Modified Julia-Kocienski Reagents for a Stereoselective Introduction of Trisubstituted Double Bonds: A Formal Total Synthesis of Limazepine e and Barmumycin

Article abstract of DOI:10.1021/acs.joc.8b00643

A formal total synthesis of pyrrolo[1,4]benzodiazepine anticancer antibiotic family member limazepine E is described. The synthesis features a stereoselective introduction of a trisubstituted double bond using novel sterically demanding Julia-Kocienski re

Full text of DOI:10.1021/acs.joc.8b00643

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Modified Julia-Kocienski reagents for a stereoselective
introduction of trisubstituted double bonds: a formal
total synthesis of Limazepine E and Barmumycin
Guna Sakaine, and Gints Smits
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00643 • Publication Date (Web): 11 Apr 2018
Downloaded from http://pubs.acs.org on April 11, 2018
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Modified JuliaꢀKocienski reagents for a stereoselective
introduction of trisubstituted double bonds: a formal total
synthesis of Limazepine E and Barmumycin
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Guna Sakaine and Gints Smits*
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, Latvia, LVꢀ1006
*gintssmits@osi.lv
N
N
Ph
N
Ph
N
N
N
SO2Et
MeO
OH
O
OH
OH
O
O
O
MeO
N
MeO
MeO
H
H
H
R
+
MeO2C
N
Julia-Kocienski
olefination
CO2H
N
N
N
H
O
trans-4-Hydroxy-L-proline
Isovanillic acid
O
O
O
Limazepine E
R= Ph
E-/Z- 89:11
97:3
E-/Z-
R
=
cHex
cHex
cHex
Abstract: A formal total synthesis of pyrrolo[1,4]benzodiazepine (PBD) anticancer
antibiotic family member Limazepine E is described. The synthesis features a
stereoselective introduction of trisubstituted double bond using novel sterically
demanding JuliaꢀKocienski reagents, allowing significantly reduce the number of
linear steps. The potential of the newly developed reagents has also been
demonstrated by the formal total synthesis of Barmumycin.
Limazepine E 6 was isolated in 2009 from Micrococus sp. strain ICBB 81771 and
belongs to a broad and expanding family of pyrrolo[1,4] benzodiazepine (PBD)
natural products. Many PBD class members posses anticancer activity owing to their
ability to covalently bind to the minor grove of DNA.2–4 A number of PBDs as well as
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their antibody drug conjugates (ADC) have been evaluated as anticancer agents and
are currently undergoing clinical trials.5
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Figure 1. Representative examples of PBD natural products containing C2
alkylidene group.
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Most PBDs possess a rightꢀhand twisted three ring system, furthermore several
naturally occurring PBD contain a C2 alkylidene group, some examples are shown in
Figure 1.1,6–9 Importantly, it has been shown that a C2 double bond significantly
increases the anticancer activity.10 Although total synthesis of Limazepine E11 6 and
several related (E)ꢀ2ꢀethylidene PBDs12–15 have been reported, a stereoselective
introduction of C2 alkylidene group still poses a considerable challenge. Moreover,
the classical olefination methods (Wittig and JuliaꢀKocienski) lack selectivity or give
the undesired Zꢀ isomer predominantly.12,16–18 An alternative method for an Eꢀ
selective introduction of trisubstituted double bond was introduced based on
stereoselective IrelandꢀClaisen rearrangement,11,19 however the desired 3ꢀ
ethylidenproline building block was obtained in a linear sequence of 9 steps. Herein,
we report a concise formal total synthesis of Limazepine E employing new sterically
demanding JuliaꢀKocienski reagents for a stereoselective introduction of C2
alkylidene substituent.
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Our retrosynthetic analysis (Scheme 1) was based on a late stage introduction of the
trisubstituted double bond, followed by selective C11 carbonyl reduction. The
prerequisite ketone 8 could be easily constructed from inexpensive and readily
available starting materials – isovanillic acid and transꢀ4ꢀhydroxyꢀLꢀproline, followed
by an oxidation of the intermediate dilactam 9.
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Scheme 1. Retrosynthetic analysis of Limazepine E
The synthesis started with conversion of isovanilic acid into the corresponding
nitrobenzoic acid 10 (Scheme 2). The latter was coupled with transꢀ4ꢀhydroxyꢀLꢀ
proline producing the intermediate 11 in a good yield.18 Hydrogenation of the amide
11, followed by treatment with benzaldehyde dimethyl acetal at elevated temperature
furnished the alcohol 12, which after oxidation gave the ketone 12 necessary for C2
olefination studies.
Scheme 2. The synthesis of ketone 13.
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With the ketone 13 in hand we began our studies for the stereoselective introduction
of the trisubstituted double bond at C2 position (Table 1).
Table 1. JuliaꢀKocienski reagent screening for the olefination of ketone 3.[a]
Entry
Sulfone 14
14a
Base
Yield
66%
16%
nr
E-/Z-
50:50[b]
55:45[b]
ꢀ
1
2
LiHMDS
NaHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
LiHMDS
3
4
13%
10%
nr
50:50[b]
50:50[b]
ꢀ
14b
14c
5
N
6
7
73%
67%
75%
63%
73:27[c]
80:20[c]
89:11[c]
56:44[c]
8
9
10
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14d
11
12
NaHMDS
KHMDS
53%
54%
77:23[c]
89:11[c]
N
N
N
N
6
tBu
o
7
8
[a] 13: 0.055 mmol, 14: 0.110 mmol, Base: 0.110 mmol, THF (0.3 mL), ꢀ78 C to rt.
[b] Determined by 1H NMR. [c] Determined by HPLC.
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Our previous studies18 determined the high potential of JuliaꢀKocienski
olefination20,21 for this transformation. In order to find the optimal olefination reagents
the classical benzothiazolyl sulfone 14a,22 2ꢀpiridyl sulfone 14b23 and tetrazole
sulfones24 14c25 and 14d were synthesized and subjected to olefination reaction with
the ketone 13 in the presence of three different bases ꢀ Li, Na and KHMDS (Table 1).
Whereas sulfones 14a and 14b (Entry 1 ꢀ 6) lack stereoselectivity and reactivity
(Yields 0 – 66%), the tetrazole sulfones 14c and 14d delivered the desired product 15
in 53% ꢀ 75% yield and good stereoselectivity using KHMDS as a base (Entry 9 and
12).
Table 2. Solvent screening[a]
Entry
Solvent
DMF
Yield
53%
10%
34%
44%
E-/Z- [a]
77:26
84:16
89:11
60:40
1
2
3
4
DME
DCM
Toluene
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Et2O
24%
82:18
4
5
6
7
8
[a] 13: 0.055 mmol, 14d: 0.110 mmol, KHMDS: 0.110 mmol, Solvent (0.3 mL), ꢀ78
oC to rt. [b] Determined by HPLC
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In order to fineꢀtune the reaction conditions we further focused on the solvent
screening (Table 2). Out of five different solvents examined only DCM (entry 3)
delivered stereoselectivity comparable to the previously employed THF (Table 1,
entry 12), albeit accompanied by decrease in reactivity.
Next we speculated that the sterical effect of the JuliaꢀKocienski reagent 14 may have
a decisive impact on stereochemical outcome of the reaction. To verify this
hypothesis we synthesized several undescribed bulky JuliaꢀKocienski reagents and
subjected to the olefination reaction (Table 3).
Table 3. Alternative JuliaꢀKocienski reagent screening for the olefination of
ketone 13.[a]
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Entry
1
Sulfone 14
Yield
68%
E-/Z- [b]
14e
14f
14g
14h
14i
83:17
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iPr
2
3
4
5
6
7
67%
58%
nr
94:6
88:12
ꢀ
iPr
tBu
tBu
tBu
tBu
tBu
cPent
cPent
63%
60%
30%
95:5
97:3
88:12
cPent
cHex
cHex
14j
14k
cHex
Ph
Ph
Ph
[a] 13: 0.055 mmol, 14: 0.110 mmol, KHMDS: 0.110 mmol, THF (0.3 mL), ꢀ78 oC to
rt. [b] Determined by HPLC
To our delight, all sulfones except 14h produced the desired alkene 15 with a good
stereoselectivity. The lack of reactivity on the part of 14h was attributed to the
excessive sterical buildꢀup. The best result in olefination of ketone 13 was obtained
with (2,4,6ꢀtricyclohexylphenyl)ꢀtetrazole sulfone 14j (Entry 6) furnishing the desired
alkene 15 with Eꢀ/Zꢀ ratio as high as 97:3.
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With the dilactam 15 in hand, the total synthesis of Limazepine E 6 can be
accomplished in one step according to the published route.11 Importantly, the newly
developed methodology allows to obtain Limazepine E 6 in 9 steps (LLS) compared
to 12 steps previously reported11 and enables late stage modification of the C2
position.
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Our newly developed modification of JuliaꢀKocienski olefination was further applied
to on the formal total synthesis of Barmumycin 19 (Scheme 3).
Scheme 3. Formal total synthesis of Barmumycin 19.
The formal total synthesis was started with an oxidation of the literature known
prolinol derivative 1626 to give the desired ketone 17 in a high yield. Next, the Julia –
Kocienski olefination of the substrate 18 was examined with the newly developed
sulfone 14j and the classical 14c as a reference. Gratifyingly, 14j provided
significantly higher stereoselectivity (Eꢀ/Zꢀ 3:1) than 14c (Eꢀ/Zꢀ 2:1). The obtained
prolinole derivative 18 can be further converted into Barmumycin by a literature
known sequence.27
In summary, we have developed a new modification of JuliaꢀKocienski olefination
employing novel sterically demanding aryltetrazole sulfones for a stereoselective
introduction of trisubstituted double bonds. The superiority of these modified Juliaꢀ
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Kocienski reagents over the literature known sulfones has been demonstrated in the
formal total synthesis of Limazepine E 6 and Barmumycin 19. Further studies on the
scope of the described olefination are ongoing in our laboratory.
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Experimental Section
General Experimental Details. All reactions were performed under an atmosphere
of argon unless otherwise indicated. Reagents and starting materials were obtained
from commercial sources and used as received. The solvents were purified and dried
by standard procedures prior to use; petroleum ether of boiling range 60–80 °C was
used. Flash chromatography was carried out using Merck Kieselgel (230–400 mesh).
NMR spectra were recorded on Varian Mercury (400 MHz) and Bruker (300 MHz)
spectrometers. Chemical shift values are referenced against residual protons in the
deuterated solvents, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad). Infrared spectra were recorded in the range 4000ꢀ500 cmꢀ1 as a
film. HRMS were obtained on Micromass AutoSpec Ultima Magnetic sector mass
spectrometer (TOF). Optical rotations were measured using Perkin Elmer 141
polarimeter. Melting points were determined using Stanford Research System
MPA100 Automated Melting Point Apparatus and are uncorrected. Chromatographic
analysis were performed on Waters 2695 Separations Module (UV visible detector
Waters 2489), Chiralpak ICꢀ1 column (4.6 x 250 mm), 30% IPA/70% Hex, flow rate
1 mL/min.
(8R,9aS)ꢀ8ꢀhydroxyꢀ3ꢀmethoxyꢀ1ꢀphenylꢀ7,8,9,9aꢀtetrahydroꢀ1Hꢀ2ꢀoxaꢀ6a,10aꢀ
diazabenzo[cd]cyclopenta[g]azuleneꢀ6,10ꢀdione 12
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The title compound was prepared according the literature procedure starting from 10,
1.52 g (45% in 3 steps).18
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1H NMR 300 MHz, CDCl3: δ 7.57 (1H, d, J = 8.9 Hz), 7.32ꢀ7.46 (6H, m), 6.84 (1H,
d, J = 8.9 Hz), 4.53ꢀ4.59 (1H, m), 4.41 (1H, t, J = 7.7 Hz), 4.25 (1H, td, J = 12.7, 2.2
Hz), 3.97 (3H, s), 3.53 (1H, dd, J = 12.7, 4.0 Hz), 2.78ꢀ2.88 (1H, m), 2.25ꢀ2.35 (1H,
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13
m); C NMR 100 MHz, CDCl3: δ 169.4, 166.3, 146.7, 137.8, 136.5, 130.0, 128.9,
128.3, 126.0, 124.0, 113.7, 110.8, 95.5, 68.7, 58.0, 56.8, 54.9, 35.9; IR (film) 3397,
o
1685, 1636 cmꢀ1; m.p. 110ꢀ113 C; [α]D20 = 338.40 (c = 0.1, CHCl3); HRMS (+ESI)
calculated for C20H19N2O5 [M+H+] 367.1294 found 367.1295.
(9aS)ꢀ3ꢀmethoxyꢀ1ꢀphenylꢀ9,9aꢀdihydroꢀ1Hꢀ2ꢀoxaꢀ6a,10aꢀ
diazabenzo[cd]cyclopenta[g]azuleneꢀ6,8,10(7H)ꢀtrione 13
The title compound was prepared according the literature procedure from 12, 1.320 g
(82%).18
1H NMR 400 MHz, CDCl3: δ 7.63 (1H, d, J = 8.8 Hz), 7.34ꢀ7.46 (6H, m), 6.90 (1H,
d, J = 8.8 Hz), 4.68 (1H, dd, J = 10.7, 4.4 Hz), 4.49 (1H, d, J = 20.2 Hz), 4.00 (3H, s),
3.86 (1H, d, J = 20.2 Hz), 3.65 (1H, dd, J = 20.2, 4.4 Hz), 2.92 (1H, dd, J = 20.2, 10.7
Hz); 13C NMR 100 MHz, CDCl3: δ 206.8, 168.1, 165.9, 147.2, 137.9, 136.2, 130.2,
129.0, 128.2, 125.9, 124.2, 113.0, 111.3, 95.4, 56.8, 56.4, 53.4, 37.3; IR (film) 1762,
1694, 1635 cmꢀ1; m.p. 116ꢀ119 oC; [α]D20 = 403.20 (c = 0.1, CHCl3); HRMS (+ESI)
calculated for C20H17N2O5 [M+H+] 365.1137 found 365.1138.
1ꢀ(tertꢀButyl)ꢀ5ꢀ(ethylsulfonyl)ꢀ1Hꢀtetrazole 14d
14d was synthesized starting from commercially available tertꢀbutyl isothiocyanate.
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NaN3 (596 mg, 9.163 mmol, 1.00 equiv) was dissolved in H2O (4 mL) and heated up
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5
6
o
to 100 C. Then a solution of tertꢀbutyl isothiocyanate (1056 mg, 9.163 mmol, 1.00
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8
9
equiv) in iꢀPrOH (4 mL) was added dropwise and the reaction mixture was stirred for
4 h at this temperature followed by 16 h at room temperature. After that 1.4 mL of
conc. HCl was diluted with 4 mL of H2O and the resulting solution was added
dropwise to the reaction mixture. Volatiles were evaporated and the crude product
was partitioned between water and DCM. Organics were separated and aq. layer
extracted with DCM (3 x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo.
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The crude 1ꢀ(tertꢀbutyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved in EtOH (7 mL) and KOH
(615 mg, 10.995 mmol, 1.20 equiv) was added, the resulting mixture was stirred for
30 min at room temperature. After that EtBr (1572 mg, 10.079 mmol, 1.10 equiv) was
added dropwise and the stirring was continued for next 16 h at room temperature. The
reaction mixture was then evaporated and the crude product partitioned between water
and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The
combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in
vacuo.
The crude 1ꢀ(tertꢀbutyl)ꢀ5ꢀ(ethylthio)ꢀ1Hꢀtetrazole was dissolved in DCM (22 mL)
and NaHCO3 (3.848 g, 45.81 mmol, 5.00 equiv) was added followed by slow addition
of 70% mCPBA (6.79 g, 27.49 mmol, 3.00 equiv) under vigorous stirring. The
resulting slurry was stirred at room temperature for 16 h and then quenched by
addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture
was stirred vigorously for the next 2 h, then organics were separated and aqueous
phase extracted twice with DCM. The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column
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chromatography (Eluent: EtOAc/petroleum ether 0:1 ꢀ> 1:2). The title compound was
obtained as a yellowish solid (800 mg, 40% in 3 steps).
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1H NMR 400 MHz, CDCl3: δ 3.84 (2H, q, J = 7.4), 1.86 (9H, s), 1.55 (3H, t, J = 7.4);
13C NMR 100 MHz, CDCl3: δ 154.6, 65.4, 51.5, 29.6, 7.1; IR (film) 2997, 2933,
1329, 1158 cmꢀ1; HRMS (+ESI) calculated for C7H14N4O2NaS [M+Na] 241.0735
found 241.0732; m.p. 53 – 55 oC.
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1ꢀ((3s,5s,7s)ꢀAdamantanꢀ1ꢀyl)ꢀ5ꢀ(ethylsulfonyl)ꢀ1Hꢀtetrazole 14e
14e
was
synthesized
starting
from
commercially
available
1ꢀ
isothiocyanatoadamantane.
NaN3 (168 mg, 2.586 mmol, 1.00 equiv) was dissolved in H2O (1 mL) and heated up
o
to 100 C. Then a suspension of 1ꢀisothiocyanatoadamantane (500 mg, 2.586 mmol,
1.00 equiv) in iꢀPrOH (1 mL) was added dropwise and the reaction mixture was
stirred 4 h at this temperature followed by 16 h at room temperature. Additional NaN3
(168 mg, 2.586 mmol, 1.00 equiv), H2O (2 mL) and dioxane (2 mL) were added and
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the reaction mixture was stirred overnight at 100 C, then cooled. After that 0.35 mL
of conc. HCl was diluted with 1 mL H2O and the resulting solution was added
dropwise to the reaction mixture. Volatiles were evaporated, and the crude product
was partitioned between water and DCM. Organics were separated and aq. layer
extracted with DCM (3 x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo.
The crude 1ꢀ((3s,5s,7s)ꢀadamantanꢀ1ꢀyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved in EtOH
(15 mL) and KOH (189 mg, 3.362 mmol, 1.30 equiv) was added, the resulting
mixture was stirred for 30 min at room temperature. After that EtBr (338 mg, 3.104
mmol, 1.20 equiv) was added dropwise and the stirring was continued for next 16 h at
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room temperature. Additional KOH (145 mg, 2.586 mmol, 1.00 equiv) and EtBr (282
mg, 2.586 mmol, 1.00 equiv) were added and the reaction mixture was stirred for next
16 h at room temperature. The reaction mixture was then evaporated and the crude
product partitioned between water and DCM. Organics were separated and aq. layer
extracted with DCM (3 x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo.
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The crude 1ꢀ((3s,5s,7s)ꢀadamantanꢀ1ꢀyl)ꢀ5ꢀ(ethylthio)ꢀ1Hꢀtetrazole was dissolved in
DCM (15 mL) and NaHCO3 (1.09 g, 12.93 mmol, 5.00 equiv) was added followed by
slow addition of 70% mCPBA (1.91 g, 7.76 mmol, 3.00 equiv) under vigorous
stirring. The resulting slurry was stirred at room temperature for 16 h and then
quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained
biphasic mixture was stirred vigorously for the next 2 h, then organics were separated
and aqueous phase extracted twice with DCM. The combined organic extracts were
dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified
by flash column chromatography (Eluent: EtOAc/petroleum ether 1:9 ꢀ> 1:1). The
title compound was obtained as a white solid (435 mg, 57% in 3 steps).
H NMR 400 MHz, CDCl3: δ 3.84 (2H, q, J = 7.4), 2.48 (6H, d J = 3.1), 2.31 (3H, s),
1.75 – 1.85 (6H, m), 1.55 (3H, t, J = 7.4); 13C NMR 100 MHz, CDCl3: δ 153.9, 66.3,
51.7, 41.9, 35.6, 29.9, 7.30; IR (film) 2943, 2916, 1339 cmꢀ1; HRMS (+ESI)
calculated for C13H21N4O2S [M+H+] 297.1385 found 297.1371; m.p.104 – 107 oC.
1ꢀ(2,6ꢀDiisopropylphenyl)ꢀ5ꢀ(ethylsulfonyl)ꢀ1Hꢀtetrazole 14f
14f was synthesized starting from commercially available 1,3ꢀdiisopropylꢀ2ꢀ
isothiocyanatobenzene.
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NaN3 (299 mg, 4.582 mmol, 1.00 equiv) was dissolved in H2O (2 mL) and heated up
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4.582 mmol, 1.00 equiv) in iꢀPrOH (2 mL) was added dropwise and the reaction
mixture was stirred 4 h at this temperature followed by 16 h at room temperature.
After that 0.7 mL of conc. HCl was diluted with 2 mL H2O and the resulting solution
was added dropwise to the reaction mixture. Volatiles were evaporated and the crude
product was partitioned between water and DCM. Organics were separated and aq.
layer extracted with DCM (3 x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo.
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The crude 1ꢀ(2,6ꢀdiisopropylphenyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved in EtOH (6
mL) and KOH (308 mg, 5.498 mmol, 1.20 equiv) was added, the resulting mixture
was stirred for 30 min at room temperature. After that EtBr (549 mg, 5.040 mmol,
1.10 equiv) was added dropwise and the stirring was continued for next 16 h at room
temperature. The reaction mixture was then evaporated and the crude product
partitioned between water and DCM. Organics were separated and aq. layer extracted
with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered
and concentrated in vacuo.
The crude 1ꢀ(2,6ꢀdiisopropylphenyl)ꢀ5ꢀ(ethylthio)ꢀ1Hꢀtetrazole was dissolved in
DCM (20 mL) and NaHCO3 (1.92 g, 22.91 mmol, 5.00 equiv) was added, followed by
slow addition of 70% mCPBA (3.39 g, 13.75 mmol, 3.00 equiv) under vigorous
stirring. The resulting slurry was stirred at room temperature for 16 h and then
quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained
biphasic mixture was stirred vigorously for the next 2 h, then organics were separated
and aqueous phase was extracted twice with DCM. The combined organic extracts
were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was
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purified by flash column chromatography (Eluent: EtOAc/petroleum ether 0:1 ꢀ> 1:5
). The title compound was obtained as a beige solid (900 mg, 61% in 3 steps).
H NMR 400 MHz, CDCl3: δ 7.57 (1H, t, J = 7.8), 7.33 (2H, d J = 7.8), 3.71 (2H, q, J
= 7.4), 1.97 – 2.07 (2H, m), 1.52 (3H, t, J = 7.4), 1.24 (6H, d, J = 7.0), 1.08 (6H, d, J
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= 7.0); C NMR 100 MHz, CDCl3: δ 154.3, 146.2, 132.4, 128.6, 124.3, 50.7, 29.2,
25.3, 22.2, 6.9; IR (film) 2978, 2936, 1154 cmꢀ1; HRMS (+ESI) calculated for Cꢀ
15H22N4O2NaS [M+Na] 345.1361 found 345.1369; m.p. 90 – 93 oC.
1ꢀ(3,5ꢀDiꢀtertꢀbutylphenyl)ꢀ5ꢀ(ethylsulfonyl)ꢀ1Hꢀtetrazole 14g
14g was synthesized starting from commercially available 3,5ꢀdiꢀtertꢀbutylaniline.
To a solution of 3,5ꢀdiꢀtertꢀbutylaniline (230 mg, 1.12 mmol, 1.00 equiv) in DCM (6
mL) was added sat. aq. NaHCO3 (6 mL) and the resulting mixture was cooled to 0 oC.
After addition of thiophosgene (167 mg, 1.456 mmol, 1.30 equiv) the reaction mixture
was allowed to warm up to room temperature and vigorously stirred for next 5 h.
After that water was added, the organic layer separated and aq. layer extracted with
DCM (3x). The combined organic extracts were dried over anh. Na2SO4, filtered and
concentrated in vacuo. The crude 1,3ꢀdiꢀtertꢀbutylꢀ5ꢀisothiocyanatobenzene was used
in the next step without further purification.
NaN3 (146 mg, 2.240 mmol, 2.00 equiv) was dissolved in H2O (3 mL) and heated up
o
to 100 C. Then a solution of 1,3ꢀdiꢀtertꢀbutylꢀ5ꢀisothiocyanatobenzene (277 mg,
1.120 mmol, 1.00 equiv) in dioxane (3 mL) was added dropwise and the reaction
mixture was stirred 4 h at this temperature followed by 16 h at room temperature.
After that 0.2 mL of conc. HCl was diluted with 0.6 mL H2O and the resulting
solution was added dropwise to the reaction mixture. Volatiles were evaporated and
the crude product was partitioned between water and DCM. Organics were separated
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and aq. layer extracted with DCM (3 x). The combined organic extracts were dried
over anh. Na2SO4, filtered and concentrated in vacuo.
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The crude 1ꢀ(3,5ꢀdiꢀtertꢀbutylphenyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved in EtOH (7
mL) and KOH (144 mg, 2.576 mmol, 2.30 equiv) was added, the resulting mixture
was stirred for 30 min at room temperature. After that EtBr (268 mg, 2.464 mmol,
2.20 equiv) was added dropwise and stirring was continued for next 16 h at room
temperature. The reaction mixture was then evaporated and the crude product
partitioned between water and DCM. Organics were separated and aq. layer extracted
with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered
and concentrated in vacuo.
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The crude 1ꢀ(3,5ꢀdiꢀtertꢀbutylphenyl)ꢀ5ꢀ(ethylthio)ꢀ1Hꢀtetrazole was dissolved in
DCM (10 mL) and NaHCO3 (470 mg, 5.60 mmol, 5.00 equiv) was added followed by
slow addition of 70% mCPBA (828 mg, 3.36 mmol, 3.00 equiv) under vigorous
stirring. The resulting slurry was stirred at room temperature for 16 h and then
quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained
biphasic mixture was stirred vigorously for the next 2 h, then organics were separated
and aqueous phase extracted twice with DCM. The combined organic extracts were
dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified
by flash column chromatography (Eluent: EtOAc/petroleum ether 0:1 ꢀ> 1:9. The
title compound was obtained as a yellow solid (160 mg, 41% in 4 steps).
H NMR 400 MHz, CDCl3: δ 7.63 (1H, s), 7.54 (2H, s), 3.77 (2H, q, J = 7.4), 1.56
13
(3H, t, J = 7.4), 1.37 (18H, s); C NMR 100 MHz, CDCl3: δ 153.3, 153.0, 132.8,
125.3, 119.4, 51.0, 35.4, 31.4, 7.1; IR (film) 2965, 1341, 1153 cmꢀ1; HRMS (+ESI)
calculated for C17H26N4O2NaS [M+Na] 373.1674 found 373.1680; m.p. 55 – 57 oC.
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5ꢀ(Ethylsulfonyl)ꢀ1ꢀ(2,4,6ꢀtriꢀtertꢀbutylphenyl)ꢀ1Hꢀtetrazole 14h
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14h was synthesized starting from 1,3,5ꢀtriꢀtertꢀbutylꢀ2ꢀisothiocyanatobenzene.28
NaN3 (321 mg, 4.942 mmol, 5.00 equiv) was dissolved in H2O (3 mL), then 1,3,5ꢀtriꢀ
tertꢀbutylꢀ2ꢀisothiocyanatobenzene (300 mg, 0.988 mmol, 1.00 equiv) and dioxane (6
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mL) were added and the obtained mixture was stirred for 16 h at 150 C. After
cooling to ambient temperature, an aqueous solution of HCl (prepared from 0.5 mL of
conc. HCl and 1.5 mL of H2O) was added to the reaction mixture. Volatiles were
evaporated and the crude product was partitioned between water and DCM. Organics
were separated and aq. layer extracted with DCM (3 x). The combined organic
extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo.
The crude 1ꢀ(2,4,6ꢀtriꢀtertꢀbutylphenyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved in EtOH
(3 mL) and KOH (83 mg, 1.482 mmol, 1.50 equiv) was added, the resulting mixture
was stirred for 30 min at room temperature. After that EtBr (140 mg, 1.284 mmol,
1.30 equiv) was added dropwise and the stirring was continued for 16 h at room
temperature. Additional KOH (83 mg, 1.482 mmol, 1.50 equiv) and EtBr (140 mg,
1.284 mmol, 1.30 equiv) were added and the reaction mixture was stirred for 4 h at
room temperature. The reaction mixture was then evaporated and the crude product
partitioned between water and DCM. Organics were separated and aq. layer extracted
with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered
and concentrated in vacuo.
The residue was purified by flash column
chromatography using petroleum ether and EtOAc as eluents. 212 mg (57% in 2
steps) of 5ꢀ(ethylthio)ꢀ1ꢀ(2,4,6ꢀtriꢀtertꢀbutylphenyl)ꢀ1Hꢀtetrazole were isolated.
The 5ꢀ(ethylthio)ꢀ1ꢀ(2,4,6ꢀtriꢀtertꢀbutylphenyl)ꢀ1Hꢀtetrazole (212 mg, 0.566 mmol,
1.00 equiv) was dissolved in DCM (10 mL) and NaHCO3 (238 mg, 2.830 mmol, 5.00
equiv) was added followed by slow addition of 70% mCPBA (418 mg, 1.698 mmol,
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3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room
temperature for 16 h. Additional NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv) and
mCPBA (418 mg, 1.698 mmol, 3.00 equiv) were added and the stirring was continued
overnight. Additional NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv), mCPBA (418 mg,
1.698 mmol, 3.00 equiv) and DCM (15 mL) were added and the reaction mixture was
stirred for 3 h at room temperature and then quenched by addition of sat. aq. solution
of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the
next 2 h, then organics were separated and aqueous phase extracted twice with DCM.
The combined organic extracts were dried over anh. Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash column chromatography
(Eluent: EtOAc/petroleum ether 0:1 ꢀ> 1:5). The title compound was obtained as a
beige solid (124 mg, 54%). The structure of the title compound was confirmed by Xꢀ
Ray crystallography.
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H NMR 400 MHz, CDCl3: δ 7.53 (2H, s), 3.69 (2H, q, J = 7.4), 1.54 (3H, t, J = 7.4),
1.36 (9H, s), 1.05 (18H, s); 13C NMR 100 MHz, CDCl3: δ 156.6, 153.1, 146.8, 125.3,
125.1, 51.2, 37.9, 35.3, 32.1, 31.3, 6.5; IR (film) 2964, 1367, 1154 cmꢀ1; HRMS
(+ESI) calculated for C21H35N4O2S [M+H+] 407.2481 found 407.2475; m.p. 104 –
106 oC.
5ꢀ(Ethylsulfonyl)ꢀ1ꢀ(2,4,6ꢀtricyclopentylphenyl)ꢀ1Hꢀtetrazole 14i
14i was synthesized starting from 2,4,6ꢀtricyclopentylaniline.29
To a solution of 2,4,6ꢀtricyclopentylaniline (460 mg, 1.546 mmol, 1.00 equiv) in
DCM (8 mL) was added sat. aq. NaHCO3 (8 mL) and the resulting mixture was
cooled to 0 oC. After addition of thiophosgene (231 mg, 2.010 mmol, 1.30 equiv) the
reaction mixture was allowed to warm up to room temperature and vigorously stirred
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for next 5 h. After that water was added, the organic layer separated and aq. layer
extracted with DCM (3x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo. The crude 1,3,5ꢀtricyclopentylꢀ2ꢀ
isothiocyanatobenzene was used in the next step without further purification.
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NaN3 (201 mg, 3.092 mmol, 2.00 equiv) was dissolved in H2O (4 mL), then a solution
of 1,3,5ꢀtricyclopentylꢀ2ꢀisothiocyanatobenzene (525 mg, 1.546 mmol, 1.00 equiv) in
o
dioxane (4 mL) was added and the reaction mixture was stirred 4 h at 100 C, then
cooled. Additional NaN3 (201 mg, 3.092 mmol, 2.00 equiv), H2O (4 mL) and dioxane
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(4 mL) were added and the reaction mixture was stirred for 16 h at 100 C, then
cooled. After that 1 mL of conc. HCl was diluted with 3 mL H2O and the resulting
solution was added dropwise to the reaction mixture. Volatiles were evaporated and
the crude product was partitioned between water and DCM. Organics were separated
and aq. layer extracted with DCM (3 x). The combined organic extracts were dried
over anh. Na2SO4, filtered and concentrated in vacuo.
The crude 1ꢀ(2,4,6ꢀtricyclopentylphenyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved in EtOH
(6 mL) and KOH (120 mg, 2.146 mmol, 2.30 equiv) was added, the resulting mixture
was refluxed for 1 h, then cooled. After that EtBr (224 mg, 2.053 mmol, 2.20 equiv)
was added dropwise and the mixture was refluxed for 16 h. The reaction mixture was
then evaporated and the crude product partitioned between water and DCM. Organics
were separated and aq. layer extracted with DCM (3 x). The combined organic
extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography using petroleum ether and EtOAc as
eluents. 406 mg (64% in 3 steps) of 5ꢀ(ethylthio)ꢀ1ꢀ(2,4,6ꢀtricyclopentylphenyl)ꢀ1Hꢀ
tetrazole were isolated.
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The 5ꢀ(ethylthio)ꢀ1ꢀ(2,4,6ꢀtricyclopentylphenyl)ꢀ1Hꢀtetrazole (400 mg, 0.974 mmol,
1.00 equiv) was dissolved in DCM (20 mL) and NaHCO3 (409 mg, 4.871 mmol, 5.00
equiv) was added followed by slow addition of 70% mCPBA (720 mg, 2.922 mmol,
3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room
temperature for 2 h. Additional 10 mL of DCM, NaHCO3 (205 mg, 2.436 mmol, 2.50
equiv), and mCPBA (360 mg, 1.461 mmol, 1.50 equiv) were added and the reaction
mixture was stirred at room temperature for 16 h and then quenched by addition of
sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred
vigorously for the next 2 h, then organics were separated and aqueous phase extracted
twice with DCM. The combined organic extracts were dried over anh. Na2SO4,
filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (Eluent: EtOAc/petroleum ether 0:1 ꢀ> 1:5). The title compound was
obtained as a beige solid (150 mg,35%).
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H NMR 400 MHz, CDCl3: δ 7.14 (2H, s), 3.69 (2H, q, J = 7.4), 2.99 – 3.08 (1H, m),
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1.32 – 2.17 (26H, m), 1.51 (3H, t, J = 7.4); C NMR 100 MHz, CDCl3: δ 154.5,
150.7, 143.9, 127.8, 123.5, 50.7, 46.4, 40.8, 36.6, 34.7, 33.9, 25.9, 25.9, 25.6, 6.8; IR
(film) 2955, 1346, 1153 cmꢀ1; HRMS (+ESI) calculated for C24H34N4O2NaS [M+Na]
465.2300 found 465.2285; m.p. 119 – 121 oC.
5ꢀ(Ethylsulfonyl)ꢀ1ꢀ(2,4,6ꢀtricyclohexylphenyl)ꢀ1Hꢀtetrazole 14j
14j was synthesized starting from 2,4,6ꢀtricyclohexylaniline.29
To a solution of 2,4,6ꢀtricyclohexylaniline (1490 mg, 4.388 mmol, 1.00 equiv) in
DCM (23 mL) was added sat. aq. NaHCO3 (23 mL) and the resulting mixture was
cooled to 0 oC. After addition of thiophosgene (656 mg, 5.714 mmol, 1.30 equiv) the
reaction mixture was allowed to warm up to room temperature and stirred vigorously
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for next 5 h. After that water was added, the organic layer separated and aq. layer
extracted with DCM (3x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo. The crude (2ꢀisothiocyanatobenzeneꢀ
1,3,5ꢀtriyl)tricyclohexane was used in the next step without further purification.
NaN3 (570 mg, 8.776 mmol, 2.00 equiv) was dissolved in H2O (11 mL), then a
solution of crude (2ꢀisothiocyanatobenzeneꢀ1,3,5ꢀtriyl)tricyclohexane in dioxane (11
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Additional NaN3 (570 mg, 8.776 mmol, 2.00 equiv), H2O (11 mL) and dioxane (11
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mL) were added and the reaction mixture was stirred at 100 C for 16 h, then cooled.
After that 3 mL of conc. HCl was diluted with 9 mL H2O and the resulting solution
was added dropwise to the reaction mixture. Volatiles were evaporated and the crude
product was partitioned between water and DCM. Organics were separated and aq.
layer extracted with DCM (3 x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo.
The crude 1ꢀ(2,4,6ꢀtricyclohexylphenyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved in EtOH
(30 mL) and KOH (566 mg, 10.092 mmol, 2.30 equiv) was added, the resulting
mixture was refluxed for 1 h, then cooled. After that EtBr (1052 mg, 9.654 mmol,
2.20 equiv) was added dropwise and the reaction mixture was refluxed for the next 16
h. The reaction mixture was then evaporated and the crude product partitioned
between water and DCM. Organics were separated and aq. layer extracted with DCM
(3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash column chromatography
using petroleum ether and EtOAc as eluents. 1646 mg (83% in 3 steps) of 5ꢀ
(ethylthio)ꢀ1ꢀ(2,4,6ꢀtricyclohexylphenyl)ꢀ1Hꢀtetrazole were isolated.
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The 5ꢀ(ethylthio)ꢀ1ꢀ(2,4,6ꢀtricyclohexylphenyl)ꢀ1Hꢀtetrazole (1646 mg, 3.636 mmol,
1.00 equiv) was dissolved in DCM (100 mL) and NaHCO3 (1527 mg, 18.180 mmol,
5.00 equiv) was added followed by slow addition of mCPBA (2689 mg, 10.908 mmol,
3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room
temperature for 16 h. Additional 40 mL of DCM, NaHCO3 (764 mg, 9.090 mmol,
2.50 equiv), and mCPBA (1345 mg, 5.454 mmol, 1.50 equiv) were added and the
reaction mixture was stirred at room temperature for 16 h and then quenched by
addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture
was stirred vigorously for the next 2 h, then organics were separated and aqueous
phase extracted twice with DCM. The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (Eluent: EtOAc/petroleum ether 1:10 ꢀ> 1:4). The title compound
was obtained as a beige solid (600 mg, 34%).
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H NMR 400 MHz, CDCl3: δ 7.10 (2H, s), 3.70 (2H, q, J = 7.4), 2.52 – 2.61 (1H, m),
13
0.95 – 1.98 (32H, m), 1.49 (3H, t, J = 7.4); C NMR 100 MHz, CDCl3: δ 154.2,
151.9, 144.6, 126.5, 123.4, 50.6, 44.9, 40.0, 35.7, 34.4, 32.4, 27.0, 26.9, 26.7, 26.2,
26.0, 7.1; IR (film) 2929, 1348, 1150 cmꢀ1; HRMS (+ESI) calculated for
C27H40N4O2NaS [M+Na] 507.2770 found 507.2779; m.p. 155 – 158 oC.
5ꢀ(Ethylsulfonyl)ꢀ1ꢀ(5'ꢀphenylꢀ[1,1':3',1''ꢀterphenyl]ꢀ4'ꢀyl)ꢀ1Hꢀtetrazole 14k
14k was synthesized starting from commercially available 2,4,6ꢀtriphenylaniline.
To a solution of 2,4,6ꢀtriphenylaniline (300 mg, 0.933 mmol, 1.00 equiv) in DCM (5
mL) was added sat. aq. NaHCO3 (5 mL) and the resulting mixture was cooled to 0 oC.
After addition of thiophosgene (140 mg, 1.213 mmol, 1.30 equiv) the reaction mixture
was allowed to warm up to room temperature and vigorously stirred for next 5 h.
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After that water was added, the organic layer separated and aq. layer extracted with
DCM (3x). The combined organic extracts were dried over anh. Na2SO4, filtered and
concentrated in vacuo. The crude 2'ꢀisothiocyanatoꢀ5'ꢀphenylꢀ1,1':3',1''ꢀterphenyl was
used in the next step without further purification.
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NaN3 (121 mg, 1.866 mmol, 2.00 equiv) was dissolved in H2O (3 mL), then a solution
of crude 2'ꢀisothiocyanatoꢀ5'ꢀphenylꢀ1,1':3',1''ꢀterphenyl in dioxane (3 mL) was added
o
and the reaction mixture was stirred 4 h at 100 C followed by 16 h at room
temperature. After that 0.2 mL of conc. HCl was diluted with 0.6 mL H2O and the
resulting solution was added dropwise to the reaction mixture. Volatiles were
evaporated and the crude product was partitioned between water and DCM. Organics
were separated and aq. layer extracted with DCM (3 x). The combined organic
extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo.
The crude 1ꢀ(5'ꢀphenylꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ1Hꢀtetrazoleꢀ5ꢀthiol was dissolved
in EtOH (6 mL) and KOH (120 mg, 2.146 mmol, 2.30 equiv) was added, the resulting
mixture was stirred for 30 min at room temperature. After that EtBr (224 mg, 2.053
mmol, 2.20 equiv) was added dropwise and the stirring was continued for the next 16
h at room temperature. The reaction mixture was then evaporated and the crude
product partitioned between water and DCM. Organics were separated and aq. layer
extracted with DCM (3 x). The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo.
The crude 5ꢀ(ethylthio)ꢀ1ꢀ(5'ꢀphenylꢀ[1,1':3',1''ꢀterphenyl]ꢀ2'ꢀyl)ꢀ1Hꢀtetrazole was
dissolved in DCM (10 mL) and NaHCO3 (392 mg, 4.665 mmol, 5.00 equiv) was
added followed by slow addition of 70% mCPBA (690 mg, 2.799 mmol, 3.00 equiv)
under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h
and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The
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obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were
separated and aqueous phase extracted twice with DCM. The combined organic
extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 1:9 ꢀ>
1:1). The title compound was obtained as a white solid (345 mg, 79% in 4 steps).
H NMR 400 MHz, CDCl3: δ 7.77 (2H, s), 7.70 – 7.74 (2H, m), 7.41 – 7.53 (3H, m),
7.24 – 7.33 (10 H, m), 2.83 (2H, q, J = 7.4), 0.97 (3H, t, J = 7.4); 13C NMR 100 MHz,
CDCl3: δ 153.6, 144.6, 141.2, 139.2, 136.8, 129.2, 129.1, 128.9, 128.7, 128.6, 128.5,
128.3, 127.6, 50.6, 6.1; IR (film) 1348, 1152 cmꢀ1; HRMS (+ESI) calculated for Cꢀ
27H23N4O2S [M+H+] 467.1542 found 467.1534; m.p. 118 – 121 oC.
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(9aS)ꢀ8ꢀethylideneꢀ3ꢀmethoxyꢀ1ꢀphenylꢀ7,8,9,9aꢀtetrahydroꢀ1Hꢀ2ꢀoxaꢀ6a,10aꢀ
diazabenzo[cd]cyclopenta[g]azuleneꢀ6,10ꢀdione 15
General procedure for the olefination of ketone 13 : To a solution of the sulfone 14
(0.110 mmol, 2.00 equiv) in dry THF (0.3 mL) under Ar atmosphere KHMDS (1M
o
solution in THF, 0.11 mL, 0.110 mmol, 2.00 equiv) was added at ꢀ78 C and the
resulting mixture was stirred for 15 min at this temperature, then a solution of the
ketone 13 (20 mg, 0.055 mmol, 1.00 equiv) in dry THF (0.4 mL) was added dropwise.
o
The reaction mixture was stirred for 40 min at ꢀ78 C and then warmed up to room
temperature (~ 15 min) and quenched with sat. aq. NH4Cl and extracted with DCM
(3x). The combined organic extracts were dried over anh. Na2SO4, filtered and
concentrated in vacuo. The crude product was purified by flash column
chromatography (Eluent: EtOAc/petroleum ether 4:6 ꢀ> 7:3).
1
Major isomer (Eꢀ15): H NMR 400 MHz, CDCl3: δ 7.58 (1H, d, J = 9.0 Hz), 7.32ꢀ
7.45 (6H, m), 6.85 (1H, d, J = 9.0 Hz), 5.48ꢀ5.57 (1H, m), 4.52 (1H, d, J = 15.5 Hz),
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4.33 (1H, dd, J = 9.8, 3.1 Hz), 4.07 (1H, d, J = 15.5 Hz), 3.98 (3H, s), 3.57 (1H, d, J =
15.5 Hz), 2.68ꢀ2.80 (1H, m), 1.72 (3H, d, J = 7.0 Hz);
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Minor isomer (Zꢀ15): H NMR 400 MHz, CDCl3: δ 7.59 (1H, d, J = 9.0 Hz), 7.31ꢀ
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7.46 (6H, m), 6.85 (1H, d, J = 9.0 Hz), 5.47ꢀ5.60 (1H, m), 4.44 (1H, d, J = 15.5 Hz),
4.26 (1H, dd, J = 9.8, 3.1 Hz), 4.15 (1H, d, J = 15.5 Hz), 3.98 (3H, s), 3.45 (1H, d, J =
15.5 Hz), 2.82ꢀ2.90 (1H, m), 1.64 (3H, d, J = 7.0 Hz)
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(S)ꢀtertꢀbutyl
2ꢀ(((tertꢀbutyldiphenylsilyl)oxy)methyl)ꢀ4ꢀoxopyrrolidineꢀ1ꢀ
carboxylate 17
To a solution of tertꢀbutyl (2S,4R)ꢀ2ꢀ(((tertꢀbutyldiphenylsilyl)oxy)methyl)ꢀ4ꢀ
hydroxypyrrolidineꢀ1ꢀcarboxylate30 16 (1.24 g, 2.721 mmol, 1.00 equiv) in DCM (35
mL) was added DMP (1.73 g, 4.082 mmol, 1.50 equiv) and the resulting mixture was
stirred at room temperature for 4 h. Additional DMP (577 mg, 1.361 mmol, 0.50
equiv) was added and the mixture was stirred for the next 16 h After being quenched
by addition of at. aq. solution of Na2S2O3, the obtained biphasic mixture was stirred
vigorously for the next 10 min, then organics were separated and aqueous phase
extracted twice with DCM. The combined organic extracts were dried over anh.
Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (Eluent: EtOAc/petroleum ether 4:1 ꢀ> 2:1). The title compound was
obtained as a yellowish solid (1.14 g, 92%).
H NMR 400 MHz, CDCl3: δ 7.53 – 7.68 (4H, m), 7.33 – 7.48 (6H, m), 4.41 (0.5H, d,
J = 9.4)4.37 (0.5H, d, J = 9.4), 3.80 – 4.15 (3H, m), 3.52 (1H, t, J = 11.3), 2.65 – 2.83
(1H, m), 2.54 (1H, t, J = 19.2), 1.51 and 1.47 (together 9H, both s), 1.00 (9H, s); 13C
NMR 100 MHz, CDCl3 (rotomers): δ 211.0, 210.3, 135.7, 132.8, 130.0, 128.0, 80.5,
66.5, 66.2, 55.8, 55.3, 54.3, 53.7, 41.0, 40.5, 28.6, 26.8, 19.2; IR (film) 2962, 2931,
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1764, 1165, 1106 cmꢀ1; [α]D20 = 11.84° (c = 1, CHCl3); HRMS (+ESI) calculated for
C26H35NO4NaSi [M+Na] 476.2233 found 476.2234; m.p. 99 – 102 oC.
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The olefination of ketone 17 was conduced according to general olefination
procedure, the obtained intermediate olefin was further subjeced to TBDPS protecting
group cleavage: To a solution of olefin in THF (3 mL) was added TBAF x 3 H2O
(139 mg, 0.440 mmol, 2 equiv) and the resulting mixture was stirred at room
temperature for 16 h, then loaded on silica and purified by flash column
chromatography (Eluent: EtOAc/petroleum ether 1:1 ꢀ> 1:0). The title compound was
isolated as a yellow wax. 29 mg (58% in 2 steps) using sulfone 14c; 31 mg (62% in 2
steps) using sulfone 14j.
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ASSOCIATED CONTENT
Supporting Information
General scheme for the synthesis of sulphones 14, ORTEP diagram of 14h,
representative examples of HPLC plots used for determination of E-/Z- ratio in Juliaꢀ
Kocienski olefination of ketone 13 with sulphones 14 as well as copies of NMR
spectrais available free of charge on ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: gintssmits@osi.lv
Notes
The authors declare no competitive financial interest.
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ACKNOWLEDGMENTS
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The authors acknowledge the Latvian Institute of Organic synthesis internal grant for
G. Sakaine (IGꢀ2017ꢀ05) and ERDF (PostDoc Latvia) project
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No.1.1.1.2/VIAA/1/16/243 for G. Smits for the financial support. We also thank Dr.
S. Belyakov (LIOS) for Xꢀray crystallographic analyses.
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