Enantioselective Total Synthesis and Assignment of the Absolute Configuration of the Furo[3,2- a]carbazole Alkaloid Furoclausine-B

Article abstract of DOI:10.1021/acs.joc.8b02426

We describe the first enantioselective total synthesis and the assignment of the absolute configuration of the furo[3,2-a]carbazole alkaloid furoclausine-B. As key steps for our approach we used a palladium(II)-catalyzed double C-H-bond activation for the

Full text of DOI:10.1021/acs.joc.8b02426

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Article
Enantioselective Total Synthesis and Assignment of the Absolute
Configuration of the Furo[3,2-a]carbazole Alkaloid Furoclausine-B
Benedikt Spindler, Olga Kataeva, and Hans-Joachim Knölker
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 28 Nov 2018
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Enantioselective Total Synthesis and Assignment of the Absolute
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Configuration of the Furo[3,2-a]carbazole Alkaloid Furoclausine-B
[
a]
[b]
[a]
Benedikt Spindler, Olga Kataeva, and Hans-Joachim Knölker*
[
a]
b]
Fakultät Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
A. M. Butlerov Chemistry Institute, Kazan Federal University, Kremlevskaya Str. 18, Kazan 420008 Russia
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ABSTRACT
In 1997, two further furo[3,2-a]carbazole alkaloids,
furoclausine-A (3) and -B (4), were obtained by Wu
and coworkers from the acetone extract of the root
bark of Clausena excavata. Since then, more
furocarbazole alkaloids have been isolated for
We describe the first enantioselective total synthesis
and the assignment of the absolute configuration of the
furo[3,2-a]carbazole alkaloid furoclausine-B. As key
steps for our approach we used a palladium(II)-
catalyzed double C–H-bond activation for the
construction of the carbazole framework, a Shi
epoxidation, and an intramolecular opening of the
epoxide for annulation of the dihydrofuran moiety.
4
example from plants of the genera Zanthoxylum and
5,6
Lonicera. We reported the first total syntheses of
furostifoline (1) and furoclausine-A (3) in 1996 and
7–9
2004, respectively.
In both syntheses an iron-
mediated construction of the carbazole framework was
applied. Annulation of the furan was achieved by
reaction of
a
phenol with bromoacetaldehyde
diethylacetal and subsequent proton-catalyzed
cyclization. In 2007, we reported the first total
synthesis of eustifoline-D (2) using a palladium(II)-
catalyzed oxidative cyclization to form the carbazole
10
framework. Several alternative synthetic approaches
11,12
towards furocarbazoles have been described.
Because of the stereogenic center at the dihydrofuran
ring, furoclausine-B (4) is a more challenging synthetic
target and no synthesis for this natural product has
been reported so far. Wu et al. isolated furoclausine-B
(4) as an optically active compound. However, the
absolute configuration of the natural product was not
determined. Herein, we describe the first total
synthesis of furoclausine-B (4) in racemic form and of
both enantiomers. Moreover, we assign the absolute
configuration for the natural product.
INTRODUCTION
In Asian folk medicine extracts of the terrestrial plants
Clausena excavata and Murraya euchrestifolia have
been used for the treatment of a wide variety of
diseases and infections.1 Thus, the constituents of
these extracts have attracted the interest of many
scientists. Among the various carbazole alkaloids
isolated from these plants, a comparatively small
group is characterized by a furan annulated at the
2
carbazole nucleus. So far, only a few furocarbazole
alkaloids have been isolated from natural sources. The
first furocarbazoles isolated from the root bark of the
Taiwanese shrub Murraya euchrestifolia Hayata by
Furukawa in 1990 were the furo[3,2-a]carbazole
RESULTS AND DISCUSSION
Our approach to furoclausine-B (4) is based on
construction of the carbazole framework by a
palladium(II)-catalyzed oxidative cyclization of the
corresponding diarylamine 5 (Scheme 1). Previously,
we have applied this strategy to the total synthesis of
furostifoline (1) and the furo[2,3-c]carbazole
eustifoline-D (2) (Figure 1).3
13
a variety of carbazoles. The sterically demanding
triisopropylsilyl (TIPS) protecting group of compound 5
should ensure that no alternative regioisomer is
13
formed in the cyclization step. Late-stage oxidation
of the methyl group should afford the aldehyde at C-4
of furoclausine-B (4). The diarylamine 5 would result
14
from Buchwald–Hartwig coupling of the protected
bromoarene 6 and the 4-amino-2,3-dihydrobenzofuran
7. The chiral dihydrobenzofuran 7 can be obtained by
Shi epoxidation of the o-prenylphenol 8 followed by
ring closure. Compound
8 should derive from
commercially available 2-methyl-5-nitrophenol (9).
Figure 1 Naturally occurring furocarbazole alkaloids.
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Scheme 1 Retrosynthetic analysis of furoclausine-B (4).
The nitrophenol 9 reacted smoothly with 2-methylbut-
3-yn-2-yl trifluoroacetate, prepared in situ from the
propargylic alcohol 10, to give the propargyl ether 11.
Hydrogenation of the triple bond in the presence of
Lindlar’s catalyst with careful reaction monitoring to
prevent reduction of the nitro group afforded the allyl
ether 12. Claisen rearrangement at 140 °C led to the
prenylated nitrophenol 8. It is noteworthy that the best
yields for compound 8 were provided when the
reaction was carried out on a multigram scale.
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Figure 2 Fructose-derived Shi catalysts 13, 14, and ent-14.
Scheme 3 Synthesis of the dihydrobenzofurans 15, ent-15,
a
and rac-15 by epoxidation and cyclization.
First, the prenylated nitrophenol
8 as a key
intermediate for the annulation of the dihydrofuran
moiety was required. Our initial approaches for
prenylation of 9 (palladium(0) catalyzed Tsuji–Trost
reaction and subsequent rearrangement, sodium-
mediated direct alkylation as reported by Tanaka and
15
coworkers, and directed ortho-lithiation followed by
1
6
reaction with prenyl bromide as described by Pettus )
gave poor results.
Scheme 2 Synthesis of the prenylated nitrophenol 8.a
aReagents and conditions: (a) 0.64 equiv 13, 3.8 mol%
Bu
then 4.8 equiv Oxone and aq. KOH over 2 h, 17% (10.5%
ee); (b) 2.3 equiv NEt , 20 mol% DMAP, CH Cl , rt, 10 min,
then 1.6 equiv TIPSCl, rt, overnight, 94%; (c) 1.) 0.64 equiv
4, 3.8 mol% Bu NHSO , DMM/MeCN (2:1), K CO /HOAc
buffer, 0 °C, then 4.8 equiv Oxone in aq. Na EDTA and aq.
KOH over 2 h; 2.) 2.3 equiv TBAF, THF, 0 °C, 1 h, 96% (over
steps; >99.9% ee); (d) 1.) 0.64 equiv ent-14, 3.8 mol%
Bu NHSO , DMM/MeCN (2:1), K CO /HOAc buffer, 0 °C,
4 4 2 3
NHSO , K CO /HOAc buffer, DMM/MeCN (2:1), 0 °C,
®
3
2
2
1
4
4
2
3
®
2
2
4
4
2
3
aReagents and conditions: (a) 1.) 1.0 equiv 10, 1.3 equiv
DBU, 1.15 equiv TFAA, MeCN, –10 °C, 40 min; 2.) 1.0 equiv
®
then 4.8 equiv Oxone and aq. KOH over 2 h; 2.) 2.3 equiv
TBAF, THF, 0 °C, 1 h, 99% (over 2 steps; >99.9% ee); (e)
1.) 1.2 equiv mCPBA, aq. NaHCO , CHCl , 0 °C, then 1.5 h
9
2 2
, 0.1 mol% CuCl ∙H O, 1.3 equiv DBU, MeCN, 1.13 equiv
3
3
2-methylbut-3-yn-2-yl trifluoroacetate, –10 °C, 60 min and
overnight, rt, 92%; (b) 10 wt% Lindlar cat., 3.0 equiv
rt; 2.) 2.3 equiv TBAF, THF, 0 °C, 1 h, 96% (2 steps). DMM
dimethoxymethane; DMAP 4-(N,N-
=
=
quinoline, 1 atm H
1
=
2
, EtOAc, rt, 1 h, 87%; (c) xylenes, 140 °C,
h, 92%. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. TFAA
trifluoroacetic anhydride.
dimethylamino)pyridine. TBAF = tetra-n-butylammonium
fluoride.
Using Godfrey’s method,17–19 in analogy to previous
With the phenol 8 we studied the enantioselective
epoxidation using the fructose-derived chiral Shi
catalysts (Figure 2, Scheme 3). A sequence of
enantioselective epoxidation and intramolecular
nucleophilic epoxide opening was successfully applied
20–23
applications in pyranocarbazole synthesis,
we
introduced the prenyl group by O-propargylation,
subsequent hydrogenation of the triple bond to a
double bond and Claisen rearrangement (Scheme 2).
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to similar compounds by Hamada and coworkers as
100
24–26
15
ent-15
rac-15
well as by other groups.
The Shi catalyst 13 is
readily available from L-fructose.27,28 However, direct
epoxidation of 8 using catalyst 13 followed by an in situ
5-exo-tet ring closure provided the dihydrobenzofuran
15 in only poor yield and with low enantiomeric excess
8
6
4
0
0
0
(
10.5% ee). Obviously, a protection of the hydroxy
group was required and thus, the phenol 8 was
transformed to the silyl ether 16. Asymmetric
epoxidation of 16 with 13 as catalyst followed by
treatment with TBAF afforded the dihydrobenzofuran
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15 in 57% yield and 87% enantiomeric excess. Shi’s
20
0
diacetate catalyst 14, which can be prepared in two
steps from catalyst 13,2
9–31
was reported to provide
generally better results in terms of yield and
enantioselectivity.2
4,29,30
Indeed,
asymmetric
20
25
30
35
time (min)
epoxidation of 16 using the diacetate 14 as catalyst
and subsequent cleavage of the silyl ether afforded the
virtually enantiopure (>99.9% ee) dihydrobenzofuran
Figure 3 Chiral HPLC of the enantiomers of the dihydro-
benzofurans 15 and ent-15, and of the racemate rac-15.
15 in 96% yield. The X-ray crystal structure
determination of compound 15 unequivocally
confirmed the R configuration of the stereogenic
center (see Supporting Information, Figure S7). The
absolute stereochemistry of 15 as determined by X-ray
analysis is consistent with the expected asymmetric
Scheme 4 Synthesis of furoclausine-B (4) from 15.a
27,31
induction resulting from the Shi expoxidation of 16.
At the beginning of our study, the absolute
configuration of the natural product was not known.
Therefore, we also started the synthesis of the
enantiomeric series (Scheme 3). Shi epoxidation of
compound 16 using the D-fructose derived diacetate
catalyst ent-14 under identical reaction conditions
provided ent-15 in virtually enantiopure form (>99.9%
ee) in 99% yield. For analytical purposes, we prepared
the racemic compound rac-15 by epoxidation of 16
with meta-chloroperbenzoic acid and subsequent
cyclization to the dihydrobenzofuran (Scheme 3). With
the racemic dihydrobenzofuran rac-15, we achieved a
baseline separation of the two enantiomers 15 and
ent-15 by chiral HPLC (Figure 3; for details of the
protocol for chiral HPLC, see the General Information
of the Experimental Section). Thus, the enantiomeric
purity for 15 and ent-15 could be confirmed by this
method with high accuracy.
aReagents and conditions: (a) 10 mol% PtO
EtOAc, rt, overnight, 91%; (b) 1.12 equiv 7, 1.0 equiv 6, 6
mol% Pd(OAc) , 12 mol% rac-BINAP, 1.33 equiv Cs CO
toluene, 110 °C, overnight, 93%; (c) 9 mol% Pd(OAc) , 2.5
equiv Cu(OAc) , AcOH, 130 °C, 30 min, 71%; (d) 3.3 equiv
DDQ, MeOH/THF/H O (16:3:1), –15 °C, 20 min, 58%; (e) 3.2
equiv TBAF, cat. H O, THF, –10 °C, 40 min, 91%. BINAP =
,2ʹ-bis(diphenylphosphino)-1,1ʹ-binaphthalene. DDQ = 2,3-
2
2
, 1 atm H ,
2
2
3
,
2
2
2
2
2
dichloro-5,6-dicyanobenzoquinone.
Hydrogenation of 15 in the presence of catalytic
amounts of platinum(IV) oxide provided the arylamine
(Scheme 4). Buchwald–Hartwig coupling of 7 with
7
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the bromoarene 623 led to the diarylamine 5 which on
precisely. However, the enantiomeric excess of ent-4
palladium(II)-catalyzed oxidative cyclization afforded
the 1,2-dihydrofuro[3,2-a]carbazole 17 in 71% yield.
Subsequent oxidation of compound 17 using
dichlorodicyanobenzoquinone (DDQ) gave the
aldehyde 18. Cleavage of the silyl protecting group
with an excess of TBAF provided furoclausine-B (4) in
can be determined accurately. Since the natural
enantiomer of furoclausine-B (4) has a lower retention
time than ent-4, minor impurities of the former are
easily separated from ent-4 as major enantiomer. The
retention times of the pure enantiomers 4 and ent-4
perfectly fit those of the racemic mixture, thus
assigning the enantiomers in the mixture. Based on
the chiral HPLC, the enantiomeric excess for our
synthetic furoclausine-B (4) and ent-furoclausine-B
(ent-4) is >99.5%. A comparison of the values for the
specific rotation found for our synthetic compounds 4
9
1% yield. Thus, the conversion of 15 into
furoclausine-B (4) has been achieved in 5 steps and
2% overall yield. The analytical data of 4 were in good
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agreement with those reported for the natural product
isolated by Wu and coworkers.4
2
0
20
(
[α]
D
–34.4) and ent-4 ([α]
D
+33.9) with that reported
4
Scheme 5 Syntheses of ent-furoclausine-B (ent-4) and rac-
for the natural product 4 ([α] –32.73) emphasizes the
D
a
furoclausine-B (rac-4).
high enantiopurity of our products and confirms the
fact that the stereogenic center of the natural product
4
has an R configuration.
CONCLUSIONS
Using our approach to carbazoles consisting of
Buchwald–Hartwig
coupling
and
subsequent
palladium(II)-catalyzed oxidative cyclization, we have
completed the first total synthesis of furoclausine-B (4)
and of its enantiomer ent-4. The natural product was
obtained in 11 steps with 21% overall yield and the
absolute configuration at the stereogenic center could
be assigned as R.
EXPERIMENTAL SECTION
General Information. All reactions were carried out in oven-
dried glassware with dry solvents under an argon
atmosphere unless stated otherwise. Acetonitrile,
dichloromethane, tetrahydrofuran, and toluene were dried
aReagents and conditions: see steps (a) – (e) in Scheme 4.
100
using
a
solvent purification system (MBraun-SPS).
4
Palladium acetate was recrystallized from acetic acid. Other
chemicals were used as received from commercial sources.
Microwave irradiations were carried out in a CEM Discover
microwave apparatus with maximum power of 300 W and
maximum pressure of 20 bar. Flash chromatography was
performed with silica gel from Acros Organics (0.035−0.070
mm). TLC was performed with TLC plates from Merck (60
F254) using UV light for visualization. Melting points were
measured on a Gallenkamp MPD 350 melting point
apparatus. UV spectra were recorded on a PerkinElmer 25
UV/Vis spectrometer. Fluorescence spectra were measured
on a Varian Cary Eclipse spectrometer. IR spectra were
ent-4
rac-4
8
6
4
0
0
0
20
0
recorded on
a
Thermo Nicolet Avatar 360 FT-IR
spectrometer by the ATR method (attenuated total
reflectance). NMR spectra were recorded on Bruker Avance
II 300, DRX 500, and Avance III 600 spectrometers.
Chemical shifts δ are reported in parts per million with the
signal for the solvent as internal standard. Standard
abbreviations were used to denote the multiplicities of the
signals. Mass spectra were recorded by GC/MS-coupling
using an Agilent Technologies 6890 N GC System equipped
with a 5973 Mass Selective Detector (electron impact, 70
eV). ESI-MS spectra were recorded on an Esquire LC with
an ion trap detector from Bruker. Positive and negative ions
were detected. ESI-HRMS were recorded on an Agilent
Technologies Q-TOF 6538. Elemental analyses were
measured on a EuroVector EuroEA3000 elemental analyzer.
X-ray crystal structure analysis was performed with a Bruker-
Nonius Kappa CCD that was equipped with a 700 series
1
5
20
25
30
time (min)
Figure 4 Chiral HPLC of the enantiomers of furoclausine-B
4 and ent-4, and of the racemate rac-4.
Finally, we also synthesized the S-enantiomer of
furoclausine-B (ent-4) and racemic furoclausine-B
(
rac-4) via the same sequence of steps as described
in Scheme 4 for furoclausine-B (4) (Scheme 5). Since
a baseline separation for racemic furoclausine-B (rac-
4) could not be achieved by chiral HPLC (Figure 4), it
is difficult to determine the enantiomeric purity of 4
Cryostream
low-temperature
device
from
Oxford
4
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Cryosystems. SHELXS-97,32 SADABS version 2.10,33
, 440.6 [2M–H] . Anal. Calcd. for C12
6.83, N 6.33. Found: C 65.17, H 7.18, N 6.52.
–
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
H15NO : C 65.14, H
3
4
SHELXL-97,
POV-Ray
for
Windows
version
3
5
3
.7.0.msvc10.win64, and ORTEP-3 for Windows were
6-Methyl-3-nitro-2-prenylphenol (8). 2-((2-Methylbut-3-
en-2-yl)oxy)-4-nitrotoluene (12) (2.01 g, 9.1 mmol) was
dissolved in xylenes (60 mL) and heated at 140 °C for 1 h
under reflux. The reaction mixture was allowed to cool to
room temperature, the solvent was evaporated, and the
residue was purified by column chromatography (silica gel;
isohexane/ethyl acetate, 9:1). The resulting oil was cooled to
induce crystallization and thus afforded 6-methyl-3-nitro-2-
prenylphenol (8) (1.85 g, 8.4 mmol, 92% yield) as colorless
crystals; mp 65 – 66 °C. UV (MeOH) λmax 242, 277, 326 (sh)
nm. IR (ATR) ν 3437, 2982, 2964, 2911, 2854, 1602, 1576,
1559, 1522, 1462, 1443, 1417, 1327, 1263, 1225, 1172,
1153, 1017, 965, 936, 844, 813, 733, 631 cm . H NMR (500
MHz, CDCl ) δ 1.79 (d, J = 1.3 Hz, 3 H), 1.85 (s, 3 H), 2.28
(s, 3 H), 3.56 (d, J = 6.9 Hz, 2 H), 5.26 (ddt, J = 8.4, 5.5, 1.4
Hz, 1 H), 5.60 (s, 1 H), 7.09 (d, J = 8.5 Hz, 1 H), 7.34 (d, J =
8.2 Hz, 1 H). C{ H} NMR and DEPT (126 MHz, CDCl
16.5 (CH ), 18.1 (CH ), 25.8 (CH ), 26.0 (CH ), 116.4 (CH),
120.2 (CH), 120.9 (C), 128.6 (CH), 130.4 (C), 136.8 (C),
used as software. The enantiomeric excess was determined
by analytical chiral HPLC using an Agilent Model 1100 with
G1315B UV-DAD; column: reversed phase cellulose, 4.6 ×
2
50 mm, Macherey Nagel Nucleocel delta-rp; isocratic
elution with 60% of H O and 40% of MeCN at 10 °C; flow
2
–
1
–1
0
1
2
3
4
5
6
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8
9
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9
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1
2
3
4
5
6
7
8
9
0
rate: 0.7 mL min for 15 and 0.3 mL min for 4.
Synthesis of furoclausine-B (4).
2
-((2-Methylbut-3-yn-2-yl)oxy)-4-nitrotoluene
(11).
2-
Methylbut-3-yn-2-ol (10) (6.31 g, 75.0 mmol) was dissolved
in acetonitrile (45 mL) and the solution was cooled to–10 °C.
After addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(14.8 mL, 99.2 mmol, 1.3 equiv), trifluoroacetic anhydride
(TFAA) (12.2 mL, 86.6 mmol, 1.15 equiv) was added over a
period of 40 min via a syringe pump to the –10 °C cold
solution. In a separate flask, 2-methyl-5-nitrophenol (10.1 g,
–
1 1
3
1
3
1
6
6.0 mmol) and copper(II) chloride dihydrate (11.3 mg, 0.066
3
) δ
mmol, 0.1 mol%) were dissolved in acetonitrile (70 mL). After
cooling to –10 °C, DBU (12.8 mL, 85.8 mmol, 1.3 equiv) was
added slowly. Then, the previously prepared solution of 2-
methylbut-3-yn-2-yl trifluoroacetate was added over 60 min
via a dropping funnel and the temperature was kept at –10
3
3
2
3
+
149.0 (C), 154.0 (C). ESIMS (+10 V) m/z 222.0 [M+H] ,
+
–
239.0 [M+NH
4
] ; ESIMS (–50 V) m/z 219.8 [M–H] , 440.7
[2M–H] . Anal. Calcd. for C12 : C 65.14, H 6.83, N
6.33. Found: C 65.51, H 6.78, N 6.29.
–
H15NO
3
°
C. After the addition, the mixture was stirred at room
temperature overnight. complete conversion was
A
6-Methyl-2-prenyl-3-nitrophenyl triisopropylsilyl ether
(16). 6-Methyl-3-nitro-2-prenylphenol (8) (2.90 g, 13.1 mmol)
and 4-(N,N-dimethylamino)pyridine (320 mg, 2.6 mmol, 0.2
equiv) were dissolved in dichloromethane (90 mL).
Triethylamine (4.2 mL, 30.3 mmol, 2.3 equiv) was added and
the reaction mixture was stirred at room temperature for 10
min, before triisopropylsilyl chloride (3.6 mL, 17 mmol, 1.3
equiv) was added dropwise. After stirring at room
temperature overnight, another portion of triisopropylsilyl
chloride (0.72 mL, 3.4 mmol, 0.26 equiv) was added and the
reaction was stirred for additional 5 h. After quenching with
water, the layers were separated, and the aqueous layer was
extracted with diethyl ether. The combined organic layers
were washed twice with a sat. aq. NH
and then dried (MgSO ). Removal of the solvent and
purification by column chromatography (silica gel;
isohexane/ethyl acetate, 9:1) provided 6-methyl-2-prenyl-3-
nitrophenyl triisopropylsilyl ether (16) (4.71 g, 12.5 mmol,
94% yield) as a colorless solid; mp 60 – 61 °C. UV (MeOH)
confirmed by TLC and the solvent was evaporated. The
residue was taken up in toluene and washed with water. The
aqueous layer was extracted twice with toluene and the
combined organic layers were washed three times with 2 M
2 3
HCl, four times with a sat. aq. K CO solution, and finally with
brine. The solvent was evaporated, and the residual oil was
cooled in order to induce crystallization. The solid was dried
under vacuum to give 2-((2-methylbut-3-yn-2-yl)oxy)-4-
nitrotoluene (11) (13.3 g, 60.7 mmol, 92% yield) as light
brown crystals; mp: 64 °C. UV (MeOH) λmax 211, 228, 279,
324 (sh) nm. IR (ATR) ν 3271, 3231, 3088, 2982, 2931,
1590, 1510, 1486, 1340, 1326, 1245, 1227, 1179, 1131,
–
1 1
1
090, 971, 866, 810, 739, 695, 671 cm . H NMR (600 MHz,
CDCl ) δ 1.73 (s, 6 H), 2.29 (s, 3 H), 2.68 (s, 1 H), 7.27 (dd,
J = 8.3, 0.8 Hz, 1 H), 7.80 (dd, J = 8.3, 2.3 Hz, 1 H), 8.37 (d,
4
Cl solution, with brine,
3
4
1
3
1
J = 2.3 Hz, 1 H). C{ H} NMR and DEPT (151 MHz, CDCl
δ 17.3 (CH ), 29.7 (2 CH ), 73.1 (C), 75.3 (C), 84.9 (CH),
12.9 (CH), 117.0 (CH), 130.9 (CH), 138.3 (C), 146.7 (C),
3
)
3
3
1
+
154.3 (C). EIMS (70 eV) m/z 219 (8) [M] , 204 (100), 174
23), 158 (66). Anal. Calcd. for C12 : C 65.74, H 5.98,
N 6.39. Found: C 65.70, H 6.14, N 6.49.
-((2-Methylbut-3-en-2-yl)oxy)-4-nitrotoluene (12). 2-((2-
λmax 240, 274, 332 (sh) nm. IR (ATR) ν 2945, 2867, 1558,
1523, 1460, 1353, 1269 cm . H NMR (500 MHz, CDCl ) δ
3
–
1 1
(
H
13NO
3
1.09 – 1.14 (m, 18 H), 1.33 (quin, J = 7.6 Hz, 3 H), 1.64 (dd,
J = 6.6, 0.9 Hz, 6 H), 2.32 (s, 3 H), 3.62 (d, J = 6.0 Hz, 2 H),
4.97 (tt, J = 6.3, 1.3 Hz, 1 H), 7.05 (d, J = 8.2 Hz, 1 H), 7.31
(d, J = 8.2 Hz, 1 H). C{ H} NMR and DEPT (126 MHz,
CDCl ) δ 14.4 (3 CH), 18.1 (6 CH ), 18.6 (2 CH ), 25.5 (CH ),
25.6 (CH ), 117.4 (CH), 121.2 (CH), 127.3 (C), 128.5 (CH),
133.6 (C), 134.0 (C), 149.8 (C), 153.9 (C). ESIMS (+25 V)
m/z 378.6 [M+H] , 395.4 [M+NH
Si: C 66.80, H 9.34, N 3.71. Found: C 67.11, H
9.67, N 3.67.
(R)-2-(2-Hydroxypropan-2-yl)-7-methyl-4-nitro-2,3-
dihydrobenzofuran (15). Nitrobenzene 16 (1.48 g, 3.92
mmol), ketone 14 (758 mg, 2.51 mmol, 64 mol%) and
Bu NHSO (50.1 mg, 0.15 mmol, 3.8 mol%) were dissolved
4 4
in a mixture of dimethoxymethane and acetonitrile (2:1, 69
mL) under air. After cooling the mixture to 0 °C, a buffer
solution (40 mL, 0.1 M K
added. Under vigorous stirring, an aqueous 1.47 M solution
of KOH (23 mL) and a solution of Oxone (5.78 g, 18.8 mmol,
4.8 equiv) in aqueous Na EDTA (40 mL, 4 ∙ 10 M) were
2
added via two different needles by syringe pump over 2 h.
Subsequently, the reaction was stirred at 0 °C for two
2
Methylbut-3-yn-2-yl)oxy)-4-nitrotoluene (11) (6.14 g, 28.0
mmol) was dissolved in ethyl acetate (120 mL) and Lindlar
catalyst (614 mg, 10 wt%) as well as quinoline (9.8 mL, 83.4
mmol, 3.0 equiv) were added. The reaction mixture was
stirred under a hydrogen atmosphere (1 atm) at room
temperature. The reaction was completed after 1 h as
13
1
3
3
3
2
3
+
+
4
] . Anal. Calcd. for
®
indicated by TLC. After filtration over Celite (ethyl acetate),
21 3
C H35NO
the organic phase was washed three times with 2 M HCl,
3
three times with sat. aq. NaHCO , with brine and was then
dried (MgSO ). Evaporation of the solvent and purification of
4
the crude product by column chromatography (silica gel;
isohexane/ethyl acetate, 9:1) provided 2-((2-methylbut-3-en-
2
-yl)oxy)-4-nitrotoluene (12) (5.38 g, 24.3 mmol, 87% yield)
1
as a red liquid. H NMR (600 MHz, CDCl
.29 (s, 3 H), 5.25 – 5.31 (m, 2 H), 6.13 (dd, J = 17.7, 10.9
Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.72 (dd, J = 8.3, 2.3 Hz,
3
) δ 1.54 (s, 6 H),
2
2 3
CO in water and 0.08 M HOAc) was
13
1
®
1
H), 7.89 (d, J = 2.3 Hz, 1 H). C{ H} NMR and DEPT (151
MHz, CDCl ) δ 17.4 (CH ), 27.3 (2 CH ), 80.9 (C), 112.7
(CH), 114.8 (CH ), 116.2 (CH), 130.7 (CH), 138.1 (C), 143.5
CH), 146.6 (C), 155.0 (C). ESIMS (–50 V) m/z 219.8 [M–H]
-
4
3
3
3
2
–
(
5
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
additional hours, quenched by addition of a sat. aq. NH
solution and the layers were separated. The aqueous layer
was extracted three times with ethyl acetate, the combined
4
Cl
added over a period of 1 h. The mixture was transferred to a
separatory funnel (EtOAc) and washed four times with brine.
The organic layer was dried over MgSO and the solvent was
removed. Purification of the residue by column
chromatography (silica gel; isohexane/ethyl acetate, 5:1 to
5:2) afforded the dihydrobenzofuran rac-15 (4.53 g, 19.1
mmol, 96% yield over 2 steps) as a yellow oil. The further
analytical data are in full agreement with those of 15.
4
organic layers were washed with brine, and dried (MgSO
4
).
Evaporation of the solvent afforded the corresponding
epoxide as crude product, which was used in the following
reaction without further purification. The crude epoxide (1.72
g) was dissolved in THF (90 mL), the solution was cooled to
0 °C, and tetra-n-butylammonium fluoride (9 mL, 9 mmol, 1
M in THF) was added over a period of 1 h. The mixture was
transferred to a separatory funnel (EtOAc) and washed four
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R)-4-Amino-2-(2-hydroxypropan-2-yl)-7-methyl-2,3-
dihydrobenzofuran (7). Dihydrobenzofuran 15 (765 mg, 3.22
mmol) was dissolved in ethyl acetate (70 mL) and
platinum(IV) oxide (70.6 mg, 0.31 mmol, 10 mol%) was
added. The mixture was stirred overnight under a hydrogen
atmosphere (1 atm). Complete conversion was monitored by
times with brine. The organic layer was dried over MgSO
4
and the solvent was evaporated. Purification of the crude
product by column chromatography (silica gel;
isohexane/ethyl acetate, 5:1 to 5:2) provided the
dihydrobenzofuran 15 (891 mg, 3.75 mmol, 96% yield over
TLC, the reaction mixture was filtered over a short pad of
®
Celite
(EtOAc), and the solvent was evaporated.
2
steps, >99.9% ee as determined by chiral HPLC) as yellow
Purification of the crude product by column chromatography
(silica gel; isohexane/ethyl acetate, 1:2) provided the
arylamine 7 (605 mg, 2.92 mmol, 91% yield) as a light brown
2
0
crystals; mp: 101 – 104 °C. [α]
D
–39.9 (c 1.0, MeOH). UV
(MeOH) λmax 218, 243, 284, 346 nm. IR (ATR) ν 3541, 2971,
2
0
2
1
926, 2863, 1600, 1508, 1340, 1312, 1207, 1150, 1124,
oil. [α]
D
–62.7 (c 1.0, MeOH). UV (MeOH) λmax 211, 289
–1
1
057, 1037, 978, 935, 817, 744 cm . H NMR (600 MHz,
) δ 1.25 (s, 3 H), 1.38 (s, 3 H), 1.81 (br s, 1 H), 2.29 (s,
3 H), 3.64 (m, J = 9.4 Hz, 2 H), 4.71 (dd, J = 9.4, 8.7 Hz, 1
nm. IR (ATR) ν 3346, 2974, 2929, 2056, 2030, 2009, 1638,
CDCl
3
1604, 1571, 1502, 1458, 1434, 1323, 1200, 1170, 1151,
–
1
1
1124, 1055, 969, 937, 862, 793 cm . H NMR (600 MHz,
CDCl ) δ 1.22 (s, 3 H), 1.35 (s, 3 H), 2.12 (s, 3 H), 2.96 (dd,
J = 9.0, 4.1 Hz, 2 H), 3.43 (br s, 2 H), 4.62 (t, J = 9.0 Hz, 1
1
3
1
H), 7.06 – 7.10 (m, 1 H), 7.63 (d, J = 8.3 Hz, 1 H). C{ H}
NMR and DEPT (151 MHz, CDCl ) δ 15.8 (CH ), 24.2 (CH ),
), 71.9 (C), 89.9 (CH), 116.1 (CH),
23.7 (C), 126.7 (C), 130.1 (CH), 143.5 (C), 159.6 (C). EIMS
3
3
3
3
1
3
1
2
1
6.2 (CH
3
), 32.8 (CH
2
H), 6.16 (d, J = 7.9 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H). C{ H}
NMR and DEPT (151 MHz, CDCl ) δ 14.7 (CH ), 24.1 (CH ),
26.3 (CH ), 28.6 (CH ), 72.0 (C), 89.1 (CH), 107.7 (CH),
3
3
3
+
m/z 237 (10) [M] , 162 (77), 131 (64), 59 (100), 43 (61). Anal.
Calcd. for C12 : C 60.75, H 6.37, N 5.90. Found: C
60.72, H 6.39, N 5.71.
Crystallographic data for the dihydrobenzofuran 15:
C
×
3
2
H15NO
4
109.8 (C), 111.4 (C), 130.1 (CH), 141.0 (C), 158.6 (C). EIMS
+
m/z 207 (36) [M] , 174 (24), 148 (100), 133 (27), 120 (45).
+
HRMS m/z [M] calcd for C12
H
17NO
2
: 207.1259. Found:
–
1
12
H15NO
4
; M = 237.25 g mol ; crystal size: 0.368 × 0.104
207.1254.
0.090 mm; orthorhombic; space group: P2 ; a =
1
2
1
2
1
(S)-4-Amino-2-(2-hydroxypropan-2-yl)-7-methyl-2,3-
dihydrobenzofuran (ent-7). Starting from the corresponding
dihydrobenzofuran ent-15, the same procedure as described
8
1
.48940(10) Å, b = 11.0722(2) Å, c = 12.8612(2) Å; V =
208.91(3) Å ; Z = 4; ρcalcd. = 1.304 g cm ; μ = 0.820 mm ;
3
–3
–1
20
λ = 1.54178 Å; T = 198(2) K; θ range = 5.271–68.218°;
reflections collected: 14656; independent reflections: 2207
(Rint = 0.0243); 162 parameters. The structure was solved by
for 7 afforded ent-7 (96% yield) as a light brown oil. [α]
D
=
+66.0 (c 1.0, MeOH). The further analytical data are in full
agreement with those of 7.
2
direct methods and refined by full-matrix least squares on F ;
rac-4-Amino-2-(2-hydroxypropan-2-yl)-7-methyl-2,3-
dihydrobenzofuran (rac-7). Starting from the corresponding
dihydrobenzofuran rac-15, the same procedure as described
for 7 afforded rac-7 (96% yield) as a light brown oil. The
further analytical data are in full agreement with those of 7.
(R)-2-(7-Methyl-4-((3-
final R indices [I > 2σ(I)]: R
1 2
= 0.0276, wR = 0.0763; maximal
–
3
residual electron density: 0.173 e Å ; absolute structure
3
6
(
Flack parameter) : χ = 0.09(3). CCDC 1866291 contains
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Center.
((triisopropylsilyl)oxy)phenyl)amino)-2,3-dihydrobenzo-
furan-2-yl)propan-2-ol (5). The arylamine 7 (128 mg, 0.62
mmol, 1.12 equiv), cesium carbonate (237 mg, 0.73 mmol,
1.33 equiv), palladium(II) acetate (7.2 mg, 0.032 mmol, 6
mol%), and rac-BINAP (38.3 mg, 0.062 mmol, 12 mol%)
were dissolved in toluene (12 mL) and heated to 110 °C.
Then, a solution of 3-bromophenyl triisopropylsilyl ether (6)
(180 mg, 0.55 mmol, 1.0 equiv) in toluene (4.5 mL) was
added dropwise to the refluxing mixture. The reaction
mixture was stirred at 110 °C overnight and subsequently
(
S)-2-(2-Hydroxypropan-2-yl)-7-methyl-4-nitro-2,3-
dihydrobenzofuran (ent-15). Using the corresponding ketone
ent-14 as catalyst, the same procedure as described for 15
afforded ent-15 (99% yield over 2 steps, >99.9% ee as
determined by chiral HPLC) as yellow crystals; mp: 101 –
20
1
02 °C. [α]
D
+41.5 (c 1.0, MeOH). The further analytical
data are in full agreement with those of 15.
rac-2-(2-Hydroxypropan-2-yl)-7-methyl-4-nitro-2,3-
dihydrobenzofuran (rac-15). Nitrobenzene 16 (7.51 g, 19.9
mmol) was dissolved in chloroform (120 mL) under air and
®
filtered through a short pad of Celite (EtOAc). Evaporation
an aq. solution of NaHCO
mixture was cooled to 0 °C and 3-chloroperoxybenzoic acid
mCPBA, 4.10 g, 23.8 mmol, 1.2 equiv) was slowly added in
3
(40 mL, 0.5 M) was added. The
of the solvent and purification of the residue by column
chromatography (silica gel; isohexane/ethyl acetate, 5:1)
provided the diarylamine 5 (231 mg, 0.507 mmol, 93% yield)
(
2
0
small portions. After stirring for 1.5 h at room temperature,
water was added to the mixture at 0 °C, the layers were
separated, and the organic phase was washed with a sat.
as a light brown oil. [α]
D
–56.7 (c 1.0, MeOH). UV (MeOH)
λ
max 215, 282 nm. IR (ATR) ν 3528, 3366, 2971, 2941, 2865,
1600, 1519, 1499, 1464, 1333, 1283, 1189, 1151, 1119,
–
aq. Na
2
S
2
O
3
solution, a sat. aq. NaHCO
3
solution, water, and
1064, 1047, 986, 940, 883, 864, 834, 799, 771, 684, 641 cm
1
1
brine. Drying (MgSO
4
) and subsequent evaporation of the
3
. H NMR (600 MHz, CDCl ) δ 1.09 (d, J = 7.2 Hz, 18 H),
solvent provided the racemic epoxide as a red oil, which was
used for the following transformation without further
purification. The crude epoxide (7.53 g) was dissolved in
THF (450 mL), the solution was cooled to 0 °C, and tetra-n-
butylammonium fluoride (45 mL, 45 mmol, 1 M in THF) was
1.21 (s, 3 H), 1.24 (spt, J = 7.9 Hz, 3 H), 1.33 (s, 3 H), 1.93
(s, 1 H), 2.17 (s, 3 H), 2.99 (d, J = 9.0 Hz, 2 H), 4.61 (t, J =
9.0 Hz, 1 H), 5.27 (s, 1 H), 6.42 (ddd, J = 7.9, 2.3, 1.1 Hz, 1
H), 6.49 (t, J = 1.9 Hz, 1 H), 6.51 (ddd, J = 7.9, 2.3, 0.8 Hz,
1 H), 6.64 (d, J = 8.3 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 7.06
6
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The Journal of Organic Chemistry
1
2
(t, J = 7.9 Hz, 1 H). 13C{ H} NMR and DEPT (151 MHz,
CDCl ) δ 12.8 (3 CH), 14.9 (CH ), 18.1 (6 CH ), 24.0 (CH ),
6.2 (CH ), 29.5 (CH ), 72.0 (C), 89.2 (CH), 109.2 (CH),
1
the same procedure as described for 17 afforded rac-17
(72% yield) as a light brown solid; mp: 200 – 202 °C. The
further analytical data are in full agreement with those of 17.
(R)-2-(2-Hydroxypropan-2-yl)-8-((triisopropylsilyl)oxy)-
1,2-dihydro-10H-furo[3,2-a]carbazole-4-carbaldehyde (18).
The carbazole 17 (50.3 mg, 0.11 mmol) was dissolved in a
mixture of methanol, THF, and water (20 mL, 16:3:1) under
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
3
3
3
2
1
1
1
3
2
10.5 (CH), 111.1 (CH), 112.3 (CH), 113.1 (C), 116.6 (C),
29.92 (CH), 129.94 (CH), 137.5 (C), 144.8 (C), 157.2 (C),
58.9 (C). EIMS m/z 455 (100) [M ], 412 (22), 396 (50). Anal.
+
Calcd. for C27
71.47, H 9.34, N 3.06.
3
H41NO Si: C 71.16, H 9.07, N 3.07. Found: C
air
and
cooled
to
–15
°C.
2,3-Dichloro-5,6-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(S)-2-(7-Methyl-4-((3-
dicyanobenzoquinone (DDQ, 84.1 mg, 0.37 mmol, 3.3 equiv)
was added in small portions and the resulting mixture was
stirred at –15 °C for 20 min. The mixture was diluted with
diethyl ether, washed three times with 2 M NaOH, and then
(
(triisopropylsilyl)oxy)phenyl)amino)-2,3-dihydrobenzo-
furan-2-yl)propan-2-ol
(ent-5).
Starting
from
the
corresponding arylamine ent-7, the same procedure as
described for 5 afforded ent-5 (83% yield) as a light brown
+57.0 (c 1.0, MeOH). The further analytical data
are in full agreement with those of 5.
4
with brine. The organic layer was dried over MgSO and the
20
oil. [α]
D
solvent was evaporated. Purification of the residue by
column chromatography (silica gel; isohexane/ethyl acetate,
5:1 to 2:1) provided the aldehyde 18 (29.9 mg, 0.06 mmol,
58% yield) as a bright yellow solid; mp: >230 °C (decomp.).
rac-2-(7-Methyl-4-((3-
(
(triisopropylsilyl)oxy)phenyl)amino)-2,3-dihydrobenzo-
furan-2-yl)propan-2-ol (rac-5). Starting from
corresponding arylamine rac-7, the same procedure as
described for 5 afforded rac-5 (95% yield) as a light brown
solid; mp: 97 – 98 °C. The further analytical data are in full
agreement with those of 5.
(R)-2-(2-Hydroxypropan-2-yl)-4-methyl-8-
(triisopropylsilyl)oxy)-1,2-dihydro-10H-furo[3,2-a]carbazole
17). A mixture of the diarylamine 5 (101 mg, 0.22 mmol),
palladium(II) acetate (2.6 mg, 0.01 mmol, 4.5 mol%),
copper(II) acetate (101.4 mg, 0.56 mmol, 2.5 equiv), and
acetic acid (1 mL) was heated to 130 °C under air for 15 min
in a sealed vessel using a microwave reactor. Then, another
portion of palladium(II) acetate (2.6 mg, 0.01 mmol, 4.5
mol%) was added and the mixture was stirred at 130 °C for
additional 15 min. The mixture was cooled to room
temperature, diluted with diethyl ether, and washed three
times with a sat. aq. solution of potassium carbonate.
Subsequently, the aqueous layer was extracted with diethyl
ether. The combined organic layers were washed with brine,
2
0
the
[α]
D
–26.5 (c 0.8, MeOH). UV (MeOH) λmax 236, 252, 301,
324 (sh), 346 nm. Fluorescence (MeOH) λex 301 nm, λem
348, 526 nm. IR (ATR) ν 3198, 2942, 2866, 1665, 1623,
1592, 1504, 1466, 1444, 1325, 1224, 1158, 1075, 995, 964,
–1
1
3
884, 834, 804, 679, 636 cm . H NMR (500 MHz, CDCl ) δ
1.12 (d, J = 7.3 Hz, 18 H), 1.26 – 1.33 (m, 6 H), 1.44 (s, 3 H),
2.03 (br s, 1 H), 3.26 (dd, J = 14.8, 9.5 Hz, 1 H), 3.35 (dd, J
= 14.8, 8.5 Hz, 1 H), 4.90 (dd, J = 9.5, 8.5 Hz, 1 H), 6.82 (dd,
J = 8.4, 2.0 Hz, 1 H), 6.88 (d, J = 1.9 Hz, 1 H), 7.78 (d, J =
8.2 Hz, 1 H), 7.88 (br s, 1 H), 8.21 (s, 1 H), 10.28 (s, 1 H).
(
(
13
1
C{ H} NMR and DEPT (126 MHz, CDCl
3
) δ 12.9 (3 CH),
18.1 (6 CH ), 24.6 (CH ), 26.3 (CH ), 27.9 (CH
3
3
3
2
), 71.9 (C),
91.5 (CH), 102.1 (CH), 107.5 (C), 114.2 (C), 114.4 (CH),
118.1 (C), 118.9 (CH), 119.5 (C), 120.8 (CH), 141.1 (C),
141.7 (C), 155.4 (C), 161.2 (C), 188.4 (CHO). ESIMS (+25
+
–
V) m/z 468.4 [M+H] ; ESIMS (–75 V) m/z 466.0 [M–H] . Anal.
Calcd. for C27 Si: C 69.34, H 7.97, N 2.99. Found: C
69.35, H 8.17, N 2.94.
H
37NO
4
(S)-2-(2-Hydroxypropan-2-yl)-8-((triisopropylsilyl)oxy)-
1,2-dihydro-10H-furo[3,2-a]carbazole-4-carbaldehyde (ent-
18). Starting from the corresponding carbazole ent-17, the
same procedure as described for 18 afforded ent-18 (60%
4
dried (MgSO ), and the solvent was evaporated. Purification
of the residue by column chromatography (silica gel;
isohexane/ethyl acetate, 5:1) provided the carbazole 17 (71
mg, 0.16 mmol, 71% yield) as a light brown solid; mp: 202 –
–53.2 (c 1.0, MeOH). UV (MeOH) λmax 213,
40, 266, 312, 325 nm. Fluorescence (MeOH) λex 240 nm,
em 353 nm. IR (ATR) ν 3576, 3373, 2942, 2864, 1621, 1497,
452, 1389, 1322, 1276, 1238, 1205, 1171, 1152, 1125,
1069, 970, 956, 884, 832, 805, 715, 688, 648 cm . H NMR
3
500 MHz, CDCl ) δ 1.11 – 1.13 (m, 18 H), 1.26 (s, 3 H), 1.29
dq, J = 14.9, 7.3 Hz, 3 H), 1.40 (s, 3 H), 2.00 (s, 1 H), 2.35
s, 3 H), 3.30 (td, J = 7.3, 0.9 Hz, 2 H), 4.74 (t, J = 8.7 Hz, 1
2
0
yield) as a bright yellow solid; mp: >230 °C (decomp.). [α]
D
2
0
2
2
03.5 °C. [α]
D
+22.1 (c 1.0, MeOH). The further analytical data are in full
agreement with those of 18.
λ
rac-2-(2-Hydroxypropan-2-yl)-8-((triisopropylsilyl)oxy)-
1,2-dihydro-10H-furo[3,2-a]carbazole-4-carbaldehyde (rac-
18). Starting from the corresponding carbazole rac-17, the
same procedure as described for 18 afforded rac-18 (57%
yield) as a light brown solid; mp: 221 – 224 °C. The further
analytical data are in full agreement with those of 18.
Furoclausine-B (4). The aldehyde 18 (97.4 mg, 0.21
mmol) was dissolved in THF (25 mL). Then, water (0.01 mL)
was added, the mixture was cooled to –10 °C, and TBAF
(0.33 mL, 1 M in THF, 1.6 equiv) was added dropwise. After
20 min, another portion of TBAF (0.33 mL, 1 M in THF, 1.6
equiv) was added and stirring was continued at –10 °C for
additional 20 min. The reaction mixture was diluted with
diethyl ether and transferred to a separatory funnel. Brine
was added, the layers were separated, and the organic layer
was washed twice with brine. The combined aqueous layers
were extracted with diethyl ether and the combined organic
1
–
1 1
(
(
(
H), 6.76 (dd, J = 8.0, 1.4 Hz, 1 H), 6.87 (d, J = 1.9 Hz, 1 H),
13
1
7
.52 (s, 1 H), 7.56 (s, 1 H), 7.71 (d, J = 8.5 Hz, 1 H). C{ H}
NMR and DEPT (126 MHz, CDCl ) δ 12.8 (3 CH), 15.7
(CH ), 18.1 (6 CH ), 24.2 (CH ), 26.3 (CH ), 29.1 (CH ), 72.1
(C), 89.4 (CH), 101.7 (CH), 106.5 (C), 112.3 (C), 113.1 (CH),
18.1 (C), 118.4 (C), 119.6 (CH), 119.8 (CH), 135.1 (C),
40.9 (C), 154.1 (C), 157.1 (C). ESIMS (+25 V) m/z 454.5
3
3
3
3
3
2
1
1
+
+
–
[
.
M+H] , 924.0 [2M+NH
Anal. Calcd. for C27
4
] ; ESIMS (–75 V) m/z 452.3 [M–H]
Si: C 71.48, H 8.66, N 3.09.
H
39NO
3
Found: C 71.67, H 9.06, N 3.06.
(S)-2-(2-Hydroxypropan-2-yl)-4-methyl-8-
((triisopropylsilyl)oxy)-1,2-dihydro-10H-furo[3,2-a]carbazole
ent-17). Starting from the corresponding diarylamine ent-5,
the same procedure as described for 17 afforded ent-17
69% yield) as a light brown solid; mp: 201 – 202 °C. [α]
D
57.6 (c 1.0, MeOH). The further analytical data are in full
agreement with those of 17.
rac-2-(2-Hydroxypropan-2-yl)-4-methyl-8-
((triisopropylsilyl)oxy)-1,2-dihydro-10H-furo[3,2-a]carbazole
4
layers were dried over MgSO . Removal of the solvent,
(
purification of the residue by column chromatography (silica
gel; isohexane/ethyl acetate/methanol, 30:70:1), and
subsequent filtration through cotton provided furoclausine-B
(4) (58.7 mg, 0.19 mmol, 91% yield, >99.5% ee as
determined by chiral HPLC) as a bright yellow solid; mp:
2
0
(
+
2
0
4
>220 °C (decomp.). [α]
D
D
–34.4 (c 1.1, MeOH) (ref. : [α] –
32.73, c 0.022, MeOH). UV (MeOH) λmax 236, 242 (sh), 252,
300, 322 (sh), 344 nm. Fluorescence (MeOH) λex 300 nm,
(
rac-17). Starting from the corresponding diarylamine rac-5,
7
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λ
em 346, 542 nm. IR (ATR) ν 3198, 2942, 2866, 1665, 1623,
Biologically Active Carbazole Alkaloids. Chem. Rev.
2012, 112, 3193–3328.
1592, 1504, 1466, 1444, 1325, 1224, 1158, 1075, 995, 964,
8
d
–
1 1
84, 834, 804, 679, 636 cm . H NMR (600 MHz, acetone-
) δ 1.28 (s, 3 H), 1.35 (s, 3 H), 3.35 – 3.45 (m, 2 H), 3.77
(3)
(4)
Ito, C.; Furukawa, H. New Carbazole Alkaloids from
Murraya euchrestifolia Hayata. Chem. Pharm. Bull.
1990, 38, 1548–1550.
Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Pyrano- and
Furocarbazole Alkaloids from the Root Bark of
Clausena excavata. Heterocycles 1997, 45, 969–
973.
Macías V., V. E.; Coy B., E. D.; Cuca, L. E. Novel
Furocarbazole Alkaloids and Antibacterial Activity of
Ethanol Extract from Zanthoxylum fagara (L.)
Sargent. Rev. Colomb. Quím. 2010, 39, 333–341.
Khan, D.; Khan, S.; Badshah, S.; Ali, H.; Ullah, H.;
Muhammad, Z.; Woodward, S. New Furocarbazole
Alkaloids from Lonicera quinquelocularis. Nat. Prod.
Res. 2016, 30, 74–78.
(a) Knölker, H.-J.; Fröhner, W. First Total Synthesis
of Furostifoline. Tetrahedron Lett. 1996, 37, 9183–
9186. (b) Knölker, H.-J.; Fröhner, W. Convergent
Iron-Mediated Syntheses of the Furo[3,2-
a]carbazole Alkaloid Furostifoline. Synthesis 2000,
2131–2136.
Knölker, H.-J.; Krahl, M. P. First Total Synthesis of
Furoclausine-A. Synlett 2004, 528–530.
Krahl, M. P.; Schmidt, A. W.; Knölker, H.-J. Iron-
Mediated Total Synthesis of Furoclausine-A.
Heterocycles 2012, 86, 357–370.
Forke, R.; Krahl, M. P.; Krause, T.; Schlechtingen,
G.; Knölker, H.-J. First Total Synthesis of Methyl 6-
Methoxycarbazole-3-carboxylate, Glycomaurrol, the
Anti-TB Active Micromeline, and the Furo[2,3-
c]carbazole Alkaloid Eustifoline-D. Synlett 2007,
6
(
s, 1 H), 4.92 (dd, J = 9.5, 7.9 Hz, 1 H), 6.76 (dd, J = 8.2, 2.2
Hz, 1 H), 6.90 (d, J = 2.2 Hz, 1 H), 7.88 (d, J = 8.2 Hz, 1 H),
.13 (s, 1 H), 8.44 (br s, 1 H), 10.26 (s, 1 H), 10.34 (br s, 1
8
1
3
1
H). C{ H} NMR and DEPT (151 MHz, acetone-d
(CH ), 26.0 (CH ), 28.5 (CH ), 71.6 (C), 92.3 (CH), 108.87
CH), 108.92 (CH), 114.5 (C), 117.0 (CH), 117.7 (C), 117.8,
6
) δ 25.8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
2
(
1
(5)
(6)
(7)
20.1 (C), 121.6 (CH), 142.3 (C), 143.6 (C), 143.8 (C), 162.6
+
(C), 187.7 (CHO). ESIMS (+10 V) m/z 312.2 [M+H] ; ESIMS
–
(
6
–25 V) m/z 309.9 [M–H] . Anal. Calcd. for C18
9.44 H, 5.50, N 4.50. Found: C 69.56, H 5.73, N 4.43.
ent-Furoclausine-B (ent-4). Starting from
H17NO
4
: C
the
corresponding aldehyde ent-18, the same procedure as
described for 4 afforded ent-4 (90% yield, >99.5% ee as
determined by chiral HPLC) as a bright yellow solid; mp:
2
0
>
220 °C (decomp.). [α]
analytical data are in full agreement with those of 4.
rac-Furoclausine-B (rac-4). Starting from
D
+33.9 (c 1.0, MeOH). The further
the
corresponding aldehyde rac-18, the same procedure as
described for 4 afforded rac-4 (87% yield) as a bright yellow
solid; mp: >220 °C (decomp.). The further analytical data are
in full agreement with those of 4.
(8)
(9)
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of all compounds;
(10)
chromatograms (chiral HPLC) of 15, ent-15, rac-15, 4,
ent-4, and rac-4; details of the X-ray crystal structure
determination of 15 (PDF). Crystallographic structure
file for 15 (CIF). The Supporting Information is
available free of charge on the ACS Publications
website at DOI:
2
68–272.
(11)
Fröhner, W.; Krahl, M. P.; Reddy, K. R.; Knölker, H.-
J. Synthetic Routes to Naturally Occurring
Furocarbazoles. Heterocycles 2004, 63, 2393–
2407.
Lebold, T. P.; Kerr, M. A. Total Synthesis of
Eustifolines A–D and Glycomaurrol via a Divergent
Diels–Alder Strategy. Org. Lett. 2007, 9, 1883–1886.
Brütting, C; Hesse, R.; Jäger, A.; Kataeva, O.;
Schmidt, A. W.; Knölker, H.-J. Synthesis of
Glycoborine, Glybomine A and B, the Phytoalexin
Carbalexin A and the β-Adrenoreceptor Antagonists
Carazolol and Carvedilol. Chem. Eur. J. 2016, 22,
(
12)
13)
AUTHOR INFORMATION
Corresponding Author
(
*E-mail: hans-joachim.knoelker@tu-dresden.de
ORCID
Hans-Joachim Knölker: 0000-0002-9631-5239
Notes
The authors declare no competing financial interest.
1
6897–16911.
(14)
(a) Murci, A. R.; Buchwald, S. L. Practical Palladium
Catalysts for C-N and C-O Bond Formation. Top.
Curr. Chem. 2002, 219, 131–209. (b) Surry, D. S.;
Buchwald, S. L. Biaryl Phosphane Ligands in
Palladium-Catalyzed Amination. Angew. Chem. Int.
Ed. 2008, 47, 6338–6361. (c) Ruiz-Castillo, P.;
Buchwald, S. L. Applications of Palladium-Catalyzed
C–N Cross-Coupling Reactions. Chem. Rev. 2016,
ACKNOWLEDGEMENT
We thank Jakob Reimann for experimental support.
1
16, 12564–12649.
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