Sceptrin – Enantioselective Synthesis of a Tetrasubstituted all-trans Cyclobutane Key Intermediate

Article abstract of DOI:10.1002/ejoc.201700882

The asymmetric synthesis of both enantiomers of tetrasubstituted all-trans dimethyl 3,4-diacetylcyclobutane-1,2-dicarboxylate with high enantiomeric purity (>98 % ee) using a valine-derived chiral auxiliary in a diastereoselective photodimerization is reported. The absolute configuration was assigned by single-crystal X-ray diffraction analysis. Because this cyclobutane is a key intermediate in the total synthesis of (–)-sceptrin and ageliferin, our findings strengthen the recently revised absolute configurations of these pyrrole-imidazole alkaloids.

Full text of DOI:10.1002/ejoc.201700882

A Journal of
Accepted Article
Title: Sceptrin - Enantioselective Synthesis of a Tetrasubstituted all-
trans Cyclobutane Key Intermediate
Authors: Lena Barra and Jeroen Sidney Dickschat
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700882
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700882
Supported by

10.1002/ejoc.201700882
European Journal of Organic Chemistry
FULL PAPER
Sceptrin – Enantioselective Synthesis of a Tetrasubstituted all-
trans Cyclobutane Key Intermediate
Lena Barra[a] and Jeroen S. Dickschat*[a]
Abstract: The asymmetric synthesis of both enantiomers of
tetrasubstituted all-trans dimethyl 3,4-diacetylcyclobutane-1,2-
dicarboxylate with high enantiomeric purity (>98% ee) using a
cyclobutane scaffolds are limited.[9] The first total synthesis of
(rac)-2 was reported in 2004 and proceeded via the
tetrasubstituted all-trans cyclobutane (rac)-6 as
a
key
valine-derived
chiral
auxiliary
in
a
diastereoselective
intermediate that was transformed into (rac)-2 in twelve linear
steps.[10] A subsequent enantioselective synthesis of (+)-6 gave
access to natural (–)-2 and confirmed the initially assigned
absolute configuration,[11] but a more recent synthetic route by
starting from L-glutamic acid resulted in a revision of the
absolute configuration for sceptrin and, consequently, for the key
intermediate (+)-6 of the first enantioselective approach towards
sceptrin.[12] Here we describe an alternative procedure for the
synthesis of both enantiomers of 6 from L- or D-valine which
confirms the recently revised absolute configuration of sceptrin.
photodimerization is reported. The absolute configuration was
assigned by single-crystal X-ray diffraction analysis. Since this
cyclobutane is a key intermediate in the total synthesis of (−)-
sceptrin and ageliferin, our findings strengthen the recently revised
absolute configurations of these pyrrole-imidazole alkaloids.
Introduction
The cyclobutane ring is a widespread structural motif that occurs
in all classes of natural products including terpenes, alkaloids,
fatty acids, nucleosides and polyketides. [1] Particularly intriguing
are cyclobutane-centered symmetric (or pseudo-symmetric)
natural products that are presumably formed by an
intermolecular [2+2] cycloaddition of two identical (or structurally
related) monomers which can usually result in a variety of regio-
and stereoisomers. Well known examples are the pseudo-
symmetric all-trans compound anisumic acid (1) from the
Chinese medicinal plant Clausena anisum-olens (Rutaceae),[2]
or sceptrin (2) that was isolated in 1981 by Faulkner and Clardy
from the marine sponge Agelas sceptrum (Figure 1).[3] This
hymenidin (3) dimer belongs to a large group of marine pyrrole-
imidazole alkaloids that exhibit remarkable structural
architectures and a broad spectrum of bioactivities,[4] including
antimicrobial, anti-muscarinic and anti-histaminic activities, and
inhibition of the cell motility of cancer cell lines without showing
cytotoxicity at the effective concentrations.[5] Besides 2, a series
of related compounds can be isolated from different Agelas
species such as ageliferin (4)[6] that can be rationalized as the
[4+2] cycloadduct of 3, and nakamuric acid (5)[7] for which the
absolute configuration was recently clarified.[8] From a synthetic
point of view these chiral natural products are challenging
targets since methods for the asymmetric construction of
Figure 1. Structures of anisumic acid (1), sceptrin (2), hymenidin (3),
ageliferin (4), nakamuric acid (5) and of the synthetic key intermediate (+)-6
towards sceptrin and ageliferin.
[a]
Prof. Dr. Jeroen S. Dickschat, Lena Barra
Kekulé-Institute of Organic Chemistry and Biochemistry
Rheinische Friedrich Wilhelms University of Bonn
Gerhard-Domagk-Straße 1, 53121 Bonn, Germany
E-mail: dickschat@uni-bonn.de
Results and Discussion
https://www.chemie.uni-
bonn.de/oc/forschung/arbeitsgruppen/ak_dickschat
For the enantioselective synthesis of 6 L-valinol (7) and levulinic
acid (8) were converted into the bicyclic lactam 9 that is a known
intermediate in the total synthesis of (−)-grandisol (Figure 2A).[13]
Introduction of an ,-unsaturation by Grieco elimination yielded
the enone 10, a compound that was previously applied in face-
selective cyclopropanations.[14] UV irradiation of 10 at 250 nm in
Supporting information for this article is given via a link at the end of
the document. CCDC-1552548 and CCDC-1552549 contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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10.1002/ejoc.201700882
European Journal of Organic Chemistry
FULL PAPER
dichloromethane resulted in the formation of two products that
were tentatively identified as [2+2] dimerization products by
GC/MS with 15% and 8% yield, respectively (Table 1).
During optimization of the reaction conditions moderately
increased yields were obtained in acetonitrile, while neat
conditions did not give any [2+2] cycloadducts even after
prolonged reaction times. Changing to a wavelength of 350 nm
did not yield any photodimerization products, but with addition of
acetophenone as photosensitizer significantly improved yields
could be obtained even with reduced reaction times, and also
minor quantities (5%) of a third product were obtained. The
photosensitizers benzophenone and acetone applied under the
same conditions proved to be ineffective.
Figure 2. Synthesis of photodimers: A) synthesis of monomer 10 from valinol,
B) representation of all possible photodimers with their point groups given in
brackets.
Table 1. Optimization of the reaction conditions for the
photodimerization of 10.
Figure 3. Methanolysis of photodimers: A) acid catalyzed cleavage of
photodimers 11b and 11d, B) further possible methanolysis products from
head-to-tail photodimers and C) from head-to-head photodimers with their
point groups given in brackets.
 [nm]
solvent
additive
time [h]
Yield
[%]
11d
11b
11c
n.d.
n.d.
0
250
250
250
350
350
350
350
DCM
−
24
24
48
48
12
48
48
15
19
0
8
The structures of the three compounds obtained under the
optimized reaction conditions were elucidated by the following
rationale. In theory, the photodimerization of 10 can lead to six
isomers, represented by three head-to-head connected isomers
11a-c and three head-to-tail cycloadducts 11d-f (Figure 2B, the
symmetry properties of the molecules discussed in the following
section are summarised in Tables S1 and S2). Among the head-
to-head compounds the cis-syn-cis stereoisomer 11a exhibits C1
symmetry, while the two cis-anti-cis stereoisomers 11b and 11c
both represent the point group C2. Analogously, the head-to-tail
isomer 11d is of C1 symmetry, while 11e and 11f belong to the
C2 point group. The main product of the photodimerization
MeCN
neat
−
10
0
−
MeCN
MeCN
MeCN
MeCN
−
0
0
0
acetophenone
benzophenone
acetone
37
0
32
0
5
0
0
0
0
DCM = dichloromethane, MeCN = acetonitrile, n.d. = not determinded.
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10.1002/ejoc.201700882
European Journal of Organic Chemistry
FULL PAPER
showed 10 signals in its 13C-NMR spectrum, in agreement with
one of the C2 symmetrical structures. The acid-catalyzed
cleavage in methanol resulted in (+)-6 (Figure 3A), the reported
synthetic intermediate towards sceptrin, which can only be
formed from 11b with epimerization of both methyl ketones, or
from 11c with epimerization of both methyl ester groups, to
result in the thermodynamically most stable all-trans cyclobutane.
Epimerization of the methyl ketones was assumed to be faster
than epimerization of the methyl esters, favouring the structure
of 11b for the main product. Indeed, the cleavage in
the only possible structures for the minor product with nine 13C-
NMR signals are the achiral compounds 12b or 12c (Table S2).
2
(2H4)methanol with H2SO4 proceeded with H/D exchange of the
cyclobutane hydrogens in the -positions only of the methyl
ketones and not of the methyl esters (Figure 4, for incorporation
rates, 13C NMR and HSQC spectra cf. Table S3, Figures S1 –
S3). The structure of 11b was further supported by X-ray
analysis, while crystallographic data of its lysis product pointed
to a (1R,2R,3S,4S)-configuration for (+)-6 (Figure 5).
Figure 5. X-ray structures of 11b and its cleavage product (+)-6. ORTEP of A)
11b and B) (1R,2R,3S,4S)-6 (crystallographic data are given in Tables S4 and
S5).
Figure 4. Result of H/D exchange experiment. A) 1H NMR spectrum of 6 (700
MHz, C6D6), B) 1H NMR spectrum of (2H14)-6 (700 MHz, C6D6).
Starting from D-valinol, ent-(–)-6 was obtained via the same
route. Both enantiomers were isolated with high enantiomeric
purity (>98% ee) as revealed by HPLC analysis on a homochiral
stationary phase (Figure 6). The delineated structure of 11b was
also supported by two-dimensional NMR spectroscopy including
1H,1H-COSY, HSQC, HMBC and NOESY, but many of the
observed correlations are also in line with the other C2
symmetrical isomers. This was also a major problem in the
identification of the other two photodimers. The second most
abundant photodimerization product exhibited 20 signals in its
13C-NMR spectrum, pointing to one of the two possible
structures of C1 symmetry (11a or 11d). Methanolysis yielded
two achiral or chiral racemic products as indicated by a missing
optical rotation. One of these products revealed six and the
other one nine signals in the 13C-NMR spectrum, requiring the
presence of symmetric elements in both cases. Taking
epimerizations (preferably at the methyl ketones) into account,
Figure 6. Analysis of the enantiomeric excess of 6 by HPLC on a chiral
stationary phase. A) Mixture of (+)- and (−)-6, B) (+)-6 obtained from cleavage
of (+)-11b, C) (−)-6 obtained from cleavage of (−)-11b, D) (−)-6 obtained from
cleavage of (+)-11c.
For all other stereoisomers of 12 with either Ci or C2v symmetry
six carbon signals are expected, while none of the
stereoisomers of 6 that could potentially arise from a head-to-
head isomer such as 11a has the correct symmetry properties to
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10.1002/ejoc.201700882
European Journal of Organic Chemistry
FULL PAPER
explain the observed 13C-NMR spectrum. The product 12b was
finally identified, because two sets of signals for the
diastereotopic methyl ester functions, but coinciding signals for
the enantiotopic methyl ketones were observed, while 12c would
require two sets of signals for the methyl ketones and just one
for the methyl esters. The major product of this methanolysis is
likely to be 12a, and the initial mixture of these two products
pointed to the structure of 11d for the second photodimer of 10.
The formation of 12b showed again the preferential
epimerization of the methyl ketone functions, while the
hypothetical isomerization of one methyl ester group would
produce 12c. No formation of the all-trans cyclobutane 12e was
observed, which also demonstrated the difficulties associated
with the epimerization of the methyl ester groups under the
applied reaction conditions. The third minor product of the
photodimerization of 10 exhibited 10 signals in the 13C-NMR, in
agreement with the structures of 11c, 11e or 11f. Methanolysis
resulted in (–)-6 which is only explainable from the second C2
symmetric head-to-head dimer 11c, again requiring
epimerization of both methyl ketones.
spectrometers, and were referenced against CDCl3 ( = 7.26 ppm), C6D6
( = 7.16 ppm) and d3-DMSO ( = 2.50 ppm) for 1H-NMR, and CDCl3 ( =
77.01 ppm), C6D6 ( = 128.06 ppm) and d6-DMSO ( = 39.52 ppm) for
13C-NMR. The multiplicities are specified as follows: singlet (s), doublet
(d), triplet (t), quartet (q), quintet (quin), sextet (sex), septet (sept). GC-
MS analyses were carried out with an Agilent HP7890B gas
chromatograph connected to a HP5977A mass detector fitted with a HP-
5MS silica capillary column (30 m, 0.25 mm i. d., 0.50 m film). The
GCMS conditions were as follows: (1) inlet pressure: 77.1 kPa, He flow
23.3 mL/min; (2) injection volume: 1 μL; (3) injection mode: split 50:1,
valve time 60 s; (4) oven temperature ramp: 5 min at 50 °C increasing at
10 °C/min to 320 °C; (5) carrier gas He at 1 mL/min; (6) transfer line:
250 °C; (7) electron energy: 70 eV. Retention indices (I) were determined
from a homologous series of n-alkanes (C8-C40). Optical rotary powers
were recorded on a P8000 Polarimeter (Krüss). UV/Vis spectra were
recorded on a Cary 100 UV/Vis spectrometer (Agilent). IR Spectra were
measured by use of an Alpha FT-IR spectrometer from Bruker.
Intensities of the signals were specified as follows: strong (s), medium
(m), weak (w), broad (br).
(3S,7aR)-3-Isopropyl-7a-methyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-
one ((+)-9): L-Valinol (7.20 g, 69.8 mmol, 1.0 equiv.) and levulinic acid
(8.11 g, 69.8 mmol, 1.0 equiv.) were dissolved in toluene (400 mL) and p-
toluenesulfonic acid (0.60 g, 3.49 mmol, 0.05 equiv.) was added. The
reaction mixture was refluxed for 16 h using a Dean-Stark-trap. After
completion of the reaction the mixture was concentrated and washed
with NaHCO3 (sat. aqueous solution). The organic phase was dried with
MgSO4 and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography on silica gel
(cyclohexane/ethyl acetate 3:1) and (+)-9 (12.0 g, 65.6 mmol, 94%) was
Conclusions
In conclusion, an alternative approach for the synthesis of both
pure enantiomers of the tetrasubstituted all-trans cyclobutane 6
via five steps and 19% overall yield was developed. The
21
isolated as a colorless oil. []D = +84.2 (c 1, acetone). Rf = 0.2. GC
stereoinformation is transfered from valinol, guiding
a
(HP-5MS): I = 1379. 1H-NMR (400 MHz, CDCl3):  = 4.14 (dd, 2JH,H = 8.7
Hz, 3JH,H = 7.3 Hz, 1H, CHH), 3.85 (dd, 2JH,H = 8.7 Hz, 3JH,H = 6.1 Hz, 1H,
CHH), 3.59 (ddd, 1H, 3JH,H = 6.3 Hz, 3JH,H = 7.3 Hz, 3JH,H = 10.4 Hz, CH),
2.73 (ddd, 2JH,H = 17.0 Hz, 3JH,H = 9.8 Hz, 3JH,H = 9.8 Hz, 1H, CHH), 2.46
diastereoselective photodimerization that yields three products
with interesting stereochemical properties. Also their
methanolysis with potential epimerization of the methyl ketones
is a peculiar and intellectually challenging stereochemical
problem. As outlined, the cyclobutane (+)-6 is a key intermediate
in the total synthesis of the pyrrole-imidazole alkaloid sceptrin
(2) that serves itself as a precursor for the synthesis of the
related natural products ageliferin (4) and nakamuric acid (5).[15]
By the work presented here the absolute configuration of (+)-6
was re-examined including X-ray diffraction analysis, which
confirms the recently revised absolute configurations of this
compound and all natural products that were synthetically
obtained from it. The efficient enantioselective approach to both
enantiomers of 6 from cheap L- and D-valinol may be of use for
the total synthesis of other cyclobutane natural products.
2
3
3
(ddd, JH,H = 17.0 Hz, JH,H = 7.0 Hz, JH,H = 5.6 Hz, 1H, CHH), 2.20 –
2.12 (m, 2H, CH2), 1.73 – 1.61 (m, 1H, CH), 1.47 (s, 3H, CH3), 1.03 (d,
3JH,H = 6.7 Hz, 3H, CH3), 0.88 (d, 3JH,H = 6.7 Hz, 3H, CH3) ppm. 13C-NMR
(100 MHz, CDCl3):  = 179.0 (Cq), 100.0 (Cq), 71.1 (CH2), 61.8 (CH), 34.2
(CH2), 33.6 (CH), 33.1 (CH2), 25.1 (CH3), 20.6 (CH3), 19.2 (CH3) ppm. IR
(ATR): ṽ = 2959 (w), 2931 (w), 2872 (w), 1704 (s), 1466 (w), 1347 (s),
1247 (w), 1190 (w), 1020 (m), 879 (m) cm-1. EI-MS (70 eV): m/z (%) =
183 (32), 168 (87), 154 (18), 140 (100), 126 (19), 112 (32), 100 (46), 82
(55), 69 (23), 55 (24), 43 (30). HRESIMS calcd. for C10H17NNaO2+: m/z =
206.1151, found: m/z = 206.1151 ([M+Na]+).
(3R,7aS)-3-Isopropyl-7a-methyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-
one ((−)-9): Lactam (−)-9 was synthesized analogously from D-valinol
(5.00 g, 48.5 mmol). Yield: 8.08 g (44.1 mmol, 91%). All recorded
spectral data, with exception of the optical rotary power, were identical to
those for (+)-9. []D21 = −81.9 (c 1, acetone).
Experimental Section
(3S,7aR)-3-Isopropyl-7a-methyl-2,3-dihydropyrrolo[2,1-b]oxazol-
5(7aH)-one ((+)-10): Diisopropylamine (0.61 g, 6.00 mmol, 2.2 equiv.)
was dissolved in dry THF (15 mL) under Ar atmosphere and cooled to
0 °C. A solution of n-butyllithium (1.6 M in hexane, 3.80 mL, 6.00 mmol,
2.2 equiv.) was added dropwise and the reaction was stirred for 30
minutes and afterwards cooled to −78 °C. A solution of (+)-9 (0.50 g, 2.73
mmol, 1.0 equiv.) in dry THF (1 mL) was added dropwise and the
reaction was stirred for 2 h, followed by dropwise addition of a cooled
solution (−78 °C) of PhSeBr (0.77 g, 3.28 mmol, 1.2 equiv.) in dry THF
(10 mL). The reaction was allowed to warm to room temperature and
stirred over night, quenched with water and extracted with EtOAc. The
combined organic phases were dried with MgSO4 and the solvent was
General Synthetic Methods: All chemicals were obtained from Acros
Organics (Geel, Belgium), Sigma Aldrich Chemie GmbH (Steinheim,
Germay) or TCI Deutschland GmbH (Eschborn, Germany). All solvents
were purified by distillation. Whenever necessary, reactions were carried
out under inert atmosphere (Ar) using vacuum-heated flasks and dried
solvents (dried according to standard protocols). Thin layer
chromatography (TLC) was performed on 0.20 mm silica plates
(Polygram SIL G/UV254) obtained from Macherey-Nagel (Düren,
Germany). Column chromatography was performed on Merck silica gel
(0.040 − 0.063 Mesh). NMR spectra were recorded on Bruker AV I (400
MHz), AV III HD Prodigy (500 MHz) and AV III HD Cryo (700 MHz)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700882
European Journal of Organic Chemistry
FULL PAPER
3
removed under reduced pressure. The crude selenylation product and
pyridine (0.54 g, 6.82 mmol, 2.5 equiv.) were dissolved in DCM (15 mL)
and cooled to 0 °C. A 35%-aqueous H2O2 solution (0.80 mL, 8.18 mmoL,
3.0 equiv.) was added dropwise and the reaction was stirred for 3 h. After
completion of the reaction the mixture was quenched with 1 M HCl-
solution. The organic phase was washed with water and brine and dried
with MgSO4. After removal of the solvent under reduced pressure, the
crude product was purified by column chromatography on silica gel
(petroleum ether/diethyl ether 3:1) and (+)-10 was obtained as a pale
yellow solid, which was repeatedly washed with cold pentane until a
colorless product was obtained (0.34 g, 1.86 mmol, 68%). []D21 = +48.6
(c 1, acetone). Rf = 0.2. GC (HP-5MS): I = 1320. Melting point: 49 –
x CH3), 0.57 (d, JH,H = 6.6 Hz, 6H, 2 x CH3) ppm. 13C-NMR (100 MHz,
C6D6):  = 176.9 (2 x Cq), 97.8 (2 x Cq), 73.0 (2 x CH2), 61.0 (2 x CH),
46.1 (2 x CH), 42.2 (2 x CH), 34.5 (2 x CH), 25.5 (2 x CH3), 20.9 (2 x
CH3), 19.0 (2 x CH3) ppm. IR (ATR): ṽ = 2957 (w), 2940 (w), 2875 (w),
1703 (s), 1466 (w), 1352 (s), 1227 (w) 1148 (w), 1047 (w), 1007 (m), 899
(w), 769 (m), 609 (w) cm-1. EI-MS (70 eV): m/z (%) = 362 (7), 347 (100),
319 (25), 291 (4), 279 (8), 261 (3), 236 (3), 219 (2), 207 (9), 193 (8), 182
(12), 166 (17), 151 (46), 138 (33), 128 (54), 108 (44), 96 (32), 80 (20), 69
(45), 55 (16), 43 (52). HRESIMS calcd. for C20H31N2O4+: m/z = 363.2278,
found: m/z = 363.2278 ([M+H]+). Optical rotary power of (−)-11b: []D
−184.2 (c 1, MeOH). Analytical data for (+)-11d: []D = +89.0 (c 1,
acetone). GC (HP-5MS): I = 2690. Melting point: 189 – 192 °C. 1H-NMR
(500 MHz, C6D6):  = 3.87 (dd, 2JH,H = 8.5 Hz, JH,H = 7.6 Hz, 1H, CHH),
21
=
21
3
3
51 °C. 1H-NMR (500 MHz, C6D6):  = 6.37 (d, JH,H = 5.8 Hz, 1H, CH),
3
2
3
5.64 (d, JH,H = 5.8 Hz, 1H, CH), 3.88 (dd, JH,H = 8.8 Hz, JH,H = 7.3 Hz,
3.79 (dd, 2JH,H = 8.2 Hz, 3JH,H = 8.2 Hz, 1H, CHH), 3.67 (ddd, 3JH,H = 10.8
Hz, 3JH,H = 7.2 Hz, 3JH,H = 7.0 Hz, 1H, CH), 3.56 (m, 1H, CH), 3.53 (m, 1H,
CHH), 3.46 (ddd, 3JH,H = 10.2 Hz, 3JH,H = 7.1 Hz, 3JH,H = 7.1 Hz, 1H, CH),
3.36 (dd, 2JH,H = 8.5 Hz, 3JH,H = 6.9 Hz, 1H, CHH), 3.00 (m, 1H, CH), 2.99
(m, 1H, CH), 2.63 (m, 1H, CH), 1.43 – 1.30 (m, 2H, 2 x CH), 1.23 (s, 3H,
CH3), 1.15 (d, 3JH,H = 6.6 Hz, 3H, CH3), 1.07 (d, 3JH,H = 6.6 Hz, 3H, CH3),
1.05 (s, 3H, CH3), 0.57 (d, JH,H = 6.6 Hz, 3H, CH3), 0.56 (d, JH,H = 6.6
Hz, 3H, CH3) ppm. 13C-NMR (125 MHz, C6D6):  = 182.0 (Cq), 178.2 (Cq),
100.8 (Cq), 97.9 (Cq), 72.6 (CH2), 69.0 (CH2), 64.0 (CH), 61.9 (CH), 45.7
(CH), 44.9 (CH), 44.1 (CH), 41.4 (CH), 34.4 (CH), 34.1 (CH), 25.9 (CH3),
21.2 (CH3), 20.9 (CH3), 20.4 (CH3), 19.0 (CH3), 18.9 (CH3) ppm. IR
(ATR): ṽ = 2924 (w), 2903 (w), 2868 (w), 1694 (s), 1463 (w), 1329 (m),
1138 (w), 1030 (w), 873 (w), 751 (w) cm-1. EI-MS (70 eV): m/z (%) = 362
(23), 347 (100), 319 (60), 279 (11), 236 (21), 220 (3), 207 (7), 182 (20),
166 (7), 151 (72), 138 (21), 128 (45), 126 (44), 108 (21), 96 (23), 84 (12),
69 (21), 56 (7), 43 (21). HRESIMS calcd. for C20H30N2NaO4+: m/z =
385.2098, found: m/z = 385.2098 ([M+Na]+). Optical rotary power of (−)-
2
3
1H, CHH), 3.64 (dd, JH,H = 8.8 Hz, JH,H = 6.0 Hz, 1H, CHH), 3.44 (ddd,
3JH,H = 10.1 Hz, 3JH,H = 7.2 Hz, 3JH,H = 6.3 Hz, 1H, CH), 1.45 (dsept, 3JH,H
= 10.1 Hz, 3JH,H = 6.6 Hz, 1H, CH), 1.17 (s, 3H, CH3), 1.10 (d, 3JH,H = 6.6
Hz, 3H, CH3), 0.58 (d, 3JH,H = 6.6 Hz, 3H, CH3) ppm. 13C-NMR (125 MHz,
C6D6):  = 177.6 (Cq), 150.6 (CH), 127.9 (CH), 100.4 (Cq), 73.7 (CH2),
62.7 (CH), 33.2 (CH), 22.3 (CH3), 20.8 (CH3), 19.2 (CH3) ppm. IR (ATR):
ṽ = 3089 (w), 2959 (w), 2930 (w), 2875 (w), 1708 (s), 1671 (m), 1320 (s),
1105 (s), 1011 (m), 892 (s), 833 (m) cm-1. UV/Vis (MeCN): max (lg ):
245 (3.187) nm. EI-MS (70 eV): m/z (%) = 181 (6), 166 (49), 151 (60),
138 (100), 124 (11), 110 (54), 96 (27), 80 (11), 59 (17), 53 (11), 41 (16).
HRESIMS calcd. for C10H15NNaO2+: m/z = 204.0995, found: m/z =
204.0999 ([M+Na]+).
3
3
(3R,7aS)-3-Isopropyl-7a-methyl-2,3-dihydropyrrolo[2,1-b]oxazol-
5(7aH)-one ((−)-10): Compound (−)-10 was synthesized analogously
from (−)-9 (5.00 g, 27.3 mmol). Yield: 3.26 g (18.0 mmol, 66%). All
recorded spectral data, with exception of the optical rotary power, were
identical to those for (+)-10. []D21 = −49.3 (c 1, acetone).
21
21
11d: []D = −91.5 (c 0.6, acetone). Analytical data for (+)-11c: []D
=
+5.2 (c 1, acetone). GC (HP-5MS): I = 2738. Melting point: 192 – 193 °C.
1H-NMR (500 MHz, d6-DMSO):  = 4.10 (dd, JH,H = 8.4 Hz, JH,H = 8.4
2
3
Hz, 2H, 2 x CHH), 3.76 (dd, 2JH,H = 8.4 Hz, JH,H = 6.9 Hz, 2H, 2 x CHH),
3
General procedure for the photochemical dimerization of 10: Enone
10 was dissolved at a concentration of 0.1 M in freshly degassed solvent
according to Table 1 and irradiated by use of a Rayonet RPR-200
photoreactor. When utilized, photosensitizers were added (5 equiv.)
directly to 10. When irradiation with  = 250 nm was conducted, reaction
vessels made of fused silica glass were used. The reaction progress was
monitored by GC and carried out until all starting material was consumed
or after no product formation was detected after 48 h. The solvent was
removed under reduced pressure and the crude products were directly
subjected to HPLC separation (system: Fa. KNAUER GmbH (Berlin,
Germany), 2 pumps S-1800, assistant 6000 with feedpump S-100 (10 mL
pumphead) and electronic injection valve (6 port), UV-Vis detector S-
2550 (190 – 900 nm); column: KNAUER Eurospher II 100-5 C18P, 5m,
250 x 20 mm; solvent: MeCN/H2O (45/55); flow rate: 24.0 mL/min).
Fractions containing the target compound were pooled and the solvent
was removed by lyophilization. For the different tested reaction
conditions see Table 1.
3
3
3
3.50 (ddd, JH,H = 10.7 Hz, JH,H = 7.5 Hz, JH,H = 7.5 Hz, 2H, 2 x CH),
3.04 (m, 2H, 2 x CH), 2.98 (m, 2H, 2 x CH), 1.76 – 1.64 (m, 2H, 2 x CH),
1.50 (s, 6H, 2 x CH3), 0.98 (d, 3JH,H = 6.6 Hz, 6H, 2 x CH3), 0.85 (d, 3JH,H
= 6.6 Hz, 6H, 2 x CH3) ppm. 13C-NMR (125 MHz, d6-DMSO):  = 181.2 (2
x Cq), 100.3 (2 x Cq), 68.0 (2 x CH2), 63.8 (2 x CH), 42.6 (2 x CH), 42.1 (2
x CH), 32.8 (2 x CH), 20.9 (2 x CH3), 19.3 (2 x CH3), 18.8 (2 x CH3) ppm.
IR (ATR): ṽ = 2963 (w), 2951 (w), 2872 (w), 1718 (s), 1459 (w), 1296 (m),
1280 (m), 1181 (m), 1071 (w), 999 (w), 986 (w), 863 (s), 695 (w) cm-1. EI-
MS (70 eV): m/z (%) = 362 (21), 347 (27), 319 (40), 295 (5), 279 (5), 235
(13), 182 (9), 151 (100), 138 (19), 128 (60), 108 (60), 96 (20), 84 (10), 69
(16), 56 (6), 43 (20). HRESIMS calcd. for C20H30N2NaO4+: m/z =
385.2098, found: m/z = 385.2098 ([M+Na]+).
(1R,2R,3S,4S)-Dimethyl
3,4-diacetylcyclobutane-1,2-dicarboxylate
((+)-6): Photodimerization product (+)-11b (62.0 mg, 0.17 mmol, 1.0
equiv.) was dissolved in MeOH (10 mL) and conc. H2SO4 (1 mL) was
added carefully. The reaction mixture was heated at 70 °C for 6 h. After
completion of the reaction, the mixture was diluted with EtOAc and
washed with water. The organic phase was dried with MgSO4 and the
solvent was removed under reduced pressure. The crude product was
purified by column chromatography on silica gel (petroleum ether/diethyl
ether 1:1) and (+)-6 (34.0 mg, 0.13 mmol, 78%, 98% ee, Figure 6) was
Photodimers (+)-11b, (+)-11d and (+)-11c: Enone (+)-10 (0.20 g, 1.10
mmol, 1.0 equiv.) was dissolved in freshly degassed dry MeCN (10 mL)
and acetophenone (0.66 g, 5.52 mmol, 5.0 equiv.) was added. The
solution was irradiated with  = 350 nm until all starting material was
consumed (12 h). The solvent was removed under reduced pressure and
the crude product mixture was purified by HPLC. After lyophilization (+)-
11b (74.0 mg, 0.20 mmol, 37%), (+)-11d (64 mg, 0.18 mmol, 32%) and
(+)-11c (10 mg, 0.03 mmol, 5%) were isolated as colorless solids.
Analytical data for (+)-11b: []D21 = +193.6 (c 1, MeOH). GC (HP-5MS): I
= 2642. Melting point: 196 – 198 °C. 1H-NMR (400 MHz, C6D6):  = 3.99
– 3.89 (m, 2H, 2 x CHH), 3.58 – 3.51 (m, 4H, 2 x CHH, 2 x CH), 3.57 –
3.48 (m, 2H, 2 x CH), 3.31 (m, 2H, 2 x CH), 2.99 (m, 2H, 2 x CH), 1.39 –
1.27 (m, 2H, 2 x CH), 1.08 (s, 6H, 2 x CH3), 1.07 (d, 3JH,H = 6.7 Hz, 6H, 2
21
isolated as a colorless solid. []D = +30.3 (c 1, CHCl3). Rf = 0.3. GC
(HP-5MS): I = 1663. Melting point: 76 – 78 °C. 1H-NMR (500 MHz,
CDCl3):  = 3.75 (s, 6H, 2 x CH3), 3.51 (dd, J = 9.5 Hz, 2.4 Hz, 2H, 2 x
CH), 3.40 (dd, J = 9.5 Hz, 2.4 Hz, 2H, 2 x CH), 2.20 (s, 6H, 2 x CH3) ppm.
13C-NMR (125 MHz, CDCl3):  = 205.0 (Cq), 171.8 (Cq), 52.7 (CH3), 46.6
(CH), 39.1 (CH), 27.9 (CH3) ppm. IR (ATR): ṽ = 2964 (w), 2922 (w), 2903
(w), 2865 (w), 1695 (s), 1461 (w), 1347 (m), 1168 (m), 1114 (m), 874 (w),
773 (w), 683 (w) cm-1. EI-MS (70 eV): m/z (%) = 256 (3), 241 (7), 224
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10.1002/ejoc.201700882
European Journal of Organic Chemistry
FULL PAPER
(33), 213 (19), 196 (1), 182 (21), 171 (10), 164 (5), 153 (25), 140 (22),
123 (12), 111 (26), 95 (14), 85 (6), 59 (11), 43 (100). HRESIMS calcd. for
C12H16NaO6+: m/z = 279.0839, found: m/z = 279.0839 ([M+Na]+).
Fa. Knauer GmbH (Berlin, Germany), HPG-pump P6.1L, oven CT 2.1,
photodiode array detector DAD 6.1L (190-1020 nm); column: DAICEL
Chiralpak IB; 5 m, 4.6 mm x 250 mm; solvent: n-hexane/2-propanole
(85/15); flow rate: 1.0 mL/min; pressure: 42 bar; temperature: 25 °C.
(1S,2S,3R,4R)-Dimethyl
3,4-diacetylcyclobutane-1,2-dicarboxylate
(−)-6: Compound (−)-6 was synthesized by acidic cleavage of either (+)-
11c (Yield: 8.00 mg, 0.03 mmoL, 71%, 98% ee, Figure 6) or (−)-11b
(Yield: 12.0 mg, 0.05 mmoL, 78%, 98% ee, Figure 6) following the same
procedure as for (+)-6. All recorded spectral data, with exception of the
optical rotary power, were identical to those for (+)-6. []D21 = −30.0 (c 1,
CHCl3).
Acknowledgements
This work was funded by the DFG (DI1536/9-1). We thank Dr.
Gregor Schnakenburg for X-ray analysis and Prof. Dr. Alexander
C. Filippou for access to the instruments for these analyses.
(1R,2R,3S,4S)-Dimethyl
(12a) and (1r,2R,3s,4S)-dimethyl
2,4-diacetylcyclobutane-1,3-dicarboxylate
2,4-diacetylcyclobutane-1,3-
Keywords: sceptrin • photochemistry • small ring systems •
chiral auxiliaries • marine natural products
dicarboxylate (12b): Photodimerization product (+)-11d (36.0 mg, 0.10
mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and conc. H2SO4 (0.3
mL) was added carefully. The reaction mixture was heated at 70 °C for
16 h. After complete reaction, the mixture was diluted with EtOAc and
washed with water. The organic phase was dried with MgSO4 and the
solvent was removed under reduced pressure. The crude product was
purified by column chromatography on silica gel (petroleum ether/diethyl
ether 1:2) and 12a (9.00 mg, 0.035 mmol, 35%) and 12b (4.00 mg, 0.016
mmol, 16%) were isolated as colorless solids. Analytical data for 12a: Rf
= 0.3. GC (HP-5MS): I = 1729. Melting point: 77 – 78°C. 1H-NMR (500
MHz, CDCl3):  = 3.84 – 3.77 (m, 2H, 2 x CH), 3.73 – 3.67 (m, 2H, 2 x
CH), 3.69 (s, 6H, 2 x CH3), 2.20 (s, 6H, 2 x CH3) ppm. 13C-NMR (125
MHz, CDCl3):  = 205.7 (2 x Cq), 171.8 (2 x Cq), 52.5 (2 x CH3), 47.2 (2 x
CH), 40.4 (2 x CH), 29.4 (2 x CH3) ppm. IR (ATR): ṽ = 3005 (w), 2954 (w),
2921 (w), 2851 (w), 1722 (s), 1706 (s), 1440 (m), 1358 (m), 1298 (w),
1233 (s), 1193 (s), 1073 (m), 1038 (w), 982 (w), 953 (w), 935 (w), 797
(m), 724 (w), 661 (w), 510 (w) cm-1. EI-MS (70 eV): m/z (%) = 256 (3),
241 (9), 225 (22), 214 (9), 209 (3), 196 (10), 182 (26), 171 (19), 155 (6),
150 (43), 140 (35), 139 (35), 123 (20), 111 (25), 95 (14), 79 (2), 69 (2),
59 (4), 43 (100). HRESIMS calcd. for C12H16NaO6+: m/z = 279.0839,
found: m/z = 279.0839 ([M+Na]+). Analytical data for 12b: Rf = 0.2. GC
(HP-5MS): I = 1689. Melting point: 99 – 101 °C. 1H-NMR (500 MHz,
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3
3
CDCl3):  = 4.06 (dd, JH,H = 10.0 Hz, JH,H = 10.0 Hz, 1H, CH), 3.78 (s,
3
3
3H, CH3), 3.67 (s, 3H, CH3), 3.67 (dd, JH,H = 9.0 Hz, JH,H = 9.0 Hz, 1H,
CH), 3.40 (dd, 3JH,H = 9.5 Hz, 3JH,H = 9.5 Hz, 2H, 2 x CH), 2.13 (s, 6H, 2 x
CH3) ppm. 13C-NMR (125 MHz, CDCl3):  = 204.6 (2 x Cq), 172.9 (Cq),
172.0 (Cq), 52.7 (CH3), 52.4 (CH3), 46.4 (2 x CH), 42.9 (CH), 41.4 (CH),
27.5 (2 x CH3) ppm. IR (ATR): ṽ = 3003 (w), 2942 (w), 2919 (w), 2851 (w),
1717 (s), 1706 (s), 1441 (m), 1378 (w), 1358 (w), 1282 (s), 1184 (m),
1158 (s), 1132 (s), 1054 (m), 1040 (w), 996 (w), 934 (m), 806 (w), 589
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214 (3), 209 (4), 193 (12), 181 (15), 171 (12), 165 (4), 155 (4), 150 (40),
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HRESIMS calcd. for C12H16NaO6
279.0839 ([M+Na]+).
:
m/z = 279.0839, found: m/z =
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(2H14)-(1R,2R,3S,4S)-Dimethyl
3,4-diacetylcyclobutane-1,2-
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dissolved in (2H4)methanol (3 mL) and (2H2)sulfuric acid (98% in D2O, 0.3
mL) were added carefully. The reaction was heated for 16 h at 70 °C,
diluted with D2O (10 mL) and extracted with DCM. The organic phase
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1650. EI-MS (70 eV): m/z (%) = 270 (3), 252 (7), 235 (33), 224 (17), 216
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Analysis of the enantiomeric excess of 6: The enantiomeric excess of
(+)- and (−)-6 obtained from acidic cleavage of either (+)-11b, (−)11b or
(+)-11c was analysed by HPLC using the following conditions: system:
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10.1002/ejoc.201700882
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
An enantioselective synthesis of a
tetrasubstituted all-trans cyclobutane,
a key intermediate in the total
synthesis of the pyrrole-imidazole
alkaloid sceptrin, facilitated by a
diastereoselective, valine-derived
chiral auxiliary guided
Cyclobutane Synthesis
Lena Barra, Prof. Dr. Jeroen S.
Dickschat*
Page No. – Page No.
Sceptrin – Enantioselective Synthesis
of a Tetrasubstituted all-trans
Cyclobutane Key Intermediate
photodimerization is reported.
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