-1 and both enantiomeric radiotracers [18F](R)1 and [18F](S)-1 are
available without installing an N-protective group in an atom-economic manner in a
four- or five-step synthesis, respectively, with high enantiomeric excess of 95.6 % ee
and 97.2 % ee, respectively.
Experimental Part
General
Unless otherwise noted, all reactions were carried out under an atmosphere of dry N2
in flame-dried glassware. Reaction temperatures are reported as the temperature of
the bath surrounding the vessel unless otherwise stated. The solvents used were
purified by distillation over the drying agents indicated in parentheses and were
transferred under N2: THF (Na-benzophenone), methanol (Mg). Commercially
available chemicals were obtained from Acros Organics, Aldrich Chemical Co., Alfa
Aesar and TCI Europe and used as received unless otherwise stated.
Analytical thin layer chromatography was performed on Merck TLC Silica gel 60 F254
plates. Flash column chromatography was performed as automatic flash column
chromatography with IsoleraTM Spektra One (Biotage®). Following cartridges were
used:
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length [cm] diameter [cm] amount of silica gel [g]
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7.5
8.5
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3.5
3.5
7
50
100
340
17
In the experimental procedure the cartridge sizes are given by the amount of silica gel.
Silica gel 60 (40 - 63 μm, Macherey-Nagel) was used as stationary phase.
1H and C NMR spectra were recorded on an Agilent DD2 400 MHz or 600 MHz
13
spectrometer in solvents as indicated. Chemical shifts (δ) are given in ppm relative to
tetramethylsilane (TMS). The residual solvent signals were used as references and the
chemical shifts were converted to the TMS scale. CDCl3: δ(H) = 7.26 ppm, δ(C) = 77.16
ppm; DMSO-d6: δ(H) = 2.50 ppm, δ(C) = 39.52 ppm.
APCI and ESI mass spectra were recorded on a Bruker Daltonics MicroTOFQII.
Infrared spectra were recorded on a Shimadzu FT/IR IRAffinity-1. The wave numbers
(ν) of the recorded IR signals are given in cm-1.
Melting points were determined with melting point apparatus MP50 (Mettler Toledo)
using an open capillary. The values are uncorrected.
HPLC: Method 1: Merck Hitachi Equipment; UV detector: L-7400; autosampler: L-
7200; pump: L-7100; degasser: L-7614; column: Lichrospher® 60 RP-select B (5µm);
LiChroCART® 250-4 mm cartridge; flow rate: 1.0 mL/min; injection volume: 5.0µL;
detection at λ = 210 nm; solvents: A: water with 0.05 % (v/v) of trifluoroacetic acid; B:
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acetonitrile with 0.05% (v/v) of trifluoroacetic acid; gradient elution: (A%): 0-4 min:
90 %, 4-29 min: gradient from 90 % to 0 %, 29-31 min: 0 %, 31-31.5 min: gradient from
0 % to 90 %, 31.5-40 min: 90 %. Method 2: Merck Hitachi equipment; UV detector: L-
7400; pump: L-6200A; column: phenomenex Gemini® 5 μm C6-Phenyl 110 Å, LC
Column 250 x 4.6 mm; flow rate: 0 - 21 min: 1.0 mL/min, 21 - 27 min: 2.0 mL/min, 27 -
30 min: 1.0 mL/min; injection volume: 5.0µL; detection at λ = 254 nm; solvents: A:
acetonitrile : 10 mM ammonium formate = 10 : 90 with 0.1 % formic acid; B:
acetonitrile : 10 mM ammonium formate = 90 : 10 with 0.1 % formic acid; gradient
elution: (A%): 0-5 min: 100 %, 5-15 min: gradient from 100 % to 0 %, 15-25 min: 0 %,
25-27 min: gradient from 0 % to 100 %, 27-30 min: 100 %. The purity of all compounds
was determined by these methods.
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Synthesis of alkylidenephthalanes
Ethyl (Z)-2-(1'-benzyl-3H-spiro[[2]benzofuran-1,4'-piperidin]-3-yliden)acetate (3)
Orthoester 2a[37] (1.18 g, 3.62 mmol, 1.0 eq) was dissolved in THF
O
OEt
(25 mL) and the solution was cooled to -78 °C. A solution of n-BuLi in
O
n-hexane (2.5 M, 1.74 mL, 4.34 mmol, 1.2 eq) was added dropwise and
N
Bn
the solution was stirred for 25 min at -78 °C. 1-Benzylpiperidin-4-one (1.16 mL,
6.52 mmol, 1.8 eq) was added dropwise via syringe pump (1.8 mL/h). Afterwards, the
reaction mixture was warmed up to room temperature within 18 h. H2O was added and
the reaction mixture was stirred for further 10 min. The aqueous layer was extracted
with CH2Cl2 (3 x). Brine was added after the first extraction step to afford better phase
separation. The combined organic layers were washed twice with an aqueous solution
of NaHSO3 (1.9 g Na2S2O5 + 20 mL water) to remove the excess of 1-benzylpiperidin-
4-one. After drying (Na2SO4), the solvents were removed in vacuo. The residue was
purified
by
flash
column
chromatography
(1.
100 g
cartridge,
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cyclohexane:CH2Cl2:MeOH = 20:80:0 → 0:100:0 → 0:95:5, 2. 100 g cartridge,
cyclohexane:ethyl acetate = 70:30 → 50:50). The product was isolated as yellow solid,
mp 113 °C, yield 822 mg (62 %). Rf = 0.68 (CH2Cl2:MeOH = 9:1); 1H NMR (600 MHz,
DMSO-d6): δ [ppm] = 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.57 (d, J = 12.3 Hz, 2H,
N(CH2CHAHB)2), 2.15 (td, J = 13.3/4.5 Hz, 2H, N(CH2CHAHB)2), 2.45 (td, J =
12.3/2.0 Hz, 2H, N(CHAHBCH2)2), 2.80 - 2.85 (m, 2H, N(CHAHBCH2)2), 3.58 (s, 2H,
NCH2Ph), 4.08 (q, J = 7.1 Hz, 2H, OCH2CH3), 5.58 (s, 1H, C=CH), 7.23 - 7.29 (m, 1H,
Hphenyl), 7.31 - 7.39 (m, 4H, Hphenyl), 7.45 (td, J = 7.6/1.0 Hz, 1H, 5-Harom.), 7.55 (td,
J = 7.5/0.8 Hz, 1H, 6-Harom.), 7.60 (d, J = 7.6 Hz, 1H, 7-Harom.), 7.86 (d, J = 7.8 Hz, 1H,
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4-Harom.); C NMR (151 MHz, DMSO-d6): δ [ppm] = 14.5 (1C, OCH2CH3), 35.7 (2C,
N(CH2CH2)2), 49.3 (2C, N(CH2CH2)2), 58.6 (1C, OCH2CH3), 62.3 (1C, NCH2Ph), 85.3
(1C, C=CH), 90.5 (1C, C-1), 121.4 (1C, C-7arom.), 122.1 (1C, C-4arom.), 126.9 (1C,
Cphenyl), 128.2 (2C, Cphenyl), 128.9 (2C, Cphenyl), 129.0 (1C, C-5arom.), 131.6 (1C,
C-6arom.), 131.9 (1C, C-3aarom.), 138.4 (1C, Cphenyl), 148.2 (1C, C-7aarom.), 165.2 (1C,
CO2Et), 165.3 (1C, C=CH). In the spectra signals for the (E)-configured isomer could
not be detected. HPLC (method 1): t = 18.4 min, purity 94.5 %; IR: [cm-1] = 2974,
휈
R
2943, 2812 (C-Haliph.), 1705 (C=O), 1639 (C=Calkene), 1493 (C=Carom.), 1466 (CH2
deform.), 1393 (CH3 deform.), 1265 (C-O-C), 1146 (CO-O-CH2CH3), 1080 (CO-O-
CH2CH3), 1049 (C-O-C), 806 (=C-Halkene), 772, 741, 698 (=C-Harom. deform.); Exact
Mass (APCI): m/z = 364.1894 (calcd. 364.1907 for C23H26NO3 [MH]+).
(Z)-2-(1'-Benzyl-3H-spiro[[2]benzofuran-1,4'-piperidin]-3-yliden) acetic acid
Ester 3 (676 mg, 1.86 mmol, 1.0 eq) was dissolved in dioxane (6 mL) and
O
OH
NaOH (2 M, 4.7 mL, 9.31 mmol, 5 eq) was added. The reaction mixture
O
was stirred for 16 h under reflux. After cooling to room temperature, the
N
Bn
reaction mixture was neutralized with HCl (1 M). H2O was added and the aqueous
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layer was extracted with CH2Cl2 (5 x). Brine was added after the first extraction step to
afford better phase separation. After drying (Na2SO4), the solvents were removed in
vacuo. The residue was purified by flash column chromatography (100 g cartridge,
CH2Cl2:MeOH = 90:10). The product was isolated as colorless solid, mp 141 °C, yield
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1
486 mg (78 %). Rf = 0.33 (CH2Cl2:MeOH = 9:1); H NMR (600 MHz, DMSO-d6): δ
[ppm] = 1.59 (d, J = 12.6 Hz, 2H, N(CH2CHAHB)2), 2.11 - 2.17 (m, 2H, N(CH2CHAHB)2),
2.43 - 2.48 (m, 2H, N(CHAHBCH2)2), 2.80 - 2.84 (m, 2H, N(CHAHBCH2)2), 3.57 (s, 2H,
NCH2Ph), 5.48 (s, 1H, C=CH), 7.25 - 7.29 (m, 1H, Hphenyl), 7.32 - 7.39 (m, 4H, Hphenyl),
7.45 (t, J = 7.5 Hz, 1H, 5-Harom.), 7.54 (t, J = 7.3 Hz, 1H, 6-Harom.), 7.58 (d, J = 6.9 Hz,
1H, 7-Harom.), 7.82 (d, J = 7.7 Hz, 1H, 4-Harom.), 11.39 (s, 1H, CO2H); 13C NMR
(151 MHz, DMSO-d6): δ [ppm] = 35.8 (2C, N(CH2CH2)2), 49.4 (2C, N(CH2CH2)2), 62.2
(1C, NCH2Ph), 86.1 (1C, C=CH), 90.3 (1C, C-1), 121.4 (1C, C-7arom.), 121.9 (1C, C-
4arom.), 126.9 (1C, Cphenyl), 128.2 (2C, Cphenyl), 128.9 (2C, Cphenyl), 128.9 (1C, C-5arom.),
131.5 (1C, C-6arom.), 132.1 (1C, C-3aarom.), 138.6 (1C, Cphenyl), 148.0 (1C, C-7aarom.),
164.7 (1C, C=CH), 166.6 (1C, CO2H). In the spectra signals for the (E)-configured
isomer could not be detected; HPLC (method 1): t = 14.9 min, purity 98.9 %; IR:
휈
R
[cm-1] = 3051, 3028 (=C-Harom.), 2940, 2920, 2812 (C-Haliph.), 1728 (C=O), 1639
(C=Calkene), 1493 (C=Carom.), 1466 (CH2 deform.), 1072 (C-O-C), 1042 (C-O-C), 814
(=C-Halkene), 772, 745, 698 (=C-Harom. deform.); Exact Mass (APCI): m/z = 336.1595
(calcd. 336.1594 for C21H22NO3 [MH]+).
Phenyl (Z)- and (E)-2-(1'-benzyl-3H-spiro[[2]benzofuran-1,4'-piperidin]-3-
yliden)acetate (4)
Carboxylic acid prepared above (95.1 mg, 0.28 mmol, 1.0 eq) was dissolved in CH2Cl2
(4 mL) and a solution of DMAP (86.6 mg, 0.71 mmol, 2.5 eq) and phenol (146 mg,
1.55 mmol, 5.5 eq) in CH2Cl2 (2 mL) was added. The solution was cooled to 0 °C and
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O
EDC·HCl (109 mg, 0.57 mmol, 2.0 eq) was added. The reaction mixture
was warmed to room temperature and stirred for 17 h. H2O was added
and the aqueous layer was extracted with CH2Cl2 (3 x). After drying
4
5
6
7
8
9
OPh
O
N
Bn
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(Na2SO4), the solvents were removed in vacuo. The residue was purified by flash
column chromatography (50 g cartridge, CH2Cl2:MeOH = 100:0 → 95:5). The product
was isolated as colorless solid, mp 167 °C, yield 68.7 mg (60 %). Rf = 0.28.
1
(cyclohexane:ethyl acetate = 1:1); H NMR (600 MHz, CDCl3): δ [ppm] = 1.75 - 1.79
(m, 2H, N(CH2CHAHB)2), 2.14 - 2.22 (m, 2H, N(CH2CHAHB)2), 2.64 (td, J = 12.1/2.4 Hz,
2H, N(CHAHBCH2)2), 2.88 - 2.92 (m, 2H, N(CHAHBCH2)2), 3.58 (s, 1.9H, NCH2Ph), 3.64
(s, 0.1H, NCH2Ph*), 5.69 (s, 0.95H, C=CH), 5.88 (s, 0.05H, C=CH*), 7.17 - 7.28 (m,
4H, Hphenyl), 7.30 - 7.37 (m, 5H, 7-Harom., Hphenyl), 7.38 - 7.42 (m, 2H, Hphenyl), 7.44 (t, J
= 7.5 Hz, 1H, 5-Harom.), 7.50 - 7.54 (m, 1H, 6-Harom.), 7.64 (d, J = 7.7 Hz, 0.95H, 4-
13
Harom.), 9.16 (d, J = 8.0 Hz, 0.05H, 4-Harom.*); C NMR (151 MHz, CDCl3): δ [ppm] =
36.5 (2C, N(CH2CH2)2), 50.1 (2C, N(CH2CH2)2), 63.3 (0.95C, NCH2Ph), 63.4 (0.05C,
NCH2Ph*), 84.9 (0.95C, C=CH), 90.5 (0.05C, C=CH*), 91.5 (1C, C-1), 121.2 (1C, C-
7arom.), 122.1 (0.95C, C-4arom.), 122.3 (2C, Cphenyl), 125.4 (1C, Cphenyl), 127.2 (1C,
Cphenyl), 128.4 (2C, Cphenyl), 128.5 (0.05C, C-4arom.*), 129.0 (1C, C-5arom.), 129.4 (2C,
Cphenyl), 129.4 (2C, Cphenyl), 131.9 (1C, C-6arom.), 132.6 (1C, C-3aarom.), 138.6 (1C,
Cphenyl), 149.1 (0.95C, C-7aarom.), 151.1 (0.05C, C-7aarom.*), 151.3 (1C, Cphenyl), 164.7
(1C, CO2Ph), 167.8 (1C, C=CH); ratio of (Z)-4 : (E)-4 = 95 : 5. Signals for minor (E)-4
are marked with an asterisk; HPLC (method 1): t = 20.4 min, purity 95.1 %; IR: [cm-1]
휈
R
= 3074, 3028 (=C-Harom.), 2940, 2913, 2820 (C-Haliph.), 1728 (C=O), 1636 (C=Calkene),
1493 (C=Carom.), 1466 (CH2 deform.), 1292 (CO-O-Ph), 1196 (C-O-C), 1111 (CO-O-
Ph), 1069 (C-O-C), 806 (=C-Halkene), 768, 745, 698 (=C-Harom. deform.); Exact Mass
(APCI): m/z = 412.1905 (calcd. 412.1907 for C27H26NO3 [MH]+).
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(Z)- and (E)-2-(1'-Benzyl-spiro[[2]benzofuran-1,4'-piperidin]-3-yliden)
5
6
acetaldehyde (5)
7
8
Diethyl acetal 2b[37] (984 mg, 3.48 mmol, 1.0 eq) was dissolved in THF
O
9
H
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(90 mL) and the solution was cooled to -90 °C with a cryostat. A solution
O
of n-BuLi in n-hexane (2.5 M, 1.67 mL, 4.17 mmol, 1.2 eq) was added
N
Bn
dropwise (17 min) and the solution was stirred for 25 min. A solution of 1-
benzylpiperidin-4-one (1.12 mL, 6.26 mmol, 1.8 eq) in THF (10 mL) was added
dropwise via syringe pump (15 mL/h). Afterwards, the reaction mixture was warmed
up to -70 °C within 1 h, followed by further warming up to room temperature within
16 h. H2O was added and the reaction mixture was stirred for further 15 min. The
aqueous layer was extracted with CH2Cl2 (3 x). Brine was added after the first
extraction step to afford better phase separation. The combined organic layers were
washed twice with an aqueous solution of NaHSO3 (3.7 g Na2S2O5 + 40 mL water) to
remove the excess of 1-benzylpiperidin-4-one. After drying (Na2SO4), the solvents
were removed in vacuo. The residue was purified by flash column chromatography
(340 g cartridge, cyclohexane:CH2Cl2:MeOH = 20:80:0 → 0:100:0 → 0:95:5). The
product was isolated as yellow solid, mp 126 °C, yield 965 mg (87 %). Rf = 0.62
(CH2Cl2:MeOH = 9:1); 1H NMR (400 MHz, CDCl3): δ [ppm] = 1.77 (dd, J = 14.3/2.2 Hz,
2H, N(CH2CHAHB)2), 2.18 (td, J = 13.4/4.7 Hz, 2H, N(CH2CHAHB)2), 2.54 (td, J =
12.2/2.4 Hz, 2H, N(CHAHBCH2)2), 2.89 - 2.99 (m, 2H, N(CHAHBCH2)2), 3.64 (s, 2H,
NCH2Ph), 5.71 (d, J = 8.5 Hz, 0.95H, C=CH), 5.93 (d, J = 8.1 Hz, 0.05H, C=CH*), 7.29
(dt, J = 7.9/2.1 Hz, 1H, Hphenyl), 7.31 - 7.41 (m, 5H, 7-Harom., Hphenyl), 7.45 (td, J =
7.6/1.0 Hz, 1H, 5-Harom.), 7.55 (td, J = 7.5/1.0 Hz, 6-Harom.), 7.60 (dt, J = 7.7/0.8 Hz,
0.95H, 4-Harom.), 8.22 (d, J = 7.9 Hz, 0.05H, 4-Harom.*), 10.20 (d, J = 8.5 Hz, 0.95H,
CHO), 10.32 (d, J = 8.1 Hz, 0.05H, CHO*); 13C NMR (101 MHz, CDCl3): δ [ppm] = 36.5
(2C, N(CH2CH2)2), 50.0 (2C, N(CH2CH2)2), 63.4 (1C, NCH2Ph), 91.5 (1C, C-1), 98.6
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(0.95C, C=CH), 105.4 (0.05C, C=CH*), 121.1 (0.95C, C-7arom.), 121.3 (0.05C, C-
7arom.*), 122.9 (0.95C, C-4arom.), 126.1 (0.05C, C-4arom.*), 127.3 (1C, Cphenyl), 128.5 (2C,
Cphenyl), 129.2 (1C, C-5arom.), 129.3 (2C, Cphenyl), 130.5 (0.05C, C-3aarom.*), 131.7
(0.95C, C-3aarom.), 132.6 (1C, C-6arom.), 138.3 (1C, Cphenyl), 148.6 (0.95C, C-7aarom.),
151.2 (0.05C, C-7aarom.*), 170.7 (0.95C, C=CH), 172.3 (0.05C, C=CH*), 187.6 (0.05C,
CHO*), 189.3 (0.95C, CHO). ratio of (Z)-5 : (E)-5 = 95 : 5. Signals for minor (E)-5 are
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marked with an asterisk; HPLC (Method 1): t = 15.5 min, purity 96.4 %; IR: [cm-1] =
휈
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3028 (=C-Harom.), 2920, 2812 (C-Haliph.), 1651 (CH=O), 1624 (C=Calkene), 1493
(C=Carom.), 1466 (CH2 deform.), 1053 (C-O-C), 802 (=C-Halkene), 764, 739, 698 (=C-
Harom. deform.) ; Exact Mass (APCI): m/z = 320.1656 (calcd. 320.1645 for C21H22NO2
[MH]+).
Aldehyde 5 was selected to prove exemplarily the relative configuration of the exocyclic
double bond of the major diastereomer. For this purpose, a 600 MHz 1H NMR spectrum
and 1D-NOE spectra were recorded. A weak nuclear Overhauser effect (NOE) was
observed between the R2C=CH-proton ( = 5.71 ppm) and 4-Harom. ( = 7.60 ppm)
confirming the (Z)-configuration of the major diastereomer (Z)-5 and the further
products 6 and 7a-g.
(Z)- and (E)-2-(1'-Benzyl-spiro[[2]benzofuran-1,4'-piperidin]-3-yliden)ethanol (6)
OH
Aldehyde 5 (1.25 g, 3.91 mmol, 1.0 eq) was dissolved in MeOH (60 mL)
and the solution was cooled to 0 °C. After stepwise addition of NaBH4
O
(443 mg, 11.7 mmol, 3 eq), the reaction mixture was stirred for 25 min at
N
Bn
0 °C. Afterwards, H2O was added slowly and the aqueous layer was extracted with
CH2Cl2 (3 x). The combined organic layers were dried (Na2SO4) and the solvents were
removed in vacuo. The residue was purified by flash column chromatography (340 g
cartridge, cyclohexane:ethyl acetate = 6:4 → 3:7). The product was isolated as
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colorless solid, mp 134 °C, yield 981 mg (78 %). Rf = 0.15 (CH2Cl2:MeOH = 95:5);
1H NMR (600 MHz, DMSO-d6): δ [ppm] = 1.55 (dd, J = 13.9/2.1 Hz, 2H,
N(CH2CHAHB)2), 2.03 (td, J = 13.2/4.5 Hz, 2H, N(CH2CHAHB)2), 2.37 (td, J =
12.2/2.4 Hz, 2H, N(CHAHBCH2)2), 2.75 - 2.81 (m, 2H, N(CHAHBCH2)2), 3.55 (s, 2H,
NCH2Ph), 4.21 (dd, J = 6.9/5.4 Hz, 1.9H, CH2OH), 4.29 (dd, J = 7.8/5.2 Hz, 0.1H,
CH2OH*), 4.52 (t, J = 5.4 Hz, 0.95H, OH), 4.62 (t, J = 5.2 Hz, 0.05H, OH*),5.11 (t, J =
7.0 Hz, 0.95H, C=CH), 5.18 (t, J = 7.8 Hz, 0.05H, C=CH*), 7.25 (tt, J = 6.6/1.6 Hz, 1H,
Hphenyl), 7.32 - 7.38 (m, 6H, 6-Harom., 5-Harom., Hphenyl), 7.41 (dd, J = 6.0/2.6 Hz, 1H, 7-
Harom.), 7.53 - 7.56 (m, 0.95H, 4-Harom.), 7.65 - 7.73 (m, 0.05H, 4-Harom.*); 13C NMR (151
MHz, DMSO-d6): δ [ppm] = 36.3 (2C, N(CH2CH2)2), 49.5 (2C, N(CH2CH2)2), 55.4
(0.05C, CH2OH*), 55.5 (0.95C, CH2OH), 62.3 (1C, NCH2Ph), 86.1 (1C, C-1), 96.0
(0.95C, C=CH), 99.7 (0.05C, C=CH*), 120.0 (0.95C, C-4arom.), 121.2 (1C, C-7arom.),
123.7 (0.05H, C-4arom.*), 126.9 (1C, Cphenyl), 128.1 (2C, Cphenyl), 128.3 (1C, C-5arom.),
128.8 (1C, C-6arom.), 128.9 (2C, Cphenyl), 131.6 (0.05C, C-3aarom.*),132.7 (0.95C, C-
3aarom.), 138.6 (1C, Cphenyl), 146.4 (0.95C, C-7aarom.), 148.2 (0.05C, C-7aarom.*), 152.5
(0.95C, C=CH), 154.6 (0.05C, C=CH*); ratio of (Z)-6 : (E)-6 = 95 : 5. Signals for minor
(E)-6 are marked with an asterisk; HPLC (method 2): tR = 12.8 min, purity 99.4 %; IR:
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[cm-1] = 3171 (O-H), 3051, 3028 (=C-Harom.), 2920, 2855 (C-Haliph.), 1678 (C=Calkene),
휈
1497 (C=Carom.), 1462 (CH2 deform.), 1053 (C-O-C), 826 (=C-Halkene), 741, 702 (=C-
Harom. deform.); Exact Mass (APCI): m/z = 322.1794 (calcd. 322.1802 for C21H24NO2
[MH]+).
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(Z)- and (E)-1'-Benzyl-3-[2-(triethylsilyloxy)ethylidene]-3H-spiro [[2]benzofuran-
5
6
1,4'-piperidine] (7a)
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8
OSiEt3
Alcohol 6 (200 mg, 0.62 mmol, 1.0 eq) was dissolved in absolute DMF
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(6 mL) and Et3N (0.87 mL, 6.22 mmol, 10 eq) was added. After
O
dropwise addition of triethylsilyl trifluoromethanesulfonate (0.21 mL,
N
Bn
0.93 mmol, 1.5 eq), the reaction mixture was stirred for 18 h at room temperature. H2O
was added and the aqueous layer was extracted with CH2Cl2 (3 x). The combined
organic layers were dried (Na2SO4) and the solvents were removed in vacuo. The
residue was purified by flash column chromatography (50 g cartridge,
cyclohexane:ethyl acetate:Et3N = 60:39.5:0.5). The product was isolated as orange
resin, yield 227 mg (84 %). Rf = 0.52 (cyclohexane:ethyl acetate = 1:1); 1H NMR (400
MHz, DMSO-d6): δ [ppm] = 0.58 (q, J = 7.9 Hz, 6H, Si(CH2CH3)3), 0.92 (t, J = 7.9 Hz,
9H, Si(CH2CH3)3), 1.53 (d, J = 12.4 Hz, 2H, N(CH2CHAHB)2), 2.06 (td, J = 13.1/4.5 Hz,
2H, N(CH2CHAHB)2), 2.34 - 2.42 (m, 2H, N(CHAHBCH2)2), 2.79 (d, J = 11.0 Hz, 2H,
N(CHAHBCH2)2), 3.56 (s, 2H, NCH2Ph), 4.38 (d, J = 7.4 Hz, 1.9H, CH2OSi), 4.49 (d, J
= 7.8 Hz, 0.1H, CH2OSi*), 5.15 (t, J = 7.4 Hz, 1H, C=CH), 7.23 - 7.28 (m, 1H, Hphenyl),
7.31 - 7.38 (m, 6H, 5-Harom., 6-Harom., Hphenyl), 7.41 - 7.44 (m, 1H, 7-Harom.), 7.54 - 7.60
(m, 1H, 4-Harom.); 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 4.2 (3C, Si(CH2CH3)3), 6.7
(3C, Si(CH2CH3)3), 36.3 (2C, N(CH2CH2)2), 49.3 (2C, N(CH2CH2)2), 56.8 (1C, CH2OSi),
62.3 (1C, NCH2Ph), 86.3 (1C, C-1), 94.3 (1C, C=CH), 120.2 (1C, C-4arom.), 121.2 (1C,
C-7arom.), 126.9 (1C, Cphenyl), 128.1 (2C, Cphenyl), 128.4 (1C, C-5arom.), 128.8 (2C,
Cphenyl), 129.1 (1C, C-6arom.), 132.4 (1C, C-3aarom.), 138.3 (1C, Cphenyl), 146.5 (1C,
C-7aarom.), 153.5 (1C, C=CH). Compound 7a was isolated as a mixture of (Z)- and (E)-
isomers. In the 1H NMR spectrum a ratio of 95:5 ((Z):(E)) is observed. Signals for the
(E)-isomer are marked with an asterisk. IR: [cm-1] = 3028 (=C-Harom.), 2947, 2913,
휈
2874 (C-Haliph.), 1678 (C=Calkene), 1493 (C=Carom.), 1462 (CH2 deform.), 1366 (CH3
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deform.), 1053 (C-O-C), 837 (=C-Halkene), 737, 698 (=C-Harom. deform.); Exact Mass
(APCI): m/z = 436.2680 (calcd. 436.2666 for C27H38NO2Si [MH]+).
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(Z)- and (E)-1'-Benzyl-3-[2-(triisopropylsilyloxy)ethylidene]-3H-
spiro[[2]benzofuran-1,4'-piperidine] (7b)
OSi(i-Pr)3
Alcohol 6 (218 mg, 0.68 mmol, 1.0 eq) was dissolved in absolute
DMF (5 mL) and Et3N (0.94 mL, 6.78 mmol, 10 eq) was added. After
O
dropwise addition of triisopropylsilyl chloride (0.22 mL, 1.02 mmol,
N
Bn
1.5 eq), the reaction mixture was stirred for 17 h at room temperature. Additional
triisopropylsilyl chloride (0.22 mL, 1.02 mmol, 1.5 eq) was added and the reaction
mixture was stirred for further 5 h. H2O was added and the aqueous layer was
extracted with CH2Cl2 (3 x). The combined organic layers were dried (Na2SO4) and the
solvents were removed in vacuo. The residue was purified by flash column
chromatography (50 g cartridge, cyclohexane:ethyl acetate:Et3N = 60:39.5:0.5). The
product was isolated as colorless resin, yield 241 mg (74 %). Rf = 0.53
(cyclohexane:ethyl acetate = 1:1); 1H NMR (600 MHz, DMSO-d6): δ [ppm] = 0.98 (d, J
= 6.5 Hz, 0.9H, Si(CH(CH3)2)3*), 1.04 (d, J = 6.7 Hz, 17.1H, Si(CH(CH3)2)3), 1.07 - 1.14
(m, 3H, Si(CH(CH3)2)3), 1.51 (dd, J = 13.9/2.1 Hz, 2H, N(CH2CHAHB)2), 2.05 (td, J =
13.2/4.6 Hz, 2H, N(CH2CHAHB)2), 2.36 (td, J = 12.3/2.4 Hz, 2H, N(CHAHBCH2)2), 2.77
- 2.80 (m, 2H, N(CHAHBCH2)2), 3.55 (s, 2H, NCH2Ph), 4.42 (d, J = 7.3 Hz, 0.1H,
CH2OSi*), 4.46 (d, J = 7.3 Hz, 1.9H, CH2OSi), 5.17 (t, J = 7.3 Hz, 1H, C=CH), 7.22 -
7.29 (m, 1H, Hphenyl), 7.31 - 7.38 (m, 6H, 5-Harom., 6-Harom., Hphenyl), 7.41 - 7.43 (m, 1H,
7-Harom.), 7.57 - 7.60 (m, 1H, 4-Harom.); 13C NMR (151 MHz, DMSO-d6): δ [ppm] = 11.6
(3C, Si(CH(CH3)2)3), 18.0 (6C, Si(CH(CH3)2)3), 36.3 (2C, N(CH2CH2)2), 49.2 (2C,
N(CH2CH2)2), 57.5 (1C, CH2OSi), 62.4 (1C, NCH2Ph), 86.3 (1C, C-1), 94.6 (1C,
C=CH), 120.2 (1C, C-4arom.), 121.2 (1C, C-7arom.), 126.9 (1C, Cphenyl), 128.1 (2C,
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Cphenyl), 128.4 (1C, C-5arom.), 128.9 (2C, Cphenyl), 129.1 (1C, C-6arom.), 132.4 (1C,
C-3aarom.), 138.2 (1C, Cphenyl), 146.5 (1C, C-7aarom.), 153.3 (1C, C=CH). Compound 7b
was isolated as a mixture of (Z)- and (E)-isomers. In the 1H NMR spectrum a ratio of
95:5 ((Z):(E)) is observed. Signals for the (E)-isomer are marked with an asterisk. IR:
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[cm-1] = 3028 (=C-Harom.), 2940, 2920, 2893, 2862, (C-Haliph.), 1678 (C=Calkene), 1493
휈
(C=Carom.), 1462 (CH2 deform.), 1366 (CH3 deform.), 1053 (C-O-C), 833 (=C-Halkene),
752, 737, 694 (=C-Harom. deform.); Exact Mass (APCI): m/z = 478.3142 (calcd.
478.3136 for C30H44NO2Si [MH]+).
(Z)-1'-Benzyl-3-[2-(dimethylphenylsilyloxy)ethylidene]-3H-spiro[[2]benzofuran-
1,4'-piperidine] (7c)
OSiMe2Ph
Alcohol 6 (258 mg, 0.80 mmol, 1.0 eq) was dissolved in absolute
DMF (6 mL) and Et3N (1.12 mL, 8.02 mmol, 10 eq) was added. After
O
dropwise addition of dimethylphenylsilyl chloride (0.31 mL,
N
Bn
1.84 mmol, 2.3 eq), the reaction mixture was stirred for 14 h at room temperature. H2O
was added and the aqueous layer was extracted with CH2Cl2 (3 x). The combined
organic layers were dried (K2CO3) and the solvents were removed in vacuo. Because
the silyl ether was rather unstable, the residue was used for the hydrogenation without
further purification. Therefore, the HPLC purity was not determined. Rf = 0.52
1
(cyclohexane:ethyl acetate = 1:1); H NMR (600 MHz, DMSO-d6): δ [ppm] = 0.34 (s,
6H, Si(CH3)2), 1.48 - 1.53 (m, 2H, N(CH2CHAHB)2), 2.02 (td, J = 13.2/4.5 Hz, 2H,
N(CH2CHAHB)2), 2.30 (td, J = 12.0/2.4 Hz, 2H, N(CHAHBCH2)2), 2.71 - 2.80 (m, 2H,
N(CHAHBCH2)2), 3.52 (s, 2H, NCH2Ph), 4.40 (d, J = 7.4 Hz, 2H, CH2OSi), 5.15 (t,
J = 7.3 Hz, 1H, C=CH), 7.26 (m, 1H, Hbenzyl), 7.32 – 7.43 (m, 10H, Hphenyl), 7.54 - 7.56
(m, 1H, 4-Harom.), 7.56 – 7.58 (m, 2H. Hphenyl); 13C NMR (151 MHz, DMSO-d6): δ [ppm]
= -1.4 (2C, Si(CH3)2), 36.2 (2C, N(CH2CH2)2), 49.4 (2C, N(CH2CH2)2), 57.2 (1C,
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CH2OSi), 62.3 (1C, NCH2Ph), 86.4 (1C, C-1), 94.0 (1C, C=CH), 120.2 (1C, C-4arom.),
121.2 (1C, C-7arom.), 126.9 (1C, Cphenyl), 127.7 (2C, Cphenyl), 128.2 (2C, Cphenyl), 128.4
(1C, C-5arom.), 128.9 (2C, Cphenyl), 129.2 (1C, C-6arom.), 129.5 (1C, Cphenyl), 132.3 (1C,
C-3aarom.), 133.2 (2C, Cphenyl), 138.0 (1C, Cphenyl), 138.5 (1C, Cphenyl), 146.6 (1C,
C-7aarom.), 153.7 (1C, C=CH). In the spectrum signals for the (E)-isomer could not be
detected. Additional signals for a dimethylphenylsilyl derivative (almost 50 %) were
found in the spectra. Exact Mass (APCI): m/z = 456.2370 (calcd. 456.2353 for
C29H34NO2Si [MH]+).
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(Z)- and (E)-1'-Benzyl-3-[2-(tert-butyldimethylsilyloxy)ethylidene]-3H-
spiro[[2]benzofuran-1,4'-piperidine] (7d)
OSit-BuMe2
Alcohol 6 (160 mg, 0.50 mmol, 1.0 eq) was dissolved in absolute
DMF (6 mL) and Et3N (0.69 mL, 4.98 mmol, 10 eq) was added.
O
After addition of tert-butyldimethylsilyl chloride (113 mg,
N
Bn
0.75 mmol, 1.5 eq), the reaction mixture was stirred for 19 h at room temperature. H2O
was added and the aqueous layer was extracted with CH2Cl2 (3 x). The combined
organic layers were dried (Na2SO4) and the solvents were removed in vacuo. The
residue was purified by flash column chromatography (50 g cartridge,
cyclohexane:ethyl acetate:Et3N = 60:39.5:0.5). The product was isolated as yellow
resin, yield 147 mg (68 %). Rf = 0.45 (cyclohexane:ethyl acetate = 1:1); 1H NMR (600
MHz, DMSO-d6): δ [ppm] = 0.06 (s, 6H, Si(CH3)2), 0.87 (s, 9H, C(CH3)3), 1.53 (d, J =
12.4 Hz, 2H, N(CH2CHAHB)2), 2.05 (td, J = 13.2/4.5 Hz, 2H, N(CH2CHAHB)2), 2.36 -
2.41 (m, 2H, N(CHAHBCH2)2), 2.79 (d, J = 11.2 Hz, 2H, N(CHAHBCH2)2), 3.56 (s, 2H,
NCH2Ph), 4.39 (d, J = 7.4 Hz, 1.9H, CH2OSi), 4.50 (d, J = 7.8 Hz, 0.1H, CH2OSi*), 5.14
(t, J = 7.3 Hz, 1H, C=CH), 7.26 (m, 1H, Hphenyl), 7.35 (m, 6H, 6-Harom., 7-Harom., Hphenyl),
7.43 (m, 1H, 5-Harom.), 7.58 (m, 1H, 4-Harom.); 13C NMR (151 MHz, DMSO-d6): δ [ppm]
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= -5.0 (2C, Si(CH3)2), 18.0 (1C, C(CH3)3), 25.9 (3C, C(CH3)3), 36.3 (2C, N(CH2CH2)2),
49.3 (2C, N(CH2CH2)2), 57.3 (1C, CH2OSi), 62.3 (1C, NCH2Ph), 86.4 (1C, C-1), 94.4
(1C, C=CH), 120.2 (1C, C-4arom.), 121.2 (1C, C-5arom.), 126.9 (1C, Cphenyl), 128.1 (2C,
Cphenyl), 128.4 (1C, C-7arom.), 128.9 (2C, Cphenyl), 129.1 (1C, C-6arom.), 132.4 (1C, C-
3aarom.), 138.4 (1C, Cphenyl), 146.6 (1C, C-7aarom.), 153.4 (1C, C=CH). Compound 7d
was isolated as a mixture of (Z)- and (E)-isomers. In the 1H NMR spectrum a ratio of
95:5 ((Z):(E)) is observed. Signals for the (E)-isomer are marked with an asterisk.
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HPLC (method 2): t = 15.7 min, purity 92.2 %; IR: [cm-1] = 3028 (=C-Harom.), 2947,
휈
R
2924, 2855 (C-Haliph.), 1678 (C=Calkene), 1493 (C=Carom.), 1466 (CH2 deform.), 1366
(CH3 deform.), 1053 (C-O-C), 833 (=C-Halkene), 752, 737, 698 (=C-Harom. deform.);
Exact Mass (APCI): m/z = 436.2664 (calcd. 436.2666 for C27H38NO2Si [MH]+).
(Z)- and (E)-1'-Benzyl-3-[2-(tert-butyldiphenylsilyloxy)ethylidene]-3H-
spiro[[2]benzofuran-1,4'-piperidine] (7e)
OSit-BuPh2
Alcohol 6 (162 mg, 0.51 mmol, 1.0 eq) was dissolved in absolute
DMF (6 mL) and Et3N (0.70 mL, 5.05 mmol, 10 eq) was added. After
O
dropwise addition of tert-butyldiphenylsilyl chloride (0.20 mL,
N
Bn
0.76 mmol, 1.5 eq), the reaction mixture was stirred for 17 h. 1 M NaOH (2 mL) was
added. After dilution with H2O, the aqueous layer was extracted with CH2Cl2 (3 x). The
combined organic layers were dried (Na2SO4) and the solvents were removed in
vacuo. The residue was purified by flash column chromatography (50 g cartridge,
cyclohexane:ethyl acetate = 9:1). The product was isolated as colorless resin, yield
1
216 mg (76 %). Rf = 0.50 (cyclohexane:ethyl acetate = 1:1); H NMR (400 MHz,
DMSO-d6): δ [ppm] = 0.91 (s, 0.45H, (C(CH3)3*), 1.00 (s, 8.55H, (C(CH3)3), 1.45 (d, J
= 13.0 Hz, 2H, N(CH2CHAHB)2), 1.98 (t, J = 12.9 Hz, 2H, N(CH2CHAHB)2), 2.16 (t, J =
11.1 Hz, 2H, N(CHAHBCH2)2), 2.67 (d, J = 10.7 Hz, 2H, N(CHAHBCH2)2), 3.45 (s, 2H,
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NCH2Ph), 4.50 (d, J = 7.1 Hz, 2H, CH2OSi), 5.25 (t, J = 7.1 Hz, 1H, C=CH), 7.19 - 7.28
(m, 1H, Hphenyl), 7.28 - 7.47 (m, 13H, 5-Harom., 6-Harom., 7-Harom., Hphenyl), 7.55 - 7.60 (m,
1H, 4-Harom.), 7.68 (dd, J = 7.3/1.4 Hz, 4H, Hphenyl); 13C NMR (101 MHz, CDCl3): δ [ppm]
= 18.8 (1C, (C(CH3)3), 26.7 (3C, (C(CH3)3), 36.1 (2C, N(CH2CH2)2), 49.3 (2C,
N(CH2CH2)2), 58.6 (1C, CH2OSi), 62.3 (1C, NCH2Ph), 86.4 (1C, C-1), 93.9 (1C,
C=CH), 120.3 (1C, C-4arom.), 121.2 (1C, C-5arom.), 126.9 (1C, Cphenyl), 127.7 (4C,
Cphenyl), 128.1 (2C, Cphenyl), 128.3 (1C, C-7arom.), 128.8 (2C, Cphenyl), 129.2 (1C, C-
6arom.), 129.7 (2C, Cphenyl), 132.4 (1C, C-3aarom.), 133.6 (2C, Cphenyl), 135.1 (4C, Cphenyl),
138.4 (1C, Cphenyl), 146.6 (1C, C-7aarom.), 153.7 (1C, C=CH). Compound 7e was
isolated as a mixture of (Z)- and (E)-isomers. In the 1H NMR spectrum a ratio of 95:5
((Z):(E)) is observed. Signals for the (E)-isomer are marked with an asterisk. HPLC
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(method 2): t = 16.7 min, purity 99.7 %; IR: [cm-1] = 3067, 3028 (=C-Harom.), 2928,
휈
R
2855 (C-Haliph.), 1678 (C=Calkene), 1493 (C=Carom.), 1466 (CH2 deform.), 1366 (CH3
deform.), 1053 (C-O-C), 823 (=C-Halkene), 752, 737, 698 (=C-Harom. deform.); Exact
Mass (APCI): m/z = 560.2990 (calcd. 560.2979 for C37H42NO2Si [MH]+).
(Z)-1'-Benzyl-3-[2-(triphenylsilyloxy)ethylidene]-3H-spiro [[2]benzofuran-1,4'-
piperidine] (7f)
OSiPh3
Alcohol 6 (217 mg, 0.67 mmol, 1.0 eq) was dissolved in absolute DMF
(5 mL) and Et3N (0.94 mL, 6.74 mmol, 10 eq) was added. After
O
addition of triphenylsilyl chloride (298 mg, 1.01 mmol, 1.5 eq), the
N
Bn
reaction mixture was stirred for 10 d at room temperature. Additional triphenylsilyl
chloride (2 x 298 mg, 1.01 mmol, 1.5 eq) was added after 2 and 8 d. H2O was added
and the aqueous layer was extracted with CH2Cl2 (3 x). The combined organic layers
were dried (Na2SO4) and the solvents were removed in vacuo. The residue was
purified by flash column chromatography (100 g cartridge, cyclohexane:ethyl acetate
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= 8:2). The product was isolated as colorless resin, yield 239 mg (61 %). Rf = 0.49
(cyclohexane:ethyl acetate = 1:1); 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.44 (d, J
= 12.3 Hz, 2H, N(CH2CHAHB)2), 1.98 (td, J = 13.1/4.4 Hz, 2H, N(CH2CHAHB)2), 2.17 (t,
J = 10.9 Hz, 2H, N(CHAHBCH2)2), 2.66 - 2.71 (m, 2H, N(CHAHBCH2)2), 3.48 (s, 2H,
NCH2Ph), 4.59 (d, J = 7.3 Hz, 2H, CH2OSi), 4.67 (d, J = 8.1 Hz, 0H), 5.23 (t, J = 7.3 Hz,
1H, C=CH), 7.25 (m, 1H, Hphenyl), 7.31 - 7.36 (m, 6H, 5-Harom., 6-Harom., Hphenyl), 7.37 -
7.44 (m, 7H, 7-Harom., Hphenyl), 7.44 - 7.50 (m, 3H, Hphenyl), 7.51 - 7.56 (m, 1H, 4-Harom.),
7.57 - 7.61 (m, 6H, Hphenyl); 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 36.1 (2C,
N(CH2CH2)2), 49.3 (2C, N(CH2CH2)2), 58.4 (1C, CH2OSi), 62.3 (1C, NCH2Ph), 86.5
(1C, C-1), 93.5 (1C, C=CH), 120.3 (1C, C-4arom.), 121.2 (1C, C-7arom.), 126.9 (1C,
Cphenyl), 127.9 (6C, Cphenyl), 128.1 (2C, Cphenyl), 128.3 (1C, C-5arom.), 128.8 (2C, Cphenyl),
129.2 (1C, C-6arom.), 130.1 (3C, Cphenyl), 132.2 (1C, C-3aarom.), 134.1 (3C, Cphenyl), 134.9
(6C, Cphenyl), 138.5 (1C, Cphenyl), 146.6 (1C, C-7aarom.), 154.0 (1C, C=CH). In the spectra
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signals for the (E)-isomer could not be detected. IR: [cm-1] = 3067, 3024 (=C-Harom.),
휈
2920, 2851 (C-Haliph.), 1678 (C=Calkene), 1493 (C=Carom.), 1466 (CH2 deform.), 1053 (C-
O-C), 841 (=C-Halkene), 756, 737, 698 (=C-Harom. deform.); Exact Mass (APCI): m/z =
580.2710 (calcd. 580.2666 for C39H38NO2Si [MH]+).
(Z)-2-(1'-Benzyl-3H-spiro[[2]benzofuran-1,4'-piperidin]-3-yliden)ethyl
acetate
(7g)
OAc
Alcohol 6 (167 mg, 0.52 mmol, 1.0 eq) was dissolved in a mixture of
TBME (10 mL) and Et2O (15 mL). After addition of Amano PS-IM lipase
(167 mg) and isopropenyl acetate (0.85 mg, 7.79 mmol, 15 eq), the
O
N
Bn
reaction mixture was stirred at room temperature. Analysis by TLC after 21 h
(cyclohexane:ethyl acetate = 1:1) showed full conversion of the alcohol. The reaction
mixture was filtered to remove the lipase and the solvents were removed in vacuo.
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Because the product was rather unstable, the residue was used without further
purification and no purity was determined by HPLC. The product was isolated together
with not converted starting material in a ratio of 10:1 as colorless resin, yield 168 mg
(89 %, calculated from the 1H NMR spectrum). Rf = 0.42 (cyclohexane:ethyl
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acetate = 1:1); H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.56 (d, J = 12.3 Hz, 2H,
N(CH2CHAHB)2), 1.99 - 2.12 (m, 2H, N(CH2CHAHB)2), 2.02 (s, 3H, CH3), 2.38 (td,
J = 12.2/2.1 Hz, 2H, N(CHAHBCH2)2), 2.77 - 2.83 (m, 2H, N(CHAHBCH2)2), 3.56 (s, 2H,
NCH2Ph), 4.77 (d, J = 7.6 Hz, 2H, CH2OAc), 5.19 (t, J = 7.6 Hz, 1H, C=CH), 7.23 -
7.28 (m, 1H, Hphenyl), 7.29 - 7.45 (m, 6H, 5-Harom., 6-Harom., Hphenyl), 7.45 - 7.48 (m, 1H,
7-Harom.), 7.61 - 7.64 (m, 1H, 4-Harom.); 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 20.8
(1C, CH3), 36.1 (2C, N(CH2CH2)2), 49.4 (2C, N(CH2CH2)2), 58.9 (1C, CH2OAc), 62.3
(1C, NCH2Ph), 87.0 (1C, C-1), 88.7 (1C, C=CH), 120.6 (1C, C-4arom.), 121.3 (1C, C-
7arom.), 126.9 (1C, Cphenyl), 128.1 (2C, Cphenyl), 128.5 (1C, C-5arom.), 128.9 (2C, Cphenyl),
129.6 (1C, C-6arom.), 131.9 (1C, C-3aarom.), 138.6 (1C, Cphenyl), 146.9 (1C, C-7aarom.),
156.2 (1C, C=CH), 170.4 (1C, CO2). In the spectra signals for the (E)-isomer could not
be detected. IR: [cm-1] = 3059, 3028 (=C-Harom.), 2943, 2916, (C-Haliph.), 1732 (C=O),
휈
1678 (C=Calkene), 1493 (C=Carom.), 1466 (CH2 deform.), 1366 (CH3 deform.), 1227
(CH3CO-O-C), 1053 (C-O-C), 795 (=C-Halkene), 756, 741, 698 (=C-Harom. deform.);
Exact Mass (APCI): m/z = 364.1907 (calcd. 364.1907 for C23H26NO3 [MH]+).
(Z)- and (E)-1'-Benzyl-3-(2-(trityloxy)ethylidene)-3H-spiro[[2]benzofuran-1,4'-
piperidine] (7h)
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OCPh3
Alcohol 6 (161 mg, 0.50 mmol, 1.0 eq) was dissolved in absolute DMF
(5 mL) and Et3N (0.70 mL, 5.01 mmol, 10 eq) was added. After addition
of triphenylmethyl chloride (210 mg, 0.75 mmol, 1.5 eq), the reaction
O
N
Bn
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mixture was stirred for 5 d at room temperature. H2O was added and the aqueous layer
was extracted with CH2Cl2 (3 x). The combined organic layers were dried (Na2SO4)
and the solvents were removed in vacuo. The residue was purified by flash column
chromatography (100 g cartridge, cyclohexane:ethyl acetate = 6:4). The product was
isolated as orange resin, yield 220 mg (78 %). Rf = 0.44 (cyclohexane:ethyl
1
acetate = 9:1); H NMR (400 MHz, CDCl3): δ [ppm] = 1.70 (d, J = 12.4 Hz, 2H,
N(CH2CHAHB)2), 1.98 - 2.11 (m, 2H, N(CH2CHAHB)2), 2.39 (t, J = 11.1 Hz, 2H,
N(CHAHBCH2)2), 2.82 (d, J = 11.3 Hz, 2H, N(CHAHBCH2)2), 3.58 (s, 2H, NCH2Ph), 3.94
(d, J = 7.2 Hz, 2H, CH2OC), 5.12 (t, J = 7.1 Hz, 0.95H, C=CH), 5.42 (t, J = 8.1 Hz,
0.05H, C=CH*), 7.15 - 7.22 (m, 1H, 5-Harom.), 7.21 - 7.40 (m, 16H, 6-Harom., 7-Harom.,
13
Hphenyl), 7.40 - 7.47 (m, 1H, 4-Harom.), 7.55 (dt, J = 8.1/1.1 Hz, 6H, Hphenyl); C NMR
(101 MHz, CDCl3): δ [ppm] = 36.8 (2C, N(CH2CH2)2), 50.1 (2C, N(CH2CH2)2), 59.2 (1C,
CH2OC), 63.5 (1C, NCH2Ph), 86.5 (1C, C-1), 86.9 (1C, OCPh3), 92.0 (0.95C, C=CH),
95.5 (0.05C, C=CH*), 120.5 (1C, C-4arom.), 120.9 (1C, C-5arom.), 126.9 (3C, Cphenyl),
127.2 (1C, Cphenyl), 127.9 (6C, Cphenyl), 128.3 (1C, C-7arom.), 128.4 (2C, Cphenyl), 128.9
(1C, C-6arom.), 129.4 (2C, Cphenyl), 129.0 (6C, Cphenyl), 133.6 (1C, C-3aarom.), 138.4 (1C,
Cphenyl), 144.7 (3C, Cphenyl), 147.0 (1C, C-7aarom.), 155.2 (1C, C=CH). Compound 7h
was isolated as a mixture of (Z)- and (E)-isomers. In the NMR spectra a ratio of 95:5
((Z):(E)) is observed. Signals for the (E)-isomer are marked with an asterisk. HPLC
(method 2): t = 16.3 min, purity 99.9 %; IR: [cm-1] = 3055, 3028 (=C-H), 2920, 2851
휈
R
(C-Haliph.), 1678 (C=Calkene), 1489 (C=Carom.), 1466 (CH2 deform.), 1053 (C-O-C), 799
(=C-Halkene), 741, 698 (=C-Harom. deform.); Exact Mass (APCI): m/z = 564.2896 (calcd.
564.2897 for C40H38NO2 [MH]+).
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Determination of the ratio of enantiomers by HPLC on a chiral stationary phase
and polarimetry
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HPLC on a chiral stationary phase: Merck Hitachi equipment; Diode array detector: L-
7455; pump: L-6200A; injection: manual, Rheodyne 7725i; column: Daicel Chiralpak
IA, 5 μm, 250 x 4.6 mm; injection volume: 10.0µL; detection at λ = 262 nm. Method 3:
mobile phase: isohexane : CH2Cl2 : EtOH = 96 : 3 : 1 with 0.1 % diethylamine; flow rate
1.0
mL/min;
stop
time:
40.0 min.
Method
4:
mobile
phase:
isohexane : MeOH = 100 : 3; flow rate 1.5 mL/min; stop time: 30.0 min. The
enantiomeric ratio of alcohols 8 was determined by method 3 and the enantiomeric
ratio of tosylates 9 was determined by method 4.
Optical rotation (α [deg]) was determined with UniPol L1000 (Schmidt+Haensch). The
linearly polarized light (589 nm, sodium D line) was passed through a sample with a
path length (l) of 1 dm at +20 °C. The specific rotation
20 was calculated according
[훼]퐷
20
to the formula
푐푎∙ 푙. Its unit [deg mL dm-1 g-1] is omitted. The concentration of the
[훼]퐷 =
sample [g/100 mL] and the solvent are given in brackets.
Synthesis of enantiomerically pure fluspidine precursors 8 and 9
(R)-2-(1'-Benzyl-3H-spiro[[2]benzofuran-1,4'-piperidin]-3-yl)ethan-1-ol ((R)-8)
OH
Ester (Z)-3 (109 mg, 0.30 mmol, 1.0 eq), CoCl2((R,R)-Naph-diPIM-dioxo-
iPr) ((R,R)-10, 2.0 mg, 0.003 mmol, 0.01 eq) and NaBH4 (22.7 mg,
O
0.6 mmol, 2.0 eq) were added to a Schlenk tube. After addition of absolute
N
Bn
CH2Cl2 (0.6 mL), the suspension was cooled to 0 °C. Absolute MeOH (0.6 mL) was
added and the reaction mixture was warmed to room temperature. After 30, 60 and
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120 min, a sample (0.4 mL) of the reaction mixture was taken and treated according to
the following procedure: a saturated solution of NH4Cl (1 mL) was added and the
sample was diluted with water. After separation of the organic layer, the aqueous layer
was extracted with CH2Cl2 (2x). The combined organic layers were dried (Na2SO4) and
the solvents were removed in vacuo. The residue was dissolved in Et2O and the
solution was cooled to -15 °C. LiAlH4 (9.5 mg, 0.25 mmol, 2.5 eq) was added and the
reaction mixture was stirred for 30 min at -15 °C and for further 45 min at room
temperature. After addition of ethyl acetate (5 mL) and a saturated solution of
potassium sodium tartrate (10 mL), the reaction mixture was stirred over night at room
temperature. CH2Cl2 and water were added and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (2x) and the combined organic layers were
dried (Na2SO4). The solvents were removed in vacuo and the residue was purified by
flash column chromatography (25 g cartridge, CH2Cl2:MeOH = 95:5). The three
samples were analyzed by HPLC on a chiral stationary phase and afterwards
combined for further reaction. The product was isolated as pale yellow resin, yield
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61.4 mg (63 %). Rf = 0.20 (cyclohexane:ethyl acetate = 1:1); H NMR (600 MHz,
CDCl3): δ [ppm] = 1.71 - 1.78 (m, 2H, N(CH2CHAHB)2), 1.92 (dtd, J = 14.4/8.5/3.8 Hz,
1H, CHAHBCH2OH), 1.96 - 2.07 (m, 1H, N(CH2CHAHB)2), 2.19 (ddt, J = 14.4/6.4/3.3 Hz,
1H, CHAHBCH2OH), 2.21 - 2.29 (m, 1H, N(CH2CHAHB)2), 2.41 - 2.55 (m, 2H,
N(CHAHBCH2)2), 2.86 - 2.97 (m, 2H, N(CHAHBCH2)2), 3.63 (s, 2H, NCH2Ph), 3.85 (ddd,
J = 10.8/6.1/3.8 Hz, 1H, CHAHBOH), 3.93 (ddd, J = 11.5/8.3/3.4 Hz, 1H, CHAHBOH),
5.41 (dd, J = 8.7/3.1 Hz, 1H, ArCHO), 7.10 - 7.13 (m, 1H, 4-Harom.), 7.16 - 7.18 (m, 1H,
7-Harom.), 7.27 - 7.31 (m, 3H, 5-Harom., 6-Harom., Hphenyl), 7.34 (t, J = 7.5 Hz, 2H, Hphenyl),
7.39 (d, J = 7.3 Hz, 2H, Hphenyl); 13C NMR (151 MHz, CDCl3): δ [ppm] = 36.8 (1C,
N(CH2CH2)2), 38.1 (1C, N(CH2CH2)2), 38.8 (1C, CH2CH2OH), 50.2 (1C, N(CH2CH2)2),
50.3 (1C, N(CH2CH2)2), 61.6 (1C, CH2OH), 63.3 (1C, NCH2Ph), 82.1 (1C, ArCHO),
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84.7 (1C, C-1), 121.2 (1C, C-4arom.), 121.2 (1C, C-7arom.), 127.5 (1C, Cphenyl), 128.1 (1C,
C-5arom.), 128.1 (1C, C-6arom.), 128.5 (2C, Cphenyl), 129.7 (2C, Cphenyl), 138.1 (1C,
Cphenyl), 141.2 (1C, C-3aarom.), 145.4 (1C, C-7aarom.); HPLC (method 1): tR = 15.1 min,
purity 97.1 %; HPLC (method 3): tR = 15.1 min, enantiomeric ratio (R)-8 : (S)-8 = 97.8
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: 2.2; Specific rotation:
20 = +30.6 (4.2; CH2Cl2).
[훼]퐷
(S)-2-(1'-Benzyl-3H-spiro[[2]benzofuran-1,4'-piperidin]-3-yl)ethan-1-ol ((S)-8)
OH
Ester (Z)-3 (109 mg, 0.30 mmol, 1.0 eq), CoCl2((S,S)-Naph-diPIM-dioxo-
iPr) ((S,S)-10, 2.0 mg, 0.003 mmol, 0.01 eq) and NaBH4 (22.7 mg,
O
0.6 mmol, 2.0 eq) were added to a Schlenk tube. After addition of absolute
N
Bn
CH2Cl2 (0.6 mL), the suspension was cooled to 0 °C. Absolute MeOH (0.6 mL) was
added and the reaction mixture was warmed to room temperature. After 30 min
saturated solution of NH4Cl (1 mL) was added and the sample was diluted with H2O.
After separation of the organic layer, the aqueous layer was extracted with CH2Cl2 (2x).
The combined organic layers were dried (Na2SO4) and the solvents were removed in
vacuo. The residue was dissolved in Et2O and the solution was cooled to -15 °C. LiAlH4
(28.5 mg, 0.75 mmol, 2.5 eq) was added and the reaction mixture was stirred for
30 min at -15 °C and for further 40 min at room temperature. After addition of ethyl
acetate (5 mL) and a saturated solution of potassium sodium tartrate (10 mL), the
reaction mixture was stirred at room temperature for 3 h. CH2Cl2 and water were added
and the organic layer was separated. The aqueous layer was extracted with CH2Cl2
(2x) and the combined organic layers were dried (Na2SO4). The solvents were removed
in vacuo and the residue was purified by flash column chromatography (25 g cartridge,
CH2Cl2:MeOH = 95:5). The product was isolated as yellow resin, yield 79.9 mg (82 %).
Rf = 0.20 (cyclohexane:ethyl acetate = 1:1); 1H NMR (600 MHz, CDCl3): δ [ppm] = 1.71
- 1.78 (m, 2H, N(CH2CHAHB)2), 1.87 - 1.96 (m, 1H, N(CH2CHAHB)2), 1.92 (dtd, J =
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