Straightforward synthesis of all stenusine and norstenusine stereoisomers

Article abstract of DOI:10.1002/ejoc.201100612

All the stereoisomers of stenusine (1) and norstenusine (21) have been efficiently synthesized by the asymmetric hydrogenation of pyridines. The (2R,3S)- and (2R,3R)-isomers of 1, that are difficult to prepare, have been synthesized for the first time using a chemoenzymatic approach in eight steps with an 8 % total yield. All the target compounds were obtained in good stereochemical purity by using very simple and inexpensive reagents and auxiliaries. All the stereoisomers of the defensive alkaloids stenusine and norstenusine produced by Stenus beetles have been synthesized in a straightforward manner. The chiral (S) side chain is derived from (S)-2-methyl-1-butanol. For the difficult preparation of (R)-3-(2-methylbutyl) pyridine, a highly efficient chemoenzymatic approach was developed.

Full text of DOI:10.1002/ejoc.201100612

FULL PAPER
DOI: 10.1002/ejoc.201100612
Straightforward Synthesis of All Stenusine and Norstenusine Stereoisomers
Tobias Müller,[a] Konrad Dettner,[b] and Karlheinz Seifert*[a]
Dedicated to Professor Dr. Dr. h.c. Gerhard Bringmann on the occasion of his 60th birthday
Keywords: Alkaloids / Asymmetric synthesis / Synthesis design / Hydrogenation
All the stereoisomers of stenusine (1) and norstenusine (21)
have been efficiently synthesized by the asymmetric hydro-
genation of pyridines. The (2R,3S)- and (2R,3R)-isomers of 1,
that are difficult to prepare, have been synthesized for the
first time using a chemoenzymatic approach in eight steps
with an 8 % total yield. All the target compounds were ob-
tained in good stereochemical purity by using very simple
and inexpensive reagents and auxiliaries.
Introduction
(2S,3R)-1 by Enders et al.[8] This natural stenusine was not
The rove beetle genus Stenus Latreille belongs to the
most species-rich genera of the animal kingdom. To date,
2377 taxa including 8 fossil species are known worldwide.[1]
Since the beginning of the last century,[2] Stenus species,
which occupy habitats near ponds or creek banks, have at-
tracted attention because of their extraordinary capability
for locomotion on the surface of water.[3] During the hunt-
ing for springtails (Collembola), the beetles often fall onto
the water’s surface. Here, they release a surface-active fluid
from their pygidial glands which tends to spread rapidly on
the water.[3] Because of the immense spreading pressure
from the secretion, the beetles are able to jet over the water
surface. For Stenus comma beetles, weighing about 2.5 mg,
velocities of up to 70 cm/s have been observed.[4]
The compound which is responsible for this property is
stenusine (1), a piperidine alkaloid, which represents the
main compound in the fluid.[3] Furthermore, 1,8-cineol, iso-
piperitenol, 6-methyl-5-hepten-2-one,[5] and the alkaloid
norstenusine (21)[6] are the minor components. The struc-
ture of the spreading alkaloid stenusine (1) was first re-
ported by Schildknecht et al. in 1975.[3] The alkaloid (6 mg)
was isolated by distillation from 1000 beetles of the species
Stenus comma.[7] The structure of 1 was elucidated mainly
by NMR spectroscopy and mass spectrometry and then fi-
nally by total synthesis.[3,7] The absolute configuration of
natural stenusine, produced by S. comma, was first deter-
mined by the enantioselective synthesis of (2S,3S)- and
diastereo- and enantiomerically pure, but rather was a mix-
ture of all stereoisomers.
A stereoisomeric ratio of
43:40:13:4 was found for (2S,3S)/(2S,3R)/(2R,3R)/(2R,3S)
by means of chiral GC data.[8]
Other Stenus species exhibit a completely different
stereoisomeric pattern. For instance, S. clavicornis produces
almost exclusively (95 %) the (2S,3R)-isomer, whereas
stenusine from S. juno shows mainly (88 %) the (2R,3R)-
configuration.[9] The reason for these intrageneric differ-
ences is currently unknown. We tested the hypothesis that
Stenus beetles impregnate the surface of their body with
the pygidial gland secretion to defend themselves against
microorganisms and found that the isomeric mixture of
synthetic stenusine, similar to that of S. comma and (Ϯ)-
norstenusine,[10] in concentrations occurring in nature, sig-
nificantly inhibits the growth of bacteria (Serratia entomo-
phila) and fungi (Beauveria bassiana).[11] A second function
for this secretion, and thus of stenusine (1) and norstenusine
(21), is that it acts as a deterrent against predators like Lep-
tothorax platythorax ants, and this could be proven by feed-
ing experiments.[12] To test the biological activity of the in-
dividual stenusine and norstenusine isomers, we are inter-
ested in a straightforward synthetic route leading to all ste-
reoisomers.
Besides the above-mentioned, a plethora of syntheses
leading to stenusine have been reported.[13] Surprisingly,
none of them lead to the (2R,3S)- and (2R,3R)-isomers in
a reasonable and economic way, as they employ building
block 10, derived from the chiral pool,[8,13b,13e] or allow no
distinct control of the configuration.[7,10,13a,13c,13d] As only
(S)-10 is commercially available in reasonable amounts, all
existing procedures would require the additional prepara-
tion of (R)-10 from alcohol (R)-9 (Scheme 2). This could
be achieved from (S)-methyl 3-hydroxy-2-methylpropionate
(Roche ester) in five steps[14] or by chiral resolution of 2-
[a] Lehrstuhl für Organische Chemie, NW II, Universität
Bayreuth,
Universitätsstraße 30, 95447 Bayreuth, Germany
Fax: +49-921-55-5358
E-mail: karlheinz.seifert@uni-bayreuth.de
[b] Lehrstuhl für Tierökologie II, Universität Bayreuth,
Universitätsstraße 30, 95447 Bayreuth, Germany
Fax: +49-921-55-2743
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100612.
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Synthesis of All Stenusine and Norstenusine Stereoisomers
methylbutanoic acid and subsequent reduction in four 10 (71 %) and then transformed into Grignard reagent (S)-
steps.[15] Furthermore, the published syntheses comprise 11. The subsequent coupling of 11 with 3-bromopyridine
challenging experimental procedures,[8] suffer from unstable (7) gave 6 (85 %) using a known procedure[21b] (Scheme 2).
intermediates,[13a] or employ starting materials which are After improving the reaction conditions, the regioselective
not commercially available.[13b,13e] All these facts encour- chlorination of 6 by the addition of BuLi-LiDMAE and
[23]
aged us to develop a new approach, suitable to overcome then C2Cl6
succeeded in a moderate yield (53 %) which
all these difficulties. In this paper, we report a straightfor- is typical for this type of conversion.[19c] Bromination of 6
ward and inexpensive synthesis providing access to all iso- using BuLi-LiDMAE followed by CBr4 proceeded, but with
mers of 1 and 21.
significantly lower yields of 5 (15–32 %). Because of the re-
duced reactivity of the chlorinated species, the copper-cata-
lyzed amidation of 4 required a much longer reaction time
in contrast to that needed for 5 (Scheme 2, e), however, this
difference did not affect the yields (88 % and 85 %, respec-
tively). All attempts to accelerate the reaction at elevated
temperatures using microwave conditions led to an in-
creased formation of side products. The diastereoselective
hydrogenation of oxazolidinones (S,S)-2 and (S,R)-2 in the
presence of acetaldehyde gave after chromatography the tar-
get compounds (2S,3R)- and (2S,3S)-1 in 74 % and 78 %
yield, respectively (Figure 1). The hydrogenations proceeded
Results and Discussion
Our retrosynthetic approach is outlined in Scheme 1. The
key step is the auxiliary-based asymmetric hydrogenation
and simultaneous N-ethylation of the pyridines 2, following
a procedure from Glorius et al.[16] who obtained an enan-
tiomeric excess of 95 %ee (81 % yield) using a similar sub-
strate. The inexpensive and easily prepared Evans auxil-
iary[17] 3 can be used and recovered unchanged.[16] The aux-
iliary is coupled through a Goldberg reaction based on a
catalytic system from CuI, the 1,2-diamine ligand, and a
base.[18] As hydrogenation of the substrate having the auxil-
iary ortho to the methylbutyl side chain would form a dia-
stereomeric mixture of 1,[16] a clean regioselective halogena-
tion of 6 is important. This can be achieved by employing
BuLi-LiDMAE [DMAE = 2-(dimethylamino)ethanolate], a
unimetal superbase, which is useful in the regioselective li-
thiation at C-6 in 3-substituted pyridines.[19] Subsequently,
the lithiated species is halogenated by the addition of a suit-
able electrophile. As an alternative, compound 6 could be
deprotonated using lithium di-tert-butyl-(2,2,6,6-tetrameth-
ylpiperidino)zincate (TMP-zincate).[20] Finally, the chiral
pyridines 6 must be prepared by different strategies. (S)-6 is
obtained simply by a Kumada coupling of 3-bromopyridine
(7) and the chiral pool derivative 11.[21] (R)-6 is available
through a five-step chemoenzymatic synthesis, starting from
nicotinaldehyde (8). Here, the stereogenic center is created
by asymmetric hydrogenation of pyridyl enone 12 with the
help of Saccharomyces cerevisiae (Scheme 3).[22]
Scheme 2. Synthesis of (2S,3R)- and (2S,3S)-stenusine. Reagents
and conditions: (a) MsCl (methanesulfonyl chloride), NEt3,
DMAP (4-dimethylaminopyridine), CH2Cl2, 0 °C 1 h; then LiBr,
acetone, reflux overnight, 71 %; (b) Mg, Et2O, room temp., 1 h;
(c) Ni(dppe)Cl2 [dppe = 1,2-bis(diphenylphosphino)ethane], Et2O,
reflux overnight, 85 %; (d) BuLi-LiDMAE, 1 h, 0 °C; then C2Cl6,
syringe pump, –78 °C Ǟ room temp., n-hexane, overnight, 53 %;
(e) (S)-3, CuI, diamine ligand, K2CO3, toluene, 140 °C, sealed tube,
4 d, (S,S)-2 88 %, (S,R)-2 85 %; 16 h, 110 °C, 91 % for (S)-5;
(f) Pd(OH)2/C, MeCHO, H2 (150 bar), AcOH, 40 °C, 4 d, (2S,3R)-
1, 74 %, 91 %de; (2S,3S)-1, 78 %, 90 %de.
Scheme 1. Retrosynthetic analysis of stenusine (1).
Figure 1. Chiral GC spectrum of synthetic (2S,3R)-stenusine. Col-
umn: BGB-176SE, 30 m, ID 0.25 mm, film 0.25 μm. Carrier gas:
H2. Oven conditions: 60 °C (20 min isothermal), heating rate 1 °C/
The synthesis of (2S,3R)- and (2S,3S)-stenusine began
with commercially available (S)-2-methyl-1-butanol [(S)-9]
which was converted into the corresponding bromide (S)- min to 100 °C, then 20 °C/min to 210 °C (20 min isothermal).
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T. Müller, K. Dettner, K. Seifert
FULL PAPER
with good diastereomeric excesses of 91 % and 90 %de, sequently subjected to a Barton–McCombie deoxygenation
respectively, but very long reaction times (4 d) were neces- to give (R)-6 (74 %).[24] To our surprise, 15 underwent clean
sary to obtain complete conversion. A constant hydrogen deoxygenation to (R)-6, but all attempts to deoxygenate the
pressure of no less than 150 bar was crucial for a clean reac- xanthates 16 failed. (R)-6 was converted into the target
tion. At temperatures below 40 °C, the hydrogenation reac- compounds (2R,3R)- and (2R,3S)-1 (33 and 35 %, respec-
tion proceeded very slowly, but with a slight increase in dia- tively) in three steps analogous to (S)-6 (Scheme 2). The
stereoselectivity.
hydrogenations proceeded with 90 %de (3R) and 91 %de
For the synthesis of (2R,3R)- and (2R,3S)-stenusine, we (3S). The stereochemical purity of (2R,3S)-1 could be
prepared enone 12 (68 %) from 2-butanone and nicotinal- slightly increased to 93% de by freezing out (R,R)-2 from
dehyde (8) using a slightly modified literature protocol n-hexane at –20 °C and lowering the hydrogenation tem-
(Scheme 3).[22] The double bond in enone 12 was subjected perature to 30 °C (Figure 2). However, this negatively affec-
to enzymatic hydrogenation to furnish chiral ketone 13. ted both the yield (62%) and reaction time (10 d).
Applying the original literature protocol and dried baker’s
yeast type II (YSC-2 Sigma), neither the published yield
(76 %) nor the enantiomeric excess value (Ͼ 95 %ee) could
be reproduced. We obtained 13 with 88 %ee (52 % yield) in
reproducible trials. If fresh baker’s yeast was employed, only
an ee value of 81 % could be achieved. The ee values were
determined by using chiral GC analysis (see Supporting In-
formation). In addition to the original approach, we devel-
oped a new procedure again using dried yeast from Sigma
which gave both an acceptable yield (62 %) and enantio-
Figure 2. Chiral GC spectrum of synthetic (2R,3S)-stenusine. Oven
meric excess (92 %ee) by changing the reaction medium
conditions are identical as indicated in Figure 1. This target com-
pound was hydrogenated at 30 °C, for 10 d.
[DMSO (dimethyl sulfoxide)/water] and slowly adding the
sucrose solution. Furthermore, we were able to reduce the
amount of required yeast by a factor of five. Ketone 13
was then reduced with sodium borohydride in methanol in
excellent yield (91 %). The diastereomeric alcohols 14 were
converted into thiocarbamates 15 (82 %) which were sub-
The norstenusine isomers (21) were analogously prepared
(Scheme 4). The preparation of 3-isobutylpyridine (18) was
achieved starting from 3-picoline (17) according to a known
procedure (81 %).[10] Regioselective chlorination (52 %) and
the coupling of auxiliaries 3 gave compounds 20 (94 %,
85 %) which were hydrogenated to the desired alkaloids 21
(81 %, 80 %) with ee values of 92 %ee [(R)-21] and 90 %ee
[(S)-21].
Scheme 4. Synthesis of (R)- and (S)-norstenusine analogous to
Scheme 2. Reagents and conditions: (a) LDA (lithium diisopro-
pylamide), THF, 0 °C; 2-bromopropane, THF, –78 °C Ǟ room
temp., 81 %;[10] (b) 52 %; (c) (S)-20, 94 %; (R)-20, 85 %; (d) (R)-21,
81 %, 92 %ee; (S)-21, 80 %, 90 %ee.
Conclusions
Scheme 3. Synthesis of (2R,3R)- and (2R,3S)-stenusine. Reagents
and conditions: (a) MEK (methyl ethyl ketone), H2SO4, AcOH,
50 °C, 3 h, 68 %; (b) Saccharomyces cerevisiae, sucrose, DMSO, tap
water, room temp., 48 h, 62 %, 92%ee; (c) NaBH4, MeOH, 0 °C,
45 min, 91 %; (d) TCDI (thiocarbonyl diimidazole), THF (tetra-
hydrofuran), 90 °C, sealed tube, 8 h, 82 %; (e) AIBN [azobis(iso-
butyronitrile)], Bu3SnH, toluene, reflux, 3 h, 74 %; (f) NaH, CS2,
MeI, THF, 1 h, 76 %.
We have developed a synthetic strategy which provides
easy access to all the stereoisomers of stenusine (1) and nor-
stenusine (21). (2S,3R)- and (2S,3S)-1 were both obtained
in a four-step sequence with 29 and 30 % yield, respectively
(Scheme 2). A chemoenzymatic approach furnished chiral
pyridine (R)-6 (Scheme 3) which led to both the (2R,3R)-
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Synthesis of All Stenusine and Norstenusine Stereoisomers
a plug of cotton wool and concentrated to a volume of about 5 mL.
This residue was placed on a short silica gel column (15 cmϫ3 cm)
and eluted first with n-hexane (300 mL) and then with n-hexane/
methyl tert-butyl ether (MTBE, 95:5, 500 mL). The second fraction
was evaporated to dryness. Purification by column chromatography
(silica gel; n-hexane/MTBE, 98:2) yielded (S)-4 (0.326 g,
1.78 mmol, 53 %) as a colorless oil. Rf = 0.4 (n-hexane/EtOAc,
and (2R,3S)-1 isomers in 8 % total yield. The norstenusine
enantiomers were easily obtained in the same manner from
compound 17 in 32 and 29 % yield, respectively. All target
compounds were obtained in good stereochemical purity by
using very simple and inexpensive reagents and auxiliaries.
1
19:1). [α]2D3 = +9.9 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3,
25 °C): δ = 8.08 (d, J = 2.5 Hz, 1 H, 6-H), 7.35 (dd, J = 8.1, 2.5 Hz,
1 H, 4-H), 7.14 (d, J = 8.1 Hz, 1 H, 3-H), 2.52 (dd, J = 13.6, 6.2 Hz,
1 H, 1Ј-Ha), 2.27 (dd, J = 13.6, 8.1 Hz, 1 H, 1Ј-Hb), 1.53 (m, 1 H,
2Ј-H), 1.29 (m, 1 H, 3Ј-Ha), 1.11 (m, 1 H, 3Ј-Hb), 0.83 (dd, J =
7.4 Hz, 3 H, 4Ј-H), 0.76 (d, J = 6.6 Hz, 3 H, 5Ј-H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 150.1 (C-6), 148.8 (C-2), 139.3 (C-4),
135.6 (C-5), 123.6 (C-3), 39.3 (C-1Ј), 36.3 (C-2Ј), 28.9 (C-3Ј), 18.6
Experimental Section
General Remarks: All reactions except for those which led to com-
pounds 1, 12, 13, 14, and 21 were performed in oven-dried glass-
ware under an argon atmosphere using standard Schlenk tech-
niques. THF and Et2O were distilled from a sodium/potassium al-
loy or sodium diphenyl ketyl. Toluene was distilled from LiAlH4,
and CH2Cl2 was distilled from P2O5. n-Hexane (HPLC grade) was
distilled from potassium metal. The solvents for chromatography
were purchased as technical grade and distilled prior to use. Thin-
layer chromatography was carried out on precoated Alugram®
SIL G/UV254 plates from Macherey–Nagel. Mass spectra were re-
corded using a Finnigan MAT 95 (EI, 70 eV) and a Bruker APEX
IV (ESI-HRMS) fourier transformation ion cyclotron resonance
mass spectrometer. IR spectra were recorded with a Perkin–Elmer
FT-IR spectrophotometer equipped with an ATR (attenuated total
reflectance) sampling unit. The NMR spectroscopic data were re-
corded under the indicated conditions with a Bruker Avance 300
spectrometer and referenced for proton resonance to the residual
solvent signal (CHCl3 = 7.26 ppm) and for carbon resonance to
the solvent signal (CDCl3, 77.0 ppm). Chiral GC data were re-
corded with a Hewlett–Packard 5890 Series II or a Carlo–Erba
HRGC 5160 gas chromatograph. All starting compounds were pur-
chased from commercial sources and used as received. Baker’s yeast
(YSC-2) was purchased from Sigma–Aldrich and stored in a refrig-
erator. The reactions were monitored by TLC or gas chromatog-
raphy using a TR-5MS column. For TLC, all aromatic compounds
were visualized by UV light (254 nm).
(C-5Ј), 11.3 (C-4Ј) ppm. FTIR (ATR): ν = 2960 (m), 2925 (m),
˜
2774 (w), 1584 (w), 1564 (m), 1455 (s), 1381 (s), 1287 (w), 1214 (w),
1137 (m), 1103 (s), 1023 (s), 1023 (m), 966 (w), 928 (w), 845 (w),
817 (m), 767 (m), 737 (m), 676 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 185 (10), 183 (31) [M]+, 129 (35), 128 (20), 127 (100), 126 (19),
91 (15), 57 (37), 41 (21). HRMS (EI): calcd. for C10H14ClN [M]+
183.0809; found 183.0802.
(R)-2-Chloro-5-(2-methylbutyl)pyridine [(R)-4]: This compound was
analogously prepared as described above from (R)-6 to yield (R)-4
(0.314 g, 1.71 mmol, 51 %). [α]2D3 = –9.2 (c = 1.0, CHCl3).
2-Chloro-5-isobutylpyridine (19): This compound was analogously
prepared as described above from 18 (452 mg, 3.35 mmol) to yield
19 (296 mg, 1.74 mmol, 52 %). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 8.07 (d, J = 2.5 Hz, 1 H, 6-H), 7.34 (dd, J = 8.1, 2.5 Hz,
1 H, 4-H), 7.13 (d, J = 8.1 Hz, 1 H, 3-H), 2.35 (d, J = 7.2 Hz, 2
H, 1Ј-H), 1.74 (m, 1 H, 2Ј-H), 0.80 (d, J = 6.7 Hz, 6 H, 3Ј-H and
4Ј-H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 149.8 (C-6),
148.6 (C-2), 139.1 (C-4), 135.4 (C-5), 123.4 (C-3), 41.2 (C-1Ј), 29.7
(C-2Ј), 21.8 (3Ј-C, C-4Ј) ppm. HRMS (ESI): calcd. for C9H12ClN
[M + H]+ 170.0731; found 170.0736.
(S)-3-(2-Methylbutyl)pyridine [(S)-6]: A Grignard solution prepared
from (S)-1-bromo-2-methylbutane (4.94 mL, 39.9 mmol) and mag-
nesium turnings (1.216 g, 50.0 mmol) in Et2O (40 mL) was added
dropwise over 20 min to a suspension of 3-bromopyridine (7,
1.93 mL, 20.0 mmol) and Ni(dppe)Cl2 (53 mg, 0.5 mol-%) in Et2O
(10 mL). The resulting bright yellow slurry was heated at reflux
conditions overnight and subsequently partitioned between EtOAc
(100 mL) and an NH4Cl solution (100 mL). The aqueous layer was
extracted with EtOAc (3ϫ100 mL). The combined organic extracts
were passed through a plug of silica/MgSO4, and the solvent was
removed under reduced pressure. The residue was purified by col-
umn chromatography (silica gel; n-hexane/EtOAc, 3:1; Rf = 0.3) to
yield (S)-6 as a colorless oil with a characteristic smell (2.537 g,
17.00 mmol, 85 %), spectroscopically identical with that obtained
previously.[10] [α]2D3 = +8.7 (c = 1.0, CHCl3).
(S)-4-Isopropyl-3-{5-[(S)-2-methylbutyl]pyridin-2-yl}-
oxazolidin-2-one [(S,S)-2]: A sealed tube with a stirring bar was
charged with CuI (114 mg, 15 mol-%) and finely ground K2CO3
(1.106 g, 8.00 mmol). (S)-4 (735 mg, 4.00 mmol), (S)-4-isopro-
pyloxazolidin-2-one [(S)-3, 1.033 g, 8.00 mmol], and N,NЈ-di-
methylethylenediamine (130 μL, 30 mol-%) premixed in 5 mL of
toluene were added by syringe. The tube was tightly sealed and
stirred for 4 d with the oil bath temperature at 140 °C. The resulting
red-brown slurry was thoroughly partitioned between water
(50 mL) and EtOAc (100 mL). The aqueous layer was extracted
with EtOAc (3ϫ80 mL). The combined organic extracts were
passed through a plug of silica/MgSO4, and the solvent was re-
moved under reduced pressure. The residue was purified by column
chromatography (silica gel; n-hexane/EtOAc, 5:1), to yield (S,S)-2
(972 mg, 3.52 mmol, 88 %) as a white waxy solid. Rf = 0.6 (n-hex-
(S)-2-Chloro-5-(2-methylbutyl)pyridine [(S)-4]: To a solution of 2- ane/EtOAc, 3:1). [α]2D3 = +62.6 (c = 1.0, CHCl3). 1H NMR
(dimethylamino)ethanol (1.01 mL, 10 mmol) in n-hexane (6.7 mL)
cooled to 0 °C was added dropwise nBuLi (2.5 m in hexane,
8.04 mL, 20 mmol). Stirring was continued for 1 h, and then (S)-6
(0.500 g, 3.35 mmol) dissolved in n-hexane (3.35 mL) was added
dropwise within 10 min. After stirring for 1 h, the resulting deep
red solution was cooled to –78 °C, and C2Cl6 (2.775 g, 11.7 mmol)
dissolved in n-hexane (20 mL) was added drop by drop over 1 h
using a syringe pump. The resultant grey-brown slurry was allowed
to reach room temp. overnight, and afterwards was quenched with
water (30 mL). The aqueous layer was extracted with n-hexane
(3ϫ30 mL). The combined organic extracts were filtered through
(300 MHz, CDCl3, 25 °C): δ = 8.02 (d, J = 2.0 Hz, 1 H, 6Ј-H), 7.96
(d, J = 8.5 Hz, 1 H, 3Ј-H), 7.42 (dd, J = 8.5, 2.0 Hz, 1 H, 4Ј-H),
4.77 (m, 1 H, 4-H), 4.29 (dd, J = 8.9 Hz, 1 H, 5-Ha), 4.20 (dd, J =
8.9, 4.0 Hz, 1 H, 5-Hb), 2.51 (dd, J = 13.7, 6.3 Hz, 1 H, 1ЈЈ-Ha),
2.40 (m, 1 H, 6-H), 2.26 (dd, J = 13.7, 8.1 Hz, 1 H, 1ЈЈ-Hb), 1.54
(m, 1 H, 2ЈЈ-H), 1.31 (m, 1 H, 3ЈЈ-Ha), 1.10 (m, 1 H, 3ЈЈ-Hb), 0.86
(d, J = 7.1 Hz, 3 H, 7-H), 0.83 (dd, J = 7.4 Hz, 3 H, 4ЈЈ-H), 0.78
(d, J = 6.6 Hz, 3 H, 5ЈЈ-H), 0.76 (d, J = 6.8 Hz, 3 H, 8-H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 155.5 (C-2), 148.5 (C-2Ј),
147.7 (C-6Ј), 138.6 (C-4Ј), 132.3 (C-5Ј), 113.9 (C-3Ј), 62.8 (C-5),
58.9 (C-4), 39.5 (C-1ЈЈ), 36.3 (C-2ЈЈ), 28.9 (C-3ЈЈ), 27.6 (C-6), 18.7
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T. Müller, K. Dettner, K. Seifert
(C-5ЈЈ), 17.9 (C-7), 14.3 (C-8), 11.3 (C-4ЈЈ) ppm. FTIR (ATR): ν = was stirred for an additional 2.5 h and heated slightly to maintain
FULL PAPER
˜
2959 (m), 2929 (w), 2874 (w), 1738 (s), 1602 (m), 1568 (m), 1484
50 °C. Afterwards, the solution was transferred into a 2-L flask
(s), 1406 (s), 1321 (m), 1308 (m), 1200 (s), 1142 (m), 1113 (m), 1050 with the aid of a water rinse (200 mL). An excess amount of
(m), 1002 (m), 771 (m), 752 (m) cm–1. MS (EI, 70 eV): m/z (%) = Na2CO3 (50 g) was added in portions to destroy the H2SO4. The
277 (17), 276 (100) [M]+, 233 (98), 217 (30), 208 (23), 191 (26), 190
(81), 189 (60), 164 (78), 134 (36), 133 (30), 132 (47), 107 (36), 41
(24). HRMS (EI): calcd. for C16H24N2O2 [M]+ 276.1832; found
276.1856.
aqueous solution was extracted with MTBE (3ϫ500 mL). The
combined organic extracts were passed through a plug of silica/
MgSO4 and concentrated under reduced pressure. The remaining
traces of acetic acid were removed by coevaporation with toluene
(100 mL). Distillation of the crude residue using a Vigreux column
(15 cm) afforded ketone 12 (11.071 g, 68.68 mmol, 68 %) as a pale
yellow distillate; b.p. 105–106 °C (0.05 mbar). Rf = 0.3 (n-hexane/
(R)-4-Isopropyl-3-{5-[(S)-2-methylbutyl]pyridin-2-yl}oxazolidin-2-
one [(S,R)-2]: This compound was analogously prepared as de-
scribed above using (R)-4-isopropyloxazolidin-2-one [(R)-3] to
yield (S,R)-2 as a colorless viscous oil (940 mg, 3.40 mmol, 85 %).
[α]2D3 = –53.8 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 8.02 (d, J = 2.3 Hz, 1 H, 6Ј-H), 7.98 (d, J = 8.6 Hz, 1 H, 3Ј-
H), 7.42 (dd, J = 8.6, 2.3 Hz, 1 H, 4Ј-H), 4.78 (m, 1 H, 4-H), 4.29
(dd, J = 8.9 Hz, 1 H, 5-Ha), 4.19 (dd, J = 8.9, 3.9 Hz, 1 H, 5-Hb),
2.51 (dd, J = 13.7, 6.2 Hz, 1 H, 1ЈЈ-Ha), 2.42 (m, 1 H, 6-H), 2.26
(dd, J = 13.7, 8.1 Hz, 1 H, 1ЈЈ-Hb), 1.53 (m, 1 H, 2ЈЈ-H), 1.32 (m,
1 H, 3ЈЈ-Ha), 1.11 (m, 1 H, 3ЈЈ-Hb), 0.85 (d, J = 7.1 Hz, 3 H, 7-H),
0.84 (dd, J = 7.4 Hz, 3 H, 4ЈЈ-H), 0.77 (d, J = 6.7 Hz, 3 H, 5ЈЈ-H),
0.76 (d, J = 7.0 Hz, 3 H, 8-H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 155.2 (C-2), 148.3 (C-2Ј), 147.5 (C-6Ј), 138.3 (C-4Ј),
132.0 (C-5Ј), 113.6 (C-3Ј), 62.6 (C-5), 58.7 (C-4), 39.3 (C-1ЈЈ), 36.2
(C-2ЈЈ), 28.8 (C-3ЈЈ), 27.4 (C-6), 18.5 (C-5ЈЈ), 17.7 (C-7), 14.1 (C-
8), 11.2 (C-4ЈЈ) ppm.
1
acetone, 3:1). H NMR (300 MHz, CDCl3, 25 °C): δ = 8.53 (d, J
= 2.1 Hz, 1 H, 2Ј-H), 8.43 (dd, J = 4.8, 1.5 Hz, 1 H, 6Ј-H), 7.63
(ddd, J = 7.9, 2.1, 1.5 Hz, 1 H, 4Ј-H), 7.35 (s, 1 H, 4-H), 7.23 (dd,
J = 7.9, 4.8 Hz, 1 H, 5Ј-H), 2.35 (s, 3 H, 1-H), 1.92 (d, J = 1.4 Hz,
3 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 199.3 (C-
2), 150.3 (C-2Ј), 149.9 (C-6Ј), 139.3 (C-3), 136.1 (C-4Ј), 135.2 (C-
4), 131.5 (C-3Ј), 123.0 (C-5Ј), 25.6 (C-1), 12.7 (C-5) ppm. FTIR
(ATR): ν = 2965 (w), 1663 (s), 1628 (m), 1565 (w), 1476 (w), 1413
˜
(m), 1364 (m), 1248 (s), 1097 (m), 1002 (m), 877 (w), 804 (m), 758
(w), 708 (s) cm–1. MS (EI, 70 eV): m/z (%) = 161 (39) [M]+, 160
(83), 146 (56), 132 (12), 118 (100), 117 (60), 91 (31), 89 (10), 79
(10), 65 (13). HRMS (ESI): calcd. for C10H11NO [M + H]+
162.09134; found 162.09133.
(S)-3-Methyl-4-(pyridin-3-yl)butan-2-one (13): A 2-L three-necked
flask with an overhead stirrer and dropping funnel was charged
with 12 (4.200 g, 26.05 mmol), DMSO (100 mL), tap water
(350 mL), and dry baker’s yeast (50 g). As the reaction mixture was
stirred, a solution of sucrose (87.5 g) in tap water (150 mL) was
added over 4 h. The batch was stirred additionally for about 48 h
at room temp., until GC analysis revealed complete consumption
of the starting material. Acetone (1.2 L) was added, and the mix-
ture was vigorously stirred for 5 min, followed by suction filtration
of the precipitated yeast. The acetone was removed under reduced
pressure, and the resulting aqueous solution was extracted with
Et2O (3ϫ0.8 L). The combined organic extracts were concentrated
to a volume of 200 mL, and the resulting mixture was passed
through a plug of silica/MgSO4. The solvents were removed under
reduced pressure leaving the crude material that was purified by
column chromatography (silica gel; n-hexane/acetone, 3:1; Rf = 0.3)
to yield 13 as a slightly yellow oil (2.626 g, 16.09 mmol, 62 %,
92 %ee). [α]2D3 = +8.5 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 8.38 (dd, J = 4.8, 1.7 Hz, 1 H, 6Ј-H), 8.36 (d,
J = 2.2 Hz, 1 H, 2Ј-H), 7.42 (ddd, J = 7.8, 2.2, 1.7 Hz, 1 H, 4Ј-H),
7.14 (ddd, J = 7.8, 4.8, 0.7 Hz, 1 H, 5Ј-H), 2.94 (dd, J = 13.7,
7.0 Hz, 1 H, 4-Ha), 2.76 (m, 1 H, 3-H), 2.50 (dd, J = 13.7, 7.3 Hz,
1 H, 4-Hb), 2.05 (s, 3 H, 1-H), 1.05 (d, J = 7.0 Hz, 3 H, 5-H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 210.6 (C-2), 149.7 (C-2Ј),
147.1 (C-6Ј), 136.2 (C-4Ј), 123.0 (C-5Ј), 47.9 (C-3), 35.1 (C-4), 28.3
(C-1), 15.9 (C-5) ppm. MS (EI, 70 eV): m/z (%) = 163 (65) [M+],
148 (58), 121 (40), 120 (54), 106 (100), 93 (24), 92 (91), 79 (27), 65
(36), 51 (17). HRMS (EI): calcd. for C10H13NO [M]+ 163.0992;
found 163.0992.
(S)-4-Isopropyl-3-{5-[(R)-2-methylbutyl]pyridin-2-yl}oxazolidin-2-
one [(R,S)-2]: Preparation from (R)-4 (278 mg, 1.52 mmol) and (S)-
3 yielded a colorless viscous oil (374 mg, 1.35 mmol, 89 %). [α]2D3
+51.7 (c = 1.0, CHCl3).
=
(R)-4-Isopropyl-3-{5-[(R)-2-methylbutyl]pyridin-2-yl}oxazolidin-2-
one [(R,R)-2]: Preparation from (R)-4 (128 mg, 0.70 mmol) and (R)-
3 yielded a white waxy solid (168 mg, 0.61 mmol, 87 %). [α]2D3
–61.5 (c = 1.0, CHCl3).
=
(S)-3-(5-Isobutylpyridin-2-yl)-4-isopropyloxazolidin-2-one [(S)-20]:
Preparation from 19 (676 mg, 4.00 mmol) and (S)-3 (774 mg,
6.00 mmol) yielded a white waxy solid (990 mg, 3.77 mmol, 94 %).
[α]2D3 = +66.1 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.99 (d, J = 2.4 Hz, 1 H, 6Ј-H), 7.96 (d, J = 8.6 Hz, 1
H, 3Ј-H), 7.39 (dd, J = 8.6, 2.4 Hz, 1 H, 4Ј-H), 4.75 (mc, 1 H, 4-
H), 4.26 (dd, J = 8.8 Hz, 5-Ha), 4.16 (dd, J = 8.9, 3.9 Hz, 5-Hb),
2.38 (mc, 1 H, 6-H), 2.32 (d, J = 7.1 Hz, 2 H, 1ЈЈ-H), 1.73 (m, 1 H,
2ЈЈ-H), 0.82 (d, J = 7.0 Hz, 3 H, 7-H), 0.80 (d, J = 6.5 Hz, 3 H, 3Ј-
H), 0.79 (d, J = 6.7 Hz, 3 H, 4Ј-H), 0.72 (d, J = 6.9 Hz, 3 H, 8-
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 155.1 (C-2), 148.3
(C-2Ј), 147.4 (C-6Ј), 138.2 (C-4Ј), 131.9 (C-5Ј), 113.5 (C-3Ј), 62.5
(C-5), 58.6 (C-4), 41.3 (C-1ЈЈ), 29.6 (C-2ЈЈ), 27.3 (C-6), 21.9, 21.8
(C-3ЈЈ and C-4ЈЈ), 17.6, 14.9 (C-7 and C-8) ppm. MS (EI, 70 eV):
m/z (%) = 262 (75) [M]+, 219 (100), 203 (29), 176 (78), 175 (60),
150 (54), 134 (37), 133 (36), 132 (49), 107 (31). HRMS (EI): calcd.
for C15H22N2O2 [M]+ 262.1676; found 262.1678.
(R)-3-(5-Isobutylpyridin-2-yl)-4-isopropyloxazolidin-2-one [(R)-20]:
Prepararation from 19 (321 mg, 1.90 mmol) and (R)-3 (490 mg,
3.80 mmol) yielded a white waxy solid (426 mg, 1.62 mmol, 85 %).
[α]2D3 = –64.8 (c = 1.0, CHCl3).
(S)-3-Methyl-4-(pyridin-3-yl)butan-2-ol (14): To a solution of 13
(5.400 g, 33.08 mmol) in MeOH (150 mL) at 0 °C was added
NaBH4 (1.513 g, 40.00 mmol) in small portions. The solution was
(E)-3-Methyl-4-(pyridin-3-yl)but-3-en-2-one (12):
necked flask with an internal thermometer, an overhead stirrer, and
dropping funnel was charged with 2-butanone (17.9 mL,
0.201 mol), nicotinic aldehyde (8, 9.5 mL, 0.101 mol), and acetic
acid (140 mL). As the reaction mixture was stirred, H2SO4 (95 %,
16.3 mL, 0.305 mol) was added dropwise over 30 min so that the
temperature did not rise over 50 °C. The resulting reddish solution
A 1-L three- stirred for 45 min. The solvent was removed, and the residue was
partitioned between MTBE (100 mL) and water (80 mL). The
aqueous layer was extracted with MTBE (3ϫ100 mL). The com-
bined organic extracts were passed through a plug of silica/MgSO4,
and the solvent was removed under reduced pressure. The residue
was purified by column chromatography (silica gel; n-hexane/ace-
tone, 3:2; Rf = 0.4) to yield a mixture of two diastereomers of 14
a
6036
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6032–6038

Synthesis of All Stenusine and Norstenusine Stereoisomers
as a colorless oil (4.957 g, 30.00 mmol, 91 %). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 8.36 (d, J = 2.5 Hz, 2 H, 2Ј-H), 8.34 (dd, J =
4.8, 1.6 Hz, 2 H, 6Ј-H), 7.45 (dd, J = 7.8, 1.6 Hz, 2 H, 4Ј-H), 7.14
(dd, J = 7.8, 4.8 Hz, 2 H, 5Ј-H), 3.72 (m, 1 H, 2-H) and 3.59 (m,
1 H, 2-H), 3.48 (br. s, 2 H, OH), 2.89 (dd, J = 13.6, 4.4 Hz, 1 H,
4-Ha), 2.83 (dd, J = 13.6, 5.6 Hz, 1 H, 4-Ha), 2.32 (dd, J = 13.6,
9.2 Hz, 1 H, 4-Hb), 2.30 (d, J = 13.6, 9.5 Hz, 1 H, 4-Hb), 1.71 (m,
2 H, 3-H), 1.14 (d, J = 6.4 Hz, 6 H, 1-H), 0.80 (d, J = 6.8 Hz, 3
H, 5-H), 0.75 (d, J = 6.8 Hz, 3 H, 5-H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 150.0 (C-2Ј), 146.6 (C-6Ј), 136.9 (C-3Ј), 136.7
(C-4Ј), 136.6 (C-4Ј), 123.1 (C-5Ј), 70.4 (C-2), 69.2 (C-2), 41.9 (C-
3), 41.5 (C-3), 35.9 (C-4), 20.0 (C-1), 14.5 (C-5), 13.4 (C-5) ppm.
identical with that obtained previously.[10] [α]2D3 = –8.0 (c = 1.0,
CHCl3).
(2S,3R)-Stenusine [(2S,3R)-1]: A mixture of wet 20 % Pd(OH)2/C
(w/w, 278 mg, 20 mol-%), substrate (S,S)-2 (0.548 g, 1.98 mmol),
acetaldehyde (0.57 mL, 10.0 mmol), and acetic acid (16 mL) was
stirred in an autoclave under a hydrogen atmosphere (150 bar) at
40 °C for 4 d. The reaction mixture was diluted with water (50 mL),
and the catalyst was removed by suction filtration. As the mixture
was cooled, the pH value was adjusted to 10 by the addition of
diluted NaOH (2 n). The mixture was extracted with CH2Cl2
(3ϫ50 mL). The combined organic extracts were washed with
water, and the solvent was removed under reduced pressure. The
residue was purified by column chromatography [silica gel; n-hex-
ane/EtOAc/TEA (triethylamine), 75:25:5; Rf = 0.5) to yield (S,R)-
1 as a colorless oil (269 mg, 1.46 mmol, 74 %, 91 %de), spectro-
FTIR (ATR): ν = 3313 (br.), 2967 (m), 2931 (w), 2878 (w), 1577
˜
(w), 1423 (m), 1377 (w), 1090 (m), 1028 (m), 928 (w), 712 (s) cm–1.
MS (EI, 70 eV): m/z (%) = 165 (1) [M]+, 147 (81) [M – H2O]+, 132
(58), 121 (25), 120 (48), 106 (100), 93 (76), 92 (65), 79 (30), 65 (28),
45 (24). HRMS (ESI): calcd. for C10H15NO [M + H]+ 166.12264;
found 166.12256.
scopically identical with that obtained by Enders et al.[8a] [α]2D3
+22.8 (c = 1.0, EtOH).
=
(2S,3S)-1: Preparation from (S,R)-2 (720 mg, 2.61 mmol) yielded a
colorless oil (373 mg, 2.04 mmol, 78 %, 90 %de), spectroscopically
identical with that obtained by Enders et al.[8a] [α]2D3 = +11.1 (c =
1.0, EtOH).
O-[(S)-1,2-Dimethyl-3-(pyridin-3-yl)propyl] Imidazole-1-carbothio-
ate (15): A sealed tube with a stirring bar was charged with 14
(4.700 g, 28.45 mmol), TCDI (15.200 g, 85.29 mmol), and THF
(200 mL). The tube was heated at 90 °C (oil bath temperature) for
8 h. After cooling, the solvent was evaporated to dryness, and the
residue was partitioned between CH2Cl2 (300 mL) and water
(300 mL). The aqueous layer was extracted with CH2Cl2
(3ϫ200 mL). The combined organic extracts were concentrated to
a volume of 80 mL, and the resulting mixture was passed through
a plug of silica/MgSO4 using EtOAc. Both solvents were removed
under reduced pressure, and the residue was purified by column
chromatography (silica gel; n-hexane/acetone, 3:2; Rf = 0.3) to yield
a mixture of two diastereomers of 15 as a slightly yellow oil
(2R,3R)-1: Preparation from (R,S)-2 (315 mg, 1.14 mmol) yielded
a colorless oil (153 mg, 0.83 mmol, 73 %, 90 %de). [α]2D3 = –10.5 (c
= 1.0, EtOH).
(2R,3S)-1: Preparation from (R,R)-2 (229 mg, 0.83 mmol) yielded
a colorless oil (120 mg, 0.66 mmol, 79 %, 91 %de). [α]2D3 = –20.3 (c
= 1.0, EtOH).
(R)-Norstenusine (R)-21: Preparation from (S)-20 (610 mg,
2.33 mmol) yielded a colorless oil (320 mg, 1.89 mmol, 81 %,
92 %ee). [α]2D3 = +3.3 (c = 1.0, MeOH). The compound was spec-
troscopically identical with that obtained previously.[10]
1
(6.423 g, 23.33 mmol, 82 %). H NMR (300 MHz, CDCl3, 25 °C):
δ = 8.36 (d, J = 2.4 Hz, 2 H, 2ЈЈ-H), 8.35 (dd, J = 4.8, 1.6 Hz, 2
H, 6ЈЈ-H) 8.26 (s, 2 H, 2-H), 7.54 (d, J = 1.5 Hz, 2 H, 5-H), 7.44
(ddd, J = 7.8, 2.4, 1.6 Hz, 2 H, 4ЈЈ-H), 7.16 (dd, J = 7.8, 4.8 Hz, 2
H, 5ЈЈ-H), 6.99 (d, J = 1.5 Hz, 2 H, 4-H), 5.56 (m, 2 H, 1Ј-H), 2.80
(dd, J = 13.5, 5.1 Hz, 1 H, 3Ј-Ha), 2.76 (dd, J = 13.9, 6.0 Hz, 1 H,
3Ј-Ha), 2.46 (dd, J = 13.8, 8.8 Hz, 1 H, 3Ј-Hb), 2.42 (dd, J = 13.6,
9.1 Hz, 1 H, 3Ј-Hb) 2.28 (m, 2Ј-H), 2.17 (m, 1 H, 2Ј-H), 1.40 (d, J
= 6.4 Hz, 6 H, 5Ј-H), 1.00 (d, J = 6.9 Hz, 3 H, 4Ј-H), 0.92 (d, J =
6.7 Hz, 3 H, 4Ј-H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
182.9 (C-6), 149.9 (C-2ЈЈ), 149.8 (C-2ЈЈ), 147.3 (C-6ЈЈ), 136.2 (C-2),
135.9 (C-4ЈЈ), 135.8 (C-4ЈЈ), 134.6 (C-3ЈЈ), 134.4 (C-3ЈЈ), 130.3 (C-
4), 122.9 (C-5ЈЈ), 117.3 (C-5), 83.6 (C-1Ј), 83.0 (C-1Ј), 39.0 (C-2Ј),
38.4 (C-2Ј), 35.8 (C-3Ј), 15.5 (C-5Ј), 14.9 (C-5Ј), 14.1 (C-4Ј) ppm.
(S)-21: Preparation from (R)-20 (309 mg, 1.18 mmol) yielded a col-
orless oil (160 mg, 0.945 mmol, 80 %, 90 %ee). [α]2D3 = –3.0 (c = 1,
MeOH). The compound was spectroscopically identical with that
obtained previously.[10]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for the key compounds and chiral
GC data are available.
Acknowledgments
Support of this research by a grant from the Deutsche Forschungs-
gemeinschaft (DFG) (SE 595/14-1, DE 258/12-1) is gratefully ac-
knowledged. We are also indebted to Dr. Holm Frauendorf and
Michael Müller (Institut für Organische und Bioorganische
Chemie, Georg-August-Universität Göttingen) for the HRMS mea-
surements. Finally, Dr. Siegfried Kehl (Tierökologie II, Universität
Bayreuth) is thanked for taking pictures of S. bimaculatus.
FTIR (ATR): ν = 3122 (w), 2972 (w), 2934 (w), 1575 (w), 1530 (w),
˜
1463 (m), 1380 (s), 1322 (s), 1280 (s), 1228 (s), 1094 (s), 985 (s),
956 (s), 831 (m), 714 (s) cm–1. MS (EI, 70 eV): m/z (%) = 147 (17),
132 (22), 106 (100), 93 (40), 92 (55), 68 (26), 65 (43), 45 (58), 41
(71), 40 (43). HRMS (ESI): calcd. for C14H17N3OS [M + H]+
276.11651; found 276.11657.
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(250 mg, 6.0 mol-%) in toluene (250 mL) was heated at reflux for
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with a distinct smell (2.670 g, 17.89 mmol, 74 %), spectroscopically
Eur. J. Org. Chem. 2011, 6032–6038
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6037

T. Müller, K. Dettner, K. Seifert
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Received: May 2, 2011
Published Online: August 22, 2011
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Eur. J. Org. Chem. 2011, 6032–6038